JP2988683B2 - Imidazoquinolone derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {X is formula II [R<2> is H, OH, alkyl, (substituted) aryl, etc.], etc.; Y is O or S; R<1> is H, alkyl, (substituted) aryl, etc.; R<3> is alkyl, cycloalkyl, alkenyl, etc.; R<4> and R<5> are H, lower alkyl, trifluoromethyl, halogen, lower alkanoyl, aroyl, etc.}. EXAMPLE:5-n-Butyl-1-methyl-1H, 5H-imidazo[4,5-c]quinoline-4-one. USE:A bronchodilator and antiallergic agent. PREPARATION:A compound expressed by formula III is reacted with a com pound expressed by the formula R<3>-Z (Z is eliminating group), preferably in the presence of a base (e.g. potassium carbonate or sodium methoxide) to pro vide the compound expressed by formula I (group X is formula II).

Description

The present invention relates to a novel imidazoquinolone derivative having a 1H, 5H-imidazo [4,5-c] quinolin-4-one skeleton, which exhibits a bronchodilator effect and an antiallergic effect. About.

2. Description of the Related Art 1H-imidazo [4,5-c] quinolines useful as bronchodilators and 1H-imidazo [4,5-c] quinolin-4-amines useful as antiviral agents represented by the following formulas: It is disclosed in JP-A-60-123488.

(Wherein ^RA is hydrogen, alkyl, benzyl, phenyl, etc.
R ^B is hydrogen, alkyl, etc. and R ^C is hydrogen, hydroxyl,
The object of the present invention is to provide a substituent at the 5-position of 1H, 5H-imidazo [4,5-c] quinolin-4-ones [formula (I) provides compounds having the corresponding 'to R ³ are, bronchodilators are useful to the process of bronchial disorders such as bronchial asthma, based on findings that show excellent effect of anti-allergy, novel imidazoquinolone derivatives in Is to do.

Means for Solving the Problems The present invention provides a compound represented by the general formula (I) Ｘwhere X is [Wherein R ² is hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, aralkyl, aralkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, — (CH ₂ ) _m CO ₂ R ⁶ Wherein R ⁶ represents hydrogen or lower alkyl, m represents an integer of 0 to 3, thiol or halogen, or a nitrogen atom, Y represents oxygen or sulfur, R ¹ represents hydrogen, Alkyl, cycloalkyl, alkenyl, aralkyl, aralkenyl or substituted or unsubstituted aryl,
R ³ is alkyl, cycloalkyl, alkoxyalkyl,
Alkenyl, aralkyl, aralkenyl, - (CH _{2) n}
-Het (wherein, Het represents a substituted or unsubstituted aromatic heterocyclic group, and n is an integer of 1 to 3) or-(C
H ₂ ) _n CO ₂ R ^6a (wherein, n is as defined above, and R ^6a is
Represent defined as the same) of R ^6, R ⁴ and R ⁵ are the same or different and each is hydrogen, lower alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxyl, lower alkoxy, lower alkylthio, nitro, amino, lower alkyl An imidazoquinolone derivative represented by｝ representing amino, lower alkanoylamino, aroylamino, lower alkanoyl or aroyl [hereinafter referred to as compound (I). The same applies to compounds of other formula numbers] or a pharmacologically acceptable salt thereof.

In the definition of each group of the formula (I), the alkyl portion of the alkyl and the alkoxyalkyl means a linear or branched alkyl having 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, heptyl, octyl, nonyl, decyl and the like. As the cycloalkyl, a cycloalkyl having 3 to 8 carbon atoms, for example, cyclopropyl , Cyclopentyl, cyclohexyl, alicyclic hydrocarbon groups such as cyclooctyl, alkenyl has 2 to 6 carbon atoms, for example,
Vinyl, allyl, propenyl, isopropenyl, butenyl, hexenyl, etc., and aralkyl has 7 carbon atoms.
Benzyl, phenethyl, benzhydryl and the like; aralkenyl includes styryl and cinnamyl having 8 to 18 carbon atoms; and aryl includes phenyl and naphthyl having 6 to 10 carbon atoms. Substituents may be the same or different and have 1 to 2 lower alkyl, trifluoromethyl, hydroxyl, lower alkoxyl, lower alkylthio, nitro, halogen, amino, lower alkylamino, lower alkanoylamino,
Examples thereof include lower alkoxycarbonyl, lower alkanoyl, aroyl and the like. As the aromatic heterocyclic group, 5 to 5
Examples thereof include a 6-membered ring thienyl, furyl, pyrazolyl, oxazolyl, imidazolyl, pyridyl and the like, and examples of the substituent are the same or different and include lower alkyl, lower alkoxyl and halogen having 1 to 2 substituents.

The alkyl moiety in lower alkyl, lower alkoxyl, lower alkylthio, lower alkylamino and lower alkoxycarbonyl means a linear or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
Examples thereof include sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and the like.

Examples of the lower alkanoyl and the alkanoyl moiety in the lower alkanoylamino include those having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyl, pivaloyl, valeryl, isovaleryl and the like.

Examples of the aroyl moiety in aroyl and aroylamino include benzoyl, toluyl, propylbenzoyl, naphthoyl and the like.

Halogen means each atom of fluorine, chlorine and bromine iodine.

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

The pharmacologically acceptable acid addition salts of compound (I) include
Inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., and organic acid salts such as acetate, maleate, fumarate, tartrate, citrate, etc., and as pharmacologically acceptable metal salts, In addition to alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts and zinc salts are also included. Examples of pharmacologically acceptable organic amine addition salts include morpholine and piperidine. And the pharmacologically acceptable addition salts of amino acids include addition salts of lysine, glycine, phenylalanine and the like.

 Next, the production method of compound (I) will be described.

In the production method described below, if the defined group changes under the conditions of the method of execution or is inappropriate to carry out the method, a method commonly used in organic synthetic chemistry, for example, protection of a functional group, It can be easily implemented by applying means such as deprotection.

Production method 1 In compound (I), X is Is a compound of the following formula: (Wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above) and the following formula R ³ -Z (III) wherein R ³ is as defined above. Wherein Z represents a leaving group), preferably in the presence of a base.

Here, examples of the leaving group represented by Z include halogen atoms such as chlorine, bromine and iodine, alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxy groups such as phenylsulfonyloxy and p-toluenesulfonyloxy. Is exemplified.

