WO1986000071A1 - Cephem compounds - Google Patents

Abstract

Novel cephem compounds represented by general formula (I), wherein R1 represents an optionally protected amino group, R2 represents hydrogen or halogen, R3 represents hydrogen or an optionally substituted hydrocarbon residue, R4 represents hydrogen or methoxy, A represents an optionally substituted thiazol-3-yl group forming a fused ring at positions 4 and 5 and n represents 0 or 1. They possess an excellent antibacterial activity.

Description

 Specification

 Cephalic compound

 Technical field

 The present invention relates to a novel septum compound having excellent antibacterial activity, a method for producing the same, and a pharmaceutical composition. Background technology

 Conventionally, a quaternary ammonium methyl group is placed at the 3-position, and a 2- (2-aminothiazo-1-yl-4-inole) -12-hydroxy (or substituted hydroxy) iminoacetamide group is placed at the 7-position. Various septum compounds or derivatives thereof have been synthesized and patent applications have been filed [for example, Japanese Patent Application Publication No.

-3 4 7 9 5, same year 5 4 — 9 2 9 6, same year 54-1 3 5 7 9 2, same year 54

-1 5 4 7 8 6, 55-1 4 9 2 9 9, 5 7-5 6 4 8 5, 5 7-1 9 8 3 9 4, 5 8-15 However, most of the quaternary ammonium groups derived from nitrogen-containing aromatic heterocycles are monocyclic pyridinyl groups or those having a substituent on the ring. Nothing is disclosed in the application specification, not to mention the synthesis of a compound having a thiazole-3-yl group forming a fused ring at the 4,5-position of the invention.

 Cefnim antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, for example, in the treatment of diseases caused by bacteria resistant to penicillin antibiotics and in the treatment of patients with penicillin sensitivity. Particularly useful. In this case, it is desirable to use a septum antibiotic that is active against both gram-positive and gram-negative bacteria. For this reason, studies on septum antibiotics having a broad antibacterial spectrum have been actively conducted.

OMPI I have been. As a result of long-term studies, the introduction of 2- (2-aminothiazol-1-ynole) -12-hydroxy (or substituted hydroxy) iminoacetamide group at the 7-position of the septum ring resulted in gram-positive bacteria and It was discovered that both gram-negative bacteria became active, leading to the development of so-called third-generation cephalosporins. At present, several third-generation cephalosporin compounds are already on the market. Another feature of these third-generation cephalosporin antibiotics is that they also show activity against the same resistant bacteria that were once experienced in penicillin, so-called cephalosporin-resistant bacteria. That is, some Escherichia coli resistant to known cephalosporins, some Citrobacter, and most indole-positive Proteus, Entero, Serothia, or Pseudomonas sp. It also exhibited antibacterial activity enough to be used clinically against classified pathogenic bacteria. Among the technical ideas of these third-generation cephalosporin-based compounds, a quaternary ammonium methyl group such as a pyridinium methyl group is located at the third position, and the above aminothiazolyloxyminoacetamide is located at the seventh position. It has been suggested that a septum compound having a class of compounds 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

[In the formula, represents an amino group which may be protected, R ₂ represents a hydrogen atom or a halogen atom, R ₃ represents a hydrogen atom or an optionally substituted hydrocarbon residue, and R ₄ represents A hydrogen atom or a methoxy group, A represents a thiazole-3-yl group which forms a condensed ring at the optionally substituted 4,5-position, and n represents 0 or 1.) The present invention relates to a physiologically acceptable salt or ester, a method for producing the same, and a pharmaceutical composition.

 The septum compound in this specification is related to “cepham” according to “The 'Journal of the American * Chemical. Society”, vol. 84, p. 3400 (1962). Is a compound having a double bond at the 3,4-position among cepham compounds.

 As described in the Background Art section, cephem compounds having a quaternary ammonium methyl group at the 3rd position and aminothiazolyloxyiminoacetamides at the 7th position have better antibacterial activity. And have a unique antibacterial spectrum. A number of 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 pyridinyl groups or on the ring. Most of them have a substituent, and none of the compounds of the present invention having a thiazole-3-yl group forming a condensed ring at the 4,5-position has been synthesized. The present inventors have succeeded in synthesizing the compounds represented by the general formula [1] having such chemical structural characteristics, and have also studied the antibacterial activity and antibacterial spectrum of those compounds. Compound (I) has a strong antibacterial activity against various bacteria, in particular, has a strong antibacterial activity against the above-mentioned cephalosporin-resistant bacteria, and exhibits a special antibacterial activity against the fungi of the genus Pseudomonas The present invention was completed by finding out the facts.

OMPI WIPO In the septum compound [I], the substituent Ri represents an optionally protected amino group, that is, an amino group or a protected amino group. (I) In the field of lactam and peptide synthesis, the protecting group for the amino group has been thoroughly studied and its protection method has already been established, and in the present invention, those known as the amino group protecting group are appropriately employed. Can be done. § Mi Bruno, for example C ₆ ~ as a protecting group for group 1 ₍₎ Ariru one Ashiru group, C i ~ ₅ Al force Roh I le group, C ₃ ~ ₅ Arukenoiru group, C ₆ ~ ₁₀ § Li one Rusuruhoniru group, (^ alkyl scan Honoré Honi Honoré group, substituted O alkoxycarbonyl group, Kanorebamoinore group, Ji Sairyoku Rubamoiru group, c ₆ ~ ₁₀ § Li Lumpur - methyl, c ₆ ~ ₁₀ § Li - Rumechi alkylene group, C ₆ ~ ₁₀ § Li - thio group, substituted silyl group, 2- (^ 8 alkoxy - carbonylation Lou 1 - methyl-1 -. etc. Eteniru group C ₆ ~ ₁₀ § reel one the Ashiru groups specifically the base Nzoiru, Examples thereof include naphthyl and phthaloyl, and these aromatic rings may be substituted with alkyl, alkoxy, halogen, nitro, etc. Specific examples of the substituted aryl-acyl group include P-toluoyl , P—tert—butinorebe Zoinore, p- main butoxy benzo I Honoré, - tert Butokishiben Zoinore, p- black port base Nzoinore, p -. Two Torobe Nzoinore Ru force s Agerare like (^ as specifically is _1-5 alkanol I le radical formyl, Asechiru, flop port Pio two Honoré, butyl Rinore, Bruno Le Rinore, Pinot port Inore, Sakunishiru, etc. Gunoreta Li Le are mentioned, these alkanol Irumoto more d ~ ₆ alkoxy, halogen, C ₆ ~ ₁₀ § Li Lumpur, C ₆ ~ ₁₀ § Li Ruokishi, C ₆ ~ ₁₀ § Li Ruchi O may be substituted and the like. substituted as the concrete is Arukanoiru group mono Kuroroasechinore, dichloro acetyl Honoré, DOO Polychloroacetinole, monobromoacetinole, monophleololoacetinole, diphnoleoloacetinole, tribenoleoloacetinole, monolide Sechinore, § cell Tasechinore, 3 - O key Examples include Sop's linole, 4-chloro- 1-3-oxox, Tyrinoles, pheninoleasetinole, p-cyclones pheninoleasetinole, phenoxyacetinole, and p-clones fenoxacetyl. c ₃ ~ ₅ The specifically Arukenoiru group Atta acryloyl, black Tonoinore, and the like maleoyl, these Arukenoiru groups may be substituted with such further C ₆ ~ ₁₀ § Li Ichiru. Specific examples of the substituted alkenoyl group include cinnamoyl. c ₆ ~ ₁₀ § Li one The Rusuruhoniru group specifically, benzene Honiru, such as naphtha Rensuruhoniru. These aromatic rings alkyl, (^ 6 alkoxy, halogen, optionally substituted with like two Toro Specific examples of the substituted arylsulfonyl group include P-to-no-rens-en-nor-honinole, p-tert-butyl-buteno-benzene-s-nor-honinole, and p-methoxy-benzene-snor-le-honinole, p-chloro. Examples of the Ct- ₁₀ alkylsulfonyl group include methanesulfonyl, ethanesulfoninole, and camphorsulfonyl. these alkylsulfonyl groups C ₆ ~ ₁₀ § Li

—, C ft ((aryloxy, halogen, etc .; substituted oxycarbonyl groups include, for example, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl) (^ To ₈ alkoxy-carbonyl groups such as bonyl and isobornyloxycarbonyl; for example, C ₆ to ₁₀ aryloxycarbonyl groups such as phenoxycarbonyl and naphthyloxycarbonyl; for example, benzylo such as C ₇ ~ ₁₂ Ararukiruokishi one carbonyl group such as Kishikaru Boniru the like.

Cl~8 alkoxy one carbonyl group further (^ 6 alkoxy, C ₂ ~ ₅ § Rukano I le, substituted Rinore, d ~ ₄ alkylsulfonyl, Bruno, androgenic, Xia Bruno -. May be substituted with such substituents Alkoxycarbonyl group Examples include methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-trimethylperylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2 ^ mouth ethoxycarbonyl, 2- Shianoetokishi force Lupo two Honoré Nadogaa (diethylene be. C ₆ ~ _{1 ()} § rie Ruo Kishi aromatic ring alkyl group and C ₇ ~ ₁₀ Ararukiruokishi one carbonyl group, (^ 6 alkoxy , Halogen, nitro, etc. Specific examples of the substituted aryloxycarbonyl group include P-methylphenoxycarbonyl, P-methoxyphenoxycanolepo, dinore, and p-alkenyl. Rolophenoxy canoleboninole, etc .; substituted. Aralkyloxycarbonyl substituted Specific examples of the group include P-methylbenzyloxycarbonyl, p-methoxybenzyloxycanolepo'binole, p-methylbenzinoleoxycanolepo'binole, and p-nitrobenzene. Ruo alkoxycarbonyl like or the like. the alkyl group is C ₆ ~ ₁₀ § Li Ichiru, may be substituted such as with halogen, specifically, base Nzuhi drill O alkoxycarbonyl of C ₇ ~ ₁₂ Ararukiruokishi one carbonyl group The substituted carbamoyl group may be substituted, and specific examples of the substituted carbamoyl group include N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethinolecanolepa ' Moinole, N-Feninolecanoleva, Moinole, N- (P-methoxyphenyl) capsulebmoyl, etc. The Tiocalbamoyl group is similarly substituted. May also be. Substituted Chiokarubamo I le groups specifically that mentioned include N- methylthio force Rubamoiru As specifically. C ₆ ~ ₁₀ § Li one Rumechiru groups benzyl, naphthyl methyl are mentioned these aromatic rings d ~ ₄ alkyl, C ₁ ~ ₆ alkoxy, halogen, nitro, etc. in may be substituted as specifically the substituted § Li Rumechiru group P -. menu Chirubenjiru, P- Methoxy Benjinore, p- black port base Njinore, p- two Toropenjinore such force 'methyl group _c also Arirumechiru groups mentioned may be substituted by another 1-2 C ₆ ~ ₁₀ Ariru group, specifically Penzhydryl and trityl are available. c ₆ to ₁₀ arylene methylene groups specifically include benzylidene and the like, and these aromatic groups may be substituted with d to ₄ alkyl, (^ 6 alkoxy, halogen, nitro, etc. . specific examples of an substituted Ari Rumechiren group p- methylbenzylidene, as is specifically p- such black hole benzylidene and the like C ₆ ~ ₁₀ § Li one thio group 0 -. two preparative port phenylene And the substituted silyl group is represented by the general formula R ₆ R ₇ R ₈ Si NH, (R ₆ R ₇ R ₈ Si) ₂ N

Others zN [; cv: _{In, R 6, 7, R 8} , 9, R 10, R 9 ', 10',

l g'Kxo 'each Re is, for example, methyl, Echiru shows a C _s ~ _i0 § Li Ichiru groups such as (^ - al Kill group or for example phenyl, such as tert- butyl, also their respective the same or different good. the Z is for example methylene, means a silyl group such as represented by showing a C ₁ ~ ₃ alkylene group such as E Ji Ren], in particular trimethylsilyl, ter t-butyldimethylsilyl,

_{- S i C CH 3) 2} CH 2 CH 2 S i C CH 3) 2 - and the like, such as. 2-C ₁ ~ ₈ Anorekokishi one carbonyl - 1 - methyl-1 - the Eteniru group (^ 8 alkoxycarbonyl As the alkoxy group for example main butoxy, et butoxy, etc. tert- butoxy and the like.

In the above-mentioned septum compound, the substituent R ₂ represents a hydrogen atom or a halogen atom. Examples of the halogen atom include fluorine, chlorine, and bromine, and chlorine is preferable.

