WO1994029320A1 - Compose de cephalosporine, procede d'obtention de ce compose et compose intermediaire - Google Patents

Compose de cephalosporine, procede d'obtention de ce compose et compose intermediaire Download PDF

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Publication number
WO1994029320A1
WO1994029320A1 PCT/JP1994/000864 JP9400864W WO9429320A1 WO 1994029320 A1 WO1994029320 A1 WO 1994029320A1 JP 9400864 W JP9400864 W JP 9400864W WO 9429320 A1 WO9429320 A1 WO 9429320A1
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compound
group
acid
formula
general formula
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PCT/JP1994/000864
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English (en)
Japanese (ja)
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Masayasu Kasai
Satoru Hatano
Ken-Ichi Nishimura
Nobuharu Kakeya
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Kyoto Pharmaceutical Industries, Ltd.
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Priority to AU68163/94A priority Critical patent/AU6816394A/en
Publication of WO1994029320A1 publication Critical patent/WO1994029320A1/fr

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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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • Cephalosporin compound its production method and intermediate compound
  • the present invention relates to a novel cephalosporin compound useful as a pharmaceutical or the like, a pharmaceutically acceptable salt thereof, a production method thereof, and a medicinal use thereof, particularly an agent for preventing and treating infectious diseases. Further, the present invention relates to an intermediate compound for producing the cephalosporin compound.
  • cephalosporin compounds as therapeutic agents for infectious diseases has been remarkable, and various cephalosporin compounds with strong antibacterial activity and a broad antibacterial spectrum have been developed, but the emergence of resistant bacteria and disease The emergence of cephalosporin compounds having distinctive antibacterial properties and antibacterial spectrum according to the situation and the like is further expected. Further, conventional cephalosporin compounds have poor absorbability from the digestive tract, and there is a demand for cephalosporin compounds suitable for oral administration.
  • the present inventors have conducted various studies to achieve the above object, and found that the novel cephalosporin compound represented by the following general formula (I) and a pharmaceutically acceptable salt thereof have excellent antibacterial properties. It has excellent gastrointestinal absorption and is extremely useful as a prophylactic / therapeutic agent for infectious diseases.It also establishes a method for producing the compound and is used for the production of the compound. The discovery of a novel intermediate compound has led to the completion of the present invention.
  • the present invention firstly provides a compound represented by the general formula (I):
  • R 1 represents a hydrogen atom, a lower alkyl group or a hydroxy protecting group
  • the R 2 is hydrogen atom or a lower alkyl group
  • R 3 is the radical (formula of the formula one C OR 5
  • R 5 is A hydrogen atom, a lower alkyl group which may have a substituent, or a lower alkenyl group.)
  • a group represented by the formula: C0 2 R 6 a group represented by the formula: S0 2 R 6 , a formula: -C0NHR
  • a group represented by 6 (wherein, R 6 represents a lower alkyl group), or a group represented by the formula C0NH 2
  • R 4 represents a carboxyl group or an esterified carboxyl group.
  • cephalosporin compound (I) A cephalosporin compound [hereinafter referred to as a cephalosporin compound (I)] and a pharmaceutically acceptable salt thereof.
  • the present invention provides, secondly, a compound represented by the general formula (II):
  • R 2 , R 3 and R 4 are each as defined above.
  • a 7-aminocephalosporin compound [hereinafter, referred to as compound (II)] and a salt thereof.
  • the present invention relates to (1) a compound (II) and a compound represented by the general formula (III):
