HETEROARYL COMPOUNDS USED AS PHARMACEUTICALS

Abstract: Compounds of formula (I) for use in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

Description: Heteroaryl compounds used as pharmaceuti cal s 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-hydroxytryptamine 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. 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-201165 (Beecham Group p.Lc)). -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-HT3 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, 14 (9) p.875 - F.D. King and G.J. Sanger). WO 91/16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhythmias and stroke. EP-A-36269 (Beecham Group p. c.) describes a group of compounds of potential use in the treatment of gastrointestinal motility disorders. WO 92/10494 (Beecham Group p.Lc.) describes 5-HT3 receptor antagonists derived from a benzoic acid nucleus 2,3 disubstituted by alkylenedioxy. WO 93/05038 (SmithKline Beecham p.Lc.) describes 5-HT4 receptor antagonists derived from a benzoic acid nucleus. EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 5-HT4 antagonist activity. It has now been discovered that certain novel compounds have 5-HT4 receptor antagonist properties; When used herein, 'treatment' includes prophylaxis as appropriate. Accordingly, the present invention provides a compound of formula (I) and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in which Xι-(CH2) X -X2 forms a 5-7 membered ring wherein: Xi is O or S; X2 is O, S, NR or NRCO wherein R is hydrogen or C 1. alkyl; x is 1, 2 or 3; Rl is hydrogen, amino, halo, Cμg alkyl, hydroxy or C g alkoxy; R2 is hydrogen, halo, C\. alkyl, C g alkoxy, nitro, amino or C j .g alkylthio; R3 is hydrogen, halo, Cμβ alkyl, Cj.g alkoxy or amino; R4 and R5 are independently hydrogen or C β alkyl; Y is O or NH; Z is of sub-formula (a): (a) wherein -(CH2) n is attached at carbon; and n 1 is O, 1, 2, 3 or 4; q is O, 1, 2 or 3; R a is (CH2) n 2-R7 wherein n^ is 2 or 3 and R7 is selected from cyano, hydroxyl, Cμ6 alkoxy, phenoxy, C(O)Cι_ 6 alkyl, COC6H5, -CONRgR 9 , NRgCOR 9 , SO2NR8 R 9 or R8SO2R9 wherein Rg and R9 are hydrogen or C 1.5 alkyl; and Rg is hydrogen or C\. alkyl; or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere; in the manufacture of a medicament for use as a 5-HT4 receptor antagonist. Examples of alkyl or alkyl containing groups include Cj , C2, C3, C4, C5, C , Cη, Cg, C ~ ^ C\Q, C\ \ or C12 branched, straight chained or cyclic alkyl, as appropriate. groups include methyl, ethyl n- and wø-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C\. alkyl and C g alkoxy. Halo includes fluoro, chloro, bromo and iodo, preferably chloro. A suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula: wherein the dotted circle represents one or two double bonds in any position in the 5- membered ring; H, J and I independently represent oxygen, sulphur, nitrogen or carbon, provided that at least one of H, J and I is other than carbon; U represents nitrogen or carbon. Suitable examples of the bioisostere are as described for X, Y and Z in EP-A-328200 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety. Suitable examples of the Xι-(CH2) X -X2 moiety include O-(CH2)2"0, O-(CH 2 )3-O, O-CH 2 -O, O-(CH 2 )2-NR, O-(CH 2 )2"S or O-CH 2 -CONR, wherein any of the methylene linkages are optionally mono- or di- substituted by C g alkyl groups, such as methyl. Preferably X}-(CH2)2-X2 ιs O-(CH2)2-O. Rj is preferably hydrogen or amino. R2 is preferably hydrogen or halo. R3 is preferably hydrogen or halo. R4 and R5 are often hydrogen. When R4/R5 is Cι_6 alkyl, it is often methyl. In particular R4 and