QUINAZOLINE DERIVATIVES

Abstract: Disclosed are quinazoline derivatives represented by formula (I): wherein R 1 represents hydrogen, lower alkyl, alkenyl, or aralkyl; R 2 , R 3 , R 4 , and R 5 represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, or the like; R 6 , R 7 , R 8 , and R 9 represent hydrogen, lower alkyl, lower alkoxy, aralkyloxy, or the like, or any adjoining two of them are combined to form methylenedioxy or the like; R 10 represents hydrogen, lower alkyl, or the like; R 11 and R 12 represent hydrogen, lower alkyl, cycloalkyl, phenyl, or aralkyl, or R 11 and R 12 are combined together with N to form a heterocyclic group; and n represents 0, 1 or 2, and pharmaceutically acceptable salts thereof. These compounds have adenosine uptake inhibitory activity and are useful for the protection of myocardium and for the prevention or treatment of inflammation such as leg and foot edema.

Description: Technical Field The present invention relates to quinazoline derivatives and pharmaceutically acceptable salts thereof which have adenosine uptake inhibitory activity and are useful for the protection of myocardium and for the prevention or treatment of inflammation such as leg and foot edema. Background Art With respect to 1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivatives having a 1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl group at the 3-position, those having a hydrogen atom, a chlorine atom or a nitro group at the 6-position are described in Chem. Pharm. Bull., 38 , 1591-1595 (1990). Further, it is known that a compound having adenosine uptake inhibitory activity exhibits myocardium protecting activity [Circul., 80 , 1400-1411 (1989); Am. J. Physiol., H1570-1577 (1991); J. Cardiovasc. Pharmacol., 20 , 173-178 (1992)]. Disclosure of the Invention The present invention relates to quinazoline derivatives represented by formula (I): wherein R 1 represents i) hydrogen, ii) C 1 -C 8 alkyl, iii) C 1 -C 8 alkyl substituted with 1 to 3 substituents, the same or different, selected from halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino and phthalimido, iv) C 2 -C 6 alkenyl, v) C 7 -C 13 aralkyl, or vi) C 7 -C 13 aralkyl substituted with 1 to 3 substituents on the benzene ring thereof, the same or different, selected from halogen, C 1 -C 8 alkyl, nitro, cyano, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, methylenedioxy, and trifluoromethyl; R 2 , R 3 , R 4 , and R 5 independently represent i) hydrogen, ii) halogen, iii) amino, iv) mono- or di(C 1 -C 8 alkyl)amino, v) C 2 -C 9 alkanoylamino, vi) nitro, vii) cyano, viii) C 1 -C 8 alkyl, ix) C 1 -C 8 alkyl substituted with 1 to 3 substituents, the same or different, selected from halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino and phthalimido, x) hydroxy, xi) C 1 -C 8 alkoxy, xii) C 1 -C 8 alkylthio, xiii) carboxy, xiv) C 1 -C 8 alkoxycarbonyl, xv) C 2 -C 9 alkanoyl, xvi) C 7 -C 13 aralkyloxy, or xvii) C 2 -C 9 alkanoyloxy; R 6 , R 7 , R 8 , and R 9 independently represent i) hydrogen, ii) C 1 -C 8 alkyl, iii) hydroxy, iv) C 1 -C 8 alkoxy, v) C 1 -C 8 alkoxy substituted with 1 to 3 substituents, the same or different, selected from halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino and phthalimido, or vi) C 7 -C 13 aralkyloxy, or any adjoining two of them are combined to form methylenedioxy or ethylenedioxy; R 10 represents i) hydrogen, ii) C 1 -C 8 alkyl, or iii) halogen; R 11 and R 12 independently represent i) hydrogen, ii) C 1 -C 8 alkyl, iii) C 1 -C 8 alkyl substituted with 1 to 3 substituents, the same or different, selected from halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino and phthalimido, iv) C 3 -C 8 cycloalkyl, v) phenyl, vi) phenyl substituted with 1 to 3 substituents on the benzene ring thereof, the same or different, selected from halogen, C 1 -C 8 alkyl nitro, cyano, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, methylenedioxy, and trifluoromethyl, vii) C 7 -C 13 aralkyl, viii) C 7 -C 13 aralkyl substituted with 1 to 3 substituents on the benzene ring thereof, the same or different, selected from halogen, C 1 -C 8 alkyl, nitro, cyano, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, methylenedioxy, and trifluoromethyl, or R 11 and R 12 are combined together with N to form ix) a heterocyclic group selected from pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, and homopiperazinyl or x) an above heterocyclic group substituted with 1 to 3 substituents, the same or different, selected from halogen, C 1 -C 8 alkyl, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, trifluoromethyl, phenyl, and C 7 -C 13 aralkyl; and n represents 0, 1 or 2, and a pharmaceutically acceptable salt thereof. The compounds represented by formula (I) are hereinafter referred to as Compounds (I). The same applies to the compounds of other formula numbers. In the definitions of the groups in formula (I), the C 1 -C 8 alkyl and the C 1 -C 8 alkyl moiety of the mono- or di(C 1 -C 8 alkyl)amino, the C 2 -C 9 alkanoylamino, the C 1 -C 8 alkoxy, the C 1 -C 8 alkylthio, the C 1 -C 8 alkoxycarbonyl, the C 2 -C 9 alkanoyl and the C 2 -C 9 alkanoyloxy mean a straight-chain or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, and octyl. The C 2 -C 6 alkenyl means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, and 5-hexenyl. The C 3 -C 8 cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The C 7 -C 13 aralkyl and the aralkyl moiety of the C 7 -C 13 aralkyloxy mean an aralkyl group having 7 to 13 carbon atoms, such as benzyl, phenethyl, benzhydryl, and naphthylmethyl. The heterocyclic group includes pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, and homopiperazinyl. The halogen includes fluorine, chlorine, bromine, and iodine atoms. The substituted C 1 -C 8 alkyl and the substituted C 1 -C 8 alkoxy each has 1 to 3 independently selected substituents. Examples of the substituents are halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino, and phthalimide. The substituted phenyl and the substituted C 7 -C 13 aralkyl each has 1 to 3 independently selected substituents on the benzene ring thereof. Examples of the substituents are halogen, C 1 -C 8 alkyl, nitro, cyano, amino, mono- or di (C 1 -C 8 -alkyl) amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, methylenedioxy, and trifluoromethyl. The substituted heterocyclic group has 1 to 3 independently selected substituents. Examples of the substituents are halogen, C 1 -C 8 alkyl, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, trifluoromethyl, phenyl, and C 7 -C 13 aralkyl. In the definitions of the substituents, the halogen, the C 1 -C 8 alkoxy, the C 1 -C 8 alkoxycarbonyl, the C 2 -C 9 alkanoyl, the C 3 -C 8 cycloalkyl, the mono- or di(C 1 -C 8 alkyl)amino, the C 1 -C 8 alkyl, and the C 7 -C 13 aralkyl have the same meanings as defined above. The pharmaceutically acceptable salts of Compounds (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts. Examples of the pharmaceutically acceptable acid addition salts of Compounds (I) are inorganic acid addition salts such as hydrochloride, sulfate, and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, tartrate, citrate, and methanesulfonate. Examples of the pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of the pharmaceutically acceptable ammonium salts are ammonium salt and tetramethylammonium salt. Examples of the pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine. Examples of the pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine. The processes for preparing Compounds (I) and the intermediates are described below. Process 1 : Process for preparing Compound (I) Compound (I) can be prepared according to the following reaction step: (In the formulae, X a represents chlorine, bromine, iodine, methanesulfonyloxy, benzenesulfonyloxy, or toluenesulfonyloxy; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12, and n have the same meanings as defined above.) (Step 1) Compound (I) can be obtained by reaction of Compound (II) with Compound (III) in an appropriate solvent, such as a lower alcohol, e.g., methanol, ethanol, and isopropanol, a cyclic ether, e.g., tetrahydrofuran (THF) and 1,4-dioxane, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidinone, dimethyl sulfoxide (DMSO), and a mixture thereof, at a temperature between room temperature and the boiling point of the employed solvent for 10 minutes to 48 hours. If necessary, the reaction is carried out in the presence of a base, such as a tertiary amine, e.g., triethylamine and pyridine, and an alkali metal carbonate, e.g., sodium carbonate and potassium carbonate. Compound (III) is used in an amount of 1 equivalent based on Compound (II) to the amount of solvent. Further, potassium iodide, sodium iodide, or the like may be added during the reaction as may be appropriate. By the use of a primary amine as Compound (III) and DMF as the solvent, Compound (I) wherein R 11 and R 12 are both methyl can be obtained. Process 2 : Process for preparing Compound (II-a), i.e., Compound (II) wherein R 1 is hydrogen Compound (II-a) can be prepared according to the following reaction steps: (In the formulae, X a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and n have the same meanings as defined above.) The starting Compound (IV) can be obtained according to the method described in Chem. Pharm. Bull., 34 , 1907-1916 (1986). (Step 2) The ethoxycarbonyl group of Compound (IV) is hydrolyzed in the presence of an acid, such as sulfuric acid, hydrochloric acid, and hydrobromic acid, in an appropriate solvent, such as water, a lower alcohol, e.g., methanol, ethanol, and isopropanol, a cyclic ether, e.g., THF and 1,4-dioxane, and a mixture thereof, at a temperature between room temperature and the boiling point of the employed solvent for 10 minutes to 48 hours. Then, Compound (II-a) can be obtained by reaction of the hydrolysis product with Compound (V) [J. Med. Chem., 11 , 130-139 (1968), etc.] in the presence of a base, such as a tertiary amine, e.g., triethylamine and pyridine, and an alkali metal carbonate, e.g., sodium carbonate and potassium carbonate, in an appropriate solvent, such as a lower alcohol, e.g., methanol, ethanol and isopropanol, a cyclic ether, e.g., THF and 1,4-dioxane, DMF, DMSO, and a mixture thereof, at a temperature between room temperature and the boiling point of the employed solvent for 10 minutes to 48 hours according to the method described in Chem. Pharm. Bull., 38 , 1591-1595 (1990). Process 3 : Process for preparing Compound (II-b), i.e., Compound (II) wherein R 1 is substituted or unsubstituted C 1 -C 8 alkyl, C 2 -C 6 alkenyl, or substituted or unsubstituted C 7 -C 13 aralkyl Compound (II-b) can be prepared according to the following reaction step. (In the formulae, R 1a represents substituted or unsubstituted C 1 -C 8 alkyl, C 2 -C 6 alkenyl, or substituted or unsubstituted C 7 -C 13 aralkyl; X b represents chlorine, bromine, iodine, methanesulfonyloxy, benzenesulfonyloxy, or toluenesulfonyloxy; and X a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and