PIPERIDINE AND PYRROLIDINE DERIVATIVES

Abstract: According to the invention there is provided a compound of formula (I): R<1>-O(CH2)mA(CH2)nXR or a pharmaceutically acceptable salt thereof, wherein R<1> is a group of formula (a or b) where Z is -(CH2)2-, -CH=CH-, -CH2-S- or -CH2-O-; R is a group of formula (c, d or Het) and A is a group of formula (e, f or g) in which the N atom is attached to the group (CH2)n; m is 1 or 2; n is an integer of from 1 to 4; p is 1, 2 or 3; R<2> and R<3> are each independently hydrogen, C1-C4 alkyl, hydroxy-(C1-C4 alkyl), hydroxy, C1-C4 alkoxy, halo, trifluoromethyl, nitro, cyano, sulphamoyl, -CO(C1-C4 alkyl), -OCO(C1-C4 alkyl), carboxy, -CO2(C1-C4 alkyl), -(CH2)qCONR<4>R<5>, -(CH2)qOCONR<4>R<5>, -(CH2)qNR<6>R<7> or -NHSO2NH2 in which R<4> and R<5> are each independently H or C1-C4 alkyl, q is 0, 1 or 2, and either R<6> and R<7> are each independently H or C1-C4 alkyl or R<6> is hydrogen and R<7> is -SO2(C1-C4 alkyl), -CO(C1-C4 alkyl) or -CONH(C1-C4 alkyl); X is a direct link, O or S; Y and Y<1> are each independently O or CH2; and Het is pyridyl, pyrazinyl or thienyl. The compounds are useful as muscarinic receptor antagonists, particularly in the treatment of irritable bowel syndrome.

Description: "Piperidine and Pyrrolidine Derivatives" This invention relates to certain pyrrolidine and piperidine derivatives. We have discovered that the pyrrolidine and piperidine derivatives provided by the present invention are muscarinic receptor antagonists which are selective for smooth muscle muscarinic sites over cardiac iraiscarinic sites and which do not have any significant ant-J staminic activity. Ihus the ccπpounds are useful in the treatment of diseases associated with altered motility and/or tone of smooth muscle which can, for example, be found in the gut, trachea and bladder. Such diseases ir lude irritable bowel syndrcme, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease. According to the invention there are provided cxampounds of the formula:- ■ (i) and their pharmaceutically acceptable salts, wherein R is a group of the formula:- where Z is -(CH.) -, -CH=CH-, -O^-S- or -O^-O-; R is a group of the foππula:- and A is a group of the formula:- in which the N atom is attached to the grcup (CH-) ; m is 1 or 2; n is an integer of from 1 to 4; p is 1, 2 or 3; R 2 and R3 are each independently hydrogen, C.-C alkyl, hydraxy-(C,-C. alkyl) , hydroxy, C.-C. alkσxy, halo, trifluorcroethyl, nitro, cyano, sulphamσyl, -CO(C,-C alkyl), -000( j -C 4 alkyl), carboxy, -CO^ j -C j alkyl), -NHSO NBL in which R 4 and R5 are each independently H or 6 7 C,-C. alkyl, g is 0, 1 or 2, and either R and R are each independently H or C.-C. alkyl or R is hydrogen and R 7 is alkyl) or "0CX ^ C l "C 4 alk Y 1 ) ; X is a direct link, O or S; Y and Y^ are each independently 0 or CH_; and Het is pyridyl, pyrazinyl or thieηyl. "Halo means F, Cl, Br or I. Alkyl and alkoxy groups of 3 or 4 carbon atoms can be straight or branched chain. The preferred alkyl and alkoxy groups are methyl, ethyl, methαxy and ethoxy. Preferably, R is (fh) 2 CH. m is preferably 1. n is preferably 1, 2 or 3.X is preferably a direct link. A is preferably a group of the formula:- R is preferably a group of the formula: - 2 3 where R and R are each independently hydroxyπet-hyl, C.-C. alkoxy, C-.-C. alta-aycarboπyl, carboxy, sulphamoyl, nitro, amino, carbamσyl, sulphamqylamino, C.-C. alkanesulphonamido, -CO(C-.- alkyl) or - HXKC j -^ alkyl) ; p is 1 or 2 and Y and IT are each 0 or CH_. Ihe pharmaceutically acceptable salts of the ccπpounds of forxπula (I) include acid addition salts such as the t drochloride, hydrobrcnd.de, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, besylate, citrate, fumarate, gluconate, lactate, maleate, mesylate, succinate and tartrate salts. For a more cxπprehensive list of pharmaceutically acceptable salts see, for example, the Journal of Eharmaceu ical 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 or ether, and recovering the acid addition salt either as a precipitate, or by evaporation of the solution. The compound of the formula (I) can be prepared by the following reaction:- ^CH^AH + QfCH^XR - Ccπpσunds (I) (II) (HI) R, R , A, X, m and n are as defined for formula (I) and Q is a leaving group, e.g. Br, d, I, C.