JPH07133280A - Cephem compound, its production and antimicrobial composition - Google Patents

Abstract

PURPOSE:To obtain a new compound having excellent antimicrobial action on gram-positive and gram-negative bacteria, especially bacteria of the genus Pseudomonas, staphylococcus bacteria and MRSA bacteria. CONSTITUTION:A compound of formula I [R<1> is an amino; R<3> is a lower alkyl; A<+> is formula II (B is a six-membered aromatic heterocycle), etc.], e.g. 7beta-[2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-isopropoxyiminoacetamide]-3-(3-amino imidazo [1,2-b]pyridazinium-1-yl)methyl-cephem-carboxylate. The compound of formula I is obtained by reacting 7-amino compounds of formula III with a carboxylic acid derivative of formula IV. The compound of formula I has antimicrobial activity having broad spectrum and it is used for various diseases caused by pathogenic bacteria in human and mammal, e.g. respiratory tract infective diseases and urinary tract infective diseases.

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 is a cephem compound having a 2- (2-aminothiazol-4-yl) -2 (Z) -isopropoxyiminoacetamide group at the 7-position, but 2- (5-amino- 1,2,4-thiadiazol-4-yl) -2 (Z)
Regarding the cephem compound having a -branched alkoxyiminoacetamide group, the compound name and synthetic example are not specifically described, and its 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. No compound name or synthetic example is specifically described for the cephem compound having a branched alkoxy group as OR ³ , and no specific antibacterial action is described at all. Further, in JP-A-1-131185, the general formula

[Chemical 14] A cephem compound represented by the formula [wherein R ¹ represents a lower alkyl group] or a salt or ester thereof has been disclosed and synthesized, but a compound in which the lower alkyl group represented by R ¹ is branched Does not specifically describe the compound name and synthesis example, and does not describe its specific antibacterial action at all.

[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 optionally protected amino group and R ³ represents a lower branched alkyl group], or a cephem compound or a salt or ester thereof having a group represented by It was found that these compounds unexpectedly have a wide range of excellent antibacterial activity against Gram-negative bacteria including Pseudomonas and Gram-positive bacteria including Staphylococcus and MRSA, and the present invention was completed based on these.

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

[Chemical 17] [Wherein the symbols in the formula are 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) (4) An antibacterial composition containing the compound according to (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 22] [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.

Examples of the lower branched alkyl group represented by R ³ include isopropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1-methylpentyl, 2-
Methylpentyl, 3-methylpentyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-
Butylpentyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 1-ethylhexyl, 2-
A branched alkyl group having 3 to 9 carbon atoms such as ethylhexyl, 3-ethylhexyl, 1-propylhexyl, 2-propylhexyl, 3-propylhexyl, 1-ethylheptyl, 1-methyloctyl is used, and among them, isopropyl is particularly preferable. A branched alkyl group having 3 to 5 carbon atoms such as 1-methylpropyl, 1-methylbutyl, 1-ethylpropyl and 2-methylpropyl is preferable. From the viewpoint of antibacterial activity, R ³ is particularly preferably a lower (preferably 3 to 5 carbon atoms) alkyl group branched at the α-position such as isopropyl and 1-ethylpropyl.

[Chemical formula 23] [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 formula 24] The following is specifically used as A ² .

[Chemical 25]

[Chemical formula 26]

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

[Chemical 27] 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 28] 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, nor Bornyloxy and the like are used. Alkoxy group "amino C _1-6 alkoxy group" is a C _1-6 alkoxy group described above is preferred, for example, using an amino methoxy, 2-aminoethoxy, 3-aminopropoxy as the amino C _1-6 alkoxy group To be 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. The aralkyl group of the “C _7-19 aralkyloxy group” is preferably the above C _7-19 aralkyl group, and C
_{As the 7-19} aralkyloxy group, for example, benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, naphthylmethyloxy, benzhydryloxy, trityloxy and the like can be used. The alkyl group of the “C _1-6 alkylthio group” is preferably the above C _1-6 alkyl group,
As the C _1-6 alkylthio group, for example, methylthio, ethylthio, n-propylthio, n-butylthio and the like are used.

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

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

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

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

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

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

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

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

[Chemical 29] Alternatively, those substituted with 1 to 2 amino groups, carbamoyl groups, ureido groups, glycylamino groups or formylamino groups are preferable.

