JPH07101958A - Cephem compound, its production and antibacterial composition - Google Patents

Abstract

PURPOSE:To provide a new cephem compound having excellent antibacterial actions against gram-positive and negative bacteria including the genus Pseudomonas bacteria and methicillin-resistant Staphylococcus aureus, low in toxicity, and excellent in stability, effect persistence, etc. CONSTITUTION:A compound of formula I [R<1> is amino; R<3> is fluorine-substituted lower alkyl; A<+> is group of formula II or III (B is six-membered aromatic heterocyclic group in which the heterogeneous atoms are one or two N astoms)] or its salt, e.g. 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(2-fluoroethoxyimino) acetoamido]-3-(6-aminoimidazo[1,2-b]pyridazium-1-yl) methyl-3-cephem-4- carboxylate. The compound is obtained by acylating a compound of formula IV with a carboxylic acid of formula V in the presence of a condensing agent such as N,N'-carbonyldiimidazole 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 Gram-positive bacteria and Gram-negative bacteria, particularly Pseudomonas bacteria, staphylococci and methicillin-resistant Staphylococcus aureus (MRSA), and a method for producing the same. And an antibacterial composition.

[0002]

2. Description of the Related Art Conventionally, an imidazol-1-ylmethyl group which forms a condensed ring at the 2,3-position or 3,4-position, which may be substituted at the 3-position of the cephem ring, has a 2-position at the 7-position.
(2-Aminothiazol-4-yl) -2 (Z) -substituted alkoxyiminoacetamide group or 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-
Various cephem compounds having a substituted alkoxyiminoacetamide group have been synthesized (JP-A-60-231).
684, JP-A-62-149682, JP-A-1-131185). That is, JP-A-60-
In Japanese Patent No. 231684, the general formula

[Chemical 12] [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 synthesized has a 2- (2-aminothiazol-4-yl) -2 (Z) -fluoroalkoxyiminoacetamide group or 2- (5-amino-1,2,4-thiadiazole-3- at the 7-position. It is a cephem compound having an (yl) -2 (Z) -alkoxyiminoacetamide group, but 2- (5
-Amino-1,2,4-thiadiazol-4-yl)-
Regarding the cephem compound having a 2 (Z) -fluoroalkoxyiminoacetamide group, the compound name and synthesis example are not specifically described, and the specific antibacterial action is not described at all.

Further, in JP-A-62-149682, a general formula

[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 have the same meanings as defined above] or a physiologically or pharmaceutically acceptable salt or ester thereof, and specifically synthesized compounds are those in which OR ³ is an alkoxy group. The compound name and synthesis example of the cephem compound having a fluoroalkoxy group as OR ³ are not specifically described, and its specific antibacterial action is not described at all. Further, in JP-A-1-131185, the general formula

[Chemical 14] Although a cephem compound represented by the formula [wherein R ¹ represents a lower alkyl group] or a salt or ester thereof is disclosed and synthesized, the lower alkyl group represented by R ¹ may be substituted. There is no description or suggestion.

[0004]

To date, various cephem compounds are already on the market. However, their antibacterial activity is not yet fully satisfactory in terms of range and strength, has a wide range of excellent antibacterial activities against Gram-positive and Gram-negative bacteria, and is particularly resistant to conventional cephalosporin compounds. It is desired to develop a compound having an excellent antibacterial action against Pseudomonas spp., Staphylococcus, methicillin-resistant Staphylococcus aureus (MRSA) and the like.

[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 15] (In the formula, B represents a 6-membered aromatic heterocycle in which the hetero atom is 1 or 2 nitrogen atoms), and is an imidazolium forming a condensed ring at the 2,3-position or the 3,4-position. -1-
A group represented by the formula

[Chemical 16] [Wherein R ¹ represents an amino group which may be protected, and R ³ represents a lower alkyl group substituted with fluorine] for the first time to synthesize a cephem compound or a salt or ester thereof, Further, it has been unexpectedly found that the synthesized compound has a wide and excellent antibacterial action against Gram-negative bacteria including Pseudomonas and Gram-positive bacteria including Staphylococcus and MRSA, and the present invention is based on these. completed.

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

[Chemical 17] [Wherein the symbols in the formula have the same meanings as defined above] or a salt or ester thereof, (2) general formula [II]:

[Chemical 18] [Wherein the symbols have the same meanings as defined above] or a compound or ester thereof or salt thereof and a general formula:

[Chemical 19] [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) General formula [III]:

[Chemical 20] [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 21] [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 the described compound, (4) General formula [V]:

[Chemical formula 22] [The symbols in the formula have the same meanings as defined above] or a compound or ester thereof or a salt thereof and a general formula [VI]: R ³ OH [VI] [the symbols in the formulas have the same meanings as described above] A method for producing the compound according to (1) above, which comprises reacting the compound or 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] which represents the free form, its salt and ester are 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 salts and esters thereof. This means that not only the compound [I] but also the compounds [II], [III], [V], [VII], [VII]
The same applies to I]. 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, optionally substituted thiocarbamoyl group, C _6-10 aryl-methyl group, di-C _6-10 aryl-methyl group Group, tri-C _6-10 aryl-methyl group, C _6-10
Aryl - methylene group, C _6-10 arylthio group, a substituted silyl group, 2-C _1-10 alkoxy - carbonyl-1-methyl-1-ethenyl group is used.

Examples of the "C _1-6 alkanoyl group" include formyl, acetyl, propionyl, butyryl,
Valeryl, pivaloyl, succinyl, glutaryl, monochloroacetyl, dichloroacetyl, trichloroacetyl, monobromoacetyl, monofluoroacetyl, 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 further include C _1-4 alkoxy groups (eg, methoxy, ethoxy, etc.), C _1-4 acyl groups (eg, acetyl). , Propionyl, etc.), substituted silyl group (substituted silyl group described later, eg, trimethylsilyl, tert-butyldimethylsilyl, etc.), C _1-4 alkylsulfonyl group (eg, methanesulfonyl, ethanesulfonyl, etc.), halogen (eg, 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-chloro Benzyloxycarbonyl, 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 -4} carbamoyl groups which may be substituted with 1 or 2 alkoxy-phenyl groups (eg, methoxyphenyl etc.) and the like can be used.
-Methylcarbamoyl, N-ethylcarbamoyl, N, N
-Dimethylcarbamoyl, N, N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N- (p-methoxyphenyl) carbamoyl and the like are used. The “optionally substituted thiocarbamoyl group” is a C _1-4 alkyl group (eg, methyl, ethyl, etc.), a phenyl group, etc.
An optionally substituted thiocarbamoyl group 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 23] [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. R ¹ is preferably an amino group from the viewpoint of antibacterial activity.

The lower alkyl group in the fluorine-substituted lower alkyl group represented by R ³ is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- A linear or branched alkyl group having 1 to 6 carbon atoms such as pentyl and n-hexyl is used, and the lower alkyl group is preferably substituted with 1 to 3 fluorines. R
Examples of the lower alkyl group substituted with fluorine represented by ³ include fluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-
Trifluoroethyl, 1-fluoroethyl, 2-fluoropropyl, 3-fluoropropyl and the like are used, and among them, fluoromethyl, 2-fluoroethyl,
2,2,2-trifluoroethyl, 2,2-difluoroethyl and the like are preferable.

[Chemical formula 24] [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.

Specifically, the following is used as A ¹ .

[Chemical 25] The following is specifically used as A ² .

[Chemical formula 26]

[Chemical 27]

Substitution in the above formulas [A ¹ ] and [A ² ] and the specific A ¹ and A ² groups

[Chemical 28] In some cases, a quaternary nitrogen atom may be applied to the 1st nitrogen atom. 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 29] 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 heterocycle 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 30] Alternatively, those substituted with 1 to 2 amino groups, carbamoyl groups, ureido groups, glycylamino groups or formylamino groups are preferable.

[0027]

[Chemical 31] 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, the compound [I] may be a pharmacologically acceptable salt or ester. 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 32] 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 30] For example, chloride ion, bromide ion, sulfate ion, p-toluenesulfonate ion, methanesulfonate ion, trifluoroacetate ion, etc.] are also included. The ester derivative of compound [I] or [V] 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. is there. 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, An _optionally substituted C _6-10 aryl ester, an _optionally substituted C _7-12 aralkyl ester,
Di C _6-10 aryl-methyl ester, tri C _6-10 aryl-methyl ester, substituted silyl ester and the like are used.

Examples of the optionally substituted C _1-6 alkyl ester include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and 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. C _3-10 forming a cycloalkyl ester
_{As the 3-10} cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl and the like are used. C
_{Examples of} C _3-10 cycloalkyl C _1-6 alkyl group forming _3-10 cycloalkyl C _1-6 alkyl ester include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like. Optionally substituted C _6-10
Examples of the “C _6-10 aryl group” forming an 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. 1 to 3 may be substituted with, and specific examples of such a group include p-nitrophenyl and p-chlorophenyl.

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 34] 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 35] And has an amino group, the amino group may be protected. Examples of such an amino-protecting group include R ¹
The protecting group for the optionally protected amino group represented by is also used as it is here. The method for producing the compound [I] of the present invention or its ester or its salt will be described in detail below.

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

[Chemical 36] [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 pyramides such as pyrazole, imidazole and benzotriazole, 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 (eg, fluorine, chlorine, bromine, etc.), an oxo group, a thioxo group, a C _1-6 alkylthio group (eg, methylthio, ethylthio, etc.) and the like) and the like. 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-hydroxybenzotriazole ester, 1-hydroxy -1H-2-pyridone ester and the like can be mentioned. 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 and the like, and inorganic acid addition salts include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphorus. Examples of the acid addition salt include organic acid addition salts such as formate, acetate, trifluoroacetate, methanesulfonate and p-toluenesulfonate. 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 are known methods (for example, JP-A-60-231684 and JP-A-6-26184).
It can be easily produced by the method described in JP-A-2-149682 or the like. The reactive derivative of compound R ^b OH is 7-as the material isolated from the reaction mixture.
It may be reacted with the amino compound [II], or the reaction mixture containing the reactive derivative of the compound R ^b OH before isolation may be directly reacted with the 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 such as N, N'-dicyclohexylcarbodiimide.
Azolides such as N'-carbonyldiimidazole, N, N'-thiocarbonyldiimidazole, such as N-
Dehydrating agents such as ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, and alkoxyacetylene, such as 2-halogenopyridinium salts such as 2-chloropyridinium methyl iodide and 2-fluoropyridinium methyl iodide. Used. When these condensing agents are used, the reaction is carboxylic acid R
^It is believed to proceed via the reactive derivative of ^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, tert.
-Butyl methyl ether, diisopropyl ether, ethylene glycol-dimethyl ether and other ethers,
Esters such as ethyl formate, ethyl acetate and n-butyl acetate, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane, such as n-hexane, benzene and toluene. Hydrocarbons such as formamide, N, N
Amides such as 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 hexamethylphosphonate Lamide 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 37] [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 38] 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 the 3,4-position represented by [the symbols in the formula are as defined above]. Here, the compound [VII] or its salt or ester as a raw material can be prepared by a known method (for example, JP-A-60-
No. 231684, JP-A No. 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 Formula 39] [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 a salt thereof represented by the general formula [IV] are reacted to synthesize the compound [I] You can

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]), and the compound is reacted by a nucleophilic substitution reaction. This is a method of synthesizing [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 40] Those already mentioned as above are also used here. The imidazole compound [IV] is also used as a salt. Examples of the salt of the compound [IV] include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, such as formate, acetate, trifluoroacetate, methanesulfonate, p
-Organic acid addition salts such as toluene sulfonate and the like. General synthetic methods for imidazole compounds [IV] and salts thereof are known, and, for example, JP-A-60-2316.
No. 84, JP-A No. 62-149682, or a method analogous thereto. Imidazole compound [IV] or its salt compound [III]
This nucleophilic substitution reaction for is usually carried out in a solvent. As the solvent used in this reaction, the solvents such as ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles and water used in the above production method (1) can be directly applied. In addition to these, alcohols such as methanol, ethanol, n-propanol, isopropanol, ethylene glycol, 2-methoxyethanol and the like can also be used. When the imidazole compound [IV] is a liquid, this compound [IV]
It may be used also as a solvent by using a large excess (for example, 10 to 200 times mol) with respect to I]. 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 compound [III]: For example, it is carried out in the presence of an organic phosphorus compound according to the method described in Japanese Patent Laid-Open Publication No. 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, se
c-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-phenylene pyrophosphate, 2-phenyl-1,3,2-benzodioxaphosphole-2-oxide, 2- (p-chlorophenyl) -1,3,2-benzo Dioxaphosphole-2-oxide, 2-butyl-1,
3,2-benzodioxaphosphole-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
-Benzodioxaphosphole-2-oxide, 2-methoxy-5-ethoxycarbonyl-1,3,2-benzodioxaphosphole-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-naphthalenemethylphosphate, 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, 9,1
0, -phenanthrene dioxytrimethoxyphosphorus,
o-phenylene phosphorochloridite, o-phenylene phosphorobromidite, o-phenylene phosphorofluoridite, methyl o-phenylene phosphite, butyl o
-Phenylene phosphite, 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-benzodioxaphosphole, 9,1
0, -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-dioxaphosphole, 2,2-dihydro-2,2-dimethoxy-2-phenoxy-4,5-
Dimethyl-1,3,2-dioxaphosphole, 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-dioxaphos Hall, 2,2-dihydro-2,2,2-trimethoxy-4-
Methyl-1,3,2-dioxaphosphole, 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 etc. as a single solvent or a mixed solvent. Used. 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 about 1 to 5 mol, about 1 to 10 mol, and more preferably about 1 to 3 mol, about 1 mol to 1 mol of the compound [III], respectively. It is 1 to 6 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 an organic base include triethylamine, tri (n-butyl) amine, di (n-butyl) amine, diisobutylamine, dicyclohexylamine, 2,6
-Amines such as lutidine. The amount of the base added is preferably about 1 to 5 mol per 1 mol of compound [III].

