HK1018274B - Oxa- and thia-diazole muscarinic receptor antagonists - Google Patents

Description

Oxa-and thia-diazole muscarinic receptor antagonists

The present invention relates to substituted oxadiazole and thiadiazole derivatives. The compounds of the present invention are muscarinic receptor antagonists which are selective for smooth muscle muscarinic sites over cardiac muscarinic sites and do not exhibit any significant antihistamine activity. Thus, the compounds of the invention are useful in the treatment of diseases associated with altered motility and/or tone of smooth muscle, such as diseases in the viscera, trachea and bladder. These include irritable bowel syndrome, diverticulosis, urinary incontinence, esophageal achalasia and chronic obstructive airways disease.

The compounds of the present invention are also useful as recognition enhancers and thus may be useful in the treatment of diseases associated with memory impairment such as Alzheimer's disease and age-related memory disorders.

The present invention provides compounds of formula (I):wherein R is¹Is C₁-C₆Alkyl, halo- (C)₁-C₆Alkyl group), C₃-C₇Cycloalkyl radical, C₂-C₆Alkynyl, hydroxy- (C)₂-C₆Alkynyl), (C)₁-C₄Alkoxy group) - (C₂-C₆Alkynyl), aryl- (C)₁-C₄Alkyl), heteroaryl or heteroaryl- (C)₁-C₄Alkyl groups);

R²is H or C₁-C₄An alkyl group;

R³is aryl, heteroaryl, 2, 3-dihydrobenzofuranyl or C₄-C₇A cycloalkyl group;

x is O or S;

and Y is a direct bond, -CH₂-，-(CH₂)₂-or-CH₂O-。

"halogen" means chlorine, bromine, fluorine or iodine.

Preferred aryl groups are phenyl and naphthyl, both of which can be substituted by up to 3 groups each independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy, halo and trifluoromethyl are optionally substituted.

More preferably aryl is selected from the group consisting of 1 or 2 each independently selected from C₁-C₄Alkyl radical, C₁-C₄Phenyl optionally substituted with substituents of alkoxy, hydroxy, halogen and trifluoromethyl; and naphthyl.

Most preferred aryl groups are phenyl, fluorophenyl, dichlorophenyl, hydroxyphenyl, methoxyphenyl or naphthyl.

Preferred heteroaryl groups are thienyl, pyridyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl and pyrimidinyl, all of which are optionally substituted with 1 or 2 substituents each independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy and halogen.

More preferred heteroaryl groups are thienyl, pyridyl, thiazolyl and benzothiazolyl.

Preferred alkyl groups are methyl or ethyl. Preferred alkoxy groups are methoxy or ethoxy. Preferred halogens are chlorine, bromine and fluorine. Preferred cycloalkyl groups are cyclobutyl, cyclopentyl and cyclohexyl, especially cyclobutyl. The preferred alkynyl group is ethynyl. Preferred hydroxy group- (C)₂-C₆Alkynyl) is HO-CH₂C.ident.C-and HO- (CH)₂)₄-C ≡ C-. Preferred haloalkyl groups are trifluoromethyl or pentafluoroethyl.

R¹Preferably C₁-C₆An alkyl group; pentafluoroethyl; c₄-C₆A cycloalkyl group; an ethynyl group; -C ≡ C-CH₂OH；-C≡C-(CH₂)₄OH; optionally 1 or 2 are independently selected from halogen and C₁-C₄Alkyl radical, C₁-C₄Phenyl substituted with substituents for alkoxy and hydroxy; a naphthyl group; or a heteroaryl group selected from thienyl, pyridyl, thiazolyl and benzothiazolyl, all of which may be substituted by halogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy or hydroxy is optionally substituted.

R²Preferably H or CH₃。

R³Preferably 1 or 2 are each independently selected from halogen, C₁-C₄Alkyl radical, C₁-C₄Phenyl optionally substituted with substituents of alkoxy and hydroxy; 2, 3-dihydrobenzofuranyl; c₄-C₇Cycloalkyl or thienyl.

X is preferably O.

Y is preferably a direct bond, -CH₂-or-CH₂O-。

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts such as the hydrochloride, hydrobromide, hydrofluoride, sulphate or bisulphate, phosphate or hydrogenphosphate, acetate, benzenesulphonate, citrate, fumarate, gluconate, lactate, maleate, methanesulphonate, succinate and tartrate salts. A wider range of pharmaceutically acceptable salts can be found, for example, in Journal of pharmaceutical Sciences, Vol.66, No.1, 1/1977, pages 1-19. These salts may be prepared in conventional manner, for example by mixing the free base solution and the acid in a suitable solvent, such as ethanol, and recovering the acid addition salt either as a precipitate or by evaporating the solution.

The compounds (I) may contain 1 or more photoactive centers, and the present invention thus includes not only isolated but also non-isolated forms. The isolated form can be obtained in a conventional manner, e.g. using high performance liquid chromatography with a chiral stationary phase, or by chemical resolution by formation of a suitable salt or derivative.

One method of preparing compound (I) is to convert ketone (II):wherein X, Y, R²And R³Is of formula (I) with a Grignard, organolithium or organocerium reagent of formula:

R¹MgHal，R¹li or R¹CeCl₂

Wherein Hal is Cl or Br.

When an organolithium or an organocerium reagent is used, the reaction is generally carried out at low temperatures, i.e., 0 ℃ or less than 0 ℃, preferably at about-78 ℃.

The preferred organic solvent is tetrahydrofuran.

The preferred Grignard reagent is magnesium bromide.

