JPH05132484A - Pyrazoloquinoline and pyrazolonaphthylidene derivative - Google Patents

Abstract

PURPOSE:To provide the subject compound having activities such as antiinflammatory activity, immunoregulating activity, analgetic activity and antipyretic activity and useful as an immunoregulating agent, antiinflammatory agent, analgetic agent, etc. CONSTITUTION:A compound of formula I (R<1> is H, lower alkyl, etc.; R<2> is H, lower alkyl, phenyl, etc.; R<3> is H, halogen; R<5> is H, lower alkanoyl, etc.; R<2> and R<4> are combined with each other to form CH2-CH2-CO or CH=CH; Y is CH or N; broken line exhibits that two double bonds exist in the pyrazole ring) and its derivative. For example, 3-amino-1,5-dimethyl-1H,5H-pyrazolo[4,3-c] quinoline-4-one. The compound of formula I is obtained e.g. by etc.,) and a compound of formula III (R<6> is lower alkyl) to a mutual alcohol-eliminating condensation reaction, halogenating the obtained compound with a halogenating agent such as oxyphosphorus chloride in the presence of ethyl aniline, and subsequently cyclizing the obtained compound of formula IV (X is halogen) with formula R<2a>-NH-NH2.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel pyrazoloquinoline and pyrazolonaphthyridine derivatives.

[0002]

BACKGROUND OF THE INVENTION The pyrazoloquinoline and pyrazolonaphthyridine derivatives of the present invention are novel compounds which have not been published in the literature.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a compound useful as a medicine as described below.

[0004]

The above object is achieved by a pyrazoloquinoline and a pyrazolonaphthyridine derivative represented by the following general formula (1).

[0005]

[Chemical 2]

[Wherein R ¹ is a hydrogen atom, a lower alkyl group,
A lower alkenyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group, a phenyl lower alkyl group or a phenyl group which may have a group selected from a halogen atom and a lower alkoxy group as a substituent, R ² represents a hydrogen atom, a lower alkyl group, a phenyl group, a hydroxy lower alkyl group, a cyano lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group or a lower alkoxycarbonyl group, and R ³ Represents a hydrogen atom or a halogen atom, and R ⁴
And R ⁵ are the same or different and each represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, a lower alkyl group, a lower alkenyl group, a formyl group or a carboxy lower alkyl group. Further, R ² and R ⁴ may be bonded to each other to form a group —CH ₂ —CH ₂ —CO— or a group —CH═CH—. Y represents a -CH = group or a nitrogen atom, and the broken line indicates that there are two double bonds in the pyrazole ring. Specific examples of the groups represented by the general formula (1) include the following.

That is, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl,
Examples thereof include 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and 6-phenylhexyl groups.

Examples of the lower alkoxyl group include methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy groups.

Examples of hydroxy lower alkyl groups include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl and 6-hydroxyhexyl groups.

Examples of the cyano lower alkyl group include cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3
Examples thereof include -cyanopropyl, 4-cyanobutyl, 5-cyanopentyl and 6-cyanohexyl groups.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl groups and the like.

Examples of the lower alkanoyl group include acetyl, propanoyl, butanoyl, pentanoyl, pivaloyl, hexanoyl and heptanoyl groups.

Examples of the lower alkylsulfonyl group include methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl and hexanesulfonyl groups.

The phenyl group which may have a group selected from a halogen atom and a lower alkoxyl group as a substituent includes, for example, 4-fluorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 3 in addition to the phenyl group.
Examples thereof include -chlorophenyl, 4-ethoxyphenyl and 2-methoxyphenyl groups.

Examples of the lower alkenyl group include vinyl, allyl, isopropenyl, 3-buten-1-yl,
Examples include 4-penten-1-yl and 5-hexen-1-yl groups.

Examples of the carboxy lower alkyl group include carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl and 6-carboxyhexyl groups.

As the lower alkoxycarbonyl lower alkyl group, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3
Examples thereof include -ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-ethoxycarbonylpentyl, 6-ethoxycarbonylhexyl, 2-butoxycarbonylethyl and hexyloxycarbonylmethyl groups.

