5-HT4 RECEPTOR ANTAGONISTS

Abstract: Compounds of formula (I): X-CO-Y-Z wherein the variable groups are as defined in the specification, of use in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

Description: 5-HT4 RECEPTOR ANTAGONISTS This invention relates to the use of compounds as 5-HT4 receptor antagonists in the treatment of gastrointestinal disorders, CNS disorders and/or cardiovascular disorders, and to certain novel compounds having 5-HT4 receptor antagonist activity. European Journal of Pharmacology 146 (1988), 187-188, and Naunyn- Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non classical 5-hyά^oxytryptamine receptor, now designated the 5-HT4 receptor, and that ICS 205-930, which is also a 5-HT3 receptor antagonist, acts as an antagonist at this receptor. PCT/GB91 00650 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhythmias and stroke. Some 5-HT3 receptor antagonists have been disclosed as of potential use in the treatment of certain aspects of irritable bowel syndrome [see EP-A-189002 (Sandoz Limited) and EP-A-200444 (Beecham Group p.l.c)]. 5-HT3 receptor interactions which are of potential use in the treatment of IBS are those associated either with the visceral pain and abnormal perception of sensation aspects of this disease, or they are related to the ability of some 5-ΗT3 receptor antagonists to cause constipation in volunteers. Some 5-HT3 receptor antagonists have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility [see EP-A-226266 (Glaxo Group Ltd.) and EP-A- 189002 (Sandoz limited)]. 5-HT3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron (see Drugs of the Future 1989, Ii (9) p.875 - F.D. King and G.J. Sanger). EP-A-189002 (Sandoz Limited) and EP-A-429984 (Nisshin Flour Mining Co., Ltd.) disclose compounds which are described as 5-HT3 receptor antagonists useful in the treatment of gastrointestinal disorders. We have now discovered that certain of these compounds and related compounds act as antagonists at 5-HT4 receptors and are of potential use in the treatment of LBS or atrial arrhythmias and stroke. The compounds of the present invention also have a potential use in the treatment of CNS disorders such as anxiety and/or migraine, in the treatment of upper gut motility disorders and as antiemetics. When used herein, 'treatment' includes prophylaxis as appropriate. The invention therefore provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: X-CO-Y-Z (I) wherein X is a group of formula (a), (b) or (c): (c) wherein L is N or CR S wherein R β is hydrogen, CI.Q alkoxy, halogen, Cι_4 alkyl or cyano; Q is NRi, CH2, O or S; W is CH or N; R a is hydrogen, halo, Cj.g alkyl, amino, nitro or Ci.g alkoxy; R D is hydrogen, halo, Cj.g alkyl or Cι_e alkoxy; l is hydrogen, Cι_ιo alkyl, C2.6 alkenyl, aralkyl, C2-6 alkanoyl or C2.6 alkanoyl C1.3 alkyl; 2 is Cj.g alkoxy; and R3 is hydrogen, chloro or fluoro; R4 is hydrogen,Cι_6 alkyl, amino optionally substituted by a C- .Q alkyl group, halo, hydroxy or Ci.ρ alkoxy; R5 is hydrogen, halo, Cj.g alkyl, Cj.g alkoxy, nitro, amino or Cj.g alkylthio; and Rg is hydrogen, halo, Cι_g alkyl, Cι_6 alkoxy or amino; , R c is hydrogen, C1.6 alkoxy, halo or C .Q alkyl; Yis O or NH; Z is of sub-formula (d) or (e): wherein n 1 is 0, 1, 2, 3 or 4; n 2 is 2, 3, 4 or 5; q is O, 1, 2 or 3; (j is hydrogen, Cι_i2 alkyl or aralkyl; R7 and Rg are hydrogen or Cj.g alkyl; and R9 is hydrogen or Cι_ιo alkyl; in the manufacture of a medicament for use as a 5-HT4 receptor antagonist. Examples of alkyl or alkyl containing groups include Ci, C2, C3, C4, C5, Cg, C7, C8, C9, Cιo » Cll or Cl2 branched, straight chained or cyclic alkyl, as appropriate. Cι_4 alkyl groups include methyl, ethyl n- and iso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Alkenyl includes all suitable values including E and Z forms. Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C-^.g alkyl and Cj. alkoxy. Halo includes fluoro, chloro, bromo and iodo. When Z is of sub-formula (d), nl is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n* is preferably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2. When Z is of sub-formula (e), n 2 is preferably 2, 3 or 4. Rg and R9 are preferably both alkyl, especially one of Rg and R9 is C4 or larger alkyl. Specific values of Z of particular interest are as follows: JMe π Bu (i ) The invention also provides novel compounds within formula (I) with side chains (i), (ii), (iii) or (iv). The invention also provides novel compounds within formula (I) wherein X is of formula (a) wherein L is C-OCH3, C-CH3 or C- Cl, in particular those wherein the side chain Z is of sub-formula (i), (ii), (iii) or (iv). Other values of Z of interest are described with reference to the Examples, such as those in Examples 19 onwards. In particular, the side chain of formula (i) or (ii) is replaced by a corresponding side chain with an alkyl or optionally substituted benzyl N-substituent and/or wherein the 4- piperidinyl group is replaced by 3-azetidinyl or 3-pyrrolidinyl. L in formula (a) is favourably C-H, C-CH3, C-Cl or C-OCH3. Q in formula (a) is favourably NRj, usually NH or N-methyl. Ri is preferably hydrogen or a methyl or ethyl group. R2 is preferably methoxy. R4 is preferably amino. R5 is preferably halo. Rg is preferably hydrogen. A substituent when halo is selected from fluoro, chloro, bromo and iodo, preferably chloro. R D when halo is preferably iodo. Y is preferably 0. Particularly suitable examples of compounds of formula (I) include those described in the Examples hereinafter and in Example 2 of EP-A-429984. The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, sucάnic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and glucose- 1-phosphoric adds. Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds Rχ-T wherein Rx is Cχ.g alkyl, phenyl-Cι_g alkyl or C5.7 cydoalkyl, and T is a radical corrτesponding to an anion of an add. Suitable examples of R % include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of T indude halide such as chloride, bromide and iodide. Examples of pharmaceutically acceptable salts also indude internal salts such as N-oxides. The compounds of the formula (I), their pharmaceutically acceptable salts, (induding quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to. 5-HT4 receptor antagonist activity may be identified according to standard methods, such as those described hereinafter. Examples of 5-HT4 receptor antagonists indude ICS 205-930 (tropisetron), which is described in the above mentioned patent references and GB 2125398A, R 50 595 (Janssen), which is described in FR76530 and Eur.J. Pharmacol., lfil 119-125 (1990), and SDZ 205-557, which is described by H. Buchheit and R. Gamse in Naunyn-Schmiedeberg's Arch. Pharmacol., S (Suppl.), R101 (1991). In one aspect, the compound of formula (I) is a more potent antagonist at 5-HT4 receptors than at 5-HT3 receptors. Preferably, the 5-HT4 receptor antagonist of formula (I) is in substantially pure pharmaceutically acceptable form. The compounds of formula (I) may be prepared as described in the aforementioned patent references, or by analogous methods thereto. The compounds of the present invention are 5-HT4 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders. They are of potential interest in the treatment of irritable bowel syndrome (LBS), in particular the diarrhoea aspects of LBS, i.e., these compounds block the ability of 5-HT to stimulate gut motility via activation of enteric neurones. In animal models of LBS, this can be conveniently measured as a reduction of the rate of defaecation. They are also of potential use in the treatment of urinary incontinence which is often assodated with LBS. They may also be of potential use in other gastrointestinal disorders, such as those assodated with upper gut motility, and as antiemetics. In particular, they are of potential use in the treatment of the nausea and gastric symptoms of gastro-oesophageal reflux disease and dyspepsia. Antiemetic activity is determined in known animal models of cytotoxic-agent/radiation induced emesis. Specific cardiac 5-HT4 receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias assodated with 5-HT, would also be expected to reduce occurrence of stroke (see A.J. Kaumann 1990, Naumyn-Schmiedeberg's Arch. Pharmacol. 