WO1983000690A1

WO1983000690A1 - Azetidine derivatives and process for their preparation

Info

Publication number: WO1983000690A1
Application number: PCT/JP1981/000192
Authority: WO
Inventors: Ltd. Takeda Chemical Industries; Taisuke Matsuo; Hirotomo Masuya; Noriyoshi Noguchi
Original assignee: Takeda Chemical Industries Ltd
Priority date: 1981-08-25
Filing date: 1981-08-25
Publication date: 1983-03-03

Abstract

1-Sulfo-2-oxoazetidine derivatives represented by the following general formula (I): <IMAGE> (wherein R1 represents an optionally acylated or protected amino group, X represents a hydrogen atom or a methoxy group, and R4 represents an azido group, a halogen atom, or a group of <IMAGE>or -S-S-R5 (wherein R5 represents an organic residue, and n represents 0, 1 or 2), and process for their preparation according to the following scheme: <IMAGE>(wherein R2 represents an acylated or protected amino group, R3 represents an acylated amino group, and R1 and R4 are the same as defined above).

Description

Specification

Azetidine derivative and method for producing the same

TECHNICAL FIELD The present invention relates to a novel 1-snolejo-3,4-substituted-2-year-old xoazetidine derivative having an antibacterial activity or inhibiting 9-lactamase, and a method for producing the same.

Background art

In recent years, various 2-year-old oxoazetidine derivatives have been synthesized.]) For example, a 41-acetoxy-2-year-old oxoazetidine compound was synthesized from vinyl ester and chlorosulfonylisocyanate, and a further demand was obtained. It is known to introduce benzoinole, xylekirch, benzinolechi, etc. into the 4th position by nuclear substitution reaction [Annaleii der. Cliemie X 1974, 539-o In this method, it is thought that the reaction proceeds via a compound having a chronoreno-sinolephonyl group at the 1-position, but the clos-nolephonyl group is liable to be eliminated and difficult to use as an intermediate.

The present inventors have conducted intensive studies for the purpose of obtaining a new and useful azetidine-based conductor, and found that an azetidine derivative having a sulfo group at the 1-position meets the above-mentioned object, and further studied the present invention. completed.

That is, the present invention provides:

[In the formula, is an amino group which may be acylated or protected, X is hydrogen or methoxy, R 4 is an azide group, a haeogen or —0R ₅ , ί 基 ° ^¾ , a group represented by -SS -R ₅ (wherein, R ₅

Represents an organic residue, and n represents 0, 1, or 2).] 1-Snolejo-2-oxoazetidine derivative represented by the formula (2)

X

No

Two

(K)

NH

Wherein R ₂ is an acylated or protected amino group, and I ′ X has the same meaning as described above, and the 2-year-old xoazetidine derivative represented by the formula _In the case where 2 is a protected amino group, a method for producing a 1-snorrepho-2-oxoxazetidine derivative represented by the general formula (I), which further comprises removing a protecting group, if necessary, 3) Killing ceremony

Wherein R ₄ and X have the same meanings as defined above, and a killing formula characterized by subjecting the 3-amino-1-snoleho-2-oxoxazetidin derivative to an asinolelation reaction.

Wherein X represents an acylated amino group, and X and R have the same meanings as described above, respectively. The present invention relates to a method for producing a 1-snolejo-1-oxoxazetidine derivative represented by the formula: In the above general formula, B ₄ is an azide group 'halogen or —◦, _R ⁵ '

^{- 5, - S - S -} . R represents a group represented by wherein the halogen 0R ₅ ting, for example fluorine, chlorine, bromine, and iodine, organic殘基represented by R ₅ is a hydrocarbon group, Means an acyl group, a heterocyclic group, etc. Hydrocarbon groups can have linear, branched or cyclic double or triple bonds. A group I or an aromatic group such as feninole and naphthinole is meant, and an acyl group is such a hydrocarbon-substituted canolepodinole group. As the heterocyclic group, for example, a 5- to 6-membered cyclic group containing a yellow atom of 丄 H and / or (and) 1 to 4 nitrogen atoms is used .. These heterocycles are condensed with a benzene ring. You may. Specifically, for example, pyridinole, tetrazolinole, thiaziazolinole, cheninore, thiazolinole, isothiazolinole, benzothiazolinole, etc. are used.

Such a hydrocarbon group, an acyl group and a heterocyclic group are, for example, halogen, phenoxy, phenoxy, phenyl, chlorine, bromine, and the like, such as lower azolexoxy having 1 to 3 carbon atoms, lower alkoxycarbinole, canoleboxyl, fluorine, chlorine, and bromine. Heterocyclic groups such as Ninore, Fri — Nore and Cheninore, heterocyclic groups having 1 to 3 carbon atoms, such as methinorecho and echinorecho, heterocyclic groups such as tetrazolinorechio, thiaziazolinolecho, etc. -A group which may be substituted with an amino group which may be converted to an amino group, cyano, etc., and among the above-mentioned amino groups which may be converted to an amino group which may be converted to an acyl group, preferred are acetinol and Propioninore.

Specific examples of the organic residue include, for example, honoleminole, acetinole, propionyl, butyrinole, isoptyrinole, t-butylinole, 2-ethoxyquinone rubinoninorecetinole, 2-hydroxyquinone, methinolechiole, methinolechiole, (1 —

O PI Methinole 5H-Tetrazonole-5-inole) Thioacetinole, chloroacetinole, phenoxyacetinole, feninoleasetinole, cheninoleasetinole, (2-aminominiso) * —oleinole * 41inolene, acetinolene 2—Krorobenzinole, 4—Aminovenzinole, Mechinore, Etchinore, Isof. Mouth pinore, butinore, t-butinore, ethoxycanoleboninolemethinolle, methoxycanoleboninolemetinole, benzinore genuine, shicanoreboninoremethyl, force, revoximetinole, methinomethinole, 1-Methinole 5H-Tetrazo-nole 1-inole) Thiometinole, Cyanometinole, Feninole 2-Cross mouth Fue-nole, —Amino-Feninole, 2—Amino-Echinole, 2-Acetinole-amino-Echinole, Benzothiazolinole, 1-methinole 5H-Tetrazonole-5-inole, etc. s Used o In the above-mentioned killing formula, the acyl group in the asinolated amino group represented by Ri, R2 and Rs is conventionally known. Group substituted on the 6-amino group of the benziline derivative, cephalosporin An amino group substituted for the 7-amino group of the derivative is used.

Examples of such an acyl group include, for example, the formula (1)

R6-CO-

[In the formula, R6 represents lower quinolene or an optionally substituted phenyl, a heterocyclic group, or an optionally substituted benzoyl. And the formula (2)

R ₇ -NH-CH-C 0—

I

During ^R 9 ^ί formula, R ₇ is hydrogen, yo amino acid residue may have a substituent, a protecting group of the Amino group of the formula _{_{_{R s - (CH 2) nl}}} - CO- wherein, R ₈ is a substituted A heterocyclic group which may have a group, a phenyl group which may have a substituent. And nl represents 0 or an integer of 1 to 4, each of which may represent a lower anoalkyl or a phenyloxy or lower anoalkylthio which may have a substituent; and — (CH ₂ ) _n i- The group may have a substituent. Wherein R ₈ ′ and R ₈ ′ are the same or different and are hydrogen, lower quinole, lower anolequinole carbamoyl, phenylcanolebonyl optionally having a substituent, or Respectively. ] Or expression

_{_{. R 8 '"-S 0 2}} - wherein, R _8" represents optionally substituted lower Anoreki Le may have a substituent. R 9 is hydrogen, optionally substituted lower alkynole, optionally substituted pheninole, optionally substituted heterocyclic group , Cycloanolekenylene, and heterocyclic carbonylamino, which may have a substituent or may be via a anorecylene chain, respectively. Group represented by}, formula (3)

^Ε 10― ^ 11— c◦—

Wherein B ₁₀ is a formula B-^-{wherein X is a nitrogen or sulfur atom,

N-X-Ri 3

Rl2 is an optionally phenyl which may have a heterocyclic group or a substituted group may have a substituent, B ₁₃ is hydrogen, off which may have a substituent We two - Honoré, lower § Shinore Ri-Ri5 (wherein: Rl4 represents lower alkylene or lower alkenylene, and R,-represents canoleboxy, its ester or heterocyclic group, respectively). , Respectively. }, Rll is a mere bond or formula +

-C0-NH-CH- (wherein, R ₁₆ has a lower alkyl group,

R16

Represents a phenyl group or a heterocyclic group which may have a substituent. ) Represents each group. A group represented by

(^ Expression

OMPI

Replacement ¾8

¾7 [In the formula, R ₁₇ is hydroxynole 'hydroxysnolehoninoleoxy' canoleboxinole, which may or may not have a substituent. Levoninole, benzyloxycanoleboninole 'holminoleoxyphthalamide, and は 8 is a group represented by hydrogen, low phenolic, lower phenol, halogen, azido, nitro, and hydroxyl, respectively.

Equation (5)

^R 19- ¾0 one ^{C j} ¾ ¹⁰ -

[In the formula, R ₁₉ represents cyano, a substituted or unsubstituted phenol, a substituted or unsubstituted phenoxy, a substituted or unsubstituted lower phenol or a substituent. And R ₂₀ represents a mere bond or -S-, respectively, which may be substituted or a heterocyclic group which may have a substituent. ] Is used.

In the above formula, the lower phenol which is represented by R ₆ preferably has 1 to 6 carbon atoms. The heterocyclic group in the heterocyclic group which may have a substituent is a 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and containing or containing one oxygen atom. You can get things. Specific examples of this heterocyclic group are-for example, isoxazolyl, piperazinyl, and imidazolinyl. Examples of the substituent of the heterocyclic group include a C 1 to C 3 C-anolequinolene, a C 1 to C 3 low phenol, a halogen, a nitrite, an amino, an oxo, a thiaxo, a substituent. Moyo Funinori Etc. are used. Examples of the substituent in benzoyl which may have a substituent and the substituent in phenyl which may have the above substituent include lower alkyl having 1 to 3 carbons and lower alkyl having 1 to 3 carbons. Alkoxy, halogen, nitro, amino and the like are used.