n have the same meanings as defined above.) (Step 3) Compound (II-b) can be obtained by reaction of Compound (II-a) with 1 to 2 equivalents of Compound (VI) in the presence of 1 to 2 equivalents of a base, such as sodium hydride, potassium carbonate, and cesium carbonate, in an inert solvent, such as THF, DMF, acetone, and methyl ethyl ketone, at a temperature of 0°C to the boiling point of the employed solvent for 10 minutes to 24 hours. Compound (II-b) can also be prepared according to the following reaction steps: (In the formulae, X a , X b , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and n have the same meanings as defined above.) (Step 4) Compound (II-b) can be obtained by preparing Compound (VII) from Compound (IV) and Compound (VI) according to the same method as in Step 3 and then treating Compound (VII) in the same manner as in Step 2. Process 4 : Process for preparing Compound (I-b), i.e., Compound (I) wherein R 1 is substituted or unsubstituted C 1 -C 8 alkyl, C 2 -C 6 alkenyl, or substituted or unsubstituted C 7 -C 13 aralkyl Compound (I-b) can also be prepared according to the following reaction step. (In the formulae, X b , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and n have the same meanings as defined above.) (Step 5) Compound (I-b) can be prepared from Compound (I-a), i.e., Compound (I) wherein R 1 is hydrogen, according to the same method as in Step 3. Process 5 : Compound (I-a) can also be prepared according to the following reaction steps. (In the formulae, X a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 have the same meanings as defined above.) (Step 6) Compound (VIII) is subjected to reaction with Compound (IX) which is obtained by the method described in Chem. Pharm. Bull., 38 , 3014-3019 (1990) and the literature cited therein in the presence of 1 to 10 equivalents of a base, such as triethylamine, pyridine, potassium carbonate, and cesium carbonate, in a solvent such as a halogenated hydrocarbon, e.g., chloroform and dichloromethane, an aromatic hydrocarbon, e.g., benzene and toluene, and an ether, e.g., THF, at a temperature of 0°C to the boiling point of the employed solvent for 10 minutes to 24 hours. The reaction product is subjected to reaction with Compound (III) in the same manner as in Step 1, followed by reduction of the nitro group by catalytic reduction or reduction using a metal to give Compound (X). The catalytic reduction is usually carried out in the presence of a catalyst, such as Raney nickel, palladium on carbon, and platinum oxide, in an appropriate solvent, such as methanol, ethanol, ethyl acetate, dioxane, THF, and acetic acid, at room temperature under an atmospheric pressure for 10 minutes to 48 hours. The reduction using a metal can be carried out in a zinc-acetic acid system, an iron-acetic acid system, an iron-ferric chloride-ethanol-water system, an iron-hydrochloric acid system, a tin-hydrochloric acid system, or the like, at a temperature between room temperature and the boiling point of the employed solvent for 10 minutes to 48 hours. Then, Compound (I-a) can be obtained by subjecting Compound (X) to ring closure reaction according to the method described in Chem. Pharm. Bull., 34 , 1907-1916 (1986). Compound (I) wherein at least one of R 2 , R 3 , R 4 and R 5 is amino, mono- or di(C 1 -C 8 alkyl)amino, or C 2 -C 9 alkanoylamino can also be prepared by reducing Compound (I) wherein the corresponding member(s) of R 2 , R 3 , R 4 and R 5 is nitro, and if necessary, alkylating or acylating the product. The reduction can be carried out in a conventional manner, for example, by catalytic reduction or reduction using a metal. The catalytic reduction is usually carried out in the presence of a catalyst, such as Raney nickel, palladium on carbon, and platinum oxide, in an appropriate solvent, such as methanol, ethanol, ethyl acetate, dioxane, THF, and acetic acid, at room temperature under an atmospheric pressure for 10 minutes to 48 hours. The reduction using a metal can be carried out in a zinc-acetic acid system, an iron-acetic acid system, an iron-ferric chloride-ethanol-water system, an iron-hydrochloric acid system, a tin-hydrochloric acid system, or the like, at a temperature between room temperature and the boiling point of the employed solvent for 10 minutes to 48 hours. The alkylation or acylation of the reduction product is carried out by using a common alkylating agent (such as an alkyl halide, e.g., methyl iodide) or acylating agent (such as an acid anhydride, e.g., acetic anhydride, and an acid halide, e.g., acetyl chloride), if necessary in the presence of a base, such as pyridine, triethylamine, an alkali metal hydroxide, and an alkali metal carbonate, and/or a solvent, such as chloroform, dichloromethane, THF, and 1,4-dioxane, at a temperature of 0°C to the boiling point of the employed solvent for 10 minutes to 48 hours. Compound (I) wherein at least one of R 2 , R 3 , R 4 and R 5 is hydroxy-substituted alkyl can also be prepared by reducing or alkylating Compound (I) wherein the corresponding member(s) of R 2 , R 3 , R 4 and R 5 is alkanoyl-substituted alkyl. The reduction can be carried out by using a reducing agent, such as lithium aluminum hydride and sodium borohydride, in an appropriate solvent, such as methanol, ethanol, ethyl acetate, dioxane and THF, usually at a temperature of -78°C to room temperature for 10 minutes to 48 hours. The alkylation is carried out by using a common organometallic reagent, such as a Grignard reagent, e.g., methylmagnesium bromide and ethylmagnesium chloride, and an organolithium reagent, e.g., methyl lithium and butyl lithium, in an appropriate solvent, such as dioxane, ether, and THF, usually at a temperature of -78°C to room temperature for 10 minutes to 48 hours. Compound (I) wherein at least one of R 2 , R 3 , R 4 and R5 is carboxyl can also be prepared by subjecting Compound (I) wherein the corresponding member(s) of R 2 , R 3 , R 4 and R 5 is acetyl to haloform reaction. The haloform reaction can be carried out by using a solution of sodium hypohalogenite prepared from chlorine or bromine and an aqueous solution of sodium hydroxide, according to the method described in J. Am. Chem. Soc., 72 , 1642 (1950) or the like. Compound (I) wherein at least one of R 6 , R 7 , R 8 and R 9 is hydroxyl can also be prepared by subjecting Compound (I) wherein the corresponding member(s) of R 6 , R 7 , R 8 and R 9 is benzyloxy to the above-mentioned catalytic reduction. Compound (I) wherein at least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is hydroxyl can also be prepared by dealkylating Compound (I) wherein the corresponding member(s) of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is C 1 -C 8 alkoxy. The dealkylation can be carried out in the presence of an acid, such as hydrobromic acid and hydroiodic acid, with or without a solvent, such as water, acetic acid, and a lower alcohol, e.g., methanol and ethanol; or in the presence of at least an equivalent amount of an alkali metal salt (e.g., a sodium salt and a potassium salt) of a thiol compound, e.g., ethanethiol and thiophenol, in a solvent, such as DMF and DMSO; or in the presence of a Lewis acid, such as boron trichloride, boron tribromide, and aluminum trichloride, in a solvent, such as dichloromethane. The reaction is carried out at a temperature between room temperature and the boiling point of the employed solvent and is completed in 30 minutes to 48 hours. Compound (I) wherein at least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is lower alkoxy can also be prepared from Compound (I) wherein the corresponding member(s) of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is hydroxyl according to the same method as in Step 3. Compound (I) wherein at least one of R 2 , R 3 , R 4 and R 5 is carboxyl can also be prepared by hydrolyzing Compound (I) wherein the corresponding member(s) of R 2 , R 3 , R 4 and R 5 is lower alkoxycarbonyl. The hydrolysis can be carried out in the presence of an acid, such as sulfuric acid, hydrochloric acid, and hydrobromic acid, or a base, such as sodium hydroxide and potassium hydroxide, in an appropriate solvent, such as water, a lower alcohol, e.g., methanol, ethanol and isopropanol, a cyclic ether, e.g., THF and 1,4-dioxane, and a mixture thereof. The reaction is carried out between room temperature and the boiling point of the employed solvent and is completed in 10 minutes to 48 hours. Compound (I) wherein R 10 is hydrogen can also be prepared by subjecting Compound (I) wherein R 10 is halogen to the above-mentioned catalytic reduction. The intermediates and desired compounds in the above-described processes can be isolated and purified by purification methods conventionally used in organic synthetic chemistry, for example, neutralization, filtration, extraction, drying, concentration, recrystallization, and various kinds of chromatography. The intermediates may be subjected to the subsequent reaction without purification. In the case where a salt of Compound (I) is desired and it is produced in the form of the desired salt, it can be subjected to purification as such. In the case where Compound (I) is produced in the free state and its salt is desired, Compound (I) is dissolved or suspended in a suitable organic solvent, followed by addition of an acid or a base to form a salt. Compounds (I) and pharmaceutically acceptable salts thereof may be in the form of adducts with water or various solvents, which are also within the scope of the present invention. Examples of Compounds (I) obtained by the above-described processes are shown in Tables 1, 2 and 3. Test Example 2 Inhibitory Effect on [ 3 H]-Nitrobenzylthioinosine (NBI) Binding (an indication of adenosine uptake inhibitory activity) The cerebral cortex of a male guinea pig of Hartley strain was homogenized with an ice-cooled 50 mM tris-HCl buffer (pH 7.4) in an amount of 25 times (w/v) that of the tissue. The homogenate was centrifuged (30,000xg, 4°C, 20 mins.), and the supernatant was discarded. To the precipitate was added the same amount of the buffer, followed by homogenization and then centrifugation in the same manner as above. The obtained precipitate was suspended in 20 times as much buffer as the precipitate to prepare a suspension for testing. To a DMSO solution of a test compound were added 1.5 nM of [ 3 H]-NBI and 5 mg (wet basis) of the tissue homogenate, and the mixture was allowed to stand at 25°C for 30 minutes. To the mixture was added 4 ml of an ice-cooled buffer, followed by rapid filtration with suction through a glass filter (GF/C, produced by Whatman Ltd.) or a Ready filter (produced by Beckman Co.) to stop the reaction. The filter was transferred to a scintillation vial, and after drying, Scintisol EX-H was added thereto. The radioactivity was measured with a liquid scintillation counter. The binding inhibitory activity was expressed in terms of an inhibition constant (K i value) as calculated according to Cheng-Prusoff's formula. The results obtained are shown in Table 5 below. The pharmacological