Antibacterial Compounds,Their Production and Use

This invention relates to novel antibacterial compounds having excellent antibacterial ac ion, a method of preparing the same and a pharmaceutical composition containing the same.

A variety of cephe compounds having a quaternary ^• ammoniomethyi group at 'the 3-position and 2-(2-amino- thiazol-4-yi) -2-hycrox (or substituted hydrαxy) imino- acetamido group at the 7-position simultaneously have so far been synthesized, and

4 patent applications [for instance, Japanese Publication of ϋnexamined Application (Kokai) Sho-53-34795, Sho- 54-9296, Shc-34-135792, Sho-54-154786, Shα-55-149289, Sho-57-35435, Sho-37-192394, Sho-58-15949S, etc.] concerning these compounds have been published. However, most of the compounds, whose quaternary ammσπiαmethyl group at the 3-position has a nitrogen-containing aromatic heterocyclic ring, are those having a monocyclic -a pyridiniu group with or without a substituent or substituents on the ring thereof, and the compounds of the present invention having an imidazolium-1-yl group

which forms a condensed ring at the 2,3-position or the 3,4-position have never been disclosed in the specifica¬ tion of any patent application, not to spea of a report of the synthesis thereof.

Cephem-type antibiotics have been widely used for the therapy of diseases of human beings and animals caused by pathogenic bacteria. These compounds are especially useful for the therapy of diseases caused by bacteria resistant to penicillin-type antibiotics as well as for the therapy of penicillin-sensitive patients. In these cases, it is desirable to use cephem-type antibiotics showing activity against both gram-positive and gram-negative bacteria. For this reason, extensive studies on cephem-type antibiotics having a wide antibacterial spectrum have been carried out. As a result of research work covering a long period of time, it has been found thar introduction of 2-(2-aminothiazol-4-yl)-2-hyάroxy (or substituted hydroxy) i inoacetamido group or nitrogen-containing heterocycle-aminσ group at the 7— osition of cephem ring renders the cephem compound ac ive against both gram-positive and gram-negative bacteria, which has led to the exploitation and develoc ent of what is called

"the third generation cephalospσrin". At present, several types of the third generation cephalosporin

compounds have already been put on the market. Another characteristic feature of these third generation cephalosporin antibiotics lies in that these substances are active against the so-called cephalαsporin-resistant bacteria, which penicillins have also encountered.

More specifically, cephem compounds of the third generation showed antibacterial action to such an extent as to make them clinically usable against some strains of Escherichia cpli some of the bacteria belonging to the genus Citrobacter and most of the bacteria belonging to the genus Proteus that are positive to indole reactions as well as against most of the phathogenic ¹ bacteria classified into the genus Enterobacter , Serratia or Pseuάomonas.

However, the third generation cephalosporin compounds are not always satisfactory. Their antibacterial activities for example against Pseudomonas are not satisfactorily strong.

^' <S

More concretely, the present invention relates to a compound of the formula:

wherein R is an amino group which may be protected,

R is a hydrogen atom or an optionally substituted hydro-

4 carbon residue; Z is S, S →- 0, 0 or CH_, R is a hydrogen atom, methoxy group or formamido group, R 13 is a hydrogen atom, methyl group, hydroxyl group or halogen atom and A-^ is an optionally substituted imidazolium-1-yl group forming a condensed ring at the 2,3- or 3,4-position or a pharmaceutically acceptable salt or ester thereof (the compound [I] , and pharmaceutically acceptable salt and ester thereof may simply be abbreviated hereinafter as the compound [I] or the antibacterial compound [I] ) .

More specifically, the antibacterial compounds of the present invention are cephem compounds represented by the formula [I] (Z=S, S-M3) as well as oxa-(Z=0) or carba-(Z=CH ₂ ) derivatives thereof.

The cephem compounds in the present specification are a group of compounds named on the basis of "cepham" disclosed in "The Journal of

the American Chemical Society" Vol. 84, p. 3400 (1962) , and mean, among the cepham compounds, those having a double bond at the the 3,4-position.

As stated hereinbefore, it has gradually become apparent that a cephem compound as well as oxa- or carba-derivatives thereof having a quaternary ammoniomethyi group at the 3-position and an amincthiazcl loxviminoacetamidc rouz or nitrocen— containing heterocycle-amino group at the 7-poεition simultaneously has especially excellent antibacterial activity and specific antibacterial spectrum. A number of compounds having a nitrogen-containing aromatic heterccyclic ring as the quaternary ammoniomethyi group at the 3-position have already been synthesized and corresponding patent applications have been published. Most of those heterocyclic rings are monocyciic pyridinium groups or those having a substituent on the ring thereof, and compounds of this invention having an imidazolium-1-yl group which forms a condensed ring at the 2,3-position or the 3,4-position have not been syn¬ thesized at all. The present inventors succeeded in synthesizing the compounds represented by the formula [I] having such structural features, and examined the antibacterial activities and antibacterial spectrum, resulting in the findings that the compounds

[I] or their phamaceutically acceptable salts or esters have strong antibacterial action against various bacteria, especially against cephalosporin-resistant bacteria, and that they show specific antibacterial action against bacteria belonging to the genus Pseudomonas, and completed the present invention.

. Reference is made as follows to the group names and symbols used in the present specification. Unless otherwise specifically defined, those groups and symbols are of the following meanings respectively.

¹¹ Alky1 group" is preferably a straight-chain or branched lower alkyl group having l-€ carbon atoms (hereinafter sometimes mentioned briefly as "C. _ , alkyl group") , which is exemplified by me hyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.

"Alkenyl group" is preferably a straight-chain or branched lower alkenyl group having 2-6 carbon atoms (hereinafter sometimes mentioned brieflv " as "C- m. "α. alkenyl group") , which is exemplified by vinyl, allyl, 1-ρropenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, methallyl, or 1,1-dimethylallyl.

"Alkynyl group" is preferably a straight-chain or branched lower alkynyl group having 2-5 carbon atoms

(hereinafter sometimes mentioned brieflv - as "C-.—o. alkynyl group"), which is exemplified by ethynyi, 1-propynyl or propargyl.

"Cycloalkyl group" is preferably a 3-7 membered alicyclic hydrocarbon group having 3-10 carbon atoms (hereinafter sometimes mentioned briefly as ^{,, (} ^2-l _Q ^c Y ^σlo ~ alkyl group"), which is exemplified by cyclopropyl.

cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbσmyl or adamantyl.

