WO1985005620A1 - Cephem compounds - Google Patents

Abstract

Novel cephem compounds of the general formula (I), wherein R1 represents an optionally protected amino group, R2 represents a hydrogen atom or a halogen atom, R3 represents a hydrogen atom or an optionally substituted hydrocarbon residue, R4 represents a hydrogen atom or a methoxy group, A represents an optionally substituted imidazol-1-yl group forming a fused ring at positions 2 and 3 or 3 and 4, and n represents 0 or 1. They have an excellent antibacterial activity.

Description

 Specification

 Cephalic compound

 Technical field

 The present invention relates to a novel cef compound having an excellent antibacterial activity, a method for producing the same, and a pharmaceutical composition. Background Technology-Conventionally, a quaternary ammonium methizole group is in the third position, and 2- (2-aminothiazole) is in the seventh position. Various sepham compounds or derivatives thereof having a hydroxy (or substituted hydroxy) iminoacetamide group have been synthesized and patented [for example, see Japanese Patent Application Laid-Open No. 53-34779 5. 1979-92, 1986, 514-139, 1982, 154-154, 1986, 545-149, 1989, 579- 5 6 4 8 5, 57-1972 3 94, 58-1 5 9 4 98, etc.) Power 'The quaternary ammonium group is derived from a nitrogen-containing aromatic heterocyclic ring Most of them have a monocyclic pyrium group or a substituent on the ring, and the imidazono-1-yl of the present invention which forms a condensed ring at the 2,3-position or the 3,4-position Let alone synthesis of compounds having a thiol group, No disclosure was made in the application specification.

 CFM antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, such as in the treatment of diseases caused by bacteria resistant to benicillin antibiotics and in the treatment of bencilin-sensitive breaths. It is especially useful for the treatment of the elderly. In this case, it is desirable to use a cefm antibiotic that is active against both gram-positive bacteria and gram-negative bacteria. For this reason, research on cefe antibiotics having a broad antibacterial spectrum has been pursued. Actively performed

ΟΜΡΙ I have been. As a result of long-term studies, introduction of ² -(( ² -aminothiazolone-14-inole) -12-hydroxy (or substituted hydroxy) iminoacetamide group at position ^{7 of the} septum ring resulted in the presence of Durum-positive bacteria and Durum. It was discovered that they became active against both negative bacteria, which led to the development of so-called third-generation cephalosporin compounds. At present, several third-generation cephalosborin compounds are already on the market. Another feature of these third-generation cephalosporin antibiotics is that they have also been active against the same resistant bacteria that were once experienced in benicillin, so-called cephalosporin-resistant bacteria. That is, some Escherichia coli, some Citrobacter, and most indians that have shown resistance to known cephalosbolins—proteus, Entero, Serratia, or Ciudamonas that are positive. It also exhibited antibacterial activity to a degree that could be used clinically against pathogenic bacteria classified into genera. Among the technical ideas of these third-generation cephalosporin-based compounds, a quaternary ammonium methyl group such as a pyridinum methinole group is placed at the third position, and the above-mentioned aminothiazolyloxyminoacetamides are placed at the seventh position. It has been suggested that a septum compound having both of these features has an even better antibacterial action and a unique antibacterial spectrum, and various compounds of that family have been synthesized.

 Disclosure of the invention

The present invention has the general formula

oi

WIPO-、 Wherein R i is an amino group which may be protected, R ₂ is a hydrogen atom or a halogen atom, R ₃ is a hydrogen atom or a hydrocarbon residue which may be substituted, and R 4 is A represents a hydrogen atom or a methoxy group; A represents an optionally substituted imidazole-11-yl group which forms a condensed ring at the 2,3-position or the 3,4-position; Or 1], or a physiologically acceptable salt or esthetic thereof, a process for producing the same, and a pharmaceutical composition.

 The chemical compound in the present specification is based on “The 'Jana' Saiji Bujiamerikan.Chemical.Society”, vol. 84, p. 3400 (1962). Named in connection with “cepham”, it refers to a compound having a double bond at the 3,4-position among cepham compounds.

As described in the background section, a cephalic compound having a quaternary ammonium methyl group at the 3rd position and an aminothiazolyl xyminoacetamide at the 7th position has a more excellent antibacterial effect and a unique antimicrobial effect. Increasingly, it has become clear that it has an antibacterial agent. Numerous compounds in which the quaternary ammonium group at the 3-position is derived from a nitrogen-containing aromatic heterocycle have already been synthesized and patent applications have been filed, but those heterocycles are monocyclic pyridinium groups or on their rings. Most of the compounds having an imidazole-1-y group forming a condensed ring at the 2,3-position or the 3-, 4-position of the present invention are completely synthesized. Not. The present inventors have succeeded in synthesizing the compounds represented by the general formula [I] having such chemical structural characteristics, and as a result of examining the antibacterial activity and antibacterial spectrum of these compounds, That the compound (I) has a strong antibacterial activity against various bacteria, in particular, it has a strong antibacterial activity against the above-mentioned cephalosporin-resistant bacteria, and that it is specific for bacteria of the genus Pseudomonas. Complete the present invention by finding antibacterial activity Done.

In the above septum compound [I], the substituent Ri represents an amino group which may be protected, that is, an amino group or a protected amino group. -In the field of synthesis of ratatam and peptide, the protecting group of amino group has been thoroughly studied and its protection method has already been established. In the present invention, those known as the protecting group of amino group are also used. It can be adopted as appropriate. Amino protecting groups as, for example C ₆ ~ ₁₀ § Li of - / Leer Shinore group, Ci ~ ₅ § / Leka Noi Honoré group, C ₃ ~ ₅ Anorekeno I, Les group, Cg i.一 一 ノ ノ レ レ (^ ~

₁₀ § Norekinoresu Le 'Honinore group, substituted O carboxymethyl Kano levo Nino les group, mosquitoes Norenokumo Lee Honoré group, Chio Kano lever Moi Honoré group -, C ₆ ~ ₁₀ § Li one Noreme Chinore group, C ₆ ~ ₁₀ § Li Nore Ichime Ji Ren group, C ₆ ~ ₁₀ § Li Norechi Saimoto, substituted Li Honoré group, 2 -

Anorekokishi-Ichiriki / Reponinore 1-Mechinori 1 1-etheninore group. C ₆ ~

Specific examples of the ₁₀ aryl / leacinole group include benzoinole, naphthoinole, and phthalonyle, and these aromatic rings are substituted with (^ to ₄ arequinole, (^ 6 anorecoxy, halogen, nitro, etc.). Specific examples of the substituted aryl / leacene group include p-tonoleinole, -tert-butynolebenzo'inole, p-methoxybensoinole, p-tert-. Butoxybenzoinole, ρ-crobenzoenore, p-2-nitrobenzonole, etc. Ci ~ 5 More specifically, the group is homizole, acechinole, pro Pio two Norre, Buchiri Honoré, Bruno Le Li Honoré, bi / black Lee Honoré, Sakunishinore, etc. Kunoreta Rinore are mentioned, these a Kanoinore groups further (^ _1-6 a Job shea, halogen, C ₆ ~ ₁₀ § Re one / Les, C ₆ ~ ₁₀ § Li Noreokishi, C ₆ ~ ₁₀ § rie Norechio etc. In may be substituted. Substituted § / Rekanoinore f or specifically {Nima mono click as a base Loroacetinole, dichloroacetinole, trichloroacetinole, monobromoacetinole, monoph: / leoloacetinole, diphnolace , Trifluoroacetyl, monoiodoacetyl, acetate acetyl, 3-oxobutylyl, 4-chloro-3-oxobutyryl, phenylacetyl, D-chloro-phenylacetyl, phenoxyacetylenol, ρ-octane Lolof enokiacetyl, and the like. C ₃ ~ ₅ Arukenoiru group as § click Li B A le in concrete is black WINCH Bruno I Honoré and maleoyl can be mentioned, Arukenoiru group of these are further substituted with such C ₆ ~ ₁₀ Ariru You may. Specific examples of the substituted alkenyl group include cinnamoyl. C ₆ ~ _{1 0} § Li Rusuruhoniru specifically, base Nze Nsuruhoniru as groups, such as naphthalene sulfonyl and the like, these aromatic rings C i to ₄ alkyl, C 'i~6 alkoxy, halogen, Two Bok port It may be replaced by, for example. Specific examples of the substituted arylsulfonyl group include p-northene sulfoninole, p-tert-butynolebenzenes zolephoninole, p-methkinbenzenebenzenesulfonyl, p-chlorobenzenesulfonyl, ρ —Power such as benzenesulfonyl; C ₁ ~ _ln alkylsulfonyl ^ and specifically is methanesulfonyl, ethanesulfonyl, etc. mosquitoes Nfasuruho sulfonyl and the like,. These alkylsulfonyl ® or C ₆ ~ _{1 0} Ariru, C

6 to 10 aryloquin 'may be substituted by halogen or the like. Examples of the substituted oxycarbonyl group include (^ to _8- alkoxycarbonyl groups such as methoxycarbonyl, ethoxyquincarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and isovonolenylcarbonyl, such as phenoxycarbonyl and naphthyl). O carboxymethyl C _6, such as carbonyl, ~ _{1 0} § Li one Ruoki I / Ichiriki Noreboni Le e.g. benzyl O Kin c ₇ ~ such as carbonyl _{1 2} Ararukiruoki Ichiriki Lupo 'sulfonyl group etc. are exemplified et. are. C alkoxy one The carbonyl group is additionally C

_1-6 alkoxy, C. 2 to ₅ A Rukano I Honoré, substituted Li Le, C i to ₄ Arukirusu Ruhoniru, halogen, optionally substituted with like £ § Bruno. Replaced Examples of the alkoxy-carbonyl group include methoxymethyloxycarbonyl, acetinolemethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methansulfonylethoxycarbonyl, 2,2,2-trichlorocarbonyl. Loro Toki i carbonyl, 2-ano Toki carbonyl and the like. Flip _6-10 § Li one Ruokin - carbonyl group and C ₇ through i ₀ § Rarukiruokishi - aromatic carbonyl groups (^ ~ alkyl, C ^ s alkoxy, halogen, optionally substituted by such as a secondary Bok port Specific examples of the substituted aryloxycarbonyl group include p-methylphenoxycarbonyl, p-methoxyphenol, if-nil, and p-chlorophenoxy-carbonyl. Specific examples of the substituted aralkyloxycarbonyl group include P-methylbenzyloxycarbonyl, P-methoxybenzyloxycarbonyl, and p-alkoxycarbonyl. σ mouth base Nji Ruo carboxymethyl Cal e * sulfonyl, [rho -. two Bok σ benzyl O, etc. Kin carbonyl and the like also alkyl C ₇ ~ ₁₂ § Lal kill O Kishi carbonyl group C ₆ ~ _{1 0} § reel, No, replace with gen, etc. The specific examples thereof include benzhydryloxycarbonyl, etc. The carbamoyl group may be substituted. Specific examples of the substituted canolebamoyl group include N— Methyl / Reca / Rebamoyl, N-Ditylcarbamoyl, N, "-Dimethylcarbamoyl, N-Phenylcarbamoyl, N-(— Meth-Xyphenyl) Lubamoyl, and the like. .. it may be substituted as the ho specifically substituted Chiokarubamoi Le group and the like N- main Chiruchio force Rubamoi Le C ₆ ~ ₁₀ Ariru - base is specifically a methyl group Njiru, Nafuchirume These aromatic rings may be substituted with (^ to ₄ alkyl, C i to ₆ alkoxy, halogen, nitro, etc.) Reel methyl group is specifically P-methyl pen , P-methoxybenzinole, p-cloth venzinole, ρ12-t venzinole, and the like. The methyl group of Arirumechiru group may be substituted by another 1-2 amino C ₆ ~ ₁₀ Ariru group, specifically base Nzuhi drill, etc. WINCH pentaerythrityl the like. C ₆ ~ ₁₀ § Li Ichiru - The methylol alkylene group specifically including benzylidene, and these aromatic rings C. 1 to 4 alkyl, C ₁ ~ ₆ alkoxy, halogen, substituted with such as a secondary Bok port May be. Specific examples of the substituted arylmethylene group include P-methylbenzylidene and p-chlorobenzylidene. The C ₆ ~ ₁₀ § Li one Lucio groups specifically such 0- two Bok σ-phenylene thioether can be mentioned. The substituted silino group is represented by the general formula R ₆ R ₇ R ₈ S i NH,

(R ₆ R ₇ R ₈ S Ri ₂ N or ZC ^; ^{9, 0,} N _{[wherein, R 6) R 7 j R} 8) R 9>

_{R 10 H 9 ', R 10} ' are each for example methyl, Echiru shows a C ₆ ~ ₁₀ Ariru group such as C ι~ ₄ alkyl or e.g. phenyl, such as tert- butyl, it may be the same or different. Or for example main styrene, it means a silyl group such as represented by showing the C. 1 to ₃ alkylene group such as Edjiren], specifically Bok Li main Chirushi Li Le, tert- Puchirujime Chirushi Lil, - Si (CH _{3 2} CH ₂ CH ₂ Si (eg, Η _{3 2} — and the like. Examples of the C alkoxy group of 2—C ^ salkoxy-carboxyl 1—methyl-1-ethenyl group include methoxy, ethoxyquin, tert-butoxy.

Substituents Ii ₂ in the above cephem compound [ί] represents a hydrogen atom or a halogen atom. Examples of the halogen atom include fluorine, chlorine, and bromine, and chlorine is preferable.