Examples of the halogen-substituted lower alkyl group include chloromethyl, bromomethyl, iodomethyl, fluoromethyl, 2-chloroethyl, 3-chloropropyl,
4-chlorobutyl, 5-chloropentyl, 6-chlorobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl group and the like can be exemplified.

The pyrazoloquinoline and pyrazolonaphthyridine derivatives of the present invention can be produced by various methods. Specific examples thereof are shown in the following reaction process formulas.

[Reaction Process Formula 1]

[0022]

[Chemical 3]

[Wherein R ³ and Y are the same as defined above]. R ^1a may have a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group, a phenyl lower alkyl group, or a substituent selected from a halogen atom and a lower alkoxy group. A phenyl group, R ^2a is a hydrogen atom, a lower alkyl group, a phenyl group, a hydroxy lower alkyl group, a cyano lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group or a lower alkoxycarbonyl group, and R ⁶ is a lower group. An alkyl group and X represents a halogen atom. The reaction between the compound (2) and the compound (3) in the reaction process formula 1 is carried out by dealcoholization condensation reaction of isatoic anhydride or its derivative (2) with an active methylene compound, a cyanoacetic acid lower alkyl ester (3). It can be carried out according to the method described in the literature (G.
M. Coppola et al., J. Heterocyclic Chem., 16 .1605 (1979)
reference). In this reaction, it is preferable to use N, N-dimethylformamide or N, N-dimethylacetamide as a solvent.

The halogenation reaction of the compound (4) obtained by the above reaction can be carried out by a usual method. For example, the halogenation reaction can be carried out using a halogenating agent such as phosphorus oxychloride and a deoxidizing agent such as diethylaniline or dimethylaniline. The above-mentioned halogenating agent also serves as a solvent, and thus is usually in an excess amount, preferably 5 to 5 relative to the compound (4).
It is preferable to use about 20 times equivalent. Further, the deoxidizing agent is preferably used in an amount of 1 to 20 times equivalent to that of the compound (4). The reaction is generally completed in about 10 minutes to 2 hours under the temperature conditions of about 60 ° C. to the boiling point of the solvent (phosphorus oxychloride). Thus, the target compound (5) can be obtained.

The cyclization reaction of the above compound (5) with the hydrazine derivative (6) is carried out, for example, with methanol, ethanol, propanol, N, N-dimethylformamide,
It is carried out in a suitable inert solvent such as N, N-dimethylacetamide, and a deoxidizing agent such as triethylamine, pyridine, sodium hydrogencarbonate, potassium carbonate or the like is added to the reaction system in an amount of about 1 to about 1 to the compound (5). It may be present in a molar amount of about 5 times. The ratio of the compound (6) used to the compound (5) is preferably about 1 to 5 equivalents. Generally, the above reaction is carried out at 1 to 72 under a temperature condition of about 20 to 100 ° C.
It takes about time. Thus, the target compound (1
a) can be obtained.

[Reaction Process Formula 2]

[0027]

[Chemical 4]

[Wherein R ³ and Y are the same as defined above]. R ^1b is a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group,
A phenyl lower alkyl group or a phenyl group which may have a group selected from a halogen atom and a lower alkoxy group as a substituent, and R ^2a represents a lower alkyl group. The alkylation reaction of compound (1b) in reaction scheme 2 can be carried out using a suitable solvent, an alkylating agent and a deoxidizing agent. Examples of the solvent include N, N-dimethylformamide, dimethylsulfoxide, N, N-dimethylacetamide, pyridine and dioxane, and examples of the alkylating agent include methyl iodide, ethyl iodide, propyl bromide and propyl iodide. , Butyl bromide, etc.
As the deoxidizing agent, for example, triethylamine, pyridine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and the like can be used. The amount of the alkylating agent used is usually about 1 to 10 times equivalent to the compound (1b), and the amount of deoxidizing agent is usually about 1 to 10 times equivalent to the compound (1b). Good to do. The temperature condition for the above reaction may be about 20 to 80 ° C., and the reaction is generally completed in about 1 to 60 hours, whereby the desired compound (1c) can be obtained.