"Cycloalkenyl group" is preferably a 5-6 membered alicyclic hydrocarbon group having one or two double bonds (herein¬ after sometimes mentioned briefly as "C_ . cycloalkenyl group"), which is exemplified by cyclopentenyi, cyclo- pentadienyl, cyciohexenyl or cyciohexadienyl.

"Aryl group" is preferably an aromatic hydrocarbon group having 6-10 carbon atoms (hereinafter sometimes mentioned briefly as "C._ _7Q aryl group"), which is exemplified by phenyi, -naphthyl, . -naphthyl or biphenylyl.

"Aralkyl group" is. preferably an arαπatically substituted alkyl group having 7-12 carbon atoms (hereinafter sometimes mentioned briefly as "C-,_,- aralkyl group") , which is exemplified by benzyl, 1-phenyiethyl, 2-phenyl- ethyl, phenylpropyl or naphthylmethyl. Incidentally, the <2 aralkyl group, in combination with the di-

C. _, _Q aryl-methyl group and tri-C ₈ _ _1Q aryl-methyl group, is sometimes stated as "C /.-1,9 _n aralkv-l σro σ".

"DiaryImethyl group" means methyl group substituted with two C _g _ _1Q aryl groups mentioned above (hereinafter sometimes mentioned briefly as ^!, di-Cg_ _1Q aryl-methyl group") , which is exemplified by benzhydryl.

"Triarylmethyl group" means methyl group substituted with three C _fi , _Q aryl groups mentioned above (herein-

after sometimes mentioned briefly as "tri-C ₈ , _Q aryl- methyl group" ) , which is exemplified by trityl.

The aryl group of the "aryl ethylene group" is preferably a ^C ₆ - ₁₀ ^ar y ¹ g" ^rou ? mentioned above; hence the "arylmethylene group" is hereinafter sometimes called a "c. _ _{ι n} aryl¬ methylene group" , which is exemplified by benzylidene

The alkyl group of the "alkoxy group" is preferably a C, . alkyl group mentioned above; hence the "alkoxy group" is hereinafter sometimes called a "C. . alkoxy group", which is exemplified by methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, amyloxy or hexyloxy.

The cycloalkyl group of the "cycloalkyloxy group" is preferably a . , _Q cycloalkyl group mentioned above; hence the "cycloalkyloxy group" is hereinafter sometimes called a"C, , _n cycloalkyloxy group", which is exemplified by cyclopropyloxy, cyclopentyloxy, cycichexyioxy or norbornyloxy.

The aryl group of the "aryloxy group" is preferably a C ₆ _ _1Q aryl group mentioned above; hence the "aryloxy group" is hereinafter sαretimes called a ^: "r ,„ arvloxy grouo", which

6-10 - is exemplified by phenoxy or naphthyloxy.

The aralkyl group of the "aralkyloxy group" is preferably a C_ , _g aralkyl group mentioned above; hence the

"aralkyloxy group" is hereinafter sometimes called a "C ₇ _ _1g aralkyloxy group", which is exemplified by benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, naphthyl ethyloxy, benzhydryloxy or trityloxy.

The alkyl group of the "alkyithio group" is preferably a C-_. alkyl group mentioned above hence the "alkyithio group" is hereinafter sometimes called a "C-^_g alkyi¬ thio gr up", which is exemplified by methylthio, ethylthic, n-propylthio or n-butylthio.

The alkyithio group of the "aminoalkylthio group" is preferably a C, 1— o. aik ithio σrouo mentioned above; hence the

"aminoalkylthio group" is hereinafter called ^' an "a inoi C, _ _g alkyithio group" , which is exemplified by a ino- methylthio , 2-amincethy ithio or 3-aminopropylthio .

The alkenyl group of the " alkenyl thio group" is preferably a C ._£ — O . al: anyl σ "rour; mentioned above ; hence the

"alkenylthio group" is hereinafter sometimes called a

"C2--o. alkenv ^* lthio crouD", which is exeπrolified by vinylthio, ailylthio, 1-propenylthio or isopropenyIthio.

The cycloalkyl grotφ of the "cycloalkyIthio group" is preferably a C, , _n cycloalkyl group mentioned above; hence the "cycloalkyIthio group" is hereinafter sometimes called a "C ₃ _ ₁₀ cycloalkylthio group, which is exemplified by cyclopropylthio or cyclohexylthio.

The aryl group of the "arylthio group" is preferably a

^C 6-10 ^ar ^ 9 ^rou P mentioned above; hence the "arylthio group" is hereinafer sometimes called a " ₆ _ιo arylthio group", which is exemplified by phenyIthio or naphthylthio.

The aralkyl group of the "aralkylthio group" is preferably a C, _lα aralkyl group mentioned above, hence the "aralkyi-hio group" 'is hereinafter sometimes called a "Cη-. aralkylthio group", which is exemplified by benzyl~hio, pheny1 thylthio, benzhydr ithio or trityIthio.

The alkyl group of the "mo oalkylamino group" is preferably a cJ,.—o. alkyl grouc mentioned above; hence the

"moncaikvlamino σro c" is hereina ~ar sometimes called a"mono-C,l-β. aikv-la ino c -rouc .", r which is exemplified by me-_. yiamino, ethylamino, n-propyiamino, n-butylamino, ter--b tyiamino, n-pentylamino or n-hexylamino.

.The alkyl group of the "dialkylamino group" is preferably m _ r. alkyl group mentioned above; hence the "dialkylamino group" is hereinafter sometimes called a "di-C-, g al_-.ylazr.inc croup", which is exemplified by dime-hyiamino, ciethylamino, methylethyla ino, di- (n-propyl) amino or di-(n-bu yl) mino.

The alkyl croup of the "trialkylammonium σrouo" is creferablv a C, _. alkvl σrouo mentioned above; hence "trialkylammonium group" is hereinafter some¬ times called a ^{' »} tri-C. _, alkylam onium grouo", which is exemplified by trimethylammonium [ (CH-) -IT"'-] or triethyl- ammonium. The trialkylammonium group is usually

accompanied by a corresponding anion exemplified by a halogenide ion (chloride ion, bromide ion, iodide ion, etc.), sulfate ion, nitrate ion, carbonate ion, organic carboxylate ion (e.g. oxalate ion or trifiucroacetate ion) , organic sulfonate ion (e.g. methanesuifonate ion or p-toluenesulfonate ion) . The organic carboxylate ion and the organic sulfonate ion may sometimes be intramolecular ones.

