JPH07173169A - Cephem compound, its production and antibacerial composition - Google Patents

Abstract

PURPOSE:To obtain a new cephem compound having excellent antibacterial action against a wide variety of Gram-positive bacteria and Gram-negative bacteria, especially bacteria of the genus Pseudomonas, staphylococci, methicillin resistant Staphylococcus aureus, etc. CONSTITUTION:This cephem compound is expressed by formula I [R<1> is amino; R<3> is a 3 to 7-membered alicyclic hydrocarbon group or a non-aromatic heterocyclic group; A<+> is group of formula II or III (B is 6-membered aromatic heterocyclic group containing one or two N atoms as the hetero atoms], its ester or salt, e.g. 7BETA-[2-(5-amino-1,2,4thiadiazol3yl)2(Z)(cyclopentyloxyimino) acetamido]-3-(imidazo[1,2-b]pyridazinium-1-yl)methyl-3-cephem-4-carbox ylate. The compound can be produced by reacting a compound of formula IV, its ester or salt with a carboxylic acid of formula V, its salt or its reactive derivative generally in a solvent such as THF preferably at -30 to +30 deg.C for 15min to 3hr.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel cephem compound having an excellent antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria, particularly Pseudomonas, Staphylococcus and Methicillin-resistant Staphylococcus (MRSA). Manufacturing method and antibacterial composition.

[0002]

2. Description of the Related Art Conventionally, a quaternary ammonium group is present at the 3-position and 2- (2-aminothiazole-at the 7-position of a cephem ring.
Various cephem compounds having a 4- (yl) or 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -substituted oxyiminoacetamide group have been reported (Japanese Patent Laid-Open No. Sho 60). No. 231684, JP-A-62.
No. 149682, JP-A-58-4789). That is, in JP-A-60-231684, the general formula

[Chemical 11] [Wherein R ⁰ represents a hydrogen atom, a nitrogen-containing heterocyclic group, an acyl group or an esterified carboxyl group, and Z represents S, S →
O, O or CH ₂ , R ⁴ is a hydrogen atom, a methoxy group or a formamide group, R ¹³ is a hydrogen atom, a methyl group, a hydroxyl group or a halogen atom, and A is an optionally substituted 2,3-position or And a physiologically or pharmaceutically acceptable salt or ester thereof represented by imidazole-1-yl group forming a condensed ring at the 3,4-position. The compound being synthesized has the formula:

[Chemical 12] There is a cephem compound represented by.

In Japanese Patent Laid-Open No. 62-149682, a general formula is used.

[Chemical 13] [In the formula, R ¹ represents an optionally protected amino group, R ³ represents a hydrogen atom or an optionally substituted hydrocarbon residue,
Other symbols represent the compound represented by the above [A]] or a physiologically or pharmaceutically acceptable salt or ester thereof, and specifically, the compound is represented by the formula:

[Chemical 14] There is a cephem compound represented by. JP-A-58-478
In the publication No. 9, the general formula

[Chemical 15] Each of which represents a heterocyclic cation group containing two or more nitrogen atoms] or a salt thereof is described.
The (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-cyclopenten-1-yloxyimino) acetamide group is replaced with 2-methyl-1- at the 3-position.
There is a cephem compound having a pyrazoliomethyl group.

[0004]

The conventional cephem compounds are, in view of the range or strength of antibacterial activity, among others, Pseudomonas spp. M
The antibacterial action against (RSA) and the like is not sufficiently satisfactory, and the emergence of new compounds that overcome this point has been desired.

[0005]

Means for Solving the Problems In view of the above circumstances, the inventors of the present invention have conducted various studies, and as a result, the formula at the 3-position of the cephem ring:

[Chemical 16] (In the formula, B represents a 6-membered aromatic heterocycle in which the hetero atom is 1 or 2 nitrogen atoms), and a group represented by the formula:

[Chemical 17] [Wherein R ¹ represents an optionally protected amino group, and R ³ represents an optionally substituted 3 to 7-membered alicyclic hydrocarbon group or non-aromatic heterocyclic group] For the first time, a cephem compound or an ester or salt thereof having a chemical structure characteristic of having a group was synthesized. It has been found that it has a wide range of excellent antibacterial action against Gram-positive bacteria including the above, and based on these, the present invention was completed.

That is, the present invention provides (1) the general formula [I]:

[Chemical 18] [The symbols in the formula are as defined above] or a compound or ester thereof, or a salt thereof,

(2) General formula [II]:

[Chemical 19] [Wherein the symbols have the same meanings as defined above] or a compound or ester thereof or salt thereof and a general formula:

[Chemical 20] [Wherein the symbols in the formula have the same meanings as defined above] are reacted with a carboxylic acid or a salt or reactive derivative thereof, the method for producing the compound according to (1), (3) the general formula III]:

[Chemical 21] [Wherein R ⁵ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group or a halogen atom, and other symbols have the same meanings as those defined above] General formula [IV]:

[Chemical formula 22] [Wherein the symbols in the formula are as defined above] reacted with an imidazole compound forming a condensed ring at the 2,3-position or 3,4-position or a salt thereof (1) Process for producing compound described in (4) general formula [V]

[Chemical formula 23] [Wherein the symbols are as defined above] or a salt or ester thereof and a general formula [VI]: R ³ OH [VI] [wherein the symbols are as defined above] Or a method of producing the compound according to (1) above, which comprises reacting with a salt or a reactive derivative thereof, and (5)
The present invention relates to an antibacterial composition containing the compound described in (1) above.

The cephem compound in the present specification is "the
Journal of the American Chemical Society "Vol. 84, page 3400 (1962), which is a group of compounds named based on" Cepham ",
The cephem compound means a compound having a double bond at the 3,4-position among the cepham compounds. The compound of the present invention includes a compound of the general formula [I] or an ester thereof or a salt thereof (a salt of the compound [I] or a salt of the ester of the compound [I]) in a free form. In the following description of the present application, except for special cases, the compound of the general formula [I] or its ester or salt thereof, which is in the free form, is simply referred to as the compound [I], the antibacterial compound [I] or the general formula [I]. ] It is abbreviated only as a compound represented by. Therefore, the compound [I] in the present specification usually includes not only the free form but also its ester and salts thereof. This is
Not only the compound [I] but also the compounds [II], [III],
The same applies to [V], [VII], and [VIII]. R ¹
Represents an optionally protected amino group. In the field of β-lactams and peptides, amino-protecting groups have been thoroughly studied and their protection methods have already been established, and in the present invention, those known as amino-protecting groups are appropriately adopted. sell. Examples of the amino-protecting group include C _1-6 alkanoyl group, C _3-5 alkenoyl group,
C _6-10 arylcarbonyl group, phthaloyl group, heterocyclic carbonyl group, C _1-6 alkylsulfonyl group, camphorsulfonyl group, C _6-10 arylsulfonyl group, substituted oxycarbonyl group, optionally substituted carbamoyl group, An optionally substituted thiocarbamoyl group, C _6-10 aryl-
Methyl group, di C _6-10 aryl-methyl group, tri C _6-10 aryl-methyl group, C _6-10 aryl-methylene group, C _6-10 arylthio group, substituted silyl group, 2-C _1-10 alkoxy -Carbonyl-1-methyl-1-ethenyl group, formula M'OCO
A group represented by — [wherein M ′ represents an alkali metal] is used.

Examples of the "C _1-6 alkanoyl group" herein include formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, succinyl, glutaryl, monochloroacetyl, dichloroacetyl, trichloroacetyl, monobromoacetyl, monofluoroacetyl. Acetyl, difluoroacetyl, trifluoroacetyl, monoiodoacetyl, 3-oxobutyryl, 4-chloro-3-oxobutyryl, phenylacetyl, p-chlorophenylacetyl, phenoxyacetyl, p-chlorophenoxyacetyl and the like are used. As the “C _3-5 alkenoyl group”, for example, acryloyl, crotonoyl, maleoyl, cinnamoyl, p-chlorocinnamoyl, β-phenylcinnamoyl and the like are used here. Examples of the “C _6-10 aryl-carbonyl group” include benzoyl, naphthoyl, p-toluoyl, p-tert-butylbenzoyl, p-hydroxybenzoyl, p-methoxybenzoyl, p-tert-butoxybenzoyl, p- Chlorobenzoyl, p-nitrobenzoyl and the like are used.

The "heterocyclic group" in the "heterocyclic carbonyl group" refers to a group formed by removing one hydrogen atom bonded to a carbon atom of the heterocyclic ring, and such a heterocyclic ring is, for example, a nitrogen atom ( 5 to 8 membered ring containing 1 to several, preferably 1 to 4 heteroatoms such as (optionally oxidized), oxygen atom and sulfur atom, or a condensed ring thereof. Specific examples of such a heterocyclic group include 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, 2-, 4-
Or 5-imidazolyl, 1,2,3- or 1,2,
4-triazolyl, 1H- or 2H-tetrazolyl,
2- or 3-furyl, 2- or 3-thienyl, 2
-, 4- or 5-oxazolyl, 3-, 4- or 5
-Isoxazolyl, 1,2,3-oxadiazole-4
-Or 5-yl, 1,2,4-oxadiazole-3
-Or 5-yl, 1,2,5- or 1,3,4-oxadiazolyl, 2-, 4- or 5-thiazolyl, 3
-, 4- or 5-isothiazolyl, 1,2,3-thiadiazol-4- or 5-yl, 1,2,4-thiadiazol-3- or 5-yl, 1,2,5- or 1,3 4-thiadiazole, 2- or 3-pyrrolidinyl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide, 3- or 4-pyridazinyl, 3- or 4-pyridazinyl-N -Oxide, 2
-, 4- or 5-pyrimidinyl, 2-, 4- or 5
-Pyrimidinyl-N-oxide, pyrazinyl, 2,3
-Or 4-piperidinyl, piperazinyl, 3H-indol-2- or 3-yl, 2-, 3- or 4-pyranyl, 2-, 3- or 4-thiopyranyl, benzopyranyl, quinolyl, pyrido [2,3-d ] Pyrimidyl,
1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl, thieno [2,3-d] pyridyl, pyrimidopyridyl, pyrazinoquinolyl, benzopyranyl and the like are used. . As the "C _1-6 alkylsulfonyl group", for example, methanesulfonyl, ethanesulfonyl and the like are used. "C _6-10 arylsulfonyl group"
Here, for example, benzenesulfonyl, naphthalenesulfonyl, p-toluenesulfonyl, p-tert-butylbenzenesulfonyl, p-methoxybenzenesulfonyl, p-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl and the like are used.

The "substituted oxycarbonyl group" is C _1-10
Alkoxy-carbonyl group (eg, methoxycarbonyl,
Ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, cyclopropyloxycarbonyl,
Cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, norbornyloxycarbonyl, etc.), C
_6-10 aryloxy-carbonyl group (eg, phenoxycarbonyl, naphthyloxycarbonyl etc.) or C _7-19
In addition to aralkyloxy-carbonyl groups (eg, benzyloxycarbonyl, benzhydryloxycarbonyl, etc.), they may further be C _1-4 alkoxy groups (eg, methoxy, ethoxy, etc.), C _1-4 acyl groups (eg, acetyl). , propionyl, etc.), a substituted silyl group (later described substituted silyl group, eg, trimethylsilyl, tert- butyldimethylsilyl, etc.), C _1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.), halogen (e.g., fluorine , Chlorine, bromine, etc., cyano, C _1-4 alkyl groups (eg,
Substituent selected from methyl, ethyl, etc.), nitro, etc. is 1
Those having 3 to 3 are also included. Specifically, for example, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-
Trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-cyanoethoxycarbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, p-chlorophenoxycarbonyl, p-Methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and the like are used. Examples of the “optionally substituted carbamoyl group” include C _1-4 alkyl group (eg, methyl, ethyl etc.), phenyl group, C _1-7 acyl group (eg, acetyl, propionyl, benzoyl etc.), C _{1 A} carbamoyl group optionally substituted by 1 or 2 alkoxy- ₄ phenyl groups (eg, methoxyphenyl, etc.) is used, and examples thereof include N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N- (p-methoxyphenyl) carbamoyl and the like are used. As the “optionally substituted thiocarbamoyl group”, a C _1-4 alkyl group (eg, methyl, ethyl, etc.), a thiocarbamoyl group optionally substituted by 1 or 2 with a phenyl group, etc. is used, For example, thiocarbamoyl, N-methylthiocarbamoyl, N-phenylthiocarbamoyl and the like are used.

Examples of the "C _6-10 aryl-methyl group" include benzyl, naphthylmethyl, p-methylbenzyl, p-
Methoxybenzyl, p-chlorobenzyl, p-nitrobenzyl and the like are used. Examples of the “di C _6-10 aryl-methyl group” include benzhydryl, di (p-tolyl) methyl and the like. Examples of the “tri C _6-10 aryl-methyl group” include trityl, tri (p-tolyl) methyl and the like. As the “C _6-10 aryl-methylene group”, for example, benzylidene, p-methylbenzylidene, p-chlorobenzylidene and the like can be used. As the "C _6-10 arylthio group", for example, o-nitrophenylthio and the like are used. The “substituted silyl group” refers to an amino group to be protected and is represented by the general formula R ⁶ R ⁷ R ⁸ SiNH —, (R ⁶ R ⁷ R ⁸ Si) ₂
N- or

[Chemical formula 24] [Wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ⁹ ′ and R ¹⁰ ′ are each a C _1-6 alkyl group or a C _6-10 aryl group,
Z'represents a C _1-3 alkylene group]. As the “C _1-6 alkyl group”, a linear or branched C _1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl and n-pentyl is used. As the "C _6-10 aryl group",
Phenyl, naphthyl, etc. are used. As the "C _1-3 alkylene group", methylene, ethylene, propylene and the like are used. Specifically trimethylsilyl as substituted silyl group, tert- butyldimethylsilyl, -Si (CH _{3) 2} C
_{H 2 CH 2 Si (CH 3} ) 2 - , etc. can be used. "2-C _1-10
The C _1-10 alkoxy-carbonyl group of the "alkoxy-carbonyl-1-methyl-1-ethenyl group" is preferably the above-mentioned one, and therefore, the 2-C _1-10 alkoxy-carbonyl-1-methyl-1-ethenyl group is For example, 2-
Methoxycarbonyl-1-methyl-1-ethenyl, 2-
Ethoxycarbonyl-1-methyl-1-ethenyl, 2-t
ert-butoxycarbonyl-1-methyl-1-ethenyl,
2-cyclohexyloxycarbonyl-1-methyl-1
-Ethenyl, 2-norbornyloxycarbonyl-1-
Methyl-1-ethenyl and the like are used. As the alkali metal represented by M ′, for example, sodium, potassium and the like are preferable, and sodium and the like are particularly preferable. R
¹ is preferably an amino group from the viewpoint of antibacterial activity.

The optionally substituted 3- to 7-membered alicyclic hydrocarbon group or non-aromatic heterocyclic group represented by R ³ is, for example, C ₃ such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. _-7
A cycloalkyl group, for example C such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl
_4-7 cycloalkenyl groups, such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and other heteroatoms such as nitrogen atom, oxygen atom, sulfur atom, etc. A 3- to 6-membered non-aromatic heterocyclic group containing 1 or 2 of is used. As C _3-7 cycloalkyl,
For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are preferable. Especially cyclobutyl,
Cyclopentyl and the like are preferable. The ^3- to 7-membered alicyclic hydrocarbon group or non-aromatic heterocyclic group represented by R ³ is, for example, a C _1-4 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.), One or two of halogen (eg, fluorine, chlorine, bromine, etc.), hydroxyl group, amino group, etc. may be substituted.

[Chemical 25] [In the formula, B represents a 6-membered aromatic heterocycle in which the hetero atom is one or two nitrogen atoms], and imidazolium forming a condensed ring at the 2,3-position or 3,4-position. -1-
Represents an yl group.

The following are specifically used as the group [A ¹ ].

[Chemical formula 26] The following are specifically used as the group [A ² ].

[Chemical 27]

[Chemical 28]

In the above formulas [A ¹ ] and [A ² ] and their specific examples,

[Chemical 29] In some cases, a positive charge can be applied to the nitrogen atom at the 1st position. Further, in some cases, the monovalent positive charge is delocalized in the imidazole ring, and in some cases, it is also delocalized in the entire condensed ring.
So for example

[Chemical 30] It is also expressed as The position of this positive charge will change fluidly depending on the state of compound [I] (solid or solution), solvent type / liquidity, temperature, substituent group, etc.
The present invention includes both the case where the positive charge is localized at the nitrogen atom and the case where it is delocalized throughout the imidazole ring or the condensed ring.

The group represented by the formula [A ¹ ] or [A ² ] is
The imidazole ring or / and ring B is preferably 1
Alternatively, it may have two substituents. Examples of such substituents include hydroxyl group, hydroxy C _1-6 alkyl group, C
_1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group,
C _3-10 cycloalkyl group, C _5-6 cycloalkenyl group, C
_3-10 cycloalkyl C _1-6 alkyl group, C _6-10 aryl group, C _7-12 aralkyl group, heterocyclic group, C _1-6 alkoxy group,
C _1-6 alkoxy-C _1-6 alkyl group, amino C _1-6 alkoxy group, C _3-10 cycloalkyloxy group, C _6-10 aryloxy group, C _7-19 aralkyloxy group, mercapto group,
Mercapto C _1-6 alkyl group, sulfo group, sulfo C _1-6 alkyl group, C _1-6 alkylthio group, C _1-6 alkylthio C _1-6
Alkyl group, C _3-10 cycloalkylthio group, C _6-10 arylthio group, C _7-19 aralkylthio group, amino C _1-6 alkylthio group, amino group, amino C _1-6 alkyl group, mono C _1-6
Alkylamino group, di-C _1-6 alkylamino group, mono-C _1-6
Alkylamino C _1-6 alkyl group, di C _1-6 alkylamino C _1-6 alkyl group, C _3-10 cycloalkylamino group, C
_6-10 arylamino group, C _7-19 aralkylamino group, cyclic amino group, cyclic amino C _1-6 alkyl group, cyclic amino C _1-6
Alkylamino group, acylamino group, ureido group, C _1-6
Alkylureido group, azido group, nitro group, halogen atom, halogeno C _1-6 alkyl group, cyano group, cyano C _1-6 alkyl group, carboxyl group, carboxy C _1-6 alkyl group,
C _1-10 alkoxy-carbonyl group, C _1-10 alkoxy-
Carbonyl C _1-6 alkyl group, C _6-10 aryloxy-carbonyl group, C _7-19 aralkyloxy-carbonyl group, C
_6-10 aryl-acyl group, C _1-6 alkanoyl group, C _2-6 alkanoyl C _1-6 alkyl group, C _3-5 alkenoyl group, C
_6-10 aryl-acyloxy group, C _2-6 alkanoyloxy group, C _2-6 alkanoyloxy C _1-6 alkyl group, C _3-5
Alkenoyloxy group, carbamoyl C _1-6 alkyl group,
Carbamoyl group, thiocarbamoyl group, carbamoyloxy group, carbamoyloxy C _1-6 alkyl group, C _1-6 alkanoylamino group, C _6-10 aryl-acylamino group, sulfonamide group, carboxyamino group, C _1-10 alkoxy −
A carboxamide group, a _C6-10 aryloxy-carboxamide group, a _C7-19 aralkyloxy-carboxamide group and the like are used.

Here, the "C _1-6 alkyl group" is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like are used. "C _2-6
An "alkenyl group" has a straight or branched carbon number of 2
Alkenyl groups of 6 are preferred, for example vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-
Butenyl, 3-butenyl, methallyl, 1,1-dimethylallyl and the like are used. As the “C _2-6 alkynyl group”, a linear or branched alkynyl group having 2 to 6 carbon atoms is preferable, and for example, ethynyl, 1-propynyl, propargyl and the like can be used. The " _C3-10 cycloalkyl group" is preferably a 3- to 7-membered alicyclic hydrocarbon group having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl and the like. The "C _5-6 cycloalkenyl group" is preferably a 5- or 6-membered alicyclic hydrocarbon group having a double bond, and examples thereof include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl and the like.

The "C _6-10 aryl group" is preferably an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include phenyl, α-naphthyl, β-naphthyl, biphenylyl and the like.
The "C _7-12 aralkyl group" is preferably an aromatic substituted alkyl group having 7 to 12 carbon atoms, and for example, benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, naphthylmethyl and the like are used. The alkyl group of the "C _1-6 alkoxy group" is preferably the above C _1-6 alkyl group, and examples of the C _1-6 alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert- Butoxy, acyloxy, hexyloxy and the like are used.
The cycloalkyl group of the “C _3-10 cycloalkyloxy group” is preferably the above C _3-10 cycloalkyl group, and examples of the C _3-10 cycloalkyloxy group include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy,
Norbornyloxy or the like is used. "Amino C _1-6
Alkoxy groups of the alkoxy group "C _1-6 alkoxy group described above is preferred, as the amino C _1-6 alkoxy group such as amino, methoxy, 2-aminoethoxy, 3-aminopropoxy is used. The aryl group of the “C _6-10 aryloxy group” is preferably the above C _6-10 aryl group, and examples of the C _6-10 aryloxy group include phenoxy and naphthyloxy. Aralkyl group "C _7-19 aralkyloxy group" C _7-19 aralkyl group mentioned above are preferred, as the C _7-19 aralkyloxy group such as benzyloxy, 1-phenylethyloxy,
2-Phenylethyloxy, naphthylmethyloxy, benzhydryloxy, trityloxy and the like are used.
The alkyl group of the “C _1-6 alkylthio group” is preferably the above C _1-6 alkyl group, and examples of the C _1-6 alkylthio group include methylthio, ethylthio, n-propylthio, n-butylthio and the like.

The alkylthio group of "an amino C _1-6 alkylthio group" C _1-6 alkylthio group described above is preferred, as the amino C _1-6 alkylthio group such as amino methyl thio, 2-aminoethylthio, 3-amino Propylthio and the like are used. Cycloalkyl group "C _3-10 cycloalkylthio group" C _3-10 cycloalkyl group mentioned above are preferred, as the C _3-10 cycloalkylthio groups such as,
Cyclopropylthio, cyclohexylthio and the like are used. The aryl group of the “C _6-10 arylthio group” is the above C
_{A 6-10} aryl group is preferred, and examples of the C _6-10 arylthio group include phenylthio and naphthylthio. Aralkyl groups C _7-19 aralkyl groups described above are preferable "C _7-19 aralkylthio group", as the C _7-19 aralkylthio group such as benzylthio, phenylethylthio, benzhydryl Lucio, such as tritylthio is used . Alkyl groups C _1-6 alkyl group described above are preferable "hydroxy C _1-6 alkyl group", as the hydroxy C _1-6 alkyl group such as hydroxy methyl, 1-hydroxyethyl, 2-hydroxyethyl, 3- Hydroxypropyl or the like is used. "C _3-10 cycloalkyl C
The cycloalkyl group of " _1-6 alkyl group" is preferably the above C _3-10 cycloalkyl group, and the alkyl group is the above C _1-6
An alkyl group is preferable, and as the C _3-10 cycloalkyl C _1-6 alkyl group, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and the like can be used. Alkyl groups C _1-6 alkyl group described above are preferable "mercapto C _1-6 alkyl group", mercapto C _1-6 alkyl as a group for example mercaptomethyl, 1-mercaptoethyl, 2-mercaptoethyl are used .

The alkoxy group of the "C _1-6 alkoxy-C _1-6 alkyl group" is preferably the above C _1-6 alkoxy group, and the alkyl group is preferably the above C _1-6 alkyl group, and the C _1-6 alkoxy group is preferable. As the C _1-6 alkyl group, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl and the like are used.
The alkylthio group of the “C _1-6 alkylthio C _1-6 alkyl group” is preferably the above C _1-6 alkylthio group, and the alkyl group is preferably the above C _1-6 alkyl group, and is a C _1-6 alkylthio C _1-6.
Examples of the alkyl group include methylthiomethyl, 2-
Methylthioethyl or the like is used. Alkyl group "amino C _1-6 alkyl group" is preferably C _1-6 alkyl groups described above, for example, aminomethyl, 2-aminoethyl, 3-aminopropyl is used as an amino C _1-6 alkyl group To be "Mono C _1-6 alkylamino C _1-6 alkyl group"
As such, for example, methylaminomethyl, ethylaminomethyl, 2- (N-methylamino) ethyl, 3- (N-methylamino) propyl and the like are used. Examples of the “di C _1-6 alkylamino C _1-6 alkyl group” include N, N
-Dimethylaminomethyl, N, N-diethylaminomethyl, 2- (N, N-dimethylamino) ethyl, 2- (N, N-
Diethylamino) ethyl, 3- (N, N-dimethylamino)
Propyl or the like is used. The cyclic amino group of the “cyclic amino C _1-6 alkyl group” is preferably the cyclic amino group described later, and the alkyl group is preferably the above C _1-6 amino group. Examples of the cyclic amino C _1-6 alkyl group include pyrrolidinomethyl, piperidinomethyl, piperazinomethyl,
Morpholinomethyl, 2- (morpholino) ethyl and the like are used.

