Quinolone carboxylic acid derivatives

Abstract

The present invention relates to the novel quinolone carboxylic acid derivatives of the following formula (I) and their pharmaceutically acceptable salts and their hydrates. ##STR1## wherein X is a hydrocarbon, fluorocarbon or nitrogen atom,Y is a hydrogen or methyl group,R.sup.1 is a hydrogen or alkyl group having 1 to 5 carbon atom,R.sup.2 is ##STR2## wherein A and B is a fluorocarbon or nitrogen atom, provided that, if A.dbd.CF, B.dbd.N and if A.dbd.N, B.dbd.CF) andR.sup.3 is ##STR3## (wherein R.sup.4 is an amino group which makes a racemate or (S)-enantiomer) or ##STR4## (wherein R.sup.5, R.sup.6 and R.sup.7 are respectively hydrogen or alkyl group having 1 to 3 carbon atom.).The compounds according to the present invention are used as antibacterial agents.

Description

BACKGROUND OF THE INVENTION

The present invention relates to the novel quinolone carboxylic acid derivatives, their esters, their pharmaceutically acceptable salts and their hydrates as shown in formula (I) and a process for preparing these compounds. Furthermore, some of the invented quinolone carboxylic acid derivatives as shown in formula (I) show broad spectrum and excellent pharmacokinetic properties and low toxicity. ##STR5## wherein X is a hydrocarbon, fluorocarbon or nitrogen atom,

Y is a hydrogen or methyl group, R.sup.1 is a hydrogen or C.sub.1 -C.sub.5 alkyl group, R.sup.2 is ##STR6## (wherein A and B are fluorocarbon or nitrogen atom, provided that if A.dbd.CF, B.dbd.N and if A.dbd.N, B.dbd.CF) R.sup.3 is ##STR7## (wherein R.sup.4 is an amino group to make a racemate or (S)-enantiomer.) or ##STR8## (wherein R.sup.5, R.sup.6 and R.sup.7 are H-- or C.sub.1 -C.sub.3 alkyl groups.)

In general, most of the quinolone-type antibiotics which have been heretofore developed are ones having small alkyl and cycloalkyl group at N-1 position [e.g. Norfloxacin: U.S. Pat. No. 4,146,719, Ciprofloxacin: [U.S. Pat. No. 4,620,007] and ones having aromatic group at N-1 position [e.g. Temafloxacin: J. Med. Chem., 34, 168 (1991), Tosufloxacin: U.S. Pat. No. 4,704,459].

However, a noticeable quinolone antibiotic having heteroaromatic group at N-1 position has not been yet developed. Otsuka, Toyama and others reported their researches upon introducing heteroaromatic group such as furyl, thienyl, thiazol, imidazol, pyridyl, pyrimidyl group at N-I position, but a compound available in vivo has not been yet developed. (JPK 61-251667-A, 62-174053-A, 02-85255-A).

In particular, the compounds developed up to now generally have good in vitro activity, but such in vitro activity could not leads to in vivo because of poor pharmacokinetics including half-life (t.sub.1/2), maximum blood level (C.sub.max), bioavilability (BA), area under curve (AUC) etc, which are important properties of a compound for good in vitro activity to be maintained in vivo.

Therefore, the object of this invention is to develope compounds having excellent pharmacokinetic properties by introducing fluoro pyridyl group which is a heteroaromatic group at N-1 position, thereby to produce compounds having good antibiotic power in vivo and long half-life (t.sub.1/2) which enable once a day of dose. Therefore, the present invention provides a series of compounds having even more excellent pharmacokinetic properties than those of the conventional quinolone antibiotics by introducing 5-fluoro-2-pyridyl group and 3-fluoro-4-pyridyl group into mother nuclei of quinolone and naphthyridine.

SUMMARY OF THE INVENTION

The present invention relates to novel quinolone carboxylic acid derivatives which have a fluoropyridine group at N-1 position.

The object of the present invention is to provide the novel quinolone carboxylic acids, their esters, their pharmaceutically acceptable salts, and their hydrates in which are some compounds having broad spectrums, excellent pharmacokinetic properties and low toxicity which are important factors for a drug to be administrated and function in the body, and a process for preparing these compounds.

Some of these quinolone derivatives have longer half-life (t.sub.1/2), even higher maximum blood level (C.sub.max) and bioavailability (BA) and even larger area under curve (AUC) compared to ciprofloxacin of the prior art. In addition, they have still far longer half-life (t.sub.1/2) and larger area under curve (AUC) compared to ofloxacin which is known to have excellent pharmacokinetics. Accordingly, some of the novel quinolone carboxylic acid derivatives of the present invention are expected to have highly increased in vivo activity.

DETAILED DESCRIPTION OF THE INVENTION ##STR9## wherein X is a hydrocarbon, fluorocarbon or nitrogen atom,

Y is a hydrogen or methyl group, R.sup.1 is a hydrogen or C.sub.1 -C.sub.5 group, R.sup.2 is ##STR10## wherein A and B are fluorocarbon or nitrogen atom, provided that if A.dbd.CF, B.dbd.N and if A.dbd.N, B.dbd.CF) R.sup.3 is ##STR11## (wherein R.sup.4 is an amino group to make a racemate or (S)-enantiomer.) or R.sup.3 is ##STR12## (wherein R.sup.5, R.sup.6 and R.sup.7 are H-- or C.sub.1 -C.sub.3 alkyl groups.)

