WO1999007696A1 - Quinolizine carboxylic acid derivatives - Google Patents

Quinolizine carboxylic acid derivatives Download PDF

Info

Publication number
WO1999007696A1
WO1999007696A1 PCT/KR1998/000247 KR9800247W WO9907696A1 WO 1999007696 A1 WO1999007696 A1 WO 1999007696A1 KR 9800247 W KR9800247 W KR 9800247W WO 9907696 A1 WO9907696 A1 WO 9907696A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxylic acid
quinolizine
oxo
cyclopropyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR1998/000247
Other languages
French (fr)
Inventor
Tae Ho Park
Young Hwan Ha
Do Yeob Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Korea Research Institute of Chemical Technology KRICT
Original Assignee
Korea Research Institute of Chemical Technology KRICT
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Korea Research Institute of Chemical Technology KRICT filed Critical Korea Research Institute of Chemical Technology KRICT
Priority to EP98938997A priority Critical patent/EP1003735A1/en
Priority to JP2000506200A priority patent/JP2001512725A/en
Publication of WO1999007696A1 publication Critical patent/WO1999007696A1/en
Priority to US09/500,283 priority patent/US6235751B1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • 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.
  • 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.
  • R ,1' is a C 1-4 alkyl group optionally substituted with one ore more halogens, or a C.,. ⁇ alkoxy group;
  • 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.
  • 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:
  • 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.
  • 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 1 and R 2 have the same meanings as defined above; and X is halogen such as F and Cl, or ⁇ ulfonyl 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
  • 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.
  • 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
  • Example 2 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)
  • Example 2 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)
  • Example 2 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)
  • 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
  • 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
  • Example 2 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)
  • Example 10 8- [ (3-amino-3-carbamoylpyrrolidine) -1-yl] -1- cyclopropyl-7-fluoro- 9 -methyl -4 -oxo-4H-quinolizine -3 - carboxylic acid
  • Example 1 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)
  • Example 12 8- [ (3 -amino-4 -aminomethylpyrrolidine) -1-yl] -1- cyclopropyl-7-fluoro- 9 -methyl -4 -oxo-4H-quinolizine -3 - carboxylic acid
  • Example 2 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)
  • Example 13 8- [ (3-aminomethyl-4-N-methoxyaminopyrrolidine) - 1-yl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine- 3 -carboxylic acid
  • Example 1 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)
  • Example 2 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)
  • 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
  • Example 2 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)
  • 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
  • Example 2 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)
  • Example 2 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)
  • 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
  • Example 2 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)
  • 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
  • Example 2 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)
  • Example 2 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)
  • 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
  • Example 1 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.
  • 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
  • Example 2 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
  • Example 2 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)
  • MIC minimal inhibitory concentrations
  • 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
  • Streptococcus pyogenes A 308 2. Streptococcus pyogenes A 77
  • 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 ⁇ ⁇ 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 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 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A quinolizine carboxylic acid derivative of formula (I) or a pharmaceutically acceptable salt thereof, wherein R?1 and R2¿ 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:
Figure imgf000004_0001
wherein
R ,1' is a C 1-4 alkyl group optionally substituted with one ore more halogens, or a C.,.^ alkoxy group;
R2 is
Figure imgf000004_0002
R13HNχ /--NHOCH3 or
Figure imgf000004_0003
Figure imgf000005_0001
R3,
Figure imgf000005_0002
R5, R6, R7, R8, R9, R10, R11, R12, R13 and Ru 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: R1 is CH3 or OCH3; R2 is
Figure imgf000005_0003
Figure imgf000005_0004
R3, R5, R6, R8, R1 and R12 are each independently H or CH3; R4 is H or a methyl group optionally substituted with a pyridyl or benzyl group; R7, R9, R10 and R13 are H or CH3; R14 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 .
Figure imgf000008_0001
R2H ( in :
wherein, R1 and R2 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 (C21H22N303F)
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 ( C21H22N303F)
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 (C22H24N303F)
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 (C20H22N3O3F)
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 (C19H20N3O3F)
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 (C20H22N3O3F)
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 ( C21H24N303F)
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 (C22H26N-,03F)
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 (C21H24N303F)
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 ( C19H2lN40 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 (C20H25N4O3F)
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 (C19H23N403F)
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 (C20H25N4O4F)
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 (C2QH25N404F)
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 (C21H27N40F)
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 (C25H27N404F)
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 (C25H27N404F)
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 (C25H27N404F)
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 (C25H28N503F)
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 (C26H29N403F)
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 (C21H22N-,03F)
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 (C21H21N303F2) 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 (C2QH23N404F)
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 107CFU/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
Figure imgf000019_0001
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.
Figure imgf000020_0001
IC 100, Gyrase
wherein, IC100 τ π is the concentration of a compound to inhibit the enzyme activity of topoisomerase II and IC100 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
Figure imgf000020_0002
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:
Figure imgf000021_0001
wherein
R >11 is a C,.4 alkyl group optionally substituted with one ore more halogens, or a C,_4 alkoxy group;
R is
Figure imgf000021_0002
Figure imgf000021_0003
R3, R4, R5, R6, R7, R8, R9, R10, R11, R2, R13 and R14 are each independently H or a C1.4 alkyl group optionally substituted with a pyridyl, arylalkyl or aryl group.
2. The quinolizine carboxylic acid derivative of claim 1, wherein: R1 is CH3 or OCH3; R2 is
HN, V-R3 HN V-R3 R4HN -NR5R6
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
R3, R5, R6, R8, R11 and R12 are each independently H or CH3; R4 is H or a methyl group optionally substituted with a pyridyl or benzyl group; R7, R9, R10 and R13 are H or CH3; and R14 is CH3.
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 Γûá
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 Γûá 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 Γûá 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:
Figure imgf000024_0001
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.
PCT/KR1998/000247 1997-08-09 1998-08-08 Quinolizine carboxylic acid derivatives Ceased WO1999007696A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP98938997A EP1003735A1 (en) 1997-08-09 1998-08-08 Quinolizine carboxylic acid derivatives
JP2000506200A JP2001512725A (en) 1997-08-09 1998-08-08 Quinolizine carboxylic acid derivative
US09/500,283 US6235751B1 (en) 1997-08-09 2000-02-08 Quinolizine carboxylic acid derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1997/38037 1997-08-09
KR1019970038037A KR100241673B1 (en) 1997-08-09 1997-08-09 Quinolizine Carboxylic acid Derivatives

