JPS63119476A - Isoxazolidone derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is (acylated) amino; R<2> is H or acyl; Y is (esterified) carboxyl] or its salt. EXAMPLE:2-{(4S)-4-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido ]-3-oxo isoxazolidinyl}-2-acetoxyacetic acid. USE:It has antibacterial activity and is useful as a remedy for microbism such as infectious diseases of respiratory system and urinary tract, suppurative diseases, infectious diseases of bile duct, intestinal infectious diseases, infectious diseases in obstetrics and gynecology, infectious diseases in surgery, etc., of mammals. It can be administered orally or parenterally. PREPARATION:The compound of formula I can be produced according to the reaction formula, by producing a compound of formula IV by the addition reaction of a compound of formula II and a glyoxylate of formula III, acylating the OH group of the compound of formula IV and subjecting the obtained compound of formula I' to hydrolysis, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel isoxazolidone derivatives having antibacterial activity.

A new antibiotic TA that exhibits antibacterial activity against Gram-positive bacteria and Gram-positive bacteria from new bacterial species belonging to the genus Enbetobacter and Rhizobacter that were recently isolated from soil.
N-588 was discovered.

The antibiotic 1TAN-588 has a completely new, hitherto unknown skeleton in which 5-oxo-2-tetrahydrofurancarboxylic acid is bonded to the nitrogen atom of the 3-oxoisoxazolidine ring.

Conventionally, 1- to the nitrogen atom of the 3-oxoisoxazolidine ring
The synthesis of compounds into which methyl acetate groups have been introduced has been reported [Tsuji, Yamana, Heterocycle
es), Vol. 8, p. 153, 1977].

However, it has been reported that the antibacterial activity of the compound into which the 1-methylacetic acid group has been introduced is not observed.

■ is about to happen. Diseases caused by bacteria have been largely overcome with the development of treatment methods using antibiotics.

However, the increase in diseases caused by changes in causative bacteria (microbial replacement phenomenon) or the emergence of resistant bacteria (resistance phenomenon) due to long-term or large-dose administration of conventional antibiotics is a major problem in the current medical field of infectious diseases. It has become. To overcome this problem, the field is constantly seeking antibiotics that have novel skeletons and exhibit new biological activities.

The inventors of the present invention conducted extensive research on substituents on the nitrogen atom of the 3-oxoisoxazolidine ring, and as a result, succeeded in synthesizing a new compound of the following formula (I). They also discovered that this compound possesses antibacterial activity, and completed the present invention.

That is, the present invention relates to the formula [wherein R1 is an optionally acylated amino group,
R2 represents a hydrogen atom or an acyl group, and Y represents a carboxyl group which may be esterified. ] The present invention relates to a novel isoxazolidone derivative or a salt thereof.

In the formula, the acyl group in the acylated amino group represented by R1 is an acyl group substituted at the 6-position amino group of a conventionally known penicillin derivative, or an acyl group substituted at the 7-position amino group of a cephalosporin derivative. Examples include substituted acyl groups.

Examples of the acylamino group include, for example, the formula % [wherein R3 is hydrogen, alkyl, alkenyl 1] (In the description of each group in this specification, a group with ' has a substituent. )Alkeninoy, cycloalkyl", ary-nobi5 heterocycle ☆, alkoxy1.
7lyloxy1, R4 represents hydrogen, alkyl, or acyl, including the case where R3 forms a ring with R'.

] A group represented by formula 1 [wherein R11 is hydrogen, an amino acid residue ", a protecting group for an amino group or 2R'-(CHz)nC(=Z)-(wherein R7 is a heterocyclic group, alkoxy 1 or amino”,
n represents an integer of 0 to 2, and Z represents 0 or S, respectively. ), R@ represents alkyl, aryl, cycloalkenyl, or a heterocyclic group, respectively. Group represented by ko.

Formula % Formula % [In the formula, Re is the formula R''-C- (wherein, R'' is hydrogen, R11 is hydrogen, heterocyclic ring, or aryl backside,
alkyluo, alkenilme, arylcarbonyl spear
, cycloalkyl, heterocycle, or formula -R12-R
I 3. (In the formula, the R eye is alkelemme.

R13 represents cycloalkylene or alkenylene, and R13 represents an aryl name, a carboxy group, or an ester thereof, or a mono- or dialkylamide, respectively. ), R@ represents a chemical bond or the formula -〇〇-NH-CH (where [R''R'' represents alkyl0.aryl1 or a heterocycle) The groups represented by .) are respectively represented by the groups represented by ).

Formula [wherein RIS is aryl9. Heterocycle 1 or cycloalkenyl, RI6 is hydroxy, carboxy".

sulfamoyl, sulfo, sulfoxy, aryloxycarbonyl 1 or acyloxy, respectively.

] A group represented by

formula %formula% [In the formula, R'7 is alkyl3. Cyano, Aryl”.

Aryloxy ", alkenylene 1. heterocycle".

Amino “or R”° =C(=S)-(wherein, R
17゛ represents alkoxy. ),
R111 represents a chemical bond or -S-, respectively. ]
Examples include groups represented by the following.

The formula RIO represents a non-isomer represented by O-, the anti-isomer represented by the formula N\O-R.1 O-c-, or a mixture thereof. The acyl group represented by R2 in the formula includes the same groups as the acyl group in the acylated amino group represented by R1. When the acyl group represented by R'' in the formula is an optionally substituted carbamoyl or thiocarbamoyl group, examples of the substituent include an alkyl group and a heterocyclic group. In addition, examples of the carboxylic acid ester represented by Y include alkyl, alkenyl 9. Examples include esters substituted with an allyl group.

The alkyl in the group in the above formula preferably has 1 to 6 carbon atoms, examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ee-butyl, t-phthyl, 1 , 1-dimethylpropyl, n-pentyl, isopentyl, n-hexyl, isohexyl and the like.

Examples of substituents that the acid alkyl group may have include halogen, nitro, amino (acyl).

It may have alkyl, alkenyl, cycloalkyl, or aryl as a substituent. ), Sulho.

Cyano, hydroxy, carboxy, cycloalkyl.

Alkoxy (amino, hydroxy, carboxy).

It may have halogen, aryl, cycloalkyl, or alkoxy as a substituent. ), oryl (halogen, alkyl, alkoxy, alkylamino, amino, carbamoyl, sulfo, alkylsulfonyl, cyano, hydroxy, carboxy.

It may have nitro, acyloxy, aralkyloxy, or sulfooxy as a substituent. ).

Arylcarbonyl which may have the same substituent as the above aryl, aryloxy which may have the same substituent as the above aryl, tro, oxo,
Aryl, alkenylene.

It may have halogenoalkyl, alkylsulfonyl, alkyl, alkoxy, alkylamino, amino, halogen, carbamoyl, hydroxy, cyano, carboxy, or sulfo as a substituent. ).

Acyl, acyloxy, alkoxycarbonyl.

Alkoxycarbonyloxy, acyloxy-ethoxy, aralkyl (alkyl, alkoxy, halogen, amine, hydroxy, nitro, cyano).

It may have carbamoyl or sulfamoyl as a substituent. ), aralkyloxy (acyloxy, alkyl, alkoxy, halogen, amine, hydroxy, nitro, cyano, carbamoyl.

It may have sulfamoyl as a substituent. ).

Alkylsulfonyl, aminosulfonyl, alkylsulfinyl, arylsulfonyl, alkylsulfinyl, alkylthio (cyan, halogen).