The cyclic amino C _1-6 alkyl group "cyclic amino C _1-6 alkylamino group" is the above-mentioned cyclic amino C _1-6 alkyl group is preferable, as the cyclic amino C _1-6 alkylamino group is, for example, Pyrrolidinoethylamino, piperidinoethylamino, piperazinoethylamino, morpholinoethylamino and the like are used. The alkyl group of the “halogeno C _1-6 alkyl group” is preferably the above C _1-6 alkyl group,
Examples of the halogeno C _1-6 alkyl group include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoro. Ethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2
-Iodoethyl and the like are used. Alkyl groups C _1-6 alkyl group described above are preferable "cyano C _1-6 alkyl group", as the cyano C _1-6 alkyl group for example, cyanomethyl, 2-cyanoethyl is used. Alkyl groups C _1-6 alkyl group described above are preferable "carboxy C _1-6 alkyl group", as the carboxy C _1-6 alkyl group for example, carboxymethyl, 1-carboxyethyl, 2
-Carboxyethyl and the like are used. Alkyl groups C _1-6 alkyl group described above are preferable "sulfo C _1-6 alkyl group", as sulfo C _1-6 alkyl group for example, sulfomethyl, 2-sulfoethyl, is used. "C _2-6
The alkanoyl group of "alkanoyl C _1-6 alkyl group" is preferably the C _1-6 alkanoyl group described later, and the alkyl group is preferably the above C _1-6 alkyl group. Examples of the C _2-6 alkanoyl C _1-6 alkyl group include acetylmethyl,
1-Acetylethyl, 2-acetylethyl and the like are used. The alkanoyloxy group of the "C _2-6 alkanoyloxy C _1-6 alkyl group" is preferably the C _2-6 alkanoyloxy group described later, and the alkyl group is preferably the above C _1-6 alkyl group. Examples of the C _2-6 alkanoyloxy C _1-6 alkyl group include acetoxymethyl, 1-acetoxyethyl, 2-acetoxyethyl and the like.

The alkoxycarbonyl group of the "C _1-10 alkoxy-carbonyl C _1-6 alkyl group" is preferably the C _1-10 alkoxy-carbonyl group described later, and the alkyl group is preferably the above-mentioned C _1-6 alkyl group. . Examples of the C _1-10 alkoxy-carbonyl C _1-6 alkyl group include methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-
Butoxycarbonylmethyl and the like are used. Alkyl group is preferably C _1-6 alkyl group "carbamoyloxy C _1-6 alkyl group", as carbamoyloxy C _1-6 alkyl group such as carbamoyloxy methyl is used. The alkyl group of the “mono C _1-6 alkylamino group” is preferably the above C _1-6 alkyl group, and examples of the mono C _1-6 alkylamino group include methylamino, ethylamino, n-propylamino, n- Butylamino, tert-
Butylamino, n-pentylamino, n-hexylamino and the like are used. The alkyl group of the “diC _1-6 alkylamino group” is preferably the above C _1-6 alkyl group, and examples of the diC _1-6 alkylamino group include dimethylamino, diethylamino, methylethylamino, di- (n -Propyl) amino, di- (n-butyl) amino and the like are used. "C
_The cycloalkyl group of the “ _3-10 cycloalkylamino group” is preferably the above C _3-10 cycloalkyl group, and examples of the C _3-10 cycloalkylamino group include cyclopropylamino, cyclopentylamino, cyclohexylamino and the like. . The aryl group of the “C _6-10 arylamino group” is preferably the above C _6-10 aryl group, and examples of the C _6-10 arylamino group include anilino and N-methylanilino. The aralkyl group of the “C _7-19 aralkylamino group” is preferably the above C _7-19 aralkyl group,
As the C _7-19 aralkylamino group, for example, benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino, tritylamino and the like can be used. "Cyclic amino group" refers to a group capable of removing one hydrogen atom bonded to a ring-forming nitrogen atom of a nitrogen-containing heterocyclic ring or a saturated double bond thereof as described later, for example, 1H-tetrazole- 1-yl, 1H-
Pyrrol-1-yl, pyrrolino, pyrrolidino, 1H-imidazol-1-yl, imidazolino, imidazolidino, 1
H-pyrazol-1-yl, pyrazolino, pyrazolidino,
Piperidino, piperazino, morpholino, etc. are used.

As the acyl group in the "acylamino group", an alkanoyl group (eg C _1-6 alkanoyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.), an alkenoyl group (eg acryloyl, crotonoyl). , C _3-5 alkenoyl groups such as maleoyl), cycloalkylcarbonyl groups (eg cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, adamantylcarbonyl etc., C _3-10 cycloalkyl-carbonyl) Groups, etc.), cycloalkenylcarbonyl groups (eg cyclopentenylcarbonyl, cyclopentadienylcarbonyl, cyclohexenylcarbonyl, cyclohexadienylcarbonyl, Carbonyl group and the like), an arylcarbonyl group (e.g., benzoyl, C _6-10 aryl such as naphthoyl - - C _5-6 cycloalkenyl such as a carbonyl group), an aralkyl group (e.g., phenylacetyl, phenylpropionyl, alpha, alpha −
C _7-19 aralkyl-carbonyl group such as diphenylacetyl, α, α, α-triphenylacetyl, etc., amino acid residue (acyl group capable of removing hydroxyl group of amino acid carboxyl group, specifically, for example, glycyl , Sarcosyl, alanyl, valyl, leucyl, isoleucyl, ceryl, threonyl, cysteinyl, cystinyl,
Methionyl, asparagyl, glutamyl, lysyl, arginyl, phenylglycyl, phenylalanyl, tyrosyl, histidyl, tryptophanyl, prolyl, etc.),
Aminoalkylcarbonyl group (eg, amino C _1-6 alkyl-carbonyl group such as 2-aminoethylcarbonyl, 3-aminopropylcarbonyl, etc.), monoalkylaminoalkylcarbonyl group (eg, methylaminomethylcarbonyl, 2-ethylamino) Mono C _1-6 alkylamino C _1-6 alkyl-carbonyl group such as ethylcarbonyl), dialkylaminoalkylcarbonyl group (eg, di C _1-6 alkylamino C ₁ -such as dimethylaminomethylcarbonyl, diethylaminomethylcarbonyl) ₆ alkyl-carbonyl group and the like), cyclic aminoalkylcarbonyl group (the above-mentioned is used as the cyclic amino group, for example, imidazolinomethyl, pyrazolinoethyl, etc.) and the like.

The alkyl group of the "C _1-10 alkoxy-carbonyl group" includes a lower alkyl group having 1 to 8 carbon atoms and the above C _3-10 cycloalkyl group. Examples of the C _1-10 alkoxy-carbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
Isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, norbornyloxycarbonyl and the like are used. The aryloxy group of the “C _6-10 aryloxy-carbonyl group” is preferably the above C _6-10 aryloxy group, and examples of the C _6-10 aryloxy-carbonyl group include phenoxycarbonyl and naphthyloxycarbonyl. To be The aralkyloxy group of the "C _7-19 aralkyloxy-carbonyl group" is preferably the above C _7-19 aralkyloxy group, and for example, benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl and the like can be used. The substituted sulfonyl group of the sulfonamide group is preferably an “alkylsulfonyl group”, and the alkyl group is preferably the above C _1-6 alkyl group, and for example, methanesulfonyl, ethanesulfonyl and the like can be used.

As the halogen atom, fluorine, chlorine, bromine or the like is used here. The alkyl group of the “C _1-6 alkylureido group” is preferably the above C _1-6 alkyl group, and examples of the C _1-6 alkylureido group include methylureido, ethylureido, n-propylureido and the like. The aryl group of " _C6-10 aryl-acyl group" is preferably the above _C6-10 aryl group, and the acyl group is preferably the acyl group of "acylamino group" above. C
_{As the 6-10} aryl-acyl group, for example, phenylacetyl or the like is used. Examples of the “C _1-6 alkanoyl group” include acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl and the like are used. As the "C _3-5 alkenoyl group", for example, acryloyl, crotonoyl, maleoyl and the like are used. The aryl group of the "C _6-10 aryl-acyloxy group" is preferably the above C _6-10 aryl group, and the acyl group is preferably the acyl group of the above "acylamino group". Examples of the C _6-10 aryl-acyloxy group include phenylacetyloxy and the like. "C
_3-5 alkenoyl group alkenoyloxy group "C _3-5 alkenoyl group mentioned above are preferred, as the C _3-5 alkenoyloxy group e.g., acryloyloxy, crotonoyloxy oxy, such as maleoyl oxy is used.
Alkyl groups C _1-6 alkyl group described above are preferable "carbamoyl C _1-6 alkyl group", carbamoyl C _1-6 alkyl group for example, carbamoylmethyl, 2-carbamoylethyl is used. The alkanoyl group of the “C _1-6 alkanoylamino group” is preferably the above C _1-6 alkanoyl group, and examples of the C _1-6 alkanoylamino group include formylamino and acetylamino. The aryl group of the “C _6-10 aryl-acylamino group” is preferably the above C _6-10 aryl group, and the acyl group is preferably the above acyl group. Examples of the C _6-10 aryl-acylamino group include phenylacetylamino and the like. The alkoxy group of the “C _1-10 alkoxy-carboxamide group” is preferably the above C _1-10 alkoxy group, and examples of the C _1-10 alkoxy-carboxamide group include methoxycarboxamide and ethoxycarboxamide. The aryl group of the “C _6-10 aryloxy-carboxamide group” is preferably the above C _6-10 aryl group, and examples of the C _6-10 aryloxy-carboxamide include phenyloxycarboxamide and the like.

The aralkyl group of the “C _7-19 aralkyloxy-carboxamide group” is preferably the above C _7-19 aralkyl group, and examples of the C _7-19 aralkyloxy-carboxamide include benzyloxycarboxamide and the like. "Heterocyclic group" refers to a group formed by removing one hydrogen atom bonded to a carbon atom of a heterocycle, and such a heterocycle is, for example, a nitrogen atom (which may be oxidized), oxygen. A 5- to 8-membered ring containing 1 to several, preferably 1 to 4 heteroatoms such as atoms and sulfur atoms, or a condensed ring thereof. Specific examples of such a heterocyclic group include 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 1, 2,
3-or 1,2,4-triazolyl, 1H- or 2
H-tetrazolyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-oxazolyl, 3
-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,2,5- or 1,3,4-oxadiazolyl, 2-, 4- or 5
-Thiazolyl, 3-, 4- or 5-isothiazolyl,
1,2,3-thiadiazol-4- or 5-yl,
1,2,4-thiadiazol-3- or 5-yl,
1,2,5- or 1,3,4-thiadiazole, 2- or 3-pyrrolidinyl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide, 3
-Or 4-pyridazinyl, 3- or 4-pyridazinyl-N-oxide, 2-, 4- or 5-pyrimidinyl, 2-, 4- or 5-pyrimidinyl-N-oxide, pyrazinyl, 2-, 3- or 4 -Piperidinyl,
Piperazinyl, 3H-indol-2- or 3-yl, 2-, 3- or 4-pyranyl, 2-, 3- or 4-thiopyranyl, benzopyranyl, quinolyl, pyrido [2,3-d] pyrimidyl, 1,5 -, 1, 6-, 1,
7-, 1,8-, 2,6- or 2,7-naphthyridyl, thieno [2,3-d] pyridyl, pyrimidopyridyl, pyrazinoquinolyl, benzopyranyl and the like are used.

[Chemical 31] [Wherein R ² and R ² 'represent a hydrogen atom on one side and an amino group which may be substituted on the other side (eg, amino group, ureido group, glycylamino group, formylamino group, etc.)] Groups are preferred.

[0027]

[Chemical 32] The silyl group is a carboxylate anion and the substituent A
It shows that it forms an inner salt by pairing with the above positive charge. On the other hand, compound [I] may form a pharmacologically acceptable ester or salt. As the pharmacologically acceptable salts, inorganic base salts, ammonium salts, organic base salts,
Inorganic acid addition salts, organic acid addition salts, basic amino acid salts, etc. are used. Inorganic bases capable of forming inorganic base salts include alkali metals (eg sodium, potassium etc.), alkaline earth metals (eg calcium etc.) and organic bases capable of forming organic base salts eg procaine, 2-phenyl. Ethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine,
Trishydroxymethylaminomethane, polyhydroxyalkylamine, N-methylglucosamine and the like are inorganic acids capable of forming an inorganic acid addition salt, such as hydrochloric acid,
Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. are organic acids capable of forming organic acid addition salts, such as p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, etc. Examples of the basic amino acid capable of forming an amino acid salt include lysine, arginine, ornithine and histidine. Of these salts, base salts (that is, inorganic base salts, ammonium salts, organic base salts,
The basic amino acid salt) is a substituent R ¹ or R ³ of the compound [I] or

[Chemical 33] Means an acid addition salt that can be formed when a basic group such as a monoalkylamino group, a dialkylamino group, a cycloalkylamino group, an arylamino group, an aralkylamino group, a cyclic amino group or a nitrogen-containing heterocyclic group is present. To do. Also, as an acid addition salt,

[Chemical 34] For example, chloride ion, bromide ion, sulfate ion, p-toluenesulfonate ion, methanesulfonate ion, trifluoroacetate ion, etc.] are also included. The ester derivative of the compound [I] means an ester that can be produced by esterifying a carboxyl group contained in the molecule, and is an ester that can be used as a synthetic intermediate and a metabolically unstable nontoxic ester. As the ester that can be used as a synthetic intermediate, an optionally substituted C _1-6 alkyl ester, C _2-6 alkenyl ester, C _3-10 cycloalkyl ester, C _3-10 cycloalkyl C _1-6 alkyl ester,
C _6-10 aryl ester which may be substituted, C _7-12 aralkyl ester which may be substituted, di C _6-10 aryl-methyl ester, tri C _6-10 aryl-methyl ester, substituted silyl ester, etc. Is used.

Examples of the optionally substituted C _1-6 alkyl ester include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-
Butyl, n-pentyl, n-hexyl and the like are used, for example, benzyloxy, C _1-4 alkylsulfonyl (eg, methylsulfonyl etc.), trimethylsilyl, halogen (eg fluorine, chlorine, bromine etc.), acetyl. , Nitrobenzoyl, mesylbenzoyl, phthalimide, succinimide, benzenesulfonyl, phenylthio, di-C
_1-3 alkylamino (eg, dimethylamino, etc.), pyridyl, C _1-4 alkylsulfinyl (eg, methylsulfinyl, etc.), cyano, etc. may be substituted one to three,
Specific examples of such a group include benzyloxymethyl, 2-methylsulfonylethyl, 2-trimethylsilylethyl, 2,2,2-trichloroethyl, 2-iodoethyl, acetylmethyl, p-nitrobenzoylmethyl, p
-Mesylbenzoylmethyl, phthalimidomethyl, succinimidomethyl, benzenesulfonylmethyl, phenylthiomethyl, dimethylaminoethyl, pyridine-1-oxide-2-methyl, methylsulfinylmethyl, 2-cyano-1,1-dimethylethyl, etc. Used. C _2-6 vinyl as C _2-6 alkenyl group forming the alkenyl ester, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, methallyl, 1,1-dimethylallyl, 3 -Methyl-3-butenyl and the like are used. _{Examples of} the C _3-10 cycloalkyl group forming a C _3-10 cycloalkyl ester include cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, etc. are used. _{Examples of} the C _3-10 cycloalkyl C _1-6 alkyl group forming C _3-10 cycloalkyl C _1-6 alkyl ester include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like. Examples of the “C _6-10 aryl group” which forms an _optionally substituted C _6-10 aryl ester include phenyl, α-naphthyl, β-naphthyl, biphenylyl and the like, and these include, for example, nitro, halogen ( (Eg, fluorine, chlorine, bromine, etc.), etc., and 1 to 3 of them may be substituted.
-Nitrophenyl, p-chlorophenyl, etc. are used.

Examples of the "C _7-12 aralkyl group" which forms an _optionally substituted C _7-12 aralkyl ester include benzyl, 1-phenylethyl, 2-phenylethyl,
Phenylpropyl, naphthylmethyl and the like are used, and they are substituted with, for example, nitro, C _1-4 alkoxy (eg, methoxy, etc.), C _1-4 alkyl (eg, methyl, ethyl, etc.), 1 to 3 with hydroxy. As such a group, for example, p-nitrobenzyl, p-methoxybenzyl, 3,5-ditert-butyl-4-hydroxybenzyl and the like are specifically used. Di C _6-10 aryl - di C _6-10 aryl to form a methyl ester - such as benzhydryl as methyl group, tri-C _6-10 aryl - The methyl - tri C _6-10 aryl to form the methyl ester trityl, etc., trimethylsilyl Examples of the substituted silyl group forming the substituted silyl ester, tert- _{butyldimethylsilyl, -Si (CH 3) 2 CH} 2 CH 2 Si (CH 3) 2 -
Are used. The above-mentioned ester also includes the 4-position ester. In this way, 4-position is the above ester group

[Chemical 35] Is formed.

The present invention includes, in addition to the above ester derivative, a pharmacologically acceptable compound which is converted into the compound [I] in vivo.

[Chemical 36] In that case, the amino group may be substituted. As such a substituent of the amino group, the protecting group for the optionally protected amino group represented by R ¹ or the like is used as it is. The production method of the compound [I] of the present invention is described in detail below.

Production method (1): For example, general formula [II]

[Chemical 37] [The symbols in the formula have the same meanings as described above] (hereinafter abbreviated as R ^b OH)
Compound [I] can be synthesized by reacting with a carboxylic acid represented by or a salt or reactive derivative thereof.

The present method is a method of acylating a 7-amino compound [II] with a carboxylic acid R ^b OH or a salt or reactive derivative thereof. In this method the carboxylic acid R ^b O
H is free or its salt or reactive derivative is used as an acylating agent for the 7-amino group of the 7-amino compound [II]. That is, the free acid R ^b OH or a reactive derivative of the free acid R ^b OH such as an inorganic base salt, an organic base salt, an acid halide, an acid azide, an acid anhydride, a mixed acid anhydride, an active amide, an active ester or an active thioester can be prepared. It is subjected to an acylation reaction. Inorganic base salts include alkali metal salts (for example, sodium salt, potassium salt, etc.), alkaline earth metal salts (for example, calcium salt, etc.), and organic base salts include, for example, trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt. , Dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt and the like, acid halides such as acid chloride and acid bromide, and mixed acid anhydrides such as mono-C _{1 -6} alkyl carbonate mixed acid anhydride
(For example, free acid R ^b OH and monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monoisobutyl carbonate, mono t
ert-butyl carbonate, monobenzyl carbonate, mixed acid anhydride with mono (p-nitrobenzyl) carbonate, monoallyl carbonate, etc., C
_1-6 aliphatic carboxylic acid mixed acid anhydride (for example, free acid R ^b
OH and acetic acid, trichloroacetic acid, cyanoacetic acid, propionic acid,
Butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, mixed acid anhydride with acetoacetic acid, etc., C _7-12 aromatic carboxylic acid mixed acid anhydride (for example, free acid R ^b OH and mixed acid anhydride of benzoic acid, p-toluic acid, p-chlorobenzoic acid, etc., organic sulfonic acid mixed acid anhydride (for example, free acid R ^b OH and methanesulfonic acid, ethanesulfonic acid, benzenesulfone) Acid, a mixed acid anhydride with p-toluenesulfonic acid, etc., is an amide with a nitrogen-containing heterocyclic compound as an active amide (for example, a free acid R ^b OH).
Acid pyramide, imidazole, benzotriazole, etc., and these nitrogen-containing heterocyclic compounds are C _1-6 alkyl groups (eg, methyl, ethyl, etc.), C _1-6 alkoxy groups (eg , methoxy, ethoxy, etc.), a halogen atom (e.g., fluorine, chlorine, bromine, etc.), oxo group, thioxo group, C _1-6 alkylthio group (e.g., methylthio, may be substituted, etc. ethylthio)), etc. Can be given. As the active ester, β-lactam and all those used for this purpose in the field of peptide synthesis can be used, for example, organic phosphates (for example, diethoxyphosphate, diphenoxyphosphate, etc.) and p-nitrophenyl ester, 2,4-Dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazol ester Examples include 1,1-hydroxy-1H-2-pyridone ester. As the active thioester, an ester with an aromatic heterocyclic thiol compound (for example, 2-
Pyridyl thiol ester, 2-benzothiazolyl thiol ester, etc., and these heterocycles are C _1-6 alkyl groups (eg, methyl, ethyl, etc.), C _1-6 alkoxy groups (eg, methoxy, ethoxy, etc.), Halogen atom (eg, fluorine, chlorine, bromine, etc.), C _1-6 alkylthio group (eg, methylthio,
Ethylthio and the like) may be substituted). On the other hand, the 7-amino compound [II] is used as its salt or ester in a free state. Examples of salts of the 7-amino compound [II] include inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, organic acid addition salts and the like. Inorganic base salts include alkali metal salts (for example, sodium salt, potassium salt, etc.), alkaline earth metal salts (for example, calcium salt, etc.), and organic base salts include, for example, trimethylamine salt, triethylamine salt, tert-butyldimethylamine. Salt, dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt,
Pyridine salt, quinoline salt, etc., inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., organic acid addition salts such as formate, acetate, trifluoroacetic acid Salt, methane sulfonate, p-toluene sulfonate, etc. may be mentioned. As the ester of the 7-amino compound [II], the ester already described as the ester derivative of the compound [I] can be directly used here. That is, C _1-6 alkyl ester, C _2-6 alkenyl ester, C _3-10 cycloalkyl ester, C _3-6 cycloalkyl C _1-6 alkyl ester, C _6-10 aryl ester,
C _7-12 aralkyl ester, di C _{6-10 arylmethyl} ester, tri C _{6-10 arylmethyl} ester, C _2-6 alkanoyloxy C _1-6 alkyl ester and the like can be mentioned. The raw material R ^b OH and its salt / reactive derivative can be easily produced by a known method (for example, the method described in JP-A-60-231684, JP-A-62-149682) or a method analogous thereto. The reactive derivative of compound R ^b OH is 7 as the material isolated from the reaction mixture.
- may be reacted with the amino compound [II], or the reaction mixture containing the isolated reactive derivative of the previous compound R ^b OH may be reacted with as 7-amino compound [II]. When the carboxylic acid R ^b OH is used in the free acid or salt form, a suitable condensing agent is used. Examples of the condensing agent include N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide, and azolides such as N, N'-carbonyldiimidazole and N, N'-thiocarbonyldiimidazole. , Such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene and other dehydrating agents, such as 2-chloropyridinium methyl iodide, 2-fluoropyridinium methyl iodide and the like. Halogenopyridinium salts and the like are used. When these condensing agents are used, the reaction is considered to proceed via the reactive derivative of carboxylic acid R ^b OH.
The reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include dioxane, tetrahydrofuran, diethyl ether, ter.
Ethers such as t-butyl methyl ether, diisopropyl ether, ethylene glycol-dimethyl ether, etc., such as ethyl formate, ethyl acetate, n-butyl acetate, etc., such as dichloromethane, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, trichlene and 1,2-dichloroethane, such as n-hexane, benzene,
Hydrocarbons such as toluene, eg formamide, N,
Amides such as N-dimethylformamide and N, N-dimethylacetamide, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, sulfolane and hexamethyl Phosphoramide and water are used alone or as a mixed solvent. The amount of the acylating agent (R ^b OH) used is usually about 1-5 mol, preferably about 1-2 mol, per 1 mol of the 7-amino compound [II]. The reaction is carried out in the temperature range of about -80 to 80 ° C, preferably about -40 to 50 ° C, most preferably about -30 to 30 ° C. The reaction time is 7-amino compound [II]
It is usually about 1 minute to 72 hours, preferably about 15 minutes to 3 hours, depending on the kind of carboxylic acid R ^b OH, the kind of solvent (also the mixing ratio in the case of a mixed solvent), the reaction temperature and the like. When an acid halide is used as the acylating agent, the reaction can be carried out in the presence of a deoxidizing agent for the purpose of removing released hydrogen halide from the reaction system. Examples of such deoxidizers include inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogencarbonate, such as triethylamine, tri (n-propyl) amine, tri (n-butyl).
Amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N
-Tertiary amines such as dimethylaniline, N-methylpiperzine, N-methylpyrrolidine and N-methylmorpholine,
Examples include alkylene oxides such as propylene oxide and epichlorohydrin.

The starting material for this reaction is a 7-amino compound [II] or its ester or salt thereof, for example, represented by the general formula [VII]

[Chemical 38] [Wherein, R ⁵ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group or a halogen atom] or a general formula which may be substituted with an ester or salt thereof [IV]

[Chemical Formula 39] It can be synthesized by reacting with an imidazole compound or a salt thereof which forms a condensed ring at the 2,3-position or 3,4-position represented by [the symbols in the formula are as defined above]. The compound [VII] or its ester or salt thereof as the starting material here can be prepared by a known method (see, for example, Japanese Patent Application Laid-Open No. 6-58242).
0-231684, JP-A-62-149682, etc.) or a method analogous thereto, and is a compound that can be easily obtained. Regarding the salt and ester of compound [VII], the same salt and ester as the salt and ester of compound [II] are used here.

The acyloxy group represented by R ⁵ includes acetoxy, chloroacetoxy, propionyloxy, butyryloxy, pivaloyloxy, 3-oxobutyryloxy, 4-chloro-3-oxobutyryloxy, 3
-Carboxypropionyloxy, 4-carboxybutyryloxy, 3-ethoxycarbamoyl propionyloxy, benzoyloxy, o-carboxybenzoyloxy, o- (ethoxycarbonylcarbamoyl) benzoyloxy, o- (ethoxycarbonylsulfamoyl) benzoyloxy, etc. Is preferred. The substituted carbamoyloxy group represented by the symbol R ⁵ is preferably methylcarbamoyloxy, N, N-dimethylcarbamoyloxy or the like. The halogen atom represented by the symbol R ⁵ is preferably chlorine, bromine, iodine or the like. The imidazole compound [IV] and its salt will be described in detail later. In this reaction, the reaction proceeds in the same manner as above even if the 7-amino group is protected. After the reaction, if necessary, the protecting group can be removed to give a 7-amino compound [II].

Production method (2): general formula [III]

[Chemical 40] [Wherein the symbols have the same meanings as defined above] or a compound or ester thereof or a salt thereof and an imidazole compound or salt thereof represented by the general formula [IV] to react the compound [I] Can be synthesized.