The compound of the formula (I) can be prepared as follows. Each compound in the formula (I) is prepared by the substantially same method except the reaction temperature, irrespective of the kind of X, Y, Z in the compound of the formula (II). ##STR13## wherein X, Y, Z, R.sup.1, R.sup.2 and R.sup.3 are each as described above.

The above reaction is carried out in a solvent selected from the alcohols such as methanol, ethanol, the ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, aromatic hydrocarbons such as benzene, toluene, xylene, and the inert solvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, pyridine etc., at 0 .degree. C. to 150 .degree. C. temperature for 5 minutes to 48 hours. In addition, the above reaction is generally carried out in the presence of an acid-acceptor, the desirable amount of which is 1 to 3 equivalent of the compound (II). Alternatively, an excess of the compound (VI) may be used as an acid-acceptor. As an acid-acceptor, a tertiary amine such as pyridine, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, or an alkali metal carbonate such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate may be used.

In order to prepare the compound of the formula (I) wherein R.sup.1 is a hydrogen, the compound of the formula (II") (wherein R.sup.1 is a hydrogen) and HR.sup.3 of the formula (VI) (wherein R.sup.3 is the same as described above) can be reacted; or otherwise the compound of the formula (II') (wherein R.sup.1 is an alkyl group) and HR.sup.3 of the formula (VI) (wherein R.sup.3 is the same as described above) can be reacted first and then hydrolysis using an acid or alkali can be carried out. At this time, in the acidic hydrolysis may be used an acid such as hydrochloric acid and sulfuric acid and in the alkaline hydrolysis may be used an alkali such as sodium hydroxide and potassium hydroxide. The acid or alkali may be used in the hydrolysis as a solution in water or water-containing ethanol or methanol.

The compound of the formula (II) can be prepared as follows. (II=II'+II") ##STR14## wherein X, Y, Z, R.sup.1 and R.sup.2 are each as defined above.

The compound of the formula (III) is prepared by the conventional method [Ger. Offen. DE 3,142,854; Ger. Offen. DE 3,318,145; J. Med. Chem., 29, 2363(1986)] and thereby obtained compound of the formula (III) is reacted with the compound of the formula (IV) prepared by the conventional method [Rocz. chem., 777-783(1964); Synthesis, 12, 905-908(1989)] in an alcohol solvent such as methanol and ethanol, or a haloformic solvent such as dichloromethane and chloroform at -10.degree. C.-30.degree. C. to obtain the compound of the formula (V) . The obtained compound of the formula (V) is subjected to a ring-closing reaction using potassium carbonate and 18-crown-6 in acetonitrile, or a ring-closing reaction using sodium hydride in N,N-dimethyl formamide, to obtain the compound of the formula (II'). At this time the reaction temperature is desirably from 0.degree. C. to the reflux temperature. The compound of the formula (II') is hydrolyzed by treatment with an acid or alkali to obtain the compound of the formula (II' ) and the compounds of the formula (II') and (II") are designated totally as the formula (II). At this time, in the acidic hydrolysis may be used an acid such as hydrochloric acid or sulfuric acid, and in the alkaline hydrolysis may he used an alkali such as sodium hydroxide or potassium hydroxide. The acid or alkali may he used in the hydrolysis as a solution in water or water-containing ethanol or methanol.

Representative examples of the novel quinolone carboxylic acid derivatives according to the present invention are as follows;

1. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 3. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 4. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 6. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 8. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-naphthyridine-3-carboxylic acid 9. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 10. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 11. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 12. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 13. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 14. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 15. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 16. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 17. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 18. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 19. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 20. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 21. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 22. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 23. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 24. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 25. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 26. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 27. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 28. 5-methyl-7-(4-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 29. 5-methyl-7-(3-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Meanwhile, the novel quinolone carboxylic acid derivatives according to this invention may be used as free compounds, acid addition salts thereof or salts of the carboxyl groups thereof. The suitable acids for salt formation include inorganic acids such as hydrochloric acid, phosphoric acid and organic acids such as acetic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid.

Pharmaceutically acceptable base salts of the above described compounds of the formula (I) are formed with alkali metals such as sodium, potassium or alkaline earth metals such as magnesium, calcium. The free compounds of the present invention, their acid addition salts and their salts of the carboxyl groups of pyridone carboxylic acid derivatives may exist as hydrates.

The following examples are provided to illustrate the desirable preparation of the compounds of the present invention.

Preparation 1

Preparation of ethyl 3-(3-fluoro-4-pyridyl)amino-2-(2,4,5-trifluorobenzoyl)acrylate

2.5 g of ethyl 2,4,5-trifluorobenzoyl acetate, 2.55 ml of triethyl o-formate, 12 ml of acetic anhydride are mixed together and refluxed for 3 to 5 hours, cooled to room temperature, and distilled under a reduced pressure. The obtained product is dissolved in 50 ml of anhydrous dichloromethane and added with 1.26 g of 4-amino-3-fluoropyridine and stirred at room temperature for 5 hours, and then concentrated under a reduced pressure. The product is used in the next reaction without further purification.

