QUINOLIZINE CARBOXYLIC ACID DERIVATIVES

Abstract: A quinolizine carboxylic acid derivative of formula (I) or a pharmaceutically acceptable salt thereof, wherein R<1> and R<2> have the same meanings as defined in the specification.

Description: QUINOLIZINE CARBOXYLIC ACID DERIVATIVES Field of the Invention The present invention relates to 4-oxo-quinolizine carboxylic acid derivatives and pharmaceutically acceptable salts thereof having an excellent antibacterial activity, a process for preparing same, and an antibacterial composition containing same as an active ingredient. Background of the Invention Quinolizine derivatives are known to exhibit excellent antibacterial activities (see PCT publication No. WO 95/10519) However, some of the conventional quinolizine compounds have limited activities against Gram-positive bacteria, while other quinolizine derivatives exhibit the problem of poor water-solubility or side effects such as high cytotoxicity . The present inventors have, therefore, endeavored to develop non-toxic compounds having a higher potency against a wide spectrum of bacteria; and have unexpectedly found that certain quinolizine carboxylic acid derivatives having an amine moiety at the 8 -position of the 4-oxo-quinolizine nucleus exhibit a broad spectrum antibacterial activity and reduced cytotoxicity. Summary of the Invention It is, therefore, a primary object of the present invention to provide novel 4-oxo-quinolizine carboxylic acid derivatives, and pharmaceutically acceptable salts thereof, having a potent antibacterial activity, especially against Gram-positive bacteria, with a low cytotoxicity. It is another object of the present invention to provide an antibacterial composition containing the inventive compounds as an active ingredient. It is a further object of the present invention to provide a process for the preparation of the inventive novel compounds. In accordance with the present invention, there is provided a 4-oxo-quinolizine carboxylic acid derivative of formula (I) or a pharmaceutically acceptable salt thereof: wherein R ,1' is a C 1-4 alkyl group optionally substituted with one ore more halogens, or a C.,.^ alkoxy group; R 2 is R 13 HN χ /--NHOCH3 or R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R u are each independently H or a C._ A alkyl group optionally substituted with a pyridyl, arylalkyl or aryl group. Detailed Description of the Invention Among the compounds of the present invention, preferred are those wherein: R 1 is CH 3 or OCH 3 ; R 2 is R 3 , R 5 , R 6 , R 8 , R 1 and R 12 are each independently H or CH 3 ; R 4 is H or a methyl group optionally substituted with a pyridyl or benzyl group; R 7 , R 9 , R 10 and R 13 are H or CH 3 ; R 14 is CH,. Particularly preferred compounds of formula (I) of the present invention are: 8-{ [(R)-2,8-diazabicyclo[4.3.0]non-5-en]-8-yl}-l- cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid; 8 - { [(S)-2,8-diazabicyclo[4.3.0] non-5-en] -8-yl}-l- cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid; 8-{ [ (R) -5-methyl-2, 8-diazabicyclo [4.3.0]non-5-en] -8-yl}-l- cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H-quinolizine-3 - carboxylic acid; 8 - [ (l-aminomethyl-3 -azabicyclo [2.1.1] hex) -3-yl] -1- cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid; 8- [ (l-amino-3-azabicyclo [2.1.1] hex) -3-yl] -l-cyclopropyl-7- f luoro- 9 -methyl- 4- oxo-4H- quinolizine- 3 -carboxylic acid; 8- [ (1-amino- 3 -azabicyclo [3.1.1] hept) -3-yl] -l-cyclopropyl-7- f luoro- 9 -methyl-4-oxo-4H-quinolizine-3 -carboxylic acid; 8 - [ (l-aminomethyl-3 -azabicyclo [3.1.1] hept) -3-yl] -1- cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid; 8- [ (l-N-methylaminomethyl-3 -azabicyclo [3.1.1] -hept) -3-yl] - l-cyclopropyl-7-f luoro- g-methyl^-oxo^H-quinolizine-S- carboxylic acid; 8- [ (l-N-methylamino-3 -azabicyclo [3.1.1] hept) -3-yl] -1- cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H -quinolizine -3 - carboxylic acid; 8- [ (3-amino-3-carbamoylpyrrolidine) -1-yl] -l-cyclopropyl-7- f luoro- 9 -methyl -4- oxo-4H- quinolizine -3 -carboxylic acid; 8- [ (3-N-methylaminomethyl-4-N-methylaminopyrrolidine) -1- yl] -l-cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H-quinolizine-3- carboxylic acid; 8- [ (3-amino-4-aminomethylpyrrolidine) -1-yl] -1-cyclopropyl- 7-f luoro- 9 -methyl -4 -oxo-4H-quinolizine -3 -carboxylic acid; 8- [ (3 -aminomethyl-4-N-methoxyaminopyrrolidine) -1-yl] -1- cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid; 8- [ ( 3 - amino- 4 -N-me t hoxyaminopyrrolidine ) -1-yl] -1- cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid; 8- [ (3-N-methoxyamino-4-N-methylaminomethylpyrrolidine] -1- yl} -l-cyclopropyl-7-f luoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid; 8-{ [3- (3-pyridylmethyl) oxy-4-aminomethylpyrrolidine] -1-yl}- l-cyclopropyl-7-f luoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid; 8-{ [3- (2-pyridylmethyl) oxy-4-aminomethylpyrrolidine] -1-yl}- l-cyclopropyl-7-f luoro- 9-methyl-4 -oxo-4H-quinolizine-3- carboxylic acid; 8-{ [3- (4-pyridylmethyl) oxy-4-aminomethylpyrrolidine] -1-yl}- l-cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H-quinolizine-3- carboxylic acid; 8-{ [3-N- (3-pyridylmethyl) amino-4-aminomethylpyrrolidine] -1- yl } - 1 - cyclopropyl - 7 - f luoro- 9 -methyl - 4 -oxo-4H-quinolizine - 3 - carboxylic acid; 8- [ (3 -N-benzylamino-4 -aminomethylpyrrolidine) -1-yl] -1- cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid; 8 - { [ (R) -2,8-diazabicyclo[4.3.0]non-5-en] -8-yl}-l- cyclopropyl-7-fluoro- 9-methoxy-4 -oxo-4H-quinolizine -3 - carboxylic acid; 8- { [ (S) -2 , 8-diazabicyclo [4.3.0] non-5-en] -8-yl } -1- cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3 - carboxylic acid; 8- [ (3 -N-methoxyimino-4 -aminomethylpyrrolidine) -1-yl] -1- cyclopropyl-7-fluoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid; and pharmaceutically acceptable salts thereof. The present invention further includes, within its scope, pharmaceutically acceptable salts of the compounds of formula (I). The non-toxic salts which fall within the scope of the present invention may include inorganic acid salts such as hydrochloride, sulfate, phosphate and nitrate, and organic acid salts such as tartrate, fumarate, citrate, mesylate and acetate. The pharmaceutically acceptable salt of the present invention may be prepared in accordance with a known method, e.g., by reacting the compounds of formula (I) with a suitable acid in the presence of a solvent, e.g., methanol, ethanol, dichloromethane, ethyl acetate or diethyl ether. The compound of formula (I) may be prepared by a process which comprises reacting a 4-oxoquinolizine-3- carboxylic acid derivative of formula (II) with an amine of formula (III) in a suitable solvent in the presence of a base . R 2 H ( in : wherein, R 1 and R 2 have the same meanings as defined above; and X is halogen such as F and Cl, or εulfonyl group. The condensation reaction of compounds (II) and (III) may be conducted at a temperature ranging from 20 to 120°C. Exemplary solvents which may be suitably used in the process of the present invention include acetonitrile, dimethylformamide, dimethylsulfoxide and pyridine. The base which can be used in practicing