The cycloalkyl group of the "cycloalkylamino group" is preferably a C, _j _ ₀ cycloalkyl group mentioned above; hence the "cycloalkylamino group" is hereinafter sαπetimes called a ^' "C ₃ _ _1Q cycloalkylamino", which is exemplified by cyclopropylamino, eyelopentylamino or cyclohexylamino.

The aryl group of the "arylamino group" is preferably a ^" ₆ -1 ₀ ^ar Y^- 9" ^rou ? mentioned above? hence "arylamino group" is hereinafter sometimes called a "C_o.—,. _n U arylamino group", which is exemplified by anilino or N-methylanilinc.

The aralkyl group of the "aralkyla ino group" is preferably a C_—- m. _Q I? araikv"i grou Ό " mentioned above; hence

"aralkyiaminc group" is hereinafter sometimes called a"C__ _{7 g} aralkylamino group", which is exemplified by benzylamino, 1-phenyiethylamino, 2-phenylethylamino, benzhydrylamino or tritylamino.

"Cyclic amino group" means a group formed by removing one of the hydrogen atoms attached to the ring- constituting nitrogen atom of a nitrogen-containing hetero- cyclic ring as described hereafter, which is exemplified by lH-tetrazσi-1-yl, IH-pyrrol-l-yl, pyrrolino, pyrrolidino, IΞ-imidazol-l-yl, imidazoiino, imidazolidino, lH-pyrazol-1-yi, pyrazoiino, pyrazolidino, piperidino , piperazino or morpholino.

The alkyl group of the "hydroxyalkyl group" is preferably a C, g alkyl group mentioned above; hence the "hydroxyalkyl group" is hereinafter sometimes called a "hydroxy - _j __ alkyl group", which is exemplified by hydroxymeth l, 1-hydfoxyethyl, 2-hydroxyethyl or 3-hydrσxypropyl.

i ^' The alkyl group of the "mercaptoalkyl group" is preferably a C, _g alkyl group mentioned above; hence the "mercaptoalkyl group" is hereinafter sometimes called a"mercaoto C. _.—o. alkv-l σrouo", which is exemDlified by mercaptomethyl, i-mercaptαethyl or 2-mercaptoethyl. The alkoxy group of the "alkoxyalkyl group" is preferablv a C- . alkoxy cro o mentioned above and the alkyl group of the "alkoxyalkyl group" is preferably a C-_. alkyl group mentioned above, ^* hence the "alkoxyalkyl group" ^is hereinafter sometimes called _a " ^c i-6 alkoxy C-, _g alkyl group", which is exemplified by methoxy- methyl, ethoxymethyl or 2-methoxyethyl.

The alkyithio group of the "alkylthioalkyl group" is preferably a c.χ—0 _. alkv~lthio c"rouo mentioned above and the alkyl group of the "alkylthioalkyl group" is preferably a C»_g alkyl group mentioned above, hence the "alkylthio¬ alkyl group" is ^• hereinafter sometimes called a

"Clm-o. alkv-lthio C,l-o. alkv-l σrouo", which is exemolified by methylthiomethyl or 2-methylthioethyl.

The alkyl group of the "aminoalkyl group" is preferably a C- - alkyl group mentioned above; hence the "aminoalkyl group" is hereinafter sometimes called an "amino C._ ₆ alkyl group", which is exemplified by aminomethyl, 2- aminoethyl or 3-aminopropyl.

"Monoalkylaminoalkyl group" is preferably a "mono- C, ₆ alkyl amino C, _g alkyl group", which is exemplified

by methylaminomethyl , ethyl aminomethyl , 2- (K-methyl- amino) ethyl or 3- (N-methy lamino) propyl .

"Diaikyl amino alkyl group" is preferably a "di-C, _g alkylamino C, _g alkyl group" , which is exemplified by N , N-dimethy la inomethyl , N , N-die h laminomethy 1 , 2- ( , N-dimethy lamino) ethyl , 2- (K ,K-diethy lamino) ethyl or - (K , -diethy lamino ) ropyl .

The cyclic amino group of the "cyclic aminoalkyl group" is preferably the one mentioned above and the alkyl group of the "cyclic aminoalkyl group" is preferably a C~ _g alkyl group mentioned above ,- hence hereinafter the "cyclic amino¬ alkyl group" is sometimes called a "cyclic amino C^_g alkyl group" , which is exemplified by pyrroiidinomethyl , piperidinomethyi , piperazinomethyl , mcrpholinom ethyl or

2- (morphplino) ethyl .

The cyclic aminoalkyl group of the "cyclic aminoal ylamino group" is preferably cyclic amino C. . aikvi σrouo mentioned above-, hence . . i— o ~ hereinafter the "cyclic aminoalky lamino group" is sometimes called a "cyclic amino C- . al ylamino grouc" , which is εx~πcϋ ied bv* pyrrolidincme -hyiaminc, piperizir icme thyisminc , oioerazincrr_: -±.vi=mino or mo rpbolinomethylamino .

The alkyl group of the "h logenoalkyl group" is preferably a C _1-6 alkyl group mentioned above; hence hereinafter the "halogenoal yl group" is sometimes called a ^' "haloσeno C, _. alkvl crouc" , which is exemplified

1-6 - ' by fluoromethyl, difluorσ ethyl, trifluorα e-hyl, cnloromethyl, di- chloromethyl, trichlorσmethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 2-chloroethyl, 2,2-^iLchloroethyl, 2,2,2-trichloroethyl, 2-brσmoethyl or 2-iodoethyl.

The alkyl group of the "cyanoalkyl group" is preferably a C ₁ _g alky group mentioned above; hence hereinafter the "cyanoalkyl group" is sometimes called a "cyano C, _g alkyl group", which is exemplified by cyanomethyl or 2-cyanoethyl.

The alkyl group of the "σarboxyalkyl group" is-pref rably a C, g alkyl group mentioned above; hence hereinafter the "carboxyalkyl group" - is called sometimes a "carboxy C _1-g alkyl group", which is exemplified by carboxymethyi, 1-carboxyethyl or 2-carboxyethyl.

The alkyl group of the "sulfoalkyl group" is preferably a C, _g alkyl group mentioned above; hence hereinafter the "sulfoalkyl group" 'is called sometimes a "sulfo C, _g alkyl group", which is exemplified by sulfomethyl or 2-sulfoethyl.

