QUINAZOLINONE DERIVATIVES

Abstract: A compound given by general formula (1): [wherein T represents oxygen or sulfur atom, Y represents alkyl, cycloalkyl group, etc., ring W represents benzene ring, etc., R 1 and R 2 represent independently hydrogen atom, lower alkyl group, etc., and R 3 represents hydrogen atom, alkyl group, etc. Z represents a group given by formula: {wherein A 1 and A 2 represent independently hydrogen atom, alkyl group, etc. and G represents straight chain alkylene having 1-6 of the carbon number, etc.} or a group given by formula: {wherein n represents 0, 1 or 2, ring E represents 4-8 membered saturated heterocyclic ring containing nitrogen atom(s), and A 3 represents hydrogen atom, alkyl group, etc.}], its prodrug or pharmaceutically acceptable salt thereof is an antagonist against muscarinic receptor that is useful as anticholinergic medicaments, and therefore it is useful as pollakiuria or urinary incontinence remedy.

Description: Technical Field The present invention relates to compounds which have an antagonistic effect on muscarinic receptor and can be useful as anticholinergic medicaments, pharmaceutically acceptable salts thereof, and their use. Antagonists against muscarinic receptor can be used, for example, as mydriatic medicament, anticonvulsant, parkinsonian remedy, antasthmatic, peptic ulcer remedy, secretagogue and motofacient for gastric and duodenal ulcer, intestinum hypersensitivity remedy, pollakiuria remedy, urinary incontinence remedy, antiarrhythmic medicament, esophageal achalasia remedy, chronic obstructive tracheal disease remedy and so on. Background Art The quinazolinone derivatives having subneural, anti-inflammatory and analgesic action are described in Japanese Unexamined Patent Publication No. sho47-14183, the quinazolinone derivatives having an effect of inhibiting central nervous system are described in French Patent No. 2,027,023, and the quinazolinone derivatives having an effect of preventing overload of calcium ions are described in Japanese Unexamined Patent Publication No. hei7-41465 (corresponding to EP-A-0626373), respectively. However, they do not refer to the use of anticholinergic medicament, especially urinary incontinence and pollakiuria remedy. GB-A-1344658 and DE-A-1932396 describe processes for preparing certain quinazolinone derivatives. JP-A-57-95966 describes quinazolinone derivatives having an antilipemic action, vasodilator action, inhibiting action on the aggregation of blood platelets, antiallergic action, etc. JP-A-56-113769 describes quinazolinone derivatives having an anti-inflammatory action, analgesic action and inhibitory action on blood platelet agglutination. Journal of Heterocyclic Chemistry, vol. 21, 1984, pages 1709-1711 describes the synthesis of certain quinazolinone derivatives as potential anticonvulsants. Certain quinazolinone derivatives are also described in Chem. Pharm. Bull., (1981), 29(8), pages 2135-2156. Disclosure of the Invention The subject of the present invention is to provide antagonists against muscarinic receptor which are useful as anticholinergic medicaments. The present inventors have earnestly studied for solving the above problem, found that the compounds given by general formula (1) below and pharmaceutically acceptable salts thereof have an antagonistic effect on muscarinic receptor, and now completed the present invention. The present invention accordingly provides: [1] Use of a compound given by general formula (1): [wherein T represents oxygen or sulfur; Y represents phenyl or substituted phenyl; ring W represents benzene; R 1 and R 2 represent, independently, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, nitro, amino, substituted amino, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; R 3 represents hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, aralkyl or substituted aralkyl; Z represents a group given by the formula: {wherein n represents 0, 1 or 2, ring E represents a 4-8 membered saturated heterocyclic ring containing one or more nitrogen atom(s), and A 3 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, saturated heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, substituted aralkyl, heteroarylalkyl, substituted heteroarylalkyl or -CH 2 R 4 (wherein R 4 represents alkenyl or alkynyl) or forms a bicyclo ring together with ring E}], or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of intestinum hypersensitivity, urinary incontinence, pollakiuria, esophageal achalasia or chronic obstructive tracheal disease, wherein the cycloalkyl group is cycloalkyl having 3-8 carbon number, the cycloalkylalkyl group is cycloalkylalkyl having 10 or less of the carbon number, the cycloalkenylalkyl group is cycloalkenylalkyl having 10 or less of the carbon number, the alkenyl group is alkenyl having 2-6 of the carbon number, the alkynyl group is alkynyl having 2-6 of the carbon number, the aralkyl group is aralkyl having 12 or less of the carbon number, the heteroaryl group is a 5-6 membered ring containing 1 or 2 nitrogen atom(s), a 5-6 membered ring containing 1 or 2 nitrogen atom(s) and one oxygen or sulfur atom, or a 5-6 membered ring containing one oxygen or sulfur atom, the heteroaryl group for the heteroarylalkyl is a 5-6 membered ring containing 1-4 nitrogen atom(s), or a 5-6 membered ring containing 1-2 nitrogen atom(s) and one oxygen or sulfur atom, the saturated heterocyclyl is the saturated heterocyclyl consisting of one oxygen or sulfur atom and 3-5 carbon atoms, the 4-8 membered saturated heterocyclic ring containing nitrogen atom for ring E is a ring containing 1 or 2 nitrogen atoms and 0 or 1 oxygen atom, the lower alkyl is straight chain or branched alkyl having 4 or less of the carbon number, the lower alkoxy group is straight chain or branched alkoxy having 4 or less of the carbon number, the lower alkylthio group is straight chain or branched allrylthio group having 4 or less of the carbon number, the lower allcylsulfinyl group is straight chain or branched alkylsulfinyl having 4 or less of the carbon number, and the lower alkylsulfonyl group is straight chain or branched allcylsulfonyl group having 4 or less of the carbon number. [2] Use as described in [1], wherein Z represents a group given by the formula: (wherein A 4 represents phenyl, substituted phenyl, cycloalkyl or cycloalkenyl). [3] Use as described in [2], wherein A 4 represents cycloalkyl or cycloalkenyl. [4] Use as described in [2], wherein A 4 represents phenyl or substituted phenyl. [5] Use as described in [4], wherein A 4 represents substituted phenyl and said substituent is cyano, alkoxyalkyl, alkanoylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. [6] Use as described in any of [1]-[5], wherein the medicament is for the prevention or treatment of urinary incontinence or pollakiuria. [7] A compound given by general formula (1a): [wherein T represents oxygen or sulfur; Y represents phenyl or substituted phenyl; ring W represents benzene; R 1 and R 2 represent, independently, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, nitro, amino, substituted amino, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; R 31 represents alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aralkyl or substituted aralkyl; Z represents a group given by the formula: {wherein n represents 0, 1 or 2, ring E represents a 4-8 membered saturated