activities of typical Compounds (I) are shown below by Test Examples. Test Example 1 Inhibitory Effect on [ 3 H]-Adenosine Uptake A blood sample was obtained from a healthy male adult under 40 years of age by brachial venipuncture using a syringe containing sodium citrate and subjected to centrifugation to obtain washed erythrocytes. To 100 µl of an erythrocyte suspension (2.5 x 10 9 /ml) was added 10 µl of a 21% DMSO solution of a test compound. After allowing the suspension to stand at room temperature for 1 hour, 100 µl of a [ 3 H]-adenosine solution was added thereto. Ten seconds later, 200 µl of a dilazep solution (1 mg/ml) was added to stop the reaction. Then, dibutyl phthalate was added dropwise to the reaction mixture, followed by centrifugation. The supernatant was removed and the erythrocyte fraction was separated. The erythrocytes were dissolved in Triton X-100, and the uptake amount of 3 H was measured with a liquid scintillation counter. The concentration of the test compound which inhibits the [ 3 H]-adenosine uptake by 50% (IC 50 ) was calculated. The results obtained are shown in Table 4. Compound No. [ 3 H]-Adenosine Uptake Inhibition IC 50 (nM) 1 35 2 64 4 72 6 29 7 62 8 50 10 97 Compound No. [ 3 H]-NBI Binding K i Value (nM) 1 2.0 3 7.6 5 2.6 6 1.5 7 3.8 8 1.4 10 2.0 Compounds (I) and pharmaceutically acceptable salts thereof can be formulated into generally employed dose forms, such as tablets, capsules, syrups, injections, drips, and suppositories, and administered orally or non-orally through intramuscular injection, intravenous injection, intraarterial injection, drip infusion, or rectal administration in the form of suppositories. For preparing these dose forms for oral or non-oral administration, generally known methods are applied. For example, the preparations may be formulated to contain various excipients, lubricants, binders, disintegrating agents, suspending agents, isotonizing agents, emulsifiers, and the like. Examples of the carriers which can be used are water, injectable distilled water, physiological saline, glucose, fructose, sucrose, mannitol, lactose, starch, cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogenphosphate, magnesium stearate, urea, silicone resins, sorbitan fatty acid esters, and glycerin fatty acid esters. The dose will vary depending upon the mode of administration, the age, body weight, and symptoms of a patient, etc. However, it is generally appropriate to administer Compound (I) or a pharmaceutically acceptable salt thereof in a dose of 1 to 900 mg/60 kg/day either orally or non-orally. Certain embodiments of the present invention are illustrated in the following Examples and Reference Examples. Best Mode for Carrying Out the Invention Example 1 3-[1-(6,7-Dimethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-[,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 1) In 15 ml of dimethylformamide was dissolved 200 mg (0.40 mmol) of 3-[1-(2-chloro-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound a) obtained in Reference Example 1, and 0.18 ml (2.0 mmol) of morpholine and 0.17 ml (1.2 mmol) of triethylamine were added to the solution. The mixture was heated under reflux at 130°C for 5 hours. After the solvent was evaporated, water was added to the residue, followed by extraction with chloroform. The organic layer was washed and dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (solvent: chloroform/methanol = 50/1) and recrystallization from ethyl acetate and ether to give 75.6 mg (yield: 35%) of Compound 1 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=2.0Hz), 7.48 (dd, 1H, J=8.6, 2.0Hz), 7.09 (d, 1H, J=8.6Hz), 7.08 (s, 1H), 6.96 (s, 1H), 5.30-5.15 (m, 1H), 4.27-4.24 (br.-d, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.83-3.81 (m, 8H), 3.58 (s, 3H), 3.15-3.00 (m, 4H), 2.42 (s, 3H), 1.81-1.78 (br.-d, 2H). IR (KBr tab.)(cm -1 ): 1702, 1653, 1482, 1232, 1207. Melting Point (ethyl acetate-ether): 256-257°C Example 2 3-{1-[6,7-Dimethoxy-2-(4-methyl-1-piperazinyl)-4-quinazolinyl]-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 2) The same procedure as in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound a was used and 0.4 ml (3.25 mmol) of N-methylpiperazine was used in place of morpholine, to give 97.3 mg (yield: 27%) of Compound 2 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=2.0Hz), 7.48 (dd, 1H, J=8.6, 2.0Hz), 7.08 (d, 1H, J=8.6Hz), 7.07 (s, 1H), 6.94 (s, 1H), 5.30-5.15 (m, 1H), 4.26-4.23 (br.-d, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.93-3.90 (m, 4H), 3.58 (s, 3H), 3.10-3.02 (m, 4H), 2.52-2.49 (m, 4H), 2.42 (s, 3H), 2.36 (s, 3H), 1.82-1.79 (br.-d, 2H). IR (KBr tab.)(cm -1 ): 1704, 1656, 1509. Melting Point: (ethyl acetate-ether-hexane): 168-171°C Example 3 3-{1-[2- (4-Ethoxycarbonylpiperidino)-6,7-dimethoxy-4-quinazolinyl]-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 3) The same procedure as in Example 1 was repeated, except that 600 mg (1.25 mmol) of Compound a was used, N-methylpyrrolidinone was used as the solvent in place of dimethylformamide, and 1.9 ml (12.5 mmol) of ethyl isonipecotate was used in place of morpholine, to give 760.0 mg (yield: 99%) of Compound 3 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=2.0Hz), 7.48 (dd, 1H, J=8.3, 2.0Hz), 7.08 (d, 1H, J=8.3Hz), 7,06 (s, 1H), 6.93 (s, 1H), 5.30-5.15 (m, 1H), 4.80-4.74 (br.-d, 2H), 4.25-4.21 (br.-d, 2H), 4.15 (q, 2H, J=7.3Hz), 3.98 (s, 3H), 3.93 (s, 3H), 3.58 (s, 3H), 3.09-2.85 (m, 6H), 2.60-2.45 (m, 1H), 2.42 (s, 3H), 2.02-1.98 (br.-d, 2H), 1.82-1.63 (m, 4H), 1.27 (t, 3H, J=7.3Hz). IR (KBr tab.)(cm -1 ): 1699, 1656, 1459. Melting Point: (methanol-water): 103-105°C Example 4 3-{1-[2-(4-Carboxypiperidino)-6,7-dimethoxy-4-quinazolinyl]-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 4) In 10 ml of methanol was dissolved 400 mg (0.65 mmol) of Compound 3 obtained in Example 3, and 5 ml of 2 N aqueous solution of sodium hydroxide was added to the solution, followed by heating under reflux for one hour. After cooling, the solvent was evaporated, and water and concentrated hydrochloric acid were added to the residue. The precipitated crystals were collected by filtration, and then washed with water and methanol to give 308.0 mg (yield: 81%) of Compound 4 as white crystals. 1 H-NMR (CDCl 3 ) δ: 7.98 (d, 1H, J=1.0Hz), 7.45 (dd, 1H, J=7.0, 1.0Hz), 7.06 (s, 1H), 7.04 (d, 1H, J=7.0Hz), 7.01 (s, 1H), 5.30-5.15 (m, 1H), 4.71-4.67 (br.-d, 2H), 4.29-4.25 (br.-d, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.55 (s, 3H), 3.10-3.01 (m, 6H), 2.60-2.40 (m, 1H), 2.40 (s, 3H), 2.05-1.99 (br.-d, 2H), 1,85-1,65 (m, 4H). IR (KBr tab.)(cm -1 ): 3400 (br), 1700, 1654, 1639, 1521. Melting Point (methanol-water): 189-190°C Example 5 3-[1-(2-Dimethylamino-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 5) The same procedure as in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound a was used and 0.3 ml (3.25 mmol) of propylamine was used in place of morpholine, to give 143.0 mg (yield: 42.4%) of Compound 5 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=2.0Hz), 7.48 (dd, 1H, J=8.3, 2.0Hz), 7.08 (d, 1H, J=8.3Hz), 7.07 (s, 1H), 6.95 (s, 1H), 5.30-5.15 (m, 1H), 4.26-4.23 (br.-d, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.57 (s, 3H), 3.24 (s, 6H), 3.10-3.01 (m, 4H), 2.42 (s, 3H), 1.81-1.78 (br.-d, 2H). IR (KBr tab.)(cm -1 ): 1695, 1656, 1553, 1512, 1503. Melting Point (ethyl acetate-ether): 220-221°C Example 6 3-{1-[2-Bis(2-hydroxyethyl)amino-6,7-dimethoxy-4-quinazolinyl]-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 6) The same procedure as in Example 1 was repeated, except that 500 mg (1.04 mmol) of Compound a was used, N-methylpyrrolidinone was used as the solvent in place of dimethylformamide, and 1.0 ml (10 mmol) of diethanolamine was used in place of morpholine, to give 163.5 mg (yield: 28%) of Compound 6 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=2.0Hz), 7.48 (dd, 1H, J=8.3, 2.0Hz), 7.09 (d, 1H, J=8.3Hz), 7.04 (s, 1H), 6.84 (s, 1H), 5.30-5.15 (m, 1H), 4.25-4.20 (br.-d, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.92-3.84 (m, 8H), 3.56 (s, 3H),3.19-3.00 (m, 4H), 2.42 (s, 3H), 1.84-1.80 (br.-d, 2H). IR (KBr tab.)(cm -1 ): 3400 (br), 1698, 1656, 1498. Melting Point (ethyl acetate-ether) : 157-161°C Example 7 3-{1-{2-[N-(2-Dimethylaminoethyl)-N-methylamino]-6,7-dimethoxy-4-quinazolinyl}-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 7) The same procedure as in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound a was used and 0.4 ml (3.2 mmol) of N,N,N'-trimethylethylenediamine was used in place of morpholine, to give 86.3 mg (yield: 24%) of Compound 7 as an amorphous solid. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=2.0Hz), 7.48 (dd, 1H, J=8.2, 2.0Hz), 7.08 (d, 1H, J=8.2Hz), 7.06 (s, 1H), 6.97 (s, 1H), 5.30-5.15 (m, 1H), 4.26-4.22 (br.-d, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.86 (t, 2H, J=7.3Hz), 3.58 (s, 3H), 3.25 (s, 3H), 3.11-3.00 (m, 4H), 2.63 (t, 2H, J=7.3Hz), 2.42 (s, 3H), 2.37 (s, 6H), 1.80-1.77 (br.-d, 2H). IR (KBr tab.)(cm -1 ): 1700, 1656, 1509. Example 8 3-[1-(6,7-Dimethoxy-2-propylamino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 8) The same procedure as in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound a was used, N-methylpyrrolidinone was used as the solvent in place of dimethylformamide, and 0.3 ml (3.2 mmol) of propylamine was used in place of morpholine, to give 124.5 mg (yield: 37%) of Compound 8 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=2.0Hz), 7.49 (dd, 1H, J=8.6, 2.0Hz), 7.09 (d, 1H, J=8.6Hz), 7.08 (s, 1H), 6.94 (s, 1H), 5.32-5.23 (m, 1H), 4.38-4.34 (br.-d, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 3.58 (s, 3H), 3.52-3.38 (m, 2H), 3.21-3.00 (m, 4H), 2.42 (s, 3H), 1.86-1.82 (br.-d, 2H), 1.67 (sext, 2H, J=7.4Hz), 1.01 (t, 3H, J=7.4Hz). IR (KBr tab.)(cm -1 ): 1703, 1654, 1508. Melting Point (ethyl acetate-ether): 156-160°C Example 9 3-[1-(2-Benzylamino-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 9) The same procedure as in Example 1 was repeated, except that 500 mg (1.04 mmol) of Compound a was used, N-methylpyrrolidinone was used as the solvent in place of dimethylformamide, and 0.5 ml (5.2 mmol) of benzylamine was used in place of morpholine, to give 31.8 mg (yield: 5.7%) of Compound 9 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.51-7.22 (m, 6H), 7.09 (d, 1H, J=8.5Hz), 7.08 (s, 1H), 6.96 (s, 1H), 5.30-5.15 (m, 1H), 4.71 (d, 2H, J=6.6Hz), 4.34-4.29 (br.-d, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.58 (s, 3H), 3.13-2.97 (m,4H), 2.42 (s, 3H), 1.82-1.78 (br.-d, 2H). IR (KBr tab.)(cm -1 ): 1703, 1659, 1560, 1511. Melting Point (ethyl acetate-ether): 136-139°C Example 10 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 10) Step 1: The same procedure as in Example 1 was repeated, except that 3.60 g (7.09 mmol) of 3-[1-(2-chloro-6,7diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound b) obtained in Reference Example 2 was used in place of Compound a, and N-methylpyrrolidinone was used as the solvent in place of dimethylformamide, to give 3.47 g (yield: 85%) of the free base of Compound 10 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.49 (dd, 1H, J=8.5, 1.5Hz), 7.11 (s, 1H), 7.08 (d, 1H, J=8.5Hz), 6.97 (s, 1H), 5.30-5.20 (m, 1H), 4.28-4.24 (br.