In the Ceph compound [I], the substituent R ₃ is a hydrogen atom or a substituted

CMPI Represents an optionally substituted hydrocarbon residue. Examples of hydrocarbon residues include

Ci ~ ₆ § Noreki group, Rei_2～6 A ^ Ke two Norre group, C ₂ ~ ₆ § Norekininore group, C ₃ ~ ₆ Shikuroanoreki group, C ₃ ~ ₆ Shikuroaruke two forces such as Norre group and Riwake C _1-3 Arukinore or substituted C 1 ~ ₃ a ^ key ^ specific examples of an group are preferred _{c Ci~ 6} a ^ Kinore group Mechinore, E Ji. n-propynole, isopropynole, n-butynole, isof * chinole, sec — '^-!, tert—butene / let, n-one; , Ethinole and η-propi / re are preferred. C as in particular _2-6 alkenyl group Bininore, § Li Le, i Sopuro Bae Ninore, meta Li Honoré, 1, 1 Jimechirua Li Le, 2-Buteninore, 3 Buteninore the like. The C ₂ ~ ₆ Arukini Honoré groups specifically Echininore, etc. Puropaginore the like. C ₃ ~ ₆ consequent lower / As specifically Rekinore group Shikuropuro bi / les, sik Robuchinore, cyclopentyl Honoré, hexyl mosquito fried 'is like the consequent filtration. (3 to 6 cycloanole keninole groups include, specifically, 2-cyclohexylbenzene, 3-cyclohexylbenzene, 2-cyclohexynole, 3-cyclohexynole, and the like. the cited _c substituent of these hydrocarbon residues such as hydroxyl, C ^ ₆ alkyl Honoré group, C ₂ ~ ₆ § Norekeninore group, C ₂ ~ ₆ a Kininore group, C ₃ ~ ₆ consequent Roanoreki Le group, c _{3 to} e cycloalkyl group, c ₆ to ₁₀ aryl group, c ₇ to ₁₂ aralkyl group, heterocyclic group, Ci to 6 alkoxy group, 〇3 to 6 cycloalkyloxy group, C ₆ ~ ₁₀ § rie Reokishi group, C ₇ ~ ₁₂ § la Kinoreokishi group, a heterocyclic Okishi group, main Norekaputo group, _Ci-6 Arukinorechi Saimoto, C ₃ - ₆ consequent Roaruki Chisaimoto, C ₆ through i ₀ Ariruchio group , C ₇ ~ ₁₂ § La / gravel Rechio group, a heterocyclic Chio group, amino group, mono Ci ~ ₄ § Norekinorea Mi amino group, Di (^ ~ Arukinorea Mi amino group, C ₃ - ₆ cycloalkyl Arukinorea Mi amino group, C ₆ ~ ₁₀ § Li Norea amino group, C ₇ ~ ₁₂ Ararukiru Amino group, a heterocyclic amino group, cyclic amino group, azido甚, Two Toro group, halo Gen atom, cyano group 'carboxy group, Ci- _8- anolecoxy monocarbonyl group,

C _fi _ ₁₀ § Li Lumpur old Kishi carbonylation Honoré group 'C ₃ ~ 6 consequent lower Kure Kino Les OXY carbonylation les group, C ₇ ~ ₁₂ § La / Rekiru year old carboxymethyl one carbonyl group, C ₆ ~ ₁₀ § Li over Reashiru group, (^ 5 Anore force Roh i le group, C ₃ ~ ₅ Anorekenoiru group, C ₆ ~ ₁₀ § Li - Lou A sheet Noreokishi group, C ₂ ~ ₅ § Norekano Lee Honoré old alkoxy group, C ₃ ~ ₅ Alkenyl group, L / M / L group, Lubamo / L substitution group, L / L moyl group. Lvamoyl group, L / Loxy group, substitution Bamoi Norre old alkoxy group, Futarui Mi de group, C ₂ ~ ₅ Arukanoizorea Mi de group, C 6 ~ 1 0 § Li - Honoré Ichia Shinorea Mi de group, force Rubokishia Mi amino group, C 1 ~ ₄ Anoreko carboxymethyl Ichiriki / Reponinorea Mi amino group, C _fi ~ ₁₀ § rie / Reoki Shikarubo two / Reami amino group, c ₇ ~ ₁₂ § La Kill old Kin -... Carbonitrile Nino like Les amino group C 1 ~ ₆ alkyl group as specifically the substituent of the hydrocarbon residue Mechinore, Echinore, n- off Russia arsenide Honoré, isophthalate b arsenide "Honoré, n- off" Chinore, Lee Sopuchi / Les, sec- butyl 'tert - Petit / Les, n- pentyl, n- hexyl and the like, C ₂ ~ ₆ Anorekeniru group f or Biel, § Li Le, Lee . soft b Bae alkenyl, meta Li Honoré, 1, 1 one dimethyl Chinorea Li Honoré, 2 - butene two / Les, 3-butenyl and the like, C ₂ ~ ₆ a Le key sulfonyl group Echininore, etc. Puropagi Les , C ₃ ~ ₆ cycloalkyl / Les group sik port Puropinore, cycloalkyl Buchizore, consequent Rope inches / Les, and hexyl consequent b, C ₃ ~ 6 consequent Roazoreke two Les group 2 - sik Rope Nteniru, 3 - consequent Ropente Nyl, 2-cyclohexenyl, 3-cyclohexenyl Etc., C ₆ ~ ₁₀ § rie / Les group phenylalanine, and naphth / Les, C ₇ ~ ₁₂ Ararukiru groups benzyl, 1 one Fueniruechinore, 2 Fueniruechiru, naphthylmethyl and the like, C. 1 to ₆ Arco Methoxy, ethoxy, and n-phenyl. Roxy, Isof. B Bo alkoxy, n - Bed DOO xylene, etc. ter t-butoxy, C ₃ ~ ₆ consequent Roaruki / Les Sai alkoxy group consequent Ropuropiru old alkoxy, - and consequent Roeki Sil old carboxymethyl, C ₆ ~ ₁₀ § rie / Reokishi groups phenoxy, Nafuchiruokishi etc., C ₇ ~ _{1 2} § la Norekiru old alkoxy group or base Njiruokishi, 2 - and full E Nino les ethyl O carboxymethyl, ^C i ~ 6 § La Zorekiruchio group or methylthio , Echiruchio, n- Puropiruchi old, and n Buchiruchio, C ₃ ~ ₆ cycloalkyl Ano gravel Lucio groups include cyclopropyl Chi old, cyclohexylthio and cyclohexane, C ₆ ~ ₁₀ § Li Ruchio group etc. Fueniruchi O, C ₇ ~ ₁₂ ara ^ quinthio group is benzyl retinyl, mono-C i- ₄ alkylamino, methinoleamino, ethylamino, n-propylamino, n-butylamino, di (^ 4alkylamino is dimethylamino, getinoleamino Bruno, Mechinoreechirua Mi Bruno, di (n -. off Robinore) § Mi Bruno, and di (n- butyl amino, Ji ₆ black alkylamidyl Groups Kurofu necked Piruamino, etc. Kinruamino to consequent opening, Ji and _6-10 Ariruamino group or § two Reno, c ₇ ~ ₁₂ Ararukiruamino group Benjiruami Bruno, 2 -. And phenylalanine E chill § amino, cyclic amino group Is virolidino, piperidino, hipperazino, morpholino, 1-pyrrolyl, etc., halogen atom is fluorine, chlorine, bromine, iodine, etc., and alkoxyl / reponyl group is methoxyl / reponyl, . d preparative Kishikaru Bo 'cycloalkenyl, n- Purohokishikarubo two Honoré, isophthalate necked Hoki Shikano levo Nino les, n- butoxy Kano levo Nino les, tert - butoxycarbonyl, etc. Lee Soboruniru Saiki deer Noreboniru, C ₆ ~ ₁₀ § Li one Norre old carboxymethyl Ichiriki Noreboniru group Fueno key sheet strength Rubo two Honoré etc., C ₃ ~ ₆ cycloalkyl O carboxymethyl Ichiriki carbonyl group increased click Full ° b Pinore old alkoxycarbonyl, a hexyl O propoxycarbonyl sulfonyl "etc. cyclohexane, etc. C ₇ ~ _{1 2} § la key / Les OXY carbonylation / Les group base Nji Ruo propoxycarbonyl two Le, c ₆ ~ _{1 ()} Ariru one § sill groups downy Nzoiru, phthaloyl, etc. Hue Niruasechiru, (^ 5 alk Noiru group Hor Mitsure, Asechiru, full opening Pioniru, butyryl, valeryl, Pibaroiru the like, c ₃ ~ ₅ Arukenoi Le group § click Li Roy Honoré, black Tonoiru, maleoyl the like, C ₆ ~ ₁₀ Arirua Ruo · The sheet group and Benzoiru old Kin, C ₂ ~ ₅ Arukanoiru old alkoxy group § Seto key sheet, off. Mouth Pioniru old carboxy, butyl re / Reokishi, etc. Pinoku Roy Rusaiki sheet, and C ₃ ~ ₅ A Rukenoiru old alkoxy group Akuri acryloyloxy old alkoxy, substituted force Rubamoiru group N- methylcarbamate Moi Le, N, N-dimethylcarnoyl, N-ethylcarnoyl, N-phenylcar / moyl, pyrrolidinocarbonyl, pyridinocarbonyl, piperazinocarbonyl, morpholinocarbonyl, etc. Substituted rubamoyl groups include N-methylthioamine and N-methylcarbamoyloxy, N, N-dimethylcarnoyl, N-ethyl / recarnomoy / reoxy, etc. the, C ₂ ~ ₅ alkanoate I Ruami de group § Se Toami de, and propylene old N'ami de, c ₆ ~ ₁₀ § Li Lumpur one § Shirua Mi de group is a base Nzua Mi de The, C i to ₄ alkoxycarbonyl one carbonylation / Rare Mi amino group beans preparative key Shikarubonirua Mi Bruno, E preparative key deer Rubonirua Mi Bruno, tert- butoxide Kishika Rubonirua Mino etc., C _{6 →} O § Li Lumpur old Kishi carbonyl § Mi Roh group and Hue Bruno alkoxycarbonyl § amino, C ₇ ~ _{1 2} § la Rukiruokishi one Karuboniruami amino group represents like base Njiru Okishika Ruboniruamino. The heterocyclic group of the heterocyclic group, the heterocyclic oxy group, the heterocyclic thio group and the heterocyclic amino group represents a heterocyclic group specifically described later as the heterocyclic group forming the substituents R _n and R _12. . The above-mentioned aralkyl group, aralkyl group, aralkylthio group and aralkylamino group are the aralkyloxycarbonyl group and the alkyl group constituting the aralkyl group of the aralkyl group. Another one.

0 may be substituted with an aryl group, and specific examples thereof include Benzhydryl, Bens “Hydrolux”, Bens “Hydroluci, Bens” Hidrilamino, Bens 'Hydroxy / reoxycarboni / re, Bence' include hydryl xycanolevonylamino. Two or more of these substituents may be the same or different May be present. Among the substituted hydrocarbon residues, more preferred are a hydroxyl group, a cycloanolekyl group, an α / recoxy group, an alkylthio group, an amino group, a nodroken atom, a force phenol group, an alkoxycarbonyl group, a carnomoyl group, a cyano group. a C Bok ₃ § Rekiru group substituted with such an azido group, their when these specifically mentioned, Siq Ropuropi / Remechi / Les, main Tokishimechiru, E Tokishimechinore, 1 over main preparative Kishechinore 1- E DOO Kishetinole, 2-Hydroxicetil, Methylthiomethyl, 2-Aminoethyl, F / Loromethinole, Difluro-methyl, Trifluoro-methyl, 2-Full-chloroform, 2,2-Difluoroethyl, Zinc 13 』, —, 2-chloroethynole, 2,2-dichloroethyl, 2,2,2-trichloroethynole, 2-— Chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, canoleboxymethyl, 2-carboxyethyl, 3-carboxypropyl, cyanomethyl, 1-carboxy-1 Methyrueti / re, methoxycarbonylmethyl, ethoxycarbonyl-methinole, tert-butoxycarbonylmethyl, 1-methoxyethoxycarbonyl-1,1-methylinoethylene, 1-ethoxycanoleboninole 1-methyl Chinoleetinole, 1-tert-butoxycarbone 1-methylethyl, 1-benzyloxycarbinole 1-methinoletinole, 1-pizokuroinolexycarbonol 1-methylethyl, dilvamoyl-norremethyl, 2-azi There are many things such as diethyl. Among the hydrocarbon residues specifically mentioned, the most preferable ones are linear C i- ₃ alkyl groups such as meth / yl, ethynole, and n-propyl; and 2-fluoroethyl, 2-chloroethyl, Reboxoxymethyl, tert-butoxycarbo-2-methynorole, 1-carboxy-1.1-methy / reethy / re, 1-tert-butoxycarbonyl-1-1-methylethyl, etc., substituted with norogen, carboxy, alkoxyl / reponyl Linear Ci ^ s alkyl group All of the compounds [I] of the present invention having these as R ₃ groups have strong antibacterial activity, and particularly have an excellent bactericidal action against resistant bacteria. Further, in this specification, all _three OR groups are in a syn-coordination (Z-coordination).

In the above-mentioned septum compound [I], the substituent R ₄ represents a hydrogen atom or a methoxy group.

In the above-mentioned septum compound [置換], the substituent A represents an imidazolyl-1-yl group which may be substituted to form a condensed ring at the 2,3-position or the 3,4-position. Here, the condensed ring means a condensed form of an imidazole ring and a 5- or 6-membered aromatic heterocycle, and this condensed ring may be condensed with another aromatic ring or an aromatic heterocycle. Good. The symbol attached to the substituent A indicates that the substituent A has a monovalent positive charge. Optionally substituted 2, 3-position, or 3, 4 ones I imidazole one to form a condensed ring 1 - I le group (A®) is the general formula or [A _2]

Where B is a group forming a 5- or 6-membered aromatic complex which may be fused with another aromatic ring or an aromatic heterocycle, and 1 ^ is a hydrogen atom or A substituent on the midazole ring; R l 2 represents a hydrogen atom or a substituent on the ring condensed with the imidazole ring; c B is a carbon atom, a nitrogen atom, an oxygen atom, and a hydrogen or sulfur atom; Forms a condensed ring with one hydrogen atom or one substituent, or with adjacent carbon atoms. A—Specifically as one unit

OMPI Here are some:

one

one

f — o —

Specifically, there are the following <

Comparing a compound with a 基 group [〖] and a compound with _two groups [I] by their antibacterial activity, the compound with a group is generally superior, although it depends on the combination with the R ₃ group. As a basis,

Nu

 --And are especially effective.

In the above formulas CA i, [A ₂ ] and the specifically mentioned At group 'A ₂ , the positive charge of the substituent was conveniently applied to the nitrogen atom at the 3-position of imidazo- / The quaternary nitrogen atom may be applied to the nitrogen atom at the first position in some cases. In addition, the monovalent positive charge is delocalized on the imidazole ring. Further, it may be delocalized on the entire condensed ring. So, for example, in the case of

-Ν-one--

It is also expressed as. The location of this positive charge changes fluidly depending on the state of compound [I] (in a solid resting solution), the type of solvent and liquidity, the temperature, the type of substituent, and the like. It includes both the case where the field charge is localized on the nitrogen atom and the case where the field charge is delocalized on the entire imidazole ring or the complex ring. Hatato example, if a hydroxyl group as a substituent Ri i and R ₁₂ on the condensed ring, C. 1 to ₄ arsenide Dorokishia Rekinore groups, C i to ₆ Anorekiru groups, C _2-6 alkenyl group - C. 2 to 6 § / gravel two '. Les group, C 4 ~ 6 Arukajie two Honoré group, C. 3 to 6 a cycloalkyl group C. 3 to 6 consequent Roaruke alkenyl group' C ₃ ~ 6 Cycloalkyl—Cι-6 anoalkyl group, C 6-1. § Li Lumpur groups, C 7 to 12 Ararukinore groups, heterocyclic groups, C. 1 to 6 Anoreko alkoxy groups, C. 1 to 6 alkoxy -C ₁ ~ ₄ alkyl groups, C ₃ ~ ₆ consequent lower Lucino les oxy groups, C 6-10 § Li Lumpur old alkoxy group, C ₇ through i 2 Ararukiru old alkoxy group, a mercapto group, C 1 ^ agate les mercapto alkyl Honoré group, scan, 'Reho group, C 1 ~ 4 ^scan', Rehoarukiru group, Ci- ₆ alkyl group, Ci- ₆ alkyl group-C-4 alkyl group. 3-6 cycloalkyl Ji Saimoto, C ₆ through i. § Riruchio group, C ₇ through i 2 Ararukiru Chisaimoto, A Mi amino group, C i to ₄ A Mi-alkyl group, mono C. 1 to 4 alkyl amino group, di C. 1 to 4 alkylamine amino group, mono C i to 4 alkylamine Mi node on C i to ₄ alkyl group, di C. 1 to 4 alkylamine Mi node on C. 1 to 4 §, gravel Le group, C ₃ ~ 6 consequent Roarukirua Mi amino group, C 6 ~ 1. Aryl amino group, C ₇ to ₁₂ aralkyl amino group. Cyclic amino group, cyclic amino C i to ₄ alkyl group, cyclic amino C to ₄ alkynoleamino group, Azide group, nitro group, halogen atom.