Carboxy, alkylamino, imino, carbamoyl,
It may have acylamino as a substituent. ), arylthio, heterocyclic group -thio (may have cyano, hydroxy, amino, alkylamino, alkyl, halogen, oxo as a substituent), heterocyclic group (cyano,
It may have hydroxy, amino, alkylamino, alkyl, halogen, or oxo as a substituent. )-alkyl-thio, iminomethylamino, iminoethylamino, silyl (which may have an alkyl or teryl as a substituent), alkyloxycarbonyl, arylcarbonyl (acyloxy, halogen, amino, hydroxy, It may have alkoxy or sulfamoyl as a substituent.)

Phthalimide, succinimide, dialkylamino, dialkylaminocarbonyl, carbonylamino.

Examples include groups represented by the formula (wherein R'91 R'' are the same or different and represent a hydroxyl group or an amino group).

The cycloalkyl in the group in the above formula or the cycloalkyl forming a ring preferably has 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Can be mentioned.

Examples of the substituents that the cycloalkyl group may have include halogen, nitro, and amino.

Examples include hydroxy, sulfo, cyano, carboxy, and oxo.

Examples of the cycloalkylene in the group in the above formula include those in which the above cycloalkyl has another bond.

Unaryl (aryl) in the group in the above formula, ok-
Examples of carbonyl, aryloxycarbonyl, aryloxy or arylthio include phenyl, naphthyl and biphenyl.

Examples include anthryl and indenyl.

Examples of substituents that the nuclear Ryl group may have include halogen, nitro, cyano, amino (which may have alkyl, alkenyl, cycloalkyl, and aryl as substituents), sulfo, hydroxy, Sulfoxy, sulfamoyl, alkyl (which may have amino, halogen, hydroxy, or cyano as a substituent), alkoxy.

Examples include aralkyloxy, alkylsulfonamide, methylenedioxy, alkylsulfonyl, and alkylsulfonylamino. Also, cycloalkyl and fused rings (e.g., tetrahydronaphthyl).

indanyl, acenaphthyl, etc.).

The alkoxy in the group in the above formula has 1 to 1 carbon atoms.
6 is preferred, and examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy and the like.

Examples of substituents that the alkoxy group may have include halogen, nitro, amino, and hydroxy.

Sulfo, cyano, carboxy, aryl (nitro.

It may have amino, hydroxy, alkyl, or alkoxy as a substituent. ), silyl (which may have alkyl, aryl, or aralkyl as a substituent), and the like.

As the alkylthio in the group in the above formula, the number of carbon atoms is 1
-6 are preferred, examples include methylthio,
Ethylthio, n-propylthio, i-propylthio, n
-butylthio, i-butylthio, n-pentylthio, n
-hexylthio and the like. Examples of the substituent which may have the alkylthio group include the same substituents as the alkoxy substituents described above.

The alkenyl or alkenylene in the group in the above formula preferably has 1 to 4 carbon atoms, examples of which include methylene, vinyl, and allyl.

Isopropenyl, 1-propenyl, 2-butenyl.

Examples include 1,3-butadienyl, ethylidene, isopropylidene, propenylene, vinylene, 3-methyl-3-butenyl, and the like.

Examples of the substituents that the alkenyl group may have include halogen, nitro, amino (which may include acyl as a substituent), sulfo, and cyano.

Examples include hydroxy, carboxy, carbamoyl, sulfamoyl, aryl, acyl, and the like.

The heterocycle in the group in the above formula or the heterocycle formed by these groups includes a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom, or oxygen atom, and 2 to 4 nitrogen atoms. 5- to 6-membered heterocyclic groups containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom; It may be bonded to a six-membered ring group containing an atom, a benzene ring, or a five-membered ring group containing one sulfur atom.

Specific examples of the above heterocyclic group include 2-pyridyl, 3-
Pyridyl, 4-pyridyl, pyrimidinyl.

Pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxasilyl, isoxazolyl, pyrido(2,3-d)pyrimidyl, benzopyranyl, 1°8-naphthyridyl, 1.5
-naphthyridyl, 1゜6-naphthyridyl, 1,7-naphthyridyl, 2゜7-naphthyridyl, 2,6-naphthyridyl, quinolyl, cheno (2,3-b)pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, chenyl , pyrrolyl.

Furyl, pyrrolidinyl, imidazolidinyl, dichetane, tetrahydropyranyl, tetrahydrofuranyl, benzothenyl, pyranyl, hexahydro-IH-azepinyl, indolyl, isointridinyl, chromanyl, and the like.

Examples of substituents that the heterocyclic group may have include amino (acyl, halogen-substituted alkylacyl, phenyl,
It may have alkyl as a substituent. ), halogen, nitro, sulfo, cyano.

Hydroxy, carboxy, oxo, thioxo, C1-I
0 Alkyl [may have aryl, halogen, amino, hydroxy, carboxy, alkoxy, alkylsulfonyl, dialkylamino, phosphoric acid (which may have alkyl as a substituent) as a substituent. ],
Cycloalkyl, alkoxy (which may have halogen or hydroxy as a substituent), acyl having 1 to 4 carbon atoms.

Aryl (halogen, nitro, alkyl, alkoxy,
It may have amino, sulfo, hydroxy, or cyano as a substituent. ), oxo, thioxo, amino acid residue-thio (Examples of amino acid residues include those similar to those described below.) C1-3゜alkyl-thio [
aryl, halogen, amino, hydroxy, carboxy, alkoxy, alkylsulfonyl, dialkylamino, phosphoric acid (which may have alkyl as a substituent).

) may have as a substituent. ], heterocycle (may have alkyl, alkoxy, halogen, nitro, cyano, carboxy, formyl, alkylsulfonyl as a substituent) 2 formula R"-CH=N-C in the formula, R2
1 is a heterocycle (alkyl).

alkoxy, halogen, nitro, cyan, hydroxy,
It may have carboxy, formyl, or alkylsulfonyl as a substituent. ) is shown.

] and the like.

Examples of the acyl represented by R4 in the above formula include phthaloyl, succinyl, maleoyl, citraconoyl, glutaryl, adipoyl and the like in a cyclic form with R3. Examples of substituents that the acyl group may have include halogen, nitro, and amino.

Examples include hydroxy, sulfo, cyano, and carboxy.

The acyl in acyloxy in the group in the above formula preferably has 1 to 4 carbon atoms, and examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, etc. Substituents thereof include, for example, alkyl (amino, It may have halogen, cyano, alkoxy, carboxy, or hydroxy as a substituent.

), etc.

In the above formula, the amino acid residue represented by R5 is glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, and cysteinyl.

cystyl, methionyl, α- or β-asparagyl,
α- or T-glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl.

Examples include tyrosyl, histidyl, tryptophanyl, and prolyl.

Examples of substituents that the amino acid residue may have include halogen, hydroxy, sulfo, carboxy, cyano, alkylamino, aralkyloxycarbonyl, aralkyloxy, and guanidino.

In the above formula, the protecting group for the amino group represented by R5 is:
Those used for this purpose in the field of β-lactam and peptide synthesis are conveniently employed.

For example, phthaloyl, 4-nitrobenzoyl, 4-t
Aromatic acyl groups such as ert-butylbenzoyl, 4-tert-butylbenzenesulfonyl, benzenesulfonyl, toluenesulfonyl, such as formyl, acetyl, propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl.