Preparation 2

Preparation of ethyl 3-(3-fluoro-4-pyridyl)amino-2-(2,6-dichloro-5-fluoronicotinyl) acrylate

A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.

Preparation 3

Preparation of ethyl 3-(5-fluoro-2-pyridyl)amino-2-(2,6-dichloro-5-fluoronicotinyl) acrylate

A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.

Preparation 4

Preparation of ethyl 3-(5-fluoro-2-pyridyl)amino-2-(2,3,4,5-tetrafluorobenzoyl) acrylate

A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.

Preparation 5

Preparation of ethyl 3-(5-fluoro-2-pyridyl)amino-2-(2,4,5-trifluorobenzoyl)acrylate

A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.

Preparation 6

Preparation of ethyl 3-(5-fluoro-2-pyridyl)amino-2-(3-methyl-2,4,5-trifluorobenzoyl)acrylate

A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.

Preparation 7

Preparation of ethyl 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

2.0 g of ethyl 3-(3-fluoro-4-pyridyl)amino-2-(2,4,5-trifluorobenzoyl)acrylate, 1.50 g of potassium carbonate and 0.43 g of 18-crown-6 are mixed with 40 ml of anhydrous acetonitrile.

The mixture is refluxed for 3 hours and then cooled, added with 100 ml of water and stirred during 30 minutes, then filtered and dried to obtain 1.3 g of the desired compound.

m.p.: 212.degree. C.

.sup.1 H-NMR (CDCl.sub.3, ppm): 1.26 (t,3H, J=7.20 Hz), 4.40(q, 2H, J=7.20 Hz), 6.50-6.80 (m, 1H), 7.40-7.60(m, 1H), 8.22-8.42(m, 2H), 8.68-8.96(m, 2H)

Preparation 8

Preparation of ethyl 1-(3-fluoro-4-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate

A procedure substantially similar to the procedure in Preparation 7 is carried out to prepare the title compound.

m.p.: 226.degree. C.

.sup.1 H-NMR (CDCl.sub.3, ppm): 1.42(t, 3H, J=7.20 Hz), 4.42(q, 2H, J=7.20 Hz), 7.46-7.50(m, 1H), 8.48-8.54(m, 2H), 8.70-8.82(m, 2H)

Preparation 9

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate

A procedure substantially similar to the procedure in Preparation 7 is carried out to prepare the title compound.

m.p.: 230.degree. C.

.sup.1 H-NMR (CDCl.sub.3, ppm): 1.36 (t, 3H, J=7.20 Hz), 4.38(q, 2H, J=7.20 Hz), 7.60-7.80(m, 2H), 8.36-8.54(m,2H), 8.94(s, 1H)

Preparation 10

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 7 is carried out to prepare the title compound.

m.p.: 210.degree.-213.degree. C.

.sup.1 H-NMR (CDCl.sub.3, ppm): 1.50(t, 3H, J=8.00 Hz), 4.70(q, 2H, J=8.00 Hz), 7.42(dd, 1H, J=3.04 Hz, J=10.04 Hz), 7.92-8.19(m, 2H), 8.50-8.79(m, 2H), 9.45(s, 1H)

Preparation 11

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,7,8-trifluoro-1,4-dihydro-4oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 7 is carried out to prepare the title compound.

m.p.: 203.degree.-205.degree. C.

.sup.1 H-NMR (CDCl.sub.3, ppm): 1.32(t, 3H, J=7.20 Hz), 4.32(q, 2H, J=7.20 Hz), 7.36-7.72(m, 2), 8.00-8.22(m, 1H), 8.30-8.50(m, 2H)

Preparation 12

Preparation of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

5 g of ethyl 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate is added with 20 ml of water, 30 ml of ethanol and 15 ml of conc. hydrochloric acid and refluxed for 8 hours. After cooling to room temperature and standing for 2 hours, filtering and drying are carried out to obtain 4.2 g of the desired compound.

m.p.: 271.degree.-273.degree. C.

.sup.1 H-NMR (CF.sub.3 COOD, ppm): 7.28-7.58(m, 1H), 8.26-8.88(m, 2H), 9.22-9.62(m, 3H)

Preparation 13

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

A procedure substantially similar to the procedure in Preparation 12 is carried out to prepare the title compound.

m.p.: 228.degree.-230.degree. C.

.sup.1 H NMR (CDCl.sub.3, ppm): 8.50-8.74(m, 2H), 9.16-9.42(m, 3H)

Preparation 14

Preparation of 1-(5-fluoro-2-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

A procedure substantially similar to the procedure in Preparation 12 is carried out to prepare the title compound.

m.p.: 275.degree.-280.degree. C.

.sup.1 H NMR (CF.sub.3 COOD, ppm): 7.40(dd, 1H, J=3.02 Hz, J=10.06 Hz), 7.92-8.18(m, 2H), 8.39-8.78(m, 2H), 9.50(s, 1H)

Preparation 15

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

A procedure substantially similar to the procedure in Preparation 12 is carried out to prepare the title compound.

m.p.: 234.degree.-238.degree. C.