The alkanoyl group of the "alkanoylalkyl group" is preferably a C ₂ _ _δ alkanoyl group mentioned hereafter and the alkyl group of the "alkanoylalkyl group" is preferably a

C _j _. alkyl group mentioned above; hence hereinafter the

"alkanoylalkv-l σrouπ-" is sometimes called a "C-—o- alkanov-l

Ci—o. alkv-l σ ^■ *rouo~", which is exemo-lified bv ^. acetv-lmethv-l,

1-acetylethyl or 2-acetylethyl.

The alkanoyloxy group of the "alkanoyloxyalkyl group" is preferably a C ₂ _galkanoyloxy group to be described hereafter and the alkyl group of the "alkanoyloxyalkyl group" is preferably a C._, alkyl group mentioned above; hence . ^" hereinafter the "alkanoyloxyalkyl group" is sometimes called a "C ₂ _ ₆ alkanoyloxy C, _g alkyl group" , which is exemplified by acetoxymethyl, 1-acetoxyethyl or 2-acetoxyethyl.

The alkoxycarbonyl group of the "alkoxycarbonylalkyl group" is preferably a ^ _Q alkoxy-carbonyl group to be described hereafter and the alkyl group of the "alkoxycarbonylakyl group" is preferably a ^c χ _« g alkyl group mentioned above?

hence hereinafter the "alkoxyσarbonylalkyl group" is sometimes called a "C ₁ _ _1Q alkoxy-carbonyl C ₁ _ ₆ alkyl group", which is exemplified by methoxycarbonylmethyl, ethoxy- carbonylmethyi or tert-butoxycarbonylmethyl.

The alkyl group of the "carbamoylalkyl group" is preferably a C-, - alkyl group; hence hereinafter the "carbamoyalkyl-group" is sometimes called a "carbamcyi C,_ _. alkyl group", which is exemplified by carbamoylmethyi.

The alkyl group of the "carbamcyloxyalkyi group" is preferably a C, _g alkyl group; hence hereinafter the "carbamoyl alkyl group" is called sometimes a ^,r carbamoyloxy C ₁ _g alkyl group", which is exemplified by carbamoyloxymethyl.

"Halogen atom" is exemplified by fluorine, chlorine, bromine or iodine.

"Alkanoyl group" is preferably an aliphatic acyl group having 1-6 carbon atoms (hereinafter sometimes called simoly *. "C,J.—o. alkanov-l σ- ^■ rouc", which is exemplified bv for yi, acetyl, propionyi, butyryl, isobutyryl, valeryi, isovaleryl or pivaloyi. These alkanoyl groups, except formyi, are sometimes called a"C 2_-o. alkanov ~l σrouo" .

"Alkenoyl group" is preferably one having 3 to 5 carbon atoms (hereinafter sometimes simply called "C~_- alkenoyl group" ) , which is exemplified by acryloyl , crotonoyl or maleoyl .

The cycloalkyl group of the "cycloalkylcarbonyl group" is preferably a C ₃ _ ₁₀ cycloalkyl group mentioned above ; hence hereinafter the "cycloalkyl carbonyl group" is sometimes called a "C ₃ _ _1Q cycloalkyl-carbonyl group" , which is

exemplified by cyclopropylcarbonyl, cyσlobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl or ada antylcarbonyl.

The cycloalkenyl group of the "cycloalkenylcarbonyi group" is preferably a Cg_ cycloalkenyl group; hence hereinafter the "cycloalkenylcarbonyi group" . is called sometimes a "C5_g ^' cycloalkenyl-carbonyl group", which is exemplified by cyclopentenylcarbonyl, cyclopentadienylcarbonyl, cycic- hexenylcarbonyl or cyclohexadienylcarbonyl.

The aryl group of the"arylcarbonyl group" is preferably Cg_, _α aryl group mentioned above; hence hereinafter the "arylcarbonyl group" is called sometimes a 'C ₈ - _i α aryl- carbonyl group", which is exemplified by benzoyi or naphthoyi.

The aralkyl group of the "aralkylcarbonyl group" is preferably a - _Q aralkyl group; hence hereinafter the "aralkyl carbonyl group" is someti ed called a "C ₇ _ _1G aralkyl¬ carbonyl group", which is exemplified by phenylacetyl, phenylpropionyl, α,α-diphenylacetyl or ,α,α-triphenylacetyl.

The alkyl group of the "alkoxycarbonyl group" includes, in this specification, a C ₃ _-, _Q cycloalkyl group mentioned above, besides lower alkyl groups having 1-8 carbon atoms; hence hereinafter the "alkoxycarbonyl group" is sometimes called a ^' "C, , _Q alkoxy-carbonyl group", which is exemplified by methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxy- carbonyl or norbornyloxycarbonyl.

The aryloxy group of the "aryloxycarbonyl group" is preferably a C _fi , _Q aryloxy group mentioneα above; hence

hereinafter the "aryloxycarbonyl group" is sometimes called a

" ^C 6-10 ^ar y ² - ^oχ y~ ^cari30n y^ group", which is exemplified by phenoxycarbonyl or naphthyioxycarbonyl.

The aralkyloxy group of -the "aralkyloxycarbonyl group" is preferably a G. -, _g aralkyloxy group mentioned above, which is exemplified by benzyioxycarbonyi, benzhydryloxy- carbonyl or tritylσxycarbαnyi.

"Substituted oxycarhαnyl group" means the above- mentioned C, ,- alkoxy-carbonyi group, C _g , _fl aryloxy¬ carbonyl group or C__.. _α aralkyioxy-carbcnyl group.

The alkyithio group of the "alkyIthiocarbσnyl group" is preferably a ^' ol— _o. alkv~ithiα σ " o ^ ~ mentioned above; hence the

"alkylthiocarbonyl group" is hereinafter called sometimes a "C,1—o- alkylthic-carbonyl σ"rouo~", which is exemplified by methylthiocarbonyl, ethylthiocarbonyl, n-propylthiocarbonyl or n-butylthiocarbonyl.

The alkanoyl group of the "alkanoyloxy group" is preferably a Cχ-6alkanoyl group mentioned above; hence the "alkanoyloxy group" is hereinafter called a ^" ' ^.g alkanoyloxy group, which is exemplified by formyloxy, acetoxy, propionyloxy, butyryloxy, valeryloxy or pivaloyloxy. These alkanoyloxy groups, except formyloxy, are sometimes called a "C 2_-6 _. alkanovloxy group".

