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WO1993013109A1 - Derive de cephalosporine - Google Patents

Derive de cephalosporine Download PDF

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Publication number
WO1993013109A1
WO1993013109A1 PCT/JP1992/001660 JP9201660W WO9313109A1 WO 1993013109 A1 WO1993013109 A1 WO 1993013109A1 JP 9201660 W JP9201660 W JP 9201660W WO 9313109 A1 WO9313109 A1 WO 9313109A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
acid
formula
reaction
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1992/001660
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English (en)
Japanese (ja)
Inventor
Akira Onodera
Tomoki Miyazawa
Shigeo Morimoto
Katsuo Hatayama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taisho Pharmaceutical Co Ltd
Original Assignee
Taisho 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
Application filed by Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Publication of WO1993013109A1 publication Critical patent/WO1993013109A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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 derivative having a substituted thiocyanate group at the 3-position. More specifically, the present invention relates to an oral cephalosporin derivative and a non-toxic salt thereof, which are novel compounds and exhibit strong antibacterial activity. Background art
  • Cephalosporins are extremely effective drugs for treating bacterial infections because of their excellent antibacterial activity and high safety.
  • a number of research and development have been carried out on cefm derivatives having an aminothiazolyl group on the substituent of the 7-amino group, in particular, because they have strong antibacterial activity and a broad antibacterial spectrum.
  • cephalosporin-based antimicrobial substances useful as pharmaceuticals are known, but many of them are administered parenterally due to poor oral absorption.
  • cephalexin and cefaclor have a phenylglycylamino group at the 7-position and exhibit high oral absorption, but their antibacterial activity is high. Is significantly inferior to Gram-negative bacteria compared to cephalosporins for injection
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, have strong antibacterial activity and high We succeeded in synthesizing a novel cephalosporin derivative that also has oral absorbability and completed the present invention.
  • Honkiaki is of the formula (I)
  • R 1 represents a hydrogen atom or an amino protecting group
  • R 2 represents a hydrogen atom, a lower alkyl group or a hydroxyl protecting group
  • R 3 represents a hydrogen atom or a carboxyl protecting group.
  • X , ⁇ , and ⁇ represent a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, or a lower alkoxycarbonyl group, and at least one of X, ⁇ , and ⁇ is a halogen atom, a lower alkyl group, A phenyl group or a lower alkoxy carboxy group.
  • the functional groups in the present invention have the following meanings. That is, the protecting group for an amino group, the protecting group for a hydroxyl group, and the protecting group for a hydroxyl group mean a protecting group that is commonly used in the field of ⁇ -lactamylamide.
  • the protecting group for the amino group represented by R 1 includes a monochloroacetyl group, a formyl group, a benzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, t —Butoxycarbonyl group, trimethylsilyl group, etc.
  • the protecting group for the hydroxyl group represented by R 2 includes formyl group, acetyl group, propyl group, methoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, benzoyl group, toluoyl group, benzenesulfinyl group, Tosyl group, phenyl group, 4-methoxybenzyl group, 2,4-dimethylbenzyl group, trityl group, tetrahydroviranyl group and the like.Lower alkyl group means methyl group, ethyl group, propyl group and the like. is there.
  • the carboxyl-protecting group represented by R 3 includes methyl, ethyl, and propyl Group, isopropyl group, t-butyl group, vinyl group, aryl group, ethynyl group, methoxymethyl group, ethoxymethyl group, 1-methoxethyl group, methylthiomethyl group, carboxymethyl group, carboxyl group, t-butyl group Butoxycarbonylmethyl group, 2- (t-butoxycarbonyl) ethyl group, benzyl group, paranitrobenzyl group, bis- (4-methoxyphenyl) methyl group, 3,4-dimethoxybenzyl group, trityl group, phenethyl group, Prodrugs of phenacyl group, 2,2,2-trichloroethyl group, trimethylsilyl group, 4-hydroxy-3,5-di (t-butyl) benzyl group, phenyl group, trilyl group, xyl
