WO1986006376A1 - Antibacterial compounds - Google Patents

Abstract

Novel compounds represented by general formula (I) (wherein Ro represents a nitrogen-containing heterocyclic group, an acyl group or an esterified carboxyl group, Z represents S, S$(1,4)$O, O or CH2, R4 represents hydrogen, methoxy or formamido, R13 represents hydrogen, methyl, hydroxy or halogen, and A represents an optionally substituted thiazol-3-yl group forming a fused ring at positions 4 and 5), possess an excellent antibacterial activity.

Description

 Details

 Antibacterial compound

Technical field

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

Background art

 Conventionally, a septum having a quaternary ammonium methyl group at the 3-position and a 2- (2-aminothiazole-4-yl) -12-hydroxy (or substituted hydroxy) iminoacetamide group at the 7-position Various compounds and derivatives thereof have been synthesized and patent applications have been filed [for example, Japanese Patent Application Laid-Open Publication Nos. 53-34979, 54-92296, 54-135, 1979] 9 2, 54- 1 5 4 7 8 6, 55- 1 4 9 2 8 9, 57-1 5 6 4 8 5, 57- 1 9 4 9 5 The same is true for the quaternary amphibinum methyl group at the 3-position derived from a nitrogen-containing aromatic heterocycle as a monocyclic pyridinum group or on the ring. Most of the compounds having a substituent and the compound having a thiazol-3-yl group forming a condensed ring at the 4- and 5-positions of the present invention are not only synthesized but also completely disclosed in the application specification. It made that are not.

Cefum antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, such as in the treatment of diseases caused by bacteria that are resistant to penicillin antibiotics and in the treatment of patients with penicillin susceptibility. It is particularly useful for treatment. In such a case, it is desirable to use a ceph antibiotic that is active against both gram-positive and gram-negative bacteria. For this reason, research on septum antibiotics having a broad antibacterial spectrum is active. It has been done. As a result of a long-term study, 2- (2-aminothiazo-l 4-yl) -1 2 -hydroxy (or substituted hydroxy) is located at the 7-position of the septum ring. It has been discovered that the introduction of an iminoacetamide group or a nitrogen-containing heterocyclic amino group leads to the activity of both gram-positive and gram-negative bacteria, leading to the development of so-called third-generation cephalosporin compounds. Was. At present, several third-generation cephalosporins are already on the market. Another feature of these third-generation cephalosporins is that they also show activity against the same resistant bacteria that were once experienced in Benicillin, so-called cephalosporin-resistant bacteria. In other words, some Escherichia coli bacteria resistant to known cephalosporins, some Citrobacter and most indole-positive Proteus, Enterobacter, Serratia or Pseudomonas sp. It exhibited any antibacterial activity that could be used clinically against the classified pathogenic bacteria. Among the technical ideas of these third-generation cephalosporin-based compounds, a quaternary ammonium methyl group such as a pyridinummethyl group is located at the third position, and the aminothiazolyloxyiminoacetamides are located at the seventh position. (4) It is suggested that cephem compounds having nitrogen-containing heterocycles, amino groups, etc., and their oxa and rubba compounds have superior antibacterial activity and a unique antibacterial spectrum. It has been.

Disclosure of the invention

 The present invention has the general formula

[Where R. Represents a nitrogen-containing heterocyclic group, an acyl group or an esterified carboxyl group, Z represents S, S → 0, 0 or CH ₂ , R represents a hydrogen atom, methoxy. R ¹³ is a hydrogen atom, a methyl group, a hydroxyl group or a halogen atom; A is a thiazole-3-yl group which forms a condensed ring at the 4,5-position which may be substituted; Or a physiologically acceptable salt or ester thereof, a process for producing the same, and a pharmaceutical composition. That is, the antibacterial compound of the present invention is a septum compound (Z = S, S → 0) represented by the general formula [I], an oxa compound thereof (Z = 0), and a fulva compound (Z = CH ₂ ). The septum compound in the present specification is described in “The Journal ♦ Ob'American'Chemical'Society”, Vol. 84, pp. 340 (1962). This is a group of compounds named based on “cepham”, and a sepham compound means a compound having a double bond at the 3.4-position among the cepham compounds.

As described in the background section, a septum compound having a quaternary ammonium methyl group at the 3-position and an aminothiazolyloxyminoacetamide compound such as a nitrogen-containing heterocyclic amino group at the 7-position. It has become increasingly clear that their oxa and larva bodies have even better antibacterial activity and a unique antibacterial spectrum. A large number of compounds in which the quaternary ammonium methyl 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 those on the ring. Most of the compounds of the present invention have a thiazol-3-yl group forming a condensed ring at the 4- and 5-positions, but none of them have been synthesized. The present inventors have succeeded in synthesizing the compounds represented by the general formula [I] having such chemical structural characteristics, and studied the antibacterial activity and antibacterial spectrum of those compounds. As a result, compound [I] has a strong antibacterial activity against various bacteria, in particular, has a strong antibacterial activity against the aforementioned cephalosporin-resistant bacteria, and a specific antibacterial activity against Pseudomonas spp. The present invention was completed by finding that Next in this specification The base names and symbols used are described. Unless otherwise specified, the meanings of each base name and each symbol in this specification are as follows.

 The “alkyl group” is preferably a linear or branched lower alkyl group having 1 to 6 carbon atoms (hereinafter sometimes abbreviated as “C t -s alkyl group”), for example, methyl, ethyl, n-alkyl. Examples include propyl, isopropyl, it-butyl, isoptyl, sec-butyl, tert-butyl, n-pentyl, and η-hexyl.

"Alkenyl group" is a lower alkenyl Le group (hereinafter - sometimes referred to as "C _{2 e} alkenyl group") of ~ 6 2 several linear or branched tricks like carbon are preferred, was example, if Bulle, Ariru, 1 —Probenyl, isopropenyl. 1-butenyl, 2-butenyl, 3-butenyl, methallyl, 1,1-dimethylaryl and the like.

[: Alkynyl group] is preferably a straight-chain or branched lower alkynyl group having 2 to 6 carbon atoms (hereinafter sometimes abbreviated as “C _{2 -S} alkynyl group”), for example, ethynyl, 1-Propinyl, propargyl and the like.

The "cycloalkyl group" is preferably a _{3- to} 7-membered alicyclic hydrocarbon group having 3 to 10 carbon atoms (hereinafter sometimes abbreviated as "03. cycloalkyl group"). Examples include cyclobutyl cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. "Cycloalkenyl group" 5-6 membered alicyclic hydrocarbon group (hereinafter, - sometimes referred to as "C _{5 e} cycloalkenyl group") having a double锆合preferably, For example other consequent σ pentenyl, consequent Pentagenenyl, cyclohexenyl, cyclohexenyl, and the like.

 The “aryl group” is preferably an aromatic hydrocarbon group having 6 to 10 carbon atoms (hereinafter sometimes abbreviated as “08. aryl group”), for example, phenyl, 1-naphthyl, 1-naphthyl, biphenylyl And so on.

“Aralkyl group” is an aromatic substituted alkyl group having 7 to 12 carbon atoms (hereinafter, referred to as “aralkyl group”). Also) is preferably abbreviated as - _"12 Ararukiru group 0 _7", for example, benzyl 1 -. Fuweniruechiru, 2 Fueniruechiru, Fuwenirupuropiru, naphthyl methyl and the like. Incidentally, 〇 ₇ - ₁₂ Ararukiru group and di C _beta one ₁₀ § reel-methylstyrene group below, tri 〇 ₆ - ₁₀ Ariru - together with methyl - sometimes referred to as "C _{7 13} Ararukiru group".

"Jiari one Rumechiru group" the above C _beta - ₁₀ Ariru group two substituted by methylation group (hereinafter - sometimes referred to as "di C ₈ -L § Li Ichiru methyl group.") Means a For example, benzhydryl.

"Triarylmethyl group" is the above Cs. A methyl group in which three aryl groups are substituted (hereinafter sometimes abbreviated as "tri- _{CE 0} aryl-methyl group"), such as trityl.

The aryl group of the "aryl methylene group" is the above Cs-t. Ariru group well, therefore hereafter - is sometimes abbreviated as "C _{S R} § Li Ichiru one methylene group.". C _S - The t Ariru one methylene group such as benzylidene (C ₈ H ₅ CH and the like.

 The alkyl group of the “alkoxy group” is preferably the above-mentioned C alkyl group, and thus may be referred to as “C alkoxy group” hereinafter. Examples of the alkoxy group include methoxy, ethoxy, n-propoquine, isopropoxy, n-butoxy, tert-butoxy, acyloxy, hexyloxy and the like.

Sik port alkyl group "Sik port Arukiruokishi group" 〇 ₃ above - preferably ₁₀ consequent opening alkyl group, thus hereinafter - sometimes referred to as "0 _{3 10} cycloalkyl O key sheet group". C ₃ - Hatato example, if a ₁₀ consequent σ Arukiruokishi group, cyclopropyl O alkoxy, cyclopentyloxy Ruo alkoxy, Kishiruo alkoxy, such as norbornyl O carboxymethyl and the like cyclohexylene.

§ Li Ichiru group of the "Ariruokishi group" 〇 ₆ of the above - preferred is ₁₀ Ariru based on Properly, and therefore thereafter, - also referred to as "〇 _{8 10} Ariruokishi group" there.

〇 ₆ - The ₁₀ Ariruokishi groups e.g., phenoxy, etc. Nafuchiruoki sheet and the like.

Ararukiru group "Ararukiruokishi group" C ₇ of the - preferably ₁₃ Ararukiru group, thus hereinafter - sometimes referred to as "〇 _{7 13} Ararukiruokishi group". C ₇ - ₁₃ The Ararukiruokishi group for example, Benjiruokishi, 1-safe We sulfonyl E chill O carboxymethyl, 2-full We sulfonyl E chill O carboxymethyl, naphthylmethyl Okishi, Benzuhi Doriruokin, etc. Torichiruokishi the like.

 The alkyl group of the “alkylthio group” is preferably the above-mentioned C t-e alkyl group, and thus may be referred to as “Cκ alkylthio group” hereinafter. Examples of the C t-s alkylthio group include methylthio, ethylthio, η-propylthio, η-butylthio, and the like.

The alkylthio group of the “aminoalkylthio group.” Is preferably the above-mentioned C ₆ alkylthio group, and hence may be referred to as “aminoaminoalkylthio group” hereinafter. Examples of the amino C alkylthio group include aminomethylthio, 2-aminoethylthio, and 3-aminopropylthio.

Alkenyl group "Aruke two thio group" the above C ₂ _ _beta alkenyl virtuous preferred, therefore hereafter - sometimes referred to as "C _{2 e} alkenylthio group". Examples of the C ₂ -s alkenylthio group include vinylthio, arylthio, 1-propenylthio, isoprobenzylthio and the like.

The cycloalkyl group of the “cycloalkylthio group” is C 3 described above. Shikuroa alkyl group is preferred, therefore hereafter - sometimes referred to as "〇 _{3 10} cycloalkylthio group". The Rei_3- ₁₀ cycloalkylthio group e.g., cyclo-propyl thio, etc. cyclohexylthio and the like cyclohexylene.

“The aryl group of the arylthio group is the above Cs-L. The aryl group is preferable. Therefore, subsequently, "Ji ₈ - _{1 0} § Li Ruchio group" is sometimes referred to as. Rei_8 - _{1 0} The § Riruchio group e.g., phenylene thioether is naphthylthio Nadogaa-up.

Ararukiru group "Ararukiruchio group" above Flip ₇ - sometimes referred to as - _{1 9} Ararukiru group virtuous preferred, therefore hereafter, _{"1 3} Ararukiruchio group Ji _7".

The C 7 ₃ Ararukiruchio group e.g., benzylthio, Fuwenirue Chiruchio, Benzuhi Doriruchio, such as preparative Richiruchio the like.

Alkyl group of the "mono Arukiruami amino group" means the above C 8 alkyl group good or properly, thus hereinafter - sometimes referred to as "乇No C _{t 6} alkylamino cyano group." Examples of the mono-C i- _e alkylamino group include methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, ペ ン -pentylamino, and η-hexylamino. . . Alkyl group "Jiasorekiruami amino group" is rather to preferred are C alkyl group as described above, thus hereinafter - sometimes referred to as "di C _{t 6} alkylamino cyano group." Di C _t -. The _e alkylamino amino group for example, Jimechiruami Roh, Jechiru § Mi Bruno Mechiruechiruami Bruno, di (n- propyl) § Mi Bruno and G. (.eta. heptyl) § Mi Bruno and the like.

The alkyl group of the “trialkylammonium group” is preferably the above-mentioned C alkyl group, and hence may be referred to as “tri-Calkylammonium group” hereinafter. Examples of the tri-C t -e alkylammonium group include trimethylammonium [(CH ₃ ) ₃ N ^: ④] and triethylammonium. Trialkylammonium groups are always accompanied by anions. Examples of such anions include halogen ions (chlorine ions, bromine ions, iodine ions, etc.), sulfate ions, nitrate ions, carbonate ions, and organic carboxylate ions (eg, oxalate ion, trifluor acetate ion). Etc.) Organic sulfonate ions (for example, methanesulfonate ion, benzene sulfonate ion, etc.). Organic ruboxyl ion, organic sulfonate ion, etc. may be in the molecule.

Cycloalkyl group "Sik port Arukiruamino group" C ₃ of the - preferably _{1 0} consequent ο alkyl group, thus hereinafter - also "〇 _{3 1 0} cycloalkyl amino group" and himself to be. 〇 ₃ - Hatato example, if a _{1 0} cycloalkyl § amino group, 'cyclopropyl § Mino, consequent opening Penchiruamino, etc. Kishirua amino and the like to the consequent opening.

The aryl group in the "arylamino group" is Cs-i described above. Ariru group is rather preferred, therefore thereafter, - sometimes referred to as "〇 _{8 1 0} Ariruamino group". Examples of the Ce-i0 arylamino group include anilino and N-methylanilin.

Aterukiru Tomb Γ Ararukiruamino group "above Rei_7 - _{1 9} Ararukiru group is preferred, therefore hereinafter" 〇 ₇ - sometimes referred to as _{1 3} Ararukiruamino group ". 0 ₇ - _{1 3} The Ararukiruamino group for example, Benjiruamino,

Examples include 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino, and tritylamino.

“Cyclic amino group” refers to a nitrogen-containing heterocyclic ring or a group formed by removing one hydrogen atom bonded to a ring-forming nitrogen atom, as described below, for example, 1 H— Tetrazole-11-yl, 1H-pyrroyl-11-yl, pyrrino, pyrrolidino, 1H-imidazole-11-yl, imidazolino, imidazolidino, 1H-virazol-1-1yl, villazolino, virazolidino, piperidino, piperazino And Perholino. The alkyl group of the “hydroxyalkyl group” is preferably the above-mentioned C alkyl group, and hence may be referred to as “hydroxy Cκ alkyl group” hereinafter. Hydroxy C κ alkyl groups include, for example, hydroxy Examples include cimethyl, 1-hydroxyl, 2-hydroxyl, and 3-hydroxyl pill.

 The alkyl group of the “mercaptoalkyl group” is preferably the above-mentioned C t -e alkyl group, and thus may hereinafter be referred to as “mercapto C t -e alkyl group”. Examples of the mercapto C L -e alkyl group include mercaptomethyl,

1-Mercaptoethyl, 2-mercapdoethyl and the like.

 The alkoxy group of the “alkoxyalkyl group” is preferably the above-mentioned C alkoxy group, and the alkyl group is preferably the above-mentioned C ^ -6 alkyl group.

It may be described as "C alkoxy C t- ₆ alkyl group". C t -8 alkoxy C t -s alkyl groups include, for example, methoxymethyl, ethoxymethyl,

2-Met'quichetil and the like.

The alkylthio group of the “alkylthioalkyl group” is preferably the above-mentioned C alkylthio group, and the alkyl group is preferably the above-mentioned C alkyl group. Therefore, hereinafter, it may be referred to as “C i -ealkylthio C alkyl group”. Examples of the d- ₈ alkylthio C alkyl group include methylthiomethyl,

2-methylthioethyl and the like.

The alkyl group of the “aminoalkyl group” is preferably the above-mentioned C-6 alkyl group, and thus may be referred to as “amino C alkyl group” hereinafter. Examples of the amino Ci- ₆ alkyl group include aminomethyl, 2-aminoethyl, 3-aminopropyl and the like.

 The “monoalkylaminoalkyl group” is preferably a “mono C t -ealkylamino C alkyl group”, such as methylaminomethyl, ethylaminomethyl, 2-(—- methylamino) ethyl, and 3-(— methylamino). Propyl and the like.

"Dialkylaminoalkyl group""di C i - _e alkyl amino C Al kill group" is preferably, for example, N, N-Jimechirua - Minomechiru, N, N- Getylaminomethyl, 2-CN.N-dimethylamino) ethyl, 2- (N,

N-Jetylamino) ethyl and 3- (N, N-dimethylamino) propyl.

 The cyclic amino group of the “瓖 -amino group” is preferably the above, and the alkyl group is preferably the above C t-e amino group.

It may be referred to as "cyclic amino C ₈ alkyl group". Examples of the cyclic amino C alkyl group include piperidinomethyl, piperidinomethyl, piperazinomethyl, morpholinomethyl, and 2- (morpholino) ethyl.

The cyclic amino group of the "cyclic amino alkylamino group" is preferably the above-mentioned cyclic amino Cts alkyl group, and henceforth may be referred to as "cyclic amino amino Ci- ₈ alkylamino group". Examples of the cyclic amino C ₆ alkylamino group include pyrrolidizmethylamino, piperidinomethylamino.piperazinomethylamino, perphorinomethylamino, and the like.

 The alkyl group of the “halogenoalkyl group” is preferably the above-mentioned C alkyl group, and thus may be referred to as “halogeno C alkyl group” hereinafter. Examples of the halogeno C κ alkyl group include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and 2-chloroethyl. Mouth ethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-odoethyl and the like. -

As the alkyl group of the “cyanoalkyl group”, the above-mentioned CiS alkyl group is preferable, and hence it may be referred to as “cyanoalkyl group” hereinafter. Examples of the cyano Cs alkyl group include cyanomethyl, 2-cyanoethyl. And so on.

Alkyl group of the "carboxyalkyl group" above C _te alkyl group virtuous preferred, therefore hereinafter sometimes referred to as "carboxy C te alkyl group". Examples of the carboxy C alkyl group include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and the like.

The alkyl group of the “sulfoalkyl group” is preferably the above-mentioned Ci-6 alkyl group, and thus may be referred to as “sulfoC alkyl group” hereinafter. Examples of the sulfo C alkyl group include sulfomethyl and 2-sulfoethyl.

C ₂ Al force Noiru group Γ Al force Noiruarukiru group "described below - ₆ Aruka Noiru group is preferred, since the alkyl group is correct preferred is C alkyl group as described above, hereinafter" C ₂ - _e Arukanoiru C ie alkyl group " Noiru also _c C ₂ _ _s Al force C _t be referred to as - the _e alkyl group e.g., Asechirumechiru, 1 Asechiruechiru, 2 Asechiruechiru the like.

 Alkyloxy group of "Alkyloxyalkyl group"

C ₂ - _e Arca Noi Ruo alkoxy group is preferred, since the alkyl group is C _L -e alkyl group as described above is preferred, hereinafter - sometimes referred to as "C _{2 8} § Luke Noi Ruo carboxymethyl C te al Kill group" . C ₂ - The _e alk Noi Ruo carboxymethyl C iota-beta alkyl group e.g., Asetokishimechiru, 1 over § cell Toki Chez chill, 2 § cell Tokishechiru the like.

The alkoxy group in the “alkoxy group” is described below. An alkoxy-carbon group is preferable, and an alkyl group is preferably the above-mentioned C alkyl group. Therefore, it may be referred to as “C i-iO alkoxy-carbonyl C t- ₈ alkyl group” hereinafter. C ^ alkoxy-carbon C _t -e alkyl groups include, for example, methoxycarbonylmethyl, ethoxyquincarbonylmethyl, tert-butoxycarbonylmethyl and the like. It is.

 The alkyl group of the “l-vamoylalkyl group” is preferably a Cκ alkyl group, and thus may be referred to as a “l-lvamoyl C i -S alkyl group” hereinafter. Examples of the carpamoyl C alkyl group include carbamoylmethyl.

Alkyl group C t of "force Luba moil O key Shiaru kill group" - is preferably _β alkyl group, thus hereinafter, also serial Succoth a "force Rubamoiruokishi C ₆ alkyl group". Power Rubamoiruokishi C t - The _e alkyl group such as force Luba moil O Kin methyl and the like.

 Examples of “halogen raw potato” include fluorine, chlorine, bromine, iodine, and the like.

The “alkanoyl group” is preferably an aliphatic alkyl group having 1 to 6 carbon atoms (hereinafter may be abbreviated as “^ -6 alkanoyl group”.). For example, formyl, acetyl, propionyl, butyryl, isobutyryl phenolyl, Isovaleril, Pipa 'Royl and the like. Sometimes referred to as - _"e Arukanoiru group C _2" Of this Arukanoiru groups except formyl i.

"Arukenoiru group" Arukenoiru group (hereinafter - is sometimes abbreviated as "〇 _{3 5} § Rukenoiru group") having 3 to 5 carbon atoms are preferred, e.g. Akuriroiru, click b Tonoiru and maleoyl the like.

Cycloalkyl group "Sik port alkylcarbonyl group" is the above 〇 ₃ - _{1 0} shea click σ alkyl group is preferred, therefore hereafter - sometimes referred to as "C ₃ one _{1 0} consequent opening alkyl force Ruponiru group". C3. Examples of the cycloalkyl monopropionyl group include cyclopropylcarbonyl, cyclobutylbutyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, adamantylcarbonyl and the like.

The cycloalkenyl group of the “cycloalkenylcarbonyl group” is the above-mentioned C ₅ _ s lay preferred cycloalkenyl group, hence hereinafter - sometimes referred to as "C _{5 beta} Shikuroaruke two Lou carbonyl group". C ₅ - The ₈ Shikuroaruke two Rukaru Boniru group e.g., consequent opening pent two Rukaruponiru, consequent opening pen data Genis ylcarbonyl, hexenyl ylcarbonyl to consequent opening, such Kisaje two Rukaruponiru is to consequent opening thereof.

Le group of the 〇 ₆ - - § Li in "§ Li one Rukaruponiru group" _{1 ()} § Li Lumpur group good or properly, therefore hereafter - be referred to as "〇 _{6 10} § Li one route group" There is also. 〇 ₈ - ₁₀ Ariru - as carbonyl groups for instance, Benzoiru and naphthoyl and the like.

Ararukiru group "§ Lal kill carbonyl group" is the above C ₇ - ₁₃ Ararukiru group laid preferred, therefore hereafter - sometimes referred to as "〇 _{7 13} Ararugiru one carbonyl group". 0 ₇ - ₁₉ Ararukiru An carbonyl group such as phenyl § cetyl, full We sulfonyl propionylamino, a, a- jitter Weniruasechiru ',,, -' like Li Fuweniruasechiru the like.

Here is an alkyl group of "alkoxycarbonyl group" other lower alkyl groups of 1-8 carbon atoms, the above C ₃ - ₁₀ consequent opening alkyl group _c Therefore alkoxycarbonyl alkylsulfonyl groups intended to include the hereafter, "C t _-L . Alkoxy-carbonyl group ". Examples of the C! -TO alkoxy-carbonyl group include, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl Examples include bonyl, cyclohexyloxycarbonyl, norbornyloxycarbonyl and the like.

§ Li one Ruokishi group "§ reel O alkoxycarbonyl group" 〇 ₈ above - lay preferred ₁₀ § Riruokishi group, thus hereinafter "C _S one ₁₀ Ariruokishi - carbonyl group" is sometimes referred to as. Cs-i. Aryloxy-carbonyl Examples of the group include phenoxycarbonyl.naphthyloxycarbonyl and the like.

The aralkyloxy group of the "aralkyloxycarbonyl group" is preferably a c-m- ₁₃ aralkyloxy group, for example, benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl and the like.

The “substituted oxycarbonyl group” is the above c L- ₁₀ alkoxy monocarbonyl group, C 1. § Li one Ruokishi - refers to carboxymethyl sulfonyl group, or c ₇ _ _{1 9} Ararukiruokishi Ichiriki Ruponiru group.

Alkylthio group "alkylthiocarbonyl group" is preferably C alkyl thio group mentioned above, hence hereinafter - sometimes referred to as _"6 alkylthio one carbonyl group". Examples of the C alkylthio monocarbonyl group include methylthiocarbonyl, ethylthiocarbonyl, I-propylthiocarbonyl, η-butylthiocarbonyl and the like.

As the alkyl group of the "alkoxy group", the above-mentioned C8 alkyl group is preferable, and hence it may be referred to as "C i -e alkyl group" hereinafter. C _t - The _β alk Noi Ruo alkoxy group e.g., Horumiruo Kin, Asetokishi, propionyl Ruo Kin, Buchiriruokishi, Bareriruokishi, etc. Bibaroiruokishi the like. Of this Arca Noi Ruo alkoxy group except for Horumiruokishi - Ru "C _{2 6} § Luke Noi Ruo alkoxy group" and that referred mower.

Arukenoiru group "alkenyl Noi Ruo alkoxy group" C ₃ of the - preferably ₅ Arukenoi group, thus hereinafter - sometimes referred to as "〇 _{3 5} § Luque Noi Ruo alkoxy group". Examples of the C ₃ -5alkenoyloxy group include acryloyloxy, crotonyloxy and the like. .

The alkyl group of the “monoalkyl group” is the above C alkyl Groups are therefore preferred, and may henceforth be referred to as "mono-Ct- _s- alkyl-rubamoyl groups". Examples of the mono-C alkyl radical group include monomethylcarbamoyl.N-ethylcarbamoyl and the like.

The alkyl group of the “dialkyl rubamoyl group” is preferably the above-mentioned C alkyl group, and thus may hereinafter be referred to as “dialkyl rubamoyl group”. The di C _t _ _e alkyl force Rubamoiru group e.g.,, N -. Dimethylcarbamoyl Ν, Ν- like GETS Chi carbamoyl is Ru mentioned. .

The monoalkyl radicals of the "monoalkyl radicals" are preferably the above-mentioned mono-C ₆ -alkylcarbamoyl groups, and henceforth may also be referred to as "mono-alkyl radicals". Examples of the mono C- ₆ alkyl rubamoyloxy group include N-methylcarbamoyloxy, N-ethylcarbamoyloxy and the like. The dialkyl rubamoyl group of the “dialkyl rubamoyloxy group” is preferably the di-C alkyl rubamoyl group described above, and henceforth may be referred to as “di-C alkyl rubamoyloxy group”. Examples of the di-C alkylcarbazyloxy group include Ν, —dimethylcarbamoyloxy, Ν, Ν, ジ ェ -ethyl carbamoyloxy and the like.