In this reaction, the imidazole compound [IV] or its salt is reacted with the compound [III] or its ester or its salt (hereinafter sometimes abbreviated as compound [III]) to give a nucleophilic substitution reaction. Is a method for synthesizing the compound [I]. The compound [III] is used as its salt or ester as it is. Compound [III]
As the salt and ester of the above, those mentioned as the salt and ester of the 7-amino compound [II] in the above-mentioned production method (1) can be directly applied here. Compound [III], its salt and ester can be prepared by known methods (for example, JP-A-60-2).
No. 31684, JP-A No. 62-149682, etc.) or a method analogous thereto. On the other hand, as the imidazole compound [IV],

[Chemical 41] The substituents mentioned above and the like are also used here. The imidazole compound [IV] is also used as a salt. Examples of the salt of compound [IV] include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., such as formate, acetate, trifluoroacetate, methanesulfonate, Examples thereof include organic acid addition salts such as p-toluenesulfonate. General methods for synthesizing imidazole compounds [IV] and salts thereof are known, and are described in, for example, JP-A-60
It can be easily produced by the method described in JP-A-231468 or JP-A-62-149682 or a method analogous thereto. The nucleophilic substitution reaction of compound [III] with imidazole compound [IV] or a salt thereof is usually carried out in a solvent. The solvent used in this reaction is the above-mentioned production method.
Ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles used in (1),
A solvent such as water can be directly applied, but in addition to these, for example, methanol, ethanol, n-propanol,
Alcohols such as isopropanol, ethylene glycol, and 2-methoxyethanol can also be used. When the imidazole compound [IV] is a liquid, this compound [IV]
May be used also as a solvent by using a large excess (for example, 10 to 200 times mol) with respect to the compound [III]. In this case, the above solvent may not be used, or the above solvent and [IV] may be used as a mixed solvent.

When R ⁵ is an acyloxy group, a carbamoyloxy group or a substituted carbamoyloxy group in the compound [III]: A more preferable solvent is water or a mixed solvent of water and an organic solvent which can be mixed with water, and the mixture is mixed with water. Among the organic solvents that can be used, more preferable ones are acetone, methyl ethyl ketone, acetonitrile and the like. The amount of the nucleophile [IV] to be used is generally about 1-5 mol, preferably about 1-3 mol, relative to 1 mol of the compound [III]. The reaction is carried out in the temperature range of about 10-100 ° C, preferably about 30-80 ° C. The reaction time depends on the type of compound [III] and compound [IV], the type of solvent
(In the case of a mixed solvent, the mixing ratio thereof), the reaction temperature, etc., and is usually about 30 minutes to 5 days, preferably about 1 to 5 hours. The reaction is pH 2-8, preferably near neutral or pH
It is advantageous to carry out 5-8. This reaction is usually 2 to
It proceeds more easily in the presence of 30 equivalents of iodide or thiocyanate. Examples of such salts include sodium iodide, potassium iodide, sodium thiocyanate, potassium thiocyanate and the like. In some cases, in addition to the above salts, a quaternary ammonium salt having a surface-active action such as trimethylbenzylammonium bromide, triethylbenzylammonium bromide and triethylbenzylammonium hydroxide can be added to allow the reaction to proceed smoothly. .

When R ⁵ is a hydroxyl group in the compound [III]: For example, it is carried out in the presence of an organophosphorus compound according to the method described in JP-A-58-43979. Examples of the organic phosphorus compound used here include
o-Phenylene phosphorochloridate, o-phenylene phosphorofluoride, methyl o-phenylene phosphate, ethyl o-phenylene phosphate, propyl o-phenylene phosphate, isopropyl o-phenylene phosphate, butyl o-phenylene phosphate , Isobutyl o-phenylene phosphate, s
ec-butyl o-phenylene phosphate, cyclohexyl o-phenylene phosphate, phenyl o-phenylene phosphate, p-chlorophenyl o-phenylene phosphate, p-acetyl o-phenylene phosphate, 2-chloroethyl o-phenylene phosphate, 2,2,2-Trichloroethyl o-phenylene phosphate, ethoxycarbonylmethyl o-phenylene phosphate, carbamoylmethyl o-phenylene phosphate, 2-cyanoethyl o-phenylene phosphate, 2-methylsulfonylethyl o-phenylene phosphate , Benzyl o-phenylene phosphate, 1,1-dimethyl-2-propenyl o-phenylene phosphate, 2-propenyl o-phenylene phosphate, 3-methyl-2-butenyl o-phenylene phosphate , 2-thienylmethyl o-phenylene phosphate, 2-furfurylmethyl o-phenylene phosphate, bis-o-phenylenepyrophosphate, 2
-Phenyl-1,3,2-benzodioxaphosphole-2
-Oxide, 2- (p-chlorophenyl) -1,3,2-benzodioxaphosphor-2-oxide, 2-butyl-
1,3,2-benzodioxaphosphor-2-oxide,
2-anilino-1,3,2-benzodioxaphosphole-
2-oxide, 2-phenylthio-1,3,2-benzodioxaphosphole-2-oxide, 2-methoxy-5
Methyl-1,3,2-benzodioxaphosphole-2-oxide, 2-chloro-5-ethoxycarbonyl-1,3,
2-Benzodioxaphospho-2-oxide, 2-methoxy-5-ethoxycarbonyl-1,3,2-benzodioxaphospho-2-oxide, 5-ethoxycarbonyl-2-phenyl-1, 3,2-benzodioxaphosphole-2-oxide, 2,5-dichloro-1,3,2-benzodioxaphosphole-2-oxide, 4-chloro-
2-methoxy-1,3,2-benzodioxaphosphole-
2-oxide, 2-methoxy-4-methyl-1,3,2-
Benzodioxaphosphole-2-oxide, 2,3-naphthalene methyl phosphate, 5,6-dimethyl-2-
Methoxy-1,3,2-benzodioxaphosphole-2-
Oxide, 2,2-dihydro-4,5,6,7-tetrachloro-2,2,2-trimethoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-4,5, 6,7-Tetrachloro-2,2,2-triphenoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-2,2-ethylenedioxy-2-methoxy-1,3 , 2-Benzodioxaphosphole, 2,2-dihydro-2-benzyl-2,2-
Dimethoxy-1,3,2-benzodioxaphosphole,
2,2-Dihydro-4,5-benzo-2,2,2-trimethoxy-1,3,2-benzodioxaphosphole, 2,2-
Dihydro-2,2,2-triphenoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-2,2- (o-
(Phenylenedioxy) -2-phenoxy-1,3,2-benzodioxaphosphole, 2-chloro-2,2-dihydro-2,2- (o-phenylenedioxy) -1,3,2- Benzodioxaphosphole, 2,2-dihydro-2-methoxy-2,2- (o-phenylenedioxy) -1,3,2-benzodioxaphosphole, 2,2-dihydro-2, 2,2-
Trichloro-1,3,2-benzodioxaphosphole,
9,10, -Phenanthrene dioxytrimethoxyphosphorus, o-phenylene phosphorochloridite, o-phenylene phosphorobromidite, o-phenylene phosphorofluoridite, methyl o-phenylene phosphite, butyl o-phenylenephos Phyto, methoxycarbonylmethyl o-phenylene phosphite, phenyl o-phenylene phosphite, p-chloro (or p-nitro) phenyl o-phenylene phosphite, 2-phenyl-
1,3,2-benzodioxaphosphole, bis-o-phenylenepyrophosphite, 2-methoxy-5-methyl-
1,3,2-benzodioxaphosphole, 5-acetyl-
2-phenoxy-1,3,2-benzodioxaphospho-
Le, 9,10-phenanthrene phosphorochloridite, 2
-Chloro-4-methyl-1,3,2-benzodioxaphosphole, 5-ethoxycarbonyl-2-phenyl-1,
3,2-benzodioxaphosphole, 2-chloro-2-
Thioxo-1,3,2-benzodioxaphosphole, 2-
Phenoxy-2-oxo-1,3,2-benzodiazaphosphole, 2-phenoxy-1,3,2-benzodioxaazaphosphole, 2,2-dihydro-2-oxo-2-methoxy 4,5-dimethyl-1,3,2-dioxaphosphole, 2,2-dihydro-2-oxo-2-chloro-4,
5-dimethyl-1,3,2-dioxaphosphole, 2,2
-Dihydro-2-oxo-2- (1-imidazolyl)-
4,5-dimethyl-1,3,2-dioxaphosphole, 2,
2-dihydro-2,2-ethylenedioxy-2-methoxy-4,5-dimethyl-1,3,2-dioxaphospho-
2,2-dihydro-2,2-dimethoxy-2-phenoxy-4,5-dimethyl-1,3,2-dioxaphospho-
2,2,2-dihydro-2,2,2-trimethoxy-4,5
-Dimethyl-1,3,2-dioxaphosphole, 2,2-
Dihydro-2,2,2-triphenoxy-4,5-dimethyl-1,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-triethoxy-4,5-diphenyl-1,
3,2-dioxaphosphole, 2,2-dihydro-2,2,
2-trimethoxy-4,5-diphenyl-1,3,2-dioxaphosphole, 2,2-dihydro-2-oxo-2
-Methoxy-4,5-diphenyl-1,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-1,3,2-dioxaphosphole, 2,2-dihydro-2 , 2,2-Trimethoxy-4-phenyl-1,3,2-
Dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-4-methyl-1,3,2-dioxaphospho-
2,2-dihydro-2,2,2-trimethoxy-4-
Methyl-5-phenylcarbamoyl-1,3,2-dioxaphosphole, 2,2,4,5,6,7-hexahydro-2,
2,2-trimethoxy-1,3,2-benzodioxaphosphole, 2,2'-oxybis (4,5-dimethyl-2,2
-Dihydro-1,3,2-dioxaphosphole), 2,2 '
-Oxybis (4,5-dimethyl-2,2-dihydro-1,
3,2-dioxaphosphole-2-oxide) and the like. The solvent used in the reaction may be one that does not inhibit the reaction, preferably the above-mentioned ethers, esters,
Halogenated hydrocarbons, hydrocarbons, amides, ketones,
Nitriles and the like are used alone or as a mixed solvent. Especially, for example, dichloromethane, acetonitrile, formamide, a mixed solvent of formamide and acetonitrile, a mixed solvent of dichloromethane and acetonitrile, and the like can be used to obtain a favorable effect. The amount of the nucleophile [IV] or its salt and the organophosphorus compound used is the compound [III]
It is about 1 to 5 mol, about 1 to 10 mol, and more preferably about 1 to 3 mol and about 1 to 6 mol per mol. The reaction is carried out in the temperature range of about -80 to 50 ° C, preferably about -40 to 40 ° C. The reaction time is usually about 30 minutes to 48 hours, preferably about 1 to 24 hours. An organic base may be added to the reaction system. Examples of such organic bases include triethylamine, tri (n-butyl) amine, di (n-
Examples thereof include amines such as butyl) amine, diisobutylamine, dicyclohexylamine and 2,6-lutidine.
The addition amount of the base is about 1 to 5 per 1 mol of the compound [III]
Mol is good.

When R ⁵ is a halogen atom in compound [III]: Preferred solvents are the above-mentioned ethers, esters,
Halogenated hydrocarbons, hydrocarbons, amides, ketones,
Examples include nitriles, alcohols and water. Nucleophile [I
The amount of V] used is usually about 1 to 1 mol of the compound [III].
It is 5 mol, preferably about 1 to 3 mol. Reaction is about 0-8
It is carried out in a temperature range of 0 ° C, preferably about 20-60 ° C. The reaction time is usually about 30 minutes to 15 hours, preferably about 1 to 5 hours. The reaction can be carried out in the presence of a dehalogenating agent to accelerate the reaction. Examples of such a dehalogenating agent include the inorganic bases, tertiary amines, and
Deoxidizing agents such as alkylene oxides are also mentioned here, but the nucleophile [IV] itself may act as a dehalogenating agent. In this case, compound [IV] is replaced with compound [III]
Use 2 mol or more per 1 mol. The halogen atom represented by R ⁵ is chlorine, bromine, iodine or the like, preferably iodine. The compound [III] in which R ⁵ is iodine can be easily produced, for example, by the method described in Japanese Patent Laid-Open No. 58-57390 or a method analogous thereto.
Compound [III] can be prepared by a known method (for example, JP-A-60-2).
No. 31684, JP-A No. 62-149682, etc.) or a method analogous thereto.

The compound [I] can be produced by the following production method (3) in addition to the above production method (1) or (2). The reaction formula is as follows.

[Chemical 42] This method is a method of synthesizing compound [I] by etherification by reacting hydroxyimino compound [V] or its ester or salt with a compound represented by the general formula R ³ OH or a reactive derivative thereof. R ³ OH is used as it is or as a reactive derivative thereof. R ³ OH
The reactive derivative may be any one capable of substituting the hydrogen atom of the hydroxyimino compound [V] with R ³ .
For example, a compound represented by the general formula R ³ Y is used. Here, Y, which is a group which leaves together with the hydrogen atom of [V], represents, for example, a halogen atom, a sulfo group, a mono-substituted sulfonyloxy group or the like. Examples of such a halogen atom include chlorine, bromine and iodine. Examples of the mono-substituted sulfonyloxy group include a C _1-6 alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy, a C _6-10 arylsulfonyloxy group and the like.

The compound [V] can be synthesized according to the acylation reaction described in the above production method (1) or the nucleophilic substitution reaction described in the production method (2). That is, each is shown by the following reaction formulas.

[Chemical 43] [Symbols in the formula have the same meanings as above] The starting compounds [IX] and [VIII] are also known methods (for example, JP-A-60-231684 and JP-A-62-14).
It can be easily synthesized by the method described in No. 9682 or the like. The compound R ³ OH and its reactive derivative are also known methods (see, for example, JP-A-60-60).
-2311684, JP-A-62-149682, etc.) or a method analogous thereto. (3-1) When R ³ OH is used: The hydroxyimino compound [V] is reacted with the compound R ³ OH using a suitable dehydrating agent to synthesize the compound [I]. Examples of the dehydrating agent used for such purpose include phosphorus oxychloride, thionyl chloride, dialkyl azodicarboxylate (usually used in the coexistence with phosphine), N, N'-dicyclolohexylcarbodiimide and the like. , And preferably diethyl azodicarboxylate in the presence of triphenylphosphine. The reaction using diethyl azodicarboxylate in the presence of triphenylphosphine is usually carried out in an anhydrous solvent, and ethers, hydrocarbons and the like as exemplified in the above production method (1) are used. The compound R ³ OH, ethyl azodicarboxylate, and triphenylphosphine are all about 1 to 1. 1 mol per 1 mol of the hydroxyimino compound [V].
5 mol is used. About 1 to 4 in a temperature range of about 0 to 50 ° C
It takes days.

(3-2) When R ³ Y is used: The reaction between R ³ Y and the hydroxyimino compound [V] is a usual etherification reaction and is carried out in a solvent. As the solvent, ethers and esters listed in the above-mentioned production method (1),
Solvents or mixed solvents such as halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols and water are also mentioned here, preferably, a mixed solvent of water and a solvent capable of mixing with water ( For example, water-containing methanol, water-containing ethanol, water-containing acetone, water-containing dimethyl sulfoxide, etc.). This reaction can also be allowed to proceed smoothly in the presence of a suitable base. Examples of such a base include alkali metal salts such as sodium carbonate, sodium hydrogen carbonate and potassium carbonate, such as sodium hydroxide,
Examples thereof include inorganic bases such as alkali metal hydroxides such as potassium hydroxide. Further, this reaction may be carried out in a buffer solution (phosphate buffer solution or the like) having a pH of 7.5 to 8.5. The mole numbers of the reagent R ³ Y and the base used with respect to 1 mol of the raw material compound [V] are about 1-5, about 1-10, respectively, preferably about 1-3, about 1-5, respectively. Reaction temperature is about -3
It is in the range of 0 to 100 ° C, preferably about 0 to 80 ° C.
The reaction time is about 10 minutes to 15 hours, preferably about 30 minutes.
5 hours. The compound [V] can be isolated and purified by a known treatment means such as an extraction method, a column chromatography, a precipitation method, a recrystallization method or the like. Manufacturing method (1)
After the reaction of (3) to (3), if desired, the protecting group is removed and purified to obtain the objective compound [I] of the present invention. The method for removing the protecting group and the method for purifying will be described below.

Protecting group removal method: As described above, the protecting group of amino group has been well studied in the field of β-lactam and peptide synthesis, and its protecting method and deprotecting method have already been established. Also in the present invention, the conventional technique can be used as it is for the removal of the protecting group. For example, a monohalogenoacetyl group (chloroacetyl, bromoacetyl, etc.) can be converted to an alkoxycarbonyl group (methoxycarbonyl,
Ethoxycarbonyl, tert-butoxycarbonyl, etc.) are acidified (for example, hydrochloric acid, etc.), and aralkyloxycarbonyl groups (benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.) The 2,2-trichloroethoxycarbonyl can be removed with zinc and an acid (such as acetic acid). On the other hand, the compound [I] as a synthetic intermediate
Even when is esterified, the ester residue can be removed by a method known per se or a method analogous thereto. For example, 2-methylsulfonylethyl ester is alkali, and aralkyl ester (benzyl ester, p-methoxybenzyl ester, p-nitrobenzyl ester, etc.) is acid (for example, trifluoroacetic acid, etc.)
Alternatively, by catalytic reduction, 2,2,2-trichloroethyl ester can be removed with zinc and an acid (such as acetic acid), and silyl ester (trimethylsilyl ester, tert-butyldimethylsilyl ester, etc.) can be removed only with water. Purification method of compound [I]: Compound produced in the reaction mixture by various production methods detailed in Production methods (1) to (3) and, if necessary, the above protecting group removal method. I] can be isolated and purified by a known treatment means such as extraction method, column chromatography, precipitation method, recrystallization method and the like. On the other hand, the isolated compound [I] can be converted into a desired physiologically acceptable salt by a known method.

The compound [I] of the present invention has a broad spectrum of antibacterial activity and is produced by various pathogenic bacteria in humans and mammals (eg, mouse, rat, rabbit, dog, cat, cow, pig etc.). It can be safely used for the prevention and treatment of diseases such as respiratory tract infection and urinary tract infection. The features of the antibacterial spectrum of the antibacterial compound [I] are as follows. (1) Very high activity against various Gram-negative bacteria. (2) It has high activity against Gram-positive bacteria (eg Staphylococcus aureus, Corynebacterium diphtheriae, etc.). (3) It has high activity against methicillin-resistant Staphylococcus aureus (MRSA). (4) It shows a remarkable effect on Pseudomonas aeruginosa, which is not susceptible to treatment with usual cephalosporin antibiotics. (5) Many β-lactamase-producing Gram-negative bacteria (e.g., Escherichia, Enterobacter, Serratia,
It also has high activity against Proteus and the like). In particular, aminoglycoside antibiotics such as amikacin and gentamicin have been used for Pseudomonas microorganisms, but the compound [I] of the present invention not only exhibits antibacterial activity comparable to these aminoglycosides, It also has great advantages as it is much less toxic to animals than aminoglycosides. Further, the antibacterial compound [I] of the present invention has excellent stability,
It also has features such as high blood concentration, long duration of effect, and remarkable tissue transferability.

Among the compounds [I] of the present invention having the above-mentioned characteristics, the compounds having the structures shown in the following (1) to (4) are the most excellent compounds.

[Chemical 44] The compound [I] of the present invention can be administered parenterally or orally as injections, capsules, tablets and granules as well as known penicillin agents and cefalosporin agents. The dose is 0.5 to 80 mg / day, more preferably 1 to 20 mg / kg body weight of a person or animal infected with the above-mentioned pathogenic bacteria.
Oral administration may be performed by dividing the day into 3 to 4 times a day. As the carrier when used as an injection, for example, distilled water, physiological saline or the like is used, and when used as a capsule, powder, granule, or tablet, a known pharmacologically acceptable excipient ( For example, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (such as starch,
Mix with gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (eg magnesium stearate, talc etc.), destructive agents (eg carboxymethylcalcium, talc etc.) Used.

[0046]

EXAMPLES The present invention will be further described in detail with reference to the following Reference Examples and Examples. However, these examples are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. You may change it. Elution by column chromatography in Reference Examples and Examples was carried out by TLC (Thin La).
yer Chromatography, thin layer chromatography). In TLC observation, TLC
Pre - the 60F ₂₅₄ Merck (Merck) manufactured by the bets, the solvent used as an elution solvent in column chromatography as a developing solvent, employing a UV detector as a detection method. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh) also manufactured by Merck was used. "Sephadex" is Pharmacia Fine Chemicals
(Pharmacia Fine Chemicals). XAD-
2 resin is Rohm & Haas (Rohm & Haa
sCo. ) Made. Diaion HP20 is manufactured by Mitsubishi Kasei. The NMR spectrum was measured with a Gemini 200 type spectrometer using tetramethylsilane as an internal or external standard, and all δ values are shown in ppm. In the mixed solvent, the value shown in parentheses is the volume mixing ratio of each solvent. Further,% in the solution represents the number of g in 100 ml of the solution. The symbols in Reference Examples and Examples have the following meanings. s: singlet d: doublet t: triplet q: quartet ABq: AB type quartet dd: double doublet m: multiplet bs : Broad singlet J: Coupling constant Hz: Herz DMSO: Dimethyl sulfoxide

Reference Example 1 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -cyclopentyloxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole- 3-yl) coumarin (14.7 g) was suspended in ethanol (120 ml), and 1N-sodium hydroxide (120 ml) was added to the suspension.
After stirring at 0 ° C for 1 hour to form a uniform solution, 6 ml of ethyl chlorocarbonate was added under ice cooling and the mixture was stirred for 5 minutes. Next, 180 ml of methylene chloride and 60 ml of 1N-hydrochloric acid were added to remove the aqueous layer, and the mixture was extracted again with methylene chloride and the organic layers were combined and cooled in a dry ice acetone bath. 3 in methylene chloride solution
After passing ozone for an hour, excess ozone was removed by passing nitrogen for 15 minutes. After adding 4.92 g of sodium acetate and 30 ml of dimethyl sulfide to the reaction solution and stirring the mixture, it was confirmed that potassium iodide-starch paper was negative.
ml and 60 ml of water were added and the mixture was extracted twice, and the aqueous layer was washed with ethyl acetate. O-Cyclopentylhydroxylamine (6.7 g) was added to the aqueous layer, the pH was adjusted to 5 with 1N-sodium hydroxide, and the mixture was stirred overnight at room temperature (25 ° C, the same applies below). The reaction mixture was adjusted to pH 1 with 80 ml of 1N hydrochloric acid and then extracted 3 times with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was crystallized from ethyl acetate to obtain 12.8 g of the title compound. Melting point: 142-143 ° C IR spectrum (KBr, cm ^-1 ): 3300, 2950, 1720, 164
0, 1520, 1400, 1180. NMR (DMSO) δ: 1.3-1.9 (8H, m), 4.74 (1H, m), 8.17
(2H, bs).

Reference Example 2 S- (2-benzothiazolyl) 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -cyclopentyloxyiminothioacetate 2- (5-amino- 1,2,4-thiadiazol-3-yl) -2 (Z) -cyclopentyloxyiminoacetic acid 5 g
Was suspended in 110 ml of acetonitrile, and 9.29 ml of tri-n-butylamine and 8.43 g of 2-mercaptobenzothiazole disulfide were added. Then, after cooling to -10 ° C, 5 ml of triethyl phosphite was added and stirred for 2 hours. The resulting precipitate was collected by filtration, washed with cold acetonitrile, and dried under reduced pressure to give the title compound (4.25 g). Elemental _{analysis: C 16 H 15 N 5 O} 2 S 3 Calculated: C, 47.39; H, 3.73 ; N, 17.27 Found: C, 47.62; H, 3.75 ; N, 17.37 IR spectrum (KBr, cm ^-1 ): 3400, 3140, 2950, 172
0, 1610, 1530, 1450, 1400. NMR (d ₆ -DMSO) δ: 1.5-2.0 (8H, m), 4.86 (1H, qu),
7.59 (2H, m), 8.07 (1H, m), 8.21 (1H, m), 8.30 (2H, bs).

Reference Example 3 Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3-hydroxymethyl-3- Cephem-4-carboxylate 7β-amino-3-hydroxymethyl-3-cephem-
2.89 g of 4-carboxylic acid was suspended in 40 ml of water and 1N-sodium hydroxide was added under ice cooling to adjust the pH to 8. To this, 50 ml of tetrahydrofuran was added, and then S- (2-
Benzothiazolyl) 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -cyclopentyloxyiminothioacetate (4.24 g) was added, and the mixture was stirred at room temperature overnight. The reaction solution was washed with ethyl acetate and then concentrated under reduced pressure. The residue was subjected to MCI gel CHP-20P column chromatography, and the fractions eluted with 5% ethanol water were collected and concentrated under reduced pressure. The residue was lyophilized to give 4.0 g of the title compound. Elemental _{analysis: C 17 H 19 N 6 NaO} 6 S 2 · 2H 2 O Calculated: C, 38.78; H, 4.40 ; N, 15.96 Found: C, 38.66; H, 4.19 ; N, 15.62 NMR spectrum (d _6- DMSO) δ: 1.4-2.0 (8H, m), 3.2
2 and 3.47 (2H, ABq, J = 18Hz), 3.74 and 4.16 (2H, ABq, J = 12.4H
z), 4.73 (1H, m), 4.92 (1H, d, J = 4.8Hz), 5.55 (1H, dd, J =
8.4Hz and 4.8Hz), 6.20 (1H, m), 8.14 (2H, bs), 9.39 (1H, d,
J = 8.4Hz).

