AZABICYCLIC COMPOUNDS AS 5-HT4 RECEPTOR ANTAGONISTS

Abstract: Compounds of formula (I), wherein X is (a), (b), wherein L is N or CRc wherein Rc is hydrogen, alkoxy, halo, alkyl or cyano; Q is NR1, CH2, O or S; Ra is hydrogen, halo, alkyl, amino, nitro or alkoxy; Rb is hydrogen, halo, alkyl or alkoxy; R1 is hydrogen, alkyl, alkenyl, aralkyl, alkanoyl, or alkanoylalkyl; R2 is alkoxy; and R3 is hydrogen, chloro or fluoro; R4 is hydrogen, alkyl, amino optionally substituted by alkyl, halo, hydroxy or alkoxy; R5 is hydrogen, halo, alkyl, alkoxy, nitro, amino or alkylthio; R6 is hydrogen, halo, alkyl, alkoxy or amino; n is 0, 1, 2, 3 or 4; p and m are independently 0, 1 or 2; and Rq is hydrogen or alkyl. 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.

Description: AZABICYCLIC COMPOUNDS AS 5-HT4 RECEPTOR ANTAGONISTS This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals. GB 2125398A (Sandoz Limited) describes a group of bridged piperidinyl ester and amide derivatives having 5-HT3 receptor antagonist activity. GB 1593146 and EP-A-36269 (Beecham Group p.l.c.) describe groups of fused azabicyclic amide derivatives having gastric motility enhancing activity. A class of novel, structurally distinct compounds has now been discovered, which compounds are fused azabicyclic ester derivatives. These compounds have 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-hydro-_yt_7pt___αine 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 airhythmias and stroke. Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof (I) wherein X is of sub-formula (a) or (b): (a) (b) wwhheerreeiinn L is N or CR C wwhheerreeiinn RR cc iiss hhyyddrrooggeenn,, CCjj..gg aallkkooxxyy,, hhaalloo,, CCιι__gg aallkkyyll or cyano; Q is NRi, CH2, O or S; Ra is hydrogen, halo, C^.g alkyl, amino, nitro or C]_g alkoxy; Rtø is hydrogen, halo, Cj.g alkyl or Cι_g alkoxy; Ri is hydrogen, Cι_ιo alkyl, C2-6 alkenyl, aralkyl, C2-6 alkanoyl, or C2-6 alkanoyl C1.3 alkyl; R2 is C]_6 alkoxy; and R3 is hydrogen, chloro or fluoro; R4 is hydrogen, C;χ_g alkyl, amino optionally substituted by a Cι_g alkyl group, halo, hydroxy or Cι_g alkoxy; R5 is hydrogen, halo, Cχ.g alkyl, C]_g alkoxy, nitro, amino or Cι_g alkylthio; Rg is hydrogen, halo, C]_g alkyl, Cχ_g alkoxy or amino; nis O, 1, 2, 3 or ; p and are independently 0, 1 or 2; and Rq is hydrogen or Cj.g alkyl. Examples of alkyl or alkyl containing groups include C]_, C2, C3, C4, C5, Cg, C7, Cg, C9 or C10 branched, straight chained or cyclic alkyl, as appropriate. C]_ alkyl groups include methyl, ethyl n- and iso-propyl, /_-, iso-, sec- and tort-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 two substituents selected from halo, Cι_g alkoxy and Cι_g alkyl. Halo includes fluoro, chloro, bromo and iodo. L in formula (a) is preferably CH, C-CH3, C-Cl or COCH3. Q in formula (a) is preferably N i and Rj is preferably hydrogen or a methyl or ethyl group. R a is often hydrogen and Rb is often hydrogen or iodo. R2 is preferably methoxy. R4 is preferably amino. R5 when halo is selected from fluoro, chloro, bromo and iodo, preferably chloro. Suitable values for p and m include p = m = 1; p = 0, m = 1; p = 1, m = 2; p = 2, m = 1. Rq is often hydrogen. Preferably X-COO-(CH2) n - is attached such that the number of carbon atoms between the ester linkage and the azabicyclic nitrogen atom is from 2 to 4 carbon atoms. Specific values of the azabicycle which are of particular interest are as follows: (i) (ϋ) (iii) Other azacycles of interest are as described with reference to the Examples 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, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric, a-glycerophosphoric, and glucose- 1-phosphoric acids. Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such, as the compounds quatemised by compounds Rχ-T wherein Rx is Cχ.g alkyl, phenyl-Cι_g alkyl or C5.7 cycloalkyl, and T is a radical corresponding 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 include halide such as chloride, bromide and iodide. Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides. The compounds of the formula (I), their pharmaceutically acceptable salts, (including 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. Some of the compounds of formula (I) have at least one asymmetric centre and exist as more than one stereoisomeric form. The invention extends to each of these forms and to mixtures thereof including racemates. It will also be realised that X-COO-(CH2) n - i compounds of formula (I) may adopt an α or β or configuration with respect to the fused azabicyclic moiety. The compounds of formula (I) are prepared by linking together X-CO2H or a reactive derivative thereof and the (azabicyclic side chain)-(CH2)_r moiety, usually by a conventional ester coupling with the -(CH2) n -OH derivative as described in the aforementioned patent publication reference in the name of Sandoz Limited. The azabicyclic side chain (CH2) n -C-_ intermediates are known compounds or may be prepared from the ketones of formula (II): (II) according to conventional methods, such as those described in the Descriptions hereinafter. Ketones of the formula (II) are known or are prepared by analogous methods to those used for preparing structurally related known compounds. 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 (IBS), in particular the diarrhoea aspects of IBS, i.e., these compounds block the ability of 5-HT to stimulate gut motility via activation of enteric neurones. In animal models of IBS, 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 associated with IBS. They may also be of potential use in other gastrointestinal disorders, such as those associated 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 associated 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 associated 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 associated with atrial fibrillation. Anxioly-ic 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 social 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 believed 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 pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Such compositions are prepared by admixture and are usually adapted for enteral such as oral.nasal or rectal, or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositories, 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 excipients 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 include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone 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 lecithin, sorbitan monooleate, or acacia; 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 acid, 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 maybe 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 vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention. The invention further provides a method of treatment of irritable bowel syndrome, gastro-oesophagal reflux disease, dyspepsia, atrial arrhythmias 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. In particular, the method comprises treatment of IBS or atrial arrhythmias and stroke. An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, 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 of the invention. 