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/500,283 Continuation US6235751B1 (en) 1997-08-09 2000-02-08 Quinolizine carboxylic acid derivatives

Publications (1)

Publication Number Publication Date
WO1999007696A1 true WO1999007696A1 (en) 1999-02-18

Family

ID=19517169

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR1998/000247 Ceased WO1999007696A1 (en) 1997-08-09 1998-08-08 Quinolizine carboxylic acid derivatives

Country Status (5)

Country Link
US (1) US6235751B1 (en)
EP (1) EP1003735A1 (en)
JP (1) JP2001512725A (en)
KR (1) KR100241673B1 (en)
WO (1) WO1999007696A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022614A1 (en) * 2000-09-12 2002-03-21 Sankyo Company,Limited Quinolizine derivatives
US6509349B1 (en) 2000-12-14 2003-01-21 The Procter & Gamble Company Antimicrobial 2-pyridones, their compositions and uses
US6645981B2 (en) 2000-12-14 2003-11-11 The Procter & Gamble Company Antimicrobial quinolones, their compositions and uses
WO2004092129A1 (en) * 2003-03-07 2004-10-28 Lg Life Sciences Ltd. New process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate
US7868021B2 (en) 1997-09-15 2011-01-11 Warner Chilcott Company, Llc Antimicrobial quinolones, their compositions and uses
WO2011031745A1 (en) 2009-09-09 2011-03-17 Achaogen, Inc. Antibacterial fluoroquinolone analogs
US8039485B2 (en) 2006-03-28 2011-10-18 Warner Chilcott Company, Llc Malate salts, and polymorphs of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid
WO2012047487A1 (en) * 2010-09-27 2012-04-12 Evolva Sa 2-pyridone antimicrobial compositions
US8158798B2 (en) 2006-03-28 2012-04-17 Taigen Biotechnology Co., Ltd. Coupling process for preparing quinolone intermediates
US9403818B2 (en) 2011-02-01 2016-08-02 Emergent Product Development Gaithersburg Inc. Antimicrobial 4-oxoquinolizines