-C alkanesulfonyloxy (e.g. methanesulfoπylαxy) , benzenesulfoπyloxy, toluenesulfoπylαxy (e.g. p-t-oluenesulfσπylσxy) or trifluora-nerUi---fliesulfoi^loxy. Preferably, Q is Cl, Br, I or methanesulfoπylαxy. The reaction is preferably carried out in the presence of an acid acceptor such as sodium or potassium carbonate, sodium bicarbonate, triethylamine or pyridine, and in a suitable organic solvent, e.g. acetonitrile, at up to the reflux temperature. Reaction teirperaturεs 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 cαr-pound (III) as a chloride or bromide but in the presence of an iodide such as sodium or potassium iodide. In the preferred technique, the σαπpounds (II) and (III) , (III) being in brαπ-ide or chloride form, are refluxed together in acetαnitrile in the presence of sodium carbonate and sodium iodide. The product (I) can be isolated and purified conventionally. The starting materials of the formula (III) are in general kncwn ccπpounds which can be prepared by conventional techniques. The p-ceparation of any novel starting materials of the formula (III) used in the Examples is described in the following Preparations section. The starting materials (II) can be prepared conventionally, e.g. as follows (see also Preparations 1 and 2) :- K ΛOffiH / trifluoroacetic acid, / dichloromethane Compounds (II) The method described in Preparations 7 and 8 can also be used. Same of the ccπpounds of the formula (I) in which R is a substituted phenyl group can be converted to other ccπpounds of the formula (I) as follows:- (a) A -C0 2 (C.-C alkyl) substituent on the phenyl group can be reduced to -CH_0H. Lithium aluminium hydride is the most suitable reducing agent. The reaction is typically carried in a suitable organic solvent, e.g. ether, at between O and room temperature. It is generally most convenient to use the starting material in the form of its methyl or ethyl ester. (b) A hydroxy substituent on the phenyl group can be converted to -OCO(C.-C alkyl) by acylation using a C.- alkanoyl chloride or bromide or a C.-C. alkanoic anhydride. The presence of an acid acceptor is preferable. The reaction is typically carried out at about rocm temperature in a suitable organic solvent, e.g. dioxan. (c) A -00(C.-C 3 alkyl) substituent on the phenyl group can be reduced to a substituent of the formula -CH(CH) (C-.-C- alkyl) . Suitable reducing agents include sodium borohydride and lithium aluminium hydride. The reaction is typically carried out at between 0 and room temperature in a suitable organic solvent, e.g. methanol for sodium borohydride and ether or THF for lithium aluminium hydride. Sodium borohydride is the preferred reducing agent. (d) A -C0 2 (C -C alkyl) substituent, preferably -C-O-OL, can be converted to -CONR 4R5 by reacti.on wi.th ammonia or the appropriate amine BX 4_R5NH. When R4 and R5 are both H, the use of aqueous (0.880) ammonia is generally most convenient, although the reaction can be carried cut using ammonia in an organic solvent such as methanol or ethanol, or ammonia neat in a bcπ-b. 4 5 Although in seme instances the reaction with the amines R R NH may proceed at a satisfactory rate at room temperature, heating at up to 120°, preferably 60 to 100 C, is generally necessary. For volatile amines, the reaction is best carried out in a bcπib. (e) A nitro substituent on the phenyl group can be reduced to amino by conventional means. The preferred reducing agent is stannous chloride dihydrate and the reaction is typically carried out in an organic solvent such as ethanol under reflux. (f) An amino substituent on the phenyl group can be converted to -NHSO (C.-C alkyl) fcy reaction with a . j -C. alkanesulphonyl chloride or bromide or C.-C. alkanesulphonic anhydride, typically in an organic solvent such as diαxane. The presence of an acid acceptor such as pyridine, triethylamine, sodium bicarfx-nate or sodium or potassium carbonate, is preferable. It is sometimes convenient, particularly when a sulphαπyl chloride is used, to carry out the reaction in pyridine, the pyridine functioning as both the solvent and the acid acceptor. Heating is not usually necessary: normally the reaction will proceed at a satisfactory rate at rocm t-e-πperature. (g) A substituent of the formula -((3L) CL where q is 0, 1 or 2 can be converted to -(OL) NHσθ(C.-C. alkyl) by reaction with a C.-C. alkanoyl chloride or bromide or C.