When R ⁵ is a halogen atom in the compound [III]: Preferred solvents are the above-mentioned ethers and 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, and can be easily produced.

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 41] 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 42] 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 (1) to (4) below are the most excellent compounds.

[Chemical 43] 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 1 kg of human and animal body infected with the above-mentioned pathogenic bacteria.
0.5-80mg / day, more preferably 1-20mg
The daily dose may be divided into 3 to 4 times a day for oral administration. When used as an injection, the carrier may be distilled water,
Physiological saline is used, and capsules, powders, granules,
When used as tablets, known pharmacologically acceptable excipients (such as starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (such as starch,
Gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg magnesium stearate, talc, etc.), destroying agents
Used as a mixture with carboxymethyl calcium, talc, etc.

[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 (P
harmacia Fine Chemicals). XAD-2 resin is a product of Rohm & Haas (Rohm & Haas
Co. ) 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 d. d: double doublet m: multiplet bs: broad singlet J: coupling constant Hz: Hertz DMSO: dimethyl sulfoxide

Reference Example 1 N- (2-Fluoroethoxy) phthalimide 32 g of N-hydroxyphthalimide was dissolved in 250 ml of dimethylformamide, and 27.5 g of N, N-diisopropylethylamine and 2-bromo-1-fluoroethane under ice cooling. After adding 25 g, the reaction solution was heated at 65 to 70 ° C for 7 hours.
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 32.4 g of the title compound as colorless needles. Melting point: 102-103 ° C. Elemental analysis value: C ₁₀ H ₈ FNO ₃ Calculated value: C, 57.42; H, 3.85; N, 6.70 Actual value: C, 57, 15; H, 3.68; N, 6.79 NMR (CDCl ₃ ) Δ: 7.83 (4H, m), 4.93 (1H, t, J = 3.8Hz),
4.69 (1H, t, J = 3.8Hz), 4.58 (1H, t, J = 3.8Hz), 4.42 (1H,
t, J = 3.8Hz).

Reference Example 2 2-Fluoroethoxyamine Hydrochloride 26 g of N- (2-fluoroethoxy) phthalimide was dissolved in a mixed solution of 310 ml of dichloromethane and 42 ml of methanol, and 6.0 ml of hydrazine monohydrate was added thereto, and the mixture was stirred at room temperature. The mixture was stirred at (25 ° C., the same below) for 2 hours. The precipitated crystals were filtered off, 55 ml of 20% alcoholic hydrochloric acid was added to the filtrate, and the solvent was distilled off under reduced pressure. The residue is ethanol 300
After dissolving in ml and heating at 80 ° C. for 2 hours, after cooling, the precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure, 200 ml of ethyl ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 10 g of the title compound as colorless scale crystals. Mp: 190-193 ° C. Elemental analysis: C ₂ H ₆ FNO · HCl Calculated: C, 20.80; H, 6.11 ; N, 12.13 Found: C, 20.65; H, 5.93 ; N, 12.30 NMR (D ₆ −DMSO) δ: 4.78 (1H, m), 4.55 (1H, m), 4.34
(1H, m), 4.20 (1H, m).

Reference Example 3 2- (5-Amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(2-fluoroethoxy) iminoacetic acid 3- (5-amino-1,2,4-thiadiazole-3-
29.4 g of coumarin) was suspended in 240 ml of ethanol, and 240 ml of 1N-sodium hydroxide was added to this to 40
After stirring at 0 ° C for 1 hour to obtain a uniform solution, 12 ml of ethyl chlorocarbonate was added under ice cooling and the mixture was stirred for 5 minutes. Next, methylene chloride (360 ml) and 1N-hydrochloric acid (120 ml) were added to remove the aqueous layer, and the mixture was extracted with methylene chloride again to combine the organic layers.
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. Sodium acetate (9.84 g) and dimethyl sulfide (60 ml) were added to the reaction solution, and the mixture was stirred for a while. After confirming that potassium iodide-starch paper was negative, 300 ml and 150 ml of water were added and the mixture was extracted twice. Was washed with ethyl acetate. 2-Fluoroethoxyamine hydrochloride (14.5 g) was added to the aqueous layer, the pH was adjusted to 5 with 130 ml of 1N sodium hydroxide, and the mixture was stirred overnight at room temperature. To the reaction solution were added 120 ml of 1N-hydrochloric acid and ethyl acetate for extraction, and 30 ml of 1N-hydrochloric acid and sodium chloride were added to the aqueous layer for saturation, followed by extraction with tetrahydrofuran 5 times. The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography, the fractions containing the title compound were collected and concentrated, and the residue was crystallized from ethyl acetate to obtain 19 g of the title compound. Melting point: 176-178 ° C IR spectrum (KBr, cm ^-1 ): 3400, 3130, 1720, 162
0, 1540, 1460, 1420, 1160, 1060. NMR spectrum (DMSO) δ: 4.31 (1H, t, J = 3Hz), 4.44
(1H, t, J = 3Hz), 4.53 (1H, t, J = 3Hz), 4.77 (1H, t, J = 3Hz),
8.17 (2H, bs).

Reference Example 4 2- (5-Amino-1,2,4-thiadiazole-3-
Iyl) -2 (Z)-(2-fluoroethoxy) iminoacetic acid chloride hydrochloride 2- (5-amino-1,2,4-thiadiazole-3-
4.68 g of (yl) -2 (Z)-(2-fluoroethoxy) iminoacetic acid was suspended in 60 ml of methylene chloride, and phosphorus pentachloride was added under cooling with a dry ice-acetone bath (-20 ° C.).
8 g was gradually added, and the mixture was stirred at -20 ° C to -5 ° C for 2 hours. Next, 80 ml of diisopropyl ether was added to precipitate crystals, and the mixture was further stirred for 30 minutes at -5 ° C to 5 ° C. The precipitated crystals were collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give the title compound (4.55 g). IR spectrum (KBr, cm ^-1 ): 3200, 1790, 1640, 146
0, 1080. Reference Example 5 Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 7β-amino-3-hydroxymethyl-3-cephem-
4-carboxylic acid _{2.3g 1N-NaOH / H 2 O} (1 /
1) Dissolve in 20 ml, add 2 g of sodium hydrogen carbonate,
After adding 20 ml of acetone, dry ice bath (-20
(C) With cooling, 2.18 g of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetic acid chloride hydrochloride was added. This is stirred at -20 ° C to 0 ° C for 2 hours, then the reaction solution is concentrated under reduced pressure, the residue is subjected to MCI gel CHP-20P column chromatography, and the fraction eluted with 5% ethanol water is collected. It was collected and concentrated under reduced pressure. The residue was lyophilized to give 2.1 g of the title compound. Elemental _{analysis: C 14 H 14 FN 6 NaO} 6 S 2 · 1.5H 2 O Calculated: C, 33.94; H, 3.46 ; N, 16.96 Found: C, 33.82; H, 3.52 ; N, 16.90 NMR ( d ₆ −DMSO) δ: 3.33 and 3.52 (2H, ABq, J = 18Hz),
4.00 (2H, m), 4.31 (1H, t, J = 3.8Hz), 4.45 (1H, t, J = 3.8H
z), 4.56 (1H, t, J = 3.8Hz), 4.80 (1H, t, J = 3.8Hz), 4.94 (1
H, d, J = 4.8Hz), 5.60 (1H, dd, J = 8Hz and 4.8Hz),
6.12 (1H, m), 8.18 (2H, bs),
9.50 (1H, d, J = 8Hz).

Reference Example 6 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy)
Iminoacetamido] -3- (3-oxobutyryloxymethyl) -3-cephem-4-carboxylic acid 7β-amino-3- (3-oxobutyryloxymethyl) -3-cephem-4-carboxylic acid 5 g It was suspended in 100 ml of dichloromethane, 7 g of bistrimethylsilylacetamide was added thereto, and the mixture was stirred at room temperature until it became a solution. Then, under ice-cooling, 2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetic acid chloride hydrochloride (7.5 g) was added and the mixture was stirred for a while, then dimethylacetamide (3 g) was added.
Was added, and the mixture was stirred for 60 minutes under ice cooling. Dichloromethane was distilled off, the residue was dissolved in methyl ethyl ketone, washed with water,
After drying, the solvent was distilled off, and diethyl ether was added to the residue to give a powder, which was then collected by filtration to obtain 6 g of the title compound. IR spectrum (KBr, cm ^-1 ): 3300, 3000, 1780, 172
0, 1610. NMR spectrum (d ₆ -DMSO) δ: 2.18 (3H, s), 3.41
3.63 (2H, ABq, J = 18Hz), 3.62 (2H, s), 4.40 and 4.26 (2H, t, J
= 29Hz and J = 3.8Hz), 4.75 and 4.51 (2H, t, J = 48Hz and J = 3.8Hz),
4.80 and 5.12 (2H, ABq, J = 12Hz), 5.18 (1H, d, J = 4.5Hz), 5.
88 (1H, dd, J = 9Hz and 4.5Hz), 9.63 (1H, d, J = 9Hz).

Reference Example 7 N- (2,2,2-trifluoroethoxy) phthalimide 150 g of trifluoromethanesulfonic anhydride were dissolved in 830 ml of dichloromethane, and 2,2,2- was carried out at 0 ° C. under a nitrogen stream.
38.8 ml of trifluoroethanol and 43.3 of pyridine
A solution of 210 ml of dichloromethane in 210 ml was added dropwise over 1.5 hours. Then, 84.9 g of N-hydroxylphthalimide and N, N-diisopropylethylamine 18
After adding 5 ml of a 600 ml solution of dichloromethane dropwise over 1.5 hours, the reaction solution was stirred at room temperature overnight. 1000 ml of 1N hydrochloric acid was added to the reaction solution, and the precipitated insoluble matter was filtered off.
The filtrate was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (2: 1). Fractions containing the target compound were collected and concentrated under reduced pressure. The residue was recrystallized from n-hexane to obtain 52 g of the title compound. Melting point: 105-106 ° C. Elemental analysis value: C ₁₀ H ₆ F ₃ NO ₃ Calculated value: C, 48.99; H, 2.47; N, 5.71 Actual value: C, 49.04; H, 2.56; N, 5.79 NMR spectrum (CDCl ₃ ) δ: 4.56 (2H, q, J = 8.0Hz),
7.77-7.91 (4H, m).

Reference Example 8 2,2,2-Trifluoroethoxyamine Hydrochloride 52 g of N- (2,2,2-trifluoroethoxy) phthalimide was dissolved in a mixed solution of 540 ml of dichloromethane and 70 ml of methanol, and hydrazine / 1 water was added. 10.3 ml of a Japanese product was added and the mixture was stirred for 1 hour at room temperature. The precipitated crystals were filtered off, and 120 ml of 20% hydrochloric acid ethanol was added to the filtrate under ice cooling.
The solvent was distilled off under reduced pressure, 100 ml of toluene was added to the residue, and the mixture was concentrated again. 50 ml of methanol was added to the residue, the insoluble matter was filtered off, n-hexane was added to the filtrate, and the precipitated crystals were collected by filtration to obtain 19.5 g of the title compound. Mp: 273-275 ° C. NMR spectrum _{(d 6 -DMSO) δ: 4.70} (2H, q, J = 8.8H
z), 8.20 (3H, bs).