[Reaction Process Formula 3]

[0030]

[Chemical 5]

[Wherein R ³ and Y are the same as defined above. R ^2c represents a hydrogen atom, a lower alkyl group, a phenyl group or a halogen-substituted lower alkyl group. ] The reaction shown in Reaction Process Formula 3 is
8% with 47% HBr in a suitable solvent such as acetic acid
It is carried out under a temperature condition of about 0 to 120 ° C. for about 2 to 70 hours, and the desired compound (1e) can be obtained by the reaction.

[Reaction Process Formula 4]

[0033]

[Chemical 6]

[Wherein R ^1b , R ³ and Y are the same as defined above]. R
^2d represents a lower alkyl group, a phenyl group, a cyano lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group or a lower alkoxycarbonyl group, and R ^4a represents a lower alkanoyl group or a lower alkylsulfonyl group. ] The compound (1
The alkanoylation reaction and sulfonylation reaction of f) are
In a suitable solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, pyridine, etc., an acid anhydride, an acid halide or the like as an alkanoylating agent, a lower alkyl sulfonic acid halide or the like as a sulfonylating agent,
It can be carried out using each. The amount of the alkanoylating agent used is usually about 1 to 10 times equivalent, the amount of the sulfonylating agent is usually about 1 to 10 times equivalent, and the reaction is carried out at a temperature condition of about 20 to 100 ° C. It takes 1 to 10 hours. Thus, the target compound (1 g) can be obtained.

[Reaction Process Formula 5]

[0036]

[Chemical 7]

[Wherein R ^2b , R ³ , X and Y are the same as defined above. R ^1c represents a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group or a phenyl lower alkyl group. The reaction of the compound (1h) shown in the reaction scheme 5 with the compound (7) is carried out in the presence of a base in an inert solvent. Examples of the above-mentioned inert solvent include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, and the like.
As the base, for example, sodium hydride, sodium ethoxide, potassium carbonate, sodium carbonate or the like can be used. The amount of homo-base used is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, and compound (7)
It is preferable that the amount of the compound used is in the range of about 1 to 2 times the molar amount of the compound (1h). The reaction is carried out at a temperature condition of 0 ° C. to the boiling point of the solvent for about 1 to 48 hours,
Thus, the compound (1i) can be obtained.

[Reaction Process Formula 6]

[0039]

[Chemical 8]

[In the formula, R ^1b , R ^2d , R ³ and Y are the same as defined above. As shown in the reaction scheme 6, the compound (1f) can be converted to the compound (1j) by formylating it. In the formylation reaction, the compound (1f) and formic acid are converted into 2
The reaction is carried out at a temperature of about 0 to 100 ° C. for about 1 to 24 hours. In the reaction, formic acid also serves as a solvent, so that another solvent is not particularly required.

[Reaction Process Formula 7]

[0042]

[Chemical 9]

[Wherein R ³ , X and Y are the same as defined above]. R ^1d
Represents a lower alkyl group, a lower alkenyl group, a halogen-substituted lower alkyl group or a phenyl group which may have a group selected from a halogen atom and a lower alkoxy group as a substituent, and R represents a lower alkyl group or two R's are bonded to each other to represent a lower alkylene group. According to the reaction scheme 7, the compound (1k) can be obtained by reacting the compound (1k) with the acetal derivative (8) and then treating with an acid. The reaction is carried out in the presence of a deoxidizing agent in an inert solvent. As the inert solvent and the deoxidizing agent, the same ones as those used in the alkylation of the reaction process formula 2 can be used, and the reaction conditions and the like can be appropriately selected from the above range. The obtained crude product is treated with dilute hydrochloric acid, dilute sulfuric acid or the like in an inert solvent such as methanol, ethanol, propanol, tetrahydrofuran or dioxane at 20 ° C. to the boiling point of the solvent for about 0.5 to 5 hours to give a compound. It can be converted to (1l).

[Reaction Process Equation 8]

[0045]

[Chemical 10]

[Wherein R ^1d , R ³ and Y are the same as defined above]. ]
The conversion reaction of the compound (1m) shown in the reaction process formula 8 to the compound (1n) is carried out in an inert solvent such as methanol, ethanol, acetic acid or the like in the presence of an acid such as concentrated hydrochloric acid or concentrated sulfuric acid at 50 ° C to the solvent. The treatment may be carried out at the boiling temperature for about 1 to 6 hours.