The alkyl group of the “alkylsulfonyl group” is preferably the above-mentioned C t -e alkyl group, and thus may be hereinafter referred to as “C alkyl-sulfonyl group”. Examples of the C t _-S alkylsulfonyl group include methanesulfonyl, ethanesulfonyl and the like.

The aryl group of the "arylsulfonyl group" is CS-i described above. § Li Ichiru group virtuous preferred, therefore hereafter - Ru mower, referred to as the "C _{e 1 0} 7 Li one Rusuruhoniru group". Examples of the CB- ₁₀ arylsulfonyl group include benzenesulfonyl. Ararukiru group "§ Lal Kill sulfonyl group" 0 ₇ above - preferably _{1 3} Ararukiru group, thus hereinafter - is a "0 _{7 1 3} § Lal kills sulfonyl group" is also serial Succoth. 0 ₇ - _{1 3} The § Lal Kill sulfonyl group e.g., Fe methane sulfonyl, such as diphenyl We methane sulfonyl and the like. The alkylsulfonyl group of the “alkylsulfonyloxy group” is preferably the above-mentioned CI-βalkylsulfonyl group, and thus may hereinafter be referred to as a “C alkylsulfonyloxy group”. Examples of the C i -e alkylsulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy and the like.

§ Li one Rusuruhoniru groups above C ₈ of "§ Li one Le sulfonyl O alkoxy group" -

_{1 0} § Li one Rusuruhoniru group is preferred, therefore hereafter - sometimes referred to as "〇 _{6 1 0} Ariru Suruhoniruokishi group". G. Examples of the arylsulfonyloxy group include benzenesulfonyloxy. - "§ Lal Kill sulfonyl O alkoxy group" of Ararukirusuruho alkenyl groups above 0 ₇ - _{1 3} § Lal kills sulfonyl group is preferred, therefore hereinafter - "0 _{7 1 9} § Li one Le sulfonyl O Kin group" There is also a note. 〇 ₇ - The _{1 9} Ararukirusuruho Niruokishi group e.g., full We methane sulfonyl O carboxymethyl, and di-phenyl-methanesulfonyl O carboxymethyl and the like.

 “Amino acid residue” refers to an acyl group formed by removing the hydroxyl group of a carboxyl group of a normal amino acid. Specifically, for example, glycyl, alanyl. Valyl, leucyl, isoleucyl, seryl, threonyl, cystinyl. , Methionyl, asparagyl, glutamyl, lysyl, arginyl, phenylglycyl. Phenylalanyl, tyrosyl, histidyl, tryptophanyl, prolyl.

"Nitrogen-containing heterocycle" refers to a 5- to 8-membered ring containing 1 to several, preferably 1 to 4 nitrogen atoms (which may be oxidized) or a fused ring thereof. Such a nitrogen-containing heterocyclic ring may contain, in addition to a nitrogen atom, one to several, preferably two to three heteroatoms such as an oxygen atom and a sulfur atom.

 “Nitrogen-containing heterocyclic group” refers to a group formed by removing one hydrogen atom bonded to the ring-forming carbon atom of the above-described nitrogen-containing heterocyclic ring.

 "Heterocyclic group" refers to a group formed by removing one hydrogen atom bonded to a carbon atom of a heterocyclic ring, and such a heterocyclic ring may be a nitrogen atom (which may be oxidized) and A 5- to 8-membered ring containing 1 to several, preferably 1 to 4 carbon atoms or sulfur atoms, or a fused ring thereof. Specific examples of such a heterocyclic group include 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, and 2, 3- or 2-, 4-. Triazolyl, 1 H— or 2 H—tetrazolyl, 2— or 3-Chenyl, 2, 4 1 or 5 — Thiazolyl, 3 —, 4 1 or 5 — Isothiazolyl, 1, 2, 3-Thiadiazol 4 or 5-yl, 1, 2, 4—thiadiazol 3—or 5-yl, 1,2,5—or 1,3,4-thiadiazolyl, 2— or 3-pyrrolidinyl. 2—, 3— 4-Pyridyl, 2-, 3- or 4-pyridyl N-oxide, 3- or 4-pyridazinyl, 3- or 4-pyridazinyl-N-oxide, 2-, 4- or 5-pyrimidinyl, 2-, 4- or 5-pyrimidinyl-N-oxide, virazinyl, 3- or 4-piperidinyl, piperazinyl, 3H-indole-1- or 3-yl, 2-, 3- or 4-thiopyranyl, quinolyl, pyrido [2.3-d] pyrimidyl, 1,5 —, 1, 6—, 1, 7—, 1, 8—. 2, 6— or 2,7—naphthyridyl, thieno [2,3—d] pyridyl, pyrimidopyryl, birazinoquinolyl, etc. .

“Heterocyclic oxy group”; “heterocyclic thio group”, “heterocyclic amino group”, “heterocyclic carbyl group 丄 heterocyclic azetyl group” and “heterocyclic carboxamide group” are all heterocyclic groups. The above “complex group” is preferred. The “quaternary ammonium group” refers to a group that is itself quaternized by an unpaired electron on one tertiary nitrogen atom of the nitrogen-containing heterocyclic ring. Therefore, an anion for this is always accompanied. Examples of the quaternary ammonium group include oxazolym, thiazoliu A, isoxazolium, isothiazolym. Viridinium, and quinolinium. Examples of the anion include a hydroxide ion, a halogen ion (chlorine ion, bromine ion, iodine ion, etc.), a sulfate ion, a nitrate ion, a carbonate ion, and an organic lipoxylate ion (for example, oxygen ion). Trifluoroacetate ion) and organic sulfonate ions (eg, p-toluenesulfonate ion). Organic carboxylate ions, organic sulfonate ions, etc. may be in the molecule. The group with the symbol * attached to the right shoulder 'indicates that the group is an “optionally substituted group”. For example, an alkyl * group represents "an alkyl group which may have a substituent". In this case, the number of substituents is not limited to 1β, but may be the same or different and may be 2 to several, preferably 2 to 3 depending on the group to be g-substituted.

, "〇 ₆ - _{1 0} Ariru ※ Moto丄" Ji 7 - _{1 2} Ararukiru ※ group ". ₈ - _{1 0} Ariru ※ O key sheet group "and" C 7 ₉ Ararukiru ※ respectively as Okin group "," Fuweniru ※ group on "benzyl ⁵⁸ Moto丄" Fuwenokishi ※ group "and I- benzyl ※ Okishi group" Gayo Is more preferable.

In the compound [I] of the present invention, the substituent R ° represents a nitrogen-containing heterocyclic group.acyl group or an esterified carboxyl group. Of these, substituent R. Is a nitrogen-containing heterocyclic group [I] or a compound [I] which is an acyl group has a strong antibacterial activity against various bacteria, especially cephalosporin-resistant bacteria, and is specific to Pseudomonas spp. It is an antibacterial compound showing antibacterial activity. On the other hand, the substituent R. Is an esterified carboxyl group Compound [I] has a substituent R. Is a useful compound that can be used as an intermediate in producing the above compound [I] wherein is a nitrogen-containing heterocyclic group or an acyl group.

Substituent R. Nitrogen-containing Hajime Tamaki as (hereafter, Ru mower when represented by the symbol R ^a) refers to the "nitrogen-containing heterocyclic group" as described above, for example 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4 one Birazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 2-oxazolyl , 4 -oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl. 5-isoxazolyl, 〖.2,3 -oxazodiazol 4-yl, and 2,3 -oxazazolyl 5-yl, 1,2,4-oxadiazol-3-yl, 1,2.4-oxadiazolyl 5-yl, then 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 2-thiazolyl, 4-Thiazolyl. 5-Thi Azolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,3-thiadiazole-4-yl, 1.2,3-thiadiazole-1-5-yl. 1.2.4-thiadiazole-13- 1,2,4-thiadiazol-5-yl, I, 2,5-thiadiazolyl. I, 3,4-thiadiazolyl.2-pyrrolidinyl.3-pyrrolidinyl, 2-pyridyl, 3- Pyridyl, 4-pyridyl, 2-pyridyl-N-oxide, 3-pyridyl-1-N-oxide, 4-pyridyl-1-N-oxide, 3-pyridazinyl, 4-pyridazinyl, 3-pyridazinyl-N— N-oxide, 4-pyridazinyl N-oxide, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrimidinyl-N-oxide, 4-pyrimidinyl-N-oxy De. 5-pyrimidinyl-N-oxy De, birazinyl. 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, piperazinyl, 3H-indole-2-yl, 3H-indole-3-yl, etc. Preferred are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl and the like.

 The above nitrogen-containing heterocyclic group may have a substituent on the ring. The number of such substituents is not limited to one, and depending on the group to be substituted, two to several, preferably two to three, may be the same or different. Examples of such a substituent on the nitrogen-containing heterocyclic ring include an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, an amino group, a dialkylamino group, a dialkylamino group. Group, halogen atom, nitro group, azide group, cyano group, carboxyl group, alkoxycarbonyl group, alkanol group, alkanoyloxy group, carbyl group, monoalkyl lbamoyl group, dialkyl carbyl group Examples thereof include a diyl group, a carbazyloxy group, a dialkylcarbyloxy group, and a dialkylcarbamoyloxy group. '

Examples of the nitrogen-containing heterocyclic group having a substituent include a 2-imidazolyl group substituted with an alkyl group, an aryl group, and a halogen atom, or a nitrogen atom of a 4-pyridyl group. An N-substituted pinidinyl 4-methyl group in which the nitrogen atom has been quaternized by substitution with an aralkyl group or the like is preferable ₍ such substituted 12-imidazolyl groups include, for example, 1-methyl-2-imidazolyl, 4-chloro- Examples of N-substituted pyridinyl 4-yl groups include 2-imidazolyl and the like, and N-methylpyridinyl 4-yl, N-ethylpyridinyl 4-yl, N ^: benzylpyridinylム ー Mu 4-yl and N- (P-fluorobenzyl) pyridinyl-mu 4-yl.

g Substituent R. (Hereinafter sometimes referred to by the symbol ^Rb ) is the acyl group substituted for the amino group at the 6-position of the conventionally known penicillin derivative. Substituted at the amino group Refers to a sil group and the like. Such acyl groups include Cie alkanol * groups,

C 3-5 alkeno I le ※ group, 0 ₃ - ₁₀ consequent opening alkyl one carbonyl group, 0 ₅ - ₆ click port alkenylcarbonyl chromatography carbonyl group, C et. Aryl * carbonyl group. Heterocycle * carbonyl group.

 Examples of the Ct-e alkanol group include formyl.acetyl, propionyl, butyryl, isobutyrylphenol, isovaleryl, and vivaloyl.

Examples of the substituent of the “C -6 alkanoyl group optionally having substituent (s)” represented by the C alkanoyl group include, but are not limited to, a alkanol group (ie, formyl). heterocyclic ※ carbonyl group if, but also ② C ₂ - ₆ alkanol I le radical (. that Asechiru, propionyl, Puchiriru, Isopuchirirunokure Lil Isobareriru, Pibaroiru etc.) "substituent S ^l J is described below when the “Substituent S ¹ ” is C 3. Cycloalkyl ※ group, C 5-Nkuroa alkenyl ※ group, ₍₈ - ₁₀ § Li - Le ※ group, hydroxyl group, C ₆ alkoxy group, 0 ₃ - ₁₀ sheet click port Arukiruokishi group, C ₆ - ₁₀ § Li Ichiru ⁸⁵ Okishi group, C ₇ -.. ₁₃ Ararukiru ※ O alkoxy group a mercapto group C te alkyl ⁵⁸ Chiomoto, § Mi Bruno C alkylthio group, C ₂ - _e alkenyl Chiomoto, 〇 ₃ - ₁₀ consequent σ alkylthio group, C _e _ _L0 § Li Lumpur ※ Chiomoto, C ₇ - ₁₃ Ararukiru ※ Chiomoto, § Mi amino group, mono Arukirua Mi amino group, di C Arukiruami amino group, C ₃ -. ₁₀ consequent opening Arukiruami amino group, C S- § re Lumpur § Mi amino group, 〇 ₇ - ₁₉ Ararukiru ※ § Mi amino group, cyclic § Mi Roh ※ group Nono b Gen atoms, two Toro group, azide de group, Shiano group, a carboxyl group, Ashiru ⁺ group, substitution Oxycarbonyl, C alkylthio-carbonyl, acyl + oxy, acyl + amino, acyl Le ⁺ amino alkylthio group, carbazyl group, mono-C alkyl group rubamoyl group, di-Cte alkyl group rubamoyl group, dimethyl carbamoyloxy group, mono-C alkyl group rubyyloxy group, di-Cie alkyl group rubyyloxy group Group, sulfo group. Hydroxysulfonyl Okishi groups, C alkylsulfonyl groups, C & - _{1 ()} § Li Ichiru ※ sulfonyl group, 〇 ₇ - ₁₃ Ararukiru ※ sulfonyl groups, C _t _ ₆ alkylsulfonyl O Kin groups, C Ariru ※ Suruhoniruokishi group, 0 ₇ _ ₁₃ Ararukiru ※ sulfonyl Ruoki shea group, Urei de ※ group, sulfa乇I le ※ group, a heterocyclic ※ group, a heterocyclic ※ Okishi group, double ring ⁵⁸ Chiomoto, heterocyclic ※ amino group, a heterocyclic ⁵⁸ Refers to a carbonyl group, a heterocyclic ⁵ ^ -carboxamide group or a quaternary ammonium ⁸⁵ group. The number of these substituents is not limited to one, and when there are two or more substituents, those substituents may be the same or different. Two of the substituents may form a C = C double bond or a C = N double bond as described later on the surface.

C ₃ - ₅ Arukenoiru ※ "optionally substituted C ₃ - ₅ Arukenoiru group" represented by group substituents (hereinafter "referred substituent S) as for example, 0 ₃ - ₁₀ cycloalkyl group, 0 ₆ - ₁₀ Ariru ※ group, C ₆ alkoxy group, shed _beta -. ₁₀ Ariru ※ Okishi group, c ₇ one ₁₃ Ararukiru ※ Okishi group Nono androgenic atom, Xia amino group, a carboxyl group Ashiru ⁺ group, a substituted Okishikarubo sulfonyl group , Acyl + oxy group, heterocycle * group, quaternary aluminum * group and the like.

C ₆ - _t0 Ariru ※ represented by substituents and heterocyclic ※ force Ruponiru group ". But it may also be substituted Cs § Li one Lou carbonyl group" represented by a carbonyl group having a "substituent a heterocyclic group which may be substituted "in the substituent (hereinafter, referred to as" location substituent S ³ ") include, for example, C alkyl, C ₂ - ₆ Arukeniru group, C 64. Ariru group .Rei ₇ - ₁₂ Ararukiru group, di-Ce-i. Ariru one methyl tri C _e -. ₁₀ Ariru - methyl, hydroxyl, C i alkoxy group, c ₆ _ _l0 Ariruokishi group, 0 ₇ - ₁₉ Ararukiruokishi group, Merukabuto group, C kappa Al Kiruchio group C _S -. _T. § Li one thio group, Rei_7- _{1 3} Ararukiruchio group, Amino group, a mono CL -! _E Arukiruami amino group, di-C Arukiruamino group, human Dorokishi C _ s alkyl group, Merukabuto C _t - _e alkyl group, a halogeno C _t - ₆ alkyl group, a force Rupoxy C alkyl group, logen atom, nitro group, azide group, cyano group. Carboxyl group, substituted oxycarbonyl group, acyl ⁺ group, acyl + oxy group.acyl + amino group, alkenyl group Group, thiocarbazyl group. Cie alkylsulfonyl group, Cs-i. § Li one Rusuruhoniru group, 〇 ₇ - like ₁₃ Ararukirusuru Honiru group.

C i one ₈ Al force Noiru groups mentioned above, C ₃ - ₅ Arukenoiru group, C ₈ - ₁₀ Ariru one carbonyl group and groups other than those described below with substituent (SS ² and S ³⁾ of the heterocyclic carbonyl group The groups mentioned above are also meant here.

〇 ₈ -. ₁₀ Ariru ⁵ ^ group, Fuweniru ※ based on Ce-t. Ariru ※ Okishi group, Fuenoki sheet ⁵⁸⁵ group, _<8 - ₁₀ § Li Ichiru ※ Chiomoto, 〇 ₆ - ₁₀ Ariru ※ Amino groups, Cs-t. Aryl * Sulfonyl group and Cs. Ariru ※ 〇 ₈ Suruhoniruokishi groups - as the ₁₀ substituent § aryl group, said substituents S ³ are as listed et here.

〇 ₇ -. ₁₂ Ararukiru ※ benzyl group, 0 ₇ - ₁₃ Ararukiru ※ Okishi group, benzyl ※ Okishi group, 〇 ₇ - _{1 3} Ararukiru ※ Chiomoto, C ₇ - _{1 3} Ararukiru ※ Amino group, C ₇ _ ₁₉ Examples of the substituent of the aromatic ring of C 7 2 or C ₇ one ₁₃ Ararukiru group Ararukiru ^ sulfonyl group and C ₇ _ ₁₉ Ararukiru ⁸⁵ Suruhoniruo alkoxy group, said substituents S ³ and the like as it is here.

Heterocyclic ※ group, a heterocyclic ※ Okishi group, heterocyclic Chiomoto, heterocyclic ※ Amino groups. Heterocyclic ※ Asechiru group and the heterocyclic ⁵ ^ Karubokisami as substituents heterocyclic de group of the substituent S ³ Gakoko But you can just give it.

The quaternary Anmoniumu ⁵⁸⁵ groups the substituents on the nitrogen-containing heterocyclic ring, the above location substituent S ³ and the like as it is here.

As the substituent of the C _t - ₆ alkyl group of the “optionally substituted C 8 alkyl group” represented by the C 8 alkyl group, the above-mentioned substituent S ¹ can be used as it is. 丄C ₃ - ₁₀ consequent opening alkyl ※ group Contact Yopi C ₅ - _beta consequent opening alkenyl ※ "0 optionally substituted ₃ - ₁₀ consequent opening alkyl group" represented by group and "optionally substituted C ₅ - Examples of the substituent of _e cycloalkenyl group ", the above substituents S ³ and the like as it is here.

Examples of the substituent (hereinafter referred to as “substituent S ⁺ ”) of the C alkylthio group of the “optionally substituted C ie alkylthio group” represented by the 5 C ie alkyl ⁵ thio group include, for example, a hydroxyl group and a C ie alkoxy group. group, 0 ₃ - ₁₀ cycloalkyl O alkoxy group, C _B - ₁₀ Ariru ※ Okishi group, 0 ₇ - ₁₃ Ararukiru ※ Okishi group, Melka butoxy group, C _t -8 alkylthio group, C st. Cycloalkylthio group .Rei_8- _{1 0} § Li

10 Ichiru ※ Chiomoto, 〇 ₇ - ₁₃ Ararukiru ※ Chiomoto, Amino group, mono C ie Arukirua amino group di CL -. ₆ alkylamino group, cyclic amino ※ group, a halogen atom, Shiano

'Group, carboxyl group, rubamoyl group, acyl ⁺ oxy group, sulfo group, quaternary ammonium * group, etc. "

C _2-beta alkenyl ※ Chio "optionally substituted represented by group C ₂ - ₈ §

15 Luque two Lucio group "0 ₂ -. ₆ Aruke two Lucio group substituents (hereinafter" that substituent S ⁵ ") as, for example, a halogen atom, Shiano group carboxyl group, a force Rubamoiru group, mono C i- 6 Alkyl radicals, di C alkyl carbamoyl groups, thiocarbamoyl groups and the like.

 The "acyl + group" is the C alkanoyl group described above. Ariel * Carbonii

20 group, 0 ₇ - ₁₉ Ararukiru ※ carbonyl group, refers to a heterocyclic ⁵ ^ carboxymethyl sulfonyl group or a heterocyclic ※ Asechiru group. Therefore, typical examples of the acyl + group include, for example, formyl, acetyl, propionyl, n-butyryl, isobutyryl, phenolyl, piperoyl, monohexanoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, 3-oxobutyryl, 4-Chloro-3-oxo 25 sobutyryl, 3-carboxypropionyl, 4-carboxybutyryl, 3-ethoxyquinylvinylpropionyl, benzoyl, naphthyl, ρ-methyl Rubenzoyl, p-hydroxybenzoyl, p-methoxybenzoyl, p-chlorobenzoyl, p-nitrobenzoyl, 0-carboquinbenzoyl, 0— (ethoxycarbonyl-lvamoyl) benzoyl, 0— (ethoxyquin Carbonylsulfamoyl) benzoyl, phenylacetyl, p-methylphenylacetyl, p-hydroxyphenylacetyl, ρ-methoxyphenylacetyl. 2, 2-diphenylacetyl, 2-phenylphenyl, 2- Prillcarbon. 2-, 4- or 5-thiazolyl acetyl, 2- or 3-Chenyl acetyl, 2- or 3-furyl acetyl, 2-amino 1, 4- or 5- thiazolyl acetyl, 5 —Amino 3—Thiadiazolylacetyl.

"Ashiru + Okishi group" and "Ashiru + § Mi Roh group" Ashiru + group refers to the Ashiru ⁺ based on the above ', and therefore "Ashiru + Okishi group" as, for example, ho Rumiruokishi, § cell butoxy, Propionibacterium Ruo carboxylate .Butyryloxy, valeryloxy, pivaloyloxy, chloroacetoxy, dichloroacetoxy, trichloroacetoxy, 3-oxobutyryloxy, 4-chloro-3-oxo-butyryloxy, 3-carboxypropionyloxy, 4-butyroxybutyryloxy, 3 —Ethoxycarbamoylpropionyloxy, benzoyloxy, naphthyloxy, ρ-methylbenzoyloxy, ρ-methoxybenzoyloxy, ρ-mouth benzoyloxy, ο-carboxybenzoyloxy, 0— (ethoxy Carbonylcarbamoyl) benzoyl Oxy, 0- (ethoxycarbonylsulfamoyl) benzoyloxy, phenylacetyloxy, ρ-methylphenylacetyloxy, ρ-methoxyphenylacetyloxy, ρ-chlorophenylacetyloxy, 2,2-diphenylacetyloxy , Enylcarbonyloxy, furylcarbonyloxy, thiazolylacetyloxy, chelylacetyloxyquin, furylacetyloxy, and the like. Examples of “acyl ⁺ amino” include acetamido (CH ₃ C ON.H-), Benzuami de (CeHsCO -), full We sulfonyl § Seto ami de _{(C e H 5 CH 2 C0NH-} ) - Choi sulfonyl § Seto Ami de (), and the like.

, S CH ₂ C0fiH-

Ashiru + Amino groups and alkylthio O group "Ashiru ⁺ § amino alkyl thio group" meaning taste Ashiru ⁺ Amino groups and C i -S alkylthio groups defined above; therefore such "Ashiru ⁺ Amino C i -e alkylthio Examples of the “group” include acetamidomethylthio, 2-acetamidoethylthio, and the like.

"Ariruashiru + group", "C 8 - _{1 0} § Li one Ruashiru ⁺ group" C., even field base Nzoiru, phthaloyl, naphthoquinone Tiru, phenyl § cetyl like et be. '

"§ Li one Ruashiru ⁺ Okishi group" is "0 8 _{1 0} § Li one Ruashiru + Okishi group"is' well, for example base Nzoiruokishi, naphthoquinone Toiruokishi, such as Fuweniruasechiru Okishi, and the like.

Examples of the substituent of the © Ray de group represented by "Urei de group", "optionally substituted Urei de group" for example, C alkyl group, 0 ₆ - _{1 0} Ariru ※ group, 〇 ₇ - _{1 3} Ararukiru * Group, acyl ⁺ group. Lubayl group, sulfo group (which may form a salt with sodium, potassium, etc. as appropriate), sulfadiyl group, amidino group.

 Examples of the substituent of the sulfadyl group of the “optionally substituted sulfamoyl group” represented by the “sulfamoyl * group” include a C alkyl group and an amidino group.

The substituent of the "Power Rubamoiru group" Oyopi "force Rubamoiru ※ Okishi group" is I is the "replacement which may be Karupamoiru group" for example, C _t - _S alkyl group, 〇 ₈ - _{1 0} Ariru ※ group, C 7 ₂ Ararukiru group. Ashiru ⁺ groups include Agerare also the nitrogen atom of the force Rubamoiru groups of nitrogen-containing heterocyclic ring formed nitrogen The case where it is an atom is also included.

The substituent of the "conversion which may be Chiokaru Bamoiru group" represented by "Chio force Rubamoiru ※ group", for example, C have s alkyl group, C ₆ - _t. § Li one le ⁵⁸ group, C 7 ₂ Ararukiru ※ groups, such Ashiru + group and the like, also Chiokaru Bamoiru nitrogen atom a nitrogen-containing heterocycle containing Murrell be a ring-forming nitrogen atom of the group.

"Cyclic Amino group" substituent of the cyclic amino group of "optionally substituted cyclic Amino group" (hereinafter, "that substituent S) represented by a, for example, C ₈ alkyl C ₂ -. _Beta alkenyl . C ₃ - ₁₀ cycloalkyl C ₈ -. ₁₀ Ariru ※ group, 〇 ₇ - ₁₂ Ararukiru ※ group, di 0 ₆ - ₁₀ § Li Ichiru - methyl, tri 0 ₈ - ₁₀ § Li one Rumechiru group, a hydroxyl group , C I ₈ alkoxy group, 0 ₈ - ₁₀ Ariru ※ Okishi group, 〇 ₇ - ₁₉ Ararukiru-Okishi group, a mercapto group, C kappa alkylthio O group C ₈ -.. one ₁₀ Ariru ※ Chiomoto C ₇ - _t3 7 aralkyl ※ Chiomoto, § Mi amino group mono- C Arukiruamino group, di C Arukiruamino group, C _e -... _t Ariru ※ § amino group, 0 ₇ - ₁₉ Ararukiru ※ § Mi amino group, a halogen atom, two Toro group, azide group, Okiso group, Chiokiso group, Shiano group, a carboxyl group, Ashiru ⁺ group, substituted O key Carbonyl group, Ashiru + Okishi group. Ashiru ⁺ amino group, a force Rubamoiru group, Cal Bamoiruokishi group, Chiokarupa乇I group, such as sulfo group.

