NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS USEFUL AS PHARMACEUTICALS

Abstract: Compounds of formula (I) and pharmaceutically acceptable salts thereof and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

Description: NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS USEFUL AS PHARMACEUTICALS This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals. 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. 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-501322 (Giaxo Group Limited) describes indole derivatives having 5-HT4 antagonist activity. EP-A-309423 (Istituto de Angeli S.p.A) and EP-A-247266 (Beecham Group p.l.c.) describe 5-HT3 receptor antagonists derived from a benzimidazolone or indoline nucleus. A class of novel, structurally distinct compounds has now been discovered, which compounds include benzimidazolone derivatives. These compounds have 5-HT4 receptor antagonist activity. Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: (l) wherein: X-I-X2 is NR 2 -CO or CR-j R2-CR3R4 where R z and R-j to R4 are independently hydrogen or C-\ .Q alkyl; and/or R1/R2 and R3/R4 together are a bond and/or R1/R2/R3/R4 are joined to form C3.6 polymethylene; R a is hydrogen, halo, C-i-e alkyl, amino, nitro or C-\.Q alkyl; R5 is hydrogen, halo, C1-5 alkyl or C-\.Q alkoxy; Y is O or NH; Z is of sub-formula (a), (b) or (c): (a) (b) (c) wherein n 1 is 1 , 2, 3 or 4; n 2 is 0, 1 , 2, 3 or 4; n 3 is 2, 3, 4 or 5; q is 0, 1 , 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2; R5 is hydrogen, C-|_12 alkyl, aralkyi or R5 is (CH2) z -Rlθ wherein z is 2 or 3 and R-io is selected from cyano, hydroxyl, C-j-β alkoxy, phenoxy, C(0)C-| .6 alkyl, COC 6 H 5 , -CONR-| \\ ~ \\2. W\-\\ \ Q,0\ ~ \^ 2 , SO \\-\^ -| R-| 2 or NRf|S02Ri2 wherein R-J -J and R-12 are hydrogen or C-μe alkyl; and Rg, R7 and RQ are independently hydrogen or C-j_6 alkyl; and Rg is hydrogen or C1-10 alkyl; or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere; having 5-HT4 receptor antagonist activity. Examples of alkyl or alkyl containing groups include C-j , C2, C3, C4, C^, CQ, C7, Cβ, Cg, C10. C-j 1 or C-j 2 branched, straight chained or cyclic alkyl, as appropriate. C1-4 alkyl groups include methyl, ethyl, n- and /so-propyl, n-, iso, sec- and tett-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-j.6 alkyl and C-\.Q alkoxy. Halo includes fluoro, chloro, bromo and iodo. A suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula (d): (d) 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 (d) are as described for X, Y and Z in EP-A-328200 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety. Suitable examples of X1-X2 when CR-j R2-CR3R4 include CH2-CH2 and CH=CH. X1-X2 is preferably NR z -CO, however, such as NH-CO or NEt-CO. R a is preferably hydrogen. R D is preferably hydrogen or halo, such as iodo. Y is preferably O or NH. When Z is of sub-formula (a), n 1 is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n 1 is preferably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2. When Z is of sub-formula (b), n 2 is preferably such that the number of carbon atoms between the ester or amide linkage is from 2 to 4 carbon atoms. Suitable values for p and m include p = m = 1 ; p = 0, m = 1, p = 1 , m = 2, p = 2, m = 1. When Z is of sub-formula (c), rβ is preferably 2, 3 or 4. Rg and Rg are preferably both alkyl, especially one of Rg and Rg is C4 or larger alkyl. Specific values of Z of particular interest are as follows: ,NMe Bu (iv) (vi) The invention also provides novel compounds within formula (I) with side chains (i), (ii), (iii), (iv), (v), (vi) or (vii). In a further aspect, the piperidine ring in (i), (ii) or (iii) may be replaced by pyrrolidinyl or azetidinyl, and/or the N-substituent in (i) or (ii) may be replaced by C3 or larger alkyl or optionally substituted benzyl. In an alternative aspect, the N-substituent in formula (i) or (ii) may be replaced by (CH2)nR as defined in EP-A-501322 in respect of formula (I) and the specific examples therein. 