WO1992002523A1 - Nouveau compose de cephalosporine - Google Patents

Nouveau compose de cephalosporine Download PDF

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Publication number
WO1992002523A1
WO1992002523A1 PCT/JP1991/001026 JP9101026W WO9202523A1 WO 1992002523 A1 WO1992002523 A1 WO 1992002523A1 JP 9101026 W JP9101026 W JP 9101026W WO 9202523 A1 WO9202523 A1 WO 9202523A1
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WO
WIPO (PCT)
Prior art keywords
formula
ester
salt
group
cephalosporin
Prior art date
Application number
PCT/JP1991/001026
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English (en)
Japanese (ja)
Inventor
Shigeo Shimizu
Hiroyuki Takano
Original Assignee
Sankei Pharmaceutical Company Limited
Nippon Pharmaceutical Development Institute Company Limited
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
Application filed by Sankei Pharmaceutical Company Limited, Nippon Pharmaceutical Development Institute Company Limited filed Critical Sankei Pharmaceutical Company Limited
Priority to KR1019920700744A priority Critical patent/KR0178011B1/ko
Publication of WO1992002523A1 publication Critical patent/WO1992002523A1/fr

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Classifications

    • 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
    • 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
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • 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 cephalosborin compound having a wide range of antibacterial properties.
  • Cephalosporin antibiotics have antibacterial activity against Gram-positive bacteria and negative bacteria, and many compounds have been actually used. Above all, compounds called third-generation cephalosporin antibiotics have a very wide spectrum of antibacterial spectrum and are especially valued clinically.
  • cephalosporin compounds have been studied, and for example, the following cephalosporin compound is disclosed in Japanese Patent Application Laid-Open No. Sho 63-152386. You.
  • R represents a hydrogen halogen or an organic group
  • the present inventors have conducted intensive studies on compounds having a strong antibacterial activity against a very wide range of pathogenic bacteria, and as a result, the compound having the following general formula (I) was found to be an excellent drug for treating bacterial infectious diseases. They have found that they have characteristics, and have completed the present invention.
  • the present invention provides a compound represented by the general formula (I):
  • R 1 , R 2 and R 3 each independently represent a hydrogen atom or a lower alkyl group: R 4 represents a hydrogen atom or a formula 10 R 6 (R 6 represents a hydrogen atom, a lower alkyl group or a protecting group): R 5 represents a hydrogen atom or an organic group)
  • examples of the lower alkyl group of R 1 , R 2 and R 3 include a linear or branched alkyl group having 1 to 3 carbon atoms. For example, methyl, ethyl, n- or isopropyl, and the like.
  • the lower alkyl group for R 6 includes a straight-chain or branched alkyl group having 1 to 4 carbon atoms.
  • methyl, ethyl, n- or isopropyl, n-butyl and the like can be mentioned.
  • the protecting group for R 6 include benzyl, p-methoxybenzyl, diphenylmethyl, trityl, 2-methoxymethoxymethyl and the like.
  • organic group for R 5 many groups are known, and as the substituent at the 3-position, those obtained by fermentation or those easily derived therefrom are commonly used.
  • substituent at the 3-position those obtained by fermentation or those easily derived therefrom are commonly used.
  • lower alkyl groups such as methyl and ethyl, vinyl groups, alkoxy groups having 1 to 3 carbon atoms such as methoxy and ethoxy, and methoxymethyl and ethoxymethyl.
  • R 5 is a group represented by the formula CH 2 —T, where T is a quaternary ammonium group or SR 7 (R 7 is a substituted or unsubstituted heterocyclic group. ).
