Cephem derivatives

Abstract: A compound represented by the following formula (9): wherein R 5 represents an amino or protected amino group and Y represents a hydrogen atom, a lower alkyl group, a halogen atom or a nitro group, or a salt thereof.

Description: BACKGROUND OF THE INVENTION 1) Field of the Invention This invention relates to intermediates for the synthesis of 3-(substituted carbamoyloxy)-3-cephem derivatives, which are useful as antibacterial drugs. 2) Description of the Related Art Japanese Patent Application Laid-Open (Kokai) No. 34794/1978 discloses unsubstituted or lower-alkylsubstituted 3-carbanoyloxy-3-cephem derivatives including the compounds represented by the following formula: wherein Y means a hydrogen atom or a nucleophile compound residuum. In addition, Japanese Patent Application No. 44714/1989 discloses the compounds represented by the following formula: wherein R 6 means an amino group or an acylamino group, R 7 denotes a carboxyl group or a protected carboxyl group, the group represented by the formula -N< R 8 / R 9 represents a di(lower) alkylamino group, a (lower) alkylamino group, a saturated, 5- or 6-membered, heterocyclic (lower) alkylamino group containing 1-4 nitrogen atoms, said alkylamino group being optionally substituted by one or more lower alkyl groups, or a saturated, 5- or 6-membered heterocyclic group containing 2-4 nitrogen atoms, said heterocyclic group being optionally substituted by one or more lower alkyl or hydroxy(lower)alkyl groups, X 1 is -S- or and the dotted line indicates a 2- or 3-cephem ring. Further, Japanese Patent Publication No. 46474/1991 discloses cephem compounds represented by the following formula: wherein R 1 is an amino or hydroxyl group which may optionally be protected, R 3 is a hydrogen atom, R 5 is a hydroxyl group or a substituted or unsubstituted alkoxyl group, R 8 is a hydrogen atom, Q denotes a carbon-carbon linkage for the formation of a 3-substituted-3-cephem-4-carboxylic acid, and R represents an ester residuum. Several types of semisynthetic cephalosporins are now used for the treatment of various infectious diseases. None of them are, however, satisfactory as antibacterial agents which have strong antibacterial activities and, in particular, are orally-dosable. SUMMARY OF THE INVENTION An object of the present invention is therefore to provide synthetic intermediates for the preparation of an antibacterial composition which has strong antimicrobial activities and, moreover, is orally dosable. As a result of an extensive investigation, the present inventors have found that certain novel 3-substituted carbamoyloxy-3-cephem derivatives have excellent antibacterial activities against various pathogenic fungi and their pharmacologically-protected derivatives are promptly absorbed through the digestive tract, form non-ester derivatives immediately after their absorption and are hence useful as antibacterial compositions for oral administration, leading to the completion of the present invention. The present invention therefore provides intermediates for the synthesis of a 7-acyl-3-substituted carbamoyloxy-3-cephem compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof: wherein A means a -CH= or -N= group; R 1 denotes a hydroxyl group, R 2 and R 3 are methyl groups, and R 4 denotes a carboxyl group, a 1-(isopropyloxycarbonyloxy) ethyloxycarbonyl group or a 1-(cyclohexyloxycarbonyloxy) ethyloxycarbonyl group; or a pharmaceutically acceptable salt thereof. The 7-acyl-3-substituted carbamoyloxy-3-cephem compound (1) and its pharmaceutically-acceptable salts have strong antibacterial activities and are orally dosable. Said intermediates are represented by the following formula (9) : wherein Y represents a hydrogen atom, a methyl or ethyl group, a halogen atom or a nitro group, and wherein R 5 represents an amino group or an amino group protected by a group selected from alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl and hexyloxycarbonyl; aralkoxycarbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl; aroyl groups such as benzoyl, toluoyl, naphthoyl, phthaloyl and indanecarbonyl; aralkanoyl groups such as phenylacetyl and