Halogenoalkyl group, Shiano group, § Roh one Ci～ ₄ alkyl group, a carboxy group, a carboxyl i (^ _-4 alkyl group. (^ _1-8 alkoxy one carbonyl group, (^ _1-8 alkoxy one carbonylation Lou Ci～ ₄ alkyl group, C ₆ ~ ₁₀ Ariruokishi Ichiriki carbonyl group, C 3, ~. consequent opening Arukiruokishi one carbonylation Le group, C 7 to 1 2 Ararukiru old carboxymethyl one carbonylation, 'Les group, C ₆ ~ _{1 ()} § Li - Lou § Sil group, C. 1 to 5 Anoreka Noiru group, _2-5 Aruka Noiru (:. _1-4 Anorekiru group, C ₃ ~ ₅ § / Rekenoiru group, C ₆ ~ ₁ 0 § Li Ru A Shinore Saiki Shi group, C ₂ ~ ₅ alkanol I le old alkoxy group, C ₂ ~ ₅ Arukanoiru old carboxymethyl one C i to ₄ alkyl groups, C ₃ ~ 5 Arukenoiru old alkoxy group, a force Rubamoiru group, force Rubamoiru C i to 4 alkyl groups, Replacement strength Luba moyl group Moyl ¾, S-substituted thiocarbemyl 'group, _5- pot olemo-moyloxy group, carbamo oleoxy-C i -4 ano-lequinole group, substitution capacity rubamo-in-reoxy group, phthalimid group, C 2 -5-alkanoyl amide group, C 6 to 1 Q § Li Lumpur - Ashiru A mi de group, sulfonamide de group, Karubokishia amino group, C ₁ ~ 4 an alkoxy one Karubonirua Mi amino group, C ₆ to 1 0 § Li Ruokishi - Kanorebonirua amino group and C ₇ ~ _{1 2} § Rano gravel Ruo carboxymethyl one Karubonirua amino group. C in the body! ~ 4 Hydroxyalkyl group is hydroxymethyl, 2-hydroxyxetizole, etc., C ~ ₆ alk. / Group is methyl, ethyl, n-propynole, isopropy, n-butyl, isobutynole, sec-f ' Chinole, tert-butynole, n-pentyl, n-hexyl, etc., C 2-6 phenol “nyl group is vinyl”, arylene, isoflurinole, metalyl, 1, 1 - dimethyl ■ Chinorea Li Honoré, 1 one Buteni Honoré, 2-butene, second, 'Les, 3 - butenyl, etc., C ₂ ~ 6 alkynylene,' Les group E Ji two Honoré, 1 one Zaro Bininore, 2 - Purohininore, Buropaginore etc., 1 C. 4 to 6 Arukajie three groups, 3 - 'etc. Les, C ₃ ~ 6 Shikuroanore kill Mashiku Russia - flop port pin ./ les, sik Russia off,' pig Jenni Ji / ' , Cyclopentinole, cyclohexyl, etc., with C 3-6 cycloalkyl group Is 1-cyclopentene.

— Cyclo. Penteninole, 3 — Cyclohexeninole, 1 — Cyclo'hexeninole, 2 — Cyclo- ヽ xeninole, 3 — Cyclo-, Xeninole, 1, 4-cyclohexene , 'Les etc., C ₃ ~ ₆ consequent b a / Rekinore - C 1 ~ 6 Arukinore groups sik port Penchirumechinore, cyclohexylmethyl and the like to the consequent b, C ₆ ~ _{1 0} Ariru group

'Phenyl,' les, naphthyl, etc., C7-ι2 aralkyl groups are benzyl, phenetinole, etc. · Heterocyclic groups are 2-pyridinole, 3-pyridinole, 4-pyridyl, N-oxide. 2-pyridyl, N-year-old xydose 3-pyridyl, N-year-old xydole 4-pyridinole, 2-bilidininole, 3-bilidininole, -piridinii. , Piperazinole, 2-villa-dininole, 2-pyrimidinole, 4-bi Li Mijiniru, 5 - pyrimidone ^Gini, les, 3 - Pirita "Gini, 'Les, 4-Pirita" Jiniru, 2-Vila two Honoré, 3-Vila two Honoré, 4 - Vila two Honoré, 2 - Ji 3 years old pyraninole, 3 — 3 years old pyranil, 4 — 3 years old viranil, 3 H—indonele 2-yl, 3 H-one timed-north-3 -inore, 1, 2, 3 —thiadiazonele 4 1,2,4-thiadiazol-5-yl, 1,2,1-thiadiazol-1-yl, 1,2,4-thiadiazol-5-yl, 1,3,4—thiadiazolyl , 1, 25 —thiadiazolyl, 1,2,3 —triazolyl, 1,2,4-triazolyl, 1H—tetrazolyl, benzovinylil, 21 furyl, 3 — Furyl, 2-Chenyl, 3-Chenolin, 2—Year-old oxazoly I, 4 Year-old oxazolyl, 5—Year-old oxazolyl, 2-Thiazolyl, 41-year-old thiazolinole, 5 Thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyrrolyl-3-pyrrolyl, 2-pyrrolidinyl, 3 —Pyrrolidinyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-virazolyl, 4-pyrazolyl, 5-pyrazolyl, etc., nitrogen atom (may be oxidized), oxygen atom, sulfur A 5- to 8-membered ring containing one or several heteroatoms such as atoms or a fused ring thereof having a bond at a carbon atom, (^ to ₆ -alkoxy groups are methoxy, ethoxy n-propoxy, Isopropoxy, n-butoxy, tert-butoxy, etc., about 1 to ₆ alkoxy.1 to 4 alkyl groups are methoxymethylenole, ethoxymethyl, 2-methoxyethoxyl, etc. Sik Roanoreki / Les year old alkoxy group ί Mashiku port Puropinore old alkoxy, consequent Roeki Shinoreokishi etc., C ₆ to 1 Q § Li Ruokishi group Fuweno key sheet, a naphthyl Okishi, C ₇ to 1 ₂ Araruki / Reokishi groups benzyl old alkoxy, 1 - off Eninoreechiru old carboxymethyl, 2 - and phenylalanine E chill O carboxymethyl, C ₁ ~ 4 mercapturic Toarukinore groups mercapto DOO methyl, and 2-mercapto Techiru, C 丄 to ₄ sulfoanorecyl groups include suzolehometinol, 2-sulfochet / ', etc., and C i-6 alkylthio groups include methylthio, echinolethi, n-provirti, n-butyl, n-butylthio, etc. ₁ to 6 al'quinolecho-C

Alkyl groups methylcarbamoyl Honoré methylthiomethyl, 2 - Mechiruchioechiru etc., C ₃ to 6 consequent opening alkylthio Saimoto cyclopropyl Chi old, cyclohexylthio and the consequent B, C ₆ through i 0 § Li Ruchio group off e and two thio, C ₇ ~ _{1 2} Araruki Norechio group and Bae Njinorechi old, C t ~ 4 § Mi Noanorekiru groups § Mi Bruno methylation, 2 - § Mi Noechi etc., mono C i ~ 4 a Kirua Mino groups include methylamino, ethylamino, π-prohylamino, n-butylamino, etc., and diCi-4alkynoleamino groups include dimethylamino, jetinorea mino, methylethylinorea mino, and G (π-provinolemino). ) Amino, di-n-phthyl) amino, etc., are converted to mono C 1 -anolequinolemino C i -4 -anolequinole group or methinorea minometinole, echinorea minometinole, 2-(N- N-N-N-dimethylaminomethyl, N, N-ethylamino, such as chinolemino) ethylenole, 3- (N-methylamino) propyl, etc. / 'Rare Mi Nomechiru, 2 - (N, N- Jimechinorea Mino) Echinore, 2 - (N, N - Jechinorea Mi Bruno) Echinore, 3 - (N, N- Jimechinoreami Roh) and pro building, C ₃ ~ 6 Cycloanole / 'Rare Mino Pama Siklov. Mouth viramino, cyclohexinoleamino, etc., C _6- } 0 arylamino group is anilino, N-methylanilino, etc .; 7-; L2 aralkylamino group is benzylamino, 111-amino.二, 'Letinoreamino' 2 — 二 2, 'reethylamino, etc., and cyclic amino groups are pyrrolidino, pyridino, virazino, mo / reholino, 1-pyrrolyl Etc.

-ΐAmino C 1-4 alkynole groups are pyrrolidinomethyl, bilidinomethyl, biradinomethinole, mo./refolinomethyl, and 2 — (mo / reholino) etinole, but are referred to as' cyclic amino C 1 ~ 4 alkynoleamino groups are pyrrolidinomethylamino, Peri-dinomethylamino, pyra-dinomethine / rare-mino, monorefolino-methyl / 'reamino, halogen atom such as fluorine, chlorine, bromine, etc.' Ci to _4- norogenoalkynole group Chinore, Zihu / Leorome Chinore, Tri-Funore Chileno Chinole, 1—Funoret Chileno Chile, 2—Funore Chile Lochinore, Monochloromethinole, Dichloromethinolle, Trichloromethinole, 1-Chlorochinolle, 2-Chloromethyle For example, domechi / -re, etc.丄 -alkyl groups include cyanomethyl, 21-cyanoethyl and the like; carboxy-Ci-4 alkyl groups ί'-carboxymethyl, 1-carboxyethynole, 2-carboxyshetyl, etc., and C t -8 alkoxycarbonyl The groups are methoxycarbonyl, ethoxy, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-methoxycarbonyl, isobonanol. and ,, les old alkoxycarbonyl, C i ~ ₈ Azorekokishi one carbonyl · - C 1 ~ 4 alkyl groups main bets alkoxycarbonylmethyl, et butoxycarbonyl methylation, tert- butoxide Kishikarubo two, 'Leme chill the like, C ₆ -1 0 § Li Noreo Kishikarubo two Honoré group ^ phenoxyethanol carbonyl, etc., C ₃ ~ ₆ Shikuroa alkyl old carboxymethyl Ichiriki carbonyl group consequent b B Piruokishi force carbonyl, and alkoxy / Les oxy Kano levo sulfonyl to consequent co, C 7 ~ 1 2 Ararukiru old carboxymethyl one local Boniru group Benjiruokishi force. 'Reboniru etc., C ₆ ~ 1 0 § Li Lumpur one § Silyl groups include benzoyl, phthaloyl, phenylacetyl, etc., and Ci to ₅ alkanoyl groups [forminole, acetyl. Propyl, butylinole, norrelyl, and vivaloyl. Neunole—C i-4 alkyl groups include acetylmethyl, 1-acetylethyl, 2-acetylethyl, etc., and C 3-5 anoreckenyl groups (macroylol, crotonoynole, male cinnole, etc .; ~ 10 aryl / reoxy groups are benzoyloxy and the like; Chiriruokishi, etc. Bibaroi old alkoxy, C. 2 to 5 Arca Noi Ruo carboxymethyl one C i to 4 alkyl groups § Seto Kishimechi / 'Les, 1 Ase Tokishechiru, and 2 Ase Tokishechinore, C ₃ ~ 5 Arukenoinoreo The xy group is acryloyl group, the carbamoyl-C i-4 alkyl group is methoxymethyl, etc., and the substituting rubamoyl group is N-methylcarbamoyl, N, N-dimethinorecanolevacoy. Le, N- Echirukarunoku moil, N, N- Jechiru force Rubamoi Le, N- Hue carbamoylmethyl, piperazinyl Li Gino Kanoreboniru, bi Perajino carbonyl, etc. Moruho re Bruno carbonyl, force Rubamoiruoki over _C ί .~ ₄ alkyl group Substituted rubamoyl groups such as Ν-methylthio rubamoyl, substituted rubamoyl groups Ruoki group N- methyl carbamoylthiopheno Ruokishi, N, N- dimethyl carbamyl Moiruokishi, and N- Echirukarubamoi Ruokin, C ₂ ~ c; Aruka Noi luer Mi de group Aseto A mi de, etc. Puropiona Mi de, C ₆ etc. Ruanrua Mi de group base Nzua Mi de, C ~ alkoxy i - - ~ _{1 0} § Li force Ruboniruami amino group is main butoxy carbonitrile Nino les amino, ethoxy Kin carbonyl § Mino, and tert- butoxycarbonyl § Mi Bruno, C ₆ ~ ₁₀ §! ; Ruo key and one force Ruboniruamino group Fueno alkoxycarbonyl § amino, C ₇

1212 aralkyloxy-carbonylamino group ^ benzyloxy carboxy carbonylamino and the like. The above C 7 to 12 full Ranorekinore group, C 7 to 1 2 § Rarukiruoki group, C 7 to 1 2 Ararukiruchio group, C ₇ ~ _{1 2} Ararukirua amino group, C 7 .~12 Ararukiruoki one carbonyl group and C _{7. 1 2} § la Rukiruokin one carbonyl § amino al kill group constituting the Ararukiru group such group may be substituted with one more C ₆ ~ ₁₀ Ariru group, specifically base Nzuhi drill. Benzuhi de Lilukin, Benzhydrylthio, Benzhydrylamino, Benzhydrylcarbonyl, Benzhydr Liloquincarbonylamino and the like. A plurality of these substituents may be the same or different and may be substituted. In, the 5, 6-position of the imidazole ring may be fused with an alicyclic, aromatic or heterocyclic ring. Examples of these are

And 、 and R ₁₂ are the same as described above. The above-mentioned substituents Ru.R may be further substituted.

In the above Cefm compound [ί :), η represents Ο or 1. In addition, the carboxyl substituent at the 4-position (㊀ added to —C 00 indicates that the carboxyl group is a sulfoxylate anion, and forms a salt with the positive charge on the S-substituent to form an inner salt. On the other hand, compound [I] may be a physiologically acceptable salt or ester, which may be an inorganic base salt, an ammonium salt, an organic base salt, an inorganic acid addition salt, or a salt thereof. Examples of the inorganic bases that can form inorganic base salts include alkali metals (eg, sodium and potassium, and alkaline earth metals (eg, Examples of organic bases that can form organic base salts such as potassium include proforce, 2-phenylene Rubenzizoleamine, dibenzylethylenediamine, ethanolanolamine, diethanolane, trishydroxymethylaminomethane, polyhydric quinalkylamine, N-methyldarcosamine, etc .; inorganic Inorganic acids capable of forming an acid addition salt include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids capable of forming an organic acid addition salt include, for example, P-toluenesulfonic acid and methanesulfonic acid. , Formic acid, trifluor sigma acetic acid, and maleic acid such as maleic acid, which can generate a salt of amino acid, include, for example, lysine, arginine, ordinine, histidine and the like. The ester derivative of the compound [I :!] means an ester that can be formed by esterifying a carboxyl group contained in the molecule, and an ester that can be used as a synthetic intermediate and a nontoxic non-toxic metabolically unstable compound. Is an ester. Esters usable as synthesis intermediates include C i- ₄ alkyl esters, C

_2. ^, 4 alkenyl esters, C ₃ to 6 'Using Synchro alkyl esters, C ₃ to 6 Shikuroa alkyl one (^ - alkyl ester, c ₆ ~ ₁₀ § reel ester, c ₇ ~ ₁₂ § La alkyl ester, substituted Li, Esters, etc., which may be further substituted Specific examples of the alkyl forming the ci- ₄ alkyl ester include methyl, ethyl, π-propyl, n-butyl, tert-butyl, etc. the, C ₂ ~ ₄ for concrete is alkenyl to form the alkenyl ester Bulle, Ariru, and I Sopuro Bae alkenyl, C ₃ ~ ₆ £ / Kuroaru kill ester specifically as click port alkyl to form a the Nkuro propyl, click Roff 'chill, click Ropenchiru, and click Roeki Le, C ₃

6 £ Specific examples of the alkyl forming the C1-4 alkyl ester include cyclo σ-propylmethyl and chlorohexylmethyl.

