WO1998058933A1 - Composes de cephalosporine, utilisation de ces derniers et composes intermediaires de ces derniers - Google Patents

Composes de cephalosporine, utilisation de ces derniers et composes intermediaires de ces derniers Download PDF

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Publication number
WO1998058933A1
WO1998058933A1 PCT/JP1998/002714 JP9802714W WO9858933A1 WO 1998058933 A1 WO1998058933 A1 WO 1998058933A1 JP 9802714 W JP9802714 W JP 9802714W WO 9858933 A1 WO9858933 A1 WO 9858933A1
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Prior art keywords
vinylthio
group
carboxylate
amino
methylthiazol
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PCT/JP1998/002714
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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 AU80350/98A priority Critical patent/AU8035098A/en
Publication of WO1998058933A1 publication Critical patent/WO1998058933A1/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

  • the present invention relates to a novel cephalosporin compound or a pharmaceutically acceptable salt thereof useful as an agent for preventing or treating bacterial infections, a pharmaceutical composition containing the compound as an active ingredient, and the cephalosporin compound.
  • the present invention relates to an intermediate compound for production or a salt thereof.
  • cephalosporin compounds having a strong antibacterial activity and a broad antibacterial spectrum have been developed as therapeutic agents for infectious diseases.
  • the emergence of new resistant bacteria and the emergence of cephalosporin compounds having antibacterial properties and antibacterial spectrum according to disease conditions are expected.
  • conventional cephalosporin compounds have poor absorption from the digestive tract and are only administered clinically as injections. Oral preparations are easier and easier to administer than injections, and their clinical utility is extremely high. Therefore, the development of a cephalosporin compound having a strong antibacterial activity and a broad antibacterial spectrum and having excellent gastrointestinal absorption properties and suitable for oral administration has been strongly desired.
  • the present inventors have conducted intensive studies to find an injectable and oral cephalosporin compound having a strong antibacterial activity and a broad antibacterial spectrum.
  • novel cephalosporin compound represented by (I) or a pharmaceutically acceptable salt thereof has a sufficiently strong antibacterial property, is extremely useful as an antibacterial agent for injection, and a prodrugized compound is excellent. It has a good gastrointestinal absorption and is extremely useful as an oral antibacterial agent. Furthermore, they have found a novel intermediate compound to be used for producing the compound, and have completed the present invention.
  • cephalosporin compound and the pharmaceutically acceptable salt thereof of the present invention are as described below.
  • R 1 represents a hydrogen atom or an amino protecting group
  • R 2 represents a hydrogen atom, a lower alkyl group or a hydroxy protecting group
  • R 3 represents a carboxyl group which may be esterified
  • R 4 represents a substituent.
  • a thiazolyl group which may be present) or a pharmaceutically acceptable salt thereof.
  • cephalosporin compound or a pharmaceutically acceptable salt thereof according to the above (1) which is selected from the group consisting of 3-cefum-4-carboxylic acid.
  • a pharmaceutical composition comprising the cephalosporin compound of (1) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the cephalosporin compound of the above (1), wherein R 3 is an esterified carboxyl group, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition c of the above (7) which is a preventive / therapeutic agent for infectious disease
  • R 3 represents a carboxyl group which may be esterified, and R 4 represents a thiazolyl group which may have a substituent) or a salt thereof.
  • amino protecting group for R 1
  • those used in the field of S-lactam synthesis and peptide synthesis are conveniently used.
  • Benzyloxycarbonyl group diphenylmethyloxycarbonyl group, methoxymethylcarbonyl group, methoxymethyloxycarbonyl group, trimethylsilyl group, 2,2,2-trichloroethoxycarbonyl group, 2-methylsulfonylethyl Methoxycarbonyl group, t-butoxycarbonyl group (hereinafter, referred to as “BOC”), trityl group and
  • the “lower alkyl group” for R 2 is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group Group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, hexyl group, isohexyl group, neohexyl group, and the like.