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-|_6 alkyl, phenyl-C-μβ 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 /sopropyl; 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. It will also be realised that the (CH2) n 2 moiety in compounds of formula (I) wherein Z is (b), may adopt an α or β or configuration with respect to the fused azabicyclic moiety. The compounds of formula (I) may be prepared by conventional coupling of the X-1/X2 moiety with Z. Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group p.l.c), EP-A-429984 (Nisshin Flour Milling Co.) and EP-A-328200 (Merck Sharp & Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group Limited). Aza(bi)cyclic side chain intermediates are known compounds or may be prepared according to the methods described in PCT/GB92/01519 and /01612 (SmithKline Beecham p.l.c). 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. Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity may be demonstrated in standard animal models, the 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 sucrras 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 ortabletting. 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, 3ΌΓ 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 as a 5-HT4 receptor antagonist in the treatment of the disorders hereinbefore described. 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 the disorders hereinbefore described. The following Examples illustrate the preparajion of compounds of formula (I); the following Descπ- ,ns illustrate the preparation of intermediates. It will be appreciated that any compound example wherein X is O may be prepared as the corresponding compound wherein Y is NH and vice versa. Examples -a Rb 1/ 2 E1 H H NH-CO E2 H H NEt-CO E3 H H CH 2 CH 2 E4 H H CH=CH E5 H H NH-CO E6 H H NMe-CO Examples (cont.) -a Rb 1/X2 E13 H H NH-CO NH 0) E14 H H Ncpm-CO NH (i) E15 H H NPrn-CO NH (i) E16 H H CHCH3CH2 O • (.) E17 H H CH(CH 3 ) 2 CH 2 O (i) E18 H H CHR 2 pCHR 4 p O (i) cpm - cyclopropylmethyl R2p and R4p are joined to form C4 polymethylene Example 1 (1-Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3H-benzimidazole-1- carboxylate (E1 ) A solution of (1-butyl-4-piperidyi)methyl 2-aminophenylcarbamate (D1b), (2.90g, 0.0095 mole) in dichloromethane (50ml) with triethylamine (1.5ml) was added to a stirred solution of trichloromethyl chloroformate (1.88g, 1.15ml, 0.0095 mole) in dichloromethane (50ml) at 50°C under nitrogen. ' After 1 h the solution was allowed to warm to room temperature and left for a further 1 h. The solution was treated with dilute HCI acid (50ml) and the white solid produced was filtered off. The solid was suspended in 10% Na2Cθ3 (aqueous) solution (50ml) and extracted with dichloromethane (3x100ml). The organic extracts were combined, dried (Na2S04) and concentrated in vacuo to afford the title compound (E1 ) as an off white solid (2.20g, 70%) mp 130-132°C. 1 H NMR 250MHz (CDCI3) δ: 9.85 (br s, 1 H), 7.92 (dd, 1 H), 7.13-7.34 (m, 3H), 4.45 (d, 2H), 3.05-3.20 (m, 2H), 2.40-2.55 (m, 2H), 1.90-2.20 (m, 5H), 1.35-1.70 (m, 6H), 1.02 (t, 3H). MS (El) MH+ 332. Example 2 (1-Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-ethylbenzimidazole-1- carboxylate hydrochloride (E2) To a stirred solution of (1-butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3H- benzimidazole-1 -carboxylate (E1, 0.5g, 0.0015 mole) in dry DMF (15ml) under nitrogen at room temperature was added, portionwise, sodium hydride as an 80% dispersion in mineral oil (45mg, 0.0015 mole). After hydrogen evolution had subsided (90min), the solution was treated with ethyl iodide (0.235g, 