JPH058199B2 - - Google Patents

Description

[Detailed description of the invention]

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

[expression] or expression

[Formula] (wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are the same or different and represent a hydrogen atom or an alkyl group),
R ³ is a hydrogen atom, R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom,
An optionally protected amino group, -A- is represented by the formula -CH ₂ - or the formula

[Formula] (In the formula, R ¹² 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 group represented by is 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 a novel cephalosporin and its salts, which have excellent therapeutic properties for human and animal diseases both orally and parenterally. The cephalosporins of the present invention have the formula

6-oxo-1,6-dihydropyrimidinyl group or formula represented by [Formula] (wherein R ⁶ , R ⁷ and R ⁸ have the above-mentioned meanings)

It is characterized by the bonding of a 2-oxo-1,2-dihydropyrimidinyl group represented by the formula: (wherein R ⁹ , R ¹⁰ and R ¹¹ have the meanings described above). Hereinafter, the present invention will be explained in further detail. In this specification, unless otherwise specified, alkyl refers to C ₁ -C ₁₄ alkyl, for example,
Methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, dodecyl or lauryl; alkoxy refers to -o-alkyl having an alkyl group as defined above; lower alkyl refers to , C _1-5 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl or pentyl; lower alkoxy refers to -o-lower alkyl having a lower alkyl group as defined above; acyl refers to C _1-12 acyl, such as acetyl, propionyl, butyryl, benzoyl, naphthoyl, pentanecarbonyl, cyclohexanecarbonyl, furoyl or thenoyl, etc.; acyloxy refers to -o-acyl having an acyl group as defined above; alkylthio refers to -S- having an alkyl group as defined above;
Alkyl; alkenyl is C _2-10 alkenyl,
For example, vinyl, allyl, isopropenyl, 2
- pentenyl or butenyl; alkynyl refers to C _2-10 alkynyl, such as ethynyl or 2-propynyl; cycloalkyl refers to C _3-7 cycloalkyl, such as cyclopropyl, cycloptyl, cyclopentyl, cyclohexyl or cycloheptyl etc.; cycloalkenyl means C _5-7 cycloalkenyl, e.g.
cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.; aryl, for example, phenyl, naphthyl or indanyl; aryloxy, -o-aryl having an aryl group as defined above; aralkyl, for example, benzyl, phenethyl, 4-methylbenzyl or naphthylmethyl; aralkyloxy means - having an aralkyl group as defined above;
o-aralkyl group; heterocyclic group refers to oxygen,
Heterocyclic groups containing at least one heteroatom selected from nitrogen and sulfur, such as furyl,
thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl,
4-(5-methyl-2-pyrrolinyl), 4-(2-
Heterocyclic alkyl is defined above. A group consisting of a heterocyclic group and an alkyl group; the 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 are eliminated by treatment under catalytic reduction, chemical reduction, or other mild conditions, or ester-forming groups that are easily eliminated in vivo, or treated with water or alcohol. Examples thereof include an organic silyl group, an organic phosphorus group, an organic tin group, etc., which are easily eliminated in this case, and various other known ester-forming groups. 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, alkoxy, oxo, cyano, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-1,3 -dioxol-4-yl-, 1-indanyl, 2-indanyl, furyl, biridyl, 4-imidazolyl, phthalimide, succinimide, azetidinoaziridino, 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-
dimethylpiperidino, 4-(5-methyl-2-
pyrrolinyl), 4-(2-pyrrolinyl), N-methylpiperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkenyloxy, Aryloxy, aralkyloxy, cycloalkyloxy, cycloalkenyloxy, heterocyclicoxy,
Alkoxycarbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, heterocyclicoxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, heterocyclic A substituted lower alkyl group which is a ring oxycarbonyl, an alkylanilino or an 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 substituted phenyl group in which the phenyl group or substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above, or a substituent 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=
Indicates CH-CO- or -CO-CO-CH=CH-. ] A group represented by (the substituent is arbitrarily selected from the substituents exemplified in (b) above) or a substituted derivative thereof. or expression [In the formula, -Y ² - represents a lower alkylene group such as -(CH ₂ ) ₃ - or -(CH ₂ ) ₄ -. ] An aryl group such as the group represented by the following or a substituted derivative thereof (the substituents are arbitrarily selected from the substituents exemplified in (b) above). (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, alicyclic phthalidyl or substituted derivatives thereof whose substituent is methyl or halogen, alicyclic tetrahydronaphthyl or substituted derivatives thereof whose substituent is methyl or halogen, trityl, cholesteryl, bicyclo[4,4 , 0] Desir et al. (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 Publications No. 2301014, No. 2253287 and No. 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】

