WO1991007413A1 - Derives de 3-(thiomethyle a noyau hetero bicyclique)cephem - Google Patents

Derives de 3-(thiomethyle a noyau hetero bicyclique)cephem Download PDF

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Publication number
WO1991007413A1
WO1991007413A1 PCT/JP1989/001176 JP8901176W WO9107413A1 WO 1991007413 A1 WO1991007413 A1 WO 1991007413A1 JP 8901176 W JP8901176 W JP 8901176W WO 9107413 A1 WO9107413 A1 WO 9107413A1
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group
thiomethyl
carboxy
carboxylate
dihydro
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PCT/JP1989/001176
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English (en)
Japanese (ja)
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Susumu Nakagawa
Koji Yamada
Ryosuke Ushijima
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Banyu Pharmaceutical Co., Ltd.
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Priority to PCT/JP1989/001176 priority Critical patent/WO1991007413A1/fr
Publication of WO1991007413A1 publication Critical patent/WO1991007413A1/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

Definitions

  • the present invention relates to a novel cephalosporin compound useful in the field of medicine, a method for producing the same, and an antibacterial agent containing the compound as an active ingredient.
  • the one similar to the present invention is Japanese Patent Application Laid-Open No. 622-234087 (A publication).
  • a publication Japanese Patent Application Laid-Open No. 622-234087
  • the substituent at the 3-position of the nucleus of C in the A publication forms a bicyclic thioalkyl group with the pyridine nucleus, it is thio-bonded at the ⁇ -position of the pyridine nucleus. It is a compound with a completely different structure.
  • the antibacterial activity of these compounds is gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Pseudomonas cepa-cia, Pseudomonas maltophilia, and Pseudomonas maltophilia. It is not sufficient for glucose non-fermen-iative gram-negative rods such as Acinetobacter calcoaceticus.
  • S-lactam antibiotics are selective toxic to bacteria only and do not affect animal cells, they are widely used as antibiotics with few side effects for the treatment of bacterial infections, and are highly useful drugs. It is.
  • non-glucose non-fermentative gram-negative bacilli especially Pseudomonas aeruginosa, and even methicillin-resistant Staphylococcus aureus have often been isolated as infectious disease-causing bacteria from patients with reduced immunity. Has been raised. Therefore, development of an antibacterial agent having improved antibacterial activity against these bacteria has been desired.
  • the present inventors have conducted intensive studies to create a cephalosporin derivative having strong antibacterial activity against gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and Gram-negative bacteria such as Pseudomonas aeruginosa.
  • the present invention has the general formula
  • R 1 is a hydrogen atom or an optionally substituted lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group, and A is a single bond or a nitrogen atom, an oxygen atom and a sulfur atom.
  • the present invention relates to a method for producing a compound or a salt thereof and a production intermediate thereof.
  • a lower alkyl group which may have a substituent is, for example, a lower alkoxy group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group or a tert-butoxy group.
  • a lower alkanoyloxy group having 2 to 4 carbon atoms such as an acetyloxy group, a propionyloxy group or a butyryloxy group; a hydroxyl group; a carboxyl group; a rubamoyl group; a sulfo group and, for example, a chlorine atom, a bromine atom or A linear, branched or cyclic lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms such as elemental atoms. I do.
  • alkyl group examples include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, Isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, 2-chloroethyl, 2 -Fluoroethyl, 2,2-difluoromethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, carboxymethyl, 1-carboxyethyl, 1-carbamoylmethyl, 1-butyl Moylethyl group, 1-potassyloxy-1-methylethyl group, 1-potumbyl group,
  • the lower alkenyl group which may have a substituent means a lower alkenyl group having 2 or 6 carbon atoms which may be substituted with an S substituent such as a carboxyl group, a carbamoyl group or a sulfo group. I do.
