JPH0454676B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel cephalosporins, specifically, the general formula "In the formula, R ¹ is a hydrogen atom or a carboxyl protecting group, R ² is a formula

【formula】

[expression] or

[Formula] (In the formula, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are the same or different and represent a hydrogen atom, a halogen atom or an alkyl group. ), R ³ is a hydrogen atom, R ⁴ is a hydrogen atom,
R ⁵ is an optionally protected amino group, A is
Formula −CH ₂ − or Formula

[Formula] (In the formula, R ¹⁵ represents an alkyl group which may be substituted with an optionally protected carboxyl group, and ~ represents a syn or anti isomer or a mixture thereof.) The groups represented by are shown below. ” Concerning cephalosporin and its salts. Therefore, the object of the present invention is to have a broad antibacterial spectrum, exhibit excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and be stable against β-lactamases produced by bacteria. The object of the present invention is to provide novel cephalosporins that have unique properties and exhibit excellent therapeutic effects on diseases of humans and animals. The cephalosporins of the present invention have the formula

[Formula] 3,6 ^- dioxo ^{- 1,2} , represented by
3,6-tetrahydropyridazinyl group or formula

6 ^- oxo- ^{1,6 -} dihydropyridazinyl group or

It is characterized by the bonding of the 2-oxo ^{- 1,2} -dihydropyrazinyl group represented by the ^formula . Hereinafter, the present invention will be explained in further detail. In this specification, unless otherwise specified, alkyl refers to C _1-14 alkyl, such as methyl,
Ethyl, n-propyl, iso.-propyl, n-butyl, iso.-butyl, sec.-butyl, tert.-butyl, pentyl, hexyl, heptyl, octyl,
dodecyl or lauryl, etc.; alkoxy refers to -O-alkyl having an alkyl group as defined above; lower alkyl refers to _C1-5 alkyl, such as methyl, ethyl, n-propyl, iso.-propyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl or pentyl, etc.
Lower alkoxy refers to -O-lower alkyl having a lower alkyl group as defined above; acyl refers to -O-lower alkyl having a lower alkyl group as defined above;
_C1-12 acyl, such as acetyl, propionyl, butyryl, benzoyl, naphthoyl, pentanecarbonyl, cyclohexanecarbonyl, furoyl or thenoyl; furthermore, acyloxy refers to -O-acyl having an acyl group as defined above; In addition, alkylthio refers to -S-alkyl having an alkyl group as defined above, and alkenyl refers to _C2-10 alkenyl, such as vinyl,
Allyl, iso-propenyl, 2-pentenyl or butenyl, etc., and then alkynyl,
_C2-10 alkynyl, such as ethynyl or 2
- Propynyl etc., cycloalkyl is C _3-7
Cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; aryl such as phenyl, naphthyl or indanyl; aralkyl such as benzyl, phenethyl, 4-methylbenzyl or haftylmethyl, etc., and the heterocyclic group refers to at least one group selected from oxygen, nitrogen and sulfur.
Heterocyclic groups containing 6 heteroatoms, such as furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiazazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl,
4-(5-methyl-2-pyrrolinyl), 4-(2-
pyrrolinyl), N-methylpiperidinyl, quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl or clarinyl, and further heterocyclic alkyl as defined above A group consisting of a heterocyclic group and an alkyl group, and a halogen atom means, for example, a fluorine, chlorine, bromine or iodine atom, respectively. R ¹ in each general formula herein is a hydrogen atom or a carboxyl protecting group, and examples of the carboxyl protecting group include those conventionally used in the field of penicillin and cephalosporin compounds. These carboxyl-protecting groups include ester-forming groups that have the property of being eliminated by treatment under catalytic reduction, chemical reduction, or other mild conditions, or ester-forming groups that are easily eliminated in vivo, or water or Organic silyl groups, organic phosphorous groups, or organic tin groups, etc., which have the property of being easily eliminated by treatment with alcohol,
A wide variety of known ester-forming groups are mentioned. Among these types of protecting groups, suitable protecting groups include:
Specifically, the following can be mentioned. (a) Alkyl group. (b) At least one of the substituents is halogen, nitro, acyl, alkoxyoxo, cyano, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-
1,3-dioxol-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4
-imidazolyl, phthalimide, succinimide, azetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-
Lower alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, coumarinyl , 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidinyl, 4-methylpiperidino, 2,6-dimethylpiperidif, 4-(5-methyl-2-prolinyl), 4-(2- pyrrolinyl), N-methylpiperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy, cyclo Alkyloxy, cycloalkenyloxy, heterocyclicoxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, heterocyclicoxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, Substituted lower alkyl groups which are cycloalkyloxycarbonyl, cyloaralkenyloxycarbonyl, heterocyclic oxycarbonyl, alkylanilino or alkylanilino substituted with halogen, lower alkyl or lower alkoxy. (c) Cycloalkyl group; lower alkyl-substituted cycloalkyl or [2,2-di-lower alkyl-
1,3-dioxol-4-yl]methyl group. (d) Alkenyl group. (e) Alkynyl group. (f) A substituted phenyl group or a substituent in which the phenyl group or substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above, or a substituted phenyl group of the formula [In the formula, -Y ¹ - is -CH=CH-O-, -CH=
CH−S−, −CH ₂ CH ₂ S−, −CH=N−CH=
N-, -CH=CH-CH=CH-, -CO-CH=
CH-CO- or -CO-CO-CH=CH-. ] A group represented by or a substituted derivative thereof (the substituents are arbitrarily selected from those exemplified in (b) above),
or expression [In the formula, -Y ² - is a lower alkylene group such as -(CH ₂ ) ₃ - or -(CH ₂ ) ₄ -. ] A group represented by or a substituted derivative thereof (the substituents are arbitrarily selected from those exemplified in (b) above)
Aryl groups such as. (g) An aralkyl group such as benzyl or a substituted benzyl in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above. (h) A substituted heterocyclic group in which the heterocyclic group or substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above. (li) Alicyclic indanyl or phthalidyl and their substituted derivatives in which the substituent is methyl or halogen, alicyclic tetrahydronaphthyl and its substituted derivatives in which the substituent is methyl or halogen, trityl, cholesteryl, bicyclo-
[4.4.0] Decyl etc. (v) Alicyclic phthalidylidene lower alkyl group or substituted derivatives thereof whose substituent is a halogen or lower alkyl group. The carboxyl protecting groups exemplified above are representative examples, and in addition to these, protecting groups described in the following documents can be arbitrarily selected. U.S. Patents 3499909, 3573296 and 3641018
No.: West German Patent Publication Nos. 2301104, 2253287 and 2337105. Among these, preferred carboxyl protecting groups include, for example, 5-lower alkyl-2-oxo-1,3-dioxol-4-yl-lower alkyl group, acyloxyalkyl group, acylthioalkyl group, phthalidyl group, and indanyl group. , a phenyl group, a phthalidylidene lower alkyl group with or without a substituent, or a group that is easily eliminated in vivo, such as a group represented by the following formula.