  • the quaternary ammonium groups include triethylamine, trimethylamine, 1-methylbiperidine, 1-methylpyrrolidine, 1-methylpyrrolidin, —Methyl-3—Ammonia of aliphatic tertiary amines or nitrogen-containing saturated heterocyclic compounds such as pyrrolidinol, 1-amino carbonyl and 4-methylpyrazine, quinuridine Or pyridin, 2—methylpyridin, 3—methylpyridin, 41-methylpyridin, 41-ethylpyridin, 2,3—dimethylpyridin, 2 , 3 — Cyclopentenoviridine, 4-Aminoviridine, 3 — Cyanopyridine, Nicotinic acid, Nicotinic acid amide, Isonicotinic acid, Isonicotinic acid amide, 3 — Pyridinesulfonic acid, 4-Pyridine sulfonic acid, 3—Hydroxypyridin, 4-Hydroxypyri
  • a 5- to 6-membered monocyclic or condensed ring having 1 to 4 heteroatoms selected from 0, S or N in the ring can be used.
  • a heterocyclic group such as a tetrazolyl group, a triazolyl group, a thiazolyl group, a thiadiazolyl group, an oxadiazolyl group, a pyridyl group, or a pyridyl group; Midyl group, pyridazinyl group, pyrazolyl group, tetrazolo [1.5-b] pyridazinyl group, 1,2,4,1-triazolo [1.5-a] pyridyl Midinyl group, pyrazo opening [1.5—a] pyrimidinyl group, imidazolyl group, triazinyl And an isothiazolyl group.
  • substituent on these hetero groups include a lower alkyl group such as methyl and ethyl, and a halogen-substituted lower alkyl group such as a nitrogen atom, trifluoromethyl, and trichloroethyl.
  • R 5 Preferred correct Examples of R 5 are methylation, ⁇ Se Bok Kishimechiru, (1 over main switch ruthenate Bok Razoru 5- I le) Chiome chill, [1 - (2 - arsenate de Loki Shechiru) Te Bok Razoru 5- I le ⁇ ⁇ Thiomethyl, (1-carboxymethyltetrazol-5-yl) thiomethyl, (1.2.3-triazoyl-5-yl) thiomethyl, (1,3,4-thia) Diazo 2 -yl) Chi-methyl, (5-methyl 1, 3-3.4-Asia di 2- 2-) Thiomethyl, (1 .2-3-Thiadiazol 5 -yl) Thiome Thiol, (4-pyridyl) thiomethyl, (1-methyl pyridine) 2-thiol, thiomethyl,
  • cephalosporin compound of the formula (I) may be left undissociated, but may be, for example, an alkali metal salt such as sodium or potassium, or triethylamine or diamine.
  • Organic amine salts such as isopropylamine and cyclohexylamine may be formed.
  • the group forming an ester is a protecting group in a reaction such as a lower alkyl group such as tertiary butyl; an aralkyl group such as benzyl, diphenylmethyl, and p-2-trobenzyl.
  • Lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, etc .: 2—methoxymethoxymethyl Lower alkoxymethyl group such as lower alkoxymethyl group; 2.2.2—halogenated lower alkoxymethyl group such as trichloro ethoxymethyl group: acetoxymethyl, propionyl group xymethyl Aliphatic oxymethyl groups such as, for example, petilyl xymethyl, and vivaloy oxymethyl, 1-methoxycarbonylcarbonyl Such as ethyl, 1-ethoxycarbonyloxy, 1-propoxycarbonyl, 1-hydroxycarbonyl, 1-cyclohexyloxycarbonyl, etc.
  • the protecting group in the reaction of these carboxy groups can be removed by treatment with an acid or a base.
  • the protecting group is diphen
  • an aralkyl group such as nilmethyl
  • it is removed by reacting with trifluoroacetic acid or by a reducing agent such as zinc monoacetic acid or by catalytic reduction.
  • cephalosporin compound of the present invention can be synthesized, for example, according to the following three methods.
  • M represents a hydrogen atom or a protecting group for a carboxy group, and R s has the same meaning as described above.
  • R 7 represents a hydrogen atom or an amino-protecting group
  • R 8 represents a hydrogen atom or a hydroxyl-protecting group
  • R 1 R 2 , R 3 and R have the same meanings as described above.
  • the compound can be obtained by reacting with the compound represented by and, if necessary, removing the protecting group.
  • the compound can be obtained by reacting with the compound of formula (I) and removing a protecting group as necessary.
  • the reaction between compound (II) and compound (III) is preferably performed using a reactive derivative of compound (III).
