DIPHENYLSULPHOXIMINE MUSCARINIC RECEPTOR ANTAGONISTS

Abstract: Compounds of formula (I), wherein R and R<1> are H or C1-C4 alkyl; and X is a group of formulae (II) or (III), wherein either R<2> is H or C1-C4 alkyl and R<3> is C1-C4 alkyl, or R<2> and R<3> represent -(CH2)r- wherein r is from 2 to 5; R<4> is C1-C4 alkyl; X<1> is a direct link, O or S; R<5> is mono or disubstituted phenyl wherein the substituents are H, halo, C1-C4 alkyl, C1-C4 alkoxy, -(CH2)sOH, -(CH2)sNR<8>R<9>, -CONR<10>R<11>, -SO2NH2 or -OCO(C1-C4 alkyl), or adjacent substituents may form a fused ring; or R<5> is thienyl, pyridinyl or pyrazinyl; R<8> and R<9> are H or C1-C4 alkyl, or R<8> is hydrogen and R<9> is -SO2(C1-C4 alkyl), -CONR<10>R<11>, -CO(C1-C4 alkyl) or -SO2NH2; R<10> and R<11> are hydrogen or C1-C4 alkyl; m is 1, 2 or 3; n is 0, 1 or 2; p is 0 or 1; and s is 0, 1 or 2, (with certain provisos); are gastrointestinal and bladder selective muscarinic receptor antagonists of utility for example in irritable bowel syndrome.

Description: Dipr.eny.su. phoximine muscarinic receptor antagonists This invention relates to diphenylsulphoximine derivatives. More specifically the invention relates to N-pyrrolidinyl(alky1)/N-piperidinyl(alkyl)- and N-aminoalkyl- substituted diphenylsulphoximine derivatives which are gastrointestinal and bladder selective muscarinic receptor antagonists. GB-A-1,168,700 discloses certain N-substituted aminoalkyl-S,S-diphenylsulphoximine derivatives which exhibit specific broncholytic-antispasmodic activity in mammals and which are useful in treating conditions generally associated with bronchial diseases. The compounds of the present invention are useful for the curative or prophylactic treatment of disease states where the gastrointestinal and bladder selective reduction of acetylcholine-mediated smooth muscle contraction would be of benefit such as in the treatment of motility disorders of the gut, in particular as in irritable bowel syndrome, and in the treatment of urinary incontinence, emesis or diverticular disease. Irritable bowel syndrome is a motility disorder characterised by altered bowel habit (i.e. constipation and/or diarrhoea), distension and abdominal pain. The muscarinic receptor antagonists of the present invention reduce the motility of the gut thus having an antispasmodic effect on the bowel without producing, or significantly reducing, bronchial or cardiac effects. Thus the present invention provides compounds of the formula : - and pharmaceutically acceptable salts thereof, wherein R and R are each independently H or C.-C, alkyl; and X is a group of the formula:- or (AH 9 ) -X^ 5 wherein either R is H or C.-C, alkyl and R is C--C, alkyl, or 2 3 R and R taken together represent -(CH„) - wherein r is an integer of from 2 to 5; 4 R is C..-C, alkyl; X is a direct link, 0 or S; R is a group of the formula:- either R and R are each independently H, halo, C.-C, alkyl, C..-C A alkoxy, -(CH^OH, -(CH 2 NR 8 R 9 , -CONR 10 R 1:L , -S0 2 NH 2 or -OCCXC^-C^ alkyl), or R and R taken 2 3 together represent a group of the formula -X -(CH„) -X - 2 3 wherein X and X are each independently 0 or CH„ and t is an integer of from 1 to 3; 8 9 8 either R and R are each independently H or C--C, alkyl, or R is hydrogen and R 9 is -SO^C-^-C, alkyl), -CONR 10 R 1:L , -C0(C -C alkyl) or -SO NH ; R and R are eaph independently hydrogen or C.-C, alkyl; "Het" is thienyl, pyridinyl or pyrazinyl; m is 1, 2 or 3; n is 0, 1 or 2; p is 0 or 1; and s is 0, 1 or 2: with the provisos that (a) when in is 1, X is a direct link and R is as defined above except for "Het"; and (b) when n is zero, the N-substituted pyrrolidinyl or piperidinyl ring is not attached via it's 2-position to the adjacent sulphoximine nitrogen atom. In the above definitions halo means F, Cl, Br or I and C, and kyl and alkoxy groups may be straight or branched chain. For the above compounds of the formula (I):- Preferably R and R are both H. 2 3 Preferably R is H or methyl and R is methyl; 4 Preferably R is methyl. Preferably X is a direct link. Preferably R is a group of the formula: More preferably R is (C.-C, alkoxy)phenyl, hydroxyphenyl or a group of the formula:- wherein t is 1 or 2. Most preferably R is 3- or 4-methoxyρhenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl or l,4-benzodioxan-6-yl. Preferably m is 2. Preferably n is 0 or 1. When X contains a pyrrolidinyl or piperidinyl group, preferably X is either N-substituted-3-piperidinyl or N-substituted-2-pyrrolidinylmethyl, where the N-substituent is a group -(CH„) -X -R as previously defined. The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts formed from acids which form non-toxic salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, mandelate, benzoate, salicylate, methanesulphonate, benzenesulphonate and para-toluenesulphonate salts. The compounds of the formula (I) contain at least one asymmetric centre and will therefore exist as a pair of enantiomers or as diastereoisomeric pairs of enantiomers. Such enantiomers or diastereoisomeric pairs of enantiomers may be separated by physical methods, for example by fractional crystallisation, chromatography or H.P.L.C. of the racemic mixture of the parent compound, or of a suitable salt or derivative thereof. Alternatively an individual enantiomer or a particular diastereoisomeric pair of enantiomers may be prepared from a corresponding optically active intermediate. The invention includes both the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof. A particularly preferred individual compound provided by the present invention is (3R)-N-[l-(4-methoxyphenethyl)piperidin-3- yl]diphenylsulphoximine or a pharmaceutically acceptable salt thereof. The compounds of the formula (I) provided by the invention may be prepared by the following methods, as illustrated in the following Examples section:- 1) All the compounds of the formula (I) may be prepared as illustrated by Scheme 1:- Scheme 1 (ID (III) Comp wherein R, R , R , R , R , R , m, n, p and X are as previously defined for the formula (I) and Y is a suitable leaving group, e.g. halo (preferably chloro or bromo), methanesulphonyloxy, trifluoromethanesulphonyloxy or p-toluenesulphonyloxy. In a typical procedure, a diphenylsulphoximine derivative of the formula (II) is deprotonated with approximately one equivalent of a suitable strong base, e.g. sodium hydride, n-butyllithium or lithium diisopropylamide, and then reacted jLn situ with an alkylating agent of the formula (III) or (IV), as required, in a suitable inert organic solvent, e.g. xylene or toluene. The reaction is preferably carried out by adding the strong base to a solution of compound (II) at about room temperature and under an inert atmosphere (e.g. of nitrogen or argon), then heating the resulting mixture at from 40°C to, and preferably at, the reflux temperature of the mixture for a short period to complete, or substantially complete, the deprotonation process. The solution containing the anion of the diphenylsulphoximine derivative (II) is then cooled, treated with a solution of the alkylating agent and the reaction heated at from room temperature to, and preferably at, the reflux temperature of the mixture. The product of the formula (I) is isolated and purified by conventional techniques. Although it is most convenient to deprotonate the diphenylsulphoximine