【formula】

【formula】

[In the formula, R ¹⁸ is an alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without a known substituent, and R ¹⁹ is a hydrogen atom or a known substituent or R ²⁰ is an alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without a hydrogen atom, a halogen atom or a known substituent; group or -(CH ₂ ) _o COOR ¹⁹ (wherein R ¹⁹ has the above-mentioned meaning, n represents 0, 1 or 2), m represents 0, 1 or 2; ]

Furthermore, specifically, for example, 5-methyl-
2-oxo-1,3-dioxol-4-yl-
Methyl, 5-ethyl-2-oxo-1,3-dioxol-4-yl-methyl, 5-propyl-2
-5-lower alkyl-2-oxo- such as -oxo-1,3-dioxol-4-yl-methyl group
1,3-dioxol-4-yl-methyl group; acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy -n
-propyl, 1-pivaloyloxyethyl, 1-
Acyloxyalkyl groups such as pivaloyloxy-n-propyl group; acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl , 1-(p-chlorobenzoylthio)
Acylthioalkyl groups such as ethyl group; alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butyloxymethyl group; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, iso Propoxycarbonyloxymethyl, n-butyloxycarbonyloxy, tert.-butyloxycarbonyloxymethyl, 1-methoxycarbonyloxy-ethyl, 1-ethoxycarbonyloxy-
Alkoxycarbonyloxy-alkyl groups such as ethyl, 1-propoxycarbonyloxy-ethyl, 1-isopropoxycarbonyloxy-ethyl, 1-butyloxycarbonyloxy-ethyl groups; alkoxycarbonylmethyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl groups group; phthalidyl group; indanyl group; phenyl group;
Phthalides such as 2-(phthalidylidene)-ethyl, 2-(5-fluorophthalidylidene)-ethyl, 2-(6-chlorophthalidylidene)-ethyl, 2-(6-methoxyphthalidylidene)-ethyl group Examples include zylidene alkyl group. In addition, as the protecting group for the optionally protected amino group of ^R5 , there are many groups conventionally used in the field of penicillin and cephalosporin compounds, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, and tribromoethoxycarbonyl. Carbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chloroacetyl, trifluorocetyl, formyl, tert.-amyloxycarbonyl , tert.-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl,
Pyridin-1-oxide-2-yl-methoxycarbonyl, 2-furfuryloxycarbonyl,
diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl,
Examples include acyl groups that are easily eliminated such as phthaloyl, succinyl, 1-adamantyloxycarbonyl, and 8-quinolyloxycarbonyl;
trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,
2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2 -Propylidene, 1-benzoyl-2-propylidene, 1-[N-(2-methoxyphenyl)carbamoyl]-2-propylidene, 1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2 -Ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-
Examples thereof include groups that are easily eliminated such as dimethyl-5-oxocyclohexylidene, and protecting groups for amino groups such as di- or tri-alkylsilyl. -A- is the formula -CH ₂ - or the formula

[Formula] (In the formula, R ¹⁵ represents an alkyl group which may be substituted with an optionally protected carboxyl group, and ~ represents a syn or anti isomer or a mixture thereof.) means a group represented by Examples of the optionally protected carboxyl group-protecting group for R ¹⁵ include the same carboxyl group-protecting groups as explained for R ¹ . next,

The oxime represented by the formula includes syn and anti isomers and mixtures thereof. Each general formula of the present invention

In the group [Formula], tautomers exist as shown in the following balanced formula, and these tautomers are also included. [In the above balanced formula, R ⁴ and R ⁵ have the above-mentioned meanings, and R ⁵ ' represents an optionally protected imino group. ] In the above formula, as the protecting group for the imino group of R ⁵ ′, groups conventionally used in the field of penicillin and cephalosporin compounds can be mentioned, and specifically, the amino group described for R ⁵ Among the protective groups for groups, the same groups as monovalent groups can be mentioned. Also, the formula −CH ₂ R ² of the general formula [] is the formula

If R ⁶ of the group represented by [Formula] (in which R ⁶ , R ⁷ and R ⁸ have the meanings described above) is a hydrogen atom, tautomerism as shown in the balanced formula below tautomers exist, and their tautomers are also included. As salts of the compound of general formula [], conventionally,
Mention may be made of the salts with basic or acidic groups well known in the field of penicillin and cephalosporin compounds. Salts on such basic groups include, for example, salts with mineral acids such as hydrochloric acid, nitric acid or sulfuric acid; salts with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid or trifluoroacetic acid; methane; Sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-
Sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid), naphthalene-1-sulfonic acid,
Naphthalene-2-sulfonic acid, phenylmethanesulfonic acid, benzene-1,3-disulfonic acid, toluene-3,5-disulfonic acid, naphthalene-
1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, naphthalene-2,7-disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene-1,2,4-trisulfonic acid, naphthalene - Salts with sulfonic acids such as 1,3,5-trisulfonic acid, and as salts with acidic groups, for example salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; salt; ammonium salt;
Brocaine, dibenzylamine, N-benzyl-
β-phenethylamine, 1-phenamine, N,
Salts with nitrogen-containing organic bases such as N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, and dicyclohexylamine can be mentioned. . The present invention also encompasses all optical isomers and racemates of cephalosporin of the general formula [ ] and its salts, as well as all crystal forms and hydrates. More specifically, in the compound represented by the general formula [], as a preferable example, A is the formula

