WO1999033839A1 - Cephem derivatives and a method for producing the compounds and an antibacterial composition containing the compounds - Google Patents

Cephem derivatives and a method for producing the compounds and an antibacterial composition containing the compounds Download PDF

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Publication number
WO1999033839A1
WO1999033839A1 PCT/KR1998/000463 KR9800463W WO9933839A1 WO 1999033839 A1 WO1999033839 A1 WO 1999033839A1 KR 9800463 W KR9800463 W KR 9800463W WO 9933839 A1 WO9933839 A1 WO 9933839A1
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Prior art keywords
phenyl
cephem
amino
carboxylic acid
oxo
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PCT/KR1998/000463
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French (fr)
Inventor
Yeo Hong Yoon
Koun Ho Lee
Seok Bum Song
Ho Sung Whang
Kwang Hyuk Lee
Je Hak Kim
Dal Hyun Kim
Young Gi Kim
Jin Ah Kang
Youn Ha Lee
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Cheil Jedang Corporation
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Priority claimed from KR1019980050525A external-priority patent/KR100294871B1/en
Application filed by Cheil Jedang Corporation filed Critical Cheil Jedang Corporation
Priority to AU16940/99A priority Critical patent/AU1694099A/en
Publication of WO1999033839A1 publication Critical patent/WO1999033839A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to novel cephem derivatives in which known phenyl oxazolidinone derivatives are chemically combined with cephem, a process for producing the cephem derivatives, and a pharmaceutical antibacterial composition containing the cephem derivatives.
  • pyridine-substituted phenyl oxazolidinone derivatives disclosed in the above patents are effective against Gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae. However, they are not active against Gram-negative bacteria such as Escherichia coli, Klebsiella, Proteus, and Seratia mar censes. Moreover, they cannot be administered as an injection solution because their free amine forms are little soluble.
  • the inventors have intensively studied to develop new antibacterial agents which have effective and excellent activity against Gram-negative bacteria and Gram-positive bacteria, and which are soluble so that they can be used as an injection solution.
  • the structurally new compounds were produced by chemically reacting known antibacterial oxazolidinone compounds with cephem compounds. They were found to be potently active against Gram-negative bacteria as well as Gram-positive bacteria.
  • the present invention provides compounds of the formula I:
  • R is hydrogen, or lower alkyl optionally substituted with carboxylic acid or inorganic cation salt thereof or protected carboxylic acid, and the alkoxyimino is a syn isomer;
  • R2 is hydrogen, fluorine, chlorine or methoxy and can be same or different;
  • R3 is hydrogen, or lower alkyl optionally substituted with carboxy or inorganic cation salt thereof, amino or alkoxy;
  • “Lower alkyl” herein means, unless indicated otherwise, straight or branched alkyl having from 1 to 6 carbons and cycloalkyl having from 3 to 6 carbons.
  • C,-C 6 alkyl include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and structural isomers thereof.
  • R3 substituents are preferably hydrogen, methyl, difluoromethyl, dichloromethyl, hydroxymethyl, or methoxy and, most preferably, methyl.
  • the most preferred absolute configuration at C-5 of the oxazolidinone ring of the compounds according to the present invention is (S) under the Cahn-Ingold-Prelog nomenclature system. It is the (S)-enantiomer which possesses excellent activities against bacteria.
  • the racemic mixture can be used in the same way and for the same purpose as the pure (S)-enantiomer. However, the difference is that twice as much reacemic material must be used to exhibit the same antibacterial activity as the pure (S)-enantiomer.
  • the pharmaceutically acceptable salts of the compounds I include inorganic cation salts such as alkaline metal salts (e.g., sodium or potassium) and alkaline earth metal salts (e.g., calcium or magnesium), inorganic salts such as hydrochloride, hydrobromide, hydroiodide and sulfate, organic salts such as malate, lactate and tartarate, organic sulfonate such as benzenesulfonate, methanesulfonate and 4-tolunesulfonate, amino acid salts such as arginine, lysine and glycine, and amine salts such as trimethylamine, ammonia, triethylamine, pyridine, and picoline.
  • inorganic cation salts such as alkaline metal salts (e.g., sodium or potassium) and alkaline earth metal salts (e.g., calcium or magnesium), inorganic salts such as hydrochloride, hydrobromide, hydroi
  • the compounds I or pharmaceutically acceptable salts thereof of the present invention can be produced by reacting the above compounds II with the compounds of the formula III:
  • Xa is the same as X defined above, except for amine and protected amine, R 4 is hydrogen or carboxylic acid-protecting group, and L is halogen atom or acetoxy.
  • the halogen atom is chlorine, bromine or iodine. Bromine or idodine is especially preferable.
  • the compounds I of the present invention can be produced by acylating the compounds of the formula V:
  • Xb is amine or protected amine
  • R 5 is hydrogen or carboxylic acid-protecting group
  • M " is anionic halogen such as chloride, bromide or iodide, or sulfonate, acetate, benzenesulfonate or citrate anions, with the compounds of the formula VI:
  • M " is chloride or bromide.
  • the inner salt formed by monovalent anion of carboxylate and monovalent cation of pyridine is also preferable.
  • the compounds V can be prepared by C-3 reacting the compounds II with the compounds of the formula IV:
  • Xb is amine or protected amine
  • R 4 is hydrogen or carboxylic acid-protecting group
  • L is the same as defined above.
  • the reaction of the compounds II and the compounds III can be carried out at the temperature of from -30°C to 70°C.
  • the preferred solvent is anhydrous solvent.
  • the suitable organic solvents include lower nitrile such as acetonitrile and propionitrile, halogenated alkane such as chloroform, tetrachloromethane and dichloromethane, ether such as tetrahydrofuran and dioxane, amide such as N,N-dimethylformamide and N,N- dimethylacetamide, ester such as ethylacetate and methylacetate, ketone such as acetone, methylethylketone and methylisobutylketone, sulfoxide such as dimethylsulfoxide, aromatic hydrocarbon such as bezene and toluene, and mixtures thereof.
  • Protecting groups which do not participate in the displacement reaction of the compounds II and III may be introduced to amine, carboxyl and alcohol groups of the compounds II and III.
  • Examples of the amine-protecting group include formyl, acetyl, chloroacetyl, dichloroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, triphenyl, benzyl, 4- methoxybenzyl, diphenylmethyl, triloweralkylsilyl and trimethylsilyl.
  • the carboxyl- protecting groups include for example t-butyl, benzyl, 4-methoxybenzyl, benzyl, 4- nitrobenzyl, diphenylmethyl, methyl, 2,2,2-trichloroethyl, pivaloyloxymethyl, triloweralkylsilyl and trimethylsilyl.
  • Examples of the alcohol-protecting group include acetoxy, methoxymethyl, tetrahydrofuranyl, t-butyl, benzyl, and 4-methoxybenzyl.
  • amine, carboxyl and alcohol groups of the compounds II and III can be simultaneously protected by silylation.
  • silylating reagents can be used as a silylating reagent.
  • the silylating reagents are advantageous in that they make it possible to simultaneously protect amine, carboxyl and alcohol groups in an anhydrous solvent such as dichloromethane .
  • the compounds V can be obtained by reacting the compounds II with a silylating reagent such as N,O-bis(tri-loweralkylsilyl)acetamide or N,O-bis(tri-loweralkylsilyl) trifluoroacetamide in an anhydrous solvent such as dichloromethane or acetone at the temperature of from -30° to 60°C, followed by, if necessary, deprotecting, and crystalizing into hydrochloride, hydroiodide or sulfate salts or chromatographing over silical gel, alumina, resin, and the like.
  • a silylating reagent such as N,O-bis(tri-loweralkylsilyl)acetamide or N,O-bis(tri-loweralkylsilyl) trifluoroacetamide in an anhydrous solvent such as dichloromethane or acetone at the temperature of from -30° to 60°C, followed by, if necessary, deprotecting, and crystal
  • the compounds V can be obtained by simultaneously protecting amine and carboxyl groups with a silylating reagent such asN,O-bis(tri-loweralkylsilyl)acetamide,N,O-bis(tri-loweralkylsilyl)trifluoroacetamide or hexamethylsilazane(HMDS) and then converting acetoxymethyl into iodomethyl using iodotrimethylsilane.
  • a silylating reagent such asN,O-bis(tri-loweralkylsilyl)acetamide,N,O-bis(tri-loweralkylsilyl)trifluoroacetamide or hexamethylsilazane(HMDS)
  • the protection and deprotection of the functional groups can be conducted by a conventional method in the art, for example, "Protective groups in Organic Synthesis, 2nd edition” (Greene, T.W., etc., John Wiley & Sons, New York, 1991).
  • the pharmaceutically acceptable salts of the compounds II and III are the same as mentioned in the compounds I.
  • the compounds I of the present invention can be isolated and purified by conventional extraction, crystallization and column chromatography in the art.
  • the antibacterial composition containing the compounds I or pharmaceutically acceptable salts thereof as an active ingredient can be formulated into solid or liquid using conventional techniques in the art.
  • the pharmaceutical composition of the present invention can be primarily adminstered by intravenous or intramuscular injections.
  • the composition of the present invention can be used in the forms of capsule, tablet, powder, suppository, and the like.
  • Examples of the solid form containing the compounds I include powder, tablet, capsule, suppository, cachet, and the like.
  • the solid form can contain at least one of thickener, flavourant, sweetener, solubilizer, lubricant, suspending agent, binder, encapsulating agent, and the like.
  • Examples of nonactive solid carrier include magnesium carbonate, magnesium stearate, talc, glucose, lactose, pectin, dextrin, starch, gelatin, wax, coccoa butter, and the like.
  • the liquid formulation can be solution, suspension or emulsion.
  • Examples of the carrier for the liquid form include water, mixture of water and propyleneglycol, mixture of water and polypropyleneglycol, and the like. Additionally, additives such as pigment, solubilizer, sweetener, stabilizer, thickener, and the like can be included in the liquid formulation.
  • the antibacterial composition of the present invention can be applied directly to human and animals. In addition, it can be used as food preservatives, agricultural chemicals, and the like. When the composition of the present invention is used in the treatment of human or animals against microbial infection, the injection or oral administration is preferable.
  • the adminstration amount of the compounds I depends on sexuality, age, weight and symptom of the patients to be treated, administration route, and the like. Generally, the daily dosage is in the range of 1 mg/kg and 1 ,000 mg/kg. The preferable daily dosage is between 100 mg/kg and 500 mg/kg.
  • the compounds I of the present invention have broad activity against Gram- positive bacteria such as Streptococcus, Staphylococcus, Conellebacterium, Baccilus, Enterococci, and the like, and Gram-negative bacteria such as Escherichia coli, Klebsiella, Serratia marcescens, Salmonella, Proteus, and the like.
  • Gram- positive bacteria such as Streptococcus, Staphylococcus, Conellebacterium, Baccilus, Enterococci, and the like
  • Gram-negative bacteria such as Escherichia coli, Klebsiella, Serratia marcescens, Salmonella, Proteus, and the like.