  • a reactive derivative of compound (III) In this case, an acid halide, a mixed acid anhydride, an active ester, an active thioester, or the like is used as a reactive inducer.
  • a free carboxylic acid can be used as it is, but in that case, a condensing reagent is preferably used.
  • the reagent for example, N, N′-dicyclohexylcarpoimide, N, N′-carbonyldiimidazole, Cyanur chloride, Vilsmeier reagent and the like are used.
  • reaction are usually carried out in a suitable solvent, such as dichloromethane, chloroform-form, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, acetate.
  • a suitable solvent such as dichloromethane, chloroform-form, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, acetate.
  • the reaction is carried out at 110 to 30 ° C. for 0.5 to 2 hours in toluene, acetate, water or a mixed solvent thereof.
  • the protecting group is removed, if necessary, followed by separation and purification by a method well known in the art.
  • the protecting group for the amino group of R 7 is used in general peptide chemistry Easily removable protecting groups for amino groups, for example, alkanol groups such as formyl and trifluoracetyl: t-butoxycarbonyl, and alkoxyoxy groups such as trichloroethoxycasolevonyl.
  • Carbonyl group an aralkyloxycarbonyl group such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl: or protected by proton.
  • the method for removing these amino-protecting groups can be carried out, for example, by the method described in JP-B-58-583533.
  • the protecting group for the hydroxyl group of R 8 is benzyl, a — (or 3 —) naphthylmethyl, difuunylmethyl, triphenylmethyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4 Aralkyl groups in which the aryl ring is substituted with lower alkoxy, such as chlorobenzyl and 4-cyanobenzyl, ditoro, halogen, and cyano: acetyl, propionyl, trichloroacetyl, Benzyl, and acyl groups such as 412-trobenzoyl.
  • the hydroxyl-protecting group is an aralkyl group, it can be removed by contacting with a reducing agent, and when the hydroxyl-protecting group is an acyl group, it can be removed by treating with a base. .
  • compound (V) can be used as it is, but preferably a salt with a mineral acid, for example, hydrochloride or P-toluene sulfonate
  • a mineral acid for example, hydrochloride or P-toluene sulfonate
  • An organic sulfonate such as the following is used.
  • Such salts are preferably used in about equimolar amounts or in slight excess.
  • the reaction is preferably carried out with a polar organic solvent, such as dimethyl
  • the reaction is performed in a solvent such as lilleform amide, dimethyl acetate amide, N-methylpyrrolidone, dimethyl sulfoxide, or acetonitril.
  • the temperature for this reaction is 0 ° C to 50 ° C.
  • the protecting group may be removed and separated and purified by the method described above, if necessary, according to a method well known in the art.
  • reaction between compound (VI) and compound (VII) is usually carried out in a suitable solvent, for example, methanol, ethanol, ibropanol, tetrahydrofuran, dioxane.
  • a suitable solvent for example, methanol, ethanol, ibropanol, tetrahydrofuran, dioxane.
  • the reaction is carried out at 0 to 30 ° C. for 1 to 5 hours in acetonitril, etc. or a mixed solvent thereof.
  • the reaction is performed using the reactive derivative of (VIII).
  • the reactive derivative for example, an acid halide, a mixed acid anhydride, an active ester and the like are used. Also, free carboxylic acid can be used as it is. In that case, an appropriate condensation reagent may be used.
  • the reagent for example, N.N'-dicyclohexyl rubodiimide, cyanochloride, Vilsmeier reagent and the like are used.
  • reaction between (VI) and compound (VIII) is usually used in an equimolar amount. These reactions are usually carried out in a suitable solvent, such as dichloromethane, macroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, The reaction is carried out at 110 to 30 ° C for 0.5 to 2 hours in acetonitrile, acetone, water or a mixed solvent thereof. After the reaction, the protecting group may be removed by a method well-known in the art, if necessary, according to the method described above. To make.