Among the oximes represented by the formula, the syn isomer is further
Mention may be made of compounds in which R ¹⁵ is an alkyl group, in particular a methyl group, an ethyl group or each group of the formula -CH ₂ COOR ¹ , in which R ¹ has the meaning given above. Next, as a preferable example of R ² , the formula

In the case of the group represented by [Formula], R ⁶ , R ⁷ and R ⁸ are the same or different, a hydrogen atom,
A halogen atom or a lower alkyl group also has the formula

In the case of the group represented by the formula, R ⁹ is a lower alkyl group, R ¹⁰ and R ¹¹ are the same or different, and a hydrogen atom or a lower alkyl group is further added to the formula

In the case of the group represented by [Formula], R ¹² , R ¹³ and R ¹⁴ are the same or different,
Examples include a hydrogen atom or a lower alkyl group. Next, the pharmacological effects obtained for some representative compounds among the compounds represented by the general formula [] will be shown. (1) Antibacterial action (Table 1) According to the standard method of the Japanese Society of Chemotherapy [(CHEMOTHERAPY) Vol. 23, pages 1-2 (1975)], in Heart Infusion broth (manufactured by Eiken Kagaku Co., Ltd.) at 37°C and 20 The cultured bacterial solution was inoculated into Heart Infusion agar medium (manufactured by Eiken Kagaku Co., Ltd.) containing the drug, and after culturing at 37℃ for 20 hours, the presence or absence of bacterial growth was observed, and the minimum concentration that inhibited bacterial growth was determined. was defined as MIC (μg/ml). However, the amount of inoculated bacteria is 10 ⁴ cells/plate (10 ⁶ cells/ml)
And so. The test compounds are as follows. (A) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-{[1-(3,6-dioxo-1,
2,3,6-tetrahydropyridazinyl)]
methyl}-△ ³ -cephem-4-carboxylic acid trifluoroacetate (B) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-{ [1-(3-methyl-6-oxo-1,6-dihydropyridazinyl)]methyl}
-△ ³ -Trifluoroacetate of cefem-4-carboxylic acid (C) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-{[1 -(2-oxo-1,2-dihydropyrazinyl)]methyl}-△ ^{3 -Cephem} -4-carboxylic acid trifluoroacetate (D) 7-[2-(2-aminothiazol-4-yl )-2-(syn)-carboxymethoxyiminoacetamide]-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-Δ ³ -cephem- Formate of 4-carboxylic acid (E) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamide]-3-{[1-(3-methyl-
Formic acid of 6-oxo-1,6-dihydropyridazinyl)]methyl}-Δ ³ -cephem-4-carboxylic acid

[Table] Note * Penicillinase-producing bacteria
** Cephalosporinas-producing bacteria 2 Urinary recovery rate Test compound was administered to mice (ICR, male, 4 weeks old) 1
1 mg per animal was orally administered, and the urinary recovery rate was determined. The results are shown in Table 2. In addition, the ester groups of all test compounds are easily eliminated in vivo after absorption, resulting in the corresponding free carboxylic acid, so the free carboxylic acid excreted in the urine was quantified and calculated as the urinary recovery rate. . Administration method The test compound was suspended in 0.5% CMC and then administered orally. Quantification method Quantification was carried out using the paper disc method using the test bacteria listed in Table 2 ^* .

【table】

[Table] * 0 to 6 hours, average of 3 in 5 cases Acute toxicity test Test compound mice below (ICR, male, body weight 20
~24g) _LD50 value for intravenous administration is 3g/
It was over Kg. The test compounds are as follows. Γ7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-{[1-(3,6-dioxo-1,
2,3,6-tetrahydropyridazinyl)]
Sodium salt of methyl}-△ ³ -cephem-4-carboxylic acid. Γ7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-{[1-(3-methyl-6-oxo-1,6-dihydropyridazine) 〕Methyl〕
^-Δ3 -Cefem-4-carboxylic acid sodium salt. Next, the manufacturing method will be explained. The compound of the present invention can be produced, for example, by the method shown below. [In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , A and ~ have the above-mentioned meanings, R ²⁶ is an amino group, Formula

[Formula] (In the formula, R ²⁶ , R ²⁷ and R ²⁸ are the same or different and represent a hydrogen atom or an organic residue that does not participate in the reaction.) or Formula

[Formula] (wherein R ²⁹ and R ³⁰ are the same or different and represent a hydrogen atom or an organic residue that does not participate in the reaction), and R ²⁵ has a substituent or An acyloxy group or a carbamoyloxy group that is not
is a halogen atom, Z is S or S→O
and the dotted line in the ring mean that the 2nd to 3rd or 3rd to 4th positions are double bonds, respectively. ] Below, to explain in detail, R ²⁴ is an amino group or a formula