[Reaction Process Formula 9]

[0048]

[Chemical 11]

[Wherein R ^1b , R ^2d , R ³ , X and Y are the same as defined above. R ^4b represents a lower alkanoyl group, and R ^5a represents a lower alkyl group, a lower alkenyl group or a lower alkoxycarbonyl lower alkyl group. The reaction of the compound (1p) shown in the reaction process formula 9 with the compound (9) is carried out in the presence of a base in an inert solvent. Examples of the inert solvent include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like, and examples of the base include:
Examples thereof include sodium hydride, sodium ethoxide, potassium carbonate, sodium carbonate and the like. The amount of the homo-base used is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, and the reaction is 1 to 4 under the temperature condition of 0 ° C. to the boiling point of the solvent.
It is carried out in 8 hours, and thus compound (1q) can be obtained.

[Reaction Process Formula 10]

[0051]

[Chemical 12]

[In the formula, R ^1b , R ³ , R ^4b , R ^5a and Y are the same as defined above. R ^2e is a lower alkyl group, a phenyl group, a cyano lower alkyl group, a lower alkoxycarbonyl lower alkyl group or a halogen-substituted lower alkyl group, and R ^1e is a lower alkyl group, a lower alkenyl group, a carboxy lower alkyl group, a halogen-substituted lower alkyl group. A phenyl lower alkyl group or a phenyl group which may have a group selected from a halogen atom and a lower alkoxy group as a substituent,
^2f represents a lower alkyl group, a phenyl group, a carboxy lower alkyl group or a halogen-substituted lower alkyl group, and R ^5b represents a lower alkyl group, a lower alkenyl group or a carboxy lower alkyl group. The hydrolysis reaction of the compound (1r) in the reaction process formula 10 is carried out in an alcohol solvent such as methanol, ethanol, propanol or in water.
It is performed using an acid such as dilute hydrochloric acid or dilute sulfuric acid. 20 reactions
It takes about 10 minutes to 6 hours under the temperature condition of ℃ to the boiling point of the solvent.

[Reaction Process Formula 11]

[0054]

[Chemical 13]

[Wherein R ³ and Y are the same as defined above]. R ^1g may have a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group, a phenyl lower alkyl group, or a substituent selected from a halogen atom and a lower alkoxy group. A phenyl group, R ^2g represents a hydrogen atom, a lower alkyl group, a phenyl group, a hydroxy lower alkyl group, a cyano lower alkyl group, a lower alkoxycarbonyl lower alkyl group or a halogen-substituted lower alkyl group. However, at least one of R ^1g and R ^2g is a lower alkoxycarbonyl lower alkyl group. R ^4c and R ^5c are the same or different and each is a hydrogen atom, a lower alkyl group or a lower alkenyl group, and R ^1h is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a carboxy lower alkyl group, a halogen-substituted lower alkyl group, a phenyl lower alkyl group. A phenyl group which may have a group selected from a halogen atom and a lower alkoxy group as a group or a substituent, R ^2h is a hydrogen atom,
A lower alkyl group, a phenyl group, a hydroxy lower alkyl group, a carboxy lower alkyl group or a halogen-substituted lower alkyl group is shown respectively. However, at least one of R ^1h and R ^2h is a carboxy lower alkyl group. The hydrolysis reaction of the compound (1t) in Reaction Scheme 11 can be carried out under either acidic conditions or alkaline conditions. When the reaction is carried out under acidic conditions, the reaction can be carried out in the same manner as in the method shown in the reaction scheme 10. When the reaction is carried out under alkaline conditions, the reaction is carried out, for example, in a solvent such as methanol, ethanol, propanol or water, as an alkali, an aqueous solution of sodium hydroxide,
It is carried out using a potassium hydroxide aqueous solution or the like at a temperature condition of 20 ° C. to the boiling point of the solvent for about 30 minutes to 24 hours.