  • the compounds I are effective against strains which are resistant to known antibiotics such as vancomycin, ⁇ -lactam antibiotics, quinolones, and the like.
  • the compounds I of the present invention are greatly valuable in that they can be used as an injection because their water solubility is at least 10%.
  • the known compounds indicated in the above Table 1 are active in vitro against Gram- positive bacteria and drug-resistant strains but their free bases cannot be used as an injection because of low solubility.
  • silylated pyridine derivative was prepared as follows. (S)-N-[[3-[3-fluoro-4-(4-pyridyl)phenyl]-2-oxo-5-oxazolidiny ⁇ ]- methyl] acetamide was used as a pyridine derivative and was synthesized according to the method described in international patent publication No. WO 93/09103. 5.65 g of the prydine derivative was mixed with 30 ml of acetonitrile.
  • the resulting oily residue was dissolved in 10 ml of anhydrous ethanol.
  • the resulting solution was mixed with an aqueous solution of 0.4 g of sodium hydroxide in 0.2 ml of distilled water and the mixture was stirred for 3 hours.
  • 10 ml of ethylacetate and 10 ml of water were added to the solution, and the solution was then stirred for 30 minutes. After the layers were separated, the organic layer was removed.2N HC1 was added to the aqueous layer to adjust its pH to 1.0.
  • This acylating reagent was dropwise added to the solution for 10 minutes and the solution was then stirred for 1 hour. After the reaction was completed, the solvent was removed and the residue was mixed with 50 ml of ethyl acetate. The resulting solid was filtered and suspended in 10 ml of dichloromethane. The suspension was reacted with 1.0 ml of trifluoracetic acid and 0.5 ml of anisol at 25°C for 1 hour. 20 ml of isopropyl ether was added to the reaction mixture and the resulting solid was filtered. After the unpurified solid was dissolved in an aqueous 50% ethanol, the pH of the solution was adjusted to 1.5 with 4N sulfuric acid and the resulting solution was concentrated under reduced pressure.
  • silylated pyridine derivative was prepared as follows.
  • Example 12 10 ml of anhydrous dichloromethane under nitrogen. After the same procedure as the Example 12 was carried out by using 1.3 ml of MSTFA and 0.5 ml of TMSI, the reaction mixture was concentrated under reduced pressure. The concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes.
  • This silylated pyridine derivative was prepared as follows. (S)-N-[[3-[3-fluoro-4- (3-pyridyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (WO 93/09103).400 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25°C for 2 hours to produce the silylated pyridine derivative. The formed solid by adding 1.0 ml of methanol and 5 ml of acetonitrile to the solution was filtered, and purified to obtain 130 mg of the title compound. mp: 183 ° C to 186°C (decomposition)
  • This silylated pyridine derivative was prepared as follows. (S)-N-[[3-[4-(4- pyridyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (USP 5,254,577).380 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25 °C for 2 hours to produce the silylated pyridine derivative. The silylated pyridine derivative was added and the solution was stirred at 25°C for 3 hours. The formed solid was filtered by adding 1.0 ml of methanol and 5 ml of acetonitrile to the solution, and purified to obtain 150 mg of the title compound, mp: 196°C to 198°C (decomposition)
  • This silylated pyridine derivate was prepared as follows. (S)-N-[[3-[3,5-difluoro-4-(4-pyridyl)phenyl]- 2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (WO 93/09103). 420 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25 °C for 2 hours to produce the silylated pyridine derivative.
  • the solution was cooled to 5°C and was reacted with 0.5 ml of TMSI at 20°C for 30 minutes.
  • the solution was concentrated under reduced pressure and the residue was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran at 5°C for 5 minutes.
  • the solution was reacted at 25 °C for 3 hours with the silylated pyridine derivatives obtained by reacting 400 mg of (S)-N-[[3-[3-fluoro-4-(4-pyridyl)phenyl]-2-oxo-5-oxazolydinyl]- methyl] acetamide with 1.0 ml of MSTFA in 10 ml of acetonitrile.
  • the formed solid by adding a mixed solvent of 1.0 ml of methanol and 5 ml of acetonirile to the solution was filtered.
  • the solid was dissolved in an aqueous 30% ethanol and the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate.
  • the solution was reacted at 25°C for 3 hours with the silylated pyridine derivatives obtained by reacting 400 mg of (S)-N-[[3-[3-fluoro-4- (3-pyridyl)phenyl]-2-oxo-5-oxazolydinyl]-methyl]acetamide with 1.0 ml of MSTFA in 10 ml of acetonitrile.
  • the resulting solid by adding a mixed solvent of 1.0 ml of methanol and 5 ml of acetoniril to the solution was filtered.
  • the solid was dissolved in an aqueous 30% ethanol and the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate.
  • the solution was reacted at 25°C for 3 hours with the silylated pyridine derivatives obtained by reacting 380 mg of (S)-N-[[3-[4-(4- pyridyl)phenyl]-2-oxo-5-oxazolydinyl]-methyl]acetamide with 1.0 ml of MSTFA in 10 ml of acetonitrile.
  • the resulting solid by adding a mixed solvent of 1.0 ml of methanol and 5 ml of acetonirile to the solution was filtered.
  • the solid was dissolved in an aqueous 30% ethanol and the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate.
  • MRSA C5100 MetalUin resistant Staphylococcus aureus
  • C CRSA C6043 (Ciprofloxacin resistant Staphylococcus aureus)
  • D Staphylococcus epidermis ATCC 12228
  • E Enterococcus faecalis ATCC29212
  • F Streptococcus pyogenes ATCC8668
  • G Escherichia coli ATCC10536
  • the compounds of the formula I according to the present invention are broadly active against Gram-positive and Gram-negative bacteria and have the pharmacological advantages of vancomycin and cefotaxime. Especially, the compounds of the formula I are advantageous in that they are effective against cephem antibiotics-registant bacteria such as MRSA and CRSA.
  • the single dose toxicity of the compounds of the present invention was evaluated in ICR mice by intravenous administration.
  • the compounds of Examples 1 , 2 and 13 along with an equivalent of sodium bicarbonate were dissolved in saline and the resulting solutions were intravenously administered.
  • LD 50 of each test compound was measured to be 1,500 mg/kg of weight.

Abstract

The present invention relates to novel cephem derivatives in which known phenyl oxazolidinone derivatives are chemically combined with cephem, a process for producing the cephem derivatives, and a pharmaceutical antibacterial composition containing the cephem derivatives. The structural formula of the cephem derivatives compounds is represented as in formula (I).

Description

CEPHEM DERIVATIVES AND A METHOD FOR
PRODUCING THE COMPOUNDS AND AN ANTIBACTERIAL
COMPOSITION CONTAINING THE COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to novel cephem derivatives in which known phenyl oxazolidinone derivatives are chemically combined with cephem, a process for producing the cephem derivatives, and a pharmaceutical antibacterial composition containing the cephem derivatives.
BACKGROUND OF THE INVENTION
International Patent Publication No. WO 93/09103 discloses substituted aryl- and heteroaryl-phenyl oxazolidinones which may be useful as antibacterial agents. The structural formula is represented as follows:
Figure imgf000003_0001
US Patent No. 5,254,577 discloses aminomethyloxooxazolidinyl arylbenzen derivatives which can be used as antibacterial agents. The structural formula is represented as follows:
Figure imgf000003_0002
Some of pyridine-substituted phenyl oxazolidinone derivatives disclosed in the above patents are effective against Gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae. However, they are not active against Gram-negative bacteria such as Escherichia coli, Klebsiella, Proteus, and Seratia mar censes. Moreover, they cannot be administered as an injection solution because their free amine forms are little soluble.
The inventors have intensively studied to develop new antibacterial agents which have effective and excellent activity against Gram-negative bacteria and Gram-positive bacteria, and which are soluble so that they can be used as an injection solution. As a result, the structurally new compounds were produced by chemically reacting known antibacterial oxazolidinone compounds with cephem compounds. They were found to be potently active against Gram-negative bacteria as well as Gram-positive bacteria.
SUMMARY OF THE INVENTION
The present invention provides compounds of the formula I:
Figure imgf000004_0001
or pharmaceutically acceptable salts or hydrates thereof wherein
X
Figure imgf000004_0002
i) hydrogen, ii) C,-C, 6 lower alkyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,-C4acyloxy,
C,-C4alkylsulfonyl, C,-C4alkylsulfenyl, C,-C4 alkylsulfmyl, C,-C4alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, iii) C2-C6 alkenyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, CrC4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,- C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, CrC4 acyloxy, CrC4alkylsulfonyl, CrC4 alkylsulfenyl, C,-C4 alkylsulfinyl, C C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, iv) C2-C6 alkynyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, CrC4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, CrC4acyloxy, C,-C4alkylsulfonyl, C C4alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, v) phenyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,- C4 acyloxy, CrC4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, vi) R4-(CH2)n- , in which n is an integer of 0 to 3, and R4 is 2-thiophenyl, 2-furyl, 2-pyrolyl, 4-thiazolyl, l,2,4-thiadiazol-3-yl, 2-oxazolyl, or 5- or 6- membered heterocyclic compound having from 1 to 4 atoms of O, S and N which are substituted with at least one selected from the group consisting of chlorine, fluorine, hydroxy, amino, CrC4 alkyl, C,-C4 acylamino, Cr z C4 alkylsulfonylamino, C,-C4 alkoxy, and C,-C4 acyloxy, vii) N H 2 in which Z is hydrogen, or C,-C6 lower alkyl, C,-C6 alkenyl, C2-C6 alkynyl, phenyl or heterocyclic compound optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, CrC4 alkylamino, CrC4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,-C4 acyloxy,
CrC4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, and carbon having optical activity R,
can be optically pure (-), (+) or racemic forms, viii)
Figure imgf000005_0001
in which W is
CH or N, R, is hydrogen, or lower alkyl optionally substituted with carboxylic acid or inorganic cation salt thereof or protected carboxylic acid, and the alkoxyimino is a syn isomer;
R2 is hydrogen, fluorine, chlorine or methoxy and can be same or different;
R3 is hydrogen, or lower alkyl optionally substituted with carboxy or inorganic cation salt thereof, amino or alkoxy; and
provided that in the compounds of the formula I the phenyloxazolidinone is substituted at 3 or 4 positions of pyridine.
DETAILED DESCRIPTION OF THE INVENTION
"Lower alkyl" herein means, unless indicated otherwise, straight or branched alkyl having from 1 to 6 carbons and cycloalkyl having from 3 to 6 carbons. For example, C,-C6 alkyl include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and structural isomers thereof.
The R3 substituents are preferably hydrogen, methyl, difluoromethyl, dichloromethyl, hydroxymethyl, or methoxy and, most preferably, methyl.
