JPS6253987A - Benzo(ij)quinolizine-2-carboxylic acid compound, production thereof and antibacterial agent comprising same as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I(A is methylene and B is carbonyl when AB bond is single bond and A and B form vinylene when AB bond is double bond; R<1> is H, 1-3C alkyl or 2-hydroxyethyl; R<2> and R<3> are H, methyl or ethyl and R<3> may be bonded to the same carbon to which R<2> is linked; R<4> is methyl or ethyl; X is halogen), its salt and hydrate. EXAMPLE:9-Fluoro-5-methyl-8-(1-piperazinyl)-6, 7-dihydro-1, 7-dioxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid ethyl ester. USE:An antibacterial agent. PREPARATION:A compound shown by the formula II(R<5> is methyl, ethyl or n-propyl) is hydrolyzed.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a benzo[ij]quinolidine-2-carboxylic acid compound, a method for producing the same, and an antibacterial agent containing the same as an active ingredient. More specifically, 9-halogeno-5-alkyl-8-(unsubstituted to trisubstituted piperazinyl)benzo[ij]quinolidine- which is easily transferred from the gastrointestinal tract into the circulating blood and has sustained antibacterial activity. The present invention relates to a 2-carboxylic acid derivative, a physiologically acceptable salt thereof, or a hydrate thereof, a method for producing the same, and a medicine containing the same as an active ingredient.

A representative example of a synthetic antibacterial agent that has a halogen atom as a substituent and has a pyridonecarboxylic acid structure is 1-ethyl-6-fluoro-1゜4-dihydro-7-
(1-Piperazinyl)-4-oxoquinoline-3-carboxylic acid (hereinafter abbreviated as norfloxacin; Japanese Patent Publication No. 55-3
4.144@publication), 9-fluoro-3-methyl-10
-(4-methyl-1-piperazinyl)-7-oxo-2
,3-dihydro0-7H-pit[1,2,3-de]
[1°4] Benzoxazine-local ponic acid (hereinafter abbreviated as ofloxacin; JP-A-57-46.986@
9-Fluoro-6°7-dihydro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1! -1,5H
-benzo[ijlquinolidine-2-carboxylic acid (hereinafter referred to as O
PC7241 abbreviation: JP-A-55-76.875
@publication) and 9-fluoro-6,7-dihydro-1゜7
-dioxo-5-methyl-18,5H-benzo[ij]
Quinolidine-2-carboxylic acid (hereinafter abbreviated as compound α; JP-A-51-127.099) and the like are known.

(Ofloxacin) (OPC-7241> (Compound α) However, when norfloxacin is orally administered to a fasting animal such as a mouse at 50 m!J/9, the degree of transfer into the serum after 30 minutes is , the highest average value is 1±o
, epg, , 'Badeo' was reported by Murayama et al. (
Japanese Society of Chemotherapy Journal Volume 29 Special Issue 4 Page 98 1
Furthermore, although norfloxacin shows excellent antibacterial activity in in vitro antibacterial tests against Gram-positive bacteria and Gram-positive bacteria, Goto et al. have discussed that it has some drawbacks in oral absorption ( Journal of the Japanese Society of Chemotherapy, Volume 32, Special Issue 1, Page 22, 1984).

Therefore, recent research into synthetic antibacterial agents with a pyridonecarboxylic acid structure has focused on improving bioavailability (biological utilization) during oral administration, rather than focusing on the superiority or inferiority of the activity as long as it has a certain degree of antibacterial activity. In the course of that research, he began to pay attention to the
This led to the development of PC-7241. This ofloxacin was administered to fasted mice at 1 m3/mouse (5
To 0mg/! (equivalent to j) when administered orally, 30
The aforementioned Goto et al. reported that the serum concentration reached 10 mcg/d after 10 minutes, and increased oral absorption was observed compared to norfloxacin (Journal of the Japanese Society of Chemotherapy, Vol. 32, Special Issue No. 1, 22). p. 1984). However, with this level of oral absorption, there is still room for improvement from the perspective of bioavailability.In addition, according to the same report, the residual concentration in serum is low after 2 hours after administration. Since it has been clearly shown that the drug concentration decreases to as low as 1.511Fl/Id, a technique for improving drug persistence is required.

Regarding the oral absorption of 0PC-7241, the 5th Medicinal Chemistry Symposium (Kyoto; December 9th and 10th, 1980)
-del-1,4-benzoxazine-6-carboxylic acid (pyri-do[1,2,3-del-
1,4-benzoxazine-6-carboxy
In a lecture titled ``Structure and antibacterial activity of peripheral compounds'', it was announced that it is almost the same as ofloxacin. Therefore, 0PC-7241 is expected to have the same problems as ofloxacin.

Regarding compound α, 9-fluoro-6゜7-dihydro-7-hydroxy-5-methyl-1-oxo-18
, is only reported to be useful as an intermediate raw material for 5H-benzo[ij]quinolidine-2-carboxylic acid (Japanese Unexamined Patent Publication No. 127,099/1989), and there are no detailed reports regarding its antibacterial activity. Not done. To confirm this, the inventors conducted a follow-up experiment on antibacterial activity, and found that the efficacy against Gram-negative bacteria was weak, and moreover, it was found that the efficacy against Gram-negative bacteria such as Pseudomonas aeruginosa and Mycobacterium marcescens, which have been particularly important in bacterial infections in recent years. It turned out to be completely ineffective.

・Measures to solve the problem The present inventors conducted a comparative study on various new compounds that have a halogen atom substituent in the molecule and contain a pyridone carboxylic acid structure, and found that ofloxacin 1-2 oxymethylene group (-〇-CH2-) and 0PC-72
A compound in which the ethylene group (-CH2-CH2-) at the 7-6 position of 41 is structurally transformed into a carbonylmethylene group (-Co-CH2-) or a vinylene group (-C) (= C)-1-) is The present invention was achieved based on the knowledge that the antibacterial activity of OPC-7241 is expressed, and it has better oral absorption and persistence than ofloxacin and 0PC-7241.

According to the present invention, the following general formula [I] (wherein, when AB is a single bond, A represents a methylene group,
B each represents a carbonyl group, or when AB is a double bond, A and B together represent a vinylene group, R1 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or 2
- represents a hydroxyethyl group, R2 and R3 are the same or different and represent a hydrogen atom, a methyl group or an ethyl group,
Here, R3 may be bonded to the same carbon to which R2 is bonded, R4 represents a methyl group or an ethyl group, and X represents a halogen atom. ) A benzo[ij]quinolidine-2-carboxylic acid derivative or a physiologically acceptable salt thereof or a hydrate thereof is provided.

Further, according to the present invention, there is provided a method for producing a benzo[ijlquinolidine-2-carboxylic acid derivative represented by the general formula [I], a physiologically acceptable salt thereof, or a hydrate thereof. .

Furthermore, according to the present invention, the benzo[ij]quinolidine-2-carboxylic acid derivative represented by the general formula [I] or a physiologically acceptable salt thereof or a hydrate thereof is used as an active ingredient. An antibacterial agent is provided.

Benzo[ij]quinolidine-2 represented by general formula [i]
- Physiologically acceptable salts of the carboxylic acid derivative (hereinafter simply referred to as the compound [I] of the present invention) include salts with inorganic acids such as hydrochloric acid or sulfuric acid, or organic acids such as methanesulfonic acid; Salts with metal or organic bases such as sodium, potassium, calcium or magnesium may be mentioned.

<Method for producing the compound [I] of the present invention> The compound [I] of the present invention is produced by the following general formula [II] (wherein A
, the bonding mode between B and AB, and R1, R2, R3, R
4 and X have the same meanings as above, and R5 represents a methyl group, ethyl group or n-propyl group. ) It can be produced by hydrolyzing the benzo[ijl quinolidine-2-carboxylic acid ester derivative represented by (hereinafter referred to as production method 1).

Hydrolysis of the benzo[ijl quinolidine-2-carboxylic acid ester derivative [II] is carried out using an acid or alkali in water, methanol, ethanol, n-propanol, acetic acid, or a mixture of two or more thereof, This is carried out over a period of 30 minutes to 48 hours, preferably 1 to 24 hours. The reaction temperature when Shun is used is set at 30-150°C, preferably 60-130°C, and when an alkali is used, the reaction temperature is set at 0-100°C, preferably 0-50'C. The acid to be used is hydrochloric acid or sulfuric acid, etc., and the alkali is 0.1 to 5N, preferably 0.5 to 5N.
3N aqueous solution of sodium hydroxide or potassium hydroxide. Note that both acids and alkalis include benzo [ij
] Quinolidine-2-carboxylic acid ester derivative []I]
Use excess amount.

Compound [I] of the present invention can be obtained as a precipitate by adjusting the pH of the resulting hydrolyzed solution. When hydrolysis is carried out with an acid, the pH is adjusted to 7-8 using aqueous ammonia or triethylamine, or to 0.
The pH is adjusted to 5-7 using a 1-5N aqueous solution of sodium hydroxide or potassium hydroxide. On the other hand, when hydrolysis is performed with an alkali, the pH is adjusted to 4-5 using acetic acid or formic acid, or 5-7 using dilute hydrochloric acid or sulfuric acid.

In addition, the hydrochloride of the compound [I] of the present invention or its hydrate can be prepared by adjusting the reaction solution obtained by hydrolysis using an alkali to pl-11 or less using concentrated hydrochloric acid, or by hydrolyzing it using hydrochloric acid. It can be obtained as a precipitate by concentrating the decomposed reaction solution.

In addition, the compound [I] of the present invention has the following general formula ll11] (wherein, the bonding mode between A, B and AB, R4 and X have the same meanings as above, and Y represents a fluorine atom or a chlorine atom.) A carboxylic acid derivative represented by the following general formula [IV] (
It can also be produced by carrying out a nucleophilic substitution reaction with a piperazine derivative represented by (in the formula, R1, R2, and R3 have the same meanings as above) (hereinafter referred to as production method 2).

This nucleophilic substitution reaction is carried out at 0 to 200°C, preferably 30 to 150°C, using no solvent or an appropriate polar solvent.
Take your time. Suitable polar solvents include water, ethanol, n-propanol, n-butanol, methylcellosolve, ethylcellosolve, pyridine, N,N-dimethylformamide, dimethylsulfoxide or hexamethylphosphorotriamide, or two or more thereof. For example, a mixed liquid may be mentioned. In addition, the reaction molar ratio is carvone!
For conductor [111, piperazine derivative [IV] is 1
The amount is set to 8 to 8 times the mole, preferably 2 to 5 times the mole.

In production method 1 and production method 2, purification of the target product can be carried out by washing with water, washing with methanol, ethanol or isopropanol, recrystallization, or, if necessary, using a chloroform-methanol mixture (volume ratio 20 to 3:1) as a developing solvent. This can be carried out by appropriately combining silica gel column chromatography and the like.

The compound [I] of the present invention produced as described above can be converted into a hydrate according to a conventional method, or converted into an inorganic acid salt thereof using hydrochloric acid, sulfuric acid, methanesulfonic acid, sodium hydroxide or potassium hydroxide according to a conventional method. Alternatively, it can be converted into an organic acid salt, a metal or organic base salt, or a hydrate thereof.

<Production method of various raw materials for the compound of the present invention [I]> In the benzo[ij]quinolidine-2-carboxylic acid ester derivative [I] which is the raw material in the above-mentioned production method 1, A is a methylene group, B is a carbonyl group, A compound represented by the following general formula [V] (wherein R1, R2, R3, R4, R5 and X have the same meanings as above) in which AB is a single bond is a compound represented by the following general formula [VI] ( In the formula, R4
, R5, X and Y have the same meanings as above. ) and the piperazine derivative [IV]
(hereinafter referred to as step a) by subjecting them to a nucleophilic substitution reaction.

The nucleophilic substitution reaction here is carried out at 0 to 200°C, preferably 0 to 100°C, without a solvent or using an appropriate reaction solvent.
It takes 48 hours. Suitable reaction solvents include solvents that can dissolve the compound [V] to be produced, such as benzene,
Examples include chloroform, dichloromethane, ethyl acetate, acetonitrile, ethanol, n-propanol, n-butanol, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphorotriamide, or a mixture of two or more thereof. The reaction molar ratio is the piperazine derivative [VI] to the compound [VI].
1v] is set to be 1 to 8 times the mole, preferably 2 to 5 times the mole.

