JP2989871B2 - Tricyclic compounds - Google Patents

Description

The present invention relates to a novel tricyclic compound having excellent antibacterial activity, that is, a benzo [b] [1,6] naphthyridine derivative, pyrido [2,3-b] [1 , 6] naphthyridine derivatives and their salts.

2. Description of the Related Art As a tricyclic compound having a structure in which a carboxylic acid moiety of a pyridone carboxylic acid is condensed and cyclized, Japanese Patent Application Laid-Open No. 62-187472 discloses isoxazolonaphthyridine, isoxazoloquinoline, isothiazolonaphthyridine, and isothiazolone. Azoloquinoline derivatives are disclosed to have antibacterial activity.

Object of the Invention The present invention provides a novel tricyclic compound having excellent antibacterial activity not only in vitro but also in animal experiments.

Constitution of the Invention The compound of the present invention is a compound not described in the literature and has the following general formula (Wherein X ₁ represents a halogen atom, A represents N or C—X ₂ , wherein X ₂ represents a hydrogen atom, a halogen atom, a cyano group or a lower alkyloxy group, and R ₁ represents A lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group or a phenyl group which may have a substituent, R ₂ represents a hydrogen atom or a lower alkyl group, and R ₃ represents a halogen atom , An amino group which may be substituted or a cyclic amino group which may be substituted.), Ie, benzo [b] [1,
6] naphthyridine derivatives, pyrido [2,3-b] [1,6] naphthyridine derivatives and salts thereof.

Here, examples of the “halogen atom” include fluorine, chlorine, bromine and the like. "Lower alkyl group"
Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and the like. As the "lower alkenyl group", for example, vinyl, allyl, 1-propenyl, isopropenyl and the like can be mentioned. As the "cycloalkyl group",
For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned. As the "substituent" in the "optionally substituted phenyl group",
For example, halogen, lower alkyl, lower alkyloxy,
Amino, nitro and the like. The “optionally substituted amino group” includes, for example, an amino group which may be substituted with lower alkyl, cycloalkyl, acyl, benzyl and the like.

The “cyclic amino group” in R ₃ of the compound represented by the general formula (I) may further contain one or more nitrogen, oxygen or sulfur atoms, for example, 1-pyrrolidinyl, piperidino, 1-piperazinyl , Morpholino, thiomorpholino, 1-homopiperazinyl and the like, and a 5- to 7-membered cyclic amino group. The above cyclic amino group includes a halogen atom, a lower alkyl group, a halogeno lower alkyl group,
It may be substituted with one or more substituents selected from a hydroxyl group, a benzyl group, an acyl group, an optionally substituted amino group and an optionally substituted amino lower alkyl group.

More specifically, examples of the “optionally substituted cyclic amino group” for R ₃ in the general formula (I) include a group represented by the following formula (a) or (b) (Where Y is an oxygen atom, a sulfur atom, Or R ₁₁ —N, R ₄ represents a hydrogen atom or a lower alkyl group, R ₅ represents a hydrogen atom, a lower alkyl group, an amino lower alkyl group, or a mono- or di-lower alkylamino lower alkyl group; R ₆ represents a hydrogen atom, a hydroxyl group, an amino group which may be substituted or an amino lower alkyl group which may be substituted, and R ₇ and R ₈ may be the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group; R ₉ represents a hydrogen atom or a lower alkyl group, R ₁₀ and R ₁₁ represent a hydrogen atom, a lower alkyl group, a benzyl group or an acyl group, and n is 1 or 2 Means ).

Here, the “optionally substituted amino lower alkyl group” includes, for example, an amino lower alkyl group which may be substituted with lower alkyl, cycloalkyl, acyl, benzyl and the like. Examples of the “acyl group” include formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, chloroacetyl, trifluoroacetyl and the like.

Salts of the compound of the present invention include salts with inorganic acids such as hydrochloric acid and phosphoric acid; organic acids such as acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, malonic acid, gluconic acid and the like. Salts with acidic amino acids such as aspartic acid and glutamic acid; or sodium, potassium, calcium, magnesium of the compound of formula (I)
Metal salts such as zinc and silver; salts with organic bases such as dimethylamine, dicyclohexylamine and benzylamine; and salts with basic amino acids such as lysine and arginine.

