JPH0530836B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [] "In the formula, R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is an alkyl group or a formula -CH ₂ R ⁷ (wherein, R ⁷ is a halogen atom, alkyl, hydroxyl, alkylcarbonylamino, carboxyalkyl , alkoxycarbonylalkyl, aralkoxycarbonylalkyl, or phenyl, alkylcarbonylamino, pyridium, which may be substituted with an alkoxycarbonylalkyl, aralkoxycarbonylalkyl, or N,N-dialkylaminoalkyl group, pyridium, a heterocyclic ring consisting of a nitrogen-containing 5-membered ring, or a nitrogen-containing 5-membered ring. R ³ is a hydrogen atom; R ⁴ is a hydrogen atom or an alkyl group; R ⁶ is an optionally protected amino or alkylamino group and that ~ is the syn or anti isomer;
Each is shown below. Moreover, Z represents S, and the dotted line in the cefem ring means that the 2nd to 3rd positions or the 3rd to 4th positions are double bonds. ” cephalosporins and their 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. A general formula that exhibits excellent properties such as low toxicity and good absorption by oral or parenteral administration.
An object of the present invention is to provide cephalosporins and salts thereof. Another object of the present invention is to provide cephalosporins represented by the general formula [] and salts thereof that exhibit excellent therapeutic effects on human and animal diseases. The structural characteristics of the cephalosporin represented by the general formula [] of the present invention are that the amino group at the 7-position has the following novel group, ``In the formula, R ⁴ , R ⁶ and ~ each have the above-mentioned meanings.'' is bonded thereto. Hereinafter, the present invention will be explained in further detail. In the present specification, R ¹ in the general formula [] is a hydrogen atom or a carboxyl protecting group, and examples of the carboxyl protecting group include protecting groups conventionally used in the field of penicillin and cephalosporin compounds. These carboxyl-protecting groups include ester-forming groups that have the property of being eliminated by treatment under catalytic reduction, chemical reduction, or other mild conditions; ester-forming groups that are easily eliminated in vivo; water or alcohol; Examples include organic silyl groups, organic phosphorus groups, and organic tin groups, which have the property of being easily eliminated by treatment with; and various other known ester-forming groups. Among these types of protecting groups, suitable protecting groups include:
Specifically, the following can be mentioned. (i) Alkyl groups; especially straight-chain or branched-chain _C1-14 alkyl groups such as methyl, ethyl, n _- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and pentyl. (b) At least one of the substituents is chloro, bromo,
Fluoro, nitro, acyl, alkyl, alkoxy, oxo, cyano, alkylmercapto,
Alkylsulfinyl, alkylsulfonyl,
Alkoxycarbonyl, 1-indanyl, 2-
indanyl, furyl, pyridyl, 4-imidazolyl, succinimide, phthalimide, azetidino, aziridino, pyrrolidino, piperidino,
Morpholino, thiomorpholino, N-lower alkylpiperazino, 2,5-dimethylpyrrolidino,
1,4,5,6-tetrahydropyrimidinyl,
4-methylpiperidino, 2,6-dimethylpiperidino, alkylamino, dialkylamino,
Acyloxy, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino,
Substituted lower alkyl groups which are alkoxycarbonyloxy or alkylanilino or alkylanilino substituted with chloro, bromo, lower alkyl or lower alkoxy. (c) Cycloalkyl or lower alkyl-substituted cycloalkyl or [2,2-dilower alkyl-1,3-dioxolan-4-yl]methyl group consisting of 3 to 7 carbon atoms. (d) Alkenyl groups having up to 10 carbon atoms. (e) Alkynyl groups having up to 10 carbon atoms. (f) A substituted phenyl group or a substituent in which the phenyl group or substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above, or a substituted phenyl group of the formula "In the formula, -X- is -CH=CH-O-, -CH=
CH−S−, −CH ₂ CH ₂ S−, −CH=N−CH=
N-, -CH=CH-CH=CH-, -CO-CH=
CH-CO- or -CO-CO-CH=CH-. ” or a substituted derivative thereof (the substituents are arbitrarily selected from those exemplified in (b) above), or a group represented by the formula "In the formula, -Y- is -(CH ₂ ) ₃ - or -(CH ₂ ) ₄
It is a lower alkylene group such as -. '' or a substituted derivative thereof (the substituents are arbitrarily selected from those 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) furyl, quinolyl, methyl-substituted quinolyl, phenazinyl, 1,3-benzodioxolanyl,
4-(5-methyl-2-pyrrolinyl), 4-(2
-pyrrolinyl) or N-methylpyridyl, or a substituted heterocyclic group in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above. (li) Alicyclic indanyl or phthalidyl and substituted derivatives thereof in which the substituent is methyl, chloro, bromo or fluoro, alicyclic tetrahydronaphthyl and substituted derivatives thereof in which the substituent is methyl, chloro, bromo or fluoro, or trityl; Cholesteryl or bicyclo[4.4.0]decyl, etc. The carboxyl protecting groups exemplified above are representative examples, and 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. Particularly preferred carboxyl protecting groups include acyloxymethyl group, acyloxy-