derivative (II) ±n_ situ to provide the necessary anion, it is also possible to react the alkylating agent directly with a suitable salt of a compound of the formula (II) , e.g. the lithium, sodium, potassium or calcium salt. The skilled man will appreciate that due to a competing rearrangement reaction the use of an alkylating agent (IV) of the formula:- (V) (VI) wherein R , m, X and Y are as previously defined for a compound of the formula (IV) , in this process may provide a mixture of products of the formula (I) wherein X is a group of the formula:- (XA) (XB) 1 5 1 wherein R, R , R , X and m are as previously defined for the formula (I) . Indeed in certain circumstances the rearrangement product may be the exclusive product of the reaction. In many instances the attempted preparation of an alkylating agent of the formula (V) or (VI) results in a mixture of the required product together with the corresponding compound of the formula (VI) or (V), respectively. In certain circumstances the rearrangement product is the exclusive product of this intermediate preparation reaction. Such (V)/(VI) mixtures may be used directly in this process and the corresponding mixture of products of the formula (I) obtained may be separated by conventional chromatographic techniques. This effect arises since a compound of the formula (V) or (VI) may readily form an aziridinium ion (VII) during preparation or, for example, under the conditions of the alkylation reaction (see the review article by M. Miocque and J. P. Duclos, Chimie Therapeutique, 1969 (5), 363-380, and references cited therein). This aziridinium ion is open to two routes of nucleophilic attack by the anion derived from a diphenylsulphoximine derivative (II) in the alkylation reaction, thus accounting for the product mixture observed (Scheme 2). Scheme 2 Compounds (V) Compounds (VI) Compounds (I) wherein X is a group of the formula (XA) or (XB) where "Nu" represents the nucleophilic anion derived by deprotonation of a compound of the formula (II). 2) All the compounds of the formula (I) may be prepared as illustrated by Scheme 3:- Scheme 3 Acid or acceptor, solvent ■ ~ Compounds (I) Y 1 -(CH- 1 ) -X^R 5 2 m (X) wherein R, R , R , R , R , R , m, n, p and X are as previously defined for the formula (I) and Y is a suitable leaving group, e.g. halo (preferably chloro, bromo or iodo), methanesulphonyloxy, trifluoromethanesulphonyloxy or p-toluenesulphonyloxy. In a typical procedure a compound of the formula (VIII) or (IX), as appropriate, is reacted with a compound of the formula (X) in the presence of a suitable acid acceptor, e.g. sodium or potassium carbonate, and, where Y is chloro or bromo, optionally in the presence of sodium or potassium iodide to accelerate the rate of the reaction. The reaction is carried out in a suitable organic solvent, e.g. acetonitrile, at from room temperature to, and preferably at, the reflux temperature of the mixture. The product of the formula (I) is then isolated and purified by conventional techniques. 3) A compound of the formula:- or t 1 2 3 4 wherein R, R , R , R , R , n and p are as previously defined for the formula (I) and "Het " is 2- or 4-pyridinyl or pyrazinyl, may be conveniently prepared by a "Michael-type" addition reaction by reacting a compound of the formula (VIII) or (IX), respectively, 1 2 3 4 wherein R, R , R , R , R , n and p are as previously defined for the formula (I), with a compound of the formula Het -CH=CH_, wherein "Het " is as previously defined in this method. The reaction may be carried out using at least one equivalent, and preferably an excess, of the vinylheterocycle of the formula Het CH=CH„ and optionally in the presence of a suitable organic solvent, e.g. 1,4-dioxane. The rate may be accelerated by elevating the reaction temperature and/or by the addition of a suitable acidic or basic catalyst, e.g. benzyltrimethylammonium hydroxide. The product of the formula (XI) or (XII) may be isolated and purified by conventional techniques. 4) A compound of the formula (I) wherein X is a group of the formula:- wherein R, R , X , m and p are as defined for the formula (I) and R is as defined for the formula (I) with the exception that when neither R 6 nor R 7 can be -CONR 10 R 1:L , -(CH.) NHC0(C--C. alkyl), 2 s 1 -(CH ) NHCONR 10 R 1:L , -(CH ^ ) NHS0 2 (C--C, alkyl) or -0C0(C--C 4 alkyl) , wherein R , R and s are as defined for the formula (I) , may be prepared by reduction of a compound of the formula:- wherein R, R , R , X , m and p are as previously defined in this method, using a suitable strong reducing agent, e.g. aluminium hydride, and in a suitable inert organic solvent, e.g. tetrahydrofuran. The reaction is typically carried out by generating aluminium hydride in situ by treating an. ice-cooled suspension of lithium aluminium hydride in tetrahydrofuran with concentrated sulphuric acid. Compound (XIII) is then added and the resulting mixture is stirred at from 0°C to the reflux temperature of the mixture, preferably at about room temperature. The product of the formula (I) is isolated and purified by conventional techniques. 5) Some of the compounds of the formula (I) wherein R is a substituted phenyl group may be prepared from other compounds of the formula (I) as follows:- a) A C.-C, alkoxy, preferably methoxy, substituent on the phenyl group may be converted to hydroxy by treatment with hydrogen bromide. Preferably aqueous hydrobromic acid is used at from room temperature to, and preferably at, the reflux temperature of the mixture. This dealkylation can also be achieved by treatment with either a C--C, alkanethiol in the presence of a strong base, e.g. sodium hydride, or directly with a suitable C.-C, alkanethiolate salt, e.g. the sodium salt, and in a suitable organic solvent. The reaction may be heated to accelerate the rate. Butanethiol is the preferred thiol. b) A -CONR R substituent on the phenyl group, wherein R and R are as previously defined for the formula (I) , may be reduced to -CH„NR R with a suitable reducing agent, e.g. diborane. The reaction is typically carried out in a suitable organic solvent, e.g. tetrahydrofuran, at from room temperature to the reflux temperature of the mixture. c) A hydroxy substituent on the phenyl group may be converted to -0C0(C.-C, alkyl) by acylation using either a C.-C, alkanoyl chloride or bromide, or a C..-C, alkanoic anhydride. The presence of an acid acceptor is preferable, e.g. sodium bicarbonate or pyridine. The reaction is typically carried out in a suitable organic solvent at from 0°C to room temperature and heating is not usually necessary. If an acid chloride is used the reaction may be carried out in pyridine, the pyridine acting as both the solvent and the acid acceptor. If an acid anhydride is used the reaction may be carried out in the presence of an excess of the acid anhydride and in the absence of additional solvent or an acid acceptor. d) A -(CH_) NH_ substituent on the phenyl group, wherein s is 0, 1 or 2, may be converted to -(CH„) NHC0(C--C, alkyl) by acylation with a C..-C, alkanoyl chloride or bromide or a C--C, alkanoic anhydride. The reaction may be carried out similarly to method 5(c) above. e) A -(CH„) NH, substituent on the phenyl group, wherein s is 0, 1 or 2, may be converted to -(CH ) NHS0„(C -C, alkyl) by reaction with either a C..