JPS6064979A - 7-piperazine-substituted-6-fluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R1 is 1-4C alkyl; R2 is aminocarbonyl, carboxyl, 1-4C alkyl, or 5-7C cycloalkyl; R3 is 1-4C alkyl, or H; R4 is H, or F) and its salt. EXAMPLE:1-Ethyl-6-fluoro-7-[ 3-(aminocarbonyl)-1-piperazinyl ]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. USE:Having a wide antibacterial action on Gram-positive and Gram-negative bacteria, extremely useful as a drug. PREPARATION:A 7-halogeno-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative shown by the formula II (X is Cl, or F) is reacted with a piperazine derivative shown by the formula III in a solventless state of in a solvent such as butanol, etc. at room temperature -200 deg.C, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The novel 7-piperazine-substituted-6-fluoro-4 of the present invention
-A xo-1,4-dihydroquinoline-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof.

In more detail, the present invention is based on the general formula (1) (in which 1
[1 is a lower alkyl group having 1 to 4 carbon atoms, (, R2 is an aminocarbonyl group, a carboxyl group, or a carbon number 1 to 4
lower alkyl! 1 (or Ncroalkyl having 5 to 7 carbon atoms JJ wo, It 3 kA hydrogen atom or carbon number 1
-4 lower alkyl group, It4 represents a hydrogen atom or a fluorine atom. ) and a pharmacologically acceptable salt thereof.

In the general formula (1) of the present invention, R1+ tt2 and R3
Examples of lower alkyl groups represented by include methyl group, ethyl group, propyl group, and isobutyl group.

Examples of the butyl group and the ncroalkyl group represented by R2 include /clopentyl'Jr + 'hexyl group and ncroheptyl group.

1) Pharmacologically acceptable salts of the compound represented by general formula (1) include acid addition salts and alkali addition salts. Examples of acid addition salts include hydrochloric acid, sulfuric acid,
Mineral acid salts such as nitric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc., or organic acid salts such as acid-resistant maleic acid, hexamaric acid, citric acid, tartaric acid, etc., are used as alkali addition salts such as sodium, Inorganic alkali salts such as potassium, calcium, and ammonium salts, or ethanolamine, N,
Examples include salts of organic bases such as N-dialkylethanolamine.

The novel 7-piperazine E-substituted-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative represented by the general formula (1) of the present invention can be produced by various methods. can.

According to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula (1) is produced by the following general formula (
1) (In the formula, n, 1 and R4 represent the same plugs as above, and X
represents a chlorine atom or a fluorine atom. ) indicates il,
67-halono-6-fur-4-oxy-14-dihydroquinoline-3-carboxylic acid derivative and the following general formula (wherein tt 2 and 1 (3 represents the same 'X! meaning as above) ) without a solvent [or in the presence of a solvent].

Examples of the solvent used in this reaction include water, alcohols such as butanol, 3-methquine butyl, and amyl alcohol, ethylene glycol dimethyl ether (monoglyme), diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether ( ethers such as triglyme),
Aprotic polar solvents such as dimethylformamide, dimethylformamide, hequinamethylphosphoric triamide, aromatic hydrocarbon solvents such as benzene and toluene, or organic bases such as pyridino, picoline, lutidine, collidine, and triethylamine. can be mentioned.

Further, the reaction is carried out at a temperature ranging from room temperature to 200[deg.], preferably appropriately selected from a range of 100 to 1800[deg.].

7-/) log/-6-Flu A-low 4- represented by the general formula (1) which is the starting material in the production method of the present invention
Oxy-1,4-dihydroquinoline-3-carboxylic acid derivatives are known substances already disclosed in JP-A-58-141286, JP-A-55-47658, JP-A-56-80964, etc. It is.

Moreover, the piperazine derivative represented by the general formula (1) is
With some exceptions, these are known substances, such as U.S. Q. I Patent No. 2,780,625, South African Patent No. Ir6807.
, No. 552, etc. In addition, the general formula (
1) For the new substances, their manufacturing methods are described in the reference examples.

According to the second mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) IJ (Lj) has the following general formula (1) where qr tt 3 is a water atom. 7-biperazine-substituted-6-furA-4-oxo-1,4-dihydroquinoline represented by the formula <+V> () (wherein R1, R2 and R4 represent the same U definition as above) -3-carboxylic acid derivative and a carbonyl represented by the following general formula (V)1 R5-0-n(V) (wherein R5 represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms) The carbonyl compound represented by the general formula (V) used in the method of the present invention can be produced by reacting the compound in the presence of formic acid.

Examples include formaldehyde, a7taldehyde, propionaldehyde, etc. Formaldehyde is preferably used as an aqueous formaldehyde solution (formalin), and when acetaldehyde and propionaldehyde are used, it is preferable to use nitrobenzene as a solvent.

Further, the reaction is carried out at a temperature in the range of 100 to 200[deg.], preferably at the reflux temperature of the reaction system.

According to the third mode of the method for producing a compound according to the present invention, the compound i represented by the general formula (1) is a 7-biperazine 1η-substituted-6-flumero-4 represented by the general formula (IY). ~: A xo-1,4-dihi 1° loginoline-3-
Carboxylic acid g conductor,! :, an alkyl halide represented by the following general formula (11) % formula % () (in the formula, +t 3 has the same meaning as in 11, and A represents a halogen atom) in m medium, It can be produced by reacting with or without a base as a deoxidizing agent.

Any solvent may be used in the method of the present invention as long as it does not inhibit the reaction, such as acetone, ethanol, ether, nitrofuran,
Examples include dimethylformamide form.

Salt λ as a deoxidizing agent used in the method of the invention
Examples include f-1) ethylamine, pyridine, potassium carbonate, and the like.

Further, the reaction is carried out at a temperature ranging from room temperature to the heating reflux temperature of the solvent used, preferably appropriately selected within the range of 50 to 100°.

The novel 7-piperazine-substituted-6-fluoro-4-oxo- represented by the general formula (1) produced in this way
1,4-dihydroquinoline-3-carboxylic acid derivatives and their pharmacologically acceptable salts have broad antibacterial activity against Gram-positive bacteria and Gram-11-negative bacteria, and are extremely useful as medicines.

The present invention will be explained below with reference to all embodiments.

