Field of the Invention

The present invention relates to novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof which possess a broad spectrum of potent antibacterial activities and are useful as antibacterials and to processes for preparing these compounds.

Description of the Prior Art

Quinolonic antibacterials such as enoxacin, norfloxacin, ofloxacin, ciprofloxacin and tosufloxacin have been commercially available. Although most of these prior art quinolones are known to have relatively good antibacterial activity against gram-negative bacteria, they are known to have relatively weak antibacterial activity against gram- positive bacteria.

Therefore, the development of new quinolone compounds which possess a broad spectrum of potent antibacterial activities and are effective against quinolone-resistant bacteria as well as methicillin-resistant Staphylococcus aureus (MRSA) is still needed.

Summary of the Invention

In order to solve the above problems, the present inventors have conducted extensive studies to develop novel quionlone compounds.

As a result, it has been surprisingly found that quinolone carboxylic acid derivatives having the substituent represented by the following formula (A) at 7-position of quinolone nucleus meet the above requirements.

In the above formula,

R,, R ₂ and R ₃ , which may be the same or different, are each hydrogen or a halogen atom, or a lower alkyl group substituted with an amino or hydroxy group; and

R, is hydrogen atom, a lower alkyl, benzyl, t-butoxycarbonyl or ethoxycarbonyl group.

Accordingly, the present invention is concerned with novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof which can meet said requirements and with processes for preparing such compounds.

Detailed Description of the Invention

An object of the present invention is to provide novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof which possess a broad spectrum of potent antibacterial activities against various microorganisms, and to provide processes for preparing these compounds.

Another object of the present invention is to provide intermediates which are useful for producing the desired compounds of the present invention.

The present invention provides novel quinolone carboxylic acid derivatives represented by the formula (I):

wherein,

R _1? R ₂ , R ₃ and R ₄ are the same as defined above; R ₅ is hydrogen or chlorine atom, or methyl or an amino group; Re is a lower alkyl group, or a cyclopropyl or a phenyl group optionally substituted with a halogen atom; and

X is nitrogen atom, or a methyne group optionally substituted with a lower alkyl or a lower alkoxy group or a halogen atom, and their pharmaceutically acceptable salts.

The term "lower alkyl" used herein refers to a straight or branched C _M alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

The term "halogen atom" used herein refers to chlorine, bromine, fluorine or iodine atom.

The term "lower alkoxy" used herein refers to C alkoxy such as methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, sec-butyloxy or tert-butyloxy.

Among the compounds of the present invention, the preferred compounds which possess a broad spectrum of potent antibacterial activities are as follows:

l-cyclopropyl-6,8-difluoro-7-[2,8-diazabicyclo[4.3.0]non- 5-en)-8-yl]-l ,4- dihydroquinoline-4-oxo-3-carboxylic acid;

l-cyclopropyl-6-fluoro-8-chloro-7-[2,8-diazabicyclo[4.3.0 ]non-5-en)-8-yl]-l ,4- dihydroquinoline-4-oxo-3-carboxylic acid;

1 -(2-fluorocyclopropyl)-6-fluoro-8-chloro-7-[2, 8-diazabicyclo[4.3.0]non-5-en)-8-yl]- 1 ,4-dihydroquinoline-4-oxo-3-carboxylic acid;

l-cyclopropyl-5,8-dichloro-6-fluoro-7-[2,8-diazabicyclo[4 .3.0]non-5-en)-8-yl]-l ,4- dihydroquinoline-4-oxo-3-carboxylic acid;

l-cyclopropyl-5-amino-6,8-difluoro-7-[2,8-diazabicyclo[4. 3.0]non-5-en)-8-yl]-l,4- dihydroquinoline-4-oxo-3-carboxylic acid ;

l-cyclopropyl-6,8-dichloro-7-[(2-methyl-2,8-diazabicyclo[4.3 .0]non-5-en)-8-yl]-l,4- dihydroquinoline-4-oxo-3-carboxylic acid;

l-(2-fluorocyclopropyl)-5 , 8-dichloro-6-fluoro-7-[(2, 8-diazabicyclo[4.3.0]non-5-en)-8- yl]-l,4-dihydroquinoline-4-oxo-3-carboxylic acid; and

l-cyclopropyl-6-fluoro-8-methoxy-7-[(2,8-diazabicyclo[4.3 .0]non-5-en)-8-yl]-l ,4- dihydroquinoline-4-oxo-3-carboxylic acid .

Among the compounds of the present invention, the more preferred compounds which possess a broad spectrum of potent antibacterial activities are as follows:

l-cyclopropyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non -5-en)8-yl]-l ,4r dihydroquinoline-4-oxo-3-carboxylic acid;

l-cyclopropyl-6-fluoro-8-chloro-7-[(2,8-diazabicyclo[4.3. 0]non-5-en)-8-yl]-l,4- dihydroquinoline-4-oxo-3-carboxylic acid;

l-cyclopropyl-5,8-dichloro-6-fluoro-7-[(2,8-diazabicyclo[ 4.3.0.]non-5-en)-8-yl]-l,4- dihydroquinoline-4-oxo-3-carboxylic acid;

l-cyclopropyl-5-amino-6,8-difluoro-7-[(2,8-diazabicyclo[4 .3.0]non-5-en)-8-yl]-l,4- dihydroquinoline-4-oxo-3-carboxylic acid;

l-(2-fluorocyclopropyl)-6-fluoro-8-chloro-7-[(2,8-diazabi cyclo[4.3.0]non-5-en)-8-yl]- 1 ,4-dihydroquinoline-4-oxo-3-carboxylic acid; and

l-cyclopropyl-6-fluoro-8-methoxy-7-[(2,8-diazabicyclo[4.3 .0]non-5-en)-8-yl]-l ,4- dihydroquinoline-4-oxo-3-carboxylic acid .

