WO1985004879A1 - Cephem compounds - Google Patents

Abstract

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

Description

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

North-Conventionally, a quaternary ammonium methyl group at position 3 and 2— (2—a and

 Various cefm compounds or their derivatives waiting for the combination of a minothiazol-4-yl-12-hydroxy (or substituted hydroxy) minoacetamide group have been formed and patent applications have been filed [for example, Japanese Patent Application Publication No. Shojutsu

5 3-3 4 7 9 5, 5 1-9 2 9 6, 5 1 3 7 7 9 2, 5 1-7 4 6 1 4 9 2 9 8, 57-1 5 6 8 5, 5 7-9 9 3 9 4, 5 8-5 9 4 9 8, etc.] force; 4th class ammonium Most of the groups derived from a nitrogen-containing aromatic heterocyclic ring are those having a monovalent pyridium group or a substituent having a substituent on the ring. The synthesis of the compound having an imidazole-11-yl group forming a condensed ring at the 1-position has not been made, nor has it been disclosed in the application specification. Cefm antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, for example, in the treatment of diseases caused by bacteria that are resistant to epsilon antibiotics and in the treatment of patients susceptible to penicillin. Particularly useful. In this case, it is desirable to use a cefm antibiotic that is active against both gram-positive and gram-negative bacteria.For this reason, research on cefm antibiotics having a broad antibacterial spectrum has been actively conducted. Done I have been. As a result of long-term studies, introduction of ² -((2-aminothiazol-1-4-yl-12-alkoxy, cyminoacetate amide) at the ^7- position of the cefm ring activates both gram-positive and gram-negative bacteria. Which led to the development of the so-called third-generation cephalosporin-based compounds, and several types of third-generation cephalosporin-based compounds are currently on the market. Another feature of the generational cephalosporin antibiotics is that they have demonstrated activity against the same ft-acting bacteria as those experienced with penicillin, the so-called cephalosporin-resistant bacteria. Some Escherichia coli strains resistant to cefa sporins, some Citrobacter, and most indole-positive Proteus, It exhibited antibacterial activity to a degree that could be used clinically against pathogenic bacteria classified into the genera Genus, Serratia, Pseudomonas, etc. Based on studies of these third-generation cephalosporins, 3 It has been suggested that a cefm compound having a quaternary ammonium methyl group at the position and the aminothiazolyloxyminoacetamides at the 7 position has a more excellent antibacterial activity and a unique antibacterial spectrum. Compound power; various compounds have been synthesized.

 The present invention has the general formula

CI

(Wherein, represents an amino group which may be protected, R ₂ represents a hydrogen atom or a halogen atom, R ₃ represents a hydrogen atom or a hydrocarbon residue which may be substituted, and R ₄ represents a hydrogen atom. A represents an atom or a methoxy group, A represents an optionally substituted imidazolyl-1-1 monoyl group forming a condensed ring at the 2,3-position or 3,4-position, and n represents 0 or 1 Or a physiologically acceptable salt or ester thereof, a process for producing the same, and a pharmaceutical composition.

 Cefem compounds in this specification are related to "cepham" according to "The Journal" of the American Chemical "Chemical" Society, Vol. 84, page 340 (1962). And refers to a compound having a double bond at the 3,4-position among cephem compounds.

As described in the background section, a cephalic compound having a quaternary ammonium methyl group at the ^3rd position and an aminothiazolyloxyminoacetamide at the 7th position is more effective than third-generation cephalosporin compounds. It has been gradually found to have even better antibacterial activity and a unique antibacterial spectrum.

Many compounds in which the quaternary ammonium group at the 3-position is derived from a nitrogen-containing aromatic heterocycle have already been synthesized and patented.These heterocycles have a monocyclic pyridinium group or a substituent on the ring. Most of the compounds have an imidazole-1-yl group forming a condensed ring at the 2,3-position or the 3,4-position of the present invention, but no synthesis has been carried out. The present inventors have succeeded in synthesizing the compounds represented by the general formula [I] having such a chemical structural expectation, and have studied the antibacterial activity and antibacterial spectrum of those compounds. As a result of the investigation, it was found that compound [I] has a strong antibacterial action against various bacteria, especially that it has a strong antibacterial action against the above-mentioned cephalosbolin-resistant bacteria, Antibacterial power- The present invention was completed by finding that

In the Ceph compound [I], the substituent Eh represents an amino group which may be protected, that is, an amino group or a protected amino group. In the field of synthesis of β-lactams and peptides, the protecting groups for amino groups have been thoroughly studied and the protection methods have already been established. In the present invention, any known protecting groups for amino groups may be appropriately used. Can be adopted. Amino group protecting groups as, for example C ₆ ~ ₁₀ § Re Ichiru - § ί le group, C i to ₅ Al force Noiru group, C ₃ ~ ₅ Arukenoiru group, Cs ^ t. Aryl sulfonyl group,

₁₀ § J Rekirusuruho group, substituted O alkoxycarbonyl group, a force Rubamoiru group, Chiokarubamoiru group, C _s ~ ₁₀ § Li one Rumechiru group, C ₆ ~ ₁₀ Ariru main styrene group, C ₆ ~ _{1 0} § Li one Lucio Group, substituted silyl group, 2-C i- _s alkoxy carboxy-l-methyl-1-ethenyl group and the like.

C ₆ ~:. 10 § Li one Ruashi base as is true somatic manner le group Nzoiru naphthoquinone collected by Lee Le, phthaloyl and the like, these aromatic rings C t~ ₄ Arukiru, C ι~ ₆ alkoxy, And it may be substituted by a rosin, a rosin or a nitro. Specific examples of the substituted aryl-acyl groups include p-toluoyl, p-tert-butylbenzoyl, p-methoxybenzoyl, p-tert-butoxybenzoyl, p-chlorobenzoyl, p- two Torobe Nzoi Le Nadogaa (Djira be. C i ₅ specific examples of an Arukanoiru groups formyl, Asechiru, Puropioniru, Buchiri Le, Nokure Li Le, Pinoku acryloyl, Sakunishiru and glutaryl is Agerare, these Arukanoiru groups further (^ _1-6 an alkoxy, Bruno, sigma Gen, C ₆ ~ i ₀ § Li Lumpur, C ₆ ~ _l0 § Li Ruokin, C ₆ ~ ₁₀ § Li - Lucio such substituted Specific examples of the substituted alkanoyl group include monochloroacetyl, dichloroacetyl, trichloroacetyl, monobromoacetyl, monofluoroacetyl, and difluoroacetyl. Oroasechi , Trifluroyl roacetyl, monoiodoacetyl, acetoacetyl, 3-oxobutyryl, 4-chloro-3-oxoxobutyryl, fueracetyl, P—cloguchi fenyl acetyl, phenoxyacetyl, ρ-chlorofuenchil, etc. can give. C ₃ ~ ₅ Arukenoiru group as Akuri acryloyl the concrete is black Tonoinore and maleoyl can be mentioned, Arukenoiru group of these may be substituted with such further C ₆ ~ ₁₀ Ariru. Specific examples of the substituted alkenoyl group include cinnamoyl. C ₆ ~ ₁₀ § The reel sulfonyl group specifically the base Nze Nsuruhoniru, such as naphthalene sulfonyl and the like, is substituted These aromatic rings C i alkyl, C i to ₆ alkoxy, halogen, etc. two preparative port It may be. Specific examples of the substituted arylsulfonyl group include p-to-norenens-norefonyl, p-tert-butylbenzenesulfonol, p-methoxybenzenesulfoninole, and p-cyclobenzenesulfonyl, —Examples include double-ended benzenesulfol. C ₁ ~ _{1 0} alkylsulfonyl ¾ |. To methanesulfonyl Specifically, the ethanesulfonyl, etc. camphorsulfonyl. These alkylsulfonyl Nirumotoma c ₆ ~ _{1 0} Ariru, C

It may be substituted with 6 to 10 aryloxy, halogen and the like. The substituted Okishi carbonyl group e.g. main butoxycarbonyl, Etoki carbonyl, I isopropoxy force carbonyl, tert- butoxycarbonyl, such as I Sobol sulfonyl Okishi carbonyl (^ _1-8 alkoxy one carbonyl ^ group, e.g. Fueno Kin force Lupo two Honoré, etc. c ₇ ~ _{1 2} Ararukiruoki Ichiriki Ruponiru group such as C ₆ ~ _{1 0} Ariruokishi Ichiriki Ruboni Le group e.g. Benjiruoki carbonyl such as naphthyl O alkoxycarbonyl is exemplified. C ₁ ~ ₈ Arukokin one carbonyl group more C Iota～ ₆ alkoxy ^, C ₂ to 5 Arukanoi Le, substituted Li Le, C ₁ ~ ₄ Arukirusu sulfo - le, halogen, are also be substituted substituted with like Shiano.

O PI Examples of the alkoxycarbonyl group include methoxymethyloxy / carbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trikyloxycarbonyl, Mouth roto xycarponyl, 2-cyanoethoxycarbonyl, etc .; C ₆ through i ₀ Ariruoki ^ - aromatic carbonyl group and the C ₇ through i ₀ § Rarukiruokishi one carbonyl group C i to ₄ alkyl, C to ₆ alkoxide ^, halogen, optionally substituted with like two preparative σ Is also good. Specific examples of the substituted aryloxycarbonyl group include ρ-methylphenoxycarbonyl, ρ-methoxyphenoxycarbonyl, and ρ-chlorophenoxycarbonyl. Specific examples of the substituted aralkyloxycarbonyl group include Ρ-methylbenzyloxycarbonyl, ρ-methoxybenzyloxycarbonyl, ρ-k —Nitoguchi benzyloxycarbonyl and the like. The C ₇ ~ ₁₂ § Rarukiruokishi force Ruponiru alkyl group C ₆ ~ ₁₀ § reel, Bruno, may be substituted with such Rogge emissions, in particular, such as base Nzuhi drill Ruokishikaru Boniru the like. The carbamoyl group may be substituted. Specific examples of the substituted carbamoyl group include N-methylcarbamoyl, N-ethylcarbamoyl, N, Ν-dimethylcarbamoyl, Ν-phenylcarbamoyl, and Ν— (ρ-methoxyphenyl) carbamoyl. And so on. Thiocarbamoyl groups may be similarly substituted. Specific examples of the substituted thiocarbamoyl group include Ν-methylthiocarbamoyl. C ₆ ~ ₁₀ § Li one Rumechiru base as specifically the base Njiru, naphthylmethyl, and these aromatic rings C _t ~ ₄ Al kill, C Iota～6 alkoxy, halogen, such as a secondary Bok port It may be replaced. Specific examples of the substituted arylmethyl group include p-methylbenzyl , P-methoxybenzinole, p-chlorobenzil, ρ12-benzil, etc. The methylation group Arirume methyl group may be substituted by another 1-2 C ₆ ~ ₁₀ Ariru group, specifically base Nzuhi drill, etc. Application Benefits chill and the like. C ₆ ~ ₁₀ Ariru - methylcarbamoyl etc. Njiriden base is specifically as alkylene groups exemplified et these aromatic rings _Ci-4 alkyl, (^ 1-6 alkoxy, halogen, optionally substituted by such as a secondary Bok port . the substitution has been § reel methylene groups specifically p- main Chirubenjiride down -., specific examples of an 0 _6-10 § Li Ruchio group such as p- black port base Njiriden the like 0- two口

The substituted ί / lyl group is combined with the protected amino group by the general formula R ₆ H ₇ R ₈ Si NH,

(R ₆ R ₇ H ₈ S r ₂ N or 2 ^; (( ⁹¹⁰ (where, ₆ , R _7> R ₈ , R _9>

Rio .Rg, Rio 'each example methylation, Echiru shows a C ₆ ~ ₁₀ § aryl group such as Ci～ ₄ alkyl or e.g. phenyl, such as tert- butyl, may be the same or different. Z represents, for example, a Ci- ₃ alkylene group such as methylene and ethylene.], Specifically, trimethylsilyl, tert-butyldimethylsilyl, and Si (CH ₃ CH ₂ CH ₂ Si (CH ₃ :> ₂ —) and the like.

2— Examples of the C _1-8 alkoxy group of the alkoxy-1-carboxy 1-methyl-1-ethenyl group include methoxy, ethoxy, tert-butoxy and the like.

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

In the above Cefm compound (I), the substituent R ₃ is a hydrogen atom or a substituted

O PI Represents an optionally substituted hydrocarbon residue. The carbide zk¾ residues e.g. c ₁ ~ ₆ alkyl group. C ₂ ~ ₆ alkenyl group, such as c ₃ ~ ₆ cycloalkyl group. Specific examples of the Cis alkyl group include methyl and ethyl. Lopinore and Isov. Mouth pinore, butinore, isobutinore, sec butinore, tert-butyl, pentyl, hexyl. Vinyl The C ₂ ~ specifically as a ₆ alkenyl group, § Li Le, isopropenyl, methallyl, 1, -1-dimethyl diethylene Xolair Lil, 2 Buteyuru, 3 Buteyuru the like. C. 3 to specifically, click port propyl as ₆ consequent opening alkyl group, Urobuchi Le, cyclopentyl, cyclohexyl, etc. force § is {de to consequent opening.

These are for example hydroxyl group as the substituent of the hydrocarbon residue, c ₃ ~ ₆ cycloalkyl group, ci~ ₆ alkoxy group ,, C ₃ ~ ₆ Kuroarukiruo alkoxy group, c ₆ ~ ₁₀ § Li one Ruokishi group, c ₇ ~ ₁₂ Ararukiruoki group, Melka script group, C. ₁ to 6 alkylthio group, C ₃ ~s black alkyl thio group, C ₆ ~ ₁₀ § Li one thio group, C ₇ through i ₂ Ararukiruchio group, Amino groups, mono (^ 4 Al Kiruamino group, di C i to ₄ alkylene J Reami amino group, C ₃ ~ ₆ consequent opening Arukiruami amino group, c ₆ ~ ₁₀ Ariruamino group, c ₇ ~ ₁₂ Ararukiruamino group, cyclic § Mi amino group, azide de group, nitro port Group, halogen atom, cyano group, carboxy group,

C I～8 alkoxy £ / one carbonyl group, C ₆ ~ ₁₀ § Li one Ruokishi - carbonyl group, C ₃ to 6 cycloalkyl O carboxymethyl - carbonyl group, C ₇ ~ ₁₂ Ararukiruo carboxymethyl one carbonyl ^ group, C ₆ ~ ₁₀ § Li one Ruashiru group, C is Arukanoiru group, C ₃ ~ ₅ Arukenoiru group, CS L. § Li one Ruashiruokishi group, C ₂ ~ ₅ Arukanoiruoki i group, C ₃ ~ ₅ alkenyl Noi Ruo alkoxy group, a force Rubamoiru group: substituted force Rubamoiru group, Chiokarubamoiru group, a substituted Chiokarubamoiru group, forces Rubamoiruokishi group, a substituted force Rubamoiruokishi group , Phthalimid group,

C ₂ to 5 Al force Noiruami de group, C ₆ ~ ₁₀ § Li one Ruashiruami de group, Cal

OMPI Bokishiami amino group, Ci~ ₄ alkoxy one Karuboniruami amino group, C ₆ ~ ₁₀ § Li

- Ruo Kishi carbonyl § amino group, such as c ₇ ~ ₁₂ Ararukiruokishi one carbonylation Ruamino group. Specifically C ₃ ~ ₆ cycloalkyl radical is shea click port propyl, sik Robuchiru, consequent opening pentyl, cyclohexyl and the like, C t~. Alkoxy groups main butoxy, et preparative alkoxy, propoxy, I Sopuropoki shea, butoxy £, tert-butoxy and the like, C ₃ ~ ₆ consequent opening Arukiruokishi groups sik port Puropiruokishi, Kishiruokishi and the consequent opening, C ₆ through i ₀ § Li one Ruokishi group Fuenokin, Nafuchiruokishi etc., C ₇ ~ ₁₂ Ararukiruo alkoxy group Benjiruokishi, and 2-phenylpropyl E chill O Kin, Rei_1～ ₆ § alkylthio groups methylthio, Echiruchio, propylthio, etc. butylthio the, C. 3 to 6 cycloalkylthio groups cyclopropylthio, and key Shiruchio cyclohexane, a C ₆ ~ ₁₀ § Li one Lucio groups such as phenylene thioether, and C ₇ ~ ₁₂ Ararukiruchio group base Njiruchio, mono Ci~ ₄ alkyl. § Mino group Mechirua Mino, Echirua Mi Roh, Puropirua Mi Roh, Buchirua Mino and the like, di ^^ 4 alkylamine Mi amino group is dimethyl Chirua Mi Bruno, Jechirua Mi Roh, methyl Echiruamino, Jipuropiruami Roh, Jibuchiruamino the like, C ₃ ~ ₆ consequent opening alkylamine Mi amino group is £ click Ropuropirua Mi Bruno, a etc. Kishiruamino cyclohexane , and c ₆ ~ ₁₀ § Li one Rua Mi amino group is § two Reno, c ₇ ~ ₁₂ Ararukirua amino group Benjirua Mi Roh, 2 Fueniruechirua Mi Roh etc., cyclic § Mi amino group pyrophosphoric Rijino. piperidino, Hiperajino, morpholino, etc. 1 one pyromellitic Lil, Bruno, androgenic atoms fluorine, chlorine, bromine and the like, (^ _1-8 alkoxy one carbonylation Le groups main Bok butoxycarbonyl, E Bok alkoxycarbonyl, Puropokishikarupo two Le, Isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, isobornyloxycarbonyl Le etc., C ₆ ~ ₁₀ § Li Ichiru; and carboxymethyl one carboxymethyl sulfonyl group phenoxyethanol carbonyl, 〇 _3-6 consequent Roaru Kiruokishi Ichiriki Ruponiru Motoma £ / Kurobu port Piruokishi force carbonyl, and cyclohexyl O alkoxycarbonyl to consequent b, c ₇ ~ ₁₂ Ararukiruokishi one carbonylation Le group and base Nji Ruo alkoxycarbonyl, c ₆ ~ ₁₀ § Li one Rusyl groups include benzoyl, phthaloisole, phenylacetyl, etc., and ci- ₅ alkanoyl groups include formyl, acetyl / propioninole, butyryl, phenolylinyl, and pinocylol.