[Formula] [In the formula, R ¹⁵ is an alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without a known substituent, and R ¹⁶ is a hydrogen atom or a known substituent. R ¹⁷ is an alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without a hydrogen atom, a halogen atom or a known substituent, a cycloalkyl, aryl or Heterocyclic group or -( _CH2 )
nCOOR ¹⁶ (However, R ¹⁶ has the above meaning,
n represents 0, 1 or 2. ), m indicates 0, 1 or 2. ] Furthermore, specifically, for example, 5-methyl-
2-oxo-1,3-dioxol-4-yl-
5-lower alkyl such as methyl, 5-ethyl-2-oxo-1,3-dioxol-4-yl-methyl, 5-n-propyl-2-oxo-1,3-dioxol-4-yl-methyl group -2-oxo-1,3-dioxol-4-yl-methyl group;
Acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isoptyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxyethyl,
Acyloxyalkyl groups such as 1-pivaloyloxy-n-propyl group; acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, p
- Acylthioalkyl groups such as chloropenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl, 1-(p-chlorobenzoylthio)ethyl groups; methoxymethyl, ethoxymethyl, n -Alkoxymethyl groups such as propoxymethyl, isopropoxymethyl, n-butyloxymethyl groups; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, n-propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl,
n-butyloxycarbonyloxymethyl, tert
-butyloxycarbonyloxymethyl, 1-methoxycarbonyloxy-ethyl, 1-ethoxycarbonyloxy-ethyl, 1-n-propoxycarbonyloxy-ethyl, 1-isopropoxycarbonyloxy-ethyl, 1-n-butyloxycarbonyloxy -Alkoxycarbonyloxy-alkyl groups such as ethyl groups; alkoxycarbonylmethyl groups such as methoxycarbonylmethyl and ethoxycarbonylmethyl groups; phthalidyl groups;
Indanyl group; Phenyl group; 2-(phthalidylidene)-ethyl, 2-(5-fluorophthalidylidene)-ethyl, 2-(6-chlorophthalidylidene)
-Ethyl, 2-(6-methoxyphthalidylidene)-
Examples include phthalidylidene alkyl groups such as ethyl group. In addition, as the protecting group for the amino group which may be protected for ^R5 , those commonly used in the field of penicillin and cephalosporin compounds are mentioned, such as trichloroethoxycarbonyl, tripromoethoxycarbonyl, benzyl oxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-
Bromobenzyloxycarbonyl, (mono, di, tri)chloroacetyl, trifluoroacetyl, formyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo)
Benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, pyridin-1-oxid-2-yl-methoxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl , isopropoxycarbonyl,
Easily eliminated acyl groups such as 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl; trityl, o-nitrophenylsulfenyl, 2,4-dinitrophenylsulfenyl , 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-ethoxycarbonylcyclobenchilidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5
Examples thereof include easily leaving groups such as -oxocyclohexylidene and protecting groups for amino groups such as di- or tri-alkylsilyl groups. -A- is the formula -CH ₂ - or the formula

[Formula] (In the formula, R ¹² represents an alkyl group that may be substituted with an optionally protected carboxyl group, and represents that it may be a syn or anti isomer or a mixture thereof.)
means. Examples of the protecting group for the carboxyl group which may be protected in R ¹² include the same carboxyl protecting groups as explained for R ¹ . next,

The oxime represented by the formula includes syn and anti isomers and mixtures thereof, all of which are included in the present invention. 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 present invention. [In the above balanced formula, R ⁴ and R ⁵ have the meanings described above, and R ⁵ ' represents an optionally protected imino group. ] In the above formula, the protecting group for the imino group of R ⁵ ' includes groups normally used in the fields of penicillin and cephalosporin, and specifically, R ⁵
Among the protecting groups for amino groups explained above, the same groups as the monovalent groups can be mentioned. Examples of the salts of the compound of general formula [] include salts with basic groups or acidic groups that are conventionally 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-1,
Salts with sulfonic acids such as 3,5-trisulfonic acid, and salts with acidic groups include, for example,
Salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts; procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N-di Benzylethylenediamine, triethylamine, trimethylamine, triptylamine, pyridine,
Examples include salts with nitrogen-containing organic chlorine such as N,N dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, and dicyclohexylamine. Furthermore, the present invention encompasses all optical isomers and racemic forms of cephalosporin of the general formula [ ] and its salts, as well as all crystal forms and hydrates. More specifically, in the compound of the general formula [], as a preferable example, -A- is the formula