  • R 1 has the same meaning as described above, and R 7 represents a hydrogen atom or an amino protecting group.
  • R 1 , R 2 , R 4 and R 7 are each as defined above.
  • R 5 is as defined above.
  • R 6 has the same meaning as described above, and X represents a halogen atom.
  • R 2 , R 3 , R 4 and R 7 are each as defined above.
  • R 1 is as defined above.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the cephalosporin compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient, a prophylactic and therapeutic agent for infectious diseases (particularly a prophylactic and therapeutic agent for bacterial infection).
  • a prophylactic and therapeutic agent for infectious diseases particularly a prophylactic and therapeutic agent for bacterial infection.
  • the lower alkyl group for R 1 , R and R 6 preferably has 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and may be linear or branched, for example, methyl, ethyl, propyl Isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and the like.
  • lower alkyl group which may have a substituent for R 5
  • lower alkyl group moiety are the same as defined above, also substituents portion Shiano group, hydroxy group, lower alkoxy group, a lower alkylthio group, Preference is given to cyano-substituted lower alkylthio groups, halogen-substituted lower alkylthio groups, lower alkanoyl groups and the like.
  • the lower alkoxy group preferably has 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and may be either linear or branched, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy. , T-butoxy, pentyloxy, hexyloxy and the like.
  • the lower alkyl moiety in the lower alkylthio group, the cyano-substituted lower alkylthio group and the halogen-substituted lower alkylthio group preferably has 1 to 6 carbon atoms, more preferably 1 to 3, and has a straight-chain or branched chain. Any one may be used.
  • halogen in the halogen-substituted lower alkylthio group examples include fluorine, chlorine, bromine and iodine.
  • the lower alkanoyl group preferably has 2 to 6 carbon atoms, more preferably 2 to 3 carbon atoms, and may be linear or branched, and may be, for example, acetyl, propionyl, butyryl, isobutylyl, norilyl, And isovaleryl, vivaloyl, hexanoyl and the like.
  • examples of the lower alkyl group having a substituent include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl, 2-cyanopropyl, 3-cyanopropyl, hydroxymethyl, 1-hydroxyethyl, methoxymethyl, Examples include ethoxymethyl, 1-methoxethyl, 2-methoxethyl, methylthiomethyl, ethylthiomethyl, cyanomethylthiomethyl, difluoromethylthiomethyl, acetylmethyl, propionylmethyl, and the like.
  • the lower alkenyl group for R 5 preferably has 2 to 6 carbon atoms, more preferably 2 to 3 carbon atoms, and may be either linear or branched, for example, vinyl, aryl, 1-propenyl. , Isopropenyl, butenyl, isobutenyl, pentenyl And hexenyl.
  • the ester in the carboxyl group esterified is a carboxyl group-protecting group or an ester that is easily hydrolyzed in a living body (that easily hydrolyzes in a living body to give a free carboxyl group).
  • carboxyl-protecting groups include t-butyl, t-amyl, benzyl, P-nitrobenzyl, p-methoxybenzyl, benzhydryl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methylthiomethyl, Trityl, 2,2,2-trichloroethyl, trimethylsilyl, dimethylsilyl, diphenylmethoxybenzenesulfonylmethyl, dimethylaminoethyl, etc.
  • Esters that are easily hydrolyzed in vivo include, for example, substituents Aryl group (eg, phenyl, tolyl, xylyl, indanyl, etc.), 1-alkanoyloxyalkyl group, 1-alkoxycarbonyloxyalkyl group, phthalidyl group, 5-methyl-1,3- Dioxolen-2-one-4-ylmethyl group and the like. That.
  • the alkanoyl moiety in the 1-alkanoyloxyalkyl group preferably has 2 to 10 carbon atoms, more preferably 2 to 7 carbon atoms, and may be linear, branched, or cyclic, and the alkyl moiety is It preferably has 1 to 3 carbon atoms, more preferably 1 or 2.
  • Such groups include, for example, acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, bivaloyloxymethyl, n-valeryloxymethyl, 2-methylbutyryloxymethyl, isopallyloxymethyl, n -Hexanoyloxymethyl, 3-methylvaleryloxymethyl, Neohexanoyloxymethyl, 2-methylhexanoyloxymethyl, 2,2-dimethylbutyryloxymethyl, Jethylacetoxy Methyl, dipropylacetoxymethyl, 2,2-dimethylvaleryloxymethyl, neoheptanyloxymethyl, cyclohexanecarbonyloxymethyl, cyclohexylacetoxymethyl, 1-acetoxetil, 1_propionylo Quixetil, 1-n-butyryloxexetil, 1-isobutyryl Kishechiru, 1-n-valeryl Ruo key shell chill, 1 Bibaroiruokishi Echir
