EP0651753A1 - Pyridonecarboxylic acid derivatives and processes for preparing the same - Google Patents

Pyridonecarboxylic acid derivatives and processes for preparing the same

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Publication number
EP0651753A1
EP0651753A1 EP93916265A EP93916265A EP0651753A1 EP 0651753 A1 EP0651753 A1 EP 0651753A1 EP 93916265 A EP93916265 A EP 93916265A EP 93916265 A EP93916265 A EP 93916265A EP 0651753 A1 EP0651753 A1 EP 0651753A1
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EP
European Patent Office
Prior art keywords
methyl
dihydro
pyrido
diazabicyclo
oxo
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.)
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EP93916265A
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German (de)
French (fr)
Inventor
Wan Joo Kim
Tae Ho Park
Moon Hwan Kim
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Korea Research Institute of Chemical Technology KRICT
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Korea Research Institute of Chemical Technology KRICT
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Publication of EP0651753A1 publication Critical patent/EP0651753A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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 novel pyridonecarboxylic acid derivatives which have a broad antibacterial spectrum.
  • the present invention also relates to processes for preparing these compounds.
  • a number of pyridonecarboxylic acid-type antibacterials are known. Of these ofloxacin is known to exhibit an excellent antibacterial activity and possesses superior characteristics in bioavailability and efficacy as compared to other quinolone antibacterials. However, ofloxacin suffers from the disadvantage that although it is active against Gram-negative bacteria, it exhibits relatively weak antibacterial activity against Gr ⁇ w-positive bacteria.
  • the compounds of the present invention have a broad antibacterial activit
  • the present invention provides compounds of Formula (I);
  • R,, R 2 , R 3 and R 4 may be the same or different and represent independently hydrogen or lower alkyl
  • X represents oxygen or sulfur
  • Y represents hydrogen or methyl
  • n denotes an integer of 0 or 1
  • Another object of the present invention is to provide stereospecific compounds of Formula (la) and Formula (lb):
  • R,, R 2 , R 3 , R,, X and n are as defined above, or a racemic mixture thereof.
  • Another object of the present invention is to provide processes for preparing compounds of Formula (I) above.
  • compounds of Formula (I) can be prepared by reacting a compound of Formula (II) with a compound (III) as illustrated in the following reaction diagram:
  • R,, R 2 , R 3 , R 4 , X, Y and n are as defined above, and Z is a leaving group such as fluoro.
  • lower alkyl refers to a straight or branched Cj- 3 alkyl, such as methyl, ethy. n-propyl or isopropyl.
  • compounds of Formula (I) can be prepared by the reaction _ n of a compound of Formula (II) above and a compound of Formula (III).
  • the process may be carried out in the presence of a solvent.
  • Suitable solvents include acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine, water, an alcohol and mixtures thereof.
  • the process is preferably carried out in the presence of a base that can bind the side product of the reaction, e.g., a hydrogen fluoride gas.
  • a base that can bind the side product of the reaction, e.g., a hydrogen fluoride gas.
  • Suitable bases for this purpose include inorganic bases such as potassium -, n carbonate and calcium carbonate and organic bases such as triethylamine, pyridine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene(DBU), and 1 ,5-diazabicyclo[4,3,0]non-5- ene(DBN).
  • inorganic bases such as potassium -, n carbonate and calcium carbonate
  • organic bases such as triethylamine, pyridine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene(DBU), and 1 ,5-diazabicyclo[4,3,0]non-5- ene(DBN).
  • the reaction may be carried out at a temperature between about 20°C and 35 about 200°C, preferably between about 60°C and about 130°C.
  • the reaction time is preferably about 1 hour to about 24 hours.
  • Example 1 Preparation of 9-fluoro-3-(5)-methyl-10-[(2,8-diazabicyclo[4.3.0]non- ,- 5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l ,2,3-de][l ,4]-benzoxazine-
  • Example 2 Preparation of 9-fluoro-3-(5)-methyl- 10-[(2-methyl-2, 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- 5 dei ⁇ .41-benzoxazine-6-carboxylic acid
  • reaction mixture was heated under reflux for 5 hours. After the reaction mixture was cooled, the solid so precipitated was filtered off and was washed successively with cold acetonitrile, water and methanol and dried in vacuo to give 0.27g of title compound.