The compound of the present invention may exist as various tautomers in addition to the structure represented by the formula (I). These tautomers are also included in the compounds of the present invention.

The compounds of the present invention may also exist as hydrates. Such forms are of course also encompassed by the compounds of the present invention.

The compounds of the present invention include those having an asymmetric carbon atom in the substituent R _3, they may exist as optically active forms. These optically active substances are also included in the compound of the present invention.

Furthermore, in the present invention compounds are those having a plurality of asymmetric carbon atoms in the substituent R _3, they may exist as different stereoisomeric forms. These stereoisomers are also included in the compounds of the present invention.

The compounds represented by the formula (I) include the following in addition to the compounds shown in the examples.

5-cyclopropyl-8-fluoro-1-hydroxy-7- (3-methylamino-1-pyrrolidinyl) -2,3,
5,10-tetrahydro-3,10-dioxobenzo [b] [1,
6] Naphthyridine. 5-cyclopropyl-6,8-difluoro-1-hydroxy-7- (3-methyl-1-piperazinyl) -2,3,5,
10-tetrahydro-3,10-dioxobenzo [b] [1,
6] Naphthyridine. 5-cyclopropyl-6,8-difluoro-1-hydroxy-7- (3,4,5-trimethyl-1-piperazinyl)
-2,3,5,10-tetrahydro-3,10-dioxobenzo [b] [1,6] naphthyridine. 5-cyclopropyl-6,8-difluoro-1-hydroxy-7- (3-methylamino-1-pyrrolidinyl)-
2,3,5,10-tetrahydro-3,10-dioxobenzo [b]
[1,6] Naphthyridine. 5-cyclopropyl-6,8-difluoro-1-hydroxy-7- (2-methylaminomethylmorpholino) -2,
3,5,10-tetrahydro-3,10-dioxobenzo [b]
[1,6] Naphthyridine. 5-cyclopropyl-6,8-difluoro-1-hydroxy-7- (2-dimethylaminomethylmorpholino)-
2,3,5,10-tetrahydro-3,10-dioxobenzo [b]
[1,6] Naphthyridine. 5-cyclopropyl-8-fluoro-1-hydroxy-6-methoxy-7- (3-methyl-1-piperazinyl) -2,3,5,10-tetrahydro-3,10-dioxobenzo [b] [1, 6] Naphthyridine. 5-cyclopropyl-8-fluoro-1-hydroxy-6-methoxy-7- (3,4-dimethyl-1-piperazinyl) -2,3,5,10-tetrahydro-3,10-dioxobenzo [b] [ 1,6] naphthyridine. 5-cyclopropyl-8-fluoro-1-hydroxy-6-methoxy-7- (3-methylamino-1-pyrrolidinyl) -2,3,5,10-tetrahydro-3,10-dioxobenzo [b] [1 , 6] naphthyridine. 5-cyclopropyl-8-fluoro-1-hydroxy-6-methoxy-7- (2-methylaminomethylmorpholino) -2,3,5,10-tetrahydro-3,10-dioxobenzo [b] [1,6 ] Naphthyridine. 5-cyclopropyl-8-fluoro-1-hydroxy-7- (3-methyl-1-piperazinyl) -2,3,5,10-
Tetrahydro-3,10-dioxopyrido [2,3-b] [1,
6] Naphthyridine. 5-cyclopropyl-8-fluoro-1-hydroxy-7- (3,4,5-trimethyl-1-piperazinyl) -2,
3,5,10-tetrahydro-3,10-dioxopyrido [2,3-
b] [1,6] naphthyridine. 5-cyclopropyl-8-fluoro-1-hydroxy-7- (3-dimethylamino-1-pyrrolidinyl) -2,
3,5,10-tetrahydro-3,10-dioxopyrido [2,3-
b] [1,6] naphthyridine. 7- (2-aminomethylmorpholino) -5-cyclopropyl-8-fluoro-1-hydroxy-2,3,5,10-tetrahydro-3,10-dioxopyrido [2,3-b] [1,6]
Naphthyridine. Next, a method for producing the compound of the present invention will be described.

(1) The compound (I) of the present invention has the following general formula (Wherein, R and R ′ are the same or different and each represent a lower alkyl group, and A, X ₁ , R ₁ and R ₃ are the same as described above), and a compound represented by the following general formula R ₂ —NH ₂ (III) (in the formula, R ₂ is the same as described above).