Substituted alkyl group or the following formula

【formula】

【formula】

[Formula] "In the formula, R ⁸ is a straight chain or branched alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without known substituents; R ⁹ is a hydrogen atom or an alkyl group; R ¹⁰ is a hydrogen atom, a halogen atom, or an alkyl with or without a known substituent;
a cycloalkyl, aryl or heterocyclic group or a group represented by the formula -(CH ₂ ) _o COOR ⁸ (wherein R ⁸ has the above-mentioned meaning; n represents 0, 1 or 2); m means 0, 1 or 2, respectively. Carboxyl protecting groups that are easily eliminated in vivo, such as acyloxymethyl groups such as acetoxymethyl or pivaloyloxymethyl groups; 1-acetoxy-ethyl, 1-
Acetoxy-n-propyl, 1-pivaloyloxy-ethyl or 1-pivaloyloxy-n-
Acyloxy-substituted alkyl groups such as propyl groups; alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl or isopropoxymethyl groups; alkoxycarbonyloxymethyl groups such as methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl groups;
an alkoxycarbonyloxy-substituted alkyl group, such as a 1-methoxycarbonyloxy-ethyl or 1-ethoxycarbonyloxy-ethyl group;
or an alkoxycarbonylmethyl group such as methoxycarbonylmethyl or ethoxycarbonylmethyl group. Moreover, ^R2 means an alkyl group or a group represented by ^the formula _-CH2R7 , and examples of the alkyl group include methyl, ethyl, and propyl groups. Furthermore, R ⁷ of the group represented by the formula -CH ₂ R ⁷ is
Phenyl optionally substituted with a halogen atom, alkyl, hydroxyl, alkylcarbonylamino, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl or N,N-dialkylaminoalkyl group,
It means an alkylcarbonylamino, pyridinium, heterocyclic group consisting of a nitrogen-containing 5-membered ring, or a heterocyclic thio group consisting of a nitrogen-containing 5-membered ring, and the alkylcarbonylamino group includes, for example, methylcarbonylamino, ethylcarbonyl. amino,
n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino,
isobutylcarbonylamino, sec.-butylcarbonylamino, tert-butylcarbonylamino,
Mention may be made of straight and branched alkylcarbonylamino groups such as pentylcarbonylamino, hexylcarbonylamino, heptylcarbonylamino, octylcarbonylamino and dodecylcarbonylamino. Further, examples of the heterocyclic group consisting of a nitrogen-containing 5-membered ring represented by R ₇ include a heterocyclic group consisting of a nitrogen-containing 5-membered ring bonded to a 3-position exomethylene group and a carbon-carbon or carbon-nitrogen bond. Examples of the heterocyclic group consisting of a nitrogen-containing five-membered ring include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl groups. In addition, isomers exist in imidazolyl, pyrazolyl, triazolyl, or tetrazolyl groups when carbon-nitrogen bonds are formed with the 3-position exomethylene group, and which nitrogen atom in the ring is bonded to the 3-position exomethylene group. Both cases are included in the present invention. Examples of the heterocyclic thio group consisting of a nitrogen-containing 5-membered ring for R ⁷ include oxazolylthio, thiazolylthio, isoxazolylthio, isothiazolylthio, imidazolylthio, pyrazolylthio, oxadiazolylthio, and thiazazolylthio. Examples include ruthio, triazolylthio, and tetrazolylthio groups. Furthermore, among the substituents of R ⁷ , the hydroxyl group or the carboxyl group of the carboxyalkyl group is
It may be protected with a suitable protecting group commonly used in the field. Here, the hydroxyl-protecting group includes all groups that can be normally used as hydroxyl-protecting groups, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-
Methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4
-methoxyphenylazo)benzyloxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,
2,2-trichloroethoxycarbonyl, 2,
Easily eliminated acyl groups such as 2,2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 8-quinolyloxycarbonyl, acetyl or trifluoroacetyl; or Examples include benzyl, trityl, methoxymethyl, 2-nitrophenylthio, and 2,4-dinitrophenylthio groups. In addition, the carboxyl group-protecting group includes all groups that can normally be used as carboxyl group-protecting groups, such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trityl, p
-Nitrobenzyl, p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p
-methanesulfonylbenzoylmethyl, phthalimidomethyl, trichloroethyl, 1,1-dimethyl-2-propenyl, 1,1-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3-methyl-3-
Butynyl, succinimidomethyl, 1-cyclopropylethyl, methylsulfenylmethyl, phenylthiomethyl, dimethylaminomethyl, quinolin-1-oxide-2-yl-methyl, pyridin-1-oxide-2-yl-methyl or when protected with a group such as bis(p-methoxyphenyl)methyl, or when protected with a nonmetallic compound such as titanium tetrachloride;
Japanese Patent Publication No. 46-7073 and Dutch National Publication