  • the alkoxy moiety in the 1-alkoxycarbonyloxyalkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 7 carbon atoms, and may be any of linear, branched or cyclic, and The alkyl moiety preferably has 1 to 3 carbon atoms, more preferably 1 or 2.
  • Such groups include, for example, 1-methoxycarbonyloxetyl, 1-ethoxycarbonyloxetyl, 1-n-propoxycarbonyloxyl, 1-isopropoxycarbonyloxyl, n-butoxycarbonyloxyl, 1-sec-butoxycarbonyloxyl, 1-t-butoxycarbonyloxyl, 1-pentyloxycarbonyloxyl, 1-cyclohexyloxycarbonylloxyl Chill and the like.
  • hydroxy protecting group for R 1 and the amino protecting group for R 7 those used for this purpose in the field of lactam synthesis and peptide synthesis are conveniently adopted. Is exemplified.
  • Hydroxy protecting groups include, for example, formyl, acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloromouth ethoxyquincarbonyl, benzoyl, trityl , Trimethylsilyl, tetrahydroviranyl, 1-methyl-11-methoxyl and the like.
  • amino protecting group examples include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and diphenylmethylo.
  • halogen atom in X examples include fluorine, chlorine, bromine and iodine.
  • the cephalosporin compound (I) may form a pharmaceutically acceptable salt at its amino group or carboxyl group.
  • An acid addition salt is formed at the amino group, but the acid for forming such an acid addition salt is not particularly limited as long as it can form a salt with the amino group and is a pharmaceutically acceptable acid. Absent.
  • acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, and toluenesulfonic acid.
  • Examples of the salt at the carboxyl group include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), and organic base salts (eg, triethylamine salt, dicyclohexylamide). Salts, pyridine salts, etc.).
  • alkali metal salts eg, sodium salt, potassium salt, etc.
  • alkaline earth metal salts eg, calcium salt, magnesium salt, etc.
  • organic base salts eg, triethylamine salt, dicyclohexylamide. Salts, pyridine salts, etc.
  • the salt of compound (II) is also preferably a pharmaceutically acceptable salt as described above.
  • cephalosboline compound (I) represented by the formula (I) there are geometrical isomers of syn-form and anti-form in the 7-position side chain, but the compound is preferably a syn-form.
  • cephalosporin compound (I) of the present invention and pharmaceutically acceptable salts thereof, particularly preferred are:
  • cephalosporin compound (I) and a pharmaceutically acceptable salt thereof are produced, for example, as follows.
  • the compound (III) is used in the present reaction (acylation reaction) as a free carboxylic acid or as a reactive derivative thereof, and any embodiment is included in the present invention. That is, as a free acid or a salt of sodium, potassium, calcium, triethylamine, pyridine or the like, or an acid halide thereof (an acid chloride, an acid promide, etc.), an acid anhydride, a mixed acid anhydride [substituted phosphoric acid (dialkylphosphoric acid) Acid), alkyl carbonic acid (monoethyl carbonic acid, etc.), active amides (amides with imidazole, etc.), and esters (cyanomethyl esters, 4-ditrophenyl esters, etc.) as reactive derivatives. Is subjected to a chemical reaction.
  • the reaction is preferably performed in the presence of a condensing agent.
  • the condensing agent include N, ⁇ , ⁇ '-disubstituted carbodiimides such as N'dicyclohexylcarbodiimide; 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, ⁇ -cyclohexyl - ⁇ '- Carbodiimide compounds such as morpholinoethyl carbodiimide, ⁇ -cyclohexyl- (4- acetylaminocyclohexyl) carbodiimide; ;, ⁇ '-carbonyldiimidazole, ⁇ , ⁇ '-thionyldiimidazole Dehydrating agents such as azolide compounds are used. When these condensing agents are used, the reaction is thought to proceed via a reactive derivative of the carboxy
  • This reaction is usually performed in an inert solvent.