[0027]

[Chemical 30] 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 31] 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 32] For example, chloride ion, bromide ion, sulfate ion, p-toluenesulfonate ion, methanesulfonate ion, trifluoroacetate ion, etc.] are also included. The ester derivative of the compound [I] 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, 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.

As the "C _6-10 aryl group" forming an _optionally substituted C _6-10 aryl ester, for example, phenyl, α-naphthyl, β-naphthyl, biphenylyl and the like are used, and they are, for example, nitro. 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, etc.) may be substituted, 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 examples thereof include nitro, C _1-4 alkoxy (eg, methoxy etc.), C _1-4 alkyl (eg, methyl, ethyl etc.), It may be substituted with 1 to 3 hydroxy groups, and specific examples of such a group include p-nitrobenzyl, p-methoxybenzyl, 3,
5-ditert-butyl-4-hydroxybenzyl and the like are 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 and the like are substituted silyl groups forming a substituted silyl ester such as trimethylsilyl, tert-butyldimethylsilyl, -S
_{i (CH 3) 2 CH 2} CH 2 Si (CH 3) 2 - , etc. can be used.
The above-mentioned ester also includes the 4-position ester. In this way, 4-position is the above ester group

[Chemical 33] 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 34] 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 35] [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 36] [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 37] 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 38] [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 Formula 39] 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 the compound [III]: For example, it is carried out in the presence of an organophosphorus compound according to the method described in JP-A-58-43979. Examples of the organic phosphorus compound used here include
o-Phenylene phosphorochloridate, o-phenylene phosphorofluoride, methyl o-phenylene phosphate, ethyl o-phenylene phosphate, propyl o-phenylene phosphate, isopropyl o-phenylene phosphate, butyl o-phenylene phosphate , Isobutyl o-phenylene phosphate, 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 a salt thereof and the organic phosphorus compound used is about 1 to 5 mol, about 1 to 10 mol, and more preferably about 1 to 3 mol, and 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 addition amount of the base is preferably about 1 to 5 mol per 1 mol of the 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.

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 40] 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 41] 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 42] [Wherein R ² and R ² ′ are the same or different and each represents an amino group, a ureido group, a carbamoyl group, a glycylamino group or a formylamino group], which is a compound [I]. Compound (I) of the present invention is a known penicillin agent, injections, capsules, as well as cefalosporin agents,
It can be administered parenterally or orally as tablets and granules.
The dose is 0.5 to 80 mg / day, preferably 1 to 20 mg / day, more preferably 1 to 20 mg / day per 1 kg of body weight of a person or animal infected with the above-mentioned pathogenic bacteria, and orally administered in 3 to 4 divided doses per day. Good. As the carrier when used as an injection, for example, distilled water, physiological saline, etc. are used, and capsules,
When used as a powder, granules, tablets, known pharmacologically acceptable excipients (for example, starch, lactose, sucrose,
Calcium carbonate, calcium phosphate, etc.), binders (eg starch, gum arabic, carboxymethylcellulose)
, Hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg magnesium stearate, talc etc.), and destructive agents (eg 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. MCI gel CHP-20P 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: Herz DMSO: dimethyl sulfoxide

Test Example 1 Test compound minimum inhibitory concentration (MIC)
concentration) is the agar dilution method
determined by d). 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 overnight incubation at 37 ° C, the minimum concentration of the test compound that completely inhibits the growth of the test strain was determined to be MIC.
And Test bacterium: (1) Staphylococcus aureus 308 A-1 (MSS
A) (2) Staphylococcus aureus N-133 (MRSA) Control Compound 1: Ceftazidime (CAZ) Control Compound 2: Cefpirome (CPR) From these results, the cephem compound [I] of the present invention or 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.

Reference Example 1 N-isopropoxyphthalimide N-hydroxyphthalimide (20.4 g) was dissolved in dimethyl sulfoxide (350 ml) and potassium carbonate (1
7.3 g) was added, and the mixture was stirred at room temperature for 30 minutes. Then 2-bromopropane (11.7 ml) was added, and the mixture was stirred on the bath at 50 ° C for 1 hr. 2-bromopropane (11.7
ml) was added, and the mixture was stirred for another 2 hours on a bath at 50 ° C., added to ice water (1 liter), and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, n-hexane was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (24.6 g). Melting point: 52-53 ° C NMR (DMSO-d ₆ ) δ: 1.28 (6H, d, J = 6.2Hz), 4.44 (1H,
m), 7.86 (4H, s) Elemental analysis value: Calculated value as C ₁₁ H ₁₁ NO ₃ : C, 64.38; H, 5.40; N, 6.83 Actual value: C, 64.44; H, 5.38; N, 6.90