-C. alkanoic anhydride. The reaction can be carried out similarly to (f) above. The use of acetic anhydride in acetonitrile with triethylamine as the acid acceptor is a preferred reaction. (h) An amino substituent on the phenyl group can also be converted to sulphamcyl by reaction with sulphamide, typically under reflux in an organic solvent such as dioxane. (i) A hydroxy substituent can be converted to C.-C. alkoxy firstly by reaction with a strong base such as sodium hydride, and then by reaction with a C.-C. alkyl iodide. The reaction is preferably carried out at about rocπt teπperature in a solvent such as dimethylformamide. (j) A hydroxy substituent of the formula -(OL) OH where q is O, 1 or 2 can be converted to -(CEL) OC0NH(C,-C alkyl) by reaction with a C.-C. alkyl isocyanate. The reaction is typically carried out at about room teπperature in a solvent such as methylene chloride. (k) A hydrαxymethyl --aibstitueπt on the phenyl group can be 6ι_7 6 7 converted to -OLNRTI where R and R are each independently H or C,-C alkyl by reaction firstly with thioπyl chloride and secondly with ammonia or the appropriate amine ΕCR NH. The reaction with thioπyl chloride is typically carried out with heating, preferably under reflux, in a solvent such as methylene chloride. The reaction with ammonia or the amine is typically carried cut at about room tatrperature in a solvent such as ethanol. (1) An acetyl substituent can be ∞πverted to -C(OH) (CR- * ) 2 by reaction with methyllithiu , methylmagnesium bromide, methyl- magnesium iodide or methyl-magnesium chloride. The reaction is typically carried out in a solvent such as ether at a temperature of from 0°C to room teπperature. ( ) An iodo substituent can be converted to C.-C. alkoxy- carbαnyl by reaction, typically at about room temperature, with carbon monoxide in a C.-C. alkanol containing a base [e.g. potassium carbonate] and a palladium (II) catalyst [e.g. bis(triphenylphosphine)pallactium (II) chloride]. (n) A cyano substituent on the phenyl group can be reduced to amincroethyl, typically by catalytic hydrogenation, e.g. using HL/P3 C in ethanol containing a small amount of concentrated hydrochloric acid. (o) A substituent of the formula -(O^J N^ where q is 0, 1 or 2 can be converted to a substituent of the formula-(OU) HCONHfC j -C^ alkyl) by reaction with a C,-C alkyl isocyanate. The reaction is typically carried out at about room teπperature in a solvent such as methylene chloride. (p) A C,-C. alkoxy substituent, preferably methoxy, can be converted to hydroxy by treatment with a C,-C. alkanethiol in the presence of a strong base, e.g. sodium hydride. The reaction is typically carried cut by refluxing the reactaπts in a suitable solvent, e.g. di-methylfαπnamide. Butanethiol is the preferred thiol. (q) A carboxy substituent can be converted to carbamαyl by reaction with oxalyl chloride and then ammonia in e.g. d-ichloromethane at about room temperature. and (r) a C.-C. alkαxycaii-oπyl substituent can be hydrolysed to carboxy using e.g. aqueous alkali, preferably aqueous sodium hydroxide, in e.g. diαxane. The selectivity of the cx-πpounds as muscaranic 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 and 5% (XL. 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 from iscmetrically recorded contractions. Dose-response curves to either acetylcholine (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 containing the lowest dose of the test coπpσund. The test cσπpound is allowed to equilibrate with the tissue for 20 minutes and the agonist dose-response curve is repeated until the maximum response is obtained. The organ bath is drained and refilled with physiological salt solution containing the second cxjncentration of test compound and the above procedure is repeated. Typically four concE-ntratiαns of the test ccπpσund are evaluated on each tissue. The σcax-eπtratiαn of the test compound which causes a doubling of the agonist concentration required to produce the original response is determined (pA_ value - Arunlakshana and Schild (1959) , Brit. J. Hiar acol., 14, 48-58) . Using the above analytical techniques, tissue selectivity for muscarinic receptor aπtagσni-sts is determined. Activity against agonist induced bronchoccnstriction, gut or bladder contractility in ccπparisσn with changes in heart rate is determined in the anaesthetised dog. Oral activity is assessed in the conscious dog determiriing ccπpound effects en, for example, heart rate, pupil diameter and gut mσtility. Ccπpound affinity for other cholinergic sites is assessed in the mouse after either intravencus or intx^eritoneal administration. 