In the above formula, examples of the amino acid residue in the amino acid residue which may have a substituent represented by R ₇ include, for example, glycyl, araninole, valinole, mouth isole, isole isole, and Linole, sininole, cystininole, cistil, methinilil, or or aspanoretyl, a- or r-gunoletaminole, lisinole, anoregininole, feninolean laninole, feninolec ricinole, chininole Shinore, Histijinore, Trif. Tofu Inore, Fu.リレ: Used. Examples of the substituents that may be substituted on the amino acid residue include amino, lower anolyalkylamino, amino-protecting group, phenolic molybdenum, methynolec bacinoyl, snorefamoynole, benzinole, and ethylethyl. , 3-dioxo _ 1 piroberazino force, 4- echinolay 2, 3-dioxo 1 -bivera dinocarbonylamino, etc. The lower alkanol in the lower alkynoleamino preferably has 1 to 3 carbon atoms. As the amino-protecting group, those similar to the amino-protecting group described below are used.

As the amino-protecting group represented by R _v , those similar to the amino-protecting group described below can be used.

Expression! The heterocyclic group in the optionally substituted heterocyclic group represented by R ₈ in the group represented by ¾-(CH ₂ ) _nl —CO- includes, for example, one sulfur atom, nitrogen atom or oxygen 5-6 membered heterocyclic group containing atoms, 5-6 membered heterocyclic group containing 2-4 nitrogen atoms, 5-6 containing 1 or 2 nitrogen atoms and 1 sulfur or oxygen atom Heterocyclic groups are used, these heterocyclic groups being 6-membered ring groups containing up to 2 nitrogen atoms, benzene rings or 1-membered ring groups.

ん ΡΙ 忘 Forget May be condensed with a 5-membered ring group containing two sulfur atoms.

Above: The ingredients侔例heterocyclic group represented by R _8, for example ,, 2-pyridyl, 3-pyridyl, 4 one Pirijinore, pyridinium Mijiniru, Pirajininore, Piridaji two Honoré, pin base Wojiniru, pyrazolinyl, Imita ' Zolizyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido [2,3-a] pyrimidinyl, benzopyranyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1, 7—Naphchil Gininole,

2,7-naphthyridinyl, 2,6-naphthyridyl, quinolyl, thieno [2,

3-¾] Pyridinyl, tetrazolinole, thiadiazolyl, thixaziazolyl, triazyl, chenyl, pyrrolyl, furyl and the like are used. Examples of the substituent of the heterocyclic group which may have a substituent represented by ₁₈ include alkyl having 1 to 12 carbons and 1 to 12 carbons which may have a substituent. 3 lower alkoxy, hydroxyl, oxo, thioxo, aldehyde, trifluoromethyl, amino, no, rhogen, lower alkylsulfoninole with 1 to 3 carbon atoms, 2,6-dichlorophenyl, coumarin 1-3 Carbo zz., —Formyl-1-piverazinyl, pyrrole aldimino, furan aldino, thiard fenaldimino, mesyl, protecting group for amino group, acylamino having 2 to 4 carbon atoms which may be substituted with halogen No. etc. are used. As the amino-protecting group, the same amino-protecting groups as those described later can be used. Examples of the group which may be substituted with alkyl having 1 to 12 carbon atoms include, for example, phenyl, halogen, hydroxyl, dialkylamino and the like. The alkyl in the dialkylamino is preferably a lower alkyl having 1 to 3 carbon atoms.

Examples of the substituent in the phenyl which may have the substituent represented by ₈ include lower alkyl having 13 carbon atoms and lower alkyl having 1 to 3 carbon atoms.

O PI

.. ― Grade alkoxy, nodogen, hydroxynole, aminoru: used. The lower alkyl in the lower anoalkylthio represented by P'8 is preferably one having 1 to 3 carbon atoms.

Examples of the substituent in the phenylthio which may have a substituent represented by R 8 include: lower alkynole having 1 to 3 primes, lower alkoxy having 1 to 3 carbons, halogen, and hydroxynorre. , Amino is used. Formula - (CH ₂₎ IIL - in as a group which may be substituted by a group represented, for example, § Mi Bruno - wherein - in NH-C0-R ₈ w [wherein, 1¾8 "is § Mi Roh or substitution And a substituent represented by R ₈ ^W. Examples of the substituent in the optionally substituted piperazi dinole represented by R ₈ ^W include, for example, carbon Lower alkyl having 1 to 3 carbon atoms, lower anoreoxy having 1 to 3 carbon atoms, hydroxynole, sodium oxo, thioxo, halogen, and the like are used.

The lower alkyl represented by Bo 'and Z or R / in the above formula preferably has 1 to 3 carbon atoms. As lower alkanols in lower alkynole-canolebamoinole, those having 1 to 3 carbon atoms are preferable. Examples of the substituent in the phenylphenol which may have a substituent include lower phenols having 1 to 3 carbon atoms, lower phenols having 1 to 3 carbon atoms, halogen, hydroxyyl, and hydroxysnorrenol phenol. Used for kishi and benzinole.

In the above _{_{formulas, R 8 "- S 0 2}} - as a low grade A Kill in lower alkyl which may have a substituent represented by R ₈ in the group represented by is preferably one having a carbon number of 1-6, The substituent may be substituted at one or two positions, and examples thereof include amino, carboxynore, benzinoleoxycaboninole, and protected amino groups. Difference As the protecting group in the protected amino group, the same as the protecting group for the amino group described below are used. -

As the lower alkynole in the low-handling alkynole which may have a substituent represented by Rg, one having 1 to 3 carbon atoms is preferable. The substituents include, for example, phenyl, canolebamoyl 'methinolecanoleno moynole, methylthio, cheluacetamide, ethoxycanoleboninole methinole, olevalmoinole, N-methinorete razorezoleogen, Nore is used.

The substituent in phenyl which may have a substituent represented by R ₉ includes, for example, lower alkynole having 1 to 3 carbon atoms, lower anolexoxy having 1 to 3 carbon atoms, norogen, hydroxynole, hydroxys honinoleoxy , Benzyloxy, benzoinoleoxy, trimethinolesilinole, C2-

A 10-oxyl or the like is used.

Examples of the heterocyclic group of the heterocyclic group optionally having a substituent represented by R ₉ include a 5-membered heterocyclic group containing a sulfur atom, a nitrogen atom or a nitrogen atom, and 1 to A 5-membered heterocyclic group containing a 21 'solid nitrogen atom and one sulfur or oxygen atom, and a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms are used. Specific examples of the heterocyclic group include, for example, thiazolinole, isothiazolinole, oxazolinole, isoxazolinole, cheninole, fury, pyrrolinole, imidazolinole, virazinole, pyrimidininole, pyridazinylene, pyridazinylene, pyridazinylin, pyridazinylin , Tetrazolinole, thiadiazolinole, oxaziaziolinole

¾ ¾. The substituent is, for example, substituted with a low phenol having 1 to 3 carbon atoms, a lower phenol having 1 to 3 carbon atoms, a norogen, a hydroxy phenol, a nitro, a hydroxysulfoninoleoxy, an amino, and a phenol. Asinorea mino with 2 to 4 carbon atoms, which may be used, is used.

OMPI

^ レ -No The cycloannolelene represented by R ₉ is preferably a 5- to e-membered ring, for example, cyclohexenolene, cyclohexadienyl and the like.

A heterocyclic group which may have a substituent represented by Rg and may be via an alkylene chain-A 6-membered heterocyclic group having two nitrogen atoms is used as the heterocyclic group of the kaleponinoleamino. Can be Examples of the heterocyclic group include piberazinyl and the like. The substituent is, for example, carbon number

Aquinole having 1 to 12 carbon atoms, lower alkoxy having 1 to 3 carbon atoms, oxo, thioxo, amino, etc. are used. As the alkylene chain, one having 13 carbon atoms is preferable, and examples thereof include methylene, ethylene, and η-propylene.

In the above formula, the heterocyclic group in the heterocyclic group which may have a substituent represented by R ₁₂ in the group represented by the formula Ri2-S— 'in 1ο is one nitrogen atom, sulfur atom or A 5-membered heterocyclic group containing an oxygen atom containing or not containing one nitrogen atom is used. Specific examples of this complex ring group include, for example, 2-thiadolinole, -thiazolinole, 5-thiazolinole, 2 -chedinore, 3 -cheninole, 2 -furinole, 3 -furinole, 2-pyrrolinole. , 3-Pyrrolidine is used. Examples of the substituent in this heterocyclic group include lower alkanoquinole having 1 to 3 carbon atoms, lower alkoxy having 1 to 3 carbon atoms, hydroxynole, mesyl, nodogen, imino, amino, mesinoleamino, Asinorea amino which may have halogen as a substituent and has 2 to 4 carbon atoms is used.

Examples of the substituent in phenyl which may have a substituent represented by R12 include lower anoalkyl having 1 to 3 carbon atoms, lower anolexoxy having 1 to 3 carbon atoms, halogen, nitro, amino, and the like. Hydroxinole or

OMPI, Roxy is used. Examples of the substituent in the substituted hydroxy group include, for example, benzinole, benzoy, and acylone having 2 to 10 carbon atoms: Γ—D—gnoletaminol, 3—amino-3—force. As the lower alkyl represented by R13, those having 1 to 3 carbon atoms are preferable.

As the substituent of phenyl which may have a substituent represented by R 13, for example, lower phenol, lower phenol, halogen, etc. are used.

As the lower acyl group which may have a substituent represented by R13, the lower acyl group preferably has 2 to 4 carbon atoms, and examples of the substituent include halogen.

As the lower anoalkylene represented by Bl4 in the group represented by the formula 1 Rl4 to Rl5 in # 3, those having 1 to 3 carbon atoms are preferable, and examples thereof include methylene, ethylene, propylene, and isopropylene.

Further, as the lower anolekelene represented by R14, those having 1 to 3 carbon atoms are preferable, and examples thereof include, for example, vinylene and probenylene.

The Esutenore force Norebokishi represented by R _15, for example Mechinoree ester, E Chino Les Este Honoré, etc. prop Honoré Este Honoré ¾ is use.

