WO1999019326A1 - Piperidine derivatives - Google Patents

Abstract

Piperidine derivatives represented by general formula (I) or pharmacologically acceptable salts thereof: wherein R1 represents hydrogen, (un)substituted lower alkyl, etc.; R?2, R3, R4 and R5¿ may be the same or different and each represents halogeno, amino, mono- or di(lower alkyl)amino, (un)substituted lower alkanoylamino, etc.; n represents 0, 1 or 2; X-Y represents either formula (a) or formula (b): and Q represents formula (i), (ii), (iii), (iv) or (v).

Description

 Specification

 Piperidine derivative

Technical field

 The present invention relates to a piperidine derivative or a pharmacology thereof, which has an adenosine uptake inhibitory activity and is useful as a drug for preventing or treating inflammation such as myocardial protection, renal diseases (nephritis, diabetic nephropathy, etc.), tengitis, and foot edema. Permissible salts.

Background art

 Among the 1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivatives having a 1- (6,7-dimethoxy-4-quinazolyl) -4-piperidinyl group at the 3-position, position 6 is hydrogen, Compounds of a chlorine atom and a nitro group are described in Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), Vol. 38, pp. 1591-1595 (1990). In addition, International Publications W094 / 19342, WO96 / 06841, and JP-A-8-151377 describe quinazoline derivatives having an adenosine uptake inhibitory action. Further, compounds having an inhibitory effect on adenosine uptake are known to have a cardioprotective effect [Circulation, Vol. 80, pp. 1400-1411 (1989); · Physiology (Am. J.

 Physiol.), 30, H1570-1577 (1991); Journal of Cardiovas Pharmacol. 'J. Cardiovas Pharmacol., 20, 173-178 (1992)].

 Disclosure of the invention

 An object of the present invention is to protect myocardium from myocardial injury due to anoxia such as ischemia and reperfusion injury or hypoxia by inhibiting nucleoside uptake into cells and increasing extracellular adenosine concentration. Another object of the present invention is to provide a piperidine derivative or a pharmacologically acceptable salt thereof useful as an agent for preventing or treating inflammation such as renal disease (nephritis, diabetic nephropathy), inflammation or foot edema.

The present invention provides a compound of the formula (I)

Wherein Ri represents hydrogen, substituted or unsubstituted lower alkyl or halogen, and R ² , R ³ , R 4 and R 5 are the same or different and are hydrogen, halogen, amino, mono or di-lower alkylamino, substituted or Unsubstituted lower alkanoylamino, nitro, cyano, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or Represents an unsubstituted lower alkanol, substituted or unsubstituted aralkyloxy or substituted or unsubstituted lower alkanoyloxy, n represents 0, 1 or 2, and X—Y represents the formula (a) or the formula (b )

,-(a) tf = (b)

R ⁶ OR ⁷

(Wherein, R ⁶ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl, and R ⁷ represents hydrogen, hydroxy, Represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted lower alkylthio. (I), equation (ii), equation (iii), equation (iv) or equation (V)

[Wherein, R ⁸ and R ⁹ are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. , Rio is hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, halogen or NR12R13 (wherein R12 and

Ri ³ is the same or different and represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or R ¹² and R ¹³ represents represents) a substituted or unsubstituted heterocyclic group formed by including a together a connexion N, Rii is hydrogen, substituted or unsubstituted lower alkyl, Shiano, carboxy or substituted or unsubstituted Represents a lower alkoxycarbonyl, and Z represents 0 or S]] or a pharmacologically acceptable salt thereof. Hereinafter, the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds having other formula numbers.

In the definition of each group of the formula (I), lower alkyl and lower alkyl of mono- or di-lower alkylamino, lower alkanoylamino, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio The moiety may be a linear or branched C1-C8, e.g., methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, etc., and the lower alkenyl is a straight-chain or branched carbon atom having 2 to 2 carbon atoms. 6, for example, vinyl, aryl, methyl crotyl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl and the like. 10, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The aralkyl portion of aralkyl and aralkyloxy includes 7 to 15 carbon atoms, such as benzyl, phenethyl, Benzhydryl, naphthylmethyl and the like. Examples of the heterocyclic group include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, hexamethyleneimino and the like. Examples of aryl include phenyl, naphthyl, biphenyl, anthryl and the like. Halogen means fluorine, chlorine, bromine and iodine atoms.

Substituted lower alkyl, substituted lower alkylthio, substituted lower alkoxy, substituted lower alkanoylamino, substituted alkoxycarbonyl, substituted lower alkanoyl, substituted lower alkanoyloxy and substituted lower alkenyl have the same or different substituents. 1-3 halogen, nitro, cyano, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanol, cycloalkyl, amino, mono- or di-lower alkylamino, phthalimid and the like. Substituents of substituted aryl, substituted aralkyl, substituted aralkyloxy and substituted cycloalkyl may be the same or different and have 1 to 3 halogen atoms, lower alkyl, nitro, cyano, amino, mono- or di-lower alkylamino, hydroxy, Lower alkoxy, carbonyl, lower alkoxycarbonyl, lower alkanol, methylenedioxy, trifluoromethyl and the like. Substituents of the substituted heterocyclic groups may be the same or different and have 1 to 3 substituents such as halogen, lower alkyl, amino, mono- or di-lower alkylamino, hydroxy, lower alkoxy, carboxy, lower alkoxyl ponyl, lower alkanol, and lower alkanol. Rifluoromethyl, aryl, aralkyl and the like.

 In the definition of each substituent, halogen, lower alkoxy, lower alkoxycarbonyl, lower alkanol, cycloalkyl, mono- or di-lower alkylamino, lower alkyl, aryl and aralkyl have the same meanings as described above.

 Examples of the pharmacologically acceptable salt of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.

 Pharmaceutically acceptable acid addition salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., acetate, maleate, fumarate, tartrate, quencher And pharmaceutically acceptable metal salts, for example, alkali metal salts such as sodium salt and potassium salt, and alkaline earth salts such as magnesium salt and calcium salt. Metal salts, aluminum salts, zinc salts, and the like, and pharmacologically acceptable ammonium salts include, for example, salts of ammonium, tetramethylammonium, and the like, and pharmacologically acceptable organic salts. Examples of amine addition salts include addition salts of morpholine and piperidine, and examples of pharmacologically acceptable amino acid addition salts include lysine, glycine, and phenylalanine. Addition salts, and the like.

 Next, the method for producing the compound (I) and the intermediate will be described.

 In the following production methods, if the defined group changes under the conditions of the method or is inappropriate for carrying out the method, methods for introducing and removing protecting groups commonly used in organic synthetic chemistry are used. [For example, Protective Groups in Organic Synthesis> Protective Groups in Organic Synthesis> TW Greene, John Wiley 'and' Sons Inc. ) (1981)] to obtain the target compound. In addition, the order of the reaction steps such as the introduction of a substituent can be changed as necessary.

Production method 1: Compound (I) can be produced according to the following reaction steps.

 (Wherein, Q, X, Y, Ri to R5 and n represent the same meaning as described above, and L represents chlorine, bromine, or iodine)

 (Process 1)

 Compound (I) is obtained by combining compound (II) (for example, it can be synthesized according to the method disclosed in International Publication W094 / 19342 or JP-A-8-151377) with 1-2 equivalents of compound (III). If necessary, 1-3 equivalents of amines such as triethylamine and pyridin, and salts of alkali metals such as sodium carbonate and potassium carbonate, etc., and a suitable solvent, for example, lower alcohols such as methanol, ethanol, isopropanol, etc. Cyclic ethers such as tetrahydrofuran (THF) and 1,4-dioxane, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidinone, dimethylsulfoxide (DMSO) and the like or a mixed solvent thereof The reaction can be performed at a temperature from room temperature to the boiling point of the solvent used for 10 minutes to 48 hours.

 Production method 2: In compound (I), Q is a compound of formula (i-a)

(Wherein Z, R ⁹ and Rio have the same meanings as described above) can also be produced according to the following reaction steps.

 (Wherein, X, Y, Z, Ri ~! 15, R9, Rio, L and n have the same meanings as above)

(Step 2-1)

 Compound (V-a) is composed of compound (II) and compound (IV) (for example,

It can be synthesized according to the method disclosed in WO94 / 06648) according to the method of Step 1.

 (Step 2-2)

Compound (Vb) can be obtained by subjecting the nitro group of compound (Va) to, for example, catalytic reduction or reduction using a metal. Catalytic reduction is usually carried out at room temperature and normal pressure in the presence of a catalyst such as a catalytic amount of 10 to 10 equivalents of Raney nickel, palladium carbon, platinum oxide, etc., and a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, and acetic acid. It can be performed in water or the like. Reduction using a metal is, for example, 1 to The reaction is carried out at a temperature from room temperature to the boiling point of the solvent used under conditions such as 100 equivalents of zinc monoacetic acid, iron monoacetic acid, iron-ferric chloride-ethanol monohydrate, iron monohydrochloride, and tin monohydrochloride.

 (Steps 2-3)

 Of the compound (Ia), the compound in which Z is 0 is the compound (Vb) and one or more equivalents of Ν, Ν′-carbonyldiimidazole, phosgene, etc., and a catalytic amount as necessary: L0 equivalent of triethylamine In the presence of a base such as amines such as pyridine and pyridine, a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol; cyclic ethers such as THF and 1,4-dioxane; halogenation such as dichloromethane and chloroform. It can be obtained by reacting in a hydrocarbon, ethyl acetate, ether, acetonitrile, DMF, DMSO, or the like, or a mixed solvent thereof at a temperature from 0 to the boiling point of the used solvent for 10 minutes to 48 hours.

 (Step 2— 4)

 Among the compounds (Ia), those in which Z is represented by S are compound (Vb) and at least one equivalent of Ν, Ν'-thiocarbonyldiimidazole, carbon disulfide, tiophosgene, etc. In the presence of a base such as amines such as triethylamine and pyridine in an amount of up to 10 equivalents, a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol; cyclic ethers such as THF and 1,4-dioxane; dichloromethane , In ethyl acetate, ether, acetonitrile, DMF, DMSO, etc., or a mixture thereof, at a temperature from 0 ° C to the boiling point of the solvent used, for 10 minutes to It can be obtained by reacting for 48 hours.

 Production method 3: In compound (I), Q is a compound represented by formula (i-b)

(ib)

(Wherein, Z, R ⁹ and Rio have the same meanings as described above, and RSa represents other than hydrogen in the definition of R ⁸ ). can do.

(Wherein, X, Y, Z, Ri~ ! L 5, R8a, R9, Rio, L and n to table the same meaning as defined above)

 (Process 3)

Compound (Ib) is obtained by combining compound (Ia) with 1-2 equivalents of a compound represented by R ⁸ aL (wherein and L have the same meanings as described above), and 1-2 equivalents of a base such as water. 10 minutes in a suitable solvent, for example, THF, DMF, acetone, methyl ethyl ketone, etc., in the presence of sodium iodide, potassium carbonate, cesium carbonate, etc., at a temperature between 0 ° C and the boiling point of the solvent used It can be obtained by reacting for up to 24 hours. Production method 4: In compound (I), Q is a compound of formula (ic)

^{(Wherein, Z, R 8, R 9} , Ri 2 and R1 ³ symbols are as defined above) and a compound represented by (Id) can also be prepared according to the following reaction step.

(Wherein, Y, Z, Ri ~ !, 15, R8, R9, R12, R13 and _n have the same meanings as above, and RlOa represents chlorine, bromine or iodine in the definition of R10)

(Step 4)

The compound (Id) is the same as the compound (Ic) in which Rio is chlorine, bromine or iodine of the compound (Ib) but in an amount of 1 equivalent to a solvent amount of the formula R ¹² R ¹³ NH (where Ri ² and Ri ³ are An amine represented by the following formula) is optionally used in the presence of a base such as an amine such as triethylamine, pyridine or an alkali metal carbonate such as sodium carbonate or potassium carbonate in an amount of 10 to 10 equivalents of a catalyst, if necessary. Solvents, for example, lower alcohols such as methanol, ethanol, and isopropanol; cyclic ethers such as THF and 1,4-dioxane; DMF, DMA, N-methylpyrrolidinone, DMSO, etc .; or a mixed solvent of these, if necessary, in a sealed tube At a temperature from room temperature to the boiling point of the solvent used for 10 minutes to 72 hours. Further, if necessary, a catalytic amount of iodinated lime, sodium iodide or the like may be appropriately added during the reaction <Ri ² Ri ³ NH (wherein Ri ² and Ri ³ represent the same meaning as described above.) When primary amine is used as the amine represented by) and DMF is used as the solvent, the compound

A compound in which both Ri ² and Ri ³ in (Id) are methyl can be obtained. Production method 5: In compound (I), Q is a compound represented by formula (ii-a)

Ten

^{(Wherein, Z, R 8, R 9} , Ri 2 and R1 ³ symbols are as defined above) and a compound represented by (If) can be prepared according to the following reaction steps.

(Wherein, X, Y, Ζ, R1 to! 5, R8, R9, R10a, R12, R13 and _n represent the same meaning as described above)

 (Process 5)

 Compound (I-f) can be obtained from compound (I-e) according to the method of Step 4.

 Production method 6: Of compound (I), (¾ is a compound of formula (iii-a)

(Wherein, Z, R ⁸ , R9, Rii, R12 and R13 represent the same meaning as described above) Compound (Ih) can also be produced according to the following reaction steps,

(Wherein, X, Y, Ζ, represents a _{R1~R5, R8, R9, Rl 0a} , Rll, R12, R13 and _n are as defined above)

 (Step 6)

Compound (Ih) is, Ru can be obtained from compound (I- _g) to the method of Step 4.

 Production method 7: In compound (I), Q is a compound of formula (iv-a)

^{(Wherein, Z, R 8, R 9} , Ri 2 and R1 ³ symbols are as defined above) and a compound represented by (Ij) can be prepared according to the following reaction steps.

 Process 7

 R, χ '

 (i-j)

(In the formula, X, Y, Ζ, R ^1- ! L ⁵ , R ⁸ , R ⁹ , R ^10a , R ¹² , R ¹³ and n represent the same meaning as described above.)

 (Step 7)

 Compound (I-j) can be obtained from compound (I-i) according to the method of Step 4.

Production method 8: In compound (I), Q is a compound of formula (iv-b)

(Wherein, Z, Rs and R ⁹ represents the same meanings as defined above) is represented by a compound Rio is table with hydrogen (1-1) can also be prepared according to the following reaction step.

One R,

(Wherein, X, Y, Z, Ri to R5, R8, R9 and _n represent the same meaning as described above)

 (Process 8)

 Compound (1-1) can be obtained by dehydrogenating compound (I-k) obtained in Production Method 1. The dehydrogenation reaction is usually carried out using 1 to 100 equivalents of potassium permanganate, palladium on carbon, etc., in a suitable solvent such as water, acetone, nitrobenzene, or a mixed solvent thereof at room temperature to the boiling point of the solvent used. At temperatures up to 1 ~: done in 168 hours.

Production method 9: In compound (III) in production method 1, Q is a compound of the formula (id)

(Wherein R ⁸ and R ⁹ have the same meanings as described above). (ΠΙ-a) can be produced according to the following reaction steps.