Furthermore, in the benzo[ijl quinolidine-2-carboxylic acid ester derivative [II], A and B together represent a vinylene group, and AS is a double bond, the following general formula [
VI] (Hereinafter in the margin) (In the formula, R1, R2, R3, R4, R5 and X have the same meanings as above.) The compound represented by [
V] is first selectively reduced to a compound represented by the following general formula [] (wherein R1, R2, R3, R4, R5 and X have the same meanings as above). Then, it can be produced by subjecting it to an intramolecular dehydration reaction (hereinafter referred to as step C).

Selective reduction in step b involves water, methanol, ethanol,
The reaction is carried out using sodium borohydride in n-propatool, isopropatool, or a mixture of two or more thereof. The reaction temperature is suitably 0 to 50°C, and the reaction time is suitably 1 to 10 hours. Sodium borohydride is used in an amount of 0.25 to 4 times the mole of compound [V]. In addition, the compound produced by this selective reduction [■]
is then hydrolyzed using an appropriate acid or alkali to produce the following general formula [(wherein, R1, R2, R3, R4 and X have the same meanings as above), which has excellent antibacterial activity. 9-halogeno-5-alkyl-8-unsubstituted to trisubstituted piperazinyl-7-hydroxy-6,7-dihydro-1-oxo-H-1,5H-benzo[ij]quinolidine-2-carboxylic acid derivatives as shown can also be manufactured.

Next, the intramolecular dehydration reaction in Step C is carried out using a dehydrating agent without a solvent or in an appropriate reaction solvent at 0 to 100°C for 1 to 48 hours. Examples of the dehydrating agent include acids such as hydrochloric acid, sulfuric acid, polyphosphoric acid, polyphosphoric acid ester, acetic acid, and toluenesulfonic acid, with polyphosphoric acid or polyphosphoric acid ester being particularly preferred. Suitable reaction solvents include water,
Benzene, chloroform, methanol, ethanol, n
- Examples include propatool and isopropatool. The dehydrating agent is used in an excess amount relative to the compound [■].

Carvone M derivative [I11
], A is a methylene group, B is a carbonyl group, AB
A compound represented by the following general formula [X] (wherein R4, (hereinafter referred to as process C).

The hydrolysis here is carried out using an excess amount of a mineral acid such as hydrochloric acid or sulfuric acid in water, methanol, ethanol, n-propanol, acetic acid, or a mixture of two or more of these.
It is carried out over a period of 0 minutes to 48 hours, preferably 1 to 5 hours. The reaction temperature is set at 30-150°C, preferably 60-130°C.

In addition, in the carboxylic acid derivative [I[[], A and B together represent a vinylene group, and AB is a double bond, the following general formula [XI] (wherein, R4, X and Y are as defined above). The compound represented by (same meaning) is the compound [X] obtained in step d above.
is selectively reduced to the following general formula [XII] (wherein R4
, X and Y have the same meanings as above. ) (hereinafter referred to as step C)), and then subjecting this to an intramolecular dehydration reaction (hereinafter referred to as step f).

The selective reduction in step C and the intramolecular dehydration reaction in step f are as follows:
It can be carried out under the same reaction conditions as the selective reduction in step b and the intramolecular dehydration reaction in step C described above.

In addition, the compound [V
I] is an aniline derivative represented by the following general formula [X (wherein, X and Y have the same meanings as above) and the following general formula [X IV ] (wherein,
R4 has the same meaning as above. ) to obtain a compound represented by the following general formula [XV] (wherein, R4, X and Y have the same meanings as above) (hereinafter referred to as Q step). ), this is subjected to a ring-closing condensation reaction to form the following general formula [X VI ] (wherein R4,
X and Y have the same meanings as above. ) to a compound represented by the formula [X VI ] (hereinafter referred to as a blank) (in the formula, R5 has the same meaning as above, and R6 is a methyl group or an ethyl group). ) is reacted with a malonic acid ester derivative represented by the following general formula [X] (wherein R4, R5, x and Y are as defined above).

) can be produced by converting it into the target compound [VI] by a ring-closing condensation reaction (hereinafter referred to as step j).

The reaction in step q is carried out without a solvent or in water, ethanol, n-propanol, isopropanol, acetic acid, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide at 70 to 130°C for 30 minutes to 5 hours. conduct. The reaction molar ratio is set so that the amount of the β-lactone derivative [X IV ] is 1 to 1.5 times the amount of the aniline derivative [XI[I].

The reaction in step j can be carried out without solvent or with benzene, nitrogen,
The reaction is carried out in n-butanol, N,N-dimethylformamide or dimethylsulfoxide at 150 to 250°C for 30 minutes to 5 hours. The reaction molar ratio is compound [X Vl
], the malonic acid ester derivative [X■] is 1 to 3
Set to double the mole.

The ring-closing condensation reaction in step h and step 2 uses polyphosphoric acid, polyphosphoric acid ester, or sulfuric acid as a condensing agent, and
Perform at 200°C. The amount of the condensing agent used is 2 to 50 times the weight of compound [XV] in the h step and compound [X■] in the k step, respectively. The reaction time is 1 to 48 hours in the h step and 10 minutes to 24 hours in the k step.
The time is appropriate.

11 In vitro antibacterial activity of the compound [I] of the present invention or its physiologically acceptable salts or hydrates thereof This is explained by the minimum inhibitory concentration against Gram-negative bacteria and Gram-negative bacteria. The gram-negative bacteria used were Bacillus subtilis, Staphylococcus aureus, and fecal streptococcus, and the gram-negative bacteria used were Escherichia coli, Enterobacter-1 Klebsiella pneumoniae, Proteus, Pseudomonas aeruginosa, S. marcescens, and S. Enteritidis. . The minimum inhibitory concentration (incubation at 37°C for 20 hours) is determined by the standard method of the Japanese Society of Chemotherapy (Journal of the Japanese Society of Chemotherapy).
29, No. 1, p. 76, 1981).

The following compounds were used as representative examples of the compound [I] of the present invention, physiologically acceptable salts thereof, or hydrates thereof. Note that the characters in parentheses after each chemical name represent the tentative names of those compounds in this specification.

9-Fluoro-5-methyl-8-(1-piperazinyl)
-6,7-dihydro-1,7-dioxo-18.5H-
Benzo[ij]quinolidine-2-carboxylic acid (compound 1
〉, 9-chloro-5-methyl-8-(1-piperazinyl)-
6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carvone M (compound 2)
, 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1°7nidioxo 18.5H-benzo[ij]quinolidine-2-carboxylic acid (compound 3), 9-Fluoro-5-ethyl-8-(4
-methyl-1-piperazinyl)-6,7-dihydro-1
゜7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid (compound 6), 9-chloro-5-methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro- 1.7-Siokin-1
)-f, 5H-benzo[ij]quinolidine-2-carboxylic acid (compound 7), 9-fluoro-5-methyl-8-(4-n-propyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ijlquinolidine-2-carboxylic acid (compound 8), 9-chloro-5-methyl-8-
(4-ethyl-1-piperazinyl)-6,7-dihydro-1,7-dioxo-18,5H-benzo[ijlquinolidine-2-carvonel1l (compound 9), 9-fluoro-5-methyl-8- (3,5-dimethyl-1-piperazinyl)-6,7-dihydro-1,7-dioxo-18
．． 5H-benzo[ij]quinolidine-2-carboxylic acid (
Compound 11), 9-fluoro-5-methyl-8-[4-
(2-hydroxyethyl)-1-piperazinyl]-6゜7-dihydro-1,7-dioxo-18,5H-benzo[ijlquinolidine-2-carboxylic acid (compound 12), 9-fluoro-5-methyl- 8-(3,3-dimethyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-18,58-benzo[ij]quinolidine-2-carboxylic acid (compound 15), 9-fluoro-5-methyl-
8-(3-methyl-1-piperazinyl)-6,7-dihydro-1°7-dioxo-1H,5H-benzo[ij]
Quinolidine-2-carboxylic acid (compound 16), 9-chloro-5-methyl-8-(3,4,5-trimethyl-1-
piperazinyl)-6,7-dihydro-1,7-dioxo-11-1.5) f-benzo[ijlquinolidine-2-
Carboxylic acid (compound 18), 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-IH,5H-benzo[ij
l-quinolidine-2-carboxylic acid (compound 19), 9-fluoro-5-methyl-8-(1-piperazinyl)
-1-oxo-18,5H-benzo[ij]quinolidine-2-carboxylic acid (compound 20>, 9-chloro-5-methyl-8-(1-piperazinyl)-1-oxo-1H,
5H-benzo[ij coquinolizine-2-carvone r! !
<Compound 22), 9-chloro-5-methyl-8-(4-
Methyl-1-piperazinyl)-1-oxo-IH, 5-benzo[ijlquinolidine-2-carboxylic acid (compound 24), 9-fluoro-5-methyl-8-(3,4-dimethyl-
1-piperazinyl)-1-oxo-1.

5-day-benzo[ij]quinolidine-2-carboxylic acid (compound 25), 9-fluoro-5-methyl-8-(3,3-dimethyl-
1-piperazinyl)-1-oxo-18°5-benzo[ij]quinolidine-2-carboxylic acid (compound 26), 9-fluoro-5-methyl-8-(3,4,5-trimethyl-1- piperazinyl)-1-oxo-1H,5H-
Benzo[ijlquinolidine-2-carboxylic acid compound 2
7), 9-Fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5-benzo[ij
] Quinolidine-2-carboxylic acid compound 29), 9-chloro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ijl
Quinolidine-2-carvone'r! i (compound 31), 9-fluoro-5-ethyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij
l-quinolidine-2-carboxylic acid (compound 32), 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1°7-dioxo-
IH, 5H-benzo[ijlquinolidine-2-carboxylic hydrochloride monohydrate (compound 35), 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1H, 5H-benzo[ij
l-quinolidine-2-carboxylic hydrochloride (compound 37), 9-fluoro-5-methyl-8-(3,4-dimethyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid hydrochloride monohydrate (compound 38), 9-fluoro-5-methyl- 8-(3,4,5-trimethyl-1-piperazinyl)-6,7-dihydro-1,7
-dioxo-IH, 5[1-benzo[ijl quinolidine-2-carboxylic hydrochloride hydrochloride 1-eternal (compound 39).

The test results are shown in Table 1. In addition, in the same table, the results of the in vitro antibacterial activity of ofloxacin, 0PC-7241, and compound α tested in the same manner as described above are also listed for comparison.

(Left below) As is clear from Table 1, the compounds of the present invention [11 or their physiologically acceptable salts or hydrates thereof] cannot be predicted from compound α, which has the same or similar basic skeleton. It is observed that it shows excellent antibacterial activity and is comparable to ofloxacin or 0PC-7241.

゛ Oral absorbability〉 The oral absorbability of a representative example of the compound [I] of the present invention or a physiologically acceptable salt thereof or a hydrate thereof was determined using ICR male mice (body weight 20±l5J) that had been fasted overnight.
It was tested using The test consisted of administering 50 doses of the test compound to each mouse.
1Q/K (J was administered orally, 30 minutes, 1 hour, 2
This was done by determining the serum concentration of the test compound at the time and after 4 hours, respectively. Five mice were used for each time period. Serum was prepared by collecting blood from mice by cardiac puncture every hour.

Serum concentration is Escherichia coli (Escherichia col)
i) Measured by the paper disk method using CI-304 as a test tube.

The results are shown in Table 2. In addition, the results of oral absorption of ofloxacin and 0PC-7241, which were tested in the same manner as above, are also listed in the same table for comparison.

Oral absorption and persistence are recognized to be significantly superior to ofloxacin and OPC-7241, or a physiologically acceptable salt thereof, or a hydrate thereof.

