MUSCARINIC RECEPTOR ANTAGONISTS

Abstract: Muscarinic receptor antagonists, particularly useful in the treatment of irritable bowel syndrome, of formula (I), or a pharmaceutically acceptable salt thereof, where m is 1 or 2; R<1> and R<2> are each independently H or C1-C4 alkyl or together represent -(CH2)p- where p is an integer of from 2 to 5; R<3> is H or C1-C4 alkyl; wherein Z is a direct link, -CH2-, -CH2O- or -CH2S-; and R<4> is a group of formulae (II), (III), (IV) or Het, where R<5> and R<6> are each independently H, C1-C4 alkyl, C1-C4 alkoxy, -(CH2)nOH, halo, trifluoromethyl, cyano, -(CH2)nNR<7>R<8>, -CO(C1-C4 alkyl), -OCO(C1-C4 alkyl), -CH(OH)(C1-C4 alkyl), -C(OH)(C1-C4 alkyl)2, -SO2NH2, -CH2)nCONR<7>R<8> or -(CH2)nCOO(C1-C4 alkyl); R<7> and R<8> are each independently H or C1-C4 alkyl; n is 0, 1 or 2; X and X<1> are each independently O or CH2; q is 1, 2 or 3; and "Het" is pyridyl, pyrazinyl or thienyl.

Description: MUSCARINIC RECEFIOR A TAGC ESTS This invention relates to certain 3-pheπylglutariπιide derivatives. The ccnpσunds of the invention are iπuscarinic receptor antagonists which are selective for smooth muscle muscarinic sites over cardiac muscarinic sites and which do not have any significant antihistaminic activity. Thus the ccπpounds are useful in the treatment of diseases associated with altered roσtility and/or tone of smooth muscle which can, for example, be found in the gut, trachea and bladder. Such diseases include irritable bσwel syndrcme, diverticular disease, urinary incontinence, oesσphageal achalasia and chronic obstructive airways disease. According to the invention there are provided compounds of the formula:- (I) and their phaπnaceutically a∞eptable salts, where π is 1 or 2; R 1 and R2 are each independently H or C,- 4 alkyl or together represent -(OL) - where p is an integer of frcm 2 to 5; R 3 is H or Cy-C alkyl; wherein Z is a direct link, -<2L-, ~ CH 2 °~ or ~ CH 2 S ~ ; and R is a group of the formula:- where R 5 and R6 are • each independently H, C.-C alkyl, C.-C alkoxy, -(OL) OH, halo, trifluorcanethyl, cyano, alkyl), aϋq/l) , -CH(QH) (C-_-C 4 alkyl), -CfCHHC^ alkyl).,, -SO^, -(CH 2 ) n O0NR 7 R 8 or -(0^000(0^ alkyl); 7 8 R and R are each ind-r_-pendently H or C.-C alkyl; n is 0, 1 or 2; X and A are each independently 0 or CH ; q is 1, 2 or 3; and "Het" is pyridyl, pyraziπyl or thienyl. "Halo" means F, Cl, Br or I. Alkyl and alkoxy groups of 3 or 4 carbon atoms can be straight or branched chain. The preferred alkyl and alkoxy groups are methyl, ethyl, methoxy and ethoxy. m is preferably 2. 1 2 R and R are preferably each H or CH_. 3 . R is preferably methyl, Z is preferably -CEL-. 4 . R is preferably a group of the formula:- where R and R are each .UTdependeritly selected from H, halo, hydroxy, and C.-C. alkyl, and X and X^ are as defined above. The pharmaceutically acceptable salts of the σoπpounds of formula (I) include acid addition salts such as the hydrochloride, hydrfcronide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, besylate, citrate, fu arate, gluoonate, lactate, maleate, mesylate, succinate and tartrate salts. For a more comprehensive list of pharmaceutically acceptable salts see, for example, the Journal of Hiarmaceutical Sciences, Vo. 66, No. 1, January 1977, pages 1-19. These salts can be prepared conventionally, e.g. by mixing a solution of the free base and the acid in a suitable solvent, e.g. ethanol, and recovering the acid addition salt either as a precipitate, or by evaporation of the solution. The coirpσunds of the formula (I) can be prepared by the following route:- Compounds (I) 1 2 3 4 R , R , R , R , Z and are as defined for formula (I) and Q is a leaving group, e.g. Br, Cl, I, C.-C. alkanesulfonyloxy (e.g. methanesulfonyloxy) , benzenesulfonyloxy, toluer-jesulfonyloxy (e.g. p-toluenesulfonyloxy) or trifluoromethanesulfonyloxy. Preferably, Q is Cl, Br, I or methanesulfonyloxy. The reaction is preferably carried out in the presence of an acid acceptor such as sodium or potassium carbonate, sodium bicarbonate, triethylamine or pyridine, and in a suitable organic solvent, e.g. acεtonitrile, at up to the reflux temperature. Reaction temperatures of 60-120 C are generally desirable and it is most convenient to carry out the reaction under reflux. In the preferred technique, the σcπpσunds (II) and (III) are refluxed together in aσetonitrile in the presence of sodium bicarbonate. The product (I) can be isolated and purified conventionally. The starting materials of the formula (II) can be obtained by conventional procedures such as those described in the following Preparations section. The starting materials of the formula (III) are in general kncwn compounds which can be prepared by conventional techniques. The preparation of any novel starting materials of the formula (III) used in the Examples is however described in the following Preparations section. A typical route to the ccmpounds (II) is as follows:- ΈΓ R Cl— (αy —C—N—Benzyl Hi K 1 1 CH- (CH 2 ) m — C— N— Benzyl I CN IT or NaOP Hi R" N—Benzyl (IV) (i) Cyclisation, Qaricentrated hydrochloric acid, Reflux (ii)Removal of benzyl group (e.g. HOOOVMeCXVP C) . Compounds (II) The compounds of the formula (I) can also be prepared by the cyclisation of the ccsn-pounds of the formula (V) :- The cyclisation is typically carried out using concentrated mineral acid, preferably concentrated hydrochloric acid, typically under reflux. The starting materials (V) can be prepared analogously to the previcusly-described method for preparing the N-benzyl intermediates (IV) . 