The alkenoyl group of the "alkenoyloxy group" is preferably a C_g alkenoyl group mentioned above; hence the "alkenoyloxy group" is hereinafter called sometimes a "C ₃ _ ₅ alkenoyloxy group", which is exemplified by acryloyloxy

or crotonoyloxy.

The alkyl group of the "monoalkylcarba oyl group" is preferably a G. -alkyl group mentioned above; hence the

J.—α

"monoalkylcarbamoyl group" is hereinafter sometimes called a "mono-C, - alkylcarbamoyl group", which is exemplified, by I-methylcarbamoyl or M-ethylcarbamoyi.

The alkyl group of ^the "dialkylcarbamoyl group" is preferably a C _j _ ₆ ally! group,- hence the "dialkylcarbamoyl group" is hereinafter sometimes called a "di-C, _-

1—σ alkylcarbamoyl group", which is exemplified by N,2T- di thylcarbamoyl or £7,LT-diethylcarbamoyl.

The monoalkylcarbamoyl group of the "monoalkylcarbamoylox group" is preferably a ^EOπ -°-*C-τ_6 alkylcarbamoyl group mentioned above; hence the "monoalkylcarbamoyloxy group" is hereinafter sometimes called "mono-Cχ-6 alkyl- carbamoyloxy group", which is exemplified by N-methyl- carbamoyloxy or N-ethylcarbamoyloxy.

The dialkylcarbamoyl group of. the "dialkylcarbamoyloxy group" is preferablya di-C, _g -alkylcarbamoyl group mentioned above; hence the "dialkylcarbamoyloxy group" is hereinafter sometimes called a "di-C, g alkylcarbamoyloxy group", which is exemplified by N,N-dimethylcarbamoyloxy or N,N-diethylcarbamoyloxy.

The alkyl group of the "alkylsulfonyl group" is preferably a C. _^ alkyl group mentioned above; hence the 1—6

"alkylsulfonyl group" is hereinafter sometimes

called "C,_g alkylsulfonyl group", which is exemplified by methanesulfonyl or ethanesulfonyl.

The aryl group of the "arylsulfonyl group" is preferably Cg_ _1Q aryl group mentioned above*, hence ^'ϊhe "arylsulfonyl group" is hereinafter sometimes called a "Cg_χo aryl¬ sulfonyl group", which is exemplified by, among others, benzenesuifonyl.

The aralkyl group of the "aralkylsulfonyl group" is preferably a.C ₇ ,Q aralkyl group mentioned above, ^* hence the "aralkyisulfonyl group" is hereinafter sometimes called a "C__ _1g aralkyisulfonyl group", which is exemplified by phenyI ethanesulfonyl or diphenylmethanesulfonyl.

The alkylsulfonyl group of the "alkylsulfonyloxy group" is preferably a C, - alkylsulfonyl group mentioned above; hence the "alkylsulfonyloxy group" is hereinafter sometimes called a "C, _g alkylsulfonyloxy group", which is exemplified by methanesulfonvloxy or ethanesulfonyloxy. The arylsulfonyl group of the "arylsulfonyloxy group" is preferablv a C. , _π arylsulfonvl grouo; hence the "arylsulfonyloxy group" is hereinafter sometimes called a " ^c s-1 ₀ ^ar Yi ulfonvloxy group", which is exemplified by, among others, benzenesuifonyloxy.

The aralkyisulfonyl group of the "aralkylsulfonyloxy group" is preferably a ^C 7_ _T _ _Q aralkyisulfonyl group mentioned above; hence the "aralkylsulfonyloxy group" is _ hereinafter sometimes called a "C7_χ9 aryl¬ sulfonyloxy group", which is exemplified by phenyl- methanesulfonyloxy or diphenyimethane≤ulfonyloxy.

"Amino acid residue" means acyl groups formed by removing hydroxyl croup cf the carboxyl group of conventional amino acids, which is exemplified by glycyi, alanyl, valyi, leucyl, i≤oleucyl, seryi, threonyi, cysteinyl, cystinyi, mεthicnyi, aspartyl, glutamyl, lysyl, arginyi, phenyigiycyi, _. phenylalanyi, tyrosyi, histidyl, triptophanyi or prolyl.

"Nitrogen-containing heterocyciic ring" means a 3.to 8 membered ring containing one *to several, preferably

1 to 4, nitrogen atoms (optionally oxidized) or condensed ring thereof, which may contain, besides nitrogen atoms, one to several, preferably l to 2 hetero atoms such as oxygen atom or sulfur atom.

"Nitrogen-containing heterocyciic group",means a group formed by removing one hydrogen atom bonding to ring-forming carbon atom of the above nitrogen- containing heterocyciic ring.

"Heterocyciic group" means a group formed by removing one hydrogen atom bonding to a carbon atom of

a heterocyciic ring, which means a 5 to 8 membered ring containing one to several, preferably 1 to 4 hetero atoms such as nitrogen atom (optionally oxidized) , oxygen atom or sulfur atom, or condensed ring thereof, which is exemplified by 2- or 3-pyrrolyl, 3-, 4- or 5- pyrazαlyi, 2-, 4- or 5-imiάazαlyl, 1,2,3- or 1,2,4- triazoiyi, IE- or 2Ξ-tetrazclyl, 2- or 3-furyl, 2- or 3-thienyi, 2-, 4- or 5-oxazolyl, 3-, 4- or 5- iscxazαlyl, l,2,3-oxadiazol-4- or 5-yl, 1,2,4- oxadiazαl-3- or 5-yl, 1,2,5- or 1,3,4-oxadiazolyi, 2-, 4- or 5 ^' -thiazolyl, 3-, 4- or 5-isothiazolyl, l,2,3-thiadiazαl-4- or 5-yl, l,2,4-thiadiazol-3- or 5-ryl, 1,2 _^ 5.- or 1,3,4-thiadiazolyl, 2- or 3- pyrrolidinyl, 2-, 3- or 4-pyridyl, 2-, 3- or 4- pyridyl-l. -oxid , 3- or 4-pyriάazinyl, 3- or 4- pyridazinyl-N-oxide, 2-, 4- or 5-pyrimidinyl, 2-, 4- or 5-pyrimidinyi-N-oxide, pyrazinyl, 2-, 3- or 4-piperidinyl, piperazinyl, 3Ξ-indol-2- or 3-yl, 2-, 3- or 4-pyranyl, 2-, 3- or 4-thiopyranyl, benzo- pyranyl, 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, pyrimidopyrimidyl, pyrazinoquinolyl, or benzopyranyl.