The starting compound (II) can be prepared by a known method (JP-A-60-12
No. 3488) or according to it.

Examples of the base used include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal hydrides such as sodium hydride, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide.

As the reaction solvent, for example, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, alcohols such as methanol and ethanol, and solvents not involved in the reaction such as dimethyl sulfoxide are used alone or in combination.

 The reaction is completed in 30 minutes to 24 hours at 0 to 180 ° C.

Process 2 Compound in (I a), the compound wherein R ² is halogen, a group other than hydroxyl or thiol (I aa) can also be obtained by the following reaction steps.

(Wherein R ^2a has the same definition as R ² except halogen, hydroxyl or thiol, Ha means halogen, and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.) Here, the halogen represented by Ha is chlorine,
Bromine and iodine are exemplified.

Starting compound (IV) can be prepared by a known method [J. Heterocyclic C
hem., 18 , 917 (1981)] or a modification thereof.

(Step 1) Compound (V) is prepared by converting compound (IV) and an amine (VIII) represented by the following formula R ¹ NH ₂ (VIII) (wherein R ¹ has the same meaning as described above) to a base, if necessary. It can be obtained by reacting in the presence.

As the reaction solvent, base and the like, those described in Production Method 1 are similarly applied.

(Step 2) Compound (V) is subjected to catalytic reduction in the presence of, for example, a palladium / carbon or platinum oxide catalyst to give compound (V).
I) can be obtained.

(Step 3) The compound (VII) is a compound (VI) and a carboxylic acid (IX) represented by the following formula: R ^2a COOH (IX) (wherein R ^2a is as defined above) or a reactive derivative thereof. Are reacted at -10 to 50 ° C.

When reacting with compound (IX), thionyl chloride,
The reaction is preferably performed in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide (DCC) or polyphosphoric acid. The reactive derivative may be an acid halide such as acid chloride or acid bromide, an acid anhydride, or chlorocarbonate. ethyl,
Examples thereof include mixed acid anhydrides such as isobutyl chlorocarbonate, active esters such as p-nitrophenyl ester and N-oxysuccinimide ester, and orthoesters.

(Step 4) Compound (VII) is optionally added in the presence of a ring closing agent in the range of 50 to 250.
The compound (Iaa) can be obtained by heating to 100C, more preferably 100 to 250C.

As the ring closing agent, polyphosphoric acid, polyphosphate ester,
Sulfuric acid, acetic acid, phosphorus pentoxide, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, thionyl chloride and the like.

Examples of the reaction solvent include hexamethylphosphoramide, diphenyl ether, glycerin triethyl ether, butyl ether, isoamyl ether, diethylene glycol, triethylene glycol, Dowtherm A (Dow Chemical Co.) and the like.

Production Method 3 In compound (I), compound (Ib) in which R ⁴ and / or R ⁵ is a group other than hydrogen can be obtained by starting from compound (Ic) in which the corresponding group is hydrogen as a starting material. Grouping (eg, nitration, halogenation, alkanoylation,
Aroylation).

For example, the nitration reaction is carried out in a solvent or without solvent in the presence of a nitrating agent such as nitric acid, fuming nitric acid, potassium nitrate or the like, preferably sulfuric acid, acetic anhydride or the like. The reaction is-
At a temperature of 50 to 100 ° C., a solvent that does not participate in the reaction, such as an organic acid such as acetic acid, or a halogenated hydrocarbon such as methylene chloride or chloroform is used.

The halogenation reaction uses, for example, a halogen such as chlorine, bromine, or iodine, a copper halide, or a halogenating agent such as N-halosuccinimide, preferably iron, iodine, or the like.
It is carried out in the presence of a catalyst such as a peroxide such as perbenzoic acid or under light irradiation. The reaction temperature is between -50 and 150C.

Alkanoylation and aroylation reactions are carried out under so-called Friedel-Crafts type reaction conditions using an acylating agent such as an acid halide, acid anhydride or active ester of the corresponding carboxylic acid and a Lewis acid catalyst such as aluminum halide. Will be implemented. The reaction is carried out at -50 to -150 ° C, and as the solvent, halogenated hydrocarbons such as methylene chloride and chloroform, and those not involved in the reaction such as carbon disulfide are used.

Production Method 4 Compound (Iab) in which R ² is hydroxyl or thiol in compound (Ia) can be obtained using compound (VI) shown in Production Method 2 as a raw material.

In the case of the compound (I ab ') wherein R ² is hydroxyl, it can be obtained by reacting the compound (VI) with, for example, phosgene, carbonyldiimidazole, urea, etc. in a solvent at 0 to 150 ° C. As the solvent, those which do not participate in the reaction, such as alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and halogenated hydrocarbons such as chloroform are used.

In the case of the compound (I ab ″) in which R ² is a thiol, the compound (VI) can be obtained using the compound (VI) and, for example, thiophosgene, thiocarbonylimidazole, thiourea, or the like, in the same manner as in the case where R ² is hydroxy.

Production method 5 Compound (Id) wherein X in compound (I) is nitrogen
Is obtained by using the compound (VI) shown in Production Method 2 as a raw material and using, for example, sodium nitrite, in an alcohol-acid-based solvent.
It can be obtained by performing the reaction at 150 ° C. The alcohol used as a solvent includes methanol and ethanol, and the acid includes hydrochloric acid and phosphoric acid phosphoric acid.

Intermediates and target compounds in the above-mentioned production method can be isolated and purified by subjecting them to purification methods commonly used in organic synthetic chemistry, for example, extraction, washing, drying, concentration, recrystallization, various chromatography, and the like. . In addition, the intermediate can be subjected to the next reaction without purification.

When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is,
When it is obtained in a free form, a salt may be formed by a usual method.

The compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

The first of the specific examples of compound (I) obtained by each production method
It is shown in the table.

Next, the bronchodilator effect, antiallergic effect, antiasthmatic effect and acute toxicity of the representative compound (I) will be described in Test Examples.