[Reaction Process Formula 12]

[0057]

[Chemical 14]

[Wherein R ^1b , 2 ^2d , R ³ and Y are the same as defined above]. R ^4d and R ^5d are the same or different and each represents a lower alkyl group. The reaction of the compound (1v) shown in the reaction process formula 12 with the aldehyde (10) is carried out in formic acid at a temperature condition of 70 to 150 ° C. for about 0.5 to 20 hours. In this reaction, since the aldehyde (10) and formic acid also serve as a solvent, another inert solvent is not particularly required.

The target compound in each step shown in each of the above reaction schemes can be isolated by a conventional separation means such as adsorption chromatography, preparative thin film chromatography,
It can be easily isolated by various methods such as recrystallization and solvent extraction.

[0060]

The pyrazoloquinoline and pyrazolonaphthyridine derivatives of the present invention represented by the above general formula (1) are
It has excellent anti-inflammatory, immunomodulatory, analgesic and antipyretic effects, and is used as an immunomodulator, anti-inflammatory / analgesic / antipyretic agent for the treatment of rheumatoid arthritis, nephritis, psoriasis, systemic lupus erythematosus, lumbago, etc. It is also useful for prevention.

[0061]

EXAMPLES Examples will be shown below to further clarify the characteristics of the present invention.

[0062]

Example 1 3-Amino-1,5-dimethyl-1H, 5
Preparation of H-pyrazolo [4,3-c] quinolin-4-one 3-Cyano-1,2-dihydro-4-hydroxy-1-
To 20 g (0.1M) of methyl-2-oxoquinoline, 30 ml of diethylaniline was added, and phosphorus oxychloride 1 was added.
20 ml was added and stirred at 90 ° C. for 30 minutes. Then
After distilling off excess phosphorus oxychloride under reduced pressure, the residue was transferred to ice water, and the precipitated crystals were collected by filtration, washed with water, further washed with ethanol, and dried to give 19 g of 4-chloro-3.
-Cyano-1,2-dihydro-1-methyl-2-oxoquinoline was obtained.

Then, 7.6 g of this compound was suspended in 50 ml of methanol, and 5.5 ml of methylhydrazine was added thereto.
Was added, and the mixture was stirred at room temperature for 1 hour and refluxed for 30 minutes,
After cooling to room temperature, the formed crystals were collected by filtration and recrystallized from a mixed solvent of methylene chloride-methanol to give 3-amino-1,5-dimethyl-1H, 5H-pyrazolo [4,3
There was obtained 6.94 g of -c] quinolin-4-one. This compound is shown in Table 1.

[0064]

Examples 2 to 18 Each compound of the present invention was obtained in the same manner as in Example 1 using appropriate starting materials. These compounds are shown in Table 1.

[0065]

Example 19 Methyl carbazate was refluxed in methanol for 3 days, and water was added to the obtained crystals to obtain silica gel chromatography (AcOEt: CH ₂ Cl ₂ =).
The compound of the present invention was obtained by purification with 1: 1).
This compound is shown in Table 1.

[0066]

Examples 20-24 2-Cyanoethylhydrazine, 6
Using cyanohexylhydrazine or hydrazineethanol, the same operation as in Example 1 was performed, and the reaction product was crystallized and purified to obtain a 1-substituted or 2-substituted pyrazoloquinoline derivative. These compounds are labeled first. In the crystallization, ethanol was used in Example 20, chloroform was used in Example 22, and ethanol was used in Examples 23 and 24 as the solvent. Further, in Example 21, purification was performed by crystallizing the chloroform-soluble component after extraction with chloroform with methylene chloride.

[0067]

Example 25 3-Acetylamino-1,5-dimethyl-1H, 5H-pyrazolo [4,3-c] quinoline-4-
Production of O-one 1.4 g of 3-amino-1,5-dimethyl-1H, 5H-pyrazolo [4,3-c] quinolin-4-one was dissolved in 30 ml of pyridine at 90 ° C., and acetyl chloride of 0.1. 87 ml was added dropwise and stirred for 10 minutes. Then, pyridine was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride.

Then, the organic layer was dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel chromatography (CH
_{2 Cl 2: MeOH = 30:} 1 → 20: 1) to afford 3-acetylamino-1,5-dimethyl-1H, 5
H-pyrazolo [4,3-c] quinolin-4-one 1.0
3 g was obtained. This compound is shown in Table 1.

