JPH0368863B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel quinoline compounds and methods for their preparation. It is known that certain substituted 4-quinolone-3-carboxylic acids have antimicrobial activity. Representative examples of these compounds are those of the following formula. [X is either H (invention of Kyorin Pharmaceutical's U.S. Patent No. 4146719 issued on March 27, 1979) or methyl (R.
Bellon/ Dainippon Pharmaceutical's U.S. Patent No. 4,292,317 issued on September 29, 1981)] In U.S. Patent No. 4,284,629, there is
Certain 4-quinoline-3-carboxylic acids with amino groups are disclosed and said to have antimicrobial activity. Examples of disclosed compounds are 1-dimethylamino-6-nitro-2-methyl-4-quinolone-3-carboxylic acid methyl ester (Example 4); 1-dimethylamino-7-chloro-6-nitro -2-Methyl-4-quinolone-3-carboxylic acid methyl ester (Example 5); 1-dimethylamino-7-(n-bukelmethylkabuto)-6-nitro-2-methyl-4-quinolone-3 -carboxylic acid methyl ester (Example 17). There are no examples of compounds having a heterocyclic group at the 7-position. The present invention is a compound represented by the following formula, a pharmaceutically acceptable acid addition salt thereof, and an alkali metal or amine salt of the compound where R' is H. [R is lower alkylamino; R' is H, and Z=N- is a heterocyclic group; (n is 2 to 3 and R″ is H, lower alkyl or acetyl) A preferred group of compounds are:
In the formula, Z=N- is the formula A: (R° is 1-piperazinyl or 4-lower alkyl-1-piperazinyl, where H is lower alkyl). Particularly preferred is
A compound in which R is methylamino, R′ is H, and R″ is methyl, and a pharmaceutically acceptable salt thereof. Formula: The compound (R' is H or lower alkyl and R'' is lower alkylamino) serves as an intermediate for the compound of formula. The antimicrobial agents of the present invention include an antibacterial effective amount of the compound of formula and one or more of the compounds of formula. A compound of the formula can be prepared by reacting a compound of the formula where R゜ is lower alkylamino with a compound of the formula: Z = NH. Bacteria can be eradicated by contacting a bacterial habitat with a compound of the formula above.
In the definition of the symbols in , _the term "lower alkyl" refers to alkyl, preferably C _1-3 alkyl, such as methyl, ethyl, propyl, isopropyl. The amino group can be prepared using an aminating agent such as chloralamine or 0-arylhydroxylamine such as 0-(2,4-dinitrophenyl)hydroxylamine (2,4.
(O ₂ N) ₂ C ₆ H ₃ ONH ₂ ] to introduce it into the 1st position of the quinolone nucleus [Tamura et al., J.Org.
See Chem. 38, 1239 (1973)]. This produces a compound (formula below) in which R° is NH ₂ . The reaction occurs in an inert organic solvent at ambient temperature in the presence of a base such as potassium carbonate. The general synthesis method for the compound represented by the formula is as follows. In the above flow sheet, when compound () is formolized with a mixture of formic acid and acetic anhydride, N-
A formyl derivative () is obtained. This is then alkylated with a lower alkyl halide (preferably iodide or bromide) in the presence of a base such as urium carbonate to obtain an N-lower alkyl-N-formyl compound (). When this is hydrolyzed with a base such as NaOH and the reaction mixture is made acidic, N
- lower alkyl carboxylic acid () is formed. The final step is the formation of a compound of the formula in which R is lower alkylamino and R' is H by reaction of a compound of the formula with a suitable heterocyclic compound Z=NH.