.sup.1 H NMR (CDCl.sub.3, ppm): 8.58-8.84(m, 2H), 9.18-9.42(m, 3H)

Preparation 16

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 0.5 g of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 0.35 g of piperazine are added to 45 ml of pyridine.

The mixture is stirred at 10.degree. C. for 1 hour and then concentrated under a reduced pressure and subjected to a column chromatography (acetone/n-hexane=5/2) to obtain 0.47 g of the desired compound, which is then subjected to the next reaction to identify its structure. (next reaction: Example 12)

Preparation 17

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 85.0%

Preparation 18

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 91.5%

Preparation 19

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 84.1%

m.p.: 165.degree. C.

.sup.1 H NMR(CDCl.sub.3, ppm): 0.94(s, 3H), 1.00(s, 3H), 1.35(t, 3H, J=6.40 Hz), 2,24-3.06(m, 4H), 4.00-4.42(m, 4H), 7.44-8.24(m, 3H), 8.38-8.52(m, 1H), 8.76(s, 1H)

Preparation 20

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 90.3%

m.p.: 200.degree.-202.degree. C.

.sup.1 H NMR (CDCl.sub.3, ppm): 1.30(t, 3H, J=6.40 Hz), 1.90-2.16(m, 5H), 3.40-3.94(m, 4H), 4.28(q, 2H, J=6.4 Hz), 4.76(m, 1H), 7.44-8.06(m, 3H), 8.32-8.46(m, 1H), 8.68(s, 1H)

Preparation 21

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 90.3%

Preparation 22

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 91.3%

Preparation 23

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 87.5%

Preparation 24

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 89.3%

Preparation 25

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 90.3%

Preparation 26

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 84.5%

Preparation 27

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 88.7%

Preparation 28

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 83.7%

Preparation 29

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 88.7%

Preparation 30

Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 92.7%

Preparation 31

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

0.22 g of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3carboxylic acid and 0.11 g of 3-acetamidopyrrolidine are added to 12 ml of pyridine, and added with 0.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is stirred at room temperature for 24 hours, and then concentrated under a reduced pressure to remove the solvent completely. The residue is added with 20 ml of acetone and stirred at room temperature for 1 hour to obtain a product, which is then filtered and dried and used in the next reaction. (next reaction: Example 5)

Preparation 32

Preparation of ethyl 5-methyl-7-(4-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 82.5%

Preparation 33

Preparation of ethyl 5-methyl-7-(3-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.

Yield: 85.0%

EXAMPLE 1

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride 0.66 g of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.22 mg of piperazine are added to 30 ml of pyridine. The mixture is added with 0.39 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, stirred at room temperature for 24 hours and concentrated under a reduced pressure. The concentrate is subjected to a column chromatography (chloroform/methanol/ammonia water:15/12/1) to seperate the desired product, which is then concentrated under a reduced pressure. After then, the residue is added with 15 ml of ethanol, 10 ml of water and 5 ml of conc. hydrochloric acid and stirred at room temperature for 3 hours, filtered and dried. The obtained product is recrystallized in a mixed solvent of methanol or ethanol and water to obtain 0.47 g of the desired compound.

m.p.: 284.degree.-286.degree. C. (dec.)

.sup.1 H NMR (CF.sub.3 COOD, ppm): 3.26-4.24(m, 8H), 6.84(d, 1H, J=4.82 Hz), 8.38(d, 1H, J=12.82 Hz), 8.70-9.02(m, 1H), 9.20-9.62(m, 3H)

EXAMPLE 2

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 274.degree.-276.degree. C. (dec.)

.sup.1 H NMR (CF.sub.3 COOD, ppm): 3.12(s, 3H), 3.28-4.32(m, 8H), 6.88(d, 1H, J=4.80 Hz), 8.38(d, 1H, J=12.80 Hz), 8.68-8.98(m, 1H), 9.20-9.60(m, 3H)

EXAMPLE 3

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 270.degree.-272.degree. C. (dec.)

.sup.1 H NMR (CF.sub.3 COOD, ppm): 1.52(d, 3H, J=5.62 Hz), 3.36-4.24(m, 7H), 6.86(d, 1H, J=4.80 Hz), 8.36(d, 1H, J=12.80 Hz), 8.70-8.92(m, 1H), 9.26-9.60(m, 3H)

EXAMPLE 4

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 285.degree.-287.degree. C. (dec.)

.sup.1 H NMR (CF.sub.3 COOD, ppm): 1.38-1.62(m, 6H), 3.20-4.28(m, 6H), 6.90(d, 1H, J=4.80 Hz), 8.38(d, 1H, J=12.80 Hz), 8.68-9.00(m, 1H), 9.20-9.56(m, 3H)

EXAMPLE 5

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

0.5 g of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-acetamido-1-pyrrolidyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is added to 15 ml of ethanol, 10 ml of water and 5 ml of conc. hydrochloric acid. The reaction mixture is refluxed for 18 hours, cooled and concentrated under a reduced pressure to remove the solvent completely.