[0069]

Example 26 4,5-Dihydro-1,5-dimethyl-
Production of 3-methanesulfonylamino-4-oxopyrazolo [4,5-c] quinoline In Example 25, acetyl chloride was replaced with 0.95 ml of methanesulfonyl chloride, and the mixture was stirred at 70 ° C for 30 minutes, and then pyridine was distilled off. After removal, water was added and the precipitated crystals were collected by filtration, further washed with a methylene chloride-methanol mixed solution under reflux, and the crystals obtained after cooling were collected by filtration to give 0.99 g of 1,5-dimethyl-. 3-Methanesulfonylamino-1H, 5H-oxopyrazolo [4,3-
c] Quinolin-4-one was obtained. This compound is shown in Table 1.

[0070]

Example 27 3-Amino-2,5-dimethyl-2H,
Preparation of 5H-pyrazolo [4,3-c] quinolin-4-one 3-amino-5-methyl-1H, 5H-pyrazolo [4,4
3-c] Quinolin-4-one (1.2 g), potassium carbonate (1.3 g) and methyl iodide (1.25 ml) were suspended in N, N-dimethylacetamide (30 ml), and the mixture was stirred at 40 ° C for 4 hr. Then, the reaction mixture was transferred to water and extracted with methylene chloride, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off, followed by silica gel chromatography (CH ₂ Cl ₂ : MeOH = 10: 1). The resulting crystals were washed with ethyl acetate, n-hexane was added to the mother liquor, and the precipitated crystals were collected by filtration to obtain 110 mg of 3
-Amino-2,5-dimethyl-2H, 5H-pyrazolo [4,3-c] quinolin-4-one was obtained. This compound is shown in Table 1.

[0071]

Example 28 Preparation of 3-amino-1H, 5H-pyrazolo [4,3-c] quinolin-4-one 3-amino-5-benzyl-1H, 5H-pyrazolo [4,3-c] quinoline- 1.0 g of 4-one was suspended in 30 ml of 47% hydrobromic acid and 5 ml of acetic acid and stirred at 100 ° C. for 6 hours. After cooling, it was made alkaline with aqueous NaOH and washed with ethyl acetate, after which the aqueous solution was adjusted to pH 4 with aqueous citric acid, the precipitated crystals were filtered off and dried, 390 mg of 3-amino-1H, 5H.
-Pyrazolo [4,3-c] quinolin-4-one was obtained.
This compound is shown in Table 1.

[0072]

Example 29 The compound of the present invention was obtained in the same manner as in Example 28 using appropriate starting materials. This compound is shown in Table 1.

[0073]

Examples 30-43 Example 1 with appropriate starting materials
Each compound of the present invention was obtained in the same manner as. The compounds are shown in Table 1.

[0074]

Examples 44-48 Example 2 using appropriate starting materials
In the same manner as in 5, each compound of the present invention was obtained. The compounds are shown in Table 1.

[0075]

Example 49 3-Amino-5-n-butyl-1-methyl-1H, 5H-pyrazolo [4,3-c] quinoline-4
-Production of ON 60% sodium hydride 0.5 g DMF (50 ml)
The suspension was ice-cooled, 2.4 g of the compound obtained in Example 29 was added thereto, and the mixture was stirred for 10 minutes, subsequently 1.8 ml of n-butyl iodide was added, and the mixture was stirred at room temperature for 2 hours. . Water was added to the reaction mixture, and the generated crystals were collected by filtration, dissolved in ethyl acetate-dichloromethane, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate-dichloromethane to obtain 1.1 g of the target compound. The melting point and ¹ H-NMR spectrum of this product were the same as those of the compound obtained in Example 33.

[0076]

Examples 50-53 Example 4 Using the Appropriate Starting Materials
In the same manner as in 9, each compound of the present invention was obtained. The compounds are shown in Table 1.

[0077]

Example 54 3- (N-acetyl-N-methylamino) -1,5-dimethyl-1H, 5H-pyrazolo [4,4
Preparation of 3-c] quinolin-4-one 60% sodium hydride 470 mg DMF (40 m
l) The suspension was ice-cooled, 2.7 g of the compound obtained in Example 25 was added thereto, and the mixture was stirred for 10 minutes, subsequently 1.7 g of methyl iodide was added, and the mixture was stirred at room temperature for 1.5 hours. did. . Water was added to the reaction mixture, the generated crystals were collected by filtration, and recrystallized from dichloromethane-methanol to give the desired compound 2.5.
g was obtained. This compound is shown in Table 1.

