Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to novel cephalosporin derivatives, a pharmaceutically acceptable salt, and physiologically hydrolyzable ester and solvate thereof.
• This invention also relates to a process for their preparation, a use thereof as an antibiotic, and a pharmaceutical composition containing the same derivatives as an active ingredient.
• cephalosporin compounds have been synthesized in which the cephem nucleus has a quarternary ammonium methyl at its 3-position and various acylamino groups at its 7-position. These compounds exhibit selective toxicity against bacteria only and present no substantial effects against animal cells. They have been widely used for the treatment of infectious diseases caused by bacteria as antibiotics having no substantial side effects. Thus, they are highly useful as drugs. In recent years, an extensive investigation has been made to develop novel cephalosporin derivatives which have more potent antibacterial activities and a broad antibacterial spectrum, especially coupled with activities against cephalosporin resistant bacteria.
• the object of the invention is to provide novel cephalosporin derivatives having strong activities and a broad antibacterial spectrum against both gram-positive and gram-negative bacteria, as well as excellent stability against ß-lactamase.
• the present invention provides novel cephalosporin derivatives having the formula:
• R 1 is hydrogen, or a lower alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl or cycloalkylalkyl group, a fluoro-substituted lower alkyl group represented by the formula: -(CH 2 ) x F in which x is an integer of 1 to 3, or a carboxy-substituted alkyl group represented by the formula: , wherein R' is a hydroxy, amino or C 1 -C 4 alkoxy group; R" and R"', which may be the same or different, represent hydrogen or a C 1 -C 3 alkyl group, or R" and R"' together with the carbon atom to which they are attached may form a C 3 -C 7 carbocyclic ring; and y is an integer of 0 to 3;
• R 2 and R 3 which may be the same or different, represent hydrogen, or a lower alkyl, amino, carboxysubstituted lower alkyl, hydroxy-substituted lower alkyl or C 3 -C 7 cycloalkyl group;
• n is an integer of 1 or 2 ;
• the 2-oxo-heterocyclic moiety is fused with the pyridine ring to form a 2,3- or 3,4-fused ring substituent at 3-position of the cephem nucleus; or a pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof.
• the compounds of the present invention show strong activities against gram-positive bacteria such as Streptococcus, Staphylococcus , Methicillin resistant Staphylococcus, Corynebacterium, Bacillus , etc.; gram-negative bacteria such as Escherichia, Enterobacter, Klebsiella, Serratia, Salmonella, Proteus, Providensia, Morganella, Pseudomonas , etc.; and various drug resistant bacteria.
• gram-positive bacteria such as Streptococcus, Staphylococcus , Methicillin resistant Staphylococcus, Corynebacterium, Bacillus , etc.
• gram-negative bacteria such as Escherichia, Enterobacter, Klebsiella, Serratia, Salmonella, Proteus, Providensia, Morganella, Pseudomonas , etc.
• various drug resistant bacteria such as Streptococcus, Staphylococcus , Methicillin
• the new cephalosporin compounds of the present invention may be in the form of either a syn- or anti-isomer, or a mixture thereof consisting of at least about
• R 1 is a carboxy-substituted alkyl group represented by the formula: -C(R") (R"') COOH wherein R" and R"' are different from each other, then the carbon atom to which R" and R"' are linked may be an asymmetrical center, resulting in diastereoisomers. Therefore, the present invention also includes such diastereoisomers of the cephalosporin derivatives of the formula (I) above, and mixtures thereof.
• non-toxic salts may be pharmaceutically acceptable salts of the compound of the formula (I).
• an inorganic salt for example, a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), ammonium salt, and so forth; an organic salt, for example, an organic amine salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, decyclohexylamine salt, N,N-dibenzylethylenediamine salt, N-methyl glucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino)methane salt, phenylethylbenzylamine salt, dibenzylethylenediamine salt, and so forth; an organic carb
• physiologically hydrolyzable esters of the compounds of the formula (I) may include, for example, indanyl, phthalidyl, methoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl or 5-methyl-2-oxo-1,3-dioxolan-4-yl esters, and other physiologically hydrolyzable esters which have been widely used in penicillin and cephalosporin antibiotics chemistry.