The formyl group substituted with a heterocycle * carbonyl group as one of the Cte alkanoyl * groups is an acyl group having the formula of heterocycle ^85— C0—C0—. The heterocyclic group includes, in addition to those described above, an oxazolyl group, an oxdiazolyl group, and the like, and more preferably an oxazolyl group, a thiazolyl group, an oxadiazolyl group, a thiadiazolyl group, and the like, which may have a substituent. Examples of such a “heterocycle ³⁵ — C O—CO—” group include, for example, 2- (2—, 4- or 5-oxazolyl) -1-oxoacetyl, 2- (2—, 4- or 5—Thiazolyl) 1 2—Xisoacetyl, 2— (2 —Amino-4-thiazolyl) -1-2-oxoacetyl, 2- (1,2.4—oxadiazolu-l 3- or 5-yl) -12-year-old xoacetyl, 2-— (1, 2.4—thiadiazole-3— or 5— And 2- (5-amino-1,2,4-thiadiazol-3-yl) -12-oxoacetyl.

C ₂ - _e Arukanoiru ※ arbitrariness preferred is Asechiru group having a substituent most as group. The number of substituents of the acetyl group having a substituent is 1-3 values, and the substituent is the above-mentioned "substituent S" as the substituent of the dealkanol group. The number of substituents is 2 to 3 values. cases, even in those g substituent identical, may be the or different, R ¹⁵ is a further 2 'by One summed the number of g substituent may form a double bond. monosubstituted Asechiru group CH ₂ CO—

, As a di-substituted acetyl group, ₇ > ΟΗ—CO—

R ¹⁷

You. On the other hand, tri-substituted acetyl groups are often those in which the binary substituents form a C = C double bond or a C = N double bond.

R ² CO—

Where the symbols R ¹⁵ to R ¹⁷ , R ² . And R ²² represent the above-mentioned substituents (means S, and the symbols R ¹⁸ , R ¹³ and R ²¹ will be described later. Hereinafter, the acetyl group having these substituents (R ¹⁵ to R ²² ) will be described in detail. .

_{^{i) R 15 CH 2 C 0}} - Power symbols R ¹⁵ is mean a substituent (S a C alkyl group above, not bird, C 5-S cycloalkenyl group, C ₈ - ₁₀ Ariru ※ group, C ₆ - ₁₀ Ariru ※ O alkoxy group, C ^ 8 alkyl ※ Chiomoto, C ₂ - ₈ Arukeniru ⁵ ^ Chiomoto, C _e -. _t Ari Le ※ Chiomoto, § Mi Roh group, a cyclic § Mi amino group, Shiano group, Ashiru ⁺ group, Ashiru ⁺ Okishi group, a heterocyclic ※ group, a heterocyclic ⁵⁸ Chiomoto, such as quaternary Anmoniumu ※ groups are frequently used You. Therefore, for example, the “asyl group R ¹⁵ CH ₂ C 0 —” is, for example, 1,4-six-hexahexenyl acetyl, phenyl acetyl, ρ-tolyl acetyl, ρ-hydroxy phenyl acetyl, ρ-methoxy Penylacetyl, ρ-chloro phenyl acetyl, 0-aminomethylphenyl acetyl, phenyloxyacetyl, ρ-hydroxyphenoxyacetyl, ρ-cyclophenoxyacetyl, cyanomethylthioacetyl, difluoro Methylthioacetyl, trifluoro σ-methylthioacetyl, (2-carboxyethyl) thioacetyl, (2-amino-2-carboxyethyl) thioacetyl, (2-vinyl vinyl) thioacetyl, (2-carboxy) (Vinyl) thioacetyl, (2-fluoro-2-force ル rubamoylvinyl) thioacetyl, (1,2-dichloro vinyl) Oacetyl (2-chloro-2-carboxyvinyl). Thioacetyl, phenylthioacetyl, Ρ-hydroxyphenyl ^ oacetyl, glycyl, 1Η—tetrazolyl-111-ylacetyl, 3,5-dichloro-4.1-oxo 1-1,4-Dihydropyridine-1-ylacetyl, cyanoacetyl, acetacetyl, benzoylacetyl, cerylcarponyl acetyl, (1Η-tetrazolyl) acetyl, 1-methyl-1 1—tetrazolylacecetyl, (2-phenyl) ) A cetyl, (3 —Chenyl) acetyl, (4 —Thiazolyl) acetyl. (2 —Amino-4 monothiazolyl) acetyl and 2,4 —Thiadiazol-3-yl) acetyl, (5 —Amino 1 , 2.4—Thiadiazole-3-yl) acetyl, (2-pyridyl) acetyl, (4-pyridyl) acetyl , (2-Imidazolyl) thioacetyl. (2-Pyridyl) thioacetyl, (4-Pyridyl) thioacetyl, (2-Chenyl) thioacetyl, Hydroxypyridylthioacetyl, (5-Isothiazolyl) thioacetyl, (3-Methylthio) (5-isothiazolyl) thioacetyl, (4-cyano-15-isothiazolyl) thioacetyl, (4 —Cyan-2-methyl-3-oxo-1,2,3-dihydroisothiazol-1-5-yl) thioacetyl, pyridinimide acetyl, quinolinium acetyl, and the like.

Π) ^ ₁₇ > CH- CO-R

Although the symbols R ^IS denotes the group (s, especially, Ji ₅ - ₆ cycloalkanone group, 0 ₈ - ₁₀ Ariru ※ group, 0 ₈ -. ₁₀ Ariru Okishi groups, C Al Kill ※ Chiomoto C ₂ -β alkenyl * thio group, aryl * thio group, cyclic amino group, cyano group, heterocyclic ⁵ ^ group, heterocyclic * thio group, heterocyclic * carboxamide group. Quaternary ammonium * group is also available here It is Shigeru甩. Although the symbols R ¹⁷ also refers to the substituent, inter alia, hydroxyl, Merukabuto group, an amino group, amino group substituted with amino acid residues, human Dorajino group, an azide group. Urei de * ¾, acyl + oxy group, acyl + amino group, carboxyl group, substituted oxocarbonyl group, sulfo group, sulfamoyl group, rubamoyl group, heterocyclic ring * carboxamide group, etc. are preferred. those R ¹⁷ is of § Mi amino group (to KazuSatoshi R ¹⁶ CH- CO-) is classified as a particular "Amino acid residue"

NH ₂

 ■ a 1 e

Sometimes. Therefore, "asyl group ,,> C H— C 0—”

R ¹⁷

For example, 2-amino 2- (1.4-hexahexenyl) acetyl, mandenyl, azidophenylacetyl, a-carboxyphenylacetyl, α- (phenyloxycarbonyl) phenylacetyl, α- (0-Hydroxyphenyl) oxycarbonylphenylacetyl, 1- (Ρ-tolyloxycarbonyl) phenylacetyl, —Sulfophenylacetyl, —Sulfo ρ— 'Hydroxyphenylacetyl, Ν-Sulfouraido) phenylacetyl, α-carboxy-ρ-hydroxyphenylacetyl, α- (formyloxy) phenylacetyl, 1 (2- Amino 3-carboxypropionamide) phenylacetyl. Α- (3-Amino-3-carboxypropionamide) phenylacetyl, 1- (3,4-dihydroxybenzamide) phenylacetyl, £ 2— ( 5—Carboxy 41-imidazolylcarboxamide) phenylacetyl, α :—( 1,3—dimethyl-14-pyrazolylcarboxamide) phenylacetyl, α— [1-1 (Ρ-methoxyphenyl) 1-141 1,2-, 3-triazo-1-ylcarboxamide] phenylacetyl, α- (4-oxo1.4-dihydropyridin-3-ylcarboxamide) phenylacetyl , Α— [2-oxo-5- (3,4—dihydroxyphenyl) 1-1,2-dihydropyridin-3-ylcarboxamide] phenylacytyl, α— (4-oxo-1 4-Η-1 3-thiocarbanamide) phenylacetyl, a- (4-hydroxy-1,5-naphthyridine-13-ylcarboxamide) phenylacetyl, α- (4-ethyl-2-, 3-dioxopiperazinocarboxamide) Peracetyl, α- (4-ethyl-1,2,3-dioxopyrazinocarboxamide) ρ-hydroxyphenylperacetyl, one (4-ethyl-2,3-dioxopiperazino carboxamide) ρ-base N-dioxocyphenylacetyl, α- (4-Ethyl-2,3-dioxopiperazinocalpoxamide) —ρ-Sulfophenylacetyl, <¾ 一 (4-Ethyl-2,3 dioxopipera) Dinocarboxamide) 1-Methoxyphenyl acetyl. Α- (2-oxoimidazoli Dinocarboxamide) phenylacetyl, α- (2— Oxo-1-3-methanesulfonylimidazoli-dinocarboxamide) phenylacetyl, α-hydroxy-2-cerylacetyl, —hydroquinone-3-cynylacetyl, α-carboxy-3-cerylacetyl, α-amino α- (2-aminothiazole-1-yl) acetyl, "1-formamide α- (2-aminothiazole-41-yl) acetyl.-acetamido α- (2-aminothiazo-1-yl-4 I-yl) acetyl, α-e Lumamido α- (2-amino-5-clothiazol-4-yl) acetyl, —acetamido-1 (2-amino-5-clothiazol-4-yl) acetyl. —Formamido α- (5-amino 1.2,4-thiadiazol-3-yl) acetyl, α-acetamido — (5-amino-1,2,4—thiadiazol-3-) Α) -Hydrazinol α- (2-aminothiazole-41-yl) acetyl, α-droquinine-11- (2-aminothiazole-41-yl) acetyl, α-ureido-1-α- (2-ami Nothiazole-4-yl) acetyl, α- [Ν 丫-(m-hydroxyphenyl) -reido] phenylacetyl, α- [Ν ^γ- (2-methyl-6-hydroxypyrimidin-5-yl) -reido ”phenyl Acetil, one [Ν 丫 — (3, 4—jase Kishibenzoiru) Ulei de] Fueniruasechiru, a one [N丫_ｰ(3, 4 dihydric mud Kishishi runner moil) Urei de] phenylene Ruase ^{Chill, α - [γ - (3} , 4 one Jiase Tokishibenzuami Doasechiru) Urei do "phenyl Acetyl, 1- (2-chlorovinylthio) phenylacetyl, 1-ylrubamoyl-α- (2-chlorovinylthio) acetyl, 1- (4-ethyl-2,3-dioxopiperazinocarboxamide) — (2-chlorovinylthio) acetyl, α. “—Bis- (4-ethyl-2,3-dioxo-1 —piperazinocarboxamide) acetyl, mono (2-amino-4-thiazolyl) 1- (4-ethyl-2-, 3-dioxo- 1-piperazinocarboxamide) acetyl— (4-hydroxy-1-6-methylnicotinamide) -1 α: 1-phenylacetyl, α— (4-hydroxy) 6-methylnicotinamide) 1- (4-hydroxyphenyl) acetyl, 1- (5,8-dihydroxy) 2- (4-formyl-1-piperazinyl) -1-5-oxopyrido [2,3-d] pyrimidine One 6-forceboxamide} —α-phenylacetyl, one (3,5-dioxo-1,2,4-triazine-6-carboxamide) one-one (4-hydroxyphenyl) acetyl, α— (4— Hydroxy-1 7-Methyl-1, 8 1-naphthyridine-1 3-carboxamide) 1-α-phenylacetyl, 1- (4-hydroxyl 7-trifluoromethylquinoline 3-carboxamide) 1 α-phenylacetyl, Ν— [2 — (2—Amino 4-1-thiazolyl) acetyl] -1-D—Phenylglycyl, α— (6-Br-1-1-ethyl-1,4-Dihydro 4—oxothieno [2,3-b] pyri Gin-1-3-carboxamide) 1-phenylacetyl, 1- (4-ethyl-2,3-dioxo1-1-piperazinocarboxamide) -1 α-Chenylacetyl, α ;—( 4-η-pentyl) 1,2,3-Dioxo- 1-piperazinocarboxamide) 1-Chenyl acetyl, 1- (4-η-octyl-2,3-dioxo- 1-piperazinocarboxamide) 1-Chenyl acetyl, 1- (4-six hexyl) twenty three Jiokiso one 1 one piperazino carboxaldehyde Mi) one alpha-Cheniruasechi Le, α- [4- (2 - Fuweniruechiru) one 2, 3 Jiokiso 1 Piperaji Nokarubokisami de] - alpha - like Chenirua chill are exemplified. Again, amino acid residues (R “CHC 0—) include, for example,

Η ₂

Examples include valyl, leucyl. Isoleucyl, seryl, threonyl, cystinyl, cystinyl, methionyl, asparagyl, glutamyl, lysyl, arginyl, fenglycyl, phenylylalanyl, tyrosyl histidyl, tributofanyl, and prolyl. You. Further, the amino group of these amino acid residues may be protected by an amino group-protecting group as described below. Examples of the “amino acid residue in which an amino group is protected” include ベ ン ジ ル -benzyloxycarbonylalanyl, Ν-benzyloxycarboxamidophenylglycyl and the like. Further, the amino group of the amino acid residue may be further substituted with another amino acid residue. Such an acyl group is a "residue of a dipeptide". Examples of such an acyl group include phenyldalicylananyl and benzyldiyl-"-benzyloxycarbonyl. Lou 7-glutamyl-aranil, aranilufrinylglycyl, arspartyl-phenylglycyl, arglutamyl-arranil and the like. Further, the amino group of the amino acid residue may be substituted with a cyclic rubamoyl group. Examples of such an acyl group include N- (4-ethyl-12,3-dioxo-1-piperazinocarbonyl) aranyl, N— (4-ethyl-2-, 3-dithio-1-1-piperazinocarbonyl) Examples include phenylglycyl and N- (4-ethyl-2,3-dioxo-1-piperazinocarbonyl) threonyl.

 D 1 e

In addition, one of the acyl groups _ ₁₇ > CH—C〇 is CH—CO—, wherein R ² and R ²⁵ are the same or different.

,

Hydrogen atom, halogen atom (fluorine, chlorine, bromine, iodine), hydroxymethyl group, difluoromethyl group, trifluoromethyl group, formyl group, cyano group, azide group, carboxyl group, carbamoyl group. C t-e alkylthio group or

C6. Aryl * indicating a thio group] is also used.

 N H 2 C 0 no \

Examples of such an acyl group include> ⁼ (ノ CH —

 NaO C 0 ヽ S,

 C O — and others.

^{iii) R 20 - C - CO} - il R eight ^{1 8} R ^{1 9}

Although the symbols R ^{2 Q} denotes the Ri said g substituent (S, especially 0 ₆ _ ₁₀ Ari le group, C et. Ariru ※ Okishi group, C et. Ariru ※ Chiomoto, heterocyclic ※ group, double-containing The symbol R ¹⁸ is a hydrogen atom or a halogen atom (fluorine, chlorine, bromine, iodine), preferably chlorine, and the symbol R ¹³ is a C! _-E alkyl group. , C ₈ - _{1 0} Ariru ※ group, C t- _e alkylthio A group of nitrogen atoms; a cyano group, an amino group, a C alkylsulfonyl group, c

_{6-1 10} Ariru ※ sulfonyl group, a force Rubamoiru group, a C Arukokishii mi de I group or heterocyclic ^ group. Where the C-alkoxymidyl group

The C 8 alkoxy group is preferably the above-mentioned C alkoxy group, and therefore, as the C! -6 alkoxyimidoyl group, for example, methoxyimidoyl

(-), Etkinimidoyl. Other

H ₃

All the radicals mentioned above are applied here as they are. Therefore, as the “acyl group R ²⁰ — C— C 0—”, for example, 2- (2-amido

R ¹⁸ R ¹⁹

No-4- (thiazolyl) -1-3-chloroacryloyl, 2- (2-amino-4-thiazolyl) crotonyl, 2- (2-amino-4-thiazolyl) simple molybdenum, 2- (2-) Amino 4- (1-thiazolyl) -1-3-methanesulfonylacryloyl, 2- (2-amino-4-thiazolyl) -13-benzenesulfonylacryloyl, 2- (5-amino-1,2) , 4-Thiadiazol-3-yl-1-2-pentenoyl, 2- (5-amino-2,4-thiadiazol-3-yl) -1-3-chloroacryloyl, 2- (5-amido 1,2,4-thiadiazol-3-yl) crotonyl, 2- (2-amino-5-chloro-14-thiazolyl) -13-chloroacryloyl, 2- (2-) And amino-5-chloro-4-1-thiazolyl) crotonyl.

iv) R ²² -C- CO-

N

R ²¹

Although the symbol R ²² means the substituent (s, especially consequent opening alkyl ※ groups, C _S -. ₆ cycloalkenyl ※ groups, C ₆ - ₁₀ Ariru ※ groups, C Al Coxy group, CSL. Ariru ※ Okishi groups, C alkyl ※ Chiomoto, amino C _T - ₆ Arukiruchio group, 〇 ₆ - ₁₀ § Li Ichiru ※ Chiomoto, 0 ₇ - ₁₉ Ararukiru ※ Chiomoto, shea Anomoto, Ashiru + group, the force Rubamoyl groups and heterocyclic groups are frequently used.

C _S Among these - ₁₀ § Li Lumpur ※ group, heterocyclic-group is particularly preferred. Substituents of these reel groups and heterocyclic groups are preferably a Cte alkyl group, a hydroxyl group, an amino group, and a logen atom (fluorine. Chlorine, bromine and iodine). Accordingly, preferred examples of the substituent R ²² include, for example, phenyl; p-hydroxy xyphenyl, 2-thienyl, 4-thiazolyl, 2-amino-41-thiazolyl, 2-amino-5-chloro-14. 1-thiazolyl, 2-amino-5-butamate 4-monothiazolyl. 2-amino-5-fluoro-4 thiazolyl. 2-amino-4, thiazolyl-1, 3-oxide, 2-imimino 3-hydroxythithiazoline, 4-yl. 3-Isothiazolyl, 5-amino-3-isothiazolyl, 1,24-thiaziazolyl-3-yl, 5-amino-1,2,4-thiadiazol-3-yl, 1,3,4-thiadiazolyl. 2-Amino-1,3,4-thiadiazole-1-yl, 1-1 (C alkyl) -1-5-amino1.2,4-Triazole-3-yl, 4- (Cκalkyl) -1 5 —A minnow 1, 2, 4—triazo 1- 3 Le, 1 one (C I ₆ alkyl) Single 2 § amino one 4 Imidazoriru, 2- amino-6-pyridyl, 4 one amino-2-pyrimidyl, 2-amino-5-pyrimidyl, 3-pyrazolyl, 4 one Virazolyl is exemplified. The symbol R ²¹ is an O R ²³ group (wherein R ²³ represents a hydrogen atom or an optionally substituted hydrocarbon residue). here

R ²² - C one group represented by C 0 is R ²² - C - Thin different represented by C 0-

! 1 II

\ ₂₃

0 ROR ²³ Isomer or anti-isomer represented by R ²² — C-C 0 — or it

N

R ²³ 0

Such a mixture is preferable, in which the substituent R ²² is a heterocyclic group * and a syn isomer. Such an acyl group has the formula

 R 22 no .C 0

 C

II

 N

Wherein the [pi ²² lambda or heterocyclic group, R ³ represents a hydrogen atom or optionally substituted hydrocarbon residue] can be expressed by. Here, the heterocycle * group R ²² is a substituted thiazolyl group or thiaziazolyl group, that is,

[Wherein, R ¹ represents an amino group which may be protected, and R ² represents a hydrogen atom, a halogen atom or a nitro group]. Thus, the most preferred R ^b group is of the formula

 Syn isomer (Z configuration) Syn isomer (Coordination)

It is. I.e. g-substituent R. As a compound [I] having an acyl group R ^b as

 i 7 this-_-_——

 [The symbols in the formula are as defined above.]

Of the structure is preferred. Hereinafter, substituents 1 ^1, 11 ² 1 ³ Ni'ite we describe in detail.

The symbol R ¹ represents an optionally protected amino group. In the field of 5-lactams and peptides, the protecting groups for amino groups have been well studied and the protection methods have been established. In the present invention, those known as protecting groups for amino groups are also used. It can be adopted as appropriate. Is a protecting group of Amino group, for example, C Arukanoiru ※ group, C ₃ _ ₅ Arukenoiru ※ group, 〇 ₈ - ₁₀ § Reel * carbonyl group, phthaloyl group, heterocyclic ⁵ ^ carbonyl group, C 6 alkyl * sulfonyl group, carbon sulfonyl group, carbon aryl * sulfonyl group, substituted oxycarbonyl group, potassium rubamoyl * group.thiocarbamoyl * group, C

₈ - ₁₀ Ariru ※ methyl, di 〇 ₆ - ₁₀ Ariru ※ methyl, Application Benefits C _e - ₁₀ § Li one Le ※ methyl, C _e - ₁₀ § Li Ichiru methylene group, C _e - ₁₀ § Li one * Thio group, substituted silyl group, 2-C alkoxy-carboxyl 1-methyl-1-ethenyl group and the like.

 Examples of rCte alkanoyl * groups include, for example, formyl, acetyl, propionyl, butyryl phenol, piperyl, succinyl, glutaryl, monochloroacetyl, dichloroacetyl, trichloroacetyl, monobutyl moacetyl, Monofluoroacetyl, difluoroacetyl, trifluoroacetyl, monoiodoacetyl, 3-oxobutyryl. 4-chloro-3-oxobutyryl, phenylacetyl, ρ-chlorophenylaceti ^, phenoxyacetyl, ρ-chlorophenyloxyacetyl, etc. Can be

. Here as - "C _{3 5} alkeno I le ※ group", for example, § click Li σ I le, click opening concert I le, maleoyl, cinnamoyl, etc. ρ- black port cinnamoyl 3 Hue Nirushin'namoiru the like.

 res. Examples of the aryl group include, for example, benzoyl, naphthyl, ρ-toluoyl, p-tert-butylbenzoyl, p-hydroxybenzoyl.P-methoxybenzoyl, ρ-tert-butoxybenzoyl.p— Benzoyl, p-nitrobenzoyl, etc.

 Heterocycle * Examples of the carbonyl group include those described below.

 Examples of the “C t-e alkyl * sulfonyl group” include methanesulfonyl, ethanesulfonyl and the like.

Here, for example as - "C _{e 10} § Li Ichiru ※ sulfonyl group", benzene sulfonyl, naphthalate Rensuruponiru, p- toluenesulfonyl, p- t Ert- Examples include butylbenzenesulfonyl, p-methoxybenzenesulfonyl, ρ-chloro benzenesulfonyl, and ρ-two-port benzenesulfonyl.

Examples of the “substituted oxycarbonyl group” include, for example, methoxycarbonyl, ethoxyquincarbonyl, η-propoxycarbonyl, isopropoxycarbonyl, η-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, nor Bornyloxycarbonyl, phenyloxycarbonyl, naphthyloxycarbonyl, benzyloxyquincarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2 , 2,2-Trichloroethoxycarbonyl, 2-Cyanethoxycarbonyl, ρ-Methylphenoxycarbonyl, ρ-Methoxyphenoxycarbonyl, ρ-Methoxyphenoxycarbonyl, ρ-Methylbenzyl Xycarbonyl, ρ-Methoxybenzyloxycarbonyl, ρ-Mouth benzyloxycarbonyl, ρ-Nitrobenzyloxycarbonyl, Benzhydryloxycarbonyl, cyclopropyloxycarbonyl, Cyclopentyloxycarbonyl And hexyloxycarbonyl.

 Examples of the “lumbamoyl * group” include, for example, livamoyl, Ν-methylcarbamoyl, Ν-ethylcarbamoyl, Ν, Ν-dimethylcarbamoyl, Ν, Ν-getylcarbamoyl, Ν-phenyl Examples include rucarbamoyl, ァ -cetylcarbamoyl, Ν-benzoylcarbamoyl, and バ-(Ρ-methoxyphenyl) rubamoyl.

Examples of the “carmoyl * oxy group” include, for example, carbamoyloxy, Ν-methylcarbamoyloxy, Ν, Ν-dimethylcarbamoyloxy, Ν-ethylcarbamoyloxy, and Ν-phenylcarbamoyloxy. Is raised. ' Examples of the “thiolbamoyl * group” include, for example, thiocarbamoyl, N-methylthiolrubamoyl, and n-fluorothiolubayl.

As - "〇 _{8 10} Ariru ※ methyl group" such as benzyl, Nafuchirume chill, .rho. methylbenzyl, .rho. main Tokishibenjiru, .rho. black port base Njiru, .rho. like nitrobenzyl and the like.

Examples of “di C. aryl * methyl group” include benzhydryl and di (p-tri-methyl) methyl.

As - "Application Benefits C _{e l0} Ariru ※ methyl group" for example, preparative rutile, etc. Application Benefits (p one preparative Lil) methyl and the like. .

As "C 8- _{1 0} Ariru ※ methylene group" for example, benzylidene. P-menu Chirube Ngiligi 'den, such ρ- black port base Njiriden the like.

Examples of the “C _e - ₁₀ aryl * group” include 0-2-nitrophenylthio.

The “substituted silyl group” has the general formula R ⁶ R ⁷ R ⁸ zS i (R ⁹ R ¹⁰ ) \

S i NH, (R ⁶ R ⁷ R ⁸ S i) ₂ N or ZN where

i (R ³ no R ¹⁰ no) Z

^{R 6, R 7, R 8} , R 9, R 10, R 9, R 10 Roh is Ku C doctor ₆ alkyl group if each C _e - indicates ₁₀ § Li Ichiru ※ groups, the same or different One, respectively You may. Z represents a C κ alkylene group such as methylene, ethylene, propylene, etc.], specifically, trimethylsilyl, tert-butyldimethylsilyl, —Si (CH ₃ ) ₂ CH ₂ CH ₂ S i (CH ₃ ) ₂ — and the like.

. "2-C ^ alkoxy one carbonyl one 1-methyl 1 Eteniru group C _t alkoxy one carboxymethyl sulfonyl group may have those described above, thus 2 -. C _t alkoxy one carbonitrile a two-Lou 1-methyl-1 Eteniru group For example, 2-methoxycarbone i-methyl-1-ethenyl, 2-ethoxycarbone-1-methyl-1-ethenyl, 2-tert-butoxycarbone-1,1-methyl-1-ethenyl, 2-cyclohexylcarbonyl-1— Methyl-1-ethenyl, 2-norbornyloxycarbonyl-1,1-methyl-1-ethenyl and the like.

The symbol R ² represents a hydrogen atom, a halogen atom or a dinitro group. Examples of the halogen atom include fluorine, chlorine, bromine and the like, preferably chlorine.