[0078]

Examples 55-59 Example 5 using appropriate starting materials
In the same manner as in 4, each compound of the present invention was obtained. The compounds are shown in Table 1.

[0079]

Example 60 Preparation of 1,5-dimethyl-3- (N-methylamino) -1H, 5H-pyrazolo [4,3-c] quinolin-4-one 2 g of the compound obtained in Example 54 was added to methanol. 50 ml
25 ml of hydrochloric acid was added, and the mixture was heated at 100 ° C. for 1.5 hours. The reaction mixture was concentrated, 1N aqueous sodium hydroxide solution was added to adjust the pH to 8, and the mixture was extracted with dichloromethane.
The dichloromethane layers were collected, dried over anhydrous magnesium sulfate and concentrated. The obtained crude crystals were washed with diethyl ether to obtain 1.5 g of the target compound. This compound is shown in Table 1.

[0080]

Examples 61-65 Example 6 with appropriate starting materials
In the same manner as in 0, each compound of the present invention was obtained. The compounds are shown in Table 1.

[0081]

Example 66 Preparation of 5-ethyl-1-methyl-3- (N-methylamino) -1H, 5H-pyrazolo [4,3-c] quinolin-4-one The compound obtained in Example 44 was used as a starting material. And 3- (N-acetyl-N-methylamino) -5-ethyl-1-methyl-1H, 5H-pyrazolo [4,3-c] quinolin-4-one in the same manner as in Example 54. Obtained. This compound is shown in Table 1.

[0082]

Examples 67-69 Example 6 using appropriate starting materials
In the same manner as in 6, each compound of the present invention was obtained. The compounds are shown in Table 1.

[0083]

Example 70 3-Amino-5-carboxymethyl-1
-Methyl-1H, 5H-pyrazolo [4,3-c] quinolin-4-one Preparation 1.5 g of the compound obtained in Example 53 was added to ethanol 10
Dissolve in 50 ml of 2N aqueous sodium hydroxide solution.
ml was added and the mixture was stirred at 70 ° C. for 1 hour. After allowing to cool, the mixture was poured into ice water, hydrochloric acid was added dropwise to neutralize, and an aqueous citric acid solution was added. The precipitated crystals are collected by filtration, washed successively with ethanol and diethyl ether to give the desired compound (1.43 g)
Got This compound is shown in Table 1.

[0084]

Example 71 Using the compound obtained in Example 31,
The compound of the present invention was obtained in the same manner as in Example 70. This compound is shown in Table 1.

[0085]

Example 72 Preparation of 1,5-dimethyl-3- (N-formylamino) -1H, 5H-pyrazolo [4,3-c] quinolin-4-one 2 g of the compound obtained in Example 1 was converted into formic acid. It was dissolved in 50 ml and heated under reflux for 20 hours. After completion of the reaction, concentrated under reduced pressure,
Diethyl ether was added to the residue, and the resulting crystals were collected by filtration,
It was washed with dichloromethane-methanol (1: 1) to obtain 2 g of the target compound. This compound is shown in Table 1.

[0086]

Example 73 11-Methyl-perhydro-1H-pyrimidine [2 ', 1': 5,1] pyrazolo [4,3-c]
Production of Quinoline-2,12 (11H) -dione 170 mg of the compound used in Example 22 was added to 3 ml of acetic acid.
Was dissolved in, and 0.5 ml of concentrated hydrochloric acid was added, and the mixture was heated at 110 ° C. for 3 hours. The reaction mixture was poured into water and the resulting crude crystals were collected by filtration. On the other hand, the filtrate was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated, and the obtained residue and the crude crystals were combined and subjected to silica gel column chromatography (eluent: chloroform: methanol =
20: 1) to give 50 mg of the desired compound. This compound is shown in Table 1.