R5 are methyl such that the disubstituent containing X\ and X2 is O-C(CH 3 ) -O. Y may be O or NH, in particular. n* is preferably 1 and the azacycle is preferably attached at a 4-position carbon atom, when q is 2. Values of R a are described for (CH2) n R 4 in formula (I), in relation to (la), preferred classes therein and the specific examples of EP-A-501322. Other values of Z of interest are described with reference to the Examples, in particular, wherein R a is hydroxypropyl and/or wherein the 4-piperidinyl group is replaced by 3-pyrrolidinyl. 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, α-keto glutaric, α-glycerophosphoric, and glucose- 1 -phosphoric acids. Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R x -T wherein R x is C g alkyl, phenyl-Cμg alkyl or C5.7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R x include methyl, ethyl and n- and wo-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. The compounds of formula (I) wherein CO-Y is an ester or amide linkage are prepared by conventional coupling of the Z moiety with the appropriate acid. Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A, EP-A-36269, EP-A-289170 and WO 92/05174 (Beecham Group p.Lc). When CO-Y is replaced by a heterocyclic bioisostere, suitable methods are described in EP-A-328200 (Merck Sharp & Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group Limited). The invention also comprises a process for preparing the novel compounds of formula (I) which comprises reacting an appropriate benzoic acid derivative with an appropriate alcohol or amine. A process comprises reacting a benzoic acid derivative wherein the aromatic substituents are as required in the end compound of formula (I), or substituents convertible thereto, with an alcohol or amine containing Z or a group convertible thereto, and thereafter if necessary, converting the benzoic acid substituents and/or Z, and optionally forming a pharmaceutically acceptable salt. Suitable examples of conversions in the aromatic substituents include chlorination of hydrogen to chloro, reduction of nitro to amino, dehydrohalogenation such as debromination, and/or elaboration of a 2,3-disubstituted benzoic acid with ethylene glycol to form the benzodioxan. Any elaboration of the benzo-fused Xj-(CH2) X -X2 containing moiety is, however, usually carried out prior to ester or amide coupling. Suitable examples of conversions in the Z containing moiety include conventional modifications of the N-substituent by substitution and or deprotection or, in the case of a 2-, 3- or 4- substituted piperidinyl desired end compound, reduction of an appropriate pyridyl derivative. 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). Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity can 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. Other CNS disorders of interest include schizophrenia, Parkinson's disease and Huntingdon's chorea. 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. 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, disinteg rants, 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 /?-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 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 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 or prophylaxis of irritable bowel syndrome, 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. 