0.12ml. 0.0015 mole) and left to stir overnight. The resulting solution was basϊfied via addition of 10% aqueous Na2Cθ3 solution (30 ml) and extracted into ethyl acetate (3x50ml). The organic extracts were combined and dried (Na2S04) and concentrated in vacuo. The residue was chromatographed on silica gel eluting initially with chloroform followed by chloroform/ethanol (95:5) to afford the free base of the title compound. This was converted to the hydrochloride salt, which was recrystallised from isopropyl alcohol/acetone (1 :1 ) to afford the title compound (E2) as a white crystalline solid (0.43g, 80%) mp 190-192°C. HCI Salt:- 1 H NMR 250MHz (CD 3 OD) δ: 7.94 (dd, 1 H), 7.20-7.40 (m, 3H), 4.45 (d, 2H), 4.01 (q, 2H), 3.65-3.77 (m, 2H), 3.00-3.23 (m, 4H), 2.13-2.30 (m, 2H), 1.70-1.90 (m, 4H), 1.40-1.60 (m, 3H), 1.37 (t, 3H), 1.08 (t, 3H). Example 3 2-Piperidylethyl 2,3-dihydroindole-1 -carboxylate hydrochloride (E3) 2,3-Dihydroindole-1-carbonyl chloride (0.75g, 4.13 mmole) was dissolved with stirring in dichloromethane (20ml) and triethylamine (0.632ml, 4.54.mmole) was added, followed by 2-piperidineethanol (0.547 ml, 4.13 mmole). The mixture was then stirred at room temp. After 72h, the reaction mixture was washed with water, the organic layer was then dried (Na2Sθ4) and evaporated under reduced pressure to give a pink oil. The oil was purified by silica gel chromatography using pentane:EtOAc (3:1 to 5:4) as eluant to give a colourless oil (0.355g, 33%) , which was converted to its hydrochloride salt (E3) mp 175-176°C. HCI Salt:- 1 H NMR (250MHz) (DMSO) δ: 7.72 (br s,1 H), 7.20(dd,2H), 6.98(t,1 H), 4.53(S,2H), 4.08(t,2H), 3.35-3.52(m,4H), 2.90-3.05(m,4H), 1.60- 1.95(m,5H), 1.48(m,1 H). Exampie 4 2-Piperidylethyl indole-1 -carboxylate (E4) 2-Piperidylethyl 2,3-dihydroindole-1 -carboxlate hydrochloride (E3) (0.1 OOg, 0.337mole) was dissolved in chloroform (10ml) with stirring. DDQ (0.084g, 0.370mmole) was then added and the mixture was heated to reflux. After 6h, the reaction mixture was allowed to cool. The reaction mixture was then diluted with CHCI3 and washed with saturated potassium carbonate solution. The aqueous layer was then extracted with chloroform, and the combined ' organic layers were dried (Na2Sθ4) and evaporated to give a yellow solid, which was purified by silica gel chromatography, using petrol:EtOAc (4:1 ) as eluant to give the title compound (E4) as a pale yellow oil (0.036g 41%), which was converted to its hydrochloride salt mp 185-186°C. Free base:- • H NMR (250MHz) (CDCI3) δ: 8.22(d,1 H), 7.52-7.68(m,2H), 7.20-7.41 (m,2H), 6.62(d,1H), 4.54(t,2H), 2.80(t,2H), 2.50(t,4H), 1.52- 1.68(m,4H), 1.45(m,2H). Examples 5 - 12 Using analogous methods to those described for the preparation of Examples 1 and 2 the following compounds were prepared: 2-Piperidylethyl 2,3-dihydro-2-oxo-3H-benzimidazole-1 -carboxylate hydrochloride (E5) mp 172-3°C (1 - Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-methyibenzimidazole-1 - carboxylate hydrochloride (E6) mp 184-187 0 C (1-Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-cyclopropylmethyl- beπzimidazole-1 -carboxylate hydrochloride (E7) mp 183-5°C 2-Pi eridylethy I 2,3-dihyd ro-2-oxo-3-ethy I enzimidazole-1 -carboxylate hydrochloride (E8) mp 176-178°C (1-Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-propylbenzimidazole-1- carboxylate hydrochloride (E9) mp 190-192°C (1-Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-isopropylbenzimidazole- 1 -carboxylate hydrochloride (E10) mp 155-157 0 C 1 -Azabicyclo[4.4.0]decan-4-ylmethyl 2,3-dihydro-2-oxo-3H- benzimidazole-1 -carboxylate hydrochloride (E11) 206-208 O C 1-Azabicyclo[4.4.0]decan-4-ylmethyl 2,3-dihydro-2-oxo-3- ethylbenzimidazole-1-carboxylate hydrochloride (E12) mp 180-183°C Example 13 (1 -Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3H-benzimidazole-1 - carboxamide hydrochloride (E13) A mixture of N-(1-buty!