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, in particular IBS or atrial airhytlimias and stroke. The invention also provides the use of a compound of formula (I) in the manufacture of a medicament for use as a 5-HT4 receptor antagonist in the treatment of irritable bowel syndrome, gastro-oesophagal reflux disease, dyspepsia, atrial _uτhythmias and stroke, anxiety and/or migraine, in particular, IBS or atrial arrhythmias and stroke. The following Examples illustrate the preparation of compounds of formula (I); the following Descriptions illustrate the preparation of intermediates. Examples X- COO - (CH^ Λ/ SΛ^^-^- Example X n attach- isomer(s) El al(H) 1 1 3 α,β E2 a!(H) 2 1 3 α,β E3 al(H) 0 1 3 α,β E4 al(H) 0 1 4 α,β E5 a!(H) 1 0 3 α,β E6 al(H) 2 0 3 α,β E7 1 1 3 α,β E8 bl 1 1 3 α,β Examples (cont'd.) Example X n p attach. isomer(s) E9 a!(H) 1 1 4 α,β E10 al(H) 2 1 4 β Ell a!(H) 0 1 5 α,β E12 al(H) 1 1 5 α,β E13 a!(H) 0 0 4 α,β E14 al(H) 1 0 4 α,β E15 a!(Me) 1 1 4 β E16 a Et) 1 1 4 β E17 a!( n Pr) 1 1 4 β E18 a^Pr) 1 1 4 β E19 al(allyl) 1 1 4 β E20 a!(iBu) 1 1 4 β E21 a!(Me) 1 0 3 α,β E22 a!(Et) 1 0 3 α,β cpm = cyclopropylmethyl chm = cyclohexylmethyl * = N-methyl iodide quaternary salt Example 1 S-ax- and 3-_ -Quinolizidin-3-ylmethylindole-3-carboxylate (Ela and Elb) A suspension of indole-3-carboxylic acid (400 mg, 0.0025 mole) in dichloromethane (25 ml) was treated with oxalyl chloride (0.24 ml, 0.0028 mole) plus 2 drops of DMF and stirred at room temperature for 2 hours, then concentrated in υacuo to give the acid chloride as a yellow solid. A solution of 3-hydroxymethylquinolizidine (H. Lewis and C. Shoppee J.C.S., 1956, 313) (mixture of isomers) (435 mg, 0.0025 mole) in THF (10 ml) at 5°C under nitrogen was treated with 1.6M n-butyllithium in hexane (1.56 ml, 0.0025 ml), stirred for 10 minutes, then treated with a solution of the above acid chloride in THF (5 ml). After 2 hours at room temperature, the mixture was treated with saturated NaHCθ3 solution (20 ml) and extracted with ethyl acetate (2 x 30 ml). The combined extracts were dried (Na2S04), concentrated in υacuo and the residue chromatographed on silica gel. The faster running component was obtained by elution with ethyl acetate and afforded the axial isomer (Ela) as a white solid mp 157-158°C. lH NMR (CDCl 3 ) δ: 1.20-2.28 (m, 14H), 2.68-2.79 (m, IH), 2.85-2.96 (m, IH), 4.45-4.60 (m, 2H), 7.21-7.30 (m, 2H), 7.37-7.45 (m, IH), 7.91 (d, IH), 8.13-8.20 (m, IH), 9.40 (br.s, IH). MS (El) M+ 312. Elution with ethyl acetate:methanol (9:1) afforded the equatorial isomer (Elb) as a white solid mp 187-188°C. !H _S V_R (CDC_3) δ: 1.07-1.50 (m, 4H), 1.53-2.15 (m, 9H), 2.15-2.37 (m, IH), 2.82-2.93 (m, IH), 3.07-3.17 (m, IH), 4.18 (d, 2H), 7.22-7.30 (m, 2H), 7.40-7.50 (m, IH), 7.90 (d, IH), 8.15-8.23 (m, IH), 9.65 (br.s, IH). MS (EI) M+ 312. Example 2 3-ax- and 3-_ςr-QuinoUzidin-3-ylethylindole-3-carboxylate (E2a and E2b) The title compounds were prepared from 3-(2-hydroxyethyl)quinoUzidine (Dl) (mixture of isomers) and indole-3-carboxylic acid chloride using the method of Example 1. The isomers were separated by chromatography on silica gel eluting with ethyl acetate. Pooling of the fractions containing the faster running component afforded the axial isomer (E2a) as a colourless oil, which was converted to its hydrochloride salt mp 207-209°C (acetone). Free base:- 1-H NMR (CDCI3) δ: 1.15-1.80 (m, 11H), 1.85-2.25 (m, 5H), 2.65-2.80 (m, 2H), 4.36 (t, 2H, J=7Hz), 7.20-7.30 (m, 2H), 7.35-7.45 (m, IH), 7.87 (d, IH), 8.10-8.18 (m, IH), 9.30 (br.s, IH). MS (CD MH+ 327. Fractions containing the lower running component afforded the equatorial isomer (E2b) as a colourless oil, which was converted to its hydrochloride salt mp. 224-225°C (acetone). Free base:- !H NMR (CDCI3) δ: 0.90-1.45 (m, 5H), 1.45-2.12 (m, 11H), 2.78-2.98 (m, 2H), 4.35 (t, 2H, J=7Hz), 7.15-7.25 (m, 2H), 7.32-7.42 (m, IH), 7.68 (d, IH), 8.10-8.18 (m, IH) and 10.0 (br.s, IH). MS (CD MH+ 327. Example 3 3-ax- and 3-e -Quino_izidin-3-ylindole-3-carboxylate (E3a and E3b) 3-Hydroxyquinolizidine (C. Rader et al., J.Org. Chem., 1964, 22, 2252) (mixture of isomers) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ether. The faster running component proved to be the axial isomer (E3a), obtained as a white solid mp 202-204°C. iH NMR ^DCls) δ: 1.20-2.60 (m, 13H), 2.86-3.00 (m, IH), 3.33-3.45 (m, IH), 5.21 (br.s, IH), 6.94-7.10 (m, 2H), 7.16-7.25 (m, IH), 7.52 (d, IH), 7.82-7.90 (m, IH) and 11.35 (br.s, IH). MS (CI) MH+ 299. The slower running component was the equatorial isomer (E3b) obtained as a beige solid mp 199-202°C (ethyl acetate petrol). iH J πVDKCDCls) δ: 1.19-1.40 (m, 2H), 1.40-2.33 (m, 11H), 2.82-2.93 (m, IH), 3.16-3.27 (m, IH), 5.10-5.24 (m, IH), 7.20-7.30 (m, 2H), 7.38-7.46 (m, IH), 7.93 (d, IH), 8.10-8.18 (m, IH), 8.95 (br.s, IH). MS (CD MH+ 299. Example 4 2-ax- and 2-eςr-Quinolizidin-2-ylindole-3-carboxylate (E4a and E4b) 2-Hydroxyquinolizidine (C. Rader et al., J.Org. Chem., 1964, 29_, 2252) (mixture of isomers) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The yellow oil obtained was treated with ether and the equatorial isomer (E4b) precipitated out as a white solid mp 215-216 0 C (ethyl acetate petrol). lH NMR (d6 DMSO) δ: 1.18-2.23 (m, 13H), 2.80-2.95 (m, 2H), 4.84-5.00 (m, IH), 7.22-7.35 (m, 2H), 7.53-7.60 (m, IH), 8.04-8.10 (m, IH), 8.15 (s, IH), 12.0 (br.s, IH). MS (El) M+ 298. The material contained in the filtrate was chromatographed on silica gel eluting with ethyl acetate and the fractions containing the slower running product afforded the axial isomer (E4a) as a white solid mp 67-72°C. iHNMR δ: 1.20-1.43 (m, 2H), 1.48-1.85 (m, 5H), 1.90-2.40 (m, 5H), 2.52-2.67 (m, IH), 2.71-2.83 (m, IH), 2.87-2.98 (m, IH), 5.35-5.43 (m, IH), 7.23-7.37 (m, 2H), 7.39-7.48 (m, IH), 7.96 (d, IH), 8.18-8.27 (m, IH), 8.97 (br.s, IH). MS (El) M+ 298. Example 5 ci_-2,9-H- and frατι_ -2,9-H-Indolizidin-2-ylmethyIindole-3- carboxylate (E5a and E5b) 2-Hydroxymethylindolizidine (PL Winterfield et al., Arch, pharm., 1958, 291. 