The most preferred absolute configuration at C-5 of the oxazolidinone ring of the compounds according to the present invention is (S) under the Cahn-Ingold-Prelog nomenclature system. It is the (S)-enantiomer which possesses excellent activities against bacteria. The racemic mixture can be used in the same way and for the same purpose as the pure (S)-enantiomer. However, the difference is that twice as much reacemic material must be used to exhibit the same antibacterial activity as the pure (S)-enantiomer.
The pharmaceutically acceptable salts of the compounds I include inorganic cation salts such as alkaline metal salts (e.g., sodium or potassium) and alkaline earth metal salts (e.g., calcium or magnesium), inorganic salts such as hydrochloride, hydrobromide, hydroiodide and sulfate, organic salts such as malate, lactate and tartarate, organic sulfonate such as benzenesulfonate, methanesulfonate and 4-tolunesulfonate, amino acid salts such as arginine, lysine and glycine, and amine salts such as trimethylamine, ammonia, triethylamine, pyridine, and picoline.
Examples of the substituents at C-3 position of cephem include the compounds of the formula II:
Figure imgf000007_0001
The specific examples of the compounds of the formula II are indicated in Table 1 below.
Table 1
Figure imgf000007_0002
Figure imgf000008_0001
The compounds I or pharmaceutically acceptable salts thereof of the present invention can be produced by reacting the above compounds II with the compounds of the formula III:
Figure imgf000008_0002
wherein Xa is the same as X defined above, except for amine and protected amine, R4 is hydrogen or carboxylic acid-protecting group, and L is halogen atom or acetoxy. The halogen atom is chlorine, bromine or iodine. Bromine or idodine is especially preferable.
Alternatevely, the compounds I of the present invention can be produced by acylating the compounds of the formula V:
Figure imgf000009_0001
wherein Xb is amine or protected amine, R5 is hydrogen or carboxylic acid-protecting group, M" is anionic halogen such as chloride, bromide or iodide, or sulfonate, acetate, benzenesulfonate or citrate anions, with the compounds of the formula VI:
Figure imgf000009_0002
wherein Y is the same as defined above. The most preferred anion M" is chloride or bromide. In the absence of M", the inner salt formed by monovalent anion of carboxylate and monovalent cation of pyridine is also preferable.
The compounds V can be prepared by C-3 reacting the compounds II with the compounds of the formula IV:
Figure imgf000009_0003
wherein Xb is amine or protected amine, R4 is hydrogen or carboxylic acid-protecting group, and L is the same as defined above.
The reaction of the compounds II and the compounds III can be carried out at the temperature of from -30°C to 70°C. The preferred solvent is anhydrous solvent. The suitable organic solvents include lower nitrile such as acetonitrile and propionitrile, halogenated alkane such as chloroform, tetrachloromethane and dichloromethane, ether such as tetrahydrofuran and dioxane, amide such as N,N-dimethylformamide and N,N- dimethylacetamide, ester such as ethylacetate and methylacetate, ketone such as acetone, methylethylketone and methylisobutylketone, sulfoxide such as dimethylsulfoxide, aromatic hydrocarbon such as bezene and toluene, and mixtures thereof.
Protecting groups which do not participate in the displacement reaction of the compounds II and III may be introduced to amine, carboxyl and alcohol groups of the compounds II and III. Examples of the amine-protecting group include formyl, acetyl, chloroacetyl, dichloroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, triphenyl, benzyl, 4- methoxybenzyl, diphenylmethyl, triloweralkylsilyl and trimethylsilyl. The carboxyl- protecting groups include for example t-butyl, benzyl, 4-methoxybenzyl, benzyl, 4- nitrobenzyl, diphenylmethyl, methyl, 2,2,2-trichloroethyl, pivaloyloxymethyl, triloweralkylsilyl and trimethylsilyl. Examples of the alcohol-protecting group include acetoxy, methoxymethyl, tetrahydrofuranyl, t-butyl, benzyl, and 4-methoxybenzyl.
Alternatively, amine, carboxyl and alcohol groups of the compounds II and III can be simultaneously protected by silylation. N,O-bis(trimethylsilyl)acetamide, N-methyl-N- (trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-
(trimethylsilyl)trifluoroacetamide and the like can be used as a silylating reagent. The silylating reagents are advantageous in that they make it possible to simultaneously protect amine, carboxyl and alcohol groups in an anhydrous solvent such as dichloromethane .
When L in the compounds IV is halogen atom such as bromine or iodine, the compounds V can be obtained by reacting the compounds II with a silylating reagent such as N,O-bis(tri-loweralkylsilyl)acetamide or N,O-bis(tri-loweralkylsilyl) trifluoroacetamide in an anhydrous solvent such as dichloromethane or acetone at the temperature of from -30° to 60°C, followed by, if necessary, deprotecting, and crystalizing into hydrochloride, hydroiodide or sulfate salts or chromatographing over silical gel, alumina, resin, and the like.
When L in the compounds IV is acetoxy, e.g., the compound IV is 7-amino-3- acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA), the compounds V can be obtained by simultaneously protecting amine and carboxyl groups with a silylating reagent such asN,O-bis(tri-loweralkylsilyl)acetamide,N,O-bis(tri-loweralkylsilyl)trifluoroacetamide or hexamethylsilazane(HMDS) and then converting acetoxymethyl into iodomethyl using iodotrimethylsilane.
The protection and deprotection of the functional groups can be conducted by a conventional method in the art, for example, "Protective groups in Organic Synthesis, 2nd edition" (Greene, T.W., etc., John Wiley & Sons, New York, 1991). The pharmaceutically acceptable salts of the compounds II and III are the same as mentioned in the compounds I.
The compounds II as the substituents at C-3 position of cephem, for example, (S)- N- [[3 - [3 -fluoro-4-(4-pyridyl)phenyl] -2-oxo-5-oxazolidinyl] -methyl]acetamide, are known and can be synthesized by methods described in International Patent Publication No. WO 93/09103 and US Patent No. 5254577.
The compounds I of the present invention can be isolated and purified by conventional extraction, crystallization and column chromatography in the art.
The antibacterial composition containing the compounds I or pharmaceutically acceptable salts thereof as an active ingredient can be formulated into solid or liquid using conventional techniques in the art. The pharmaceutical composition of the present invention can be primarily adminstered by intravenous or intramuscular injections. In addition, the composition of the present invention can be used in the forms of capsule, tablet, powder, suppository, and the like.
Examples of the solid form containing the compounds I include powder, tablet, capsule, suppository, cachet, and the like. The solid form can contain at least one of thickener, flavourant, sweetener, solubilizer, lubricant, suspending agent, binder, encapsulating agent, and the like. Examples of nonactive solid carrier include magnesium carbonate, magnesium stearate, talc, glucose, lactose, pectin, dextrin, starch, gelatin, wax, coccoa butter, and the like. The liquid formulation can be solution, suspension or emulsion. Examples of the carrier for the liquid form include water, mixture of water and propyleneglycol, mixture of water and polypropyleneglycol, and the like. Additionally, additives such as pigment, solubilizer, sweetener, stabilizer, thickener, and the like can be included in the liquid formulation.
The antibacterial composition of the present invention can be applied directly to human and animals. In addition, it can be used as food preservatives, agricultural chemicals, and the like. When the composition of the present invention is used in the treatment of human or animals against microbial infection, the injection or oral administration is preferable.
The adminstration amount of the compounds I depends on sexuality, age, weight and symptom of the patients to be treated, administration route, and the like. Generally, the daily dosage is in the range of 1 mg/kg and 1 ,000 mg/kg. The preferable daily dosage is between 100 mg/kg and 500 mg/kg.
The compounds I of the present invention have broad activity against Gram- positive bacteria such as Streptococcus, Staphylococcus, Conellebacterium, Baccilus, Enterococci, and the like, and Gram-negative bacteria such as Escherichia coli, Klebsiella, Serratia marcescens, Salmonella, Proteus, and the like. Particularly, the compounds I are effective against strains which are resistant to known antibiotics such as vancomycin, β-lactam antibiotics, quinolones, and the like.
The compounds I of the present invention are greatly valuable in that they can be used as an injection because their water solubility is at least 10%. In comparison, the known compounds indicated in the above Table 1 are active in vitro against Gram- positive bacteria and drug-resistant strains but their free bases cannot be used as an injection because of low solubility.
The invention will now be described with reference to the following illustrative
Examples.