  • Example 3 Preparation of 9-fluoro-3-(S)-methyl- 10-[(5-methyl-2 , 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- ,5 dei ⁇ .41-benzoxazine-6-carboxylic acid
  • Example 7 Preparation of 9-fluoro-3-(5)-methyl- 10-[(4-methyl-2, 7- diazabicyclo[3.3.0]oct-4-en)-7-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- de][l .4]-benzoxazine-6-carboxylic acid
  • Example 8 Preparation of 9-fluoro-3-(S)-methyl- 10-[(3-methyl-2 ,7- diazabicyclo[3.3.0]oct-4-en)-7-yl]-7-oxo-2 , 3-dihydro-7H-pyrido[ 1 ,2,3- de "
  • Example 9 Preparation of 9-fluoro- 10-[(2 , 8-diazabicyclo [4.3.0]non-5-en)-8-yl] -7- oxo-2, 3-dihydro-7 ⁇ -pyrido[l ,2,3-de][l ,4]-benzothiazine-6-carboxylic acid
  • Example 11 Preparation of 9-fluoro-3-(R,5)-methyl-10-[(2,8-diazabicyclo [4.3.0] non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l ,2,3-de][ l ,4]- benzoxazine-6-carboxylic acid
  • Example 14 Preparation of hydrochloric acid salt of 9-fluoro-3-(S)-methyl- 10- [(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- dein .4]-benzoxazine-6-carboxylic acid
  • Example 1 Example 1 was added to 5 ml of a 3N HCl-methanol solution at 0°C, and the resulting mixture was stirred for 2 hours. The solvent was removed under reduced pressure and the residue was washed with methanol-ethylether (1:4) and filtered off to produce 0.29g of a light yellow title compound.
  • Example 15 Preparation of tartaric acid salt of 9-fluoro-3-(5 -methyl-10-[(2,7- diazabicyclo[3.3.0]oct-4-en)-7-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- de][l .41-benzoxazine-6-carboxylic acid
  • the antibacterial activity of the quinolone derivatives of the present invention was evaluated in accordance with the agar culture medium two-fold dilution method(Hoechst 345) by using a Muller-Hinton agar medium. Hoechst standard strains were used as the test strains. The strains having 10 7 CFU/ml were inoculated on the culture medium, and the growth of the strains was observed after incubating them at 37°C for 18 hours, in which ciprofloxacin and ofloxacin were used as a control material. The result of these Test are described in Table 1 and 2. ⁇ *_*-> N) t o i 1- ⁇ t- ⁇

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

Abstract

The present invention relates to novel antibacterial pyridonecarboxylic acid derivatives of formula (I) and their stereoisomers and pharmaceutically acceptable salts, wherein R1 R2, R3 and R4 may be the same or different and represent independently hydrogen or lower alkyl, X represents oxygen or sulfur, Y represents hydrogen or methyl, and n denotes an integer of 0 or 1. The present invention also relates to processes for preparing these compounds.

Description

Novel P ridonecarboxylic Acid Derivatives and Processes for Preparing the Same
Technical Field
The present invention relates to novel pyridonecarboxylic acid derivatives which have a broad antibacterial spectrum. The present invention also relates to processes for preparing these compounds.
Background Art
A number of pyridonecarboxylic acid-type antibacterials are known. Of these ofloxacin is known to exhibit an excellent antibacterial activity and possesses superior characteristics in bioavailability and efficacy as compared to other quinolone antibacterials. However, ofloxacin suffers from the disadvantage that although it is active against Gram-negative bacteria, it exhibits relatively weak antibacterial activity against Grαw-positive bacteria.
Disclosure of nvention
The compounds of the present invention have a broad antibacterial activit)
The present invention provides compounds of Formula (I);
wherein
R,, R2, R3 and R4 may be the same or different and represent independently hydrogen or lower alkyl,
X represents oxygen or sulfur,
Y represents hydrogen or methyl, n denotes an integer of 0 or 1, and stereoisomers thereof, and pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide stereospecific compounds of Formula (la) and Formula (lb):
wherein R,, R2, R3, R,, X and n are as defined above, or a racemic mixture thereof.
Another object of the present invention is to provide processes for preparing compounds of Formula (I) above.
The present invention is further explained hereinbelow. In accordance with the present invention, compounds of Formula (I) can be prepared by reacting a compound of Formula (II) with a compound (III) as illustrated in the following reaction diagram:
in the above formulae,
R,, R2, R3, R4, X, Y and n are as defined above, and Z is a leaving group such as fluoro.