• the present invention further provides a process for preparing the novel cephalosporin derivatives of the formula (I) comprising the steps of:
• R 4 is an amino protecting group
• R 5 is hydrogen, or a lower alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl or cycloalkylalkyl group, a fluoro- substituted lower alkyl represented by the formula: -(CH 2 ) x F, in which x is an integer of 1 to 3, or a carboxy-substituted alkyl group represented by the formula: ,
• R' is a hydroxy, amino or C 1 -C 4 alkoxy group
• R" and R"' may be the same or different and represent hydrogen or a C 1 -C 3 alkyl group, or R" and R"' together with the carbon atom to which they are attached may form a C 3 -C 7 carbocyclic ring
• y is an integer of 0 to 3
• R 6 is a carboxyl protecting group
• X is a leaving group
• the compound of the formula (II) is preferably used in an amount of from 1 to 2 equivalents based on 1 equivalent of the compound of the formula (III).
• lower as used herein above and elsewhere in this specification, for example, with reference to “lower alkyl,” means those group having 1 to 6, preferably 1 to 4 carbon atoms.
• the amino protecting group may include an acyl group; a substituted or unsubstituted aryl-lower alkyl group, for example, benzyl, diphenylmethyl, triphenylmethyl and 4-methoxybenzyl; a halo-lower alkyl group, for example, trichloromethyl and trichloroethyl; tetrahydropyranyl; a substituted phenylthio group; a substituted alkylidene group; a substituted aralkylidene group; and a substituted cyclolidene group.
• an acyl group a substituted or unsubstituted aryl-lower alkyl group, for example, benzyl, diphenylmethyl, triphenylmethyl and 4-methoxybenzyl
• a halo-lower alkyl group for example, trichloromethyl and trichloroethyl
• tetrahydropyranyl
• the acyl group as an amino protecting group may include, for example, a C 1 -C 6 alkanoyl group such as formyl and acetyl; a C 2 -C 6 alkoxy carbonyl group, for example, methoxycarbonyl and ethoxycarbonyl; a lower alkane sulfonyl group, for example, methane sulfonyl and ethane sulfonyl; or an aryl-lower alkoxy carbonyl group such as benzyloxycarbonyl.
• One to three substituents such as a halogen atom, or a hydroxy, cyano or nitro group can further be substituted for the acyl group.
• the amino protecting group may include the reaction products formed by a reaction of an amino group with silane, boron, or phosphorous compounds.
• the carboxyl protecting group such as R 6 may include, for example, a lower alkyl group such as methyl and t- butyl; a lower alkenyl group such as vinyl and allyl; a lower alkoxy-lower alkyl group such as methoxymethyl; a lower alkylthio-lower alkyl group such as methylthiomethyl; a halo-lower alkyl group such as 2,2,2-trichloroethyl; a substituted or unsubstituted aralkyl group such as benzyl and p-nitrobenzyl; or a silyl group.
• a lower alkyl group such as methyl and t- butyl
• a lower alkenyl group such as vinyl and allyl
• a lower alkoxy-lower alkyl group such as methoxymethyl
• a lower alkylthio-lower alkyl group such as methylthiomethyl
• amino or carboxyl protecting groups mentioned above may be readily removed under mild conditions by using a known method(See: Protecting Groups in Organic Synthesi ⁇ , 3rd Ed.).
• the leaving group, X may include; for example, a halogen atom such as fluorine, chlorine, and iodine; a lower alkanoyloxy group such as acetoxy; a lower alkanesulfonyloxy group such as methanesulfonyloxy; an arenesulfonyloxy group such as p-toluenesulfonyloxy; an alkoxy carbonyloxy group; and the like.
• a halogen atom such as fluorine, chlorine, and iodine
• a lower alkanoyloxy group such as acetoxy
• a lower alkanesulfonyloxy group such as methanesulfonyloxy
• an arenesulfonyloxy group such as p-toluenesulfonyloxy
• an alkoxy carbonyloxy group and the like.