4 Some of the compounds of the formula (I) in which R is a substituted pheπyl group can be converted to other ccmπpσunds of the formula (I) as follows:- (a) A -00 (C,-C. alkyl) substituent on the phenyl group can be selectively reduced to -Cϊ- OH. Lithium aluminium hydride is the most suitable reducing agent. The reaction is typically carried in a suitable organic solvent, e.g. ether, at between 0 and room tøxperature. It is generally most convenient to use the starting material in the form of its methyl ester. (b) A hydroxy substituent on the phenyl group can be converted to -CC0(C,-C alkyl) by acylation using a C.-C alkanoyl chloride or bromide, or an alkanoic anhydride of the formula (C,-C alkyl.00)_0. The presence of an acid acceptor is preferable. The reaction is typically carried out at about room • temperature in a suitable organic solvent, e.g. dioxan. (c) A -00(C,-C. alkyl) substituent on the phenyl group can be reduced to a substituent of the formula -CH(OH) (C-.-C. alkyl) . A suitable reducing agent is sodium borohydride. The reaction is typically carried out at between 0 and room temperature in a suitable organic solvent, e.g. methanol. (d) A -(CH_) COO(C,-C alkyl) substituent, preferably where the alkyl group is methyl, can be converted to -(CH_. OONR 7R8 by reaction with ammonia or the appropriate amine R 7R8NH. When R7 o and R are both H, the use of aqueous (0.880) ammonia is generally most convenient, although the reaction can be carried out using ammonia in an organic solvent such as methanol or ethanol, or ammonia neat in a bcmπb. The reaction with methylamine is most conveniently carried out in ethanol. thσugh in some instances the reaction may proceed at a satisfactory rate at room temperature, heating at up to 120°, preferably 60 to 100°C, is generally necessary. For volatile amines, the reaction is best carried out in a boπib. (e) A hydroxymethyl or hydroxyethyl substituent on the phenyl group can be converted to -CELNR 7R8 or -(OL) NR7R8 firstly by reaction with thionyl chloride and secondly by reaction with 78 ammonia or the appropriate amine R R NH. The reaction with thioπyl chloride is typically carried out with heating, preferably under reflux, in a solvent such as methylene chloride. The reaction with ammonia or the amine is typically carried out at in a solvent such as ethanol, and heating, e.g. under reflux, may be necessary. (f) A -O0(C,-C 4 alkyl) substituent can be converted to -C(OH) (C j -C. alkyl) 2 by reaction with a C.-C. alkyllithium or G.-C. aHq^lmagnesium brcmide, chloride, or iodide (e.g. methyllithium, methylmagnesium bromide, methylmagnesium iodide or methylmagnesium chloride) . The reaction is typically carried out in a solvent such as ether at a terrperature of from 0°C to room temperature. and (g) An iodo substituent can be converted to C,-C alkoxycarboπyl by reaction, typically at about rocm teirperature, with carbon monoxide in a C-.-C alkanol containing a base [e.g. potassium carbonate] and a palladium (II) catalyst [e.g. b__^(triphenylphosphine)palladium (II) chloride]. The selectivity of the compounds as muscarinic receptor antagonists can be measured as follows. Male guinea pigs are sacrificed and the ileum, trachea, bladder and right atrium are removed and suspended in physiological salt solution under a resting tension of 1 g at 32 C aerated with 95% 0 and 5% CD . Contractions of the ileum, bladder and trachea are recorded using an isotonic (ileum) or isometric transducer (bladder and trachea) . The frequency of contraction of the spontaneously beating right atrium is derived from isαπϊetrically recorded contractions. Dose-response curves to either aσetylcholine (ileum) or carbachol (trachea, bladder and right atrium) are determined using a 1-5 minute contact time for each dose of agonist until the ■ maximum response is achieved. The organ bath is drained and refilled with physiological salt solution containing the lowest dose of the test compound. The test compound is allowed to equilibrate with the tissue for 20 minutes and the agonist dose-response curve is repeated until the maximum response is obtained. The organ bath is drained and refilled with physiological salt solution containing the second concentration of the test ∞mpcund and the above procedure is repeated. Typically four concentrations of the test σcmpσund are evaluated on each tissue. The concentration of the test compound which causes a doubling of the agonist concentration to produce the original response is determined ( value - Arunlakshana and Schild (1959), Brit. J. Hiarmacol., 14, 48-58). Using the above analytical techniques, tissue selectivity for muscarinic receptor antagonists is determined. Activity against agonist induced bronchoconstriction or gut or bladder contractility in comparison with changes in heart rate is det_e_cmined in the anaesthetised dog. Oral activity is assessed in the conscious dog deteπt ning compound effects on, for example, heart rate, pupil diameter and gut motility. Gaπpσund affinity for other cholinergic sites is assessed in the mouse after either .