  • the lower alkyl group represented by X, ⁇ , or ⁇ represents a methyl group, an ethyl group, or a propyl group
  • the lower alkoxycarbonyl group includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, or the like. It is.
  • the non-toxic salt of the compound represented by the formula (I) of the present invention means a pharmacologically acceptable salt, for example, an inorganic base containing sodium, potassium, magnesium, ammonium and the like.
  • Salts with organic bases such as triethylamine and cyclohexylamine, salts with basic amino acids such as arginine and lysine, salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, or acetic acid, lactic acid, tartaric acid, fumaral Examples thereof include salts with organic acids such as acid, maleic acid, trifluoroacetic acid, and methyl sulfonic acid.
  • a preferred example of R 1 is a hydrogen atom
  • a preferred example of R 2 is a hydrogen atom
  • R 3 can be exemplified hydrogen atom, respectively, to the compound represented by the formula of the present MizunotoAkira (I) may exist as geometric isomers derived from Okishiimino group 7-position side chain '(E body and ⁇
  • the present invention encompasses any one of the above, and is preferably an isomer.
  • Compound represented by the general formula of the present Mizunoto March ( ⁇ ) for example, it can be obtained by the production method shown in the reaction ⁇ shown in the following synthetic g path. m
  • R 1 R 3 is X. Y and Z are as defined above, and R 4 is phenylacetyl, phenoxyacetyl, trityl, fluoryl, formyl, benzoyl] And a protecting group for an amino group such as a group.
  • R 5 represents a lower alkyl group or a hydroxyl group shown by the R 2
  • R 6 represents a hydrogen atom or a lower alkyl group shown above.
  • R is a group that can be hydrolyzed in vivo, which is known from the ⁇ -lactam agent prodrug-forming technology shown in R 3 above
  • W, A, and B are each a halogen atom (eg, a chlorine atom, a bromine Atom, iodine Atoms), leaving groups such as methanesulfonyloxy, trifluoromethylsulfonyloxy, diphenylsulfonyloxy, and toluenesulfonyloxy.
  • Step a dissolving a known compound of the formula (II) in an organic solvent which does not participate in the reaction and stirring with 1.0 to 1.2 molar equivalents of sodium hydrosulfide in the presence of a base to obtain a 3-mercapto compound .
  • the reaction temperature is from 150 to 100 ° C, preferably from -40 to 5 ° C.
  • the reaction time is ⁇ 0 minutes ⁇ to 4 hours, preferably 10 minutes to 1 hour.
  • the reaction time varies depending on the kind of the base used, the kind of the compound of the formula (III) and the reaction temperature, but is 10 minutes to 5 hours, usually 10 minutes to 2 hours.
  • preferred organic solvents include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric acid triamide, acetate nitrile, tetrahydrofuran, dichloromethane and the like. They can be used alone or in combination.
  • Preferred bases include organic bases such as diisoprovirethylamine, N, N-dimethylaminopyridine, N, N-dimethylaniline, triethylamine, and the like.
  • concentration is 1.0 to 2.0 moles per compound.
  • the 3-mercapto form obtained by the above operation can be used for the next reaction after isolation. That is, a 3-mercapto compound is reacted with a compound of the formula (II) in the presence of the same base and organic solvent as described above to obtain a 3-thio-substituted compound of the formula (IV). The same applies to the reaction conditions.
  • Step b Next, the protecting group for the 7-amino group of the compound of the formula (IV) obtained in the above step a is removed by a method commonly used in the field of ⁇ -lactam chemistry to obtain a compound of the formula (V) is obtained.
  • the protecting group R 4 of the compound of formula (IV) may be substituted with a quinoxyacetyl group,
  • the compound of formula (IV) is dissolved in dichloromethane or benzene, and 1.5 to 2.0 molar equivalents of phosphorus pentachloride and pyridin 2.0 to 3.0.
  • the protecting group R 4 of the compound of the formula (IV) is a trityl group
  • the compound of the formula (IV) is dissolved in a solvent that does not participate in the reaction (eg, ethyl acetate), and the solution is cooled under ice-cooling.
  • a solvent that does not participate in the reaction eg, ethyl acetate
  • a paratoluenesulfonic acid salt of the compound of the formula (V) can be obtained.
  • This paratoluenesulfonate can be treated with a base, if necessary, to give a free compound of the formula (V).