The oxime represented by [Formula], among them, the syn isomer, furthermore, R ¹² is an alkyl group, especially a methyl group, an ethyl group or a formula CH ₂
COOR ¹ (wherein R ¹ has the meaning described above)
Each of the groups represented by the above also includes groups. 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,
or a lower alkyl group also has the formula

In the case of the group represented by the formula, R ⁹ , R ¹⁰ and R ¹¹ may be the same or different and may be a hydrogen atom or a lower alkyl group. Some representative compounds of the general formula [] exhibit antibacterial activity. Antibacterial activity (Table 1) Cultured at 37°C for 20 hours in Heart Infusion broth (manufactured by Eiken Chemical Co., Ltd.) according to the standard method of the Japanese Society of Chemotherapy [(CHEMOTHERAPY) Vol. 23, pages 1-2 (1975)]. Heart Infusion agar medium containing bacterial solution and drug (manufactured by Eiken Chemical Co., Ltd.)
After culturing at 37°C for 20 hours, the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as the MIC (μg/ml). However, the amount of inoculated bacteria is
¹⁰⁴ pieces/plate ( ¹⁰⁴ pieces/ml). The test compounds are as follows. (A) 7-[2-(2-aminothiazol-4-yl-)-2-(syn)-methoxyiminoacetamide]-3-{[1-(4-methyl-6-oxo-
1,6-dihydropyrimidinyl)]methyl}-
Trifluoroacetate of Δ ³ -cephem-4-carboxylic acid (B) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamide]-3-{[1 -(2,4-dimethyl-6-oxo-1,6-dihydropyrimidinyl)]methyl} ^{-Δ 3} -cephem-4-carboxylic acid formate (C) -yl)-2-(syn)-methoxyiminoacetamide]-3-{[1-(2-oxo-1,2-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-
Trifluoroacetate of 4-carboxylic acid

【table】

[Table] Note * Penicillinase-producing bacteria ** Cephalosporinase-producing bacteria Next, the method for producing the compound of the present invention 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 , A and have the above-mentioned meanings, R ²¹ amino group, formula

[Formula] (In the formula, R ²³ , R ²⁴ and R ²⁵ are the same or different and represent a hydrogen atom or an organic residue that does not participate in the reaction.) or Formula

A group represented by [Formula] (wherein R ²⁶ and R ²⁷ are the same or different and represent a hydrogen atom or an organic residue that does not participate in the reaction),
In addition, R ²² is an acyloxy or carbamoyloxy group with or without a substituent, X is a halogen atom, Z is S or S→O,
And the dotted line in the ring means that the 2nd to 3rd or 3rd to 4th positions are double bonds, respectively. ] Below, to explain in detail, R ²¹ is an amino group, the formula

