WO1991010651A1

WO1991010651A1 - Anticholinergic agents

Info

Publication number: WO1991010651A1
Application number: PCT/EP1990/002262
Authority: WO
Inventors: David Alker; Peter Edward Cross
Original assignee: Pfizer Corp Belgium; Pfizer Ltd Great Britain; Pfizer Corp SRL
Current assignee: Pfizer Corp Belgium; Pfizer Ltd Great Britain; Pfizer Corp SRL
Priority date: 1990-01-06
Filing date: 1990-12-18
Publication date: 1991-07-25
Anticipated expiration: 1992-07-06
Also published as: ES2065668T3; FI97131C; FI922835A0; GR3014927T3; DK0511222T3; CA2072575A1; PT96422B; EP0511222B1; IE64206B1; GB9000305D0; FI97131B; EP0511222A1; ATE115130T1; IE910021A1; DE69014903T2; CA2072575C; PT96422A; DE69014903D1; JPH0730019B2; JPH05501882A

Abstract

Selective muscarinic receptor antagonists of formula (I), wherein R?1 and R2¿ are both optionally substituted phenyl, the broken line is an optional bond, X is (a), (b) or CH- when the double bond is absent or is (c) when the double bond is present, X being attached to a carbon atom of A, A is selected from certain piperidine and pyrrolidine groups, n is 1 to 3 and R3 is optionally substituted phenyl or thienyl, pyridyl or pyrazinyl.

Description

Anticholinergic Agents

1

This invention relates to certain disubstituted piperidine and pyrrolidine derivatives as selective muscarinic receptor antagonists.

GB-780,027 discloses, amongst other compounds,

3-(benzhydryloxy)- and 3-(xanthyloxy)-N-aralkylpiperidines as oxytocic agents, being devoid of antispasmodic activity at the therapeutic doses employed. No N-phenethyl substituted examples were synthesised or exemplified within the scope.

US-2,974,146 provides N-aralkyl-3-piperidyl benzhydryl ethers having activity as sedatives and in prolonging the hypnotic effect of barbiturates, with only the corresponding quaternary ammonium salts being stated to possess gastro-intestinal

antispasmodic activity. Although N-phenethyl-3-piperidyl benzhydryl ether is listed as "a specific compound provided by the invention", no preparative details or pharmacological data are presented and it is clear that the compound was never actually made.

US Patent 4632925 describes N-substituted diphenyl- piperidines which exhibit insulin-lowering activity.

It has now unexpectedly been discovered that the substituted piperidine and pyrrolidine derivatives provided by the present invention are muscarinic 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 compounds are useful in the treatment of diseases associated with altered motility and/or tone of smooth muscle which can, for example, be found in the gut, trachea and bladder. Such diseases include irritable bowel syndrome, diverticular disease, urinary incontinence, oesphageal achalasia and chronic obstructive airways disease.

According to one aspect of the invention, there are provided compounds of the formula (I):

and their pharmaceutically acceptable salts,

wherein R¹ and R² are the same or different and each is phenyl which is unsubstituted or substituted by at least one group selected from C₁-C₄ alkyl and halo,

the broken line represents an optional double bond and X is COH, SiOH- or CH- when said double bond is absent or is C=

when said double bond is present, X being attached to a carbon atom of A,

A is

when said double bond is absent or A is

or

when said double bond is present

n is from 1 to 3,

m is 1 or 2,

p is 0 or 1,

q is 0 or 1

R³ is or Het,

R⁴ and R⁵ are each independently H, C₁-C₄ alkyl, C₁-C₄ alkoxy or

(CH₂)_rOH wherein r is 0, 1 or 2, or R⁴ and R⁵ together form a -Y-(CH₂)_s-Z- group wherein Y and Z are independently -O- or -CH₂- and s is 1, 2 or 3, and Het is thienyl, pyridyl or pyrazinyl, with the provisos that when q is O or A is then n is 2 or 3,

and that when A is =CH — or- CH₂- -then R³ is not Het.

In the above definitions "thienyl" includes 2- and 3-thienyl and pyridyl includes 2-, 3- and 4- pyridyl. "Halo" means F, Cl, Br or I. Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched-chain. The preferred alkyl and alkoxy groups are methyl, ethyl, methoxy and ethoxy.