Aliphatic acyl groups such as methanesulfonyl, ethanesulfonyl, trifluoroacetyl, malonyl, succinyl, e.g. methoxycarbonyl, ethoxycarbonyl, t
-butoxycarbonyl, isopropoxycarbonyl, 2
-cyanoethoxycarbonyl, 2.2.2-) ricfuroethoxycarbonyl, benzyloxycarbonyl, 4-
Esterified carboxyl groups such as nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, (hexahydro-LH- methylene groups such as azepin-1-yl)methylene, sulfonyl groups such as 2-amino-2-carboxyethylsulfonyl, and further examples include trityl, 2-nitrophenylthio, and benzylidene.

Examples include gl groups holding amino groups other than acyl groups, such as 4-nitrobenzylidene, di- or trifurkylsilyl, benzyl, and 4-nitrobenzyl.

The selection of the protecting group is not particularly limited in the present invention, but monochloroacetyl is particularly preferred.

Benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl are preferred.

In the above formula, the cycloalkenyl represented by R&lIS includes cyclohexene, cyclohexadiene, cycloheptene, cyclopentene, cyclooctene, and the like.

Examples of the substituent in the carboxy group which may have a substituent in the group in the above formula include alkyl (halogen,
It may have cyano or hydroxy as a substituent.

), Aryl (Full Kill.

It may have alkoxy, halogen, hydroxy, acyloxy, sulfo, cyano, or sulfamoyl as a substituent. ), cyrill (alkyl).

It may have aryl or aralkyl as a substituent. ), heterocycle (amino, alkylamino.

Sulfamoyl, carbamoyl, halogen, cyano,
It may have nitro as a substituent. ).

Amino (alkyl, aryl, cycloalkyl).

It may have sulfo or aracyl as a substituent. In addition, a 5- to 6-membered heterocycle may be formed together with the nitrogen in the nucleon mino group.

Examples of the substituent for amino which may have a substituent in the group in the above formula include amidine, iminomethinokamoimino(aryl-substituted)methyl, guanidylcarbonyl,
Examples include "heterocycle" (which may have the same substituents as the above-mentioned heterocycle), imino (heterocycle-substituted) methyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, alkyl, and the like.

When R3 and R4 form a cyclic group, examples of the group include 2,2-dimethyl-5-oxo-4-
Examples include phenyl-imidazolidine.

Specific examples of the acylamino group represented by 9 formula % formula % in the above acyl group include 3-(2
,6-dichlorophenyl)-5-methylisoxazol-4-yl-carbonylamino, 4-ethyl-2,3-
Dioxo-1-piperazinoluponylamino, 3-phenyl-5-methylisoxazol-4-yl-carbonylamino, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl-carbonylamino, 3- (
2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl-carbonylamino, nicotinylamino, benzoylamino, 4-bromobenzoylamino, 2,6-cymethoxybenzoylamino, formylamino, acetyl Amino, propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, methoxycarbonylamino, benzyloxycarbonylamino, 1-amino-cyclohexylcarbonylamino, 2
-amino-cyclohexylcarbonylamino, 3-ethoxynaphthoylamino, 2-(2-amino-4-thiazolyl)-2-ethylidene-acetylamino, 2-(2-
Amino-4-thiazolyl)-2-chloromethylene-acetylamino, phthalimide, succinimide, 1.2-
Cyclohexanedicarboximide, 2-(trimethylsilyl)ethoxycarbonylamino, 2,2-dimethyl-
Examples include 5-oxo-4-phenyl-imidazolidine, 4-(carbamoylcarboxymethylene)-1,3-dicetan-2-yl-carbonylamino, and the like.

Specific examples of the acylamino group include D-alani-modified amino, benzyl N-carbobenzoxy-T-D-
Glutamyl-D-alanylamino, D-phenylglycyl-D-alanylamino, N-carbobenzoxy-D-
Alanylamino, N-carbobenzoxy-D-phenylglycylamino, D-alanyl-D-phenylglycylamino, γ-riglutamin-D-alanylamino, 2
- (4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-phenylacetylamino, 2-
(4-cyclohexyl-2,3-dioxo-1-piperazinocarboxamide)-2-phenylacetylamino,
2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-(4-sulfoxyphenyl)
acetylamino, N-(4-ethyl-2,3-dioxo-1-piperazinocarbonyl)-D-alanylamino,
N-(4-ethyl-2,3-dioxo-1-piperazinocarbonyl)-D-phenylglycylamino.

2-(2-amino-4-thiazolyl)-2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)acetylamino, 2-(4-hydroxy-6-methylnicotinamide)-2 -phenylacetylamino, 2
-(4-hydroxy-6-methylnicotinamide)-2
-(4-hydroxyphenyl)acetylamino, 2-
(5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido(2,3-d)pyrimidine-6-carboxamide)-2-phenylacetylamino, 2-(3,5-dioxopyrido) -1,2,4-triazine-
6-carboxamide)-2-(4-hydroxyphenyl)acetylamino, 2-(3-furfridenamino-2
-Oxoimidazolidine-1-carboxamide)-2-
Phenylacetylamino, 2-(coumarin-3-carboxamide)-2-phenylacetylamino, 2-(4-
Hydroxy-7-methyl-1,8-naphthylidene-3-
carboxamide)-2-phenylacetylamino, 2-
(4-hydroxy-7-dolifluoromethylquinoline-3-carboxamide)-2-phenylacetylamino,
N-(2-(2-amino-4-thiazolyl)acetyl)
-D-phenylglycylamino, 2-(6-promo 1
-Ethyl-1゜4-dihydro-4-oxocheno [2
,3-b]pyridine-3-carboxamide)-2-phenylacetylamino, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-chenylacetylamino, 2-(4 -n-pentyl-2,3-
dioxo-1-piperazinocarboxamide)-2-chenylacetylamino, 2-(4-n-octyl-2,3
-dioxo-1-piperazinocarboxamide)-2-chenylacetylamino, 2-(4-cyclohexyl-2
,3-dioxo-1-piperazinocarboxamide)-2
-thhenylacetylamino, 2- (4-(2-phenylethyl)-2,3-dioxo-1-piperazinolupoxamide)-2-thhenylacetylamino, 2-(3-
Methylsulfonyl-2-oxoimida solid/-1
-carboxamide)-2-phenylacetylamino, 2
- (3-furfrideneamino-2-oxoimidazolidine-1-carboxamide)-2-(4-hydroxyphenyl)acetylamino, 2-(4-ethyl-2,3-
Dioxo-1-piperazinocarboxamide)-2-(4
-benzyloxyphenyl)acetylamino.

2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-(4-methoxyphenyl)acetylamino, 2-(8-hydroxy-1,5-naphthyridine-7-carboxamide)= 2-phenylacetylamino, 2-(2-amino-4-thiazolyl)-2-formamidoacetylamino, 2-(2-amino-4-thiazolyl)-2-acytamideacetylamino, 2-phenyl-2 -ureidoacetylamino, 2-phenyl-2
-Sulfouridoamino, 2-thenyl-2-ureidoacetylamino, 2-amino-3-sulfamoylpropionylamino, 2-amino-2-(LH-indol-3-yl)acetylamino, 2-amino-2 -(3-
Benzo(b)chenyl)acetylamino, 2-amino-
2-(2-naphthyl)acetylamino, D-phenylglycyl, D-2-amino-(4-hydroxyphenyl)
Acetylamino, D-2-amino-2-(1,4-cyclohexagenyl)acetylamino, D-2-amino-
2-(1-cyclohexenyl)acetylamino, D-2
-amino-2-(3-chloro-4-hydroxyphenyl)acetylamino, 2-hydroxymethylamino-2-
Phenylacetylamino, 2-(1-cyclohexenyl)-2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)acetylamino, N-(2-(4
-ethyl-2,3-dioxo-1-piperazinocarbonyl))-D-threonylamino, 2-geanylcarboxamide-2-phenylacetylamino, 2-(4-ethyl-2,3-dioxo-1-pipe Radinocarboxamide-2-(3,4-dihydroxyphenyl)acetylamino, 2-(4-carboxy-5-imidazolylcarboxamide)-2-phenylacetylamino, 2-ami/-
Examples include 2-(3-methylsulfonamidophenyl)acetylamino.