Symbol R ³ is to Table Wa hydrogen atom or optionally substituted hydrocarbon residue. The hydrocarbon residue for example, C alkyl, C ₂ - _e alkenyl, C ₂ - ₆ alkynyl group, C ₃ - _{1 0} consequent opening alkyl group, C ₅ - _beta Shikuroaruke two the like le group, especially A C alkyl group or a substituted C alkyl group is preferred. Again as a C-e alkyl group

Examples of the C alkyl group include methyl, ethyl, n-propyl, isopyl, η-butyl, isobutyl, sec-butyl, tert-butyl, η-pentyl, and η-hexyl. Methyl, ethyl, and η-propyl are preferred. C ₂ - _e alkenyl as specifically well C alkenyl le groups above again based on vinyl, Ariru, isopropenyl, methallyl, 1, 1 one Jimechiruariru, 2-butenyl, 3-butenyl. C As specifically ₂ _ ₆ alkynyl group Echiniru, 1-propynyl, 2-pro pinyl, such as propargyl and the like. 〇 ₃ - _{1 0} consequent opening alkyl group and to cyclopropyl to C cycloalkyl group may specifically mentioned above Again, cyclobutyl, cyclopentyl, carboxymethyl les cyclohexane, Petit Le cyclohexane, etc. Adamanchiru the like. C _{5 -6} cycloalkenyl As specifically based on 2-sik port pentenyl, 3-sik port pentenyl, cyclohexenyl 2-cyclopropyl, the 3-sik port cyclohexenyl, cyclopentadienyl, the consequent opening hexa Jenil and the like.

These are for example hydroxyl group as the substituent of the hydrocarbon residue, C i - _e alkyl le group, C 2-S alkenyl, C 2-6 alkynyl group, Cs-i. Sik port alkyl group, C ₅ -. _Beta cycloalkenyl group C S- _{1 0} Ariru group, 0 ₇ - ₁₃ Ararukiru group, the heterocyclic group, C ts alkoxy group, C ₃ - ₁₀ consequent opening Arukiruokishi group, C B- ₁₀ § Li one Ruokishi group, 〇 ₇ - ₁₃ Ararukiruokishi group, a heterocyclic Okishi group, a mercapto group, C _t - _e alkylthio group, 0 ₃ - ₁₀ cycloalkylthio group, 〇 ₆ - ₁₀ Ariruchi O group, 0 ₇ - ₁₃ Ararukiruchio group , heterocyclic Chio group, § Mi amino group, mono C Al Kiruami amino group, di-C Arukiruami amino group, door Li c _t _ _e alkyl Anne乇Niu-time group, C ₃ -. ₁₀ consequent opening Arukiruami amino group C ₈ - ₁₀ arylamino group, C ₃ aralkylamino group; heterocyclic amino group, cyclic amino group, azide group, nitro group, halogen atom, cyano group, carboxyl group, C ^ alkoxy-carboyl group, C ₆ - ₁₀ Ariruokishi Ichiriki Ruponi les group, C ₇ - ₁₃ § Ralkyloxyl radical, C _β . Ariru -. Ashiru ⁺ groups, C alkanol I le radical C 3-5 alkeno I le groups, C ₆ _ ₁₀ Ariru - Ashiru ⁺ Okishi groups, C ₂ -. ₆ alkanol I le Okishi group c ₃ _ ₅ alkeno Iruokishi group, Lebamoyl * group. Thiocarbayl group, diluvamoyl * oxy group, phthalimid group, Ct-S alkanoylamino group, Ce-i. Aryl-plus-amino group, carboxamino group, CLo-alkoxy-l-boxamido group, C. § Li one Ruo Kishi carboxamide Mi de group, ₍₇ - is a ₁₃ Ararukiruokishi one Karubokisami such de group and the like, the same or different may be present two or more substituents of the hydrocarbon residue. Specifically, the alkenyl group is as defined above, ie, methyl ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl, η-pentyl, η-hexyl, etc. C ₂ - ₆ alkenyl groups as mentioned above, i.e. vinyl, Ariru, isobutylene port Bae alkenyl, methallyl, 1, 1 - Jimechiruariru, 2-butenyl, 3-butenyl and the like, C ₂ - _e alkynyl Groups those mentioned above, namely Echiniru, 1 one-propynyl, 2-propynyl and the like flop port Parugiru, 〇 ₃ -. Cyclohexyl ₁₀ consequent opening alkyl groups as described above, i.e., cyclo-propyl, cyclobutyl, cyclopentyl, to consequent sigma. heptyl cyclohexane, Adamanchiru the like, C _s - cyclohexenyl _s Shikuroaruke alkenyl groups as described above, ie consequent opening propenyl, 2-sik port pentenyl, 3-sik port pentenyl, to 2-sik port, 3 - cyclohexenyl consequent opening, consequent opening Pentajeniru, Kisajeniru and the consequent opening, the C _e _ ₁₀ 7 Li Ichiru group as described above, i.e. phenyl, naphthyl, Bifuweniriru etc., C ₇ - ₁₃ Ararukiru groups those of the Benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, naphthylmethyl, benzhydryl, etc. Those mentioned above, namely main butoxy, ethoxy, n- flop sigma 'epoxy, isoproterenol epoxy, .eta. butoxy, tert- butoxy, n- Penchiruokishi, the n- and hexyl Okishi, Cs-i. Sik port Arukiruokishi groups those mentioned above, namely Kuropuropiruo 'alkoxy, Kishiruokishi and cyclohexane, C St 0 Ariruoki shea groups those mentioned above, namely phenoxy, Nafuchiruokishi etc., C ₇ - ₁₃ Ararukiruokishi groups those above, That Benjiruokishi, 1 one phenylene Ruechiruokishi, 2 full We sulfonyl E chill O Kin, etc. Benzuhi Doriruokishi those C kappa alkylthio groups mentioned above, i.e. methylthio, Echiruchio, n- propylthio, .eta. Puchiruchio the like, 0 _{3 -1 ()} cycloalkylthio groups are as defined above, ie, propylthio, cyclohexylthio and the like. § Li one Lucio groups those mentioned above, namely phenylthio, etc. Nafuchiruchi O, 〇 ₇ - ₁₃ Ararukiruchio groups those mentioned above, i.e. benzylthio, phenyl E Ji thio, and the like Benzuhi Doriruchio, mono C Arukirua amino group of the And the di C -8 alkylamino group is as described above, that is, dimethylamino, getylamino, methylethylamino, di- (n-methylamino, ethylamino, n-propylamino, n-butylamino, etc.). One propyl) § Mi Bruno, di- and (n- heptyl) § Mi Bruno, ones Application Benefits C alkyl § emissions乇Niumu group of the, i.e. preparative trimethyl ammonium Niu arm, preparative Rye Chiruanmoniumu etc., 0 ₃ - ₁₀ consequent opening Arukiruami amino group as described above, i.e. cyclopropyl amino, cyclopentyl amino, and cyclohexyl § Mi Bruno cycloheteroalkyl, C ₆ - ₁₀ Ariruami amino group is that of the, i.e. Anirino, - Mechiruanirino the like, The C-ma- ₁₃ aralkylamino group is as described above, that is, benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino, etc., and the cyclic amino group is as described above. Such as pyrrolidino, piperidino, piperazino, morpholino, and 1-pyrrolyl, and the halogen atom is fluorine, chlorine, or odor here. C, iodine, iodine, etc. The alkoxy-carbonyl group is as defined above, ie, methoxycarbonyl.ethoxycarbonyl, η-butoxycarbonyl, isopropoxycarbonyl, η-butynecarbonyl, isobutoxycarbonyl, 'tert-butoxycarbonyl, cyclopentylo. alkoxycarbonyl, Kishiruokishi force Le Poniru cyclohexane, and the like norbornyl O carboxymethyl Cal Poni Le, C ₆ - ₁₀ § Li one Ruokishi - carboxymethyl sulfonyl group as described above, i.e., full We Roh Kin carbonyl, etc. Nafuchiruo alkoxycarbonyl, 〇 ₇ _ ₁₃ Ararukiruokishi - carboxymethyl sulfonyl group as described above, namely benzyl O Kin carbonyl, etc. Benzuhi Doriruokishikaru Poniru, C 8- _{1 0} Ariruashiru ⁺ groups as mentioned above, namely Ben Zoiru, naphthoyl, phthaloyl, Fuweniruasechiru And so on. The C 3-5 alkenyl group is as defined above, ie, acryloyl, crotonyl, and the C 3-5 alkenyl group is as defined above, ie, formyl.acetyl, propionyl, butyryl, pareryl, pivaloyl, succinyl, glutaryl, and the like. Cs-t. § Li one Ruashiru ⁺ Okishi groups those mentioned above, namely base Nzoiruokishi naphthoquinone Toiruokishi, etc. Fuweniruase butoxy, C ₂ - _s 7 Rukano Iruokishi groups those mentioned above, namely § Se butoxy, Puropioniruo Alkoxy, Puchiriruokishinoku Reriruokishi, Bibaroiruokishi the like, C ₃ - ₅ alkenyl Noi Ruo carboxymethyl those mentioned above, namely § methacryloyl Ruo xylene, etc. black bets Noiruokishi force Rubamoiru ※ groups those mentioned above, namely carba乇I le , N-Methylcarbamoyl, N-Ethylcarbamoyl, Ν, Ν-Dimethylcarbamoyl, Ν-Ethylcarbamoyl, Ν, Ν1-Jethylcarbamoyl, Ν-Phenylcarbamoyl, Ν-Acetylcarbamoyl, Ν— In addition to benzoylcarbamoyl and Ν- (ρ-methoxyphenyl) potassium rubamoyl, there are also pyridine carbinoyl, piperidinocarbonyl, piperazinocarbonyl, morpholinocarbonyl, etc .; That is, thiocarbamoyl, Ν-methylthio-potamoyl, Ν-phenylthio And the like, and the rubamoyl * oxy group is as defined above, ie, rubamoyloxy, Ν-methylcarbamoyloxy, Ν, Ν-dimethylcarbamoyloxy, ェ -ethylcarbamoyloxy, Ν-phenylcarbamoyloxy. For example, “C κ alkenyl amino group” refers to acetoamide, propionamide, petit σ amide, etc., and “C _s - _{i 0} arylyl + amino group” Is, for example, benzamide, naphtoylamide, phthalimid, etc., and “C _t - ₁₀ alkoxy-carboxamide group” is, for example, methoxycarboxamide (CH ₃₀ C0NH-), ethoxycarboxamide, tert-butoxycarboxyl. Pokisami de etc., "C 8 ₀ Ariruokishi one carboxyalkyl Kisami de group" for example full We Roh carboxymethyl carboxaldehyde mi de (C _s H ₅ 0C0 -) and the like, "C ₇ - _{1 3} Ararukiruokishi - force Rupokisami de group", for example base Njiruoki Shikarubokisami de _{(Cs H s CH 2 0C0NH -} ), represents the like Benzuhi drill O carboxymethyl carboxamide Mi de. The heterocyclic group such as a heterocyclic group, a heterocyclic oxy group, a heterocyclic thio group and a heterocyclic amino group also means a group formed by removing one hydrogen atom bonded to a carbon atom of a heterocyclic ring. Such heterocycles may contain nitrogen atoms (which may be oxidized) and heteroatoms such as Z or sulfur atoms. Is a 5- to 8-membered ring containing 1 to several, preferably 1 to 4, or a fused ring thereof. Examples of such a heterocyclic group also include 2-pyrrolyl and below, specifically, those described above. Accordingly, the “heterocyclic thio group” includes, for example, thiazolyloxy, and the “heterocyclic thio group” includes, for example, thiazolylthio. Examples of the "heterocyclic amino group" include thiazolylamino, thiadiazolylamino, and the like.

More preferred substituted hydrocarbon residues are hydroxyl, cycloalkyl, alkoxy, alkylthio, amino, trialkylammonium, nitrogen, carboxyl, alkoxycarbonyl, carbamoyl. group, Shiano group, azide de groups, C Bok ₃ alkyl group substituted with such a heterocyclic group (C t one ₃ alkyl groups are methyl, Echiru, .eta. propyl, will have like Isopuropiru), and their Specifically, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 1-methoxethyl, 2-methoxethyl, 1-ethoxyxethyl, 2-hydroxyxethyl, methylthiomethyl, 2-aminoethyl, 2- (tox (Methyltrimethylammonium) ethyl, 2- (triethylammonium) ethyl, fluoromethyl, difluoromethyl, tri Fluoromethyl, 2-fluoroethyl, 2.2-difluoroethyl, chloromethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-odoethyl, 2, 2,2-Trifluoroethyl, carboxymethyl, 1-carboxyl, 2-carboxypropyl, 2-carboxypropyl, 1-carboxybutyl, 1-carboxybutyl, cyanomethyl, 1-carboxy-1-methylethyl, methoxy Carbonylmethylethoxycarbonylmethyl, tert-butoxycarbonylmethyl. 1-methoxycarboxy 1-methylethyl, 1-ethoxycarbone 1-methylethyl, 1 tert-butoxycarbone 1-methylethyl, 1—benzyl Xycarbonyl 1-methylethyl, 1-bivaloyloki Mosquitoes Luponyl 1-methylethyl, rubamoylmethyl, 2-azidoethyl, 2- (birazolyl) ethyl, 21- (imidazolyl) ethyl, 2- (2-oxopyrrolidine-1-yl) ethyl, 2-amido There are many other things such as No. 4 thiazolylmethyl. Among the hydrocarbon residues specifically mentioned, the most preferred are straight-chain C κ alkyl groups such as methylethyl and η-propyl, and 2-fluoroethyl, 2-chloroethyl, and 2-hydroxyethyl. Halogen atoms, hydroxyl group, hydroxyl group, such as droxicetyl, 2-methoxethyl, cyanomethyl, carboxymethyl, tert-butoxycarbonylmethyl, 1-carboxy-1-methylethyl, 〖-tert-butoxycarbo-2-methylethyl, etc.

10 A linear or branched 又 は κ alkyl group substituted with a alkoxy group, a carboxyl group, an alkoxycarbonyl group, or a cyano group, an aryl group, and a propargyl group. Here, when the symbol R ³ represents the most preferred hydrocarbon residue or hydrogen atom exemplified above, the substituent R ° is an acyl group.

I

So

Or

[v

 Ten

[The symbols in the formula indicate the above.]

 The structure having the following structure is most preferable.

A good example of the “asyl group R ^{2 2} — C— C 0—” is

Two

Hekinoxymino) acetyl, 2- (2-aminothiazol-4-y) 1) 2 (Z)-(cyclopropylmethyloxymino) acetyl, 2- (2-aminothiazole-4-yl) 1-2 (Z)-(benzyloxymino) acetyl, 2- (2- Aminothiazol-4-yl) 1-2 (Z) — (aryloxyminino) acetyl, 2- (2-aminothiazol-4-yl) 1-2 (Z) — (propargyloxyimino) acetyl, 2- (2-aminothiazole-4-yl) -1 2 (Z) — (Methoxymethyloxyimino) acetyl, 2- (2-aminothiazole-1-yl) -1 2 (Z) — (Ethoxymethyloxymino) acetyl, 2- (2-aminothiazole-4-yl) -1 2 (Z) — {(1-methoxyxethyl) oxyminino} acetyl, 2- (2-aminothiazole-4 1-yl) 1 2 (Z) — {(2-methoxyxyl) oxymino} acetyl, 2— (2-ami Thiazole-4-1) 1 2 (Z) — {(2-ethoxyethoxy) oxymino} acetyl, 2- (2-aminothiazole-4-yl) -1 2 (Z) -1 {(1—ethoxyquinethyl) oxy (Mino) acetyl, 2- (2-aminothiazole-4-yl) -1 2 (Z) —K2-Hydroxyshetyl) oxymino} acetyl, 2- (2-aminothiazole-4-yl) 1-2 (Z) — (Methylthiomethyloxymino) acetyl, 2- (2-aminothiazole-4-yl) -1 2 (Z) — {(2-Aminoethyl) oxymino] .acetyl, 2- (2- Aminothiazole-1-4yl) -1 2 (Z) — (Fluoromethyloxymino) acetyl, 2- (2-aminothiazole-4-yl) -1 2 (Z) — (difluoro mouth Methyloxymino) acetyl.2- (2-aminothiazole-4-yl) -1 2 (Z) — (trifluro Methyloxymino) acetyl, 2- (2-aminothiazole-1-yl) -1 2 (Z) — {(2-Fluoroethyl) oxyminino) acetyl.2 -— (2-aminothiazole-4 2- (Z) — {(2,2-difluoroethyl) oxymino} acetyl, 2- (2-aminothiazol-4-yl) 1-2 (Z) — (chloromethyloxyimidyl) (No) acetyl.2 one (2-aminothiazol-4-yl) one 2 (Z) — {(2-chloroethyl) Oxymino ¹ / acetyl, 2- (2-aminothiazoyl 4-yl) -1 2 (Z) —K2, 2-dichloroethyl) oxyminino} acetyl, 2- (2-aminothiazole) 4- (yl) -1 2 (Z) — ((2,2,2-trichloroethyl) oxymino) acetyl, 2- (2-aminothiazole- (yl) -1 2 (Z) — ((2-1-Prodethyl) oxymino) acetyl, 2— (2-Aminothiazole) 4- (Z) — {(2-iodoethyl) oxymino] .Acetyl, 2-— (2-Aminothiazol-4-yl) -1 2 (Z) — {(2,2,2—Trifluoroσethyl) oxyimino} acetyl, 2- (2-aminothiazol-4-yl) ) ー 2 (Ζ) — (Carboxymethyloxymino) acetyl, 2— (2—Aminothiazole-1 4-yl) -1 2 (Ζ) — (1 Carboxyethyloxymin) (No) acetyl, 2- (2-aminobutiazoru 4-yl) -1 2 (Ζ) — {(2-diboxyloxy) minino) acetyl, 2— (2-aminothiazol 4-yl) 1) 2 (Ζ) — (1 carboxypropyloxymino) acetyl, 2— (2—aminothiazolu-l 4-yl) 1 2 (Ζ) — ί (3—force 2- (2-aminothiazole-14-yl) -1-2 (Ζ) —Κ1-carboxybutyl) oxy-mino-acetyl.2 -— (2-aminothiazoyl-1-4-) 1) 2 (Ζ) — (Cyanomethyloxymino) acetyl, 2— (2— (Aminothiazoyl 4-41) 1 2 (Ζ) — {(1 carboxy-1-i-methylethyl) oxymi No} acetyl, 2- (2-aminothiazole-4-yl) 1-2 (Z) — (methoxycarbonylmethyloxyimidium) ) Acetyl, 2- (2-aminothiazole-4-yl) -1 (Z) 1-1 (ethoxycarbonylmethyloxyminino) acetyl, 2- (2-aminothiazole-4-yl) -1 (Z ) — {(Ten-butoxycarbonylmethyl) oxyimino} acetyl, 2- (2-aminothiazole-4-yl) -1- {1— (tert-butoxycarbonyl) ethoxymino} acetyl, 2- (2 —Amino thiazol-4-yl) -1 2 (Z) — {(1—Methoxycarbinyl 1 2-methyl-2-ethylaminoethyl acetyl, 2- (2-aminothiazole-14-yl) -1 2 (Z) — {(1-ethoxyethoxycarbonyl-1-methylethyl) oxyminino} acetyl-2. Aminothiazo 4-yl) -1 2 (Z) 1-((1-tert-butoxycarbonyl 1-methylethyl) oxymino} acetyl, 2- (2-aminothiazole-4-yl) -1 2 ( Z) — {1-(tert-butynecarbonyl) propoxymino} acetyl, 2- (2-amino-thiazol-4-yl) -1 2 (Z) — {(1-benzyloquincarbo) 2- (1-methylethyl) oxymino} acetyl, 2- (2-aminothiazole-14-yl) -1 2 (Z) — {(1-Bivaloyloxycarbo-2-yl 1-methyl0-luethyl) oxyimi (No) acetyl, 2- (2-aminothiazole-4-yl) -1 2 (Z) — Ilmethyloxymino) acetyl, 2- (2-aminothiazol-4-yl) -1 2 (Z) —ί1- (1-ylrubamoyl i-methyl) ethyloxyminino} acetyl, 2- (2-α Mino thiazole-4-1-yl) (Z) — ((2-azidoethyloxymino) acetyl, 2- (25-aminothiazole-4-yl) 1-2 (Z) — (Phenoxycarbonyloxymino) ) Acetyl, 2- (2-amino-5-chlorothiazole-4-yl) -1 2 (Z) — (Hydroxyimino) acetyl, 2- (2-amino-5-chlorothiazole-4-1) 1) 2 (Z) — (Methoxyimino) acetyl. 2— (2—amino 5-clothiazole-41-yl) 1-2 (2:) — (ethoxyimino) acetyl, 2 — (2-amino-5—clothiazole-41-yl) 1 2 (Z) — (n-proboxymino) a Cetyl, 2- (2-amino 5-alkoxythiazole-4-yl) -1 2 (Z) — {(2-fluoroethyl) oxymino;! Acetyl, 2- (2-amino 5-chloro Mouth thiazole-4 (yl) -1 2 (Z) — {(2-Chloroethyl) oxymino} acetyl ..2-((2-Amino-5-cloth) — (Carboxymethyloxymino) acetyl.2 -— (2-amino-5-clothiazole-4-) 1) 2 (Z) — {(tert-butynecarbonylmethyl) oxymino} acetyl, 2- (2-amino-5-cyclothiazole-4-yl) 1-2 (Z)-( (I-Carboxy-1-methylethyl) oxyimino} acetyl, 2- (2-amino-5-chlorothiazol-1-yl) -1 2 (Z) — {(1—tert—butoxycarboryl 1-methylethyl) oxymino} acetyl, 2- (2-amino-5-bromothiazole-4-yl) -1 2 (Z) — (ethoxyminino) acetyl.2— (5-amino-2.4 —Thiadiazol-3-yl) 1-2 (Z) — (Hydroxymino) acetyl, 2 -— (5-amino-1,2,4—Thiadiazol-3-yl) 1-2 (Z) — ( Methoxymino) acetyl, 2- (5-amino-1,2,4-thiadiazol-3-yl) -1 2 (Z) — (ethoxyminino) a Chill, 2- (5-amino I, 2,4-thiadiazol-3-yl) -1 2 (Z) -ethoxymino) acetyl, 2- (5-amino-1 1,2,4- Thiadiazole-3-yl> -1 2 (Z) — {(2-fluoroethyl) oxymino} acetyl, 2- (5-amino-1,2,4-thiadiazole-3-yl) 1-2 (Z ) — {(2-Chloroethyl) oxymino} acetyl 0.21 (5-amino-1,2,4-thiadiazol-3-yl) 1 2 (Z) — (Ruboxymethyloxyimidino) No) acetyl, 2- (5-amino-1,2,4-thiadiazol-3-yl) -1 2 (Z) — {(1—carboxy-1 1-methylethyl) oxymino) acetyl, 2— (5-amino 1.2, 4-thiadiazol 3-yl-2 (Z) — ((1-tert-butoxycarbone-2-methyl-2-ethyl) oxyimino} acetyl, 2 — (2—ino 3—hydroxythiazolin 1-41) -1 2 (Z) — (ethoxymino) acetyl, 2- (2—amino-3-oxoxythiazol-4-yl) 1 2 (Z) — (Ethoxymino) acetyl, 2—Chenyl 2 (Z) — (Methoxymino) acetyl, 2 1 チ ェ 2hru 2 (Z) — (Ethkinimino) acetyl, 2— ( 1.3.4—thia diazolyl) -1 2 (Z) — (ethoxymino) acetyl, 2- (P—hydroxy 2- (Z) — (Ethoxymino) acetyl, 2-Phenyl-2 (Z) One- (ethoxymino) acetyl, 2-Phenyl-2 (Z) — (Hydroxyimino) acetyl, 2 — {P— (y—D—glutamyloxy) phenyl} -1 2 (Z) — (hydroxyminino) acetyl, 2- {p— (3—amino-3—carboxypropoquine) phenyl} 1 2 ( Z) — (Hydroxymino) acetyl etc. are shown.

As described above, the C i- ₈ alkyl group * described as one of the acyl groups (R ^b ) includes the above C _t − _e alkyl group and the heterocyclic ring * C 0—C 0—, R ¹⁵ CH ₂

R ¹⁶

CO—,> CH— CO—, R ² . One C one CO—, R ²² — C— CO—

R ¹⁷ II II

 .

 / \

R ¹⁸ R ¹⁹ R ²¹

In addition, trifluoroacetyl, 4-carboxybutyryl, 5-amino-5-carboxyvaleryl, 5-oxo-5-carboxyvaleryl, N- {2-1 (2-amino-4-thiazolyl) 1-2 ( Z) — (Methoxymino) acetyl} -D-aralanyl, N— {2- (2-amino-4 thiazolyl) 2 (Z) — (Methoxymino) acetyl} —D-phenylglycyl, 2- (2—amino-4 monothiazolyl) -12— {2— (2—amino4-thiazolyl) -12 (Z) — (methoxymino) acetamido} acetyl.

