EP0677052A1 - Novel quinolone derivatives and processes for preparing the same - Google Patents

Novel quinolone derivatives and processes for preparing the same

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Publication number
EP0677052A1
EP0677052A1 EP94903115A EP94903115A EP0677052A1 EP 0677052 A1 EP0677052 A1 EP 0677052A1 EP 94903115 A EP94903115 A EP 94903115A EP 94903115 A EP94903115 A EP 94903115A EP 0677052 A1 EP0677052 A1 EP 0677052A1
Authority
EP
European Patent Office
Prior art keywords
oxo
diazabicyclo
cyclopropyl
dihydroquinoline
fluoro
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.)
Withdrawn
Application number
EP94903115A
Other languages
German (de)
French (fr)
Inventor
Wan Joo Kim
Tae Ho Park
Jewn Giew Park
Moon Hwan Kim
Jae Du Ha
Neil Pearson
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.)
SmithKline Beecham Ltd
Korea Research Institute of Chemical Technology KRICT
Original Assignee
SmithKline Beecham Ltd
Korea Research Institute of Chemical Technology KRICT
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Application filed by SmithKline Beecham Ltd, Korea Research Institute of Chemical Technology KRICT filed Critical SmithKline Beecham Ltd
Publication of EP0677052A1 publication Critical patent/EP0677052A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel quinolone compounds, optical isomers and salts thereof which possess a broad antibacterial spectrum.
  • the present invention also relates to processes for " preparing these quinolone compounds.
  • quinolone antibacterial agents include enoxacin, norfloxacin, ofloxacin, ciprofloxacin and tosufloxacin.
  • enoxacin norfloxacin
  • ofloxacin norfloxacin
  • ciprofloxacin ciprofloxacin
  • tosufloxacin tosufloxacin.
  • An object of the present invention is to provide novel quinolone compounds of Formula (I), optical isomers and salts thereof:
  • R is as defined above or represents a straight chain or cyclic lower alkyl group having 1 to 3 carbon atoms or a straight chain or cyclic lower alkyl group having 1 to 3 carbon atoms which is substituted with a halogen atom, a phenyl group or a phenyl group substituted with one or two halogen atoms;
  • R 2 and R 3 may be the same or different and represent independently hydrogen, nitro, methoxycarbonyl and ethoxycarbonyl;
  • R 4 represents hydrogen, lower alkyl, lower alkoxy or an amino-protecting group
  • R 5 , Rg, R 7 and R g may be the same or different and represent independently hydrogen, lower alkyl optionally substituted by amino, hydroxyl or halogen
  • X represents hydrogen, halogen, amino or lower alkyl
  • Lower alkyl is preferably C,_ 6 alkyl, more preferably C alkyl, such as methyl or ethyl.
  • Acyl is preferably C,. 6 alkanoyl, optionally substituted phenylC,. 6 alkanoyl, alkyl groups optionally substituted by halogen such as fluorine.
  • Substituents on phenyl may be selected from halogen, carboxylic acid, carboxy ester, amino, quatenary ammonium, Cj. 6 alkoxy, hydroxy or phosphorous acids.
  • Esters include C,. 6 alkoxy carbonyl.
  • Y is preferably fluorine, chlorine or methoxy.
  • R is preferably ethyl, cyclopropyl or 2,4-difluorophenyl.
  • R, amino-protecting groups include lower alkyl such as methyl, ethyl and lower. alkoxycarbonyl such as butoxycarbonyl.
  • R 4 is preferably hydrogen.
  • R 5 , R 6 , R 7 and R 8 include hydrogen, methyl and ethyl.
  • at least three of R 5 , R 6 , R 7 and R 8 are hydrogen. Most preferably all are hydrogen.
  • Examples of X include hydrogen, fluorine, chlorine, amino and methyl, preferably hydrogen.
  • Preferred compounds of the present invention are;
  • optical isomers and pharmaceutically acceptable salts thereof are optical isomers and pharmaceutically acceptable salts thereof.
  • R,, R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 , R g and X are as defined above.
  • quinolone compounds of Formula (I) can be prepared as illustrated below.
  • a mixture of a compound of Formula (II) and carbonyldiimidazole (CDI) or thiocarbonyldiimidazole (TDI) in an organic solvent such as chloroform, acetonitrile and tetrahydrofuran is heated under reflux at a temperature between about 80°C and about 100°C for about 10 hrs. to about 16 hrs. with stirring.
  • a compound of Formula (III) is allowed to react with a base such as sodium hydride, potassium carbonate and calcium carbonate in tetrahydrofuran at a temperature between about 0°C and about 50°C for about 2 hrs. to about 4 hrs.
  • a base such as sodium hydride, potassium carbonate and calcium carbonate
  • step (a) The reaction mixture obtained in step (a) is added to the reaction mixture obtained in step (b), and the combined mixture is heated under reflux for about 8 hrs. to about 14 hrs. to give the desired compounds of Formula (I).