  • hydroxy protecting group for R 2, those used in the field of / S-lactam synthesis and peptide synthesis are conveniently used. Specifically, formyl, acetyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 2,2,2- Ethoxycarbonyl group, benzoyl group, trityl group, trimethylsilyl group, tetrahydrovinylyl group, 1-methyl-1-methoxyl group, etc., and preferably acetyl group, trityl group, tetrahydroviranyl group and It is a methyl-1-methoxyl group.
  • the ester of the "optionally esterified carboxyl group" in R 3 is- Carboxyl-protecting group, or an ester that is hydrolyzed in vivo (which is easily hydrolyzed in vivo to give a free carboxylic acid group and is hydrolyzed in blood), etc. .
  • R 3 is an ester hydrolyzed in vivo
  • prodrugs which are easily absorbed from the gastrointestinal tract by oral administration and are excellent after being hydrolyzed. Demonstrates antibacterial properties.
  • the “protecting group for carboxyl group” includes, for example, t-butyl group, t_amyl group, benzyl group, p-methoxybenzyl group, p-methoxybenzyl group, benzhydryl group, p-nitrophenyl group, A methoxymethyl group, an ethoxymethyl group, a benzyloxymethyl group, a methylthiomethyl group, a trityl group, a 2,2,2-trichloroethyl group, a trimethylsilyl group, a diphenylmethoxybenzenesulfonylmethyl group, and a dimethylaminoethyl group.
  • Preferred are a p-nitrobenzyl group, a p-methoxybenzyl group and a benzylhydryl group.
  • Esters that are hydrolyzed in vivo include aryl groups which may have a substituent (eg, phenyl, tolyl, xylyl, indanyl, etc.), 1-alkanoyl A xyalkyl group, a monoalkoxycarbonyloxyalkyl group, a phthalidyl group and a 5-methyl-2-oxo-1,3-dioxolen-14-ylmethyl group, and preferably a monoalkanoyloxyalkyl group A 1-alkoxycarbonyloxyalkyl group and a 5-methyl-2-oxo-1,3-dioxolen-14-ylmethyl group.
  • aryl groups which may have a substituent (eg, phenyl, tolyl, xylyl, indanyl, etc.), 1-alkanoyl A xyalkyl group, a monoalkoxycarbonyloxyalkyl group, a phthalidyl group
  • the “optionally substituted aryl group” is preferably an unsubstituted or substituted aryl group which may be substituted with 1 to 3 substituents, and the substituents may be the same or different. Is also good. Specific examples of the substituent include an alkyl group having 1 to 6 carbon atoms such as a methyl group and an ethyl group.
  • the number of carbon atoms of the alkanoyl moiety in the “1-alkanoyloxyalkyl group” is preferably 2 to 10, more preferably 2 to 7, and may be any of linear, branched or cyclic.
  • the number of carbon atoms in the alkyl moiety is preferably 1 to 3, More preferably, it is one or two.
  • the “1-alkanoyloxyalkyl group” include an acetyloxymethyl group, a propionyloxymethyl group, an n-butylyloxymethyl group, an isoptyryloxymethyl group, a bivaloyloxymethyl group, and a Valeryloxymethyl group, 2-methylbutyryloxymethyl group, isovaleryloxymethyl group, n-hexanoyloxymethyl group, 3-methylvaleryloxymethyl group, neohexanoyloxymethyl group, 2- Methylhexanoyloxymethyl group, 2,2-dimethylvaleryloxymethyl group, neoheptanyloxymethyl group, cyclohexanecarbonyloxymethyl group, cyclohexylacetoxymethyl group, 1-acetoxethyl Group, 1-propionyloxyxetyl group, 1-n-butyryloxethyl group, 1-isobutyryl Kisechyl group, 1-n-Valeryloxy
  • the number of carbon atoms in the alkoxy moiety in the “1-alkoxycarbonyloxyalkyl group” is preferably 1 to 10, more preferably 1 to 7, and may be any of linear, branched or cyclic.
  • the number of carbon atoms in the alkyl moiety is preferably 1 to 3, more preferably 1 or 2.
  • 1-alkoxycarbonyloxyalkyl group specifically refers to a 1-methoxycarbonyloxyl, a 1-ethoxycarbonyloxyl, a 1-n-propoxycarbonylloxyl group. , 1-isopropoxycarbonyloxyethyl, 1-n-butoxycarbonyloxy, 1-sec-butoxycarbonyloxy, 1-t-butoxycarbonyloxy, and 1-pentyl Oxycarbonyloxyl and 1-cyclohexyloxycarbonyloxyl and the like.