For example, it is protected with a silyl compound such as dimethylchlorosilane, as described in No. 7105259. In alkyl groups with or without substituents, examples of the alkyl groups include methyl, ethyl, propyl and butyl groups. Furthermore, examples of substituents include halogen atoms, alkyl groups, aryl groups, hydroxyl groups, alkoxy groups, carboxyl groups, carbamoyl groups, alkoxycarbonyl groups, sulfamoyl groups, amino groups, alkylamino groups, and dialkylamino groups. Can be mentioned. These hydroxyl groups, amino groups or carboxyl groups are
Furthermore, it may be protected with a protecting group as described for R ₇ above and R ⁶ below. R ⁶ means an optionally protected amino or alkylamino group, and the protecting group for the amino or alkylamino group includes all groups that can normally be used as a protecting group for an amino group, such as trichloro Ethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-trienesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, o-nitrophenylsulfenyl,
(mono-, di-, tri-)chloroacetyl, trifluoroacetyl, formyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-
Methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4
-methoxyphenylazo)benzyloxycarbonyl, pyridin-1-oxide-2-yl-methoxycarbonyl, 2-furfuryloxycarbonyl, diphenymethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclo Easily eliminated acyl groups such as propyl ethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl or 8-quinolyloxycarbonyl; trityl, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5- Chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene,
1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1-[N-(2-methoxyphenyl)carbamoyl]-2-propylidene,
1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene or 3,3-dimethyl-5- Examples thereof include easily leaving groups such as oxocyclohexylidene; and silyl groups such as di- or trialkylsilyl. These protecting groups further include, for example, a halogen atom, an alkyl group, a nitro group, a hydroxyl group, an alkoxy group, an oxo group, a thioxo group, an alkylthio group, an acylamino group, an acyl group, an acyloxy group, an aryloxy group, a carboxyl group,
Carbamoyl group, hydroxyalkyl group, alkoxyalkyl group, carboxyalkyl group, alkoxycarbonyl group, amino group, alkylamino group, aminoalkyl group, N-alkylaminoalkyl group, sulfoalkyl group, sulfo group, sulfamoyl group, carbamoylalkyl group , an aryl group or a heterocyclic group such as furyl or thienyl. The hydroxyl group, amino group, and carboxyl group as substituents herein may be further protected with a commonly used suitable protecting group, and the protecting group for the hydroxyl group, amino group, or carboxyl group is the aforementioned hydroxyl group. ,
Examples include protecting groups for amino groups and carboxyl groups. In addition, the general formula [] and the general formula [] described below

The oxime represented by the formula can include syn and anti isomers, and the present invention includes both isomers and mixtures thereof. General formula [] and general formula [] described later

In the group [Formula], tautomers exist as shown in the following balanced formula, and the present invention also includes these tautomers. "In the formula, R ⁶ has the same meaning as above; R ^6a
means an imino group corresponding to R ⁶ . ” Examples of the salts of the compounds represented by the general formula [] and the general formula [] described below include salts with basic groups or acidic groups commonly known in the field of penicillin and cephalosporin compounds. Salts on basic groups include, for example, salts with mineral acids such as hydrochloric acid or sulfuric acid; salts with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid or trifluoroacetic acid; or methanesulfonic acid, ethane Sulfonic 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
- salts with sulfonic acids such as trisulfonic acid, benzene-1,2,4-trisulfonic acid or naphthalene-1,3,5-trisulfonic acid, and as salts with acidic groups, for example sodium or potassium salts with alkali metals such as calcium or magnesium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts; procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine or N,N-dibenzylethylenediamine, etc. or with other nitrogenous organic bases such as triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine or dicyclohexylamine. Salt is an example. In addition, examples of derivatives of the compound represented by the general formula [] described below include compounds in which the carboxyl group is protected with the carboxyl protecting group explained in ^R1 , and reactive derivatives often used in acylation and esterification reactions. Specifically, the reactive derivatives include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides and active esters, and the reactivity of the compound represented by the general formula [] with Vilsmeier reagents. Examples include derivatives. Specifically, the mixed acid anhydride includes, for example, a mixed acid anhydride with a carbonic acid monoester such as carbonic acid monoethyl ester or carbonic acid monoisobutyl ester; or a halogen-substituted acid anhydride such as pivalic acid or trichloroacetic acid. good.