485) (mixture of isomers) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The isomers were separated by chromatography on silica gel eluting with ethyl acetate:methanol (98:2). The faster running component gave the cis isomer E5a as a colourless oil and converted to its hydrochloride salt mp 191-194°C (acetone). HCl salt:- !H NMR (d^DMSO) ' δ: 1.30-2.10 (m, 7H), 2.28-2.45 (m, IH), 2.74-2.96 (m, 2H), 3.04-3.25 (m, 2H), 3.35-3.56 (m, 2H), 4.34 (d, 2H), 7.14-7.26 (m, 2H), 7.45-7.55 (m, IH), 7.90-8.00 (m, IH), 8.18 (d, IH), 10.95 (br.s, IH) and 12.10 (br.s, IH). MS (El) M+ 298. The slower nuining component gave the trans isomer E5b as a colourless oil and converted to its hydrochloride salt, mp 199-201°C (acetone). HCl salt:- *H NMR (d 6 DMSO) δ: 1.32-1.50 (m, IH), 1.55-2.15 (m, 8H), 2.75-2.95 (m, 2H), 3.10-3.27 (m, IH), 3.45-3.54 (m, IH), 3.60-3.70 (m, IH), 4.18-4.37 (m, 2H), 7.17-7.24 (m, 2H), 7.47-7.54 (m, IH), 7.92-7.99 (m, IH), 8.14 (d, IH), 10.95 (br.s, IH) and 12.15 (br.s, IH). MS (El) M+ 298. Example 6 cis -2,9-H- and frαns -2,9-H-Indolizidin-2-ylethylindole-3- carboxylate (E6) A mixture of the title compounds was prepared from 2-(2- hydroxyethyDindolizidine (K. Winterfield et al., Arch. Pharm., 1958, 291. 485) (mixture of isomers) and indole-3-carboxylic add chloride using the method of Example 1. The material was chromatographed on silica gel eluting with ethyl acetate:methanol (19:1), but the isomers were not separated. The colourless oil was converted to its hydrochloride salt, which proved to be a hygroscopic white solid mp 45-50°C. *H NMR showed a 3:2 mixture of isomers. Free base:- *H NMR (CDCI3) δ: 1.10-1.35 and 1.45-2.45 (each m, together 14H), 2.85-2.95 (dd, IH major isomer), 3.02-3.17 (m, IH), 3.26-3.35 (m, IH minor isomer), 4.33 (t, 2H), 7.20-7.30 (m, 2H), 7.37-7.45 (m, IH), 7.87 (d, IH minor isomer), 7.90 (d, IH major isomer), 8.12-8.23 (m, IH) and 9.60 (br.s, IH). MS (El) M+ 312. Example 7 S-ax- and 3-€g-Quinolizidin-3-ylmethyl-l-methylindazole-3- carboxylate (E7a and E7b) The title compounds were prepared from 3-hydroxymethylquinolizidine (H. Lewis and C. Shoppee J.Chem. Soc, 1956, 313) (mixture of isomers) and l-methylindazole-3-carboxylic add chloride using the method of Example 1. The isomers were separated by chromatography on silica gel eluting with ethyl acetate. Fractions containing the faster running component afforded the axial isomer (E7a) as a colourless oil, which was converted to its hydrochloride salt mp 238-239°C (acetone). Free base:- *H NMR (CDCI3) δ: 1.19-1.35 (m, 2H), 1.38-2.03 (m, 10H), 2.16-2.32 (m, 2H), 2.65-2.75 (m, IH), 2.80-2.90 (m, IH), 4.18 (s, 3H), 4.62-4.75 (m, 2H), 7.29-7.37 (m, IH), 7.43-7.49 (m, 2H), 8.19 (d, IH). MS (CD MH+ 328. Fractions containing the lower running component afforded the equatorial isomer (E7b) as a colourless oil, which was converted to its hydrochloride salt mp 199-201°C (acetone). HCl salt:- *H NMR (d^DMSO) δ: 1.30-1.95 (m, 11H), 2.73-3.05 (m, 3H), 3.25-3.42 (m, 2H), 4.18 (s, 3H), 4.22-4.35 (m, 2H), 7.33-7.42 (m, IH), 7.48-7.57 (m, IH), 7.80 (d, IH), 8.06 (d, IH), 10.9 (br.s, IH). MS (CI) MH+ 328. Example 8 3-ax- and 3-e -Quinolizidin-3-ylmethyl-4-amino-5-chloro-2- methoxybenzoate (E8a and E8b) A solution of 4-amino-5-chloro-2-methoxybenzoic add (500 mg, 0.0025 mole) in acetonitrile (30 ml) was treated with N,N-carbonyldiimidazole (400 mg, 0.0025 mole) and stirred at room temperature under nitrogen for 3 hours, then concentrated in υacuo to give a yellow oil containing the imidazolide. A solution of 3-hydroxymethylquinolizidine (H. Lewis and C. Shoppee J.Chem. Soc, 1956, 313) (mixture of isomers) (425 mg, 0.0025 mole) in THF (20 ml) at 5°C under nitrogen was treated with 1.6M n- butyllithium in hexane (1.6 ml, 0.0025 mole), stirred for 10 minutes, then treated with the above imidazolide. After 16 hours at room temperature, the mixture was treated with 10% Na2C03 solution (20 ml) and extracted with ethyl acetate (2 x 30 ml). The combined extracts were dried (Na2S04), concentrated in υacuo and the residue chromatographed on silica gel eluting with ethyl acetate:ether (1:1). Fractions containing the faster running component afforded the axial isomer (E8a) as a white solid mp 158-161°C. lH NMR (CDC_3+D 2 0) δ: 1.18-2.00 (m, 12H), 2.05-2.22 (m, 2H), 2.65-2.85 (m, 2H), 3.84 (s, 3H), 4.38-4.50 (m, 2H), 4.80 (br.s, 2H), 6.30 (s, IH), 7.83 (s, IH). MS (CD MH+ 353. Fractions containing the lower running component afforded the equatorial isomer (E8b) as a white solid mp 92-96°C. H NMR (CDC1 3 ) δ: 1.10-1.55 (m, 4H), 1.65-2.35 (m, 10H), 2.90-3.00 (m, IH), 3.05-3.15 (m, IH), 3.94 (s, 3H), 4.05-4.28 (m, 2H), 4.55 (br.s, 2H), 6.38 (s, IH), 7.90 (s, IH). Example 9 a) α»-QιιinoIizidin-2-y_methylindole-3-carboxyla_e (E9a) The title compound was prepared from _cc-2-hydroxymethylquinohzidine (D4) and indole-3-carboxyHc add chloride using the method of Example 1. The product was purified by chromatography on neutral alumina eluting with ethyl acetate, followed by crystallisation from ether/pentane, to give the title compound (E9a) as a white solid mp 156-157°C. lH NMR (CDCl 3 ) δ: 9.40 (br.s, IH), 8.10-8.20 (m,lH), 7.93 (d, IH), 7.37-7.45 (m,lH), 7.22- 7.33 (m,2H), 4.35-4.50 (m,2H), 2.77-2.93 (m,lH), 2.63-2.75 (m,lH), 2.23- 2.43 (m,2H), 1.43-2.20 (m,10H), 1.17-1.40 (m,2H). MS (El) M+ 312. b) eg-Quinolizidin-2-ylmethylindole-3-carboxylate (E9b) The title compound was prepared from eg-2-hydroxyιnethylquinolizidine (N.J. Leonard et al, J. Org. Chem., 1957, 22, 1445) andindole-3-carboxylic add cWoride using the method of Example 1. The yellow oil obtained was crystallised from ether to afford the title compound (E9b) as a beige solid mp 154-157 0 C. lHNMR (CDCl 3 ) δ: 9.40 (br.s,lH), 8.10-8.20 (m,lH), 7.87 (d,lH), 7.35-7.45 (m,lH), 7.20- 7.30 (m,2H), 4.20 (d,2H), 2.80-2.97 (m,2H), 1.43-2.20 (m,HH), 1.10-1.40 (m,3H). MS (El) M+ 312. Example 10 e _ -QuinoH-ridin-2-ylethyHndole-3-carboxylate (E 10) e -2-(2-Hydroxyethyl)quinolizidine (D5) was reacted with indole-3- carboxylic add chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate/methanol (95:5). The resulting beige solid was recrystallised from ethyl acetate/petrol (60- 80) to afford the title compound (E10) as a white solid mp 170-172°C. lH NMR (CDCl 3 ) δ: 9.15 (br.s.lH), 8.12-8.22 (m,lH), 7.91 (d,lH), 7.36-7.45 (m,lH), 7.20- 7.30 (m,2H), 4.38 (t,2H), 2.80-2.92 (m,2H), 1.93-2.17 (m,3H), 1.20-1.83 (m,12H), 1.00-1.18 (m,lH). MS (El) M+ 326. Example 11 a) e^-Quinolizidin-l-ylindole-3-carboxylate (Ella) eg-1-Hydroxyquinolizidine (H.S. Aaron et al, J. Org. Chem. 1964, 22, 2248) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ether to afford the title compound (Ella) as a white solid, mp 230- 232 0 C. iH NMR CCDC ) δ: 8.88 (br.s.lH), 8.11-8.20 (m,lH), 7.93 (d,lH), 7.38-7.46 (m,lH), 7.22- 7.32 (m,2H), 4.80-4.94 (m,lH), 2.75-2.98 (m,2H), 1.92-2.32 (m,5H), 1.38- 1.88 (m,6H), 1.15-1.35 (m,2H). MS (CD MH+ 299. b) α-c-Quinolizidin-l-ylindole-3-carboxylate (Ellb) σ -1-Hydroxyquinolizidine (H.S. Aaron et al, J. Org. Chem., 1964, 2, 2248) was