The ₅ alkeno I le ※ group - - C ₃ as C Al force Bruno I le except group Ashiru group (R ^b). § click Li Royle described above again, black concert I le, Mareo I Le, cinnamoyl P - black port cinnamoyl;.. .delta. such off We sulfonyl cinnamoyl is, C as ₃ _ ₁₀ consequent opening alkyl one carbonyl group again cyclopropylcarbonyl and the cyclobutylcarbonyl, consequent σ pentyl carbonyl, hexyl consequent opening carbonyl, Sik σ heptylcarbonyl, etc. § Damman chill carbonyl, C ₅ - the ₆ consequent opening alkenylcarbonyl over group cyclopentenyl carbonyl described above again, cyclopenta Jenny ylcarbonyl, etc. Kisajeni Le carbonyls to consequent opening into hexenyl ylcarbonyl consequent _{opening, C e -.. 1 0} 7 reel ※ Again As the carbonyl group Benzoiru naphthoyl, .rho. toluoyl, [rho-t er t-Buchirubenzoiru , Ρ-Hydroxybenzoyl, ρ-Methoxybenzoyl, ρ-tert-Butkinbenzoyl, ρ-Chlorobenzoyl, ρ-Nitrobenzoyl, etc. Or 3-pyrrolylcarbonyl, 3-, 4-mono or 5-pyrazolylcarbonyl, 2-, 4-mono or 5-imidazolylcarbonyl, 1,2,3- or 1,2,4-triazolylcarbonyl, 1 Η— or 2Η-tetrazolylcarbonyl, 2- or 3-phenylcarbonyl, 2-, 4- or 5-thiazolylcarbonyl, 2-amino-4 Azolylcarbonyl, 3-, 4- or 5-isothiazolylcarbonyl, 1,2,3-thiadiazole-41- or 5-ylcarbonyl, 1,2.4-thidiazoyl 3- or 5-ylcarbonyl, 5-amido 1,2,4-thiadiazol-3-ylcarbonyl, 1,2,5- or 1,3.4-thiadiazolylcarbonyl, 2- or 3-pyrrolidinyl carbonyl, 2-, 3- or 4-Pyridylcarbonyl, 2-, 3- or 4-pyridylcarbonyl-dioxide, 3- or 4-pyridazinylcarbonyl, 3- or 4-pyridazinyl carbonyl, 2-, 4-, or 5- Pyrimidinylcarbonyl, 2-, 4- or 5-pyrimidinylcarbonyl dioxide, birazinylcarbonyl, 2-, 3- or 4-piperidinylcarbonyl, Radinylcarbonyl. 2—, 31- or 4-thiopyranylcarbonyl, quinolylcarbonyl, pyrido [2,3-d] pyrimidylcarbonyl, 1,5—, 1,6—, 1,7—, Examples include 1,8—, 2,6—or 2,7-naphthyridylcarbonyl, thieno [2,3—b] pyridylcarbonyl, pyrimidopyridylcarbonyl, and pyrazinoquinolylcarbonyl. The esterified carboxyl group as the substituent R ^Q (hereinafter, may also be represented by the symbol R ^c ) is the same as the substituent described above as a protecting group for the optionally protected amino group represented by the symbol R ^1. The xycarbonyl group is applied here as it is. Therefore, methoxycarbonyl. Ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butynecarbonyl, cyclohexyloxycarbonyl, norbornyloxycarbonyl, also mentioned above. Phenoxycarbonyl, naphthyloxycarbonyl, benzyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methansulfonylethoxycarbonyl. 2.2.2.2 — Trichloroethoxycarbonyl, 2-cyanoethoxycarbonyl, p-methylphenoxycarbonyl, ρ-methoxyphenoxycarbonyl, ρ-chlorophenoxycarbonyl, ρ-methylbenzoyloxycarbonyl, ρ-methylbenzoyloxycarbonyl Xybenzyloxycarbonyl, ρ-chloro benzyloxycarbonyl, ρ-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, cyclopropyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl And so on. In the compound [I] of the present invention, the substituent R ⁺ represents a hydrogen atom, a methoxy group or a formamide group (HCONH-).

In the compound [I] of the present invention, the substituent R ¹³ represents a hydrogen atom, a methyl group, a hydroxyl group or a halogen atom. Here, the halogen atom means fluorine, chlorine, bromine or iodine.

In the compound [I], the substituent A represents a thiazol-3-yl group which forms a condensed ring at the optionally substituted 4,5-position. 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 a condensed ring with an alicyclic ring is more preferable. The fused ring is further different May be condensed with a benzene ring or a 5- or 6-membered aromatic heterocyclic ring. Further, ㊉ added to the substituent A indicates that the substituent A has a monovalent positive charge. The thiazole-3-yl group fused to an alicyclic ring has the general formula

 τ ® ® ,,,

 \ \

 [Α

 , / Ss-■

(CH ₂ ) m

Wherein m is from 2 to 6, preferably from 3 to 5. I mentioned above.

Thus, the alicyclic moiety of A ¹ is thiazole fused with another A alicyclic or benzene ring

 _

-3 -yl group is a general formula

¾

\ One / 「Α ²¹

Is represented by As mentioned above, the benzene ring portion of A ² may be further condensed with another alicyclic ring, benzene ring or 5- or 6-membered aromatic heterocyclic ring. The 5- or 6-membered aromatic heterocycle means a 5- or 6-membered aromatic heterocycle having a nitrogen atom, oxygen atom and / or sulfur atom as a hetero atom. Thus, a thiazole-3-yl group fused to a 5- or 6-membered aromatic heterocycle is represented by the general formula

Is represented by Β in the formula is 3 to 4 carbon atoms, nitrogen atoms, consisting of oxygen and or sulfur atoms, of which carbon atoms are bonded to one hydrogen atom or form another fused ring with adjacent carbon atoms. Form. Specific examples of the 5- to 6-membered aromatic heterocycle forming Β in A ³ include For example, pyridine. Pyridazine, pyrimidine, piperazine, 1.2, 3-triazine. 1, 2, 4-triazine, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, pyrrole, pyrazole, imidazole, etc. Is raised. The hydrogen atom on the substituent A represented by A ^l , A ² or A ³ may be substituted by one or more same or different substituents. When there is a substituent on the substituent A, the number of the substituent is more preferably from 1 to 3. Such as the substituent on a substituted group A for example, a hydroxyl group, hydroxycarboxylic C te alkyl groups, C alkyl groups, C ₂ - _e alkenyl groups, C _2-beta al Kiniru groups, C * - _e Al force Jeniru group , C ₃ - ₁₀ consequent opening alkyl group, C ₅ - link Roarukeniru group, 〇 ₃ - ₁₀ consequent opening alkyl C alkyl group,: _Cs-l0 7 Li one group, 〇 ₇ -. ₁₂ Ararukiru group di 〇 ₈ - ₁₀ Arirumechiru group, tri C ₈ - _L0 § Li

- Rumechiru groups, heterocyclic groups, C alkoxy groups, C alkoxy - C 6 § alkyl groups, C ₃ -LO cycloalk ^ Ruokishi groups, C ₆ _ ₁₀ Ariruokishi groups, C ₇

- ₁₉ Ararukiruokishi group, a mercapto group mercapto C _t -. _S alkyl group, sulfo group, sulfo C ie alkyl groups, C alkylthio groups, C ie alkylthio O CK alkyl group, 〇 ₃ - ₁₀ cycloalkylthio group, 0 ₆ _ ₁₀ § Li one Lucio based on .Rei ₇ -.. ₁₃ Ararukiruchio based on Amino group, Amino C β alkyl group mono C!

- _s Arukiruamino group, di C Arukiruamino group, mono C Arukiruami Bruno C alkyl group, di C _t - _e Arukiruamino C alkyl group, Rei_3- ₁₀ click port Arukiruami amino group, 〇 ₆ - ₁₀ Ariruamino group, C ₇ - ₁₃ . Ararukiruami amino group cyclic Amino group, cyclic Amino C alkyl group, cyclic Amino C _t - _e al Kiruamino group, azido group, two preparative port group Nono androgenic atom Nono Rogeno C i_ _e alkyl group, Shiano group, Shiano C _T - S alkyl group, carboxyl group, carboquine C!

- ₆ alkyl groups, C WINCH ^ alkoxy one carbonyl groups, C ₁₀ alkoxy - force carbonyl C te alkyl group, 〇 ₈ - ₁₀ Ariruokin - carbonyl group, ₃ Ararukiruokishi one carbonyl group, 08- ₁₀ § Li one Ruashiru ⁺ groups, C ! -e Arukanoiru group, C ₂ - ₈ Arukanoiru C iS alkyl radical C ₃ -. ₅ Arukenoi Le group, C _S - ₁₀ Ariru - Ashiru ⁺ Okishi groups, C ₂ - ₆ alkanoyloxy Noi Ruo alkoxy group, C ₂ - ₈ alk Noi Ruo carboxymethyl C alkyl radical C ₃ -.. ₅ alkenyl Noi Ruo Kin groups force Rubamoiru C Bok ₆ alkyl group, a force Rubamoiru ※ group, Chio force Rubamoiru ※ group, force Rubamoiru ※ Okishi group, force Rubamoiruokishi C _iota-beta alkyl group, C te § Rukanoiruamino group, 0 ₆ - ₁₀ Ariru one Ashiru + amino group, sulfonamide de group, Karubokin'ami amino group, C _t - ₁₀ alkoxy one Karubokisami de group. Ariruokishi - Karubokisami de group, 〇 ₇ - like ₁₃ Ararukiruokishi one carboxyalkyl Kisami de group. In the above substituents, rc ₊ - _e alkadienyl group ", for example, 1,3 Butajeniru the like," 0 ₃ _ ₁₀ consequent opening alkyl C _t - ₆ alkyl group ", for example, cyclopentylmethyl, etc. cyclohexylmethyl cyclohexylene the Here, rho and logen represent fluorine, chlorine, bromine, etc., respectively. All other groups are as described herein above. These substituents may be the same or different and may be substituted plurally, and these substituents may further have a substituent.

When A ¹ of the substituent A is specifically represented by, for example,

 10 ¾ "

 Then

 Y ,, / \ S

And so on. When A ² of the substituent す る と is specifically represented by, for example,

For example,

The good one is mentioned above

Is (

Wherein A ^1, A ² of the. A ³ Contact ^ has been fitted positively charged substituent A㊉ for convenience nitrogen atom of the thiazole ring in the fine specifically mentioned groups, the nitrogen atom if the other containing a nitrogen atom In some cases, the positive charge is delocalized to the thiazole ring. So for example the above

In the case of

It is also expressed as such. The present position of the positive charge changes fluidly depending on the state of compound [I] (solid or in solution), solvent type, liquidity, temperature, type of substituent, and the like. It includes both the case where the charge is localized on the nitrogen atom and the case where the charge is delocalized on the entire thiazole ring or fused ring.

In the above compound [I], Θ attached to the right shoulder of the 4-hydroxyl group (1-C00) indicates that the carboxyl group is a carboxylate anion, and is paired with a positive charge on the substituent Α to form an intramolecular bond. Indicates that a salt is formed. On the other hand, compound [I] may be a physiologically acceptable salt or ester. Physiologically acceptable salts include inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, organic acid addition salts, basic amino acid salts and the like. Inorganic bases that can form inorganic base salts include alkali metal (for example, sodium and calcium) and alkaline earth metals (for example, potassium hydroxide), and organic base salts can be formed. Examples of organic bases that can be produced include proforce, 2-phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, trihydroxymethylaminoaminomethane, polyhydroxyalkylamine, and the like. Examples of inorganic acids that can form inorganic acid addition salts such as N-methylglucosamine include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids that can form organic acid addition salts. For example, p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, etc., form basic amino acids. It is a cormorant Ru basic § Mi Roh acids such as lysine, arginine, ornithine, such as a non-Suchijin, and the like. Among these salts, base salts (ie, inorganic base salts, ammonium salts, organic base salts, and basic amino salts) are the substituents R of compound [I]. Or a base salt that can be formed when an acidic group such as a carboxyl group or a sulfo group is present in A, and an acid addition salt (ie, an inorganic acid addition salt or an organic acid addition salt) is a compound [I: A substituent R; Or A contains an amino group; a basic group such as a monoalkylamino group, a dialkylamino group, a cycloalkylamino group, an arylamino group, an aralkylamino group; a cyclic amino group or a nitrogen-containing heterocyclic group; Means an acid addition salt which can be formed into In addition, as the acid addition salt, an acid is added to a portion forming an inner salt of the compound [I], that is, a carboxylate portion at the 4-position (C 00 〇) and a CΗ ₂ Α® portion at the 3-position. The carboxyl group (COOH) at position 4 and CH ₂ A® · M が at position 3 after the addition of mol, where M is an aniline formed by removing proton H ^ from inorganic or organic acids. Indicates ON. For example, chloride ion, bromide ion, sulfate ion, ρ-toluenesulfonate ion, methanesulfonate ion, trifluoroacetate ion, etc. are included. The ester derivative of the compound [I] means an ester that can be produced by esterifying a carboxyl group contained in the molecule, and is an ester that can be used as a synthetic intermediate and a nontoxic non-toxic ester that is metabolically unstable. The ester which can be utilized in the synthetic intermediate C te alkyl ※ esters, C ₂ - ₈ Aruke Niruesuteru, C ₃ - ₁₀ cycloalkyl esters, C ₃ _ _t0 consequent opening alkyl C

K alkyl esters, C _e - ₁₀ Ariru ※ esters, 〇 ₇ - ₁₂ Ararukiru ※ E ester, di C _e - ₁₀ Ariru - methyl ester, Application Benefits 〇 ₆ - ₁₀ § Li Ichiru - methylcarbamoyl glycol ester, such as substituted silyl ester can give. Examples of the “C κ alkyl group” forming a C alkyl * ester include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl , Benzyloxymethyl, 2-methylsulfonylethyl, 2-trimethylsilylethyl, 2,2,2-trichloroethyl, 2-iodoethyl, acetylmethyl, ρ-methodyl benzoylmethyl, ρ-mesyl Benzylmethyl, phthalimidmethyl, succinimidomethyl, benzenesulfonylmethyl, phenylthiomethyl, dimethylaminoethyl, pyridin-l-hydroxyl 2-methyl, methylsulfinylmethyl, 2-cyano-1,1-dimethylethyl, etc. , C ₂ - C ₂ to form formed of _β alkenyl esters - the ₆ alkenyl group wherein And the like, namely vinyl, aryl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, methallyl, 1,1-dimethylaryl.3-methyl-3-butenyl, etc. 0 ₃ - ₁₀ consequent opening alkyl ester to form 〇 ₃ - ₁₀ Shikuroa the alkyl group as the Again, heptyl i.e. consequent opening propyl, consequent opening butyl, cyclopentyl, to consequent opening hexyl, the consequent opening, Noruporuniru, Such as Adamantill, C34. 〇 form a cycloalkyl C ie alkyl esters ₃ - The ₁₀ consequent opening alkyl C alkyl group as the Again, i.e. cyclopropylmethyl cyclopentylmethyl, cyclohexylmethyl and the like cyclohexane, C ₃ -. _T. Forming a § Li Ichiru ※ ester "〇 ₈ - ₁₀ § Li Ichiru ※ group" include e.g. phenyl, One naphthyl, 5-naphthyl, bi full et two Li Le, .rho. two trough Weniru, .rho. chlorophyll Weniru etc., for example, as "Rei_7- _{1 2} Ararukiru ※ group" forming a C ₇ _ _l2 § La alkyl ※ esters, benzyl, i Fuweniruechiru, 2 Fuweniruechiru, Fuwenirupuropiru, naphthylmethyl, P- double filtrated base Njiru , P- main Tokishibenjiru, 1 one indanyl, Fuwenashiru, 3, and etc. 5-di tert- butyl one 4-hydroxycarboxylic benzyl, di C ₈ - ₁₀ Ariru - di C ₆ to form a methyl ester - ₁₀ Aryl—The methyl group is again as described above, ie, benzhydryl, bis

(P- main Tokishifeniru) methyl and the like, Application Benefits Rei_8- _{1 0} Ariru -. Mechirue form the ester Application Benefits C _e _ _t. The arylmethyl group is also the same as described above, that is, trityl, and the substituted silyl group forming the substituted silyl ester is also the same as described above, that is, trimethylsilyl, tert-butyldimethylsilyl, iSi ( CH ₃ ) ₂ CH ₂ CH ₂ Si (CH ₃ ) ₂ — and so on. The above-mentioned esters include esters at the 4-position. Thus, those in which the 4-position is an ester group as described above form a salt such as CH ₂ A® ♦ in the 3-position where is as defined above.

 As metabolically unstable nontoxic esters, those already established in the fields of penicillin and cephalosporin can be conveniently employed in the present invention. Such metabolically unstable non-toxic esters include, for example,

C 2-8 alkanol Iruokishi C alkyl esters, 1 one (C ts an alkoxy) C te alkyl ester, 1-(C alkylthio) such as C Arukirue ester are exemplified, C ₂ _ _beta alkanol Iruokishi C alkyl ester Examples of the ester include acetomethyl ester, 1-acetoxethyl ester, 1-acetooxybutyl ester, 2-acetoxethyl ester, propionyloxymethyl ester, and piperoyloxymethyl ester. , 1 — (C te alkoxy) C ie alkyl esters include, for example, methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxethyl ester, and 11-ethoxyl ester. Examples of the alkylthio) C alkyl ester include methylthiomethyl ester and ethylthiomethyl ester. The present invention also includes, in addition to the above ester derivatives, physiologically acceptable compounds that are converted into compound [I] in vivo. Esters usable as synthetic intermediates and non-toxic metabolically labile esters include esters at the 4-position. Thus, those in which the 4-position is the above-mentioned ether group usually form a salt such as CH ₂ A® · Μ © [wherein, ^ Ξ). ing.

When compound [I] has a hydroxyl group, the hydroxyl group may be protected. As the protective group for a hydroxyl group, ^ - lactam and normal in the field of organic chemistry, everything that can be used as a protective group for the hydroxyl group are available, the C ₂ in - _beta alkanol I group, substituted O butoxycarbonyl group, tert —Butyl, C 7-12 aralkyl ⁸⁵ , di C _β - ₁₀ arylmethyl, tri. et. Aryl-methyl group, 1- (C! -E alkoxy) C alkyl group, 11- (C ts alkylthio) C te alkyl group, substituted silyl group, etc., for example, 2-tetrahydrobiranyl Acetal residues such as, 4-methoxy-14-tetrahydrobiranyl and the like are used.

When compound [I] further has an amino group other than the above-mentioned amino group, the amino group may also be protected. Examples of such an amino-protecting group include the above-mentioned amino-protecting groups as they are. The substituent R in the compound [I] of the present invention. There has broad antimicrobial activity of spectrum is that of the nitrogen-containing Hajime Tamaki (R ^a) or Ashiru group (Rb), various diseases caused by pathogenic bacteria in humans and animals, for example respiratory tract infection, urinary Can be used for the prevention and treatment of tract infections. Antibacterial compound

The following points can be cited as features of the antibacterial spectrum of [I] (R ° = ^Ra or ^Rb ).

 (1) Very high activity against various Gram-negative bacteria.

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

 (3) It is not sensitive to the usual cephalosporin antibiotic treatment: it has a remarkable effect on Udomonas and Aeruginosa.

 (4) It has high activity against many / 3-lactamase-producing Gram-negative bacteria (eg, Escherichia, Enterobacter, Serratia, Proteus).

In particular, aminoglycoside antibiotics such as amycin and gentamicin have been used in the past against microorganisms of the genus Pseudomonas, but the antibacterial compound [I] has an antibacterial activity comparable to these aminoglycosides II. Not only is it shown, but it has significant advantages because it is much less toxic to humans and animals than aminoglycosides.

The antibacterial compound [I] (R ° = ^Ra or ^Rb :) of the present invention has excellent stability, high blood concentration, long duration of effect, and remarkable tissue transferability. It also has features such as.

The method for producing the compound [I] of the present invention or a salt or ester thereof will be described in detail below. The methods described below are all known as reactions, and any of those known methods or methods analogous thereto can be applied. Process (1): Compound [1 ³ "(!. = 1 ^3"; if the R ^a represents a nitrogen-containing heterocyclic group) For example,

(1 - 1): 7 Amino compounds shown below [[pi], or a salt or S. ether (salt, described later for the ester) and the general formula R ^a Hal (R ^a nitrogen-containing heterocyclic group, Hal is fluorine, Compounds [ ^Ia ] (R. ^Ra ) can be synthesized by reacting a halogen atom such as chlorine, bromine or iodine with a compound or a salt thereof as shown in Table N. That is, it is represented by the following reaction formula: c H

 A ®

 CD]

[In the formula, the symbol Ra represents ^a nitrogen-containing heterocyclic group, and the symbols Z, R ⁺ , R ¹³ , A and Hal have the same meanings as described above.]

As the compound R ^a Hal halogen atom (Hal) is fluorine is most frequently used. Compound R ^a H al The salts such as hydrochloride, hydrobromide, sulfate, inorganic acid addition salts such as nitric acid salts.-Phosphate salts. Formiate, acetate, Torifuruoro舴酸salt, methanesulfonic acid Salts and organic acid addition salts such as ρtoluenesulfonate. The reaction is generally carried out at room temperature (about 15 to 30) in water or a water-containing solvent. ° C) with a compound R ^a H al or its salt with 7-Amino Compound [[pi] or carried out by mixing a salt or ester thereof. To prevent the compound R ^a H al is hydrolyzed before reacting with the compound [[pi], it is necessary to adjust the PH of the reaction solution. The optimal pH is 6, 8.5. A deoxidizing agent may be used for the purpose of removing hydrogen halide generated by the reaction from the reaction system. Examples of such a deoxidizing agent include inorganic bases such as sodium carbonate, carbonated carbonate, calcium carbonate, sodium hydrogencarbonate, etc., for example, triethylamine, tri (η-propyl) amine, tri (n-butyl). ) Amine, disopropyruethylamine, cyclohexyldimethylamine, pyridine, lutidine, 7-collidine, N, N-dimethylaniline, N-methylbiperidine, N'-methylrubyrolidine, —methylmorpholine And tertiary amines such as alkylene oxides such as propylene oxide and epichlorohydrin. In addition, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid may be used to prevent them from becoming too alkaline. When a water-containing solvent is used, examples of the organic solvent used by mixing with water include ethers such as dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, and diisopropyl ether; formamide; Amides such as N-dimethylformamide and N, N-dimethylacetamide, such as ketones such as acetone, methylethylketone and methylisobutylketone, as well as dimethylsulfoxide. Examples include sulfolane and hexamethylphosphoramide. The amount of the compound R ^a H al 7 - Amino compound [II] Usually 1-3乇Ru per 1 mol, preferably 1-2 mol. The reaction time is 7 - Amino compound [[pi] and the type of the compound R ^a H al, type of solvent, and depends on the reaction temperature, usually 1 minute to 48 hours, preferably 15 minutes to 3 hours..

The 7-amino compound [Π] has, for example, the general formula

And a compound represented by the general formula Α ′ [Α ”may be substituted with a compound represented by the following formula: A thiazole that forms a condensed ring at the 5-position]] or a salt thereof. That is, <

,-ΙΝ ^Γ Η ₅

 Man.

 -Θ

A

[Wherein the symbols sigma, 11 ^+, 11 ^13, 11 ⁵ Oyobi as defined above]

 This reaction is essentially the same as the nucleophilic substitution reaction described in the production method (2-2).

Compound R ^a Hal and its salts can be readily synthesized by methods analogous thereto, or a known method.

According to this method, for example, a compound of the following formula can be synthesized.

When the compound R ^a H a1 is too active to be easily hydrolyzed, the reaction may be carried out, for example, in anhydrous dimethyl sulfoxide, for example, in the presence of an organic base such as anhydrous triethylamine. By this method, for example, a compound of the following formula can be synthesized. ®

Further, for example, the above reaction may be performed in the presence of an organic acid such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, and butyric acid, or an inorganic acid such as hydrochloric acid, sulfuric acid, and carbonic acid. Also in this case, as the halogen atom (Hal) of the compound R ^a Hal, f-sodium is most frequently used. The reaction is usually carried out in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, chloroform, methanol, acetonitrile, benzene, acetone, water, or a mixture thereof. The reaction temperature is 0 to 150 ° C, preferably 20 to 80 ° C. The reaction time is usually 30 minutes to 20 hours. By this method, for example, a compound of the following formula can be synthesized.

©

(1-2): Compound [IX] or a salt thereof described above as a raw material of compound [1 [] Alternatively, the ester is reacted with the compound R ^a Hal or a salt thereof, and then reacted with a thiazole compound [Α 'is as defined above] or a salt thereof to give a compound [I ^a ] (R ° = R ^a ) can also be synthesized. That is, it is represented by the following reaction formula.

A

R ^a Hal + H _:

 -

COOH

 ! _-"H E

13

,, (M ⁵

 Ouri

(Including salt and ester)

[Wherein, the symbol Ra represents ^a nitrogen-containing heterocyclic group, and the symbols Z, R ⁺ , R ¹³ , R ⁵ , A and Hal have the same meanings as described above.]

The starting compound [IX] and its salts, esters, those mentioned above can be mentioned here for the compound R ^a Hal and its salts. Thiazole compounds and their salts The details will be described later. For the reaction, the method described in the production method (111) can be applied as it is.

Production method (2): Synthesis method of compound [I ^b ] (R. = R ^b ; R ^b represents an acyl group) For example, (2-1): 7-amino compound [Π] or a salt or ester thereof Compound [I ^b ] (R. = R ^b ) by reacting with a compound represented by the general formula R ^b OH, wherein R ^b represents an acyl group; Can be synthesized. That is, it is represented by the following reaction formula.

RboH ten

 [I

[In the formula, the symbol R ^b represents an acyl group, and the symbols Z, R ⁺ , R ¹³ , and A have the same meanings as described above.]