<Therapeutic effect on experimental mouse infections> Escherichia coli (Es
cherichia cot i) CI-304
ddY male mice (5 mice per group, 20% body weight) infected with
±IS? The therapeutic effects of the compound [I] of the present invention, a physiologically acceptable salt thereof, or a representative example of a hydrate thereof were tested using The therapeutic effect was determined from the ED50flI calculated from the number of surviving mice after 7 days of oral administration of the test compound to infected mice. Infected mice are 5
It was prepared by intraperitoneally inoculating the above-mentioned Escherichia coli suspended in a % mucin solution.

The amount of inoculated bacteria is the minimum lethal dose ()l determined in advance by preliminary tests.
The amount was 10 times that of initial Lethal [)ose). Oral administration of the test compound is conducted after inoculation of the test bacteria.
I went when the time was up.

The results are shown in Table 3. In addition, the results of ofloxacin and 0PC-7241, which were tested in the same manner as above, are also listed in the same table for comparison.

It is also recognized that Schiff's physiologically acceptable salts or their hydrates exhibit excellent therapeutic effects against bacterial infections.

<Acute Toxicity> Compound 3 and Compound 29, which are representative examples of the compound [I] of the present invention or a physiologically acceptable salt thereof or a hydrate thereof, were administered intravenously to male ICR mice weighing 23 to 27 g. was administered, and the LD5o value was determined. The l-[)50 value is 317 m3/'J for compound 3 and 2 for compound 29.
It was 25mg per drink.

When the compound [I] of the present invention or its physiologically acceptable salt or hydrate thereof is used as an antibacterial agent for humans, the dosage depends on age, body weight, symptoms, administration route, and number of administrations. It varies depending on the situation, but approximately 3m3 to 4I per day.
j, preferably 50Ir1! Set in the range of J to 29. The dosage is divided into one or several doses and administered orally or parenterally.

The compound [I] of the present invention or a physiologically acceptable salt thereof or a hydrate thereof may be used as a bulk powder, but if necessary, excipients, binders, disintegrators, etc. Add agents, diluents, solubilizing agents, emulsifiers, suspension aids, or preservatives as appropriate, and prepare solid preparations such as powders, granules, tablets, gunpowders, or capsules, or oral liquid preparations, or suspensions using conventional methods. Alternatively, a liquid preparation such as an injection may be used.

The present invention will be further explained with reference examples and examples.

Reference Example 1 (Production Example of Compound [VI] Part 1) (q Step) 3-chloro-4-fluoroani', J'/146 g (1
, 00 mol) was added to 86 g (1,00 mol) of β-butyrolactone, stirred at 80 to 90°C for 30 minutes, and then allowed to cool in air. Ether 10100O was added to this reaction solution, insoluble matter was filtered off, and the obtained filtrate was extracted with 750ml of 2N aqueous sodium hydroxide solution. This extract was made acidic using 130 ml of concentrated hydrochloric acid, and then diluted with ether io
Extracted with ooy. This ether layer was dried with anhydrous sodium sulfate, then solidified under reduced pressure to 3-(3-chloro-4
111 g (yield: 4γ, 9%) of pale yellow oil of -fluoroanilino)butyric acid was obtained.

(h step) 3-(3-chloro-4-fluoroanilino)butyric acid92.
66 g (0.40 mol) was added with 1400 g of polyphosphorus, and the mixture was stirred at 110° C. for 1.5 hours. After cooling in the air, this reaction solution was diluted with 3 J of water, and the pH was adjusted to pH 4 to 5 using an aqueous sodium hydroxide solution. Then, the precipitated solid was extracted with chloroform, the extract was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (the developing solvent was chloroform). The fraction containing the target product was dried under reduced pressure, and the residue was recrystallized from benzene to obtain yellow crystals of 5-chloro-6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline. 7.43 g (yield 8.7%) was obtained. In addition, from other fractions, 7-chloro-6, which is a structural isomer, was similarly obtained.
-Fluoro-2-methyl-4-oxo-1,2,3,4
8.55 g (yield 10.0%) of yellow crystals of -tetrahydroquinoline were also obtained.

(Step j) 5-chloro-6-fluoro-2-methyl-4=oxo-
1,2,3,4-tetrahydroquinoline 6.419 (
0.03 mol) and 6.499 (0.03 mol) of hexymethylene malonic acid diethyl ester were stirred in the absence of solvent at 200 to 210'C for 1.5 hours, and then allowed to cool in air. and (5-chloro-6-fluoro-2-methyl-
4-oxo-1,2,3,4-tetrahydroquinoline-
11.509 of a pale yellow oil of aminomethylene malonic acid diethyl ester (1-yl) was obtained.

(k step) The above (5-chloro-6-fluoro-2-methyl-4-
Oxo-1,2,3,4-tetrahydroquinoline-1-
yl) aminomethylene malonic acid diethyl ester 11,
509 (0.03 mol), add 60 g of borric acid,
Stirred at 110-120°C for 30 minutes.

After this reaction solution was allowed to cool in the air, 500 ml of water was added, and the precipitate deposited was collected by filtration. This precipitate was recrystallized from acetic acid and 8-chloro-9-fluoro-5-methyl-6,7
-dihydro-1,7-dioxo-1H,5H-benzo[
ij] 8.29 g (yield: 81.8%) of pale yellow crystals of quinolidine-2-carboxylic acid ethyl ester were obtained. The melting point (min w!-) of this crystal was 240-244°C.

In each of the above steps, the operations were almost the same as above, except that the corresponding raw materials (the number of reaction moles were the same as above) and the conditions such as reaction temperature, reaction time, and reaction solution tS were changed as appropriate. Five compounds were prepared.

8.9-difluoro-5-methyl-6,7-dihydro-
1,7-dioxo-1. ,,H,5H-benzo[ij]
Quinolidine-2-carboxylic acid ethyl ester [melting point 23
1-235°C (decomposition)],]8-chloro9-fluoro5-ethyl6°7-dihydro-1,7-dioxo-1
H,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester, 8,9-dichloro-5-ethyl-6,7-dihydro-1
, 7-dioxo-1 day, 5+-f-benzo[ij]quinolidine-2-carboxylic acid n-propyl ester, 8-chloro-9-fluoro-5-methyl-6°7-dihydro-1,7-dioxo -IH,5H-benzo[ij]
Quinolidine-2-carboxylic acid methyl ester, 8-chloro-9-bromo-5-methyl-6,7-dihydro-1,7-dioxo-18.5H-benzo[ijl Quinolidine-2-carboxylic acid methyl ester.

Consideration] 2 (Compound Vl) Production Example Part 2 (Q Step) 3. Add β-butyrolactone 86y (1,00 mol) to 182 g (1,00 mol) of 4-dichloroaniline,
After stirring at 110 to 120°C for an hour, the mixture was allowed to cool in air. 100 ml of ether was poured into this reaction solution, insoluble matter was filtered off, and the resulting filtrate was extracted with 750 d of 2N aqueous sodium hydroxide solution. This extract was made acidic using 1130m salt, and then extracted with ether ioooy. This ether layer was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain 1 q of pale yellow crystals of 3-(3°4-dichloroanilino)acetic acid 1289 (yield 51.6%).

(H step) 99.24 g of 3-(3,4-dichloroanilino)acetic acid
(0.40 mol) was added with 300 g of polyphosphoric acid, and 9
Stirred at 0-100°C for 4 hours. After cooling in the air, this reaction solution was diluted with 31 parts of water, and the liquid properties were adjusted to I) 84-5 using an aqueous sodium hydroxide solution. The precipitated solid matter was then extracted with chloroform, and the extract was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (developing solvent was chloroform). The fraction containing the target product was dried under reduced pressure, and the residue was recrystallized from benzene to obtain 5,6-dichloro-2-methyl-4-oxo-1,2.
, 3゜Yellow crystals of 4-tetrahydroquinoline 9.94
g (yield 10.8%) was obtained. In addition, 13.53 g of yellow crystals of 6,7-dichloro-2-methyl-4-oxo-'I,2,3.4-tetrahydroquinoline, which is a structural isomer, was similarly obtained from other fractionated liquids ( A yield of 14.7%) was also obtained.

(Step j) 5.6-dichloro-2-methyl-4-oxo-1,2,
6.909 (0.03 mol) of 3,4-tetrahydroquinoline and diethyl ethoxymethylenemalonate 6.
499 (0.03 mol) in the absence of solvent, 190 to 2
Stirred at 00"C for 3 hours, then allowed to cool at room temperature, (5,
6-dichloro-2-methyl-4-oxo-1,2,3,
Pale yellow oil of 4-tel-lahydroquinolin-1-yl) aminomethylene malonic acid diethyl ester 12.01
I got a 9.

(k step) (5,6-dichloro-2-methyl-4-oxo-1,2
,3,4-tetrahydroquinolin-1-yl)aminomethylenemalonic acid diethyl ester 12.01 g (0,
03 mol) and added 60 g of polyphosphoric acid to 110-120
Stirred at ℃ for 20 minutes. After this reaction solution was allowed to cool at room temperature, 50 (7!) of water was poured into it, and the precipitate was collected by filtration. This precipitate was recrystallized with acetic acid,
-Methyl-6,7-dihydro-1,7-dioxo-IH
, 9.05 g of pale yellow crystals of 5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester (yield: 85.2
%) is 19. The melting point (decomposition) of this crystal is 234-23
The temperature was 7°C.

Reference example 3 (Production example of compound [V] Part 1 (a step) 8-chloro-9-fluoro-5-methyl-6.

7-dihydro-1,7-dioxo-1t-1,5H-benzo[ijlquinolidine-2-carboxylic acid ethyl ester 6,75 g<0.02 mol) in chloroform 12
6.89 g of piperazine (
0.08 mol) and stirred at 20-25°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [the developing solvent was a chloroform-methanol mixture (volume ratio 10:1)]. The fraction containing the target product was dried under reduced pressure, and the residue was recrystallized from benzene to obtain 9-fluoro-5-methyl-8-(1
-piperazinyl)-6.

4.799 yellow crystals (yield 61.8%) of 7-dihydro-1.7-dioxo-18.51-1-benzo[ij]quinolidine-2-carboxylic acid ethyl ester were obtained.

In step a above, the procedure was almost the same as above, except that the corresponding raw materials (the number of reaction moles were the same as above) and the conditions such as reaction temperature, reaction time, and reaction solvent were changed as appropriate. Ten compounds were obtained as yellow crystals or oil. The yield was within the range of 58.3-86.1%.

9-chloro-5-methyl-8-(1-piperazinyl)-
6.7-dihydro-1,7-dioxo-IH,51-1
-benzo[ij coquinolidine-2-carboxylic acid ethyl ester [melting point (decomposition) 197-b 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-6.7-dihydro-1.

7-dioxo-18,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester [melting point (decomposition) 247
~b 9-Fluoro-5-methyl-8-(4-ethyl-1-piperazinyl)-6.7-dihydro-1.

7-Cioquin-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester, 9-chloro-5-ethyl-8-(1-piperazinyl)-6,7-dihydro-
1,7-dioxo-IH,5N-benzo[ij]quinolidine-2-carboxylic acid n-propyl ester, 9-fluoro-5-ethyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro -1.

7-dioxo-1H,5H-benzo[ij coquinolidine-2-carboxylic acid ethyl ester, □9-chloro5-methyl-8-(4-methyl-1-piperazinyl)-
6,7-dihydro-1,7-dioxo-1H,5l-f
-Benzo[ij]quinolidine-2-carboxylic acid ethyl ester [melting point (decomposition) 230-b 9-fluoro-5-methyl-8-(4-n-propyl-
1-Piperazinyl)-6,7-dihydro1,7-dioxo-1t-1,5-benzo[ij]quinolidine-
2-Carboxylic acid methyl ester, 9-fluoro-5-methyl-8-(3,4-dimethyl-1-piperazinyl)-
6,7-dihydro-1,7-dioxo-IH,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester, 9-fluoro-5-methyl-8-(3,4,5-trimethyl-1- piperazinyl)-6,7-dihydro-1
, 7-dioxo-18.5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester, 9-fluoro-5-ethyl-8-(1-piperazinyl)
-6,7-dihydro-1,7-dioxo-IH,5H-
Benzo[ij]quinolidine-2-carboxylic acid ethyl ester.