reacted with indole-3-carboxylic add chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ether, followed by trituration with ether, to afford the title compound (Ellb) as a white solid mp 80-85°C. iH NMR ^DC-s) δ: 9.75 (br.s, IH), 8.27-8.36 (m,lH), 7.83 (d,lH), 7.17-7.45 (m,3H), 5.20 (s,lH), 2.90-3.05 (m,2H), 1.15-2.30 (m,13H). MS (El) MH+ 299. Example 12 o_r-and eqr-Quinolizidin-l-ylmethylindole-3-carboxylate (E12a and E12b) 1-Hyd-roxymethylquinolizidine (G.R. Clemo et al, J. Chem. Soc, 1937, 965 and 1938, 1574) (mixture of isomers) was reacted with indole-3-carboxylic add chloride using the method of Example 1. The isomers were separated by chromatography on silica gel eluting with ethyl acetate/methanol (97:3). Fractions cont ning the faster running component afforded the axial isomer (E12a) as a white solid mp 173-177°C. iHNMR O∑DCls) δ: 9.75 (br.s, IH), 8.12-8.23 (m,lH), 7.92 (s,lH), 7.36-7.47 (m,lH), 7.20- 7.32 (m,2H), 4.60-4.72 (m,lH), 4.40-4.53 (m,lH), 2.80-2.95 (m,2H), 1.15- 2.25 (m,14H). MS (El) M+ 312. Combining fractions containing the slower running component gave the equatorial isomer (El2b) as a white solid mp 55-60°C. lH NMR (CDC1 3 ) δ: 10.35 (br.s.lH), 8.15-8.25 (m,lH), 7.94 (d,lH), 7.37-7.47 (m,lH), 7.22- 7.32 (m,2H), 4.22-4.43 (m,2H), 2.83-2.97 (m,2H), 1.50-2.20 (m,HH), 1.20- 1.46 (m,3H). MS (CD MH+ 313. Example 13 cis- 1,9-H- and trans- l,9-H-Indolizidin-l-ylindole-3-carboxylate (E13a and E13b) 1-Hydroxyindolizidine (H.S. Aaron, J. Org. Chem., 1966, 31, 3502) (mixture of isomers) was reacted with indole-3-carboxylic add chloride using the method of Example 1. The isomers were separated by chromatography on silica gel eluting with ether. The faster runing component was obtained as a white solid mp 169-170°C. lH NMR (CDCl 3 ) δ: 8.85 (br.s,lH), 8.10-8.20 (m,lH), 7.95 (d,lH), 7.39-7.50 (m,lH), 7.20- 7.35 (m,2H), 5.05-5.20 (m,lH), 3.00-3.20 (m,2H), 1.20-2.65 (m,HH). MS (CD MH+ 285. The slower running component was obtained as a white solid mp 179- 181°C. IH NMR (CDCI3) δ: 10.70 (br.s,lH), 8.20-8.35 (m,lH), 8.10 (br.s,lH), 7.35-7.45 (m,lH), 7.20- 7.33 (m,2H), 5.63-5.75 (m,lH), 3.25-3.50 (m,2H), 2.35-2.50 (m,lH), 1.50- 2.30 (m,9H), 1.20-1.45 (m,lH). MS (CD MH+ 285. Example 14 cι_r-l,9-H-Indolizi_in-l-ylmethylindole-3-carboxylate (E14a) ci_-l,9-H-l-Hydro_grmethylindoHzidine (D6a) was reacted with indole-3- carboxylic add chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate/methanol (19:1) to afford a colourless oil, which was crystallised from ether to give E14a as a white solid mp 140-141<>C. lH NMR (CDCl 3 ) δ: 9.00 (br.s,lH), 8.15-8.25 (m,lH), 7.90 (d,lH), 7.37-7.45 (m,lH), 7.20- 7.30 (m,2H), 4.40-4.50 (dd,lH), 4.08-4.20 (dd,lH), 3.00-3.20 (m,2H), 2.50- 2.68 (m,lH), 1.35-2.15 (m,10H), 1.10-1.30 (m,lH). MS (El) M+ 298. fr τι_f-l,9-H-Indolizidin-l-ylmethylindole-3-carboxylate (E14b) ^rans-l,9-H-l-HydroxymethylindoKzidine (D6b) was reacted with indole- 3-carboxylic add chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate/methanol (19:1) followed by crystallisation from ether to afford the title compound (E14b) as a white solid mp 116-118°C. lH NMR (CDCl ) δ: 9.30 (br.s,lH), 8.12-8.23 (m,lH), 7.90 (d,lH), 7.37-7.47 (m,lH), 7.22- 7.33 (m,2H), 4.28-4.40 (m,2H), 3.05-3.18 (m,2H), 1.95-2.35 (m,5H), 1.47- 1.85 (m,5H), 1.13-1.43 (m,2H). MS (El) M+ 298. Example 15 eqr-Quinolizidin-2-ylmethyl-l-methylindole-3-carboxylate (E15) e<7-2-Hydroxymethylquinoli-adine (N.J. Leonard et al, J. Org. Chem., 1957, 22, 1445) was reacted with the add chloride of l-methylindole-3- carboxylic add using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate. The resulting pale yellow oil was crystallised from n-pentane to afford the title compound (E15) as a white ciyst-dline solid mp 115-116°C. lH NMR (CDCl 3 ) δ: 8.12-8.20 (m,lH), 7.80 (s,lH), 7.23-7.38 (m,3H), 4.18 (d,2H), 3.84 (s,3H), 2.80-2.93 (m,2H), 1.42-2.15 (m,HH), 1.08-1.35 (m,3H). MS (El) M+ 326. Example 16 ec/-Quinolizidin-2-ylmethyl-l-ethylindole-3-carbox la-e (E16) e^-2-HydroxymethylquinoKzidine (N.J. Leonard et al, J. Org. Chem., 1957, 2, 1445) was reacted with the add chloride of l-ethylindole-3- carboxylic add using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (E16) as a pale yellow oil. This was converted to its hydrochloride salt mp 168-172°C. lH NMR (HCl salt) (CDC1 3 ) δ: 12.10 (br.s.lH), 8.14 (s,lH), 8.07-8.18 (m,lH), 7.35-7.43 (m,lH), 7.23- 7.32 (m,2H), 4.18-4.28 (d,2H and q,2H), 3.38-3.55 (m,2H), 2.30-2.83 (m,5H), 2.00-2.22 (m,3H), 1.75-2.00 (m,5H), 1.55 (t,3H), 1.35-1.60 (m,lH). MS (El) M+ 340. Example 17 eςr- uinoli_ din-2-ylnιethyl-l-n ropylindole-3-carboxylate O-17) e -2-Hydroxymethylquinolizid_ne (N. J. Leonard et al, J. Org. Chem, 1957, 22. 1445) was reacted with the add chloride of l-n-propylindole-3- carboxylic add using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate. The resulting yellow oil was crystallised fromn-pentane to afford the title compound (E17) as a white solid mp 75-76°C. lH NMR (CDCl ) δ: 8.12-8.20 (m,lH), 7.84 (s,lH), 7.33-7.42 (m,lH), 7.23-7.32 (m,2H), 4.18 (d,2H), 4.10 (t,2H), 2.80-2.95 (m,2H), 1.42-2.15 (m,13H), 1.06-1.36 (m,3H), 0.95 (t,3H). MS (El) M+ 354. Example 18 e -Quinolizidin-2-ylmethyl-l-isopropylindole-3-carboxylate (E18) A solution of eg-quinolizidin-2-ylmethy__ndole-3-carboxylate (E9b) (320 mg, 1.08 mmole) in dry THF (15 ml) at room temperature under nitrogen was treated with potassium t-butoxide (125 mg, 1.1 mmole) and stirred for 20 minutes. The solution was then treated with 2-iodopropane (0.11 ml, 1.1 mmole) and stirred for 18h. The reaction mixture was treated with 10% Na2Cθ3 solution (25 ml) and extracted with ethyl acetate (2x50 ml). The combined extracts were dried (Na2Sθ4), concentrated in υacuo and the residue chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E18) as a colourless oil (240 mg, 63%). This was converted to the hydrochloride salt mp 235- 238°C (acetone). !H NMR (HCl salt) (d6DMSO) δ: 10.60 (br.s,lH), 8.32 (s,lH), 8.00-8.05 (m,lH), 7.62-7.67 (m,lH), 7.20- 7.30 (m,2H), 4.84 (septet,lH), 4.15 (d,2H), 3.25-3.40 (m,2H), 2.77-3.12 (m,3H), 2.05-2.18 (m,lH), 1.70-1.95 (m,7H), 1.55-1.70 (m,2H), 1.53 (d,6H), 1.40-1.52 (m,lH). MS (El) + 354. Example 19 eqr-Quinolizidin-2-ylmethyl- l-allylindole-3-carboxylate (E 19) eg-Quinolizidin-2-ylmethylindole-3-carboxylate (E9b) was alkylated with allyl iodide using the method in Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E19) as a colourless oil. This was converted to its hydrochloride salt mp 190-192°C (acetone) H NMR (HCl salt) (d β DMSO) δ: 10.45 (br.s,lH), 8.26 (s,lH), 7.98-8.05 (m,lH), 7.52-7.57 (m,lH), 7.20- 7.28 (m,2H), 5.98-6.10 (m,lH), 5.20 (d,lH,J=10Hz), 5.10 (d,lH,J=16Hz), 4.93 (d,2H,J=6Hz), 4.14 (d,2H), 3.25-3.38 (m,2H), 2.77-3.13 (m,3H), 2.04- 2.17 (m,lH), 1.70-1.95 (m,7H), 1.37-1.68 (m,3H). MS (El) M+ 352. Example 20 βςr-Quinolizidin-2-ylmethyl-l-isobutylindole-3-carboxylate (E20) e -Quinolizidin-2-ylmethylindole-3-carboxylate (E9b) was alkylated with l-bromo-2-methylpropane using the method in Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E20) as a colourless oil. This was converted to its hydrochloride salt mp 174-175°C (acetone/ether). iH NMR (HCl salt) (d 6 DMSO) δ: 10.55 (br.s,lH), 8.28 (s,lH), 7.98-8.04 (m,lH), 7.58-7.63 (m,lH), 7.20- 7.28 (m,2H), 4.13 (d,2H), 4.08 (d,2H), 3.25-3.40 (m,2H), 2.78-3.13 (m,3H), 2.05-2.23 (m,2H), 1.70-1.95 (m,7H), 1.52-1.70 (m,2H), 1.38-1.50 (m,lH), 0.85 (d,6H). MS (El) M+ 368. Example 21 cιβ-2,9-H- and frατιβ-2,9-H-___ιdoIizidin-2-ylmethyI-l-methylindole-3- carboxylate (E21a and E21b) 2-Hydroxymethylindolizidine (H. Kato et al, Chem. Pharm. Bull., 1980, 28(7). 