Specific examples of the acylamino group represented by the formula % include N-(
2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl)-D-alanylamino, N-(2-(2
-amino-4-thiazolyl)-2-methoxyiminoacetyl)-D-phenylglycylamino, 2-(2-amino-4-thiazolyl)-2-(2-(2-amino-4-
thiazolyl)-2-methoxyiminoacetamidocoacetylamino, 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetylamino, 2-(
2-(2-amino-4-thiazolyl)-2-methoxyiminoacetylamino, 2-(2-amino-4-thiazolyl)
-2-ethoxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2
-butoxyiminoacetylamino, 2-(2-amino-
4-thiazolyl)-2-cyclopropylmethyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-benzyloxyiminoacetylamino, 2
-(2-amino-4-thiazolyl)-2-allyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-((1-methyl-1-carboxyethyl)
Oxyiminocoacetylamino, 2- (2-amino-
4-thiazolyl)-2-[(1-methyl-1-methoxycarbonylethyl)oxyiminocoacetylamino.

2-(2-amino-4-thiazolyl)-2-carboxymethyloxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-carboxyvinyloxyiminoacetylamino, 2-(2-amino-4 -thiazolyl)-2-carboxyethyloxyiminoacetylamino, 2- (2-amino-4-thiazolyl)-2-
Methoxycarbonylethyloxyiminoacetylamino, 2-(2-amino-5-chloro-4-thiazolyl)-
2-methoxyiminoacetylamino, 2-(2-amino-5-bromo-4-thiazolyl)-2-methoxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2-oxyiminoacetylamino, 2 -Chenil-
2-Methoxyiminoacetylamino, 2-furyl-2-
Methoxyiminoacetylamino, 2- (1,2,4-
Thiadiazol-3-yl)-2-methoxyiminoacetylamino.

2-(1,2,4-thiadiazol-5-yl)-2
-Methoxyiminoacetylamino, 2- (1°3.4
-thiadiazolyl)-2-methoxyiminoacetylamino, 2-(4-hydroxyphenyl)-2-methoxyiminoacetylamino, 2-phenyl-2-methoxyiminoacetylamino, 2-phenyl-2-oxyiminoacetylamino, 2 -(4-(T-D-glutamyloxy)phenyl]-2-oxyiminoacetylamino, 2-
(4-(3-amino-3-carboxypropoxy)phenyl]-2-oxyiminoacetylamino, 2-thenyl-2-oxyiminoacetylamino, 2-(5-amino-1,2,4-thiadiazole-3) -il)-2-
Methoxyiminoacetylamino.

2-(5-amino-1,2,4-thiadiazole-3-
yl)-2-ethoxyiminoacetylamino, 2-(5
-amino-1,2,4-thiadiazol-3-yl)-
2-carboxymethyloxyiminoacetylamino, 2
-(5-amino-1゜2.4-thiadiazol-3-yl)-2-[(1-methyl-1-carboxyethyl)oxyiminoacetylamino, 2-(2-amino-4-thiazolyl)-2 -(2-amino-2-carboxy)ethyloxyiminoacetylamino, 2-(2-amino-4
-thiazolyl)-2-(dimethylamidomethyloxyimino)acetylamino.

2-(2-amino-4-thiazolyl)-2-(3゜4-
diacetoxy-benzoyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2-(
1-Carboxycyclobrobyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2
-(1-carboxy-cyclobutyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2
-(2-imidazolylmethyloxyimino)acetylamino.

2-(2-amino-4-thiazolyl) -2-(2-/
-1-4-nitro-1-imidazolylethyloxyimino)acetylamino, 2-(2-amino-4-thiazolyl)-2-(3-pyrazolylmethyloxyimino)
Acetylamino, 2-(2-amino-4-thiazolyl)
)-2-(1)(-tetrazol-5-yl-methyloximino)acetylamino, 2-(2-amino-4-
thiazolyl)-2-(2-oxo-3-pyrrolidinyloxyimino)acetylamino, 2-(2-(2-amino-2-carboxyethylthio)]-]4-thiazolyl-2-methoxyiminoacetylamino 2 -(2-thioxo-4-thiazolidinyl)-2-methoxyiminoacetylamino and the like.

Specific examples of the acylamino group represented by the formula % include 2-phenyl-2-sulfoacetylamino, 2-hydroxy-2
-phenylacetylamino, 2-phenyl-2-sulfamoylacetylamino, 2-carboxy-2-phenylacetylamino, 2-(4-hydroxyphenyl)-
2-carboxyacetylamino, 2-phenoxycarbonyl-2-phenylacetylamino, 2-phenyl-2
-tolyloxycarbonylacetylamino, 2-(5-
indanyloxycarbonyl)-2-phenylacetylamino, 2-formyloxy-2-phenylacetylamino, 2-alanyloxy-2-phenylacetylamino, 2-carboxy-2-chenylacetylamino, 2
-(2-methylphenoxycarbonyl)-2-chenylacetylamino, 2-(2-amino-4-thiazolyl)
-2-hydroxyacetylamino, 2-C4-(2-
Examples include amino-2-carboxyethoxycarboxamido)phenyl]-2-hydroxyacetylamino.

Specific examples of the acylamino group represented by the formula % are cyanoacetylamino and phenylacetylamino.

Phenoxyacetylamino, trifluoromethylthioacetylamino, cyanomethylthioacetylamino, difluoromethylthioacetylamino.

IH-tetrazolyl-1-acetylamino, chenylacetylamino, 2-(2-amino-4-thiazolyl)acetylamino, 4-pyridylthioacetylamino, 2-
Chenylthioacetylamino.

3.5-dichloro-1,4-dihydro-4-oxopyridine-1-acetylamino, β-carboxyvinylthioacetylamino, 2-(2-aminomethylphenyl)acetylamino, 2-chloroacetylamino, 3- Aminopropionylamino.

(2-amino-2-carboxy)ethylthioacetylamino, 4-amino-3-hydroxybutyrylamino, 2
-carboxyethylthioacetylamino, 2-benzyloxycarbonylamino-acetylamino, β-carbamoyl-β-fluorovinylthioacetylamino, 2-
(1-isopropyliminomethylthio)acetylamino, 2-(1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl-thiocoacetylamino, 2-(1-methyl-1, 3゜5-
triazol-2-yl)acetylamino.

Examples include 2-(4-cyano-3-hydroxy-5-isothiazolylthio)acetylamino.

In the formula, specific examples of the acyl group represented by RZ include the same groups as the acyl group in the acylated amino group represented by /) RI above.

In the formula, specific examples of the optionally substituted carbamoyl or thiocarbamoyl group in the acyl represented by R2 include carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, t-butylaminocarbonyl, isobutylaminocarbonyl, and dimethylaminocarbonyl. carbonyl,
2-methylphenylaminocarbonyl, phenylaminocarbonyl, 3-chlorophenylaminocarbonyl, 4
-Nitrophenylaminocarbonyl, 4-bromophenylaminocarbonyl, thiocarbamoyl.

Examples include methylaminothiocarbonyl, ethylaminothiocarbonyl, phenylaminothiocarbonyl, dimethylaminocarbonyl, and the like.