  • R 5 , R ⁇ , R 7 , R g and X are as defined above.
  • quinolone compounds of Formula (I) can be prepared as illustrated below.
  • Bases for use in the above Process (B) include organic bases such as pyridine and diisopropylethylamine, inorganic bases such as potassium carbonate and calcium carbonate and metal oxides such as alumina.
  • the process may be conveniently carried out in a polar solvent such as acetonitrile, pyridine or dimethylsulfoxide.
  • a polar solvent such as acetonitrile, pyridine or dimethylsulfoxide.
  • a process for seperating optical isomers of compounds of Formula (VI) are as follows:
  • Compound (VI) is reacted with N-tosyl-L-prolyl chloride in an organic solvent such as methylene chloride or chloroform or in a mixture of water and the said organic solvents in the presence of an organic base such as triethylamine, DBU and DBN or an inorganic base such as sodium bicarbonate or sodium carbonate at -20°C to 30°C to give Compound (VII).
  • Compound (VII) may also be prepared by reacting Compound (VI) with N-protected L-proline in a solvent such as DMF, DMSO, acetonitrile or chloroform in the presence of an organic base such as triethylamine, DBU or DBN and dicyclohexyl carbodiimide.
  • Compound (VII) is subjected to column chromatography arid acid-catalized hydrolysis to obtain Compound (la) and Compound (la'). The reaction scheme of the process is illustrated hereinbelow.
  • R 5 , 1 ⁇ , R 7 and R 8 are as defined above, and R represents amine-protecting group such as toluenesulfonyl or t-butoxycarbonyl.
  • reaction mixture A 120mg of 60% NaH was added to a solution of 480mg of diethyl malonate in 10ml of THF. The mixture was allowed to react at room temperature for 3 hours (reaction mixture A). 385mg of l-cyclopropyl-6,8-difluoro-7-[(N-t-butoxycarbonyl-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline-3-carboxylic acid and 324mg of CDI were dissolved in 10ml of chloroform and the resulting mixture was heated under reflux for 12 hours with stirring.
  • reaction mixture B THF
  • reaction mixture B was added to the reaction mixture A and refluxed for 12 hours with stirring.
  • the solvent was evaporated under reduced pressure.
  • the remaining residue was dissolved in 20ml of water, neutralized with acetic acid and extracted with ethyl acetate (3 x 20ml).
  • the filtrate was dried on anhydrous magnesium sulfate and the solvent was removed in vacuo.
  • 310mg of alumina is added to a solution of the compound obtained from the above step (1) and 138mg of 2,8-diazabicyclo[4.3.0]non-5-ene in 10ml of acetonitrile.
  • the resulting mixture is stirred at 60°C for 10 hours.
  • the reaction mixture is concentrated in vacuo and the residue is then suspended in methanol, and stirred at room temperature for 10 minutes.
  • the resulting mixture is filtered off and the filtrate is stripped off in vacuo to obtain the desired compound.
  • Example 7 Preparation of l-cyclopropyl-S-CdiethoxycarbonyDacetyl- ⁇ -fluoro- ⁇ - chloro-7-l ⁇ 2.8-diazabicvclor4.3.01non-5-en')-8-vn-4-oxo- 1 .4- dihydroquinoline hydrochloride
  • optical isomers and parmaceutically acceptable salts thereof are optical isomers and parmaceutically acceptable salts thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to novel quinolone compounds of formula (I), optical isomers and pharmaceutically acceptable salts thereof. In formula (I), A represents nitrogen or (a), in which Y represents hydrogen, halogen, lower alkyl or lower alkoxy or together with R1 forms -CH2CH2CH2-, -CH2CH2CH(CH3)-, -OCH2CH2-, -OCH2CH(CH3)-, -SCH2CH2- or -SCH2CH(CH3)-; R1 is as defined above or represents a straight chain or cyclic lower alkyl group having 1 to 3 carbon atoms or a straight chain or cyclic lower alkyl group having 1 to 3 carbon atoms which is substituted with a halogen atom, a phenyl group or a phenyl group substituted with one or two halogen atoms; R2 and R3 may be the same or different and represent independently hydrogen, nitro, methoxycarbonyl and ethoxycarbonyl; R4 represents hydrogen, lower alkyl, lower alkoxy or an amino-protecting group; R5, R6, R7 and R8 may be the same or different and represent independently hydrogen, lower alkyl optionally substituted by amino, hydroxyl or halogen; X represents hydrogen, halogen, amino or lower alkyl; and optical isomers and pharmaceutically acceptable salts thereof.

Description

Novel Quinolone Derivatives and Processes for Preparing the Same
Technical Field
The present invention relates to novel quinolone compounds, optical isomers and salts thereof which possess a broad antibacterial spectrum.
The present invention also relates to processes for "preparing these quinolone compounds.