[expression] or expression

[Formula] As shown, the formula

Group represented by [Formula] has the formula whose isomer is

A group represented by the formula is also included in the present invention. and
Organic residues that do not participate in the reaction in R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ include organic residues known in the art, such as aliphatic residues with or without substituents. , alicyclic residues, aromatic residues, araliphatic residues, heterocyclic residues, acyl groups, etc., and specific examples include the following groups. (1) Aliphatic residues: for example, alkyl groups such as methyl, ethyl, propyl, n-butyl, isobutyl, and bentyl; alkenyl groups such as vinyl, propenyl, and putenyl. (2) Alicyclic residues: For example, cycloalkyl groups such as cyclopentyl, cyclohexyl, and cycloheptyl; cycloalkenyl 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 derived from an organic carboxylic acid. Examples of such organic carboxylic acids include aliphatic carboxylic acids; alicyclic carboxylic acids; alicyclic aliphatic carboxylic acids; Aromatic substituted aliphatic carboxylic acids, aromatic oxyaliphatic carboxylic acids, aromatic thioaliphatic carboxylic acids, heteroaromatics in which an aromatic residue or a heterocyclic group is bonded to a carboxylic acid with or without an oxygen or sulfur atom Ring-substituted aliphatic carboxylic acid, heterocyclic oxyaliphatic carboxylic acid, heterocyclic thioaliphatic carboxylic acid; aromatic residue, aliphatic residue or alicyclic residue via an oxygen, nitrogen or sulfur atom to the carbonyl group Organic carboxylic acids such as organic carboxylic acids bound to; aromatic carboxylic acids; and heterocyclic carboxylic acids can be mentioned. Here, the aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid,
pentanoic acid, methoxyacetic acid, methylthioacetic acid,
Examples of alicyclic carboxylic acids include acrylic acid and crotonic acid; examples of alicyclic carboxylic acids include cyclohexanoic acid; and examples of alicyclic aliphatic carboxylic acids include cyclopentane acetic acid, cyclohexane acetic acid, cyclohexane propionic acid, and cyclohexadiene acetic acid. Examples include. 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,
Examples include residues of heterocyclic compounds containing one or more heteroatoms in the ring, such as thiadiazole, oxadiazole, thiatriazole, oxatriazole, tetrazole, benzoxazole, and benzofuran. The groups constituting these organic carboxylic acids include, 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 carboxyl group. basis,
It may be further substituted with a substituent such as a protected carboxyl group. Furthermore, examples of the acyloxy and carbamoyloxy groups for ^R22 include acetoxy,
Alkanoyloxy groups such as propionyloxy or butyryloxy; alkenoyloxy groups such as acryloyloxy; aroyloxy groups such as benzoyloxy or naphthoyloxy; and carbamoyloxy groups, which are halogen atoms, nitro groups, amino groups, alkyl groups, alkoxy groups, alkylthio groups, acyloxy groups, acylamino groups, hydroxyl groups, carboxyl groups, sulfamoyl groups, carbamoyl groups, carbalkoxycarbamoyl groups, aroylcarbamoyl groups, carbalkoxysulfamoyl groups, aryl groups, carbamoyloxy groups, etc. It may be substituted with one or more substituents. Among the substituents for R ²² 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 compound of general formula [] or its salt is reacted with general formula [a] in the presence of an acid or an acid complex compound.
6-oxo-1,6-dihydropyrimidines of formula [b] or 2-oxo-1,2- of general formula [b]
7-substituted or unsubstituted amino-3-substituted methyl cefemcarboxylic compound of the general formula [] is obtained by reacting dihydropyrimidines or their salts, and optionally removing the protecting group or protecting or converting the carboxyl group into a salt. Acids or salts thereof can be produced with good yield and high purity through industrially 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 Δ ³ -cephem compound but also the Δ ² -cepheme compound can be used, and when the Δ ² -cepheme compound is also used, the Δ ² -cepheme compound obtained after the reaction can be used as the Δ ³ -cepheme compound. can be converted into compounds. In addition, not only 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, 6-oxo 1,6- of general formula [a] used as a reaction reagent in this reaction
