JP2973126B2 - Novel penam derivatives and their salts - Google Patents

Description

The present invention relates to a novel penam derivative and a salt thereof, and more particularly, to a general formula During the "formula, R ¹ represents a hydrogen atom, an amino protecting group or an acyl group; R ² is a hydrogen atom or a lower alkyl group; R ³ is a hydrogen atom, lower alkoxy, lower alkylthio, or formamide group; R ⁴ Is an optionally protected carboxyl or carboxylate group; R is a group of the formula —NHR ⁵ or (Wherein R ⁵ and R ⁶ are the same or different and each may be an optionally protected hydroxyl group, cyano group, sulfo group or optionally substituted lower alkyl, aryl, acyl, carbamoyl, sulfamoyl, lower alkyl A sulfonyl or heterocyclic group). (Wherein R ⁷ and R ⁸ are the same or different and are each a hydrogen atom, an optionally protected carboxyl group, a cyano group or an optionally substituted lower alkyl, lower alkenyl, lower alkynyl, aryl, amino, forming Further, R ⁷ and R ^8, a cycloalkene ring or a heterocyclic ring together with the adjacent carbon atoms; acyl, acyloxy, carbamoyl, carbamoyloxy, sulfamoyl, lower alkylthio, showing a ureido or heterocyclic group. And n is 1 or 2
Are respectively shown. And a salt thereof.

It is an object of the present invention to exhibit a broad antibacterial spectrum, i.e., exhibiting excellent antibacterial activity against Gram-positive and Gram-negative bacteria, and particularly stable against β-lactamase,
An object of the present invention is to provide a novel compound which exerts a strong antibacterial activity against resistant bacteria and is useful as a medicament for humans and animals.

Another object of the present invention is to provide a compound useful as an intermediate of another penum derivative.

[Prior Art] A conventionally known penum derivative, for example,
The compounds described in -183588 have a relatively broad antibacterial spectrum. However, the antibacterial activity against resistant bacteria is not always satisfactory.

[Problems to be Solved by the Invention] Under such circumstances, a penum-derived pair having a broad antibacterial spectrum, being stable against β-lactamase, and exhibiting a strong antibacterial activity against resistant bacteria has been developed. Was desired.

[Means for Solving the Problems] As a result of intensive studies on compounds for solving the above problems, the present inventors have found a penum derivative represented by the general formula [I] and a salt thereof, and have completed the present invention. .

 Hereinafter, the present invention will be described in detail.

In this specification, unless otherwise specified, each term has the following meaning. A halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a lower alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or a linear or branched C _{1 to 5} alkyl groups such as pentyl, and the lower alkenyl group, for example, vinyl, allyl, isopropenyl, straight or branched chain C _{2 to 5} alkenyl such as butenyl or 2-pentenyl _{C 2 to 5} of the lower alkynyl group, such as ethynyl or 2-propynyl; a group
An alkynyl group; a cycloalkyl group is, for example, a C _3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a lower alkoxy group is, for example, a C _1-5 group such as methoxy, ethoxy or propoxy; An alkoxy group; a lower alkylthio group, for example, a C _1-5 alkylthio group such as methylthio, ethylthio or propylthio; a lower alkylthio lower alkyl group, for example,
A C _1-5 alkylthio C _1-5 alkyl group such as methylthiomethyl, ethylthiomethyl or ethylthioethyl; a halo-lower alkyl group is substituted by a halogen atom such as chloromethyl, bromoethyl or trifluoromethyl A C _1-5 alkyl group; a hydroxy lower alkyl group is, for example, a hydroxy C _1-5 alkyl group such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl; an amino lower alkyl group is, for example, amino Amino C such as methyl, 2-aminoethyl or 3-aminopropyl
_A carboxy lower alkyl group;
For example, carboxy C, such as carboxymethyl, 2-carboxyethyl or 3-carboxypropyl
_A lower alkoxycarbonyl-lower alkyl group is, for example, methoxycarbonylmethyl,
C _1-5 alkyl-O—CO—C _1-5 such as ethoxycarbonylmethyl or 2-ethoxycarbonylethyl
Alkyl group; a cyano lower alkyl amino lower alkyl group, for example, the NC-C _{1 to 5} alkyl -NH-C _{1 to 5} alkyl group such as cyanomethyl aminomethyl or 2-cyanoethyl aminomethyl; N, N- the di-lower alkylamino group, for example, N, N- N, such as dimethylamino, N- di -C _{1 to 5} alkylamino group; and a lower alkylsulfonyl group, for example, such as methylsulfonyl or ethylsulfonyl the C _{1 to 5} alkyl sulfonyl group; and sulfamoyl lower alkyl group, e.g., sulfamoyl C _{1 to 5} alkyl groups, such as sulfamoyl, methyl or 2-sulfamoyl ethyl; and lower alkoxycarbonylamino group, C _{1 -5} alkyl-O-CO-NH- group; a lower alkoxyimino group is
The C _{1 to 5} alkyl -O-N = group; Cycloalkyl oxyimino _group, a _{C 3 to 7} cycloalkyl -O-N = group; and a lower alkylidene group, eg, _{C 1} such as methylidene or ethylidene the ₅ alkylidene group; and a lower alkenylidene group, for example, a _{C 2 to 5} alkenylidene group such as ethenylidene or propenylidene; a lower alkoxy methylene _group, a _{C 1 to 5} alkyl -O-CH = group; and halomethylene group Is, for example, a methylene group substituted with a halogen atom such as chloromethylene or bromomethylene; a lower alkanoyloxy group is a C _1-5 alkyl-CO—O— group; a lower alkoxycarbonyl group is a C _{1 A} carboxy lower alkoxy group is defined as HOOC-C _1-5
An alkoxy group; a carboxy lower alkylthio group
The _{HOOC-C 1 to 5} alkylthio groups; and acyl groups, e.g., formyl group, _{C 2 to 5} alkanoyl group such as acetyl or propionyl, _{C 3 to 5} alkenoyl group such as acryloyl or crotonoyl, aroyl such as benzoyl or naphthoyl Group, thenoyl, furoyl, isonicotinoyl, nicotinoyl, 1,4-dihydropyridin-2-yl-carbonyl or 4-ethyl-
An acyl group such as a heterocyclic carbonyl group such as 2,3-dioxopiperazin-1-yl-carbonyl; an acyloxy group is an acyl-O- group; an acylamino group is an acyl-NH- group; An alkyl group is a benzyl, phenethyl, 4-methylbenzyl or naphthylmethyl group; an aryl group is a phenyl, naphthyl or indanyl group; a haloaryl group is an aryl group substituted by a halogen atom; - the di-lower alkylamino aryl group, for example, N, N- N, such as dimethyl amino phenyl, N- di -C _{1 to 5} alkylamino aryl group; and arylamino group, an aryl -NH- group ; the arylcarbonylamino group, the aryl -CO-NH- groups; and sulfamoylamino arylamino group, H ₂ NSO ₂ - aryl -NH- group; Aruarukiruo The xyimino group is
An aralkyl-ON = group; a cycloalkene ring is
For example, a C _5-6 cycloalkene ring such as cyclopentene or cycloheptene; a heterocyclic group means 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms as heteroatoms forming the ring. Containing 4- to 7-membered, fused or bridged heterocyclic groups such as azetidinyl, thienyl, furyl, pyrrolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, thiazolyl, Tetrazolyl, 1,3-dithiolanyl, pyridyl, 1-hydroxy-4-oxo-1,4-dihydropyridyl, 1,4-dihydropyridyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrazolinyl, pyrrolidinyl, 2-oxazolinyl, imidazolinyl, frazanil, Isothiazolyl, 4,5-dihydrothiazolyl,
2,3-dihydrofuryl, 2,5-dihydrofuryl, tetrahydrofuryl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl , Pyrazolyl, 3-pyrrolinyl, 4,5
-Dihydropyrazolyl, isoxazolyl, isoxazolidinyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, piperidinyl, piperazinyl, tetrahydropyrazinyl, morpholinyl, pyrimidinyl, pyrazinyl , 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-3,4-dihydropyranyl, 2H-5,6-dihydropyranyl, 1,4-oxazinyl,
Pyridazinyl, 2H-thiazinyl, perhydrooxazinyl, dihydrooxazinyl, chromenil, benzothienyl, benzoisothiazolidinyl, imidazo [1,2-b]
[1,2,4] triazinyl, thieno [3,2-b] thienyl,
Benzotriazolyl, 1,2,3-benzothiadiazolyl,
Tetrazolo [5,1-b] pyridazinyl, 2,1,3-benzoxaziazolyl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyrimidinyl, imidazo [1,2-b]
[1,3] thiazolyl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyridyl, imidazo [1,2-a] pyrazinyl, 1,4-benzomorpholinyl, benzothiazolyl, isoindolinyl, benzofuranyl , 1,4-benzothiomorpholinyl, 1,3-benzoxazolidinyl, triazolo [1,5-a] pyrimidinyl, indolinyl, indazolyl, benzoxazolyl, benzisoxazolyl,
Purinyl, isoquinolyl, quinolyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 1,1-dioxo-1,2-benzisothiazolidinyl, 1,2-dihydro-4H-3,1-benzoxazinyl , 1,2-benzoxazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl,
Quinuclidinyl, perhydroazaepinyl or 3-
A heterocyclic group is a heterocyclic group-
H; a heterocyclic amino group refers to a heterocyclic -NH- group; a heterocyclic oximino group refers to a heterocyclic -ON = group; a heterocyclic thio group refers to a heterocyclic -S- group. I do. In addition, the heterocyclic group containing a nitrogen atom may be quaternized.

Examples of the amino protecting group for R ¹ include commonly known amino protecting groups such as formyl, tert-butyloxycarbonyl, p-nitrobenzyloxycarbonyl,
tert-amyloxycarbonyl, triphenylmethyl,
Examples include trimethylsilyl, benzylidene, 2,2,2-trichloroethyloxycarbonyl or p-nitrobenzylidene.

As the acyl group for R ^1, an acyl group conventionally known in the field of penicillin and cephalosporin compounds, for example, formyl, 2,6-dimethyloxyphenylcarbonyl or 5-methyl-3-phenylisopropyl Xazol-4-ylcarbonyl or the like, or a formula "Wherein, R ⁹ is optionally substituted lower alkyl, lower alkenyl, aryl or heterocyclic group; Z is an oxygen or sulfur atom or a bond; Y ¹ is a hydrogen atom; Y ²
Is a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected carboxyl group,
A sulfo group, a sulfoamino group, an amino group which may be protected or a compound represented by the formula R ¹⁰ CONH-, wherein R ¹⁰ represents an optionally substituted aryl, arylcarbonylamino, heterocyclic amino or heterocyclic group )). An optionally substituted lower alkoxyimino, cycloalkyloxyimino, aralkyloxyimino, lower alkylidene, lower alkenylidene, lower alkoxymethylene, which is formed by combining Y ¹ and Y ² ;
Shows a halomethylene or heterocyclic oximino group. And the like.

In R ⁹ , the optionally substituted lower alkyl, lower alkenyl, aryl or heterocyclic group includes, for example, a halogen atom, a hydroxyl group, an amino group, an amino lower alkyl group, an acyloxy group, a carboxyl group, a lower alkoxy group, a ureido group, an acylamino group, a cyano group, a sulfo group, a carbamoyloxy group, a sulfamoyl group, a nitro group, such as oxo group or a heterocyclic group, and lower alkyl at R ^9, lower alkenyl, aryl or heterocyclic Each of the cyclic groups may be substituted with one or more of these substituents.

In R ¹⁰ , the optionally substituted aryl, arylcarbonylamino, heterocyclic amino or heterocyclic group includes, for example, a halogen atom, a hydroxyl group, an oxo group, a lower alkyl group, a halo-lower alkyl group, Hydroxy lower alkyl group, lower alkylthio group,
Lower alkylthio-lower alkyl group, an aryl group, a haloaryl group, a cycloalkyl group, an arylamino group, such as lower alkylsulfonyl group or a sulfamoylamino arylamino group, and aryl in R ^10, arylcarbonylamino, heterocyclic amino or heterocyclic Each of the cyclic groups may be substituted with one or more of these substituents.

Further, Y ¹ and Y ² is an optionally substituted formed together lower alkoxyimino, cycloalkyl oximino, aralkyl oximino, lower alkylidene, lower alkenylidene, lower alkoxy methylene, halomethylene or heterocyclic oximino Examples of the substituent of the group, for example, a halogen atom, such as acyloxy group or a protected or unprotected carboxyl group and the like, Y ¹
And Y ² together form a lower alkyloxyimino, cycloalkyloxyimino, aralkyloxyimino, lower alkylidene, lower alkenylidene, lower aralkyloxymethylene, halomethylene, or heterocyclic oxyimino group. It may be substituted with at least one substituent.