heterocyclic ring containing one or more nitrogen atom(s), and A 3 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, saturated heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, substituted aralkyl, heteroarylalkyl, substituted heteroarylalkyl or -CH 2 R 4 (wherein R 4 represents alkenyl or alkynyl), or forms a bicyclo ring together with ring E}], or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is cycloalkyl having 3-8 carbon number, the cycloalkylalkyl group is cycloalkylalkyl having 10 or less of the carbon number, the cycloalkenylalkyl group is cycloalkenylalkyl having 10 or less of the carbon number, the alkenyl group is alkenyl having 2-6 of the carbon number, the alkynyl group is alkynyl having 2-6 of the carbon number, the aralkyl group is aralkyl having 12 or less of the carbon number, the heteroaryl group is a 5-6 membered ring containing 1 or 2 nitrogen atom(s), a 5-6 membered ring containing 1 or 2 nitrogen atom(s) and one oxygen or sulfur atom, or a 5-6 membered ring containing one oxygen or sulfur atom, the heteroaryl group for the heteroarylalkyl is a 5-6 membered ring containing 1-4 nitrogen atom(s), or a 5-6 membered ring containing 1-2 nitrogen atom(s) and one oxygen or sulfur atom, the saturated heterocyclyl is the saturated heterocyclyl consisting of one oxygen or sulfur atom and 3-5 carbon atoms, the 4-8 membered saturated heterocyclic ring containing nitrogen atom for ring E is a ring containing 1 or 2 nitrogen atoms and 0 or 1 oxygen atom, the lower alkyl is straight chain or branched alkyl having 4 or less of the carbon number, the lower alkoxy group is straight chain or branched alkoxy having 4 or less of the carbon number, the lower alkylthio group is straight chain or branched alkylthio group having 4 or less of the carbon number, the lower alkylsulfinyl group is straight chain or branched alkylsulfinyl having 4 or less of the carbon number, and the lower alkylsulfonyl group is straight chain or branched alkylsulfonyl group having 4 or less of the carbon number. [8] A pharmaceutical composition comprising a compound or salt as described in [7] together with a pharmaceutically acceptable carrier or diluent. [9] A compound or salt as described in [7] or a composition as described in [8], for use in a method of treatment of the human or animal body by therapy. As the compounds given by general formula (1a) are a part of the compounds given by general formula (1), the explanation of the compounds given by general formula (1) should be construed as the explanation of the compounds given by general formula (1a). Further, the compounds given by general formula (1) or pharmaceutically acceptable salts thereof may be referred to as the present compound in this description. The various groups in the present invention are explained in detail below. The explanation for each group is also applied to the parts of the other substituents unless specifically noted. Examples of the alkyl group include straight chain or branched alkyl group having 1-8 of the carbon number, typically methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, 3-pentyl, 3-hexyl, 4-heptyl and 4-octyl. The cycloalkyl group is cycloalkyl having 3-8 carbon number, typically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkylalkyl group is cycloalkylalkyl having 10 or less of the carbon number, typically cyclopropylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 3-cyclohexylpropyl and 4-cyclohexylbutyl. The cycloalkenylalkyl group is cycloalkenylalkyl having 10 or less of the carbon number, typically 4-cyclohexenylmethyl, 4-cyclopentenylmethyl and 4-(4-cyclohexyenyl)butyl. The alkenyl group is alkenyl having 2-6 of the carbon number, typically vinyl, allyl, 1-propenyl, 1-butenyl, 2-pentenyl and 5-hexyenyl, preferably , allyl, 1-propenyl and 1-butenyl group. The alkynyl group is alkynyl having 2-6 of the carbon number, typically ethynyl, propargyl, 2-butynyl and 3-pentynyl, preferably ethynyl and propargyl. The aralkyl group is aralkyl having 12 or less of the carbon number, typically benzyl, 1-phenylethyl, 2-phenylethyl and 2-naphthylmethyl. Preferable group is benzyl group for A 3 . The heteroaryl group is a 5-6 membered ring containing 1 or 2 nitrogen atom(s), a 5-6 membered ring containing 1 or 2 nitrogen atom(s) and one oxygen or sulfur atom, or a 5-6 membered ring containing one oxygen or sulfur atom, typically 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-oxadiazolyl, 2-imidazolyl, 2-thiazolyl, 3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 2-furyl and 3-pyrrolyl. The heteroaryl group for the heteroarylalkyl is a 5-6 membered ring containing 1-4 nitrogen atom(s), or a 5-6 membered ring containing 1-2 nitrogen atom(s) and one oxygen or sulfur atom. Typical heteroarylalkyl group is exemplified by 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-(2-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 2-thienylmethyl, 3-thienylmethyl, 3-oxadiazolylmethyl, 2-imidazolylmethyl, 2-thiazolylmethyl, 3-isothiazolylmethyl, 2-oxazolylmethyl, 3-isoxazolylmethyl, 2-furylmethyl, 3-furylmethyl and 2-pyrrolylmethyl. The saturated heterocyclyl is the saturated heterocyclyl consisting of one oxygen or sulfur atom and 3-5 carbon atoms, typically tetrahydropyran-4-yl, tetrahydrofuran-3-yl and tetrahydrothiophen-3-yl. The 4-8 membered saturated heterocyclic ring containing nitrogen atom for ring E is a ring containing 1 or 2 nitrogen atoms and 0 or 1 oxygen atom, typically pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl, homopiperidin-4-yl and morpholin-2-yl. When n is 0, piperidin-4-yl is preferable. Examples of the bicyclo ring formed by ring E and A 3 include quinuclidin-3-yl and quinuclidin-4-yl. The lower alkyl group is straight chain or branched alkyl having 4 or less of the carbon number, typically methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl and 1,1-dimethylethyl. Examples of the halogen atom include fluorine, chlorine, bromine and iodine atom. The lower alkoxy group is straight chain or branched alkoxy having 4 or less of the carbon number, typically methoxy, ethoxy, propoxy, 2-propoxy, butoxy and 1,1-dimethylethoxy. The lower alkylthio group is straight chain or branched alkylthio group having 4 or less of the carbon number, typically methylthio, ethylthio, 2-propylthio and butylthio. The lower alkylsulfinyl group is straight chain or branched alkylsulfinyl having 4 or less of the carbon number, typically methylsulfinyl, ethylsulfinyl, propylsulfinyl, 2-propylsulfinyl and butylsulfinyl. The lower alkylsulfonyl group is straight chain or branched alkylsulfonyl group having 4 or less of the carbon number, typically methylsulfonyl, ethylsulfonyl, propylsulfonyl, 2-propylsulfonyl and butylsulfonyl. Examples of the substituent for the substituted amino group include alkyl or -CH 2 R 4 - group (wherein R 4 represents alkenyl or alkynyl group), and the substituent may be one or two which are the same or different from each other. Preferable substituted amino groups are exemplified by methylamino, ethylamino, allylamino, propargylamino, propylamino, 2-propylamino, butylamino, N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino and N,N-diallylamino. Examples of the substituent for the substituted aryl, substituted phenyl, substituted aralkyl, substituted benzyl, substituted heteroaryl and substituted heteroarylalkyl group