Background Art
Representatives of the commercially available quinolone antibacterial agents include enoxacin, norfloxacin, ofloxacin, ciprofloxacin and tosufloxacin. However, it is generally known that these quinolone antibacterials exhibit relatively weak antibacterial activity against Gram-positive bacteria. Furthermore, quinolone-resistant strains have been frequently reported.
Thus, there is still a need for the development of quinolone antibacterials which show a broad antibacterial spectrum.
Disclosure of Invention
An object of the present invention is to provide novel quinolone compounds of Formula (I), optical isomers and salts thereof:
wherein,
A represent nitrogen or -C = ,
I
Y in which Y represents hydrogen, halogen, lower alkyl or lower alkoxy or together with R, forms -CH2CH2CH2-, -CH2CH2CH(CH3)-, -OCH2CH2-, -OCH2CH(CH3)-, -SCH2CH2- or -SCH2CH(CH3)-;
R, is as defined above or represents a straight chain or cyclic lower alkyl group having 1 to 3 carbon atoms or a straight chain or cyclic lower alkyl group having 1 to 3 carbon atoms which is substituted with a halogen atom, a phenyl group or a phenyl group substituted with one or two halogen atoms;
R2 and R3 may be the same or different and represent independently hydrogen, nitro, methoxycarbonyl and ethoxycarbonyl;
R4 represents hydrogen, lower alkyl, lower alkoxy or an amino-protecting group; R5, Rg, R7 and Rg may be the same or different and represent independently hydrogen, lower alkyl optionally substituted by amino, hydroxyl or halogen; X represents hydrogen, halogen, amino or lower alkyl; and their optical isomers and pharmaceutically acceptable salts thereof.
Lower alkyl is preferably C,_6alkyl, more preferably C alkyl, such as methyl or ethyl. Acyl is preferably C,.6alkanoyl, optionally substituted phenylC,.6alkanoyl, alkyl groups optionally substituted by halogen such as fluorine. Substituents on phenyl may be selected from halogen, carboxylic acid, carboxy ester, amino, quatenary ammonium, Cj.6alkoxy, hydroxy or phosphorous acids. Esters include C,.6 alkoxy carbonyl.
Y is preferably fluorine, chlorine or methoxy. R, is preferably ethyl, cyclopropyl or 2,4-difluorophenyl. Examples of R, amino-protecting groups include lower alkyl such as methyl, ethyl and lower. alkoxycarbonyl such as butoxycarbonyl. R4 is preferably hydrogen. Examples of R5, R6, R7 and R8 include hydrogen, methyl and ethyl. Preferably at least three of R5, R6, R7 and R8 are hydrogen. Most preferably all are hydrogen. Examples of X include hydrogen, fluorine, chlorine, amino and methyl, preferably hydrogen.
Preferred compounds of the present invention are;
l-cyclopropyl-3-(diethoxycarbonyl)acetyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5- en)-8-yl]-4-oxo-l,4-dihydroquinoline;
9-fluoro-10-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-2,3-dihydro-3-(S)-methyl-6- (diethoxycarbonyl)acetyl-7-oxo-7H-pyrido[ 1 ,2 , 3-de] [ 1 ,4]benzoxazine;
l-cyclopropyl-3-(dimethoxycarbonyl)acetyl-5-amino-6,8-difluoro-7-[((+)-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline;
l -cyclopropyl-6-fluoro-8-methoxy-3-(dimethoxycarbonyl)acetyl-7-[(2 , 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline;
l-cyclopropyl-6-fluoro-8-chloro-3-(dimethoxycarbonyl)acetyl-7-[(2 , 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline;
9-fluoro-10-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-2,3-dihydro-3-(S)-methyl-6- (dimethoxycarbonyl)acetyl-7-oxo-7H-pyrido[l,2,3-de][l,4]benzoxazine;
l -cyclopropyl-3-(diethoxycarbonyl)acetyl-6-fluoro-8-chloro-7-[(2 , 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline;
l-cyclopropyl-3-(diethoxycarbonyl)acetyl-6-fluoro-8-methoxy-7-[(2 , 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline;
l-ethyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l ,4- dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo- 1 ,4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6-fluoro-7-[2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo- 1 ,4-dihydro- 1 , 8-naphthyridine;
l-(2,4-difluoro)phenyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]- 4-oxo-l ,4-dihydro-l ,8-naphthyridine; 1 -cyclopropyl-3-nitroacetyl-5 , 8-dichloro-6-fluoro-7-[(2 , 8-diazabicyclo[4.3.0]non-5-en)- 8-yl]-4-oxo- 1 , 4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4- oxo-l ,4-dihydroquinoline;
1 -cyclopropyl-3-nitroacetyl-6-fluoro-8-chloro-7-[(2 , 8-diazabicyclo[4.3.0]non-5-en)-8- yl]-4-oxo- 1 ,4-dihydroquinoline;
9-fluoro-10-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-2,3-dihydro-3-methyl-6- nitroacetyl-7-oxo-7H-pyrido[l ,2,3-de][l ,4]benzoxazine;
l-cyclopropyl-3-nitroacetyl-5-amino-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)- 8-yl]-4-oxo- 1 ,4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6-fiuoro-8-methoxy-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8- yl]-4-oxo-l ,4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-5-methyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8- y 1] -4-oxo- 1 , 4-dihydroquinoline ;
l-cyclopropyl-3-nitroacetyl-6-fluoro-8-methoxy-7-[(2,8-diazabicyclo[4.3.0]non-5-en-3- methyl)-8-yl]-4-oxo- 1 ,4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en-5-methyl)-8- yl]-8-methoxy-4-oxo- 1 ,4-dihydroquinoline;
1 -cyclopropyl-3-nitroacetyl-6, 8-difluoro-7-[(2 , 8-diazabicyclo[4.3.0]non-5-en-2-methyl)- 8-yl]-4-oxo-l ,4-dihydroquinoline; and
optical isomers and pharmaceutically acceptable salts thereof.