ύitravenous or intraperitoneal admiiistration. Thus, the dose which causes a doubling of pupil size is determined as well as the dose which inhibits the salivation and tremor responses to intravenous oxotremorine by 50%. For administration to man in the curative or prophylactic treatment of diseases associated with the altered motility and/or tone of smooth muscle, such as irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease, oral dosages of the compounds will generally be in the range of from 3.5 to 350 mg daily for an average adult patient (70 kg) . Thus for a typical adult patient, individual tablets or capsules will typically contain from 1 to 250 mg of active coπpσund, in a suitable phaπiaceutically acxeptable vehicle or carrier for administration singly or in multiple doses, once or several times a day. Dosages for intravenous administration will typically be within the range 0.35 to 35 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there will, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. For human use, the compounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. In a further aspect the invention provides a pharmaceutical composition ccmprising a compound of the formula (I) , or a phrmaσeutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. The invention also includes a compound of the formula (I) , or of a pharmaceutically accepable salt thereof, for the manufacture of a medicament for the treatment of diseases associated with the altered motility and or tone of smooth muscle, such as irritable bowel syndrome, diverticular diseases, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease. The invention yet further includes a method of treatment of a human being to cure or prevent a disease associated with the altered motility and or tone of smooth muscle, such as irritable bowel syndrome, which comprises treating said human being with an effective amount of a compound of the formula (I) , or a pharmaceutically acceptable salt or composition thereof. The invention also include the novel intermediates of the formula (II) . Th following Examples, in which all temperatures are in °C, illustrate the invention: EXfiMPIE 1 Preparation of (R.S) -3-(3-fN-4-hvdroxy^ene1^yl-N-methylamino) -3- methylbut-1-yl ) -3-pheπylqlutarimide A mixture containing (R,S)-3-(3-ιtethyl-3-roethylamirκ±ιut-l- yl)-3-phenylglutar.unide (0.58 g - see Preparation 11), 4-hyd.roxyphenethyl bromide (0.41 g) , sodium bicarbonate (2 g) and acetonitrile (20 ml) was heated under reflux for 20 hours. The mixture was partitioned between dichloromethane (50 ml) and water (50 ml) , the layers were separated, and the aqueous layer was further extracted with dichlorometharie (2 x 50 ml) . The combined dichloromethane extracts were dried ( gSO.) and concentrated in vacuo to give a foam which was purified by column chromatography on silica elutirxj with dichloromethane containing methanol (0% up to 5%) . The pi ucΛ-conteining fractions were combined and concentrated in vacuo to give the title compound as a foam, yield, 0.26 g. Analysis %:- Found: C,70.33 ; H,7.95; N,6.30; Calculated for ^gli^N 0 .1/2 EtOH.1/2 EJD: C,70.87; H,8.23 ; N,6.36. - ϊ-N.M-R. (CDC1 3 ) § = 8.80-7.80 (brs, 1H) ; 7.45-7.20 (m, 5H) ; 7.10-7.00 (d, 2H) ; 6.85-6.75 (d, 2H) ; 2.80-2.45 (m, 5H) ; 2.45-2.10 (m, 3H) ; 2.30 (s, 3H) ; 2.10-1.85 (m, 2H) ; 1.60-1.40 (brm, 1H) ; 1.35-1.20 (m, 1H) ; 1.00 (s, 6H) ppm. EXAMPLE 2 Preparation of (R,S)-3-f3-(N-4- iloroc)henethyl-N-me1^ylamino)-3- methylbut-1-yl)-3-rhenylqlutarimide A mixture containing (R,S)-3-(3-methyl-3-methylaminobut-l- yl)-3-pher lglutarimide (0.58 g - see Preparation 11), 4-chlorophenethyl bromide (0.47 g) , sodium bicarbonate (2 g) and acetonitrile (20 ml) was heated under reflux for 17 hours. Ηie mixture was partitioned between dichloromethane (50 ml) and water (50 ml) , the layers were separated and the aqueous layer was further extracted with dichloromethane (2 x 50 ml) . The combined dichloromethane extracts were dried (MgSO and concentrated in vacuo to give an oil which was purified fcy column c±ι_raratography on silica eluting with dichloromethane containing methanol (0% Lip to 4%) . The product-containing fractions were ccmibined and concentrated in vacuo to give the title compound as an oil which crystallised from ethanol, yield 0.09 g, m.p. 135-138°C. Analysis %:- Found: C,70.44; H,7.53; N,6.52; Calculated for ^gH-^Cl O : C,70.32; H,7.32; N,6.56. •' H-N.M.R. (CDC1 3 ) ζ = 7.95-7.85 (brs, 1H) ; 7.45-7.10 (m, 9H) ; 2.75-2.15 (m, 8H); 2.20 (s, 3H) ; 2.05-1.95 (m, 1H) ; 1.90-1.85 (m, 1H); 1.45-1.35 ( , 1H); 1.30-1.20 (m, 1H) ; 0.95 (s, 6H) pp . EXAMPLE 3 Preparation of (R.S)-3-(3-(N-4-πιethyl^±ter^thyl-N-methylamino)- 3-methylbut-l-yl)-3-Aenylqltιtarimide Me Me NaHCO, CH CN H A mixture containing (R,S)-3-(3-methyl-3-ιifethylam__i( fut-l- yl)-3-phenylglutari.mide (0.58 g - see Preparation 11), 4-methylphenethyl bromide (0.40 g) , sodium bicarbonate (2 g) and acetonitrile (20 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichlorcanethane (50 ml) and water (50 ml) , the layers were separated, and the aqueous layer further extracted with dichlorcanethane (2 x 50 ml) . The combined dichloromethane extracts were dried (MgSO.) and concentrated in vacuo to give an oil which was