Example 1 ■-Ethyl-6-fluoro-7-(3-(7minocarbonyl)-l-piperazinyl)-4-Aquin-1.4-
';Hydroquinoline-3-carboxylic acid! -Eech 6-fluoro-7-riuri - 4~
Mexo! ,4-nohydrogynoline-3-calphone/I
Q +. 5 8.9 + 220 g of (ami7carponyl)piperazine and birinone Inmi'dJ.
The mixture is heated and refluxed to 71 U for 44 hours. After removing the solvent, dissolve the obtained liquid in a 30% aqueous acid solution. Then, a 20% hydroxide water bath solution is added to neutralize. After cleaning the aqueous layer with chloro;j, lumini-Cf,l: collect the precipitate. f1 Torimonori rJ rl
11j was crystallized from a mixture of form and methanol and melted 1.
034 g of the title compound are obtained as a brown blob of 246-250° (decomposition).

Original analysis value CI 7111 9FN404 theoretical value 1
j, 56.85; II, 5.26; N, 15.4
6 Experimental value C, 56.0+, II, 5.4 (1;
N, 15.19 Reference Example 1 2-chlorohexylpiperazine 2-chlorohexylpiperazine 2-chlorohexylglyoxal 20.09% methanol 250% water solution, water-cooled with stirring, engineered diamine 9
Add a solution of 4 g in 20 ml of methanol and stir for 5 minutes. Next, 132 g of sodium borohydride was added, and the mixture was stirred at room temperature for 2 hours.

After the reaction, the solvent was distilled off, water was added to the residue, and the mixture was extracted with chloroform. Chloroform fL! I is washed with an aqueous solution of sodium ffJ and IU, and then dehydrated. The solvent is evaporated and the residue is dissolved in inpropanol.

Add ethanolic hydrochloric acid to the impropatul solution and collect the precipitate. After dissolving the F powder in water, it is made alkaline with a 20% aqueous sodium hydroxide solution and extracted with chloroborm. After the chloroform layer is dehydrated, the solvent is distilled off. The residue was recrystallized from acetone to give the title compound 7. as colorless crystals with a melting point of 82-825°. I get 9.

Elemental analysis I/(010112ON2 Theoretical value 0.71.87.11.11.98.N, 1
6.65 Experimental value 0.7'1.21, u, 11.8
8:N, 16.43 The starting material nclohexylglyoxal was published in The Journal of Organic Chemistry (TI+a, IournalofOr
gani+01+emisLry) 6 volumes 260 pages (+
941).

Example 2 Amount of 1-ethyl-6-fluoro-7-(3-nochlorophenol-I-hyperazinyl)-4-iquin-1,4-dihydrofluori/phosphorus-3-carboxylic acid 1-ethyl-6-fluoro Subroute 7 - 1.50 q of 4-oxo-1,4-nohydroxyphosphorus-3-carboxylic acid, I in Reference Example 1
A mixture of 280 g of nohequin rubiperanone and 10 yl of pyrinone is heated under reflux for 22 hours. After the reaction, the solvent is distilled off. Water is added to the residue and extracted with phosphorus. The chloroform layer is extracted after dehydration. , the solvent is distilled off.

After washing the residue with a mixture of benzene and isopropyl erthyl, the benzene is converted to P), with a melting point of 1755-1765°.
054 g of the title compound is obtained as colorless crystals.

Elemental analysis value a22n2BFN3o3 Theoretical value C, 65, 82, 11, 7, 08iN, I
O, 47 experimental value 0.65.81; II, 6.90
iN+ 10.47 Example 3 ■-Ethyl-6-fluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ■-Ethyl-6-fluoro-fu Chloro 4-mequin-1,4-dihydroquinoline-3-carboxylic acid 1500g
+ 1670g of 2-methylpiperazine and 70g of pyrinone
The ml mixture is heated to reflux for 14 hours. After the reaction, the solvent is distilled off, and the resulting residue is made acidic with a 50% aqueous acid solution.

After treating the aqueous layer with activated carbon, it is neutralized with an 11 um aqueous solution (20% hydroxide). e) and treated with activated carbon and then concentrated. Take 1 portion of the precipitate. Dissolve in IP + Torimono Kinko tanol and add ethanolic hydrochloric acid. Concentrate the solvent
P collect the precipitate. The P dispersion was crystallized from a wet portion of water and ethanol to obtain 819 g of the hydrochloride of the title compound as pale yellow crystals with a melting point of 300° or higher.

Elemental analysis value 0171120FN3(-,)34+CI
Theoretical value C, 55, 21; II, 5.72; N, 1
1.36 Actual d1 value C, 55, 18; 11.5.72
;N, 11.17 Example 4 1-ethyl-6-fluoro-7-(3,4-dimethyl-
1~Hyperazinyl) -4-: Aquine-1,4-dihydroquinoline-3-carboxylic acid Example 3? ! 7ta l-
Ethyl-6-fur-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid/hydrochloride 2.69g, 90% formic acid 54 resistance.

37% formalin 3.5 yi and potassium carbonate No.7
0 g of the mixture is heated to reflux for 5 hours. After the reaction, a 20% aqueous sodium hydroxide solution is added to neutralize, and the precipitate is collected as F. The P product is recrystallized from a mixture of trifluorol and methanol to give the title compound 1.70y as colorless needles with a melting point of 244-2460.

Elemental analysis value 01za I22FN303 Theoretical value C, (I2.24; II, 638; N,
12. IQ actual value 0.62.02: 11.6.8
7 iN+ + 2.05 Example 5 ■-Ethyl-6-fluoro-7-(4-ethyl-3-methyl-1-piperazinyl) -4-mquin-1,4-dihydroquinoline-3-carboxylic acid implementation l-ethyl-6-fluoro-7-(3-
Methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline - 3-carphonic acid hydrochloride 1.0 (+/
, ethethyl iodide 1.291 + ethylamine to9
A solution of 20 g of trimethylformamide, 70-80
Heat and stir at °C for 15 hours. After the reaction, the solvent is distilled off, and
The residual liquid was made acidic with a 50% acetic acid aqueous solution. Water R4
Add a 20% aqueous sodium hydroxide solution to neutralize the solution, and collect the precipitate. Column chromatography of P dispersion (
Processing process: Treat with a mixture of covolum and methanol (9°I) to obtain 047 g of the title compound as colorless crystals. Chloroform and methanol.
Pj crystallizes from a mixture of
colorless needle crystals are obtained.

Elemental analysis value Cl91124FN 303I! 1iIrun (1/f O, '6L14; IL (i, 69; N11.
63 actual measurement value -C, 62, 82, II, 6.78 i
s, + 1.66 Example 6 1-ethyl-6-fluoro-7-(3-ethyl-1-piperazinyl)-4-n giso-1,4-diacid dolox/phosphorus-3-carbon A mixture of the acid l-ethyl-6-fluoro-twochloro-4-oxo-1,4-dihydroquil-3-carboxylic acid 4.49Q, 570 g of 2-edylbiverazine and 80 ml of pyridine is heated under reflux for +5 hours. After the reaction, the solvent is distilled off. The obtained residue was dissolved in a 50% aqueous acetic acid solution to make it acidic, and then neutralized with a 20% aqueous sodium hydroxide solution. Concentrate the aqueous layer and count the precipitate. After dissolving F powder in chloroporum and treating with activated carbon, ethanolic hydrochloric acid is added. Concentrate the solvent
Take 1 portion of the precipitate. The scattered product was recrystallized from a mixture of water and acetone to obtain 181 g of the hydrochloride of the title compound as colorless crystals with a melting point of 3000 or higher.