This reaction occurs by heating the reactants at a temperature of about 100 to about 150°C in the presence of an acid acceptor that absorbs the HC formed. The acid acceptor can be an alkali metal carbonate or a t-amine such as pyridine, triethylamine, (diisopropyl)ethylamine, etc. Alternatively, an excess of the heterocyclic reactant can be used as the acid acceptor. In a preferred method, the reactant mixture is heated to reflux in another solvent such as pyridyl or 2-methoxyethanol using 3 to 6 moles of heterocyclic reactant per mole of compound (). Compounds in which R is 2-propenylamino are prepared in an entirely analogous manner using allyl halide instead of lower alkyl halide in the N→V conversion. Again in the flow sheet, if desired,
Compounds in which R' is lower alkyl can be hydrolyzed to the free acid (R'=H). This is N-
It can be formylated to a formyl compound (,R'=H). Subsequent alkylation esterifies the carboxyl group to form (R'=lower alkyl). The lower alkyl ester () can be produced by a conventional esterification reaction or selective hydrolysis of the compound (R'=lower alkyl). This lower alkyl ester () is a potential intermediate for preparing compounds in which R' is lower alkyl. However, since the reaction of ester () with Z=NH tends to form amides, esters of formula are preferably prepared by direct esterification of free acids of formula. A compound in which R is amino (NH ₂ ) is
Produced by reaction of intermediate () with Z=NH. Compounds in which R is N-formyl-lower alkylamino are prepared by formylation of compounds in which R is lower alkylamino. The compound in which R is lower alkylamino is prepared as follows. N-alkylation of a lower alkyl ester of a compound of the formula by heating with a di-lower alkyl sulfate forms a compound in which R' is lower alkyl and R° is di-lower alkylamino. Hydrolysis with an alkaline aqueous solution yields a compound in which R' is H and R° is lower alkylamino. This is then reacted with a heterocyclic compound Z=NH to yield the desired compound of the formula where R is di-lower alkylamino. It is clear that this synthetic route allows the preparation of compounds in which the lower alkyl group of the di-lower alkylamino is separate, for example methylethylamino. The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula. The properties of this acid addition salt are:
It is immaterial as long as the anion is derived from an acid that is essentially non-toxic to the animal body. Examples of suitable acid addition salts are hydrochloride, hydrobromide, sulfate, methanesulfonate, maleate, citrate, tartrate, p-toluenesulfonate, cyclohexane sulfamate. etc. Although compounds of the formula theoretically have one or more N atoms, they tend to form only stable monoacid addition salts. Compounds in which R' is H can also be prepared and are used in the form of alkali metal or amine salts, preferably Na, K or N-methylglucamine salts. The following is an illustration of the invention. Production example 1 a 1-amino-7-chloro-6-fluoro-
Ethyl 1.4-dihydro-4-oxo-3-quinolinecarboxylate [;R'=C ₂ H ₅ ] 15.0 g (0.0556 mol) of 7-chloro-6-fluoro-1,4-dihydro-4-oxo-3 -A mixture of ethyl quinolinecarboxylate, 15.3 g (0.1112 mol) potassium carbonate and 500 ml dimethylformamide was stirred at room temperature for 6 hours. Then 0-(2.4-
dinitrophenyl) hydroxylamine (14.3
g, 0.072 mol) and stirred for about 16 hours. Thin layer chromatography (t ₁ c) showed that the reaction was incomplete, so 5.0 g of 0-(2,4-dinitrophenyl)
Additional hydroxylamine was added and stirring continued for 2 hours. Then 2.8 g of 0-(2,4-dinitrophenylhydroxylamine was added and stirring continued for 2 hours. The solvent was removed in vacuo at 50°C and the residue was stirred with 600 ml of water for 2 hours and filtered. The resulting solid
Slurry with 700ml of refluxing acetonitrile,
passed. After cooling the liquid, add 5.4 g of 1-amino-
7-chloro-6-fluoro-1,4-dihydro-
ethyl 4-oxo-3-quinolinecarboxylate,
mp254-258℃ crystallized. The solid remaining on the filter was recrystallized from dimethylformamide to obtain an additional 6.7 g of pure product. Total yield 12.1g. b 1-amino-7-chloro-6-fluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [;R'=H] Dissolve NaOH (0.91 g, 0.0228 mol) in 100 ml of water, and dissolve 2.6 g (0.0091 mol) of 1-amino-7-
Ethyl chloro-6-fluoro-1,4-oxo-3-quinolinecarboxylate was added. The mixture was stirred in a steam bath for 2 hours and neutralized with acetic acid (1.6 ml) while hot. The solid suspension was stirred at room temperature for about 16 hours, and the solids were collected and washed with water. The product was recrystallized from dimethylformamide to give 2.0 g of 1-amino-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, beige powder, mp 312-315°C, I got it. Alternatively, 7-chloro-
6-Fluoro-1,4-dihydro-4-oxo-
By aminating 3-quinolinecarboxylic acid, 1-amino-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid could be produced. The former is 7-chloro-6-fluoro-1,
Ethyl 4-dihydro-4-oxo-3-quinolinecarboxylate was hydrolyzed with aqueous NaOH to obtain a colorless solid, mp 274°C (decomposed). Production example 2 7-chloro-6-fluoro-1-(formylamino)-1,4-dihydro-4-oxo-3-
Ethyl quinolinecarboxylate [N; R′=C ₂ H ₅ ] After dropping formic acid (24.5 ml, 0.625 mol) into 59 ml (0.625 mol) of acetic anhydride while stirring at 0°C, the mixture was stirred at 0°C for 15 minutes. The mixture was stirred at 50°C for 15 minutes and then cooled to 0°C. Ethyl 1-amino-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate [Production Example 1(a), 17.8g
(0.0625 mol)] in formic acid (130 ml) was added dropwise.