R ¹ is the formula Wherein R ⁹ , Y ¹ , Y ² and Z each have the same meaning as described above. Specific examples of the acyl group represented by the formula: 4-aminomethylphenylacetyl, hydroxyacetyl Phenoxyacetyl, 1-tetrazolylacetyl, cyanomethylthioacetyl, carboxyethylthioacetyl,
(2-thienyl) acetyl, α-bromo-α- (2-thienyl) acetyl, α-amino-α- (2-thienyl)
Acetyl, (5-methoxy-2-thienyl) acetyl,
Phenylacetyl, (3-bromophenyl) acetyl,
α-aminophenylacetyl, α-amino-α- (p-
Hydroxyphenyl) acetyl, α-amino-α- (2
-Aminothiazol-4-yl) acetyl, α-sulfoamino-α- (4-acetyloxyphenyl) acetyl, α-hydroxyphenylacetyl, α-carboxyphenylacetyl, α-carboxy-α- (p-hydroxyphenyl) acetyl , Α-carboxy-α- (o-
(Hydroxyphenyl) acetyl, α-carboxy-α-
(M-hydroxyphenyl) acetyl, α-carboxy-α- (p-fluorophenyl) acetyl, α-carboxy-α- (p-acetyloxyphenyl) acetyl,
α-carboxy-α- (p-carbamoyloxyphenyl) acetyl, α-carboxy-α- (3-fluoro-
4-hydroxyphenyl) acetyl, α-carboxy-
α- (3,4-dihydroxyphenyl) acetyl, α-carboxy-α- (o-chlorophenyl) acetyl, α-
Carboxy-α- (3-chloro-4-hydroxyphenyl) acetyl, α-carboxy-α- (2-chloro-4,
5-dihydroxyphenyl) acetyl, α-carboxy-α- (3,4-diacetyloxy-6-chlorophenyl) acetyl, α-carboxy-α- (2-thienyl)
Acetyl, α-carboxy-α- (3-thienyl) acetyl, α-sulfophenylacetyl, α-sulfo-α-
(P-acetyloxyphenyl) acetyl, α-sulfo-α- (m-acetyloxyphenyl) acetyl, α-
Sulfo-α- (p-nitrophenyl) acetyl, α-sulfo-α- (p-aminophenyl) acetyl, α-sulfo-α- (2-chloro-5-nitrophenyl) acetyl, α-sulfo-α- (3,4-dihydroxyphenyl)
Acetyl, α-sulfo-α- (3,4-diacetyloxyphenyl) acetyl, α-sulfo-α- (4-acetyloxy-3-fluorophenyl) acetyl, α-sulfo-α- (3,4-diacetyl Oxy-5-chlorophenyl) acetyl, α-sulfo-α- (3,4-diacetyloxy-6-chlorophenyl) acetyl, α-sulfo-α
-(3,4-diacetyloxy-2-chlorophenyl) acetyl, α-sulfo-α- (5-amino-2-chlorophenyl) acetyl, α-sulfo-α- (4-acetyloxy-3-chloro-6- Fluorophenyl) acetyl,
α-sulfo-α- (4-acetyloxy-6-fluorophenyl) acetyl, α-sulfo-α- (3,4-diacetyloxy-6-fluorophenyl) acetyl, α-sulfo-α- (o-chlorophenyl ) Acetyl, α-sulfo-α- (p-chlorophenyl) acetyl, α-sulfo-α- (2-aminothiazol-4-yl) acetyl,
α-sulfo-α- (3,4-diacetyloxy-5,6-dichlorophenyl) acetyl, α-sulfo-α- (p-hydroxyphenyl) acetyl, α-sulfo-α- (2-chloro-4,5 -Dihydroxyphenyl) acetyl, α-sulfo-α- (4-acetyloxy-2-chlorophenyl) acetyl, α-sulfo-α- (4-acetyloxy-3-chlorophenyl) acetyl, α-sulfo-α-
(3,4-diacetyloxy-5-fluorophenyl) acetyl, α-sulfo-α- (4-acetyloxy-3-
Nitrophenyl) acetyl, α-sulfo-α- (4-acetyloxy-2,5-dichlorophenyl) acetyl, α
-Sulfo-α- (4-acetyloxy-2-chloro-5
-Methoxyphenyl) acetyl, α-sulfo-α- (2
-Chloro-4-nitrophenyl) acetyl, α-sulfo-α- (4-amino-2-chlorophenyl) acetyl,
α-sulfo-α- (4-ureidophenyl) acetyl,
α-sulfo-α- (3-acetylamino-4-hydroxyphenyl) acetyl, α-sulfo-α- (2-chloro-4-hydroxyphenyl) acetyl, α-sulfo-α
-(2-fluoro-4-hydroxyphenyl) acetyl, α-sulfo-α- (3-fluoro-4-hydroxyphenyl) acetyl, α-sulfo-α- (2-chloro-
4-ureidophenyl) acetyl, α-sulfonylamino-α- (4-acetyloxyphenyl) acetyl, α
-Sulfo-α- (4,5-diacetyloxy-3-fluorophenyl) acetyl, α-sulfo-α- (3-fluoro-4,5-hydroxyphenyl) acetyl, α-sulfo-α- (2-chloro -4-hydroxy-5-methoxyphenyl) acetyl, α-sulfo-α- (4-acetylaminocarbonyloxy-3-fluorophenyl) acetyl, α-formyloxy-α-phenylacetyl, α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α-phenylacetyl, α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-
α- (p-hydroxyphenyl) acetyl, α- (4-
Ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (p-acetyloxyphenyl) acetyl,
α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (methylthio) acetyl, α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (3,4-dihydroxyphenyl) acetyl, α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (3,4-diacetyloxyphenyl) acetyl, α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (3,4-diacetyloxy-6-chlorophenyl) acetyl, α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (3,4-diacetyloxy-6-fluorophenyl) acetyl, α- (4-ethyl-2,3-dioxo-1-piperazine Carboxamide) -α- (6-
Chloro-3,4-dihydroxyphenyl) acetyl, α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (6-fluoro-3,4-dihydroxyphenyl) acetyl, α- (4-cyclopropyl-2,3
-Dioxo-1-piperazinecarboxamide) -α-phenylacetyl, α- (4-ethyl-2,3-dioxo-
1-piperazinecarboxamide) -α- (2-thienyl) acetyl, α- (4-ethyl-2,3-dioxo-1
-Piperazinecarboxamide) -α- (3-benzothienyl) acetyl, α- (4-ethyl-2,3-dioxo-
1-piperazinecarboxamido) -α- (2-naphthyl) acetyl, 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl, 2- (2-aminothiazol-4-yl) -2- ( 2-fluoroethoxyimino) acetyl, 2- (2-aminothiazole-4-
Yl) -2-carboxymethoxyiminoacetyl, 2-
(2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetyl, 2- (2
-Aminothiazol-4-yl) -2- [1-carboxy-1- (3,4-diacetyloxyphenyl) methyloxyimino] acetyl, α- (2-oxo-1-imidazolidincarboxamide) -α-phenyl Acetyl, α
-(3-methylsulfonyl-2-oxo-1-imidazolidinecarboxamide) -α-phenylacetyl, α-
(4-hydroxy-1,5-naphthyridine-3-carboxamide) -α-phenylacetyl, α- (4-phenyl-2,3-dioxo-1-piperazinecarboxamide)-
α-phenylacetyl, α- [4- (2,4-dichlorophenyl) -2,3-dioxo-1-piperazinecarboxamide] -α-phenylacetyl, α-[(1,4-dihydroxy-4-oxopyridazine- 2-yl) carboxamide] -α-phenylacetyl, α-[(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)
Carboxamide] -α-phenylacetyl, α- [4-
Hydroxy-4-oxopyridin-2-yl) carboxamide] -α-phenylacetyl, α-[(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-
Yl) carboxamide] -α- (p-hydroxyphenyl) acetyl, α- (2-aminothiazol-4-yl) -α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) acetyl, α -(2-aminothiazol-4-yl) -α-[(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) carboxamido] acetyl or α-[(4-oxo-4H-thiopyran- 3-yl) carboxamide] -α-phenylacetyl and the like.

Examples of the protecting group for the carboxyl group which may be protected for R ⁴ include carboxyl protecting groups conventionally known in the field of penicillin and cephalosporin compounds, for example, catalytic reduction, chemical reduction or other An ester forming group which is eliminated by treatment under mild conditions; an ester forming group which is easily eliminated in vivo;
Or an ester-forming group such as an organic silyl group, an organic phosphorus group or an organic tin group which is easily eliminated by treatment with water or alcohol. Among these protecting groups, suitable protecting groups include, for example, lower alkyl groups such as methyl, propyl or tert-butyl; aryl groups; benzyl, 4-methoxybenzyl,
Aralkyl groups such as -nitrobenzyl, 3,4-dimethoxybenzyl, 4-hydroxy-3,5-di (tert-butyl) benzyl, phenethyl, diphenylmethyl, triphenylmethyl or bis (methoxyphenyl) methyl; phthalidyl group A halo-lower alkyl group such as 2-iodoethyl or 2,2,2-trichloroethyl; acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, 1-acetyloxyethyl, 1-pivaloyloxyethyl, 1-acetyloxy-n-propyl or 1-pivaloyloxy-n
Acyloxy lower alkyl groups such as -propyl; 5-lower alkyl-2-oxo-1,3-dioxol-4-yl lower such as 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl Alkyl group; methoxymethyl,
Lower alkyloxy lower alkyl groups such as ethoxymethyl, propoxymethyl or isopropoxymethyl;
And lower alkoxycarbonyloxy lower alkyl groups such as methoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl and 1-propoxycarbonyloxyethyl.

R ⁵ , R ⁶ , R ⁷ and R ⁸ are each a group other than a hydrogen atom, a hydroxyl group, a carboxyl group, a cyano group or a sulfo group, for example, a halogen atom; a halo-lower alkyl group;
Lower alkyl groups; lower alkoxy groups; carboxy lower alkoxy groups; lower alkylthio groups; carboxy lower alkylthio groups; lower alkanoyloxy groups; lower alkoxycarbonyl groups; diphenylmethyloxycarbonyl groups; aryloxycarbonyl groups; Imino group; imino group; amino lower alkyl group; carboxy lower alkyl group; lower alkoxycarbonyl lower alkyl group; lower alkoxycarbonylamino group; nitrobenzyloxycarbonylamino group; cyano lower alkylamino lower alkyl group; N, N-di lower Alkylamino group, lower alkylsulfonyl group, sulfamoyl lower alkyl group, aryl group, aralkyl group, carbamoyl group, sulfo group, acyl group, oxo group, carboxyl group; Toro group; cyano group; amino group;
Hydroxyl group; ureido group; aralkyloxy group;
Sulfamoyl group; thioxo group; methylenedioxy group;
Heterocyclic-CO-group; may be substituted with one or more substituents selected from a heterocyclic group or a heterocyclic thio group.

Further, the substituents of the groups R ⁵ , R ⁶ , R ⁷ and R ⁸ further include a lower alkyl group, an amino group, an oxo group, a hydroxyl group, a carbamoyl group, a hydroxy lower alkyl group, a carboxy lower alkyl group, , N-di-lower alkylamino group, acylamino group, heterocyclic group, ureido group, trimethylammonioacetyl group, guanidino group, or the like, and may be substituted with one or more substituents.

When each of these groups R ¹ and R ^{4 to} R ⁸ has a group such as an amino group, a hydroxyl group or a carboxyl group, or R ¹ , each group of R ^{4 to} R ¹⁰ and Y ¹ and Y ^When an amino group, a hydroxyl group or a carboxyl group is bonded to each of the groups formed together, these groups may be protected with a commonly known protecting group.
As the amino-protecting group, for example, it includes the same amino-protecting group and mentioned in R ^1, the protecting group of the hydroxyl group, for example, formyl, acetyl, benzyl,
4-methoxybenzyl, tetrahydropyranyl, benzyloxycarbonyl or trimethylsilyl group. As the carboxyl protecting group, for example, it includes the same carboxyl protecting group and mentioned R ^4.

Examples of the salt of the penum derivative of the general formula [I] include a generally known basic group such as an amino group or carboxyl;
Salts on acidic groups such as sulfo or hydroxyl groups are mentioned.

As the salt in the basic group, for example, a salt with a mineral acid such as hydrochloric acid or sulfuric acid; a salt with an organic carboxylic acid such as formic acid, citric acid, trichloroacetic acid or trifluoroacetic acid; or methanesulfonic acid, benzenesulfonic acid,
Salts with sulfonic acids such as p-toluenesulfonic acid, mesitylenesulfonic acid or naphthalenesulfonic acid and the like, and salts in the acidic group include, for example, salts with an alkali metal such as sodium or potassium; Salts with alkaline earth metals; ammonium salts; or trimethylamine, triethylamine, tributylamine, pyridine, N, N-
Dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β
-Phenethylamine, 1-ephenamine or N, N '
And salts with nitrogen-containing organic bases such as -dibenzylethylenediamine.

When isomers (for example, optical isomers, geometric isomers, tautomers, and the like) are present in the penum derivative of the general formula [I] and salts thereof, the present invention includes all such isomers. And extends to all crystal forms, hydrates and solvates.

Further, the penum derivatives of the general formula [I] and salts thereof may form internal salts.

 Next, a method for producing the compound of the present invention will be described.

The penum derivative of the general formula [I] and a salt thereof can be obtained by known methods or an appropriate combination thereof, and for example, can be produced according to the following production route.

In ^{"wherein, R, R 1, R 2} , R 3, R 4, R 7, R 8 and n each have the same meaning as described above; and R ^1a CO-, it said at R ¹ A similar acyl group; R ^3a is a lower alkoxy, lower alkylthio or formamide group as described for R ³ ; R ^4a is a protected carboxyl group as described for R ⁴ ; R ¹¹ CO- is , the same optionally substituted acyl group as mentioned in R ⁵ and R ^6; R ¹² SO ₂ - is the same optionally substituted lower alkylsulfonyl group as mentioned in R ⁵ and R ^6; R ¹³ represents a hydrogen atom or a substituent of the same carbamoyl group as described for R ⁵ and R ⁶ ; and X ¹ represents a leaving group. ”In the general formulas [I b] and [IV] Penam derivatives are important intermediates for producing the compounds of the present invention.

Examples of the salts of the compounds of the general formulas [Ia], [Ib], [Ic] and [IV] include the same salts as described for the salts of the compound of the general formula [I].

Examples of the salt of the compound of the general formula [VIII] include a salt with an alkali metal such as sodium or potassium, and a salt with an alkaline earth metal such as calcium or magnesium.

The leaving group for X ¹ includes a halogen atom; a lower alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy; an arylsulfonyloxy group such as phenylsulfonyloxy and toluenesulfonyloxy; and acetyloxy and benzoyloxy. Acyloxy group and the like.

Further, as the reactive derivative at the amino group of the compound of the general formula [Ib] or [IV] or a salt thereof,
A Schiff base (imino-type or enamine-type isomer thereof) formed by reacting a compound of the general formula [Ib] or [IV] or a salt thereof with a carbonyl compound such as an aldehyde or a ketone; ] Or a compound thereof, or a salt thereof, with an organic silyl compound such as N, O-bis (trimethylsilyl) acetamide, trimethylsilylacetamide or trimethylsilyl chloride; a silyl derivative; a general formula [Ib] Or the compound of [IV] or a salt thereof is 2-chloro-1,3,2-dioxaphosphorane,
Phosphorus compounds such as 2-chloro-4-methyl-1,3,2-dioxaphosphorane, 2-chloro-1,3,2-dioxaphosphorinane, chlorodiethyloxyphosphine, chlorodiethylphosphine or phosphorus trichloride A phosphorus derivative formed by reacting with a compound represented by the general formula [I b]
Or reactive derivatives commonly used in acylation such as tin derivatives produced by reacting the compound of [IV] or a salt thereof with a tin compound such as chlorotriethylstannane.

Specific examples of the reactive derivative of the carboxylic acid of the general formula [III] include an acid halide; an acid anhydride; a mixed acid anhydride with a monoalkyl ester such as monoethyl carbonate or monoisobutyl carbonate; Mixed anhydrides with lower alkanoic acids which may be substituted with halogens such as pivalic acid or trichloroacetic acid; N
-Acylimidazole, N-acylbenzoylamide,
N, N'-dicyclohexyl-N-acylurea or N-
Active acid amides such as acylsulfonamides; and active esters such as cyanomethyl esters, substituted phenyl esters, substituted benzyl esters or substituted thienyl esters, and carboxylic acids of the general formula [III] can be converted to Vilsmeier reagents (N, N-dimethylformamide or Acting on acid amides such as N, N-dimethylacetamide with halogenating agents such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl-chloroformate or oxalyl chloride And a reactive derivative formed by reacting the compound.

Next, the production method of the compound of the general formula [I] will be described in more detail according to the aforementioned structural route.

(1) Ring Closure The compound of the general formula [Ia] or a salt thereof can be obtained by subjecting a compound of the general formula [II] to a ring closure reaction in the presence of a base.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran;
Nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethylsulfoxide;
In addition, solvents such as phosphoric amides such as hexamethylphosphoric triamide may be mentioned, and these solvents may be used alone or in combination of two or more.

The base used in this reaction includes, for example, an alkali hydroxide such as sodium hydroxide or potassium hydroxide; an alkali hydrogen carbonate such as sodium hydrogen carbonate; an alkali carbonate such as sodium carbonate; sodium hydride or hydrogen Metal hydrides such as calcium iodide; alkali acetates such as sodium acetate; potassium te
rt-butoxide, diethylamine, triethylamine,
Lithium diisopropylamide, lithium bis (trimethylsilyl) amide, cyclohexylamine, pyridine, 2,6-lutidine, N-methylpiperidine, N-methylmorpholine, tetramethylguanidine, 1,8-diazabicyclo [5.4.0] undec-7- Inorganic or organic bases such as ene, methylmagnesium bromide or 2,4,6-trimethylphenylmagnesium bromide.

The amount of the base used is 1 to the compound of the general formula [II].
The amount is from 5 to 5 times, preferably from 1.0 to 1.5 times.

The reaction temperature and the reaction time are not particularly limited, but are usually -60 to 30 ° C, preferably -40 to 5 ° C and 5
It may be carried out for minutes to 2 hours.

The compound of the formula [Ia] or a salt thereof thus obtained may be used in the next reaction without isolation.

In this reaction, when a group having an acidic proton such as an amide group is bonded to the compound of the general formula [II], for example, a silylating agent such as N, O-bis (trimethylsilyl) acetamide is added. This can increase the yield.

(2) Deacylation The compound of the general formula [Ib] or a salt thereof has the general formula [Ib]
a) or a salt thereof is subjected to a conventional deacylation (for example, a compound of the general formula [Ia] or a salt thereof is reacted with phosphorus pentachloride to give imino chloride, and then reacted with an alcohol to give imino ether. , And further hydrolyze).

The deacylation includes deacylation conventionally used in the field of penicillin and cephalosporin-based compounds, such as Lacue de Travo Simic de Peiba (Recl. Trav. Chim. Pays-Bas-Bas). Vol. 89, No. 1081
P. (1973) and JP-B-55-38954, or a method analogous thereto.