Quinolone compounds of Formula (I) may be prepared by processes illustrated hereinbelow. Process (A)
( II ) ( I )
In the above formulae,
A, R,, R2, R3, R4, R5, Rή, R7, Rg and X are as defined above.
In accordance with Process (A), quinolone compounds of Formula (I) can be prepared as illustrated below.
a) A mixture of a compound of Formula (II) and carbonyldiimidazole (CDI) or thiocarbonyldiimidazole (TDI) in an organic solvent such as chloroform, acetonitrile and tetrahydrofuran is heated under reflux at a temperature between about 80°C and about 100°C for about 10 hrs. to about 16 hrs. with stirring.
b) Meanwhile, a compound of Formula (III) is allowed to react with a base such as sodium hydride, potassium carbonate and calcium carbonate in tetrahydrofuran at a temperature between about 0°C and about 50°C for about 2 hrs. to about 4 hrs.
c) The reaction mixture obtained in step (a) is added to the reaction mixture obtained in step (b), and the combined mixture is heated under reflux for about 8 hrs. to about 14 hrs. to give the desired compounds of Formula (I).
Compounds of Formula (II) for use in Process (A) as the starting materials were prepared for the first time by the present inventors, and these compounds are disclosed in Korean Patent Application No. 91-25883.
Process CB
In the above formulae, A, R,, R2, R3, R4) R5, R^, R7, Rg and X are as defined above.
In accordance with Process (B), quinolone compounds of Formula (I) can be prepared as illustrated below.
Compounds of Formula (IV) which are known in the prior art (cf. P.D. Fernandes, International Telesymposium on Ouinolone. J.R. Prous Science, Barcelona, Spain, 1- 134, 1989) are treated by a method similar to that described in the above Process (A) to give compounds of Formula (V). The compounds of Formula (V) are then reacted with 2, 8-diazabicyclo[4.3.0]non-5-ene compounds of Formula (VI) in the presence of an appropriate base at a temperature between about 60°C and about 100°C for about 6 hrs. to 14 hrs. to give the desired compounds of Formula (I).
Bases for use in the above Process (B) include organic bases such as pyridine and diisopropylethylamine, inorganic bases such as potassium carbonate and calcium carbonate and metal oxides such as alumina.
The process may be conveniently carried out in a polar solvent such as acetonitrile, pyridine or dimethylsulfoxide.
Compounds of Formula (VI) for use in the above process (B) were prepared for the first time by the present inventors, and these compounds are disclosed in Korean Patent Application No. 92-13212.
A process for seperating optical isomers of compounds of Formula (VI) are as follows:
Compound (VI) is reacted with N-tosyl-L-prolyl chloride in an organic solvent such as methylene chloride or chloroform or in a mixture of water and the said organic solvents in the presence of an organic base such as triethylamine, DBU and DBN or an inorganic base such as sodium bicarbonate or sodium carbonate at -20°C to 30°C to give Compound (VII). Compound (VII) may also be prepared by reacting Compound (VI) with N-protected L-proline in a solvent such as DMF, DMSO, acetonitrile or chloroform in the presence of an organic base such as triethylamine, DBU or DBN and dicyclohexyl carbodiimide. Compound (VII) is subjected to column chromatography arid acid-catalized hydrolysis to obtain Compound (la) and Compound (la'). The reaction scheme of the process is illustrated hereinbelow.
less polar somer more polar isomer
In the above formulae, R5, 1^, R7 and R8 are as defined above, and R represents amine-protecting group such as toluenesulfonyl or t-butoxycarbonyl.