EXAMPLES
Reference Example 1
Preparation of 7β-amino-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l,3- oxazol-3 -yljphenyl]- 1 -pyridiniomethyl] -3 -cephem-4-carboxylate
Figure imgf000013_0001
3.8 ml of hexamethyldisilazane was added to a suspension of 4.15 g of 7- aminocephalosporinic acid (7-ACA) in 50 ml of dichloromethane. 1 or 2 drops of iodotrimethylsilane were then added and the solution was refluxed with heat under nitrogen for 2 hours. 1.95 ml of chloromethylsilane was added and the solution was refluxed with heat for 30 minutes. The reaction mixture was cooled to 25°C. 8.35 ml of dimethylaniline was added and the solution was stirred for 30 minutes. 2.84 ml of iodotrimethylsilane was added under nitrogen and the solution was stirred at 20°C for 1.5 hours. The resulting solution was mixed with the silylated pyridine derivative at 5°C, and the solution was stirred at 20°C for 2 hours. This silylated pyridine derivative was prepared as follows. (S)-N-[[3-[3-fluoro-4-(4-pyridyl)phenyl]-2-oxo-5-oxazolidinyι]- methyl] acetamide was used as a pyridine derivative and was synthesized according to the method described in international patent publication No. WO 93/09103. 5.65 g of the prydine derivative was mixed with 30 ml of acetonitrile. The resulting solution was reacted with 9.57 ml of N,O-bis(trimethylsilyl)acetamide at 25°C for 2 hours to produce the silylated pyridine derivative. After the reaction was completed, a mixed solvent of 2.0 ml of methanol, 145 ml of acetone and 2.2 ml of water was slowly dropwise added so that deprotection took place. The reaction mixture was stirred at 5°C for 1 hour and the resulting solid was filtered under reduced pressure. The solid was washed with 3 x 20 ml of acetone and 2 x 30 ml of diethylether, and was dried under vaccum at 35°C to obtain 9.2 g of the title compound as hydroiodide salt. 5.0 g of the hydroiodide salt was mixed with 25 ml of water and 25 ml of acetone. The resuting solution was cooled to 10°C, and then 2 ml of concentrated hydrochloric acid was added to the solution and the reaction mixture was stirred for 30 minutes. 1 g of activated carbon was added to the solution, and the solution was then stirred for 30 minutes, and filtered. The filtrated was warmed to 25 °C, and 25 ml of anhydrous ethanol and 100 ml of isopropylalcohol were slowly added to the solution. The reaction mixture was cooled to 5°C to yield precipitating crystals. 100 ml of isopropylalcohol was added to the solution and the resulting solution was stirred for 30 minutes. The solution was filtered under reduced pressure, washed with 3 x 20 ml of isopropylalcohol, 2 x 20 ml of acetone and 2 x 30 ml of diethylether, and dried under vacuum at 35°C to obtain 2.5 g of dihydrochloride salt of the title compound. mp: 140°C to 169°C (decomposition). NMR(400MHz, DMSO-d6):
9.08-9.1 l(2H,d,J=7.1 Hz), 8.43~8.46(2H,d,J=6.3 Hz), 8.32(lH,t), 7.96~8.02(lH,dd), 7.73-7.79(1 H,dd), 7.60~7.63(lH,dd), 5.58~5.67(lH,dd), 5.17~5.23(3H,m), 4.82(lH,m), 4.20~4.24(lH,t), 3.84~3.88(lH,dd), 3.54~3.68(2H,ABq,J=18.2Hz), 3.44~3.47(2H,m), 1.84(3H,s) Reference Example 2
Preparation of 2-(4-methoxybenzyloxy)acetic acid
1 g of ethylglycolate was dissolved in 10 ml of dimethylformamide. The solution was cooled to 5°C.0.38 g of 60% sodium hydride was added to the solution. The solution was stirred for 10 minutes and was reacted with 1.3 ml of 4-methoxybenzylchloride at 25 °C for 2 hours. The solution was extracted with 10 ml of water and 20 ml of ethylacetate. The aqueous layer was extracted with 10 ml of ethylacetate, and the collected orgaic layer was washed with 2 x 20 ml of water and 10 ml of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oily residue was dissolved in 10 ml of anhydrous ethanol. The resulting solution was mixed with an aqueous solution of 0.4 g of sodium hydroxide in 0.2 ml of distilled water and the mixture was stirred for 3 hours. 10 ml of ethylacetate and 10 ml of water were added to the solution, and the solution was then stirred for 30 minutes. After the layers were separated, the organic layer was removed.2N HC1 was added to the aqueous layer to adjust its pH to 1.0. The solution was extracted with 2 x 10 ml of dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.3 g of the title compound, mp: 52°C to 53°C NMR(400MHz,DMSO-d6):
8.07(lH,s), 7.25(2H,m), 6.86(2H,m), 4.54(2H,s), 4.08(2H,s), 3.79(3H,s)
Reference Example 3
Preparation of 2-(4-methoxybenzyloxy)propanoic aicd
Following the above Reference Example 2, but using ethyl(S)-(-)-lactate as a starting material, the title compound was prepared. mp: 53°C to 54°C
NMR(400MHz,CDC13): 7.29(2H,d), 6.89(2H,d), 4.62~4.48(2H,dd), 4.08(lH,q), 3.80(3H,s), 1.47(3H,d) Reference Example 4
Preparation of lH-1-imidazole acetic acid hydrochloride
5 g of immidazole was added to 50 ml of tetrahydrofuran and the resulting solution was cooled to -30°C. The cold solution was mixed with 3.2 g of 60% sodium hydride and the solution was stirred for 10 minutes. The solution was then reacted with 10.8 ml of tert-butylbromoacetate at the same temperature for 1 hour. The solution was slowly warmed to 25 °C and was stirred for 1 hour. The reaction mixture was extracted with 30 ml of water and 100 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure. Oily unpurified substances were mixed with 50 ml of ethyl ether and the mixture was stirred for 30 minutes. The resulting solid was isolated and dried to obtain 12.9 g of tert-butyl-lH-1-imidazole acetate. 2 g of tert-butyl-lH-1-imidazole acetate was dissolved in 20 ml of tetrahydrofuran and the resulting solution was reacted with 0.5 ml of 6N HCl at 55°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was added to 10 ml of ethylether, and the resulting solid was filtered and dried to obtain 1.0 g of the title compound. mp: 208°C to 210"C NMR(400MHz,DMSO-d6): 9.41(lH,s), 7.92(lH,s), 7.67(lH,s), 5.17(2H,s)
Example 1
Preparation of 7β-acetamido-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo- l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate
Figure imgf000016_0001
1.0 g of dihydrochloride salt of the title compound in the Reference Example 1 was dissolved in 20 ml of dichloromethane and 3 ml of methanol, and the resulting solution was cooled to 5°C. The cold solution was mixed with 0.74 ml of triethylamine, and the solution was stirred for 10 minutes. 0.7 ml of acetic anhydride was dropwise added to the solution for 10 minutes, and the solution was then stirred for 30 minutes. After the reaction was completed, the solvent was removed under reduced pressure. The residue was dissolved in an aqueous 50% ethanol, and the solution was concentrated under reduced pressure. The residue was chromatographed on silica gel using a mixed solvent of acetonitrile and water (4:1), concentrated under reduced pressure, and lyophilized to obtain 50 mg of the title compound. NMR(400MHz, DMSO-d6):
9.49~9.52(2H,d), 8.75~8.78(lH,d), 8.37~8.40(2H,d), 8.27(lH,t),
7.93~7.98(lH,t), 7.73~7.78(lH,dd), 7.59~7.62(lH,dd),
5.54~5.59( 1 H,dd,J=3.8Hz),5.03-5.70(2H,ABq,J= 13.4Hz), 5.02-5.04(1 H,d),
4.82(lH,m),4.20~4.25(lH,t), 3.84~3.88(lH,dd), 3.08~3.58(2H,ABq,J=17.5Hz),
3.45-3.48(2H,m), 1.85(3H,s), 1.84(3H,s)
Example 2
Preparation of 7β-[2-hydroxy-acetamido]-3-[4-[2-fluoro-4-[5-[(S)- methylcarboxamidomethyl] -2-oxo- 1 ,3 -oxazol-3 -yl]phenyl] - 1 -pyridiniomethyl] -3 - cephem-4-carboxylate
Figure imgf000017_0001
1.0 g of dihydrochloride salt of the title compound in the Reference Example 1 was dissolved in 20 ml of dichloromethane and 3 ml of methanol and the resulting soltion was cooled to 5°C. The cold solution was mixed with 0.74 ml of triethylamine and the solution was then stirred for 10 minutes. 1 g of 2-(4-methoxybenzyloxy)acetic acid in the Reference Example 2 was dissolved in 10 ml of dichloromethane and the resulting solution was cooled to -30°C. The solution was reacted with 0.72 ml of triethylamine and 0.62 ml of pivaloylchloride for 1 hour and stirred at 25°C for 1 hour. This acylating reagent was dropwise added to the solution for 10 minutes and the solution was then stirred for 1 hour. After the reaction was completed, the solvent was removed and the residue was mixed with 50 ml of ethyl acetate. The resulting solid was filtered and suspended in 10 ml of dichloromethane. The suspension was reacted with 1.0 ml of trifluoracetic acid and 0.5 ml of anisol at 25°C for 1 hour. 20 ml of isopropyl ether was added to the reaction mixture and the resulting solid was filtered. After the unpurified solid was dissolved in an aqueous 50% ethanol, the pH of the solution was adjusted to 1.5 with 4N sulfuric acid and the resulting solution was concentrated under reduced pressure. The residue was chromatographed on silica gel by using a mixed solvent of acetonitrile and water (4:1), concentrated under reduced pressure and lyophilized to obtain 50 mg of the title compound as sulfate salt. NMR(400MHz,DMSO-d6):
9.14(2H,d,J=7.0Hz), 8.40(2H,d,J=6.3Hz), 8.20~8.40(2H,m), 7.94(lH,t), 7.73~7.77(lH,dd), 7.59~7.62(lH,dd), 5.80-5.84(lH,dd), 5.43~5.65(2H,ABq,J=14.5Hz), 5.56(lH,s), 5.20(lH,d),4.82(lH,m),4.22(lH,t), 3.90(2H,s), 3.83~3.85(2H,m), 3.34~3.68(2H,Abq,J=18.2Hz), 3.44-3.47(2H,m),
1.84(3H,s)
Example 3
Preparation of 7β-[2 -hydroxy-2-methyl-acetamido]-3-[4-[2-fluoro-4-[5-[(S)- methylcarboxamido-methyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000018_0001
1.0 g of dihydrochloride salt of the title compound in the Reference Example 1 was dissolved in 20 ml of dichloromethane and 3 ml of methanol and the resulting soltion was cooled to 5°C. The cold solution was mixed with 0.74 ml of triethylamine and the solution was stirred for 10 minutes. 1.07 g of 2-(4-methoxybenzyloxy)propanoic acid in the Reference Example 3 was added to 10 ml of dichloromethane and the solution was cooled to -30°C. The cold solution was reacted with 0.62 ml of pivaloylchloride for 1 hour and was stirred at 25°C for 1 hour. This acylating reagent was dropwise added and the solution was stirred for 1 hour. 70 mg of the title compound was obtained by the same method in the Example 2. NMR(400MHz,DMSO-d6):
9.01~9.06(2H,d), 8.42~8.45(2H,d), 8.20~8.40(2H,t), 7.95~8.00(lH,t), 7.73~7.77(lH,dd), 7.60-7.62(1 H,dd), 5.75~5.80(lH,dd), 5.45~5.64(2H,ABq), 5.20(1 H,d), 4.82(lH,m),4.22(lH,t), 4.07-4.11(1 H,m), 3.83~3.85(lH,m), 3.35~3.69(2H, ABq), 3.44~3.47(2H,m), 1.85(3H,s)
Example 4
Preparation of 7 β - [2-cyclopropyl-acetamido] -3 - [4- [2-fluoro-4- [5 -[(S)- methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000019_0001
0.1 g of dihydrochloride salt of the title compound in the Reference Example 1 was dissolved in 3.0 ml of dimethylformamide and 0.015 ml of cyclopropanecarboxylic acid was added to the solution. Subsequently, 0.03 ml of diethylcyanophosphate was added at 25°C and 0.08 ml of triethylamine was dropwise added for 5 minutes. The solution was stirred at the same temperature for 1 hour. 0.9 ml of isopropyl ether was added to the solution and the resulting solid was filtered. The unpurified solid was purified as described in the Example 2 to obtain 10 mg of the title compound as sulfate salt.