Reference Example 2 Isopropoxyamine Hydrochloride N-isopropoxyphthalimide (22.0 g) was dissolved in ethanol (95 ml), hydrazine monohydrate (5.2 ml) was added, and the mixture was heated under reflux for 5 minutes. Then, concentrated hydrochloric acid (11.4 ml) was added, the mixture was heated under reflux for further 5 minutes, then hot water (37.0 ml) was added and the mixture was returned to room temperature. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as crystals (10.
5g). Melting point: 87-88 ° C NMR (DMSO-d ₆ ) δ: 1.23 (6H, d, J = 6.2Hz), 4.35 (1H,
m), 10.01 (3H, bs ) Elemental analysis: C ₃ H ₉ NO · HCl Calculated: C, 32.30; H, 9.03 ; N, 12.55 Found: C, 32.59; H, 8.88 ; N, 12. 70

Reference Example 3 2- (5-amino-1,2,4-thiadiazole-3-
Yl) -2 (Z) -isopropoxyiminoacetic acid 3- (5-amino-1,2,4-thiadiazol-3-yl) coumarin (7.0 g) was suspended in ethanol (56 ml), and 1N sodium hydroxide was added. (57.1 ml) was added and 4
Stir for 1 hour at 0 ° C. Then, ethyl chlorocarbonate (2.86 ml) was added under ice cooling, the mixture was stirred for 15 minutes, and 1N hydrochloric acid (28.6 ml) and dichloromethane (88 ml) were added. The dichloromethane layer was separated and the aqueous layer was extracted again with dichloromethane. The organic layers were combined, passed through ozone in a dry ice-acetone bath for 1 hour under cooling, and then passed through nitrogen for 15 minutes to remove excess ozone. Sodium acetate (2.
35 g) and methyl sulfide (14 ml) were added and stirred at room temperature until potassium iodide-starch paper showed negative. The reaction solution was extracted with water, the extract was washed with ethyl acetate, and isopropoxyamine hydrochloride (3.47 g) and sodium acetate (2.57 g) were added. After stirring at room temperature for 1.5 hours, sodium acetate (0.7 g) was added and the mixture was washed again with ethyl acetate. Adjust the pH to 1 with concentrated hydrochloric acid under ice cooling,
After adding sodium chloride and saturating, the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was distilled off. Hexane was added to the residue to give the title compound as crystals (4.
86 g). Melting point: 152-154 ° C IR (KBr) cm ^-1 : 3425, 2990, 1720, 1620 NMR (DMSO-d ₆ ) δ: 1.23 (6H, d, J = 6.2Hz), 4.40 (1H,
m), 8.18 (2H, s)

Reference Example 4 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyiminothioacetic acid S-
(2-Benzothiazolyl) ester 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetic acid (4.6
g) was suspended in acetonitrile (120 ml) and tri-n-
Butylamine (10.0 ml) was added dropwise. Then 2-benzothiazolyl disulfide (8.64 g) was added,
Triethyl phosphite (5.14 ml) was added dropwise at 10 ° C. The mixture was stirred at -10 ° to 0 ° C for 2 hr, the precipitated powder was collected by filtration, and washed with cold acetonitrile and hexane to give the title compound (5.52 g). IR (KBr) cm ^-1 : 3400, 3150, 2990, 1700, 1620 NMR (DMSO-d ₆ ) δ: 1.28 (6H, d, J = 6.4Hz), 4.50 (1H,
m), 7.58 (2H, m), 8.07 (1H, m), 8.21 (1H, m), 8.30 (1H, s)