^C 6 to 10 § Li - and Hue sulfonyl specifically as § Li Ichiru forming a glycol ester, as Ararukiru forming teeth ₇ to _{1 2} § Lal Kill ester Specifically, benzyl, phenethyl and the like. Specific examples of the substituted silyl which forms the substituted silyl ester include trimethylnilyl and tert-butyldimethylsilyl. The alkyl that make up the § Lal kill ester may be substituted by another 1-2 C ₆ ~ ₁₀ § Li Lumpur, base specifically Nzuhi de Riruesuteru, such forces fried preparative salicylic ester 'is You. As the nontoxic ester which is metabolically unstable, those already established in the field of penin phosphorus and cephalosporin can be conveniently employed in the present invention. Such metabolically labile esters of non-toxic, even or C, ~ alkanol I Ruoki methyl esters, C ₁ ~ ₅ alkanol I Ruoki Echiruesuteru, Ci～ ₆ alkoxy one Ci～ ₄ alkyl esters, c alkylthio - C Les And _4- alkyl esters, specifically, aceto- and methoxymethyl esters. Examples include loyloxy methyl ester, methoxymethyl ester, ethoxyquin methyl ester, isopropoxy methyl ester, 1-methoxyl ethyl ester, 1-ethoxyethyl ester, methylthiomethyl ester, and ethylthiomethyl ester. The present invention includes, in addition to the above ester derivatives, physiologically acceptable compounds which are converted into the compound [I] in vivo.

 * The compound [I] of the present invention has a broad spectrum antibacterial activity and is used for prevention and treatment of various diseases caused by pathogenic bacteria in humans and animals, for example, respiratory tract infection and urinary tract infection. Can be done. Characteristics of the antibacterial spectrum of the compound [I] are as follows.

 (1) It shows abnormally high activity against various gram-negative bacteria.

(2) Gram-positive bacteria (for example, Staphylococcus. It has high activity against J, such as Nebacterium 'dibuteriae.

(3) It has a remarkable effect on Pseudomonas aeruginosa, which is not susceptible to treatment with usual cephalosporin antibiotics.

 (4) It has high activity against many lactamase-producing Gram-negative bacteria (eg, Escherichia, Enterobacter, Genus Serratia, Proteus).

Aminoglycoside antibiotics such as amicane and gentamicin have been used for microorganisms of the genus Pseudomonas in particular.

[CI] has not only an antibacterial activity comparable to these aminoglycosides, but also has a great advantage because its toxicity to humans and animals is much lower than that of aminoglycosides.

The process for producing the cefm compound [I], a salt or ester thereof of the present invention is described in detail below. Compound [〔] can be produced by four methods known per se (1) to ( ⁴ ). Ie

 (1) — General formula

[H]

 Wherein the symbols in the formula are as defined above, or a salt or ester thereof, and the general formula OOH (m)

ヽ OR ₃

The symbols in the formula have the same meanings as above: reacting with the compound represented by! Or its reactive derivative, or- (2) General formula

(IV)

[Wherein, R 5 is a hydroxyl group, an acyloxy group, a carbamoyloxy group 'substituted rubamoyloxy group or a halogen: an atom, and the other symbols have the same meanings as described above], or a salt or ester thereof and a compound represented by the general formula: A '[A! Represents imidazole which forms a condensed ring at the optionally substituted 2,3-position or the 3,4-position. Ability to react with the compound represented by 塩 or its salt. (3) General Expression

 R2

V]

[The symbols in the formula are as defined above.] Or a salt or ester thereof and a general formula I 0H [wherein, R ₃ ′ represents an optionally substituted hydrocarbon residue]. Reacting with the compound represented or its reactive derivative, or

(4) General formula

xcu ₂ C 0

', In the formula, X is a halogen compound, and other symbols are as defined above.] Or a salt or ester thereof represented by the general formula Ri C (= S)

The compound [I] can be produced by reacting with a compound represented by NH ₂ [wherein R i has the same meaning as described above], and then, if necessary, removing the protecting group. The production method will be described in order) to (4), the method for removing the protecting group, and the method for purifying Compound II. Manufacturing method (1)

[I]

In this method, a 7-amino compound [—] is acylated with a carboxylic acid [II] or a reactive derivative thereof. In this method, the carboxylic acid [M] is free or its salt or a reactive derivative is used as an acylating agent for the 7-amino group of the 7-amino compound [III]. Reactive derivatives such as inorganic salts, organic salts, acid halides, acid azides, acid anhydrides, mixed acid anhydrides, active amides, active esters, active thioesters and the like of the free acid r I or the free acid [M] Is subjected to an acylation reaction. Inorganic salts include alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, etc.). Organic salts include, for example, trimethylamine. Salt, triethylamine salt, tert-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt,,

JM - dimethyl Chiruaniri down salts, pyridinium Jin salts, and keno re down salts, acids payment de The example thunk port Lai de, an acid Buromai de is mono C 1 ~ ₄ alkyl as a mixed acid anhydride Carbonic acid mixed acid anhydrides (eg free acid [: 111] Mixed acid anhydrides of acetic acid with monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monoisobutyl carbonate, monotert-butyl carbonate, monobenzyl carbonate, mono (P-nitrobenzyl) carbonate, monoaryl carbonate, etc.) , (^^ 6 Aliphatic carboxylic acid mixed anhydrides (eg free acid [11] and acetic acid trichloroacetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, Shun Yoshikusa, Isokoshikusa) Mixed acid anhydrides with pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetate acetic acid, etc., C7-11 aromatic carboxylic acid mixed acid anhydrides (for example, free acid [1 Mixed acid anhydrides with Ί and benzoic acid, p-toluic acid, P-chlorobenzoic acid, etc., and organic sulfonic acid mixed acid anhydrides (eg, methanesulfonate, ethanesnolefonic acid, benzensnorefonic acid, p — Tono Enns sulfo mixed acid anhydride and the like phosphate) and the like, and § mi de (e.g. free acid as the active A mi de a nitrogen-containing heterocyclic compound [III] Birazo - le, I Midazo

- substituted Le, an acid Ami de and the like Benzoto Riazor, these nitrogen-containing heterocyclic compound C i to ₄ alkyl, C ₁ ~ ₆ alkoxy, halogen, O Kiso, Chiokiso, like in C. 1 to ₆ alkylthio Etc.). As active esters, all those used for this purpose in the field of / 3-lactam and peptide synthesis can be used. P-Nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthanolamide ester , 1-hydroxybenzotriazole ester, 6-hydroxyl-1-hydroxybenzotriazole ester, 1-hydroxylH-12-pyridone ester and the like. Active thioesters include esters of aromatic heterocyclic thiols (eg, 2-pyridylthio). Esters, 2-benzothiazolyl thiol esters, etc. These heterocycles are represented by Ct-4 alkyl'Cie alkoxy, halogen atom'C

Which may be substituted with I- ₆ alkylthio, etc.). on the other hand,

The 7-amino compound [I] is used as a salt or ester as it is. Compounds [IIΊ include inorganic base salts, ammonium salts, organic base salts, inorganic ^! "Salts and organic acid addition salts. Examples of inorganic base salts are alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, etc.). However, as organic base salts, for example, trimethylamine salts, triethylamine salts, tert-butyldimethylamine salts, dibenzylmethylamine salts, benzyldimethylmethylamine salts, N, N-dimethylaminophenyl salts And inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, — nitrate and phosphate, and organic acid addition salts as inorganic acid addition salts. Formate, acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, etc. The compound II] is an ester derivative of the compound [ί] Ester mentioned already can be given as here. Ie C 1 ~ 4 § Honoré Kino les Este Honoré, C 2 ~ 4 § Honoré en Honoré Este Honoré, C ₃ to 6 consequent RoRyo Rukiruesutenore, C 3 6 to 6 cycloalkyl-C 1-4 alkyl ester '6 to 10 aryl ester' C 7 to 12 aralkyl ester, 1 to 5 alkanoyloxymethyl ester, C 1 to 5 alkanoyl enoleoxicetyl Esters and those in which they have been further substituted with hydroxyl groups, C ₆ -alkoxy greens, halogen atoms ^, nitro groups, cyano groups, mercapto groups, C te alkylthio groups, oxo groups, thioxo groups, and the like. Raw material [! 1] Salts and esters, raw material [mJ and its reactive conductors can be obtained by any known method or a method similar thereto. And easy to manufacture. The reactive derivative of the compound [n] can be reacted with the compound [II] as a substance isolated from the reaction mixture, or a reaction mixture containing the reactive derivative of the compound [II] before isolation. When the carboxylic acid [III] is used in the form of a free acid or salt, an appropriate condensing agent is used. Examples of the condensing agent include Ν, Ν′-dicyclohexylcarbodiimide and other Ν, Ν′-disubstituted rubodiimides, such as Ν, N′-force rubonyldiimidazole, Ν, N′-thiocarbo ^ Dehydrating agents such as azirazides, such as ruzimidazole, for example, diethoxycarbonyl-2-ethoxy-1,2,2-dihydroxyquinoline, oxychlorine, and alkoxyacetylene, for example, 2-cyclopentyl 2-Halogenopyridinium salts such as diphenylmethyiodide and 2-fluoropyridinidimethyi iodide are used. When these condensing agents are used, the reaction is thought to proceed via the reactive derivative of carboxylic acid [m]. The reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction can be appropriately selected. Examples of such solvents include ethers such as dioxane, tetrahydrofuran 'ethethyl ether, tert-butyl methyl ether ether, diisopropyl ether ether, ethylene glycol-dimethyl ether, such as ethyl formate, and the like. Esters such as ethyl acetate and n-butyl acetate, for example, halogenated hydrocarbons such as dichloromethan, chloroform, carbon tetrachloride, trichlorene, 1,2-dichloroethane, etc. For example, hydrocarbons such as n-hexane, benzene, and toluene. For example, amides such as formamide, N, N-dimethylformamide, and N, N-dimethylacetamide, for example, 'acetate , Methylethyl ketone, methylinolesobutyl ketone and other ketones such as acetonitril, You two door Lil two door Lil class of any intensification, such as, dimethyl Chirusunorehokishi de, - Suruhora down, to Kisame Chiruhosuhoru Amides and water are used alone or as a mixed solvent. The use of the acylating agent [19: 1] is usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound :: II). The reaction is carried out in a temperature range from -80 to 80 ° C, preferably from 140 to 50 ° C, most preferably from -30 to 30 ° C. The reaction time depends on the type of compounds II] and [II:], the type of solvent (and the mixing ratio if a mixture is used), the reaction temperature, etc., and is usually 1 minute to 72 hours, preferably 15 minutes. ~ 3 hours. When an acid halide is used as the acylating agent, the reaction can be carried out in the presence of a deoxidizing agent for the purpose of removing released hydrogen halide from the reaction system. Such deoxidizing agents include, for example, inorganic salts such as sodium carbonate, calcium carbonate, calcium carbonate, and sodium hydrogencarbonate, such as triethylamine, tri (n-propynole) amine, and tri (n- (Butyl) amine, cyclohexinoresimetylamine, pyridine, norethidine, _r- collidine, N, N-dimethylphenylaniline, N-methylpyridinine, N-methylpyridine mouth, N —Tertiary amines such as methyl morpholine, and alkylene oxides such as propylene oxide and epichlorohydrin.

 Production method (2):

This method is a method in which an imidazole compound A 'is reacted with a septum compound [:], and a compound [1] is synthesized by a nucleophilic substitution reaction. In the compound [IV], R ₅ represents a hydroxyl group, an acyloxy group, a rubamoyloxy group, a substituent rubamoyloxy group or a halogen atom. Here asillo Alkoxy groups optionally substituted C ₂ ~ ₅ alkano Iruokishi group or C 6 to 1 0 § Li - Le - represents a § Shiruokishi group, a substituted C 2 ~ 5 Arca Noi Ruo alkoxy group Is II in terms of acetoxy, chloroacetoxy, propionyloxy, butyryloxy, pipa'royoxy,

3 - Okisobuchiri Ruokishi, 4-click throat one 3 - Okisobuchiri Ruokishi, 3 - Power Rubokishipuro Pioniruokishi, 4 - force Rubokishibuchiri Ruokishi, 3 - E Tokishikarubamoi Rupuro Pioniruokishi like, optionally substituted C 6 to 1 ₀ Ryori — Specific examples of the rusiloxy group are 0 — Carboxybenzoyloxy, o — (Ethoxycarbinolecarpa'moinole) Benzo'inoleoxy, o — (Ethoxycarboninole) ) Benzo'loxy. Specific examples of the substituting rubamoyloxy group include methylcarno'moinoleoxy, N, N-dimethylmethylnoreoxy and the like. (Halogen) Izumi includes chlorine, bromine and iodine. The compound [IV1 is used as it is as a salt or ester of the compound as it is free. As the W and the ester of the compound [W], those given as the salts and esters of the compound [H] in the production method (1) can be applied as they are. Compound [IV], salts and esters thereof can be easily produced by a method known per se or a method analogous thereto. On the other hand, imidazole compound A 'represents imidazole which forms a condensed ring at the optionally substituted 2,3-position or the 3,4-position. The fused ring here is an imidazole ring and 5- to

It means a form in which a 6-membered aromatic heterocycle is fused. This fused ring may be further fused to another aromatic ring or an aromatic heterocycle. 2 may be substituted, 3-position, or 3, 4-position b to form a condensed ring imidazole (A) is the general formula Ai or [A ₂ ']

In expressed write, 'the AO group is the above At base of the target compound capable synthesis when reacted with a [〖], compound [IV] Compound Alpha _2' compound [IV] Compound At the The @@ groups of the target compound [I] which can be synthesized when reacted are the aforementioned _two groups, respectively. Chijimigoi Midazo IchiruIri ₁ 'and Alpha _2' symbols B in the formula A, ¾, those previously mentioned as B in A ₂ groups fitted directly Again, therefore specifically as compound

 ,

,

 N = J O

But, specifically, as Α ₂ '

,- h- ¹

 ο

 , ヽ

C

N

And so on. The substituents Rii 'and Ri ² ' on the compound are

What has already been given as the substituents Ri 1 and R 12 of A applies here as well, respectively. In, the 5,6-position of the imidazole ring may be condensed with an alicyclic, aromatic or heterocyclic ring. Examples of these are

l2 'etc., where Β; Ri2' is the same as described above. The substituents R 11 ′ and Ri 2 ′ described above may be further substituted. Compound A! Is also used as a salt. Salts of chemical prosthesis A 'include, for example, inorganic acid addition salts such as hydrochloride, hydrobromic acid, sulfate, nitrate, phosphate, and the like, for example, formate, vinegar salt, trifluoroacetate, Organic acid addition salts such as sulfonic acid salts and p-toluene sulfonic acid salts. The general method for synthesizing compound A 'is known, and can be performed by methods described in the literature or by methods analogous thereto.