As the heterocyclic group represented by R15, a 6-membered heterocyclic group containing one nitrogen atom and one oxygen atom is used, and specific examples thereof include monorefolino.

The lower alkyl represented by Ri ₆ in the group represented by the formula —CO—NH— (H— in ¾1 is preferably a lower alkyl having 1 to 3 carbon atoms.

OMPI

I ON ―

■ if-! : Examples of the substituent in the phenylene which may have a substituent represented by H16 include lower phenols having 1 to 3 carbon atoms, lower alkenyl groups having 1 to 3 carbon atoms, nodogen, nitrite, and the like. B, amino, and an acylone with 2 to 10 carbon atoms are used.

Examples of the optionally substituted heterocyclic group represented by Ri 6 include a 5-membered heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, one to two nitrogen atoms and one or more nitrogen atoms. A 5-membered heterocyclic group containing two sulfur atoms or oxygen atoms and a 5-membered heterocyclic group containing 2 to 4 nitrogen atoms are used. Specific examples of the heterocyclic group include, but are not limited to, thiazolinole, isotizazolinole, oxazolinole, isoxazolinole, cheninore, frinole, pyrrolinole, thiadiazolinole, oxaziazolinore, torizinore, torizinori, torizinori, torizinori, torizoni Imidazolinore, pyrazinole, pyrimidinii./re, pyridazinole, and piberazinole are used. Examples of the substituent include lower alkyl having 1 to 3 carbon atoms, 1 to 3 carbon atoms, lower anoreoxy, nodogen, hydroxyxinole, amino, no, and benzene. For example, acylamino having 2 to 4 carbon atoms is used.

As the substituent in the Snorrefamoinole which may have a substituent represented by Ri7, for example, a low-strength anorealkyl having 1 to 3 carbon atoms, amidino and the like 'are used.

As the substituent in the phenoxycarbonyl which may have a substituent represented by Ri7, lower alkyl having 1 to 3 carbon atoms, lower anoreoxy having 1 to 3 carbon atoms and the like are used.

The lower anoalkyl and the lower alkoxy represented by R 18 each preferably have 1 to 3 carbon atoms.

In the above formula, and location Sa换E of phenylene Some we 'have a substituent represented by ¾9 ο ₃ As the substituent, for example, a lower alkyl having 1 to 3 carbon atoms, a lower anolexoxy 'norogen, nitro, amino, hydroxyamino' having 1 to 3 carbon atoms, and a substituted aminoamino can be used. Examples of the substituent in the substituted amino methinolate include, for example, Rinoremomoyl 'C2 1 year old oxo-3- (benzylideneaminoinoita) zolidine-1 1-inole) Gin — 1-inole) is used.

Examples of the substituent of the phenoxy which may have a substituent represented by R ₁₉ include lower alkanol having 1 to 3 carbon atoms, lower alkoxy having 1 to 3 carbon atoms, halogen, nitro and amino. , Hydroxyinole, aminomethinole, etc. The same substituents as those described above for the phenyl group represented by R ₁₉ can be used. The optionally substituted lower A key Honoré have a substituent represented by ¾ _9, preferably those having 1 to 6 carbon atoms, Hatato example, if Nono androgenic as a substituent, hydroxy Honoré, Shiano, Torifunoreo port Mechinore etc. : ^ Used.

The Anorekeniren good alkenylene may have a substituent represented by H _19, for example, bi - Ren, Purobe = Len, also has as its substituent, for example, Kanorebokishi, etc. Shiano is used .

The heterocyclic group in the heterocyclic group which may have a substituent represented by R ₁₉ is a 5- to 6-membered heterocyclic group containing one sulfur atom or 1-4 nitrogen atoms, A 5- to 6-membered heterocyclic group containing a sulfur atom and one nitrogen atom or one oxygen atom is used. Specific examples of the heterocyclic group include, for example, 2-Cheninole, benzocheninole, 31-Cheninole, 2-pyridinole, 3-pyridinole, 4-pyridinole, 2-thiazolinole, 4-thiazolinole, 5 — Thiazolinole, isothiazolinole, 1-tetrazolinole, 5-tetrazolinole, pyrrolidinole, imidazolinole, 1,4-oxantine frit.

, S: ii / L,-':' Examples of the substituent in the heterocyclic group which may have a substituent represented by R ₁₉ include lower alkyl having 1 to 3 carbon atoms, lower alkoxy having 1 to 3 carbon atoms, halogen, nitro and phenyl. Droxinole, optionally protected amino, carboxyl, thioxyl, acinoreamino having 2 to 4 carbon atoms which may have a halogen as a substituent, and acyl having 2 to 4 carbon atoms may be used. It is.

Among the terms used in the description of the above acyl group, specific examples of the alkyl having 1 to 12 carbon atoms include, for example, methinole and trifnoroleolomethyl etinole n ni フ. Mouth Pinore, Isof. Mouth pinore, n-futinore, isobuchinore, sec-butinole, "fcert 1 buchinore, benchinore, isobeninore, hexinole, isohexinole 'hen. Chinore, 31 heptinore, okinore, Noninole, desinole, pendecinole 'dodecinole' and cyclohexyl 'rude' are also used as specific examples of lower alkynoles having 1 to 6 carbon atoms, such as methinole, trifinoremethyl and etinole ' Mouth pinore, Isofu, Mouth pinore, n-futinole, isobuchinore, sec-futinore, iert—butinole, benchinore, isopentinole, hexinole, isohexinole, etc. Examples of lower phenols having 1 to 3 carbon atoms include, for example, methinole, trifnoroleolomethinole, ethinole, n — M. Pinole, Isof. Mole pinole is used, and examples of lower alkoxy having 1 to 3 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, and isopropho. : ^ Is used.

In the above formula, specific examples of the halogen include chlorine, bromine, iodine, and fluorine. Examples of lower anolequinolenolehoninole having 1 to 3 carbon atoms include, for example, methinolesnorehoni, etylsnolehonyl, n-f. Mouth Pilsnorehoni, 'le, isopropylsulfonyl, etc. are used. Specific examples of acylamino with 2 to 4 carbon atoms include:

Propionylamino, n-butyri / raremino, and i-sobutyrinoreamino are used. Specific examples of the acyloxy having 2 to 10 carbon atoms include, for example, acetoxy, n-propionyloxy, π-butylinyloxy, isof-tylinolexy, n-ventanoyloxy, n— Hexanoinoleoxy, n-hexanoreoxy, n-octanoreoxy, n-nonanoyloxy, n-decanoyoleoxy, etc. In the above-mentioned acyl group, specific examples of the acyl group represented by the formula B ₆ -CO-(wherein R ₆ has the same meaning as described above) include, for example, 3-

(2, 6-diclo mouth fever)-5-methinorei soxazo-no 4-innore 1 ノレボボ 4 ーーー, 2 3 3 ピ 3 Gin-1-inole is used. Formula — NH— (wherein R ₇ and R ₉ are as defined above.

R9

I do. Specific examples of the acyl group represented by) are, for example, D-alanine, D-phenyleno-alaninole, 1-benzinole-N "-force-no-revobenzoxy-ΓD-gunoleta-minole-D-araninole, D-pheninolec" 1 D—Alaninole, N ”—Norevobenzoxy—D—Feninolegricinole, D—Araninole D-Feninolegricinole, A—D—Gnoleta Minolei D—Aranil, N—Norrevobenzoxine D— D-Feninolegri-Sinole, D-Feninole-Moinole Trif, D-Feninole-Greinole, Mechinolea Midoszo Lagininole-D-Feninolegri-Sinole, N-Nenolevobenzoxymethinorea Mi Doasno ^ La Guinole-D-Pheninolegri-Sinole, N-Power-N-Revobenzoxy-D-Pheninoleg Syl-1 D-Pheninolegri Sinole, 2- (2,3-Diaminopropionamide) -1 2—Pheninoleacetinole, D-Araninole-1 D-Araninole, 2- [2-Amino-3 — (N—Metinore force) — Propion Amid] a Cetyl '2— (2—Amino—3—Snorefamoinolepropion

2-Fe2; vace, 2- [2-amino-3- (4-ethyl-1,2,3-dioxo-11-biverazino force ^ boxamide) brobionamide] 1-2-fe-acet u, D- 2-C 4-echinole 2, 3-dioxole 11-biperazinocarboxamide) 1-2-(4-methoxyphenyl) acetinole, D-2-[2-(4-ethy-1, 2-3- Dioxo-1 11-piverazinocarboxamido) 1-3— (N-method Λmoi) pubi; amide] 1-2-phenacetyl, D—2— [2—1 (4—et2,3,1 Dioxo-one 11-piperazino force boxamide;) acetamide] -1-2-phenylacetium ', D- 2- (3-snorrefamoinole 2-benzinole ^ kisika bokisami dobrobionamide) -1 2 —Feninoreasechi, D— 2— ζ2 1-year-old xycarboxamido 3— (4-Methoxy fuze: Reoki ^ (Carboxamido) brobionamide] -2-Fu-acetyl, 2- [2-benzyloxy; boxamido 3 ((N "-methyl carbamoy) probionamide] aceti, 21 (N-force bobenzoki-D 1-fu = nore dari sinoreamino) 13-(N-methyl phenol) propio =, N ".carbobenzoki D-arani, 1 (benzy / oxycaboxamide) r« 2-7 enylacetyl, 2 —Benzoxyka boxamido 3 N—methine power Nomoiprobione, N— (4-Echi-1,2,3-dithiophene) 1-Biperazinocanoleboninole) D—Pheninolegrisino, 2-( 2-Aminothiazo-North-4-1 :)-2— (4-Et-2,3-Dioxo-11-Biberazino-force-N-Revoxamide) Aset, 2- (2-Feninolease-tamide) P-Bioninore , 2-C -Ji-KiO—1 Bibirazino Power Boxomidoku — 2 —Chenylacetinole, D—2-(4-II-Dodecyl-2,3-Dioxo—1—Biberazino Power) 1 2 -Phenylacetinole, D-2-(4, 6-Gel-2,

