JPH0454677B2 - - 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] (In the formula, R ⁶ represents a hydrogen atom or an alkyl group, and R ⁷ represents a phenyl group which may be substituted with an alkyl or halogen atom.) optional 1,2,6-thiadiazin-1,1-dioxide-2-yl, tetrahydro-1,2-thiazine-1,1-dioxide-
2-yl or isothiazolidin-1,1-dioxide-2-yl group, R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom, R ⁵ is an optionally protected amino group, -A- is the formula -CH ₂ - or the formula

[Formula] (wherein R ⁸ 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.) Indicates the group represented. ” 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

1,2,6-thiadiazine- which may be substituted with a sulfonamide group or an alkyl group represented by the formula: (wherein R ⁶ and R ⁷ have the above meanings)
1,1-dioxido-2-yl, tetrahydro-
It is characterized by the fact that a 1,2-thiazin-1,1-dioxido-2-yl or isothiazolidine-1,1-dioxido-2-yl group is bonded thereto. 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, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
such as 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 _C1-12 acyl, such as acetyl, propionyl, butyryl, benzoyl, naphthoyl , pentanecarbonyl, cyclohexanecarbonyl, furoyl or thenoyl; 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, iso-propenyl,
2-pentenyl or butenyl, etc.; alkynyl refers to C _2-10 alkynyl, such as ethynyl or 2-propynyl; cycloalkyl refers to C _3-7 cycloalkyl, such as cyclopropylcyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; cycloalkenyl refers to C _5-7 cycloalkenyl, such as cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.; aryl refers to, for example, phenyl, naphthyl or indanyl; aryloxy refers to Having an aryl group defined in −
O-aryl; aralkyl is, for example,
benzyl, phenethyl, 4-methylbenzyl or naphthylmethyl; aralkyloxy means -o- having an aralkyl group as defined above;
Aralkyl group; heterocyclic group refers to a heterocyclic group containing at least one heteroatom selected from oxygen, 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-pyrrolinyl), N-methylpiperidinyl), pyridazinyl,
quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl or coumarinyl; heterocyclic alkyl refers to a group consisting of a heterocyclic group and an alkyl group as defined above; ; The halogen atom means, for example, 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, 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-dimethylpiperidino, 4-(5-methyl-2-pyrrolidino), 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, heterocyclicoxycarbonyl, alkylanilino or A substituted lower alkyl group which is 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 or a substituted derivative thereof (the substituents are arbitrarily selected from the substituents exemplified in (b) above), or a group represented by the formula [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] 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 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】

[In the formula, R ¹¹ is an alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without a known substituent, and R ¹² is a hydrogen atom or a known substituent or R ¹³ 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 ¹² (wherein R ¹² has the above-mentioned meaning, n represents 0, 1 or 2), and 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-n-propyl-2-oxo-1,3-dioxol-4-yl-
5-lower alkyl-2-oxo- such as 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, n-propoxymethyl, isopropoxymethyl, and n-butyloxymethyl groups; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, n-propoxycarbonyl Oxymethyl, 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 group; alkoxycarbonylmethyl groups such as methoxycarbonylmethyl and ethoxycarbonylmethyl groups; phthalidyl group; indanyl group; phenyl group; 2-(phthalidylidene)
-Ethyl, 2-(5-fluorophthalidylidene)-
Examples include phthalidylidene alkyl groups such as ethyl, 2-(6-chlorophthalidylidene)-ethyl, and 2-(6-methoxyphthalidylidene)-ethyl groups. 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, tribromoethoxycarbonyl, 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-ethoxycarbonylcyclopentylidene, 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 trialkylsilyl groups. -A- is the formula -CH ₂ - or the formula

[Formula] (In the formula, R ⁸ 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 protecting group for the optionally protected carboxyl group in R ⁸ 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 represented by the 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 ⁶ and R ⁸ have the above-mentioned meanings, and R ⁵ ' represents an optionally protected imino group. ] As the protecting group for the imino group of R ⁵ ' in the above formula, groups usually used in the field of penicillin and cephalosporin can be mentioned, and specifically,
One of the amino protecting groups explained for R ⁵
Groups similar to the valence 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; brocaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N-di Benzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine,
Dimethylaniline, N-methylpiperidine, N-
Examples include salts with nitrogen-containing organic bases such as methylmorpholine, diethylamine, and dicyclohexylamine. 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 of the general formula [], as a preferable example, -A- is the formula

Among the oxime bodies represented by [Formula], there are syn isomers, and R ⁸ is an alkyl group,
In particular, a methyl group, an ethyl group or a formula -
Examples include each group represented by CH ₂ COOR ¹ (wherein R ¹ has the meaning described above). Next, as a preferable example of R ² , the formula