[Formula] or a group represented by the formula R ²⁹ R ³⁰ C=N -, but the formula

The group represented by [Formula] Expressions that are gender bodies

A group represented by the formula is also included. and R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹
The organic residues that do not participate in the reaction in R ³⁰ include organic residues known in the art, specifically aliphatic residues with or without substituents, alicyclic residues, aromatic residues, etc. Examples include group residues, aromatic aliphatic residues, heterocyclic residues, and acyl groups, and specific examples include the following groups. (1) Aliphatic residues: for example, alkyl groups such as methyl, ethyl, propyl, butyl, isobutyl, pentyl; alkenyl groups such as vinyl, propenyl, butenyl. (2) Alicyclic residues: For example, cycloalkyl groups such as cyclopentyl, cyclohexyl, and cycloheptyl; chloroalkenyl groups such as cyclopentenyl and cyclohexenyl. (3) Aromatic residues: for example, aryl groups such as phenyl and naphthyl. (4) Aroaliphatic residues: for example, aralkyl groups such as benzyl and phenethyl. (5) Heterocyclic residues: For example, heteroatoms (oxygen , nitrogen or sulfur atoms). (6) Acyl group: An acyl group that can be derived from an organic carboxylic acid, such as an aliphatic carboxylic acid, an alicyclic carboxylic acid, an alicyclic aliphatic carboxylic acid, or an aliphatic carboxylic acid. Aromatic substituted aliphatic carboxylic acids, aromatic oxyaliphatic carboxylic acids, aromatic thioaliphatic carboxylic acids, in which aromatic residues or heterocyclic groups are bonded to carboxylic acids with or without oxygen or sulfur atoms; An aromatic ring, aliphatic group, or alicyclic group is bonded to a heterocyclic-substituted aliphatic carboxylic acid, a heterocyclic oxyaliphatic carboxylic acid, a heterocyclic thioaliphatic carboxylic acid, or a carbonyl group via an oxygen, nitrogen, or sulfur atom. Examples include organic carboxylic acids and organic carboxylic acids such as aromatic carboxylic acids and heterocyclic carboxylic acids. Here, examples of aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic acid, crotonic acid, etc., and examples of alicyclic carboxylic acids include: Examples of the alicyclic aliphatic carboxylic acids include cyclohexanoic acid, cyclopentaneacetic acid, cyclohexaneacetic acid, cyclohexanepropionic acid, and cyclohexadieneacetic acid. Further, aromatic residues in the above-mentioned organic carboxylic acids include phenyl, naphthyl, etc., and further examples of the above-mentioned heterocyclic groups include furan,
Thiophene, pyrrole, pyrazole, imidazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, thiatriazole,
Examples include residues of heterocyclic compounds containing one or more heteroatoms in the ring, such as oxatriazole, tetrazole, benzoxazole, and benzofuran. Each group constituting these organic carboxylic acids includes, for example, a halogen atom, a hydroxyl group, a protected hydroxyl group, an alkyl group, an alkoxy group, an acyl group, a nitro group, an amino group, a protected amino group, and a carboxy group. It may be further substituted with a substituent such as a group or a protected carboxyl group. Examples of the acyloxy and carbamoyloxy groups for ^R25 include alkanoyloxy groups such as acetoxy, propionyloxy, or butyryloxy; alkenoyloxy groups such as acryloyloxy; aroyloxy groups such as benzoyloxy or naphthoyloxy; and carbamoyloxy These groups include halogen atoms, nitro groups, alkyl groups, alkoxy groups, alkylthio groups, acyloxy groups, acylamino groups, hydroxyl groups, carboxyl groups, sulfamoyl groups, carbamoyl groups, carboalkoxycarbamoyl groups, aroylcarbamoyl groups, and carboalkoxycarbamoyl groups. Alkoxysulfamoyl group, aryl group,
It may be substituted with one or more substituents such as a carbamoyloxy group. Among the substituents for R ²⁵ described above, the hydroxyl group, amino group, carboxyl group, etc. may be protected with a commonly used protecting group. (a) Three-position conversion reaction A cephalosporanic acid of the general formula [] or a salt thereof in the presence of an acid or a complex compound of an acid,
3,6-dioxo-1 of general formula [-a],
2,3,6-tetrahydropyridazines, 6-oxo-1,6-dihydropyridazines of general formula [-b] or 2-oxo-1,2-dihydrapyridazines of general formula [-c] or salts thereof 7-substituted or unsubstituted amino-3-substituted methylcefemcarboxylic acids or salts thereof of the general formula [] can be produced industrially by removing the protecting group or protecting or converting the carboxyl group into a salt, if desired. It can be produced with high yield and high purity through easy operations. Furthermore, if desired, the substituent on the 7-position amino group can be removed by a conventional method to obtain a 7-unsubstituted amino compound. According to this method, not only the △ ³ -cephem compound but also the △ ² -cepheme compound can be used, and when the △ ² -cepheme compound is used, the △ ² -cepheme compound obtained after the reaction is converted into △ ³ -cepheme compound. can be converted into compounds. In addition to compounds where Z is S,
Compounds in which Z is S→O can also be used as starting materials, in which case S→O can be converted to S during the reaction or in the work-up step. In addition, 3,6-dioxo-1 of the general formula [-a] used as a reaction reagent in this reaction,
2,3,6-tetrahydropyridazines, 6-oxo-1,6-dihydropyridazines of general formula [-b] and 2-oxo-1,2-dihydropyrazines of general formula [-c],
When these substituents have a basic group or an acidic group, they may be subjected to the reaction in the form of their respective salts, if necessary. In this case, the salts for the basic group and the salts for the acidic group are generally Examples include the same salts with basic groups and acidic groups as explained in the salts of cephalosporin of formula []. In addition, examples of the salts of the compounds of general formulas [] and [] include salts with basic groups or acidic groups, and the same salts as those explained for the salts of the compounds of general formulas [] are mentioned. It will be done. Note that the salts of the compound of general formula [] may be used after being isolated in advance, or may be prepared in-system. The acid or acid complex used in this reaction includes, for example, a protonic acid, a Lewis acid, or a Lewis acid complex.