Heterocyciic groups of "heterocycle-oxy group", "heterocycle-thio jroup", "heterocycle-amino

- 2* -

group", "heterocycle-carbonyl group", "heterocycle- acetyl group" and "heterocycle-carboxamido group" are all preferably "heterocyciic group" mentioned above. "Quaternary ammonium group" means a group in which the bonding hand is the unpaired electron located on one of the tertiary nitrogen atoms of the above-mentioned nitrogen-containing heterocyciic ring, and per se quaternarize , necessarily being accompanied with cor¬ responding anion. The quaternary ammonium group is exemplified by oxazoiium, thiazσliu , isoxazolium, isothiazoliu , pyridiniu or quinolinium. The anion is exemplified by hydroxide ion, haiogenide ^' ion (e.g. chlorid ion, bromide ion or iodide ion) , sulfate ion, nitrate ion, carbonate ion, organic carboxylate ion (e.g. oxalate ion or trifluoroacetate ion) or organic sulfonate ion (e.g. p-toluenesulfonate ion) , the latter two being sometimes intramolecular ones.

The groups bearing asterisk * at the right shoulder are "optionally substituted groups". For example, alkyl* group means "optionally substituted alZ-yl group". The number of substituents is not restricted to one, two to four, preferably, 2 to 3, which may be the same or different.

" ^C 6-10 ^ar y ¹ * ? ^rou P"' " ^C 7-12 ^aralk l ^7:L * g ou ", " ^C 6-10 ^ar yi* ^oχ y group" and " -j_ _1Ci aralkyl*oxy group" are

i i ^' preferably "phenyl* group", "benzyl* group", "phenoxy* group" and "benzyl*oxy group", respectively.

The substituents of "optionally substituted

C.—o. alkanoy ^■* l crouo" represented bv- Cl,—o. alkanovl* group are exemplified by (1) heterocycie*-carbonyl group in case of C_ alkanoyl (i.e. formyi) and i ( 2 ) "substituent S~ ^π described below in case of C-_ _g alkanoyl group (i.e. acetyi, propionyl, butyryl, isobutyryl vaieryl, isovaleryl, pivaloyi, etc.). The "substituent

S " is exemπlified by C 3-,-l,u _n cv*cloalky•l* σrouα C3.-6 _■ cycloalkenyl* group, C._, _Q aryl* group, hydroxyl group,

Cl,-o. alkoxv- σ-ro -o, Cj.-i,Q _n cv-cioalkv_ioxv- σ-rouo. , ^• C_6.-1,0 _n aryl*oxy group, C__ _{τ c} aralkyi*αxygroup, ercapto group,

C,_~ aikyl*thio group, a inc C, _ _g alkyithio group,

C_ . alkenvl*thio crouo, C _{l n} cvcloalkvlthio σrouo,

Cc.——, _n u arv ^■* l*thio σ"rouα, C_— X, _* „ araikv ~i*thio grouc, amino σrouc, mono-C,l-o. alkv-lanino c -rouo -,di-Cl,-o. alkvlamino group, C- , _Q cycloalkylamino group, C. _, _Q aryl*amino group, C ,g aralkyl*amino group, cyclic amino* group, halogen atom, nitro group, aiido group, cyano group, carboxyl group, acyl ^÷ group, substituted oxycarbonyl group, C, _g alkyithio-carbonyl group, acyl ⁺ oxy group, acyl ^÷ amino group, acyl ^" * ^" aminoalkylthio group, carbamoyl group, mono-C, _g alkylcarbamoyl group,di-C, _g alkyl-

carbamoyl group, carbamoyloxy group , mono-C, _. alkyl- carba oyloxy group , di-C, _. alky lcarbamoyloxy group , sulfo group , hydroxysulf onyloxy group , C, . alkylsulfonyl group , Cg , _Q aryl*sulfonyl group , C__ _{1 g} aralkyl*sulfonyl group , C, _g alkylsulfonyloxy group , C.. _ _{T Q} aryi*"sulf onyloxy group , _ , g aralkyl*sulf onyloxy group , ureicα* group , sulfamoyl* group , heterocyciic* group , hetero cycle *oxy croup , heterocycle*thio group , hetarocycie*a~inc- group , heterocycle*σarbonyl group , heterocycle* carboxacido group or quaternary ammonium* group . The number of these substituents is not restricted to one* But it is preferably one to four , in case there are two or more substituents, these substituents may be the same or dif¬ ferent. To state further, two of these substituents may be combined to form C=C double bond or ON double bond as described below.

The substituents (hereinafter referred to as

2

"substituent S ") of "optionally substituted C,_- alkenoyl group" are exemplified by ,_ ₁₀ cycloalkyl group, C _g _- _Q aryl* group, C, . alkoxy group, ^c g_τ_g arvl*oxv- σ-rou-o, ' C/.-1,9„ aralkv-l*ox-v c-rouo-,' halogen atom, cvano group, carboxyl group, acyl÷ group, substituted oxvcarbonyl group, acyl÷oxv group, heterocyciic* group or quaternary ammonium* group.

The substituents of "optionally substituted C. _, _Q aryl-carbonyl group" represented by C _ _Q aryl*- carbonyl group as well as "optionally substituted

heterocyclic group" represented by heterocycle*- carbonyl group (hereinafter collectively referred to as "substituent S " are exemplified by C, _g alkyl group, C ₂ _- alkenyl group, C _g _, _Q aryl group, C_ , ₂ aralkvi croun- _. ^r di-Cα.-1,0- ary ^■■ l- ethvl g ³ rouo, tri-C6 _. -1, _n 0 aryl-methyl group, hydroxyl group, C,_ _. alkoxy group, ^C 6-10 ^ar - ^oχ ?roup, C_ , _g aralkyloxy group, mercapto grouo, C 1.—o. alkyithio σ-rouσ", Cb,—,U- arv—lthio σ"rouo,

C-7 _f -1,9 _a aralkv-ithio c-rouo, amino σ-rouo, mono-C1,-6- alkylaminα c -rouo-, di-C,l—o- alkv ^■ *lamino σ ^■ *rouo~, hv—droxy

CX,—α. alkv~l crouc, mercao-to Cl,—o. alkv-l σrouc, halogeno-

C,l—o. alkv-l σrouπ, carboxv ^■ * C,l—o. alkv~l σrouσ- , halogen atom, nitro group, azido group, cvano group, carboxyl group, substituted oxvcarbonyl group, acyi÷ group, acyl÷oxv group, acyl÷a inσ group, carbamoyl group, thiocarbamovi σrouo, C 1,—α. alkv-lsulfonv ^■* l σrouo", Co _c —, _π u ary ^*■ lsulfonv -l σ ^m rouo ^m or C--i,„9 aralkv" ^• isulfonv"l grouσ.