Test Example 1 passive Schultz-Dale effect on (Schultz-Dale) reaction (bronchodilation) Eda et al [Japan Pharmacology Journal, 66, 237 (1970)] of the weight of the previously prepared rabbit anti-ovalbumin serum in a way 350~500g Hartley male guinea pigs were passively sensitized by intraperitoneal administration, and after 24 hours the trachea was excised and used for experiments. Trachea
The method of Emmerson and Mackay [J. Pharm. Pharmacol., 31 ,
798 (1979)] and prepare a zig-zag strip at 37 ° C.
And suspended in a Krebs-Henseleit solution under a gas mixture of 95% oxygen and 5% carbon dioxide, and stabilized for about 1 hour. Then, ovalbumin as an antigen was added (final concentration; 1%).
μg / ml) isotonic transducer (TD-112)
S; Nihon Kohden) and recorded on a recorder (TYPE3066; Yokogawa Hokushin Electric). After the shrinkage reaches a certain level, the test compound is added cumulatively and its relaxation rate is determined from the regression line to 50%.
The concentration showing the% relaxation rate (IC ₅₀ ) was calculated. The results are shown in Table 2.

Test Example 2 Antiallergic Action Test The antiallergic action was examined according to a passive cutaneous anaphylaxis (PCA) test using rats. As an experimental animal, a Wistar male rat weighing 180 to 220 g was used for collecting antiserum, and a Wistar male rat weighing 120 to 140 g was used for the PCA test.

A) Preparation of anti-ovalbumin (EWA) rat serum Stotlan
d and Share method (Can.J.Physiol.Pharmacol., 52 , 11
14 (1974)] to prepare anti-EWA rat serum. That is, 1 mg of EWA was mixed with aluminum hydroxide gel 20 mg and pertussis diphtheria tetanus combination vaccine 0.5 ml,
The rats were subcutaneously injected into the footpad in four divided doses. After 14 days, blood was collected from the carotid artery, serum was separated and stored frozen at -80 ° C.
The 48 hour homologous PCA titer of this antiserum was 1:32.

B) 48-hour homologous PCA test in rats Using three rats per group, 0.05 ml each of anti-EWA rat serum diluted 8-fold with physiological saline was injected into two sites in the back skin of which the hair had been depilated passively. I was sensitized. 47 hours later, the test compound or its solution (saline or CMC solution) was orally administered, and one hour later, 0.5 ml / 100 g of 1% Evans blue saline containing 2 mg of antigen EWA was administered into the tail vein. Thirty minutes later, the animal was exsanguinated to death, the skin was peeled off, and the amount of the leaked pigment in the blue stain was determined by the method of Katyama et al. (Microbiol.Immunol., 22 , 89.
(1978)]. That is, the blue dyed part was cut off with scissors, placed in a tester containing 1 ml of 1N potassium hydroxide, and incubated at 37 ° C. for 24 hours. Add 0.6 ml of 0.6N phosphoric acid: acetone (5:13) mixture, shake, add 2500r
Centrifuged at pm for 10 minutes. The absorbance at 620 nm of the supernatant was measured, and the amount of the leaked dye was quantified from a calibration curve prepared in advance. The average value of two places was used as the value of one individual, and the inhibition rate for each individual was calculated from the following equation.

When the inhibition rate was 50% or more, the PCA inhibitory action was considered positive, and the minimum effective dose (MED) was defined as the minimum dose at which a positive example was observed in at least one of the three individuals.

 Table 2 shows the results.

Test Example 3 Effect on Experimental Asthma Passive sensitization of guinea pigs was performed as follows. Rabbit anti-EWA serum prepared in advance by the method of Eda et al. [Nichiraku-jinshi, 66 , 237 (1970)] was intraperitoneally administered to a Hartley-type guinea pig (male) weighing 350 to 500 g.

30 minutes before administration of test compound, diphenhydramine 20 mg / kg
And 5 mg / kg of propranolol were administered intraperitoneally to sensitized guinea pigs for pretreatment. 17 hours after sensitization, 50 mg / kg of the test compound was orally administered to guinea pigs. Drug administration 1
After an hour, the cells were placed in a plastic observation box and sprayed with a 1.5% EWA antigen solution using a nebulizer. The time until the animals developed rollover symptoms due to dyspnea (Collapse time) was measured.

The results are shown in Table 2. According to Table 2, the compounds
The Collapse time of all test compounds except 31 was longer than that of the control to which physiological saline was administered. The effect was equal to or better than theophylline.

Test Example 4 Acute toxicity test The test compound was orally administered to a dd-type mouse male body weight of 20 to 25 g. LD ₅₀ (50% lethal dose) was determined by measuring the mortality 7 days after administration.

 Table 2 shows the results.

Compound (I) or a pharmaceutically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition of the present invention contains an effective amount of compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Can be produced by uniformly mixing the resulting salt with a pharmacologically acceptable carrier. 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 pharmaceutically acceptable carrier can be used. Oral liquid preparations, such as, for example, suspensions and syrups,
Water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil, soybean oil, preservatives such as p-hydroxybenzoic acid esters, strawberry flavor, peppermint, etc. It can be manufactured by using flavors and the like. Powders, pills, capsules and tablets are excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, polyvinyl alcohol, hydroxypropyl It can be produced using a binder such as cellulose and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration. When manufacturing tablets and capsules, a solid pharmaceutical carrier is used.

Injectable solutions can be prepared using a carrier comprising distilled water, a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.

The effective dose and the number of administrations of the compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, the age, weight, and symptoms of the patient, but are usually 1 to 50 mg / k per day.
g is preferably administered in three to four divided doses.

Alternatively, Compound (I) can be administered by inhalation in the form of an aerosol, finely divided powder or a spray solution. For aerosol administration, the compound may be dissolved in a suitable pharmaceutically acceptable solvent, such as ethyl alcohol or a combination of miscible solvents, and mixed with a pharmaceutically acceptable propellant. it can. Such an aerosol composition is used by filling it into a pressure-resistant container equipped with an aerosol valve suitable for discharging a pressurized composition. The aerosol valve is preferably a metered valve that releases an effective dosage of the predetermined aerosol composition.

Hereinafter, Examples, Reference Examples and Formulation Examples of the present invention are shown. Table 3 shows the yield and physicochemical properties of the compounds obtained in Examples 1 to 35.