purified by column chromatography on silia eluting with dichloromethane containing methanol (1% up to 5%) . The pi xJuct-containing fractions were cαribined and concentrated in vacuo to give the title compound as a colourless oil which crystallised from ethanol, yield, 0.3 g, m.p. 145-148°C. Analysis %:- Found: C,76.81; H,8.51; N,6.83; Calculated for C l j N O : C,76.81; H,8.43; N,6.89. • ^I-N.M.R. (CDC1 3 ) g = 7.95-7.85 (brs, 1H) ; 7.40-7.25 (m, 5H) ; 7.10 (s, 4H); 2.75-2.20 (m, 8H) ; 2.35 (s, 3H) ; 2.25 (s, 3H) ; 2.10-2.00 (m, 1H); 1.95-1.85 (m, 1H) ; 1.50-1.40 (m, 1H) ; 1.30-1.20 (m, 1H) ; 0.95 (s, 3H); 0.90 (s, 3H) ppm. EXAMPLE 4 Preparation of (R,S)-3-(3-(N-pherethyl * ^-ιιret-hylam 1-yl)-3-phenylqlutarimide NaHCO, CH CN A mixture containing (R,S)-3-(3-methyl-3-methylaιnin±>ut-l- yl)-3-phenylglutarimide (0.58 g - see Preparation 11), phenethylbrcmiide (0.38 g) , sodium bicarbonate (1.0 g) and acetonitrile (20 ml) was heated under reflux for 5 hours. Water (30 ml) was added and the mixture was extracted with dichlorcmethane (2 x 50 ml) . The ccmibined dichloixmtethane extracts were dried (MgSO.) and concentrated in vacuo to give a gum which was purified by column chrαmatography on silica eluting with dichlσranethane containing methanol (0% up to 10%) . The product-CMntaining fractions were ccmibined and concentrated in vacuo to give the title ccmpound as a colourless solid, yield, 0.14 g, m.p. 135-137°C. Analysis %:- Found: C,75.78; H,8.17; N,6.99; Calculated for C^gH^N^: C,76.49; H,8.22; N,7.14. ^H-N.M.R. (CDC1 3 ) ζ = 8.20-8.00 (brs, IB) ; 7.40-7.15 (m, 10H) ; 2.80-2.20 (m, 8H); 2.25 (s, 3H) ; 2.10-2.00 (m, IH) ; 1.95-1.85 (m, IH); 1.50-1.40 (m, H) ; 1.35-1.20 (m, IH) ; 1.00 (s, 3H) ; 0.95 (s, 3H) pp . EXAMPLE 5 Preparation of (R,S)-3-f3-(N-4-c orophenethyl-N-methylamijκ))prσp * ^ 1-yl}-3-pheπylglutar.uιade B NaHCO, CH CN A mixture containing (R,S)-3-(3-methylaιιώτqprop-l-yl)-3- pher lglutarimide formate (0.5 g - see Preparation 4) , 4-chloro- phenethyl brcm de (0.42 g) , sodium bicarbonate (1.0 g) and acetonitrile (20 ml) was heated under reflux for 8 hours then partitioned between dichloromethane (50 ml) and water (50 ml) . The layers were separated and the aqueous layer was further extracted with dichloromethane (3 x 50 ml) . The ccmibined dichloromethane extracts were dried (MgSO ) and concentrated in vacuo to give an oil which was purified by column ch_romatography on silica eluting with dichloromethane cxsntairiing methanol (0% L_p to 8%) . The product-x5nteinir_g fractions were combined and 20 concentrated in vacuo to give a foam which was further purified by column ch_ι mιatography on silica elutirig with chloroform containing methanol (0% up to 8%) . The produtct * x>nteining fractions were combined and concentrated in vacuo to give the title cxxtpσund as a colourless foam, yield, 0.06 g. Analysis %:- Found: C,68.17; H,6.76; N,6.74 ; Calculated for C^H^ClN^.l ^ 1^0: C,67.71; H,6.92; N,5.87. 1 H- .M.R. (CDC1 3 ) S = 8.00-7.95 (brs, IH) ; 7.40-7.25; (m, 7H) ; 7.15-7.10 (d, 2H) ; 2.75-2.20 (m, 10H) ; 2.25 (s, 3H) ; 2.05-1.80 (m, 2H) ; 1.60-1.30 (m, 2H) ppn. EXAMPLE 6 Preparation of (R.S)-3-(3-(N-4-roethylT^enethyl-N-metoyla]Tiino) - prop-1-yl ) -3- eπylqlutarimide NaliCO, CH CN A mixture containing (R,S)-3-(3-iiethylamin¥)rop-l-yl)-3- pheriylglutarimide (0.5 g - see Preparation 4) , 4-methylphenethyl bromide (0.38 g) , sodium bicarbonate (1.0 g) and acetonitrile (20 ml) was heated under reflux for 8 hours then partitioned between dichloromethane (50 ml) and water (50 ml) . The layers were separated and the aqueous layer was further extracted with dichlorcanethane (3 x 50 ml) . The combined dichlorαnethane extracts were dried (MgSO ) and concentrated in vacuo to give a foam which was purified by column C-hrcmatography on silica eluting with dichloromethane containing methanol (0% up to 6%) . The p_coduct-ccntaining fractions were comibined and concentrated in vacuo to give a foam which was further purified by column hixmatography on silica eluting with chloroform containing methanol (0% up to 8%) . The product-cxintaining fractions were comibined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.09 g. Analysis %:- Found: C,70.55; H,7.47; N,6.81; Calculated for C^IL^O .1^0.1/4 CHC1 3 : C,70.96; H,7.92; N,6.83. • ϊ-N.M.R. (CDC1 3 ) g = 7.95-7.85 (brs, IH) ; 7.45-7.25 ( , 5H) ; 7.15-7.05 (Abq, 4H) ; 2.75-2.50 (m, 5H) ; 2.50-2.20 (m, 4H) ; 2.35 (s, 3H); 2.25 (s, 3H) ; 2.10-1.85 (m, 2H) ; 1.75-1.35 (m, 3H) ppm. EXAMPLE 7 Preparation of (R,S)-3-r3-rN-f2-(indan-5-yl)ethyl)-N-methylamino1- prop-1-yl]-3-^ιeπylqlutarimide NaHCO, CH CN A mixture containing (R,S)-3-(3-metlylam_i_nop_cop-l-yl)-3- phenylglutarύnide (0.5 g - see Preparation 4), 5-(2-brcanoethyl)- indane (0.43 g - see Preparation 12), sodium bicarbonate (1.0 g) and acetonitrile (20 ml) was heated under reflux for 8 hours then partitioned between dichloromethane (50 ml) and water (50 ml) . The layers were separated and the aqueous layer was further extracted with dichloromethane (3 x 50 ml) . The combined dichloromethane extracts were dried (MgSO ) and concentrated in vacuo to give a foam which was purified by column ch___-omatography on silica eluting with dichlorcanethane containing methanol (0% up to 8%) . The p:roduΛ-containiιxr fractions were ccmibined and 90/02040 