C ₃ to 5 Arukenoiru fried or § click Royle, black concert I le, maleoyl the like,

And C ₆ ~io § one Ruashiruokishi group base Nzoiruokishi, C ₂ ~ ₅ § Rukanoi Ruokishi group Aseto alkoxy, propionyl Ruo alkoxy, Buchiriruoki ^, etc. Bibaroi Ruokishi, c ₃ ~ ₅ alkenyl Noi Ruo alkoxy group § click And substituted carbamoyl groups such as N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N "-phenylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, and morpholinyl. A substituted thiocarbamoyl group such as N-methylthiocarbamoyl group, a substituted rubamoyl group i / group is N-methylcarbamoyloxyN, N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, etc. C ₂ ~ ₅ alkano Iruami de group § cell Toami de Etc. Puropion'a mi de, etc. Cg_ ₁₀ § Li one luer Ruami de group group base Nzuami de, (^^^ 4 alkoxy one carbonyl § amino groups main bets alkoxycarbonyl § amino, ethoxy alkoxycarbonyl § Mino, tert -. the butoxy carbonyl § amino, and C ₆ ~ ₁₀ Ariruokishi one carbonyl § amino group phenoxyethanol carbonyl § amino, C ₇ ~ ₁₂ Ararukiruokishi one carboxyalkyl Boniruamino groups represent like base Njiruokishi force Ruboniruamino the above § The alkyl group that constitutes the aralkyl group of the rualkyloxy group, the aralkylthio group, the aralkylamino group, the aralkyloxycarbonyl group, and the aralkyloxy group is another aryl group.

OMPI It may be substituted with a group, and specific examples include benzhydryloxy 'benzhydrylthio, benzhydrylamino. Benzhydrylcarbonyl, benzhydryloxycarbonyl, and the like. Specific examples of the substituted hydrocarbon residue include methoxymethyl, 1-methoxyethyl, 1-ethoxyquinethyl, 2-hydroxyhexyl, 2-aminoethyl, 2-fluoroethyl, 2-chloroethyl and 2-chloroethyl. Moethyl, carboxymethyl, 1-carboxy-1- 1-methylethyl, 1-carboxycyclopropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,

1-Methoxycarbonylcyclof. Mouth pill, tert-butoxycarbonylmethyl, 1-methoxycarbonyl-1-methylethyl, .1-ethoxycarbonyl-1-methylethyl, 1-tert-butoxycarboxyl 1-methyllechinole, 1-benzyloxycarbo Nil-1-methylinoethyl, 1-pivaloyloxycarbonyl-1-methylethyl, etc. Further, in the present specification, all _three OR groups are in a syn-coordination (Z-coordination).

In the above Cefm compound [the substituent R _{4 in} IJ represents a hydrogen atom or a methoxy group. ,

 The substituent A may be substituted in the cefm compound [I].

Represents an imidazo-1-yl group that forms a condensed ring at the 2,3-position or the 3,4-position. Here, the condensed ring means a form in which an imidazole ring and a 5- or 6-membered aromatic heterocycle are condensed, and this condensed ring is further condensed with another aromatic ring or an aromatic heterocycle. Is also good. The @ added to the substituent A indicates that the substituent A has a monovalent positive charge. 2 may be substituted, 3 - position or 3, 4 ones I to form a condensed ring Midazo - rule 1 Ichii Le group (A® J general formula CAJ or [A _2]

Where B is a group forming a 5- or 6-membered aromatic heterocyclic ring which may be condensed with another aromatic ring or an aromatic heterocyclic ring, and i is a hydrogen atom or an imidazole ring. And Ri 2 represent a hydrogen atom or a substituent on the ring condensed with the imidazo ring. B consists of a carbon atom, a nitrogen atom _{s an} oxygen atom and / or a sulfur atom, of which a carbon atom is bonded to one hydrogen atom or one substituent, or is a fused ring with an adjacent carbon atom The following are specific examples of the A i group.

O PI

J? N

 Specific examples include the following:

OMPI

Although fit the 3-position nitrogen atom of Les, - the above formula [A i], [A 2] and specifically exemplified with A i groups, Oite the A ₂ groups are conveniently Imidazo the positive charge of the substituents In some cases, the quaternary nitrogen atom is assigned to the nitrogen atom at the first position. In some cases, the monovalent positive charge is delocalized on the imidazo monocyclic ring, and sometimes on the entire condensed ring. So even if

 §What

If -Ν-above, -N: -N It is also expressed as. The location of this positive charge is a compound! : I], which changes fluidly depending on the state (solid or in solution), type of solvent, liquidity, temperature, type of substituent, etc., so that the present invention localizes the positive charge to the nitrogen atom. And all cases where delocalization occurs throughout the imidazole or fused ring. Hatato example, if a hydroxyl group as a substituent and R ₁₂ on the condensed ring A, C ι~ ₄ hydroxycarboxylic alkyl groups, C i to 6 alkyl groups, C

2-6 alkenyl groups. C ₂ ~ 6 alkynyl, C ₄ ~ 6 alkadienyl group, C ₃ ~ 6 Shikuroarukinore group, C ₃ ~ ₆ cycloalkenyl group, C ₃ ~

6 cycloalkyl one C i to 6 alkyl / Les group, C ₆ to 10 § Li Nore group, C ₇ ~ ₁₂ Ararukiru group, a heterocyclic group, C 1 ~ 6 alkoxy group, C. 1 to 6 alkoxy one C ₁ ~ 4 Arukinore group, C. 3 to 6 cycloalkyl Anore kill O alkoxy group, C ₆ to 10 § Riruokishi group, C ^^ IL 2 Aranorekiru old alkoxy group, Menorekapu preparative group,. C mercaptoalkyl group, a sulfo group, C 1 ~ 4 Sunorehoanoreki group, Ci ~ ₆ alkylthio group, C. 1 to 6 Arukinorechio one C. 1 to 4 alkyl groups, C ₃ ~ ₆ cycloalkylthio group, C 6 to 10 § Li Norechio group, C ₇ ~ 12 § la kill Chisaimoto, amino group, C i to ₄ 7 Mi Noarukiru group, mono C 1 ~ 4 Arukinore amino group, di C. 1 to 4 Anorekirua amino group, mono C ₁ ~ 4 Arukirua Mi no C i to 4 alkyl group, di C i to 4 Anoreki / Reami node on C i to 4 Anoreki Le group, C ₃ ~ 6 Sik Roarukirua Mi amino group, C 6 to 10 § Li Rua Mi amino group, C 7 to 12 § la Lucino les amino group, ring Fushimi Amino group, cyclic Amino C. 1 to ₄ § alkyl group, a cyclic A minnow C ~ ₄ Arukinore amino group, azido group, two collected by filtration group 'Bruno, androgenic atom. (^ _1-4 halogenoalkyl group, Shiano group, Shiano c ₁ - ₄ alkyl group, Karubokin group, Karubokin one (^ - alkyl, (^ _1-8 Alkoki

^ One carbonyl group, C ₁ ~ ₈ alkoxy one carbonylation Lou C ^^^ alkyl group, C ₆ ~ ₁₀ Ariruokishi one carboxymethyl sulfonyl group, c ₃ ~ cycloalkyl O carboxymethyl one Nore group, C _{7 to} i 2 Aralkyloxy group, C 6 to 10 Aryl group, C 1 to 5 Nole group, C 2 to 5 Nole group C 1 to 4 Nole group, C ₃ to ₅ alkenoyl groups, C 6 to 10 alkanol groups, C ₂ to 5 alkanoyloxy groups, C ₂ to 5 alkanoinoleoxy C ₁ to ₄ alkyl groups, C ₃ ~ 5 alkenyl groups, canolebamoyl groups, carbamoyl-Ci- ₄ alkyl groups, substituted carbamoyl groups, thiocarpa moynole groups, substituted thiocanole bemoyloxy groups, dynamyl-bemoyloxy groups, canolebamoyloxy-C 1-4 alkanoyl groups C-lvamo-inoreoxy group, phthalimid group, C2-5-anorecanolamide group, C6-10-alumina-sinoleamide group, snorehonamide group, carboxyamino group, ^ ~ Alkoxy Sea carbonyl § amino group, C ₆ ~ 1 0 § Li Ruokishi Ichiriki Norebonirua amino groups, C 7 to 1 2, etc. § Rano gravel Honoré OXY carbonyl § amino group. Specifically, C i to ₄ The hydroxyalkynole group is hydroxymethinole, 2-hydroxydecynole, etc., and the Ci to 6-anolekyl group is methynole, ethyl, propynole, isopropynole, butyl, isobutynole, sec-butynole, tert-butyl, pentyl. C ₂ to ₆ anolekenyl groups include bier, aryl, isoproleninole, methallyl, 1,1-dimethinorea linole, 1-butenyl, 2-butenyl, 3-butenyl, and the like. _2-6 alkyl - Le group E Chi: two Honoré, 1 one Puropieru, 2 Puropieru, propargyl and the like, the C ₄ ~ ₆ Arukajie alkenyl group 1, 3- Butajeni etc. _3-6 cycloalk Kinore group or Shikuropuropinore, consequent Roguchino 'Les, sik Ropenchinore, ^ click Roeki sills etc., C _3-6 cycloalkyl Anore Ke cycloalkenyl group 1 Shikuropente two Honoré, 2 one consequent -. Mouth pent two Nore, 3-cyclopenteninole, 1-cyclohexeninole, 2-cyclohexenole, 3-cyclohexeninole, 1,4-cyclohexenyl, C3-6 cycloalkyl-Ci ~ _s alkyl group is

O PI Pentylmethyl, cyclohexylmethyl, etc., C ₆ -ioaryl groups include phenyl, naphthyl, etc., C 2 -aralkyl groups include benzylinole, phenyl, etc., and heterocycles are 2-pyridyl. , 3-Pyridinole, 4-pyridyl, N-oxide 2-pyridyl, N-oxide 3-pyridyl, N-oxidone 4-pyridinole, 2-pyridinole, 3-pyridinole, 4 1-pidininole, piberazinore, 2-biradininole, 2-pyrimidinole, 4-pyridininole, 5 — binimi-dininole, 3 — pirita, 'dininole, 4-pirita'-gininole, 2-viraninole, 3 —Vilanil, 4-pyraninole, 2-thiopyranyl, 3-thiovirale, 4-year-old pyranyl, 3H-indol-2-yl, 3H-indolone-3-3-inole, 1,2,3— Thiadiazo 4-ino 1,2,4-thiadiazol-5-yl, 1,2,4—thiadiazol-3-inole, 1,2,4—thiadiazol-5-yl, 1,3,4—thiadiazolyl, 1, 2,5 —thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H—tetrazolinole, benzovirane 2, 're, 21-furyl, 3-furyl, 2-— Chenonoré, 3-Cher, 2-oxazolyl, 4-year-old xazolyl, 5-oxazolyl, 2-thiazolinole, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl

5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolinole, 2-pyrrolyl, 3-pyrrolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl 5- to 8-members containing one to several heteroatoms such as nitrogen atoms (which may be oxidized) such as, 3-birazolyl, 4-pyrazolyl, and 5-pyrazolyl, and oxygen atoms and sulfur atoms those having a ring or a bond to a carbon atom in a condensed ring thereof, C ₁ ~ ₆ alkoxy groups main bets alkoxy, et preparative alkoxy Purobokishi, Lee isopropoxy, butoxy, and etc. tert- butoxy, C i ~ 6 Alkoxy mono C 1-4 Al

OMPI Examples of the killing group include methoxymethyl, ethoxymethyl, 2-methoxethyl and the like. C 3 to 6.Dichlorophenolic groups include cyclopropynoleoxy and cyclohexanoloxy, and C 6 to 10 arylesoxy groups include phenoxy, Naphthyloxy and the like; C ₇ to 12 aralkyloxy groups such as benzyloxy '1-phenyl ethenyl / reoxy, 2 — phenyl / ethynoleoxy and the like; C i to 4 menolecaptoquinoleno groups are menolecaptomethyl; 2-mercaptoethyl, C-4 sulfoalkyl group f

Ci to 6 anoalkylthio groups include methiothio, ethylthio, propylthio, isoprobi, / recio, butylthio, etc., and C1 to ₆ alkyl groups. Ci to 4 acrylyl groups are methinolethiomethyl and 2-methylthioethynole. etc., C ₃ ~ ₆ consequent opening alkylthio group sik port propylthio, cyclohexylthio and the consequent opening, and C 6 to 1 0 § Li Norechio groups off e = Ruchio, C ₇ ~ _{1 2} Araruki Lucio groups Such as N. disoletio, C i -4 aminoalkyl groups include aminoamino, 2-aminoethyl, etc. Mono C -4 alkylamino groups include methylamino, ethylamino, propylamino, butinoreamino, etc.

The 1-4 alkynoleamino groups include dimethylamino, getiamino, methylethylamino, dipropylamino, dibutylamino, etc., and the mono-Ci-4alkylamino C1-4alkyl groups are methylaminomethyl, ethinoreaaminomethyl, 2 - (N-Mechiruami Roh) Echinore, 3 - (N - Mechirua Mi Roh) Puropinore etc., di C i to ₄ alkylamine plasminogen C i ~ ₄ Anorekiru groups N, N-dimethylaminomethyl, N, N-Jechirua Minomechiru, 2 one (N »N-Jimechinoreamino) Echinore, 2- (N, N - Jechiruamino) Echiru, 3- (N, N-Jimechiruamino) Puropinore etc., C ₃ ~ ₆ cyclo Anore Kino Rea amino group sik Methyl propinoreamino, cyclohexinoleamino, etc., and C6-Ioarylamino are anilino, N-methyl Aniri Roh of For example, CT ^^ i 2 aralkylamino groups include benzylamino'-l-phenylethylamino, 2-phenylethylamino, and ring λ-amino groups include pyrrolidino, pyridino, biradino, morpholino. , 11-Virolyl, etc .; Amino C-4 phenolic alkyl groups include pyrrolidinomethyl, piperidinomethyl, piperazinomethyl, morpholinomethyl, 2- (morpholino) ethyl and the like, and cyclic amino C1-4 alkyl. Noreamino groups include pyrrolidinomethine / 'reamino, pyridinomethylamino, pyrazinomethylamino, morpholinomethylamino, and halogen atoms such as fluorine, chlorine, and bromine. Nohonorekinore group or monophnore group, diphnole group, trichnole group, 1-phnole group, 2 Phenoleochinole, Monochloromethinole, Dichloromethinole, Trichloromethinole, 1-Chlorochinole, 2-Chloroethyl, Bromomethinole, Iodomethinole, etc., and Cyano C i-4 ethyl groups such as cyanoethyl and 2cyanomethyl Carboxy-Ci-4 alkyl group is carboxymethyl, 1-carboxyethyl, 2-carboxystyl and the like, C i-8 alkoxy-carbonyl group is methoxycarbonyl, ethoxycanolebonii //, propoxycanoleboniz Les, Isof. Rho ¹ "xycarbonyl, carbonyl, butoxycarbonyl, tert-butoxycarbonyl, isobornyloxycarbonyl, etc., C i- ₈ alkoxy-carbocarbonyl C 1-4 alkyl groups and methoxycarbonylmethy Toxylcarbonylmethyl, tert-butoxycarbonylmethyl, etc., C ₆ to _1. Aryl xyl alcohol group is phenoxycarbonyl, etc., C ₃ to 6 cycloalkyl alcohol xylboninole group ^ cyclopropyl alcohol X-carbonyl, cyclohexyloxycarbonyl, etc., C-I 2 aralkyloxy-carboxyl group is a benzyl group, 'leboninole, etc., C ₆ -i 0-ary Le group base Nzoiru, phthaloyl, full We two / Reasechiru etc., C ₁ ~ ₅

Ο ΡΙ Arukanoi Le group formate Honoré, Asechinore, propionitrile - Honoré, Buchiri Le, Barre Rinore, etc. Viva port Inore, C ₂ to 5 Arukanoiru C 1 to 4 Anorekiru group Asechirumechiru, 1 one Asechiruechiru, 2 Asechiruechiru etc. 'C 3-5 alkenoyl groups include acryloyl, crotonoyl, maleoyl, etc., and C ₆ -ι0 aryl-asyloxy groups include benzoyloxy.