  • the ⁇ thiazolyl group optionally having substituent (s) '' for R 4 is preferably a thiazolyl group which may be unsubstituted or optionally substituted by 1 to 2 substituents, wherein the substituents are the same or different. You may. Specific examples of the substituent include carbon atoms of 1 to 6 And a straight-chain or branched-chain alkyl group and the like, preferably a methyl group and an ethyl group.
  • Z-isomer and E-isomer both of which are included in the scope of the present invention.
  • it is Z-shaped.
  • cephalosporin compound (I) can form a pharmaceutically acceptable salt at its amino group or carboxyl group by a method known per se. Further, various isomers of the compound (I) can also be produced by a known method.
  • the cephalosporin compound (I) can form an acid addition salt at its amino group, and the acid for forming the acid addition salt is not particularly limited as long as it is a pharmaceutically acceptable acid.
  • examples of such 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 and methanesulfonic acid.
  • the cephalosporin compound (I) can form a salt at its carboxyl group.
  • the salt in the carboxyl group include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, potassium salt, magnesium salt, etc.), organic base salts (eg, triethylamine salt, Dicyclohexylamine salt, pyridine salt, etc.).
  • Examples of the salt of the 7-aminocephalosporin compound (II) include salts similar to those of the cephalosporin compound (I).
  • cephalosporin compounds (I) preferred are 7yS — [(Z) —2— (2-aminothiazo-l-41-yl) -1-2-hydroxyiminoacetamide] —3 — [( Z) — 2 — (4-Methylthiazol-5-yl) vinylthio] 1-3-cefm 14-sodium rubonate, ⁇ ⁇ -[( ⁇ )-2-(2-aminothiazole 1-4-) 1) 2-Methoxyiminoacetamide] — 3— [( ⁇ ) — 2— (4-methylthiazolyl-5-yl) vinylthio] 13-cef-14-force Sodium rubonate, Bivaloyloxymethyl ⁇ ⁇ — [( ⁇ ) — 2— (2-Aminothiazoyl 4-41) 1 2-Methoxyiminoacetamide] 1 3— [( ⁇ )-2-(4— Methylthiazole-5-yl) vinylthio] —3-cef
  • the cephalosporin compound (I) of the present invention can be produced by any one of the following production methods 1 to 3.
  • R 1 , R 2 , R 3 and R 4 have the same meanings as described above, respectively, and Y is a halogen atom such as chlorine, bromine or iodine, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy and butanesulfonyl.
  • a leaving group such as an arylsulfonyloxy group such as ethoxy, and an arylsulfonyloxy group such as phenylsulfonyloxy and tolylsulfonyloxy.
  • the compound (IV) or a salt thereof is added in an amount of about 1 to 5 moles, preferably about 1 to 5 moles.
  • a solvent that does not inhibit the reaction eg, water, acetone, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethyl acetate, dimethyl sulfoxide, etc., or a mixture thereof.
  • the reaction is preferably performed in the presence of a base.
  • the base to be used is not particularly limited. Examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal carbonates such as sodium hydrogen carbonate.
  • alkali metal hydroxides such as sodium hydroxide and potassium hydroxide
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • alkali metal carbonates such as sodium hydrogen carbonate.
  • the reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at 120 to 80 ° C, preferably at 120 to 30 ° C.
  • the reaction time varies mainly depending on the reaction temperature, the type of the reaction reagent, and the like, but is usually 30 minutes to 10 hours.
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • Compound (VI) is described in the literature (J. Antibiotics. 44, 1422-1431, 1991 and J. Antibiotics.
  • I) is also prepared by a conventional method based on the above two documents.
  • the compound (VI) or a salt thereof is added in an amount of about 1 to 5 moles, preferably about
  • This is a method for producing the compound (I) or a salt thereof by reacting the compound (VII) in an amount of 1 to 3 moles.
  • a solvent that does not inhibit the reaction eg, water, acetone, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, etc., or a mixture thereof.