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 70kg adult will normally contain 0.05 to lOOOmg for example 0.5 to 500mg, 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 50mg/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-oesophageal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine. The following Example illustrates the preparation of compounds of formula (I), the following Descriptions relate to the preparation of intermediates. It will be appreciated that any compound prepared wherein Y is O may be provided as the corresponding compound wherein Y is NH. Examples The corresponding compounds to those of the Examples but wherein R a is (CH 2 )2SO 2 NHCH3 or (CH 2 )2CONH 2 (wherein Y is O or NH) are also prepared as described herein and with reference to EP-A-501322 (Glaxo Group Limited). Example 1 [l-(3-Hydroxypropyl)-4-piperidinγI]methyl 8-amino-7-chloro-l,4-benzodioxan- 5-carboxylate hydrochloride (El) To a solution of 4-piperidinylmethyl 8-amino-7-chloro-l,4-benzodioxan-5- carboxylate (lOOmg) and triethyla ine (60 μl) in acetone (15 ml) was added 3-bromo-l-propanol (30 μl). The reaction mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and the solvent concentrated in vacuo. The residue was chromatographed on silica using chloroform and ethanol as the eluant to afford pure product (73mg). Treatment with ethereal HCl afforded title compound. X - l H NMR 250 MHz (CD3OD) δ: 7.44(s,lH), 4.35(s,4H), 4.18(d,2H), 3.65-3.7 l(m,4H), 3.24(t,2H), 3.04(t,2H), 1.92-2.16(m,5H), 1.59-1.80(m,2H) Example 2 [l-(2-Cyanoethyl)-4-piperidinyl]methyl 8-amino-7-chloro-l,4-benzodioxan-5- carboxylate (E2) 4-Piperidinylmethyl 8-amino-7-chloro- 1 ,4-benzodioxan-5-carboxylate (0.180g, 0.55mmol) was dissolved in acetone (10ml) and treated with acrylonitrile (0.040ml; 0.61 mmol). The solution was heated at reflux (18 hours), cooled and evaporated in vacuo to an orange gum. The gum was purified by flash silica-gel chromatography with CHCl3→2 MeOH/CHCl3 as eluant to yield the title compound as a colourless oil (0.035g; 17%) which was converted to the oxalate salt, mp 101-103°C. *H NMR (250MHz, CDCI3) (free base) 5: 7.47 (s, 1H), 4.47 (s, 2H), 4.40-4.30 (m, 4H), 4.10 (d, 2H), 2.90 (d, 2H), 2.70 (t, 2H), 2.50 (t, 2H), 2.17-2.03 (m, 2H), 1.85-1.70 ( . 3H), 1.50-1.30 (m, 2H). Example 3 [l-(3-Oxobutyl)-4-piperidinyl]methyl 8-amino-7-chloro-l,4-benzodioxan-5- carboxylate (E3) 4-Piperidinylmethyl 8-amino-7-chloro- 1 ,4-benzodioxan-5-carboxylate (O.lOOg; 10.31mmol) was dissolved in acetone (10ml) and treated with triethylamine (0.043ml; 0.31mmol) and methyl vinyl ketone (0.026ml; 0.34mmol). The solution was heated at reflux (18 hours), cooled and evaporated in vacuo to a yellow gum. The gum was purified by flash silica-gel chromatography with CHCI3 as eluant to yield the title compound as a colourless gum (0.050g; 41%) which was converted to the oxalate salt. m.p. 160°C (Dec) 2 H NMR (250 MHz, CDCI3) (Free base) δ: 7.47 (s, 1H), 4.47 (s, 2H), 4.40-4.30 (m, 4H), 4.10 (d, 2H), 2.90 (d, 2H), 2.65 (s, 4H), 2.17 (s, 3H), 2.00 (t, 2H), 1.85-1.70 (m, 2H), 1.47-1.25 (m, 3H) Example 4 [l-(2-MethylsulphonylaminoethyI)-4-piperidinyl]methyl 8-amino-7-chloro- 1 ,4-benzodioxan-5-carboxyIate (E4) 4-Piperidinylmethyl-8-amino-7-chloro-l,4-benzodioxan-5-carboxylate (0.144g, 0.441mmol) in acetonitrile (10ml) was treated with diisopropylethylamine (0.154ml; 0.882mmol), followed by N-(2-bromoethyl)methanesulphonamide (D2) (0.107g, 0.529mmol). The mixture was then heated to reflux under N2- After 7h, the reaction mixture was allowed to cool, and was then evaporated under reduced pressure, and the residue partitioned between CH2CI2 and water. The aqueous layer was then extracted with CH2CI2 (IX), and the combined organic layers were then dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow oil. The oil was then purified by Siθ2 chromatography (5% MeOH/CHCl3 as eluant) to give the title compound as a