the present invention may be an inorganic base, or an organic base such as triethylamine, pyridine, diazabicyclo [5.4.0] undec-7-ene and diisopropylamine . The compound of formula (II) may be prepared in accordance with the method disclosed in PCT Publication No. WO 95/10519. The compound of formula (III) may be prepared in accordance with the procedure disclosed in U.S. Patent No. 5,631,266 and 35th ICAAC, San Francisco, 1995, Abstract No. F204. The compounds of the present invention may be administered, either orally or intraperitoneally, in an effective amount ranging from 0.01 mg/kg to 100 mg/kg, preferably from 0.01 mg/kg to 50 mg/kg to a subject patient per day. The present invention also includes within its scope an antibacterial composition comprising one or more of the inventive compounds as an active ingredient, in association with a pharmaceutically acceptable carrier, excipient and/or other additives, if necessary. The active ingredient present in the composition may range from 5% to 20% by weight thereof. The following Examples are given for the purpose of illustration only, and are not intended to limit the scope of the invention. Example 1: 8- { [ (R) -2 , 8-diazabicyclo [4.3.0] non-5-en] -8-yl} - l-cyclopropyl-7-fluoro- 9 -methyl^-oxo^H-quinolizine-S- carboxylic acid lOOmg of 8-chloro-l-cyclopropyl-7-fluoro- 9-methyl-4- oxo-4H-quinolizine-3 -carboxylic acid, 70mg of (R)-2,8- diazabicyclo [4.3.0] non-5-ene • 2HC1 and 200mg of diazabicyclo [5. .0] undec-7-ene were added to 5ml of acetonitrile and the mixture was refluxed for 10 hours. Then, the resulting mixture was cooled and the solvent was distilled off under a reduced pressure. The residue was dissolved in 10ml of methylene chloride, washed with water, dried over anhydrous magnesium sulfate and passed through a column filled with alumina. After removing the solvent, the residue was dissolved in methanol and activated charcoal was added thereto. The mixture was stirred to remove brown impurities and the solvent was distilled off to obtain 98mg of the title compound as a yellow solid. Element Analysis (C 21 H 22 N 3 0 3 F) Exp. (%) : C 65.71; H 5.73; N 10.88 Calc. (%) : C 65.78; H 5.78; N 10.96 Example 2: 8- { [ (S) -2 , 8-diazabicyclo [4.3.0] non-5-en] -8-yl} - l-cyclopropyl-7-fluoro- 9-methyl-4 -oxo-4H-quinolizine-3- carboxylic acid The procedure of Example 1 was repeated except that (S) -2, 8-diazabicyclo [4.3.0] non-5-ene • 2HC1 was used as a starting material in place of (R) -2, 8 -diazabicyclo [4.3.0] - non-5-ene- 2HC1 to obtain 84mg of the title compound as a yellow solid. Element Analysis ( C 21 H 22 N 3 0 3 F) Exp. (%) : C 65.71; H 5.73; N 10.88 Calc. (%) : C 65.78; H 5.78; N 10.96 Example 3: 8- { [ (R) -5-methyl-2 , 8 -diazabicyclo [4.3.0] non-5- en] - 8 -yl }- 1 -cyclopropyl - 7 - f luoro- 9 -methyl -4 -OXO-4H- quinolizine-3 -carboxylic acid The procedure of Example 1 was repeated except that 84mg of (R) -5-methyl-2 , 8-diazabicyclo [4.3.0] non-5-ene • 2HC1 was used as a starting material in place of (R)-2,8- diazabicyclo [4.3.0] non-5-ene- 2HC1 to obtain 88mg of the title compound as a yellow solid. Element Analysis (C 22 H 24 N 3 0 3 F) Exp. (%) : C 66.21; H 6.13; N 10.58 Calc. (%) : C 66.48; H 6.09; N 10.57 Example 4 : 8- [ (l-aminomethyl-3-azabicyclo [2.1.1] hex) -3-yl] - l-cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3 - carboxylic acid The procedure of Example 1 was repeated except that 74mg of l-aminomethyl-3 -azabicyclo [2.1.1] hexane • 2HC1 was used as a starting material in place of (R)-2,8- diazabicyclo [4.3.0] non-5-ene- 2HC1 to obtain 70mg of the title compound as a yellow solid. Element Analysis (C 20 H 22 N 3 O 3 F) Exp.