phenylpropionyl; aryloxyalkanoyl groups such as phenoxyacetyl and phenoxypropionyl; heterocyclic carbonyl groups such as furoyl, thenoyl and nicotinoyl; heterocyclic glyoxyloyl such as thienylglyoxyloyl and thiazolylglyoxyloyl; and heterocyclic alkanoyl groups such as thienyl and thiazolylacetyl, or a salt thereof. DETAILED DESCRIPTION OF THE INVENTION Illustrative examples of the pharmaceutically acceptable salt include alkali metal salts such as the sodium and potassium salts; the ammonium salt; quaternary ammonium salts such as the tetraethylammonium and betaine salts; alkaline earth metal salts such as the calcium and magnesium salts; inorganic acid salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, carbonate and bicarbonate; organic carboxylates such as the acetate, maleate, lactate and tartrate; organosulfonates such as the methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, taurine salt, benzenesulfonate and toluenesulfonate; amino acid salts such as the arginine salt, lysine salt, serine salt, aspartate, glutamate and glycine salt; and amine salts such as the trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt and phenethylbenzylamine salt. Intermediates useful in the preparation of the compounds represented by formula (1) can be prepared, for example, by the processes to be described below. a) Preparation Process A A compound represented by the following formula: wherein R 2 and R 3 are both methyl groups, R 4 is a carboxyl group or a carboxyl group protected by a protecting group as defined hereinafter, and R 5 represents an amino or protected amino group as defined in claim 1, or a salt thereof can be prepared by reacting a compound represented by the following formula (9) : wherein Y is a hydrogen atom, a methyl group, an ethyl group, a halogen atom or a nitro group, and R 5 has the same meanings as described above for formula (8) or a salt thereof with a compound represented by the following formula: wherein R 2 and R 3 are both methyl, or a salt thereof in an inert solvent and, if necessary, protecting the carboxyl group. Illustrative of the protecting group for the carboxyl group represented by R 4 include lower alkyl groups such as methyl, ethyl and t-butyl;lower alkyl groups substituted by one or more substituted or unsubstituted phenyl groups such as p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl or phenethyl; halogenated lower alkyl groups such as 2,2,2-trichloroethyl and 2-iodoethyl; loweralkanoyloxy-lower-alkyl groups such as pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and 2-pivaloyloxyethyl; higher-alkanoyloxy-lower-alkyl groups such as palmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl; lower-alkoxycarbonyloxy-lower-alkyl groups such as methoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl, 1-(t-butoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl and 1-(isopropoxycarbonyloxy)ethyl; carboxy-lower-alkyl groups such as carboxymethyl and 2-carboxyethyl; heterocyclic groups such as 3-phthalidyl; benzoyloxy-lower-alkyl groups such as 4-glycidyloxybenzoyloxymethyl and 4-[N-(t-butoxycarbonyl)glycyloxy]benzoyloxymethyl, said benzoyloxy-lower-alkyl groups optionally containing one or more substituent groups; (substituted dioxolene)-lower-alkyl groups such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; cycloalkyl-substituted lower-alkanoyloxy-lower-alkyl groups such as 1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy-lower-alkyl groups such as 1-cyclohexyloxycarbonyloxyethyl. In effect, any protecting group can be used as long as it can be removed by any means to form a carboxylic group. Preferred examples of the protecting group include 1-(isopropyloxycarbonyloxy)ethyl group, 1-(ethoxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, pivaloyloxymethyl group and isopropyloxycarbonyloxymethyl group, with 1-(isopropyloxycarbonyloxy)ethyl group being more preferred. The reaction is conducted generally in an inert solvent such as water, methanol, ethanol, propanol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, methylene chloride or chloroform; or in a mixed solvent of two or more of such inert solvents. Although the reaction can be conducted generally