R¹ and R² may be unsubstituted phenyl. X is preferably C(CH)-. Preferred examples of R³ are pyridyl, 2,3-dihydro- benzofuranyl, 3,4-methylenedioxyphenyl, tolyl, methoxyphenyl and hydroxymethylphenyl.

A particularly preferred compound is 3-(diphenylhydroxy- methyl)-1-(3,4-methylenedioxyphenethyl)piperidine.

The compounds of the formula (I) contain at least one asymmetric centre and will therefore exist as a pair of

enantiomers or diastereomeric pairs of enantiomers. Such

enantiomers or diastereomeric pairs of enantiomers may be resolved by physical methods, e.g. by fractional recrystallisation, chromatography or H.P.L.C. of a racemic mixture of the compound of the formula (I), or of a suitable salt or derivative thereof.

Most preferably, the individual enantiomers of the compounds of the formula (I) containing one asymmetric centre are prepared from optically pure intermediates.

The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts such as the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, besylate, citrate, fumarate, gluconate, lactate, maleate, mesylate, succinate and tartrate salts. For a more comprehensive list of pharmaceutically acceptable salts see, for example, the Journal of Pharmaceutical Sciences, Vol. 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 compounds of the formula (I) can be prepared by a number of routes, including the following:- Route A

This can be illustrated as follows:- 1 A CH₂)_n

R

(II) (III)

R¹, R², A, X, n and R³ are as defined for formula (I) and Q is a leaving group, e.g. Br, Cl, I, C₁-C₄ alkanesulphonyloxy (e.g. methanesulphonyloxy), benzenesulphonyloxy, toluenesulphonyloxy

(e.g. p-toluenesulphonyloxy) or trifluoromethanesulphonyloxy.

Preferably, Q is Cl, Br, I or methanesulphonyloxy. In formula

(II) the hydrogen atom shewn is attached to the nitrogen atom of

A.

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. acetonitrile, 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. Iodo is generally the most suitable leaving group but since the starting materials (III) are generally most conveniently available as chlorides or bromides, the reaction is often most suitably carried out using the compound (III) as a chloride or bromide but in the presence of an iodide such as sodium or potassium iodide. In the preferred technique, the compounds (II) and (III), (III) being in bromide or chloride form, are refluxed together in acetonitrile in the presence of sodium carbonate and sodium iodide. 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

Preparations below. The starting materials of the formula (III) are in general known compounds which can be prepared by

conventional techniques.

The preparation of the novel starting materials of the formula (III) used in the Examples is described in the following Preparations section.

Route B

This route is useful for preparing compounds in which n is 2 and R³ is 2- or 4-pyridyl or pyrazinyl and can be described as follows:-

R¹, R², A and X are as defined for formula (I). Clearly the vinyl group must be attached to the 2- or 4-position of the pyridine ring.

The reaction is typically carried out with heating at up to

160°C, preferably 80° to 140ºC, in a suitable organic solvent, e.g. 1-butanol. The use of a basic (preferably a strong base which is soluble in an organic solvent such as N-benzyltrimethyl- ammonium hydroxide ["Triton B"- Trade Mark] or acidic (preferably a C₁-C₄ alkanoic acid) catalyst is useful. The preferred

procedure is to reflux the reactants in an organic solvent in the presence of a basic catalyst such as "Triton B".

Route C

Tins route may be used when R¹ and R² are phenyl and X is C(OH)- and may be illustrated as follows:

RO-CO-A-(CH₂)_nR³ → Compounds (I)

Excess PhLi

wherein R is a C₁-C₁ alkyl group such as ethyl. In this process a carboxylate of the appropriate piperidine or pyrrolidine

derivative is allowed to react with excess pheiryllithium to convert the RO-CO- group to a Ph₂C(OH)- group. The reaction may be conducted by adding the phenyllithium to the carboxylate in a suitable solvent such as diethyl ether at lew temperature, allowing the mixture to warm to room temperature, quenching the remaining phenyllithium with water and extracting the desired compound of formula (I) with a suitable organic solvent. The carboxylate starting compounds may be prepared as described in the Preparations below. 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% O₂ and 5% CO₂. 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 isometrically recorded contractions.