15
The term "lower alkyl" used herein refers to a straight or branched Cj-3 alkyl, such as methyl, ethy. n-propyl or isopropyl.
As stated above, compounds of Formula (I) can be prepared by the reaction _n of a compound of Formula (II) above and a compound of Formula (III).
The process may be carried out in the presence of a solvent. Suitable solvents include acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine, water, an alcohol and mixtures thereof.
25
The process is preferably carried out in the presence of a base that can bind the side product of the reaction, e.g., a hydrogen fluoride gas.
Suitable bases for this purpose include inorganic bases such as potassium -,n carbonate and calcium carbonate and organic bases such as triethylamine, pyridine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene(DBU), and 1 ,5-diazabicyclo[4,3,0]non-5- ene(DBN).
The reaction may be carried out at a temperature between about 20°C and 35 about 200°C, preferably between about 60°C and about 130°C. The reaction time is preferably about 1 hour to about 24 hours.
Syntheses of compounds of Formula (II) which are used herein as the starting materials are disclosed in Chem. Pharm. Bull. 34, 4098 (1986).
Syntheses of compounds of Formula (III) which are used herein as the starting materials are disclosed in detail in Korean Patent Application No. 92-13212, entitled
"Novel Diazabicycloalkene Derivatives and Processes for Preparing the Same," filed in the names of the present inventors. 0
The following examples are intended to further explain the present invention, without limiting the scope of the invention.
Example 1: Preparation of 9-fluoro-3-(5)-methyl-10-[(2,8-diazabicyclo[4.3.0]non- ,- 5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l ,2,3-de][l ,4]-benzoxazine-
6-carboxylic acid and its hydrochloride
0.2G of 2,8-diazabicyclo[4.3.0]non-5-en dihydrochloride and 0.28g of 9, 10- difluoro-3-(5)-methyl-7-oxo-2 ,3-dihydro-7H-pyrido[ 1 ,2 , 3-de] [ 1 ,4]-benzoxazine-6- o carboxylic acid were added to 5ml of anhydrous acetonitrile and then 0.36ml of DBU was added thereto with stirring. The reaction mixture was heated under reflux for 5 hours. After the reaction mixture was cooled, the solid so precipitated was filtered off and washed successively with cold acetonitrile and water and dried under reduced pressure to give 0.25g theof title compound. 5
Analysis : Calculated (%) C; 62.33 Η; 5.17 N; 10.90 Found (%) C; 62.28 Η; 5.18 N; 11.21
After dissolving this title compound in 10ml of 20% methanolic hydrochloride 0 and stirring for about 3 hours, the reaction mixture was dried under reduced pressure to give 0.2g of the hydrochloride of the title compound.
Example 2: Preparation of 9-fluoro-3-(5)-methyl- 10-[(2-methyl-2, 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- 5 deiπ .41-benzoxazine-6-carboxylic acid To a suspension of 0.2g of 2-methyl-2,8-diazabicyclo [4.3.0] non-5-en dihydrochloride and 0.30g of 9,10-difluoro-3-(5)-methyl-7-oxo-2,3-dihydro-7H- pyrido[l,2,3-de][l,4]-benzoxazine-6-carboxylicacid in 5ml of anhydrous acetonitrile, , was added 0.32ml of DBN with stirring. The reaction mixture was heated under reflux for 5 hours. After the reaction mixture was cooled, the solid so precipitated was filtered off and was washed successively with cold acetonitrile, water and methanol and dried in vacuo to give 0.27g of title compound.
10 Analysis : Calculated (%) C; 63.15 H; 5.55 N; 10.52 Found (%) C; 63.21 H; 5.58 N; 10.49
Example 3: Preparation of 9-fluoro-3-(S)-methyl- 10-[(5-methyl-2 , 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- ,5 deiπ .41-benzoxazine-6-carboxylic acid
To a suspension of 0.2g of 5-methyl-2,8-diazabicyclo [4.3.0] non-5-en dihydrochloride and 0.29g of 9, 10-difluoro-3-(S)-methyl-7-oxo-2,3-dihydro-7H- pyrido[l,2,3-de][l,4]-benzoxazine-6-carboxylic acid in 5ml of anhydrous 0 acetonitrile, was added 0.32ml of DBN with stirring. The reaction mixture was heated under reflux for 5 hours. After the reaction mixture was cooled to room temperature, the solid so precipitated was filtered off and washed successively with cold acetonitrile, water and methanol and dried to yield 0.3g of title compound.