The following examples are intended to further explain the present invention, without limiting the scope of the invention. Exa ple 1: Preparation of 1 -cyclopropyl-3-fdiethoxycarbony acetyl-6.8-difluoro-7- [f2.8-diazabicyclor4.3.01non-5-en1-8-yn-4-oxo-1.4-dihydroquinoline hydrochloride
Process 1
120mg of 60% NaH was added to a solution of 480mg of diethyl malonate in 10ml of THF. The mixture was allowed to react at room temperature for 3 hours (reaction mixture A). 385mg of l-cyclopropyl-6,8-difluoro-7-[(N-t-butoxycarbonyl-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline-3-carboxylic acid and 324mg of CDI were dissolved in 10ml of chloroform and the resulting mixture was heated under reflux for 12 hours with stirring. The solvent was removed in vacuo and the resulting residue was dissolved in THF (reaction mixture B). The reaction mixture B was added to the reaction mixture A and refluxed for 12 hours with stirring. The solvent was evaporated under reduced pressure. The remaining residue was dissolved in 20ml of water, neutralized with acetic acid and extracted with ethyl acetate (3 x 20ml). The filtrate was dried on anhydrous magnesium sulfate and the solvent was removed in vacuo. The resulting residue was purified by a column chromatography using CHCl3:MeOH (900: 80) to obtain l-cyclopropyl-3-(diethoxy- carbonyl)acetyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l ,4- dihydroquinoline. This compound was added to 5ml of 10% HCl-methanol solution and stirred for 4 hours at room temperature, and then trituated with 5ml of ethyl ether. The resulting solid was filtered off and dried in vacuo to obtain 344mg of the desired compound (yield: 61 %).
Η-NMR(DMSO-d6, δ): 1.21(4H, m), 1.32(6H, t), 2.06(1H, m), 2.32(1H, m),
2.95(1H, m), 3.25(1H, m), 3.60(1H, m), 3.85(1H, m), 4.00~4.08(7H, m), 5.81(1H, s), 6.21(1H, s), 7.80(1H, d), 8.23(2H, br s), 8.74(1H, s)
Process 2
(1) Preparation of l-cyclopropyl-3-(diethoxycarbonyl)acetyl-6,7,8-trifluoro-4-oxo- 1 ,4-dihydroquinoline 1 -cy clopropyl-6 , 7 , 8-trifluoro-4-oxo- 1 , 4-dihydroquinoline-3-carboxylicacid and 648mg of CDI are added to 20ml of THF, and the resulting mixture is heated under reflux for 24 hours with stirring (solution A). 240mg of 60% NaH is added to a mixture of 480mg of diethyl malonate and 5ml of THF, and the resulting mixture is stirred at room temperature for 4 hours. Solution A above is then added. The resulting mixture is heated under reflux for 14 hours with stirring. The reaction mixture is cooled and the solvent is removed in vacuo. The residue is purified by a silica gel column chromatography using hexane: ethyl acetate (5: 1) to obtain the desired compoumnd.
(2) Preparation of l-cyclopropyl-3-(diethoxycarbonyl)acetyl-6,8-difluoro-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline
310mg of alumina is added to a solution of the compound obtained from the above step (1) and 138mg of 2,8-diazabicyclo[4.3.0]non-5-ene in 10ml of acetonitrile. The resulting mixture is stirred at 60°C for 10 hours. The reaction mixture is concentrated in vacuo and the residue is then suspended in methanol, and stirred at room temperature for 10 minutes. The resulting mixture is filtered off and the filtrate is stripped off in vacuo to obtain the desired compound.
Process 3
l-cyclopropyl-3-(diethoxycarbonyl)acetyl-6,7,8-trifluoro-4-oxo-l ,4-dihydroquinoline, 154mg of 2,8-diazabicyclo[4.3.0]non-5-en-3-methyl and 200mg of diazabicyclo[5.4.0]undecene (DBU) dissolved in 10ml of acetonitrile are heated under reflux for 10 hours with stirring. The solvent is removed in vacuo and ethyl ether is added to the residue. The resulting mixture is placed in a refrigerator for 14 hours to yield a solid. Said solid is filtered off and dried under reduced pressure to obtaine the desired compound.
Example 2: Preparation of 9-fluoro-10-[f2.8-diazabicyclor4.3.0lnon-5-enV8-yl1-2.3- dihydro-S-CSI-methyl-ό-Cdiethoxycarbonyπacetyl^-oxo^H-pyridori^.S- deiπ.4"lbenzoxazine hydrochloride
396mg of diethyl malonate and 383mg of 9-fluoro-10-[(2,8-diazabicyclo[4.3.0]non-5- en)-8-yl]-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[l ,2,3-de][l ,4]benzoxazin-6- carboxylic acid were treated by a method similar to that described in Example 1 to obtain 304mg of the desired compound (yield: 57%).
Η-NMR(CDC13, δ): 1.34(6H, t), 1.62(3H, d), 2.11(1H, m), 2.32(1H, m), 2.95(1H, m), 3.27(1H, dxd), 3.40~ 3.90(5H, m),
4.0(2H, m), 4.25-4.80(4H, m), 5.75(1H, s), 6.01(1H, s), 7.72(1H, d), 8.70(1H, s).