Specific examples of the carboxylic acid ester represented by Y above include methyl ester and ethyl ester.

n-propyl ester, isopropyl ester.

t-7'' thyl ester, t-amyl ester, benzyl ester, 4-bromobenzyl ester, 4-nitrobenzyl ester, 2-nitrobenzyl ester, 3,5
-Dinitrobenzyl ester.

4-methoxybenzyl ester, benzhydryl ester, phenacyl ester, 4-bromo-phenacyl ester, phenyl ester, 4-nitrophenyl ester, methoxymethyl ester.

Methoxyethoxymethyl ester, ethoxymethyl ester, benzyloxymethyl ester, acetoxymethyl ester, pivaloyloxymethyl ester, 2-methylsulfonylethyl ester, 2-trimethylsilylethyl ester, methylthiomethyl ester, trityl ester, 2°2.2 - IJ chloroethyl ester,
2-iodoethyl ester, cyclohexyl ester,
Cyclopentyl ester, allyl ester 2 Cinnamyl ester, 4-picolyl ester, 2-tetrahydropyranyl ester, 2-tetrahydrofuranyl ester, trimethylsilyl ester, 1-butyldimethylsilyl ester, t-butyldiphenylsilyl ester, acetylmethyl ester.

4-nitrobenzoyl methyl ester, 4-mesylbenzoyl methyl ester, phthalimidomethyl ester,
Propionyloxymethyl ester.

1.1-dimethylpropyl ester, 3-methyl-3-
butenyl ester, succinimide methyl ester, 3
．． 5-di-t-butyl-4-hydroxybenzyl ester, mesylmethyl ester.

Benzenesulfonyl methyl ester, phenylthiomethyl ester, iminomethyl 7-minoethyl ester, 1-
Iminoethylaminoethyl ester.

Dimethylaminoethyl ester, pyridine-1-oxide-2-methyl ester, methylsulfinylmethyl ester, bis-(4-methoxyphenyl)methyl ester, 2-cyano-1,1-dimethylester, t
-Butyloxycarbonylmethyl ester, benzoylaminomethyl ester, 1-acetoxyethyl ester, 1-isobutyryloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, phthalide ester, 4-t-butylbenzyl ester, 5-yne Danyl ester, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, 5-t-butyl-2-
Examples include oxo-1,3-dioxolen-4-ylmethyl ester.

Examples of the carboxylic acid salt represented by Y include inorganic bases such as sodium, potassium, lithium, calcium, magnesium, and ammonia, and organic bases such as pyridine, collidine, triethylamine, and triethanolamine.

Compound (I) of the present invention can be produced, for example, by the following reaction sequence.

(I') (I) (In the formula, R1, R,! and Y have the same meanings as above.

R'', R2'', and Yo have the same meaning as R1, R2, and Y, respectively, or represent a group that can be derived from R1, R1, and Y.) The first step is to convert (If) into glyoxylate 'W4. (I[
This is the step of performing an addition reaction with I) to obtain (rV). In carrying out the reaction of this step, (n) is preferably mixed in an inert solvent such as dichloromethane, chloroform, benzene, toluene, or tetrahydrofuran in an amount of 1 to 2 moles of glyoxygenate per mole of (I). This is carried out by reacting with the rates (]I[). The reaction temperature is about -10°C to 40°C, and the reaction time is usually 1 to 48 hours. The glyoxylates (I[I) include p-nitrobenzylglyoxylate.

Allyl glyoxylate and the like are preferably used.

Since glyoxylate i is often obtained as a hydrate, it is preferable to coexist a dehydrating agent such as molecular sieves in this reaction.

The second step is a step in which the hydroxyl group of (TV) is acylated (including carbamoylation or thiocarbamoylation) to obtain (I'). Acylation of (IV) is described later (1'
: R"=NHz). Carbamoylation or thiocarbamoylation of (IV) can be carried out using a substituted isocyanate containing a group represented by (1'/) and R2' or a substituted isocyanate in a solvent. This is carried out by reacting thiocyanate. Examples of the substituted isocyanate include methyl isocyanate, ethyl isocyanate, chloroacetyl isocyanate, chlorocarbonyl isocyanate, chlorosulfonyl isocyanate, phenyl isocyanate, p-bromophenyl isocyanate, and methyl isocyanate. Isothiocyanate phenyl isothiocyanate and the like are used.

In this reaction, the substituted isocyanate or substituted isothiocyanate is usually used in about an equivalent amount to the compound (rV), but it can also be used in excess as long as it does not hinder the reaction. Examples of the solvent used include tetrahydrofuran, diethyl ether, ethyl acetate, chloroform, dichloromethane, and toluene. The reaction temperature is about -20°C to around 50°C, and the reaction time is usually about 10 minutes to 5 hours.

(I゛) obtained in this way is also included in the target compound (1), but in the third step, i) if the substituted bone of R'' in N') contains a protective group, it is removed. or converting R1' to R1 having another acylamino group, or 1i) If a protecting group is included in one conversion of R2', removing it and converting it to R2. or iii) a step of hydrolyzing the ester to form a free carboxylic acid.

These steps include i), ii), and iii, as necessary.
) Can be implemented alone or in appropriate combinations.

Specifically, in (I゛), a compound in which R1' is a protected amino group and Yo is a protecting group for a carboxyl group is converted into a compound in which R'' is an amino group and Yo is a carboxyl group, and this amino group is converted into an acyl group. This acylation reaction model (1': R"-NH!) can also be carried out by the same method as the acylation reaction described below. .

In the above-mentioned reaction of introducing an acylamino group into the acylamino group represented by R' or conversion reaction from the acylamino group represented by R1', for example, when R1' in (I゛) is a protected amino group, the protecting group is R1' is removed to produce a compound in which R1' is an amino group, and this amino group is acylated to form R1'.
(I) having an acylamino group as 1 can be produced. This acylation reaction is carried out in a solvent (I')(R
This can be carried out by reacting an acylating agent containing an acyl group in the group R1, such as a reactive derivative of carboxylic acid. Examples of the reactive derivative of carboxylic acid include acid halides, acid anhydrides, etc. thing.

Amide compounds, active esters, active thioesters, etc. are used, and specific examples of such reactive derivatives are as follows.

l) Acid halide: As the acid halide, acid chloride, acid bromide, etc. are used here.

2) Acid anhydride: Here, the acid anhydride includes monoalkyl carbonic acid mixed acid anhydride, aliphatic carboxylic acid (for example, acetic acid).

pivalic acid, valeric acid, isovaleric acid 2, trichloroacetic acid, etc.)
mixed acid anhydrides, aromatic carboxylic acids (e.g.
Mixed acid anhydrides, symmetrical acid anhydrides, etc. consisting of benzoic acid, etc.) are used.

3) Amide Compound: As the amide compound, for example, a compound in which an acyl group is bonded to the nitrogen in the ring such as pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole, etc. is used.

4) Active ester: Here, the active ester is methyl ester.

In addition to esters such as ethyl ester, methoxymethyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, 1-hydroxy-IH-2-pyridone , N-hydroxysuccinimide, N-hydroxyphthalimide, etc. are used.

5) Active thioester: As the active thioester, thioesters with heterocyclic thiols such as 2-pyridylthiol and 2-benzthiazolylthiol are used.

The various reactive derivatives described above are appropriately selected depending on the type of carboxylic acid.