342, 619-622, for appropriate animal test method). It is believed that platelet-derived 5-HT induces atrial arrhythmias which encourage atrial fibrillation and atrial disorders are assodated with symptomatic cerebral and sytemic embolism. Cerebral embolism is the most common cause of ischaemic stroke and the heart the most common source of embolic material. Of particular concern is the frequency of embolism assodated with atrial fibrillation. Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity may be demonstrated in standard animal models, the sodal interaction test and the X-maze test. Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, 1985, Migraine, Pan Books, London). It has also been observed that during and within 48 hours of a migraine attack, cyclic AMP levels are considerably increased in the cerebrospinal fluid (Welch et al., 1976, Headache 16, 160-167). It is beHeved that a migraine, including the prodomal phase and the associated increased levels of cyclic AMP are related to stimulation of 5-HT4 receptors, and hence that administration of a 5-HT4 antagonist is of potential benefit in relieving a migraine attack. The invention also provides a 5-HT4 antagonist pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a phaπnaceutically acceptable carrier. Such compositions are prepared by admixture and are usually adapted for enteral such as oral, nasal or rectal, or parenteral aόjmmstration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositri.es, injectable and infusable solutions or suspensions. Sublingual or transdermal administration is also envisaged. Orally administrable compositions are preferred, since they are more convenient for general use. Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional exdpients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating. Suitable fillers for use indude cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrroHdone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example ledthin, sorbitan monooleate, or acada; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic add, and if desired conventional flavouring or colouring agents. Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents. The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art. For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehide. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is induded in the composition to facilitate uniform distribution of the compound of the invention. The invention further provides a method of treatment or prophylaxis of irritable bowel syndrome, gastro-oesophagal reflux disease, dyspepsia, atrial arrhythπήas and stroke, anxiety and/or migraine in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. An amount effective to treat the disorders hereinbefore described depends on the relative efficades of the compounds to be administered, the nature and severity of the disorder being treated and the weight of the mammal. However, a unit dose for a 70 kg adult will normally contain 0.05 to 1000 mg for example 0.5 to 500 mg, of the compound. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50 mg/kg/day, more usually 0.0002 to 25 mg/kg/day. No adverse toxicological effects are indicated within the aforementioned dosage ranges. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of irritable bowel syndrome, gastro-oesophagal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine. The following Examples illustrate the preparation of compounds of formula (I); the following descriptions relate to the preparation of side chain (Z containing) intermediates. Examples X Y z El (a), O CH 2 -(l-ethyl-4-piperidyl) L = CH, R a /Rb =s H, Q = NH. E2 (b),Rg=H O (CH 2 )2-(l-piperidyl) R2 = OMe, R3 = H, R 4 = NH 2 , R 5 = C1. E3 (b),Rg=H NH CH2-(l-ethyl-4-piperidyl) R2 = OMe, R3=F, R 4 = NH 2 , R 5 = Cl. E4 (b),Rg=H O CH 2 -(l-butyl-4-piperidyl) R2 = OMe, R3=H, R 4 = NH 2 , R 5 = Cl. E5 (asE3) O CH 2 -(l-butyl-4-piperidyl) E6 (as El) 0 CH 2 -(l-butyl-4-piperidyl) Examnlβs (contd.) E7 (c),* O CH2-(l-butyl-4-piperidyl) W = CH, R c = 3-OMe E8 (c),* 0 CH 2 -(l-butyl-4-piperidyl) W = N E9 (c),** 0 CH2-(l-butyl-4-piperidyl) W = N E10 (a), O CH2-(l-butyl-4-piperidyl) L = N, R a Rb = H, Q = NMe Ell (as El) O (CH2)2-(l-homopiperidyl) E12 (as El) 0 (CH 2 )3-(l-piperidyl) E13 (as El) o (CH 2 )4-(l-piperidyl) E14 (a), o (CH 2 )2-(l-piperidyl) L = CH, R a = 5-Br, R b = H Q = NH * 1-substituted **3-substituted Examplgs (contd.) O (CH 2 ) 2 -(l-piperidyl) 0 (CH 2 )2-(l-piperidyl) 0 (CH 2 -(l-butyl-4-piperidyl) 0 (CH 2 )2-(l-piperidyl) 0 CH2-(l-butyl-3-pyrroHdinyl) 0 CH2-(l-butyl-3-pyrrolidinyl) E21 (as E2) O (CH 2 )2-(l-pentyl-3-pyrrolidinyl) E22 (as El) O (CH 2 )2-(l-pentyl-3-pyrrolidinyl) E23 (as E2) 0 CH2-(hexahydro-l-butyl-3- azepinyl) Examples (contd.) E24 (as El) 0 CH2-(hexahydro-l-butyl-3- azepinyl) E25 (as E2) 0 (CH2)2-d-butyl-3-piperidyl) E26 (as El) 0 (CH 2 )2-(l-butyl-3-piperidyl) E27 (as E2) 0 (CH 2 )2-(l-butyl-2-piperidyl) E28 (as E2) 0 CH 2 -(l-butyl-3-piperidyl) E29 (as El) 0 CH 2 -(l-butyl-3-piperidyl) E30 (as E2) O l-butyl-4-piperidyl E31 (as E2) 0 CH2-(l-butyl-l,2,5,6- tetrahydropyridyl) E32 (a), 0 (i) L = CH, R a /Rb = H, Q = NEt E33 (a), 0 (i) L = CH, R a Rb = H, Q = NCH 3 E34 (as E33) 0 (ii) E35 (as E2) 0 CH2-(l-butyl-3-azetidinyl) Description 1 (intermediates for Examples 19 and 20) a) l-Butyl-3-carbomethoxypyιτolid-5-one To a cooled solution of butylamine (9.4 ml) in methanol (10 ml) was added, dropwise, dimethyl itaconate (15g). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to afford crude l-butyl-3-carbomethoxy-pyrroHdin-5-one (17.9g). b) l-Butyl-3-hydroxvmethylpyrrolidine To a stirred slurry of Uthium aluminium hydride (4.29g) in diethyl ether (70 ml) was added l-butyl-3-carbomethoxypyrrolid-5-one (lOg) in diethyl ether (20 ml). The reaction mixture has maintained at reflux for 3h under a nitrogen atmosphere, and stirring continued overnight at room temperature. The mixture was cooled and water (4 ml), 10% aqueous NaOH (6 ml) and water (8 ml) were added sequentially. Diethyl ether was added and the mixture stirred for lh. The resultant preάpitate was removed by filtration through keiselguhr and the filtrate concentrated under reduced pressure. Distillation at reduced pressure gave pure 1- butyl-3-hyά^oxymethylpyrrτoHdine (Dl) (5.13g). lH NMR (CDC1 3 ) 250 MHz δ: 3.69 (dd, IH), 3.51 (dd, IH), 2.80 (dt, IH), 2.64 (dd, IH), 2.24-2.53 (m, 5H), 1.92-2.07 (m, IH), 1.60-1.73 (m, IH), 1.26-1.55 (m, 4H), 0.92 (t, 3H). Description 2 (intermediate for Examples 21 and 22) a) Following the procedures outlined in Description 1, the following compound was obtained: l-pentyl-3-hydroxymethylpyrroh ' dine b) 3-Chloromethyl-l-pentylpyrrolidine (6.54g) in chloroform (10 ml) was saturated with hydrogen chloride and the mixture heated to reflux. A solution of thionyl chloride (5.6 ml) in chloroform (10 ml) was added dropwise and stirring continued for lh. The reaction mixture was cooled to room temperature and stirring continued overnight. The reaction mixture was concentrated to half-volume and azeotroped with ethanol (2 x 10 ml). The residue was diluted with water and extracted with diethyl ether. The aqueous phase was basified with 50% aqueous sodium hydroxide