-d, 2H), 4.20 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 3.84-3.81 (m, 8H), 3.58 (s, 3H), 3.20-2.95 (m, 4H), 2.42 (s, 3H), 1.85-1.81 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1699, 1656, 1563, 1459, 1237, 1180, 1109. Melting Point (ether): 228-229°C Step 2: In 20 ml of ethyl acetate was dissolved 1.0 g (1.74 mmol) of the free base obtained in Step 1, and an excess of a saturated solution of hydrogen chloride in ethyl acetate was added dropwise to the solution at room temperature, followed by stirring for 10 minutes. The precipitated crystals were collected by filtration, and washed with ethyl acetate to give 0.87 g (yield: 82%) of Compound 10 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.49 (br-s, 1H), 8.00 (s, 1H), 7.50 (d, 1H, J=8.5Hz), 7.11 (d, 1H, J=8.5Hz), 7.07 (s, 1H), 5.45-5.30 (m, 1H), 4.66-4.61 (br.-d, 2H), 4.34-4.32 (br.-d, 2H), 4.13-4.08 (m, 6H), 3.84 (br.-s, 4H), 3.57 (s, 3H), 3.40-3.31 (br.-t, 2H), 3.01-2.89 (m, 2H), 2.43 (s, 3H), 1.92-1.88 (br.-d, 2H), 1.50 (t, 3H, J=7.0Hz), 1.48 (t, 3H, J=7.0Hz). Melting Point (ethyl acetate): 193-195°C Example 11 3-{1-[2-(cis-2,6-Dimethylmorpholino)-6,7-diethoxy-4-quinazolinyl]-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 11) The same procedure as in Example 10 was repeated, except that 2,6-dimethylmorpholine (trans-cis mixture) was used in place of morpholine, to give Compound 11 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.48 (dd, 1H, J=8.5, 1.5Hz), 7.10 (s, 1H), 7.08 (d, 1H, J=8.5Hz), 6.92 (s, 1H), 5.30-5.15 (m, 1H), 4.66-4.61 (br.-d, 2H), 4.21-4.07 (m, 6H), 3.70-3.69 (m, 2H), 3.58 (s, 3H), 3.10-2.99 (m, 4H), 2.65-2.55 (br.-t, 2H), 2.42 (s, 3H), 1.82-1.76 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz), 1.28 (d, 6H, J=6.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1702, 1658, 1591, 1460, 1262. Melting Point (ether): 241-242°C Example 12 3-[1-(6,7-Diethoxy-2-thiomorpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 12) The same procedure as in Example 10 was repeated, except that thiomorpholine was used in place of morpholine, to give Compound 12 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.49 (dd, 1H, J=8.5, 1.5Hz), 7.09 (s, 1H), 7.09 (d, 1H, J=8.5Hz), 6.90 (s, 1H), 5.25-5.10 (m, 1H), 4.25-4.08 (m, 10H), 3.58 (s, 3H), 3.10-2.99 (m, 4H), 2.80-2.60 (m, 4H), 2.42 (s, 3H), 1.81-1.77 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1698, 1657, 1587, 1458, 1270. Melting Point (ether): 179-182°C Example 13 3-{1-(6,7-Diethoxy-2-(1-piperazinyl)-4-quinazolinyl]-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline dihydrochloride (Compound 13) The same procedure as in Example 10 was repeated, except that piperazine was used in place of morpholine, to give Compound 13 as a colorless amorphous solid. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=1.5Hz), 7.48 (dd, 1H, J=8.5, 1.5Hz), 7.10 (s, 1H), 7.09 (d, 1H, J=8.5Hz), 7.00 (s, 1H), 5.35-5.10 (m, 1H), 4.29-4.24 (br.-d, 2H), 4.20 (q, 2H, J=7.0Hz), 4.13 (q, 2H, J=7.0Hz), 4.10-4.00 (m, 4H), 3.58 (s, 3H), 3.17-2.99 (m, 8H), 2.42 (s, 3H), 1.81-1.76 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1701, 1656, 1651, 1626, 1585, 1459, 1257. Example 14 3-{1-[6,7-Diethoxy-2-(4-methyl-1-piperazinyl)-4-quinazolinyl]-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline dimethanesulfonate (Compound 14) The same procedure as in Example 10 was repeated, except that N-methylpiperazine was used in place of morpholine in Step 1 and methanesulfonic acid was used in place of a saturated solution of hydrogen chloride in Step 2, to give Compound 14 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.48 (dd, 1H, J=8.3, 1.5Hz), 7.10 (s, 1H), 7.08 (d, 1H, J=8.3Hz), 6.92 (s, 1H), 5.30-5.15 (m, 1H), 4.25-4.23 (br.-d, 2H), 4.19 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 3.89-3.83 (m, 4H), 3.58 (s, 3H), 3.08-2.96 (m, 4H), 2.51-2.48 (m, 4H), 2.41 (s, 3H), 2.34 (s, 3H), 1.81-1.78 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.48 (t, 3H, J=7.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1705, 1658, 1637, 1195. Melting Point (ethyl acetate-ether): 187-189°C Example 15 3-[1-(6,7-Diethoxy-2-piperidino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 15) The same procedure as in Example 10 was repeated, except that piperidine was used in place of morpholine, to give Compound 15 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=1.5Hz), 7.48 (dd, 1H, J=8.5, 1.5Hz), 7.09 (s, 1H), 7.09 (d, 1H, J=8.5Hz), 6.90 (br.-s, 1H), 5.30-5.15 (m, 1H), 4.30-4.05 (m, 6H), 3.90-3.75 (m, 4H), 3.58 (s, 3H), 3.15-2.95 (m, 4H), 2.42 (s, 3H), 1.81-1.75 (br.-d, 2H), 1.64-1.53 (m, 6H), 1.51 (t, 3H, J=7.0Hz), 1.48 (t, 3H, J=7.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1706, 1648, 1586, 1459, 1271. Melting Point (ethanol-ether): 189-191°C Example 16 3-{1-[6,7-Diethoxy-2-(1-pyrrolidinyl)-4-quinazolinyl]-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 16) The same procedure as in Example 10 was repeated, except that pyrrolidine was used in place of morpholine, to give Compound 16 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=1.5Hz), 7.48 (dd, 1H, J=8.5, 1.5Hz), 7.10 (s, 1H), 7.08 (d, 1H, J=8.5Hz), 6.95 (br.-s, 1H), 5.30-5.15 (m, 1H), 4.40-4.24 (m, 2H), 4.20 (q, 2H, J=7.0Hz), 4.11 (q, 2H, J=7.0Hz), 3.70-3.50 (m, 4H), 3.58 (s, 3H), 3.08-2.99 (m, 4H), 2.42 (s, 3H), 2.00-1.96 (m, 4H), 1.80-1.77 (br.-d, 2H), 1.50 (t, 3H, J=7.0Hz), 1.48 (t, 3H, J=7.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1706, 1648, 1626, 1601, 1538, 1462, 1270. Melting Point (ether): 220-222°C Example 17 3-[1-(6,7-Diethoxy-2-hexamethyleneimino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 17) The same procedure as in Example 10 was repeated, except that hexamethyleneimine was used in place of morpholine, to give Compound 17 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=2.0Hz), 7.48 (dd, 1H, J=8.6, 2.0Hz), 7.10 (s, 1H), 7.08 (d, 1H, J=8.6Hz), 6.90 (br.-s, 1H), 5.30-5.10 (m, 1H), 4.21-4.14 (m, 4H), 4.10 (q, 2H, J=7.0Hz), 3.90-3.70 (m, 4H), 3.58 (s, 3H), 3.07-2.95 (m, 4H), 2.42 (s, 3H), 1.95-1.80 (m, 6H), 1.56-1.40 (m, 4H), 1.50 (t, 3H, J=7.0Hz), 1.47 (t, 3H, J=7.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1700, 1660, 1650, 1592. Melting Point (ether): 154-163°C Example 18 3-[1-(2-Dipropylamino-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 18) The same procedure as in Example 10 was repeated, except that dipropylamine was used in place of morpholine, to give Compound 18 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=1.5Hz), 7.48 (dd, 1H, J=8.5, 1.5Hz), 7.09 (s, 1H), 7.09 (d, 1H, J=8.5Hz), 6.88 (s, 1H), 5.30-5.15 (m, 1H), 4.21-4.18 (br.-d, 2H), 4.18 (q, 2H, J=7.0Hz), 4.10 (q, 2H, J=7.0Hz), 3.65-3.50 (m, 4H), 3.57 (s, 3H), 3.10-2.95 (m, 4H), 2.42 (s, 3H), 1.80-1.66 (m, 6H), 1.50 (t, 3H, J=7.0Hz), 1.48 (t, 3H, J=7.0Hz), 0.95-0.91 (m, 6H). (as the free base) IR (KBr tab.)(cm -1 ): 1708, 1659, 1627, 1593, 1543, 1361. Melting Point (ether): 240-242°C Example 19 3-[1-(6,7-Diethoxy-2-propylamino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 19) The same procedure as in Example 10 was repeated, except that propylamine was used in place of morpholine, to give Compound 19 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.49 (dd, 1H, J=8.3, 1.5Hz), 7.10 (d, 1H, J=8.3Hz), 7.09 (s, 1H), 6.93 (s, 1H), 5.40-5.20 (m, 1H), 4.52-4.48 (br.-d, 2H), 4.20 (q, 2H, J=7.0Hz), 4.09 (q, 2H, J=7.0Hz), 3.58 (s, 3H), 3.47-3.40 (m, 2H), 3.29-3.19 (br.-t, 2H), 3.04-2.97 (m, 2H), 2.42 (s, 3H), 1.88-1.84 (br.-d, 2H), 1.67 (sext, 2H, J=7.0Hz), 1.50 (t, 3H, J=7.0Hz), 1.48 (t, 3H, J=7.0Hz), 1.00 (t, 3H, J=7.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1702, 1657, 1524. Melting Point (ether): 225-227°C Example 20 3-[1-(6,7-Diethoxy-2-isopropylamino-4-quinazolinyl)-4-piperidinyl]-[,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 20) The same procedure as in Example 10 was repeated, except that isopropylamine was used in place of morpholine, to give Compound 20 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.00 (d, 1H, J=1.5Hz), 7.50 (dd, 1H, J=8.5, 1.5Hz), 7.10 (d, 1H, J=8.5Hz), 7.08 (s, 1H), 6.99 (br.-s, 1H), 5.40-5.20 (m, 1H), 4.70-4.65 (br.-d, 2H), 4.22-4.06 (m, 5H), 3.57 (s, 3H), 3.39-3.31 (br.-t, 2H), 2.97-2.93 (m, 2H), 2.42 (s, 3H), 1.87-1.84 (br.-d, 2H), 1.49 (t, 3H, J=7.0Hz), 1.47 (t, 3H, J=7.0Hz), 1.32 (d, 6H, J=6.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1699, 1659, 1634, 1542, 1518. Melting Point (ethanol-ethyl acetate-ether): 170-172°C Example 21 3-[1-(2-Cyclohexylamino-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 21) The same procedure as in Example 10 was repeated, except that cyclohexylamine was used in place of morpholine, to give Compound 21 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.49 (dd, 1H, J=8.5, 1.5Hz), 7.09 (d, 1H, J=8.5Hz), 7.09 (s, 1H), 6.91 (s, 1H), 5.40-5.20 (m, 1H), 4.37-4.23 (br.-d, 2H), 4.19 (q, 2H, J=7.0Hz), 4.10 (q, 2H, J=7.0Hz), 4.00-3.80 (m, 1H), 3.58 (s, 3H), 3.22-3.13 (br.-t, 2H), 3.05-2.97 (m, 2H), 2.42 (s, 3H), 2.06-2.03 (m, 2H), 1.85-1.75 (m, 4H), 1.50 (t, 3H, J=7.0Hz), 1.48 (t, 3H, J=7.0Hz), 1.38-1.27 (m, 6H). (as the free base) IR (KBr tab.)(cm -1 ): 1702, 1654, 1635, 1599, 1542. Melting Point (ethyl acetate): 170-173°C Example 22 3-[1-(2-Cyclooctylamino-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 22) The same procedure as in Example 10 was repeated, except that cyclooctylamine was used in place of morpholine, to give Compound 22 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.15 (br.-d, 1H, NH), 8.01 (d, 1H, J=1.5Hz), 7.50 (dd, 1H, J=8.5, 1.5Hz), 7.10 (d, 1H, J=8.5Hz), 7.08 (s, 1H), 6.92 (s, 1H), 5.40-5.20 (m, 1H), 4.69-4.64 (br.-d, 2H), 4.20 (q, 2H, J=7.0Hz), 4.07 (q, 2H, J=7.0Hz), 4.20-4.00 (m, 1H), 3.58 (s, 3H), 3.40-3.31 (br.-t, 2H), 3.02-2.94 (m, 2H), 2.43 (s, 3H), 2.00-1.50 (m, 16H), 1.50 (t, 3H, J=7,0Hz), 1.47 (t, 3H, J=7.0Hz). (as the hydrochloride) IR (KBr tab.)(cm -1 ): 1704, 1699, 1657, 1636, 1359. Melting Point (ether) : 231-234°C Example 23 3-[1-(6,7-Methylenedioxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 23) The same procedure as in Example 10 was repeated, except that 3-[1-(2-chloro-6,7-methylenedioxy-4-quinazolinyl)-4-piperidinyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound c) obtained in Reference Example 3 was used in place of Compound b, to give Compound 23 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=2.0Hz), 7.49 (dd, 1H, J=8.6, 2.0Hz), 7.09 (s, 1H), 7.09 (d, 1H, J=8.6Hz), 6.90 (s, 1H), 6.01 (s, 2H), 5.30-5.10 (m, 1H), 4.20-4.10 (br.-d, 2H), 3.90-3.70 (m, 8H), 3.58 (s, 3H), 3.10-2.95 (m, 4H), 2.42 (s, 3H), 1.86-1.75 (br.-d, 2H). (as the free base) IR (KBr tab.)