(%) : C 64.51; H 5.99; N 11.34 Calc. (%) : C 64.68; H 5.97; N 11.31 Example 5: 8- [ (l-amino-3-azabicyclo [2.1.1] hex) -3-yl] -1- cyclopropyl-7-fluoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid The procedure of Example 1 was repeated except that 1- amino-3 -azabicyclo [2.1.1] hexane -2HC1 was used as a starting material in place of (R) -2 , 8-diazabicyclo- [4.3.0] non-5- ene-2HCl to obtain 72mg of the title compound as a yellow solid. Element Analysis (C 19 H 20 N 3 O 3 F) Exp. (%) : C 63.87; H 5.86; N 11.69 Calc. (%) : C 63.86; H 5.94; N 11.76 Example 6: 8- [ (l-amino-3-azabicyclo [3.1.1] hept) -3-yl] -1- eyelopropyl-7-fluoro- 9 -methyl -4 -oxo-4H- quinolizine -3 - carboxylic acid The procedure of Example 1 was repeated except that 82mg of l-amino-3-azabicyclo [3.1.1] heptane • 2HC1 was used as a starting material in place of (R) -2 , 8-diazabicyclo- [4.3.0] non-5-ene • 2HC1 to obtain 112mg of the title compound as a yellow solid. Element Analysis (C 20 H 22 N 3 O 3 F) Exp. (%) : C 64.86; H 5.91; N 11.32 Calc. (%) : C 64.68; H 5.97; N 11.31 Example 7: 8- [ (l-aminomethyl-3 -azabicyclo [3.1.1] hept) -3- yl] -l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid The procedure of Example 1 was repeated except that 90mg of l-amino-3 -azabicyclo [3.1.1] heptane • 2HC1 was used as a starting material in place of (R) -2 , 8-diazabicyclo- [4.3.0] non-5 -ene-2HCl to obtain 112mg of the title compound as a yellow solid. Element Analysis ( C 21 H 24 N 3 0 3 F) Exp. (%) : C 66.47; H 6.26; N 10.90 Calc. (%) : C 66.44; H 6.28; N 10.90 Example 8: 8- [ (l-N-methylaminomethyl-3-azabicyclo [3.1.1] - hept) -3-yl] -1-cyclopropyl- 7 - fluoro- 9 -methyl-4 -oxo-4H- quinolizine-3 -carboxylic acid The procedure of Example 1 was repeated except that 99mg of l-N-methylaminomethyl-3 -azabicyclo [3.1.1] - heptane -2HC1 was used as a starting material in place of (R) -2, 8-diazabicyclo [4.3.0] non-5-ene • 2HC1 to obtain 137mg of the title compound as a yellow solid. Element Analysis (C 22 H 26 N-,0 3 F) Exp. (%) : C 66.21; H 6.57; N 10.61 Calc.(%) : C 66.15; H 6.56; N 10.52 Example 9: 8- [ (l-N-methylamino-3 -azabicyclo [3.1.1] hept) -3- yl] -l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid The procedure of Example 1 was repeated except that 92mg of l-N-methylamino-3 -azabicyclo [3.1.1] heptane • 2HC1 was used as a starting material in place of (R)-2,8- diazabicyclo [4.3.0] non-5-ene • 2HC1 to obtain 112mg of the title compound as a yellow solid. Element Analysis (C 21 H 24 N 3 0 3 F) Exp. (%) : C 66.38; H 6.09; N 10.61 Calc.(%) : C 65.45; H 6.23; N 10.90 Example 10: 8- [ (3-amino-3-carbamoylpyrrolidine) -1-yl] -1- cyclopropyl-7-fluoro- 9 -methyl -4 -oxo-4H-quinolizine -3 - carboxylic acid The procedure of Example 1 was repeated except that 92mg of 3-amino-3-carbamoylpyrrolidine • 2HC1 was used as a starting material in place of (R) -2 , 8 -diazabicyclo [4.3.0] - non-5-ene- 2HC1 to obtain 107mg of the title compound as a yellow solid. Element Analysis ( C 19 H 2l N 4 0 F) Exp . ( % ) : C 58 . 71 ; H 5 . 41 ; N 14 . 39 Calc . ( % ) : C 58 . 76 ; H 5 . 45 ; N 14 . 43 Example 11: 8- [ (3-N-methylaminomethyl-4-N-methylamino- pyrrolidine) -1-yl] -l-cyclopropyl-7-fluoro-9-methyl-4-oxo- 4H-quinolizine-3 -carboxylic acid The procedure of Example 1 was repeated except that 102mg of 3-N-methylaminomethyl-4-N-methylaminopyrrolidine • 2HC1 was used as a starting material in place of (R)-2,8- diazabicyclo- [4.3.0] non-5-ene- 2HC1 to obtain 127mg of the title compound as a yellow solid. Element Analysis (C 20 H 25 N 4 O 3 F) Exp. (%) : C 62.91; H 6.98; N 14.20 Calc.