at -78°C to 80°C, it is preferred to conduct it at a temperature ranging from ice cooling to room temperature. As the reaction time, it is generally sufficient to conduct the reaction for only 10 minutes to 1 hour. The compound prepared by this process can be utilized as an intermediate for the compound represented by the formula (1) by removing the amino-protecting group or protecting the carboxyl group with a protecting group as needed. The removal of the amino-protecting group or the protection of the carboxyl group can be carried out by a method known per se in the art. For instance, esterification can be performed by the reaction with an alcohol-reactive derivative after optional conversion into an alkali metal salt or an organic amine salt. The conversion into the alkali metal salt is carried out using an alkali metal salt of an organic acid such as sodium acetate, potassium acetate, sodium 2-ethylhexanonate, potassium 2-ethylhexanonate; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; or an alkali metal carbonate such as sodium carbonate, potassium carbonate or sodium hydrogencarbonate; or the like. The conversion into the organic amine salt can be carried out using trimethylamine, triethylamine, dichlorohexylamine or pyridine. The reaction is generally conducted in an inert solvent such as water, methanol, ethanol, propanol, tetrahydrofuran, N,N-dimethylformamide, dioxane, methylene chloride, ethyl acetate, methyl acetate or acetonitrile or in a mixed solvent of two or more of such inert solvents. The reaction with the alcohol-reactive derivative is generally conducted in an inert solvent such as water, methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, tetrahydrofuran, dioxane, methylene chloride, ethyl acetate, methyl acetate, acetonitrile, benzene or toluene; or in a mixed solvent of two or more of such inert solvents. The reaction can be conducted generally at -78°C to 80°C, but preferably at a temperature ranging from ice cooling to room temperature. The removal of the protecting group from the protected amino group can be conducted in the presence of an acid according to a common method. Preferred examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid. The reaction is conducted generally in an inert solvent such as water, methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, tetrahydrofuran, dioxane or methylene chloride; or in a mixed solvent of two or more of such inert solvents. The reaction can be conducted generally at -50°C to 50°C, but preferably at a temperature ranging from ice cooling to room temperature. b) Preparation Process B A compound represented by the following formula (7): wherein R 4 and R 5 have the same meanings as in Preparation Process A is prepared by reacting a compound represented by the following formula (12): wherein R 4 and R 5 have the same meanings as defined above or a salt thereof, with phosgene or a phosgene derivative in the presence of a base. Then, the resulting compound is reacted with a compound represented by the following formula: wherein R 2 and R 3 are both methyl, or a salt thereof, thereby obtaining a compound represented by the following formula (8): wherein R 2 , R 3 , R 4 , R 5 have the same meanings as in Preparation Process A. Suitable examples of the base in' the above reaction include the hydroxides or carbonates of alkali metals or alkaline earth metals, such as sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate; tertiary amines such as triethylamine, tributylamine, N-methylmorpholine, pyridine, toluidine, lutidine, and N,N-dimethylaminopyridine. Examples of the phosgene derivative include trichloromethylchloroformate and bis(trichloromethyl)carbonate. The reaction is conducted generally in an inert solvent such as N,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform or ethyl acetate; or in a mixed solvent of two or more of such inert solvents. The reaction can be conducted generally at -100°C to 30°C, but preferably at a temperature ranging from -78°C to 0°C. Compounds prepared by this process can be utilized as intermediates for the compounds represented by the formula (1) by removing the above-defined amino-protecting