Elemental analysis I1tj C1BII22FN303・llC
lTheoretical value 0.56J2.11.6.04 iN, 10
．． 95 actual value C, 56, 10; II, 6. fll
;N, 10.89 Example 7 1-Ethyl-6-FurAlow7-(3-ethyl-4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid implementation l-ethyl-6-fluoro-7-(3-
ethyl-1-piperazinyl) ~4-oxo-1,4-nohydroxylyc-3-carboxylic acid hydrochloride Q, 50i7
, 90% formic acid 12th layer 1st degree 37% acid layer 2nd layer 0.77 m
A mixture of 0.1 g of potassium carbonate and 0.1 g of potassium carbonate was heated and heated for 5 hours. Jy-tri: After that, add 20% sodium hydroxide (solution) to neutralize and take one precipitate. 11 points 213-215° force! (Obtain the title compound OaBg as a colored sword.

Elemental analysis value C191124FN 303 theoretical value Q,
63. +4 ill, 6.69, N, +1.
63 measured candy 0.6i3. I 1 ill, 7.01
;N, 11.54 Example 8 1-ethyl-6,8-noflu'A[J-7-(3-
Methyl-1-piperazinyl)-4-Aquin-II 4
-dihydroquinoline-3-carphonic acid 6.7.8-)
Lifluoro-1-ethyl-4-oxo-1,4-dihydroxy,'phosphorus-3-carboxylic acid 1. A mixture of 110 g of 2-methylbiveranone and Oml of pyridine I is heated to reflux for 15 minutes. After the reaction, the solvent is distilled off. Methanol is added to the obtained residue, and the precipitate is collected as F.

6 dispersion was recrystallized from ethanol, melting point 239-24
Compound 0369 as a colorless Φ1-shaped product of 05° 7!
Jru.

Elemental analysis value C171119F2N303 theoretical value C,
58,11+11.5.45 iN, 11.96 real 1
lll value C, 57, 98, II, 5.47iN,
12.18 Example 9! -Ediru6,8-difluoro-7-(3゜4-dimethyl-1-piperazinyl), -4-: Aquin-1,4
-dihydroquinoline-3-carboxylic acid 1-ethyl-6,8-difluoro-7- obtained in Example 8
(8-m+l-piperazinyl)-4-oxo-1,
4-dihydroquinoline-3=carphonic acid 1.40 g, 9
2.8 ml of 0% formic acid and 2.2 y of 37% formalin
1 mixture is heated to reflux for 4 hours. Evaporate with cold solvent. After dissolving the obtained residue in water, it is neutralized with sodium hydrogen carbonate, and the precipitate is collected. The F dispersion is recrystallized from ethanol to obtain 032 g of the title compound as colorless shime crystals with a melting point of 2115-212°.

Elemental analysis value Cl81121F2N3'3 Theoretical value C,
59,17; II, 5.79 IN, 11.50 actual value 0.59.29; II, 5.87; N,
+ 1.55 Special iT'l Applicant Hokuriku Pharmaceutical Co., Ltd. Summoning procedure amendment (method) % formula % 1 Case indication 1981 Special J1 Application No. 171271
No. 2 Title of the invention 7-Biberazine-substituted-6-fluoro-4-oxo-1,4-dihydroquinoline-ro-carboxylic acid derivative Book 6 Relationship with the case of the person making the amendment Patent applicant 4 Date of the amendment order Showa IJJ 11, 1959 (Development date: January 31, 1980) The full text of the specification will be corrected as shown in the attached correction details 4).

Correction details Damage 1, Title of the invention 7-Piperazine-substituted-6-fluoro-4-Aquin-1,
4-dihydroquinoline-6-carboxylic acid derivative 21,! Claim 1
wo, R2 is an Amizuka I levonyl group, a carboxyl group, or a lower 7'-alkyl group having 1 to 4 carbon atoms), (or a cycloalkyl group having 5 to 7 carbon atoms), and +13 is an unwater atom or a carbon number of 1 to 4. In the lower alkyl group of 4, R4 represents a water atom or a 7) elementary atom. 7-biverazine-substituted-6--7rv'AIJ-4-oxo-1,4-dihydroquinoline-ro-carboxylic acid derivatives represented by the following formulas and their physically capable salts.

3. Detailed Description of Ming The present invention relates to a fluoro-4-oxo 1,4-dihydroquinoline-6 monocarboxylic acid derivative and a pharmacologically acceptable salt thereof.

More specifically, the present invention relates to general formula (1) (wherein R1
represents a lower alkyl group having 1 to 4 carbon atoms, R2 represents an aminocarbodiρ group, a carpoxyl group, or a lower alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms, and R3 represents a hydrogen atom or a carbon atom. In the lower alkyl group of numbers 1 to 4, R4 represents a hydrogen atom or 7 atoms. ) Novel 7-piperazine-substituted-6-fluoro-4-A
This invention relates to gin-1,4-dihydroquinoline-3-carboxylic acid derivatives and pharmacologically acceptable salts thereof.

In the general formula (1) of the present invention, R1 , R2 and R
The lower alkyl group represented by 3 is a methyl group, an ethyl group, a proL"/l' group, and an isobutyl group.

butyl group, etc., and cycloalkyl/l represented by R2
/ As a base, cyclopliers/vAJ + Schiff 11
Examples include hexyl group and cycloheguti/l/ group.

1)i. Examples of the pharmacologically acceptable salts of the compound represented by the general formula (1) in section I include acid (q salts) or alkaline addition salts.
Ore of sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc.1
%2 salt, or organic acid I'l of acetic acid, maleic acid, fumaric acid, citric acid + tartaric acid part! Examples of salts added are alkaline salts such as NaI, Liu A, potassium, calcium, ammonium salts, etc.
Alternatively, salts of organic bases such as ethanolamine and N,N-dialkylethanolamine may be used.

Novel 7 represented by general formula (1) in t'+iJ of the present invention
-hyperazine l]-6-furmelow 4-mexo 1.
The 4-dihydroquinoline-tribo/acid derivative can be prepared by one of a variety of methods.