In the above Cefm compound U], the substituent R ₃ is a hydrogen atom or a substituted Represents an optionally substituted hydrocarbon residue. Examples of hydrocarbon residues include

Cl ~ ₆ alkyl group, C ₂ ~ ₆ alkenyl group, C ₂ ~ ₆ alkynyl group, C ₃ ~ ₆ cycloalkyl group, and c ₃ ~ ₆ cycloalkenyl group, a Riwake (: ₃ alkyl group or A substituted alkyl group is preferred, and specific examples of the d- ₆ alkyl group include methyl, ethyl, n-propyl, isopropynole, n-butyltinole, isoptinole, sec-butylinole, and tert. -. off ', Ji Honoré, n- Penchinore, methyl especially the like cyclohexyl n- and the like, Echiru, n- propyl are preferred vinyl on Ushitoratai manner as C ₂ ~ ₆ alkenyl group, Arinore, Lee Sopuro Bae, cycloalkenyl, meta Li Honoré, 1, 1 Jimechirua Lil, 2-butenyl, 3-butenyl, and the like. C ₂ - ₆ Arukini Le specific examples of an group Echiniru, ₀ .C _3, and the like propargyl- ₆ consequent lower The Kill groups specifically the consequent opening propyl, cyclobutyl, cyclopentyl, cyclohexyl and the like C ₃ Specific examples of an _1-6 cycloalk Kenyir group 2 -. Shikuropuro Bae sulfonyl, 3-Shikuropurope alkenyl, 2-cyclohexylene cyclohexenyl, 3 - as, for example hydroxyl _c substituent of these hydrocarbon residues such as cyclohexenyl and the like, d ~ ₆ alkyl le group, C ₂ ~ ₆ alkenyl group, C ₂ ~ ₆ alkynyl group , C ₃ ~ ₆ consequent Roaruki group, C ₃ ~ ₆ cycloalkenyl group, C ₆ ~ ₁₀ § Li Lumpur group, C ₇ ~ ₁₂ Araruki group, a heterocyclic group, (^ 6 alkoxy group, C ₃ ~ ₆ cycloalkyl O alkoxy group, C ₆ ~ ₁₀ Ariruokishi group, C ₇ ~ ₁₂ Ararukiruokishi group, a heterocyclic Okishi group, a mercapto group, (^ 6 alkylthio group, C ₃ ~ ₆ cycloalkylthio group,

Rei_6 ~ 10 Ariruchio group 'C ₇ - ₁₂ Ararukiruchio group, a heterocyclic Chio group, amino group, _mono-d-4 alkylamine amino group, di-alkylamino group, C ₃ - ₆ cycloalkyl amino group, Cs ^^. § Li Norea amino group, C ₇ ~ ₁₂ Ararukiru amino group, a heterocyclic Amino group, cyclic amino group, azido group, two collected by filtration group, halo Gen atom, cyano group, carboxy group, (^ 8 alkoxy-carbonyl group,

C ₆ ~io Ariruokishi one carbonyl group, C ₃ - ₆ consequent Roarukiruokishi one carbonyl group, C ₇ ~ ₁₂ Ararukiruokishi one carbonyl group, C ₆ ~ ₁₀ § rie Ruashiru group, (^ _1-5 alkanol I le group, C ₃ ~ ₅ alkenoyl group, C ₆ to _{1 ()} aryloxy group, C ₂ to ₅ alkanoyloxy group, C ₃ to ₅ alkenoyloxy group, carbamoyl group, substitutional rubamoyl group, thiocarbamoyl group, substituted thiol group a carbamoyl group, a force Rubamoiruokishi group, a substituted Cal Bamoiruokishi group, Futarui Mi de group, c ₂ ~ ₅ alkano Iruami de groups, C

6-10 § Li Lumpur one Ashirua Mi de group, Karubokishia Mi cyano group 'Ci~ ₄ alkoxy one Karuboniruami amino group, C ₆ through i ₀ § Li Ruokishi one Karuboniruami amino group, c ₇ ~ ₁₂ Ararukiruokishi one carbonyl § Mino And the like. Specific examples of the substituent of the hydrocarbon residue include C ^^ alkyl groups such as methyl, ethynole, n-propynole, izpropinole, n-bu, chinole, isof, 'tinole, sec-butyl, tert-butyl. , n- pentyl, and hexyl n-, C ₂ ~ ₆ Anorekeniru group Bulle, § Rinore, Lee Sopuro Bae alkenyl, meta Lil, 1, 1 - Jimechirua Li Le, 2-butenyl, 3-butenyl, etc. , C ₂ ~ ₆ Arukini Le group Echiniru, propargyl and the like, C ₃ ~ ₆ cycloalkyl group cycloprothrin Pinore, Shikurobuchinore, cyclopentyl Honoré, Kishinore and cyclohexane, C. 3 to ₆ cycloalkenyl groups 2 - cyclo pentenyl, 3 - consequent opening pent two le, 2 - cyclohexenyl, 3 - hexenyl, and the like cycloalkyl, C ₆ ~ ₁₀ § Li Ichirumoto is phenyl, naphthyl, etc., (:. § ^^ Ararukiru group Benzyl, 1 Fuweniruechiru, 2 - Fuweninoreechiru, and naphthylene Honoré methylate Honoré, C alkoxy groups main butoxy, et butoxy, n- propoxy, i Sopuropo xylene, _n - butoxy, tert- butoxy and the like, C ₃ ~ ₆ cycloalkyl The oxy group is cyclopropyloxy, cyclohexyloxy, etc. ^ — C 6 ~ 10 Ariruokishi groups phenoxy, Nafuchiruokishi etc., C ₇ ~ ₁₂ Araru Kiruokishi group Benjiruokishi, and 2-phenylpropyl E chill O carboxymethyl, Ci e Ararukiruchio groups methylthio, Echiruchio, n- pro Piruchio, n- butylthio and the like, C ₃ ~ ₆ cycloalkylthio groups cyclopropylthio, cyclohexylthio and cyclohexane, etc. C ₆ ~ ₁₀ Ariruchio groups phenylene thioether, and C ₇ ~ ₁₂ Ararukiruchio group base Njiruchio, mono Ci alkyl Ruami Roh group Methylamino, ethylamino, n-propylamino, n-butylamino, etc., and di (^ 4 alkylamino groups are dimethylamino, diethylamino, methylethylamino, di (n-propyl) amino, di- (n-butyl) amino etc., C ₃ ~ ₆ cycloalkylamino group consequent opening Puropiruamino , Etc. Kishiruamino cyclohexane, etc. C ₆ ~ ₁₀ Ariruami amino group is Anirino, C ₇ ~ ₁₂ Ararukiruamino group Benjiruamino, and 2-off We sulfonyl E chill § amino, cyclic amino groups include pyromellitic Li Gino, Piperi Gino , Hipperazino, morpholino, 1-pyrrolinole, etc., haguchigen atom is fluorine, chlorine, bromine, iodine, etc. (^ 8 alkoxy-carbonyl group is methoxy canoleponinole, ethoxy canoleboninole, n-propoxy) Kanoreboni Honoré, Lee Seo propoxy Kano levo Nino les, n- butoxycarbonyl two Honoré, t er t-butoxide aryloxycarbonyl, and i zone Pol sulfonyl O alkoxycarbonyl, C _e ~ ₁₀ § Li Ruokishi one carboxymethyl sulfonyl group phenoxyethanol carbonyl, etc., C ₃ ~ ₆ consequent opening Arukiruokishi one carbonyl group consequent opening propyl O carboxymethyl carbonylation Honoré, consequent To and hexyl O alkoxycarbonyl, and C ₇ ~ 12 Ararukiruokishi Ichiriki Ruponiru group base Nji Ruo alkoxycarbonyl, _(6-10 § Li one Ruashi Le group base Nzoiru lid Russia yl, etc. Fueniruasechiru, C ₁ ~ ₅ Anore Kanoi Honoré groups Honore Mi Honoré, Asechinore, propionyl, Buchirinore, Bruno Le Li Honoré, pivaloyl and the like, C ₃ ~ ₅ Arukenoiru groups § click Li Royle, black Tonoi Le, maleoyl the like, and C ₆ ~ ₁₀ § Li Lumpur one Ashiruokishi group Benzoiru Okishi, C ₂ ~ ₅ Arca Noi Ruo alkoxy group § Se butoxy, propionitrile two Ruokishi, Buchiriruokishi, Bibaroiruokishi the like, C _{3 1-5} alkeno Iruokishi groups etc. § click Li Roiruokishi, substituted force Rubamoiru group N- methyl carbamoylthiopheno Honoré, N, N- dimethyl carbamoylthiopheno Honoré, N one Echirukaru Bamoinore, N one-phenylene Rukarubamoinore, pyrosulfate Li Gino Kanoreboniru, Piperidinocanolebonyl, piperazinocarbonyl, monorefulino, etc., substituted thiocarbamoyl group is N-methylthiofunctional rubamoyl, etc .; N-Ethylcarbamoylo Sheet, etc., C ₂ ~ ₅ Al force Roh Iruami de group § Se Ta Mi de, and pro Pion'ami de, and C ₆ ~ ₁₀ § Li Ichiru one Ashiruami de group base Nzuami de, d ~ ₄ alkoxy one local Bonirua Mi amino group is main butoxy carbonitrile Nino rare Mi Bruno, et Toki Shikano levo Nino rare Mi Bruno, tert- butoxy and the like carbonyl § Mi Roh, C ₆ ~ ₁₀ § Riruokishi - force Ruponirua Mi amino group is Fueno butoxycarbonyl § Mino etc., C7 _→ . The aralkyloxy-carbonylamino group represents benzyloxycanolevonylamino and the like. 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 a substituent on the substituent A. The above aralkyl group, aralkyloxy group, aralkylthio group and aralkylamino group are the aralkyl groups of the aralkyloxycarbonyl group and the aralkyloxycarbonylamino group, and the other alkyl group is another alkyl group. may be substituted by C ₆ ~ ₁₀ § Lil group, concrete the base Nzuhi Dorinore, Benzuhi Dorinoreokishi, Benzuhi Dorinorechio, Benzuhi Dorirua Mi Bruno, Benzuhi drill O propoxycarbonyl Nino les, Benzuhi drill O butoxycarbonyl And amino. These substituents are the same

OMPI Alternatively, two or more different groups may be present. More preferred of the substituted hydrocarbon residues are a hydroxyl group, a cycloalkyl group, an alkoxy group, an alkylthio group, an amino group, a halogen atom, a carboxy group, an alkoxycarbonyl group, a carbamoyl group, a cyano group, an azide group, and the like. A substituted d to ₃ alkyl group, which is specifically exemplified by cyclopropylmethyl, methoxymethinole, ethoxymethinole, 1-methoxetin ^ 1 -ethoxyquininole,

2—Hydroxishechnole, Mechinolethiomechinore, 2-Aminoethinole, Florome chinole, Difnoleolomechinore, Tri-Floromethinolle, 2-Floorochechinore, 2, 2

—Diphnoleolochinole, 2 _S 2, 2 — Triphenyloleoletyl, Chloromethinole, 2 —Chlorochinole, 2,2-Dichloronetino, 2,2,2—Trichlorechinole, 2-B ′ mouth Moetinole, 2-yo Doetinore, Canolebokshechinore, 2-Canolebokshechinore, 3—Kinoreboxypropinole, Cyanome Chinore, 1-strength sticky boxy 1 1—Mechinoreetchinoret, Methoxycanolepo ' Ninolemethinole, ethoxycanole Boninolemethinole, tert—Butoxycanoleboninolemechinole, 1-Methoxycanole Boninole-1—Methinolechinole, 1-Ethoxycarboninole 1—Methinooletinole, 1-tert-butylinolenate Echinore, 1—Benzi Norexica Norepo, Ninolay 1—Methinole Echinore, 1 Ippino Leinole Kishikanorebo Ninore 1 - Mechinoreechinore, Kanoreba 'Moi Noremechinore, 2 - include those and many others, such as horse mackerel Doechinore. Among the above-listed hydrocarbon residues, the most preferred are straight-chain (^ 3 alkyl groups such as methyl, ethyl, n-propyl and the like, 2-fluoroethyl, 2-chloropi-ethynole, and phenolic methoxy). ^, Tert-Butoxycanoleboninolemethinole, 1-hydroxynorreboxyl, 1-methynoleethyl, 1-tert-butoxycanoleboninole, 1-methinolethynole, etc., straight-chain alkyl substituted with halogen, carboxy, alkoxycarbonyl Group of the present invention having these groups as R ₃ groups

ΟΜΡΙ All have strong antibacterial activity, and particularly have an excellent bactericidal action against resistant bacteria. In this specification, all OR ₃ groups are in a syn-coordinate (Z-coordinate). In the above cefume compound [I], the substituent R ₄ represents a hydrogen atom or a methoxy group.

 Substituent A in the above-mentioned septum compound [I] represents a thiazole-3-yl group which may form a condensed ring at the 4,5-position which may be substituted. Here, the condensed ring means a form in which a thiazole ring and an alicyclic ring, a benzene ring or a 5- or 6-membered aromatic heterocyclic ring are condensed, and among them, a condensed ring with an alicyclic ring is more preferable. The condensed ring may be further condensed with another alicyclic ring, benzene ring or 5- or 6-membered aromatic heterocyclic ring. Further, ④ added to the substituent A indicates that the substituent A has a monovalent positive charge. Thiazole-3-yl group condensed with an alicyclic ring is

©

 — N S

 ,, []

fCH ₂ ) m

Where m is 2-6, preferably 3-5. As described above, the alicyclic moiety of k may be further condensed with another alicyclic ring, a benzene ring or a 5- or 6-membered aromatic heterocyclic ring. A thiazole 1-3-yl group fused to a benzene ring has the general formula

Is represented by As mentioned above, the benzene ring of A ゥ Alicyclic, it may be condensed with a benzene ring or a ^5-6-membered aromatic heterocyclic ring.