This reaction is carried out in a solvent such as water, alcohols such as ethanol, ethers such as dioxane, or a mixture thereof at 0 to 150 ° C., preferably 20 to 60 ° C., to obtain the starting compounds (II) and (III). 30 minutes to 7 days, usually 1 to 72
It can be carried out by stirring for a time, under normal pressure or under pressure. In this reaction, the starting compound (III) is converted to the starting compound (I
In general, it is carried out using an equivalent or excess amount to I).

If possible, the starting compound (II) used in this reaction is used in a form in which a group not involved in the reaction is protected, and after the reaction is completed, the protecting group may be removed by a conventional method.

Starting compound (II) is a novel compound and can be produced according to the following reaction formula.

(Wherein X ₃ , X ₄ and X ₅ are the same or different and each represents a halogen atom, and A, X ₁ , R ₁ , R ₃ , R and R ′ are the same as those described above.) a) is reacted with α-haloacetic acid ester in the presence of zinc to form a diester (b),
Then, this is treated with an oxidizing agent such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), whereby the starting compound (II) can be produced.

Also, reacting the acetone dicarboxylic acid ester (c) with the amine (d) to obtain a glutaconate (e), which is reacted with the acid halide (f), and then treated with a base such as sodium hydride. As a result, the starting compound (II) can be produced.

Furthermore, the starting compound R ₃ is a group other than a halogen atom (II) are mentioned Compound Compound R ₃ is a halogen atom (II) a (V), is reacted in the same manner as in the method (2) Can also be obtained by

(2) The compound of the present invention wherein R ₃ is a group other than a halogen atom in the general formula (I) is represented by the following general formula: (Wherein, X denotes a halogen atom, A, R _1, R ₂ and X ₁ are the same. As cited above) compound represented by the following general formula R ₃ '-H (V) (wherein represented by, R ₃ 'Means a group other than a halogen atom in the definition of R ₃ above.)

This reaction is carried out using alcohols such as ethanol, ethers such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide and pyridine. In an inert solvent such as 10 ~ 180 ° C., preferably 20 ~ 1
At 20 ° C., the starting compounds (IV) and (V) are mixed for 10 minutes to 24 hours.
It can be carried out by stirring for a time, usually 30 minutes to 4 hours.

This reaction is generally carried out in the presence of an acid acceptor by using the starting compound (V) in an equivalent amount or a slightly excessive amount relative to the starting compound (IV). It may be used to also serve as an acid acceptor. Examples of the acid acceptor include hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium bicarbonate, and 1,8-diazabicyclo [5,4,0. And organic bases such as undecene-7 (DBU) and triethylamine.

If possible, the starting compound (V) used in the present reaction may be used in a form in which a group not involved in the reaction is protected, and after the reaction is completed, the protecting group may be removed by a conventional method.

The compound of the present invention thus produced is isolated and purified according to a conventional method. Depending on the conditions for isolation and purification, the compound of the present invention can be obtained in the form of a salt or in a free form, and these are mutually converted according to the purpose to produce the desired form of the compound of the present invention.

The stereoisomers of the compounds of the invention can be separated from one another by conventional methods, for example by fractional crystallization, chromatographic separation and the like. In addition, the compound of the present invention having a corresponding configuration can also be produced by each of the above methods using a starting compound having a specific configuration.

The optically active form of the compound of the present invention can be separated by applying a known method.

Effect of the Invention Compound (I) and salts thereof thus obtained are both novel compounds and exhibit excellent antibacterial activity, and are therefore valuable as antibacterial agents. The compound (I) or a salt thereof can be used not only as a medicine for the human body and animals, but also as a fish disease drug, a pesticide, a preservative for food, and the like.

 Next, the antibacterial activity data of the compound of the present invention will be described.

^{* 1} Minimum growth inhibitory concentration (MIC: μg / ml) is based on Chemotherapy, 2
9 Measured according to the method described in (1), 76 (1981), and the results are shown in the above table. ^{* 2} A: Staphylococcus aureus 209P JC-1
(S. aureus 209P JC-1). B: E. coli NIHJ JC-2
2) C: Pseudomonas aeruginosa 12 (P.aeruginosa 1)
2). ^{* 3} Means the compound of Example 9 (the same applies hereinafter).