The Grignard reagent can be generated in situ, for example, by reacting the formula R at a rate sufficient to maintain reflux¹Hal halide is generated in situ by dropwise addition to a suspension of magnesium turnings in an organic solvent, such as diethyl ether. After stirring at room temperature for about 30 minutes, the solution of the Grignard reagent formed is added dropwise to a solution of the ketone (II) in a suitable organic solvent, generally at from 0 ℃ to-20 ℃.

The product can be isolated from the reaction mixture by conventional methods.

The novel intermediates (II) also form part of the invention.

The intermediate (II) wherein X is O can be prepared by conventional techniques as described below:another synthetic route for intermediate (IIA) is as follows:

(TBDMS ═ t-butyldimethylsilyl)The synthetic route of the thiadiazole intermediate is as follows:or (b)

Another process for preparing the compounds (I) is carried out starting from the hydroxy compounds (III) or their basic salts by the following reaction:

wherein R is¹And X is as defined for formula (I), (a) is reacted with a compound of formula (IV):

Q-CH(R²)-Y-R³ ---(IV)

wherein Q is a leaving group such as tosyloxy, mesyloxy, trifluormesyloxy, Cl or Br, and R is²，R³And Y is as defined for formula (I); or (b) with an aldehyde or ketone of formula (V) in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable organic solvent such as tetrahydrofuran, typically at room temperature:

wherein R is²，R³And Y is as defined for formula (I).

When the free base of compound (III) is used in (a), the reaction is generally carried out in the presence of an acid acceptor such as sodium bicarbonate or ethyldiisopropylamine.

The compound of formula (III) can be prepared by removing the benzyl group (wherein the group "-CH (R) is present in the compound of formula (I)²)-Y-R³"is benzyl") is typically prepared by reaction with a suitable chloroformate, such as α -chloroethyl chloroformate, in a suitable organic solvent, such as dichloromethane or toluene, preferably under reflux conditions.

The selectivity of compound (I) as a muscarinic receptor antagonist can be determined as follows.

Male guinea pigs were sacrificed, the ileum, trachea, bladder and right atrium removed and suspended under 1g resting tension in a medium containing 95% O₂And 5% CO₂In normal saline at 32 ℃. Using isoosmotic energy conversionThe contraction of the ileum, bladder and trachea is recorded by the instrument (for the ileum) or isometric transducer (for the bladder and trachea). The contraction frequency of the right atrium with spontaneous beating is deduced from the contraction results recorded by the isometric method.

Dose-response curves for acetylcholine (ileum) or carbachol (trachea, bladder and right atrium) were determined for each dose of agonist using a 1-5 minute contact time. Until the maximum reaction is obtained. The organ bath was emptied and re-infused with physiological saline solution containing the lowest dose of test compound. Test compounds were allowed to equilibrate with tissue for 20 minutes and the dose-response curve for agonist was repeated until maximal response was obtained. The organ bath is emptied and a physiological saline solution containing the test compound at a second concentration is reinjected, and the above steps are repeated. For each tissue, four concentrations of test compound are typically selected for the assay.

Determination of the concentration of test Compound (pA) which results in doubling the concentration of agonist to produce the initial response₂Value one of Arunlaksha and Schild (1959), journal of British pharmacology, 14, 48-58). The tissue selectivity of muscarinic receptor antagonists is determined using the analytical techniques described above.

Activity against agonist-induced bronchoconstriction or ileal or bladder contraction was determined by comparison with changes in heart rate using anesthetized dogs. Oral activity is assessed by the conscious dog by measuring the effect of the compound on, for example, heart rate, pupil diameter and intestinal motility.

The affinity of the test compounds to other choline sites was determined after intravenous or intraperitoneal administration to mice. For example, the dose at which doubling of pupil size is induced and the dose required to inhibit 50% of salivation and tremor response caused by intravenous oxotremorine administration is determined.

When one administers the compounds of the present invention for prophylactic or preventative treatment of diseases associated with altered motility and/or tone of smooth muscle, such as irritable bowel syndrome, diverticulosis, urinary incontinence, esophageal achalasia and chronic obstructive airways disease, the oral dose of the compounds is generally from 3.5 to 350mg per day for an average weight adult patient (70 kg). Thus, for the average adult patient, a single tablet or capsule will generally contain from 1 to 250mg of the active compound in a suitable pharmaceutically acceptable excipient or carrier, which may be administered in single or divided doses, one or more times per day. The dosage for intravenous administration is generally 0.35 to 35mg per single dose, as required. The physician will determine the actual dosage which will be most suitable for an individual patient at the time of actual administration, and such dosage will vary with the age, weight and response of the particular patient. The above dosages are merely illustrative in general terms and, of course, there may be specific instances where higher or lower dosage ranges are desired, all of which are intended to be within the scope of this invention.

For human use, the compounds of formula (I) may 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 separately or in capsules or eggs mixed with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. The compounds of the invention may also be administered by parenteral (e.g. intravenous, intramuscular or subcutaneous) injection. For parenteral administration, they are best administered as a sterile aqueous solution which may contain other substances, for example, enough salts to make the solution isotonic with blood or glucose.

In another aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

The invention also includes a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament, particularly for the treatment of urinary incontinence or irritable bowel syndrome.

The invention further comprises the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases associated with altered motility and/or tone of smooth muscle, such as irritable bowel syndrome, diverticulosis, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease.

The present invention further includes any of the novel intermediates described herein.

The synthesis of the compounds of formula (I) and certain intermediates used therein is illustrated by the following examples and preparations, respectively.