Examples include mixed acid anhydrides with lower alkanoic acids. In addition, as the active acid amide, for example, N-
Acylsactucalin, N-acylimidazole, N
-acylbenzoylamide, N,N'-dicyclohexyl-N-acylurea or N-acylsulfonamide. Furthermore, examples of the active ester include cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, and substituted thienyl ester. Furthermore, as a reactive derivative of the compound represented by the general formula [] and the Vilsmeier reagent, the compound represented by the general formula [] and an acid amide such as N,N-dimethylformamide or N,N-dimethylacetamide can be used. , phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride,
Examples include derivatives reactive with Vilsmeier's reagent obtained by the action of a halogenating agent such as phosphorus oxybromide, phosphorus pentachloride, trichloromethyl chloroformate, or oxalyl chloride. Furthermore, the present invention covers all optical isomers and racemates, as well as all crystalline and hydrated cephalosporins represented by the general formula [] and their salts. Among the compounds represented by the general formula [] of the present invention,
As a preferable example, for example, △ ³ −
a cefem compound or its syn isomer, or
Further, R ⁷ is a triazolyl or tetrazolyl group which may be substituted with a halogen atom, alkyl, alkylcarbonylamino or alkoxycarbonylalkyl group, or alkyl, hydroxyl, carboxyalkyl, aralkoxycarbonyl, which has a carbon-nitrogen bond with the exomethylene group at the 3-position. Examples include compounds that are a heterocyclic thio group consisting of a nitrogen-containing five-membered ring which may be substituted with an alkyl or N,N-dialkylaminoalkyl group. Next, the results of antibacterial activity of representative compounds of the present invention will be shown. Antibacterial action According to the standard method of the Japanese Society of Chemotherapy [CHEMOTHERAPY, Vol. 23, pp. 1-2 (1975)], heart infusion broth [manufactured by Eiken Kagaku Co., Ltd.] was used for 37 days. The bacterial solution cultured for 20 hours at
Infusion Agar) medium [manufactured by Eiken Kagaku Co., Ltd.] was inoculated, and after culturing at 37℃ for 20 hours, the presence or absence of bacterial growth was observed.