This method is Ku 7- Amino compound [H] carboxylic acid R ^b 0 H or a salt thereof if a is a method of Ashiru with reactive derivatives. Carbonitrile phosphate R ^b OH in this process remains free or salt or reactive derivative 7 - used as Ashiru agent at position 7 § Mi amino group of § Mi Roh compound [[pi]. Inorganic salts ie the free acid R ^¾ OH or the free acid R ^b OH. The organic salts, acids Hara I 'de, acid Ajido, acid anhydrides, mixed acid anhydrides, active § Mi de, active ester, active Chioesuteru Is subjected to the acylation reaction. Examples of inorganic salts include alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, potassium salt, etc.). Organic salts such as trimethylamine salt, etc. Triethylamine salt, tert-butyldimethyla Acid salts, dibenzylmethylamine salts, benzyldimethylamine salts, Ν, Ν-dimethylaniline salts, pyridine salts, quinoline salts, etc. are examples of acid halides, such as acid mouth light, acid such Puromai soil. mixed acid mono C ₆ alkyl carbonate mixed acid anhydride as the anhydride (e.g. the free acid R ^¾ 0 Eta and Monomechi Le carbonate, Monoechiru carbonate, Monoisopuropiru carbonate. Monoisobuchiru carbonate, mono t Ert- butyl carbonate , Monobe Njiru carbonate, mono (P- two preparative port benzyl) carbonate, mixed acid anhydride and the like Monoariru carbonate), C _t - _e aliphatic carboxylic acid mixed acid anhydride (e.g. the free acid R ^b OH with acetic acid, Trichlorobutanoic acid, cyanoacid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, mixed anhydride with trifluroacetic acid, trichloroacetic acid, acetate acid, etc.), C _{7 -t 2} aromatic carboxylic acid mixed acid anhydride (for example, mixed acid anhydride of free acid R ^b OH with benzoic acid. P-toluic acid, Ρ-chlorobenzoic acid, etc.), organic sulfonic acid mixed acid anhydride things (e.g. the free acid R ^b O Eta methanesulfonic acid, ethacrylic - Nsuruhon acid, benzenesulfonic acid, .rho. mixed acid free ^ things with toluenesulfonic acid) soil forces active nitrogen-containing heterocyclic compound as Ami de Ami de (e.g. the free acid R ^b OH with pyrazole Ichiru with, Imidazoru, acid § Mi de and the like benzotriazoles § tetrazole, C alkyl groups of these nitrogen-containing heterocyclic compounds wherein,

A C alkoxy group, a halogen atom, an oxo group, a thioxo group, a C _t - _e alkyl thio group, etc.). As the active ester, any one used for this purpose in the field of ^ -lactam and peptide synthesis can be used. For example, in addition to organic phosphates (eg, ethoxy phosphate, diphenyloxyphosphate, etc.), P- 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimid ester, 1-hydroxybenzotriazole ester, 6 — Black mouth 1 — Hydroxybenzotriazo —Hylester, 1—Hydroxy— 1H—2-Pyridone ester. The active thioester is an ester with an aromatic heterocyclic thiol compound (eg, 2-pyridylthiol ester, 2-benzothiazolyl thiol ester, etc.), and these heterocyclic rings are the above-mentioned C alkyl group, C alkoxy group, halogen atom, ^ 8 alkylthio group or the like). On the other hand, the 7-amino compound [Π] is used as a salt or ester as it is. Salts of the 7-amino compound [K] include inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, and organic acid addition salts. Alkali metal salts (for example, sodium salt, potassium salt, etc.) and alkaline earth metal salts (for example, calcium salt), etc. as inorganic base salts, and-Organic base salts, for example, trimethylamine salt, etc. Triethylamine salt, tert-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt, etc., are inorganic acid addition salts. For example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like are used. As organic acid addition salts, formate, acetate, trifluorophosphate, methanesulfonate, p-toluenesulfonate, etc. Acid salts and the like. As the ester of the 7-amino compound [Π], the ester already described as the ester derivative of the compound [I] can be used as it is. That C ie alkyl esters, C ₂ - _e alkenyl Niruesuteru, C ₃ - ₁₀ cycloalkyl esters, C ₃ - _s cycloalkyl

C _t one ₈ alkyl esters, C ₆ - ₁₀ § Li Lumpur 'ester, 0 ₇ - ₁₂ Araruki esters, di C ₆ - ₁₀ § Li - methyl ester, Application Benefits C _e - _l0 § Li Rume Chiruesuteru, C ₂ - _β alkanoyloxy C alkyl esters and the like. Raw material R ^b OH and their salts, reactive derivatives may be readily prepared by methods analogous to known methods or to it. The reactive derivative of the compound R ^b OH is a 7-amino compound as a substance isolated from the reaction mixture. [[Pi] and may be reacted, or compound before isolation R ^b p reaction mixture as 7- Amino compounds containing reactive induction of H may be reacted with [[pi]. When using the carboxylic acid R ^b OH in the form of free acid or salt using an appropriate condensing agent. Examples of the condensing agent include,, Ν '-dicyclohexyl carpo imides, such as Ν, —'-disubstituted carpo imides, such as Ν, N '-carbonylsimidazole, Ν, Ν'- Dehydrating agents such as thiocarbodiludimidazoles and other azolides, for example, diethoxycarbonyl 2-, ethokin-1,2, -dihydroquinoline, oxychloride, alkoxyacetylene, for example, 2-chloropyridinium methyl Iodide, 2-loginopyridinium salts such as 2-fluoropyridinium methyl iodide are used. When this is used also condensing agent, the reaction is when to proceed via a reactive derivative of the carboxylic acid R ^b OH considered Erareru. The reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. 'Examples of such solvents include ethers such as dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol-dimethyl ether, and the like, for example, ethyl ethyl formate, ethyl ethyl acetate, and ethyl acetate. Esters such as n-butyl, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane, for example, hydrocarbons such as n-hexane, benzene, toluene, for example, formamide Amides such as N, N, -dimethylformamide, N, Ν-dimethylacetamide; ketones such as acetone, methylethylketone, and methylisobutylketone, for example, acetonitrile, propionodiamide Strength such as nitriles such as toril, Methyl sulfoxide, sulfolane, hexa methyl phosphoramide § Mi de. Water avenues are used alone or as a mixed solvent into. The amount of the acylating agent (R ^b 0 H) is usually 1 to 5 mol per 1 mol of the 7-amino compound [Π], Preferably it is 1-2 mol. The reaction is -80-80. C, preferably in the temperature range from 40 to 50 ° C, most preferably from -30 to 30 ° C. The reaction time depends on the type of the 7-amino compound [Π] and the carboxylic acid RboH, the type of solvent (and the mixing ratio if a mixed solvent is used), the reaction temperature, etc., and is usually 1 minute to 72 hours. It lasts 15 minutes to 3 hours. When an acid halide is used as the acylating agent, the reaction can be carried out in the presence of a deoxidizing agent for the purpose of removing released hydrogen halide from the reaction system. Examples of such deoxidizing agents include inorganic bases such as sodium carbonate, carbonated calcium carbonate, calcium carbonate and sodium hydrogencarbonate, such as triethylamine, tri (η-propyl) amine, and tri (n- Butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, acoridine, N, N-dimethylaniline, N-methylpyridine, N-methylpyrrolidine, N— Tertiary amines such as methyl perforin, for example, alkylene oxides such as propyrene oxide and epichlorohydrin.

For example, the compound [W] described above can be synthesized by the methods described here. The reaction formula is as shown below.

-Θ

 .

 J carvone [ΠΙ] can be easily produced by a known method or a method analogous thereto.

 (2 2): General formula

[Wherein, R ^b is an acyl group and other symbols are as defined above] or a salt or ester thereof and a thiazo represented by the general formula Α '[Α' is as defined above] The compound [ ^1¾ ] (11 ° = 1) can be synthesized by reacting the compound [ ^1¾ ] or a salt thereof. That is, it is represented by the following reaction formula. . A㊉

 [X t) []

Wherein the symbols R ^¾ is Ashiru group, the symbols Z, R ^+, it is R ^13, R ⁵ and A also shows same as defined above]

This reaction involves reacting compound [X] or a salt or ester thereof with thiazole compound A 'or a salt thereof and synthesizing compound [I ^b ] (R ° = R ^¾ ) by nucleophilic substitution. is there. In the compound [X], R ⁵ also represents a hydroxyl group, an acyloxy group, a hydroxypropyl group, a substituted hydroxypropyl group or a halogen atom. Compound [X] is used as a salt or ester as it is. As the salts and esters of compound [X], those given as the salts and esters of 7-amino compound [Π] in the production method (2-1) can be applied here as they are. Compound [X], salts and esters thereof can be easily produced by a known method or a method analogous thereto. On the other hand, the thiazole compound A 'represents a thiazole which forms a condensed ring at the optionally substituted 4,5-position. Here, the condensed ring means a form in which a thiazole ring and a 5- to 6-membered aromatic heterocyclic ring are condensed. And it may be condensed. The thiazole which forms a condensed ring at the 4.5-position of the thiazole (A) which forms a condensed ring at the optionally substituted 4, δ-position is represented by the following general formula: ,. S S

 \

, (CH ₂ ) 'm-B'

[A ^l H LA ² '] [A ³ ']

A thiazole compound that can be represented by the formula: wherein the A © group of the target compound [I ^b ] which can be synthesized by reacting the compound [X] with AA ² 'or A ³ ' The A ¹ and A ² groups correspond to the A ³ group. Therefore, m of A and B of A have the same meanings as those described above, and A, A ² ′ and A ³ ′ may be further condensed similarly to A, A ² and A ^3. It may have a substituent similar to the substituents on AA ² and A ³ . A ¹ '

And so on. For example, if you show Α

And so on. A ³ '

-82

 Coo

20

 And so on.

 The thiazole compound A ′ is also used as a salt. Salts of compound A 'include, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., for example, formate, acetate, trifluoroacetate, methanesulfonate 25 And salts of organic acids such as salts and ρ-toluenesulfonate.

General methods for synthesizing thiazole compound A 'and its salts are known, It can be easily produced by the known method described or a method analogous thereto. This nucleophilic substitution reaction of compound [X] with thiazole compound A 'is a reaction known per se, and is usually performed in a solvent. Solvents used in this reaction include ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, and water used in the production method (2-1). In addition to these, alcohols such as methanol, ethanol, n-propanol, isopropanol, ethylene glycol, and 2-methoxethanol are also used. When the thiazole compound A ′ is a liquid, the compound A ′ may be used as a solvent by using a large excess (for example, 10 to 200-fold mol) of the compound [X]. In this case, the above solvent may not be used, or the above solvent and A ′ may be used as a mixed solvent. '

(2 - 2 - 1 :): R 5 is § Shi) Reokin group, forces Rubamoiruokishi group, when the substituent Karunoku Moiruokishi 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 acetonitrile. The amount of the nucleophile A 'to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound [X]. The reaction is carried out at a temperature in the range of 10 to 100 ° C, preferably 30 to 80 ° C. The reaction time depends on the type of compound [X] and compound A ', the type of solvent (the 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 It is. 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 an oxide or thiosuccinate. Examples of such salts include sodium iodide / potassium iodide, sodium thiocyanate, potassium thiocyanate and the like. In addition to the above salts, For example, by adding a quaternary ammonium salt having a surface active action such as trimethylbenzylammonium bromide, triethylbenzylammonium bromide, or triethylbenzylammonium hydroxide, the reaction is performed. In some cases, it can proceed smoothly.

(2-2-2): When 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 phosphorus compound used herein include 0-phenylene phosphorochlorideate, 0-phenylene phosphorofluorideate, methyl 0-phenylene phosphite, ethyl 0-phenylene phosphite, Propyl 0-phenylene phosphate, isopropyl 0-phenylene phosphate, butyl 0-phenylene phosphate, isopti / le 0-phenylene phosphate, Sec-butyl 0-phenylene phosphate, cyclo Hexyl 0-phenylene phosphate, phenylazole 0-phenylene phosphate, p-chloro phenyl 0-phenylene phosphate, P-acetyl 0-phenylene phosphite, 2-cycloethyl ethyl 0-phenylene Phosphate, 2, 2, 2—Trichloroethyl 0—Phenylenephosphite, Ethoxycarbo Nylmethyl 0-phenylene phosphate, rubamoylmethyl 0-phenylene phosphate, 2-cyanoethyl 0-phenylene phosphate, 2—methylsulfonyletyl 0-phenylene phosphate, benzyl 0-phenylene phosphate 1, 1-Dimethyl-2-propenyl 0-phenylene phosphate, 2-Pro-denyl 0-phenylene phosphate, 3-methyl-2-butenyl 0-phenylene phosphate, 2 — Chenylmethyl 0-phenylene phosphate, 2 —furfurylmethyl 0-phenylene phosphate, bis-1 0-phenylene pyrophosphate,

2 —Phenyl-1,3,2 —Benzodioxaphosphorus 2-oxoxide, 2- (p-chlorophenyl) -1-1,3,2-benzodioxaphosphol-12-oxide, 2-butyl-1,3-, 2-benzodioxaphosphorool-2-oxide, 2 —Anilino-1,3,2-benzodioxaphosphol-12-oxide, 2-fluorothio-1,3,2-benzodioxaphosphor-12-oxide, 2 —Methoxy-5-methyl-1,3,2-benzodioxaphosphoryl 2-oxide, 2-chloro-5-ethoxyquincarbonyl 1,3,2-benzodioxaphosphoryl-2-oxide, 2—Methoxy 5—Ethoxycarbone 1,3,2—Benzodioxaphosphoryl 1—2oxide, 5-ethoxyethoxycarbonyl 2—Phenol 1,3,2—benzodioxaphosphoryl 2-oxide, 2,5-dichloro-1,3,2-benzodioxaphosphoryl 2-oxide, 4-chloride Port—2—Methoxy-1,3,2-benzodioxaphosphoryl 2-oxide, 2-methoxy-4—methyl-1,3,2-benzodioxaphosphor-2 —Oxide, 2,3-Naphthalene methyl phosphate, 5,6-Dimethyl-2-methoxide 3,2, -benzodioxaphosphol-12-oxide, 2,2-Dihydro 4,5,6,7-Tetrachloro-2,2,2-Trimethoxy 1,3,2-benzodioxaphosphol, 2.2-Dihydro 4,5,6,7-Tetraclo 2,2,2-Triphosphinoquinone 1,3,2-benzodioxaphoshole, 2,2-dihydro 2.2-ethylenedioxy-2-methoxy-1,3,2-benzodioxaphos Hall, 2,2-dihidroxy 2-benzyl-2,2-dimethoxy-1,3,2-benzodioxaphosphor, 2,2-dihidro4,5-benzo 1,2,2,2-Trimethoxy 3.2-Benzoxoxaphosphol, 2,2-Dihydro2,2,2,2-Trienoxy-1,1,3,2-benzodioxa Phosphor, 2,2-dihydro-2,2- (0-phenylenedioxy) -1,2-phenoxy-1,3,2-benzodioxaphosphor, 2-chloro-2,2-dihydrodraw 2,2 — (0—Phenylene Dioxy) 1, 3, 2-benzodioxaphosphol, 2, 2-dihidro

2-Methoxy-1,2,2- (0-phenylenedioxy) 1-1,3,2-benzodioxaphosphol, 2,2-dihydro2,2,2—Trichloro-1,3,

2-benzodioxaphosphol, 9,10, -phenylenedioxytrimethoxyphosphorus, 0-phenylene phosphorochloridite, 0-phenylene phosphorobromide, 0-phenylene phosphorofluoride , Methyl 0-phenylene phosphite, butizole 0-phenylene phosphite, methoxycarbonylmethyl 0-phenylene phosphite, phenyl 0-phenylene phosphite, ク ロ -black (or Ρ-2) Toro) phenyl 0—phenylene phosphite, 2-phenyl-11,3,2-benzodioxaphosphol, bis-10-phenylene pyrophosphite, 2-methoxy-5-methyl-1, 3,2-benzodioxaphosphol, 5-acetyl-2, -phenoxy-1,3,2-benzodioxaphosphol, 9,10, -phenanthrene phosphoro Roridai DOO, 2 Black port one 4-methyl-one 1, 3, 2-benzodioxanyl O hexa phosphole, 5-eth Kin carbonyl - 2- Fuweniru one

1,3,2-benzodioxaphosphol, 2-chloro-1,2-thioxo-1,

3,2-benzodioxaphosphol, 2-phenoxy-1-oxo-1,3,2-benzodiazaphosphol, 2-phenoxy-1,3,2-benzodioxazaphos Whole, 2,2-dihydro-2-oxo-2-methoxy-1,5-dimethyl-1,3,2-dioxaphosphol, 2,2-dihydro-2-oxo-1-chloro 4,5-Dimethyl-1, 3,2-dioxaphosphol, 2,2-Dihydro 2-oxo-2- (1-imidazolyl) —4,5-Dimethyl-1,3,2-dioxaphosphol , 2,2-Dihydroxy-2,2-Ethylenedioxy-2-methoxy-4,5-dimethyl-1,3,2-dioxaphosphol, 2,2-Dihydro1-2,2-dimethoxy-2- Phenoxy-1,4,5-dimethyl-1,3,2-dioxaphosphol, 2,2 —Dihydro-1,2,2,2—trimethoxy-1,4,5—dimethyl-1,3,2—dioxaphosphol, 2,2—dihydro-1,2,2,2—triphenoxy-1 , 5 — dimethyl-1,3,2 —dioxaphosphol, 2.2 —dihydro2,2,2, -triethoxy-1,4,5 —diphenyl-1,3,2 —dioxafoshole, 2,2 — Dihydro 2.2,2—trimethoxy 4.5—diphenyl—1,3,2-dioxaphosphol, 2,2—dihydro 2—oxo 1-2—methoxy 1,4,5 —Diphenol 1, 3,2 —Dioxaphosphol, 2,2 —Dihidro 2,2,2 —Trimethoxy-1,3,2 —Dioxaphoshole, 2,2 —Dihidro 2,2 , 2 — Trimethoxy 4-1, 2, 3-dioxaphosphor, 2, 2-dihydro 1, 2, 2-2-Trimethyl 4-methyl 1 .3,2—Dioxaphosphol, 2,2—Dihydro2,2,2—Trimethoxy-4-monomethyl-1-5—Phenylcarbazyl-1,3,2-dioxaphosphol, 2,2 , 4,5,6,7 —hexahydro-1,2,2,2 —trimethoxy 1,3,2 —benzodioxaphosphol, 2,2'—oxybis (4,5—dimethyl 2.2 —Dihydro-1,3,2—dioxaphosphol) and 2,2′-oxybis (4,5—dimethyl-2,2—dihydro1,3,2—dioxaphosphoru-2-oxoxide) and the like. can give. The solvent used in the reaction may be any solvent that does not hinder the reaction, and preferably the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles and the like are used alone. Or used as a mixed solvent. In particular, a good effect can be obtained by using, for example, dichloromethane, acetonitrile, formamide, a mixed solvent of formamide and acetonitrile, or a mixed solvent of dichloromethane and acetonitrile. The amount of the nucleophilic reagent A 'and the amount of the organophosphorus compound to be used are 1 to 5 mol. Per mol of the compound [X]. 1 to 10 mol, more preferably 1 to 3 mol, and 1 to 3 mol, respectively.

6 moles. The reaction is carried out at a temperature in the range of 80 to 50 ° C, preferably 14 to 40 ° C. Done. The reaction time is generally 1 minute to 15 hours, preferably 5 minutes to 2 hours. An organic base may be added to the reaction system. Examples of such organic bases include triethylamine, tri (n-butyl) amine, di (n-butyl) amine, diisobutylamine, dicyclohexylamine, 2,6-lutidine, and the like. Amines are mentioned. The amount of the base added is 1 mole of compound [X].

1 to 5 moles or 'good. '(2-2-3): When R ⁵ is a halogen atom

Preferred solvents are the above-mentioned ethers, esters and nodogenated hydrocarbons. Hydrocarbons, amides, ketones, nitriles, alcohols, water and the like. The amount of the nucleophile A ′ to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound [X]. The reaction is carried out at a temperature of 0 to 80 ° C, preferably 20 to 60 ° C. The reaction time is usually 30 minutes to time, preferably 1 to 5 hours. Anti-) S may be performed 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 (2-1). A 'You may work as a dehalogenating agent. In this case, compound A 'is used in an amount of 2 mol or more per 1 mol of compound [X]. Halogen atom represented by R ⁵ is chlorine, bromine, although Ru der and iodine, preferably iodine. The compound [X] in which R ⁵ is iodine can be easily produced by, for example, the method described in Japanese Patent Application Laid-Open No. 58-57390 or a method analogous thereto.

For example, the compound [W] or [VI] described above can be synthesized by the methods described here. The reaction formula is as shown below.

[W]

Compounds [m] and can be easily produced by a known method or a method analogous thereto. .

 i

 The following compound [XI] including the compounds [W] and [VI] was prepared according to the above-mentioned production method (2-1).

 In addition to the method of 1: :) or (2-2), it can also be produced by the method of the following production method (2-3). Compound [W] can be produced by the following method (2-4) in addition to the method (2-1), (2-1-2) or (213).

 (2-3): The reaction formula is as follows.

Θ

[In the formula, the symbol R ²² ′ represents an optionally substituted heterocyclic group, and the symbols Z, R, R ¹³ , A and R ³ have the same meanings as described above.]

This method is a method of synthesizing a compound [XI] by reacting a compound represented by the general formula R ³ "OH or a reactive derivative thereof with a hydroxyimino compound [V], and by a well-known etherification reaction. Where R ² is l \.

If or, the product [XI] is

Which is compound [VI] or [VI]. 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. 0 H is used as it is or as a reactive derivative thereof. The reactive derivative of R ³⁰ H means a derivative of R ³ ″ OH having a group capable of leaving with the hydrogen atom of the hydroxyamino compound [V], 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 mo-substituted sulfonyloxy group or the like. Examples of the halogen atom include chlorine, bromine and iodine. . Monosubstituted sulfo The Niruokishi group e.g. meta Nsuruhoniru: f xylene, ethacrylic down sulfonyl O carboxymethyl, benzenesulfonyl O carboxymethyl, .rho. toluenesulfonic C alkylsulfonyl O alkoxy groups such Honiruokishi, 0 ₆ - ₁₀ § Li - Le sulfonyl And the like. In particular, in the case of producing a C alkyl ether compound of the compound [V], in addition to the above-mentioned reactive derivatives, for example, C ₊ diazo alkane such as diazomethane and diazoethane, for example, dimethyl sulfate, dimethyl sulfate and the like. C-alkyl sulfate is also used.

Compound [V] can be synthesized according to the acylation reaction described in the production method (2-1) or the nucleophilic substitution reaction described in the production method (2-2). That is, each is represented by the following reaction formula. θ

 [ΧΊ (including salts and esters) The starting compounds [M] and [ΧΊ can also be easily synthesized by a known method or a method analogous thereto. Compound 0H and its reactive derivative can also be easily synthesized by a known method or a method analogous thereto.

(2—3—1): When using R ³ '' 0H

 Reaction with hydroxyimino compound [V] using an appropriate dehydrating agent

[Synthesize ΧΠ. Examples of dehydrating agents used for this purpose include oxylin chloride, thionyl chloride, dialkyl azodicarboxylate (usually used in the presence of phosphine), N, N'-dicyclo-hexylcarbodiimidine. And the like. Preferred is getyl azodicarboxylate in the presence of triphenylphosphine. The reaction using getyl azodicarboxylate in the presence of triphenylphosphine is usually carried out in an anhydrous solvent, and the above-mentioned ethers and hydrocarbons are used. The compound 0 H.Ethyl azodicarboxylate and triphenylphosphine are each used in an amount of 1 to 1.5 mol per 1 mol of the hydroxyimino compound [V]. 0-50. C It takes 1 to 4 days in the temperature range.

(2— 3— 2): When using R ³ "Y

The reaction between R ³ ″ Y and the hydroxyamino compound [V] is a normal etherification reaction, and is performed in a solvent. Examples of the solvent include ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, and water described in the section of the production method (2-1). The solvent or mixed solvent of the above is also mentioned here, and preferably a mixed solvent of water and a water-miscible solvent (eg, aqueous methanol, aqueous ethanol, aqueous acetone, aqueous dimethyl sulfoxide, etc.). This reaction can be allowed to proceed smoothly in the presence of a suitable base. Examples of such a base include inorganic bases such as sodium carbonate and sodium bicarbonate. Alkali metal salts such as carbonated lime, and alkali metal hydroxides such as sodium hydroxide and hydroxylated lime. Is raised. This reaction may be carried out in a buffer solution having a pH of 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, preferably 1 to 3, and 1 to 5, respectively, per 1 mole of the starting compound [V]. The reaction temperature is in the range of −30 to 100 ° C., preferably 0 to 80 ° C. The reaction time is 10 minutes to 15 hours, preferably 30 minutes to 5 hours.

(2— 3— 3): When using C n 'diazonal force

 The reaction is usually performed in a solution. As the solution, the above-mentioned ethers, hydrocarbons and the like are used. After the hydroxyimino compound [V] is dissolved in the solution, the reaction proceeds when a solution of the diazoalkane compound is added. The reagent is used in an amount of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound [V]. The reaction is carried out at a relatively low temperature-50 to 20 ° C, preferably -30 to 0 ° C. The reaction time is 1 minute to 5 hours, preferably 10 minutes to 1 hour.

(2 - 3 4): When using di _d-+ alkylsulfate

The reaction is usually carried out in water or a mixed solvent of water and a water-miscible solvent. Be done. As the mixed solvent, the hydrated solvent mentioned in the production method (2-3-2) can also be used. The reaction is usually carried out in the presence of an inorganic base such as sodium hydroxide, alkali metal hydroxide such as hydroxide lime. 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.

(2-4): The reaction formula is as follows.

[Wherein the symbols 2,1 ^4, 11 ^13, eight, 11 ^1, 11 ² Oyopi 11 ³ have the same meanings as defined above] In this method the compound [YI] and general formula RiCC- S) NH _{2 c} compound Chio urea or a method of synthesizing the target compound [W] by reacting the Chio urea derivative represented [VI] is still free, is used as a salt or ester. X in the compound ["VI" represents a halogen atom such as chlorine, bromine, iodine, etc. As the salt of the compound, the 7-amino compound [Π] mentioned in the section of the production method (2-1) Salts (inorganic base salts, ammonium salts. Organic base salts, inorganic acid addition salts, Organic acid addition salts) are also applied here. Compound same method of preparation as esters [VI] - E ester of (2 1) 7-Amino compounds mentioned in the paragraph of [H] (C beta alkyl ※ esters, C ₂ - ₈ alkenyl esters, C 3- ₁₀ Shi black alkyl esters, C ₃ - ₈ cycloalkyl C tS alkyl esters, C _s - ₁₀ § Li - Le ※ esters, C ₇ -. ₁₂ Ararukiru 'X · esters, di C ₆ § Li

- le - methyl ester, Application Benefits C ₈ - ₁₀ § Li Lumpur one methyl ester, €) ₂ - ₆ § Rukano Iruokishi C _t - like _e alkyl esters Ru fitted here. The starting compound [VI] has the general formula XCHC 0 C-C 00 H

R ²

"OR ³

A compound or a salt or a reactive derivative thereof represented by the above definition] with the above 7 namino compound [Π] or a salt or ester thereof according to the method described in the production method (2-1). In this way, it can be easily manufactured. General formula X C H C O C-C O O H

R ² M,

, R 3 or a reactive derivative thereof can be easily produced by a method known per se or a method analogous thereto. The reaction of compound [VI] with R LC (S =) NH ₂ is usually performed in a solvent. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, and getyl ether; alcohols such as methanol, ethanol, and η-propanol; dimethylformamide, dimethylacetamide, and the like. Amide glue is used. The amount of the thiourea or its derivative R (S =) NH ₂ to be used is generally 1 to 5 mol, preferably 1 to 3 mol, relative to compound [V]. Reaction is 0-100. C, preferably in the temperature range of 20-60 ° C. The reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours.

Compound [I ^b ] produced by the above-mentioned production methods (2-i) to (2-4) When a hydroxyimino group (or a substituted hydroxyimino group) is present in the substituent R ^b (for example, compound [W], [VI], etc.), compound [I ^b ] is converted to syn [Z] mono, anti [E] — May be obtained as a mixture of isomers. In order to separate the desired syn isomer from the mixture, a method known per se or a method analogous thereto is applied. These methods include, for example, fractionation methods utilizing differences in solubility and crystallinity, separation by chromatography, and separation methods utilizing differences in hydrolysis rates of ester derivatives.