• a compound of the formula (II) in which X is an acetoxy group is first silylated with a silylating agent to protect the carboxy group at 4-position and the amino group of the substituent at 7-position.
• a silylating agent mono- or bis-trimethylsilylacetamide, N-methyl-N-(trimethylsilyl) acetamide, N,O-bis (trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA) and hexamethyldisilazane (HMDS) may be used.
• the silylated compound of the formula (II) is then reacted with trimethylsilyliodide (TMSI) at ambient temperature to form a compound of the formula (II) in which X is iodine.
• TMSI trimethylsilyliodide
• This reaction can be carried out in accordance with a known method, for example, as taught by U.S. Patent No. 4,266,049 to Bonjouklian.
• the fused pyridine of the formula (III) is silylated at room temperature in an aprotic organic solvent using the same silylating agent as mentioned above.
• silylated 3-iodomethyl cephalosporin of the formula (II) is then reacted with the silylated fused pyridine of the formula (III) to give a silylated compound of the formula (I).
• Hydrolysis of the silyl groups provides a compound of the formula (I) according to the present invention.
• the reaction for introducing the substituent of the formula (III) at 3-position of the compound of the formula (II) to prepare the compound of the formula (I) is carried out in the presence of an organic solvent such as an anhydrous aprotic solvent.
• a nitrile solvent such as acetonitrile and propionitrile
• an alkyl halide solvent such as chloroform, carbon tetrachloride and dichloromethane
• an ether solvent such as tetrahydrofuran and dioxane
• an amide solvent such as N,N-dimethyl formamide
• an ester solvent such as ethylacetate and methylacetate
• a ketone solvent such as acetone, methyl ethyl ketone and methyl isobutyl ketone
• a sulfoxide solvent such as dimethylsulfoxide
• an aromatic carbohydrogen solvent such as benzene and toluene.
• the compounds of the formula (I) according to the invention are prepared directly from a 3-acetoxymethyl compound, for example, a compound of the formula (II) in which X is an acetoxy and
• R 4 is H.
• This reaction is carried out in a conventional manner, for instance, in an aqueous medium, for example in an organic solvent in admixture with water. Addition of a small amount of an alkali iodide such as potassium iodide can enhance the rate of the reaction. This reaction is carried out at a temperature between about 35 °C and about 70 °C.
• Useful water miscible organic solvents include acetone, acetonitrile, tetrahydrofuran, and dimethylacetamide.
• the former method i.e., reacting a compound of the formula (II) in which X is iodine with a compound of the formula (III) in view of the reactivity and yields.
• the amino or acid protecting groups can be readily removed by a conventional deprotection method well known in cephalosporin antibiotics chemistry.
• acid- or base-hydrolysis or reduction are generally applicable.
• the protecting group is an amido group
• such compound is subjected to imino-halogenation and imino-etherification, followed by hydrolysis.
• Acid hydrolysis is preferably applicable to the removal of the groups such as tri (di)-phenylmethyl or alkoxycarbonyl.
• organic acids such as formic acid, trifluoroacetic acid and p-tolueneacetic acid; or an inorganic acid such as hydrochloric acid and the like.
• a stabilizing agent can be used to stabilize reaction products and their intermediates.
• a stabilizing agent one or more salts selected from the group consisting of sodium iodide, potassium iodide, sodium bromide, potassium bromide and potassium thiocyanate can be mentioned.
• the compounds of the formula (I) have the same stereochemistry as the known cephalosporin antibiotics. That is, the side chain at 7-position has a ß-configuration (6R,7R), while the oxyimino group in the side chains may be in either a syn- or anti-form, or as a mixture thereof.
• the compounds of the present invention are prepared in either form by employing the 2-(heterocyclic)-2-oxyiminoacetic acid in the syn- or anti-form and coupling reagents.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising, as an active ingredient, one or more of the compounds of the formula (I) according to the present invention, a non-toxic salt, physiologically hydrolyzable ester or solvate thereof, in association with pharmaceutically acceptable carriers, excipients, or other additives.