Reference Example 4 (Preparation Example of Compound [V, Part 2) (Step a) 8.9-difluoro-5-methyl-6,7-dihydro-
1,7-dioxo-1)-1,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester 6.43 g
(0.02 mol) in N,N-dimethylformamide 60
Suspended in WJi and added 2-methylpiperazine 6.01
g (0.06 mol) and stirred at 90-100'C for 1 hour. The reaction solution was then concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [the developing solvent was a chloroform-methanol mixture (volume ratio 10:1)].
], and a fraction containing the target product was collected. This fraction was dried under reduced pressure, and the residue was recrystallized from benzene to obtain 9-fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-6゜7-dihydro-1,7-dioxo- 1H, 51
5.149 yellow crystals (yield: 64.0%) of 1-benzo[ij]quinolidine-2-carboxylic acid ethyl ester were obtained.

In step a above, the procedure was almost the same as above, except that the corresponding raw materials (the number of reaction moles were the same as above) and the conditions such as reaction temperature, reaction time, and reaction solvent were changed as appropriate. Two compounds were prepared. Both had yellow crystal appearance, and the yields were 71.5% and 66.4%, respectively.

9-Fluoro-5-methyl-8-(4-ethyl-2,5
-dimethyl-1-piperazinyl)-6゜7-dihydro-
1,7-dioxo-IH, 5-benzo[ij]quinolidine-2-carboxylic acid ethyl ester, 9-chloro-5-methyl-8-(3,4,5-trimethyl-1-piperazinyl)-6, 7-dihydro-1,7-
Dioxo-IH,5H-benzo[ij]quinolidine-2
-Carboxylic acid ethyl ester.

] 5 (Production of compound vI 1) (Step a) 8-chloro-9-fluoro-5-methyl-6゜7-dihydro-1,7-dioxo-1H,5H-benzo[ij]
Quinolidine-2-carboxylic acid ethyl ester 16.89
g (0.05 mol) was suspended in 300 ml of chloroform, and to this was added 20.03 g (0.2 mol) of N-methylpiperazine.
0 mol) was added and stirred at 40-50°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [the developing solvent was a chloroform-methanol mixture (volume ratio 10:1)]. The fraction containing the target product was dried under reduced pressure, and the residue was recrystallized from benzene to give 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1°7.
-dioxo-18.5H-benzo[ij coquinolidine-
Yellow crystals of 2-carboxylic acid ethyl ester 12.89
g (yield 64.2%) was obtained.

(Step b) 12.04 g (0.03 mol) of the obtained crystals was dissolved in 400 m of methanol, and 1.13 tj (0.03 mol) of sodium borohydride was added thereto in small portions, Stirred at 20-25°C for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [
The developing solvent was a chloroform-methanol mixture (volume ratio 7).
:1)]. A fraction containing the target product was collected and dried under reduced pressure to obtain 9-fluoro-5-methyl-8.
-(4-Methyl-1-piperazinyl)-7-hydroxy6,7-dihydro-1-oxo-18,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester pale yellow crystalline solid7. 32 g (yield 60.5%) was obtained.

(Step C) 6.05 g (0,015 mol) of the above-mentioned solid was added to 30 g of Polyrin M, and stirred at 60 to 70°C for 7 hours. After cooling at room temperature, 200 d of water was poured into the reaction solution, which was then neutralized using sodium hydrogen carbonate, and extracted with 400 ml of chloroform. This extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily residue. This oily residue was injected with 100 g of n-hexane and shaken to give 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-IH,5H-benzo[ij] A pale yellow solid of quinolidine-2-carboxylic acid ethyl ester (5.589 g) (yield 96.5%) was obtained as a precipitate.

In each of the above steps, operations were carried out in almost the same manner as above, except that the corresponding raw materials (the number of reaction moles were the same as above) and the conditions such as reaction temperature, reaction time, reaction solvent, etc. were changed as appropriate. Compound 10 was obtained as a pale yellow solid.

9-Fluoro-5-methyl-8-(1-piperazinyl)
-1-oxo-IH, 5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester, 9-fluoro-5-
Methyl-8-(4-ethyl-1-piperazinyl)-1-
Oxo-1H,5H-benzo'i']]quinolidine-2
-Carboxylic acid ethyl ester 9-chloro-5-methyl-8-(1-piperazinyl)-
1-oxo-1H,5H-benzo[ijlquinolidine-
2-Carboxylic acid ethyl ester, 9-chloro-5-ethyl-8-(1-piperazinyl)-1-oxo-IH, 5
H-benzo[ij]quinolidine-2-carboxylic acid n-propyl ester, 9-chloro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij]
Quinolidine-2-carboxylic acid ethyl ester, 9-fluoro-5-methyl-8-(3,4-dimethyl-
1-piperazinyl)-1-oxo-1175H-benzo[ij]quinolidine-2-carboxylic acid methyl ester, 9-fluoro-5-methyl-8-(3,3-dimethyl-
1-piperazinyl)-1-oxo-IH.

5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester, 9-fluoro-5-methyl-8-(3,4,5-trimethyl-1-piperazinyl)-1-oxo-1H,5H-
Benzo[ij]quinolidine-2-carboxylic acid ethyl ester, 9-chloro-5-methyl-8-(4-ethyl-3-methyl-1-piperazinyl)-1-oxo-1,5H-
benzo[ij Coquinolidine-2-carboxylic acid ethyl ester, 9-fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij
l-quinolizine-2-carribonated ethyl ester, 9-fluoro-5-methyl-8-(2,5-dimethyl-
1-piperazinyl)-1-oxo-IH.

5th-benzo[ij]quinolidine-2-carboxylic acid ethyl ester.

Reference 6 (a.
Step) 8.9-dichloro-5-methyl-6,7-dihydro-1
．． 7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester 14.17 g (0
,04 mol) was suspended in 250 d of 2-methylpiperazine, 12.029 (0.12 mol) of 2-methylpiperazine
was added to this and stirred at 50 to 60°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [the developing solvent was a chloroform-methanol mixture (volume ratio 10:1)]. The fractionated solution containing the target product was dried under reduced pressure, and the residue was recrystallized from benzene.
9-chloro5-methyl-8-(3-methyl-1-piperazinyl)-6,7-dihydro-1,7-dioxo-1
12.75 g of yellow crystals of H,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester (yield 76.
3%).

(Step b) The above crystal 12.543 (0,030 mol) was dissolved in ethanol 400 rriI2, and 0.87 g (0,023 mol) of sodium borohydride was added thereto in small portions to give a solution of 20 to 25 mol. Stirred at °C for 10 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [the developing solvent was a chloroform-methanol mixture (
volume ratio 7:1)]. The fraction containing the target product was dried under reduced pressure to give 9-chloro-5-methyl-8-(3-
Methyl-1-piperazinyl)-7-hydroxy6.7
-dihydro-1-okine-18°5 days-benzo[ij]
4.817 pale yellow crystalline solids (yield 38.3%) of quinolidine-2-carboxylic acid ethyl ester were obtained.

(Step C) 4.629 (0,011 mol) of this solid substance and 40 g of polyphosphoric acid were mixed and left at 20 to 25°C for 26 hours. Add 300 r/l of water to this reaction solution! was injected and neutralized with sodium bicarbonate. This neutralized solution was extracted with 600 d of chloroform, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily residue. The oily residue was shaken in 60 g of n-hexane and 9-chloro-5
-Methyl-8-(3-methyl-1-piperazinyl)-1
-oxo-1H,5H-benzo[ij]quinolidine-2
- Pale yellow solid of ethyl nitroxycarciboxate 4.3
4 g (yield 98.2%) was obtained as a precipitate.

In each of the above steps, the following steps were carried out in almost the same manner as above, except that the corresponding raw materials (the number of reaction moles were the same as above) and the conditions such as reaction temperature, reaction time, reaction solvent, etc. were changed as appropriate. A compound was prepared. The appearance was a pale yellow solid.

9-Fluoro-5-ethyl-8-(3-methyl-1-piperazinyl)-1-oxo-1 day, 5-1-benzo[i
jl quinolidine-2-carboxylic acid ethyl ester.

Reference example 7 (Production example of compound X) (d step) 8.9-dichloro-5-methyl-6,7-dihydro-1
．． 7-dioxo-18.5H to benzo[ij]quinolidine-2-carboxylic acid ethyl ester 7.089 (0,0
2 moles) was suspended in a mixture of 14 m of concentrated hydrochloric acid and 56 m of acetic acid, and the suspension was stirred at 110 to 120°C for 3 hours to be hydrolyzed. The reaction solution was allowed to cool at room temperature, and the precipitate was collected by filtration and washed with water to give 8,9-dichloro-5-methyl-6,7-dihydro-1,7-dioxo-1N, 51-1-benzo[ ij] Pale yellow crystals of quinolidine-2-carboxylic acid 5
．． 619 (yield 86.0%) was obtained.

In the above step, replacing the corresponding compound [VI] (the number of reaction moles is the same as above), the reaction temperature, reaction time,
The following compound was produced by operating in substantially the same manner as described above, except that conditions such as the reaction solvent were changed as appropriate. The appearance was pale yellow crystals, and the yield was 65.5%.

8-chloro-9-fluoro-5-methyl-6゜7-dihydro-1,7-dioxo-111.5H-benzo[ij
] Quinolidine-2-carboxylic acid [melting point 247-254°C
(Disassembly)].

Reference Example 8 (Production Example of Compound [XI) (d Step) 8-chloro-9-fluoro-5-ethyl-6°7-dihydro-1,7-dioxo-1 day, 5-1-benzo[ij
] Quinolidine-2-carciboxylic acid ethyl A/varnish 7/L/
24.62 'iJ (0,07-E/L/) Make salt! Suspend in a mixture of 50m and 200d of acetic acid, and add 1
Hydrolysis was carried out by stirring at 10-120°C for 3 hours. The reaction solution was allowed to cool at room temperature, and the precipitate was collected by filtration and washed with water to give 8-chloro-9-fluoro-5-ethyl-6,7-dihydro-
1,7-dioxo-1t-1,5)-1-benzo[ij
]Pale yellow crystals of quinolidine-2-carboxylic acid 16.95
ff (yield 74.8%) was obtained.

('e process) 16.18 g (0.05 mol) of this crystal was mixed with 500 d of water.
5.679% of sodium borohydride (
Add 0.15 mol) in small portions until 20 to 25 mol.
Stirred at ℃ for 10 hours. The reaction solution was made acidic with dilute hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from acetic acid to give 8
Pale yellow crystals of -chloro-9-fluoro-5-ethyl-7-hydroxy6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid8.
799 (yield 54.0%) was obtained.

(Step f) 8.14 g (0,025 mol) of the above crystals were added to polyphosphoric acid 409 and stirred at 60 to 70°C for 7 hours. After cooling in the air, 200 m of water was poured into the reaction solution, and the precipitated crystals were collected by filtration and then washed with water. The obtained crystals were recrystallized from acetic acid to give 8-chloro-9-fluoro-5-ethyl-
1-oxo-1H,5H-benzo[ij]quinolidine-
5.73 g pale yellow crystals of 2-carboxylic acid (74.5%
) was obtained.

In each of the above steps, the following steps were carried out in almost the same manner as above, except that the corresponding raw materials (the number of reaction moles were the same as above) and the conditions such as reaction temperature, reaction time, reaction solvent, etc. were changed as appropriate. A compound was prepared. The appearance was pale yellow crystals.

8-chloro-9-fluoro-5-methyl-1-oxo-
IH,5H-benzo[(j]quinolidine-2-carboxylic acid.