  • the reaction is preferably performed in the presence of a base.
  • the base to be used is not particularly limited. Examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal carbonates such as sodium hydrogen carbonate.
  • alkali metal hydroxides such as sodium hydroxide and potassium hydroxide
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • alkali metal carbonates such as sodium hydrogen carbonate.
  • This reaction may be carried out in the presence of sodium iodide, sodium thiocyanate and the like.
  • the reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at 120 to 80 ° C, preferably at ⁇ 20 to 30 ° C.
  • the reaction time varies mainly depending on the reaction temperature, the type of the reaction reagent, and the like, but is usually 30 minutes to 10 hours.
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • the compound (VIII) is c
  • Preparation 3 are those prepared according to per se known methods, the compound (II) or a salt thereof, about 1 to 3 molar equivalents, preferably about 1 to 1. This is a method for producing a compound (I) or a salt thereof by reacting a 5-fold molar amount of the compound (VIII) or a reactive derivative at a carboxyl group or a salt thereof. In the reaction, the compound (VIII) is used as a free carboxylic acid or as a reactive derivative thereof.
  • a free acid or a salt thereof such as sodium, potassium, calcium, triethylamine, pyridine or the like; an acid halide (eg, acid chloride, acid bromide, etc.); an acid anhydride; a mixed acid anhydride [eg, Substituted phosphoric acid (eg, dialkyl phosphoric acid), alkyl carbonate (eg, ethyl ethyl carbonate), active amide (eg, amide with imidazole), ester (eg, cyanomethyl ester, 412-trophy) , Etc.) as a reactive derivative.
  • an acid halide eg, acid chloride, acid bromide, etc.
  • an acid anhydride eg, a mixed acid anhydride
  • a mixed acid anhydride eg, Substituted phosphoric acid (eg, dialkyl phosphoric acid), alkyl carbonate (eg, ethyl ethyl carbonate), active
  • the reaction is preferably performed in the presence of a condensing agent.
  • a condensing agent examples include ⁇ , N'-disubstituted carbodiimides such as ⁇ , ⁇ '-dicyclohexyl carbodiimide, and 1-ethyl-3--3- (3-dimethylaminopropyl) carbodiimide.
  • Carbodiimid compounds such as imido, ⁇ -cyclohexyl ⁇ , morpholinoethylcarbodiimide, ⁇ -cyclohexyl mono-, mono (4-ethylethylcyclohexyl) carbodiimid, ⁇ , N
  • Dehydrating agents such as azolide compounds such as' -carbonyldiimidazole, ⁇ , N'-thionyldiimidazole. When these condensing agents are used, the reaction is considered to proceed via a reactive derivative of the carboxylic acid.
  • This reaction is usually performed in an inert solvent.
  • the solvent include water, acetone, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethyla. Cetamide, dimethyl sulfoxide, etc., or a mixture thereof).
  • the reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, usually at 120 to 20 ° C, preferably at 120 to 0 ° C.
  • the reaction time varies depending mainly on the reaction temperature, the type of the reaction reagent, and the like, but is usually 30 minutes to 10 hours.
  • the 7-aminocephalosporin compound (II) can be produced by the following production method 4 or 5.
  • R 3 R 4 and Y have the same meanings as described above, and R 7 represents a hydrogen atom or an amino protecting group.
  • reaction of compound (IX) or a salt thereof with compound (V) or a salt thereof can be carried out in the same manner under the conditions described in Production method 1.
  • R 7 of compound (IX) is an amino protecting group It is preferred that In this case, a compound in which the amino group at the 7-position in the general formula (II) is protected is obtained, and the protecting group can be eliminated by a method known per se.
  • amino protecting group for R 7 a protecting group generally used in the art can be used. Examples thereof include phenylacetyl, phenyloxyacetyl, 2-ceenylacetyl, 2-furylacetyl, D-5-amino-5-carboxyvaleryl, BOC, trityl, phthaloyl, and 0-hydroxybenzylidene.
  • a method for removing the amino protecting group a method known per se is used.