As shown in the preceding table, the compounds of the present invention were tested in vitro from E. coli and P. aerugi from Gram-positive bacteria such as S. aureus.
Shows broad and strong antibacterial activity across Gram-negative bacteria such as nosa. The compounds of the present invention also show excellent antibacterial activity in animal experiments.

When the compound of the present invention is used in humans as an antibacterial agent,
The dosage varies depending on age, body weight, symptoms, administration route, etc., but it is recommended to administer 5 mg to 5 g per day in one or several divided doses. The administration route may be oral or parenteral.

The compounds of the present invention may be in bulk, but are usually administered in a form prepared with a pharmaceutical carrier. Specific examples thereof include tablets, liquids, capsules, granules, fine granules, powders, syrups, injections, and ointments. These preparations are prepared according to a conventional method. Pharmaceutical carriers for oral use include starch, mannitol, microcrystalline cellulose, CMC Na,
Substances that are commonly used in the pharmaceutical field such as water and ethanol and do not react with the compound of the present invention are used. Injectable carriers include carriers commonly used in the field of injectables, such as water, physiological saline, glucose solutions, and infusion solutions.

Further, the above-mentioned liquid preparations and ointments can also be used for treatment in otolaryngology and ophthalmology.

EXAMPLES Next, the production method of the compound of the present invention will be described more specifically with reference to Examples and Reference Examples.

Reference Example 1 Ethyl 1-cyclopropyl-2-ethoxycarbonylmethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: (1) Known compound, 1-cyclopropyl -6,7,8-Trifluoro-1,4-dihydro-4-oxoquinoline-3-
Ethyl carboxylate 5.0g, zinc powder 2.32g, ethyl bromoacetate 6
g and 100 ml of tetrahydrofuran are heated to reflux for 4 hours. After cooling, the insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. Ice water is added to the residue, acidified with 1N hydrochloric acid, and extracted with chloroform. After drying the extract, the solvent was distilled off under reduced pressure to give 1-cyclopropyl-2-ethoxycarbonylmethyl-6,7,8-trifluoro-1,2-dihydro-4-hydroxyquinoline-3-carboxylic acid. 6.4 g of ethyl are obtained as an oil.

(2) A mixture of 6.4 g of the above compound, 4.4 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and 100 ml of toluene is stirred at 100 ° C. for 1 hour. After cooling, the reaction solution is filtered, and the filtrate is washed with water and dried. The solvent is distilled off under reduced pressure,
The residue is purified by silica gel column chromatography.
The obtained crystals are recrystallized from ether to obtain 4.5 g of the desired product. mp 117-118 ° C. Reference Examples 2 to 5 Using the corresponding starting compounds, the reaction was carried out in the same manner as in Reference Example 1 to obtain the compounds shown in Table 1.

Reference Example 6 Ethyl 1-cyclopropyl-2-ethoxycarbonylmethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: 15.7 g of cyclopropylamine, 31.4 ml of diethylamine and 200 ml of toluene 50 ml of ethyl acetonedicarboxylate is added to the mixture, and the mixture is stirred at room temperature for 5 days to obtain 64 g of diethyl 3-cyclopropylaminoglutaconate as an oil. This is mixed with 500 ml of toluene, 11.7 g of 60% sodium hydride is added, and the mixture is stirred at room temperature for 1 hour. 2,4,5
-Reaction of 57 g of trifluorobenzoyl chloride to give 3-
106 g of diethyl cyclopropylamino-2- (2,4,5-trifluorobenzoyl) glutaconate are obtained as an oil. A mixture of 106 g of this compound, 77 g of anhydrous potassium carbonate and 500 ml of dioxane was heated under reflux for 5 hours to obtain 55 g of the desired product.

mp 92-94 ° C. Reference Examples 7 to 11 Using the corresponding starting compounds, the reaction was carried out in the same manner as in Reference Example 6 to obtain the compounds shown in Table 2.