Example 1 5-n-butyl-1-methyl-1H, 5H-imidazo [4,5-
c] Quinolin-4-one (compound 1) 4-hydroxy-1-methyl-1H-imidazo [4,5-
c] 3.0 g (0.015 mol) of quinoline was suspended in 50 ml of dimethylformamide, and 0.80 g of 60% sodium hydride was added under ice cooling.
(0.020 mol) and stirred at 50 ° C. for 30 minutes. The mixture was cooled again on ice, 2.6 ml (0.023 mol) of n-butyl iodide was added, and the mixture was stirred at 50 ° C for 2 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and after evaporation, the solvent was distilled off under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (elution solvent: chloroform / methanol = 17).
/ 1) and recrystallized from isopropanol-isopropyl ether to obtain 2.5 g of a compound 1.

The following Examples 2 to 7 were carried out according to the method of Example 1.

Example 2 5-tert-butoxycarbonylmethyl-1-methyl-1
H, 5H-Imidazo [4,5-c] quinolin-4-one (Compound 2) Example 3.5 5-furfuryl-1-methyl-1H, 5H-imidazo [4,5-
c] Quinolin-4-one (compound 3) Example 4. 1,5-Dimethyl-1H, 5H-imidazo [4,5-c] quinolin-4-one (compound 4) Example 5.5 5-ethyl- 1-methyl-1H, 5H-imidazo [4,5-c]
Example 6 1-Methyl-5-n-propyl-1H, 5H-imidazo [4,5
-C] Quinolin-4-one (compound 6) Example 7. 1-benzyl-5-n-butyl-1H, 5H-imidazo [4,5
-C] Quinolin-4-one (compound 7) Example 8. 5-n-butyl-1H, 5H-imidazo [4,5-c] quinolin-4-one (compound 8) Compound obtained in Example 7 7 2.4 g (0.071 mol) was dissolved in acetic acid (115 ml), 10% palladium / carbon (0.48 g) was added, and the mixture was stirred at 70 ° C. for 4 hours under a hydrogen stream. The reaction solution was filtered, the solution was concentrated under reduced pressure, neutralized by adding a saturated aqueous solution of sodium hydrogen carbonate, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol-water to obtain 1.5 g of Compound 8.

Example 9. 5-Carboxymethyl-1-methyl-1H, 5H-imidazo [4,5-c] quinolin-4-one (compound 9) 2.3 g (0.0074 mol) of the compound 2 obtained in Example 2 was methylene chloride Dissolve in 50 ml and add trifluoroacetic acid 50 under ice-cooling.
ml was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure,
Diethyl ether was added, and the generated crystals were collected by filtration. The obtained crystals were recrystallized from dimethylformamide-isopropyl alcohol to obtain 1.5 g of a compound 9.

Example 10 5-n-butyl-1-methyl-2-phenyl-1H, 5H-
Example 1 from 0.85 g (3.1 mmol) of compound c obtained in Reference Example 3 and 0.80 ml (6.2 mmol) of n-butyl iodide obtained from imidazo [4,5-c] quinolin-4-one hydrochloride (Compound 10W) In a similar manner, 0.75 g of compound 10 was obtained.

The above compound was dissolved in ethyl acetate, and an ethyl acetate solution containing hydrogen chloride was added to obtain a compound 10W.

Example 11.5-n-butyl-1,2-dimethyl-1H, 5H-imidazo [4,
5-c] quinolin-4-one hydrochloride (compound 11W) 0.24 g (1.1 mmol) of 4-hydroxy-1,2-dimethyl-1H, 5H-imidazo [4,5-c] quinoline and n-
From 0.25 ml (2.2 mmol) of butyl iodide, 0.21 g of compound 11 was obtained in the same manner as in Example 1.

The above compound was dissolved in ethyl acetate, and an ethyl acetate solution containing hydrogen chloride was added to obtain compound 11W.

Example 12.2,8-dibromo-5-n-butyl-1-methyl-1H, 5H
-Imidazo [4,5-c] quinolin-4-one (compound 1
2) and 8-bromo-5-n-butyl-1-methyl-1
H, 5H-imidazo [4,5-c] quinolin-4-one (compound 13) Sodium acetate 6 was added to a solution of 100 mg (0.39 mmol) of compound 1 obtained in Example 1 in 5 ml of chloroform.
3 mg (0.78 mmol) and 0.071 ml (0.39 mmol) of bromine were added, and the mixture was stirred at room temperature for 30 minutes, and then neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by preparative thin-layer chromatography (developing solvent; chloroform / methanol = 20/1) to obtain 12,20 mg of Compound 1 and Compound 1
3,20 mg were obtained.

Example 13. 5-n-Butyl-1-methyl-8-nitro-1H, 5H-imidazo [4,5-c] quinolin-4-one (Compound 14) 100 mg of the compound 1 obtained in Example 1 (0.39 Mmol) in 0.13 ml of sulfuric acid, and 0.045 ml of 61% nitric acid.
And a mixture of 0.35 ml of 96% sulfuric acid under ice-cooling, followed by stirring for 30 minutes. After neutralization with a 50% aqueous sodium hydroxide solution, the mixture was extracted with chloroform. After washing the organic layer with saturated saline,
The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by preparative thin-layer chromatography (developing solvent; chloroform / methanol = 10/1) to obtain 13 mg of compound 14.

Example 14. 5-n-Butyl-2-furyl-1-methyl-1H, 5H-imidazo [4,5-c] quinolin-4-one hydrochloride (Compound 15W) 2-furyl-4-hydroxy-1 -Methyl-1H, 5H-
From 0.31 g (1.2 mmol) of imidazo [4,5-c] quinoline and 0.27 ml (2.3 mmol) of n-butyl iodide, 0.24 g of compound 15 was obtained in the same manner as in Example 1.

The above compound was dissolved in ethyl acetate, and an ethyl acetate solution containing hydrogen chloride was added to obtain a compound 15W.

Example 15.5-n-butyl-1-ethyl-1H, 5H-imidazo [4,5-
c] Quinolin-4-one hydrochloride (compound 16W) 3.3 g (0.011 mol) of compound e obtained in Reference Example 5 was suspended in 100 ml of ethanol, and 10% palladium / carbon 0.7
0 g was added, and hydrogen was bubbled at room temperature for 4 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure. Ethyl orthoformate (19 ml, 0.11 mol) was added to the obtained residue, and the mixture was stirred at 110 ° C. for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was dissolved in chloroform, and the residue was added with 10 ml of ethyl acetate saturated with hydrogen chloride and triturated with ethyl acetate. The precipitated crystals were collected, washed with ethyl acetate and dried to give compound 16W.
3.0 g was obtained.