Purity of the compound Using Merck Kieselgel 60F₂₅₄The plates were routinely monitored by thin layer chromatography.¹H nuclear magnetic resonance (nmr) spectra were recorded on Bruker AC-300 and Varian Unity 300 spectrometers and were in all cases consistent with the proposed structure. Chemical shifts are expressed in parts per million (. delta.) downfield from tetramethylsilane and are indicated using conventional standard abbreviations for major peak labeling, such as singlet(s), doublet (d), doublet (dd), triplet (t), quartet (q), multiplet (m), and broad (b). LRMS refers to low resolution mass spectrometry. The room temperature means 20-25 ℃. Preparation example 11-Acetylpiperidine-4-carboxylic acid

Piperidine-4-carboxylic acid (208g, 1.63 moles) was dissolved in acetic anhydride and the resulting solution was heated to reflux under nitrogen for 48 hours. The flask contents were cooled and then concentrated under reduced pressure to give a pale yellow oil which solidified on standing. Recrystallization from propan-2-ol gave the title compound as an off-white solid (160g, 0.94mol, 58%), mp 164-_H(300 HMz；CDCl₃)1.7(2H, m), 2.0(2H, m), 2.2(3H, s), 2.6(1H, m), 2.85(1H, m), 3.2(1H, m), 3.8(1H, m), and 4.4(1H, m.) preparation 21-acetylpiperidine-4- (2-oxo-2-phenylethyl) carboxamide

To a stirred suspension of 1-acetylpiperidine-4-carboxylic acid (200.0g, 1.17mol) in anhydrous dichloromethane under nitrogen at room temperature was added Carbonyl Diimidazole (CDI) (212.0g, 1.31mol) in portions[ note that there is CO₂Escape]. The resulting solution was then stirred at room temperature for 2 hours under nitrogen atmosphere. alpha-Aminoacetophenone hydrochloride (210g, 1.22mol) was added followed by triethylamine (170 cm)²1.22mol) resulting in a slight exotherm. The resulting mixture was stirred at room temperature under nitrogen overnight. The flask contents were then washed with hydrochloric acid (2l, 2M) and deionized water (2X 1l) and dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give the title compound as an orange solid (300g, 1.04mol, 79%), Rf0.15 (95: 5 CH)₂Cl₂：MeOH)，mp 161-162℃，δ_H(300MHz；CDCl₃)1.7(2H, m), 1.9(2H, m), 2.1(3H, s), 2.5(1H, m), 2.7(1H, t), 3.1(1H, t), 3.9(1H, d), 4.6(1H, d), 4.8(2H, d), 6.6(1H, s), 7.5(2H, m), 7.6(1H, m), and 7.9(2H, d). preparation 33-benzoyl-5- {4- (1-acetylpiperidinyl) } -1.2.4-oxadiazole

1-Acetylpiperidine-4- (2-oxo-2-piperidineethyl) carboxamide (294g, 1.02mol) was dissolved in glacial acetic acid (1.51) under warm conditions. Sodium nitrite (100g) in deionized water (120 cm) was then added dropwise over a period of 2 hours with gentle cooling in an ice-water bath³) And (3) solution. The resulting reaction mixture was stirred at room temperature for 144 hours, to which sodium nitrite (100g) in deionized water (120 cm) was further added every 48 hours³) And (3) solution. The flask contents were then flushed with nitrogen and concentrated under reduced pressure to give a solid residue which was dissolved in dichloromethane (2.51) and in turn deionized water (500 cm)³) Aqueous sodium hydroxide solution (200 cm)³10% w/v), and deionized water (500 cm)³) And (6) washing. The resulting orange fraction was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a pale yellow solid (231g, 0.77mol, 77%), Rf 0.26 (95: 5CH₂Cl₂：MeOH)，mp 97-100℃.δ_H(300MHz；CDCl₃)1.9(2H, m), 2.1(3H, s), 2.2(2H, m), 2.9(1H, t), 3.3(2H, m), 3.9(1H, d), 4.5(1H, d), 7.5(2H, t), 7.6(1H, t), and 8.2(2H, d); m/z (LRMS)322 (MNa)⁺)，317(MNH₄ ⁺) And 300 (MH)⁺) Preparation 43-benzoyl-5- (4-piperidinyl) -1, 2, 4-oxadiazole hydrochloride

3-benzoyl-5- {4- (1-acetylpiperidinyl) } -1, 2, 4-oxadiazole (230g, 0.77mol) was dissolved in HCl-saturated methanol (2.5l) and heated at reflux for 24 h. The flask contents were then cooled and concentrated hydrochloric acid (10 cm) was added³). After tlc showed no starting material remaining, the reaction mixture was heated to reflux for a further 20 hours. The flask contents were then cooled with an ice-acetone bath to yield a white solid, filtered and washed with ethyl acetate to give the title compound (175g, 0.58mol, 75%), mp 224-_H(300MHz；CDCl₃)2.1(2H, m), 2.3(2H, m), 3.1(2H, m), 3.3(2H, m), 3.6(1H, m), 7.6(2H, m), 7.8(1H, m), and 9.1(1H, s); m/z (LRMS)258 (MH)⁺) Preparation 53-benzoyl-5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole

Benzyl bromide (67 cm)³0.56mol) was added to a mixture of 3-benzoyl-5- (4-piperidinyl) -1, 2, 4-oxadiazole hydrochloride (165g, 0.56mol) and solid potassium carbonate (194g, 1.40mol) in butan-2-one (1.6 l). The flask contents were then stirred at room temperature for 48 hours under a nitrogen atmosphere. Deionized water (1.31) was then added and the mixture was stirred vigorously for 1 hour. The organic layer was collected, and the remaining aqueous layer was partially washed with ethyl acetate (500 cm)³) And (4) extracting. The combined organic portions were then dried over anhydrous sodium sulfate and concentrated to give a pale yellow oil. Flash chromatography (1kg "Kiseslgel 60" silica gel) eluting with 8% methanol in dichloromethane afforded the title compound as a colourless oil which was subsequently azeotroped with toluene to give the title compound as a white solid (177g, 0.51mol, 91%), Rf 0.6 (95: 5 CH)₂Cl₂：MeOH)，mp 67-69℃.δ_H(300MHz；CDCl₃)2.1(6H, m), 2.9(2H, d), 3.1(1H, m), 3.6(2H, s), 7.3(5H, m), 7.5(2H, t), 7.7(1H, t), and 8.3(2H, d); m/z (LRMS))348(MH⁺) Preparation example 62-tert-butyldimethylsilyloxyphenylacetonitrile

Mandelonitrile (50g, 0.38mol) and imidazole (64g, 0.94mol) were dissolved in DMF (100 cm)³) And the resulting solution was cooled with an ice-water bath. Tert-butyldimethylsilyl chloride (68g, 0.45mol) was then added portionwise over 20 minutes. The flask contents were then warmed to 35 ℃ and stirred at this temperature for 18 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (3X 100 cm)³) And deionized water (100 cm)³) In the meantime. The combined organic fractions were washed with brine (100 cm)³) Washed, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude product as a yellow oil. Flash chromatography (600g kieselgel60 silica gel) eluting with 20% dichloromethane/pentane afforded the title compound as an oil (77g, 0.31mol, 82%), delta_H(300MHz；CDCl₃)0.1(3H, s), 0.2(3H, s), 1.0(9H, s), 5.5(1H, s) and 7.4(5H, m.) preparation of 7 α -tert-butyldimethylsilyloxybenzyl amidoxime

Solid potassium carbonate (54g, 0.39mol) was added to a mixture containing 2-tert-butyldimethylsilyloxyphenylacetonitrile (45g, 0.18mol), hydroxylamine hydrochloride (25g, 0.36mol) and ethanol (450 cm)³) And the resulting mixture was heated to reflux under a nitrogen atmosphere for 2 hours. The flask contents were then cooled and concentrated under reduced pressure. The residue (100 cm)³) Partition into dichloromethane (3X 150 cm)³) And deionized water (100 cm)³) In the meantime. Followed by brine (100 cm)³) The combined organic portions were washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a yellow solid (53.2g, 0.18mol, 100%). delta._H(300MHz；CDCl₃)0.1(3H, s), 0.2(3H, s), 1.0(9H, s), 4.8(2H, bs), 5.3(1H, bs), 7.3(3H, m), and 7.5(2H, m). preparation 83- (. alpha. -tert-butyldimethylsilyloxy) -5- {4- (1-benzylpiperidinyl) } -1, 2, 3-oxadiazole

Alpha-tert-butyldimethylsilyloxybenzyl amidoxime (53.2g, 0.18mol) was dissolved in THF (400 cm)³) And 4 * molecular sieve (10g) was added. The resulting mixture was then heated to reflux under nitrogen for 15 minutes, followed by cooling in an ice bath. Sodium hydride (8.0g, 60% dispersion, 0.2mol) was added portionwise and the flask contents allowed to warm slowly (to prevent effervescence) to room temperature. After no hydrogen evolution, N-benzylpiperidine-4-carboxylic acid ethyl ester (45g, 0.18mol) in THF (125 cm)³) And (3) solution. The flask contents were stirred at room temperature for 30 minutes and then heated to reflux under nitrogen for 1.5 hours. After cooling, the reaction mixture was partitioned between ethyl acetate (2X 200 cm)³) And deionized water (200 cm)³) Among them. Followed by brine (100 cm)³) The combined organic portions were washed, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a brown oil (62g, 0.13mol, 72%). delta._H(300MHz；CDCl₃)0.1(3H, s), 0.2(3H, s), 1.0(9H, s), 2.0(6H, m), 2.9(3H, m), 3.5(2H, s), 6.0(1H, s), 7.3(8H, m), and 7.5(2H, m). Preparation 93- (. alpha. -hydroxybenzyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole

To a stirred solution of 3- (. alpha. -tert-butyldimethylsilyloxybenzyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole (62g, 0.13mol) in THF (200 cm) at 0 deg.C³) Tetrabutylammonium fluoride (237 cm) was added dropwise to the solution³1M THF solution). The resulting mixture was then warmed to room temperature and stirred for a further 30 minutes. The flask contents were then partitioned into ethyl acetate (3X 200 cm)³) And deionized water (200 cm)³) Of the organic fractions, the combined organic fractions were washed with brine (100 cm)³) Washed, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (45.0g) as a yellow solid (elemental analysis C)₂₁H₂₃N₃O₂·0.5H₂O: found C, 70.5; h, 6.5; n, 11.8, calcd for C, 70.4; h, 6.8; n, 11.7%); delta_H(300MHz；CDCl₃)2.0(6H, m), 2.9(4H, m), 3.5(2H, s), 5.9(1H, d), and 7.3(10H, m); m/z (LRMS)350 (MH)⁺) Preparation 103-benzoyl-5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole

3- (. alpha. -hydroxybenzyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole (45.0g, 0.19mol) in anhydrous THF (300 cm) was stirred mechanically at room temperature over 2 hours³) Manganese dioxide (206g, 2.37mol) was added to the solution in portions. The resulting mixture was then stirred at room temperature for 45 minutes, filtered through a pad of "Arbocel" and concentrated under reduced pressure to give a sticky solid. This residue was redissolved in a small amount of hot diisopropyl ether and the resulting solution was filtered and subsequently cooled in an ice-water bath to give the title compound as a beige crystalline solid (26g, 75mmol, 58%). The material has the same properties in all respects as the product prepared in preparation example 5. Preparation 113- (1, 1-Diphenyl-1-hydroxymethyl) -5- (4-piperidinyl) -1, 2, 4-oxadiazole

To a stirred solution of 3- (1, 1-diphenyl-1-hydroxymethyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole (1.00g, 2.30mmol) in anhydrous dichloromethane (10 cm) at 0 deg.C under nitrogen³) α -chloroethyl chloroformate was added dropwise to the solution, and the resulting solution was stirred at 0 ℃ for 40 minutes, followed by concentration under reduced pressure. The residue obtained was dissolved in methanol (20 cm)³) And heated to reflux for 40 minutes. The flask contents were then cooled, concentrated under reduced pressure and partitioned in dichloromethane (100 cm)³) And saturated aqueous sodium bicarbonate solution (50 cm)³) Among them. The organic portion was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Flash chromatography (25g kieselgel60 silica gel) eluting with 5-15% methanol in dichloromethane afforded the title compound as a white foam (0.68g, 2.0mmol, 80%), Rf0.05 (90: 10 CH)₂Cl₂∶MeOH)，δ_H(300MHz；CDCl₃)1.9(2H, m), 2.2(2H, m), 2.8(2H, t), 3.1(1H, m), 3.3(2H, m), 4.2(1H, b), and 7.4(10H，m)；m/z(LRMS)336(MH⁺) Preparation 123- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- (4-piperidinyl) -1, 2, 4-oxadiazole

To a stirred solution of 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole (8.52g, 21.0mmol) in dry toluene (100 cm)³) Alpha-ethyl chloroformate was added dropwise to the solution. The resulting mixture was then heated to reflux under nitrogen for 90 minutes. The flask contents were then cooled and the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in methanol (50 cm)³) And heated to reflux for 40 minutes. The flask contents were then cooled, concentrated under reduced pressure and partitioned in dichloromethane (100 cm)³) And saturated aqueous sodium bicarbonate solution (50 cm)³) In the meantime. The organic portion was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Flash chromatography (25g "Kieselgel 60" silica gel) eluting with 5-15% methanol in dichloromethane afforded the title compound as a white foam (1.63g, 5.2mmol, 23%), delta_H(300MHz；CDCl₃)1.7(6H, m), 2.0(4H, m), 2.7(4H, m), 3.1(1H, m), 3.2(2H, m), 3.3(1H, m), 7.3(3H, m), and 7.5(2H, d); m/z (LRMS)315 (MH)⁺).

Example 13- (1, 1-Diphenyl-1-hydroxymethyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole

To a stirred solution of 3-benzoyl-5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole (3.0g, 8.6mmol) in anhydrous tetrahydrofuran (40 cm) at-78 deg.C under a nitrogen atmosphere³) Phenyl lithium (5.0 cm) was added dropwise to the solution³(ii) a 1.8M cyclohexane solution, 9.0 mmol). The resulting solution was allowed to warm to room temperature over 2 hours and then partitioned into ethyl acetate (3X 50 cm)³) And saline (20 cm)³) In the meantime. The combined organic portions were then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography (30g "Kieselgel 60" silica gel) eluting with 35% ethyl acetate/methane gave the title compound (2.9g, 6.8mmol, 76%) Rf0.8 (ethyl acetate), (C)₂₂H₂₇N₃O₂·0.5H₂O: found C, 75.45; h, 6.4; n, 9.8; calcd for C, 75.4; h, 6.45; n, 9.8%); delta_H(300MHz；CDCl₃)2.0(6H, m), 2.9(2H, m), 3.5(2H, s), 3.7(1H, s), and 7.3(15H, m); m/z (LRMS)426 (MH)⁺).

Example 23- (1-n-butyl-1-phenyl-1-hydroxymethyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole

The title compound was prepared in a similar manner as described in example 1 using butyllithium (2.5M in hexane, 1.1 molar equivalent) instead of phenyllithium to give the title compound, (C)₂₅H₃₁N₃O₂: found C, 73.5; h, 7.8; n, 10.0; calcd for C, 74.0; h, 7.7; n, 10.4%); delta_H(300MHz；CDCl₃)0.8(3H, m), 1.3(4H, m), 2.1(8H, m), 2.9(3H, m), 3.2(1H, s), 3.5(2H, m), 7.3(8H, m), and 7.5(2H, d); m/z (LRMS)406 (MH)⁺).