The 5- to 6-membered aromatic heterocycle means a 5- to 6-membered aromatic heterocycle having a nitrogen atom, an oxygen atom and / or a sulfur atom as a hetero atom. Therefore, the thiol-3-yl group condensed with a 5- or ^6- membered aromatic heterocyclic ring has the general formula

@

 -N S

== i CA ₃ J

-, 'B B in the formula consists of 3 to "solid carbon atoms, nitrogen atoms, oxygen atoms and / or sulfur atoms, of which the carbon atoms are bonded to one hydrogen atom or are combined with adjacent carbon atoms by another atom. for example Specifically as 5-6 membered aromatic heterocyclic ring to form a B in a ₃ to form a fused ring pyridinium Jin, pyridinium Dajin arsenide. Li Mi Jin, piperidines Rajin, 1, 2, 3 — Triazines, 1, 2, and 41 triazines, furans, thiophenes, oxazonoles, thiazos, monozores, isoxazonozoles, isothiazonozoles, pyromonozores, pyrazo'ichinoles, imidazoles, etc. and the like. a _P a on the substituent a represented by ₂ or a ₃ hydrogen atoms of one or two or more identical or different substituents may be substituted. substituted on the substituent a In some cases, the number of substituents is more preferably 1-3. . Arbitrary Hatato example, if a hydroxyl group as a substituent on such substituents A, C p ^ hydroxyalkyl group, ₍₆ alkyl group, C ₂ ~ ₆ alkenyl group, c ₂ ~ ₆ alkynyl group, c ₄ ~ ₆ alkadienyl group, c ₃ ~ ₆ cycloalkyl group, c ₃ ~ ₆ cycloalkenyl group, c ₃ ~ ₆ cycloalkyl primary alkyl group, C ₆ ~ ₁₀ § Li Lumpur group, C ₇ ~ ₁₂ Ararukiru group, a heterocyclic group, an alkoxy group, alkoxy one Ci～ ₄ alkyl group, C ₃ ~ ₆ consequent Roarukiruokishi group, c ₆ ~ ₁₀ § Riruokishi group, C ₇ ~ ₁₂ Ararukiru

ΟΜΡΙ Okishi group, a mercapto group, (^ 4 mercaptoalkyl group, a sulfo group, (^ _1-4 sulfoalkyl group, an alkylthio group, (^ _1-6 alkylthio - (^ 4 alkyl group, C ₃ - ₆ cycloalkylthio group, C ₆ ~ ₁₀ arylthio group, C

_7-12 Ararukiruchio group, an amino group, A Mi Noarukiru group, mono C

Alkylamino group, di (^ - alkylamino group, mono (^ _1-4 alkyl Rua Mi Bruno - alkyl group, a di (^ 4 Arukirua Mi Bruno - (^ 4 alkyl le group, c ₃ ~ ₆ cycloalkylamino group 'c _6-10 Ariruamino group, c ₇ ~ ₁₂ Ararukiruamino group, cyclic amino group, cyclic amino i (^ 4 alkyl, cyclic amino one C i alkylamino group, azido group, two collected by filtration group, a halogen atom, C ^^ halogeno alkyl group, Shiano group, Shiano (^ _1-4 alkyl group, a carboxy group, Karubokishi _d-4 alkyl group, ^ s alkoxy one carbonyl group, d ^ ₈ alkoxy one carbonylation Lu _Ci-4 alkyl group,

C ₆ ~ io § Li Ruokishi - carbonyl group, C ₃ ~ ₆ cycloalkyl O carboxymethyl one carbonyl group, c ₇ ~ ₁₂ Ararukiruokishi - carbonyl group, c ₆ ~ ₁₀ § rie Ruashiru group, d ~ ₅ alkanol I group, C ₂ ~ ₅ alkanol I Lumpur -. ^ 4 § alkyl group, c ₃ ~ ₅ alkeno I le group, c ₆ ~ ₁₀ § Li one Ruashiruokishi group,

C ₂ ~ ₅ Al force Roh Iruokishi group, C ₂ ~ ₅ alkanol Iruokishi - (^ 4 Al kill group, C ₃ ~ ₅ alkeno Iruokishi group, Karupamoiru group, Karupamoiru one Ci alkyl group, a substituted force Rubamoiru group, Chiokarubamoiru group, replacement Chiokarubamoiru group, force Rubamoiruokishi group, force Luba Moyle O Kishi ^ ~ ^! alkyl group, a substituted Kalpa Moyle O carboxymethyl group, Futarui Mi de group, c ₂ ~ ₅ Al force Roh Irua Mi-de-based, C st. § Li one Ruashiruami de group, Suruhona Mi de group, Karubokishia Mi amino group, d ~ ₄ alkoxy one Karuboniruami amino group, c ₆ ~ _{1 ()} § Li one Ruo Kishi carbonyl § Mi amino group, c ₇ ~ ₁₂ Ararukiruokishi one local Boniruamino group For example, d ~ ₄ hydroxy

 O PI

, AT \ 0 The radicals include hydroxymethyl, 2-hydroxyhexyl, etc. (^ «^ alkynole groups are methyl, ethyl, n-propynole, isopropynole, n-butynole, izof ', chinole, sec-butylinole, tert - off, 'Chinore, n- Penchinore, and carboxymethyl Le to n-, C ₂ ~ ₆ alkenyl groups vinyl, Ariru, Lee Sopuro Bae alkenyl, meta Rinore, 1, 1 Jime Chinorea Li Honoré, 1 Buteniru, 2- Buteninore, 3-butenyl and the like, C ₂ ~ ₆ alkynyl group Echiniru, 1 one pro pinyl, 2 one Puropieru, propargyl and the like, the C ₄ ~ ₆ Arukajie alkenyl group 1, 3 pigs Jeniru the like, C. ~ ₆ a cycloalkyl group Shikuropuro pills, sik Robuchinore, cyclopentyl Honoré, Kishinore and cyclohexane, C ₃ ~ 6 Shikuroanore Keninore group 1- cyclopent two Honoré, 2- consequent L-penteninole, 3-cyclopenteninole, 1-cyclohexeninole, 2-cyclohexeninole, 3-cyclohexeninole, 1,4-cyclohexene hexagenyl, etc., C.- ₆ cycloalkyl-. 1-6 § alkyl or cyclopentylmethyl, cyclohexylmethyl and the like cyclohexane, C ₆ ~ _{1 ()} § Li

- Le group Fuweniru, naphthyl and the like, c ₇ ~ ₁₂ § aralkyl group Baie Njiru, Fuwenechiru the like, heterocyclic group pyridylmethyl, 3-pyridyl, 4 one pyridyl, N- Okishi dough 2- Pyridyl, N-oxydoxy 3-pyridyl, N-oxydoxy 4-pyridyl, 2-pyridinyl, 3-pyridinole, one-piridininole, pipera-gininole, 2-pyrazininole, 2 —Pyrimidininole, 4-pyrimidininole, 5-pyrimidininyl, 3-pyridazinole, 4-pyridininole, 2-pyramel, 3-pyranyl, 4-pyraninole, 2-thiopyranil, 3-thiopyranyl, 4-thiopyranil , 3 H-indolone 2-yl, 3 H-indole 3 -inole, 1,2,3-thiadiazole 4-inole, 1,2,4-thiadiazole-5-yl, 1, 2, 4—Chia Asia Zone 3-I Honoré, 1, 2, 4-thiadiazole one Norre one 5- I Honoré, 1, 3, 4 Chiajiazorinore, 1, 2, 5-Chiajiazorinore, 1, 2, 3 Application Benefits 1,3,4,1-triazolyl, 1H-tetrazolinole, Ponzopiraninore, 2-furinore, 3-funinole, 2-cheinore, 3-cheninore, 2-oxinolinore, 4 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolinole, 5-thiazolinole, 3-isoxazolinole, 4-isoxazolyl, 5-isoxazolinole, 3-isothiazolinole, 4-isothiazolinole, 4-isothiazolinole, 5-Izothiazolyl, 2-pyrrolinole, 3-pyrrolinole, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinole, 4-imidazolyl, 5-imidazolinole, 3-virazolyl, 4-birazolyl 5- to 8-membered ring containing 1 to several π-atoms such as nitrogen atom (optionally oxidized), oxygen atom, sulfur atom, etc. Those having a bond to a carbon atom, d ~ ₆ alkoxy groups main butoxy, et butoxy, n- pro epoxy, Lee Sopurobokishi, n- butoxy, tert- butoxy and the like, C i ~ ₆ alkoxy one C i alkyl group Is methoxymethyl, ethoxymethyl,

2 main Tokishechiru etc., C ₃ ~ ₆ cycloalkyl O alkoxy group Shikuropuro Piruokishi, Kishiruokishi and cyclohexane, C ₆ ~ _{1 (3} § re Ruokishi groups phenoxy, Nafuchiruokishi etc., C ₇ ~ ₁₂ Ararukiruokishi group Benzinoleoxy, 1-phenylenoletinoxy, 2-phenynoleethynoleoxy, etc., d- ₄ mercaptoalkyl groups include mercaptomethyl, 2-mercaptoethyl, and d- ₄ sulfoanorekil groups are sulfometinole, 2-sulfo Alkylthio group, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, etc., ~ "alkylthio mono (^ ~ alkyl group is methylthiomethyl, 2-methylthioethyl, etc.) , carboxymethyl C ₃ ~ ₆ cycloalkylthio groups Shikuropuro Piruchio, cyclohexylene Thio and the like, a C ₆ ~ ₁₀ Ariruchio groups such as phenylene Lucio, such as C 7 ~ 12 Ararukiruchio group base Njiruchio, (^ ~ A Mi-alkyl

! O PI― ヽ Groups are aminomethyl, 2-aminoethyl, etc., monoalkylamino groups are methylamino, ethylamino, n-propylamino, n-butylamino, etc., and di (: alkylamino groups are dimethylamino, getylamino). Amino, methylethinoreamino, di- (n-propynole) amino, g- (n-butyl) amino, etc., and mono (^ to alkylamino (^ 4 alkyl groups are methylaminomethyl, ethylamino) Nomechiru, 2-(N-menu Chirua Mi Roh) Echiru, and 3- (N- main Chiruami Roh) propyl, di (^ _1-4 aralkyl Kiruami no alkyl group is N, N Jimechiruami Roh methyl, N, N- Jethylaminomethyl, 2- (N, N-dimethylamino) ethyl, 2- (N, .N-dimethylamino) ethyl, 3- (N, N-dimethylamino) pro Le etc., C ₃ ~ ₆ cycloalkyl § Mi amino group is consequent opening propyl completion Mino, and key i Ruamino cyclohexane, (: _6-10 § Li one Ruamino group Aniri Bruno, N- Mechiruaniriso the like, C ₇ '~ ₁₂ Ararukirua amino group base Njiru § Mi Bruno, 1 - off Eni Honoré ethyl Bruno rare Mi Bruno, 2 - and full We sulfonyl E Chino les amino, cyclic § amino group pyro Li Gino, Piperi Gino , Piperazino, morpholino, 1-pyrrolyl and the like, and cyclic amino d- ₄ alkyl groups are pyrrolidinomethyl, pyridinomethyl, piperazinomethyl, morpholinometinole, 2-( Monole holino) ethyl, etc., cyclic amino-d alkylamino group is pyrrolidino methylamino, piperidino methylamino, piperazinomethylamino, morpholinomemethylamino, etc., and halogen atom is Fluorine, chlorine, bromine, etc. (^ ~ ₄ noperogenoalkyl groups are monofluoromethyl, difluoromethinole, trifnorolelomethinole, 1-phnolerotechnole, 2-phnolerotechnole, monochloromethinole, dichloromethinole, trichloromethyl, trichloromethinole, trichloromethylol click Roroe Chinore, 2-click b Roechiru, Buromomechinore, etc. ® one Domechinore, Shiano -C ₁ ~ ₄ alkyl groups Shiano methyl, 2-Shianoechiru

Xy Ci-4 alkyl groups include carboxymethyl, 1-potoxyloxyethyl, 2-carboxyethyl, and the like; two Norre, i Sopu o epoxy force Noreboni ^, n-butoxide Shikano levo Nino les, tert- butoxy carbonyl, and the like Lee Seo bornyl o alkoxycarbonyl, (^ _1-8 alkoxy - carbonylation Lou _d-4 alkyl group main butoxy carbonyl-methyl, E Toki Shikarubo two Rumechinore, tert - and butoxycarbonyl methyl, and C ₆ ~ ₁₀ § rie Ruo Kishi carboxymethyl sulfonyl group off We Roh alkoxycarbonyl, C ₃ ~ ₆ cycloalkyl Anore Kino Les oxy Ichiriki Niboninore groups consequent opening pro Pinot Les oxy Kano les Boni Honoré, hexyl O alkoxycarbonyl cyclohexane and the like, C ₇ ~ ₁₂ § La Rukiruokishi and one carbonyl group base Nji Ruo alkoxycarbonyl, C ₆ ~ ₁₀ § Li one Lou Ashiru group base Nzoi Le, lid B A Honoré, Fueniruasechiru the like,

Anorekanoi Norre group Honoremi Honoré, Asechinore, propionitrile two Honoré, flop, Ji Rinore, Nono Les Lil, pivaloyl and the like, C ₂ ~ ₅ alkanol I le primary alkyl groups § Sechirumechiru, 1 Asechiruechiru, 2 Asechiruechiru the like, C ₃ ~ 5 alkeno i le groups § click Li Royle, black concert Inore, and Ma Reoiru, and C. 6 to ₁₀ § Li Lumpur one Ashiruokishi group Benzoiruokishi, C ₂ ~ ₅ § Rukano Lee Noreokishi group § Seto carboxymethyl, pro Pioniruokishi, butyryl Okishi, Bibaroiruokishi the like, C ₂ ~ ₅ alkanol Iruokishi one (^ 4 alkyl groups § Se Tokishimechiru, 1 § Se Tokishechiru, 2 Asetoki Shechiru etc., c ₃ ~ ₅ alkeno Iruokishi groups of etc. § click re Roiruokishi force Rubamoiru C ₁ ~ ₄ alkyl groups force Rubamoirumechi And substituted carpamoyl groups include N-methylcarbamoinole, N, N-dimethynole, N-ethylamine, N-ethynolecanolebamoine, N, N-Jetinolecanolenomore Norekanorepa 'Moinore, Piperi Gino Canoleboninole, Piperazino Canolevo

O PI Quinolone, mo ^ / holinocarbonyl, etc., canolebamoinoleoxy-C i ^!