(%) : C 62.69; H 6.72; N 13.93 Example 12: 8- [ (3 -amino-4 -aminomethylpyrrolidine) -1-yl] -1- cyclopropyl-7-fluoro- 9 -methyl -4 -oxo-4H-quinolizine -3 - carboxylic acid The procedure of Example 1 was repeated except that 96mg of 3 -amino-4 -aminomethylpyrrolidine • 2HC1 was used as a starting material in place of (R) -2, 8-diazabicyclo- [4.3.0] non-5-ene • 2HC1 to obtain 116mg of the title compound as a yellow solid. Element Analysis (C 19 H 23 N 4 0 3 F) Exp. (%) : C 60.91; H 6.21; N 14.88 Calc.(%) : C 60.95; H 6.19; N 14.96 Example 13 : 8- [ (3-aminomethyl-4-N-methoxyaminopyrrolidine) - 1-yl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine- 3 -carboxylic acid The procedure of Example 1 was repeated except that llOmg of 3-aminomethyl-4-N-methoxyaminopyrrolidine • 2HC1 was used as a starting material in place of (R)-2,8- diazabicyclo [4.3.0] non-5-ene • 2HC1 to obtain 107mg of the title compound as a yellow solid. Element Analysis (C 20 H 25 N 4 O 4 F) Exp. (%) : C 59.31; H 6.26; N 13.78 Calc.(%) : C 59.40; H 6.23; N 13.85 Example 14 : 8- [ (3-amino-4-N-methoxyaminopyrrolidine) -1-yl] - 1-cyclopropyl- 7- fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid The procedure of Example 1 was repeated except that llOmg of 3-amino-4-N-methoxyaminopyrrolidine • 2HC1 was used as a starting material in place of (R) -2, 8-diazabicyclo- [4.3.0] non-5-ene-2HCl to obtain 122mg of the title compound as a yellow solid. Element Analysis (C 2Q H 25 N 4 0 4 F) Exp. (%) : C 59.41; H 6.29; N 13.91 Calc.(%) : C 59.40; H 6.23; N 13.85 Example 15: 8- [ (3-N-methoxyamino-4-N-methylaminomethyl- pyrrolidine) -1-yl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo- 4H-quinolizine-3 -carboxylic acid The procedure of Example 1 was repeated except that 92mg of 3-N-methoxyamino-4-N-methylaminopyrrolidine • 2HC1 was used as a starting material in place of (R)-2,8- diazabicyclo [4.3.0] non-5-ene • 2HC1 to obtain 107mg of the title compound as a yellow solid. Element Analysis (C 21 H 27 N 4 0F) Exp. (%) : C 60.21; H 6.54; N 13.37 Calc.(%) : C 60.27; H 6.50; N 13.39 Example 16: 8- { [3- (3 -pyridylmethyl) oxy- 4 -aminomethylpyrrolidine] -1-yl} - 1 -cyclopropyl- 7- f luoro- 9 -methyl- 4- oxo- 4H-quinolizine-3 -carboxylic acid The procedure of Example 1 was repeated except that 120mg of 3 - ( 3 -pyridylmethyl ) oxy- 4 - aminomethyl pyrrolidine • 2HC1 was used as a starting material in place of (R) -2, 8-diazabicyclo- [4.3.0] non-5-ene • 2HC1 to obtain 137mg of the title compound as a yellow solid. Element Analysis (C 25 H 27 N 4 0 4 F) Exp. (%) : C 55.59; H 5.21; N 18.11 Calc. (%) : C 64.38; H 5.79; N 12.02 Example 17: 8- { [3- (2 -pyridylmethyl) oxy-4-aminomethyl- pyrrolidine] -1-y1 } - 1-cyclopropyl-7-fluoro-9-methyl-4 -oxo- 4H-quinolizine-3 -carboxylic acid The procedure of Example 1 was repeated except that 120mg of 3 -( 2 -pyridylmethyl ) oxy- 4 - aminomethyl pyrrolidine • 2HC1 was used as a starting material in place of (R) -2, 8-diazabicyclo- [4.3.0] non-5-ene • 2HC1 to obtain 146mg of the title compound as a yellow solid. Element Analysis (C 25 H 27 N 4 0 4 F) Exp. (%) : C 64.48; H 5.85; N 12.14 Calc. (%) : C 64.38; H 5.79; N 12.02 Example 18: 8- { [3- (4 -pyridylmethyl) oxy-4-aminomethyl- pyrrolidine] -1-yl } -l-cyclopropyl-7-fluoro-9-methyl-4 -oxo- 4H-quinolizine-3 -carboxylic acid The procedure of Example 1 was repeated except that 120mg of 3 - (4 -pyridylmethyl ) oxy-4 - aminomethyl - pyrrolidine • 2HC1 was used as a starting material in place of (R) -2, 8-diazabicyclo- [4.3.0] non-5-ene • 2HC1 to obtain 131mg of the title compound