Quinolone compounds represented by formula (I) according to the present invention can be prepared by either process(A) or (B) set forth hereinafter.

ProcessCA.

In the above formula,

R R ₂ , R ₃ , R ₄ , R ₅ , R« and X are the same as defined previously; and Y is a halogen atom or a mesyl or a tosyl group.

In accordance with the above process(A), quinolone compounds represented by formula (I) of the present invention can be prepared by reacting a compound of formula (II) with a compound of formula (HI) in a solvent, preferably in the presence of an inorganic or organic base. Solvents used in this process include water, a lower alkanol, acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide and a mixture thereof. Inorganic bases used herein include calcium carbonate, potassium carbonate and the like. Organic bases used herein include l,8-diazabicyclo[5.4.0]undec-7-ene(DBU), triethylamine and the like. The above reaction may be carried out at a temperature between about 20°C and about 200°C, preferably between about 60°C and about 130°C. The reaction time is about 1 to about 24 hours.

Processes')

In the above formula,

R _{1 ;} R ₂ , R ₃ , R ₄ , R ₅ , Rή, X and Y are the same as defined above; and R is hydrogen atom or a lower alkyl group.

The above Process(B) comprises the following four steps;

Step (1):

The compound of formula (V) can be prepared by reacting a compound of formula (IV) with a compound of formula (II). The above reaction can be conducted in the presence of a solvent such as a lower alkanol, acetonitrile, dimethylformamide. dimethylsulfoxide, tetrahydrofuran or a mixture thereof, preferably in the presence of an inorganic base such as sodium hydroxide and sodium carbonate or an organic base such as l,8-diazabicyclo[5.4.0]undec-7-ene and triethylamine at a temperature ranging from about 0°C to the refulx temperature of the solvent employed.

Step (2):

The compound of formula (VII) can be obtained by condensing with an amine compound of formula (VI) after a compound of formula (V) is heated under reflux with ethyl orthoformate and acetic anhydride. The condensation reaction is preferably carried out with a solvent such as ethanol, dimethylsulfoxide, acetone, 1,4-dioxane or a mixture thereof at a temperature ranging from 0 to 50°C.

Step (3):

The compound of formula (VIII) can be obtained by cyclizing a compound of formula (VII); and said cyclization reaction is preferably carried out by employing a reaction solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture thereof, preferably in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium fluoride and potassium fluoride or an organic base such as triethylamine and pyridine at a temperature ranging from 0°C to the reflux temperature of the solvent employed.

Step (4):

The compound of formula (I) can be prepared by hydrolyzing a compound of formula (VIII) obtained from Step (3) above. The hydrolysis can be carried out by employing a conventional method such as acid or base treatment.

The intermediates obtained in process(B), i.e., the respective compounds of formula (V), (VII) and (VIII) are novel compounds; and therefore, the present invention also includes these compounds.

The compounds employed as starting materials in accordance with the present invention are commercially available and also can be obtained through known processes in the art. For example, the compound of formula (III) can be prepared by the process described in J. Med. Chem. 31, 503(1988) and Drug of the Future. 14, 931(1989); and the compound of formula (IV) by using the process described in Chem. Pharm. Bull.. 38, 2472(1989).

The compound of formula (I) can be converted into their pharmaceutically acceptable salts by employing conventional methods. For example, the compound of formula (I) can be converted into the salt with an inorganic acid such as hydrochloric, sulfuric and phosphoric acids, or an organic acid such as methanesulfonic, lactic, oxalic and acetic acids, or a salt of an alkaline metal such as sodium and potassium.

The following examples are intended to further illustrate the present invention, without limiting the scope of the invention.

Example 1: Preparation of l-cyclopropyl-6,8-difluoro-7-[(2,8 diazabicyclo[4.3.0.]non-5-en)-8-yl]-l ,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.43g of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydroquinoline-4-oxo-3-c arboxylic acid and 0.96g of 2,8-diazabicyclo[4.3.0.]non-5-ene dihydrochloride were suspended in 10ml of acetonitrile and then 3m£ of l,8-diazabicyclo[5.4.0]undec-7-ene was added thereto. The resulting mixture was heated at 60°C for 4 hours, and then cooled to room temperature. The resulting white solid was filtered, washed twice with chilled acetonitrile, and then dried to obtain 1.8g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.10(1H, m), 2.30(1H, m), 2.95(1H, m),

3.25(1H, m), 3.60(1H, m), 3.85(1H, m), 4.00(3H, m), 5.66(1H, m), 7.80(1H, d), 8.65(1H, s)

Example 2: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-[2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]- 1 ,4-dihydroquinoline- 4-oxo-3-carboxylic acid

1.50g of l-cyclopropyl-6,7-difluoro-8-chloro-l ,4-dihydroquinoline-4-oxo-3-carboxy- lie acid and 0.97g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were dissolved in lOmt of dimethylformamide, and then Ami of pyridine was added thereto. The reaction mixture was heated at 100°C for 6 hours. The reaction solvent having boiling point below 40°C was removed under reduced pressure, and the residue was washed with water, then with chilled acetonitrile, and dried to obtain 1.2g of the desired compound as a white solid.