The compound of the general formula [Ib] or a salt thereof obtained by this reaction may be used for the next reaction without isolation.

(3) (i) Acylation The compound of the general formula [Ia] or a salt thereof is represented by the general formula [Ia]
The compound [b] or a salt thereof or a reactive derivative at the amino group thereof can be obtained by reacting with a carboxylic acid of the general formula [III] or a reactive derivative thereof.

This acylation may be usually carried out in a suitable solvent in the presence or absence of a base.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane; -Dimethylformamide and N, N-
Examples thereof include amides such as dimethylacetamide; ketones such as acetone; and water. These solvents may be used alone or in combination of two or more.

The base used as necessary in this reaction includes:
The same base as mentioned in (1) can be mentioned.

When the carboxylic acid of the general formula [III] is used in a free acid state, an appropriate condensing agent is used. Such condensing agents include, for example, N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide;1,1'-
Carbonyldiimidazole; N-ethoxycarbonyl-2
A dehydrating agent such as ethoxy-1,2-dihydroxyquinoline, phosphorus oxychloride or alkoxyacetylene; or 2 such as 2-chloropyridinium methyl iodide or 2-fluoropyridinium methyl iodide.
-Halogenopyridinium salts and the like.

The amount of the carboxylic acid represented by the general formula [III] or the reactive derivative thereof is determined based on the amount of the compound represented by the general formula [Ib] or a salt thereof or a reactive derivative thereof at an amino group.
1.0 to 1.5 times mol.

In addition, the reaction temperature and the reaction time are not particularly limited, but usually, the reaction may be carried out at −50 to 40 ° C. for 10 minutes to 48 hours.

(Ii) Alternatively, the compound of the general formula [Ia] or a salt thereof may be a compound of the general formula [IV] or a salt thereof or a reactive derivative of the amino group thereof with a compound of the general formula [V] , A compound of the general formula [VI] or [VII] or a reactive derivative thereof, a compound of the general formula [VIII] or a salt thereof, or sulfuric anhydride.

These reactions are carried out by a method known per se, for example, the above-mentioned acylation of (3) (i), Advanced Organic Chemistry: Reactions, Mechanisms and Structures Second Edition (Ad)
vanced Organic Chemistry: Reactions Mechanisms and
Structures secondedition) pp. 382-388 and 823
(1977), The Journal of Antibiotics (J. Antibiot.), Vol. 31, pp. 546-560 (1978)
Years) and 42, 1418 (1988) and the Journal of American Chemical Society (JA)
m. Chem. Soc.), pp. 5349-5351 (1956), or a method analogous thereto.

In each of the production routes described above, a compound having a hydroxyl group, an amino group, or a carboxyl group is
These hydroxyl group, amino group or carboxyl group are protected with a usual protecting group in advance, and after the reaction,
If necessary, these protecting groups can be eliminated by a method known per se.

Further, the compound of the general formula [Ic] or a salt thereof in which R ^3a is a lower alkoxy group can be converted by a conventional method from the compound of the general formula [Ia] or a salt thereof. R ^3a
Is a lower alkylthio group, or a salt thereof, is obtained by protecting the amino group of the compound of the general formula [Ib] or a salt thereof with, for example, the above-mentioned amino protecting group, Or, if desired, after deprotection, or after deprotection, subjected to the acylation of (3) (i) described above. General formula [I c] wherein R ^3a is a formamide group
Or a salt thereof can be obtained, for example, by subjecting a compound of the general formula [Ic] wherein R ^3a is a lower alkylthio group or a salt thereof to formamidation. Specific methods for introducing a lower alkylthio group and formamidating include, for example, the method described in JP-A-58-38288 or a method analogous thereto.

Moreover, the general formula R ⁴ is a carboxyl group [I a], [I
b] and [Compound of I c], the general formula is a carboxyl group which R ⁴ is a protected [I a], [I b] and [I c]
Can be obtained by subjecting each compound to a conventional elimination reaction of a carboxyl protecting group.

The compound of the present invention thus obtained is, for example,
Esterification, hydrolysis, addition, acylation, oxidation, reduction,
Other compounds of the present invention can also be derived by appropriately combining commonly known reactions such as cyclization, halogenation, alkylation, amidation, alkylidation or Wittig reaction. Specific examples of these methods include, for example, Lucian Chemical Review (Russian Chemical Review).
s. Chem. Revs.), Vol. 33, pp. 66-77 (1964), or a method analogous thereto.

The compound of the general formula [Ia] or a salt thereof in the above-mentioned production method; the compound of the general formula [II]; A carboxylic acid of the general formula [III] or [VI] or a reactive derivative thereof; and a compound of the general formula [VII] or a reactive derivative thereof, as isomers (eg, optical isomers, geometric isomers,
When tautomers are present, all these isomers can be used and all crystal forms, hydrates and solvates can be used.

The thus-obtained compound of the general formula [I] of the present invention or a salt thereof can be isolated and purified according to a conventional method such as extraction, crystallization, distillation and column chromatography.

Next, a method for producing a compound of the general formula [II], which is a raw material for producing the compound of the present invention; and a compound of the general formula [IV] or a salt thereof or a reaction derivative at an amino group thereof will be described.

The compound of the general formula [IV] or a salt thereof or a reactive derivative at the amino group thereof can be prepared by a method known per se, for example, Tetrahedron Lett.
t.) It can be obtained by the method described on pages 375 to 378 and 4917 to 4920 (1972) or a method analogous thereto.

Further, the compound of the general formula [II] can be obtained by a known method or an appropriate combination thereof. For example, it can be produced according to the following production route.

Wherein R ² , R ³ , R ^1a CO—, R ^4a , X ¹ and n each have the same meaning as described above; ^Ra is an amino group, a formula
_-NHR ⁵ or Wherein R ⁵ and R ⁶ have the same meanings as described above, respectively. (Wherein, R ⁷ and R ⁸ have the same meanings as described above, respectively); and X ² means the same leaving group as described for X ¹ . The general formulas [IX], [X], [XI], [XII] and [XII
Examples of the salt of the compound of the formula [I] include the same salts as described for the compound of the formula [I].

Examples of the reactive derivative at the amino group of the compound of the general formula [XIII] or a salt thereof include the same reactive derivative at the amino group as described for the compound of the general formula [Ib] or [IV] or a salt thereof. Is mentioned.

Next, a method for producing the compound of the general formula [II] will be described in more detail according to the aforementioned production route.

The reaction with the carboxylic acid of the general formula [III] or a reactive derivative thereof and the reaction such as deacylation in the above-mentioned production route are the same as those described in the above-mentioned production methods (2) and (3) (i). The method can be implemented.

The compound of the general formula [II] can be obtained by reacting a compound of the general formula [XII] or a salt thereof with a halogenating agent, a sulfonylating agent or an acylating agent in the presence or absence of a base. .

This reaction is preferably carried out under anhydrous conditions, and the solvent used is not particularly limited as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as tetrahydrofuran; nitriles such as acetonitrile; and solvents such as amides such as N, N-dimethylformamide and N, N-dimethylacetamide. These solvents may be used alone or in combination of two or more. May be used.

Further, as the halogenating agent used in this reaction,
For example, thionyl halides such as thionyl chloride or thionyl bromide; sulfonylating agents include, for example, arylsulfonyl chlorides such as lower alkanesulfonyl chloride such as methanesulfonyl chloride or p-toluenesulfonyl chloride; Examples thereof include acid anhydrides such as acetic anhydride and acid chlorides such as acetyl chloride and benzoyl chloride.

Examples of the base used as necessary in this reaction include the same inorganic or organic bases as described in the above-mentioned production method (1).

The amounts of the halogenating agent, the sulfonylating agent, the acylating agent, and the base used if necessary are represented by the general formula [XI
With respect to the compound of the formula I] or a salt thereof, respectively.
The molar ratio is 1.0 times, preferably 1.0 to 1.2 times.

The reaction temperature and reaction time are not particularly limited, but are usually -30 ° C to 50 ° C, preferably 0 to 30 ° C,
It may be carried out for a minute to one hour.

The compounds of the general formulas [IX], [XI] and [XII] and salts thereof can be produced, for example, according to the method described in JP-A-63-183588 or a method analogous thereto.

Further, the compound of the general formula [IIa] is subjected to a commonly known method such as elimination or reduction of an amino protecting group, whereby the group corresponding to ^Ra is an amino group. a] wherein R is an amino group;
I]).

In each of the production routes described above, a compound having a hydroxyl group, an amino group, or a carboxyl group is
These hydroxyl group, amino group or carboxyl group may be protected with a usual protecting group in advance, and after the reaction, if necessary, these protecting groups may be eliminated by a method known per se.

Further, the general formula [IX] in the above-mentioned production method,
In the compounds of the formulas [X], [XI] and [XII] or their salts and the compounds of the general formula [XIII] or their salts or their reactive derivatives at the amino group, isomers (eg, optical isomers, geometric isomers) , Tautomers, etc.), all these isomers can be used and all crystal forms, hydrates and solvates can be used.

The thus obtained general formulas [IX], [XI], [XI]
The compounds of [I] and [XIII] may be used in the next reaction without isolation.

When the compound of the present invention is used as a medicament, excipients usually used in the preparation of pharmaceutical preparations, and formulation auxiliaries such as ordinary pharmaceutical carriers may be appropriately mixed. Capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions, solutions, powders, suppositories, ointments or subcutaneous, intramuscular, intravenous or drip injection forms It can be administered orally or parenterally.

The method of administration of the compound of the present invention, the dose and the number of administration,
It can be appropriately selected according to the age, weight and condition of the patient, and is usually administered to an adult orally or parenterally (eg, by injection, infusion, administration to a rectal site, etc.) at a rate of 1 per day. 250250 mg / kg may be administered in one to several divided doses.

Next, the antibacterial action of the representative compound of the present invention will be described.

1. Antimicrobial activity test method Standard method of the Japanese Society of Chemotherapy [Chemothera
py) Vol. 29, No. 1, pp. 76-79 (1981)]
Peptone broth (Eiken Chemical Co., Ltd.)
At 37 ° C. for 20 hours, and a platinum loop of the bacterial solution adjusted to a cell count of 10 ⁸ cells / m was added to a Heart Infusion agar medium containing a drug (manufactured by Eiken Chemical Co., Ltd.). And incubated at 37 ° C for 20 hours.Then, observe the presence or absence of bacterial growth.
C (μg / m).

 Table 2 shows the results.

The following symbols used in Table 1 of the test compounds have the following meanings.

Ac; acetyl group, Me; methyl group, Et; ethyl group Also, R ^1a and R in Table 1 of the test compound
Each represents a substituent of the following formula.

* Indicates a β-lactamase producing bacterium.

Control compound; (3R, 5R, 6R) -3-carboxy-6- [D-α- (4-
Ethyl-2,3-dioxo-1-piperazinecarboxamide) -α-phenylacetamide] -3- (3-methyl-
2-oxoimidazolidin-1-yl) -7-oxo-
Sodium salt of 4-thia-1-azabicyclo [3.2.0] heptane (JP-A-63-183588, Example 9, compound No. 72) From the above test results, the compound of the present invention is an excellent antibacterial agent. It can be understood that it exerts its activity.

[Effects of the Invention] Therefore, it is clear that the compound of the present invention is a very useful compound as an antibacterial agent.

[Examples] Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

The carrier in the column chromatography was Kieselgel 60, Art 7334 (Kieselgel60, Art.7734).
(Merck); LC-SORB SP-B-ODS (Chemco) as a carrier in reverse phase column chromatography;
Amberlite IR-120B (manufactured by Rohm and Haas) was used as a carrier for ion exchange chromatography.
Further, all mixing ratios in the mixed solvent are volume ratios.

Further, symbols used in Reference Examples and Examples are
Each has the following meaning.

Me; methyl group, Et; ethyl group, n-Pr; n-propyl group,
Ac; acetyl group, Ph; phenyl group, Bzl; benzyl group, PNB;
p-nitrobenzyl group, PMB; p-methoxybenzyl group, DP
M; diphenylmethyl group The wave number of IR indicates absorption of carbonyl.

Reference Example 3, Examples 5, 13, 24, 26, 35, 36, 39
D and L at ~ 45 and 48 are estimates.

Reference Example 1 The following production route: Wherein R and n each have the same meaning as described above; R ¹⁴ represents the same carboxyl protecting group as described for R ⁴ . According to the method described in -183588, the compounds shown in Table 3 are obtained.

Note that R and R ¹⁴ in Table 3 each represent a substituent of the following formula, and n is, as shown in Table 3,
Means 1 or 2.

Reference Example 2 (2-chloro-4,5-diacetoxyphenyl) acetic acid 15 g
Is dissolved in 75 m of methylene chloride. To this solution, 9.67 g of a sulfur trioxide-dioxane complex is added under ice cooling, and the mixture is stirred at room temperature for 12 hours. Ethanol was added to the reaction mixture under ice cooling.
225 m and an aqueous solution containing sodium acetate trihydrate (16.38 g) (18.75 m) were added. The resulting mixture was stirred at room temperature for 1 hour, and then ethanol (150 m) was added.
Stir for hours. Then, the mixture is cooled to 5 to 10 ° C., and the precipitated crystals are collected and dried. The crude crystals of disodium salt of DL-α- (2-chloro-4,5-diacetoxyphenyl) -α-sulfoacetic acid are obtained. obtain. Next, the obtained crude crystals are suspended in 155 m of methanol, and after this suspension is stirred at room temperature for 10 minutes, insolubles are removed. 15.5 m of an aqueous solution containing 10.24 g of sodium acetate trihydrate is added to the liquid, and the resulting mixture is stirred at 30 ° C. for 8 hours. The precipitated crystals are collected, washed with 16m of methanol, and then dried under reduced pressure to obtain DL-α-.
There are obtained 11.10 g (yield 65.0%) of the disodium salt of (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetic acid.

IR (KBr) cm ^-1 ; 1610,1580 Reference Example 3 (1) 50 g of disodium salt of DL-α- (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetic acid was added to 400 m of water.
After dissolving in an ion exchange resin (Amberlite IR
-120B: H ⁺ type) and adjust to pH 2.1. Then, the resin is washed twice with 100 m of water after passing through the ion exchange resin. Combine the washing solution and the previously obtained solution, and add this to cinchonidine.
Add 40.1 g at 90-95 ° C over 30 minutes, stir at the same temperature for 3 hours, and then stand at room temperature overnight. Remove the precipitated crystals,
After sequentially washing with water and acetone, it is dried under reduced pressure. The obtained crystals were suspended in 300m of ethanol, and then dissolved by heating.
And leave at room temperature overnight. The precipitated crystals are collected, washed sequentially with water and acetone, and then dried under reduced pressure to obtain α.
-(2-chloro-4,5-dihydroxyphenyl) -α-
51.2 g (38.8% yield) of the disinconidine salt of sulfoacetic acid are obtained.

IR (KBr) cm ^-1 ; 1655,1590,1570 (2) A mixed solvent of 20.0 g of α- (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetic acid disinconidine salt in 40 m of ethanol and 40 m of chloroform To dissolve. The obtained solution is added to a mixed solvent of 30 m of an aqueous solution containing 4.60 g of potassium hydrogen carbonate and 40 m of chloroform, and the mixture is stirred at room temperature for 1.5 hours, and then the aqueous layer is separated. After washing the separated aqueous layer twice with chloroform 40 m each,
Add ion exchange resin (Amberlite IR-120B; H ⁺ type) and adjust to pH2. Next, the resin is passed through an ion exchange resin and washed with 30 m of water. The washings and the previously obtained liquid are combined and concentrated under reduced pressure to about 30 m. After the obtained residue is subjected to ion exchange column chromatography (H ⁺ type, elution solvent: water), the eluate is concentrated under reduced pressure. The obtained residue is acetonitrile 20m
And 8.48 m of tri-n-butylamine was added dropwise to the solution under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The precipitated crystals are collected, washed with acetonitrile and diethyl ether, and dried under reduced pressure to give D-α- (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetic acid ditri-n-butylamine. 10.2 g (67.7% yield) of the salt are obtained.