Process 9 1 2 (Wherein, L, R ⁸ and R ⁹ have the same meanings as above, and Ri ⁴ represents hydrogen or lower alkyl)

Here, the lower alkyl represented by Ri ⁴ has the same meaning as the lower alkyl. (Step 9-1 1)

 Compound (VII) is obtained by subjecting compound (VI) (for example, which can be synthesized according to the method disclosed in JP-A-61-207388) to alkylation according to the method of Step 3, and then adding acetic acid Using a solvent such as sulfuric acid, sulfuric acid or the like, or without a solvent, reducing the nitrous body obtained by the action of an equivalent or excessive amount of a nitrifying agent such as nitric acid or fuming nitric acid according to the method of Step 2-2 Can be obtained. The nitration reaction is usually performed at -30 to: 1 OCTC for 1 minute to 24 hours.

 (Step 9-1 2)

 Compound (VIII) can be obtained by reacting compound (VII) with a large excess of formamide in the absence of a solvent at room temperature to the boiling point of formamide for 1 to 24 hours.

 (Step 9-3)

 Compound (ΠΙ-a) is obtained by reacting compound (VIII) with a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride or phosphorus tribromide in an amount of 1 equivalent to solvent without solvent or dichloromethane or 1,2-dichloromethane. It can be obtained by reacting in an inert solvent such as a solvent at room temperature to the boiling point of the solvent used, or in the absence of solvent at a temperature from room temperature to the boiling point of the halogenating agent used for 1 to 24 hours it can.

 Production method 10: Of compound (III) in production method 1, Q is a compound represented by the formula (i-e)

(Wherein R ⁸ , R ⁹ and Rioa have the same meanings as described above) (III- b) can be produced according to the following reaction steps

 (Wherein, R8, R9, R10a, R14 and L are as defined above)

 (Step 1 0— 1)

 Compound (IX) is obtained by reacting compound (VII) obtained in step 911 with a large excess of urea in the absence of a solvent at room temperature to the boiling point of urea for 1 to 24 hours. Can be.

 (Step 10 _ 2)

 Compound (ΠΙ-b) can be obtained by halogenating compound (IX) according to the method of Steps 9-13.

 Production method 1 1: In compound (III) in production method 1, Q is a compound of formula (ii-b)

(Wherein R ⁸ , R ⁹ and Rioa have the same meanings as described above). (III-c) can be produced according to the following reaction steps.

 (Wherein, R8, R9, R10a, R "and L are as defined above)

 (Step 1 1— 1— 1)

 Compound (XI) can be synthesized according to the method described in compound (X) [for example, Journal of Heterocycl. Chem., 10, 891 (1973). Is cyclized according to the method of Step 2-3, and then alkylated according to the method of Step 3.

 (Step 1 1— 1— 2)

 Compound (XII) can be obtained by converting compound (XI) with 1 equivalent to a solvent amount of hydrazine, if necessary, in the presence of a 1 equivalent to a solvent amount of a suitable base such as triethylamine, in a suitable solvent, for example, a lower solvent such as methanol or ethanol. It can be obtained by reacting in an alcohol at a temperature from room temperature to the boiling point of the solvent used for 1 to 24 hours. Compound (XII) can also be obtained according to the following method.

 (Step 1 1—2-1)

The compound (XIV) can be synthesized from the compound (XIII) according to the method described in Step 3 (for example, the compound can be synthesized according to the method described in Tetrahedron Lett., Vol. 28, p. 1389 (1987)). After alkylation according to And can be obtained by Oxidation is carried out, for example, with 1 to 10 equivalents of an appropriate oxidizing agent such as potassium permanganate, chromium trioxide, sodium dichromate, etc.

In the presence of 1 to 10 equivalents of a suitable base such as sodium hydroxide, in a suitable solvent, for example, water, acetone, acetic acid, sulfuric acid, t-butyl alcohol, etc. At a temperature of

 (Process 1 1 1 2 _ 2)

 Compound (XII) can also be obtained according to the method of Step 111, except that compound (XIV) is used instead of compound (XI).

 (Step 11-3)

 Compound (III-c) can be obtained by halogenating compound (XII) according to the method of Step 9-13.

 Production method 1 2: Of compound (III) in production method 1, Q is a compound of formula (iii-b)

(Wherein R ⁸ , R ⁹ , Rio and R ¹¹ are as defined above) can be produced according to the following reaction steps.

( _Wherein , R8, _R9 , R10, R11 and L are as defined above)

 (Process 1 2)

Compound (Illd) can be synthesized according to the method disclosed in compound (XV) (for example, JP-A-54-154797, JP-A-56-7784). ) Can be obtained by halogenating according to the method of Step 9_3.

Production method 13: Of compound (III) in production method 1, Q is represented by formula (iii-c)

(Wherein R ⁸ , R ⁹ , Rioa and Rii have the same meanings as described above) can be produced according to the following reaction steps.

 (Wherein, R8, R9, R10a, R11 and L are as defined above)

 (Process 13)

 Compound (ΙΠ-e) can be obtained by converting compound (XVI) (for example, which can be synthesized according to the method disclosed in JP-A-54-154797) with halogen according to the method of Steps 9-1-3. Can be obtained.

 Production method 14: Of compound (III) in production method 1, Q is a compound of formula (iv-c)

(Wherein R ⁸ , R ⁹ and Rioa have the same meanings as described above) can be produced according to the following reaction steps.

(Wherein, R ⁸ , R ⁹ , Rioa and L are as defined above)

 (Process 1 4 1 1)

 The compound (XVIII) is the same as the compound (XVII) [for example, J. Heterocycl. Chem., 18, 85, 1981, Tetrahedron Lett ), P. 79 (1976) or a method analogous thereto], and, for example, 1-2 equivalents of 3-chloropropionyl chloride and the like, and 1-2 equivalents of aluminum chloride and zinc chloride. In a suitable solvent, for example, nitrobenzene, carbon disulfide, dichloromethane, at a temperature from 0 to the boiling point of the used solvent for 1 to 24 hours, and then 1 equivalent to a solvent amount of sulfuric acid, etc. Under the temperature of 0 ° C. to the boiling point of the solvent used for 10 minutes to 24 hours.

 (Step 14-2)

Compound (ΙΠ-f) is prepared by combining compound (XVIII) with 1 equivalent to a solvent amount of isoamyl nitrite or the like in the presence of a suitable acid such as hydrochloric acid in a suitable solvent such as a lower alcohol such as methanol or ethanol. After reacting at -20 to the boiling point of the solvent used for 1 to 24 hours to obtain an oxime compound, 1 equivalent to the solvent amount of halogen such as phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, etc. A solvent and, if necessary, in the presence of a suitable acid such as hydrochloric acid, in a solvent-free or in an inert solvent such as dichloromethane or 1,2-dichloroethane, at a temperature from room temperature to the boiling point of the solvent used. In this case, it can be obtained by reacting at a temperature from room temperature to the boiling point of the halogenating agent used for 1 to 24 hours. Production method 15: Of compound (III) in production method 1, Q is a compound of formula (iv-b) (iv-b)

(Wherein, Rs and R ⁹ represents as defined above) and a compound represented by _(III-g) can be prepared by the following reaction steps.

 (in-g)

(Wherein, R ⁸ , R ⁹ and L represent the same meaning as described above)

 (Step 15-1) ''

 Compound (XX) is synthesized according to the method described in Compound (XIX) [for example, the method described in the journal “Job Med.”, J. Med. Chem., 23, 506 (1980)). Can be obtained according to the method of Step 8.

 (Process 1 5 _ 2)

 Compound (III-g) can be obtained by halogenating compound (XX) according to the method of Step 9-3.

 Production method 16: Of compound (III) in production method 1, Q is a compound of formula (v-a)

(Wherein, Rs and R ⁹ have the same meanings as described above). (ΙΠ-h) can be produced according to the following reaction steps.

(Wherein, R ⁸ , R ⁹ and L represent the same meaning as described above)

 (Step 16)

 Compound (Ill-h) can be obtained from compound (XX) in Production Method 15 by halogenation according to the method of Steps 9-13.

In compound (I), a compound having at least one amino group, mono- or di-lower alkylamino group or a lower alkanoyloxy Noi Rua amino group R ² to R ⁵ are the corresponding R ² ~! It can also be produced by reducing the compound (I) having a nitro group at ⁵ , and further alkylating or acylating the compound if necessary. The reduction can be performed by a conventional method using, for example, catalytic reduction or a metal. Contact reduction is usually carried out at room temperature and atmospheric pressure in the presence of a catalyst such as a catalytic amount of 10 equivalents of Raney Nickel Palladium Carbon, Platinum Oxide, etc., and a suitable solvent such as methanol, ethanol, ethyl acetate. , Dioxane, THF, acetic acid and the like for 10 minutes to 48 hours. The reduction using a metal can be carried out under the conditions of, for example, 1 to 100 equivalents of zinc monoacetic acid, iron-acetic acid, iron monoferric chloride monoethanol monohydrate, iron monohydrochloric acid, tin monohydrochloric acid, and the like. It takes 10 minutes to 48 hours at the boiling point. Alkylation and acylation of the reduction product can be carried out by using 1 to 2 equivalents of a conventional alkylating agent (eg, an alkyl octide such as methyl iodide) or an acylating agent (eg, an acid anhydride such as acetic anhydride). 1 to 2 equivalents of a base such as pyridine, triethylamine, an alkyl metal hydroxide, or an alkyl metal carbonate, and Z or chloroform, dichloromethane, THF, 1,4-dioxane. The reaction is carried out for 10 minutes to 48 hours at 0 to the boiling point of the used solvent in the presence of a solvent such as a solvent. In compound (I), R2 ~! Compounds having at least one hydroxy-substituted alkyl group at 15 have the corresponding R ² ! And cowpea in reducing or alkylating Compound (I) which have a Al force Noiru substituted alkyl group in I ⁵ can also be produced. The reduction is performed using a reducing agent such as lithium aluminum hydride or sodium borohydride in a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, etc., usually at -78: to room temperature. It can take 10 minutes to 48 hours. Alkylation is carried out using a conventional organometallic reagent, for example, a Grignard reagent such as methylmagnesium amide, ethylmagnesium chloride, or the like, an organic lithium reagent such as methyllithium, butyllithium, or the like, using a suitable solvent, for example, dioxane, It is usually carried out in ether, THF, etc. at -78 to room temperature for 10 minutes to 48 hours.

In the compound (I), R ² ~! Compounds having at least one carboxy group in I ⁵ can be cowpea in subjecting the corresponding compounds having a Asechiru group R ² to R ⁵ (I) is in the haloform reaction can be produced. The haloform reaction is carried out according to the method described in Journal of American's Chemical Society (J. Am. Chem. Soc .;), Vol. 72, p. 1642 (1950), etc., by chlorine or bromine and water. This is performed using a sodium hypohalite solution prepared from an aqueous sodium oxide solution.

In the compound (I), the compound having at least one hydroxy group in R ^{2 to} R ⁵ corresponds to the corresponding R ² to! ^The compound (I) having a lower alkoxy group in ⁵ can also be produced by dealkylation. The dealkylation is carried out, for example, in the presence of 1 equivalent to a solvent amount of an acid such as hydrobromic acid or hydroiodic acid, in the absence of a solvent or in a solvent such as water, acetic acid, methanol, or a lower alcohol such as ethanol, or Force in a solvent such as DMF, DMSO, etc. in the presence of one or more equivalents of a thiol, such as ethanethiol or thiophenol, in the presence of a metal salt (sodium salt, potassium salt, etc.), or 1 to: L0 equivalent of trichloride The reaction can be carried out in a solvent such as dichloromethane in the presence of a Lewis acid such as hydrogen, boron tribromide or aluminum trichloride. The reaction is room The reaction is carried out at a temperature from the boiling point of the solvent used and ends in 30 minutes to 48 hours.

In the compound (I), the compound having at least one lower alkoxy group in R ^{2 to} R ⁵ corresponds to the corresponding R ² to! ⁵ to 1 to 2 equivalents of a lower alkyl halide from a compound (I) having a hydroxy group in an inert solvent such as 1 to 2 equivalents of a base such as sodium hydride, potassium carbonate, cesium carbonate, etc. It can also be produced by reacting in THF, DMF, acetone, methyl ethyl ketone or the like at 0 to the boiling point of the used solvent for 10 minutes to 24 hours.

In compound (I), a compound having at least one carboxy sheet group R2~R5 or Rii the corresponding R ² ~; R ⁵ or a compound having a lower Arukokishikaru Boniru group R ¹¹ (I) hydrolyzes It can also be manufactured. The hydrolysis is carried out, for example, in the presence of 1 equivalent to a solvent amount of an acid such as sulfuric acid, hydrochloric acid, or hydrobromic acid, or 1 to 10 equivalents of a base such as sodium hydroxide or hydroxylic lime, a suitable solvent such as water or methanol. The reaction can be carried out in a lower alcohol such as ethanol, ethanol or isopropanol, a cyclic ether such as THF or 1,4-dioxane, or a mixed solvent thereof. The reaction is carried out at room temperature to the boiling point of the solvent used, and is completed in 10 minutes to 48 hours.

In compound (I), compounds having a lower alkyl group R ^6, the corresponding compound having hydrogen in R ⁶ and lower alkyl payment de 1-2 equivalents from (I), 1 to 2 equivalents of a base, for example, The reaction is carried out in the presence of sodium hydride, potassium carbonate, cesium carbonate, etc. in an inert solvent such as THF, DMF, acetone, methyl ethyl ketone, etc. at 0 to the boiling point of the used solvent for 10 minutes to 24 hours. Can also be manufactured. In compound (I), a compound having hydrogen at Rio can also be produced by subjecting compound (I) having a corresponding halogen at Rio to the above-mentioned catalytic reduction reaction.

The intermediates and target compounds in the above production method are isolated and purified by purification methods commonly used in organic synthetic chemistry, for example, neutralization, filtration, extraction, drying, concentration, recrystallization, various chromatographies can do. In the case of intermediates, It can be used for the next reaction without purification.

 When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is, and if it can be obtained in the free form, it can be purified with an appropriate organic solvent. The salt may be formed by dissolving or suspending and adding an acid or a base.

 Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents. These adducts may also be used as the drug of the present invention. it can.

 Some of the compounds (I) may have stereoisomers such as optical isomers, cis-trans isomers, and diastereoisomers, but the present invention relates to all possible stereoisomers and Also included are mixtures thereof.

Table 1, Table 2, Table 3, Table 4, and Table 5 show specific examples of the compound (I) obtained by the above production method.