The mixture was stirred at room temperature for 3.5 days. At this point, t ₁ c indicated the presence of a small amount of starting material, so 48 ml of mixed anhydride was added to the reaction mixture, which was then stirred for 6 more hours.
The solid product was taken and washed thoroughly with water to obtain 19.65 g of solid. This was recrystallized from a dimethylformamide-ethanol mixture and heated to 110°C with phosphorus pentoxide.
7-chloro-6-fluoro-1
Ethyl (formylamino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate, mp263~
264°C (decomposition). Similarly, 1-amino-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was formylated to give 7-chloro-6-
Fluoro-1-(formylamino)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [N; R'=H] was obtained. Production example 3A 7-chloro-6-fluoro-1,4-dihydro-1(formyl)methylamino]-4-oxo-
Ethyl 3-quinolinecarboxylate [V; lower alkyl = CH ₃ , R' = C ₂ H ₅ ] 14.65 g (0.047 mol) of 7-chloro-6-fluoro-1(formylamino)-1,4-dihydro-
Ethyl 4-oxo-3-quinolinecarboxylate (Production Example 2), 12.9 g (0.094 mol) potassium carbonate,
200ml dimethylformamide mixture at 25℃
Stirred for 90 minutes. Methyl iodide (20.0 g, 0.141 mol) was added and stirred at room temperature for 90 minutes. The dimethylformamide was removed under high vacuum at 50°C and the residue was partitioned between 250ml water and 500ml chloroform. The chloroform layer was separated and dried over anhydrous Mg sulfate. Concentration of the chloroform solution yielded 13.8 g of 7-chloro-6-
Fluoro-1,4-dihydro-1-[(formyl)
Ethyl methylamino]-4-oxo-3-quinolinecarboxylate, mp 213-216°C, was obtained. Production example 3B 7-chloro-6-fluoro-1-[(formyl)
ethylamino]-1,4-dihydro-4-oxo-3-quinolinecarboxylate [V; lower alkyl = C ₂ H ₅ , R' = C ₂ H ₅ ] 12 g of 7- Chloro-6
Ethyl -fluoro-1-(formylamino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate, prepared from 10.5 g potassium carbonate, 9.4 ml ethyl iodide in 163 ml dimethylformamide. 11.5g product, tan-colored powder, mp185~
187℃ was obtained. Production example 3C 7-chloro-6-fluoro-1-[(formyl)
Ethyl propylamino]-1,4-dihydro-4-oxo-3- _{quinolinecarboxylate} [lower alkyl=( _CH2 ) _2CH3 ,R'= _{C2H5 ]} 163 ml of dimethyl 12 g of 7-chloro-6-fluoro-1 in formamide
Prepared from ethyl -(formylamino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 10.5 g potassium carbonate, 10.6 ml n-propyl bromide. 12g product, light yellow powder, mp185~
187℃ was obtained. Production example 3D Ethyl 7-chloro-6-fluoro-1-(formyl(1-methylethyl)amino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate [V; lower alkyl=(CH ₃ ) ₂ CH, R′=C ₂ H ₅ ] 11.3 g of 7-chloro-6-fluoro-
1-(formylamino)-1,4-dihydro-4-
Prepared from ethyl oxo-3-quinolinecarboxylate, 8 g potassium carbonate, 8.3 ml isopropyl bromide. 10g product, tan peel powder, mp148~
155℃ was obtained. Production example 3E 7-chloro-6-fluoro-1 [formyl (2
-propenyl)amino]-1,4-dihydro-
Ethyl 4-oxo-3-quinolinecarboxylate [;R'=C ₂ H ₅ , R゜=OCH-N (CH ₂ CH=
CH ₂ )] 10 g of 7-chloro-6-fluoro-1 in 137 ml of dimethylformamide according to the method of Preparation Example 3A above.
Prepared from ethyl -(formylamino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 8.8 g potassium carbonate, 8.4 ml allyl bromide.
9.4 g of product, pale orange powder, mp 178-182°C, was obtained. Production Example 4A 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid [-lower alkyl= _CH3 ] 11.8 g of 7-chloro-6-fluoro- 1,4-
Dihydro-1-[(formyl)methylamino]-4
A mixture of ethyl -oxo-3-quinolinecarboxylate (Preparation Example 3A), 5.8 g of NaOH, and 300 ml of water was stirred in a steam bath for 2 hours. The reaction mixture was decolorized with activated charcoal, and the hot solution obtained above was acidified with 9.5 g of acetic acid. Stir at 0°C for 30 minutes, remove solid product,
Washed with water. The product was recrystallized from 150 ml of dimethylformamide to give 8.7 g of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-
4-oxo-3-quinolinecarboxylic acid, pale yellow crystals, mp 275-279°C (decomposed), was obtained. 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid was tested using the biological method described below and was found to have antibacterial activity. 1.0 and 1.95 for Escherichia coli, Klebsiella pneumoniae, and Myomorphic bacteria, respectively.