include lower alkyl, lower alkoxy, methylenedioxy group, halogen atom, cyano, trifluoromethyl, nitro, hydroxy, alkanoyloxy, carboxyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido group, a group of formula -NR 6 R 7 (wherein R 6 and R 7 independently represent hydrogen atom, alkyl, -CH 2 R 4 (wherein R 4 represents the meaning defined above), di- lower alkylamino-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, alkoxycarbonyl, heteroarylmethyl or aralkyl group, or R 6 and R 7 are combined together to form saturated cyclic amino group having 4 to 8 carbons, which constitute the ring, and further optionally one -NR 8 - (R 8 represents hydrogen atom, lower alkyl, phenyl, lower alkoxycarbonyl or benzyl group) or one oxygen atom, with the nitrogen atom to which R 6 and R 7 are bonded), -C(=O)NR 6 R 7 (R 6 and R 7 represent the same meanings defined above), -NR 5 C(=O)Q 1 (R 5 represents hydrogen atom or lower alkyl group, and Q 1 represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl group), or E 1 -M 1 -E 2 -Q 2 {E 1 represents bond or divalent hydrocarbyl group having 1-4 of the carbon number, M 1 represents bond, oxygen or sulfur atom, or -NR 5 - (R 5 represents the same meaning defined above). E 2 represents divalent hydrocarbyl group, which may contains unsaturated bond, having 1-6 of the carbon number, provided that E 1 and M 1 are combined to form one bond when both of E 1 and M 1 represent bond. Q 2 represents hydrogen atom, hydroxy, carboxyl, alkoxycarbonyl, alkanoyloxy, benzyloxycarbonyl group, halogen atom, cyano, benzyloxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsubstituted or unsabstituted benzenesulfonyloxy (e.g. p-toluenesulfonyloxy), alkoxycarbonylamino, alkylsulfonamido, phthalimido, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl group, a group of formula -NR 6 R 7 (R 6 and R 7 represent the same meaning defined above), -C(=O)NR 6 R 7 (R 6 and R 7 represent the same meanings defined above), -NR 5 C(=O)Q 1 (R 5 and Q 1 represent the same meanings defined above)}. Examples of the substituent for substituted aryl, substituted aralkyl, substituted heteroaryl and substituted heteroarylalkyl group of Q 1 and Q 2 include lower alkyl group, halogen atom, trifluoromethyl and cyano group, and the substituents may be plural and the same or different from each other. Further, the lower means that the alkyl part of said group is lower alkyl, and examples of the lower alkyl include the alkyl having 1-4 of the carbon number such as methyl, ethyl, propyl, 2-propyl and butyl. The saturated cyclic amino groups constituted by 4 to 8 carbons and further optionally one -NR 8 - (R 8 represents the same meaning defined above) or one oxygen atom, which R 6 and R 7 are combined together to form with the nitrogen atom to which R 6 and R 7 are bonded, are typically exemplified by 1-pyrrolidinyl, piperidino, 1-homopiperidinyl, morpholino and 4-methylpiperazin-1-yl. The divalent hydrocarbyl groups having 1-4 of the carbon number for E 1 are exemplified by typically straight chain or branched alkylene group, more typically methylene, ethylene, propylene, trimethylene, tetramethylene and 1-ethylethylene. Examples of the divalent hydrocarbyl group, which may contain unsaturated bond, having 1-6 of the carbon number for E 2 include straight chain or branched alkylene group such as methylene, ethylene, trimethylene, tetramethylene and 1-ethylethylene; straight chain or branched alkenylene group such as vinylene, 1-propenylene, 2-butenylene and 4-methyl-2-pentenylene; straight chain or branched alkynylene group such as ethynylene, 2-propynylene, 2-butynylene and 4-methyl-2-pentynylene; and o-, m- and p-phenylene group. Examples of the substituent for substituted alkyl, substituted alkenyl, substituted alkynyl and substituted cycloalkyl include hydroxy, amino, lower alkylamino, di-lower alkylamino, carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl group, halogen atom, cyano, benzyloxy, alkoxy, lower alkanoyloxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, alkanoylamino, lower alkoxycarbonylamino and lower alkylsulfonamido group, herein lower means that the alkyl part of said group is lower alkyl. Such lower alkyl is exemplified by the alkyl group having 1-4 of the carbon number such as methyl, ethyl, propyl, 2-propyl and butyl. Pharmaceutically acceptable salts can be exemplified by acid addition salts and quaternary ammonium salts. Examples of the acid for the acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, and organic acids such as acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, maleic acid and methanesulfonic acid. Examples of the quaternary ammonium salts include the quaternary ammonium salts prepared by the reaction with an alkylating agent of formula: R 9 -G 1 (wherein R 9 represents lower alkyl group and G 1 represents a leaving group), and optionally changing an anion to another physiologically acceptable anion. Preferable lower alkyl groups are exemplified by methyl and ethyl group. Examples of the physiologically acceptable anion include halogen ion, sulfate, phosphate, nitrate, acetate, citrate, fumarate, succinate and so on. Preferable leaving groups are exemplified by chlorine, bromine and iodine atom. The present compounds have one or more asymmetric carbon atoms and there exist stereoisomers. The present compounds contain a mixture of each isomer and isolated isomer. The present compounds may be their anhydrides or solvate such as hydrate. The present compounds, especially the compounds among them, wherein Z represents formula: are selective in muscarinic part of smooth muscle rather than muscarinic part of cor. Therefore, they are useful for curing a disease relating to alteration and/or tension of exercise of smooth muscle observed in intestine, trachea and bladder in particular. These disease include intestinum hypersensitivity, unrinary incontinence, pollakiuria, esophageal achalasia and chromic obstructive tracheal disease. Further, among the above-mentioned compounds, the compounds wherein A 3 represents cycloalkymethyl, cycloalkenylmethyl, benzyl or substituted benzyl group are especially useful as pollakiuria and/or urinary incontinence remedy. When the above-mentioned compounds given by formula (1), their acid addition salts or quaternary ammonium salts are utilized as anticholinergic medicament, they can be administered parenterally or orally. Namely, liquid formulations such as solution, emulsion and suspension may applied as injections, to which buffer, dissolving assistant, isotonic agent and so on may be optionally added. They can also be administered via rectum as suppository. These formulations are prepared by mixing a usual carrier, excipient, binder, stabilizer and so on with the active ingredient according to general methods. Further, usual preparations such as tablet, capsule, syrup, suspension and so on may be administered orally. The dose and frequency vary depending on the symptom, age, body weight, type of formulation and so on. In case of injecting administration, they may be applied in general, in an amount of 0.1 to 100mg at once or in several times for adult. They may also be administrated by intravenous drip. In case of oral administration, an amount of 0.1 to 1000mg, preferably 1 to 400mg, may be applied once or in several times, for example 2 to 4 times, a day. In the