  • Step c In order to obtain a compound of the formula (VII) from a compound of the formula (V), a compound of the formula (V) is reacted with a 2-aminothiazolacetic acid derivative of the formula (VI) in the presence of a condensing agent. Or reacting a compound of formula (V) with a reactive derivative of a compound of formula (VI).
  • the condensing agent is N, N-dicyclohexylcarpoimidide, 1-ethoxydiphenyl-1,2-ethoxy-1,2-dihydroquinoline, carbonyldiimidazole, diphenylphosphoric azide, Vilsmeier reagent And so on.
  • the reactive derivative of the compound of the formula (VI) includes an acid halide (for example, an acid chloride or an acid bromide of the formula (VI)), an acid anhydride (for example, a symmetrical acid anhydride of the compound of the formula (VI) or Mixed acid anhydrides with chlorocarbonate, diphenylphosphoric acid, methanesulfonic acid, etc.), and activated esters (for example, esters with paranitrophenol, titanium phenol, N-hydroxysuccinimide, etc.) .
  • an acid halide for example, an acid chloride or an acid bromide of the formula (VI)
  • an acid anhydride for example, a symmetrical acid anhydride of the compound of the formula (VI) or Mixed acid anhydrides with chlorocarbonate, diphenylphosphoric acid, methanesulfonic acid, etc.
  • activated esters for example, esters with paranitrophenol, titanium phenol, N-hydroxysuccinimide, etc.
  • a mixed acid anhydride of the compound of the formula (VI) with methanesulfonate is described.
  • the compound of the formula (VI) is dissolved in a solvent which does not participate in the reaction.
  • a base at a temperature of from 70 to 130 ° C, 1.0 to 1.1 molar equivalents of methanesulfonic acid chloride are added, and the mixture is stirred for 20 to 40 minutes and mixed acid anhydride of the compound of the formula (VI) Is prepared.
  • 0.5-0.7 mol equivalent of the compound of the formula (V) is added within a range of 170--30, and stirred for 20-40 minutes.
  • Preferred solvents in the present step include N, N-dimethylmethylammonium, tetrahydrofuran, acetonitrile, dichloromethanyl chloride form and the like.
  • Suitable bases are diisopropylethylamine, triethylamine, N, N-dimethylaniline, N.N-dimethylamino pyridine, pyridine and the like, and the amount of the base used is 1.0 to 1 with respect to the compound of the formula (V). 0 to 2.2 molar equivalents.
  • the compound of the formula (V ()) is dissolved in a solvent that does not participate in the reaction, and is dissolved in the presence of a base at 30 to 110. Then, 1.0 to 1.1 molar equivalents of phosphorus pentachloride are added, and the mixture is stirred for 10 to 30 minutes to prepare an acid chloride of the compound of the formula (VI).
  • a solution in which ⁇ 1.0 molar equivalent is dissolved in a solvent which does not participate in the same reaction as described above is added within a range of 130 to 0 ° C, and stirred for 10 to 30 minutes to obtain a compound of the formula (VII).
  • the preferred solvent for the step is dichloromethane, black hole Holm, Asetonitori Le, r N-dimethyl formamidine de, etc.
  • suitable bases are pyridine, Toryechiruamin, N, N-dimethylamino pyridine, N, N-Jimechiruaniri And diisoprovirethylamine, etc. It is from 4.0 to 5.5 molar equivalents against the compound of formula (V).
  • Step d Next, in order to obtain a compound of the formula (VIII) from the compound of the formula (VII) obtained in the above step c, the protecting group of the compound of the formula (VIi) is converted to ⁇ -lactam chemical Elimination is carried out by hydrolysis and reduction methods commonly used in the field. (1) Hydrolysis
  • the hydrolysis is preferably carried out in the presence of an acid.
  • an acid examples include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, formic acid, acetic acid, acetic acid with triflic acid, methanesulfonic acid, and benzene.
  • Organic acids such as sulfonic acid and para-toluenesulfonic acid are exemplified.
  • Lewis acids and acid ions such as boron trifluoride, boron trifluoride etherate, aluminum trichloride, antimony pentachloride, ferric chloride, tin chloride, titanium tetrachloride, zinc chloride, etc.
  • An exchange resin or the like may be used.
  • a scavenger such as anisol.
  • Preferred solvents for the hydrolysis are, for example, water, methanol, ethanol, tetrahydrofuran, N, N
  • the reduction is performed by a chemical reduction or a catalytic reduction method.
  • the reducing agent used in the chemical reduction include a combination of a metal such as zinc and iron with an organic or inorganic acid such as formic acid, acetic acid, trifluroic acid, hydrochloric acid, and hydrobromic acid.