And N- methylthio force Rubamoiru, substituted force Rubamoiruokishi group N- methyl carbamoylthiopheno Honoré O carboxymethyl, N, N one Jimechinore force Luba Moi Honoré O carboxymethyl, etc. N-E Ji carbamoyl O carboxymethyl, C ₂ ~ ₅ Arukanoirua Mi de group § Se Toami de, etc. Puropion'a Mi de, C ₆ ~ and ₁₀ § Li one Ruashiruami de group base Nzuami de, d ~ ₄ alkoxy Ichiriki Ruponiruamino groups main Toki Shikano repo Nino rare Mi Bruno, et Toki Shikano repo Nino rare Mi Bruno, t er t-butoxy Shikarubonirua Mi Roh etc., C _fi ~ ₁₀ § Riruokishi one Karuboniruami Roh group and phenoxyethanol carbonyl § Mi Roh, C ₇ ~ ₁₂ Ararukiruokishi Ichiriki Ruponiruamino group Represents benzyloxycarbonylamino and the like. Or above C ₇ ~ ₁₂ Ararukiru group, C ₇ ~ ₁₂ Ararukiruokishi group, C ₇ ~ ₁₂ § la alkylthio group, C ₇ ~ ₁₂ Ararukiruamino group, C ₇ ~ ₁₂ Ararukiruokishi - carbonyl group and C ₇ ~ ₁₂ Ararukiruokishi one carbonyl alkyl group constituting the Ararukiru group such as amino groups may be substituted with one more C ₆ ~ ₁₀ Ariru group, specifically base Nzuhi drill, Benzuhi de Riruo alkoxy, Benzuhi Dorinorechio, Penn, human Dorinorea mino, benzhydrinoreoxycarbonyl, benz, and hydroxylaminolevino are also listed. : For example, when At in the substituent A is specifically expressed,

And so on. The specific formula of Α ₂ among the substituents た と え ば is, for example,

For example

And so on. Of these Ai, A2 and A _s preferred 'ones is the

CMPI As expected

Yeah

In the above formula AA ^ Ag and the groups specifically mentioned, the positive charge of the substituent A® was applied to the nitrogen atom of the thiazole ring for convenience, but if it contains other nitrogen atoms, the positive charge is applied to the nitrogen atom. Sometimes. In some cases, the monovalent positive charge is delocalized in the thiazole ring, and in A ₂ and A ₃ , it is delocalized in the entire condensed ring. So, for example,

In the case of

N s

It is also expressed as. The location of this positive charge is a compound! : I] because it changes fluidly depending on the state (: solid or in solution :), the type of solvent, liquidity, temperature, and the type of substituent. It includes all cases of localization and cases of delocalization throughout the thiazole or fused ring.

 In the Ceph compound [I], π represents 0 or 1. In addition, に added to the carboxyl substituent at the 4-position (—COO) indicates that the carboxyl group is a carboxylic acid anion, which forms a pair with the positive charge on the substituent A to form an inner salt. Is shown. On the other hand, the compound [I] may be a physiologically acceptable salt or ester. Physiologically acceptable

O PI Salts include inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, organic acid addition salts, and basic amino salts. Inorganic bases that can form inorganic base salts include alkali metal (eg, sodium, potassium, etc.) and alkaline earth metals (eg, calcium, etc.), and organic bases that can form organic base salts. Bases include, for example, proforce, 2-phenylphenylbenzinoleamine, dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, polyhydroxyquinamine, N —Inorganic acids that can form inorganic acid addition salts such as methylglucosamine are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids that can form organic acid addition salts are, for example, P— Toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, etc. Made, for example lysine and Amino acids can not, arginine, Ol two Chin, and histidine. The ester derivative of compound [I] means an ester that can be produced by esterifying a carboxy group contained in the molecule, and is a nontoxic ester that can be used as a metabolically unstable ester during synthesis. . C ₁ ~ ₄ alkyl esters as available ester as a synthetic intermediate, C ₂ ~ ₄ alkenyl esters, C ₃ ~ ₆ cycloalkyl esters,

( ₃ to ₆ cycloalkyl-C ^ A alkyl esters, C ₆ to ₁₀ aryl esters, C ₇ to ₁₂ aralkyl esters, substituted silyl esters, etc., which may be further substituted . (^ - _{4-methyl-specifically} as alkyl to form an alkyl ester, Echiru, n - propyl, n- heptyl, tert - butyl, etc., and a § alkenyl to form a C ₂ - ₄ alkenyl ester Specifically, vinyl, aryl, isopropenyl, and the like are specific examples of cycloalkyls that form Cs-6 cycloalkyl esters.

O PI To or consequent opening, cyclobutyl, consequent opening pentyl, and alkoxy Le to consequent opening, C ₃ to 6 consequent opening alkyl one C I～4 specifically, cyclopropylmethyl and the alkyl to form a alkyl ester specific the like Kinrume chill to consequent b, phenyl, etc. More specifically as § Li Ichiru forming a c ₆ ~ ₁₀ § Li one glycol ester, as Araruki Le to form a C ₇ ~ ₁₂ § Lal kill ester Specifically, they represent benzyl, phenethyl, etc., and specific examples of the substituted silyl that forms the substituted silyl ester are tri-J'methylnyl and tert-butyldimethylsilyl. The § Lal alkyl constituting Kill ester may be substituted by another ^1-2 amino C ₆ ~ 1 _((§ Li Lumpur, in particular base Nzuhi drill glycol ester, etc. Application Benefits Chiruesuteru is mentioned As metabolically unstable non-toxic esters, those already established in the fields of penicilliso and cephalosporin can be conveniently used in the present invention. Examples of the ester include Ci- ₅ alkanoyloxymethyl ester, Ci- ₅ alkanoyloxyshethyl ester, alkoxy — (^ 4 alkyl ester,

^C L～6 alkylthio one such A alkyl ester are exemplified, specifically {Nima § Seto carboxymethyl methylate Honoré ester, 1 - § Se Bok key shell chill Este Honoré, 1 one § Se Bok carboxybutyl ester, 2- § Se Methoxyshester, vivalloyoxymethylester, methoxymethylester, ethoxymethylester, isopropoxymethylester, 1-methoxylester, 1-quinquinethylester, methylthiome Chilster, ethylthio methyl ester and the like. 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,

Ο ΡΙ It can be used for the prevention and treatment of various diseases caused by pathogenic bacteria in animals, such as respiratory tract infections and urinary tract infections. The characteristics of the antibacterial vector of the compound [I] are as follows.

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

 (2) It has high activity against Gram-positive bacteria (for example, Staphylococcus aureus, Corynebacterium diphtheriae, etc.).

 (3; shows a significant 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, Serratia, Proteus).

In particular, for amino acids belonging to the genus Pseudomonas, amino acids such as amican and gentamicin have been used in the past. 'J Cosid antibiotics have been used; compound [I] is comparable to these amino glycosides. In addition to exhibiting antibacterial activity, it has significant advantages because it has significantly lower toxicity to humans and animals than aminoglycosides. Compound [I] is also characterized by a longer duration of effect than conventional third-generation cephalosporin antibiotics.

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

 (1) — General formula

(H)

OMPI [The symbols in the formula are the same as defined above, and the compound represented by J or a salt or ester thereof and a general formula

[I]

\ OR ₃

 [The symbols in the formula are as defined above] or a reactive derivative thereof,

 (2) General formula

N (IV)

[Wherein, R ₅ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted rubamoyloxy group or a halogen atom, and the other symbols have the same meanings as described above]; [^ Represents a thiazole that forms a condensed ring at the optionally substituted 4,5-position] or a salt thereof

 (3) General formula

[V] A ©

[The symbols in the formula have the same meanings as described above] or a salt or ester thereof and a general formula R ₃ ′ OH [wherein, R ₃ ′ represents an optionally substituted hydrocarbon residue] Or a reactive derivative thereof The force to react with or

 (4) General formula

XCH ₂ C 0 [VI]

[Wherein X is a halogen atom, and other symbols are as defined above] or a salt or ester thereof and a general formula ^ cc ^ s)

Compound [I] can be produced by applying a force V to react with a compound represented by NH ₂ [wherein Hi has the same meaning as described above], and then removing the protecting group if necessary. The production methods (1) to (4), the method for removing the protecting group, and the method for purifying the compound [I] will be sequentially described.

 Manufacturing method (1): '

H ₂ Α Θ- CI)

In this method, the 7-amino compound [Π] is acylated with a carboxylic acid [I] or a reactive derivative thereof. In this method, the carboxylic acid [] is free or a salt or a reactive derivative thereof is used as an acylating agent for the ^7- amino group of the ^7- amino compound [II]. Inorganic salts, organic salts, acid halides, acid azides, acid anhydrides, mixed acid anhydrides, active amides, active esters, active thioesters of the free acid [I] or free acid [H].

 OMPI

wipo And a reactive derivative such as thiol is subjected to the acylation reaction. Examples of inorganic salts include alkali metal salts (eg, sodium salts and potassium salts) and alkaline earth metal salts (eg, calcium salts). Examples of organic salts include trimethylamine salts and triethylamine salts. Examples of acid halides such as mine salts, tert-butyldimethylamine salts, dibenzylmethylamine salts, benzyldimethylamine salts, N, N-dimethylethylaniline salts, pyridin salts, quinoline salts, and the like. Mixed acid anhydrides such as acid gloide and acid σ-mide are mixed acid anhydrides of mono C 〖to ₄ alkyl carbonic acid (for example, free acid [I] and monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monosodium carbonate). Isobutyl carbonate, mono tert-butyl carbonate, monobenzyl carbonate, mono (ρ-nitrobenzyl): carbonate, monoaryl carbonate, etc. Mixed acid anhydrides), <^ ~ 6 aliphatic carboxylic acid mixed acid anhydrides (eg, free acid [I] and acetic acid, trichloroacetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isoic acid) valeric acid, pivalic acid, Bok Li Furuo σ acetate, Bok Li click every mouth acetic, mixed acid anhydride with etc. § Se Bok acetate), C ₇ through i 1 aromatic carboxylic acid mixed acid anhydride (for example free Acids [M and benzoic acid, mixed anhydrides of P-toluic acid, P-chloro succinic benzoic acid, etc.], and organic sulfonic acid mixed anhydrides (for example, methane snolefonic acid, ethanesulfonic acid, benzenes Examples of active amides include amides with nitrogen-containing complex compounds (eg, free acid [II] and pyrazolyl, imidazolone).

- le, in acid § Mi de and the like benzo Bok Riazor, these nitrogen-containing heterocyclic compound C 1 ~ ₄ alkyl, C 1 ~ ₆ Arukokishi, halogen atom, O Kiso, Chiokiso, C. 1 to 6 alkylthio, etc. May be replaced by :). All active esters used for this purpose in the field of ^ -lactam and peptide synthesis can be used as active esters. Phosphoric acid esters (for example, jet xylinic acid ester, diphenyloxylinic acid ester, etc.); p-dinitrophenyl ester, 2,4-dinitropropyl-toluene ester, cyanometyl ester, pentachlorofluoroethanol Nore ester, N-hydroxyl ester, succinimide ester, N-hydroxybutanolamide, 1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazole ester, 1-hydroxyl ester Examples include 1H-2-pyridone esters. Active f raw Chioesuteru aromatic heterocyclic esters of a thiol compound (e.g. 2-pyridyl Jiruchio one Noreesuteru is 2 - like base emission zone thiazolyl thiol ester, these heterocyclic rings is C 1 ~ ₄ alkyl, C t ~ ₆ alkoxy, Bruno, androgenic atom, may be substituted, etc. C 1 - 6 alkylthio) are mentioned.