Example 33- {1- (2-thienyl) -1-phenyl-1-hydroxymethyl } -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole

To a stirred thiophene (0.3 cm) at-78 ℃ under nitrogen³3.0mmol) of anhydrous tetrahydrofuran (30 cm)³) N-butyllithium (1.3 cm) was added dropwise to the solution³(ii) a 2.5M hexane solution, 3.25mmol), and the resulting solution was stirred at-78 ℃ for 10 minutes to yield 2-thienyllithium. Then 3-benzoyl-5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole (1.0g, 2.9mmol) in dry tetrahydrofuran (10 cm) was added in one portion³) The solution was dissolved and the resulting mixture was stirred at-78 ℃ for 1 hour. The cooling bath was then removed and the flask contents warmed to room temperature over a 1 hour period. The reaction mixture was then partitioned between ethyl acetate (3X 50 cm)³) And saline (20 cm)³) In the meantime. The combined organic fractions are then washed with waterDried over sodium sulfate and concentrated under reduced pressure. Flash chromatography (30g "Kieselgel 60" silica gel) eluting with 40% ethyl acetate/hexanes afforded the title compound (0.83g, 1.9mmol, 66%) (C)₂₅H₂₅N₃O₂S·0.25H₂O: found C, 68.6; h, 5.9; n, 9.5; calcd for C, 68.9; h, 5.9; n, 9.6%); delta_H(300MHz；CDCl₃)2.1(6H, m), 2.9(3H, m), 3.5(2H, s), 3.95(1H, s), 6.9(2H, m), 7.3(9H, m), and 7.5(2H, m); m/z (LRMS)432 (MH)⁺) Examples 4 to 9

The following example compounds of the general formula were prepared by reacting 3-benzoyl-5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole with the appropriate organolithium reagent using a similar procedure as described in example 3.Example 103- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole

To magnesium turnings (5.7g, 0.23mol) in anhydrous ether (50 cm)³) Adding cyclobutylbromide (21.7 cm) dropwise into the suspension³0.23mol) was added at a rate such that reflux was maintained. The resulting mixture was then stirred at room temperature for 30 minutes, then added dropwise to a stirred ether (400 cm) of 3-benzoyl-5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole (40.0g, 0.115mol) at-10 ℃ under a nitrogen atmosphere³) And tetrahydrofuran (100 cm)³) In solution. The resulting mixture was then allowed to warm to room temperature over 2 hours. The flask contents were then cooled and saturated aqueous ammonium chloride (30 cm) was carefully added³). Followed by the addition of deionized water (500 cm)³) And the mixture was extracted with ethyl acetate (2X 200 cm)³) And (4) extracting. The combined organic portions were then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography (500g "Kieselgel 60" silica gel) eluting with pentane containing 40-70% ethyl acetate afforded the title compound (31.5, 0.7)8mol, 68%) (assay C₂₅H₂₉N₃O₂·0.25H₂O: found C, 73.0; h, 7.4; n, 10.1, calcd for C, 73.5; h, 7.3; n, 10.3%); delta_H(300MHz；CDCl₃)1.9(12H, m), 2.9(3H, m), 3.2(1H, s), 3.3(1H, m), 3.5(2H, s), 7.3(8H, m), and 7.5(2H, d); m/z (LRMS)403 (MH)⁺).

HPLC ("Chiralpak AD" column, 2.5X 25cm), eluent 20% isopropanol, 0.06% trifluoroacetic acid, 0. 03% diethylamine in hexane, elution rate 7cm³Per minute, (-) -3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole, [ alpha ] -is then obtained]_D-48 °, c0.1, dichloromethane; and (+) -3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole, [ alpha ] -]_D+51 °, c0.1, dichloromethane; ) Analysis C₂₅H₂₉N₃O₂: found C, 74.3; h, 7.2; n, 10.4 calcd for C, 74.4; h, 7.2; n, 10.4%). Examples 11 to 15

The following compounds of the examples of the general formula were prepared by reacting 3-benzoyl-5- {4- (1-benzylpiperidinyl) } -1, 2, 4-oxadiazole with the appropriate Grignard reagent using a similar procedure as described in example 10.

Examples	R1	LRMS	Analysis/deltaH(300 MHz；CDCl3)
				11	Cyclopentyl group	418(MH+)	Found C, 74.9; h, 7.7; n, 10.0.C26H31N3O2Calcd for C, 74.8; h, 7.5; n, 10.1% deltaH(300MHz；CDCl3)1.4(2H, m), 1.6(6H, m), 2.05(6H, m), 2.9(4H, m), 3.2(1H, s), 3.5(2H, s), 7.3(8H, m), and 7.6(2H, d).
12	Cyclohexyl radical	432(MH+)	Found C, 74.3; h, 7.5; n, 9.55.C27H33N3O2.*H2O calcd for C, 74.4; h, 7.7; n, 9.6% deltaH(300MHz；CDCl3)1.05(3H, m), 1.15(3H, m), 1.5(3H, m), 1.7(2H, m), 2.1(6H, m), 2.9(3H, m), 3.2(1H, s), 3.5(2H, s), 7.3(8H, m), and 7.6(2H, d).
				13	2-naphthyl radical	475(MH+)	Found C, 77.7; h, 5.0; n, 8.8.C31H24N3O2Calculated C, 78.3; h, 6.2; n, 8.8% deltaH(300MHz；CDCl3)2.0(6H, m), 2.9(3H, m), 3.5(2H, s), 3.9(1H, s), 7.3(8H, m), 7.5(5H, m), and 7.9(4H, m).
14	Pentafluoroethyl group	468(MH+)	Found C, 59.1; h, 4.7; n, 9.0.C23H22N3O2F5Calculated C, 59.1; h, 4.7; n, 8.9% deltaH(300MHz；CDCl3)2.0(6H, m), 2.9(3H, m), 3.5(2H, s), 4.4(1H, s), 7.3(5H, m), 7.4(3H, m), and 7.9(2H, m).
				15	Ethynyl group	374(MH+)	Found C, 73.2; h, 6.5; n, 10.9.C23H23N3O2.1/20H2O calcd for C, 73.3; h, 6.2; n, 11.1% deltaH(300MHz；CDCl3)2.0(6H, m), 2.9(4H, m), 3.5(2H, s), 3.9(1H, b), 7.3(8H, m), and 7.8(2H, m).