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 oxσt-remorine. For admini-stration to man in the curative or prophylactic treatment of diseases associated with the altered morality and/or tone of smooth muscle, such as irritable bowel syndrome, diverticular disease, urinary incαntinenσe, oesphageal achalasia and chronic cbstructive airways disease, oral dosages of the ccπpσunds will generally be in the range of from 3.5 to 350 mg daily for an 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 ccπpound, in a suitable pharmaceutically acceptable vehicle or carrier for administration singly or in multiple doses, once or several times a day. Dosages for intravenous administration 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 the 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 rates are merited, and such are within the scope of this invention. For human use, the ccπpounds of the formula (I) can be administered alone, tut will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing 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 containing flavouring or colouring agents. They may be injected pareπterally, for example, intravenously, intramuscularly or subcutaneously. For pareπteral 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 composition comprising a ccπpound 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 syndrome. The invention further includes the use of a ccπpound of the formula (I) , or of a pharmaceutically acceptable-salt thereof, for the manufacture of a medicament for the treatment of diseases associated with the altered motility anc3/ or tone of smooth muscle, such as irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease. The following Examples, in which all temperatures are in °C, -- Llustxat-e the invention: Example 1 3- (DiT^eπv-bmethoxymethyl) -1- (3-methoxyphenethyl) piperidine A mixture of 3-(diphenylmethαxymethyl)piperidine (1.40 g, 5.0 mmol - see Preparation 1), 3-methαxyphenethyl bromide (1.08 g, 5.0 mmol), sodium carbonate (1.08 g) and sodium iodide (0.10 g) in acetonitrile (30 ml) was heated under reflux for 18 hours , diluted with ethyl acetate and water and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by (--hrαmatography on silica using dichloromethane plus 0-3% methanol as eluaπt. Appropriate fractions were combined and evaporated to give the title ccπpound (1.12 g) as a colourless oil which was characterised containing a third of an equivalent of water. Analysis:- Found: C,79.8; H,7.8; N,3.5; C 28 H 3 O .0.331^0 requires: C,79.8; H,7.8; N,3.3. Example 2-6 The following compounds were prepared by reacting 3- (diphenylmethoxymethyl)piperidine with the appropriate alkylating agent of the formula R(CH 2 ) Hal in the presence of NaI/Na_C0_ as described in Example 1. The free base products from Examples 4 and 5 were each converted to their hydrochloride salts by treatment of a solution in ether with excess ethereal hydrogen chloride followed by evaporation. The residue obtained in Example 5 was crystallised from ethyl acetate. OCHPh, (CHZ_)nR Example 7 4- (Dipheπy-hrethoxymethyl) -1- (3-methoxyrhenethyl) piperidine A mixture of 4-(dipher -1-methαxyιr-ethyl)piperidine (1.40 g, 5.0 mmol - see Preparation 2), 3-methoxyphenethyl bromide (1.08 g, 5.0 mmol), sodium carbonate (1.06 g) and sodium iodide (0.50 g) in acetonitrile (30 ml) was heated under reflux for 16 hours, diluted with ethyl acetate and water and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chrαπatography on silica using dichlorcmethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title ccπpound (1.12 g) as a colourless oil. Analysis %:- Found: C,80.4; H,8.0; N,3.4; C 28 H 33 0 2 requires: C,81.0; H,7.95; N,3.4. Examples 8-17 The following compounds were prepared by reacting 4-(diphenylmethαxymethyl)piperidine with the appropriate alkylating agent of the formula R(OL) Hal in the presence of Nal/Na^CO as described in Example 7 and and were characterised in the form indicated. In those cases where the form characterised was the hydrochloride salt, these were prepared by treating a solution of the appropriate free base in ether with excess ethereal hydrogen chloride. The