Example 1 (Compound 1) 9-fluoro-5-methyl-8-(1-piperazinyl)
-6,7-dihydro-1,7-dioxo, -II-
3.87 g (0.01 mol) of 1,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester was suspended in 12 ml of ethanol, 50 d of 2N aqueous sodium hydroxide solution was added thereto, and the mixture was heated at 20 to 25°C. Hydrolysis was carried out by stirring for 2 hours. The pH of the reaction solution was adjusted to pH 4 to 5 using acetic acid while cooling with water, and the precipitate was collected by filtration. This precipitate was recrystallized from ethanol and 9-fluoro-
5-Methyl-8-(1-piperazinyl)-6,7-dihydro-1,7-dioxo-18.51-1-benzo[i
j] Yellow crystals of quinolidine-2-carboxylic acid 2.91y
(yield 81.0%). Melting point (decomposition) of this crystal
was 261-263°C.

'yrJ, analysis iM (013813F N304 Toshite) 2 calculated value (%) C, 60,161+, 5.05
N, 11.70 actual value (%”) C, 59,901+
4.83 N, 11.43 infrared absorption spectrum (
cm-1; KBr): 1720, 1675.1620 1H-nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.86 (3tl, d), 3.27~3.70 (2t
l, m), 3.70-4°50 (8H, m),
5.15-5.60 (ltl, m), 8.43 (i
H,d), 9.47(IH,5)9-fluoro-5-
Methyl-8-(1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij ] Quinolidine-2-carboxylic acid ester derivative [■], especially compound [V] (0,
The following compounds of Examples 2 to 8 were produced in substantially the same manner as in Example 1 above, except that 01 mol) was changed as appropriate.

Yoshiki MJ2 (Compound 2) 9-chloro-5-methyl-8-(1-piperazinyl)-
6,7-dihydro-1,7-dioxo=IH,5)-1
-Benzo[ij]quinolidine-2-carboxylic acid yellow crystals; yield 3.19 g Melting point (decomposition), 245-250'C (ethanol) Elemental analysis value (as C18H18CpN304): Calculated value (%) C, 57, 52H, 4,83N, 11.18
Actual value (%) C, 57,68H, 4,66N, 11.
02 Infrared absorption spectrum/L/ (Cm-'; KBr)
:1715, 1670.1615 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
:1.85(3H,d), 3.25~4.50(1
ON, m), 5.17-5.60 (IH, m), 8
．． 83 (IH, s), 9.45 (IN, s) Example 3 (Compound 3) 9-Fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1° 7-dioxo-
18,58-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; Yield 2.659 Melting point (decomposition); 220-229°C (ethanol) Elemental analysis value (as C19H2oFN304): Calculated value (%
) C, 61,11H, 5,40N, 11.213 Actual value (%) C, 61°24 H, 5,41N, 11.
17 Infrared absorption spectrum (cm-1; Br): 1
715, 1665.1620 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.82 (3H, d), 3.23 (3H, s),
3.30~3.77 (2N, m), 3.77~
4.50 (8N, m), 5.10~5.70 (IH
, m), 8.37 (IN, d), 9.37 (1M,
S) Daio-mawari A 9-fluoro-5-methyl-8-(4-ethyl-1-piperazinyl)-6,7-dihydro-1°7-dioxo-
1H,5H-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; Yield 2.32 g Melting point (decomposition); 256-258°C (ethanol) Elemental analysis value (as C2oH22FN3o4): Calculated value (
%) C, 62,001-1,5,72N, 10.8
5 Actual value (%) C, 62, 24) -1, 5, 81N
, 10.71 infrared absorption spectrum (cm-1; KBr
): 1715, 1670.1620 1 day - Nuclear magnetic resonance subectel (δ; CF3GOOD
): 1.55 (3H, t), 1.83 (3N, d),
3.20~4.50 (12H, m), 5.10~5
．． 65 (IH, m), 8.43 (1N, d).

9, 37 (IN, S) Ohata 11 9-chloro-5-ethyl-8-(1-piperazinyl)-
6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; Yield 2.569 Melting point (decomposition); 255-260°C (ethanol) Elemental analysis value (C19H2oCpN304 ): Calculated value (
%) C, 58,54H, 5,17N, 10.78 Actual value (%) C, 58,46H, 4,98N, 11.
00 Infrared absorption spectrum 1-1 (Cm-1; KBr):
1720, 1670.1620 1 day - Nuclear magnetic resonance spectrum (δ, CF3GOOD)
: 1.15 (3N, t), 2.00~2.50 (2H
, m), 3.30-4.50 (IOH, m), 5
．． 15-5.60 (IH, m), 8.80 (1M,
S), 9.44(IH,S) −
1 day, 5H-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; Yield 2.159 Melting point (decomposition); 230-237°C (ethanol) Elemental analysis value (as C2oH22FN304): Calculated value (%
) C, 62,001-1,5,72N, 10.85
Actual value (%) C, 61,821-1,6,01N,
10.73 infrared absorption spectrum (cm'; 13r
): 1715, 1670.1620 1 day - Nuclear magnetic resonance subectel (δ; CF3c00o
): 1.10 (3H, t), 2.00-2.50 (2
H, m), 3.20 (3H, S), 3.30-4.
50 (1 leaf, m), 5.15-5.70 (IN, m)
), 8.40 (IH, d), Hunger 40 (II-1
,S)
H,5H-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; Yield 3.24 g Melting point (decomposition); 230-233°C (ethanol) Elemental analysis value (as C19H2oC, l!N304); Calculated value (% ) C, 58, 54H, 5, 17N, 10.7
8 Actual value (%) C, 58, 31H, 4, 98N, 1
1.01 Infrared absorption spectrum (cm-'; Br)
:1715, 1670.1615 1 day - Nuclear magnetic resonance spectrum (δ; CF3GOOD)
: 1.83 (3H, d), 3.20 (3N, s),
3.25 ~ 4.50 (10 fl, m), 5.17 ~
5.56 (IH, m), 8.80 (1) 1. s).

9,40(18,S) Example 8 (Compound 8) 9-Fluoro-5-methyl-8-(4-n-propyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-18,5H-benzo[ijlquinolidine-2-carboxylic acid yellow crystals; Yield 3.01 g Melting point (decomposition); 26B-272°C (ethanol ) Elemental analysis value (as C21st 24FN304) Second calculated value (
%) C, 62,83H, 6,03N, 10.47 Actual value (%) C, 63,10H, 5,98N, 10.
33 Infrared absorption spectrum/L/ (cm-'; KBr)
:1720, 1665.1620 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.05 (3N, t), 1.85 (3tl, d),
1.90~2.50 (2N, m), 3.25~4
．． 30 (12H, m), 5.10-5.70 (1N,
m), 8.45 (IH, d), 9.40 (IH, s
) big dust f? J9 (Compound 9) 8.9-dichloro-5-methyl-6,7-dihydro-1
,7-dioxo-111.5H-benzo[ij]quinolidine-2-carboxylic acid (3.26 g (0.01 mol)) was suspended in 30 ml of methyl cellosolve, and to this was added 3.439 g (0.01 mol) of N-ethylpiperazine. 03 mol) and 10
Stirred at 0-110°C for 2 hours. This reaction solution was dried under reduced pressure, 30 ml of methanol was added to the resulting residue, and the mixture was stirred, and then the insoluble matter was filtered off.

This insoluble matter was recrystallized from ethanol and 9-chloro-5-
Methyl-8-(4-ethyl-1-piperazinyl>-6,
Yellow crystals of 7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid 3.2
3 g (yield: 80.0%) was obtained. The melting point (decomposition) of this crystal was 295-298°C.

Elemental analysis value (C201122cJ! as N304)
Two calculations fil! (%) C, 59,481-1,5,
49N, 10.41 actual value (%>C, 59,241
-1,5,31N, 10.29 infrared absorption spectrum (cm'; [Sr): 1720, 1675.161
5 1H-nuclear magnetic resonance spectrum (δ: CF3 C00D
): 1.60 (311, t), 1.87 (3H, d
), 3.20-4.55 (12H, m), 5.15
~5.60 (1M, m), 8.90 (ltl, s).

9.45(IH,s) 8.9-dichloro-5-methyl-6,7-dihydro-1
．． 7-Dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid (0.01 mol) and N-ethylpiperazine (0.03 mol) were combined with the corresponding carboxylic acid derivatives [1[1], especially the compound [X] (0.01 mol) and the piperazine derivative [IV] (0.03 mol) were respectively changed as appropriate, but the procedure was almost the same as in Example 9 above,
The following compounds of Examples 10-15 were prepared.

Example 10 9-Fluoro-5-ethyl-8-(3-methyl-1-piperazinyl)-6,7-dihydro-1°7-dioxo-
11-1.5H-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; yield 2.529 Melting point (decomposition): 242-247°C (ethanol)
Elemental analysis value (as C2oH22FN304): Calculated value (%) C, 62,00H, 5,72N, 10.85
Actual value (%) C, 62, 35H, 6, 01N, 10
．． 87 Infrared absorption spectrum (cm-1; KBr):
1715, 1675.1615 1 day - nuclear magnetic resonance vector (δ; CF3CO0D)
:1.10(311,t), 1.55(3H,d),
2.00-2.50 (2H, m), 3.20-4.
40 (98, m), 5.20-5.70 (IH, m)
, 8.45 (1B, d), 9.40 (IH, s)
1-Piperazinyl)-6,7-dihydro-1,7-dioxo-1 day, 5H-benzo[ij]quinolidine-2-carboxylic acid Yellow crystals; Yield 3.109 Melting point (decomposition); 243-247°C (ethanol ) Elemental analysis value (as C2o)-122FN3o4): Calculated value (%) C, 62,00F1, 5.72 N, 10.
85 actual value (%) C, 61, 82H, 5, 57N,
10.57 Infrared absorption spectrum (cm'; KBr)
:1705, 1685.1620 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.30-2.10 (9M, m), 3.25-4.
45 (8H, m).

5.10-5.60 (IH, m), 8.39 (1M,
d), 9.35 (IH, s)
1,7-dioxo-111.511-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; Yield 1.45 cJ Melting point (decomposition): 266-268°C (ethanol) Elemental analysis value (C2oH22 "as N305): Calculated value (%) C, 59, 54H, 5, 50N, 10.4
2 Actual measurement value (%) C, 59, 22H, 5, 51N, 1
0.31 infrared absorption spectrum (cm-1; Br)
:1720, 1670.1620 1H-nuclear magnetic resonance spectrum (δ; CF3CO0D)
:1.85(3H,d), 3.00~4.60(1
4H, m), 5.15-5.60 (IH, mL
8.45 (IN, d), 9.55 (1H, s) -dihydro-1
,7-dioxo-01.5H-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; Yield 3.029 Melting point (decomposition); 292-293°C (ethanol) elemental analysis value <C2oH22CMN3o, as): Calculation Value (%) C, 57, 21H, 5, 28N, 10.0
1 Actual value (%) C, 56,94H, 5,17N,
9.82 Infrared absorption spectrum (cm”; KBr):
1720, 1670.1620 1 day - Nuclear magnetic resonance spectrum (δ; CF3cooD):
1.85(3)1. d), 3.00-4.50 (14
) f, m), 5.15 to 5.60 (IH, m), 8
．． 86(1H,S), 9.43(IN,S) ふ凰■ゆA 9-Fluoro-5-methyl-8-(3,3,4-trimethyl-1-piperazinyl)-6,7-dihydro- 1,7
-Dioxo-11-1.58-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; Yield 3.01 (j Melting point (decomposition): 233-239°C (ethanol)
Elemental analysis value (as C21H24FN3o4) Calculated value (%) C, 62,83H, 6,03N, 10.47
Actual value (%) C, 63,00H, 5,99N, 10
．． 18 Infrared absorption spectrum (cm'; KBr): 1
710, 1685.1615 1 day - nuclear magnetic resonance spectrum/L, (+5; CF3
CO0D): 1.35-2.15 (9H, m), 3.
20 (3H, s), 3.35-4.40 (8H, m)
, 5.15-5.60 (1N, m), 8.40 (I
H,d), 9.40(1H,S) Example 15 (Compound 15) 9-Fluoro-5-methyl-8-(3,3-dimethyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-11-1.5H-benzo[ij]quinolidine-2
-Carboxylic acid yellow crystals, yield 2.639 Melting point (decomposition): 250-254℃ (ethanol) Elemental analysis value (as C2oH22FN304) Two calculated values (%
) C, 62,00H, 5°72 N, 10.85 Actual value (%) C, 61,85F1, 5.68 N, 1
0.88 infrared absorption spectrum (cm-1; Br)
:1710, 1680.1620 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0[)
): 1.35-2.15 (9N, m), 3.20-4.
50(8)1. m).