23 concentrated in vacuo to give a foam -vΛiich was further purified by column ch_romatography on silica eluting with chloroform containing methanol (0% up to 5%) . The p_ x_x3uct-σoπt_a-ijrιing fractions were cαtibined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.09 g. Analysis %:- Found: C,75.07; H,7.82; N,6.87; Calculated for C^gH j -N-O-.l/Z H^O: C,75.51; H,7.80; N,6.77. " ϊ-N.M.R. (CDC1 3 ) § = 8.05-7.95 (brs, IH) ; 7.45-7.20 (m, 5H) ; 7.20-7.15 (d, IH); 7.05 (s, IH) ; 6.95-6.90 (d, IH) ; 2.95-2.85 (t, 4H); 2.75-2.70 (m, 2H) ; 2.65-2.50 (m, 2H) ; 2.50-2.30 (m, 4H) ; 2.30-2.20 (m, 2H); 2.30 (S, 3H) ; 2.15-1.85 (m, 4H) ; 1.60-1.35 (m, 2H) pp . EXAMPLE 8 Preparation of (R,S)-3-(3-(N * ^phenetAyl * ^-methylamino)-p_roιp-l- yl)-3-pheπylglxitarimide NaHC0„ CH CN ■ V A mixture cxsntaining (R,S)-3-(3-methylamir^)rop-l-yl)-3- pher lglutarimide (0.5 g - see Preparation 4) , phenethyl bromide (0.35 g) , sodium bicarbonate (1.0 g) and acetonitrile (20 ml) was heated under reflux for 8 hours then partitioned between dichloromethane (50 ml) and water (30 ml) . The layers were separated and the aqueous layer was further extracted with dichlorcmethane (3 x 30 ml) . The ccmibined dichlorcanethane extracts were dried (MgSO.) and concentrated in vacuo to give a gum which was purified by column dtircmatography on silica eluting with dichlorcEtnethane containing methanol (0% up to 8%) . The p_roduct-^x>ntairιing fractions were combined and concentrated in vacuo to give the title cc pσund as a foam, yield, 0.09 g. Analysis %:- Found: C,73.95; H,7.65; N,7.59; Calculated for C^H^N^.l/^ 1^0: C,73.96; H,7.55; N,7.50. -Η-N.M-R. (CDC1 3 ) g = 8.05-7.95 (brs, IH) ; 7.45-7.10 (m, 10H) ; 2.80-2.70 (m, 2H) ; 2.70-2.50 (m, 3H) ; 2.50-2.30 (m, 4H) ; 2.30-2.20 (m, IH); 2.25 (s, 3H) ; 2.10-1.85 ( , 2H) ; 1.60-1.30 (m, 2H) ppm. EXAMPLE 9 Preparation of (R,S) -3-(3-(N-benzyl-N-methylamino)prop-l-yl)-3- T-hemrlqlutarimide Ph A solution of (R,S)-6-(N-ben2yl-N-ιnethylaιn__j >)-l,3-di- cyano-3-pheπylhexane (19.0 g - see Preparation 3) in concentrated hydrochloric acid (100 ml) was heated under reflux for 2 hours. Water (500 ml) was added cautiously and the mixture neutralised (pH 8) by the addition of sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 150 ml) , the extracts were ccmibined then dried (MgSO-) and concentrated in vacuo to give the title compound as a gum, yield, 15.0 g. 2 H-N.M.R. (CDC1 3 ) = 8.30-8.20 (brs, IH) ; 7.45-7.20 (m, 10H) ; 3.45 (S, 2H); 2.65-2.55 (m, IH) ; 2.50-2.25 (m, 4H) ; 2.15 (s, 3H) ; 2.10-1.85 (m, 3H); 1.65-1.40 (m, 2H) ppm. EXAMPLE 10 Preparation of (R,S)-3-f3-(N-berιzyl-N-meiAylamijrø)-3-metbylbut-l- yl)-3-pheπylqlutarimide A solution of (R,S)-6-(N-berιzyl-N-methylamino)-l,3-dicyano-6- metftyl-3-pher_ylheptane (14.0 g - see Preparation 10) in concentrated hydrochloric acid (70 ml) was heated under reflux for 2 hours. The mixture was diluted with water (100 ml) and basified (pH 8) by the addition of sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 150 ml) and the ccmibined extracts dried (MgSO ) and concentrated in vacuo to give the title compound as a brown oil which crystallised on standing, yield, 11 g. A sample recrystallised from ethanol had m.p. 104-106°C. Analysis %:- Found: C,76.48; H,7.90; N,7.24; Calculated for C^^: C,76.15; H,7.99; N,7.40. • ^Ϊ-N.M.R. (CDC1 3 ) = 7.90-7.80 (brs, IH) ; 7.40-7.20 (m, 10H) ; 3.45 (s, 2H); 2.65-2.05 (m, 5H) ; 2.00 (s, 3H) ; 1.65-1.50 ( , 2H) ; 1.45-1.30 (m, IH) ; 1.05 (s, 6H) ppm. The following Preparations illustrate the preparation of the novel starting materials in the previous Examples:- Preparation 1 Preparation of 3-(N-benzyl-N-methylamino)-1-chloropropane hvdrochloride [See also J. Chem. Sec., (1944), 269.] Thioπyl chloride (22 ml) was added d_ropwise to a cooled (0 C) solution of 3-(N-beri2yl-N-methylamino)-propan-l-ol (32.8 g) in chloroform (100 ml) . The mixture was allowed to warm to room temperature and then heated under reflux for 1 hour. The mixture was concentrated in vacuo to give an oil which was triturated with ethyl acetate to give the title compound as a colourless powder, yield, 32 g. ^H-N.M.R. (CDC1 3 ) Sτ7.70-7.60 (m, 2H) ; 7.50-7.40 (m, 3H) ; 4.35-4.15 (m, 2H) ; 3.75-3.60 (m, 2H) ; 3.35-3.25 (m, IH) ; 3.15-3.00 (m, IH) ; 2.75 (d, 3H) ; 2.60-2.50 (m, IH) ; 2.45-2.30 (m, IH) ppm. Preparation 2 Preparation of (R,S)-4-(N-benzyl-N-methylamino)-l-cvano-l- pheπylbutane Sodium hydride (4.5 g of a 60% dispersion in mineral oil) was added in portions to a solution of phenylacetonitrile (11.7 g) in anhydrous tetrahydrofuran (100 ml) . When the addition was complete, the mixture was heated under reflux for 20 minutes then allowed to cool to roam teiφerature. 