IR (KBr) cm ^-1 ; 1605 ▲ [α] ²⁰ _D ▼ -3.5 ゜ (C = 3.0, methanol) Reference Example 4 DL-α- (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetic acid 4.0 g of the disodium salt was subjected to ion exchange column chromatography (H ⁺ type, elution solvent: water), and the eluate was concentrated under reduced pressure. The obtained residue is dissolved in 20 m of acetonitrile, and 5.72 m of tri-n-butylamine is added dropwise to this solution under ice cooling, followed by stirring at the same temperature for 30 minutes. The precipitated crystals are collected, washed with acetonitrile and diethyl ether, and then dried under reduced pressure to obtain DL-α- (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetic acid ditri-n-butylamine. Salt 5.
0 g (62.5% yield) are obtained.

IR (KBr) cm ^-1 ; 1610 Example 1 (3R, 4R) -4- [1- (3-benzylideneamino-
2-oxoimidazolidin-1-yl) -1- (p-nitrobenzyloxycarbonyl) methylthio] -1-hydroxymethyl-3-phenylacetamidoazetidine-
30.00 g of 2-one is dissolved in 420 m of anhydrous tetrahydrofuran. To this solution, 6.72 m of 2,6-lutidine and 3.95 m of thionyl chloride are sequentially added under ice-cooling, and the mixture is stirred at room temperature for 10 minutes, and the insoluble matter is removed. The solvent is distilled off under reduced pressure,
The residue obtained is dissolved in 600 m of anhydrous tetrahydrofuran. To this solution, add N, O-bis (trimethylsilyl)
After adding 13.6 m of acetamide and stirring at room temperature for 15 minutes,
Cool to -60 ° C. 40.4 m of hexamethylphosphoric triamide and a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (0.8 mmol / m
) 69.6m is added in sequence at -40 ° C or lower, and after raising the temperature to -15 ° C over 1 hour, 3.16m of acetic acid is added to the reaction mixture while maintaining the temperature at -15 ° C. 500m of the resulting mixture in water
Then, the mixture is introduced into a mixed solvent of 500 m2 and ethyl acetate, adjusted to pH 2.0 with 6N hydrochloric acid, and then the organic layer is separated. The separated organic layer is washed with dilute hydrochloric acid of pH 2.0, then, 200 m of water is added, and the pH is adjusted to 7.0 with an aqueous solution of sodium hydrogen carbonate, and then the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: n-hexane; ethyl acetate = 1: 1 to 2: 1) to give (3R, 5R, 6R)- 3-
(3-benzylideneamino-2-oxoimidazolidin-1-yl) -3- (p-nitrobenzyloxycarbonyl) -7-oxo-6-phenylacetamide-4-thia-1-azabicyclo [3.2.0 13.32 g of heptane (yield 45.
7%).

IR (KBr) cm ^-1 ; 1780, 1720, 1660 Similarly, the compounds shown in Table 4 are obtained.

Note that R and R ¹⁴ in Table 4 each represent a substituent of the following formula, and n is, as shown in Table 4,
Means 1 or 2.

Example 2 (3R, 5R, 6R) -3- (3-benzylideneamino-2-
Oxoimidazolidin-1-yl) -3- (p-nitrobenzyloxycarbonyl) -7-oxo-6-phenylacetamide-4-thia-1-azabicyclo [3.2.0]
Dissolve 6.6 g of heptane in 132 m of methylene chloride, and
Cool. To this solution, N, N-dimethylaniline 4.66m
And 3.3 g of phosphorus pentachloride are sequentially added, and the mixture is stirred at -40 to -20 ° C for 1 hour, and then cooled to -60 ° C. 13.8 m of anhydrous methanol is added to the reaction mixture, the temperature is raised to 0 ° C. over 30 minutes, and 66 m of water is added to the reaction mixture. The resulting mixture is stirred under ice-cooling for 15 minutes, and the precipitated crystals are collected. The obtained precipitated crystals are 50 m in water and 100 m in methylene chloride.
And then adjusted to pH 7.5 with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer is separated. After the separated organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain (3R, 5R, 6R) -6-amino-3-
(3-benzylideneamino-2-oxoimidazolidin-1-yl) -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.
2.0] 4.5 g heptane (84.0% yield) are obtained.

IR (KBr) cm ^-1 ; 1770, 1720 Similarly, the compounds shown in Table 5 are obtained.

Incidentally, R and R ¹⁴ in Table 5 show respectively a substituent of the formula.

Example 3 (1) (3R, 5R, 6R) -6-amino-3- (3-benzylideneamino-2-oxoimidazolidin-1-yl)
-3- (p-Nitrobenzyloxycarbonyl) -7-
13.2 g of oxo-4-thia-1-azabicyclo [3.2.0] heptane is dissolved in a mixed solvent of 200 m of methylene chloride and 70 m of methanol. To this solution was added 10.4 g of 2,4-dinitrophenylhydrazine and p-toluenesulfonic acid.
9.83 g of monohydrate are sequentially added and stirred at room temperature for 1.5 hours. The insolubles are separated, and the insolubles are washed with a mixed solvent of methylene chloride 60m and methanol 20m. The washing solution and the previously obtained solution are combined, 50 m of water is added thereto, and the aqueous layer is separated. On the other hand, add 30 m of water to the organic layer, and add
After adjusting to H1.2, separate the aqueous layer. Combine the separated aqueous layer and the previously obtained aqueous layer, and adjust the pH with sodium bicarbonate.
After adjusting to 7, add sodium chloride until saturation, then
Extract with 150m of methylene chloride. The aqueous layer is further extracted seven times with 50 m of methylene chloride each, combined with the organic layer obtained above, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (elution solvent; chloroform; methanol = 50: 1 to 1: 1).
5: 1), (3R, 5R, 6R) -6-amino-3-
(3-amino-2-oxoimidazolidin-1-yl)
-3- (p-Nitrobenzyloxycarbonyl) -7-
8.93 g (81.8% yield) of oxo-4-thia-1-azabicyclo [3.2.0] heptane are obtained.

IR (KBr) cm ^-1 ; 1775,1740,1700 NMR (CDCl ₃ / D ₂ O) δ value; 3.29 (1H, dd, J = 1 Hz, J = 13 Hz), 3.53 (4H, s), 4.54 (1H , dd, J = 1Hz, J = 4Hz), 4.88 (1H, d, J = 13Hz), 5.30 (2H, s), 5.45 (1H, d, J = 4Hz), 7.56 (2H, d, J = 9Hz) ), 8.24 (2H, d, J = 9 Hz) Similarly, (3R, 5R, 6R) -6-amino-3- (3-
Amino-2-oxoimidazolidin-1-yl) -3-
(Diphenylmethyloxycarbonyl) -7-oxo-
4-Thia-1-azabicyclo [3.2.0] heptane is obtained.

IR (KBr) cm ^-1 ; 1775,1720,1700 (2) (3R, 5R, 6R) -6-amino-3- (3-amino-2-oxoimidazolidin-1-yl) -3- (p −
Nitrobenzyloxycarbonyl) -7-oxo-4-
5.00 g of thia-1-azabicyclo [3.2.0] ethane is added to 30 m of water.
And methanol (30 m), and 2.96 m of concentrated hydrochloric acid is added to the suspension under cooling with water to dissolve the suspension. To the resulting solution, 1.36 g of sodium cyanate is added over 10 minutes, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is passed, 50 m of ethyl acetate and 50 m of water are added to the liquid, and the aqueous layer is separated. On the other hand, the organic layer was extracted three times with 30 m of water each time, combined with the previously obtained aqueous layer, and extracted with sodium hydrogen carbonate.
After adjusting to pH 6.9, the solvent is distilled off under reduced pressure. The obtained residue is azeotropically dehydrated four times with ethanol, and a mixed solvent of methylene chloride (50 m) and methanol (10 m) is added to the obtained residue to remove insolubles. Concentrate the solution under reduced pressure,
If the obtained residue is purified by column chromatography (elution solvent; chloroform: methanol = 10: 1 to 5: 1), (3R, 5R, 6R) -6-amino-3- (p-nitrobenzyloxy) Carbonyl) -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-
4.29 g of thia-1-azabicyclo [3.2.0] heptane (yield
77.9%).

IR (KBr) cm ^-1 ; 1775, 1720, 1680 NMR (d ₆ -DMSO / D ₂ O) δ value; 3.15 to 3.80 (5H, m), 4.57 (1H, d, J = 4 Hz), 4.59 (1H , d, J = 13Hz), 5.27 (2H, s), 5.48 (1H, d, J = 4Hz), 7.65 (2H, d, J = 9Hz), 8.23 (2H, d, J = 9Hz) , (3R, 5R, 6R) -6-amino-3- (diphenylmethyloxycarbonyl) -7-oxo-3-
(2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane is obtained.

IR (KBr) cm ^-1 ; 1780, 1720, 1680 Similarly, in hydrous tetrahydrofuran,
(R, 5R, 6R) -6-methoxy-3- (p-nitrobenzyloxycarbonyl) -6- [DL-α- (p-nitrobenzyloxycarbonyl) -α-phenylacetamide]-
7-oxo-3- (2-oxo-3-ureidoimidazolidine-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane is obtained.

IR (KBr) cm ^-1 ; 1775,1720,1680 Example 4 (1) (3R, 5R, 6R) -3- {3- (2-furfurylideneamino) -2-oxoimidazolidin-1-yl} −
Dissolve 300 mg of 3- (p-nitrobenzyloxycarbonyl) -7-oxo-6-phenylacetamide-4-thia-1-azabicyclo [3.2.0] heptane in 8 m of methylene chloride and cool to -50 ° C. . To this solution, N, N-dimethylaniline 0.18m and phosphorus pentachloride 141mg were sequentially added,
After stirring at 40 to -20 ° C for 1 hour, the mixture is cooled to -60 ° C.
1.4 m of anhydrous methanol was added to the reaction mixture, and
After stirring at for 30 minutes, 5 m of water are added to the reaction mixture. The resulting mixture is stirred for 10 minutes under ice cooling, adjusted to pH 7.5 with a saturated aqueous sodium hydrogen carbonate solution, and then the organic layer is separated. The separated organic layer was washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate to obtain (3R, 5R,
6R) -6-amino-3- {3- (2-furfurylideneamino) -2-oxoimidazolidin-1-yl} -3-
A solution of (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane in methylene chloride is obtained.

(2) Meanwhile, 190 mg of D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) phenylacetic acid
Is dissolved in 13 m of methylene chloride. Under ice-cooling, a catalytic amount of N, N-dimethylformamide and oxalyl chloride 0.05m was added to this solution, and the resulting mixture was added at room temperature for 3 hours.
After stirring for 0 minutes, the reaction mixture is evaporated to dryness under reduced pressure,
D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) phenylacetic chloride is obtained. This is dissolved in methylene chloride (3 m) and added dropwise to the solution prepared in (1) at -30 to -20 ° C. This mixture is brought to the same temperature for 15 minutes.
The mixture is stirred for 20 minutes under ice-cooling, and further washed with water and saturated saline in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (elution solvent: chloroform: acetone = 9: 1 to 4: 1) to give (3R, 5R, 6
R) -6- [D-α- (4-ethyl-2,3-dioxo-1
-Piperazinecarboxamide) -α-phenylacetamide] -3- {3- (2-furfurylideneamino) -2-
Oxoimidazolidin-1-yl} -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-
260 mg of 1-azabicyclo [3.2.0] heptane (yield 66.8
%).

IR (KBr) cm ^-1 ; 1780, 1710, 1680 NMR (CDCl ₃ ) δ value; 1.25 (3H, t, J = 7 Hz), 3.28 (1H, d, J = 13 Hz), 3.30 to 4.30 (10H, m ), 4.57 (1H, d, J = 13Hz), 5.20 to 5.80 (5H, m), 6.49 (1H, dd, J = 2Hz, J = 3.5Hz), 6.73 (1H, d, J = 3.5Hz), 7.20 to 7.65 (9H, m), 7.97 (1H, d, J = 9.5Hz), 8.18 (2H, d, J = 9Hz), 9.95 (1H, d, J = 6Hz) Similarly, N, N'- Compounds shown in Table 6 were acylated in the presence of a condensing agent such as dicyclohexylcarbodiimide or with a mixed acid anhydride obtained by the action of ethyl chlorocarbonate or an acid chloride obtained by the action of oxalyl chloride. Get.

Incidentally, R ^1a in Table 6, R ¹⁴ and R are each a substituted group of the formula, also, n is as shown in Table 6, it refers to one or two.

Example 5 DL-α- (p-methoxybenzyloxycarbonyl)
-Α- [4- (p-methoxybenzyloxy) phenyl] acetic acid and (3R, 5R, 6R) -6-amino-3- [3- (1,
3-dithiolan-2-ylideneamino) -2-oxoimidazolidin-1-yl] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane Dehydration condensation using N-hydroxysuccinimide and N, N'-dicyclohexylcarbodiimide to give (3R, 5R, 6R) -3- [3-
(1,3-dithiolan-2-ylideneamino) -2-oxoimidazolidin-1-yl] -6- {DL-α- (p-
Methoxybenzyloxycarbonyl) -α- [4- (p
-Methoxybenzyloxy) phenyl] acetamide
3- (p-Nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane is obtained.

IR (KBr) cm ^-1 ; 1785, 1720, 1670 Similarly, the compounds shown in Table 7 are obtained.

Incidentally, R ^1a in Table -7, R ¹⁴ and R are each a substituent of the formula.

Example 6 (3R, 5R, 6R) -3- (3-benzylideneamino-2-
Oxoimidazolidin-1-yl) -3- (p-nitrobenzyloxycarbonyl) -7-oxo-6-phenylacetamide-4-thia-1-azabicyclo [3.2.0]
3.00 g of heptane was added to methylene chloride 30m and methanol 15
Dissolve in mixed solvent of m. 1.89 g of 2,4-dinitrophenylhydrazine and 850 mg of p-toluenesulfonic acid monohydrate are sequentially added to this solution, and the mixture is stirred at room temperature for 1.5 hours. Then, the insoluble matter is removed, and the solution is concentrated under reduced pressure. A mixed solvent of methylene chloride (30 m) and methanol (7 m) is added to the obtained residue to remove insolubles. The solution was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography (elution solvent: chloroform: methanol = 100: 1).
2525: 1), (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidin-1-yl) -3- (p
-Nitrobenzyloxycarbonyl) -7-oxo-6
-1.56 g (60.5% yield) of -phenylacetamide-4-thia-1-azabicyclo [3.2.0] heptane are obtained.

IR (KBr) cm ^-1 ; 1780, 1720, 1700, 1670 NMR (CDCl ₃ ) δ value; 3.30 (1H, d, J = 13 Hz), 3.48 (4H, s), 3.59 (2H, s), 4.69 ( 1H, d, J = 13Hz), 5.14 (2H,
s), 5.47 (1H, d, J = 4Hz), 5.66 (1H, dd, J = 4Hz, J = 8Hz), 6.66 (1H, d, J = 8Hz), 7.29 (5H, s), 7.49 (2H , d, J = 9 Hz), 8.23 (2H, d, J = 9 Hz) Similarly, the compounds shown in Table 8 are obtained.

Note that R ^1a and R ¹⁴ in Table-8 each represent a substituent of the following formula, and n is as shown in Table-8.
Means 1 or 2.

Example 7 In the same manner as in Example 6, (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidin-1-yl) -6-methoxy-3- (p-nitrobenzyloxycarbonyl )
-6- [DL-α- (p-nitrobenzyloxycarbonyl) -α-phenylacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane is obtained.