Reference Example 4 3-Amino-6-chloroimidazo [1,2-b] pyridazine 6-chloro, while stirring a suspension of 3.39 g of stannous chlorotin dihydrate and 5 ml of concentrated hydrochloric acid under ice cooling. 0.502 g of -3-nitroimidazo [1,2-b] pyridazine was added, the temperature was gradually raised, and the mixture was stirred in an oil bath (bath temperature 100 ° C) for 15 minutes. After cooling, dilute the reaction mixture with 10 ml of ice water, 2NN
The pH was adjusted to 5.0 by adding aOH, and the mixture was extracted with ethyl acetate-tetrahydrofuran (2: 1), washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, 0.29 g of the title compound was obtained as yellowish brown crystals. Melting point 160-164 ° C NMR spectrum (CDCl ₃ ) δ: 4.0 (2H, broad s), 6.83
And 7.78 (1H, d, J = 9Hz each), 7.26 (1H, s).

Reference Example 5 3-aminoimidazo [1,2-b] pyridazine hydrochloride 3-amino-6-chloro [1,2-b] pyridazine 2.
0 g was dissolved in 80 ml of ethanol and 10% palladium-
Carbon (1.5% water content) (1.5 g) was added, and the mixture was stirred in a hydrogen stream for 2 hours. The catalyst was filtered off and the crystals obtained by concentrating the filtrate were collected by filtration to give 1.55 g of the title compound. Melting point: 250 ° C. (decomposition) NMR spectrum (d ₆ -DMSO) δ: 7.39 (1H, s), 7.5-9.
0 (3H, m). Reference Example 6 3-Formylaminoimidazo [1,2-b] pyridazine Formic acid (15 ml) was stirred with ice-cooling, while acetic anhydride (5 ml) was added and the mixture was stirred with ice-cooling for 30 minutes. 0.75 g of 3-aminoimidazo [1,2-b] pyridazine hydrochloride was added thereto, and the mixture was returned to room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure, the residue was dissolved in a small amount of ice water, and an aqueous sodium hydrogen carbonate solution was added to adjust the pH to 7.0. The precipitated crystals were collected by filtration and dried to obtain 0.602 g of the title compound as pale yellow crystals. Melting point 242-244 ° C NMR spectrum (d ₆ -DMSO) δ: 7.1-8.7 (3H, m), 7.9
1 (1H, s), 8.42 (1H, s).

Reference Example 7 N-Cyclobutyloxyphthalimide 9.88 g of N-hydroxyphthalimide was dissolved in 200 ml of dimethyl sulfoxide, 5.0 g of potassium carbonate was added, and the mixture was stirred at room temperature for 10 minutes. Then, 9.0 g of cyclobutyl bromide was added, the reaction solution was heated and stirred at 100 ° C. for 3 hours, and 1.66 g of potassium carbonate was further added to give 1
The mixture was heated and stirred for an hour. After cooling, the reaction solution was added to 500 ml of ice water, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give the title compound (9.12 g) as colorless needles. Mp: 104-105 ° C. Elemental analysis: C ₁₂ H ₁₁ NO ₃ Calculated: C, 66.35; H, 5.10 ; N, 6.45 Found: C, 66.19; H, 5.15 ; N, 6.44 NMR spectrum (CDCl ₃₎ δ: 1.4-1.9 (2H, m), 2.2-2.
5 (4H, m), 4.78 (1H, m), 7.7-7.9 (4H, m).

Reference Example 8 O-Cyclobutylhydroxylamine / hydrochloride 8.33 g of N-cyclobutyloxyphthalimide was dissolved in a mixed solution of 200 ml of methylene chloride and 20 ml of methanol, and 3.72 ml of hydrazine monohydrate was added thereto. The mixture was stirred at room temperature (25 ° C, the same applies below) for 2 hours. The precipitated crystals were removed by filtration, 200 ml of 5N-ammonia water was added to the filtrate,
It was extracted twice with methylene chloride. The extract was dried over magnesium sulfate, ammonia was removed under reduced pressure, 6.38 ml of concentrated hydrochloric acid was added, and the mixture was dried under reduced pressure. Ethanol was added to the residue, the mixture was concentrated again, and ethyl ether 1 was added to the residue.
00 ml was added and the precipitated crystals were collected by filtration to obtain 4.23 g of the title compound as colorless scale crystals. Melting point: 134-136 ° C NMR spectrum (d ₆ -DMSO) δ: 1.7-1.9 (2H, m), 1.9
5-2.2 (4H, m), 4.64 (1H, m), 11.1 (3H, bs).

Reference Example 9 2- (5-Amino-1,2,4-thiadiazole-3-
Iyl) -2 (Z) -cyclobutyloxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
Ill) coumarin 7.93 g was suspended in ethanol 65 ml, and 1N-sodium hydroxide 64.8 ml was added thereto 4
After stirring at 0 ° C for 1 hour to form a uniform solution, 3.24 ml of ethyl chlorocarbonate was added under ice cooling and the mixture was stirred for 5 minutes. Next, 100 ml of methylene chloride and 32.4 ml of 1N-hydrochloric acid were added to remove the aqueous layer. The aqueous layer was extracted with methylene chloride and the organic layers were combined and cooled in a dry ice acetone bath. After passing ozone through the methylene chloride solution for 2 hours, excess ozone was removed by passing nitrogen for 15 minutes. Sodium acetate 2.66
g and 16 ml of dimethyl sulfide were added to the reaction solution and stirred, and after confirming that the potassium iodide-starch paper was negative, the reaction solution was extracted twice with 100 ml and 50 ml of water. The aqueous layer was washed with ethyl acetate, 4.0 g of O-cyclobutylhydroxylamine hydrochloride was added to adjust the pH to 5 with 1N-sodium hydroxide, and the mixture was stirred overnight at room temperature. The reaction mixture was adjusted to pH 1 with 45 ml of 1N-hydrochloric acid and then extracted with 100 ml of ethyl acetate three times. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was crystallized from isopropyl ether to obtain 4.31 g of the title compound. Melting point: 94-96 ° C NMR spectrum (d ₆ -DMSO) δ: 1.4-1.8 (2H, m), 1.9
-2.3 (4H, m), 4.71 (1H, m), 8.16 (2H, bs).

Reference Example 10 S- (2-benzothiazolyl) 2- (5-amino-
1,2,4-thiadiazol-3-yl) -2 (Z)-
Cyclobutyloxyiminothioacetate 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z) -cyclobutyloxyiminoacetic acid 2.
Using 26 g of 2-mercaptobenzothiazole disulfide (4 g) and the same operation as in Reference Example 2, 3.1 g of the title compound was obtained. NMR spectrum (d ₆ -DMSO) δ: 1.
5-1.8 (2H, m), 2.0-2.3 (4H, m), 4.84 (1H, m), 7.58 (2H,
m), 8.07 (1H, m), 8.22 (1H, m), 8.31 (2H, bs). Reference Example 11 Sodium 7β- [2- (5-amino-1,2,4-)
Thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 7β-amino-3-hydroxymethyl-3-cephem-
1.41 g of 4-carboxylic acid and S- (2-benzothiazolyl) 2- (5-amino-1,2,4-thiadiazole-
3-yl) -2 (Z)-(cyclobutyloxyimino)
The same procedure as in Reference Example 3 was carried out using 2.0 g of thioacetate to obtain 0.99 g of the title compound. Elemental analysis value: C ₁₆ H ₁₇ N ₆ NaO ₆ S ₂ · 2.5H ₂ O Calculated value: C, 36.85; H, 4.25; N, 16.11 Actual value: C, 36.93; H, 4.34; N, 16.25 NMR spectrum (D ₆ −DMSO) δ: 1.4-1.8 (2H, m), 2.1
-2.3 (4H, m), 3.25 and 3.48 (2H, ABq, J = 18Hz), 3.76 and 4.17
(2H, ABq, J = 12.8Hz), 4.73 (1H, m), 4.94 (1H, d, J = 4.8Hz),
5.58 (1H, dd, J = 8.8Hz and 4.8Hz), 6.14 (1H, bs), 8.15 (2H,
bs), 9.44 (1H, d, J = 8.8Hz).

Reference Example 12 N-Cyclohexyloxyphthalimide 32.63 g of N-hydroxyphthalimide was dissolved in 500 ml of dimethyl sulfoxide, and 55.28 of potassium carbonate was added.
g was added and the mixture was stirred at room temperature for 30 minutes. Then 1 in the reaction mixture
5.29 g of 8-crown-6 was added and heated to 110 ° C., and a mixed solution of 98.5 ml of bromocyclohexane and 100 ml of dimethyl sulfoxide was added dropwise over 1 hour. After further heating and stirring at 110 ° C. for 1 hour, 300 ml of ethyl acetate was added to the reaction solution, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate and the solvent was distilled off. The residue was washed with hexane to obtain 33.05 g of the title compound. Melting point: 121-124 ° C. Elemental analysis value: C ₁₄ H ₁₅ NO ₃ calculated value: C, 68.56; H, 6.16; N, 5.71 actual value: C, 68.37; H, 6.12; N, 5.48 NMR spectrum (CDCl ₃ ). δ: 1.26-2.06 (10H, m), 4.2
4 (1H, m), 7.73-7.87 (4H, m).

Reference Example 13 O-Cyclohexylhydroxylamine hydrochloride 32.67 g of N-cyclohexyloxyphthalimide was dissolved in 250 ml of ethanol, and 8.26 ml of hydrazine monohydrate was added thereto, and the mixture was refluxed for 1 hour. Concentrated hydrochloric acid (14.7 ml) was added to the reaction solution, the mixture was refluxed for 5 minutes, hot water (46 ml) was added, and the mixture was allowed to stand at room temperature. The insoluble material was filtered off, the filtrate was concentrated, ethanol was added to the residue, the insoluble material was filtered off again, and the filtrate was concentrated to dryness. The residue was recrystallized from ethanol to give the title compound 1
9.87 g was obtained. Melting point: 189-192 ° C. Elemental analysis value: C ₆ H ₁₂ NO.HCl calculated value: C, 47.84; H, 8.70; N, 9.30 Actual value: C, 47.76; H, 8.84; N, 9.18 NMR spectrum (d ₆ −DMSO) δ: 1.15-1.98 (10H, m),
3.97-4.05 (1H, m), 10.69-10.81 (3H, br).

Reference Example 14 2- (5-Amino-1,2,4-thiadiazole-3-
Yl) -2 (Z) -cyclohexyloxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
(Il) Coumarin (14.7 g) and O-cyclohexylhydroxylamine hydrochloride (10 g) were used, and the same procedure as in Reference Example 9 was carried out to obtain 4.5 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.28-1.91 (10H, m),
4.15-4.20 (1H, m), 8.17 (2H, s).

Reference Example 15 S- (2-benzothiazolyl) 2- (5-amino-
1,2,4-thiadiazol-3-yl) -2 (Z)-
(Cyclohexyloxyimino) thioacetate 2- (5-amino-1,2,4-thiadiazole-3-
(Yl) -2 (Z) -cyclohexyloxyiminoacetic acid (3.65 g) and 2-mercaptobenzothiazole disulfide (5.39 g) were used in the same manner as in Reference Example 2 to give the title compound (3.4 g). Melting point: 130 ° C. (decomposition) Elemental analysis value: C ₁₇ H ₁₇ N ₅ O ₂ S Calculated value: C, 48.67; H, 4.08; N, 16.69 Actual value: C, 48.89; H, 4.39; N, 16.48 NMR spectrum (CDCl ₃ ) δ: 1.26-1.98 (10H, m), 4.4
1-4.47 (1H, m), 6.38-6.43 (2H, br), 7.45-7.59 (2H, m),
7.94 (1H, d, J = 8.4Hz), 8.07 (1H, d, J = 7.4Hz).

Reference Example 16 Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z) -cyclohexyloxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 7β-amino-3-hydroxymethyl-3-cephem-
1.91 g of 4-carboxylic acid and S- (2-benzothiazolyl) 2- (5-amino-1,2,4-thiadiazole-
The same procedure as in Reference Example 3 was carried out using 3.15 g of 3-yl) -2 (Z)-(cyclohexyloxyimino) thioacetate to obtain 2.24 g of the title compound. Elemental _{analysis: C 18 H 21 N 6 NaO} 6 S 2 · 2.5H 2 O Calculated: C, 39.34; H, 4.77 ; N, 15.29 Found: C, 39.47; H, 4.75 ; N, 15.14 NMR spectrum (D ₆ −DMSO) δ: 1.17-1.97 (10H, m),
3.23 (1H, d, J = 18Hz), 3.46 (1H, d, J = 17.8Hz), 3.75 (1H, d,
J = 13.4Hz), 4.16 (1H, d, J = 12.8Hz), 4.10-4.20 (1H, m),
4.92 (1H, d, J = 4.8Hz), 5.58 (1H, dd, J = 5.0Hz and 8.6Hz), 6.
18-6.23 (1H, br), 8.13 (2H, brs), 9.39 (1H, d, J = 8.6Hz).

Reference Example 17 6-Amino-3-nitroimidazo [1,2-b] pyridazine 6-Chloro-3-nitroimidazo [1,2-b] pyridazine 10.5 g was added to 25% aqueous ammonia-tetrahydrofuran (1 1) Dissolve in 200 ml of the mixed solution, and put 120 in a sealed tube.
Heated at ° C for 7 hours. After cooling, the precipitated crystals are collected by filtration,
It was washed with water, ethanol and then diethyl ether to obtain 7.5 g of the title compound. Melting point: 250 ° C. (decomposition) NMR spectrum (d ₆ -DMSO) δ: 6.99 (1H, d, J = 9.4H
z), 7.02 (2H, s), 7.97 (1H, d, J = 9.4Hz), 8.43 (1H, s). Reference Example 18 3,6-diaminoimidazo [1,2-b] pyridazine 6-amino- 5.13 g of 3-nitroimidazo [1,2-b] pyridazine was dissolved in 500 ml of tetrahydrofuran, and the mixture was stirred in the presence of 5 g of Raney nickel under a hydrogen atmosphere of 2-3 atm at room temperature for 2.5 hours. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with diethyl ether to obtain 3.18 g of the title compound. Melting point: 200 ° C. (decomposition) NMR spectrum (d ₆ -DMSO) δ: 4.83 (2H, brs), 6.06
(2H, brs), 6.13 (1H, d, J = 9.6Hz), 6.68 (1H, s), 7.47 (1H,
d, J = 9.6Hz).

Reference Example 19 6-Amino-3-formylaminoimidazo [1,2-
b] Pyridazine Formic acid-acetic anhydride prepared by stirring 1.79 ml of acetic anhydride and 0.86 ml of formic acid at room temperature for 1 hour was dissolved in 10 ml of dimethylformamide. Then, a solution of 2.02 g of 3,6-diaminoimidazo [1,2-b] pyridazine in 40 ml of dimethylformamide was added dropwise to this solution under ice cooling.
After stirring for a further 1 hour, the reaction mixture was concentrated and the residue was washed with ethanol and diethyl ether to give the title compound 1.4.
6 g was obtained. NMR spectrum (d ₆ -DMSO) δ: 6.29 (2H, brs), 6.60
(1H, d, J = 9.4Hz), 7.49 (1H, s), 7.67 (1H, d, J = 9.6Hz), 8.
32 (1H, d, J = 1.2Hz), 10.34 (1H, brs). Reference Example 20 3-Amino-6-methoxyimidazo [1,2-b] pyridazine 3-amino-6-chloroimidazo [1,2] -B] 3.88 g of pyridazine was dissolved in 90 ml of methanol, 6.17 g of 28% sodium methylate solution was added, and the mixture was refluxed for 24 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with methylene chloride-methanol (75: 1) to give 2.57 g of the title compound. Melting point: 90-92 ° C NMR spectrum (CDCl ₃ ) δ: 3.94-4.00 (2H, br), 4.0
2 (3H, s), 6.48 (1H, d, J = 9.4Hz), 7.08 (1H, s), 7.65 (1H,
d, J = 9.6Hz).

Reference Example 21 3-Formylamino-6-methoxyimidazo [1,2-
b] Pyridazine Acetic anhydride 7.5 ml and formic acid 4 ml were stirred at room temperature for 0.5 hours to prepare formic acid-acetic anhydride, and 3-amino-6-methoxyimidazo [1,2-b] pyridazine 2.22 g was added. In addition, the mixture was stirred at room temperature for 1.5 hours. The reaction solution is concentrated under reduced pressure,
A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the precipitated crystals were collected by filtration. The crystals were washed with water and isopropyl ether and then dried to obtain 1.78 g of the title compound. Mp: 210-211 ° C. Elemental _{analysis: C 8 H 8 N 4 O} 2 Calculated: C, 50.00; H, 4.20 ; N, 29.15 Found: C, 49.93; H, 4.26 ; N, 29.25 NMR spectrum (d ₆ −DMSO) δ: 4.02 (3H, s), 6.81 (1H, d, J = 9.8
Hz), 7.73 (1H, s), 7.96 (1H, d, J = 9.8Hz), 8.43 (1H, s), 1
0.72 (1H, br).

Reference Example 22 7β-t-Butoxycarbonylamino-3- (3-formylaminoimidazo [1,2-b] pyridazinium-1
-Yl) methyl-3-cephem-4-carboxylate sodium 7β-t-butoxycarbonylamino-3
3.52 g of hydroxymethyl-3-cephem-4-carboxylate and 3-formylaminoimidazo [1,2]
-B] 1.95 g of pyridazine was added to dimethyl sulfoxide 5
It was dissolved in 0 ml, 10 g of ethyl o-phenylene phosphate was added thereto, and the mixture was stirred at room temperature for 4 hours. 300 ml of ethyl ether was added to the reaction solution, and the precipitated oily substance was separated and subjected to silica gel column chromatography. Elution with an acetone-water (7: 3) mixture, collecting fractions containing the desired product, concentrating under reduced pressure, and freeze-drying to give the title compound 1.8.
g was obtained. NMR spectrum (d ₆ -DMSO) δ: 1.38 (9H, s), 3.08
3.46 (2H, ABq, J = 15.8Hz), 4.91 (1H, d, J = 4.8Hz), 5.36 (2H,
m), 5.53 (1H, m), 7.93 (1H, m), 8.54 (1H, s), 8.82 (1H,
s), 9.11 (1H, m), 9.33 (2H, m).

Reference Example 23 N- (2-cyclopenten-1-yl) oxyphthalimide 58.2 g of N-hydroxyphthalimide was suspended in 370 ml of acetonitrile, 92 ml of triethylamine was added, and the mixture was stirred at room temperature for 5 minutes. Then, 50 g of (2-cyclopenten-1-yl) chloride was added dropwise and the reaction was stirred overnight at room temperature. Add the reaction mixture to 1500 ml of ice water,
The precipitated crystals were collected by filtration, washed with water and hexane, and dried under reduced pressure to give the title compound (79.1 g). mp = 96.0-98.0 ° C. NMR spectrum (CDCl ₃ ) δ: 2.0-2.8 (4
H, m), 5.42 (1H, m), 5.96 (1
H, m), 6.25 (1H, m), 7.7-7.9.
(4H, m).

Reference Example 24 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(2-cyclopenten-1-yl)
Oxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
Ill) coumarin 9.8 g was suspended in ethanol 80 ml, 1N-sodium hydroxide 80 ml was added thereto, and the temperature was 40 ° C.
After stirring for 1 hour, a uniform solution was obtained, and then 4 ml of ethyl chlorocarbonate was added under ice cooling and stirred for 5 minutes. Next, 120 ml of methylene chloride and 40 ml of 1N-hydrochloric acid were added to remove the aqueous layer, and the mixture was extracted again with methylene chloride and the organic layers were combined and cooled in a dry ice acetone bath. 3 in methylene chloride solution
After passing ozone for a period of time, excess ozone was removed by passing through nitrogen for 15 minutes. 3.28 g of sodium acetate and 20 ml of dimethyl sulfide were added to the reaction solution and stirred for a while, and after it was confirmed that potassium iodide-starch paper was negative, 80 ml and 40 ml of water were added to extract twice, and the aqueous layer was further extracted. Was washed with ethyl acetate. Separately, 9.17 g of N- (2-cyclopenten-1-yl) oxyphthalimide was suspended in 50 ml of ethanol to give hydrazine monohydrate 1.8.
4 ml was added and reacted for 15 minutes to prepare an O- (2-cyclopenten-1-yl) hydroxylamine solution, which was added to the above aqueous layer. Then, the pH was adjusted to 5 with 1N-sodium hydroxide, and the mixture was stirred overnight at room temperature. 1N- in the reaction solution
After adjusting the pH to 1 by adding 80 ml of hydrochloric acid, the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to obtain 8.7 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.7-2.5 (4H, m), 5.3
6 (1H, m), 5.87 (1H, m), 6.15 (1H, m), 8.18 (2H, bs).

Reference Example 25 Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(2-cyclopenten-1-yl) oxyiminoacetamide] -3
-Hydroxymethyl-3-cephem-4-carboxylate 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(2-cyclopenten-1-yl)
Oxyiminoacetic acid was suspended in 140 ml of acetonitrile, and 15 ml of tri-n-butylamine and 13.6 g of 2-mercaptobenzothiazole disulfide were added. Then, after cooling to -10 ° C, triethyl phosphite 8.1
ml was added and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran to prepare an active ester solution. Separately, 5.4 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid was suspended in 75 ml of water, and 1N-sodium hydroxide was added thereto under ice cooling to adjust the pH to 8. To this, add 100 ml of tetrahydrofuran, and then add the active ester solution prepared above,
This was stirred at room temperature overnight. The reaction solution was washed with ethyl acetate and then concentrated under reduced pressure. The residue was subjected to MCI gel CHP-20P column chromatography, and the fractions eluted with 10% ethanol water were collected and concentrated under reduced pressure. The residue was lyophilized to give 2.27 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.8-2.5 (4H, m), 3.2
2 and 3.45 (2H, ABq, J = 18Hz), 3.74 and 4.16 (2H, ABq, J = 12.8H
z), 4.90 (1H, d, J = 4.6Hz), 5.33 (1H, m), 5.54 (1H, dd, J =
8.4Hz and 4.6Hz), 5.88 (1H, m), 6.11 (1H, m), 8.13 (2H, b)
s), 9.39 (1H, d, J = 8.4Hz).

Reference Example 26 N- (3,3-Dimethylcyclobutyl) oxyphthalimide 8.3 g of 3,3-dimethylcyclobutanol, 16.2 g of N-hydroxyphthalimide and 32.6 g of triphenylphosphine were dissolved in 480 ml of tetrahydrofuran. ,
Under ice cooling, 19.6 ml of diethyl azodicarboxylate dissolved in 20 ml of tetrahydrofuran was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography twice, and the title compound (1) was eluted with hexane: ethyl acetate (6: 1).
Obtained 6.1 g. Mp: 106.0-107.0 ℃ Elemental analysis: C ₁₄ H ₁₅ NO ₃ Calculated: C, 68.56; H, 6.16 ; N, 5.71 Found: C, 68.52; H, 6.44 ; N, 5.72 NMR spectrum (CDCl ₃ ) δ: 1.10 (3H, s), 1.23 (3H, s), 2.16 (4
H, d), 4.82 (1H, m), 7.80 (4H, m).

Reference Example 27 O- (3,3-dimethylcyclobutyl) hydroxylamine hydrochloride 8.9 g of N- (3,3-dimethylcyclobutyl) oxyphthalimide was added to 170 ml of dichloromethane and 1 part of methanol.
Dissolve in 7 ml of mixture and add hydrazine monohydrate to it 3.
52 ml was added, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were filtered off, 200 ml of 3% aqueous sodium carbonate was added to the filtrate,
It was extracted twice with methylene chloride. The organic layers were combined, dried over magnesium sulfate, added with 6 ml of concentrated hydrochloric acid and concentrated under reduced pressure. Ethanol was added to the residue, water was completely concentrated under reduced pressure, ethyl acetate: ethyl ethyl (1: 1) was added, and the precipitated crystals were collected by filtration to obtain 4.4 g of the title compound. Mp: 173.0-175.0 ℃ Elemental analysis: C ₆ H ₁₄ NOCl Calculated: C, 47.53; H, 9.31 ; N, 9.24 Found: C, 47.17; H, 9.26 ; N, 9.57 NMR spectrum ( d ₆ −DMSO) δ: 1.08 (3H, s), 1.13 (3
H, s), 1.85 (2H, m), 2.14 (2H, m), 4.65 (1H, m), 10.93 (3
H, bs).

Reference Example 28 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(3,3-dimethylcyclobutyl)
Oxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
Ill) coumarin 9.8g suspended in ethanol 80ml,
80 ml of 1N-sodium hydroxide was added to this and the mixture was mixed at 40 ° C for 1 hour.
After stirring for an hour to form a uniform solution, 4 ml of ethyl chlorocarbonate was added under ice cooling and the mixture was stirred for 5 minutes. Next, 120 ml of methylene chloride and 40 ml of 1N-hydrochloric acid were added to remove the aqueous layer, and the mixture was extracted again with methylene chloride and the organic layers were combined and cooled in a dry ice acetone bath. After passing ozone through the methylene chloride solution for 2 hours, excess ozone was removed by passing nitrogen for 15 minutes. After adding 3.28 g of sodium acetate and 20 ml of dimethyl sulfide to the reaction solution and stirring the mixture for a while, it was confirmed that potassium iodide-starch paper was negative.
ml and 100 ml of water were added for extraction twice, and the aqueous layer was washed with ethyl acetate. O- (3,3-Dimethylcyclobutyl) hydroxylamine hydrochloride (6.06 g) was added to the aqueous layer to adjust the pH to 5 with 1N-sodium hydroxide, and the mixture was stirred overnight at room temperature. The reaction solution was adjusted to pH 1 by adding 80 ml of 1N hydrochloric acid and then extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ether-hexane (1: 1) to give 7.0 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.10 (3H, s), 1.13 (3
H, s), 1.86 (2H, s), 2.15 (2H, s), 4.71 (1H, q), 8.16 (2H,
bs).