On the other hand, the 7-amino compound [II] is used as its salt or ester as it is. Examples of the salt of the compound [n] include inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, and organic acid addition salts. Alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, etc.) are examples of inorganic base salts. Salts, triethylamine salts, tert-butyldimethylamine salts, dibenzylmethylamine salts, benzyldimethylamine salts, N-dimethylaniline salts, pyridine salts, quinoline salts, etc., and inorganic acid addition salts. For example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., and organic acid addition salts such as formate, acetate, trifluoroacetate, methanesulfonate, p-toluene Sulfonates, etc. As the ester of compound [〔], the ester already described as the ester derivative of compound [I] is used here as it is. Galley is. That is C 1 ~ ₄ alkyl esters, C ₂ ~ ₄ alkenyl Este Le, C ₃ ~ ₆ cycloalkyl esters, C ₃ ~ 6 cycloalkyl one CI ~ ₄ alkyl esters, C ₆ ~ 〖0 § Li Ruesuteru, C ₇ ~ i ₂ Araruki glycol ester, C i ~ ₅ alkanol I Ruokishime Chiruesuteru, C i ~ ₅ 7 Rukano i Ruo key shell chill esters and their further hydroxyl, C i to ₆ alkoxy group, a halogen atom, two collected by filtration group, Shiano group, main mercapto groups, C alkylthio group, Okiso group, etc. Chiokiso group Examples include those that have been replaced. Raw material [11]. The salts and esters thereof, and the raw material [I and its reactive derivatives] can be easily produced by a known method or a method analogous thereto. The reactive derivative of compound [I] can be reacted as a substance isolated from the reaction mixture, or the reaction mixture containing the reactive derivative of compound [II] before isolation can be directly reacted with compound [Π]. it can. When the carboxylic acid [I] is used in the form of a free acid or salt, use an appropriate condensing agent. Examples of the condensing agent include ,, Ν'-disubstituted carbodiimides such as N, Γ ^ -dicyclohexylcarboimide, and た と え ば, Ν'-carbonyldiimidazole, Ν, Ν'-thiocarbodiimide. Dehydrating agents such as azolides, such as ruzimidazole, for example, methoxy-carbonyl-1,2-diethoxy-1,2-dihydroxyquinoline, oxychlorideline, and alkoxyacetylene, for example, 2 2-Halogeno-vinylidene salts such as —co-lipidindium methyl iodide, and 2—fluorinidine methyl 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 performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include ethers such as dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisof "piru-tel, ethylene glycol-1-dimethyl ether, fr

OMPI For example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate, and hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorene, and 1,2-dichloroethane, and hydrogenated hydrocarbons such as n — ^ 'Hexanes, benzene, hydrocarbons such as toluene, for example, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, for example, acetone, Ketones such as methylethylketone and methylisobutylketone, for example, nitriles such as acetate and propionitol, etc., as well as dimethyl sulfoxide, sulfolane and hexamethyl phosphoramido , Water or the like is used alone or as a mixed solvent. The cloudiness of the acylating agent [I] is usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound [II]. The reaction one 8 0 to 8 0 C, preferably single 4 0 to 5 0 ° C, and most preferably - [. Ir] 3 0~ 3 0 ° _c The reaction time is in the temperature range of C compounds and [n] The reaction time is usually 1 minute to 72 hours, preferably 15 minutes to 3 hours, depending on the type of solvent, the type of solvent (and the mixing ratio if a mixed solvent is used), and the reaction temperature. When an acid halide is used as a gelling 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. Examples of such a deoxidizing agent include inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, etc., for example, triethylamine, tri (II-propyl). ) Amine, tri (n-butyl) amine, cyclohexyldimethylamine, pyridine, lutidine, r-collidine, N, N-dimethylaniline, N-methylbiperidine, N-methylpyrrolidine, Tertiary amines such as N-methylmorpholine, for example, alkylene oxides such as propylene oxide and epichlorohydrin.

 Production method (2):

OMPI + A <I]

In this method, the thiazole compound ^Af is reacted with the septum compound [IV], and the compound [I] is synthesized by a nucleophilic substitution reaction. In the compound [IV, R ₅ represents a hydroxyl group, an acyloxy group, a rubamoyloxy group, a substituted rubamoyloxy group or a halogen atom. Here Ashiruokishi groups optionally substituted C ₂ even though _1-5 alk Noi Ruo alkoxy group, or represents a C ₆ ~ _{1 0} Ariru one Ashiruokishi group, as optionally substituted C ₂ even though _1-5 alk Noi Ruo alkoxy group, Are concretely acetoxy, chloroacetoxy, fluoryloxy, butyryloxy-, bivaloyloxy, 3-oxobutyryloxy, 4-chloro-3-oxobutyryloxy, 3-carboxy. Mouth Pio two Ruoki, 4 one local Boki Shiv dust Ruo carboxymethyl, 3 Etokin force such Luba moil propionyloxy Ruo kin, as in particular the optionally substituted C ₆ ~ ₁₀ Ariru one Ashiruoki group ο- force Norebo Xybenzoyloxy, 0- [ethoxycarbonylcarbamoyl) benzoyloxy, O- (ethoxy-norrebonylsnorrefamoyl) benzoinoleoxy. Specific examples of the substituted carbamoyloxy group include methylcarbamoyloxy and N, N-dimethylcarbamoyloxy. Halogen atoms include chlorine, bromine, and iodine. Compound [IV] can be used as a salt or ester as it is. As the salts and esters of the compound [IV], those given as the salts and esters of the compound [n] in the production method (1) can be applied here 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, thiazole compound AT

O PI Represents a thiazole which forms a condensed ring at the optionally substituted 4,5-position. Here, the condensed ring means a condensed form of a thiazole ring and an alicyclic ring, a benzene ring or a 5- to 6-membered aromatic heterocyclic ring. It may be condensed with a 6-membered aromatic heterocycle. The thiazole which forms a condensed ring at the 4,5 position of the optionally substituted thiazole (Α ') which forms a condensed ring at the 4,5 position may be represented by the following general formula:

 N S

• CH ₂ ) _-m

[A A thiazole compound that can be represented by any of [Α ₃ '] and is a compound !; I? ] Or with ^ ₃ with the target compound which can be synthesized when reacted with (;. Ί] Α® group before each 'Symbol of A _t group, corresponding to the A ₂ group or A was although the connexion Α'ι m, A'3 of B represents the same meanings as defined above, and a _'3 is Ai, may be condensed in the same manner as a ₂ and a _3, also i, a ₂ and It may have the same substituent as the substituent on A _{3. If} ΑΊ is specifically shown, for example,

And so on. If you show A'2 specifically,

And so on. If you show A'3 specifically, for example

And so on. The compounds are also used as salts. As a salt of compound A ',

OMPI For example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., for example, formate, acetate, trifluoroacetate, methanesulfonate, P-toluenesulfonate And organic acid addition salts. The general method for synthesizing compound A 'is known and can be easily produced by a method described in a literature or a method analogous thereto. This nucleophilic substitution reaction of compound [IV] with compound A is a well-known reaction per se, and is usually carried out in a solvent. Solvents used in this reaction include solvents such as ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, and water used in the production method). These can be applied as they are, for example, methanol, ethanol, η-propanol, and isov. Alcohols such as ronanol, ethylene glycol, and 2-methokineethanol are also used.

(2 - 1): R ₅ is Shiruokishi group, force Rubamoi Ruokishi group, when substituted Cal Bamoi Ruokishi group

A more preferred solvent is water or a mixed solvent of water and an organic solvent miscible with water, and among the organic solvents miscible with water, more preferred are acetone, methylethylketone, and acetate tritol. And so on. The amount of the agent A 'to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound [W]. The reaction is carried out in a temperature range of 10 to 100 ° C, preferably 30 to 80 ° C. The reaction time depends on the type of compound [IV] and A ', the type of solvent (mixing ratio if a mixed solvent is used), the reaction temperature, etc., and is usually 30 minutes to 5 days, preferably 1 to 5 hours. is there. The reaction is advantageously carried out at pH 2-8, preferably near neutral, ie pH 5-8. This reaction usually proceeds more easily in the presence of 2 to 30 equivalents of iodide or thiocyanate. Such salts include sodium iodide, potassium iodide, and titanium iodide. Examples include sodium ocyanate and potassium thiocyanate. The above-mentioned salts have a surface activity such as trimethylbenzylammonium bromide, triethylbenzylammonium bromide, triethylbenzylammonium bromide or the like. In some cases, the reaction can proceed smoothly by adding a grade of ammonium salt. C When C 2 -2: R ₅ is a hydroxyl group

For example, the reaction is carried out in the presence of an organic phosphorus compound according to a method described in Japanese Patent Laid-Open Publication No. 58-43979. Examples of the organic phosphorous compounds used here include 0-phenylene phosphorophthalate, ο—phenylene phosphorofluoride, methylinole 0—phenylene phosphate, ethyl 0—phenylene phosphate, and propyl 0—phenylene. Dilen phosphate, isopropyl 0 — phenylene phosphate, butyl 0 — phenylene phosphate, isobutyl 0 — phenylene phosphate, sec-butyl 0 — phenylene phosphate, σ 0-phenylene phosphate, phenyl 0-phenylene phosphate, ρ-chloro σphenyl 0—phenylene phosphate, ρ-acetyl phenyl 0—phenylene phosphate, 2-chloroethyl 0—phenylene phosphate, 2, 2, 2 — tricycloroethyl 0 — fenirenho Sulfate, ethoxycarbonylmethyl 0-phenylene phosphate, rubamoyl lmethyl 0—phenylene phosphate, 2-cyanoethyl ο—phenylene phosphate, 2—methylsulfonylechinole 0—phenylene phosphate , Benzyl ο — phenylene phosphate, 1,1-dimethyl-12-propenyl 0 — phenylene phosphate, 2-propenyl 0 — phenylene phosphate, 3 — methyl-12 — butenyl 0 — phenylene Phosphate, 2—Chenylmethyl 0—Phenylene Phosphate, 2—furfurylmethyl 0—Phenylene phosphate, bis-1 0—Phenylene pyrophosphate, 2-phenyl-1,3,2-benzodioxaphosphol-12-oxide , 2- (p-chlorophenyl) — 1,3,2—benzodioxaphosphoryl 2-oxide, 2-butyl —1,3,2-benzodioxaphosphoryl 2-oxo , 2-anilino 1,3,2-benzodioxaphosphoryl 2-oxoxide, 2-phenylthio-1,3,2, -benzodioxaphosphol 2-oxide, 2-methoxy 5-methyl-1,3,2 ^^-zodioxaphosphol-12-oxide, 2-chloro-1-5-ethoxycarbonyl-1,3 , 2—Benzodioxaphosphoruyl 2-oxoxide, 2—Methoxyl 5-ethoxyquinone 1-Ru 2-oxide, 5-Ethoxydicarboxy 2 * -Phenyl-1,3,2-benzodioxafoshol-1 2-oxide, 2,5—Dichloro mouth 1,3,2-Benzodioxaphosphol-1 2— Oxide, 4-chloro σ — 2—Methoxy 1, 3,2—Benzodioxaphosphorous 2 —Oxide, 2 —Methoxy 1—Methyl 1,3,2 — Benzodioxaphosphol-12-oxide, 2,3-naphthalenemethyl phosphate, 5,6-dimethyl-12-methyloxy 1,3,2-benzodioxaphosphol-12-oxide, 2,2—Dihydro 4,5,6,7 —Tetracro σ — 2,2,2 —Trimetric Kinichi 1,3,2—Venzodioxaphosphol, 2,2 —Dihydro-1,4,5,6,7—Tetracloth 1,2,2—Triphenoxy 1,3,2 1 ^^ Zinodioxaphosphol, 2,2 Dihydro 2,2-ethylenedioxy 2-methoxy 1,3,2-benzodioxaphosphol, 2,2-dihydro-2-benzyl-2,2-dimethoxy 1, 3,2-Benzodioxaphosphol, 2,2-Dihydro4,5—Benzo-1,2,2—Tri Methoxy-i, 3,2 -benzodioxaphosphol, 2,2-dihydro -2,2,2-triphenoxy-1,3,2-benzodioxaphospho-1 2,2—Dihydro-1,2— (0—Phenylenedioxy 1,2-phenoxy 1,3,2-Benzodioxaphosphol, 2-Chloro-1,2,2-Dihi Dro-2,2— (0—Fenylenedioxy) 1-1,3,2-Benzodioxaphosphol, 2,2-Dihydro-1-2—Methoxy-1 2,2-(0—Fue Diene dioxy) 1,1,3,2-benzodioxaphosphoryl, 2,2-dihydro-1,2,2, trik σ mouth 1,1,2, benzodioxaphosphol, 9, 1 0—Phenanthylene oximetry phosphorous, 0—Phenylene phosphorochloromid, 0—Phenylene phosphorobromidite, 0—Phenylene phosphorofluoridite , Methyl 0 — phenylene phosphite, butyl 0 — phenylene phosphite, methoxy carbonyl methyl 0 — phenylene phosphite, phenyl 0 — phenylene phosphite, p — cyclo σ (; or Ρ Ρ 2 卜Mouth) Phenyl 0—phenylene phosphite, 2—phenyl-1,3,2—benzodioxaphosphol, bis-1 0—phenylene pyrophosphite, 2-methoxy 5-methyl-1,3,2— Benzodoxaphosphol, 5-acetyl 2-phenoxy-1,3,2-benzodoxaphosphol, 9,10 1-phenanthrene phosphorochloridite, 2-cyclohexyl 4—Methyl-1,3,2-benzodioxaphosphol, 5-ethoxycarbonyl-2-phenyl-1,3,2-benzodioxaphosphol, 2—Cro 1-2 —Choxo 1, 3, 2 Benzodioxaphosphol, 2-phenoxy i 1 2-oxo- 1,3,2-benzodiazaphosphol, 2-phenoxy-1,3,2-benzobenzoxazaphosphol, 2, 3-dihydro-2-oxo-1 2-methoxy 4-, 5-dimethyl-1,3,2-dioxaphosphol, 2,2—Dihydro 2 —oxo 1 2 —Chloro 4,5 —Dimethyl 1,1,3,2 —Dioxaphosphol, 2, 2 —Dihydro 2 —Oxo 1 2 — (11-Imidazolyl) 1,4,5-Dimethyl-1,3,2-dioxaphosphol, 2,2-Dihydro-1,2,2-ethylenedioxy-12-Methoxy 4,5-Dimethyl-1,3 , 2-Dioxaphosphol, 2,2-Dihydric 1,2,2-Dimethoxy 2 -Phenoxy-1,4,5 -Dimethyl-1,3,2 -Dioxaphosphonyl, 2,2 -Dihydro 2,2,2-trimethoxy-1,4,5-dimethyl-1,3,2-dioxaphosphor, 2,2-dihydro-1,2,2,2-triphenoxy-1,4 5 — Dimethyl 1, 3, 2 — dioxaphosphol, 2, 2 — dihydro-1, 2, 2, 2 — triethoxy — 4, 5 — diphenyl-1- 1, 3, 2 — dioxaphospho 2,2—dihydro-1,2,2′-trimethoxy-1,4,5—diphenyl-1,3,2 dioxaphosphor, 2,2-dihydro-1 —Oxo-1-2-methoxy —4,5-diphenyl-1,3,2-dioxaphosphol, 2,2—dihydro σ—2,2,2—trimethoxy-1,3, 2 — dioxaphosphor, 2, 2 — dihydro-1,2,2 — trimethoxy-1 4 —phenyl-1,3,2 —dioxaphosphol, 2,2—dihydro 1,2,2—trimethyl-1-4-methyl-1,3,2-dioxaphosphol, 2,2—dihydro-1,2,2,2—trimethoxy-1 4-methyl-1 5 —Phenyl potato rubamoyl-1,3,2—Dioxaphosphol, 2,2,4,5,6,7 —Hexahydro-1,2,2,2-Trimetrine 1,3 , 2-benzodioxaphoshole, 2, 2'-oxybis 4,5-Dimethyl 2,2-dihydro 1,3,2-dioxaphosphor), 2,2'-oxybis (4,5-dimethyl-2,2-dihydro 1,3,2-Dioxaphospho One roux 2-oxide :). Solvent used in the reaction does not inhibit the reaction