NMR(400MHz,DMSO-d6):
9.06(3H,m), 8.43(2H,d), 8.24(lH,t), 7.96(lH,t), 7.74(lH,dd), 7.62(lH,dd), 5.82(lH,dd), 5.45~5.65(2H,ABq), 5.15(lH,d), 5.27(lH,m), 4.83(lH,m), 3.91(lH,m), 3.84(lH,m), 4.22(lH,t), 3.48~3.57(2H, Abq,J=18.2Hz), 3.45(2H,m), 1.93(3H,s), 1.75(lH,m), 0.73(4H,m)
Example 5
Preparation of 7β-[2-methyl-acetamido]-3-[4-[2-fluoro-4-[5-[(S)- methylcarboxamidomethyl]-2-oxo-l ,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000020_0001
0.5 g of dihydrochloride salt of the title compound in the Reference Example 1 was dissolved in 15 ml of dichloromethane and 2.5 ml of methanol and the solution was cooled to 5°C. 0.37 ml of triethylamine was added and the solution was stirred for 10 minutes. 0.6 g of propionic acid was dissolved in 20 ml of dichloromethane and the solution was cooled to -30°C. The cold solution was reacted with 1.23 ml of triethylamine and 0.99 ml of pivaloylchloride for 1 hour and stirred at 25°C for 1 hour. This acylating reagent was dropwise added and the solution was stirred for 1 hour. After the reaction was completed, the solvent was removed and the residue was dissolved in 50% ethanol. The solution was purified as described in Example 2 to obtain 50 mg of the title compound as sulfate salt. NMR(400MHz,DMSO-d6): 8.98(2H,d), 8.72(lH,d), 8.37(2H,d), 8.20(lH,t), 7.91 (lH,t), 7.69(lH,dd), 7.54(lH,dd), 5.75(lH,dd), 5.50(2H,ABq), 5.19(lH,d), 4.76(lH,m), 4.15(lH,t), 3.78(lH,dd), 3.48~3.57(2H,ABq,J=18.1Hz), 3.42(2H,m), 2.10(2H,q), 1.77(3H,s), 0.95(3H,t)
Example 6
Preparation of 7β-[2-amino-acetamido]-3-[4-[2-fluoro-4-[5-[(S)- methylcarboxamidomethyl]-2-oxo-l ,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000021_0001
0.3 g of dihydrochloride salt of the title compound in the Reference Example 1 was used as a starting material and 0.12 g of aminoacetylchloride hydrochloride was used as an acylating reagent. 30 mg of the title compound as hydrochloride salt was obtained by the same procedure in Example 1.
NMR(400MHz,DMSO-d6): 9.47(2H,d), 8.66(lH,d), 8.37(2H,d), 8.26(lH,t), 7.95(lH,t), 7.73-7.77(1 H,dd), 7.59~7.62(lH,dd), 5.60~5.70(lH,dd), 5.05~5.20(2H,q), 5.56(lH,s), 4.91(lH,d), 4.82(lH,m), 4.22(lH,t), 3.90(2H,s), 3.80~3.85(3H,m), 3.34-3.68(2H, ABq,J=18.2Hz), 3.44~3.47(2H,m), 1.84(3H,s)
Example 7
Preparation of 7β-[2-(N,N'-dimethylamino]-3-[4-[2-fluoro-4-[5-[(S)- methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000022_0001
0.3 g of dihydrochloride salt of the title compound in the Reference Example 1 was used as a starting material and 0.18 g of N,N'-dimethylaminochloride hydrochloride was used as an acylating reagent. 20 mg of the title compound as hydrochloride salt was obtained by the same procedure in Example 1. NMR(400MHz,DMSO-d6):
9.47(2H,d), 8.66(lH,d), 8.37(2H,d), 8.26(lH,t), 7.95(lH,t), 7.73~7.77(lH,dd), 7.58~7.60(lH,dd), 5.90(lH,dd), 5.61~5.66(2H,m), 5.08-5. l(2H,m),
4.83(lH,m), 4.22(lH,t), 4.00-4.10(2H,q), 3.83(lH,dd), 3.40~3.75(2H,ABq), 3.08(6H,s),1.84(3H,s)
Example 8 Preparation of 7β-[perhydro-2-pyrolyl-carboxamido]-3-[4-[2-fluoro-4-[5-[(S)- methylcarboxamido-methyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000022_0002
0.5 g of N-(tert-butoxycarbonyl)-L-pyroline was dissolved in 5.0 ml of tetrahydrofuran. The solution was reacted with 0.38 g of 1-hydroxybenzotriazol and 0.51 g of 1 ,3-dicyclohexylcarbodiimide at 25°C for 1 hour. The resulting solid was filtered and the parent liquid was concentrated to obtain an acylating ester reagent.
0.2 g of dihydrochloride salt of the title compound in the Reference Example 1 was dissolved in 5.0 ml of dimethylformamide and the solution was cooled to 5°C. The 0.1 ml of triethylamine was added and the solution was stirred for 10 minutes. The above prepared acylating reagent in 3.0 ml of dimethylformamide was dropwise added for 10 minutes. Then, the solution was stirred for 1 hour. After the reaction was completed, 10.0 ml of isopropylether was added to the solution and the resulting solid was filtered. The solid was suspended in 5.0 ml of dichloromethane and the suspension was reacted with 1.0 ml of trifluoroacetic acid at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure. 10.0 ml of isopropylether was added and the resulting solid was filtered. The solid was dissolved in 50% ethanol and the solution was concentrated under reduced pressure. The residue was chromatographed over silica gel using a mixed solvent of acetonitrile and water (4:1), concentrated under reduced pressure, and lyophilized to obtain 50 mg of the title compound as trifluoroacetate salt.
NMR(400MHz,DMSO-d6):
9.52(lH,d), 9.03(2H,d), 8.44(2H,d), 8.27(lH,t), 7.97(lH,t), 7.76(lH,dd), 7.62(lH,dd), 5.90(lH,dd), 5.45~5.63(2H,ABq), 5.25(lH,d), 4.84(lH,m), 4.22(2H,m), 3.84(lH,m), 3.63(lH,m), 3.40~3.60(2H,q), 3.20(2H,br),
2.52(lH,m), 1.94(2H,m), 1.85(3H,s), 1.20(2H,m)
Example 9
Preparation of 7 β- [2-carboxy-(Z)- 1 -ethenyl-carboxamido] -3 - [4- [2-fluoro-4- [5 - [(S)- methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000023_0001
1.0 g of dihydrochloride of Reference Example 1 was used as a starting material and 0.1 g of maleic anhydride was used as an acylating reagent. 10 mg of the title compound as hydrochloride salt was obtained by the same procedure in Example 1. NMR(400MHz,DMSO-d6):
9.85(lH,br), 9.40~9.43(lH,d,J=6.3Hz), 8.37~8.40(2H,d,J=6.3Hz), 8.28(lH,m), 7.92-7.98(1 H,m), 7.72~7.76(lH,m), 7.57~7.60(lH,m), 6.28-6.32(1 H,d,J=12.3Hz), 6.17~6.21(lH,d,J=12.3Hz), 5.65~5.68(2H,m), 5.07~5.20(2H,m), 4.80(lH,m), 4.22(2H,m), 4.21(lH,m), 3.84(lH,m), 3.10~3.60(lH,ABq), 3.54(2H,m), 1.85(3H,s)
Example 10
Preparation of 7β-[((lH)-l-imidazolyl)-carboxamido]-3-[4-[2-fluoro-4-[5-[(S)- methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000024_0001
1.0 g of dihydrochloride salt of the title compound in the Reference Example 1 was used as a starting material and 0.22 g of lH-1-imidazolylacetic acid hydrochloride of the title compound in the Reference Example 4 was used as an acylating reagent. 5 mg of the title compound as sulfate salt was obtained. NMR(400MHz,DMSO-d6):
9.45(lH,d), 9.20(lH,d), 8.38(2H,m), 8.25(lH,t), 7.95(lH,dd), 7.73(lH,dd), 7.58(2H,m),7.08(lH,s), 6.88(lH,s), 5.66(2H,m), 5.15(lH,d), 5.05(lH,m), 4.73~4.84(3H,m), 4.21(lH,t), 3.83(lH,dd), 3.44(2H,m), 1.84(3H,s) Example 11
Preparation of 7β-[((lH)-l-tetrazolyl)-acetamido]-3-[4-[2-fluoro-4-[5-[(S)- methylcarboxamido-methyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-ρyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000025_0001
0.5 g of dihydrochloride salt of the title compound in the Reference Example 1 was dissolved in 15 ml of dichloromethane and 2.5 ml of methanol and the solution was cooled to 5°C. The cold solution was mixed with 0.37 ml of triethylamine and the mixture was stirred for 10 minutes. 0.2 g of tetrazoleacetic acid was dissolved in 5 ml of dichloromethane and the solution was cooled to -30°C. The cold solution was reacted with 0.22 ml of triethylamine and 0.2 ml of pivaloylchloride for 1 hour and was stirred at 25 °C for 1 hour. This acylating reagent was dropwise added for 10 minutes and the solution was stirred for 1 hour. After the reaction was completed, the solvent was concentrated. The residue was dissolved in 50% ethanol and was purified as described in the Example 1 to obtain 30 mg of the title compound. NMR(400MHz,DMSO-d6):
9.30~9.47(3H,m), 9.37(lH,s), 8.38(2H,d), 8.27(1 H,t), 7.95(lH,t), 7.77(1 H,dd), 7.58(2H,dd), 5.16~5.67(2H,ABq,J=13.7Hz), 5.62(1 H,dd),
5.30~5.38(2H,ABq,J=16.8Hz), 5.05(lH,d),4.85(lH,m),4.22(3H,m), 3.83(lH,t), 3.44(2H,m), 3.15~3.57(2H,ABq,J=17.1Hz), 1.84(3H,s)
Example 12 Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[4-[2- fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l ,3-oxazol-3-yl]phenyl]-l - pyridiniomethyl]-3-cephem-4-carboxylate
Figure imgf000026_0001
500 mg of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 ml of anhydrous dichloromethane under nitrogen.0.8 ml ofN-methyl-N-(trimethylsylyl)trifluoro acetamid (MSTFA) was added and the solution was stirred for 1.5 hour. After the silylation was completed, the solution was cooled to 5°C and was reacted with 0.5 ml of iodotrimethylsilane at 20°C for 30 minutes. The solution was concentrated under reduced pressure and the residue was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran at 5°C for 5 minutes. The prepared silylated pyridine derivative was added to the solution at 5°C and the solution was stirred at 25 °C for 3 hours. This silylated pyridine derivative was prepared as follows. (S)-N-[[3-[3-fluor-4-(4- pyridyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (WO 93/19103).400 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25 °C for 2 hours to produce a silylated pyridine derivative. The formed solid by adding 1.0 ml of methanol and 5 ml of acetonitrile to the solution was filtered. After the solid was dissolved in an aqueous 30% ethanol, the pH of the resulting solution was adjusted to 6.5 with saturated sodium bicarbonate and was concentrated under reduced pressure. The residue was chromatographed over silica gel using a mixed solvent of acetonitrile and water (4:1), concentrated under reduced pressure, and lyophilized to obtain 100 mg of the title compound, mp: 178°C to 183°C (decomposition). IR(cm-'): 3411, 1760, 1617, NMR(400MHz,DMSO-d6): 9.60(1 H,d,J=8.2Hz), 9.07~9.09(2H,m), 8.40-8.4 l(2H,m), 8.26~8.28(lH,m), 7.93~7.98(lH,m), 7.57~7.76(2H,m), 7.18(2H,s), 6.72(lH,s), 5.87~5.89(lH,dd), 5.36~5.62(lH,ABq), 5.18~5.20(lH,d), 4.74~4.83(lH,m), 4.22-4.25(1 H,m), 3.82~3.87(lH,m), 3.80(3H,s), 3.40~3.50(2H,m), 3.36~3.62(2H,ABq), 1.84(3H,s)