Reference Example 29 S- (2-benzothiazolyl) 2- (5-amino-
1,2,4-thiadiazol-3-yl) -2 (Z)-
(3,3-Dimethylcyclobutyl) oxyiminothioacetate 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(3,3-dimethylcyclobutyl)
5.4 g of oximinoacetic acid was suspended in 80 ml of acetonitrile, and 9.53 ml of tri-n-butylamine and 8.64 g of 2-mercaptobenzothiazole disulfide were added. Then, after cooling to -10 ° C, 5.14 ml of triethyl phosphite was added, and the mixture was stirred for 2 hours. The resulting precipitate was collected by filtration, washed with cold acetonitrile and dried under reduced pressure to obtain 8.05 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.12 (3H, s), 1.15 (3
H, s), 1.89 (2H, m), 2.17 (2H, m), 4.87 (1H, m), 7.59 (2H,
m), 8.07 (1H, m), 8.22 (1H, m), 8.30 (2H, bs).

Reference Example 30 Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(3,3-dimethylcyclobutyl) oxyiminoacetamide] -3-
Hydroxymethyl-3-cephem-4-carboxylate 7β-amino-3-hydroxymethyl-3-cephem-
3.39 g of 4-carboxylic acid was suspended in 46 ml of water, and 1N-sodium hydroxide was added thereto under ice cooling to adjust the pH to 8.
To this was added 60 ml of tetrahydrofuran, then S-
(2-benzothiazolyl) 2- (5-amino-1,
2,4-thiadiazol-3-yl) -2 (Z)-
5.0 g of (3,3-dimethylcyclobutyl) oxyiminothioacetate was added, and this was stirred at room temperature overnight.
The reaction solution was washed with ethyl acetate and then concentrated under reduced pressure to concentrate the residue on MC.
I-gel CHP-20P column chromatography was performed, and the fractions eluted with 10% ethanol water were collected and concentrated under reduced pressure. The residue was lyophilized to give 1.96 g of the title compound. Elemental analysis value: C ₁₈ H ₂₁ N ₆ NaO ₆ S ₂ · 2.0H ₂ O Calculated value: C, 40.00; H, 4.66; N, 15.55 Actual value: C, 39.96; H, 4.61; N, 15.25 IR spectrum (KBr, cm ^-1 ): 3300, 2950, 1760, 167
0, 1600, 1520, 1460, 1400, 1360, 1280, 1040. NMR spectrum (d ₆ -DMSO) δ: 1.12 (3H, s), 1.13 (3
H, s), 2.06 (4H, m), 3.24 and 3.49 (2H, ABq, J = 18Hz), 3.77
And 4.18 (2H, ABq, J = 12.6Hz), 4.76 (1H, m), 4.95 (1H, d, J =
4.8Hz), 5.58 (1H, dd, J = 8.2Hz and 4.8Hz), 6.06 (1H, m), 8.
14 (2H, bs), 9.45 (1H, d, J = 8.2Hz).

Reference Example 31 N- (1-methylcyclopentyl) oxyphthalimide 24.4 g of N-hydroxyphthalimide and 15 g of 1-methylcyclopentanol were dissolved in 750 ml of methylene chloride, to which 75 g of 4A-molecular sieves was added and argon was added. The mixture was stirred under an air stream for 20 minutes at room temperature. Then, 15 ml of boron trifluoride etherate was added, and the mixture was heated in an oil bath at 50 ° C for 7 minutes.
Stir for hours. After cooling, the reaction solution was filtered and the mother liquor was washed with water,
The extract was washed successively with M-sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Hexane was added to the residue, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 6.8.
5 g of the title compound was obtained. Mp: 85.0-86.0 ℃ Elemental analysis: C ₁₄ H ₁₅ NO ₃ Calculated: C, 68.56; H, 6.16 ; N, 5.71 Found: C, 68.48; H, 6.23 ; N, 5.61 NMR spectrum (CDCl ₃ ) δ: 1.48 (3H, s), 1.5-2.3 (8
H, m), 7.80 (4H, m).

Reference Example 32 O- (1-methylcyclopentyl) hydroxylamine hydrochloride 6.5 g of N- (1-methylcyclopentyl) oxyphthalimide was added to 130 ml of dichloromethane and 13 ml of methanol.
Hydrazine monohydrate 2.57
ml was added, and the mixture was stirred at room temperature for 3 hours. The precipitated crystals were filtered off, the filtrate was washed with 3% aqueous sodium carbonate solution and saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. Ethanol was added to the residue, 4.42 ml of concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure. After adding ethanol again and concentrating under reduced pressure to remove water, hexane was added and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 3.31 g of the title compound. Mp: 110.0-112.0 ℃ Elemental analysis: C ₆ H ₁₄ NOCl Calculated: C, 47.53; H, 9.31 ; N, 9.24 Found: C, 47.30; H, 8.94 ; N, 9.58 NMR spectrum ( d ₆ −DMSO) δ: 1.44 (3H, s), 1.5-2.
0 (8H, m), 10.75 (3H, bs).

Reference Example 33 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(1-methylcyclopentyl) oxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
Ill) coumarin 7.35 g was suspended in ethanol 60 ml, 1N-sodium hydroxide 60 ml was added thereto, and the temperature was 40 ° C.
After stirring for 1 hour, a uniform solution was obtained, and then 3 ml of ethyl chlorocarbonate was added under ice cooling and stirred for 5 minutes. Next, 90 ml of methylene chloride and 30 ml of 1N hydrochloric acid were added to remove the aqueous layer,
The mixture was extracted again with methylene chloride, the organic layers were combined, and cooled in a dry ice acetone bath. After passing ozone through the methylene chloride solution for 3 hours, excess ozone was removed by passing nitrogen for 15 minutes. After adding 2.46 g of sodium acetate and 15 ml of dimethyl sulfide to the reaction solution and stirring the mixture for a while, after confirming that potassium iodide-starch paper was negative, water was added to extract twice, and the aqueous layer was further extracted with ethyl acetate. Washed. To the aqueous layer was added O- (1-methylcyclopentyl) hydroxylamine (4.55 g), the pH was adjusted to 5 with 1N-sodium hydroxide, and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted to pH 1 with 50 ml of 1N hydrochloric acid and then extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 2.86 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.40 (3H, s), 1.4-2.
0 (8H, m), 8.12 (2H, bs).

Reference Example 34 Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(1-methylcyclopentyl) oxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 2- (5-amino-1,2,4-thiadiazole -3-
2.86 g of (yl) -2 (Z)-(1-methylcyclopentyl) oxyiminoacetic acid was suspended in 50 ml of acetonitrile, and 5.05 ml of tri-n-butylamine and 4.58 g of 2-mercaptobenzothiazole disulfide were added. Then, after cooling to -10 ° C, 2.73 ml of triethyl phosphite was added, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran to prepare an active ester solution. 2.43 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid was added to water 3
The suspension was suspended in 0 ml, and 1N-sodium hydroxide was added thereto under ice cooling to adjust the pH to 8. 37 ml of tetrahydrofuran
Was added, followed by the active ester solution prepared above, which was stirred at room temperature overnight. The reaction solution was washed with ethyl acetate and concentrated under reduced pressure, and the residue was MCI gel CHP-20.
Fractions subjected to P column chromatography and eluted with 10% ethanol water were collected and concentrated under reduced pressure. The residue was lyophilized to give 0.65 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.39 (3H, s), 1.4-2.
1 (8H, m), 3.23 and 3.47 (2H, ABq, J = 17.8Hz), 3.76 and 4.17 (2
H, ABq, J = 13Hz), 4.93 (1H, d, J = 4.6Hz), 5.58 (1H, dd, J = 8.
4Hz and 4.6Hz), 6.10 (1H, m), 8.
16 (2H, bs), 9.33 (1H, d, J = 8.
4 Hz).

Reference Example 35 N- (Tetrahydrofuran-3-yl) oxyphthalimide 17.9 g of N-hydroxyphthalimide was dissolved in 550 ml of tetrahydrofuran, 8.82 g of 3-hydroxytetrahydrofuran was added, and further 31.5 g of triphenylphosphine was added. It was 100 ml of a tetrahydrofuran solution containing 21.0 g of azodicarboxylic acid diethyl ester was added dropwise at room temperature over 80 minutes. After stirring at room temperature for another 2.5 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. Fractions eluted with methylene chloride were collected and concentrated, and the residue was subjected to silica gel column chromatography again. Fractions eluted with methylene chloride: ethyl acetate (30: 1) were collected and concentrated under reduced pressure. The obtained residue was washed well with hexane-ether, collected by filtration, and dried. Further, recrystallization from ethyl acetate-hexane gave 21.3 g of the title compound as colorless needle crystals. Melting point: 116.0-117.0 ° C. Elemental analysis value: C ₁₂ H ₁₁ NO ₄ Calculated value: C, 61.80; H, 4.75; N, 6.01 Actual value: C, 61.52; H, 4.88; N, 5.91 NMR spectrum (CDCl ₃ ) δ: 2.08 (1H, m), 2.34 (1H,
m), 3.86-3.96 (2H, m), 4.08-4.20 (2H, m), 5.05 (1H, m),
7.75-7.89 (4H, m).

Reference Example 36 O- (Tetrahydrofuran-3-yl) hydroxylamine hydrochloride 18.66 g of N- (tetrahydrofuran-3-yl) oxyphthalimide was dissolved in 80 ml of ethanol, and hydrazine monohydrate 3. 88 ml was added. After heating under reflux for 30 minutes, 8.8 ml of concentrated hydrochloric acid was added. After heating under reflux for a further 5 minutes, 27 ml of water were added. After cooling to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added 35 ml of ethanol, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
150 ml of ethyl acetate was added to the residue and heated. After cooling, the solid was collected by filtration and dried to give the title compound as a colorless solid.
33 g was obtained. Melting point: 21.0-23.0 ° C. Elemental analysis value: C ₄ H ₁₀ NO ₂ Cl Calculated value: C, 34.42; H, 7.22; N, 10.03 Actual value: C, 34.36; H, 7.00; N, 10.70 NMR Spectrum (d ₆ -DMSO) δ: 2.03-2.14 (2H, m),
3.61-3.95 (4H, m), 4.84 (1H, m).

Reference Example 37 2- (5-Amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(tetrahydrofuran-3-yl)
Oxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
14.7 g of (yl) coumarin was suspended in 120 ml of ethanol, and 120 ml of 1N sodium hydroxide was added at room temperature.
After stirring at 40 ° C. for 1.5 hours to form a homogeneous solution, 6.02 ml of ethyl chlorocarbonate was added under ice cooling, and the mixture was stirred for 15 minutes. 60 ml of 1N hydrochloric acid and 60 ml of methylene chloride were added. After separating the organic layer, the aqueous layer was extracted with 90 ml of methylene chloride. Stayed on organic for 2.5 hours. After nitrogen was passed through for 15 minutes to remove excess ozone, 4.92 g of sodium acetate and 30 ml of dimethyl sulfide were added and stirred. After warming to room temperature, the mixture was extracted 3 times with 100 ml of water. Combine the water layers,
It was washed twice with 100 ml of ethyl acetate. O- at room temperature in the water layer
(Tetrahydrofuran-3-yl) hydroxylamine hydrochloride (9.21 g) and sodium acetate (5.41 g) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution is ethyl acetate 150
After washing 3 times with ml, 80 ml of 1N hydrochloric acid and 150 ml of ethyl acetate were added to the ice-cooled lower aqueous layer. The organic layer was separated and the aqueous layer was extracted 3 times with 150 ml of ethyl acetate. The aqueous layer was saturated with sodium chloride and mixed with ethyl acetate-tetrahydrofuran (2: 1) 1
Extracted 6 times with 50 ml. The organic layers were combined and dried over magnesium sulfate. After concentration under reduced pressure, ethyl acetate was added to the residue to dissolve it, and isopropyl ether and hexane were added to precipitate a solid. The solid was collected by filtration, washed with isopropyl ether-hexane, and dried to give 7.67 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.91-2.18
(2H, m), 3.57-3.81 (4H, m),
4.97 (1H, m), 8.20 (2H, s).

Reference Example 38 S- (2-benzothiazolyl) 2- (5-amino-)
1,2,4-thiadiazol-3-yl) -2 (Z)-
[(Tetrahydrofuran-3-yl) oxyimino] thioacetate 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(tetrahydrofuran-3-yl)
Oxyiminoacetic acid 2.58 g, acetonitrile 30 ml
And tri-n-butylamine (4.8 ml) at room temperature,
2-Mercaptobenzothiazole disulfide 4.32
g was added. Then, after cooling with an ice-acetone bath, 2.57 ml of triethyl phosphite was added dropwise over 10 minutes. After stirring at the same temperature for 2 hours, the precipitated solid was collected by filtration, washed with cold acetonitrile and hexane, and dried under reduced pressure to obtain 1.88 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.98-2.27 (2H, s),
3.68-3.92 (4H, m), 5.07 (1H, m), 7.52-7.67 (2H, m), 8.08
(1H, m), 8.22 (1H, m), 8.31 (2H, s).

Reference Example 39 Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(tetrahydrofuran-3-yl) oxyiminoacetamide] -3
-Hydroxymethyl-3-cephem-4-carboxylate 7β-amino-3-hydroxymethyl-3-cephem-
0.576 g of 4-carboxylic acid was suspended in 10 ml of water, and the pH was adjusted to 8 by adding 1N sodium hydroxide under ice cooling. In addition to this S- (2-benzothiazolyl) 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-[(Tetrahydrofuran-3-yl) oxyimino]
15 ml of a tetrahydrofuran solution containing 1.019 g of thioacetate was added under ice cooling, and the mixture was stirred at room temperature for 22 hours. After adding a few drops of an antifoaming agent, tetrahydrofuran was distilled off under reduced pressure. The residue was washed twice with ethyl acetate, and the aqueous layer was concentrated under reduced pressure to about 3 ml. It was subjected to MCI gel CHP-20P column chromatography, and the fractions eluted with 5% ethanol water were collected and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.853 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 2.00-2.20 (2H, m),
3.24 (1H, d, J = 18.0Hz), 3.48 (1H, d, J = 18.0Hz), 3.66-3.9
9 (5H, m), 4.10 (1H, dd, J = 12.4Hz, J = 4.6Hz), 4.93 (2H, m, J
= 4.8Hz), 5.57 (1H, dd, J = 8.4Hz, J = 4.8Hz), 6.11 (1H, m),
8.12 (2H, s), 9.46 (1H, d, J = 8.4Hz).

Reference Example 40 N- (Tetrahydropyran-4-yl) oxyphthalimide 16.31 g of N-hydroxyphthalimide was dissolved in 200 ml of dimethyl sulfoxide, and potassium carbonate 27.64 was added.
g was added and the mixture was stirred at room temperature for 30 minutes. 18-crown-
6 2.64 g was added, and the mixture was stirred at room temperature for 15 minutes. 80
4-Bromotetrahydropyran 19.
80 ml of a dimethyl sulfoxide solution (80 g) was added dropwise over 1 hour. After stirring at the same temperature for 3 hours, the mixture was cooled to room temperature. Ethyl acetate (500 ml) was added, and the mixture was washed with water and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was washed with hexane and dried under reduced pressure to obtain 7.94 g of the title compound. Melting point: 117.0-119.0 ° C NMR spectrum (d ₆ -DMSO) δ: 1.81-2.11 (4H, m),
3.43-3.55 (2H, m), 4.01-4.12 (2H, m), 4.45 (1H, m), 7.73
-7.87 (4H, m).

Reference Example 41 O- (Tetrahydropyran-4-yl) hydroxylamine hydrochloride 7.42 g of N- (tetrahydropyran-4-yl) oxyphthalimide was dissolved in 30 ml of ethanol and hydrazine monohydrate 1 was added at room temperature. 0.46 ml was added. After heating under reflux for 40 minutes, 3.3 ml of concentrated hydrochloric acid was added. After heating under reflux for another 10 minutes, 9 ml of water was added. After cooling to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethanol 4 in the residue
2 ml was added, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. 50 ml of ethyl acetate was added to the residue and heated. After cooling, the solid was collected by filtration and dried to obtain 4.54 g of the title compound as a colorless solid. Melting point: 145.0-147.0 ° C. Elemental analysis value: C ₅ H ₁₂ NO ₂ Cl Calculated value: C, 39.10; H, 7.87; N, 9.12 Found: C, 38.84; H, 7.65; N, 9.51 NMR Spectrum (d ₆ -DMSO) δ: 1.43-1.61 (2H, m),
1.92-2.05 (2H, m), 3.30-3.52 (5H, m), 3.67-3.87 (2H, m),
4.30 (1H, m).

Reference Example 42 2- (5-Amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(tetrahydropyran-4-yl)
Oxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
7.36 g of yl) coumarin was suspended in 60 ml of ethanol, and 60 ml of 1N sodium hydroxide was added at room temperature. Four
After stirring at 0 ° C. for 1.5 hours to make a uniform solution, 3.0 ml of ethyl chlorocarbonate was added dropwise under ice cooling. After stirring for 15 minutes at the same temperature, 30 ml of 1N hydrochloric acid and 45 ml of methylene chloride were added. After separating the organic layer, the aqueous layer was extracted with 45 ml of methylene chloride. The organic layers were combined and ozone was bubbled through for 1 hour while cooling to -78 ° C. After nitrogen was purged for 1 hour to remove excess ozone, 2.46 g of sodium acetate and 15 ml of dimethyl sulfide were added. After warming to room temperature, water 150
Extracted 3 times with ml. Combine the aqueous layers and add 150 ml of ethyl acetate.
It was washed twice with. 5.07 g of O- (tetrahydropyran-4-yl) hydroxylamine hydrochloride and 2.71 g of sodium acetate were added to the aqueous layer at room temperature, and the mixture was stirred at room temperature for 13 hours. The reaction solution was washed twice with 100 ml of ethyl acetate, and then 50 ml of 1N hydrochloric acid and 150 ml of ethyl acetate were added to the ice-cooled lower aqueous layer. The organic layer was separated and the aqueous layer was extracted 3 times with 150 ml of ethyl acetate. Further, the aqueous layer was saturated with sodium chloride and continuously extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate. After concentration under reduced pressure, ethyl acetate was added to the residue to dissolve it, and isopropyl ether and hexane were added to precipitate a solid. The solid was collected by filtration, washed with isopropyl ether-hexane, and dried to obtain 2.87 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.49-1.65
(2H, m), 1.65-2.00 (2H, m),
3.38-3.50 (2H, m), 3.69-3.8
4 (2H, m), 4.40 (1H, m), 8.18
(2H, m).

Reference Example 43 S- (2-benzothiazolyl) 2- (5-amino-)
1,2,4-thiadiazol-3-yl) -2 (Z)-
[(Tetrahydropyran-3-yl) oxyimino] thioacetate 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(tetrahydropyran-3-yl)
2.72 g of oximinoacetic acid and 23 ml of acetonitrile
And tri-n-butylamine (4.8 ml) at room temperature, 2
-Mercaptobenzothiazole disulfide 4.32 g
Was added. After cooling with an ice-acetone bath, 2.57 ml of triethyl phosphite was added dropwise over 5 minutes. After stirring at the same temperature for 2 hours, the precipitated solid was collected by filtration, washed with cold acetonitrile and hexane, and dried under reduced pressure to obtain 2.01 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.45-2.10 (4H, m),
3.32-3.90 (4H, m), 4.52 (1H, m), 7.56-7.65 (2H, m), 8.09
(1H, m), 8.22 (1H, m), 8.32 (2H, s).

Reference Example 44 Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(tetrahydropyran-3-yl) oxyiminoacetamide] -3
-Hydroxymethyl-3-cephem-4-carboxylate 7β-amino-3-hydroxymethyl-3-cephem-
0.576 g of 4-carboxylic acid was suspended in 10 ml of water, and the pH was adjusted to 8 with 1N sodium hydroxide under ice cooling. S- (2-
Benzothiazolyl) 2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-[(tetrahydropyran-3-yl) oxyimino] thioacetate (1.265 g) in tetrahydrofuran (15 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 20 hr. After adding a few drops of an antifoaming agent, tetrahydrofuran was distilled off under reduced pressure. The residue was washed twice with ethyl acetate, and the aqueous layer was concentrated under reduced pressure to about 3 ml.
It was subjected to MCI gel CHP-20P column chromatography, and the fractions eluted with 5% ethanol water were collected and concentrated under reduced pressure. Lyophilization gave 0.386 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 1.52-2.00 (4H, m),
3.18-3.50 (4H, m), 3.73 (1H, d, J = 12.4Hz), 3.76-3.91 (2
H, m), 4.14 (1H, d, J = 12.4Hz), 4.35 (1H, m), 4.93 (1H, d, J
= 4.8Hz) ,. 5.58 (1H, dd, J = 8.4Hz, J = 4.8Hz), 6.26 (1H, m),
8.14 (1H, s), 9.43 (1H, d, J = 8.4Hz).

Reference Example 45 N- (oxetane-3-yl) oxyphthalimide 15.8 g of N-hydroxyphthalimide was dissolved in 400 ml of tetrahydrofuran, and 6.00 g of 3-hydroxyoxetane and 31.9 g of triphenylphosphine were added. 50 ml of a tetrahydrofuran solution containing 21.2 g of azodicarboxylic acid diethyl ester was added dropwise over 40 minutes under ice cooling. After stirring at room temperature for 8 hours, the reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a mixed solution of ethyl acetate-hexane (1: 4), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography again and eluted with a mixed solution of methylene chloride and methylene chloride-ethyl acetate (20: 1). Fractions containing the desired product were collected, the solvent was concentrated under reduced pressure, the residue was washed with hexane-ether, collected by filtration and dried. Further, it was subjected to silica gel column chromatography and eluted with methylene chloride-hexane (1: 3), methylene chloride-hexane (1: 2), and methylene chloride. Fractions containing the desired product were collected, the solvent was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to obtain 1.90 g of the title compound as colorless needles. Melting point: 142.0-144.0 ° C. Elemental analysis value: C ₁₁ H ₉ NO ₄ calculated value: C, 60.28; H, 4.14; N, 6.39 Found value: C, 60.02; H, 4.09; N, 6.61 NMR spectrum (CDCl ₃ ) δ: 4.82-5.01 (4H, m), 5.27
(1H, m), 7.76-7.90 (4H, m).

Reference Example 46 O- (oxetan-3-yl) hydroxylamine N- (oxetan-3-yl) oxyphthalimide 1.
87 g of methylene chloride was dissolved in 8.5 ml of methylene chloride and 1.1 ml of methanol, and 0.83 ml of hydrazine monohydrate was added at room temperature. After stirring at room temperature for 17 hours, the precipitated solid was filtered off. After adding 4.5 ml of 5N-ammonia water to the filtrate, the aqueous layer was separated. The aqueous layer was extracted 8 times with methylene chloride. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate. Concentration under reduced pressure gave 0.819 g of the title compound. NMR spectrum (CDCl ₃ ) δ: 4.60-4.80 (5H, m), 5.48
(2H, s).

Reference Example 47 2- (5-Amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(oxetan-3-yl) oxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
(Il) coumarin (1.81 g) was suspended in ethanol (14 ml), and 1N-sodium hydroxide (14.8 ml) was added at room temperature. It stirred at 40 degreeC for 1 hour, and set it as the homogeneous solution. below freezing,
After adding 0.74 ml of ethyl chlorocarbonate dropwise, at the same temperature 15
Stir for minutes. 1N-hydrochloric acid 7.4 ml and methylene chloride 10
ml was added. After separating the organic layer, the aqueous layer was washed with methylene chloride 10
extracted with ml. The organic layers were combined and ozone was bubbled through for 35 minutes while cooling to -78 ° C. After nitrogen was purged for 15 minutes to remove excess ozone, 0.605 g of sodium acetate and 3.6 ml of dimethyl sulfide were added. After warming to room temperature, extraction was performed 3 times with 15 ml of water. The aqueous layers were combined and washed twice with 15 ml of ethyl acetate. 0.810 g of O- (oxetan-3-yl) hydroxylamine was added to the aqueous layer at room temperature, and the mixture was stirred at room temperature for 15.7 hours. The reaction solution was washed 3 times with 20 ml of ethyl acetate, and then 11 ml of 1N hydrochloric acid and 30 ml of ethyl acetate were added to the ice-cooled lower aqueous layer. The organic layer was separated, the aqueous layer was saturated with sodium chloride, and extracted 6 times with 20 ml of a mixed solution of ethyl acetate-tetrahydrofuran (2: 1). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue to dissolve it, and isopropyl ether and hexane were added to precipitate a solid. The solid was collected by filtration, washed with isopropyl ether-hexane, and dried to give the title compound (0.890 g). NMR spectrum (d ₆ -DMSO) δ: 4.55-4.59 (2H, m),
4.77-4.85 (2H, m), 5.33 (1H, m), 8.22 (2H, s).

Reference Example 48 Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(oxetan-3-yl) oxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 2- (5-amino-1,2,4- Thiadiazole-3-
Yl) -2 (Z)-(oxetane-3-yl) oxyiminoacetic acid (0.950 g) was suspended in acetonitrile (22 ml), and tri-n-butylamine (1.85 ml) and 2-mercaptobenzothiazole disulfide (1.68 g) were added at room temperature. . While cooling with an ice-acetone bath, 1.0 ml of triethyl phosphite was slowly added dropwise. After stirring at the same temperature for 2 hours, the reaction solution was concentrated under reduced pressure. 7β-Amino-3-hydroxymethyl-3-cephem-4-carboxylic acid 1.0
0 g was suspended in 15 ml of water and adjusted to pH 8 with 1N sodium hydroxide under ice cooling. Under ice cooling, 20 ml of a tetrahydrofuran solution of the above concentrated residue was added thereto, and the mixture was stirred at room temperature for 17 hours. A few drops of an antifoaming agent were added, tetrahydrofuran was distilled off under reduced pressure, and the residue was washed with ethyl acetate three times. About 5 ml of water layer
After concentration under reduced pressure, the residue was subjected to MCI gel CHP-20P column chromatography and eluted with water. Fractions containing the desired product were collected, concentrated under reduced pressure, and freeze-dried to obtain 0.317 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 3.30 (1H, d, J = 18.0H
z), 3.50 (1H, d, J = 18.0Hz), 3.78 (1H, d, J = 12.8Hz), 4.18
(1H, d, J = 12.8Hz), 4.62-4.87 (4H, m), 4.96 (1H, d, J = 4.8H
z), 5.32 (1H, m), 5.59 (1H, dd, J = 8.6Hz, J = 4.8Hz), 6.20
(1H, bs), 8.20 (2H, s), 9.56 (1H, d, J = 8.6Hz).