¾ ； ..- し-OMPI 3-Dioxo-1 11-Biberazinokaboxamide)-2-Fenacetinol- 'D- 2— (4-3-hexyloxy-2,3-Di-oxo-1-11-Viberazinoca) 2) Phenylacet, D-2-1 (4-cyclohexyl 2.3-dioxo-1-1 biverazinocaboxamide) 1-2-Che-acet, D-2-1 (41-n-ami-6 (S)) Methyl-2,3-dioxo-1 11-Biberazino force boxamid) -1 2-Ceninoreacet A-, D-2 ((4-ethinolate 5 CR) -methyl-2,3-dioxo1-biperazinoca boxamido) 1-2-Che2 Asechi, D—2— (4—Echi—5 (S) —Methinolay 2,3-Dioxoe 1—Biberazino force Boxamid;) — 1—Che = Acetinolle, 2—CC 3—Frilidenamino 1 2 —Okso mida * —Lysine 1-11a :) Carboxamid]-21 8-hydroxy-1, 5 one Nafuchiri Jin one Ί Ichiriki - Bokisami de) Single 2 Hue - two Asechi, 2 - (4 - n Okuchi

- 2, 3-Jiokiso - 1- Biberajinoka Bokisami de] one 2-unloading - Le § - isethionate _f 2 - C 4-Echiru, 3 - Jiokiso one 1- Biberajinoka Bokisami de) Single 2 i (4 Hido I Nesis shows = Oxifue =) ase 1000, 2-C 4 チ ;; — 2, 3 ジ y — y-1-Biberazinoka Bokamido) 1 2 2 (4 クロクロ =) acetyl 2-C 4 ~ η Chi-2,3-dioxo-1: I-Biberazinocaboxamide) -1 2- (4—Hydrosulfonyloxyfie; =) aceti, 2.— (4-Echi-2,3-dioxoxo 1-Viberazino Carboxamide) 2- (4-trimethysilyphene-noreth) acetyl, 2-(-ethynoleh 2,3, -dioxo- 11-biverazinocaboxamide) 1-2- (3-Chloro-4-methoxyphenylacetate) 2— (4 -2,3—Dioxo1-111 Bibera Zinokaboxamide) -1— (3—C sigma-law

¾., ~ OMPI ヽ

' 2- (4-eth-2,3-dioxo- 1-piverazino-force-reboxamide) 1-2- (3-chloro-open-4-4-hydroxypheni / 1) acetinol, 2- (4 2-, 3-—Digitary 1—Vivera Ginocarbo) 1—2— (4—1 Benzinole ^^^ Feninore) acetyl, 2-(-II-2,3-Dioxo-1 1-Piberazinocarbo Kisamide) 1 2-(4-Hydroxyfuel) acetyl, N-(4-1 -2, 3-dioxo-1: I-biperazinocarbo-) Glutaminino 'N-1 (2-2.3-dioxor 11) Biverazino carbinoure) Hua-ara, N— (4,2,3—Kiyo 1-11 Viberazinoka) —D—Arani, 2— (4,2,3—Ji kisaw 1) C) 2- (4-hydroxypheno) acetic acid, 2,2—-bis (4-1) 1,2,3-dioxo1-1-biverazino carboxamide) aceti, 2- (4-ethyl / -1,2,3-dioxo-1 1-biverazinoca boxamite *] 1 2 -— (1-six π · hexene) 1 ^^ f) acechi, 2— (4-II octane 2, 3-dioxo-i-viverazinocarboxamide) -1- 2-thi-acet 〃, 2 -— (4-et / no2, a gioxone 1-biperazino) Ruboxamido) -1- (2-chloroacetamidothiazole-4 //); aceti, 2-C4-ethyl-2,3-dioxo-1-1-biradinocarboxamide) 1-2- (2-methinoretia Zol—4)) acet, 2-C 4 一 1, 2,3 — dioxo 11 ビ 11 Biberazinokaboxamide) 1 — 2 — (2 ァ acetamidothiazol 1 44 ノ inole) acet, 2-(4 -II octy) 1,2,3-dioxo-1 1-Biberazinocanoleboxamide) 2- (2-Aminochiazo - 4 I) Asechiru, 2 - (4 Echiru 2, 3 - Jiokiso one 1 one Biberajino Dioxo 1-biverazino force; u-boxamid) 1 2- (2-pyrroli) aceti, 2- (2-, 2,3-dithio-l-oxo) 1-1-piperazinoca boxa amide 1-2- (4-hydroxyf) ^-1 no) acetinole, 2- (4-n-year-old 2,3-dioxo1-1-biperazinocanoleboxamide) 1-2- (2-chloroacetamidothiazole-4-y) acetium, N- (4,2,3-Dioxo-1-11-Biberazino force) 1-D-Metio, D-2- [4 ((2-Feti-2,3,3-Doxo-1-1-Biberazinokaboxamide) 1-Fu-acetyl, D—2— (4-ethyl-1,2,3-dioxo-11-Biberazinocanoleboxamide) 1-2- (4,1-benzoxy-) acetyl, 2,5-bis ( 4-Echi 1, 2,3-Dioki y—1-biperazino force; t-boxamido) pentanoy, 2-(—Edno 1 2, 3 Dioxo-1 11-biberazino force; t / boxamido) — 3— · (N-methcarbamoy) bupio-, 2,3, bis (: 1-, 2,3-dioxo- 1-biberazinocanoleboxami B) Boo =>, 2— C 4—2,3—Dioxo— 1-piperazinoka Bomi Sami) 1—3—Clob Pio—, 2 — (— 1 チ 2,3—Zoki) y— 1—Biberazino boxa amide) 1—2— (4—1 a—Octano xy oxy) = 2,1— (4—2,3-dioxo 1 1 biperazino carboxamide) 1—3—Spha 2,3-1-1 [2- (4-ethinole 2,3-dioxo-1-11-biperazinocarboxamide) -1-3 -— (1-meth-1-1H-te-trazo-1-5-) ] Probionii, 2- (4-Echinole-1,2,3-Dioxo1-1,11 Biberazino carboxamide) acetinole, D—2— [4-1 (2 Human Dorokishechi A

-2,3-Doxoxo 1-Biberazinocasoleboxamide] -1-2-phenylacetium, D-2- [4- (2-chloroeth) 1-2,3 1-Biberazino force boxamid) -1 2-Fenacet. 2-(4 -Bet 1 -2,3 -Ji-Kiso- 1 -Biberazino force boxamid) -1 3-(Etoki ^ Carbo- Lumeti canolenoc) Bropio-, 2- (4-ethyl J-2,3-diamine) 11- (Bivalazinocarboxamide) -1 3- (Tini-rucetamide) propio-, 21- 4 1/2, 3-dioxo 1-biverazinoca boxamid) 1-3-[2-(1 H-tetrazo-1-1) acetamide] broby-, 2-(4-1- 2,3-dioxin (boxol 11-biradino-forced oxamide) 2- (1H-tetrazole-11-yl) acetyl, 21-((3-furideneamino-2-oxomidazolidine-1) 1-) Carboxa 5-d) 1- 2-fluoroacetic acid, 2--(3-phenylideneamino-2-oxisomidazolidin) (Mid) 1-2 (4-Hydroxyphene) acetyl, 2-((3-butylideneamino-2-oxoimidazolidin-1-1) force Boxamid) 1-2 (4-Hydroxypheny) acetyl , 2 — [(3-furidyleneamino-2-oxisomidazolidin-1-yl) caboxamide] 1-12- (4-hydroxysoxypheny) acet〃, 2 _- [[2-oxo-3- (thiophene) 2—Aldimino:) midazolidine-1 1] carboxamide] 2 一 -L-acet V, 2 — [(3-furideneamine 2- 2-oxomidazolidine-1 1] carboxamide), 2 —Cheninoleasetinole, 2-[(3-Meth-S-Lu 2-oxo-Mita * Zori.Jin-1-1-yl) Power / Boxamide] -1-2-Fu-acet u, 2— [(3— Bufri Ridden Amino-1-oxo-mita * zolidine-1-1-kaboxamide) 1-2- (2-aminothiazo-141-yl) acetyl, 2-[(3-fluoromidamine 2-oxomita'-zori Jin-ichi

-.-,

---- Two- Mid 1-2-(2-chloroacetamide-4-1) acetinole '2- 1-(3--2-oxo-midazolidin-1-1-------------- Vacetinole, 2-[[2-oxo-1- (thiophene-2-anoredimino) imita * zolidine-1 1-] carboxamide] 1-2-Che-noreseti, 2--, (3-mesi-one 2-oxo-mita'-zolidine 1--11-a-boxamid) -1 2--Chenaceti, D- 2-((3--furideneamino-2- 2-oxo-midazolidine-1-1-ka-boxamido) Probio : =, 2- (4-hydroxy-6-methylnicotinamide 1-2- fu-acetyl, 2- (4-hydroxy-6-methyl-cotinamide) 1-2- [4-droxyphenyl) acetyl, 2 -— [5,8 —Dihydro 2-(1 Homi, 1 Bibera -) 1-5-oxopyrido [2,3–d] birimidine-1 6-force boxamide] 1 27e => aceti, 2— (3,5 dioxo. 1-1,2,4-triazine 6—force; boxamid;) 1—2— (4-hydroxyphene;) aceti, D—2 — [(3—furididenamino 2—oxoimidazolidin 1—1) boxa amide] bubionbiani, D—3— [(2-oxo-one 3-—s-homidazolidine-1-1) -boxamid] -1—2-chloro-, D—2-— ((5-methoxy-bo-3-meth-^-2—oxo-midazolidine-1 1-ylcarboxamide) 1 2—Fu-aceti, D to 2-C (5-benzinoleoxycaboninole 3-1-methyi 12-oxo y-midazolidin 1 1-) carboxamido) 1 2—Fu-laceti u, D-2-(5-carboxy-3-methyl-21-oxoimidazolidin-1 1-) Force / No-homo-amide] 2-Fe-n-acetyl, 2- (coumarin-1 3--force A * boxamide) 1-2-Fe-2! -Acetinol, 2-- (4-N-rich 2, 3) —Dioxo 1-11 Biberazino Canolevoxa (Mido) 1-2 (2-Chloro-1-1 hexene 1-1) Asechi, D-2-(4-n-Ami-1, 2-3-Dioxo-1-1-Biberazinocanolejo ') 1- 2-fe-acetinole, D-2-1 (4-n-ami-6- (B) -meth ^^-1,2,3-dioxo-1-1-piverano-force-revoxamide)-21-Cheryasset, 2-(4 -Hydroxy-1 7 -Meth 1, 8 -Naphthyridine-1 3 -Norethoxamine Doc 2 -Fen 2 Rarecetinole, 2-(4 -Hydroxy 1 7 -1 Trif ^ "Romethinolequinoline 13 -Carboxamide ) 1-2-Fen Acet, Ν-[2-(2-Aminothia 1-4-1) Acet]]-1-D-Ferglycinol, 2-(6-1 * Mouth 1, 4-1 Hydro) 4-oxothieno [2,3- "] viridine-1 3-carboxamide) 1- 2-phenyl-2-, 2- [2-1- (2- Aminothiazonole-'4 Idano) acetamide] -1-2-phenazine, 2- [2- (2-Chloroacetamidothiazole-4-1-) acetamide] 1-21-Fusec, 2-C2 , 5-dioxo-1, 2, 2, 4-triazinone S—force boxamide) 1-acetinole, 2- [2,4 dioxobili midino 5—force boxamide) 1-2, chain acechi 2 — (6-Droxy 1, 5—Naphthyl di-force boxamid) 1-2 1-Feninoreacet, 2— [2—, (4-et y—2,3 dioxor 1—Biberazino force / Novoxamide) 1 2—Chenacetami] —2-phenylacetate, 21 (2-peroxide—2—cenacetamide) 1—2-1 Phenoleacetyl, 2— (2—ureide 1—2—ceninoreacetamide) 1 2 1 (4 Hydroxy 5 Sunorehoni Oxyfe-Nore) Cetyl, 2- (2-ureido 2-cheninoleacetamide) 1-2- (4-hydroxydroxyphene) acetinole, 2- (N-cabobenzoxy brobiamino) 1-2-furinolacetinore, naichi ( Cheninore Mechinoreka E'Ninore;) ARANI /! / , twenty four