2194) (mixture of isomers) was reacted with the add chloride of 1- methylindole-3-carboxylic add using the method of Example 1. The isomers were separated by chromatography on silica gel eluting with ethyl acetate. The faster running isomer was crystallised from ether/pentane to afford the cis isomer (E21a) as a white solid mp 109-110°C. lHNMR(CDCl 3 ) δ: 8.13-8.20 (m,lH), 7.78 (s,lH), 7.25-7.36 (m,3H), 4.21-4.33 (m,2H), 3.82 (s,3H), 3.00-3.08 (m,2H), 2.48-2.60 (m,lH), 2.31 (t,lH), 2.04-2.12 (m,lH), 1.92-2.00 (m,lH), 1.72-1.90 (m,3H), 1.52-1.67 (m,2H), 1.17-1.25 (m,3H). MS (El) M+ 312. The slower running component gave the trans isomer (E21b) as a white solid from ether/pentane mp 94-96°C. lH NMR (CDCl 3 ) δ: 8.10-8.18 (m,lH), 7.78 (s,lH), 7.25-7.38 (m,3H), 4.18-4.31 (m, 2H), 3.84 (s,3H), 3.32 (t,lH), 3.05-3.13 (m,lH), 2.65-2.78 (m,lH), 1.50-2.06 (m,9H), 1.17-1.30 (m,2H). MS (El) M+ 312. Example 22 cis-2,9-H- and frαn«-2,9-H-Indolizidin-2-y_methyl l-ethylindole-3- carboxylate (E22a and E22b) 2-Hydroxymethylindolizidine (H. Kato et al, Chem. Pharm. Bull., 1980, 28(7). 2194) (mixture of isomers) was reacted with the add chloride of 1- ethylindole-3-carboxylic add using the method of Example 1. The isomers were separated by chromatography on silica gel eluting with ethyl acetate. The faster running component gave the cis isomer (E22a) as a colourless oil and converted to its hydrochloride salt mp 168-169°C. IH NMR (HCl salt) (d β DMSO) δ: 10.90 (br.s,lH), 8.29 (s,lH), 7.92-8.02 (m,lH), 7.56-7.66 (m,lH), 7.20- 7.32 (m,2H), 4.22-4.38 (m,4H), 3.32-3.57 (m,2H), 3.05-3.23 (m,2H), 2.73- 2.96 (m,2H), 2.30-2.44 (m,lH), 1.40 (t,3H), 1.25-2.05 (m,7H). MS (El) M+ 326. The slower rxinning component afforded the trans isomer (E22b). Hydrochloride salt mp 146-148°C. lH NMR (HCl salt) (d 6 DMSO) δ: 10.90 (br.s,lH), 8.20 (s,lH), 7.93-8.03 (m,lH), 7.55-7.65 (m,lH), 7.15- 7.33 (m,2H), 4.15-4.40 (m,4H), 3.40-3.75 (m,2H), 2.70-3.30 (m,4H), 1.38 (t,3H), 1.15-2.10 (m,8H). MS (El) M+ 326. Example 23 cis-2,9-H- and ^ n_t-2,9-H-Indolizidin-2-ylmethyl-l-n-propylindole- 3-carboxylate (E23a and E23b) 2-HydroxymethylindoHzidine (H. Kato et al, Chem. Pharm. Bull., 1980, 28(7). 2194) (mixture of isomers) was reacted with the add chloride of 1-n- propylindole-3-carboxylic add using the method of Example 1. The isomers were separated by chromatography on silica gel eluting with ethyl acetate. The faster running component gave the cis isomer (E23a), which was crystallised from pentane mp 54-55°C. HCl salt mp 172-173°C (acetone/ether). !H NMR (HCl salt) (d 6 DMSO) δ: 10.90 (br.s,lH), 8.28 (s,lH), 7.91-8.01 (m,lH), 7.56-7.66 (m,lH), 7.18- 7.31 (m,2H), 4.31 (d,2H), 4.24 (t,2H), 3.34-3.54 (m,2H), 3.04-3.24 (m,2H), 2.72-2.94 (m,2H), 2.28-2.43 (m,lH), 1.94-2.06 (m,lH), 1.30-1.90 (m,8H), 0.83 (t,3H). MS (El) M+ 340. The slower running component afforded the trans isomer (E23b), which also crystallised from pentane mp 81-82°C. X H NMR (free base) (CDC1 3 ) δ: 8.10-8.20 (m,lH), 7.83 (s,lH), 7.34-7.42 (m,lH), 7.23-7.33 (m,2H), 4.18- 4.32 (m,2H), 4.12 (t,2H), 3.28-3.38 (t,lH), 3.04-3.15 (m,lH), 2.64-2.81 (m,lH), 1.47-2.07 (m,HH), 1.13-1.35 (m,2H), 0.95 (t,3H). MS (El) M+ 340. Example 24 ciβ-4,7-H- and frαn_t-4,7-H-l-Azabicyclo[5.4.0]undecan-4- ylmethylindole-3-carboxylate (E24a and E24b) The two title compounds (E24a and E24b) were prepared by reaction of indole-3-carboxylic acid chloride with cϊs-4,7-H-4-hydroxymethyl-l- azabicyclo[5.4.0]undecane (D2a) and imns-4,7-H-4-hydroxymethyl-l- azabicyclo[5.4.0]undecane (D2b) respectively, using the method of Example 1. Each product was purified by chromatography on silica gel eluting with chloroform/methanol (19:1) to give a colourless oil. The two isomers had different rf values. Higher rf isomer:- HCl salt mp 130-135°C. IH NMR (HCl salt) (CDC1 3 ) δ: 11.30 (br.s,lH), 10.10 (br.s,lH), 8.03-8.15 (m,2H), 7.48-7.58 (m,lH), 7.20-7.30 (m,2H), 4.12 (d,2H), 3.30-3.55 (m,2H), 2.50-2.93 (m,3H), 1.60- 2.50 (m,12H), 1.30-1.50 (m,lH). MS (CD MH+ 327. Lower rf isomer:- HCl salt mp 160-162°C (acetone) *H NMR (HCl salt) (d 6 DMSO) δ: 12.05(s,lH), 10.30(br.s,lH), 8.10(d,lH), 7.94-8.02(m,lH), 7.45- 7.54(m,lH), 7.14-7.25(m,2H), 4.08(d,2H), 2.85-3.60(m,5H), 1.30- 2.65(m,13H). MS (FAB) MH+ 327 Example 25 cis-5,7-H- and *rαra*-5,7-H-l-Azabicyclo[5.4.01 undecan-5- ylmethylindole-3-carboxylate (E25a and E25b) Indole-3-carboxylic add chloride was reacted separately with cis-5,7-H-5- hydroxymethyl-l-azabicyclo[5.4.03undecane (D3a) and trans-5,7-ΕL-5- hydroxymethyl-l-azabiςyclo[5.4.0]undecane (D3b) using the method of Example 1. Each product was purified by chromatography on silica gel eluting with ethyl acetate then ethyl acetate, methanol (95:5). The two isomers had different rf values. Higher rf isomer:- off-white solid mp 109-110°C. lH NMR (CDCl 3 ) δ: 9.05 (br.s,lH), 8.15-8.23 (m,lH), 7.92 (d,lH), 7.35-7.45 (m,lH), 7.20- 7.30 (m,2H), 4.15 (d,2H), 2.80-2.90 (m,lH), 2.45-2.72 (m,2H), 2.18-2.42 (m,3H), 1.90-2.05 (m,lH), 1.35-1.87 (m,9H), 1.10-1.35 (m,2H). MS (CD MH+ 327. Lower rf isomer:- white solid mp 138-140°C. lH MR (CDCl 3 ) δ: 9.30 (br.s,lH), 8.11-8.21 (m,lH), 7.92 (s,lH), 7.38-7.47 (m,lH), 7.22-7.32 (m,2H), 4.07-4.26 (m,2H), 2.83-2.98 (m,2H), 2.05-2.60 (m,5H), 1.15-1.98 (m,HH). MS (CD MH+ 327. Example 26 eςr-Quinolizidin-2-ylmethyl-2-methoxyindole-3-carboxylate (E26) A stirred solution of N-chlorosucdnimide (220 mg, 0.0016 mole) in chloroform (6 ml) at room temperature under nitrogen was treated with a solution of eg-quinoli_idin-2-ylmethylindole-3-carboxylate (E9b) (330 mg, 0.0011 mole) in chloroform (6 ml) and stirred for 2h. The solution was then treated with methanol (0.71 ml, 0.022 mole) and stirring continued. After 3h a beige predpitate began to form and after a further lh this was filtered off, washed with chloroform, and dried to afford the title compound (E26) as its hydrochloride salt mp 212-213°C. !H NMR (HCl salt) (d β DMSO) δ: 12.10 (s,lH), 10.20 (br.s.lH), 7.80 (d,lH), 7.30 (d,lH), 7.01-7.17 (m,2H), 4.10 (s,3H), 4.07 (d,2H), 3.23-3.43 (m,2H), 2.73-3.15 (m,3H), 2.00-2.15 (m,lH), 1.35-1.95 (m,10H). MS (El) MH+ 343. Example 27 4-Iodo-3-(eqr-quinolizidin-2-yl)methyl-l-isopropylindole carboxylate (E27) To a solution of eg-quinolizidin-2-ylmethyl-l-isopropyl-indole-3- carboxylate (E18) (122 mg) in TFA (5 ml), was added thallium trifluoroacetate (170 mg). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in υacuo. The residue was treated with E-2O to give a grey solid that was collected by filtration. This was suspended in H2O (5 ml) and a solution of KI (500 mg) in H2O (2 ml) was added. The reaction mixture was stirred at room temperature overnight then extracted thoroughly with CHCI3 (pH 9). The CHCI3 extracts were dried and concentrated in υacuo to give a yellow gum that was purified by column chromatography on Siθ2 (CHCI3 95%, MeOH 5%). The product was isolated as the HCl salt. lH NMR (250 MHz) (CDC1 3 ) (free base) δ: 7.79 (s, IH), 7.8 (dd, IH), 7.4 (dd, IH), 6.95 (t, IH), 4.6-4.77 (m, IH), 4.2 (d, 2H), 2.98-3.15 (m, 2H), 1.2-2.35 (m, 20H inc. d, 6H). Example 28 e -Quinolizidin-2-ylmethyl l-cyclopropylmethylindole-3- carboxylate (E28) eg-Quinolizidin-2-ylme_hyl indole-3-carboxylate (E9b) was alkylated with cydopropylmethyl bromide using the method in Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E28) as a colourless oil. This was converted to its hydrochloride salt mp 167-169°C (acetone ether). lH NMR (HCl salt) (d^DMSO) δ: 10.55 (br.s,lH), 8.35 (s,lH), 7.97-8.05 (m,lH), 7.60-7.70 (m,lH), 7.20- 7.30 (m,2H), 4.13 (d,2H and d,2H), 3.22-3.40 (m,2H), 2.74-3.15 (m,3H), 2.02-2.20 (m,lH), 1.25-1.98 (m,HH), 0.40-0.60 (m,4H). MS (El) M+ 366. Example 29 eςr-Quinolizidin-2-ylmethyl l-cyclohexylmethylindole-3- carboxylate (E29) eg-Quinolizidin-2-ylmethyl indole-3-carboxylate (E9b) was alkylated with cyclohexylmethyl bromide using the method of Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford a colourless oil, which crystallised from n-pentane to give the title compound (E29) as a white solid mp 98-100°C. lH NMR (CDC1 3 ) δ: 8.13-8.20 (m,lH), 7.79 (s,lH), 7.20-7.40 (m,3H), 4.18 (d,2H), 3.96 (d,2H), 2.80-2.95 (m,2H), 1.42-2.18 (m,17H), 0.93-1.38 (m,8H). MS (El) M+ 408. Example 30 eςr-Quinolizidin-2-ylmethyl l-acetylindole-3-carboxylate (E30) eg-Quinolizidin-2-ylmethyl indole-3-carboxylate (E9b) was acylated with acetyl chloride using the method of Example 18. The product was chromatographed on silica gel eluting with ethyl acetate to give a pale yellow oil, which crystallised from ether to afford the title compound (E30) as a white solid mp 127-129°C. lH NMR (CDCl 3 ) δ: 8.42-8.47 (m,lH), 8.10-8.20 (m,2H), 7.35-7.45 (m,2H), 4.23 (d,2H), 2.85- 3.00 (m,2H), 2.72 (s,3H), 1.55-2.20 (m,HH), 1.15-1.45 (m,3H). MS (El) M+ 354. Example 31 e -Quinolizidin-2-ylmethyl l-acetylmethylindole-3-carboxylate (E31) A stirred solution of eg-quinolizidin-2-ylmethylindole-3-carboxylate (E9b) (300 mg, 0.96 mmole) in acetone (10 ml) was treated with anhydrous potassium carbonate (270 mg, 2 mmole) and bromoacetone (150 mg, 1.1 mmole) and kept at room temperature for 3 days. The mixture was treated with 10% Na2Cθ3 solution (10 ml) and extracted with ethyl acetate (2x25 ml). The combined extracts were dried (Na2S04), concentrated in υacuo and the residue chromatographed on silica gel eluting with ethyl acetate/methanol (95:5). The pale yellow oil obtained was crystallised from ether to afford the title compound (E31) as a beige solid (14 mg) mp 139-142°C. lH NMR (CDCl ) δ: 8.17-8.25 (m,lH), 7.81 (s,lH), 7.26-7.35 (m,2H), 7.14-7.22 (m,lH), 4.88 (s,3H), 4.19 (d,2H), 2.82-2.97 (m,2H), 2.14 (s,3H), 1.45-2.20 (m,HH), 1.10- 1.40 (m,3H). MS (El) M+ 368. Example 32 cr_-2,9-H-N-Methylindolizidin-2-ylmethyl l-n-propylindole-3- carboxylate iodide (E32) A stirred solution of cis-2,9-H-indolizidin-2-ylme_hyl indole-3-carboxylate (E23), 100 mg, 0.30 mmole) in acetone (10 ml) was treated with iodomethane (0.095 ml, 1.5 mmole) and heated under reflux for 4h. The solution was then concentrated in υacuo and the residual solid recrys tallised from acetone to afford the title compound as a white solid (60 mg, 42%) mp 195-196°C. M.S. (CD 341 Description 1 (intermediate for Example 2) 3-(2-Hydroxyethyl)quinolizidine (Dl) a) A stirred solution of diisopropylamine (2.25 ml, 0.016 mole) in dry THF (20 ml) at -50°c under nitrogen was treated with 1.6M n- butyllithium in hexane (9.4 ml, 0.015 mole). After 10 minutes the solution was cooled to -65°C and treated with a solution of quinolizidin-4-one (I. Murakoshi, Yakugaku Zasshi, 1958, _£, 594) (2.0g, 0.013 mole) in ether (20 ml), stirred for a further 10 minutes and then ethylene oxide (1.23g, 0.028 mole) bubbled into the solution, which was allowed to warm -to room temperature over 1 hour and then heated under reflux for 1.5 hours. The reaction mixture was treated with concentrated potassium carbonate solution (30 ml) and extracted with ethyl acetate (2 x 60 ml). The combined extracts were dried (Na2S04), concentrated in υacuo and the residue chromatographed on silica gel eluting with chloroform/methanol (98:2) to afford 3-(2-hydroxyethyl)quinoKzidin-4-one as a pale yellow oil (1.4g, 55%). lH NMR (CDCl 3 ) δ: 1.16-2.10 (m, 12H), 2.30-2.58 (m, 2H), 3.18-3.36 (m, IH), 3.62-3.85 (m, 2H), 4.20-5.20 (v.br.s, IH, OH) and 4.70-4.85 (m, IH). b) A solution of3-(2-hydroxyethyl)quinolizidin-4-one (1.4g, 0.0071 mole) in THF (40 ml) was added to a stirred suspension of lithium aluminium hydride (0.5g, 0.013 mole) in THF (50 ml) under nitrogen and the mixture heated under reflux for 2.5 hours, then cooled to ice bath temperature and treated dropwise with water (0.5 ml), 10% sodium hydroxide solution (0.5 ml) and water (1.5 ml). The mixture was filtered through kieselguhr and the filtrate concentrated in υacuo. The residue was distilled in a Kugelrohr apparatus (bp approx. 