C ₂ ~ 5 alkanoylthio Honoré group is § Se butoxy, propionitrile Two, 'Reokishi, blanking Chirinoreokishi, etc. Pibaroi / Reokishi, C. 2 to 5 § Honoré Kano I Ruo carboxymethyl one C ι .~ 4 alkyl group § Se Toximeti, 1-Acetokischinore, 21-Acetokischinore, etc., C3-5 alkenoyloxy group is acryloyloxy, etc., C1-4 anolexyl- group is C1-4 anorecyl-methyl, etc., Substituting power rubamoyl group is N-methylcarbamoyl, N, N-methyl tylcarno; moyl, N-ethylcarbamoyl, N, N-getyl, molybdenum, N-phenylcanolenomoyl, pyridinoyl olevonyl, Pi Perajino carbonyl, etc. Moruho Reno carbonyl, force Rubamoiruoki Sea C 1, ~ ₄ alkyl groups force Luba moil O carboxymethyl etc. , And substituted Chio force Rubamoiru group N- methylthio force Rubamoiru, substituted Karupamoi Ruokishi group - methylcarbamoyl O carboxymethyl, N, N- dimethyl carbamyl Moiruokishi, N "- Echirukarubamoi Ruokishi etc., C ₂ ~ _c Al force Noirua Mi de groups § Se store Mi de, etc. Puropion'ami de, C ₆ ~ _{1 0} § Li - Rua and luer Mi de group base Nzua Mi de, C alkoxy Ichiriki Ruboniruami amino group is main butoxycarbonyl § Mino, eth Kin carbonyl § amino, tert- etc. butoxycarbonyl § amino, and C ₆ ~ ₁₀ § Li Ruo Kishi carbonyl § amino group Fueno butoxycarbonyl § amino, C ₇

The -12-aralkyloxycarbonylamino group represents benzyloxycarbonylamino and the like. The above C ₇ ~ ₁₂ Ararukiru group, C ₇ ~ ₁₂ §

OMPI Al constituting the Rarukiruokishi group, c ₇ ~ _{1 2} Ararukiruchio group, c ₇ ~ _{1 2} Ararukirua amino group, c ₇ ~ ₁₂ Ararukiruokin one carbonyl group, and c ₇ ~ _{1 2} § la Rukiruokishi Ararukiru groups, such as single carbonyl § amino group kill group may be substituted with one more C ₆ ~ ₁₀ Ariru group, specifically {Both or Benzuhi drill, Benzuhi de Riruokishi, Benzuhi de Riruchio, Benzuhi drill Rua Mino, Benzuhi drill O butoxycarbonyl Benzhydrylcarbonylcarbonylamino and the like. A plurality of these substituents may be the same or different and may be substituted. In Ai, the 5- and 6-positions of the imidazole ring may be condensed with an alicyclic, aromatic or heterocyclic ring. Examples of these are

Where B,: ₁₂ is the same as described above. The above substituents R _u , R ₁₂ may be further substituted.

In the above cefm compound [I], n represents O or 1. In addition, a carboquinol substituent at the 4-position (㊀ added to 1 C 00 indicates that the carboxylic group is a propyloxydione, which is paired with a positive charge on the substituent A to form an inner salt. On the other hand, compound [I] is physiologically It may be an acceptable salt or ester. Physiologically acceptable salts include inorganic salts, ammonium salts, organic salts, inorganic acid addition salts, organic acid addition salts, and basic amino salts. An inorganic base capable of forming an inorganic salt is, for example, an alkali metal [eg, sodium or potassium such as J; an alkaline earth metal (eg, such as calcium ^)] An organic base capable of forming an organic salt S¾ is, for example, procaine. N-methyldalcosamine, 2-phenylenebenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, polyhydroxyalkylamine and N-methyldalcosamine. Inorganic acids that can form inorganic acid addition salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid nitrate. Organic acids that can form organic acid addition salts include, for example, P-toluenesulfonic acid, methanesulfonic acid, and the like. , Formic acid, trifluoroacetic acid, maleic acid, etc. For example, lysine, arginine, ordinine, histidine, etc. are opened. Compound! : I] means an ester that can be formed by esterifying a carboxyl group contained in a molecule, and is an ester usable as a synthetic intermediate and a metabolically unstable nontoxic ester. Esters usable as synthetic intermediates include C alkyl esters. C

2-4 alkenyl esters, ^C 3 to 6 cycloalkyl esters, C ₃ to 6 Shikuroa alkyl - (^ - alkyl esters' C ₆ ~ ₁₀ § reel esters, C ₇ ~ ₁₂ § La alkyl ester, substituted Siri, Reesuteru and Gerare, it may be further substituted. specific examples thereof include methyl as alkyl to form the C t~ ₄ alkyl esters, Echiru, propyl, butyl, tert- butyl and the like, the C. 2 to ₄ alkenyl esters Specific examples of the alkenyl to be formed include vinyl, aryl and isopropyl, and C ₃ to ₆ cycloalkyl.

OMPI Specifically, click port propyl as consequent opening alkyl which forms Kill ester, evening Robuchiru, ^ Kuropenchiru, and cyclohexyl, and alkyl to form a C ₃ ~ 6 click port alkyl one C i to ₄ alkyl esters cyclohexylmethyl and Te to consequent opening propyl methyl Sik port Specifically, C ₆ ~ ₁₀ § Li - the specifically § re Ichiru forming the glycol ester Hue - Le etc., C ₇ ~ _{1 2} Specific examples of aralkyl for forming an aralkyl ester include benzyl and phenethyl, and specific examples of substituted silyl for forming a substituted silyl ester include trimethylsilyl and tert-butyldimethylmethyl. Further, the alkyl constituting the aralkyl ester may be substituted with one or two C _{6 -lflaryl} , and specific examples include a benzylhydryl ester and a trityl ester. . As non-toxic esters that are metabolically unstable, those already established in the fields of ぺ niline and cephalosporin can be conveniently employed in the present invention. As such metabolically labile esters of non-toxic, even JIC ^ alkanol I Ruo carboxymethyl ester ♦ C i to ₅ alkanol Iruoki shell chill esters, C ₁ ~ ₆ alkoxy one C i to ₄ alkyl esters, C ₁ ~ ₆ alkylthio-(^ 4 alkyl esters, etc., specifically, acetoximethinole ester, 1-acetoxethyl ester, 1-acetoxoxybutyl ester, 2-acetoxicetyl Ester, pinoylooxymethyl ester, methoxymethylester, ethoxymethylester, isof.Mouth oxymethylester, 1-methoxyxethyl ester, 1-ethoxyxyl ester, methylthiomethylester , Ethyl thiomethyl ester, etc. In addition to the above ester derivatives, the present invention provides Compounds physiologically acceptable which is converted to compound [I] Te also encompasses,

 / ¾ 、

O PI The compound [I] of the present invention has broad spectrum antibacterial activity and can be used for the prevention and treatment of various diseases caused by pathogenic bacteria in humans and animals, for example, respiratory tract infection and urinary tract infection. . The features of the antibacterial spectrum of compound [I] include the following.

 (1) It has an unusually high activity against a variety of Durham negative bacteria.

 (2) It has high activity against Gram-positive bacteria (eg, Staphylococcus aureus, Corynepacterium diphtheria).

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

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

In particular, against amino acids belonging to the genus Eudomonas, amino acids such as amikacin and gentamicin have been used. * Compound [I] only shows antibacterial activity comparable to these amino acids. It has significant advantages because it is much less toxic to humans and animals than aminoglycosides.

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

 (1) General formula

NH

 Wherein the symbols in the formula are as defined above, or a compound thereof

O PI Salt or ester and general formula

ヽ

0 R ₃

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

 (2) General formula

(IV)

[Wherein I is a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted rubamoyloxy group or a halogen atom, and the other symbols are as defined above] or a salt or ester thereof and a general formula A ′ [ A 'represents an imidazole which forms a condensed ring at the optionally substituted 2,3- or 3,4-position] or a salt thereof;

 (3) General formula

[Ό

H ₂ A. ®

Wherein the symbols in the formula are as defined above, or a salt or ester thereof, and a general formula I 0H wherein R ₃ ′ represents an optionally substituted hydrocarbon residue. Reacting the compound or its reactive derivative with (4) General formula

[Wherein X is a halogen atom, and other symbols are as defined above] or a salt or ester thereof and a general formula Ri C (= S) NH ₂

 In the formula, Ri has the same meaning as defined above, and the compound [1] can be produced by reacting with a compound represented by the following formula or, if necessary, removing the protecting group. The production methods (1) to (4), the method for removing the protecting group, and the method for purifying the compound [1] will be sequentially described. .

 Manufacturing method (1):

In this method, a 7-amino compound [—] is acylated with a carboxylic acid [II] or a reactive derivative thereof. In this method, the carboxylic acid [H] is free or its salt or a reactive derivative is used as an acylating agent for the 7-amino group of the 7-amino compound [I]. That is, free acid [I] or free acid! : H], an inorganic salt, an organic salt, an acid halide, an acid azide, an acid anhydride, a mixed acid anhydride, an active amide, an active ester, an active thioester, and other reactive derivatives are subjected to the acylation reaction. Al as an inorganic salt Potassium metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, etc.), and organic salts such as trimethylammine salt, triethylaminium salt, etc. Acid salts, tert-butyldimethylamine, dibenzylmethylamine, benzyldimethylamine, N, N-dimethylaniline, pyridine, quinoline salts, and the like. de, an acid Puromai de is mono C i to ₄ alkyl carbonate mixed acid anhydride is a mixed acid anhydride (e.g. the free acid [Jl] and mono methylation carbonate, mono Echiru carbonate, monoi an isopropyl carbonate, mono Lee Mixed acid anhydride with sodium butyrate, mono-tert-butyl carbonate, monobenzyl carbonate, mono (P-nitrobenzyl) carbonate, monoallyl carbonate ), C ₁ ~ ₆ aliphatic carboxylic acid mixed acid anhydride (e.g. the free acid [HI] acetate Application Benefits click Rollo acetate, Shiano acetic acid, propionic acid, butyric acid, Lee Seo butyric acid, valeric acid, Lee Seo valerate. Pivalic acid, tri Furuoro acid, preparative land port acetate, mixed acid anhydride with etc. § Seto acetate), C ₇ to 1 1 aromatic carboxylic acid mixed acid anhydride (for example a free acid [ΪΙ] benzoic acid, Mixed acid anhydrides with P-toluic acid, P-chlorobenzoic acid, etc., and organic sulfonic acid mixed acid anhydrides (for example, methanesnolefonic acid, ethanesnolefonic acid, benzenesnolefonic acid, p-tonolenesulphonic acid) The active amides include amides (eg, free acid [M] with virazole, imidazole, benzotriazole, etc.) as active amides. With acid amide, These nitrogen-containing heterocyclic compounds C. 1 to ₄ alkyl, 6 alkoxy, halogen, O Kiso. Chiokiso, etc. C i ~ 6 may be substituted, etc. alkylthio) of the like. All active esters used for this purpose in the field of 3-lactam and peptide synthesis can be used as active esters, for example, organic phosphoric esters (eg ethoxylinyl ester, diphenyloxylinyl ester). Acid esters, etc.), p-ditrophenyl ester, 2,4-dinitrophenyl earthester, cyanometinoleester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxy Droxif tasolei mide estenole, 1-hydroxy benzotriatriester monoester, 6-hydroxyl 1-hydroxy benzotriazolone oleestenole, 1-hydroxyl lH-12-pyridone ester, etc. . Activity Chioesuteru The ester of an aromatic heterocyclic thiol compound (e.g. ² - pyridinium Jiruchio Rue - ester, etc. 2 base emission zone thiazolyl thiol ester, these heterocyclic rings is C 1 ~ 4 alkyl, C ₁ ~ ₆ alkoxy, halogen atom, C 1-6 alkylthio, etc.). on the other hand,

The 7-amino compound [I] is used as a salt or ester as it is. Examples of the salt of compound [H] include inorganic base salts, ammonium salts, organic base salts, inorganic salt addition salts, and organic salt addition salts. Inorganic base salts include alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salts), and organic base salts include, for example, trimethylamine salt and triethylamine salt. , Tert-butyldimethylamine, dibenzylmethylamine, benzyldimethylamine, N, N-dimethylaniline, pyridine, quinoline, and the like. Examples of inorganic acid addition salts include hydrochloride and odorant. Hydrocarbonates, sulfates, nitrates, phosphates, etc., and organic acid addition salts include formate, acetate, trifluorate, methane-sulfonate, p-toluenesulfonate, etc. can give. Compound !: The esters already mentioned as the ester derivative of compound [I] as the ester of ： :) can also be used here as they are. That is, C1-4 anolequinoleester, C2-4 anolekeninoleestenole, Cg-6 cycloalkyl ester, C3-6 cycloalkyl—C1-4 alkyl Esters, C 6 to 1 0 § Li Ruesuteru, C 7 to 1 2 § Lal kill esters, C. 1 to ₅ alkano Iruokishime Chiruesuteru, C. 1 to 5 Arukanoiruo key shell chill esters and their further hydroxyl, C i to ₆ alkoxy group , halogen atom, nitro group, Shiano group, main mercapto group, C ₁ ~ ₆ Al Kiruchio group, Okiso group, such as those substituted with such Chiokiso groups like et be. The raw material [II], its salts and esters, the raw material [n] and its reactive derivatives can all be easily produced by a known method or a method analogous thereto. The compound [JI]) can be reacted with the compound [H] as a substance isolated from the reaction mixture or a reaction mixture containing the reactive derivative of the compound [H] before isolation as it is. When the carboxylic acid [m] is used in the form of a free acid or salt, an appropriate condensing agent is used. Examples of the condensing agent include N, N-disubstituted carbodimids such as N, N-dicyclohexylcarbodiimide, for example, N, Ν'-force carbonylylimidazole, Ν, N'-thiocarbonyldiimidazole, and the like. Dehydrating agents such as diethoxycarbonyl-12-ethoxy-1,2, -dihydroxyquinoline, oxychlorine, alkoxyacetylene, etc., for example, 2 Odide and 2-fluoropyridinium salts such as 2-fluoropyridinium methyl iodide are used. When these condensing agents are used, the reaction is thought to proceed via the reactive derivative of carboxylic acid [H]. The reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include ethers such as dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropinole ether, ethyl glycol monomethyl ether, and esters such as ethyl formate, ethyl acetate, and butyl acetate. Kind, for example, dichloro

OMPI

WIPO Π-Genated hydrocarbons such as methane, chloroform, carbon tetrachloride, trichlorene, 1,2-dichloroethane, and hydrocarbons such as n-hexane, benzene, and toluene. For example, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetate, ketones such as acetate, methylethylketone, methylisobutylketone, etc. Nitrites such as acetonitrile and propionitrile, cadmium thioresulfoxide, sulfolane, hexamethyl phosphoramide, water, etc. are used alone or as a mixed solvent. The amount of the acylating agent [I] to be used is generally 1 to 5 mol, preferably 12 mol, per 1 mol of compound [H]. The reaction is carried out in a temperature range from 180 to 80 ° C, preferably from 140 to 50 ° C, most preferably from 130 to 30 ° C. The reaction time depends on the type of the compounds CH] and [HI], 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, preferably 15 minutes. ~ 3 hours. When an acid halide is used as the acylating agent, the reaction can be carried out in the presence of a deoxidizing agent for the purpose of removing released hydrogen hydride from the reaction system. Examples of such a deoxidizing agent include inorganic bases such as sodium carbonate, calcium carbonate, calcium carbonate, sodium hydrogencarbonate, etc., for example, triethylamine, tripropylamine, tributylamine, cyclobutylamine. Tertiary compounds such as hexyldimethylamine, pyridine, lutidine, r-colysine, N, N-dimethylaniline, N-methylpyridinine, N-methylbiphenyl, N-methylmorpholine And alkylene oxides such as propylene oxide and epichlorohydrin.

O PI Production method (2):

+ A '→ [I]

In this method, the imidazole compound A 'is reacted with the cefum compound [IV], and the compound [1] is synthesized by a nucleophilic substitution reaction. In the compound [IV], R ₅ represents a hydroxyl group, an acyloxy group, a rubamoyloxy group, a substituent rubamoyloxy group or a halogen atom. Here Ashiruo alkoxy groups optionally substituted C ₂ ~ ₅ Arca Noi Ruo alkoxy group or,

C 6-10 ary represents a monosulfoxy group, optionally substituted C

Specific examples of the 2 to 5 alkanoyloxy groups include acetoxy, chloroacetoxy, propionyloxy, butyryloxy, pyrryloxy, 3-oxobutyryloxy, 4-chloro-3-oxobutyryloxy, 3-carboxypropionyloxy, 4 monocarboxybutyryloxy, 3 —ethoxycarbamoylpropionyloxy and the like may be optionally substituted C 6-ιοοry-l-acyloxy groups, specifically, o-carboxybenzo. Examples include inoleoxy, o- (ethoxycanoleboninole), benzoinoleoxy, and 0— (ethoxycarbonylsnorefamoinole) benzoyloxy. Specific examples of the rubamoyloxy group include methylcarba'moyloxy and N, N-dimethylcarnomoyloxy. Halogen atoms include chlorine, bromine and iodine. Compound [IV] can be used as it is as a salt or ester. As the salts and esters of the compound [ιν], those given as the salts and esters of the compound [B] in the production method (1) can be applied here as they are.

f OMPI Can be Compound [iy], salts and esters thereof can be easily produced by a method known per se or a method analogous thereto. On the other hand, imidazole compound A 'represents imidazole which forms a condensed ring at the optionally substituted 2,3-position or the 3,4-position. Here, the condensed ring means a condensed form of an imidazole ring and a 5- or 6-membered aromatic heterocycle. This condensed ring may be further condensed with another aromatic ring or an aromatic heterocycle. Optionally substituted 2, 3-position, or 3, 4 ones i to form a condensed ring imidazole (A) has the general formula:! Αι ') or (A _2']

R ii '

 R12

 No, one

 N

 N = B

N = J [A ₂ ']

 R12

In expressed write, 'a is A④ group of said At group, compound [IV] Compound Alpha _2' objective compound capable synthesis when reacted with compound [ff] and compound [〖] reacting The human groups of the target compound [I] which can be synthesized in this case are the above _two groups, respectively. The symbol B in the formulas of the condensed imidazoles Αι 'and A2' is the same as that mentioned above for B in the At group and A ₂ group.