colourless oil (0.112g, 57%), which was converted to its hydrochloride salt. m.p. 248-250°C *HNMR (200MHz, CDCI3) (free base) δ: 7.50 (s, 1H), 4.50 (s, 2H), 4.35 (s, 4H), 4.12 (d, 2H), 3.22 (t, 2H), 3.00 (s, 3H), 2.90 (m, 2H), 2.55 (t, 2H), 2.08 (t, 2H), 1.90-1.60 (m, 3H), 1.50-1.22 (m, 3H) Example 5 [l(2-Acetylamino)ethyl]-4-piperidinyl]methyl 8-amino-7-chloro-l,4- benzodioxan-5-carboxylate (E5) 4-Piperidinylmethyl 8-amino-7-chloro- 1 ,4,-benzodioxan-5-carboxylate (0.138g, 0.423mmol) was dissolved in CH3CN (8ml) and treated with N-(2- chloroethyDacetamide (0.051ml, 0.507mmol), followed by diisopropylethylamine (0.147ml, 0.846mmol), and a catalytic amount of sodium iodide. The mixture was then heated to reflux with stirring. After 2 days , the reaction mixture was allowed to cool, before being evaporated under reduced pressure to give a pale yellow foam. The foam was then purified by silica-gel chromatography (CH2θ2/10%MeOH) to give the title compound (0.025g, 14%) as a colourless oil, which was converted to its oxalate salt m.p. 180-182°C. 1H NMR (270MHz. CD3SOCD3) (oxalate salt) δ: 8.15 (s, 1H), 7.30 (s, 1H), 5.70 (s, 2H), 4.30 (s, 4H), 4.05 (d, 2H), 3.50-3.25 (m, 4H), 3.05-.75 ( , 4H) 2.00-1.80 (m, 3H), 1.80 (s, 3H), 1.50 (m, 2H). Description 1 4-PiperidinylmethyI 8-amino-7-chloro-(l,4-benzodioxan-5-carboxylate hydrochloride a) To a stirred solution of 8-amino-7-chloro- 1 ,4-benzodioxan-5-carboxylic acid (prepared from the corresponding 7-H acid (prepared as in GB 1571278) by chlorination of the protected form) (1.10g) in acetonitrile was added bis- carbonyldiimidazole (0.77g). The reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to afford crude 8- amino-7-chloro- 1 ,4-benzodioxan-5-imidazolide. b) To a solution of N-tert-butoxycarbonyl-4-hydroxymethyl piperidine (0.25g) in dry THF (10ml) was added methyllithium (1.5M in diethylether; 0.78ml) at 0°C under a nitrogen atmosphere. Stirring was continued at ambient temperature for 10 min. 8-Amino-7-chloro-l,4-benzodioxan-5-imidazolide (0.33g) in THF (10ml) was added to the reaction mixture and stirring continued for 2 hours. The reaction mixture was cooled to 0°C and water was added. The solvent was removed under reduced pressure and the residue partitioned between chloroform and water. The organic phase was washed with water (3x), dried (Na2SO4) filtered and concentrated in vacuo. Flash chromatography on silica using chloroform and ethanol as eluant gave the title compound (0.26g). 1H NMR 250MHz (CDC1 3 ) δ: 7.47(s,lH), 4.49(s,2H), 4.08-4.22(m,4H), 2.64-2.80(m,2H), 1.84-2.01(m,lH), 1.70-1.83(m,2H), 1.46(s,9H), 1.18-1.38(m,2H) c) HCl(g) was bubbled into a cooled solution of 8-amino-7-chloro-(N-tert- butoxycarbonyl-4-piperidylmethyl)-l,4-benzodioxan-5-carboxylate (0.26g) in dioxan (50ml) for 25 min. The solvent was concentrated in vacuo and the residue triturated with Et2θ to afford pure title compound (Dl) (0.12g). mp 249-251°C l H NMR 250MHz (DMSO) δ: 8.99-9.10(m,lH), 8.59-8.78(m,lH), 7.29(s,lH), 5.73(s,2H), 4.25-4.34(s,4H), 4.03(d,2H), 3.20-3.42(m,2H), 2.75-2.97(m,2H), 1.76-2.06(m,3H), 1.48- 1.57(m,2H) Description 2 N-(2-Bromoethyl)methanesulphonamide 2-Bromoethylamine hydrobromide (5.10g; 0.025mol) was dissolved in dichloromethane (200ml) with stirring, and treated with triethylamine (6.96ml, 0.050mol). The mixture was then cooled in ice and methanesulphonyl chloride (1.96ml, 0.025mol) added slowly. The reaction mixture was then allowed to warm to room temperature. After 16h, the reaction mixture was washed with water (IX) and 5M HCl (IX), dried (Na 2 SO4), and evaporated under reduced pressure to give the title compound (D2) as a colourless oil that crystallised on standing to give a white solid (3.50g, 69%). 