compounds given by general formula (1), the compound wherein R 3 represents hydrogen atom can be prepared by the methods described in Japanese Unexamined Patent Publication No. hei7-41465 or their variations. Further, the compound except the compounds wherein R 3 represents hydrogen atom can be prepared by the method below: wherein ring W, Y, Z, T, R 1 and R 2 represent the meanings as defined above. R 31 means the definition of R 3 except hydrogen atom. Y 1 , Z 1 , R 11 , R 21 and R 32 represent the same groups as Y, Z, R 1 , R 2 and R 31 respectively, provided that amino, alkylamino, hydroxy, carboxyl and the other reactive groups are protected when these substituents are contained. G 2 represents a leaving group. The compound given by general formula (4) can be prepared by the reaction of the compound given by general formula (2) with an alkylating agent given by general formula (3) in a solvent, and optionally deprotection. The reaction may be usually carried out in a solvent at 0-100°C, preferably room temperature to 70°C in the presence of a base. Examples of the solvent include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; ketones such as acetone and 2-butanone; and dimethylformamide. Examples of the base include sodium hydride, potassium carbonate, sodium carbonate and triethylamine. In case of utilizing potassium carbonate or sodium carbonate, an addition of sodium iodide or potassium iodide may raise the yield. The leaving group given by G 2 is usually halogen atom such as chlorine, bromine and iodine and aromatic sulfonyloxy group such as p-toluenesulfonyloxy group. Examples of the protecting group for amino, alkylamino, hydroxy, carboxyl group and so on include usual protecting groups (e.g. benzyl and acetyl group for protecting hydroxy group, benzyl group for protecting amino group, etc.) used in organic synthesis field in general. These groups can be derived and eliminated by usual methods. (cf. Protective Groups in Organic Synthesis, 2 nd ed., John Wiley & Sons, Inc., New York) Examples Hereinafter, the present invention will be explained in detail by preparation examples and test examples, which do not limit the present invention. Preparation example 1 Preparation of 3-[1-(cyclopropylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone To a solution of 200mg (0.65mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 5ml of N,N-dimethylformamide (DMF), 270mg (1.95mmol) of potassium carbonate and 176mg (1.30mmol) of bromomethylcyclopropane were added at room temperature subsequently and stirred at about 50°C for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to afford a residue, which was purified by silica gel column chromatography (chloroform - 10% methanol/chloroform) to give 231mg (0.64mmol) of the title compound as colorless oil. To the solution of the above oily product in 15ml of methanol, 1.0ml of 1M hydrochloric acid/ether was added and the mixture was concentrated under reduced pressure. To the obtained residue, 30ml of ether were added, and stirred at room temperature for one hour and under ice-cooling for one hour. The precipitated crystals were collected and recrystallized from isopropanol to give 133mg of the title compound hydrochloride as colorless crystals. mp 276-281°C Preparation example 2 Preparation of 3-[1-(2-methylpropyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone In similar way as in Preparation example 1, the title compound hydrochloride was prepared from 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and 1-bromo-2-methylpropane. mp 215-225°C Preparation example 3 Preparation of 1-butyl-3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone To a solution of 100mg (0.25mmol) of 3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 2ml of DMF, 22mg (0.55mmol) of sodium hydride (60%) were added at room temperature and stirred at about 60°C for one hour. After allowing the reaction mixture to stand cool, a solution of 69mg (0.38mmol) of 1-iodobutane in 1ml of DMF was added thereto at room temperature and stirred at about 60°C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform - 10% methanol/chloroform) to give 88mg (0.19mmol) of the title compound as colorless oil. To the solution of the above oily product in 3ml of ether, 0.23ml of 1M hydrochloric acid/ether was added and stirred at room temperature for one hour. Isopropyl ether was added to the solution, followed by stirring at room temperature for one hour and under ice-cooling for one hour. The precipitated crystals were collected to give 78mg of the title compound hydrochloride as colorless crystals. mp 115-117°C The compounds of Preparation examples 4-10 were prepared in similar way as in Preparation example 3. Preparation example 4 Preparation of 1-propyl-3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride mp 135-137°C Preparation example 5 Preparation of 1-ethyl-3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride mp 137-138°C Preparation example 6 Preparation of 1-methyl-3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride mp 140-142°C Preparation example 7 Preparation of 1-hexyl-3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride mp 60-62°C Preparation example 8 Preparation of 1-(2-methoxyethyl)-3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride mp 223-225°C Preparation example 9 Preparation of 1-benzyl-3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride mp 246-248°C Preparation example 10 Preparation of 1-cyclohexylmethyl-3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride mp 104-106°C Preparation example 11 Preparation of 3-[1-(4-cyanobenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone To a solution of 100mg (0.32mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 3ml of methanol, 0.08ml (0.32mmol) of 4N hydrochloric acid/dioxane, 170mg (1.3mmol) of 4-cyanobenzaldehyde, 82mg (1.3mmol) of sodium cyanoborohydride were added subsequently under ice-cooling, and stirred at room temperature for 10 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extracting with ethyl acetate, washing with water and saturated brine, and drying over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform - 2% methanol/chloroform) to give the title compound as colorless oil. To the solution of the above oily product in 2ml of methylene chloride, 0.6ml of 1M hydrochloric acid/ether and 1ml of ethanol were added and stirred. Under a nitrogen atmosphere, ether and methylene chloride were gradually evaporated. The precipitated crystals were collected to give 118mg of the title compound hydrochloride as colorless crystals. mp 189-192°C Preparation example 12 Preparation of 3-[1-(2-cyanobenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone In similar way as in Preparation example 1, the title compound hydrochloride was prepared from 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and α-bromo-2-tolunitrile. mp 220°C (decomp.) Preparation example 13 Preparation of 1-propyl-3-[1-(3-hydroxymethylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone To a solution of 100mg (0.234mmol) of 3-[1-(3-hydroxymethylbenzyl) piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 2ml of DMF, 11.2mg (0.28mmol) of sodium hydride (60%) were added under ice-cooling and stirred at the same temperature for 5 minutes and at room temperature for 5 minutes. After ice-cooling again, 0.032ml (0.35mmol) of 