Reference Example 12 1-Cyclopropyl-2-ethoxycarbonylmethyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate ethyl: 1 -Cyclopropyl-2-ethoxycarbonylmethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 4.5 g, a mixture of 1-methylpiperazine 2.83 g and dimethylsulfoxide 25 ml To 100
After stirring at 2.5 ° C for 2.5 hours, the mixture is left to cool. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. After drying the extract, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ether to obtain the desired product (4.5 g).
Get. mp 97-98 ° C. Reference Example 13 ethyl 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-2-ethoxycarbonylmethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: 1-cyclo Ethyl propyl-2-ethoxycarbonylmethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 700 mg, 3-aminopyrrolidine 5
A mixture of 00 mg and 20 ml of dimethyl sulfoxide is stirred at 90 ° C. for 1 hour to obtain 560 mg of the desired product.

Reference Examples 14 to 54 Using the corresponding starting compounds, the compounds were treated in the same manner as in Reference Examples 12 and 13 to obtain the compounds shown in Table 3.

Reference Example 55 Ethyl 7- (4-acetyl-1-piperazinyl) -8-chloro-1-cyclopropyl-2-ethoxycarbonylmethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate : (1) ethyl 1-cyclopropyl-2-ethoxycarbonylmethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 5.0 g, anhydrous piperazine 4.0
A mixture of g and 30 ml of acetonitrile is heated at reflux for 5 hours. The reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The extract is concentrated and the residue is chloroform
Dissolve in 30 ml. To this, 1.5 ml of acetic anhydride was added and stirred for 1 hour. Water is added to the reaction solution, and the mixture is neutralized with aqueous ammonia, and then the chloroform layer is separated. Chloroform is distilled off under reduced pressure, and ethyl acetate and ipropyl ether are added to the residue, and the precipitated crystals are collected by filtration. Recrystallized from ethyl acetate to give 7- (4-acetyl-1-piperazinyl) -1-cyclopropyl-2-ethoxycarbonylmethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5.61 g of ethyl are obtained.

mp 159-160 ° C. (2) 2.78 g of the above compound, 1.6 g of N-chlorosuccinimide
And a mixture of 50 ml of chloroform are stirred at room temperature for 6 hours. Water is added to the reaction solution, the chloroform layer is separated, and chloroform is distilled off. The residue is purified by silica gel column chromatography (eluted with ethyl acetate-hexane) to obtain 420 mg of the desired product. Recrystallize from ethyl acetate.

mp 170-171 ° C. Example 1 5-cyclopropyl-6,7,8-trifluoro-1-hydroxy-2,3,5,10-tetrahydro-3,10-dioxobenso [b] [1,6] naphthyridine: 1-cyclopropyl Ethyl-2-ethoxycarbonylmethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 8.1 g, 28% aqueous ammonia 2
Ammonia gas is introduced into a mixture of 00 ml and 100 ml of ethanol at room temperature. After sealing and stirring for one day, the crystals are collected by filtration. The crystals are stirred in 1N hydrochloric acid for 10 minutes, filtered, and washed with water to obtain 3.8 g of the desired product. Recrystallize from a mixture of chloroform and ethanol.