Among the above-mentioned substituents (S ,

2 3 S and S ) of Cl,-o. alkanov-l c-rouD-, Cj--5_ alkenoyl group,. _* ,_-. _* 4 aryl-carbonyi group and heterocycle*- carbonyl group, those which arenot described below are of the same meaning as afore-mentioned.

The substituents of the C-_ _{7 Q} aryl group of ^C 6-10 ^ar yi* ζT^oup, pheyl* group, Cg_ _1Q aryl*oxy group, phe _h oxy* group, Cg_ _1Q aryl*thio group.

^C 6-10 ^r yi* ^{am no} group, C _g , _Q aryl*sulfonyl group and

^C 6-1 ₀ ^ar yi* ^s ' ^α l onyloxy group are also named here by

3 the above-mentioned substituents S

The substituents of the aromatic ring of the

C- /—,X- or C./—,- _Q araikv ^* l croups of C ₇ I—,A_ aralkv 'l* crouo, benzyl* group, C_ . _Q aralkyl*oxy group, benzyi*oxy group, C__. _{j Q} arallyi*thio group, C_ , _Q aralkyl*aπinα group, C__, _Q aralkyl*sulfonyl group an C-_. _Q aralkyl*sulfonvloxy group are also named here by the above-mentioned substituents Ξ" ¹ .

The substituents of the heterocyciic ring of the heterocyciic* group, heterocycle*oxy group, heterocycle*thio group, heterocycle*amino group, hεterocycie*acetyl group and heterocycle*carbcxamido group are also named here by the above-mentioned substituents S .

The substituents on the nitrogen-containing heterocyciic ring of quaternary ammonium* group are also- named here by the above mentioned substituents S .

The substituents of the C,—o. alkv~l group of

"optionally substituted C,_g alkyl group" represented bv C, _. alkyl* group are also named here by the above- ^■* 1—o mentioned substituents S ..

The substituents of the "optionally substituted ^C ₃ -1 ₀ y ioaikyi group" and "optionally substituted C ₅ _g

cycloalkenyl group" representable by C__. _n cycloalkyl group and ^' C__ _g cycloalkenyl* group are also named here by the above-mentioned substituents S .

The substituents of the C,_. alkyithio groups of

"optionally substituted C,_. alkyithio group" represent¬ able by_C ₁ _- al yi*thio group (these substituents are hereinafter referred to as "substituent S ^" ") are exemplified by hydroxyl group, ₇ _. alkoxy group, -_., _Q cycloalkyloxy group, C. __, _Q aryl*oxy group, C- , _a araikyi*oxy group, ercaptα group, C-,_. alkyithio group, ' C-. _^ . _JQ eyeloalkyithio group, C _. _, _Q aryl*thio group, C._ _τg aralkyl*thiα group, amino group, mono-C,_g alkyi- a ino group, di-C, . alkyla—ino group, cyclic amino* group, halogen atom, cyano group, carboxyl group, carbamoyl group, acyl÷oxv group, sulfo group, or quaternary ammonium*grouo.

The substituents of the C- . alkenylthio group of "optionally substituted C__. alkenylthio group" representable by « . alkenyi*thio group (these substituents are hereinafter referred to as "substituent S~") are exemplified by halogen atom, cyano group, carboxyl group, carbamoyl group, mono-C, . alkylcarbamoyl group, di-C,_ _g alkylcarbamoyl group or thiocarbamoyl group.

"Acyl÷ group" means the abσve-roentioned C, g alkanoyl group, Cg_^ _Q aryl*carbonyl group, C _? _ ₁₉ aralkyl*carbonyl group,

- 30 - , ,

heterocycle*carbonyl group or heterocycle*acetyl group. Representable acyl÷ groups are exemplified by formyi, acetyl, propionyi, n-butyryl, isσbutyryl, valeryl, pivaloyi, n-hexanoyi, chloroacetyi, cichloro- acetyl, trichloroacetyi, 3-oxcbutyryl, 4-chlαro-3-oxcbutyryl, 3-carbαxypropionyi, 4-carboxybutyryi, 3-ethαxycarbamoyl- propionyi, benzσyi, naphthoyi, p-methyibezizoyi, p- hydroxybenzoyi, p-methoxybenzoyi, p-chicrobεnzoyi, p- nitrσbenzoyl, o-carboxybenzoyl, o-(ethoxycarbonyi- carbamoyl)benzoyl, o-(ethoxycarbonylsulf moyi)benzoyi, phenyiacetyl-, p-methylphεnylacetyl, p-hycroxyphenyi- acetyi, p-mεthαxyphenyiacatyl, 2,2-diphenyiacetyl, 2- thienylcarbcnyl, 2-furylcarbonyl, 2-, 4- or 5-thiazoiyi- acetyl, 2- or 3-thienylacεtyi, 2- or 3-furylacεtyi, 2- amino-4- or 5-thiazciyiacetyl or 5-amino-3-thiadiazσiyi- acetyl.