Reference Example 9 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetic acid 3- (5-amino) 10.0 g of -1,2,4-thiadiazol-3-yl) -coumarin was suspended in 80 ml of ethanol, and 81.6 mmol of a 1N sodium hydroxide aqueous solution was added,
The mixture was stirred at 40 ° C for 1 hour. The reaction mixture was ice-cooled, ethyl chloroformate (4.08 ml) was added, and the mixture was stirred for 10 min. 125 ml of dichloromethane and 40 ml of 1N hydrochloric acid were added and the organic layer was separated. The aqueous layer was extracted with 125 ml of dichloromethane. The organic layers were combined and cooled with dry ice-acetone. Ozone was bubbled through the solution for 1 hour and 15 minutes, followed by nitrogen for 15 minutes. Anhydrous sodium acetate (3.35 g) and methyl sulfide (20 ml) were added and the temperature was raised to room temperature. It was confirmed to be negative with potassium iodide starch paper. The reaction solution is 500 ml of water
After extraction with, the aqueous layers were combined and washed with 500 ml of ethyl acetate. To the aqueous layer, 6.74 g of 2,2,2-trifluoroethoxyamine hydrochloride and 3.68 g of sodium acetate were added, and the mixture was stirred at room temperature for 1 hour. 2.02 g of 2,2,2-trifluoroethoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was filtered off, and the filtrate was washed with 500 ml of ethyl acetate. The aqueous layer was adjusted to pH 1 with 1N hydrochloric acid, saturated with sodium chloride, extracted with 500 ml of ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (100 g, 2.8 × 42 cm).
Attached to. Elution with dichloromethane (100 ml), dichloromethane-methanol (10: 1, 100 ml), dichloromethane-methanol (5: 1, 100 ml) and dichloromethane-methanol (2: 1, 400 ml) in this order. Fractions of the target compound were collected and concentrated under reduced pressure. Hexane was added to the residue to obtain 5.7 g of the title compound. Mp: 130-135 ° C. Elemental _{analysis: C 6 H 5 F 3 N} 4 O 3 S · 0.2H 2 O Calculated: C, 26.32; H, 1.99 ; N, 20.46 Found: C, 26.69; H, 1.97 ； N, 20.07 NMR spectrum (d ₆ -DMSO) δ: 4.86 (2H, q, J = 9.0H
z), 8.31 (2H, bs).

Reference Example 10 Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide]- 3-Hydroxymethyl-3-cephem-4-carboxylate 7β-amino-3-acetoxymethyl-3-cephem-
The 4-carboxylic acid was suspended in 4.57 g and 40 ml of water, and 33.6 ml of a 1N sodium hydroxide aqueous solution was added at 0 ° C to obtain 1.5.
Stir for hours. 60 ml of acetone and 5.87 g of sodium hydrogen carbonate were added to this reaction solution, and then 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-was added.
(2,2,2-Trifluoroethoxy) iminoacetic acid chloride / hydrochloride (5.0 g of carboxylic acid and 4.13 of phosphorus pentachloride)
(prepared from g) was added and stirred at 0 ° C. for 1 hour. Acetone was distilled off under reduced pressure, the residue was subjected to CHP column chromatography, and eluted with water and a 5% ethanol aqueous solution,
Fractions containing the desired product were collected and concentrated under reduced pressure. The residue was freeze-dried to obtain 2.88 g of the title compound. Elemental _{analysis: C 14 H 12 F 3 N} 6 O 6 S 2 Na · 2H 2 O Calculated: C, 31.11; H, 2.98 ; N, 15.55 Found: C, 31.05; H, 3.21 ; N, 15.79 IR Spectrum (KBr, cm ^-1 ): 3400, 1760, 1670, 160
0, 1530. NMR spectrum (d ₆ -DMSO) δ: 4.70 (2H, q, J = 9.4H
z), 4.99 (1H, d, J = 4.8Hz), 5.24 and 5.49 (2H, ABq, J = 12.2H
z), 6.65 (1H, dd, J = 4.8Hz and 8.4Hz), 7.95 (1H, dd, J = 4.4
Hz and 9.4Hz), 8.19 (2H, bs), 8.76 (2H, s), 9.05 (1H, d, J =
4.4Hz), 9.56 (1H, d, J = 9,4Hz), 9.66 (1H, d, J = 8.4Hz).

Reference Example 11 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3 -(3-oxobutyryloxymethyl) -3-cephem-4-carboxylic acid 7β-amino-3- (3-oxobutyryloxymethyl) -3-cephem-4-carboxylic acid 10 g (200 ml)
14 g of bistrimethylsilylacetamide was added thereto, and the mixture was stirred at room temperature until it became a solution. Then, under ice cooling, 2- (5-amino-1,2,
4-thiadiazol-3-yl) -2 (Z)-(2,2,2
After adding 17 g of (trifluoroethoxy) iminoacetic acid chloride / hydrochloride and stirring for a while, 6 g of dimethylacetamide was added, and the mixture was stirred for 60 minutes under ice cooling. Dichloromethane was distilled off, the residue was dissolved in methyl ethyl ketone, washed with water and dried, the solvent was distilled off, ethyl ether was added to the residue to obtain a powder, and the title compound 1 was obtained by filtration.
1 g was obtained. IR spectrum (KBr, cm ^-1 ): 3280, 3000, 1782, 172
0, 1620. NMR spectrum (d ₆ -DMSO) δ: 2.16 (3H, s), 3.40 and 3.60 (2H, A)
Bq, J = 18Hz), 3.62 (2H, s), 4.67-4.75 (2H, m), 4.80 and 5.1
2 (2H, ABq, J = 12Hz), 5.16 (1H, d, J = 4.5Hz), 5.90 (1H, dd,
J = 9Hz and 4.5Hz), 9.65 (1H, d, J = 9Hz).

Reference Example 12 2- (5-chloroacetamido-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetic acid 2- (5-amino-1,2,4-thiadiazole- 2.34 g of 3-yl) -2 (Z) -fluoromethoxyiminoacetic acid methyl ester was dissolved in 30 ml of dimethylacetamide, 1.46 g of chloroacetyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. Ice water was poured into the reaction solution, which was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The crystals obtained by concentration under reduced pressure were collected by filtration, suspended in 30 ml of ethanol, added with 16.6 ml of 1N aqueous sodium hydroxide solution, and stirred at room temperature for 8 hours. Almost all the ethanol was distilled off under reduced pressure, the residue was diluted with water and washed with ethyl ether. The aqueous layer was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Crystals obtained by concentration under reduced pressure are collected to give 1.63 g of the title compound.
Got Melting point: 172-175 ° C. (decomposition) NMR spectrum (CDCl ₃ ) δ: 4.32 (2H, s), 5.80 (2H,
d, J = 55Hz), 13.0 (1H, broad s).

Reference Example 13 Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamide] -3-hydroxymethyl-3- Cephem-4-carboxylate 2- (5-chloroacetamido-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetic acid 0.297 g was suspended in 10 ml of dichloromethane and stirred with ice cooling. Triethylamine (0.12 g) was added, phosphorous pentachloride (0.23 g) was added, and the mixture was stirred under ice cooling for 30 minutes. Dichloromethane is distilled off under reduced pressure and the residue is washed with hexane. Insoluble matter 5 ml of tetrahydrofuran
Suspended in 7β-amino-3-hydroxymethyl-3-
Cefem-4-carboxylic acid (0.277 g), sodium hydrogencarbonate (0.504 g) and H ₂ O (5 ml) were added to the solution under ice cooling, and the mixture was stirred under ice cooling for 1 hour. Tetrahydrofuran is distilled off under reduced pressure, and the residue is Amberlite XAD
-2 column refine | purified and it eluted with 5% ethanol. The target fraction was collected and concentrated to a total volume of 10 ml, 0.149 g of sodium N-methyldithiocarbamate was added, and the mixture was stirred at room temperature for 2 hours. Concentrate under reduced pressure and purify the residue on an Amberlite XAD-2 column, wash with water and 5
% Ethanol, the eluate was concentrated, and the residue was passed through Dowex 50W (manufactured by Dow Chemical Co.) (Na type) ion exchange resin (20 ml) and eluted with 120 ml of water.
The eluate was concentrated and freeze-dried to obtain 0.265 g of the title compound. Elemental analysis value: C ₁₃ H ₁₂ FNaN ₆ O ₆ S ₂ · 1.5H ₂ O Calculated value: C, 32.43; H, 3.14; N, 17.46 Actual value: C, 32.15; H, 3.38; N, 17.33 NMR spectrum (D ₂ O) δ: 3.49 and 3.72 (1H, d, J = 18H each)
z), 4.30 (2H, s), 5.26 (1H, d, J = 5Hz), 5.88 (1H, d, J = 5H
z), 5.91 (2H, d, J = 54Hz).

Reference Example 14 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (3-oxobutyryloxymethyl) ) −
3-cephem-4-carboxylic acid 7β-amino-3- (3-oxobutyryloxymethyl) -3-cephem-4-carboxylic acid 11 g 200 ml
14 g of bistrimethylsilylacetamide was added thereto, and the mixture was stirred at room temperature until it became a solution. Then, under ice cooling, 2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetic acid chloride-hydrochloride 14 g was added and stirred for a while, then dimethylacetamide 6 g was added,
Stir for 60 minutes under ice cooling. Distill off the dichloromethane,
The residue was dissolved in methyl ethyl ketone, washed with water, dried and the solvent was distilled off. Diethyl ether was added to the residue to give a powder, which was then collected by filtration to obtain 10 g of the title compound. IR spectrum (KBr, cm ^-1 ): 3300, 3000, 1780, 172
0, 1620. NMR spectrum (d ₆ -DMSO) δ: 2.18 (3H, s), 3.41
3.63 (2H, ABq, J = 18Hz), 3.62 (2H, s), 4.80 and 5.12 (2H, AB
q, J = 12Hz), 5.18 (1H, d, J = 4.5Hz), 5.72 (2H, d, J = 55Hz),
5.88 (1H, dd, J = 9Hz and 4.5Hz), 9.63 (1H, d, J = 9Hz).

Reference Example 15 6-ureidoimidazo [1,2-b] pyridazine 6-aminoimidazo [1,2-b] pyridazine 4.02
g was suspended in 60 ml of tetrahydrofuran, 3.0 ml of chlorosulfonyl isocyanate was added under ice-cooling, and 1 under ice-cooling.
The mixture was stirred for 1 hour at room temperature. Next, 1N-
60 ml of hydrochloric acid was added, and the mixture was stirred at 80 ° C for 1 hour. The reaction solution is cooled and pH = 1 by addition of 1N-sodium hydroxide.
Adjusted to 0. The precipitated crystals were collected by filtration, washed with water and acetone, and dried under reduced pressure to give the title compound (2.14 g).
Got Mp: 244.0-245.5 ℃ Elemental _{analysis: C 7 H 7 N 5 O} · 0.2H 2 O Calculated: C, 46.47; H, 4.09 ; N, 38.72 Found: C, 46.33; H, 4.11 ； N, 38.62 NMR (d ₆ -DMSO) δ: 6.98 (2H, bs), 7.53 (1H, d, J = 9.8
Hz), 7.59 (1H, s), 7.98 (1H, d, J = 9.8Hz), 8.06 (1H, s),
9.61 (1H, bs).