Table 1

Compound number ZR ⁸ R ⁹ R ¹⁰

1 0 H C2H5 H

Δ 0 CH ₃ n

3 Π3 2H5 H

4 0 C ₂ H ₅ H

5 0 nC ₃ H ₇ C ₂ H ₅ H

6 o nC ₃ H ₇ nC ₃ H ₇ n

7 0 nC ₄ H ₉ nC ₄ H ₉ H

8 0 CH ₃ CH ₃ CI

9 0 C ₂ H ₅ C ₂ H ₅ CI

12 0 C ₂ H ₅ C ₂ H ₅ r ~ \

13 0 nC ₃ H ₇ nC ₃ H ₇ r ~ \

 0

14 SHC ₂ H ₅ H

Table 2

Compound number ZR ⁸ R ⁹ R ¹⁰

15 0 HC ₂ H ₅ H

16 0 CH ₃ ^C 2 ^H 5 H

17 0 C ₂ H ₅ C ₂ H ₅ H

18 0 nC ₃ H ₇ ^C 2 ^H 5 H

19 SHC ₂ H ₅ H

Table 3 (1)

 10 Compound number R 'R

20 CH ₃ CH ₃ H

21 2 ^C 2 ^H 5 H

Δ2 ^η then 3 ^η 7 3 "7 H

23 iC ₃ H ₇ iC ₃ H ₇ H

24 I1-C4H9 nC ₄ H ₉ H

25 CH ₃ CH ₃ CI

26 C ₂ H ₅ C ₂ H ₅ CI

27 nC ₃ H ₇ nC ₃ H ₇ CI

28 iC ₃ H ₇ iC ₃ H ₇ CI

29 1 -C4H9 nC ₄ H ₉ CI

30 丄 i-C4H9 CI

31 CH ₂ CH = CH ₂ CH ₂ CH = CH ₂ CI

Table 3 (2)

Compound number R R 10

 R

32 CH2 CI

 a)

42 C ₂ H ₅ ^C 2 ^H 5 N (nC ₃ H ₇ ) ₂ a) Hydrochloride

b) dihydrochloride

 Compound No. 10

R ⁸ RR

 a)

43 C ₂ H ₅ C ₂ H ₅ NH (CH ₂ ) ₂ CH ₃ a)

) ₂

47 nC ₃ H _v nC ₃ H ₇

48 iC ₃ H ₇ iC ₃ H _v

49 nC ₄ H ₉ nC ₄ H ₉

_{50 nC 4 H 9 nC 4 H} 9 co N oH (CH 2) 2 CH 3 51 iC 4 H 9 1-C4H9

 N

52 CH2CH ⁼ CH2 CH ₂ CH = CH2

N .0 53 CH _{2 6} ii ₅ CH ₂ C ₆ H ₅

N \ IO a) Hydrochloride

Table 4

Compound number R ⁸ R ⁹ R ¹⁰ R ¹¹

54 C ₂ H ₅ HH

55 ^C 2 ^H 5 H C0 ₂ C ₂ H ₅

56 ^C 2 ^H 5 CH ₃ H

57 C ₂ h ₅ C ₂ H ₅ C ₂ H ₅ H

58 ^C 2 ^H 5 nC ₃ H ₇ H

59 psi 2 ⁿ 5 C ₂ H ₅ iC ₃ H _v H

60 C ₂ H ₅ CI H

Table 5

 Compound number Q

Next, the pharmacological action of a representative compound (I) will be described with reference to test examples.

Test Example 1: [ ³ H] —adenosine uptake inhibitory action

Blood of monosodium citrate was collected from the brachial vein of a healthy adult male (age less than 40 years), and washed red blood cells were obtained by centrifugation. To a red blood cell suspension (2.5 × 10 ⁹ / ml) 100 1 was added 10% of a 21% DMS0 solution of a test compound, and the mixture was allowed to stand at room temperature for 1 hour, followed by addition of 10 t 1 of [ ³ H] -adenosine solution. After 10 seconds, the reaction was stopped by adding 200 1 of dirazep solution (lmg / ml). Erythrocytes lysed with Triton Χ-1Ό0 Thereafter, the amount of ³ H taken in by a liquid scintillation counter was measured. The concentration (IC ₅₀ ) of the test compound that inhibited the incorporation of [ ³ H] -adenosine by 50% was calculated, and the results are shown in Table 6.

 Table 6

Compound number [ ³ H] —adenosine uptake inhibition

IC _o (nM)

 3 4 7

 1 7 3 2

 2 0 4 4

 2 1 2 3

 3 3 1 5

 4 2 5 4

 5 4 1 9

 Test Example 2: [3H] -Nitrobenzylthioinosine (NBI) binding inhibitory activity (an indicator of adenosine binding inhibitory activity)

A 1/25 volume (v / w) of ice-cold 50 mM Tris-HCl buffer, pH 7.4, was added to the cerebral cortex of a Hartle strain male guinea pig and homogenized. The homogenate was centrifuged (30000 × _g , 4 ° C., 20 minutes), the supernatant was discarded, and the same amount of buffer was added to the remaining precipitate. It was homogenized again and centrifuged similarly. The remaining precipitate was suspended by adding a 20-fold volume of buffer solution and used for the test.

1.5 nM of [ ³ H] -NBI and 5 mg (wet weight) of a tissue homogenate were added to a DMSO solution of the test compound, and the mixture was left at 25 ° C. for 30 minutes. Then, 4 ml of ice-cold buffer was added, and the reaction was stopped by rapid suction filtration on a glass filter Yuichi (GFZC Whatman) or a ready filter (Beckman). The filter was transferred to a scintillation vial, dried, added with Scintisol EX-H (Wako Pure Chemical Industries), and the radioactivity was measured with a liquid scintillation counter. The binding inhibitory action was represented by an inhibition constant (Ki value) calculated by the Cheng-Prusoff equation. The results are shown in Table 7. Table 7

Compound number [ ³ H]-NBI binding

 Value (n M) ―

 3 1 .5 0

 4 0. 4 4

 5 0 .6 3

 2 1 0. 2 4

 3 4 0. 1 2

 Compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmacologically acceptable salt thereof with a pharmacologically acceptable carrier as an active ingredient. Desirably, these pharmaceutical compositions are in unit dosage form suitable for administration orally or by injection.

 In preparing the compositions in oral dosage form, any useful pharmacologically acceptable carrier can be used. For example, oral liquid preparations such as suspensions and mouthwashes include water, sugars such as sucrose, sorbitol, fructose, daricols such as polyethylene glycol and propylene glycol, sesame oil, olive oil, It can be produced using oils such as soybean oil, preservatives such as P-hydroxybenzoic acid esters, and flavors such as stove belly flavor and peppermint. Powders, pills, capsules and tablets include lactose, glucose, sucrose, mannitol, etc., excipients, starch, sodium alginate, etc., disintegrants, magnesium stearate, talc, etc., polyvinyl alcohol, hydroxy It can be produced using a binder such as propylcellulose and gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unitary oral dosage forms because of their ease of administration. When producing tablets and capsules, solid pharmaceutical carriers are used.

Injectables are distilled water, salt solution, glucose solution or saline and glucose It can be prepared using a carrier consisting of a mixture of solutions. At this time, it is prepared as a solution, suspension or dispersion using an appropriate auxiliary according to a conventional method.

 Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally as an injection in the above-mentioned pharmaceutical form. Depending on age, weight, symptoms, etc., l ~ 900mg

/ 60kg _g day is appropriate.

 Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples.

Examples and EtOH in Reference Example, Et ₂ 0 and EtOAc respectively ethanol, representative of oxygenate chill ether and acetic acid Echiru.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Example 1 3-Ethyl-2,3-dihydro-8- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl)- 1-piperidinyl] -1Η-imidazo [4,5-g] quinazolin-2-one (Compound 1)

 First step: 3- [1- (7-ethylamino-6-nitroquinazoline-4-yl) -4-piperidinyl] -1,2,3,4-tetrahydro-1,6- obtained in Reference Example 1 Dissolve 320 mg (0.65 mmol) of dimethyl-2,4-dioxoquinazoline (compound a) in 20 ml of DMF, add 30 mg of 10% Pd / C, and vigorously stir at room temperature under a hydrogen atmosphere for 4 hours. Stir vigorously for hours. After allowing to cool, the reaction solution is separated by filtration using a filter aid, and the filtrate is concentrated to give 3- [1- (6-amino-7-ethylaminoquinazoline-4-yl) -4-piperidinyl]- 1,2,3,4-Tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline was obtained as 298 mg of a white oil.

Second step: 3- [1- (6-amino-7-ethylaminoquinazoline-4-yl) -4-piperidinyl] -1,2,3,4-tetrahydro-1 obtained in the first step , 6-Dimethyl-2,4-dioxoquinazoline 298 mg (0.65 mmol) was dissolved in acetonitrile 40 ml, Ν, Ν-carbonyldiimidazole 317 mg (1.95 mmol) was added, and the mixture was heated with stirring at 60 for 2 hours. . After allowing the reaction solution to cool, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: black-mouthed form Z methanol = 501). The residue was recrystallized from ethyl acetate to give the title compound (216 mg, yield 69%) as white crystals.

iH-NMR (CDCl ₃ ) δ (ppm): 8.72 (s, 1H), 8.01 (d, 1H, J = 1.3 Hz), 7.53 (s, 1H), 7.50 (dd, 1H, J = 8.6, 1.3 Hz) ), 7.43 (s, 1H), 7.11 (d, 1H, J = 8.6Hz), 5.35-5.26 (m, 1H), 4.32-4.29 (br.d, 2H), 4.03 (q, 2H, J = 7.0 Hz), 3.59 (s, 3H), 3.23-3.07 (m, 4H), 2.43 (s, 3H), 1.88-1.84 (br.d, 2H), 1.42 (t, 3H, J = 7.0Hz).

IR (KBr tab.) (Cm ¹ ): 1719, 1702, 1656, 1543, 1483, 1350, 1263.

mp (EtOAc): 226-229

 Example 2 2,3-Dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl) -1-piperidinyl] -1 , 3-Dimethyl-1H-imidazo [4,5-g] quinazolin-2-one (Compound 2)

 First step: 2,3,7,8-tetrahydro-1,3-dimethyl-1H, 7H-imidazo [4,5-g] quinazoline-2,8-dione obtained in Reference Example 2 (compound b) 230 mg (1.00 mmol) was dissolved in 5 ml of phosphorus oxychloride, a catalytic amount of triethylamine was added, and the mixture was heated under reflux for 1 hour. After allowing the reaction solution to cool, the solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, followed by extraction with chloroform. The organic layer is washed, dried, and the solvent is distilled off. 8-chloro-2,3-dihydro-1,3-dimethyl-1H-imidazo [4,5-g] quinazolin-2-one

 A crude product of (compound bb) was obtained.

Second step: The compound bb obtained in the first step is dissolved in 20 ml of methanol, and 0.4 ml (3.00 mmol) of triethylamine and 1,2,3,4- can be synthesized by the method described in International Publication W094 / 19342. Add 354 mg (l.OO mmol) of tetrahydro-1,6-dimethyl-2,4-dioxo-3- (4-pyridinyl) quinazoline hydrobromide, heat the mixture for 1 hour, and depressurize the solvent. After evaporation, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed, dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 50/1), recrystallized from a mixed solvent of ether and ethyl acetate, and the title compound was 221.7 mg (two-step yield: 46%) As white crystals. iH-NMR (CDCl ₃ ) δ (ppm): 8.72 (s, 1H), 8.02 (d, 1H, J = 2.0Hz), 7.49 (dd, 1H, J = 8.6, 2.0Hz), 7.34 (s, 1H ), 7.26 (s, 1H), 7.10 (d, 1H, J = 8.6Hz), 5.34-5.25 (m, 1H), 4.35-4.30 (br.d, 2H), 3.59 (s, 3H), 3.51 ( s, 3H), 3.50 (s, 3H), 3.25-3.03 (m, 4H), 2.43 (s, 3H), 1.89-1.84 (br.d, 2H).

IR (KBr tab.) (Cm ": 1733, 1652, 1488, 1437, 1360, 1263.

mp (Et ₂ 0-EtOAc): 260-261 ^:

Example 3 3-Ethyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl)- 1-piperidinyl] -1-methyl-1H-imidazo [4,5-g] quinazolin-2-one (compound 3)

 300 mg (0.62 mmol) of the compound 1 obtained in Example 1 was suspended in 10 ml of DMF, 30 mg (0.68 mmol) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes. When the reaction solution became homogeneous, 0.01 ml (0.68 mmol) of methyl iodide was added dropwise, and the mixture was further stirred at room temperature for 3 hours. To this, a saturated aqueous solution of ammonium chloride was added, followed by dilution with ice water, and the precipitated crystals were separated by filtration and washed with water to obtain a crude product as a white solid. After drying the crude crystals, the residue is purified by silica gel column chromatography (developing solvent: black form Z methanol = 501) and recrystallized from a mixed solvent of ether and ethyl acetate to give 190.8 mg of the title compound.

(62% yield) as white crystals.

iH-NMR (CDC) δ (ppm): 8.73 (s, 1H), 8.03 (d, 1H, J = 1.3Hz), 7.51 (dd, 1H, J = 8.6, 1.3Hz), 7.42 (s, 1H) , 7.35 (s, 1H), 7.10 (d, 1H, J = 8.6Hz), 5.35-5.26 (m, 1H), 4.36-4.32 (br.d, 2H), 4.03 (q, 2H, J = 7.3Hz ), 3.59 (s, 3H), 3.52 (s, 3H), 3.26-3.05 (m, 4H), 2.43 (s, 3H), 1.89-1.85 (br.d, 2H), 1.40 (t, 3H, J IR (KBr tab.) (Cm- ¹ ): 1719, 1698, 1656, 1559, 1476, 1355, 1205.

mp (Et ₂ 0-EtOAc): 244-245 ° C

Example 4 1,3-Getyl-2,3-dihydro-8- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3-y )-1-piperidinyl] -1Η-imidazo [4,5-g] quinazolin-2-one (compound 4)

ヽ 52%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.69 (s, 1H), 8.02 (d, 1H, J = 2.0Hz), 7.52-7.48 (m, 2H), 7.36 (s, 1H), 7.10 (d , 1H, J = 8.3Hz), 5.33-5.28 (m, 1H), 4.45-4.41 (br.d, 2H), 3.96 (q, 2H, J = 7.3Hz), 3.94 (q, 2H, J = 7.3 Hz), 3.59 (s, 3H), 3.31-3.22 (br.-t, 2H), 3.16-3.02 (m, 2H), 2.43 (s, 3H), 1.90-1.82 (m, 6H), 1.01 (t , 3H, J = 7.3Hz), 1.00 (t, 3H, J = 7.3Hz).

IR (KBr tab.) (Cm- ¹ ): 1726, 1699, 1655, 1487, 1359.

mp (Et ₂ 0-EtOAc): 233-235

 Example 7 1,3-Dibutyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3-y 1) -Piperidinyl] -1Η-imidazo [4,5-g] quinazolin-2-one (Compound 7)

 1,3-Dibutyl-2,3,7,8-tetrahydro-1H, 7H-imidazo [4,5-g] quinazoline-2,8-dione obtained in Reference Example 4 in place of compound b (compound d) The title compound was obtained as white crystals (two-step yield: 60%) according to the method of Example 2 except for using.

iH-NMR (CDCl ₃ ) δ (ppm): 8.71 (s, 1H), 8.02 (d, 1H, J = 1.7Hz), 7.50 (dd, 1H, J = 8.0, 1.7Hz), 7.41 (s, 1H ), 7.37 (s, 1H), 7.10 (d, 1H, J = 8.6Hz), 5.33-5.27 (m, 1H), 4.37-4.32 (br.d, 2H), 3.97 (q, 2H, J = 7.3 Hz), 3.94 (q, 2H, J = 7.3Hz), 3.59 (s, 3H), 3.26-3.08 (m, 4H), 2.43 (s, 3H), 1.88-1.78 (m, 6H), 1.50-1.36 (m, 4H), 0.98 (t, 3H, J = 7.3Hz), 0.97 (t, 3H, J2 7.3Hz).