IR (KBr) cm ^-1 ; 1780,1740,1680 Example 8 (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidin-1-yl) -6- [DL-α- ( 4-ethyl-
2,3-dioxo-1-piperazinecarboxamide) -α
-Phenylacetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo- [3.2.0] heptane (500 mg) is dissolved in a mixed solvent of methylene chloride (5 m) and methanol (5 m). . To this solution are added 100 mg of 5-formyl-1,2,3-thiadiazole and a catalytic amount of p-toluenesulfonic acid monohydrate, and the mixture is stirred at room temperature overnight. Then, the solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (elution solvent: chloroform: acetone = 10: 1 to 4: 1) to obtain (3
R, 5R, 6R) -6- [D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α-phenylacetamide] -3- (p-nitrobenzyloxycarbonyl)- 7-oxo-3- [2-oxo-3- (1,2,3-
Thiadiazol-5-ylmethylideneamino) imidazolidin-1-yl] -4-thia-1-azabicyclo-
[3.2.0] 400 mg of heptane (70.7% yield) is obtained.

IR (KBr) cm ^-1 ; 1780, 1710, 1670 NMR (CDCl ₃ ) δ value; 1.25 (3H, t, J = 7 Hz), 3.32 (1H, d, J = 13 Hz), 3.20 to 4.30 (10H, m ), 4.63 (1H, d, J = 13 Hz), 5.26 (2H, s), 5.20 to 5.80 (3H, m), 7.37 (5H, s), 7.52 (2H, d, J = 9 Hz), 7.78 (1H , d, J = 9Hz), 7.92 (1H, s), 8.16 (2H, d, J = 9Hz), 8.79 (1H,
s), 9.95 (1H, d, J = 6 Hz) Similarly, the compounds shown in Table 9 are obtained.

Note that R ^1a , R ¹⁴ and R in Table 9 each represent a substituent represented by the following formula, and n means 1 or 2, as shown in Table 9.

Example 9 (3R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -6- {DL-α- (p-methoxybenzyloxycarbonyl) -α- [4- (P-methoxybenzyloxy) phenyl] acetamide} -3- (p
-Nitrobenzyloxycarbonyl) -7-oxo-4
Dissolve 300 mg of thia-1-azabicyclo [3.2.0] heptane in 7 m of methylene chloride. 0.035 m of methanesulfonyl chloride, 0.042 m of pyridine and a catalytic amount of 4- (N, N-dimethylamino) pyridine are added to this solution, and the mixture is stirred at room temperature for 3 days. After adding 5 m of water to the reaction mixture and adjusting the pH to 1.5 with 1N hydrochloric acid, the organic layer is separated. 5 m of water is added to the separated organic layer, and a saturated aqueous solution of sodium hydrogen carbonate is used.
After adjusting to pH 7.5, the organic layer is separated. After the separated organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (elution solvent; benzene: ethyl acetate = 10: 1 to 3: 2). Purification by (3R, 5R, 6R) -3- (3-methanesulfonylamino-2-oxoimidazolidin-1-yl) -6
-{DL-α- (p-methoxybenzyloxycarbonyl) -α- [4- (p-methoxybenzyloxy) phenyl] acetamide} -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia 250 mg (76.2% yield) of -1-azabicyclo [3.2.0] heptane are obtained.

IR (KBr) cm ^-1 ; 1785, 1720, 1670 Similarly, using the reactants shown in Table 10, the compounds shown in Table 10 are obtained.

Note that R ^1a , R ¹⁴ and R in Table 10 each represent a substituent of the following formula.

Example 10 (3R, 5R, 6R) -3- [3- (2-Chloroethylideneamino) -2-oxoimidazolidin-1-yl] -6
[D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (p-hydroxyphenyl) acetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4- 390 mg of thia-1-azabicyclo [3.2.0] heptane was added to N, N-dimethylformamide 5
Dissolve in m. To this solution was added 5-mercapto-1,2,3-
Thiadiazole sodium salt (70 mg) and a catalytic amount of sodium iodide are sequentially added, and the mixture is stirred at room temperature overnight.
The reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: acetone = 5: 1 to 1: 1) to give (3R, 5R, 6R) -6- [ D
-Α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (p-hydroxyphenyl) acetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia- 3- {3- [2- (1,2,
3-Thiadiazol-5-ylthio) ethylideneamino] -2-oxoimidazolidin-1-yl｝ -1-azabicyclo [3.2.0] heptane 190 mg (44.8% yield) is obtained.

IR (KBr) cm ^-1 ; 1780, 1710, 1670 Similarly, the compounds shown in Table 11 are obtained.

Incidentally, R ^1a and R in Table -11, respectively, a substituent of the formula.

Example 11 (3R, 5R, 6R) -6- [D-α- (4-ethyl-2,3-
Dioxo-1-piperazinecarboxamide) -α-phenylacetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-3- (2-oxo-3-propynylideneaminoimidazolidin-1-yl ) 4-Thia-1-azabicyclo [3.2.0] heptane (400 mg) is dissolved in a mixed solvent of methylene chloride (5 m) and methanol (5 m). To this solution are added 110 mg of sodium salt of 5-mercapto-1,2,3-thiadiazole and 198 mg of pyridine salt of p-toluenesulfonic acid, and the mixture is stirred at room temperature for 2 days. 10 m of water and 10 m of methylene chloride are added to the reaction mixture, the pH is adjusted to 7.0 with a saturated aqueous solution of sodium hydrogen carbonate, and then the organic layer is separated. Add 10m of water to the separated organic layer, and add 2N
After adjusting the pH to 2.0 with hydrochloric acid, the organic layer is separated. After treating the separated organic layer with activated carbon, the solvent was distilled off under reduced pressure,
If the obtained residue is purified by column chromatography (elution solvent; chloroform: acetone = 20: 1 to 3: 2), (3R, 5R, 6R) -6- [D-α- (4-ethyl −2,3
-Dioxo-1-piperazinecarboxamide) -α-phenylacetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-3- {2-oxo-3-
[3- (1,2,3-thiadiazol-5-ylthio) arylideneamino] imidazolidin-1-yl} -4-thia-1-azabicyclo [3.2.0] heptane (mixture of cis and trans) 290 mg ( Yield 63.6%).

IR (KBr) cm ^-1 ; 1780, 1710, 1675 Similarly, the compounds shown in Table 12 are obtained.

Note that R ^1a and R in Table 12 each represent a substituent of the following formula.

Example 12 (3R, 5R, 6R) -6- [D-α- (4-ethyl-2,3-
Dioxo-1-piperazinecarboxamide) -α-phenylacetamide] -3- {3- (2-furfurylideneamino) -2-oxoimidazolidin-1-yl} -3-
220 mg of (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane
And 200 mg of 5% palladium-carbon were added to a mixed solvent of 5 m of ethyl acetate and 5 m of water.
After stirring for an hour, the insoluble matter is removed. The solution is adjusted to pH 6.5 with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer is separated. If the separated aqueous layer is freeze-dried, (3R, 5R, 6R)-
3-carboxy-6- [D-α- (4-ethyl-2,3-
Dioxo-1-piperazinecarboxamide) -α-phenylacetamide] -3- {3- (2-furfurylideneamino) -2-oxoimidazolidin-1-yl} -7-
50 mg (yield 26.5%) of the sodium salt of oxo-4-thia-1-azabicyclo [3.2.0] heptane are obtained.

IR (KBr) cm ^-1 ; 1770,1710,1670,1620 NMR (D ₂ O) δ value; 1.17 (3H, t, J = 7 Hz), 3.20 to 4.20 (11H, m), 5.40 (1H, d, J = 4Hz), 5.48 (1H, s), 5.54 (1H, d, J = 4Hz), 6.58 (1H, dd, J = 2Hz, J = 3Hz), 6.80 (1H, d, J = 3Hz), 7.48 (5H, s), 7.40-7.70 (2H, m) Similarly, the compounds shown in Table 13 are obtained.

Incidentally, R ^1a in Table-13 R ¹⁵ and R ^a are each represents a substituent of the formula, also, n is as shown in Table-13 means 1 or 2.

The compound in which R ¹⁵ is a hydrogen atom, after the completion of hydrogenation, removes insolubles, adds a mixed solvent of ethyl acetate and tetrahydrofuran to the solution, adjusts the pH to 2.0 with 1N hydrochloric acid, and then removes the organic layer. After separating, the obtained organic layer is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off.

Example 13 In the same manner as in Example 12, the compounds shown in Table 14 are obtained.

Incidentally, R ^a and R ^1a in Table-14, respectively, a substituent of the formula.

Example 14 In the same manner as in Example 12, (3R, 5R, 6R) -3-carboxy-6- [DL-α-carboxy-α-phenylacetamide] -6-methoxy-7-oxo-3- (2-oxo-
3-ureidoimidazolidin-1-yl) -4-thia-
1-Azabicyclo [3.2.0] heptane disodium salt is obtained.

IR (KBr) cm ^-1 ; 1770,1670,1600 Example 15 (1) (3R, 5R, 6R) -3- (diphenylmethyloxycarbonyl) -6- [D-α- (4-ethyl-2, 3-dioxo-1-piperazinecarboxamide) -α-phenylacetamide] -3- [3- (4-nitrobenzylideneamino) -2-oxoimidazolidin-1-yl] -7
-Oxo-4-thia-1-azabicyclo [3.2.0] heptane (210 mg) is dissolved in a mixed solvent of methylene chloride (1 m) and anisole (1 m), and cooled to -30 ° C.

(2) On the other hand, 95 mg of anhydrous aluminum chloride
1m and dissolve this solution in the solution prepared in (1),
Add at -30 ° C. After stirring this mixture at −20 ° C. for 20 minutes, the reaction mixture was introduced into a mixed solvent of 10 m of tetrahydrofuran, 20 m of ethyl acetate and 10 m of water, and the pH was adjusted with 1N hydrochloric acid.
After adjusting to 1.0, the insolubles are removed and the organic layer is separated. 10 m of water is added to the separated organic layer, and the pH is adjusted to 6.5 with a saturated aqueous solution of sodium hydrogen carbonate, and then the aqueous layer is separated. If the separated aqueous layer is freeze-dried, (3R, 5R, 6R) -3
-Carboxy-6- [D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α-phenylacetamide] -3- [3- (4-nitrobenzylideneamino) -2- Oxoimidazolidin-1-yl] -7
120 mg (72.5% yield) of the sodium salt of -oxo-4-thia-1-azabicyclo [3.2.0] heptane are obtained.

IR (KBr) cm ^-1 ; 1770, 1710, 1675, 1615 Similarly, the compounds shown in Table 15 are obtained.

Note that R ^1a , R ¹⁵ and R in Table 15 each represent a substituent of the following formula.

Example 16 (1) (3R, 5R, 6R) -3- (3-acetylamino-2)
-Oxoimidazolidin-1-yl) -6- {DL-α-
(P-methoxybenzyloxycarbonyl) -α- [4
-(P-methoxybenzyloxy) phenyl] acetamide {-3- (p-nitrobenzyloxycarbonyl)-
Dissolve 300 mg of 7-oxo-4-thia-1-azabicyclo [3.2.0] heptane in 6 m of methylene chloride and cool to -30 ° C. After 2 m of an anisole solution containing 280 mg of anhydrous aluminum chloride is added dropwise to this solution while maintaining the temperature at -20 ° C or lower, the mixture is stirred at -10 to 0 ° C for 30 minutes. The reaction mixture was treated with water 10m, ethyl acetate 15m and tetrahydrofuran 10
m, and adjusted to pH 1.0 with 2N hydrochloric acid.
Separate the organic layer. Add 10m of water to the separated organic layer,
After adjusting the pH to 7.5 with saturated aqueous sodium bicarbonate,
Separate the aqueous layer. 15 m of ethyl acetate and 10 m of tetrahydrofuran are added to the separated aqueous layer, the pH is adjusted to 1.0 with 2N hydrochloric acid, and then the organic layer is separated. After the separated organic layer was washed with saturated saline, it was dried over anhydrous magnesium sulfate,
By evaporating the solvent under reduced pressure, (3R, 5R, 6R) -3- (3-
Acetylamino-2-oxoimidazolidin-1-yl) -6- [DL-α-carboxy-α- (p-hydroxyphenyl) acetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4 160 mg of thia-1-azabicyclo [3.2.0] heptane are obtained.

(2) (3R, 5R, 6R) -3- (3-acetylamino-2
-Oxoimidazolidin-1-yl) -6- [DL-α-
Carboxy-α- (p-hydroxyphenyl) acetamide] -3- (p-nitrobenzyloxycarbonyl)-
160 mg of 7-oxo-4-thia-1-azabicyclo [3.2.0] heptane is dissolved in a mixed solvent of 3 m of water, 3 m of methanol and 3 m of tetrahydrofuran. 5 in this solution
After adding 150 mg of palladium-carbon and stirring at room temperature for 2 hours under a hydrogen atmosphere, insoluble materials are removed. The solution was concentrated under reduced pressure, and the obtained residue was combined with 5 m of water and 10 ml of ethyl acetate.
After adding m and adjusting the pH to 6.5 with a saturated aqueous sodium hydrogen carbonate solution, the aqueous layer is separated. The separated aqueous layer is purified by reverse phase column chromatography (elution solvent: water), and then lyophilized to give (3R, 5R, 6R) -3- (3-acetylamino-2-oxoimidazolidin-1. -Yl) -3-carboxy-6- [DL-α-carboxy-α- (p-hydroxyphenyl) acetamide] -7-oxo-4-thia-
Disodium salt of 1-azabicyclo [3.2.0] heptane 1
20 mg (64.2% yield) are obtained.

IR (KBr) cm ^-1 ; 1770, 1710, 1650, 1600 Similarly, the compounds shown in Table 16 are obtained.

Note that R ^1a and R in Table 16 each represent a substituent of the following formula.

Example 17 (1) (3R, 5R, 6R) -3- (3-acetylamino-2)
-Oxoimidazolidin-1-yl) -6- {DL-α-
(P-methoxybenzyloxycarbonyl) -α- [4
-(P-methoxybenzyloxy) phenyl] acetamide {-3- (p-nitrobenzyloxycarbonyl)-
Instead of 7-oxo-4-thia-1-azabicyclo [3.2.0] heptane, (3R, 5R, 6R) -3- (3-amino-
2-oxoimidazolidin-1-yl) -6- {DL-α
-(P-methoxybenzyloxycarbonyl) -α-
[4- (p-methoxybenzyloxy) phenyl] acetamide} -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.
0] Using heptane, in the same manner as in Example 16 (1),
(3R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -6- [DL-α-carboxy-α-
(P-Hydroxyphenyl) acetamide] -3- (p-
Nitrobenzyloxycarbonyl) -7-oxo-4-
Thia-1-azabicyclo [3.2.0] heptane is obtained.

IR (KBr) cm ^-1 ; 1780,1720,1670 (2) (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidin-1-yl) -6- [DL-α-carboxy -Α- (p-hydroxyphenyl) acetamide] -3
-(P-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane 250
mg is dissolved in 3m of N, N-dimethylformamide. 130 mg of sulfur trioxide-pyridine complex is added to this solution, and the mixture is stirred at room temperature for 1 day. The reaction mixture is maintained at pH 6.0-7.0 with saturated aqueous sodium bicarbonate solution and
Pour over a minute. The obtained reaction mixture was concentrated under reduced pressure, and the obtained residue was treated with 10 m of water and 1 ml of ethyl acetate.
After dissolving in a mixed solvent of 0 m and adjusting the pH to 2.0 with 1N hydrochloric acid, the aqueous layer is separated. The separated aqueous layer is adjusted to pH 6.0 with a saturated aqueous solution of sodium hydrogen carbonate, and then concentrated under reduced pressure. The obtained residue is purified by reverse-layer column chromatography (eluent: water) to give (3R, 5R, 6R) -6-
[DL-α-carboxy-α- (p-hydroxyphenyl) acetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-3- (2-oxo-3-sulfoaminoimidazolidin-1-yl ) -4-Thia-1-
Disodium salt of azabicyclo- [3.2.0] heptane 30m
g (yield 9.9%) are obtained.