(cm -1 ): 1702, 1654, 1649, 1510. Melting Point (ethanol-ether): 278-280°C Example 24 3-[1-(2-Morpholino-6,7-dipropoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 24) The same procedure as in Example 10 was repeated, except that 3-[1-(2-chloro-6,7-dipropoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound d) obtained in Reference Example 4 was used in place of Compound b, to give Compound 24 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=1.5Hz), 7.48 (dd, 1H, J=8.3, 1.5Hz), 7.10 (s, 1H), 7.08 (d, 1H, J=8.3Hz), 6.91 (s, 1H), 5.30-5.25 (m, 1H), 4.30-4.20 (br.-d, 2H), 4.07 (t, 2H, J=6.5Hz), 4.00 (t, 2H, J=6.5Hz), 3.90-3.81 (m, 8H), 3.58 (s, 3H), 3.09-2.99 (m, 4H), 2.42 (s, 3H), 1.94-1.80 (m, 6H), 1.07 (t, 6H, J=6.5Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1704, 1656, 1631, 1596, 1511. Melting Point (ethanol-ether-hexane): 160-163°C Example 25 3-[1-(6,7-Diisopropoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 25) The same procedure as in Example 10 was repeated, except that 3-[1-(2-chloro-6,7-diisopropoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound e) obtained in Reference Example 5 was used in place of Compound b, to give Compound 25 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=1.5Hz), 7.58 (dd, 1H, J=8.5, 1.5Hz), 7.22 (s, 1H), 7.08 (d, 1H, J=8.5Hz), 6.92 (s, 1H), 5.30-5.10 (m, 1H), 4.69 (sept, 1H, J=6.0Hz), 4.41 (sept, 1H, J=6.0Hz), 4.29-4.26 (br.-d, 2H), 3.90-3.75 (m, 8H), 3.58 (s, 3H), 3.09-2.98 (m, 4H), 2.42 (s, 3H), 1.82-1.79 (br.-d, 2H), 1.42 (d, 6H, J=6.0Hz), 1.34 (d, 6H, J=6.0Hz). (as the free base) IR (KBr tab.)(cm -1 ): 1704, 1652, 1543, 1510. Melting Point (ethanol-ethyl acetate-ether): 189-192°C Example 2 3-[1-(7-Benzyloxy-6-methoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline hydrochloride (Compound 26) The same procedure as in Example 10 was repeated, except that 3-[1-(7-benzyloxy-2-chloro-6-methoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound f) obtained in Reference Example 6 was used in place of Compound b, to give Compound 26 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=1.5Hz), 7.51-7.26 (m, 6H), 7.10 (s, 1H), 7.08 (d, 1H, J=8.5Hz), 6.99 (s, 1H), 5.40-5.20 (m, 3H), 4.30-4.20 (br.-d, 2H), 3.92 (s, 3H), 3.90-3.60 (m, 8H), 3.58 (s, 3H), 3.21-2.95 (m, 4H), 2.42 (s,3H), 1.83-1.75 (br.-d, 2H). (as the free base) IR (KBr tab.)(cm -1 ): 1704, 1657, 1649, 1540, 1273. Melting Point (ether): 176-178°C Example 27 3-[1-(6,7-Dimethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]methyl-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 27) The same procedure as in Example 1 was repeated, except that 300 mg (0.59 mmol) of 3-[1-(2-chloro-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]methyl-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound h) obtained in Reference Example 9 was used in place of Compound a, and N-methylpyrrolidinone was used as the solvent in place of dimethylformamide, to give 250 mg (yield: 76%) of Compound 27 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (s, 1H), 7.48 (d, 1H, J=8.4Hz), 7.12 (d, 1H, J=8.4Hz), 6.98 (s, 1H), 6.92 (br.-s, 1H), 4.16-4.04 (br.-d, 4H), 3.97 (s, 3H), 3.92 (s, 3H), 3.80 (br.-s, 8H), 3.65 (s, 3H), 3.07-2.98 (m, 2H), 2.42 (s, 3H), 2.28-2.10 (m, 1H), 1.83-1.59 (m, 4H). Melting Point (methanol-water): 255-256°C Example 28 3-{1-[2-Bis (2-hydroxyethyl)amino-6, 7-dimethoxy-4-quinazolinyl]-4-piperidinyl}methyl-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 28) The same procedure as in Example 27 was repeated, except that diethanolamine was used in place of morpholine, to give Compound 28 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (s, 1H), 7.50 (d, 1H, J=8.6Hz), 7.12 (d, 1H, J=8.6Hz), 6.96 (s, 1H), 6.87 (br.-s, 1H), 4.17-4.04 (br.-d, 4H), 3.98 (s, 3H), 3.91 (s, 3H), 3.91-3.82 (m, 8H), 3.60 (s, 3H), 3.04-2.95 (br.-t, 2H), 2.42 (s, 3H), 2.31-2.13 (m, 1H), 1.88-1.77 (br.-d, 2H), 1.71-1.57 (m, 2H). Melting Point (methanol-water): 223-224°C Example 29 3-(2-[1- (6,7-Dimethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]ethyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound 29) Ethyl chlorocarbonate (10 ml) was added to 540 mg (1.01 mmol) of 4-[2-(2-amino-5-methylbenzoylamino)ethyl]-1-(6,7-dimethoxy-2-morpholino-4-quinazolinyl)piperidine (Compound i) obtained in Reference Example 13, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, followed by addition of hexane and ether to the residue. The precipitated crystals were collected by filtration to give 430 mg of crude 4-[2-(2-ethoxycarbonylamino-5-methylbenzoylamino)ethyl]-1-(6,7-dimethoxy-2-morpholino-4-quinazolinyl)piperidine, which was then dissolved in 10 ml of ethanol. To the solution was added 210 mg of potassium hydroxide, and the mixture was heated under reflux for one hour. After evaporation of the solvent under reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was washed and dried, and the solvent was evaporated to give 360 mg (overall yield: 64%) of Compound 29 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.95 (br.-s, 1H, NH), 7.92 (s, 1H), 7.42 (d, 1H, J=8.3Hz), 6.99-6.96 (m, 3H), 4.20-4.12 (m, 4H), 4.00 (s, 3H), 3.92 (s, 3H), 3.80 (br.-s, 8H), 3.14-3.00 (br.-t, 2H), 2.40 (s, 3H), 2.01-1.97 (br.-d, 2H), 1.74-1.54 (m, 5H). Melting Point (methanol-water): 185-188°C Example 30 3-{2-[1-(6,7-Dimethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]ethyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound 30) In 5 ml of dimethylformamide was suspended 350 mg (0.7 mmol) of Compound 29 obtained in Example 29, and 42 mg (1.05 mmol) of 60% sodium hydride and 0.1 ml (1.54 mmol) of methyl iodide were added to the suspension. The mixture was stirred at room temperature for one hour, and then a saturated aqueous solution of ammonium chloride was added thereto to stop the reaction. After extraction with ethyl acetate, the organic layer was washed and dried. The solvent was evaporated under reduced pressure, and the resulting crude crystals were washed with a solvent mixture of ethanol and ether to give 190 mg (yield: 48%) of Compound 30 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (s, 1H), 7.50 (d, 1H, J=8.6Hz), 7.11 (d, 1H, J=8.6Hz), 6.98 (s, 1H), 6.95 (br.-s, 1H), 4.18-4.06 (m, 4H), 3.99 (s, 3H), 3.92 (s, 3H), 3.81 (br.-s, 8H), 3.59 (s, 3H), 3.12-2.95 (m, 2H), 2.42 (s, 3H), 2.05-1.91 (m, 2H), 1.80-1.42 (m, 5H). Melting Point (ethanol-ether): 138°C Example 31 3-{2-{1-[2-Bis(2-hydroxyethyl)amino-6,7-dimethoxy-4-quinazolinyl]-4-piperidinyl}ethyl}-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound 31) The same procedure as in Example 29 was repeated, except that 4-[2-(2-amino-5-methylbenzoylamino)ethyl]-1-[2-bis (2-hydroxyethyl)amino-6,7-dimethoxy-4-quinazolinyl] piperidine (Compound j) obtained in Reference Example 14 was used in place of Compound i, to give Compound 31 as white crystals. 1 H-NMR (CDCl 3 ) δ: 7.91 (s, 1H), 7.40 (d, 1H, J=8.6Hz), 6.99-6.95 (m, 3H), 4.16-4.11 (m, 4H), 3.96 (s, 3H), 3.91 (s, 3H), 3.94-3.84 (m, 8H), 3.09-3.00 (br.-t, 2H), 2.40 (s, 3H), 2.02-1.97 (br.-d, 2H), 1.80-1.49 (m, 5H). Melting Point (methanol-water): 167-169°C Example 32 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-[,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 32) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound p) obtained in Reference Example 15 was used in place of Compound b, to give Compound 32 as white crystals. 1 H-NMR (CDCl 3 ) δ: 9.67 (br.-s, 1H, NH), 8.13 (dd, 1H, J=6.9, 1.8Hz), 7.59 (ddd, 1H, J=6.9, 6.9, 1.8Hz), 7.23 (ddd, 1H, J=6.9, 6.9, 1.8Hz), 7.11 (s, 1H), 7.00 (dd, 1H, J=6.9, 1.8Hz), 6.95 (br.-s, 1H), 5.30-5.15 (m, 1H), 4.32-4.27 (br.-d, 2H), 4.21 (q, 2H, J=7.0Hz), 4.11 (q, 2H, J=7.0Hz), 3.83-3.77 (m, 8H), 3.19-2.98 (m, 4H), 1.84-1.80 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.46 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1705, 1656, 1560, 1441, 1234, 764. Melting Point (ether): 193-194°C Example 33 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound 33) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound q) obtained in Reference Example 16 was used in place of Compound b, to give Compound 33 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.30 (dd, 1H, J=7.9, 1.0Hz), 7.68 (ddd, 1H, J=7.9, 7.9, 1.0Hz), 7.26 (ddd, 1H, J=7.9, 7.9, 1.0Hz), 7.19 (dd, 1H, J=7.9, 1.0Hz), 7.11 (s, 1H), 6.92 (br.-s, 1H), 5.30-5.15 (m, 1H), 4.30-4.25 (br.-d, 2H), 4.20 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 3.84-3.81 (m, 8H), 3.60 (s, 3H), 3.15-2.96 (m, 4H), 1.82-1.79 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1702, 1658, 1562, 1510, 1238. Melting Point (ether): 238-241°C Example 34 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound 34) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound r) obtained in Reference Example 17 was used in place of Compound b, to give Compound 34 as white crystals. 1 H-NMR (CDCl 3 ) δ: 9.05 (br.-s, 1H, NH), 7.92 (d, 1H, J=2.0Hz), 7.40 (dd, 1H, J=8.0, 2.0Hz), 7.10 (s, 1H), 6.92 (br.-s, 1H), 6.90 (d, 1H, J=8.0Hz), 5.25-5.15 (m, 1H), 4.30-4.15 (m, 4H), 4.10 (q, 2H, J=7,0Hz), 3.83-3.80 (m, 8H), 3.13-2.99 (m, 4H), 2.40 (s, 3H), 1.83-1.80 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.47 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1710, 1659, 1560, 1433. Melting Point (ether): 229-232°C Example 35 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound 35) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound s) obtained in Reference Example 18 was used in place of Compound b, to give Compound 35 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=2.0Hz), 7.48 (dd, 1H, J=8.3, 2.0Hz), 7.10 (s, 1H), 7.09 (d, 1H, J=8.3Hz), 6.92 (br.-s, 1H), 5.30-5.10 (m, 1H), 4.40-4.20 (m, 4H), 4.16 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 3.95-3.81 (m, 8H), 3.20-2.96 (m, 4H), 2.41 (s, 3H), 1.82-1.79 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz), 1.35 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1707, 1653, 1542, 1457. Melting Point (ether): 227-230°C Example 36 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1-propylquinazoline (Compound 36) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1-propylquinazoline (Compound t) obtained in Reference Example 19 was used in place of Compound b, to give Compound 36 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=2.0Hz), 7.46 (dd, 1H, J=8.3, 2.0Hz), 7.10 (s, 1H), 7.06 (d, 1H, J=8.3Hz), 6.92 (br.-s, 1H), 5.25-5.10 (m, 1H), 4.22-4.19 (br.-d, 2H), 4.17 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 4.08-4.02 (br.-t, 2H), 3.90-3.81 (m, 8H), 3.07-2.99 (m, 4H), 2.41 (s, 3H), 1.81-1.78 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz), 1.04 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1701, 1658, 1573, 1509, 1460, 1238. Melting Point (ether): 162-163°C Example 37 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-5-methyl-2,4-dioxoquinazoline (Compound 37) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-5-methyl-2,4-dioxoquinazoline (Compound u) obtained in Reference Example 20 was used in place of Compound b, to give Compound 37 as white crystals. 1 H-NMR (CDCl 3 ) δ: 9.43 (br.-s, 1H, NH), 7.40 (dd, 1H, J=7.9, 7.9Hz), 7.11 (s, 1H), 6.99 (d, 1H, J=7,9Hz), 6.95 (br.-s, 1H), 6.82 (d, 1H, J=7.9Hz), 5.25-5.10 (m, 1H), 4.27-4.15 (br.