: Α OM∑L- Can be easily manufactured. This nucleophilic substitution reaction to a compound L. R "with Compound A ¹ is a per se well-known reaction usually carried out in a solvent. In preparation As the solvent used in this reaction (1) Solvents such as ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, and water that are used can be applied as they are. Alcohols such as methanol, ethanol, n-prononol, isopronodiol ⁰ , ethylene glycol, and 2-methoxyethanol are also used.

(2-1): When R ₅ is an acyloxy group, a carbamoyloxy group or a substituted carbamoyloxy group More preferable solvent is water or a mixed solvent of water and an organic solvent miscible with water, and an organic solvent miscible with water. Of these, more preferred are acetone, methylethylketone, and acetonitrile. The amount of the nucleophilic reagent ^Ar to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound CIV]. The reaction is carried out in the temperature range of 10 to: I 0 (C, preferably 30 to 8 (f C.) The reaction time depends on the type of compound '1 \' and A 'and the type of solvent (mixed solvent The reaction time is usually 30 minutes to 5 days, preferably 1 to 5 hours. The reaction is carried out at pH 2 to 8, preferably near neutral, that is, PH 5 to 8 The reaction is usually more easily carried out in the presence of a thiocyanate or a thiocyanate of 2 to 30 ′ i: F. Such a salt includes sodium iodide. And potassium iodide, sodium thiocyanate, potassium thiocyanate, etc. The strength of the above salts, for example, trimethylbenzylammonium bromide, triethylpentene Noreammonium mouth mouth, Triethylbenzinoreammo Quaternary ammonium with surface-like surfactant action

O PI In some cases, the reaction can proceed smoothly by adding a salt.

(2-2): When R ₅ is water

 For example, according to the method described in JP-A-58-43997, etc., in the presence of a ^ 璣 line compound. Examples of the organic phosphorus compound used herein include 0-phenylene phosphorochloride and 0-phenylene phosphorochloride.

—Phenylene phosphorophosphate, methyl 0 —Phenylenephosphoethyl o-phenylene phosphate, propynole 0 —Phenylene phosphate, isoprene building o-phenylene phosphate , Butyl phosphate, cyclohexyl o-phenylene phosphate, cyclohexyl o-phenylene phosphate Phosphate, monophenyl O — phenylene phosphate p — black mouth phenylene 0-phenyl-phenylene phosphate, p-acetylinophenyl 0 — phenylene phosphate , 2 — chlorocinole o-phenyrene phosphate, 2, 2, 2-tho I! Chloroethenole o-fenylene phosphate, ethoxycanolebon a- -f. —Fune Renho Swayt, Carpa 'Moi Noreme Chinole o--f- 2 reno phosphates, 2-Cyanoe Chinore o-.. Phenilen phosphate, 2-Mechinoresnorehoninorechinore o 1 Phenylene phosphate, benzene o — Phenylene phosphate, 1, 1 1-dimethyltin 1 2 — F. Robinini o — Phenylene phosphate, 2-Ph. 0 0 Phenylenphosphate, 3-methylen-2-yl 0-phenylene phosphate, 2—Chenylmethyl 0—phenylenphos fate, 2—furenole quinole o-phenylenphos , Bis — 0 — phenylene pyrophosphate, 2 — phenyl 1, 3, 2 — benzodioxaphosphorin 1 — 2-oxide, 2 — (p-phenyl) 1, 3'2—benzodi Kisahosuho Lumpur - 2-year old sulfoxide - 2 - butyl 0 — 1,3,2 —Benzodioxaphosphoryl 1 2 —Oxide, 2 —Annilino and 3,2 —Benzoxoxaphosphol 1 2 —Aged oxide, 2 —Fenrthio-1 , 3,2-benzodioxaphosphol-l- 2-oxide, 2-methoxy-l-5-methinole-l, 3,2-benzo-dioxaphosphol-l- 2-oxide, 2 —Cross mouth 5 —Ethoxycarbonyl 1,3,2 —Benzodioxaphosphol —2 —Oxide, 2 —Methoxy 1 5 —Ethoxycarbonyl—1,3,2 —Benzodi Oxaphosphol- 1 2 — Oxide, 5 — Ethoxycanolepon 2 2 2 — Phenyl 1, 3, 2 — Benzo-dioxaphophorol 2 — Oxide, 2, ό — Dichloro mouth — 1, 3 , 2 — benzodioxaphosphoryl 2 — oxide, 4 — black mouth-2 — methoxy 1, 3, 2 — benzodioxaxaho Hall 1 2-oxide, 2-Methoxy 4- 4-methyl-1,3,2-benzodioxy-2-phosphoxide 2-, oxide, 2,3-naphthalene methyl phosphate,, 6-dimethyl Chinolay 2—Methoxy

 1, 3, 2 — benzodioxafos. 1, 2-oxide, 2, 2-dihydro-, 5, 6, 7-tetrac ',-2, 2, 2-g Remethoxy 1

3, 2 — benzodioxaphospho ', £, 2-dihydro-1, 4, 6,

7—Tetraclo mouth 1,2,2: i-phenoxy 1,3,2—Benzodioxaphosphol, 2,2-di-hydro-mouth -2,2-Ethylenedioxy

 2-Methoxy-1,3-, 2-benzodioxaphosphol, 2,2-dihydro-2, benzyl-2-, 2-dimethoxy-1,3,2-benzodioxaphosphol, 2,2-dihydroー 4, 5 —Venzo-2,2,2 — Trimethoxy 1, 3,2 —Benzodioxaphosphonyl, 2, 2 —Dihydro

— 2,2,2—triphenoxy-1,3,2—benzodioxaphosphor, 2,2—dihydro-1,2,2— (0—phenylenedioxy) 1-2—phenoxy — 1,3,2 —Venzo'dio-xaphosphol, 2 —Black mouth 1, 1 2-dihydro-1,2,2— (0—phenylenedioxy) 1,1,3,2—benzodioxaphosphol, 2,2—dihydro1-2, methoxy-2-, 2— (0—phenylenedioxy) 1,3,2—Benzodioxaphosphonyl, 2,2—Dihydro2,2,2—Tricyclo mouth 1,1,3,2—Benzodioxaxol, 9,10—Fenance Rangeoxytrimethoxyphosphoric acid ο —Phenylene phosphorochrome ^^ it, 0 — Phenylene phosphorochromite, ο —Phenylene phosphorofluoridite, methinolate 0 — Phenylene phosphite, butyl 0 — phenylene phosphite, methoxycarbonylmethyl 0 — ph- τ-direnphosphite, phenyl 0 — phenylene phosphate, ρ-.- ',! :; Mouth (or ρ—Nitro) phenyl 0—phenylene phosphite, 2-7 phenyl-1,3,2—benzodioxaphoshole, bis-1ο—phenylene pyrophosphite, 2—methoxy One 5 — Methynole — 1, 3, 2 — Henzoxoxafoshol, 5 — Acetyl — 2 — Phenyloxy 1, 1, 3, 2 Benzodioxaphosphor, 9, 10 0-Fenance , 2-chloro 4-methinole 1,3,2-benzodioxaphospho- ', 5-ethoxycanole 2-feninole 1, 3, 2-benzodio , 2 — chloro-2 — thioxo-1,3,2 —benzodioxaphosphor, 2 —phenoxy1-2 —oxo-1,3,2 —benzodiazaphosphor, 2—Phenoxy-1,3,2—Benoxaxazaphosphor, 2 , 3 — dihydro 2 — oxo 1 2 — methoxy 4, 5 — dimethyl 1, 3, 2 — dioxaphosphol, 2, 2 — ji draw 2 — oxo 1 2 — chloro 4, 5 — Dimethyl-1,2,3-dioxaphosphoryl, 2,2-Dihydro-1-2-oxo-1 — (1-imidazoline) 1,4,5-Dimethyl-1,3,2-dioxaphosphor , 2, 2 — dihydro 2, 2 — ethylenedioxy 2 — methoxy , 5—Dimethyl—1,3,2-Dioxaphosphor, 2'2-Dihydro 1,2,2—Dimethoxy 2-phenoxy-1,4,5-Dimethyl 1,3

2-dioxaphosphor, 2,2-dihydro-1,2,2,2-trimethoxy-1,4,5-dimethyl-1,1,3,2-dioxaphosphoryl, 2,2-dihydroxy Doro-2,2,2—triphenoxy-1,5-dimethyl-2,3,2

—Dioxaphosphor, 2,2—dihydro-1,2,2—Triethoxy-1,4,5-diphenyl 1,3,2-dioxaphosphol, 2,2-dihydroxy Doro-1,2,2-trimethoxy-1,4,5-diphenyl 1,3,2 dioxaphosphol, 2,2—dihidr-2-oxo-1 2-methoxy

— 4, 5 — Diphene-1,3,2 —Dioxaphosphol, 2, 2 —Dihydro 2,2,2— Trimethoxy-1,3,2-Dioxaphosphol ,

2, 2-dihydro 1, 2, 2, 2-trimethoxy 1-4-Feuniru 1, 3,

2—Dioxaphosphol, 2,2 dihydro-1,2,2—Trimethoxy-1 41-methyl-1,1,3,2-Dioxaphosphol, 2,2-dihydro

— 2, 2, 2— Trimetoxy 1 4- Methinole 5—Feninolecanoleno

— 1,3,2—Dioxaphosphoryl, 2,2,4,5,6,7—Hexahydro 2,2,2—Trimethoxy 1,3,2—Venzodioxaphoshole, 2,2 '—Oxybis (4,5-dimethyl-1,2,2-dihidro)

1,3,2-dioxaphosphol) and 2,2'-oxybis (4,5-dimethyl-2,2-dihydro--1,3,2-dioxaphosphoryl-2-oxoxide) and the like. can give. The solvent used in the reaction may be any solvent that does not hinder the reaction, and is preferably the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles and the like. Is used alone or as a mixed solvent. Among others, for example, dichloromethane, acetonitrile, honolemuamide, honolemuamid and acetonitrile Use of a mixed solvent, such as a mixed solvent of dichlorometh- ane and acetonitrile, provides good effects. The amount of the nucleophile A 'and the organophosphorus compound used is 1 to 5 mol, 1 to 10 mol, more preferably 1 to 3 mol, 1 to 6 mol, respectively, per 1 mol of the compound fIV]. It is. The reaction is carried out in a temperature range of -80 to 50 ° C, preferably 140 to 40 "C. The reaction time is usually 1 minute to 15 hours, preferably 5 minutes to 2 hours. Organic bases may be added to the system, such as triethylamine, tri (n-butyl) amine, di (n-butyl) amine, disobutylamine, dicyclohexylamine, and the like. , 2, 6-Lutidine, etc. Addition of a base-1 to 5 mol per 1 mol of compound [IV].

(2-3): When R ₅ is a halogen atom

Preferred solvents are the above-mentioned r-ters, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water and the like. The use of the nucleophile A 'is usually 1 to 5 moles, preferably 1 to 3 moles per mole of the compound !: 1 \; The reaction is carried out in a temperature range from 0 to 80 ° C, preferably from 20 to 60 ° C. The reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours. The reaction can be carried out in the presence of a dehalogenating agent to promote the reaction. Examples of such dehalogenating agents include the deacidifying agents such as the inorganic bases, tertiary amines, and alkylene oxides described in the section of the production method (1). It may work as a dehalogenating agent. In this case, A 'is used in an amount of 2 mol or more per 1 mol of the compound [IV]. The halogen atom represented by R ₅ is a force s ′ such as chlorine, bromine, iodine, etc., preferably iodine. Compound [IV] wherein R ₅ is iodine [IV] can be easily produced, for example, by the method described in Japanese Patent Application Laid-Open No. 58-57390 or a method analogous thereto. Manufacturing method (3)

This method is a way to synthesize human Dorokishii amino compound [formula R ₃ with respect to V Ί 'to a compound or compounds by reacting a reactive derivative thereof represented by OH i'], well-known ether Reaction. R ₃ 'represents an optionally substituted hydrocarbon residue, and as such a hydrocarbon residue, those already mentioned as the optionally substituted hydrocarbon residue in R ₃ can be directly applied here. . R ₃ ′ 0H is used as it is or as a reactive derivative thereof. Is the reactive derivative of Rs'0H a hydrogen source of compound [V]? A derivative of R 3 ′ 0H which represents a group that leaves with the compound, that is, a compound represented by the general formula I′Y. Where is the hydrogen field? The group Y leaving with is a halogen atom, a sulfonyl group, a sulfonyloxy group. Halogen atoms include chlorine, bromine and iodine. Examples of the mono-substituted sulfonyloxy group include (^ -alkylsulfonyloxy group, Cg ^ iO aryl, Sulfoninoleoxy ^ j; etc. In addition to the above-mentioned anti-tS derivatives, especially when producing the (: t- ₄ alkyl ether compound) of the compound [V], for example, diazomethane, diazozeta C! -4 diazoline, such as dimethyl sulfate, getyl sulfate, etc., are also used.

(3-1): When using R ₃ 'OH The compound [V J 'is reacted with a suitable dehydrating agent to synthesize the compound [〖:). Examples of the dehydrating agent used for this purpose include oxyl chloride 'thionyl chloride, dialkyl azodicarboxylate + phosphine, N, N-cyclohexylcarbodiimide, and the like. Is azodicarboxylic acid getyl carbonate + triphenylphosphine. The reaction using azodicarboxylic acid dimethyl dibenzoate + triphenylphosphine is usually carried out in an anhydrous solvent, and the above-mentioned ethers and hydrocarbons are used. Compound IXL 1 R ₃ moles' OH, Azojikarubon acid Echiru, Truffe Weniruhosu off fin are both used 1 :. 5 mol. It takes 1-4 days in the temperature range of 0-5 (C).

(3-2): When using R ₃ 'Y

The reaction between R ₃ ′ Y and the compound [V: 1 is a normal etherification reaction and is carried out in a solvent. Examples of the solvent include ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water, etc. mentioned in the section of the production method (1). Examples of the solvent and the mixed solvent include water, and preferably a mixed solvent of water and a water-miscible solvent (eg, hydrated methanol, hydrated ethanol, hydrated acetone, hydrated dimethyl sulfoxide, etc.). ). This reaction can be allowed to proceed smoothly in the presence of a suitable base. Examples of such a base include alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, and potassium carbonate, and alkali metal water such as sodium hydroxide and potassium hydroxide. Examples include inorganic bases such as oxides. This reaction may be performed in a buffer solution of pH 7.5 to 8.5. The number of moles of the reagent R ₃ ′ γ and the base used is 1 to 5,:! To 10, preferably 1 to 3, and 1 to 5, respectively, per mole of the starting compound [y. The reaction temperature is between −30 and −100 ° C., preferably between 0 and 80 ° C. Range. The reaction time is 10 minutes to 15 hours, preferably 30 minutes to 5 hours.

 (3 — 3): When using C 1 ^ 4 diazoalkane

 The reaction is usually performed in a solvent. As the solvent, the above-mentioned ethers, hydrocarbons and the like are used. After dissolving V] in a solvent, the reaction proceeds when a solution of the diazoal compound is added. The reagent is used in an amount of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound. The reaction is carried out at a relatively low temperature and is between 150 and 20 ° C, preferably between −30 and 0 ° C. The reaction time is 1 minute to time, preferably 10 minutes to 1 hour.