Reference Example 5 Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamido] -3-hydroxymethyl-3-cephem- 4-carboxylate 7β-amino-3-hydroxymethyl-3-cephem-
4-Carboxylic acid (2.30 g) was suspended in water (30 ml), and 1N sodium hydroxide was added under ice cooling to adjust the pH to 8. Then, 2- [5-amino-1,2,4-thiadiazol-3-yl] -2 (Z) -isopropoxyiminothioacetic acid S- (2-benzothiazolyl) ester (4.1
7 g) and tetrahydrofuran (65 ml) were added, and the mixture was stirred at room temperature for 19 hr. Tetrahydrofuran was distilled off under reduced pressure, and the insoluble matter was filtered off. The filtrate was washed with ethyl acetate and then concentrated under reduced pressure to about 10 ml, and MCI gel CHP-20 was used.
It was subjected to P column chromatography. After elution with water, the target fractions were collected, concentrated under reduced pressure and freeze-dried to obtain 3.32 g of the title compound. IR (KBr) cm ^-1 : 3400, 1760, 1660, 1600 NMR (DMSO-d ₆ ) δ: 1.24 (3H, t, J = 7.2Hz), 1.27 (3H,
d, J = 4.4Hz), 3.77 and 4.16 (2H, ABq, J = 12.4Hz), 4.39 (1H,
m), 4.93 (1H, d, J = 5.2Hz), 5.98 (1H, dd, J = 5.2Hz and 8.8H
z), 6.10 (1H, bs), 8.15 (2H, s), 9.39 (1H, d, J = 8.8Hz) Elemental analysis value: C ₁₅ H ₁₇ N ₆ O ₆ S ₂ Na ・ 1.5H ₂ O Calculated value: C, 36.66; H, 4.10; N, 17.10 Measured value: C, 36.58; H, 4.22; N, 17.28

Reference Example 6 N- (1-ethylpropoxy) phthalimide N-hydroxyphthalimide (39.6 g), 3-pentanol (21.4 g), triphenylphosphine (6
Diethylazodicarboxylic acid (42.3 g) was added dropwise to a tetrahydrofuran solution of 3.7 g) under ice cooling. 2 at room temperature
Stir for a while, and add diethyl azodicarboxylic acid (4.
23 g) was added. The solvent was evaporated under reduced pressure with stirring at room temperature for 24 hours. Isopropyl ether was added to the residue and the precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure and ethyl acetate (1
Liter), and the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel chromatography and eluted with dichloromethane-methanol (30: 1) to collect the desired fractions to give the title compound as an oil (28.0).
g). IR (neat) cm ⁻¹ : 2960, 2940, 2875, 1780, 1730 NMR (CDCl ₃ ) δ: 1.05 (6H, t, J = 7.2Hz), 1.73 (4H, m),
4.15 (1H, m), 7.73 (2H, m), 7.85 (2H, m)

Reference Example 7 1-Ethylpropoxyamine Hydrochloride The title compound was obtained from N- (1-ethylpropoxy) phthalimide and hydrazine in the same manner as in Reference Example 2 (yield 59.5%). Melting point: 56-58 ° C NMR (DMSO-d ₆ ) δ: 0.86 (6H, t, J = 7.2Hz), 1.59 (4H, m),
3.99 (1H, m), 11.04 (3H, bs)

Reference Example 8 2- (5-Amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(1-ethylpropoxyimino) acetic acid 3- (5-amino-1,2,4-thiadiazole-3-
The title compound was obtained as crystals from (yl) coumarin and 1-ethylpropoxyamine hydrochloride in the same manner as in Reference Example 3. Melting point: 136-137 ° C. IR (KBr) cm ⁻¹ : 3300, 3200, 1720, 1620 NMR (DMSO-d ₆ ) δ: 0.87 (6H, t, J = 7.4Hz), 1.58 (4H, m),
4.02 (1H, m), 8.18 (2H, s)

Reference Example 9 2- (5-Amino-1,2,4-thiadiazole-3-
Yl) -2 (Z)-(1-ethylpropoxyimino) thioacetic acid S- (2-benzothiazole) ester 2- (5-amino-1,2,4-thiadiazole-3-
In the same manner as in Reference Example 4, the title compound was obtained quantitatively from (yl) -2 (Z)-(1-ethylpropoxyimino) acetic acid. IR (KBr) cm ⁻¹ : 3250, 3100, 2950, 1700, 1610 NMR (DMSO-d ₆ ) δ: 0.89 (6H, t, J = 7.2Hz), 1.64 (4H, m),
4.15 (1H, m), 7.60 (2H, m), 8.06 (1H, m), 8.22 (1H, m),
8.32 (2H, s)