It was active in vitro with a minimum inhibitory concentration (MIC) of 1.0mig/ml. 50% of 56, 186mg/Kg respectively
It was active in vivo in mice against Escherichia coli and Klebsiella pneumoniae at protective doses. Production example 4B 7-chloro-1-ethylamino-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [;lower alkyl=C ₂ H ₅ ] 7-chloro-6-fluoro-1 - (formyl)
ethylamino]-1,4-dihydro-4-oxo-3-quinolinecarboxylate [Production Example 3B,
10g (0.029mol)] of absolute ethanol (260ml)
The solution was heated to reflux and a solution of 85% KOH [4.3 g (0.068 mol)] in water (14.4 ml) was added. Then about 100
ml of 95% ethanol was added, and the mixture was stirred and refluxed for 1 hour. After heating, the collected solid was washed with absolute ethanol and ether, and dried under vacuum at 70°C to give 5.4 g of 7-
Chloro-1-ethylamino-6-fluoro-1,
4-dihydro-4-oxo-3-quinolinecarboxylic acid was obtained in the form of K salt hemihydrate, mp 258°C (decomposition). 3.8g more from alcohol liquid, mp260
~262℃, was obtained. 7-Chloro-1-ethylamino-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is effective against Staphylococcus aureus (MIC=15.6mcg/
ml), Escherichia coli (MIC=19.5mcg/ml)), Klebsiella pneumoniae (MIC=3.9mcg/ml), Mycobacterium (MIC=
3.9mcg/ml), P. vulgaris (MIC=0.25mcg/
ml), P. aureginosa (MIC=31.3mcg/ml)),
It was discovered that it has antibacterial activity against Streptococcus nigra (MIC=31.3mcg/ml). Production Example 4C 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-propylamino-3-quinolinecarboxylic acid [;lower alkyl=(CH ₂ ) ₂ CH ₃ ] As described above in Production Example 4B. in ethanol solution by method
10.5 g of 7-chloro-6-fluoro-1-[(formyl)-propylamino]-1,4-dihydro-4
-Ethyl-oxo-3-quinolinecarboxylate (Preparation Example 3C), prepared from 4.4 g of 85% KOH. 5.7 g of product were obtained in the form of K salt hemihydrate, mp 267°C (decomposition). 7-Chloro-6-fluoro-1,4-dihydro-4-oxo-1-propylamino-3-quinolinecarboxylic acid can be used to treat Staphylococcus aureus (MIC=
15.6mcg/ml), Escherichia coli (MIC=15.6mcg/ml),
Klebsiella pneumoniae (MIC=31.3mcg/ml), M. vulgaris (MIC=3.9mcg/ml), Streptococcus pyogenes (MIC=
15.6 mcg/ml), was found to have in vitro antibacterial activity. Production example 4D 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-(2-propenylamino)-
3-quinolinecarboxylic acid [;R'=H, R゜=
HNCH ₂ CH=CH ₂ ] In Production Example 4A, 8.4 g of 7-chloro-
6-Fluoro-1-[formyl-(2-propenyl)amino]-1,4-dihydro-4-oxo-
Ethyl 3-quinolinecarboxylate (Production Example 3E), 5.5
It was prepared from g of NaOH. 6.96 g of product was obtained in the form of a hydrate (4:1), mp 240-242°C. Production Example 5 Ethyl 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylate [;R゜= _CH3NH ,R'=
C ₂ H ₅ ] 148 g of 7-chloro-6-fluoro-1,4-
Dihydro-1-[(formyl)methylamino]-4
-Ethyl oxo-3-quinolinecarboxylate, 70g
A mixture of 3 parts NaOH and 3 parts water was stirred at 60°C for 3.5 hours. At this point the reaction mixture contained a significant amount of insoluble material and was removed to yield 23 g of solid. This was slurried in 2.5 ml of boiling ethanol and passed through a steam funnel. 12.4 after cooling the liquid
g of ethyl 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylate, mp 202-207°C.
Tan leather powder recrystallized from ethanol, mp206
Samples were obtained at ~209°C. This ethyl ester was transesterified with methanol to obtain the corresponding methyl ester (:R゜=CH ₂ NH,
R′=CH ₃ ), mp 228-232°C was obtained. Production Example 6 7-chloro-1-dimethylamino-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [;R ⁰ =(CH ₃ ) ₂ N,R′=H] 5 g 7-chloro-1-dimethylamino-6-
A mixture of ethyl fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylate (Production Example 5) and 50 ml of dimethyl sulfate was added.