Η-NMR(CDC1 ₃ , δ): 1.20(4H, m), 2.10(1H, m), 2.30(1H, m),

2.65~-4.15(7H, m), 4.95(lH, ^* m) 5.10(1H, m), 5.60(1H, m), 7.56(1H, d), 8.61(1H, s)

Example 3: Preparation of l-cyclopropyl-6-fiuoro-8-methoxy-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.47g of l-cyclopropyl-6,7-difluoro-8-methoxy-l ,4-dihydroquinoline-4-oxo-3- carboxylic acid and 0.97g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.31g of the desired compound.

^* H-NMR(CDC1 ₃ , δ): 1.16(4H, m), 2.11(1H, m), 2.70-4.15(7H, m), 4.02(3H, s), 4.65(1H, d), 5.70(1H, s), 7.84(1H, d),

8.80(1H, s)

Example 4: Preparation of l-cyclopropyl-6-fluoro-7-[2,8-diazabicyclo

[4.3.0]non-5-en)-8-yl]-l ,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.32g of l-cyclopropyl-6,7-difluoro-l ,4-dihydroquinoline-4-oxo-3-carboxylicacid and 0.97g of 2, 8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.56g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.23(1H, m), 2.32(1H, m), 2.95(1H, m),

3.25(1H, m), 3.60(1H, m), 3.81(1H, m), 4.0(3H, m), 4.65(1H, d), 5.75(1H, s), 6.99(1H, d), 7.82(1H, d), 8.62(1H, s)

Example 5: Preparation of l-cyclopropyl-6-fluoro-8-methyl-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl] - 1 , 4-dihydroquinoline-4- oxo-3-carboxylic acid

l-40g of l-cyclopropyl-6,7-difluoro-8-methyl-l,4-dihydroquinoline-4-o xo-3-carboxy-

lic acid and 0.97g of 2, 8-diazabicyclo[4.3.0]-non-5-ene dihydrochloride were suspended in 15mf of acetonitrile, and then 4g of l,8-diazabicyclb[5.4.0]undec-7-ene was added thereto. The resulting mixture was heated under reflux for 10 hours. The reaction solvent was evaporated under reduced pressure, and the residue was suspended in water, stirred and filtered. The resulting solid was treated with aqueous sodium bicarbonate solution to dissolve the solid, and then adjusted to pH 2 with 10% hydrochloric acid to obtain the pure solid product. The resulting solid was filtered, and then evaporated under reduced pressure to obtain 0.87g of the desired compound as a white solid.

Η-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.10(1H, m), 2.3(3H, s),

2.70~-4.16(7H, m), 4.95(1H, m), 5.10(1H, m), 5.62(1H, m), 7.61(1H, d), 8.61(1H, s)

Example 6: Preparation of l-cyclopropyl-5-amino-6,8-difluoro-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l ,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.50g of l-cyclopropyl-5-amino-6,7,8-trifluoro-l ,4-dihydroquinoline-4-oxo-3- carboxylic acid and 0.98g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.60g of the desired compound.

^* H-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.12(1H, m), 2.30(1H, m), 2.95(1H, m),

3.25~4.0(6H, m), 4.65(1H, d), 5.75(1H, s), 8.92(1H, s)

Example 7: Preparation of l-cyclopropyl-6-fluoro-7-[(2,8-diazabicyclo

[4.3.0.]non-5-en)-8-yl]-4-oxo-l,8-naphthyridine-3-carboxy lic acid

1.41g of l-cyclopropyl-6,7-difluoro-4-oxo-l,8-naphthyridine-3-carboxy lic acid and 0.97g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.87g of the desired compound.

^* H-NMR(CDC1 ₃ + d ₆ -DMSO, δ): 1.15(4H, m), 2.23(1H, m), 2.32(1H, m),

2.95(1H, m), 3.25(1H, m), 3.60(1H, m), 3.81(1H, m), 4 ^* .0(3H, m), 4.65(1H, d), 5.75(1H, s), 7.99(1H, d), 8.71(1H, s)

Example 8: Preparation of l-ethyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5- en.-8-yll-l .4-dihydroquinoline-4-oxo-3-carboxylic acid

1.26g of l-ethyl-6,7-difluoro-l ,4-dihydroquinoline-4-oxo-3-carboxylic acid and 0.98g of 2,8-diazabicyclo[4.3.0]non-5-enedihydrochloride were subjected to the same process as described in Example 1 to obtain 1.43g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.26(3H,t), 2.12(1H, m), 2.30~4.15(10H, m),

4.95(1H, m), 4.0(2H, m), 5.10(1H, m), 5.60(1H, m), 7.01(1H, d), 7.51(1H, d), 8.68(1H, s)

Example 9: Preparation of l-(2,4-difluorophenyl)-6-fluoro-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo- 1 , 8-naphthyridine- 3-carboxylic acid