The residue is recrystallized in a mixed solvent of ethanol and water to obtain 0.22 g of the desired compound.

m.p.: 274.degree.-276.degree. C. (dec.)

.sup.1 H NMR (CF.sub.3 COOD, ppm): 2.38-2.70(m,2H), 3.60-4.08(m, 2H), 4.10-4.52(m, 3H), 6.24(d, 1H, J=4.80 Hz), 8.22(d, 1H, J=12.82 Hz), 8.68-9.00(m, 1H), 9.16-9.60(m, 3H)

EXAMPLE 6

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 225.degree.-227.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 2.38-2.72(m, 2H), 3.60-3.98(m, 2H), 4.18-4.60(m, 3H), 6.26(d, 1H, J=4.80 Hz), 8.28(d, 1H, J=12.82 Hz), 8.58-8.84(m, 1H), 9.12-9.52(m, 3H)

EXAMPLE 7

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 273.degree.-275.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 3.42-4.60(m, 8H), 8.32(d, 1H, J=12.02 Hz), 8.60-8.86(m, 1H), 9.10-9.58(m, 3H)

EXAMPLE 8

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 275.degree. C.

.sup.1 H NMR(CF.sub.3 COOD, ppm): 3.10(s, 3H), 3.14-4.10(m, 6H), 4.26-4.92(m, 2H), 8.30(d, 1H, J=12.00 Hz), 8.60-8.88(m, 1H), 9.20-9.50(m, 3H)

EXAMPLE 9

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 277.degree.-279.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 1.32-1.68(m, 3H), 3.32-4.08(m, 5H), 4.34-4.84(m, 2H), 8.32(d, 1H, J=12.02 Hz), 8.60-8.90(m, 1H), 9.20-9.50(m, 3H)

EXAMPLE 10

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 270.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 1.30-1.60(m, 6H), 3.32-3.92(m, 4H), 4.44-4.92(m, 2H), 8.36(d, 1H, J=12.02 Hz), 8.62-8.90(m, 1H), 9.16-9.52(m, 3H)

EXAMPLE 11

Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 269.degree. C.

.sup.1 H NMR(CF.sub.3 COOD, ppm): 2.14-2.84(m, 2H), 3.56-4.64(m, 5H), 8.23(d, 1H, J=12.04 Hz), 8.62-8.96(m, 1H), 9.10-9.52(m, 3H)

EXAMPLE 12

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

0.5 g of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is added to 10 ml of water and 10 ml of conc. hydrochloric acid. The mixture is refluxed for 24 hours, cooled to room temperature and concentrated under a reduced pressure. The concentrate is added with 20 ml of ethanol and stirred at room temperature for 2 hours, filtered and dried. The product is recrystallized in a mixed solvent of water and methanol to obtain 0.39 g of the desired compound.

m.p.: >300.degree. C.

.sup.1 H NMR(CF.sub.3 COOD, ppm): 3.60-3.80(m, 4H), 4.14-4.46(m, 4H), 7.92-8.50(m, 3H), 8.70(bs, 1H), 9.40(s, 1H)

EXAMPLE 13

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 275.degree.-277.degree. C.

.sup.1 H NMR(CF.sub.3 COOD, ppm): 3.10(s, 3H), 3.60-5.00(m, 8H), 7.84-8.50(m, 3H), 8.68(bs, 1H), 9.38(s, 1)

EXAMPLE 14

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 268.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 1.40-1.80(m, 3H), 3.50-3.90(m, 5H), 4.58-4.80(m, 2H), 8.12-8.48(m, 3H), 8.74(bs, 1H), 9.40(s, 1H)

EXAMPLE 15

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 289.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 1.30-1.64(m, 6H), 3.28-4.00(m, 4H), 4.52-4.92(m, 2H), 7.96-8.48(m, 3H), 8.78(bs, 1H), 9.40(s, 1H)

EXAMPLE 16

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

0.5 g of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is added to 10 ml of water and

10 ml of conc. hydrochloric acid. The mixture is refluxed for 24 hours, cooled to room temperature and concentrated under a reduced pressure. The concentrate is added with 20 ml of ethanol and dissolved completely. After then, 70 ml of ethyl ether is added for precipitation, and then stirred at room temperature for 2 hours, filtered and dried. The product is recrystallized in a mixed solvent of methanol and water to obtain 0.35 g of the desired compound

m.p.: 208.degree.-210.degree. C.