  • the catalyst used in the catalytic reduction include platinum black, platinum oxide, palladium black, palladium carbon, Raney nickel and the like.
  • the reduction is usually carried out in a conventional solvent which does not adversely affect the reaction, such as water, methanol, ethanol, vinegar, tetrahydrofuran, N, N-dimethylformamide, dioxane, or a mixture thereof. It takes place inside.
  • a conventional solvent which does not adversely affect the reaction, such as water, methanol, ethanol, vinegar, tetrahydrofuran, N, N-dimethylformamide, dioxane, or a mixture thereof. It takes place inside.
  • the reaction temperature of the above-mentioned hydrolysis and reduction is not particularly limited, but it is usually carried out under cooling or under heating.
  • the compound of the formula (X) is prepared by reacting the compound of the formula (VIII) with the compound of the formula (IX) in the presence of a base or reacting the compound of the formula (IX) with a salt of the compound of the formula (VIII) Can be obtained.
  • Suitable bases in this reaction include triethylamine, diisoprovirethylamine, N, N-dimethyl Organic bases such as aminoviridine or inorganic bases such as sodium bicarbonate, sodium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.
  • the salt of the compound of the formula (VI [I]) is a salt with a metal such as silver, sodium, potassium, calcium, and magnesium.
  • This reaction will be described by taking a sodium salt as an example of the salt of the compound of the formula (VIII).
  • the sodium salt of the compound of the formula (VIII) is dissolved or suspended in a solvent that does not participate in the reaction, and is used in an amount of 1.0 to 2.0 molar equivalents. Is added, and the mixture is stirred at 50 to 50, preferably -30 to 20 ° C for 5 minutes to 2 hours, preferably 10 minutes to 1 hour.
  • Suitable solvents for this reaction are acetone, chloroform, dichloromethane, tetrahydrofuran, acetoneonitrile, getyl ether, methanol, ethanol, benzene, N, N-dimethyl wood amide, N, N-dimethyl acetate. Evening dimethyl, dimethyl sulfoxide, hexamethyl thiocyanate, water, etc.
  • the best form for carrying out KIKI is acetone, chloroform, dichloromethane, tetrahydr
  • the reaction solution was dropped into 100 ml of isopropyl ether, and the precipitated crystals were collected by filtration. Next, the crystals were dissolved in 9.0 ml of formic acid and stirred at room temperature for 1 hour. The insolubles were removed by filtration, and the filtrate was added dropwise to 120 ml of isopropyl ether.
  • Example 2 300 mg (0.6 mM) of the sodium salt obtained in Example 1 (d) was The solution was dissolved in 4.5 ml of dimethylformamide, added with 204 mg (0.8 mM) of bivaloyloxymethyl iodide under ice cooling, and stirred for 1 hour. After the reaction, 30 ml of water was added, extracted with 50 ml of ethyl acetate, washed with 30 ml of saturated saline, and dried over anhydrous magnesium sulfate.
  • Example 3 (b) 330 mg (0.6 mM) of the sodium salt obtained in Example 3 (b) above was dissolved in 4.5 ml of N, N-dimethylformamide, and 219 mg of bivaloyloxymethyl iodide was added under ice cooling. CO. 9 mM) and stirred for 1 hour.
  • G indicates a phenylasemid group
  • Tr indicates a trityl group
  • PMB ' indicates a paramethoxybenzyl group
  • nd indicates unmeasured.
  • the compound of formula (I) and the non-toxic salt thereof of the present invention not only have a strong antibacterial activity against various pathogenic bacteria including gram-positive bacteria and negative bacteria, but also have an excellent oral absorbability. As an antibacterial agent for oral administration Useful.
  • the compound of the present invention can be orally administered in the form of tablets, pills, capsules, granules, etc., manufactured according to conventional formulation techniques.
  • usual additives such as a bulking agent, a binder, a pH adjusting agent, and a solvent can be used.
  • the dosage of the compound of the present invention for a treated patient may vary depending on the age of the patient, the type and condition of the disease, and the like, but usually, 10 to 300 mg per day is divided into 1 to several doses. can do. Next, the antibacterial activity of the compound of the present invention is shown.
  • Drug dosage 20mgZkg (5% gum arabic suspension)
  • Quantitative S Bioassay method (Test bacterium: Bacillus cellureus S ⁇ 101) 3 cloud 7 to 7 "