When dihydropyrimidines or 2-oxo-1,2-dihydropyrimidines of general formula [b] have a basic group or an acidic group as a substituent, they can be reacted in the form of their respective salts, if necessary. In this case, examples of the salt with a basic group or the salt with an acidic group include the same salts with a basic group or an acidic group as explained for the salts of the compound of general formula []. In addition, salts of the compounds of general formulas [] and [] include salts with basic groups or acidic groups, and these salts include salts with basic groups or acidic groups similar to those explained for the salts of compounds of general formulas []. Mention may be made of salts at acidic groups. 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, and fluorosulfuric acid; alkyl (mono- or di-)sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; or aryl (mono-)sulfonic acids such as p-toluenesulfonic acid; , di- or tri-)sulfonic acids;
perchloric acid, magicic acid ( _FSO3H - _SbF5 ),
_{FSO3H - AsF5} , _CF3SO3H - _SbF5 , HF-
Examples include super strong acids such as BF ₃ and H ₂ SO ₄ −SO ₃ . Furthermore, examples of the Lewis acid include boric trifluoride. In addition, examples of complex compounds of Lewis acids include dialkyl ether complexes of trifluoroboric acid and diethyl ether, di-n-propyl ether, di-n-butyl ether, etc.; ethylamine, n-propylamine, n- Examples include amine complex salts with butylamine, toluethanolamine, etc.; carboxylic acid esters with ethyl formate, ethyl acetate, etc.; fatty acid complex salts with acetic acid, propionic acid, etc.; nitrile complex salts with acetonitrile, propionitrile, etc. 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; diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, dimethyl cellosolp, etc. Ethers; esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, and butyl acetate; nitrites such as acetonitrile and butyronitrile; halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane Examples include sulfolanes such as sulfolane, and two or more of these solvents may be used as a mixture. 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 itself be used as a solvent,
A mixture of two or more types of complexing compounds may be used. Furthermore, 6-oxo-1,6-dihydropyrimidines of general formula [a] or 2-oxo-1,2-dihydropyrimidines of general formula [b] or salts thereof used as a reaction reagent in this reaction may be used. 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 moisture is present in the reaction system, undesirable side reactions such as lactonization of the raw material or product and cleavage of the β-lactam ring may occur, so 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, boriphosphoric acid, phosphorus pentachloride, phosphorus trichloride, or phosphorus oxychloride; N,O-bis(trimethylsilyl)acetamide, Organic silylating agents such as trimethylsilylacetamide, trimethylchlorosilane, 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 , molecular sheep, calcium carbide, and other inorganic desiccants 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 It is also possible to obtain compounds of the general formula [ ] where ¹ is a hydrogen atom. In the 6-oxo-1,6-dihydropyrimidines of the general formula [a] or the 2-oxo-1,2-dihydropyrimidines of the general formula [b] or their salts used as a reaction reagent in this reaction, those When the substituent group is substituted with a hydroxyl group, an amino group, a carboxyl group, etc. In carrying out this reaction, these groups are each protected with a corresponding commonly used protecting group, and after the reaction is completed, conventional removal is carried out. A desired compound can be obtained by subjecting it to a dissociation 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 ²¹ 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 reactive derivative at the amino group, or a salt thereof, is added to the compound of the general formula [], [],
If a compound of [], [] or [] or a reactive derivative thereof at the carboxyl group or a salt thereof is reacted, the general formula [],
Compounds of [ ], [ ], [ ] or [ ] or salts thereof are obtained. Also, the general formula [], [], [], [],
〔〕,〔〕,〔〕,〔〕or〔〕
Examples of the salts of the compound represented by formula (2) include salts with a basic group or an acidic group, and salts thereof include salts with a basic group or an acidic group similar to those described for the salts of the compound represented by the general formula []. Examples of reactive derivatives at the amino group of the compound of general formula [] include isocyanates, compounds of general formula [] or salts thereof, and silyl compounds such as N,O-bis(trimethylsilyl)acetamide, trimethylsilylacetamide, and trimethylsilyl chloride; phosphorus trichloride,