It was defined as MIC (μg/ml). However, the amount of inoculated bacteria is 10 ⁴ per plate (10 ⁶
pieces/ml). Test compound A...7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-(3-chloro-1,2,4-triazolyl)methyl- ^Δ3 -cephem-4-carboxylic acid trifluoroacetate B...7- 2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(1,2,3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid C...7-[2- (2-aminoxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-acetamide-1,2,
Trifluoroacetate D of 3,4-tetrazolyl)methyl]-△ ³ -cephem-4-carboxylic acid...7-[2-(2-aminoxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,
4-tetrazolyl)methyl-△ ³ -cephem-
Trifluoroacetate of 4-carboxylic acid E...7-[2-(2-aminoxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[5-(1-methyl-1,2,3,
4-tetrazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid trifluoroacetate F...7-[2-(2-aminoxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[5-(1-carboxymethyl-1,
2,3,4-tetrazolyl)thiomethyl]-△ ³
-Trifluoroacetate of cefem-4-carboxylic acid G...7-[2-(2-aminoxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,3,4-
thiadiazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid trifluoroacetate H...7-[2-(2-aminoxazole-4-
yl)-2-(syn)-methoxyaminoacetamide]-3-[5-(1,2,3-triazolyl)
thiomethyl]-△ ³ -cephem-4-carboxylic acid hydrochloride I...7-[2-(2-aminoxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-(1-pyridiniummethyl)-△ ³ −
Cefem-4-carboxylate

[Table] Next, the method for producing the compound of the present invention will be explained. The compound of the present invention can be produced by known methods or a combination thereof, for example, by the method shown below. "In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , ~ and Z and the dotted line in the cefem ring have the same meanings as described above; R ^2a is an alkyl group of R ² ;R ^4a
is a hydroxy protecting group or a hydroxyl protecting group among R ⁴ ; R ^7a is a halogen atom among R ⁷ ,
Heterocycle consisting of phenyl, alkylcarbonylamino, or a nitrogen-containing 5-membered ring optionally substituted with alkyl, hydroxyl, alkylcarbonylamino, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, or N,N-dialkylaminoalkyl group or a heterocyclic thio group consisting of a nitrogen-containing 5-membered ring; R ¹¹
is a halogen atom; R ¹² is an amino group or a formula

[Formula] (In the formula, R ¹³ , R ¹⁴ and R ¹⁵ 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 ¹⁶ and R ¹⁷ are the same or different and represent a hydrogen atom or an organic residue that does not participate in the reaction); R ¹⁸ is
It means an acyloxy or carbamoyloxy group, respectively, with or without a substituent. (a) Three-position conversion reaction By subjecting a cephalosporanic acid of the general formula [] or its salts to a three-position conversion reaction,
To obtain cephalosporanic acids or salts thereof of the general formula [], for example,
Examples include methods described in No. 98987, No. 54-76591, No. 55-9048, and No. 57-99592. In addition, salts of the compounds of general formulas [], [], and [] include salts with basic groups or acidic groups, and these salts are as explained in the above section regarding the salts of compounds of general formula []. Examples include salts similar to . In addition, cephalosporanic acids of general formula [] or their salts are described, for example, in the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry).
Medicinal Chemistry), Volume 18, No. 4, No.
It can be obtained by the method described on pages 403-408 (1975). (b) Acylation (1) Next, the compound of the general formula [] or [] or a salt thereof obtained in this way is reacted with the compound of the general formula [] or a salt thereof or a reactive derivative thereof. By doing so, the compound of the general formula [] or its salts of the present invention can be obtained. Suitable reactive derivatives of the compound of general formula [] include the aforementioned acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, and active esters. Further, when the compound of general formula [] is used in the form of a free acid or a salt, a suitable condensing agent is used. Examples of condensing agents used include:
N,N'-disubstituted carbodiimides, such as N,N'-dicyclohexylcarbodiimide;
azolide compounds such as N,N'-thionyldiimidazole; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline, phosphorus oxychloride or alkoxyacetylene; or 2-chloropyridinium methyl iodide or 2-
Examples include 2-halogenopyridinium salts such as fluoropyridinium methyl iodide. This acylation is generally carried out in a suitable solvent in the presence or absence of a base. Solvents used include, for example, halogenated hydrocarbons such as chloroform or methylene chloride; ethers such as tetrahydrofuran or dioxane; N,N-dimethylformamide, N,N-dimethylacetamide, acetone or water, etc. or mixtures thereof. Examples include. Bases used include inorganic bases such as alkali hydroxide, alkali hydrogencarbonate, alkali carbonate or alkali acetate; trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-
Tertiary amines such as methylmorpholine, lutidine or collidine; or secondary amines such as dicyclohexylamine or diethylamine. Further, the amount of the compound of general formula [] or its salt or reactive derivative thereof to be used is usually about 1 to several moles per 1 mole of the compound of general formula [] or []. The reaction temperature is generally -50 to 40°C, and the reaction time is generally 10 minutes to 48 hours. Furthermore, the compound of the general formula [] or a salt thereof is reacted with the compound of the general formula [] or a salt thereof or a reactive derivative thereof in the same manner as above to obtain the compound of the general formula [] or a salt thereof, A compound of the general formula [] in which R ⁷ is a pyridinium group can be obtained by reacting pyridine in a conventional manner. The amount of pyridine used is usually 1.0 per mol of the compound of general formula [] or its salt.