According to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula (1) in No. 111 is prepared by the following general formula (II) (wherein R1 and R4 are as defined above). Represents nourishment, X
represents a chlorine atom or a Funo F, E atom. ) 7-no-sogeno 6-fluoro-4-oxo 1,4-
Dihydroquinol/-6 monocarboxylic acid derivative and the following general formula (Ill) (wherein, R2 and R3 have the same meanings as above)
It can be produced by reacting the piperazine derivative represented by the formula without a solvent or in a solvent.

Examples of the solvent used in this reaction include water, butanol, 3-methylbutanol/l/, and alcohol such as alcohol.
= Difficult 1, ethylene glycol dimethyl ether monoglyme), ethylene glycol dimethyl ether/L/(di-glyl-L triethylene glycol dimethyl ether/l/(+re-glyl,) mouse f
Jv class. Non-fluorinated polar solvents such as dimethylformamide, dimethylsulf+I (gin 1-, hekinamethi/l/-74 shumelinok 1-liami F), aromatic hydrocarbon solvents such as benzene and luene, or pyridine and hycoline. Examples include organic bases such as I/l/.-1-syn, colicin, and 1-ethylamine.

Further, the heating is carried out at a temperature in the range of 200° from room temperature, preferably in the range υ11 of 'IDD to 1800°.

In the production method of the present invention, the starting material is
The 7-ha1lgeno-6-fluororJ-4-% quin-1,4-dihydro1Jquinoline-3 monocarboxylic acid derivative represented by the general formula (II) is, for example, disclosed in JP-A-53-1989.
This is a known substance which has already been disclosed in Japanese Patent Application Laid-open No. 1412'86, Japanese Patent Application Laid-open No. 55-47658, and Japanese Patent Application Laid-Open No. 56-30964.

In addition, the piperazine derivative represented by the general formula ([1,) is a known substance except for a part, for example, U.S. Patent No. 2,780,625, South African Patent No. 680 Otsu 55
This has already been disclosed in No. 2, etc. In addition, the general formula (II
For the new substances in I), the manufacturing method is described in the reference examples.

According to the second mode of the method for producing a compound according to the present invention, the compound represented by the general formula (1) described in n1j is 1) 1
The following general formula (1) in which R3 is a hydrogen atom (
IV) 2 (In the formula, R1, R2 and R4 represent the same sounds as above.

) 7-piperazine-substituted-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative represented by the following general formula (V)1 R50, -H(V) (in the formula, R5 represents a hydrogen atom or a lower alkyl group having 1 to 2 carbon atoms.

The carbonyl compound represented by the general formula (v) in t3fJ used in Method C of the present invention includes formaldehyde 1 package, ace1-aldehyde, propicinaldehyde 4S, and poly/l/lv aldehyde. is preferably used as an aqueous solution of formaldehyde (polmarin), and when ace1-aldehyde and fluorobinaldehyde are used, dibenzene is preferably used as the solvent.

Further, the reaction is carried out at a temperature in the range of 100 to 200[deg.], preferably at the reflux temperature of the reaction system.

According to the third mode of the method for producing a compound according to the present invention, the compound represented by the general formula (1) is: -4-4xo-1,4-cyhydroxylin-3-
A carboxylic acid derivative and a γ-alkyl halide represented by the following general formula (Vl) R3-A(Vl) (wherein R3 has the same meaning as above and A represents a halogen atom) are mixed in a solvent. It can be produced by reacting in the presence or absence of a base as a deoxidizing agent.

The 'ffJ'A used in the method of the present invention may be of any type as long as it does not harm the rhinoceros; for example, acetone, ethanol, ether, tetrahydrofuran, dimethylpolamide, siloxane, benzene. , toluene, chloroborm and the like.

Examples of the base used as a deoxidizing agent in the method of the present invention include triethylamine, pyridine, potassium carbonate, and the like.

Further, the reaction is carried out at a temperature ranging from room temperature to the heating reflux temperature of the solvent used, and is preferably selected as appropriate within the range of 50 to 1000.

A novel 7-biperazine 1ζ represented by the above general formula (+) produced in this way -C? Convert-6--) /l/oro-4-mexo-1,4-dihydroquinoline=5-carboxylic acid derivatives and their permissible salts are:
Broad antibacterial activity against Durham-positive bacteria and Gram-negative bacteria.
It is extremely useful as a medicine.

Hereinafter, the present invention will be explained using examples.

Example 1 1-ethyl-6-fluoro-7-mi7carzanyl)-1-piperazinyl)i-oxo-1
．． 1-ethyl-6-fluoro-2-chloro-4-oxo-4-dihydroquinoline-3-caldζanoate
1,4-dihydroquinoline-rocarphonic acid 1.53
A mixture of 220 g of g,2-(aminocarbonyl)piperazine and 10 ml of pyridine is heated under reflux for 411 hours. After repulsion, the solvent was distilled off, and the resulting residue was dissolved in a 30% aqueous acetic acid solution. Then, a 20% sulfur hydroxide aqueous solution is added to neutralize. After washing the aqueous layer with a trowel using rotoform, take one portion of the precipitate. The p dispersion was recrystallized from a mixture of chloroborum and methanol, and the melting point was 246-25.
Compound 03 described as brown prismatic crystals at 0° (decomposition)
Obtain 4g.

Elemental analysis value 017H19FN404 Theoretical value 0, 56.55; H, 5.26; N.
1 5.46 experimental value 0, 56.01 iH, 5
．． 40; N+ 15.19 Reference Example 1 2-cyclohexyfrepiperazine cyclohexylglyoxer/l' 2 0. 0g
A 50 ml solution of methanoic acid/I/2 of 94 g of ethylenecyamine was prepared under water-cooling and stirring.
Add ml'fd solution and stir for 5 minutes. Next, 162 g of 1 LiJ of borohydride was added, and the mixture was stirred at room temperature for 2 hours.

After repulsion, the solvent was distilled off, water was added to the residue, and the mixture was extracted with chloroform. Chloroform/W Ha, 144 Sum 1/1 (
After washing with an aqueous sodium chloride solution, it is dehydrated. The solvent was distilled off, and the residue was dissolved in isopropanol.

Add ethanolic hydrochloric acid to the isopropano/I/solution and collect one portion of the precipitate. After dissolving the P dispersion in water, it is anolyzed with a 20% aqueous solution of sodium hydroxide and extracted with chloroform. After the chloroporum layer is dehydrated, the solvent is distilled off. The residue was recrystallized from acetate 1-7, melting point 82-8
7.1 g of the title compound are obtained as colorless crystals at 25°.