5 Analysis : Calculated (%) C; 63.15 Η; 5.55 N; 10.52 Found (%) C; 63.19 Η; 5.51 N; 10.46
Example 4: Preparation of 9-fluoro-3-(S)-methyl- 10-[(3-methyl-2 , 8- diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2 ,3-dihydro-7H-pyrido[ 1,2,3- 0 dell"! ,41-benzoxazine-6-carboxylic acid
To a suspension of 0.2g of 3-methyl-2,8-diazabicyclo [4.3.0] non-5-en dihydrochloride and 0.3g of 9,10-difluoro-3-(s)-methyl-7-oxo-2,3-dihydro-7H- pyrido[l ,2,3-de][l ,4]-benzoxazine-6-carboxylicacid in 5ml of anhydrous acetonitrile, 5 was added 0.32ml of DBN with stirring. The reaction mixture was heated under reflux for 5 hours. After the reaction mixture was cooled, the solid so formed was filtered off and washed successively with cold acetonitrile, water and methanol and dried to give 0.27g of title compound.
Analysis : Calculated (%) C; 63.15 H; 5.55 N; 10.52 Found (%) C; 63.19 H; 5.50 N; 10.49
Example 5: Preparation of 9-fluoro-3-(S)-methyl- 10-[(4-methyl-2 ,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- 0 delfl .4]-benzoxazine-6-carboxyric acid
To a suspension of 0.2g of 4-methyl-2,8-diazabicyclo [4.3.0] non-5-en dihydrochloride and 0.29g of 9,10-difluoro-3-(S)-methyl-7-oxo-2,3-dihydro-7H- pyridofl ,2,3-de][l ,4]-benzoxazine-6-carboxylicacid in 5ml of anhydrous acetonitrile, <; was added 0.32ml of DBN with stirring. The reaction mixture was heated under reflux for 5 hours. After the reaction mixture was cooled to room temperature, the resulting solid was filtered off and washed successively with cold acetonitrile, water and methanol and dried under reduced pressure to produce 0.35g of title compound.
0 Analysis : Calculated (%) C; 63.15 Η; 5.55 N; 10.52 Found (%) C; 63.10 Η; 5.55 N; 10.48
Example 6: Preparation of 9-fluoro-3-(S)-methyl-10-[(2,7-diazabicyclo [3.3.0]oct-
4-en)-7-yl] -7-oxo-2 , 3-dihydro-7H-pyrido[ 1 ,2 , 3-de] [ 1 ,4]-benzoxazine- 5 6-carboxylic acid
To a suspension of 0.2g of 2,7-diazabicyclo[3.3.0]oct-4-en dihydrochloride and0.26gof9, 10-difluoro-3-(s)-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]- benzoxazine-6-carboxylic acid in 5ml of anhydrous acetonitrile, was added 0.32ml of DBN with stirring. The reaction mixture was heated under reflux for 10 hours. After the reaction mixture was cooled, the solid so formed was fitered off and washed successively with cold acetonitrile, water and methanol and washed again with mixture of water and methanol and dried under reduced pressure to produce 0.32g of title compound. 5 Analysis : Calculated (%) C; 61.45 H; 4.89 N; 11.31 Found (%) C; 61.51 H; 4.83 N; 11.27
Example 7: Preparation of 9-fluoro-3-(5)-methyl- 10-[(4-methyl-2, 7- diazabicyclo[3.3.0]oct-4-en)-7-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- de][l .4]-benzoxazine-6-carboxylic acid
To a suspension of 0.2g of 4-methyl-2,7-diazabicyclo [3.3.0] oct-4-en dihydrochloride and 0.25g of 9, 10-difluoro-3-(5)-methyl-7-oxo-2,3-dihydro-7H- pyrido[l ,2,3-de][l ,4]-benzoxazine-6-carboxylicacid in 5ml of anhydrous acetonitrile, was added 0.32ml of DBU with stirring. The reaction mixture was heated under reflux for 7 hours. After the reaction mixture was cooled to room temperature, the resulting solid was filtered off and washed successively with cold acetonitrile, water and methanol and dried under reduced pressure to give 0.33g of title compound.