"

ϊ

^Ν ^ Ν

 ■!

 Ν

ΟΜΡΙ

N = J _ ~ 0

But, specifically, as Α ₂ '

ΟΜΡΙ

OMPI ?

0-N

N = J. As the substituents' and Ri ₂ 'on the compound A', those already mentioned as the substituents Ri 1 and Ri ₂ of the group A can be directly applied here, respectively. In, the 5,6-position of the imidazole ring may be fused with an alicyclic, aromatic or heterocyclic ring. Examples of these are

,

I, Β

'¾2'

Where Β and Ri ₂ ′ are the same as described above. Up

f OMPI Noted substituents Ri i ', R i 2 ^f may be further substituted. 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, and the like, for example, formate, acetate, trifluoroacetate, methansulfone, and the like. Acid salts, p-toluenesulfonic acid salts and other organic acid addition salts. The general synthesis method of compound A 'is known and can be easily produced by a method described in a literature or a method analogous thereto. The present substitution reaction of compound [iy] with a compound is a reaction known per se, and is usually carried out in a solvent. Solvents used for this reaction include ethers, esters, hydrogen halides, hydrocarbons, amides, ketones, nitriles used in the production method (1). Although a solvent such as water is fit as it is, these Toebame Tano Lumpur was Besides, ethanol, Purobanoru, Sopuronoヽ⁰ Bruno Lumpur, E Ji glycol, 2 - also alcohols such as main butoxy ethanol Used 0

(2-1): when ₅ is an acyloxy group, a carbamoyloxy group, or a substituted carbamoyloxy 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, methylethylketon, and acetonitrile. . The amount of the nucleophilic reagent A 'to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound []. The reaction is carried out in a temperature range of 10 to 10 (C, preferably 30 to 8 (f C.) The reaction time depends on the type of compound [iy] and Α ', and the type of solvent (or mixed solvent if mixed). The reaction time is usually 30 minutes to 5 days, preferably 1 to 5 hours, and the reaction is carried out at pH 2 to 8, preferably near neutral, ie, pH 5 to 8. The reaction is usually carried out

 SEAl

O PI Proceeds more easily in the presence of 2-30 equivalents of iodide or thiocynate. Examples of such salts include sodium iodide, potassium iodide, sodium thiocyanate, and potassium thiocyanate. In addition to the above-mentioned salts, quaternary hydroxides having surface active properties such as trimethylbenzylammonium bromide, triethylenolbenzilammonium bromide and trietinolevenzilammonium bromide are also available. In some cases, the reaction can be allowed to proceed smoothly by adding a graded ammonium salt.

(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 phosphorochloride, 0-phenylene phosphorofluoride, methinole o-phenylene phosphate, and 0-phenylene phosphate and propynoleate. Phenylene phosphate, Isopropyl 0—Phenylene phosphate, Butyl 0—Phenylene phosphate, Isobutynole 0—Phenylene phosphate, sec—Butinole 0—Phenylene phosphate, cyclohexynole 0—Phe Diene phosphate, phenylene 0-phenylene phosphate, p-cloth phenylene o-phenylene phosphate, p-acetinole phenylene 0-phenylene phosphate, 2—chloroethynole 0—phenylene Renphosphate, 2,2,2-trichloroethynole Dilen phosphate, ethoxy canolepo'-dinoleme chinole o-phenylene phosphate, canoleno ヾ moylmethyl 0—phenylene phosphate, 2—cyano etizole 0—phenylene phosphate, 2—methinoles Ethynole 0-phenylene phosphate, benzyl 0—phenylene phosphate, dimethinolate 2—propenyl o-phenylene phosphate, 21 OMPI: orchid 1-Propenyl o-phenylene phosphate, 3-methyl-2-butenylene 0-phenylene phosphate, 2-Chenylmethyl 0-phenylene phosphate, 2-Fenolefurinol methinolate 0 —Phenylene phosphate, bis-1 0 —Phenylene pyrophosphate, 2-phenylenino 1,3,2—benzodioxaphosphoryl 2-oxide, 2- (P—phenyl phenyl) — 1,3,2-benzozo Xaphosphol-l- 2-oxide, 2-butyl-l-l, 3,2-benzodioxaphosphol-l- 2-oxide, 2-anilinol-l, 3,2-benzodioxaphosphol 1- 2-oxide, 2-phenylthio-1,3,2-benzodioxaphosphol-12-oxide, 2-methoxy-5-methyl-1,3,2-benzodioxaphosphol 1 2 — Oxide, 2 — Black mouth 5-Ethoxycarboniー 1,3,2-benzodioxaphosphol-l-oxide, 2-methoxy-5-ethoxy-norreboninole 1,3,2-benzodioxaphosphol-l-oxide, 5-1e Toxic canoleboninole 2—Fenisolate 1,3,2-Venzo'dioxaphos-one 2-oxide, 2,5-dichloro-1,3,2-benzodioxaphosphone-one 2-oxide, 4-1 1-Methoxy-1,2,3,2-benzodioxaphosphol-12-oxide, 2-methoxy-4-methyl-1,3,2-benzodioxaphosphol-2-oxoxide , 2,3-Naphthalenemethyl phosphate, 5,6-Dimethyl-2-methoxy

 1,3,2-Benzodioxaphosphol-1-2-oxide, 2,2-dihydro-1,4,5,6,7-Tetrachloro-2,2,2-Trimethoxy-1,3 2-benzodioxaphosphorinole, 2,2-dihydro-1,4,5,6,7-tetrachloro-1,2,2, triphenoxy-1 1,3,2-benzodi Kisaphosphol, 2,2-dihydro 2,2-ethylenedioxy

 2-methoxy-1,3,2-benzodioxaphosphol, 2,2-dihi

RE " Draw 2-benzyl-1,2,2-dimethoxy 1,3,2-benzodioxaphosphorol, 2,2-dihydro 1,4,5-benzo-2,2,2-trimethoxy 1,3 , 2-Benzodioxaphosphol, 2,2—Dihydro-1,2,2,2-Triphenoxy-1,2,3,2-Benzodioxaphosphor, 2,2— Dihydro-1,2— (0—phenylenedioxy) 1-2, phenoxy-1,3,2-benzodioxaphosphonore, 2-chloro-2,2-dihydro-1,2 — (Ο—Fenylenedioxy) 1,3,2—benzodioxaphosphol, 2, .2—Dihydro 2—Methoxy2,2— (0—Fenylenedioxy) 1-1,3 , 2-benzodioxaphosphol, 2,2-dihydrodraw 2,2,2-tricyclo-1,1,3,2-benzodioxaphosphol, 9,10-Fenance range Toxiphos Holase, ο-phenylene phosphorochlorite, 0-phenylene phosphorobromide, 'it, 0 —phenylene phosphorofluoride, methylinole 0 —phenylene phosphite, butyl 0-phenylene phosphite G, methoxycanolepo'ninoleme chinore 0—phenylene phosphite, feninole 0—phenylene phosphite, ρ—black mouth (or ρ—nitro) phenyl ο—phenylene phosphite, 2-phenylene 1 , 3,2-Benso'dioxaphosphol, Bis0-phenylene pyrophosphite, 2-Methoxy 5-methyl-1,3,2-benzodioxaphosphonole, 5-Acet 1,2-phenoxy-1,3,2-benzodioxaphosphol, 9,10-phenanthrene phosphorochloridite, 2-chloro-4-methyltin 1.1,3 , 2-Benzodioxaphosphol, 5-Ethoxycarbonyl 2-pheninole-1,3,2-Benzo'dioxaphosphonole, 2-chloro-2-thioxone1, 3,2-benzodioxaphosphol, 2-phenoxy-1-2-oxo-1,3,2-benzodiazaphosphol, 2-phenoxy-1,1, 3,2-benzoxazaphosphol, 2,3-dihydro-1-2-oxo-2-methoxy-4,5-dimethyl-1,3,2-dioxaphosphol, 2,2-dihydro 2-oxo-1,2-chloro-4,5-dimethyl-1,3,2-dioxaphosphol, 2,2-dihydro 2-oxo-1- 2- (1-imidazolinole) -1,4,5-dimethyl-1, 3,2-dioxaphosphol, 2,2-dihydro 2,2-ethylenedioxy 2-methoxy 4,5-dimethyl-1,3,2-dioxaphosphol, 2,2-dihydro 1,2,2-Dimethoxy-2-phenoxy-1,4,5-dimethyl-1,3,2-dioxaphosphol, 2,2-dihydro-1,2,2, trimethoxy4,5-dimethyl 1,3,2-dioxaphosphor, 2,2-dihydro-2,2,2-triphenoxy-1,4,5-dimethyl-1,3,2-dioxaphosphol, 2,2 Dihydro 2,2,2-triethoxy-1,4,5-diphenyl 1,3,2-dioxaphosphol, 2,2-dihydro-1,2,2, trimethoxy 4,5 —Diphenyl 1,3,2 dioxaphosphol, 2,2 —Dihydro-1-2-oxo-2-methoxy-1,4,5-diphenyl-1,3,2-dioxaphosphol 1,2,2-dihydro-1,2,2,2-trimethoxy-1,3,2-dioxaphosphol, 2,2-dihydro-1,2,2,2-trimethoxy-1-4-1 Lu 1,3,2-Dioxaphosphol, 2,2-dihydro-2,2,2-trimethoxy 4-methyl-1,3,2-dioxaphosphol, 2,2-dihydro —2 , 2,2-to " ¹ J methoxy-4-methyl-5-phenylcarba, moyl — 1,3,2-dioxaphosphol, 2,2,, 5,6,7-hexahydro-1,2 2,2—trimethoxy-1,3,2-benzoji Oxaphoshole, 2,2'-oxybis (4,5-dimethyl-2,2-dihydro 1,3,2-dioxaphosphol), 2,2'-oxybis (4,5-di Methyl-2,2-dihydro-1,3,2-dioxaphosphol-12-oxide). The solvent used in the reaction may be any solvent as long as it does not inhibit the reaction, and is preferably the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles and the like. Used alone or as a mixed solvent. In particular, favorable effects can be obtained by using, for example, dichloromethane, acetonitrile, formamide, a mixed solvent of formamide and acetonitrile, and a mixed solvent of dichloromethane and acetonitrile. The amounts of the nucleophile A 'and the organophosphorus compound used are 1 to 5 mol, 1 to 10 mol, more preferably 1 to 3 mol, and 1 to 1 mol, respectively, per 1 mol of the compound [IV]. 6 moles. The reaction is carried out at a temperature of 180 to 50 ° C, preferably ¹ "to 40 to 40 ° C. The reaction time is usually 1 minute to 15 hours, preferably 5 minutes to 2 hours. An organic base may be added to the reaction system, such as triethylamine, tributylamine, dibutylamine, diisobutylamine, dicyclohexylamine, 2,6-lutidine. Amines such as etc. The amount of the base to be added is preferably 1 to 5 mol per 1 mol of the compound [W.

(2-3): When R ₅ is a halogen atom

Preferred solvents are the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water and the like. The amount of the nucleophile A 'to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound [IV]. The reaction is carried out in a temperature range from 0 to 80 ° C, preferably from 20 to 60 ° C. The reaction time is usually between 30 minutes and 15 minutes, preferably between 1 and 5 hours. The reaction can be carried out in the presence of a dehalogenating agent to promote the reaction. Examples of such dehalogenating agents include the inorganic tertiary amines and alkylene oxides described in the section of the production method (1). Such deoxidizing agents are also mentioned here, but the nucleophile itself may act as a dehacogenating agent. In this case, A! Is used in an amount of 2 mol or more per 1 mol of the compound [IV]. The halogen atom represented by I is chlorine, bromine, iodine, etc., and is preferably iodine. The compound [] in which I is iodine can be produced, for example, by the method described in Japanese Patent Application Laid-Open No. 58-57390.

 Manufacturing method (3):

Ten R | OH—> Π

This method is a method for synthesizing a compound [I] by reacting a compound represented by the general formula Rs'OH or a reactive derivative thereof with a hydroxyamino compound [V], and by a well-known etherification reaction. is there. R ₃ 'represents an optionally substituted hydrocarbon residue, and as such a hydrocarbon residue, those already mentioned as the optionally substituted hydrocarbon residue in R ₃ can be directly applied here. . R ₃ 'OH is used as it is or as a reactive derivative thereof. The reactive derivative of R ₃ 'OH means a derivative of I' OH having a group leaving together with a hydrogen atom of the compound [V], that is, a compound represented by the general formula I'Y. Here, the group Y released with a hydrogen atom represents a halogen atom, a sulfo group, a mono-substituted sulfonyl ^, or the like. Halogen atoms include chlorine, bromine and iodine. mono

 Substituted sulfonino ^ is, for example, methanesulfonino ethanesulfoni.

3 and non-oxy

ノ ^ benzenesulfonino p — toluenesulfonino ^: which C i ~ 4 Oxy

 Kirsulfonino l ^, C 6 ~ 10 ary —Rusulfonino ^ and the like. In particular, when producing a C! -4 alkyl ether compound of the compound [Y], in addition to the above reactive derivatives, for example, C1-4 diazoalkanes such as diazomethane and diazoethane, for example, dimethyl sulfate, getyl DiCi-4 alkyl sulfuric acid such as sulfuric acid is also used.

(3-1: In the case of using R ₃ 'OH, compound [V] is reacted with an appropriate dehydrating agent to synthesize compound [I:!. As a dehydrating agent used for this purpose, for example, Examples thereof include phosphorus chloride, dialkyl thionyl chloride / dialkyl azodicarboxylate + phosphine, N,]> 1-zinc hexylcarbodiimide and the like, and preferably, acetyl diphenyl carboxylate + triphenylphosphine. Azojikarubon di Echiru + Application Benefits Fuweniruhosufu I. reactions using emissions are typically conducted in anhydrous solvents, the ethers, such as hydrocarbons are used. compound «0 1 R moles ₃ ' OH, ethyl azodicarboxylate, and tolphenylphosphine are all used in an amount of 1 to 1.5 moles, and 0 to 5 (1 ° C in the temperature range of fC).

Take ~ 4 days.

(3-2): When using R ₃ 'Y

The reaction between R ₃ ″ Y and the compound [Y] is a usual etherification reaction, which is carried out in a solvent. Examples of the solvent include polyesters and esters mentioned in the section of the production method (1). Or mixed solvents such as halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water, etc., and preferably water-miscible solvents. (Eg, aqueous methanol, aqueous ethanol, aqueous acetate, aqueous dimethyl sulfoxide, etc.) This reaction can proceed smoothly in the presence of a suitable base. Such bases include, for example, sodium carbonate and carbonate.

OMPI Examples include alkali metal salts such as sodium hydrogen and potassium carbonate, and inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Also this reaction PH ^7.. 5 to 8. may be performed in a buffer solution of 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 raw material compound [V]. The reaction temperature ranges from 130 to 100 ° C, preferably from 0 to 80 ° C. The reaction time is 10 minutes to 15 hours, preferably 30 minutes to 5 hours.

 (3-3): When using C i ~ 4 diazoal power ·

 The reaction is usually performed in a solvent. As the solvent, the above-mentioned ethers, hydrocarbons and the like are used. After dissolving the compound [Y] in a solvent, the reaction proceeds when a solution of the diazoalgan 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 and is between 150 and 20 ° C, preferably between 130 and 0 ° C. The reaction time is 1 minute to 5 hours, preferably 10 minutes to 1 hour.

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

 The reaction is usually carried out in water or a mixed solvent of water and a water-miscible solvent. Examples of the mixed solvent include the water-containing solvents mentioned in the section (a-2). This reaction is carried out, for example, in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The reagent is a compound [γ]

It is used in an amount of 0.5 to 10 mol, preferably 1 to 2 mol, per 1 mol. The reaction temperature is between 2 and 100 ° C, preferably between 50 and 100 ° C. The reaction time is 10 minutes to 5 hours, preferably 30 minutes to 3 hours. Production method (4):

~~> [I]

This method is a ceph Wemu compound [ "W] and the general formula Ri C (= S) is reacted with a Chi O urea or Chio urea derivative represented with H ₂ you synthesize the desired compound [I] method. Compound ["VI" is used as a salt or ester as it is. X in the compound [VI] represents a halogen atom such as chlorine, bromine and iodine. As the salt of [], the salts of the compound [H] (inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, organic acid addition salts, etc.) mentioned in the section of the production method (1) are also used here. Can be applied. Este also preparation as ester le of [W] compounds mentioned in the section of (1) [11] (C ^ 4 alkyl ester Honoré, C. 2 to 4 alkenyl ester Honoré, 0 _3-6 consequent Roanore kill ester, C 3-6 cycloalkynole C 1-4 olenoquinole ester, C 6-10 aryl ester, C 7-12 aralkyl ester, 0; 1-5 alkano isoleoxymethyl ester, C ι-5 alkanoinoleoxyethynolesters and their further substitutions) also apply here. The reaction is usually performed in a dish. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, and methyl ether, alcohols such as methanol, ethanol, prono, and ⁰ -nor, and dimethylformol. Amides such as amide and dimethylacetamide; and the like. Chio urea or a derivative thereof Ri C (== S) The amount of the NH ₂ is usually 1 to 5 moles relative to the compound 00, preferably 1 to 3 mol. Reaction is from 0 to: 100. C, preferably in the temperature range of 20 to 60 ° C. Reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours. In this production method, the compound [I] is usually obtained as a mixture of syn [Z] mono and anti [E] mono isomers. For separating the desired syn isomer from the mixture, a method known per se or a method analogous thereto is applied. Examples of such methods include a fractionation method utilizing differences in solubility and crystallinity, a separation method using chromatography, and a separation method utilizing a difference in the hydrolysis rate of an ester derivative.