Οί.ίΡΙ ΛΡθ One-necked benzoinole urei) 1—2-Chenacetinole, 2- (2-Chenacetamide) acetinole, N—Benzi Canoleboxamido D-Carainole, N— (4-Hydroxybenso) 'Iruu D-Araninole, 21- (4-chlorobenzamide) Bubi-nii, 2- (4-aminobenzamide) -a Sechinore, N- (4-Echi-2,3, Gioxo 1-11 Biberazino Carbo 2 Nore) methioni-D-fe-glyci, D-2- [21- (2,6-jik-mouth-fe-2 / u-chio) acetamide] -12-fue-acet, D-2-1 ([3 — (2,6-dioctanol-) -5-Methyl isoxazo1-1-4-inole] carboxamide] — 2-Che-u-queset〃, 2- (power bamoy) amino-2—Che, νace , Ν-power; u-no-moi no D-fue 2 glyci, 2- (3- 1-ureido) — 2-phenylphenyl, 2— (3-methyl thiocyanate) 3-methyl—11-ureido) 1-2— (4-hydrocyclopheno) acetyl, 2— (3— Met power Bamoy 3-Met 1-Raid :) 1- 2-Cheninoleacetyl, 2- [3- (2-Hydroxy-Penzo A- 1-Ureido) 1- 2-Fer-Lacech, 2- [3-1-1 (2-benzoxybenzoy) -I-ureid] -1 2- (4-Hydctoxyshonoxyeni;) acetyl, 2- [3- (2-hydroxybenzoy A-1-1-ray 2) (2-(4-Hydroxy fu-norre) aceti / no, 2-(4-Hydroxy fueno A aceti), 2-(3-Hydroxy fu-nore) aceti -C 3-Benzoxybenzoy;) — 1— ゥ Raid] 1 2 — Funi = / u acetinole, 2-C 3-(2 — Benzium ^ " Nzoi) - 1 Urei de] one 2- (4-arsenate Dorokishifue -) Asechi Le, D-2- [2- (benzylidene; 1 Okishika Bokisami de) Single 2- (benzyl N-mesh-one-D-feline

Examples of the acyl group represented by the formula S _in —R _u —CO— (wherein R ₁₀ and R have the same meanings as above) include, for example, N- [2 -— (2-aminothiazole) 1 4-y / n) -1 2-Methoxyminoacetinole] -D-ara-nore, N- [2- (2-aminothiazolyl-yl) -1 2-Methoxyminoacetino] -1 D-Feninolegri Shinore, 2- (2-aminothiazo-1-4-1inole;) 1-2- [2- (2-Aminothiazonol-4-1) -1 2-Methoxyiminoacetamide] acetinole, 2- (2 —Chloroacetamidothiazonole 4—) — 2— [2—C 2 -Chloroacetamidothiazo-1,4-ino;)-1-2-Methoxyxyminoacetamido] acetyl, 2- (2-chloroacetamidothiazole 4-) Ii) 2-Methoxyi-minoacetyl, 2- (2-aminothia) Zonore 4-Yi) One 2-Isoproho. Xyminoacetinole, 2- (2-aminothiazol-4, yl) -1-2-methoxyoxyminoacetyl, 2-1 (2-aminothiazo1-14-1) 1-2-oxyxyminoacetinole, 2—Chelou 2, methoxy-iminoacetinole, 2-free 2-methoxyminoacetin, 2- (4-hydroxyphenyl) -2-methoxinominacetyl, 2-buen-2-2-methoxyminoacetinole, 2-phenyl w—2—oxyminoacetinole, 2—2-hydroxy 2-aminoxy, 2-cheninolei 2-dichloroacetylinoxyminoacetyl, 2- (4-1 (a-D-gutaminoreoxy) phenyl) 1—2-oxy Minoacetyl, 2-[4-(3-amino-3-force V pho 'xypropho' xy) fu 2 / u] 1-2-oxyminoacetinole, 2-= = 2 2-C 3 モHolinoblovinole ^ xyminino) aceti, 2- (2- (2-aminothiazo-1--4-inole:)-12-methoxyminoacetamide) -2-phen-noreacetchi, 2- (5-crotin-1-2-c

Sa ^ ·,

Hmm 1 Toamidothiazono 4- 1) 2-Methoxyoxime / acetinol '2— (5-Chloro-2-aminothiazoi 1-41) -1 2-Methoxyiminoaceti, 2- (2-aminothiazo14) 1- 2- (; 7 / re, "Yashi-mu-xi-imino) acetyl, 2-[-1-1- (p-to-poxy-carbonyl) /iso-5-pi-.xi-mino] 1-2-1 (2--s-aminoaminothiazo-) ― 4- (a) acetinole, 2-1- (t-ptoxicabo2): isopropoxyimino) 1 2-((2-tri-methyl-aminothiazo-mono-4-)) acet, 2-(2-chloroacetamide thiazoline 1-4 Λ-2-isopoxy minoacetii, 2-methoxy minnow 2-(2-sphere

10 Minothiazoe 1-4-) aceti, 2-1 [2- (2-octacetamide thithiazole ^ -14-)-2-methoxyminoacetamide] 1-2-phenylase;, 21-F--21: ρ-trithiomininoacetinole,, 2- [2- (2-aminothiazo1-14-1:)-12-methoxymininoacetamido] aceti, 2- (2-mesinoleaminothiazole)

15 — 2-isopropoxy- ³ minosine

^Λ 1Β

Examples of the asinole group represented by the formula ^(/ j ~ CH-CO- (where ¾ ₇ ^ and ₈ have the same meaning as above) are as follows: Huerasset, Nahidroxys Honoxif Engineering Noaseti,

Ε0 ヒドロキシキシキシキシキシキシキシキシキシヒヒヒヒキシキシヒキシキシキシヒヒキシヒキシヒヒキシヒヒキシキシヒキシヒキシヒキシキシキシキシキシキシ Ε キシキシキシヒキシ Ε キシ Ε キシ p キシ Ε p キシH, 1-carboxyphenylacetino V, a: n-inoreoxyca-norefe- / uacetinole, 2- (N, N-dimethylsnorefamoy) 1-2-

25 Cao. 2-1-phenylacetinole, 2-phthalanolide-2-chenylacetinole, 2-azido-1-2-(3-mouth feninole) acetinole, etc. Specific examples of the acyl group represented by the formula ¾9 — 0—CH ₂ —CO— (wherein, R ₁₉ and R ₂₀ have the same meanings as described above) include, for example, cyanoacetinole, pheninoleasetinole, Enoxyacetinole, Trifnoreolomethine Norethioacetinole, Cyanometinolethioacetinole, 1H—Tetrazoinole 1—Acetinole, 21-Chenylacetyl, 2 -— (2-Aminothiazol-4-inole) acetinole 2- (2-chloro-acetamide-dothiazo-one-4-inole) acetinole, 4-pyridinolethioacetinole, 2—che2rethioacetinole, 3,5-dichloro1-1,4 dighidrone 4-oxopyridine-11 1-acetinole, β-forceboxininolethiothioacetinole, 2- (2-aminomethylpheninole) acetinole, 2 -— (2-Ν-force-norebo Nzoxyaminomethinolefeninore) acetinole, 2— (2- ゥ demethinolebueninole) acetyl, 2- [2— (2— (2oxo-midazolidine-1—innole) canoleponinoreaminometinolefe2nore] 2 -(3-benzylideneamino 1-2-oxomidazolidine 1 1-inole) canolepoxyaminomethinolefeninole] acetinole, 2— (5,6, dihydro-1,4, oxinatin 1-2-2-inole) acetinole, For example, 2- (2,5-dioxopyrrolidine-1-3-y) acetinole, 2-succinimidacetyl, 2- (1-acetyl-1,2,4-dioxomidazolidin-3-inole) acetyl and the like are used.

The amino group and / or the carboxyl group in the above-mentioned asinole group include those having a protecting group.

As the aa group of the amino group, those similar to the “protecting group for an amino group” described later are used.