Dose-response curves to either acetylcholine (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 test compound and the above procedure is repeated. Typically four concentrations of the test compound are evaluated on each tissue.

The concentration of the test compound which causes a doubling of the agonist concentration required to produce the original response is determined (pA₂ value - Arunlakshana and Schild (1959), Brit. J. Pharmacol., 14, 48-58). Using the above analytical techniques, tissue selectivity for muscarinic receptor antagonists is determined. Activity against agonist induced bronchoconstriction, gut or bladder contractility in comparison with changes in heart rate is determined in the anaesthetised dog. Oral activity is assessed in the conscious dog determining compound effects on, for example, heart rate, pupil diameter and gut motility.

Compound affinity for other cholinergic sites is assessed in the mouse on either intravenous or intraperitoneal administration. Thus, the dose to cause a doubling of pupil size is determined as well as the dose to inhibit by 50% the salivation and tremor responses to intravenous oxotremorine.

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 any 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 compound, in a suitable pharmaceutically acceptable 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 age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, 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 comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a

pharmaceutically acceptable diluent or carrier.

The invention also includes a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use as a

medicament, particularly for use in the treatment of irritable bowel syndrome.

The invention further includes the use of a compound of the formula (I), or of a pharmaceutically acceptable 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 bcwel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease.

The following Examples, in which all temperatures are in °C, illustrate the invention.

Example 1

1-[ (2- (2 ,3-Dihydro-5-benzofuranyl)ethyl]-3-(diphenylhydroxy- methyl)-piperidine

A mixture of 3-(diphenylhydroxymethyl)piperidine (135 mg, 0.50 mmol) (see J. Org. Chem., 4084, 26, 1961 for preparation), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (115 mg, 0.50 mmol), sodium carbonate (0.50 g) and sodium iodide (50 mg) in acetonitrile (20 ml) was heated under reflux for 16 hours, filtered and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by

chromatography on SiO₂ (6 g) using dichloromethane plus 0-20% ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give the title compound (110 mg) as a colourless oil which was characterised as a hemihydrate.

Analysis %:-

Found: C,79.7; H,7.5; N,3.1;

C₂₈H₃₁NO₂.0.5H₂ requires: C,79.6; H,7.6; N,3.3.

Examples 2-9

The compounds of Table 1 were prepared by the method of

Example 1 by reacting the appropriate piperidine derivative with the appropriate alkylating agent Q(CH₂)_n R³ and were obtained in the form shown. The starting materials for Examples 4 and 5 were each used as their hydrochloride salts.

Table 1

Example 10

3-(Diphenylhydroxymethyl)-1-[2-(2-pyridyl)ethyl]piperidine

A mixture of 3-(diphenylhydroxymethyl)piperidine (267 mg, 1.0 mmol), 2-vinylpyridine (0.32 g, 3.0 mmol) and Triton B (3 drops) in 1-butanol (10 ml) was heated under reflux for 18 hours, diluted with water and ethyl acetate and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was twice taken up in toluene and evaporated and it was then purified by chromatography on SiO₂ using dichloromethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (80 mg) as a pale brown oil which was characterised containing 0.25 equivalents of water.

Analysis %:-

Found: C,79.7; H,7.4; N,7.4;

C₂₅H₂₈N₂0.0.25H₂O requires: C,79.7; H,7.6; N,7.4.

Example 11

1-[2-(2 ,3-Dihydro-5-benzofuranyl)ethyl]-4-(2 ,2-diphenyl-2- hydroxyethyl)piperidine

A 1.9 M solution of phenyllithium (1.0 ml, 1.9 mmol) was added dropwise over 10 minutes to a stirred solution of ethyl 1-[2-(2,3-dihydro-5-benzofuranyl)ethyl]piperidine-4-acetate (130 mg, 0.40 mmol) in ether (10 ml) with cooling in an acetone/CO₂ bath. The mixture was stirred at -70°C for 1 hour, allowed to warm to room temperature and stirred for 16 hours. The mixture was quenched cautiously with water and extracted into ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on SiO₂ using dichloromethane plus 20% ethyl acetate plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (100 mg) as a colourless foam which was characterised as a hemihydrate.

