TECHNICAL FIELD This invention relates to a novel cephem compound having excellent antibacterial activities on a broad range of Gram-positive and Gram-negative bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA) and bacteria belonging to the genus Pseudomonas , to a method of producing the compound and to an antibacterial composition containing the compound.

BACKGROUND ART Various cephem compounds having, at the 7- position, 2-(5-amino-l,2,4-thiadiazol-3-yl)-2 (Z)- oxyiminoacetamido group have been reported. Namely, compounds having, at the 3-position of the cephem nucleus, tetrazolo[4,5-b]pyridazin-6-ylthiovinyl group are described in USP4,307,116 corresponding to JP-B S62( 1987)-17592, and compounds having, at the 3- position, condensed heterocyclic-thiovinyl group or monocyclic heterocyclic-thiovinyl group containing N as a ring-constituent atom are described in EP-A-630899 corresponding to JP-A H6 ( 1994)-206886. However, no specific compound having, at the 3-position, condensed heterocyclic-thiovinyl group containing N as a ring- constituent atom has been reported yet.

And, (1) in EP-A-229639 corresponding to JP-A S62 ( 1987)-228092, compounds having imidazopyridazinium- thiomethyl group at the 3-position,

(2) in EP-A-192210 corresponding to JP-A S61(1986)- 246189, the alkenyl group substituted with heterocyclic thio group at the 3-position, and

(3) in EP-A-111281 corresponding to JP-A S59(1984)- 130292, compounds having, at the 3-position, monocyclic heterocyclic-thiovinyl group having N as an atom of

forming the ring, are described. In these official patent gazettes, one of the specific examples in each gazette is disclosed as follows, respectively:

So far known cephem compounds are not sufficiently satisfactory in the range and strength of antibacterial activities, especially antibacterial activities against bacterial belonging to the genus Pseudomonas resistant to conventional cephalosporin compounds, Staphylococcus aureus and methicillin resistant Staphylococcus aureus (MRSA) . Circumstances being such, creation of novel compounds overcoming this point has been desired.

DISCLOSURE OF INVENTION Taking the foregoing circumstances into consideration, the present inventors conducted diligent studies extensively and synthesized, for the first

time, a cephem compound characterized by having, at the 3-position of its cephem nucleus, a group of the formula

-CH=CH-S-A ^® wherein A is an optionally substituted group of the formula

(wherein B is a 6-membered aromatic heterocyclic ring having, other than carbon atoms, one or two nitrogen atoms as ring-constituent atoms, and R is an optionally substituted hydrocarbon group), and at the 7-position, a group of the formula

wherein R is an optionally protected amino group, and R is H or a group bonded through a carbon atom, or an ester or salt thereof, and further found that the compound thus synthesized showed unexpectedly broad excellent antibacterial activities, based on its specific chemical structure, against Gram-negative bacteria including the genus Pseudomonas and against Gram-positive bacteria including Staphylococcus aureus and MRSA. Based on these findings, the present invention was accomplished.

More specifically, the present invention relates to (1) a cephem compound of the formula

- 4 -

wherein R is an optionally protected amino group; R ² is H or a group bonded through a carbon atom; and A is an optionally substituted group of the formula

wherein B is a 6-membered aromatic heterocyclic ring having, other than carbon atoms, one or two nitrogen atoms as ring-constituent atoms and R is an optionally substituted hydrocarbon group, or an ester or salt thereof, (2) the compound described in the above (1), wherein R is an amino group optionally protected with C^g alkanoyl, C ₃ . ₅ alkenoyl, C ₆ . ₁₀ aryl-carbonyl, phthaloyl, heterocyclic-carbonyl, C^ _s alkylsulfonyl, camphorsulfonyl, C ₆ . ₁₀ arylsulfonyl, substituted oxycarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, C ₆ . ₁₀ aryl-methyl, di-C ₆ . ₁₀ aryl-methyl, tri-C ₆ . ₁₀ aryl-methyl, C ₆ . ₁₀ aryl- methylene, C ₆ . ₁₀ arylthio group, substituted silyl, 2-C^ ₁₀ alkoxy-carbonyl-1-methyl-l-ethenyl or a group of the formula M'OCO- (wherein M' is an alkali metal),

(3) the compound described in the above (1) , wherein R is amino group,

(4) the compound described in the above (1), wherein R ² is H, an optionally substituted hydrocarbon group or an optionally substituted non-aromatic heterocyclic group,

(5) the compound described in the above (1), wherein R is a C _ ₆ alkyl, C ₂ . ₆ alkenyl or 3- to 7-membered non- aromatic cyclic hydrocarbon group each of which may be substituted with 1 to 4 substituent(s) selected from the group consisting of heterocyclic group, C^ ₆ alkoxy, C ₃ _ ₇ cycloalkyloxy, C ₆ . ₁₀ aryloxy, C ₇ . ₁₉ aralkyloxy, heterocyclic-oxy, mercapto, C _j . ₆ alkylthio, C ₃ . ₁₀ cycloalkylthio, C ₆ . ₁₀ arylthio, C ₇ . ₁₉ aralkylthio, heterocyclic-thio, amino, alkylamino, tri-C _1-6 alkylammonium, C ₃ . ₁₀ cycloalkylamino, C ₆ . ₁₀ arylamino, C ₇ . ₁₉ aralkylamino, heterocyclic-a ino, cyclic-amino, azido, nitro, halogen, cyano, carboxyl, _x . _l0 alkoxy-carbonyl, C ₆ . ₁₀ aryloxy-carbonyl, C ₇ . ₁₉ aralkyloxy-carbonyl, C ₆ . ₁₀ aryl- acyl, C ₆ alkanoyl, C ₃ . ₅ alkenoyl, C ₆ . ₁₀ aryl-acyloxy, C ₂ . ₆ alkanoyloxy, C ₃ . ₅ alkenoyloxy, carbamoyl, thiocarbamoyl, carbamoyloxy, phthalimido, C^ alkanoylamino, C ₆ . ₁₀ aryl-acylamino, alkoxy-carboxamido, C ₆ . ₁₀ aryloxy- carboxamido and C ₇ . ₁₉ aralkyloxy-carboxamido, (6) the compound described in the above (1), wherein R is a Ci_ ₆ alkyl group which may be substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C ₃ . ₇ cycloalkyl, C^ alkoxy, C^ alkylthio, amino, tri-C _1-6 alkylammonium, halogen, carboxyl, C _1-10 alkoxy-carbonyl, carbamoyl, cyano, azido, and a group formed by removing one hydrogen atom bonded to a carbon atom of 5- to 8-membered heterocyclic ring having 1 to 4 hetero-atoms selected from N (which may be oxidized) , 0 and S or a condensed ring thereof, (7) the compound described in the above (1), wherein R ² is (1) a C _1-3 alkyl group, (2) a C _1-3 alkyl group substituted with halogen, hydroxyl, Cι_ ₆ alkoxy, carboxyl, C _1-10 alkoxy-carbonyl or cyano, or (3) allyl group, (8) the compound described in the above (1), wherein

R ² is H, a C _J . _J alkyl group or a C ₃ . ₇ cycloalkyl group,

(9) the compound described in the above (1), wherein R ² is H, a C ₂ _ ₄ alkenyl group, cyclopentyl or a C^ alkyl group which may be substituted with 1 to 3 halogen atoms,

(10) the compound described in the above (1), wherein R ² is cyclopentyl,

(11) the compound described in the above (1), wherein R ² is a Cι_ ₄ alkyl group which may be substituted with 1 to 3 halogen atoms,

(12) the compound described in the above (1), wherein R ² is a alkyl group,

(13) the compound described in the above (1), wherein A ^® is a group of the formula

wherein B is a 6-membered aromatic heterocyclic ring having, other than carbon atoms, one or two nitrogen atoms as ring-constituent atoms; R is a C _x _ ₆ alkyl, C ₂ . ₆ alkenyl or C ₂ . ₆ alkynyl group each of which may be substituted with 1 to 4 substituents selected from the group consisting of heterocyclic group, hydroxyl, C^ alkoxy, C ₃ . ₇ cycloalkyloxy, C ₆ . ₁₀ aryloxy, C ₇ . ₁₉ aralkyloxy, heterocyclic-oxy, mercapto, Ci_ ₆ alkylthio, C ₃ . ₁₀ cycloalkylthio, C ₆ . ₁₀ arylthio, C ₇ _ ₁₉ aralkylthio, heterocyclic-thio, amino, mono-C _j . ₆ alkylamino, di-C^ alkylamino, tri-C^ alkylammonium, C ₃ . ₁₀ cycloalkylamino, C ₆ . ₁₀ arylamino, C ₇ . ₁₉ aralkyla ino, heterocyclic-amino, cyclic-amino, azido, nitro, halogen, cyano, carboxyl, Ci_ ₆ alkoxy-carbonyl, C ₆ . ₁₀ aryloxy-carbonyl, C ₇ . ₁₉ aralkyloxy-carbonyl, C ₆ . ₁₀ aryl- acyl, C _Z - ₆ alkanoyloxy, C ₂ . ₅ alkenoyloxy, cabamoyl,

thiocarba oyl, carbamoyloxy, phthalimido, C^ alkanoylamino, C ₆ . ₁₀ aryl-acylamino, Cι. ₁₀ alkoxy- carboxamido, C ₆ _, ₀ aryloxy-carboxamido and C ₇ . ₁₉ aralkyloxy-carboxamido; and the imidazole ring and/or ring B in the group of the formula [A ¹ ] or [A ² ] may have 1 or 2 substituents selected from the group consisting of hydroxyl, alkyl, Ci_ ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ _ ₁₀ cycloalkyl, C ₅ . ₆ cycloalkenyl, C ₃ . ₁₀ alkyl, C ₆ . ₁₀ aryl, C ₇ . ₁₂ aralkyl, heterocyclic group, C _1-6 alkoxy, C _x _ ₆ alkoxy-C^ alkyl, amino-Cj.e alkoxy, C ₃ . _l0 cycloalkyloxy, C ₆ . ₁₀ aryloxy, C ₇ . ₁₉ aralkyloxy, mercapto, mercapto-Ci. _j alkyl, sulfo, sulfo-C ₆ alkyl, C _1-6 alkylthio, C,_ ₆ alkylthio-Ci. ₆ alkyl, C ₃ . _I0 cycloalkylthio, C ₆ . ₁₀ arylthio, C ₇ . ₁₉ aralkylthio, amino-Cj.β alkylthio, amino, a ino-Ci. ₆ alkyl, mono-C ₆ alkylamino, alkylamino-Ci. ₆ alkyl, di-C^ alkylamino-Ci.e alkyl, C ₃ . ₁₀ cycloalkylamino, C ₆ . ₁₀ arylamino, C ₇ . ₁₉ aralkylamino, cyclic amino, cyclic-a ino-Cj.β alkyl, cyclic-amino-C _j .g alkylamino, acylamino, ureido, Ci_ ₆ alkylureido, azido, nitro, halogen, halogeno-Cj.g alkyl, cyano, cyano-C^ alkyl, carboxyl, carboxy-C^ alkyl, C^ alkoxy- carbonyl, Cj.g alkoxy-carbonyl-C _j .g alkyl, C ₆ . ₁₀ aryloxy- carbonyl, C ₇ . ₁₉ aralkyloxy-carbonyl, C ₆ . ₁₀ aryl-acyl, Ci_ ₆ alkanoyl, C ₂ . ₆ alkanoyl-C ₆ alkyl, C ₃ . ₅ alkenoyl, C ₆ . ₁₀ aryl-acyloxy, C ₂ . ₆ alkanoyloxy, C ₂ . ₆ alkanoyloxy-C^ alkyl, C ₃ . ₅ alkenoyloxy, carbamoyl-Cj.g alkyl, carbamoyl, thiocarbamoyl, carbamoyloxy, carbamoyloxy-C _j .g alkyl, Cj. ₆ alkanoylamino, C ₆ . ₁₀ aryl-acylamino, sulfonamido, carboxamido, C _J^JO alkoxy-carboxamido, C ₆ _ ₁₀ aryloxy- carboxamido and C ₇ . ₁₉ aralkyloxy-carboxamido, (14) the compound described in the above (1), wherein A is an optionally substituted group of the formula

wherein B and R are as defined above,

(15) the compound described in the above (1), wherein A ^® is an optionally substituted imidazo[l,2- a]pyridinium-5-yl group,

(16) the compound described in the above (1), wherein

AΦ is an optionally substituted imidazo[l,2- b]pyridazinium-6-yl group,

(17) the compound described in the above (1), wherein A ^® is an optionally substituted imidazo[l,5- a]pyridinium-5-yl group, (18) the compound described in the above (1), wherein R is a Ci_ ₆ alkyl group which may be substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C ₃ . ₇ cycloalkyl, C^ alkoxy, C^ alkylthio, amino, halogen, carboxyl, C^ _Q alkoxy-carbonyl, carbamoyl, cyano, azido and heterocyclic group,

(19) the compound described in the above (1), wherein R ³ is a C _x . ₃ alkyl group or a C^e alkyl group substituted with hydroxyl, carboxyl or carbamoyl,

(20) the compound described in the above (1), wherein R ³ is methyl, ethyl, 2-hydroxyethyl, carbamoylmethyl, acetonyl or allyl,

(21) the compound described in the above (1), wherein R ³ is methyl or carbamoylmethyl,

(22) the compound described in the above (1), which is a compound of the formula

wherein R is an optionally protected amino group, R is H, a C ₂ _ ₄ alkenyl group, cyclopentyl or a C _j . _* , alkyl group which may be substituted with halogen, A' ^® is a group of the formula

wherein R is a C ₂ . ₄ alkenyl group or a C^ alkyl group which may be substituted with hydroxyl, carboxyl or

₃ " carbamoyl, R is H, amino or carbamoyl, or an ester or salt thereof, (23) the compound described in the above (22), which is a compound of the formula

wherein R is an optionally protected amino group, R ² is H, a C ₂ . _A alkenyl group, cyclopentyl or a C alkyl group which may be substituted with halogen, R ^3'" is a

C ₂ _ ₄ alkenyl group or a C _w alkyl group which may be substituted with carbamoyl, or an ester or salt thereof,

(24) the compound described in the above (23), wherein R is cyclopentyl or a C^ alkyl group which may be substituted with halogen, and R is a C^ alkyl group

which may be substituted with carbamoyl,

(25) the compound described in the above (1), which is 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyl- oxyiminoacetamido]-3-[ (E)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate,

(26) the compound described in the above (1), which is 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-ethoxyimino- acetamido]-3-[ (E)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate, (27) the compound described in the above (1), which is 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-fluorometho- xyiminoacetamido]-3-[ (E)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate,

(28) the compound described in the above (1), which is 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-fluorometho- xyiminoacetamido]-3-[ (E)-2-( 1- carbamoylmethylimidazof1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate,

(29) a method for producing the compound described in the above (1), which comprises reacting a compound of the formula

wherein each symbol has the same meaning as defined above, or an ester or salt thereof, with carboxylic acid of the formula

wherein each symbol has the same meaning as defined

above, or a salt or reactive derivative thereof, if necessary, followed by removal of the protective group, (30) a method for producing the compound described in the above (1), which comprises reacting a compound of the formula

wherein A is a group of the formula

and other symbols have the same meaning as defined above, or an ester of salt thereof, with a compound of the formula R ³ -X wherein X is a leaving group; and R has the same meaning as defined above, if necessary, followed by removal of the protective group,

(31) a method for producing the compound described in the above (1), which comprises deoxidizing a compound of the formula

wherein each symbol have the same meaning as defined above, or an ester or salt thereof, if necessary, followed by removal of the protective group.

(32) An antibacterial composition which comprises an effective amount of the compound described in above (1) and a pharmaceutically acceptable carrier, diluent or excipient, and the like. The cephem compound in the present specification includes a group of compounds named on the basis of "chepham" disclosed in "The Journal of The American Chemical Society" Vol. 84, p.3400 (1962), which means a compound, among the cepham compounds, having a double bond at the 3,4-positions . The compounds of this invention include the compound of the formula [I] showing the free form or an ester or salt thereof (a salt of the compound [I] or a salt of the ester of the compound [I]). In the present specification, hereinafter, unless otherwise specified, the compound of the formula [I] shown in the free form or an ester or salt thereof is simply referred to as the compound [I], the antibacterial compound [I] or the compound of the formula [I]. Accordingly, the compound [I] in the present specification include, usually, not only the free form but also an ester or salt thereof. This is applicable as well to the starting compounds, for example, compounds [II], [III], [V] and [VI] described in the following. R stands for an optionally protected amino group. In the fields of β-lactam and peptide, amino-protective groups have been sufficiently studied, and the method of protecting amino group has been established. In the present invention, as amino-protective groups, those conventional ones can be adequately employed. Examples of amino-protective groups to be employed include optionally substituted C^ alkanoyl groups, optionally substituted C ₃ . ₅ alkenoyl groups, optionally substituted C ₆ . ₁₀ aryl-carbonyl groups, phthaloyl group, heterocyclic-carbonyl groups, optionally substituted Ci_ ₆ alkylsulfonyl groups, camphorsulfonyl group,

optionally substituted C ₆ . ₁₀ arylsulfonyl groups, substituted oxycarbonyl groups, optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, optionally substituted C ₆ . ₁₀ aryl-methyl groups, optionally substituted di-C ₆ . ₁₀ aryl-methyl groups, optionally substituted tri-C ₆ . ₁₀ aryl-methyl groups, optionally substituted C ₆ . ₁₀ aryl-methylene groups, optionally substituted C ₆ . ₁₀ arylthio group, substituted silyl groups, 2-Cι_ ₁₀ alkoxy-carbonyl-1-methyl-l-ethenyl groups and groups represented by the formula M'OCO- (wherein M' is an alkali metal) .

As "optionally substituted C^ alkanoyl groups", use is made of, for example, Cj. ₆ alkanoyl groups which may optionally be substituted with 1 to 3 substituents selected from halogen, oxo, C _j .g alkoxy, C _j _ ₆ alkanoyl,

C ₆ -ιo ^ar y!' halogeno-C ₆ . ₁₀ aryl, C ₆ . ₁₀ aryloxy, halogeno-C ₆ . ₁₀ aryloxy and C ₆ . ₁₀ arylthio. More specifically, use is made of, for example, formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, succinyl, glutaryl, monochloroacetyl, dichloroacetyl, trichloroacetyl, monobromoacetyl, monofluoroacetyl, difluoroacetyl, trifluoroacetyl, monoiodoacetyl, acetoacetyl, 3- oxobutyryl, 4-chloro-3-oxobutyryl, phenylacetyl, p- chlorophenylacetyl, phenoxyacetyl and p- chlorophenoxyacetyl.

As "optionally substituted C ₃ . ₅ alkenoyl groups", use is made of, for example, C ₃ . ₅ alkenoyl groups optionally substituted with 1 to 3 substituents selected from halogen and C ₆ . ₁₀ aryl, more specifically, for example, acryloyl, crotonoyl, aleoyl, cinnamoyl, p-chlorocinnamoyl and β-phenylcinnamoyl.

As "optionally substituted C ₆ . ₁₀ aryl-carbonyl groups", use is made of, for example, C ₆ . ₁₀ aryl- carbonyl groups optionally substituted with 1 to 3 substituents selected from halogen, nitro, hydroxy, C _x _ ₆

alkyl and C^ alkoxy, more specifically, for example, benzoyl, naphthoyl, p-toluoyl, p-tert-butylbenzoyl, p- hydroxybenzoyl, p-methoxybenzoyl, p-tert-butoxybenzoyl, p-chlorobenzoyl and p-nitrobenzoyl. "Heterocyclic group" in "heterocyclic-carbonyl group" means a group formed by removing one hydrogen atom bonded to carbon atom of the heterocyclic ring. The heterocyclic ring means a 5- to 8-membered ring containing 1 to several numbers, preferably 1 to 4 hetero-atoms such as nitrogen atom (which may be oxidized) , oxygen atom and sulfur atom, or a condensed ring thereof. As such heterocyclic group, use is practically made of, for example, 2- or 3-pyrrolyl; 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-oxadiazol-4-yl or 1,2,3-oxadiazol-5- yl; l,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-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-yl or 1,2,3- thiadiazol-5-yl; 1,2,4-thiadiazol-3-yl or 1,2,4- thiadiazol-5-yl; 1,2,5- or 1, 3,4-thiadiazolyl; 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-yl or 3H-indol-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; and benzopyranyl .

As "optionally substituted C _1-6 alkylsulfonyl group", use is made of a Cj_ ₆ alkylsulfonyl group optionally substituted with 1 to 3 substituents selected from, for example, halogen, C ₆ . ₁₀ aryl and C ₆ . ₁₀

aryloxy. More specifically, use is made of, for example, methanesulfonyl and ethanesulfonyl.

As "optionally substituted C ₆ . ₁₀ arylsulfonyl group", use is made of, a C ₆ . ₁₀ arylsulfonyl group optionally substituted with 1 to 3 substituents selected from, for example, halogen, nitro, C _j _ ₆ alkyl and Cj. ₆ alkoxy. More specifically, for example, benzenesulfonyl, naphthalenesulfonyl, p- toluenesulfonyl, p-tert-butylbenzenesulfonyl, p- methoxybenzenesulfonyl, p-chlorobenzensulfonyl and p- nitrobenzenesulfonyl.