.sup.1 H NMR(CF.sub.3 COOD, ppm): 2.30-2.80(m, 2H), 3.78-4.68(m, 5H), 7.96-8.32(m, 3H), 8.70(bs, 1H), 9.32(s, 1H)

EXAMPLE 17

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 300.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 3.51-4.05(m, 8H), 6.80(d, 1H,J=7.60 Hz), 7.84-8.21(m, 2H), 8.32(d, 1H, J=12.04 Hz), 8.70(bs, 1H), 9.30(s, 1H)

EXAMPLE 18

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: >300.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 3.12(s, 3H), 3.28-4.29(m, 5H), 6.81(d, 1H, J=7.60 Hz), 7.84-8.15(m, 2H), 8.33(d, 1H, J=12.20 Hz), 8.71 (bs, 1H), 9.29(s, 1H)

EXAMPLE 19

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 295.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 1.51(d, 3H, J=4.40 Hz), 3.23-4.11(m, 7H), 6.80(d, 1H, J=6.20 Hz), 7.96-8.16(m, 2H), 8.30(d, 1H, J=14.00 Hz), 8.69(s, 1H), 9.30(s, 1H)

EXAMPLE 20

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 297.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 1.30-1.65(m, 6H), 3.10-4.57(m, 6H), 6.89(d, 1H, J=6.20 Hz), 7.93-8.20(m, 2H), 8.70(d, 1H, J=12.82 Hz), 8.48(s, 1H), 9.32(s, 1H)

EXAMPLE 21

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 16 is carried out to prepare the title compound.

m.p.: 275.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 2.40-2.73(m, 2H), 3.60-4.56(m, 5H), 6.33(d, 1H, J=6.20 Hz), 7.98-8.37(m, 3H), 8.75(s, 1H), 9.24(s, 1H)

EXAMPLE 22

Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.

m.p.: 268.degree.-272.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 2.40-2.73(m, 2H), 3.60-4.56(m, 5H), 6.33(d, 1H, J=6.20 Hz), 7.98-8.37(m, 3H), 8.75(s, 1H), 9.24(s, 1H)

EXAMPLE 23

Preparation of 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 300.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 3.76-4.02(m, 5H), 8.00-8.48(m, 3H), 8.68(bs, 1H), 9.32(s, 1H)

EXAMPLE 24

Preparation of 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 247.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 3.10(s, 3H), 3.20-4.00(m, 5H), 7.98-8.38(m, 3H), 8.58(bs, 1H), 9.30(s, 1H)

EXAMPLE 25

Preparation of 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 295.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 1.45-1.60(d, 3H, J=3.20 Hz), 3.38-4.02(m, 7H), 7.92-8.50(m, 3H), 8.70(bs, 1H), 9.30(s, 1H)

EXAMPLE 26

Preparation of 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 297.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 1.32-1.60(m, 6H), 3.38-3.90(m, 6H), 7.96-8.41(m, 3H), 8.64(bs, 1H), 9.32(s, 1H)

EXAMPLE 27

Preparation of 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 16 is carried out to prepare the title compound.

m.p.: 275.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 2.40-2.60(m, 2H), 3.98-4.24(m, 5H), 8.08-8.38(m, 3H), 8.64(s, 1H), 9.24(s, 1H)

EXAMPLE 28

Preparation of 5-methyl-7-(4-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 262.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 2.99(s, 3H), 3.10(s, 3H), 3.15-4.20(m, 8H), 6.60(d, 1H, J=7.20 Hz), 8.02(m, 2H), 8.70(s, 1H), 9.24(s, 1H)

EXAMPLE 29

Preparation of 5-methyl-7-(3-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride

A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.

m.p.: 276.degree. C. (dec.)

.sup.1 H NMR(CF.sub.3 COOD, ppm): 1.60(d, 3H, J=6.00 Hz), 2.97(s, 3H), 3.15-4.21(m, 7H), 6.60(d, 1H, J=8.00 Hz), 8.40(m, 2H), 8.65(s, 1H), 9.25(s, 1H)

The in vitro antibiotic activity of the present compound is measured using 2-fold dilution method with a micro-well plate and the bacteria are inoculated in about 10.sup.5 cfu/ml after an overnight culture in a brain-heart infusion (BHI) broth at 37.degree. C. The novel compounds of the present invention are converted to a hydrochloride salt form and diluted with a sterilized distilled water to make 10 mg/ml aqueous solution. After the mother liquor wherein the compound is diluted to the two-fold concentration has been obtained in the form of an aqueous solution, the respective 0.1 ml of diluted liquor is transferred to a well and is inoculated with 0.1 ml of the culture fluid to make about (10.sup.5 -10.sup.6)/2 cfu/ml.

After cultivation at 37.degree. C., the minimum inhibitory concentration (MIC) is measured and recorded in Table I-V.

Table I-V show the minimum inhibitory concentrations (MIC).