IR (KBr tab.) (Cm- ¹ ): 1715, 1654, 1597, 1553, 1485, 1362.

mp (Et ₂ 0-EtOAc): 202-203X:

Example 8 6-chloro-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl) -1-piperidinyl] -1,3-dimethyl-1H-imidazo [4,5- _g ] quinazolin-2-one (compound 8)

Instead of compound b, 5,8-dichloro-2,3-dihydro-1,3-dimethyl-1H-imidazo [4,5-g] quinazolin-2-one (compound e) obtained in Reference Example 5 was used. Other than using According to the method of the second step of Example 2, the title compound was obtained as white crystals (yield: 55%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.02 (d, 1H, J = 2.0Hz), 7.50 (dd, 1H, J = 8.6, 2.0Hz), 7.34 (s, 1H), 7.29 (s, 1H ), 7.11 (d, 1H, J = 8.6Hz), 5.37-5.28 (m, 1H), 4.48-4.43 (br.d, 2H), 3.59 (s, 3H), 3.51 (s, 3H), 3.49 ( s, 3H), 3.31-3.22 (br.-t, 2H), 3.14-3.01 (m, 2H), 2.43 (s, 3H), 1.91-1.87 (br.d, 2H).

IR (KBr tab.) (Cm-i): 1730, 1702, 1651, 1562, 1475, 1359, 1279.

mp (Et ₂ 0):> 300

 Example 9 6-chloro-1,3-getyl-2,3-dihydro-8- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline- 3-yl) -1-piperidinyl] -1Η-imidazo [4,5-g] quinazolin-2-one (compound 9)

Instead of compound b, 5,8-dichloro-1,3-getyl-2,3-dihydro-1H-imidazo [4,5- _g ] quinazolin-2-one (compound f) obtained in Reference Example 6 was used. Except for using it, the title compound was obtained as white crystals (yield: 86%) according to the method of the second step of Example 2.

iH-NMR (CDCl ₃ ) δ (ppm): 8.02 (d, 1H, J = 1.3Hz), 7.51 (dd, 1H, J = 8.6, 1.3Hz),

7.40 (s, 1H), 7.32 (s, 1H), 7.10 (d, 1H, J = 8.6Hz), 5.34-5.25 (m, 1H), 4.48-

4.44 (br.d, 2H), 4.02 (q, 2H, J = 7.3Hz), 4.00 (q, 2H, J = 7.3Hz), 3.59 (s, 3H),

3.32-3.23 (br.-t, 2H), 3.13-3.06 (m, 2H), 2.43 (s, 3H), 1.90-1.87 (br.d, 2H),

1.40 (t, 3H, J = 7.3Hz), 1.39 (t, 3H, J = 7.3Hz).

IR (KBr tab.) (Cm- ¹ ): 2922, 1717, 1655, 1522, 1484, 1336.

mp (Et ₂ 0): 164-165 ° C

 Example 10 06-chloro-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3-yl ) -1-Piperidinyl] -1,3-dipropyl-1H-imidazo [4,5-g] quinazolin-2-one (Compound 10)

5,8-Dichloro-2,3-dihydro-1,3-dipropyl-pyr-1H-imidazo [4,5-g] quinazolin-2-one (Compound g) obtained in Reference Example 1 in place of Compound b Except that According to the method of the second step in Example 2, the title compound was obtained as white crystals (yield: 33%).

iH-NMR (CDC) δ (ppm): 8.02 (d, 1H, J = 2.0Hz), 7.50 (dd, 1H, J = 8.3, 2.0Hz), 7.31 (s, 1H), 7.26 (s, 1H) , 7.10 (d, 1H, J = 8.3Hz), 5.38-5.30 (m, 1H), 4.53- 4.48 (br.d, 2H), 3.94 (q, 2H, J = 7.3Hz), 3.92 (q, 2H , J = 7.3Hz), 3.59 (s, 3H), 3.35-3.26 (br.-t, 2H), 3.13-3.00 (m, 2H), 2.43 (s, 3H), 1.91-1.77 (m, 6H) , 1.00 (t, 3H, J2 7.3Hz), 0.98 (t, 3H, J = 7.3Hz).

 IR (KBr tab.) (Cm-i): 1711, 1656, 1599, 1538, 1484, 1466, 1362, 1268.

mp (Et ₂ 0-EtOAc): 235-236

 Example 11 1,2,3-dihydro-8- [4- (1,2,3,4 · tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl) -1-piperidinyl ] -1,3-Dimethyl-6-morpholino-1H-imidazo [4,5-g] quinazolin-2-one (Compound 11)

 210 mg (0.40 mmol) of compound 8 obtained in Example 8 was dissolved in 5 ml of N-methylpyrrolidinone, 0.2 ml (2.0 mmol) of morpholine was added, and the mixture was heated with stirring at 140 for 1 hour. The reaction solution was cooled to room temperature, water was added, and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from ether to give the title compound as white crystals (207.7 mg, yield 91%).

 ! H-NMR (CDCl3) 6 (ppm): 8.02 (d, 1H, J-2.0Hz), 7.51 (dd, 1H, J = 8.6,2.0Hz), 7.27 (s, 1H), 7.18 (s, 1H ), 7.11 (d, 1H, J = 8.6Hz), 5.34-5.25 (m, 1H), 4.39-4.32 (br.d, 2H), 3.94-3.83 (m, 8H), 3.59 (s, 3H), 3.46 (s, 6H), 3.20-3.04 (m, 4H), 2.43 (s, 3H), 1.86-1.83 (br.d, 2H).

IR (KBr tab.) (Cm- ¹ ): 1703, 0654, 1608, 1560, 1490, 1443, 1361, 1240, 1211.mp (Et ₂₀ ): 198-199 ° C

 Example 1 2 1,3-Getyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -6-morpholino-1H-imidazo [4,5-g] quinazolin-2-one (Compound 12)

Example 11 except that Compound 9 obtained in Example 9 was used instead of Compound 8 OM 13d7 <K

/ 66 Ο, 9ζε699 / 86fcy3ld

 ((sI S9-.

 (H) Hffi090 ((fI £ ε-s6 ε6ζε0Ls¾Z =-"..."

(3¾) HI size ^ 8 size 99 G9s Ri J ..

 0 (v93) ε00_ <. d says

S ^ s, 2i 9 Λ "9 ports 8 ports ss dimension H, :: ;; --- -.--- * According to the method of 3, the title compound was obtained as white crystals (yield 31%). iH-NMR (CDCl ₃ ) δ (ppm): 8.75 (s, 1H), 8.13 (s, 2H), 7.65-7.58 (m, 2H), 7.49 (s, 1H), 7.29 (s, 1H), 5.21 -5.12 (m, 1H), 4.48-4.43 (br.d, 2H), 4.04 (q, 2H,

J = 7.3Hz), 3.53 (s, 3H), 3.44-3.35 (br.-t, 2H), 2.52 (s, 3H), 2.34-2.14 (m, 4H), 1.41 (t, 3H, J = 7.3 Hz).

IR (KBr tab.) (Cm- ¹ ): 1654, 1603, 1554, 1491, 1257.

mp (Et ₂ 0-EtOAc): 255-2561:

Example 17 1,3-Getyl-2,3-dihydro-8- [4- (3,4-dihydro-6-methyl-4-oxoquinazolin-3-yl) -1-piperidinyl 1H-imidazo [ 4,5- _g ] quinazoline-2-one

 (Compound 17)

 The title compound was obtained as white crystals according to the method of Example 3 except that the compound 15 obtained in Example 15 was used instead of the compound 1 and that methyl iodide was used instead of methyl iodide. (Yield 28%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.75 (s, 1H), 8.13 (s, 2H), 7.65-7.57 (m, 2H), 7.49 (s, 1H), 7.31 (s, 1H), 5.21 -5.12 (m, 1H), 4.47-4.42 (br.d, 2H), 4.05 (q, 2H,

 J = 7.3Hz), 4.04 (q, 2H, J = 7.3Hz), 3.44-3.34 (br.-t, 2H), 2.52 (s, 3H), 2.33- 2.14 (m, 2H), 1.42 (t, 3H, J = 7.3Hz), 1.41 (t, 3H, J = 7.3Hz).

 IR (KBr tab.) (Cm-i): 1668, 1593, 1494, 1448, 1248.

mp (Et ₂ 0-EtOAc): 189-192

 Example 1 8 3-Ethyl-2,3-dihydro-8- [4- (3,4-dihydro-6-methyl-4-oxoquinazolin-3-yl) -1-piperidinyl] -1-propyl- 1H-imidazo [4,5-g] quinazolin-2-one (compound 18)

 The title compound was obtained as white crystals according to the method of Example 3 except that the compound 15 obtained in Example 15 was used instead of the compound 1 and propyl iodide was used instead of methyl iodide. (Yield 26%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.74 (s, 1H), 8.12 (s, 2H), 7.65-7.58 (m, 2H), 7.53 (s, 1H), 7.28 (s, 1H), 5.21 -5.15 (m, 1H), 4.51-4.46 (br.d, 2H), 4.04 (q, 2H, J = 7.0Hz), 3.95 (t, 2H, J = 7.0Hz), 3.49-3.37 (br.-t, 2H), 2.52 (s, 3H), 2.28-2.17 (m, 4H), 1.90-1.79 ( m, 2H), 1.41 (t, 3H, J = 7.0Hz), 1.02 (t, 3H, J = 7.0Hz). IR (KBr tab.) (cm-i): 1664, 1603, 1554, 1491, 1483 , 1380, 1285.

mp (Et ₂ 0-EtOAc): 201-202

Example 19 9-Ethyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl) 1-piperidinyl] -1Η-imidazo [4,5-g] quinazolin-2-thione (compound 19)

 3- [1- (6-amino-7-ethylaminoquinazoline-4-yl) -4-piperidinyl] -1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dio 3- [1- (6-Amino-7-ethylaminoquinazoline-4-yl) -4-piperidinyl] -3,4-obtained in the first step of Example 15 in place of oxoquinazoline The title compound was obtained as white crystals (yield 39%) according to the method of Example 14 except that dihydro-1,6-dimethyl-4-oxoquinazoline was used.

 iH-NMR (DMSOde) δ (ppm): 8.89 (s, 1H), 8.73 (s, 1H), 8.04 (s, 1H), 7.74-7.63 (m, 3H), 5.29-5.20 (m, 1H), 5.01-4.97 (br.d, 2H), 4.38 (q, 2H, J = 7.0Hz), 3.82-3.73 (br.-t, 2H), 2.53 (s, 3H), 2.41-2.32 (br.-t , 2H), 2.20-2.15 (br.d, 2H), 1.34 (t, 3H, J = 7.0Hz).

IR (KBr tab.) (Cm- ¹ ): 1678, 1601, 1559, 1470, 1327, 1243.

mp (CHCl ₃ ):> 300:

 Example 20 8-chloro-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3-yl ) -1-Piperidinyl] -1,3-dimethyl-1H-imidazo [4,5-g] phthalazin-2-one (compound 25)

 First step: 2,3,5,6,7,8-hexahydro-1,3-dimethyl-1H, 6H, 7H-imidazo [4,5-g] obtained in Reference Example 9 in place of compound b Except that phthalazine-2,5,8-trione (compound j) was used, the method of Example 1, Step 1 was followed to prepare 5,8-dichloro-2,3-dihydro-1,3-dimethyl-1H -Imidazo [4,5-g] phthalazin-2-one was obtained (yield 64%).

Second step: Dissolve 710 mg (2.50 mmol) of the compound obtained in the first step in 20 ml of DMF 890 mg (2.50 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3- (4-piperidinyl) quinazoline hydrobromide and potassium carbonate 1.04g

(7.50 mmol) and 20 mg (0.12 mmol) of potassium iodide were added, and the mixture was heated at 130 for 5 hours. After allowing the reaction mixture to cool, water was added, and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from a mixed solvent of ethanol and ether to give 1.12 g (yield 86%) of the title compound as white crystals.

 ! H-NMRCCDCla) δ (ppm): 8.03 (d, 1H, J = 1.7Hz), 7.64 (s, 1H), 7.56 (s, 1H), 7.50 (dd, 1H, J = 8.6, 1.7Hz), 7.11 (d, 1H, J = 8.6Hz), 5.31-5.23 (m, 1H), 3.95-3.91 (br.d, 2H), 3.61 (s, 3H), 3.60 (s, 3H), 3.59 (s, 3H), 3.28-3.13 (m, 4H), 2.43 (s, 3H), 1.90-1.86 (br.d, 2H).

 IR (KBr tab.) (Cm ": 1738, 1657, 1506, 1446, 1362, 1267.

mp (Et ₂ 0-EtOH): 226-228

 Example 2 1 8-chloro-1,3-getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo Quinazoline-3-yl) -1-piperidinyl] -1,3-dimethyl-1H-imidazo [4,5-g] phthalazin-2-one (compound 26)

 1,3-Jetyl-2,3,5,6,7,8-hexahydro-1H, 6H, 7H-imidazo [4,5-g] phthalazine- obtained in Reference Example 10 in place of compound j The title compound was obtained as white crystals according to the method of Example 20 except that 2,5,8-trione (compound k) was used.

(Two-step yield 63%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.03 (d, 1H, J = 1.7Hz), 7.66 (s, 1H), 7.58 (s, 1H), 7.50 (dd, 1H, J = 8.3, 1.7Hz ), 7.11 (d, 1H, J = 8.3Hz), 5.30-5.24 (m, 1H), 4.15-4.06 (m, 4H), 3.95-3.91 (br.d, 2H), 3.61 (s, 3H), 3.34-3.08 (m, 4H), 2.43 (s, 3H), 1.89-1.86 (br.d, 2H), 1.47-1.42 (m, 6H).

 IR (KBr tab.) (Cm-i): 1722, 1686, 1498, 1362, 1265.

mp (Et ₂₀ -EtOH): 290-292 ° C

Example 22 2-cyclo-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3-yl ) -1-Piperidinyl] -1,3-dipropyl-1H-imida Zo [4,5-g] phthalazin-2-one (Compound 27)

 2,3,5,6,7,8-Hexahydro-1,3-dibutylpyr-1H, 6H, 7H-imidazo [4,5-g] phthalazine obtained in Reference Example 11 in place of compound j -The title compound was obtained as white crystals according to the method of Example 20 except that 2,5,8-trione (compound m) was used.

(Two-step yield 58%).

! H-NMRCCDCla) δ (ppm): 8.03 (d, 1H, J = 1.7Hz), 7.64 (s, 1H), 7.58 (s, 1H), 7.50 (dd, 1H, J = 8.6, 1.7Hz), 7.11 (d, 1H, J = 8.6Hz), 5.33-5.16 (m, 1H), 4.06- 3.98 (m, 4H), 3.95-3.92 (br.d, 2H), 3.60 (s, 3H), 3.28- 3.13 (m, 4H), 2.43 (s, 3H), 1.96-1.82 (m, 6H), 1.06-0.99 (m, 6H).

IR (KBr tab.) (Cm ¹ ): 1726, 1657, 1496, 1362, 1265.

mp (Et ₂ 0-EtOH): 218-220:

 Example 2 3 8-Chloro-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl ) -1-Piperidinyl] -1,3-diisopropyl-1H-imidazo [4,5-g] phthalazin-2-one (compound 28)

 2,3,5,6,7,8-Hexahydro-1,3-diisopropyl-1H, 6H, 7H-imidazo [4,5-g] phthalazine- obtained in Reference Example 12 in place of compound j The title compound was obtained as white crystals (40% yield in two steps) according to the method of Example 20 except that 2,5,8-trione (compound n) was used.

iH-NMR (CDCl ₃ ) δ (ppm): 8.04 (d, 1H, J = 1.7Hz), 7.76 (s, 1H), 7.71 (s, 1H), 7.50 (dd, 1H, J = 8.6, 1.7Hz ), 7.10 (d, 1H, J = 8.6Hz), 5.31-5.24 (m, 1H), 4.87-4.77 (m, 2H), 3.96-3.93 (br.d, 2H), 3.60 (s, 3H), 3.28-3.09 (m, 4H), 2.43 (s, 3H), 1.90-1.86 (br.d, 2H), 1.65 (d, 6H, J = 6.9Hz), 1.64 (d, 6H, J = 6.9Hz) .