• the antibiotic compounds of the formula (I), as well as a non-toxic salt, physiologically hydrolyzable ester or solvate thereof may be formulated for administration, which may be presented in an unit dose form or in a multidose container.
• the formulation may be in various forms such as solutions, suspensions, or emulsions in oily or aqueous vehicles, which can contain conventional additives such as dispersing agents, suspending agents, stabilizing agents, and the like.
• the compounds of the present invention may be formulated into a dried powder that can be normally dissolved in an aqueous solution of sterile, pyrogen-free water, prior to use.
• the compounds of the present invention may also be formulated into a suppository containing conventional suppository bases such as cocoa and other glycerides.
• PREPARATION 1 PREPARATION OF 2,3(1H,4H)-DIOXO-PYRAZINO ⁇ [5,6-c]PYRIDINE
• a solution of 4.3 g of dimethyloxalate in 40 ml of methanol was added dropwise to the mixture over 30 minutes and the resulting mixture heated to reflux for 7 hours.
• the mixture was concentrated under reduced pressure, diluted with 240 ml of water, and then cooled in an ice bath.
• the reaction mixture was adjusted to pH 6.5 with 10 % hydrochloric acid.
• the precipitated solids were collected by filtration, washed with water, and dried to give 4.5 g of the title compound as a white solid.
• PREPARATION 2 PREPARATION OF l-METHYL-2.3 (4H)-DIOXOPYRAZINO[5.6-c]PYRIDINE 3-Amino-4-methylaminopyridine was reacted in the manner similar to that described in Preparation 1 to give the title compound.
• PREPARATION 3 PREPARATION OF 4-METHYL-2,3(1H)-DIOXOPYRAZINO[5,6-c]PYRIDINE 3-Methylamino-4-aminopyridine was reacted in the manner similar to that described in Preparation 1 to give the title compound.
• PREPARATION 5 PREPARATION OF 1-CYCLOPROPYL-2,3(4H)-DIOXOPYRAZINO[5,6-c]PYRIDINE
• PREPARATION 6 PREPARATION OF 2 (1H,3H)-OXO-IMIDAZO[4,5-c]PYRIDINE
• PREPARATION 8 PREPARATION OF 1-AMINO-2(3H)-OXO-IMIDAZO ⁇
• PREPARATION 9 PREPARATION OF 1-(2-HYDROXYETHYL)-2(3H)-OXO-IMIDAZO[4,5-c]PYRIDINE
• PREPARATION 10 PREPARATION OF 2 (1H , 3H) -OXO-IMIDAZO [ 4 , 5-b] PYRIDINE 2,3-Diaminopyridine was reacted in the manner similar to that described in Preparation 6 to give the title compound.
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 1.0 ml of methanol and 2 ml of acetonitrile at 0 °C. The mixture was stirred at 0 °C for 30 minutes. The precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid, and the mixture was neutralized with saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 100 mg of the title compound,
• the reaction mixture was concentrated. The concentrate was dissolved in a mixture of 10 ml of acetonitrile and 1 ml of tetrahydrofuran to give a solution. Separately, 200 mg of 2,3 (1H,4H)-dioxo-pyrazino[5,6-c]pyridine was reacted with 0.8 ml of N,O-bistrimethylsilylacetamide in 5 ml of acetonitrile to give a silylated pyridine derivative, which was then added to the solution previously obtained. The mixture was reacted at room temperature for 3 hours. Then, to the reaction mixture, 1 ml of methanol was added to effect deprotection. The precipitated solids were filtered out and purified to give 200 mg of the title compound,
• EXAMPLE 3 SYNTHESIS OF 7-ß-[(Z)-2-AMINOTHIAZOL-4-YL)-2- PROPYNYLOXYIMINOACETAMIDO]-3-[2,3(1H,4H)-DIOXO-PYRAZINO[5,6-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• EXAMPLE 5 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-2-CARBOXYMETHOXYIMINOACETAMIDO]-3-[2,3(1H,4H)-DIOXO-PYRAZINO[ 5 ,6-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was concentrated. The concentrate was dissolved in a mixture of 15 ml of acetonitrile and 1 ml of tetrahydrofuran to give a solution. Separately, 200 mg of 2,3 (1H,4H)-dioxo-pyrazino[5,6-c]pyridine was reacted with 0.8 ml of N,0-bistrimethylsilylacetamide in 5 ml of acetonitrile to give a silylated pyridine derivative, which was then added to the solution previously obtained. The mixture was reacted at room temperature for 3 hours. Then, to the reaction mixture, 1 ml of methanol was added to effect deprotection. The precipitated solids were filtered out and purified to give 250 mg of the title compound.