Reference Example 10 Sodium 7β [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(1-ethylpropoxyimino) acetamido] -3-hydroxymethyl-3 -Cephem-4-carboxylate 7β-amino-3-hydroxymethyl-3-cephem-
In the same manner as in Reference Example 5 from 4-carboxylic acid and 2- (5-amino-1,2,4-thiadiazole) -2 (Z)-(1-ethylpropoxyimino) thioacetic acid S- (2-benzothiazolyl) ester. Gave the title compound (41.8)
%). IR (KBr) cm ⁻¹ : 2920, 2360, 1760, 1665 NMR (DMSO-d ₆ ) δ: 0.88 (6H, m), 1.60 (4H, m), 3.21 and
3.45 (2H, ABq, J = 17.6Hz), 3.73 and 4.14 (2H, ABq, J = 12.6Hz),
3.99 (1H, m), 4.93 (1H, d, J = 4.8Hz), 5.57 (1H, dd, J = 4.8
And 8.4Hz), 6.23 (1H, bs), 8.15 (2H, s), 9.35 (1H, d, J = 8.
4 Hz) Elemental _{analysis: C 17 H 21 N 6 O} 6 S 2 Na · 3H 2 O Calculated: C, 37.36; H, 4.98 ; N, 15.3
8 Found: C, 37.53; H, 4.87; N, 15.5.
7

Example 1 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamide] -3- (3-formylaminoimidazo [1 , 2
-B] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical 43] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate (697 mg) A solution of 3,3-formylaminoimidazo [1,2-b] pyridazine (292 mg) in dimethyl sulfoxide (11 ml) was treated with ethyl-o-
Phenylene phosphate (900 mg) in DMSO (0.
3 ml) solution was added dropwise and stirred at room temperature for 24 hours. Ether was added, the supernatant was removed, and the residue was subjected to silica gel column chromatography. Acetone was then eluted with water-containing acetone (30 to 35%) to collect the target fractions and concentrate under reduced pressure. The residue was subjected to MCI gel CHP-20P column chromatography, and eluted with 20% ethanol to collect the target fraction, which was concentrated under reduced pressure and lyophilized to give the title compound (2
25 mg) was obtained. IR (KBr) cm ^-1 : 3400, 1770, 1670, 1640, 1600 NMR (DMSO-d ₆ ) δ: 1.19 (6H, d, J = 6.2Hz), 3.05 and 3.4
0 (2H, ABq, J = 18.4Hz), 4.33 (1H, m), 4.99 (1H, d, J = 4.4H
z), 5.27 and 5.55 (2H, ABq, J = 15.8Hz), 5.66 (1H, dd, J = 4.4H)
z and 8.0Hz), 7.92 (1H, dd, J = 4.4Hz and 9.8Hz), 8.11 (2H, s),
8.52 (1H, s), 8.84 (1H, s), 9.10 (1H, d, J = 4.4Hz), 9.37
(1H, d, J = 9.8Hz ), 9.47 (1H, d, J = 8.0Hz) Elemental _{analysis: C 21 H 22 N 10 O} 5 S 2 · 2.5H 2 O Calculated: C, 41.78; H, 4.51; N, 23.20 Found: C, 41.48; H, 4.37; N, 23.47

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

[Chemical 44] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamide] -3- (3-formylaminoimidazo [1,2]
-B] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate (170 mg) was suspended in methanol (7.5 ml), 1N hydrochloric acid (3.8 ml) was added under ice cooling, and the mixture was stirred at room temperature for 7 hr. It was After adjusting to pH 4 with 1N sodium hydroxide, methanol was distilled off under reduced pressure, and the residue was treated with M
It was subjected to CI gel CHP-20P column chromatography. The target fractions eluted with 20% ethanol were collected, concentrated under reduced pressure and then freeze-dried to obtain the title compound (120 mg). IR (KBr) cm ^-1 : 3400, 1770, 1660, 1610 NMR (DMSO-d ₆ ) δ: 1.20 (6H, d, J = 6.4Hz), 3.02 and 3.4
0 (2H, ABq, J = 16Hz), 4.36 (1H, m), 4.99 (1H, d, J = 4.8Hz),
5.15 and 5.35 (2H, ABq, J = 15.4Hz), 5.64 (1H, dd, J = 4.8Hz and
8.0Hz), 6.39 (2H, s), 7.65 (1H, dd, J = 3.2Hz and 9.6Hz), 7.
87 (1H, s), 8.14 (2H, s), 8.90 (1H, d, J = 3.2Hz), 8.98 (1H,
d, J = 9.6Hz), 9.43 (1H, d, J = 8Hz) Elemental analysis value: Calculated as C ₂₁ H ₂₂ N ₁₀ O ₅ S ₂ · H ₂ O: C, 43.74; H, 4.20; N, 24.29 Found: C, 43.77; H, 4.47; N, 24.58.