-C, alkanesulphonyl chloride or bromide, or a C--C, alkanesulphonic anhydride and in a suitable organic solvent. The presence of an acid acceptor, such as pyridine, sodium bicarbonate or sodium or potassium carbonate, is preferable. When a sulphonyl chloride is used the reaction is most conveniently carried out in pyridine, the pyridine functioning as both the solvent and the acid acceptor. The reaction usually proceeds at from 0°C to room temperature and heating is not necessary. f) A -(CH,) NH„ substituent on the phenyl group, wherein s is 0, 1 or 2, may be converted to -(CH,) NHS0,NH, by reaction with sulphamide. The reaction is typically carried out at the reflux temperature in a suitable organic solvent, e.g. 1,4-dioxane. g) A hydroxy substituent on the phenyl group may be converted to C.-C, alkoxy, firstly by reaction with a suitable strong base, such as sodium hydride, and then by reaction with a C--C, alkyl bromide or iodide. The reaction is preferably carried out at about room temperature in a suitable solvent, e.g. N,N-dimethylformamide. h) A -(CH,) NH, substituent on the phenyl group, wherein s is 0, 1 or 2, may be converted to -(CH ) NHC0NH(C -C, alkyl) by reaction with a C.-C, alkyl isocyanate. The reaction is typically carried out at about room temperature in a suitable organic solvent, e.g. dichloromethane. i) A -(CH.) NHC0(C 1 -C. alkyl) substituent on the phenyl Δ S 1 group, wherein s is 0, 1 or 2, may be hydrolysed to -(CH,) NH, under aqueous conditions using a suitable strong acid (e.g. hydrochloric acid) or base (e.g. sodium or potassium hydroxide) . The reaction is usually heated to accelerate the rate. j) A -CH,0H substituent on the phenyl group may be 8 9 8 9 converted to -CH.NR R , wherein R and R are each independently H or C.-C, alkyl, by reaction firstly with a suitable halogenating agent, e.g. thionyl chloride, and 8 9 secondly with ammonia or the required amine R R NH. The reaction with thionyl chloride is typically carried out with heating, preferably under reflux, and optionally in a suitable organic solvent, e.g. dichloromethane. The reaction with ammonia or the amine is typically carried out in a suitable organic solvent, e.g. ethanol, at from room temperature to the reflux temperature of the solvent: most conveniently a bomb is used as the reaction vessel. The intermediates used in the preparation of the compounds of the formula (I) provided by the invention may be prepared by the following methods, as illustrated in the following Preparations section:- 1) The diphenylsulphoximine derivatives of the formula (II) may be prepared by the routes, or similar routes, to those disclosed in the literature references a) F. Misani, T. W. Fair, L. Reiner, J.A.C.S., 7_3, 459 (1951); and b) G. Satzinger, P. Stoss, Arz. Forsch., 20_, 1214 (1970). An alternative method of preparation is disclosed in Preparation 26. 2) The intermediates of the formula (III) may be prepared as illustrated in Scheme 4:- Y 1 -( Acid R = methyl) (XVI) (XVII) (III) wherein R , R , R , R , m, X and Y are as previously defined for the formula (III) and Y is as previously defined for the formula (X). In a typical procedure an aminoalcohol of the formula (XIV) or (XV) is alkylated with a compound of the formula (X) in the presence of a suitable acid acceptor, e.g. sodium or potassium carbonate, and in a suitable organic solvent, e.g. acetonitrile. The reaction is preferably heated under reflux and, when Y is chloro or bromo, the reaction is optionally carried out in the presence of sodium or potassium iodide, in order to accelerate the rate of reaction. The secondary amine of the formula (XVI) may be methylated to 4 provide the tertiary amine (XVII), wherein R is methyl, using conventional procedures. The methylation may be carried out by reacting (XVI) with either an aqueous solution of formaldehyde in formic acid under reflux conditions, or by reacting (XVI) with a solution of formaldehyde in methanol in the presence of sodium cyanoborohydride. The alcohol of the formula (XVII) may be converted to a compound of the formula (III) by conventional techniques, e.g. when Y represents chloro or bromo, by reaction with thionyl chloride or bromide respectively; most preferably, when Y is chloro, a compound (III) is formed by reaction with methanesulphonyl chloride in dichloromethane in the presence of triethylamine. The intermediates of the formula (XIV), (XV), (XVI) and (XVII) used in the preparation of compounds of the formula (III) may be advantageously used in this process with a protected hydroxy group. Suitable protecting groups for this purpose may include those listed in "Protective Groups in Organic Synthesis", Theodora W. Greene (John Wiley & Sons) . Triphenylmethyl is the preferred protecting group. A protected compound (XVII) may then be deprotected by a conventional procedure prior to conversion to compound (III), e.g. when the hydroxy group is protected with triphenylmethyl the protecting group may be removed by refluxing in aqueous acetic acid. 3) The intermediates of the formula (IV) may be prepared as illustrated in Scheme 5:- Scheme 5 p (XVIII) Y 1 -(CH ) -X 1 -R , Acid acceptor 2 m (X) (XIX) (IV) wherein R , m, n, p, X and Y are as previously defined for the formula (I) and Y is as previously defined for the formula (X) . Compounds of the formula (XVIII) , which are either commercially available or prepared by conventional literature procedures, may be alkylated using a compound (X) in the presence of an acid acceptor by a similar method to that previously described for the alkylation of compounds (XIV) and (XV) (see intermediate preparative method (2) above). A compound of the formula (XIX) may be converted to a compound (IV) by conventional procedures. Y is preferably chloro and such compounds are prepared by reaction of compound (XIX) with either methanesulphonyl chloride or thionyl chloride, the reaction being carried out in a suitable organic solvent, e.g. dichloromethane, in the presence of an acid acceptor, e.g. triethylamine or pyridine, or with thionyl chloride in chloroform. As previously discussed in method (1) for the preparation of compounds of the formula (I) above, an attempt to prepare an intermediate (V) or (VI) may result in a product mixture of (V) and (VI) being obtained due to aziridinium ion (VII) formation under the preparative conditions used. Indeed in certain circumstances the rearrangement product may be the exclusive product of the reaction. Such (V/VI) product mixtures, when formed, are usually used directly in the synthesis of compounds of the formula (I) without further purification. 4) The intermediates of the formula (VIII) and (IX) may be prepared as illustrated in Scheme 6:- Scheme 6 1) Strong base, Compounds (VIII) or (IX) 1 2 3 4 wherein R , R , R , R , n and p are as previously defined for the 2 formula (I), Y is a suitable leaving group, e.g. p-toluene- sulphonyloxy, and Z is a suitable protecting group, e.g. p-toluenesulphonyl or benzyloxycarbonyl. Compound (II) is alkylated with either a compound (XX) or (XXI), as appropriate, by a similar method to that disclosed in method (1) for the preparation of compounds of the formula (I) above, where an alkylating agent of the formula (III) or (IV) is used instead. The resulting product, (XXII) or (XXIII), may be deprotected under conventional conditions, e.g. when Z is p-toluenesulphonyl using sodium bis(2-methoxyethoxy)aluminium hydride (Red-A]_" in toluene, to provide a compound of the formula (VIII) or (IX), respectively. 