Elemental analysis value 010H201N2 Theoretical value 0, 71.37iH, 11.98iN, 1
6.65 Experiment A, 71.21; H, 11.
83;N, 16.43 The starting material cyclohexylglyoxal was obtained from The Journal of Organic Chemistry (The, To+1rnalofor).
gan1achemistry) Volume 6, page 260 (194
1) It is a well-known compound.

Example 2 1-ethy)v-6-7)voro7-(rhocyclohequine/I/-1-piperaziniw)-4-oxo-1+ 4-dihydroquinoline-rhocarboxylic acid 1
-ethyl/l/-6-fluoro-twochloro-4-megiso 1.4-v hydroquinoline-6-carboxylic acid 1. 5
0 g, a mixture of 2.80 g of 2-cyclohexylpiperazine obtained in Reference Example and 10 ml of pyridine was added to 22
Heat to reflux for an hour. After repulsion, the solvent is distilled off. Add water to the residue and extract with chloroform. The chloroform layer is after dehydration. 'fB medium is distilled off. After washing the residue with a mixture of benzene and isopropyl diether, it is recrystallized from benzene to obtain 0.54 g of the title compound as colorless crystals with a melting point of 175.5-1765°.

Elemental analysis value "22S28FN303 Theoretical value 0, 65.82; H. 7.03, N
．． 1 0.47 experimental value C, 65 filtration 1; H. 6
．． 90;N. 1 0.47 Example 3 1-Ethyl-6-fluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-shy10k/phosphorus-6-carboxylate 1-ethyl-6 -Fluoro-7-chlorol:I-4-
Oxo-1,4-dihydroquinoline-6-carboxylic acid 1
5.00 g12-Methylbiperazine 16,70g
and pyridine 70* which mixture is heated to reflux for 11!1 hours. After repulsion, the solvent is distilled off, and the resulting residue is made acidic with a 50% acetic acid aqueous solution.

After treating the aqueous layer with activated carbon, neutralize with a 20% aqueous 1-lium hydroxide solution [trowel]. Treat again with activated carbon and then concentrate. Take 1 portion of the precipitate. Dissolve the powder in ethanol and add ethanolic hydrochloric acid. Concentrate the solvent and count the precipitate. The P dispersion was recrystallized from a mixture of water and ethanol to obtain 819 g of the hydrochloride of the title compound as pale yellow polymorphic crystals with a melting point of 7)00° or higher.

Elemental analysis value 017H20FN303 ・HOI theoretical value a, 55.21; H, 5,72; N, 11
．． 36 actual measurement value a, 55.13; H, 5, 72; N,
11.17 Example 4 1-ethyl-6-fluor-7-(3
, 4-dimethy1-1-piperazine tv) -4-oxo-1,4-dihydroquinoline-6-carboxylic acid odor 11
a 1-Methyl/l/-6-fluoro-7-(3
-methy/I/-1-piperazinyl)-4=Axo1,
4-dihydroquinoline-6-carboxylic acid hydrochloride 2.6
9 g, 5.4 ml of 90% formic acid.

A mixture of 37% formalin filter, 5d and 070 g of potassium carbonate is heated under reflux for 5 hours. After the reaction, a 20% aqueous sodium hydroxide solution is added to neutralize, and the precipitate is collected. p
The dispersion is recrystallized from a mixture of chloroform and methanol to give 1.70 g of the title compound as colorless needles with a melting point of 244-246°.

Elemental analysis value (!16H22FN303 theoretical value C, 6
2,24; H, 6,38; N, 1210 actual measurement value
0.62.02; H, 6,37iN, 12.05 Example 5 1-Methyl/l/-6-fluoro-7-(4-ethyl-ro-methy)L7-i-biperazini/l/) - 4-Oxo-1,4-dihydroquinoline-ro-carboxylic acid Example 3
+-7-(6-methy71z-1-piperazi=7v)-4
- A solution of 1.00 g of Schiso 1,4-dihydroquinoline-6-carboxylic acid hydrochloride, 129 g of ethyl iodide, and 09 g of triethylcyamine in dimenalformamide was heated and stirred at 70 to 80° for 15 hours. do. After the reaction, the solvent is distilled off, and the resulting residue is made acidic with a 50% acetic acid aqueous solution. Add a 20% aqueous sodium hydroxide solution to the aqueous layer to neutralize it, and remove the precipitate. The dispersion was treated with column chromatography (supported by silica gel and eluted with a mixture of chloroform and methanol (9: L)) to obtain 0.47 g of the title compound as colorless crystals. Gru. Recrystallization from a mixture of chloroform and methanol yields colorless monomorphic gold crystals with a melting point of 203-205°.

Elemental analysis value 01gH24FN303 Theoretical value a, 63.14; H, 669; N, 11.63
Actual value a, 62.82; H, 6,78; N,
11.66 Example 6 1-Ethyl-6-7 Luo-7-(3
-ethyl-1-biperazinyl)-4-auxiliary xo1.
4-dihydroquinoline-3-carboxylic acid 1-methy)v -6-7/l/olor 7-chloro 4-
Oxo 1,4-dihydroquinoline-local phonic acid 4
．． A mixture of 49 g of pyridine, 570 g of 2-ethylpiperazine, and 30 ml of pyridine is heated under reflux for 15 hours. After the reaction, the solvent is distilled off. The resulting residue was made acidic by dipping into a 50% aqueous acetic acid solution, and then neutralized with a 20% sulfur hydroxide solution. Concentrate the aqueous layer and collect the precipitate. After dissolving it in loloform and treating it with activated carbon, it becomes ethanolic! I, (Add acid. Concentrate the powerful medium and count the precipitate. Recrystallize from a mixture of dispersible water and Achton to obtain hydrochloric acid '7i1 of the title compound as colorless crystals with a melting point of less than 00°. i, 81 i< is obtained.

Elemental analysis value 01BH22F'N;50; U-HCI theoretical value 0.56.32; H, 6,04; N, 1
0.95 Actual value 0.56.10 iH+ 6.01
i N, 10.89 Example 7 1-ethyl-6-) le A mouth-7-(
3-ethyl-4-methyl-1-piperazinyl)-4-
A, 1,4-dihydroquinoline-6-carboxylic acid 1-ethyl/I/-6-furukari II-7- obtained in Example 6
(6-nityl-1-piperazinyl)-4-oxo-1,
4-dihydroquinoline-6-carboxylic acid hydrochloride 0.6
0 g, 90% formic acid 1.2 txt.

37% formalin 0.77 ml and potassium carbonate 01
7 g of the mixture is heated to reflux for 5 hours. After the reaction, a 20% sodium hydroxide aqueous solution was added to neutralize, and the precipitate was collected. The scattered substance is recrystallized from a mixture of chloroform and methanol to obtain 033 g of the title compound as colorless monomorphic gold crystals with a melting point of 213-215°.