1.20g of l-(2,4)-difluorophenyl)-6,7-difluoro-4-oxo-l,8-naphthyridine -3-carboxylic acid and 0.65g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 2 to obtain 1.31g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.17(4H, m), 2.12(1H, ), 2.29(1H, m), 2.36(1H, m), 3.25(1H, m), 3.60(1H, m), 3.39(1H, m), 4.0(3H, m),

4.71(1H, d), 5.75(1H, s), 7.45(1H, m), 7.73(1H, m), 7.94(1H, m), 7.95(1H, d), 8.80(1H, s)

Example 10: Preparation of l-cyclopropyl-6,8-difluoro-7-[(2-methyl-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.42g of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydroquinoline-4-oxo-3-c arboxylic acid and 1.05g of 2-methyl-2,8-diazabicyclo[4.3.0]non-5-enedihydrochloride were subjected to the same process as described in Example 1 to obtain 1.96g of the desired compound.

¹ H-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.10-4.15(12H, m), 4.95(1H, m),

5.10(1H, m), 7.78(1H; d); 8.71(1H, s)

Example 11: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-[(2-methyl-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l ,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.50g of l-cyclopropyl-6,7-difluoro-8-chloro-l ,4-dihydroquinoline-4-oxo-3-carboxy- lic acid and 1.04g of 2-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Exmple 1 to obtain 1.96g of the desired compound.

Η-HMR(CDC1 ₃ , δ): 1.08(4H, m), 2.10~- 2.30(5H, m), 2.95(1H, m),

3.25(1H, m), 3.60(1H, m), 3.85(1H, m), 4.0(3H, m), 4.65(1H, d), 7.54(1H, d), 8.64(1H, s)

Example 12: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-[(2-methyl- 2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-l,4-dihydroquinoline- 4- oxo-3-carboxylic acid

1.48g of l-cyclopropyl-6,7-difluoro-8-methoxy-l ,4-dihydroquinoline-4-oxo-3- carboxylic acid and 1.04g of 2-methyl-2,8-diazabicyclo[4.3.0]non-5-enedihydrochloride were subjected to the same process as described in Example 1 to obtain 2.16g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.11(1H, m), 2.30(1H, m), 2.95(1H, m),

3.25(1H, m), 3.60(1H, m), 3.85(1H, m), 4.0(3H, m), 4.10(3H, s), 4.65(1H, d), 7.86(1H, d), 8.84(1H, s)

Example 13: Preparation of l-cyclopropyl-5-amino-6,8-difluoro-7-[(2-methyl- 2 , 8-diazabicyclo[4.3.0]non-5-en)-8-yl] - 1 ,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.50g of l-cyclopropyl-5-amino-6,7,8-trifluoro-l,4-dihydroquinoline-4 -oxo-3- carboxylic acid and 1.04g of 2-methyl-2,8-diazabicyclo[4.3.0]non-5-enedihydrochloride

were subjected to the same process as described in Example 1 to obtain 2.06g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.12~2.30(5H, m), 2.95(1H, m), 3.25 ~4.0(6H, m), 4.68(1H, d), 8.94(1H, s)

Example 14: Preparation of l-cyclopropyl-6-fluoro-7-[(2-methyl-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l,8-dihydronaphthyridine-

3-carboxylic acid

1.41g of l-cyclopropyl-6-fluoro-7-chloro-l,8-dihydronaphthyridine-3-c arboxylic acid and 1.04g of 2-methyl-2, 8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.91g of the desired compound.

^* H-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.12~2.30(5H, m), 2.95(1H, m),

3.25~4.0(6H, m), 4.68(1H, d), 7.85(1H, d), 8.68(1H, s)

Example 15: Preparation of l-cyclopropyl-6,8-difluoro-7-[(3-methyl-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l ,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.41g of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydroquinoline-4-oxo-3-c arboxylic acid and 1.04g of 3-methyl-2,8-diazabicyclo[4.3.0]non-5-enedihydrochloride were subjected to the same process as described in Example 1 to obtain 2.20g of the desired compound.

^* H-NMR(CDC1 ₃ , δ): 1.15 ~ 1.27(7H, m), 2.16~2.36(2H, m), 2.95(1H, m),

3.25~4.10(6H, m), 5.52(1H, m), 7.78(1H, d), 8.76(1H, s)

Example 16: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-[(3-methy 1-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.50g of l-cyclopropyl-6,7-difluoro-8-chloro-l,4-dihydroquinoline-4-o xo-3-carboxy-

lie acid and 1.04g of 3-methyl-2, 8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 ^' to obtain 1.83g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.16-~ 1.22(4H, m), 2.08 ~4.16(9H. m), 4.95(1H, m),

5.49(1H, m), 7.81(1H, d), 8.78(1H, s)

Example 17: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-[(3-methyl- 2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-l,4-dihydroquinoline- 4- oxo-3-carboxylic acid

1.48g of l-cyclopropyl-6,7-difluoro-8-methoxy-l,4-dihydroquinoline-4- oxo-3- carboxylic acid and 1.04g of 3-methyl-2 , 8-diazabicyclo[4.3.0]non-5-enedihydrochloride were subjected to the same process as described in Example 1 to obtain 1.91g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.16-~ 1.25(4H, m), 2.10~4.16(9H, m), 4.05(3H, s),

4.95(1H, m), 5.49(1H, m), 7.89(1H, d), 8.81(1H, s)