and extracted with diethyl ether. The organic phase was washed with water, dried (Na2S04) and concentrated in vacuo to afford an oil. Distillation under reduced pressure gave pure 3-chloromethyl-l- pentylpyrrolidine (5.79g). A stirred solution of 3-chloromethyl-l-pentyl pyrrolidine (5.415g), tricaprylmethyl ammonium chloride (375 mg), and sodium cyanide (7.25g) in water (12.5 ml) was heated at 100°C for 24h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2Sθ4) and concentrated in vacuo to afford crude 3-cyanomethyl-l-pentylpyrrolidine (5.04g). d) A solution of 3-cyanomethyl-l-pentylpyrrolidine (2.982g) in methanolic HCl (60 ml) was allowed to stand at room temperature for 16h. The solvent was removed under reduced pressure, the residue diluted with water, basified with aqueous sodium hydroxide solution and extracted with diethyl ether. The organic phase was washed with water, dried (Na2S04) filtered and concentrated in vacuo to afford crude methyl 3-(l-pentyl pyrrolidino) acetate. Distillation under reduced pressure (100°C at 0.2 mm Hg) gave title compound (2.13g). e) To a suspension of Hthium aluminium hydride (0.7g) in diethyl ether (40 ml) was added methyl 3-(l-pentyl pyirolidino) acetate (1.967g) under a nitrogen atmosphere. The mixture was heated to reflux and stirring continued for 4h. The reaction mixture was cooled to room temperature and stirring continued overnight. Water (5 ml) was added dropwise and the resultant predpitate removed by filtration and washed with dichloromethane. The combined organic filtrate was concentrated in vacuo to afford an oil. Distillation under reduced pressure (150°C / 1.0 mm Hg) gave pure 3-hydroxyethyl-l-pentylpyrrolidine (D2) (1.48g). *H NMR (250 MHz) (CDCI3) δ: 4.18-4.41 (s, IH), 3.52-3.73 (m, 2H), 2.76- 2.85 (m, IH), 2.33-2.52 (m, 6H), 1.92-2.08 (m, IH), 1.45-1.80 (m, 5H), 1.22- 1.38 (m, 4H), 0.88 (t, 3H). Description 3 (intermediate for Examples 23 and 24) a) Hexahydro-l-butyl-azepin-2-one To a solution of hexahydro-LH-azepin-2-one (lOg) in dry THF (300 ml) was added potassium tert-butoxide (9.86g). The reaction mixture was heated to reflux. 1-Bromobutane (9.45 ml) was added after lh. Stirring was continued for 2h. The reaction mixture was cooled to room temperature and water (10 ml) added. The solvent was concentrated under reduced pressure and the residue dissolved in ethyl acetate (250 ml) and washed with brine. The organic phase was dried (Na2S04) filtered and concentrated in vacuo to afford an oil. Kugelrόhr distillation afforded pure title compound (12.0g). b) Hexahydro-l-butyl-3-carboxyazepin-2-one To a solution of hexahydro-l-butylazepin-2-one (6.0g) in dry THF (30 ml) was added Uthium diisopropylamide in cydohexane (1.5M, 23.3 ml) at 0°C. Stirring was continued at ambient temperature for 30 min. CO2 peUets was added to the reaction mixture which were subsequently poured into ice-water (200 ml). The THF was concentrated in vacuo and the aqueous phase adjusted to pH2 with 5N HCl. The aqueous phase was extracted with chloroform (4 x 200 ml) and the combined organic extracts were dried (Na2S0 ), filtered and concentrated in vacuo to afford an oil. Flash chromatography on siUca using chloroform and ethanol as the eluant gave pure title compound (1.90g). c) Hexahydro-l-butyl-3-hydroxymethylazepine To a slurry of Uthium aluminium hydride (1.03g) in THF (50 ml) was added a solution of hexahydro-1-butyl 3-carboxyl azepin-2-one (1.90g) in THF (50 ml) under a nitrogen atmosphere. Stirring was continued at ambient temperature for 70h. The reaction mixture was heated to reflux for 5h, cooled and quenched by the sequential addition of water (1 ml), 10% aqueous NaOH (V ml) and water (2V-2 ml). Stirring was continued at room temperature for lh. The resultant preάpitate was removed by filtration and the filtrate concentrated in vacuo to afford an oil. Kughlerohr distillation gave pure title compound (D3) (0.76g). lH NMR (CDCI3) 250 MHz δ: 4.71 (m, IH), 3.81 (dd, IH), 3.49-3.57 (m, IH), 2.70-2.85 (m, 3H), 2.43 (dt, 2H), 2.07-2.30 (m, IH), 1.41-1.90 (m, 9H), 1.22-1.37 (m, 2H), 0.92 (t, 3H). Description 4 (intermediate for Examples 25 and 26) a) Ethyl l-butyl-3-pyridylacetate iodide To a cooled solution of ethyl 3-pyridylacetate (12g) in acetone (50 ml) was added 1-iodobutane (12.90 ml). The reaction mixture was stirred at room temperature overnight and then heated to reflux. The reaction mixture was cooled to room temperature and diethyl ether was added. Stirring was continued for 15 min. The resultant predpitate was removed by filtration and dried to afford crude title compound (23.76g). b) Ethyl-l-butyl-3-piperidylacetate A solution of ethyl l-butyl-3-pyridylacetate iodide (21g) in ethanol was hydrogenated over Ptθ2 (2g) at atmospheric pressure and room temperature. The catalyst was removed by filtration through keiselguhr and the filtrate concentrated in vacuo. The residue was dissolved in water, basified from K2CO3 and extracted with chloroform. The organic phase was dried (Na2S04) filtered and concentrated in vacuo to afford ethyl l-butyl-3-piperidylacetate (13.6g) as an oil. c) l-Butyl-3-piperidylethanol To a slurry of Uthium aluininium hydride (3.51g) in diethyl ether (50 ml) was added, dropwise, a solution of ethyl l-butyl-3-piperidyl acetate (7.0g) in diethyl ether (50 ml) at 0°C under a nitrogen atmosphere. Stirring was continued at ambient temperature for 60h. The reaction mixture was cooled to 0°C and treated sequentially with water (3.5 ml), 10% aqueous NaOH (5.2 ml) and water (8.7 ml). Stirring was continued for lh. The predpitate was removed by filtration through Keiselguhr and the filtrate evaporated under reduced pressure to afford crude product. Vacuum distiUation gave pure title compound (D4) (4.0g). lH NMR (CDCI3) 250 MHz δ: 3.59-3.77 (m, 2H), 2.64-2.69 (m, 2H), 2.23- 2.35 (m, 2H), 2.11-1.96 (m, IH), 1.40-1.88 (m, 9H), 1.22-1.38 (m, 2H), 0.98- 1.14 (m, IH), 0.92 (t, 3H). MH+ 186 Description 5 (intermediate for Example 27) a) Ethyl l-butyl-2-piperidylacetate To a solution of ethyl lH-piperidyl-2-acetate (8.3g) in ethanol (100 ml) was added potassium carbonate (14.35g) and 1-bromo butane (11.7 ml). The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered through keiselguhr. The filtrate was evaporated under reduced pressure to afford an oil. Flash chromatography on silica eluting with chloroform and ethanol gave pure title compound (5.85g). b) l-Butyl-2-piperidylethanol Following the procedure outlined in Description 4c), ethyl l-butyl-2- piperidyl acetate (4.44g) gave the title compound as an oil after kugelrohr distillation (2.27g). lH NMR (CDCI3) 250 MHz δ: 5.45 (m, LH), 3.82-3.94 (m, IH), 3.70-3.80 (m, IH), 3.00-3.09 (m, IH), 2.73-2.85 (m, IH), 2.61-2.72 (m, IH), 2.40-2.52 (m, LH), 2.21-2.34 (m, IH), 1.81-1.96 (m, IH), 1.23-1.75 (m, HH), 0.90 (t, 3H). MH+ 186 Description 6 (intermediate for Example 28) a) Ethyl-l-butyl-3-piperidyl carboxylate Following the procedure outlined in description 5a), ethyl- IH-piperidyl 3- carboxylate (15.7g) gave title compound (17.1g). b) l-Butyl-3-piperidylmethanol FoUowing the procedure outlined in Description 5b), ethyl 1-butyl -3- piperidyl carboxylate (17. lg) gave 1-butyl 3-piperidinyl methanol (D6) (3.9g). IH NMR (250 MHz) (CDC1 3 ) δ: 3.38-3.53 (m, 2H), 2.82-3.03 (m, 2H), 2.23-2.34 (m, 2H), 1.98-2.02 (m, IH), 1.36-1.97 (m, 8H), 1.22-1.35 (m, 2H), 0.92 (t, 3H). Description 7 (intermediate for Example 30) a) Dimethyl-2, 2'-butyliminodiethanoate Methyl acrylate (11.78g) was added dropwise to n-butylamine (5g), at 0°C. The reaction mixture was heated to reflux for 24h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water (3x). The organic phase was dried (Na2Sθ4), filtered and concentrated under reduced pressure to afford an