  • a suitable solvent such as dichloromethane, macroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide
  • the salt or ester of the present invention obtained by each of the above methods may be further converted to a free carboxylic acid by a known method, if necessary, and the free carboxylic acid obtained by each of the above methods may be converted to a free carboxylic acid as necessary. It can also be converted to a pharmaceutically acceptable salt or ester by a known method.
  • novel cephalosporin compound of the present invention can be orally or parenterally administered to a human or animal in various known modes of administration.
  • the compound may be used alone or in combination with a pharmaceutically acceptable carrier, liquid diluent, binder, lubricant, humectant, etc., for example, for injections, tablets, granules, dragees, It is used in the form of general pharmaceutical compositions such as powders, capsules, gels, dry syrups, suspensions, solutions, emulsions, ointments, pastes, creams, suppositories and the like. Furthermore, as other additives that can be blended, dissolution retardants, absorption promoters, surfactants and the like can be mentioned. In any case, any known pharmaceutically acceptable substances can be used.
  • novel cephalosporin compounds of the present invention can be used alone or as a mixture of two or more different derivatives, the amount of which is about 0.1 based on the weight of the total drug composition. ⁇ 99.5%, preferably in the range of 0.5-95.0%.
  • other pharmacologically active compounds can be further mixed as an active ingredient in addition to the compound or a mixture thereof.
  • the daily dose of the novel cephalosporin compound of the present invention to patients varies depending on the human or the type of animal, its body weight and disease state. Weight per kg It is in the range of 1-1.000 mg, preferably 5-80 mg. It is orally or parenterally administered in 3 to 4 times a day.
  • Example 2 (sodium salt of the compound of Example 1) 7- ⁇ 2-(2-amino 1.3-thiazol-41-yl) 1 2-[1-1 (1.5-dihydroxyl-4-pyridone-1 2-il-methylene 3-(5-methyl 1.3.4. 4-thiadiazol 2-i-luciomethyl) 1 3-cefume 4 Rubonic acid sodium salt
  • Example 1 1.0 g of the compound obtained in Example 1 was suspended in 30 ml of water, adjusted to pH 7.0 with a 5% aqueous sodium hydrogen carbonate solution, and dissolved. This solution is applied to a column chromatograph on an adsorption resin (Mitsubishi Kasei Diaion HP-20), eluted with a mixture of water and methanol, and the fraction containing the target compound is concentrated, followed by freezing. Drying afforded 0.63 g of the title compound.
  • adsorption resin Mitsubishi Kasei Diaion HP-20
  • the solution was adjusted to pH 7 by adding 2N-hydrochloric acid, and then stirred at 65 ° C for 5 hours.
  • the reaction solution was stirred while dropping into 4 ml of acetate, and the precipitate was collected by filtration and dried to obtain a powder.
  • This powder was dissolved in water, subjected to reverse phase preparative chromatography, eluted with a mixture of water and methanol, concentrated, and lyophilized to give 0.52 g of the title compound. Obtained.
  • Example 1 3, 4 and the minimum deter concentration of the obtained the following compounds 1-4 in 6 [MIC (m / ml: 1 0 6 CFU / ml)] is shown in Table 1.
  • a novel cephalosporin compound can be provided.
  • the compound of the present invention represented by the above formula (I) exhibits excellent antibacterial activity against a wide range of Gram-negative bacteria and Gram-positive bacteria.
  • novel cephalosporin compounds of the present invention can be effectively used for humans or animals for the prevention or treatment of the above-mentioned bacterial infectious diseases. it can.

