WO1991005789A1 - Derives de 3-[(pyridinium-4-yle substitue en 1)thiomethyl]-cephalosporine - Google Patents

Derives de 3-[(pyridinium-4-yle substitue en 1)thiomethyl]-cephalosporine Download PDF

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Publication number
WO1991005789A1
WO1991005789A1 PCT/JP1989/001042 JP8901042W WO9105789A1 WO 1991005789 A1 WO1991005789 A1 WO 1991005789A1 JP 8901042 W JP8901042 W JP 8901042W WO 9105789 A1 WO9105789 A1 WO 9105789A1
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WIPO (PCT)
Prior art keywords
group
carboxylate
compound
general formula
thiomethyl
Prior art date
Application number
PCT/JP1989/001042
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English (en)
Japanese (ja)
Inventor
Susumu Nakagawa
Ryuji Mitomo
Ryosuke Ushijima
Original Assignee
Banyu Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/028,576 external-priority patent/US4880797A/en
Application filed by Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Priority to PCT/JP1989/001042 priority Critical patent/WO1991005789A1/fr
Publication of WO1991005789A1 publication Critical patent/WO1991005789A1/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 derivative useful in the field of medicine. More specifically, the present invention relates to a novel cephalosporin compound, a method for producing the same, and an antibacterial agent containing the compound as an active ingredient.
  • EP 153709 A publication
  • U.S. Pat. No. 4,495,182 B publication
  • EP 227953 C publication
  • Publications A and C disclose a group of cefm compounds having a 1- (fluoroethyl) pyridiniumthiomethyl group as the 3-position side chain of the cefm nucleus.
  • the xyimino group on the 7-side acyl side chain is limited to (alkyl or carboxyalkyl) oxyimino groups.
  • Publication B discloses a group of cefm compounds having a 3- (trialkylpyridiniumthiomethyl) group.
  • the isyl side chain at position 7 is a 1- (1,2,4-thiadiazolyl-3-yl) acetamide group, which is a group of compounds having a different structure from the compound of the present invention.
  • the antibacterial activity of these prior art compounds is gram-positive bacteria such as methicillin-resistant Staphylococcus aureus; Pseudomonas aeruginosa, Pseudomonas seno, Pseudomonas cepacia, It is not sufficient for glucose non-fermentative gram-negative rods such as Pseudomonas nialtophilia and Acinetobacter calcoacetieus. Furthermore, there is no known cephalosporin derivative having a well-balanced and good antibacterial spectrum with respect to the resistant Gram-positive bacteria and Gram-negative bacteria. .
  • Lacam antibiotics are selectively used only for bacteria and have no effect on animal cells, so they are widely used as antibiotics with few side effects for the treatment of bacterial infections and have high utility. It is a drug.
  • R 1 represents a lower alkyl group which may be substituted with a halogen atom
  • a process for producing the same and a use of the compound as an active ingredient as an antibacterial agent.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and a fluorine atom is particularly preferable.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6, preferably 1 to 4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec- Butyl, tert-butyl, pentyl, Hexyl groups and the like are preferred, and methyl groups, ethyl groups, and isopropyl groups are particularly preferred.
  • the lower alkyl group which may be substituted with a halogen atom means the above-mentioned lower alkyl group which may be substituted with 1 to 3, preferably 1 of the above-mentioned halogen atoms.
  • the non-toxic salt of the compound (I) of the present invention is a pharmaceutically acceptable addition salt with a base or acid, specifically, a salt with an acid at the amino group at the 7-position side chain and a carboxyl at the 7-position side chain.
  • the salt with the base in the group is fisted.
  • the addition salt with a base include an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; an ammonium salt; for example, a trimethylamine salt, a triethylamine salt, and a dicyclohexylamine salt.
  • Ethanolamine salt diethanolamine salt, triethanolamine salt, professional power Aliphatic amine salts such as insalts; aralkylamine salts such as N, N-dibenzylethylenediamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, and izquinoline salts; Salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium salt And quaternary ammonium salts such as arginine salts and lysine salts.
  • Aliphatic amine salts such as insalts
  • aralkylamine salts such as N, N-dibenzylethylenediamine salts
  • heterocyclic aromatic amine salts such as pyr
  • addition salt with an acid examples include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, and perchlorate; for example, acetate, propionic acid Organic salts such as salt, lactate, maleate, fumarate, tartrate, malate, citrate, and ascorbate; for example, methanesulfonate, isethionate, benzenesulfonate, P- Sulfonates such as toluenesulfonate; and acidic amino acids such as aspartate and glutamate.
  • inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, and perchlorate
  • acetate propionic acid
  • Organic salts such as salt, lactate, maleate, fumarate, tartrate, malate, citrate, and ascorbate
  • the non-toxic ester of the compound [I] of the present invention means a pharmaceutically acceptable monoester, specifically, an ester at the carboxyl anion at the 4-position side chain or an ester at the carboxyl group at the 7-position side chain.
  • I can fist.
  • a lower alkoxymethyl group such as a methoxymethyl group
  • a lower alkanoyloxymethyl group such as an atoxymethyl group, a propionyloxymethyl group, a bivaloyloxymethyl group