• EXAMPLE 7 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-2-METHOXYIMINOACETAMIDO]-3-[1-METHYL-2,3(4H)-DIOXO ⁇
• EXAMPLE 8 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)- 2-METHOXYIMINOACETAMIDO]-3-[1-ETHYL-2,3(4H)-DIOXO-PYRAZINO[5,6-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE 500 Mg of 7-ß-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid was suspended in 10 ml of dry dichloromethane and reacted with 0.8 ml of N-methyl-N-(trimethylsilyl
• the reaction mixtue was concentrated. The concentrate was dissolved in a mixture of 10 ml of acetonitrile and 1 ml of tetrahydrofuran to give a solution. Separately, 250 mg of 1- ethyl-2,3(4H)-dioxo-pyrazino[5,6-c]pyridine was reacted with 0.8 ml of N,O-bistrimethylsilylacetamide in 5 ml of acetonitrile to give a silylated pyridine derivative, which was then added to the solution previously obtained. The mixture was reacted at room temperature for 3 hours. Then, to the reaction mixture, 1 ml of methanol was added to effect deprotection. The precipitated solids were filtered out and purified to give 250 mg of the title compound.
• EXAMPLE 9 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-2-METHOXYIMINOACETAMIDO]-3-[1-CYCLOPROPYL-2,3(4H)-DIOXOPYRAZINO[5,6-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• EXAMPLE 10 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-2-(2-CARBOXYPROP-2-YL)OXYIMINOACETAMIDO]-3-[1-METHYL-2,3(4H)-DIOXO-PYRAZINO[5,6-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• EXAMPLE 11 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)- 2-(2-CARBOXYPROP-2-YL)OXYIMINOACETAMIDO]-3-[1-ETHYL- 2,3(4H)-DIOXO-PYRAZINO[5,6-c]PYRIDINIUMMETHYL]-3-CEPHEM-4- CARBOXYLATE
• the reaction mixture was concentrated. The concentrate was dissolved in a mixture of 15 ml of acetonitrile and 1 ml of tetrahydrofuran to give a solution. Separately, 270 mg of 1-cyclopropyl-2,3(4H)-dioxo-pyrazino[5,6-c]pyridine was reacted with 0.8 ml of N,O-bistrimethylsilylacetamide in 5 ml of acetonitrile to give a silylated pyridine derivative, which was then added to the solution previously obtained. The mixture was reacted at room temperature for 3 hours. Then, to the reaction mixture, 2 ml of methanol was added to effect deprotection. The precipitated solids were filtered out and purified to give 250 mg of the title compound.
• EXAMPLE 13 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)- 2-METHOXYIMINOACETAMIDO]-3- [4-METHYL-2,3(1H)-DIOXOPYRAZINO[5 , 6-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 1.0 ml of methanol and 2 ml of acetonitrile at 0 °C.
• the precipitated solids were collected by filtration to give a solid product.
• 10 Ml of water was added to the solid, and the mixture was neutralized with a saturated NaHCO 3 solution and then concentrated.
• the resultant residue was purified by chromatography over silica gel eluting with acetonitrile:H 2 O (4:1) and concentrated to give 40 mg of the title compound.