  • the amino-protecting group is phenylacetyl, phenyloxyacetyl, 2-phenylacetyl, 2-furylacetyl, D-5-amino-5-carboxyvaleryl, etc.
  • amino-protecting group is BOC, trityl, 0-hydroxybenzylidene, etc.
  • a method of treating with an acid for example, hydrochloric acid, formic acid, trifluoroacetic acid, etc.
  • an amino-protecting group When is phthaloyl or the like, an Ing-Manske method using hydrazine and the like can be mentioned.
  • Compound (X) is a compound described in the literature (L Antibiotics. 44, 1422-1431, 1991 and J. Antibiotics. 43, 1160-1168, 1990), or is a conventional compound based on these documents. It is prepared by a technique.
  • the compound (X) or a salt thereof is added in a molar amount of about 1 to 5 times, preferably about 1 to 5 times.
  • reaction between compound (X) or a salt thereof and compound (VII) or a salt thereof can be carried out in the same manner under the conditions described in Production method 2, but R 7 of compound (X) is an amino protecting group Is preferred.
  • R 7 of compound (X) is an amino protecting group Is preferred.
  • a compound in which the amino group at the 7-position in the general formula (II) is protected is obtained, and the protecting group can be removed by a method known per se.
  • amino protecting group to be used and the method for elimination thereof are the same as those described in the above-mentioned Production method 4.
  • cephalosporin compound (I) thus synthesized can be converted to an arbitrary purity by appropriately performing known separation and purification means, for example, concentration, extraction, chromatography, reprecipitation, and recrystallization. Can be collected.
  • cephalosporin compound (I) obtained by the above method when R 3 is a lipoxyl group or a salt thereof, a reactive derivative thereof (for example, an alkali metal salt such as a sodium salt or a potassium salt) may be used if necessary. Salt, an alkaline earth metal salt such as calcium, an organic base salt such as triethylamine salt, pyridine salt, etc.), and R 3 is esterified with a ester of a prodrug that is easily hydrolyzed in vivo by a known method.
  • the cephalosporin compound (I) obtained by the above-mentioned method usually has a protecting group, and the elimination of the protecting group.
  • Decomposes with an acid depending on the type of the protecting group for example, formyl, BOC, trityl, tetrahydroviranyl, etc.
  • Decomposition by acid such as chloroacetic acid
  • decomposition by hydrazine for example, phthaloyl is decomposed by hydrazine
  • decomposition by catalytic reduction for example, benzyl, benzyloxycarbonyl, etc. is decomposed by palladium-carbon etc.
  • Cephalosporin compound (I) and its pharmaceutically acceptable salts are in addition, it is useful as a prophylactic / therapeutic agent for bacterial infections.
  • diseases caused by bacteria in mammals eg, humans, dogs, cats, dogs, dogs, rats, mice, etc.
  • mammals eg, humans, dogs, cats, dogs, dogs, rats, mice, etc.
  • parenterally intravenously or intramuscularly
  • orally as a preventive and therapeutic agent for suppurative diseases, respiratory infections, biliary tract infections, urinary tract infections, etc.
  • cephalosporin compound (I) and a pharmaceutically acceptable salt thereof are used as a pharmaceutical preparation, usually a pharmaceutically acceptable carrier and excipient (eg, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.) Binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.), disintegrants (eg, calcium carboxymethylcellulose, talc, etc.) Or the like to form a pharmaceutical composition, which can be orally administered in the form of capsules, tablets, fine granules, granules, dry syrups and the like into a formulation suitable for oral administration.
  • a pharmaceutically acceptable carrier and excipient eg, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.
  • Binders eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose
  • an organic acid to the pharmaceutical composition from the viewpoint that solubility in the digestive tract is increased and absorption into the blood becomes easier.
  • the organic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include maleic acid, fumaric acid, tartaric acid, citric acid, succinic acid, malic acid, oxalic acid, mandelic acid, malonic acid, and benzoic acid. And organic carboxylic acids.
  • the amount of the organic acid is usually 0.01 to 20 mol, preferably 0.02 to 2 mol, per 1 mol of the cephalosporin compound (I) or a pharmaceutically acceptable salt thereof. .