The mixture was stirred at 100°C for about 16 hours. Leave it at room temperature for 2 days,
It was then poured into 500 ml of ice-water containing approximately 75 g of KOH. After stirring for 1 hour, the solid product was removed, slurried with tetrahydrofuran, recollected, and dried to give 1.3 g of product, mp 243-248°C.
It consisted of the mixed ethyl-methyl ester of 7-chloro-1-dimethylamino-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. 0.5g part of this mixed ester
The mixture was added to 13 ml of water containing 0.128 g of NaOH and stirred in a steam bath for 2 hours. After heating, the mixture was made acidic with hydrochloric acid. The separated solid product was collected, washed with water, and dried under vacuum to yield 0.22 g of 7-chloro-1-dimethylamino-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 255-256 ℃ was obtained. Example 1 6-fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)
-4-oxo-3-quinolinecarboxylic acid [IA; R= _CH3NH , R'=H, R''= _CH3 ] 5.0 g (0.0185 mol) of 7-chloro-6-fluoro-1,4-dihydro -1-methylamino-4
-Oxo-3-quinolinecarboxylic acid (manufacturing example
A mixture of 4A), 7.4 g (0.0739 mol) N-methylpiperazine, and 30 ml pyridine was refluxed under N for 15 hours. It was then cooled and the solid was collected and washed with ether. 4.3 g of the product thus obtained was added to 125
ml of boiling dimethylformamide,
Washed with dimethylformamide and ether and dried under high vacuum at 70°C for 1 day to obtain 4.0 g of 6-fluoro-1,
4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)-4-exo-3-quinolinecarboxylic acid, colorless powder, mp299-301℃
(decomposition), was obtained. 6-fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1
-piperazinyl)-4-oxo-3-quinolinecarboxylic acid was converted into the monohydrochloride salt, mp>300°C, by boiling with an equimolar amount of hydrochloric acid. 6-Fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)-
4-Oxo-3-quinolinecarboxylic acid is treated with a slightly excess amount of methanesulfonic acid aqueous solution, and when the dissolution is complete, acetone is added to precipitate it, thereby converting it into methanesulfonate, mp287-289℃ (decomposition). Ta. This salt was recrystallized from aqueous acetonitrile. 6-Fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)-
4-Oxo-3-quinolinecarboxylic acid was converted to the fumarate salt, mp 253-254°C (decomposition), by heating with equimolar amounts of fumaric acid in an aqueous medium. 6-Fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)-
4-oxo-3-quinolinecarboxylic acid was prepared in an equimolar amount containing some ethanol to aid in dissolution.
It was converted into a Na salt hydrate, mp256°C (decomposed), by treatment with an aqueous NaOH solution. The product obtained by solvent evaporation was crystallized from aqueous acetone. 6-Fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)-
4-oxo-3-quinolinecarboxylic acid, its
An aqueous solution of Na salt was treated with twice the molar amount of H ₂ O ₂ and 45
4′-oxide, mp2.31 by stirring for 20 hours at °C.
℃ (decomposition), changed to The solution was treated with 50 mg of Pd/c catalyst to remove excess H ₂ O ₂ and then acidified to obtain the oxidized product. 4′-oxide was found to be effective against Escherichia coli (MIC=16mcg/ml) and Klebsiella pneumoniae (MIC=32mcg/ml).
ml), was found to have in vitro antibacterial activity against Mycobacteria (MIC = 32 mcg/ml). Example 1A The preparation of the compound of Example 1 was carried out on a large scale as follows. 52 g (0.192 mol) of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-
Oxo-3-quinolinecarboxylic acid, 53ml (0.478
A mixture of 260 ml of N-methylpiperazine and 260 ml of pyridine was heated under reflux for about 16 hours. Then N-
Additional methylpiperazine (10ml) was added and reflux continued for 6 hours. Upon cooling, the solid product was removed and washed with cold pyridine and ether to yield 46 g of material. This was combined with the product from another experiment using 5 g of 7-chloro compound, recrystallized from dimethylformamide, washed with cold dimethylformamide and ether, dried under vacuum at 80°C, and 48.5 g of 6-chloro Fluoro-1,4-dihydro-1-methylamino-7-
(4-methyl-1-piperazinyl)-4-oxo-
3-quinolinecarboxylic acid, mp>300°C, was obtained. Example 1B The compound of Example 1 was prepared on a larger scale as follows. 970 g of 7-chloro-6-fluoro-1,4-
dihydro-1-methylamino-4-oxo-3-
A mixture of quinoline carboxylic acid, 1600 ml of N-methylpiperazine, and 8 parts of 2-methoxyethanol was heated under reflux (approximately 127°C) for 3 hours. After 20 hours at reflux, it was cooled to 10°C and filtered. The mass was washed with cold methoxyethanol followed by methanol. The product was dried at 40°C to give 925g of 6
-Fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)-4-
Oxo-3-quinolinecarboxylic acid was obtained which was purified in the form of the methanesulfonate salt. Example 2 6-fluoro-1,4-dihydro-1-methylamino-4-oxo-7-(1-piperazinyl)
-3-quinolinecarboxylic acid [IA; R= _CH3NH , R'=H, R''=H] 20.3 g of 7-chloro-6-fluoro-1,4-dihydro-1- methylamino-
4-oxo-1-methylamino-4-oxo-3
- Prepared using quinoline carboxylic acid (Preparation Example 4A) and 64.5 g of piperazine in 850 ml of pyridine.