• EXAMPLE 14 SYNTHESIS OF 7-ß-[(Z)-2-(AMINOTHIAZOL-4-YL)-2-FLUOROMETHOXYIMINOACETAMIDO] -3- [2,3(1H,4H)-DIOXO-PYRAZINO- [5,6-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 1.0 ml of methanol and 2 ml of acetonitrile at 0 °C. The mixture was stirred at 0 °C for 30 minutes. The precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid, and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 250 mg of the title compound.
• EXAMPLE 15 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)- 2-METHOXYIMINOACETAMIDO]-3-[2 (1H,3H)-OXO-IMIDAZO[4,5-c]- PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 5 minutes at 25 °C under a nitrogen atmosphere.
• To the stirred solution was added by pipette 0.38 ml of iodotrimethylsilane at 0 °C, and the reaction mixture was then stirred at room temperature for 30 minutes. Thereafter, the reaction mixture was evaporated under reduced pressure to remove the solvent and then give an oil.
• the oil was dissolved in a mixture of 10 ml of acetonitrile and 1 ml of tetrahydrofuran. The resultant solution was stirred for 5 minutes.
• EXAMPLE 16 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-2-METHOXYIMINOACETAMIDO]-3-[1-METHYL-2(3H)-OXO-IMIDAZO[4,5-c]PYRIDINIUMMETHYL] -3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 5 minutes at 25 °C under a nitrogen atmosphere.
• To the stirred solution was added by pipette 0.24 ml of iodotrimethylsilane at 0 °C, and the reaction mixture was then stirred at room temperature for 30 minutes. Thereafter, the mixture was evaporated under reduced pressure to remove the solvent and then give an oil.
• the oil was dissolved in a mixture of 10 ml of acetonitrile and 1 ml of tetrahydrofuran. The resultant solution was stirred for 5 minutes.
• the stirred solution was added, in one portion, to a solution of 90 mg of 1-methyl-2(3H)-oxo-imidazo[4,5-c]pyridine silylated with 0.5 ml of N,O-bis(trimethylsily)acetamide in 10 ml of acetonitrile.
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 0.5 ml of methanol and 5 ml of acetonitrile at 0 °C.
• the mixture was stirred at 0 °C for 30 minutes.
• the precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid, and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 50 mg of the title compound.
• EXAMPLE 17 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)- 2-METHOXYIMINOACETAMIDO] -3-[1-AMINO-2(3H)-OXO-IMIDAZO[4,5- c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 0.5 ml of methanol and 5 ml of acetonitrile at 0 °C. The mixture was stirred at 0 °C for 30 minutes. The precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 120 mg of the title compound,
• EXAMPLE 18 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-2-METHOXYIMINOACETAMIDO]-3-[1-(2-HYDROXYETHYL)-2(3H)-OXO-IMIDAZO[4,5-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 0.6 ml of methanol and 6 ml of acetonitrile at 0°C. The mixture was stirred at 0 °C for 30 minutes. The precipitated solids were collected by filtration to give a solid product. 70 Ml of water was added to the solid, and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 115 mg of the title compound,
• EXAMPLE 19 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-2-METHOXYIMINOACETAMIDO] -3-[2(1H,3H)-OXO-IMIDAZO[4'5-b]-PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 0.5 ml of methanol and 5 ml of acetonitrile at 0°C. The mixture was stirred at 0°C for 30 minutes. The precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid, and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 110 mg of the title compound.
• EXAMPLE 20 SYNTHESIS OF 7-ß-[( Z)-2-(2-AMINOTHIAZOL-4-YL)-2-FLUOROMETHOXYIMINOACETAMIDO]-3-[2(1H,3H)-OXO-IMIDAZO-[4,5-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 1.0 ml of methanol and 2 ml of acetonitrile at 0 °C. The mixture was stirred at 0 °C for 30 minutes. The precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid, and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 110 mg of the title compound,
• EXAMPLE 21 SYNTHESIS OF 7-ß-[ (Z)-2-(2-AMINOTHIAZOL-4-YL)-2-FLUOROMETHOXYIMINOACETAMIDO] -3-[1-METHYL-2(3H)-OXO-IMIDAZO[4,5-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 0.3 ml of methanol and 2 ml of acetonitrile at 0 °C. The mixture was stirred at 0°C for 30 minutes. The precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid, and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 60 mg of the title compound,
• EXAMPLE 22 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-2-FLUOROMETHOXYIMINOACETAMIDO] -3-[1-AMINO-2(3H)-OXO-IMIDAZO[4,5-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 1.0 ml of methanol and 2 ml of acetonitrile at 0 °C. The mixture was stirred at 0 °C for 30 minutes. The precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 105 mg of the title compound.