3-(N-Benzyl-N-methylami.no)- 1-chloropropane hydrochloride (15.0 g - see Preparation 1) was ground up with sodium hydroxide pellets to give an oil which was dissolved in anhydrous tetrahydrofuran (100 ml) and added dropwise to the phenylacetonitrile solution. The mixture was heated under reflux for 1.5 hours. The tetrahydrofuran was evaporated in vacuo and the residue partitioned between dichloromethane (200 ml) and water (100 ml) . The mixture was adjusted to pH7 by the addition of solid carbon dioxide, the layers were separated, and the aqueous layer was further extracted with dichloromethane (2 x 100 ml) . The ccmibined diciilorαnethane extracts were dried (MgSO ) and concentrated in vacuo to give an oil which was purified by column c_h_romatograj4ιy on silica eluting with dichloromethane containing methanol (0% up to 8%) . The p_roduct-σαntaining fractions were ccmibined and concentrated in vacuo to give the title compound as an oil, yield, 15.4 g. • ^-N.M.R. (CDCl 3 )£ 7.50-7.25 (m, 10H) ; 3.85-3.75 (t, IH) ; 3.50 (s, 2H); 2.50-2.40 (t, 2H) ; 2.20 (s, 3H) ; 2.05-1.90 (m, 2H) ; 1.75-1.65 (m, 2H) ppm. Preparation 3 Preparation of (R.S) 6-(N-benzyl-N-πιethylamino)-1.3-di-σvano-3- pheπylhexane dioxane Sodium hydride (0.2 g of a 60% dispersion in mineral oil) was added to propan-2-ol (2 ml) and the resulting solution was added to a solution of 4-(N-benzyl-N-methylamino)-1-cyano-l- pheπyibutane (15.0 g - see Preparation 2) and acrylonitrile (4.0 ml) in 1,4-dioxane (100 ml) . The mixture was stirred at room temperature for 20 hours then concentrated in vacuo. Water (100 ml) was added and the mixture was neutralised (pH 7) by the addition of solid carbon dioxide then extracted with dichloromethane (3 x 50 ml) . The ∞mbined dichloromethane extracts were dried (MgSO.) and concentrated jn vacuo to give the title compound as a gum, yield, 19 g. ^Η-N.M.R. (CDC1 3 ) =7.50-7.25 (m, 10H) ; 3.45 (s, 2H) ; 2.65-2.20 (m, 5H); 2.20-2.00 (m, 3H) ; 2.10 (s, 3H) ; 1.75-1.60 (m, IH) ; 1.40-1.25 (m, IH) ppm. Preparation 4 Preparation of (R,S)-3-(3-methyla3fiuJicθ-cσp-l-yl)-3-rAeπyl- qlutarimide formate 10% Palladium-on-carbon (5 g) was added in portions to a cooled (0°C) solution of (R,S)-3-{3-(N-benzyl-N-methylam__.no)prop- l-yl}-3-pheπylglutarimide (15.0 g - see Example 9) in methanol (100 ml) and formic acid (15 ml) . The mixture was allcwed to warm to room -temperature and stirred for 16 hours then filtered and concentrated in vacuo to give the title compound as a gum, yield, 15 g. • 'Ή-N.M.R. (CDC1 ) = 9.60-9.20 (brs, IH) ; 8.35-8.20 (s, 2H) ; 7.40-7.15 ( , 5H); 3.00-2.85 (m, 2H) ; 2.65 (s, 3H) ; 2.65-2.45 (IH); 2.40-2.20 (m, 3H) ; 2.10-1.75 (m, 3H) ; 1.70-1.50 (brs, IH) pp . Preparation 5 Preparation of ethyl 3-methyl-3-methylamirκ3butanoate [see also J. Org. Chem., 33, 1322, (1968)] M A mbcture containing ethyl 3,3-dimethylacrylate (100 g) and methylamine (140 ml of a 33% solution in ethanol) in ethanol (400 ml) was allcwed to stand at room teπperature for 2 weeks. The mixture was concentrated in vacuo to give an oil which was fractionally distilled in vacuo to give the title ccmpound as a colourless, mobile oil, yield 95.0 g, b.p. 68-75 /20 mm.Hg. 1 H-N.M.R. (CDC1 3 ) S = 4.1 (q, 2H) ; 2.40 (s, 2H) ; 2.30 (s, 3H) ; 1.60 (brs, H); 1.25 (t, 3H) ; 1.15 (s, 6H) pp . Preparation 6 Preparation of ethyl 3-(N-berιzyl-N-methylanύno)-3-methylbutar 3ate A mixture containing ethyl 3-methyl-3-methylam_i__nobutarκ3ate (95 g - see Preparation 5) , benzyl bromide (72 ml) , anhydrous potassium carbonate (138 g) and acetonitrile (500 ml) was heated under reflux for 1.5 hours. The mixture was concentrated _ vacuo and the residue partitioned between dichloromethane (500 ml) and 10% aqueous potassium carbonate (300 ml) . The layers were separated and the aqueous layer extracted with dichlorcanethane (2 x 100 ml) . The ccmibined dichloromethane extracts were dried (MgSO ) and concentrated in vacuo to give the title ccmpound as a mobile, colourless oil, yield 150 g. • ^-N.M.R. (CDC1 3 ) C ) = 7.40-7.20 (m, 5H) ; 4.20 (q, 2H) ; 3.60 (s, 2H) ; 2.55 (s, 2H) ; 2.15 (s, 3H) ; 1.35 (s, 6H) ; 1.30 (t, 3H) ppm. Preparation 7 Preparation of 3-(N-ben2yl-N-methylamino)-3-met-h^^ A solution of ethyl 3-(N-benzyl-N-xnethylam_i_no)-3-inethyl- Ixttanoate (23.6 g - see Preparation 6) in anhydrous tetrahydro¬ furan (100 ml) was added, dropwise, over 20 minutes to a stirred suspension of lithium alimiinium hydride (7.2 g) in anhydrous tetrahydrofuran (300 ml) . When the addition was σcmplete, the mixture was stirred at room temperature for 3 hours. Water (7 ml) was carefully added dropwise followed by 15% aqueous sodium hydroxide (7 ml) and finally more water (20 ml) . The resulting solid precipitate was filtered off and washed with ethyl acetate (3 x 50 ml) . The filtrate and washings were combined and concentrated in vacuo to give the title ccmpound as a colourless, mobile oil, yield 19.0 g. " Sϊ-N.M.R. (CDC1 3 ) J = 7.40-7.20 (m, 5H) ; 6.15 (brs, IH) ; 3.95 (t, 2H); 3.65 (s, 2H) ; 2.15 (s, 3H) ; 1.80 (t, 2H) ; 1.25 (s, 6H) ppm. Preparation 8 Preparation of 2- (N-benzyl-N-methylamino) -4-chloιx>-2-roethv_l±ιutane hydrochloride A solution of 3-(N-benzyl-N-methylamino)-3-methyl-butan-l-ol (6.9 g - see Preparation 7) in chloroform (20 ml) was added dropwise over 30 minutes to a solution of thioπyl chloride (4.9 ml) in chloroform (20 ml) at 0 . When the addition was ccβiplete, the mixture was stirred at room teπperature for 18 hours. Ethanol (5 ml) was added and the mixture concentrated in vacuo to give an oil which was crystallised f om ethyl acetate to give the title compound as a colourless powder, yield 2.62 g, m.p. 164-166 . ^H-N.M-R. (CDC1 3 ) = 7.75 (m, 2H) ; 7.50-7.40 ( , 3H) ; 4.70 (dd, IH); 3.80-3.65 (m, 3H) ; 2.60-2.45 ( , 5H) ; 1.70 (d, 6H) ppm. Preparation 9 Preparation of (R.S)-4-(N-benzyl-N-methylamino)-l-σvano-4-methyl- 1-pheπylpentane Sodium hydride (4.4 g of a 