  • alkenyl group examples include, for example, vinyl group, 1-propenyl group, aryl group, 1-methylvinyl group, 2-methyl -Topropropenyl group, 1,3-butadienyl group, 1,1-dimethylaryl group, 2-butenyl group, 3-butenyl group, 3-methylbutenyl group, 1-carboxyvinyl group, 2-carboxyvinyl group, 1 -Carboxy-1-propenyl group, 2-carboxy-1-propenyl group, 3-carboxy-1-propenyl group, 1-carboxy-2-methyl-1-propyl group, 1 -Carboxyaryl, 2-carboxyaryl, 3-carboxyaryl, 1-carboxy-3-butenyl, 1-carboxy-3-methyl-2-butenyl, 1-sulfovinyl, 1-force Rubamoyl vinyl group, 1-sulfoallyl group, 1-force rubamoylaryl group, 3-carboxy-1,1-
  • the lower alkynyl group which may have a substituent is, for example, a alkynyl group or a sulfo group which may be substituted with, for example, an ethynyl group, a 1-propyl group, a 2-propynyl group or It means a lower alkynyl group having 2 to 6 carbon atoms such as a 1-dimethyl-2-propynyl group.
  • alkynyl group examples include, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1,1-dimethyl-2-propynyl group, 2-carboxyethynyl group, 2-sulfethynyl group, 1-propynyl group, Carboxy-2-propynyl group, 1-sulfo-2-propynyl group, 3-carboxy-1,1-dimethyl-2-propynyl group or 3-sulfo-1,1-dimethyl-2-propynyl group. I can do it.
  • the aralkyl group which may have a substituent is, for example, one to four selected from the group consisting of a hydroxyl group, an acetyl group, a propionyloxy group, a carboxy group, a sulfo group, a carboxymethyl group or a sulfomethyl group.
  • aralkyl group include, for example, benzyl, phenethyl, ⁇ -carboxyphenethyl, tricarboxy-3-phenylpropyl, ⁇ -carboxy-1-naphthylmethyl, ⁇ -carboxynaphthyl Methyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 3-acetoxybenzyl, 4-acetoxybenzyl, 2-carboxybenzyl, 3-carboxybenzyl, 4-carboxybenzyl, 2-carboxy Methylbenzyl, 3-carboxymethylbenzyl, 4-carboxymethylbenzyl, 2-sulfobenzyl, 3-sulfobenzyl, 4-sulf
  • Cyclic side chains Sefuwemu nuclear position 3 of Pirijiniumu nuclei formula - (CH 2) mA- (CH 2) n - ( in the formula, A barrel selected from the group consisting of a single bond or a nitrogen atom, an oxygen atom and a sulfur atom A heteroatom, m represents an integer of 0 to 3, and n represents an integer of 2 or 3.)
  • -Suitable cyclic side chains include those in the following table.
  • the lower alkyl group in the table refers to an alkyl group having 1 to 4 carbon atoms such as a methyl group or an ethyl group
  • the lower alkanol group refers to a carbon atom having 1 carbon atom such as a formyl group, an acetyl group, or a propionyl group. Or 4 alkanoyl groups.
  • the bicyclic heterocyclic group formed by the pyridine ring and its cyclic side chain is, for example, a group having 1 carbon atom such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a tert-butyl group.
  • lower alkyl groups for example, a lower alkoxy group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an izpropoxy group, a butoxy group, an isobutoxy group or a tert-butoxy group, a formyl group, It may have 1 to 3 identical or different substituents selected from the group consisting of a carboxyl group, a carbamoyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an N-methylcarbamoyl group, a hydroxyl group and the like.
  • bicyclic heterocyclic group examples include, for example, a 2,3-dihydro-1H-indolizindium-7-yl group, a 2,3-dihydro-3-methyl-1H-indolizinium_7-yl group, 2,3-dihydro-6-methoxy-3-methyl-1H-indolizinum-7-yl group, 5-force ruboxylate-2,3-dihydro-3-methyl-1H-indolizinium-7-yl group, 6 , 7,8,9-Tetrahydroquinolinidin-2-yl group, 3,4-dihydro-1H-pyrido [2,1-c] [1,4] oxazidin-8-yl group, 2 2,3-dihydro-7H-oxazolo [3,2-a] pyridinium-7-yl group, 2,3-dihydro-7H-thiazolo [3,2-a] pyridinium-7-yl group, 2 , 3-Dihydro-7H-
  • Particularly preferred examples include a 2,3-dihydro-1H-indolizindium-7-yl group, a 6,7,8,9-tetrahydroquinolizinidine-2-yl group and a 3,4-dihydro-1H group.
  • the non-toxic salt of the compound of the general formula (I) means a pharmaceutically acceptable conventional salt, and is a carboxyl group at the 4-position of the cefm nucleus, a bicyclic heterocyclic group or a carboxyl group substituted with R 1 .