(3-4): When using di C i- ₄ alkyl sulfate

 The reaction is usually carried out in water or a mixed solvent of water and a water-miscible solvent. Examples of the mixed solvent include the water-containing solvents mentioned in the section (3-2). This reaction is carried out, for example, in the presence of an alkali metal hydroxide of sodium hydroxide or potassium hydroxide. The reagent is used in an amount of 0.5 to 10 mol, preferably 1 to 2 mol, per 1 mol of the compound [Y]. The reaction temperature ranges from 20 to 100 ° C, preferably from 50 to 100 ° C. The reaction time is 10 minutes to 5 hours, preferably 30 minutes to 3 hours. Manufacturing method (4)

"~ D

 [们

This method is ceph ^: be synthesized beam compound [W] Formula C (= S) and Ji O urea or Chio urea derivatives by reacting the object compound represented by NH ₂ [I] It is a method. Compound [M] is used as a salt or ester as it is. X in the compound [VI] represents a halogen atom such as chlorine, bromine and iodine. As the salt of [VI], the salt of the compound [B] (inorganic base salt, ammonium salt, organic base salt, inorganic acid addition salt, organic acid addition salt, etc.) mentioned in the production method (1) may be used. But that's true. Ester (C alkyl esters of also producing methods as ester le of (VI) compounds mentioned in the section of (1) [II], C ₂ ~ 4 alkenyl esters, C ₃ ~ 6 consequent Roaru kill esters, C. 3 to 6 Cycloanolequinolene C 1-4 Anolequine Estenole, C 6-10 aryl ester, C 7-ι2 aralkyl ester 'C i- ₅ alkanoyloxymethyl ester, C 1-5 alkano inoleoxy (Ethyl esters and their further substitutions) also apply here. The starting compound [VI] has the general formula XCH ₂ COC-COOH

 N

ヽ OR ₃

Are the same as defined above) or a reactive derivative thereof and the above-mentioned 7-amino conjugate [Π] or a salt or ester thereof in the same manner as in the production method (1). It can be manufactured using a method. General formula XCH ₂ CO C— A compound represented by COOH or its reactivity ft

ヽ OR ₃

The conductor can be easily manufactured by a method known per se or a method analogous thereto. Compound [VI] ί ^ ((= 3) Η reaction with ₂ is usually carried out in a solvent. As the solvent for example di-old hexane, Te preparative Rahi mud furans, ethers such as Jechi ethers, for example methanol over Alcohols such as mouth / ethanol, amides such as dimethylformamide, dimethylacetamide, etc. are used. or normal 1-5 moles' to a derivative conductor) the amount of Nyuita ₂ compound [VI 3; Preferably it is 1-3 mol. The reaction 0~: L 0 0 ° C, preferably carried out in a temperature range of 2 0~ 6 0 ^a C. The reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours.

 In the above production methods (1) to (.4), compound '1! There is a field that can be obtained as a mixed snout of isomers. In order to separate the desired syn isomer from the mixture, a known S-isomer method or a method analogous thereto is applied. Examples of such methods include fractionation using differences in solubility and crystallinity, chromatographic separation, and separation using ester-decomposition rate ^ -differences.

Protecting method: 瘦 ^ removal method: As mentioned above, in the field of β-lactam and peptide synthesis, protecting groups for amino groups have been thoroughly studied, and the protection method has already been established. In addition, a method for removing amino protection ^ has been established in the same manner, and in the present invention, the conventional technique can be used as it is for removing ^. For example, 'monohalogenoacetyl' (chloroacetyl, bromoacetyl, etc.) can be converted to an acid (eg, salt completed) by alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxydicarbonyl). As a result, aralkyloxycarbonyl (such as benzyloxy carbonyl), p-methinolebenzinoleoxy canolepo, and p-nitrobenzinoleoxycarbonyl can be converted to 2,2 .- 2— Trichloroethoxycarbonyl can be removed with Φlead and acid (such as acetic acid). On the other hand, when the compound [I] is esterified as a synthetic intermediate, the ester residue can be removed by a method known per se or a method analogous thereto. For example, 2-methylsulfonyletyl stenole is an acid, but aralkyl estenole (benzinole ester, p-meth ^ cibenzyl ester, P- '=-trobenzyl ester) is acid. 2,2,2-Tricycloethyl ester can be converted to sulfuric acid (for example, with trifluoroacetic acid) or acid (for example, acetic acid) by catalytic reduction. , Tert-phenyl thioresin dimethyl styrene ester) can be removed only with water.

Purification method of compound [1]: The compound [1] produced in the reaction mixture by various production methods detailed in (1) to (4) and, if necessary, by following the protective group removal method described above. ] Can be isolated and purified by known processing means such as extraction, column chromatography, precipitation, and recrystallization. On the other hand, the isolated compound [I] can be converted into a desired physiologically acceptable salt or a metabolically unstable nontoxic ester by a known method. The sulphoxide (n = 1) of the septum compound is obtained by the oxidation reaction of the compounds I, 1 '] (n = 0). Such an oxidation reaction is a well-known reaction. Oxidizing agents suitable for the oxidation of sulfur atoms in the cefum ring include, for example, oxygen, peracid, hydroperoxide, and hydrogen peroxide. Can also be manufactured. The reaction is usually performed in a solvent. Solvents used in this reaction include, for example, ethers such as dioxane and tetrahydrofuran; for example, halogenated carbons such as dichloromethane, chloroform-form and cyclo-benzene. Danihydrogens, for example, organic acids such as formic acid, acetic acid, and trifluoroacetic acid. Examples include amides such as dimethylformamide and dimethylacetamide. The reaction is carried out at a temperature in the range of 120 to 80 ° C., but preferably at a temperature as low as possible, preferably at −20 to 20 ° C. It is generally known that sulfoxides having the S-configuration are mainly produced during the oxidation of the compound of the formula I: IΊ showing π = 0. R- and S-sulphoxides differ in their different solubilities and in the chromatographic separation Separated by moving speed. The above oxidation reaction for obtaining the sulfoxide may be performed before the above-mentioned reactions (1) to (4), or may be performed after the reactions (1) to (4). The compound [I] of the present invention can be parenterally or orally administered as injections, capsules, tablets, or granules in the same manner as known penicillins and cephalosporins. The dosage is 0-5 to 80 W per day, more preferably 1 to 20 z days per body weight of humans and animals infected with the pathogenic bacteria, and more preferably 1 to 20 z days divided into 3 to 4 times a day. Administration. When used as an injection, the carrier is, for example, distilled water or physiological saline, and when used as a capsule, powder, granule, or tablet, a known pharmaceutically acceptable excipient is used. (Eg, starch, lactose, sucrose, calcium carbonate, phosphoric acid phosphate, etc.), binders (eg, starch, gum arabic, dexamethasinolenoleose, hydroxycopene-pinoresenorelose, crystalline cenorreose, etc.), It can be mixed with lubricants (eg, magnesium stearate, talc, etc.) and disintegrants (eg, carboxymethyl calcium, talc, etc.). The present invention will be further described in the following Reference Examples and Examples, but these examples are only examples, and do not limit the present invention, and may be changed without departing from the scope of the present invention. Is also good.

Elution in the column chromatography was performed under observation by TLC (Thin Layer Chromatography). In TLC observation, BOF ₂₅₄ manufactured by Merck was used as a TLC plate, a solvent used as an eluting solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. Silica gel for column is also Kieselgel 60 (230 ~ 400 mesh). ¹¹ SEF Adex is a product of Pharmacia Fine Chemicals _c XAD-H resin is available from Rohm & Haas Co. .). NMR spectrum was measured inside or using te Toramechirushi run-as external reference XL- lOOA (lOOMHz), EM 390 (9θΜΗ ζ) or T60 (6 θΜΗζ) Katasupeku Torome over data mono-, total <5 values are given in ppm. In the mixed solvents, the numerical values shown in parentheses are volume mixing ratios of the respective solvents. In the solution, represents the number ⁹ in the solution 100. The symbols in the reference example's examples have the following meanings.

 s: singlet (s ing 1 e t)

 d: doublet

 t: triplet (trip1et)

 q: Quoretetet. (quartet)

 ABq: AB type quartet

 d. d: TA, 'double doubl'et'

 m: machino lepret (mu 1 tip 1 e t).

 b r.: Broad

 J: Coupling, constant (coup 1 ing constant)

 Hz: Henoretsu (Herζ ·)

 : Mirik, 'lam (m i 11 i g r am)

 9: Gram (gr am)

 m £: mili litter (mi 1 l i l i ter)

 Ά: Reiter (1iter)

%: No ^0- cent (pe rcent)

 DMSO: Dimethylsulfoxide (dimethy1su1foXide)

"^ Ao D ₂₀ : Heavy water

 BEST MODE FOR CARRYING OUT THE INVENTION

 Reference example 1 '

 7 β-I 2 — (2—Chloroacetamide) 1- (一) —Methoxy-acetonate-amide) 1—3— (3-oxobutyryl oxomethyl) 1—3-Sef M-1 4 rubonic acid.

7 1-Amino 3- (3-oxobutyryloxymethyl) -13-Cefum 1-4-Carboxylic acid 157 9 in a solution of 500 W of tetrahydrofuran and 50% of water Suspend and add sodium bicarbonate 14-19 little by little with stirring. Then, while stirring at 5 C, 2- (2-chloroacetate-m-dithiazol-l-41-yl) 1-2 (キ シ) -Methoxy-minosetyl-k-l-id salt-salt salt 150? Is added over 20 minutes, and the reaction mixture is stirred at the same temperature for another hour. After completion of the reaction, the mixture is adjusted to ΡΗ3.0 with 10% hydrochloric acid, and the reaction mixture is extracted twice with 1 ^ each of a mixture of ethyl acetate tetrahydrofuran (1: 1). The extract is extracted with anhydrous magnesium sulfate. After drying, the solvent is distilled off under reduced pressure, and the obtained colorless powder is washed with dimethyl acetate 200) ^ and removed to give the title compound 2539. - Elemental analysis: as _{C 2 oH 2 () ClN 5} 0 9 S 2,

 Calculated value ^): C, 41.85: H, 3.51: N, 12.20.

 Obtained value (¾): C, 1.39 = H, 3.57; N, 11.94-

IR spectrum No. 1 cm-1; 1780, 1740, 1700, 1655, 1540, 1410.

NiR spectrum (d6—DMS0) 3: 2.20 (3H, s), 3.45 and 3.68 (2H, ABq, J-18Hz), 3.6δ (2H, s), 3.92 (3Η, s), 4.38 (2Η, s), 479 and 5.09 (f2il, ABq, J = 13Hz), 5.18 (lH, d, J = 5Hz), 5.85 (lH, dd, J = 5Hz and 8H2), 7.44

(1H, s), 9.66 (1H, d, J = 8Hz), 12.85 (1H, br.s) ₀ Reference example 2

 7 β-2-(2 ミ ミ ノ ル ー ー ー 一) 2 1 (2 (Zj (((一 セ ト ト ア レ〕 一 一 — — — — 3 （(3 一 ソ ブ ブ ブ チ リ ル メ メ 4 一 一) Acid-

7 (3—2— [2— (Chloroacetamidothiazole) 4- 2 (Z) —Methoxyxyminoacetamide—3— (3—3 years old) (Chill) 1-3-CEM-4 Dissolve sodium rubonic acid 150 in a mixed solution 500 of tetrahydrofuran monohydrate (1: 1), and then dissolve sodium sodium methyldithioate. Add 5 19 and stir for 3 hours at 20 C. Add ethyl acetate 200 (^) to the reaction mixture, remove the organic layer, and adjust the aqueous layer to pH with 10 hydrochloric acid. This is extracted with a mixture 1 of tetrahydrofuran-ethyl acetate (1: 1), and the aqueous layer is further extracted with n-butanol 200. The extract is dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure, and ethyl acetate (200 W) was added to the residue, followed by stirring. Obtained.

Elementary analysis: as _{C 18 H 19 N 5 0 8} S 2,

 Calculated value 6¾: C, 42.19; H, 4.30, N, 13.55-Measured value (: C, 41.94, H, 4.1 1,, 1 3.59 ·

IR spectrum ^ cm-1: 1770, 1710, 1620, 1520.

NM R spectrum _{(d 6 - DMS 0) δ} : 2.20 (3Η, s), 3.43 and 3.65 (2 H, ABq, J = 18Hz), 3.63 (2 H, s), 3.86 (3 Η, s ), 4.78 and 5.06 (2Η, ABq, J2-13Hz), 5.14 (lH, d, J = 5Hz), 5.79 (1H, d.d, J = 5Hz and 8Hz, 6.73 (1H, sJ, 7.1 7

0ίλ? C 2H, br.j, 9.56 lH, d, J-8 Hz; _o

 Reference example 3

 Ίβ- [2- (2-Aminothiazo-l- 4-inole) -1 2 (Ζ) -ethoxyminoacetamide] -1 3— (3-year-old oxobutyryloxymethyl) 1-3-Sef X-Mu 4-carboxylic acid.

 2-(2-Aminothiazole 4-yl) 1 2 (Ζ) 1-Ethoxyminosinamic acid 2 39 is dissolved in dimethylformamide 100 is and 1-hydroxybenzotriazole 1 59 to the mouth Add Kisil Carbodimid 2 0.69 and stir at 20C for 1-5 hours. After removing the insoluble matter, the liquor was washed with 7 3 -amino-3 1- (3-oxobutyryloxymethyl) 13 -cefum 4 1-butyric acid rubonic acid 3 1 and small ethylamine 2 8 W dimethylformamide 100 »Add to the solution under ice-cooling. Stir the reaction solution at 20'C for 3 hours, add ether 50, and collect the solid precipitate. After dissolving this in water 100 », the pH is adjusted to 3.0 with 10% hydrochloric acid, and then extracted twice with each 200 i of methylethyl ketone. The extract is washed with water, dried over ice-free sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained solid is washed with ethyl acetate to give the title compound 31 1? Is obtained.

IR spectacle J off " ¹ : 1780, 1720, 1660.

N M R Spectral (d 6— D M S 0) S: 1.30 (3H, t, J = 7.5Hz),

 2.25 C 3 H, s), 3.45 -3.65 (4H, m), 4.20 (2E q, J = 7.5Hz),

4.70 and 5Λ 0 (2H, ABq, J = 1 8Hz), 5.25 (2H, d, J = 5Hz), 5.90 (1H, d.d, J = 5Hz and 8Hz), 6.90 (1H, s), 7.20—

7.80 (2H, br.), 9.80 (lH, d, J = 7.5Hz) ₀

 Reference example 4

Ί β — [2 — (2 — aminothiazo-1-4-レ) 1 2 (Ζ)-ル Oxyminoacetamide] 1-3-(3-oxopyryl xymethyl)-3-cefm-4-carboxylic acid.

2- (2-Aminothiazole-1 4 -—) yl 2 (Z) -aryloxyaminoacetic acid 13 9 is replaced with dimethylformamide 50, and 1-hydroxybenzotriazole 89 and di- / Add 10.3 ^ of calohexylcarbodiimide and stir at 20 "C for 3 hours. After removing insolubles, remove the solution by 7-amino-3-(3-oxobutyryloxymethyl) 1-3- Sefue厶_ｰ4- carboxylic acid 16 9 and Application Benefits Echirua Mi down 1 0 9 dimethyl Chiruhorumua mi de 5 0 solution is added under ice-cooling. After stirring for 3 hours the reaction solution at 20C, the ether ⁵ 0 0 W The ether layer was removed, and the resulting insoluble material was dissolved in water 50 and then adjusted to Η3.0 with 10% hydrochloric acid to obtain the crude title compound, which was treated with ethyl acetate-tetrahydrofura. Dissolved in a mixed solution of 500: 1 (1: 1) and dried over anhydrous magnesium sulfate The title and the solvent is distilled off followed vacuo treated with activated carbon compound 2 5 ^ is obtained as an amorphous powder.