  • the solvent include water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, ⁇ , ⁇ -dimethylformamide, pyridine, and the like. Mixtures are mentioned.
  • This reaction is preferably performed at room temperature to under cooling (_20 ° C to 0 ° C).
  • Compound (II) has the general formula (XI)
  • R 2 and R 4 have the same meanings as above, and R 8 represents a hydrogen atom or an amino protecting group.
  • compound (XI) Using the compound [hereinafter referred to as compound (XI)] or a salt thereof according to the method (1) to (5) of the above-mentioned method (2) for producing the cephalosporin compound (I). sulfoxidation performs reduction of the sulfoxide can be produced by a method of removing Amino protecting group R 8 in accordance with the.
  • the reaction is usually carried out under cooling at ⁇ 20 to 40, preferably ⁇ 20 to 0 ° C., and a solvent that does not inhibit the reaction (eg, water, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, benzene, acetic acid) Methyl, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulfoxide, etc., and mixtures thereof).
  • a solvent that does not inhibit the reaction eg, water, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, benzene, acetic acid
  • amino-protecting group for R 8 of compound (XI) examples include known amino-protecting groups, for example, phenylacetyl, phenoxyacetyl, 2-chenylacetyl, 2-furylacetyl, D-5-amino-5- Carboxyvaleryl, BOC; trityl, phthaloyl, 0-hydroxybenzylidene and the like.
  • R 8 in compound (XI) is preferably an amino-protecting group.
  • R 8 in compound (XI) is preferably an amino-protecting group.
  • a compound in which the amino group at position 7 in general formula (II) is protected by a reaction using compound (XI) can be deprotected by a means known per se.
  • the means for deprotecting the amino-protecting group include the following methods. That is, the deprotection of phenylacetyl, phenoxyacetyl, 2-chenylacetyl, 2-furylacetyl, D-5-amino-5-carboxyvaleryl, etc. can be performed, for example, by iminochlorination with phosphorus pentachloride.
  • Deprotection of BOC, trityl, 0-hydroxybenzylidene, etc. includes, for example, treatment with an acid (hydrochloric acid, formic acid, trifluoroacetic acid, etc.).
  • Deprotection of phthaloyl, etc. Examples include the Ing-Manske method using hydrazine.
  • This reaction is usually carried out at a temperature of 120 to 40 ° C, preferably at a temperature of 120 to 0 ° C, under a solvent that does not inhibit the reaction (e.g., water, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, Benzene, ethyl acetate, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulfoxide, etc., and mixtures thereof).
  • a solvent that does not inhibit the reaction e.g., water, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, Benzene, ethyl acetate, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulfoxide, etc., and mixtures thereof).
  • R 1 , R 4 and R 7 have the same meanings as described above, and Y represents a hydroxy group or a halogen atom (fluorine, chlorine, bromine or iodine). ]
  • R 2 and R 6 are each as defined above.
  • This reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, acetonitrile, dioxane, tetrahydrofuran, alcohol or other solvents that do not adversely affect the reaction, or a mixture of these with water.
  • a solvent such as dimethylformamide, dimethylacetamide, acetonitrile, dioxane, tetrahydrofuran, alcohol or other solvents that do not adversely affect the reaction, or a mixture of these with water.
  • the time required for the reaction is usually 30 minutes to 10 hours.
  • the reaction temperature is not particularly limited, but is usually room temperature to 60 ° C.
  • Compound (VI) can be prepared by a known method, that is, the compound represented by the general formula (XVI) X— CH 2 -C ⁇ CH 2 -C0 2 H (XVI)
  • the compound (II) is acylated with a compound [hereinafter, referred to as compound (XVI)] or a reactive derivative thereof, and then nitrosated or oxidized.
  • This reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, acetonitrile, dioxane, tetrahydrofuran, alcohol or other solvents that do not adversely affect the reaction, or a mixture of these with water.