Elemental analysis value 019H24FN303 Theoretical value C, 63, 14, H, 669iN, 1163
Actual value C, 63,11; H, 7,01; 11.1
1.54 Example 8 1-ethyl-6,8-difluor subro-
7- (3-methy/I/-1-piperazinyl)-4-
Oxo-1,4-dihydroquinoline-5-carboxylic acid 6.7.8-1-Refluor-1-ethyl-4-Oxo-1,4-dihydroquinoline-3-
Carvone ll #1.00g, 2-methylbiperazine 11
A mixture of 0 g and 10*t of pyridine is heated to reflux for 15 minutes. After the reaction, the solvent is distilled off. Ethanol is added to the obtained residue, and the precipitate is collected.

The p dispersion was recrystallized from ethanol and had a melting point of 269-240.
036 g of the title compound is obtained as colorless gold crystals of 5°.

Elemental analysis value 0-r7H19FzN30s Theoretical value 0.5
8.11; H, 5,45; N, 1196 actual value 0.57.98; 11.5.47. hl, 12.1
8 Example 9 1-ethyl-6,8-difluoro-7-(3゜4-dimethyl-1-piperazinyl)-4-=1 giso 1,4-dihydroquinoline-ro-carphonic acid obtained in Example 8 1-ethyl-6,8-difluoro-7-
(6-methyl-1-piperazini/l/)-4-oxo-1,,4'hydroquinoline-6-carboxylic acid 1.40
g, 90% formic acid 28 resistant and 67% formalin 2.2 m
1 mixture is heated to reflux for 4 hours. The solvent will then be distilled off. After dissolving the obtained residue in water, 1-lium hydrogen carbonate [
Neutralize with a trowel and remove any precipitates. The p dispersion is recrystallized from ethanol to obtain 0.32 g of the title compound as colorless button-like crystals with a melting point of 2115-212°.

Elemental analysis value 018H21F2N303 Theoretical value C,5
9,17iH,5,79;N, 11.50 actual value c
, 59.29; H, 5,87; N, 11.55 Patent Applicant Hokuriku Pharmaceutical Co., Ltd. Procedure Supplement I1:, Voluntary Author) June 1980 NopI+ Commissioner of the Japan Patent Office Kazuo Wakasu 1 Display of Case 1981 Special Request No. 171271
υ2 Name of invention 7-Viberan i? '5 conversion-6-
Flulero-4-Aquino-1,4-dihydroki/phosphorus-3
- Carboxylic acid, tX conductor 6 Relationship with old cases to be amended 1. Applicant 911 Address Omoi Prefecture 1, Tachikawa-cho, Aoyama-shi, I Jl, +3-, 1
45 Contents of amendments Contents of 5 amendments as attached
Correct to "Actual Measured Value".

(2) Change the description “experimental value” in the first line of page 12 of the specification to “
Correct to "Actual Measured Value".

(6) The statement in the first line of page 12 of the specification, "Re-crystallization from benzene" is corrected to "+Tj crystal from bezene."

(4) On page 16 of the specification, line 5 “Description of I “Experimental value”
is corrected to 1 actual measurement value.

(5) Description in the first line of page 12 of the specification “Graphy (
``Carrier Nijirica Gel'' is corrected to ``Graphy (Carrier Nijirica Gel-1)''.

(6) Add the following sentence between the 16th line on page 18 of the specification and the 14th line on the same cylinder.〇 [According to the conventional method, the hydrochloride of the indicated compound is defined as the hydrochloride.

Recrystallization from water gives colorless nail-shaped crystals with a melting point of 290-300° (decomposition).

Elemental analysis value C17H19F'2N303・HCI theoretical value C, 52,65; H, 5,20iN, 10.8'
Add Chapter 4.

"The antibacterial activity of the compounds of the present invention is shown in the following test example. At that time, as control substances, pipemide # (hereinafter referred to as "PPA"), norphlogi-4-nosine (hereinafter referred to as "AM-715") and 1-ethyl -6,8-Diflu A Rho 1.4-No I
Nidro 7-(1-piperazinyl)ky/phosphorus-6-carboxylic acid (compound described in JP-A-55-47658, hereinafter referred to as known compound) was used.

Test Example 1 The antibacterial test was carried out using the method specified by the Japanese Society of Chemotherapy (1).
81)). The results are shown in Table 1.

Test Example 2 SD pigs and cats weighing 180 to 210 g were used in an experiment with 8 animals per group.

Test compound el was suspended in 05% carboxymethylcellulose aqueous solution, fasted, and 20111! ? The animals were orally administered at 9 days and placed in a urinary cage.

The urine excreted from the feces to which the test compound was administered was collected over time, and the urinary concentration was measured by a biological quantitative method (assay test, Escherichia Colli N I HJ-J C-2). The excretion rate was determined for up to 24 hours. The results are shown in Table 2.

Table 2 Urinary Concentration and Excretion Rate *Values for Free Base Test Example 3 Four-week-old ddY male mice were used in the experiment with 10 mice per group.

The test compound is either suspended in a 0.5% aqueous carpoxymemethycellulose solution and administered to a patient by LJ, or dissolved in a 0.1N aqueous hydrochloric acid solution and neutralized with a 0.1N aqueous sodium hydroxide solution. was administered intravenously. After administration 1o(1
The number of mouthfuls between each was observed, and the 50% lethal dose (LD50) was calculated based on the propylene method. The results are shown in Table 3.

Table 6 Acute toxicity value * 195% confidence limit * 2 Value for free base J Procedural amendment (voluntary) June 1980/Japanese Patent Office Commissioner Kazuo Wakasugi 1 Indication of case 1988 Patent application no. No. 171271 2 Title of the invention 7-piperazine-substituted-6-7-luoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative 3 Person making the amendment At the time of relation to the case 3'1 Applicant's address Fukui Prefecture 1-3-144 Tatsuyomachi, Katsuyama City The “Claims” column and [Details of the Invention 5] in the specification to be amended
Contents of amendment (1) The claims are amended as shown in the attached sheet.

(2) The statement "jR3 represents a butyl group, etc." from line 2, line 2 to line 4, line 11 of page 3 of the specification is corrected as follows.

The lower alkyl group represented by rR3 includes a methyl group,
Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, etc. (3) Same as line 5 on page 9 of the specification. −j'
The following sentence is added between I-1.

According to the fourth mode of the method for producing a compound according to the present invention, the compound represented by the general formula (1) has the following general formula (I'11) (wherein R1+ RLl!l R3 and R4 has the same meaning as above, and R6 represents a lower alkyl group.) 7-piperazine-substituted-6-fluoro-
It is produced by hydrolyzing a 4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester derivative.