group or protecting the carboxyl group with an above-defined protecting group as needed. Their removal or protection can be carried out by a method known per se in the art, said method having been described in Preparation Process A. c) Preparation Process C N,N'-carbonyldiimidazole is reacted with a compound represented by the following formula (13) wherein R 4 has the same meaning as in Preparation Process A and R 5 a represents a protected amino group as defined above or with a salt thereof to convert the latter to an active derivative. The active derivative is reacted further with a compound represented by the formula: wherein R 2 and R 3 are both methyl groups, or a salt thereof. If necessary, the amino group may be deprotected, thereby obtaining a compound represented by the following formula (8): wherein R 2 , R 3 , R 4 , R 5 have the same meanings as in Preparation Process A. The reaction is conducted generally in an inert solvent such as water, methanol, ethanol, propanol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, methylene chloride or chloroform; or in a mixed solvent of two or more of such inert solvents. Compounds prepared by this process can be utilized as intermediates for the compounds represented by the formula (1) by removing any amino- and/or carboxyl-protecting group or protecting the carboxyl group with an above-defined protecting group as needed. The protection of the carboxyl group and the removal of the amino-protecting group can be carried out by the method known per se in the art, said method having been described in Preparation Process A. The deprotection of the protected carboxyl group can be effected by hydrolysis in the presence of an acid. Here, preferred examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as boron trifluoride, aluminum trichloride, stannic chloride, ferric chloride, titanium tetrachloride an zinc chloride. It is preferred to conduct the reaction in the presence of a cation scavenger such as anisole, if necessary. The hydrolysis is generally conducted in an inert solvent such as water, methanol, ethanol, propanol, tetrahydrofuran, N,N-dimethylformamide, dioxane or methylene chloride, or in a mixed solvent of two or more of such inert solvents. The acids exemplified above can be used as a solvent. Although the reaction can be conducted generally at -78°C to 80°C, it is preferred to conduct it at a temperature ranging from ice cooling to room temperature. d) Preparation Process D A compound represented by the following formula (14) : wherein R 2 , R 3 and R 4 have the same meanings as in Preparation Process A and X represents a halogen atom can be prepared by reacting the compound represented by the formula (2) wherein R 2 and R 3 are both methyl groups and R 4 is a carboxyl group or a carboxyl group protected by a protecting group as defined above, or a salt thereof with a compound represented by the following formula: XCH 2 COCH 2 COOH wherein X has the same meaning as defined above, or with a salt or carboxyl-reactive derivative thereof. Illustrative of the reactive derivative include acid halides such as the acid chloride and acid bromide. These acid halides can each be obtained by reaction with its corresponding diketene and halogen. The reaction is conducted generally in an inert solvent such as water, methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, tetrahydrofuran, dioxane, methylene chloride, ethyl acetate, methyl acetate, acetonitrile, benzene, toluene or pyridine; or in a mixed solvent of two or more of such inert solvents. The reaction can be conducted generally at -78°C to 80°C, but preferably at a temperature ranging from ice cooling to room temperature. The compound represented by the following formula (4) : wherein R 2 , R 3 and R 4 have the same meanings as in Preparation Process A and X represents a halogen atom or a salt thereof can be prepared by reacting a nitrosating agent with the compound represented by the formula (14) or its salt. Examples of the nitrosating agent include nitrous acid and its derivatives, for example, alkali metal nitrites such as sodium nitrite and potassium nitrite; and alkyl nitrites such as butyl nitrite, pentyl