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

Abstract

L'invention se rapporte à un nouveau composé de céphalosporine, qui est représenté par la formule génerale (I) et qui possède un large spectre antibactérien. Dans la formule (I), A représente un groupe de formule -N=CH-, -NHCO-(CH=CH)m-, -CH2- ou -O-CH2; m est égal à 0 ou à 1; R?1, R2 et R3¿ représentent séparément un hydrogène ou un alkyle inférieur; R4 représente un hydrogène ou un groupe de formule -OR?6, où R6¿ représente un hydrogène, un alkyle inférieur ou un groupe protecteur; et R5 représente un hydrogène ou un groupe organique.
PCT/JP1991/001026 1990-08-02 1991-07-31 Nouveau compose de cephalosporine WO1992002523A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019920700744A KR0178011B1 (ko) 1990-08-02 1991-07-31 신규 세팔로스포린계 화합물

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2/203857 1990-08-02
JP20385790 1990-08-02
JP6530591 1991-03-07
JP3/65305 1991-03-07

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WO1992002523A1 true WO1992002523A1 (fr) 1992-02-20

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WO (1) WO1992002523A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016275A1 (fr) 2001-08-10 2003-02-27 Shionogi & Co., Ltd. Agent antiviral

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5387392A (en) * 1976-11-30 1978-08-01 Glaxo Lab Ltd Antibiotic compound and process for preparing same
JPS5519267A (en) * 1978-07-17 1980-02-09 Fujisawa Pharmaceut Co Ltd 3,7-disubstituted-3-cephem-4-carboxylic acid, its salts, their preparation, and preventive and remedy for microbism comprising them as active constituents
JPS56142287A (en) * 1980-03-13 1981-11-06 Squibb & Sons Inc Hydroxamic acid derivatives of aminothiazolyl-oxyiminoacetylaminocephalosporins
JPS59219282A (ja) * 1983-05-28 1984-12-10 Kyowa Hakko Kogyo Co Ltd β−ラクタム化合物およびその中間体
JPS63239287A (ja) * 1986-07-21 1988-10-05 Sankei Yakuhin Kk β−ラクタム化合物、該化合物の製造方法及び該化合物を含有する細菌感染症治療用医薬組成物並びに該化合物の合成中間体
JPH01125384A (ja) * 1987-11-11 1989-05-17 Meiji Seika Kaisha Ltd 新規セファロスポリン化合物及び抗菌剤
JPH02152982A (ja) * 1988-12-05 1990-06-12 Meiji Seika Kaisha Ltd 新規セファロスポリン化合物及び抗菌剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5387392A (en) * 1976-11-30 1978-08-01 Glaxo Lab Ltd Antibiotic compound and process for preparing same
JPS5519267A (en) * 1978-07-17 1980-02-09 Fujisawa Pharmaceut Co Ltd 3,7-disubstituted-3-cephem-4-carboxylic acid, its salts, their preparation, and preventive and remedy for microbism comprising them as active constituents
JPS56142287A (en) * 1980-03-13 1981-11-06 Squibb & Sons Inc Hydroxamic acid derivatives of aminothiazolyl-oxyiminoacetylaminocephalosporins
JPS59219282A (ja) * 1983-05-28 1984-12-10 Kyowa Hakko Kogyo Co Ltd β−ラクタム化合物およびその中間体
JPS63239287A (ja) * 1986-07-21 1988-10-05 Sankei Yakuhin Kk β−ラクタム化合物、該化合物の製造方法及び該化合物を含有する細菌感染症治療用医薬組成物並びに該化合物の合成中間体
JPH01125384A (ja) * 1987-11-11 1989-05-17 Meiji Seika Kaisha Ltd 新規セファロスポリン化合物及び抗菌剤
JPH02152982A (ja) * 1988-12-05 1990-06-12 Meiji Seika Kaisha Ltd 新規セファロスポリン化合物及び抗菌剤

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016275A1 (fr) 2001-08-10 2003-02-27 Shionogi & Co., Ltd. Agent antiviral
EP3042894A1 (fr) 2001-08-10 2016-07-13 Shionogi & Co., Ltd. Agent antiviral

Also Published As

Publication number Publication date
KR0178011B1 (ko) 1999-03-20
KR920702364A (ko) 1992-09-03

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