Example 18: Preparation of l-cyclopropyl-5-amino-6,8-difluoro-7-[3-methyl- 2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-l,4-dihydroquinoline- 4- oxo-3-carboxylic acid

1.50g of l-cyclopropyl-5-amino-6,7,8-trifluoro-l ,4-dihydroquinoline-4-oxo-3- carboxylic acid and 1.04g of 3-methyl-2,8-diazabicyclo[4.3.0]non-5-enedihydrochloride were subjected to the sampe process as described in Example 1 to obtain 1.68g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.14*- 1.21(7H, m), 2.10~4.10(9H, m), 4.95(1H, m), 5.56(1H, m), 8.76(1H, s)

Example 19: Preparation of l-cyclopropyl-6,8-difluoro-7-[(5-methyl-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-dihydroquinoline-4- oxo-3-carboxylic acid

1.42g of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydroquinoline-4-oxo-3-c arboxylic acid and 1.04g of 5-methyl-2,8-diazabicyclo[4.3.0]non-5-ene ^' dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.69g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.23 ~2.35(5H, m), 2.95(1H, m),

3.25(1H, m), 3.60(1H, m), 3.81(1H, m), 4.0(3H, m), 4.65(1H, d), 5.75(1H, s), 7.80(1H, d), 8.71(1H, s)

Example 20: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-[(5-methyl-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.50g of l-cyclopropyl-6,7-difluoro-8-chloro-l ,4-dihydroquinoline-4-oxo-3-carboxy- lic acid and 1.04g of 5-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the sampe process as described in Example 1 to obtain 1.87g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.14(4H, m), 2.10~4.12(12H, m), 4.95(1H, m),

5.10(1H, m), 5.62(1H, m), 7.81(1H, d), 8.81(1H, s)

Example 21: Preparation of l-cyclopropyl-6,8-difluoro-7-[(2,8-diazabicyclo [4.3.0]non-5-en)-8-yl]-l ,4-dihydroquinoline-4-oxo-3-carboxylic acid hydrochloride

0.388g of l-cyclopropyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5- en)-8-yl]-l,4- dihydroquinoline-4-oxo-3-carboxylic acid obtained from Example 1 was dissolved in methanol saturated with hydrogen chloride, and the reaction solution was stirred for 1 hour. The resulting solid was filtered, washed with chilled methanol, and then dried to obtain 0.403g of the desired compound as a light yellow solid.

Η-NMR(d ₆ -DMSO, δ): 1.16(4H, m), 2.21 ~4.06(9H, m), 4.65(1H, d),

5.75(1H, s), 7.81(1H, d), 8.81(1H, s)

Example 22: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-[(2,8- diazabicylo[4.3.0]non-5-en)-8-yl]-l ,4-dihydroquinoline-4-

oxo-3-carboxylic acid lactate

0.404g of l-cyclopropyl-6-fluoro-8-chloro-7-[(2,8-diazabicyclo[4.3.0]n on-5-en-8-yl]- 1 ,4-dihydroquinoline-4-oxo-3-carboxylic acid obtained from Example 2 was dissolved in 5mi of mixture of chloroform-methanol(5: 1 , v/v), and then 0.09g of lactic acid was added thereto. The resulting reaction solution was stirred for 4 hours, evaporated under reduced pressure, washed twice with acetonitrile, and then dried under reduced pressure to obtain 0.40g of the desired compound.

Η-NMR(CD ₃ OD, δ): 1.14(1H, m), 2.20*- 4.06(11H, m), 4.65(1H, d),

5.75(1H, s), 7.81(1H, d), 8.81(1H, s)

Example 23: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-[(5-methyl-

2 , 8-diazabicyclo[4.3.0]non-5-en)-8-yl]- 1 ,4-dihydroquinoline-4- oxo-3-carboxylic acid

Step (1): Preparation of etlιyl{2,5-difluoro-3-methoxy-4-[(5-methyl-2,8- diazabicylof4.3.01non-5-en)-8-yl}benzoyl acetate

1.06g of ethyl(2,4,5-trifluoro-3-methoxy)benzoyl acetate, 0.91g of 5-methyl-2,8- diazabicyclo[4.3.0]non-5-ene and lg of calcium carbonate were added to 10m.? of acetonitrile and the resulting solution was heated at 60°C for 6 hours. The solvent was evaporated under reduced pressure and the residue was suspended in ethyl acetate, and then washed with water. The solvent was evaporated again under reduced pressure. The residue was purified on a silica gel- column chromatography using hexane: ethyl acetate (3: 1, v/v) to obtain 1.36g of the desired compoumnd.

Steps (2) and (3): Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-[(5- methyl-2 , 8-diazabicyclo[4.3.0]non-5-en)-8-yl]- 1 ,4- dihydroquinoline-4-oxo-3-carboxylic acid ethyl ester

1.16g of benzoyl acetate obtained from the above step (1) was dissolved in lOmi. of acetic anhydride, and then 2g of triethyl carbonate was added thereto. The resulting mixture was heated for 1 hour. After being cooled to room temperature the reaction mixture was pured into lOOmf of ice water. The reaction product was extracted with

ethyl acetate, dried over magnesium sulfate, and then evaporated under reduced pressure. The residue was dissolved in ethanol, arid 0.5 lg of cyclopropylamine was added thereto, and then stirred at room temperature for 3 hours. The reaction mixture was then evaporated under reduced pressure, and the residue was dissolved in 5mi of dimethylsulfoxide. 0.96g of calcium fluoride was added to the resulting solution, and then heated at 60°C for 1 hour. The reaction mixture was pured into 50m-? of ice water and the reaction product was extracted with ethyl acetate. The extract was dried over magnesium sulfate and then evaporated under reduced pressure. The resulting residue was purified on a silica gel column chromatography using hexane: ethyl acetate(5: 1, v/v) to obtain 0.78g of the desired compound.