Example 13
Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-( 1 -carboxy- 1 -methyl-ethoxyimino) acetamido]-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3- yljphenyl]- 1 -pyridiniomethyl]-3-cephem-4-carboxylate
Figure imgf000027_0001
530 mg of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(l-carboxy-l-methyl-l- ethoxyimino)acetamido] -3 -acetoxymethyl-3 -cephem-4-carboxylic acid was dissolved in
10 ml of anhydrous dichloromethane under nitrogen. After the same procedure as the Example 12 was carried out by using 1.3 ml of MSTFA and 0.5 ml of TMSI, the reaction mixture was concentrated under reduced pressure. The concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes. The solution was reacted at 25°C for 3 hours with the silylated pyridine derivatives obtained by silylating 400 mg of (S)-N-[[3 - [3 -fluoro-4-(4-pyridyl)phenyl] -2-oxo-5 -oxazolydinyl] -methyl] acetamide with MSTFA in 10 ml of acetonitrile. The solution was deprotected by adding 1 ml of methanol, filtered and purified to obtain 120 mg of the title compound, mp: 174°C to 177°C (decomposition) IR(cm-l): 3433, 1760, 1617, 1467, 1151 NMR(DMSO-dό): 9.42~9.45(lH,d,J=8.3Hz), 9.03~9.04(2H,m), 8.42~8.43(2H,m), 8.23~8.24(lH,m), 7.94-7.96(1 H,m), 7.59~7.77(2H,m), 7.25(2H,s), 6.70(lH,s), 5.95~5.96(lH,dd), 5.45~5.63(2H,ABq), 5.23~5.24(lH,d), 4.78~4.82(lH,m), 4.22~4.26(lH,m), 3.82~3.88(lH,m), 3.40~3.52(2H,m), 3.30~3.62(2H,q), 1.83(3H,s), 1.41~1.43(6H,d)
Example 14
Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-[2- fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridinio methyl] -3 -cephem-4-carboxylate
Figure imgf000028_0001
500 mg of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 ml of anhydrous dichloromethane under nitrogen. After the same procedure as Example 12 was carried out by using 0.8 ml of MSTFA and 0.5 ml of TMSI, the reaction mixture was concentrated under reduced pressure. The concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes. The preprepared silylated pyridine derivative was added to the solution at 5°C and the solution was stirred at 25°C for 3 hours. This silylated pyridine derivative was prepared as follows. (S)-N-[[3-[3-fluoro-4- (3-pyridyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (WO 93/09103).400 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25°C for 2 hours to produce the silylated pyridine derivative. The formed solid by adding 1.0 ml of methanol and 5 ml of acetonitrile to the solution was filtered, and purified to obtain 130 mg of the title compound. mp: 183°C to 186°C (decomposition)
IR(cm-l): 3416, 1760, 1627, 1540, 1040 NMR(DMSO-dό):
9.60(1 H,d,J=8.0Hz), 9.37(lH,s), 9.01~9.04(lH,m), 8.86~8.89(lH,m), 8.25~8.31(2H,m), 7.73~~7.84(2H,m), 7.56~7.58(lH,m), 7.19(2H,s),6.71(lH,s), 5.91~5.94(lH,dd), 5.20~5.21(lH,d), 5.62~5.70(2H,ABq), 4.77~4.82(lH,m), 4.18~4.22(lH,m), 3.81~3.83(lH,m), 3.80(3H,s), 3.40~3.53(2H,m), 3.30~3.63(2H,q), 1.84(3H,s)
Example 15
Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-( 1 -carboxy- 1 -methyl- 1 -ethoxyimino) acetamido] -3 - [3 - [2-fluoro-4- [ 5 - [( S)-methylcarboxamidomethyl] -2-oxo- 1 ,3 -oxazol-3 - yl]phenyl]-l-pyridinio methyl] -3 -cephem-4-carboxy late
Figure imgf000029_0001
530 mg of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(l -carboxy- 1 -methyl- 1- ethoxyimino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 ml of anhydrous dichloromethane under nitrogen. After the same procedure as Example 12 was carried out by using 1.3 ml of MSTFA and 0.5 ml of TMSI, the reaction solution was concentrated under reduced pressure. The concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes. The solution was reacted at 25°C for 3 hours with the silylated pyridine derivatives obtained by silylating 400 mg of (S)-N- [ [3 - [3 -fluoro-4-(3 -pyridyl)phenyl] -2-oxo-5-oxazolydinyl] -methyl]acetamide with MSTFA in 10 ml of acetonitrile. The solution was deprotected by adding 1 ml of methanol, filtered and purified to obtain 100 mg of the title compound. mp: 175°C to 177°C (decomposition)
IR(cm-'): 3433, 1760, 1617, 1467, 1151 NMR(DMSO-dό):
9.40~9.44(2H,m), 9.06-9.08(1 H,m), 8.84-8.86(1 H,m), 8.25~8.30(2H,m), 7.72~7.83(2H,m), 7.55~7.57(lH,m), 7.2(2H,s), 6.69(lH,s), 5.94~5.98(lH,dd), 5.20~5.22(lH,d), 5.60~5.66(2H,ABq), 4.78~4.83(lH,m), 4.16~4.20(lH,m), 3.81~4.84(lH,m), 3.4.~3.51(2H,m), 1.84(3H,s), 1.37~1.40(6H,d)
Example 16
Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-mthoxyiminoacetamido]-3-[4-[4-[5-
[(S)-methyl-carboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate
Figure imgf000030_0001
500 mg of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 ml of anhydrous dichloromethane under nitrogen. After the same procedure as the Example 12 was carried out by using 0.8 ml of MSTFA and 0.5 ml of TMSI, the reaction mixture was concentrated under reduced pressure. The concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes. The preprepared silylated pyridine derivative was added to the solution at 5°C and the solution was stirred at 25 °C for 3 hours. This silylated pyridine derivative was prepared as follows. (S)-N-[[3-[4-(4- pyridyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (USP 5,254,577).380 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25 °C for 2 hours to produce the silylated pyridine derivative. The silylated pyridine derivative was added and the solution was stirred at 25°C for 3 hours. The formed solid was filtered by adding 1.0 ml of methanol and 5 ml of acetonitrile to the solution, and purified to obtain 150 mg of the title compound, mp: 196°C to 198°C (decomposition)
IR(cm-'): 3415, 1791, 1750, 1617, NMR(DMSO-dό):
9.60(lH,d,J=7.9Hz), 8.78~8.96(2H,d), 8.54~8.56(2H,d), 8.24~8.26(lH,m), 8.16~8.19(2H,m), 7.80~7.82(2H,m), 7.25(2H,s), 6.73(lH,s), 5.87~5.89(lH,dd), 5.22(lH,d), 5.41~5.57(2H,ABq), 4.77-4.84(1 H,m), 4.23-4.26(1 H,m),
3.82~3.85(lH,m), 3.81(3H,s), 3.40~3.50(2H,m), 3.35~3.65(2H,q), 1.83(3H,s)
Example 17
Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-( 1 -carboxy- 1 -methyl- 1 -ethoxyimino) acetamido]-3-[4-[4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l- pyridiniomethyl] -3 -cephem-4-carboxylate
Figure imgf000031_0001
530 mg of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(l-carboxy-l-methyl-l- ethoxyimino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 ml of anhydrous dichloromethane under nitrogen. After the same procedure as Example 12 was carried out by using 1.3 ml of MSTFA and 0.5 ml of TMSI, the reaction mixture was concentrated under reduced pressure. The concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes. The solution was reacted at 25 °C for 3 hours with the silylated pyridine derivatives obtained by silylating 380 mg of (S)-N- [ [3 - [4-(4-pyridyl)phenyl] -2-oxo-5 -oxazolydinyl] -methyl]acetamide with MSTFA in 10 ml of acetonitrile. The solution was deprotected by adding 1 ml of methanol, filtered and purified to obtain 120 mg of the title compound. mp: 175°C to 177°C (decomposition)
IR(cm-l): 3433, 1760, 1617, 1467, 1151 NMR(DMSO-dό):
9.43-9.46(1 H,d), 8.98~9.00(2H,d), 8.54~8.56(2H,d), 8.24~8.27(lH,m), 8.16-8.18(2H,d), 7.89~7.91(2H,d), 7.28(2H,s), 6.70(lH,s), 5.90~5.95(lH,dd), 5.22~5.23(lH,d), 5.45~5.61(2H,ABq), 4.76~4.82(lH,m), 4.18~4.24(lH,m), 3.79~3.84(lH,m), 3.40~3.49(2H,m), 3.30~3.64(2H,q), 1.83(3H,s), 1.38~1.40(6H,d)
Example 18
Preparation of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[4-[2,6- difluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l- pyridiniomethyl] -3 -cephem-4-carboxylate
Figure imgf000032_0001
500 mg of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 ml of anhydrous dichloromethane under nitrogen. After the same procedure as Example 12 was carried out by using 0.8 ml of MSTFA and 0.5 ml of TMSI, the reaction mixture was concentrated under reduced pressure. The concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes. The preprepared silylated pyridine derivative was added to the solution at 5°C and the solution was stirred at 25°C for 3 hours. This silylated pyridine derivate was prepared as follows. (S)-N-[[3-[3,5-difluoro-4-(4-pyridyl)phenyl]- 2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (WO 93/09103). 420 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25 °C for 2 hours to produce the silylated pyridine derivative. The formed solid by adding 1.0 ml of methanol and 5 ml of acetonitrile to the solution was filtered, and purified to obtain 10 mg of the title compound, mp: 175°C to 177°C (decomposition) IR(cm"1): 3412, 1760, 1615, NMR(DMSO-dό):
9.60(lH,d), 9.08-9.10(2H,d), 8.37~8.39(2H,d), 8.23~8.37(lH,m), 7.58~7.61(lH,d), 7.50~7.53(lH,d), 6.74(lH,s), 5.87-5.89(1 H,dd),
5.52~5.64(lH,ABq), 5.18~5.21(lH,d), 4.82-4.97(1 H,m), 4.21~4.26(lH,m), 3.82~3.87(lH,m), 3.80(3H,s), 3.41~3.51(2H,m), 3.30~3.62(2H,q), 1.85(3H,s)
Example 19 Preparation of 7β-[(Z)-2-(5-amino- 1 ,2,4-thiazol-3-yl)-2-methoxyiminoacetamido]-3-[4- [2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l- pyridiniomethyl]-3-cephem-4-carboxylate.