nitrite and amyl nitrite. When an alkali metal nitrite such as sodium nitrite or potassium nitrite is used, it is preferred to conduct the nitrosation in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid or acetic acid. The reaction is carried out generally in an inert solvent such as water, methanol, ethanol, propanol, N,N-dimethylformamide, acetone, tetrahydrofuran, dioxane or methylene chloride; or in a mixed solvent of two or more of such inert solvents. The reaction can be conducted generally at -78°C to 80°C, but preferably at a temperature ranging from ice cooling to room temperature. e) Preparation Process E A compound represented by the following formula (17) : wherein R 4 a represents a protected carboxyl group as defined above , R 5 and Y have the same meanings as in Preparation Process A or a salt thereof can be obtained at a high yield by reacting, in the presence of a base, a compound represented by the following formula (15) : wherein R 4 a and R 5 have the same meanings as defined above or a salt thereof, with a compound represented by the following formula (16): wherein Y has the same meaning as defined above and X represents a halogen atom. In the next place, the carboxyl-protecting group is removed from the resulting compound, thereby obtaining the compound represented by the following formula (9) : wherein R 5 and Y have the same meanings as defined above or a salt thereof. Removal of carboxyl-protecting group is carried out by the method described in Preparation Process C. Examples of the above-described salt of the compound represented by the formula (15) include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salt, organic amine salts (trimethylamine salt, triethylamine salt, etc.), organic acid salts (formate, trifluoroacetate, toluenesulfonate, etc.), and inorganic acid salts (hydrochloride, sulfate, etc.). Suitable examples of the base include alkali metal salts and alkaline earth metal salts, such as sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate; alkali metal or alkaline earth metal salts of organic acids, such as sodium acetate, potassium acetate, barium acetate and magnesium acetate; and tertiary amines such as triethylamine, tributylamine, N-methylmorpholine, pyridine, toluidine, lutidine, and N,N-dimethylaminopyridine. The reaction is usually conducted in an inert solvent such as N,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, ethyl acetate, methyl acetate, benzene, toluene or hexane, or in a mixed solvent of two or more of such inert solvents. Although the reaction can be conducted generally at -78°C to 80°C, it is preferred to conduct it at a temperature ranging from ice cooling to room temperature. In Preparation Processes A-E for intermediate compounds, the target compounds (4), (8) and (9) can also be obtained by using, instead of the starting compound (9), (12), (13), (14) and (15), their sulfoxido derivatives and then conducting reduction after the reactions. Dosable preparation forms of compounds represented by formula (1) include tablets, granules, powders, capsules, syrups, liquids, etc. Each of these preparations can be formulated in a manner known per se in the art, by adding a known excipient. Examples will next be set out to describe how the intermediates according to the present invention can be used for the synthesis of compounds represented by formula (1). Throughout the examples, "Tr" stands for a (C 6 H 5 ) 3 C- group, "BH" for a (C 6 H 5 ) 2 CH- group, and Me for a methyl group. Example 1 Benzhydryl 7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate To a suspension of benzhydryl 7-phenylacetamide-3-hydroxymethyl-3-cephem-4-carboxylate (15.8 g; 0.031 mol) and p-nitrophenylchloroformate (6.19 g; 0.031 mol) in tetrahydrofuran (160 mℓ), pyridine (2.43 g; 0.031 mol) was added dropwise under ice cooling, followed by stirring at the same temperature for 25 minutes. The reaction mixture was poured into a mixed solvent of ethyl acetate and water and the ethyl acetate layer was collected. The resulting ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was added with diisopropyl ether and triturated. The resulting mixture was filtered so that