Examples of "substituted oxycarbonyl group" include, in addition to a C^ _Q alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, cyclopropyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and norbornyloxycarbonyl) , a C ₆ . ₁₀ aryloxycarbonyl group (e.g. phenoxycarbonyl and naphthyloxycarbonyl) or a C ₇ _ ₁₉ aralkyloxy-carbonyl group (e.g. benzyloxycarbonyl and benzhydryloxycarbonyl), those further having 1 to 3 substituents selected from a Cj_ ₄ alkoxy group (e.g. methoxy and ethoxy) , a Cι_ ₄ acyl group (e.g. acetyl and propionyl), a substituted silyl group (the substituted silyl group described later, e.g. trimethylsilyl and tert-butyldimethylsilyl) , a Cj_ ₄ alkylsulfonyl group (e.g. methanesulfonyl and ethanesulfonyl), halogen (e.g. fluorine, chlorine and bromine), cyano, a Cι_ ₄ alkyl group (e.g. methyl and ethyl) and nitro. Practically, use is made of, for example, ethoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2- trimethylsilylethoxycarbonyl, 2- methanesulfonylethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-cyanoethoxycarbonyl, p- methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, p- chlorophenoxycarbonyl, p-methylbenzyloxycarbonyl, p-

methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, and p-nitrobenzyloxycarbonyl.

As "optionally substituted carbamoyl group", use is made of a carbamoyl group optionally substituted with one or two substituents selected from, for example, a Cι_ ₄ alkyl group (e.g. methyl and ethyl), phenyl group, a C ₇ acyl group (e.g. acetyl, propionyl and benzoyl) and a C^ alkoxy-phenyl group (e.g. methoxyphenyl) . More specifically, use is made of, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N,N- dimethylcarbamoyl, N,N-diethylcarbamoyl, N- phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl and N-(p-methoxyphenyl)carbamoyl.

As "optionally substituted thiocarbamoyl group", use is made of thiocarbamoyl group optionally substituted with one or two substituents selected from, for example, a C ₄ alkyl group (e.g. methyl and ethyl) and phenyl. More specifically, for example, thiocarbamoyl, N-methylthiocarbamoyl and N- phenylthiocarbamoyl are used.

As "optionally substituted C ₆ . ₁₀ aryl-methyl group", use is made of a C ₆ . ₁₀ aryl-methyl group optionally substituted with 1 to 3 substituents selected from, for example, halogen, nitro, C^ ₆ alkyl and C^ alkoxy. More specifically, for example, benzyl, naphthylmethyl, p-methylbenzyl, p- methoxybenzyl, p-chlorobenzyl and p-nitrobenzyl are used.

As "optionally substituted di-C ₆ . ₁₀ aryl-methyl group", use is made of a di-C ₆ . ₁₀ aryl-methyl group optionally substituted with 1 to 3 substituents selected from, for example, halogen, nitro, C _1-6 alkyl and Ci.g alkoxy. More specifically, for example, benzhydryl and di(p-tolyl)methyl are used. As "optionally substituted tri-C ₆ . ₁₀ aryl-methyl

group", use is made of a tri-C ₆ . ₁₀ aryl-methyl group optionally substituted with 1 to 3 substituents selected from, for example, halogen, nitro, C^ alkyl and Ci. ₆ alkoxy. More specifically, for example, trityl and tri(p-tolyl)methyl are used.

As optionally substituted C ₆ . ₁₀ aryl-methylene group", use is made of, a C ₆ . ₁₀ aryl-methylene group optionally substituted with 1 to 3 substituents selected from, for example, halogen, nitro, C^ alkyl and C _x . ₆ alkoxy. More specifically, for example, benzylidene, p-methylbenzylidene and p- chlorobenzylidene are used.

As "optionally substituted C ₆ _ι ₀ arylthio group", use is made of a C ₆ . ₁₀ arylthio group optionally substituted with 1 to 3 substituents selected from, for example, halogen, nitro, Ci_ ₆ alkyl and C ₆ alkoxy. More specifically, for example, o-nitrophenylthio is used.

"Substituted silyl group" forms, together with the amino group to be protected, a group represented by the formula R ^δ R ⁷ R ⁸ SiNH-, (R ⁶ R ⁷ R ⁸ Si) ₂ N- or

Si(R ⁹ R ^1B )

N'

Si(H ^a K ^1Ba )

wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^9a and R ^10a each stand for a C _1-6 alkyl group or a C ₆ . ₁₀ aryl group, and Z ^a stands for a Cj _. , ₃ alkylene group. Herein, as "C^ alkyl group", use is made of, for example, a straight-chain or branched C^ alkyl group such as methyl, ethyl, n- propyl, isopropyl, n-butyl and n-pentyl. As "C ₆ . ₁₀ aryl group", use is made of, for example, phenyl and naphthyl. As "C^ alkylene group", use is made of, for example, methylene, ethylene and propylene.

Preferable examples of "substituted silyl group" include trimethylsilyl, tert-butyl di ethylsilyl and - Si(CH ₃ ) ₂ CH ₂ CH ₂ Si(CH ₃ ) ₂ -.

As the C^ _JO alkoxy of "2-Cj.io alkoxy-carbonyl-1- methyl-1-ethenyl group", use is made of straight-chain, branched or cyclic C^o alkoxy such as methoxy, ethoxy, tert-butoxy or cyclohexyloxy. Specific examples of the 2-C _j .io alkoxy-carbonyl-1-methyl-l-ethenyl group include 2-methoxycarbonyl-l-methyl-l-ethenyl, 2-ethoxycarbonyl- 1-methyl-l-ethenyl, 2-tert-butoxycarbonyl-l-methyl-l- ethenyl, 2-cyclohexyloxycarbonyl-l-methyl-l-ethenyl and 2-norbornyloxycarbonyl-1-methyl-1-ethenyl .

Preferable examples of "alkali metal" shown by M' include sodium and potassium, sodium being especially preferable.

R is preferably amino group, when the anitbacterial activity is taken into consideration.

R stands for H or a group bonded through a carbon atom. Preferable examples of "group bonded through a carbon atom" include an optionally substituted hydrocarbon group (e.g. an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aralkyl group or an optionally substituted cyclic hydrocarbon group) or an optionally substituted non-aromatic heterocyclic group having a bond at the carbon atom. Especially, the optionally substituted alkyl group, the optionally substituted alkenyl group and the optionally substituted cyclic hydrocarbon group are preferable. Preferable examples of "alkyl group" of "optionally substituted alkyl group" include Ci_ ₆ alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl and n-hexyl . Especially, methyl, ethyl and isopropyl are preferable. Preferable examples of

"alkenyl group" of "optionally substituted alkenyl group" include C ₂ . ₆ alkenyl groups such as vinyl, allyl, isopropenyl, methallyl, 1, 1-dimethylallyl, 2-butenyl and 3-butenyl. Examples of "alkynyl group" of "optionally substituted alkynyl group" include C ₂ . ₆ alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl and 2-hexynyl. Preferable examples of "aralkyl group" of "optionally substituted aralkyl group" include C ₇ . ₁₉ aralkyl groups such as benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, naphthyl ethyl and benzhydryl . Preferable examples of "cyclic hydrocarbon group" of "optionally substituted cyclic hydrocarbon group" include 3- to 7-membered non- aromatic cyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2- cyclopenten-1-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl and 3-cyclohexen-l-yl. Especially, C ₃ . ₇ cycloalkyl groups such as cyclobutyl and cyclopentyl are preferable. Preferable examples of "non-aromatic heterocyclic group" of "optionally substituted non- aromatic heterocyclic group" include 3- to 6-membered non-aromatic heterocyclic groups containing, other than carbon atoms, one or two hetero-atoms such as N, O and S; specifically, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl.

Examples of the substituents which the above- mentioned "hydrocarbon group" has include heterocyclic groups, hydroxyl group, Cι_ ₆ alkoxy groups, C ₃ . ₇ cycloalkyloxy groups, C ₆ . ₁₀ aryloxy groups, C ₇ . ₁₉ aralkyloxy groups, heterocyclic-oxy groups, mercapto group, Cj. ₆ alkylthio groups, C ₃ . ₁₀ cycloalkylthio groups, C ₆ . ₁₀ arylthio groups, C ₇ . ₁₉ aralkylthio groups, heterocyclic-thio groups, amino group, mono-C ₁ . ₆ alkylamino groups, di-Cι_ ₆ alkylamino groups, tri-C _j .j

alkylammonium groups, C ₃ . ₁₀ cycloalkylamino groups, C ₆ . ₁₀ arylamino groups, C ₇ . ₁₉ aralkylamino groups, heterocyclic amino groups, cyclic-amino groups, azido group, nitro group, halogen atoms, cyano group, carboxyl group, C,_ ₁₀ alkoxy-carbonyl groups, C ₆ . ₁₀ aryloxy-carbonyl groups, C ₇ . ₁₉ aralkyloxy-carbonyl groups, C ₆ . ₁₀ aryl-acyl groups, C _l . ₆ alkanoyl groups, C ₃ . ₅ alkenoyl groups, C ₆ . ₁₀ aryl-acyloxy groups, C ₂ . ₆ alkanoyloxy groups, C ₃ . ₅ alkenoyloxy groups, optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, optionally substituted carbamoyloxy groups, phthalimido group, C ₆ alkanoylamino groups, C ₆ . ₁₀ aryl-acylamino groups, C ₁₀ alkoxy-carboxamido groups, C ₆ . ₁₀ aryloxy-carboxamido groups and C ₇ . ₁₉ aralkyloxy-carboxamido groups . The number of these substituents, which may be the same as or different from one another, ranges from 1 to 4.

Among specific examples of the substituents of "hydrocarbon group", "Cι _. _ ₆ alkoxy group" includes e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert- butoxy, n-pentyloxy and n-hexyloxy; "C ₃ . ₁₀ cycloalkyloxy group" includes e.g. cyclopropyloxy and cyclohexyloxy; "C ₆ -ιo ^ar yl° ^χ y group" includes e.g. phenoxy and naphthyloxy; "C ₇ . ₁₉ aralkyloxy group" includes e.g. benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy and benzhydryloxy; "Cj.g alkylthio group" includes e.g. methylthio, ethylthio, n-propylthio and n-butylthio; "C ₃ -ιo cycloalkylthio group" includes cyclopropylthio and cyclohexylthio; "C ₆ . ₁₀ arylthio" includes e.g. phenylthio and naphthylthio; "C ₇ . ₁₉ aralkylthio group" includes e.g. benzylthio, phenylthio and benzhydrylthio; "mono-Ci. ₆ alkylamino group" includes e.g. methyla ino, ethylamino, n-propylamino and n- butylamino; "di-C^g alkylamino group" includes e.g. dimethylamino, diethylamino, methylethylamino, di-(n-

propyl)amino and di-(n-butyl)amino; alkyl ammonium group" includes e.g. tri ethyl ammonium; "C ₃ . ₁₀ cycloalkylamino group" includes e.g. cyclopropylamino, cyclopentylamino and cyclohexylamino; "C ₆ . ₁₀ arylamino group" includes e.g. anilinσ and N-methylanilino; "C ₇ . ₁₉ aralkylamino group" includes e.g. benzylamino, 1- phenylethylamino, 2-phenylethylamino and benzhydrylamino; "cyclic amino group" includes e.g. pyrrolidino, piperidino, piperazino, morpholino and 1- pyrrolyl; "halogen atom" includes fluorine, chlorine, bromine and iodine; "Cj. ₁₀ alkoxy-carbonyl group" includes e.g. methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and norbornyloxycarbonyl; "C ₆ _ ₁₀ aryloxy-carbonyl group" includes e.g. phenoxycarbonyl and naphthyloxycarbonyl; "C ₇ . ₁₉ aralkyloxy-carbonyl group" includes e.g. benzyloxycarbonyl and benzhydryloxycarbonyl; "C ₆ _ ₁₀ aryl-acyl group" includes e.g. C ₆ . ₁₀ aryl-carbonyl group such as benzoyl, naphthoyl, phthaloyl and phenylacetyl; "C,_ ₆ alkanoyl group" includes e.g. formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, succinyl and glutaryl; "C ₃ . ₅ alkenoyl group" includes e.g. acryloyl, crotonoyl and maleoyl; "C ₆ . ₁₀ aryl-acyloxy group" includes e.g. C ₆ . ₁₀ aryl-carbonyloxy group such as benzoyloxy, naphthoyloxy and phenylacetoxy; "C ₂ . ₆ alkanoyloxy group" includes e.g. acetoxy, propionyloxy, butyryloxy, valeryloxy and pivaloyloxy; and "C ₃ . ₅ alkenoyloxy group" includes e.g. acryloyloxy and crotonoyl. As "optionally substituted carbamoyl group", use is made of, for example, carbamoyl group optionally substituted with one or two substituents selected from, for example, C ₄ alkyl group (e.g. methyl and ethyl), phenyl group, C^ acyl group (e.g.

acetyl, propionyl and benzoyl) and Cι__, alkoxy-phenyl group (e.g. methoxyphenyl) , and cyclic aminocarbonyl group, more specifically, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N-(p-methoxyphenyl)carbamoyl, pyrrolidinocarbonyl, piperidionocarbonyl, piperazinocarbonyl and morpholinocarbonyl . As "optionally substituted thiocarbamoyl group", use is made of thiocarbamoyl group optionally substituted with one or two substituents selected from, for example, C^ alkyl group (e.g. methyl and ethyl) and phenyl group, for example, thiocarbamoyl, N-methylthiocarbamoyl and N-phenylthiocarbamoyl . As "optionally substituted carbamoyloxy group", use is made of carbamoyloxy group optionally substituted with one or two substituents selected from, for example, Cι__, alkyl group (e.g. methyl and ethyl) and phenyl, more specifically, exemplified by carbamoyloxy, N-methylcarbamoyloxy, N,N- dimethylcarbamoyloxy, N-ethylcarbamoyloxy and N- phenylcarbamoyloxy. As "C^ alkanoylamino", mention is made of, for example, acetamido, propionamido, butyramido, valeramido and pivalamido; as "C ₆ . ₁₀ aryl- acylamino group, mention is made of, for example, C ₆ . ₁₀ aryl-carbonylamino group such as benzamido, naphthoylamido and phthalimido; as "C _j .^ alkoxy- carboxamido group", mention is made of, for example, methoxycarboxamido (CH ₃ OCONH-), ethoxycarboxamido and tert-butoxycarboxamido; as "C ₆ . ₁₀ aryloxy-carboxamido group", mention is made of, for example, phenoxycarboxamido (C ₆ H ₅ OCONH-) ; and, as "C ₇ . ₁₀ aralkyloxy-carboxamido group", mention is made of, for example, benzyloxycarboxamido (C ₆ H ₅ CH ₂ OCONH-) and benzhydryloxycarboxamido. The heterocyclic group of the heterocyclic group, heterocyclic-oxy group, heterocyclic-thio group and

heterocyclic-amino group in the substituents of "hydrocarbon group" means a group formed by removing one hydrogen atom bonded to the carbon atom of heterocyclic ring, and the heterocyclic ring includes 5- to 8-membered ring containing one to several hetero- atoms, preferably 1 to 4 hetero-atoms, e.g. nitrogen atom (which may be oxidized) , oxygen atom and sulfur atom. Examples of such heterocyclic groups 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-oxadiazol-4- yl or 1,2, 3-oxadiazol-5-yl; 1,2,4-oxadiazol-3-yl or l,2,4-oxadiazol-5-yl; 1,2,4- or 1, 3,4-oxadiazolyl; 2-, 4- or 5-thiazolyl; 3-, 4- or 5-isothiazolyl; 1,2,3- thiadiazol-4-yl or 1,2, 3-thiadiazol-5-yl; 1,2,4- thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl; 1,2,5- or 1, 3,4-thiadiazolyl; 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-yl or 3H-indol-3-yl; 2-, 3- or 4-pyranyl; 2-, 3- or 4-thiopyranyl; benzopyranyl; quinolyl; pyrido[2,3-d]pyrimidinyl; 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2 , 7-naphthylidyl; thieno[2,3-d]pyridyl; pyrimidopyridyl; pyrazinoquinolyl; and benzopyranyl.

As substituents which "alkyl group" of the "optionally substituted alkyl group", "alkenyl group" of the "optionally substituted alkenyl group", "aralkyl group" of the "optionally substituted aralkyl group" and "cyclic hydrocarbon group" of the "optionally substituted cyclic hydrocarbon group" may optionally have, use is made of, for example, those similar to the substituents which "hydrocarbon group" of the above- mentioned "optionally substituted hydrocarbon group"

may optionally have.

Preferable examples of the said "optionally substituted hydrocarbon group" include C,_ ₆ alkyl groups (e.g. methyl, ethyl, n-propyl and isopropyl) optionally substituted with one to three substituents selected from, for example, hydroxyl group, C ₃ . ₇ cycloalkyl group (e.g. similar ones to those described above), C^ alkoxy group (e.g. similar ones to those described above), C^g alkylthio group (e.g. similar ones to those described above), amino group, tri-C^ alkylammonium group (e.g. similar ones to those described above), halogen atom (e.g. similar ones to those described above), carboxyl group, C _x . ₁₀ alkoxycarbonyl group (e.g. similar ones to those described above), optionally substituted carbamoyl group, cyano group, azido group and heterocyclic group (e.g. similar ones to those described above), more specifically exemplified by cyclopropylmethyl, methoxymethyl, ethoxymethyl, 1- methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2- hydroxyethy1, methylthiomethyl, 2-aminoethyl, 2-

(trimethylammonium)ethyl, 2-(triethylammonium)ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2-difluoroethyl, chloroethyl, chloromethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2- trichloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2- trifluoroethyl, carboxymethyl, 1-carboxyethyl, 2- carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1- carboxybutyl, cyanomethyl, 1-carboxy-l-methylethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert- butoxycarbonylmethyl, 1-methoxycarbonyl-l-methylethyl, 1-ethoxycarbonyl-l-methylethyl, 1-tert-butoxycarbonyl- 1-methylethyl, 1-benzyloxycarbonyl-l-methylethyl, 1- pivaloyloxycarbonyl-1-methylethyl, carbamoylmethyl, 2- azidoethyl, 2-(pyrazolyl)ethyl, 2-(imidazolyl)ethyl, 2- (2-oxopyrrolidin-3-yl)ethyl, 2-amino-4 or 5- thiazolylmethyl, 5-amino-l,2,4-thiadiazol-3-ylmethyl,

l-carboxy-l-(2,3,4-trihydroxyphenyl)methyl and 2-oxo-3- pyrrolidyl. The number of the substituent of said "hydrocarbon group" is not limited to one but may be plural (2 to 4) independently. Most preferable examples of "optionally substituted hydrocarbon group" include straight-chain and branched C^ alkyl groups such as methyl, ethyl, n-propyl and isopropyl; straight-chain or branched C^ alkyl groups substituted with, for example, halogen atom, hydroxyl group, C _{ _ ₆ alkoxy group, carboxyl group, C^ _K , alkoxycarbonyl group or cyano group, as exemplified by fluoromethyl, 2- fluoroethyl, 2-chloroethyl, 2-hydroxyethyl, 2- methoxyethyl, cyanomethyl, carboxyπiethyl, tert- butoxycarbonyl ethyl, 1-carboxy-l-methylethyl, 1-tert- butoxycarbonyl-1-methylethyl; and allyl group. As non-aromatic heterocyclic group of said "optionally substituted non-aromatic heterocyclic group having a bond at the carbon atom", use is made of, among others, 3- to 6-membered non-aromatic heterocyclic groups containing, other than carbon atoms, one or two hetero-atoms such as nitrogen atom, oxygen atom or sulfur atom, as exemplified by oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl . As substituents of "optionally substituted non-aromatic heterocyclic group having a bond at the carbon atom", mention is made of, for example, the hydrocarbon groups exemplified for said "optionally substituted hydrocarbon group" and their substituents.

As preferable groups of R , mention is made of, for example, hydrogen atom or optionally substituted hydrocarbon groups, especially, for example, C^ alkyl groups (e.g. methyl, ethyl, propyl and isopropyl), and C ₃ . ₇ cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl) .

R is preferably H, a C ₂ . _A alkeny group (e.g. allyl), cyclopentyl or a C^ alkyl group (e.g. methyl, ethyl, propyl, isopropyl) which may be substituted with 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine), more preferably a fluoro-C,__, alkyl group (e.g. fluoromethyl, 2-fluoroethyl) .

In the present invention, the substituent A is an optionally substituted group of the formula

wherein B is a 6-membered aromatic heterocyclic ring having, other than carbon atoms, one or two nitrogen atoms as ring-constituent atoms, and R is an optionally substituted hydrocarbon group. The 6- membered aromatic heterocyclic ring for B means a 6- membered aromatic heterocyclic ring whose hetero atom(s) is/are one or two nitrogen atoms.

Practical examples of the group [A ] include the following.

Practical examples of the group [A ] include the following.

Among these groups, are more preferable, for example,

ιιaιdasα[l,2-a]pyrιdmιuaι-5-yl group ( )

imidazo[l, 2-b]pyridaziniura-6-yl group ( )

and iι.idazo[ l , 5-a]pyridinium-5-yl qroup )

In the above formulae [A ¹ ], [A ] and their practical examples, while the positive charge of s is localized, for convenience' sake, on the nitrogen atom at the 3-position of the imidazole ring, it is localized, depending on cases, on the nitrogen atom at the 1-position. And, when the monovalent positive charge is non-localized on the imidazole ring, it may, depending on cases, non-localized on the whole condensed ring. Therefore, the above case of

can be shown by the following

Since the position of this positive charge varies with, for example, the state of the compound [I] (solid or in a solution), kinds of solvent, pH, temperature and kinds of substituent, the present invention includes all the cases where the positive charge is localized on the nitrogen atom and where the nitrogen atom is non- localized on the imidazole ring or the whole condensed ring.