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6706528B2 (en) * 2000-03-24 2004-03-16 The United States Of America As Represented By The Department Of Health And Human Services Fluorescent magnesium indicators
US6900224B2 (en) * 2002-07-31 2005-05-31 The Procter & Gamble Company Antimicrobial quinolones, their compositions and uses

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0308019A2 (en) * 1987-09-18 1989-03-22 Merck & Co. Inc. 4-Oxo-4H-quinolizine-3-carboxylic acids and derivatives thereof for treating bacterial infections
WO1995010519A1 (en) * 1993-10-14 1995-04-20 Abbott Laboratories Quinolizinone type compounds
WO1996039407A1 (en) * 1995-06-06 1996-12-12 Abbott Laboratories Quinolizinone type compounds

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5789591A (en) * 1996-10-23 1998-08-04 Abbott Laboratories Process for preparing 1-substituted 8-chloro-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester compounds
US5977133A (en) * 1998-08-19 1999-11-02 Abbott Laboratories Pyridone antibiotic with improved safety profile

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0308019A2 (en) * 1987-09-18 1989-03-22 Merck & Co. Inc. 4-Oxo-4H-quinolizine-3-carboxylic acids and derivatives thereof for treating bacterial infections
WO1995010519A1 (en) * 1993-10-14 1995-04-20 Abbott Laboratories Quinolizinone type compounds
WO1996039407A1 (en) * 1995-06-06 1996-12-12 Abbott Laboratories Quinolizinone type compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 122, No. 21, 22 May 1995, (Columbus, Ohio, USA), page 49, Abstract No. 255624m, ALDER J. et al., "Efficacies of ABT-719 and Related 2-Pyridones, Members of a New Class of Antibacterial Agents Against Experimental Bacterial Infections"; & ANTIMICROB. AGENTS CHEMOTHER., 1995, 39(4), 971-5, (Eng). *
CHEMICAL ABSTRACTS, Vol. 125, No. 17, 21 October 1996, (Columbus, Ohio, USA), page 1073, Abstract No. 221511u, LI Q. et al., "Synthesis and Structure-Activity Relationships of 2-Pyridones: A Novel Series of Potent DNA Gyrase Inhibitors as Antibacterial Agents"; & J. MED. CHEM., 1996, 39(16), 3070-3088, (Eng). *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7868021B2 (en) 1997-09-15 2011-01-11 Warner Chilcott Company, Llc Antimicrobial quinolones, their compositions and uses
WO2002022614A1 (en) * 2000-09-12 2002-03-21 Sankyo Company,Limited Quinolizine derivatives
US6509349B1 (en) 2000-12-14 2003-01-21 The Procter & Gamble Company Antimicrobial 2-pyridones, their compositions and uses
US6645981B2 (en) 2000-12-14 2003-11-11 The Procter & Gamble Company Antimicrobial quinolones, their compositions and uses
WO2004092129A1 (en) * 2003-03-07 2004-10-28 Lg Life Sciences Ltd. New process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate
RU2303029C2 (en) * 2003-03-07 2007-07-20 Эл Джи Лайф Сайенсиз Лтд. Novel method for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate (variants), intermediate compounds and method for preparing quinolone antibiotics
US7271272B2 (en) 2003-03-07 2007-09-18 Lg Life Sciences Ltd. Process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate
US7687629B2 (en) 2003-03-07 2010-03-30 Lg Life Sciences Ltd. Process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate
US8158798B2 (en) 2006-03-28 2012-04-17 Taigen Biotechnology Co., Ltd. Coupling process for preparing quinolone intermediates
US8039485B2 (en) 2006-03-28 2011-10-18 Warner Chilcott Company, Llc Malate salts, and polymorphs of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid
WO2011031745A1 (en) 2009-09-09 2011-03-17 Achaogen, Inc. Antibacterial fluoroquinolone analogs
WO2012047487A1 (en) * 2010-09-27 2012-04-12 Evolva Sa 2-pyridone antimicrobial compositions
US8962842B2 (en) 2010-09-27 2015-02-24 Evolva Sa 2-pyridone antimicrobial compositions
US10517865B2 (en) 2010-09-27 2019-12-31 Emergent Product Development Gaithersburg Inc. 2-pyridone antimicrobial compositions
US9403818B2 (en) 2011-02-01 2016-08-02 Emergent Product Development Gaithersburg Inc. Antimicrobial 4-oxoquinolizines
US10155021B2 (en) 2011-02-01 2018-12-18 Emergent Product Development Gaithersburg Inc. Antimicrobial 4-oxoquinolizines