Production method (3): Method for synthesizing compound [I ^c ] (R ° = R ^C ; R ^c represents an esterified carboxyl group)

For example, it can be synthesized by reacting a 7-amino compound [[] or a salt or ester thereof with an oxycarbonyl reagent. Examples of the oxycarbonylating reagent include substituted oxycarbonyl halides (eg, chlorine, bromine, and iodine as halogens), substituted oxycarbonyl azides, g-substituted oxycarbonic anhydrides, and substituted oxycarbonyl sulfides. And substituted oxycarbonyl azolides (as azoles, such as imidazole, ダ -methylimidazole, triazole, 2-thioxazolidine, 2-oxoxazolidine, etc.) are used. The reaction is generally performed in a solvent, with anhydrous solvents being more preferred. Examples of such a solvent include ethers such as dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropyl ether, and ethylene glycol-dimethyl ether, such as dichloroethane, chloroform, carbon tetrachloride, trichlene, and the like. Halogenated hydrocarbons such as 1,2-dichloromethane and nitriles such as acetonitrile; alcohols such as methanol, ethanol, propanol and butanol; n-hexane, benzene and toluene Hydrocarbons such as dimethylformamide, dimethylacetamide, hexamethylphosphorustriamide Amides such as amides, for example, sulfoxides such as dimethylsulfoxide are commonly used and used alone or as a mixed solvent. The amount of the oxycarbonylating reagent to be used is generally 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the 7-amino compound [Π]. The reaction is carried out in a temperature range from -80 to 80 ° C, preferably from -40 to 50 ° C, most preferably from 130 to 30 ° C. The reaction time depends on the type of the 7-amino compound [Π] and the oxycarbonylating reagent, the type of the solvent, the reaction temperature and the like, and is usually 1 minute to 48 hours, preferably 10 minutes to 2 hours. When a substituted oxycarbonyl halide is used as the oxycarbonylating reagent, 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, carbonated calcium carbonate, calcium carbonate, sodium hydrogencarbonate, etc., for example, triethylamine, tri (η-butyl pill) amine, tri (n-butyl). Diamine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, acollidine, N, -dimethylaniline, Ν-methylpyridinine, Ν-methylpyrrolidine.

Tertiary amines such as Ν-methylmorpholine and the like, for example, alkylene oxides such as propylene oxide and epichlorohydrin. After the above-mentioned production methods (1) to (3), the desired compound [I] of the present invention can be obtained by removing and purifying the protective group, if necessary. Hereinafter, the method for removing the protecting group and the method for purification will be described.

Protecting group removal method: As described above, in the field of β-lactam and peptide synthesis, protecting groups for amino groups have been thoroughly studied and the protection method has already been established. Also, a method for removing the amino protecting group has been established in the same manner, and in the present invention, the conventional technique can be used for removing the protecting group as it is. For example, a monohalogenoacetyl group (cloacetyl, bromoacetyl, etc.) is converted to an alkoxycarbonyl group (methoxycarbonyl, ethoxy) by thiourea. Silcaprolponyl, tert-butoxycarbonyl, etc. can be converted to aralkyloxycarbonyl groups (benzyloxycarbonyl, ρ-methylbenzyloxycarbonyl, ρ-nitrobenzoyloxycarbonyl, etc.) by acid (eg, hydrochloric acid). ) Can be removed by catalytic reduction, and 2,2,2-trichloromouth ethoxycarbonyl can be removed with zinc and an acid (such as acetic acid). On the other hand, when the compound [I] is esterified as a synthetic intermediate, the ester residue can be removed by a method known per se or a method analogous thereto. For example, 2-methylsulfonylethyl ester can be converted to an aralkyl ester (benzyl ester, ρ-methoxybenzyl ester, ρ-dimethoxybenzyl ester, etc.) by acid (eg, trifluoroacetic acid) or catalytic reduction. Can remove 2,2,2-trichloroethyl ester with zinc and acid (for example, acid), and silyl ester (trimethylsilyl ester, tert-butyldimethylsilyl ester, etc.) with water only. .

 Purification method of compound [I]: The reaction mixture can be purified by the various production methods detailed in production methods (1) to (3) and, if necessary, by following the above protective group removal method. The resulting compound [I] 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 ([1], Z = S → 0) of the septum compound ([I], Z = S) is obtained by the oxidation reaction of the compound ([I], Z = S). Such an oxidation reaction is a well-known reaction. Oxidizing agents suitable for the oxidation of sulfur atoms in the septum ring include, for example, oxygen, peracids, hydroperoxides, and hydrogen peroxide. Peracids must be prepared by mixing acid and peroxide in situ. Also it can. Peracetic acid, perbenzoic acid and p-chloroperbenzoic acid are commonly used as peracids. The reaction is usually performed in a solvent. Examples of the solvent used in this reaction include ethers such as dioxane and tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform and benzene; and formic acid, acetic acid and trifluorofluoroacid. Organic acids, for example, amides such as dimethylformamide and dimethylacetamide. The reaction is carried out at a temperature in the range of -20 to 80 ° C, preferably at a temperature as low as possible, preferably at 20 to 20 ° C. It is generally known that sulfoxides having S-configuration are mainly formed during oxidation of septum compounds ([I], Z = S). R — and S — sulfoxides are separated by their different solubilities and different migration velocities in a single chromatographic separation. The above oxidation reaction for obtaining the sulfoxide may be carried out before the reaction of the above-mentioned production methods (1) to (3), or after the reaction of (1) to (3). Good.

The compound [I] of the present invention, including the compounds [YE] and [VI], can be administered parenterally or orally as injections, capsules, tablets, or granules in the same manner as known penicillins and cephalosporins. . The dose should be 5 to 80 mgZ / kg, preferably 1 to 20 mg / day, divided into 3 to 4 times a day per kg of the body weight of humans and animals infected with the pathogenic bacteria. Good. As carriers for use as injections, for example, distilled water, physiological saline and the like are used. When used as capsules, powders, contraceptives, and tablets, known carriers are used. Excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxyquinpropyl cellulose, crystalline cell mouth, etc.), lubrication (For example, magnesium stearate. Talc) and lyophilizer (for example, potassium ruboxymethyl calcium, talc) Can be

BEST MODE FOR CARRYING OUT THE INVENTION

 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 in Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, B0F25 ₊ 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 the UV detector was used as the detection method. Used. Kirizelgel 60 (230-400 mesh), also manufactured by Merck, was used as the color gel for the color. "Sephadex" is manufactured by Pharmacia Fine Chemicais. XAD-Π resin is manufactured by Rohm & Haas Co. NMR. spectrum is X L.- 100A using tetramethyl Sila in as an internal or external reference (100MHz), EM 360 (60MHz ), in EM 390 (90 MHz) or T _eo (60 MHz) Katasupeku Toro meter Measurements were performed and all 5 values were expressed in ppm, and the values in parentheses in the mixed solvents are the volume mixing ratio of each solvent, and% in the solution represents the number of g in 100 ml of the solution. The symbols in the examples have the following meanings.

 s: synclet (singlet)

 d: Doublet

 t: triplet

 q: quartet

 A B q: AB type quartet

d. d: double doublet m multiplet

 br. Broad

 J force, coupling constant

 Hz Herz

 mg millislam, mi 11 igram)

 g Nuram (gram)

 ml Milliliter — milliliter

 J2 Liter (liter)

 % Percent

 10 DMS 0 dimethylsiUfoxide

D ₂₀ Heavy water

CDC 1 ₃ double black hole Holm

 Reference example 1 j.

 7 3-[2- (5-tert-Butoxycarbonylamino-1,2,4-thiadiazo-l- 3-yl)-1 2 (Z) -Methoxyiminoacetamide]-3-( 3-oxobutyryloxymethyl) -1-3-carboxy-4-carboxylic acid.

2- (5-tert-Butoxycarbonylamino-1, 2,4-thiadiazo-1-yl) -1 2 (Z) -Methoxyiminoacetic acid 302 mg was added to 4 ml of methane at the mouth of the flask. Then add 208 mg of phosphorus pentachloride and stir under ice-cooling for 15 minutes. The solvent is distilled off under reduced pressure and hexane is added to the residue. Re-dry under reduced pressure and dissolve the residue in dichloromethane. This solution was prepared by dissolving 300 mg of 7 / 3-amino-3-(3-oxobutyryloxymethyl) -3 -cepum-4-carbonic acid and 0.6 ml of triethylamine in 5 ml of dimethylacetamide. Add to the solution and stir on ice for 30 minutes. Phosphoric acid lg

Is dissolved in 10 ml of water, extracted with methylethyl ketone (iOml), and the extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure Add ethyl ester to the residue and evaporate again to obtain 390 mg of the title compound.

IR spectrum ^, cnT ¹ : 2980, 2940, 1780, 1715, 1540, 1370, 1245, 1150, 1040.855.

 NMR spectrum (c — DMS0) (5: 1.56 (9H, s), 2.20 (3H, s), 3.43 and 3.70 (2H, ABq, J = 18 Hz), 3.65 (2H, s), 4.00 (3H, s) ), 4.80 and 5.12 (2H, ABd, J = 12Hz), 5.18 (lH.d, J = 4.5Hz), 5.88 (lH, dd, J = 9Hz and 4.5Hz), 9.63 an, d, j = gHz: ).

Reference example 2

 7 / 3— [2- (5-a, mino-1,2,4-thiadiazol-3-yl) -1 2 (Ζ) -ethoxyiminoacetamide] —3— (3-oxoptyryloxy Cimethyl) —3-Cefum-4-carboxylic acid.

 Ί β-Ryno-3- (3-oxobutyryloxymethyl) -13-cefum-4-carboxylic acid Ug is suspended in 200 ml of dichloromethane, and 14 g of bistrimethylsilyl acetoamide is added thereto. Stir at room temperature until a solution is obtained. Then, cool on ice, add 14 g of 2- (5-amino-1,2,4-thiadiazole-3-yl) -2 (Z) -ethoxyiminoacetyl chloride, and stir for a while, then add 6 g of dimethylacetamide And stir on ice for 60 minutes. Dichloromethane is distilled off, and the residue is dissolved in methylethylketone. After washing with water and drying, the solvent is distilled off, and the residue is added with getyl ether and collected as a powder by filtration to obtain 12.5 g of the title compound.

I R spectrum ^ cm— 3300, 3000, 1780, 1720, 1620, 1520,

 Hid

 1410, 1260, 1150, 1040.

NMR spectrum (ds-DMSO) (: 1.25 (3H, t, J = 7 Hz), 2.18 (3H, s), 3.41 and 3.63 (2H, ABq, J = 18 Hz), 3.62 (2H, s), 4.18 (2H, q, J = 7Hz), 4.76 and 5. 06 (2H, ABq, J = 13Hz), 5.14 (1H, d, J = .8Hz), 5.82 (1H, d.d, J = 8Hz and 4.

8Hz), 8.00 (2H, br.), 9.48 (1H, d, J = 8Hz) ₀

Reference example 3

 4,5,6,7-tetrahydro 6-methylbenzothiazole.

A mixture of 24 g of 4-methylcyclohexanone, 63 mi of isoprovenil acid and 0.4 g of paratoluenesulfonic acid is refluxed for 7.5 hours under heating, and then the isopropenyl acid is distilled off under reduced pressure. 0.5 g of sodium bicarbonate was added to the residue and distilled under reduced pressure to obtain 30.7 g (pb _{+ o} 100-105 °) of enolacetate. Dissolve this in 100 ml of methane at the dichloromethane outlet, cool to -40 ° C, and drop 32 g of bromine. Then, 100 ml of methanol is added, and the mixture is left at room temperature for 2 days. The solvent is distilled off under reduced pressure, 60 ml of dimethylacetamide and 12 g of thioformamide are added to the residue, and the mixture is heated at 70 ° C for 3 hours. After adding 100 ml of water and 100 ml of ethyl acetate to the reaction solution, the mixture is neutralized with sodium bicarbonate, the organic layer is separated, dried (magnesium sulfate anhydrous), and then the solvent is distilled off under reduced pressure by-pass. The residue is subjected to vacuum distillation to give 13 g of the title compound. bp ₃ . 125 ° C.

Spectrum _{(CDC1 3) 5: 1.10 (} 3H, d, J = 6Hz), 1.58 -3.33 (7H, in),

Reference example

 4,5,6,7-tetrahydro-5- (or 7-) methylbenzothiazole.

In the same manner as in Reference Example 3, 25.89 g (bp _3, 95 ° C) of enolacetate was obtained from 25 nU of 3-methylcyclohexanone, 63 ml of isopropenyl acetate, and 0.4 g of paratoluenesulfonic acid. things get even bromine 31g followed Chioho Rumuami de U.Sg reacted title compound _{.7g (bp 7 75-90 ° C)} . NMR spectrum _{(CDC1 3) <5: 1.10} (3H.d, J = 6Hz), 1. 0 -3.30 (7H, m), 8.

53 (lH, s) ₀ Reference example 5

 7-Methoxy 4-, 5,6,7-tetrahydrobenzothiazole.

A 9-drop mixture of 19 g of xenon, 31 g of N-bromosuccinic acid, and 100 ml of methanol was added with 9 drops of concentrated sulfuric acid under ice-cooling to produce a vigorous reaction, resulting in a homogeneous solution. While the crystalline substance starts to come out, stirring is continued for 60 minutes under ice cooling, and then methanol is distilled off under reduced pressure to dissolve the residue in hexane. After washing with water and drying (anhydrous magnesium sulfate), the solvent is distilled off under reduced pressure. 100 ml of dimethylacetamide and 12 g of thioformamide were added to the residue, and the mixture was heated in an oil bath for 30 hours.The reaction solution was added with 10 Qtn of water and 300 ml of ethyl sulphate, and then bicarbonate. Neutralize with sodium. The organic layer was concentrated under connexion reduced pressure, the residue was purified by silica gel chromatography (Si0 ₂ 150 g, solvent詐酸E

Chill: Hexane = 1.:4 (V / O). The fractions containing the target compound are combined and concentrated to dryness to give 3.7 g of the title compound as an oil. - NMR spectrum _{(CDC1 3) 5:. I.70} -2.30 (4H, m), 2.70 -3.00 (2H, m), 4. '33-4.67 (2H, m) 8.6Q (lH, s).

Reference example 6

 7 8— [2- (5-amino-1,2,4-thiadiazol-3-yl) -12 (Z) -methoxyiminoacetamide] -3- (3-oxobutyryloxymethyl) One 3—Sefmu 4 One-strength rubonic acid.

While stirring 50 tnl of trifluorofluoric acid under ice-cooling, 7; 3- [2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazoyl-3-yl) 1-2 (.Z) -Methoxyiminoacetamide] -1- (3-oxobutyryloxymethyl) -13-cefumu 4 Add 13 g of rubonic acid. Remove the cooling bath and stir for 30 minutes, then evaporate the acid under reduced pressure under reduced pressure. 100 ml of ethyl acetate was added to the residue, and ethyl acetate was distilled off under reduced pressure.100 ml of dimethyl ether was added, and the powder was loosened and collected to obtain the title compound iOg. IR spectrum max cm ^_1 : 1770, 1730, 1700, 1680, 1520, 1400,

1180, 1140, 1040.

NMR spectrum (d ₈ — DMS0) (5: 2.20 (3H, s), 3.43 and 3.64 (2H, ABq, J = 1

8Hz), 3.64 (2H, s), 3.93 (3H, s) 4.77 and 5.07 (2H, ABq, J = 12Hz), 5.14 (1

H, d, J = 4.8Hz), 5.82 (lH, d.d.J = 4.8Hz and 8Hz), 8.00 -9.00 (2H, br.).

9..53 (lH, d, J = 8Hz) ₀

Reference Example 7

 i) 7 ^ — [2- (5-chloro-2-chloroacetamidothiazol-1-4-yl) -12 (Z) -methoxyiminoacetamide] —3- (3-oxobutyrylo Xymethyl) 1-3-Cefum 1-4-Carbonic acid.

2- (5-Chloro-2-chloroacetamidothiazol-1-yl) -12 (Z) -Methoxyimino acid 2,39 g is added to 50 mi of dichloromethane, and then cooled to 8 ° C. While adding 2.13 g of phosphorus pentachloride and stir for 45 minutes. 150 ml of hexane is added little by little to the reaction solution, and the dark oily substance to be precipitated is separated out. The crude corresponding chloride is obtained by washing with hexane. To a solution of sodium bicarbonate 2.0 dissolved in 15 ml of water was added 7 ^ 8-amino-3-(3-oxobutyryloxymethyl)-3 -serum 4-carboxylic acid 2. Q6 g in 15 ml of tetrahydrofuran Add the dissolved solution and then add the above chloride while keeping the internal temperature at 0 ° C to 3. Stir at room temperature for 1 hour 5 or less for 1 hour after the addition, add methylmiethyl ketone 50mi, acidify with concentrated hydrochloric acid, and separate the organic layer. The aqueous layer is oiled with methyl ethyl ketone, the organic layer and the extract are combined, dried (anhydrous sodium sulfate), and the solvent is distilled off under reduced pressure to give 2.94 g of the title compound as a pale orange-yellow powder. NMR spectrum _{(CDCl 3 + d e - DMSO} ) 5: 2.23 (3H, s), 3.24-3.73 (2H, m),

3.50 (2H, s), 4.01 (3H, s), 4.21 (2H, s), 4.91 and 5.18 (2H, ABq, J = 13Hz) .5.05 (lH, d, J-4.5Hz), 5.88 (lH, dd, J = 4.5 Hz and 9 Hz), 6.43 (2H, br.), 8.79 (lH, d, J = 9 Hz).

ii) 7 / 3- [2- (2-amino-5-clothiazol-4-yl) -1 2

(Z) -Methoxyiminoacetamide] -1- (3-oxobutyryloxymethyl) -1-3-Cefem-4.

 7 / S— [2- (5-chloro-1--2-chloroacetamidothiazole-4-yl) -12 (Z) -methoxyiminoacetamide] -13- (3-oxobutyryloxymethyl) -13-cefum 1. Dissolve 2.94 g of rubonic acid in a mixture of 13 ml of water and 13 ml of tetrahydrofuran and stir at room temperature for 3 hours while adding 3.15 g of sodium N-methyldithiocarbamate in three portions. Ethyl acetate is added to the reaction solution, acidified with concentrated hydrochloric acid, and the ethyl acetate layer is separated and drained. The aqueous layer was extracted with a total of 200 ml of methyl ethyl ketone, and the extract was washed with brine, dried (anhydrous sodium sulfate) and evaporated to give 2.28 g of the title compound.

NMR spectrum (ds—DMSO + CDCl ₃ ) 5: 2.21 (3H, s), 3.3-3.75 (2Η, πι), 3.57 (2H, s), 3.90 (2H, s), 4.81 and 5.09 (2H, ABq , J = 13 Hz), 5.07 (lH, d, J = 5 Hz), 5.77 (lH, dd, J = 5 Hz and 9 Hz), 7.10 (2H, br.), 9.46 (1H, d, J = 9 Hz).

Reference Example 8

 7 ^ —tert-Butoxycarbonylamino-3- (3-oxobutyryloxymethyl) -3-cefuemu 4 One-strand rubonic acid.

7 / 3-Amino-3- (3-oxobutyryloxymethyl) -13-cefm-4 Add 200 g of rubonic acid to 500 ml of dimethyl sulfoxide and add 200 g of di-tert-butyl dicarbonate at room temperature. Stir for 16 hours. Anti Add 200 g of ice, 2 g of water, and 1 g of ethyl ethyl acetate to the reaction mixture, stir and distribute to form an upper layer. To the aqueous layer, add 1E2 of acid ethyl ester, and add 129 g of phosphoric acid dropwise with stirring (PH4). After thoroughly stirring, partition and take the upper layer, and extract the lower layer with ethyl acetate 1 J2. The combined organic layers are washed twice with 2 J2 each of ice water and then with 1 J2 of saturated saline. After dehydration with magnesium sulfate, concentrating, adding methylene chloride LOOml and concentrating and drying, 194 g (74% yield) of the title compound is obtained as a glassy solid.

As C 17 H 22 N 20 a S · 1 / 2H 2 0,: elemental圻値

 Calculated value (%): C, 48.22; H.5.47; N ', 6.62.

Found (%): C, 48.16; H.5.30;, 6.32 0

IR spectrum ^ 'cnT ¹ : 1780, 1720, 1520, 1370, 1320.

NMR spectrum _{(d e - DMS0) <5} :. 1.42 (9H, s), 2.18 (3H, s), 3.41 and 3.62 (2H, ABq, J- 18Hz) 3.62 (2H, "s), 4.7S- And 5.06 (2H, ABq.J = 14Hz), 5.03 (lH.d, J = 5Hz), 5.45 (lH, dd, J = 5Hz and 8Hz), 7.83 (1H, d, J = 8Hz) ₀ Reference example 9

 7, β— [2 — (5 —amino-1,2,4 —thiadiazol-3 —yl) -1 2 (Ζ) —methoxyiminoacetamide] 1 3 — (3 —oxobutyryloxymethyl) 1 3 —Sefemu 4-carboxylic acid.

While stirring 50 ml of trifluoroacetic acid under ice-cooling, 7 ^ — [2— (5—tert-butoxycarponylamino—1,2,4-thiadiazol-3-yl) -1-2 (Z) -methoxy Iminoacetamide] —3— (3-oxobutyryloxymethyl) -13—cebum-4-carboxylic acid 13 g is added. Remove the cooling bath and stir for 30 minutes, then distill off trifluoroacetic acid under reduced pressure. Ethyl acetate (100 ml) was added to the residue.Ethyl acetate was distilled off under reduced pressure, and then ethyl ether (100 ml) was added.The powder was loosened and collected to obtain 10 g of the title compound. You.

IR spectrum cnT ¹ : 1770, 1730, 1700, 1680, 1520, 1400, max

 1180, 1140, 1040.

NMR spectrum (d _e — MS0) (5: 2.20 (3H, s), 3.43 and 3.64 (2H, ABq, J = 18 Hz), 3.64 (2H.s), 3.93 (3H, s), 4.77 and 5.07 (2H, ABq, J = 12Hz), 5.14 (lH.d, J = 4.8Hz), 5.82 (lH, dd, J = 4.8Hz and 8Hz) .8.00 -90 .. (2H, br.), 9.53 ( lH, d, J = 8Hz).

 Reference Example 10

 2- (5-tert-butoxycarbonylamino-1, 2,4-thiadiazo0

 -3-yl)-2 (Z)-tert-butoxycarbonyl methoxyimino

 13 g of 2- (5-teft-butoxycarbonylamino-1.2,4-thiadiazo-1-yl-3-yl) acetic acid; 10.9'g of selenium dioxide and 200 ml of dioxane Ripen in the bath for 40 minutes. Dioxane is distilled off under reduced pressure, 200 ml of ethyl acetate is added to the residue, and the insoluble matter is removed by filtration. After the ethyl acetate is distilled off under reduced pressure, the residue is dissolved in 100 ml of ethanol, and 6.2 g of 0- (tert-butoxycarbonylmethyl) hydroxyamine is added under ice cooling. After stirring at room temperature for 4 hours, ethanol is distilled off under reduced pressure. Ethyl acetate lOOtnl, 200 ml of water were added to the residue, and the insoluble matter was removed by filtration.

 Then separate the organic layer and shake well with 5 g of sodium bicarbonate and 300 ml of water. The aqueous layer was separated, and ethyl acetate (OOOml) was placed thereon. The mixture was acidified with 1N hydrochloric acid, the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off to obtain 1 lg of the title compound as crystals. Can be

 Melting point 128 ° C (decomposition)

NMR spectrum (CDC15: 1.43C9H, s), 1.55 (9H, s), 4.73 (2H, s). Reference Example 11

 7 3-[2- (5-tert-butoxycarbonylamino) 1.2.4 —thiadiazol-3-yl) -1 2 (Z) — (tert-butoxycarbonylmethoxyimino) acetamide] —3 — (3— Oxobutyryloxymethyl) 1-3-septum-4-carboxylic acid.

 2 — (5 itert—butoxycarbonylamino-1.2.4—thiadiazo-1-yl) -3- (Z) —tert-butoxycarbonylmethoximinoacetic acid Dissolve 13 g in 100 ml of dichloromethane and stir under ice-cooling. While adding 7 g of phosphorus pentachloride. After stirring for 20 minutes under ice-cooling, the solvent is distilled off under reduced pressure. The residue is dissolved in hexane, hexane is distilled off under reduced pressure, and the residue is dissolved in a small amount of dichloromethane. This solution is added to a solution consisting of 10 g of 7 / 3-amino-3- (3-oxobutyryloxymethyl) -3-cef-4-carboxylic acid, 16 g of bistrimethylsilyl acetate amide and dichloromethane. . After stirring under ice-cooling for 1 hour, dichloromethane was distilled off under reduced pressure, methane was distilled off, the residue was dissolved in ethyl acetate 300nd, washed twice with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Leave. Hexane was added to the residue, and the resulting precipitate was collected by filtration to obtain 23 g of the title compound.

IR spectrum ^ ^KB cnT ¹ : 3250, 2960, 1780, 1715, 1540, 1370, max

1205, 1150.1060 _o

NMR spectrum (d _e — DMS0) (5: 1.43 (9H, s), 1.50 (9H, s), 2.18 (3H, s), 3.41 and 3.65 (211 89, ₁ 1 = 18112), 3.62 (2H, s), 4.66 (2H, s), 4.78 and 5.0 6 (2H.ABq, J = 12Hz), 5.15 (1H.d, J = 4.8Hz), 5.86 (1H, d.d, J = 4.8Hz i 8Hz ), 9.56 (lH, d, J = 8Hz) _Q

 Reference Example 12

7 ^ — [2— (5-amino-1, 2,4 —thiadiazole-1 —yl) 1 -110-

2 (Z) -Carboxymethoxyiminoacetamide] -1- (3-oxobutyryloxymethyl) -1-3-Cefem-4 mono-rubonic acid.

 Stir in 50 ml of trifluoroacetic acid under ice-cooling while stirring with 7- [2— (5—tert-butoxycarbonylamino—1,2,4-thiadiazole-13-yl) 1-2 (Z) — (tert-butoxy Carbonyl methoxyimino) acetamide] —3— [3—oxobutyryloxymethyl-13-cefm-14 Add 23 g of rubonic acid, remove the cold bath, stir for 1.5 hours, and mix with ethyl acetate. And the solvent is distilled off under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was loosened and collected by filtration to obtain 17 g of the title compound.

 Ten

IR spectrum ^ cnT ¹ : 1760, 1720, 1630, 1520, 1400, 1310, max

NMR spectrum (d _e —DMSO) (5: 2.20 (3H, s), 3,41 and 3.65 (211 83, '' = 18 Hz), 3.63 (2H, s), 4.65 (2H, s), 4.78 5.07 (2H, ABq, J = 12Hz), 5.15 (lH.d, J = 4.8Hz), 5.85aH, dd, J = 4.8Hz and 8Hz), 8.10 (2H, br.), 9.4

1) 2 (Z) —Methoxy lacquer draw 6—Methyl fumu 4

7 ^ 5— [2— (2—Aminothiazole—4-yl) -1 2 (Z) —Methoxyiminoacetoamide] 1 3— (3—Oxoptyryloxymethyl) 1 3— Cefume 4-carboxylic acid ^) g.4, 5,6.7 -tetrahydro 6 -methylbenzothiazole iOg and iodinated water IOg of acetonitrile and water (1: 1, V / V) Dissolve in 200 ml of the mixture and stir at 70 ° C for 1.5 hours. The organic layer is removed by adding 200 ml of ethyl acetate to the reaction mixture, and the aqueous layer is subjected to XAD-2 force column chromatography. The fraction is eluted with 20% ethanol water, the fraction containing the target compound is collected, freeze-dried, and the obtained solid product is subjected to LH-20 column chromatography and eluted with water. Lyophilization of the fraction of interest yields 2.5 g of the title compound.