  • a solvent such as dimethylformamide, dimethylacetamide, acetonitrile, dioxane, tetrahydrofuran, alcohol or other solvents that do not adversely affect the reaction, or a mixture of these with water.
  • the time required for the reaction is usually 30 minutes to 10 hours.
  • the reaction temperature is not particularly limited, but is usually room temperature to 60 ° C.
  • compound (XVII) (Hereinafter referred to as compound (XVII)) or a reactive derivative thereof, which can be produced by a method of acylating compound (II).
  • cephalosporin compound (I) or compound (II) obtained by each of the above methods when R 4 is a carboxyl group or a salt thereof, a reactive derivative thereof (for example, sodium salt, R 4 is an esterified carboxyl group by performing esterification by a known method, such as alkaline metal salts such as calcium salts, alkaline earth metal salts such as calcium salts, triethylamine salts, pyridine salts, etc. It can be compound (I) or compound (II).
  • cephalosporin compound (I) and the pharmaceutically acceptable salt thereof obtained by each of the above methods usually have a protecting group.
  • a protecting group for example, formyl, BOC, Trityl, tetrahydroviranyl, etc. are decomposed with an acid such as hydrochloric acid or trifluoroacetic acid), decomposition with a base (for example, dichloroacetyl, trifluoroacetyl, etc.
  • a base such as sodium hydroxide or sodium bicarbonate
  • hydrazine for example, phthaloyl and the like are decomposed with hydrazine
  • catalytic reduction for example, benzyl and benzyloxycarbonyl are decomposed by hydrogenation using palladium-carbon or the like as a catalyst.
  • cephalosporin compound (I) can be converted to a pharmaceutically acceptable salt thereof by a method known per se.
  • cephalosporin compound (I) and a pharmaceutically acceptable salt thereof can be collected at an arbitrary purity by using a purification method known per se, for example, a method such as extraction, chromatography, or recrystallization. .
  • the cephalosporin compound (I) wherein R 4 is a carboxyl group and a pharmaceutically acceptable salt thereof have excellent antibacterial activity, and include Staphylococcus aureus, Staphylococcus aepidermidis and Staphylococcus aureus.
  • Gram-positive bacteria such as (Staphylococcus epidermidis), Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Proteus mirabill of Proteus mirabilis It has extremely good antibacterial activity against any of the negative bacteria.
  • cephalosporin compound (I) in which R 4 is an esterified carboxyl group and a pharmaceutically acceptable salt thereof have good absorption from the gastrointestinal tract, and after absorption, are hydrolyzed by in vivo enzymes. And Cephalosporin compound (I) wherein R 4 is a carboxyl group, and pharmaceutically acceptable salts thereof.
  • the cephalosporin compound (I) and a pharmaceutically acceptable salt thereof are valuable antibacterial agents that have significantly improved antibacterial activity against Gram-positive bacteria while maintaining their antibacterial activity against Gram-negative bacteria. Moreover, it has extremely low toxicity.
  • the cephalosporin compound (I) and its pharmaceutically acceptable salts It is useful as an agent for preventing and treating diseases, especially for preventing and treating bacterial infections.
  • the infectious disease preventive / therapeutic agents include diseases caused by bacteria in, for example, warm-blooded animals including humans (dogs, cats, cows, horses, rats, mice, etc.) (eg, purulent diseases, respiratory infections, biliary tract infections). Disease, urinary tract infection, etc.).
  • cephalosporin compound (I) and a pharmaceutically acceptable salt thereof can be used alone or as a pharmaceutical composition, and can be used as an agent for preventing and treating infectious diseases.
  • the cephalosporin compound (I) in which R 4 is a carboxyl group and a pharmaceutically acceptable salt thereof can be prepared by a known method together with a usual combination drug together with a rectal composition (for example, a suppository or a storage enema) or an injection. And can be administered parenterally.
  • a rectal composition for example, a suppository or a storage enema