5) The alkylating agents of the formula (X) and the vinylheterocycles of the formula Het CH=CH, are either known compounds which may be commercially available, or are prepared by conventional procedures in accordance with literature precedents. 6) The intermediates of the formula (XIII) may be prepared as illustrated in Scheme 7:- (XXVII) R j Strong base wherein R, R , R , X , m and p are as defined for the formula (I) and Y 3 and Y4, which may be the same or different, are suitable leaving groups, e.g. halo (preferably chloro or bromo). Most 3 4 preferably Y and Y are both bromo. A compound of the formula (XXVI) may be prepared from an amine of the formula (XXV) either by acylation with an acid chloride of the formula (XXIV, Cl) in a suitable solvent, e.g. toluene, and in the presence of a suitable acid acceptor, e.g. pyridine or triethylamine, or by reacting with a carboxylic acid of the formula (XXIV, OH) under conventional peptide coupling conditions. An amide (XXVI) may be cyclised to a lactam (XXVII) under 3 4 standard conditions, for example where Y and Y are both bromo by stirring the amide (XXVI) with Amberlite® IRA-400 (Cl) ion exchange resin, dichloromethane and aqueous sodium hydroxide solution at about room temperature. A lactam (XXVII) may be then reacted with an anion formed from a diphenylsulphoximine derivative (II) to provide a compound (XIII) using a similar alkylation method to that described in method (1) for the preparation of compounds of the formula (I) above. The starting materials of the formulae (XXIV) and (XXV) are either known compounds which may be commercially available or are prepared by conventional procedures in accordance with literature precedents. Pharmaceutically acceptable acid addition salts are readily prepared by mixing solutions containing equimolar amounts of the free base and the desired acid. The salt generally precipitates from solution and is collected by filtration, or is recovered by evaporation of the solvent. The selectivity of the compounds 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 and aerated with 95% 0, and 5% CO,. 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 isometrically 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 compound. The test compound 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 concentration of test compound and the above procedure is repeated. Typically four concentrations of the test compound are evaluated on each tissue. The concentration 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, Brit. J. Pharmacol., 1959, _14_, 48-58). Using the above analytical techniques, tissue selectivity for muscarinic receptor antagonists is determined. Activity against agonist induced 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 determining compound effects on, for example, heart rate, pupil diameter and gut motility. Compound affinity for other cholinergic sites is assessed in the mouse after either intravenous or intraperitoneal 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 oxotremorine. For administration to man in the curative or prophylactic treatment of diseases where the gastrointestinal and bladder selective reduction of acetylcholine-mediated smooth muscle contraction would be of benefit such as in the treatment of motility disorders of the gut, in particular as in irritable bowel syndrome, and in the treatment of emesis, diverticular disease or urinary incontinence, oral dosages of the compounds 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 compound 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 ranges are merited, and such are within the scope of this invention. For human use, the compounds of the formula (I) can be administered alone, but 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 parenterally, for example, intravenously, intramuscularly 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. Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a compound 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 or composition thereof, for use as a medicament, particularly for use in the treatment of irritable bowel syndrome. The invention further includes the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the treatment of diseases associated with motility disorders of the gut such as irritable bowel syndrome, and for the treatment of emesis, diverticular disease and urinary incontinence. The invention yet further provides a method of treating a human being to cure or prevent either a disease associated with a motility disorder of the gut, such as irritable bowel syndrome, or emesis, diverticular disease or urinary incontinence, which comprises treating said human being with an effective amount of a compound of the formula (I), or with, as appropriate, a pharmaceutically acceptable salt or composition thereof. The invention also includes any novel intermediates disclosed herein, such as those of the formulae (VIII), (IX) and (XIII). The following Examples illustrate the invention: EXAMPLES 1A and IB (3R)-N-[l-(4-Methoxyphenethyl)piperidin-3-yl]diphenylsulphoximine (Example 1A) and (2S)-N-f (l-f4-τnethoxyphenethyl]pyrrolidin-2- yl)methyl]diphenylsulphoximine (Example IB) Sodium hydride (80% dispersion in oil, 0.42 g) was added to a solution of diphenylsulphoximine (2.39 g) in xylene (50 ml). The mixture was heated under reflux for 15 minutes, cooled, and treated with a solution of (3R)-chloro-l-(4-methoxyphenethyl)- piperidine (2.50 g) (see Preparation 1) in xylene (25 ml). The resulting mixture was heated under reflux for 17 hours. The reaction was cooled, diluted with ethyl acetate and water and the layers were separated. The organic layer was dried (magnesium sulphate) and concentrated ^ri vacuo. Column chromatography on silica gel using ethyl acetate as the eluant provided two distinct products. The fractions containing the less polar material were combined and concentrated in vacuo to provide the title compound 25 (Example 1A) as a pale yellow oil (0.45 g, 10%), l -~-] - Q9 +69.5° (c = 1.0 in ethanol). Found: C.71.5; H,7.0; N,6.3; C -) ,H.-N.0 S Δ > 3U Δ Δ requires: C,71.7; H,7.2; N,6.4%. The fractions containing the more polar material were combined and concentrated ±n_ vacuo to provide the title compound (Example IB) as a pale yellow oil (1.50 g, 34%), [<^-] 2 g g -80.5° (c = 1.0 in ethanol). Found: C,71.3; H,6.7; N,6.1; C„,H f .N 0 n S Δb JU Δ I requires: C,71.7; H,7.2; N,6.4%. EXAMPLES 2A, 2B, 3A, 3B, 4A, 4B, 5A and 5B The following tabulated Examples are for compounds of the general formula:- The Examples were each prepared by a similar method to that described for Examples 1A and IB by reacting diphenylsulphoximine with sodium hydride in refluxing xylene and then treating the mixture with the appropriate alkylating agent, followed by work-up The starting material used in the preparation of Examples 4A and 4B was obtained as described in Preparation 4 as the hydrochloride salt. This was converted to the corresponding free base for use in the reaction by basifying with 2M aqueous sodium hydroxide solution, extracting the aqueous mixture with diethyl ether, drying the organic extract over sodium sulphate followed by concentration thereof in vacuo to provide the required material. EXAMPLE 6 N-[l-(4-Methoxyphenethyl)piperidin-3-yl]diphenylsulphoximine A solution of concentrated sulphuric acid (82 mg) in tetrahydrofuran (2 ml) was added dropwise over 15 minutes to a stirred, ice-cooled suspension of lithium aluminium hydride (64 mg) in tetrahydrofuran (2 ml) . The mixture was stirred with ice-cooling for one hour, treated with a solution of N-.l-(4- methoxyphenethyl)-2-oxopiperidin-3-yl]diphenylsulphoximine (0.37 g) (see Preparation 11) in tetrahydrofuran (6 ml) and then further stirred at room temperature for 4 hours. The mixture was quenched by the dropwise addition of saturated aqueous ammonium chloride solution and filtered. The filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel, performing a gradient elution using 0-2% methanol/dichloromethane as the eluant. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless solid (117 mg, 33%), m.p. 133-135°C, which was characterised by T.-NMR spectroscopy. 1 H-NMR (CDC1_) £ = 8.00 (dd , J = 8 and 2Hz , 4H) , 7.43-7.59 (to, 6H) , 7.14 (d , J = 8Hz , 2H) , 6.82 (d , J = 8Hz , 2H) , 3.81 (s , 3H) , 3.13-3.31 (m, 2H) , 2.55-2.90 (m, 5H) , 2.19 (t , J = 7Hz , 1H) , 1.4-2.1 (m, 5H) ppm. EXAMPLE 7 (3R)-N-[ l-(4-Hydroxyphenethyl)piperidin-3-yl] diphenylsulphoximine A solution of (3R)-N-[l-(4-methoxyphenethyl)piperidin-3- yl]diphenylsulphoximine (0.20 g) (see Example 1A) in 48% aqueous hydrobromic acid (8 ml) was heated under reflux for 1.5 hours then cooled and evaporated jLti vacuo. The residue was basified with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulphate and evaporated in vacuo to give the title compound as a pale brown solid (60 mg, 31%), m.p. 115-118°C, l ^ l c a q +50.8° (c = 1.0 in methanol). Found: C,69.8; H.6.4; N,6.7; C^H^N^S.O.S H 2 0 requires: C,69.9; H,6.8; N,6.5%. EXAMPLE 8 N- [ 2- (N ' - [ 4-Methoxyphenethy 1] -N ' -methyl) amino-2-methy lprop-1- yl] diphenylsulphoximine Sodium hydride (80% dispersion in oil, 33 mg) was added to a solution of diphenylsulphoximine (217 mg) in toluene (15 ml) and the mixture was heated under reflux for 15 minutes, cooled and treated with a solution of l-chloro-2-(N-[4-methoxyphenethyl]- N-methyl)amino-2-methylpropane (256 mg) (see Preparation 18) in toluene (5 ml). The mixture was heated under reflux for 8 hours, allowed to cool to room temperature and diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water, dried over sodium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica gel performing a gradient elution using 0-5% methanol/dichloromethane as the eluant. The appropriate fractions were combined and evaporated in vacuo to give the title compound (85 mg, 19%) as a colourless foam. Found: C.71.2; H,7.5; N.6.4; C_,H_ -1 N„0-,S Δb ±Δ Δ Δ requires: C.71.5; H,7.4; N,6.4%. EXAMPLE 9 N-[ (2S)-[N' -(4-Methoxyphenethyl)-N' -methyl] aminoprop-1- yl] diphenylsulphoximine The title compound of the formula: - was prepared by a similar method to that used in Example 8 using l-chloro-2(S)-(N-f4-methoxyphenethyl]-N-methyl)aminopropane (see Preparation 21) instead of l-chloro-2-(N-[4-methoxyphenethyl]- N-methyl)amino-2-methylpropane as the starting material. The title compound was obtained as an oil. Found: C,70.45; H,7.4; N,6.5; C 25 H 3Q N 2 0 2 S.0.25 H 2 0 requires: C.70.3; H.7.2; N,6.6%. The following Preparations illustrate the preparation of starting materials used in the preceding Examples:- Preparation 1 (3R)-Chloro-l-(4-methoxyphenethyl)piperidine A mixture of methanesulphonyl chloride (1.3 ml), triethylamine (1.7 g) and (2S)-[l-(4-methoxyphenethyl)]- pyrrolidinemethanol (4.0 g) (see Preparation 6) in dichloromethane (30 ml) was stirred at room temperature for 2.5 hours, diluted with dichloromethane, washed with 10% aqueous sodium carbonate solution, dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a pale brown oil (4.0 g) which was characterised by H-NMR spectroscopy and used directly in the preparation of Examples 1A and IB without further purification. 1 H-NMR (300 MHz, CDC1 3 = 7.17 (d, 2H, J = 8Hz) , 6.84 (d, 2H, J = 8Hz), 4.01-4.13 (m, 1H) , 3.82 (s, 3H) , 3.19 (d, 1H, J = 14 Hz), 2.58-2.84 (m, 5H) , 2.32 (t, 1H, J = 14 Hz), 1.6-2.3 (m, 4H) ppm. Preparation 2 (3R)-Chloro-l-(3 , 4-methylenedioxyphenethyl)piperidine and (2S)-chloromethyl-l-(3 ,4-methylenedioxyphenethyl)pyrrolidine C1 2 , Pyridine Thionyl chloride (4 ml) was added cautiously to a mixture of (2S)-[l-(3,4-methylenedioxyphenethyl)]pyrrolidinemethanol (5.0 g) (see Preparation 7) and pyridine (0.2 ml) in dichloromethane (70 ml) . The resulting mixture was heated under reflux for 3 hours then cooled and evaporated ±~ vacuo. The residue was triturated with diethyl ether and the resulting solid was collected by filtration, dissolved in water, basified with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and evaporated in vacuo to give a pale brown oil (2.7 g, 51%), which was shown by H-NMR spectroscopy to consist of a mixture of the two title compounds. This mixture was used directly in the preparation of Examples 2A and 2B without further purification. Preparation 3 (3R)-Chloro-l-[2-(l,4-benzodioxan-6-yl) ethyl]piperidine and (2S)-chloromethyl-l-[2-(benzodioxan-6-yl) ethyl] pyrrolidine CH 2 C1 2 , Pyridine Thionyl chloride (0.8 ml) was added cautiously to a mixture of (2S)-(l-[2-(l,4-benzodioxan-6-yl)ethyl])ρyrrolidinemethanol (1.0 g) (see Preparation 8) and pyridine (0.10 g) in dichloromethane (20 ml). The mixture was heated under reflux for 3 hours then cooled and evaporated ua vacuo. The residue was triturated with diethyl ether and the resulting solid was collected by filtration then dissolved in water, basified with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and evaporated in vacuo to give a brown oil (0.80 g, 75%) which was shown by tl-NMR spectroscopy to consist of a mixture of the two title compounds. This mixture was used directly in the preparation of Examples 3A and 3B without further purification. Preparation 4 3-Chloro-l- (3-methoxyphene hy 1) piperidine hydrochloride S0C1 2 , CHC1 3 A solution of l-(3-methoxyphenethyl)-3-piperidinol hydrochloride (2.72 g) (see Preparation 10) and thionyl chloride (3 ml) in chloroform (50 ml) was heated under reflux for 1.5 hours then cooled and evaporated in vacuo. The residue was crystallised from 2-propanol/dichloromethane to give the title compound as a colourless solid (1.31 g, 44%), m.p. 192-196°C. Found: C.56.0; H.7.2; N.4.6; H 2 0 requires: C.56.2; H . 7.4; N,4.7%. Preparation 5 (3R)-Chloro-l-(3-methoxyphenethyl)piperidine A solution of methanesulphonyl chloride (1.38 g) in dichloromethane (5 ml) was added dropwise over 5 minutes to a stirred solution of (2S)-[l-(3-methoxyphenethyl)]pyrrolidine- methanol (2.35 g) (see Preparation 9) and triethylamine (1.01 g) in dichloromethane (25 ml). The mixture was stirred at room temperature for 1.5 hours, diluted with ethyl acetate, washed twice with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated j_n ^ vacuo. The residue was purified by chromatography on silica gel, performing a gradient elution using 0-5% ethyl acetate/dichloromethane as the eluant. The appropriate fractions were combined and evaporated jL vacuo to give the title compound as a pale yellow oil (2.06 g, 81%) which was characterised by H-NMR spectroscopy. 1 H-NMR (CDC1 ) £ = 7.20-7.35 ( , 1H) , 6.74-6.88 (m, 3H) , 4.00-4. 