 I R Sukto Nore! cm-1: 1780, 1720, 1660, 1 620.

NMR spectra (d6-DMS 0) δ: 2.30 (3Η, s), 3.45-3.66 (4H, m), 4.64 (2.d, J6Hz), 4.80-5.10 (2H, ABq, J = 18Hz), 5.23 (2H d, J-9Hz), 5.26 (2H, d, J = 5Hz), 5.90 (1H, d.d, J = 5Hz and 9Hz), 5.90-6.20 (lH , m), 6.80 (. lH, s), 7.20-8.00 C 2H, b r .;, 9.83 · (lH, d, J = 9 Hz ₀ Reference example 5

 7 / 3— [2- (2-aminothiazoyl 4-inole) 2— (Z) — (tert-butoxycarbonylmethoxymino) acetamide] 1 3— (3-oxobutyric) (Roximetyl) 1-3-CFM-4 carboxylic acid.

 2— (2-Aminothiazo-l 4-inole) 2 2 (Z—t er t—butoxycarbo-

O P1 Apply Nilmethoxyminosidic acid 6.0 to dimethylformamide 20, add 3.59 1-hydroxybenzotriazole and 4.49 dicyclohexylcarbodiimide and stir at 20 "C for 3 hours. After removing the liquid

7 3—Amino 3— (3-oxobutyryloxymethyl) 1-3-Cephem-14 4-Carboxylic acid 6.2 and Triethylamine 4.0 9 Add to a solution of dimethylformamide 20 in ice-cooled 20 under ice-cooling. Stir the reaction mixture at 20 for 8 hours. Add ether 200 to the reaction mixture, remove the ether layer, dissolve the residue in 50 W of water, and adjust the pH to 4 with 10% hydrochloric acid to precipitate crystals. This was collected, washed with water, washed with ethyl ether, and dried to give the title compound 10

You get 9 or '.

 IR Spectral OB-1: 1790, 1730. 1710, 1660,

1530.

NMR spectra (d ₆ — DMS O) <5: l.50 (9H, s), 2.20 C3E s), 3.40-3.60 (4H, m), 4.40 (2H, s), 4.80 and 5.10 ( 2 AB q, J-1 Hz), 5.20 (1H, d, J-5Hz), 5.80 (lH.d.d, J2 5Hz and 8Hz), 6.70 (ls), 7.20-7.80 (2H, br .), 9.30 (1 d, J = 8Hz) ₀

 Reference example 6

 3- (3-oxobutyryloxymethyl) 1 7 / 9— [2- (2-tritylamino thiazole-4-y) 1 2 (Z) — (1-methyl 1-tert-butoxycarbonyl) ethoxyi [Minoacetamide]] 1-3-CFM — 4-carboxylic acid.

2-f (2-tritylamino-thiazo-l- 4-n-ole) 1-2 (Z)-(11-methyl-11-tert-butoxycarbonyl) ethoxyminoacetic acid Combine 20 to 1-hydroxydroxybenzene Add 3.5 §> and dicyclohexylcarbodiimide 4.4 9 and stir for 20 hours with 20 scoops. Remove insolubles and elute the solution with 7 / 9—amino-3— (3—oxobutyryloxymethyl) -13—cefum4. Add to the solution under ice-cooling. The reaction mixture was stirred for 24 hours at 20 "C, and then a mixture of ethyl ether and petroleum ether (1: 1) 200) ^ was added. After removing the ether layer, water 5 was added to the residue, and then 10 ^ p with hydrochloric acid. A crystalline powder precipitates when the pH is adjusted to 4.0, which is washed with water, washed with ethyl ether and dried to give the title compound 139.

 I R Spectrum ^ f ^ cm-i: 1780, 1730, 1700, 1680,

 1530, 1 150.

 NMR spectrum (d6—DMS0): 1.35 (15H, s), 2.25 (3H, s), 3.40 -3.60 (4H, m), 5.80 and 5 · 10 (2H, AB q , J = 14Hz),

5.25 (1H, d, J-5Hz), 5.80 (1H, d.d, J = 5Hz and 8Hz), 6.70 (1H, s ;, 7.20-7.80 (2H, br ·), 7.30 (15 H, s),

9.30 (1 H, d, J = 8Hz) '

OMPI Reference example 7.

 7-C2- (2-aminothiazole-1-4-inole) 1-2- (Z) -Propoxyminoacetamide-1-3-(: 3-oxobutyryloxymethyl) -3-Sefumeu4-Carbon acid.

2- (2-aminothiazole-141-alk-2- (Z) -propoxyiminoacetic acid 1.) is applied to dimethylformamide 1 Οπ ^ to give 1-hydroxybenzotriazole 1.5 and Add dicyclohexylcarboximide 1.73 and stir for 1.5 hours at 20 ° C After removing insolubles, remove the solution from ⁷ ? 1) 3-Cefem Acetonitrile 2.7 ^ and triethylamine 3.2π ^ are added to a 1Οχη solution of dimethylformamide under ice-cooling, and the reaction mixture is stirred at 20.C for 3 hours and then ether 10 Add Om ^, extract the solid from Yide, dissolve in 5 Qn ^ in water, adjust the pH to 3.0 with 10% hydrochloric acid, and extract ³ times with 5 Om ^ each of η-butanol. After washing the Yuzu solution with water and anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the resulting solid is washed with ethyl acetate. Serial compound 1.7? Force is obtained.

IR spectrum ^ ma ^ " ¹ : 1790, 1750, 1720, 1680,

 1640, 1555.

NMR spectrum (d ₆ — DMS 0 <5: 0.91 (3H, t, J = 7Hz),

 1.4- 1.85 C 2H, m, 2.18 (3H, s ;, 3.45 and 3.70 (2 H, ABq, J = 16 Hz ;, 3.64 C 2 H, s, 4.10 (2 H, t, J = 7 Hz, 4.76-5.08 C2H, ABq, J = 13 Hz, 5.04 ClH, d, J = 4.5 Hz), 5.80 (lH, d. D, J = 4.5Hz and J = 8Hz), 6.87 (lH, s),

7.13 C2H, br.s ;, 9.70 lH, d, J = 8Hz) ₀

Reference Example 8. LEA1 m Ί β ~ 2 -C 2—Aminothiazole 1—4—Ilk 1— (Z) —Isopropoxyminoacetamide] 1—3— (3-oxobutyryloxymethyl) 1 3 —Cefum-1-4-carboxylic acid.

 2- (2-aminothiazol-1-yl-1-2- (Z) -isopropoxyminoacetic acid and 7? -Amino3— (3-oxo7 "tiloxymethyl

The title compound is obtained by operating in the same manner as in Reference Example 3 using 3) -sefumu 4-carboxylic acid.

IR spectrum i ⁰ " ^-1 : 1780, 1745, 1720, 1670,

 1 620, 1 530.

NMR spectrum (d ₆ — DMS 0) «5: ι, ι 8 (6H, d, J = 6Hz ;, 2.20C 3H, s), 3.46 and 3.66 (2H, ABq, J = 1 8Hz :) , 3.64 (2H, s, 4.93 and 5.21 (2H, ABq, J = 13 Hz, 5.03 (1 H, d, J = 4.5 Hz ;, 5.6-5.9 (lH, m, 6.69 (lH, s, 7.20 (2H , br. s, 9.46 (1 H, d, J = 8 Hz; ₀

 Reference example 9.

 7 ^-C 2— (2-Aminothiazole—4-Ilk-1 2— (Z) — (2-Hydroxixoxyminoacetamide) 1-3— (3—Oxopetit Riloximetyl 1-3-Sefemu 4 High-strength rubonic acid.

 2-C 2-aminothiazole 1-4-1-2-(-(2-hydroxyethoxyquinino:) acetic acid and 7 ^-amino 3-(: 3-oxobutyryl methoxymethyl The same procedure as in Reference Example 3 was carried out using 1-3-CFM-4-1 carboxylic acid to obtain the title compound.

IR Spectrum Nog ^ gx ^ ^-1 : 1780, 1750, 1720, 1670,

 1630, 1550.

N MR spectrum (d ₆ — DMS 0: 2.20 (3H, s), 2.9-3.2 (2 H, m, 3.4-3.7 (2H, m), 3.65 (3H, s), 4.32 (2H, t, J = 6 Hz), 4.95 and 5.12 (2H, ABq, J = l 3 Hz), 5.04 ( 1 H, d, J = 4.5 Hz ;, 5.6-5.9 C lH, m), 6.70 (lH, s, 7.20 (2H, br.s included 9.46 C lH, d, J = 8 Hz ₀₎

 Reference example 10.-

7-C2-C2-Aminothiazole 1-4-yl :) 1 2- (Z) -cyclo-σ-pyrmethoxyiminoacetamide] 1-3- (3-oxobutyryloxymethyl) 1 3—Cefem 4 Rubinic acid.

 2- (2-aminothiazol-1-yl--2- (Ζ) -cyclopropyl xyminoxyacetic acid and 7? -Amino-13-(: 3-oxobutyryloxymethyl) 1-3-cefm — The title compound is obtained in the same manner as in Reference Example 3 using 4-carboxylic acid.

IR spectrum ^ c " ¹ : 1760, 1635, 1540, 100,

 1365, 1270, 1 150.

N MR spectrum (d ₆ — DMS 0) 3: 0.1 -0.6 (4H, m, 0.7-1.5 lH, m), 2.20 C 3H, s, 3.42 and 3.66 (2H, ABq, J "= 18Hz ), 3.64 2H, s, 3.91 (2H, d, J = 7 Hz, 4.80 and 5.08 (2H, ABq, J = 14 Hz), 5.15 (lH, d, J = 5 Hz, 5.78 C 1H, dd, 0 " = 5 ^ 2 and << 1 = 8112), 6.70 (1s), 7.22C2H, br.s, 9.52C1H, d, J = 8Hz :).

7? — [2— (2-Aminothiazoyl 4-yl) -1 2— (Z—Carbamoylmethoxyminoacetamide) -3— (3-oxobutyryloxymethyl :) 1 3-Cefem 4-Carboxylic acid.

a) 2-(2-Cross amithiazole-4 -Ilk-2-(Ζ) -Dissolve 24 ^ ^ potassium bromoimine acetic acid in 100 parts dimethylformamide, add 11.4 hydroxybenzotriazole 11.4 and dihexyl hexyl carpoimide 22 and add 20 hours for 2 hours. Stir. The insolubles Sanochi, ^ liquid ⁷ ^ - ^amino-3 - (3-O key Sopuchiri Ruoki Shimechiru one 3 - Sefuemu 4-carboxylic acid 2 2 Bok Riechirua Min 2 0 1 dimethylformamidine de 7 O mf solution Stir the reaction solution at 20 ° C for 1 hour, then add 500 m of methyl ethyl ketone, 60 m of phosphoric acid and saturated saline 1 and stir. Then, the residue is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, ethyl acetate 20 O mf is added to the residue, and the precipitated solid substance is collected.ア ミ 4 ィ — — — — — — — — — — 1 — — — ア ミ — — — — — — — — — — — — 4 One-strength rubonic acid 199 is obtained.

IR spectrometer ^ cm ^-1 : 1770, 1720, 1640, 1550.

 ill α Λ.

 b) — [2— (2-Chloroacetamide amide thiazole—41 yl) -1 2 -—— obtained above

1-3- (3-oxobutyryloxymethyl 3 -cef-m-r-rubonic acid 19.9 is dissolved in water 15 O n ^, and methyl dithio-l-rubber sodium sodium 20? And ethyl acetate 15 O r ^ And stirred for 8 hours at 20 ° C. After adding acetic acid to the reaction solution to adjust the pH to 4.0, the aqueous layer is separated, concentrated under reduced pressure, and the residue is freeze-dried. The solid product is dissolved in water (10 π π ^) and extracted with a mixture of tetrahydrofuran (10 Om ^) and methylethyl ketone (200) The extract is dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The solvent is removed by distillation to give the title compound 6.0. IR spectrum; ^cm_1 : 1780, 1720, 1660.

N MR spectrum (d ₆ — DMS 0) <5: 2.10 C 3 H, s), 3.40 and 3.65 2H, ABq, J = 1 8Hz ;, 3.63 2H, s, 4.40 (2H, s), 4.80 and

5.06 (2H, ABq, J = 13Hz), 5.16 (lH, d, J = 5 Hz ;, 5.80 (lH, dd, J = 5 Hz and 8 Hz), 6.74 (lH, s ;, 7.05-7.40 (4H, m, 9.60 ClH, d, J = 8 Hz.

 Reference Example 12.

 7- [2- (2-Aminothiazole-14-Irk-1-2- (Z)-(2-Chloroxoximino) acetamide]] 13- (3-Oxobutyryloxymethyl) One 3-Sefume 4-Carboxylic acid.

 2— (2—Aminothiazo-1-yl) 4- (Z) — (2-σσσethoxymino:) acetic acid and 7 /? — Amino-1-3- (3-oxobutyric) The title compound is obtained in the same manner as in Reference Example 3 using -3-CeFM-4-carboxylic acid.

IR spectrum ^ ¹ : 1770, 1705, 1660, 1630,

 1520.

NMR spectra (d ₆ -DMS 0) d: 2.20 C 3H, s, 3.05 and 3.50 C 2H, ABq, J = l 8 Hz, 3.60 (2H, s), 3.73 -3.90 (2H, m), 4.20 -4.50 C 2H, m ;, 4.76 and 5.06 (2H, ABq, J = 14Hz :), 5.16 (lH, d, J = 5Hz), 5.80 (lH, d.d, J "= 5Hz and 8Hz),

6.76 C 1 H, s), 7.20 (2H, br.s, 9.60 (lH, d, J = 8 Hz). Reference Example 13.

7-C2-2-Aminothiazole-1-4-yl) I2- (Z)-(2-Fluoromethoxymino) acetamide] I3- (3-oxobutyri) Roxymethyl) 1-3-Cefum 4-carboxylic acid. .. ·. 2- (2-aminothiazol-4-yl) -1- (Z) — (: 2-fluoroaminoquinoacetic acid and 7? -Amino-3— (3-oxobutyri) The title compound can be obtained in the same manner as in Reference Example ³ using (roxymethoxy) -3-cef-4-carboxylic acid.

I II spectrum ^^ cm— ¹ : 1770, 1740, 1680, 1620,

 1540.

N MR vector (d ₆ — DMS 0) «5: 2.20 (3 s), 3.50- 3.70 (2H, m), 3.66 (2H, s ;, 4.10-4.30 (1 H, m, 4.43- 4.66 (3H, m), 4.80-5.03 (2H, m), 5.20 (lH, d, J = 4.5 Hz ;, 5.86 (lH, dd, J = 4.5 Hz and 8 Hz), 6.80 (lH, s, 7.13 ( 2H, br.s), 9.70 (lH, d, J = 8Hz) ₀

 Example 1.

 1 β-2-(2-Ami / thiazole-14-Irk-2-(Z)-propoxymino) acetate amide] 1-3-[(Imidazo [1, 2-aJ Ginidimu 1-yl methyl) 1-3-Sefume 41-carboxylate.