Reference Example 49 N- (thietan-3-yl) oxyphthalimide 19.6 g of N-hydroxyphthalimide was dissolved in 500 ml of tetrahydrofuran to give 3-hydroxythietane 9.
01 g and triphenylphosphine 39.3 g were added.
20 ml of a tetrahydrofuran solution containing 26.1 g of azodicarboxylic acid diethyl ester was added dropwise over 40 minutes under ice cooling. After stirring at room temperature for another 1.5 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with methylene chloride. The differentiation containing the target substance was collected, concentrated under reduced pressure, and subjected to silica gel column chromatography again, and ethyl acetate-hexane (1:
Fractions eluted in 3) were collected and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 12.02 g of the title compound as colorless needle crystals. Melting point: 164.0-167.0 ° C. Elemental analysis value: C ₁₁ H ₉ NO ₃ S Calculated value: C, 56.16; H, 3.86; N, 5.95 Actual value: C, 56.05; H, 3.75; N, 6.02 NMR Spectrum (CDCl ₃ ) δ: 3.21-3.31 (2H, m), 3.70
-3.80 (2H, m), 5.43 (1H, m), 7.73-7.89 (4H, m).

Reference Example 50 O- (thietan-3-yl) hydroxylamine hydrochloride N- (thietan-3-yl) oxyphthalimide 7.0
6 g was dissolved in 60 ml of methylene chloride and 3.7 ml of methanol, and 8.72 ml of hydrazine monohydrate was added at room temperature. After stirring at room temperature for 4.5 hours, the precipitated solid was filtered off. After adding 18 ml of 5N-ammonia water to the filtrate, the aqueous layer was separated. The aqueous layer was extracted twice with methylene chloride. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate.
To the residue obtained by concentration under reduced pressure, 60 ml of 1N hydrochloric acid was added and stirred, and then concentrated under reduced pressure. 180 ml of ethanol was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ether, collected by filtration and dried under reduced pressure to obtain 3.94 g of the title compound. Melting point: 119.0-120.0 ° C NMR spectrum (d ₆ -DMSO) δ: 3.21-3.31 (2H, m),
3.37-3.47 (2H, m), 5.20 (1H, m).

Reference Example 51 2- (5-Amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(thietan-3-yl) oxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
7.36 g of yl) coumarin was suspended in 60 ml of ethanol, and 60 ml of 1N sodium hydroxide was added at room temperature. Four
After stirring at 0 ° C for 1.5 hours to form a uniform solution, 3.01 ml of ethyl chlorocarbonate was added dropwise under ice cooling. After stirring for 15 minutes at the same temperature, 30 ml of 1N hydrochloric acid and 45 ml of methylene chloride were added. After separating the organic layer, the aqueous layer was extracted with 45 ml of methylene chloride. While combining the organic layers and cooling to -78 ° C,
Ozone was bubbled through for 1 hour. After nitrogen was passed for 20 minutes to remove excess ozone, 2.46 g of sodium acetate and 15 ml of dimethyl sulfide were added. After warming to room temperature, water 6
Extract 3 times with 0 ml. Combine the aqueous layers and add ethyl acetate 150
Washed twice with ml. O- (thietan-3-
Ilyl) hydroxylamine hydrochloride (4.67 g) and sodium acetate (2.71 g) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed twice with 100 ml of ethyl acetate, and then added to the ice-cooled lower water layer to give 1
50 ml of N-hydrochloric acid and 150 ml of ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate three times. The organic layers were combined and dried over magnesium sulfate. After concentration under reduced pressure, ethyl acetate was added to the residue to dissolve it, and isopropyl ether and hexane were added to precipitate a solid. The solid is filtered off,
It was washed with isopropyl ether-hexane and dried to obtain 3.58 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 3.24-3.55 (4H, m),
5.38 (1H, m), 8.24 (2H, s).

Reference Example 52 Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(thietane-
3-yl) oxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 2- (5-amino-1,2,4-thiadiazole-3-
1.58 g of (yl) -2 (Z)-(thietan-3-yl) oxyiminoacetic acid was suspended in 20 ml of acetonitrile, and 2.90 ml of tri-n-butylamine and 2.63 g of 2-mercaptobenzothiazole disulfide were added at room temperature. ..
After adding 1.57 ml of triethyl phosphite under ice cooling, the mixture was stirred at the same temperature for 3 hours and concentrated under reduced pressure. 7β-Amino-3-hydroxymethyl-3-cephem-4-carboxylic acid 1.41 g
Was suspended in 21 ml of water and adjusted to pH 8 with 1N sodium hydroxide under ice cooling. Under ice-cooling, 30 ml of a tetrahydrofuran solution of the above concentrated residue was added dropwise, and the mixture was stirred at room temperature for 17 hours. After adding a few drops of an antifoaming agent, tetrahydrofuran was distilled off under reduced pressure. The residue was washed with ethyl acetate three times, and the aqueous layer was washed with MCI.
It was subjected to gel CHP-20P column chromatography. Elution was performed with 5% ethanol water, and fractions containing the desired product were collected and concentrated under reduced pressure. The residue was lyophilized to give 0.227 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 3.23-3.67 (6H, m),
3.79 (1H, d, J = 12.4Hz), 4.18 (1H, d, J = 12.4Hz), 4.97 (1H,
d, J = 4.8Hz), 5.33 (1H, m), 5.59 (1H, dd, J = 8.2Hz, J = 4.8H
z), 8.20 (2H, s), 9.51 (1H, d, J = 8.2Hz).

Example 1 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (imidazo [1,2 -B] pyridazinium-1-yl) methyl-3-cephem-4-
Carboxylate

[Chemical formula 45] 0.38 g of 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate dihydrochloride was dissolved in 6 ml of methanol, and tributylamine was added under ice cooling. 0.53 ml and S- (2
-Benzothiazolyl) 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) thioacetate (0.2 g) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fractions eluted with a mixed solution of acetone-water (7: 3) were collected and concentrated under reduced pressure. Then, it was subjected to MCI gel CHP-20P column chromatography, and the fractions eluted with a water-ethanol (3: 1) mixed solution were collected and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.126 g of the title compound. Elemental _{analysis: C 23 H 23 N 9 O} 5 S 2 · 2H 2 O Calculated: C, 45.61; H, 4.49 ; N, 20.81 Found: C, 45.56; H, 4.68 ; N, 20.83 NMR spectrum (d ₆ −DMSO) δ: 1.4-1.9 (8H, m), 3.0
4 and 3.36 (2H, ABq, J = 17.2Hz), 4.67 (1H, m), 4.98 (1H, d, J =
5Hz), 5.28 and 5.46 (2H, ABq, J = 14Hz), 5.63 (1H, dd, J = 8.4H
z and 5Hz), 7.95 (1H, dd, J = 9Hz and 4.6Hz), 8.12 (2H, bs), 8.
75 (2H, m), 9.04 (1H, d, J = 4.6Hz), 9.31 (1H, d, J = 9Hz), 9.
44 (1H, d, J = 8.4Hz).

Example 2 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (6-aminoimidazo [ 1,
2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical formula 46] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.245g
And 6-aminoimidazo [1,2-b] pyridazine 0.1
34 g was dissolved in 4 ml of dimethylformamide, 2 g of a solution of 0.5 g of ethyl o-phenylene phosphate in dimethylformamide was added, and the mixture was stirred at room temperature for 4 hours.
100 ml of ether was added to the reaction solution to form a precipitate, and 1
Stir for 5 minutes. Then the solvent was decanted, the residue was dissolved in a small amount of acetone-water and subjected to silica gel column chromatography. Fractions eluted with an acetone-water (7: 3) mixture were collected and concentrated, and the residue was treated with MCI gel CHP.
It was subjected to -20P column chromatography, eluted with 25% ethanol water, the fractions containing the desired product were collected and concentrated under reduced pressure, and the residue was freeze-dried to obtain 0.068 g of the title compound. Elemental _{analysis: C 23 H 24 N 10 O} 5 S 2 · 3H 2 O Calculated: C, 43.25; H, 4.73 ; N, 21.93 Found: C, 43.05; H, 4.65 ; N, 22.04 NMR spectrum (d ₆ −DMSO) δ: 1.4-1.9 (8H, m), 3.1
7 and 3.33 (2H, ABq, J = 17.2Hz), 4.68 (1H, m), 4.97 (1H, d, J =
4.8Hz), 5.15 and 5.31 (2H, ABq, J = 13.6Hz), 5.61 (1H, dd, J =
8.4Hz and 4.8Hz), 7.20 (2H, bs), 7.21 (1H, d, J = 9.8Hz), 8.
12 (2H, bs), 8.17 (1H, d, J = 2Hz), 8.32 (1H, d, J = 2Hz), 8.7
7 (1H, d, J = 9.8Hz), 9.43 (1H, d, J = 8.4Hz).

Example 3 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (3-formylaminoimidazo) [1,2-b] Pyridazinium-1-yl) methyl-
3-cephem-4-carboxylate

[Chemical 47] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.736g
And 3-formylaminoimidazo [1,2-b] pyridazine (0.292 g) and ethyl o-phenylene phosphate (1.5 g) were treated in the same manner as in Example 2 to give the title compound 0.2.
86 g was obtained. Elemental _{analysis: C 24 H 24 N 10 O} 6 S 2 · 2.5H 2 O Calculated: C, 43.86; H, 4.44 ; N, 21.30 Found: C, 43.89; H, 4.42 ; N, 21.36 NMR spectrum (D ₆ −DMSO) δ: 1.4-1.9 (8H, m), 3.0
6 and 3.35 (2H, ABq, J = 17.4Hz), 4.67 (1H, m), 4.98 (1H, d, J =
5Hz), 5.31 and 5.53 (2H, ABq, J = 15Hz), 5.64 (1H, dd, J = 5Hz
And 8.2Hz), 7.92 (1H, dd, J = 4.4Hz and 9.4Hz), 8.13 (2H, bs),
8.52 (1H, s), 8.83 (1H, s), 9.09 (1H, d, J = 4.4Hz), 9.34
(1H, d, J = 9.4Hz), 9.47 (1H, d, J = 8.2Hz).

Example 4 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (3-aminoimidazo [ 1,
2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 48] 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (3-formylaminoimidazo [1,2-b ] Pyridazinium-1-yl) methyl-
0.21 g of 3-cephem-4-carboxylate was suspended in 10 ml of methanol, 5 ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 15 hours. Concentrate under reduced pressure and subject the residue to MCI gel CHP-20P column chromatography, 25
Elution was performed with% ethanol water. Fractions containing the desired compound were collected and concentrated, and the residue was lyophilized to give the title compound 0.1
58 g were obtained. Elemental _{analysis: C 23 H 24 N 10 O} 5 S 2 · 2H 2 O Calculated: C, 44.51; H, 4.55 ; N, 22.57 Found: C, 44.34; H, 4.70 ; N, 22.73 NMR spectrum (d ₆ −DMSO) δ: 1.4-1.9 (8H, m), 3.02 and 3.47 (2
H, ABq, J = 18Hz), 4.68 (1H, m), 4.99 (1H, d, J = 5Hz), 5.20
And 5.36 (2H, ABq, J = 13.8Hz), 5.64 (1H, dd, J = 5Hz and 8.4Hz),
6.46 (2H, bs), 7.64 (1H, dd, J = 4.4Hz and 9.4Hz), 7.86 (1H,
s), 8.14 (2H, bs), 8.90 (1H, d, J = 4.4Hz), 8.98 (1H, d, J =
9.4Hz), 9.45 (1H, d, J = 8.4Hz).

Example 5 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3- (imidazo [1, 2-b] pyridazinium-1-yl) methyl-3-cephem-4-
Carboxylate

[Chemical 49] 0.771 g of 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate dihydrochloride was added to 12 ml of a mixture of acetone-water (1: 1). Dissolve, and add 1.05 ml of tributylamine and S- (2-benzothiazolyl) under ice cooling.
2- (5-amino-1,2,4-thiadiazole-3
-Yl) -2 (Z)-(cyclobutyloxyimino) thioacetate (0.4 g) was added, and the mixture was stirred at room temperature for 4 hours.
The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fractions eluted with a mixed solution of acetone-water (7: 3) were collected and concentrated under reduced pressure. Then MC
I-gel CHP-20P column chromatography was performed, and the fractions eluted with a water-ethanol (4: 1) mixture were collected, concentrated under reduced pressure and freeze-dried to obtain 0.147 g of the title compound. Elemental _{analysis: C 22 H 21 N 9 O} 5 S 2 · 4.0H 2 O Calculated: C, 42.10; H, 4.66 ; N, 20.08 Found: C, 41.92; H, 4.70 ; N, 19.83 NMR spectrum (D ₆ −DMSO) δ: 1.4-1.8 (2H, m), 2.0
-2.3 (4H, m), 3.06 and 3.51 (2H, ABq, J = 17.4Hz), 4.68 (1H,
m), 5.0 (1H, d, J = 4.8Hz), 5.29 and 5.49 (2H, ABq, J = 14Hz),
5.66 (1H, dd, J = 8.4Hz and 4.8Hz), 7.96 (1H, dd, J = 8.8Hz and 4.
8Hz), 8.14 (2H, bs), 8.77 (2H, s), 9.05 (1H, d, J = 4.8Hz),
9.34 (1H, d, J = 8.8Hz), 9.51 (1H, d, J = 8.4Hz).

Example 6 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3- (3-formylamino) Imidazo [1,2-b] pyridazinium-1-yl) methyl-
3-cephem-4-carboxylate

[Chemical 50] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.476
g, 3-formylaminoimidazo [1,2-b] pyridazine (0.195 g) and ethyl o-phenylene phosphate (1.0 g) were treated in the same manner as in Example 2 to give the title compound.
166 g was obtained. Elemental _{analysis: C 23 H 22 N 10 O} 6 S 2 · 2.5H 2 O Calculated: C, 42.92; H, 4.23 ; N, 21.76 Found: C, 42.60; H, 4.26 ; N, 22.12 NMR spectrum (D ₆ −DMSO) δ: 1.4-1.7 (2H, m), 2.0
-2.2 (4H.m), 3.07 and 3.40 (2H, ABq, J = 17Hz), 4.67 (1H, m),
5.00 (1H, d, J = 4.8Hz), 5.29 and 5.56 (2H, ABq, J = 13.6Hz),
5.65 (1H, dd, J = 4.8Hz and 8.4Hz), 7.92 (1H, dd, J = 4.4Hz and 9.4Hz), 8.13 (2H, bs), 8.52
(1H, s), 8.84 (1H, s), 9.09
(1H, d, J = 4.4 Hz), 9.37 (1H,
d, J = 9.4 Hz), 9.52 (1H, d, J =
8.4 Hz).

Example 7 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamide] -3- (3-aminoimidazo [1,
2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 51] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3- (3-formylaminoimidazo [1,2- b] pyridazinium-1-yl) methyl-
0.15 g of 3-cephem-4-carboxylate was suspended in 8 ml of methanol, 4 ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 15 hours. Concentrate under reduced pressure and residue to CHP
Purified by -20 column chromatography and eluted with 20% ethanol. After concentrating the target fraction, the residue was freeze-dried to obtain 0.115 g of the title compound. Elemental _{analysis: C 22 H 22 N 10 O} 5 S 2 · 4H 2 O Calculated: C, 41.12; H, 4.71 ; N, 21.79 Found: C, 41.07; H, 5.05 ; N, 21.71 NMR spectrum (d ₆ −DMSO) δ: 1.4-1.8 (2H, m), 2.0
-2.2 (4H, m), 3.03 and 3.37 (2H, ABq, J = 17Hz), 4.67 (1H, m),
5.00 (1H, d, J = 5Hz), 5.17 and 5.37 (2H, ABq, J = 14Hz), 5.65
(1H, dd, J = 5Hz and 8.4Hz), 6.43 (2H, bs), 7.65 (1H, dd, J = 4.
4Hz and 9.6Hz), 7.88 (1H, s), 8.13 (2H, bs), 8.91 (1H, d, J =
4.4Hz), 8.99 (1H, d, J = 9.6Hz), 9.49 (1H, d, J = 8.4Hz).

Example 8 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclohexyloxyimino) acetamide] -3- (imidazo [1,2 -B]
Pyridazinium-1-yl) -3- (imidazo [1,2
-B] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 52] 0.397 g of 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate dihydrochloride was dissolved in 6 ml of 50% water-containing acetone and cooled with ice. Lower tributylamine 0.62 ml and S- (2-benzothiazolyl) 2- (5-amino-1,
A solution of 0.3 g of 2,4-thiazol-3-yl) -2 (Z)-(cyclohexyloxyimino) thioacetate in 4 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fractions eluted with a mixed solution of acetone-water (4: 1) were collected and concentrated under reduced pressure. Then C
It was subjected to HP-20P column chromatography, and the fractions eluted with a mixed solution of water-ethanol (2: 1) were collected and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.16 g of the title compound. Elemental _{analysis: C 24 H 25 N 9 O} 5 S 2 · 2.5H 2 O Calculated: C, 45.85; H, 4.81 ; N, 20.05 Found: C, 45.91; H, 4.66 ; N, 20.36 NMR spectrum (D ₆ −DMSO) δ: 1.16-1.89 (10H, m),
3.05 and 3.30 (1H, d, J = 17.6Hz each), 4.03-4.10 (1H, m), 4.99
(1H, d, J = 4.8Hz), 5.27 (1H, d, J = 13.6Hz), 5.46 (1H, d, J = 1
4Hz), 5.66 (1H, dd, J = 4.9Hz and 8.3Hz), 7.95 (1H, dd, J = 4.6
Hz and 9.4Hz), 8.11 (2H, bs), 8.73 (1H, d, J = 2.2Hz), 8.76
(1H, d, J = 2.2Hz), 9.05 (1H, d, J = 4.6Hz), 9.31 (1H, d, J = 10
Hz), 9.45 (1H, d, J = 8.8Hz).

Example 9 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclohexyloxyimino) acetamide] -3- (6-aminoimidazo [ 1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 53] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclohexyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.505
g and 6-aminoimidazo [1,2-b] pyridazine 0.
174 g, ethyl o-phenylene phosphate 1.0
g was operated in the same manner as in Example 2 to obtain 0.12 g of the title compound. Elemental _{analysis: C 24 H 26 N 10 O} 5 S 2 · 3.5H 2 O Calculated: C, 43.56; H, 5.03 ; N, 21.17 Found: C, 43.71; H, 5.04 ; N, 20.91 NMR spectrum (D ₆ −DMSO) δ: 1.16-1.91 (10H, m),
3.03 and 3.38 (2H, ABq, J = 17.2Hz), 4.03-4.12 (1H, m), 4.98
(1H, d, J = 4.8Hz), 5.15 and 5.31 (2H, ABq, J = 15Hz), 5.65 (1
H, dd, J = 4.9Hz and 8.3Hz), 7.20 (1H, d, J = 9.6Hz), 7.21 (2H,
bs), 8.12 (2H, bs), 8.18 (1H, d, J = 2Hz), 8.31 (1H, d, J = 2H
z), 8.75 (1H, d, J = 10.2Hz), 9.45 (1H, d, J = 8.6Hz).

Example 10 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclohexyloxyimino) acetamide] -3- (3-formylaminoimidazo) [1,2-b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 54] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclohexyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.757
g, 3-formylaminoimidazo [1,2-b] pyridazine 0.324 g and ethyl o-phenylene phosphate 1.5 g were treated in the same manner as in Example 2 to give the title compound 0.
33 g was obtained. Elemental _{analysis: C 25 H 26 N 10 O} 6 S 2 · 3H 2 O Calculated: C, 44.11; H, 4.74 ; N, 20.58 Found: C, 43.91; H, 4.88 ; N, 20.60 NMR spectrum (d ₆ −DMSO) δ: 1.15-1.89 (10H, m),
3.06 and 3.41 (2H, ABq, J = 18Hz), 4.00-4.10 (1H, m), 4.98 (1
H, d, J = 4.8Hz), 5.30 (1H, d, J = 14.4Hz), 5.54 (1H, d, J = 14.
2Hz), 5.67 (1H, dd, J = 5.2Hz and 8.4Hz), 7.92 (1H, dd, J = 4.0
Hz and 9.8Hz), 8.11 (2H, bs), 8.53 (1H, s), 8.83 (1H, s),
9.10 (1H, d, J = 3.6Hz), 9.35 (1H, d, J = 8.8Hz), 9.47 (1H, d, J
= 8.4Hz), 11.70-12.00 (1H, br).

Example 11 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclohexyloxyimino) acetamide] -3- (3-aminoimidazo [ 1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 55] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclohexyloxyimino) acetamido] -3- (3-formylaminoimidazo [1,2-b 0.26 g of pyridazinium-1-yl) methyl-3-cephem-4-carboxylate was treated in the same manner as in Example 3 to obtain 0.17 g of the title compound. Elemental _{analysis: C 24 H 26 N 10 O} 5 S 2 · 3.5H 2 O Calculated: C, 43.56; H, 5.03 ; N, 21.17 Found: C, 43.28; H, 5.37 ; N, 20.89 NMR spectrum (D ₆ −DMSO) δ: 1.15-1.90 (10H, m),
3.03 and 3.40 (2H, ABq, J = 17.6Hz), 4.02-4.12 (1H, m), 4.99
(1H, d, J = 5.2Hz), 5.17 and 5.35 (2H, ABq, J = 14.6Hz), 5.66 (1
H, dd, J = 5.0Hz and 8.6Hz), 6.42 (2H, bs), 7.65 (1H, dd, J = 2.
5Hz and 9.3Hz), 7.86 (1H, s), 8.11 (2H, bs), 8.90 (1H, d, J =
2.5Hz), 8.97 (1H, d, J = 9.6Hz), 9.44 (1H, d, J = 8.4Hz).

Example 12 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (3-formylamino- 6
-Methoxyimidazo [1,2-b] pyridazinium-1
-Yl) methyl-3-cephem-4-carboxylate

[Chemical 56] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.736
g, 3-formylamino-6-methoxyimidazo [1,
2-b] Pyridazine (0.384 g) and ethyl o-phenylene phosphate (1.5 g) were treated in the same manner as in Example 2 to obtain the title compound (0.37 g). Elemental analysis value: C ₂₅ H ₂₆ N ₁₀ O ₇ S ₂ · 2.5H ₂ O Calculated value: C, 43.66; H, 4.54; N, 20.37 Actual value: C, 43.24; H, 4.91; N, 20.11 NMR spectrum (D ₆ −DMSO) δ: 1.40-1.82 (8H, m),
3.03 and 3.39 (2H, ABq, J = 17.4Hz), 4.14 (3H, s), 4.65-4.70
(1H, m), 4.98 (1H, d, J = 4.8Hz), 5.22 and 5.48 (2H, ABq, J = 14
Hz), 5.64 (1H, dd, J = 5.1Hz and 8.1Hz), 7.60 (1H, d, J = 10H
z), 8.12 (2H, bs), 8.56 (1H, s), 8.66 (1H, s), 9.19 (1H,
d, J = 10Hz), 9.47 (1H, d, J = 8.6Hz), 11.55-11.80 (1H, br).

Example 13 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (6-amino-3) -Formylaminoimidazo [1,2-b] pyridazinium-1-
Iyl) methyl-3-cephem-4-carboxylate

[Chemical 57] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.736
g, 6-amino-3-formylaminoimidazo [1,2
-B] Pyridazine (0.4 g) and ethyl o-phenylene phosphate (1.5 g) were used in the same manner as in Example 2 to obtain the title compound (0.4 g). Elemental _{analysis: C 24 H 25 N 11 O} 6 S 2 · 4H 2 O Calculated: C, 41.20; H, 4.75 ; N, 22.02 Found: C, 41.21; H, 4.77 ; N, 21.70 NMR spectrum (d _6- DMSO) δ: 1.43-1.84 (8H, m),
3.07 and 3.39 (2H, ABq, J = 17.2Hz), 4.68-4.71 (1H, br), 4.9
8 (1H, d, J = 4.8Hz), 5.19 and 5.32 (2H, ABq, J = 12.4Hz), 5.64
(1H, dd, J = 5.0Hz and 7.8Hz), 7.19 (2H, bs), 7.20 (1H, d, J =
9.4Hz), 8.12 (2H, bs), 8.42 (1H, s), 8.44 (1H, s), 8.77
(1H, d, J = 10.2Hz), 9.46 (1H, d, J = 8.0Hz), 11.20-11.35 (1
H, br).

Example 14 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (3,6-diamino Imidazo [1,2-b] pyridazinium-1-yl) methyl-
3-cephem-4-carboxylate

[Chemical 58] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (6-amino-3-formylaminoimidazo [1 , 2-b] pyridazinium-1-
0.13 g of (yl) methyl-3-cephem-4-carboxylate was treated in the same manner as in Example 3 to give the title compound (0.13 g).
07 g were obtained. Elemental _{analysis: C 23 H 25 N 11 O} 5 S 2 · 3H 2 O Calculated: C, 42.26; H, 4.78 ; N, 23.57 Found: C, 42.30; H, 4.93 ; N, 23.30 NMR spectrum (d ₆ −DMSO) δ: 1.42-1.86 (8H, m), 2.99 and 3.38
(2H, ABq, J = 17.6Hz), 4.67-4.73 (1H, m), 4.98 (1H, d, J = 4.
8Hz), 5.07 and 5.22 (2H, ABq, J = 14.6Hz), 5.62 (1H, dd, J = 4.6
Hz and 8.4Hz), 5.77 (2H, bs), 7.00 (1H, d, J = 9.8Hz), 7.00
(2H, bs), 7.47 (1H, s), 8.13 (2H, bs), 8.52 (1H, d, J = 10H
z), 9.43 (1H, d, J = 8.2Hz).