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

Abstract

Médicament présentant un excellent effet sur les bactéries Gram positif et Gram négatif. Dérivé de céphalosporine représenté par la formule générale (I), et sel non toxique issu de ce dérivé; dans la formule R1 représente hydrogène ou un groupe protecteur; R2 représente hydrogène, alkyle inférieur ou un groupe protecteur; R3 représente hydrogène ou un groupe protecteur; et X, Y et Z représentent chacun hydrogène, halogène, alkyle inférieur, phényle ou alcoxycarbonyle inférieur, pourvu que l'un au moins de X, Y ou Z représente halogène, alkyle inférieur, phényle ou alcoxycarbonyle inférieur.
PCT/JP1992/001660 1991-12-24 1992-12-18 Derive de cephalosporine Ceased WO1993013109A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP34122991 1991-12-24
JP3/341229 1991-12-24

Publications (1)

Publication Number Publication Date
WO1993013109A1 true WO1993013109A1 (fr) 1993-07-08

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ID=18344384

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Application Number Title Priority Date Filing Date
PCT/JP1992/001660 Ceased WO1993013109A1 (fr) 1991-12-24 1992-12-18 Derive de cephalosporine

Country Status (2)

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AU (1) AU3171593A (fr)
WO (1) WO1993013109A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112295578A (zh) * 2020-11-20 2021-02-02 广西钦江药业有限公司 一种合成头孢西丁酸的催化剂

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283492A (en) * 1976-01-01 1977-07-12 Ciba Geigy Ag 7betaaaminoo33thioosephemm44 carboxylate compound
JPS60100585A (ja) * 1983-08-01 1985-06-04 Fujisawa Pharmaceut Co Ltd 新規セフエム化合物およびその製造法
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
JPS62174086A (ja) * 1985-08-12 1987-07-30 Taisho Pharmaceut Co Ltd セフアロスポリン誘導体
JPH01250386A (ja) * 1987-12-25 1989-10-05 Taisho Pharmaceut Co Ltd セファロスポリン誘導体
JPH0421685A (ja) * 1990-05-17 1992-01-24 Taisho Pharmaceut Co Ltd セファロスポリン誘導体

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283492A (en) * 1976-01-01 1977-07-12 Ciba Geigy Ag 7betaaaminoo33thioosephemm44 carboxylate compound
JPS60100585A (ja) * 1983-08-01 1985-06-04 Fujisawa Pharmaceut Co Ltd 新規セフエム化合物およびその製造法
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
JPS62174086A (ja) * 1985-08-12 1987-07-30 Taisho Pharmaceut Co Ltd セフアロスポリン誘導体
JPH01250386A (ja) * 1987-12-25 1989-10-05 Taisho Pharmaceut Co Ltd セファロスポリン誘導体
JPH0421685A (ja) * 1990-05-17 1992-01-24 Taisho Pharmaceut Co Ltd セファロスポリン誘導体

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112295578A (zh) * 2020-11-20 2021-02-02 广西钦江药业有限公司 一种合成头孢西丁酸的催化剂
CN112295578B (zh) * 2020-11-20 2022-08-12 广西钦江药业有限公司 一种合成头孢西丁酸的催化剂

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