mp300 ℃ or more. IR spectrum (KBr) cm ^-1 : 3400,1650,1600. Mass spectrum m / z: 323 (MH ⁺ ), 307,289. NMR spectrum (DMSO-d ₆ ) δ: 5.61 (1H, s, C ₄ -H) ), 7.
_{86 (1H, ddd, C 9} -H). Example 2 7- (3-Amino-1-pyrrolidinyl) -5-cyclopropyl-8-fluoro-1-hydroxy-2,3,5,10-
Tetrahydro-3,10-dioxopyrido [2,3-b] [1,
6] Naphthyridine: 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-2-ethoxycarbonylmethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-
1.6 g of ethyl 3-carboxylate and 60 ml of 28% aqueous ammonia in 50 ml
After stirring at 5 ° C for 5 hours, the mixture was cooled on ice and the crystals were collected by filtration. This is dissolved in an aqueous acetic acid solution and neutralized with aqueous ammonia. The precipitated crystals are collected by filtration to obtain 1.0 g of the desired product. mp300 ℃ or more. IR spectrum (KBr) cm ^-1 : 3335,1650,1600. Mass spectrum m / z: 371 (M ⁺ ). Example 3 8-Fluoro-5- (2,4-difluorophenyl)-
1-hydroxy-7- (4-methyl-1-piperazinyl) -2,3--5,10-tetrahydro-3,10-dioxopyrido [2,3-b] [1,6] naphthyridine: 2-ethoxycarbonylmethyl -6-fluoro-1-
(2,4-difluorophenyl) -7- (4-methyl-1
-Piperazinyl) -1,4-dihydro-4-oxo-1,8-
1.2 g of ethyl naphthyridine-3-carboxylate and 40 ml of 28% aqueous ammonia are stirred at 50 ° C. for 4 hours and then cooled with ice. The precipitated crystals are collected by filtration and recrystallized from chloroform to give the desired product.
0.12 g is obtained. mp 300-303 ° C (decomposition). Example 4 5-Cyclopropyl-6,8-difluoro-1-hydroxy-2-methyl-7- (4-methyl-1-piperazinyl) -2,3,5,10-tetrahydro-3,10-dioxobenzo [ b] [1,6] Naphthyridine: 1-cyclopropyl-2-ethoxycarbonylmethyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3 Stir a mixture of 0.5 g of ethyl carboxylate and 10 ml of a 40% aqueous solution of methylamine at room temperature overnight. Water and chloroform are added to the reaction solution, the aqueous layer is adjusted to pH 8 with 10% hydrochloric acid, and the chloroform layer is separated. The chloroform layer was dried and concentrated under reduced pressure.
The residue is recrystallized from chloroform to obtain 0.26 g of the desired product. mp 268-269 ° C. Example 5 6-chloro-5-cyclopropyl-8-fluoro-1
-Hydroxy-2,3,5,10-tetrahydro-7- (1-piperazinyl) -3,10-dioxobenzo [b] [1,6] naphthyridine: (1) 7- (4-acetyl-1-piperazinyl) -8-
350 mg of ethyl chloro-1-cyclopropyl-2-ethoxycarbonylmethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was added to a mixture of 2 ml of 11% ammonia-ethanol and 4 ml of 28% ammonia water. In addition,
Seal and stir for 6 days. The precipitated crystals are collected by filtration and washed with ethanol. After adding water thereto, the mixture is acidified with 10% hydrochloric acid, and the crystals are collected by filtration. The crystals are dissolved in glacial acetic acid, added with water, neutralized with 28% aqueous ammonia, and cooled with ice. The precipitated crystals are collected by filtration, washed with ethanol, and treated with 7- (4-acetyl-1).
-Piperazinyl) -6-chloro-5-cyclopropyl-
8-fluoro-1-hydroxy-2,3,5,10-tetrahydro-3,10-dioxobenzo [b] [1,6] naphthyridine 1
Get 10 mg.

mp300 ℃ or more. IR spectrum (KBr) cm ^-1 : 2950,1600,1550,1510. Mass spectrum m / z: 447 (MH ⁺ ) (2) 100 mg of the above compound was mixed with acetic acid-water-sulfuric acid (8: 6: 1) Add to 5 ml and heat for 2 hours. Ice water is added to the reaction solution, and the precipitated crystals are collected by filtration. The crystals are dissolved in an aqueous acetic acid solution, neutralized with 28% aqueous ammonia, and cooled with ice. The precipitated crystals are collected by filtration and washed with ethanol to obtain 60 mg of the desired product.

mp 280-285 ° C (decomposition). IR spectrum (KBr) cm ^-1 : 3400, 2950, 1650, 1600. Mass spectrum m / z: 404 (M ⁺ ), 362. Examples 6 to 48 Using the corresponding starting compounds, In the same manner, the compounds shown in Table 4 are obtained.

Example 49 5-cyclopropyl-6,8-difluoro-1-hydroxy-7- (4-methyl-1-piperazinyl) -2,3,5,
10-tetrahydro-3,10-dioxobenzo [b] [1,
6] Naphthyridine: 0.10 g, 1 of 5-cyclopropyl-6,7,8-trifluoro-1-hydroxy-2,3-5,10-tetrahydro-3,10-dioxobenzo [b] [1,6] naphthyridine Stir a mixture of 0.4 ml of methylpiperazine and 3.5 ml of dimethylsulphoxide at 120 ° C. for 2.5 hours. Ice water is added to the reaction solution, and the precipitated crystals are collected by filtration and washed with water. Recrystallization from a mixture of chloroform and methanol gives 60 mg of the desired product.