5.10-5.65 (E, m), 8.40 (IH,
d), 9.35 (IH,s) Example 16 (Compound 16) 9-Fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-6,7-dihydro-1°7-dioxo-
11-f, 51-1-benzo[ij]quinolidine-2-
4.01 g (0.01 mol) of carboxylic acid ethyl ester was suspended in a mixture of 2 ethanol (7!) and 20 d of 6N hydrochloric acid, and the mixture was stirred at 80 to 90°C for 5 hours to perform hydrolysis. This reaction The pH of the liquid was adjusted to pH 7 to 8 using a 28% ammonia aqueous solution under water cooling, and then the precipitate was collected by filtration.
;1) to give 9-fluoro-5-methyl-8-(
3-Methyl-1-piperazinyl)-6,7-dihydro-
2.69 g (yield 72.0%) of yellow crystals of 1,7-dioxo-'lH,5H-benzo[ij]quinolidine-2-carboxylic acid were obtained. Melting point (decomposition) is 231-234
It was ℃.

Elemental analysis value (as C19H2oFN304): Calculated value (%) C, 61, 11H, 5, 40N, 11.26
Actual value (%) C, 60,971-1,5,23N,
11.21 Infrared absorption spectrum (cm-1; KBr)
:1710, 1680.1620 1 day - Nuclear magnetic resonance spectrum (δ; CF3 GOOD
): 1.40-2.10 (6H, m), 3.25-4.
45 (9H, m).

5.15-5.70 (IH, m), 8.40 (IH
, d), 9.40(1H,5) 9-fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-6,7-dihydro-1°7-dioxo-
18,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester (0.01 mol) was converted into the corresponding benzo[ij]quinolidine-2-carboxylic acid ester derivative [
The following compounds of Examples 17 and 18 were produced in substantially the same manner as in Example 16 above, except that IIL was appropriately changed, particularly to compound [V] (0.01 mol).

Example 17 9-Fluoro-5-methyl-8-(4-ethyl-2,5
-dimethyl-1-piperazinyl)-6゜7-dihydro-
1.7-dioxo-11-1.5H-benzo[ij]quinolidine-2-carboxylic acid yellow crystals; Yield 2.08g Melting point (decomposition), 215-222°C (ethanol) Elemental analysis value (as 0221-126FN304) : Calculated value (%) C, 63,60H, 6,31N, 10.12 Actual value (%) C, 63,78H, 6,28N, 10.
35 Infrared absorption spectrum (cm”; 8F): 17
10, 1680.1615 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.20~2.45 (12H, m), 3.20~
4.45 (IOH, m).

5.20-5.65 (IH, m), 8.75 (IH
, d), 9.45 (IH,S) Example 18 (Compound 18) 9-chloro-5-methyl-8-(3,4,5-trimethyl-1-piperazinyl)-6,7-dihydro-1 ,7-
Dioxo-18,5H-benzo[ij]quinolidine-2
-Carboxylic acid yellow crystals; yield 3.55 g Melting point (decomposition): 227-233°C (ethanol)
Elemental analysis value (C21) 124 (as Q N3 o4): Calculated value (%) 0.60.351-1.5.79
N, 10.06 Actual value (%) C, 60,291-1
, 5,77N, 10.10 Infrared absorption spectrum (C
m-'; KBr): 1710, 1680.1620 廿1-Nuclear magnetic resonance spectrum (δ; CF3CO0D
): 1.25-2.10 (91, m), 3.20
(3tf, s), 3.25-4.50 (8) 1. f
f1), 5.10-5.60(1)1. m),
8.75 (IH, S), 9.40 (1) 1. S) The following compounds were also produced by operating in substantially the same manner as in each of the above-mentioned Examples.

9-Bromo-5-methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1,7-dioxo-1
1.5H-benzo[ij coquinolidine-2-carboxylic acid, '9-fluoro-5-methyl-8-(3,4-dimethyl-
1-piperazinyl)-6,7-dihydro-1,fusioquine-1H,5H-benzo[ij]quinolidine-2-carboxylic acid, 9-fluoro-5-methyl-8-(3,5-dimethyl-
4-n-propyl-1-piperazinyl)-6,7-dihydro-1,7-dioxo-IH.

5th-benzo[ij]quinolidine-2-carboxylic acid, 9-chloro-5-ethyl-e-(3,4-diethyl-5
-methyl-1-piperazinyl)-6,7-dihydro-1
．． 7-dioxo-IN, 5H-benzo[ij]quinolidine-2-carboxylic acid, 9-fluoro-5-methyl-8-
(5-ethyl-2-methyl-1-piperazinyl)-6,
7-dihydro-1,7-dioxo-1H,5H-benzo[ijlquinolidine-2-carboxylic acid, 9-fluoro-
5-methyl-8-[4-(2-hydroxyethyl)-3
-methyl-1-piperazinyl]-6,7-dihydro-1
．． 7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid, 9-chloro-5-ethyl-8-(3-ethyl-1-piperazinyl)-6,7-dihyde[1-1,7 -dioxo-
18,5H-benzo[ijlquinolidine-2-carboxylic acid, 9-fluoro-5-ethyl-8-(4-isopropyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-IH, 5H-benzo'i'coquinolidine-2-carboxylic acid.

Daiketsu Uni (Compound 19) 9-Fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij
] Quinolidine-2-carboxylic acid ethyl ester 3.85
50 ml of 1N aqueous sodium hydroxide solution was added to g (0.01 mol), and the mixture was stirred at 20 to 25°C for 17 hours for hydrolysis. The liquid property of the reaction solution was adjusted to 1) H6-7 using 1N hydrochloric acid under water cooling. This adjusted solution was concentrated under reduced pressure,
The residue was subjected to silica gel column chromatography [the developing solvent was a chloroform-methanol mixture (volume ratio 2:1)].
] and purified. The fraction containing the target product was dried under reduced pressure, and the residue was recrystallized with ethanol to give 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1F for 1.5 days. -benzo[ijlquinolizine-2-
2.16 q pale yellow crystals of carboxylic acid (yield 60.4
%) was obtained. The melting point (decomposition) was 190-195°C.

Elemental analysis value (as C19H2oFN303): Calculated value (%) C, 63,851-f, 5.64 N, 11
．． 76 actual value (%) C, 63,59H, 5,66N,
11.47 Infrared absorption spectrum (cm'; Br
): 1715, 1615 1 day- Nuclear magnetic resonance spectrum (δ; CDC, I) 3-
CD30D): 1.56 (31-1, d), 2.75 (3tl, s)
, 3.00-3,70 (8H, m), 5.00-5.
35 (IH, m), 6.25 (IH, dd).

6.95 (IH, d), 7.75 (IH, d), 8
．． 70(IH,5)9-fluoro-5-methyl-8-(
4-methyl-1-piperazinyl)-1-oxo-1H,
Day 5 - Benzo[ij]quinolidine-2-carboxylic acid ethyl ester (0.01 mol) was added to the corresponding benzo[i
j] Quinolidine-2-carboxylic ester derivative [■]
In particular, Compound [V][ ] (Other than changing the amount appropriately to 00.01 mol, the operations were substantially the same as in Example 19 above, to produce the compounds of Examples 20 to 30 below.

1 liter fM2 (Compound 20) 9-Fluoro-5-methyl-8-(1-piperazinyl)
-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid pale yellow crystals, yield 2.079 Melting point (decomposition); 236-240°C (ethanol) Elemental analysis value (C, 31-1,8FN3o3 (as) Two count value (%) C, 62,961-1,5,28N, 12.
24 real light 1 to I (%) C,62,6711,5
, 17N, 11.97 infrared absorption spectrum (cm
8r): 1690, 1620 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
:1.80(3H,d), 3.30~4.30(8H
, m), 5.40-5.80 (IH, m), 6.5
0 (IH, dd), 7.10 (1H, d).

8.15 (IH, d), 9.31 (IH, S) Example 21 9-Fluoro-5-methyl-8-(4-ethyl-1-t
″Verazinyl-1-oxo-IH,5H-benzo[ij
] Quinolidine-2-carboxylic acid pale yellow crystals; yield 2.3
3 g Melting point (decomposition): 197-204°C (ethanol)
Elemental analysis value (as C2oH22FN303) Double calculated value (%) C, 64,67H, 5,97N, 11.32 Actual value (%) C, 64,51H, 5,98N, 11.
20 Infrared absorption spectrum (cm'; KBr): 17
20, 1615 1H-nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.55 (3N, t), 1.80 (3H, d),
3.20 ~ 4.50 (1ON, m), 5.4
5 ~ 5.80 (IH, m), 6.52 (IH, d
d), 7.00 (IH, d), 8.12 (il
l, d).

9, 40 (1) 1. S) Compound 2 (Compound 22) 9-chloro-5-methyl-8-(1-piperazinyl)-
1-oxo-18,5H-benzo[ij]quinolidine-
2-carboxylic acid pale yellow crystal; Yield 2.689 Melting point (decomposition); 200-210°C (ethanol) Elemental analysis value (as CIBHlBCN N3 C3): Calculated value (%) C, 60,08H, 5,04N, 11 .6
8 Actual measurement value (%) C, 60, 19H, 5, 14N, 1
1.47 Infrared absorption spectrum (cm'; KBr):
1720, 1615 1 day - Nuclear magnetic resonance spectrum (δ; DH3O-d6
)21.42 (3H, d), 2. γ0~3.40(
8H, m), 5.15-5.45 (lt-1, mL
6.30 (1N, dd), 6.87 (E, d)
.

7.90(1)1. s), 8.85 (1N, s) Example 23 9-chloro-5-ethyl-8-(1-goberazinyl)-
1-oxo-18,5-day-benzo[i,j]quinolidine-2-carboxylic acid pale yellow crystals: Yield 2.799 Melting point (decomposition): 186-190°C (ethanol) Elemental analysis value (C191-12oCu N303 ) Two calculated values (%) C, 61,041-1,5,39N, 1
1.24 Actual value (%) C, 61,301-1,5,4
4N, IL23 infrared absorption spectrum (Cm”; KB
r'): 1γ20.1620 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0I)
): 1.1o (3u, t), 2. Oo ~ 2.50 (2
tl, m), 3.30-4.30 (8Fl, m),
5.40-5.80 (IN, m), 6.50 (
IH, dd), 7.10 (IN, (1), 8.5
0(1)1. S), 9.35 (1N, S)! 24 (Compound 24) 9-chloro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1 day, 5-1-benzo[ij
] Quinolidine-2-carboxylic acid pale yellow crystals: Yield 2.3
79 Melting point (decomposition): 190-191°C (ethanol)
Elemental analysis 1f1 (as C19H2oCflN303)
Two calculated values (%) C, 61, 04H, 5, 39N, 1
1.24 Actual value (%) C, 61, 3D H, 5, 27
N, 11.01 Infrared absorption spectrum (cm”; KB
r): 1720, 1605 1 day-nuclear magnetic resonance spectrum (δ: cocp 3-CD
30D): 1.57 (3H, d), 2.66 (3) 1. S),
2.85 - 3.75 (8) 1. m), 4.92-5
．． 25 (IN, m), 6.15 (1) 1. dd).

6.95 (111, (1), 8.12 (1) 1.S
), 8. E)3(1)1. S) X dust ■ 2 branches (Compound 25) 9-Fluoro-5-methyl-8-(3,4-dimethyl-
1-piperazinyl)-1-oxo-11-1°5 days-benzo[ij]quinolidine-2-carboxylic acid pale yellow crystals; Yield 2.14g Melting point (decomposition): 188-192°C (ethanol) Elemental analysis value ( C20H22FN303): Calculated value (
%) C, 64,67H, 5,97N, 11.32 Actual value (%) C, 64,39H, 5,68N, 11.
04 Infrared absorption spectrum (cm-1; Br): 1
720, 1615 1H-nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.55 (3H, d), 1.82 (3M, d),
3.20 (3H, s).