This reaction may be carried out in the presence of a base, and the bases used include aliphatic tertiary amines (e.g., trimethylamine, triethylamine, tripropylamine, tri-n-butylamine, etc.), N-methylpiperidine, N-methyl Tertiary amines such as pyrrolidine, cyclohexyldimethylamine, N-methylmorpholine, dialkylamines such as di-n-butylamine, diisobutylamine, dicyclohexylamine, aromatic amines such as pyridine, lutidine, T-collidine, etc. Lithium, sodium.

Hydroxides or carbonates of alkali metals such as potassium, alkaline earth metals such as calcium and magnesium, and the like are used. In this method, the reactive derivative of carboxylic acid is usually used in an amount equivalent to that of compound (I''), but it can be used in excess as long as it does not interfere with the reaction.

When using a base, the amount of the base used varies depending on the starting material compound (I') used, the type of reactive derivative of carboxylic acid, and other reaction conditions, but is usually about equivalent to 30 equivalents relative to compound (Bi). , preferably about equivalents to 10 equivalents.

This reaction is usually carried out in a solvent. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, propylene oxide and butylene oxide, esters such as ethyl acetate and ethyl formate, such as chloroform, dichloromethane, 1,2-dichloroethane, 1.1. Halogenated hydrocarbons such as 1-trichloroethane, benzene, toluene.

Common organic solvents such as hydrocarbons such as n-hexane, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and nitriles such as acetonitrile are used alone or in combination. Also,
Among the above-mentioned bases, liquid ones can also be used as a solvent.The reaction temperature is not particularly limited as long as the reaction proceeds, but is usually about -50°C to 100°C, preferably about -30°C to 40°C. It will be held in The reaction usually completes in about several tens of minutes to several tens of hours, depending on the raw materials, base, reaction temperature, and type of solvent used, but it may sometimes take several tens of days.

(I) thus obtained can be isolated and purified by means known per se, such as concentration, liquid conversion, dissolution, solvent extraction, lyophilization, crystallization, recrystallization, and chromatography.

Compound (I) also has stereoisomers (e.g., D-isomer, L-isomer,
-isomers, diastereomers) may exist.

In this case, each of their isomers.

and mixtures thereof are also included in the invention.

These isomers can be used alone or as a mixture as a medicine.

Further, when these isomers are obtained as a mixture, each isomer can be isolated by conventional methods such as various chromatography and recrystallization, if necessary.

Compound (n) used as a raw material compound in the method of the present invention can be produced by various known methods. For example, the compound itself is known from the following documents, or compound (II) can be obtained according to the methods described therein.

(1) P 1 , A. Plattner et.
al,, Helvetica Chimica Acta (He1
v, Chimica Acta) Tsui, 1531 (1
957), (2) C, H, Stam+aereta1. , Journal of the American Chemical Society
Tea (Journal of the Aa+er
ican Chemical Society) 79.3
236 (1957).

(3) C.H. Stammer et al.
Journal of Medicinal Chemistry (J
Our own of Medicinal Chemi
str31) 21.709 (1978).

Compound (III) is a compound itself known from the following literature, etc., or can be obtained according to the method described therein (R, B).

Woodward et al., Journal of
The American Chemical Society (Jou
rnalof the American Chem
ical 5ociety) 100+8214 (1
978) ).

The compound (T) thus obtained is useful as a medicine, for example certain Gram-positive compounds.

It has antibacterial activity against Gram-negative bacteria.

Compound (1) of the present invention is useful, for example, in treating mammals (eg, mice, rats, etc.) infected with the above-mentioned bacteria.

The compound (1) of the present invention can be used as a therapeutic agent for bacterial infections, for example, for respiratory tract infections, urinary tract infections, purulent diseases, biliary tract infections, and intestinal infections in the mammals mentioned above.

It can be used to treat obstetric and gynecological infections, surgical infections, etc. Compound (1) or a physiologically acceptable salt may be prepared by conventional means such as tablets, capsules, etc.
It can be administered orally in the form of a drop or the like, or it can be formed into an injection by conventional means, for example.
It can be formulated into a sterile carrier prepared by conventional means and administered parenterally.

The present invention will be explained in more detail with reference to Reference Examples and Examples below.

Example 1 2-((4S)-4-benzyloxycarbonylamino-3-oxoisoxabridinyl)-2-acetoxyacetic acid p-nitrobenzyl ester (4S)-4-benzyloxycarbonylamino-3-isoxa Molecular sieves 4A (approximately 20 g) was added to the suspension of 945 mg of zolidinone and glyoxylic acid p-nitrobenzyl ester hydrate e+1 g in dichloromethane 50 mj!Q, and the mixture was allowed to stand overnight at room temperature.

When the molecular sieves are filtered off and the filtrate is concentrated (4
S)-2-(4-benzyloxycarbonylamino-3
-oxoisoxazolidinyl)-2-hydroxyacetic acid
p-Nitrobenzyl ester was obtained as an oil.

NMR (90MH2, CDCb) δ:3,85-4
．． 35 (18, m), 4.45-4.90 (28, m
), 5°06 (28,s ), 5.75 (IH
, m), 5.87 (LH, bs), 7.29 (5H,
s ), 7.46 (2H, d, J = 8Hz
), 8. 13. 8. 15 (eachI
H, dx2. J=8Hz) Dissolve this oil in 40rml of anhydrous dichloromethane,
Under ice-cooling, 633 mg of pyridine and then 613B of acetic anhydride were added. After stirring this solution at room temperature for 2 hours, it was washed successively with water, potassium hydrogen sulfate, and brine, and dried (Mg
5 Oe) and then concentrated. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (2:1→1:2) to obtain 1.2 g of the title compound as a colorless oil. The main island crystallized when treated with ether.

Melting point 120-135°C I Rv'' 11., cm-': 3310.
1770.1750.1710°1525.135O NMR (90MHz, CDCl+) δ: 2.
1 8 (3)1. s).

3, 85-4. 35 (IH, m), 4.
51-4, 90 (2H, ta), 5. 1
2 (2H,s).

5, 33 (2H,S), 6. 78.
6. 85 (totalIH,each,s)
, 7. 32 (5H,s), ? ,
46°8, 20 (each2H, d, J=9
Hz ) [α) I, 24・'-18,2" (C
= 0. 34. CHCl3”) Elemental analysis value: C
zJz+NsO+.

Calculated value: C, 54,21; H, 4,34; N; 8.6
2 Actual measurement value FC, 54, 17, H, 4, 32; N, 8.
49 Example 2 2- ((4S)-4-(2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamide-3-oxoisoxalidinyl)-2- Acetoxyacetic acid sodium salt To a solution of 325 mg of the compound obtained in Example 1 in 10 mf of tetrahydrofuran and 5 ml of water, 100 mg of 10% palladium-carbon was added and hydrogenated at room temperature under normal pressure for 4 hours. After the catalyst was filtered off, the filtrate was Tetrahydrofuran 10I11
1 and 224 mg of sodium hydrogen carbonate were added. This compound was added to 2-(2-chloroacetamidothiazole-
266 mg of 4-yl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride was added, and the mixture was stirred for 30 minutes under water cooling and then for 30 minutes at room temperature.

Then N-methyldithiocarbamate sodium salt 12
After adding 9 mg and stirring at room temperature for 1 hour, the mixture was washed with ether and the aqueous layer was concentrated. Amberlite XAD-n
The residue was purified by column chromatography (water-10% ethanol) using 100% water and lyophilized to give the title compound as a white powder (260 mg).

I Rv ”' m1lX Cff1-' : 340
0. 1735. 1660. 1530°1385,
1235 NMR (90MHz, DMSO-d6) δ: 2.
02 (3H, S).