Example 163- (1, 1-diphenyl-1-hydroxymethyl) -5- [4- {1- (4-fluorophenylmethyl) piperidinyl }]-1, 2, 4-oxadiazole

To a stirred mixture of 3- (1, 1-diphenyl-1-hydroxymethyl) -5- (4-piperidinyl) -1, 2, 4-oxadiazole (0.20g, 0.6mmol) and 4-fluorophenylmethyl chloride (0.075 cm)³0.6mmol) of anhydrous dimethylformamide (1 cm)³) Solid sodium bicarbonate (0.20g) was added to the solution. The resulting mixture was stirred at room temperature for 24 hours under nitrogen and then partitioned between ethyl acetate (3X 20 cm)³) And a saturated aqueous sodium carbonate solution (20 cm)³) In the meantime. The combined organic portions were then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography (40g "Kieselgel 60" silica gel) eluting with 30-50% ethyl acetate in hexane afforded the title compound (0.07g, 0.16mmol, 26%) (assay C)₂₇H₂₆N₃O₂F: found C, 72.6; h, 5.95; n, 9.4 calculation C, 73.1; h, 5.9; n, 9.5%); delta_H(300MHz；CDCl₃)2.1(6H, m), 2.9(3H, m), 3.5(2H, s), 3.75(1H, s), 6.95(2H, d), and 7.4(12H, m); m/z (LRMS)444 (MH)⁺).

Examples 17 and 18

The following example compounds of the general formula were prepared by reacting 3- (1, 1-diphenyl-1-hydroxymethyl) -5- (4-piperidinyl) -1, 2, 4-oxadiazole with the appropriate alkyl halide using a similar procedure as described in example 16.Example 193- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- [4- {1- (4-methoxybenzyl) piperidinyl }]-1, 2, 4-oxadiazole

To 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- (4-piperidinyl) -1, 2, 4-oxadiazole (0.16g, 0.5mmol) in anhydrous tetrahydrofuran (15 cm) at room temperature under nitrogen³) Acetic acid (0.04g, 0.6mmol) was added to the stirred solution. 4-methoxybenzaldehyde (0.082g, 0.6mmol) and sodium triacetoxyborohydride (0.212g, 1.0mmol) were then added and the resulting mixture was stirred at room temperature under nitrogen for 6 hours. The contents of the flask were then partitioned into dichloromethane (100 cm)³) And saturated aqueous sodium bicarbonate. The organic portion was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown oil. Flash chromatography ("Kieselgel 60" silica gel) eluting with 30-50% ethyl acetate in hexanes afforded the title compound (0.125g, 0.28mmol, 56%) (assay C)₂₆H₃₁N₃O₃·1/3H₂O: found C, 71.1; h, 7.25; n, 8.6 calcd for C, 71.7; h, 7.2; n, 9.6%); delta_H(300MHz；CDCl₃)1.6-2.2(12H, m), 3.2(1H, s), 3.3(1H, t), 3.4(2H, s), 3.8(3H, s), 6.95(3H, m), 7.3(4H, m), and 7.5(2H, m); m/z (LRMS)434 (MH)⁺).

Examples 20 and 25

The following example compounds of the general formula shown below were prepared by reacting 3- (1-cyclobutyl-1 phenyl-1-hydroxymethyl) -5- (4-piperidinyl) -1, 2, 4-oxadiazole with the appropriate aldehyde using a similar procedure as described in example 19.Example 263- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- [4- {1- (2-phenoxyethyl) piperidinyl }]-1, 2, 4-oxadiazole

To 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- (4-piperidinyl) -1, 2, 4-oxadiazole (0.16g, 0.5mmo1) in anhydrous tetrahydrofuran (15 cm) at room temperature under nitrogen³) To the stirred solution was added 2-phenoxybromoethane (0.10g, 0.5 mmol). Ethyldiisopropylamine (0.13g, 1.0mmol) was then added and the resulting solution was stirred at room temperature for 7 days. The contents of the flask were then partitioned into ethyl acetate (3X 30 cm)³) And saturated aqueous sodium bicarbonate solution (10 cm)³) In the meantime. The combined organic extracts were then dried and concentrated under reduced pressure. Flash chromatography ("Kieselgel 60" silica gel) eluting with 3% methanol in dichloromethane then afforded the title compound (0.022g, 0.05mmol, 10%) delta_H(300MHz；CDCl₃)1.6-2.2(10H, m), 2.3(2H, t), 2.8(2H, t), 2.9(1H, m), 3.0(2H, m), 3.2(1H, s), 3.3(1H, q), 4.1(2H, t), 6.9(3H, m), 7.3(5H, m), and 7.5(2H, m); m/z (LRMS)434 (MH)⁺).

Example 273- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- [4- {1- (. alpha. -methylbenzyl) piperidinyl }]-1, 2, 4-oxadiazole

The above compound was prepared by reacting 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- (4-piperidinyl) -1, 2, 4-oxadiazole with α -methylbenzyl bromide using a similar procedure as described in example 26.