resulting precipitated oil or solid was collected, washed with ether and dried to give the desired compound. Ph 2 CH.O Example 16 -bϊ- MR (CDC1 3 ) c = 7.2-7.45 (14H,m) 5.38 (lH,s) , 4.68(2H,s), 3.39(2H, d, J = 4Hz), 3.20(2H, d J = 6Hz) , 2.91-3.01, (2H,m) , 2.68-2.82 (2H,m), 2.23 (2H, t, J = 6Hz) , 1.75-2.0(3H,m) and 1.50-1.70(2H,m). Example 15 " l-N R (CDCl 3 )ci= 7.2-7.45 (10H,m) , 6.60-6.82 (3H,m) , 5.96 (2H,s), 5.37 (1H,S), 3.37(2H, d, J = 4Hz) , 2.5-3.15 (6H,m) , 1.6-2.15 (5H,m) and 1.25-1.50 (2H,m) . Example 18 4- (Dipheπylmethoxymethyl)-1-(4-hvdroxyιnethylbenzyl)- piperidine hydrochloride A solution of 4-(diphery.hnethaxymethyl)-l-(4-efc benzyl)piperidine (0.79 g, 1.8 mmol) (see Exaπple ll) in ether (5 ml) was added drcpwise over 5 minutes to a stirred suspension of lithium aluminium hydride (68 mg, 1.8 mmol) in ether (5 ml) and the mixture stirred at room temperature for 1 hour, quenched by the cautious sequential addition of water (0.07 ml) , 15% aqueous sodium hydroxide solution (0.07 ml) and water (0.21 ml) and filtered. The filtrate was dried over magnesium sulphate and treated with excess ethereal hydrogen chloride. The mixture was decanted and the residual oil triturated with ether to give the title compound (0.70 g) as a colourless foam. Analysis %:- Found: C,73.6; H,7.5; N,3.2; ^.-JL N0 2 .HC1 requires: C,74.0; H,7.4; N,3.2. Example 9 1- (4-Carboxyphenethyl) -4- f dipheny nethoxymethyl) piperidine hydrochloride A mixture of 4-(dιphe-r -_methoxymethyl)-l-(4^ phenethyl)piperidine (1.40 g, 3.2 mmol) (see Example 14) and sodium hydroxide (0.38 g, 9.5 mmol) in a mixture of dioxane (20 ml) and water (20 ml) was stirred at 100°C for 2 hours, allcwed to cool to room temperature, acidified with acetic acid and evaporated. The residue was partitioned between ethyl acetate and water and the layers separated. The aqueous layer was extracted into ethyl acetate and the combined organic layers were dried over magnesium sulphate and evaporated. The residue was dissolved in ethyl acetate and the solution treated with excess ethereal hydrogen chloride. The resulting precipitate was collected, washed with ethyl acetate and dried to give the title ccπpound (1.03 g) as an off-^white solid, m.p. 209-212°C decamp. Analysis %:- Found: C,72.0; H,7.0; N,3.0; C^ϊ^^^RCl requires: C,72.2; H,6.9; N,3.0. Example 20 Oxalyl chloride (272 mg, 2.14 mmol) was added drcpwise to a stirred suspension of l-(4-ca--±χ-5xyphe-nethyl)-4-(diΛeny-l---tethojQ?- methyl) iperidine hydrochloride (0.50 g, 1.07 mmol) (see Example 19) and N,N-dimethylformamide (2 drops) in dichlorαmethane (20 ml) and the mixture stirred at room temperature for 1 hour. Gaseous ammonia was then bubbled through the solution for 15 minutes and the mixture evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate solution and the layers separated. The aqueous layer was extracted into ethyl acetate and the combined organic layers were dried over magnesium sulphate and evaporated. The residue was crystallised from ethyl acetate to give the title ocπpσund (250 mg) as an off-white solid, m.p. 172-174°C, which was characterized as a hemihydrate. Analysis %:- Found: C,77.2; H,7.5; N,6.7; C H_ N O .0.5IL0 requires: C,76.8; H,7.6; N,6.4. Example 21 1- ( 4-Aminophenethyl ) -4- (di eπylrnethoxymethyl ) piperidine A mixture of 4-(diphenylπethoxymethyl)-l^^ piperidine (1.40 g, 3.3 mmol) (see Example 13) and stannσus (II) dichloride dihydrate (3.68 g, 16.3 mmol) in ethanol (20 ml) was heated at 70 C for 2 hours, allowed to cool to room teπperature and filtered. The filtrate was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The layers were -separated and the aqueous layer extracted into ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulphate and evaporated. The residue was triturated with ether and the resulting solid collected, washed with ether and dried to give the title compound (0.66 g) as a fawn solid, rni.p. 188-190°C, which was characterised by its " TIHNMR --qpectrum. " bϊ→lMR (CDC1 3 ),6= 7.20-7.45 (10H,m) , 7.04 (2H,d,J = 8Hz) , 6.63(2H, d,J = 8Hz), 5.37 (1H,S) , 3.55-3.8 (4H,m) , 3.40 (2H,broad s), 3.05-3.25 (4H,m), 2.55-2.75 (2H,m) and 1.80-2.20 (5H,m) . Example 22 4-(Dipheπylmethoxymethyl)-1-(4-sulphamoylaπ-ir-pherethyl)- piperidine A solution of l-(4-am--j y ^enethyl)-4-(diphenylmethθ--qαnethyl)- piperidine (200 mg, 0.50 mmol) (see Example 21) and sulphamide (480 mg, 5.0 mmol) in dioxane (5 ml) was heated under reflux for 3 hours and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate solution and the layers separated. The aqueous layer was extracted into ethyl acetate and the combined organic layers were dried over magnesium sulphate and evaporated. The residue was purified by ch-romatography on silica using dic-hlorcπethane plus 0-4% methanol as eluant. Appropriate fractions were combined and evaporated and the residue triturated with dϋsoprcpyl ether. The resulting solid was collected, washed with diisopropyl ether and dried to give the title ccπpound (100 mg) as a pale yellow solid, m.p. 172-174°C, which was characterised by its " TH-NMR spectrum. " hϊ-NMR 7.0-7.5 (14H,m) , 5.37 (lH,s), 4.6-5.6 (3H, broad s), 3.34 (2H,d,J = 4Hz) , 3.02-3.20 (2H,m) , 2.55-2.90 (4H,m) , 2.0-2.25 (2H,m), 1.5-1.90 (5H,m) . Example 2.3 4- ( Dipheπylmethoxymethyl) -1- (4-mrethanesult^orιamido henethyl) • piperidine hydrochloride Ph 2 CH.O Methanesulphonyl chloride (69 mg, 0.60 mmol) was added drcpwise to a stirred solution of l-(4-ai-t---nopherethyl)-4-^iphenyl- methαxymethyl)piperidine (200 mg, 0.50 mmol) (see Exampl-e 21) and triethylamine (61 mg, 0.60 mmol) in dioxane (5 ml) and the mixture heated under reflux for 2 hours and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate solution. The layers were separated and the aqueous layer extracted into ethyl acetate. The combined organic layers were dried over magnesium sulphate and evaporated. The residue was purified by chrαmatography on silica using dichloromethane plus 0-4% methanol as eluaπt. Appropriate fractions were combined and evaporated. The residue was dissolved in ether and the solution treated with excess ethereal hydrogen chloride. Die mixture was decanted and the residual oil was washed with ether and dried to give the title ccπpound (90 mg) as a pale yellcw foam which was characterised containing 0.25 equivalents of water. Analysis %:- Found: C,64.7; H,7.1; N,5.2; <^ g H 34 N 2 O 3 S.H&.0.25H 2 0 requires: C,64.7; H,6.9; N,5.4. Example 24 1- (4-Acetamidophenethyl) -4- (diphenv-br-ethoxymethyl) piperidine Acetic anhydride (68 mg, 0.67 mmol) was added dropwise to a stirred solution of l-(4-a-minophenethyl)-4-(diphenyl-methoj£y- methyl) iperidine (180 tag, 0.45 mmol) (see Example 21) and triethylamine (55 mg, 0.54 mmol) in acetonitrile (5 ml) and the mixture heated under reflux for 2 hours and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate and the layers separated. The aqeuous layer was extracted in ethyl acetate and the combined organic layers were dried over magnesium sulphate and evaporated. The residue was triturated with ethyl acetate and the resulting solid collected, washed with ethyl acetate and dried to give the title ccπpound (35 mg) as an off-white solid which was characterised containing 0.25 equivalents of water. Analysis %:- Found C,77.8; H,7.7; N,6.4; C^H^N^.0.25^0 requires: C,77.9; H,7.8; N,6.3. EXAMPLE 25 3- (Di^eny-l-m-ethoxymethyl) -1- (3 ,4-methylenedioxychenethyl) - pyrrolidine A mixture of 3-(diphenylmethαxymethyl)pyrrolidine (267 mg) (Preparation 7), 3,4-methylenediαxyphenethyl bromide (250 mg) , sodium carbonate (1.0 g) and sodium iodide (100 mg) in acetonitrile (30 ml) was heated under reflux for 24 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 purified by chrσπatography on silica using dichlo-t-omethane plus 0-20% ethyl acetate followed by dichloromethane plus 20% ethyl acetate plus l-5%jmethanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (217 mg) as a colourless oil which was characterised cxjntaining 0.25 equivalents of water. Analysis %:- Found: C,77.0; H,7.1; N,3.3 ; C 2? H 2g NO 3 .0.25 ^O requires: C,77.2; H,7.0; N,3.3. EXAMPLE 26 3- (Diphenv-bnethoxymethyl) -1- (3.4-methylenedioxybenzyl) pyrrolidine This was prepared as described in Example 25 using 3,4-methylenediαxybenzyl chloride instead of 3,4-methylene- dioxyphenethyl brcπ de. The title ccπpound was obtained as a colourless oil. Analysis %:- Found: C,77.7; H,6.9; N,3.5; C 2f -H 27 N0 3 requires: C,77.8; H,6.7; N,3.5. Preparation 1 3- (Dipheπylmethoxymethyl ) piperidine Trifluoroacetic acid (20 ml) was added cautiously to a vigorously stirred solution of piperidine-3-methanol (5.75 g, 50 mmol) in dichlorcmethane (20 ml) and the mixture treated with benzhydrol (9.2 g, 50 mmol) portionwise over 5 