  • an injection an aqueous solvent or a non-aqueous solvent (for example, distilled water for injection, physiological saline, Ringer's solution, vegetable oil, propylene glycol, etc.) is prepared by a known means to obtain a solution or suspension.
  • cephalosporin compound (I), in which R 4 is an esterified carboxyl group, and a pharmaceutically acceptable salt thereof are rapidly absorbed into blood by oral administration, and R 4 as a metabolite thereof
  • a high blood concentration of the cephalosporin compound (I) or a pharmaceutically acceptable salt thereof, which is a carboxyl group, is obtained, and the high blood concentration lasts for a long time.
  • cephalosporin compound (I) in which R 4 is an esterified carboxyl group has a pharmaceutically acceptable salt, thereby significantly increasing the solubility in the digestive tract and further improving the absorption efficiency. , Absorption is further enhanced.
  • cephalosporin compounds wherein R 4 is an esterified carboxyl group (I) or infection consisting pharmaceutically acceptable salt thereof prophylactic, therapeutic agent is excellent as by connexion above the orally administered It is usually administered orally as an oral preparation.
  • the infectious disease preventive / therapeutic agent can be produced by diluting with a pharmaceutical excipient or the like according to a method known per se.
  • a pharmaceutical excipient for example, starch, lactose, sugar, calcium carbonate, calcium phosphate and the like are used.
  • an organic acid to the agent for preventing and treating infectious diseases.
  • the organic acid is not particularly limited as long as it is pharmaceutically acceptable.
  • examples include maleic acid, fumaric acid, tartaric acid, citric acid, succinic acid, lingic acid, oxalic acid, mandelic acid, malonic acid, benzoic acid, etc.
  • Organic carboxylic acids and the like are preferred.
  • the amount of the organic acid to be added is usually 0.01 to 20 mol per 1 mol of the cephalosporin compound (I) wherein R 4 is an esterified carboxyl group or a pharmaceutically acceptable salt thereof. And preferably 0.02 to 2 mol.
  • the infectious disease preventive / therapeutic agent may further contain other additives, if desired.
  • a binder eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.
  • a lubricant Preferred additives include, for example, magnesium stearate, talc, etc., and disintegrants (eg, carboxymethylcellulose cellulose, talc, etc.).
  • the mixture is formulated into a dosage form suitable for oral administration such as capsules, tablets, fine granules, granules, dry syrup, etc. Infectious disease prevention and treatment products are manufactured.
  • the dosage of the cephalosporin compound (I) and its pharmaceutically acceptable salt will vary depending on the subject of administration, symptoms, and the like. Oral administration of about 40 mg / kg body weight about 1 to 4 times a day.
  • cephalosporin compound (I) and a pharmaceutically acceptable salt thereof may contain other antibacterial active substances such as antibacterial agents (penicillins, aminoglucosides, cephalosporins, etc.) or systemic symptoms due to bacterial infection. May be used in combination with anti-pyretics, analgesics, anti-inflammatory agents, etc.
  • Example 1 (2) 7.0 g of the compound of Example 1 (2) was dissolved in a mixture of 50 ml of methanol and 14 ml of N, N-dimethylformamide, and triethylamine 0.83 ml at 5 ° C. Then, 4.95 ml of a 10% hydrazine hydranol solution was added, and the mixture was stirred at the same temperature for 15 minutes. Then, 2.34 g of formic acid N-hydroxysuccinimide ester was added, and the mixture was stirred at the same temperature for 30 minutes, and methanol was distilled off under reduced pressure.
  • Tetrahydrofuran was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with ethyl benzene-monoacetate, and the solvent of the target fraction was distilled off under reduced pressure to give 7-t-butoxycarbonylamine 3-chloromethyl- 3-Sefmu 4 3% g of p-methoxybenzyl ester of rubonic acid was obtained.
  • the residue was dissolved in 200 ml of ethyl acetate, washed with 200 ml of 10% citric acid-1.5% saline, and the aqueous layer was further extracted with 100 ml of ethyl acetate.