Protecting group removal method: as described above—In the field of lactam and peptide synthesis, protecting groups for amino groups have been well studied and their protection methods have been established. In addition, the method for removing the amino-protecting group is similarly confirmed: Si, and in the present invention, the conventional technique can be used for removing the protecting group as it is. For example, a monohalogenoacetyl group (chloroacetyl, bromoacetyl, etc.) is treated with thiourea, an alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.) is treated with an acid, and an aralkyloxycarbonyl group (benzyloxy). Xyloxycarbonyl, p-methisolebenzyloxycarbonyl, ρ12-nitrobenzyloxycarbonyl, etc.) can be removed by catalytic reduction, and 2,2,2-trichloroethoxycarbonyl can be removed by zinc and acid. it can. 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. For example, 2-methylsulfonylethyl ester is converted to alkali, and aralkyl esters (benzyl ester, p-methoxybenzylester, p-nitrobenzyl ester, etc.) are converted to acid or catalytic reduction. 2,2-Tricycloethyl ester can be removed with zinc and acid, and silinole ester (trimethylsilyl ester, tert-butyldimethylsilyl ester, etc.) can be removed with water only. Purification method of compound [1]: The compound [1] produced in the reaction mixture by various production methods detailed in (1) to ( ⁴ ) and, if necessary, by following the above-mentioned protective group removal method. ] Can be isolated and purified by known processing means such as extraction, column chromatography, precipitation, and recrystallization. On the other hand, the isolated compound [1] can be converted into a desired physiologically acceptable salt or a metabolically unstable nontoxic ester by a known method.

 The sulfoxide (π = 1) of the compound [1] is converted to the compound [1] (π

= 0). 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. Can also be manufactured. The reaction is usually performed in a solvent. Solvents used in this reaction include, for example, ethers such as dioxane and tetrahydrofuran, for example, dichloromethane, chloroform, and benzene, and the like, for example, formic acid, acetic acid, and the like. And organic acids such as trifluoroacetic acid, and amides such as dimethylformamide and dimethylacetamide. The reaction is carried out at a temperature in the range of −20 to 80 ° C., but is preferably carried out at a temperature as low as possible, preferably at 120 to 20 ° C. It is generally known that when oxidizing a compound of the formula [I] showing η = 0, a sulfoxide having an S—configuration is mainly produced. : R- and S-sulphoxides are separated by their different solubilities and by different migration velocities per chromatographic separation. The above-mentioned oxidation reaction for obtaining the sulfoxide may be carried out before the reactions (i) to (4) or after the reactions (1) to (4).

 The compound [1] of the present invention can be used with known dinulin and cephalosporins.

OMPI Similarly, it can be administered parenterally or parenterally as injections, capsules, tablets, or granules. The dosage is 0.5 to 80 days per body weight, more preferably 1 to 20 days per body weight of humans and animals infected with pathogenic bacteria as described above, and more preferably 1 to 20 days divided into 3 to 4 times a day. It may be administered. As the carrier when used as an injection, for example, distilled water or physiological saline is used. When used as a capsule, powder, granule, or tablet, a known pharmaceutically acceptable excipient ( For example, starch, lactose, sucrose, calcium carbonate, phosphoric acid, calcium, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (eg, Stear! / It is used as a mixture with magnesium phosphate, talc, etc., and a disintegrant (eg, carboxymethyl calcium, talc, etc.).

 The present invention will be further described in the following Reference Examples and Examples, but these examples are merely examples and do not limit the present invention, and may be changed without departing from the scope of the present invention. Good.

 Elution in column chromatography in Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography). For TLC observations, use a TLC plate

The (Merck) manufactured by BOF _254, a solvent used as an elution solvent in column chromatography I as developing solvent, employing a UV detector as a detection method. As the force gel for force ram, Kieselgel 60 (230 to 400 mesh) also manufactured by Merck was used. "Sephadex" is from Pharmacia Fine Chemicals, Inc. XAD-Ϊ resin is from Rohm & Haas Co. NMR spectra are tetramethylsilyl as internal or external reference. Using a run, measured with an XL-lOOAClOOMHz), EM390 (9θΜΗ _ζ ) or T60 (6 OMHz) type spectrometer, and in < _c > mixed solvent with all <5 values in ppm Are the volume mixing ratios of each solvent. ^ In the solution represents a number in the solution 100 «. The symbols in the reference examples and working examples have the following meanings.

 S: Singlet (s inglet)

 d: doublet

 t: triplet

 q: quartet

 ABq: AB type quartet

 d .. d: double doub let

 m: Matinole prep (mu 1 t i 1 e t)

 br .: Broad

 J: Coupling cons t an t

 Hz: Henore (Her z)

 : Milligram (m i 11 i g r am)

 9: Gram (gr am)

 : Milli Reiter (mi 11 i 1 i ter)

 Ά:: Rewriter

%:: No ⁰ -cent (percent)

 Image 0:: Dimethinoresnorreoxide (dimethyl sulfoxide)

CDCI ₃ : Deuter ochloroform

O PI BEST MODE FOR CARRYING OUT THE INVENTION

 Reference example 1

 7 / 9— [2— (2-Chloroacetamidothiazole-4-1iso) -1 2 (Z) —Methoxyxyminoacetamide] 1-3 -— (3-oxobutyryloxymethyl) 1-3—Sefume 4 Rubonic acid.

7 / 3—Amino 3- (3-oxobutyryloxymethyl) -1-3-cefum-4-carboxylic acid 157 is suspended in a mixture of 500 W of tetrahydrofuran and 500 W of water, and the mixture is stirred and stirred. Sodium ί 4 1? In small quantities. Then with stirring at 5 ² - (2 - Kuroroase DOO amino Dochiazo one route 4-I Honoré) Single 2 (Zeta) - added in main Toki I Mino § cetyl chlorambucil I de hydrochloride 1 5 0 9 20 minutes Stir the reaction solution for another hour at the same temperature. After completion of the reaction, adjust to ΡΗ3.0 with 10% hydrochloric acid, and then extract the reaction mixture twice with each 1 mixture of ethyl acetate-tetrahydrofuran (1: 1). The extract is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the obtained colorless powder is washed with ethyl acetate 200 and collected to obtain the title compound 253 ?.

Elemental analysis: as C _2e H ₂₀ ClN ₅ O ₉ S ₂

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

 Measured: C, 41.39; H, 3.57; N, 11.94.

IR Suction Control 311- ^m ~ ^l 5 1780, 1740, 1700, 1655, 1540, 1410.

NMR spectra (d ₆ — DMS 0) δ: 2.20 (3H, s), 3.45 and 3.68 (2H, ABq, J = 18 Hz), 3.65 (2H, s), 3.92 (3H, s), 4.38 ( 2H, s), 4.79 and 5.09 (2¾ABq, J = 13Hz), 5.18 (lH, d, J = 5Hz), 5.85 (iH, dd, J-5Hz and 8Hz, 7.44 (lH, s), 9.66 (lH, d, J = 8Hz), 12.85 (lH, br. s). Reference example 2

 7 / 9— [2- (2-Aminothiazol-4-inole)) 1-2 (Zj-Methoxyminoacetamide) -1-3— (3-Oxobutyryloxymethyl) 1-3—Sephmu4 Rubonic acid.

 7 / 9— 2— [2— (Chloroacetamidothiazole-4-ynole) -1 2 (Z) —Methoxyxyminoacetamide] 1—3— (3-oxobutyryloxymethyl) 1—3-Sef After dissolving the 4- (4-) carboxylic acid in a mixed solution of tetrahydrofuran-water (1: 1) 500 », sodium sodium methyldithiocarbamate 519 was added. In addition, stir at 20 for 3 hours. Ethyl acetate (200) was added to the reaction solution, the organic layer was removed, and the aqueous layer was made 114 with 10% hydrochloric acid, whereby an oily substance was deposited. This is extracted with a mixture 1 of tetrahydrofuran-ethyl acetate (1: 1), and the aqueous layer is further extracted with π-butanol 200. The extract is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Ethyl acetate (200) is added to the residue and the mixture is stirred, and the precipitated crystals are collected to give the title compound (909).

Elemental _{analysis: C 18 H 19 N 5 0} 8 S 2 as' Calculated: C, 42.19; H, 4.30 , N, 13.55.

 Measured value ^): C, 41.94, H, 4.11, N, 13.59.

IR spectacle! ^-1 : 1770, 1710, 1620, 1520.

NMR spectrum _{(d 6 -DMSO) «5:} 2.20 (3H, s), 3.43 and 3.65 (2H, ABq, J = 18Hz), 3.63 (2H, s), 3.86 (3H, s), and 4.78 5.06 (2H, ABq, J = 13Hz), 5.1 (lH, d, J = 5Hz), 5.79 (lH, d.d, J = 5Hz and 8Hz, 6.73 1H, s, 7.17

 (2H, br.), 9.56 C lH, d, J = 8 Hz,

OMPI Reference example 3

 7 β— 2— — (2-Aminothiazole-4-inole) 1 2 (P-ethoxyminoacetamide) 1 3— (3-Oxobutyryloxymethyl) -1 3-Cefum 4 .

 2-aminothiazole 4-yl2 (Zj-ethoxymininoacetic acid 2 3

Dissolve 9 in dimethylformamide 100, add 1-hydroxybenzotriazolone 159 and dicyclohexylcarbodiimide 20.69 and stir at 20 ° C for 1.5 hours. After removing the insoluble matter, the solution was washed with 73-amino-3- (3-oxobutyryloxymethyl) -13-cefume 4 monocarboxylic acid 319 and triethylamine 28 W dimethylform Add to the solution under ice-cooling. Stir the reaction solution at 20 ° C for 3 hours, add ether 50, and collect the precipitated solid. This is dissolved in water (10), adjusted to pH 3.0 with 10 hydrochloric acid, and extracted twice with 200 ml of methylethyl ketone. The extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained solid is washed with ethyl dichloride to give the title compound 319.

IR spectrum! /

car ¹ 1780, 1720, 1660.

NMR spectrum (d ₆ — DMS O) δ: 1.30 (3H, t, J "= 7.5 Hz),

 2.25 (3H, s), 3.45-3.65 (4H, m), 4.20 (2H J = 7.5 Hz), 4.70 and 5.10 (2H, ABq, J = l 8 Hz), 5.25 (2H, d, J = 5 Hz),

5.90 (lH, d. D, J = 5 Hz and 8 Hz), 6.90 (lH, s), 7.20- 7.80 (2H, br.), 9.80 (1 H, d, J = 7.5 Hz) ₀

 Reference example 4

7 β—2 — [(2-aminothiazo-l 4-inole) -12 [2) -aryloxyminoacetamide] -3- (3-oxobutyryloxymethyl) One 3—Cefem 14

 2-aminothiazole-4-yl2 (Z-aryloxyminoacetate 13 9 to dimethylformamide 50, 1-hydroxybenzotriazole 89 and dicyclohexylcarbodimid 10.3 Stir at 20 ° C for 3 hours After removing the insoluble matter, the reactor solution was removed from the reactor with 7 / 9-amino-3- (3-oxobutyryloxymethyl) 1-3-serum-1 4-1-1 To a solution of carboxylic acid 16 and triethylamine 109 in dimethylformamide 50a under ice-cooling, stir the reaction mixture at 20 ° C for 3 hours, add ether 500 »and add ether layer. After removing the insoluble material and dissolving the resulting insoluble material in water 5 水 β, adjust to ρ Η 3.0 with 10 ^ hydrochloric acid to obtain the crude title compound, which is then mixed with ethyl acetate tetrahydrofuran (1: 1). Dissolve the solution in 500 m and dry with anhydrous magnesium sulfate. After the treatment with activated carbon, the solvent is distilled off under reduced pressure to obtain the title compound 25 as an amorphous powder.

IR Spectacle V

ca ~ i: 1780, 1720, 1660, 1620.

NMR spectrum Honoré (d ₆ one DMS 0) 3: 2.30 (3¾ s), 3.45-3.66 (4¾ m), 4.64 (2H, d, J = 6Hz), 4.80 · - 5.10 (2H, AB q, J = 18Hz), 5.23 (2H, d, J = 9Hz), 5.26 (2H, d, J = 5Hz), 5.90 (lH, d.d, J = 5Hz and 9Hz), 5.90-6.20 (lH, m), 6.80 C lH, s, 7.20-8.00 C 2H, br., 9.83 (lH, d, J = 9 Hz ₀ Reference example 5

 7 β-2- (2, aminothiazole-14-inole) 2- (Z) -tert-butoxycarbonylmethoxyminoacetamide] -3- (3-oxobutyryloxymethyl) -13-cefmu 4-carboxylic acid.

 2-Aminothiazoyl 4--1-ino 2 — tert-butoxycarbonylmethoxyaminoacetic acid 6.0 9 was dissolved in dimethylformamide 20.

O PI 1-Hydroxybenzotriazole 3.59 and dicyclohexynolenolide 4.49 are added, and the mixture is stirred at 20 ° C for 3 hours. After removing the insolubles, the solution was diluted with 7 (3-amino-3- (3-oxobutyryloxymethyl)-13-cefume 4 dimethylformate of 6.29 and triethylamine 4,09. The amide was added to a 20 W solution under ice-cooling, and the reaction solution was stirred for 8 hours at 20 ° C. Ether 200 »was added to the reaction solution, the ether layer was removed, and the residue was dissolved in 50 nl of water. After that, crystals are precipitated when the pH is adjusted to 10 with 10% hydrochloric acid, collected, washed with water, washed with ethyl ether, and dried to obtain the title compound 109.

I R spectrum! / cm-i: 1790, 1730, 1710, 1660,

1530.

NMR spectrum (d ₆ — DMS 0) 3: 1:50 (9H, s), 2.20 (3H, s), 3.40-3.60 (4H, ra), 4.40 (2H, s), 4.80 and 5.10 (2¾AB) q, J = 1 Hz), 5.20 (lH, d, J = 5Hz), 5.80 (lH, d.d, J = 5Hz and 8Hz), 6.70 (1¾s), 7.20-7.80 (2H, br.) ,

9.30 (lH, d, J = 8Hz) ₀

 Reference example 6

 3— (3—oxobutyryl xymethyl) -1 7) 9—! 2- (2-tritylaminothiazo-1-yl) -1 2 (ZJ— (1-methinolyi-tert-butoxycarbonyl) ethoxyminoacetamide) -1-3-cefm-14-force rubonic acid.

2-[(2-Tritylaminothiazole-4-inole) -12 (Z) -1 (1-methyl-11-tert-butoxycarbonyl) ethoxymininoacid 1229 is dissolved in dimethylformamide 20. Add 1-hydroxybenzotriazole 3.59 and dicyclohexylcarbodiimide 4.49 and add at 20 ° C Stir for 20 hours. The insoluble material is removed, and the solution is concentrated to 7 /?-Amino-3- (3-oxobutyryl quinquinyl) -13-cefum-4. One-sided rubonic acid 6.29 and triethylamine 4.09 dimethylformamide 2 0 Add to the solution under ice-cooling. The reaction mixture was stirred at 20 C for 24 hours, and then a mixed solution of ethyl ether and petroleum ether (1: 1) (200 W) was added. After removing the ether layer, 50 »of water was added to the residue, and then the mixture was adjusted to pH with 10 ^ hydrochloric acid. When set to 4.0, crystalline powder is precipitated. This was collected, washed with water, washed with methyl ether, and dried to give the title compound 139.

IR spectrum! /

OB " ¹ : 1780, 1730, 1700, 1680,

 1530, 1150-

NMR spectrum (d ₆ — DMS 0) <5: 1.35 (15H, s), 2.25 (3 s), 3.40 -3.60 (4H, m), 5.80 and 5.10 (2 ¾ AB q, J = 14 Hz), 5.25 (1 H, d, J = 5 Hz), 5.80 (1 H, d. D, J = 5 Hz and 8 Hz), 6,70 (lH, s), 7.20 -7.80 (2H, br), 7.30 (15H, s), 9.30 (lH, d, J = 8Hz) ₀

 Reference Example 7

 The imidazo [1,2a] pyridine derivative and the imidazo [1,5-a] pyridine derivative can be prepared by known methods [for example, WW Paudler and H. L-Blewi 11 J. Org. Chem. 30, 4081 ( 1965), JP

Paol ini and K. Rob ius J. Org. Chem., 30, 4085

 (1965), J. P. Paolini and K. Robius J. Heterocyclic Chem., 2, 53 (1965)].