In the case of the group represented by the formula, R ⁶ is a hydrogen atom or a lower alkyl group, R ⁷ is a lower alkyl group, and 1,2,6-thiadiazine which may be further substituted with a lower alkyl group. −
A 1,1-dioxido-2-yl group is mentioned. Among the compounds of the general formula [], some representative compounds 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
10 ⁴ pieces/plate (10 ⁶ pieces/ml). The test compounds are as follows. (A) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(3,5-dimethyl-1,2,6-thiadiazine-1,1 -dioxide-2-yl)
Trifluoroacetate of methyl-Δ ³ -cephem-4-carboxylic acid. (B) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(methanesulfonamido)methyl-
Δ ³ -Cefem-4-carboxylic acid trifluoroacetate (C) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamide]-3-(3, 5-dimethyl-1,
2,6-thiadiazine-1,1-dioxide-
Formate salt of 2-yl)methyl-Δ ³ -cephem-4-carboxylic acid.

【table】

[Table] ** Cephaloporinase-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 , A, W and 〓 have the meanings given above; R ¹⁷
is an amino group, the formula

[Formula] (In the formula, R ¹⁹ , R ²⁰ and R ²¹ 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 ²² and R ²³ are the same or different and represent a hydrogen atom or an organic residue that does not participate in the reaction), and R ¹⁸ has a substituent or acyloxy or carbamoyloxy group, X is a halogen atom, Z is
S or 〓S→O, and the dotted line in the ring is 2-3
Or each means that there is a double bond between the 3rd and 4th positions. ] Below, to explain in detail, R ¹⁷ is an amino group, the formula

[expression] or expression

[Formula] Indicates the group represented by the formula

The group represented by [Formula] has the isomer of the formula

A group represented by the formula is also included in the present invention. and R ¹⁹ , R ²⁰ , R ²¹ , R ²² and
Organic residues that do not participate in the reaction in R ²³ include organic residues known in the art, such as aliphatic residues with or without substituents, alicyclic residues, aromatic residues, aromatic aliphatic residues,
Examples include heterocyclic residues and acyl groups, and specific examples include the following groups. (1) Aliphatic residues: for example, alkyl groups such as methyl, ethyl, propyl, n-butyl, isobutyl, pentyl; alkenyl groups such as vinyl, propenyl, butenyl. (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, 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 cyclohexane. Examples of the alicyclic aliphatic carboxylic acids include cyclopentane acetic acid, cyclohexane acetic acid, cyclohexane propionic acid, and cyclohexadiene acetic 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 hetero atoms in the ring, such as 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. It may be further substituted with a substituent such as a group or a protected carboxyl group. Examples of the acyloxy and carbamoyloxy groups of R ¹⁸ include alkanoyloxy groups such as acetoxy, propionyloxy or butyryloxy; alkenoyloxy groups such as acryloyloxy; aroyloxy groups such as benzoyloxy or naphthoyloxy; and carbamoyloxy These include halogen atoms, nitro groups, amino groups, alkyl groups, alkoxy groups, alkylthio groups, acyloxy groups,
Even if it is substituted with one or more substituents such as acylamino group, hydroxyl group, carboxyl group, sulfamoyl group, carbamoyl group, carbalkoxycarbamoyl group, aroylcarbamoyl group, carbalkoxysulfamoyl group, aryl group, carbamoyloxy group, etc. good. Among the substituents for R ¹⁸ 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.
1,2,6-thiadiazine- which may be substituted with a sulfonamide or an alkyl group
1,1-dioxide, tetrahydro-1,2-
By reacting thiazine-1,1-dioxide or isothiazolidine-1,1-dioxide or salts thereof, and optionally removing the protecting group or protecting or converting the carboxyl group into a salt, the compound of the general formula [] 7-Substituted or unsubstituted amino-3-substituted methyl cefemcarboxylic 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 △ 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. Moreover, not only compounds where 〓Z is 〓S, but also 〓