1-bromopropane was added thereto and stirred under ice-cooling for 3 hours and at room temperature for 6 hours. To the reaction mixture, 2mg of tetrabutylammonium iodide were added and further stirred at room temperature for 5 hours. It was poured into water, extracted with ethyl acetate, washed with water, aqueous saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform - 2% methanol/chloroform) to give 47mg (0.10mmol) of the title compound as colorless oil. To the solution of the above oily product in 1ml of ethanol, 0.2ml of 1M hydrochloric acid/ether was added and the mixture was concentrated under reduced pressure. To the obtained residue, 1ml of isopropyl alcohol was added and stirred at room temperature for one hour and under ice-cooling for one hour. The precipitated crystals were collected to give 13mg of the title compound hydrochloride as colorless crystals. mp 108-112°C Preparation example 14 Preparation of 1-(2-hydroxyethyl)-3-[1-(3-hydroxymethylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone (a) Preparation of 1-(2-tert-butyldimethylsilyloxyethyl)-3-[1-(3-hydroxymethylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone To a solution of 200mg (0.468mmol) of 3-[1-(3-hydroxymethylbenzyl) piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 3ml of DMF, 22mg (0.55mmol) of sodium hydride (60%) were added under ice-cooling and stirred at the same temperature for 5 minutes and at room temperature for 10 minutes. After ice-cooling again, 224mg (0.55mmol) of 2-tert-butyldimethylsilyloxyethylbromide and 2mg of tetrabutylammonium iodide were added thereto and stirred under ice-cooling for 4 hours. It was poured into aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with water, aqueous saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform - 3% methanol/chloroform) to give 92mg (0.16mmol) of the title compound as colorless oil. 1 H NMR(CDCl 3 ); δ 0.04(6H,s), 0.86(9H,s), 3.34(2H,s), 4.39(1H,m), 4.66(2H,s), 5.48(1H,s).6.92(1H,dt,J=1Hz,7.4Hz), 7.06-7.31(13H,m) (b) Preparation of 1-(2-hydroxyethyl)-3-[1-(3-hydroxymethylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone To a solution of the oil obtained by (a) in 2ml of tetrahydrofuran (THF), 0.31ml of IN tetrabutylammonium fluoride/THF solution was added and stirred for 30 minutes at room temperature. Saturated brine was added thereto and the reaction mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform - 5% methanol/chloroform) to give 63mg (0.13mmol) of the title compound as colorless oil. To the solution of the above oily product in 1ml of isopropyl alcohol, 12.2mg (0.13mmol) of oxalic acid were added, dissolved by heating and stirred at room temperature. The precipitated crystals were collected to give 50mg of the title compound oxalate as colorless crystals. mp 185-187°C Preparation example 15 Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone In similar way as in Preparation example 11, the title compound hydrochloride was prepared from 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and 3-methoxymethylbenzaldehyde. mp 152-157°C In similar way as in Preparation example 3, the following compounds were prepared. Preparation example 16 1-(3-cyanopropyl)-3-[1-(cyclohexymethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride mp 136-140°C Preparation example 17 1-(2-methoxyethyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.92(1H, d, J=11.0Hz), 3.35(3H, s), 3.44(2H, s), 3.65(2H, t, J=6.5Hz), 4.00(1H, dt, J=6.6Hz, 14.5Hz), 4.29(1H, dt, J=6.6Hz, 14.5Hz), 4.42(1H, m), 5.49(1H, s), 6.96(2H, t, J=7.7Hz) Preparation example 18 1-(2-methoxycarbonylethyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.79(1H, d, J=10.8Hz), 2.83(1H, m), 3.44(2H, s), 3.67(3H, s), 4.22(2H, m), 4.41(1H, m), 5.50(1H, s), 6.87(1H, d, J=8.1Hz), 6.96(1H, t, J=7.0Hz) Preparation example 19 1-methoxycarbonylmethyl-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.78(1H, d, J=11.7Hz), 2.94(1H, d, J=11.4Hz), 3.76(3H, s), 4.40(1H, m), 5.55(1H, s), 6.63(1H, d, J=8.1Hz) Preparation example 20 1-(3-cyanopropyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.82(1H, d, J=11.6Hz), 2.92(1H, d, J=10.8Hz), 3.45(2H, s), 3,93(1H, m), 4.14(1H, m), 4.41(1H, m), 5.52(1H, s), 6.85(1H, t, J=8.2Hz) Preparation example 21 Preparation of 1-(2-hydroxyethyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone In similar way as in Preparation example 3, 1-[2-(tetrahydropyran-2-yl)oxyethyl]-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone was prepared from 99.4mg (0.25mmol) of 3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and 157mg (0.75mmol) of 2-(tetrahydropyran-2-yl)oxyethyl bromide as colorless oil. To a solution of the obtained oil in 4ml of methanol, 57mg (0.30mmol) of p-toluenesulfonic acid monohydrate were added and stirred at room temperature for one hour. The reaction liquid was poured into aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. It was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate, 1/1 to 1/4) to give 100mg (0.23mmol) of the title compound as colorless amorphous. 1 H NMR(CDCl 3 ); δ 2.74(1H, d, J=11.0Hz), 3.41(2H, s), 3.95(3H, s), 6.11(1H, s), 6.64(1H, d, J=7.9Hz), 7.37(2H, dt, J=1.5Hz, 7.9Hz) Preparation example 22 Preparation of 1-(3-hydroxypropyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone In similar way as in Preparation example 21, the title compound was prepared from 3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and 3-(tetrahydropyran-2-yl)oxypropyl bromide. 1 H NMR(CDCl 3 ); δ 2.78(1H, d, J=11.2Hz), 2.93(1H, d, J=7.7Hz), 3.45(1H, s), 3.92(1H, m), 5.53(1H, s) Preparation example 23 Preparation of 1-(3-aminopropyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone In similar way as in Preparation example 3, 1-(3-phthalimidopropyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone was prepared from 3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and 3-bromo-1-phthalimidopropane as pale yellow amorphous. 1 H NMR(CDCl 3 ); δ 2.77(1H, d, J=11.9Hz), 2.92(1H, m), 3.43(2H, s), 3.80(2H, t, J=7.0Hz), 3.93(1H, m), 4.04(1H, m), 4.38(1H, m), 5.49(1H, s), 6.80(1H, d, J=7.9Hz), 7.13-7.27(12H, m) To a solution of 96mg (0.164mmol) of the above oily product in 2ml of ethanol, 3.0ml of 30% methylamine/ethanol solution were added and stirred under reflux-heating for one hour. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (10% methanol/chloroform - 20% methanol/chloroform) to give 55mg (0.12mmol) of the title compound as colorless amorphous. 1 H NMR(CDCl 3 ); δ 2.92(1H, d, J=11.0Hz), 3.45(2H, s), 3.95(1H, m), 4.09(1H, m), 4.39(1H, m), 5.51(1H, s), 6.88(1H, d, J=8.1Hz) Preparation example 24 Preparation of 1-(2-carboxyethyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone To a solution of 78mg (0.16mmol) of 1-(2methoxycarbonylethyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 1ml of methanol, 0.5ml of 1N aqueous sodium hydroxide solution was added and stirred at room temperature for 2.5 hours. After neutralization with 1N hydrochloric acid, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Ether was added to the residue and precipitated crystals were collected to give the title compound as colorless powder. 