as a yellow solid. Element Analysis (C 25 H 27 N 4 0 4 F) Exp. (%) : C 64.21; H 5.63; N 11.86 Calc. (%) : C 64.38; H 5.79; N 12.02 Example 19: 8- { [3 -N- (3 -pyridylmethyl) amino-4-aminomethyl- pyrrolidine] -1 -yl } -1-cyclopropyl-7-fluoro- 9-methyl-4 -oxo- 4H-quinolizine-3 -carboxylic acid The procedure of Example 1 was repeated except that 112mg of 3 -N- (3 -pyridylmethyl) amino-4 -aminomethylpyrrolidine • 2HC1 was used as a starting material in place of (R) -2, 8 -diazabicyclo- [4.3.0] non-5-ene • 2HC1 to obtain 107mg of the title compound as a yellow solid. Element Analysis (C 25 H 28 N 5 0 3 F) Exp.(%) : C 64.41; H 6.31; N 15.32 Calc. (%) : C 64.52; H 6.02; N 15.05 Example 20: 8- [ (3 -N-benzylamino-4 -aminomethylpyrrolidine) - 1-yl] -l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine- 3 -carboxylic acid The procedure of Example 1 was repeated except that 118mg of 3 -N-benzylamino-4 -aminomethylpyrrolidine • 2HC1 was used as a starting material in place of (R)-2,8- diazabicyclo- [4.3.0] non-5-ene- 2HC1 to obtain 137mg of the title compound as a yellow solid. Element Analysis (C 26 H 29 N 4 0 3 F) Exp. (%) : C 67.48; H 6.56; N 12.32 Calc.(%) : C 67.24; H 6.25; N 12.07 Example 21: 8-{ [ (R) -2, 8-diazabicyclo [4.3.0]non-5-en] -8-yl}- 1-cyclopropyl- 7- fluoro-9 -methoxy-4-oxo-4H-quinolizine-3- carboxylic acid The procedure of Example 1 was repeated except that 8- chloro-l-cyclopropyl-7-f luoro-9 -methoxy-4 -oxo-4H- quinolizine-3 -carboxylic acid was used as a starting material in place of 8 -chloro-1-cyclopropyl-7-fluoro-9- methyl-4-oxo-4H-quinolizine-3-carboxylic acid and the amount of (R) -2 , 8 -diazabicyclo [4.3.0] non-5-ene • 2HC1 used was 80mg to obtain 92mg of the title compound as a yellow solid. Element Analysis (C 21 H 22 N-,0 3 F) Exp. (%) : C 65.71; H 5.73; N 10.88 Calc.(%) : C 65.80; H 5.74; N 10.97 Example 22 : 8-{ [ (S) -2, 8-diazabicyclo [4.3.0] non-5-en] -8-yl}- l-cyclopropyl-7-f luoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid The procedure of Example 1 was repeated except that 8- chloro-l-cyclopropyl-7-fluoro-9 -met hoxy -4 -oxo-4H- quinolizine- 3 -carboxylic acid and 80mg of (S)-2,8- diazabicyclo [4.3.0] non-5-en- 2HC1 were used as starting materials in place of 8 -chloro-1 -cyclopropyl- 7- f luoro-9- methyl-4-oxo-4H-quinolizine-3-carboxylic acid and 70mg of (R) -2, 8-diazabicyclo- [4.3.0] non-5-ene • 2HC1, respectively, to obtain 89mg of the title compound as a yellow solid. Element Analysis (C 21 H 21 N 3 0 3 F 2 ) Exp. (%) : C 65.86; H 5.46; N 10.90 Calc.(%) : C 65.97; H 5.50; N 10.99 Example 23 : 8- [ (3-N-methoxyimino-4-aminomethylpyrrolidine) - 1-yl] - 1-cyclopropyl-7-fluoro- -methyl- -oxo-4H-quinolizine- 3 -carboxylic acid The procedure of Example 1 was repeated except that 104mg of 3 -N-methoxyimino-4 -aminomethylpyrrolidine was used as a starting material in place of 70mg of (R)-2,8- diazabicyclo- [4.3.0] non-5-ene • 2HC1 to obtain 142mg of the title compound as a yellow solid. Element Analysis (C 2Q H 23 N 4 0 4 F) Exp. (%) : C 59.92; H 5.73; N 13.97 Calc. (%) : C 59.70; H 5.72; N 13.93 Test 1. Antibacterial activity in vitro In order to measure antibacterial activities of the compounds of the present invention, minimal inhibitory concentrations (MIC, μg/ml) of representative compounds against standard strains were determined and compared with ciprofloxacin and sparfloxacin, which were used as control compounds . The MIC values were determined employing a two-fold dilution method and Muller Hinton agar medium. Each of the Hoechst 345 standard strains having the concentration of 10 7 CFU/ml was inoculated onto the