【formula】

【formula】

[Formula], (CH ₃ CH ₂ O) ₂ PCl, (CH ₃ CH ₂ ) ₂ PCl or other phosphorus compounds or (C ₄ H ₉ ) ₃
It includes all those commonly used in acylation reactions, such as silyl derivatives, phosphorus derivatives, or tin derivatives produced by reaction with tin compounds such as SnCl. Specifically, the reactive derivatives at the carboxyl group of the compound of the general formula [], [], [], [], or [] include acid halogen compounds, acid anhydrides, mixed acid anhydrides, and activated acid amides. , active ester and general formula [], [],
Examples include reactive derivatives of the compound [ ], [ ], or [ ] and the Vilsmeier reagent. Examples of mixed acid anhydrides include mixed acid anhydrides with carbonic acid monoalkyl esters such as carbonic acid monoethyl ester and carbonic acid monoisobutyl ester, and lower alkanoic acids which may be substituted with halogen such as pivalic acid and trichloroacetic acid. Mixed acid anhydrides with and the like are used. Examples of active acid amides 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 thienyl 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 When using each compound of the general formula [], [], [], [], or [] in the form of a free acid or salt, a suitable condensing agent is used.
Such condensing agents include, for example, N,
N,N'-disubstituted carbodiimides such as N'-dicyclohexylcarbodiimide;N,N'-
Azolide compounds such as thionyldiimidazole; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline, phosphorus oxychloride, alkoxyacetylene; 2-
2-halogenopyridinium salts such as chloropyridinium methyl iodide and 2-fluoropyridinium methyl iodide are used. This acylation reaction is generally carried out in a suitable solvent.
Performed in the presence or absence of a base. Examples of solvents include halogenated hydrocarbons such as chloroform and methylene chloride; ethers such as tetrahydrofuran and dioxane; N,N
-Dimethylformamide, N,N-dimethylacetamide, acetone, water, or mixtures thereof can be used. In addition, as a base, inorganic bases such as alkali hydroxide, alkali hydrogen carbonate, alkali carbonate or alkali acetate; trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiveridine, N-
Examples include organic bases such as tertiary amines such as methylmorpholine, lutidine, and collidine, and secondary amines such as dicyclohexylamine and diethylamine. In addition, general formula [a] or [
The compound of the general formula [] or its salts which can be derived from the compound of b] or its salts can also be produced as follows. 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 chlorine or a halogen such as 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. In addition, salts of the compound of general formula [] can be easily obtained according to conventional methods. Mention may be made of salts at acidic groups. The resulting compound of general formula [] or its salts may be isolated and purified by conventional methods, but may also be used in the next reaction without isolation. In addition, the amount of the compound of the general formula [], [], [], [], or [] or its reactive derivative at the carboxyl group or their salts is the same as the amount of the compound of the general formula [] or its reactive derivative at the amino group. Or each is preferably about 1 to several mol each per 1 mol of the salt. These reactions are usually carried out at -50 to 40°C,
Completes in 10 minutes to 48 hours. In addition, in this acylation reaction, introduction and removal of a protecting group and conversion to a salt can be carried out according to conventional methods to convert the compound into the corresponding target compound. The compounds of the general formula [], [], [], [] or [] or their salts obtained as described above can be isolated and purified by known means, but the compounds of the general formula [],
The compounds [ ], [ ] or [ ] or their salts can also be used as raw materials for the next reaction without being isolated. (c) Nitronization reaction Next, to obtain the compound of general formula [] or its salts from the compound of general formula [] or its salts, the compound of general formula [] or its salts is reacted with a nitronation 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 nitroning 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 bentyl 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 alkyl ester 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 at -15 to 30°C and is completed in 10 minutes to 10 hours. In addition, the salts of the compound of general formula [] can be easily obtained according to the conventional method, and the salts can be prepared using the same basic or acidic groups as explained for the salts of the compound of general formula []. Salt is an example. moreover,
Introduction and removal of protecting groups are carried out according to conventional methods.
It can be converted into the corresponding target compound. The compound of the general formula [] or its salts thus obtained may be isolated and purified by a conventional method, but it can also be used in the next reaction without being isolated. (d) Etherification reaction and phosphorylation reaction Next, in order to obtain the compound of general formula [] or its salts from the compound of general formula [] or its salts, the compound of general formula [] or its salts is subjected to an etherification reaction. Or subjected to phosphorylation reaction. This etherification reaction and phosphorylation reaction are described in JP-A-53-137988 and JP-A-55-
It can be carried out by conventional methods such as etherification reaction and phosphorylation reaction described in No. 105689 and JP-A-55-149295. For example, the alkylation reaction can be carried out according to conventional methods. The reaction is generally carried out at -20 to 60°C, and
Complete in 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-himethylformamide, N,N-dimethylacetamide, Water or a mixture thereof may be used. As the alkylating agent, for example, lower alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, and ethyl bromide, dimethyl sulfate, diethyl sulfate, diazomethane, diazoethane, or methyl p-toluenesulfonate are used. . When using alkylating agents other than diazomethane and diazoethane, alkylating agents such as alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine,