Analysis : Calculated (%) C; 62.33 Η; 5.17 N; 10.90 Found (%) C; 62.30 Η; 5.13 N; 10.81
Example 8: Preparation of 9-fluoro-3-(S)-methyl- 10-[(3-methyl-2 ,7- diazabicyclo[3.3.0]oct-4-en)-7-yl]-7-oxo-2 , 3-dihydro-7H-pyrido[ 1 ,2,3- de"|[l .4"|-benzoxazine-6-carboxylic acid
To a suspension of 0.2g of 3-methyl-2,7-diazabicyclo [3.3.0] oct-4-en dihydrochloride and 0.26g of 9,10-difluoro-3-(S)-methyl-7-oxo-2,3-dihydro-7H- pyridofl ,2,3-de][l ,4]-benzoxazine-6-carboxylicacid in 5ml of anhydrous acetonitrile, was added 0.32ml of DBU with stirring. The reaction mixture was heated under reflux for 10 hours. After the reaction mixture was cooled to room temperature, the resulting solid was filtered off and washed succesively with cold acetonitrile, water and methanol and dried under reduced pressure to produce 0.35g of title compound.
Analysis : Calculated (%) C; 62.33 Η; 5.17 N; 10.90 Found (%) C; 62.30 Η; 5.11 N; 11.20
Example 9 : Preparation of 9-fluoro- 10-[(2 , 8-diazabicyclo [4.3.0]non-5-en)-8-yl] -7- oxo-2, 3-dihydro-7Η-pyrido[l ,2,3-de][l ,4]-benzothiazine-6-carboxylic acid
To a suspension of 0.2g of 2,8-diazabicyclo[4.3.0]non-5-endihydrochlorid and 0.35g of 9, 10-difluoro-7-oxo-2,3-dihydro-7H-pyrido[l ,2,3-de][l ,4]-benzothiazine-6- carboxylic acid in 5ml of anhydrous acetonitrile was added 0.32ml of DBU with stirring. The reaction mixture was heated under reflux for 5 hours. After the reaction mixture was cooled to room temperature, the precipitate was fitered off and washed succesively with cold acetonitrile, water and methanol and dried under reduced pressure to privide 0.36g of title compound.
Analysis : Calculated (%) C; 58.90 H; 4.68 N; 10.85 Found (%) C; 58.81 H; 4.59 N; 10.27
Example 10: Preparation of 9-fluoro-10-[(2,7-diazabicyclo [3.3.0]oct-4-en)-7-yl] -7- oxo-2,3-dihydro-7H-pyrido[l ,2,3-de][l ,4]-benzothiazine-6-carboxylic acid
To a suspension of 0.2g of 2,7-diazabicyclo[3.3.0]oct-4-en dihydrochlorid and 0.35g of 9, 10-difluoro-7-oxo-2,3-dihydro-7H-pyrido[l ,2,3-de][l ,4]-benzothiazine-6- carboxylic acid in 5ml of anhydrous acetonitrile, was added 0.3ml of DBU with stirring. The reaction mixture was heated under reflux for 5 hours. After the reaction mixture was cooled to room temperature, the resulting solid was filtered off and washed succesively with cold acetonitrile, water and methanol and dried under reduced pressure to give 0.35g of title compound.
Analysis : Calculated (%) C; 66.44 Η; 4.96 N; 12.91 Found (%) C; 66.51 Η; 5.02 N; 12.88
Example 11: Preparation of 9-fluoro-3-(R,5)-methyl-10-[(2,8-diazabicyclo [4.3.0] non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l ,2,3-de][ l ,4]- benzoxazine-6-carboxylic acid
0.2G of 2,8-diazabicyclo[4.3.0]non-5-en dihydrochloride and 0.28g of 9, 10- difluoro-3-(R.S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]-benzoxazine-6- carboxylic acid were treated by a method similar to that described in Example 1 to give 0.27g of title compound.
Analysis : Calculated (%) C; 62.33 H; 5.17 N; 10.90 Found (%) C; 62.28 H; 5.19 N; 10.11
Example 12: Preparation of 9-fluoro-3-(R,5)-methyl-10-[(2,7-diazabicyclo
[3.3.0]oct-4-en)-7-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l ,4]- benzoxazine-6-carboxylic acid
0.2G of 2,7-diazabicyclo[3.3.0]oct-4-en dihydrochloride and 0.26g of 9,10- difluoro-3-(R,S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]-benzoxazine-6- carboxylic acid were treated by a method similar to that described in Example 6 to give 0.24g of title compound.