Example 16 5-n-butyl-1-n-propyl-1H, 5H-imidazo [4,5-c] quinolin-4-one hydrochloride (Compound 17W) Reference Example in place of Compound e in Example 15 Compound 17W was obtained by substantially the same method using compound f obtained in 6.

Example 17. 5-n-butyl-1-isopropyl-1H, 5H-imidazo [4,5-c] quinolin-4-one hydrochloride (compound 18W) In Reference Example 7 in place of compound e in Example 15, Using the obtained compound g, compound 18W was obtained in substantially the same manner.

Example 18. 1,5-Di-n-butyl-1H, 5H-imidazo [4,5-c] quinolin-4-one hydrochloride (Compound 19W) In Reference Example 8 in place of Compound e in Example 15, Using the obtained compound h, compound 19W was obtained in substantially the same manner.

Example 19. 5-n-butyl-2- (4-methoxyphenyl) -1-
Methyl-1H, 5H-imidazo [4,5-c] quinolin-4-one hydrochloride (Compound 20W) Using Compound m obtained in Reference Example 13, Compound 20W was obtained in the same manner as in Example 10.

Example 20 5-n-butyl-2- (3,4-dichlorophenyl) -1
-Methyl-1H, 5H-imidazo [4,5-c] quinoline-4-
On hydrochloride (Compound 21W) Using compound i obtained in Reference Example 9, an intermediate was obtained in the same manner as in Reference Examples 2 and 3. Using the intermediate without purification, compound 21W was obtained in the same manner as in Example 10.

Example 21 5-n-butyl-2-cyclopentyl-1-methyl-1
H, 5H-Imidazo [4,5-c] quinolin-4-one hydrochloride (Compound 22W) Using Compound o obtained in Reference Example 15, Compound 22W was obtained in the same manner as in Example 10.

Example 22 5-n-butyl-7,8-dimethoxy-1-methyl-1H, 5H
-Imidazo [4,5-c] quinolin-4-one hydrochloride (Compound 23W) Using compound q obtained in Reference Example 17, compound 23W was obtained in the same manner as in Example 10.

Example 23. 5-n-butyl-7-chloro-1-methyl-1H, 5H-imidazo [4,5-c] quinolin-4-one hydrochloride (compound 24W) The compound r obtained in Reference Example 18 was Using this, compound 24W was obtained in the same manner as in Example 10.

Example 24 5-n-butyl-8-chloro-1-methyl-1H, 5H-imidazo [4,5-c] quinolin-4-one (Compound 25) Using the compound s obtained in Reference Example 19, Compound 25 was obtained in the same manner as in Example 10.

Example 25 5-n-butyl-1,8-dimethyl-1H, 5H-imidazo [4,
5-c] Quinolin-4-one (compound 26) Using compound t obtained in Reference Example 20, compound 26 was obtained in the same manner as in Example 10.

Example 26 5-n-butyl-1,9-dimethyl-1H, 5H-imidazo [4,
5-c] Quinolin-4-one hydrochloride (compound 27W) Using compound u obtained in Reference Example 21, compound 27W was obtained in the same manner as in Example 10.

Example 27 5-n-butyl-1-methyl-1H, 5H-imidazo [4,5-
c] Quinoline-4-thione hydrochloride (Compound 28W) Compound 1, 0.30 g (1.2 mmol) obtained in Example 1
Was suspended in 10 ml of toluene, and 0.48 g (1.2 mmol) of Lawesson's reagent was added, followed by heating under reflux for 1 hour. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 50/1) to obtain 0.25 g (78%) of Compound 28.

Compound 28 was dissolved in 2 ml of chloroform, ethyl acetate saturated with hydrogen chloride gas was added, and the resulting crystals were collected to obtain compound 28W.

Example 28 1-phenyl-5-n-butyl-1H, 5H-imidazo [4,5
-C] Quinolin-4-one (compound 29) Using compound v obtained in Reference Example 22, compound 29 was obtained in the same manner as in Example 15.

Example 29 5-n-butyl-2-hydroxy-1-methyl-1H, 5H
-Imidazo [4,5-c] quinolin-4-one (compound 3
0) Compound 1.7 g (0.0061 mol) obtained in Reference Example 23 was dissolved in ethanol 85 ml, and 10% palladium / carbon 0.34 g
Was added and hydrogen gas was bubbled at room temperature for 4 hours. After removing the catalyst, the solvent was distilled off under reduced pressure, and 30 ml of tetrahydrofuran and 1.5 g (0.0093 mol) of carbodiimidazole were added.
Heated to reflux for an hour. The reaction solution was cooled to room temperature, and the precipitated crystals were washed with isopropyl ether. Recrystallized from dimethylformamide-water to give Compound 30 1.
2 g were obtained.

Example 30 5-n-butyl-1-methyl-2-mercapto-1H, 5H
-Imidazo [4,5-c] quinolin-4-one (compound 3
1) 1.79 g (0.0061) of the compound obtained in Reference Example 23 was dissolved in 85 ml of ethanol, 0.34 g of 10% palladium / carbon was added, and hydrogen gas was passed at room temperature for 4 hours. After removing the catalyst, the solvent was distilled off under reduced pressure, and 50 ml of tetrahydrofuran and 1.8 g (0.0092 mol) of thiocarbonylimidazole were also added.
The mixture was refluxed for 30 minutes. The reaction solution was cooled to room temperature, and the precipitated crystals were washed with isopropyl ether. The obtained crystals were recrystallized from ethanol to obtain 1.5 g of compound 31.

Example 31 5-n-butyl-1-methyl-1H, 5H-triazolo [4,5
-C] Quinolin-4-one (compound 32) The compound w1.7 g (0.0061 mol) obtained in Reference Example 23 was dissolved in ethanol (85 ml), 10% palladium / carbon (0.34 g) was added, and hydrogen gas was added at room temperature for 4 hours. Ventilated. After separating the catalyst, the solvent was distilled off under reduced pressure, 20 ml of ethanol was added, and 0.55 ml and 15 ml of concentrated hydrochloric acid were added with stirring at 0 ° C. Then 0.56 g (0.0080 mol) of sodium nitrite dissolved in 6 ml of water
Was dropped. 30 minutes after dropping, the precipitated crystals were collected and recrystallized from dimethylformamide-water to give Compound 32.
1.1 g were obtained.