-4-piperidyl)methyl-N * -(2-aminopheny!)urea (D2b, 4.5g, 0.015mole) and triethylamine (2.5ml) in dichloromethane (100ml) was added to a solution of diphosgene (2.93g, 1.8ml, 0.015mole) in dichloromethane (50ml) under nitrogen. After addition was complete (1 hour) the solution was treated with 5M HCI (100ml). The precipitate was filtered off and dried to ' afford the title compound (E13) as a white solid mp 240-243°C. Examples 14 and 15 The following compounds were prepared by an analogous procedure to that described for Example 2. (1 -Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3- cyclopropylmethylbenzimidazoie-1 -carboxamide hydrochloride (E14) mp 175-177 0 C (1-Butyl-4-piperidyl)rτ.ώthyl 2,3-dihydro-2-oxo-3-propylbenzimidazole-1- carboxamide hydrochloride (E15) mp135-136°C Examples 16 - 18 The following compounds were prepared by an analogous procedure to that described for Example 3. (1-Butyl-4-piperidyl)methyl 2,3-dihydro-3-methylindole-1 -carboxylate hydrochloride (E16) mp 73-175°C 2-Piperidylethyl 2,3-dihydro-3,3-di methyl indole-1 -carboxylate hydrochloride (E17) 174-176°C (1-Butyl-4-piperidyl)methyl 1 ,2,3,4-tetrahydrocarbazole-9-carboxylate oxalate (E18). mp 187-189°C Preparation of N-(1- n butyl-4-piperidyl)methylamine A stirred solution of isonipecotamide (70g, 0.55 mole) and 1 -bromobutane (58.8 ml, 0.55 mole) in ethanol (700 ml) was treated with anhydrous potassium carbonate (152g, 1.10 mole) and heated under reflux for 3h. The mixture was allowed to cool, then filtered and the filtrate concentrated under vacuum. The residual oil was dissolved in chloroform (400 ml) and washed with water (1 x 300 ml), then dried (Na2S04) and concentrated under vacuum to leave a yellow oil (77.5g). This oil was mixed thoroughly with phosphorus pentoxide (75g) and the mixture heated at 160-180°C under nitrogen for 2.5h with gentle stirring. The reaction mixture was allowed to cool, then treated with water (500 ml). When the solid mass had dissolved, the solution was basified by addition of solid K2CO3 and extracted with ethyl acetate (2x400 ml). The combined extracts were dried (Na2S04) and concentrated in vacuo to leave a brown oil (78g). This was dissolved in dry ether (400 ml) and added dropwise over 30 minutes to a stirred suspension of lithium aluminium hydride (25g, 0.66 mole) in ether (200ml) at 0°C under nitrogen. When addition was complete, the mixture was allowed to warm upto room temperature and stir for 18h. It was re-cooled to 0°C and treated cautiously with water (25ml), 10% NaOH solution (25 ml) and water again (75ml). The mixture was filtered through kieselguhr and the filtrate concentrated in vacuo to leave a brown oil, which was distilled under vacuum to afford the title compound as a colourless oil (66g, 71%) bp 96-99°C at 3 mm Hg. Η NMR (CDCI3) δ: 2.90-3.02(m,2H), 2.58(d,2H), 2.25-2.38(m,2H), 1.65-2.00(m,4H), 1.08- 1.58(m,9H), 0.92(t,3H). Preparation of (1- n butyl-4-piperidinyl)methanol A mixture of ethyl isonipecotate (102g, 0.65 mole) and 1-bromobutane (72 ml, 0.67 mole) in ethanol (1.2L) was treated with anhydrous potassium carbonate (180g, 1.3 mole) and heated under reflux for 2h. The mixture was allowed to • cool and then filtered through kieselguhr. The filtrate was concentrated in vacuo to leave a yellow oil, which was dissolved in ether (300 ml) and added dropwise over 20 minutes to a stirred suspension of lithium aluminium hydride (50g, 1.3 mole) in either (500 ml) at 0°C under nitrogen. The mixture was stirred at room temperature for 18h, then cooled to 0°C and treated with water (50 ml), 10% NaOH solution (50ml) and water (150ml). The mixture was filtered through keiselguhr and the filtrate concentrated under vacuum to leave a pale yellow oil, which was