Example 15 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- [3-amino-6 -Methoxyimidazo [1,2-b] pyridazinium-1-yl)
Methyl-3-cephem-4-carboxylate

[Chemical 59] 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (3-formylamino-6
-Methoxyimidazo [1,2-b] pyridazinium-1
-Yl) methyl-3-cephem-4-carboxylate (0.31 g) was operated in the same manner as in Example 3 to give the title compound.
13 g were obtained. Elemental _{analysis: C 24 H 26 N 10 O} 6 S 2 · 3H 2 O Calculated: C, 43.11; H, 4.82 ; N, 20.95 Found: C, 42.88; H, 4.89 ; N, 20.75 NMR spectrum (d ₆ −DMSO) δ: 1.39-1.83 (8H, m),
2.98 and 3.39 (2H, ABq, J = 17.4Hz), 4.08 (3H, s), 4.65-4.69
(1H, m), 4.98 and 5.09 (2H, ABq, J = 14Hz), 5.62 (1H, dd, J = 4.
6Hz and 8.4Hz), 6.29 (2H, bs),
7.32 (1H, d, J = 10 Hz), 7.71 (1
H, s), 8.11 (2H, bs), 8.86 (1
H, d, J = 9.8 Hz), 9.42 (1H, d, J
= 8.6 Hz).

Example 16 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (5-aminoimidazo [ 1,2-a] pyridinium-1-yl) methyl-3-
Cephem-4-carboxylate

[Chemical 60] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.736
g and 5-t-butoxycarbonylaminoimidazo [1,
2-a] pyridine 0.42 g was added to dimethylformamide 1
After dissolving in 2 ml, a solution of 1.5 g of ethyl o-phenylene phosphate in 2 ml of dimethylformamide was added, and the mixture was stirred at room temperature for 6 hours. Ethyl ether 1 in the reaction solution
20 ml was added, and the precipitated oily substance was separated and subjected to silica gel column chromatography. Acetone-water (7:
3) Fractions eluted by the mixed solution were collected and concentrated to dryness under reduced pressure. The residue was suspended in 15 ml of dichloromethane, 1 ml of anisole and 5 ml of trifluoroacetic acid were added, and the reaction solution was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was adjusted to pH 7 by adding aqueous sodium hydrogen carbonate. After washing the aqueous layer with ethyl ether, it was subjected to MCI gel CHP-20P column chromatography, the fractions eluted with 30% aqueous ethanol were collected and concentrated, and the residue was freeze-dried to give 0.094 g of the title compound. Obtained. Elemental analysis value: C ₂₄ H ₂₅ N ₉ O ₅ S ₂ · 4.5H ₂ O Calculated value: C, 43.37; H, 5.16; N, 18.96 Actual value: C, 43.38; H, 4.84; N, 19.05 NMR spectrum (D ₆ −DMSO) δ: 1.40-1.90 (8H, m),
2.98 and 3.40 (2H, ABq, J = 17Hz), 4.69 (1H, m), 4.97 (1H, d, J
= 4.8Hz), 5.24 (2H, s), 5.62 (1H, dd, J = 8.2Hz and 4.8Hz),
6.52 (1H, d, J = 7.8Hz), 7.54 (1H, d, J = 8.8Hz), 7.75 (1H,
m), 7.88 (2H, bs), 8.13 (2H, bs), 8.25 (1H, s), 8.35 (1H,
s), 9.44 (1H, d, J = 8.2Hz).

Example 17 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (6-carbamoylimidazo [ 1,2-b] pyridazinium-1-yl) methyl-
3-cephem-4-carboxylate

[Chemical formula 61] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.49
g, 6-carbamoylimidazo [1,2-b] pyridazine 0.195 g and ethyl o-phenylene phosphate 1.0 g were treated in the same manner as in Example 2 to give the title compound 0.
146 g were obtained. Elemental analysis value: C ₂₄ H ₂₄ N ₁₀ O ₆ S ₂ · 4.5H ₂ O Calculated value: C, 41.55; H, 4.79; N, 20.19 Actual value: C, 41.79; H, 4.60; N, 20.40 NMR spectrum (D ₆ −DMSO) δ: 1.4-1.9 (8H, m), 3.0
4 and 3.43 (2H, ABq, J = 17.2Hz), 4.68 (1H, m), 5.00 (1H, d, J =
5Hz), 5.31 and 5.50 (2H, ABq, J = 13.8Hz), 5.65 (1H, dd, J = 8.
6Hz and 5.0Hz), 8.11 (2H, bs),
8.21 (1H, s), 8.54 (1H, s),
8.36 (1H, d, J = 9.6Hz), 8.69
(1H, d, J = 2.2Hz), 8.92 (1H,
d, J = 2.2 Hz), 9.39 (1H, d, J =
9.6 Hz), 9.44 (1H, d, J = 8.6H
z).

Example 18 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (6-ureidoimidazo [ 1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical formula 62] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.49
g, 6-ureidoimidazo [1,2-b] pyridazine 0.213 g and ethyl o-phenylene phosphate 1.0 g were treated in the same manner as in Example 2 to give the title compound 0.
116 g were obtained. Elemental analysis value: C ₂₄ H ₂₅ N ₁₁ O ₆ S ₂ · 4.5H ₂ O Calculated value: C, 40.67; H, 4.84; N, 21.74 Actual value: C, 40.61; H, 4.64; N, 21.43 NMR spectrum (D ₆ −DMSO) δ: 1.4-1.9 (8H, m), 3.0
4 and 3.42 (2H, ABq, J = 17.2Hz), 4.68 (1H, m), 5.00 (1H, d, J =
4.8Hz), 5.20 and 5.39 (2H, ABq, J = 13.8Hz), 5.64 (1H, dd, J =
8.7Hz and 4.8Hz), 7.06 (2H, bs), 8.11 (2H, bs), 8.17 (1H,
d, J = 10.4Hz), 8.48 (1H, d, J = 2Hz), 8.55 (1H, d, J = 2Hz),
9.05 (1H, d, J = 10.4Hz), 9.45 (1H, d, J = 8.4Hz), 10.36 (1H, b
s).

Example 19 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3- (6-aminoimidazo) [1,
2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical formula 63] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.238
g, 6-aminoimidazo [1,2-b] pyridazine 0.
134 g, ethyl o-phenylene phosphate 0.5
Using the same procedure as in Example 2 using g, the title compound 0.0
4 g was obtained. Elemental _{analysis: C 22 H 22 N 10 O} 5 S 2 · 4.3H 2 O Calculated: C, 40.77; H, 4.76 ; N, 21.61 Found: C, 40.95; H, 4.50 ; N, 21.27 NMR spectrum (D ₆ −DMSO) δ: 1.4-1.8 (2H, m), 2.0
-2.3 (4H, m), 3.05 and 3.50 (2H, ABq, J = 17Hz), 4.68 (1H, m),
4.99 (1H, d, J = 5Hz), 5.14 and 5.32 (2H, ABq, J = 14.2Hz), 5.
64 (1H, dd, J = 8.4Hz and 5.0Hz), 7.18 (2H, bs), 7.20 (1H, d, J
= 10Hz), 8.12 (2H, bs), 8.17 (1H, d, J = 2.2Hz), 8.33 (1H,
d, J = 2Hz), 8.77 (1H, d, J = 10Hz), 9.49 (1H, d, J = 8.4Hz).

Example 20 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamide] -3- (6-amino- 3-Formylaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 64] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.714
g, 6-amino-3-formylaminoimidazo [1,2
-B] The same procedure as in Example 2 was carried out using 0.4 g of pyridazine and 1.5 g of ethyl o-phenylene phosphate to obtain 0.09 g of the title compound. Elemental _{analysis: C 23 H 23 N 11 O} 6 S 2 · 5.5H 2 O Calculated: C, 38.76; H, 4.81 ; N, 21.62 Found: C, 38.74; H, 4.42 ; N, 21.35 NMR spectrum (D ₆ −DMSO) δ: 1.5-1.8 (2H, m), 2.0
-2.15 (4H, m), 3.05 and 3.47 (2H, ABq, J = 17Hz), 4.69 (1H,
m), 5.00 (1H, d, J = 5.2Hz), 5.17 and 5.40 (2H, ABq, J = 14Hz),
5.64 (1H, dd, J = 8.4Hz and 5.2Hz), 7.15 (2H, bs), 7.16 (1H,
d, J = 9.8Hz), 8.13 (2H, bs), 8.39 (1H, s), 8.40 (1H, s),
8.79 (1H, d, J = 9.8Hz), 9.53 (1H, d, J = 8.4Hz).

Example 21 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamide] -3- (3,6- Diaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 65] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3- (6-amino-3-formylaminoimidazo [ 1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate 0.
07 g was suspended in 4 ml of methanol and 1N-hydrochloric acid 2 was added under ice cooling.
ml was added, and the mixture was stirred at room temperature for 16 hours. Concentrated under reduced pressure,
It was purified by MCI gel CHP-20P column chromatography, eluted with 25% ethanol water, the fractions containing the target compound were collected, concentrated under reduced pressure, and the residue was freeze-dried to obtain 0.048 g of the title compound. Elemental _{analysis: C 22 H 23 N 11 O} 5 S 2 · 4H 2 O Calculated: C, 40.18; H, 4.75 ; N, 23.43 Found: C, 40.09; H, 4.43 ; N, 23.06 NMR spectrum (d ₆ −DMSO) δ: 1.4-1.8 (2H, m), 2.0
-2.3 (4H, m), 3.00 and 3.45 (2H, ABq, J = 17.4Hz), 4.69 (1H,
m), 5.01 (1H, d, J = 5Hz), 5.04 and 5.23 (2H, ABq, J = 13.6Hz),
5.64 (1H, dd, J = 8Hz and 5Hz), 5.76 (2H, bs), 6.98 ((2H, b
s), 7.00 (1H, d, J = 10.2Hz), 7.50 (1H, s), 8.14 (2H, bs),
8.53 (1H, d, J = 10.2Hz), 9.49 (1H, d, J = 8Hz).

Example 22 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopropyloxyimino) acetamide] -3- (imidazo [1, 2-b]
Pyridazinium-1-yl) methyl-3-cephem-4
-Carboxylate

[Chemical formula 66] 2- (5-Tritylamino-1,2,4-thiadiazol-3-yl) -2 (Z) -cyclopropyloxyiminoacetic acid 0.4 g was suspended in acetonitrile 9 ml, and tri-n-butylamine 0.405 ml was suspended. , 2-mercaptobenzothiazole disulfide (0.367 g) was added. Then, the reaction solution was cooled to -10 ° C, 0.22 ml of triethyl phosphite was added, and the mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained active ester was dissolved in 2 ml of tetrahydrofuran. 7β-amino-3- (imidazo [1,
2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate.dihydrochloride 0.77 g was dissolved in 10 ml of a mixture of acetone-water (1: 1), and tri-n was added thereto under ice cooling. -Butylamine (0.972 ml) and the active ester solution synthesized above were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with acetone-water (7: 3). Fractions containing the desired product were collected and concentrated under reduced pressure to dryness. The residue was suspended in 10 ml of dichloromethane, 10 ml of 90% formic acid was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to MCI gel CHP-20P column chromatography, eluted with 15% ethanol water, and fractions containing the target compound were collected and concentrated under reduced pressure. The residue was lyophilized to give 0.102 g of the title compound. Elemental _{analysis: C 21 H 19 N 9 O} 5 S 2 · 4.2H 2 O Calculated: C, 40.86; H, 4.48 ; N, 20.42 Found: C, 41.19; H, 4.42 ; N, 20.20 NMR spectrum (D ₆ −DMSO) δ: 0.5-0.8 (4H, m), 3.0
5 and 3.38 (2H, ABq, J = 17.6Hz), 4.03 (1H, m), 4.98 (1H, d, J =
5Hz), 5.27 and 5.49 (2H, ABq, J = 13.6Hz), 5.62 (1H, dd, J = 8.
6Hz and 5Hz), 7.95 (1H, dd, J = 9.4Hz and 4.6Hz),
8.11 (2H, bs), 8.75 (2H, m),
9.04 (1H, d, J = 4.6 Hz), 9.31
(1H, d, J = 9.4 Hz), 9.44 (1H,
d, J = 8.6 Hz).

Example 23 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopropyloxyimino) acetamide] -3- (3-formylamino Imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical formula 67] 0.47 g of 2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2 (Z) -cyclopropyloxyiminoacetic acid was suspended in 10 ml of dichloromethane,
0.182 ml of triethylamine was added. Reaction liquid -1
After cooling to 0 ° C., 0.25 g of phosphorus pentachloride was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was dissolved in 2 ml of tetrahydrofuran to prepare an acid chloride solution. 7
β-t-butoxycarbonylamino-3- (3-formylaminoimidazo [1,2-b] pyridazinium-1-
0.57 g of (yl) methyl-3-cephem-4-carboxylate was suspended in 16 ml of dichloromethane, 1.2 ml of anisole and 6 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 1 hour. 40 ml of ethyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals obtained were dissolved in 20 ml of water, the pH was adjusted to 8 with aqueous sodium hydrogen carbonate, and the temperature was -10 ° C.
After cooling to 1, the acid chloride solution previously synthesized was added to this reaction solution, the pH was adjusted to 8 again, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with a mixed solution of acetone-water (7: 3). Fractions containing the target compound were collected and concentrated under reduced pressure to dryness. The residue was suspended in 15 ml of dichloromethane, and 90% formic acid 30% was added thereto under ice cooling.
ml was added and the mixture was stirred at room temperature for 4 hours. The reaction solution is concentrated under reduced pressure,
The residue was adjusted to pH 4 with aqueous sodium hydrogen carbonate, the insoluble material was removed with ethyl ether, and the aqueous layer was washed with MCI gel CHP.
It was subjected to -20P column chromatography and eluted with 15% ethanol water. Fractions containing the desired compound were collected and concentrated under reduced pressure, and the residue was freeze-dried to obtain 0.259 g of the title compound. Elemental _{analysis: C 22 H 20 N 10 O} 6 S 2 · 3H 2 O Calculated: C, 41.38; H, 4.10 ; N, 21.93 Found: C, 41.67; H, 4.30 ; N, 22.22 NMR spectrum (d ₆ −DMSO) δ: 0.5-0.9 (4H, m), 3.0
7 and 3.49 (2H, ABq, J = 16.8Hz), 4.03 (1H, m), 4.98 (1H, d, J =
4.8Hz), 5.29 and 5.57 (2H, ABq, J = 13.8Hz), 5.63 (1H, dd, J =
8.8Hz and 4.8Hz), 7.92 (1H, dd, J = 9.6Hz and 4.6Hz), 8.11 (2
H, bs), 8.52 (1H, s), 8.84 (1H, s), 9.09 (1H, d, J = 4.6Hz),
9.36 (1H, d, J = 9.6Hz), 9.48 (1H, d, J = 8.8Hz).

Example 24 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopropyloxyimino) acetamide] -3- (3-aminoimidazo [1,2-b] Pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 68] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(cyclopropyloxyimino) acetamido] -3- (3-formylaminoimidazo [1,2- b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate (0.12 g) was suspended in methanol (2.6 ml), and methanesulfonic acid (0.04)
ml was added and the mixture was stirred at room temperature for 2 hours. 5 ml of water was added to the reaction solution, which was subjected to MCI gel CHP-20P column chromatography, and eluted with 15% ethanol water. Fractions containing the desired compound were collected, concentrated under reduced pressure, lyophilized to give the title compound.
084 g was obtained. Elemental _{analysis: C 21 H 20 N 10 O} 5 S 2 · 4H 2 O Calculated: C, 40.12; H, 4.49 ; N, 22.28 Found: C, 39.96; H, 4.68 ; N, 21.95 NMR spectrum (d ₆ −DMSO) δ: 0.5-0.9 (4H, m), 3.0
2 and 3.41 (2H, ABq, J = 17.2Hz), 4.03 (1H, m), 4.97 (1H, d, J =
5Hz), 5.15 and 5.36 (2H, ABq, J = 14Hz), 5.62 (1H, dd, J = 8.6H
z and 5Hz), 6.41 (2H, bs), 7.64 (1H, dd, J = 9.4Hz and 4.8Hz),
7.87 (1H, s), 8.12 (2H, bs), 8.90 (1H, d, J = 4.8Hz), 8.97
(1H, d, J = 9.4Hz), 9.44 (1H, d, J = 8.6Hz).

Example 25 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-cyclopentene-1
-Yl) oxyiminoacetamido] -3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 69] 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(2-cyclopenten-1-yl)
500 mg of oximinoacetic acid was suspended in 10 ml of acetonitrile, and 0.94 ml of tri-n-butylamine and 0.85 g of 2-mercaptobenzothiazole disulfide were added. Then, after cooling to -10 ° C, 0.5 ml of triethyl phosphite was added and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran to prepare an active ester solution. Separately, 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-
0.8 g of 3-cephem-4-carboxylate dihydrochloride
Was dissolved in 10 ml of a mixed solution of tetrahydrofuran-water (1: 1), 0.97 ml of tributylamine and the active ester solution prepared above were added thereto under ice cooling, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fractions eluted with a mixed solution of acetone-water (7: 3) were collected and concentrated under reduced pressure. Then M
It was subjected to CI gel (CHP-20P) column chromatography, and the fraction eluted with a water-ethanol (3: 1) mixture was concentrated under reduced pressure and freeze-dried to obtain 72 mg of the title compound. Elemental analysis value: C ₂₃ H ₂₁ N ₉ O ₅ S ₂ · 3.5H ₂ O Calculated value: C, 43.80; H, 4.48; N, 19.99 Actual value: C, 43.72; H, 4.08; N, 19.66 NMR spectrum (D ₆ −DMSO) δ: 1.8-2.5 (4H, m), 3.0
4 and 3.30 (2H, ABq, J = 17Hz), 4.98 (1H, d, 6-H, J = 4.8Hz), 5.
2-5.6 (3H, m), 5.64 (1H, dd, J = 8.8Hz and 4.8Hz), 5.86 (1H,
m), 6.07 (1H, m), 7.97 (1H, dd, J = 9.6Hz and 4.8Hz), 8.14 (2
H, bs), 8.77 (2H, s), 9.04 (1H, d, J = 4.8Hz), 9.34 (1H, d, J
= 9.6Hz), 9.47 (1H, d, J = 8.8Hz).

Example 26 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-cyclopentene-1
-Yl) oxyiminoacetamido] -3- (3-formylaminoimidazo [1,2-b] pyridazinium-1
-Yl) methyl-3-cephem-4-carboxylate

[Chemical 70] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(2-cyclopenten-1-yl) oxyiminoacetamide] -3
-Hydroxymethyl-3-cephem-4-carboxylate 0.977 g, 3-formylaminoimidazo [1,
2-b] Pyridazine (0.39 g) and ethyl o-phenylene phosphate (2.09 g) were treated in the same manner as in Example 2 to obtain the title compound (0.143 g). Elemental _{analysis: C 24 H 22 N 10 O} 6 S 2 · 5.5H 2 O Calculated: C, 40.62; H, 4.69 ; N, 19.74 Found: C, 40.79; H, 4.88 ; N , 19.51 NMR spectrum (d ₆ -DMSO) δ: 1.8-2.5 (4H, m), 3.0
5 and 3.44 (2H, ABq, J = 18Hz), 4.97 (1H, d, J = 5Hz), 5.2-5.6
(3H, m), 5.65 (1H, dd, 7-H, J = 8.4Hz and 5Hz), 7.90 (1Hdd, 7 '
-H, J = 9Hz and 4Hz), 8.11 (2H, bs), 8.52 (1H, s), 8.83 (1H,
s), 9.10 (1H, d, J = 4Hz), 9.35 (1H, d, J = 9Hz), 9.48 (1H, d,
J = 8.4Hz).

Example 27 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-cyclopentene-1
-Yl) oxyiminoacetamido] -3- (3-aminoimidazo [1,2-b] pyridazinium-1-yl)
Methyl-3-cephem-4-carboxylate

[Chemical 71] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-cyclopentene-1
-Yl) oxyiminoacetamido] -3- (3-formylaminoimidazo [1,2-b] pyridazinium-1
0.12 g of -yl) methyl-3-cephem-4-carboxylate was treated in the same manner as in Example 3 to obtain 0.077 g of the title compound. Elemental analysis value: C ₂₃ H ₂₂ N ₁₀ O ₅ S ₂ · 4.0H ₂ O Calculated value: C, 42.20; H, 4.62; N, 21.39 Actual value: C, 42.31; H, 4.22; N, 21.76 NMR spectrum (D ₆ −DMSO) δ: 1.8-2.5 (4H, m), 3.0
0 and 3.41 (2H, ABq, J = 17.4Hz), 4.97 (1H, d, J = 5Hz), 5.18 and
5.36 (2H, ABq, J = 14.6Hz), 5.26 (1H, m), 5.63 (1H, dd, J = 8.
4Hz and 5Hz), 5.84 (1H, m), 6.06 (1H, m), 6.44 (2H, bs), 7.
65 (1H, dd, J = 9.4Hz and 4.4Hz), 7.86 (1H, s), 8.13 (2H, bs),
8.90 (1H, d, J = 4.4Hz), 8.98 (1H, d, J = 9.4Hz), 9.45 (1H,
d, J = 8.4Hz).

Example 28 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(3,3-dimethylcyclobutyl) oxyiminoacetamide] -3- (Imidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 72] 0.72 g of 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate dihydrochloride was added to acetone-water (1:
1) It was dissolved in 12 ml, and under ice cooling, 0.98 ml of tributylamine and S- (2-benzothiazolyl) 2- (5
-Amino-1,2,4-thiadiazol-3-yl)-
0.4 g of 2 (Z)-(3,3-dimethylcyclobutyl) oxyiminothioacetate was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fractions eluted with a mixed solution of acetone-water (7: 3) were collected and concentrated under reduced pressure. Then M
It was subjected to CI gel (CHP-20P) column chromatography, and the fraction eluted with 25% ethanol water was concentrated under reduced pressure and freeze-dried to obtain 156 mg of the title compound. Elemental analysis value: C ₂₄ H ₂₅ N ₉ O ₅ S ₂ · 2.5H ₂ O Calculated value: C, 45.85; H, 4.81; N, 20.05 Actual value: C, 46.02; H, 4.79; N, 19.91 NMR spectrum (D ₆ −DMSO) δ: 1.05 (3H, s), 1.08 (3
H, s), 1.8-2.3 (4H, m), 3.05 and 3.31 (2H, ABq, J = 17.6Hz),
4.71 (1H, m), 5.01 (1H, d, J = 5Hz), 5.33 and 5.49 (2H, ABq, J =
14.4Hz), 5.66 (1H, dd, J = 8Hz and 5Hz), 7.96 (1H, dd, J = 4.4H
z and 9.6Hz), 8.14 (2H, bs), 8.77 (2H, s), 9.06 (1H, d, J = 4.
4Hz), 9.35 (1H, d, J = 9.6Hz), 9.51 (1H, d, J = 8Hz).

Example 29 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(3,3-dimethylcyclobutyl) oxyiminoacetamide] -3- (3-Formylimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical formula 73] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(3,3-dimethylcyclobutyloxyimino) acetamide] -3
-Hydroxymethyl-3-cephem-4-carboxylate 0.503 g, 3-formylaminoimidazo [1,
2-b] Pyridazine (0.195 g) and ethyl o-phenylene phosphate (1.0 g) were treated in the same manner as in Example 2 to obtain the title compound (0.119 g). Elemental analysis value: C ₂₅ H ₂₆ N ₁₀ O ₆ S ₂ · 3.5H ₂ O Calculated value: C, 43.54; H, 4.82; N, 20.31 Actual value: C, 43.88; H, 4.41; N, 19.98 NMR spectrum (D ₆ −DMSO) δ: 1.06 (3H, s), 1.07 (3
H, s), 1.8-2.2 (4H, m), 3.06 and 3.40 (2H, ABq, J = 17Hz), 4.
70 (1H, m), 4.99 (1H, d, J = 5Hz), 5.33 and 5.54 (2H, ABq, J = 14
Hz), 5.65 (1H, dd, J = 8.8Hz and 5Hz), 7.92 (1H, dd, J = 8.8Hz
And 3.6Hz), 8.11 (2H, bs), 8.52 (2H, s), 8.82 (1H, s), 9.0
9 (1H, d, J = 3.6Hz), 9.34 (1H, d, J = 8.8Hz), 9.51 (1H, d, J =
8.8Hz).

Example 30 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(3,3-dimethylcyclobutyl) oxyiminoacetamide] -3- (3-aminoimidazo [1,2-b] pyridazinium-1-yl)
Methyl-3-cephem-4-carboxylate

[Chemical 74] 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(3,3-dimethylcyclobutyloxyimino) acetamide] -3- (3-formylaminoimidazo [1,2-b] pyridazinium-1
0.1 g of (-yl) methyl-3-cephem-4-carboxylate was prepared in the same manner as in Example 3.
65 g were obtained. Elemental analysis value: C ₂₄ H ₂₆ N ₁₀ O ₅ S ₂ · 3.0H ₂ O Calculated value: C, 44.16; H, 4.94; N, 21.46 Actual value: C, 44.07; H, 4.82; N, 21.48 NMR spectrum (D ₆ −DMSO) δ: 1.04 (3H, s), 1.07 (3
H, s), 1.8-2.2 (4H, m), 3.00 and 3.37 (2H, ABq, J = 17.2Hz),
4.71 (1H, m), 5.00 (1H, d, J = 5Hz), 5.21 and 5.37 (2H, ABq, J =
13.4Hz), 5.64 (1H, dd, J = 8.4Hz and 5Hz), 6.42 (2H, bs), 7.
64 (1H, dd, J = 9.6Hz and 4.2Hz), 7.86 (1H, s), 8.10 (2H, bs),
8.90 (1H, d, J = 4.2Hz), 8.99 (1H, d, J = 9.6Hz), 9.48 (1H,
d, J = 8.4Hz).