As "optionally substituted hydrocarbon group" shown by R , use is made of similar ones to "optionally substituted hydrocarbon group" exemplified for the above-mentioned R .

More preferable examples of "optionally substituted hydrocarbon group" shown by R ³ include C^g alkyl groups (C ₆ alkyl group means methyl, ethyl, n- propyl, isopropyl, etc.) optionally substituted with one to three substituents selected from, for example, hydroxyl group, C ₃ . ₇ cycloalkyl group, C _1-6 alkoxy group, Ci_ ₆ alkylthio groups, amino group, halogen atom, carboxyl group, Cι. ₁₀ alkoxycarbonyl group, optionally substituted carbamoyl group, cyano group, azido group and heterocyclic group, which are more specifically exemplified by cyclopropylmethyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1- ethoxyethyl, 2-hydroxyethyl, ethylthiomethyl, 2- aminoethyl, 2-fluoroethyl, 2,2-difluoroethyl, chloromethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2- trichloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2- trifluoroethyl , carboxymethyl, 1-carboxyethyl, 2- carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1- carboxybutyl, cyanomethyl, 1-carboxy-l-methylethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-

butoxycarbonylmethyl, 1-methoxycarbonyl-l-methylethyl, 1-ethoxycarbonyl-l-methylethyl, 1-tert-butoxycarbonyl- 1-methylethyl, 1-benzyloxycarbonyl-l-methylethyl, 1- pivaloyloxycarbonyl-1-methylethyl, carbamoylmethyl, N- methylcarbamoylmethyl, N,N-dimethylcarbamoylmethyl, 2- azidoethyl, 2-(pyrazolyl)ethyl, 2-(imidazolyl)ethyl, 2- (2-oxopyrrolidin-3-yl)ethyl and l-carboxyl-l-(2 ,3,4- trihydroxyphenyl)methyl . The number of said substituents of "hydrocarbon group" is not limited to one, but may be plural (2 to 4) independently. Most preferable examples of "optionally substituted hydrocarbon group" include straight-chain and branched Cj. ₃ alkyl groups such as methyl, ethyl, n-propyl and isopropyl, and straight-chain C^g alkyl groups optionally substituted with 1 to 3 substituents selected from halogen atom, hydroxyl group, Ci. alkoxy group, carboxyl group, C _M0 alkoxycarbonyl group, cyano group and carbamoyl group, which are exemplified by 2- fluoroethyl, 2-chloroethyl, 2-hydroxyethyl, 2- methoxyethyl, cyanomethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, carbamoylmethyl, N-methylcarbamoylmethyl and N,N- dimethylcarbamoylmethyl .

As R , Ci_ ₃ alkyl groups (e.g. methyl and ethyl) are preferable.

The group represented by the formula [A ¹ ] or [A ² ], may have, preferably, one or two substituents at its imidazole ring or/and ring B. Examples of these substituents include hydroxyl group, hydroxy-Cj.g alkyl group, Cj. alkyl group, C ₂ . ₆ alkenyl group, C ₂ . ₆ alkynyl group, C ₃ _ι ₀ cycloalkyl group, C ₅ . ₆ cycloalkenyl group, C ₃ . ₁₀ cycloalkyl-Ci.g alkyl group, C ₆ . ₁₀ aryl group, C ₇ . ₁₂ aralkyl group, heterocyclic group, Cj._ ₆ alkoxy group, Cι_ ₆ lkoxy-Ci.g alkyl group, amino-C _x . ₆ alkoxy group, C ₃ . ₁₀ cycloalkyloxy group, C ₆ . ₁₀ aryloxy group, C ₇ . ₁₉ aralkyloxy

group, mercapto group, mercapto-Ci.g alkyl group, sulfo group, sulfo-Ci.g alkyl group, Cj. alkylthio group, C _j .g alkylthio-Cj.g alkyl group, C ₃ . ₁₀ cycloalkylthio group, Cg. ₁₀ arylthio group, C ₇ . ₁₉ aralkylthio group, alkylthio group, amino group, a ino-Ci. alkyl group, mono-Cj. alkylamino group, di-Ci. alkylamino group, mono-Cj.g alkylamino group, di-C _j .g alkylamino- Cj _. _ ₆ alkyl group, C ₃ . ₁₀ cycloalkylamino group, C ₆ . ₁₀ arylamino group, C ₇ . ₁₉ aralkylamino group, cyclic-amino group, cyclic-amino-Cj.g alkyl group, cyclic-amino-C _j .g alkylamino group, ureido group, C^g alkylureido group, azido group, nitro group, halogen atom, alkyl group, cyano group, alkyl group, carboxyl group, carboxy-Ci.g alkyl group, C _J . _JQ alkoxy- carbonyl group, Cι_ ₁₀ alkoxy-carbonyl-C _j .g alkyl group, Cg-io aryloxy-carbonyl group, C ₇ . ₁₉ aralkyloxy-carbonyl group, C ₆ . ₁₀ aryl-acyl group, Cι_ ₆ alkanoyl group, C ₂ . ₆ alkanoyl-Ci.g alkyl group, C ₃ . ₅ alkenoyl group, C ₅ . ₁₀ aryl- acyloxy group, C ₂ . ₆ alkanoyloxy group, C ₂ . ₆ alkanoyloxy- Cj. alkyl group, C ₃ . ₅ alkenoyloxy group, alkyl group, carbamoyl group, thiocarbamoyl group, carbamoyloxy group, carba oyloxy-Ci.g alkyl group, Cι_ ₆ alkanoylamino group, C ₆ . ₁₀ aryl-acylamino group, sulfona ido group, carboxamido group, C _! . ₁₀ alkoxy- carboxamido group, C ₆ . ₁₀ aryloxy-carboxamido group and C ₇ . ₁₉ aralkyloxy-carboxamido group.

As "Ci.g alkyl group", straight-chain or branched C _j .g alkyl groups, for example, are preferable, and use is made of, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl and n-hexyl .

As "C ₂ . ₆ alkenyl group", straight-chain or branched C ₂ . ₆ alkenyl groups, for example, are preferable, and use is made of, for example, vinyl, allyl, 1-propenyl,

isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, methallyl and 1, 1-dimethylallyl.

As "C ₂ . ₆ alkynyl group", straight-chain or branched C ₂ . ₆ alkynyl groups, for example, are preferable, and use is made of, for example, thienyl, 1-propynyl and propargyl.

As "C ₃ . ₁₀ cycloalkyl group", C ₃ . ₁₀ 3- to 7-membered alicyclic hydrocarbon groups, for example, are preferable, and use is made of, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl .

As "C ₅ . ₆ cycloalkenyl group", 5- to 6-membered cyclic hydrocarbon groups having double bond, for example, are preferable, and use is made of, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl .

^As "C .io aryl group", use is made of, for example, phenyl, α-naphthyl, β-naphthyl and biphenylyl .

As "C ₇ . ₁₂ aralkyl group", use is made of, for example, 1-phenylethyl, 2-phenylethyl, phenylpropyl and naphthylmethyl.

As "Ci.g alkoxy group", use is made of, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, tert-butoxy, n-pentyloxy and hexyloxy. As "C ₃ . ₁₀ cycloalkyloxy group", use is made of, for example, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and norbornyloxy.

As "amino-Ci.g alkoxy group", use is made of, for example, aminomethoxy, 2-aminoethoxy and 3- aminopropoxy.

As "C ₆ . ₁₀ aryloxy group", use is made of, for example, phenoxy and naphthyloxy.

As "C ₇ . ₁₉ aralkyloxy group", use is made of, for example, benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, naphthylmethyloxy, benzhydryloxy and trityloxy.

As "C _l . ₆ alkylthio group", use is made of, for

example, methylthio, ethylthio, n-propylthio and n- butylthio.

As "amino-C ₆ alkylthio group", use is made of, for example, aminomethylthio, 2-aminoethylthio and 3- aminopropylthio.

^As " ₃ -ιo cycloalkylthio group", use is made of, for example, cyclopropylthio and cyclohexylthio.

^As "C ₆ .ιo arylthio group", use is made of, for example, phenylthio and naphthylthio. As "C ₇ . ₁₉ aralkylthio group", use is made of, for example, benzylthio, phenylethylthio, benzhydrylthio and tritylthio.

As "hydroxy-Cj.g alkyl group", use is made of, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl .

As "C ₃ . ₁₀ cycloalkyl-Ci.g alkyl group, use is made of, for example, cyclopropylmethyl, cyclopropylethyl and cyclobutylmethyl.

As "mercapto-Ci.g alkyl group", use is made of, for example, mercaptomethyl, 1-mereaptoethyl and 2- mercaptoethyl .

As "Cι_ ₆ alkoxy-Ci.g alkyl group", use is made of, for example, methoxymethyl, ethoxymethyl and 2- methoxyethyl . As "Cj.g alkylthio-Ci.g alkyl group", use is made of, for example, methylthiomethyl and 2- methylthioethyl .

As "amino-Cj.g alkyl group", use is made of, for example, aminomethyl, 2-aminoethyl and 3-aminopropyl . As "mono-Cj.g alkylamino-Cx.g alkyl group", use is made of, for example, methylaminomethyl, ethylaminomethyl, 2-(N-methylamino)ethyl and 3-(N- methylamino)propyl .

As "di-C _I . ₆ alkylamino-C _j . alkyl group", use is made of, for example, N,N-dimethylaminomethyl, N,N- diethylamino ethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-

diethylamino)ethyl and 3-(N,N-dimethylamino)propyl.

Preferable cyclic-amino groups of "cyclic-amino-

Cj.g alkyl group" are cyclic-amino groups described in the following. As "cyclic-amino-Ci.g alkyl group", use is made of, for example, pyrrolidinomethyl, piperidino ethyl, piperazinomethyl, morpholinomethyl and 2-(morpholino)ethyl.

Preferable cyclic-amino-Cx.g alkyl groups of

"cyclic-amino-Cj.g alkylamino group" are cyclic-amino-Ci. ₆ alkyl groups described above, and, as "cyclic-amino-

C,_ ₆ alkylamino group", use is made of, for example, pyrrolidinoethylamino, piperidinoethylamino, piperazinoethylamino and morpholinoethylamino.

As "halogeno-Ci.g alkyl group", use is made of, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,

2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl,

2-bromoethyl and 2-iodoethyl. As alkyl group", use is made of, for example, cyanomethyl and 2-cyanoethyl.

As "carboxy-Cj.g alkyl group, use is made of, for example, carboxymethyl, 1-carboxyethyl and 2- carboxyethyl. As alkyl group", use is made of, for example, sulfomethyl and 2-sulfoethyl.

As the alkanoyl group of "C ₂ . ₆ alkanoyl-C ₆ alkyl group", Cj.g alkanoyl groups to be described later are preferable. As "C ₂ . ₆ alkanoyl-C g alkyl group", use is made of, for example, acetylmethyl, 1-acetylethyl and

2-acetylethyl.

As the alkanoyloxy group of "C ₂ . ₆ alkanoyloxy-Cj.g alkyl group", C ₂ . ₆ alkanoyloxy groups to be described later are preferable. As "C ₂ . ₆ alkyl group", use is made of, for example, acetoxymethyl, 1-

acetoxyethyl and 2-acetoxyethyl.

As the alkoxycarbonyl group of "C^ _Q alkoxy- carbonyl-Cx. alkyl group", Cι_ ₁₀ alkoxy-carbonyl groups to be described later are preferable. As "C _j ., ₀ alkoxy- carbonyl C _x _ ₆ alkyl group", use is made of, for example, methoxycarbonyl, ethoxycarbonyl and tert- butoxycarbonylmet yl.

As "carba oyloxy-Cj.g alkyl group", use is made of, for example, carbamoyloxymethyl. As "mono-Cj. alkylamino group", use is made of, for example, methylamino, ethylamino, n-propylamino, n- butylamino, tert-butylamino, n-pentylamino and n- hexylamino.

As "di-Cj.g alkylamino group", use is made of, for example, dimethylamino, diethylamino, methylethylamino, di-(n-propyl)amino and di-(n-butyl)amino.

As "C ₃ _ ₁₀ cycloalkylamino group", use is made of, for example, cyclopropylamino, cyclopentylamino and cyclohexylamino. As "C ₆ . ₁₀ arylamino group", use is made of, for example, anilino and N-methylanilino.

As "C ₇ . ₁₉ aralkylamino group", use is made of, for example, benzylamino, 1-phenylethylamino, 2- phenylethylamino, benzhydrylamino and tritylamino. "Cyclic-amino group" means a group formed by removing one hydrogen atom bonding to the ring-forming nitrogen atom of the N-containing heterocyclic ring or of the group formed by saturating the double bond of the N-containing heterocyclic ring, and, as the cyclic amino group, use is made of, for example, lH-tetrazol- 1-yl, lH-pyrrol-1-yl, pyrrolino, pyrrolidino, 1H- imidazol-1-yl, imidazolino, imidazolidino, lH-pyrazol- 1-yl, pyrazolino, pyrazolidino, piperidino, piperazino and morpholino. The alkyl group of "C^ _o alkoxy-carbonyl group" includes, besides C ₆ alkyl groups (e.g. similar ones

to those mentioned above), C ₃ _ ₁₀ cycloalkyl groups (e.g. similar ones to those mentioned above. As "C _J . _JQ alkoxy-carbonyl group", use is made of, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and norbornyloxycarbonyl .

As "Cg. ₁₀ aryloxy-carbonyl group", use is made of, for example, phenoxycarbonyl and naphthyloxycarbonyl.

As "C ₇ . ₁₉ aralkyloxy-carbonyl group", use is made of, for example, benzyloxycarbonyl, benzhydryloxycarbonyl and trityloxycarbonyl.

As the substituted sulfonyl group of "sulfonamido group", use is made of "C^ alkylsulfonyl group", for example, methanesulfonyl and ethanesulfonyl.

As "halogen atom", use is made of, for example, fluorine, chlorine and bromine.

As "Ci. alkylureido group", use is made of, for example, methylureido, ethylureido and n-propylureido.

As "Cg. ₁₀ aryl-acyl group", use is made of, for example, phenylacetyl.

As "Cι_ ₆ alkanoyl group", use is made of, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl .

As "C ₃ _ ₅ alkenoyl group", use is made of, for example, acryloyl, crotonoyl and maleoyl .

As "Cg. ₁₀ aryl-acyloxy group", use is made of, for example, phenylacetyloxy. As "C ₃ _ ₅ alkenoyloxy group", use is made of, for example, acryloyloxy, crotonoyloxy and maleoyloxy.

As "carbamoyl-Ci. alkyl group", use is made of, for example, carbamoylmethyl and 2-carbamoylethyl .

As "Cj.g alkanoylamino group", use is made of, for example, formylamino and acetylamino.

As "C ₆ . ₁₀ aryl-acylamino group", use is made of, for example, phenylacetylamino.

As "C,_ ₁₀ alkoxy-carboxamido group", use is made of, for example, methoxycarboxamido and ethoxycarboxamido.

As "C ₆ . ₁₀ aryloxy-carboxamido group", use is made of, for example, phenyloxycarboxamido.

As "C ₇ . ₁₉ aralkyloxy-carboxamido group", use is made of, for example, benzyloxycarboxamido. "Heterocyclic group" means a group formed by removing one hydrogen atom bonded to the carbon atom of the heterocyclic ring. Examples of such heterocyclic ring include a 5- to 8-membered ring containing one to several number, preferably 1 to 4, of hetero-atoms, e.g. nitrogen atom (which may be oxidized), oxygen atom and sulfur atom. Practical examples of such heterocyclic group to be used 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-oxadiazol-4-yl or 1,2, 3-oxadiazol- 5-yl; 1,2, 4-oxadiazol-3-yl or 1,2 ,4-oxadiazol-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-yl or 1,2,3- thiadiazol-5-yl; 1,2,4-thiadiazol-3-yl or 1,2,4- thiadiazol-5-yl; 1,2,5- or 1, 3,4-thiadiazol; 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-N-oxide; pyrazinyl; 2-, 3- or 4-piperidinyl; piperazinyl; 3H-indol-2-yl or 3H- indol-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- naphthylidyl; thieno[2 ,3-d]pyridyl; pyrimidopyridyl; pyrimidopyridyl; pyrazinoquinolyl; and benzopyranyl.

Preferable examples of the compound [I] include a

- 37 -

compound of the formula [I-a]

[wherein symbols are of the same meanings as defined above], an ester or salt thereof. Most preferable compounds of the formula [I-a] are those wherein (1) R is amino group, R ² is a C,_ ₆ alkyl group (e.g. methyl, ethyl, propyl and isopropyl) and R is a Cι_ ₆ alkyl group (e.g. methyl, ethyl, propyl and isopropyl) or (2) R is amino group, R ² is a C ₃ . ₆ cycloalkyl group (e.g. cyclopentyl) and R ³ is a Ci.g alkyl group (e.g. methyl, ethyl, propyl and isopropyl) .

More preferable examples of the compound [I] include a compound of the formula

wherein R is an optionally protected amino group, R is H, a C ₂ . alkenyl group, cyclopentyl or a Cι_ ₄ alkyl group which may be substituted with halogen, A' Φ is a group of the formula

wherein R is a C ₂ . ₄ alkenyl group or a Cj_ ₄ alkyl group which may be substituted with hydroxyl, carboxyl or carbamoyl, R is H, amino or carbamoyl, or an ester or

salt thereof.

Most preferable examples of the compound [I-b] include a compound of the formula

wherein R 1 is an optionally protected amino group, R 2 ' is H, a C ₂ _ ₄ alkenyl group, cyclopentyl or a C^ alkyl group which may be substituted with halogen, R ^3' is a C ₂ .i, alkenyl group or a C _1-4 alkyl group which may be substituted with carbamoyl, or an ester or salt thereof. R is preferably cyclopentyl or a C _j . ₄ alkyl group which may be substituted with halogen and R ^{3 "} is preferably a Cj _. .., alkyl group which may be substituted with carbamoyl.

In the above-mentioned compound [I], the mark Θ attached on the right shoulder of -COO at the 4- position shows that the carboxyl group is carboxylate anion and forms, making a pair with the positive charge on the substituent A, an internal salt. On the other hand, the compound [I] may optionally form a pharmaceutically acceptable ester or salt. As the pharmaceutically acceptable salt, use is made of, for example, inorganic basic salts, ammonium salts, organic basic salts, inorganic acid addition salts, organic acid addition salts and basic amino acid salts. As the inorganic base capable of forming an inorganic basic salt, use is made of, for example, alkali metal salts (e.g. sodium and potassium) and alkaline earth metals (e.g. calcium); as the organic base capable of forming an organic basic salt, use is made of, for example, procaine, 2-phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine,

trishydroxymethylaminomethane, polyhydroxyalkylamine and N-methylglucosamine; as an inorganic acid capable of forming an inorganic acid addition salt, use is made of, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; as an organic acid capable of forming an organic acid addition salt, use is made of, for example, p- toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid and maleic acid; and, as a basic amino acid capable of forming a basic amino acid salt, use is made of, for example, lysine, arginine, ornithine and histidine. Among these salts, basic salts (i.e. inorganic basic salts, ammonium salts, organic basic salts and basic amino acid salts) mean those capable of being formed in the case where an acid group such as carboxyl group and sulfo group exists in the substituents R ¹ , R ² , R ³ or A ^® of the compound [I] or where carboxyl group exists at the 4-position; and acid addition salts (i.e. inorganic acid addition salts and organic acid addition salts) mean those capable of being formed in the case where a basic group such as amino group, monoalkylamino group, dialkylamino group, cycloalkylamino group, arylamino group, aralkylamino group, cyclic amino group and N-containing heterocyclic group exists in the substituents R 1, R 2, R3 or AΘ of the compound [I]. And, the acid addition salts include salts in which one mol. of acid is added to the moiety forming the internal salt of the compound [I], i.e. the carboxylate moiety (C00 ^θ ) at the 4-position and CH=CH- A ^® moiety at the 3-position to form a salt in which the 4-position is carboxyl group (COOH) and the 3-position of CH=CH-A ^® -Y [wherein Y ^θ stands for anion formed by removing proton Hφ from inorganic acid or organic acid, the anion being exemplified by chloride ion, bromide ion, sulfate ion, p-toluenesulfonate ion, methanesulfonate ion and trifluoroacetate ion] . Ester

derivatives of the compound [I] mean esters producible by esterifying the carboxyl group in the molecule which are utilizable as intermediate of the synthesis and are metabolically unstable and non-toxic esters. Examples of the ester utilizable as intermediate include optionally substituted Cι_ ₆ alkyl ester, C ₂ . ₆ alkenyl ester, C ₃ . ₁₀ cycloalkyl ester, C ₃ . ₁₀ cycloalkyl-Cj.g alkyl ester, optionally substituted C ₆ . ₁₀ aryl ester, optionally substituted C ₇ . ₁₂ aralkyl ester, di-C ₆ . ₁₀ aryl- methyl ester, tri-C ₆ . ₁₀ aryl-methyl ester and substituted silyl ester.