17.9 g of product was obtained after recrystallization from a pale yellow solid dimethylformamide, mp 288-290°C (decomposition). The above compound [IA; R=CH ₃ NH, R′=R″=H]
A sample of 4-methylbenzenesulfonic acid was treated with an aqueous solution of p-methylbenzenesulfonic acid to produce 4-methylbenzenesulfonate.
Obtained as straw colored crystals with mp 278-280°C (after recrystallization from water). Example 3 1-ethylamino-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)
-4-Oxo-3-quinolinecarboxylic acid [IA; R= _C2H5NH , R'=H, _R ''= _CH3 ] 4.7 g in 18.5 ml of pyridine by the method of Example 1
of 7-chloro-1-ethylamino-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Preparation Example 4B) and 7.3 ml of N-methylpiperazine. 3.7g product, mp255
~256℃, was obtained. Example 4 6-fluoro-1,4-dihydro-7-(4-
Methyl-1-piperazinyl)-4-oxo-1
-Propylamino-3-quinolinecarboxylic acid [IA; R=CH ₃ (CH ₂ ) ₂ NH, R′=H, R″=CH ₃ ] 5 g of 7 in 19 ml of pyridine according to the method of Example 1.
-chloro-6-fluoro-1,4-dihydro-4
-oxo, 1-propylamino-3-quinolinecarboxylic acid (Preparation Example 4C) and 7.4 ml of N-methylpiperazine. 3.7g product, mp210~
212℃ was obtained. Example 5 7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid [IA; R= _CH3NH ,R' =H, R″=C ₂ H ₅ ] 3.5 g in 14.4 ml of pyridine according to the method of Example 1
7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation Example 4A) and 5.9 g of N-ethylpiperazine. 2.5 g of product was obtained as a pale yellow powder, mp 260°C. Example 6 6-Fluoro-1,4-dihydro-1-methylamino-7-[4-(1-methylethyl)-1-
Piperazinyl]-4-oxo-3-quinolinecarboxylic acid [IA; R=CH ₃ NH, R′=H, R″=
(CH ₃ ) ₂ CH] 5 g of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4 was prepared using the method of Example 1, but using (diisopropyl)ethylamine (70 ml) instead of pyridine. -Oxo-3-quinolinecarboxylic acid (Preparation Example 4A) and 14.6 g of N-isopropylpiperazine dihydrochloride.
2.4 g of product as a grayish tan solid;
Obtained as mp245-250℃. Example 7 6-fluoro-1,4-dihydro-1-methylamino-4-oxo-7-(4-propyl-1
-piperazinyl)-3-quinolinecarboxylic acid [IA; R=CH ₃ NH, R′=H, R″=
CH ₃ CH ₂ CH ₂ ] 5 g of 7-chloro-6-fluoro-1,4-dihydro-
It was prepared from 1-methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation Example 4A) and 21.5 g of N-propylpiperazine dihydrobromide. 4.8
g of product, mp 272-277°C, was obtained. Example 8 7-(4-acetyl-1-piperazinyl)-6-
Fluoro-1,4-dihydro-1-methylamino-4-oxo- ₃ -quinolinecarboxylic acid [I; R=CH3NH, R'=H, Z=N=4-acetyl-1-piperazinyl] Example 4.3 g of 7-chloro-6-fluoro-1,4-dihydro- in 35 ml of pyridine according to method 1.
Prepared from 1-methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation Example 4A) and 6.5 g of N-acetylpiperazine. 3g product, mp295~
300℃ was obtained. Example 9 6-fluoro-1,4-dihydro-1-methylamino-4-oxo-7-(1-piperidinyl)
-3-quinolinecarboxylic acid [I; R=
CH ₃ NH, R' = H, Z = N = 1-piperidinyl] 4.8 g of 7 in 50 ml of pidine according to the method of Example 1.