Ο ΡΙ Any of the above ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles and the like are preferably used alone or as a mixed solvent. Particularly good results are obtained by using, for example, dichloromethane, acetonitrile, formamide, a mixed solvent of formamide and acetonitril, or a mixed solvent of dichloromethane and acetonitrile. Is obtained. The amounts of the nucleophile A 'and the organic phosphorus compound used are 1 to 5 mol, 1 to 10 mol, more preferably 1 to 3 mol, and 1 to 6 mol, respectively, per 1 mol of the compound [IT]. is there. 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. An organic base may be added to the reaction system. Such organic bases include, for example, triethylamine, tri (n-butyl) amine, di (n-butyl) amine, diisobutylamine, dicyclo ^ .xylamine, 2,6- Examples include amines such as lutidine, etc. The amount of the base to be added is 1 to 5 mol per 1 mol of the compound.

C 2-3: When R ₅ is a halogen atom

 Preferred solvents are the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water and the like. The amount of the nucleophile Α ′ ′ to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound [IV]. Is carried out in a temperature range of 0 to 80 ° C, preferably 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); and the nucleophilic reagent A 'itself. Dehalogenating agent

. 'PI You may work as. In this case, A is used in an amount of 2 mol or more per 1 mol of the compound []. Force halogen atom represented by R ₅ which is a chlorine, bromine, and iodine; preferably iodine. The compound [IV] in which U s is iodine can be easily produced, for example, by the method described in Japanese Patent Application Laid-Open No. 58-57390 or a method analogous thereto.

 Production method (3):.

+ R q OH ~> [f] A @

In this method, the compound [化合物] is synthesized by reacting a compound represented by the general formula Rs' OH or a reactive derivative thereof with a hydroxyimino compound [V]. It is. 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. . Us'OH is used as it is or as a reactive derivative thereof. The reactive derivative of R ₃ 'OH means a compound [a derivative of OH having a group capable of leaving with the hydrogen atom of VJ, that is, a compound represented by the general formula R ₃ ' Y. Here, the group Y released with a hydrogen atom represents a halogen atom, a sulfo group, a mono-substituted sulfonyloquine group, or the like. Halogen atoms include chlorine, bromine and iodine. Examples of the mono-substituted sulfonyloxy group include CI-4 alkylsulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and C 6-10.

ΟΜ? Ι IPO Arylsulfonyloxy group and the like. The particular addition to the reactive derivatives of the above in the case of producing C t~ 4 alkyl ethers of the compounds [V], for example Jiazometan, C. 1 to ⁴ Jiazoa glucan such Jiazoetan, for example dimethyl sulfate, di such Jechiru sulfate CI-4 alkyl sulfate is also used.

One- ^ ϋ (3-l): When using R ₃ 'OH

Compound [I] is synthesized by reacting with compound [V] using an appropriate dehydrating agent. Examples of the dehydrating agent used for such a purpose include phosphorus oxychloride, chlorodithiol chloride, dialkyl sulfonic acid dialkyl + phosphine, N, N'-dichlorohexyl hexylcarbodiimide, and the like. Preferred is azozica / diethyl benzoate triphenylphosphine. The reaction using getyl azodicarbonate + triphenylphosphine is usually carried out in an anhydrous solvent, and the above-mentioned ethers and hydrocarbons are used. Of compound (V) 1 R ₃ moles' 0H, Azojikarubon acid Echiru APPLICATION riff We two sulfo; ^ Both full fin is 1: used I. 5 mol. It takes 1 to 4 days in a temperature range of 0 to 50 ° C.

 (3-2): When using R g'Y

The reaction between R ₃ ′ Y and the compound [ν ·] 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, alcohols, and the like described in the section of the production method (1). A solvent such as water or a mixed solvent is also mentioned here. Preferably, a mixed solvent of water and a solvent miscible with water (eg, hydrated methanol / water, hydrated ethanol, hydrated acetate, 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 hydroxides such as sodium hydroxide and hydroxide hydroxide. And inorganic bases. This reaction may be carried out in a buffer solution described in section 7.5 to 8.5. The number of moles of the reagent R ₃ ′ Y and the base used is 1 to 5, 1 to 10 and preferably 1 to 3, respectively, relative to 1 mole of the starting compound [V].

O PI 1 to 5. The reaction temperature is in the range of −30 to: I 0 ° C, preferably 0 to 80 ° C. The reaction time is 10 minutes to 15 hours, preferably 30 minutes to 5 hours.

(3-3): When using C i- 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 the compound [V] in the solvent, the reaction proceeds when a solution of the diazoalnic 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 [V]. The reaction is carried out at a relatively low temperature—50 to 20 ° C., preferably—30 to 0 ° (: ぁ₍ : reaction time is 1 minute to 5 hours, preferably 10 minutes to 1 hour. is there.

(3-4): When using di C- 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 in the presence of alkali metal hydroxides such as sodium hydroxide and sodium hydroxide. The reagent is used in an amount of 0.5 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound [V]. 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.

 Production method (4):

 (0) n

CONH- "-■ ノ^S-

XCH ₂ COC "

N, CH ₂ A © + R ₁ C (= S) NH ₂ → [; T Ί

N 0

 οοοβ

OR ₃

 CI]

This method is Sefuwemu compound [; VI] and the general formula I ^ C (= S) Chi O by reacting urea or Chio urea derivatives objective compound represented by NH ₂ (I) to synthesize an -. : ヽ w 丄 ' It is a method. The compound (VI) 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 [Π] (inorganic base salt, ammonium salt, organic base salt, inorganic acid addition salt, organic acid addition salt, etc.) mentioned in the section of the production method (1) can be used. But that's true. Esters likewise preparation as beauty Honoré of [W] compounds mentioned in the section of (1) [II] ((^ _1-4 alkyl Honoré esters, C '2 - 4 Anorekeniruesu ether. 3-6 consequent Roaru Kiruesute / C, C 3 to 6 cycloalkyl mono C 1 to ₄

C s ~ 10 aryl ester, C ₇ ~ 12 aralkyl ester, 〇1 ~ 5 alkanol / oxyester / ester, Cis / lecanyl oxyshetyl ester and those further substituted by This applies here as well. The starting compound [π] has the general formula XCH ₂ CO C -CO OH

 .! 1

 '. N

, OR ₃

The symbols are as defined above.) Or a reactive derivative thereof and the symbol 7-amino compound [II] or a salt or ester thereof in the same manner as in the production method (1). It can be manufactured using a method. Compound represented by general formula XCH ₂ C 0 C-C 00 H or its reactivity

0R ₃

The conductor can be easily manufactured by a method known per se or a method analogous thereto. The reaction of compound [VI] with RiC (= 5) NH ₂ is usually performed in a solvent. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, and methyl ether; alcohols such as methanol, ethanol, n-pronanol, dimethylformamide, and dimethylformamide. Amides such as thiacetamide are used. Thiourea or its derivative

) The amount of the NH ₂ is usually 1 to 5 moles relative to compound (VI), The

'PI'. Preferably it is 1-3 mol. The reaction is carried out at a temperature in the range of 0 to 100 ° C, preferably 20 ° C. The reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours.

 In the above-mentioned production method (in the method (4), the compound [I] may be obtained as a mixture of syn [Z]-and anti [E]-isomers. The desired syn isomer is separated from the mixture. For this purpose, a method known per se or a method analogous thereto is applied, for example, a fractionation method utilizing differences in solubility, crystallinity, etc., separation by chromatography, rate of hydrolysis of an ester derivative, and the like. Separation method utilizing the difference between the two.

Protecting group removal method: As described above-in the field of lactam and peptide synthesis, protecting groups for amino groups have been well studied and the protection method has already been established. In addition, a method for removing an amino protecting group has been established in the same manner, and in the present invention, the conventional technique can be used as it is for removing the protecting group. For example, 'monoperogenoacetyl groups (chloroacetyl, bromoacetyl, etc.) are substituted by urea, and alkoxycarbonyl groups (methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.) are converted to acids (eg, hydrochloric acid, etc.). As a result, the aralkyl radical carbonyl group (benzyloxy benzoyl benzoyl, p-methynolebenzinoleoxy carbyl, p-2 trobenzinoleoxy carbonyl, etc.) is reduced by catalytic reduction, and 2,2,2-trichloroethoxy carbonyl is converted to zinc. And an acid (for example, 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-methylsulfonyleester ester (from aralkyl esters (benzyl ester, p-methoxybenzyl ester, p-dibenzyl ester, etc.) The 2,2,2,1-trichloroethyl ester can be converted to zinc (by acetic acid, for example) or by catalytic reduction (e.g., trichloroacetic acid) to give 2,2-, 2-trichloroethyl ester with zinc and an acid (such as acetic acid). Can be removed only with water.

 Purification method of compound [I]: Compound [I] produced in the reaction mixture by the various production methods detailed in (a) to (4) and, if necessary, by following the above-mentioned protective group removal method. 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 sulfoxide (π = 1) of the cefm compound [I] is obtained by an oxidation reaction of the compound [I] (n = 0). Such an oxidation reaction is a well-known reaction. Oxidizing agents suitable for the oxidation of sulfur atoms in the cefm ring include, for example, oxygen, peracids, hydroxy peroxides, hydrogen peroxide and the like. It can also be produced by mixing. The reaction is usually performed in a solvent. Solvents used in this reaction include, for example, ethers such as dioxane and tetrahydrofuran; for example, dichloromethane, chloroform, benzene, etc .; For example, organic acids such as formic acid, acetic acid, and trifluoroacetic acid, and 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 upon oxidation of a compound of the formula [I] showing n = 0, a sulfoxide having an S-configuration is mainly produced. R— and S—S / rephoxides differ in their different solubilities and chromatographies in one separation.

Police. Separated by moving speed. The above oxidation reaction for obtaining the sulfoxide may be carried out before the above-mentioned reactions (1) to (4), or may be carried out after the above-mentioned reactions (1) to (4).

 The compound [I] of the present invention can be administered parenterally or orally as injections, capsules, tablets, and granules in the same manner as known penicillins and cephalosporins. The dosage is 0.5 to 80 days per body weight of humans and animals infected with pathogenic bacteria as described above, more preferably 1-2 days divided into 3 to 4 times a day. do it. When used as an injection, the carrier is, for example, distilled water, physiological saline and the like, and is used as a capsule, powder, granule. When used as a tablet, a known pharmaceutically acceptable excipient ( For example, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (for example, starch, gum arabic, carboxymethy / recellulose, heptadroxyfif. Mouth pinorecellulose, crystalline cellulose, etc.), lubrication (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 merely examples and do not limit the present invention, and may be changed without departing from the scope of the present invention. Good.

Elution in the column chromatography of the reference example and the example was performed under observation by TLC (Thin Layer Chromatography). In TLC observation, BOF ₂₅₄ manufactured by Merck was used as the TLC plate, the solvent used as the elution solvent in the column chromatography was used as the developing solvent, and a UV detector was used as the detection method. did. The silica gel for the column is also Kieselgel 60 (230

OMPI ~ 400 mesh) was used. * Sef Adetta scan "in Pharmacia-off § Lee emissions' Chemicals, Inc. (Pharmac ic Fine Chemi cal s) is made of _c X AD -.. _Π resin is ROHM A down-de Haas Company (Rohm & Haas Co. The NMR spectrum is an XL-lOOA (lOOiz), EM390 (90MHz) or T60 (60MHz) type spectrometer using tetramethylsilane as an internal or external reference. All S values were measured in ppm.