Analysis : Calculated ( ) C; 61.45 Η; 4.89 N; 11.31 Found (%) C; 61.36 Η; 4.79 N; 11.24
Example 13: Preparation of 9-fiuoro-3-(R)-methyl-10-[(2,8-diazabicyclo[4.3.0]non-
5-en)-8-yl]-7-oxo-2 , 3-dihydro-7H-pyrido[ 1 ,2 , 3-de] [ 1 ,4]-benzoxazine- 6-carboxylic acid
0.2G of 2,8-diazabicyclo[4.3.0]non-5-en dihydrochloride and 0.28g of 9, 10- difluoro-3-(R)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1 ,2,3-de][l ,4]-benzoxazine-6- carboxylic acid were treated by a method similar to that described in Example 1 to give 0.26g of title compound.
Analysis : Calculated (%) C; 62.33 Η; 5.17 N; 10.90 Found (%) C; 62.45 Η; 5.19 N; 10.97
Example 14: Preparation of hydrochloric acid salt of 9-fluoro-3-(S)-methyl- 10- [(2,8- diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- dein .4]-benzoxazine-6-carboxylic acid
0.30G of 9-fluoro-3-(5)-methyl-10-[2,8-diazabicyclo[4,3,0]non-5-en)-8-yl]-7- oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]-benzoxazine-6-carboxylic acid obtained - lo ¬
in Example 1 was added to 5 ml of a 3N HCl-methanol solution at 0°C, and the resulting mixture was stirred for 2 hours. The solvent was removed under reduced pressure and the residue was washed with methanol-ethylether (1:4) and filtered off to produce 0.29g of a light yellow title compound.
Η-NMR(DMSO-d6, δ): 1.55(3H, d), 1.85(1H, m), 2.20(2H, m),
3.05(1H, m), 3.56(1H, m), 4.00(3H, m),
4.38(2H, m), 4.65(1H, m), 5.90(1H, s(broad)),
7.60(1H, d), 8.30(1H, s), 8.25(NH3+, s)
Example 15: Preparation of tartaric acid salt of 9-fluoro-3-(5 -methyl-10-[(2,7- diazabicyclo[3.3.0]oct-4-en)-7-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- de][l .41-benzoxazine-6-carboxylic acid
0.25G of 9-fluoro-3-(5)-methyl-10-[2,7-diazabicyclo[3,3,0]oct-4-en)-7-yl]-7- oxo-2,3-dihydro-7H-pyrido[l ,2,3-de][l ,4]-benzoxazine-6-carboxylic acid obtained in Example 6 was added to 10 ml of chloroform-methanol(10: 1) containing 0.15g of tartaric acid and the resulting mixture was stirred for 10 hours at room temperature. The solvent was removed under reduced pressure, and the residue was treated with 5ml of acetonitrile and stirred. The solid was recovered by filtration to give 0.16g of a white title compound.
Η-NMR(DMSO-d6, δ): 1.55(3Η, d), 2.25(2H, m), 3.05(1H, m),
3.56(1H, m), 4.00(3H, m), 4.10(2H, m), 4.38(2H, m), 4.62(1H, m), 5.90(1H, s),
7.60(1H, d), 8.16(NH3, s), 8.30(1H, s).
The antibacterial activity of the quinolone derivatives of the present invention was evaluated in accordance with the agar culture medium two-fold dilution method(Hoechst 345) by using a Muller-Hinton agar medium. Hoechst standard strains were used as the test strains. The strains having 107 CFU/ml were inoculated on the culture medium, and the growth of the strains was observed after incubating them at 37°C for 18 hours, in which ciprofloxacin and ofloxacin were used as a control material. The result of these Test are described in Table 1 and 2. ω *_*-> N) t o i 1-Λ t-Λ
Table 1. In vitro antibacterial activity test (MIC: minimum inhibitory concentration, //g/ml)
note) A compound of Example 1 B compound of Example 6 C compound of Example 1 1 D compound of Example 13
Table 2. In vitro antibacterial activity against methicillin resistant Staphylococcus aureus
(MIC: minimum inhibitory concentration, g/ml)
note) A: compound of Example 1
B: compound of Example 2

Claims

What is claimed is:
Compounds of Formula (I);
wherein
R1, R2, R3 and R4 may be the same or different and represent
independently hydrogen or lower alkyl,
X represents oxygen or sulfur,
Y represents hydrogen or methyl, and
n denotes an integer of 0 or 1, and their stereoisomers and pharmaceutically acceptable salts.