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, 1,2,
When 6-thiadiazine-1,1-dioxide, tetrahydro-1,2-thiazine-1,1-dioxide or isothiazolidine-1,1-dioxide has a basic group or acidic group as a substituent, If necessary, each salt may be subjected to the reaction in the form of a salt, and in that case, the salt with a basic group or the salt with an acidic group may be the same basic group as explained for the salts of the compound of general formula []. Or a salt at an acidic group. 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. In addition, the salts of the compound of general formula [] may be isolated beforehand and used, 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 (FSO ₂ H−SbF ₅ ),
FSO ₂ H−AsF ₅ , CF ₃ SO ₃ H−SbF ₅ , HF−
Examples include super strong acids such as BF ₃ and H ₂ SO ₄ −SO ₃ . Furthermore, examples of the Lewis acid include boron trifluoride. In addition, examples of complex compounds of Lewis acids include dialkyl ether complex salts of boron trifluoride and diethyl ether, di-n-propyl ether, di-n-butyl ether, etc.; ethylamine, n-propylamine, 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.; nitrile complex salts with acetonitrile, propionitrile, etc., and the like. 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; Esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, and butyl acetate; Nitriles such as acetonitrile and butyronitrile; Halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane; Sulfolane and the like, 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 complex compounds may be used. In addition, sulfonamides of general formula [a] or 1,2,6-thiadiazine-1,1-dioxide, tetrahydro-1,2-thiazine, which may be substituted with an alkyl group, are used as reaction reagents in this reaction. The amount of -1,1-dioxide or isothiazolidine-1,1-dioxide or salts thereof to be used is determined by the general formula []
The amount may be at least one equivalent molar amount, but it is particularly preferable to use an amount of 1.0 to 5.0 times the molar amount of the compound or its salt. 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, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, or phosphorus oxychloride; N,O-bis(trimethylsilyl)acetamide. , trimethylsilylacetamide, trimethylchlorosilane, dimethyldichlorosilane; organic acid chlorides such as acetyl chloride, p-toluenesulfonyl chloride; acid anhydrides such as acetic anhydride, trifluoroacetic anhydride; anhydrous magnesium sulfate, anhydrous chloride Inorganic desiccants such as calcium, molecular sieves, calcium carbide, etc. 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. 1,2,6-thiadiazine-1,1-dioxide, tetrahydro-1, which may be substituted with a sulfonamide of general formula [a] or an alkyl group of general formula [b], used as a reaction reagent in this reaction. ,2-thiazine 1,1
-dioxide or isothiazolidine-1,1
When the substituents in the dioxide or their salts are substituted with a hydroxyl group, an amino group, a carboxyl group, etc., in carrying out this reaction, each of these groups is replaced with a corresponding commonly used protecting group. After the reaction is completed, by subjecting it to a conventional elimination reaction,
A desired compound can be obtained. Further, in the compound of general formula [], the carboxyl group can be protected or salted 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 ¹⁷ 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 [ ], [ ], [XI] or [ ] or salts thereof are obtained. Also, the general formula [], [], [], [],
Salts of the compound of [], [], [XI], [], or [] include salts in basic or acidic groups, and these salts are the same as those described for the salts of the compound of general formula []. Examples include salts with basic or acidic groups similar to . Examples of reactive derivatives at the amino group of the compound of general formula [] include isocyanates, compounds of general formula [] or their salts, silyl compounds such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide, trimethylsilyl chloride, and phosphorus trichloride. ,