Analysis %:-

Found: C,79.7; H,7.7; N,3.5;

C₂₉H₃₃NO₂.0.5H₂O requires: C,79.8; H,7.8; N,3.2.

Example 12

4-(2,2-Diphenyl-2-hydroxy)ethyl-1-(3,4-methylenedioxybenzyl)- piperidine

The title compound was prepared by the method of Example 11 by reacting phenyllithium with ethyl 1-(3,4-methylenedioxybenzyl)- piperidine-4-acetate. The title compound was obtained as a colourless solid, m.p. 142-145°C, which was characterised containing 0.25 equivalents of water.

Analysis %:-

Found: C,77.2; H,7.1; N,3.2;

C₂₇H₂₉NO₃.0.25H₂O requires: C,77.2; H,7.0; N,3.3. Example 13

3-(Diphenylhydroxymethy)-1-(4- methoxyphenethyl)piperidine The title compound was prepared by the method of Example 11 by reacting phenyllithium with ethyl 1-(4-methoxyphenethyl)- piperidine-3-carboxylate. The title compound was obtained as a colourless oil.

Analysis %:-

Found: C,80.3; H,7.7; N,3.5;

C₂₇H₃₁NO₂ requires: C,80.8; H,7.8; N,3.5.

Example 14

3-(2,2-Diphenyl-1-ethenyl)-1-(3,4-methylenedioxyphenethyl)- piperidine Hydrochloride

A solution of 3-(2,2- diphenyl-2-hydroxyethyl)-1- (3, 4-methylenedioxyphenethyl) piperidine hydrate (162mg) (Example 3) in 2M hydrochloric acid (4.5ml) was heated at 100°C for 30 minutes and evaporated to give the title compound as a colourless foam (165mg, 98%) , which was characterised as a hydrate.

Analysis %:-

Found: C, 72.4; H, 6.7; N, 3.0;

C₂₈H₂₉NO₂.HCL.H₂O requires: C, 72.2; H, 6.9; N, 3.0. Example 15

3-(2 ,2-Dip henylethyl) -1-(3 ,4-methylenedioxyphenethyl) - piperidine

A solution of 3-(2,2-diphenyl-1-ethenyl)-1- (3,4-methylenedioxyphenethyl)piperidine hydrochloride (135mg) (Example 14) in EtOH (20ml) was stirred at 40°C under a hydrogen atmosphere of 45 psi in the presence of 10% palladium on charcoal. The mixture was filtered and the filtrate evaporated. The residue was partitioned between dichloromethane and 2M aqueous sodium hydroxide solution and the organic layer was dried over sodium sulphate and evaporated. The residue was purified by

chromatography on silica using dichloromethane plus 2.5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (60mg, 50%) which was characterised as a hemihydrate.

Analysis %:-

Found: C, 79.7; H, 7.4; N, 3.2;

C₂₈H₃₁NO₂.0.5H₂O requires: C, 79.6; H, 7.6; N, 3.3. Preparation 1

3-Diphenylmethylenepiperidine Hydrochloride

A mixture of 3-(diphenylhydroxymethyl) (801 mg, 3.0 mmol) and 2M hydrochloric acid (12 ml) was stirred at 100°C for 2 hours and evaporated. The residue was triturated with toluene and recrystallised from methanol to give the title compound (730 mg) as a colourless solid, m.p. 236-237ºC.

Analysis %:-

Found: C,75.3; H,7.1; N,4.6;

C₁₈H₁₉N.HCl requires: C,75.6; H,7.0; N,4.9.

Preparation 2

3-Diphenylmethylpiperidine Hydrochloride

A solution of 3-diphenylmethylenepiperidine hydrochloride (200 mg, 0.7 mmol) in ethanol (40 ml) was stirred under one atmosphere of hydrogen at 40ºC in the presence of 10% palladium on charcoal (20 mg) for 24 hours and filtered. The filtrate was concentrated to give the title compound (200 mg) as a pale brown gum which was characterised by its ¹H-NMR spectrum.