  • salts of an acidic residue such as a sulfo group, or a basic residue such as a 2-aminothiazole group or a quaternary ammonium group at the 7-position of the nucleus.
  • the salts of the compound may be mono-, di- or tri-salts.
  • bases that form addition salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, such as trimethylamine salts and triethylamine salts.
  • Aliphatic amines such as dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, glucamine, N-methyldalcamine or procaine; for example, ⁇ , ⁇ '-dibenzylethylenediamine Aralkylamine salts such as pyridine salts, picoline salts, heterocyclic aromatic amine salts such as quinoline salts or isoquinoline salts;
  • tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt or tetrabutylammonium salt or tetrabutylammonium salt
  • a quaternary ammonium salt such as a dimethyl salt or a basic amino acid salt such as an arginine salt or a lysine
  • Examples of the acid forming an addition salt include an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate or perchlorate, for example, acetate.
  • Organic salts such as propionate, lactate, maleate, fumarate, tartrate, malate, citrate or ascorbate, for example, methanesulfonate, isethionate, benzenesulfonate Salts or sulfonates, such as P-toluenesulfonate, or acidic amino acid salts, such as, for example, aspartate or glutamate.
  • the compound of the general formula (I) can be converted into its pharmaceutically acceptable non-toxic ester by a conventional method.
  • the non-toxic ester which can be hydrolyzed in vivo, is formed by the carboxyl group at the 4-position of the cefm nucleus.
  • an externally added anion paired with the pyridinium group is required.
  • the anion include a halogen ion such as a chloride ion, a bromide ion, and an iodine ion.
  • ester residue capable of forming a nontoxic ester that can be hydrolyzed in a living body examples include, for example, an alkanoloxymethyl group such as an acetooxymethyl group and a bivaloyloxymethyl group, a 1- (ethoxycarbonyloxy) ethyl group, and a 1- (isopropoate).
  • Alkoxycarbonyloxyalkyl group such as ethyl group, phthalidyl group, for example, (5-methyl-2-oxo-1,3-dioxo-1-yl) And (5-substituted-2-oxo-1,3-dioxol-4-yl) methyl groups such as methyl group.
  • the partial structure of the oxyimino group of the general formula (I) includes a syn isomer (Z configuration) and an anti isomer (E configuration).
  • the syn isomer (Z configuration) exhibits excellent antibacterial activity.
  • all OR 1 groups are syn isomers (Z configuration).
  • the EZZ nomenclature is described in the Journal of the American Chemical Society (J. Am. Cheni. So), Vol. 90, p. 509 (1968).
  • the method for producing the compound of the present invention will be described.
  • the compound of the present invention has the general formula
  • R 3 is a hydrogen atom or an amino-protecting group
  • R 4 is a hydrogen atom, which may have a protected substituent, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or an aralkyl
  • R 5 is a hydrogen atom or a carboxyl protecting group
  • X is a leaving group.
  • A represents a single bond or a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom
  • fn represents an integer of 0 to 3
  • n represents an integer of 2 or 3.
  • the bicyclic heterocyclic ring formed by the pyridine ring and the cyclic side chain thereof may be replaced with the same or different 1 to 3 appropriately protected substituents. Reacting the compound with the general formula
  • R 3 , RR 5 , A, m and n have the above-mentioned meanings, and ⁇ means a yion.
  • the bicyclic heterocyclic group formed by the pyridine ring and the cyclic side chain thereof may be substituted with the same or different 1 to 3 substituents which may be protected as appropriate.
  • X in the general formula (II) represents a leaving group, specifically, a halogen atom such as chlorine, bromine or iodine, or an acetyl group.
  • ⁇ in the general formula (IV) represents an anion of a leaving group.
  • the compound represented by the general formula (IV) is obtained by converting the compound represented by the general formula ( ⁇ ) and the bicyclic heterocyclic pyridothione derivative ( ⁇ ) into methylene chloride, chloroform, dimethyl ether, ethyl acetate, butyl acetate, and tetrahydrofuran. , Acetonitrile, N, N-dimethylformamide, dimethylsulfoxide or a mixed solvent thereof in the presence or absence of a deoxidizing agent.