As "optionally substituted C^g alkyl ester", use is made of, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl and n-hexyl, which may be substituted with one to three of, for example, benzyloxy, Cι _. _ ₄ alkyl sulfonyl (e.g. methyl sulfonyl), trimethyl silyl, halogen (e.g. fluorine, chlorine and bromine), acetyl, nitrobenzoyl, mesylbenzoyl, phthalimido, succinimide, benzenesulfonyl, phenylthio, di-C^ alkylamino (e.g. dimethylamino), pyridyl, C alkyl sulfinyl (e.g. methyl sulfinyl) and cyano. Examples of such groups include benzyloxymethyl, 2-methylsulfonylethyl, 2- trimethylsilylethyl, 2,2,2-trichloroethyl, 2-iodoethyl, acetylmethyl, p-nitrobenzoylmethyl, p- mesylbenzoylmethyl, phthalimidomethyl, succinimidomethyl, benzenesulfonylmethyl, phenylthiomethyl, dimethylaminoethyl, pyridine-oxido-2- methyl, methylsulfinylmethyl and 2-cyano-1,1- dimethylethyl.

As the C ₂ _ ₆ alkenyl group forming "C ₂ . ₆ alkenyl ester", use is made of, for example, vinyl, allyl, 1- propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, methallyl, 1,1-dimethylallyl and 3-methyl-3-butenyl. As the C ₃ . ₁₀ cycloalkyl group forming "C ₃ . ₁₀ cycloalkylester", use is made of, for example,

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl.

As the C ₃ . ₁₀ cycloalkyl-Cj.g alkyl group forming "C ₃ _ ₁₀ cycloalkyl-C,_ ₆ alkyl ester", use is made of, for example, cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl.

As "C ₆ . ₁₀ aryl group" forming "optionally substituted C ₆ . ₁₀ aryl ester", use is made of, for example, phenyl, α-naphthyl, β-naphthyl and biphenylyl, which may optionally be substituted with one to three of, for example, nitro and halogen (e.g. fluorine, chlorine and bromine) . Such groups as above are specifically exemplified by p-nitrophenyl and p- chlorophenyl . As "C ₇ . ₁₂ aralkyl group" forming "optionally substituted C ₇ . ₁₂ aralkyl ester", use is made of, for example, benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl and naphthylmethyl, which may optionally be substituted with one to three of, for example nitro, Cj. ₄ alkoxy (e.g. methoxy), C^ alkyl (e.g. methyl and ethyl) and hydroxy. Specific examples of such groups include p-nitrobenzyl, p-methoxybenzyl and 3,5-di-tert- butyl-4-hydroxybenzyl .

As the di-C ₆ . ₁₀ aryl-methyl group forming "di-C ₆ . ₁₀ aryl-methyl ester", use is made of, among others, benzhydryl . As the tri-C ₆ . ₁₀ aryl-methyl group forming tri C ₆ . ₁₀ aryl-methyl ester, use is made of, among others, trityl . As the substituted silyl group forming substituted silyl ester, use is made of, for example, trimethylsilyl, tert-butyldimethylsilyl and -

Si(CH ₃ ) ₂ CH ₂ CH ₂ Si(CH ₃ ) ₂ -. The above-mentioned esters include ester at 4-position. The compound, wherein the 4-position is the above-mentioned ester group, forms a salt in which the 3-position is CH=CH-S-A ^® -Y ^θ [wherein each symbol is of the same meaning as defined above] .

The present invention includes, besides the above-

described ester derivatives, phamacologically acceptable compounds convertible into the compound [I] in a living body.

Where [A 1] or [A 2] shown by Aφ has amino group as the substituent, the amino group may optionally be substituted. As substituents on the amino group, use is made of, for example, protective groups of the optionally protected amino groups shown by R ¹ .

The compound [I] of this invention includes a solvate thereof. As the solvent of the solvate, use is made of, for example, water; alcohols such as methanol, ethanol, propanol, isopropanol and the like; ketones such as acetone and the like; ethers such as tetrahydrofuran, dioxane and the like. The compound [I] and starting compounds of this invention include cis-isomer (Z-compound), trans-isomer (E-compound) and a cis-trans mixture. The compound [I] of this invention is preferably a trans-isomer (E- compound) . Referring to the compound [I], the cis-isomer (Z- compound) , for example, means one of the geometrical isomers having the partial structure represented by the formula [VII], and the trans-isomer means a geometrical isomer having the partial structure represented by the formula [VIII].

CVI ID (VT i n

Preferable examples of the compound [I] are set forth as follows:

(1) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- cyclopentyloxyiminoacetamido]-3-[ (E)-2-(1- methylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3-

cephem-4-carboxylate,

(2) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2 (Z)- cyclopentyloxyiminoacetamido]-3-[ (E)-2-( 1- ethylimidazo[ 1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate,

(3) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- cyclopentyloxyiminoacetamido]-3-[ (E)-2-( 1- carbamoylmethylimidazo[ 1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate, (4) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- cyclopentyloxyiminoacetamido]-3-[ (E)-2-( 1- hydroxyethylimidazof1,2-b]pyridazinium-6-yl)thio]vinyl- 3-cephem-4-carboxylate,

(5) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- isopropoxyiminoacetamido]-3-[ (E)-2-( 1- methy1imidazo[ 1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate,

(6) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- isopropoxyiminoacetamido]-3-[ (E)-2-( 1-ethylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate,

( 7 ) 7β-[2-(5-amino-l,2 ,4-thiadiazol-3-yl)-2 (Z )- isopropoxyiminoacetamido]-3-[ (E)-2-( 1- carbamoylmethylimidazof 1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate, (8) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- isopropoxyiminoacetamido]-3-[ (E)-2-( 1- hydroxyethy1imidazo[1,2-b]pyridazinium-6-yl)thio]vinyl- 3-cephem-4-carboxylate, ( 9 ) 7β-[2-(5-amino-l,2 ,4-thiadiazol-3-yl)-2 (Z)- ethoxyiminoacetamido]-3-[ (E)-2-( 1-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate, (10) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- ethoxyiminoacetamido]-3-[ (E)-2-( 1-ethylimidazo[ 1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate, (11) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- ethoxyiminoacetamido]-3-[ (E)-2-(l-

carbamoylmethylimidazo[ 1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate,

(12) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- ethoxyiminoacetamido]-3-[ (E)-2-( 1- hydroxyethylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl- 3-cephem-4-carboxylate,

(13) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- fluoromethoxyiminoacetamido]-3-[ (E)-2-( 1- methylimidazo[ 1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate,

( 14) 7β-[2-(5-amino-l,2 ,4-thiadiazol-3-yl)-2 (Z)- fluoromethoxyiminoacetamido]-3-[ (E)-2-( 1- ethylimidazo[ 1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate, (15) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- fluoromethoxyiminoacetamido]-3-[ (E)-2-( 1- carbamoylmethylimidazo[ 1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate,

(16) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- fluoromethoxyiminoacetamido]-3-[ (E)-2-( 1- hydroxyethy1imidazo[ 1,2-b]pyridazinium-6-yl)thio]vinyl- 3-cephem-4-carboxylate,

(17) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-(2- fluoroethoxyimino)acetamido]-3-[ (E)-2-( 1- methylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate,

( 18) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- methoxyiminoacetamido]-3-[ (E)-2-( l-methylimidazo[ 1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate, and

(19) 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- methoxyiminoacetamido]-3-[ (E)-2-( 1- carbamoylmethylimidazo[ 1, 2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate. Methods of producing the compound [I] of this invention are hereinafter described in detail.

Method ( 1 ) :

The compound [I] can be synthesized by reacting, for example, a 7-amino compound of the formula [II]

wherein symbols are of the same meaning as defined above, or an ester or salt thereof with carboxylic acid of the formula

wherein symbols are of the same meaning as defined above (hereinafter referred to as R ^b 0H) or a salt or reactive derivative thereof.

This method comprises acylation of the 7-amino compound [II] with carboxylic acid R OH or a salt or reactive derivative thereof. In this method, the carboxylic acid R OH in the free state or in the form of a salt or reactive derivative thereof can be used as an agent for acylating the amino group at 7-position of the 7-amino compound [II]. More specifically, carboxylic acid R OH or its reactive derivatives such as inorganic basic salts, organic basic salts, acid halides, acid azides, acid anhydrides, mixed acid anhydrides, active amides, active ester and active thioesters of carboxylic acid R ^b OH are used for the acylation. Examples of inorganic basic salts include alkali metal salts (e.g. sodium salt and potassium salt) and alkaline earth metal salts (e.g. calcium salt); examples of organic basic salts include

trimethylamine salt, triethylamine salt, tert- butyldimethylamine salt, dibenzylmethyla ine salt, benzyldimethyla ine salt, N,N-dimethylaniline salt, pyridine salt and quinoline salt; examples of acid halides include acid chloride and acid bromide; examples of mixed acid anhydrides include mono C _l . ₆ alkyl carbonate mixed acid anhydride (e.g. mixed acid anhydride of carboxylic acid R ^b OH with, for example, monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monoisobutyl carbonate, mono tert-butyl carbonate, monobenzyl carbonate, mono(p- nitrobenzyl)carbonate or monoallyl carbonate), C^g aliphatic carboxylic acid mixed anhydride (e.g. mixed acid anhydride of carboxylic acid R ^b OH with, for example, acetic acid, trichloroacetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid or acetoacetic acid) , C ₇ . ₁₂ aromatic carboxylic acid mixed anhydride (e.g. mixed acid anhydride of carboxylic acid R OH with, for example, benzoic acid, p-toluic acid or p-chlorobenzoic acid) and organic sulfonic acid mixed anhydride (e.g. mixed acid anhydride of carboxylic acid R OH with, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p- toluenesulfonic acid) ; and examples of active amides include amide with an N-containing heterocyclic compound (e.g. acid amide of carboxylic acid R OH with pyrazole, imidazole or benzotriazole, and these N- containing heterocyclic compounds may optionally be substituted with, for example, C^ alkyl group (e.g. methyl and ethyl), C ₆ alkoxy group (e.g. methoxy and ethoxy), halogen atom (e.g. fluorine, chlorine and bromine), oxo group, thioxo group, or C _1-6 alkylthio group (e.g. methylthio and ethylthio) . As the active ester, any one usable for this purpose in the field of

synthesizing β-lactam and peptide can be utilized, examples of which include, besides organic phosphoric acid ester (e.g. diethoxyphosphoric acid ester and diphenoxyphosphoric acid ester), p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimdie ester, N- hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-l-hydroxybenzotriazole ester and 1-hydroxy-lH- 2-pyridone ester. As the active thioester, mention is made of ester with an aromatic heterocyclic thiol compound [e.g. 2-pyridylthiol ester or 2- benzothiazolylthiol ester, and these heterocyclic ring may optionally be substituted with a C _ι _ ₆ alkyl group (e.g. methyl or ethyl), a Cj.g alkoxy group (e.g. methoxy or ethoxy), a halogen atom (e.g. fluorine, chlorine or bromine), or a C^g alkylthio group (e.g. methylthio or ethylthio) . On the other hand, the 7- amino compound [II] can be used in the free state, as a salt or ester thereof. Examples of salts of the 7- amino compound [II] include inorganic basic salts, ammonium salts, organic basic salts, inorganic acid addition salts and organic acid addition salts. Examples of inorganic basic salts include alkali metal salts (e.g. sodium salt and potassium salt) and alkaline earth metal salts (e.g. calcium salt); examples of organic basic salts include trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N,N-dimethylaniline salt, pyridine salt and quinoline salt; examples of inorganic acid addition salts include hydrochloride, hydrobromide, sulfate, nitrate and phosphate; and examples of organic acid addition salts include formate, acetate, trifluoroacetate, methanesulfonate and p-toluenesulfonate. As the ester of 7-amino compound [II], mention is made of esters already described as the ester derivatives of compound

[I], as exemplified by, more specifically, C, _. _ ₆ alkyl ester, C ₂ . ₆ alkenyl ester, C ₃ . ₁₀ cycloalkyl ester, C ₃ . ₆ cycloalkyl-Ci.g alkyl ester, C ₆ . ₁₀ aryl ester, C ₇ . ₁₂ aralkyl ester, di-C ₆ . ₁₀ arylmethyl ester, tri-C ₆ . ₁₀ arylmethyl ester and C ₂ . ₆ alkanoyloxy-C _j . alkyl ester. The starting compound R OH, its salts and reactive derivatives can readily be produced by known methods (e.g. methods disclosed in JPA S60( 1985)-231684 or JPA S62( 1987)-149682) or methods analogous thereto. The reactive derivative of carboxylic acid R ^b 0H can be allowed, after isolating from the reaction mixture, to react with the 7-amino compound [II], or the reaction mixture containing the reactive derivative of carboxylic acid R OH can be allowed, as it is, to react with the 7-amino compound [II]. When carboxylic acid R OH is used in the sate or free acid or salt, a proper condensing agent is employed. As the condensing agent, use is made of N,N'-disubstituted carbodiimides such as N,N'-dicyclohexylcarbodiimide; azolides such as N,N'- carbonyldiimidazole and N,N'-thiocarbonyldiimidazole; a dehydrating agent such as N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline, phosphorus oxychloride and alkoxyacetylene; and 2-halogenopyridinium salts such as 2-chloropyridinium methyliodide and 2-fluoropyridinium methyliodide. When these condensing agents are used, the reaction is considered to proceed via a reactive derivative of carboxylic acid ROH. The reaction is conducted generally in a proper solvent which does not hamper the reaction. As the solvent, use is made of ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether; esters such as ethyl formate, ethyl acetate and n-butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane; hydrocarbons such as n-hexane, benzene and toluene;

amides such as formamide, N,N-dimethyIformamide and N,N-dimethylacetamide; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitriles such as acetonitrile and propionitrile; and, besides, dimethyl sulfoxide, sulfolane, hexamethyl phosphoramide and water, for example, are employed singly or as a mixture solvent. The amount of an acylating agent (R ^b OH) to be used ranges usually from about 1 to 5 mol., preferably from about 1 to 2 mol . , relative to one mol. of the 7-amino compound [II]. The reaction is conducted at temperatures ranging from about -80 to 80°C, preferably from about -40 to 50°C, most preferably from about -30 to 30°C. The reaction time depends on the kinds of 7-amino compound [II] and carboxylic acid R OH, kinds of solvent (when a mixed solvent is employed, the mixing ratio) and reaction temperature, and ranges usually from about 1 minute to 72 hours, preferably from about 15 minutes to 3 hours. When acid halide is employed as the acylating agent, the reaction can be conducted in the presence of a deacidifier for the purpose of eliminating liberated hydrogen halogenide from the reaction mixture. Examples of the deacidifier include inorganic base such as sodium carbonate, potassium carbonate, calcium carbonate and sodium hydrogencarbonate; tertiary amine such as triethylamine, tri(n-propyl)amine, tri(n- butyl)amine, diisopropylethylamine, cyclohexyl dimethylamine, pyridine, lutidine, γ-collidine, N,N- dimethylaniline, N-methylpiperidine, N- methylpyrrolidine and N-methylmorpholine; and alkylene oxide such as propylene oxide and epichlorohydrin.

The starting 7-amino compound [II] of this reaction or an ester or salt thereof can be produced by, for example, the following steps: the compound [IX] of the formula

wherein R is a protecting group of carboxyl group, R is a protecting group of amino group, and other symbols are of the same meaning as defined above, is allowed to react with an optionally substituted imidazole compound, forming a condensed ring at 2 ,3-positions or 3,4-positions, represented by the formula [IV]

wherein symbols are of the same meaning as defined above, to give the compound represented by the formula [X]

wherein symbols are of the same meaning as defined above, or a salt thereof, then

S-oxide is reduced by the method described in, for example, JPA S55( 1980)-154978 to give the compound of the formula [XI]

wherein symbols are of the same meaning as defined

above, or a salt thereof, followed by allowing the compound [XI] to react with a compound represented by the formula R -X (X stands for halogen atom) to remove the protecting group from the compound of the formula [XII]

wherein symbols are of the same meaning as defined above.

As the carboxyl-protecting group shown by R , mention is made of the above-mentioned ester. Especially, readily removable carboxyl-protecting groups, which are conventionally employed in this field, such as tri(lowerJalkylsilyl group e.g. trimethylsilyl group, benzhydryl group, p-methoxybenzyl group, tert-butyl group, p-nitrobenzyl group and phenacyl group, are preferable.

As the amino-protecting group shown by R , mention is made of the above-mentioned amino-protecting group. Especially, tri(lower)alkylsilyl groups such as trimethylsilyl group; acyl type protecting groups such as formyl group, trifluoroacetyl group, acetyl group, tert-butoxycarbonyl group, methoxy acetyl group, benzyloxy carbonyl group and p-nitrobenzyloxy carbonyl group; and aralkyl type protecting group such as benzyl group, benzhydryl group and trityl group are preferable.

Preferable examples of X include halogen atoms such as chlorine, bromine and iodine; acyloxy groups such as acetoxy, propionyloxy, butyryloxy and 3- oxobutyryloxy; alkylsulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; and arylsulfonyloxy groups such as benzenesulfonyloxy,

naphthalenesulfonyloxy, p-toluenesulfonyloxy, p-tert- butylbenzenesulfonyloxy, p-methoxybenzenesulfonyloxy, p-chlorobenzenesulfonyloxy and p- nitrobenzenesulfonyloxy. Especially, benzenesulfonyloxy and p-toluenesulfonyloxy groups are preferable.

As the imidazole compound [IV], use is practically made of the following:

As substituents on the imidazole compound [IV], use is made of those already mentioned as substituents on the above-described group A ^® . The imidazole compound [IV] is also used as a salt thereof. Examples of the salt include alkali metal salts such as lithium salt, sodium salt and potassium salt; and addition salts with trialkylamine such as triethylamine and diisopropylamine. The general method for synthesizing the imidazole compound [IV] and salts thereof are known, as exemplified by methods disclosed in EP-225634 and EP-381132 or methods analogous thereto. These

compounds can be readily produced by those methods .

The full nucleophilic substitution reaction between the compound [IX] and the compound [IV] is conducted, in general cases, preferably in an inactive solvent, as exemplified by ketones such as acetone; halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile; alcohols such as methanol, ethanol and n-propanol; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. The amount of the nucleophilic reagent [IV] to be used ranges usually from 1 to 5 mol., preferably from about 1 to 3 mol. relative to 1 mol. of the compound [IX]. The reaction temperature ranges from 0°C to 100°C, preferably from 10°C to 50°C. The reaction time ranges from 30 minutes to 24 hours, preferably from 1 to 10 hours. This reaction can be accelerated by the addition of a base or a salt. As the base and the salt, mention is made of, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; and organic amine including trialkylamine such as triethylamine and and diisopropylethylamine. And, as the salt, use is made of, for example, quaternary ammonium salt such as tetrabutyl ammonium salt.

Examples of the halogen compound represented by R ³ X to be reacted with the compound (X) include C _1-6 lower alkyl halide, C ₂ . ₆ lower alkenyl halide, C ₂ . ₆ lower alkynyl halide, hydroxy lower alkyl halide, carboxy lower alkyl halide, carbamoyl lower alkyl halide and lower alkenoyl lower alkyl halide. As the above- mentioned halides, mention is made of chloride, bromide and iodide. The reaction between the compound [X] and R ³ X is usually conducted preferably in an inactive

solvent, for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile; alcohols such as methanol, ethanol and n- propanol; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. The amount of RX to be employed ranges from 1 to 20 mol., preferably from 5 to 10 mol. The reaction time ranges from 1 to 48 hours, preferably from 5 to 24 hours. The protective group of the compound [XI] obtained as above, when the protecting group is tri(lower)alkylsilyl group, can be removed by processing the compound with water. When the protective group is, for example, benzhydryl group, trityl group, p-methoxybenzyl group, tert-butyl group, tert-butoxycarbonyl group or formyl group, it can be removed by processing the compound with, for example, formic acid, hydrochloric acid, trifluoroacetic acid, phenol or cresol .

By the above-mentioned deprotection reaction, the 7-amino compound [II] can be obtained. Method (2): A method of producing the compound described in the above (1), which comprises allowing, for example, a compound of the formula [III]

wherein n denotes 0 or 1, and other symbols are of the same meaning as defined above, to react with an imidazole compound forming a condensed ring on the 2,3- position or 3,4-position of the formula

wherein symbols are of the same meaning as defined above, to produce a compound of the formula [V]

wherein A is

and other symbols are of the same meaning as defined above, which is then allowed to react with a halogen compound of the formula R X to produce a compound of the formula [VI]

wherein symbols are of the same meaning as defined above, followed by removing the protective group. The nucleophilic substitution between the compound

[III] and the compound [IV] can be conducted under substantially the same conditions as those for the reaction between the compound [IX] and the compound

[IV] in Method (1) . To produce quaternary ammonium salt of the compound [V] by the reaction with R X can be conducted

under substantially the same conditions as those for the reaction between the compound [X] and R ³ X in Method (1). The protective group on the compound [VI] thus obtained can be removed by the method described in Method (1) to lead to the compound [I] of this invention.

Method (3): A method of producing the compound described in (1) above, which is characterized by allowing, for example, a compound represented by the formula [III]

wherein symbols are of the same meaning as defined above, to react with an imidazolium compound forming a condensed ring on 2,3-position or 3,4-position of the formula [VII]

wherein symbols are of the same meaning as defined above, to produce a compound of the formula [VI], followed by removing the protective group. The reaction between the compound [III] and the compound [VII] can be conducted under substantially the same conditions as those between the compound [IX] and the compound [IV] in (1) described above. The protective group on the compound [VI] thus obtained can be removed by the method described in Method (1) to obtain the compound of the formula [I] of this

invention.