oil. Purification by kugelrohr distillation gave the title compound (9.95g). b) l-Butyl-4-piperidone Potassium fert-butoxide (6.82g) was added to a solution of dimethyl-2,2 - butyl iminodiethanoate (9.95g) in diethyl ether under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The mixture was extracted into 5N HCl (100 ml) and heated under reflux for 2h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was basified with 2CO3 and extracted with ethyl acetate. The organic phase was dried (Na2Sθ4) filtered and concentrated in vacuo. Flash chromatography on siUca using ethyl acetate as the eluant gave pure l-butyl-4-piperidone (3.68g). c) l-Butyl-4-piperidol To a slurry of Uthium aluminium hydride (0.96g) in diethyl ether (50 ml) was added l-butyl-4-piperidinone (2.6g) in diethyl ether (50 ml), at 0°C under a nitrogen atmosphere. The reaction mixture was stirred overnight at ambient temperature, cooled to 0°C and treated sequentially with water (1.0 ml), 10% NaOH (1.4 ml) and water (2.4 ml). The mixture was stirred at ambient temperature for lh and the predpitate removed by filtration through keiselguhr. The filtrate was concentrated under reduced pressure to afford an oil. Purification by vacuum distillation gave l-butyl-4-piperidol (D7) (1.98g). IH NMR (CDC1 3 ) 250 MHz δ: 3.61-3.74 (m,l H), 2.71-2.82 (m, 2H), 2.26- 2.34 (m, 2H), 2.04-2.16 (m, 2H), 1.82-1.95 (m, 3H), 1.38-1.67 (m, 4H), 1.22- 1.37 (m, 2H), 0.9 (t, 3H). Description 8 (intermediate for Example 31) a) Ethyl l-butyl-4-pyridyl carboxylate iodide FoUowing the procedure outlined in Description 4a), ethyl 4-pyridine carboxylate (lOg) gave the title compound (22.2g). b) Ethyl 2-butyl-(l^,5,6)-tetrahydropiperidyl-4-carboxylate To a suspension of sodium borohydride (4.6g) in ethanol (300 ml), at 0°C, was added ethyl l-butyl-4-pyridyl carboxylate iodide (lOg) under an atmosphere of nitrogen. The reaction mixture was stirred for 2h at ambient temperautre. The mixture was poured into water and the solvent concentrated under reduced pressure. The residue was extracted into chloroform and the organic phase dried (Na2Sθ4), filtered and concentrated to afford an oil. Flash chromatography on silica using chloroform and ethanol as eluant gave pure title compound (2.59g). c) l-Butyl-(l,2,5,6)-tetrahydropiperidyl-4-methanol FoUowing the procedure outUned in Description 4c), ethyl 1-butyl- (1,2,5,6)- tetrahydropiperidyl-4-carboxylate (2g) gave pure title compound (D8) (630 mg). lH NMR (CDC1 3 ) 250 MHz δ: 5.59 (s, IH), 3.92 (s, 2H), 2.95 (s, 2H), 2.59 (t,2H), 2.35 -2.50 (m, 2H), 2.10-2.20 (m, 2H), 1.25-1.60 (m, 6H), 0.92 (t, 3H). M+ 169 Description 9 (intermediate for Example 35) a) l-Benzyl-4-chloro-3-hydroxybutylamine To a solution of epichlorohydrin (150ml) in cydohexane (11) was added benzylamine (240ml). The reaction mixture was stirred at room temperature for 24h. The predpitate was removed by filtration, washed with petrol (bp 60-80°C) and dried (327.7g) b) l-Benzyl-3-trimethylsiloxyazetidine To a solution of imidazole (112g) and triethyl amine (825ml) in acetonitrile (1.51) was added, dropwise chlorotrimethylsilane (203ml) at - 5°C under nitrogen. Stirring was continued at room temperature for l-benzyl-4-chloro-3-hydroxybutylamine (310g) was added to the reaction and the resulting mixture heated to reflux for 72h, with vigorous stirring. The mixture was cooled to room temperature, toluene (21) was added and the mixture left to stand overnight. The predpitate was removed by filtration, sluπied in petrol (bp 60-80°C) (21) and washed with water (200ml). The filtrate was concentrated in vacuo and the residue partitioned between water and petrol (bp 60-80°C) (11). The organic layers were dried (MgSθ4), filtered and concentrated in vacuo to afford an oil. Purification by vacuum distillation gave l-benzyl-3-trimethylsiloxy azetidine (130g) as a colourless oil. c) l-Benzyl-3-hydroxyazetidine A solution of l-benzyl-3-trimethylsiloxyazetidιne (89g) in cHCl water (53/350ml) was stirred vigorously at room temperature for lOmin. The mixture was basified with K2CO3 and extracted with diethyl ether. The ethereal extracts were dried ( gSO ), filtered and concentrated in vacuo to afford l-benzyl-3-hydroxyazetidine (59.6g) as a white soUd. d) l-Benzyl-3-cyanoazetidine To a stirred solution of l-benzyl-3-hydroxyazetidine (83. lg) and triethylamine (71ml) in toluene (610ml) and triethylamine (71ml) was added, dropwise, over 20min methane sulphonyl chloride (39.5ml). During addition the internal temperature was maintained between 0 and 5°C. On completion of addition stirring was continued for a further 30min. Water (20ml) was added to the reaction mixture and the separated toluene layer removed. The aqueous layer was further extracted with toluene (2x100ml). The organic extracts were combined and washed with brine. The organic phase was treated with Adogen 464 (25g) and a solution of sodium cyanide (29.5g) in water (173ml). The reaction mixture was heated to reflux for 1 l/2h and allowed to cool to room temperature. The mixture was transferred to a separatory funnel and the aqueous layer removed. The organic phase was washed with water (3x200ml) and brine (200ml), dried (MgS0 ), filtered, and concentrated in vacuo. Distillation of the residue gave pure l-benzyl-3- cyanoazetidine (62.9g). e) Methyl l-benzyl-3-azetidinyl carboxylate To a solution of l-benzyl-3-cyanoazetidine (lOg) in methanol (40ml) was added CH2SO4 (35ml), dropwise, so as to maintain the reaction at a maximum 55°C. The reaction mixture was heated to 80°C for 2h, cooled to r.t. and poured into ice (240g). The mixture was basified with aq. ammonia and extracted into dichloromethane. The organic phase was washed with water, dried Na2Sθ4), filtered and concentrated in vacuo to afford crude title compound (10.18g). f) Methyl- lH-3-azetidinyl carboxylate acetate A solution of methyl l-benzyl-3-azetidinyl carboxylate (5.45g) in ethanol (100ml) and acetic add (6ml) was hydrogenated over 10% Pd/C at 50psi and 50°C for 6h. The catalyst was removed by filtration through keiselguhr and the filtrate concentrated in vacuo to afford methyl l-H-3- azetidinyl carboxylate acetate (3.65g). g) Methyl l-butyryl-3-azetidinyl carboxylate To a solution of methyl l-H-3-azetidinyl carboxylate acetate (2.80g) and triethylamine (4.6ml) in dichloromethane (60ml) was added, dropwise, butyryl chloride (1.6ml). The reaction mixture was stirred at ambient temperature for 70h. The mixture was washed with water and the organic phase dried (Na2S04), filtered and concentrated under reduced pressure to afford crude methyl l-butyryl-3-azetidinyl carboxylate (2.60g). h) l-Butyl-3-hydroxymethylazetidine To a solution of Lithium aluminium hydride (2.20g) in dry THF (25ml) was added a solution of methyl l-butyryl-3-azetidinyl carboxylate (3.60g) in dry THF, at 0°C, under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched by sequential addition of water (2 2ml), 10% aq. NaOH (4ml) and water (5ml). Diethyl ether (20ml) was added and stirring continued for lh. The predpitate was removed by filtration through Keiselguhr and the filtrate concentrated in vacuo to afford an oil. Kughlerohr distillation afforded pure title compound (D9) (l.lg). lH NMR 250MHz (CDC1 ), δ: 3.67 (d,2H), 3.23-3.47 (m,2H), 2.97-3.08 (m,2H), 2.55-2.68 (m,lH), 2.35-2.7 (m,2H), 1.27-1.38 (m,4H), 0.86-0.98 (m,3H), MH+ 144 Description 10 (intermediate for Example 4) l-Butyl-4-piperidinemethanol A mixture of ethyl isonipecotate (31.4g, 0.2mole), K2CO3 (54g, 0.4mole) and n BuBr (27.4g, 0.2mole) in EtOH (400ml) was stirred under reflux for 3 hours. The reaction mixture was allowed to cool, filtered through keiselguhr and the filtrate concentrated to give a pale yeUow oil. This was dissolved in dry E12O (200ml) and