12 ( , 1H) , 3.82 (s , 3H) , 3.15 (d , J = 7Hz , 1H) , 3.6-3.9 (m, 5H) , 2.36 (t , J = 7Hz , 1H) , 2.15-2.27 (m, 1H) , 1.5-1.9 (m, 2H) ppm. Preparation 6 (2S)-[l-(4-Methoxyphenethyl)]pyrrolidinemethanol A mixture of (2S)-pyrrolidinemethanol (3.0 g) , 4-methoxyρhenethyl bromide (7.0 g) , sodium carbonate (3.5 g) and sodium iodide (100 mg) in acetonitrile (40 ml) was heated under reflux for 16 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer washed with water and extracted with 2M hydrochloric acid. The acidic extract was washed with ethyl acetate, basified with solid sodium carbonate and extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless oil (4.0 g, 57%). 1 H-NMR (300 MHz , CDC1.. ) & = 7. 16 (d, 2H, J = 8Hz) , 6.83 (d, 2H, J = 8Hz) , 3.81 (s, 3H) , 3.59 (dd, 1H, J = 8 and 2Hz) , 3.26-3.40 (m, 2H) , 2.3-3.1 (m, 7H) , 1.6-2.0 (m, 4H) ppm. Preparations 7, 8 and 9 The following tabulated Preparations are of compounds of the general formula:- These compounds were each prepared by a similar method to that described in Preparation 6 by reacting (2S)-pyrrolidine- methanol with the appropriate alkylating agent in the presence of sodium carbonate and sodium iodide and using acetonitrile as the solvent. In each case the product was obtained as a colourless oil. The product of Preparation 9 was characterised by H-NMR spectroscopy. Preparation 10_ 1-(3-Methoxyphenethyl)-3-piperidinol hydrochloride This was obtained by a similar method to that described in Preparation 6 using 3-piperidinol instead of (2S)-pyrrolidine- methanol and 3-methoxyphenethyl bromide instead of 4-methoxy- phenethyl bromide as the starting materials. The free base obtained upon work-up was dissolved in ether and treated with excess ethereal hydrogen chloride. The resulting precipitate was collected by filtration and dried to give the title compound as a colourless solid (17.7 g, 66%), m.p. 140-144°C. Found: C.59.1; H,8.2; N,5.3; C 14 H 21 NO 2 .HC1.0.75 H 2 0 requires: C.58.9; H,8.3; N,4.9%. Preparation 11 N-[ l-(4-Methoxyphenethyl)-2-oxopiperidin-3-yl] diphenylsulphoximine Sodium hydride (60% dispersion in oil, 0.44 g) was added to a suspension of diphenylsulphoximine (2.28 g) in xylene (25 ml) and the mixture was heated under reflux for 15 minutes then treated with a solution of 3-bromo-l-(4-methoxyphenethyl)-2-piperidone (3.3 g) (see Preparation 12) in xylene (10 ml). The reaction was heated under reflux for 3 hours, cooled and diluted with ethyl acetate. The organic phase was washed with water, dried over sodium sulphate and evaporated ^n vacuo. The residue was purified by chromatography on silica gel performing a gradient elution using 0-1% methanol/dichloromethane as the eluant. The appropriate fractions were combined and evaporated i vacuo to give the title compound as a pale yellow oil (1.80 g, 38%). Found: C,69.9; H,6.5; N,6.2; C 2 6 H 28 N 2°3 S requires: C,69.6; H,6.3; N,6.2%. Preparation 12 3-Bromo-l- (4-methoxyρhenethyl) -2-piperidone 1_ A mixture of 2,5-dibromo-N-(4-methoxyphenethyl)pentanamide (13.0 g) (see Preparation 13), Amberlite® IRA-400 (Cl) ion exchange resin (3.5 ml), dichloromethane (40 ml) and 50% aqueous sodium hydroxide solution (40 ml) was stirred at room temperature for 24 hours and filtered. The filtrate was diluted with dichloromethane and water and the layers separated. The organic layer was washed with water, dried over sodium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica gel using dichloromethane as the eluant. The appropriate fractions were combined and evaporated iτ\_ vacuo to give the title compound as a colourless oil (8.94 g, 86%). Found: C.54.7; H,6.1; N.4.7; C 1 ,H lg BrN0 2 requires: C.53.9; H,5.8; N,4.5%. Preparation 13 2,5-Dibromo-N-(4-methoxyphenethyl)pentanamide Br 2,5-Dibromopentanoyl chloride (30.6 g) (see Chem. Pharm. Bull. Japan, 3_0_, 1225 (1982)) was added dropwise over 10 minutes to a stirred, ice-cooled solution of 4-methoxyphenethylamine (16.8 g) and triethylamine (11.2 g) in toluene (130 ml). The mixture was stirred at room temperature for 4 hours and then evaporated jln vacuo. The residue was partitioned between 5% aqueous hydrochloric acid and dichloromethane and the layers were separated. The organic layer was washed with 5% aqueous sodium bicarbonate solution and water, dried over sodium sulphate and evaporated jLi3 vacuo to give the title compound as a colourless solid (34.1 g, 79%), m.p. 84-86°C. A portion of the product was recrystallised from ethyl acetate/hexane to give analytically pure material, m.p. 86-87°C. Found: C,42.8; H.5.1; N,3.5; C ,H. BrN0 2 requires: C,42.8; H,4.9; N,3.6%. Preparation 14 3 ,4-Methylenedioxyphenethyl alcohol 3,4-Methylenedioxyphenylacetic acid (18.0 g) was added portionwise over 30 minutes to a stirred, ice-cooled suspension of lithium aluminium 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 organic layer was washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated a j i vacuo to give the title compound as a pale yellow oil (15.01 g, 90%) which was characterised by H-NMR spectroscopy. 1 H-NMR (CDC1 3 ) ξ = 6.69-6.83 (m, 3H) , 5.98 (s, 2H) , 3.82 (dt, J = 7 and 6Hz, 2H) , 2.81 (t, J = 7Hz, 2H) , 1.44 (t, J = 6Hz, 1H, exchangeable with D.O) ppm. Preparation 15 3 ,4-Methylenedioxyphenethyl bromide A solution of phosphorus tribromide (8.1 g) in carbon tetrachloride (50 ml) was added dropwise over 30 minutes to a stirred solution of 3,4-methylenedioxyphenethyl alcohol (15.0 g) (see Preparation 14) in carbon tetrachloride (200 ml) and the mixture was heated under reflux for 3 hours, cooled, washed sequentially with water (twice) , 5M aqueous sodium hydroxide solution and water, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica gel using carbon tetrachloride as the eluant. Appropriate fractions were combined and evaporated iτ vacuo to give the title compound as a pale yellow oil (8.3 g, 40%), which was characterised by H-NMR spectroscopy. " ' " H-NMR (CDC1 3 ) S » 6.80 (d, J = 8Hz, IH) , 6.75 (s, IH) , 6.71 (d, J = 8Hz, IH), 6.00 (s, 2H), 3.56 (t, J = 7Hz, 2H) , 3.13 (t, J - 7Hz, 2H) ppm. Preparation 16 6-(2-Hydroxyethyl)-l,4-benzodioxan This was prepared as described in Preparation 14 using (l,4-benzodioxan-6-yl)acetic acid instead of 3,4-methylenedioxy- phenylacetic acid. The title compound was obtained as a colourless oil (19.8 g, 92%), which was characterised by H-NMR spectroscopy. 1 H-NMR (CDC1 3 ) £ = 6.84 (d, J = 8Hz, IH) , 6.77 (d, J = 2Hz, IH) , 6.73 (dd, J = 8 and 2Hz, IH) , 4.28 (s, 4H) , 3.59 (t, J = 7Hz, 2H) , 3.08 (t, J = 7Hz, 2H) ppm. Preparation 17 6-(2-Bromoethy1)-1,4-benzodioxan This was prepared as described in Preparation 15 using 6-(2-hydroxyethyl)-1,4-benzodioxan (see Preparation 16) instead of 3,4-methylenedioxyphenethyl alcohol. The title compound was obtained as a pale yellow oil (21.4 g, 80%) which was characterised by H—NMR spectroscopy. 