7 — [2— (2-Aminothiazolyl—4—Noire 1—2— (Z—Propoxyminoacetamide) 1 3— (3—Oxobutyrioxymethyl-3-3-Cefm-1 4-Carboxylic acid 1.59, Calidium iodide 1.5 and imidazo (: 1,2-a) pyridine 1.5 ^ mixed with acetonitrile and water (1: 1) And agitate for 2 hours at 70 ° C. Evaporate under reduced pressure to remove the residue, apply the residue to column gel chromatography, and mix acetate and water (: 4: 1). The eluate is concentrated under reduced pressure and the residue is lyophilized The solid obtained is dissolved in water ⁵ and subjected to XAD-— column chromatography to give a 20% aqueous ethanol solution. Combine the fractions containing the target compound under reduced pressure ^ Concentrate and -lyophilize to give the title compound 0.2 5,,

(. "One Is given.

Elementary analysis: as _{C 23 H 23 N 7 0 5} S 2 4H 2 0,.

 Calculations: C, 45.02; H, 5.09 ;, 15.98.

 Found: C, 44.95 ·, H, 4.66 «, N, 15.80.

 R spectrum ^ ^ cm- 775, 1650, 1610, 1530.

NMR spectrum (d ₆ — D MS 0) δ: 0.86 (3H, t, J = 7Hz),

 1.36 -1.80 C 2H, m], 2.97 and 3.37 (2H, ABq, J = l 8Hz),

 3.96 C 2H, t, J = 7 Hz, 4.99 (lH, d, J = 5 Hz), 5.27 and 5.45 C 2H, ABq, J = l 3 Hz ;, 5.61 (lH, d.d, J = 5 Hz and 8 Hz,

 6.65 (lH, s ;, 7.13 (2H, br.s, 7.35-7.66 (lH, m),

 7.84-8.14 (lH, m, 8-3— 8.76 (3H, m), 8.8-9.05 (lH, m,

9.40 C 1H, d, -J = 8Hz ₀

Using the same method as described in Example 1, 7?-[2- (2-aminothiazolyl-141-yl) -1 2-((2-fluoro succinoxyminoacetate) Amido: 3- (3-oxobutyryloxymethyl) -13-sefm- ₄ General formula from the reaction between rubonic acid and various imidazolic conductors

[]

The following compounds of Examples 2 to 12 represented by can be produced.

 Example 2.

Compound [r] (R ₃

Elementary analysis: as _{C 22 H 20 N 7 O 5} S 2 F. 4H 2 0,

 Calculated (¾) C, 42.78; H, 4.57; N, 15.87.

 Found (D C, 42.57; H, 4.27-; N, 15.71.

, IR spectrum ^? Cm "" ¹ : 1760, 1610, 1525.

NM I spectrum Bok Honoré _{(d 6 -DMS O) δ:} 2.96 and 3.43 (2Η, ABq, J = 18Hz), 4.0-4.2 C 1H, m), 4.2- 4.5 (2H, m, 4.7 - 5.0 ( lH, m), 5.00 (lH, d, J = 5Hz), 5.2-5.6 (2H, m), 5.61 (lH, dd, J = 4Hz and 8Hz), 6.70 (1H, s, 7.16 (2H, br.s, 7.4 -7.7 (2H, m, 7.8- 8.2 (2H, m, 8.3-8.8 (3H, m), 8.97 (lH, d, J = 7 Hz), 9.50 (lH, d, J = 8 Hz) .

 Example 3.

Elementary analysis: as _{C 22 H 20 N 7 O 5} S 2 Cl · 5/2 H 2 0,

 Total value: C, 43.53 H, 4.15; N, 16.15.

 Actual values: C, 43.25, H, 4.03 ;, 15.94.

 JR factory

L 760, 1605, 1520.

NMR spectrum (d ₆ — DMS 0) 8: 2.98 and 3.43 (2H, ABq, J = 18Hz), 3.7-3.9C2H, m), 4.1-4.4 (2H, m), 5.00 (1H, d, J = 5Hz, 5.25 and 5.47 (2H, ABq, J = l 6Hz input 5.62 (lH, dd, J = 5Hz and 8Hz), 6.74 ClH, sj, 7.16 2H, br.s ;, 7.4-7.6 ( 2H, m, 7.9-8.2 C 2H, m), 8.3-8.8 (3H, m, 8.93 (lH, d, J = 7Hz), 9.45C lH, d, J "= 8Hz).

 Example 4.

Compound [1 'Ba R ₃

Elementary analysis: as _{C 23 H 23 N 7 0 5} S s 2 0,.

 Calculated values: C, 43.1 1, · H, 5.35 ·, N, 1 5.30.

 Found: C, 42.81; H, 4.86; N, 15.0 0.

 丄 R

The Kuno! m KBax ^r _m -1770, 1650, 1610, 1530? NMR spectrum (d ₆ — DMS O) S: 1.18 (6H, d, J = 6 Hz; 5.00 ClH, d, J = 4.5 Hz, 5.28 and 5.48 (2H, ABq, J = 13 Hz), 5.46 C lH, d. D, J = 4.5 Hz and 8 Hz], 6.64 [lH, s), 7.13

• H, br.s, 7.3-7.6 C lH, m), 7.8-8.15 (lH, m), 8.28-8.75 C 3H, m), 8.8—9.15 (lH, m), 9.35 (lH, d, J = 8Hz). Example 5.

 Compound [I '] (

As _{4H 2 0, - C 22 H} 2l N 7 0 6 S 2: Elementary analysis

 Calculated: C, 42.92; H, 4.75 N, 15.93.

 Found: C, 42.86; H, 4.54 ·, N, 15.70.

IR Supekubokuru ^{_{Les; c oT L: 1770, 1650}} , 1610, 1530.

NMR spectrum (: d ₆ — DMS 0) δ: 2.97 and 3.43 (2Η, ABq, J = 18Hz), 3.44-3.72 C 2H, m), 4.02 (2H, t, J = 6Hz), 4.50 C lH, br.s, 4.98 C lH, d, J = 4.5 Hz, 5,26 and 5.46 (2Η »ABq, J = l 3 Hz, 5.60 (lH, dd, J" = 4.5 Hz and 8 Hz :), 6.67 (1 H, s), 7.15 C 2H, br.s ;, 7.36— 7.60 (lH, m), 7.80— 8.12 (lH, m), 8.30— 8.76 (3H, m, 8.84-9.04 (lH, m, 9.36 (lH, d, J = 8Hz.

 Example 6.

Compound [Γ] (R ₃

Elementary analysis: as _{C 24 H 23 N 7 0 5} S 2/2 H 2 0,

 Calculated: C, 42.98; H, 5.41;, 1.62.

 C, 43.09; H, 5.60; N, 14.74.

 R-Spectral ^ 770, 1620, 1530

NMR spectrum (d _fi — DMS O) <5: o.1-0.6 (4H, m), 0.7—1.3

. C lH, m, 2.95 (lH, ABq, J = l 8 Hz), 3.84 (2H, d, J = l 4 Hz), 4.99 (lH, d, J = 5 Hz ;, 5.28 and 5.46 (2H, ABq, J = l 3 Hz), 5.62 (lH, dd, J = 5 Hz and 8 Hz, 6.64 1 H, s, 7.12 (2H, br.s ;, 7.30-7.60 (1 H, m), 7.86- 8.20 (lH, m , 8.20-8.80 (3H, m), 8.80-9.02 (lH, m), 9.40 (lH, d, J = 8 Hz. Reference Example ⁷ .

Compound [I '] (R ₃ =-CH ₂ CONH ₂ , A® = il- pit yarn analysis value: C ₂₂ H ₂ o N ₈ o ₆ s ₂ · ^l ₂ H ₂₀

 Calculated: C, 40.30; H, 4.77; N, 17.09. Found: C, 40.54; H, 4.15; N, 17.09.

IR spectrum J ^^ CTT ¹ : 1770, 1675, 1610, 1530.

NMR spectrum (d ₆ — DMS 0) S: 3.00 and 3,44 (2H, ABq, J = 18Hz), 4.36 (2H, s), 5.02ClH, d, J = 4.8Hz, 5.28 and 5.47 (2H, ABq, J = l 4 Hz, 5.66 (lH, dd, J = 4.8 Hz and J = 8 Hz ;, 6.78 C 1¾ s, 7.00-7.60 (5H, m, 7.86-8.10 (1 H, m; , 8.28 -8.70 (3H, m), 8.86-9.00 (lH, m), 9.70 C lH, d, J = 8 Hz) ₀ Example 8.

 Compound (I'J (

Elementary analysis: as _{C 22 H 18 N 7 0 5} S 2 3 · 3H 2 0, Calculated ^:. C, 1.58; H , 3.81; N, 1 5.43 Found ^: C, 41.30; H, 3.99; N, 15.25. IR spectrum ^^ CTT ¹ : 1770, 1620, 1530, 1380,

1 2 8 0, 1 0 6 0.- Νλί R spectrum (D ₂₀ δ: 3.15 and 3.56 (2Η, ABq, J = l 8Hz, 5.20-5.50 (SH, m, 5.80 (lH, d, J = 4.5 Hz, 6.93 (lH, s, 7.40-7.60 C lH, m, 7.90-8.20 (4H, m), 8.66 (lH, d, J = 6 Hz.

 Example 9.

Compound C I'3 C

) Element analysis value: C ₂₂ H ₂₁ N ₇ 0 ₅ S ₂ · J ₂ H ₂₀

 Calculated value. ): C, 43.2 H, 4.97;, 16.11.

 Actual value 6: C, 43.72; H, 4.47; N, 16.00.

I R.-spectrum le ^{_{c cm "1: 1760, 1600}} , 1520, 1380.

NMR-spectrum le _{(d 6 0 3: 1.18 (} 3H, t, J = 7Hz,

3.12 and 3.55 (2H, ABq, Jl 8 Hz), 4.05 C 2H, q, J = 7 Rz), 5.02 C lH, d, J = 5 Hz, 5.07 and 5.53 (2H, ABq, J = l Hz, 5.63 (lH, d. d, J "= 5Hz and 8Hz], 6.67 1¾s ;, 7.0—7.2 C 5H, m), 7.8—7.9 (lH, m), 8.5—8.8 (2H, m, 9.37 (1H, d, J = 8Hz) ₀

 Example 10.

Compound [] CR ₃

Elementary analysis: as _{C 22 H 19 N 7 0 5} S 2 C1F '3H 2 0,

 Calculated: C, 1.68 H, 3.98, N, 15.47.

 Found: C, 41.49; H, 4.26; N, 15.31.

 β-Spectral ^ 1765, 1670, 1610, 1530,

NMR spectrum Honoré _{(d 6 - MS 0 δ:} 2.95 and 3.20 (2Η, ABq, J = 18Hz), 4.00- 4.25 C lH, m, 4.30 -4.53 C 2H, m, 4.65- 5.01 2H, m), 5.06 (lH, d, J = 5Hz ;, 5.30-5.56 (1 H, m 5.66 (lH, dd, J = 4.5Hz and 8112), 6.73 (11 "1, 5, 7.20 (2H, br.s, 8.10 (1H, d, J = 9Hz, 8.30 (lH, s, 8.60 (lH, s), 8.76 (lH, d, J = 9Hz), 9.30 (lH, s, 9.55 (1H, d, J = 8Hz).

Chemical compound [I '] (R ₃ = CH ₃ , A ^fe

Elemental folding value: as _{C 19 H 17 N 7 0 5} S 3 · 3H 2 0,

 Calculated value ^: C, 39.80 H, 4.04 N, 17.10.

 Found (¾): C, 39.65 H, 3.99 N, 16.73.

IR spectacle raf ¹ 1770 1 660, 1610, 1530.

N MR vector (d ₆ — DMS 0; «3 2.90 and 3.26 (2H, ABq, J =

18 Hz), 3.76 (3H, s ;, 4.85 and 5.20 (2H, ABq J = l 3Hz

5.66 (lH, d.d, J = 5 Hz and J = 8 Hz), 6.15 (lH \, N d, J = 5 Hz),

6.70 (lH s, 7.20 C 2H, br .s 7.80-- 7.90 (2 H m 9.50

(lH, d, J = 8Hz ₀

Example 12. CH _T CH _T

 Θ

Compound [i] CR ₃ = CH _3i A -N Elementary analysis: as _{C 20 H 20 N 8 O 5} S 3 9/2 H 2 0,.

 Calculated value ^: C, 38.15, Η, 4.64 Η, 17.80.

 Found: C, 38.18., 4.23Η, 18.02.

 I R ぺ ヽ I I KB KB χr-770, 1670, 1610, 1530.

N MR spectrum Bok Le _{(d 6 -DMS 0: 2.52 (} 3H, s, 2.78 (3H, s, 3.09 and 3.52 (2H, ABq, J = l 8Hz), 3.84 (3H, s), 4.86 and 5.26 (2 H, ABq, J = 5 Hz and 8 Hz, 6.72 (1 H, s), 7.16 (2H, br.s), 8.39 (lH, s), 9.46 (lH d J = 8 Hz)

W1PO

Claims

 -70-

 General formula

0

 O R g

[Wherein Ri is an amino group which may be protected, R ₂ is a hydrogen atom or a halogen atom, R ₃ is a hydrogen atom or a hydrocarbon residue which may be substituted. A represents a methoxy group. A represents an optionally substituted imidazo-l-uyl group forming a condensed ring at the 2,3-position or the 3, -position, and n represents 0 or 1.] A septum compound or a physiologically acceptable salt or ester thereof. ·,

 2.) General

COO © [wherein, R ₄ is a hydrogen atom or a methoxy group. A is an optionally substituted imidazole-1-yl group that forms a condensed ring at the 2,3-position or the 3,4-position And η represents 0 or 1), or a salt or aesthetic thereof, and the general formula T COOH

 II

 N

 , O¾

[Wherein, represents an amino group which may be protected, R ₂ represents a hydrogen atom or a halogen atom, and R ₃ represents a hydrogen atom or an optionally substituted hydrocarbon residue]. Or its reactivity, the force that reacts with the conductor,

 (2) General formula

R5

In the formula, R s is a hydroxyl group, an acyloxy group, a force / rebamoyloxy group, or a substitution force.'A rebamoyioxy group or a Haguchigen atom, and other symbols are as defined above.] Or a compound represented by the general formula A [A represents an imidazole which forms a condensed ring at the optionally substituted 2,3-position or 3,4-position] Or make the salt

 (3) General formula

[The symbols in the formula have the same meanings as described above] or a salt or ester thereof with-胶 formula i'OH (wherein I 'represents an optionally substituted hydrocarbon residue) Reacting with the compound represented or its reactive derivative, or

 ί4) General formula

A '®

Ten

[Wherein X represents a halogen atom, and the other symbols have the same meanings as in the preceding paragraph.]〕 The compound or its salt or ester and a single-arm T i-.C (= S) NH ₂ [Where R i has the same meaning as in the previous fS].

 After L5, if necessary; general formula that changes the removal of Zugo Haruka

Ceph Wemu compound [the symbols in the formula are as defined above] represented by or preparation of a physiologically acceptable salt or ester _c

3. — 1¾ formula 0 ®

[Wherein, R i is an amino group which may be protected, R ₂ is a hydrogen atom or a halogen atom, and R ₃ is a hydrogen atom or an optionally substituted char! And R 4 is a J element atom or methoxy. A is an optionally substituted imidazole-1 -yl group forming a condensed ring at the 2,3-position or the 3,4-position. And n represents 0 or 1], or a pharmaceutical composition comprising at least one physiologically acceptable salt or estenole thereof.