added dropwise to a suspension of LLALELJ. (20g, 0.26mole) in dry E12O. The reaction mixture was stirred at room temperature overnight then cooled in an ice bath. Water (20ml) was carefully added, foUowed by 20% aq. NaOH (20ml), followed by water (60ml). The mixture was stirred at room temperature for 30 minutes then filtered through keiselguhr. The filtrate was concentrated in vacuo to give a colourless oil (25.0g). iNMR 250MHz (CDCI3) δ: 3.48(d,2H), 2.93-2.99(bd,2H), 1.18-2.4(m,14H), 0.9(t,3H) Preparation of Intermediate Acid for Example 3 a) Methyl-4-acetamido-5-chloro-2-methoxybenzoate (10.9g) was dissolved in chloroform (40 ml), cooled to -10 C under nitrogen. A three molar excess of trifluoromethyl hypofluorite was slowly bubbled through the stirred, cooled solution for 6 hours. A slow positive nitrogen stream was maintained throughout the reaction. After warming to room temperature and thoroughly purging with nitrogen, the chloroform was removed in vacuo. The residue was chromatographed on silica using chloroform with increasing amounts of methanol as eluant. Methyl-4-acetamido-5-chloro- 3-fluoro-2-methoxybenzoate was isolated as an off white solid. iH NMR (CDC1 3 ) 250MHz; δ: 7.64 (d, IH), 7.37 (bs, IH), 3.98 (bs, 3H), 3.9 (s, 3H), 2.2 (s, 3H) b) Methyl-4-acetømido-5-chloro-3-fluoro-2-methoxybenzoate (1.89g) in 25 ml ethanol was treated with a solution of sodium hydroxide (1.15g) in 15 ml water. The mixture was heated under reflux for 16 hours then cooled. The solvent was removed in vacuo and the residue acidified. The predpitated solid was collected by filtration to give 1.48g of 4-amino-5- chloro-3-fluoro-2-methoxybenzoic add. !H NMR (DMSO) 250MHz; δ: 7.49 (d, IH), 6.19 (bs, 2H), 3.80 (s, 3H) Example 1 (l-Ethyl-4-piperidyl)methyl-lH-indole-3-carboxylate (El) A suspension of indole-3-carboxyUc add (500 mg, 0.003 mole) in dichloromethane (50 ml) was treated with oxalyl chloride (0.635, 0.005 mole) and two drops of όjmethylformamide. The mixture was stirred at room temperature for one and a half hours then the solvent was removed in vacuo. The residue was redissolved in dichloromethane (50 ml) and a solution of triethylamine (612 mg, 0.006 mole) and l-ethyl-4- hydroxymethylpiperidine (430 mg, 0.003 mole) in dichloromethane (20 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight then washed with aqueous potassium carbonate solution and water, dried and concentrated to give a gummy soUd which was purified by column chromatography on silica gel using chloroform 95%, methanol 5% as eluant to give a white soUd 405 mg, mp 135-6°C. iH NMR (250MHz) CDCI3; δ: 10.08 (bs, IH), 8.10 - 8.20 (m, IH), 7.76 (d, IH), 7.35 - 7.45 (m, IH), 7.20 - 7.28 (m, 2H), 4.20 (d, 2H), 3.0-3.12 (bd, 2H), 2.5 (dd, 2H), 1.4-2.10 (m, 7H), 1.10 (t, 3H). Example 2 4-A^nino-5-chloro-2-methoxy-(2-(l-piperidyl)ethyl)benzoate (E2) A solution of 4-anτino-3-chloro-2-methoxybenzoic add (2.01g, 0.01 mole) in acetonitrile (30 ml) was treated with bis-carbonyldiimidazole (1.62g, 0.01 mole) and the mixture was stirred at room temperature for one and a half hours. The solvent was removed in vacuo to leave the crude imidazoUde. A solution of l-(2-hydroxyethyl)piperidine (1.29g, 0,01 mole) in dry THF (10 ml) under an atmosphere of nitrogen, was cooled in an ice bath, n- ButylUthium (6.25 ml of 1.6M solution in hexane) was added dropwise and the resulting solution stirred at 0°C for 15 minutes. The imidazoUde was dissolved in dry THF (20 ml) and the resulting solution added dropwise to the solution of the Uthium alkoxide at 0°C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. The solvent was removed in vacuo and the residue partitioned between chloroform and water. The chloroform was separated, washed several times with water, dried and concentrated to give a white > solid (recrystaUised from ether/petroleum ether) yield 2.6g, mp 135-6°C. iH NMR (250MHz) CDCI3; δ: 7.82 (s, IH), 6.30 (s, IH), 4.48 (bs, 2H), 4.38 (t, 2H), 3.82 (s, 3H), 2.72 (t, 2H), 2.45-2.55 (m, 4H), 1.52-1.66 (m, 4H), 1.40-1.50 (m, 2H). Example 3 4-Anιino-5-chloro-3-fluoro-2-nιethoxy- ( l-ethyl-4- piperidyDmethylbenzamide (E3) A solution of 4-amino-5-chloro-3-fluoro-2-methoxybenzoic add (210mg, 0.001 mole) in acetonitrile (15ml) was treated with bis- carbonyldiimidazole (162mg, 0.001 mole). The mixture was stirred at room temperature for one and a half hours. A solution of l-ethyl-4-aminomethylpiperidine (142 mg, 0.001 mole) in acetonitrile (10 ml) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue partitioned between chloroform and water. The chloroform layer was removed, washed several times with water, dried and concentrated to give a beige soUd which was converted to the hydrochloride salt, 110 mg, mp 208-9°C. iH NMR (250 MHz) CDCI3 (free base); δ: 7.82 (d, IH), 7.65-7.75 (bt, IH), 4.30 (bs, 2H), 4.40 (s, 3H), 3.25 (t, 2H), 2.82-2.95 (bd, 2H), 2.28-2.38 (dd, 2H), 1.10-1.90 (m, 7H), 1.0 (t, 3H). Example 4 4-Amino-5-chloro-2-methoxy-(l-butyl-4-piperidyl)methyl benzoate (E4) The title compound was prepared from 4-amino-5-chloro-2- methoxybenzoic add and l-butyl-4-piperidinemethanol by the method described for Example 2. It was isolated as a white soUd, mp 52-53°C. !H NMR (250 MHz) CDCI3; δ: 7.80 (s, IH), 6.28 (s, IH), 4.42 (bs, 2H), 4.10 (d, 2H), 3.85 (s, 3H), 2.92-3.02 (bd, 2H), 2.35 (m, 2H), 1.20-2.02 (m, 11H), 0.92 (t, 3H). Example 5 4-A^nino-5-chloro-3-fluoro-2-methoxy-(l-butyl-4-piperidyl)methyl benzoate (E5) The title compound was prepared from 4-amino-5-chloro-3-fluoro-2- methoxybenzoic add and l-butyl-4-piperidinemethanol by the method described for Example 2. It was isolated as a colourless gum and converted to the hydrochloride salt, mp 195-7°C. ^ NMR (250 MHz) CDCI3 (free base); δ: 7.62 (d, IH), 4.45 (bs, 2H), 4.12 (d, 2H), 3.90 (s, 3H), 2.92-3.15 (bd, 2H), 2.28-2.38 (m, 2H), 1.20-2.00 (m, 11H), 0.90 (t, 3H). Example 6 (l-Butyl-4-piperidyl)methyl-lH-indole-3-carboxylate (E6) A suspension of indole-3-carboxyUc add (500mg, 0.003 mole) in dichloromethane (50 ml) was treated with oxalyl chloride (0.635g, 0.005 mole) and two drops of άimethylformaimde. The mixture was stirred at room temperature for one and a half hours then the solvent was removed in vacuo to leave the add chloride. A solution of l-butyl-4-piperidinemethanol (513 mg, 0.003 mole) in dry THF (10 ml) under an atmosphere of nitrogen, was cooled in an ice bath. n-ButylUthium (1.88 ml of 1.6m solution in hexane) was added dropwise and the resulting solution stirred at 0°C for 15 minutes. The add chloride was dissolved in dry THF (20 ml) and the solution added dropwise to the solution of the Uthium alkoxide at 0°C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. The solvent was removed in vacuo and the residue partitioned between chloroform and water. The chloroform was separated, washed several times with water, dried and concentrated to give a pale brown gum. !H NMR (250 MHz) CDC1 3 ; δ: 9.90 (bs, IH), 8.10-8.18 (m, IH), 7.78 (d, IH), 7.37-7.46 (m, IH), 7.16-7.28 (m, 2H), 4.19 (d, 2H), 3.05-3.15 (bd, 2H), 2.40-2.49 (m, 2H), 1.20-2.18 (m, HH), 0.90(t, 3H). Example 7 3-Methoxy-2-(l-butyl-4-piperidyl)methylnaphthoate (E7) The title compound was prepared from 3-methoxy-2-naphthoic add and 1- butyl-4-piperidinemethanol by the method described for Example 2. It was isolated as a pink solid MP 65-6°C. iH NMR (250 MHz) CDCI3; δ: 8.28 (s, IH), 7.84 (d, IH), 7.75 (d, IH), 7.51 (t, IH), 7.37 (t, IH), 7.19 (s, IH), 4.22 (d, 2H), 3.98 (s, 3H), 3.00 (bd, 2H), 2.32-2.40 (m, 2H), 1.24-2.03 (m, HH), 0.92 (t, 3H). Example 8 ( l-Butyl-4-piperidyl)methyl-isoquinoline- 1-carboxylate (E8) The title compound was prepared from isoquinoUne-1-carboxyUc add and l-butyl-4-piperidine-methanol by the method described for Example 2. It was isolated as a