Example 3 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamido] -3- (6-amino-3-formyl) Aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate

[Chemical formula 45] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate, 6- Amino-3-formylaminoimidazo [1,2-b] pyridazine and ethyl-o
The title compound was obtained from phenylene phosphate in the same manner as in Example 1 (yield 21.7%). IR (KBr) cm ⁻¹ : 3400, 1770, 1610 NMR (DMSO-d ₆ ) δ: 1.21 (6H, d, J = 6.2Hz), 3.06 and 3.3
8 (2H, ABq, J = 17.2Hz), 4.35 (1H, m), 4.98 (1H, d, J = 4.6H
z), 5.14 and 5.38 (2H, ABq, J = 14.2Hz), 5.65 (1H, dd, J = 4.6H
z and 8.4Hz), 7.16 (2H, s), 7.18 (1H, d, J = 9.8Hz), 8.11 (2
H, s), 8.43 (2H, s), 8.80 (1H, d, J = 9.8Hz), 9.46 (1H, d, J =
8.4 Hz) Elemental _{analysis: C 22 H 23 N 11 O} 6 S 2 · 4.5H 2 O Calculated: C, 38.71; H, 4.72 ; N, 22.57 Found: C, 38.96; H, 4.85 ; N ， 22.38

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

[Chemical formula 46] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamido] -3- (6-amino-3-formylaminoimidazo [1,2] -B] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate was obtained in the same manner as in Example 2 to obtain the title compound (yield 56.4%). IR (KBr) cm ⁻¹ : 3400, 1770, 1610 NMR (DMSO-d ₆ ) δ: 1.21 (6H, d, J = 6.2Hz), 2.98 and 3.3
6 (2H, ABq, J = 17.2Hz), 4.34 (1H, m), 4.98 (1H, d, J = 4.8H
z), 5.02 and 5.21 (2H, ABq, J = 14Hz), 5.63 (1H, dd, J = 4.8Hz
And 8.4Hz), 5.75 (2H, s), 6.97 (2H, s), 6.98 (1H, d, J = 9.8H
z), 7.51 (1H, s), 8.12 (2H, s), 8.52 (1H, d, J = 9.8Hz), 9.
41 (1H, d, J = 8.4Hz) Elemental _{analysis: C 21 H 23 N 11 O} 5 S 2 · 3.5H 2 O Calculated: C, 39.62; H, 4.75 ; N, 24.20 Found: C , 39.45; H, 4.83; N, 24.04

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

[Chemical 47] 7β-Amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylic acid (918 mg) was added to 50% acetone aqueous solution (9 ml).
And tri-n-butylamine (0.951
ml), 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(isopropoxyimino)
Thioacetic acid S- (2-benzothiazolyl) ester (41
7 mg) and tetrahydrofuran (6 ml) were added.
The mixture was stirred at room temperature for 2 hours, subjected to silica gel chromatography, and eluted with hydrous acetone. The target fractions were collected, acetone was removed under reduced pressure, and the residue was subjected to MCI gel CHP-20P chromatography, eluted with 20% ethanol to collect the target fractions, concentrated under reduced pressure, and lyophilized to give the title compound (257 mg). Got IR (KBr) cm ⁻¹ : 3400, 1770, 1670, 1610 NMR (DMSO-d ₆ ) δ: 1.21 (6H, d, J = 6.2Hz), 4.34 (1H, m),
5.00 (1H, d, J = 4.6Hz), 5.27 and 5.48 (2H, ABq, J = 14.4Hz),
5.67 (1H, dd, J = 4.6 and 8.8Hz), 7.97 (1H, dd, J = 4.9 and 9.2H
z), 8.15 (2H, s), 8.77 (2H, s), 9.06 (1H, d, J = 4.4), 9.33
(1H, d, J = 9.2Hz ), 9.46 (1H, d, J = 8.8Hz) Elemental _{analysis: C 21 H 21 N 9 O} 5 S 2 · 3H 2 O Calculated: C, 42.20; H, 4.55; N, 21.09 Found: C, 42.15; H, 4.36; N, 21.23