Figure imgf000033_0001
500 mg of 7β-[(Z)-2-(5-amino- 1 ,2,4-thiazol-3-yl)-2-methoxyiminoacetamido]-3- acetoxymethyl-3-cephem-4-carboxylic acid [THE JOURNAL OF ANTIBIOTICS: VoLXXXVI, No.8 pl020-1033(1983), Vol.XXXVII, No.5 p557-571(1984)] was dissolved in 10 ml of anhydrous dichloromethane under nitrogen. 0.8 ml of MSTFA was added and the solution was stirred for 1.5 hour. After the silylation was completed, the solution was cooled to 5°C and was reacted with 0.5 ml of TMSI at 20°C for 30 minutes. The solution was concentrated under reduced pressure and the residue was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran at 5°C for 5 minutes. The solution was reacted at 25 °C for 3 hours with the silylated pyridine derivatives obtained by reacting 400 mg of (S)-N-[[3-[3-fluoro-4-(4-pyridyl)phenyl]-2-oxo-5-oxazolydinyl]- methyl] acetamide with 1.0 ml of MSTFA in 10 ml of acetonitrile. The formed solid by adding a mixed solvent of 1.0 ml of methanol and 5 ml of acetonirile to the solution was filtered. The solid was dissolved in an aqueous 30% ethanol and the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate. The pH of the solution was then adjusted to 2.0 with 4N sulfuric acid and ethanol was added to the solution to obtain 100 mg of the title compound as sulfate salt, mp: 165°C or more (decomposition) IR(cm-l): 3416, 1757 NMR(DMSO-dό):
9.58(1 H,d,J=8.3Hz), 9.10(2H,d), 8.44(2H,d), 8.26(lH,m), 7.94~7.97(lH,m), 7.74~7.77(2H,m), 7.59~7.61(lH,m), 5.82~5.90(lH,dd),
5.18~5.20(lH,d,J=4.9Hz), 5.44~5.62(2H,ABq,J=4.5Hz), 4.74~4.83(lH,m),
4.22~4.25(lH,m), 3.80~3.87(lH,m), 3.88(3H,s), 3.40~3.50(2H,m),
2.9-3.6(2H,m), 1.84(3H,s)
Example 20
Preparation of 7β-[(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3- [3 - [2-fluoro-4- [5 - [(S)-methylcarboxamidomethyl] -2-oxo- 1 ,3 -oxazol-3 -yljphenyl] - 1 - pyridiniomethyl] -3 -cephem-4-carboxylate
Figure imgf000034_0001
500 mg of 7β-[(Z)-2-(5-amino- 1 ,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]- 3-acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 ml of anhydrous dichloromethane under nitrogen. The solution was reacted with 0.8 ml of MSTFA and 0.5 ml of TMSI by the same method as the Example 19. The solution was concentrated under reduced pressure and the concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes. The solution was reacted at 25°C for 3 hours with the silylated pyridine derivatives obtained by reacting 400 mg of (S)-N-[[3-[3-fluoro-4- (3-pyridyl)phenyl]-2-oxo-5-oxazolydinyl]-methyl]acetamide with 1.0 ml of MSTFA in 10 ml of acetonitrile. The resulting solid by adding a mixed solvent of 1.0 ml of methanol and 5 ml of acetoniril to the solution was filtered. The solid was dissolved in an aqueous 30% ethanol and the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate. The pH of the solution was then adjusted to 2.0 with 4N sulfuric acid and ethanol was added to the solution to obtain 110 mg of the title compound as sulfate salt, mp: 145°C or more (decomposition) IR(cm-l): 3418, 1760
NMR(DMSO-dό):
9.50~9.56(2H,m), 9.20(lH,s), 8.80~8.85(lH,m), 8.25~8.32(2H,m), 7.70~7.85(2H,m), 7.50-7.60(1 H,m), 5.82~5.89(lH,dd), 5.20(lH,d), 5.50~5.70(2H,ABq), 4.76-4.82(1 H,m), 4.18~4.23(lH,m), 3.80~3.85(lH,m), 3.86(3H,s), 3.40~3.50(2H,m), 1.85(3H,s)
Example 21
Preparation of 7β-[(Z)-2-(5-amino- 1 ,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3- [4-[4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l ,3-oxazol-3-yl]phenyl]-l - pyridiniomethyl]-3-cephem-4-carboxylate
Figure imgf000035_0001
500 mg of 7β-[(Z)-2-(5-amino- 1 ,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]- 3-acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 ml of anhydrous dichloromethane under nitrogen. The solution was reacted with 0.8 ml of MSTFA and 0.5 ml of TMSI by the same method as the Example 19. The solution was concentrated under reduced pressure and the concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes. The solution was reacted at 25°C for 3 hours with the silylated pyridine derivatives obtained by reacting 380 mg of (S)-N-[[3-[4-(4- pyridyl)phenyl]-2-oxo-5-oxazolydinyl]-methyl]acetamide with 1.0 ml of MSTFA in 10 ml of acetonitrile. The resulting solid by adding a mixed solvent of 1.0 ml of methanol and 5 ml of acetonirile to the solution was filtered. The solid was dissolved in an aqueous 30% ethanol and the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate. The pH of the solution was then adjusted to 2.0 with 4N sulfuric acid and ethanol was added to the solution to obtain 150 mg of the title compound as sulfate salt, mp: 170°C or more (decomposition) IR(cm-l): 3415, 1760
NMR(DMSO-dό):
9.58(lH,d), 8.80~9.00(2H,d), 8.54~8.58(2H,d), 8.24-8.26(1 H,m), 8.16~8.20(2H,m), 7.80~7.84(2H,m), 5.85~5.90(lH,dd), 5.18~5.20(lH,d), 5.42~5.60(2H,ABq), 4.78~4.83(lH,m), 4.22-4.25(1 H,m), 3.80~3.85(lH,m), 3.87(3H,s), 3.40~3.50(2H,m), 1.84(3H,s)
Antibacterial Activity Test
The in vitro antibacterial activities of the compounds prepared by Examples 1 through 21 were tested as described in Chemotheraphy, 29(1), 76, 1981. Vancomycin and cefotaxime were used as control. Their MICs (Minimum Inhibition Concentration: μg/ml) by agar dilution were measured and the result is indicated in Table 2 below. Table 2
Figure imgf000037_0001
A: Staphylococcus aureus ATCC29213
B: MRSA C5100 (MethiciUin resistant Staphylococcus aureus) C: CRSA C6043 (Ciprofloxacin resistant Staphylococcus aureus) D: Staphylococcus epidermis ATCC 12228 E: Enterococcus faecalis ATCC29212 F: Streptococcus pyogenes ATCC8668 G: Escherichia coli ATCC10536
H: Klebsiella pneumoniae ATCC 10031 I: Proteus mirabilis ATCC25933
Cl: (S)-N-[[3-[3-fluoro-4-(4-pyridyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide C2: Cefotaxime C3: Vancomycin
As can be seen from the above Table 2, the compounds of the formula I according to the present invention are broadly active against Gram-positive and Gram-negative bacteria and have the pharmacological advantages of vancomycin and cefotaxime. Especially, the compounds of the formula I are advantageous in that they are effective against cephem antibiotics-registant bacteria such as MRSA and CRSA.
Toxicity Test
The single dose toxicity of the compounds of the present invention was evaluated in ICR mice by intravenous administration. The compounds of Examples 1 , 2 and 13 along with an equivalent of sodium bicarbonate were dissolved in saline and the resulting solutions were intravenously administered. LD50of each test compound was measured to be 1,500 mg/kg of weight.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula I:
Figure imgf000039_0001
or pharmaceutically acceptable salts or hydrates thereof wherein
X is i) amine or protected amine, ii)
Figure imgf000039_0002
in which Y is i) hydrogen, ii) C,-C6 lower alkyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,-C4acyloxy, C,- C4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, CrC4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, iii) C2-C6 alkenyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, CrC4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, CrC4acyloxy, C,-C4alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, iv) C2-C6 alkynyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,- C4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,-C4acyloxy, CrC4 alkylsulfonyl, C,-C4 alkylsulfenyl, CrC4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, v) phenyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, CrC4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,- C4 acyloxy, C,-C4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, vi) R4-(CH2)n-, in which n is an integer of 0 to 3, and R4 is 2-thiophenyl, 2-furyl, 2-pyrolyl, 4-thiazolyl, l,2,4-thiadiazol-3-yl, 2-oxazolyl, or 5- or 6- membered heterocyclic compound having from 1 to 4 atoms of O, S and N which are substituted with at least one selected from the group consisting of chlorine, fluorine, hydroxy, amino, C,-C4 alkyl, C,-C4 acylamino, C,- S Z C4 alkylsulfonylamino, C,-C4 alkoxy, and C,-C4 acyloxy, vii) N H 2 in which
Z is hydrogen, or C,-C6 lower alkyl, C,-C6 alkenyl, C2-C6 alkynyl, phenyl or heterocyclic compound optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, C,-C4 dialkylamino, 0 hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, CrC4 alkoxy, C,-C4acyloxy, C,-
C4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, and carbon having optical activity can
5 be optically pure (-), (+) or racemic forms, viii)
Figure imgf000040_0001
in which W is CH or
N, R, is hydrogen, or lower alkyl optionally substituted with carboxylic acid or inorganic cation salt thereof or protected carboxylic acid, and the alkoxyimino is a syn isomer;
R2 is hydrogen, fluorine, chlorine or methoxy and can be same or different; 0
R3 is hydrogen, or lower alkyl optionally substituted with carboxy or inorganic cation salt thereof, amino or alkoxy; and
provided that in the compounds of the formula I the phenyloxazolidinone is substituted 5 at 3 or 4 positions of pyridine.
2. The compound according to claim 1 in which R2 is independently hydrogen or fluorine.
0 3. The compound according to claim 1 in which R3 is hydrogen, methyl, difluoromethyl, trichloromethyl, hydroxymethyl or methoxy.