colourless gum. !H NMR (250 MHz) CDCI3; δ: 8.70 (dd, IH), 8.65 (d, IH), 7.88 (dd, IH), 7.81 (d, LH), 7.60-7.78 (m, 2H), 4.39 (d, 2H), 3.00 (bd, 2H), 2.28-2.39 (m, 2H), 1.20-2.05 (m, HH), 0.90 (t, 3H). Example 9 (l-Butyl-4-piperidyl)methyl-isoquinoline-3-carboxylate (E9) The title compound was prepared from isoquinoline-3-carboxyUc add and l-butyl-4-piperidinemethanol by the method described for Example 2. It was isolated as a white soUd, mp 82-3°C. iHNMR (250 MHz) CDCI3; δ: 9.38 (s, IH), 8.60 (s, H), 8.10 (dd, IH), 7.98 (dd, IH), 7.70-7.87 (m, 2H), 4.35 (d, 2H), 3.00 (bd, 2H), 2.26-2.40 (m, 2H), 1.20-2.05 (m, HH), 0.91 (t, 3H). Example 10 (l-Butyl-4-piperidyl)methyl-l-methyUndazole-3-carboxylate (E10) The title compound was prepared in a similar manner to the compound of Example 6, from the 1-methylindazole add (EP-A-323105) m.p. 190°C. (hydrochloride salt). Reference: il K. Patent 1571278 (Soc D'Etudes Sci. et Ind. D'Dle de Fr.) Examples 11 to 14 The following compounds were prepared (as hydrochloride salts), in a similar manner to that described in EP-A-429984. (l-Homopiperidyl)ethyl-lH-indole-3-carboxylate (Ell) m.p. 123-125°C (l-Piperidyl)propyMH-indole-3-carboxylate (E12) m.p. 184-187°C (l-Piperidyl)butyl-lH-indole-3-carboxylate (E13) m.p. 170-173°C (l-Piperidyl)ethyl-5-bromo-lH-indole-3-carboxylate (E14) m.p. 186-188°C Example 15 5-Chloro-2-methoxy-4-methyl-(2-(l-piperidyl)ethyl)benzoate (E15) The title compound was prepared in a similar manner to the compound of example 2, from 5-chloro-2-methoxy-4-methylbenzoic add (J. Chem. Soc, 1963, p.730), and isolated as the hydrochloride salt, m.p. 185-186°C. Example 16 (l-Piperidylethyl)-2-methoxyindole-3-carboxylate hydrochloride (E16) Following the procedure outlined in GB 2125398A, Example A-5, (N- piperidylethyl)indole-3-carboxylate (0.21g) was converted to the title compound (38mg, 16%). iH NMR (CDC1 3 ) 250MHz (free base) δ: 9.25(brs,LH), 8.0(d,lH), 7.29(d,LH), 7.25-7.05(m,2H), 4.55(t,2H), 4.12(s,3H), 2.90(t,2H), 2.67(brs,4H), 1.75-1.6(m,4H), 1.55-1.35(m,2H). Example 17 (l-Butyl-4-piperidyl)methylindene- 1-carboxylate hydrochloride (E17) A solution of indene-1-carboxylic add (187mg) (N.H. CromweU and D.B. Capps, J. Amer. Chem. Soc, J , 44448, 1952) in dichloromethane (10ml) was treated with oxalyl chloride (lOOmg) and two drops of dimethylformamide. The mixture was stirred at room temperature for one and a half hours then the solvent was removed in vacuo to leave the add chloride. A solution of l-butyl-4-piperidinemethanol (120mg) in dry THF (5ml) under an atmosphere of nitrogen, was cooled in an ice bath, n- ButyUithium (0.5ml of 1.6m solution in hexane) was added dropwise and the resulting solution stirred at 0°c for 15 minutes. The add chloride was dissolved in dry THF (10ml) and the solution added dropwise to the solution of the Uthium alkoxide at 0°C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. The solvent was removed in vacuo and the residue partitioned between chloroform and water. The chloroform was separated, washed several times with water, dried and concentrated to give a pale gum which was converted to the hydrochloride salt 120mg, mp 131-3°C. iH NMR (250MHz) CDCI3 δ: 8.02(d,LH), 7.55-7.45(m,2H), 7.38(t,lH), 7.28(t,LH), 4.21(d,2H), 3.55(d,2H), 3.20(brd,2H), 2.65-1.25(m,13H), 0.95(t,3H). Example 18 2-(l-Piperidyl)ethyl-3-benzothiophene carboxylate (E18) Benzothiophene-3-carboxylic add (J. Matsuki, J. Chem. Soc. Jpn, 1966, ≤7_, 18b) (400mg) was heated under reflux with SOCI2 (0.7ml) in dry toluene (15ml) for 30 minutes. The toluene was removed in vacuo and the residue dried under high vacuum. 1-Piperidineethanol (290mg) was dissolved in dry THF (5ml) and n BuLi (1.4ml of 1.6M Sol n in hexane) was added. The mixture was stirred at room temperature for 15 minutes then a solution of the add chloride from above in dry THF (10ml) was added. The reaction mixture was stirred at room temperature for 2hrs then the solvent was removed in vacuo. The residue was partitioned between H2O and EtOAc and the EtOAc layer ~ removed wased several times with H2O, dried (MgS04) and concentrated to give a pale yellow oil. This was purified by column chromatography on Siθ2 using EtOAc as eluant. The product was isolated as a pale yellow oil and converted to the hydrochloride salt, 30mg mp 192-4°C. iH NMR (250MHz) (DMSO) (free base) δ :9.70(s,lH), 8.5(dd,lH), 8.12(dd,lH), 7.5(dt,2H), 4.4(t,2H), 2.68(t,2H), 3.28-2.49(m,4H), 1.30-1.55(m,6H). Example 19 (l-Butyl-3-pyιrτoUdinyl)methyl-4-amino-5-chloro-2- methoxybenzoate hydrochloride (E19) To a slurry of 4-amino-5-chloro-2-methoxy benzoic add (l.OOg) in acetonitrile (25 ml) was added bis carbonyl diimidazole (820 mg). The reaction mixture was stirred at ambient temperature for 2h. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with water. The organic phase was dried and filtered and concentrated in vacuo. Crystallisation from hexane/dichloromethane afforded the intermediate imidazoUde as a beige soUd (983 mg). To a solution of l-butyl-3-hyfiroxymethylpyrroHdine (Dl) (485 mg) in dry (THF (20 ml) was added n Buli (1.6M in hexane, 1.92 ml) at 0°C under a nitrogen atmosphere. Stirring was continued at ambient temperature for 30 min. The imidazoUde (776 mg) in THF (20 ml) was added to the reaction mixture and stirring continued for 20h. Water (1ml) was added and the solvent concentrated in vacuo. The residue was partitioned between chloroform and water. The organic phase was dried (NaS04) filtered and concentrated in vacuo to afford crude product. Flash chromatography on silica using chloroform and ethanol gave (l-butyl-3- pyrroUdinyl)methyl-4-aiLLino-5-chloro-2-methoxy benzoate, which was treated with ethereal HCl to afford the title compound (154 mg). mp 181-184°C. !H NMR (CD3OD) 400 MHz δ: 7.69 (IH, s), 6.47 (IH, s), 4.15-4.32 (4H, m), 3.81 (s, 3H), 3.50-3.59 (IH, m), 3.34-3.41 (2H, m), 3.11-3.16 (3H, m), 2.74-2.83 (IH, m), 2.23-2.34 (IH, m), 1.88-1.99 (IH, m), 1.66-1.75 (2H, m), 1.38-1.48 (2H, m), 0.98 (3H, t) MH+ 341 (C1+). Example 20 (l-Butyl-3-pyrroUdinylmethyl)-lH-indole-3-carboxylate hydrochloride (E20) To a slurry of indole-3-carboxyUc add (l.OOg) in dichloromethane (20 ml) was added oxalyl chloride (1.1 ml) and N,N'dimethyl formamide (2 drops). The reaction mixture was stirred at ambient temperature for 2h. The solvent was evaporated under reduced pressure to afford crude indole-3 carbonyl chloride (960 mg). To a solution of l-butyl-3-hydroxymethylpyrroUdine (Dl) (500 mg) in dry THF (20 ml) was added BuU (1.6M in hexanes, 1.99 ml) at 0°C under a nitrogen atmosphere. Stirring was continued at ambient temperature for 30 min. Indole-3-carbonylchloride (571 mg) in dry THF (10 ml) was added to the reaction mixture and stirring continued for 20h. Water (1 ml) was added to the reaction mixture and the solvent concentrated in vacuo. The residue was partitioned between chloroform and water. The organic phase was dried (NaSθ4), filtered and concentrated in vacuo to afford j crude product. Flash chromatography on siUca using chloroform and ethanol gave (l-butyl-3-pyrrolidinylmethyl)-lH-indole-3-carboxylate which was treated with ethereal HCl to afford title compound. m.p 59-62 0 C iH NMR (CD3OD) 270 MHz δ: 7.98-8.05 (m, 2H), 7.41-7.48 (m, IH), 7.15-7.26 (m, 2H), 4.28-4.47 (m, 2H), 3.51-3.93 (m, 2H), 3.42-3.56 (m, IH), 2.81-3.25 (m, 4H), 2.19-2.47 (m, IH), 1.82-2.16 (m, IH), 1.60-1.80 (m, 2H), 1.34-1.50 (m, 2H), 0.94-1.02 (m, 3H). M+ 300 Example 21 (l-Pentyl-3-pyrrolidinyl)ethyl 4-amino-5-chloro-2- methoxybenzoate hydrochloride (E21) Following the procedure outlined in Example 19, 3-hydroxymethyl-l- pentyl pyrrolidine (D2) (500 mg) gave the title compound (158 mg). iH NMR (dg-DMSO) 270 MHz δ: 7.58 (s, IH), 6.47 (s, IH), 4.05-4.22 (m, 2H), 3.74 (s, 3H), 3.58-3.70 (m, IH), 3.36-3.57 (m, IH), 3.21 (t, 2H), 2.87- 3.12 (m, 3H), 2.68-2.84 (q, IH), 2.28-2.45 (m, IH), 2.03-2.27 (m, IH), 1.51- 1.91 (m, 5H), 1.18-1.37 (m, 4H), 0.87 (t, 3H). M+ 368 (Free base) Example 22 (l-Pentyl-3-pyrroUdinyl)ethyl-lH-indole-3-carboxylate hydrochloride (E22) The title compound was prepared in a similar manner to the compound of Example 20. mp 48-51 0 C iH NMR (dg-DMSO) 270 MHz δ: 12.05 (bs, IH), 8.08 (d, IH), 7.96-8.03 (m, LH), 7.45-7.52 (m, LH), 7.14-7.22 (m, 2H), 4.20-4.33 (m, 2H), 3.42-3.72 (m, 3H), 3.23 (t, IH), 2.90-3.15 (m, 2H), 2.73 (q, IH), 2.35-2.82 (m, LH), 2.06-2.30 (m, IH), 1.49-1.98 (m, 4H), 1.29-1.47 (m, 4H), 0.88 (t, 3H). M+ 328 (Free base) Example 23 (Hexahydro-l-butyl-3-azepinyl-methyl)-4-amino-5-chloro-2- methoxy benzoate (E23) FoUowing the procedure outlined in Example 19, reaction of hexahydro 1- butyl-3-hydroxymethyl azepine (D3) (500 mg) gave the title compound, as a free base, (318 mg). mp 72-75°C iH NMR (CDC1 3 ) 250 MHz δ: 7.82 (s, LH), 6.29 (s, IH), 4.50 (bs, 2H), 3.96-4.18 (m, 2H), 3.84 (s, 3H), 2.83 (dd, LH), 2.61-2.75 (m, 2H), 2.43-2.60 (m, 3H), 2.05-2.20 (m, IH), 1.21-1.86 (m, 10H), 0.89 (t, 3H). Example 24 (Hexahydro- l-butyl-3-azepinylmethyl)- lH-indole-3-carboxylate hydrochloride (E24) Following the procedure outUned in Example 20, reaction of hexahydro- 1- butyl 3-hydroxymethyl azepine (D3) (500 mg) gave the title compound (155 mg). mp 75-78°C lH NMR (CDCl3) 250 MHz Free base δ: 9.45 (m, IH), 8.14-8.22 (m, IH), 7.95 (d, IH), 7.40-7.48 (m, IH), 7.22- 7.31 (m, 2H), 4.10-4.28 (m, 2H), 3.00 (dd, IH), 2.51-2.89 (m, 5H), 2.23-2.48 (m, IH), 1.40-1.94 (m, 8H), 1.18-1.33 (m, 2H), 0.82 (t, 3H). MH+ 329 Example 25 4-Amino-5-Chloro-2-methoxy-(l-butyl-3-piperidyl)ethyl-benzoate (E25) Following the procedure outlined in Example 19, reaction of l-butyl-3- piperidyl ethanol (D4) (lg) gave the title compound as a free base (1.41g). mp 102-104 O C iH NMR (CDC1 3 ) 250 MHz δ: 7.80 (s, IH), 6.28 (s, IH), 4.45 (s, 2H), 4.27 (t, 2H), 3.84 (s, 3H), 2.81-2.96 (m, 2H), 2.25-2.33 (m, 2H), 1.40-1.90 (m, HH), 1.22-1.48 (m, 2H), 0.92 (t, 3H). M+ 368 Example 26 (l-Butyl-3-piperidylethyl)-lH-indole-3-carboxylate hydrochloride (E26) FoUowing the procedure outlined in Example 21, reaction of l-butyl-3- piperidyl ethanol (D4) (500 mg) gave the title compound (205 mg). iH NMR (CDC1 3 ) 250 MHz Free base δ: 10.02 (s, IH), 8.13-8.20 (m, IH), 7.79-7.81 (m, IH), 7.32-7.44 (m, LH), 7.19-7.30 (m, 2H), 4.30-4.47 (m, 2H), 2.92-3.08 (m, 2H), 2.31-2.42 (m, 2H), 1.44-1.98 (m, 10H), 1.21-1.35 (m, 2H), 0.83-1.06 (m, 4H). M+ 328 Example 27 4-Amino-5-chloro-2-methoxy-(l-butyl-2-piperidylethyl)-benzoate (E27) FoUowing the procedure outlined in Example 19, reaction of 1-butyl 2- piperidyl ethanol (D5) (750 mg) gave the title compound (650 mg). mp 75-77°C iH NMR (CDCI3) 250 MHz δ: 7.81 (s, IH), 6.29 (s, IH), 4.48 (s, 2H), 4.19- 4.35 (m, 2H), 3.82 (s, 3H), 2.77-2.88 (m, IH), 2.22-2.70 (m, 4H), 1.99-2.13 (m, LH), 1.21-1.86 (m, HH), 0.90 (t, 3H). M+ 368 Example 28 4-Amino-5-chloro-2-methoxy-(l-butyl 3-piperidylmethyl)- benzoate hydrochloride (E28) Following the procedure outlined in Example 19, l-butyl-3-piperidyl methanol (D6) (500 mg) gave title compound (100 mg). mp 218-221 0 C lH NMR (CDCl 3 ) 250 MHz Free base δ: 7.81 (s, IH), 6.27 (s, IH), 4.46 (s, 2H), 4.00-4.19 (m, 2H), 3.84 (s, 3H), 2.84-3.06 (m, 2H), 2.29-2.38 (m, 2H), 2.01-2.18 (m, IH), 1.22-1.98 (m, HH), 0.91 (t, 3H). M+ 354 Example 29 (l-Butyl-3-piperidylmethyl) lH-indole-3-carboxylate hydrochloride (E29) Following the procedure outlined in Example 20, 1-butyl 3-piperidyl methanol (D6) (500 mg) gave pure title compound (36 mg). iH NMR (CDCI3) 250 MHz - Free base δ: 9.96 (s, IH), 8.17-8.21 (m, IH), 7.90-7.95 (m, IH), 7.36-7.44 (m, IH), 7.21-7.29 (m, 2H), 4.19 (d, 2H), 3.12-3.22 (m, IH), 2.95-3.04 (m, IH), 2.31- 2.45 (m, 2H), 2.10-2.30 (m, IH), 1.42-2.06 (m, 6H), 1.03-1.40 (m, 4H), 0.90 (t, 3H). MH+ 315 Example 30 4-Amino-5-chloro-2-methoxy- ( l-butyl-4-piperidyl)benzoate (E30) FoUowing the procedure outUned in Example 19, 1-butyl 4-piperidinol (D7) (500 mg) gave the title compound (150 mg). mp 83-85°C iH NMR (CDC1 3 ) 250 MHz δ: 7.80 (s, IH), 6.28 (s, IH), 4.94-5.05 (m, LH), 4.47 (s, 2H), 3.83 (s, 3H), 2.66-2.81 (m, 2H), 2.29-2.45 (m, 4H), 1.93-2.08 (m, 2H), 1.76-1.90 (m, 2H), 1.43-1.58 (m, 2H), 1.23-1.41 (m, 2H), 0.93 (t, 3H). M+ 340 Example 31 4-A^nino-5-chloro-2-methoxy-(l-butyl-l,2,5,6-tetrahydro- pyridylmethyDbenzoate (E31) FoUowing the procedure outUned in Example 19, 1-butyl (1,2,5,6) tetrahydropiperidyl-4-methanol (D7) (300 mg) gave pure title compound (220 mg). mp 75-77 0 C iH NMR (CDCI3) 250 MHz δ: 7.83 (s, IH), 6.28 (s, IH), 5.76 (s, LH), 4.63 (s, 2H), 4.48 (s, 2H), 3.81 (s, 3H), 3.00 (s, 2H), 2.61 (t, 2H), 2.36-2.56 (m, 2H), 2.25 (m, 2H), 1.46-2.09 (m, 2H), 1.28-1.41 (m, 2H), 0.93 (t, 3H). MH+ 353 Example 32 (l-Butyl-4-piperidyl)methyl-l-ethyl-lH-indole-3-carboxylate (E32) A suspension of 1-ethyl indole-3-carboxylic add (500 mg) in dichloromethane (50 ml) was treated with oxalyl chloride (0.635g, 0.005 mole) and two drops of dimethylformamide. The mixture was stirred at lOom temperature for 1V_* hours then the solvent was removed in vacuo to leave the add chloride. A solution of l-butyl-4-piperidinemethanol (513 mg, 0.003 mole) in dry THF (10 ml) under an atmosphere of nitrogen, was cooled in an ice bath. n-ButylUthium (1.88 ml of 1.6M solution in hexane) was added dropwise and the resulting solution stirred at 0°C for 15 minutes. The add chloride was dissolved in dry THF (20 ml) and the solution added dropwise to the solution of the Uthium alkoxide at 0°C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. The solvent was removed in vacuo and the residue partitioned between chloroform and water. The chloroform was separated, washed several times with water, dried and concentrated to give a pale brown gum which was converted to the hydrochloride salt, mp 158-9°C. iH NMR (250 MHz) (CDC1 3 ) (free base) δ: 8.10-8.19 (m, IH), 7.88 (s, IH), 7.2-7.38 (m, 3H), 4.20 (m, 4H), 2.92-3.03 (bd, 2H), 2.28-2.40 (m, 2H), 1.20-2.0 (m, 14H), 0.90 (t, 3H). Examples 33 and 34 The foUowing compounds were prepared from the corresponding indole carboxyUc add by the method described for Example 32. (l-Butyl-4-piperidyl)methyl-l-methyl-lH-indole-3-carboxylate (E33) mp 187-8°C (hydrochloride salt) iH NMR (250 MHz) (CDC1 3 ) (free base) δ: 8.10-8.19 (m, IH), 7.88 (s, IH), 7.2-7.38 (m, 3H), 4.20 (d, 2H), 3.82 (s, 3H), 2.82-2.98 (bd, 2H), 2.28-2.39 (m, 2H), 1.20-2.18 (m, HH), 0.90 (t, 3H). (l-Cyclohexylmethyl-4-piperidyl)methyl- 1-methyl- lH-indole-3- carboxylate (E34) mp 164-5°C (hydrochloride salt) iH NMR (250 MHz) (CDCI3) (free base) δ: 8.10-8.19 (m, LH), 7.80 (s, IH), 7.22-7.4 (m, 3H), 4.20 (d, 2H), 3.82 (s, 3H), 2.86-2.96 (bd, 2H), 2.12 (d, 2H), 0.80-1.98 (m, 18H). Example 35 (l-Butyl-3-azetidinyhnethyl)-4-amino-5-chloro-2-methoxybenzoate (E35) FoUowing the procedures outlined above, l-butyl-3-hydroxymethyl azetidine (D9) (500mg) gave the title compound (240mg). M+ 326 iH NMR 250MHz, CDCI3, δ:7.83 (s,LH), 6.28 (s,lH), 4.50 (bs,2H), 4.33 (d,2H), 3.84 (s,3H), 3.38-3.49 (m,2H), 2.81-3.00 (m,3H), 2.38-2.45 (m,2H), 1.26-1.37 (m,4H), 0.85-0.94 (m,3H) Example 36 (N-Butylpiperid-4-ylmethyl)-2-methylindole-3-carboxylate (E36) FoUowing the procedure outUned in Example 6 (except that methyllithium used in place of n-butyllithium), 2-methylindole-3- carboxylic add (Dl) (950mg) was converted to the title compound (134mg, 8%) mp 128-130 O C iH NMR (CHC1 3 ) 200MHz δ: 8.1-8.0 (m, IH), 7.38-6.9 (m, 4H), 4.22 (d, 2H), 3.05 (brd, 2H), 2.75 (s, 3H), 2.5-2.25 (m, 2H), 2.15-1.70 (m, 4H), 1.70-1.15 (m, 7H), 0.92 (t, 3H) Example 37 (N-Butylpiperid-4-ylmethyl)-2-chloro-l-methylindole-3-carboxylate