Step (4): Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-[(5-methyl- 2 , 8-diazabicyclo[4.3.0]non-5-en)-8-yl]- 1 ,4-dihydroquinoline-4- oxo-3-carboxylic acid

0.71g of the ester derivative obtained from the above steps (2) and (3) was suspended in 10m-? of 6N hydrochloric acid, and then heated under reflux for 8 hours. The solvent was evaporated under reduced pressure, and the residue was treated with an queous saturated sodium carbonate solution to remove the insoluble material. The resulting solution was washed twice with ethyl acetate, adjusted to pH 3 with 2N hydrochloric acid, and then cooled in an ice water bath to produce white solid which was filtered and then dried under reduced pressure to obtain 0.46g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.16(4H, m), 2.11(1H, m), 2.70-4.16(10H, m),

4.02(3H, s), 4.65(1H, d), 5.70(1H, d), 7.84(1H, d), 8.80(1H, s)

Example 24: Preparation of l-cyclopropyl-5-methyl-6-fluoro-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l ,4-dihydroquinoline-4- oxo-3-carboxylic acid

32g of l-cyclopropyl-5-methyl-6,7-difluoro-l ,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04g of 2, 8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.67g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.14(4H, m), 2.10~2.30(5H, m), 2.65 -4.15(7H, m),

4.95(1H, m), 5.60(1H, m), 7.71(ΪH, d), 8.69(1H, s)

Example 25: Preparation of l-cyclopropyl-6,8-difluoro-7-[(3-hydroxymethyl- 2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-l ,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.43g of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydroquinoline-4-oxo-3-c arboxylic acid and 1.13g of 3-hydroxymethyl-2,8-diazabicyclo[4,3,0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.38g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.10~2.31(2H, m), 2.76- 3.25(5H, m),

4.0(3H, m), 5.62(1H, m), 7.82(1H, d), 8.67(1H, s)

Example 26: Preparation of l-cyclopropyl-6,8-difluoro-7-[(3-aminomethyl- 2 , 8-diazabicyclo[4.3.0]non-5-en)-8-yl]- 1 ,4-dihydroquinoline-4- oxo-3-carboxylic acid

1.43g of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydroquinoline-4-oxo-3-c arboxylic acid and 1.20g of 3-aminomethyl-2,8-diazabicyclo [4,3,0]non-5-ene were subjected to the same process as described in Example 1 to obtain 1.52g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.14(4H, m), 2.14~2.31(2H, m), 2.76- 3.18(7H, m), 4.0(1H, m), 5.61(1H, m), 7.80(1H, d), 8.71(1H, s)

Examle 27: Preparation of l-cyclopropyl-5-amino-7-[(5-fluoro-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-6, 8-difluoro- 1 ,4- dihydroquinoline-4-oxo-3-carboxylic acid

1.49g of l-cyclopropyl-5-amino-6,7,8-trifluoro-l ,4-dihydroquinoline-4-oxo-3- carboxylic acid and 1.06g of 5-fluoro-2 , 8-diazabicyclo [4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.87g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.14(4H, m), 2.10-2.30(2H, m), 2.95 ~3.25(4H, m),

3.90- 4.00(4H, m), 8.71(lH, ^' s) ^'

Example 28: Preparation of l-cyclopropyl-5,8-dichloro-6-fluoro-7-[(2,8- diazabicyclo [4.3.0]non-5-en)-8-yl]-l,4-dihydroquinoline-4-oxo-

3-carboxylic acid

1.67g of l-cyclopropyl-5,8-dichloro-6,7-difluoro-l ,4-dihydroquinoline-4-oxo-3- carboxylic acid and 0.98g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.42g of the desired compound.

Η-NMR(CDC1 ₃ , δ): 1.15(4H, m), 2.10(1H, m), 2.30(1H, m), 2.91 ~ 3.25(4H, m), 3.90(1H, m) 4.00(3H, m), 5.60(1H, m), 8.65(1H, s)

Example 29: Preparation of l-(2-fluorocyclopropyl)-6-fluoro-8-chloro-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-l,4-dihydroquinoline-4-ox o- 3-arboxylic acid

1.58g of l-(2-fluorocyclopropyl)-6,7-difluoro-8-chloro-l ,4-dihydroquinoline-4-oxo-3- carboxylic acid and 0.98g of 2,8-diazabicylo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.21g of the desired compound.