-chloro-6-fluoro-1,4-dihydro-1
-Methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation Example 4A) and 14.8 mg of piperidine. 1.7 g of product, mp 208-211 DEG C., was obtained after recrystallization from dimethylformamide. Example 10 6-fluoro-7-(hexahydro-1H-1,
4-diazapin-1-yl)-1,4-dihydro-1-methylamino-4-oxo- ₃ -quinolinecarboxylic acid [I; R=CH3NH, R″=H,
Z=N=hexahydro-1H-1,4-diazapin-1-yl] 6 g of 7-chloro-6-fluoro-1,4-dihydro- in 240 ml of pyridine as in Example 1.
1-Methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation Example 4A) and 22 g of hexahydro-
1,4-diazepine was produced. 1.3 g of product were obtained in the form of the hydrochloride salt as a yellow powder, mp 305°C (decomposition). Example 11 6-fluoro-7(hexahydro-4-methyl-1H-1,4-diazapin-1-yl)-1,
4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid [I; R=
CH ₃ NH, R′=H, Z=N=hexahydro-4
-Methyl-1H-1,4-diazapin-1-yl] 5 g of 7 in 30 ml of pyridine according to the method of Example 1.
-chloro-6-fluoro-1,4-dihydro-1
-Methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation Example 4A) and 8.3 g of hexahydro-4
-Methyl-1,4-diazapine.
1.7 g of product were obtained in the form of the hydrochloride salt, hemihydrate, as a pale yellow powder, mp 288°C. The in vitro antibacterial activity of the compounds of the invention was determined by the conventional serial dilution method. Cultures were grown overnight at 37°C in tryptose phosphate broth or brain heart infusion broth (heat-inactivated normal horse serum was included for testing with S. pyogenes) and then diluted to 2 medium concentrations. diluted in broth to approximately 2×10 ⁵ pieces/ml
Bacteria for inoculation were prepared. Aqueous solutions of compounds of the invention were prepared by dissolving the free acid form in 0.5N NaOH. These were diluted with sterile distilled water to prepare a compound having a concentration of 1000 mcg/ml in terms of free acid. Prepare serial 2-fold dilutions of these compound stock solutions with water,
0.5 ml of each dilution was transferred to several sets of tubes (one set for each inoculum). Each tube was then contacted with 0.5 ml of the appropriate culture to give a final bacterial concentration of approximately 1 x 10 ⁵ cells/ml. Minimum inhibitory concentration (MIC), defined as the lowest concentration of a test compound that inhibits macroscopic bacterial growth, at 18 to 18 °C at 37 °C.
Recordings were made after 20 hours of static culture. The results are shown in the table.

Table: The in vivo antibacterial activity of the compounds of the invention was determined in female mice weighing 18-20 g each by the following method. An aqueous solution of the test compound is diluted with its free acid form.
It was prepared by dissolving in NaOH and diluting the resulting solution with distilled water to the desired volume. E. coli Voge ^1x culture prepared in brain heart infusion broth, K. hepatitis 39645 culture grown in tryptose phosphate broth using 5% rabbit serum diluted in the same broth, brain heart infusion - on agar. A culture of Pseudomonas aureginosa MGH-2 grown and suspended in physiological saline was used to infect mice as follows. E. coli and P. aureginosa: mice were given 0.5 ml of test bacteria (1.87 x 10 ⁷ and 5 x 10 ⁶ cells/respectively).
ml) was inoculated intraperitoneally. Klebsiella hepatitis: Mice were inoculated intramuscularly in the right hind leg with 0.2 ml of test bacteria (2.05 x ¹⁰⁴ cells/ml). Mice infected with E. coli were dosed with 0.5 ml 0.5 h after infection. Test compound subcutaneously (sc)
Orally (po). Mortality was recorded every 7 days. K. hepatitis infected mice were dosed at the following time points: 17 hours and 1 hour before infection, 6 hours after infection, and then twice a day for 3 days. Test compound subcutaneously (0.2ml) and orally (0.5ml)
It was administered at Mortality was recorded every 14 days. P. aureginosa-infected mice infected with 0.5, 4,
Dosing was administered 7 hours later. Test compounds were administered subcutaneously (0.2
ml) or orally (0.5 ml). Mortality was recorded every 7 days. Each group of 10 animals was treated as described above at 4-5 doses and the number of survivors in each group was recorded. The 50% protective dose ( _PD50 ) was then calculated. The results obtained are shown in the table.

Table: Active in vitro, but relatively ineffective in vivo, the compounds of the present invention can be used topically to disinfect inanimate objects. 6-fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-
20 mg of methanesulfonate (1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (herein referred to as the compound of the present invention) was orally administered to female rats, and its urinary excretion was investigated. For comparison, 1-ethyl-6-fluoro-7-(1-
piperazinyl)-4-oxo-1,4-dihydroquinolinecarboxylic acid (referred to herein as Control 1) and 1-ethyl-6- Fluoro-7-(4-methyl-1-piperazinyl)-4
-Oxo-1,4-dihydro-quinoline-3-carboxylic acid (herein referred to as Control 2) was used.