1 H NMR(CDCl 3 ); δ 2.60-3.10(4H, m), 3.40(2H, s), 4.10-4.30(3H, m), 5.43(1H, s), 6.79-6.88(2H, m), 7.00-7.27(12H, m) Preparation example 25 Preparation of 1-carboxymethyl-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone In similar way as in Preparation example 24, the title compound was prepared from 1-methoxycarbonylmethyl-3-(benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone. 1 H NMR(CDCl 3 ); δ 1.45-1.60(2H, m), 2.10-2.35(3H, m), 4.20-4.45(2H, m), 5.60(1H, s), 6.79-6.89(2H, m) Preparation example 26 Preparation of 3-(1-benzylpiperidin-4-yl)-4-(3-methoxyphenyl)-3,4-dihydro-2(1H)-quinazolinone (a) Preparation of 2-trichloroacetylamino-3'-methoxybenzophenone To a solution of 2.89g (12.7mmol) of 2-amino-3'-methoxybenzophenone and 2.13ml (15.2mmol) of triethylamine in 16ml of tetrahydrofuran (THF), 1.56ml (14mmol) of trichloroacethyl chloride were added dropwise under ice-colling and stirred for 2 hours. Water was added to the reaction mixture, which was followed by extraction with ethyl acetate. The organic layer was washed with satured brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 15/1) to give 4.51g (12.1mmol) of the title compound. 1 H NMR(CDCl 3 ); δ 3.87(3H, s), 7.14-7.28(4H, m), 8.63(1H, d, J=8.3Hz) (b) Preparation of N-(1-benzylpiperidin-4-yl)-2-trichloroacetylamino-3'-methoxybenzophenoneimine To a solution of 4.51g (12.1mmol) of 2-trichloroacetylamino-3'-methoxybenzophenone in 22ml of dimethyl sulfoxide (DMSO), 3.70ml (18.1mmol) of 4-amino-1-benzylpiperidine were added at room temperature and stirred at about 50°C for 5 hours. After allowed to stand cool, the reaction mixture was extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 7/1 to 5/1) to give 4.51g (7.1mmol) of the title compound as pale yellow amorphous. 1 H NMR(CDCl 3 ); δ 1.52-1.59(2H, m), 1.81(2H, m), 2.03(2H, m), 2.84(2H, m), 3.45(2H, s), 3.83(3H, s), 6.72(1H, d, J=7.5Hz) (c) Preparation of α-(2-aminophenyl)-N-(benzylpiperidin-4-yl)-3-methoxybenzylamine To a suspension of 3.92g (7.19mmol) of N-(1-benzylpiperidin-4-yl)-2-trichloroacetylamino-3'-methoxybenzophenoneimine in 200ml of methanol, sodium borohydride was added by portions and stirred. After the disappearance of the above starting compound was confirmed, water was added dropwise to the reaction mixture at room temperature and stirred. After concentrated under reduced pressure, the reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The liquid was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 4/1 to ethyl acetate) to give 2.65g (6.6mmol) of the title compound as colorless oil. 1 H NMR(CDCl 3 ); δ 3.46(2H, s), 3.78(3H, s), 4.73(1H, brs), 5.05(1H, s), 6.59-6.65(2H, m) (d) Preparation of 3-(1-benzylpiperidin-4-yl)-4-(3-methoxyphenyl)-3,4-dihydro-2(1H)-quinazolinone To a solution of 2.65g (6.60mmol) of α-(2-aminophenyl)-N-(benzylpiperidin-4-yl)-3-methoxybenzylamine in 53ml of THF, 1.50g (9.24mmol) of carbonyldiimidazole were added and stirred under reflux-heating for 3 hours. After allowed to stand cool, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (1% methanol/chloroform) to give 2.8g (6.5mmol) of the title compound as colorless amorphous. 1 H NMR(CDCl 3 ); δ 2.79(1H, d, J=9.3Hz), 2.93(1H, d, J=10.1Hz), 3.45(2H, s), 3.75(3H, s), 4.38(1H, m), 5.52(1H, s), 6.66(1H, d, J=7.7Hz) The compounds of Preparation examples 27-36 were prepared in similar way as in Preparation example 26. Preparation example 27 Preparation of 3-(1-benzylpiperidin-4-yl)-4-(4-methoxyphenyl)-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.44-1.62(3H, m), 1.93-2.12(3H, m), 2.80(2H, d, J=10.6Hz), 2.93(1H, d, J=8.3Hz), 3.46(1H, s), 3.74(3H, s), 4.35(1H, m), 5.52(1H, s), 6.66(1H, d, J=7.9Hz), 6.78(2H, d, J=8.8Hz) Preparation example 28 Preparation of 3-(1-benzylpiperidin-4-yl)-4-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.94-2.14(3H, m), 3.46(2H, s), 4.39(1H, m), 5.54(1H, s), 7.05(1H, s) Preparation example 29 Preparation of 3-(1-benzylpiperidin-4-yl)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.93(1H, d, J=11.1Hz), 3.46(2H, s), 4.42(1H, m), 5.54(1H, m), 6.69(1H, d, J=7.7Hz) Preparation example 30 Preparation of 3-(1-benzylpiperidin-4-yl)-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.40-1.65(3H, m), 1.90-2.20(3H, m), 2.75-2.95(2H, m), 3.44(2H, s), 3.72(3H, s), 5.50(1H, s), 6.59(1H, d, J=8.6Hz) Preparation example 31 Preparation of 3-(1-benzylpiperidin-4-yl)-4-(2-methoxyphenyl)-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.92-2.13(3H, m), 2.76(1H, d, J=11.2Hz), 2.93(1H, d, J=10.3Hz), 3.45(2H, s), 3.95(3H, s), 4.35(1H, m), 6.11(1H, s), 6.64(1H, d, J=7.7Hz) Preparation example 32 Preparation of 3-(1-benzylpiperidin-4-yl)-4-(4-fluorophenyl)-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.38-1.72(3H, m), 1.80-2.15(3H, m), 2.77-3.00(2H, m), 3.46(2H, s), 4.38(1H, m), 5.55(1H, s), 6.70(1H, d, J=8.4Hz), 6.88-6.97(3H, m), 7.15(2H, m), 7.21-7.37(8H, m) Preparation example 33 Preparation of 3-(1-benzylpiperidin-4-yl)-4-(3-fluorophenyl)-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.40-1.76(3H, m), 3.46(2H, s), 4.42(1H, m), 5.55(1H, s), 6.73(1H, d, J=8.0Hz), 6.85-6.99(2H, m), 7.60(1H, s) Preparation example 34 Preparation of 3-(1-benzylpiperidin-4-yl)-4-(2-fluorophenyl)-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.40-1.76(3H, m), 3.46(2H, s), 4.38(1H, m), 6.00(1H, s), 6.69(1H, d, J=7.0Hz), 6.88-7.32(12H, m) Preparation example 35 Preparation of 3-(1-benzylpiperidin-4-yl)-4-phenyl-7-chloro-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.76-2.94(2H, m), 3.44(2H, s), 4.30-4.42(1H, m), 5.52(1H, s), 6.68(1H, d, J=2.0Hz), 6.86(1H, dd, J=2.0Hz, 8.1Hz), 7.05-7.08(2H, m) Preparation example 36 Preparation of 3-(1-benzylpiperidin-4-yl)-4-phenyl-6-fluoro-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.76-2.94(2H, m), 3.45(2H, s), 4.30-4.44(1H, m), 5.50(1H, s), 6.62(1H, dd, J=4.6Hz, 8.6Hz), 7.04(1H, br) Preparation example 37 Preparation of 3-[1-(3-methoxymethybenzyl)piperidin-4-yl]-4-(3-methoxy)phenyl-3,4-dihydro-2(1H)-quinazolinone (a) Preparation of 3-(piperidin-4-yl)-4-(3-methoxy)phenyl-3,4-dihydro-2(1H)-quinazolinone To a solution of 2.48g (5.81mmol) of 3-(1-benzylpiperidin-4-yl)-4-(3-methoxy)phenyl-3,4-dihydro-2(1H)-quinazolinone in 50ml of methanol, 1.46g (23.2mmol) of ammonium formate and 125mg of 10% palladium/carbon were added and stirred under reflux-heating for one hour. Further, 1.46g (23.2mmol) of ammonium formate and 125mg of 10% palladium/carbon were added and stirred under reflux-heating for additional one hour. After allowed to stand cool, the reaction mixture was subjected to celite filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved with chloroform, washed with dilute aqueous ammonia and saturated brine, subsequently, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Precipitated crystals from isopropanol were collected to give 1.69g (5.01mmol) of the title compound as colorless crystal. 1 H NMR(CDCl 3 ); δ 3.87(3H, s), 7.14-7.28(4H, m), 8.63(1H, d, J=8.3Hz) 1 H NMR(CDCl 3 ); δ 1.55-1.67(3H, m), 2.54-2.74(2H, m), 2.98(1H, dd, J=1.8Hz, 10.4Hz), 3.12(1H, dd, J=1.5Hz, 13.8Hz), 3.76(3H, s), 4.40(1H, m), 5.52(1H, s), 6.68(1H, d, J=7.9Hz) (b) Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-(3-methoxy)phenyl-3,4-dihydro-2(1H)-quinazolinone In similar way as in Preparation example 11, the title compound was prepared from 3-(piperidin-4-yl)-4-(3-methoxy)phenyl-3,4-dihydro-2(1H)-quinazoline and 3-methoxymethylbenzaldehyde. 