~25 moles. This reaction is preferably carried out in a solvent, and the solvent used is preferably
Examples include water or a mixed solvent of water and an organic solvent such as N,N-dimethylformamide, dioxane, N,N-dimethylacetamide, acetone, methanol, ethanol, dimethylsulfoxide, acetonitrile, or tetrahydrofuran. This reaction is usually complete within 48 hours. Furthermore, the compound of the general formula [] where R ¹ is a carboxyl protecting group is a compound of the general formula [] ^{where R 1 is} a hydrogen atom or its salt; , a compound of the general formula [] in which R ¹ is a carboxyl protecting group or ^a salt thereof; Each compound can be converted according to a conventional method. In addition, in this acylation, if there is a reactive group in R ¹ , R ⁶ and R ^7a , it can be optionally protected with a normal protecting group during the reaction, and after the reaction , the protecting group can also be removed by a conventional method. The compound of the general formula [] of the present invention or its salts obtained as described above can be isolated by a conventional method. (2) In another method, in order to obtain a compound of general formula [] or a salt thereof from a compound of general formula [] or [] or a salt thereof, The reaction of diketene with a halogen such as chlorine or bromine [Journal of the Chemical Society, No. 97]
Vol., p. 1987 (1910)] may be reacted according to a conventional method. The reaction conditions and operations are well known in the art, and those known conditions and operations apply. In addition, salts of the compound of the general formula [] can be easily obtained according to conventional methods, and examples of the salts include the same salts as explained above for the salts of the compound of the general formula []. It will be done. The obtained compound of general formula [ ] or its salts may be isolated and purified by a conventional method, but it can also be used as it is in the next reaction without isolation. (c) Nitrosation 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 can be reacted with a nitrosating agent. good. This reaction is usually carried out in a solvent, and the solvents used include, for example, water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, or other solvents that do not affect the reaction. The nitrosating agents used are preferably nitric acid and its derivatives, for example nitrosyl halides such as nitrosyl chloride and nitrosyl bromide; alkali metal salts of nitrite such as sodium nitrite and potassium nitrite; and butyl nitrite esters. and nitrite alkyl esters such as nitrite pentyl ester. When using a salt of nitrous acid as the 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 using an alkyl nitrite ester as a nitrosating agent, the reaction is preferably carried out in the presence of a strong base such as an alkali metal alkoxide. The reaction temperature is not particularly limited, but generally preferred is cooling to room temperature. In addition, salts of the compound of the general formula [] can be easily obtained according to conventional methods, and examples of the salts include the same salts as explained above for the salts of the compound of the general formula []. It will be done. 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 as it is in the next reaction without isolation. (d) Alkylation or acylation Next, in order 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 alkylated or acylated. You can attach it to etc. This alkylation can be carried out according to a conventional method. For example, if it is carried out in a solvent under ice cooling or around room temperature, it is often completed within several minutes to several hours. Any solvent may be used as long as it does not inhibit this reaction, such as tetrahydrofuran, dioxane, methanol,
Examples include ethanol, chloroform, methylene chloride, ethyl acetate, butyl acetate, N,N-dimethylformamide or water, or mixtures thereof. Alkylating agents used include, for example, alkyl halides such as methyl iodide, methyl bromide, ethyl iodide or ethyl bromide; dimethyl sulfate; diethyl sulfate; diazomethane; diazoethane; or methyl p-toluenesulfonate. can be mentioned. When alkylating agents other than diazomethane or diazoethane are used, they are typically alkali metal carbonates such as sodium or potassium carbonate; alkali metal hydroxides such as sodium or potassium hydroxide; triethylamine; pyridine; or N , N-dimethylaniline or the like in the presence of a base. In addition, acylation can be carried out by a commonly used method, for example, using an acid anhydride or an acid halide. In addition, the salts of the general formula [] can be easily obtained according to conventional methods, and the same salts as explained above in connection with the salts of the compound of the general formula [] are examples of the salts. Can be mentioned. 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 as it is in the next reaction without isolation. (E) Ring-closing reaction Next, by reacting the compound of the general formula [] or [] or a salt thereof with the urea of the general formula [], the compound of the general formula [] or a salt thereof of the present invention is obtained. be able to. This reaction is usually carried out in a solvent, and any solvent may be used as long as it does not inhibit this reaction, such as water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide, etc. , N,N-dimethylacetamide, or N-methylpyridone, or a mixture of two or more thereof. Although the addition of a deoxidizing agent is not particularly necessary, the reaction may proceed smoothly by adding a deoxidizing agent as long as the cephalosporin skeleton is not changed. Deoxidizers used for this purpose include alkali metal hydroxides, alkali metal hydrogencarbonates, inorganic or organic bases such as triethylamine, pyridine or N,N-dimethylaniline. This reaction is carried out under ice cooling, room temperature, or heating. The amount of the urea of the general formula [] to be used is usually 1 to several equivalents relative to the compound of the general formula [] or [] or a salt thereof. Reaction time is 1 to 48 hours. As explained above, the target compound of the present invention can be easily obtained by the above-mentioned method (b) or (e), but there is a double bond between the 2nd and 3rd positions in the cefem ring ^. - Cefem compounds are the aforementioned (a), (b)(2) or