  • deoxidizing agent examples include metal salts such as sodium carbonate, potassium carbonate and magnesium carbonate, and, for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine or N, N-dimethylaniline. And the like.
  • metal salts such as sodium carbonate, potassium carbonate and magnesium carbonate
  • Bicyclic heterocyclic thione derivative examples include sodium carbonate, potassium carbonate and magnesium carbonate, and, for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine or N, N-dimethylaniline.
  • (II) can be used after being silylated with a silylating agent such as N, 0-bis (trimethylsilyl) acetamide.
  • a silylating agent such as N, 0-bis (trimethylsilyl) acetamide.
  • the reaction is based on 1 mole of the compound of the general formula ( ⁇ ).
  • the reaction temperature and reaction time are 0 to 40 ° C and 0.5 to 5 hours using 1 to 2 mol of the bicyclic heterocyclic thione derivative (II).
  • the reaction with the bicyclic heterocyclic thione derivative ( ⁇ ) is performed, for example, with water, phosphate buffer, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, N, N -Dimethylformamide, dimethylsulfoxide or a mixed solvent thereof.
  • the reaction is preferably performed near neutrality, the reaction temperature is from room temperature to 90 ° C, and the reaction time is 1 to 15 hours.
  • reaction is carried out with 1 to 20 moles of iodide such as sodium iodide or potassium iodide, thiocyanate such as sodium thiocyanate or potassium thiocyanate or trimethylbenzyl ammonium per 1 mole of compound (II). It is promoted by conducting in the presence of a quaternary ammonium salt such as bromide.
  • iodide such as sodium iodide or potassium iodide
  • thiocyanate such as sodium thiocyanate or potassium thiocyanate or trimethylbenzyl ammonium
  • a quaternary ammonium salt such as bromide.
  • the reaction between the compound ( ⁇ ) and the pyridothione derivative ( ⁇ ) is carried out, for example, by reacting the compound ( ⁇ ) in acetic acid, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof.
  • 1 to 50 mol of an acid such as sulfuric acid, P-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, chlorosulfonic acid, boron trifluoride or boron trifluoride getyl ether complex, etc.
  • Compound (IV) can be produced even in the presence at room temperature to 60 ° C for 1 to 10 hours.
  • cefm compound (I) of the present invention can be produced, if necessary, by removing the protecting group from the compound of the general formula (IV).
  • the method for protecting the carboxyl group, amino group or hydroxyl group in the above general formula and removing the same is selected from methods commonly used in the field of lactam synthesis. Can be used. Methods for introducing and removing protecting groups include, for example,
  • Examples of the carboxyl-protecting group include lower alkyl groups such as tert-butyl group; halo-substituted lower alkyl groups such as 2,2,2-trichloroethyl group; acetomethyl group, propionyloxymethyl group, and vivaloyl
  • a lower alkanoyloxyalkyl group such as an oxymethyl group, a 1-acetoxyl group or a propionyloxyl group; for example, a 1- (methoxycarbonyloxy) ethyl group, a 1- (ethoxycarbonyloxy) ethyl group Or a lower alkoxycarbonyloxyalkyl group such as 1- (isopropoxycarbonyloxy) ethyl group; for example, a benzyl group, a 4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a 4-nitrobenzyl group, a benzhydryl group or An aralkyl group
  • amino protecting group examples include benzyl, 4-methoxybenzyl, and 3,4- Aralkyl groups such as dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group or bis (4-methoxyphenyl) methyl group; for example, formyl group, acetyl group, propionyl group, butyryl group, oxalyl group, succinyl group Or a lower alkanoyl group such as a pivaloyl group; a halogen-substituted lower alkanol group such as a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group or a trifluoroacetyl group; a phenylacetyl group or a phenoxyacetyl group; Arylalkanol group; for example, lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxy
  • hydroxyl-protecting groups include 2-methoxyethoxymethyl, methoxymethyl, methylthiomethyl, tetrahydroviranyl, phenacyl, isopropyl, tert-butyl, benzyl, 4-methoxybenzyl, -Nitrobenzyl, acetyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, trimethylsilyl, tert-butyldimethylsilyl, methylene acetal, ethylene acetal, benzylidene acetal Cyclic ortho-esters such as methoxymethylidene or methoxyethylidene; and cyclic ketals or cyclic carbonates such as isopropylidene ketal.