3.30-4.25 (7H, m), 5.40-5.
80 (IH, m).

6.45 (IH, dd), 7.10 (IH, d)
, 8.12 (IH, d).

9.35 (IH, s) Large ■126 (Compound 26) 9-Fluoro-5-methyl-8-(3,3-dimethyl-
1-piperazinyl)-1-oxo-1H.

5 days-Benzo[ij]quinolidine-2-carboxylic acid pale yellow crystals; yield 2.60 g Melting point (decomposition): 201-203°C (ethanol)
Elemental analysis value (as C20H22FN"303): Calculated value (%) C, 64, 67H, 5, 97N, 11.3
2 Actual measurement value (%) C, 64,901-1,6,07N,
11.31 Infrared absorption spectrum (Cm'; KBr)
:1725, 1615 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
:1.30-2.15 (9H, m), 3.30-4.
20 (6N, m).

5.50-5.85 (IH, m), 6.50 (IH,
dcl), 1.08 (1M, d), 8.15 (1
H,d), 9.25(1H,S) Example 27 (Compound 27) 9-Fluoro-5-methyl-8-(3,4,5-trimethyl-1-piperazinyl)-1-oxo-IH, 5H-
Benzo[ij]quinolidine-2-carboxylic acid pale yellow crystals: Yield 2.559 Melting point (decomposition): 174-111°C (ethanol) Elemental analysis value (as C21H24FN303): Calculated value (
%) C, 65,44H, 6,28N, 10.90 Actual value (%) C, 65,45H, 6,01N, 11.
07 Infrared absorption spectrum (cm-1; KBr): 1
720, 1620 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0[)
): 1.25-2.20 (9H, m), 3.20 (
3H, S), 3.30-4.40 (6H, m),
5.40 to 5.80 (IH, m), 6. ．． 54
(IH, dd), 7.10 (1H, d), 8.
12 (IH, d), 9.20 (IH, S) 9-chloro-5-methyl-8-(4-ethyl-3-methyl-1-piperazinyl)-1-oxo-IH, 5H-benzo[ij]quinolidine-2-carboxylic acid pale yellow crystals; yield 1.98'j Melting point (decomposition): 179-184°C (ethanol)
Elemental analysis value (C211124C, Q N303 LT
): Calculated value (%) C, 62,761-1,6,02
N, 10.46 Actual value (%') C, 63,00F+
, 6.24 N, 10.51 Infrared absorption spectrum (
cm-1; 8r): 1720, 1620° 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.20-2.10 (9H, mL 3.30-4.
25 (9H, m).

5.35-5.80 (1) 1. m), 8.50(I
H, dd), 7.10 (1N, d), 8.49
(1!-1, s), 9.35 (1N, s) Example 2
9 (Compound 29) 9-Fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij
] Quinolidine-2-carboxylic acid pale yellow crystals: Yield 3.
069 Melting point (decomposition): 205-210°C (ethanol) Elemental analysis Ir1M (as C19H2oFN303) Two calculated values (%) C, 63,851-1,5,64N, 11
．． 76 Actual value (%) C, 63,621-1,5,40
N, 11.70 infrared, line absorption spectrum (cm-1;
KBr): 1730.1617 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0O)
: 1.57 (3H, d), 1.80 (3H, d),
3.35-4.20 (7H, m), 5.45-5
．． 80 (1H, m), 6.50 (1H, dd).

7.05 (IH, d), 8.10 (IH, d),
9.30(IH,S) Example 30 9-Fluoro-5-methyl-8-(2,5-dimethyl-
1-piperazinyl)-1-oxo-IH.

5 days-benzo[ij]quinolidine-2-carvone pale yellow crystals; Yield 1.779 Melting point (decomposition): 180-185°C (ethanol) Elemental analysis fa (as C2o1-122FN3 C3) Bicalculated value (%) C, 64,67H,5,97N,11.
32 actual measurement value (%”) C, 84,72H, 6,00N
, 11.28 infrared absorption spectrum (cm”; Br
): 1720, 1615 1H-nucleus 'ik ki co'4she') To/L/ (6;
CF3CO0D): 1.25-2.12 (9) 1. m
), 3.30-4°40 (6N, l1l).

5.40-5.80 (IH, m), 6.45 (IH
, dd), 7.08 (1H, d), 8.12 (1M
, d), 9.33 (IH,s) Example 31 (Compound 31) 9-chloro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-18,5H-benzo[ij ]
Quinolidine-2-carboxylic acid ethyl ester 4.029
(0,01-E/lz) D. 120 m of a mixed solution of 1N water, 1M sodium aqueous solution, and ethanol (volume ratio 5:1)! ! The mixture was then stirred at 20-25°C for 2 hours for hydrolysis. The PTI value of this reaction solution was adjusted to 6 to 7 using 1N hydrochloric acid under water cooling, and then it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [the developing solvent was a chloroform-methanol mixture (volume ratio 2:1)], and a fraction containing the target product was collected. This fraction was dried under reduced pressure, and the residue was recrystallized from ethanol to give 9-chloro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij] 2.89!9 pale yellow crystals of quinolidine-2-carboxylic acid (yield 77.3%) were obtained. Melting point (decomposition)
was 200-205°C.

Elemental analysis value (C19112oC, l! as N5o3): Calculation 1 shift (%) 0. 61.04 H, 5, 3
9N, 11.24 Actual value (%) C, 61,011
75.15 N, 11.07 infrared absorption spectrum (
Cm-'; K[Sr): 1720.1615 1 day - nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.55 (3N, d), 1.82 (3H, d),
3.35 ~ 4.30 (7H, m), 5.40 ~
5.80 (IH, m), 6.52 (IH, dd).

7.13 (IH, d), 8.52 (IH, s), 9
．． 33(IH,s)9-fluoro-5-ethyl-8-(
3-methyl-1-piperazinyl)-1-oxo-1H,
The following Example 3 was prepared in almost the same manner as in Example 31 above, except that 3.999 (0.01 mol) of 5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester was used.
Compound No. 2 was prepared.

Dog Blood ■Uni (Compound 32) 9-Fluoro-5-ethyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij
] Quinolidine-2-carboxylic acid pale yellow crystals; yield 2.6
2 (J Melting point (decomposition): 201-204°C (ethanol) Elemental analysis value (as C2oH22FN3o3): Calculated value (
%) C, 64,67H, 5,97N, 11.32 Actual value (%) C, 64,73H, 5,96N, 11.
28 Infrared absorption spectrum (cm-1; Br): 1
725, 1615 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.05 (3H, t), 1.55 (3H, d),
2.00 to 2.50 (2t-f, m), 3.
20-4.35 (7tf, m), 5.45-5.8
0 (IH, m), 6.51 (11'1.dd),
7.03 (1H, d), 8.13 (IH, d),
9.28 (IH,S) Example 33 8-chloro-9-fluoro-5-ethyl-1-oxo-
18,5H-benzo[ij]quinolidine=2-carbonii! 4.62 g (0.015 mol) was suspended in 45 ml of dimethyl sulfoxide, 7.69 g (0.06 mol) of N-isopropylpiperazine was added, and 1
Stirred at 00-110°C for 8 hours. This reaction solution was dried under reduced pressure, 40 d of methanol was added to the resulting residue, and after stirring, the insoluble matter was filtered. This insoluble material was recrystallized from ethanol and 9-fluoro-5-ethyl-8-(4-isopropyl-1-piperazinyl)-1-oxo-1)(,5
3.88 g (yield: 64.7%) of pale yellow crystals of H-benzo[ij]quinolidine-2-carboxylic acid were obtained. The melting point (decomposition) of this crystal was 186-195°C.

Elemental analysis 1a (C22H26FN303 ToshiT):
Calculated value (%) C, 66, 14H, 6, 56N, 10
．． 52 Actual value (%) C, 85, 85H, 6, 51N,
10.61 Infrared absorption spectrum (cm-1; KBr
): 1720, 1615 1H-nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.07 (3H, d), 1.65 (6H, d),
2.10 (2H,Q).

3.27-4.60 (9H, m), 5.40-5.8
0(IH, m).

6.50 (IH, dd), 7.10 (IN, d),
8.10 (IH, d).

9,30(IH,5) 8-chloro-9-fluoro-5-ethyl-1-oxo-
1H,5H-benzo[ij]quinolidine-2-carboxylic acid (0,015 mol) and N-isopropylpiperazine (0,06 mol) in 8-chloro-9-fluoro-5-methyl-1-oxo-1 day. , 5to1-benzo[ij]quinolidine-2-carboxylic acid (0,015 mol) and N-(
The following compound of Example 34 was produced in substantially the same manner as in Example 33 above, except that each compound was changed to 2-hydroxyethyl)piperazine (0.06 mol).

X dust ■ Yu A 9-fluoro-5-methyl-8-[4-(2-hydroxyethyl)-1-piperazinyl]-1-oxo 1H,
5H-benzo[ij]quinolidine-2-carboxylic acid pale yellow crystals; yield 3.16 (j melting point (decomposition); 203-211°C (ethanol) elemental analysis value (as C2oH22FN303) two calculated values (%
) C,64,67H,5,97N, 11.32 Actual value (%) C,64,32+1.5.88 N, 11
．． 54 Infrared absorption spectrum 1 to 1 Br (cm'; Br):
1715.1615 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
:1.80(3N,d), 3.00~4.60(12
H, m), 5.40-5.80 (IH, m), 6
．． 50 (IH, dd), 7.07 (1N, d).

8.12 (1M, d), 9.30 (IN, S) Compounds of the following formulas were also produced by operating in substantially the same manner as in each of the above examples.

9-chloro-5-methyl-8-(3,3-dimethyl-1
-piperazinyl)-1-oxo-1H.

5th-benzo[ij]quinolidine-2-carboxylic acid, 9-fluoro-5-ethyl-8-(3,4,5-trimethyl-1-piperazinyl)-1-oxo-1H,5H-
Benzo[ijlquinolidine-2-carboxylic acid, 9-chloro-5-ethyl-8-(3,4-dimethyl-1
-piperazinyl)-1-oxo-IH.

5H-benzo[ij]quinolidine-2-carboxylic acid, 9-fluoro-5-methyl-8-(2,4-dimethyl-
1-piperazinyl)-1-oxo-1H.

5th-benzo[ij]quinolidine-2-carboxylic acid, 9-fluoro-5-methyl-8-(3,3,4-trimethyl-1-piperazinyl)-1-oxo-1H,5H-
Benzo[ij]quinolidine-2-carboxylic acid, 9-bromo-5-medyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij]
Quinolidine-2-carboxylic acid.

Example 35 (Compound 35) 9-Fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1°7-dioxo-
1.879 (0,005 mol) of 1H,5H-benzo[ij]quinolidine-2-carboxylic acid was dissolved at room temperature in a mixture of 25 d of 2N aqueous sodium hydroxide solution and 5 rni of ethanol. To this solution, m-hydrochloric acid was added under water cooling to adjust to I) 81, and the precipitated crystals were collected by filtration and washed successively with a small amount of water and ethanol. The obtained crystals were recrystallized from water to give 9-fluoro-5-methyl-8-(
4-Methyl-1-piperazinyl)-6,7-dihydro-
Yellow crystals of 1,7-dioxo-IH,5H-benzo[ij]quinolidine-2-carboxylic hydrochloride monohydrate 1.7
7 g (yield 82.7%) was obtained. Melting point (decomposition) is 225
The temperature was ~228°C.

Elemental analysis value (C191-12oFN304-HC, 9-
(as H2O): Calculated value (%) C, 53, 33H, 5, 42N, 9
．． 82 Actual value (%) C, 53, 50H, 5, 49N,
9.80 infrared absorption spectrum (cm'; Br)
:1730, 1885.1630 1 day - Nuclear magnetic resonance spectrum (δ; CF3CO0D)
: 1.85 (3N, d), 2.93-4.75 (10
H, m), 3.08 (3tl, s), 5.07~
5.67 (IH, m), 8.43 (IH, d).