After the reaction (c), it may be converted into the corresponding △ ³ -cephem compound by a conventional method, but after the reaction (b) or (e), it may be isolated or not isolated and subsequently converted to a conventional method. Thus, a Δ ² -cephem compound can be converted into a Δ ³ -cepheme compound. The compound of general formula [] or its salt or reactive derivative thereof is a new compound and is useful as an intermediate for various β-lactam compounds including the compound of general formula []. The compound of general formula [] or its salt or reactive derivative thereof can be produced by known methods or a combination thereof, for example, by the method shown below. "In the formula, R ¹ , R ⁴ , R ^4a , R ⁶ , R ¹¹ and ~ each have the same meaning as defined above." Hereinafter, the compound of the general formula [ ] or its salt or its reactivity The method for producing the derivative will be explained according to the method described above. Journal of Medicinal Chemistry, No. 16
Vol. 9, No. 9, pp. 978-984 (1973), the compound of the general formula Compound [XII] can be obtained. In addition, the compound of this general formula [ ] is described in Nippon Kagaku Zasshi, Vol. 78, No. 9, pp. 1254-1256 (1957
General formula [XII] obtained by the method described in
The compound can also be obtained by subjecting it to conventional halogenation. Next, a compound of general formula [] can be obtained by reacting a compound of general formula [XI] or [] with a urea of general formula []. This ring-closing reaction is usually carried out in a solvent using the general formula [XI]
Alternatively, one to several equivalents of the ureas of the general formula [] are used with respect to the compound []. Solvents used include, for example, water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-
Examples include one or a mixed solvent of two or more such as methylpyridone, and preferably N,N-dimethylformamide. Moreover, the reaction time is 1 to 48 hours. At this stage, a protecting group can be introduced into or removed from the thus obtained compound of the general formula [] by a conventional method. Here, the protecting group includes the amino group protecting group and the hydroxyl group protecting group explained in R ⁶ and R ⁷ . Then, the compound of the general formula [] can be obtained by subjecting the compound of the general formula [] to a conventional hydrolysis reaction. Moreover, it can be derived into its salts or derivatives thereof by conventional methods. The compound of the general formula [] or its salts of the present invention can be provided to humans and animals in the form of a free acid, a non-toxic salt, a physiologically acceptable ester, or a non-toxic salt of the ester. However, in particular, the compounds of general formula [] of the present invention in the form of non-toxic salts or physiologically acceptable esters or non-toxic salts of their esters can be administered orally and parenterally to humans and animals. is well absorbed. When administered to humans and animals, it is usually prepared in the form of a cephalosporin drug, such as a tablet, capsule, syrup, or injection, and can be administered by oral or parenteral methods. Ru. The dosage is appropriately selected depending on the patient's symptoms, but in general, for adults, 0.1 to 5.0 g is
It can be administered in one to several divided doses per day. Next, the present invention will be further explained with reference to reference examples and examples, but the present invention is not limited thereto. Reference example 1 (1) Dissolve 120 g of methyl 4-bromo-3-oxo-2-methoxyiminobutyrate in 700 ml of N,N-dimethylformamide, and add 151 g of urea to this solution.
and react at room temperature for 48 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, the resulting residue is introduced into a mixed solvent of 500 ml of water and 500 ml of diethyl ether, and the aqueous layer is separated. Add 700 ml of ethyl acetate to the separated aqueous layer, adjust the pH to 7.0 with sodium hydrogen carbonate, and then separate the organic layer. The separated organic layer is washed with 400 ml of water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If the obtained residue is washed with isopropyl alcohol and the crystals are removed, the melting point is 148 ~
35.2 g (yield 35.1%) of methyl 2-(2-aminoxazol-4-yl)-2-(syn)-methoxyiminoacetate having a temperature of 150 DEG C. (decomposition) is obtained. IR (KBr) cm ^-1 ; ν _C=0 1735 NMR (d ₆ -DMSO) ppm value; 3.82 (3H; S; -COOCH ₃ ), 3.90 (3H; S; = N - OCH ₃ ), 6.40 (2H ;bs; _−NH2 ), 7.36(1H;s;

[Formula]) The compounds shown in Table 2 were obtained by reacting and treating in the same manner. Note that R ¹ , R ⁴ and R ⁶ in Table 2 each represent a substituent of the following formula.