Protonic acids include, for example, sulfuric acids, sulfonic acids, or super strong acids (super strong acids mean acids stronger than 100% sulfuric acid, and also include some of the aforementioned sulfuric acids and sulfonic acids); Specifically, sulfuric acids such as sulfuric acid, chlorosulfuric acid or fluorosulfuric acid; alkyl (mono- or di-)sulfonic acids such as methanesulfonic acid or trifluoromethanesulfonic acid, or p
- Sulfonic acids such as aryl (mono-, di- or tri-)sulfonic acids such as toluenesulfonic acid; perchloric acid, magicic acid (FSO ₂ H-
SbF ₅ ), FSO ₂ H−AsF ₅ , CF ₂ SO ₂ H−SbF ₅ ,
Examples include super strong acids such as HF- _BF2 and _{H2SO4 -SO2 .} Furthermore, examples of the Lewis acid include boron trifluoride. In addition, examples of complex compounds of Lewis acids include boron trifluoride and diethyl ether, di-n-propyl ether, di-
Dialkyl ether complex salts with n-butyl ether, etc.; ethylamine, n-propylamine,
Examples include amine complex salts with n-butylamine, triethanolamine, etc.; carboxylic acid ester complex salts with ethyl formate, ethyl acetate, etc.; fatty acid complex salts with acetic acid, propionic acid, etc.; or nitrile complex salts with acetonitrile, propionitrile, etc. It will be done. In addition, it is preferable to use an organic solvent in this reaction, and examples of organic solvents that can be used include all organic solvents that are inert to the reaction, such as nitroalkanes such as nitromethane, nitroethane, and nitropropane; formic acid, acetic acid, Organic carboxylic acids such as trifluoroacetic acid, dichloroacetic acid, and propionic acid; Ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; Ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, and dimethyl cellosolve; Examples include esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, and butyl acetate; nitriles such as acetonitrile and butyronitrile; and sulfolanes such as sulfolane; two or more of these solvents may be mixed. It may also be used. Moreover, a complex compound formed by these organic solvents and a Lewis acid can also be used as a solvent. The amount of the acid or acid complex compound to be used may be at least the equivalent molar amount of the compound of general formula [] or its salt, and can be increased or decreased as appropriate depending on the individual case. In particular, it is preferable to use 2 to 10 times the molar amount. When using an acid complex compound, it can be used itself as a solvent, or a mixture of two or more kinds of complex compounds may be used. In addition, 3,6-dioxo-1,2, of the general formula [-a] used as a reaction reagent for this reaction,
3,6-tetrahydropyridazines, 6-oxo-1,6-dihydropyridazines of general formula [-b] and 2-oxo-1,2-dihydropyrazines of general formula [-c] or their salts. The amount used may be at least the equivalent molar amount of the compound of general formula [] or its salt, but it is particularly preferred to use 1.0 to 5.0 times the molar amount. This reaction is usually carried out at 0 to 80°C for several minutes to
It can be completed in a few dozen hours. If there is water in the reaction system, lactonization of the raw materials or products and β
- Since undesirable side reactions such as cleavage of the lactam ring may occur, it is desirable to maintain the reaction system in an anhydrous state. In order to satisfy this condition, a suitable dehydrating agent is added to the reaction system, such as a phosphorus compound such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, or phosphorus oxychloride;
-Organic silylating agents such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide, trimethylchlorosilane, and dimethyldichlorosilane; Organic acid chlorides such as acetyl chloride and p-toluenesulfonyl chloride; Acid anhydrides such as acetic anhydride and trifluoroacetic anhydride ;
Anhydrous magnesium sulfate, anhydrous calcium chloride,
An inorganic desiccant such as a molecular sieve or calcium carbide may be added. General formula in which R ¹ represents a carboxyl protecting group []
When a compound of the formula [] is used as a raw material, the corresponding compound of the general formula [] in which R ¹ is a hydrogen atom may be obtained by post-reaction treatment, but if desired, the protecting group can be removed by a conventional method, and R A compound of the general formula [] where ¹ is a hydrogen atom can be obtained. 3,6-dioxo-1,2, of the general formula [-a] used as a reaction reagent in this reaction,
In 3,6-tetrahydropyridazines, 6-oxo-1,6-dihydropyridazines of general formula [-b] and 2-oxo-1,2-dihydropyrazines of general formula [-c] or their salts , if those substituents are substituted with hydroxyl groups, amino groups, carboxyl groups, etc., these groups are protected with the aforementioned protecting groups before carrying out this reaction, and after the reaction is completed, conventional elimination A desired compound can be obtained by subjecting it to the reaction. Further, in the compound of general formula [], the carboxyl group can be protected or converted into a salt according to a conventional method, if desired, and the desired compound can also be obtained. Further, the compound of the general formula [] in which R ²⁴ is an amino group can be converted into a reactive derivative at the amino group as described below by a conventional method. (b) Acylation reaction The compound of the general formula [] obtained by the above method or its salt or its reactive derivative at the amino group is treated with the compound of the general formula [], [],
By reacting a compound of [], [] or [], or a salt thereof, or a reactive derivative thereof, a compound of general formula [], [], [], [XI] or [] or a salt thereof can be obtained. . In addition, salts of the compound of the general formula [], [], [], [] or [] include salts in a basic group or an acidic group; The same ones as those described are mentioned. Examples of reactive derivatives at the amino group of the compound of general formula [] include Schiff's bases (imino type or Its enamine type isomer), general formula []
or its salts, silyl compounds such as N,O-bis(trimethysilyl)acetamide, trimethylsilylacetamide, trimethylsilyl chloride, phosphorus trichloride,