the solid was collected. The solid was dried in air, whereby benzhydryl 7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate was obtained (yield: 18.8 g; 90.2%). NMR (CDCl 3 , δ) : 3.40,3.60(2H,ABq,J=18.5Hz), 3.61,3.66(2H,ABq, =13.6Hz), 4.97(1H,d,J=8.8Hz), 4.97,5.24 (2H,ABq,J=13.2Hz), 5.88 (1H,dd,J=4.9Hz,8.8Hz), 6.30(1H,d,J=8.8Hz), 6.92(1H,s), 7.24-7.42(17H,m), 8.23-8.28(2H,m) Example 2 7 -Phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylic acid To a solution of benzhydryl 7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate (6.79 g, 0.01 mol) in dichloromethane (14 mℓ), trifluoroacetic acid (17 mℓ) was added dropwise under ice cooling, followed by stirring for 50 minutes. The reaction mixture was poured into diisopropyl ether. The precipitate thus obtained was collected by filtration, washed with diisopropyl ether and dried in air, whereby 7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylic acid was obtained (yield: 4.50 g; 87.7%). NMR (DMSO, δ): 3.49,3.57(2H,ABq,J=14.0Hz), 3.60,3.71(2H,ABq, =18.1Hz), 4.95,5.24 (2H,ABq,J=12.5Hz), 5.12(1H,d, J=4.9Hz), 5.72(1H,dd,J=4.9,8.6Hz), 7.19-7.28(5H,m), 7.53-7.58(2H,m), 8,28-8.35(2H,m), 9.12(1H,d,J=8.6Hz) Example 3 Sodium 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate To a solution of benzhydryl 7-phenylacetamide-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate (5.13 g, 0.01 mol) in tetrahydrofuran (36 m ℓ ) and water (4 m ℓ ), a 50% aqueous solution of dimethylamine (1.8 g; 0.02 mol) was added dropwise under ice cooling. At the same temperature, the resulting solution was stirred for 10 minutes. The reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid and an organic layer was collected. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was suspended in methanol and the resulting suspension was added with a solution of sodium acetate (984 mg; 0.012 mol) in methanol. The vlrst solution thus obtained was concentrated under reduced pressure. The concentration was stopped when a precipitate had appeared. After the addition of 2-propanol, the precipitate was collected by filtration and dried in air, whereby sodium 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate was obtained (yield: 2.25 g; 51.0%). NMR (D 2 O, δ): 2.74(6H,s), 3.21,3.47(2H,ABq,J=17.9Hz), 3.51,3.57 (2H,ABq,J=14.8Hz), 4.51,4.74 (2H,ABq,J=12.6Hz), 4.92(1H,d,J=4.6Hz), 5.48(1H,d,J=4.6Hz), 7.18-7.28(5H,m) Example 4 1-(Isopropoxycarbonyloxy)ethyl 7-phenylacetamido-3-N, N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate To a solution of sodium 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.2 g; 5 mmol) in N,N-dimethylformamide (20 mℓ), isopropyl-1-iodoethylcarbonate (1.29 g; 5 mmol) was added under ice cooling, followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water and the ethyl acetate layer was collected. The ethyl acetate layer was successively washed with water and a saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 1-(isopropoxycarbonyloxy)ethyl 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate was obtained (yield : 1.43 g; 52.1%). NMR (CDCl 3 , δ) 1.22-1 29(6H,m), 1.26(3H,d,J=5.5Hz), 2.85(6H,s), 3.35,3.48(1H,ABq,J=18.4Hz), 3.36,3.49(1H,ABq, J=18.4Hz), 3.55(2H,s), 4.75-4.88(3H,m), 5.04,5.10 (2H,ABq,J=13.9Hz), 5.71-5.76(1H,m), 6.77-6.82 (1H,m), 6.91(0.5H,q,J=5.5Hz), 6.94 (0.5H,d,J=8.9Hz), 7.19-7.29(5H,m) Example 5 1-(Isopropoxycarbonyloxy) ethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephemcarboxylate hydrochloride In tetrahydrofuran (440 -m ℓ ), 1-(isopropoxycarbonyloxy) ethyl 7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylate hydrochloride (22 g; 47 mmol) was dissolved, to which N,O-bistrimethylsilylacetamide (35 mℓ) was added. To the resulting solution, 2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetic chloride hydrochloride (15.8 g) was gradually added under ice cooling. The reaction mixture was heated tack to room temperature, at which it was stirred for 30 minutes. The reaction mixture was added with ethyl acetate (600 mℓ) , water (40 mℓ) and saturated aqueous sodium chloride solution (25 mℓ) and the organic layer was collected. The organic layer was then washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby the title compound was obtained (yield: 31.5 g; 99%). NMR (CD 3 OD, δ) : 1.27-1.29(6H,m), 1.54(3H,d,J=5.5Hz), 2.23(3H,s), 2.92(6H,d,J=8.4Hz), 3.60(1H,d,J=18Hz), 3.74(1H, dd,J=9Hz,18Hz), 4.81-5.16(3H,m), 5.22(1H,dd, J=5Hz,12Hz), 5.97(1H,dd,5Hz,15Hz), 6.85(0.5H,dd, J=5Hz,10Hz), 6.94(0.5Hz,dd,J=5Hz,10Hz), 7.19(1H,s) Example 6 1-(Isopropoxycarbonyloxy) ethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyiminoacetamidol-3-N,N-dimethylcarbamoyloxymethyl-3-cephemcarboxylate hydrochloride In methanol (108 ℓ), 1-(isopropoxycarbonyloxy)ethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephemcarboxylate (10.8 g; 15.9 mmol), which had been obtained in example 5 was dissolved, to which concentrated hydrochloric acid (8.6 m ℓ ) was added dropwise under ice cooling. After the dropwise addition was completed, the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was added with ethyl acetate (540 mℓ). The organic layer was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was added with isopropyl ether and the resulting solid was collected by filtration, whereby the title compound was obtained (yield: 8 g; 80%). NMR (CD 3 OD, δ): 1.27 1.29(6H,m), 1.54(3H,d,J=5.5Hz), 2.91(3H,s), 2.93(3H,s), 3.57,3.67(1H,ABq,J=14.7Hz), 3.57,3.69 (1H,ABq,J=14.7Hz), 4.78 4.9(2H,m), 5.06(0.5H,d, J=13.6Hz), 5.17(0.5Hz,d,J=13.4Hz), 5.19(0.5H,d, J=5Hz), 5.22(0.5H,d,J=5Hz), 5.91(0.5H,d,J=5Hz), 5.95(0.5H,d,J=5Hz), 6.85(0.5H,q,J=5.5Hz), 6.94(0.5H,q,J=5.5Hz), 6.97(1H,s) Example 7 Benzhydryl 7-formamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate ester Benzhydryl 7-formamido-3-hydroxymethyl-3-cephem-4-carboxylate ester (106 g) and p-nitrophenyl chloroformate (50.4 g) were stirred in tetrahydrofuran (700 mℓ) under ice cooling. To the resulting suspension, pyridine (19.8 g) was added dropwise over 5 minutes. After 35 minutes, the mixture was poured into a mixed solvent of ethyl acetate (1 ℓ) and water (1ℓ). The organic layer was washed twice with water (0.5 mℓ) and once with saturated sodium chloride solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure until its volume was decreased to about 400 mℓ. The residue was gradually poured into isopropyl ether (2 ℓ) and the resulting crystals were collected by filtration, whereby the title compound was obtained (yield: 133 g; 90%). NMR (DMSO-d 6 , δ) : 3.67,3.77(2H, ABq,J=18Hz), 4.91,5.11(2H,ABq,J=12Hz), 5.21(1H,J=4.8Hz), 5.91(1H,dd,J=4.8Hz, 8.5Hz), 6.91(1H,s), 7.2-7.5(12H,m), 8,14(2H,d,J=9Hz), 8.31(2H,d,J=9Hz), 9.11(1H,d,J=8.5Hz) Example 8 7 -Formamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylic acid The compound (133 g), which had been obtained in Example 7, was suspended in dichloromethane (265 mℓ) under stirring. To the suspension, trifluoroacetic acid (200 m ℓ) was added dropwise over 25 minutes under ice cooling. Ten 10 minutes later, the resulting suspension was poured into isopropyl ether (2.5 ℓ). The resulting crystals were collected by filtration and then washed with isopropyl ether, whereby the title compound was obtained (yield 103 g; 97.4%). NMR (DMSO-d 6 , δ): 3.62,3.72(2H,ABq,J=18Hz), 4.94,5.23(2H,ABq, J=12.6Hz), 5.15(1H,J=4.9Hz), 5.81(1H,dd, J=4.9Hz,8.8Hz), 7.56(2H,d,J=9Hz), 8.13(1H,s), 8.30(2H,d,J=9Hz), 9.07(1H,d,J=8.8Hz) Example 9 Benzhydryl 7-thienylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate ester Benzhydryl 7-thienylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate (1.6 g) and p-nitrophenylchloroformate (0.6 g) were treated in a similar manner to Example 7, whereby the title compound was obtained [yield: 2.3 g (stoichiometric)]. NMR (CDCl 3 , δ): 3.43,3.62(2H,ABq,J=19Hz), 4.85(2H,s), 4.97,5.24 (2H,ABq,J=13Hz), 5.01(1H,d,J=4.5Hz), 5.91(1H,dd, J=4.5Hz,9Hz), 6.93 (1H, s), 6.97-7.02(2H,m), 7.24-7.38(11H,m), 7.4'2(2H,d,J=8Hz), 8.26(2H,d,J=8Hz) Example 10 7-Thienylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylic acid The compound (1.4 g), which had been obtained in Example S trifluoroacetic acid (1 mℓ) and anisole (2 mℓ) were stirred for 30 minutes under ice cooling. The reaction mixture was added with isopropyl ether (50 m ℓ ) and the resulting precipitate was collected by filtration, whereby the title compound was obtained (yield: 900 mg; 