【table】

【table】

Claims (1)

[Claims] 1. General formula: "In the formula, R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is an alkyl group or a formula -CH ₂ R ⁷ (wherein, R ⁷ is a halogen atom, alkyl, hydroxyl, alkylcarbonylamino, carboxyalkyl , phenyl optionally substituted with alkoxycarbonylalkyl, aralkoxycarbonylalkyl or N,N-dialkylaminoalkyl group, alkylcarbonylamino, pyridinium, a heterocyclic system consisting of a nitrogen-containing 5-membered ring or a nitrogen-containing 5-membered ring R ³ is a hydrogen atom; R ⁴ is a hydrogen atom or an alkyl group; R ⁶ is an optionally protected amino or alkylamino group and that ~ is the syn or anti isomer;
Each is shown below. Moreover, Z represents S, and the dotted line in the cefem ring means that the 2nd to 3rd positions or the 3rd to 4th positions are double bonds. ” Cephalosporins and their salts. 2. Cephalosporins and salts thereof according to claim 1, wherein the cefem ring is a Δ ³ -cephem ring. ^3. Cephalosporins and salts thereof according to claim 2, wherein R2 is a group represented ^by the formula _-CH2R7 (wherein ^R7 has the meaning described above). 4. Cephalosporins and salts thereof according to claim 3, wherein R ⁷ is a phenyl group. 5. The cephalosporins and salts thereof according to claim 3, wherein R ⁷ is an alkylcarbonylamino group. 6 A patent in which R ⁷ is a heterocyclic group consisting of a nitrogen-containing 5-membered ring optionally substituted with a halogen atom, alkyl, alkylcarbonylamino, or alkoxycarbonylalkyl group that forms a carbon-nitrogen bond with the exomethylene group at the 3-position Cephalosporins and salts thereof according to claim 3. 7 Claims in which ^R7 is a heterocyclic thio group consisting of a nitrogen-containing 5-membered ring optionally substituted with an alkyl, hydroxyl, carboxyalkyl, aralkoxycarbonylalkyl, or N,N-dialkylaminoalkyl group The cephalosporins and salts thereof according to item 3. 8. Cephalosporins and salts thereof according to claim 3, wherein R ⁷ is a pyridinium group. 9 Claim 1 in which ~ is a syn isomer
Cephalosporins and salts thereof according to any one of items 1 to 8. 10. Cephalosporins and salts thereof according to claim 9, wherein R ⁴ is an alkyl group. 11. Cephalosporins and salts thereof according to any one of claims 1 to 10, wherein R ⁶ is an amino group. 12 7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-(3-chloro-1,2,4-triazolyl)methyl-△ ³ -cephem-4-carboxylic acid,
7. The compound according to claim 6, which is an ester thereof or a salt thereof. 13 7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(1,2,3,4-tetrazolyl)
7. The compound according to claim 6, which is methyl]-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 14 7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-acetamide-1,2,3,
4-tetrazolyl)methyl]-△ ³ -cephem-4
- The compound according to claim 6, which is a carboxylic acid, an ester thereof, or a salt thereof. 15 7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,4-
7. The compound according to claim 6, which is [tetrazolyl)methyl]-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 16 7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[5-(1-methyl-1,2,3,4-
Tetrazolyl)thiomethyl]-△ ³ -Cefem-4
- The compound according to claim 7, which is a carboxylic acid, an ester thereof, or a salt thereof. 17 7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[5-(1-carboxymethyl-1,2,
8. The compound according to claim 7, which is 3,4-tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 18 7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,3,4-thiazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid, its esters or their esters 8. The compound according to claim 7, which is a salt. 19 7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-[5-(1,2,3-triazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid, its ester, or a salt thereof A compound according to claim 7. 20 7-[2-(2-aminooxazole-4-
yl)-2-(syn)-methoxyiminoacetamide]-3-(1-pyridiniummethyl) ^-Δ3 -cephem-4-carboxylate, an ester thereof, or a salt thereof, according to claim 8. Compound.