Examples of the carboxyl-protecting group include β-lactam and organic chemistry, ^ ν ·: ^. It includes all groups which can normally be used in the field as protecting groups for carboxyl groups, for example, where the ester moiety is, for example, methyl, ethyl, propyl, isopropyl, tertiary butyl, tertiary amino, benzinole, p —Nitoguchi Benginore, p-Methoxybenzinole, Benz-Gadodori Noreno, Fenasinore, Fueninole, p-2-trofeninole, methoxymetinole, ethoxymetin Jre, Benzinoleximetinole, Tismeinole Chinore, β-methinoles norehoninolechinore, methylthiomethinole, tritinole, β, β, 3-trichloroechinole, β-3-doetinole, trimethinolesilinole, dimethinolesinoleme, acetinoleme ρ —Nito Mouth Benzoinolemethinole, p—Mesinoleben Zinoleme Chinore, Futanorei Domechinore, Propionioleoxymethinole, 1, 1-Dimethizolepropinole, 3—Methinole 31-buteninole, Succinimi Dometinole, 3, 5-5 j, benzensenorehoninoremethinore, pheninolethiomethinole, dimethyleneaminoetinore, pyridin 1-1-oxide-1-methine Jre, methinoresnorefininolemethinore, bis (p-methoxyphenyl) methyl , 2-Cyanyl-1,1 dimethylinoethyl and the like, such as esters and silyl compounds. The present invention provides the novel mono-compounds, and the selection of the protecting group is not limited to the above, but in particular, benzyl, β, β, β-i) chloroethyl, and the like. Nginole, ρ-methoxybenzine; preferred.

As the protecting group for the amino group in the above-mentioned one formula, those used for this purpose in the field of / 3-lactam and peptide synthesis are conveniently adopted. For example, ί-phthaloynole, ρ12 benzoinole, ρ-t ert butisleben zoinole, p-t ert -butynole benzenesnolehoninole, benzeneszolehoni / re, aromatic sulfonyl group such as toluenesulfonyl, For example, formyl, acetyl, pioinole, monochloroacetinole, dichloroacetinole, chloroa Aliphatic groups such as cetinole, methansnolehoninole, ethansnorehoninole, trifnoroleoloacetinole, macoil, and succinyl; for example, methoxycarbinole; and, for example, trityl, 2— Protecting groups for amino groups other than asinole groups, such as ditrophenylthio, benzylidene, 412 trobenzylidene, di- or trialkylsilyl, benzyl, and p-nitrobenzinole, are used. In the present invention, the choice of the protecting group is, as in the case of the canolepoxy protecting group, particularly limited, but is not limited to monochloroacetyl, benzozoleoxycanoleboninole, and p-methoxypentinoleoxycanolefo '. Nore, P—2 benzyloxycarbonyl-preferred.

In the general formula, among the acylated or ^ amino groups which may be represented by the following formulas, those exhibiting excellent antibacterial activity and 3-lactamase inhibitory activity are more specifically expressed by:

A-C-C ONH-W Z

[In the formula, A is a lower alkyl group such as hydrogen, methyl, ethyl, and isobutyl; an alicyclic group such as cyclohexyl and cyclohexeninole; an aryl group such as phenyl; a phenyloxy group such as phenoxybenzinole; Represents a heterocyclic group such as an arano quinole group, a cheno ole, a benzo ceno ole, a pyrrolyl, an isoxazolin ole, a piberazino, a thiazo linole, a tetrazole, an oxaxiano or the like, and these A are amino, a lower alkynole, or a lower alkanol. It may have one or two substituents such as coxyphenoxy, oxo, hydroxyxine, haguchigen or chloroacetamide. W is hydrogen when Z is hydrogen, a carboxyl group which may be esterified, a snolepho group, a sulfamoyl group, a hydroxysolephonipoxy group, an amino group which may be protected, and a feninolecarboxamide. Amido groups such as arylcarboxamides and lower alkylcarboxamides, for example, 1 and 2

Pee

Ί ηο Giazonole, (2,3-dioxo1-11-biperazino) -forced revoxamide, imidazolidinocarboxamide, oxoimidazolidinocarboxamide, (1,2-diazo-1-one) canolepoxamide, 4-isoxazolu力力ボ 2 ボボボ 2 2 2 2 ボボボボボボボボボボボボボボボボボボボボボ — ボボボ — 2 Complex carboxamide groups such as aminopropionamide, etc., and W and Z are combined to form the formula N—X—G (where X is a sulfur, sulfur or sulfoxide group, G is a lower alkynole group, And a carboxy-substituted lower alkyl group such as na-dimethyl-carboxymethylene, an aryl group such as pheninole, and an acyl group such as acetyl. It may be a group,

0

— One may indicate a bond or one C-1. In the above formula, the lower anoalkyl represented by A is preferably a C 1 -C 4 chain or branched anoalkyl group, and these are N-methylcarbamoinole and carboxybenzyloxy outside _b ^. No., for example, a phenyl group such as feninole, tetrazylacetamide, 4-ethynolene 2, 3-dioxo1-1-biperazino phenolic amide, and feninole, methyl, and ethyl in the 3-position. And may be substituted with a heterocyclic group such as 1,2 diazole and the like. Examples of halogens that can be substituted for A include fluorine, chlorine, and bromine; lower alkyl groups include methyl and ethyl; and lower alkoxy groups include methoxy and ethoxy. Examples of the protected amino group represented by W include chloroacetylamino, alkynoleamino, aralkyloxyamino and the like. The complex in the carboxamide group represented by W is phenyl, an alkyl group of 1 to 12 carbon atoms, a saturated aliphatic group, a alkenyl group of 2 to 8 carbon atoms, such as methoxy and ethoxy.ても Alkoxy radicals may have alkoxy groups, furfurylidenoamino, sulfo groups,

OM? I iS ^ It may be substituted with a koxycanoleponinole group, an alanolequinoleoxycanoleponinole group, or a carboxylic acid group. The lower alkyl in the lower alkynolecarboxamide group represented by W is preferably a linear or branched alkyl group having 1 to ⁴ carbon atoms, and these are substituted with halogen such as chlorine, bromine and fluorine. You can.

Of these, A is pheninole, phenoxy, thiazolinole, chenyl, piperazino, and further substituted with amino, lower anorekyl, or lower alkoxy, and is unsubstituted or substituted at any position. And those having a methoxyamino group are preferred.

Since the compound (I) has a sulfo group, it can generally act with a base to form a salt. Therefore, the chemical compound I) may be collected as a salt, and the salt obtained may be in the form of a free salt or another salt. Further, the compound (I) obtained in a free form may be converted into a salt. Examples of the above base include inorganic bases such as lithium, calcium, sodium, calcium, and ammonia, and organic bases such as pyridine, collidine, triethylamine, and triethanolamine. Salts of compound (I) of the present invention are also included in the present invention. As a method for converting a compound obtained as a salt into a free form, for example, a method using Jun is used. The acid used varies depending on the type of protecting group and other conditions. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, sulfuric acid, and P-toluenesulfonic acid. Organic tombs are used frequently. In addition, an acidic ion exchange resin is used. As the solvent, a hydrophilic organic solvent such as acetone, tetrahydrofuran, methanol, ethanol, dioxane, etc., water or a mixed solvent is often used.

Compound (I) has stereoisomers (eg, D-isomer, L-isomer) May be present. In this case, each of these isomers and a mixture thereof are also included in the present invention.

These isomers can be used as a medicine either alone or in a mixture. When these isomers are obtained as a mixture, each of them can be easily treated by a usual optical resolution method if necessary.

The compound (I) thus obtained is useful as a medicine, for example, has antibacterial activity against certain gram-positive and gram-negative bacteria. The acute toxicity of the compound (I) of the present invention by intravenous administration to mice is 500 or more.

The compound (I) of the present invention is useful, for example, for treating mammals (eg, mice, rats, humans, etc.) infected with the above-mentioned bacteria. The compound (I) of the present invention can be used as a therapeutic agent for bacterial infection, for example, in the above mammals for respiratory tract infections, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetrics and gynecology infections, and surgical treatments. It can be used for treatment of infectious diseases and the like. The daily dose is about 20 to about 200 as compound (I), and it is divided into 2 to 4 times a day, and about 5 to about 100 times a day. It is appropriate to administer a certain amount. Compound (I) or a physiologically acceptable salt can be administered by conventional means, for example, in the form of tablets, capsules, drops, or the like, or can be administered by conventional means, such as injection. It can be formed into a medicament, mixed with the bacteria produced by conventional means, and administered parenterally.

In addition, compound (I) has a ^ -lactamase inhibitory action and is useful as a β-lactamase inhibitor.

The compound (I) of the present invention is useful for the treatment and prevention of bacterial infections in humans and livestock. It is used when administering jS-lactam antibiotics.

When the compound (I) of the present invention is formulated alone, it is used before or after administration of the β.-lactam antibiotic, or mixed at the time of use. It can also be formulated as a mixture with a / 9-lactam antibiotic. In this case, the / 3-lactam antibiotics include, for example, benzylpenicillin, phenoxymethinorenedicillin, sulpenicillin, potenolenicillin, ampicillin, amoxicillin, mecillinam, and kuxicillin. , Dicloxacillin, piracillin, ahalesillin, ticanoresillin, cephalolysin, cephalotin, cefazolin, cephalexin, cefacetrinole, cephamandio 1 J lenaftoate, cefoxime, cefoxime, cefoxime, cefoxime, cefoxime. , Cefsulodin, cefaclonore, cefatridine, cefataxime, cefmenoxime, cefazidine, ceftezoxime, and other known penicillins and cephalosporins; and hetacillin, metaampirin Li down, data Ranpishirin, mosquitoes Rindashirin force Ruff Eshiri down, Pibume silicon down is used, injections, Doraishi σ-up agents, granulocyte, tablets, prepared according to a conventional method to put agent. Preferably, it is used in the form of a salt or hydrate as an injection. In such a usage, the compound (I) of the present invention can be used in 1/0 to 10 times (weight) with respect to the β-lactam antibiotic 1, but 1 to 1/8. For example, a ratio of 1Ζ5 or 1Ζ6 is advantageous, and the compounds of the present invention are generally administered between 50 and 1.0000 daily and more usually between 20 and I 5 per day. 0 ^ no is administered, for example, 1 to 6 times, more usually 2 to 4 times.