1H-NMR (d₆-DMSO) δ =8.7-9.1(1H,broad s), 7.0-7.45(10H,m),

2.4-3.8(4H,m), 1.4-1.8(4H,m) and 1.0-1.25(2H,m).

Preparation 3

Ethyl 1-(3,4-methylenedioxybenzyl)piperidine-4-acetate

A mixture of ethyl piperidine-4-acetate (0.34 g, 2.0 mmol), 3,4-methylenedioxybenzyl chloride (0.34 g, 2.0 mmol), sodium carbonate (1.0 g) and sodium iodide (0.10 g) in acetonitrile (30 ml) was heated under reflux for 16 hours and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on SiO₂ using dichloromethane plus 0-20% ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give the title compound (0.52 g) as a colourless oil which was

characterised by its ^{1H-NMR spectrum.}

¹Η-NMR (CDCl₃) δ = 6.87(1H,s), 6.77(2H,s), 5.97(2H,s),

4.13(2H,q,J=7Hz), 3.41(2H,s), 2.94(2H,d,J=8Hz), 2.23(2H,d,J=6Hz), 1.6-2.05(5H,m), 1.2-1.45(2H,m) and 1.25(3H,t,J=7Hz).

Preparation 4

Ethyl 1-[2-(2,3-dihydro-5-benzofuranyl)ethyl]piperidine-4- acetate

This compound was prepared as described in Preparation 3 but using 5-(2-bromoethyl)-2,3-dihydrobenzofuran instead of 3,4- methylenedioxybenzyl chloride. The title ccnpcund was obtained as a colourless oil which was characterised by its ^{1H-NMR spectrum.} ¹H-NMR (CDCl₃) δ = 7.08(1H,s), 6.95(1H,d,J=8Hz), 6.74(2H,d,J=8Hz),

4.58(2H,t,J=7Hz), 4.16(2H,q,J=7Hz), 3.21(2H,t,J=7Hz),

3.03(2H,d,J=8Hz), 2.5-2.8(4H,m), 2.23(2H,d,J=4Hz), 2.04(2H,dt,J=8 and 1.5 Hz), 1.6-1.95(2H,m), 1.3-1.5(2H,m) and 1.25(3H,t,J=7Hz). Preparation 5

3,4-Methylenedioxyphenethyl alcohol

3,4-Methylenedioxyphenylacetic acid (18.0 g) was added portionwise over 30 minutes to a stirred, ice-cooled suspension of lithium aluminium hydride (4.0 g) in ether (400 ml) and the mixture was stirred at room temperature for two hours, quenched by the cautious addition of saturated aqueous ammonium chloride solution and filtered. The filtrate was washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated to give the title compound as a pale yellow oil (15.01 g, 90%), which was characterised by its ^{1H-NMR spectrum.} ¹H-NMR (CDCl₃) δ = 6.69-6.83 (3H,m); 5.98(2H,s); 3.82(2H,dt J = 7 and 6Hz); 2.81(2H,t,J = 7Hz) and 1.44(1H,t, J = 6Hz, exchangeable with D₂O).

Preparation 6

3,4-Methylenedioxyphenethyl bromide

A solution of phosphorus tribromide (8.1 g) in carbon tetrachloride (50 ml) was added dropwise over 30 minutes to a stirred solution of 3,4-methylenedioxyphenethyl alcohol (15.0 g) (see Preparation 5) in carbon tetrachloride (200 ml) and the mixture was heated under reflux for 3 hours, washed sequentially with water (twice), 5M aqueous sodium hydroxide solution and water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica (100 g) using carbon tetrachloride as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a pale yellow oil (8.3 g, 40%), which was characterised by its ¹H-NMR speccrum. ¹ H-NMR (CDCl₃) δ = 6.80(1H,d,J = 8Hz) , 6.75(1H,s) ,

6.71(1H,d,J=8Hz) , 6.00(2H,s) , 3.56(2H,t,J = 7Hz) and 3.13 (2H,t,J = 7Hz) .