140°C at 2 mmHg) to give the title compound as a colourless oil (0.97g, 75%). lH NMR (CDCl 3 ) δ: 0.88-1.07 and 1.15-2.25 (each m, together 17H), 2.65-2.86 (m, 2H), 3.59- 3.85 (m, 2H). Description 2 (intermediate for Example 24) a) Diethylpiperidine-l,2-diprop_onate A stirred solution of ethyl piperidinyl-2-propionate (I Murakoshi, Yakugaku Zasshu, 1958, __£, 598) (0.12 mole) in ethanol (350 ml) was treated with ethyl acrylate (26 ml, 0.24 mole) and heated under reflux for 4 h. The solution was concentrated in υacuo and the residue chromatographed on silica gel eluting with ether to afford the title compound as an yellow oil 9.6g, (28%). lH NMR (CDCl 3 ) δ: 4.14 (q, 4H), 2.93-3.17 (m, IH), 2.70-2.88 (m, 2H), 2.46 (t, 2H), 2.18-2.40 (m, 4H), 1.40-2.00 (m, 6H), 1.25 (t, 6H), 1.15-1.38 (m, 2H) b) l-Azabicyclo[5.4.0]undecan-4-one A solution of diethyl piperidine-l,2-dipropionate (9.60g, 0.034 mole) in xylene (100 ml) was added dropwise over 4h to a flask containing 250 ml of xylene, which was being fed υia a continuous extraction apparatus to a stirred, refluxing, suspension of sodium hydride (4.2g of 80%, 0.14 mole) in xylene (100 ml) contεdning ethanol (0.5 ml) under nitrogen. The reaction mixture was heated under reflux for a total of 40 h, then cooled in an ice bath and treated with 5M HCl add (250 ml). The aqueous layer was separated, treated with concentrated HCl add (30 ml) and heated under reflux for 18 h. The solution was cooled, basified with potassium carbonate and extracted with ether (3 x 100 ml). The combined extracts were dried (Na2C03), concentrated in υacuo and the residue distilled in a Kugelrδhr apparatus to give the title compound as a colourless oil (4.6 g, 84%) bp approx. 110°C at 0.25 mm Hg. lHNMR (CDCl 3 ) δ: 2.75-3.05 (m, 4H), 2.44-2.70 (m, 4H), 2.15-2.30 (m, IH), 2.00-2.15 (m, IH), 1.15-1.90 (m, 7H) c) cis-4,7-H- and £r_ms-4-7-H-4-cyano-l- azabicyclo[5.4.0] undecane A stirred solution of l-azabicyclo[5.4.0]undecan-4-one (4.60 g, 0.028 mole) and 4-toluenesulphonylmethyl isocyanide (6.73 g, 0.035 mole) in dimethoxyethane (125 ml) together with ethanol (3.2 ml., 0.055 mole) at 5°C under nitrogen was treated portionwise over 15 minutes with potassium t-butoxide (6.17g, 0.055 mole) keeping the temperature below 15°C. The mixture was allowed to warm to room temperature over 2h, then warmed to 45°C for 0.75h followed by 18h at room temperature. The solution was concentrated in υacuo and basified with 10% Na2C03 solution, then extracted with ethyl acetate (3 x 100 ml). The combined extracts were dried (Na2S04), concentrated in υacuo and the residue chromatographed on a short neutral alumina column eluting with ethyl acetate to afford a mixture of the title compounds as a pale yellow oil (4.18g, 84%). This was used without further purfication. iH NMR ^DCls) δ: 2.60-2.95 (m, 4H), 1.15-2.55 (m, 14H) d) Ethyl cis-4,7-H- and *rαns-4,7-H-l-Azabicyclo[5.4.0]-undecan- 4-ylcarboxylate A mixture of cis-4,7-H and £ran--4,7-H-4-cyano-l- azabicyclo[5.4.0]undecane (D2a and D2b) (3.18 g, 0.018 mole) in concentrated HCl add (80 ml) was heated under reflux for 12 h, then concentrated in υacuo. The residue was treated with ethanol (80 ml) and concentrated HCl add (2 ml) and heated under reflux for 6 h, then concentrated in υacuo. The residue was basified with 10% Na2C03 solution (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined extracts were dried (Na2S04) and concentrated in υacuo to leave a brown oil, which was chromatographed on silica gel eluting initially with ether, then ethyl acetate, to separate each title compound as a yellow oil. Higher rf isomer: iH NMR (CDCI3) δ: 4.10 (q, 2H), 2.62-2.90 (m, 2H), 2.35-2.60 (m, 2H), 1.25 (t, 3H), 1.15-2.30 (m, 14H) Lower rf isomer: iH MR (CDCI3) δ: 4.12 (q, 2H), 2.53-2.93 (m, 4H), 2.18-2.36 (m, IH), 1.92-2.15 (m, 4H), 1.25 (t, 3H), 1.15-1.90 (m, 9H) e) c£s-4,7-H- and *rα_w-4,7-H-4-Hydroxy_net_ιyl-l- 8__abicyclo[5.4.01undecane (D2a and D2b) A stirred suspension of lithium aluminium hydride (232 mg, 0.0061 mole) in THF (20 ml) at room temperature under nitrogen was treated with a solution of one isomer of ethyl l-azabicyclo[5.4.0]undecan-4-ylcarbo_ylate (1.10 g, 0.0049 mole) in THF (20 ml). The mixture was stirred for 1 h then treated with water (0.2 ml), 10% NaOH solution (0.2 ml) and water (0.6 ml). The mixture was filtered through a plug of Eαeselguhr, the filtrate concentrated in υacuo and the residue distilled in a Kugelrδhr apparatus to give one of the title compounds as a colourless oil. The alternative title compound was prepared from the alternative isomer of ethyl 1- azabicydo[5.4.0Jundecan-4-ylcarboxylate using the same procedure, as a colourless oil. The two isomers had different rf values. Higher rf isomer; Ϊ HNMR ^DCls) δ: 3.50 (d, 2H), 2.82-2.95 (m, IH), 2.68-2.80 (m, IH), 2.41-2.55 (m, IH), 2.14-2.30 (m, IH), 1.95-2.10 (m, IH), 1.78-1.95 (m, 2H), 1.20-1.77 (m, 12H) Lower rf isomer: *H NMR (CDCI3) δ: 3.45 (d, 2H), 2.65-2.90 (m, 2H), 2.48-2.62 (m, IH), 2.20-2.35 (m, IH), 1.15-2.05 (m, 15H) Description 3 (intermediate for Example 25) a) Ethyl-l-(3-ethoxycarbonylpropyl)piperidin-2-ylacetate A stirrred solution of ethyl piperidin-2-ylacetate (8.0g, 0.047 mole) and ethyl 4-bromobutyrate (6.7 ml, 0.047 mole) in acetone (100 ml) was treated with potassium carbonate (13g, 0.094 mole) and heated under reflux for 32 h. A further 1.5 ml of ethyl 4-bromobutyrate and 3g of potassium carbonate was added and reflux continued for 16 h. The mixture was concentrated in υacuo and the residue treated with water (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined extracts were dried (Na2S04), concentrated in υacuo and the residue chromatographed on silica gel eluting with ether/petrol (60-80) to afford the title compound as a pale yellow oil (ll.δg, 86%) lH NMR (CDC_3) δ: 4.13 (q, 4H), 2.87-3.02 (m, IH), 2.25-2.75 (m, 8H), 1.25 (t, 6H), 1.15-1.87 (m, 8H) b) l-Azabicyclo[5,4,0]undecan-5-one The title compound was prepared from ethyl- 1-(3- ethoxycarbonylpropyl)piperidin-2-ylacetate using the method of Description 2b). The crude product was purified by distillation in a Kugelrδhr apparatus (bp approx, 105°C at 0.5 mm Hg) to give a colourless oil. iH NMR CCDC ) δ: 2.80-3.20 (m, 3H), 1.55-2.65 (m, 12H), 1.18-1.50 (m, 2H). c) c£s-5,7-H- and -τ*_ s-5,7-H-5-Cyano-l- azabicyclo[5.4.0] undecane The title compounds were prepared from l-azabicyclo[5.4.0]undecan-5-one using the method of Description 2c). The crude product was purified by chromatography on neutral alumina eluting with ethylacetate to afford a yellow oil containing a rαixture of the title compounds. lH NMR (CDCl ) δ: 2.97-3.10 (m), 2.75-2.90 (m), 2.55-2.68 (m), 2.23-2.45 (m), 1.20- 2.15 (m). IR (film) C=N 2240 cm" 1 . d) Ethyl cis-5,7-H- and frαw_t-5,7-H-l-azabicyclo[5.4.0]undecan- 5-ylcarboxylate The title compounds were prepared from a mixture of ci_-5,7-H-5-cyano-l- azabicyclo[5.4.0_undecane and _ra#.s-5,7-H-5-cyano-l- azabicyclo[5.4.0]undecane (mixture from Description 3c)) using the method of Description 2d). The mixture was chromatographed on silica gel eluting initially with ether, then ethylacetate, to afford the separate isomers as yellow oils. Higher rf isomer:- ^H NMR (CDC1 3 ) δ: 4.12 (q, 2H), 2.75-2.86 (m, 2H), 2.59-2.71 (m, IH), 2.42-2.55 (m, IH), 2.15-2.32 (m, 2H), 1.80-2.05 (m, 3H), 1.25 (t, 3H), 1.15-1.78 (m, 9H). Lower rf isomer:- iH NMR O-DC-s) δ: 4.12 (q, 2H), 2.95-3.10 (m, IH), 2.78-2.90 (m, IH), 2.59-2.73 (m, IH), 2.37-2.49 (m, IH), 2.15-2.28 (m, IH), 1.25 (t, 3H), 1.20-2.10 (m, 13H). e) e£s-5,7-H- and /rαi-s-5,7-H-5-Hydro_ymethyl-l- azabicyclo[5.4.0]undecane The title compounds (D3a and D3b) were prepared respectively from ethyl cis-5,7-H-l-azabicyclo[5.4.0]undecan-5-ylcarboxylate and et yl-trans-5,7- H-l-azabicyclo[5.4.0]undecan-5-ylcarboxylate using the method of Description 2e). Each isomer was distilled in a kϋgelrδhr apparatus to give the title compounds as colourless oils. The isomers had different rf values. Higher rf isomer:- *H NMR (CDCI3) δ: 3.45-3.60 (m, 2H), 2.78-2.92 (m, IH), 2.63-2.74 (m, IH), 2.35-2.56 (m, 3H), 1.92-2.08 (m, IH), 1.20-1.85 (m, 13H). Lower rf isomer:- δ: 3.40-3.60 (m, 2H), 2.93-3.10 (m, IH), 2.68-2.90 (2H, m), 2.38-2.52 (m, IH), 2.15-2.30 (m, IH), 1.15-2.10 (m, 14H). Description 4 (Intermediate for Example 9) α -2-Hydroxymethylquinolizidine Ethyl x-quinolizidin-2ylcarboxylate (E. Koshinaka et al, Yakugaku Zasshi, 1980, 100 ( 1 ) . 