2. Compounds of Claim 1, 3-(R)-methylpyridonecarboxylic acid derivatives represented by Formula (Ia);
wherein
R1, R2, R3, R4, X and n are the same as defined in Claim 1, and their pharmaceutically acceptable salts. 3. Compound of Claim 1,
3-(S)-methyl pyridonecarboxylic acid derivatives representd by Formula (Ib);
wherein
R1, R2, R3, R4, X and n are the same as defined in Claim 1.
4. Compounds of Claim 1 wherein the compounds of Formula (I) is one of the following compounds;
9-fluoro-3-(5)-methyl-10-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3- dihydro -7H-pyrido [1,2,3-de] [1,4]-benzoxazine-6-carboxylic acid,
9-fluoro-3-(5)-methyl-10-[(2-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-7- oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid,
9-fluoro-3-(5)-methyl-10-[(5-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-7- oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 9-fluoro-3-(S)-methyl-10-[(3-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1 ,4]-benzoxazine-6-carboxylic acid,
9-fluoro-3-(-S)-methyl-10-[(4-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][1,4]-benzoxazine-6-carboxylic acid,
9-fluoro-3-(5)-methyl-10-[(2,7-diazabicyclo[3.3.0]oct-4-en)-7-yl]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid,
9-fluoro-3-(5)-methyl- 10-[(4-methyl-2 , 7-diazabicyclo[3.3.0]oct-4-en)-7-yl] -7- oxo-2, 3-dihydro-7H-pyrido[l ,2,3-de][1 ,4]-benzoxazine-6-carboxylic acid,
9-fluoro-3-(5)-methyl-10-[(3-methyl-2,7-diazabicyclo[3.3.0]oct-4-en)-7-yl]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 9-fluoro-10-[(2,8-diazabicyclo [4.3.0]non-5-en)-8-yl] -7-oxo-2,3-dihydro-7Η-pyrido [l,2,3-de][l,4]-benzothiazine-6-carboxylic acid,
9-fluoro-10-[(2,7-diazabicyclo [3.3.0]oct-4-en)-7-yl] -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][l,4]-benzothiazine-6-carboxylic acid,
9-fluoro-3-(R,5)-methyl-10-[(2,8-diazabicyclo [4.3.0] non-5-en)-8-yl]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid,
9-fluoro-3-(R,S)-methyl-10-[(2,7-diazabicyclo [3.3.0]oct-4-en)-7-yl]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid,
9-fluoro-3-(R)-methyl-10-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-7-oxo-2,3-dihydro -7H-pyrido[l,2,3-de][1,4]-benzoxazine-6-carboxylic acid. dihydro -7H-pyrido[l,2,3-de][1,4]-benzoxazine-6-carboxylic acid.
5. A process for preparing compounds of Formula (I)
wherein
R1, R2, R3 and R4 may be the same or different and represent
independently hydrogen or lower alkyl,
X represents oxygen or sulfur,
Y represents hydrogen or methyl, and
n denotes an integer of 0 or 1 and their stereoisomers and pharmaceutically acceptable salts, which comprises reacting a compound of formula (II)
X and Y are as defined above, and Z is a leaving group such as fluoro, with a compound of Formula (III)
wherein
R1, R2, R3, R4 and n are as defined above.
EP93916265A 1992-07-23 1993-07-23 Pyridonecarboxylic acid derivatives and processes for preparing the same Ceased EP0651753A1 (en)

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KR1019920013213A KR960003616B1 (en) 1992-07-23 1992-07-23 New pyridone carboxylic acid derivatives having potent antibacterial activities and the preparation process thereof
KR1302139 1992-07-23
PCT/KR1993/000064 WO1994002487A1 (en) 1992-07-23 1993-07-23 Novel pyridonecarboxylic acid derivatives and processes for preparing the same
CN93119572A CN1102184A (en) 1992-07-23 1993-10-25 Novel pyridonecarboxylic acid derivatives and processes for preparing the same

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JP2552101B2 (en) 1996-11-06

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