The results are shown in the attached Figures 1 to 3. FIG. 1 is a graph showing the urinary concentration (mcg/ml) of the drug at a certain time after oral administration of 20 mg/Kg of the drug to female rats. This graph shows that the urinary concentration of the compound of the present invention is significantly higher than that of Controls 1 and 2. Figure 2 shows the total excretion amount (mg) of the drug up to a certain time after oral administration of 20 mg/Kg of the drug to female rats.
This is a graph showing. From this graph, the excretion amount of the compound of the present invention is compared with that of Controls 1 and 2.
It can be seen that the value is significantly higher. Figure 3 is a graph showing urinary antibacterial activity in rats, and a graph showing maximum inhibitory dilution curves (logarithmic scale) for five bacterial strains 4 to 8 hours after oral administration of 20 mg/Kg of drug to rats. . From this graph, it can be seen that the antibacterial activity of the compounds of the present invention is different from that of controls 1 and 2.
It can be seen that this is significantly higher than that of These results suggest that the compound of the present invention is well absorbed and has a high urinary excretion amount and urinary antibacterial activity when administered orally to rats, and that the compound of the present invention is useful as an antibacterial agent. The compounds of the present invention can be prepared and used by conventional pharmaceutical methods. that is, by dissolving or suspending them in a pharmaceutically acceptable vehicle such as water, aqueous alcohol, glycol, oil solution or oil-water emulsion (for parenteral or oral administration), or by encapsulating them in capsules for oral administration. or alone as a tablet or with the usual adjuvants or excipients such as Ca carbonate, starch, lactose, talc, Mg stearate,
acacia gum, etc., in a unit dosage form.

[Brief explanation of drawings]

FIG. 1 is a graph showing the urinary concentration of a drug at a certain time after drug administration. FIG. 2 is a graph showing the total amount of drug excreted up to a certain time after drug administration. FIG. 3 is a graph showing urine antibacterial activity.

Claims (1)

[Scope of Claims] A compound of the primary formula, a pharmaceutically acceptable acid addition salt thereof, or an alkali metal salt thereof, or an amino acid thereof. (wherein R is lower alkylamino,
R′ is hydrogen, Z=N is a heterocyclic group; (In the formula, n is 2 to 3, and R'' is hydrogen, lower alkyl, or acetyl)] Claim 1, wherein R'' is hydrogen or lower alkyl in the secondary formula A compound. 3 6-Fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)
The compound according to claim 2, which is -4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof. 4 6-Fluoro-1,4-dihydro-1-methylamino-4-oxo-7-(1-piperazinyl)
The compound according to claim 2, which is -3-quinolinecarboxylic acid. 5 1-ethylamino-6-fluoro-1,4-
Dihydro-7-(4-methyl-1-piperazinyl)
-4-oxo-3-quinolinecarboxylic acid,
A compound according to claim 2. 6 6-fluoro1,4-dihydro-7-(4
-methyl-1-piperazinyl)-4-oxo-1
-Propylamino-3-quinolinecarboxylic acid, the compound according to claim 2. 7 7-(4-ethyl-1-piperazinyl)-6-
fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid,
A compound according to claim 2. 8 6-fluoro1,4-dihydro-1-methylamino-7-[4-(1-methylethyl)-1-
The compound according to claim 2, which is piperazinyl]-4-oxo-3-quinolinecarboxylic acid. 9 6-Fluoro-1,4-dihydro-1-methylamino-4-oxo-7-(4-propyl-1
-Piperazinyl)-3-quinolinecarboxylic acid. 10 7-(4-acetyl-1-piperazinyl)-
The compound according to claim 1, which is 6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid. 11 6-fluoro7-(hexahydro-1H-
The compound according to claim 1, which is 1,4-diazapin-1-yl)-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid. 12 6-fluoro7-(hexahydro-4-
Methyl-1H-1,4-diazapin-1-yl)-
The compound according to claim 1, which is 1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid. 13 Formula: [wherein R is lower alkylamino,
R′ is hydrogen, Z=N is a heterocyclic group; (wherein n is 2 to 3 and R'' is hydrogen, lower alkyl or acetyl), a method for producing a compound of the formula: (wherein R゜ is lower alkylamino) is reacted with the corresponding compound of Z=NH (Z=N- is as defined above) and, if desired, the resulting free base can be reacted with The method for producing the above-mentioned method comprises converting the resulting compound in which R' is hydrogen into its pharmaceutically acceptable acid addition salt and, if desired, into its alkali metal salt or amine salt.