minutes, stirred at room temperature for 2 hours and evaporated. The residue was dissolved in dioxane (50 ml) and the solution treated with 4M aqueous sodium hydroxide solution (100 ml) , stirred at room temperature for 2 hours, diluted with ether and water and the layers separated. The organic layer was washed with water and extracted into 2M hydrochloric acid. The acidic extract was washed with ether, basified with solid sodium carbonate, extracted into ether, washed with water, dried over magnesium sulphate and evaporated to give the title compound (4.31 g) as a pale yellcw oil which was characterised by its " T*-NMR spectrum. • ^ϊ-NMR (CDC1 3 )£= 7.2-7.45 (10H,m) , 5.34 (1H,S) , 3.18-3.36 (3H,m) , 3.03 (lH,dt,J = 8 and 2Hz) , 2.57 (lH,tt,J = 10 and 2.5Hz) , 2.39 (lH,dd,J = 10 and 8Hz) and 1.1-1.95 (6H,m) . Preparation 2 4- (Dipheπylmethoxymethyl) piperidine This was prepared as described in Preparation 1 using piperidine-4-methanol instead of piperidine-3-methanol. The title ccπpound was obtained as a colourless oil. Analysis %:- Found: C,81.5; H,8.4; N,5.3; C, H^ O requires: C,81.1; H,8.2; N,5.0. Preparation 3 3,4-Methylenedioχyphenethyl alcohol 3,4-Methylenedioxyphenylaσetic acid (18.0 g) was added portionwise over 30 minutes to a stirred, ice-cooled suspension of lithium alvm nium 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 compound as a pale yellow oil (15.0 g) , which was characterised by its " TI-NMR spectrum. ^H-NMR (CDCl ) <f= 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_0) . Preparation 4 3,4-Methyler^ioxyohenethyl bromide PBr. A solution of phosphorus t-ribromide (8.1 g) in carbon tetrachloride (50 ml) was added dropwise over 30 minutes to a stirred solution of alcohol (15.0 g) (see Preparation 3) in carbon tetrachloride (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 --hrαmatography on silica (100 g) using carbon tetrachloride as the eluant. Appropriate fractions were combined and evaporated to give the title ccπpound as a pale yellcw oil (8.3 g) , which was characterised by its " TI-NMR spectrum. • ^- R (CDC1 3 )^= 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 5 6- (2-Hvdroχyethyl) benzodioxan This was prepared as described in Preparation 3 using (benzodioxan-6-yl)acetic acid instead of 3,4-methylenedioxy- pheπylaσetic acid. The title compound was obtained as a colourless oil which was characterised by its TI-NMR spectrum. • ^- MR (CDCl.) £= 6.84 (lH,d,J = 8Hz) ; 6.77 (lH,d,J = 2Hz) ; 6.73 (lH,dd,J = 8 and 2Hz) ; 4.28 (4H,s) ; 3.59 (2H,t,J = 8Hz) and 3.08 (2H,t,J = 7HZ) . Preparation 6 6-(2-Brσmoethyl)benzodioxan This was prepared as described in Preparation 4 using 6-(2-hydroxyethyl)benzodioxan (see Preparation 5) instead of • I 3,4-mιethylenediαxyphenethyl alcohol. The title compound was obtained as a pale yellow oil which was characterised by its " Tϊ-NMR spectrum. " ϊ-NMR (CDCl 3 )g= 6.83 (lH,d,J = 8Hz) ; 6.77 (lH,d,J = 2Hz) ; 6.72(lH,dd,J = 8 and 2Hz) ; 4.28 (4H,s); 3.59 (2H,t,J = 7Hz) and 3.10 (2H,t,J = 7Hz). Preparation 7 3- ( Dipheπyhmethoxymethyl) pyrrolidine ' x 11 A solution of l-ben2yl-3-(dipheny---m-ethoxyme^ (1.43 g, Preparation 8) in ethanol (50 ml) containing acetic acid (1.0 ml) was stirred at room tettperature for six days under an atmosphere of hydrogen in the presence of 5% palladium on charcoal. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution and water, dried over magnesium sulphate and evaporated to give the title coπpound (0.84 g) as a pale yellow oil which was characterised by its " TI-NMR spectrum. H^-NMR (CDC1 3 )£ = 7.25-7.45 (10 H, m) , 5.35 (1H, s) , 2.4-3.5 (8H, m), 1.83-2.05 (1H, m) and 1.42-1.58 (1H, m) . Preparation 8 l-Benzyl-3- (diϋheπylmethoxymethyl) pyrrolidine A mixture of l-ber-zylpyrrolidine-3-methanol (1.72 g) (J. Org. Chem. , 1961, 26, 1521) and b-t-omκxiLpher ---ιterhane (4.94 g) in xylene (150 ml) was heated under reflux for 3 hours, allowed to cool to ream teπperature, diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by chroatografhy on silica using di-hlorαrnethane plus 20% ethyl acetate plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title ccπpound (1.57 g) as a pale brown oil which was characterised by its " Ti-NMR spectrum. ^Η-NMR (CDC1 3 ) g= 7.15-7.6 (15H, m) , 5.35 (1H, s) , 4.01 (2H, AB, J = 14Hz), 3.47 (2H, d, J = 7Hz) , 2.65-3.45 (5H, m) , 2.12-2.32 (1H, m) and 1.75-1.91 (1H, m) .