The compound [III] can be produced by allowing a compound of the formula [XIII]

wherein symbols are of the same meaning as defined above, to react with carboxylic acid represented by the formula

wherein symbols are of the same meaning as defined above or a salt or reactive derivative thereof, in substantially the same manner as in Method (1) .

Further, the compound [VII] in this production method can be produced by allowing the compound [IV] to react with a halogen compound represented by R X under substantially the same conditions as those for leading the compound [XI] to the corresponding quaternary ammonium salt in Method (1).

In the above-described Methods (1) to (3), when necessary, by conducting removal of the protective group and purification, the object compound [I] of this invention can be obtained. On the method of removing the protective group and the purification method, explanation is given hereinafter.

Method of removing the protective group: As described in the foregoing, amino-protective groups have been sufficiently studied in the fields of β-

lactam and peptide synthesis, and the protection method and the deprotection method have already been established. In the present invention also, for removing the protective group, conventional technique can be utilized as it is. For example, a monohalogenoacetyl group (e.g. chloroacetyl and bromoacetyl) can be removed by using thiourea; an alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl) can be removed by using an acid (e.g. hydrochloric acid); an aralkyloxycarbonyl group (e.g. benzyloxycarbonyl, p- methylbenzyloxycarbonyl and p-nitrobenzyloxycarbonyl) can be removed by means of catalytic reduction; and 2 ,2 ,2-trichloroethoxycarbonyl can be removed by using zinc and an acid (e.g. acetic acid). On the other hand, even in the case where the compound [I] is esterified as an intermediate for the synthesis, the ester residual group can be removed by a per se known method or an analogous method thereto. For example, 2- methylsulfonylethyl ester can be removed by using alkali; aralkyl ester (e.g. benzyl ester, benzhydryl ester, p-methoxybenzyl ester and p-nitrobenzyl ester) can be removed by using an acid (e.g. trifluoroacetic acid) or by means of catalytic reduction; 2,2,2- trichloroethyl ester can be removed by using zinc and an acid (e.g. acetic acid); and silyl ester (e.g. trimethylsilyl ester and tert-butyldimethylsilyl ester) can be removed by using only water.

For the reduction of S-oxide, a method established in the field of β-lactam can be employed, and, in the present invention also, a conventional technique can be utilized as it is. For example, phosphorus trichloride and phosphorus tribromide can be employed.

Purification of the compound [I]: The compound [I] produced in the reaction mixture by any method described in detail in Methods (1) to (3) or, depending

on necessity, followed by conducting the above- mentioned removal of the protective group, can be isolated and purified by means of a conventional process such as extraction, column chromatography, precipitation and recrystallization. On the other hand, it is also possible that the compound [I] thus isolated can be converted to a desired physiologically acceptable salt by a conventional method.

The compound [I] of this invention has antibacterial activities of a broad spectrum and can be used safely for prophylaxis and therapy of various diseases, in man and mammals (e.g. mouse, rat, rabbit, dog, cat, cow and pig), caused by pathogenic bacteria, for example, respiratory infection and urinary tract infection. Characteristic features of the antibacterial spectrum of the antibacterial compound [I] are as follows, among others: (1) showing a remarkably high activity against a variety of Gram- negative bacteria, (2) having high activities against Gram-positive bacteria (e.g. Staphylococcus aureus and Corynebacterium diphtheriae , ,

(3) having high activities against ethicillin- resistant Staphylococcus aureus (MRSA) , (4) showing remarkable effects against Pseudomonas aeruσinosa which is not sensitive to the therapy by using common cephalosporin-type antibiotics, and (5) having high activities even against a number of β- lactamase-producing Gram-negative bacteria (e.g. genera Escherichia, Enterobacter and Proteus , .

Besides, the antibacterial compound [I] of this invention has such characteristic features as (1) having excellent stability, (2) showing high concentration in blood, (3) showing long duration of effects and (4) being remarkable in tissue-transition. The compound [I] of this invention can be

administered, like known penicillin preparations or cephalosporin preparations, non-orally or orally as injectable preparations, capsules, tablets or granular preparations (injectable preparations are especially preferable). The daily dose ranges from 0.5 to 80 mg, preferably from 1 to 40 rag relative to 1 Kg of the body weight of a man or an animal infected with pathogenic bacteria as described above, which may be administered in two to three divided doses. As carriers for injectable preparations, use is made of, for example, distilled water and physiological saline solution, and, carriers for capsules, powdery preparations, granular preparations or tablets are used as a mixture with known pharmaceutically acceptable excipients (e.g. starch, maltose, sucrose, calcium carbonate or calcium phosphate), binders (e.g. starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose or crystalline cellulose), lubricants (e.g. magnesium stearate or talc) and disintegrants (e.g. carboxymethyl calcium and talc).

BEST MODE FOR CARRYING OUT THE INVENTION

Examples

The present invention will be illustrated in further detail in the following Reference Examples and Working Examples, which are mere examples and do not limit this invention, and may be modified within the range not deviating from the scope of this invention. Elution in the column chromatography conducted in Reference Examples and Working Examples was carried out while monitoring with TLC (Thin Layer Chromatography) . In the TLC monitoring, as the TLC plate, use was made of 60F ₂₅₄ manufactured by Merck & Co., Inc., as the developing solvent, use was made of the same solvent as employed for eluting in the column chromatography, and the detection was conducted with a UV detector. The silica gel for the column was Kieselgel 60 manufactured by Merck & Co. Inc. (70 to 230 mesh). "Sephadex" is a product of Pharmacia Fine Chemicals. XAD-2 resin is a product of Rohm & Haas Co. Diaion CHP-20P is a product of Mitsubishi Chemical Industries, Ltd. NMR spectra were measured using tetramethylsilane as an internal or external standard with a spectrometer Gemini 200 and all δ values were expressed in ppm. The value shown in ( ) for a mixed solvent is a mixing ratio in volume of constituent solvents. The percent (%) for a solution indicates the number of grams in 100 ml of the solution. And, the symbols in Reference Examples and Working Examples have the following meaning.

bs : broad singlet J : coupling constant Reference Example 1

2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)- cyclopentyloxyimino acetic acid

In 120 ml of ethanol was suspended 14.7 g of 3-(5- amino-1,2,4-thiadiazol-3-yl)coumarin. To the suspension was added 120 ml of IN-NaOH, and the mixture was stirred for one hour at 40°C to give a homogeneous solution, to which was added 6 ml of ethyl chlorocarbonate under ice-cooling, and the mixture was stirred for 5 minutes. To the mixture were added 180 ml of methylene chloride and 60 ml of 1N-HC1. The aqueous layer was separated and again subjected to extraction with methylene chloride. The organic layers were combined and cooled on a dry ice-acetone bath. Into the methylene chloride solution was introduced ozone for 3 hours, then nitrogen was introduced for 15 minutes to purge excess ozone. To the reaction mixture were added 4.92 g of sodium acetate and 30 ml of dimehtyl sulfide. The mixture was stirred. After confirming that the test with potassium iodide starch paper showed negative, the mixture was extracted with 120 ml of water, and the aqueous layer was separated. The organic layer was again extracted with 60 ml of water, and the aqueous layers were combined. Further, the aqueous layer was washed with ethyl acetate. To the aqueous layer was added 6.7 g of 0- cyclopentylhydroxylamine, and the pH of the mixture was adjusted to 5 with IN-NaOH, which was stirred overnight at room temperature (25°C, the same shall apply hereinafter) . To the reaction mixture was added 80 ml of 1N-HC1 to make the pH to 1, followed by extraction with ethyl acetate three times. The extract solution was washed with a saturated aqueous saline solution, dried over magnesium sulfate and concentrated under

reduced pressure. The concentrate was crystallized from ethyl acetate to afford 12.8 g of the titled compound. m.p.l42-143°C. IR(KBr,cm ^"1 ) : 3300, 2950, 1720, 1640, 1520, 1400, 1180.

NMR(DMSO-d ₆ ,δ) : 1.3-1.9 ( 8H,m) , 4.74(lH,m), 8.17(2H,bs) . Reference Example 2 2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)- cyclopentyloxyiminoacetyl chloride hydrochloride

In 30 ml of dichloromethane was suspended 3.84 g of 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- cyclopentyloxyimino acetic acid. The suspension was cooled to -40°C, to which was added 3.43 g of phopshorus pentachloride . The mixture was stirred for one hour at -20°C or lower. To the reaction mixture was added 60 ml of isopropyl ether. Precipitating crystals were collected by filtration and dried to afford 3.26 g of the titled compound. Reference Example 3

2-(5-Amino-l,2 ,4-thiadiazol-3-yl)-2 (Z)- isopropoxyiminoacetic acid

In 56 ml of ethanol was suspended 7.0 g of 3-(5- amino-1,2,4-thiadiazol-3-yl)coumarin. To the suspension was added 57.1 ml of IN-NaOH, which was stirred for one hour at 40°C. To the mixture was then added, under ice-cooling, 2.86 ml of ethyl chlorocarbonate, which was stirred for 15 minutes. To the mixture were added 28.6 ml of IN-HCl and 88 ml of dichloromethane. Dichloromethane layer was separated, and the aqueous layer was again subjected to extraction with dichloromethane. The organic layers were combined, to which was introduced ozone for one hour under cooling on a dry ice-acetone bath, followed by introducing nitrogen for 15 minutes to purge excess ozone. To the resultant were added 2.35 g of sodium

acetate and 14 ml of methyl sulfide. The mixture was stirred at room temperature until potassium iodide - starch paper showed negative. The reaction mixture was subjected to extraction with water, and the extract solution was washed with ethyl acetate, to which were added 3.47 g of isopropoxyamine hydrochloride and 2.57 g of sodium acetate. The mixture was stirred for 1.5 hour at room temperature, to which was then added 0.7 g of sodium acetate. The mixture was again washed with ethyl acetate, whose pH was adjusted to 1 with cone. HCl. To the mixture was saturated with sodium chloride, followed by extraction with ethyl acetate. The extract solution was dried over magnesium sulfate, then the solvent was distilled off. To the residue was added hexane to afford 4.86 g of the titled compound as crystals . m.p.l52-154°C

IR(KBr,cm ^"1 ) : 3425, 2990, 1720, 1620. NMR(DMSO-d ₆ ,δ) : 1.23(6H,d,J=6.2Hz) , 4.40(lH,m), 8.18(2H,s).

Reference Example 4

2-(5-Amino-l,2 ,4-thiadiazol-3-yl)-2(Z)- isopropoxyiminoacetyl chloride hydrochloride

In 20 ml of dichloromethane was suspended 2.3 g of 2-(5-amino-l,2,4-thiadiazol-3-yl)-2 (Z)- isopropoxyiminoacetic acid. The suspension was cooled to -40°C, to which was then added 2.29 g of phosphorus pentachloride. The mixture was stirred for one hour at -20°C or below. To the reaction mixture was added 30 ml of isopropyl ether. Resulting crystalline precipitate was collected by filtration and dried to give 1.74 g of the titled compound.

Reference Example 5

7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[ 1,2-b]pyrid- azin-6-yl)thio]vinyl-l-oxido-3-cephem-4-carboxylic acid benzhydryl ester

In 20 ml of dimethylformamide was dissolved 2.0 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-tosyloxy]vinyl-l- oxido-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 1.0 g of 6-mercaptoimidazo[ 1,2- b]pyridazine sodium salt, and the mixture was stirred for one hour at room temperature. The reaction mixture was diluted with ethyl acetate, which was washed with water twice and dried over magnesium sulfate, followed by concentration under reduced pressure to afford 2 g of the titled compound.

NMR(CDCl ₃ ,δ) : 1.47(9H,s), 3.27&4.15(2H,ABq,J=18Hz) , 4.53(lH,d,J=3.6Hz) , 5.85(2H,m), 6.77 ( lH,d,J=9.4Hz) , 6.97(lH,s), 7.1-7.6(12H,m) , 7.68(1H,S), 7.75(lH,d,J=9.4Hz), 7.89(1H,S) . Reference Example 6

7β-t-Butoxycarbonylamino-3-[ (E)-2-(imidazo[ 1,2-b]pyrid- azin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester

In a mixture of 32 ml of methylene chloride and 1.2 ml of dimethylacetamide was dissolved 2.0 g of 7β- t-butoxycarbonylamino-3-[ (E)-2-(imidazo[ 1,2-bJpyrid- azin-6-yl)thio]vinyl-l-oxido-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 0.51 ml of phosphorus trichloride under cooling at -10°C, and the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. To the concentrate were added ethyl acetate and an aqueous solution of sodium hydrogen carbonate, which was subjected to extraction. The ethyl acetate layer was washed with a saturated aqueous saline solution, dried over magnesium sulfate and concentrated under reduced pressure to give 1.76 g of the titled compound. NMR(CDCl ₃ ,δ) : 1.48(9H,s), 3.56&3.70(2H,ABq,J=17.6Hz) , 4.98(lH,d,J=4.8Hz) , 5.66 ( lH,dd,J=4.8&9.2Hz) , 6.30(lH,d,J=9.2Hz) , 6.73( lH,d,J=9.2Hz) , 6.95(lH,s), 7.1-7.6(12H,m) , 7.69(lH,s), 7.78( lH,d,J=9.2Hz) ,

7.87(lH,s) . Reference Example 7

7β-t-Butoxycarbonylamino-3-[ (Z)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-1-oxido-3-cephem-4- carboxylic acid benzhydryl ester

In 3 ml of dimethylformamide was dissolved 0.3 g of 7β-t-butoxycarbonylamino-3-[ (Z)-2-tosyloxy]vinyl-l- oxido-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 0.15 g of 6-mercaptoimidazo[1,2- bjpyridazine sodium salt, and the mixture was stirred for one hour at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water twice and dried over magnesium sulfate, which was concentrated under reduced pressure to give 0.24 g of the titled compound.

NMR(CDCl ₃ ,δ) : 1.47(9H,s), 3.45&4.16(2H,ABq,J=18Hz) , 4.57(lH,d,J=3.6Hz) , 5.86(2H,m), 6.78(lH,d,J=9.4Hz) , 6.97(lH,s), 7.2-7.6(12H,m) , 7.71(lH,s), 7.79(lH,d,J=9.4Hz) , 7.89(lH,s). Reference Example 8

7β-t-Butoxycarbonylamino-3-[ (Z)-2-(imidazo[1,2-b]pyrid- azin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester

In a mixture of 3.8 ml of methylene chloride and 0.15 ml of dimethylacetamide was dissolved 0.23 g of

7β-t-butoxycarbonylamino-3-[ (Z)-2-(imidazo[l,2-b]ρyrid- azin-6-yl)thio]vinyl-l-oxido-3-cephem-4-carboxylic acid benzhydryl ester. The solution was added 0.061 ml of phosphorus trichloride under cooling at -10°C, and the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. To the concentrate were added ethyl acetate and an aqueous solution of sodium hydrogen carbonate, which was subjected to extraction. The ethyl acetate layer was washed with a saturated aqueous saline solution, dried over magnesium sulfate and concentrated under reduced

pressure to give 0.18 g of the titled compound.

NMR(CDCl ₃ ,δ) : 1.47(9H,s), 3.73(2H,m),

5.04(lH,d,J=3.6Hz) , 5.66(lH,m), 6.80( lH,d,J=9.4Hz) ,

6.96(lH,s), 7.2-7.6(12H,m) , 7.72(lH,s), 7.81(lH,d,J=9.4Hz) , 7.88(lH,s).

Reference Example 9

7β-t-Butoxycarbonylamino-3-[(E)-2-butoxycarbonylaminoi- midazo[l,2-b]pyridazin-6-yl)thio]vinyl-1-oxido-3- cephem-4-carboxylic acid benzhydryl ester In 22 ml of dimethylformamide was dissolved 2.14 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-tosyloxy]vinyl-l- oxido-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 1.0 g of 3-t- butoxycarbonylamino-6-mercaptoimidazo[ l,2-b]pyridazine sodium salt. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was diluted with 300 ml of ethyl acetate, which was washed twice with an aqueous saline solution and dried over magnesium sulfate, followed by concentration under reduced pressure. The concentrate was subjected to a silica gel column chromatography (50 g) for purification. Elution with ethyl acetate afforded 1.39 g of the titled compound.

NMR(CDCl ₃ ,δ) : 1.48(9H,s), 1.56(9H,s), 3.31&4.17(2H,ABq,J=17Hz) , 4.56( lH,d,J=3.8Hz) ,

5.80(2H,m), 6.77 ( lH,d,J=9.4Hz) , 6.99(lH,s),

7.1~7.6(13H,m) , 7.74( 1H,d,J=9.4Hz) .

Reference Example 10

7β-t-Butoxycarbonylamino-3-[ (E)-2-( 3-t-butoxycarbonyla- minoimidazof 1,2-b]pyridazin-6-yl)thio]vinyl-3-cephem-4- carboxylic acid benzhydryl ester

In a mixture of 22 ml of methylene chloride and

0.78 ml of dimethylacetamide was dissolved 1.38 g of

7β-t-butoxycarbonylamino-3-[ (E)-2-( 3-t-butoxycarbonyla- minoimidazo[ l,2-b]pyridazin-6-yl)thio]vinyl-1-oxido-3- cephem-4-carboxylic acid benzhydryl ester. To the

solution was added 0.41 ml of phosphorus trichloride under cooling at -10°C. The mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. To the concentrate were added 200 ml of ethyl acetate and 100 ml of an aqueous solution of sodium hydrogen carbonate, which was subjected to extraction. The ethyl acetate layer was washed with a saturated aqueous saline solution, which was dried over magnesium sul ate, followed by concentration under reduced pressure to give 1.3 g of the titled compound. NMR(CDCl ₃ ,δ) : 1.48(9H,s), 1.56(9H,s), 3.62&3.73(2H,ABq,J=17Hz) , 5.03(lH,d,J=4.8Hz) , 5.35(lH,m), 5.63(lH,m), 6.77(lH,d,J=9.2Hz) , 6.99(lH,s), 7.1~7.6(13H,m) , 7.75(lH,d,J=9.2Hz) . Reference Example 11

7β-Amino-3-[ (E)-2-(3-amino-l-methylimidazo[1,2-b]pyrid- azinium-6-yl)thio]vinyl-3-cephem-4-carboxylate trifluoroacetate

In 3.7 ml of dimethylformamide was dissolved 1.3 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(3-t- butoxycarbonylaminoimidazo[1,2-b]pyridazin-6- yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 3.2 ml of iodomethane, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the concentrate was added 200 ml of a mixture of ethyl ether and hexane (1:1), which was decanted. The residue was dissolved in 12 ml of methylene chloride, to which were added 2 ml of anisole and 6 ml of trifluoroacetic acid. The mixture was stirred for 2 hours at room temperature. To the reaction mixture was added 100 ml of ethyl ether. Resulting precipitate was collected by filtration and dried under reduced pressure to give 1.1 g of the titled compound.

NMR(DMSO-d ₆ ,δ) : 3.89&4.25(2H,ABq,J=17.2Hz) ,

4.01(3H,s), 5.23(lH,d,J=5.4Hz) , 5.29 ( lH,d,J=5.4Hz) , 7.37(lH,d,J=15.8Hz) , 7.45(lH,s), 7.65( lH,d,J=15.8Hz) , 7.68(lH,d,J=9.8Hz) , 8.52 ( lH,d,J=9.8Hz) . Reference Example 12 7β-t-Butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2-a]pyrid- in-5-yl)thio]vinyl-l-oxido-3-cephem-4-carboxylic acid benzhydryl ester

In 30 ml of dimethylacetamide was dissolved 3.0 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-tosyloxy]vinyl-l- oxido-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added, under ice-cooling, 0.99 g of 5- mercaptoimidazo[1,2-a]pyridine sodium salt, which was stirred for one hour. The reaction mixture was diluted with 300 ml of a mixture of ethyl acetate and tetrahydrofuran (3:1), which was washed twice with 400 ml of an aqueous saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography (40 g) for purification. Elution with ethyl acetate afforded 0.37 g of the titled compound. NMR(CDCl ₃ ,δ) : 1.45(9H,s), 3.19&3.94 (2H,ABq,J=18Hz) , 4.54(lH,d,J=2Hz) , 5.80(2H,m), 6.47 ( lH,d,J=15.8Hz) , 6.93(lH,s), 7.0~7.6(16H,m) . Reference Example 13 7β-t-Butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2-a]pyrid- in-5-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester

In a mixture of 5.5 ml of methylene chloride and 0.2 ml of dimethylacetamide was dissolved 0.35 g of 7β- t-butoxycarbonylamino-3-[ (E)-2-(imidazo[ 1, 2-a]pyridin- 5-yl)thio]vinyl-l-oxido-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added, under cooling at -10°C, 0.09 ml of phosphorus trichloride, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the concentrate were added 200 ml of

ethyl acetate and 200 ml of an aqueous solution of sodium hydrogen carbonate, which was subjected to extraction. The ethyl acetate layer was washed with 200 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate and dried under reduced pressure, followed by concentration under reduced pressure to leave 0.285 g of the titled compound. NMR(CDCl ₃ ,δ) : 1.45(9H,s), 3.45&3.55(2H,ABq,J=18Hz) , 4.98(lH,d,J=4.8Hz) , 5.47(lH,d,J=9.8Hz) ,

5.65(lH,dd,J=4.8&9.8Hz) , 6.44(lH,d,J=15.6Hz) ,

6.95(lH,s), 7.0~7.8(16H,m) .