It is generally carried out in the presence of a base such as pyridine, N,N-dimethylaniline. In addition, the salts of the compound of general formula [] can be easily obtained according to the conventional method, and the salts can be prepared using the same basic or acidic groups as explained for the salts of the compound of general formula []. Salt is an example. Furthermore, the introduction and removal of a protecting group can be carried out according to a conventional method to convert the compound into the corresponding target compound. The compound of the general formula [] or its salts thus obtained may be isolated and purified by a conventional method, but it can also be used in the next reaction without being isolated. (e) Ring-closing reaction Next, each compound of the general formula [], [] or [] or a salt thereof is combined with the general formula [
], the compound of general formula [a] or [b] of the present invention or salts thereof can be 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-dimethylacetamide, N-methylpyridone, or a mixed solvent of two or more of these solvents is used. Although the addition of a deoxidizing agent is not particularly necessary, the reaction may proceed smoothly if the deoxidizing agent is added in an amount within a range that does not change the cephalosporin skeleton. The deoxidizers used in this reaction include alkali metal hydroxide, alkali metal hydrogencarbonate, triethylamine, pyridine,
Mention may be made of inorganic or organic bases such as N,N-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 [] or a salt thereof. The reaction time is usually 1~
48 hours, preferably 1 to 10 hours. In addition, in this ring-closing reaction, the introduction and removal of a protecting group and the conversion to a salt can be carried out according to conventional methods to convert it into the corresponding target compound. The target compound of the general formula [a] or [b] of the present invention obtained as described above or a salt thereof can be isolated by a conventional method. (f) Oxime formation reaction A compound of general formula [b] or a salt thereof can be obtained by reacting a compound of general formula [] or a salt thereof with a compound of general formula [] or a salt thereof. Examples of the salts of the compound of general formula [] include hydrochloride, hydrobromide, and sulfate. This reaction usually involves water,
In addition to solvents such as alcohol and N,N-dimethylacetamide, the reaction is usually carried out in an inert solvent or a mixed solvent thereof.
It is carried out at a temperature of 0 to 100°C, preferably 10 to 50°C, and is completed in 10 minutes to 48 hours. One to several equivalents of the compound of general formula [] or a salt thereof is used per equivalent of the compound of general formula [] or a salt thereof. Incidentally, the salts of the compound of general formula [] can be used as they are in this reaction, but for example,
Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali carbonates such as magnesium carbonate and calcium carbonate. Earth metals, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate, hydrogen phosphate 2
Inorganic bases such as alkali metal hydrogen phosphates such as sodium and dipotassium hydrogen phosphate, or alkali metal acetates such as sodium acetate and potassium acetate, trialkylamides such as trimethylamine and triethylamine, picoline, N-methylpyrrolidine, N-methyl Morpholine, 1,
5-diazabicyclo[4,3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,
The reaction can also be carried out in the presence of a base such as an organic base such as 0]-7-undecene. In addition, in this oximation reaction, the introduction and removal of a protecting group and the conversion to a salt can be carried out according to conventional methods to convert it into the corresponding target compound. The compound of the general formula [] of the present invention or its salts obtained as described above can be isolated by a conventional method. The compound of the general formula [] or its salts obtained as above can be used in the treatment and prevention of bacterial infections in the form of free acid, non-toxic salt or physiologically acceptable ester. 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, it should be prepared in the dosage forms normally applied to cephalosporin drugs, such as tablets, capsules, powders, granules, fine granules, syrups, injections (including infusions), and suppositories. Bye. When preparing the above drug, if necessary, excipients such as starch, lactose, sugar, calcium phosphate, calcium carbonate; binders such as gum arabic, starch, microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose; talc Diluents and/or additives such as lubricants such as , magnesium stearate; and disintegrants such as carboxymethylcalcium, talc, etc. may also 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, adults
A single dose of about 50 to 5000 mg per person 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 Add 7 to an ethyl acetate solution containing 2.71 g of boron trifluoride.
-Aminocephalosporanic acid (hereinafter referred to as 7-ACA)
It is abbreviated as ) 2.72g and 2,4-dimethyl-6
After adding and dissolving 1.36 g of -oxo-1,6-dihydropyrimidine, the mixture was allowed to react at room temperature for 16 hours. After the reaction is completed, the reaction solution is introduced into 50 ml of methanol under cooling, and then 3.16 g of pyridine is added dropwise.
After removing the precipitated crystals and thoroughly washing them with methanol,
7-amino- exhibiting a melting point of 200°C or higher when dried
3-{[1-(2,4-dimethyl-6-oxo-1,
1.88 g (yield 55.9%) of 6-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-4-carboxylic acid is obtained. IR (KBr) cm ^-1 ; νc=o 1800, 1675, 1610 NMR (CF ₃ COOD) δ value; 2.60 (3H, s,