As _{C 22 H 24 N e S 3} 0 5 · 9 / 2H 2 0,: elemental圻値

 Calculations (%): C, 41.96; Η.5.28; Ν, 13.35.

Found (%): C, U.96; H, 4.23; N, 13.13 0

IR spectrum! Cm "" ¹ : 2950, 1770, 1675, 1620, 1535, 1385, max

 1350, 1040.

NMR spectrum _{(d e - DMS0) S:} (. 7H, br) 1.05 (3H, d, j = 6Hz), 1.84- 2. ί5 and 2.70 -3.10, 3.82 (3H, s ), 5.04 (1H, d , J = 4.8Hz), 5.24C2H, r.s), 5.65 <aH, dd, J = 8Hz and 4.8Hz), 6.72 (lH, s), 7.16 (2H, br.s), '9.48 (1H , D, J = 8 Hz), 10.32 and 10.37 (total 111, 3 each).

Using the same method as that described in Example 1, 73- [2- (2-aminothiazolyl-4-yl) -2 (Z)-(substituted oxymino) acetamide] 1 3 — (3 —oxobutyryloxymethyl) -1 3 —Cefem-1 4 —General formula from the reaction of carboxylic acids with various thiazole derivatives

The following compounds of Examples 2 to 4 represented by can be produced.

Example 2

 7 ^ — [2- (2-aminothiazole-4-yl) -1 2 (Z) -methoxyiminoacetamide] -1 3 — [(6,7-dihydro-1-4H-pyrano [4, 3-d] thiazolium-1-yl) methyl] —3-sefmue 4-carboxylate. .

 Θ,

 w -s

Compound [W '] (P, ³ = -CH ₃ , A Θ — 0 Elemental Ki value: C 2oH ₂ o ₈ OeS 3-11 / 2H ₂₀

Calculated value (%): C, 37.79; H.4.92; N, 13.22 ₀

 Found (%): C, 37.78: H.3.56; N, 12.96.

IR spectrum ^ ^ cnT ¹ : 1770, 1670, 1620, 1535, 1385,

1360, 1040.

NMR spectrum _{(d e - DMS0) 5:} 3.83 (3H, s), 5.04 (1H, d, J = 4.8Hz), 5.

27 (2H, br.s), 5.65 (111, d.d, J = 8Hz and 4.8Hz), 6.71 (lH, s), 7.18 (2H, brs), 9.49 (lH, d, J = 8Hz) , 10.49 (lH, br.s) _o

Example 3 7 ^ 8— [2-((2-aminothiazole-1-4-yl))-1 2 (Z) — (2-methoxyethoxymino) acetoamide] -1 3 — [(4,5,6,7 —Tetrahid benzothiazolyl-1-yl) methyl] —3-Cefem—4-Carboxylate.

Compound [VT] (R ³

Elemental Xin value: C ₂₃ H ₂₅ N _e O _e S ₃ · 7 / 2H ₂₀

Calculated value (%): C, 43.12; H, 5.03; N, 13.12 ₀

 Found (%): C, 43.42; H.4.92; 2, 12.98. ·

IR spectrum ^ cnT ¹ : 1780, 1670, 1620, 1535, 1040.

 max

MR spectrum _{(d e - MSO) <5} : l.oO-2.00 (4H (tn), 2.55-3.00 (4H, m), 3.

26 (3H, s), 3.4-3.8 (2H, m), 3.9-4.3 (4H, m), 5.06 (1H, d, J-.5Hz), 5, 27 (2H, br.s), 5.71 ( 1H, d.d, J = 4.5Hz and 8Hz), 6.69 (lH, s), 7.17 (2H, brs), 9.42 (lH, d, J = 8Hz). 10.29 (lH, s) _o

Example 4

 7 ^ 8— [2— (2-aminothiazoyl 4-yl) -1 2 (Z) —methoxyiminoacetamide] —3 — [(4,5,6,7—tetrahi Draw 7—Methoxybenzothiazol-1-yl) methyl] —3-Cefem—41-carboxylate.

Θ

 、, S

Compound [VT] (R ³ =-CH ₃ , A Θ

/ Elemental folding value: as _{C 22 H 2 + N e 0} 8 S 3 · 10H 2 O,

 Calculated (%): C, 35.48; H. 4.60; N, 11.28.

 Found (%): C, 35.82; H.3.57; N, 11.53.

IR spectrum max cm- ¹ : 2950, 1775, 1680, 1620, 1540,

1390, 1355, 1145, 1115, 1040.

MR spectra _{(D 2 0) (5:} .. 2.0o (4H, br), 2.84 (3H, br), 3.55 (3H, s), 4. 00 (3H, s), 5.27 (lH, d, J = 4.8 Hz), 5.16 i 5.39 (2H, ABq, J = 14 Hz), 5.86 (lH, d, J = 4.8 Hz), 7.00 (1H, S), 9.88 (trace, s).

 Using the same method as described in Example 1, 7; 3- [2- (5-amino-1, 2,4-thiadiazol-3-yl) -2 (Z) — (substituted oxymino) [Acetamide] —3-oxobutyryloxymethyl) -1-cefume 4 General formula from the reaction of rubonic acid with various thiazole derivatives

The following compound of Example 5 ^ 10 represented by can be prepared.

Example 5

7; 8— [2— (5-amino-1,2,4-thiadiazol-3-yl) -1 2 (Z) —ethoxyiminoacetoamide] —3 — [(4,5,6, 7—Tetrahydrobenzobenzthiazolium—3-yl) methyl] —3-Sefmue 4-Carboxylate. Θ

Compound Hi (R ³ =-CH ₂ CH ₃ , A

Elemental folding value: as _{C 21 H 23 N 7 0 5} S 3 · 3H 2 0,

Calculated value (%): C, 41.78; H.4.84;, 16.24 ₀

 Found (%): C, 41.60; H.4.86; N.16.01.

IR spectrum ί cm— ¹ : 2950, 1770, 1670, 1610, 1520,

 max

NMR spectrum (d _e — DMS0) <5: 1.23 (3H, t, J = 7 Hz), 1.82 (br.s) and [

 2.82 (br.s) (total 8H), 4.16 (2H, q, J = 7Hz i)

 ), 5.04 (1H, d, J = 4.8Hz), 5.

 ^ /

 25 (2H, br. ^), 5.68 (1H, d.d.J = 8Hz and 4.8Hz), 8.10 (2H.br.S), 9.41 (1

H.d, J = 8 Hz), 10.32 (lH, s).

Example 6

 7 5 [2— (5-amino 1,2,4-thiadiazoyl 3-yl) -1 2 (Z) —ethoxyiminoacetamido] -1 3 — [(4,5,6,7 —Tetrahydro — 6-Methylbenzothiazolium 3-yl) methyl] -1-3-cef-14-carboxylate.

Compound [V! T] ( ³

Elemental analysis value: C ₂₂ H ₂₅ N ₇ 0 ₅ S ₃ · 5 / 2H ₂ 0

Calculated (%): C, 43.41; H.4.97; N, 16.11 0 Found (%): C. 43.46; H. 4.61; N, 16.17.

IR spectrum max cnT ¹ : 2950, 1775, 1680, 1615, 1520, 1390,

NMR spectra (d _e — DMS0) (5: 1.05 (3H, d, J = 6 Hz), 1.24 (3H, t, J = 7 Hz), 1.90 (1) Γ.) And 2.90 (br.) (Total 7H), 4.16 (2H, q, J = 6Hz), 5.05 (iH, d, J = 4.8Hz), 5.29 (2H, br.s), 5.69 (1H, dd J = 8Hz and 4.8Hz), 8.16 ( 2H, brs), 9.46 (lH, d, J = 8Hz), 10.28 and 10.32 (0.5H each, s).

Example 7

 7 3— [2 — (5 —amino 1,2 2,, /, .4-thiadiazole-3-yl) -1 2 (Z) —ethoxyiminoacetamide] — 3 — [(4, 5, 6,7-Tetrahydro-5- (or 7-) methylbenzothiazolium-3-yl) methyl] — 3 —Sefume 4-carboxylate.

Θ

 -Ψ, s -r

Compound [vir] ³ =-CH ₂ CH _: or -CH _£

Elemental analysis value: C ₂₂ H ₂₅ N ₇ 0 ₅ S ₃ · 5 / 2H ₂ 0

 Calculated value (%): C, 43.41; H.4.97;, 16.11ο

Found (%): C, 43.39; H.4.49; N, 16.43 ₀

IR spectrum ^ cnT ¹ : 2960, 1775, 1680, 1620, 1520, 1385,

1350, 1040 _o

NMR spectrum _{(d e - DMS0) 5:} 1.24 (3H, t, J = 7Hz), 1.00 -1.30 (3H, tn),

1.70_2.10 1 \) and 3.00-2.600)] :.) (710, 4.15 (2H, q, J = 7Hz), 5.04 ClH.d, J = 4.8Hz), 5.22 (2H, br.s) , 5.68 (1H, d.d, J = 8Hz and 4.8Hz), 8.

f I 255 12 (2H, br.s), 9.42 (1H, d, J = 8Hz), 10.38 (lH.s) _o

 Example 8

 7- [2— (5-amino-1,2,4-thiadiazol-3-yl) -1 2 (Z) —ethoxyquiniminoacetamide] —3 — [(4,5-cyclopentenothiazolidamide) 3- (yl) methyl] —3-Sefm—4-carboxylate

© to '

-Ψ ^κゝ S

The compound `` \ (^ ³ = -CH Cii,

10 Elemental analysis value: C ₂₀ H ₂₁ N ₇ O ₅ S ₃ · 3H ₂₀ as',

 Calculated value (%): C, 40.7 H, 4.62; N, 16.63.

Obtained value (%): C, 40.53; H, 4.39; N, 16.36 _0-

IR spectrum ^KBr cm ^_1 : 1770, 1680, 1615, 1525, 1390,

 max

 1360, 1040.

NMR spectrum (d _e — MSO) 5: 1.24 (3H, t, J = 7 Hz), 4.16 (2H, q, J = 7 Hz). 5.05 (lH, d, J = 4.8 Hz), 5.70 (1H, d.d, J = 8 Hz and 4.8 Hz), 8.10 (2H, br.s), 9.44 (lH, d, J = 8 Hz) ₀

 20

 Example 9

7 3— [2— (5-amino-1,2,4-thiadiazol-3-yl) -1 2 (Z) —ethoxydiiminoacetamide] 1 3 — [(6,7—dihydro-4H 1-Pyrano [4,3-d] thiazolymethylene 3-yl) methyl] —3-Sefmue monocarboxylate. ®

To compound [V] (R ³ =-CH ₂ CH ₃ , A

Elemental folding value: as _{C 20 H 21 N 7 0 6} S 3 · 4H 2 0,

Calculated value (%): C, 38.52; H.4.69; N, 15.72 ₀

Found (%): C, 38.45; H.3.82; N, i5.29 ₀

IR spectrum! / cnT ¹ : 1770, 1680, 1620, 1520, 1390,

 max

 1360, 1040.

NMR spectrum (d _e — DMSO) <5: 1.24 (3H, t, J = 7 Hz), 4.15 (2H, q, J = 7 Hz), 4.76-4.90 (2H, m), 5.04 (1H, d, J-4.8Hz), 5.28 (2H, br.s), 5.68 (1 Hdd J = 8Hz and 4 _: 8Hz), 8.12 (2H, br.s), 9.4 (1H, d, J = 8Hz), 10.44 (1 H, s) ₀

Example 10

 7 — [2— (5-amino-1,2,4-thiadiazole-3-yl) 1-2 (Ζ) —ethoxyiminoacetamide] —3 — [(4,5,6,7—te Traffic Draw 7-Methoxybenzothiazol (3-yl) -13-Cefenyl carboxylate.

Compound PV1 '] 0? ^Three

IR spectrum i ^ ^KB]: cm ^-1 : 2950, 1775, 1680, 1620, 1525, 1390, max

NMR spectrum _{(D 2 0) <5:} (. 4H, br) 1.33 (3H, t, J = 7Hz), 2.04, 2.83 (3 H.br.), 3.24 and 3.57 (211,489, ₁ [= 18112) , 3.53 (3H, s), 4.35 (2H, q, J = 7 Hz), 5.15 and 5.37 (211.8. ₍ 1 = 14112), 5.26 (lH.d.J = 4.8Hz), 5.88 (1H, d, J = 4.8 Hz), 9.87 and 9.89 (total 111, each s).

Example 11 '

 7 ー [2— (5—amino 1,2,4—thiadiazole-1-yl) 1

2 (Z) —Methoxyiminoacetamide] -1—3 — [(4.5, 6, 7—tetrahydrobenzobenzothiazolyl-1-yl) methyl] —3-Cefem-4-carboxylate.

Compound

7 ^ — [2- (5-amino-1,2,4-thiadiazole-13-yl) -12 (Z) -methoxyiminoacetamide] -3- (3-oxobutyryloxymethyl 1) 3-Cefume 4-carboxylic acid l g. Potassium iodide lg, 4, 5, 6, 6-, 7-tetrahydrodrobenzothiazole 1 g, water 10 ml, acetonitrile 1 Oml Immerse in a 75 ° C oil bath and stir for 1.5 hours. After cooling, mix well with 30 ml of ethyl acetate, allow to stand, and separate the aqueous layer. After concentration, apply it to gel gel column chromatography, develop it in Aceton, and then develop it in Acetone-Ice (7: 3). Concentrate the target fraction and freeze-dry to obtain 0.12 g of the title compound.

Elemental folding value: as _{C 20 H 21 N 7 O 5} S 3 '3H 2 O,

Calculated value (%): C, 40.74: H, 4.62; N, 16.S3. Found (%): C, 41.06; H, 3.84; N, 16.34.

IR spectrum ^KB cnT 1770, 1670, 1610, 1520, 1385,

 max

Example 12

 7 1 [2— (5—Amino-1.2,4-thiadiazol-3-yl) -1 2 (Z) —Ripoxymethoximinoacetamide] —3 — [(4,5,6,7 ーTetrahidrobenzothiazolium-3-yl) methyl] —3—Cefem—4 Monocarboxylate monosodium salt.

Compound

7 / 3— [2— (5—Amino-1,2,4-thiadiazoyl3—yl) -1 2 (Z) —Carboxymethoxyiminoacetamide] 1-3— (3-oxobutyryloxymethyl ) 1-Cefem-4 A mixture of 2 g of rutile sorbic acid, 2 g of sodium iodide, 4,5,6,7-tetrahydrobenzothiazole 2 g, acetonitrile 20 ml and water 20 ml Stir for 5.5 hours while heating in an oil bath at 70-75 ° C. After allowing to cool, add 50 ml of ethyl acetate to the reaction solution, shake, separate the aqueous layer, apply to D-2 column chromatography, and elute and elute with 20% ethanol water. The fractions containing the target compound are combined, concentrated, then subjected to silica gel column chromatography, and developed and eluted with acetate and then with acetone-water (7: 3). The fractions containing the target compound are combined, concentrated and freeze-dried to obtain 38 g of the title compound.

Elemental Xin value: ₂₀ ^ 1 ₁₃ 1 ^ ₇ 0 ₇ 3 ₃ 3 'As H ₂ 0, Calculated value (%): C, 39.60: H'3.49: N, 16.16.

Found (%): C, 39.53; H.3.80; N.15.10 _o

IR spectrum ^ ma ^ x cnT ¹ : 1760, 1600, 1520, 1390, 1350,

NMR spectrum (D ₂₀ ) (5: 1.92 and 2.86 (total 811.1) 1 \). 3.25 and 3.57 (2H, ABq, J = 18 Hz), 5.29 (lH, d, J = 4.8 Hz), 5.28 (2H , br.), 5.93 (1H, d, J = 4.8Hz), 9.69 (lH, s) ₀

Example 13

 7 β-tert-Butoxycarbonylamino — 3 — [(4,5.6,7—tetrahydrobenzothiazolymethylene 3-yl) methyl] —3-cefum 4-hydroxylboxylate.

7, S-tert-butoxycarbonylamino 3- (3-oxobutyryloxymethyl) -3-cefume 4-carboxylic acid 4.0g, 4,5,6,7-tetrahydrobenzothiazole 3.0g. Dissolve 4 g of the rim in 10 ml of acetonitrile and 10 ml of water, and stir at 70 ° C for 1.5 hours.

After the reaction, add 30 ml of ethyl ether and stir, stir, and remove the upper layer by tilting. Add 30 ml of ethyl acetate to the lower layer and repeat the same procedure. The lower layer was washed with 200 ml of aceton and a 20: 1 solvent of aceton: water using 70 g of silica gel gel chromatography, and developed with a 3: 1 solvent of aceton: water. Concentrate the fraction and freeze-dry to obtain 0.71 g (yield 15%) of the title compound.

I 1770, 1710, 1615, 1510, 1390, 1370,

NMR spectrum (de-DMS0) <5: 1.40 (9H.s), 1.82 (4Η, πι). 2.83 (411, br.), 3.18 (1Η of ABq, d, J = 18 Hz), 4.96 (lH, d, J = 5Hz), 5.29 (2H, br.s), 5.35 (lH, dd, J = 5Hz and 8Hz), 7.78 (1H, d, J = 8Hz), 10.28 (lH, s) _o Example 14

 7 y3— [2— (2-amino 5-clothiazole-41-yl) -1 2 (Z) —methoxyiminoacetamide] 1-3 — [(4, 5, 6, 7-te Trahydrobenzothiazolymethylene 3-yl) methyl] —3-Sefm—4-carboxylate. .

 7 ^ — [2- (2-amino-5-clothiazole-4-yl) -1-2 (Z) -methoxyiminoacetamido] -3- (3-year-old oxobutyryloxymethyl) The title compound is obtained in the same manner as in Example 1 from 13-cef-14-carboxylic acid and 4.5, 6, 7-tetrahydrobenzothiazole.

IR spectrum ^KBr cm ^-1 : 3300, 1765, 1665, 1610, 1520, 1030.

 max

NMR spectrum (d _e — DMS0) 5: 1, 82 (4H, br.), 2.84 (4H, br.), 3.24 and 3.53 (2H, ABq J = 18 Hz), 5.03 (1H, d, J = 5 Hz) ), 5.31 (2H, br.), 5.67 (1 Hdd, J = 5Hz and 8Hz), 9.48 (1H, d, J = 8Hz), i0.33 (lH, s) _o Example 15

 7 3— [2— (2-Aminothiazo-Lou 41yl) —2 (Z) —Propargyloxyiminoacetamide] -1 3 — [(4,5,6,7—Tetrahydrobenzothiazoli ゥ3- (yl) methyl] -1-3-carboxylate.

Compound [VINO] (R ³ = — CH) ₂ C≡CH,

 Elemental analysis value 23H22N6O503 * on 2O i

Calculated value (%) C45.10; H.4.61; Ji, 13.72 _c

Found (%) C 44.85; H.4.74; N, 14.0i c

 KBr

 I R spectrum cm '1770, 1610, 1540'

 max

NMR spectra) (d _e -DMS0) <5: 1.50-3.00 (SH, m), 3.13 and 3.46 (2H, ABq, J = i 8Hz), 5.00 (lH, d, J = 4.8Hz), 5.20 -5.35 (4H, in), 5.70 (1H, d.d, J = 4.8Hz i8Hz), 6.65 (lH ₍ s), 7.20 (2H, br.s), 9.30 (lH _> d ₎ J = 8Hz) , 10.20 (lH, s) _o Using the same method as described in Example 1, 73- [2- (2-aminothiabour-4-yl) -1-2 (Z) -propargyloxymino [Acetamido] -1-3- (3-oxobutyryloxymethyl) -13-cefm-4 carboxylic acid and 4,5,6,7-tetrahidrobenzodiazole This gives the title compound.

Example 16

7,5—Amino 3 [(4,5.6,7—Tetrahydrobenzobenzothiazolym-13-yl) methyl] -13-cefum—41-carboxylate trifluorophosphate.

 7β-tert-butoxycarbonylamino 3-([4,5.6,7-tetrahydrobenzozothiazolymethylene-3-yl) methyl] -13-cefume-4-carboxylate obtained in Example 13 0.70 g is suspended in 10¾2 of dichloromethane under ice-cooling, and 10 and 2 of trifluoroacetic acid are added and stirred for 30 minutes. After distilling off the solvent under a reduced pressure, add 30 ml of Jetil ether and stir, and collect the precipitated powder by filtration. -Wash twice with 1 ozfi each of getyl ether and once with hexane 1 and dry to obtain 0.68 g (83% yield) of the title compound as a pale yellow powder.

Elemental analysis value: C ₁₅ H ₁₇ N ₃ 0 ₃ S ₂ · 2CF ₃ C00H · 3H ₂₀

Calculated (%): C 40.07; H.4.42 ;, 7.38 0

"Found (%): C 40.00; H.4.71 ; ίί, 7.09 ο

 KBr

IR spectrum cm " ¹ 1780, 1680, 1400, 1340, 1200.

 max

NMR spectrum _{(d e -DMS0) δ: (} . 4H, br) (. 4H, br) (. 2H, br) 1.82, 2.6-3.0, 3. 5, 5.08 (lH, d, J = 5Hz). 5.17 (4H, br.), 5.4 (2H, br.), 6-7 (2H, br.), 10.0Q (lH, s).

Claims

 The scope of the claims

 General formula

Θ

 A

[Where R. Is a nitrogen-containing heterocyclic group, an acyl group or an esterified carboxyl group, Z is S, S → 0, 0 or CH ₂ , R * is a hydrogen atom, a methoxy group or a formamide group, R is ¹³ represents a hydrogen atom, a methyl group, a hydroxyl group or a halogen atom, and A represents an optionally substituted thiazole-3-yl group which forms a condensed ring at the 4,5-position. Or a physiologically acceptable salt or ester thereof.

2. (1) General formula

Θ

[In the formula, Z is S, S → 0,0 or CH ₂ , R ⁺ is a hydrogen atom, a methoxy group or a formamide group, and R ¹³ is a hydrogen atom, a methyl group, a hydroxyl group or a halogen atom. And A represents a thiazole-3-yl group which forms a condensed ring at the 4,5-position which may be substituted, or a compound or a salt or ester thereof represented by the general formula R Hal wherein , R represents a nitrogen-containing heterocyclic group, Hal represents a halogen atom, respectively] or a salt thereof, or (2) —general formula,

R ^d H r

, CH, R ^£

 C00H

[Wherein, R ⁵ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted carboxyloxy group or a halogen atom], or a salt or ester thereof, and a compound represented by the general formula A: Represents a thiazole which forms a condensed ring at the 4,5-position which may be substituted], or a thiazole compound represented by the formula:

R ^a A Θ

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

3. (1) General formula

Where Ζ is S.S → 0.0 or CH ₂ , and R ⁴ is a hydrogen atom or a methoxy group Five

Or a formamide group, R ¹³ is a hydrogen atom, a methyl group, a hydroxyl group or a halogen atom, and A is an optionally substituted thiazole-3-yl group which forms a condensed ring at the 4, δ-position. Is reacted with a carboxylic acid represented by the general formula R 0 Η, wherein R represents an acyl group, or a salt or a reactive derivative thereof, with a compound represented by the formula: , Or

 (2) —general formula

[Wherein, R ⁵ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group or a hagen atom, respectively] or a compound or a salt or ester thereof represented by the general formula [where A is substituted And a thiazole which forms a condensed ring at the 4- and 5-positions which may be reacted with a thiazole compound represented by the formula or a salt thereof:

[The symbols in the formula are as defined above.]

25 A method for producing a chemically acceptable salt or ester.

4. General formula- 13

 -CONH-, Z ヽ

, CH ₂ A @

 θ

 COO

 "OH

[Wherein, R ^{22 represents an} optionally substituted heterocyclic group, Z represents S, S → 0, 0 or CH ₂ , R ⁴ represents a hydrogen atom, a methoxy group or a formamide group, R ¹³ represents a hydrogen atom; a methyl group; a hydroxyl group or a halogen atom; and A represents an optionally substituted thiazole-3-yl group which forms a condensed ring at the 4, δ-position. wherein, R ³ 〃 is shown to the hydrocarbon residue which may optionally be substituted] one general formula R ³ ^ OH and salt or ester thereof that and allowed the reaction έ compound or its reactive derivative represented by the Special formula ''

R ²

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

• 5. General formula

@

[Wherein, X is a halogen atom, R ² is a hydrogen atom, a logen atom or a nitro group, R ³ is a hydrogen atom or an optionally substituted hydrocarbon residue, and Z is S, S— 0, 0 or CH ₂ , R ⁺ represents a hydrogen atom, a methoxy group or a formamide group, R ¹³ represents a hydrogen atom, a methyl group, a hydroxyl group or a halogen atom, and A may be substituted 4,

A thiazolyl-3-yl group forming a condensed ring at the 5-position, respectively, and a salt or ester thereof and a general formula R 〖C (= S) NH, wherein R ¹ is A compound represented by the general formula:

©

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

6. General formula

Θ

[Wherein, Z is S, S → 0, 0 or CH ₂ , is a hydrogen atom, a methoxy group or a formamide group, R ¹³ is a hydrogen atom, a methyl group, a hydroxyl group or a halogen atom, and A is Represents a thiazol-3-yl group which forms a condensed ring at the 4,5-position which may be substituted, respectively. Which is characterized by reacting a salt or ester of

 C,.,

 R ra

 4 to N,

, CH ₂ A θ

 θ

 COO

[Wherein, R represents an esterified carboxyl group, and other symbols have the same meanings as described above], or a method for producing a physiologically acceptable salt or ester thereof.

7. General formula

,

-S,,, CH ₂ A ©

 θ

 COO

[In the formula, R ° is a nitrogen-containing heterocyclic group, an acyl group or an esterified hydroxyl group, Ζ is S, S → 0, 0 or CH ₂ , R ⁺ is a hydrogen atom, a methoxy group. Or a formamide group, R ¹³ represents a hydrogen atom, a methyl group, a hydroxyl group or a halogen atom, and A represents an optionally substituted thiazole-3-yl group forming a condensed ring at the 4,5 position. A pharmaceutical composition comprising at least one compound represented by the formula: or a physiologically acceptable salt or ester thereof.