3.81 (3H,s), 3.62-4.30 (I
H, m), 4. 33-5. 18 (2H,
m).

6, 24 (IH,s), 6. 91
(ill,s).

7, 16-7, 28 (2H, b), 9.
15 (IH, d, J = 8Hz) [α] o ” + 1.0' (C = 0.59.
HzO) Elemental analysis value: C+:+L 4Nsos
sNa ・3 H20 calculated value: C, 32, 71; H,
4,22; N; 14.67° Actual value: C, 32, 30; H, 4,03; N, 15
．． 25 Example 3 2- ((4S)-4-(2-chenylacetamide)-
3-oxoisoxazolidinyl]-2-acetoxyacetic acid sodium salt 325 mg of the compound obtained in Example 1, 10 mA of tetrahydrofuran, and 5 ml of water? 100 mg of 10% palladium-carbon was added to the solution, and hydrogenated at room temperature under normal pressure for 4 hours. After filtering off the catalyst, return 224 m of sodium hydrogen oxide under water cooling.
g and a solution of 321 mg of chenyl acetate chloride in 10 mf of tetrahydrofuran were added, and the solution was stirred at room temperature for 30 minutes under water cooling.
Stirred for 0 minutes. Sodium hydrogen carbonate was added to the mixture to adjust the pH to 8, and tetrahydrofuran was distilled off. The residue was purified by column chromatography (water, 110% ethanol) using Amberlite
) was obtained.

IRν",,, cm-': 3400.174
0.1655.1375°NMR (90MHz, DM
SO-da) δ: 2. 05 (3H, s).

3.72 (2H, S), 3.60-4.20 (18,
m), 4.15-4.98 (2H, m).

6, 23. 6. 28 (total IH, e
achs).

6.83-7.00.7.25-7.39 (tota
13H,m), 8. 82 (IH, d, J
=8Hz) [α]n"-18,5' (C=0.3
35. HtO) Elemental analysis value: C+J++Nz07SN
a ・3/2 LO calculation value: C, 39, 90; H, 4
, 12; Ni7.16° Actual value: C, 39,49; H, 4,26; N, 7.53 Example 4 2-((4R)-4-benzyloxycarbonylamino-3-oxoisoxazoli [dinyl]-3-acetoxyacetic acid p-nitrobenzyl ester Example 1 (4S)
When reacting and treating in the same manner as in Example 1 using the (4R) form in place of -4-benzyloxycarbonylamino-3-isoxazolidinone, compound No. 8 was obtained as a colorless oil.

The IRl and NMR spectra of the main island were consistent with those of the compound obtained in Example 1.

Example 5 2-((4R)-4-(2-chenylacetamide)-
3-oxoisoxazolidinyl]-2-acetoxyacetic acid sodium salt 2-((4S)-4-benzyloxycarbonylamino-3-oxoisoxazolidinyl:/Lz) of Example 3
-3-acetoxyacetic acid When the (4R) form was used in place of p-nitrobenzyl ester and the reaction and treatment were carried out in the same manner as in Example 3, compound No. 8 was obtained as a white powder.The IR and NMR spectra of this product were as follows. The results were consistent with those of the compound obtained in Example 3.

Example 6 2-((43)-(4-Benzyloxycarbonylamino-3-oxoisoxazolidinyl)]-]2-benzoyloxyacetic acid p-nitrobenzyl ester Benzoyl instead of acetic anhydride in Example 1 When the reaction and treatment were carried out in the same manner as in Example 1 using chloride, compound No. 8 was obtained as a colorless oil.

IRν""',, c+a-': 3340.17
80-1700.152ONMR (90MHz, CD
C1x) δ: 3.95-4.30 (18, m),
4.50 4.90 (2H, m).

5, 11 (2H,s), 5. 36 (2
H,s).

7, O4, 7, 13 (total IH, eac
hs).

7.33 (5H,s), 7.15-8.30 (9
B1m)? 71.71. Vector: m/e 549 (M'
) Example 7 2- ((4S)-4-(2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido-3-oxoisoxazolidinyl)-2 -benzoyloxyacetic acid sodium salt Example 2Φ2- ((4S)
-4-benzyloxycarbonylamino-3-oxoisoxazolidinyl]-2-acetoxyacetic acid When reacted and treated in the same manner as in Example 2 using the compound obtained in Example 6 instead of p-nitrobenzyl ester, Compound No. 8 was obtained as a white powder.

I Rv"'□xcm-': 3380.1720
．． 1660.1530°NMR (90MHz, DMS
O-da) δ: 3. 85 (31(,s)
.

3.90-4.75 (2H, m), 4.80-5.
23 (1B, m), 6.54 (IH, s).

6, 93. 6. 95 (total 1'H,
each s).

7.00-7.30 (2B, b), 7.35-8.
13 (5H, m), 9.15. ! L 24 (t
otalIH, each d, J-7Hz)
(α)D”-51,7” (C-0,375,HtO
) Elemental analysis value: C+J+JLsO@SNa ・3fl
tO calculated value: C, 40,08; H, 4,11; N; 12
．． 98 Actual value: C, 40,28; H, 3,89SN, 13.2
0 Example 8 2- ((43)-4-(2-chenylacetamide)-
3-Oxoisoxazolidinyl]-2-benzoyloxyacetic acid sodium salt 2-((4S)-4-benzyloxycarbonylamino-3-oxoisoxazolidinyl)-2-
When the compound obtained in Example 6 was used in place of acetoxyacetic acid p-nitrobenzyl ester and the reaction and treatment were carried out in the same manner as in Example 3, compound No. 8 was obtained as a white powder.

I Rv"',,xc++-': 1730.1
640.1480.1250°NMR (90MHz,
DMSOJi) δ1.9-5.3 (31, m),
6. 58. 6. 60 (totalH.

each 5), 7. 30-8. 15 (8
H,m,).

(α) b ”-25,1° (C-0,295,Hz
O) Example 9 2-(43)-4-Benzyloxycarbonylamino-3-oxoisoxazolidinyl]-2-carbamoyloxyacetic acid p-nitrobenzyl ester (4S)-4-benzyloxycarbonylamino-3 −
Isoxazolidinone 472 mg and glyoxylic acid p-
Nitrobenzyl ester hydrate 454 mg dichloromethane 20 m A! Molecular sieves 4A (approximately 5 g) was added to the L%S solution and left at room temperature for 16 hours. After removing the molecular sieves by filtration and concentrating the filtrate, the residue was dissolved in 20 mβ of anhydrous tetrahydrofuran. To this solution was added 0.3 mf of chlorocarbonyl isocyanate under water cooling, and after stirring for 1 hour, some sodium bicarbonate water was added.
was added and extracted with ethyl acetate.

The extract was washed with brine, dried (MgSO4) and concentrated to obtain compound No. 8 as colorless crystals (370 mg). A further 572 mg of compound No. 8 was obtained as a foamy substance from the mother liquor.

Melting point 17B-180°C (decomposition) I Rv ”', 11.crs-': 3500.
3320. 1760. 1720°1530.10
10 75N (90MHz, DMSO-db) δ
: 3.90-4, 23 (18,m), 4.5
0-4. 96 (2H.

m), 5. 10 (2B, s), 5.43
(2H, s).

6.71 (IH,s), 7. 35 (5H
,s).

6, 85-7. 20 (2B, b), 7.
80-8, 10 (LH, m), 7. 65.
8. 25 (2HX2.dx2.J=9
Hz) [α]. zs, 5-74.2° (C=0.25
6゜THF) Elemental analysis value: C21H2゜N40. .