  • removing the protecting group For the method of removing the protecting group, a commonly used method is appropriately selected according to the type of the protecting group. You can do it. For example, removal of protecting groups such as trityl group, formyl group, tert-butoxycarbonyl group, benzhydryl group or tert-butyl group, 2-methoxyethoxymethyl group is performed by removing hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid or P- The reaction can be carried out with an inorganic acid such as toluenesulfonic acid or an organic acid, and trifluoroacetic acid is particularly preferred.
  • protecting groups such as trityl group, formyl group, tert-butoxycarbonyl group, benzhydryl group or tert-butyl group, 2-methoxyethoxymethyl group is performed by removing hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulf
  • reaction temperature and the reaction time are appropriately selected according to the chemical properties of the compound (IV) and the cefm compound (I) of the present invention, and the type of the protecting group, and the reaction temperature is a moderate condition of about -10 to 60 ° C. It is preferred to do so.
  • the step of converting the free form of the cefm compound (I) of the present invention into its non-toxic salt can be carried out, for example, by applying a technique commonly used in the art to the free form produced by the above-mentioned production method. .
  • the step of converting a free form of the cefm compound (I) of the present invention into a physiologically hydrolyzable non-toxic ester can be carried out, for example, by the method described in US Pat. No. 4,388,460 and US Pat. No. 4,260,607. It can be easily implemented by an equivalent method.
  • Isolation and purification of the cefm compound (I) of the present invention and the nontoxic salt or ester thereof produced by the above steps can be carried out by a known method, for example, crystallization or column chromatography.
  • R 3 and R 4 have the above-mentioned meanings] or a reactive derivative of a carboxyl group thereof.
  • the acylation reaction is carried out, for example, in water, acetone, dioxane, getyl ether, tetrahydrofuran, ethyl methyl ketone, chloroform, methylene chloride, dichloroethane, ethyl acetate, ethyl formate, ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide or
  • the reaction is completed in a solvent that does not adversely affect the reaction, such as a mixed solvent thereof, under water cooling or at room temperature for 1 to 10 hours.
  • Reactive derivatives of the carboxyl group of the compound (VI) include, for example, a condensing agent such as ⁇ , ⁇ -dicyclohexylcarbodiimide and a compound formed by ⁇ -hydroxysuccinimide or 1-hydroxybenzotriazole.
  • a condensing agent such as ⁇ , ⁇ -dicyclohexylcarbodiimide and a compound formed by ⁇ -hydroxysuccinimide or 1-hydroxybenzotriazole.
  • Acid esters formed with halogenating agents such as, for example, thionyl chloride, phosphorus pentachloride or oxalyl chloride; in the presence of a deoxidizing agent such as, for example, triethylamine or ⁇ -methylmorpholine, for example, methyl chloroform Ichito or Isobuchirukuro port Hol Ma, c in which one preparative black hole mixed acid anhydride by being re formed formate such as and the like
  • a base in order to allow the reaction to proceed smoothly.
  • bases examples include inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate or carbonated lime, and organic bases such as trimethylamine, triethylamine, N, N-dimethylaniline or pyridine. Is mentioned.
  • a condensing agent such as N, N-dicyclohexylcarpoimide or N, N-getylcarpoimide.
  • Separation and purification of the starting compound ( ⁇ ) produced in the above step is carried out by a conventional method such as crystallization or column chromatography, but may be used as a starting material in the next step without separation and purification. It is possible.
  • the compound represented by the general formula (V) can be prepared by a known method such as British Patent No. 1459212, European Patent No. 29557, Journal of Antibiotics
  • pyridine ring and the bicyclic heterocyclic ring formed by the cyclic side chain thereof are the same or different, and may be substituted with 1 to 3 appropriately protected protecting groups.
  • the compound is a novel compound not described in the literature.
  • the bicyclic pyridothiones represented by the general formula ( ⁇ ) are, for example, tetrahedrons
  • the reaction for converting the compound (W) into the compound (VI) is carried out in an inert organic solvent such as tetrahydrofuran, dimethyl ether or dioxane, for example, phosphine such as triphenylphosphine and dimethyl ester or azodicarboxylic acid azodicarboxylate.
  • the reaction is completed by reacting compound (W) at 0 to 80 ° C for 0.5 to 10 hours in the presence of an azodicarboxylic acid ester such as an acid getyl ester.