Also Published As

Publication number Publication date
US6235751B1 (en) 2001-05-22
KR100241673B1 (en) 2000-03-02
EP1003735A1 (en) 2000-05-31
KR19990015746A (en) 1999-03-05
JP2001512725A (en) 2001-08-28

Similar Documents

Publication Publication Date Title
CA1340285C (en) Novel quinolonecarboxylic acid derivatives having at 7-position a piperidin-1-yl substituent
SK2212000A3 (en) Enantiomerically pure derivatives of quinolone carboxylic acid and naphthyridone carboxylic acid, process for their preparation, drugs containing these substances and their use
Cooper et al. Preparation and in vitro and in vivo evaluation of quinolones with selective activity against Gram-positive organisms
EP0591808A1 (en) Quinolonecarboxylic acids
EP1003735A1 (en) Quinolizine carboxylic acid derivatives
NZ231368A (en) Crystalline di- and tri- hydrate forms of a 1-carbacephalosporin derivative
EP0109284B1 (en) 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1h,5h-benzo(ij)quinolizine-2-carboxylic acid and derivatives
HU187449B (en) Process for producing new quiniline-carboxylic acid derivatives and pharmaceutical compositions containing them as active agents
US4472406A (en) Antimicrobial 6,7-dihydro-8-(imidazol-1-yl)-5-methyl-1-oxo-1H,5H-benzo [ij]quinolizine-2-carboxylic acids and derivatives
EP0516861A1 (en) Pyridonecarboxylic acid derivative
DE2914258C2 (en)
EP0090424B1 (en) New quinolone compounds and preparation thereof
DE3880953T2 (en) Quinoline derivatives, process for their preparation and antibacterial agent containing them.
EP0028778B1 (en) Antibacterial compositions comprising a beta-lactam-type compound and a 3-substituted propenoate
EP0481274A1 (en) 7-(2,7-Diazabicyclo[3.3.0]octyl)-3-quinolone- and -naphthyridonecarboxylic acid derivatives
OKADA et al. Synthesis and Structure-Activity Relationships of 7-(3'-Amino-4'-methoxypyrolidin-1'-yl)-1-cyclopropyl-6, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic Acids
WO1993013090A1 (en) Novel quinolone carboxylic acid derivatives and processes for preparing same
US4962112A (en) 7-(2-methyl-4-aminopyrrolidinyl)naphthryidine and quinoline compounds
Hagen et al. Synthesis and antibacterial activity of new quinolones containing a 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl] moiety. Gram-positive agents with excellent oral activity and low side-effect potential
Ziegler Jr et al. Synthesis and antibacterial activity of some 7‐substituted 1‐ethyl‐6‐fluoro‐1, 4‐dihydro‐4‐oxoquinoline‐3‐carboxylic acids: Ethers, secondary amines and sulfides as c‐7 substituents
EP0726269A1 (en) Quinolinecarboxylic acid derivative and salt thereof
CZ280594A3 (en) Derivatives of 1-(2-fluorocyclopropyl)-quinolonecarboxylic acid and 1-(2-fluorocyclopropyl)-naphthyridonecarboxylic acid, process of their preparation and use in medicaments
KR0139946B1 (en) Pyridone carboxylic acid derivatives and method of production thereof
JPS6270370A (en) Quinolonecarboxylic acid derivative and production thereof
US4567269A (en) Intermediates for the preparation of 6,7-dihydro-8-(imidazol-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acids

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 09500283

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1998938997

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1998938997

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998938997

Country of ref document: EP