distilled to afford the title compound as a colourless oil (88.5g, 80%) bp 102-108°C at 0.1 mm Hg. 1H NMR (CDCI 3 ) δ: 3.48(d,2H), 2.88-3.03(m,2H), 2.25-2.38(m,2H), 2.10(brs, 1H), 1.66- 2.00(m,4H), 1.17-1.60(m,7H), 0.90(t,3H) Descriptions Description 1 (Intermediate for Examples 1 and 2) a) (1-Butyl-4-piperidyl)methyl 2-nitrophenylcarbamate A stirred suspension of 2-nitrophenylisocyanate (3.60g, 0.22mole) in dry toluene (50ml) at room temperature under nitrogen was treated with (1-butyl- 4-piperidyl)methanol (2.00g, 0.0118mole). The mixture was heated under reflux for 4h with stirring. The resulting solution was concentrated in vacuo to • afford the crude title compound as an orange brown oil (3.40g. 50%). 1 H NMR (CDCI 3 ) δ: 9.85 (s, 1 H), 8.57 (dd, 1 H), 8.23 (dd, 1 H), 7.60-7.70 (m, 1 H), 7.10-7.18 (m,1 H), 4.08 (d, 2H), 2.94-3.06 (m, 2H), 2.30-2.40 (m, 2H), ' 1.86-2.04 (m, 2H), 1.65-1.84 (m, 3H), 1.30-1.60 (m, 6H), 0.93 (t, 3H). b) (1-Butyl-4-piperidyl)methyl 2-aminophenylcarbamate A solution of (1-butyl-4-piperidyl)methyl 2-nitrophenylcarbamate (3.00g, 0.009 mole) in ethanol (100ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst. The catalyst was removed and the resulting solution concentrated in vacuo to afford the title compound as pale yellow solid (2.40g, quantitative). - NMR 250MHz (CDCI3) δ: 7.20-7.35 (m, 1 H), 6.95-7.10 (m, 1 H), 6.60-6.90 (m, 3H), 4.03 (d, 2H), 3.75 (br s, 2H), 2.93-3.10(m, 2H),- 2.30-2.45 (m, 2H), 1.90-2.10 (m, 2H), 1.17-1.83 (m, 9H), 0.90 (t, 3H). Description 2 (intermediate for Example 13) a) N-(1 -Butyl-4-piperidyl)methyl-N'-(2-nitrophenyl)urea A solution of 2-nitrophenylisocyanate (3.00g, 0.183mole) in dichloromethane (50ml) was treated with a solution of (1 -butyl-4-piperidyl)methylamine (3.11 g, 0.183mole) in dichloromethane (50ml) and the mixture stirred at room temperature for 16 hours then heated under reflux for 1 hour. The solvent was removed in vacuo and the residue purified by column chromatography on silica gel using CHCI3/ MeOH (9:1 ) as eluant. The product was isolated as a yellow solid. 1 H NMR (CDCI3) δ : 9.80 (br s, 1 H), 8.65 (d, 1 H), 8.15 (d, 1 H), 7.55 (t, 1 H), 7.02 (t, 1 H), 5.60 (br s, 1 H), 3.20 ( t, 2H), 2.92 (br d, 2H), 2.20-2.35 (m, 2H), 1.20-1.97 (m, 11H), 0.90(t, 3H) b) N-(1-Butyl-4-piperidyl)methyl-N'-(2-aminophenyl)urea A solution of N-(1 -butyl-4-piperidyl)methyl-N'-(2-nitrophenyl)urea (5.4g, • 0.0163mole) in ethanol (200ml) was hydrogenated over 10% Pd/C at room temperature and pressure. After 2 hours the catalyst was removed by filtration through keiseiguhr and the filtrate concentrated in vacuo to give a white solid. 1 H NMR (CDCI3) δ : 6.98-7.17 (m, 2H), 6.92 (s, 1 H), 6.67-6.78 (m, 2H), 5.25 (brt, 1 H), 3.95 (br s, 2H), 3.05 (t, 2H), 2.87 (brd, 2H), 2.2-2.35 (m, 2H), 1.15- 1.95 (m, 11 H), 0.90 (t, 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% CO2 in O2 and maintained at 37°C. In all experiments, the Krebs solution also contains methiothepin 10" 7 M and granisetron 10" 6 M to block effects at 5-HT-j , 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" 9 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, dimethyiphenylpiperazinium (DMPP). After obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of a putative 5-HT4 receptor antagonist are then added to the bathing solution. The effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, PIC50 values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%. A compound which reduces the response to 5-HT but not to DMPP is believed to act as a 5-HT4 receptor antagonist. Compounds were generally active in the range of concentrations of the order °f PO50 = 6.5 or more, E2, E6 and E7 showing particularly good activity. 2) 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 (100μM 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).