-d, 2H), 4.21 (q, 2H, J=7.0Hz), 4.11 (q, 2H, J=7.0Hz), 3.83-3.71 (m, 8H), 3.18-2.97 (m, 4H), 2.79 (s, 3H), 1.83-1.79 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.47 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1710, 1653, 1469, 1433, 1233. Melting Point (ether): 261-263°C Example 38 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,5-dimethyl-2,4-dioxoquinazoline (Compound 38) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,5-dimethyl-2,4-dioxoquinazoline (Compound v) obtained in Reference Example 21 was used in place of Compound b, to give Compound 38 as white crystals. 1 H-NMR (CDCl 3 ) δ: 7.51 (t, 1H, J=7.6, 7.6Hz), 7.11 (s, 1H), 7.05 (d, 2H, J=7.6Hz), 6.93 (br.-s, 1H), 5.25-5.10 (m, 1H), 4.28-4.24 (br.-d, 2H), 4.20 (q, 2H, J=7.0Hz), 4.13 (q, 2H, J=7.0Hz), 3.84-3.80 (m, 8H), 3.58 (s, 3H), 3.14-2.98 (m, 4H), 2.82 (s, 3H), 1.81-1.78 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1699, 1655, 1560, 1236. Melting Point (ether): 170-172°C Example 39 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-8-methyl-2,4-dioxoquinazoline (Compound 39) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-8-methyl-2,4-dioxoquinazoline (Compound w) obtained in Reference Example 22 was used in place of Compound b, to give Compound 39 as white crystals. 1 H-NMR (CDCl 3 ) δ: 9.12 (br.-s, 1H, NH), 8.00 (d, 1H, J=7.6Hz), 7.40 (d, 1H, J=7.6Hz), 7.13 (dd, 1H, J=7.6, 7.6Hz), 7.10 (s, 1H), 6.95 (br.-s, 1H), 5.30-5.15 (m, 1H), 4.32-4.28 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.10 (q, 2H, J=7.0Hz), 3.83-3.78 (m, 8H), 3.18-2.99 (m, 4H), 2.35 (s, 3H), 1.84-1.80 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.46 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1720, 1659, 1649, 1510, 1235, 756. Melting Point (ether): 222-226°C Example 40 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,8-dimethyl-2,4-dioxoquinazoline (Compound 40) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,8-dimethyl-2,4-dioxoquinazoline (Compound x) obtained in Reference Example 23 was used in place of Compound b, to give Compound 40 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.06 (d, 1H, J=7.0Hz), 7.45 (d, 1H, J=7.0Hz), 7.18 (dd, 1H, J=7.0, 7.0Hz), 7.10 (s, 1H), 6.93 (br.-s, 1H), 5.20-5.00 (m, 1H), 4.30-4.20 (br.-d, 2H), 4.20 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 3.85-3.80 (m, 8H),3.67 (s, 3H), 3.09-2.97 (m, 4H), 2.61 (s, 3H), 1.83-1.80 (br.-d, 2H), 1.51 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1722, 1675, 1580, 1466, 1257. Melting Point (ethyl acetate-ether): 141-143°C Example 41 6-Chloro-3-[1-(6,7-diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 41) The same procedure as in Example 10, Step 1 was repeated, except that 6-chloro-3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound y) obtained in Reference Example 24 was used in place of Compound b, to give Compound 41 as white crystals. 1 H-NMR (CDCl 3 ) δ: 10.00 (br.-s, 1H, NH), 8.09 (d, 1H, J=2.0Hz), 7.55 (dd, 1H, J=8.5, 2.0Hz), 7.10 (s, 1H), 6.97 (s, 1H), 6.94 (d, 1H, J=8.5Hz), 5.30-5.15 (m, 1H), 4.32-4.27 (br.-d, 2H), 4.21 (q, 2H, J=7.0Hz), 4.11 (q, 2H, J=7.0Hz), 3.82-3.78 (m, 8H), 3.19-2.99 (m, 4H), 1.81-1.77 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.48 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1715, 1658, 1562, 1471, 1342, 1235. Melting Point (ether): 126-129°C Example 42 6-Chloro-3-[1-(6,7-diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound 42) The same procedure as in Example 10, Step 1 was repeated, except that 6-chloro-3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound z) obtained in Reference Example 25 was used in place of Compound b, to give Compound 42 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.18 (d, 1H, J=2.6Hz), 7.62 (dd, 1H, J=8.9, 2.6Hz), 7.14 (d, 1H, J=8.9Hz), 7.09 (s, 1H), 6.93 (br.-s, 1H), 5.30-5.10 (m, 1H), 4.30-4.20 (br.-d, 2H), 4.19 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 3.84-3.80 (m, 8H), 3.58 (s, 3H), 3.10-2.93 (m, 4H), 1.81-1.77 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1705, 1699, 1667, 1543, 1422, 1231. Melting Point (ether): 213-215°C Example 43 6-Bromo-3-[1-(6,7-diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound 43) The same procedure as in Example 10, Step 1 was repeated, except that 6-bromo-3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound aa) obtained in Reference Example 26 was used in place of Compound b, to give Compound 43 as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.33 (d, 1H, J=2.3Hz), 7.75 (dd, 1H, J=8.9, 2.3Hz), 7,09 (s, 1H), 7.07 (d, 1H, J=8.9Hz), 6.93 (br.-s, 1H), 5.30-5.15 (m, 1H), 4.30-4.20 (br.-d, 2H), 4.19 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 3.90-3.80 (m, 8H), 3.58 (s, 3H), 3.10-2.96 (m, 4H), 1.81-1.77 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1726, 1682, 1462, 1256. Melting Point (ether-hexane): 206-207°C Example 44 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline (Compound 44) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline (Compound bb) obtained in Reference Example 27 was used in place of Compound b, to give Compound 44 as white crystals. 1 H-NMR (CDCl 3 ) δ: 9.01 (d, 1H, J=2.0Hz), 8.48 (dd, 1H, J=8.5, 2.0Hz), 7.09 (s, 1H), 7.03 (d, 1H, J=8.5Hz), 7.00 (s, 1H), 5.30-5.15 (m, 1H), 4.34-4.30 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 3.81-3.77 (m, 8H), 3.23-3.14 (br.-t, 2H), 3.01-2.97 (m, 2H), 1.81-1.78 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.48 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ); 1719, 1659, 1648, 1561, 1337, 1233. Melting Point (ether): 154-156°C Example 45 3-[1-(6,7-Diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline (Compound 45) The same procedure as in Example 10, Step 1 was repeated, except that 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline (Compound cc) obtained in Reference Example 28 was used in place of Compound b, to give Compound 45 as white crystals. 1 H-NMR (CDCl 3 ) δ: 9.09 (d, 1H, J=2.6Hz), 8.51 (dd, 1H, J=9.2, 2.6Hz), 7.31 (d, 1H, J=9.2Hz), 7.09 (s, 1H), 6.94 (br.-s, 1H), 5.30-5.15 (m, 1H), 4.30-4.15 (br.-d, 2H), 4.18 (q, 2H, J=7.0Hz), 4.12 (q, 2H, J=7.0Hz), 3.90-3.80 (m, 8H), 3.67 (s, 3H), 3.10-2.96 (m, 4H), 1.83-1.79 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1720, 1672, 1331, 1234. Melting Point (ether): 158-160°C Example 46 6-Acetyl-3-[1-(6,7-diethoxy-2-morpholino-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound 46) The same procedure as in Example 10, Step 1 was repeated, except that 6-acetyl-3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound dd) obtained in Reference Example 29 was used in place of Compound b, to give Compound 46 as white crystals. 1 H-NMR (CDCl 3 ) 8: 8.77 (d, 1H, J=2.0Hz), 8.31 (dd, 1H, J=8.9, 2.0Hz), 7.27 (d, 1H, J=8.9Hz), 7.10 (s, 1H), 6.93 (br.-s, 1H), 5.30-5.10 (m, 1H), 4.30-4.20 (br.-d, 2H), 4.21 (q, 2H, J=7.0Hz), 4.13 (q, 2H, J=7.0Hz), 3.84-3.82 (m, 8H), 3.64 (s, 3H), 3.12-2.98 (m, 4H), 2.67 (s, 3H), 1.83-1.79 (br.-d, 2H), 1.52 (t, 3H, J=7.0Hz), 1.49 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1707, 1685, 1649, 1510. Melting Point (ether): 153-154°C Reference Example 1 3-[1-(2-Chloro-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound a) Step 1: In 50 ml of 48% hydrobromic acid was dissolved 5.0 g (14.5 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound g) obtained in Reference Example 7, and the mixture was heated under reflux for 1.5 hours. After evaporation of the solvent, ethanol was added to the residue. The precipitated crystals were collected by filtration to give 5.04 g (yield: 99%) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide as white crystals. 1 H-NMR (DMSO-d 6 ) δ: 7.85 (d, 1H, J=2.0Hz), 7.60 (dd, 1H, J=8.6, 2.0Hz), 7.35 (d, 1H, J=8.6Hz), 5.16-5.07 (m, 1H), 3.49 (s, 3H), 3.41-3.36 (br.-d, 2H), 3.13-3.05 (m, 2H), 2.86-2.73 (m, 2H), 2.38 (s, 3H), 1.81-1.77( br.-d, 2H). IR (KBr tab.)(cm -1 ): 1696, 1627, 1512. Melting Point (ethanol): >300°C Step 2: In 40 ml of methanol were suspended 2.0 g (5.65 mmol) of the hydrobromide obtained in Step 1 and 1.47 g (5.65 mmol) of 2,4-dichloro-6,7-dimethoxyquinazoline, and 2.0 ml (14.1 mmol) of triethylamine was added to the suspension, followed by heating under reflux for 2 hours. After cooling, the solvent was evaporated and water was added to the residue. The precipitated crystals were collected by filtration and washed with water and methanol to give 2.27 g (yield: 81%) of Compound a as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.0Hz), 7.49 (dd, 1H, J=8.5, 1.0Hz), 7.26 (s, 1H), 7.14 (s, 1H), 7.10 (d, 1H, J=8.5Hz), 5.38-5.26 (m, 1H), 4.50-4.45 (br.-d, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.58 (s, 3H), 3.29-3.20 (br.-t, 2H), 3.11-2.96 (m, 2H), 2.42 (s, 3H), 1.90-1.85 (br.-d, 2H). IR (KBr tab.)(cm -1 ): 1706, 1655, 1512, 1480, 1218. Melting Point (ether): 234-236°C Reference Example 2 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound b) The same procedure as in Reference Example 1 was repeated, except that 2,4-dichloro-6,7-diethoxyquinazoline was used in place of 2,4-dichloro-6,7-dimethoxyquinazoline, to give Compound b as pale yellow crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.3Hz), 7.49 (dd, 1H, J=8.6, 1.3Hz), 7.16 (s, 1H), 7.15 (s, 1H), 7.09 (d, 1H, J=8.6Hz), 5.31-5.25 (m, 1H), 4.46-4.39 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.17 (q, 2H, J=7.0Hz), 3.58 (s, 3H), 3.25-3.16 (br.-t, 2H), 3.10-2.99 (m, 2H), 2.42 (s, 3H), 1.88-1.83 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.52 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1694, 1657, 1511, 1336, 1033. Melting Point (methanol-water): 209-210°C Reference Example 3 3-[1-(2-Chloro-6,7-methylenedioxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound c) The same procedure as in Reference Example 1 was repeated, except that 2,4-dichloro-6,7-methylenedioxyquinazoline was used in place of 2,4-dichloro-6,7-dimethoxyquinazoline, to give Compound c as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.49 (dd, 1H, J=8.6, 1.5Hz), 7.18 (s, 1H), 7.15 (s, 1H), 7.09 (d, 1H, J=8.6Hz), 6.12 (s, 2H), 5.34-5.24 (m, 1H), 4.37-4.32 (br.-d, 2H), 3.58 (s, 3H), 3.22-2.96 (m, 4H), 2.42 (s, 3H), 1.86-1.82 (br.-d, 2H). IR (KBr tab.)(cm -1 ): 1703, 1649, 1620, 1509, 1464. Melting Point (ethyl acetate-ether) : 278-280°C Reference Example 4 3-[1-(2-Chloro-6,7-dipropoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound d) The same procedure as in Reference Example 1 was repeated, except that 2,4-dichloro-6,7-dipropoxyquinazoline was used in place of 2,4-dichloro-6,7-dimethoxyquinazoline, to give Compound d as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=2.0Hz), 7.49 (dd, 1H, J=8.6, 2.0Hz), 7.16 (s, 1H), 7.14 (s, 1H), 7.09 (d, 1H, J=8.6Hz), 5.35-5.10 (m, 1H), 4.46-4.40 (br.-d, 2H), 4.09 (t, 2H, J=6.5Hz), 4.05 (t, 2H, J=6.5Hz), 3.58 (s, 3H), 3.25-3.16 (br.-t, 2H), 3.08-2.99 (m, 2H), 2.42 (s, 3H), 1.95-1.84 (m, 6H), 1.09 (t, 3H, J=6.5Hz), 1.08 (t, 3H, J=6.5Hz). IR (KBr tab.)