Reference Example 16 6- (2-tert-Butoxycarbonyl) aminoacetaminoimidazo [1,2-b] pyridazine 6-aminoimidazo [1,2-b] pyridazine 1.8 g
Is suspended in 200 ml of tetrahydrofuran and 1,4
-Diazabicyclo [5,4,0] -7-undecene (DB
U) 3.3 ml and phthalimidoacetyl chloride 4.
5 g was added, and the mixture was stirred in an oil bath at 90 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with 50 ml of water and 10 ml of ethyl acetate.
0 ml was added and the resulting insoluble material was collected by filtration. The aqueous layer of the filtrate was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and then evaporated under reduced pressure. The residue and the insoluble matter collected by filtration were dissolved in 200 ml of ethanol, and hydrazine monohydrate 2.1 was added to the solution.
9 ml was added and stirred in an oil bath at 90 ° for 3 hours. The reaction mixture was concentrated under reduced pressure, and 100 ml of water and 50 ml of 1N hydrochloric acid were added to the residue.
The resulting insoluble matter was filtered off, and the filtrate was washed with ethyl acetate. The aqueous layer was separated, 1N-sodium hydroxide (80 ml) and di-tert-butyl dicarbonate (11.5 ml) were added, and the mixture was stirred at room temperature overnight. 300 ml of ethyl acetate in the reaction solution
Was added, extracted, dried over magnesium sulfate, and then evaporated under reduced pressure. Ether was added to the residue and the resulting crystals were collected by filtration, washed with ether and dried to give 1.
Obtained 85 g. Mp: 186.0-187.0 ℃ Elemental _{analysis: C 13 H 17 N 5 O} 3 · 0.5H 2 O Calculated: C, 51.99; H, 6.04 ; N, 23.32 Found: C, 51.88; H , 6.24; N, 23.25 NMR (d ₆ -DMSO) δ: 1.40 (9H, s), 3.82 (2H, d, J = 5.8H
z), 7.08 (1H, t, J = 5.8Hz), 7.70 (1H, d, J = 1Hz), 7.88 (1H,
d, J = 10Hz), 8.10 (1H, d, J = 10Hz), 8.11 (1H, d, J = 1Hz), 1
0.82 (1H, bs).

Reference Example 17 5- (2-tert-Butoxycarbonyl) aminoacetaminoimidazo [1,2-a] pyridine 2.0 g of 5-aminoimidazo [1,2-a] pyridine was dissolved in 150 ml of tetrahydrofuran, 1,4-
Diazabicyclo [5,4,0] -7-undecene (DB
U) (3.68 ml) and phthalimidoacetyl chloride (5.0 g) were added, and the mixture was stirred in an oil bath at 90 ° C for 16 hr. The reaction solution was concentrated under reduced pressure, 100 ml of water and 200 ml of ethyl acetate were added to the residue, and the resulting insoluble material was collected by filtration. The aqueous layer of the filtrate was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and then evaporated under reduced pressure. The residue and the insoluble matter collected by filtration were dissolved in 200 ml of ethanol, 2.92 ml of hydrazine monohydrate was added thereto, and the mixture was stirred in an oil bath at 90 ° C. for 3 hours.
The reaction mixture was concentrated under reduced pressure, and the residue was mixed with 100 ml of water and 1N-.
After adding 30 ml of hydrochloric acid and removing the resulting insoluble matter by filtration, the filtrate was washed with ethyl acetate. The aqueous layer was separated, and 1N-sodium hydroxide (50 ml) and di-tert-butyl dicarbonate (11.5) were collected.
ml was added, and the mixture was stirred overnight at room temperature. Ethyl acetate 3 in the reaction solution
00 ml was added for extraction, the extract was dried over magnesium sulfate and then evaporated under reduced pressure. The residue was dissolved in a small amount of dichloromethane and subjected to silica gel column chromatography, and the fraction eluted with a mixed solution of dichloromethane-methanol (20: 1) was concentrated under reduced pressure to obtain 1.92 g of the title compound. NMR (d ₆ -DMSO) δ: 1.42 (9H, s), 3.89 (2H, d, J = 6H
z), 7.00 (1H, d, J = 6.2Hz), 7.20 (1H, t, J = 6Hz), 7.27 (1H,
t, J = 6.2Hz), 7.45 (1H, d, J = 6.2Hz), 7.60 (1H, s), 7.88 (1
H, s), 10.41 (1H, bs).

Reference Example 18 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 with 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 (each 1H, d, J = 9Hz), 7.26 (1H, s). Reference Example 19 3-aminoimidazo [1,2-b] pyridazine hydrochloride 3-amino-6-chloroimidazo [1,2] -B] Pyridazine (2.0 g) was dissolved in ethanol (80 ml), 10% palladium-carbon (containing 50% water) (1.5 g) was added, and the mixture was stirred in a hydrogen stream for 2 hours. The catalyst was filtered off and the filtrate was concentrated and the crystals obtained were collected by filtration to give the title compound 1.5
5 g was obtained. Melting point: 250 ° C. (decomposition) NMR spectrum (d ₆ -DMSO) δ: 7.39 (1H, s), 7.5-9.
0 (3H, m).

Reference Example 20 3-Formylaminoimidazo [1,2-b] pyridazine Formic acid (15 ml) was stirred with ice-cooling, 5 ml of acetic anhydride 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 21 3-Ureidoimidazo [1,2-b] pyridazine 3-aminoimidazo [1,2-b] pyridazine hydrochloride 1
To a solution of 0 g of dichloromethane in 150 ml, 19.7 ml of triethylamine and then 17.6 ml of phenyl chloroformate were added dropwise under ice cooling. The mixture was stirred under ice cooling for 1 hour, washed with water and dried (MgSO ₄ ). The solvent was distilled off to obtain 3- (diphenoxycarbonyl) aminoimidazo [1,2-b] pyridazine as crystals. It was collected by filtration and washed with ethanol (7.5 g). To a solution of the crystals in 25 ml of dioxane, 25 ml of concentrated aqueous ammonia was added and stirred at room temperature for 20 minutes. The solvent was distilled off to obtain 2.95 g of the title compound as crystals. Recrystallization from methanol gave yellow needle crystals. Melting point> 300 ° C. Elemental analysis value: C ₇ H ₇ N ₅ O Calculated value: C, 47.46; H, 3.98; N, 39.53 Measured value: C, 47.25; H, 4.14; N, 39.61

Reference Example 22 3-Ureidoimidazo [1,2-a] pyridine In the same manner as in Reference Example 21, 3-aminoimidazo [1,2-a]
a] The title compound was obtained by using pyridine as a starting material. Melting point 274-277 ° C. (decomposition) Elemental analysis value: C ₈ H ₈ N ₄ O Calculated value: C, 54.54; H, 4.58; N, 31.80 Actual value: C, 54.67; H, 4.87; N, 31.80 Reference Example 23 3- (tert-butoxycarbonyl) aminoacetylaminoimidazo [1,2-b] pyridazine N-tert-butoxycarbonylglycine 6.3 g in a solution of 6.3 g of dichloromethane in carbonyldiimidazole 6.
4 g was added under ice cooling. After stirring under ice-cooling for 15 minutes, 5.1 g of 3-aminoimidazo [1,2-b] pyridazine hydrochloride was added, and then 4.62 ml of triethylamine was added. The mixture was stirred under ice cooling for 15 minutes and then at room temperature for 20 hours. Was washed with saturated brine dried (MgSO _4), gave the title compound 8.0g as a crystal by distilling off the solvent. Recrystallization from ethanol gave pale yellow prism crystals. Mp 155-156 ° C. Elemental _{analysis: C 13 H 17 N 5 O} 3 Calculated: C, 53.60; H, 5.88 ; N, 24.04 Found: C, 53.43; H, 5.89 ; N, 23.94

Reference Example 24 Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2-difluoroethoxy) iminoacetamide] -3-hydroxy Methyl-3-cephem-4-carboxylate 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2-difluoroethoxy) iminoacetic acid 0.505 g in acetonitrile Dissolve in 20 ml, 2
-Mercaptobenzothiazole diflufide 0.798
g, 0.951 ml of tributylamine and 0.363 ml of triethyl phosphite were added with stirring under ice cooling, and the mixture was further stirred under ice cooling for 1.5 hours. The acetonitrile was distilled off under reduced pressure, the residue was dissolved in 10 ml of acetone, and this solution was added to 7β.
-Amino-3-hydroxymethyl-3-cephem-4-
0.461 g of carboxylic acid was suspended in 10 ml of water and added to a solution adjusted to pH 8.0 with sodium hydrogencarbonate under ice cooling. Then, the mixture was stirred at room temperature for 15 hours, and acetone was distilled off under reduced pressure. 20 ml of ethyl acetate was added to the residue, the insoluble material was filtered off, and the aqueous layer was separated. The aqueous layer was concentrated under reduced pressure, and the residue was subjected to CHP-20 column chromatography,
Elution was performed with water and a 5% aqueous ethanol solution, and the fractions containing the desired product were collected and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.554 g of the title compound. Elemental _{analysis: C 14 H 13 F 2 N} 6 O 6 S 2 Na · 2H 2 O Calculated: C, 34.29; H, 3.50 ; N, 17.14 Found: C, 34.02; H, 3.59 ; N, 17.27 NMR (D ₆ −DMSO) δ: 3.47 and 3.67 (each 1H, d, J = 18Hz),
4.28 (2H, s), 4.57 (2H, dt, J = 4Hz and 14Hz), 5.22 (1H, d, J = 5
Hz), 5.83 (1H, d, J = 5Hz), 6.21 (1H, tt, J = 4Hz and 54Hz)

Reference Example 25 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 it in a sealed tube.
Heated at 0 ° C. for 7 hours. After cooling, the precipitated crystals are collected by filtration,
It was washed with water, ethanol and then ethyl ether to obtain 7.5 g of the title compound. Melting point 250 ° C. (decomposition) NMR (d ₆ -DMSO) δ: 6.99 (1H, d, J = 9.4Hz), 7.02 (2H,
s), 7.97 (1H, d, J = 9.4Hz), 8.43 (1H, s). Reference Example 26 3.6-Diaminoimidazo [1,2-b] pyridazine 6-amino-3-nitroimidazo [1, 2-b] Pyridazine (5.13 g) was dissolved in tetrahydrofuran (500 ml), and the mixture was stirred at room temperature for 2.5 hours in the presence of Raney nickel (5.0 g) under a hydrogen stream at 2-3 atm. 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 (d ₆ -DMSO) δ: 4.83 (2H, bs), 6.06 (2H, brs), 6.
13 (1H, d, J = 9.6Hz), 6.68 (1H, s), 7.47 (1H, d, J = 9.6Hz).

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

[Chemical 44] 7β-Amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate dihydrochloride (0.163 g) was added to acetone-water (1:
1) Dissolve in 6 ml, dry ice bath (-10 ℃)
Under cooling, 0.417 ml of tributylamine and 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-
0.1 g of (2-fluoroethoxy) iminoacetic acid chloride hydrochloride was added, and the mixture was stirred at -10 ° C to 5 ° C for 2 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
It was subjected to I-gel CHP-20P column chromatography (manufactured by Mitsubishi Kasei), and the fraction eluted with a water-ethanol (9: 1) mixed solution was concentrated under reduced pressure and then freeze-dried to obtain 0.075 g. The title compound was obtained. Elemental _{analysis: C 20 H 18 N 9 O} 5 S 2 F · 3.0H 2 O Calculated: C, 39.90; H, 3.99 ; N, 20.95 Found: C, 40.13; H, 3.79 ; N, 20.72 IR (KBr, cm ^-1 ): 3400, 1780, 1680, 1620, 1520, 13
80, 1180, 1060. NMR spectrum (d ₆ -DMSO) δ: 3.02 and 3.42 (2H, ABq,
J = 17.6Hz), 4.25 (1H, t, J = 3.6Hz), 4.39 (1H, t, J = 3.6Hz),
4.50 (1H, t, J = 3.6Hz), 4.74 (1H, t, J = 3.6Hz), 5.0 (1H, d,
J = 4.8Hz), 5.27 and 5.49 (2H, ABq, J = 14Hz), 5.65 (1H, dd, J =
8.4Hz and 4.8Hz), 7.96 (1H, dd, J = 9.8Hz and J = 4.4Hz), 8.14
(2H, bs), 8.77 (2H, m), 9.05 (1H, d, J = 4.4Hz), 9.35 (1H,
d, J = 9.8Hz), 9.54 (1H, d, J = 8.4Hz).

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

[Chemical formula 45] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3- (3-oxobutyryloxymethyl)- 2.2 g of 3-cephem-4-carboxylic acid, 2.0 g of imidazo [1,2-b] pyridazine, and 2.2 g of potassium iodide were dissolved in 30 ml of 50% water-containing acetonitrile and stirred at 60 to 70 ° C. for 2 hours. .. After cooling, the reaction solution was subjected to silica gel column chromatography and eluted with acetone and hydrous acetone successively, and the fractions containing the target compound were combined and concentrated under reduced pressure. The residue was subjected to column chromatography by XAD-II, eluted with water and then with hydrous alcohol, and the fractions containing the desired product were combined and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.28 g of the title compound. It was confirmed that this product was the same as the compound obtained in Example 1 from the agreement of the IR spectrum and the NMR spectrum.