  • the dosage of the cephalosporin compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the subject to be administered, the condition, and the like. Administer parenterally or orally about 1 to 40 mg / kg body weight about 1 to 4 times a day.
  • R 3 is an esterified carboxyl group that is hydrolyzed in vivo
  • the orally administered cephalosporin compound (I) and its pharmaceutically acceptable salts are rapidly absorbed into the blood from the gastrointestinal tract, and the metabolite R 3 is a cephalosporin whose lipoxyl group is It becomes compound (I) and its pharmaceutically acceptable salt, shows a high blood concentration, and maintains this high blood concentration.
  • cephalosporin compound (I) wherein R 3 is a carboxyl group and a pharmaceutically acceptable salt thereof can be administered rectally, for example, after being formulated in a suppository or a storage enema or the like.
  • the compound or a salt thereof can be formulated as an injection.
  • cephalosporin compound (I) and a pharmaceutically acceptable salt thereof may be used for treating other systemic symptoms caused by other antibacterial active substances, such as antibacterial agents (benicillins, aminoglycosides, cephalosporins, etc.) or bacterial infection. May be used in combination with drugs (eg, antipyretics, analgesics, anti-inflammatory agents).
  • antibacterial active substances such as antibacterial agents (benicillins, aminoglycosides, cephalosporins, etc.) or bacterial infection.
  • drugs eg, antipyretics, analgesics, anti-inflammatory agents.
  • cephalosporin compound (I) and the amino cephalosporin compound (II) of the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. Absent.
  • the aqueous layer was extracted with 100 ml of ethyl acetate.
  • the ethyl acetate layers were combined, washed with 300 ml of a saturated saline solution, dried (Glauber's salt), and the ethyl acetate was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography (eluted with benzene-ethyl acetate), and the solvent of the desired fraction was distilled off under reduced pressure to obtain 1.63 g of 4-methyl-5-ethenylthiazol. .
  • the ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with ethyl benzene monoacetate). The solvent of the target fraction was distilled off under reduced pressure to obtain diphenylmethyl 7-phenylacetamido 3 — 4.0 g of a foamy powder of [(Z) —2- (4-methylthiazol-5-yl) vinylthio] -13-cephe-4-carboxylate was obtained.
  • Ethyl acetate 150 ml was added, and the mixture was washed successively with 10% aqueous citric acid, 2% saline, saturated aqueous sodium bicarbonate, and 100 ml of saturated saline, dried (glauberin), and then dried under reduced pressure. Stay I left. To the residue was added 100 ml of a mixed solution of n-hexane-isopropyl ether (2: 1), and the precipitate was collected by filtration.
  • Ethyl acetate 15 Om1 was added, and the mixture was washed successively with 10% aqueous citric acid, 2% saline, saturated aqueous sodium bicarbonate and 100 ml of saturated saline, dried (malt salt), and then dried under reduced pressure. Was distilled off. Isopropyl ether was added to the residue, the precipitate was collected by filtration, and (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methyl 7 ⁇ -phenylacetamide- 1-((Z)-2- (4-Methylthiazole-5-yl) vinylthio] —3-cefume-4-carboxylate powder (717 mg) was obtained.
  • the mixture was cooled to ⁇ 40 ° C., 4.77 ml of methanol was added dropwise, and the mixture was stirred at ⁇ 40 to ⁇ 30 for 25 minutes.
  • 50 ml of methylene chloride and 50 ml of 10% saline were added, and the pH was adjusted to 3.0 with 5% aqueous sodium hydrogen carbonate. And the two layers were separated.
  • the aqueous layer was extracted with methylene chloride (30 ml), combined with the methylene chloride layer, washed with 50 ml of 10% saline, and dried (glauberin).
  • IRV (ujor) cm- 1 1785, 1750, 1655.
  • the minimum inhibitory concentrations (M I C) of the cephalosporin compound (I) of the present invention (compounds of Examples 1, 2 and 13) and the control compound (cefpodoxime) against various bacteria were measured.
  • Table 1 shows the results.
  • the unit in the table is ⁇ g / m1.
  • cephalosporin compounds (I) include Staphylococcus aureus, Staphylococcus aureus, Gram-yang bacteria such as Staphylococcus epidermides, and Escherichia coli.