TABLE I______________________________________Minimum Inhibitory Concentration (.mu.g/ml) ExampleStrains 1 2 3 4 5 6______________________________________A. calcoaceticus 0.625 0.625 0.625 2.50 0.313 0.156ATCC8090C. freundii 1.25 0.625 1.25 1.25 0.313 0.313ATCC8090E. aerogenes 1.25 1.25 1.25 1.25 0.156 0.313ATCC13048E. cloacae 0.625 0.625 0.625 0.625 0.313 0.156ATCC13048E. coli 1.25 1.25 0.625 1.25 0.156 0.078ATCC25922H. influenzae 0.625 0.625 1.25 1.25 0.313 0.313ATCC35056K. pneumoniae 0.625 0.625 0.625 0.625 0.156 0.156ATCC13883P. vulgaris 0.625 0.625 0.625 0.625 0.078 0.078ATCC13315P. aerugirnosa 0.625 0.625 0.625 0.625 0.313 0.156ATCC27853S. typhisurium 0.625 0.625 0.625 1.25 0.313 0.156ATCC14028S. flexneri 0.625 0.625 2.50 1.25 0.625 0.313ATCC12022S. sonnei 0.625 0.625 0.625 0.625 0.078 0.020ATCC25931S. marcescens 0.313 0.625 0.625 1.25 0.313 0.078ATCC8100S. faecalis 5 5 2.50 5 2.50 1.25ATCC19433S. faecalis 5 5 5 5 2.50 2.50ATCC29212S. pneuinoniae 2.50 10 5 10 2.50 2.50ATCC6303S. pyrogenes 5 10 10 10 5 2.50ATCC19615______________________________________ TABLE II______________________________________Minimum Inhibitory Concentration (.mu.g/ml) ExampleStrains 7 8 9 10 11 12______________________________________A. calcoaceticus 2.50 1.25 10 10 1.25 0.625ATCC8090C. freundii 1.25 1.25 1.25 1.25 0.156 1.25ATCC8090E. aerogenes 0.625 0.625 0.625 1.25 0.156 0.625ATCC13048E. cloacae 0.625 0.625 0.625 0.625 0.156 0.625ATCC13048E. coli 0.625 0.313 0.625 1.25 0.078 0.313ATCC25922H. influenzae 0.313 0.625 1.25 0.625 0.156 1.25ATCC35056K. pneumoniae 0.625 0.625 1.255 0.625 0.156 0.625ATCC13883P. vulgaris 0.313 0.313 0.625 0.625 0.313 0.625ATCC13315P. aerugirnosa 0.625 0.625 0.625 0.25 0.156 1.25ATCC27853S. typhisurium 0.313 0.313 0.625 0.625 0.156 1.25ATCC14028S. flexneri 0.156 0.313 0.625 0.625 0.156 0.625ATCC12022S. sonnei 0.313 0.625 0.625 0.625 0.010 0.313ATCC25931S. marcescens 1.25 0.625 1.25 2.50 0.156 1.25ATCC8100S. faecalis 2.50 5 2.50 2.50 0.625 5ATCC19433S. faecalis 5 5 2.50 5 0.625 5ATCC29212S. pneuinoniae 2.50 5 5 5 1.25 5ATCC6303S. pyrogenes 5 10 10 10 2.50 5ATCC19615______________________________________ TABLE IV______________________________________Minimum Inhibitory Concentration (.mu.g/ml) ExampleStrains 13 14 15 16 17 18______________________________________A. calcoaceticus 0.313 0.625 0.625 0.156 2.50 0.625ATCC8090C. freundii 0.156 0.625 0.313 0.078 1.25 0.625ATCC8090E. aerogenes 0.625 1.25 1.25 0.313 1.25 0.25ATCC13048E. cloacae 0.313 0.625 0.625 0.156 1.25 0.625ATCC13048E. coli 0.156 0.313 0.625 0.078 0.313 0.625ATCC25922H. influenzae 0.625 1.25 2.50 0.078 1.25 0.625ATCC35056K. pneumoniae 0.625 1.25 0.625 0.078 0.625 0.625ATCC13883P. vulgaris 0.625 0.625 1.25 0.078 0.625 0.313ATCC13315P. aerugirnosa 1.25 1.25 1.25 0.156 1.25 1.25ATCC27853S. typhisurium 0.313 1.25 1.25 0.313 1.25 1.25ATCC14028S. flexneri 0.156 0.156 0.313 0.039 0.625 0.625ATCC12022S. sonnei 0.156 0.078 0.078 0.020 0.625 0.625ATCC25931S. marcescens 0.313 0.313 1.25 0.078 2.50 1.25ATCC8100S. faecalis 5 5 5 1.25 5 5ATCC19433S. faecalis 5 2.50 5 0.625 2.50 2.50ATCC29212S. pneuinoniae 2.50 5 10 1.25 5 5ATCC6303S. pyrogenes 5 10 10 2.50 5 5ATCC19615______________________________________ TABLE IV______________________________________Minimum Inhibitory Concentration (.mu.g/ml) ExampleStrain 19 20 21 22 23 24______________________________________A. calcoaceticus 1.25 1.25 0.156 0.313 1.25 0.625ATCC8090C. freundii 1.25 0.625 0.078 0.039 0.625 0.625ATCC8090E. aerogenes 0.625 1.25 0.156 0.078 0.625 0.625ATCC13048E. cloacae 0.625 0.625 0.156 0.078 0.625 0.625ATCC13048E. coli 0.078 0.625 0.078 0.039 0.625 0.625ATCC25922H. influenzae 0.625 1.25 0.078 0.078 0.625 0.313ATCC35056K. pneumoniae 1.25 0.625 0.078 0.039 1.25 0.625ATCC13883P. vulgaris 0.156 0.625 0.078 0.078 0.313 0.625ATCC13315P. aerugirnosa 0.625 1.25 0.313 0.156 1.25 0.625ATCC27853S. typhisurium 0.313 1.25 0.156 0.078 0.313 0.313ATCC14028S. flexneri 0.313 0.625 0.078 0.156 0.313 0.625ATCC12022S. sonnei 0.313 0.313 0.020 0.039 0.078 0.156ATCC25931S. marcescens 0.625 0.625 0.078 0.078 0.625 0.625ATCC8100S. faecalis 5 5 1.25 0.625 5 5ATCC19433S. faecalis 5 2.50 1.25 1.25 5 2.50ATCC29212S. pneuinoniae 5 5 2.50 1.25 2.50 5ATCC6303S. pyrogenes 10 10 2.50 2.50 5 10ATCC19615______________________________________ TABLE V______________________________________Minimu Inhibitory Concentration (.mu.g/ml) ExampleStrain 25 26 27 28 29______________________________________A. calcoaceticus 1.25 1.25 0.313 1.25 0.625ATCC8090C. freundii 0.625 1.25 0.156 2.50 0.625ATCC8090E. aerogenes 0.625 0.625 0.156 0.625 0.313ATCC13048E. cloacae 0.625 1.25 0.313 0.625 0.313ATCC13048E. coli 0.625 0.625 0.078 1.25 1.25ATCC25922H. influenzae 0.625 1.25 0.078 0.313 0.625ATCC35056K. pneumoniae 0.625 0.625 0.156 1.25 1.25ATCC13883P. vulgaris 0.625 0.255 0.156 0.625 1.25ATCC13315P. aerugirnosa 0.313 0.625 0.313 1.25 1.25ATCC27853S. typhisurium 0.625 0.625 0.078 1.25 0.625ATCC14028S. flexneri 0.156 0.313 0.078 0.625 0.625ATCC12022S. sonnei 0.156 0.313 0.005 1.25 0.625ATCC25931S. marcescens 1.25 1.25 0.313 1.25 1.25ATCC8100S. faecalis 5 5 1.25 10 5ATCC19433S. faecalis 5 5 2.50 5 5ATCC29212S. pneuinoniae 5 5 2.50 10 10ATCC6303S. pyrogenes 10 10 2.50 10 10ATCC19615______________________________________