Example 3: Preparation of l-cyclopropyl-3-(dimethoxycarbonyl)acetyl-5-amino-6.8- difluoro-7-rrf+V2.8-diazabicvclor4.3.01non-5-en -8-vn-4-oxo-1.4- dihydroquinoline hydrochloride
420mg of dimethyl malonate and 399mg of l-cyclopropyl-5-amino-6,8-difluoro-7- [((+)-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid were treated by a method similar to that described in Example 1 to obtain 420mg of the desired compound (yield: 76.6%).
Η-NMR(CDC13, δ): 1.20(4H, m), 1.94(1H, m), 2.40(1H, m), 2.90(1H, m),
3.20(1H, m), 3.80(6H, s), 3.90~4.30(6H, m), 5.60(1H, s), 5.80(1H, br s), 8.80(1H, s), 9.80(1H, br s),
10.45(1H, br s).
Example 4: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-3-(dimethoxy- carbonyπacetyl-7-r 2.8-diazabicvclor4.3.01non-5-en)-8-yl1-4-oxo-1.4- dihydroquinoline hydrochloride
400mg of dimethyl malonate and 397mg of l-cyclopropyl-6-fluoro-8-methoxy-7-[(2,8- diazabicyclo-[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline-3-carboxylic acid were treated by a method similar to that described in Example 1 to obtain 373mg of the desired compound (yield: 68.1 %).
Η-NMR(CDC13, δ): 0.8 - 1.33(4H, m), 1.94(1H, m), 2.40(1H, m), 2.90(1H, m), 3.15(1H, m), 3.63(3H, s), 3.73(1H, m), 3.80(6H, s), 3.93(1H, m), 4.20(2H, ), 4.60(1H, ), 5.67(1H, s), 5.93(1H, br s), 7.78(1H, d), 8.68(1H, s), 9.95(1H, br s), 10.55(1H, br s).
Example 5: Preparation of l-cyclopropyl-6-fluoro-8-chloro-3-(ciimethoxycarbonyl)- acetyl-7-r(2.8-diazabicvclor4.3.01non-5-en >-8-vn-4-oxo- 1 .4- dihydroquinoline hydrochloride
660mg of dimethyl malonate and 400mg of l-cyclopropyl-6-fluoro-8-chloro-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline-3-carboxylicacidwere treated by a method similar to that described in Example 1 to obtain 360 mg of the desired compound (yield: 65.5%).
Η-NMR(CDC13) δ): 0.8- 1.40(4H, m), 2.05(1H, m), 2.40(1H, m), 2.90(1H, m), 3.15(1H, m), 3.70(6H, s), 3.90~4.40(6H, m), 5.58(1H, s), 5.90(1H, br s), 7.82(1H, d), 8.76(1H, s), 9.82(1H, br s), 10.5(1H, br s).
Example 6: Preparation of 9-fluoro- 10-IY2.8-diazabicyclor4.3.01non-5-en)-8-yl1-2.3- dihydro-3-fS -methyl-6-('dimethoxycarbonyl acetyl-7-oxo-7H- pyridof 1 ,2.3-de ri .4"]benzoxazine hydrochloride
400mg of dimethyl malonate and 383mg of 9-fluoro-10-[(2,8-diazabicyclo[4.3.0]non-5- en)-8-yl]-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[l ,2,3-de][l ,4]benzoxazin-6- carboxylic acid were treated by a method similar to that described in Example 1 to obtain 392mg of the desired compound (yield: 73.5%).
'H-NMR^DCl^ δ): 1.60(3H, m), 2.10~ 2.50(2H, d), 2.85(lH, m), 3.18(1H, m), 3.80(6H, s), 3.90~4.70(1H, s), 5.88(1H, br s), 7.60(1H, dxd), 8.55(1H, s), 9.73(1H, br s), 10.45(1H, br s).
Example 7: Preparation of l-cyclopropyl-S-CdiethoxycarbonyDacetyl-ό-fluoro-δ- chloro-7-lΥ2.8-diazabicvclor4.3.01non-5-en')-8-vn-4-oxo- 1 .4- dihydroquinoline hydrochloride
480mg of diethyl malonate and 401.5mg of l-cyclopropyl-6-fluoro-8-chloro-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l,4-dihydroquinoline-3-carboxylicacid were treated by a method similar to that described in Example 1 to obtain 377mg of the desired compound (yield: 65%).