1 H-NMR (CDC1 3 ) ξ = 6.83 (d, J = 8Hz, IH) , 6.77 (d, J = 2Hz, IH), 6.72 (dd, J = 8 and 2Hz, IH) , 4.28 (s, 4H) , 3.59 (t, J = 7Hz, 2H) , 3.10 (t, J = 7Hz, 2H) ppm. Preparation 18 l-Chloro-2-(N-[4-methoxyphenethyl]-N-methyl)amino-2-methylpropane 3 , Methanesulphonyl chloride (0.78 ml) was added to a solution of 2-[N-(4-roethoxyphenethyl)-N-methyl]amino-2-methylpropan-l-ol (2.37 g) (see Preparation 19) and triethylamine (1.01 g) in dichloromethane (40 ml) and the mixture was stirred at room temperature for 2 hours then evaporated in vacuo. The residue was taken up in ethyl acetate, washed with 10% aqueous sodium carbonate solution, dried over sodium sulphate and evaporated in vacuo to give the title compound as a pale yellow oil (2.30 g, 90%) which was used directly in Example 8 without characterisation or further purification. Preparation 19 2-[N-(4-Methoxyphenethyl)-N-methyl]amino-2-methylpropan-l-ol 37% Aqueous formaldehyde solution (2.68 g) was added to a stirred solution of 2-(4-methoxyphenethylamino)-2-methylpropan- l-ol (3.35 g) (see Preparation 20) in formic acid (3.45 g) and the mixture was heated under reflux for 2.5 hours, acidified with 2M hydrochloric acid, washed with ether, basified with solid sodium hydroxide and extracted into ethyl acetate. The organic extract was dried over sodium sulphate and evaporated j i vacuo. The residue was triturated with hexane to give the title compound as a colourless solid (3.20 g, 90%), m.p. 40°C. Found: C,71.1; H,10.0; N,6.0; C 14 H 23 N0 2 requires: C,70.8; H.9.8; N,5.9%. Preparation 20 2-(4-Methoxyphenethylamino)-2-methylpropan-l-ol A mixture of 2-amino-2-methylpropan-l-ol (4.46 g) , 4-methoxy- phenethyl bromide (10.76 g) , potassium carbonate (13.8 g) and potassium iodide (8.3 g) in acetonitrile (100 ml) was heated under reflux for 20 hours and evaporated ji j vacuo. The residue was partitioned between ethyl acetate and water and the organic layer was separated, dried over sodium sulphate evaporated in vacuo. The residual solid was recrystallised from ethyl acetate/hexane to give the title compound (6.6 g, 60%), m.p. 114-115°C. Found: C.70.1; H,9.8; N.6.2; C 13 H 2] N0 2 requires: C.69.9; H,9.5; N,6.3%. Preparation 21 l-Chloro-2 (S)-(N-[4-methoxyphenethyl] -N-methyl)aminopropane CH 2 C1 2 . This was prepared as described in Preparation 18 using (2S)-(N-[4-methoxyphenethyl]-N-methyl)aminopropan-l-ol (see Preparation 22) instead of 2-[N-(4-τnethoxyphenethyl)-N- methyl]amino-2-methylproρan-l-ol. The title compound was obtained as an oil which was characterised by H-NMR spectroscopy. " 'Έ-NMR (CDC1 3 ) = 7.14 (d, J = 8Hz, 2H) , 6.85 (d, J = 8Hz, 2H) , 4.06 (sextet, J = 7Hz, IH) , 3.80 (s, 3H) , 2.50-2.85 (m, 6H) , 2.39 (s, 3H), 1.48 (d, J = 7Hz, 3H) ppm. Preparation 22 (2S)-[N-(4-Methoxyphenethyl)-N-methyl] aminopropan-l-ol A solution of (2S)-[N-(4-methoxyphenethyl)-N-methyl]amino- 1-triphenylmethoxypropane (1.6 g) (see Preparation 23) in 80% aqueous acetic acid (20 ml) was heated under reflux for 3 hours, cooled and evaporated ±a_ vacuo. The residue was taken up in dichloromethane and extracted three times with 2M hydrochloric acid. The combined acidic extracts were basified with 2M aqueous sodium hydroxide solution and extracted with dichloromethane, The organic extract was washed three times with water, dried over sodium sulphate and evaporated jlii vacuo. The residue was purified by chromatography on silica gel performing a gradient elution using 1-2% 0.880 aqueous ammonia/ethyl acetate as the eluant. The appropriate fractions were combined and evaporated ^n vacuo to give the title compound (0.25 g) as an oil. Found: C,68.6; H.9.4; N.6.4; C 13 H 21 N0 2 .0.25 H 2 0 requires: C,68.6; H.9.5; N,6.2%. Preparation 23 (2S)-[N-(4-Methoxyphenethyl)-N-methyl] amino- 1-triphenyl- methoxypropane CN 37% Aqueous formaldehyde solution (0.6 ml) was added to a solution of (2S)-(4-methoxyphenethylamino)-l-triphenylmethoxy- propane (450 mg) (see Preparation 24) in methanol (10 ml) and the mixture stirred at room temperature for 5 minutes, treated with sodium cyanoborohydride (400 mg) and stirred at room temperature for 21 hours. The reaction was basified with 15% aqueous sodium hydroxide solution and evaporated ^n vacuo. The residue was partitioned between ethyl acetate and water and the organic layer separated, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica gel performing a gradient elution using 0-2% methanol/dichloromethane as the eluant. The appropriate fractions were combined and evaporated ±τi vacuo to give the title compound as a colourless oil (321 mg, 69%). Found: C,80.8; H,7.5; N.2.8; C 32 H 35 N0 2 .0.5 H O requires: C,81.0; H.7.7; N,3.0%. Preparation 24 (2S)-(4-Methoxyphenethylamino) -l-triphenylmethoxypropane A mixture of (2S)-amino-l-triphenylmethoxypropane (13.16 g) (see Preparation 25), 4-methoxyphenethyl bromide (8.60 g) , sodium carbonate (20.0 g) and sodium iodide (1.0 g) in acetonitrile (100 ml) was heated under reflux for 40 hours, allowed to cool to room temperature and diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water, dried over sodium sulphate and evaporated ^n vacuo. The residue was purified by chromatography on silica gel performing a gradient elution using 0-3% saturated methanolic ammonia/dichloromethane as the eluant. The appropriate fractions were combined and evaporated in vacuo to give the desired product (7.9 g, 44%) as a colourless oil. Found: C,82.0; H,7.3; N,2.9; C ^ H ^ NO. requires: C,82.5; H,7.6; N,3.1%. Preparation 25 (2S)-Amino-l-triphenylmethoxypropane CH 3 (C 6 H 5 ) 3 CC1 HO CH. (C 6 H 5 ) 3 C0 ^ NH, NH, Triphenylmethyl chloride (5.6 g) and (2S)-aminopropan-l-ol (1.5 g) were mixed to a paste and heated at 140°C for 25 minutes. The resulting hot syrup was poured into dichloromethane and the solution evaporated ±n_ vacuo. The residue was purified by chromatography on silica gel performing a gradient elution using 0-4% methanol/dichloromethane plus 0.1% 0.880 aqueous ammonia as the eluant. The appropriate fractions were combined and evaporated in vacuo to give the title compound (5.13 g) , m.p. 176°C. Found: C,83.2; H,7.2; N,4.4; C ^ H^NO requires: C,83.3; H.7.3; N,4.4%. Preparation 26 Diphenylsulphoximine 1) NCNH ,Acetone, (C β H 5 ) 2 S=NH (a) N-Cyanodiphenylsulphoximine A mixture of diphenylsulphide (18.3 g, 0.1 mol) and cyanamide (4.62 g, 0.11 mol) in acetone (100 ml) was treated with iodobenzene diacetate (35.4 g, 0.11 mol) portionwise over 5 minutes with shaking and the resulting mixture was stirred for 15 minutes at room temperature. The reaction was diluted with acetone (40 ml) and water (60 ml) then treated cautiously with potassium permanganate (19.0 g, 0.12 mol) portionwise with stirring over 5 minutes. The mixture was stirred at room temperature for 15 minutes, diluted with water, evaporated in vacuo to half-volume, treated with sodium hydrogen sulphite and extracted with chloroform. The combined organic extracts were filtered and the filtrate evaporated n_ vacuo. The residue was crystallised from ether to give N-cyanodiphenylsulphoximine (17.6 g, 72%) as colourless crystals, m.p. 113-116°C. Found: C,64.3; H.4.1; N . 11.6; C 13 H 1() N 2 0S requires: C.64.4; H,4.2; N,11.6%. (b) Diphenylsulphoximine A solution of the product of part (a) (15 g, 62 m ol) in water (30 ml) and concentrated sulphuric acid (30 ml) was heated under reflux for 1.5 hours. The reaction was allowed to cool to room temperature, poured cautiously into a mixture of concentrated aqueous ammonia solution (80 ml) and ice (80 g) and the mixture extracted with ethyl acetate. The combined organic extracts were washed with water then brine, dried over potassium carbonate and evaporated ±n_ vacuo. The residue was recrystallised from aqueous methanol to give the title compound (9.2 g, 68%) as colourless crystals, m.p. 99-102°C. Found: C.66.2; H,5.0; N.6.7; C.^ NOS requires: C,66.5; H . 5.1; N,6.45%.