[0087]

Example 74 10-methyl-1H-imidazo [2 ′,
1 ′: 5,1] pyrazolo [4,3-c] quinoline-11
Preparation of (10H) -one 60% sodium hydride 2.05 g DMF (100 m
l) The suspension was ice-cooled, 10 g of the compound obtained in Example 5 was added thereto, and the mixture was stirred for 10 minutes, subsequently, 8.4 ml of promoacetaldehyde diethyl acetal was added, and the mixture was heated at 60 ° C.
And stirred for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and concentrated. 10 ml of ethanol and 50 ml of 4N hydrochloric acid-dioxane were added to the residue, and the mixture was heated at 90 ° C. for 1 hour. After the reaction, the deposited precipitate was collected by filtration, dissolved in water and the insoluble matter was filtered off, and aqueous ammonia was added to the filtrate to make it alkaline. The resulting crude crystals were collected by filtration, purified by silica gel column chromatography (eluent: chloroform: methanol = 30: 1 → 20: 1), and recrystallized from chloroform-methanol to obtain 1.7 g of the target compound. It was This compound is shown in Table 1.

[0088]

Example 75 Preparation of 1,5-dimethyl-3- (N, N-dimethylamino) -1H, 5H-pyrazolo [4,3-c] quinolin-4-one 1 g of the compound obtained in Example 60 , 1.1 ml of formic acid and 3.5 g of 37% formaldehyde were mixed and heated at 100 ° C. for 1 hour. Water was added to the reaction mixture, extraction was performed with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from diethyl ether, and the obtained crystals were further purified by silica gel column chromatography (eluent: chloroform: methanol = 50: 1) to obtain 190 mg of the target compound. This compound is shown in Table 1.

The structures (melting points and ¹ H-NMR analysis results) of the compounds of the present invention obtained in each of the above Examples are shown in Table 1 below. In the table, t-Bu represents a tert-butyl group.

[0090]

[Table 1]

[0091]

[Table 2]

[0092]

[Table 3]

[0093]

[Table 4]

[0094]

[Table 5]

[0095]

[Table 6]

[0096]

[Table 7]

[0097]

[Table 8]

[0098]

[Table 9]

[0099]

[Table 10]

[0100]

[Table 11]

[0101]

[Table 12]

[0102]

[Table 13]

[0103]

[Table 14]

[0104]

[Table 15]

[0105]

[Table 16]

[0106]

[Table 17]

[0107]

[Table 18]

[0108]

[Table 19]

[0109]

[Table 20]

[0110]

[Table 21]

[0111]

[Table 22]

[0112]

[Table 23]

[0113]

[Table 24]

[0114]

[Table 25]

Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/47 ABE 7252-4C ABG ACV (72) Inventor Toshiko Kuwahara Nakakira Nakashira, Nakashirai, Matsushige-cho, Itano-gun, Tokushima Prefecture Nogoshi 14-21 (72) Inventor Yukio Sugimoto 79-1 Yoshinaga, Otsu-cho, Naruto City, Tokushima Prefecture (72) Inventor Takuji Kamisako 6 51-51 Minamikawa, Minamikawa, Matsushige-cho, Itano-gun, Tokushima Prefecture

Claims (1)

[Claims] 1. A general formula: [Wherein R ¹ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group,
A phenyl lower alkyl group or a phenyl group which may have a group selected from a halogen atom and a lower alkoxy group as a substituent, R ² is a hydrogen atom, a lower alkyl group, a phenyl group, a hydroxy lower alkyl group, a cyano lower alkyl group , A carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a halogen-substituted lower alkyl group or a lower alkoxycarbonyl group, R ³ represents a hydrogen atom or a halogen atom, and R ⁴ and R ⁵ are the same or different and are hydrogen atoms, A lower alkanoyl group, a lower alkylsulfonyl group, a lower alkyl group, a lower alkenyl group, a formyl group or a carboxy lower alkyl group is shown.
R ² and R ⁴ are bonded to each other to form a group —CH ₂ —C.
H ₂ -CO- or a group -CH = CH- may be formed.
Y represents a -CH = group or a nitrogen atom, and the broken line indicates that there are two double bonds in the pyrazole ring. ] The pyrazoloquinoline and the pyrazolonaphthyridine derivative represented by these.