4. The compound according to claim 1 which is
7╬▓-acetamido-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3- yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate;
7╬▓-[2-hydroxy-acetamido]-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo- l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate;
7╬▓-[2-hydroxy-2-methyl-acetamido]-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamido- methyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate; 7╬▓-[2-cyclopropyl-acetamido]-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2- oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate; 7╬▓-[2-memyl-acetamido]-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo- 1 ,3- oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate; 7╬▓-[2-amino-acetamido]-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l,3- oxazol-3-yl]phenyl]-l -pyridiniomethyl]-3-cephem-4-carboxylate ; 7╬▓-[2-(N,N'-dimethylamino]-3-[4-[2-f-uoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo- l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate;
7╬▓-[perhydro-2-pyrolyl-carboxamido]-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamido- methyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate; 7 ╬▓- [2-carboxy-(Z)- 1 -ethenyl-carboxamido]-3- [4- [2-fluoro-4- [5 - [(S)-methylcarbox- amidomethyl]-2-oxo-l ,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4- carboxylate ;
7╬▓-[((lH)-l-imidazolyl)-carboxamido]-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamido- methyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate; 7╬▓-[((lH)-l-tetrazolyl)-acetamido]-3-[4-[2-fluoro-4-[5-[(S)-methylcarboxamido-methyl]- 2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4-carboxylate; 7╬▓-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[4-[2-fluoro-4-[5-[(S)- methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate;
7β-[(Z)-2-(2-aminotWazol-4-yl)-2-(l-carboxy-l-memyl-emoxyiιτύrιo)acetamido]-3-[4-[2- fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l ,3-oxazol-3-yl]phenyl]-l- pyridiniomethyl] -3 -cephem-4-carboxylate ;
7╬▓-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3 - [3 - [2-fluoro-4- [5 - [(S)- methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate;
7╬▓-[(Z)-2-(2-aminothiazol-4-yl)-2-( 1 -carboxy- 1 -methyl- 1 -ethoxyimino)acetamido]-3-[3- [2-fluoro-4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l- pyridiniomethyl]-3-cephem-4-carboxylate;
7╬▓-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[4-[4-[5-[(S)-methyl- carboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3-cephem-4- carboxylate;
7╬▓-[(Z)-2-(2-an╬╣inotMazol-4-yl)-2-(l-carboxy-l-memyl-l-ethoxyimino)acetamido]-3-[4- [4-[5-[(S)-methylcarboxamidomethyl]-2-oxo-l ,3-oxazol-3-yl]phenyl]- l - pyridiniomethyl]-3-cephem-4-carboxylate;
7β-[(Z)-2-(2-aminotWazol-4-yl)-2-methoxyiπιinoacetamido]-3-[4-[2,6-difluoro-4-[5-[(S)- methylcarboxamidomethyl]-2-oxo-l ,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate; 7β-[(Z)-2-(5-amino-l,2,4-thiazol-3-yl)-2-methoxyiminoacetamido]-3-[4-[2-fluoro-4-[5-
[(S)-methylcarboxamidomethyl]-2-oxo- 1 ,3-oxazol-3-yl]phenyl]-l -pyridiniomethyl]-3- cephem-4-carboxylate;
7╬▓- [(Z)-2-(5-amino- 1 ,2,4-thiadiazol-3 -yl)-2-methoxyiminoacetamido] -3 - [3 - [2-fluoro-4-
[5-[(S)-memylcarboxan╬╣idomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate; or
7╬▓-[(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[4-[4-[5-[(S)- methylcarboxamidomethyl]-2-oxo-l,3-oxazol-3-yl]phenyl]-l-pyridiniomethyl]-3- cephem-4-carboxylate.
5. A process for producing a compound of the formula I:
Figure imgf000042_0001
or pharmaceutically acceptable salts or hydrates thereof wherein
O
X is i) amine or protected amine, ii) ' N in which Y is i) hydrogen, ii) C,-C6 lower alkyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, CrC4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,-C4acyloxy, C,- C4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, iii) C2-C6 alkenyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, CrC4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,-C4acyloxy, C,-C4alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, iv) C2-C6 alkynyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C -
C4 alkylamino, C,-C4 dialkylamino, hydroxylamino, CrC4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, CrC4acyloxy, C,-C4alkylsulfonyl, C C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, v) phenyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, CrC4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,- C4 acyloxy, C,-C4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, vi) R4-(CH2)n-, in which n is an integer of 0 to 3, and R4 is 2-thiophenyl, 2-furyl, 2-pyrolyl, 4-thiazolyl, l,2,4-thiadiazol-3-yl, 2-oxazolyl, or 5- or 6- membered heterocyclic compound having from 1 to 4 atoms of O, S and N which are substituted with at least one selected from the group consisting of chlorine, fluorine, hydroxy, amino, C,-C4 alkyl, CrC4 acylamino, C,-
C4 alkylsulfonylamino, C,-C4 alkoxy, and C,-C4 acyloxy, vii) 2 in which Z is hydrogen, or CrC6 lower alkyl, C,-C6 alkenyl, C2-C6 alkynyl, phenyl or heterocyclic compound optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, CrC4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,-C4acyloxy, C,- C4 alkylsulfonyl, C,-C4alkylsulfenyl, CrC4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, and carbon having optical activity can
be optically pure (-), (+) or racemic forms, viii)
Figure imgf000044_0001
in which W is CH or
N, R, is hydrogen, or lower alkyl optionally substituted with carboxylic acid or inorganic cation salt thereof or protected carboxylic acid, and the alkoxyimino is a syn isomer; R2 is hydrogen, fluorine, chlorine or methoxy and can be same or different; R3 is hydrogen, or lower alkyl optionally substituted with carboxy or inorganic cation salt thereof, amino or alkoxy; and provided that in the compounds of the formula I the phenyloxazolidinone is substituted at 3 or 4 positions of pyridine, which comprises reacting a compound of the formula II:
Figure imgf000044_0002
wherein R2 and R3 are same as defined above, with a compound of the formula III:
Figure imgf000044_0003
wherein Xa is the same as X defined above, except for amine and protected amine, R4 is hydrogen or carboxylic acid-protecting group, and L is halogen atom or acetoxy, to produce the compound of the formula I.
6. A process for producing a compound of the formula I:
Figure imgf000045_0001
or pharmaceutically acceptable salts or hydrates thereof wherein
X is i) amine or protected amine,
Figure imgf000045_0002
in which Y is i) hydrogen, ii) C,-C6 lower alkyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, C C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, C,-C4acyloxy, C,- C4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, iii) C2-C6 alkenyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C C4 alkoxyamino, C,-C4 alkoxyimino, C,-C4 alkoxy, CrC4acyloxy, C,-C4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, iv) C2-C6 alkynyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C , - C4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, C,-C4 alkoxyimino, CrC4 alkoxy, C,-C4acyloxy, C,-C4alkylsulfonyl, C,-C4alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, v) phenyl optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, CrC4 alkoxyimino, C,-C4 alkoxy, C,- C4 acyloxy, CrC4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, vi) R4-(CH2)n-, in which n is an integer of 0 to 3, and R4 is 2-thiophenyl, 2-furyl, 2-pyrolyl, 4-thiazolyl, l,2,4-thiadiazol-3-yl, 2-oxazolyl, or 5- or 6- membered heterocyclic compound having from 1 to 4 atoms of O, S and N which are substituted with at least one selected from the group consisting of chlorine, fluorine, hydroxy, amino, C,-C4 alkyl, C,-C4 acylamino, C,-
C4 alkylsulfonylamino, CrC4 alkoxy, and C,-C4 acyloxy, vii) N H 2 in which Z is hydrogen, or CrC6 lower alkyl, C,-C6 alkenyl, C2-C6 alkynyl, phenyl or heterocyclic compound optionally substituted with at least one selected from the group consisting of chlorine, fluorine, cyano, nitro, hydroxy, amino, C,-C4 alkylamino, C,-C4 dialkylamino, hydroxylamino, C,-C4 alkoxyamino, CrC4 alkoxyimino, C,-C4 alkoxy, C,-C4acyloxy, Cr
C4 alkylsulfonyl, C,-C4 alkylsulfenyl, C,-C4 alkylsulfinyl, C,-C4 alkylaminosulfonyl, and carboxylic acid and inorganic cation salt thereof, and carbon having optical activity can
be optically pure (-), (+) or racemic forms, viii)
Figure imgf000046_0001
in which W is CH or
N, R, is hydrogen, or lower alkyl optionally substituted with carboxylic acid or inorganic cation salt thereof or protected carboxylic acid, and the alkoxyimino is a syn isomer;
R2 is hydrogen, fluorine, chlorine or methoxy and can be same or different;
R3 is hydrogen, or lower alkyl optionally substituted with carboxy or inorganic cation salt thereof, amino or alkoxy; and provided that in the compounds of the formula I the phenyloxazolidinone is substituted at 3 or 4 positions of pyridine, which comprises reacting a compound of the formula II:
Figure imgf000046_0002
wherein R2 and R3 are same as defined above, with a compound of the formula IV:
Figure imgf000047_0001
wherein Xb is amine or protected amine, R4 is hydrogen or carboxylic acid-protecting group, and L is the same as defined above, to produce a compound of the formula V:
Figure imgf000047_0002
wherein R2 and R3 are the same as defined above, Xb is amine or protected amine, R5 is hydrogen or carboxylic acid-protecting group, M" is anionic halogen, or sulfate, acetate, benzenesulfonate or citrate anions, with the compounds of the formula VI:
Figure imgf000047_0003
wherein Y is the same as defined above, to produce the compound of the formula.
7. An antibacterial composition comprising antibacterially effective amount of the compound according to claim 1 and pharmaceutically acceptable carrier.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056819A1 (en) * 2002-12-19 2004-07-08 Astrazeneca Ab Oxazolidinone derivatives as antibacterial agents
WO2005061468A1 (en) * 2003-12-17 2005-07-07 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
WO2006104141A1 (en) * 2005-03-29 2006-10-05 Shionogi & Co., Ltd. 3-propenylcephem derivative
US7148219B2 (en) 2003-06-03 2006-12-12 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7335753B2 (en) 2002-09-26 2008-02-26 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles
US8883773B2 (en) 2010-04-05 2014-11-11 Shionogi & Co., Ltd. Cephem compound having pseudo-catechol group
US9145425B2 (en) 2010-04-05 2015-09-29 Shionogi & Co., Ltd. Cephem compound having catechol group
US9238657B2 (en) 2008-10-31 2016-01-19 Shionogi & Co., Ltd. Cephalosporin having catechol group

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009103A1 (en) * 1991-11-01 1993-05-13 The Upjohn Company Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents
US5254577A (en) * 1988-07-29 1993-10-19 The Du Pont Merck Pharmaceutical Company Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5254577A (en) * 1988-07-29 1993-10-19 The Du Pont Merck Pharmaceutical Company Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents
WO1993009103A1 (en) * 1991-11-01 1993-05-13 The Upjohn Company Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents

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US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7335753B2 (en) 2002-09-26 2008-02-26 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
WO2004056819A1 (en) * 2002-12-19 2004-07-08 Astrazeneca Ab Oxazolidinone derivatives as antibacterial agents
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US8895741B2 (en) 2003-06-03 2014-11-25 Melinta Therapeutics, Inc. Process for the synthesis of biaryl oxazolidinones
US7456206B2 (en) 2003-06-03 2008-11-25 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7705026B2 (en) 2003-06-03 2010-04-27 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US9550783B2 (en) 2003-06-03 2017-01-24 Melinta Therapeutics, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7148219B2 (en) 2003-06-03 2006-12-12 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7129259B2 (en) 2003-12-17 2006-10-31 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
WO2005061468A1 (en) * 2003-12-17 2005-07-07 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8841263B2 (en) 2004-02-27 2014-09-23 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same
WO2006104141A1 (en) * 2005-03-29 2006-10-05 Shionogi & Co., Ltd. 3-propenylcephem derivative
US8796465B2 (en) 2005-06-08 2014-08-05 Melinta Therapeutics, Inc. Process for the syntheses of triazoles
US9376400B2 (en) 2005-06-08 2016-06-28 Melinta Therapeutics, Inc. Process for the synthesis of triazoles
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles
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US9145425B2 (en) 2010-04-05 2015-09-29 Shionogi & Co., Ltd. Cephem compound having catechol group

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