(cm -1 ): 1700, 1665, 1655, 1510. Melting Point (ether): 171-173°C Reference Example 5 3-[1- (2-Chloro-6,7-diisopropoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound e) The same procedure as in Reference Example 1 was repeated, except that 2,4-dichloro-6,7-diisopropoxyquinazoline was used in place of 2,4-dichloro-6,7-dimethoxyquinazoline, to give Compound e as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.49 (dd, 1H, J=8.5, 1.5Hz), 7.26 (s, 1H), 7.18 (s, 1H), 7.09 (d, 1H, J=8.5Hz), 5.32-5.24 (m, 1H), 4.69 (sept, 1H, J=6.0Hz), 4.55 (sept, 1H, J=6.0Hz), 4.52-4.50 (br.-d, 2H), 3.58 (s, 3H), 3.26-3.18 (br.-t, 2H), 3.09-2.94 (m, 2H), 2.42 (s, 3H), 1.87-1.83 (br.-d, 2H), 1.44 (d, 3H, J=6.0Hz), 1.38 (d, 3H, J=6.0Hz). IR (KBr tab.)(cm -1 ): 1699, 1657, 1479, 1460, 1246. Melting Point (ether): 130-132°C Reference Example 6 3-[1-(7-Benzyloxy-2-chloro-6-methoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound f) The same procedure as in Reference Example 1 was repeated, except that 7-benzyloxy-2,4-dichloro-6-methoxyquinazoline was used in place of 2,4-dichloro-6,7-dimethoxyquinazoline, to give Compound f as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (d, 1H, J=1.5Hz), 7.51-7.32 (m, 6H), 7.21 (s, 1H), 7.16 (s, 1H), 7.09 (d, 1H, J=8.3Hz), 5.40-5.20 (m, 1H), 5.27 (s, 2H), 4.45-4.41 (br.-d, 2H), 3.98 (s, 3H), 3.58 (s, 3H), 3.26-3.17 (br.-t, 2H), 3.10-3.00 (m, 2H), 2.42 (s, 3H), 1.88-1.85 (br.-d, 2H). IR (KBr tab.)(cm -1 ): 1701, 1645, 1503, 1429. Melting Point (ethyl acetate-ether) : 146-150°C Reference Example 7 3-(1-Ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound g) The same procedure as in Example 30 was repeated using 1.0 g (3.02 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline obtained by the method described in Chem. Pharm. Bull., 34 , 1907-1916 (1986) to give 745.6 mg (yield: 72%) of Compound g as white crystals. 1 H-NMR (CDCl 3 ) δ: 7.99 (d, 1H, J=2.0Hz), 7.45 (dd, 1H, J=8.6, 2.0Hz), 7.07 (d, 1H, J=8.6Hz), 5.17-5.06 (m, 1H), 4.40-4.20 (m, 2H), 4.14 (q, 2H, J=7.3Hz), 3.55 (s, 3H), 2.96-2.82 (br.-t, 2H), 2.77-2.64 (m, 2H), 2.41 (s, 3H), 1.66-1.61 (br.-d, 2H), 1.27 (t, 3H, J=7.3Hz). IR (KBr tab.)(cm -1 ): 1702, 1680, 1658, 1240. Melting Point (ether): 156-157°C Reference Example 8 3-(1-Ethoxycarbonyl-4-piperidinyl)methyl-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound k) The same procedure as in Reference Example 7 was repeated, except that 2.74 g (7.94 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)methyl-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline was used in place of 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline, to give 2.40 g (yield: 84%) of Compound k as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.01 (s, 1H), 7.50 (d, 1H, J=8.6Hz), 7.11 (d, 1H, J=8.6Hz), 4.28-4.07 (m, 4H), 4.02 (d, 2H, J=7.3Hz), 3.59 (s, 3H), 2.74-2.65 (br.-t, 2H), 2.42 (s, 3H), 2.10-1.96 (m, 1H), 1.66-1.62 (br.-d, 2H), 1.39-1.16 (m, 5H). Reference Example 9 3-[1-(2-Chloro-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]methyl-1,2,3,4-tetrahydro-1,6-dimethyl-2, 4-dioxoquinazoline (Compound h) The same procedure as in Reference Example 1 was repeated, except that Compound k obtained in Reference Example 8 was used in place of Compound g, to give Compound h as white crystals (overall yield: 64%). 1 H-NMR (CDCl 3 ) δ: 8.03 (s, 1H), 7.51 (d, 1H, J=8.6Hz), 7.16 (s, 1H), 7.13 (d, 1H, J=8.6Hz), 7.05 (s, 1H), 4.29-4.24 (br.-d, 2H), 4.12 (d, 2H, J=6.9Hz), 3.99 (s, 3H), 3.97 (s, 3H), 3.61 (s, 3H), 3.12-3.04 (br.-t, 2H), 2.43 (s, 3H), 2.38-2.24 (m ,1H), 1.89-1.85 (br.-d, 2H), 1.71-1.64 (m, 2H). Melting Point (methanol-water): 270-271°C Reference Example 10 1-(2-Chloro-6,7-dimethoxy-4-quinazolinyl) -4-[2-(5-methyl-2-nitrobenzoylamino)ethyl]piperidine (Compound m) To 2.5 g (11.8 mmol) of 5-methyl-2-nitrobenzoic acid was added 10 ml of thionyl chloride, followed by heating at 100°C for 1.5 hours. The solvent was evaporated under reduced pressure, and 50 ml of dichloromethane was added to the residue to prepare Solution A. In dichloroethane was dissolved 2.5 g of 4-(2-aminoethyl)-1-(2-chloro-6,7-dimethoxy-4-quinazolinyl)piperidine obtained by the method described in Chem. Pharm. Bull., 38 , 3014-3019 (1990) and the literature cited therein. To the mixture was added 9.7 ml of triethylamine, and after stirring at room temperature, Solution A was added dropwise to the mixture. The resulting mixture was subjected to reaction at room temperature for 30 minutes and then was added dropwise to water, followed by extraction with dichloromethane. The organic layer was washed and dried, and the solvent was evaporated under reduced pressure. The residue was washed with a solvent mixture of ethanol and ether to give 5.0 g (yield: 83%) of Compound m as white crystals. 1 H-NMR (CDCl 3 ) δ: 7.99 (d, 1H, J=8.2Hz), 7.35 (d, 1H, J=8.2Hz), 7.30 (s, 1H), 7.16 (s, 1H), 7.06 (s, 1H), 5.82 (br.-s, 1H, NH), 4.34-4.29 (br.-d, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 3.61-3.54 (m, 2H), 3.20-3.10 (m, 2H), 2.46 (s, 3H), 1.99-1.94 (br.-d, 2H), 1.79-1.47 (m, 5H). Reference Example 11 1-(6,7-Dimethoxy-2-morpholino-4-quinazolinyl)-4-[2-(5-methyl-2-nitrobenzoylamino)ethyl]piperidine (Compound n) The same procedure as in Example 1 was repeated, except that 2.5 g (4.87 mmol) of Compound m obtained in Reference Example 10 was used, and N-methylpyrrolidinone was used as the solvent in place of dimethylformamide, to give 2.29 g (yield: 83%) of Compound n as white crystals. 1 H-NMR (CDCl 3 ) δ: 8.00 (d, 1H, J=8.2Hz), 7.35 (d, 1H, J=8.2Hz), 7.30 (s, 1H), 6.99 (s, 1H), 6.93 (br.-s, 1H), 5.74 (br.-s, 1H, NH), 4.17-4.12 (br.-d, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.81 (br.-s, 8H), 3.61-3.48 (m, 2H), 3.07-2.99 (br.-t, 2H), 2.46 (s, 3H), 1.94-1.89 (br.-d, 2H), 1.70-1.32 (m, 5H). Reference Example 12 1-[2-Bis(2-hydroxyethyl)amino-6,7-dimethoxy-4-quinazolinyl]-4-[2-(5-methyl-2-nitrobenzoylamino)ethyl]piperidine (Compound o) The same procedure as in Reference Example 11 was repeated, except that 4.0 g (7.80 mmol) of Compound m was used, and diethanolamine was used in place of morpholine, to give 3.24 g (yield: 71%) of Compound o as white crystals. 1 H-NMR (CDCl 3 ) δ: 7.99 (d, 1H, J=8.6Hz), 7.35 (d, 1H, J=8.6Hz), 7.30 (s, 1H), 7.02 (br.-s, 1H), 6.95 (s, 1H), 5.86 (br.-s, 1H, NH), 4.21-4.16 (br.-d, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.92-3.84 (m, 8H), 3.60-3.52 (m, 2H), 3.13-3.04 (br.-t, 2H), 2.47 (s, 3H), 1.98-1.93 (br.-d, 2H), 1.85-1.45 (m, 5H). Reference Example 13 4-[2-(2-Amino-5-methylbenzoylamino)ethyl]-1-16,7-dimethoxy-2-morpholino-4-quinazolinyl)piperidine (Compound i) In 60 ml of ethanol was suspended 2.06 g (3.65 mmol) of Compound n obtained in Reference Example 11, and 500 mg of 10% palladium/carbon was added to the suspension, followed by stirring at room temperature for 20 hours in an atmosphere of hydrogen. The reaction mixture was filtered using a filter aid, and the filtrate was evaporated under reduced pressure to give 1.60 g (yield: 82%) of Compound i as white crystals. 1 H-NMR (CDCl 3 ) δ: 7.10 (s, 1H), 7.03 (d, 1H, J=8.2Hz), 6.98 (s, 2H), 6.62 (d, 1H, J=8.2Hz), 6.10 (br.-s, 1H), 4.18-4.14 (br.-d, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 3.84-3.79 (m, 8H), 3.54-3.47 (m, 2H), 3.07-2.98 (br.-t, 2H), 2.24 (s, 3H), 1.93-1.89 (br.-d, 2H), 1.80-1.47 (m, 5H). Reference Example 14 4-[2-(2-Amino-5-methylbenzoylamino)ethyl]-1-[2-bis(2-hydroxyethyl)amino-6,7-dimethoxy-4-quinazolinyl] piperidine (Compound j) The same procedure as in Reference Example 13 was repeated, except that 2.87 g (4.93 mmol) of Compound o obtained in Reference Example 12 was used, to give 2.12 g (yield: 78%) of Compound j as white crystals. 1 H-NMR (CDCl 3 ) δ: 7.10 (s, 1H), 7.04 (d, 1H, J=8.2Hz), 6.94 (s, 2H), 6.62 (d, 1H, J=8.2Hz), 6.10 (br.-s, 1H), 4.15-4.10 (br.-d, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.90-3.83 (m, 8H), 3.54-3.47 (m, 2H), 3.07-2.98 (br.-t, 2H), 2.24 (s, 3H), 1.96-1.91 (br.-d, 2H), 1.79-1.46 (m, 5H). Reference Example 15 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound p) The same procedure as in Reference Example 2 was repeated using 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline obtained by the method described in Chem. Pharm. Bull., 34 , 1907-1916 (1986) to give Compound p as white crystals. 1 H-NMR (CDCl 3 ) δ: 9.78 (br.-s, 1H, NH), 8.12 (dd, 1H, J=6.9, 1.8Hz), 7.63 (ddd, 1H, J=6.9, 6.9, 1.8Hz), 7.24 (ddd, 1H, J=6.9, 6.9, 1.8Hz), 7.19 (s, 1H), 7.15 (s, 1H), 7.03 (dd, 1H, J=6.9, 1.8Hz), 5.33-5.24 (m, 1H), 4.49-4.44 (br.-d, 2H), 4.23 (q, 2H, J=7.0Hz), 4.16 (q, 2H, J=7.0Hz), 3.31-3.22 (br.-t, 2H), 3.09-2.97 (m, 2H), 1.89-1.86 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.50 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1708, 1659, 1560, 776. Melting Point (ethyl acetate-ether): 248-250°C Compounds q-dd (Reference Examples 16-29) which are used in Examples 33-46 are obtained as white crystals according to the same procedure as in Reference Example 1, using the corresponding compounds obtained by the methods described in Chem. Pharm. Bull, 34 , 1907-1916 (1986) or WO 94/19342 in place of 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline, as well as using 2,4-dichloro-6,7-diethoxyquinazoline in place of 2,4-dichloro-6,7-dimethoxyquinazoline. Reference Example 16 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound q) 1 H-NMR (CDCl 3 ) δ: 8.23 (dd, 1H, J=7.9, 1.3Hz), 7.69 (ddd, 1H, J=7.9, 7.9, 1.3Hz), 7.26 (ddd, 1H, J=7.9, 7.9, 1.3Hz), 7.20 (dd, 1H, J=7.9, 1.3Hz), 7.17 (s, 1H), 7.15 (s, 1H), 5.34-5.25 (m, 1H), 4.45-4.40 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.17 (q, 2H, J=7.0Hz), 3.60 (s, 3H), 3.25-3.16 (br.-t, 2H), 3.10-3.00 (m, 2H), 1.89-1.84 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.52 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1704, 1657, 1508, 1148, 754. Melting Point (ethyl acetate-ether): 191-193°C Reference Example 17 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound r) 1 H-NMR (CDCl 3 ) δ: 9.39 (br.-s, 1H, NH), 7.92 (d, 1H, J=2.0Hz), 7.42 (dd, 1H, J=8.0, 2.0Hz), 7.17 (s, 1H), 7.15 (s, 1H), 6.93 (d, 1H, J=8.0Hz), 5.26-5.10 (m, 1H), 4.47-4.42 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.17 (q, 2H, J=7.0Hz), 3.29-3.20 (br.-t, 2H), 3.09-2.97 (m, 2H), 2.41 (s, 3H), 1.89-1.85 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.51 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1705, 1655, 1560, 1458. Melting Point (ethyl acetate-ether): 187-190°C Reference Example 18 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound s) 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=2.0Hz), 7.47 (dd, 1H, J=8.6, 2.0Hz), 7.15 (s, 2H), 7.10 (d, 1H, J=8.6Hz), 5.32-5.24 (m, 1H), 4.44-4.40 (br.-d, 2H), 4.21 (q, 2H, J=7.0Hz), 4.17 (q, 2H, J=7.0Hz), 4.16 (q, 2H, J=7.0Hz), 3.25-3.16 (br.t, 2H), 3.10-2.97 (m, 2H), 2.41 (s, 3H), 1.88-1.83 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.52 (t, 3H, J=7.0Hz), 1.35 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1702, 1655, 1526, 1459. Melting Point (methanol-water): 202-203°C Reference Example 19 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1-propylquinazoline (Compound t) 1 H-NMR (CDCl 3 ) δ: 8.02 (d, 1H, J=2.0Hz), 7.47 (dd, 1H, J=8.3, 2.0Hz), 7.15 (s, 2H), 7.07 (d, 1H, J=8.3Hz), 5.33-5.24 (m, 1H), 4.45-4.40 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.17 (q, 2H, J=7.0Hz), 4.08-4.02 (br.