'H-NMR(DMSO-d6, δ): 1.20(4H, m), 1.34(6H, t), 2.00(1H, m), 2.28(1H, m),
2.95(1H, m), 3.24(1H, m), 3.60(1H, m), 3.85(1H, m), 4.00-4.10(7H, m), 5.81(1H, s), 5.88(1H, s), 7.82(1H, d), 8.70(1H, s)
Example 8: Preparation of l-cyclopropyl-3-(diethoxycarbonyl)acetyl-6-fluoro-8- dihydroquinoline hydrochloride
480mg of diethyl malonate and 397mg of l-cyclopropyl-6-fluoro-8-methoxy-7-[(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l ,4-dihydroquinoline-3-carboxylicacid were treated by a method similar to that described in Example 1 to obtain 339mg of the desired compound (yield: 59%).
1H-NMR(DMSO-d6, δ): 1.10- 1.35(10H, m), 2.10(1H, m), 2.35(1H, m), 2.97(1H, m), 3.29(1H, m), 3.52(1H, m), 3.60(3H, s),
3.8 ~4.1(7H, m), 5.78(1H, s), 6.12(1H, s), 7.85(1H, d), 8.81(1H, s)
Following compounds may be prepared by the processes described in the above.
l-ethyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-l ,4- dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo- 1 ,4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6-fluoro-7-[2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo- 1 ,4-dihydro- 1 , 8-naphthyridine;
l-(2,4-difluoro)phenyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]- 4-oxo- 1 ,4-dihydro- 1 , 8-naphthyridine;
l-cyclopropyl-3-nitroacetyl-5,8-dichloro-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)- 8-yl]-4-oxo- 1 ,4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6, 8-difluoro-7-[(2, 8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4- oxo-1 ,4-dihydroquinoline;
1 -cyclopropyl-3-nitroacetyl-6-fluoro-8-chloro-7-[(2 , 8-diazabicyclo[4.3.0]non-5-en)-8- yl]-4-oxo- 1 ,4-dihydroquinoline;
9-fluoro-10-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-2,3-dihydro-3-methyl-6- nitroacetyl-7-oxo-7H-pyrido[l ,2,3-de][l ,4]benzoxazine;
l-cyclopropyl-3-nitroacetyl-5-amino-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)- 8-yl]-4-oxo- 1 ,4-dihydroquinoline;
1 -cyclopropyl-3-niuOacetyl-6-fluoro-8-methoxy-7-[(2 , 8-diazabicyclo[4.3.0]non-5-en)-8- yl] -4-oxo- 1 ,4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-5-methyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8- yl]-4-oxo-l ,4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6-fluoro-8-methoxy-7-[(2,8-diazabicyclo[4.3.0]non-5-en-3- methyl)-8-yl]-4-oxo- 1 ,4-dihydroquinoline;
1 -cyclopropy l-3-nitroacetyl-6-fluoro-7-[(2 , 8-diazabicyclo[4.3.0]non-5-en-5 -methy l)-8- yl]-8-methoxy-4-oxo- 1 ,4-dihydroquinoline;
l-cyclopropyl-3-nitroacetyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en-2-methyl)- 8-yl]-4-oxo-l ,4-dihydroquinθline; and
optical isomers and parmaceutically acceptable salts thereof.
In vitro antibacterial activity test to o o ~J\ U\
C &D*
o
3 cr.
3 c
8.

Claims

What is claimed is:
1. Compounds of Formula (I):
wherein,
A represent nitrogen or -C = ,
in which Y represents hydrogen, halogen, lower alkyl or lower alkoxy or together with
R1 forms -CH2CH2CH2-, -CH2CH2CH(CH3)-, -OCH2CH2-, -OCH2CH(CH3)-,
-SCH2CH2- or -SCH2CH(CH3)-;
R1 is as defined above or represents a straight chain or cyclic lower alkyl group having
1 to 3 carbon atoms or a straight chain or cyclic lower alkyl group having 1 to 3 carbon atoms which is substituted with a halogen atom, a phenyl group or a phenyl group substituted with one or two halogen atoms;
R2 and R3 may be the same or different and represent independently hydrogen, nitro, methoxycarbonyl and ethoxycarbonyl;
R4 represents hydrogen, lower alkyl, lower alkoxy or an amino-protecting group; R5, R6, R7 and R8 may be the same or different and represent independently hydrogen, lower alkyl optionally substituted by amino, hydroxyl or halogen;
X represents hydrogen, halogen, amino or lower alkyl; and optical isomers and pharmaceutically acceptable salts thereof.