Example 3 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3- (6-amino) Imidazo [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)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- Carboxylate 0.468 g and 6-aminoimidazo [1,2-b] pyridazine 0.3 g
Was dissolved in 8 ml of dimethylformamide, 1.0 g of ethyl o-phenylene phosphate dissolved in 2 ml of dimethylformamide was added, and the mixture was stirred overnight at room temperature. 120 ml of ether was added to the reaction solution to precipitate a precipitate, which was stirred for 30 minutes. The solvent was then decanted, the residue dissolved in a small amount of acetone-water and chromatographed on silica gel. Fractions eluting with acetone-water (7: 3) were collected and concentrated, the residue was subjected to MCI gel CHP-20P column chromatography, and the fractions eluted with 15% ethanol water were concentrated. Freeze-dried 0.147g
The title compound was obtained. Elemental _{analysis: C 20 H 19 FN 10 O} 5 S 2 · 2.5H 2 O Calculated: C, 39.54; H, 3.98 ; N, 23.05 Found: C, 39.29; H, 4.14 ; N, 22.83 NMR spectrum (D ₆ −DMSO) δ: 2.99 and 3.45 (2H, ABq,
J = 17.6Hz), 4.26 (1H, t, J = 3.6Hz), 4.41 (1H, t, J = 3.6Hz),
4.51 (1H, t, J = 3.6Hz), 4.75 (1H, t, J = 3.6Hz), 4.99 (1H,
d, J = 4.8Hz), 5.13 and 5.35 (2H, ABq, J = 14.2Hz), 5.64 (1H, d
d, J = 8.8Hz and 4.8Hz), 7.22 (2H, bs), 7.22 (1H, d, J = 10Hz),
8.15 (2H, bs), 8.18 (1H, d, J = 2Hz), 8.35 (1H, d, J = 2Hz),
8.81 (1H, d, J = 10Hz), 9.56 (1H, d, J = 8.8Hz).

Example 4 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3- (6-carbamoyl) Imidazo [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)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- 0.468 g of carboxylate,
Using the same procedure as in Example 3, 0.167 g of the title compound was obtained using 0.324 g of 6-carbamoylimidazo [1,2-b] pyridazine, 1.0 g of ethyl o-phenylene phosphate and 8 ml of dimethylformamide. Elemental _{analysis: C 21 H 19 FN 10 O} 6 S 2 · 3.5H 2 O Calculated: C, 38.59; H, 4.01 ; N, 21.43 Found: C, 38.74; H, 3.83 ; N, 21.44 NMR spectrum (D ₆ −DMSO) δ: 3.03 and 3.51 (2H, ABq,
J = 17Hz), 4.25 (1H, t, J = 3.8Hz), 4.39 (1H, t, J = 3.8Hz),
4.50 (1H, t, J = 3.8Hz), 4.74 (1H, t, J = 3.8Hz), 5.01 (1H, d,
J = 4.8Hz), 5.31 and 5.53 (2H, ABq, J = 13.8Hz), 5.67 (1H, dd,
J = 8.6Hz and 4.8Hz), 8.15 (2H, bs), 8.36 (1H, d, J = 9.6Hz),
8.21 (1H, bs), 8.55 (1H, bs), 8.69 (1H, d, J = 2Hz), 8.95 (1
H, d, J = 2Hz), 9.42 (1H, d, J = 9.6Hz), 9.56 (1H, d, J = 8.6H
z).

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

[Chemical 48] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- 0.468 g of carboxylate,
6-ureidoimidazo [1,2-b] pyridazine 0.2
12 g, ethyl o-phenylene phosphate 1.0
g and 25 ml of dimethylsulfoxide were operated in the same manner as in Example 3 to obtain 0.118 g of the title compound. Elemental analysis value: C ₂₁ H ₂₀ FN ₁₁ O ₆ S ₂ · 3.5H ₂ O Calculated value: C, 37.72; H, 4.07; N, 23.04 Actual value: C, 37.52; H, 3.89; N, 22.74 NMR spectrum (D ₆ −DMSO) δ: 3.02 and 3.42 (2Hz, AB
q, J = 17.2Hz), 4.24 (1H, t, J = 3.6Hz), 4.39 (1H, t, J = 3.6H
z), 4.50 (1H, t, J = 3.6Hz), 4.74 (1H, t, J = 3.6Hz), 5.00 (1
H, d, J = 4.8Hz), 5.17 and 5.40 (2Hz, ABq, J = 14.2Hz), 5.65 (1
H, dd, J = 8.4Hz and 4.8Hz), 7.04 (2H, bs), 8.13 (2H, bs), 8.
15 (1H, d, J = 10Hz), 8.47 (1H, d, J = 2Hz), 8.56 (1H, d, J = 2H
z), 9.06 (1H, d, J = 10Hz), 9.54 (1H, d, J = 8.4Hz), 10.30 (1
H, bs).

Example 6 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamide] -3- (5-amino Imidazo [1,2
-A] pyridinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 49] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- 0.351 g of carboxylate,
0.2 g of 5-aminoimidazo [1,2-a] pyridine,
Using 0.225 g of ethyl o-phenylene phosphate and 8 ml of dimethylformamide, the reaction was carried out for 2 hours under ice cooling, and the title compound was converted to 0.0 by the same procedure as in Example 3.
58 g were obtained. Elemental analysis value: C ₂₁ H ₂₀ FN ₉ O ₅ S ₂ · 3.5H ₂ O calculated value: C, 40.38; H, 4.36; N, 20.18 measured value: C, 40.17; H, 4.08; N, 19.91 NMR spectrum (D ₆ −DMSO) δ: 2.95 and 3.42 (2Hz, AB
q, J = 16.6Hz), 4.26 (1H, t, J = 3.8Hz), 4.40 (1H, t, J = 3.8H
z), 4.51 (1H, t, J = 3.8Hz), 4.75 (1H, t, J = 3.8Hz), 4.98 (1
H, d, J = 4.8Hz), 5.18 and 5.28 (2Hz, ABq, J = 14.2Hz), 5.64 (1
H, dd, J = 8.4Hz and 4.8Hz), 6.51 (1H, d, J = 8.6Hz), 7.56 (1H,
d, J = 8.6Hz), 7.75 (1H, t, J = 8.6Hz), 7.84 (2H, bs), 8.14
(2H, bs), 8.23 (1H, d, J = 2Hz), 8.37 (1H, d, J = 2Hz), 9.54
(1H, d, J = 8.4Hz).

Example 7 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamide] -3- (imidazo [1 , 2-a] Pyridinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 50] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- 0.351 g of carboxylate,
Using 0.177 g of imidazo [1,2-a] pyridine, 0.75 g of ethyl o-phenylene phosphate and 8 ml of dimethylformamide, the same procedure as in Example 3 was carried out to obtain 0.171 g of the title compound. Elemental analysis value: C ₂₁ H ₁₉ FN ₈ O ₅ S ₂ · 3.5H ₂ O Calculated value: C, 41.34; H, 4.27; N, 18.37 Actual value: C, 41.27; H, 4.31; N, 18.23 NMR spectrum (D ₆ −DMSO) δ: 2.95 and 3.40 (2H, ABq,
J = 17.2Hz), 4.24 (1H, t, J = 3.8Hz), 4.39 (1H, t, J = 3.8Hz),
4.50 (1H, t, J = 3.8Hz), 4.73 (1H, t, J = 3.8Hz), 4.99 (1H,
d, J = 4.8Hz), 5.27 and 5.43 (2H, ABq, J = 14.2Hz), 5.63 (1H, d
d, J = 8.4Hz and 4.8Hz), 7.51 (1H, m), 7.99 (1H, m), 8.13 (2
H, bs), 8.37 (1H, d, J = 2.2Hz), 8.52 (1H, d, J = 2.2Hz), 8.6
8 (1H, d, J = 9Hz), 8.92 (1H, d, J = 6.8Hz), 9.52 (1H, d, J = 8.4
Hz).

Example 8 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamide] -3- (5-ureido Imidazo [1,
2-a] pyridinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 51] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- 0.468 g of carboxylate,
5-Ureidoimidazo [1,2-a] pyridine 0.21
1 g, ethyl o-phenylene phosphate 1.0 g,
Using 4 ml of dimethylformamide, the same procedure as in Example 3 was carried out to obtain 0.052 g of the title compound. Elemental _{analysis: C 22 H 21 FN 10 O} 6 S 2 · 4.0H 2 O Calculated: C, 39.05; H, 4.32 ; N, 20.70 Found: C, 39.25; H, 4.05 ; N, 20.50 NMR spectrum (D ₆ −DMSO) δ: 3.01 and 3.50 (2H, ABq,
J = 17.4Hz), 4.25 (1H, t, J = 3.6Hz), 4.39 (1H, t, J = 3.6Hz),
4.50 (1H, t, J = 3.6Hz), 4.73 (1H, t, J = 3.6Hz), 5.12 (1H,
d, J = 5Hz), 4.97 and 5.15 (2H, ABq, J = 13.6Hz), 5.73 (1H, dd,
J = 8.4Hz and 5Hz), 7.70 (1H, m), 7.87 (2H, m), 8.13 (2H, b)
s), 8.46 (1H, s), 8.56 (1H, s), 9.57 (1H, d, J = 8.4Hz), 1
1.98 (1H, bs).

Example 9 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamide] -3- (6-gly Silaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate / hydrochloride

[Chemical 52] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- 0.468 g of carboxylate and 0.32 g of 6- (2-tert-butoxycarbonyl) aminoacetaminoimidazo [1,2-b] pyridazine are dissolved in 3 ml of dimethylformamide, and 1.0 g of ethyl o-phenylene phosphate is added to room temperature. And stirred for 3 hours. 30 ml of ethyl ether was added to the reaction solution, and the separated oily substance was subjected to silica gel column chromatography and eluted with acetone: H ₂ O (4: 1). Fractions containing the target compound were collected and concentrated under reduced pressure. The residue was freeze dried. The lyophilized product obtained was suspended in 5 ml of dichloromethane, 1 ml of anisole and 2 ml of trifluoroacetic acid were added under ice cooling, and the reaction solution was stirred at room temperature for 1 hour. Concentrate under reduced pressure and residue is C
It was subjected to HP-20 column chromatography and eluted with 10% ethanol: 1N hydrochloric acid (100: 1). Fractions containing the target compound were collected and concentrated under reduced pressure. The residue was passed through Amberlite IRA-401 (Cl type) ion exchange resin (Organo) (12 ml) and eluted with 50 ml of water. The eluate was concentrated and freeze-dried to obtain 0.169 g of the title compound. Elemental _{analysis: C 22 H 22 FN 11 O} 6 S 2 · 2HCl · 8.0H
₂ O Calculated value: C, 31.58; H, 4.82; N, 18.42 Measured value: C, 31.51; H, 4.57; N, 18.69 NMR spectrum (d ₆ -DMSO) δ: 3.29 and 3.63 (2H, ABq,
J = 18Hz), 3.99 (2H, m), 4.27 (1H, t, J = 3.6Hz), 4.41 (1H,
t, J = 3.6Hz), 4.52 (1H, t, J = 3.6Hz), 4.77 (1H, t, J = 3.6H
z), 5.18 (1H, d, J = 5Hz), 5.47 (2H, m), 5.90 (1H, dd, J = 8.4
Hz and 5 Hz), 8.15 (3H, bs), 8.50
(4H, m), 8.32 (1H, d, J = 2.2H
z), 8.72 (1H, d, J = 2.2 Hz),
8.91 (1H, d, J = 10Hz), 9.64 (1
H, d, J = 8.4 Hz), 12.19 (1H, b
s).

Example 10 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamide] -3- (5-gly Silaminoimidazo [1,2-a] pyridinium-1-yl) methyl-3
-Cephem-4-carboxylate / hydrochloride

[Chemical 53] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- 0.468 g of carboxylate,
5- (2-tert-Butoxycarbonyl) aminoacetaminoimidazo [1,2-a] pyridine 0.32 g, ethyl o-phenylene phosphate 1.0 g, and dimethylformamide 4 ml were used, and the same procedure as in Example 9 was performed. This gave 0.059 g of the title compound. Elemental _{analysis: C 23 H 25 Cl 2 FN} 10 O 6 S 2 · 6.5H 2 O Calculated: C, 34.16; H, 4.74 ; N, 17.32 Found: C, 34.93; H, 4.48 ; N, 17.32 NMR spectrum (d ₆ -DMSO) δ: 3.23 and 3.61 (2H, ABq,
J = 18Hz), 4.18 (2H, m), 4.32 (1H, m), 4.41 (1H, m), 4.51
(1H, m), 4.76 (1H, m), 5.17 (1H, d, J = 5.2Hz), 5.44 (2H,
m), 5.89 (1H, dd, J = 9Hz and 5.2Hz), 7.76 (1H, m), 8.10 (3H,
bs), 8.13 (2H, m), 8.43 (3H, bs), 8.25 (1H, m), 8.95 (1H,
m), 9.64 (1H, d, J = 9Hz).