1HNMR (250 MHz, CDCI3), δ: 4.92 (s, 1H), 3.62-3.48 (m, 4H), 3.05 (s, 3H). 5-HT4 RECEPTOR ANTAGONIST ACTIVITY 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% CO in O 2 and maintained at 37°C. In all experiments, the Krebs solution also contains methiothepin 10 " ^M and granisetron 10 " 6M to block effects at 5-HTj, 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"^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, dimethylphenylpiperazinium (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. The compounds generally had a PIC50 of at least 8 and El had a PIC50 of 10.2. 2) Piglet Atria Compounds are tested in the piglet spontaneous beating screen (Naunyn- Schmiedeberg's Arch. Pharmacol 342, 619-622) and pKg (-logjo Kg) values determined. 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% ^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. A compound of formula (I), or a pharmaceutically acceptable salt thereof: (I) in which Xι-(CH2) X -X2 forms a 5-7 membered ring wherein: Xl is O or S; X2 is O, S, NR or NRCO wherein R is hydrogen or C\. alkyl; x is 1, 2 or 3; R\ is hydrogen, amino, halo, C\. alkyl, hydroxy or Cj.g alkoxy; R2 is hydrogen, halo, Cμg alkyl, C . alkoxy, nitro, amino or Ci .g alkylthio; R3 is hydrogen, halo, C\.β alkyl, Cj.g alkoxy or amino; R4 and R- are independently hydrogen or C1 _g alkyl; Y is O or NH; Z is of sub- formula (a): (a) wherein -(CH2) n is attached at carbon; and nMs O, 1, 2, 3 or 4; q is 0, 1, 2 or 3; R a is (CH2) n 2-R7 wherein n^ is 2 or 3 and R7 is selected from cyano, hydroxyl, Cι_6 alkoxy, phenoxy, C(O)Cι_6 alkyl, COC 6 H 5 , -CONRgR 9 , NRgCOR 9 , SO2NRgR 9 or NRgSO 2 9 wherein Rg and R9 are hydrogen or C 1.5 alkyl; and R is hydrogen or Ci.g alkyl; or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere; having 5-HT4 receptor antagonist activity. 2. A compound according to claim 1 wherein Xj-(CH2) -X2 moiety is O-(CH 2 )2-O, O-(CH 2 )3-O, O-CH 2 -O, O-(CH 2 )2-NR, O-(CH 2 )2"S or O-CH2-CONR, wherein R is as defined in claim 1 and any of the methylene linkages are optionally mono- or di- substituted by Cμg alkyl groups. 3. A compound according to claim 2 wherein Xj-(CH2)2-X2 i -(CH2>2-O. 4. A compound according to claim 1, 2 or 3 wherein Ri is hydrogen or amino, R2 is hydrogen or halo, and R3 is hydrogen or halo. 5. A compound according to claim 1, 2, 3 or 4 wherein R a is (CH2)3OH, (CH 2 )2CN, (CH )2COCH 3 , (CH 2 )2NHSO 2 CH 3 , or (CH 2 )2NHCOCH 3 . 6. A compound according to any one of claims 1 to 5 wherein n s 1 and the azacycle is attached at a 4-position carbon atom, when q is 2. 7. A compound according to claim 6 wherein Z is N-substituted 4-piperidylmethyl. 8. A compound according to any one of claims 1 to 7 wherein Y is O or NH. 9. A compound according to claim 1 selected from the compounds El to E5 inclusive, as described herein, including pharmaceutically acceptable salts thereof. 10. A process for preparing the ester or amide compounds according to claim 8, which comprises reacting an appropriate Xι-X 2 containing acid derivative with an appropriate alcohol or amine. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier. 12. A compound 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.

Inventors: GASTER LARAMIE MARY, KING FRANCIS DAVID, MULHOLLAND KEITH RAYMOND, GASTER, LARAMIE, MARY, KING, FRANCIS, DAVID, MULHOLLAND, KEITH, RAYMOND
Applicants: GASTER LARAMIE MARY, KING FRANCIS DAVID, MULHOLLAND KEITH RAYMOND, SMITHKLINE BEECHAM PLC
Application year: 1993
Main classification: C07D405
IPC codes: A61K31, A61P1, A61P9, A61P25, A61P43, C07D405