88) was reduced with lithium aluminium hydride using the method of Description 2e). The crude product was distilled in a kugelrδhr apparatus (bp approx. 140°C at 0.2 mm Hg) to afford the title compound (D4) as a colourless oil. *H NMR (CDC1 3 ) δ: 3.70 (d, 2H), 2.75-2.86 (m, IH), 2.55-2.66 (m, IH), 1.40-2.24 (m, 13H), 1.15-1.37 (m, 2H). Description 5 (Intermediate for Example 10) _<7-2-(2-Hydroxyethyl)quinolizidine Ethyl-_ζ»-quinolizidin-2-ylacetate (U.S. A. Patent 3692791) was reduced with lithium aluminium hydride using the method of Description 2e). The product was purified by distillation in a Kugelrόhr apparatus (bp approx. 120°C at 0.15 mm Hg) to afford the title compound (D5) as a colourless oil. !H NMR (CDC1 3 ) δ: 3.63-3.75 (m, 2H), 2.84 (dt, 2H), 1.90-2.13 (m, 2H), 1.15-1.80 (m, 14H), 0.90-1.10 (m, IH). Description 6 (intermediate for Example 14) c£β-l,9-H-and trans- 1,9-H-l-Hydroxymethylindolizidine (D6a and D6b) The title compounds (D6a and D6b) were prepared respectively from ethyl cis-l,9-H- and £rans-l,9-H-indofi_idin-l-y_carboxylates (H. Kato et al, Chem Pharm Bull., 1980, 2S, 2194) using the method of Description 2e). Each isomer was obtained as a colourless oil. cis isomer:- *H NMR (CDCI3) δ: 4.50 (br.s, IH), 3.86 (dd, IH), 3.46 (dd, IH), 3.03-3.18 (m, 2H), 1.38-2.17 (m, 11H), 1.15-1.32 (m, IH). trans isomer:- iH NMR (CDCI3) δ: 3.57-3.72 (m, 2H), 2.97-3.13 (m, 2H), 1.74-2.20 (m, 7H), 1.40-1.70 (m, 4H), 1.12-1.35 (m, 2H). 5-HT RECEPTOR ANTAGONIST ACTIVITY 1) Guinea pig colon Male guinea-pigs, weighing 250-400g are used. Longitudinal musde- 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 all experiments, the Krebs solution also contains methiothepin lO'^M and granisetron 10 _ ^M to block effects at 5-HT 1, 5-HT2 and 5-HT3 receptors. After construction of a simple concentration-response curve with 5-HT, using 30s contact times and a 15min dosing cycle, a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40- 70% maximum(10-9M approx). The tissue is then alternately dosed every lδmin with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, c____ethylphenylpipera_άmum (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, P-C50 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 generally active in the range of concentrations of the order of pIC5_=6 or more, E22a and E26 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 Kβ) value for the compounds were generally 6 or more, E5a, E9b, E16, E18, E21a, E22a, E24a, E24b, E26, E27 and E30 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 υiυo 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. A compound of formula (I), or a pharmaceutically acceptable salt thereof (D wherein X is of sub-formula (a) or (b): (a) (b) wherein L is N or CR C wherein R c is hydrogen, Cχ.g alkoxy, halo, Cj.g alkyl or cyano; Q is NRi, CH2, O or S; R a is hydrogen, halo, Cχ.g alkyl, amino, nitro or Cχ.g alkoxy; R D is hydrogen, halo, C^.g alkyl or Cχ,g alkoxy; l is hydrogen, Cχ_ιo alkyl, C2- alkenyl, aralkyl, C2- alkanoyl, or C2-g alkanoyl C]_3 alkyl; 2 is Cι_g alkoxy; and R3 is hydrogen, chloro or fluoro; R4 is hydrogen, alkyl, amino optionally substituted by a Cι.g alkyl group, halo, hydroxy or Cχ.g alkoxy; R5 is hydrogen, halo, Cχ.g alkyl, Cj.g alkoxy, nitro, amino or Cχ.g alkylthio; Rg is hydrogen, halo, C]_g alkyl, Cj.g alkoxy or amino; n is O, 1, 2, 3 or 4; p and m are independently 0, 1 or 2; and Rq is hydrogen or Cχ.g alkyl. 2. A compound according to claim 1 wherein X is of sub-formula (a) and L is CH, C-CH3, C-Cl or COCH3. 3. A compound according to claim 1 or 2 wherein X is of sub-formula (a) and Q is NR wherein R;χ is hydrogen or a methyl or ethyl group. 4. A compound according to any one of claims 1, 2 or 3 wherein X is of sub-formula (a) and R a is hydrogen and R D is hydrogen or iodo. 5. A compound according to claim 1 wherein X is of sub-formula (b) and R2 is methoxy, R4 is amino and R5 is halo. 6. A compound according to any one of claims 1 to 5 wherein p = m = 1; p = 0, m = 1; p = 1 or m = 2; p = 2, m = 1. 7. A compound according to any one of claims 1 to 6 wherein Rq is hydrogen. 8. A compound according to any one of daims 1 to 7 wherein the X-COO-(CH2) n - is attached such that the number of carbon atoms between the ester linkage and the azabicycHc nitrogen atom is from 2 to 4 carbon atoms. 9. A compound according to claim 1 selected from the compounds El to E32 indusive, as described herein, including pharmaceutically acceptable salts thereof. 10. A process for the preparation of a compound according to claim 1 which process comprises linking together X-CO2H or a reactive derivative thereof and the (azabicycHc side chain (CH2) n - moiety, by a conventional ester coupling with the -(CH2) -OH derivative 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier. 12. A compoimd according to claim 1 for use as an active therapeutic substance. 13. The use of a compound according to claim 1 in the manufacture of a medicament for use as a 5-HT4 receptor antagonist. 14. The use according to claim 13 for use as a 5-HT4 antagonist in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders. 15. The use according to daim 14 for use in the treatment of IBS. 16. The use according to claim 14 for use in the treatment of atrial arrhythmias and stroke. 17. A method of treatment of IBS in mammals which comprises the administration of an effective amount of a compound according to daim 1. 18. A method of treatment of atrial arrhythmias and stroke in mammals which comprises the administration of an effective amount of a compound according to claim 1.

Inventors: GASTER LARAMIE MARY, KING FRANCIS DAVID, SANGER GARTH JOHN, WARDLE KAY ALISON, WYMAN PAUL ADRIAN, GASTER, LARAMIE, MARY, KING, FRANCIS, DAVID, SANGER, GARTH, JOHN, WARDLE, KAY, ALISON, WYMAN, PAUL, ADRIAN
Applicants: SMITHKLINE BEECHAM PLC
Application year: 1992
Main classification: C07D471
IPC codes: A61K31, A61P9, A61P43, C07D405, C07D413, C07D455, C07D471, C07D487