Elemental analysis: c₂₆H₃₁N₃O₂·1/3H₂O：

Measured value: c, 73.8; h, 7.4; n, 9.6;

calculated values: c, 73.8; h, 7.5; n, 9.9%;

δH(300MHz)；CDCl₃)1.3(3H, S), 1.6-2.2(12H, m), 2.8(2H, m), 3.0(1H, m), 3.2(1H, S), 3.3(1H, t), 3.5(1H, m), 7.2(8H, m) and 7.5(2H, m); m/z (LRMS)419 (MH)⁺)。

Claims (24)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof;wherein R is¹Is C₁-C₆Alkyl, halogen- (C)₁-C₆Alkyl group), C₃-C₇Cycloalkyl radical, C₂-C₆Alkynyl, hydroxy- (C)₂-C₆Alkynyl), (C)₁-C₄Alkoxy group) - (C₂-C₆Alkynyl), aryl- (C)₁-C₄Alkyl), heteroaryl or heteroaryl- (C)₁-C₄Alkyl radical)；

R²Is H or C₁-C₄An alkyl group;

R³is aryl, heteroaryl, 2, 3-dihydrobenzofuranyl or C₄-C₇A cycloalkyl group;

x is O or S;

and Y is a direct bond, -CH₂-，-(CH₂)₂-or-CH₂O-。

2. The compound of claim 1 wherein aryl is phenyl and naphthyl, both of which are optionally substituted with up to 3 substituents each independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy, halogen and trifluoromethyl.

3. The compound of claim 2 wherein aryl is selected from the group consisting of 1 or 2 each independently selected from C₁-C₄Alkyl radical, C₁-C₄Phenyl optionally substituted with substituents of alkoxy, hydroxy, halogen and trifluoromethyl; and naphthyl.

4. The compound of claim 3 wherein aryl is phenyl, fluorophenyl, dichlorophenyl, hydroxyphenyl, methoxyphenyl, or naphthyl.

5. A compound according to any one of the preceding claims wherein heteroaryl is thienyl, pyridyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl and pyrimidinyl, all of which are optionally substituted with 1 or 2 substituents each independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy and halogen.

6. The compound of claim 5, wherein heteroaryl is thienyl, pyridyl, thiazolyl, or benzothiazolyl.

7. Compound according to any of the preceding claimsIn which R is¹Is C₁-C₆An alkyl group; pentafluoroethyl; c₄-C₆A cycloalkyl group; an ethynyl group; -C ≡ C-CH₂OH；-C≡C-(CH₂)₄OH; optionally 1 or 2 are independently selected from halogen and C₁-C₄Alkyl radical, C₁-C₄Phenyl substituted with substituents for alkoxy and hydroxy; a naphthyl group; or a heteroaryl group selected from thienyl, pyridyl, thiazolyl and benzothiazolyl, all of which may be substituted by halogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy or hydroxy is optionally substituted.

8. A compound according to any one of the preceding claims wherein R is²Is H or CH₃。

9. A compound according to any one of the preceding claims wherein R is³Is selected from 1 or 2 independently of each other from halogen, C₁-C₄Alkyl radical, C₁-C₄Phenyl optionally substituted with substituents of alkoxy and hydroxy; 2, 3-dihydrobenzofuranyl; c₄-C₇Cycloalkyl or thienyl.

10. A compound according to any one of the preceding claims wherein X is O.

11. A compound according to any one of the preceding claims wherein Y is a direct bond, -CH₂-or-CH₂O-。

12. The compound of claim 1 which is 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- [4- (1-benzylpiperidinyl) ] -1, 2, 4-oxadiazole; or (+) -3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- [4- (1-benzylpiperidinyl) ] -1, 2, 4-oxadiazole.

13. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, in association with a pharmaceutically-acceptable diluent or carrier.

14. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 12, in the manufacture of a medicament for the treatment of irritable bowel syndrome, diverticulosis, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease.

15. A compound of formula (II):wherein X, Y, R²And R³Is as defined in claim 1.

16. A process for the preparation of a compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II) as described in claim 15 with a grignard, organolithium or organocerium reagent of the formula: r¹MgHal，R¹Li or R¹CeCl₂Wherein Hal is Cl or Br, and R¹Is as defined in claim 1;

the resulting product of formula (I) is then optionally converted into a pharmaceutically acceptable salt.

17. The process of claim 16, wherein formula R is used¹MgBr or R¹Li reagent, wherein R¹The definition is the same as claim 17.

18. A process for preparing a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (III):

wherein R is¹And X is as defined in claim 1, (a) is reacted with a compound of formula (IV):

Q-CH(R²)-Y-R³ ---(IV)

wherein Q is a leaving group, and R²，R³And Y is as defined in claim 1; or (b) with an aldehyde or ketone of formula (V) in an organic solvent in the presence of a reducing agent:wherein R is²，R³And Y is as defined in claim 1,

the resulting product of formula (I) is then optionally converted into a pharmaceutically acceptable salt.

19. The process of claim 18 wherein the leaving group is tosyloxy, mesyloxy, trifluormesyloxy, Cl or Br and wherein the reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.

20. The process of claim 18 or 19, wherein when compound (III) free base is used in (a), the reaction is carried out in the presence of an acid acceptor.

21. The process according to claim 20, wherein the acid acceptor is sodium bicarbonate or ethyldiisopropylamine.

22. Process according to any one of claims 16 to 21, characterized by preparing a compound according to any one of claims 2 to 12.

23. A process according to claim 18 for the preparation of the compound 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- [4- (1-benzylpiperidinyl) ] -1, 2, 4-oxadiazole, characterized in that cyclobutyl magnesium bromide is reacted with 3-benzoyl-5- [4- (1-benzylpiperidinyl) ] -1, 2, 4-oxadiazole and subsequently, if desired, the compound is isolated in its (+) and (-) enantiomers.

24. The process according to claim 23, characterized in that the separation is carried out by HPLC.