IR (KBr tab.) (Cm- ¹ ): 1722, 1703, 1659, 1514, 1489, 1446, 1362.

_{mp (Et 2 0-EtOH)} : 263-264 ° C

Example 2 4 1,3-Dibutyl-8-cyclo-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo Quinazoline-3-yl) -1-piperidinyl] -1Η-imidazo [4,5-g] phthalazin-2-one (compound 29) 1,3-Dibutyl-2,3,5,6,7,8-hexahydro-1H, 6H, 7H-imidazo [4,5-g] phthalazine- obtained in Reference Example 13 in place of compound j The title compound was obtained as white crystals according to the method of Example 20 except that 2,5,8-trione (compound o) was used.

(Two-step yield 68%).

iH-NMR (CDCla) δ (ppm): 8.03 (d, 1H, J = 2.0Hz), 7.63 (s, 1H), 7.57 (s, 1H), 7.50 (dd, 1H, J = 8.3, 2.0Hz) , 7.11 (d, 1H, J = 8.3Hz), 5.29-5.20 (m, 1H), 4.08-4.01 (m, 4H), 3.96-3.92 (br.d, 2H), 3.60 (s, 3H), 3.27 -3.09 (m, 4H), 2.43 (s, 3H), 1.88-1.77 (m, 6H), 1.51-1.37 (m, 4H), 1.03-0.96 (m, 4H).

IR (KBr tab.) (Cm- ¹ ): 1730, 1655, 1497, 1458, 1362.

mp (Et ₂ 0-EtOH): 241-242 ^:

Example 25 5-cyclo-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3-yl ) -1-Piperidinyl] -1,3-diisobutyl-1H-imidazo [4,5-g] phthalazin-2-one (Compound 30)

 2,3,5,6,7,8-Hexahydro-1,3-diisobutyl-1H, 6H, 7H-imidazo [4,5-g] phthalazine obtained in Reference Example 14 in place of Compound I The title compound was obtained as white crystals according to the method of Example 20 except that 2,5,8-trione (compound p) was used (two-step yield: 23%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.04 (d, 1H, J = 2.0Hz), 7.62 (s, 1H), 7.57 (s, 1H), 7.50 (dd, 1H, J = 8.3, 2.0Hz ), 7.11 (d, 1H, J = 8.3Hz), 5.31-5.23 (m, 1H), 3.95-3.84 (m, 6H), 3.60 (s, 3H), 3.27-3.13 (m, 4H), 2.43 ( s, 3H), 2.38-2.25 (m, 2H), 1.89-1.85 (br.d, 2H), 1.04 (d, 6H, J = 6.6Hz), 1.02 (d, 6¾ J = 6.6Hz).

IR (KBr tab.) (Cm- ¹ ): 1732, 1653, 1597, 1514, 1456, 1362.

mp (Et ₂ 0-EtOH): 236-237 X:

 Example 2 6 1,3-Diaryl-8-chloro-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo Quinazoline-3-yl) -1-piperidinyl] -1Η-imidazo [4,5-g] phthalazin-2-one (compound 31)

1,3-Diaryl-2,3,5,6,7,8-hexahyd obtained in Reference Example 15 in place of compound j The title compound was converted to a white crystal according to the method of Example 20 except that dro-1H, 6H, 7H-imidazo [4,5-g] phthalazine-2,5,8-trione (compound Q) was used. Got as

(Two-step yield 63%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.03 (d, 1H, J = 2.0Hz), 7.64 (s, 1H), 7.63 (s, 1H), 7.50 (dd, 1H, J = 8.6, 2.0Hz ), 7.11 (d, 1H, J = 8.6Hz), 6.04-5.87 (m, 2H), 5.50-5.27 (m, 5H), 4.71-4.66 (m, 4H), 3.93-3.90 (m, 2H), 3.60 (s, 3H), 3.23-3.10 (m, 4H), 2.43 (s, 3H), 1.88-1.86 (br.d, 2H).

IR (KBr tab.) (Cm.i): 1732, 1653, 1514, 1498, 1456, 1362.

_{mp (Et 2 0-EtOH)} : 235-237

Example 2 7 1,3-Dibenzyl-8-chloro-2,3-dihydro-5- [4- (1,2,3,4-tetrahydrido-1,6-dimethyl-2,4-dithio Oxoquinazolin-3-yl) -1-piperidinyl] -1Η-imidazo [4,5-g] phthalazin-2-one (compound 32)

 1,3-Dibenzyl-2,3,5,6,7,8-hexahydro-1H, 6H, 7H-imidazo [4,5-g] phthalazine- obtained in Reference Example 16 in place of Compound I The title compound was obtained as white crystals (yield 26%) according to the method of Example 20 except that 2,5,8-trione (compound) :) was used.

Ή- negation _{R (CDC1 3) δ (ppm} ): 8.06 (d, 1H, J = 2.0Hz), 7.54-7.23 (m, 13H), 7.13 (d, 1H, J = 8.6Hz), 5.26-5.17 ( m, 5H), 3.68-3.64 (br.d, 2H), 3.63 (s, 3H), 3.14- 2.96 (m, 4H), 2.45 (s, 3H), 1.78-1.75 (br.d, 2H).

IR (KBr tab.) (Cm- ¹ ): 1718, 1655, 1626, 1514, 1495, 1362.

mp (Et ₂₀ -EtOH): 286-288 ° C

 Example 2 82,3-Dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl) -1-piperidinyl ] -1,3-Dimethyl-1H-imidazo [4,5-g] furazin-2-one (Compound 20)

0.40 g (0.769 mmol) of compound 25 obtained in Example 20 was dissolved in 10 ml of acetic acid, 0.10 g of 10% Pd / C was added, and the mixture was vigorously stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was separated by filtration using a filter aid, and the residue obtained by concentrating the filtrate was treated with silica. Osa 9A: ££ AVsa / 6dTL8

* (% Size 6 ST

 Q (Hf) ¾ p) (H) () 3aoWNH9Ss6) H dimension or6H SZ: day dd S-.--.

 H (f ¾ p (HHfs W98) izssSsεεΔI98 G IS = Z = 8 Z- .. ".

 HHρ¾ () () s dimensionΐ 9Ss96ε00 dimension ί¾-. "*,

 CO δbu () Δ Η) u 86τεs dimension s

n

1H), 4.06-3.98 (m, 6H), 3.61 (s, 3H), 3.29-3.14 (m, 4H), 2.43 (s, 3H), 1.94-

1.86 (m, 6H), 1.05-1.00 (m, 6H).

 IR (KBr tab.) (Cm-i): 1732, 1655, 1497, 1362, 1209.

mp (Et ₂ 0-EtOH): 212-214

Example 3 1 2,3-Dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl) -1-piperidinyl ] -1,3-Diisopropyl-1H-imidazo

[4,5-g] phthalazin-2-one (compound 23)

 The title compound was obtained as white crystals according to the method of Example 28 except that compound 28 obtained in Example 23 was used instead of compound 25 (yield: 32%).

iH-NMR (CDCl ₃ ) δ (ppm): 9.13 (s, IH), 8.04 (d, IH, J = 1.3Hz), 7.71 (s, IH), 7.50 (dd, IH, J = 8.6, 1.3Hz ), 7.44 (s, IH), 7.11 (d, IH, J = 8.6Hz), 5.30-5.22 (m, 1H), 4.87-4.77 (m, 2H), 4.01-3.97 (br.d, 2H), 3.61 (s, 3H), 3.29-3.15 (m, 4H), 2.43 (s, 3H), 1.91-1.87 (br.d, 2H), 1.65 (d, 6H, J = 6.9Hz), 1.63 (d, 6H, J = 6.9Hz) .IR (KBr tab.) (Cm ¹ ): 1722, 1701, 1655, 1599, 1513, 1483, 1362.

mp (Et ₂ 0-EtOH): 186-187T:

 Example 3 2 1,3-Dibutyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -1Η-imidazo [4,5-g] furazin-2-one (compound 24)

 The title compound was obtained as white crystals (yield: 22%) according to the method of Example 28 except that the compound 29 obtained in Example 24 was used instead of the compound 25. iH-NMR (CDC) δ (ppm): 9.16 (s, IH), 8.04 (d, IH, J = 1.7Hz), 7.58 (s, IH), 7.50 (dd, 1H, J = 8.6, 1.7Hz) , 7.32 (s, IH), 7.11 (d, IH, J = 8.6Hz), 5.32-5.24 (m, 1H), 4.08-3.98 (m, 6H), 3.61 (s, 3H), 3.28-3.11 (m , 4H), 2.44 (s, 3H), 1.97-1.76 (m, 6H), 1.51-1.38 (m, 4H), 0.99 (t, 6H, J = 7.3Hz).

IR (KBr tab.) (Cm ¹ ): 1722, 1701, 1654, 1495, 1461, 1362.

mp (Et ₂₀ -EtOH): 128-130 ° C

Example 3 3 1,3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl Tyl-2,4-dioxoquinazolin-3-yl) -1-piperidinyl] -8-morpholino-1H-imidazo [4,5- _g ] phthalazin-2-one hydrochloride (Compound 34)

First step: 1.70 g (3.10 mmol) of compound 26 obtained in Example 21 was dissolved in 12 ml of N-methylpyrrolidinone, and 1.35 ml (15.5 mmol) of morpholine was added thereto. The mixture was heated and stirred at 150 for 5 hours. did. The reaction solution was cooled to room temperature, water was added, and the precipitated crystals were collected by filtration. The crude crystals were purified by silica gel column chromatography (developing solvent: chloroform / methanol = 50Zl) and recrystallized from a mixed solvent of ethanol and ether to give 1.4 g of the free base of the title compound (57% yield). As white crystals.

Second step: 1.05 g (1.75 mmol) of the free base obtained in the first step was dissolved in 20 ml of ethyl acetate, and an excess amount of a saturated hydrogen chloride / monoethyl acetate solution was added dropwise at room temperature and stirred for 10 minutes. . The precipitated crystals were collected by filtration, washed with ethyl acetate, and recrystallized from ethanol to give 0.93 _g (yield 84%) of the title compound as white crystals.

 ! H-NMRCCDCls) 6 (ppm): 8.02 (d, 1H, J = 2.0Hz), 7.67 (s, 1H), 7.54 (s, 1H), 7.55 (dd, 1H, J = 8.6, 2.0Hz ), 7.10 (d, 1H, J = 8.6Hz), 5.45-5.29 (m, 1H), 4.16-4.09 (m, 6H), 4.04-3.95 (m, 4H), 3.70-3.60 (m, 4H), 3.59 (s, 3H), 3.22-3.08 (m, 4H), 2.42 (s, 3H), 2.00-2.16 (br.d, 2H), 1.49-1.43 (m, 6H).

IR (KBr tab.) (Cm- ¹ ): 1730, 1701, 1650, 1507, 1443, 1363.

 mp (EtOH): 188-190

 Example 3 4 2,3-Dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl) -1-piperidinyl ] -1,3-Dimethyl-8-morpholino -1H-imidazo [4,5-g] phthalazin-2-one (Compound 33)

 The title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 25 obtained in Example 20 was used instead of the compound 26 (44% yield). .

iH-NMR (CDCl ₃ ) δ (ppm): 8.03 (d, 1H, J = 1.7 Hz), 7.58 (s, 1H), 7.52-7.47 (m, 2H), 7.11 (d, 1H, J = 8.6 Hz) ), 5.33-5.17 (m, 1H), 4.02-3.99 (m, 4H), 3.90- 3.87 (br.d, 2H), 3.61, 3.59, 3.56 (eac, s, 3H), 3.47-3.44 (m, 4H), 2.43 (s, 3H), 1.90-1.86 (br.d, 2H).

 IR (KBr tab.) (Cm-i): 1731, 1659, 1504, 1417, 1362, 1269.

mp (Et ₂ 0-EtOH): 272-274

Example 3 5 1,3-Detyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-Piperidinyl] -8- (1-piperazinyl) -1H-imidazo [4,5-g] phthalazin-2-one dihydrochloride (Compound 35)

 The title compound was obtained as white crystals according to the method of Example 33, except that piperazine was used instead of morpholine (two-step yield: 56%).

iH-NMR (CDCl ₃ ) <5 (ppm): 8.04 (d, 1H, J = 1.7 Hz), 7.59 (s, 1H), 7.52-7.48 (m, 2H), 7.11 (d, 1H, J = 8.6Hz), 5.28-5.18 (m, IH), 4.16-4.04 (m, 4H), 3.87- 3.84 (br.d, 2H), 3.61 (s, 3H), 3.41-3.37 (m, 4H), 3.24 -3.13 (m, 8H), 2.43 (s, 3H), 1.88-1.85 (br.d, 2H), 1.47-1.41 (m, 6H) (as free base).

IR (KBr tab.) (Cm- ¹ ): 1718, 1701, 1653, 1548, 1508, 1419, 1362.

mp (Et ₂ 0-EtOH): 240-242 ^:

 Example 36 1, 3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -8- (4-methyl-1-piperazinyl) -1H-imidazo [4,5-g] phthalazin-2-one dihydrochloride (Compound 36)

 The title compound was obtained as white crystals according to the method of Example 33 except that N-methylbiperazine was used instead of morpholine (two-step yield: 44%).

 ! H-NMRiCDCls) δ (ppm): 8.03 (d, 1H, J = 1.3Hz), 7.59 (s, IH), 7.52-7.49 (m, 2H), 7.11 (d, IH, J = 8.6Hz) , 5.28-5.18 (m, IH), 4.14-4.04 (m, 4H), 3.87- 3.83 (br.d, 2H), 3.61 (s, 3H), 3.51-3.47 (m, 4H), 3.24-3.08 ( m, 8H), 2.43 (s, 6H), 1.87-1.85 (br.d, 2H), 1.47-1.42 (m, 6H) (as free base).

IR (KBr tab.) (Cm- ¹ ): 1718, 1648, 1506, 1420, 1355.

mp (Et ₂₀ -EtOH): 250-252 ° C

Example 3 7.1,3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl S9366 OS / 8¾V1ζ £ 6ϊ / AV6-

 ^, / V ΛΛΛ w ¾】 W29:, ---.

¾ ¾¾? , Ύ 长 1 public f :: ,, The title compound was obtained as white crystals (two-step yield 38%).