medium, and incubated at 37°C for 18 hours. The standard test strains used are as follows: Gram-positive bacteria 1. Streptococcus pyogenes A 308 2. Streptococcus pyogenes A 77 3. Streptococcus faecium MD 8b 4. Staphylococcus aureus SG 511 5. Staphylococcus aureus 285 6. Staphylococcus aureus 503 Gram-negative bacteria 7. Escherichia coli 078 8. Escherichia coli DC 0 9. Escherichia coli DC 2 10. Escherichia coli TEM 11. Escherichia coli 1507 E 12. Pseudomonas aeruginosa 9027 13. Pseudomonas aeruginosa 1592 E 14. Pseudomonas aeruginosa 1771 15. Pseudomonas aeruginosa 1771 M 16. Salmonella typhimurium 17. Klebsiella oxytoca 1082 E 18. Klebsiella aerogenes 1552 E 19. Enterobacter cloacae P 99 20. Enterobacter cloacae 1321 E The results of the MIC tests are shown in Table I Table I. Minimal Inhibitory Concentration (MIC) μg/ml note : ciprofloxacin: l-cyclopropyl-6-fluoro-7- (piperazin-1-yl) ■ 4 -oxoquinoline-3 -carboxylic acid sparfloxacin : l-cyclopropyl-5-amino-6 , 8-difluoro-7- (3 , 5- dimethylpiperazin-1-yl) -4-oxoquinoline- 3 -carboxylic acid Test 2. Selectivity Index Selectivity indexes of the compounds of the present invention and control compounds were measured using gyrase purified from of E * ^ coli and calf thymus topoisomerase II obtained from Topogen. Co. The selectivity index (S.I.) was calculated by the equation 1. IC 100, Gyrase wherein, IC 100 τ π is the concentration of a compound to inhibit the enzyme activity of topoisomerase II and IC 100 Gyrase is the concentration of a compound to inhibit the enzyme activity of gyrase of E .^ coli . The results are shown in Table II. Table II Selectivity Index As can be seen from Tables I and II, the quinolizine carboxylic acid derivatives of the present invention generally exhibit excellent antibacterial activities against Gram-positive and Gram-negative bacteria and much lower toxicity as compared with the known compounds . While the embodiments of the subject invention have been described and illustrated, it is obvious that various changes and modifications can be made therein without departing from the spirit of the present invention which should be limited only by the scope of the appended claims.

Claims: What is claimed is: 1. A 4-oxo-quinolizine carboxylic acid derivative of formula (I) or a pharmaceutically acceptable salt thereof: wherein R >1 1 is a C,. 4 alkyl group optionally substituted with one ore more halogens, or a C,_ 4 alkoxy group; R is R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 2 , R 13 and R 14 are each independently H or a C 1.4 alkyl group optionally substituted with a pyridyl, arylalkyl or aryl group. 2. The quinolizine carboxylic acid derivative of claim 1, wherein: R 1 is CH 3 or OCH 3 ; R 2 is HN, V-R 3 HN V-R 3 R 4 HN - N R 5 R 6 R 3 , R 5 , R 6 , R 8 , R 11 and R 12 are each independently H or CH 3 ; R 4 is H or a methyl group optionally substituted with a pyridyl or benzyl group; R 7 , R 9 , R 10 and R 13 are H or CH 3 ; and R 14 is CH 3 . 3. The quinolizine carboxylic acid derivative of claim 1, selected from the group consisting of: 8-{ [ (R) -2, 8-diazabicyclo[4.3.0]non-5-en] -8-yl}-l- cyclopropyl -7-fluoro-9 -methyl -4 - oxo-4H- quinolizine -3 - carboxylic acid; 8-{ [ (S) -2,8-diazabicyclo[4.3.0]non-5-en] -8-yl}-l- cyclopropyl-7-fluoro-9 -methyl -4 - oxo -4H- quinolizine - 3 - carboxylic acid; 8-{ [ (R) -5-methyl-2, 8 -diazabicyclo [4.3.0]non-5-en] -8-yl}-l- cyclopropyl-7-fluoro- 9 -methyl -4 - oxo -4H- quinolizine- 3 - carboxylic acid; 8- [ (1 -aminomethyl -3-azabicyclo [2.1.1] hex) -3-yl] -1- cyclopropyl-7-f luoro- 9 -methyl -4 - oxo -4H- quinolizin -3 - carboxylic