【formula】), 3.13(3H,s,

[Formula]), 3.72 (2H, bs, C ₂ -H), 5.50 (2H, bs, C ₆ -H, C ₇ -H), 5.73 (2H, bs,

【formula】), 6.80 (1H, s,

[Formula]), Reference Example 2 (1) 100ml of sulfolane solution containing 27.1g of boron trifluoride
, 27.2 g of 7-ACA and 2,4-dimethyl-
6-oxo-1,6-dihydropyrimidine
Add 12.4g and react at room temperature for 4 hours. After completion of the reaction, the reaction solution was introduced into 500 ml of methanol under ice cooling, and 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-(2,
4-dimethyl-6-oxo-1,6-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-4
- Obtain 30.5 g (yield 90.8%) of crude crystals of carboxylic acid. In the same manner, crude crystals of the following compound were obtained. ○ 7-Amino-3-{[1-(6-oxo-1,
6-dihydropyrimidinyl)]methyl}-Δ ³ −
Cefem-4-carboxylic acid○ 7-amino-3-{[1-(4-methyl-6-
oxo-1,6-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-4-carboxylic acid○ 7-amino-3-{[1-(2-methyl-6-
7-Amino- ³ -{[1-(2-oxo-1,
2-dihydropyrimidinyl)]methyl}-Δ ³ −
Cefem-4-carboxylic acid (2) 7-amino-3-{[1-(2,
4-dimethyl-6-oxo-1,6-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-4
-25g of crude crystals of carboxylic acid in 250ml of methanol
and suspended in p-toluenesulfonic acid.
Add 12.7g of monohydrate. Then, 43.3 g of diphenyldiazomethane was gradually added, and the mixture was allowed to react at room temperature for 15 minutes. After the reaction, the solvent was distilled off under reduced pressure, and 250 ml of ethyl acetate and 250 ml of water were added to the resulting residue, and sodium hydrogen carbonate was added.
Adjust to PH7.0. Then, after separating the insoluble matter,
The organic layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography (Wako silica gel C-
200; eluent, benzene:ethyl acetate = 1:3)
Diphenylmethyl 7-amino-3-{[1-
(2,4-dimethyl-6-oxo-1,6-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-4-carboxylate 14.6 g (yield 39.1%)
get. IR (KBr) cm ^-1 ; νc=o 1770, 1720, 1675 NMR (d ₆ -DMSO) δ value; 2.15 (6H, s,

【formula】,

[Formula]), 3.31 (2H, bs, C ₂ −H), 4.80, 5.34 (2H, ABq, J=15Hz,

[Formula]), 4.92 (1H, d, J=5Hz, C ₆ -H), 5.90 (1H, d, J=5Hz, C ₇ -H), 6.22 (1H, s,

[Formula]), 7.02 (1H, s, -CH), 7.12~7.71 (10H, m,

【formula】), Similarly, the compounds shown in Table 3 are 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] or the formula [formula] (wherein, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are (which are the same or different and represent a hydrogen atom or an alkyl group),
R ³ is a hydrogen atom, R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom,
-A- represents an optionally protected amino group, -CH ₂ - or formula [Formula] (wherein R ¹² is an alkyl group optionally substituted with an optionally protected carboxyl group) and ~ indicates that it may be a syn or anti isomer or a mixture thereof. ” Cephalosporins and salts. 2. Claim 1 in which R ⁵ is an amino group
Cephalosporin and its salts as described in Section. 3 -A- is represented by the formula [Formula] (wherein R ¹² and ~ each have the above-mentioned meanings.)
The cephalosporin and its salts according to claim 1 or 2, which is a group represented by: 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. Any one of claims 1 to 4, wherein -A- is a group represented by the formula [Formula] (wherein is a syn isomer and R ¹ has the meaning described above) Cephalosporin and its salts as described. 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. Any one of claims 1 to 5, 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 as described in Section. 8 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
7. The compound according to claim 6, which is {[1-(6-oxo-1,6-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 9 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
-3-{[1-(2-methyl-6-oxo-1,6
-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 10 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
-3-{[1-(4-methyl-6-oxo-1,6
-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 11 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
-3-{[1-(2,4-dimethyl-6-oxo-
1,6-dihydropyrimidinyl)]methyl}-Δ ³
-Cefem-4-carboxylic acid, an ester thereof, or a salt thereof. 12 7-[2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamide]-3-{[1-(2,4-dimethyl-6
7. The compound according to claim 6, which is oxo-1,6-dihydropyrimidinyl)]methyl}-Δ ³ -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-dihydropyrimidinyl)]methyl}-Δ ³ -cephem-4-carboxylic acid, an ester thereof or a salt thereof, according to claim 7 Compound.