  • a 1- (ethoxycarbonyloxy) ethyl group for example, a 1- (ethoxycarbonyloxy) ethyl group;
  • esters (Isopropoxycarbonyloxy) lower alkoxycarbonyldialkyl group such as ethyl group; phthalidyl group; or, for example, (5-methyl-2-oxo-1,3- Non-toxic esters that can be hydrolyzed in vivo such as (5-substituted-2-oxo-1,3-dioxo-1-yl) methyl groups such as dioxol-4-yl) methyl ' I can do it. These esters form a diion with an inner salt or an externally added anion.
  • Externally added anions include chloride ion, bromide ion, halogen ion such as iodide ion, sulfate ion, hydrogen sulfate ion, methyl sulfate ion, p-toluenesulfonic acid ion, methanesulfonic acid ion, trifluorosulfonic acid Acetate ion and the like.
  • the compound [I] of the present invention has a syn isomer (Z configuration) and an anti-isomer (E configuration) in the oximino group, and the syn isomer generally exhibits excellent antibacterial activity.
  • the compounds of the present invention are all syn isomers.
  • the EZZ nomenclature is described in Journal of the American 'Chemical' Society, U. Am. Chem. Soc., Vol. 90, p. 509 (1968).
  • a preferred compound group of the compound [I] of the present invention is a lower alkyl group in which R 1 may be substituted with a fluorine atom, preferably a compound having an alkyl group having 1 to 4 carbon atoms.
  • preferred compounds are (2), (6), (7), (12), (15), and (16), and particularly preferred are (2) and (7).
  • R 2 is a hydrogen or amino protecting group
  • R 3 is a hydrogen or hydroxyl protecting group
  • R 4 and R 5 are carboxyl protecting groups
  • X is a halogen atom.
  • R 1 represents a lower alkyl group which may be substituted with a halogen atom
  • the step of reacting the compound represented by the general formula [ ⁇ ] with the compound represented by the general formula [ ⁇ ] includes, for example, methylene chloride, chloroform, dimethyl ether, Ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide or a mixed solvent of the general formula
  • the reaction can be carried out by using 1 to 2 moles of the 4-pyrididothione derivative [m] with respect to 1 mole of the compound represented by [ ⁇ ] and reacting at 0 ° C or 40 ° C for 0.5 to 5 hours.
  • 0.1 to 3 mol of an iodide such as sodium iodide or potassium iodide is added to 1 mol of the compound represented by the general formula ( ⁇ ), It can be carried out efficiently without side reactions.
  • the step of removing the protecting group will be described. Depending on the type of the protecting group, the step of removing the protecting group can be carried out, for example, by Protective Eve Group in Organic Synthesis, published in 1981 by Wiley and written by TW Greene. Groups In Organic Synthesis) and Plenum Press (published in 1973) by feJ.FW Mccomy
  • protecting group for the carboxyl group amino group and hydroxyl group of the compound represented by the general formula [ ⁇ ]
  • a protecting group usually used in the field of 0-lactam compound chemistry can be used. Specific examples are shown below.
  • carboxyl-protecting group examples include tert-butyl group, 2,2,2-tri-ortho-ethyl group, acetooxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1- (ethoxycarbonyloxy) Ethyl, phthalidyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4- Nitrobenzyl group, benzhydryl group, bis (4-methoxyphenyl) methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, trimethylsilyl group, tert-butyldimethyl A silyl group and the like are preferred, and a benzylhydryl group, a tert-butyl group, a tri-lower alkylsilyl group and the like are particularly preferable.
  • the carboxyl-protecting groups may be the same or different, and the above-mentioned carboxyl-protecting groups suitable for the reaction are appropriately selected and used.
  • Examples of the protecting group for an amino group include a trityl group, a formyl group, a chloroacetyl group, a trifluoroacetyl group, a tert-butoxycarbonyl group, a trimethylsilyl group, and a tert-butyldimethylsilyl group.
  • hydroxyl-protecting groups include 2-methoxyethoxymethyl, methoxymethyl, methylthiomethyl, tetrahydrovinyl, phenacyl, isopropyl, tert-butyl, benzyl, and 4-nitrobenzyl.
  • the method for removing the protecting group is as follows.
  • the reaction can be carried out with an inorganic or organic acid such as hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, P-toluenesulfonic acid, etc., and trifluoroacetic acid is particularly preferred.
  • trifluoroacetic acid is used as the acid, the reaction is promoted by adding anisol, thioanisole, phenol, and the like, and further, side reactions are suppressed.
  • the reaction for removing the protecting group can be carried out in water, methylene chloride, chloroform, ethylene chloride, benzene or a mixed solvent thereof.
  • the reaction temperature and the reaction time are appropriately selected according to the poor chemical properties of the reaction product and the compound [I] of the present invention, and the kind of the protective group.
  • the step of converting the free form of the compound of the present invention [I] into its non-toxic salt may be carried out, for example, by applying a salt formation reaction commonly used in the art to the free form manufactured by the above-mentioned manufacturing method. Can be.
  • the step of converting the free form of the compound [I] of the present invention into its physiologically hydrolyzable non-toxic ester can be easily carried out by a known method.
  • Isolation and purification of the compound [I] of the present invention and its non-toxic salt produced by the above steps can be performed by a known method, for example, crystallization or column chromatography.
  • R z , R 3 and R 4 have the above-mentioned meanings