The 1-sulfo-2-oxoazetidine derivative (I) of the present invention can be produced, for example, by subjecting the compound (III) to a sulfonation reaction. This sulfonation reaction is a reaction to introduce a sulfo group,

s

The reaction can be carried out by reacting 1 (II) with, for example, sulfuric anhydride or a reactive derivative of sulfuric anhydride.

As the reactive derivative of sulfuric anhydride, for example, adducts such as anhydrous pyridine-pyridin, anhydrous dioxane sulfate, anhydrous sulfuric acid-trimethylamine, and anhydrous sulfur-5-chlorosulfonic acid are used.

In the above reaction, about 1 to about 5 mol, more preferably about 1 to about 2 mol, of sulfuric anhydride or a reactive derivative of sulfuric anhydride is added to 1 mol of the compound (III).

Reaction temperatures are from about 0 to about 80, more preferably from about 10 to about 40. In the above reaction, a solvent may be used. Examples of the solvent include esters such as dioxane, tetrahydrofuran, ethinoleether, ethers such as ethinole, and gishunethyl, kuchiguchi form, and methylene chloride. Halogenated hydrocarbons such as benzene, toluene, η-hexane, etc., dimethylformamide, dimethinoleacetamide, etc.

I ⁵ : Normal organic solvents such as amides are used alone or in combination. After completion of the reaction, the compound (I) can be obtained in any purity by subjecting the reaction mixture to a purification / separation means known per se such as solvent extraction, recrystallization, and mouth chromatography. The starting compound (（) can be subjected to the reaction as various salts, estenole, silyl derivatives and the like. -

20 Further, 1-Snorrehoe 2-oxoxetidine (F) of the invention can be produced, for example, by subjecting compound (m) to an acylation reaction. This acylation is performed by causing the compound (IE) to have an acylating agent anti-IS. The acylating agent used in this reaction is a carboxylic acid containing an acyl group represented by R ₃ , or an acid thereof.

It may be 25 reactions. Here, examples of the reactive derivative of the organic acid include an acid anhydride, an active amide, an active ester, and the like. Such a reactive derivative of an organic acid is specifically described as follows. j?

1) Acid anhydride:

Examples of the acid anhydride include, for example, mixed anhydrides of hydrogen halides (eg, hydrochloric acid, hydrobromic acid, etc.), mixed anhydrides of monoalkyl carbons, and aliphatic oleonic acids (eg, acetic acid, bival acid) Acid, Yoshi: ^, isopentanoic acid, tric-sigma oleic acid, etc.) mixed acid anhydride, aromatic power / repon (eg, benzoic acid, etc.) mixed {anhydride, symmetrical acid anhydride, etc. .

2) Active amide:

Here, as the active amide, for example, an amide with pyrazole, imidazole, monosubstituted imidazole, dimethylpyrazole, benzotriazole or the like is used.

3) Active ester:-Examples of the active ester include methyl ester, ethyl ester, methoxymethinole ester, buguchi reginole ester, 412 trofinole ester, 2-, 4-dinit In addition to esthenoles such as rofenenole estenole, triclone fenezole 7 pentanes, pentak mouth feninolenestenore-mesinole feninolenestenore, etc., 1—hydroxy 1 1Η—2—pyridone, Ν—hydroxysuccinimide And esters of carboxylic acid and the like, and carboxylic acid and the like.

Such reactive derivatives of Aristolomon are appropriately selected depending on the type of acid used. Further, when using a fungicide as an acylating agent, the reaction is carried out in the presence of a complexing agent. Examples of such a compound include N, -dicyclohexynolecanoleposite, N-cyclohexynole-

Replacement N-cyclohexanol (N-cyclohexinole), N-cyclohexinole (N-cyclohexanol), N- (N-cyclohexene) N'- (3-dimethylamine knob), etc. Used.

The acylation reaction is usually performed in a solvent. Solvents include water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethinole, dimethinolefozolemamide, pyridine or other organic solvents that do not participate in the reaction. A solvent is used, and among these, a hydrophilic solvent can be used by mixing with water.

In addition, the acylation reaction may be performed, for example, using inorganic bases such as sodium hydrate, sodium charcoal, sodium carbonate, sodium bicarbonate, etc., trimethinoleamine / trietinoreamin, tributyreamine, N-methinolemonoreholinate. Trialkylamines such as N-methylpiperidine, N, N-dialkylaniline,

N, isr-dia / lequinole pendinoleamine, pyridine, picolin, noretidine, tertiary amine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2, 2, 2] Okutan, 1, 8 - Jiaza bicyclo [5, 4, ^4] Kundesen can be carried out in the presence of nucleated fence group one 7 such as a liquid out of the base or the above-mentioned synthesis agent It can be used also as a solvent. Although the reaction temperature is not limited to a waiting time, it is usually carried out at room temperature with or without cooling.

In addition, in the asinolation reaction, when the reactive derivative at the amino group in the raw material compound (M) or the salt thereof and the acylating agent have a non-carbon in such a compound, a straight lipstick is used. It can be used with a knob or in a mixed state. When these isomers are mixedly produced in this reaction, the premature death is performed by a conventional method such as column chromatography or recrystallization if necessary! ? Can be simple.

OMPI

\ VlPO

' The compound used as a starting compound in the acylation reaction may be in the form of a salt or a silyl derivative. As the salt, those similar to the ones mentioned for the example of the salt of compound (I) can be used. When the starting compound is in the form of a salt in the acylation reaction, the compound (F) to be produced may be obtained as a salt. When obtained as a salt, it can be collected as another salt in the same manner as in the exchange of the salt of the compound (I).

Further, the compound (W) obtained in the form of a salt can be collected as a free form. In order to convert the salt to the free form, a method similar to the method for converting the salt of compound (I) into the free form is used.

In the compound (I) of the present invention, the compound having a protecting group is useful as a synthetic intermediate for producing a useful medicine, and for example, by removing the protecting group, the compound (I) ) Can lead to a compound having no protecting group.

The protecting group of the azetidine derivative (I) can be isolated by an acid method, a base method, a reduction method, a hydrazine method, thiourea or N-methyldithiol, depending on the kind of the protecting group. A common method such as a method using sodium carpamic acid can be appropriately selected and used. Here, in the case of the method using an acid, it varies depending on the type of protecting group and other conditions, but examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, acetic acid, trif-noreo, and propionic acid. , Benzenesnolephonic acid, ρ tonorenesnorehonone, etc., such as organic acids, and ion exchange resins. In the case of the method using a base, the method differs depending on the type of protecting group and other conditions.

Examples of the base include hydroxides of alkali metals such as sodium and calcium or alkali earth metals such as calcium and magnesium and carbonates such as carbonates.

OMPI Organic bases such as organic bases, metal alkoxides, organic amines, and quaternary ammonium salts, as well as basic ion exchange resins are used.

When a solvent is used in the above-mentioned acid or base method, a hydrophilic organic solvent, water or a mixed solvent is often used.

In the case of the reduction method, it depends on the kind of the protecting group and other conditions.For example, a metal such as tin or zinc or a metal compound such as chromium dichloride or chromium acetate and acetic acid, propionic acid, hydrochloric acid, etc. A method using an acid such as an organic or inorganic acid, a method for reducing in the presence of a metal catalyst for catalytic reduction, and the like are used.Here, the catalyst used in the method by catalytic reduction includes, for example, platinum wire, platinum White financial media such as sponge, platinum black, platinum oxide, and co-d platinum, palladium sponge, palladium black, palladium oxide, palladium sulfate, palladium carbonate, palladium carbonate, palladium carbon, palladium silica gel, co-sigma A palladium catalyst such as palladium, reduced nickel, nickel oxide, Raney nickel, Urushibara nickel and the like are used.

In the case of a reduction method using a metal and an acid, a metal compound such as iron and chromium, an inorganic acid such as hydrochloric acid, and an organic acid such as chi, acid, and pionic acid are used. The reduction method is usually carried out in a solvent. For example, in the tangential reduction method, alcohols such as methanol, ethanol, propinole alcohol, isopropyl alcohol, etc., and ethyl acetate are frequently used. In the method using a metal and an acid, water, acetate, etc. are frequently used. However, when the acid is a liquid, the acid itself can be used as a solvent.

The reaction is usually carried out under cooling or heating.

Further, for example, when the protecting group is a residue of organic olevonic acid and there is a substituent such as a free amino group, a hydroxy group, a mercapto group, a carboxy group, a sulfo group, etc. on the carbon adjacent to the liponinole group. Is the direct effect of these groups

OMH

WIPO,-. It is advantageous to remove the protecting group by increasing the reactivity of the carbonyl group by performing a treatment for further increasing the carbonyl group, which is advantageous. As an example of such a case, for example, when the substituent on the carbon adjacent to the above carbonyl group is a free amino group, the free amino group is converted into a thioperido group and then deaminated. A method of removing a protecting group by applying a known method used for a method of decomposing a butide bond is used. The temperature of this reaction is not particularly limited, and is appropriately selected depending on the type of the protecting group, the type of the deprotection method, and the like. However, it is preferable to carry out the reaction under cooling and moderate heating conditions. :

In this reaction, when is a compound of a group having a carboxy group, the derivative in the carboxy group may be converted to a carboxy group, but this case is of course included in the scope H of the present invention.

The thus obtained compound (I) from which the protecting group has been eliminated can be converted into a desired salt by a conventional method.

The starting compound (Π). (ΙΠ) of the present invention can be produced, for example, by the following method.

When the starting compound (Π) of the present invention is an asinoleoxy group, for example, it is disclosed in Tetrahedron Letters 4059 (1978) or JP-A-54-76570. The method described, or when R ₄ is a substituted dithio group (—S—S—R ₅ ), is described, for example, in ChemiCommunication 845 (1971). It is easily manufactured by a method that is known or a method analogous thereto. In the above formula, when I is other than an acyloxy or substituted dithio group, for example, the following 1), 2) according to the method described in Annalen der Cheriiie, i. O PI Λ By the route of! ) Can be synthesized)

In each of the above steps, ¾, R ₃ , R ₄ , and X have the same meanings as described above, and indicates a protected amino group.