  • an azodicarboxylic acid ester such as an acid getyl ester.
  • the amount of phosphine and azodicarboxylic acid ester used is
  • the reaction for converting the compound ( ⁇ ) into the compound (m) is carried out in an organic base such as pyridine, colizine or lutidine, for example, phosphorus pentasulfide or loetzone.
  • organic base such as pyridine, colizine or lutidine, for example, phosphorus pentasulfide or loetzone.
  • a phosphorus sulfide compound such as (Lawesson) reagent (see Tetrahedron, Vol. 35, p. 2433 (1979)).
  • This reaction can be carried out by diluting with an inert solvent such as toluene, benzene or tetrahydrofuran.
  • the compound (II) produced by the above reaction can be subjected to the next reaction step, without purification, or purified by appropriately combining purification methods such as solvent extraction, crystallization or chromatography.
  • Compound (W) has an equilibrium as described above due to tautomerism. Further, on the pyridine nucleus or the side chain at the 2-position of the compound (YD), 1 to 3 substituents which are the same or different and are optionally protected are present.
  • Compound (VI), which is a raw material for producing compound ( ⁇ ), is obtained by reacting 4-hydroxy-2,6-pyridinedicarboxylic acid or 2-carboxy-4-hydroxy-5-methoxypyridine [Acta Chem. Scand. Vol. 16, page 78 to page 82 (1962)] from the picoline derivative (VI, XII, W) obtained by a known synthesis reaction and further extending the side chain at the 2-position of the pyridine ring. It is produced by functional group conversion and cyclization reaction.
  • R 1 D is a protecting group for a hydroxyl group such as a benzyl group, a P-methoxybenzyl group, a 2-methoxyethoxymethyl group or a tert-butyldimethylsilyl group
  • R 11 is a methyl group or a Indicates a carboxyl-protecting group such as a benzhydryl group.
  • substituents which may be appropriately protected and is a substituent of the compound ( ⁇ ).
  • the reaction for converting 4-hydroxy-2,6-pyridinedicarboxylic acid (K) to the compound (X) is carried out by reacting the compound (K) with the disulfide in an inert solvent such as, for example, diethyl ether, ethyl acetate or methanol. Nyldiazomethane or diazomethane is reacted at 20 to 80 ° C.
  • a diester (X) for 1 to 10 hours to obtain a diester (X), and the diester (X) is further reacted with, for example, N, N-dimethylformamide, dimethyl
  • an inert solvent such as sulfoxide or tetrahydrofuran, for example, in the presence of carbon dioxide or a base such as N, N-diisopropylethylamine, an alkylating agent such as benzyl or benzyl bromide is added.
  • the reaction is completed by reacting at 20-80 ° C for 1-10 hours.
  • the simultaneous protection of the hydroxyl group and the carboxyl group is carried out by changing the required amount of the alkylating agent.
  • the step of converting the compound (X) into the compound (XI) may be performed, for example, using methanol or te.
  • the compound (X) is treated with an aqueous solution containing 1 equivalent of a base such as carbonated sodium carbonate or sodium hydroxide in an inert solvent such as trahydrofuran to form a monoester.
  • a catalyst such as copper powder may be added if necessary, followed by heating at 160 to 200 ° C for 1 to 20 hours.
  • the step of converting the compound (XI) into the compound (XH) is carried out in an inert solvent such as benzene, toluene, methylene chloride or tetrahydrofuran at a low temperature, preferably in the range of -70 to -50 ° C.
  • (XI) is carried out by operating 1 to 3 equivalents of a metal hydride such as lithium aluminum hydride or diisopropyl aluminum hydride.
  • R 1 (> , R 11 , A, m and n have the above-mentioned meanings
  • X is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom
  • Y is an oxygen atom, a nitrogen atom Or a sulfur atom
  • R 12 represents a hydrogen atom or a protecting group for a hydroxyl group such as a benzyl group, a P-methoxybenzyl group, a 2-methoxyethoxymethyl group or a tert-butyldimethylsilyl group, provided that a pyridine nucleus is present.
  • a substituent On the side chain or on the 2-position side, there is a substituent which may be appropriately protected and is a substituent for compound ( ⁇ ).