In the mixed solvent, the numerical value shown in parentheses is the volume mixing ratio of each solvent. Represents the number in solution 100. The symbols in the reference examples and working examples have the following meanings.

 s: sink "singlet"

 d: Double stub do u b 1 e t)

 t: triplet (t r i p 1 e t)

 q: quartet

 A B q: AB type quartet

 d. d: 、, フ 'レ タ タ---"レ (

 m: Multiplet (mu 1 t i 1 e t)

 b r.: Broad (b ro a d)

 J: Coupling 1 constant

 Hz: Hertz

 : Mi 1 "i gr am"

 9: gram

 m £: Milli Reiter (mi 11 i 1 i t er)

&: Reiter (1 i t e r)

: No ^0— cent (percent)

 DMSO: dimethyl sulfoxide (dim thy 1 sul fox ide)

 CMPI

'i V / IFO. D ₂₀ : Heavy water

 BEST MODE FOR CARRYING OUT THE INVENTION

— [2 (2-Chloroacetamidothiazole-4-1yl) -1 2 (Z) -methoxyiminoacetamide] -1 3- (3-oxobutyryloxymethylin) -3-cefumo4 1-Rubonic acid.

 7 ^ —Amino 3 -— (3-oxobutyryloxymethyl) -1—3-cephemu 4—Rubonic acid 1 5 7 ^ is suspended in a mixture of 500 ml of tetrahydrofuran and 500 parts of water, and stirred. Add sodium hydrogen carbonate 1 41 ^ little by little. Then, while stirring at 5 ° C, add 2- (2-chloroacetamidothiazo-1-yl) -1- (Z) -methoxyminoacetyl chloride hydrochloride 150. ^ over 2Q minutes, Stir the reaction solution for another 1 'hour at the same temperature. After completion of the reaction, the pH is adjusted to 3.0 with 10% hydrochloric acid, and the reaction mixture is extracted twice with each 1 mixture of ethyl acetate-tetrahydrofura (1: 1). The extract is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the obtained colorless powder is washed with ethyl acetate 200 and collected to obtain the title compound 253 ^.

Elemental analysis: as C _{2 0} H 2 ₀ CIN ₅ O ₉ S ₂

 Calculated)): C, 41.85; H, 3.51; N, 12.20.

 Found ^: C. 41.39; H, 3.57; N, 11.94.

IR spectrum? ^ Α ¹ : 1780, 1740, 1700, 1655,

 1540, 1410.

NMR spectrum (d ₆ —DMSO) 3: 2.20 (3Η, s), 3.45 and 3.68 C 2H, ABq, J = l 8 Hz), 3.65 (2H, s), 3.92 (3H, s), 4.38 (2H, s), 4.79 and 5.09 (2H, ABq, J = l 3Hz), 5.18

, OM? I (lH, d, J = 5 Hz), 5.85 (lH, d. d, J = 5 Hz and 8 Hz), 7.

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

 7-[2-(2-Aminothiazole-4-yl)-1-2 (Z) -Methoxymethylnoacetoamide]-3-(3-oxobutyryloxymethyl)-3-Sef-emu-4- carboxylic acid.

 Ίβ—2— [2-('Chloroacetoamidothiazole-4-yl) -1 2 (Ζ) -Methoxyiminoacetoamide] 1 3— (3-oxobutyri / reokiseki / re) -1 3 —Sef-Emu 4 Dissolved rubonic acid 15 O in a mixed solution 500 of tetrahydrofuran mono-water (.1 · 1), then dissolved methyl dithioca / sodium levamine 5 1 Add ^ and stir at 20 ° C for 3 hours. To the reaction mixture, ethyl acetate (200) was added, the organic layer was removed, and the aqueous layer was made up to pH 4 with 10 hydrochloric acid to precipitate an oil. This is extracted with 1 ml of a mixture of tetrahydrofuran and ethyl acetate (1: 1), and the aqueous layer is further extracted with n-butanol 200π. The extract is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Ethyl acetate 20 is added to the residue and stirred, and the precipitated crystals are collected to give the title compound 90.

Elemental analysis:. _{1 8 1 9} ? ^ ₅ 0 ₈ 8 ₂

 Calculated)): C, 42.19; Η, 4.30; Ν, 13.55.

 Found (): C, 41.94; H, 4.11; N, 13.59.

IR-spectrum Honoré Les ^{cm - 1: 1770, 1710,} 1620, 1520. NMR -spectrum le _{(d 6 - DMSO): (} . 3 s) 2..20, 3.43 and 3.65 (2H = ABq, J = i 8Hz), 3.63 (2H, s), 3.86 (3H, s), 4.78 and 5.06 (2H, ABq, J = l 3Hz), 5.1 (lH, d, J = 5Hz)., 5.79 (1H, d d, J = 5Hz and 8Hz), 6.73 (1H, s), 7.17 (2H, br.), 9.56 (lH, d, J = 8Hz).

 Reference example 3

 1 β-i 2— (2-aminothiazole-14yl) -1 2 (Z) -ethoxyminoacetamide] -1 3— (3-oxobutyryloxymethyl) 1-3 —Sef Emu 4 rubonic acid.

 2- (2-aminothiazol-1-yl) -1 2 (Z) -ethoxyminoacetic acid 23 3 ^ is converted to dimethyl * lumamide 100 me, 1-hydroxybenzotriazole 1 Add 5 ^ and dicyclohexylcarbodiimide 20.6 ^ and stir at 20 ° C for 1.5 hours. After removing the insoluble matter, the liquid —amino 3 ′ — (3-year-old oxobutylyl-year-old xymethyl) 1-3—cefume 4 monocarboxylic acid 31 1 ^ and triethylamine 28 dimethyl / reforma Add to the mid 10 solution under ice-cooling. Stir the reaction solution at 20 ° C for 3 hours, add ether 50, and remove the precipitated solid. After dissolving this in water 100π, making it Ή.3.0 with 10 hydrochloric acid, extract twice with 200 each of methylethyl ketone. The extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained solid is washed with ethyl acetate to obtain the title compound 31 ^. .

IR spectrum i-cm " ¹ : 1780, 1720, 1660.

NMR-spectrum le _{(d 6 -DMSO) S: 1.30} (3H, t, J = 7.5Hz), 2.25 (3H, s), 3.45- 3.65 (4H, m), 4.20 (2H, q, J = 7.5Hz ),

4.70 and 5.10 (2H, ABq, J = l 8Hz), 5.25 (2H, d, J = 5Hz \ 5.90 (lH, d.

And 8112), 6.90 (lH, s), 7.20-

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

 Reference example 4

7 ^ — [2-(2-Aminothiazole-1-4l) -1 2 (Z) -Aryl 1- (3-oxobutyryloxymethyl) 1-3-Cef- 4

2-(2-aminothiazole 14-yl-1 2 (Z) -aryloxyminoacetic acid 13 ^ is applied to dimethylformamide 5 O ra to form 1-hydroxybenzotriazole. Add azole 8 and dicyclohexyl carbodiimide 10.3 and add 2 (stir with TC for 3 hours. After removing the insoluble matter, remove the ^ solution and add 7-amino 3-(3-oxobutyryloxymethyl) -3 —CefM-4 Add to a solution of 16 ^ rubonic acid 16 ^ and triethylamine 10 ^ in 50 ml of dimethylformamide under ice-cooling, stir the reaction mixture at 20 ° C for 3 hours, and then add 50 ml of ether. 0 was added to remove the ether layer, the resulting insolubles were dissolved in 50¾ of water, and then adjusted to pH 3.0 with 10 hydrochloric acid to obtain the crude title compound. : Dissolve in mixed solution 500 of 1) and dry with anhydrous magnesium sulfate. After treatment with activated carbon and removal of the solvent under reduced pressure, the title compound 25 ^ is obtained as an amorphous powder IR spectrum level ¾cm- ¹ : 1780, 1720, 1660, 1620.

NMR spectrum (d ₆ — DMSO) S: 2.30 (3H, s), 3.45-3.66 (4H, m), 4.64 (2H, d, J = 6Hz), 4.80-5.10 (2H, ABq, J = l 8Hz), 5.23 (2H, d, J = 9 Hz), 5.26 (2¾ (1, J = 5 Hz), 5.90 (lH, d.d, J = 5 Hz and 9 Hz), 5.90-6.20 (1 H, m), 6.80 (lH, s), 7.20—8.00 (2H, br.), 9.83 (1¾d, J = 9Hz) ₀ Reference example 5

 Ί β- [2- (2-aminothiazol-1-yl) -1 2 (Z)-(tert-butoxycarbonylmethoxy-aminoacetamide) -1 3- (3-year-old Sobutyryl oxymethyl) 1-Sephem 4 Rubinic acid.

2-(2-aminothiazole-4-yl) -1 2 (Z)-tert-butoxy Cicarboemethoximinino acid 6.0 ^ was added to dimethylformamide 20 m £ (two-sided, 1-hydroxybenzotriazole 3.5 ^ and dicyclohexyl force rubodiimid 4.4 ^ were added at 20 ° C) After removing the insoluble matter, remove the solution and remove the solution of β-mamino-3- (3-year-old oxobutyryloxymethyl) -13-cefm-4 monocarboxylic acid 6.2 ^ and triethylamine 4.0 Dimethylformamide is added to a 20 2 solution under ice-cooling, and the reaction mixture is stirred for 8 hours at 20 ° C. Ether 200 0 is added to the reaction mixture, and the ether layer is removed. When dissolved in 0 J ^ and adjusted to pH 4 with 10% hydrochloric acid, crystals precipitate, which are washed with water, washed with ethyl ether, and dried to give the title compound 10.

IR spectrum

: 1790, 1730, 1710, 1660, 1530.

NMR spectrum (d 6-DMSO) S: ? 1.50 (9H, s), 2.20 (3H, s), 3.40 -3.60 (4H, m) 4.40 (2H, s), 4.80 and 5.10 (2 ABq, J = 14Hz), 5.20 (lH, d, J = 5Hz), 5.80 (lH, d.d, J = 5Hz and 8Hz), 6.70 (lH, s), 7.20-7.80 (2H, b 9.30 (lH, d, J = 8 Hz).

O PI

f _Tb ⁰ Reference example 6

1 β-i 2— (2-aminothiazol-4-yl-2ZJ- (1-methyl-1-tert-butoxycarbonyl) ethoxyminoacetamide) 1-3-CFM-1 Rubonic acid.

2-(2-aminothiazole-4-1-yl-2--methyl-11-tert-butoxycarbonyl) ethoxyminoacetate 16 ^ dimethylformamide 30 m £ l: Then, add 1 ^ -hydroxybenzodiazole 8.0 ^ and dicyclohexylcarbodiimide 11 ^, and stir at 20 ° C for 10 hours. After removing the insoluble matter, the solution was diluted with 7 ^ -amino-3- (3-year-old oxobutyryl-x-methyl) -13-cef-emu-4 dimethylforma of sulfonic acid 16 and triethylamine 10 ^. Add the solution to the mid 50 solution under ice-cooling, and stir the reaction mixture at 2 Q ° C for 24 hours. Ether 500 was added to the reaction solution to remove the ether layer, and the residue was dissolved in water 100 ^. Then, the pH was adjusted to 4.0 with 10 hydrochloric acid. This is taken, washed with water, washed with ethyl ether, and dried to give the title compound 25. IR spectrum ¹ : 1780, 1730, 1700, 1680, 1530.

NMR spectrum (d ₆ — DMSO) δ: 1.35 (15H, s), 2.25 (3H, s), 3.40-3.60 (4H, m), 4.80-5.10 (2H, ABq, J = 1 Hz), 5.25 ( lH, d, J = 5Hz), 5.80 (lH, d. d, J "= 5Hz and 8Hz), 6.70 (lH, s), 7.20-7.80 (2H, br. \ 9.30 (1¾d, J = 8Hz) ₀ Example 1

— [2— (2-Aminothiazol 4-yl j-1 2, Petroximiaminoacetamide) -1 3— [(4,5-cyclohexenothiazolium 1—3 Nole) methyl] 1-3-Cef-14-carboxylate.

OMPI WIPO 7? — [2— (2-aminothiazole-4-yl-1 2 (Z—methoxyiminoacetoamide)] 1-3— (3-oxobutyryloxymethyl) 1-3—sef emou 4 The acid 10 ^, 4,5-cyclohexenothiazole 10 ^ and lithium 10 ^ are dissolved in 200 W of a mixture of acetonitrile and water (1: 1). Heat and stir for 1.5 hours at 70 ° C. Add 200 mL of ethyl acetate to the reaction mixture to remove the organic layer, and then apply the aqueous layer to XAD- カ ラ ム column chromatography. Elute with water, collect the fractions containing the desired product, freeze-dry the obtained solid, apply it to LH-20 column chromatography, and elute with water. The title compound 2.0 is obtained.

Elementary analysis: as _{C 2 iH 2 2 N 6 0} 5 S 3 .5Z2 H 2 O,

 Calculated values): C, 43.51; H, 4.69; N, 14.50.

 Obtained): C, 43.66; H, 4.55; N, 14.25.