 New imidazo [1,2-a] pyridine derivatives are described below.o

 7 — 1) 6—Lubamoy Louis Mi Dazo [1,2—a] pyridine.

ΟΜΡΙ 6 —Aminonicotinamide 109, 40% Closacetaldehyde 11

9 and sodium bicarbonate 12.59 are added to ethanol 10 and heated under reflux for 4 hours. Ethanol is distilled off under reduced pressure, water 10 is added to the residue, the pH is adjusted to 10 with 10 aqueous sodium hydroxide solution, and then extracted four times with 50 parts each of tetrahydrofuran-ethyl acetate (50: 1 mixture). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was recrystallized from a mixture of methanol and ether (1: 1) to give the title compound 3.59 as colorless crystals. Can be

 Melting point 202—S O C

IR spectrum

«8-1: 3350, 3120, 1 & 70, 1620, 1420, 1320.

NMR spectrum (d ₆ -DMS 0 -D ₂₀ ) δ: 7.65 3H, s, 8.03. LH, sj, 9.10 lH, s ₀

 7-2) 5-Methylthioimidazo [1,2-a] pyridine.

 Suspend 5-chloroimidazo [1,2-a] pyridine 5 and methylthionadium 5 in 100 dimethylformamide and stir at 20 ° C for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in 200 nl of dichloromethane, washed with saturated saline, dried over anhydrous magnesium sulfate and purified using silica gel column chromatography to obtain the title compound. Is obtained as an oil.

NMR spectrum _{(CDC1 3) <5: 2.55} (3 s), 6.63 (lH, d,

J = 7Hz), 7.07 (1H, d.d, J = 7Hz and 9Hz), 7.43 (lH, d,

J = 9Hz), 7.61 (2H, s) ₀

7-3) 5-Acetamidoimidazo [1,2−a] pyridine.Acetic acid 5-aminoaminodazo [1,2, a] pyridine.hydrobromide 10.9 Dissolve in 1N sodium hydroxide solution 200 and extract with dichloromethane 500. The extract is concentrated to dryness, and the residue is suspended in acetic anhydride 5 and heated under reflux for 6 hours. After evaporating the solvent under reduced pressure, the residue is crystallized by adding ethyl acetate to obtain the title compound 3.6 ^.

 Melting point 1 1 0— 1 1 2 ° C

NMR-spectrum Honoré _{(CDC1 3) S: 2.33 (} 6H, s), 6.73 (lH, d,

J = 7Hz), 7.05-7.4 (2 E m), 7.6-8.8 (3H, m) ₀

 Example 1

 7 β-2-(2-aminothiazo-1-4-inole)-1 2 (Z)-methoxyminoacetamide]-3-[(imidazo [1, 2-a] pyridinyl mu 1-yl) methyl] One 3-Sepmu 4-carboxylate.

 7 / 3- [2- (2-aminothiazole-4-inole) -2 (Z) -methoxyminoacetamide] 1- 3- (3-year-old oxobutyryloxymethyl) one

3-Cefem-4 4-Rubonic acid 49, imidazo [1,2-a] pyridine

Dissolve 49 and potassium iodide 49 in a mixture of acetonitrile and water (1: 1) 4 and stir at 70 ° C for 2 hours. The solvent is distilled off under reduced pressure. Acetonitrile 100 is added to the residue to solidify, and the powder is collected. The powder was subjected to silica gel column chromatography, and acetonitrile and water

 Elute with a mixture of (4: 1). Concentrate the eluate under reduced pressure and freeze-dry the residue. The obtained solid is dissolved in water 5 and subjected to column chromatography using XAD-]! Resin, and eluted with a 10% aqueous ethanol solution. Fractions containing the target compound are combined, concentrated under reduced pressure, and lyophilized.

 Is obtained. :

Elementary analysis: as _{C 21 H 19 N 7 0 5} S 2 · 7 Main 2 Eta ₂ 0

 Calculated value ^: C 43.74; Η, 4.54; Ν, 17.00.

 O PI

: WIPO _ Actual value (^: C 44.00 'Η, 4 · 29; N, 17; 23.

 I R spectrum ^ J レ f J cm-1: 17 65, 1670, 1605, 1520,

 1030o

NMR spectra (d ₆ — DM SO) δ: 2.95 and 3.44 (2Η, ABq,

 J = 18Hz), 3.80 (3H, s), 4.99 (lH, d, J = 4.5Hz),

 5.27 and 5.74 (2H, ABq, J = 14Hz), 5.59 (lH, d. D,

 J "= 4.5 Hz and 8 Hz), 6.68 (lH, s), 7.16 (2H, b r.s),

7.4-7.6 (lH, m), 7.85-8.15 (lH, m), 8.4-8.9 (2H, m), 8.9 (lH, d, J = 7 Hz), 9.46 (lH, d, J = 8 Hz) ₀

 Example 2

 7 β-2— (2-aminothiazoyl 4-yl) -1 2 (Z) —ethoxyminoacetamide] 1—! : (Imidazo [1,2-a] bili- dine-1-yl) methyl] -3-Sef-emu 41-carboxylate.

7 / 3- [2- (2-aminothiazole-4-inole) -1 2 (Z) -ethoxyminoacetamide] -3- (3-oxobutyryloxymethyl) -1 3-cefumu 4 5.0 9, Imidazo [1,2-a] pyridin 5.0 and potassium iodide 5.0 are dissolved in a mixture of acetonitrile and water (1: 1) and stirred at 70 ° C for 2 hours. Evaporate the solvent under reduced pressure, dissolve the residue in water 20, and extract twice with ethyl acetate (2 OaZ). After removing the organic layer, apply the aqueous layer to XAD-I column chromatography. The fraction containing the target compound is eluted with 20 ethanol water, and the residue is concentrated under reduced pressure. The residue is lyophilized. The obtained solid is dissolved in 10 W of water, and then subjected to column chromatography on Sephadex LH-20, eluting with TR. The fractions containing the target compound are collected, concentrated, and lyophilized to give 0.5 ^ of the title compound. As _{C 22 H 21 N 7 0 5} S 2 .3H 2 0: elemental沂値

OMPI Calculated: C, 45.43; H, 4.68'N, 16.86.

 Found (%): C, 45.64; H, 4.26; N, 16.78.

IR spectrum torque cm ' ¹ : 1770, 1610, 1530, 1200,

 1030o

NMR spectrum (d ₆ —DMSO) <5: 1.19 (3H, t, J = 7Hz),

 3.00 and 3.45 (2H, ABq, J = 18Hz), 4:06 (2H, q,

 J = 7 Hz), 5.01 (lH, d, J = 4.8 Hz), 5.28 and 5.48 (2¾

 ABq, J = 14Hz), 5.63 (1H, d.d, J = 4.8Hz and 8Hz),

• 6.66 (lH, s), 7.15 (lH, br. S), 7.40- 7.64 (lH, m),

 7.86- 8.10 (lH, m), 8.36-8.70 (3 H, m), 8.88- 9.00

(IE d, J = 7 Hz), 9.42 (lH, d, J = 8 Hz) ₀

 Example 3

 7 3-C 2 ·-(2-aminothiazolu 4-inole) 1 2 (Ζ)-aryloxyminoacetamide] 1-3-[(imidazo [1, 2-a] Le) Methyl] 1-3-Sefmu 4

 7 3-C 2-(2-Aminothiazole 1-4-) 1-2 (Z)-aryloxyminoacetamide]-1-3-(3-year-old oxobutyryloxymethyl)-3-cef-emu 4 Dissolve 2.09 rubonic acid, imidazo [1,2-a] pyridine 2.09 and potassium iodide 2.0 in a mixture of acetonitrile and water (1: 1) 40 ». , 7 (C) for 1.5 hours, and the reaction mixture is concentrated under reduced pressure. Acetonitrile 5 is added to the residue, and the solidified powder is collected. The solid is dissolved in water 10 and XAD-I column chromatography. The fractions containing the target compound are collected, concentrated under reduced pressure, and the residue is lyophilized to give the crude title compound.

This is dissolved in a small amount of water and subjected to silica gel gel chromatography. Elute with a mixture of acetonitrile and water (4: 1 J. Collect the fractions containing the desired product, remove the residue under reduced pressure, freeze-dry the residue to obtain the title compound 0.25 ^. as _{C 23 H 21 N 7 0 5} S 2 .3H 2 O:

 Calculation II: C, 46.53; H, 4.59; N, 16.52.

 Found ^): C, 46.70; H '4.1; N, 16.75.

 I R Spectrum V cm-i: 1770/1670, 1610, 1530,

1390 _o

NMR spectrum (d ₆ -DMS 0 D ₂₀ ) 3: 3.00 and 3.50 (2

ABq, J = l 8Hz), 4.60 (2¾ d, J = 4.5Hz) _f 5.05 (lH, d, J = 5Hz), 5.23 (2¾ d, J = l 5Hz), 5.40 (2¾ s),

5.70 (lH, d, J = 5Hz), 6.80-6.10 (1 H, m), 6.73 (lH, s), 7.50 -7.60 (1H, m), 7.90— 8.10 (lH, m),

 8.30 -8.46 (3H, m), 8.83 (lH, d, J = 6Hz.

 Example 4

 7 | 9— [2- (2-aminothiazol-4-ynole) -1 2 (Z) —Carboxymethoxyminoacetamide] 1 3 — [(imidazo [1,2-a] pyridinidum 1-yl) methyl] -1-3-efumu 4-carboxylate 'mono-natrium salt.

a) 7β-2- (2-aminothiazol-4-yl) -1 2 (Ζ) -tert-butoxycarbonylmethyoxyaminoacetamide] — 3— (3-oxobutyryloxymethyl) -1 3-cefume 4 Dissolve 3.09 monocarboxylic acid, 3.09 imidazo [1,2-a] pyridine and 3.09 potassium iodide in a mixture 60 of acetonitrile and water (1: 1). 7 0. Stir with C for 2 hours to react. The reaction mixture is concentrated under reduced pressure, water (20 W) is added to the residue, and the mixture is extracted twice with ethyl acetate (20 times) to remove insolubles. XAD—] the water layer! Apply to column chromatography and elute with 20% ethanol water. The fractions containing the target compound are collected, concentrated under reduced pressure, and the residue is lyophilized to give "1- [2- (2-amino thiazole-4-yl) -12 (Z) -tert-butoxycarbonylmethoxyminase". Toamide] -3-[(imidazo [1,2-a] pyridinium-1-1-inole) methyl] -13-sefm-14-carboxylate force s' 0.99.

b) 7 / 9— [2- (2-aminothiazole-41-yl) -1 2 (Z) —te rt-butoxycarbonyl methoxyminoacetamide] 1-3 — ((imidazo [1,2-a] pyridinium (methyl)-3-serum-4-carboxylate 0.8 is dissolved in trifluoroacetic acid 4 »and stirred at 20 ° C for 2 hours. Concentrate the reaction mixture under reduced pressure, dissolve the residue in 5 nl <D water, add sodium bicarbonate to adjust the pH to 8.0, and apply to XAD-]! Column chromatography. Elution with water The fractions containing the desired product, Ru and freeze dried after concentration the title compound 0.4 ⁹ are obtained in vacuo.

Elemental analysis: C ^ Hi ₈ N ₇ O ₇ S ₂ Na'4H ₂₀

 Calculated ^): C, 40.56; H, 4.02; N, 15.05.

 Found ^): C, 40.39, H, 3.75; N, 15.22.

I R Sukto Nore! / m-I: 1770, 1660, 1605, 1530.

NMR spectrum (d ₆ — DMS 0 — H ₂ O) 5: 3.03 and 3.45 (2 H,

 ABq, J = 18Hz), 4.30 (2H, s), 5.03 (lH, d, J = 4.5Hz),

5.33 (2H, s), 5.66 (1H, d, J = 4.5Hz), 6.80 (1H, s),

7.46-7.60 (lH, m), 7.95-8.10. (1 H, m), 8.30-8.50

 (3H, m), 8.86 (1 ¾ d, J = 6 Hz).

 Example 5

 -0 REACT O PI

One v 7 | S— [2— (2-aminothiazole-141) 1 2 (Ζ) 1-1 (1-methyl-1-butoxy) ethoxyminoacetamide] 3 — (:( imidazo [ 1,2—a] pyridinyl (11-yl))]-3-sf emu 4-carboxylate 'mono sodium salt.

 a) 3— (3-Oxoseptiyloxymethyl) -7 | 9— [2— (2-Tritylaminothiazole-4-inole) 1-2 (Z- (1-methyl-11-tert-butoxycarbonyl) ethoxyminoacetamide 1) 3-Chemium 4 1-Rubonic acid 4.09, Imidazo [1,2-a] pyridine 4.09 and potassium iodide 4.09 are treated with acetonitrile and water (1: 1). Dissolve the mixture in 60) ^ and react at 70 ° C for 2 hours. The reaction mixture is concentrated under reduced pressure. The residue is extracted four times with 50 parts each of a mixture of tetrahydrofuran and ethyl acetate (1: 1), dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. You. The residue was subjected to silica gel column chromatography, and eluted with a mixture of acetonitrile and water (: 9: 1; 3 – [(imidazo [1,2–a J pyridinidum 1-yl). Methyl: | −7 ^ — [2- (2-tritylaminothiazo-l-l-irq-l-2ZJ-C1-methyl-l-tert-butoxycarboninole) ethoxyminoacetamide] -13-cefmu Carboxylate 1.2 ^ is obtained.

 b) 3 — [(Imidazo [1,2-a] pyridinium 1-methyl) methyl] 1 7 / 3— [2— (2-tritylaminothiazo-loo 4-yl) 1 2 (Z)-(1-Methyl-1-1-tert-butoxycarbonyl) ethoxyminoacetamide] -1-3-Efmu-4-Carboxylate 1.29 Dissolve in trifluoracetic acid 6W, 20 ° C Stir for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water 5, and sodium hydrogen carbonate was added to adjust the pH.

8.0 and then applied to XAD-Π column chromatography 5 ^ etano One S3—

 -Elute with water. The fraction containing the desired product is concentrated under reduced pressure and freeze-dried to obtain 0.39 of the title compound.

Elemental analysis: as C ₂₄ H ₂₂ N ₇ 0 ₇ S ₂ Na.3H ₂ 0

 Calculated: C, 43.44; H, 4.56-. N, 14.78- Found: C, 43.67; H, 4.39; N, 14.60.

Investor IR

«S- ¹ : 1765, 1670, 1600, 1530.

NMR spectra (d ₆ -DMSO-H2O) S: 1.50 (6H, s),

 3.10 and 3.55 (2¾ ABq, J = 18 Hz), 5.06 (1 H, d, J = 5 Hz), 5.43 (2H, s), 5.75 (lH, d, J = 5 Hz), 6.73 (1 H, s), 7.45-7.65 (1 H, m), 7.96-8.15 (1 H, m), 8.40-8.55

(3H, m), 8.9'6 (lH, d, J = 8Hz).

 Example 6

 7 β-C2- (2-aminothiazoyl 4-yl) -1 2 (Z—methoxyiminoacetamide) 1-3 — [(6-methylimidazo [1,2, a] pyridinium 1 1 1) methyl) 1-3-cephem 1-4-carboxylate 0

 7 β--(2-amino thiazole-4-1yl) -1 2 (Ζ) -methoxyminoacetamide] -1 3- (3-oxobutyryl methoxymethyl) 1-3-sefomu 4 The title compound is obtained in the same manner as in Example 1 below using an acid and 6-methylimidazo [1,2-a] pyridine.

Elemental analysis: C ₂₂ H ₂₁ N ₇ 0 ₅ S ₂ '11 2 H ₂ 0

 Calculated: C, 42.17; H, 5.15; N, 15.65.

Found: C, 41.86; H, 4.21 _; N, 15.46.

IR z c-i: 1765, 1610, 1535, 1035.

NMR spectrum (d ₆ — DMS 0) 3: 2.41 (3H, s), 2.95 and 3.43 (2H, ABq, J = 18 Hz), 3.78 (3H, s),

 4.79 (lH, d, J = 4.5 Hz), 5.20 and 5.41 (2H, ABq, J = 1 Hz),

5.54 (lH, d.d, J = 4.5 Hz and 8 Hz), 6.68 (1H, s),

7.14 (2H, br .s, 7.7 -7.96 (lH, m), 8.2-8.65 (3H m), 8.72 (lH, br s). 9.45 (lH, d) ₀

 Example 7

7 3— [2— (2-aminothiazoyl 4-yl) -1 2 (Z) —methoxyiminoacetoamide] -1 3 — [(7-methylimidazo [1,2-a] pyridinium 1 1-inole) methyl] 1- 3-sef emu 4 1 carboxylate 1 ₀

 7 / 9— [2— (2-Aminothiazolu-l 4-)) 1 2 (Z) —Methoxyminoacetamide] 1—3— (3-oxobutyryloxymethyl) 1—3— The title compound is obtained in the same manner as in Example 1 below using sefmu-4 rubonic acid and 7-methylimidazo [1,2-a] pyridine.

Elementary analysis: as _{C 22 H 21 N 7 0 5} S 2 .7Z2 H 2 0

 Calculated: C, 44.74; H, 4.78; N, 16.60.

Obtained: C, 44.72; H, 4.40; N, 16.31 ₀

IR spectacle cm ~ ^l : 1770, 1660, 1615, 1535.