Hydrolysis is carried out using an acid or an alkali using a method known per se. For acidic hydrolysis, an acid such as hydrochloric acid or sulfuric acid is used, and for alkaline hydrolysis, an alkali such as sodium hydroxide or potassium hydroxide is used. , used in the reaction as an aqueous solution of these acids or alkalis, or as a solution in ethanol, methanol, etc., or as a solution in a water-containing organic solvent.

Further, the reaction is carried out at room temperature while heating and refluxing the solvent used.

・In addition, the 7-piperazine-substituted-6- represented by the general formula (Hl), which is the starting material in the production method of the present invention,
Fluoro-4-oxy-1゜4-'; h) Armpit/phosphorus-
The 3-carboxylic acid ester derivative is a new substance, and its production has been described in Reference Examples. (4) The following sentence is added between page 19, top line 10 of the specification and line 11.

[Example 9 1-Methyl-6-fluoro-7-(3-methyl-1-piperazinyl)-4-oxo 1゜4-dihydroxy/phosphorus-3-carboxylic acid l-medyl-6-fluoro-7-chloro -4-oxo-1,4-dihydroginoline-3-carvone 1'1121.50.9.2-medilbiveranone 1
．． A mixture of 809 and 8 ml of pyridine is heated to reflux for 23 hours. After the reaction, the solvent is distilled off.

The resulting residue was mixed with methanol and needle d,'.

Add the liquid and count the precipitate. Dissolve the σ5 extract in methanol and add ethanolic hydrochloric acid.

1') I+
'11'n'+, the hydrochloride of the indicated compound as a colorless φ1-shaped product with a melting point of 3000 or more 0.671? r get.

Elemental analysis value C16H18F'N5O-HCI ・%H
,20 theoretical value C,5B,84 iI(,5,45;N
, 11.66 Experimental value c, 5s, st; H, 5,
75; N, 1 i56 Reference Example 2 1-ethyl-6,8-difluoro-7-(3-methyl-
ethyl ester (1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate Ester 1.50!9.2-Methylpiperazine 1.50,9
and pyridine 5m? The mixture is heated to reflux for 3 hours.

After the reaction, the solvent is distilled off, and the resulting residue is dissolved in chloroborm. The chloroform layer is washed with water, dehydrated, and the solvent is distilled off. The residual liquid is recrystallized from a mixture of benzene and isopropyl ether to obtain the title compound 1.00.9 as colorless needles with a melting point of 1265-127.5°.

Elemental analysis value 019H23F2N303 Theoretical value C,6
0,15; H, 6,11; N, 11.08 experimental value C
,60,80iH,6,34;N, 10.84Example 10 1-ethyl-6,8-difluoro-7-(3-methyl-
1-ethyl-6,8-difluoro-7- obtained in Reference Example 2
(3-methyl-1-piperazinyl)-4-oxo-1,
°4-dihydroquinoline-3-carboxylic acid ethyl ester in a solution of 0.55.9 ethanol in 5.5 yrtl;
Add 18% aqueous hydrochloric acid solution and heat under reflux for 4 hours. Collect the cold weld precipitate. The Ne-J dispersion was sequentially washed with ethanol and ether and recrystallized from water to give a melting point of 290-300.
° (Decomposition) 043 g of the hydrochloride of the title compound is obtained as colorless Φ1 crystals.

Motoichi's NMR and o:xR spectra matched the compound obtained in Example 8.

Example 11 1-Methyl-6,8-difluoro-7-(3-methyl-
1-Methyl-6,7,8-)lifluoro-4-oxo-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate
1,4-dihydroquinoline-3-carboxylic acid 2.00.
9.2-Methylpiperazine 2.80.9 and pyridine 2
0 ml of the mixture is heated to reflux for 30 minutes. After the reaction, the solvent is distilled off. Methanol is added to the obtained liquid, and the precipitate is collected. The residue is recrystallized from a mixture of chloroporum and ethanol to obtain 140 g of the title compound as yellow flakes with a melting point of 249-250°.

Elemental analysis value C16H17F"2N303 theoretical value C,
56,98; H, 5,08; N, 12.46 experimental value
C, 56,86iH, 5,86iN, 12.17 Reference Example 3 1-isopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroxy/phosphorus-3-carboxylic acid 2.3.4 -) Riful A loaniline 370g, sodium acetate 10.80.17. 20 parts acetone, 1 part acetic acid
To the 41-compound in 9.6 mJ and 89 ml of water, 770 g of sodium borohydride was added in a water-cooled stirring dish, and the mixture was heated for 2 hours ((
Stir. After the reaction, the mixture is made alkaline by adding potassium carbonate and extracted with benzene. Benzene layer i was washed with saturated saline and then dehydrated. The solvent was distilled off, leaving 317 g of 2,3,4-trifluorol-N-isopropylaniline as a colorless liquid.

IR spectrum　ν(film)Cm　.

8450 (:NH) 2, 3. 4- trifle vice-rho N-iso-/'I
IIM combination of J biraniline 2.50.9 and ethgyne methylene malonic acid diethyl ester 2.809 4'/1
are heated and stirred at 160 to 170° for 1 hour.

Add hexane to the reaction mixture and cool. The precipitate was collected as colorless crystals to obtain diethyl 2-(2,8,4-)refluoro-N-imbuviranilino)methylene malonate 2.45J7. Recrystallization from hexane gives colorless needles with a melting point of 92.5-93°.

Elemental analysis value C17H20F3NO4 Theoretical value C,56,82:H,5,61iN, 8.9
0 Experimental value C, 56,88; H, 5,67; N, 8.
91 diezyl 2-(2,8,4-1lifluoro-N-inpropylanilino)methylene malona-)9.00,9
A mixture of 90.19 and polyphosphoric acid is heated and stirred at 80 to 85° for 1 hour.

After the reaction, the mixture is poured into ice water and extracted with chloroporum. The chloroform layer was washed with water and then dehydrated.

The solvent was distilled off, and 18% aqueous hydrochloric acid solution was added to the resulting residue.
Add #Ie and 45 ml of ethanol, and heat under reflux for 15 hours. After cold welding, the precipitate was filtered and washed with ethanol to obtain 140 g of the title compound as a brown solid. Recrystallized from a mixture of chloroform and ethanol, melting point 261
Light brown needles of ~262.5° are obtained.