Reference Example 14

7β-Amino-3-[ (E)-2-(1-methylimidazo[1,2-a]pyridinium-5- yl)thio]vinyl-3-cephem-4-carboxylate trifluoroacetate

In 0.84 ml of dimethylformamide was dissolved 0.28 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- a]pyridin-5-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 0.82 ml of iodomethane, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added 100 ml of a mixture of ethyl ether and hexane (1:1), followed by decantation. The residue was dissolved in 2.4 ml of methylene chloride, to which were added 0.48 ml of anisole and 1.2 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 100 ml of ethyl ether. Resulting precipitate was collected by filtration, which was dried under reduced pressure to give 0.278 g of the titled compound.

NMR(DMSO-d ₆ ,δ) : 3.76&4.02(2H,ABq,J=17Hz) , 4.12(3H,s), 5.20(lH,d,J=5Hz) , 5.26( lH,d,J=5Hz) , 7.14(2H,s), 7.84(lH,d,J=7.4Hz) , 8.07(lH,m), 8.27(lH,d,J=8.4Hz) , 8.40(lH,d,J=2Hz) , 8.43(lH,d,J=2Hz) . Working Example 1

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyl- oxyiminoacetamide]-3-[(E)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 20 ml of dimethylformamide was dissolved 2.1 g of 7β-t-butoxycarbonylamino-3-[ (E) -2-(imidazo[ 1,2- b]pyridazin-6-y1)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 20 ml of iodomethane, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate was added 800 ml of a mixture of ether and hexane (1:1). The supernatant was removed by decantation. The residue was dissolved in 50 ml of methylene chloride, to which were added 20 ml of anisole and 25 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 800 ml of ether. Resulting precipitate was collected by filtration and dried under reduced pressure. The precipitate was dissolved in 300 ml of a mixture of water and tetrahydrofuran (1:1), whose pH was adjusted to 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 1.22 g of 2-(5-amino-l,2 ,4-thiadiazol-3-yl) -2 (Z) - cyclopentyloxyiminoacetyl chloride hydrochloride, which was stirred for 30 minutes while adjusting the pH at 8 with an aqueous solution of sodium hydrogen carbonate. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P columm chromatography.

Fractions eluted with 30% aqueous solution of ethanol were collected and concentrated under reduced pressure.

The concentrate was lyophilized to give 0.93 g of the titled compound. Elemental Analysis for C ₂₅ H ₂₅ N ₉ 0 ₅ S ₃ •5.5H ₂ 0: Calcd.: C, 41.31; H, 4.99; N, 17.34 Found : C, 41.57; H, 4.77; N, 17.38

NMR(DMSO-d ₆ ,δ) : 1.3-2.0(8H,m) , 3.60(2H,ra) , 4.08(3H,s),

4.74(lH,m), 5.09(lH,d,J=5Hz) , 5.6 (lH,dd,J=5&8.2Hz) , 6.62(lH,d,J=16Hz), 7.48(lH,d,J=16Hz) ,

7.95(lH,d,J=9.8Hz) , 8.15(2H,bs), 8.37(lH,d,J=2Hz) ,

8.64(lH,d,J=9.8Hz), 8.69( lH,d,J=2Hz) ,

9.51(lH,d,J=8.2Hz) .

Working Example 2 7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-isopropoxyi- minoacetamido]-3-[ (E)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 6 ml of dimethylformamide was dissolved 0.6 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 5.8 ml of iodomethane, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate was added 200 ml of a mixture of ether and hexane (1:1). The supernatant was discarded by decantation. The residue was dissolved in 15 ml of methylene chloride, to which were added 6 ml of anisole

and 7.5 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 200 ml of ether. Resulting precipitate was collected by filtration, which was dried under reduced pressure. The precipitate was dissolved in 100 ml of a mixture of water and tetrahydrofuran (1:1). The solution was adjusted to pH 7.5 with an aqueous solution of sodium hydrogen carbonate under ice-cooling. To this solution was added 0.4 g of 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- isopropoxyiminoacetyl chloride hydrochloride, which was stirred for 30 minute while adjusting the pH at 8 with an aqueous solution of sodium hydrogen carbonate. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 25% aqueous solution of ethanol were collected and concentrated under reduced pressure, which was lyophilized to give 0.29 g of the titled compound. Elemental Analysis for C ₂₃ H ₂₃ N ₉ 0 ₅ S ₃ •5.5H ₂ 0: Calcd.: C, 39.42; H, 4.89; N, 17.99 Found : C, 39.41; H, 4.54; N, 18.10 NMR(DMSO-d ₆ ,δ) : 1.28(6H,m), 3.60(2H,m), 4.08(3H,s), 4.42(lH,m), 5.10(lH,d,J=5Hz) , 5.66(lH,dd,J=5&8.6Hz) , 6.61(lH,d,J=15.4Hz) , 7.48(lH,d,J=i5.4Hz) ,

7.94(lH,d,J=10.2Hz), 8.16(2H,bs), 8.37(lH,s), 8.65(lH,d,J=10.2Hz), 8.69(lH,s), 9.52(lH,d,J=8.6Hz) . Working Example 3 7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-methoxyimin- oacetamido]-3-[ (E)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 6 ml of dimethylformamide was dissolved 0.6 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 5.8 ml of iodomethane, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate was added 200 ml of a mixture of ether and hexane (1:1). The supernatant was discarded by decantation. The residue was dissolved in 15 ml of methylene chloride, to which were added 6 ml of anisole and 7.5 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 200 ml of ether. Resulting precipitate was collected by filtration and dried under reduced pressure. The precipitate was dissolved in 100 ml of a mixture of water and tetrahydrofuran (1:1). Under ice-cooling, pH of the solution was adjusted to 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 0.36 g of 2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 15% aqueous solution of ethanol were collected and concentrated under reduced pressure. The concentrate was lyophilized to give 0.26 g of the

titled compound.

Elemental Analysis for C ₂ ιH ₁₉ N ₉ 0 ₅ S ₃ - 5.0H ₂ O: Calcd.: C, 38.00; H, 4.40; N, 18.99 Found : C, 38.03; H, 4.09; N, 19.04 NMR(DMSO-d ₆ ,δ) : 3.60(2H,m), 3.94(3H,s), 4.08(3H,s),

5.08(lH,d,J=5Hz) , 5.65 ( lH,dd, J=5&8.6Hz ) , 6.61(lH,d,J=16.2Hz) , 7.48 ( lH,d, J=16.2Hz ) , 7.95(lH,d,J=9.6Hz) , 8.17(2H,bs), 8.37 ( lH,d, J=2Hz ) , 8.65(lH,d,J=9.6Hz) , 8.69 ( lH,d, J=2Hz ) , 9.57(lH,d,J=8.6Hz) . Working Example 4

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2 (Z)-ethoxyimino¬ acetamido]-3-[ (E)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.2 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[ 1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 1.9 ml of iodomethane, which was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate was added 100 ml of a mixture of ether and hexane (1:1) . The supernatant was discarded by decantation. The residue was dissolved in 5 ml of methylene chloride. To the solution were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 100 ml of ether. Resulting precipitate was

collected by filtration and dried under reduced pressure. The precipitate was dissolved in 40 ml of a mixture of water and tetrahydrofuran (1:1). Under ice- cooling, pH of the solution was adjusted to 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 0.13 g of 2-(5-amino-l,2,4- thiadiazol-3-yl)-2(Z)-ethoxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes while adjusting the pH to 8 with an aqueous solution of sodium hydrogen chloride. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated under reduced pressure. The concentrate was lyophilized to give 95 mg of the titled compound.

Elemental Analysis for C ₂₂ H ₂₁ N ₉ 0 ₅ S ₃ • 4.5H ₂ 0: Calcd.: C, 39.51; H, 4.52; N, 18.85 Found : C, 39.73; H _r 4.58; N, 19.19 NMR(DMSO-d ₆ ,δ) : 1.28 ( 3H, t , J=6.8Hz ) , 3.60(2H,m), 4.08(3H,s), 4.20(2H,q,J=6.8Hz) , 5.09(lH,d,J=4.8Hz) , 5.66(lH,dd,J=4.8&8.4Hz) , 6.61( lH,d,J=15.4Hz) , 7.46(lH,d,J=15.4Hz) , 7.95(lH,d,J=10Hz) , 8.17(2H,bs), 8.37(lH,d,J=2Hz) , 8.64(lH,d,J=10Hz) , 8.68(lH,d,J=2Hz) , 9.56(lH,d,J=8.4Hz) . Working Example 5

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-hydroxyimin¬ oacetamido]-3-[ (E)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.2 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 1.9 ml of iodomethane. The mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added a mixture of ether and hexane (1:1). The supernatant was discarded by decantation. The residue was dissolved in 5 ml of methylene chloride. To the solution were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 100 ml of ether. Resulting precipitate was collected by filtration and dried under reduced pressure. The precipitate was dissolved in 40 ml of a mixture of water and tetrahydrofuran (1:1). To this solution, under ice-cooling, were added 0.52 ml of tri- n-butylamine and 0.23 g of 2-(5-amino-l,2,4-thiadiazol- 3-yl)-2(Z)-trityloxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added 6 ml of a 90% aqueous solution of formic acid. The mixture was stirred for one hour at room temperature, which was concentrated under reduced pressure. To the concentrate was added an aqueous solution of sodium hydrogen carbonate to adjust the pH to 7, followed by washing with ethyl acetate. The aqueous layer was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 15% aqueous solution of ethanol were collected and concentrated under reduced pressure, which was lyophilized to give 67 mg of the titled compound. Elemental Analysis for C ₂₀ H ₁₇ N ₉ O ₅ S ₃ ■4.5H ₂ 0: Calcd.: C, 38.03; H, 3.99; N, 19.96

Found : C, 38.15; H, 4.25; N, 19.69 NMR(DMS0-d ₆ ,δ) : 3.60(2H,m), 4.08(3H,s), 5.09(lH,d,J=5.2Hz) , 5.70(lH,dd,J=5.2&8Hz) , 6.62(lH,d,J=15.8Hz) , 7. 7(lH,d,J=15.8Hz) , 7.96(lH,d,J=9.8Hz) , 8.05(2H,bs), 8.37(lH,s),

8.63(lH,d,J=9.8Hz) , 8.70(lH,s), 9. 5(lH,d,J=8Hz) , 11.99(lH,bs) . Working Example 6

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyl- oxyiminoacetamido]-3-[ (E)-2-(1-ethylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.1 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 1.25 ml of iodoethane. The mixture was stirred for 16 hours at room temperature and, then, for two days at 40°C. To the reaction mixture was added 50 ml of a mixture of ether and hexane (1:1). The supernatant was discarded by decantation. The residue was dissolved in 2.5 ml of methylene chloride. To the solution were added 1 ml of anisole and 1.25 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 50 ml of ether, then resulting precipitate was collected by filtration and dried under reduced pressure. The precipitate was dissolved in 20 ml of a mixture of water and tetrahydrofuran (1:1). The solution was adjusted to pH

7.5 with an aqueous solution of sodium hydrogen carbonate under ice-cooling. To this solution was added 73 mg of 2-(5-amino-l,2 ,4-thiadiazol-3-yl)-2 (Z)- cyclopentyloxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 30% aqueous solution of ethanol were collected and concentrated under reduced pressure. The concentrate was lyophilized to give 45 mg of the titled compound. Elemental Analysis for C ₂₆ H ₂₇ N ₉ 0 ₅ S ₃ • 4.5H ₂ 0: Calcd.: C, 43.20; H, 5.02; N, 17.44 Found : C, 43.12; H, 4.79; N, 17.24

NMR(DMSO-dg, δ ) : 1.47 ( 3H,t,J=7Hz ) , 1.5-2.0( 8H,m) , 3.60(2H,m), 4.51(2H,q,J=7Hz) , 4.75(lH,m), 5.09(lH,d,J=5.2Hz) , 5.64 ( lH,dd,J=5.2&8Hz) , 6.62(lH,d,J=15.8Hz) , 7.48 ( lH,d,J=15.8Hz) , 7.96(lH,d,J=9.8Hz) , 8.16(2H,bs), 8.47 ( lH,d, J=2Hz) ,

8.70(lH,d,J=9.8Hz) , 8.72 ( lH,d,J=2Hz ) , 9.52 ( lH,d,J=8Hz ) . Working Example 7

7β- [2- ( 5-Amino-l,2 , 4-thiadiazol-3-yl) -2 (Z )-isopropoxyi- minoacetamido]-3-[ (E)-2-( 1-ethylimidazo[ 1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.1 g of 7β-t-butoxycarbonylamino-3-[ (E) -2-( imidazo[ 1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid

benzhydryl ester. To the solution was added 1.25 ml of iodoethane. The mixture was stirred for 16 hours at room temperature, then for two days at 40°C. To the reaction mixture was added 50 ml of a mixture of ether and hexane (1:1). The supernatant was discarded by decantation. The residue was dissolved in 2.5 ml of methylene chloride. To the solution were added 1 ml of anisole and 1.25 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 50 ml of ether, then resulting precipitate was collected by filtration, followed by drying under reduced pressure. The precipitate was dissolved in 20 ml of a mixture of water and tetrahydrofuran (1:1). The solution was adjusted to pH 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 66 mg of 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- isopropoxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The reaction mixture was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 25% aqueous solution of ethanol were collected and concentrated under reduced pressure. The concentrate was lyophilized to give 53 mg of the titled compound.

Elemental Analysis for C ₂₄ H ₂₅ N ₉ 0 ₅ S ₃ • 4.5H ₂ 0: Calcd. : C, 41.37; H, 4.92; N, 18.09 Found : C, 41.33; H, 4.62; N, 18.47 NMR(DMSO-d ₆ ,δ) : 1.28(6H,m), 1.47 ( 3H, t , J=6.8Hz ) ,

3.61(2H,m), 4.41(1H,S), 4.51 ( 2H,q, J=6.8Hz ) , 5.10(lH,d,J=5.2Hz) , 5.65 ( lH,dd, J=5.2&8.4Hz ) , 6.61(lH,d, J= 15.4Hz) , 7.48 ( lH,d, J=15.4Hz ) , 7.96(lH,d, J=9.8Hz) , 8.18(2H,bs), 8.48(lH,s), 8.71(lH,d,J=9.8Hz) , 8.73(lH,s), 9.53 ( lH,d, J=8.4Hz ) .

Working Example 8

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)- cyclopentyloxyiminoacetamido]-3-[ (E)-2-{1-(2- hydroxyethyl)imidazo[1,2-b]pyridizinium-6- yl}thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.2 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b)pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 2.43 ml of 2-iodoethanol, and mixture was stirred for two days at 40°C. To the reaction mixture was added 100 ml of a mixture of ether and hexane (1:1). The supernatant was discarded by decantation. The residue was dissolved in 5 ml of methylene chloride, to which were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 100 ml of ether. Resulting precipitate was collected by filtration, which was dried under reduced pressure. The precipitate was dissolved in 40 ml of a mixture of water and tetrahydrofuran (1:1), whose pH was adjusted to 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 0.15 g of S-(2- benzothiazolyl)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- cyclopentyloxyiminothioacetate. The mixture was stirred for 16 hours at room temperature. The reaction mixture was washed with ethyl acetate. The aqueous layer was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 25% aqueous solution of ethanol were collected

and concentrated under reduced pressure. The concentrate was lyophilized to give 25 mg of the titled compound.

Elemental Analysis for C ₂₆ H ₂₇ N ₉ 0 ₆ S ₃ •5.5H ₂ 0: Calcd.: C, 41.26; H, 5.06; N, 16.66

Found : C, 41.50; H, 4.97; N, 16.47

NMR(DMSO-d ₆ ,6) : 1.4-1.9(8H,m) , 3.61(2H,m), 3.79(2H,m),

4.58(2H,m), 4.74(lH,m), 5.10(lH,d,J=5.2Hz) , 5.42(lH,m),

5.65(lH,dd,J=5.2&8.4Hz) , 6.65( lH,d,J=15.8Hz) , 7.45(lH,d,J=15.8Hz) , 7.93(lH,d,J=9.6Hz) , 8.16(2H,bs),

8.40(lH,s), 8.65(lH,d,J=9.6Hz) , 8.70(lH,s),

9.52(lH,d,J=8.4Hz) .

Working Example 9

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyl- oxyiminoacetamido]-3-[ (E)-2-(1- carbamoylmethylimidazof1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.2 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 1.73 g of iodoacetamide. The mixture was stirred for 21.5 hours at room temperature. To the reaction mixture was added 100 ml of ether. The mixture was stirred for 5 minutes, then the supernatant was discarded by decantation. The residue was dissolved in 5 ml of methylene chloride. To the solution were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature,

and then resulting precipitate was collected by filtration. The precipitate was dissolved in 40 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 150 mg of 2-(5-amino-l,2,4-thiadiazol-3- yl)-2(Z)-cyclopentyliminoacetylchloride hydrochloride, while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 15 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 30% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 98 mg of the titled compound.

Elemental Analysis for C ₂₆ H ₂₆ N ₁₀ O ₆ S ₃ • 7.0H ₂ O: Calcd.: C, 39.19; H, 5.06; N, 17.58 Found : C, 39.12; H, 4.89; N, 17.59 NMR(DMSO-d ₆ ,δ) : 1.4-2.0 ( 8H,m) , 3.61(2H,m), 4.75(lH,m), 5.10(lH,d,J=4.8Hz) , 5.27(2H,bs),

5.64(lH,dd,J=8.4&4.8Hz) , 6.64&7.48(each lH,d,J=16Hz) , 7.61&7.93(each lH,bs), 7.98&8.62(each lH,d,J=9.4Hz) , 8.15(2H,bs), 8.39&8.74(each lH,d,J=2.2Hz) , 9.52(lH,d,J=8.4Hz) . Working Example 10

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyl¬ oxyiminoacetamido]-3-[ (E)-2-(1-acetonylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In a mixture of 1.18 ml of methylene chloride and 0.46 ml of acetonitrile was dissolved 0.2 g of 7β-t- butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2-b]pyridazin- 6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution were added 0.138 ml of chloroacetone and 0.26 g of sodium iodide. The mixture was stirred for 17.5 hours at room temperature. To the reaction mixture was added 100 ml of a mixture of ether and hexane (1:1). The mixture was stirred for 5 minutes, then the supernatant was discarded by decantation. The residue was dissolved in 5 ml of methylene chloride. To the solution were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid. The mixture was stirred for 3.5 hours at room temperature. To the reaction mixture was added 150 ml of ether, then resulting precipitate was collected by filtration. The precipitate was dissolved in 40 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice- cooling, 180 mg of 2-(5-amino-l,2 ,4-thiadiazol-3-yl)- 2 (Z)-cyclopentyloxyiminoacetyl chloride hydrochloride, while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 40 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 30% aqueous solution of ethanol were collected and concentrated under reduced pressure. The concentrate was lyophilized to give 71 mg of the titled compound. Elemental Analysis for C ₂₇ H ₂₇ N ₉ 0 ₆ S ₃ • 7.0H ₂ O: Calcd.: C, 40.75; H, 5.19; N, 15.84 Found : C, 40.98; H, 4.96; N, 16.28 NMR(DMSO-dg, δ) : 1.4-2.0( 8H,m) , 2.30(3H,s), 3.60(2H,m), 4.74(lH,m), 5.10( lH,d,J=4.8Hz) , 5.6-5.7 (3H,m) , 6.64S.7.48(each lH,d,J=16Hz) , 8.00&8.58(each

lH,d,J=10.2Hz) , 8.14(2H,bs), 8.24&8.75 (each lH,d,J=2Hz), 9.51(lH,d,J=8.2Hz) .