【formula】

【formula】

[Formula] Silyl derivatives and phosphorus derivatives produced by reaction with phosphorus compounds such as (CH ₃ CH ₂ O) ₂ PCl, (CH ₃ CH ₂ ) ₂ PCl, or tin compounds such as (C ₄ H ₉ ) ₃ SnCl. Also included are all those frequently used in acylation reactions, such as tin derivatives. General formula [], [], [], [] or [
Specifically, reactive derivatives of compounds of formulas [], [], [], [] or [] include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, and ) Reactive derivatives of the compound with Vilsmeier's reagent, etc. The mixed acid anhydride includes, for example, a mixed acid anhydride with a carbonic acid monoalkyl ester such as carbonic acid monoethyl ester and carbonic acid monoisobutyl ester, and a lower alkanoic acid which may be substituted with a halogen such as pivalic acid and trichloroacetic acid. Mixtures of acid hydrides and the like are used. Examples of the active acid amide include N-acyl saccharin, N-acylimidazole, N-acylbenzoylamide, N,
N'-dicyclohexyl-N-acylurea, N
-Acylsulfonamide etc. are used. Next, as the active ester, for example, cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, substituted thier ester, etc. are used. In addition, examples of derivatives reactive with the Vilsmeier reagent include N,N-dimethylformamide,
Acid amides such as N,N-dimethylacetamide are treated with halogenating agents such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl chloroformate, and oxalyl chloride. Examples include derivatives reactive with Vilsmeier's reagent obtained by General formula [], [], [], [] or [
] When using each compound in the form of a free acid or salt, a suitable condensing agent is used. Such condensing agents include, for example, N,N'-
N such as dicyclohexylcarbodiimide,
N′-disubstituted carbimides, azolide compounds such as N,N′-thionyldiimidazole, N
-ethoxycarbonyl-2-ethoxy-1,2
Dehydrating agents such as -dihydroxyquinoline, phosphorus oxychloride, and acid alkoxyacetylene, 2-halogenopyridinium salts (eg, 2-chloropyridinium methyliodide, 2-fluoropyridinium methyliodide), and the like are used. This acylation reaction is generally carried out in a suitable solvent with or without a base. Examples of solvents that can be used include chloroform, halogenated hydrocarbons such as methylene chloride, tetrahydrofuran, ethers such as dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, water, and mixtures thereof. The bases used here include inorganic bases such as alkali hydroxide, alkali hydrogen carbonate, alkali carbonate or alkali acetate, or trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, etc. Examples include tertiary amines and secondary amines such as dicyclohexylamine and diethylamine. In addition, general formula [a] and [
The compound of the general formula [] and its salts which can be derived from the compound of b] and its salts can also be produced as follows. In order to obtain the compound of the general formula [] or its salts using the compound of the general formula [] or its salts, the reaction of diketene with a halogen such as chlorine or bromine [Journal of the Chemical Society, 97] , 1987 (1910)] and a compound of the general formula [] or a salt thereof may be reacted according to a conventional method. Conditions and operations known in the art can be applied to this reaction condition and operation. Also, general formula []
The salts of the compound can be easily obtained according to conventional methods, and the salts include the same salts as explained above for the salts of the compound of the general formula []. The resulting compound of general formula [] and its salts may be isolated and purified by conventional methods, but may also be used in the next reaction without isolation. The amount of the compound of the general formula [], [], [], [] or [] or its reactive derivative to be used is per mole of the compound of the general formula [], its salt or its reactive derivative in the amino group. On the other hand, it is usually preferable to use about 1 to several moles each. Reaction temperature is usually -50 to 40℃
It is carried out within the range of Reaction time is usually 10 minutes to 48
It's time. Furthermore, general formulas [], [], [], [XI] and [] in which R ¹ is a carboxyl protecting group
In the case of compounds of the general formula [], [], [], [XI] and [], where R ¹ is a hydrogen atom, or their salts; General formula [], where R ¹ is a hydrogen atom, In the case of compounds of [], [], [XI] and [], the general formula [], [], [], [XI] where R ¹ is a carboxyl protecting group
and [ ] or their salts; and in the case of salts of compounds of the general formulas [ ], [ ], [ ], [ can be converted. In addition, in this acylation reaction, R ¹ , R ² ,
When there is a reactive group in the R ³ group,
During the reaction, it can be optionally protected with a conventional protecting group, and after the reaction, the protective group can be removed by a conventional method. The compound of the general formula [] of the present invention obtained as described above and its salts can be isolated by a conventional method. (d) Nitrosation reaction Next, to obtain a compound of general formula [] or a salt thereof from a compound of general formula [] or a salt thereof, the compound of general formula [] or a salt thereof is reacted with a nitrosation agent. This reaction is usually carried out in a solvent, and examples of the solvent that can be used include water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, and other solvents that are inert to the reaction. Preferred examples of nitrosating agents include nitric acid and its derivatives, such as nitrosyl halides such as nitrosyl chloride and nitrosyl bromide, sodium nitrite,
alkali metal salts of nitrite, such as potassium nitrite;
Examples include alkyl nitrites such as butyl nitrite and pentyl nitrite. When using a salt of nitrous acid as a nitrosating agent, the reaction is preferably carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, or acetic acid. When a nitrite is used as a nitrosating agent, it is preferably carried out in the presence of a strong base such as an alkali metal alkoxide. The reaction is generally carried out in the range of -15 to 30°C,
The reaction time is usually 10 minutes to 10 hours. Also,
Salts of the compound of general formula [] can be easily obtained according to conventional methods, and examples of the salts include the same salts as explained for the salts of the compound of general formula []. The compound of general formula [] and its salts thus obtained can be isolated and purified by known means, but can also be used as a raw material for the next reaction without being isolated. (d) Alkylation reaction Next, in order to obtain the compound of general formula [XI] or its salts from the compound of general formula [] or its salts, the compound of general formula [] or its salts is subjected to an alkylation reaction. This alkylation reaction can be carried out according to a conventional method. The reaction is generally carried out in the range of -20 to 60°C, and the reaction time is