IR spectrum

: 1 775, 16 75, 16 1 5, 1 540. NMR spectrum (d ₆ —DMSO—D ₂ Ο) δ: 1.70-3.00 (8Η, m),

 3.23 and 3.55 (2H, ABq, J = l 8Hz), 3.98 (3H, s), 5.20 (lH, d, J = 4.8Hz), 5.81 (lH, d, J = 4.8Hz), 6.93 (lH, s), 7.72 (lH, s),

 Using the same method as described in Example 1, — [2— (2—Aminothiazol-4-yl) -12 (Z) — (Substituted amino) acetamide] -3- ( _ 3 -oxobutyryloxymethyl)-1-cefm-4 General formula from the reaction of sulfonic acid with various thiazole derivatives

[I ']

The following compounds of Examples 2 to 9 represented by can be prepared. -Example 2.

 s

Compound [I '] _{(R 3 = -CH 2 CH 3} , Α¾ =) Elementary analysis: as _{C 2 2 H 2 4 N 6} 0 5 S 3 · 7Ζ2Η 2 0, Calcd): C, 43.20; Η, 5.11; Ν, 13.74-found): C, 43.09; Η, 4.87; Ν, 13.64.

R spectrum KBr ^-mar ¹ 770, 1620, 1530, 1385.

NMR-spectrum le _{(d 6 -DMS 0) <5} : 1.21 (3H, t, J = 7Hz), 1.47- 3.00 (8H, m), 3.13 and 3.44 (2H, ABq, J = 18Hz), 4.08 (2H, q, J = 7Hz), 5.04 (lH, d, J = 4.8Hz), 5.26

(2H, br.s, 5.661 lH, dd, J = 4.8 Hz and 8 Hz, 6.68 (lH.s, 7.14C 2H, br.s, 9.41 (lH, d, J = sHz, 10.32 lH, s. 3. to

Compound [I '] _{(R 3 = -CH 3, A} © =) Elemental analysis: C ₂ oH ₂ oN ₆ as 05 S ₃ · 3H ₂ 0, calc ^): C, 41.80; H , 4.56; N , 1.62 Found):.. C, 1.74; H, 4.20; N, 14.61 IR -spectrum Le ^{^ CTT 1: 1770, 1610,} 1530, 1340. NMR -spectrum le (d ₆ -DMSO) δ : 1.80— 2.20 (2H, m), 2.70 -3.20 (4Η, m), 3.83 (3H, s), 5.07 (lH, d, J =

4.8 Hz), 5.32 (2H, br.s), 5.60-5.80 (lH, m), 6.70 (lH, s), 7.12 (2H, br.s), 9.47 (lH, d, J = 8Hz), 10.14 Example 1 Compound [s] (R ₃ = — CH ₂ CH ₃ ,)

OMPI Elemental analysis: C ₂ iH _{2 2} N ₆ 0 ₅ S ₃ · 2H ₂₀

 Calculated (%): C, 43.92; H, 4.63; N, 14.63.

 Found (C, 44.09; H, 4.53; N, 14.37.

IR spectrum ¹ : 1770, 1620, 1530.

NM 丄 v R spectrum (d ₆ -DMSO) δ 1.21 (3Η, t, J = 7Hz), 2.70 -3.10 (2H, m), 3.70-4.40 (6H, m), 5.05 (lH, d, J = 4.8Hz), 5.31 (2H, m), 5.67 (lH, d.d, J = 4 ^ .8Hz and 8Hz), 6.68 (lH, s), 7.14 (2H, brs), 9.43 (lH, d , J = 8Hz), 10.20 (lH, s)

Ridge compound [Γ] (R ₃ =-. CH ₃ ,

Elemental analysis: C _{2 2} H _{2 4} N ₆ O ₅ S ₃ · 3H ₂ O

 Calculated value): C, 43.86; H, 5.02; N, 13.95.. Actual fee (%): C, 43.45,; H, 4.60 ;, 13.84.

IR spectrum ¹ : 1770, 1620, 1530, 1355. NMR spectrum (d6-DMSO) δι · 45-2.00 (6Η, m),

 2.60 -3.20 (4Η, m), 3.82 (3 H, s), 5.01 (IB, d, J = 4.8Hz)

5.20-5.50 (2H, m), 5.63 (1 H, d. D, = 4.8112 and 8112),

6.69 C lH, s), 7.13 C 2H, br .s), 9.44 (lH, d, J = 8Hz

10.20 (lH, s) Example ⁶ .

Compound. 'KR ₃ -one CH ₃ ,)

Elemental analysis: C _{2 2} H ₂₄ N ₆₀

As

 Calculated values): (:, 40.24; H, 5.52; N, 12.80.

Found: C, 39.87; H, 4.99; N, 12.99. IR spectrum ¹ : 1765, 1670, 1610, 1530,

 1380.

NMR-spectrum le _{(d 6 - DMSO) 5:} 1.60 - 1.98 (6H, m),

 2.60-2.90 (4H, m), 3.00 (3H, s), 3.82 (3H, s),

 4.99 (lH, d, J = 4.8Hz), 5.40-5.70C3H, m), 6.69 (1Hs), 7.1C2H, br.s), 9.47 (lH, d, J = 8Hz). Example 7.

Compound [I '] (R = -CH ₂₎

Elemental _{analysis: C 2 3 H 2 4 N} 6.

,

 Calculated values): C, 44.27; H, 5.01; N, 13.47.

 Found ^: C, 44.22; H, 4.76; N, 13.32

IR spectrum max ⁰ " ¹ ' ¹ 770, 1620, 1530, 1380,

 1340.

NMR spectrum (d ₆ -DMSO) δ: ι · 82 (4H, m), 2.84 (4H, m),

 4.46 -4.66 (2H, m), 5.03 (1H, d, J = 4.8 Hz), 5.08-6.00 (6H, m), 6.69 (lH, s), 7.14 (2H, b r. S),

 9.48 (lH, d, J = 8Hz), l0.36 (lH, s).

 Example 8. ^

Compound [1 '] (R ₃ = — C (CH ₃ ) ₂ COONa, Αθ =)

Elemental analysis: C 2 ₄ H _{2 6} N ₆ 0 ₇ S ₃ Na · 5H ₂ 0

 Calculated)): C, 39.95; H, 5.06; N, 11.65.

 Found (C, 39.91; H, 4.59; N, 11.80.

IR spectrum ^ cm- ¹ : 1770, 1600, 1530, 1400,

 1360

NMR spectrum (d ₆ -DMSO) δ: 1.2 (3Η, s), l.46 (¾ s),

ΟΜΡΙ

0- 1.40-2.00 (4H, m), 2.84 (4H, m), 5.05 (1¾d, J = 4.8 Hz), 5.16-5.48 (2H, br.), 5.60 (5.80 (lH, m), 6.71 (lii s ), 7.16 (2H, br.s), l 0.30 (lH, s).

 Example 9.

 Compound (1 '

Elemental analysis value

As

 (Calculated) C, 1.44; H, 4.74; N, 13.18.

 Found) C, 41.72; H, 4.72; N, 13.40.

 R spectrum KB-r

 max cm: 1770, 1670, 1610, 1530,

 1390, 1360.

 NMR spectrum (d6-DMSO) <5: 1.80 (4H, m), 2.83 (5 m), 3.30 (lH, ABq, J = l8Hz, 4.10-.23 (.lH, m, 4.30 -4.56 (2H, m), 4.83-5.00 (lH, m), 5.06 (lH, d, J = 4.5 Hz), 5.26 (2H, m), 5.80 (lH d .d, J = 4.5 Hz and 8 Hz ),

 6.73 (lH, s), 7.20 (2H, b r .s), 9.56 (lH, d, J = 8 Hz),

10.36 (lH, s).

 Example 1 o.

 7 ^-2-(2-aminothiazole -1 yl) -1 2 (Z-methoxyimianoacetic acid) -1 3-[(4,5-cyclohexenothiazoli リ) 3-yl) Methyl] 1- 3-FM-4.

 7?-C 2-(2-aminothiazole-4-1-2 (z-toxinimi-acetoamide)-1-3-acetoxymethyl-3-cef-emu 4 1-rubonic acid 3.0, Dissolve 4,5-cyclohexenothiazole 3.0 and lithium iodide 3.0 in a mixture of acetonitrile (1: 1) in 60π and stir at 70 ° C for 3 hours. And concentrate the residue in ethyl acetate.

ΟΜΡΙ After washing twice with 20 π, dissolve in 50 ffl of water and apply it to XAD-Π column chromatography. Elute with 20% ethanol water, collect the fractions containing the desired compound, concentrate under reduced pressure, and subject the residue to LH-20 column chromatography. The fractions containing the target compound eluted with water are collected, concentrated under reduced pressure, and the residue is lyophilized to give 0.2 S of the title compound. It was confirmed that the product was the same as the compound obtained in Example 1 and the like in the IR and NMR spectra.

 Example 11.

 7 ^ — [2— (2-Aminothiazolyl 4-yl) 1 2 [Z—Methoxyimioacetoamid] -1 3 [(4,5-Cyclohexenothiazoli-mum3—Innole) Methyl.] One 3-Sef-Emu 3-R-boxylate.

 7 ^ — [2-(-aminothiazole-41-yl) -2 [Z) -methoxyiminoacetamide] -3-hydroxymethyl-3-cefumeu 4-carboxylate 4.1 ^ Suspended in a mixture of 20 w of tonitrile and 20 冷却 of formamide, and cooled to 130 ° C, 4,5-cyclohexenothiazole 5.59 was added. Add phenylene phosphine in dichloromethane solution (2 nmolZ) 2 and stir for 2 hours. After evaporating the solvent under reduced pressure, add acetonitrile 4 to the residue and remove the solid. This is suspended in water 20 and adjusted to pH 8.0 by adding sodium hydrogen carbonate, and then subjected to XAD-III column chromatography. Elute with 20% ethanol water, collect the fractions containing the desired compound, concentrate under reduced pressure, and freeze-dry to obtain 3.5 ^ of the title compound. This product was confirmed to be the same as the compound obtained in Example 1 by the coincidence of IR and NMR spectra.

 Example 12.

OMPI

 Nozo, "^ ¾.

,. 7? — [2 — (2 —Aminothiazole-4 —Ilk 1 (Z—Methoxyiminoacetoamide) -1 3— [C 4, 5— Cyclohexenothiazolium 3 — ) Methyl] 1-3-CFM-41-carboxylate.

 — [22 (2-aminothiazole-141-yl) -1 2 [Z-methoxyiminoacetamide] 1-3-acetoxime-ethyl 3- 3-ephemone 14 Suspend in chlorophonolem 20 and add N-methyl / le-N-trimethylsilylfur / leoloacetamide 4 and stir at 20 ° C until a homogeneous solution is obtained. Then add trimethylsilyl iodide 3.3 ^ to this solution, stir at 20 ° C for 10 minutes, concentrate the reaction mixture under reduced pressure, and add 9 me of acetonitrile and 0.8 π of tetrahydrofuran to the residue. And mix for 40 minutes. Next, 5-cyclohexenothiazole 2.4

After stirring at 20 ° C for 3 hours, cool the reaction mixture under ice-cooling and add water.

 Add 1 π. The precipitated solid is collected, subjected to gel chromatography on silica gel, and eluted with a mixed solution of acetonitrile water (4: 1). The fractions containing the target compound are collected, concentrated under reduced pressure, and lyophilized to give the title compound 0.4. This product was confirmed to be the same as the compound obtained in Example 1 by the coincidence of IR and NMR spectra.

ΟΜΡΙ WIPO. ^ J

Claims

 Sought

 L. General formula

Wherein the is protected Also an amino group, an R ₂ represents a hydrogen atom or a halogen atom, R ₃ is a hydrocarbon Motozanmoto hydrogen atom or may be substituted, '; R ₄ is A hydrogen atom or a methoxy group, A represents an optionally substituted thiazole-3-yl group forming a condensed ring at the 4,5-position, and n represents 0 or 1.] Or a physiologically acceptable salt or ester thereof.

 2. (1) General formula

[Wherein, R ₄ represents a hydrogen atom or a methoxy group, A represents a thiazole-3-yl group which forms a condensed ring at the optionally substituted 4,5-position, and n represents 0 or 1 And a compound or a salt or ester thereof represented by the formula 071 1 6 4 1

OR

 Three

[In the formula, 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 a hydrocarbon residue which may be substituted.] Reacting with the compound or its reactive derivative,

 (2) General formula

[Wherein, R ₅ is a hydroxyl group, an acyl group, a carbamoyl group, a substituted rubamoyloxy group or a hapogen atom, and other symbols are as defined above] or a salt or a salt thereof. Ability to react ester with a compound represented by the general formula A '(A' represents a thiazole which forms a condensed ring at the 4,5-position which may be substituted) or a salt thereof

 (3) General formula

[The symbols in the formula are as defined above] or a salt or ester thereof and a general formula R ₃ 'OH [wherein, R ₃ ' represents an optionally substituted hydrocarbon residue] Reacting with the compound represented by or a reactive derivative thereof, or

 (4) General formula A 'Θ

Wherein X is a halogen atom, and other symbols are as defined above, or a salt or ester thereof and a general formula i ^ c -s)

The ability to react with a compound represented by NH ₂ [wherein is as defined above],

And then, if necessary, removing the protecting group.

N

[The symbols in the formula are as defined above.] Or a method for producing a physiologically acceptable salt or ester thereof.

 3. —General formula

-

[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 an optionally substituted hydrocarbon residue, and R ₄ is a hydrogen atom. An atom or a methoxy group, A represents a thiazole-3-yl group which may form a condensed ring at the optionally substituted 4,5-position, and n represents 0 or 1.] Pharmaceutical composition _c containing at least one or more salts or esters that are