Claims: Claims . A compound of formula (I), or a pharmaceutically acceptable salt thereof (I) wherein: X-j -X2 is NR z -CO or CR-| R2-CR3R4 where R z and R-j to R4 are independently hydrogen orC-ι-6 alkyl; and/or R-J/R2 and R3/R4 together are a bond and/or R1/R2/ 3/R4 are joined to form C3-6 polymethylene; R a is hydrogen, halo, C-j .g alkyl, amino, nitro or C-| .Q alkyl; Rtø is hydrogen, halo, C-j .Q alkyl or C-j .Q alkoxy; Y is O or NH; Z is of sub-formula (a), (b) or (c): (a) (b) (C) wherein n 1 is 1 , 2, 3 or 4; n 2 is 0, 1 , 2, 3 or 4; n 3 is 2, 3, 4 or 5; q is 0, 1 , 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2; R5 is hydrogen, C1-12 alkyl, aralkyi or R5 is (CH2) Z - R 10 wherein z is 2 or 3 and R-JO is selected from cyano, hydroxyl, C-j-6 alkoxy, phenoxy, 0(0)^ .6 alkyl. COC 6 H 5 , -CONR-| -ι R 12 . NRn CORi 2 , S0 2 NR-| R-j 2 or NR-j 1SO2R12 wherein R-| 1 and R12 are hydrogen or C-μe alkyl; and RQ, R7 and Rs are independently hydrogen or C-μβ alkyl; and Rg is hydrogen or C^.-JO 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 R a is hydrogen. 3. A compound according to claim 1 or 2 wherein R D is preferably hydrogen or halo. 4. A compound according to claim 1 , 2, or 3 wherein X-\ -X2 is CH2-CH2 or CH=CH. 5. A compound according to claim 1 , 2, 3 or 4 wherein X-| -X2 is NR z -CO. 6. A compound according to any one of claims 1 to 5 wherein Y is O or NH. 7. A compound according to any one of claims 1 to 6 wherein Z is of sub-formula (a) and (CH2) n 1 is attached at a carbon atom of the azacycle. 8. A compound according to claim 7 wherein Z is N-substituted 4-piperidylmethyl. 9. A compound according to claim 8 wherein the N-substituent is C2 or greater alkyl, or optionally substituted benzyl. 10. A compound according to claim 1 selected from the compounds E1 to E18 inclusive, as described herein, including pharmaceutically acceptable salts thereof. 11. A process for preparing the ester or amide compounds according to claim 6, which comprises reacting an appropriate 1-X2 containing acid derivative with an appropriate alcohol or amine. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, and a pharmaceutically acceptable carrier. 13. A compound according to claim 1 for use as an active therapeutic substance. 14. The use of a compound according to claim 1 in the manufacture of a medicament for use as a 5-HT4 receptor antagonist. 15. The use according to claim 14 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, WYMAN PAUL ADRIAN, GASTER, LARAMIE, MARY, KING, FRANCIS, DAVID, WYMAN, PAUL, ADRIAN
Applicants: SMITHKLINE BEECHAM PLC
Application year: 1993
Main classification: C07D401
IPC codes: A61K31, A61P9, A61P43, C07D209, C07D235, C07D401, C07D455