9.44(IH,5) 9-Fluoro-5-ethyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1°7-dioxo-
The following Example 3 was carried out in substantially the same manner as in Example 35 above, except that 1.94 g (0,005 mol) of 1H,511-benzo[ij]quinolidine-2-carboxylic acid was used.
Compound 6 was prepared.

9-Fluoro-5-ethyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1゜7-dioxo-
1H,5H-benzo[ij coquinolidine-2-carboxylic acid hydrochloride 1-eternal yellow crystals: Yield 1.75'J Melting point (decomposition): 226-229°C (water) Elemental analysis value (C
20H22FN304-1-IC, Q - as H2O): Calculated value (%) C, 54, 36H, 5, 70N, 9
．． 51 actual value (%) C, 54,151-i5.74
N, 9.50 infrared absorption spectrum (cm'; KB
r): 1730, 1680.1625 1 day - nuclear magnetic resonance spectrum (δ; CF3CO0[)
): 1.07 (3H, t), 1.83-2.50 (
2H, m), 2.97-4.73 (10H, m),
3.28 (3M, S), 4.83-5.40 (1
N, m), 8.45 (1N, d), 9.35 (
IH, s) Large dust ■ Uni (Compound 37) 9-Fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij
] Quinolidine-2-carboxylic acid 1.79 g (0,00
5 mol) was dissolved at room temperature in a mixed solution of 3N aqueous sodium hydroxide solution 17d and isopropanol 5r111. To this solution, while cooling with water, concentrated hydrochloric acid was added to adjust to I) H1, and the precipitated crystals were collected by filtration and washed successively with a small amount of water and isopropanol. The obtained crystals were recrystallized from water to give 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid hydrochloride. 1.50 g (yield 76.0%) of pale yellow crystals of the salt were obtained. The melting point (decomposition) was 193-197°C.

Elemental analysis value (as C19H2oFN303・HCρ)
: Calculated value (%) C, 57, 94H, 5, 37N, 10
．． 67 Actual value (%) C, 58,01H, 5,28N,
10.49 Infrared absorption spectrum (Cm”; KBr)
:1725, 1620 1H-nuclear magnetic resonance spectrum (δ; CF3GOOD)
: 1.58 (3H, d); 3.20 (3H, S),
3.35 ~ 4.30 (8H, m), 5.40
~5.80 (IH, m), 6.50 (IH, dd).

7.10 (IH, d), 8.12 (IH, d),
9.31 (IH,s) The following two compounds were also produced in substantially the same manner as in Example 37 above.

9-chloro-5-methyl-8-(1-piperazinyl)-
1-oxo-1H,5H-benzo[ij coquinolidine-
2-Carboxylic hydrochloride, 9-fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij
] Quinolidine-2-carboxylic hydrochloride.

Example 38 (Compound 38) 9-Fluoro-5-methyl-8-(3,4-dimethyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-1 (75 days-benzo[ij]quinolidine-2-carboxylic acid ethyl ester 2.089 (0,005 mol)
was suspended in 5rr11 of ethanol, and to this was added 30mf of a 2N aqueous sodium hydroxide solution! was added and stirred at 15 to 20°C for 3 hours to perform hydrolysis. The reaction solution was adjusted to pH 1 by adding concentrated hydrochloric acid under water cooling, and the precipitated crystals were collected by filtration and washed successively with a small amount of water and ethanol.

The obtained crystals were recrystallized from water to give 9-fluoro-5-methyl-8-(3,4-dimethyl-1-piperazinyl)-
6,7-dihydro-1,7-dioxo-1H151-1
-benzo[ij]quinolidine-2-carboxylic hydrochloride 1
1.62 g (yield 73.2%) of yellow crystals of the hydrate were obtained. The melting point (decomposition) was 226-228°C.

Elemental analysis value (C2o1-122FN3o4-Heρ・H
20): Calculated value (%) C, 54, 38H, 5, 70N, 9
．． 51 Actual value (%) C, 54, 70H, 5, 38N,
9.44 Infrared absorption spectrum (cm-1; Br
): 1735, 1690.1625 1H-nuclear magnetic resonance spectrum (δ; CF3GOOD)
: 1.67 (30, d), 1.72 (3H, d),
3.00-4.67 (9H, m), 3.23 (
38, S), 5.17 to 5.73 (1H, m).

8.43 (IN, d), 9.43 (IN, 5) 9-Fluoro-5-methyl-8-(3,4,5-trimethyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-11-1.51-1-benzo[ij]quinolidine-2-carboxylic acid ethyl ester 2.159 (0,00
5 mol) or 9-fluoro-5-ethyl-8-(1-piperazinyl)-6,7-dihydro-1,7-cyoquin-1H,5H-benzo[ij]quinolidine-2-carboxylic acid ethyl ester 2.017 The following compounds of Examples 39 and 40 were produced in substantially the same manner as in Example 38 above, except that (0,005 mol) was used.

Jojinsotandan (Compound 39) 9-Fluoro-5-methyl-8-(3,4,5-trimethyl-1-piperazinyl)-6,7-dihydro-1,7
-dioxo-1H,5H-benzo[ij]quinolidine-
2-Carboxylic hydrochloride monohydrate yellow crystals: Yield 1.55C1 Melting point (decomposition); 25i~252℃ (water) Elemental analysis value (
C211n24FN3o4 ・HC,I!・1-120
): Calculated value (%) C, 55, 32H, 5, 97N, 9
．． 22 Actual value (%) C, 55, 51F+, 5.56
N, 9.09 Infrared absorption spectrum (cm-1; Br): 1720, 1690.1625 1 day - Nuclear magnetic resonance spectrum (δ; CF3GOOD)
:1.43~1.73(6H,m), 1.85(3
H, d), 2.92-4.53 (8H, m),
3.25 (3+1.S), 5.07~5.60 (1
M, m), 8.42 (IH, d), 9.42 (IN
, s) Takeshi IM 4th base 9-Fluoro-5-ethyl-8-(1-piperazinyl)
-6,7-dihydro-1,7-dioxo-01,5H-
Benzo[ij]quinolidine-2-carboxylic acid hydrochloride yellow crystals; Yield 1.37Cl Melting point (decomposition), 271-273°C (water) Elemental analysis 1a
(as C19H20FN304-HC,l!): Calculated value (%) C, 55, 68H, 5, 16N, 10
．． 26 Actual value (%) C, 55, 56H, 5, 18N,
10.10 Infrared absorption spectrum (cm”; KBr)
:1730, 1685.1620

Claims (10)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, when AB is a single bond, A represents a methylene group and B represents a carbonyl group, or AB is a double bond. When , A and B together represent a vinylene group, R^1 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a 2-hydroxyethyl group, and R^2 and R^
3 are the same or different and represent a hydrogen atom, a methyl group, or an ethyl group, where R^3 may be bonded to the same carbon to which R^2 is bonded, and R^4 is a methyl group or an ethyl group. where X represents a halogen atom. ) A benzo[ij]quinolidine-2-carboxylic acid derivative or a physiologically acceptable salt thereof or a hydrate thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a hydrogen atom, methyl group, ethyl group, n-
Represents a propyl group or 2-hydroxyethyl group, R^
2 represents a hydrogen atom or a methyl group, R^3 represents a hydrogen atom or a methyl group, where R^3 may be bonded to the same carbon to which R^2 is bonded, and R^4 is methyl group or an ethyl group, and X represents a fluorine atom or a chlorine atom. ) The benzo [ij] according to claim 1, which is represented by
A hydrate of a quinolidine-2-carboxylic acid derivative or a physiologically acceptable salt thereof. (3) 9-fluoro-5-methyl-8-(4-methyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid, 9-chloro-5-methyl-8-(4-ethyl-1-piperazinyl) )-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-
Carboxylic acid, 9-fluoro-5-methyl-8-(3,5
-dimethyl-1-piperazinyl)-6,7-dihydro-
1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid, 9-fluoro-5-methyl-8
-(3,3-dimethyl-1-piperazinyl)-6,7-
dihydro-1,7-dioxo-1H,5H-benzo[i
j] Quinolidine-2-carboxylic acid or 9-fluoro-5
-Methyl-8-(3-methyl-1-piperazinyl)-6
, 7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid. (4) 9-fluoro-5-methyl-8-(4-methyl-
1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic hydrochloride monohydrate or 9-fluoro-5-methyl-8-(3 ,4-dimethyl-1-piperazinyl)-6,
The compound according to claim 2, which is any one of 7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic hydrochloride monohydrate. (5) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents a hydrogen atom or a methyl group, and R^
2 represents a hydrogen atom or a methyl group, R^3 represents a hydrogen atom or a methyl group, where R^3 may be bonded to the same carbon to which R^2 is bonded, and R^4 is a methyl group. or represents an ethyl group, and X represents a fluorine atom or a chlorine atom. ) The benzo [ij] according to claim 1, which is represented by
A quinolidine-2-carboxylic acid derivative or a physiologically acceptable salt thereof. (6) 9-Fluoro-5-methyl-8-(3,4-dimethyl-1-piperazinyl)-1-oxo-1H,5H-
benzo[ij]quinolidine-2-carboxylic acid, 9-fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid or 9-chloro-5-methyl-8
-(3-methyl-1-piperazinyl)-1-oxo-1
6. The compound according to claim 5, which is either H, 5H-benzo[ij]quinolidine-2-carboxylic acid. (7) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, when AB is a single bond, A represents a methylene group and B represents a carbonyl group, or AB is a double bond. When , A and B together represent a vinylene group, R^1 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a 2-hydroxyethyl group, and R^2 and R^
3 are the same or different and represent a hydrogen atom, a methyl group, or an ethyl group, where R^3 may be bonded to the same carbon to which R^2 is bonded, and R^4 represents a methyl group or an ethyl group. , R^5 represents a methyl group, ethyl group or n-propyl group, and X represents a halogen atom. ) There are general formulas ▲mathematical formulas, chemical formulas, tables, etc. that are characterized by hydrolyzing the compound represented by
^2, R^3, R^4 and X have the same meanings as above. )
A method for producing a benzo[ij]quinolidine-2-carboxylic acid derivative or a physiologically acceptable salt thereof or a hydrate thereof. (8) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, when AB is a single bond, A represents a methylene group and B represents a carbonyl group, or AB is a double bond. , A and B together represent a vinylene group, R^4 represents a methyl group or ethyl group, X represents a halogen atom, and Y represents a fluorine atom or a chlorine atom.) There are compounds with general formulas, numerical formulas, chemical formulas, tables, etc.
^3 are the same or different and represent a hydrogen atom, a methyl group, or an ethyl group, and R^3 may be bonded to the same carbon to which R^2 is bonded. ) is a general formula characterized by a nucleophilic substitution reaction with a piperazine derivative represented by ▲ There are mathematical formulas, chemical formulas, tables, etc.
^2, R^3, R^4 and X have the same meanings as above. )
A method for producing a benzo[ij]quinolidine-2-carboxylic acid derivative or a physiologically acceptable salt thereof or a hydrate thereof. (9) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, when AB is a single bond, A represents a methylene group and B represents a carbonyl group, or AB is a double bond. When , A and B together represent a vinylene group, R^1 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a 2-hydroxyethyl group, and R^2 and R^
3 are the same or different and represent a hydrogen atom, a methyl group, or an ethyl group, where R^3 may be bonded to the same carbon to which R^2 is bonded, and R^4 is a methyl group or an ethyl group. where X represents a halogen atom. ) An antibacterial agent characterized by containing as an active ingredient a benzo[ij]quinolidine-2-carboxylic acid derivative represented by the following formula, a physiologically acceptable salt thereof, or a hydrate thereof. (10) The active ingredient is 9-fluoro-5-methyl-8-(
4-Methyl-1-piperazinyl)-6,7-dihydro-
1,7-dioxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid or 9-fluoro-5-methyl-
8-(3-methyl-1-piperazinyl)-1-oxo-
The antibacterial agent according to claim 9, which is 1H,5H-benzo[ij]quinolidine-2-carboxylic acid.