IR (KBr) cm ^-1 ; 1780,1740,1655,1600 Example 18 (3R, 5R, 6R) -3- (p-nitrobenzyloxycarbonyl) -6- [DL-α- (p-nitrobenzyloxy) Carbonyl) -α-phenylacetamide] -7-oxo-3- [2-oxo-3- (4-sulfo-2-butenylideneamino) imidazolidin-1-yl] -4-thia-
1-azabicyclo [3.2.0] heptane 100 mg, iron powder 200 mg
And 200 mg of ammonium chloride in 2 m of tetrahydrofuran
Then, the mixture was added to a mixed solvent of 2 m of methanol and 2 m of water, stirred at room temperature for 6 hours, and insoluble materials were removed. The solution was concentrated under reduced pressure, and the obtained residue was combined with 5 m of ethyl acetate and water.
After adding 5 m and adjusting the pH to 6.0 with a saturated aqueous solution of sodium hydrogen carbonate, the aqueous layer is separated. If the separated aqueous layer is purified by reverse-layer column chromatography (elution solvent: water),
(3R, 5R, 6R) -3-carboxy-6- (DL-α-carboxy-α-phenylacetamide) -7-oxo-3-
Trisodium salt of [3- (4-sulfo-2-butenylideneamino) 2-oxoimidazolidin-1-yl] -4-thia-1-azabicyclo [3.2.0] heptane 30 mg (yield 39.5%) Get.

IR (KBr) cm ^-1 ; 1770,1710,1660,1600 Example 19 (3R, 5R, 6R) -3- [3- (2-chloroethylideneamino) -2-oxoimidazolidin-1-yl]- 6-
[D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (p-hydroxyphenyl) acetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4- 300 mg of thia-1-azabicyclo [3.2.0] heptane was added to N, N-dimethylformamide 5
Dissolve in m. 3 m of pyridine and a catalytic amount of sodium iodide are added to this solution, and the mixture is stirred at room temperature for 1 day, and the reaction mixture is dried under reduced pressure. The obtained residue was dissolved in a mixed solvent of 5 m of water, 5 m of methanol and 5 m of ethyl acetate.
g was added thereto, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere, and insoluble materials were removed. The solution is concentrated under reduced pressure, 20 m of water and 20 m of ethyl acetate are added to the obtained residue, the pH is adjusted to 7.0 with a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer is separated. The separated aqueous layer is purified by reverse layer column chromatography (elution solvent: water: acetonitrile = 9: 1 to 6: 1), and lyophilized to give (3R, 5R, 6R) -6- [D-α −
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (p-hydroxyphenyl) acetamide] -7-oxo-3- {2-oxo-3- [2- (1
-Pyridinium) ethylideneamino] imidazolidine-
67 mg of 1-yl} -4-thia-1-azabicyclo [3.2.0] heptane-3-carboxylate are obtained (yield 25.3%).

IR (KBr) cm ^-1 ; 1770, 1710, 1665, 1615 Similarly, the compounds shown in Table 17 are obtained.

Here, R ^1a and R in Table 17 each represent a substituent of the following formula.

Example 20 (1) 250 mg of p-acetoxyphenylacetic acid is dissolved in 5 m of methylene chloride. Under ice cooling, a catalytic amount of N,
N-dimethylformamide and oxalyl chloride 0.1
After adding 2 m and stirring at room temperature for 1 hour, the reaction mixture is concentrated under reduced pressure to obtain p-acetoxyphenylacetic acid chloride. This was dissolved in 5 m of methylene chloride, 260 mg of a sulfur trioxide-dioxane complex was added to the solution under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, DL-2- (p -Acetoxyphenyl) -2-sulfoacetic acid chloride is obtained. This is anhydrous tetrahydrofuran 5m
To dissolve.

(2) On the other hand, (3R, 5R, 6R) -6-amino-3- (p-
Nitrobenzyloxycarbonyl) -7-oxo-3-
(2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane 3
00 mg was dissolved in a mixed solvent of 5 m of tetrahydrofuran and 5 m of water, and DL-2- (p) prepared in (1) was added to this solution.
A solution of -acetoxyphenyl) -2-sulfoacetic acid chloride in tetrahydrofuran is added dropwise with ice-cooling while maintaining a pH of 7.0 to 7.5 with a saturated aqueous sodium hydrogen carbonate solution. After the dropwise addition, the mixture was stirred at the same temperature for 10 minutes, and ethyl acetate (5 m) was added.
After adjusting the pH to 6.0 with hydrochloric acid, the aqueous layer is separated. Water is distilled off under reduced pressure, and the obtained residue is purified by reverse phase column chromatography (elution solvent: water: acetonitrile = 1: 0 to 9: 1) to give (3R, 5R, 6R) -6. -[DL-α- (p-acetoxyphenyl) -α-sulfoacetamide] -3- (p
-Nitrobenzyloxycarbonyl) -7-oxo-3
340 mg (70.8% yield) of sodium salt of-(2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane are obtained.

IR (KBr) cm ^-1 ; 1775, 1720, 1670 Similarly, the compounds shown in Table 18 are obtained.

Note that R ^1a and R in Table 18 each represent a substituent of the following formula.

Example 21 (3R, 5R, 6R) -6-amino-3- (p-nitrobenzyloxycarbonyl) -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4- Instead of thia-1-azabicyclo [3.2.0] heptane, (3
(R, 5R) -6-amino-3- (3-benzylideneamino-
2-oxoimidazolidin-1-yl) -6-methoxy-3- (p-nitrobenzyloxycarbonyl) -7-
Using oxo-4-thia-1-azabicyclo [3.2.0] heptane, DL-α- (p-nitrobenzyloxycarbonyl) -α-phenylacetic acid was reacted in the same manner as in Example 20 to obtain (3R, 5R, 6R) -3- (3-benzylideneamino-
2-oxoimidazolidin-1-yl) -6-methoxy-3- (p-nitrobenzyloxycarbonyl) -6
[DL-α- (p-nitrobenzyloxycarbonyl)-
α-Phenylacetamide] -7-oxo-4-thia-1
Obtaining azabicyclo [3.2.0] heptane.

IR (KBr) cm ^-1 ; 1780,1740,1710,1690 Example 22 (3R, 5R, 6R) -6- [DL-α- (p-acetoxyphenyl) -α-sulfoacetamide] -3- (p- Nitrobenzyloxycarbonyl) -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-
330 mg of sodium salt of thia-1-azabicyclo [3.2.0] heptane and 150 mg of 5% palladium-carbon in 10 m of water
After stirring at room temperature under a hydrogen atmosphere for 2 hours, insoluble materials are removed. After adding 10 m of ethyl acetate to the liquid and adjusting the pH to 6.0 with a saturated aqueous solution of sodium hydrogencarbonate, the aqueous layer is separated. Water was distilled off under reduced pressure, and the obtained residue was purified by reversed-phase column chromatography (elution solvent: water) and freeze-dried to obtain (3R, 5R, 6R) -6- [DL-α −
(P-acetoxyphenyl) -α-sulfoacetamide]
-3-Carboxy-7-oxo-3- (2-oxo-3
-Ureidoimidazolidin-1-yl) -4-thia-1
-Disodium salt of azabicyclo [3.2.0] heptane 210
mg (47.1% yield).

IR (KBr) cm ^-1 ; 1760, 1710, 1670, 1610 Similarly, compounds shown in Table 19 are obtained.

Here, R ^1a and R in Table 19 each represent a substituent of the following formula.

Example 23 (3R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -3-carboxy-6- (DL-α
-Carboxy-α-phenylacetamide) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane, 200 mg, is dissolved in 5 m of water. 1 in this solution
0.5 M N hydrochloric acid and 31 mg of sodium cyanate were added, and the mixture was stirred at room temperature for 30 minutes.
After adjusting to 6.5, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by reversed-phase column chromatography (elution solvent: water) and lyophilized to give (3R, 5R, 6R)
-3-Carboxy-6- (DL-α-carboxy-α-phenylacetamide) -3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2. 0] 160 mg of disodium salt of heptane (yield 7
3.7%).

IR (KBr) cm ^-1 ; 1760, 1705, 1660, 1600 NMR (D ₂ O) δ value; 3.60 (4H, s), 5.48 to 5.64 (2H, m), 7.40 (5H, s) The compounds shown in Table 20 are obtained.

Incidentally, R ^1a in the table -20 indicates a substituent of the formula.

Example 24 In the same manner as in Example 23, the compounds in Table 21 are obtained.

Note that R and R ^1a in Table 21 each represent a substituent of the following formula.

Example 25 1,4-Dihydro-5-hydroxy-4-oxo-2-
53 mg of pyridinecarboxylic acid, 40 mg of N-hydroxysuccinimide and N, N'-dicyclohexylcarbodiimide 7
1 mg is dissolved in 2m of N, N-dimethylformamide and stirred at room temperature for 2 hours. (3R, 5R, 6R) -6 was added to the reaction mixture.
-(D-α-amino-α-phenylacetamide) -3-
Carboxy-3- [3- (1,3-dithiolan-2-ylideneamino) -2-oxoimidazolidin-1-yl]
-7-oxo-4-thia-1-azabicyclo [3.2.0]
Heptane (150 mg) and triethylamine (0.06 m) are sequentially added, and the mixture is stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was ethyl acetate 15m.
And 10 m of water, adjust the pH to 7.0 with a saturated aqueous solution of sodium hydrogen carbonate, and separate the aqueous layer. Water was distilled off under reduced pressure, and the obtained residue was purified by reversed-phase column chromatography (elution solvent; water: acetonitrile = 1: 0 to 9: 1), and then lyophilized to give (3R, 5R , 6R) -3- [3-
(1,3-Dithiolan-2-ylideneamino) -2-oxoimidazolidin-1-yl] -3-carboxy-6
{D-α-[(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) carboxamide] -α-phenylacetamide} -7-oxo-4-thia-1-azabicyclo [3.2. 0] 35 mg of sodium salt of heptane (yield 1
7.9%).

IR (KBr) cm ^-1 ; 1770, 1710, 1660, 1610 Similarly, the compounds shown in Table 22 are obtained.

Incidentally, R ^1a in the table -22 indicates a substituent of the formula.

Example 26 (3R, 5R, 6R) -6- [DL-α- (p-acetoxyphenyl) -α-sulfoacetamide] -3-carboxy-7
-Oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.
0] 100 mg of the disodium salt of heptane is dissolved in 20 m of water and the solution is treated with saturated aqueous sodium hydrogen carbonate solution to pH 6.8.
Adjust to To this solution was added 20 mg of esterase (Boehringer Mannheim) which had been desalted using a continuous countercurrent dialyzer (Zeineh dialyzer, Funakoshi) under ice-cooling. Stir at 35 ° C. for 4 hours while maintaining 6.86.8. The reaction mixture is ultrafiltered using a hollow fiber membrane (membrane type: HI, manufactured by Asahi Kasei Corporation). After adjusting the solution to pH 5.0 with 0.1 N hydrochloric acid, the solvent is distilled off under reduced pressure, and the obtained residue is purified by reverse-phase column chromatography (elution solvent: water) and then lyophilized. (3R, 5R, 6R) -3-carboxy-6- [DL-α-
(P-hydroxyphenyl) -α-sulfoacetamide]
62.5 mg of the disodium salt of -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane (yield 67.0)
%).

IR (KBr) cm ^-1 ; 1760, 1705, 1665, 1600 Similarly, the compounds in Table 23 are obtained.

Incidentally, R ^1a in the table -23 illustrate the following formula replacer.

Example 27 In the same manner as in Example 26, (3R, 5R, 6R) -3-carboxy-6- [D-α-2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetamide] -7-oxo -3-
This gives the disodium salt of (2-oxo-3-semicarbazonoethylideneaminoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane.

IR (KBr) cm ^-1 ; 1765,1720,1700,1670,1620 Example 28 (3R, 5R, 6R) -3- (3-benzylideneamino-2-
83.0 g of oxoimidazolidin-1-yl) -3-diphenylmethyloxycarbonyl-7-oxo-6-phenylacetamide-4-thia-1-azabicyclo [3.2.0] heptane was dissolved in 664 m of methylene chloride, Cool to -60 ° C. To this solution, N, N-dimethylaniline 55.8m and phosphorus pentachloride 39.3g are sequentially added, and it takes -30 ° C over 30 minutes.
After the temperature is raised to −60 ° C., it is cooled again. 66.3 m of anhydrous methanol was added to the reaction mixture, and the
Heat up to ° C. After stirring at the same temperature for 30 minutes, 664 m of ethyl acetate is added. The resulting mixture is stirred under ice-cooling for 15 minutes, and the precipitated crystals are collected. The obtained precipitate was washed twice with 83 m of methylene chloride and once with 83 m of ethyl acetate, and then dried under reduced pressure to obtain (3R, 5R, 6R) -6-
57.5 g of hydrochloride of amino-3- (3-benzylideneamino-2-oxoimidazolidin-1-yl) -3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane (79.0% yield).

IR (KBr) cm ^-1 ; 1790, 1720, 1705 Similarly, the compounds in Table 24 are obtained.

Note that R and R ¹⁴ in Table 24 each represent a substituent of the following formula.

Example 29 (1) (3R, 5R, 6R) -6-amino-3- (3-benzylideneamino-2-oxoimidazolidin-1-yl)
60.0 g of hydrochloride of -3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane was suspended in a mixed solvent of methylene chloride (450 m), anisole (63 m) and nitromethane (80 m). Cool to ° C.

(2) On the other hand, 31.8 g of anhydrous aluminum chloride is dissolved in 70 m of nitromethane, and this solution is added dropwise to the suspension prepared in the above (1) at −30 ° C., followed by stirring at −20 ° C. for 10 minutes. Next, the reaction mixture was introduced into 1.5N hydrochloric acid (1.2), and stirred at room temperature for 30 minutes.
Adjust to 1.5. The precipitate is removed and the precipitate is washed with water 2.4
After being suspended in, adjusted to pH 9.0 with concentrated aqueous ammonia,
Celite insolubles. The obtained liquid is ethyl acetate
After washing with 500 m, the pH is adjusted to 3.5 with 6N hydrochloric acid, and the mixture is stirred under ice-cooling for 15 minutes. Take the precipitated crystals and dry them,
(3R, 5R, 6R) -6-amino-3- (3-benzylideneamino-2-oxoimidazolidin-1-yl) -3-carboxy-7-oxo-4-thia-1-azabicyclo [3.
2.0] Heptane 36.0 g (92.0% yield) is obtained.

IR (KBr) cm ^-1 ; 1780, 1705, 1640 Similarly, the compounds in Table 25 are obtained.

 In addition, R in Table 25 shows the substituent of the following formula.

Example 30 (3R, 5R, 6R) -6-amino-3- (3-benzylideneamino-2-oxoimidazolidin-1-yl) -3-
Carboxy-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane 10.0 g was suspended in methanol 150 m, and 2,4-dinitrophenylhydrazine.
9.2 g of the hydrochloride are added at 20-25 ° C. and stirred at the same temperature for 3 hours. Then, after adding 100 m of water to the reaction mixture, the pH is adjusted to 8.0 with concentrated aqueous ammonia. The precipitated crystals are removed, concentrated hydrochloric acid is gradually added to the resulting solution to adjust the pH to 1.5, 2.5 g of activated carbon is added, and the mixture is stirred at room temperature for 5 minutes. Then, the activated carbon was removed, the activated carbon was washed with water, and the washing mixture and the previously obtained liquid were treated with 3.9 g of sodium cyanate at room temperature for 60 minutes while maintaining the reaction mixture at pH 1.6 to 2.1 with concentrated hydrochloric acid. Is added. After completion of the addition, the mixture is further stirred at the same temperature for 60 minutes, and the precipitated crystals are collected. The obtained precipitated crystals are suspended in 50 m of water, the suspension is adjusted to pH 9.0 with concentrated aqueous ammonia, 0.4 g of activated carbon is added, and the mixture is stirred at room temperature for 5 minutes. Then, the activated carbon is removed, the activated carbon is washed with water, the washing solution and the previously obtained solution are combined, adjusted to pH 4.5 with concentrated hydrochloric acid, and further stirred at room temperature for 30 minutes. The precipitated crystals are collected, washed successively with water and acetone, and dried under reduced pressure to give (3R, 5R, 6R) -6-amino-3-carboxy-7-
Oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.
0] 5.81 g of heptane (66.0% yield) are obtained.