60% dispersion in mineral oil) was added in portions to a solution of phenylacetonitrile (11.7 g) in arihydrous tetrahydrofuran and the mixture was heated under reflux for 15 minutes. The resulting yellcw suspension was cooled to room teπperature whereupon 2-(N-benzyl-N-methylam_ijrκ3)-4-chloro- 2-methylbutane (20 g - freshly prepared frcrni its hydrochloride salt by partitioning between dichlororoethane and 15% aqueous sodium hydroxide - see Preparation 8) was added and the mixture heated under reflux for 0.5 hour. The tetrahydrofuran was evaporated in vacuo and the residue partitioned between dichloromethane (200 ml) and water (100 ml) . The layers were separated and the aqueous layer was neutralised (pH 7) by the addition of solid carbon dioxide. The aqueous solution was extracted with dichloromethane (2 x 100 ml) , the dichloromethane extracts were combined then dried (MgSO ) and concentrated in vacuo to give a waxy solid which was purified by coljumn chrcmatography on silica eluting with toluene cxjnteining diethyl ether (10% up to 40%) . The product-conteύ ing fractions were ccmibined and concentrated in vacuo to give the title ccmpound as an orange oil, yield, 17.1 g. • ^-N.M.R. (CDC1 3 ) ξ = 7.50-7.20 (m, 10H) ; 3.85-3.75 (m, 2H) ; 3.50; (s, IH) ; 2.20-2.05 (m, 2H) ; 2.05 (s, 3H) ; 1.75-1.60 ( , 2H) ; 1.10 (s, 6H) ppm. Preparation 10 Preparation of (R.S)-6-(N-ber>2yl-N-methylamino)-l,3-dicvano-6- methyl-3-phenylheptane NaOEt dioxan Sodium (0.46 g) was dissolved in ethanol (10 ml) and the resulting solution added dropwise to a solution of (R,S)- 4-(N-benzyl-N-methylamino)-l-cyano-4-methyl-l-phenylpentane (17.5 g - see Preparation 9) and acrylonitrile (3.18 g) in 1,4-dioxane (30 ml) . The mixture was warmed to 55°C then allowed to cool. A further quantity of acrylonitrile (4 ml) was added and the mixture was stirred at room terrperature for 2 hours. The mixture was partitioned between dichlorαnethane (150 ml) and water (100 ml) then neutralised (pH 7) by the addition of solid carbon dioxide. The layers were separated and the aqueous layer was further extracted with dichloromethane (2 x 100 ml) . The ccmibined dichloromethane extracts were dried (MgSO.) and concentrated in vacuo to give an oil whicii was partially purified by column chrcanatography on silica eluting with diciilor nethane containing methanol (0% up to 10%) . The pπxiuct-cxDntairiing fractions were ccmibined and concentrated in vacuo to give an oil which was further purified ty column chrαnatography on silica eluting with toluene containing ethyl acetate (15%) . The product-containing fractions were ccmibined and concentrated in vacuo to give the title ccmpound as a gum, yield, 14 g. HH-N.M.R. (CDC1 3 ) = 7.45-7.15 (m, 10H) ; 3.50-3.35 (Abq, 2H) ; 2.60-2.05 (m, 4H); 2.00 (s, 3H) ; 1.70-1.60 (m, 2H) ; 1.30-1.20 (m, 2H); 1.10 (s, 3H); 1.00 (s, 3H) ppm. Preparation 11 Preparation of (R,S)-3-(3-methyl-3-methylaminobut-l-yl)-3- phenylqlutarimide 10% Palladium-on-carbon (5 g) was added in portions to a cooled (0°C) solution of (R,S)-3-{3-(N-ber_zyl-N-methylamino)- 3-methy_l±ιut-l-yl}-3-^eιψlglutar_i_mide (10.5 g - see Example 10) in methanol (100 ml) ∞ntaining formic acid (11 ml) . The mixture was allowed to warm to room teπperature and stirred for 16 hours then filtered and concentrated in vacuo to give the title (xmpσund as a gum, yield 7.1 g. " hl-N. .R. (CDC1 3 ) £ = 7.45-7.25 ( , 5H) ; 2.65-2.55 (m, IH) ; 2.50-2.20 (m, 3H) ; 2.30 (s, 3H) ; 2.10-1.95 (m, IH) ; 1.95-1.85 (m, IH) ; 1.55-1.45 (m, IH) ; 1.35-1.25 (m, IH) ; 1.10 (s, 3H) ; 1.05 (s, 3H) ppm. Preparation 12 Preparation of 5-(2-brcanciethyl) indane Phosphorus tribrc de (3.5 ml) was added, dropwise, to a solution of 5-(2-hydroxyethyl) indane (14.0 g) (FR-A-2139628) in carbon tetrachloride (100 ml) . The mixture was stirred at room temperature for 0.5 hour and then heated under reflux for 2 hours. Ice (100 g) was added and the mixture partitioned between dichloromethane and 10% aqueous sodium carbonate. The layers were separated and the aqueous layer extracted with didilorαnethane (2 x 100 ml) . The comibined dicdilorαnethane extracts were dried (MgSO. ) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichlorOmethane. The product-∞ntaύiing fractions were σαtibined and concentrated in vacuo to give the title compound as a colourless oil, yield 10.5 g. " ^L-N.M.R. (CDC1 3 ) £ = 7.30-7.00 (m, 3H) ; 3.60 ( , 2H) ; 3.20 (m, 2H) ; 3.00-2.85 (m, 4H) ; 2.20-2.05 (m, 2H) ppm. It will be appreciated from the foregoing that what we will claim may include the following:- (1) The compounds of the formula (I) and their pharmaceutically acceptable salts; (2) Processes as described herein for preparing the compounds of the formula (I) and their salts; (3) Riarmaceutical compositions comprising a ccmpound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier; (4) Any novel intermediates described herein; (5) A ccmpound of the formula (I) , or a pharmaceutially acceptable salt thereof, for use as a medicament. (6) The use of a compound of the formula (I) , for the manufacture of a medicament for the treatment of diseases associated with the altered motility and or tone of smooth muscle, such as irritable bcwel syndrαne, diverticular disese, urinary incontinence, oesophageal aάhalasia and chronic obstructive airways disease.