Example 11 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamide] -3- (3-formyl Aminoimidazo [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)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- Carboxylate 0.47g and 3
-Formylaminoimidazo [1,2-b] pyridazine 0.32 g, ethyl o-phenylene phosphate 1.
0.1 g of the title compound by the same procedure as in Example 3.
Got Elemental analysis value: C ₂₁ H ₁₉ FN ₁₀ O ₆ S ₂ · 4.5H ₂ O Calculated value: C, 37.55; H, 4.20; N, 20.85 Actual value: C, 37.55; H, 3.88; N, 20.93 IR spectrum (KBr, cm ^-1 ): 3400, 1760, 1678, 163
7, 1599, 1548, 1522, 1383. NMR spectrum (d ₆ -DMSO) δ: 3.02 and 3.40 (2H, ABq,
J = 17Hz), 4.37 (1H, m), 4.49 (1H, m), 4.73 (1H, m), 4.98
(1H, d, J = 5Hz), 5.27 and 5.55 (2H, ABq, J = 14.5Hz), 5.64 (1
H, dd, J = 5Hz and 8.5Hz), 7.91 (1H, dd, J = 4.5Hz and 9.5Hz), 8.
12 (2H, bs), 8.50 (1H, s), 8.81 (1H, s), 9.08 (1H, d, J = 4.5
Hz), 9.36 (1H, d, J = 9.5Hz), 9.55 (1H, d, J = 8Hz).

Example 12 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamide] -3- (3-amino Imidazo [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)-(2-fluoroethoxy) iminoacetamide] -3- (3-formylaminoimidazo [1,2 -B] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate (0.12 g) was suspended in methanol (4 ml), 1N hydrochloric acid (2 ml) was added, and the mixture was stirred at room temperature for 6 hr. Concentrate under reduced pressure and residue is CHP-20.
Purified by column chromatography and eluted with 10% ethanol. After concentrating the target fraction, the residue was freeze-dried to obtain 0.09 g of the title compound. Elemental _{analysis: C 20 H 19 FN 10 O} 5 S 2 · 3H 2 O Calculated: C, 38.96; H, 4.09 ; N, 22.72 Found: C, 38.86; H, 4.15 ; N, 22.47 IR spectrum (KBr , cm ^-1 ): 3400, 1770, 1652, 161
0, 1521, 1385. NMR spectrum (d ₆ -DMSO) δ: 3.01 and 3.47 (2H, ABq,
J = 17Hz), 4.24 (1H, m), 4.39 (1H, m), 4.51 (1H, m), 4.74
(1H, m), 5.00 (1H, d, J = 5Hz), 5.16 and 5.36 (2H, ABq, J = 13.5
Hz), 5.65 (1H, dd, J = 5Hz and 8.5Hz), 6.41 (2H, bs), 7.66 (1
H, dd, J = 4.5Hz and 9.5Hz), 7.84 (1H, s), 8.13 (2H, bs), 8.9
0 (1H, d, J = 4.5Hz), 8.98 (1H, d, J = 9.5Hz), 9.52 (1H, d, J =
8.5Hz).

Example 13 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxy) iminoacetamide] -3- (3-ureido Imidazo [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)-(2-fluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem-4- Carboxylate 0.47g, 3
-Ureido imidazo [1,2-b] pyridazine 0.36
In the same manner as in Example 3, 0.21 g of the title compound was obtained from 1.0 g of ethyl o-phenylene phosphate. Elemental _{analysis: C 21 H 20 FN 11 O} 6 S 2 · 4H 2 O Calculated: C, 37.22; H, 4.16 ; N, 22.74 Found: C, 37.25; H, 3.92 ; N, 22.67 IR spectrum (KBr , cm ^-1 ): 3410, 1766, 1670, 160
1, 1550. NMR spectrum (d ₆ -DMSO) δ: 3.02 and 3.33 (2H, ABq,
J = 17.5Hz), 4.24 (1H, m), 4.38 (1H, m), 4.50 (1H, m), 4.74
(1H, m), 4.99 (1H, dd, J = 5Hz), 5.27 and 5.56 (2H, ABq, J = 14H
z), 5.65 (1H, dd, J = 5Hz and 8.5Hz), 6.75 (2H, bs), 7.83 (1
H, dd, J = 4.5Hz and 9.5Hz), 8.13 (2H, bs), 8.47 (1H, s), 9.0
2 (1H, d, J = 4.5Hz), 9.30 (1H, d, J = 9.5Hz), 9.56 (1H, d, J =
8.5Hz), 9.95 (1H, bs).

Example 14 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3 -(Imidazo [1,2
-B] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 57] 0.5 g of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetic acid was suspended in 10 ml of dichloromethane and dried with ice. After adding 0.47 g of phosphorus pentachloride under cooling with an acetone bath (-20 ° C), the mixture was stirred at 0 ° C for 2 hours. The solvent was distilled off under reduced pressure, n-hexane was added to the residue, and the crystals were collected by filtration to give 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2, 2,2-trifluoroethoxy) iminoacetic acid chloride.hydrochloride was obtained. This acid chloride was treated with 7β-amino-3- (imidazo [1,2-
b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate hydrochloride (1.44 g) and sodium hydrogencarbonate (1.17 g) were added to 19 ml of 50% tetrahydrofuran aqueous solution at 0 ° C, and the mixture was stirred at the same temperature for 1 hour. . The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with acetone and then with water-containing acetone. Fractions containing the target compound were collected and concentrated under reduced pressure. The residue was subjected to MCI gel column chromatography, eluted with water and then with hydrated ethanol, and the fractions containing the desired product were collected and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.1 g of the title compound. Elemental _{analysis: C 20 H 16 F 3 N} 9 O 5 S 2 · 2H 2 O Calculated: C, 38.77; H, 3.25 ; N, 20.35 Found: C, 38.72; H, 3.41 ; N, 20.65 IR spectrum (KBr, cm ^-1 ): 1770, 1680, 1610, 152
0. NMR spectrum (d ₆ -DMSO) δ: 4.70 (2H, q, J = 9.4H
z), 4.99 (1H, d, J = 4.8Hz), 5.24 and 5.49 (2H, ABq, J = 12.2H
z), 5.65 (1H, dd, J = 4.8Hz and 8.4Hz), 7.95 (1H, dd, J = 4.4Hz)
And 9.4 Hz), 8.19 (2H, bs), 8.7
6 (2H, s), 9.05 (1H, d, J = 4.4H
z), 9.36 (1H, d, J = 9.4 Hz),
9.66 (1H, d, J = 8.4 Hz).

Example 15 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3 -[(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)-(2,2,2-trifluoroethoxy) iminoacetamide] -3- (3-oxobutyi Ryloxymethyl) -3-cephem-4-carboxylic acid 2.
2 g, imidazo [1,2-b] pyridazine 2.0 g, and potassium iodide 2.2 g were added to 50% water-containing acetonitrile 30.
It was dissolved in ml and stirred at 60 to 70 ° C. for 2 hours. After cooling
The reaction solution was subjected to silica gel column chromatography,
Acetone and hydrous acetone were sequentially eluted, and the fractions containing the target compound were combined and concentrated under reduced pressure. The residue was subjected to column chromatography by XAD-II, eluted with water and then with hydrous alcohol, and the fractions containing the desired product were combined and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.3 g of the title compound. This product was confirmed to be the same as the compound obtained in Example 14 from the agreement of the IR spectrum and the NMR spectrum.

Example 16 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3 -(Imidazo [1,2
-B] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 59] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamido] -3-hydroxymethyl-3 -Cephem-4-carboxylate 0.
0.21 g of the title compound was prepared in the same manner as in Example 3 except that 4 g, 0.19 g of imidazo [1,2-b] pyridazine and 0.8 g of ethyl o-phenylene phosphate were used.
Got This product was confirmed to be the same as the compound obtained in Example 14 from the agreement of the IR and NMR spectra.

Example 17 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3 -(Imidazo [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)-(2,2,2-trifluoroethoxy) iminoacetamido] -3-hydroxymethyl-3 -Cephem-4-carboxylate 0.
4 g, imidazo [1,2-a] pyridine 0.2 g and ethyl o-phenylene phosphate 0.8 g were reacted in the same manner as in Example 3 to obtain 0.14 g of the title compound. Elemental _{analysis: C 21 H 17 F 3 N} 8 O 5 S 2 · 3H 2 O Calculated: C, 39.62; H, 3.64 ; N, 17.60 Found: C, 39.65; H, 3.59 ; N, 17.30 IR spectrum (KBr, cm ^-1 ): 1780, 1680, 1610, 153
0. NMR spectrum (d ₆ -DMSO) δ: 4.72 (2H, q, J = 4.6H
z), 4.98 (1H, d, J = 5Hz), 5.25 and 5.42 (2H, ABq, J = 14Hz),
5.61 (1H, dd, J = 5Hz and 8Hz), 7.52 (1H, t, J = 6.4Hz), 8.0 (1
H, t, J = 9Hz), 8.20 (2H, bs), 8.36 (1H, bs), 8.52 (1H, bs),
8.70 (1H, d, J = 9Hz), 8.92 (1H, d, J = 6.4Hz), 9.65 (1H, d, J
= 8.2Hz).

Example 18 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3 -(6-aminoimidazo [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)-(2,2,2-trifluoroethoxy) iminoacetamido] -3-hydroxymethyl-3 -Cephem-4-carboxylate 0.
5 g, 6-aminoimidazo [1,2-b] pyridazine 0.27 g and ethyl o-phenylene phosphate 1.0 g were reacted in the same manner as in Example 3 to obtain 0.12 g of the title compound. Elemental _{analysis: C 20 H 17 F 3 N} 10 O 5 S 2 · 3H 2 O Calculated: C, 36.81; H, 3.55 ; N, 21.46 Found: C, 36.99; H, 3.33 ; N, 21.32 IR spectrum (KBr, cm ^-1 ): 3400, 3200, 1770, 161
0, 1510. NMR spectrum (d ₆ -DMSO) δ: 4.72 (2H, m), 4.95 (1H, d, J = 5H
z), 5.10 and 5.34 (2H, ABq, J = 14.6Hz), 5.62 (1H, dd, J = 5Hz
And 8.8Hz), 7.16-7.27 (3H, m), 8.14-8.19 (3H, m), 8.38 (1
H, bs), 8.82 (1H, d, J = 9.5Hz), 9.62 (1H, d, J = 8.8Hz).

Example 19 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (imidazo [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) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0. 273 g and 0.143 g of imidazo [1,2-b] pyridazine were dissolved in 5 ml of dimethylformamide, 0.6 g of ethyl o-phenylene phosphate was added, and the mixture was stirred at room temperature for 3 hours. 50 ml of ethyl ether was added to the reaction solution, and the oily substance that separated was purified by silica gel column chromatography and eluted with acetone: H ₂ O (4: 1), and the eluate was concentrated. The residue was purified by Amberlite XAD-2 column chromatography and eluted with 5% ethanol (EtOH). The target fraction was concentrated and lyophilized to give the title compound (0.1%).
107 g were obtained. Elemental analysis value: C ₁₉ H ₁₆ FN ₉ O ₅ S · 1.5H ₂ O Calculated value: C, 40.71; H, 3.42; N, 22.49 Actual value: C, 40.64; H, 3.77; N, 20.65 NMR spectrum ( d ₆ −DMSO) δ: 3.02 and 3.51 (1H, d, each
J = 17Hz), 5.00 (1H, d, J = 5Hz), 5.24 and 5.49 (1H, d, J = 14H each)
z), 5.64 (1H, dd, J = 5,8Hz), 5.72 (2H, d, J = 55Hz), 7.4-9.4
(5H, m), 8.20 (2H, s), 9.65 (1H, d, J = 8Hz).