hydrochloride (E37) Following the procedure outlined in GB 2125398A, Example A5, N- Butylpiperid-4-ylmethyl-l-methyl)indole-3-carboxylate (E33) (300mg) was converted to the title compound (65mg, 15%) mp 238-40°C iH NMR (CDCI3) 200MHz (free base) δ: 8.18-8.05 (m, IH), 7.33-7.20 (m, 3H), 4.24 (d, 2H), 3.77 (s, 3H), 3.05 (brd, 2H), 2.49-2.3 (m, 2H), 2.12-1.7 (m, 5H), 1.65-1.15 (m, 6H), 0.92 (t, 3H) Example 38 (N-Butylpiperid-4-ylmethyl)-2-methoxyindole-3-carboxylate hydrochloride (E38) FoUowing the procedure outUned in GB 2125398A Example A5, (N- butylpiperid-4-ylmethyl)indole-3-carboxylate (E6) (0.25g) was converted to the title compound (108mg, 36%) mp 168-170°C. iH NMR (CDC1 3 ) 250MHz (free base) δ: 7.95 (d, IH), 7.3-7.05 (m, 3H), 4.20 (d, 2H), 4.07 (s, 3H), 3.07 (brd, 2H), 2.49-2.36 (m, 2H), 2.09 (br t, 2H), 1.99-1.75 (m, 3H), 1.7-1.2 (m, 6H), 0.91 (t, 3H) Example 39 (N-Butylpiperid-4-ylmethyl)indole-3-carboxamide (E39) To a stirring solution of indole-3-carboxylic add (lg) in dichloromethane (20ml) at 0°C under nitrogen was added oxalyl chloride (0.81 ml) and dry di-methylformamide (3 drops). After 3 hours, the solvents were evaporated under reduced pressure. A portion of the residual add chloride (420mg) was dissolved in dichloromethane (12ml) and added dropwise to a solution of N-butylpiperid-4-ylmethylamine (400mg) in dichloromethane 12ml) foUowed by triethylamine (0.36ml). After stirring at ambient temperature overnight, the reaction mixture was washed with saturated NaHCθ3 and the organic phase was dried (Na2Sθ4). The solvent was evaporated under reduced pressure and the residue recrystaUised from ethylacetate to give the title compound (467mg, 64°C). iH NMR (CDCI3) 250MHz δ: 9.29 (br s, IH), 8.05-7.9 (m, IH), 7.81 (d, IH), 7.55-7.4 (m, IH), 7.39-7.2 (m, 2H), 6.28 (br s, LH), 3.39 (t, 2H), 3.0 (br d, 2H), 2.45-2.25 (m, 2H), 2.1- 1.1 (m, HH), 0.9 (t, 3H) Example 40 (N-Butylpiperid-4-ylmethyl)-2-methoxyindole-3-carboxamide hydrochloride (E40) Following the procedure outlined in GB 2125398A, Example A5, (N- Butylpiperid-4-ylmethyl)indole-3-carboxamide (E39) (220mg) was convered to the title compound (230mg, 86%). Mp 138-144°C iH NMR (CDC1 3 ) 250MHz (free base) δ 9.85 (br s, IH), 8.25 (d, IH), 7.4-7.0 (m, 3H), 6.78 (t, IH), 4.18 (s, 3H), 3.35 (t, 2H), 2.98 (br d, 2H), 2.45-2.25 (m, 2H), 1.95 (br t, 2H), 1.82-1.2 (m, 9H), 0.91 (t, 3H) Example 41 l-Piperidylethyl-2-methylindole-3-carboxylate hydrochloride (E41) Following the procedure outlined in Example 36, 2-methylindole-3- carboxylic add (490 mg) was converted to the title compound (76mg) mp 147-9 0 C. iH NMR (CDCI3) 200 MHz δ: 8.65(br s,lH), 8.15-8.00(m,lH), 7.35-7.00(m,3H), 4.49(t,2H), 2.82(t,2H), 2.68(s,3H), 2.6-2.45(m,4H), 1.7-1.35(m,6H). Example 42 4-Amino-3,5-dichloro-2-methoxy-(l-butyl-4-piperidyl)methyl benzoate (E42) The title compound was prepared from 4-amino-3,5-dichloro-2- methoxybenzoic add and l-butyl-4-piperidylmethanol by the method described in Example 2, except that MeLi was used in place of n BuLi. The product was isolated as the hydrochloride salt. mp 190-191°C Η NMR (200MHz) CDC1 3 (free base) δ: 7.72(s,lH), 4.9(bs,2H), 4.12(d,2H), 3.85(s,3H), 2.85-3.0(bd,2H), 2.2-2.34(m,2H), 1.2-2.00(m,HH), 0.90(t,3H). Further compounds of potential use in the invention which were prepared are as follows: R a l Ri R m.p. H Et O 2 1-piperidyl 175-177°C H n Pr 0 2 1-piperidyl 198-199°C H n Bu O 2 1-piperidyl 202-204°C MeO H O 2 1-piperidyl 142-144°C Cl H O 2 1-piperidyl 153.5- 154.5°C H H O 2 NHBz 233-235°C H H O 4 N(CH 3 ) 2 153-4°C H H O 2 N(CH 3 ) 2 108-9°C H H O 3 N(CH 3 ) 2 208-210°C H H O 2 N(Et) 2 156-7°C H H NH 2 N(CH 3 ) 2 194-5°C H H NH 2 N(Et) 2 97-98°C H Bz O 2 N(CH 3 ) 2 165-166°C H Bz 0 4 N(CH 3 ) 2 138-9°C 5-HT4 RECEPTOR ANTAGONIST ACTrVTTY 1) Guinea pig colon Male guinea-pigs, weighing 250-400g are used. Longitudinal muscle- myenteric plexus preparations, approximately 3cm long, are obtained from the distal colon region. These are suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% CO2 in O2 and maintained at 37°C. In aU experiments, the Krebs solution also contains methiothepin 10'^M and granisetron lO'^M to block effects at 5-HTχ, 5-HT2 and 5-HT3 receptors. After construction of a simple concentration-response curve with 5-HT, using 30s contact times and a 15ιmn dosing cycle, a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40- 70% maximumdO'^M approx). The tissue is then alternately dosed every 15min with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, όjmethylphenylpiperazinium (DMPP). After obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of a putative 5-HT4 receptor antagonist are then added to the bathing solution. The effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, PIC50 values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%. A compound which reduces the response to 5-HT but not to DMPP is believed to act as a 5-HT4 receptor antagonist. Compounds were generaUy active in the range of concentrations of the order of pIC50=6 or more, E4 and E7 showing particularly good activity. 2) Piglet Atria Compounds were tested in the piglet spontaneous beating screen (Naunyn-Schmiedeberg's Arch. Pharmacol 342, 619-622). pKβ (-logio Kg) value for the compounds were generaUy of the order of 6 or more, E6 and E16 showing particularly good activity. 3) Rat oesophagus Rat oesophageal tunica muscularis mucosae is set up according to Baxter et. al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991). The inner smooth muscle tube of the muscularis mucosae is isolated and mounted for isometric tension recording in oxygenated (95% 02/5% CO2) Tyrodes solution at 37°C. All experiments are performed in pargyline pre- treated preparations (lOOμM for 15 min followed by washout) and in the presence of cocaine (30μM). Relaxant responses to 5-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3μM). 4) 5-HT-induced motility in dog gastric pouch Compounds are tested for inhibition in the in vivo method described in "Stimulation of canine motility by BRL 24924, a new gastric prokinetic agent", Bermudez et al, J. Gastrointestinal Motility, 1990, 2(4), 281-286.

Claims: Claims 1. The use of a compound of formula (I) or a pharmaceuticaUy acceptable salt thereof; X-CO-Y-Z (I) wherein X, Y and Z are as defined in the specification, in the manufacture of a medicament for use as a 5-HT4 receptor antagonist. 2. The use according to daim 1 for use as a 5-HT4 antagonist in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders. 3. The use according to daim 2 for use in the treatment of LBS. 4. The use according to claim 2 for use in the treatment of gastro- oesophagal reflux disease and dyspepsia. 5. The use according to daim 2 for use in the treatment of atrial arrhythmias and stroke. 6. The use according to daim 2 for use in the treatment of anxiety. 7. The use according to daim 2 for use in the treatment of migraine. 8. The use of 2-piperidinoethyl LH-indole-3-carboxylate or any one of the compounds of the Examples, El to E42, in the manufacture of a medicament for use as a 5-HT4 receptor antagonist. 9. A compound selected from the compounds of Examples 1 to 42, or a pharmaceuticaUy acceptable salt thereof. 10. A pharmaceutical composition comprising a compound according to daim 9, and a pharmaceutically acceptable carrier.

Inventors: GASTER LARAMIE MARY, JOINER GRAHAM FRANCIS, KING FRANCIS DAVID, RAHMAN SHIRLEY KATHERINE, SANGER GARETH JOHN, GASTER, LARAMIE, MARY, JOINER, GRAHAM, FRANCIS, KING, FRANCIS, DAVID, RAHMAN, SHIRLEY, KATHERINE, SANGER, GARETH, JOHN
Applicants: SMITHKLINE BEECHAM PLC
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61P1, A61P9, A61P25, A61P43, C07D205, C07D207, C07D209, C07D211, C07D223, C07D295, C07D333, C07D401