Claims: CLAIMS A cxaipound of the formula:- or a pharmaceutically acceptable salt thereof, where m is 1 or 2; 1 2 R and R are each independently H or C,-C alkyl or together represent -(CH_) - where p is an integer of from 2 to 5; 3 . R is H or C..-C. alkyl; wher-ein Z is a direct link, -CΪL,-, -CH_0- or -CH_S-; and R is a group of the formula: - 5 6 where R and R are each independently H, C,-C. alkyl, C,-C. alkoxy, -(CH ) OH, halo, trifluoromethyl, cyano, 2'n ,7 ^ 8 -(CH 2 ) n NR R , -COfC^-C. j alkyl), -0C0(C 1 -C 4 alkyl), -CH(OH) (C j -C j alkyl) , -C(OH) (C-_-C 4 alkyl) 2 , -S0 2 NH 2 , -(CH 2 ) n CONR 7 R 8 or -(CH 2 ) n O0O(C 1 -C 4 alkyl); R7 and R8 are each independently H or C,'-C. alkyl; n is 0, 1 or 2; X and ^ are each independently O or CH_; q is 1, 2 or 3; and "Het" is pyridyl, pyrazinyl or thienyl. 2. A compound as claimed in claim 1 in which m is 2. 3. A ccmpound as claimed in claim 1 or 2 in which R 1 and R2 are each H or CH . 4. A cαπpcund as claimed in any one of the preceding claims 3 . in which R is methyl and Z is -CH_-. 5. A ccmpound as claimed in any one of the preceding claims ui which R 4 i.s a group of the formula:- where R 5 and R6 are each _ϊ_rκlependently selected from H, halo, hydroxy, and .-C alkyl, and X and λ are as defined in claim 1. 6. A pharmaceuticalcomposition comprising a ccmpound of the formula (I) as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 7. A compound of the formula (I) as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use as a medicament. 8. The use of a compound of the formula (I) as claimed in any one of claims 1 to 5, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as a muscarinic receptor antagonist. 9. A process for preparing a compound of the formula: or a pharmaceutically acceptable salt thereof, where m is 1 or 2; R 1 and R2 are each ιnd(=_pendently H or C- -C * alkyl or together represent -(CH-,) - where p is an integer of from 2 to 5; ΈΓ is H or C,-C. alkyl; wherein Z is a direct link, -CH -, -CH-O- or "CH_S- 4 . and R is a group of the formula:- or Het where R5 and R6 are each independently H, C,-C alkyl, C,-C alkoxy, -(CH-J OH / halo, trifluoromethyl, cyano, -(CH^NR^ 8 , -00(0^ alkyl), -000(0^ alkyl) , -CH(CΗ) (C.J-C 4 alkyl), -C(OH) ( ,-C 4 alkyl) y -S0 2 NH 2 , -(CK^) n 00NR 7 R 8 or -(CH 2 ) n COO(C 1 -C 4 alkyl); R 7 and R8 are each independently H or C,-C alkyl; n is 0, 1 or 2; X and XX 11" are each independently O or CH ; q is 1, 2 or 3; and "Ηet" is pyridyl, pyrazinyl or thienyl, characterised by either (a) reacting a ccmpound of the formula:- where R 1 , R2 , R 3 , and m are as defined above, with a ccmpound of the formula:- K^ -Z-R * (III) where Z and R are as defined above and Q is a leaving group, or (b) cyclising a compound of the formula:- with a concentrated mineral acid, 1 2 3 4 where R , R , R , R , m and Z are as defined above, said processes (a) or (b) being followed by, optionally, conversion of the product of the formula (I) into a pharmaceutically acceptable salt. 10. A process as claimed in claim 9, characterised in that in part (a) , Q is Cl, Br, I or methanesulfonyloxy and the reaction is carried out in the presence of an acid acceptor, and in that in part (b) , the concentrated mineral acid is concentrated hydrochloric acid. 11. A method of treating irritable bowel syndrome in a patient characterised by administering to said patient an effective amount of a ccmpound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5.

Inventors: CROSS PETER EDWARD, MACKENZIE ALEXANDER RODERICK, CROSS, PETER, EDWARD, MACKENZIE, ALEXANDER, RODERICK
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER, LIMITED
Application year: 1990
Main classification: C07D211
IPC codes: C07D211, C07D405