1 H NMR(CDCl 3 ); δ 2.79(1H, d, J=11.7Hz), 2.93(1H, d, J=8.4Hz), 3.39(3H, s), 3.45(2H, s), 3.75(3H, s), 4.37(1H, m), 4.44(2H, s), 5.52(1H, s), 6.66(1H, d, J=7.9Hz), 6.71(1H, dd, J=1.6Hz, 8.2Hz) The compounds of Preparation examples 38-41 were prepared in similar way as in Preparation example 37. Preparation example 38 Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-(4-methoxy)phenyl-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.97-2.12(3H, m), 3.45(2H, s), 3.74(3H, s), 4.34(1H, m), 4.44(2H, s), 5.51(1H, s), 6.65(1H, d, J=7.7Hz), 6.76-6.80(3H, m) Preparation example 39 Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-(4-fluoro)phenyl-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.90-2.13(3H, m), 2.76-2.99(2H, m), 3.39(3H, s), 3.46(2H, s), 4.37(1H, m), 4.44(2H, s), 5.55(1H, s), 6.70(1H, d, J=7.2Hz), 7.46(1H, s) Preparation example 40 Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-(3-fluoro)phenyl-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.75-2.99(2H, m), 3.38(3H, s), 3.46(2H, s), 4.43(1H, m), 4.44(2H, s), 5.55(1H, s), 6.75(1H, d, J=7.9Hz), 8.02(1H, s) Preparation example 41 Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-(2-fluoro)phenyl-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.77-2.96(2H, m), 3.39(3H, s), 3.47(2H, s), 4.40(1H, m), 4.44(2H, s), 6.00(1H, s), 6.71(1H, d, J=7.7Hz), 6.98-7.05(2H, m), 7.44-7.51(2H, m) Preparation example 42 Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone (a) Preparation of 3-(piperidin-4-yl)-4-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone To a solution of 1.40g (3.25mmol) of 3-(1-benzylpiperidin-4-yl)-4-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone in methylene chloride, α-chloroethyl chloroformate was added dropwise under ice-cooling and stirred for one hour. After concentration under reduced pressure, the residue was dissolved with 28ml of methanol and stirred at room temperature for 2 hours and under ice-cooling for one hour. The precipitated crystals were collected to give 1.08g (3.16mmol) of the title compound as colorless crystal. 1 H NMR(CDCl 3 ); δ 3.16-3.38(2H, m), 4.19(1H, m), 5.68(1H, s), 6.80-6.88(2H, m), 7.24(1H, d, J=7.3Hz) (b) Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone In similar way as in Preparation example 11, the title compound was prepared from 3-(piperidin-4-yl)-4-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone and 3-methoxymethylbenzaldehyde. 1 H NMR(CDCl 3 ); δ 2.80(1H, d, J=13.2Hz), 2.93(1H, d, J=10.1Hz), 3.39(3H, s), 3.46(2H, s), 4.38(1H, m), 4.44(2H, s), 5.54(1H, s), 6.68(1H, d, J=7.9Hz), 7.01-7.16(3H, m) The compound of Preparation example 43 was prepared in similar way as in Preparation example 42. Preparation example 43 Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 1.95-2.18(3H, m), 2.93(1H, d, J=10.6Hz), 3.39(3H, s), 3.46(2H, s), 4.40(1H, m), 5.54(1H, s), 6.68(1H, d, J=7.9Hz), 6.96(1H, s), 7.11-7.36(10H, m) The compounds of Preparation examples 44 and 45 were prepared in similar way as in Preparation example 42(a) and Preparation example 1. Preparation example 44 Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.75-2.94(2H, m), 3.38(3H, s), 3.45(2H, s), 4.28-4.41(1H, m), 4.43(2H, s), 5.50(1H, s), 6.63(1H, d, J=8.3Hz), 7.07(1H, dd, J=2.2Hz, 8.4Hz), 7.13(1H, d, J=2.2Hz) Preparation example 45 Preparation of 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-phenyl-7-chloro-3,4-dihydro-2(1H)-quinazolinone 1 H NMR(CDCl 3 ); δ 2.76-2.94(2H, m), 3.38(3H, s), 3.45(2H, s), 4.37-4.46(3H, m), 5.52(1H, s), 6.75(1H, d, J=1.8Hz), 6.85(1H, dd, J=1.8Hz, 8.3Hz), 7.06(1H, d, J=8.3Hz) Test example Antagonism effect on muscarinic receptor of the compounds described in the present specification was measured. The tests were performed generally according to the methods by T. Yamamoto, et al (Drug Development Research, 34 , 9-18, 1995), L. Noronha-Blob et al (J. pharmacol. Exp. Ther., 256 , 562-567, 1991) and M. Eltze et al (Eur. J. Pharmacol., 151, 205-211,1988). Namely, urinary bladder and atrium cordis were isolated from Hartley strain male guinea pig (310-750g) and vas deferens was isolated from New Zealand white male rabbit (2.2-2.6kg). Urinary bladder, right atrium and vas deferens were suspended with a Krebs-Henseleit solution in organ bath at 31°C (37°C in case of urinary bladder) and mixed gas (95% of O 2 and 5% of CO 2 ) was insufflated. One side was fixed at a support device and the other side was connected with an isometric transducer. To the specimen, 0.5 to 1.0g of resting tension (1.0g in case of urinary bladder and 0.75g in case of vas deferens) was charged in advance and stabilized. The tension change of the urinary bladder, right atrium and vas deferens was given by a recorder. In the case of vas deferens, the twitch contractions induced by electrical stimulation (condition : 0.05Hz, 20V, 0.5ms) was obtained in Krebs-Henseleit solution containing 1µM of yohimbine hydrochloride. Acetylcholine (urinary bladder), carbachol (atrium cordis) and McN-A343 (vas deferens) were applied into the organ bath until a maximum reaction, accumulatively. After discarding the Krebs-Henseleit solution in the organ bath, a Krebs-Henseleit solution containing a test compound in low concentration was filled again, treated for 30 minutes and then the cholinergic agents were accumulatively applied into the organ bath. In similar way, the test compounds in higher concentration were treated and the above procedures were repeated. Each of the organs was evaluated respectively at two to three concentrations of test compounds. The reaction ratio in the presence of the test compounds was calculated as a percentage of the maximum reaction elicited by the cholinergic agents without test compounds. After plotting a concentration-reaction curve, pA 2 (the negative logarithm of the concentrations of the test compounds for parallel shifting the concentration-reaction curve of the cholinergic agents to double the concentration) was calculated (Shiro MORIMOTO, Yakurigaku-Jisshusho published by Hirokawa-Shoten). The results were shown in Table 1. Test compound 1 : 3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride Test compound 2 : 3-[1-(3-carbamoylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride Test compound 3 : 3-[1-(3-methoxymethylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone Test compound 4 : 3-[1-[(3-cyclohexen-1-yl)methyl]piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone hydrochloride Test compound 5 : 3-(1-benzylpiperidin-4-yl)-4-(2-fluorophenyl)-3,4-dihydro-2(1H)-quinazolinone hydrochloride Test compound 6 : 3-(1-benzylpiperidin-4-yl)-4-(3-methoxyphenyl)-3,4-dihydro-2(1H)-quinazolinone hydrochloride Test compound 7 : 3-(1-benzylpiperidin-4-yl)-4-phenyl-7-chloro-3,4-dihydro-2(1H)-quinazolinone hydrochloride pA 2 value Test compounds M1(seminiferous duct) M2(atrium cordis) M3(urinary bladder) 1 <6 <6 7.90 2 7.37 6.71 8.58 3 7.13 6.85 8.44 4 7.39 6.43 7.93 5 7.1 6.4 8.5 6 7.2 6.5 8.4 7 6.5 6.1 7.9 Industrial Availability The present compounds have antagonism effect on muscarinic receptor and can be used for anticholinergic medicaments. Therefore, they can be used, for example, as mydriatic medicament, anticonvulsant, parkinsonian remedy, antasthmatic, peptic ulcer remedy, secretagogue and motofacient for gastric and duodenal ulcer, intestinum hypersensitivity remedy, pollakiuria remedy, urinary incontinence remedy, antiarrhythmic medicament, esophageal achalasia remedy, chronic obstructive tracheal disease remedy and so on.