Working Example 11

3-[ (E)-2-(l-Allylimidazo[1,2-b]pyridazinium-6- yl)thio]vinyl-7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-

2(Z)-cyclopentyloxyiminoacetamido]-3-cephem-4- carboxylate

In 2 ml of dimethylformamide was dissolved 0.2 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 2.70 ml of allyl bromide. The mixture was stirred for 14.5 hours at room temperature, then for 22 hours at 40°C on an oil bath. To the reaction mixture was added 100 ml of a mixture of ether and hexane (1:1). The mixture was stirred for 10 minutes, followed by discarding the supernatant by decantation. The residue was dissolved in 5 ml of methylene chloride. To the solution were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid, which was stirred for two hours at room temperature. To the reaction mixture was added 150 ml of ether, then resulting precipitate was collected by filtration. The precipitate was dissolved in 40 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 190 mg of 2-(5-amino-l,2,4-thiadiazol-3- yl)-2(Z)-cyclopentyloxyiminoacetyl chloride

hydrochloride, while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 20 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 30% aqueous solution of ethanol were collected, which was concentrated under reduced pressure. The concentrate was lyophilized to give 83 mg of the titled compound. Elemental Analysis for C ₂₇ H ₂₇ N ₉ 0 ₅ S ₃ • 5.0H ₂ O:

Calcd. : C, 43.60; H, 5.01; N, 16.95 Found : C, 43.88; H, 4.74; N, 17.16 NMR(DMSO-d ₆ ,δ) : 1.4-2.0 ( 8H,m) , 3.61(2H,m), 4.75(lH,m), 5.09(lH,d,J=5.2Hz) , 5.16(2H,m), 5.25-5.37 ( 2H,m) , 5.64(lH,dd,J=8&5.2Hz) , 6.06(lH,m), 6.63&7.47(each lH,d,J=15.8Hz) , 7.98&8.62(each lH,d,J=10Hz) , 8.16(2H,bs), 8.38&8.75(each lH,d,J=l.8Hz) , 9.51(lH,d,J=8Hz) . Working Example 12 7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyl¬ oxyiminoacetamido]-3-[ (Z)-2-( 1-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 1 ml of dimethylformamide was dissolved 0.12 g of 7β-t-butoxycarbonylamino-3-[ (Z)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 0.12 ml of iodomethane, which was stirred for 16 hours at room temperature. The reaction mixture was concentrated

under reduced pressure, to which was added 100 ml of a mixture of ether and hexane (1:1). The supernatant was discarded by decantation. The residue was dissolved in 5 ml of methylene chloride, to which were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 100 ml of ether, then resulting precipitate was collected by filtration, which was dried under reduced pressure and dissolved in 40 ml of a mixture of water and tetrahydrofuran (1:1). Under ice-cooling, pH of the solution was adjusted to 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 0.06 g of 2-(5- amino-1,2,4-thiadiazol-3-yl)-2 (Z)-cyclopentyloxyimin- oacetyl chloride hydrochloride. The mixture was stirred for 30 minutes, while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 30% aqueous solution of ethanol were collected and concentrated under reduced pressure. The concentrate was lyophilized to give 64 mg of the titled compound. Elemental Analysis for C ₂₅ H ₂₅ N ₉ 0 ₅ S ₃ • 6.0H ₂ O: Calcd. : C, 40.81; H, 5.07; N, 17.13 Found : C, 40.94; H, 4.87; N, 17.49 NMR(DMSO-d ₆ ,δ) : 1.4-1.9 ( 8H,m) ,

3.66&3.85(2H,ABq,J=15Hz) , 4.08(3H,s), 4.74(lH,m), 5.08(lH,d,J=4.8Hz) , 5.64 ( lH,dd,J=4.8&8.6Hz) , 6.56(lH,d,J=10.8Hz) , 7.36 ( lH,d,J=10.8Hz) ,

7.96(lH,d,J=9.8Hz) , 8.15(2H,bs), 8.38( lH,d,J=2Hz) , 8.65(lH,d,J=9.8Hz) , 8.74 ( lH,d,J=2Hz) , 9.49(lH,d,J=8.6Hz) . Working Example 13 7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-isopropoxyi- minoacetamido]-3-[ (E)-2-( 1-carbamoylmethylimidazo[ 1,2-

b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.2 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 1.73 g of iodoacetamide, which was stirred for 24 hours at room temperature. To the reaction mixture was added 100 ml of ether, which was stirred for 5 minutes, followed by discarding the supernatant by decantation. The residue was dissolved in 5 ml of methylene chloride, to which were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid, followed by stirring for two hours at room temperature. To the reaction mixture was added 150 ml of ether, then resulting precipitate was collected by filtration. The precipitate was dissolved in 20 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 134 mg of 2-(5-amino- 1,2,4-thiadiazol-3-yl)-2(Z)-isopropoxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 25% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 83 mg of the titled compound. Elemental Analysis for C ₂₄ H ₂₄ N ₁₀ 0 ₆ S ₃ •5.0H ₂ O: Calcd.: C, 39.23; H, 4.66; N, 19.06

Found : C, 39.17; H, 4.45; N, 18.94 NMR(DMSO-d ₆ ,δ) : 1.27(6H,m), 3.60(2H,m), 4.41(lH,m), 5.10(lH,d,J=5.2Hz) , 5.29(2H,s), 5.65(lH,dd,J=8&5.2Hz) , 6.63&7.47(each lH,d,J=16Hz) , 7.60&8.03(each lH,bs), 7.97&8.62(each lH,d,J=9.8Hz) , 8.17(2H,bs), 8.39&8.72(each lH,s), 9.52(lH,d,J=8Hz) . Working Example 14

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-methoxyimin- oacetamido]-3-[ (E)-2-(l-carbamoylmethylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.2 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 1.73 g of iodoacetamide, which was stirred for 24 hours at room temperature. To the reaction mixture was added 100 ml of ether, followed by discarding the supernatant by decantation. The residue was dissolved in 5 ml of methylene chloride, to which were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid, followed by stirring for two hours at room temperature. To the reaction mixture was added 150 ml of ether, then resulting precipitate was collected by filtration. The precipitate was dissolved in 20 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice- cooling, 121 mg of 2-(5-amino-l,2,4-thiadiazol-3-yl)- 2(Z)-methoxyiminoacetyl chloride hydrochloride, while

adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 103 mg of the titled compound.

Elemental Analys is for C ₂₂ H ₂₀ N ₁₀ OgS ₃ • 5 . 5H ₂ 0 : Calcd . : C , 36 . 92 ; H , 4 . 37 ; N , 19 . 57 Found : C, 36.82; H, 4.01; N, 19.45 NMR(d ₆ -DMSO,δ) : 3.60(2H,m), 3.93(3H,s), 5.09(lH,d,J=5.2Hz), 5.31(2H,s), 5.65(lH,dd,J=8&5.2Hz) . 6.63&7.49(each lH,d,J=15. Hz) , 7.58&8.08(each lH,bs), 7.95&8.62(each lH,d,J=9. Hz) , 8.16(2H,bs), 8.40&8.72(each lH,d,J=2Hz) ,9.57(lH,d,J=8Hz) . Working Example 15

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-ethoxyimino¬ acetamido]-3-[ (E)-2-(l-carbamoylmethylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.28 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 2.42 g of iodoacetamide, which was stirred for 24 hours at room temperature. To the reaction mixture was added 100 ml of ether, which was stirred for 5 minutes, followed by discarding the supernatant by decantation. The residue was dissolved in 5 ml of methylene chloride, to which were added 2 ml of anisole and 2.5 ml of

trifluoroacetic acid, followed by stirring for two hours at room temperature. To the reaction mixture was added 100 ml of ether, then resulting precipitate was collected by filtration. The precipitate was dissolved in 40 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 177 mg of 2-(5-amino- 1,2,4-thiadiazol-3-yl)-2(Z )-ethoxyiminoacetyl chloride hydrochloride, while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 146 mg of the titled compound. Elemental Analysis for C ₂₃ H ₂₂ N ₁₀ O ₆ S ₃ -5.5H ₂ 0: Calcd.: C, 38.33; H, 4.47; N, 19.43 Found : C, 38.49; H, 4.13; N, 19.41

NMR(DMSO-d ₆ ,δ) : 1.28( 3H,t,J=7Hz) , 3.60(2H,m), 4.20(2H,q,J=7Hz) , 5.10( lH,d,J=5Hz) , 5.31(2H,s), 5.67(lH,dd,J=8.2&5Hz) , 6.64&7.48(each lH,d,J=15.4Hz) , 7.59&8.09(each lH,bs), 7.95&8.63(each lH,d,J=9.4Hz) , 8.17(2H,bs), 8.40&8.71(each lH,d,J=2Hz), 9.56(lH,d,J=8.2Hz) . Working Example 16

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2 (Z) -isopropoxyi- minoacetamido]-3-[ (E)-2-( 1-hydroxyethylimidazo[ 1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2.5 ml of dimethylformamide was dissolved 0.25 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 3.0 ml of 2-iodoethanol, which was stirred for 5 days at 0°C. To the reaction mixture was added 100 ml of a mixture of ether and hexane (1:1), then the supernatant was discarded by decantation. The residue was dissolved in methylene chloride, to which were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid, followed by stirring for two hours at room temperature. To the reaction mixture was added 100 ml of ether, then resulting precipitate was collected by filtration, which was dried under reduced pressure. The precipitate was dissolved in 20 ml of a mixture of water and tetrahydrofuran (1:1), whose pH was adjusted to 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 0.166 g of 2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-isopropyloxyiminoa- cetyl chloride hydrochloride, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 25% aqueous solution of ethanol were collected and concentrated under reduced pressure. The concentrate was lyophilized to give 61 mg of the titled compound. Elemental Analysis for C ₂₄ H ₂₅ N ₉ 0 ₆ S ₃ •5.0H ₂ O: Calcd.: C, 39.94; H, 4.89; N, 17.46 Found : C, 40.04; H, 4.68; N, 17.30

NMR(DMSO-d ₆ ,δ) : 1.26(6H,m), 3.61(2H,m), 3.78(2H,m), 4.58(2H,m), 4.41(lH,m), 5.11( lH,d,J=4.8Hz) , 5.46(lH,m), 5.67(lH,dd,J=4.8&7.8Hz) , 6.64(lH,d,J=16.2Hz) , 7.45(lH,d,J=16.2Hz) , 7.92(1H,d,J=10Hz) , 8.18(2H,bs), 8.40(lH,s), 8.66(lH,d,J=10Hz) , 8.70(lH,s), 9.53(lH,d,J=7.8Hz) .

Working Example 17

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-ethoxyimino¬ acetamido]-3-[ (E)-2-(1-hydroxyethylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2.5 ml of dimethylformamide was dissolved 0.25 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 3.0 ml of 2-iodoethanol, which was stirred for 5 days at 40°C. To the reaction mixture was added 100 ml of a mixture of ether and hexane (1:1). The supernatant was discarded by decantation. The residue was dissolved in 5 ml of methylene chloride, to which were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid, followed by stirring for two hours at room temperature. To the reaction mixture was added 100 ml of ether, then resulting precipitate was collected by filtration, which was dried under reduced pressure. The precipitate thus collected by filtration was dissolved in 20 ml of a mixture of water and tetrahydrofuran (1:1), whose pH was adjusted to 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 0.158 g of 2-(5-amino-l,2,4- thiadiazol-3-yl)-2(Z)-ethoxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol

were collected and concentrated under reduced pressure.

The concentrate was lyophilized to give 77 mg of the titled compound.

Elemental Analysis for C ₂₃ H ₂₃ N ₉ 0 ₆ S ₃ • 5.0H ₂ O: Calcd.: C, 39.03; H, 4.70; N, 17.81

Found : C, 39.05; H, 4.32; N, 17.62

NMR(DMSO-d ₆ ,δ) : 1.29(3H,t,J=7Hz) , 3.61(2H,m),

3.80(2H,m), 4.59(2H,m), 4.20(2H,q,J=7Hz) ,

5.10(lH,d,J=4.8Hz), 5.49 ( lH,m) , 5.67(lH,dd,J=4.8&8.8Hz) , 6.65( lH,d,J=15.8Hz) ,

7.46(lH,d,J=15.8Hz) , 7.92 ( 1H,d,J=9.4Hz) , 8.18(2H,bs),

8.41(lH,s), 8.67(lH,d,J=9.4Hz) , 8.70(lH,s),

9.57(lH,d,J=8.8Hz) .

Working Example 18 Sodium 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2 (Z )- cyclopentyloxyiminoacetamido]-3-[ (E)-2-( 1- carboxymethylimidazo[ 1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate

₂ Na

In 1 ml of dimethylformamide was dissolved 0.1 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[ 1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 2.5 ml of bromoacetic acid-t-butyl ester. The mixture was stirred for 16 hours at room temperature. To the reaction mixture was added 50 ml of a mixture of ether and hexane (1:1), then the supernatant was discarded by decantation. The residue was dissolved in 2.5 ml of methylene chloride, to which were added 1 ml of anisole and 1.25 ml of trifluoroacetic acid. The mixture was

stirred for two hours, to which was added 50 ml of ether, then resulting precipitate was collected by filtration, followed by drying under reduced pressure. The precipitate was dissolved in 10 ml of a mixture of water and tetrahydrofuran (1:1), whose pH was adjusted to 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 73 mg of 2-(5- amino-1,2,4-thiadiazol-3-yl)-2 (Z)-cyclopentyloxyimin¬ oacetyl chloride hydrochloride. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 10% aqueous solution of ethanol were collected and concentrated under reduced pressure, which was lyophilized to give 54 mg of the titled compound. Elemental Analysis for C ₂₆ H ₂₄ N ₉ 0 ₇ S ₃ Na- 6.0H ₂ O: Calcd.: C, 38.95; H, 4.53; N, 15.72 Found : C, 38.87; H, 4.23; N, 15.52 NMR(DMSO-d ₆ ,δ) : 1.4-2.0( 8H,m) , 3.62(2H,m), 4.75(lH,m), 4.79(2H,s), 5.11(lH,d,J=5Hz) , 5.64 ( lH,dd,J=5&8.4Hz) , 6.68(lH,d,J=16.2Hz) , 7.49 ( lH,d,J=16.2Hz) , 7.86(lH,d,J=9.6Hz) , 8.17(2H,bs), 8.31( lH,d,J=2Hz) , 8.48(lH,d,J=9.6Hz) , 8.63 ( lH,d,J=2Hz) , 9.52(lH,d,J=8.4Hz) . Working Example 19

Sodium 7β-[2-(5-amino-1,2 ,4-thiadiazol-3-yl)-2(Z)- isopropoxyiminoacetamido]-3-[ (E)-2-( 1- carboxymethylimidazo[ 1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate

In 1 ml of dimethylformamide was dissolved 0.1 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 2.5 ml of bromoacetic acid-t-butyl ester, which was stirred for 16 hours at room temperature. To the reaction mixture was added 50 ml of a mixture of ether and hexane (1:1), followed by discarding the supernatant by decantation. The residue was dissolved in 2.5 ml of methylene chloride, to which were added 1 ml of anisole and 1.25 ml of trifluoroacetic acid, followed by stirring for two hours at room temperature. To the reaction mixture was added 50 ml of ether, then resulting precipitate was collected by filtration, which was dried under reduced pressure. The precipitate was dissolved in a mixture of water and tetrahydrofuran (1:1), whose pH was adjusted to 7.5 with an aqueous solution of sodium hydrogen carbonate. To this solution was added 67 mg of 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- isopropyloxyiminoacetyl chloride hydrochloride, which was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 5% aqueous solution of ethanol were collected and concentrated under reduced pressure. The concentrate was lyophilized to give 42 mg of the titled compound. Elemental Analysis for C ₂ H ₂₂ N ₉ 0 ₇ S ₃ Na- 5.5H ₂ 0: Calcd.: C, 37.59; H, 4.34; N, 16.44 Found : C, 37.62; H, 4.24; N, 16.24

NMR(DMSO-d ₆ ,δ) : 1.28(6H,m), 3.62(2H,m), 4.41(lH,m), 4.80(2H,s), 5.11(lH,d,J=5.2Hz) , 5.67(lH,dd,J=5.2&9.2Hz) , 6.67 ( lH,d,J=16Hz) , 7.50(lH,d,J=16Hz) , 7.85( lH,d,J=9.6Hz) , 8.17(2H,bs), 8.31(lH,d,J=2Hz) , 8.47 ( lH,d,J=9.6Hz) , 8.62 ( lH,d,J=2Hz) , 9.53(lH,d,J=9.2Hz) .

Working Example 20

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-isopropoxyi- minoacetamido]-3-[ (E)-2-(2-carbamoyl-1- methylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate

In 1 ml of dimethylformamide was dissolved 0.1 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(2- carbamoylimidazo[1,2-b]pyridazin-6-yl)thio]vinyl-3- cephem-4-carboxylic acid benzhydryl ester, to which was added 1 ml of iodomethane, followed by stirring for 3 days at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added 50 ml of a mixture of ether and hexane (1:1). The supernatant was discarded by decantation. The residue was dissolved in 2.5 ml of methylene chloride, to which were added a 1 ml of anisole and 1.25 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 50 ml of ether, then resulting precipitate was collected by filtration. The precipitate was dissolved in 20 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 64 mg of 2-(5-amino- 1,2,4-thiadiazol-3-yl)-2(Z)-isopropoxyiminoacetyl chloride hydrochloride, while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The

reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P aqueous solution of ethanol column chromatography. Fractions eluted with a 25% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 40 rag of the titled compound.

Elemental Analysis for C ₂₄ H ₂₄ N ₁₀ O ₆ S ₃ • 4.5H ₂ 0: Calcd. : C, 39.72; H, 4.58; N, 19.30 Found : C, 39.65; H, 4.56; N, 19.22 NMR(DMSO-d ₆ ,δ) : 1.25(6H,m), 3.61(2H,m), 4.22(3H,s),

4.42(lH,m), 5.11 ( lH,d, J=4.8Hz ) ,

5.67(lH,dd,J=7.8&4.8Hz) , 6.62&7.47(each lH,d,J=15Hz) , 8.03&8.73(each lH,d,J=10Hz) , 8.21&8.75(each lH,bs), 8.16(2H,bs), 9.20(lH,s), 9.53(lH,d,J=7.8Hz) . Working Example 21

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-ethoxyimino¬ acetamido]-3-[(E)-2-(2-carbamoyl-1-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 1 ml of dimethylformamide was dissolved 0.1 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(2- carbamoylimidazo[1,2-b]pyridazin-6-yl)thio]vinyl-3- cephem-4-carboxylic acid benzhydryl ester. To the solution was added 1 ml of iodomethane, which was stirred for 3 days at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added 50 ml of a mixture of ether and hexane (1:1). The supernatant was discarded by decantation, and the residue was dissolved in 2.5 ml of methylene chloride. To the solution were added 1 ml of anisole

and 1.25 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 50 ml of ether, then resulting precipitate was collected by filtration. The precipitate was dissolved in 20 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice- cooling, 61 mg of 2-(5-amino-l,2,4-thiadiazol-3-yl)- 2(Z)-ethoxyiminoacetyl chloride hydrochloride, while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 40 mg of the titled compound. Elemental Analysis for C ₂₃ H ₂₂ N ₁₀ O ₆ S ₃ - 5.5H ₂ 0: Calcd.: C, 37.85; H, 4.56; N, 19.19 Found : C, 37.78; H, 4.34; N, 19.01 NMR(DMSO-d _6/ δ) : 1.24(3H,t,J=7Hz) , 3.61(2H,m), 4.19(2H,q,J=7Hz) , 4.22(3H,s), 5.11( lH,d,J=5Hz) , 5.67(lH,dd,J=8.2&5Hz) , 6.63&7.47 (each lH,d,J=15.8Hz) , 8.03&8.73(each lH,d,J=9.4Hz) , 8.21&8.75(each lH,bs), 8.18(2H,bs), 9.20(lH,s), 9.57 ( lH,d,J=8.2Hz) . Working Example 22

7β-[2-( 5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-cyclopent- yloxyiminoacetamido]-3-[ (E)-2-(2-carbamoyl-1- methylimidazo[ 1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.22 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(2- carbamoylimidazo[ l,2-b]pyridazin-6-yl)thio]vinyl-3- cephem-4-carboxylic acid benzhydryl ester. To the solution was added 2 ml of iodomethane, which was stirred for 3 days at room temperature. The reaction mixture was concentrated, to which was added 100 ml of a mixture of ether and hexane (1:1), followed by discarding the supernatant by decantation. The residue was dissolved in 5 ml of methylene chloride. To the solution were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. To the reaction mixture was added 100 ml of ether, then resulting precipitate was collected by filtration. The precipitate was dissolved in 40 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 141 mg of 2-(5-amino- 1,2,4-thiadiazol-3-yl)-2 (Z )-cyclopentyloxyiminoacetyl chloride hydrochloride, while the pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI CHP-20P column chromatography. Fractions eluted with a 35% aqueous solution of ethanol were collected and concentrated. The concentrate was lyophilized to give 63 rag of the titled compound. Elemental Analysis for C ₂ gH ₂ gN ₁₀ OgS ₃ •4.5H ₂ 0:

Calcd.: C, 41.54; H, 4.69; N, 18.63 Found : C, 41.35; H, 4.34; N, 18.48

NMR(DMSO-d ₆ ,δ) : 1.4-2.0(8H,m) , 3.60(2H,m), 4.23(3H,s),

4.74(lH,m), 5.11( lH,d,J=4.8Hz) , 5.66(lH,dd,J=8.6&4.8Hz) , 6.65&7.46 (each lH,d,J=15.6Hz) ,

8.03&8.74(each lH,d,J=8Hz), 8.22&8.82 (each lH,bs),

8.18(2H,bs), 9.22(lH,s), 9.54 ( lH,d,J=8.6Hz) .

Working Example 23

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2 (Z)-ethoxyimino- acetamido]-3-[ (E)-2-( 1-ethylimidazo[ 1, 2-b]pyridazinium-

6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethyIformamide was dissolved 0.2 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazof 1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 2.5 ml of iodoethane, and the mixture was stirred for two days at 40°C. To the reaction mixture was added 100 ml of a mixture of ether and hexane (1:1), followed by discarding the supernatant by decantation. The residue was dissolved in 5 ml of methylene chloride. To the solution were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid. The mixture was stirred for two hours at room temperature. The reaction mixture was added 100 ml of ether, then resulting precipitate was collected by filtration. The precipitate was dissolved in 40 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 127 mg of 2-(5-amino-

1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetyl chloride hydrochloride, while the pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated. The concentrate was lyophilized to give 96 mg of the titled compound. Elemental Analysis for C ₂₃ H ₂₃ N ₉ 0 ₅ S ₃ • 4.5H ₂ 0:

Calcd.: C, 40.46; H, 4.72; N, 18.46 Found : C, 40.36; H, 4.35; N, 18.62 NMR(DMSO-d ₆ ,δ) : 1.28 ( 3H, t , J=7Hz ) , 1.47 ( 3H, t , J=7Hz ) , 3.60(2H,m), 4.20 ( 2H,q, J=7Hz ) , 4.51 ( 2H,q, J=7Hz ) , 5.10(lH,d,J=5Hz) , 5.66(lH,dd,J=8.6&5Hz) , 6.61&7.48(each lH,d,J=15.8Hz) , 7.97&8.71(each lH,d,J=9.8Hz) , 8.48&8.73(each lH,d,J=2Hz), 8.18(2H,bs), 9.56(lH,d,J=8.6Hz) . Working Example 24 7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-methoxyimin- oacetamido]-3-[ (E)-2-(l-ethylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 2 ml of dimethylformamide was dissolved 0.2 g of 7β-t-butoxycarbonylamino-3-[ (E)-2-(imidazo[1,2- b]pyridazin-6-yl)thio]vinyl-3-cephem-4-carboxylic acid benzhydryl ester. To the solution was added 2.5 ml of iodoethane, which was stirred for two days at 40°C. To the reaction mixture was added 100 ml of a mixture of ether and hexane (1:1), then the supernatant was

discarded by decantation. The residue was dissolved in 5 ml of methylene chloride, to which were added 2 ml of anisole and 2.5 ml of trifluoroacetic acid, and the mixture was stirred for two hours at room temperature. To the reaction mixture was added 100 ml of ether, then resulting precipitate was collected by filtration. This precipitate was dissolved in 40 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice- cooling, 120 mg of 2-(5-amino-l,2 ,4-thiadiazol-3-yl)- 2(Z)-methoxyiminoacetyl chloride hydrochloride, while the pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 98 mg of the titled compound.