  • the ethyl acetate layers were combined, extracted twice with 100% aqueous 5% sodium bicarbonate, acidified with citric acid, and extracted twice with 200 ml of ethyl acetate.
  • the ethyl acetate layer was washed with 100 ml of saturated saline and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure.
  • IR (nujol, cm _1) 3580 , 3270, 3170, 1800, 1720
  • Example 5 0.92 g of the compound of Example 5 was suspended in 18 ml of methylene chloride, 2.39 g of N-trimethylsilyl acetoamide was added, and the mixture was stirred at 30 ° C. for 30 minutes. And dissolved uniformly. After cooling at 110 ° C, the above solution was added dropwise and stirred at the same temperature for 30 minutes. After washing with 100 ml of 100% citric acid aqueous solution, the aqueous layer was further extracted with 500 ml of methylene chloride, and the methylene chloride layers were combined, washed with 100 ml of saturated saline, and dried over anhydrous sodium sulfate. And dried.
  • the obtained aqueous layer was acidified with citric acid, extracted twice with 200 ml of ethyl acetate, washed with saturated saline and dried over anhydrous sodium sulfate. The resulting solution was added diphenyl di ⁇ zone methane 5.
  • Example 9 (1) To 3.6 g of the compound, 3.6 ml of anitool and 10.8 ml of trifluoroacetic acid were added, and the mixture was stirred at 5 ° C. for 30 minutes. The mixture was poured into 300 ml of isopropyl ether, the precipitate was collected by filtration, and 7- (2-phenylacetoamide) -13-methylsulfonylaminooxymethyl-3-cefume 4 rubonic acid 2.
  • Example 5 7.2 g of the compound of (3) was dissolved in 100 ml of methanol and 50 ml of N, N-dimethylformamide, and 2.5 ml of triethylamine was added at 5 ° C. 11.4 ml of a 0% hydrazine hydratomer solution was added, and the mixture was stirred at the same temperature for 30 minutes. 13 ml of 35% formaldehyde was added dropwise, and after stirring at the same temperature for another 15 minutes, methanol was distilled off under reduced pressure.
  • the residue was dissolved in 200 ml of ethyl acetate, washed with 150 ml of 10% citric acid-5% saline, and the aqueous layer was further extracted with 100 ml of ethyl acetate.
  • the ethyl acetate layers were combined, extracted twice with 100 ml of 5% aqueous sodium bicarbonate, made acidic with citric acid, and extracted twice with 200 ml of ethyl acetate.
  • the ethyl acetate layer was washed with 100 ml of saturated saline and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure.
  • N-formyloxysuccinimide (1.93 g) was added, and the mixture was stirred at the same temperature for 30 minutes, washed with 100% citric acid solution (100 ml) and saturated saline solution (100 ml), and dried. It was dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-benzene. The solvent of the target fraction was distilled off under reduced pressure to give 7-t-butoxycarbonylamino-3- ( N-methyl-N-formyl) aminooxymethyl-3-cef-4-carboxylic acid benzhydryl ester 4.5 g was obtained.
  • the compounds of Examples 16 and 17 are produced according to any of the methods of Examples 1 to 15.
  • an antibacterial test and an oral absorption test were conducted as follows.
  • the minimum inhibitory concentrations (MIC) of the compound of the present invention and the control compound against various bacteria were measured. Table 1 shows the results.
  • mice The serum concentration of the hydrolyzed compound when 2 OmgZkg of the compound of the present invention was orally administered to mice (4 mice per group) was determined by a paper disk bioassay method using Escherichia coli as a test bacterium. Table 2 shows the results.
  • a tablet having the following composition is produced by a usual method.
  • a tablet having the following composition is produced by a usual method.
  • a tablet having the following composition is produced by a usual method.
  • Example 15 The compound of 15 and tartaric acid are added and mixed, and a capsule is produced according to a usual capsule filling method.
  • Fine granules having the following composition are produced by a usual method.
  • Example 15 Compound 62.5mg titer