Claims: Use of a compound given by general formula (1): [wherein T represents oxygen or sulfur; Y represents phenyl or substituted phenyl; ring W represents benzene; R 1 and R 2 represent, independently, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, nitro, amino, substituted amino, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; R 3 represents hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, aralkyl or substituted aralkyl; Z represents a group given by the formula: {wherein n represents 0, 1 or 2, ring E represents a 4-8 membered saturated heterocyclic ring containing one or more nitrogen atom(s), and A 3 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, saturated heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, substituted aralkyl, heteroarylalkyl, substituted heteroarylalkyl or -CH 2 R 4 (wherein R 4 represents alkenyl or alkynyl) or forms a bicyclo ring together with ring E}], or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of intestinum hypersensitivity, urinary incontinence, pollakiuria, esophageal achalasia or chronic obstructive tracheal disease, wherein the cycloalkyl group is cycloalkyl having 3-8 carbon number, the cycloalkylalkyl group is cycloalkylalkyl having 10 or less of the carbon number, the cycloalkenylalkyl group is cycloalkenylalkyl having 10 or less of the carbon number, the alkenyl group is alkenyl having 2-6 of the carbon number, the alkynyl group is alkynyl having 2-6 of the carbon number, the aralkyl group is aralkyl having 12 or less of the carbon number, the heteroaryl group is a 5-6 membered ring containing 1 or 2 nitrogen atom(s), a 5-6 membered ring containing 1 or 2 nitrogen atom(s) and one oxygen or sulfur atom, or a 5-6 membered ring containing one oxygen or sulfur atom, the heteroaryl group for the heteroarylalkyl is a 5-6 membered ring containing 1-4 nitrogen atom(s), or a 5-6 membered ring containing 1-2 nitrogen atom(s) and one oxygen or sulfur atom, the saturated heterocyclyl is the saturated heterocyclyl consisting of one oxygen or sulfur atom and 3-5 carbon atoms, the 4-8 membered saturated heterocyclic ring containing nitrogen atom for ring E is a ring containing 1 or 2 nitrogen atoms and 0 or 1 oxygen atom, the lower alkyl is straight chain or branched alkyl having 4 or less of the carbon number, the lower alkoxy group is straight chain or branched alkoxy having 4 or less of the carbon number, the lower alkylthio group is straight chain or branched alkylthio group having 4 or less of the carbon number, the lower alkylsulfinyl group is straight chain or branched alkylsulfinyl having 4 or less of the carbon number, and the lower alkylsulfonyl group is straight chain or branched alkylsulfonyl group having 4 or less of the carbon number. Use according to claim 1, wherein Z represents a group given by the formula: (wherein A 4 represents phenyl, substituted phenyl, cycloalkyl or cycloalkenyl). Use according to claim 2, wherein A 4 represents cycloalkyl or cycloalkenyl. Use according to claim 2, wherein A 4 represents phenyl or substituted phenyl. Use according to claim 4, wherein A 4 represents substituted phenyl and said substituent is cyano, alkoxyalkyl, alkanoylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Use according to any one of claims 1-5, wherein the medicament is for the prevention or treatment of urinary incontinence or pollakiuria. A compound given by general formula (1a): [wherein T represents oxygen or sulfur; Y represents phenyl or substituted phenyl; ring W represents benzene; R 1 and R 2 represent, independently, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, nitro, amino, substituted amino, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; R 31 represents alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aralkyl or substituted aralkyl; Z represents a group given by the formula: {wherein n represents 0, 1 or 2, ring E represents a 4-8 membered saturated heterocyclic ring containing one or more nitrogen atom(s), and A 3 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, saturated heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, substituted aralkyl, heteroarylalkyl, substituted heteroarylalkyl or -CH 2 R 4 (wherein R 4 represents alkenyl or alkynyl), or forms a bicyclo ring together with ring E}], or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is cycloalkyl having 3-8 carbon number, the cycloalkylalkyl group is cycloalkylalkyl having 10 or less of the carbon number, the cycloalkenylalkyl group is cycloalkenylalkyl having 10 or less of the carbon number, the alkenyl group is alkenyl having 2-6 of the carbon number, the alkynyl group is alkynyl having 2-6 of the carbon number, the aralkyl group is aralkyl having 12 or less of the carbon number, the heteroaryl group is a 5-6 membered ring containing 1 or 2 nitrogen atom(s), a 5-6 membered ring containing 1 or 2 nitrogen atom(s) and one oxygen or sulfur atom, or a 5-6 membered ring containing one oxygen or sulfur atom, the heteroaryl group for the heteroarylalkyl is a 5-6 membered ring containing 1-4 nitrogen atom(s), or a 5-6 membered ring containing 1-2 nitrogen atom(s) and one oxygen or sulfur atom, the saturated heterocyclyl is the saturated heterocyclyl consisting of one oxygen or sulfur atom and 3-5 carbon atoms, the 4-8 membered saturated heterocyclic ring containing nitrogen atom for ring E is a ring containing 1 or 2 nitrogen atoms and 0 or 1 oxygen atom, the lower alkyl is straight chain or branched alkyl having 4 or less of the carbon number, the lower alkoxy group is straight chain or branched alkoxy having 4 or less of the carbon number, the lower alkylthio group is straight chain or branched alkylthio group having 4 or less of the carbon number, the lower alkylsulfinyl group is straight chain or branched alkylsulfinyl having 4 or less of the carbon number, and the lower alkylsulfonyl group is straight chain or branched alkylsulfonyl group having 4 or less of the carbon number. A pharmaceutical composition comprising a compound or salt according to claim 7 together with a pharmaceutically acceptable carrier or diluent. A compound or salt according to claim 7 or a composition according to claim 8, for use in a method of treatment of the human or animal body by therapy.

Inventors: MATSUI KAZUKI, MORISHITA KOJI, MURAOKA MASAMI, OHASHI NAOHITO, MATSUI, KAZUKI, MORISHITA, KOJI, MURAOKA, MASAMI, OHASHI, NAOHITO
Applicants: SUMITOMO PHARMA, SUMITOMO PHARMACEUTICALS COMPANY, LIMITED
Application year: 1999
Main classification: C07D401
IPC codes: C07D401, A61P13