Preparation 7

5-(2-Hydroxyethyl)-2,3-dihydrobenzofuran

A solution of (2,3-dihydro-5-benzofuranyl)acetic acid (4.9 g - see EP-A-132130) in anhydrous tetrahydrofuran (50 ml) was added dropwise over 10 minutes to a stirred suspension of lithium aluminium hydride (1.57 g) in anhydrous tetrahydrofuran (50 ml) at 0°C. The mixture was allowed to warm to room temperature and stirred for 1 hour. Water (1.5 ml) was cautiously added dropwise followed by 10% aqueous sodium hydroxide solution (1.5 ml) and water (4.5 ml). The mixture was filtered and the inorganic salts were washed with ethyl acetate. The filtrate and washings were combined and evaporated to give the title compound as an oil, (3.3 g), which was characterised by its ^{1H-NMR spectrum.} ¹H-NMR (CDCl₃) δ = 7.10 (s,1H), 7.00 (d,1H), 6.75(m,1H),

4.65-4.55(m,2H), 3.90-3.75(m,2H), 3.30-3.15(m,2H),

2.90-2.80(m,2H) and 1.85-1.75(brs,3H).

Preparation 8

5-(2-Bromoethyl)-2,3-dihydrobenzofuran

Phosphorus tribomide (0.37 g) was added to a solution of 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran (0.612 g) (Preparation 7) in carbon tetrachloride (3 ml) and the mixture heated under reflux for 3 hours and partitioned between 10% aqueous sodium carbonate solution (20 ml) and dichoromethane (20 ml) . The layers were separated and the aqueous layer was extracted with

dichloromethane. The combined dichloromethane extracts were dried (MgSO₄) and evaporated to give the title compound (0.584 g) as an oil which crystallised en standing, m.p. 60-62°C, and which was characterised by its ^{1H-NMR spectrum.} ¹H-NMR (CDCl₃) δ = 7.10(s,1H) , 7.00-6.95(d,1H) , 6.80-6.70(d,1H) , 4.65-4.55(t,2H) , 3.60-3.50 (t, 2H) , 3.25-3.15(t,2H) and

3.15-3.10(t,2H) .

Preparation 9

Ethyl 1-(4-methoxyphenethyl)piperidine-3 -carboxylate

This compound was prepared as described in Preparation 3 using ethyl piperidine-3-carboxylate and 4-methoxyphenethyl bromide as reagents. The title compound was obtained as a colourless oil.

Analysis %:-

Found: C,69.2; H,8.3; N,4.8;

C₁₇H₂₅NO₃ requires: C,70.1; H,8.6; N,4.8.

The following compounds may be prepared by methods described in the respective publications given below:

3-(Diphenylhydroxymethyl)piperidine Journal of Organic

Chemistry, 4084, 26, (1961).

3-(2,2-diphenyl-2-hydroxy)ethyl British Patent piperidine Specification

765853.

Ethyl piperidine-4-acetate Journal of American

Chemical Society, 6249, 75, (1953).

It will be appreciated from the foregoing that what we will claim may include the following:-

(1) The compounds of the formula (I) and pharmaceutically

acceptable salts thereof;

(2) Processes as described herein for preparing the compounds of the formula (I) and their salts;

(3) Pharmaceutical compositions comprising a compound 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 compound of the formula (I), or a pharmaceutically

acceptable salt thereof for use as a medicament.

(6) The use of a compound of the formula (I), or of a

pharmaceutically acceptable salt thereof, for themanufacture 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 disease, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease.

Claims

1. A compound of the formula (I) :

or a pharmaceutically acceptable salt thereof,

the broken line represents an optional double bond and X is

COH-,

SiOH- or

CH- when said double bond is absent or is

C= when said double bond is present, X being attached to a carbon atom of A,

A is

when said double bond is absent or A is or

when said double bond is present

n is from 1 to 3,

m is 1 or 2,

p is 0 or 1,

q is 0 or 1

R³ is or Het,

R⁴ and R⁵ are each independently H, C₁-C₄ alkyl, C₁-C₄ alkoxy or (CH₂)_rOH wherein r is 0, 1 or 2, or R⁴ and R⁵ together form a -Y-(CH₂)_s-Z- group wherein Y and Z are independently

-O- or -CH₂- and s is 1, 2 or 3, and Het is thienyl, pyridyl or pyrazinyl, with the provisos that when q is 0 or A is

then n is 2 or 3, and that when A is

=CH- or -CH₂ then R³ is not Het.