The following Examples 32 to 35 were performed according to the method of Example 1.

Example 32. 5-Methoxyethyl-1-methyl-1H, 5H-imidazo [4,5-c] quinolin-4-one (Compound 33) Example 33. 5-Isobutyl-1-methyl-1H, 5H- Imidazo [4,5-
c] Quinolin-4-one (compound 34) Example 34 1-Methyl-5-n-pentyl-1H, 5H-imidazo [4,5
-C] Quinolin-4-one (compound 35) Example 35. 5-Benzyl-1-methyl-1H, 5H-imidazo [4,5-
c] Quinolin-4-one (compound 36) Reference Example 1 1-methyl-2-phenyl-1H-imidazo [4,5-
c] Quinoline (compound a) 2.1 g of crude 3-amino-4- (methylamino) quinoline
(0.012 mol) was dissolved in 20 ml of pyridine, 1.5 ml (0.013 mol) of benzoyl chloride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated, 20 ml of phosphorus oxychloride was added, and the mixture was heated under reflux for 3 hours. The residue obtained by concentration under reduced pressure was dissolved in water, and the solid precipitated by making the solution alkaline with aqueous ammonia was collected. After washing with water, the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 30/1) to obtain 2.1 g of compound a.

_{NMR (CDC 3) δ (ppm} ); 4.23 (s, 3H), 7.51~7.78
(M, 7H), 8.23-8.33 (m, 2H), 9.35 (s, 1H) Reference Example 2 1-methyl-2-phenyl-1H-imidazo [4,5-c]
Quinoline-5-oxide (compound b) 1.75 g (0.067 mol) of compound a obtained in Reference Example 1 was dissolved in 26 ml of methylene chloride, and 3.0 g of m-chloroperbenzoic acid was dissolved.
(0.14 mol) and stirred at room temperature for 1 hour. After a saturated aqueous solution of sodium sulfite was added to reduce excess peracid, aqueous sodium bicarbonate was added and the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 1.30 g of compound b.

_{NMR (DMSO-d 6) δ} (ppm); 4.28 (s, 3H), 7.46~7.87
(M, 8H), 8.18 (d, 1H, J = 8 Hz), 9.10 (s, 1H) Reference Example 3 4-hydroxy-1-methyl-2-phenyl-1H-imidazo [4,5-c] quinoline ( Compound c) 20 ml of acetic anhydride was added to 1.0 g of compound b obtained in Reference Example 2, and the mixture was heated under reflux for 5 hours. Methanol was added to the residue obtained after concentration of the reaction solution, and the pH was adjusted to 9 to 10 with sodium methoxide.
Was adjusted. The precipitated crystals were collected and washed with methanol to obtain 0.63 g of a compound c.

_{NMR (DMSO-d 6) δ} (ppm); 4.15 (s, 3H), 7.46~7.73
(M, 8H), 8.21 (d, 1H, J = 8 Hz), 11.5 (s, 1H) Reference Example 4 1-n-butyl-4-chloro-3-nitro-2 (1H)-
Quinolinone (Compound d) Ethyl nitroacetate (2.4 ml, 0.026 mol) was added to 30 ml of N, N '.
-Dissolved in dimethylacetone amide (DMA), add 1.0 g (0.026 mol) of 60% sodium hydride with stirring under ice-cooling, and further stir for 30 minutes, and then add 1-butyl-2H-3,1-benzoxazine-2. , 4 (1H) -dione [J. Heterocycl. Chem.,
A solution of 12,565 (1975) (5.2 g, 0.024 mol) in DMA (20 ml) was added, and the mixture was heated to 120 ° C. After stirring for 5 hours, the solvent was distilled off under reduced pressure, and 15 ml of water and 15 ml of methylene chloride were added to the resulting residue to collect crystals. In the liquid, the aqueous layer was acidified with concentrated hydrochloric acid, and the precipitated crystals were collected again and dried together with the crystals collected earlier.

16 ml (0.17 mol) of phosphorus oxychloride was added to the dried crystals and heated at 100 ° C. for 1 hour. The solvent was evaporated under reduced pressure, 10 ml of ice water was added to the residue obtained, and the mixture was neutralized with 2N sodium hydroxide solution under ice cooling, and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
After that, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform) to obtain 1.1 g (16%) of compound d.

MS (m / z); 280 (M +), 282 (M + +2) NMR (CDC 3) δ (ppm); 1.01 (t, 3H, J = 7Hz), 1.28~
1.97 (m, 4H), 4.34 (t, 2H, J = 7 Hz), 7.28 to 7.52 (m, 2
H), 7.75 (t, 1H, J = 8 Hz), 8.11 (d, 1H, J = 8 Hz) Reference Example 5 1-n-butyl-4-ethylamino-3-nitro-2
(1H) -quinolinone (Compound e) 3.5 g (0.013 mol) of compound d obtained in Reference Example 4 was dissolved in 30 ml of tetrahydrofuran, 8.0 ml (0.13 mol) of ethylamine was added under ice cooling, and the mixture was stirred at room temperature overnight. Ice water was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected and dried to obtain 3.5 g (97%) of compound e.

NMR (CDC ₃ ) δ (ppm); 0.98 (t, 3H, J = 7 Hz), 1.37
(T, 3H, J = 7Hz), 1.26-2.00 (m, 4H), 3.30-3.68 (m, 2
H), 4.24 (t, 2H, J = 7 Hz), 6.15-6.42 (m, 1H), 7.10-
7.85 (m, 4H) Reference Example 6 1-n-butyl-3-nitro-4-n-propyl-2
(1H) -quinoline (compound f) Compound f (95% yield) was obtained in substantially the same manner as described in Example 5, except that n-propylamine was used instead of ethylamine.

NMR (CDC ₃ ) δ (ppm); 0.80 to 1.20 (m, 6H), 1.22 to
1.98 (m, 6H), 3.20-3.60 (m, 2H), 4,30 (t, 2H, J = 7H
z), 6.50 to 6.82 (m, 1H), 7.12 to 7.86 (m, 4H) Reference Example 7 1-n-butyl-3-nitro-4-isopropyl-2
(1H) -Quinoline (Compound g) Compound g (yield 90%) was obtained in substantially the same manner as in Reference Example 5 except that isopropylamine was used instead of ethylamine.