Example 20 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamide] -3-[(imidazo [1,2- b] Pyridazinium-1-yl) methyl] -3-cephem-4-carboxylate

[Chemical formula 63] 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (3-oxobutyryloxymethyl)-
1.1 g of 3-cephem-4-carboxylic acid, 1.0 g of imidazo [1,2-b] pyridazine and 1.1 g of potassium iodide were dissolved in 30 ml of acetonitrile containing 50% water,
It stirred at 60-70 degreeC for 2 hours. After cooling, the reaction solution was subjected to silica gel column chromatography and eluted with acetone and hydrous acetone successively, and the fractions containing the target compound were combined and concentrated under reduced pressure. The residue was subjected to column chromatography with MCI gel CHP-20 (manufactured by Mitsubishi Kasei),
The product was eluted with water and then with hydrous alcohol, and the fractions containing the desired product were combined and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.15 g of the title compound. This product was confirmed to be the same as the compound obtained in Example 19 from the agreement of the IR spectrum and the NMR spectrum.

Example 21 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (imidazo [1,2-a ] Pyridinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 64] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0. 26 g, imidazo [1,2-a] pyridine 0.135 g, ethyl o-phenylene phosphate 0.572 g, and dimethylformamide 5 ml were used in the same manner as in Example 3 to obtain 0.1 g of the title compound. Elemental _{analysis: C 20 H 17 FN 8 O} 5 S 2 · 3H 2 O Calculated: C, 40.95; H, 3.95 ; N, 19.10 Found: C, 40.85; H, 3.73 ; N, 19.10 NMR spectrum (d ₆ −DMSO) δ: 2.94 and 3.41 (2H, ABq,
J = 17Hz), 5.00 (1H, d, J = 5Hz), 5.25 and 5.44 (2H, ABq, J = 14H
z), 5.63 (1H, dd, J = 5 and 8Hz), 5.72 (1H, d, J = 55Hz), 7.4-9.
0 (6H, m), 8.19 (2H, s), 9.68 (1H, d, J = 8Hz).

Example 22 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamide] -3- (6-aminoimidazo [1, 2-b] pyridazinium-1-yl) methyl-3-cephem-4-
Carboxylate

[Chemical 65] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0. 228 g, 6-aminoimidazo [1,2-b] pyridazine 0.134 g, ethyl o-phenylene phosphate 0.5 g, and dimethylformamide 4 ml were used in the same manner as in Example 3 to obtain the title compound 0.051 g. . Elemental analysis value: C ₁₉ H ₁₇ FN ₁₀ O ₅ S ₂ · 3.5H ₂ O Calculated value: C, 37.31; H, 3.96; N, 22.90 Actual value: C, 37.14; H, 3.96; N, 22.14 NMR spectrum (D ₂ O) δ: 3.20 and 3.57 (1H, d, J = 18H each)
z), 5.25 (1H, d, J = 5Hz), 5.26 (2H, s), 5.85 (2H, d, J = 54H
z), 5.88 (1H, d, J = 5Hz), 7.29-8.3 (4H, m).

Example 23 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (6-ureidoimidazo [1, 2-b]
Pyridazinium-1-yl) methyl-3-cephem-4
-Carboxylate

[Chemical formula 66] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0. 318 g, 6-ureidoimidazo [1,2-b] pyridazine 0.149 g,
The same procedure as in Example 3 was conducted using 0.561 g of ethyl o-phenylene phosphate and 10 ml of dimethyl sulfoxide to obtain 0.051 g of the title compound. Elemental _{analysis: C 20 H 18 FN 11 O} 6 S 2 · 2.5H 2 O Calculated: C, 37.73; H, 3.64 ; N, 24.20 Found: C, 37.97; H, 3.69 ; N, 24.38 NMR spectrum (D ₂ O) δ: 3.20 and 3.64 (each 1H, d, J = 18H
z), 5.27 (1H, d, J = 5Hz), 5.46 (2H, s), 5.83 (2H, d, J = 54H
z), 5.87 (1H, d, J = 5Hz), 8.3-9.0 (4H, m).

Example 24 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (6-carbamoylimidazo [1, 2-
b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical formula 67] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0. 228 g, 6-carbamoylimidazo [1,2-b] pyridazine 0.163
g, ethyl o-phenylene phosphate (0.5 g) and dimethylformamide (4 ml) were used in the same manner as in Example 3 to obtain the title compound (0.046 g). Elemental _{analysis: C 20 H 17 FN 10 O} 6 S 2 · 4H 2 O Calculated: C, 37.04; H, 3.88 ; N, 21.60 Found: C, 37.50; H, 3.63 ; N, 21.46 NMR spectrum (D ₂ O) δ: 3.20 and 3.61 (1H, d, J = 18H each)
z), 5.26 (1H, d, J = 5Hz), 5.35 (2H, s), 5.83 (1H, d, J = 5Hz),
5.83 (2H, d, J = 54Hz), 7.7-8.6 (4H, m).

Example 25 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (6-glycylaminoimidazo [ 1,2
-B] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate hydrochloride

[Chemical 68] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0. 273g and 6- (2
0.21 g of -tert-butoxycarbonyl) aminoacetaminoimidazo [1,2-b] pyridazine was dissolved in 3 ml of dimethylformamide, 0.6 g of ethyl o-phenylene phosphate was added, and the mixture was stirred at room temperature for 2.5 hours. 30 ml of ethyl ether was added, and the separated oily substance was purified by silica gel column chromatography and eluted with acetone: H ₂ O (4: 1). The eluate was concentrated and then freeze-dried. The lyophilized product obtained was suspended in 5 ml of dichloromethane, and 1 ml of anisole and 2 ml of trifluoroacetic acid under ice cooling.
Was added and the mixture was returned to room temperature and stirred for 1 hour. After concentration under reduced pressure, the residue was purified by Amberlite XAD-2 column and eluted with 10% ethanol: 1N HCl (100: 1). The desired fraction was concentrated, and the residue was passed through Amberlite IRA-401 (Cl type) ion exchange resin (12 ml) and eluted with 50 ml of water. The eluate was concentrated and freeze-dried to obtain 0.096 g of the title compound. Elemental _{analysis: C 21 H 20 FN 11 O} 6 S 2 · 2HCl · 5H 2 O Calculated: C, 32.82; H, 4.20 ; N, 20.05 Found: C, 33.12; H, 3.87 ; N, 19.88 NMR spectrum (D ₂ O) δ: 3.27 and 3.69 (each 1H, d, J = 18H
z), 4.22 (2H, s), 5.32 (1H, d, J = 5Hz), 5.42 and 5.52 (1 each)
H, d, J = 16 Hz), 5.87 (2H, d, J =
55Hz), 5.92 (1H, d, J = 5Hz),
8.2-8.8 (4H, m).

Example 26 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (3-aminoimidazo [1, 2-b]
Pyridazinium-1-yl) methyl-3-cephem-4
-Carboxylate

[Chemical 69] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0. 236 g, 3-formylaminoimidazo [1,2-b] pyridazine 0.16
7 g, ethyl o-phenylene phosphate 0.52
g, dimethylformamide (3 ml) and dimethyl sulfoxide (1.5 ml) were used in the same manner as in Example 3 to give
[2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (3-formylaminoimidazo [1,2-
b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate 0.071 g was obtained. This compound was suspended in 4 ml of methanol, 2 ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 6 hours. After concentration under reduced pressure, the residue was purified by Amberlite XAD-2 column and eluted with 7% EtOH. The desired fraction was concentrated and lyophilized to give the title compound.
054 g was obtained. Elemental analysis value: C ₁₉ H ₁₇ FN ₁₀ O ₅ S ₂ · 3.5H ₂ O Calculated value: C, 37.31; H, 3.95; N, 22.90 Actual value: C, 37.29; H, 3.60; N, 22.42 NMR spectrum (D ₂ O) δ: 3.18 and 3.57 (1H, d, J = 18H each)
z), 5.25 (1H, d, J = 5Hz), 5.26 and 5.36 (1H, d, J = 1 each)
5Hz), 5.84 (2H, d, J = 55Hz),
5.88 (1H, d, J = 5Hz), 7.53 (1
H, s), 7.6-8.9 (3H, m).

Example 27 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (3-ureidoimidazo [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) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate 0. 228 g, 3-ureidoimidazo [1,2-b] pyridazine 0.177 g,
The same procedure as in Example 3 was conducted using 0.5 g of ethyl o-phenylene phosphate and 3 ml of dimethylformamide to obtain 0.121 g of the title compound. Elemental _{analysis: C 20 H 18 FN 11 O} 6 S 2 · 3H 2 O Calculated: C, 37.21; H, 3.75 ; N, 23.86 Found: C, 37.57; H, 3.92 ; N, 23.76 NMR spectrum (D ₂ O) δ: 3.23 and 3.62 (1H, d, J = 18H each)
z), 5.27 (1H, d, J = 5Hz), 5.42 (2H, s), 5.85 (2H, d, J = 55H
z), 5.89 (1H, d, J = 5Hz), 7.8-9.0 (3H, m), 8.23 (1H, s).

Example 28 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (3-glycylaminoimidazo [ 1,2
-B] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate hydrochloride

[Chemical 71] Sodium 7β- [2- (5-amino-1,2,4-thiadiazole) -2 (Z) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4
-Carboxylate 0.273 g, 3- (2-tert-butoxycarbonyl) aminoacetaminoimidazo [1,
2-b] Pyridazine (0.21 g), ethyl o-phenylene phosphate (0.6 g) and dimethylsulfoxide (3 ml) were used, followed by the same procedure as in Example 25 to give the title compound 0.1.
05 g was obtained. Elemental _{analysis: C 21 H 20 FN 11 O} 6 S 2 · 2HCl · 7H 2 O Calculated: C, 31.35; H, 4.51 ; N, 19.15 Found: C, 31.22; H, 4.32 ; N, 18.83 NMR spectrum (D ₂ O) δ: 3.27 and 3.71 (each 1H, d, J = 18H
z), 4.25 (2H, s), 5.32 (1H, d, J = 5Hz), 5.44 and 5.61 (each 1H,
d, J = 15Hz), 5.83 (2H, d, J = 54Hz), 5.91 (1H, d, J = 5Hz), 7.
8-9.1 (3H, m), 8.49 (1H, s).

Example 29 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (5-aminoimidazo [1, 2-a]
Pyridinium-1-yl) methyl-3-cephem-4-
Carboxylate

[Chemical 72] Sodium 7β- [2- (5-amino-1,2,4-thiadiazole) -2 (Z) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4
-Carboxylate 0.273 g and 5-tert-butoxycarbonylaminoimidazo [1,2-a] pyridine.
161 g was dissolved in 3 ml of dimethylformamide, 0.6 g of ethyl o-phenylene phosphate was added, and the mixture was stirred at room temperature for 2.5 hours. The oily substance separated by adding 30 ml of ethyl ether was purified by silica gel column chromatography and eluted with acetone: H ₂ O (4: 1). The eluate is concentrated, the residue is purified on an Amberlite XAD-2 column and eluted with 40% ethanol. The target fraction was concentrated and freeze-dried. 5 ml of this compound in dichloromethane
Suspended in ice-cold anisole 1 ml, trifluoroacetic acid 2 under ice cooling
After adding ml, the mixture was returned to room temperature and stirred for 1 hour. Concentrate under reduced pressure, dissolve the residue in water, add aqueous sodium hydrogen carbonate solution to pH 6.0, and then add Amberlite XAD.
-2 column purified. The target fraction eluted with 10% ethanol was collected, concentrated and lyophilized to give the title compound 0.0
57 g were obtained. Elemental _{analysis: C 20 H 18 FN 9 O} 5 S 2 · 4H 2 O Calculated: C, 38.77; H, 4.23 ; N, 20.35 Found: C, 38.82; H, 4.22 ; N, 20.22 NMR spectrum (D ₂ O) δ: 3.22 and 3.49 (1H, d, J = 18H each)
z), 5.14 and 5.29 (1H, d, J = 16Hz each), 5.23 (1H, d, J = 5Hz),
5.86 (2H, d, J = 54Hz), 5.88 (1H, d, J = 5Hz), 6.6-8.0 (5H,
m).