  • a reactive derivative of a carboxyl group thereof For example, water, acetone, dioxane, getyl ether, tetrahydrofuran, ethyl methyl ketone, chloroform, salt methylene, dichloroethane, ethyl acetate, ethyl formate, N, N-dimethylformamide, dimethyl sulfoxide or a mixture thereof
  • the reaction can be carried out in a solvent such as a mixed solvent which does not adversely affect the reaction, under the conditions of cooling to room temperature as the reaction temperature and 1 hour to 10 hours as the reaction time.
  • Examples of the reactive derivative of the carboxyl group of the compound [V] include a condensing agent such as ⁇ , ⁇ '-dicyclohexylcarposimide; for example, an activity formed by ⁇ -hydroxysuccinimide, 1-hydroxybenzotriazole, etc.
  • Esters for example, acid halides formed with halogenating agents such as thionyl chloride, phosphorus pentachloride, oxalyl chloride; deoxidizing agents such as triethylamine, ⁇ -methylmorpholine;
  • a mixed acid anhydride formed by a chromate formate such as isobutyl chromate formate is exemplified.
  • the reaction may proceed smoothly in the presence of a base.
  • a base include inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate;
  • organic bases such as trimethylamine, triearth tilamine, N, N-dimethylaniline, and pyridin can be used.
  • a condensing agent such as ⁇ , ⁇ ′-dicyclohexylcarbodiimide, ⁇ ⁇ , ⁇ ′-getylcarposimide. preferable.
  • the separation and purification of the raw material compound [ ⁇ ] produced in the above step can be carried out by a known method such as crystallization or column chromatography, but in some cases, without separation and purification, It can also be used as a raw material for the process.
  • the compound represented by the general formula [ ⁇ ] is described in a known manner, for example, in Journal of Chemical Society (J. Chem. Soc.), P. 3610 (1958) and JP-A-61-134390. It is easily manufactured by the method described above.
  • Compounds represented by the general formula [V] can be prepared by known methods, for example, Chemical and Pharmaceutical Bulletin (Chem. Phan. Bull), Vol. 25, pp. 3115-3119 (1977), and the Chemical Society of Japan, 785- 2- (2-Aminothiazol-4-yl) glyoxylic acid derivative or 2- (2-aminothiazol-4-yl) -2-hydroxy according to the method described on page 801 (1981), etc. It can be produced using an iminoacetic acid ester derivative.
  • Staphylococcus pereus JS1 is methicillin if.
  • CTX Cefotaxime or lower margin
  • the compound [I] of the present invention contains methidillin-resistant Staphylococcus aureus, and is a Gram-positive bacterium and a crumb-negative bacterium that are resistant to / 3-lactam antibiotics, especially Pseudomonas aeruginosa, Pseudomonas cepacia, and Acinetobacter. It showed excellent antibacterial activity and a broad, well-balanced and good antibacterial spectrum against non-glucose-negative crumb-negative bacteria such as lucoaceticus.
  • the compound of the general formula [I] and non-toxic salts thereof are useful as antibacterial agents.
  • the compounds of the present invention can be mixed with solid or liquid excipient carriers known in the art and used in the form of pharmaceutical preparations suitable for parenteral, oral or external administration.
  • Pharmaceutical preparations include, for example, 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 distilled water, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, talc, etc. can be used as additives.
  • the dose varies depending on the age, sex, symptoms, etc. of the patient, but it is usually used in the range of 1 to L00 mg / kg per day. It is preferable to administer the drug at 3030 mg / k in 2 to 4 divided doses.
  • the present invention will be described in more detail with reference to the following examples and reference examples.However, these 0 examples are merely examples and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed.
  • thin layer chromatography using (TLC) is a Kieselgel 60F 2 6 4 Merck (Merck) manufactured as a TLC plate and a UV detector as a detection method.
  • silica gel for the column Co-gel C-300 manufactured by Wako Pure Chemical Industries, Ltd. or LC-SORB® RP-18 manufactured by Chemco was used.
  • NM R spectrum as an internal standard, when measured in deuterated dimethyl sulfoxide (DMS0-d e) or heavy black port Holm (CDC1 3) solution tetramethylsilane
  • TMS 2,2-dimethyl-2-silapentane-5-sulfonate
  • D 20 heavy water
  • XL-200 200 MHz
  • R-40 90 MHz
  • the residue is dissolved in a mixture of 5 ⁇ of methylene chloride and 1 ⁇ £ of anisol, and 5ml of trifluoroacetic acid is added dropwise while cooling with water. After stirring at room temperature for 1 hour, the solvent is distilled off under reduced pressure, and diisopropyl ether is added to the residue. The resulting insolubles are collected by filtration, suspended in 5 mL of water, and adjusted to pH 7.0 using saturated aqueous sodium hydrogen carbonate.
  • Benzhydryl 7 j8- [[(Z) -2- [a-Benzhydryloxycarbonyl-3,4-di (2-methoxyethoxymethoxy) benzyl] oxyimino] -2- (2-Tritylaminothiazol-4-yl) acetamide] Dissolve 200 mg (0.15 OJ &) of 3-chloromethyl-3-cef-4-carboxylate in 4 m of N, N-dimethylformamide And add 124 mg (0.75 mmoJ2) of potassium iodide.
  • IR (KBr) crn 1830, 1510, 1470, 1220, 1200, 1110, 1030, 820, 540
  • reaction mixture is poured into IN hydrochloric acid, extracted with methylene chloride, and the organic layer is washed with 1N aqueous sodium hydroxide solution and saturated saline. After the extract is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure to obtain the title compound.
  • the compound of the present invention is a novel compound that has not been described in the literature, and contains a methicillin-resistant S