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

Abstract

Composé de céphalosporine représenté par la formule générale (I) ou sel pharmaceutiquement acceptable de ce composé, procédé d'obtention et utilisation médicale de ce composé, notamment pour la prévention ou le traitement des maladies infectieuses. Dans cette formule chaque symbole est tel que défini dans les spécifications. Composé ou sel de composé de 7-aminocéphalosporine, représenté par la formule générale (II), dans laquelle chaque symbole est tel que défini dans les spécifications. Le composé de céphalosporine et son sel se distinguent par leur activité antibactérienne contre les bactéries gram-positives et gram-négatives ainsi que par leur facilité d'absorption par le tube digestif, et se révèlent ainsi utiles pour la prévention ou le traitement de certaines maladies infectieuses. Ce composé de 7-aminocéphalosporine et son sel sont de nouveaux composés intermédiaires utilisables pour la production du composé de céphalosporine sus-visé.
PCT/JP1994/000864 1993-06-04 1994-05-30 Compose de cephalosporine, procede d'obtention de ce compose et compose intermediaire WO1994029320A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68163/94A AU6816394A (en) 1993-06-04 1994-05-30 Cephalosporin compound, process for producing the same, and intermediate compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5134953A JPH06345775A (ja) 1993-06-04 1993-06-04 セファロスポリン化合物、その製造法および中間体化合物
JP5/134953 1993-06-04

Publications (1)

Publication Number Publication Date
WO1994029320A1 true WO1994029320A1 (fr) 1994-12-22

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Application Number Title Priority Date Filing Date
PCT/JP1994/000864 WO1994029320A1 (fr) 1993-06-04 1994-05-30 Compose de cephalosporine, procede d'obtention de ce compose et compose intermediaire

Country Status (3)

Country Link
JP (1) JPH06345775A (fr)
AU (1) AU6816394A (fr)
WO (1) WO1994029320A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9975905B2 (en) 2013-03-12 2018-05-22 Gladius Pharmaceuticals Corporation Derivatized 3-styryl-cephalosporins
US10239890B2 (en) 2007-10-09 2019-03-26 Gladius Pharmaceuticals Corporation Broad spectrum beta-lactamase inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100400498B1 (ko) * 2000-11-16 2003-10-08 씨제이 주식회사 세펨 유도체 또는 그 염의 신규한 제조방법

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6216486A (ja) * 1985-07-16 1987-01-24 Teijin Ltd ３−ヨ−ドメチルセフアロスポリン化合物の製造法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6216486A (ja) * 1985-07-16 1987-01-24 Teijin Ltd ３−ヨ−ドメチルセフアロスポリン化合物の製造法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10239890B2 (en) 2007-10-09 2019-03-26 Gladius Pharmaceuticals Corporation Broad spectrum beta-lactamase inhibitors
US9975905B2 (en) 2013-03-12 2018-05-22 Gladius Pharmaceuticals Corporation Derivatized 3-styryl-cephalosporins
US11028103B2 (en) 2013-03-12 2021-06-08 Gladius Pharmaceuticals Corporation Derivatized 3-styryl-cephalosporins

Also Published As

Publication number Publication date
AU6816394A (en) 1995-01-03
JPH06345775A (ja) 1994-12-20

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