【formula】

【formula】

_{[ Formula} ] _{Silyl derivatives , phosphorus derivatives , or} All compounds frequently used in acylation reactions, such as tin derivatives, are included. General formula [], [], [], [] or [
] Specifically, the reactive derivatives at the carboxyl group of the compound include acid halides, acid anhydrides, mixed acid anhydrides, activated acid amides,
Active ester and general formula [], [],
Examples include reactive derivatives of the compound of [], [] 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 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 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'-dicyclohexylcarbodiimide,
N'-disubstituted carbodiimides; azolide compounds such as N,N'-thionyldiimidazole;
N-ethoxycarbonyl-2-ethoxy-1,
Dehydrating agents such as 2-dihydroxyquinoline, phosphorus oxychloride, and alkoxyacetylene; 2-halogenopyridinium salts such as 2-chloropyridinium methyl iodide and 2-fluoropyridinium methyl iodide are used. This acylation reaction is generally carried out in a suitable solvent.
It is carried out 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 a mixture thereof can be used. In addition, as a base, an inorganic base such as alkali hydroxide, alkali hydrogen carbonate, alkali carbonate or alkali acetate;
Examples include organic bases such as tertiary amines such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-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. 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 of formula [] can be easily obtained according to conventional methods, and the salts include the same basic or acidic group salts as explained above for the salts of the compound of the general formula []. It will be done. 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. 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. General formula obtained as above [],
Compounds of [], [], [XI] or [] or their salts can be isolated and purified by known means, but furthermore, compounds of the general formula [], [],
The compound [XI] or [] or a salt thereof can also be used as a raw material for the next reaction without being isolated. (c) 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
The reaction is usually carried out in a solvent, and water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, and other solvents inert to the reaction can be used as the solvent. Preferred examples of nitrosating agents include nitric acid and its derivatives, such as nitrosyl halides such as nitrosyl chloride and nitrosyl bromide; alkali metal salts of nitrite such as sodium nitrite and potassium nitrite; butyl nitrite and pentyl nitrite. Examples include alkyl esters of nitrite such as esters. 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 starts from 10 minutes.
Complete in 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 [XI] or its salts from the compound of general formula [] or its salts, the compound of general formula [] or its salts is etherified. reaction or phosphorylation reaction. This etherification reaction and phosphorylation reaction are described in JP-A-53-137988, JP-A-55-105689,
It can be carried out by conventional methods such as etherification reaction and phosphorylation reaction described in JP-A-55-149295. For example, the alkylation reaction can be carried out according to a conventional method. The reaction is generally carried out at -20 to 60°C and is completed in 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, water, or a mixture thereof is 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 [XI] can be easily obtained according to a conventional method, and the salts can be prepared using the same basic group or acidic group as explained for the salts of the compound of general formula []. Examples include salt. 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 general formula [XI] 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 isolation. (e) Ring-closing reaction Next, each compound of the general formula [XI], [] or [XI] or a salt thereof is combined with the general formula [XII].
If thioformamide or thiourea is reacted, the general formula [a] or [
b] or their salts 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-dimethylacetamide, N-methylpyridone, or a mixed solvent of two or more of these is used. Although it is not particularly necessary to add a deoxidizing agent, 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 hydrogen carbonate, triethylamine, pyridine, 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
Usually 1 to 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 is usually carried out using solvents such as water and alcohol, as well as solvents that are inert to the reaction.
Alternatively, the reaction is carried out in a mixed solvent thereof, and the reaction is usually 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. The salts of the compound of the general formula [] can be used as they are in this reaction; for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth hydroxides such as magnesium hydroxide and calcium hydroxide. Metals; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali phosphates such as magnesium phosphate and calcium phosphate Earth metals; inorganic bases such as alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; or alkali metal acetates such as sodium acetate and potassium acetate; trialkylamines such as trimethylamine and triethylamine; 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. In addition, in this oximation reaction, introduction and removal of a protecting group and 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 general formula [] or its salts obtained as described 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, 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 Sulfolane solution containing 13.6 g of boron trifluoride (50 ml)
7-aminocephalosporanic acid (hereinafter referred to as 7-
Abbreviated as ACA. ) and 4.75 g of methanesulfonamide were added and dissolved, and then reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution was introduced into 250 ml of methanol under ice cooling, and then 15.8 g of pyridine was added.
drip. If you remove the precipitated crystals, thoroughly wash them with methanol, and then dry them, the melting point is 188-191℃ (decomposition).
7-Amino-3-(methanesulfonamide)
Methyl-△ ³ -cephem-4-carboxylic acid 7.85g
(yield 51.1%). Ir (KBr) cm ^-1 ; C=o 1790, 1610 NMR (CF ₃ COOD) δ value; 3.26 (3H, a, -CH ₃ ), 3.90 (2H, bs, C ₂ -H), 4.55 (2H , bs,

[Formula]), 5.49 (2H, s, C ₆ -H, C ₇ -H) In the same manner, the following compound was obtained. Γ7-amino-3-[(p-chlorobenzenesulfonamido)methyl]-△ ³ -cephem-4-carboxylic acid Melting point: 197-199°C (decomposition) IR (KBr) cm ^-1 ; νC=O 1790, 1610 NMR (CF ₃ COOD) δ value; 3.80 (2H, s, C ₂ −H), 4.24 (2H, bs,