Example 30 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (5-glycylamino [1,2] -A] Pyridinium-1-yl) methyl-3-cephem-4-carboxylate / hydrochloride

[Chemical formula 73] Sodium 7β- [2- (5-amino-1,2,4-thiadiazole) -2 (Z) -fluoromethoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4
-Carboxylate 0.273 g, 5- (2-tert-butoxycarbonyl) aminoacetaminoimidazo [1,
2-a] Pyridine (0.21 g), ethyl o-phenylene phosphate (0.6 g) and dimethylformamide (3 ml) were used in the same manner as in Example 25 to give the title compound (0.02).
g was obtained. Elemental _{analysis: C 22 H 21 FN 10 O} 6 S 2 · 2HCl · 7H 2 O Calculated: C, 33.55; H, 4.74 ; N, 17.78 Found: C, 33.30; H, 4.79 ; N, 17.51 NMR spectrum (D ₂ O) δ: 3.27 and 3.66 (each 1H, d, J = 18H
z), 4.29 (2H, s), 5.31 (1H, d, J = 5Hz), 5.41 and 5.54 (each 1H,
d, J = 15Hz), 5.84 (2H, d, J = 54Hz), 5.93 (1H, d, J = 5Hz), 7.
6-8.3 (5H, m).

Example 31 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3 -(3-formylaminoimidazo [1,2-b] pyridazinium-1-yl)
Methyl-3-cephem-4-carboxylate

[Chemical 74] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamido] -3-hydroxymethyl-3 -Cephem-4-carboxylate 0.
The same reaction as in Example 3 was carried out using 0.154 g of 4-g, 3-formylaminoimidazo [1,2-b] pyridazine and 0.476 g of ethyl o-phenylene phosphate to obtain 0.062 g of the title compound. Elemental analysis value: C ₂₁ H ₁₇ F ₃ N ₁₀ O ₆ S ₂ · 3.5H ₂ O Calculated value: C, 36.58; H, 3.51; N, 20.31 Actual value: C, 35.56; H, 3.39; N, 20.04 NMR (d ₆ -DMSO) δ: 3.00 (1H, d, J = 17.2Hz), 4.72 (2
H, m), 4.99 (1H, d, J = 4.8Hz), 5.26 (1H, d, J = 13.6Hz), 5.5
7 (1H, d, J = 13.6Hz), 5.66 (1H, dd, J = 4.8Hz and 8.4Hz), 7.89
(1H, dd, J = 4.6Hz and 9.4Hz), 8.21 (2H, s), 8.49 (1H, s), 8.
79 (1H, s), 9.06 (1H, d, J = 4.6Hz), 9.37 (1H, d, J = 9.4Hz),
9.71 (1H, d, J = 8.4Hz)

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

[Chemical 75] 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3- (3-formylamino (Imidazo [1,2-b] pyridazinium-1-yl)
Methyl-3-cephem-4-carboxylate 0.04
Using the same procedure as in Example 12, 5 g of the title compound 0.02
5 g was obtained. Elemental _{analysis: C 20 H 17 F 3 N} 10 O 5 S 2 · 2H 2 O Calculated: C, 37.86; H, 3.34 ; N, 22.07 Found: C, 37.61; H, 3.34 ; N, 22.13 NMR ( d ₆ −DMSO) δ: 2.97 (1H, d, J = 18Hz), 3.42 (1H,
d, J = 18Hz), 4.69 (2H, m), 5.00 (1H, d, J = 4.8Hz), 5.15 (1H,
d, J = 15.8Hz), 5.39 (1H, d, J = 15.8Hz), 5.64 (1H, dd, J = 4.8
Hz and 8.2Hz), 6.42 (2H, s), 7.65 (1H, dd, J = 3.6Hz and 9.2H
z), 7.90 (1H, s), 8.18 (2H, s), 8.91 (1H, d, J = 3.6Hz), 9.
02 (1H, d, J = 9.2Hz), 9.66 (1H, d, J = 8.2Hz)

Example 33 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2-difluoroethoxy) iminoacetamide] -3- (imidazo [1,2-
b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 76] 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2-difluoroethoxy) iminoacetic acid (0.303 g) was dissolved in acetonitrile (15 ml) to give 2
-Mercaptobenzothiazole disulfide 0.479
g was added, 0.57 ml of tributylamine and 0.312 ml of triethyl phosphite were added under stirring with ice cooling, and the mixture was further stirred under cooling with ice for 2 hours. Acetonitrile was distilled off under reduced pressure, the residue was dissolved in 4 ml of acetone, and this solution was mixed with 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-
Iyl) methyl-3-cephem-4-carboxylate
Hydrochloride 0.405 g, tributylamine 0.951 ml,
The mixture was added to a solution of 8 ml of acetone and 8 ml of water under ice cooling, and then stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with acetone: water (4: 1). The target fractions were collected and concentrated under reduced pressure. The residue was subjected to XAD-II column chromatography, and the target fractions eluted with 10% ethanol were collected and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.212 g of the title compound. Elemental _{analysis: C 20 H 17 F 2 N} 9 O 5 S 2 · 3H 2 O Calculated: C, 38.77; H, 3.74 ; N, 20.35 Found: C, 39.02; H, 3.84 ; N, 20.31 NMR ( D ₂ O) δ: 3.19 and 3.58 (1H, d, J = 18Hz each), 4.53 (2
H, dt, J = 4Hz and 14Hz), 5.23 (1H, d, J = 5Hz), 5.35 and 5.42 (each)
1H, d, J = 15Hz), 5.85 (1H, d, J = 5Hz), 6.16 (1H, tt, J = 4Hz and
54Hz), 7.8-9.0 (5H, m)

Example 34 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2-difluoroethoxy) iminoacetamide] -3- (3 -Aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 77] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2-difluoroethoxy) iminoacetamido] -3-hydroxymethyl-3-cephem- 4-carboxylate 0.29
The same procedure as in Example 3 was conducted using 0.14 g of 4-g, 3-formylaminoimidazo [1,2-b] pyridazine and 0.6 g of ethyl o-phenylene phosphate to give 7β.
-[2- (5-amino-1,2,4-thiadiazole-3
-Yl) -2 (Z)-(2,2-difluoroethoxy) iminoacetamido] -3- (formylaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate was obtained. This compound was suspended in 5 ml of methanol, and 2.5 ml of 1N hydrochloric acid was added,
Stir at room temperature for 8 hours. Concentrate under reduced pressure and residue is CHP
Subjected to -20 column chromatography, eluted with 12.5% ethanol, the target fraction was concentrated and freeze-dried to obtain 0.045 g of the title compound. Elemental _{analysis: C 20 H 18 F 2 N} 10 O 5 S 2 · 3.5H 2 O Calculated: C, 37.32; H, 3.92 ; N, 21.76 Found: C, 37.29; H, 3.94 ; N, 21.49 NMR (D ₂ O) δ: 3.16 and 3.54 (each 1H, d, J = 18Hz), 4.53 (2
H, dt, J = 4Hz and 14Hz), 5.22 (1H, d, J = 5Hz), 5.29 (2H, d, J = 6
Hz), 5.85 (1H, d, J = 5Hz), 6.16 (1H, tt, J = 4Hz and 55Hz), 7.
51 (1H, s), 7.6-9.0 (3H, m)

Example 35 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3 -(6-Amino-3-formylaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 78] Sodium 7β [2- (5-amino-1,2,4-thiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamido] -3-hydroxymethyl-3- Cephem-4-carboxylate
0.504 g, 6-amino-3-formylaminoimidazo [1,2-b] pyridazine 0.266 g, ethyl o-
The title compound (0.062 g) was obtained in the same manner as in Example 3 from 1.0 g of phenylene phosphate. Elemental analysis value: C ₂₁ H ₁₈ F ₃ N ₁₁ O ₆ S ₂ · 3.5H ₂ O Calculated value: C, 35.80; H, 3.58; N, 21.87 Measurement site: C, 36.05; H, 3.23; N, 22.15 NMR spectrum _{(d 6 -DMSO) δ: 2.99} (1H, d, J = 14.8Hz),
3.48 (1H, d, J = 14.8Hz), 4.71 (2H, m), 4.98 (1H, d, J = 5.0H
z), 5.12 (1H, d, J = 14.4Hz), 5.40 (1H, d, J = 14.4Hz), 5.63
(1H, dd, J = 5.0Hz and 8.8Hz), 7.12 (2H, s), 7.18 (1H, d, J = 9.
8Hz), 8.17 (2H, s), 8.43 (1H, s), 8.45 (1H, s), 8.84 (1H,
d, J = 9.8Hz), 9.67 (1H, d, J = 8.8Hz).

Example 36 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3 -(3,6-Diaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 79] 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(2,2,2-trifluoroethoxy) iminoacetamide] -3- (6-amino- 3-formylaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate 0.045 g was suspended in methanol 4 ml,
2 ml of 1N hydrochloric acid was added under ice cooling. The mixture was stirred at room temperature for 7 hours, adjusted to pH 4 with 1N-sodium hydroxide, and concentrated under reduced pressure. The residue was subjected to MCI gel CHP-20p column chromatography, eluting with water-ethanol (4: 1),
Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was freeze-dried to obtain 0.027 g of the title compound. Elemental _{analysis: C 20 H 18 N 11 O} 5 S 2 F 3 · 3.5H 2 O Calculated: C, 35.50; H, 3.72 ; N, 22.77 Found Location: C, 35.48; H, 3.86 ; N, 22.45 NMR spectrum (d ₆ -DMSO) δ: 3.11 (1H, d, J = 13.6Hz),
3.46 (1H, d, J = 13.6Hz), 4.74 (2H, m), 4.98 (1H, d, J = 4.6H
z), 5.00 (1H, d, J = 14.4Hz), 5.24 (1H, d, J = 14.4Hz), 5.62
(1H, dd, J = 8.0Hz and 4.6Hz), 5.76 (2H, s), 6.97 (2H, s), 6.
97 (1H, d, J = 10Hz), 7.51 (1H, s), 8.18 (2H, s), 8.55 (1H, d,
J = 10Hz), 9.63 (1H, d, J = 8Hz).

Test Example 1 Minimum inhibitory concentration (MIC) of the 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 (Staphylococcus aureus N- 133) (MRSA) (3) Pseudomonas aeruginosa P9 (Pseudomonas aeruginosa P9) Control Compound 1: Ceftazidime (CAZ) Control Compound 2: Cefpirome (CPR) From these results, the cephem compound [I] of the present invention or a salt or ester thereof is a representative strain of a pathogenic bacterium clinically regarded as important. On the other hand, it is clear that it exhibits a well-balanced and excellent antibacterial action.

[0105]

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 (21)

[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). 2. The compound according to claim 1, wherein R ³ is fluoromethyl. 3. R ³ is 2-fluoroethyl.
The described compound. 4. The compound according to claim 1, wherein R ³ is 2,2,2-trifluoroethyl. 5. A chemical formula: The compound according to claim 1, which is a group. 6. A chemical formula: The compound according to claim 1, which is a group. 7. embedded image The compound according to claim 1, which is a group. 8. A chemical formula: The compound according to claim 1, which may be substituted with a milamino group. 9. R ¹ is an amino group and R ³ is fluoromethyl or 2-fluoroethyl. [Wherein one of R ² and R ² 'is a hydrogen atom and the other is a hydrogen atom, an amino group, a carbamoyl group, a ureido group, a glycylamino group or a formylamino group]. The described compound. 10. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxyimino) acetamido] -3- (6-aminoimidazo [1,2-b] pyridazinium-1-yl)
The compound according to claim 1, which is methyl-3-cephem-4-carboxylate. 11. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(2-fluoroethoxyimino) acetamido] -3- (5-aminoimidazo [1,2-a] pyridinium-1-yl) methyl-3-cephem-4- The compound according to claim 1, which is a carboxylate. 12. 7β- [2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (6-aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-
The compound according to claim 1, which is 3-cephem-4-carboxylate. 13. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (6-glycylaminoimidazo [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)-(2-fluoroethoxyimino) acetamido] -3- (3-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)-(2-fluoroethoxyimino) acetamido] -3- (3-ureidoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4- The compound according to claim 1, which is a carboxylate. 16. β- [2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (3-aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-
The compound according to claim 1, which is 3-cephem-4-carboxylate. 17. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z) -fluoromethoxyiminoacetamido] -3- (3-ureidoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate. Claim 1
The described compound. 18. A general formula: [Wherein the symbols in the formula have the same meaning as in claim 1] or a salt or ester thereof and a compound of 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. 19. A 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. 20. A general formula: [Symbols in the formula have the same meaning as in claim 1] or a compound or ester thereof or salt thereof and a general formula: R ³ OH [symbols in the formula have the same meaning as in claim 1]. The method for producing a compound according to claim 1, which comprises reacting with a compound or a salt or a reactive derivative thereof. 21. An antibacterial composition containing the compound according to claim 1.