Usually it takes 5 minutes to 10 hours. Any solvent may be used as long as it does not inhibit this reaction, such as tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene chloride, ethyl acetate, butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, and water. etc. or a mixture thereof can be used. As the alkylating agent, for example, lower alkyl halides such as methyl iodide, methyl bromide, methyl iodide, and ethyl bromide, dimethyl sulfate, diethyl sulfate, diazomethane, diazoethane, or methyl p-toluenesulfonate are used. . When using an alkylating agent other than diazomethane or diazoethane, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, triethylamine, pyridine, N, It is generally carried out in the presence of a base such as N-dimethylaniline. Further, salts of the compound of general formula [XI] can be easily obtained according to conventional methods, and examples of the salts include the same salts as explained in connection with the salts of the compound of general formula []. The compound of general formula [XI] and its salts thus obtained can be isolated and purified by known means, or can be used as a raw material for the next reaction without further purification. (e) Ring-closing reaction Next, by reacting each compound of the general formula [], [] or [XI] or a salt thereof with the thioformamide or thiourea of the general formula [XII], the compound of the general formula [] of the present invention can be obtained. A] or [b] compounds or salts thereof are obtained. This reaction is usually carried out in a solvent. Any solvent may be used as long as it does not inhibit this reaction, but examples include water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-
One or more mixed solvents such as dimethylacetamide and N-methylpyridone are used. Addition of deoxidizing agent is not particularly necessary, but
The reaction may proceed smoothly if a deoxidizing agent is added within a range that does not change the cephalosporin skeleton. The materials used in this reaction are:
Alkali metal hydroxide, alkali metal hydrogencarbonate, triethylamine, pyridine and N,N
- Inorganic or organic bases such as dimethylaniline. The reaction is generally carried out at a temperature in the range of 0 to 100°C. Generally, one to several equivalents of thioformamide or thioureas are used per equivalent of the compound of general formula [], [] or [XI] or a salt thereof. The reaction time is 1
~48 hours, preferably 1 to 10 hours. Furthermore, in each compound of general formula [a] or [b], protection of the carboxyl group, removal of the protecting group, and further conversion into salts can be carried out according to conventional methods to convert them into the corresponding target compounds. Also,
When R ¹ , R ² , and R ³ in the formula have a group active in this reaction, they are optionally protected with a conventional protecting group during the reaction, and after the reaction, the protection can be carried out by a conventional method. Groups can also be eliminated. The target compound of the general formula [a] or [b] of the present invention obtained as described above or its salts can be isolated by a conventional method. (f) Oxime formation reaction The compound of the general formula [] or its salts,
A compound of general formula [b] or a salt thereof can be obtained by reacting general formula [] or a salt thereof. Examples of the salts of the compound of general formula [] include hydrochloride, hydrobromide, and sulfate. This reaction is usually carried out in a solvent such as water, alcohol, and N,N-dimethylacetamide, a solvent inert to the reaction, or a mixed solvent thereof, and the reaction is carried out at 0 to 100°C, preferably. is 10~50℃
It is carried out within the range of. The reaction time is usually 10 minutes to 48 hours. 1 to several equivalents of the compound of the general formula [] or a salt thereof per equivalent of the compound of the general formula []
] or its salts are used.
Note that salts of the compound of general formula [] can be used as they are in this reaction, but for example, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., hydroxide, etc.) magnesium, calcium hydroxide, etc.), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.),
Alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal phosphates (e.g., magnesium phosphate, calcium phosphate, etc.), phosphoric acid Hydrogen alkali metals (e.g.
inorganic bases such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.) or alkali metal acetates (such as sodium acetate, potassium acetate, etc.),
Trialkylamines (e.g. trimethylamine, triethylamine, etc.), picoline, N
-Methylpyrrolidine, N-methylmorpholine,
1,5-diazabicyclo[4,3,0]-5-
nonene, 1,4-diazabicyclo[2,2,
2] Octane, 1,5-diazabicyclo[5,
The reaction can also be carried out in the presence of a base such as an organic base such as 4,0]-7-undecene.
The general formula of the present invention thus obtained [
In the compound b] or a salt thereof, R ¹ can be converted as explained in the ring-closing reaction, and it can also be isolated by a conventional method. The compound of the general formula [] and its salts obtained as above can be used in the treatment and prevention of bacterial infections in humans and in the form of free acids, non-toxic salts or physiologically acceptable esters. Preference is given to applying parenteral administration methods, in the form of free acids or non-toxic salts, or oral administration methods, which can be administered to animals, in the form of physiologically acceptable esters. In that case, the dosage form usually applied to cephalosporin drugs, such as tablets, capsules, powders, granules, fine granules, syrups, injections (including drips),
It may be prepared in the form of a suppository or the like. When preparing the above drug, if necessary, for example, starch,
Excipients such as lactose, sugar, calcium phosphate, calcium carbonate; gum arabic, starch, crystalline cellulose, carboxymethyl cellulose,
a binder such as hydroxypropyl cellulose;
Diluents and/or additives such as lubricants such as talc, magnesium stearate, and disintegrants such as carboxymethylcalcium, talc may be used. In addition, when administering the compound of general formula [] or its salts, the dosage, frequency of administration, and administration method can be selected as appropriate depending on the symptoms, but in general, a single dose of about 50 to 5000 mg per adult is used.
may be administered orally or parenterally about 1 to 4 times a day. Next, the present invention will be explained with reference to Reference Examples and Examples, but the present invention is not limited thereto. Reference example 1 (1) Ethyl acetate solution containing 27.13g of boron trifluoride
27.2 g of 7-aminocephalosporanic acid (hereinafter abbreviated as 7-ACA) and 12.32 g of maleic hydrazide were added to 100 ml and reacted at room temperature for 16 hours. After the reaction is complete, add the reaction solution to 150ml of ice water.
PH with 28% ammonia water under ice-cooling.
Adjust to 3.5. The precipitated crystals are collected, washed with 100 ml of water and 100 ml of acetone, and dried to produce 7-amino-3-, which has a melting point of 200°C or higher.
{[1-(3,6-dioxo-1,2,3,6-
Tetrahydropyridazinyl)]methyl}-△ ^3-
28.75 g of cefem-4-carboxylic acid (yield 88.7
%). IR (KBr) cm ^-1 : νC=O 1790, 1655, 1630,
1600 NMR (CF ₂ COOD) δ value: 3.72 (2H, bs, C ₂ -H), 5.41, 5.72 (2H, ABq, J = 15Hz,