-t, 2H), 3.25-3.16 (br.-t, 2H), 3.09-2.97 (m, 2H), 2.41 (s, 3H), 1.88-1.83 (br.-d, 2H), 1.81-1.72 (m, 2H), 1.53 (t, 3H, J=7.0Hz), 1.52 (t, 3H, J=7.0Hz), 1.04 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1699, 1655, 1511, 1507, 1249. Melting Point (ether): 227-230°C Reference Example 20 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-5-methyl-2,4-dioxoquinazoline (Compound u) 1 H-NMR (CDCl 3 ) δ: 9.22 (br.-s, 1H, NH), 7.44 (dd, 1H, J=7.5, 7.5Hz), 7.18 (s, 1H), 7.15 (s, 1H), 7.00 (d, 1H, J=7.5Hz), 6.85 (d, 1H, J=7.5Hz), 5.28-5.18 (m, 1H), 4.48-4.43 (br.-d, 2H), 4.24 (q, 2H, J=7.0Hz), 4.16 (q, 2H, J=7.0Hz), 3.28-3.18 (br.-t, 2H), 3.10-2.94 (m, 2H), 2.79 (s, 3H), 1.88-1.84 (br.-d, 2H), 1.54 (t, 3H, J=7.0Hz), 1.52 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1717, 1654, 1252, 794. Melting Point (methanol-water): 259-261°C Reference Example 21 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,5-dimethyl-2,4-dioxoquinazoline (Compound v) 1 H-NMR (CDCl 3 ) δ: 7.51 (dd, 1H, J=7.6, 7.6Hz), 7.16 (s, 2H), 7.07 (d, 2H, J=7.6Hz), 5.31-5.22 (m, 1H), 4.46-4.41 (br.-d, 2H), 4.20 (q, 2H, J=7.0Hz), 4.17 (q, 2H, J=7.0Hz), 3.58 (s, 3H), 3.25-3.16 (br.-t, 2H), 3.05-2.99 (m, 2H), 2.82 (s, 3H), 1.88-1.83 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.52 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1704, 1698, 1659, 1649, 1573, 1475, 755. Melting Point (methanol-water): 199-201°C Reference Example 22 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-8-methyl-2,4-dioxoquinazoline (Compound w) 1 H-NMR (CDCl 3 ) δ: 8.63 (br.-s, 1H, NH), 8.01 (d, 1H, J=8.0Hz), 7.43 (d, 1H, J=8.0Hz), 7.19 (s, 1H), 7.14 (dd, 2H, J=8.0, 8.0Hz), 7.14 (s, 1H), 5.30-5.20 (m, 1H), 4.48-4.43 (br.-d, 2H), 4.23 (q, 2H, J=7.0Hz), 4.16 (q, 2H, J=7.0Hz), 3.25-3.21 (br.-t, 2H), 3.07-2.99 (m, 2H), 2.35 (s, 3H), 1.89-1.85 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.51 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1707, 1656, 1650, 755. Melting Point (methanol-water): 246-248°C Reference Example 23 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,8-dimethyl-2,4-dioxoquinazoline (Compound x) 1 H-NMR (CDCl 3 ) δ: 8.06 (d, 1H, J=7.0Hz), 7.46 (d, 1H, J=7.0Hz), 7.17 (dd, 1H, J=7.0, 7.0Hz), 7.15 (s, 1H), 7.14 (s, 1H), 5.20-5.05 (m, 1H), 4.43-4.39 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.18 (q, 2H, J=7.0Hz), 3.67 (s, 3H), 3.24-2.99 (m, 4H), 2.61 (s, 3H), 1.89-1.85 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.52 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1726, 1674, 1514, 1269. Melting Point (methanol-water): 206-207°C Reference Example 24 6-Chloro-3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound y) 1 H-NMR (CDCl 3 ) δ: 9.50 (br.-s, 1H, NH), 7.92 (d, 1H, J=2,0Hz), 7.43 (dd, 1H, J=8.5, 2.0Hz), 7.19 (s, 1H), 7.15 (s, 1H), 6.94 (d, 1H, J=8.0Hz), 5.31-5.23 (m, 1H), 4.48-4.43 (br.-d, 2H), 4.23 (q, 2H, J=7.0Hz), 4.16 (q, 2H, J=7.0Hz), 3.29-3.20 (br.-t, 2H), 3.09-2.97 (m, 2H), 1.89-1.85 (br.-d, 2H), 1.53 (t, 3H, J=7.0.Hz), 1.50 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1709, 1667, 1431, 1247. Melting Point (ether): 236-239°C Reference Example 25 6-Chloro-3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound z) 1 H-NMR (CDCl 3 ) δ: 8.18 (d, 1H, J=2.5Hz), 7.62 (dd, 1H, J=8.9, 2.5Hz), 7.16 (s, 1H), 7.14 (s, 1H), 7.14 (d, 1H, J=8.9Hz), 5.40-5.20 (m, 1H), 4.44-4.39 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.17 (q, 2H, J=7.0Hz), 3.58 (s, 3H), 3.25-3.16 (br.-t, 2H), 3.02-2.96 (m, 2H), 1.87-1.83 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.52 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1705, 1659, 1573, 1511, 1493, 754. Melting Point (methanol-water): 227-228°C Reference Example 26 6-Bromo-3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound aa) 1 H-NMR (CDCl 3 ) δ: 8.33 (d, 1H, J=2.6Hz), 7.76 (dd, 1H, J=8.9, 2.6Hz), 7.18 (s, 1H), 7.14 (s, 1H), 7.08 (d, 1H, J=8.9Hz), 5.30-5.20 (m, 1H), 4.45-4.40 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.17 (q, 2H, J=7.0Hz), 3.58 (s, 3H), 3.25-3.16 (br.-t, 2H), 3.06-2.93 (m, 2H), 1.86-1.82 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.52 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1727, 1683, 1594, 1514, 1270. Melting Point (methanol-water): 247-248°C Reference Example 27 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline (Compound bb) 1 H-NMR (CDCl 3 ) δ: 11.86 (br.-s, 1H, NH), 8.92 (d, 1H, J=2.0Hz), 8.36 (dd, 1H, J=8.5, 2.0Hz), 7.31 (d, 1H, J=8.5Hz), 7.19 (s, 1H), 7.15 (s, 1H), 5.30-5.20 (m, 1H), 4.51-4.46 (br.-d, 2H), 4.23 (q, 2H, J=7.0Hz), 4.18 (q, 2H, J=7.0Hz), 3.30-3.21 (br.-t, 2H), 3.04-2.95 (m, 2H), 1.90-1.85 (br.-d, 2H), 1.53 (t, 3H, J=7.0Hz), 1.53 (t, 3H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1721, 1691, 1675, 1334. Melting Point (ether): 177-180°C Reference Example 28 3-[1-(2-Chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline (Compound cc) 1 H-NMR (CDCl 3 ) δ: 9.08 (d, 1H, J=2.6Hz), 8.51 (dd, 1H, J=9.0, 2.6Hz), 7.32 (d, 1H, J=9.0Hz), 7.17 (s, 1H), 7.14 (s, 1H), 5.31-5.23 (m, 1H), 4.46-4.41 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.18 (q, 2H, J=7.0Hz), 3.67 (s, 3H), 3.27-3.18 (br.-t, 2H), 3.06-2.92 (m, 2H), 1.88-1.85 (br.-d, 2H), 1.53 (t, 6H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1710, 1665, 1616, 1334, 1230, 1025. Melting Point (methanol-water): 239-241°C Reference Example 29 6-Acetyl-3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound dd) 1 H-NMR (CDCl 3 ) δ: 8.76 (d, 1H, J=2.0Hz), 8.31 (dd, 1H, J=8.9, 2.0Hz), 7.29 (d, 1H, J=8.9Hz), 7.17 (s, 1H), 7.15 (s, 1H), 5.30-5.10 (m, 1H), 4.45-4.41 (br.-d, 2H), 4.22 (q, 2H, J=7.0Hz), 4.18 (q, 2H, J=7.0Hz), 3.64 (s, 3H), 3.27-3.18 (br.-t, 2H), 3.07-3.00 (m, 2H), 2.67 (s, 3H), 1.89-1.85 (br.-d, 2H), 1.53 (t, 6H, J=7.0Hz). IR (KBr tab.)(cm -1 ): 1708, 1685, 1655, 1615, 1543, 1512, 1235. Melting Point (methanol-water): 204-206°C Industrial Applicability The present invention provides quinazoline derivatives and pharmaceutically acceptable salts thereof which have adenosine uptake inhibitory activity and are useful for the protection of myocardium and for the prevention or treatment of inflammation such as leg and foot edema.

Claims: A quinazoline derivative represented by formula (I): wherein R 1 represents i) hydrogen, ii) C 1 -C 8 alkyl, iii) C 1 -C 8 alkyl substituted with 1 to 3 substituents, the same or different, selected from halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino and phthalimido, iv) C 2 -C 6 alkenyl, v) C 7 -C 13 aralkyl, or vi) C 7 -C 13 aralkyl substitued with 1 to 3 substituents on the benzene ring thereof, the same or different, selected from halogen, C 1 -C 8 alkyl, nitro, cyano, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, methylenedioxy, and trifluoromethyl; R 2 , R 3 , R 4 , and R 5 independently represent i) hydrogen, ii) halogen, iii) amino, iv) mono- or di(C 1 -C 8 alkyl)amino. v) C 2 -C 9 alkanoylamino, vi) nitro, vii) cyano, viii) C 1 -C 8 alkyl, ix) C 1 -C 8 alkyl substituted with 1 to 3 substituents, the same or different, selected from halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino and phthalimido, x) hydroxy, xi) C 1 -C 8 alkoxy, xii) C 1 -C 8 alkylthio, xiii) carboxy, xiv) C 1 -C 8 alkoxycarbonyl, xv) C 2 -C 9 alkanoyl, xvi) C 7 -C 13 aralkyloxy, or xvii) C 2 -C 9 alkanoyloxy; R 6 , R 7 , R 8 , and R 9 independently represent i) hydrogen, ii) C 1 -C 8 alkyl, iii) hydroxy, iv) C 1 -C 8 alkoxy, v) C 1 -C 8 alkoxy substituted with 1 to 3 substituents, the same or different, selected from halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino and phthalimido, or vi) C 7 -C 13 aralkyloxy, or any adjoining two of them are combined to form methylenedioxy or ethylenedioxy; R 10 represents i) hydrogen, ii) C 1 -C 8 alkyl, or iii) halogen; R 11 and R 12 independently represent i) hydrogen, ii) C 1 -C 8 alkyl, iii) C 1 -C 8 alkyl substituted with 1 to 3 substituents, the same or different, selected from halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino and phthalimido, iv) C 3 -C 8 cycloalkyl. v) phenyl. vi) phenyl substituted with 1 to 3 substituents on the benzene ring thereof, the same or different, selected from halogen, C 1 -C 8 alkyl, nitro, cyano, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, methylenedioxy, and trifluoromethyl, vii) C 7 -C 13 aralkyl, viii) C 7 -C 13 aralkyl substitued with 1 to 3 substituents on the benzene ring thereof, the same or different, selected from halogen, C 1 -C 8 alkyl, nitro, cyano, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, methylenedioxy, and trifluoromethyl, or R 11 and R 12 are combined together with N to form ix) a heterocyclic group selected from pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, and homopiperazinyl or x) an above heterocyclic group substituted with 1 to 3 substituents, the same or different, selected from halogen, C 1 -C 8 alkyl, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, trifluoromethyl, phenyl, and C 7 -C 13 aralkyl; and n represents 0, 1 or 2, and a pharmaceutically acceptable salt thereof. The compound according to claim 1 wherein R 1 represents hydrogen or C 1 -C 8 alkyl. The compound according to claim 1 wherein R 2 , R 3 , R 4 , and R 5 independently represent hydrogen, halogen, nitro, C 1 -C 8 alkyl, or C 2 -C 9 alkanoyl. The compound according to claim 1 wherein R 6 , R 7 , R 8 , and R 9 independently represent hydrogen or C 1 -C 8 alkoxy, or any adjoining two of them are combined to form methylenedioxy. The compound according to claim 1 wherein R 11 and R 12 independently represent i) hydrogen, ii) C 1 -C 8 alkyl, iii) C 1 -C 8 alkyl substituted with 1 to 3 substituents, the same or different, selected from halogen, nitro, cyano, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, C 3 -C 8 cycloalkyl, amino, mono- or di(C 1 -C 8 alkyl)amino and phthalimido, or iv) C 7 -C 13 aralkyl, or R 11 and R 12 are combined together with N to form v) a heterocyclic group selected from pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, and homopiperazinyl or vi) an above heterocyclic group substituted with 1 to 3 substituents, the same or different, selected from halogen, C 1 -C 8 alkyl, amino, mono- or di(C 1 -C 8 alkyl)amino, hydroxy, C 1 -C 8 alkoxy, carboxy, C 1 -C 8 alkoxycarbonyl, C 2 -C 9 alkanoyl, trifluoromethyl, phenyl, and C 7 -C 13 aralkyl. The compound according to claim 1 wherein n represents 0. The compound according to claim 5 wherein said heterocyclic group formed by R 11 and R 12 combined together with N is morpholino.

Inventors: FUJIWARA SHIGEKI, KARASAWA AKIRA, MORIYAMA TAKAHIRO, NONAKA HIROMI, OKAMURA YUKO, TAKI HARUKU, YAO KOZO, FUJIWARA, SHIGEKI, KARASAWA, AKIRA, MORIYAMA, TAKAHIRO, NONAKA, HIROMI, OKAMURA, YUKO, TAKAI, HARUKI, YAO, KOZO
Applicants: KYOWA HAKKO KOGYO KK, KYOWA HAKKO KOGYO CO., LTD.
Application year: 1995
Main classification: C07D401
IPC codes: A61K31, A61P43, A61P9, C07D401