NMR (CDC ₃ ) δ (ppm); 0.99 (t, 3H, J = 7 Hz), 1.31
(D, 6H, J = 6 Hz), 1.15 to 1.92 (m, 4H), 3.61 to 4.35 (m, 3
H), 5.97-6.35 (m, 1H), 7.03-7.88 (m, 4H) Reference Example 8 1-n-butyl-4-n-butylamino-3-nitro-
2 (1H) -quinoline (Compound h) Reference Example Compound n (96% yield) was obtained in substantially the same manner as described above, except that n-butylamine was used instead of 5-ethylamine.

_{NMR (CDC 3) δ (ppm} ); 0.78~1.10 (m, 6H), 1.12~
1.92 (m, 8H), 3.30 to 3.61 (m, 2H), 4.23 (t, 2H, J = 7H
z), 6.40-6.72 (m, 1H), 7.02-7.35 (m, 4H), 7.45-7.
82 (m, 2H) Reference Example 9 2- (4-methoxyphenyl) -1-methyl-1H-imidazo [4,5-c] quinoline (compound i) 4-methoxybenzoyl instead of benzoyl chloride of Reference Example 1 Compound i (yield 72%) was obtained in substantially the same manner using chloride.

_{NMR (CDC 3) δ (ppm} ); 4.28 (s.3H), 7.04~7.13
(M, 2H), 7.61 ~ 7.77 (m, 4H), 8.21 ~ 8.40 (m, 2H), 9.3
5 (s, 1H) Reference Example 10 2- (3,4-dichlorophenyl) -1-methyl-1H-imidazo [4,5-c] quinoline (compound j) 3,4 in place of benzoyl chloride in Reference Example 1. Compound j (yield 59%) was obtained in substantially the same manner using -dichlorobenzoyl chloride.

_{NMR (CDC 3) δ (ppm} ); 4.20 (s, 3H), 7.57~7.65
(M, 4H), 7.86 to 7.89 (m, 1H), 8.19 to 8.29 (m, 2H), 9.2
8 (s, 1H) Reference Example 11 2- (2-furyl) -1-methyl-1H-imidazo [4,5
-C] Quinoline (compound k) Compound k was obtained in substantially the same manner as in Reference Example 1, except that 2-furoyl chloride was used instead of benzoyl chloride.
(73% yield).

_{NMR (CDC 3) δ (ppm} ); 4.47 (s, 3H), 6.62~6.68
(M, 1H), 7.18 to 7.22 (m, 1H), 7.60 to 7.71 (m, 3H), 8.2
5-8.45 (m, 2H), 9.32 (s, 1H) Reference Example 12 2-cyclopentyl-1-methyl-1H-imidazo [4,5
-C] Quinoline (Compound 1) Compound 1 (yield 62%) was obtained in substantially the same manner as described in Example 1, except that cyclopentanoyl chloride was used instead of benzoyl chloride.

_{NMR (CDC 3) δ (ppm} ); 1.65~2.15 (m, 8H), 3.10~
3.35 (m, 1H), 4.13 (s, 3H), 7.53 to 7.70 (m, 2H), 8.21
8.38.32 (s, 2H), 9.23 (s, 3H) Reference Example 13 4-hydroxy-2- (4-methoxyphenyl) -1-
Methyl-1H-imidazo [4,5-c] quinoline (Compound m) Using Compound i obtained in Reference Example 9, Compound m (54% yield) was obtained in the same manner as in Reference Examples 2 and 3. Obtained.

NMR (CDC ₃ ) δ (ppm); 3.86 (s, 3H), 4.13 (s, 3H),
7.13 to 7.75 (m, 7H), 8.21 (d, 1H, J = 8 Hz), 11.58 (s, 1
H) Reference Example 14 2- (2-furyl) -4-hydroxy-1-methyl-1H
-Imidazo [4,5-c] quinoline (Compound n) Compound n (41% yield) was obtained in the same manner as in Reference Examples 2 and 3 using Compound k obtained in Reference Example 11.

_{NMR (CDC 3) δ (ppm} ); 4.31 (s, 3H), 6.76~6.78
(M, 1H), 7.17 ~ 7.49 (m.4H), 7.99 (brs, 1H), 8.23
(D, 1H, J = 8 Hz), 11,63 (s, 1H) Reference Example 15 2-cyclopentyl-4-hydroxy-1-methyl-1H
-Imidazo [4,5-c] quinoline (compound o) Using compound l obtained in Reference Example 12, compound o (yield 39%) was obtained in the same manner as in Reference Examples 2 and 3.

_{NMR (DMSO-d 6) δ} (ppm); 1.62~2.11 (m, 8H), 3.38~
3.47 (m, 1H), 4.08 (s, 1H), 7,20 to 7.50 (m, 3H), 8.18
(D, 1H, J = 8 Hz), 11.48 (s, 1H) Reference Example 16 1,2-dimethyl-4-hydroxy-1H-imidazo [4,5-
c) Quinoline (Compound p) Using 1,2-dimethyl-1H-imidazo [4,5-c] quinoline (Japanese Patent Application Laid-Open No. 60-123488), the same method as in Reference Examples 2 and 3 was used. Compound p (yield 52%) was obtained.

_{NMR (DMSO-d 6) δ} (ppm); 2.52 (s, 3H), 4.04 (s, 3
H), 7.22 to 7.45 (m, 3H), 8.14 (d, 1H, J = 8 Hz), 11.46
(S, 1H) Reference Example 17 7,8-dimethoxyl-4-hydroxy-1-methyl-1H
-Imidazo [4,5-c] quinoline (compound q) 7,8-dimethoxyl-1-methyl-1H-imidazo [4,5
-C] Using quinoline (JP-A-60-123488) and the same method as in Reference Examples 2 and 3, compound q
(Yield 51%) was obtained.

_{NMR (DMSO-d 6) δ} (ppm); 3.82 (s, 3H), 3.88 (s, 3
H), 4.17 (s, 3H), 7.05 (s, 1H), 7.49 (s, 1H), 7.98
(S, 1H), 11.26 (s, 1H) Reference Example 18 7-chloro-4-hydroxy-1-methyl-1H-imidazo [4,5-c] quinoline (compound r) 7-chloro-1-methyl- 1H-imidazo [4,5-c]
Reference Example 2 using quinoline (JP-A-60-123488)
In the same manner as in Reference Example 3, compound r (yield 48
%).