2. A compound according to claim 1, in which R¹ and R² are both unsubstituted phenyl

3. A compound according to claim 1 or 2, in which x is

C(OH)-.

4. A compound according to any preceding claim, in which R³ is pyridyl, 2,3-dihydro-benzofuranyl, tolyl, methoxyphenyl, hydroxymethylphenyl or CH )_s

5. A compound according to claim 4, in which R³ is

3,4-methylenedioxyphenyl.

6. 3-(Diphenylhydroxymethyl)-3-(3,4-methylenedioxyphenethyl) piperidine.

7. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 6 and a pharmaceutically acceptable diluent or carrier.

8. A compound according to any one of claims 1-6, for use in medicine.

9. Use of a compound according to any one of claims 1-6 for

making a medicament for use in treating diseases associated with altered motility and/or tone of smooth muscle.

10. A compound of formula RO₂C-A-(CH₂)_n R³ wherein A, n and R³ are as defined in any one of claims 1 to 5 and R is a C₁-C₄ alkyl group.

11. A method of making a compound of the formula (I) :

or a pharmaceutically acceptable salt thereof,

the broken line represents an optional double bond and X is

COH-,

SiOH- or

CH- when said double bond is absent or is

C= when said double bond is present, X being attached to a carbon atom of A,

A is

when said double bond is absent or A is or

when said double bond is present

n is from 1 to 3,

m is 1 or 2,

p is 0 or 1,

q is 0 or 1

R³ is or Het,

R⁴ and R⁵ are each independently H, C₁-C₄ alkyl, C₁-C₄ alkoxy or (CH₂)_rOH wherein r is 0, 1 or 2, or R⁴ and R⁵ together form a -Y-(CH₂)_s-Z- group wherein Y and Z are independently -O- or -CH₂- and s is 1, 2 or 3, and Het is thienyl, pyridyl or pyrazinyl, with the provisos that when q is 0 or A is

then n is 2 or 3, and that when A is

or -CH₂ then R³ is not Het

in which either i) a compound of formula (II)

wherein H is attached to the nitrogen atom of A is caused to react with a compound of formula Q (CH₂)_n R³ to yield a compound of formula (I) wherein R¹, R², X, A, the broken line, n and R³ are as defined above and Q is a leaving group, or

ii) a compound of formula (II) as defined above is cansed to

react with 2- or 4- vinylpyridine or vinylpyrazine to yield a compound of formula (I) in which n is 2 and R³ is 2- or 4- pyridyl or pyrazinyl

or

iii) a compound of formula RO-CO-A-(CH₂)_n R³ wherein A, n and R³ are as defined above and R is a C₁-C₄ alkyl group is allowed to react with phenyllithium to yield a compound of formula (I) in which R¹ and R² are both phenyl and X is C(OH)-.

12. A method according to claim 11 alternative i) in which

leaving group Q is Br, Cl, I, C₁-C₄ alkanesulphonyloxy, benzenesulphonyloxy, toluenesulphonyloxy or

trifluoromethanesulphonyloxy.

13. A method according to claim 11 alternative i) or claim 12, in which the reaction is carried cut in the presence of an acid acceptor.

14. A method according to claim 11 alternative ii) in which the reaction is carried out in the presence of an acidic or basic catalyst.

15. A method according to any one of claims 11 to 14, in which R¹ and R² are both unsubstituted phenyl.

16. A method according to any one of claims 11 to 15, in which X is

C(OH)-.

17. A method according to any one of claims 11 to 13 in which R³ is pyridyl, 2,3 -dihydrobenzofuranyl, tolyl, methoxyphenyl, or hydroxymethylphenyl.

18. A method according to any one of claims 11 to 13, in which R³ is 3,4-methylenedioxyphenyl.

19. A method according to claim 11, in which the compound made is 3-(diphenylhyd roxymethyl)-3-(3,4-methylenedioxyphenyl) piperidine.