! H-NMRiCDCls) δ (ppm): 8.04 (d, 1H, J = 1.7Hz), 7.64 (s, 1H), 7.63 (s, 1H), 7.51 (dd, 1H, J = 8.6, 1.7Hz), 7.11 (d, 1H, J = 8.6Hz), 5.27-5.17 (m, 1H), 4.15-4.03 (m, 4H), 3.84-3.76 (m, 6H), 3.61 (s, 3H), 3.22-3.10 ( m, 4H), 2.43 (s, 6H), 2.11-2.01 (m, 4H), 1.87-1.85 (br.d, 2H), 1.49-1.41 (m, 6H) (as free base). IR (KBr tab .) (cm- ¹ ): 1706, 1648, 1595, 1510, 1452, 1421, 1362.

mp (Et ₂ 0-EtOH): 202-205

Example 4 0 1,3-Jetyl-8-hexamethyleneimino-2,3-dihydro-5- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-2,4- Dioxoquinazolin-3-yl) -1-piperidinyl] -1Η-imidazo [4,5-g] phthalazin-2-one hydrochloride (compound 40)

 The title compound was obtained as white crystals (two-step yield: 46%) according to the method of Example 33 except that hexamethyleneimine was used instead of morpholine.

iH-NMR (CDCl ₃ ) δ (ppm): 8.04 (d, 1H, J = 1.7Hz), 7.59 (s, 1H), 7.57 (s, 1H), 7.49 (dd, 1H, J = 8.6, 1.7Hz ), 7.10 (d, 1H, J = 8.6Hz), 5.28-5.19 (m, 1H), 4.13-4.02 (m, 4H), 3.83-3.79 (br.d, 2H), 3.66-3.62 (m, 4H ), 3.60 (s, 3H), 3.23-3. Ll (m, 4H), 2.43 (s, 3H), 1.94-1.75 (m, 10H), 1.47-1.41 (m, 6H) (as free base).

IR (KBr tab.) (Cm- ¹ ): 1730, 1701, 1653, 1591, 1508, 1439, 1362.

mp (Et ₂ 0-EtOH): 209-211 ° C

 Example 4 1 1,3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-Piperidinyl] -8-dimethylamino-1H-imidazo [4,5-g] phthalazin-2-one hydrochloride

 The title compound was obtained as white crystals according to the method of Example 33 except that propylamine was used instead of morpholine and DMF was used instead of N-methylpyrrolidinone (two-step yield: 29%).

! H-NMRCCDC) δ (ppm): 8.04 (d, 1H, J = 1.7Hz), 7.59 (s, 1H), 7.56 (s, 1H), 7.49 (dd, 1H, J = 8.6, 1.7Hz), 7.10 (d, 1H, J = 8.6Hz), 5.28-5.18 (m, 1H), 4.14-4.04 (m, 4H), 3.85-3.82 (br.d, 2H), 3.61 (s, 3H), 3.21- 3.14 (m, 4H), 3.08 (s, 6H), 2.43 (s, 3H), 1.87-1.85 (br.d, 2H), 1.47-1.40 (m, 6H) (as free base).

IR (KBr tab.) (Cm- ¹ ): 1718, 1658, 1508, 1410, 1363.

mp (Et ₂ 0-EtOH): 193-195

Example 4 2 1,3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-Piperidinyl] -8-dipropylamino-1H-imidazo [4,5- _g ] phthalazin-2-one hydrochloride (compound 42)

 The title compound was obtained as white crystals according to the method of Example 33 except that dipropylamine was used instead of morpholine (two-step yield: 13%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.04 (d, 1H, J = 1.7Hz), 7.63 (s, 1H), 7.58 (s, 1H), 7.50 (dd, 1H, J = 8.6, 1.7Hz ), 7.11 (d, 1H, J = 8.6Hz), 5.28-5.18 (m, 1H), 4.16-4.04 (m, 4H), 3.87-3.84 (br.d, 2H), 3.61 (s, 3H), 3.37-3.31 (m, 4H), 3.25-3.12 (m, 4H), 2.43 (s, 3H), 1.88-1.85 (br.d, 2H), 1.75-1.61 (m, 4H), 1.47-1.40 (m , 6H), 0.92 (t, 6H, J = 7.4Hz) (as free base).

IR (KBr tab.) (Cm ¹ ): 1734, 1699, 1653, 1576, 1506, 1446, 1362.

_{mp (Et 2 0-EtOH)} : 215-217

 Example 4 3 1,3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -8-propylamino-1H-imidazo [4,5-g] phthalazin-2-one hydrochloride (compound 43)

 The title compound was obtained as white crystals (two-step yield: 65%) according to the method of Example 33 except that propylamine was used instead of morpholine.

 O-NMRiCDCla) δ (ppm): 8.04 (d, 1H, J = 1.7Hz), 7.63 (s, 1H), 7.49 (dd, 1H, J = 8.6, 1.7Hz), 7.13 (s, 1H), 7.10 (d, 1H, J = 8.6Hz), 5.26-5.16 (m, 1H), 4.13-4.03 (m, 4H), 3.70-3.63 (m, 4H), 3.60 (s, 3H), 3.22-3. ll (m, 4H), 2.43 (s, 3H), 1.86-1.76 (m, 4H), 1.47-1.40 (m, 6H), 1.07 (t, 3H, J = 7.3Hz) (as free base). IR ( KBr tab.) (Cm-i): 1730, 1703, 1657, 1510, 1439, 1362.

mp (Et ₂ 0-EtOH): 289-291

Example 4 4 1,3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl

Κ6Ϊ OV / 1/1: A-1-,

s ΐρ) 卜 09.

66 o / il / w 39: dsa / ¾vl> 86

 Z sub: “L:

 ^^ ε ¾ ^ Ύ w Λ Λ mouth: 围 () H () says dd: S-Dimension 9

 H) Η 80) sεε dimensionεioS09ε dimension says ^ s -...

H (Η6) H)) 96000 18 inch 188 / τt3ss-- ... "" ((: «) HI i¾ il S9I: .. Example 5 1 2,3-Dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazolin-3-yl) -1-piperidinyl ] -1,3-Diisobutyl -8-morpholino -1H-imidazo [4,5-g] phthalazin-2-one (Compound 51)

 The title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 30 obtained in Example 25 was used instead of the compound 26 (yield: 50%). .

iH-NMR (CDCl ₃ ) δ (ppm): 8.03 (d, 1H, J = 1.7Hz), 7.59 (s, 1H), 7.49 (dd, 1H, J = 8.6, 1.7Hz), 7.46 (s, 1H ), 7.10 (d, 1H, J = 8.6Hz), 5.29-5.20 (m, 1H), 4.01- 3.97 (m, 4H), 3.87-3.81 (m, 6H), 3.60 (s, 3H), 3.44- 3.41 (m, 4H), 3.24-3.07 (m, 4H), 2.43 (s, 3H), 2.38-2.20 (m, 2H), 1.87-1.84 (br.d, 2H), 1.03 (d, 6H,

 J = 6.6Hz), 1.03 (d, 6H, J = 6.6Hz).

IR (KBr tab.) (Cm- ¹ ): 1726, 1654, 1512, 1474, 1421, 1362.

mp (Et ₂ 0-EtOH): 175-177 ^:

 Example 5 2 1,3-Diaryl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -8-morpholino-1H-imidazo [4,5-g] phthalazin-2-one (compound 52)

 The title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 31 obtained in Example 26 was used instead of the compound 26 (37% yield). .

 iH-NMR (CDC) δ (ppm): 8.04 (d, 1H, J = 2.0Hz), 7.64 (s, 1H), 7.60-7.48 (m, 2H), 7.10 (d, 1H, J = 8.6Hz) , 6.07-5.88 (m, 2H), 5.50-5.23 (m, 5H), 4.67-4.65 (m, 4H), 4.05-3.95 (m, 4H), 3.86-3.83 (br.d, 2H), 3.60 ( s, 3H), 3.42-3.39 (m, 4H), 3.19-3.10 (m, 4H), 2.43 (s, 3H), 1.88-1.86 (br.d, 2H).

 IR (KBr tab.) (Cm-i): 1726, 1657, 1514, 1471, 1360.

mp (Et ₂ 0-EtOH): 221-222 ° C

Example 5 3 1,3-Dibenzyl-2,3-dihydro-5- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -8-morpholino-1H-ii Midazo [4,5-g] phthalazin-2-one (compound 53)

 The title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 32 obtained in Example 27 was used instead of the compound 26 (46% yield). .

iH-NMR (CDCl ₃ ) δ (ppm): 8.06 (d, 1H, J = 1.3 Hz), 7.53-7.19 (m, 13H), 7.12 (d, 1H, J = 8.6 Hz), 5.26-5.17 (m , 5H), 3.83-3.80 (m, 4H), 3.63 (s, 3H), 3.62-3.59 (br.d, 2H), 3.16-3.13 (m, 4H), 3.10-2.89 (m, 4H), 2.45 (s, 3H), 1.77-1.74 (br.d, 2H).

IR (KBr tab.) (Cm- ¹ ): 1720, 1659, 1405, 1508, 1475, 1421, 1362.

mp (Et ₂ 0-EtOH): 281-282

 Example 5 4 1,3-Getyl-2,3-dihydro-8- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -1Η-imidazo [4,5-g] quinolin-2-one (compound 54)

 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3- (4-piperidinyl) quinazolinehydrobromide 2.30 g (6.49 mmol) in 20 ml of N-methylpyrrolidinone After dissolution, the 8-chloro-1,3-dimethyl-2,3-dihydro-1H-imidazo [4,5-g] quinolin-2-one (compound s) obtained in Reference Example 17 1.40 g (5.08 mmol) and 2.65 ml (15.2 mmol) of N, N-diisopropylethylamine, heated at 150 ° C for 4 hours, left to cool the reaction solution, and added water to precipitate crystals. Was collected by filtration. The crude crystals were purified by silica gel column chromatography (developing solvent: black-mouthed form Z methanol = 100/1) and recrystallized from a mixed solvent of ethanol and ether to give 1.23 g of the title compound (yield 47%). ) As white crystals.

iH-NMR (CDCl ₃ ) d (ppm): 8.64 (d, 1H, J = 5.0 Hz), 8.04 (d, 1H, J = 1.7 Hz), 7.57 (s, 1H), 7.55 (s, 1H), 7.51 (dd, 1H, J = 8.6, 1.7Hz), 7.11 (d, 1H, J = 8.6Hz), 6.89 (d, 1H, J = 5.0Hz), 5.28-5.17 (m, 1H), 4.12-4.00 (m, 4H), 3.74-3.69 (br.d, 2H), 3.61 (s, 3H), 3.27-3.12 (m, 2H), 3.04-2.96 (m, 2H), 2.44 (s, 3H), 1.88 -1.84 (br.d, 2H), 1.67-1.39 (m, 6H). I Army Br tab.) (Cm ¹ ): 1698, 1649, 1516, 1490.

mp (Et ₂ 0-EtOH): 260-261

Example 5 51 1,3-Getyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -2-oxo-1H-imidazo [4,5-g] quinoline-7-ethyl carboxylate (Compound 55)

 8-chloro-1,3-dimethyl-2,3-dihydropen-2-oxo-1H-imidazo [4,5-g] quinoline-7-carboxylic acid obtained in Reference Example 18 in place of compound s The title compound was obtained as white crystals according to the method of Example 54 except that ethyl (compound! :) was used.

(Yield 70%).

iH-NMR (CDCl ₃ ) «5 (ppm): 8.84 (s, 1H), 8.04 (d, 1H, J = 1.7Hz), 7.90 (s, 1H), 7.57 (s, 1H), 7.50 (dd, 1H, J = 8.6, 1.7Hz), 7.10 (d, 1H, J = 8.6Hz), 5.38-5.29 (m, 1H), 4.48 (q, 2H, J = 6.9Hz), 4.14 (q, 2H, J = 7.3Hz), 4.05 (q, 2H, J = 7.3Hz), 3.60 (s, 3H), 3.49-3.43 (m, 4H), 3.27-3.12 (m, 2H), 2.44 (s, 3H), 1.83 -1.78 (br.d, 2H), 1.54-1.40 (m, 9H).

IR (KBr tab.) (Cm ¹ ): 1716, 1653, 1572, 1487, 1450, 1363.

mp (Et ₂ 0-EtOH): 188-190

 Example 5 6 1,3-Getyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -6-methyl-1H-imidazo [4,5-g] quinolin-2-one (compound 56)

 8-chloro-1,3-getyl-2,3-dihydro-6-methyl-1H-imidazo [4,5-g] which can be synthesized by the method described in JP-A-54-154797 in place of compound S The title compound was obtained as white crystals (yield 39%) according to the method of Example 54 except that quinolin-2-one was used.

iH-NMR (CDCl ₃ ) δ (ppm): 8.04 (d, 1H, J = 1.0Hz), 7.52-7.49 (m, 3H), 7.11 (d, 1H, J = 8.6Hz), 6.77 (s, 1H ), 5.26-5.16 (m, 1H), 4.11-3.98 (m, 4H), 3.72- 3.68 (br.d, 2H), 3.61 (s, 3H), 3.25-3.11 (m, 2H), 3.01-2.93 (br.-t, 2H), 2.68 (s, 3H), 2.44 (s, 3H), 1.88-1.84 (br.d, 2H), 1.69-1.37 (m, 6H). IR (KBr tab.) (Cm-i): 1726, 1659, 1581, 1513, 1456, 1360.

mp (Et ₂ 0-EtOH): 261-263 ^

Example 5 7 1,3,6-Triethyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline -3-yl) -1-piperidinyl] -1Η-imidazo [4,5-g] quinolin-2-one (compound 57)

 8-chloro-1,3,6-triethyl-2,3-dihydro-1H-imidazo [4,5-g] quinoline which can be synthesized by the method described in JP-A-54-154797 in place of compound S The title compound was obtained as white crystals according to the method of Example 54 except for using 2-one.

(Yield 25%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.04 (d, 1H, J = 1.7 Hz), 7.55-7.49 (m, 3H), 7.11 (d, 1H, J = 8.3 Hz), 6.89 (s, 1H ), 5.27-5.18 (m, 1H), 4.11-3.98 (m, 4H), 3.73- 3.69 (br.d, 2H), 3.61 (s, 3H), 3.25-3.13 (m, 2H), 3.03-2.90 (m, 2H), 2.44 (s, 3H), 1.88-1.84 (br.d, 2H), 1.46-1.37 (m, 9H).

IR (KBr tab.) (Cm- ¹ ): 1697, 1655, 1578, 1512, 1448, 1360.

mp (Et ₂ 0-EtOH): 211-212

 Example 5 8 1,3-Getyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl)-1-piperidinyl] -6-propyl-1H-imidazo [4,5-g] quinolin-2-one (compound 58)

 8-Chloro-1,3-getyl-2,3-dihydro-6-propyl-1H-imidazo [4,5-g] which can be synthesized by the method described in JP-A-54-154797 in place of compound S The title compound was obtained as white crystals (yield 32%) according to the method of Example 54 except for using quinolin-2-one.

! H-NMRCCDCls) δ (ppm): 8.05 (d, 1H, J = 1.7Hz), 7.56-7.49 (m, 3H), 7.11 (d, 1H, J = 8.6Hz), 6.78 (s, 1H), 5.27-5.18 (m, 1H), 4.11-3.98 (m, 4H), 3.72- 3.68 (br.d, 2H), 3.61 (s, 3H), 3.25-3.13 (m, 2H), 3.02-2.94 (br .-t, 2H), 2.88 (t, 2H, J = 7.9Hz), 2.44 (s, 3H), 1.89-1.77 (m, 4H), 1.46- 1.37 (m, 6H), 1.04 (t, 3H, J = 7.3Hz). IR (KBr tab.) (Cm ¹ ): 1701, 1655, 1604, 1578, 1512, 1458, 1362.mp (Et ₂ 0-EtOH): 233-234 "

Example 5 9 1,3-Detyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -6-isopropyl-1H-imidazo [4,5- _g ] quinolin-2-one (compound 59)

 8-Chloro-1,3-getyl-2,3-dihydro-6-isopropyl-1H-imidazo [4,5-g] which can be synthesized by the method described in JP-A-54-154797 in place of compound S The title compound was obtained as white crystals (yield 16%) according to the method of Example 54 except for using quinolin-2-one.

iH-NMR (CDCl ₃ ) <5 (ppm): 8.04 (d, 1H, J = 1.7 Hz), 7.57-7.49 (m, 3H), 7.11 (d, 1H, J = 8.6 Hz), 6.82 (s, 1H), 5.27-5.18 (m, 1H), 4.11-3.98 (m, 4H), 3.73- 3.68 (br.d, 2H), 3.61 (s, 3H), 3.24-3.14 (m, 3H), 3.04- 2.95 (br.-t, 2H), 2.44 (s, 3H), 1.89-1.85 (br.d, 4H), 1.46-1.38 (m, 12H), 1.04 (t, 3H, J = 7.3Hz).