mp300 ℃ or more. IR spectrum (KBr) cm ^-1 : 3400,1650,1600. Mass spectrum m / z: 402 (M ⁺ ). Example 50 7- (2-Aminomethylmorpholino) -5-cyclopropyl-6,8-difluoro-1-hydroxy-2,3,5,10
-Tetrahydro-3,10-dioxobenzo [b] [1,6]
Naphthyridine: (1) 5-cyclopropyl-6,7,8-trifluoro-1
A mixture of -hydroxy-2,3,5,10-tetrahydro-3,10-dioxobenzo [b] [1,6] naphthyridine 644 mg, 2-formylaminomethylmorpholine 1.15 g and dimethylsulfoxide 12 ml was stirred at 125 ° C for 4 hours. I do. The solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is acidified with acetic acid. The crystals were collected by filtration and recrystallized from a mixture of chloroform and ethanol to give 5-cyclopropyl-7- (2-formylaminomethylmorpholino) -6,8-difluoro-1-hydroxy-2,3,5,10 250 mg of tetrahydro-3,10-dioxobenzo [b] [1,6] naphthyridine are obtained. mp297-300
° C (decomposition). (2) The above compound 220 mg, 20% hydrochloric acid 5 ml and ethanol 1
Heat 0 ml of the mixture to reflux for 1.5 hours. The solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is neutralized with aqueous ammonia. After cooling on ice, the crystals were collected by filtration, washed with water and ethanol, and the desired product was collected.
Get 16g.

mp300 ℃ or more. IR spectrum (KBr) cm- ¹ : 2900, 1630 (sh), 1580. Mass spectrum m / z: 418 (M ⁺ ). Example 51 5-Cyclopropyl-6,8-difluoro-1-hydroxy-7- (cis-3,5-dimethyl-1-piperazinyl) -2,3,5,10-tetrahydro-3,10-dioxobenzo [ b] [1,6] naphthyridine: 5-cyclopropyl-6,7,8-trifluoro-1-hydroxy-2,3,5,10-tetrahydro-3,10-dioxobenzo [b] [1,6] Naphthyridine 0.50 g, cis-2,6-dimethylpiperazine 0.71 g and dimethyl sulfoxide 10 ml
Is stirred at 125 ° C. for 4 hours. The precipitated crystals are collected by filtration and washed with water. The crystals are dissolved in an aqueous acetic acid solution and neutralized with aqueous ammonia. The precipitated crystals are collected by filtration and the desired product is 0.52 g.
Get.

mp300 ℃ or more. IR spectrum (KBr) cm ^-1 : 3100 to 2800, 1650, 1600. Mass spectrum m / z: 416 (M ⁺ ), 346. Examples 52 to 75 Using the corresponding starting compounds, In the same manner, the compounds shown in Table 5 are obtained.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/495 601 A61K 31/495 601 31/535 606 31/535 606 31/54 601 31/54 601 (72) Inventor Matsumoto Junichi 2-15-15 Shikadaidaihigashi, Ikoma City, Nara Prefecture (72) Inventor Shinichi Nakamura 1-12-20 Tsukawaki, Takatsuki City, Osaka Prefecture (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 471 / 04,471 / 14 CAPLUS (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] (1) General formula (Wherein X ₁ represents a halogen atom, A represents N or C—X ₂ , wherein X ₂ represents a hydrogen atom, a halogen atom, a cyano group or a lower alkyloxy group, and R ₁ represents A lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group or a phenyl group which may have a substituent, R ₂ represents a hydrogen atom or a lower alkyl group, and R ₃ represents a halogen atom , An amino group which may be substituted or a cyclic amino group which may be substituted.) And a salt thereof. 2. A group in which R ₃ is represented by the following formula (a) or (b): (Where Y is an oxygen atom, a sulfur atom, Or R ₁₁ —N, R ₄ represents a hydrogen atom or a lower alkyl group, R ₅ represents a hydrogen atom, a lower alkyl group, an amino lower alkyl group, or a mono- or di-lower alkylamino lower alkyl group; R ₆ represents a hydrogen atom, a hydroxyl group, an optionally substituted amino group or an optionally substituted amino lower alkyl group, and R ₇ and R ₈ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group; R ₉ represents a hydrogen atom or a lower alkyl group, R ₁₀ and R ₁₁ represent a hydrogen atom, a lower alkyl group, a benzyl group or an acyl group, and n is 1 or 2 Means The tricyclic compound according to claim 1 or a salt thereof.