Calculation Direct: C, 51, 64; H, 4, 13; Null
, 47° Actual measurement: C, 51, 60, H, 3,97; N, 11.2
2 Example 10 2- ((4S)-4-C2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamidogo-3-oxoisoxazolidinyl)-2- Carbamoyloxyacetic acid sodium salt Example 2 2-((43
)-4-benzyloxycarbonylamino-3-oxoisoxazolidinyl]-2-acetoacetic acid React and treat in the same manner as in Example 2 using the compound obtained in Example 9 instead of p-nitrobenzyl ester Then, compound No. 8 was obtained as a white powder.

I Rv ”', cm-': 3380.1
730.1650.1380°NMR (90MHz,
DMSO-δ6) δ: 3. 84 (38,s)
.

3.54-5.13 (3H, m), 6.18 (LH,
S), 6.37-6.66 (2H,b).

6.95 (IH,s)+6.90-7.30
(2H.

b), 8.95-9.31 (IH, mL [α) a
"0' (C=0.325.N20) Elemental analysis value: C+J+ffN60sSNa ・4)1
20 calculated value: C, 29,04; H, 4,26; N, 16
．． 93°Actual measurement: C, 29,19; H, 3,99; N, 16
．． 83 Example 11 2-((4S)-4-(2-chenylacetamide)-
3-oxoisoxazolidinyl]-2-carbamoyloxyacetic acid sodium salt 2-((4S)-4-benzyloxycarbonylamino-3-oxoisoxazolidinyl)-2-
When the compound obtained in Example 9 was used in place of acetoxyacetic acid p-nitrobenzyl ester and the reaction was carried out in the same manner as in Example 3, compound No. 8 was obtained as a white powder.

IRνKBr, cm-j: 3380.173
0.1650.1385°NMR (90MHz, DM
SO-da) δ: 3.70°3, 73 (to
tal 2H, each s), 3. 50-4.
95 (3H, m), 6.20 (LH, s)
.

6.40-6.70 (2)1. b), 6.85-7
, 10. 7. 20-7. 37 (total
3H, m).

8, 80 (IH, d, J=7Hz)C(X
]o ”'+ 32.1° (C= 0.34,820
>.

Elemental analysis value: Cl2H12N307SNa-4H20
Calculated value: C, 36,91; H, 3,82; N; 10.7
6. Actual value: C, 37,02; H, 4,14; N, 10
．． 70 Example 12 2-((4S)-4-t-butoxycarbonylamino-3-oxoisoxazolidinyl)-2-(4-(2-
Chloroacetamidothiazolyl)carbonyloxy]acetic acid p-nitrobenzyl ester (4S)-4-t-butoxycarbonylamino-3-isoxazolidinone 404 mg, glyoxylic acid
A suspension of 454 mg of p-nitrobenzyl ester hydrate and Molecular Sheeps 4A (about 10 g) in 15 LIll of dichloromethane was heated under reflux for 30 minutes. Filter off the molecular sieves and add 0.5 pyridine to the filtrate under ice cooling.
nj! and 551 mg of 4-(2-chloroacetamidothiazolyl)carbonyl chloride were added and stirred for 1 hour.

Dichloromethane was distilled off, and ethyl acetate-tetrahydrofuran (2:1) was added to the residue, which was washed successively with 3N hydrochloric acid, aqueous potassium hydrogen sulfate, aqueous sodium hydrogen carbonate, and brine.

After drying (MgSOa), the solvent was distilled off, and the residue was purified by column chromatography using silica gel. Elution with hexane-ethyl acetate (1:1-1:2) gave 860 mg of compound No. 8 as a colorless foam.

I Rv ”' o, cm-': 3370.29
70.1745.1520°NMR (90MHz, C
DCh) δ:l, 45. (9B.

s), 3.90-4.40 (2H, m), 4.28 (
2H, m), 4.40-4.90 (IH, m).

5.40 (2)1. s), 8.05 (IH, s)
.

7.52, 8.25 (2Hx2.dx2.J=9Hz
) Example 13 2- ((4S)-4-(2-(2-aminothiazol-4-yl')-(Z)-2-methoxyiminoacetamide-3-oxoisoxazolidinyl)- 2-(4-(
2-aminothiazolyl)carbonyloxy]acetic acid p-
Nitrobenzyl ester Compound 860 obtained in Example 12
mg and anisole Q, 2 ml dichloromethane 5
ml of trifluoroacetic acid at -40 °C.
was added, and the temperature was raised to 0°C over 2 hours. Dichloroethane was added to the reaction solution, and the solvent was distilled off. Add 2Qml of tetrahydrofuran and 10ml of pH7 phosphate buffer to the residue, and adjust the pH to 7 with sodium bicarbonate water.
Under water cooling 2 (2-chloroacetamidothiazole-4-
590 mg of (Z)-2-methoxyiminoacetyl chloride hydrochloride was added and stirred for 1 hour. Add N-methyldithiocarbamic acid sodium salt 2 to this mixture.
29 mg was added, stirred at room temperature for 2 hours, and extracted with ethyl acetate-tetrahydrofuran (1:1). The extract was washed with water, dried (MgSOn), and the solvent was distilled off. The residue was purified by column chromatography using silica gel (chloroform-chloroform-methanol=10:1) to obtain compound No. 8 as a white powder (0.9 g).

I Rv"',,,cs-': 1740.1
6B0.1610.1520°35O NMR (90MHz, DMSO-da) δ: 3.
80. (3H, s).

4.00-4.35 (2H, m), 4.50-4.9
0 (IH, m), 5.43 (2H, s).

6, 85. 6. 88 (total IH
,ea+J)s).

6, 98. 7. OO(total IH,
each).

7.00-7.18.7.18-7.40 (2HX
2. br), 7.82 (2H, m), 8.12-8
．． 38 (2H, m), 9.25 (IH, d.

J=8Hz) Example 14 2-((4S)-4-(2-aminothiazole-4-
)-(Z)-2-methoxyiminoacetamide 3
-oxoisoxazolidinyl)-2-(4-(2-aminothiazolyl)carbonyloxy]acetic acid sodium salt 1.0 g of the compound obtained in Example 13 was added to a mixture of 10 mj! of tetrahydrofuran and 10 mj! of pH 7 phosphate buffer. 1 g of 10% palladium-carbon was added and hydrogenated for 4 hours under normal pressure. The solvent was filtered off, the filtrate was washed with ether, and column chromatography using Amberlite XAn-n (water-5% ethanol) was carried out. ) and freeze-drying to obtain compound No. 8 as a white powder (250 mg).

I Rv ”' □, cm-': 3390.17
30.1655.1535°NMR (90MHz, D
MSO-da) δ: 3. 80 (3H, s).

4.35-4.70 (2B, m), 4.70-5.1
0 (IH, m), 6.34-6.35 (total
IH, each s), 6. 89. 6. 91
(total IH, each s), 6. 80
-7. 30°7.20-7.55 (2)1 x2.
b), 7.46 (IH,S), 9. 18 (L
H, d, J=8Hz ) (α) D ”-52,0
” (C=0.275.H2O) Elemental analysis value:
Cl5HIJ? 10aszNa ・2.5HzO Calculated value: C, 32,61; H, 3,47; N; 17.75° Actual value: C, 32,83; H, 3,65; N, 17.6
4

Claims (1)

[Claims] 1. Formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 represents an optionally acylated amino group, and R^2 represents hydrogen. atom or acyl group, and Y represents a carboxyl group which may be esterified, or a salt thereof.