^* H-NMR(CDC1 ₃ , δ): 1.18(2H, m), 2.12(1H, m), 2.30(1H, m), 2.95(1H, m),

3.25(1H, m), 3.90~4.00(7H, m), 5.62(1H, m), 8.72(1H, s)

1) Preparation of 2.8-diazabicyclof4.3.01non-5-ene dihydrochloride

(1) Preparation of l-benzyl-3-carboethoxy-4-benzylaminopyrrolidine

24.7g of l-benzyl-3-carboethoxy-4-pyrrolidone and 10.7g of benzylamine were added to 100ml of benzene, and then dehydrated with Dean-Stark distillation apparatus. The residual benzene was evaporated. The residue and a small amount of methyl orange

were dissolved in 200ml of tetrahydrofuran, and methanol saturated with hydrogen chloride was adjusted to about pH 4, and then 7g of sodium borocyanohydride was added thereto. A solution of methanol saturated with hydrogen chloride was added dropwise to the reaction solution with stirring until the pink-color of the solution did not disappear. The reaction solution was basified with 15% aqueous caustic soda solution, and then the aqueous layer was removed by addition of ether. The organic phase was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and then subjected to silica gel column chromatography (hexane:ethyl acetate, 5: l(v/v)) to obtain 24g of the desired compound (yield:71 %).

Η-NMR(CDC1 ₃ , δ): 1.27(3H, t), 2.6~ 3.0(5H, m), 3.57(1H, m), 3.63(2H, d),

3.80(2H, s), 4.18(2H, q), 7.31(10H, m)

(2) Preparation of N.N'-dibenzyl-2.8-diazabicyclo_4.3.0 ^" |non-5-ene

33.8g of l-benzyl-3-carboethoxy-4-benzylaminopyrrolidineand 50 ml of ethyl acrylate were added to 100ml of ethanol, and then refluxed with stirring for 3 days. The ethanol and ethyl acrylate were removed by using a vacuum evaporator. The residue was dissolved in 100ml of toluene, and then the reaction mixture was cooled in an ice water bath. 8g of potassium t-butoxide was added thereto, and then stirred at room temperature over night. 100ml of water was added to the reaction mixture, and then stirred well. The aqueous layer was separated, and then neutralized with concentrated sulfuric acid. The aqueous layer was extracted three times with ethyl acetate, and the solvent was then evaporated under reduced pressure. To the residue was added 100ml of concentrated hydrochloric acid, and the resulting solution was stirred under reflux for 4 hours. The reaction solution was concentrated to a volume of 50ml by using a reduced pressure evaporator, neutralized with IN NaOH solution, extracted twice with ethyl acetate, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then purified on a silica gel column chromatography (hexane:ethyl acetate, 3:l(v/v)) to obtain 17. lg of the desired compound (yield:53.4%).

Η-NMR(CDC1 ₃ , δ): 2.3 - 3.0(9H, m), 3.20~- 3.70(2H, ABq), 3.50(2H, s), 3.40(1H, q), 7.15(101-1, m)

(3) Preparation of N.N'-dibenzyl-2.8-diazabicyclor4.3.0 ^" lnon-5-ol

To a suspension of 4.0g of NaBH ₄ in 100ml of ethanol was added dropwise a solution of 32. Og of N,N'-dibenzyl-2,8-diazabicyclo[4.3.0]non-5-one dissolved in 100ml of ethanol. After the reaction mixture was stirred at room temperature for 3 hours, 20ml of 15% NaOH was added thereto, and then filtered. The filtrate was evaporated under reduced pressure, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to obtain the desired compound in an quantitative amount as a light yellow syrup.

Η-NMR(CDC1 ₃ , δ): 1.60~3.00(11H, m), 3.20- 3.60(3H, m), 3.70(2H, d), 3.90(1H, m), 7.30(10H, m)

(4) Preparation of N. N ' -di-t-butoxycarbonyl-2.8-diazabicyclor4.3.0 lnon-5-ol

32.2g of N,N'-dibenzyl-2,8-diazabicyclo[4.3.0]non-5-ol was added to 250ml of methanol containing 10ml of formic acid together with 3g of 10% Pd/C, and hydrogen gas (initial pressure of 60psi) was injected into the solution. After the reaction was completed, the reaction solution was filtered through celite, neutralized with saturated sodium bicarbonate solution, and then stirred for 14 hours after an addition of 40g of di-t-butoxycarbonate. The reaction solution was evaporated under reduced pressure, and the residue was purified on a silica gel column chromatography (hexane: ethyl acetate, 5:l(v/v)) to obtain 30.78g of the desired compound (yield:90%).

Η-NMR(CDC1 ₃ , δ): 1.50(8H, s), 1.70~2.00(2H, m), 2.20(1H, m), 2.50(1H, m),

2.80~4.10(7H, m), 4.60(1H, m)

(5) Preparation of N . N' -di-t-butoxycarbonyl-2.8-diazabicyclo .4.3.01 non-5-ene

17. lg of N,N'-di-t-butoxycarbonyl-2,8-diazabicyclo[4.3.0]non-5-ol and 7ml of triethylamine were dissolved in 100ml of methylene chloride. The reaction solution was cooled in an ice water bath, and then 4.2ml of methane sulfonylchloride was added dropwise thereto. The reaction mixture was stirred at room temperature for 10 hours,

washed with water, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. The residue was dissolved in 50ml of dimethylsulfoxide, and then 10ml of DBU was added thereto. The reaction mixture was poured into 200ml of ice water, extracted three times with ethyl acetate and then dried over anhydrous magnesium sulfate. The ethyl acetate layer was evaporated under reduced pressure and subjected to a silica gel column chromatography(hexane:ethyl acetate, 6:1 (v/v)) to obtain 9.8g of the desired compound (yield: 61 %).