Example 31 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(1-methylcyclopentyloxyimino) acetamido] -3- (imidazo [ 1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 75] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(1-methylcyclopentyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.22 g, imidazo [1,2-b] pyridazine 0 .0
62 g, ethyl o-phenylene phosphate 0.43
6 g of the title compound 0.017 in the same manner as in Example 2.
g was obtained. Elemental analysis value: C ₂₄ H ₂₅ N ₉ O ₅ S ₂ · 4.5H ₂ O Calculated value: C, 43.37; H, 5.16; N, 18.96 Actual value: C, 43.36; H, 5.14; N, 19.10 NMR spectrum (D ₆ −DMSO) δ: 1.34 (3H, s), 1.3-2.
1 (8H, m), 3.05 and 3.49 (2H, ABq, J = 17.4Hz), 4.99 (1H, d, J =
5Hz), 5.28 and 5.48 (2H, ABq, J = 14Hz), 5.65 (1H, dd, J = 8.6H
z and 5Hz), 7.95 (1H, dd, J = 9.4Hz and 4.4Hz), 8.14 (2H, bs),
8.76 (2H, m), 9.05 (1H, d, J = 4.4Hz), 9.32 (1H, d, J = 9.4H
z), 9.39 (1H, d, J = 8.6Hz).

Example 32 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(1-methylcyclopentyloxyimino) acetamide] -3- (3- Formylaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 76] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(1-methylcyclopentyloxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.454 g, 3-formylaminoimidazo [1,2-
b] Pyridazine (0.175 g) and ethyl o-phenylene phosphate (0.9 g) were treated in the same manner as in Example 2 to obtain 0.093 g of the title compound. Elemental analysis value: C ₂₅ H ₂₆ N ₁₀ O ₆ S ₂ · 3.5H ₂ O Calculated value: C, 43.54; H, 4.82; N, 20.31 Actual value: C, 43.53; H, 4.75; N, 20.09 NMR spectrum (D ₆ −DMSO) δ: 1.33 (3H, s), 1.3-2.
1 (8H, m), 3.06 and 3.40 (2H, ABq, J = 17Hz), 4.99 (1H, d, J = 5H
z), 5.30 and 5.56 (2H, ABq, J = 14.2Hz), 5.66 (1H, dd, J = 8.6H
z and 5Hz), 7.92 (1H, dd, J = 9.4Hz and 4.4Hz), 8.15 (2H, bs),
8.53 (1H, s), 8.84 (1H, s), 9.10 (1H, d, J = 4.4Hz), 9.37 (1
H, d, J = 9.4Hz), 9.42 (1H, d, J = 8.6Hz).

Example 33 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(1-methylcyclopentyloxyimino) acetamide] -3- (3- Aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 77] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(1-methylcyclopentyloxyimino) acetamido] -3- (3-formylaminoimidazo [1, 2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate 0.
071 g as described in Example 3 to give the title compound 0.0
47 g was obtained. Elemental analysis value: C ₂₄ H ₂₆ N ₁₀ O ₅ S ₂ · 4.0H ₂ O Calculated value: C, 42.98; H, 5.11; N, 20.88 Actual value: C, 42.75; H, 4.82; N, 20.71 NMR spectrum (D ₆ −DMSO) δ: 1.34 (3H, s), 1.3-2.
2 (8H, m), 3.02 and 3.48 (2H, ABq, J = 17.8Hz), 5.00 (1H, d, J =
5Hz), 5.20 and 5.38 (2H, ABq, J = 13.8Hz), 5.65 (1H, dd, J = 9H
z and 5Hz), 6.42 (2H, bs), 7.65 (1H, dd, J = 9Hz and 3.8Hz), 7.
88 (1H, s), 8.13 (2H, bs), 8.90 (1H, d, J = 3.8Hz), 8.99 (1
H, d, J = 9Hz), 9.39 (1H, d, J = 9Hz).

Example 34 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(tetrahydrofuran-3
-Yl) oxyiminoacetamido] -3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 78] 0.918 g of 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate dihydrochloride was added to acetone-water (1:
1) Dissolved in 9 ml of mixed solution, 0.951 ml of tri-n-butylamine and S- (2-benzothiazolyl) 2 under ice cooling
-(5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-[(tetrahydrofuran-3-yl)
6 ml of a tetrahydrofuran solution containing 0.448 g of oximino] thioacetate was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fractions eluted with a mixed solution of acetone-water (7: 3) were collected and concentrated under reduced pressure. MC for residue
It was subjected to I-gel CHP-20P column chromatography, and the fractions eluted with a water-ethanol (9: 1) mixture were collected and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.227 g of the title compound. Elemental analysis value: C ₂₂ H ₂₁ N ₉ O ₆ S ₂ · 2.5H ₂ O Calculated value: C, 42.85; H, 4.25; N, 20.44 Actual value: C, 43.03; H, 4.11; N, 20.04 NMR spectrum (D ₆ −DMSO) δ: 1.98-2.11 (2H, m),
3.06 (1H, d, J = 17.2Hz), 3.43 (1H, d, J = 17.2Hz), 3.64-3.8
6 (4H, m), 4.90 (1H, m), 5.00 (1H, d, J = 4.8Hz), 5.29 (1H,
d, J = 13.8Hz), 5.48 (1H, d, J = 13.8Hz), 5.65 (1H, dd, J = 8.8
Hz, J = 4.8Hz), 7.96 (1H, dd, J = 9.6Hz, J = 4.8Hz), 8.13 (2H,
s), 8.74-8.78 (2H, m), 9.06 (1H, dd, J = 4.8Hz, J = 1.2Hz),
9.32 (1H, d, J = 8.8Hz), 9.52 (1H, dd, J = 9.6Hz).

Example 35 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(tetrahydrofuran-3
-Yl) oxyiminoacetamido] -3- (3-formylaminoimidazo [1,2-b] pyridazinium-1
-Yl) methyl-3-cephem-4-carboxylate

[Chemical 79] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(tetrahydrofuran-3-yl) oxyiminoacetamide] -3
-Hydroxymethyl-3-cephem-4-carboxylate 0.492 g, 3-formylaminoimidazo [1,
2-b] Pyridazine (0.195 g) and ethyl o-phenylene phosphate (1.0 g) were treated in the same manner as in Example 2 to obtain the title compound (0.118 g). Elemental analysis value: C ₂₃ H ₂₂ N ₁₀ O ₇ S ₂ · 3.5H ₂ O Calculated value: C, 40.76; H, 4.31; N, 20.67 Actual value: C, 40.85; H, 4.42; N, 20.61 NMR spectrum (D ₆ −DMSO) δ: 1.99-2.08 (2H, m),
3.04 (1H, d, J = 19.8Hz), 3.38 (1H, d, J = 19.8Hz), 3.61-3.8
3 (4H, m), 4.86 (1H, m), 4.99 (1H, d, J = 5.0Hz), 5.29 (1H,
d, J = 14.0Hz), 5.54 (1H, d, J = 14.0Hz), 5.64 (1H, dd, J = 8.4
Hz, J = 5.0Hz), 7.92 (1H, dd, J = 9.6Hz, J = 4.4Hz), 8.15 (2H,
s), 8.52 (1H, s), 8.82 (1H, s), 9.10 (1H, dd, J = 4.4Hz, J =
1.2Hz), 9.36 (1H, d, J = 8.4Hz), 9.52 (1H, d, J = 9.6Hz).

Example 36 3- (3-Aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-7β- [2- (5-amino-
1,2,4-thiadiazol-3-yl) -2 (Z)-
(Tetrahydrofuran-3-yl) oxyiminoacetamido] -3-cephem-4-carboxylate

[Chemical 80] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(tetrahydrofuran-3
-Yl) oxyiminoacetamido] -3- (3-formylaminoimidazo [1,2-b] pyridazinium-1
0.080 g of -yl) methyl-3-cephem-4-carboxylate was treated in the same manner as in Example 3 to obtain 0.061 g of the title compound. Elemental _{analysis: C 22 H 22 N 10 O} 6 S 2 · 3H 2 O Calculated: C, 41.25; H, 4.41 ; N, 21.86 Found: C, 41.36; H, 4.39 ; N, 22.06 NMR spectrum (d ₆ −DMSO) δ: 1.98-2.12 (2H, m),
3.01 (1H, d, J = 17.2Hz), 3.39 (1H, d, J = 17.2Hz), 3.59-3.8
9 (4H, m), 4.88 (1H, m), 4.99 (1H, d, J = 4.5Hz), 5.17 (1H,
d, J = 13.8Hz), 5.35 (1H, d, J = 13.8Hz), 5.63 (1H, dd, J = 8.5
Hz, J = 4.5Hz), 6.40 (2H, s), 7.65 (1H, dd, J = 9.3Hz, J = 4.5H
z), 7.86 (1H, s), 8.13 (2H, s), 8.91 (1H, dd, J = 4.5Hz, J =
1.2Hz), 8.99 (1H, d, J = 8.8Hz), 9.49 (1H, dd, J = 9.3Hz, J =
1.2Hz).

Example 37 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(tetrahydropyran-3
-Yl) oxyiminoacetamido] -3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 81] 0.459 g of 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate dihydrochloride (44% purity) was added to acetone-water (1: 1). ) The mixture was dissolved in 4.5 ml, and 0.475 ml of tri-n-butylamine was added under ice cooling. Under ice cooling, S
-(2-benzothiazolyl) 2- (5-amino-1 ,,
2,4-thiadiazol-3-yl) -2 (Z)-
[(Tetrahydropyran-3-yl) oxyimino] thioacetate 0.253 g tetrahydrofuran solution 3
ml was added, and the mixture was stirred at room temperature for 1.3 hours. The reaction solution was subjected to silica gel column chromatography, and the fractions eluted with a mixed solution of acetone-water (7: 3) were collected and concentrated under reduced pressure. Next, it was subjected to MCI gel CHP-20P column chromatography, and the fractions eluted with 15% ethanol water were collected and concentrated under reduced pressure. Lyophilization gave 0.51 g of the title compound. Elemental analysis value: C ₂₃ H ₂₃ N ₉ O ₆ S ₂ · 3.5H ₂ O Calculated value: C, 42.59; H, 4.66; N, 19.43 Actual value: C, 42.75; H, 4.87; N, 18.76 NMR spectrum (D ₆ −DMSO) δ: 1.50-1.96 (4H, m),
3.01-3.52 (4H, m), 3.68-3.82 (2H, m), 4.31 (1H, m), 5.00
(1H, d, J = 4.8Hz), 5.26 (1H, d, J = 14.6Hz), 5.46 (1H, d, J = 1
4.6Hz), 5.57 (1H, dd, J = 8.8Hz, J = 4.8Hz), 7.95 (1H, dd, J =
9.6Hz, J = 4.4Hz), 8.04-8.18 (2H, m), 8.75 (2H, s), 9.04
(1H, d, J = 4.4Hz), 9.32 (1H, d, J = 8.8Hz), 9.48 (1H, d, J = 9.
6Hz).

Example 38 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(tetrahydropyran-3
-Yl) oxyiminoacetamido] -3- (3-formylaminoimidazo [1,2-b] pyridazinium-1
-Yl) methyl-3-cephem-4-carboxylate

[Chemical formula 82] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(tetrahydropyran-3-yl) oxyiminoacetamide] -3
-Hydroxymethyl-3-cephem-4-carboxylate 0.35 g, 3-formylaminoimidazo [1,2
-B] Pyridazine 0.146 g and ethyl o-phenylene phosphate 0.75 g were treated in the same manner as in Example 2 to obtain 0.107 g of the title compound. Elemental analysis value: C ₂₄ H ₂₄ N ₁₀ O ₇ S ₂ · 4.0H ₂ O Calculated value: C, 41.14; H, 4.60; N, 19.99 Actual value: C, 40.96; H, 4.59; N, 19.60 NMR spectrum (D ₆ −DMSO) δ: 1.51-1.69 (2H, m),
1.78-1.97 (2H, m), 3.10 (1H, d, J = 16.4Hz), 3.21-3.46 (3
H, m), 3.72-3.83 (2H, m), 4.31 (1H, m), 5.00 (1H, d, J = 4.8
Hz), 5.28 (1H, d, J = 14.0Hz), 5.54 (1H, d, J = 14.0Hz), 5.6
7 (1H, dd, J = 9.0Hz, J = 4.8Hz), 7.93 (1H, dd, J = 8.4Hz, J = 4.2
Hz), 8.11 (2H, s), 8.52 (1H, s), 8.83 (1H, s), 9.10 (1H, d,
J = 4.2Hz), 9.34 (1H, d, J = 9.0Hz), 9.52 (1H, d, J = 8.4Hz).

Example 39 3- (3-Aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-7β- [2- (5-amino-
1,2,4-thiadiazol-3-yl) -2 (Z)-
(Tetrahydropyran-3-yl) oxyiminoacetamido] -3-cephem-4-carboxylate

[Chemical 83] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(tetrahydropyran-3
-Yl) oxyiminoacetamido] -3- (3-formylaminoimidazo [1,2-b] pyridazinium-1
0.082 g of -yl) methyl-3-cephem-4-carboxylate was treated in the same manner as in Example 3 to obtain 0.059 g of the title compound. Elemental analysis value: C ₂₃ H ₂₄ N ₁₀ O ₆ S ₂ · 4.0H ₂ O Calculated value: C, 41.07; H, 4.79; N, 20.82 Actual value: C, 41.34; H, 4.66; N, 20.83 NMR spectrum (D ₆ −DMSO) δ: 1.15-1.70 (2H, m),
1.81-1.96 (2H, m), 3.04 (1H, d, J = 17.0Hz), 3.30-3.50 (3
H, m), 3.72-3.88 (2H, m), 4.31 (1H, m), 5.00 (1H, d, J = 5.0
Hz), 5.17 (1H, d, J = 14.0Hz), 5.35 (1H, d, J = 14.0Hz), 5.6
7 (1H, dd, J = 8.8Hz, J = 5.0Hz), 6.41 (2H, s), 7.65 (1H, dd, J
= 8.7Hz, J = 4.6Hz), 7.85 (1H, s), 8.13 (2H, s), 8.91 (1H, d,
J = 4.6Hz), 8.96 (1H, d, J = 8.8Hz), 9.49 (1H, d, J = 8.7Hz).

Example 40 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(oxetan-3-yl)
Oxyiminoacetamide] -3- (imidazo [1,2
-B] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 84] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(oxetan-3-yl) oxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.
093 g, imidazo [1,2-b] pyridazine 0.02
8 g, ethyl o-phenylene phosphate 0.194
g in the same manner as in Example 2 to give 0.016 g of the title compound.
Got NMR spectrum (d ₆ -DMSO) δ: 3.03 (1H, d, J = 16.8H
z), 3.40 (1H, d, J = 16.8Hz), 4.53-4.73 (1H, m), 5.00 (1H,
d, J = 5.0Hz), 5.16-5.27 (2H, m), 5.45 (1H, d, J = 13.2Hz),
5.64 (1H, dd, J = 8.4Hz, J = 5.0Hz), 7.93 (1H, dd, J = 8.8Hz, J =
4.4Hz), 8.15 (2H, s), 8.73 (2H, s), 9.02 (1H, d, J = 4.4H
z), 9.28 (1H, d, J = 8.8Hz), 9.59 (1H, d, J = 8.4Hz).

Example 41

[Chemical 85] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(oxetan-3-yl)
Oxyiminoacetamido] -3- (3-formylaminoimidazo [1,2-b] pyridazinium-1-yl)
Methyl-3-cephem-4-carboxylate sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(oxetan-3-yl) oxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.
239 g, 3-formylaminoimidazo [1,2-b]
Pyridazine (0.0973 g) and ethyl o-phenylene phosphate (0.50 g) were treated in the same manner as in Example 2 to obtain the title compound (0.106 g). NMR spectrum (d ₆ -DMSO) δ: 3.17 (1H, d, J = 16.8H
z), 3.48 (1H, d, J = 16.8Hz), 4.55-4.82 (2H, m), 5.08 (1H,
d, J = 5.2Hz), 5.19-5.37 (2H, m), 5.52 (1H, d, J = 14.4Hz),
5.75 (1H, dd, J = 8.8Hz, J = 5.2Hz), 7.96 (1H, dd, J = 9.4Hz, J =
4.4Hz), 8.16 (2H, s), 8.52 (1H, s), 8.74 (1H, s), 9.12 (1
H, d, J = 4.4Hz), 9.22 (1H, d, J = 9.4Hz), 9.67 (1H, d, J = 8.8H
z).

Example 42 3- (3-Aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-7β- [2- (5-amino-
1,2,4-thiadiazol-3-yl) -2 (Z)-
(Oxetane-3-yl) oxyiminoacetamide]
-3-Cephem-4-carboxylate

[Chemical 86] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(oxetan-3-yl)
Oxyiminoacetamido] -3- (3-formylaminoimidazo [1,2-b] pyridazinium-1-yl)
Methyl-3-cephem-4-carboxylate 0.08
3 g were treated as in Example 3 to give the title compound 0.016
g was obtained. NMR spectrum (d ₆ -DMSO) δ: 3.07 (1H, d, J = 17.6H
z), 3.45 (1H, d, J = 17.6Hz), 4.55-4.76 (4H, m), 5.04 (1H,
d, J = 4.8Hz), 5.12-5.46 (3H, m), 5.68 (1H, dd, J = 8.4Hz, J =
4.8Hz), 6.41 (2H, s), 7.66 (1H, dd, J = 9.2Hz, J = 4.8Hz),
7.83 (1H, s), 8.17 (2H, s), 8.89-8.98 (2H, m), 9.61 (1H,
d, J = 8.4Hz).

Example 43 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(thietan-3-yl) oxyiminoacetamido] -3- (imidazo) [1,2-
b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 87] 2- (5-amino-1,2,4-thiadiazole-3-
2.60 g of (yl) -2 (Z)-(thietan-3-yl) oxyiminoacetic acid was suspended in 30 ml of acetonitrile, and 4.8 ml of tri-n-butylamine and 4.32 g of 2-mercaptobenzothiazole disulfide were added at room temperature. . Triethyl phosphite 2.5 while cooling in ice-acetone bath
7 ml was dropped slowly. After stirring at the same temperature for 4 hours, the reaction solution was concentrated under reduced pressure. 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate dihydrochloride (purity 44
%) 0.921 g was dissolved in 8 ml of water and 4 ml of acetone, and 0.95 ml of tri-n-butylamine was added under ice cooling. Then, add 4 ml of acetone solution to the above concentrated residue, and
Stir for 6.5 hours. The reaction solution was subjected to silica gel column chromatography, and fractions eluted with a mixed solution of acetone-water (7: 3) were collected and concentrated. The residue is MCI gel CH
It was subjected to P-20P column chromatography and eluted with 25% ethanol water. Fractions containing the desired product were collected and concentrated under reduced pressure, and the residue was lyophilized to give the title compound 0.14
0 g was obtained. NMR spectrum (d ₆ -DMSO) δ: 3.04-3.58 (6H, m),
5.03 (1H, d, J = 4.8Hz), 5.23-5.33 (2H, m), 5.49 (1H, d, J = 1
4.2Hz), 5.67 (1H, dd, J = 8.4Hz, J = 4.8Hz), 7.95 (1H, dd, J =
9.2Hz, J = 4.4Hz), 8.18 (2H, s), 8.76 (2H, s), 9.05 (1H, d,
J = 4.8Hz), 9.31 (1H, d, J = 9.2Hz), 9.58 (1H, d, J = 8.4Hz).

Example 44 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(thietan-3-yl) oxyiminoacetamide] -3- (3 -Formylaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 88] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(thietane-
3-yl) oxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0.2
80 g, 3-formylaminoimidazo [1,2-b] pyridazine 0.115 g and ethyl o-phenylene phosphate 0.56 g were treated in the same manner as in Example 2 to obtain 0.047 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 3.15-3.56 (6H, m),
5.02 (1H, d, J = 4.8Hz), 5.22-5.77 (4H, m), 7.92 (1H, dd, J =
10.0Hz, J = 4.0Hz), 8.18 (2H, s), 8.51 (1H, s), 8.84 (1H,
s), 9.09 (1H, d, J = 4.0Hz), 9.37 (1H, d, J = 8.4Hz), 9.60 (1
H, d, J = 9.2Hz).

Example 45 3- (3-Aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-7β- [2- (5-amino-
1,2,4-thiadiazol-3-yl) -2 (Z)-
(Thietan-3-yl) oxyiminoacetamide]-
3-cephem-4-carboxylate

[Chemical 89] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(thietan-3-yl) oxyiminoacetamide] -3- (3-formylaminoimidazo [1 , 2-b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate 0.019
Was operated in the same manner as in Example 3 to obtain 0.01 g of the title compound. NMR spectrum (d ₆ -DMSO) δ: 3.01-3.56 (6H, m),
5.02 (1H, d, J = 4.8Hz), 5.14-5.42 (3H, m), 5.67 (1H, dd, J =
8.4Hz, J = 4.8Hz), 6.42 (2H, s), 7.65 (1H, dd, J = 8.4Hz, J =
4.8Hz), 7.86 (1H, s) ,. 8.18 (2H, s), 8.90 (1H, d, J = 4.4H
z), 8.98 (1H, d, J = 4.4Hz), 9.57 (1H, d, J = 8.4Hz).

Test Example 1 Minimum inhibitory concentration (MIC) of test compound
ry concentration is agar dilution meth
od). That is, 1.0 ml of the diluted test compound aqueous solution was poured into a petri dish,
Next, trypticase soy agar
9.0 ml of agar) was poured and mixed. A suspension of the test bacteria (about 10 ⁶ CFU / ml) was spread on the mixed agar plate. After incubation at 37 ° C. overnight, the minimum concentration of the test compound that completely inhibits the growth of the test strain was determined to be MI.
It was set to C. Test bacterium: (1) Staphylococcus aureus 308 A-1 (MSS
A) (2) Staphylococcus aureus N-133 (MRSA) Control Compound 1: Ceftazidime (CAZ) Control Compound 2: Cefpirome (CPR) From these results, the cephem compound [I] of the present invention or its ester or salt thereof is a representative strain of a pathogenic bacterium clinically regarded as important. It is clear that it shows an excellent antibacterial action against the above.

[0141]

INDUSTRIAL APPLICABILITY The cephem compound [I] or a salt or ester thereof of the present invention has a broad antibacterial spectrum and an excellent antibacterial activity against Gram-negative bacteria including Pseudomonas spp. An antibacterial agent having an action and effective against infectious diseases based on these bacteria can be provided.

Claims (22)

[Claims] 1. A general formula: (In the formula, B represents a 6-membered aromatic heterocycle in which the hetero atom is 1 or 2 nitrogen atoms). Wherein R ³ is C _1-4 alkyl group, a halogen, a hydroxyl group and 1 or optionally substituted by two C _3-7 cycloalkyl selected from amino group, C _4-7 cycloalkenyl or A 3- to 6-membered non-aromatic heterocyclic group.
The described compound. 3. R ³ is C _3-7 cycloalkyl, C _4-7 cycloalkenyl or 3 to 6 membered non-aromatic heterocyclic group which may be substituted with 1 or 2 C _1-4 alkyl groups. The compound according to claim 1, which is 4. The 3- or 6-membered non-aromatic heterocyclic group is an oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl or thiomorpholinyl group. Compound. 5. R ³ is cyclohexyl, cyclopentyl,
The compound according to claim 1, which is a cyclobutyl or cyclopropyl group. 6. embedded image 7. A chemical formula: 8. embedded image 9. embedded image 10. embedded image The compound according to claim 1, wherein one of R ² and R ² 'is a hydrogen atom and the other is an amino group, a ureido group, a glycylamino group or a formylamino group. 11. The compound according to claim 1, wherein R ¹ is NaO.CO.NH-. 12. 7β- [2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate. 13. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (3-aminoimidazo [1,2-b] pyridazinium-1-yl)
The compound according to claim 1, which is methyl-3-cephem-4-carboxylate. 14. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (6-aminoimidazo [1,2-b] pyridazinium-1-yl)
The compound according to claim 1, which is methyl-3-cephem-4-carboxylate. 15. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(cyclopentyloxyimino) acetamido] -3- (imidazo [1,2-a] pyridinium-1-yl) methyl-3-
The compound according to claim 1, which is cephem-4-carboxylate. 16. β- [2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate. 17. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3- (3-aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4- The compound according to claim 1, which is a carboxylate. 18. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(cyclobutyloxyimino) acetamido] -3- (6-aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4- The compound according to claim 1, which is a carboxylate. 19. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(cyclohexyloxyimino) acetamido] -3- (3-aminoimidazo [1,2-b] pyridazinium-1-yl)
The compound according to claim 1, which is methyl-3-cephem-4-carboxylate. 20. A general formula: [Wherein the symbols in the formula have the same meanings as those defined in claim 1] and the compound or ester or salt thereof and the general formula: The method for producing a compound according to claim 1, wherein a carboxylic acid represented by the formula has the same meaning as in claim 1 or a salt or reactive derivative thereof. 21. The general formula: [Wherein R ⁵ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group or a halogen atom, and other symbols have the same meanings as those defined in claim 1], or an ester or salt thereof. General formula which may be substituted: The method for producing the compound according to claim 1, wherein the compound represented by the formula has the same meaning as in claim 1 or a salt thereof. 22. An antibacterial composition containing the compound according to claim 1.