IR (KBr tab.) (Cm- ¹ ): 1718, 1653, 1579, 1514, 1485, 1362.

mp (Et ₂ 0-EtOH) 273-274

 Example 6 0 6-Chloro-1,3-getyl-2,3-dihydro-8- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline -3-yl) -1-piperidinyl] -1Η-imidazo [4,5-g] quinolin-2-one (compound 60)

Instead of compound s, the 6,8-dikeguchi-1,3-diethyl-2,3-dihydro-1H-imidazo [4,5-g] quinolin-2-one obtained in Reference Example 19 (compound The title compound was obtained as white crystals (yield 8%) according to the method of Example 54 except for using U). iH-NMR (CDCl ₃ ) δ (ppm): 8.04 (d, 1H, J = 1.7 Hz), 7.53-7.45 (m, 3H), 7.11 (d, 1H, J = 8.6 Hz), 6.85 (s, 1H ), 5.29-5.18 (m, 1H), 4.11-3.98 (m, 4H), 3.75- 3.70 (br.d, 2H), 3.61 (s, 3H), 3.26-3.11 (m, 2H), 3.04-2.96 (br.-t, 2H), 2.44 (s, 3H), 1.89-1.85 (br.d, 2H), 1.67-1.37 (m, 6H).

IR (KBr tab.) (Cm- ¹ ): 1714, 1657, 1651, 1564, 1514, 1462, 1362.

mp (Et ₂ 0-EtOH): 270-272 Example 6 1 1,3-Getyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3di L) -1-Piperidinyl] -6-morpholino-1H-imidazo [4,5-g] quinolin-2-one (compound 61)

 The title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 60 obtained in Example 60 was used instead of the compound 26 (yield: 39%). .

iH-NMR (CDCl ₃ ) δ (ppm): 8.04 (d, IH, J = 1.7 Hz), 7.50 (dd, IH, J = 8.6, 1.7 Hz), 7.41 (s, IH), 7,27 (s , IH), 7.10 (d, IH, J = 8.6Hz), 6.44 (s, IH), 5.25-5.16 (m, IH), 4.07-3.95 (m, 4H), 3.90-3.86 (m, 6H), 3.67-3.64 (m, 4H), 3.61 (s, 3H), 3.25- 3.10 (m, 2H), 2.98-2.89 (br.-t, 2H), 2.43 (s, 3H), 1.86-1.82 (br. d, 2H), 1.45- 1.36 (m, 6H).

IR (KBr tab.) (Cm ¹ ): 1718, 1697, 1606, 1513, 1466, 1417, 1362.

mp (Et ₂ 0-EtOH): 274-276:

Example 6 27-chloro-1,3-diethyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo Quinazolin-3-yl) -1-piperidinyl] -1Η-imidazo [4,5- _g ] isoquinolin-2-one (compound 63)

 Dissolve 448 mg (1.26 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3- (4-piperidinyl) quinazoline hydrobromide in 7 ml of DMF, To this, 358 mg (1.15 mmol) of 5,7-dichloro-1,3-getyl-2,3-dihydro-1H-imidazo [4,5-g] isoquinolin-2-one (compound w) obtained in Reference Example 20 ), 800 mg (5.78 mmol) of potassium carbonate and 80 mg (0.482 mmol) of potassium iodide were added, and the mixture was heated with stirring at 130 ° C for 15 hours. The reaction solution was allowed to cool, concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer is washed, dried, and the solvent is distilled off. The residue is purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1), and recrystallized from a mixed solvent of ethanol and ether. This gave 289 mg (yield 42%) of the title compound as white crystals.

iH-NMR (CDCl ₃ ) δ (ppm): 8.03 (d, IH, J = 1.5 Hz), 7.58 (s, IH), 7.49 (dd, IH, J = 8.2, 1.5Hz), 7.28 (s, 1H), 7.11 (s, 1H), 7.10 (d, 1H, J = 8.2Hz), 5.31-5.25 (m, 1H), 4.12-3.87 (m, 6H ), 3.60 (s, 3H), 3.21-3.04 (m, 4H), 2.43 (s, 3H), 1.91-1.83 (m, 2H), 1.43 (t, 3H, J = 7.3Hz), 1.40 (t, (3H, J = 7.3Hz).

Example 6 3 1,3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -1H-imidazo [4,5-g] isoquinolin-2-one (compound 62)

 To a solution of 170 mg (0.310 mmol) of compound 63 obtained in Example 62 in 10 ml of acetic acid was added 80 mg of 10% Pd / C, and the mixture was stirred at room temperature under a hydrogen stream for 12 hours. After the catalyst was filtered off using a filter aid, the filtrate was neutralized with a 2N aqueous sodium hydroxide solution and extracted with chloroform. After washing and drying the organic layer, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (developing solvent: hexane Z ethyl acetate).

 Purified in 1) and recrystallized from a mixed solvent of ethanol and ether to obtain 96.2 mg (yield 62%) of the title compound as white crystals.

iH-NMR (CDCl ₃ ) δ (ppm): 8.08 (d, IH, J = 5.6 Hz), 8.03 (d, IH, J = 1.5 Hz), 7.68 (s, IH), 7.49 (dd, 1H, J = 8.6, 1.5Hz), 7.28 (d, 1H, J = 5.6Hz), 7.22 (s, IH), 7.10 (d, 1H, J = 8.6Hz), 5.31-5.27 (m, IH), 4.13-3.98 (m, 4H), 3.91-3.83 (br.d, 2H), 3.60 (s, 3H), 3.22-3.05 (m, 4H), 2.42 (s, 3H), 1.91-1.82 (m, 2H), 1.45 (t, 3H, J = 6.9Hz), 1.41 (t, 3H, J = 7.3Hz).

 Example 6 4 1,3-Detyl-2,3-dihydro-5- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -7-morpholino-1H-imidazo [4,5-g] isoquinolin-2-one (compound 64)

 The title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 63 obtained in Example 62 was used instead of the compound 26 (yield: 12%). .

iH-NMR (CDCl ₃ ) δ (ppm): 8.03 (d, IH, J = 1.5 Hz), 7.49 (dd, IH, J = 8.6, 1.5 Hz), 7.48 (s, IH), 7.10 (d, IH , J = 8.6Hz), 7.03 (s, 1H), 6.44 (s, IH), 5.39-5.14 (m, 1H), 4.08-3.85 (m, 10H), 3.60 (s, 3H), 3.50 (t, 4H, J = 5.6Hz), 3.22-3.04 (m, 4H), i6A:> didTL§ / 66 oϊ-

Phosphorus-2,8-dione (compound b)

First step: methyl 2,3-dihydro-2-oxo-1H-benzimidazol-5-carboxylate which can be synthesized by a known method (for example, a method described in JP-A-61-207388) 5.76 g (30.0 mmol) suspended in 50 ml of DMF, 60% sodium hydride

2.64 g (66.0 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. When the reaction mixture became homogeneous, 3.73 ml (60.0 mmol) of methyl iodide was added dropwise, and the mixture was further stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added thereto, and the precipitated crystals were separated by filtration, washed with water, and washed with methyl 2,3-dihydro-1,3-dimethyl-2-oxo-1H-benzimidazole-5-carboxylate. g of crude product was obtained (76% yield).

 Second step: 4.4 g (20.0 mmol) of the compound obtained in the first step was dissolved in 10 ml of acetic anhydride, and 1.02 ml (25.0 mmol) of fuming nitric acid was added dropwise, followed by stirring at room temperature for 20 minutes. Ice water was added thereto, and the precipitated crystals were filtered off and washed with water to give 2,3-dihydro-1,3-dimethyl-6-dito-2-oxo-1H-benzoimidazole-5. -A crude product of methyl carboxylate 4.0 g was obtained (yield 75%).

 Third step: 2.0 g (7.54 mmol) of the compound obtained in the second step was dissolved in 110 ml of ethanol, 200 mg of 10% Pd / C was added, and the mixture was vigorously stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution is filtered off using a filter aid, and the filtrate is concentrated to give 6-amino-2,3-dihydroxy-1,3-dimethyl-2-oxo-1H-benzoimidazoyl-5-butane. Methyl acid

 1.71 g of a crude product was obtained (96% yield).

Fourth step: 410 mg (1.74 mmol) of the compound obtained in the third step was suspended in 10 ml of formamide and stirred at 170 for 3 hours. After allowing the reaction solution to cool, water was added thereto, and the mixture was extracted with chloroform. The organic layer was washed and dried, and the solvent was distilled off. The residue was recrystallized from ether to give the title compound as white crystals (71.4 mg, yield 18%), iH-NMR (CDCl ₃ ) δ (ppm): 8.50 (s, 1H), 7.61 (s, 1H), 7.26 (s, 1H), 3.45 (s, 3H), 3.43 (s, 3H).

Reference Example 3 2,3,7,8-Tetrahydro-1,3-dipropyl-1HJH-imidazo [4,5-g] quinazoline-2,8-dione (Compound c) The title compound was obtained as white crystals according to the method of Reference Example 2 except that propyl iodide was used instead of methyl iodide (4-step yield: 39%).

Ή- negation _{R (CDC1 3) d (ppm} ): 8.15 (s, 1H), 7.83 (s, 1H), 7.34 (s, 1H), 3.97 (q, 2H, J = 7.3Hz), 3.92 (q, 2H, J = 7.3Hz), 1.92-1.78 (m, 4H), 1.01 (t, 3H, J = 7.3Hz), 1.00 (t, 3H, J = 7.3Hz).

Reference Example 4 1,3-Dibutyl-2,3,7,8-tetrahydro-1HJH-imidazo [4,5-g] quinazoline-2,8-dione (Compound d)

 The title compound was obtained as white crystals according to the method of Reference Example 2 except that butyl iodide was used instead of methyl iodide (4-step yield: 18%).

iH-NMR (CDCl ₃ ) δ (ppm): 8.16 (s, 1H), 7.84 (s, 1H), 7.34 (s, 1H), 4.00 (t, 2H, J = 6.9Hz), 3.97 (t, 2H , J = 6.9Hz), 1.82-1.70 (m, 4H), 1.43-1.31 (m, 4H), 1.01 (t, 3H, J = 7.3Hz), 0.99 (t, 3H, J = 7.3Hz).

 Reference Example 5 5,8-dichloro-2,3-dihydro-1,3-dimethyl-1H-imidazo [4,5-g] quinazoline-2-one (Compound e)

 First step: methyl 6-amino-2,3-dihydro-1,3-dimethyl-2-oxo-1H-benzoimidazole-5-carboxylate obtained in the second step of Reference Example 2. 1.70 g (7.23 mmol) and a mixture of 1.74 g (28.9 mmol) of urea were stirred at 180 ° C. for 2 hours. After allowing the reaction solution to cool, water was added, and the precipitated crystals were separated by filtration, washed with water, and washed with 2,3,5,6,7,8-hexahydro-1,3-dimethyl-1H-imidazo [4, 5-g] quinazoline-2,6,8-trione 1.44 g of a crude product was obtained (yield 81%).

 Second step: The title compound was obtained as white crystals (yield 79%) according to the method of the first step of Example 2, except that the compound obtained in the first step was used.

 ! H-NMRiCDCls) δ (ppm): 7.62 (s, 1H), 7.45 (s, 1H), 3.58 (s, 3H), 3.55 (s, 3H). Reference Example 65,8-dichloro-1,3 -Getyl-2,3-dihydro-1H-imidazo [4,5-g] quinazolin-2-one (Compound f)

6-Amino-2,3-dihydro-1,3-dimethyl-2-oxo-1H-benzimidazole-5-force obtained in accordance with the method of the second step of Reference Example 2 in place of methyl rubonate. 6-a The title compound was converted into white crystals according to the method of Reference Example 5, except that methyl mino-1,3-getyl-2,3-dihydro-2-oxo-1H-benzimidazol-5-carboxylate was used. (Two-step yield 70%).

 ! H-NMRCCDCls) δ (ppm): 7.60 (s, 1H), 7.46 (s, 1H), 4.08 (q, 2H, J = 7.3Hz), 4.05 (q, 2H, J = 7.3Hz), 1.44 ( t, 3H, J = 7.3Hz), 1.41 (t, 3H, J = 7.3Hz).

Reference Example 7 5,8-dichloro-2,3-dihydro-1,3-dipropyl-1H-imidazo [4,5-g] quinazolin-2-one (Compound g)

 6-Amino-2,3-dihydro-1,3-dimethyl-2-oxo-1H-benzimidazole-5-force obtained in accordance with the method of the second step of Reference Example 2 in place of methyl rubonate 6 According to the method of Reference Example 5, except that methyl 2-amino-1,3-dimethyl-2,3-dihydro-2-oxo-1,3-dipropyl-1H-benzimidazole-5-carboxylate was used. Thus, the title compound was obtained as white crystals (two-step yield: 55%).

 ! H-NMRCDMSO-de) <5 (ppm): 7.79 (s, 1H), 7.77 (s, 1H), 3.97 (q, 2H, J = 7.3Hz), 3.94 (q, 2H, J = 7.3Hz) , 1.73-1.70 (m, 4H), 0.89 (t, 3H, J = 7.3Hz), 0.87 (t, 3H, J = 7.3Hz).

 Reference Example 8 3- [l- (7-ethylamino-6-nitroquinazoline-4-yl) -4-piperidinyl] -3,4-dihydro-1,6-dimethyl-4-oxoquinazoline (Compound h)

 Instead of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3- (4-piperidinyl) quinazolinehydrobromide, a method described in JP-A-8-151377 is used. Using 3,4-dihydro-6-methyl-4-oxo-3- (4-piberidinyl) quinazoline hydrobromide, which can be synthesized, can be synthesized by the method described in International Publication WO94 / 06648 instead of compound b. The title compound was obtained as white crystals (yield 64%) according to the method of the second step of Example 2, except that 4-chloro-7-ethylamino-6-nitroquinazoline was used.

 iH-NMR (DMSO-de) δ (ppm): 8.87 (s, 1H), 8.58 (s, 1H), 8.11 (s, 1H), 8.10 (s, 1H), 7.65-7.56 (m, 2H), 7.03 (s, 1H), 5.24-5.16 (m, 1H), 4.70-4.65 (br.d, 2H), 3.51-3.35 (m, 4H), 2.51 (s, 3H), 2.20-2.14 (m, 4H ), 1.42 (t, 3H, J = 7.3Hz).