NMR spectrum (d ₆ — DMS 0) δ: 2.52 (3Η, s),

 2,98 and 3.44 (2¾ ABq, J = l 8Hz), 3.80 (3H, s),

 5.00 (lH, d, J = 4.5 Hz), 5.20 and 5.37 (2 ΑΒ J = 14 Hz),

5.60 (lH, d. D, J = 4.5 Hz and 8 Hz), 6.68 (lH, s),

 7.12 (2H, b r.s), 8.2-8.5 (lH, m), 8.1-8.5 (3H, m),

8.80 (lH, d, J = 7 Hz), 9.45 (lH, d, J = 8 Hz) ₀

Example 8 7 β-2-(2-aminothiazole-1-4yl)-2 (Z)-methoxyiminoacetamide]-3-[(6-chloroimidazo [1,2-a] pyri Gen 1-Inore) Mechinore 1-3-Sefmu 4-Canolepo'xile

- door ₀

 7 9— [2— (2-Aminothiazolu-l 4-inole) -1 2 (Z) —Methoxymethylaminoacetamide] 1 3— (3-Oxobutyryloxymethyl) 1 3— The title compound is obtained in the same manner as in Example 1 below using cefum 4-monocarboxylic acid and 6-chloromidazo [1,2-a] pyridine.

Elementary analysis: as _{C 21 H 18 N 7 0 5} S 2 C1 · 4Η 2 0

 Calculated value ^): C, 40.68; ¾ 4.23 Ν, 15.81 ·

 Found ^): C, 40.63; Η, 3.96; Ν, 15.92.

IR spectrum ト fj ^m ~ ^{l 1} 1765, 1660, 1610, 1520.

NMR spectrum (d ₆ — DM SO) 3: 2.96 and 3.34 (2H, AB q,

 J = 18Hz), 3.69 (3H, s), 4.98 (lH, d, J = 4.5Hz),

 5.23 and 5.50 (2H, ABq, J = 1 Hz), 5.60 (1 H, d.d,

 J = 4.5Hz and 8Hz), 6.67 (1H, s), 7.12 (2H, br.s),

8.0-8.2 (1 H, m), 8.34 (lH, br .s), 8.58 (1 E br .s), 8.78 (lH, d, J = 1 OHz), 9.28 (1 H s), 9.45 (lH , d, J = 8Hz) ₀

 Example 9

7 jS-C 2-(2-Aminothiazole 1-4 -inole) 1 2 (Z) -Methoxy aminoacetamide]-3-[<3 -Chloroimidazo [1, 2-a] Pyridinyl 1-methyl) methyl 3--1- carboxylate ₀

7 β-C 2-(2-aminothiazo-l 4-inole) -1 2 (Ζ) -method f OMPI Example 3) 3- (3-oxobutyryloxymethyl) -1-3-cefthum 4-carboxylic acid and 3-chloroimidazo [1,2-a] pyridine The title compound is obtained in the same manner as 1.

Elemental analysis: C ₂ iHi ₈ N ₇ 0 ₅ S ₂ CI · 5H ₂₀

 Calculated ^): C, 39.53; H, 4.42; N, 15.37.

 Found ^): C, 39.87; H, 3.90; N, 15.61.

IR spectrum ^ ^ ^-1 : 1770, 1670, 1615, 1525.

NMR spectrum (d ₆ —DMS 0) δ: 3.03 and 3.40 (2H, ABq, J = 18 Hz), 3.80 (3H, s), 5.00 (lH, d, J = 5 Hz), 5.25 and 5.50 (2H , AB, J = 1 Hz), 5.60 (1 H, d. D,

J "= 4.5 Hz and 8 Hz), 6.68 (lH, s), 7.12 <2Ebr.s), 7.5-7.78 (2H, m), 7.95-8.25 (lH, m), 8.65-8.95 (2H, m), .9.44 (lH, d, J = 8Hz) ₀

 Example 10

7/3-[[2- (2-aminothiazole-4-inole) -1 2 (Z) -ethoxyminoacetamide] -1 3-[(6-chloroimidazo [1,2-a] pyridinimu 1-yl) methyl] _-3 sef emou 4

—T 0

 7 β- [2- (2-aminothiazole-14-inole) -12 (Ζ) -ethoxyminoacetamide] -1 3- (3-oxobutyryloxymethyl) -1 3-cefumu 4 —The title compound is obtained in the same manner as in Example 2 using chloromidazo [1,2-a] pyridine.

Elemental analysis: C ₂₂ H _{2 ft} N ₇ 0 ₅ S ₂ Cl · 4Η ₂₀

 Calculated values: C, 41.67; ¾ 4.45; Ν, 15.46.

Measurement: C, 41.85; Η, 4.09 _; Ν: 15.69. IR spectrum ¾ J CM " ¹ : 1760, 1660, 1615, 1520, 1380 _o

NMR spectrum (d ₆ — DMS O) d: ll 9 (3Et, J = 7Hz), 3.00 and 3.37 (2H, ABq, J = 1.8Hz), 4.06 (2H, q, J = 7Hz), 5.01 ( lH, d, J = 4.5Hz), 5.27 and 5.50 (2H, AB q, J = l4Hz),

5.63 (lH, d. D, J = 4.5 Hz and 8 Hz), 6.67 (1 H, s),

 7.16 (2H, b r .s), 8.00-8.19 (1 H, m), 8.26 -8.44 (lH m), 8.25- 8.64 (lH, m), 8.66 -8.86 (lH, m),

 9.43 (lH, d, J = 8Hz :).

 Example 11 1.

 7 β ~ 2-(2-aminothiazole-4-inole) 1 2 (Z)-(1 -methyl- 1 -carboxy) ethoxyiminoacetamide]-3-[(6 -chloroimidazo [1 , 2—a] pyridinium 1-methyl) methyl 3--1-efumecarboxylate.

 3- (3-oxobutyryloxymethyl) -1- 7 / 9- [2- (2-tritylaminothiazol-4-ynole) -1-2 (Z) -1- (1-methyl-1-tert-butoxycarbonyl) ethoxy The title compound can be obtained in the same manner as in Example 5 using [minoacetamide] -13-cef-14-carboxylic acid and 6-chloromidazo [1,2-a] pyridine.

Elementary analysis: as _{C 22 H 20 N 7 O 5} S 2 Cl · 4Η 2 0, Calcd: C, 41.68; Η, 4.45 ; Ν, 15.47.

 Found: C, 1.42;, 4.67; Ν, 15.42.

IR spectrum! /

CM- ¹ : 1760, 1610, 1520.

NMR spectrum (d ₆ — DMSO) S: l.38 (3 s),

1.42 (3H, s), 3.01 (2H, ABq, J = 18Hz), 4.97 (1H, d, J = 4.8Hz), 5.20- 5.52 (2H m), 5.60-5.79 (1 H, m),

6.67 (1 H, s), 7.10 (2 H, br .s), 7.96- 8.16 (lH, m),

8.30-8.80 (3H, m), 9.32 (lH, s), 11.45 (lH, d, J = 9¾) ₀ Example 1 2

 7 jS— [2- (2-aminothiazol-4-yl) -12 (Z)-(1-methyl-11-carboxy) ethoxyiminoacetamide] -13-[(6-methylimidazo [1,2-a Pyridinium (1-inole) Methyl] 1-3-Cefume 41-Carboxylate mononatridium salt.

 3- (3-oxobutyryloxymethyl) -one 7 / 3- [2- (2-tritylaminothiazono-one-one-one) -one- (Z) -one (1-methino-one-one-tert-one) Butoxycarbyl) ethoxyiminoacetamide] -1-Cefem-4 is used in the same manner as in Example 5 using rubonic acid and 6-methylimidazo [-1,2-a] pyridine.

Elemental analysis: C ₂₅ H ₂₄ N ₇ 0 ₇ S ₂ Na * 4H ₂₀

 Calculated: C, 43.29; H, 4.65; N, 14.13.

 Found: C, 43.76; H, 4.55; N, 13.59.

IR spectrum ^ f ^ CM " ¹ : 1770, 1660, 1600, 1525.

NMR spectrum (d ₆ -DM S 0) δ: 1.43 (6Η, s),

 2.43 (3H, s), 4.99 (1¾d, J = 4.5Hz), 5.33 (2¾br.s), 5.66 (lH, d.d, J = 4.5Hz and 8Hz), 6.70 (lH, s),

7.13 (2H, b r.s), 7.68-8.02 (1 H, m), 8.06 -8.6C3H, m), 8.64-8.88 (lH, m), 11.54 (lH, d, J = 8 Hz) ₀

 Example 13

7 / 3— [2- (2-aminothiazole-41-yl) -1 2 (Z) -methoxyminoacetamide] -1 3-r (imidazo [1,5-a] pyridini) 1-in-one) methyl] 1-3-se-f-m 4

 7 / 9— [2- (2-aminothiazole-4-inole) -1 2 (Z) -methoxyminoacetamide] -1-3- (3-oxobutyryloxymethyl) -1 3-cef The title compound is obtained in the same manner as in Example 1 below using M-41-rubic acid and imidazo [; 1,5-a] pyridine.

Elemental analysis: as C ₂₁ H ₁₉ N ₇ O ₅ S ₂ '7/2 H ₂₀

 Calculated value ^): C, 43.74; H, 4.54; N, 17.00 ·

 Found: C, 43.79; H, 4.30; N, 16.79.

 I R Sek Tonore V carl: 1770, 1660, 1615, 1515.

NMR spectrum (d ₆ —DMSO) δ: 3.15 and 3.56 (2Η, ABq,

 J = 18Hz), 3.80 (3H, s), 5.03 (lH, d, J = 4.5Hz),

 5.11 and 5.54 (2H, ABq, J = 13Hz), 5.64 (1H, d.d,

 J = 4.5Hz and 8Hz), 6.68 (lH, s), 6.9-7.4 (4H, m),

7.24-7.45 (lH, m), 8.53 (lH, s), 8.68 (lH, d, J = 6 Hz), 9.43 (lH, d, J = 8 Hz), 10.03 (lH, br .s) ₀

 Example 1

 7 / 9— [2— (2-aminothiazole-4-inole) 1-2 (Z) -methoxyminoacetamide] 1-3— [(imidazo [1,2, a] pyridinium 11 Inore) Mechinore] 1-Sef Emu 4

 7-1- [2- (2-aminothiazol-1-4-inole) -1-2 (Z) -methoxyminoacetamide] -3-3-acetoxymethyl 3-cis-FM-14-carboxylic acid 3.0 ^, a Dissolve midazo [1,2-a] pyridin 3.09 and sodium iodide 3.09 in a mixture of 60 parts of acetonitrile (1: 1) and stir at 70 ° C for 3 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate 20 and dissolved in water 50.

ΟΜΡΙ Attached to the graph. The fraction containing the target compound is eluted with 20% ethanol water, and the fraction containing the target compound is reduced under reduced pressure. The resulting residue is subjected to silica gel column chromatography. Elution with a mixture of acetonitrile and water (4: 1), collection of fractions containing the desired compound, concentration under reduced pressure, and lyophilization of the residue give the title compound 0.39 as a colorless powder. The product was confirmed to be the same as the compound obtained in Example 1 from the coincidence of I, and NMR spectra.

 Example 15

 7 β-2-(2-aminothiazole-41-yl) 1 2 (Ζ)-methoxyiminoacetoamide] 1-3-[(imidazo [1, 2-a] pyridinyl-1-yl) ) Methyl] 13 sefum 4-carboxylate.

7/3-[2-(2-aminothiazole-41-1)-1 2 (Z)-methoxymethyl-acetamide] 1-3-Hydroxymethyl-3-cefume-4-carboxylic acid 4-19 Suspended in a mixture of cetonitrile 20 and formamide 20 and imidazo [1,2-a] pyridin 4.79 was added while cooling to 130 ° C. Add 20 ml of dichloromethane solution of methyl o-phenylene phosphite (2nmo \ / _nl ) and stir for 2 hours. After evaporating the solvent under reduced pressure, add 20 W of acetonitrile to the residue and remove the solid. This is suspended in 20 水 of water, and sodium hydrogen carbonate is added to adjust to ΐΗ8.0, and then subjected to XAD-I column chromatography. Elute with 10% aqueous ethanol, collect the fractions containing the desired compound, concentrate under reduced pressure, and freeze-dry to obtain the title compound 3.0. This product was identified as the same compound by the coincidence of physical constants with the compound obtained in Example 1.

 Example 16

7 / 3— [2— (2-aminothiazol-4-inole) -1 2 (Ζ) Siminoacetamide] 1-3-((imidazo [1,2-a] pyridinimu 1-nore) methyl) -3-cefum-4

7 / 3— [2— (2-aminothiazoyl 4-yl-1-2 (Z-methoxyminoacetamide) -13—acetoxymethyl-3—cefum-4-carbonic acid 3.09 suspended in Holm 2 0 Ml, N-methylation - N- Application Benefits Mechirushiriruto Riffle O b acetamidine de 4 was added average at 20 ^J C -. stir until ing the solution then iodine Kato trimethylsilyl to this solution Add 3.39 and stir at 20 ° C for 10 minutes.Concentrate the reaction mixture under reduced pressure, add acetonitrile 9 に ^ to the residue, and add tetrahydrofuran 0,8 to add 40%. Next, add imidazo [1,2-a] pyridine 29 to this solution, stir at 20 ° C for 3 hours, cool the reaction mixture under ice-cooling, and add 1 W of water. The precipitated solid was collected, subjected to silica gel column chromatography, Nitrile and water. (4: 1) eluting with a mixture of the title compound 0.3 9 intended compound was concentrated under reduced pressure The fractions containing the freeze-dried to obtain.

'• ^ U ii A hi, OMPI Example 1 7.

 Ίβ-2-2-Aminothiazole-4—Il-2CZ) -Methoxyoximinoacetamide-1-3 — [(Imidazo [1,2—a] pyridinium 1- (Inore) Methyl J-1-3-Cef-41-carboxylate

 a; 7—Aminnow 3— (3—oxobutyryloxymethyl) -1 3—Cefem-4 1-Rubonic acid 6.2 ^, imidazo [1,2, -a J pyridine 6.0 ^ and potassium iodide Dissolved in a mixture of acetate nitrile and water (1: 1), and stirred with '70 for 1 hour. The solvent is distilled off under reduced pressure, and the residue is washed three times with 30 portions each of ethyl acetate. Take the solid and dissolve it in 30 si water, then XAD! Perform column chromatography and elute with water. The fractions containing the target compound are collected, concentrated under reduced pressure, and the residue is freeze-dried to give 7 ^ -amino-3-([imidazo !: 1, 2-a] pyridini ゥ mu 1-inole) methinole] 1 3-Sef-e-mu 4 One-strength ruboxylate ΐ 1.3 ^ obtained.

b 2— ('2 -aminothiazole-4-yl) -1 2 (Z) -methoxyaminoacetic acid 0.94 9, 1'-Droquinbenzotriazole 0.64 ^ dimethylhonoleamide 20 0 ^ Solution I: Add cyclohexane i / norecarbodiimide 1.0 and stir 2 (TCC for 2 hours. Remove the precipitated ^^, and remove the solution from 7 ^ -amino-3-(I Add midazo [1,2-a] pyridinium-1-yl] methyl] -13-cefum-4-carboxylate 1.3 ^ to a solution of 1.3 ^ in dimethylformamide 20 ^, and stir 3 B at 20 ° C. After adding ethyl ether 20 to the mixture, the ether layer was removed. The residue was dissolved in water 20 and eluted with XAD-Π column chromatography with ^ ₀ 10% ethanol z. Collect and concentrate the fractions under reduced pressure Separation, drying and drying yields the title "^ 0.25 ^ force; Sina is of ^^ and physical constants that obtained in Girei 1

REA ^ —Yes.

 Example 1

 1 β-2-2-Aminothiazoyl 4-yl) -2 (Ζ) -Methoxyxyminoacetamide] 1-3— [C6 1-Lubamoylimidazo [1,2— a J Pyridinyl mu I-Ilk methyl J—3—Sefmu

 Boxylate.

7-C 2-C 2-aminothiazo 1-4-yl) 1-2 (Z-methoxyminoacetamide)-1-3-(3-oxobutyryloxymethyl) 1-3-cefume 4 . 6 force Rubamoi Louis Midazo [1, 2 - a] the title compound was synthesized in the same manner as in example 1 using pyridine is obtained elemental analysis: as _{C 22 H 20 N 8 O. 6} S 2 · 9Ζ2Η 2 0

 Calculated values): C, 41.44; Η, 4.58; Ν, 17.57

 Measured value): C, 41.65; Η, 4.36; Ν, 17.66

 IR spectrum ^ "1 1770, 1680, 1620, 1520.

NMR spectrum _{(d -DMSO-D 2 O)} : 2.90 and 3.43 (2H, AB q,

J = l 8Hz J, 3.65 (3H, s), 4.93 C lH, d, J = 4.5Hz, 5.30

(2H, br.s ;, 5.55 (lH, d, J = 4.5Hz), 6.60C1H, s),

8.15-8.50 C 4H, m), 9.30 (1 H, s; ₀

Example 1 9.

7 C 2-(2-aminothiazol-4-1-yl-1 (Z)-methoxyiminoacetamide J-3-!: C 3-methylimidazo [1, 2-3] pyridinium 1 1 1 1) Methyl J — 3 — seveum 4-carboxylate ₀

 1-1 2 (2-aminothiazole 4-1yl) -1 2 (Ζ) -Methoxymethoxyminoacetamide -1 3-(3-oxobutyryloxymethyl)

Οίλ'ΡΙ The title compound is obtained in the same manner as in Example 1 using 1-3-CFM-14-rubric acid and 3-methylimidazo [1,2-a] pyridine.