85%) NMR (CD 3 OD, δ) : 3.57,3.73(2H,ABq,J=19Hz), 3.80(2H,s), 5.06,5.33 (2H,ABq,J=12Hz), 5.09 (1H, d, J=4.5Hz ) , 5.77(1H,d, J=4.5Hz), 6.9-7.0(2H,m), 7.23-7.28(1H,m), 7.46(2H,d,J=8Hz), 8.29(2H,d,J=8Hz) Example 11 Benzhydryl 7-formamido-3-phenoxycarbonyloxymethyl-3-cephem-4-carboxylate In a similar manner to Example 7 except that p-nitrophenyl chloroformate was replaced by phenyl chloroformate, the title compound was obtained (yield 90%) . NMR (DMSO-d 6 , δ) : 3.66,3.75(2H,ABq,J=19Hz), 4.85,5.05(2H,ABq,J-14Hz) 5.21(1H,d,J=4.5Hz), 5.91(1H,dd,J=4.8Hz,8Hz), 6.90 (1H,s), 7,17-7.50(15H,m), 8.14(1H,s), 9.11(1H,d,J=8Hz) Example 12 7-Formamido-3-phenoxycarbonyloxymethyl-3-cephem-4-carboxylic acid The compound, which had been obtained in Example 11, was treated in a similar manner to Example 8 whereby the title compound was obtained (yield 90%). NMR (DMSO-d 6 , δ): 3.61,3.72(2H,ABq,J=18Hz), 4.89,5.19(2H,ABq,J=12Hz) 5.14 (1H,d,J=4.5Hz,8Hz), 7.20-7.45(5H,m), 8.12(1H,s), 9.06(1H,d,J=8Hz) Example 13 Sodium 7-formamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate The compound (103 g), which had been obtained in Example 8, was dissolved in methanol (600 mℓ). Tetrahydrofuran (44 mℓ) containing 22 g of dimethylamine was added dropwise to the resulting solution over 5 minutes under ice cooling. One hour later, the resulting solution was added with sodium acetate (24 g), followed by concentration under reduced pressure. To the residue, isopropyl alcohol (0.8 ℓ) and then isopropyl ether (1.5 ℓ) were added, respectively. The resulting precipitate was collected by filtration. The solid thus obtained was dissolved in methanol (0.5 ℓ). After the crystals were formed, isopropyl ether (1.5 ℓ ) was added and then, the resulting solution was filtered, whereby the title compound was obtained (yield: 72 g; 84%). NMR (DMSO-d 6 , δ): 2.79(6H,s), 3.22,3.46 (2H,ABq,J=17.2Hz), 4.68,4.94 (2H,ABq, J=12.0Hz), 4.96(1H,d,J=4.8Hz), 5.55(1H,dd, J=4.8Hz,9Hz), 8.10(1H,s), 8.93 (1H,d,J=9Hz) Example 14 7-Thienylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylic acid The compound (100 mg), which had been obtained in Example 10, was dissolved in N,N-dimethylformamide (1 mℓ). The resulting solution was added with a 50% aqueous solution of dimethylamine (50 mg) under ice cooling, followed by reaction for 15 minutes. To the reaction mixture, ethyl acetate (50 mℓ) and water (30 mℓ) were added. Then, the organic layer was collected, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was added with isopropyl ether. The resulting solid was collected by filtration, whereby the title compound was obtained (yield: 60 mg; 75 %). NMR (DMSO-d 6 , δ) : 2.82(3H,s), 2.84(3H,s), 3.48,3.60(2H,ABq,J=19Hz), 3.78(2H,s), 4.48,4.99(2H,ABq,J=11Hz), 5.09(1H, d,J=4.5Hz), 5.64 (1H/dd,J=4.5Hz/8Hz), 6.92-7.00(2H,m), 7.38(1H,d,J=3Hz), 9.12(1H,d,J=8Hz) Example 15 Sodium 7-formamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate The compound, which had been obtained in Example 12, was treated in a similar manner to Example 13 whereby the title compound was obtained (yield: 35%). The compound obtained in this example conformed with the compound obtained in Example 13 in all physicochemical properties such as HPLC (high performance liquid chromatography), TLC (thin-layer chromatography) and NMR spectrum.

Claims: A compound represented by the following formula (9): wherein Y represents a hydrogen atom, a methyl or ethyl group, a halogen atom or a nitro group, and wherein R 5 represents an amino group or an amino group protected by a group selected from alkanoyl groups, alkoxycarbonyl groups, aralkoxycarbonyl groups, aroyl groups, aralkanoyl groups, aryloxyalkanoyl groups, heterocyclic carbonyl groups, heterocyclic glyoxyloyl groups and heterocyclic alkanoyl groups or a salt thereof.

Inventors: KAMATA ATSUSHI, KATSU KANEMASA, KOMATU YUUKI, MACHIDA YOSHIMASA, NEGI SHIGETO, SUGIYAMA ISAO, TSURUOKA AKIHIKO, YAMANAKA MOTOSUKE, KAMATA, ATSUSHI, KATSU, KANEMASA, KOMATU, YUUKI, MACHIDA, YOSHIMASA, NEGI, SHIGETO, SUGIYAMA, ISAO, TSURUOKA, AKIHIKO, YAMANAKA, MOTOSUKE
Applicants: EISAI CO LTD, EISAI CO., LTD.
Application year: 1991
Main classification: C07D501
IPC codes: C07D501, A61K31, A61P31