Next, the present invention will be specifically described with reference to Examples and Reference Examples. The NMR spectrum was measured with a Varian HA 100 (100 MHz) ヽ EM 390 (90 MHz) or T60 (60 MHz), and the three values are expressed in _ppm with reference to tetramethylinoresilane. S is a singlet, br. S is a wide singlet, d is a doublet, dd is a double doublet, t is a triplet, q is a quartet, m is a multilett, ABq is an AB type quartet, and J is a quartet. Coupling constant, THF is tetrahydrofuran, DMF is dimethylformamide, DMSO is dimethylsnoreoxide, br. Or broad is bromide arom is aromatic. BEST MODE FOR CARRYING OUT THE INVENTION

Reference example 'Z

2-((1-Carboxysobroboxymino)) 2-((2-Trithiaminothiazole-4-yl) acetic acid 1.133 Methylene diazide of 1133 15 ^ jg Add 0.44 s of potassium carbodiimide and stir at room temperature for 20 minutes to remove insolubles, while the (3S, 4S) -3-amino-4-azidido-2-azetidinone p To a solution of 1-toluenesulfonic acid (0.598 g) in methylene trioxide 1 under ice-cooling, 0.19 g of pyridine and then! 10 W of F10W was added to the solution obtained above. And stir at room temperature for 3 hours. After condensing and purifying the remaining residue with silica gel, (3S, 4S) —4-azir 3— [2-((1-strength boxisoproboxoximino) 1-2— (2-tritium) 0.63 g of diaminothiazole-4-1) acetamide] —2-azetidinone is obtained.

D RV ^ ca- ¹ : 3400-3200, 2105, 1768, 1600, 1520

NMR (DMS0-d ₆ , ppm): 1.36 (s, CH ₃ ), 1.41 (3, CH ₃ ), 4.49 (dd, J = 2, 8Η ζ, C ₃ -H), 4.96 (d, J = 2Hz, C ₄ -H), 6.73 (s, 1Γ ^Η ), 7.1 --7.55 (m, aromH), 8.94 (s, NH), 9.88 (d, J = 8 Hz, NH)

Reference example2

2- (1-1- (2-trimethylsilethoxycarbonyl) isopropo "xyminino] -1-2- (2-trithiaminothiazolic) acetic acid 0.65 g, N-hydroxy-5 Chloroform 0.18 g of novanone-2,3-dicaboximide and 0.210 g of DCC

OMPI Stir in methylene 6 at room temperature to remove the precipitate. To this solution was added 0.35 g of (3R, 4R) -3 -amino-4-methylthiol-2-azetidinone p-toluenesulfonic acid, and 0.15 g of triethylamine. Add 1 g of methylene chloride solution and stir for 4 hours. The reaction mixture was contracted and purified with silica gel to give (3R, 4R) -3-C2-Cl-1 (2-trimethyletoxycarbo) isopropoxyimino] 1-2- ( 2-triaminothiazoi- 14-) acetamide] 1-4-methithio-2-azetidinone 0.4 Og is obtained.

IR

: 1 760, 1 670, 1520

NR (D SO-d ₆ , ppm): 0.03 (β, CH ₃ ), 0.9 (t, J = 8Hz

, -CH _2- ), 1.5 (s, CH ₃ ), 2.10 (a, CH ₃ ), 4.90 (d, J = 4 Hz, C ₄ -HL), 5.40 (dd, J = 4, 8 Hz, C ₃ ~ H), 0 ~ 7.6 (m, arom Η)

_ ΟΜΡΙ Example Ζ

1) (33, 43) —4-azido-3 -— [2- (1-carboxyisopropo * xyminino) -1 2 -— (2-trithiaminothiazo1-14-acetamide) -1 2— To the azetidinone 0.625 g ODF4 solution, add a 1.8 W solution of sulfuric anhydride-: DMF Combrex 0.445 S in DMF and react at 0 for 2 days. Add 0.238 s of pyridine and wash with ether. Dissolve the residue in 50% ethanol, add 0.54 g of sodium bicarbonate under permanent cooling, and stir for 30 minutes. Ethanol was distilled off, and the residue was purified with an XAD-I column. As a result, dinatrium (3S, 4H) -4--4-azido 3- [2-((1 force 一 boxysobu mouth † T xymino) 1 2 1 (2— Triaminothiazol-1-4) acetamido] -1 2 -azetidinone-1 ss-phosphate 0.183 s is obtained.

IRV ^CT- ¹ : 3390, 2105, 1770, 1615, 1520,

1 2 '70, 1245, 1 045

_{NMR (D S0 ~ d 6,} ppia): 1.58 (s, CE 3), 1. δ 5 (s, CH 3),

4.46 (d, J = 2He, C ₃ -H), 5.43 (d, J = 2flz, C ₄ -H), β.δ 3 (s, Γ ^Ξ ), 7.00 ~ 7.50 (a, aromH)

2) Dinatrium (3S.4R) —4-Azido 3— [2— (1—force bokisobokibinominino) 1-2— (2—tritylaminothiazol-4-y) acetoa Mid] 1-azetidinone 1-sulfonate

O PI 'ヽ ¾? AT10 ^ To a 0 · 15 gg solution of 50% methanol A5 *, add N-HC1 0.8 under permanent cooling and stir at room temperature for 2.5 hours. Under ice-cooling, add sodium hydrogen carbonate (0.070 s), stir for 20 minutes, and distill off methanoic acid. After removing the insoluble matter and purifying the solution with XAD-I force, the solution was converted to dinatrium (3S, 4R) —3- [2- (2-amino-2-azo-1--4-)-1—— Force bokisiso boxymino) acetamide] 1-41-azido 2-azetidinone 1-sulfonate 0.067 g is obtained.

IR re mllcsT ¹ : 33390. 2 115, 1775, 1605, 1512.

1 270, 1 240, 1 048

NMH (DMSO- ds, ppa): 1. δ 7 (s, CH 3), 4.70 (d, J = 2 Hz f C 3 -H), 5.80 (d, J

) Example << 2

1) (3 11, 4) 1-3-[2-[1-(2-trimethylsilyl; uetoki 5 / carb-1) isopropokimino] 1-2-(2-trimethylaminothiol 4 ー) acetamide] —4-Methylthio-2-azetidinone 0 · 40 gOD To a 2 W solution, add 0 · 80 g of n-thiobutane 乇-ゥ mfluoride and add at room temperature. 3 Stir for 3 minutes. The DMF is distilled off, the residue is dissolved in ethyl acetate, and after water, the solvent is distilled off to give (3R, 4R) —3— [2— (1-carboxyisopropoxymino) 1-2— ( 2 — Trithiaminothiazole 4) acetamide 0.40 g of n-tetrabutylammonium 4-methylthio-1-azetidinone is obtained. This was dissolved in DMF 2, sulfuric anhydride - a DMF complex ^{0. 5 1 ί g CDM ί 1} 2 W solution - 7 at 0, allowed to react for 2 days. By adding pyridine 0. and treating in the same manner as in Example II, dinatrium (3R, 4R) —3- [2- (1-force boxyisopropoxymino) 1-2— (2-triaminotinthiazole— 4- (i) acetamide] —0.150 g of 4-methylthi-2-azetidinone-1 source is obtained.

IRV

: 1 760, 1 660, 1 61 0, 1 525, 1250 NMR (DMS0-d 6, ppm): 1.50 (s, CH 3), 1.63 (a, CH 3),

2.1 0 (a, CH ₃ ), 5.24 (d, J = 4 Hz, C ₄ -H)

2) Dinatridium (311, 411) — 3— [2- (1-carboxyisobroboxymino) -1-2- (2-triti71-aminothiazo-4-1-acetamide) -1-methylthio-12-azetidino To a solution of 0.18 g of 50% methanolic A 5 "in 0.18 g of N-SCl 1 under ice-cooling, stir at room temperature for 2 hours. Same as in Example Z 2) When processed in this way, dinatrium (3R, 4R)-3-[2- (2-aminothia zo-4-yl)-1--(1-boxy sobroxymino)-4-methyl 2-azetidinone-1 sulphonate 0.3 1 g ^ obtained.

OMPI

^

( ^£ H0 ⁸ s) 827 '( ^e H0' s) o 9 Ί: (mdd «9p-0SHQ) H Ά R

093 1 '0 1 9 1 * 099 1 * 592 1

-~

^ 6I00 / I8Jf / ID <i 06900/88 OA Industrial applicability

The 2-oxoazetisone derivative (I) of the present invention is used as an excellent antibacterial agent and a 3 / 3-lactamase inhibitor for the treatment and prevention of bacterial infections in humans or livestock.

Replacement

Claims

The scope of the claims

(1) General formula

X ■ 4

R

-N,

, S0 ₃ H

[Wherein, ¾ is an amino group which may be asinolated or protected, X is hydrogen or methoxy, is an azido group, and halogen is “0R ₅ , 1-R ₅ ,

-PC, — a group represented by —S—S—R ₅ (wherein is an organic residue, and n is

, 0R ₅

0, 1 or 2).] 1-sulfo-2-oxozetidine derivative represented by the formula:

(2) Expression '

[Wherein, ¾ is an amino group which is asinolated or protected, and X is hydrogen

5, n is

0, 1 before means 2)). 2-Oxazetidine is subjected to a sulfonation reaction, and if ¾ is a protected amino group, it may be further protected, if necessary. General formula that expects to escape

Wherein ¾ is an amino group which may be acylated or protected, X

R ₄ has the same meanings as described above.] A method for producing a 1-sulfo-2-oxoxazetidine derivative represented by the formula:

(3) — General formula

H

[Wherein X is hydrogen or methoxy, R ₄ is an azide group, halogen or

A group represented by -OR ₅ , one S—,, one S—S—R ₅ (wherein R ₅

(ό) _η

Represents an organic residue, and η represents 0, 1 or 2). A simple formula characterized by subjecting a 3 -amino-1 -sulfo 2 -oxoazetidine derivative to an acylation reaction

[In the formula, represents an acylated amino group, and X and R ₄ have the same meanings as described above, respectively. A method for producing a 1-sulfo 2-oxoxetidine derivative represented by the formula:

aim exchange