  • the reaction of converting compound (M) to compound 01) by subjecting it to a carbon enrichment reaction is carried out by adding a compound (M) to a phosphorus ylide compound in an inert solvent such as dioxane, tetrahydrofuran, N, N-dimethylformamide or methanol.
  • a compound (M) to a phosphorus ylide compound in an inert solvent such as dioxane, tetrahydrofuran, N, N-dimethylformamide or methanol.
  • the reaction is completed at 10-80 ° C for 1-10 hours.
  • the phosphorus ylide compound used in the carbon-enrichment reaction can also be obtained by reacting a phosphonium salt with a base such as sodium hydride, butyllithium, sodium methoxide or sodium hydrogen carbonate. You.
  • the removal of the protecting group of compound (M) can be performed by a known method.
  • R "is a P-methoxybenzyl group or a 2-methoxyethoxymethyl group treatment with an acid such as hydrochloric acid or trifluoroacetic acid in an inert solvent such as, for example, diethyl ether or tetrahydrofuran
  • an inert solvent such as tetrahydrofuran, for example, with potassium fluoride, tetrabutylammonium fluoride, etc.
  • R " is a benzyl group, for example, in an inert solvent such as methanol, tetrahydrofuran or N, N-dimethylformamide, for example, 10% palladium
  • a metal catalyst such as carbon, palladium black or platinum oxide
  • Protecting groups can be removed by elementary decomposition.
  • a commercially available or known compound is appropriately used as the phosphorus compound or the phosphonium compound used in the carbon increasing reaction.
  • the step of converting the compound (XH) into the compound (W) includes, for example, sodium borohydride in a methanol solvent and lithium hydride in a tetrahydrofuran solvent.
  • the reaction is performed under conditions such as sodium aluminum borohydride in a solvent of aluminum or acetic acid, and particularly preferred is sodium borohydride sodium in an acetic acid solvent.
  • the step of converting the compound (XI) into the compound () /) is carried out by treating the compound (XI) with a reducing agent such as lithium aluminum hydride in an inert solvent such as tetrahydrofuran.
  • a reducing agent such as lithium aluminum hydride in an inert solvent such as tetrahydrofuran.
  • the step of converting compound (HV) into compound (XV) is carried out by converting compound (XIV) in the presence of an organic base such as, for example, pyridin, triethylamine, N, N-dimethylaniline, for example, for example, thionyl chloride or phosphorus pentachloride or the like. This is carried out by treating with a halogenating agent of 1 to 5 equivalents for 1 to 10 hours at 0 to 80 ° C. This step may be performed, if necessary, with an inert solvent such as methylene chloride, benzene or tetrahydrofuran. It can be carried out by diluting with a solvent.
  • an organic base such as, for example, pyridin, triethylamine, N, N-dimethylaniline, for example, for example, thionyl chloride or phosphorus pentachloride or the like.
  • a halogenating agent of 1 to 5 equivalents for 1 to 10 hours at
  • the step of converting the compound (XV) to the compound () is performed by the general formula HA- (CH 2 ) n-0R 12 [wherein, Y, ⁇ , ⁇ and R 12 have the same meaning as described above. However, a substituent which may be appropriately protected and which is a substituent of the compound (IE) may be optionally substituted.) With a base such as sodium hydride or butyllithium. After the treatment, the reaction is carried out by reacting the compound (XV) in an inert solvent such as N, N-dimethylformamide, tetrahydrofuran or dioxane at -70 to 80 ° C for 1 to 20 hours. Compound (W) is produced by removing the hydroxyl-protecting group of compound ().
  • the compound represented by the general formula (VI) can be produced by a known method such as a chemical and According to the method described in Pharmaceutical Bulletin (Chem. Pharm. Bull), Vol. 25, pp. 3115-3119 (1977), and the Chemical Society of Japan, 785-801 (1981), etc. It is produced using a diaminothiazol-4-yl) glyoxylic acid derivative or a 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester derivative.
  • the compound of the present invention represented by the general formula (I) is useful as an antibacterial agent, especially for the treatment of bacterial infections in humans caused by Gram-negative bacteria including Gram-positive bacteria and non-glucose non-fermentative Gram-negative bacilli such as S. aeruginosa. Can be used for
  • the cefm compound of the present invention can be mixed with a solid or liquid excipient carrier known in the art and used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration.
  • a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration.
  • the pharmaceutical preparation include liquid preparations such as injections, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.