2. Compounds of Claim 1 , wherein the compound of Formula(I) is one of the following compounds:
1-cyclopropyl-3-(diethoxycarbonyl)acetyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5- en)-8-yl]-4-oxo-1 ,4-dihydroquinoline; 9-fluoro-10-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-2,3-dihydro-3-(S)-methyl-6- (diethoxycarbonyl)acetyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine;
1-cyclopropyl-3-(dimethoxycarbonyl)acetyl-5-amino-6,8-difluoro-7-[((+)-2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-1,4-dihydroquinoline;
1 -cyclopropyl-6-fluoro-8-methoxy-3-(dimethoxycarbonyl)acetyl-7-[(2, 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-1,4-dihydroquinoline; 1-cyclopropyl-6-fluoro-8-chloro-3-(dimethoxycarbonyl)acetyl-7-[(2, 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-1,4-dihydroquinoline;
9-fluoro-10-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-2,3-dihydro-3-(S)-methyl-6- (dimethoxycarbonyl)acetyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine;
1 -cyclopropyl-3-(diethoxycarbonyl)acetyl-6-fluoro-8-chloro-7- [(2 , 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-1,4-dihydroquinoline;
1-cyclopropyl-3-(diethoxycarbonyl)acetyl-6-fluoro-8-methoxy-7-[(2 , 8- diazabicyclo[4.3.0] non-5-en)-8-yl]-4-oxo-1,4-dihydroquinoline;
1-ethyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-1 ,4- dihydroquinoline; 1-cyclopropyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo- 1 ,4-dihydroquinoline;
1-cyclopropyl-3-nitroacetyl-6-fluoro-7-[2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo- 1,4-dihydro-1,8-naphthyridine;
1-(2,4-difluoro)phenyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]- 4-oxo-1 ,4-dihydro-1,8-naphthyridine;
1-cyclopropyl-3-nitroacetyl-5,8-dichloro-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)- 8-yl]-4-oxo-1 ,4-dihydroquinoline; 1-cyclopropyl-3-nitroacetyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4- oxo-1,4-dihydroquinoline;
1-cyclopropyl-3-nitroacetyl-6-fluoro-8-chloro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8- yl]-4-oxo-1,4-dihydroquinoline;
9-fluoro-10-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-2,3-dihydro-3-methyl-6- nitroacetyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine; 1-cyclopropyl-3-nitroacetyl-5-amino-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)- 8-yl]-4-oxo-1,4-dihydroquinoline;
1-cyclopropyl-3-nitroacetyl-6-fluoro-8-methoxy-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8- yl]-4-oxo-1,4-dihydroquinoline;
1-cyclopropyl-3-nitroacetyl-5-methyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8- yl]-4-oxo-1,4-dihydroquinoline;
1-cyclopropyl-3-nitroacetyl-6-fluoro-8-methoxy-7-[(2,8-diazabicyclo[4.3.0]non-5-en-3- methyl)-8-yl]-4-oxo-1,4-dihydroquinoline;
1-cyclopropyl-3-nitroacetyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en-5-methyl)-8- yl]-8-methoxy-4-oxo-1 ,4-dihydroquinoline; 1-cyclopropyl-3-nitroacetyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en-2-methyl)- 8-yl]-4-oxo-1,4-dihydroquinoline; and optical isomers and pharmaceutically acceptable salts thereof.
3. A process for preparing compounds of Formula (I) which comprises:
(a) reacting a compound of Formula (II) with an activating agent such as carbonyldiimidazole or thiocarbonyldiimidazole in a solvent;
(b) allowing a compound of Formula (III) to react with a base; and (c) adding the reaction mixture obtained in step (a) to the reaction mixture obtained in step (b);
wherein, A, R1 to R8 and X are the same as defined in Claim 1, and thereafter optionally forming a salt and/or separating isomers.
4. A process for preparing compounds of Formula (I) which comprises:
(a) reacting a compound of Formula (IV) with an activating agent such as carbonyldiimidazole or thiocarbonyldiimidazole in a solvent;
(b) allowing a compound of Formula (III) to react with a base;
(c) adding the reaction mixture obtained in step (a) to the reaction mixture obtained in step (b) to give a compound of Formula (V); and (d) reacting compound (V) with a compound of Formula (VI) in the presence of a base in a solvent;
wherein, A, R1 to R8 and X are the same as defined in Claim 1, and thereafter optionally forming a salt and/or separating isomers.
5. A pharmaceutical composition which contains as an active ingredient a compound of Formula (I), an optical isomer or a pharmaceutically acceptable salt thereof according to Claim 1 in an effective amount.
6. A compound of Formula (I) , an optical isomer or a pharmaceutically acceptable salt thereof according to Claim 1 for use as an antibacterial agent in a method for therapeutic treatment of the human or animal body.
7. Use of a compound of Formula (I), an optical isomer or a pharmaceutically acceptable salt thereof according to Claim 1 for the preparation of an antibacterial medicament.
8. A method for the treatment of bacterial infection characterized in that a pharmaceutical composition according to Claim 5 is administered to a host in the need of such treatment in the therapeutically effective amount.
9. Compounds of Formula (V):
wherein A, R1 to R3 and X are the same as defined in Claim 1.
EP94903115A 1992-12-29 1993-12-29 Novel quinolone derivatives and processes for preparing the same Withdrawn EP0677052A1 (en)

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NZ222047A (en) * 1986-10-08 1991-01-29 Bristol Myers Co Quinoline - or naphthyridine - carboxylic acid anti-bacterial agents
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