Reference Example 9 2,3,5,6,7,8-Hexahydro-1,3-dimethyl-1H, 6H, 7H-imidazo [4,5-g] Phthalazine-2,5,8-trione (Compound j)

First step: can be synthesized by a known method [for example, the method described in J. Heterocycl. Chem., 10, 891 (1973)]. Dissolve 9.24 g (41.2 mmol) of dimethyl 5-diaminofurate in 100 ml of acetonitrile, and add 10.4 g of Ν, Ν-carbonyldiimidazole

(63.9 mmol) was added, and the mixture was heated with stirring at 60 for 5 hours. After allowing the reaction mixture to cool, water was added, and the precipitated crystals were separated by filtration and washed with water to give 8.24 g of methyl 2,3-dihydro-2-oxo-1H-benzoimidazole-5,6-dicarboxylate. The product was obtained (yield 73%). Second step: 2.50 g (10.0 mmol) of the compound obtained in the first step was suspended in 45 ml of DMF, 0.88 g (22.0 mmol) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes. When the reaction solution became homogeneous, 1.37 ml (22.0 mmol) of methyl iodide was added dropwise, and the mixture was further stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added thereto, and the precipitated crystals were separated by filtration, washed with water, and 2,3-dihydro-1,3-dimethyl-2-oxo-1H-benzoimidazole-5,6-. 2.78 g of a crude product of methyl dicarboxylate was obtained (yield: 99%).

 Third step: 2.7 g (9.70 mmol) of the compound obtained in the second step was dissolved in 50 ml of methanol, 7.0 ml of hydrazine monohydrate and 7.0 ml of triethylamine were added, and the mixture was heated under reflux for 3 hours. After allowing the reaction solution to cool, the precipitated crystals were separated by filtration and washed with ethanol to obtain 1.85 g of a crude product of the title compound (yield: 77%).

 ! H-NMRiDMSO-de) <5 (ppm): 7.71 (s, 2H), 3.45 (s, 6H).

 Reference Example 10 1,3-Getyl -2,3,5,6,7,8-Hexahydro-1H, 6H, 7H-imidazo [4,5-g] phthalazine-2,5,8-trione (compound k)

 First step: In place of methyl 2,3-dihydro-2-oxo-1H-benzimidazole-5,6-dicarboxylate, a known method [for example, tetrahedron-residues]

 (Tetrahedron Lett.), Vol. 28, p. 1389 (1987)], 2,3-dihydro-5,6-dimethyl-1H-benzimidazole.

Reference example except that 2-one is used and iodide tyl is used instead of methyl iodide According to the method of the second step of 9, a crude product of 1,3-getyl-2,3-dihydro-5,6-dimethyl-1H-benzoimidazoyl-2-one was obtained (yield 68 %).

Second step: Dissolve 1.00 _g (4.58 mmol) of the compound obtained in the first step in a mixed solvent of 10 ml of 2-methyl-1-propanol and 15 ml of water. 3.62 g (22.9 mmol) of lithium was gradually added. After heating and stirring at 110 for 1 hour, 1.45 g (9.16 mmol) of potassium permanganate was further added gradually,

The mixture was heated and stirred at 110 for 1 hour. Thereafter, the mixture was filtered while hot using a filter aid, and the filtrate was concentrated. The obtained residue was dissolved in water, a 2N aqueous hydrochloric acid solution was added dropwise thereto, and the precipitated crystals were separated by filtration and washed with water to give 1,3-dimethyl-2,3-dihydro-2-oxo-1H-benzene. 779 mg of a crude product of zimidazole-5,6-dicarboxylic acid was obtained (yield: 61%).

Third stage: the compound obtained in the second stage 300mg of (1.08 mm _O l) was dissolved in a mixed solvent of acetic acid 3ml, water 3ml, hydrazine monohydrate 0.26ml a (5.40 mmol) was added, heated between at 1.5 Refluxed. After cooling, the precipitated crystals were separated by filtration and washed with methanol to obtain a crude product of the title compound (102 mg, yield 34%).

iH-NMR (DMSO-d ₆ ) δ (ppm): 7.75 (s, 2H), 4.01 (q, 4H, J = 7.3 Hz), 1.25 (t, 6H, J = 7.3 Hz).

 Reference Example 1 1 2,3,5,6,7,8-Hexahydro-1,3-dipropyl-1H, 6H, 7H-imidazo

 [4,5-g] phthalazine -2,5,8-trione (compound m)

 The title compound was obtained as white crystals according to the method of Reference Example 9 except that propyl iodide was used instead of methyl iodide (three-step yield: 57%).

 iH-NMR (DMSO-de) δ (ppm): 7.75 (s, 2H), 3.94 (t, 4H, J = 7.3Hz), 1.77-1.64 (m, 4H), 0.89 (t, 6H, J = 7.3 Hz).

 Reference Example 1 2,2,3,5,6,7,8-Hexahydro-1,3-diisopropyl-1H, 6H, 7H imidazo [4,5-g] phthalazine-2,5,8-trione (compound n)

 The title compound was obtained as white crystals according to the method of Reference Example 10 except that isopropyl iodide was used in place of iodinated chill (three-step yield: 19%).

iH-NMR (DMSO-de) 6 (ppm): 7.79 (s, 2H), 4.80-4.70 (m, 2H), 1.51 (d, 12H, J = 6.9Hz).

Reference Example 13 1,3-Dibutyl-2,3,5,6,7,8-hexahydro-1H, 6H, 7H-imidazo [4,5-g] phthalazine-2,5,8-trione (compound o)

 The title compound was obtained as white crystals (33% yield) according to the method of Reference Example 10 except that butyl iodide was used instead of iodinated chill.

iH-NMR (DMSO-de) 6 (ppm): 7.74 (s, 2H), 3.98 (t, 4H, J = 6.9Hz), 1.72-1.61 (m, 4H), 1.38-1.25 (m, 4H), 0.90 (t, 6H, J = 7.3Hz).

 Reference Example 1 4 2,3,5,6,7,8-Hexahydro-1,3-diisobutyl-1H, 6H, 7H-imidazo [4,5-g] phthalazine-2,5,8-trione (compound )

 The title compound was obtained as white crystals according to the method of Reference Example 10 except that isobutyl iodide was used instead of iodide tyl (three-step yield: 20%).

 iH-NMR (DMSO-de) δ (ppm): 7.75 (s, 2H), 3.81 (d, 4H, J = 7.6Hz), 2.23-2.07 (m, 2H), 0.90 (d, 12H, J = 6.6 Hz).

 Reference Example 15 1,3-Diaryl-2,3,5,6,7,8-hexahydro-111,611,711-imidazo [4,5-g] phthalazine-2,5,8-trione (Compound Q)

 The title compound was obtained as white crystals according to the method of Reference Example 9 except that aryl bromide was used instead of methyl iodide (three-step yield: 46%).

 iH-NMR (DMSO-de) δ (ppm): 7.55 (s, 2H), 6.02-5.89 (m, 2H), 5.22-5.06 (m, 4H), 4.65-4.64 (m, 4H).

 Reference Example 16 1,3-dibenzyl-2,3,5,6,7,8-hexahydro-1H, 6H, 7H-imidazo [4,5-g] phthalazine-2,5,8-trione (compound r)

 The title compound was obtained as white crystals according to the method of Reference Example 9 except that benzyl bromide was used instead of methyl iodide (57% in three steps).

iH-NMR (DMSO-d ₆ ) δ (ppm): 7.74-7.25 (m, 12H), 5.21 (s, 4H).

 Reference Example 1 7 8-chloro-1,3-getyl-2,3-dihydro-1H-imidazo [4,5-g] quinolin-2-one (Compound S)

1,3-Jetyl-2,3,5,6-tetra can be synthesized by the method described in JP-A-56-7784. Using hydro-2,5-dioxo-1H-imidazo [4,5-g] quinoline-7-carboxylate, according to the method described in New Experimental Chemistry, Vol. 14, p. 2075 (Maruzen, 1978). To give the title compound.

Ή-image R (CDC1 ₃ ) δ (ppm): 8.61 (d, 1H, J = 4.9Hz), 7.64 (s, 1H), 7.62 (s, 1H), 7.42 (d, 1H, J = 4.9Hz) , 4.12-4.02 (m, 4H), 1.63-1.39 (m, 6H).

Reference Example 1 8 8-chloro-1,3-getyl-2,3-dihydro-2-oxo-1H-imidazo [4,5-g] quinoline-7-carboxylate (Compound t)

 Example 2 was repeated except that ethyl 1,3-getyl-2,3,5,6-tetrahydro-2,5-dioxo-1H-imidazo [4,5-g] quinolin-7-carboxylate was used. The title compound was obtained according to a one-step procedure (95% yield).

iH-NMR (CDCl ₃ ) δ (ppm): 9.11 (s, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 4.50 (q, 2H, J = 7.3Hz), 4.13-4.02 (m , 4H), 1.50-1.40 (m, 9H).

 Reference Example 1 96,8-Dichloro-1,3-getyl-2,3-dihydro-1H-imidazo [4,5-g] quinolin-2-one (Compound U)

 The title compound was obtained according to the method described in JP-A-54-154797, except that getyl malonate was used in place of ethyl acetate.

iH-NMR (CDCl ₃ ) δ (ppm): 7.59 (s, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 4.11-4.00 (m, 4H), 1.46- 1.38 (m, 6H) .

 Reference Example 20 5,7-dichloro-1,3-getyl-2,3-dihydro-1H-imidazo [4,5-g] isoquinolin-2-one (compound w)

 First step: Commercially available 2-hydroxybenzimidazole is used in place of methyl 2,3-dihydro-2-oxo-1H-benzimidazol-5-carboxylate, and methyl iodide is used instead of methyl iodide. In the same manner as in the first step of Reference Example 2, except for using 1,1,3-getyl-2,3-hydroxy-1H-benzimidazol-2-one was obtained.

Second step: 875 mg (6.56 mmol) of aluminum chloride are suspended in 3 ml of carbon disulfide, and 1.04 _g (5.46 mmol) of the compound obtained in the first step and 0.55 ml (5.76 mmol) of 3-chloropropionyl chloride are obtained. Drop 5 ml of carbon disulfide solution over 5 minutes under ice-cooling The mixture was stirred at 50 for 4 hours. After allowing the reaction solution to cool, the solvent was distilled off under reduced pressure, and 15 ml of sulfuric acid was added dropwise to the obtained residue under ice-cooling, and the mixture was heated and stirred at 100 for 1.5 hours. After allowing the reaction solution to cool, it was poured into ice water, extracted with ethyl acetate, and the organic layer was washed and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1) to give 1,3-dimethyl-2,3,6,7-tetrahydro-1H 292 mg (yield 22 ° /.) Of -indeno [5,6d] imidazole-2,5-dione were obtained. Third step: To a solution of 621 mg (2.54 mmol) of the compound obtained in the second step in 5 ml of methanol was added 1 ml (7.45 mmol) of isoamyl nitrite and 5 ml of hydrochloric acid under ice-cooling, followed by stirring at room temperature for 3 hours. The deposited precipitate was collected by filtration to obtain yellow crystal A. On the other hand, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/2) to obtain yellow crystals B. Combine A and B and 584 mg of 1,3-getyl-2,3,6,7-tetrahydro-6-hydroxyimino-1H, 6H-indeno [5,6d] imidazole-2,5-dione (yield 84%).

 Fourth step: 5 ml of hydrochloric acid was added to a solution of 316 mg (1.15 mmol) of the compound obtained in the third step and 270 mg (1.29 mmol) of phosphorus pentachloride in 7 ml of phosphorus oxychloride, and the mixture was heated and stirred at 70 ° C for 4.5 hours. After allowing the reaction solution to cool, the solvent was distilled off under reduced pressure, the residue was poured into ice water, and extracted with ethyl acetate. After washing and drying the organic layer, the solvent was distilled off under reduced pressure to obtain 358 mg (yield: 100%) of the title compound.

iH-NMR (CDCl ₃ ) δ (ppm): 7.46 (1H, s), 7.20 (1H, s), 6.95 (1H, s), 4.07-3.92 (4H, m), 1.46-1.27 (6H, m) .

 Reference Example 2 1 5-Chloro-1,3-getyl-2,3,7,8-tetrahydro-1H-imidazo [4,5-g] quinolin-2-one (Compound X)

First step: Using 5-amino-1,3-dimethyl-2,3-hydroxy-1H-benzimidazol-2-one, which can be synthesized by a known method, using the journal 'OB' Medicinal Chemistry (J. Med. Chem.), 23, p. 506 (1980), based on the method described in 1,3-Getyl-2,3,5,6,7,8-hexahydro-1H, 6H- The imidazo [4,5-g] quinoline-2,7-dione was obtained. Second step: The title compound was obtained as white crystals according to the method of the first step of Example 2 except that the compound obtained in the first step was used (yield: 88%).

iH-NMR (CDCl ₃ ) δ (ppm): 7.40 (s, 1H), 6.81 (s, 1H), 4.02-3.91 (m, 4H), 3.87-3.82 (m, 2H), 2.87 (t, 2H, J = 7.6Hz), 1.43-1.32 (m, 6H).

Industrial applicability

 INDUSTRIAL APPLICABILITY According to the present invention, a piperidine derivative or a drug having adenosine uptake inhibitory activity and useful for preventing or treating inflammation such as myocardial protection, renal diseases (nephritis, diabetic nephropathy, etc.), tengitis, or foot edema A physically acceptable salt is provided.

Claims

The scope of the claims

 1. Formula (I)

(Wherein Ri represents hydrogen, substituted or unsubstituted lower alkyl or halogen, and R2, R3, R4 and R5 are the same or different and are hydrogen, halogen, amino, mono or di-lower alkylamino, substituted or unsubstituted Lower alkylamino, nitro, cyano, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or Represents an unsubstituted lower alkanoyl, substituted or unsubstituted aralkyloxy or substituted or unsubstituted lower alkanoyloxy, n represents 0, 1 or 2, and X—Y represents formula) or formula (b) ( b)

(Wherein, R ⁶ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl, and R ⁷ represents hydrogen, hydroxy, Represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted lower alkylthio. (I), equation (ii), equation (iii), equation (iv) or equation (V)

[Wherein, R ⁸ and R ⁹ are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl. , Rio is hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, halogen or NR ¹² Ri3 (where Ri2 and Ria are the same or different hydrogen , substituted or unsubstituted lower alkyl, substituted also properly unsubstituted cycloalkyl, substituted or unsubstituted Ariru, or substituted or represents unsubstituted Ararukiru, Ri ² and R1 ³ a is together such connexion N Rii represents hydrogen, substituted or unsubstituted lower alkyl, cyano, etc. It represents carboxy or substituted or unsubstituted lower grade alkoxycarbonyl, salt Z is acceptable O or piperidine derivative or a pharmacologically represented by represents a represents a S]}.

 2. Q

Is)

The piperidine derivative according to claim 1, or a pharmaceutically acceptable salt thereof.

3. Ri, R2, R4, R5 and Rio are hydrogen, R3 is methyl, R8 and R9 are ethyl, and X—Y is

3. The piperidine derivative according to claim 2, wherein Z is 0, or a pharmaceutically acceptable salt thereof.

4. Ri, R2, R4 and R5 are hydrogen, R3 is methyl, R8 and R9 are ethyl, Rio is morpholino, and X—γ is

 3. The piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein Z is 0.

 5 Q

 The piperidine derivative according to claim 1, or a pharmaceutically acceptable salt thereof.

6. Rl, R2, R4 and R5 are hydrogen, R3 is methyl, R8 and R9 are ethyl, Rio is morpholino, and X—Y is

 \

The piperidine derivative according to claim 5, which is H ₃ C ′ 0, or a pharmaceutically acceptable salt thereof.