  • these preparations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters and surfactants, if necessary.
  • Additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.
  • the dosage varies depending on the age, sex, etc. of the patient, but is generally used in the range of l to 100 mg / kg per day, and is preferably 5 to 100 mg / kg per day. It is preferable to administer the drug at a dose of 30 m 2/2 to 4 times.
  • TLC Matogurafi one
  • Silica gel for the column is Wako Pure Chemical Industries Co., Ltd.'s Co-Gel C-300® or Chemco's LC-SORB® RP-18, The rate used was Merck Art 5717 manufactured by Merck.
  • the NMR spectrum is used as an internal standard for deuterated dimethyl sulfoxide (DMS0-d e ) or deuterated chloroform (tetramethylsilane for measurement with CDC1J solution).
  • TMS heavy water
  • D 2 0 heavy water
  • DSS heavy water
  • Vrian Varian
  • XL- 200 200 MHz
  • R-40 90 MHz
  • Example 27- (2) The same reaction as in Example 27- (2) was carried out from 2.72 g (10.7 mmol) of the compound obtained in the above reaction (6), and 478 mg of 2,3-dihydro-3-methyl-7 (1H) -indolidinone was obtained. (Yield from 4-benzyloxy-2-pyridinecarboxaldehyde in step (4) above: 48%).
  • Example 27- (3) The same reaction as in Example 27- (3) was carried out using 0.78 g (5.23 mmol) of the compound obtained in the above reaction (7), and 2,3-dihydro-3-methyl-7 (1H)- Obtain 0.44 g (51% yield) of indolizinthion.
  • Example 30- (3) The same reaction as in Example 30- (3) was performed using 2.45 g of the compound obtained in the above reaction (2).
  • the reaction yields 2.24 g of 4- (4-benzyloxy-5-methoxy-2-pyridyl) -3-buten-2-one (containing a small amount of triphenylphosphinoxide).
  • Example 27- (3) The same reaction as in Example 27- (3) was carried out from 481 mg of the compound obtained in the above reaction (5), and 2,3-dihydro-6-methoxy-3-methyl-7 (1H) -indolizinethione was obtained. 294 mg (56% yield) are obtained.
  • the compound of the present invention is a novel compound that has not been described in the literature. It has unexpectedly strong antibacterial activity, has excellent stability against lactamase, and is effective as an antibacterial agent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés représentés par la formule générale (I), où R1 représente hydrogène ou un alkyle inférieur, un alkynyle inférieur ou un aralkyle éventuellement substitués, A représente une liaison simple ou un atome hétéro sélectionné dans le groupe composé d'azote, d'oxygène et de soufre, m représente un nombre entier compris entre 0 et 3, et n représente un nombre entier valant 2 ou 3, à condition que le groupe à noyau hétéro bicyclique formé par le noyau pyridine et sa chaîne latérale cyclique puisse être substitué par 1 à 3 substituants qui peuvent être identiques ou différents. On décrit également des sels de ce composé acceptables en médecine, ainsi qu'un procédé de préparation de ces produits et leur utilisation.
PCT/JP1989/001176 1989-11-17 1989-11-17 Derives de 3-(thiomethyle a noyau hetero bicyclique)cephem WO1991007413A1 (fr)

Priority Applications (1)

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PCT/JP1989/001176 WO1991007413A1 (fr) 1989-11-17 1989-11-17 Derives de 3-(thiomethyle a noyau hetero bicyclique)cephem

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Application Number Priority Date Filing Date Title
PCT/JP1989/001176 WO1991007413A1 (fr) 1989-11-17 1989-11-17 Derives de 3-(thiomethyle a noyau hetero bicyclique)cephem

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60178890A (ja) * 1984-02-23 1985-09-12 Meiji Seika Kaisha Ltd 新規セフアロスポリン誘導体およびその製造法
JPS63146887A (ja) * 1986-07-01 1988-06-18 Kaken Pharmaceut Co Ltd 新規なセファロスポリン化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60178890A (ja) * 1984-02-23 1985-09-12 Meiji Seika Kaisha Ltd 新規セフアロスポリン誘導体およびその製造法
JPS63146887A (ja) * 1986-07-01 1988-06-18 Kaken Pharmaceut Co Ltd 新規なセファロスポリン化合物

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