Claims: CLAIMS A compound of the formula:- ■ (i) or a pharmaceutically acceptable salt thereof, wherein R is a group of the formula:- where Z is -(OL),-, -CH=CH-, -O -S- or -O -0-; R is a group of the formula:- and A is a group of the formula:- or Xx in which the N atom is attached to the group (CH ) ; m is 1 or 2; n is an integer of from 1 to 4; p is 1, 2 or 3; R 2 and R3 are each independently hydrogen, C,-C alkyl, hydroxy-(C.-C alkyl), hydroxy, C-.-C. alkoxy, halo, trifluo-rønethyl, nitro, cyano, sulphamoyl, -CO(C.-C alkyl), -OO-KC j -C alkyl), carboxy, -∞ 2 ' l~ C 4 alkyl) , -(O^) C0NR 4 R 5 , -(O^) 0CCNR 4 R 5 , -(CH^) NR 6 R 7 or -NHSO ML. in which R 4 and R5 are each independently H or 6 7 C j -C. alkyl, q is 0, 1 or 2, and either R and R are each independently H or C.-C. alkyl or R is hydrogen and R 7 is -SO^C j -C alkyl), -αofC -C j alkyl) or -CONHfC^-C alkyl); X is a direct link, O or S; Y and are each independently 0 or CEL; and Het is pyridyl, pyraziπyl or thienyl. 2. A compound as claimed in claim 1 in which R is (Fh)_CH. 3. A compound as claimed in claim 1 or 2 in which m is 1. 4. A c-αmpαund as claimed in any one of the. preceding claims in which n is 1, 2 or 3. 5. A coπpound as claimed in any one of the preceding claims wherein X is a direct link. 6. A ccπpound as claimed in any one of the preceding claims wherein A is a group of the formula:- 7. A ccπpound as claimed in any one of the preceding claims in which R is a group of the formula:- 2 3 where R and R are each independently hydro-xymethyl, C.-C alkoxy, C.-C. alkαxycarbαnyl, carboxy, sulphamoyl, nitro, amino, carbamoyl, sulpha-moylamino, C.-C alkanesulphonamido, -CXHCL-C alkyl) or -MBDOCC j -^ alkyl) ; p is 1 or 2 and Y and Y^ are each O or OL. 8. A pharmaceutical σcπposition comprising a ccπpound of the formula (I) as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 9. A ccπpound of the formula (I) as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use as a medicament. 10. The use of a ccπpound of the formula (I) as claimed in any one of claims 1 to 7, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating irritable bcwel syndrome. 11. A process for preparing a cαtpound of the formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterised by reacting a cαtpound of the formula:- Axαy^ — (ID with a compound of the formula:- QfCH^XR (III) where R, R , A, X, m and n are as defined in claim 1 and Q is a leaving group; said process being followed by, optionally, one or more of the following steps:- (a) reduction of a -C0 2 (C.-C. alkyl) substituent to -CH-QH; (b) reduction of a nitro substituent to amino; (c) conversion of an amino substituent to alkyl) by reaction with a C, - . alkanesulfonyl chloride or bromide or a C,-C. aikanesulphonic anhydride; (d) conversion of a substituent of the formula -(CHL) NH_ where q is 0, 1 or 2 to -(CHL) NHC0(C-,-C 4 alkyl) by reaction with a C,-C. alkanoyl chloride or bromide or C,-C. alkanoic anhydride; (e) conversion of an amino substituent to sulphamoyl by reaction with sulphamide; (f) conversion of a carboxy substituent to cartamoyl by reaction with oxalyl chloride and then ammonia; (g) hydrolysis of a (C-.-C alkoxy) carbonyl substituent to carboxy; and (h) conversion of a product of the formula (I) into a pharmaceutically acceptable salt. 12. A process as claimed in claim 11, characterised in that Q is Cl, Br, I or methanesulfoπyloxy, and in that the cσπpσunds (II) and (III) are reacted together in the presence of 'an acid acceptor. 13-. A method of treating irritable bcwel syndrome in a patient in need of such treatment, characterised by administering to said patient an effective amount of a coπpound of the formula (I) or pharmaceutcally accepable salt thereof as claimed in any one of claims 1 to 7.

Inventors: ALKER DAVID, CROSS PETER EDWARD, ALKER, DAVID, CROSS, PETER, EDWARD
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 1990
Main classification: C07D207
IPC codes: A61K31, A61P1, A61P11, A61P13, A61P15, A61P25, C07D207, C07D211, C07D401, C07D405, C07D409