The following are the original names for strains in Table I-V.

Acinetobacter calcoaceticus ATCC 19606 Citrobacter freundii ATCC 8090 Enterobacter aerogenes ATCC 13048 Enterobacter cloacae ATCC 23355 Escherichia coli ATCC 25922 Haemophilus influenza ATCC 35056 Klebsiella pneumoniae ATCC 13883 Proteus vulgaris ATCC 13315 Pseudomonas aeruginosa ATCC 27853 Salmonella typhimurium ATCC 14028 Shigella flexneri ATCC 12022 Shigella sonnei ATCC 25931 Serratia marcescens ATCC 8100 Streptococcus faecalis ATCC 19433 Streptococcus faecalis ATCC 29212 Streptococcus pneumoniae ATCC 6303 Streptococcus pyrogens ATCC 19615

The pharmacokinetic properties are tested by orally administrating and subcutaneously injecting a test compound and a substance for control to a ICR Mouse with 22 g.+-.10% weight, drawing blood after 10, 20, 30, 45, 60, 90, 120, 150, 180 and minutes and analyzed by Bio-Assay (Agar well method).

The average values from four tests for each compound are recorded in the following Table VI.

TABLE VI__________________________________________________________________________ AUC Dose t.sub.1/2 C.sub.max T.sub.max (.mu.g .multidot. h/ Bioavail- UrineExample Route (mg/kg) (h) (.mu.g/ml) (h) ml) ability (%) Recovery (%)__________________________________________________________________________13 P.O 40 8.07 11.46 1.12 41.05 73.95 19.59 S.C 40 11.46 8.00 0.81 55.51 30.8214 P.O 40 3.81 2.12 0.87 12.46 44.00 58.89 S.C 40 7.28 4.28 0.60 28.07 21.1018 P.O 40 3.44 9.18 0.94 42.24 68.56 28.14 S.C 40 3.15 19.56 1.00 63.45 39.8519 P.O 40 8.42 3.11 0.87 16.92 72.74 29.00 S.C 40 5.32 5.11 0.87 23.26 48.6928 P.O 40 7.57 6.36 0.87 62.44 81.28 25.24 S.C 40 7.26 6.94 1.00 76.12 13.3629 P.O 40 N.D N.D N.D N.D N.D. 9.35 S.C 40 2.31 8.34 1.25 32.59 12.80Ciproflo- P.O 40 0.92 1.71 1.47 2.27 14.60 21.10xacin S.C 40 2.37 7.77 1.56 15.55 61.80Ofloxacin P.O 40 N.D 9.41 0.75 12.79 89.75 32.20 S.C 40 0.42 12.93 0.42 14.25 39.10__________________________________________________________________________

The LD.sub.50 of example 13 was about 1,000 g/kg and example 18 about >3,000 g/kg. (Oral, mice)

Claims

1. The quinolone carboxylic acid derivative 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, or a pharmaceutically acceptable salt or hydrate thereof.

2. The quinolone carboxylic acid derivative 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a pharmaceutically acceptable salt or hydrate thereof.