acid; 8- [ (l-amino-3 -azabicyclo [2.1.1] hex) -3-yl] -l-cyclopropyl-7- f luoro- 9 -methyl -4 - oxo -4H- quinolizine- 3 -carboxylic acid; 8- [ (l-amino-3-azabicyclo [3.1.1] hept) -3-yl] -1 -cyclopropyl- 7- f luoro- 9 -methyl -4 -oxo-4H-quinolizine- 3 -carboxylic acid; 8 - [ (1 -aminomethyl -3 -azabicyclo[3.1.1]hept) -3-yl] -1- cyclopropyl -7-f luoro- 9 -methyl -4 - oxo -4H- quinolizine -3 - carboxylic acid; 8- [ (l-N-methylaminomethyl-3 -azabicyclo [3.1.1] -hept) -3-yl] - l-cyclopropyl-7-f luoro- 9 -methyl -4 -oxo-4H-quinolizine-3 - carboxylic acid; 8- [ (1-N-methylamino- 3 -azabicyclo [3.1.1] hept) -3-yl] -1- cyclopropyl - 7 - f luoro - 9 -me thy 1 - 4 - oxo -4H-quinolizine-3- carboxylic acid; 8- [ (3-amino-3-carbamoylpyrrolidine) -1-yl] -1 -cyclopropyl- 7 - f luoro- 9 -methyl -4 -oxo -4H- quinolizine- 3 -carboxylic acid; 8- [ (3-N-methylaminomethyl-4-N-methylaminopyrrolidine) -1- yl] -l-cyclopropyl-7-f luoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid; 8- [ (3-amino-4-aminomethylpyrrolidine) -1-yl] - 1 -cyclopropyl ■ 7-f luoro -9 -methyl- 4- oxo- 4H- quinolizine -3 -carboxylic acid; 8- [ (3 -aminomethyl-4 -N-methoxyaminopyrrolidine) -1-yl] -1- cyclopropyl-7-f luoro- 9 -methyl -4 - oxo -4H- quinolizine -3 ■ carboxylic acid; 8- [ ( 3 - amino - 4 -N-me t hoxyaminopyrrol idine ) -1-yl] -1- cyclopropyl-7-f luoro- 9 -methyl -4 - oxo -4H- quinolizine -3 ■ carboxylic acid; 8- [ (3-N-methoxyamino-4-N-methylaminomethylpyrrolidine] -1- yl} -l-cyclopropyl-7-f luoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid; 8-{ [3- (3 -pyridylmethyl) oxy-4-aminomethylpyrrolidine] -1-yl}- l-cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid; 8-{ [3- (2 -pyridylmethyl) oxy-4-aminomethylpyrrolidine] -1-yl}- l-cyclopropyl-7-fluoro- 9 -methy1-4 -oxo-4H-quinolizine-3- carboxylic acid; 8-{ [3- (4 -pyridylmethyl) oxy-4 -aminomethylpyrrolidine] -1-yl}- l-cyclopropyl-7-fluoro- 9 -methyl-4 -oxo-4H-quinolizine- 3 - carboxylic acid; 8-{ [3-N- (3 -pyridylmethyl) amino-4 -aminomethylpyrrolidine] -1- yl} -l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid; 8- [ ( 3 -N-benzylamino-4 -aminomethylpyrrolidine) -1-yl] -1- cyclopropyl-7-fluoro- 9 -methyl -4 - oxo-4H- quinolizine -3 - carboxylic acid; 8-{ [(R) -2,8-diazabicyclo[4.3.0] on-5 -en] -8-yl}-l- cyclopropyl-7-fluoro- 9 -methoxy-4 -oxo-4H-quinolizine-3 - carboxylic acid; 8-{ [ (S) -2,8-diazabicyclo[4.3.0]non-5-en] -8-yl}-l- cyclopropyl-7-fluoro-9-methoxy-4 -oxo-4H- quinolizine -3 - carboxylic acid; and 8- [ (3 -N-methoxyimino-4-aminomethylpyrrolidine) -1-yl] -1- cyclopropyl-7-fluoro- 9 -methyl -4 - oxo -4H-quinolizine -3 - carboxylic acid; and pharmaceutically acceptable salts thereof. 4. A process for preparing a quinolizine carboxylic acid derivative of formula (I), which comprises reacting a compound of formula (II) with a compound of formula (III) in a solvent in the presence of a base: R H ( I I I ) wherein, R 1 and R * ? have the same meanings as defined in claim 1; and X is a halogen or sulfonyl group. 5. An antibacterial composition comprising an effective amount of the quinolizine carboxylic acid derivative or a pharmaceutically acceptable salt thereof of claim 1 as an active ingredient, and a pharmaceutically acceptable carrier and/or adjuvant.

Inventors: HA YOUNG HWAN, KIM DO YEOB, PARK TAE HO, HA, YOUNG, HWAN, KIM, DO, YEOB, PARK, TAE, HO
Applicants: HA YOUNG HWAN, KIM DO YEOB, KOREA RES INST CHEM TECH, PARK TAE HO, HA, YOUNG, HWAN, KIM, DO, YEOB, KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY, PARK, TAE, HO
Application year: 1998
Main classification: C07D401
IPC codes: A61K31, A61P31, C07D455, C07D471