Claims: CLAIMS 1. A compound having the formula: - or a pharmaceutically acceptable salt thereof, wherein R and R are each independently H or C.-C, alkyl; and X is a group of the formula:- CH„— C —N —(CH_) - •X J ■ R II 3 II R R or (CH.) -X^R 5 Δ m 2 3 wherein either R is H or C--C, alkyl and R is C.-C, alkyl, or 2 3 R and R taken together represent -(CH.) - wherein r is an integer of from 2 to 5; 4 R is C -C, alkyl; X is a direct link, 0 or S; R is a group of the formula:- either R and R are each independently H, halo, C.-C, alkyl, C 1 -C 4 alkoxy, - CH 2 ) OH, -(CH 2 NR 8 R 9 , -CONR 10 R 1:L , -S0 2 NH 2 or -0C0(C -C, alkyl), or R and R taken together represent a group of the formula -X -(CH 9 ) fc --Xx 3 t 2 3 wherein X and X are each independently 0 or CH. and t is an integer of from 1 to 3; 8 9 8 either R and R are each independently H or C--C, alkyl, or R is hydrogen and R is -S0 2 (C..-C, alkyl), -CONR R 11 , -C0(C 1 -C 4 alkyl) or -S0 2 NH 2 ; R and R are each independently hydrogen or C..-C, alkyl; "Het" is thienyl, pyridinyl or pyrazinyl; m is 1, 2 or 3; n is 0, 1 or 2; p is 0 or 1; and s is 0, 1 or 2: with the provisos that (a) when m is 1, X is a direct link and R is as defined above except for "Het"; and (b) when n is zero, the N-substituted pyrrolidinyl or piperidinyl ring is not attached via it's 2-position to the adjacent sulphoximine nitrogen atom. 2. A compound according to claim 1 wherein R and R are both H. 3. A compound according to claim 1 or claim 2 wherein X is a group of the formula:- R 2 1 1 5 -CH„- C -N -(CH„) —X —R R l 3 1 * 2 3 and R is H or methyl and R is methyl. 4 4. A compound according to claim 3 wherein R is methyl. 5. A compound according to claim 1 or claim 2 wherein X is a group of the formula:- and m is 2. 6. A compound according to claim 5 wherein n is 0 or 1. 7. A compound according to any one of claims 1 to 6 wherein X is a direct link. 8. A compound according to any one of claims 1 to 7 wherein R is 3- or 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxy- phenyl or l,4-benzodioxan-6-yl. 9. The compound (3R)-N-fl-(4-methoxyphenethyl)piperidin-3-yl]- diphenylsulphoximine or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition comprising a compound of the formula (I) as claimed in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. 11. A compound of the formula (I) as claimed in any of claims 1 to 9 or a pharmaceutically acceptable salt or composition thereof for use as a medicament, particularly for use in humans for the treatment of irritable bowel syndrome. 12. The use of compounds of the formula (I), as claimed in claim 1 or a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the treatment of diseases associated with motility disorders of the gut including irritable bowel syndrome, and for the treatment of emesis, diverticular disease and urinary incontinence. PROCESS CLAIMS 13. A process for preparing a compound of the formula-: or a pharmaceutically acceptable salt thereof,wherein R and R are each independently H or C--C, alkyl; and X is a group of the formula:- —CH, ) p CI ) -X 1 ^ 5 (CH 2 ) , 2 3 wherein either R is H or C..-C, alkyl and R is C.-C, alkyl, or SUBSTITUTE SHEET 2 3 R and R taken together represent -(CH.) - wherein r is an integer of from 2 to 5; R is C -C 4 alkyl; X is a direct link, 0 or S; R is a group of the formula:- either R and R are each independently H, halo, C -C, alkyl, C 1 -C 4 alkoxy, - CH 2 ) OH, -(CH 2 s R 8 R 9 , -C0NR 10 R 1:L , 6 7 -S0 2 H 2 or -0C0(C--C alkyl), or R and R taken 2 3 together represent a group of the formula -X -(CH„) -X - 2 3 wherein X and X are each independently 0 or CH. and t is an integer of from 1 to 3; 8 9 8 either R and R are each independently H or C..-C, alkyl, or R is hydrogen and R is -S0 2 (C.,-C 4 alkyl), -CONR R 11 , -C0(C -C^ alkyl) or -S0 2 NH ; R and R are each independently hydrogen or C,-C, alkyl; "Het" is thienyl, pyridinyl or pyrazinyl; m is 1, 2 or 3; n is 0, 1 or 2; p is 0 or 1; and SUBSTITUTE SHEET s is 0, 1 or 2: with the provisos that (a) when m is 1, X is a direct link and R is as defined above except for "Het"; and (b) when n is zero, the N-substituted pyrrolidinyl or piperidinyl ring is not attached via it's 2-position to the adjacent sulphoximine nitrogen atom which comprises: (a) reacting a compound of the formula: (ID with a compound of the formula: R ^ I CH.— C—N (CH_) __. X""— R J (in) 2 j i 2 m R R or SUBSTITUTE SHEET wherein R and R to R , m, n, p and X are as previously defined and Y is a leaving group; or (b) reacting a compound of the formula: or with a compound of the formula: Y 1 -(CH„) -X^R 5 Δ m (X) 1 1 wherein R, R to R , m, n, p, and X are as previously defined and Y is a leaving group; or SUBSTITUTE (c) reacting a compound of the formula (VIII) or (IX) wherein R, R to R , n and p are as previously defined, with a compound of the formula: Het^-CH = CH 2 wherein Het is 2 or 4-ρyridyl or pyrazinyl, to give compounds of the formula (I) wherein Het is as defined in Het above; or (d) reducing a compound of the formula-: using a strong reducing agent, in an inert organic solvent, to give compounds of the formula (I) wherein X is a group of the formula: wherein R, R , X , m and p are as defined for the formula (I) and R is as defined for the formula (I) with the exception that when neither R nor R can be -CONR R 11 , -(CH ) NHC0(C -C, λ s 1 10 l 1 alkyl), -(CH 2 s NHC0NR R x , -(CH 2 ) NHSO^C- j -C^ alkyl) or -0C0(C -C, alkyl), wherein R , R and s are as defined for the formula . I) ; and in each of the above (a) to (d) optionally forming a pharmaceutically acceptable salt of the product. 14. A process as claimed in claim 13, part (a), wherein Y is chloro, bromo, methanesulphonyloxy, trifluororaethanesulphonyloxy or p-toluenesulphonyloxy and wherein the diphenylsulphoxime of formula (II) is deprotonated with sodium hydride, n-butyllithium or lithium diisopropylamide and then reacted in situ with the compound of formula (III) or formula (IV) in an inert organic solvent. 15. A process as claimed in claim13, part (b) wherein Y is chloro, bromo, iodo, methanesulphonyloxy, trifluoromethane- sulphonyloxy or p-toluenesulphonyloxy and wherein the compound of formula (VIII) or (IX) is reacted with the compound of formula (X) in the presence of sodium or potassium carbonate in an organic solvent. 16. A process as claimed in claim13 part (c) wherein the compound of formula (VIII) or (IX) is reacted with an excess of the vinylheterocycle of formula Het -CH = CH. in an organic solvent. 17. A process as claimed in claim 13 part (d) wherein the reducing agent is aluminium hydride and the reaction is performed in tetrahydrofuran. SUBSTITUTE SHEET 18. A process as claimed in claim13 for obtaining the compound of formula (I) wherein R and R are both H and X is a group of the formula R 2 1 1 5 -CH.-C-N -(CH.) — X —R l . , / m '3 '4 R R 2 3 4 wherein R is H or methyl, R is methyl and R is methyl. 19. A process as claimed in claim13 for obtaining the compound of formula (I) wherein R and R are both H and X is a group of the formula: p (CH 9 ) -x -R 2 m wherein n is 0 or 1. 20. A process as claimed in claim18 or claim19 wherein, in the compound of formula (I) X is a direct link. 21. A process as claimed in clai 18, 19 or20wherein R is 3- or 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedroxyphenyl or 1,4- benzodioxan-6-yl. 22. A process as claimed in claim 13 wherein the compound of formula (I) is (3R)-N-[l-(4-methoxyphenethyl)piperidin-3-yl]- diphenylsulphoximine. SUBSTITUTE SHEET

Inventors: ALKER DAVID, CROSS PETER EDWARD, KEMP JOHN EDWARD GLYN, ALKER, DAVID, CROSS, PETER, EDWARD, KEMP, JOHN, EDWARD, GLYN
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 1990
Main classification: C07D405
IPC codes: A61K31, A61P1, C07C381, C07D207, C07D211, C07D405