Example 6 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamide] -3- (6-aminoimidazo [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) -isopropoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylate, 6 The title compound was obtained from -aminoimidazo [1,2-b] pyridazine and ethyl o-phenylene phosphate in the same manner as in Example 1 (yield 29.2%). IR (KBr) cm ^-1 : 3400, 1770, 1610 NMR (DMSO-d ₆ ) δ: 1.21 (6H, d, J = 6.2Hz), 3.03 and 3.36
(2H, ABq, J = 18.2Hz), 4.33 (1H, m), 4.98 (1H, d, J = 5.2Hz),
5.13 and 5.31 (2H, ABq, J = 15.0Hz), 5.65 (1H, dd, J = 5.2 and 8.
8Hz), 7.23 (3H, m), 8.15 (2H, s), 8.18 (1H, d, J = 1.8Hz),
8.33 (1H, d, J = 1.8Hz), 8.76 (1H, d, J = 9.6Hz), 9.47 (1H, d,
J = 8.8 Hz) Elemental _{analysis: C 21 H 22 N 10 O} 5 S 2 · 2.5H 2 O Calculated: C, 41.78; H, 4.51 ; N, 23.20 Found: C, 41.48; H, 4.38 ; N, 23.47

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

[Chemical 49] Sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z)-(1-ethylpropoxyimino) acetamido] -3-hydroxymethyl-3-cephem-4 The title compound was obtained in the same manner as in Example 1 from -carboxylate, 3-formylaminoimidazo [1,2-b] pyridazine and ethyl o-phenylene phosphate (yield 25.5%). IR (KBr) cm ^-1 : 3400, 2970, 1760, 1660 NMR (DMSO-d ₆ ) δ: 0.83 (6H, t, J = 6.6Hz), 1.54 (4H, m),
3.05 and 3.38 (2H, ABq, J = 17.6Hz), 3.96 (1H, m), 4.98 (1H,
d, J = 5.0Hz), 5.28 and 5.52 (2H, ABq, J = 13.8Hz), 5.65 (1H, d
d, J = 5.0 and 8.8Hz), 7.92 (1H, dd, J = 4.2 and 9.8Hz), 8.11 (2
H, s), 8.82 (1H, s), 9.09 (1H, d, J = 4.2Hz), 9.33 (1H, d, J =
9.8Hz), 9.44 (1H, d, J = 8.8Hz) Elemental analysis value: C ₂₄ H ₂₆ N ₁₀ O ₆ S ₂ · 4.5H ₂ O Calculated value: C, 41.43; H, 5.07; N, 20.13 Found: C, 41.92; H, 5.18; N, 20.01.

Example 8 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(1-ethylpropoxyimino) acetamido] -3- (3-amino Imidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 50] 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(1-ethylpropoxyimino) acetamido] -3- (3-formylaminoimidazo [1,2] -B] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate was used as the starting material in the same manner as in Example 2 to obtain the title compound (59.2).
%). IR (KBr) cm ^-1 : 3400, 3180, 1770, 1670, 1610 NMR (DMSO-d ₆ ) δ: 0.84 (6H, t, J = 7.2Hz), 1.54 (4H, m),
3.01 and 3.39 (1H, d, J = 16.8Hz), 4.98 (1H, d, J = 5.2Hz), 5.1
5 and 5.34 (2H, ABq, J = 14.2Hz), 5.65 (1H, dd, J = 5.2 and 8.0H
z), 6.39 (2H, s), 7.64 (1H, dd, J = 4.0 and 9.6Hz), 7.87 (1H,
s), 8.10 (2H, s), 8.90 (1H, d, J = 4.0Hz), 8.97 (1H, d, J = 9.
6Hz), 9.40 (1H, d , J = 8.0Hz) Elemental _{analysis: C 23 H 26 N 10 O} 5 S 2 · 3H 2 O Calculated: C, 43.12; H, 5.03 ; N, 21.86 Found: C, 43.17; H, 5.07; N, 21.64.