IR (KBr) cm ^-1 ; 1770,1710,1660,1620 Also, (3R, 5R, 6R) -6-amino-3-carboxy-
3- (3-p-methylbenzylideneamino-2-oxoimidazolidin-1-yl) -7-oxo-4-thia-
1-azabicyclo [3.2.0] heptane and (3R, 5R, 6
R) -6-Amino-3- (3-anisylideneamino-2
-Oxoimidazolidin-1-yl) -3-carboxy-7-oxo-4-thia-1-azabicyclo [3.2.0]
Each heptane is treated in the same manner to obtain (3R, 5R, 6R)
-6-amino-3-carboxy-7-oxo-3- (2
-Oxo-3-ureidoimidazolin-1-yl) -4
-Thia-1-azabicyclo [3.2.0] heptane is obtained.

The physical properties (IR) of these compounds were consistent with the physical properties (IR) of the compound obtained in Example 30.

Example 31 (3R, 5R, 6R) -6-amino-3- (3-benzylideneamino-2-oxoimidazolidin-1-yl) -3-
Diphenylmethyloxycarbonyl-7-oxo-4-
7.50 g of thia-1-azabicyclo [3.2.0] heptane was dissolved in 80 m of methylene chloride, and 5 g of Sp-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine was added to this solution. Stir for hours.
After adding 80 m of water to the reaction mixture and adjusting the pH to 7.0 with a saturated aqueous solution of sodium hydrogen carbonate, the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (elution solvent: chloroform: acetone = 1: 0 to 25: 1) to give (3R, 5R, 6R) -3- ( 3-benzylideneamino-
2-oxoimidazolidin-1-yl) -3-diphenylmethyloxycarbonyl-6- (p-methoxybenzyloxycarbonylamino) -7-oxo-4-thia-
8.36 g of 1-azabicyclo [3.2.0] pentane (yield 85.2
%).

IR (KBr) cm ^-1 ; 1795,1710 Example 32 (3R, 5R, 6R) -3- (3-formylmethylideneamino-2-oxoimidazolidin-1-yl) -3- (p-
Nitrobenzyloxycarbonyl) -6- [DL-α-
0.20 g of (p-nitrobenzyloxycarbonyl) -α-phenylacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane is dissolved in a mixed solvent of 10 m of methylene chloride and 10 m of methanol. 26 mg of methoxyamine hydrochloride is added to this solution, and the mixture is stirred at room temperature for 1 hour. Then, 10 m of water is added to the reaction mixture, the pH is adjusted to 7 with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent: chloroform: acetone = 20: 1 to
Purification by 10: 1) yields (3R, 5R, 6R) -3- (p-nitrobenzyloxycarbonyl) -6- [DL-α- (p-nitrobenzyloxycarbonyl) -α-phenylacetamide ] -3- [3- (N-Methoxyiminoethylideneamino) -2-oxoimidazolidin-1-yl] -7-
Obtain 0.15 g (72.1% yield) of oxo-4-thia-1-azabicyclo [3.2.0] heptane.

IR (KBr) cm ^-1 ; 1790, 1710 Similarly, the compounds in Table-26 are obtained.

Here, R ^1a and R in Table 26 each represent a substituent of the following formula.

Example 33 (3R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -3-diphenylmethyloxycarbonyl-6- {DL-α- (p-methoxybenzyloxycarbonyl) 0.70 g of -α- [4- (p-methoxybenzyloxy) phenyl] acetamide} -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane was dissolved in 7 m of methylene chloride, and heated to -30 ° C. Cooling. To this solution is added 0.085 m of chlorosulfonyl isocyanate, and the mixture is stirred for 30 minutes under ice cooling. Then, the reaction mixture was added under ice cooling to 16
0.2m% ammonia-methanol solution, and at the same temperature
Stir for 30 minutes. 5m of water is added to the reaction mixture, and 1N hydrochloric acid is used.
After adjusting to pH 2, the organic layer is separated. After the separated organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent: chloroform: methanol = 30: 1 to 10:
Purification in 1) gives (3R, 5R, 6R) -3- [3- (3-aminosulfamoylureido) -2-oxoimidazolidin-1-yl] -3-diphenylmethyloxycarbonyl-6- {DL-α- (p-methoxybenzyloxycarbonyl) -α- [4- (p-methoxybenzyloxy) phenyl] acetamide} -7-oxo-4-thia-
0.60 g of 1-azabicyclo [3.2.0] heptane (77.7 yield)
%).

IR (KBr) cm ^-1 ; 1790,1710 Example 34 (3R, 5R, 6R) -3-diphenylmethyloxycarbonyl-6- (DL-α-diphenylmethyloxycarbonyl-α-phenylacetamide) -3 -(3-formylmethylideneamino-2-oxoimidazolidin-1-yl)
-7-oxo-4-thia-1-azabicyclo [3.2.0]
Dissolve 0.23 g of heptane in 5 m of benzene. 0.12 g of triphenylphosphoranylideneacetonitrile
And stirred at room temperature for 2 days. Then, 10 m of water and 10 m of ethyl acetate are added to the reaction mixture, the pH is adjusted to 7 with a saturated sodium hydrogen carbonate solution, and then the organic layer is separated.
After the separated organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; benzene: ethyl acetate = 3: 1 to 2: 1) to give (3R, 5R, 6R) -3- [3-
(3-cyano-2-propenylideneamino) -2-oxoimidazolidin-1-yl] -3-diphenylmethyloxycarbonyl-6- (DL-α-diphenylmethyloxycarbonyl-α-phenylacetamide) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane 0.1
0 g (42.4% yield) are obtained.

IR (KBr) cm ^-1 ; 1790, 1710 The following compound is obtained in the same manner.

○ (3R, 5R, 6R) -3-diphenylmethyloxycarbonyl-6- (DL-α-diphenylmethyloxycarbonyl-α-p-methoxybenzyloxyphenylacetamide) -7-oxo-3- [2- Oxo-3- (5-piperidinocarbonyl-2,4-pentadienylideneamino)
Example 35 (3R, 5R, 6R) -6- [D-Imidazolidin-1-yl] -4-thia-1-azabicyclo [3.2.0] heptane IR (KBr) cm ^-1 ; 1785,1720,1605 α- (p-acetoxyphenyl) -α- (p-methoxybenzyloxycarbonylamino) acetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-3- (2-oxo-3-
Ureidoimidazolidin-1-yl) -4-thia-1-
320 mg of azabicyclo [3.2.0] heptane in 5 m of methylene chloride
And cooled to -20 ° C. To this solution was added 0.78 m of an anisole solution containing 160 mg of anhydrous aluminum chloride,
After dropwise addition at 20 to -10 ° C, the mixture is stirred at -10 to 0 ° C for 30 minutes. The reaction mixture is introduced into a mixed solvent of 10 m of water and 15 m of ethyl acetate, adjusted to pH 1.0 with 2N hydrochloric acid, and then the aqueous layer is separated. 10 m of ethyl acetate and 10 m of tetrahydrofuran are added to the separated aqueous layer, and the pH is adjusted to 7.5 with a saturated aqueous solution of sodium hydrogencarbonate. After removing insolubles, the organic layer is separated. After washing the separated organic layer with saturated saline,
After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, (3R, 5R, 6R) -6- [D-α- (p-acetoxyphenyl) -α-aminoacetamido] -3- (p-nitro Benzyloxycarbonyl) -7-oxo-3-
(2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane 1
40 mg (54.9% yield) are obtained.

Example 36 (3R, 5R, 6R) -6- [D-α- (p-acetoxyphenyl) -α-aminoacetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-3- (2- Oxo-3-ureidoimidazolidin-1-yl) -4-
220 mg of thia-1-azabicyclo [3.2.0] heptane are suspended in 22 m of methylene chloride. To this suspension was added 110 mg of sulfur trioxide-pyridine complex at room temperature, and the mixture was stirred at the same temperature for 3 hours, and then the solvent was distilled off under reduced pressure. 15 m of ethyl acetate and 15 m of water are added to the obtained residue, the pH is adjusted to 7.0 with a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer is separated. If the separated aqueous layer is purified by reverse phase column chromatography (elution solvent; water: acetonitrile = 1: 1 to 10: 1), (3R, 5R, 6R) -6- [D-α- (p- Acetoxyphenyl) -α-sulfoaminoacetamide] -3- (p-
Nitrobenzyloxycarbonyl) -7-oxo-3-
40 mg (15.7% yield) of the sodium salt of (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane are obtained.

IR (KBr) cm- ¹ ; 1770,1710,1670,1600 Example 37 (3R, 5R, 6R) -3- (3-carboxymethylideneamino-2-oxoimidazolidin-1-yl) -3-diphenyl Methyloxycarbonyl-6- (DL-α-diphenylmethyloxycarbonyl-α-phenylacetamide) -7-oxo-4-thia-1-azabicyclo [3.2.
0] 170 mg of heptane is dissolved in 5 m of methylene chloride, and -20
Cool to ~ -10 ° C. To this solution was added triethylamine 0.03
4m and 0.023m of ethyl chlorocarbonate were added sequentially, and -20
Stir for 30 minutes at ~ -10 ° C. The reaction mixture is
0.14m of 7.4N ammonia-methanol solution is added, and the mixture is stirred for 1 hour under ice cooling. Then, the reaction mixture was introduced into a mixed solvent of methylene chloride 10m and water 10m, and the pH was adjusted with 2N hydrochloric acid.
After adjusting to 2.0, the organic layer is separated. The separated organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (elution solvent: chloroform: acetone = 10: 1 to 2: 1) to give (3R, 5R, 6R) -3.
-(3-carbamoylmethylideneamino-2-oxoimidazolidin-1-yl) -3-diphenylmethyloxycarbonyl-6- (DL-α-diphenylmethyloxycarbonyl-α-phenylacetamide) -7-oxo −
4-Thia-1-azabicyclo [3.2.0] heptane 150 mg
(88% yield).

IR (KBr) cm ^-1 ; 1780, 1720, 1670 The following compound is obtained in the same manner.

○ (3R, 5R, 6R) -3- [3- (3-carbamoyl-2-
Arylidene) amino-2-oxoimidazolidin-1-
Yl] -3-diphenylmethyloxycarbonyl-6-
(DL-α-diphenylmethyloxycarbonyl-α-phenylacetamide) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane IR (KBr) cm ⁻¹ ; 1790,1730,1670 38 (3R, 5R, 6R) -3- (3-carbamoylmethylideneamino-2-oxoimidazolidin-1-yl) -3-diphenylmethyloxycarbonyl-6- (DL-α-diphenylmethyloxycarbonyl-α -Phenylacetamide) -7-oxo-4-thia-1-azabicyclo [3.2.
0] Dissolve 280 mg of heptane in 10 m of methylene chloride.
0.095 m of trifluoroacetic anhydride and 0.108 m of pyridine are added to this solution, and the mixture is stirred at room temperature for 20 minutes. Next, 5 m of water is added to the reaction mixture, the pH is adjusted to 3.0 with 1N hydrochloric acid, and the organic layer is separated. The separated organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent: chloroform: acetone = 10: 1 to
Purification by 5: 1) gives (3R, 5R, 6R) -3- (3-cyanomethylideneamino-2-oxoimidazolidin-1-yl) -3-diphenylmethyloxycarbonyl-6-
110 mg (40.1% yield) of (DL-α-diphenylmethyloxycarbonyl-α-phenylacetamide) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane is obtained.

Example 39 (1) DL- (4-acetoxy-2-chlorophenyl)
6.0 g of acetic acid are suspended in 90 m of methylene chloride. Oxalyl chloride (2.75m) and N, N-dimethylformamide (50μ) were added to the suspension under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. To dissolve. To this solution, under ice cooling, 5.30 g of sulfur trioxide-dioxane complex was added. After stirring at room temperature overnight, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 50 m of anhydrous acetonitrile.

(2) On the other hand, (3R, 5R, 6R) -6-amino-3-carboxy-7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azavicillo [3.2.0] 5.70 g of heptane are suspended in 100 m of water. To this suspension was added a 20% aqueous sodium carbonate solution under ice-cooling,
Adjust to 9.0 to make a homogeneous solution. To this solution, the acetonitrile solution prepared in (1) is added over 20 minutes while maintaining pH 7.0 to 7.5 with a 20% aqueous sodium carbonate solution under ice-cooling. After stirring at the same temperature for 10 minutes, ethyl acetate 50m
And separate the aqueous layer. PH of the separated aqueous layer with 2N hydrochloric acid
After adjusting to 5.5, concentrate under reduced pressure. The obtained residue is purified by reversed-phase column chromatography (elution solvent: water), and then lyophilized to give (3R, 5R, 6R) -6- [α-
(4-acetoxy-2-chlorophenyl) -α-sulfoacetamide] -3-carboxy-7-oxo-3- (2
-Oxo-3-ureidoimidazolidin-1-yl)-
An isomer of 4-thia-1-azabicyclo [3.2.0] heptane disodium salt (the diastereomer at the 6-position) is obtained.

○ L-form (eluted first by reversed phase column chromatography; yield 2.18 g; yield 20.0%) IR (KBr) cm ^-1 ; 1765, 1700, 1690, 1670, 1620 ○ D-form (reverse phase column chromatography 2.38 g; 21.8%) IR (KBr) cm ^-1 ; 1765,1700,1685,1670,1620 In the same manner, the compounds in Table-27 are obtained.

Note that R ^1a in Table 27 represents a substituent represented by the following formula.

Example 40 (3R, 5R, 6R) -3-diphenylmethyloxycarbonyl-6- (p-methoxybenzyloxycarbonylamino) -7-oxo-3- [2-oxo-3- (2-semicarbazonoethylidene Amino) imidazolidin-1-yl] -4-thia-1-azabicyclo [3.2.0] heptane
1.5 g is suspended in a mixed solvent of 15 m of methylene chloride and 2.2 m of anisole, and cooled to -30 ° C. To this suspension is added 7 m of a nitromethane solution containing 1.4 g of anhydrous aluminum chloride, and the mixture is stirred at -20 ° C for 3 hours. 10 m of water is added, and the pH is adjusted to 8.5 with a saturated aqueous sodium hydrogen carbonate solution. After filtering the precipitated insoluble matter through Celite, the aqueous layer of the liquid is separated. 10 m of acetonitrile solution containing 1.23 g of DL-α- (4,5-diacetoxy-2-chlorophenyl) -α-sulfoacetyl chloride prepared in the same manner as in Example 39 (1) was added to the separated aqueous layer, Under cooling, the solution is added over 20 minutes while maintaining pH 7 to 8 with a 20% aqueous sodium carbonate solution.
Next, the reaction mixture is adjusted to pH 6 with 1N hydrochloric acid, 10 m of ethyl acetate is added, and the aqueous layer is separated. The separated aqueous layer is concentrated under reduced pressure. The obtained residue is subjected to reverse phase column chromatography (elution solvent: water: acetonitrile = 20: 1-
10: 1), (3R, 5R, 6R) -3-carboxy-
6- [α- (4,5-diacetoxy-2-chlorophenyl) -α-sulfoacetamide] -7-oxo-3- [2
Each diastereomer of -oxo-3- (2-semicarbazonoethylideneamino) imidazolidin-1-yl] -4-thia-1-azabicyclo [3.2.0] heptane is obtained.

○ L-form (eluted first by reversed-phase column chromatography. Yield 0.15 g; 9.2% yield) IR (KBr) cm ^-1 ; 1770, 1710, 1680, 1620 ○ D-form (late after reversed-phase column chromatography) IR (KBr) cm ^-1 ; 1765,1710,1680,1620 Example 41 (3R, 5R, 6R) -3-carboxy-6- [D-α- ( 4
-Nitrophenyl)-[alpha] -sulfoacetamide] -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0]
460 mg of the disodium salt of heptane are dissolved in 10 m of water. To this aqueous solution was added 200 mg of 5% palladium-carbon,
After stirring at room temperature under a hydrogen atmosphere for 3 hours, the insoluble matter is removed. The solution was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase column chromatography (eluent: water) and lyophilized to give (3R, 5R, 6R) -6- [D-α- ( 4-Aminophenyl)-[alpha] -sulfoacetamide] -3-carboxy-7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane 300 mg of disodium salt (yield 68.5
%).