  • Escherichia Coli ⁇ Crab sill ⁇ Has excellent antibacterial activity against gram-negative bacteria such as Klebsiella pneumon iae, Proteus vulgaris, and Proteus mirabillis Things.
  • 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. These compounds are extremely low-toxic.
  • the cephalosporin compound (I) or a pharmaceutically acceptable salt thereof is excellent in gastrointestinal absorption by oral administration and has sufficient antibacterial properties against a wide variety of bacterial species, and is useful for infectious diseases ( In particular, it is extremely useful as a prophylactic and therapeutic agent for bacterial infections.
  • infectious disease preventive and therapeutic agents include, for example, warm-blooded animals including humans (dogs, cats, cattle, horses, Parenteral (intravenous or intramuscular) as a prophylactic / therapeutic agent for diseases caused by bacteria (eg, mouse, mouse, etc.) (eg, purulent diseases, respiratory infections, biliary tract infections, urinary tract infections, etc.) Injection) and orally.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de céphalosporine (1) représentés par la formule générale (I) ou leurs sels pharmaceutiquement acceptables: dans laquelle R1 est un hydrogène ou un groupe protecteur amino; R2 est un hydrogène, un alkyle inférieur ou un groupe protecteur hydroxy; R3 est un carboxy facultativement estérifié; et R4 est un thiazolyle facultativement substitué. Ces composés (I) ou leurs sels pharmaceutiquement acceptables présentent une excellente absorbabilité dans le tube digestif lorsqu'ils sont administrés oralement et une activité antimicrobienne suffisante contre une large gamme de bactéries, ce qui les rend très utiles comme traitement préventif ou comme remède dans les maladies infectieuses (en particulier, les microbismes).
PCT/JP1998/002714 1997-06-23 1998-06-17 Composes de cephalosporine, utilisation de ces derniers et composes intermediaires de ces derniers WO1998058933A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU80350/98A AU8035098A (en) 1997-06-23 1998-06-17 Cephalosporin compounds, use thereof and intermediate compounds of the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP16627597A JP2002332288A (ja) 1997-06-23 1997-06-23 セファロスポリン化合物、その用途およびその中間体化合物
JP9/166275 1997-06-23

Publications (1)

Publication Number Publication Date
WO1998058933A1 true WO1998058933A1 (fr) 1998-12-30

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Country Status (3)

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JP (1) JP2002332288A (fr)
AU (1) AU8035098A (fr)
WO (1) WO1998058933A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2006234532A1 (en) * 2005-04-12 2006-10-19 Meiji Seika Kaisha, Ltd. 2-Thioethenyl carbapenem derivative
JPWO2006109823A1 (ja) * 2005-04-12 2008-11-20 明治製菓株式会社 ２位チオエテニル系カルバペネム誘導体
US7687490B2 (en) 2005-04-12 2010-03-30 Meiji Seika Kaisha, Ltd. 2-thioethenyl substituted carbapenem derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6236385A (ja) * 1985-08-05 1987-02-17 Fujisawa Pharmaceut Co Ltd ３，７−ジ置換−３−セフエム化合物およびその製造法
EP0268307A2 (fr) * 1983-08-01 1988-05-25 Fujisawa Pharmaceutical Co., Ltd. Composés de départ pour des composés céphem et leurs procédés de préparation
JPH08259572A (ja) * 1995-01-24 1996-10-08 Toyama Chem Co Ltd 新規なセファロスポリン誘導体またはその塩

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0268307A2 (fr) * 1983-08-01 1988-05-25 Fujisawa Pharmaceutical Co., Ltd. Composés de départ pour des composés céphem et leurs procédés de préparation
JPS6236385A (ja) * 1985-08-05 1987-02-17 Fujisawa Pharmaceut Co Ltd ３，７−ジ置換−３−セフエム化合物およびその製造法
JPH08259572A (ja) * 1995-01-24 1996-10-08 Toyama Chem Co Ltd 新規なセファロスポリン誘導体またはその塩

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JP2002332288A (ja) 2002-11-22
AU8035098A (en) 1999-01-04

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