Elementary analysis: as _{C 22 H 21 N 7 0 5} S 2 · 13 2H 2 0

 Calculated: C, 40.99; H, 5.32; N, 15.21

 Obtained value (: C, 40.98; H, 5.42; N, 14.91

IR spectrum, ¹ : ¹ : 1770, 1660, 1620, 1530.

NMR spectrum Honoré _{(d 6 -DMS 0; <5} : 2.57 C 3H, s), 2.94 and 3.24 (2H, ABq, J = l 8Hz;, 3.84 C 3Η, s, 5.00 [lH, d, J = 4.5Hz;, 5.23 and 5.48 (2H, ABq, J = 1 4Hz, 5.60lH, d.d, J = 4.5Hz and 8Hz), 6.68lH, s, 7.14 (2H, br.s), 7.4-7.7 C lH, m), 7.75-8.18 C 2H, m), 8.28 lH, s, 8.41-8.85 C lH, m), 9.43 lH, d, J = 8Hz) ₀ Example 20.

 7-ί 2-C 2-Aminothiazole-4-inole :) 1 2 (Z)-MET £ £ / : (5,7-dimethinorei midazo [1,2-a] pyridinyl-1 11-yl) methyl] -1 3-sefumu 4

7 ^ — [2 -C 2 -Aminothiazol-1-yl)-2 CZ) -Methoxyxyminoacetamide] -1 3-(3 -oxobutyryloxymethyl-1-3 -sephem-14- 5, 7 Jimechirui Midazo title compound was synthesized in analogy to example 1 using [1, 2 one a] pyridine is obtained elemental analysis value:. as _{C 23 H 23 N 7 0 5} S 2 · 4H 2 0

 Calculated value): C, 45.02; H, 5,09; N, 15.98

 Found ^: C.44.89; H, 4.69; N, 16.10

 Ιίί Ιίί cm cm.

max 765, 1 660, 1 605, 1520 NMR spectrum (d ₆ -DMSO δ: 2.70 C 3H, s;, 2.71 (3H, s), 2.94, 3.44 (2 (, ABq, J = l 8 Hz), 3.78 (3Η, s ;, 4.98 C lH, d, J = 4.5Hz), 5.20 and 5.40 (2H, ABq, J = l4Hz), 5.60 (1H, d.d, J = 4.5Hz and 8Hz), 6.67C lH, s), 7.13 ( , 7.25 ClH, s), 8.12-8.4 C2H, m), 8.50 ClH, s, 9.44 ClH, d, J = 8 Hz)

Example 2 1.

 7/9-2— (2-aminothiazole 4-yl-1 (Z) —methyminoacetamide) -1 3- !: (5-acetamidomidazo [ 1.2-a] Pyridinyl-1-yl) methyl-3-1-cefum 4-carboxylate.

1 β-2-2-Aminothiazolu-l 4-yl-l- 2-Methoxymethoxymino-acetamide] -l- (3-Oxobutyryloxymethyl) 1-3-Sefmu 4 The title compound is obtained in the same manner as in Example 1 below using 5-acetamidomidazo [1,21a] pyridine. Elementary analysis: as _{C 23 H 22 N s 0 6} S 2 · 5H 2 0

 Calculated value (%): C, 41, 81; H, 4.88; N, 16.96

 Found): C, 42.10; H, 4.63; N, 16.46.

IR spectrum ^; _v cm: 1765; 1650.1610, 1520,

1 3 70, 1 280, 1 1 7 0

NMR spectrum _{(d 6 -DMSO δ: 2.30 (} 3Η, s, 3.03 and 3.48

C 2H, ABq, J = l 8Hz;, 3.79 (3Η, s;, 5.00 C lH, d,

J = 4.5Hz), 5.36C2H, br.s), 5.62 (lH, d.d, J = 4.5Hz and 8Hz), 6.68ClH, s), 7.12 (2H, br.s ;, 7.5- 8.6 C 5H,

Implementation example 2 2.-

7 ^ — [2— [2—Aminothiazolone 4 yl 1 2 [Z J—Methoxyximinoacetamide :! One 3—! : C 6—Promoy midazo !: 1, 2—a J pyridinyl (1-11) methyl) 1—3—cephem— 1—1 carboxy

7 β-2-2-Aminothiazol-4-yl :) 1-2 (Ζ) 1-Methoxyxyminoacetamide 1-3-(: 3-Oxopti !; Roxymethyl) — 3-Cefem-41 The title compound can be obtained in the same manner as in Example 1 using carboxylic acid and 6-bromoimidazo [1,2-a] pyridine.

Elementary analysis: as _{C 21 Hi 8 N 7 0 5} S 2 Br · 2H 2 0

 Na): C, 40.13; H, 3.53; N, 15.60

 Obtained value): C, 40.30; H, 3,74; N, 15.29

 X ^ D

丄 Spectrum _ma "an- ¹ : 1765, 1670, 1610, 1520 NMR spectrum C d ₆ -DMSO δ: 2.95 and 3.31 (2Η, ABq, J =

 18Hz ;, 3.79 3Η, s), 4.98 (lH, d, J = 4.5Hz ;, 5.1-5, 52Η, m), 5.60C1H, d.d, J = 4.5Hz and 8Hz, 6.67C lH , s), 7.12 C 2H, b r.s, 8.04-8.44 C 2H, m), 8.48 -8.81 C lH, mj, 9.32 C lH, s, 9.42 C lH, d, J = 8 Hz) .

 7-2-C 2-Aminothiazole 1-4 1] 1 2 [Z)-Methoxyminoacetamide 1-3! : C8—Metinorei Midazo! 1, 2 — a) pyridinimu 1-ylmethyl J-1-3-sevuemu 4-carboxylate

 The title compound is obtained in the same manner as in Example 1 using 8-methylimidazo [1,2-a] pyridine.

O PI Elementary analysis: as _{C 22 H 21 N 7 0 5} S 2 · 7 / 2H 2 0

 Calculated: C, 44.74 H. 4.78; N, 16,60

 Found: C, 44.48; H, 4.43; N, 16.85.

IR spectrum ¹ : 1 780, 16 65, 16 15, 1 540

NMR spectrum _{(d 6 -DMSO) «5:} 2.80 (3H, s), 3.11 and 3.49 C 2H, ABq, J = l 8Hz, 3.80 C 3H, s, 5.01 (1 H, d, J = 4.5 Hz J, 5.43 C 2H, b r. S, 5.63 (lH, d. D, J = 4.5 Hz and 8 Hz, 6.69 (lH, s), 7.15 C 2H, b r. S, 7.37 C lH, t, J = 7Hz, 7.73 ClH, d, J = 7Hz, 8.38 ClH, d, J = 2Hz, 8.58 (lH, d, J = 2Hz, 8.64-8.97ClH.m, 9.48ClH, d, J = 8Hz )

Example 2 4.

 7 ^-C .2-C 2 -aminothiazole-4-1-2 (Z)-methoxyminoacetamide J-3-[C5-methylimidazo [1, 2-a] pyri The title compound can be obtained in the same manner as in Example 1 using dinium-1-yl) methyl j-3-sefumu 4-carboquinate 5-methylimidazo [1,2-a] pyridine.

Elemental analysis: C 2 ₂ H ₂₁ N ₇ 05 S 2 · 9 no 2H ₂₀

 Calculated value (%): C, 43.42; H, 4.96; N, 16.11

 Obtained value): C, 43.06; H, 4.73; N, 16.13

 IR spectrum: cm .: 17770.680, 160.50.1530

 ma

NMR spectrum (d ₆ -DMSO δ: 2.77 (3H, s, 2.94 and 3.44

 C 2Η, ABq, J = l 8Hz ;, 3.79 C 3H, s;, 4.99 C lH, d,

 J = 4.5Hz), 5.37 and 5.50 (2H, ABq, J = 14Hz, 5.60 lH, d. (1, -cho = 4.5112 and 8112, 6.68 (111, 5)), 7.15 (211, 1> 1 ".5 )

O PI

WIPO 7.25— 7.50 (lH,, 7.7— 8.1 (lH, m), 8.28-8.68 C 3H, m), 9.5 C lH, d, J = 8 Hz

Example 2 5.

 1 β ~ 2-(2-aminothiazol-4-ylc-2CZ) -methoxyminoacetamide amide-1-3- [C5-chloroimidazo [1,2, a] pyridinimuyl) Methyl j—3—Cephem 4

The title compound is obtained in the same manner as in Example 1 below using 5-chloroimidazo [1,2-a] pyridine.

Elemental analysis value: C ₂₁ H ₁₈ N ₇ 0 ₅ .S ₂ C · 4H ₂₀

 C, 40.68; H, 4.23; N, 15.81

 Obtained): C, 40.78; H, 3.93; N.15.91

IR spectrum

: 1 770, 1 6 70, 1 6 1 0, 1 53 5, 1 5 1 0

NMR spectra d ₆ -DMSO J δ: 2.97 and 3.40 (2H, AB q,

 J = l 8Hz, 3.79 C 3H, s, 4.90 lH, d, J = 4.5Hz, 5.37 and 5.54 (2H, ABq, J = 14Hz), 5.60 (lH, d.d, J = 4.5Hz and 8Hz, 6.68 , 7.62-8.18 C2H, m), 8.4—8.86 (3H, m), 9.46 (_lH, d, J = 8Hz; C1H, sJ, 7.1C2H.br.s;

Example 2 6.

 7-2-C 2 -Aminothiazole 4-yl) 1-2 (Z)-Methoxyminoacetamide 1-3-[5-Methoxythimidazo [1, 2-a] Pyridinium 1-yl) Methyl] 1 3-Cefum 4 1 Carboxylate o

Example 1 PI using 5-methoxymidazo [1,2-a] pyridine To give the title compound.

Elementary analysis: as _{C 22 H 21 N 7 0 6} S 2 · 7 2H 2 0

 Calculated): C, 43.56; H. 4.65; N, 16.16

 Obtained value): C, 43.63; H, 4.57; N, 16.22

IR Skoke 'Torre ¹ m ^ a ^ xcm: 1765 to 16.50.16 20.1.53 0.

NMR spectra (d ₆ -DMSO δ: 2.96 and 3.45 (2Η, AB q,

 J = l 8Hz, 3.80 C 3Η, s ;, 4.25 C 3Η, s, 4.95 (lH, d, J = 4.5Hz, 5.24 and 5.44 (2Η, ABq, J = l 4Hz, 5.61 (lH, d.d, J = 4.5 Hz and 8 Hz, 6.68 (lH, s;, 6.9-7.3 (.3H, m 7.9-8.35 C 3H,, 8.4-8.62 (1 H, m), 9.46 C 1 H, d,

 J = 8Hz

Example 2 7.

 7 ^ 1 [2-(2-aminothiazol-4-1-1-2-methoxyminoacetamide) 1 3-!: (5-Methylthioimidazo [1, 2-a] pyridine 1-1 1-methyl-3-1-carboquinate o

 The title compound is obtained in the same manner as in Example 1 below using 5-methylthioimidazo [1,2-a:) pyridine.

Elementary analysis: as _{C 22 H 21 N 7 0 5} S 3 4H 2 0.

 Calculated values: C, 41.83; H, 4.63; N, 15.52

 Measured (: C. 41.91; H, .4.40; N, 15.20

 IR spectrum ^ ^ χ ^-770, 1660, 1620, 1530

NMR spectrum (d ₆ -DMSO J δ: 2.83 (3H, s, 3.16 (2H,

 ABq, J = l 8 Hz, 3.80 (3H, s), 4.99 C lH, d, J = 4.5 Hz · 5.27 and 5 · 49 (2H, ABq, J = l 4 Hz, 5.61 (lH. D. D,

OMPI J = 4.5Hz and 8Hz), 6.68 C1H, s ;, 7.12H, br.s, 7.32-7.58 (1H, m, 7.78-8.12 [lH, mj, 8.34-8.36lH, m, 8.40- 8.72 (2H, m), 9.46 (lH.d, J = 8Hz)

 7 ^ 1 [2 — (_ 2 -aminothiazole-41 yl) 1 2-methoxyaminoacetamide] 1 3-[C 3 -N, Ν-dimethylaminomethylimidazo [ 1 * 2-aj pyridinum 1-methyl) 1 3-cefum 4-carboxylate.

 The title compound is obtained in the same manner as in Example 1 below using 3 —Ν, Ν-dimethylaminomethylimidazo [1,2-pyridine].

Elementary analysis: as _{C 24 H 26 N 7 0 5} S 2 · 4H 2 0

 Calculated): C, 44.85; H, 5.33; N, 1 7.43

 Obtained): C, 45.04; H, 4.81; N, 17.68

Ifl vector ^ _ma ', an: 1770, 1660, 1610, 1520

NMR spectrum Honoré _{(d 6 -DMSO): 2.90 (} 3H, s) · 2.98 C 3H, s)

 3.84 (3H, s), 5.06 C 2H, bs, 5.19 (lH, d, J = 4.5 Hz, 5.65 C lH, d. D, J = 4.5 Hz and 8112 _), 6.72 [1 {1, 5 ^ ), 7.16 C 2H, b r.s, 7.0-7.25 C lH, m, 7.27-7.52 1 H m;, 7.6-7.72 C lH, m, 7.93 (lH, s, 8.82-9.00 (lH, m, 9.5 3 C lH, d, J = 8Hz)

Example 2 9.

 — [2— (2-Aminothiazole-4-yl) ー 2 (Z) —Methoxyxyminoacetamide] ー 3— [C3 One-piece Lubamoy Louis Midazo [1,2—a Pyridini mu 1) Methyl] 1-3-Sefume 4-carboxylate. .

O PI The title compound can be obtained in the same manner as in Example 1 below using 3-potassium rubimiyid midazo [1,2-a] pyridine.

Elementary analysis: as _{C 22 H 20 N 8 O 6} S 2 · 9Z2H 2 0

 (Calculation leg): C, 41.44; H, 4,58; N, 17.57

 Obtained value (9¾: C, 41.54; H, 4.32; N, 1 7.37

IR-spectrum Relais _{^ χ ^: 1 775, 1} 6 8 0, 1 6 20, 1 520

NMR spectrum (d ₆ - DMSO): 3.09 and 3.49 (2H, AB q,

 J = l 8Ηζ, 3.80 (3Η, s ;, 5.01 C lH, d, J = 4.5Hz,

 5.37 and 5.67 (2H, ABq, J = l 4 Hz, 6.69 (lH, S), 7.14 C 2H, br.s ;, 7.54-7.76 C lH, m, 7.92- 8.28 C lH, m,

8.78-9.00 (lH, m ;, 9.16 (1H, s), 9.46 (lH, d, J = 8Hz), 9.76 (lH, d, J = 7Hz)

Claims

The scope of the claims

 -General formula

Θ

O ₃

[Wherein Ri is an amino group which may be protected, R ₂ is a hydrogen atom or a halogen atom, I is a hydrogen atom or an optionally substituted hydrocarbon residue, and R ₄ is a hydrogen atom. A represents an atom or a methoxy group, A represents an optionally substituted imidazole-11-yl group forming a condensed ring at the 2,8-position or the 3,4-position, and n represents 0 or 1.] A septum compound or a physiologically acceptable salt or ester thereof.

2. (1) General formula

 COO © [wherein, IU represents a hydrogen atom or a methoxy group, and Α represents an imidazole-11-yl group which forms a condensed ring at the optionally substituted 2,3- or 3.4-position; n represents 0 or 1) or a compound or a salt or ester thereof represented by the general formula:

O PI

WIPO Rl / ^R 2

 N— ^ no COOH

 c

 II

 N

 , O

Wherein R i represents an amino group which may be protected, R 2 represents a hydrogen atom or a halogen atom, and R ₃ represents a hydrogen atom or a hydrocarbon residue which may be substituted. React with the reactive derivative or

 (2) General formula

R5

 N COOH

 \

OR ₃

Wherein, in the formula, is a hydroxyl group, a hydroxyl group, a labamoyloxy group, a substituted rubamoyloxy group or a halogen atom. Other symbols are as defined above, or a salt or ester thereof. And a compound represented by the general formula A [A represents an imidazole that forms a condensed ring at the optionally substituted 2,3- or 3,4-position] or a salt thereof.

 (3) General formula

[The symbols in the formula have the same meanings as described above] or a salt thereof or an esthetic and a general formula! The ability to react with a compound represented by ^ OH (wherein R 3 'represents an optionally substituted hydrocarbon residue) or a reactive derivative thereof, or

 (4) General formula

Wherein X is a halogen atom, and other symbols have the same meanings as defined above, or a salt or ester thereof represented by the general formula C (= S) NH ₂ [wherein, is as defined above. The ability to react with the compound represented by

 After that, if necessary, a general formula characterized in that the protective group is removed

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

 3. —General formula

OMPI

[Wherein Ri is an amino group which may be protected, R ₂ is a hydrogen atom or a halogen atom, R ₃ is a hydrogen atom or an optionally substituted hydrocarbon residue, and I is a hydrogen atom. A represents an atom or methoxy, A represents an optionally substituted imidazo-l-yl group forming a condensed ring at the 2,3-position or 3,4-position, and n represents 0 or 1 ] A pharmaceutical composition comprising at least one of the septum compound or a physiologically acceptable salt or ester thereof. '

O PI WIPO