Elemental analysis value C13H10F3NO3 Theoretical value c, 54.74; H, 3,51; N, 4.
91 experimental value C, 54, 64; H, 3, 47; N, 4
．． 98 Example 12 - Isopropyl-6,8-difur sub-7-(3-methyl-1-piperazinyl)-4-ogine-1,4-dihydroxylino-3-carboxylic acid? d Consideration Example 3 Obtained 1-isopropyl-6,7゜8-triful-4rJ-4-mexo-1,4-dihydroquinoline-
3-carboxylic acid 0.68 y.

A mixture of 072 g of 2W tilpiperazine and 10 ml of pyridine was treated in the same manner as in Example 8, and the melting point was 217~
7 of the title compound 0.42.9 as colorless crystals at 218°
11.

Elemental analysis value Cl8H21F2N303・H20 theoretical value C, 57,75; H, 5,92; N, 11.22
Experimental value C, 57,58; H, 5,97iN, 11.
18J (5) Specification ↑ The description "Example 9" on the 11th line of page 19 is corrected to "Example 18."

Attachment Claim 2 (In the formula, R is a lower alkyl group having 1 to 4 carbon atoms. a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R4 is a hydrogen atom or 7)
Represents an elementary atom. ) 7-Biverazine substituted-6-fluoro-4, -
] Kin-1,4-dihydroxyline 3-carboxylic acid derivatives and their biologically acceptable salts 0 Procedural amendments February 1982 decision ρ11 Commissioner of the Japan Patent Office Manabu Shiga 1 Indication of tenancy IM (Japanese) 58i [Patent Application No. 17127
182 Title of the invention 7-piperazine-substituted-6-fur-substituted 4-mexo 1,4-dihydroxyphosphorus-3-carboxylic acid derivative Address 1'118-144 Katsuyamayamaqyo-cho 1, Fukui Prefecture 911 tlYl-1-,/5 Contents of amendments to ``Wholesale 1ζ1shi-1-Detailed Description of the Invention'' (1) Circular for amendment of procedures submitted on March 12, 1980;
Description from line 14 on page 1 to line 8 above [The following sentence is added between line 13 on page 18 of the specification and line 8 above. ” is corrected to the following statement.

"Continuing from the 10th line on page 19 of the specification, the following sentence is added." (2) Procedural Supplementary City Circular submitted on March 12, 1980;
"Rat" in the fifth line on page 6 is corrected to "mouse."

(3) Procedural amendment circular submitted on March 12, 1981;
On page 6, from the 7th line to the 8th line of the same page, ``rat'' is changed to ``mouse'' by 31.

(4) IM (Procedure Supplementary City Circular Submitted on June 12th, 1995, line 18, directly above section 4, r C16H18F”N3
0" is corrected to r C16H1aFN303J.

(5) Procedural amendment circular submitted on June 12, 1982;
Examples 14 to 20 are added after Example 13, which was corrected in (5) from line 18 to line 8 of the same page on page 10.

"Example 14 1-Methyl-6 7,8-) Riffle sub-rho 4-oxo 1,4-dihydroky7phosphorus-3-carboxylic acid 700In
9.1. A mixture of 9BOm9 of 2-dimethylpiperazine and 5 vtl of pyridine is heated to reflux for 20 minutes. The reaction minor solvent is distilled off. Methanol is added to the obtained residue, and the precipitate is collected. Dissolve the debris in a mixture of chloroform and methanol, and add ethanolic hydrochloric acid. Collect the precipitate, add water to the t-dust, and neutralize with sodium hydrogen carbonate. Extract with 1J Roporum, and after dehydrating the chloroform layer, the solvent is distilled off. Add methanol to the residue, collect the precipitate, and obtain the title compound '18 as colorless crystals.
Obtain 0m9. Recrystallization from a mixture of chloroform and eq/l gives colorless needle crystals with a melting point of 231-2325°.

Elemental analysis value C17H19F2N303 theoretical value C,5
8,11iH, 5,45iN, 11.96 experimental value C
,58,18iH,5,54;N, 11.99 or less,
Example 1. Examples 15-20 by the same method as ~14
The compound is obtained.

Example 15 1-Methyl-6-fluoro-7-(8,4-dimethyl-
1-piperazinyl)-4-oxo-1,4-dihydroxy-1-quinoline-3-carboxylic acid Colorless gold monomorphic crystal Melting point 262-263° (dichloromethane-ethanol) Elemental analysis value C17H20''N303 Theoretical value C,61,25iH , 6, 05; N, 12.
60 experimental value C, 60, 94:H: 6.38;N,
12.51 Example 16 1-propyl-6-fluoro-7-(8-methyl-1-
piperazinyl)-4-oxo-1+4-dihydroquinoline-3-carphonic acid pale yellow crystals Melting point 163-164° (ethanol-benzene) Elemental analysis Cl8H22FN303 ・1/4 N2
0 theory, logical value C, 61, 48; H, 6, 44iN, 1
1.94 experimental value C, 61, 20; H, 6, 58; N,
117'1 Example 17 1-Propyl-6-furJlow7-(3゜4-dimethyl-1-piperazinyl)-4-Jquin-1,4-dihydroquinoline-3-carboxylic acid pale yellow needles Melting point 157-1'58° (benzene-hexane) Elemental analysis value C19, H24FN3Q3 theoretical value C,6
8,14iH,6,69;N, 11.61 experimental value C
,62,98;H,6,98iN, 11.61 Example 18 1-isopropyl-6,8-difluoro-7-<8.4
-dimethyl-1-piperazinyl)-4-oxo-1,4
-Dihydroquinoline-3-carboxylic acid pale yellow $1 crystal Melting point 190.5-191.5° (benzene-hexane) Elemental analysis value C19H23F2N303 Theoretical value C,6
0,15iH,6,11;N, 11.08 experimental value c
, 6o, oo; Summer (+ 6.85; N, 11.18
Example 19 1-Propyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid pale yellow needles Melting point 211-212° (Chloroform-ethanol) Elemental analysis value Cl8H21F2N303 Theoretical value C,5
9,17; H, 579iN, 11.50 experimental value C,
58J36; exit 6. l4iN, 11.88 Example 20 1-Propyl-6,8-difluoro-7-(3,4-dimethyl-1-piperazinyl) to 4-oxo 1,4-dihydroquinoline-3-carboxylic acid pale yellow scaly Product melting point 1865-187.5° (ethanol)

Claims (1)

[Claims] (In the formula, 1 is lower alkyl having 1 to 4 carbon atoms, 1 (
2 is an ami7 carbonyl group, a carboxyl group, or a lower alkyl group having 1 to 4 carbon atoms or a 7 chloroalkyl group having 5 to 7 carbon atoms, It3 is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, n4i '1 Represents all hydrogen atoms or fluorine atoms. )? -piperazine-substituted-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives and pharmacologically acceptable salts thereof.