Η-NMR(CDC1 ₃ , δ): 1.46(18H, s), 2.10(1H, ), 2.70~- 4.20(7H, m), 5.30(1H, m), 5.80(1H, m)

(6) Preparation of 2.8-diazabicyclo[4.3.01non-5-ene dihydrochloride

To 30ml of methanol saturated with 3N hydrochloric acid was added 9.72g of N,N'- di-t-carbonyl-2,8-diazabicyclo[4.3.0]non-5-ene _s stirred at room temperature for4 hours, and then evaporated under reduced pressure to obtain 5.85g of the desired compound.

^* H-NMR(CD ₃ OD, δ): 2.10(1H, m), 2.70-4.20(7H, m), 5.10(1H, m),

5.60(1H, m)

In vitro antibacterial activity test

In order to demonstrate the superior antibacterial activity of the quinolone derivatives of the present invention, the minimal inhibitory concentration (MIC, μg/ml) of several compounds synthesized in Examples hereof was determined in accordance with the agar culture medium two-fold dilution method(Hoechst 345) by using a Muller-Hinton agar medium. The strains having 10 ⁷ CFU/ml were inoculated on the culture medium, and the growth of the strains was observed after incubating them at 37°C for 18 hours, in which ofloxacin, ciprofloxacin and spafloxacin were used as control materials. Hoechst standard strains were used as the test strains. The results of the MIC tests are shown in Tables 1 and 2.

Table 1: In vitro anti acterial activity test

Strain A B D

Streptococcus pvogenes 308A 0.391 0.195 0.781 3.125 3.125 1.563

Streptococcus pvogenes 77A 0.195 0.098 0.195 1.563 0.781 0.391

Streptococcus faecium MD 8b 0.195 0.195 0.195 0.781 0.781 0.391

Streptococcus aureus SG 511 0.025 0.013 0.025 0.391 0.391 0.049

Streptococcus aureus 285 0.025 0.013 0.049 0.391 0.781 0.098

Streptococcus aureus 503 0.025 0.013 0.013 0.391 0.781 0.025

Escherichia coli 0 55 0.004 0.004 < 0.002 0.013 < 0.002 < 0.002

Escherichia coil DC 0 0.098 0.098 0.391 0.781 0.195 0.391

Escherichia coil DC 2 0.025 0.013 0.049 0.195 0.098 0.049

Escherichia coil TEM 0.007 0.007 0.013 0.049 0.007 0.025

Escherichia coil 1507E 0.013 0.013 0.013 0.049 0.007 0.025

Pseudomonas aeruginosa 9027 0.781 0.781 0.781 1.563 0.391 1.563

Pseudomonas aeruginosa 1592E 0.391 0.391 0.391 1.563 0.391 0.781

Pseudomonas aeruginosa 1771 0.391 0.391 0.391 1.563 0.391 0.781

Pseudomonas aeruginosa 1771M 0.195 0.195 0.195 0.391 0.098 0.195

Salmonella tvphimurium 0.007 0.004 < 0.002 0.049 0.007 0.013

Klebsiella aerogenes 1082E 0.004 0.004 0.025 0.013 < 0.002 < 0.002

Klebsiella aerogenes 1552E 0.013 0.013 0.007 0.098 0.007 0.049

Enterobacter cloacae P 99 0.007 0.007 < 0.002 0.049 0.007 0.025

Enterobacter cloacae 132 IE 0.004 0.004 0.004 0.025 0.004 0.007

A The compound prepared in Example 1 B The compound prepared in Example 2 C The compound prepared in Example 21 D Ofloxacin

E Ciprofloxacin F Spafloxacin

Table 2: In vitro antibacterial activity against methicillin resistant Staphylococcus aureus

Strain A B D

Staphylococcus aureus 88 E 0.049 0.195 0.391 0.781 Staphylococcus aureus 121 E 0.098 0.195 0.391 0.781 Staphylococcus aureus 208 E 0.098 0.195 0.391 0.781 Staphylococcus aureus 256 E 0.098 0.195 0.391 1.563 Staphylococcus aureus 690 E 0.049 0.098 0.391 0.781 Staphylococcus aureus 692 E 0.049 0.098 0.391 0.391 Staphylococcus aureus 693 E 0.049 0.098 0.391 0.781 Staphylococcus aureus 694 E 0.098 0.195 0.781 0.781 Staphylococcus aureus 695 E 0.049 0.098 0.391 0.781 Staphylococcus aureus 697 E 0.049 0.098 0.195 0.391 Staphylococcus aureus 701 E 0.098 0.195 0.391 0.781 Staphylococcus aureus 703 E 0.098 0.195 0.391 0.781 Staphylococcus aureus 705 E 0.098 0.195 0.391 0.781 Staphylococcus aureus 706 E 0.098 0.195 0.391 0.391 Staphylococcus aureus 707 E 0.098 0.195 0.391 0.781 Staphylococcus aureus 708 E 0.025 0.049 0.195 0.195 Staphylococcus aureus 711 E 0.025 0.098 0.391 0.781 Staphylococcus aureus 714 E 0.049 0.195 0.391 0.781 Staphylococcus aureus 725 E 0.098 0.195 0.391 0.781

A: The compound prepared in Example 1

B: The compound prepared in Example 2

D: Ofloxacin

E: Ciprofloxacin