Example 9 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)-(1-ethylpropoxyimino) acetamido] -3- (6-amino) Imidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate

[Chemical 51] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(1-ethylpropoxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate, 6-aminoimidazo [1,2-b] pyridazine and ethyl The title compound was obtained from o-phenylene phosphate in the same manner as in Example 1 (yield 21.8%). IR (KBr) cm ^-1 : 3350, 3180, 2970, 1770, 1670, 1610 NMR (DMSO-d ₆ ) δ: 0.85 (6H, t, J = 7.6Hz), 1.59 (4H, m),
3.02 and 3.37 (2H, ABq, J = 17.6Hz), 3.95 (1H, m), 4.98 (1H,
d, J = 4.8Hz), 5.14 and 5.30 (2H, ABq, J = 14.6Hz), 5.65 (1H, d
d, J = 4.8 and 8.4Hz), 7.20 (1H, d, J = 9.6Hz), 7.21 (2H, s),
8.12 (2H, s), 8.15 ((1H, d, J = 1.8Hz), 8.31 (1H, d, J = 1.8H
z), 8.75 (1H, d , J = 9.6Hz), 9.42 (1H, d, J = 8.4Hz) Elemental _{analysis: C 23 H 26 N 10 O} 5 S 2 · 3H calcd ₂ O: C, 43.12; H, 5.03; N, 21.86 Found: C, 42.90; H, 4.92; N, 21.63

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

[Chemical 52] Sodium 7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2 (Z)-(1-ethylpropoxyimino) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylate, imidazo [1,2-b] pyridazine and ethyl o-phenylene The title compound was obtained from phosphate in the same manner as in Example 1 (31.0%). IR (KBr) cm ^-1 : 3400, 3170, 1770, 1665, 1610 NMR (DMSO-d ₆ ) δ: 0.84 (6H, t, J = 7.4Hz), 1.56 (4H, m),
3.06 and 3.53 (2H, ABq, J = 17.0Hz), 3.95 (1H, m), 4.99 (1H,
d, J = 4.8), 5.30 and 5.47 (2H, ABq, J = 14.4Hz), 5.68 (1H, dd, J
= 4.8 and 8.6Hz), 7.96 (1H, dd, J = 4.6 and 9.4Hz), 8.13 (2H,
s), 8.76 (2H, s), 9.05 (1H, d, J = 4.6Hz), 9.30 (1H, d, J = 9.
4Hz), 9.44 (1H, d , J = 8.6Hz) Elemental _{analysis: C 23 H 25 N 9 O} 5 S 2 · 3H 2 O Calculated: C, 44.15; H, 4.99 ; N, 20.15 Found: C, 44.21; H, 5.01; N, 21.36

[0068]

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 a lower alkyl group branched at the α-position. 3. The compound according to claim 1, wherein R ³ is isopropyl. 4. The method of claim 1 R ³ is 1-ethylpropyl
The described compound. 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 an yl 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 is an yl group. 9. embedded image The compound according to claim 1, which may be substituted with a rumilamino group. 10. R ¹ is an amino group and R ³ is isopropyl or 1-ethylpropyl. The compound according to claim 1, wherein R ² and R ² 'are the same or different and each represents a hydrogen atom, an amino group, a carbamoyl group, a ureido group, a glycylamino group or a formylamino group. 11. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamido] -3- (3-aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate. 12. 7β- [2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamide] -3- (3,6-diaminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate The compound according to claim 1, which is 13. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(1-ethylpropoxyimino) acetamido] -3- (3-aminoimidazo [1,2-b] pyridazinium-1-yl)
The compound according to claim 1, which is methyl-3-cephem-4-carboxylate. 14. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(1-ethylpropoxyimino) acetamide] -3- (3,6-
Diaminoimidazo [1,2-b] pyridazinium-1-
2. A compound according to claim 1 which is yl) methyl-3-cephem-4-carboxylate. 15. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamido] -3- (6-aminoimidazo [1,2-b] pyridazinium-1-yl) methyl-3
-Cephem-4-carboxylate. 16. β- [2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamido] -3- (5-aminoimidazo [1,2-a] pyridinium-1-yl) methyl-3-
The compound according to claim 1, which is cephem-4-carboxylate. 17. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z)-(1-ethylpropoxyimino) acetamido] -3- (6-aminoimidazo [1,2-b] pyridazinium-1-yl)
The compound according to claim 1, which is methyl-3-cephem-4-carboxylate. 18. β- [2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2 (Z) -isopropoxyiminoacetamide] -3- (imidazo [1,2-
The compound according to claim 1, which is b] pyridazinium-1-yl) methyl-3-cephem-4-carboxylate. 19. A general formula: [Wherein the symbols 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. 20. The general formula: [Wherein, R ⁵ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group or a halogen atom, and other symbols have the same meanings as 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. 21. An antibacterial composition containing the compound according to claim 1.