_{NMR (DMSO-d 6) δ} (ppm); 4.15 (s, 3H), 7.28 (brd, 1
H, 7Hz), 7.50 (brs, 1H), 8.10 ~ 8.14 (m, 2H), 11.59
(S, 1H) Reference Example 19 8-chloro-4-hydroxy-1-methyl-1H-imidazo [4,5-c] quinoline (compound s) 8-chloro-1-methyl-1H-imidazo [4,5 -C]
Reference Example 2 using quinoline (JP-A-60-123488)
In the same manner as in Reference Example 3, compound s (yield 26
%).

_{NMR (DMSO-d 6) δ} (ppm); 4.17 (s, 3H), 7.44~7.52
(M, 2H), 8.05 (brd, 1H), 8.11 (s, 1H), 11.63 (s, 1H) Reference Example 20 1,8-dimethyl-4-hydroxy-1H-imidazo [4,5-
c) Quinoline (Compound t) Using 1,8-dimethyl-1H-imidazo [4,5-c] quinoline (Japanese Patent Application Laid-Open No. 60-123488), the same method as in Reference Examples 2 and 3 was used. Compound t (40% yield) was obtained.

_{NMR (DMSO-d 6) δ} (ppm); 2.42 (s, 3H), 4.16 (s, 3
H), 7.29-7,37 (m, 2H), 7.90 (s, 1H), 8.04 (brs, 1
H), 11.38 (s, 1H) Reference Example 21 1,9-dimethyl-4-hydroxy-1H-imidazo [4,5-
c) Quinoline (Compound u) Using 1,9-dimethyl-1H-imidazo [4,5-c] quinoline (JP-A-60-123488), in the same manner as in Reference Examples 2 and 3, Compound u (40% yield) was obtained.

_{NMR (DMSO-d 6) δ} (ppm); 2.76 (s, 3H), 4.04 (s, 3
H), 7.07 (brd, 1H, J = 7 Hz) d, d, 7.28 to 7.36 (m, 2H), 8.
10 (brs, 1H), 11.44 (s, 1H) Reference Example 22 4-anilino-1-n-butyl-3-nitro-2 (1H)
-Quinoline (Compound v) Compound v (75% yield) was obtained in substantially the same manner using aniline instead of ethylamine of Reference Example 5.

_{NMR (CDC 3) δ (ppm} ); 1.01 (t, 3H, J = 6Hz), 1.22~
1.98 (m, 4H), 4.30 (t, 2H, J = 7 Hz), 6.80 to 7.70 (m, 9
H), 8.63 (brs, 1H) Reference Example 23 1-n-butyl-4-methylamino-3-nitro-2
(1H) -quinoline (compound w) 11 g (0.039 mol) of compound d obtained in Reference Example 4 was dissolved in 100 ml of tetrahydrofuran, 30 ml (0.39 mol) of 40% methylamine was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. did.
After the reaction, the solvent was distilled off under reduced pressure, and crystals precipitated by adding water to the residue were collected and dried to obtain 9.2 g of compound w (yield 87).
%).

Melting point: 225 to 227 ° C (isopropanol-diisopropyl ether) MS (m / z); 275 (M ⁺ ) NMR (CDC ₃ ) δ (ppm); 0.95 (t, 3H, J = 6 Hz), 1.19 to
1.89 (m, 4H), 3.10 (d, 3H, J = 5Hz), 4.22 (t, 2H, J = 7H
z), 6.72-7.04 (m, 1H), 7.06-7.40 (m, 2H), 7.58 (t,
1H, J = 8 Hz), 7.94 (d, 1H, J = 8 Hz) Formulation Example 1 Tablet A tablet having the following composition is prepared by a conventional method.

 Compound 1 50 mg Lactose 113 mg Potato starch 30 mg Hydroxypropylcellulose 6 mg Magnesium stearate 0.6 mg Formulation Example 2 Powder A powder having the following composition is prepared by a conventional method.

 Compound 1 50 mg Lactose 750 mg Formulation Example 3 Syrup A syrup having the following composition is prepared by a conventional method.

 Compound 1 50 mg Purified sucrose 75 mg P-hydroxybenzoic acid ethyl ester 100 mg P-hydroxybenzoic acid propyl ester 25 mg Strawberry flavor 0.25 cc Add water to make the total amount 100 cc.

Formulation Example 4 Capsule A capsule having the following composition is prepared by a conventional method.

 Compound 1 50 mg Avicel 69.5 mg Magnesium stearate 0.5 mg Mix this and fill into gelatin capsules.

Formulation Example 5 Injection An injection having the following composition is prepared by an ordinary method.

 Compound 1 10mg Buffer appropriate amount Water Make the total volume 1.0ml.

Effects of the Invention According to the present invention, a novel imidazoquinolone derivative having a bronchodilator effect and an antiallergic effect is provided.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ identification code FI A61K 31/47 610 A61K 31/47 610 (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 471/04 CAPLUS ( STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) Expression Ｘwhere X is [Wherein R ² is hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, aralkyl, aralkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, — (CH ₂ ) _m CO ₂ R ⁶ Wherein R ⁶ represents hydrogen or lower alkyl, m represents an integer of 0 to 3, thiol or halogen, or a nitrogen atom, Y represents oxygen or sulfur, R ¹ represents hydrogen, Alkyl, cycloalkyl, alkenyl, aralkyl, aralkenyl or substituted or unsubstituted aryl,
R ³ is alkyl, cycloalkyl, alkoxyalkyl,
Alkenyl, aralkyl, aralkenyl, - (CH _{2) n}
-Het (wherein, Het represents a substituted or unsubstituted aromatic heterocyclic group, and n is an integer of 1 to 3) or-(C
H ₂ ) _n CO ₂ R ^6a (wherein, n is as defined above, and R ^6a is
Represents the definition of R ⁶ to be identical), R ⁴ and R ⁵ are the same or different and each is hydrogen, lower alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxyl, lower alkoxyl, lower alkylthio, nitro, amino, lower alkyl An imidazoquinolone derivative represented by｝ representing amino, lower alkanoylamino, aroylamino, lower alkanoyl or aroyl, or a pharmaceutically acceptable salt thereof.