[Formula]), 5.47 (2H, a, C ₆ -H, C ₇ -H), 7.58 (2H, s,

[Formula]), (2) The results when the three-position conversion reaction of (1) was carried out under the following conditions are shown in Table 3.

[Table] Reference example 2 (1) 100 sulfolane solution containing 27.13g of boron trifluoride
ml, 27.2 g of 7-ACA and 3-methyl-6
-oxo-1,6-dihydropyridazine 13.2g
and react at room temperature for 3 hours. After the reaction is complete,
The reaction solution was introduced into 500 ml of methanol under ice cooling,
Then, 31.6 g of pyridine was added dropwise. The precipitated crystals are collected, thoroughly washed with methanol, and then dried to give 7-amino-3-{[1-(3-methyl-6
-oxo-1,6-dihydropyridazinyl)]
29.5 g of crystals of methyl}-Δ ³ -cephem-4-carboxylic acid (yield 91.6%) are obtained. Similarly,
The compounds shown in Table 4 were obtained.

【table】

[Table] (2) 7-amino-3-{[1-(3-
29.5 g of methyl-6-oxo-1,6-dihydropyridazinyl)]methyl}-△ ³ -cephem-4-carboxylic acid was suspended in 300 ml of methanol,
In this, p-toluenesulfonic acid monohydrate 15.7
After adding and dissolving 53.3 g of diphenyldiazomethane, the mixture was allowed to react for 15 minutes at room temperature. After the reaction is complete, the solvent is distilled off under reduced pressure, and 200 ml of ethyl acetate and 200 ml of water are added to the resulting residue, and the pH is adjusted to 7.0 with sodium hydrogen carbonate.
Then, insoluble matter is separated, the organic layer is separated and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. If the residue is purified by column chromatography (Wako silica gel C-200, developing solvent: chloroform:methanol = 100:1),
Diphenylmethyl 7-amino-3-{[1-(3-methyl-6-
Oxo-1,6-dihydropyridazinyl)]methyl}-△ ³ -cephem-4-carboxylate
Obtain 10.5 g (yield 23.5%). IR (KBr) cm ^-1 : νC=O 1770, 1720, 1660 NMR (d ₂ -DMSO) δ value: 22.5 (3H, s, -CH ₂ ), 3.43 (2H, bs, C ₂ -H), 4.90 (1H, d, J = 5Hz, C ₆ -H), 4.92, 5.28 (2H, ABq, J = 15Hz,

[Formula]), 5.10 (1H, d, J=5Hz, C ₇ -H), 6.97, 7.41 (2H, ABq, J=10Hz,

【formula】), 7.06 (1H, s, CH), 7.20~7.84 (10H, m,

[Formula] ×2) In the same manner, the compounds shown in Table 5 were obtained.

【table】

Claims (1)

[Claims] 1. General formula "In the formula, R ¹ is a hydrogen atom or a carboxyl protecting group, R ² is the formula [Formula] [Formula] or [Formula] (wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are the same or different and represent a hydrogen atom, a halogen atom or an alkyl group), R ³ is a hydrogen atom, and R ⁴ is a hydrogen atom. of,
R ⁵ is an optionally protected amino group, A is
Formula -CH ₂ - or Formula [Formula] (wherein R ¹⁵ represents an alkyl group optionally substituted with a carboxyl group that may be protected, and ~ is a syn or anti isomer or a mixture thereof ). ” Cefirosporin and its salts. 2. Claim 1 in which R ⁵ is an amino group
Cephalosporin and its salts as described in Section. 3. The cephalosporin and its salts according to claim 1 or 2, wherein A is a group represented by the formula [Formula] (wherein R ¹⁵ and ~ each have the above-mentioned meanings) . 4. The cephalosporin and its salts according to any one of claims 1 to 3, wherein A is a group represented by the formula [Formula] (in which it is a syn isomer). 5. The cephalosporin according to any one of claims 1 to 3, wherein A is a group represented by the formula [Formula] (wherein R 1 represents the syn isomer and R ¹ has the meaning described above). and its salts. 6 Claim 1, wherein R ² is a group represented by the formula [Formula] (wherein R ⁶ , R ⁷ and R ⁸ each have the above-mentioned meanings)
Cephalosporin and its salts according to any one of items 1 to 5. 7 Claim 1, wherein R ² is a group represented by the formula [Formula] (wherein R ⁹ , R ¹⁰ and R ¹¹ each have the above-mentioned meanings)
Cephalosporin and its salts according to any one of items 1 to 5. 8. Any one of claims 1 to 5, wherein R ² is a group represented by the formula [Formula] (wherein R ¹² , R ¹³ and R ¹⁴ each have the above-mentioned meanings). Cephalosporin and its salts as described in Section. 9 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
-3-{[1-(3,6-dioxo-1,2,3,
6-tetrahydropyridazinyl)]methyl}-△ ³
-Cefem-4-carboxylic acid, an ester thereof, or a salt thereof. 10 7-[2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamide-3-{[1-(3,6-dioxo-1,
Claim 6 which is 2,3,6-tetrahydropyridazinyl)]methyl}-△ ³ -cephem-4-carboxylic acid, its ester or its salt
Compounds described in Section. 11 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
-3-{[1-(3-methyl-6-oxo-1,6
-dihydropyridazinyl)]methyl}-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 12 7-[2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamide]-3-{[1-(3-methyl-6-oxo-1,6-dihydropyrin) dadinyl)]methyl}-
8. The compound according to claim 7, which is ^Δ3 -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 13 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
-3-{[1-(2-oxo-1,2-dihydropyrazinyl)]methyl}-△ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof Claim 8 Compounds described.