• EXAMPLE 23 SYNTHESIS OF 7-ß-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-2-FLUOROMETHOXYIMINOACETAMIDO]-3-[2 (1H,3H)-OXO-IMIDAZO-[4,5-b]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 5 minutes at 25 °C under a nitrogen atmosphere.
• To the stirred solution was added by pipette 0.33 ml of iodotrimethylsilane at 0 °C, and the reaction mixture was then stirred at room temperature for 30 minutes. Thereafter, the solvent was evaporated off under reduced pressure to give an oil.
• the oil was dissolved in a mixture of 15 ml of acetonitrile and 0.3 ml of tetrahydrofuran, and the solution was stirred for 5 minutes.
• the stirred solution was added, in one portion, to a solution of 100 mg of 2(1H,3H)-oxo-imidazo[4,5-b]-pyridine silylated with 0.90 ml of N,O-bis(trimethylsilyl)-acetamide in 3 ml of acetonitrile.
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 0.5 ml of methanol and 2 ml of acetonitrile at 0°C.
• the mixture was stirred at 0 °C for 30 minutes.
• the precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid, and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 20 mg of the title compound.
• EXAMPLE 24 SYNTHESIS OF 7-ß-[ (Z)-2-(2-AMINOTHIAZOL-4-YL)-2-CARBOXYMETHOXYIMINOACETAMIDO]-3-[2 (1H,3H) -OXO-IMIDAZO-[4,5-c]PYRIDINIUMMETHYL]-3-CEPHEM-4-CARBOXYLATE
• the reaction mixture was stirred for 5 minutes at 25 °C under a nitrogen atmosphere.
• To the stirred solution was added by pipette 0.40 ml of iodotrimethylsilane at 0 °C, and the reaction mixture was then stirred at room temperature for 30 minutes. Thereafter, the solvent was evaported off under reduced pressure to give an oil.
• the oil was dissolved in a mixture of 10 ml of acetonitrile and 1.0 ml of tetrahydrofuran, and the solution was stirred for 5 minutes.
• the stirred solution was added, in one portin, to a solution of 180 mg of 2(1H,3H)-oxo-imidazo[4,5-c]pyridine silylated with 0.80 ml of N,O-bis(trimethylsilyl) acetamide in 10 ml of acetonitrile.
• the reaction mixture was stirred for 3 hours at 25 °C and then added to a mixture of 1.0 ml of methanol and 2 ml of acetonitrile at 0 °C.
• the mixture was stirred at 0 °C for 30 minutes.
• the precipitated solids were collected by filtration to give a solid product. 10 Ml of water was added to the solid, and the mixture was neutralized with a saturated sodium bicarbonate solution and then concentrated. The residue was purified by chromatography over silica gel to give 80 mg of the title compound.
• EXPERIMENTAL EXAMPLE 1 in vitro ACTIVITY
• CX cefotaxime
• CAZ ceftazidime
• MIC minimal inhibitory concentrations thereof against various gram-positive and gramnegative microorganisms
• CX cefotaxime
• CAZ ceftazidime
• test compounds and reference compounds were made and dispersed in Muller-Hinton agar medium. Then, 2 pi of standard test strain which had 10 4 cfu/spot was inoculated on the medium, and was incubated at 37 °C for 20 hours. After the incubation, MICs ( ⁇ g/ml) of the test and reference compounds were measured. The results are shown in Table 3 below.

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