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

Composés représentés par la formule générale (I), dans laquelle R1 représente un groupe alkyle inférieur éventuellement substitué par un ou plusieurs atomes d'halogène, procédé de préparation de ces composés et leurs utilisation en tant qu'ingrédients actifs d'agents antifongiques.
PCT/JP1989/001042 1987-03-20 1989-10-11 Derives de 3-[(pyridinium-4-yle substitue en 1)thiomethyl]-cephalosporine WO1991005789A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP1989/001042 WO1991005789A1 (fr) 1987-03-20 1989-10-11 Derives de 3-[(pyridinium-4-yle substitue en 1)thiomethyl]-cephalosporine

Applications Claiming Priority (2)

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US07/028,576 US4880797A (en) 1986-03-20 1987-03-20 Cephalosporin derivatives and antibacterial agents
PCT/JP1989/001042 WO1991005789A1 (fr) 1987-03-20 1989-10-11 Derives de 3-[(pyridinium-4-yle substitue en 1)thiomethyl]-cephalosporine

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5890590A (ja) * 1981-11-16 1983-05-30 サノフイ・ソシエテ・アノニム 新規なセフアロスポリンおよびその製法
JPS59128391A (ja) * 1983-01-11 1984-07-24 Asahi Chem Ind Co Ltd セフアロスポリン誘導体
JPS62192387A (ja) * 1986-02-19 1987-08-22 イ−ライ・リリ−・アンド・カンパニ− Ｏ−置換オキシイミノセフアロスポリン類

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5890590A (ja) * 1981-11-16 1983-05-30 サノフイ・ソシエテ・アノニム 新規なセフアロスポリンおよびその製法
JPS59128391A (ja) * 1983-01-11 1984-07-24 Asahi Chem Ind Co Ltd セフアロスポリン誘導体
JPS62192387A (ja) * 1986-02-19 1987-08-22 イ−ライ・リリ−・アンド・カンパニ− Ｏ−置換オキシイミノセフアロスポリン類

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