[Formula]), 5.35 (2H, s, C ₆ -H, C ₇ -H), 7.53, 7.92 (4H, ABq, J = 8Hz,

[Formula]) Reference example 2 (1) 100 sulfolane solution containing 27.1 g of boron trifluoride
27.2 g of 7-ACA and 16.0 g of 3,5-dimethyl-1,2,6-thiadiazine-1,1-dioxide were added to and dissolved in the resulting solution, and the mixture was allowed to react at room temperature for 4 hours. After the reaction was completed, the reaction solution was introduced into 500ml of methanol under ice cooling, and then pyridine was added.
Drop 31.6g. 7-Amino-
Crude crystals of 3-(3,5-dimethyl-1,2,6-thiadiazin-1,1-dioxid-2-yl)methyl- ^Δ3 -cephem-4-carboxylic acid
Obtain 30.5 g (82.0% yield). In the same manner, crude crystals of the following compound were obtained. Γ7-amino-3-(N-methylmethanesulfonamido)methyl-Δ ³ -cephem-4-carboxylic acid Γ7-amino-3-(1,2,6-thiadiazin-1,1-dioxide-2-yl) Methyl-△ ³ -cephem-4-carboxylic acid Γ7-amino-3-(tetrahydro-1,2-
thiazin-1,1-dioxide-2-yl)
Methyl-△ ³ -cephem-4-carboxylic acid Γ7-amino-3-(5-methyl-isothiazolidin-1,1-dioxide-2-yl)methyl-△ ³ -cephem-4-carboxylic acid (2) ( 7-amino-3-(3,5-dimethyl-1,2,6-thiadiazine-1,1-
30g of crude crystals of dioxide-2-yl)methyl-△ ³ -cephem-4-carboxylic acid were dissolved in methanol.
Suspend in 300 ml and add 12.3 g of p-toluenesulfonic acid monohydrate. Then, 46.9 g of diphenyldiazomethane was gradually added and the mixture was heated at room temperature.
Incubate for 15 minutes. After the reaction, the solvent was distilled off under reduced pressure, and 300 ml of ethyl acetate was added to the resulting residue.
Add 300ml of water and adjust the pH to 7.0 by adding sodium bicarbonate. After separating the insoluble matter, the organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography (Wako silica gel C = 200, eluent: benzene: ethyl acetate =
3:1), diphenylmethyl 7-amino-3-(3,
5-dimethyl-1,2,6-thiadiazine-
1,1-dioxido-2-yl)methyl-△ ³
-Cefem-4-carboxylate 20.5 g (yield 47.2%) are obtained. IR (KBr) cm ^-1 ; C=O 1780, 1720 NMR (CDCl ₃ ) δ value; 1.90 (3H, s, -CH ₂ ), 2.22 (3H, s, -CH ₂ ), 3.44 (2H, bs , C ₂ -H), 4.75 (1H, d, J = 5Hz, C ₆ -H), 4.92 (1H, d, J = 5Hz, C ₇ -H), 5.01 (2H, bs,

【formula】), 5.73 (1H, s,

【formula】), 7.03 (1H, s, -CH), 7.23~7.70 (10H, m,

[Formula] ×2) In the same manner, the compounds shown in Table 2 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 a hydrogen atom or a carboxyl protecting group, R ⁶ is a hydrogen atom or an alkyl group, and R ⁷ is an alkyl or halogen atom substituted. 1,2,6-thiadiazin-1,1-dioxide-2-yl, tetrahydro-1,2-thiazine-, which may be substituted with a group represented by (a phenyl group which may be substituted with a phenyl group) or an alkyl group. 1,1-dioxide-
2-yl or isothiazolidin-1,1-dioxide-2-yl group, R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom, R ⁵ is an optionally protected amino group, -A- is the formula -CH ₂ - or the formula [formula] (wherein R ⁸ is an optionally protected represents an alkyl group which may be substituted with a suitable carboxyl group, and represents a group represented by (- represents a syn or anti isomer or a mixture thereof). ” Cephalosporin 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 ⁸ and ~ 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. Any one of claims 1 to 3, 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. The cephalosporin according to any one of claims 1 to 5, wherein R ² is a group represented by the formula [Formula] (wherein R ⁶ and R ⁷ have the above-mentioned meanings). and its salts. 7. The cephalosporin according to any one of claims 1 to 5, wherein R ² is a 1,2,6-thiadiazin-1,1-dioxid-2-yl group optionally substituted with an alkyl group. and its salts. 8 Claims ^{1 to 2} , wherein R 2 is a tetrahydro-1,2-thiazin-1,1-dioxide-2-yl group which may be substituted with an alkyl group.
Cephalosporin and its salts as described in any of Item 5. 9. The cephalosporin and its salts according to any one of claims 1 to 5, wherein ^R2 is an isothiazolidin-1,1-dioxide-2-yl group which may be substituted with an alkyl group. 10 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
7. The compound according to claim 6, which is -3-(methanesulfonamido)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-(3,5-dimethyl-1,2,6-thiadiazin-1,1-dioxid-2-yl)methyl-△ ³ -cephem-4-carboxylic acid, its ester, or a salt thereof A compound according to item 7 within the scope of the invention. 12 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
-3-(tetrahydro-1,2-thiazine-1,
9. The compound according to claim 8, which is 1-dioxid-2-yl)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-(5-methylisothiazolidine-1,1-
10. The compound according to claim 9, which is dioxido-2-yl)methyl-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 14 7-[2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamide]-3-(3,5-dimethyl-1,2,
6-thiadiazin-1,1-dioxid-2-yl)methyl- ^Δ3 -cephem-4-carboxylic acid,
The compound according to claim 7, which is an ester thereof or a salt thereof.