Elemental Analysis for C ₂₂ H ₂₁ N ₉ 0 ₅ S ₃ ■ 3.0H ₂ O: Calcd.: C, 41.18; H, 4.24; N, 19.64 Found : C, 41.05; H, 4.13; N, 19.79 NMR(DMSO-dg, δ) : 1.47 (3H,t,J=7Hz) , 3.60(2H,m), 3.94(3H,s), 4.52 (2H,q,J=7Hz) , 5.09( lH,d,J=4.8Hz) .

5.66(lH,dd,J=8.4&4.8Hz) , 6.61&7.49(each lH,d,J=15.8Hz) , 7.96&8.74(each lH,d,J=10Hz) , 8.49&8.73(each lH,s), 8.20(2H,bs), 9.59(lH,d,J=8.4Hz) . Working Example 25 7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2 (Z )-allyloxyimi- noacetamido]-3-[ (E)-2-( 1-methylimidazo[ 1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 40 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.23 g of 7β-amino-3-[ (E)-2-( 1- methylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 300 mg of 2-(5-amino-l,2,4-thiadiazol-3- yl)-2 (Z)-allyloxyiminoacetyl chloride hydrochloride, while the pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 25% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 130 mg of the titled compound.

Elemental Analysis for C ₂₃ H ₂₁ N ₉ 0 ₅ S ₃ • 4.0H ₂ O: Calcd.: C, 41.13; H, 4.35; N, 18.77 Found : C, 40.96; H, 4.06; N, 18.56 NMR(DMSO-d ₆ ,δ) : 3.59(2H,m), 4.08(3H,s), 4.68(2H,d,J=5.4Hz) , 5.09 ( lH,d,J=5.2Hz) , 5.30(2H,m), 5.67(lH,dd,J=8.4&5.2Hz) , 5.99(lH,m), 6.61&7.46 (each lH,d,J=16.2Hz) , 7.955.8.66(each lH,d,J=10Hz) , 8.38&8.69(each lH,d,J=2Hz), 8.20(2H,bs), 9.61(lH,d,J=8.4Hz) . Working Example 26

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-(2-fluoroet- hoxy)iminoacetamido]-3-[ (E)-2-( 1-methylimidazo[ 1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

- -

In 40 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.2 g of 7β-amino-3-[ (E)-2-(1- methylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 140 mg of 2-(5-amino-l,2,4-thiadiazol-3- yl)-2(Z)-(2-fluoroethoxy)iminoacetyl chloride hydrochloride, while the pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 25% aqueous solution of ethanol were collected and concentrated. The concentrate was lyophilized to give 89 mg of the titled compound. Elemental Analysis for C ₂₂ H ₂₀ FN ₉ O ₅ S ₃ •3.5H ₂ 0: Calcd.: C, 39.52; H, 4.07; N, 18.85 Found : C, 39.84; H, 3.80; N, 18.74 NMR(DMSO-d ₆ ,δ) : 3.59(2H,m), 4.08(3H,s),

4.40(2H,dt,J=28Hz & 3.4Hz), 4.69(2H,dt,J=48Hz & 3.4Hz) , 5.10(lH,d,J=4.8Hz) , 5.66(lH,dd,J=8.8&4.8Hz) , 6.61&7.46(each lH,d,J=15.8Hz) , 7.95&8.64(each lH,d,J=9.6Hz) , 8.37&8.70(each lH,d,J=2Hz), 8.21(2H,bs),

9.63(lH,d,J=8.8Hz) .

Working Example 27

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-fluorometho- xyiminoacetamido]-3-[ (E)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 160 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 1.6 g of 7β-araino-3-[ (E)-2- ( 1-methylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 1.07 g of 2-(5-amino-l,2,4-thiadiazol-3- yl)-2 (Z)-fluoromethoxyiminoacetyl chloride hydrochloride, while the pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. The reaction mixture was stirred for 30 minute at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 483 mg of the titled compound. Elemental Analysis for C ₂₁ H ₁₈ FN ₉ 0 ₅ S ₃ • 3.0H ₂ O: Calcd. : C, 39.06; H, 3.75; N, 19.52 Found : C, 39.15; H, 3.69; N, 19.27 NMR(DMSO-d ₆ ,δ) : 3.60(2H,m), 4.08(3H,s), 5.11(lH,d,J=5Hz) , 5.67 ( lH,dd,J=8&5Hz) , 5.80(2H,d,J=55Hz) , 6.61&7.47 (each lH,d,J=15.8Hz) , 7.95&8.66(each lH,d,J=9.6Hz) , 8.37&8.69 (each lH,d,J=2Hz), 8.26(2H,bs), 9.78 ( lH,d,J=8Hz) . Working Example 28

7β-[2-(5-Amino-l,2 , 4-thiadiazol-3-yl)-2(Z )-fluorometho- xyiminoacetamido]-3-[ (E)-2-( 1- carbamoylmethylimidazo[ 1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylate

In 40 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.19 g of 7β-amino-3-[ (E)-2-( 1- carbamoylmethylimidazo[ 1,2-b]pyridazinium-6- yl)thio]vinyl-3-cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 119 mg of 2-(5- amino-1,2 ,4-thiadiazol-3-yl)-2 (Z)-fluoromethoxyimino- acetyl chloride hydrochloride, while the pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C, and the reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated, which was lyophilized to give 80 mg of the titled compound. Elemental Analysis for C ₂₂ H ₁₉ FN ₁₀ O ₆ S ₃ • 3.5H ₂ 0: Calcd.: C, 37.87; H, 3.76; N, 20.08 Found : C, 37.98; H, 3.63; N, 20.18 NMR(DMSO-d ₆ ,δ) : 3.61(2H,m), 5.12 ( lH,d,J=4.8Hz) , 5.30(2H,s), 5.67(lH,dd,J=8&4.8Hz) , 5.81(2H,d,J=56Hz) , 6.64&7.49(each lH,d,J=15.6Hz) , 7.62&8.00(each lH,bs), 7.98&8.63(each lH,d,J=9.6Hz) , 8.40&8.74(each lH,d,J=2Hz), 8.26(2H,bs), 9.79 ( lH,d,J=8Hz) . Working Example 29

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-fluorometho- xyiminoacetamido]-3-[ (E)-2-( l-ethylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 40 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.2 g of 7β-amino-3-[ (E)-2-(1- ethy1imidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 131 mg of 2-(5-amino-l,2,4-thiadiazol-3- yl)-2(Z)-fluoromethoxyiminoacetyl chloride hydrochloride, while the pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated. The concentrate was lyophilized to give 67 mg of the titled compound. Elemental Analysis for C ₂₂ H ₂₀ FN ₉ O ₅ S ₃ •5.0H ₂ O: Calcd.: C, 37.98; H, 4.35; N, 18.12 Found : C, 38.07; H, 3.90; N, 18.46

NMR(DMSO-d ₅ ,δ) : 1.47(3H,t,J=7.4Hz) , 3.61(2H,m) , 4.51(2H,q,J=7.4Hz) , 5.11(lH,d,J=5Hz) , 5.65(lH,dd,J=8.4&5Hz) , 5.80(2H,d,J=56Hz) , 6.61&7.49(each lH,d,J=15.4Hz) , 7.96&8.71(each lH,d,J=10Hz) , 8.47&8.73(each lH,d,J=2Hz), 8.25(2H,bs), 9.78(lH,d,J=8.4Hz) . Working Example 30

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-(2,2,2-trif- luoroethoxy)iminoacetamido]-3-[ (E)-2-(1- methylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate

In 40 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.2 g of 7β-amino-3-[ (E)-2-( 1- methylimidazo[ 1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 5 ml of a tetrahydrofuran solution of 2- (5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-(2,2,2- trifluoroethoxy)iminoacetylchloride prepared from 270 mg of 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-(2,2,2- trifluoroethoxy)iminoacetic acid and 229 mg of phosphorus pentachloride, while adjusting the pH at 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to a MCI gel CHP-20P column chromatography. Fractions eluted with a 25% aqueous solution of ethanol were collected and concentrated. The concentrate was freeze-dried to give 15 mg of the titled compound. Elemental Analysis for C ₂₂ H ₁₈ F ₃ N ₉ 0 ₅ S ₃ - 5.0H ₂ O: Calcd.: C, 36.11; H, 3.86; N, 17.23 Found : C, 36.03; H, 3.86; N, 17.02 IR(KBr,cm ^"1 ) : 3400, 1770, 1680, 1605, 1520, 1380. NMR(DMSO-d ₆ ,δ) : 3.59(2H,m), 4.08(3H,s), 4.80(2H,m), 5.10(lH,d,J=5.2Hz) , 5.67 ( lH,dd,J=8&5.2Hz) , 6.62&7.47(each lH,d,J=15.8Hz) , 7.95&8.66 (each lH,d,J=9.4Hz) , 8.38&8.69(each lH,s), 8.25(2H,bs), 9.73(lH,d,J=8Hz) . Working Example 31

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z )-fluorometho-

xyiminoacetamido]-3-[ (Z)-2-(1-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 20 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.4 g of 7β-amino-3[ (Z)-2-(1- methylimidazof1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling while adjusting the pH at 8 with an aqueous solution of sodium hydrogen carbonate, 0.23 g of 2-(5- amino-l,2,4-thiadiazol-3-yl)-2(2)- fluoromethoxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to a MCI gel CHP-20P column chromatography. Fractions eluted with a 15% aqueous solution of ethanol were collected and concentrated. The concentrate was freeze-dried to give 113 mg of the titled compound.

Elemental Analysis for C ₂₂ H ₁₈ FN ₉ 0 ₅ S ₃ • 4.0H ₂ O: Calcd.: C, 38.00; H, 3.95; N, 18.99 Found : C, 38.16; H, 4.21; N, 18.83 IR(KBr,cm ^_1 ) : 3400, 1760, 1670, 1600, 1520, 1390, 1130. NMR(DMSO-d ₆ ,δ) : 3.68&3.84 ( 2H, ABq, J=16.2Hz ) ,

4.09(3H,s), 5.09(lH,d,J=5Hz), 5.67(lH,dd,J=8.4&5Hz) , 5.79(2H,d,J=55Hz) , 6.56&7.35(each lH,d,J=10.8Hz) , 7.95&8.66(each lH,d,J=9.8Hz) , 8.39&8.74(each lH,d,J=2Hz), 8.24(2H,bs), 9.75(lH,d,J=8.4Hz) . Working Example 32

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-ethoxyimino-

- Ill -

acetamido]-3-[ (Z)-2-(l-methylimidazo[1,2- b]pyridazinium-6-yl)thio]vinyl-3-cephem-4-carboxylate

In 20 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.25 g of 7β-amino-3-[ (Z)-2-(1- methy1imidazo[l,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling while adjusting the pH at 8 with an aqueous solution of sodium hydrogen carbonate, 0.16 g of 2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to a MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated. The concentrate was freeze-dried to give 117 mg of the titled compound.

Elemental Analysis for C ₂₂ H ₂₁ N ₉ 0 ₅ S ₃ • 3.5H ₂ 0: Calcd.: C, 40.61; H, 4.34; N, 19.37 Found : C, 40.81; H, 4.20; N, 19.27 IR(KBr,cm ^"1 ) : 3400, 1760, 1670, 1600, 1520, 1380, 1130. NMR(DMSO-d ₆ ,δ) : 1.27 ( 3H, t , J=7Hz ) ,

3.676.3.83(2H,ABq,J=16Hz) , 4.09(3H,s), 4.19(2H,q,J=7Hz) , 5.08(lH,d,J=5Hz) , 5.67(lH,dd,J=8.4&5Hz) , 6.56&7.32(each lH,d,J=HHz) , 7.95&8.66(each lH,d,J=9.2Hz) , 8.40&8.73(each lH.s), 8.20(2H,bs), 9.55(lH,d,J=8.4Hz) . Working Example 33

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyl-

oxy iminoacetamido ] -3- [ ( E ) -2- ( 3-amino-l- methylimidazo [ 1 , 2-b ] pyridazinium-6-yl ) thio ] vinyl -3- cephem-4-carboxylate

In 40 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.3 g of 7β-amino-3-[ (E)-2-(3-amino -1-methylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling while adjusting the pH at 8 with an aqueous solution of sodium hydrogen carbonate, 0.19 g of 2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxyimin¬ oacetyl chloride hydrochloride, and the mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to a MCI gel CHP- 20P column chromatography. Fractions eluted with a 35% aqueous solution of ethanol were collected and concentrated. The concentrate was freeze-dried to give 95 mg of the titled compound. Elemental Analysis for C ₂₅ H ₂ gN ₁₀ O ₅ S ₃ •4.0H ₂ O: Calcd.: C, 42.01; H, 4.79; N, 19.60 Found : C, 41.98; H, 4.69; N, 19.39

IR(KBr,cm ^"1 ) : 3350, 1760, 1650, 1600, 1540, 1390, 1360. NMR(DMSO-d ₆ ,δ) : 1.4~2.0(8H,m) ,

3.56&3.77(2H,ABq,J=17Hz) , 3.98(3H,s), 4.75(lH,m) , 5.08(lH,d,J=5.2Hz) , 5.64(lH,dd,J=8.4S.5.2Hz) , 6.62(2H,bs), 6.79&7.49(each lH,d,J=16.2Hz) , 7.38(lH,s), 7.57&8.43(each lH,d,J=9.4Hz) , 8.17(2H,bs),

9 . 52 ( lH , d , J=8 . 4Hz ) .

Working Example 34

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-fluorometho- xyiminoacetamido]-3-[ (E)-2-(3-amino-1- methylimidazo[ 1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate

In 40 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.3 g of 7β-amino-3-[ (E)-2-(3-amino -l-methylimidazo[l,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylic acid trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate, 0.2 g of 2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyimino- acetyl chloride hydrochloride. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to a MCI gel CHP-20P column chromatography. Fractions eluted with a 20% aqueous solution of ethanol were collected and concentrated. The concentrate was freeze-dried to give 83 mg of the titled compound.

Elemental Analysis for C ₂₁ H ₁₉ FN ₁₀ O ₅ S ₃ • 4.0H ₂ O: Calcd.: C, 37.16; H, 4.01; N, 20.64 Found : C, 37.05; H, 4.20; N, 20.36 IR(KBr,cm ^"1 ) : 3350, 1760, 1650, 1600, 1540, 1390, 1360, 1130, 1060.

NMR(DMSO-d ₆ ,δ) : 3.54&3.87(2H,ABq,J=17Hz) , 3.98(3H,s),

5.09(lH,d,J=4.8Hz), 5.66 ( lH,dd,J=8.2&4.8Hz) , 5.81(2H,d,J=56Hz) , 6.62(2H,bs), 6.78&7.51(each lH,d,J=15.8Hz) , 7.38(lH,s), 7.58&8.43(each lH,d,J=9.6Hz) , 8.26(2H,bs), 9.77( lH,d,J=8.2Hz) . Working Example 35

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2{Z)-fluorometho- xyiminoacetamido]-3-[ (E)-2-( 1-methylimidazo[ 1,2- a]pyridinium-5-yl)thio]vinyl-3-cephem-4-carboxylate

In 40 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.2 g of 7β-amino-3-[ (E)-2-( 1- methylimidazo[l,2-a]pyridinium-5-yl)thio]vinyl-3- cephem-4-carboxylate trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate, 0.116 g of 2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z )-fluoromethoxyimino- acetyl chloride hydrochloride, and the mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated. The concentrate was subjected to a MCI gel CHP-20P column chromatography. Fractions eluted with a 30% aqueous solution of ethanol were collected and concentrated. The concentrate was freeze-dried to give 69 mg of the titled compound. Elemental Analysis for C ₂₂ H ₁₉ FN ₈ 0 ₅ S ₃ • 3.0H ₂ O: Calcd.: C, 40.99; H, 3.91; N, 17.38 Found : C, 41.17; H, 3.65; N, 16.96

IR(KBr,cm ^"1 ) : 3400, 1760, 1670, 1610, 1510, 1380, 1350.

NMR(DMSO-d ₆ ,δ) : 3.52S.3.70(2H,ABq,J=17Hz) , 4.07(3H,s), 5.10(lH,d,J=5.2Hz) , 5.67 ( lH,dd,J=8.8&5.2Hz) , 5.80(2H,d,J=55Hz), 6.42&7.58(each lH,d,J=15Hz) , 7.57(lH,m), 7.9~8.1(2H,m) , 8.26(2H,bs), 8.37(lH,d,J=2Hz), 8.40( lH,d,J=2Hz) , 9.77 ( lH,d,J=8.8Hz) Working Example 36

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2 (Z)- cyclopentyloxyiminoacetamido]-3-[ (E)-2-( 1- methylimidazof 1,2-a] pyridinium-5-yl)thio]vinyl-3- cephem-4-carboxylate

In 40 ml of a mixture of tetrahydrofuran and water (1:1) was dissolved 0.2 g of 7β-amino-3-[ (E)-2-( 1- methylimidazo[1,2-a]pyridinium-5-yl)thio]vinyl-3- cephem-4-carboxylate trifluoroacetate, whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate, 0.131 g of 2-(5- amino-1,2,4-thiadiazol-3-yl)-2 (Z)- cyclopentyloxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was concentrated, which was subjected to a MCI gel CHP-20P column chromatography. Fractions eluted with a 35% aqueous solution of ethanol were collected and concentrated. The concentrate was freeze-dried to give 72 mg of the titled compound. Elemental Analysis for C ₂₆ H ₂₆ N ₈ 0 ₅ S ₃ • 3.0H ₂ O: Calcd.: C, 41.79; H, 4.09; N, 18.28

Found : C, 41.77; H, 4.23; N, 17.96

IR(KBr,cra ^"1 ) : 3400, 1760, 1630, 1610, 1510, 1380, 1350. NMR(DMSO-d _6/ δ) : 1.6~1.9 ( 8H,m) , 3.60(2H,m), 4.07(3H,s), 4.73(lH,m), 5.08( lH,d,J=5Hz) , 5.64 ( lH,dd,J=8.4&5Hz) , 6.435.7.57 (each lH,d,J=15Hz) , 7.60(lH,m), 7.9~8.2 (2H,m) , 8.15(2H,bs), 8.37(lH,d,J=2Hz) , 8.39 ( lH,d,J=2Hz) , 9.50(lH,d,J=8.4Hz) . Working Example 37

Sodium 7β-[2-(5-carboxylatoamino-l,2,4-thiadiazol-3-yl) -2 (Z )-fluoromethoxyiminoacetamido]-3-[ (E)-2-( 1- methylimidazo[1,2-b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate

In a mixture of 60 ml of a 50% aqueous solution of ethanol and 1 ml of IN hydrochloric acid was dissolved 591 mg of 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2 (Z)- fluoromethoxyiminoacetamido]-3-[ (E)-2-( 1- methy1imidazo[1,2 -b]pyridazinium-6-yl)thio]vinyl-3- cephem-4-carboxylate. To this solution was added 5 ml of a IN aqueous solution of sodium hydrogen carbonate, then the reaction mixture was left for 6 hours at room temperature. The reaction mixture was then concentrated under reduced pressure. The concentrate was subjected to a sephadex LH-20 column chromatography (1000 ml). Fractions eluted with water were collected and concentrated. The concentrate was freeze-dried to give 96 rag of the titled compound.

NMR(DMSO-d ₆ ,δ) : 3.55&3.68(2H,ABq,J=17Hz) , 4.08(3H,s), 5.12(lH,d,J=5Hz) , 5.69 ( lH,dd,J=8&5Hz) , 5.80(2H,d,J=57Hz) , 6.64&7.50(each lH,d,J=15.8Hz) , 7.965.8.66 (each lH,d,J=9.8Hz) , 8.385.8.71(each

lH,d,J=2Hz), 9.74(lH,d,J=8Hz) , 9.99(lH,bs) .

INDUSTRIAL APPLICABILITY The cephem compounds [I] or their esters or salts have a broad antibacterial spectrum and an excellent antibacterial activity against Gram-negative bacteria including those belonging to the genus Pseudomonas and Gram-positive bacteria including Staphylococcus aureus and MRSA. Thus, antibacterial agents effective against infectious diseases caused by these bacteria are provided.