IR (KBr) cm ^-1 ; 1770, 1700, 1660, 1615 In the same manner, the following compound is obtained.

○ (3R, 5R, 6R) -6- [D-α- (4-amino-2-chlorophenyl) -α-sulfoacetamide] -3-carboxy-7-oxo-3- (2-oxo-3-ureidoimidazo Disodium salt of Lysin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane IR (KBr) cm ^-1 ; 1765,1705,1660,1620 Example 42 (3R, 5R, 6R)- 6- [D-α- (4-aminophenyl) -α-sulfoacetamide] -3-carboxy-7-
Oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.
0] Dissolve 150 mg of the disodium salt of heptane in 5 m of water. Under ice-cooling, 120 mg of sodium cyanate was added little by little while maintaining pH 4 to 5 with 1N hydrochloric acid under ice-cooling.
After stirring for 0 minutes, the reaction mixture is concentrated under reduced pressure. The obtained residue is purified by reversed-phase column chromatography (eluent: water) and lyophilized to give (3R, 5R, 6R) -3
-Carboxy-7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -6- [D-α-sulfo-α- (4-ureidophenyl) acetamide] -4
120 mg (yield 74.5%) of the disodium salt of thia-1-azabicyclo [3.2.0] heptane are obtained.

IR (KBr) cm ^-1 ; 1770, 1700, 1660, 1605 In the same manner, the following compound is obtained.

○ (3R, 5R, 6R) -3-carboxy-6- [D-α- (2
-Chloro-4-ureidophenyl) -α-sulfoacetamide] -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane Disodium salt IR (KBr) cm ^-1 ; 1760,1700,1660,1610 Example 43 (3R, 5R, 6R) -6- [D-α- (4-acetoxy-3)
-Nitrophenyl) -α-sulfoacetamide] -3-carboxy-7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane Dissolve 200 mg of the disodium salt in 20 m of methanol. Acetic anhydride 0.14m
And 150 mg of 5% palladium-carbon are sequentially added, and the mixture is stirred at room temperature under a hydrogen atmosphere for 3 hours, and insoluble materials are removed.
After adding 50 m of water to the liquid, the reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by reversed-phase column chromatography (eluent: water) to give (3R, 5R, 6R) -6-
[D-α- (3-acetamido-4-hydroxyphenyl) -α-sulfoacetamide] -3-carboxy-7-
Oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.
0] 160 mg (78.4% yield) of dinatrium salt of heptane are obtained.

IR (KBr) cm ^-1 ; 1770,1660,1615 Example 44 (1) N-Tri-n-butylamine salt of D-α- (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetic acid
3.27 g are suspended in 16.4 m of methylene chloride. Under ice-cooling, 1.30 m of trimethylchlorosilane and 2.73 m of tri-n-butylamine are added to the suspension, and the mixture is stirred at the same temperature for 30 minutes. Then isopropyl chlorocarbonate at -15 ~ -10 ° C
Add 0.60 m and stir at the same temperature for 1 hour to obtain a mixed acid anhydride solution.

(2) On the other hand, (3R, 5R, 6R) -6-amino-3-carboxy-7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] 1.75 g of heptane is suspended in 16.4 m of methanol, and 1.70 m of tri-n-butylamine is added to this suspension and dissolved. After the mixed acid anhydride solution prepared in (1) is dropped at -50 ° C or lower to the obtained solution, the reaction mixture is heated to room temperature over 1 hour and stirred at the same temperature for 1 hour. To the reaction mixture are sequentially added 2.86 m of acetic acid and 4.5 m of a methanol solution containing 1.50 g of sodium acetate trihydrate, and the mixture is stirred at room temperature for 1 hour. The resulting precipitated crystals are dissolved in 10m of water and purified by reversed-phase column chromatography (elution solvent: water) to give (3R, 5R, 6
R) -3-carboxy-6- [D-α- (2-chloro-
4,5-dihydroxyphenyl) -α-sulfoacetamide] -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane 2.08 g of sodium salt (yield 65.2
%).

IR (KBr) cm ^-1 ; 1760, 1700, 1670, 1610 Similarly, the following compound is obtained.

○ (3R, 5R, 6R) -3- (3-benzylideneamino-2-
Oisoimidazolidin-1-yl) -3-carboxy-
Disodium salt of 6- [DL-α- (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane IR (KBr) cm ^-1 ; 1760,1720,1700,1660,1615 ○ (3R, 5R, 6R) -3- (3-benzylideneamino-2-
Oxoimidazolidin-1-yl) -3-carboxy-
Disodium salt of 6- [D-α- (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane ○ (3R, 5R, 6R) -6- (D-α- (2-chloro-4,5-
Dihydroxyphenyl) -α-sulfoacetamide] -3
-Diphenylmethyloxycarbonyl-7-oiso-3
Sodium salt of-(2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane ○ (3R, 5R, 6R) -3- (3-benzylideneamino- 2-
Oxoimidazolidin-1-yl) -6- [D-α-
(2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetamide] -3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo [3.2.
0] Sodium salt of heptane Example 45 (3R, 5R, 6R) -3- (3-benzylideneamino-2-
Oxoimidazolidin-1-yl) -3-carboxy-
3.70 g of the disodium salt of 6- [D-α- (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane was treated with acetonitrile. Dissolve in a mixed solvent of 55m and 18.5m of water. To this solution is added 2.54 g of 2,4-dinitrophenylhydrazine hydrochloride, and the mixture is stirred at room temperature for 3 hours. After adding 37 m of water to the reaction mixture, the insoluble matter is separated and washed with 8 m of water. The washing solution and the solution obtained above are combined, 50 m of ethyl acetate is added, the pH is adjusted to 6.0 with a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer is separated. The separated aqueous layer was washed with 50 m of ethyl acetate, and 1N
After adjusting the pH to 4.0 with hydrochloric acid, 370 mg of activated carbon is added, and the mixture is stirred at room temperature for 5 minutes, and then the activated carbon is removed. The activated carbon is washed with water, the washings and the previously obtained liquid are combined and concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography (elution solvent: water), and the obtained eluate was purified by about 10
Concentrate to m. The residue obtained is ethanol 100m
And stirred for another 30 minutes. The precipitated crystals are collected, washed with 10m of ethanol, and then dried under reduced pressure.
R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -3-carboxy-6- [D-α-
2.04 g of disodium salt of (2-chloro-4,5-dihydroxyphenyl) -α-sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane (yield
63.3%).

IR (KBr) cm ^-1 ; 1765, 1700, 1665, 1615 In the same manner, the following compound is obtained.

(3R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -3-carboxy-6- [DL-α
-(2-chloro-4,5-dihydroxyphenyl) -α-
Sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane disodium salt IR (KBr) cm ^-1 ; 1765,1720,1700-1660,1615 Example 46 (3R, 5R, 6R ) -3-Diphenylmethyloxycarbonyl-6- {DL-α- (p-methoxybenzyloxycarbonyl) -α- [4- (p-methoxybenzyloxy)
Phenyl] acetamide {-3- (3-p-nitrobenzyloxycarbonylaminomethylcarbonylamino-2
-Oxoimidazolidin-1-yl) -7-oxo-4
Example 1 -thia-1-azabicyclo [3.2.0] heptane
6, then reacted in the same manner as in Example 12, (3R, 5R, 6
R) -3- (3-Aminomethylcarbonylamino-2-
Oxoimidazolidin-1-yl) -3-carboxy-
The disodium salt of 6- [DL-α-carboxy-α- (p-hydroxyphenyl) acetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane is obtained.

IR (KBr) cm- ¹ ; 1770,1720-1660,1600 Example 47 (3R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -3-carboxy-6 [DL-α
-(2-chloro-4,5-dihydroxyphenyl) -α-
100 mg of disodium salt of sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane was added to water.
Dissolve in a mixed solvent of 1 m and 1 m of acetonitrile. 0.022 m of acrolein and a catalytic amount of p
-Add toluene sulfonic acid sequentially and stir at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by reverse-phase column chromatography (elution solvent: water: acetonitrile = 1: 0 to 97: 3), and then lyophilized.
(3R, 5R, 6R) -3-carboxy-6- [DL-α- (2-
Chloro-4,5-dihydroxyphenyl) -α-sulfoacetamide] -7-oxo-3- (2-oxo-3-allylideneaminoimidazolidin-1-yl) -4-thia-
Disodium salt of 1-azabicyclo [3.2.0] heptane 6
4 mg (60.0% yield) are obtained.

IR (KBr) cm ^-1 ; 1770,1720,1700 to 1660,1620,1600 Further, instead of acrolein, cis-β-formylacrylic acid was used, and (3R, 5R, 6R) -3- [3- ( 3-carboxy-2-allylideneamino) -2-oxoimidazolidin-1-yl] -3-carboxy-6- [DL-α
-(2-chloro-4,5-dihydroxyphenyl) -α-
This gives the trisodium salt of [sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane.

IR (KBr) cm ^-1 ; 1770,1720,1710,1630,1620 Example 48 (3R, 5R, 6R) -3-carboxy-6- [D-α- (2
-Chloro-4,5-dihydroxyphenyl) -α-sulfoacetamide] -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] 0.64 g of disodium salt of heptane
Dissolve in 3m of N, N-dimethylformamide. 0.12 m of benzyl bromide is added to this solution, and the mixture is stirred at room temperature for 2 days. The reaction mixture is evaporated to dryness under reduced pressure, and the obtained residue is dissolved in a mixed solvent of 5 m of water and 10 m of ethyl acetate, adjusted to pH 6 with a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer is separated. The separated aqueous layer was subjected to reverse phase column chromatography (elution solvent: water: acetonitrile = 93: 7-
90:10), (3R, 5R, 6R) -3-benzyloxycarbonyl-6- [D-α- (2-chloro-4,5-
Dihydroxyphenyl) -α-sulfoacetamide] -7
-Oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.
0] 0.32 g of heptane sodium salt (yield 45.2%) is obtained.

IR (KBr) cm ^-1 ; 1775,1720,1700,1670 In the same manner, the following compound is obtained.

○ (3R, 5R, 6R) -6- [D-α- (2-chloro-4,5-
Dihydroxyphenyl) -α-sulfoacetamide] -3
Sodium salt of -methoxycarbonyl-7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane IR (KBr) cm ^-1 ; 1770,1710,1670,1650 Example 49 (3R, 5R, 6R) -6-amino-3- (3-benzylideneamino-2-oxoimidazolidin-1-yl) -3-
1.00 g of (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane
Then, 30 m of benzene is added to 0.46 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, and the mixture is subjected to azeotropic dehydration for 1 hour under reflux using a Dean-Stark apparatus. After cooling the reaction mixture, the solvent is distilled off under reduced pressure to give (3R, 5R, 6R) -3- (3-benzylideneamino-2-oxoimidazolidin-1-yl) -6-
(3,5-Di-tert-butyl-4-hydroxybenzylideneamino) -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.
0] 1.40 g of heptane (98.6% yield) are obtained.

Example 50 (3R, 5R, 6R) -3- (3-benzylideneamino-2-
Oxoimidazolidin-1-yl) -6- (3,5-di-t
ert-butyl-4-hydroxybenzylideneamino)-
3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane 6
40 mg of 1.2-dichloroethane 3.2 m and anhydrous benzene
Dissolve in 9.6m of mixed solvent. Under ice-cooling, 640 mg of anhydrous magnesium sulfate and 980 mg of nickel peroxide are sequentially added to this solution, and the mixture is stirred at room temperature for 2.5 hours. The obtained residue is dissolved in a mixed solvent of 5 m of methanol and 5 m of methylene chloride. After stirring at room temperature for 1 hour, the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (elution solvent: chloroform) to give (3R, 5R, 6R) -3
-(3-benzylideneamino-2-oxoimidazolidin-1-yl) -6- (3,5-di-tert-butyl-4-
(Hydroxybenzylideneamino) -6-methoxy-3-
(P-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane 580 mg
(87.1% yield).

IR (KBr) cm ^-1 ; 1770,1720 Example 51 (3R, 5R) -3- (3-benzylideneamino-2-oxoimidazolidin-1-yl) -6- (3,5-di-ter
t-butyl-4-hydroxybenzylideneamino) -6
-Methoxy-3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.
0] 740 mg of heptane is dissolved in a mixed solvent of 15 m of methanol, 6 m of tetrahydrofuran, 1.5 m of water and 6 m of methylene chloride. A Girard reagent (2-hydrazino-N, N, N-trimethyl-2-oxoethanaminium) was added to this solution.
Chloride) and stirred at room temperature for 1 hour. 30 m of methylene chloride and 10 m of water were sequentially added to the reaction mixture,
After adjusting the pH to 7.0 with a saturated aqueous sodium hydrogen carbonate solution,
Separate the organic layer. The separated organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If the obtained residue is purified by column chromatography (elution solvent: benzene: ethyl acetate = 5: 1 to 1: 1), (3R, 5R) -6-amino-3- (3-benzylideneamino-2) is obtained. -Oxoimidazolidin-1-yl) -6-methoxy-3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane (320 mg, yield 60.6%). obtain.

IR (KBr) cm ^-1 ; 1770,1710 Formulation Example 1 (3R, 5R, 6R) -3-carboxy-6- [D-α- (2
-Chloro-4-hydroxyphenyl) -α-sulfoacetamide] -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0] heptane An aqueous solution of the disodium salt is treated in a conventional manner to obtain a sterile lyophilized disodium salt. 1 g (potency) of disodium salt is dissolved in 20 m of physiological saline to obtain an injection solution.

Formulation Example 2 (3R, 5R, 6R) -3-carboxy-6- [D-α- (2
-Chloro-4,5-didroxyphenyl) -α-sulfoacetamide] -7-oxo-3- (2-oxo-3-ureidoimidazolidin-1-yl) -4-thia-1-azabicyclo [3.2.0 An aqueous solution of heptane disodium salt is treated in a conventional manner to obtain a sterile freeze-dried disodium salt. 1 g (potency) of disodium salt is dissolved in 20 m of physiological saline to obtain an injection solution.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 499/70 C07D 499/70 Z 499/72 499/72 499/78 499/78 // A61K 31/00 631 A61K 31/00 631C 31/43 601 31/43 601 (72) Inventor Toshio Hayashi 16-27, Fushiki Kokokufu, Takaoka City, Toyama Prefecture (72) Inventor Kaihide Momoi 1-1-28 Honmachi, Shinminato City, Toyama Prefecture Examiner Junko Uchida (56) References JP-A-63-183588 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 499/00-499/82 A61K 31/00-31/80 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula During the "formula, R ¹ represents a hydrogen atom, an amino protecting group or an acyl group; R ² is a hydrogen atom or a lower alkyl group; R ³ is a hydrogen atom, lower alkoxy, lower alkylthio, or formamide group; R ⁴ Is an optionally protected carboxyl or carboxylate group; R is a group of the formula —NHR ⁵ or (Wherein R ⁵ and R ⁶ are the same or different and each may be an optionally protected hydroxyl group, cyano group, sulfo group or optionally substituted lower alkyl, aryl, acyl, carbamoyl, sulfamoyl, lower alkyl A sulfonyl or heterocyclic group). (Wherein R ⁷ and R ⁸ are the same or different and are each a hydrogen atom, an optionally protected carboxyl group, a cyano group or an optionally substituted lower alkyl, lower alkenyl, lower alkynyl, aryl, amino, forming Further, R ⁷ and R ^8, a cycloalkene ring or a heterocyclic ring together with the adjacent carbon atoms; acyl, acyloxy, carbamoyl, carbamoyloxy, sulfamoyl, lower alkylthio, showing a ureido or heterocyclic group. And n is 1 or 2
Are respectively shown. ] The penum derivative represented by these, and its salt.