The acyl÷ group of "acyl÷oxv group and "acyl÷aminc group" means the above-mentioned acyl÷ group. Therefc ε, "acyl÷oxy group" is exemplified by formyloxy, acεtoxy, propionyloxy, butyryioxy, valeryloxy, pivaloyloxy, chloroacetoxy, dichloroacatoxy, trichloroacetoxy, 3- oxobutyryloxy, 4-chloro-3-oxobutyryloxy, 3-carboxy- propionyloxy, 4-carboxybutyryloxy, 3-ethoxycarbamoyl- prcpiorylκy, benzoyloxy, naphthoyloxy, p-methylbenzoyloxy, p-methcxy- benzo loxy, p-chlorobenzoyloxy, o-carboxybenzoyloxy, o-

(ethoxycarbonylcarbamoyl)benzoyloxy, o-(ethoxycarbonyl- sulfamoyl)benzoyloxy, phenylacetyloxy, p-methylphenyl- acetyloxy, p-methoxyphenylacetyloxy, p-chlorophenyl- acεtyloxy, 2,2-diphenylacεtyloxy, thienyicarbonyloxy, furylcarbonyloxy, thiazolylacetvloxv, thienylacetyloxy or furylacetyloxy, and "acyl+amino group" is exemplified by acetamico (CΞ- 3CCNE-) , benza ido (Co. Eα.CONH-) , pheny1acetamido (CgH-CΞ-CONE-) or 2-thienvlacεtamido

^S ^/ ^CΞ ₂ CO H-'' ^*

The acyl+amino group and alkyithio group of

"acyl÷aminoalkyIthio group" mean respectively the above-mentioned acyl+amino group and C,_ _g alkyithio group, hence such "acyl÷amino C,__ alkyithio group" being exemplified by acetamidomethyithio or 2- acetamidoethylthio.

"Arylacyl÷ group" is praferably "Cg_ ₁₀ aryi-acyi÷ group", which is exemplified by benzoyl, phthaloyl. naphthoyl or phenylacetyi.

"Arylacyl+oxy group" is preferably "C. - _Q aryl- acyl+oxy group", as exemplified by benzoyloxy, naphthoyloxy or phenylacetyloxy.

The substituents of the ureido group of

"optionally substituted ureido group" represented by

"ureido* group" are exe αlified bv - Ci,—o. alkv~l group,

^C 6-10 ^ar y~* g ^rou ?/ ^C ₇ - _T Q ^a ralkyl* group, acyl÷ group, carbamoyl group, sulfo group (which may form a salt with e.g. sodium or potassium) , suifamoyl group or amidino group.

The subsύituents of the suifamoyl group of "optionally substituted suifamoyl group" represented by "suifamoyl* group" are exemplified by C, . alkyl group or amidino group.

The substituents of "optionally substituted carbamoyl group" reprεsεntable by "carbamoyl* group" and "carbamoyl*oxy group" are exemplified by C, _g alkyl group, C_. , _n aryl* grouc, C_ ,- aralkyl* group or acyl÷ group, including the case where the nitrogen atom of carbamoyl group is the ring-forming nitrogen atom of the nitrogen-containing hetεrocyclic ring.

The substituents of "optionally substituted thiocarbamoyl group" representedby "thiocarbamoyl* group" are exemplified by Cl.—o. alkv"l group, Co.—, _n U aryl* group, C__,-, aralkyl* group or acyl÷ group, including the case where the nitrogen atom of a thiocarbamoyl group is the ring-forming nitrogen atom of the nitrogen-containing heterocyciic ring.

The substituents of the cyclic amino group of the "optionally substituted cyclic amino group" represented ^' by"cyclic amino* group" (these sub¬ stituents are hereinafter referred to as "substituent

S ") are exemp -lified bv-* ^■ C,—o. a-lkv~l grouα-,• C-ώ,—o *, alkenyl group, ₃ _, _Q cycloalkyl group, C. _- ~ aryl* group,

C_ ₁₂ aralkyl* group, di-C._ _7Q aryl-methyl group, tri-Co..—1, _n U arv~l-methv-l c-roup- , hv-droxy-l group, C, _l —o _r alkoxy group, C _g , _Q aryl*oxy group, C-_,„ aralkyl*oxy group, mercapto group, C,_ _. alkyithio group, C _8- _, _Q aryl*thio g ^■* roup~, C-/ —, _α y aralkyl*thio group, amino group, mono-C, . alZ<ylamino group, di-C, _g alkylamino group, C _g _, _Q aryl*amino group, C ₇ _,„ aralkyl*amino group, halogεn atom, nitrσ group, azido group, oxo group, thioxo group, cyano group, carboxyl group, acyl÷ group, substitutεd oxycarbonyl group, acyl÷oxy group, acyl ⁺ amino group, carbamoyl group,

carba oyloxy group, thiocarbamoyl group or sulfo group.

The formyi group substituted with the heterocycle*- carbonvl group mentioned above as one of the Cl,—o. alkanoyl* groups is an acyl group having a formula of heterocycle*-CO-CO-, and the heterocyciic* group is also mentioned here -as one exemplified above, but preferably, an optionally substituted oxazolyl group, thiazolyl group, oxadiazoiyl group or thiaciazolyl group, fo. example. These heterocycle*-CO-CO- groups are exemplified by 2-(2-, 4- or 5-oxazolyl)-2-oxoacetyl, 2-(2-, 4- or 5- thiazolyl) -2-oxo.acetyl, 2-(2-a~ιino-4-thiazolyl) -2- oxoacetyl, 2-(l,>2,4-oxadiazol-3- or 5-yl) -2-oxoacetyl, 2-(l,2,4-thiadiazol-3- or 5-yl) -2-oxoacetyl or 2-(5- amino-l,2,4-thiadiazol-3-yl) -2-oxoacetyi.

The ^' C-ώ—O _. alkanoyl* group~ is most preferably a substituted acetyl group. The nu bεr of substituεnts of the substituted acetyl group is 1-3, and, as thesε substituents, "substituent S ^~ " mentioned above as substituents of C, . alkanoyl groups are also mentioned here. When the number of substituents is 2-3, these s bstituents may be the same or different, and two of them may be combined to form a double bond.

A detailed description about the substituents R^-, and R^ follows.

R ^~ stands for an optinonaily protected amino group. In the field of synthesis of .-iactam and pεptide, protecting groups of amino group have been sufficiently studied, and the methods of protection and depro-b≥ction have already been established. In the present invention as well, any of those known amino-protecting groups may suitably be employed. As such amino-protec uing groups, there may be mentioned for example C, _. alkanoyl* group, C,_- alkenoyl* group, C._, _Q aryi*carbonyi group, phthaloyi group, heterocycie* carbonyl grcuo, ^c i-g alyi*sulfonyi croup, camphorsulfcnyi croup, ^' C _s _-.g aryi*s ifcnyi group,

substituted oxvcarbonyl group, carbamoyl* group, carbamoyloxy* group, thiocarbamoyl* group, _g _, _π aryl*methyi group, di- C._ _7Q aryi*mεthyl group, tri-C__, _Q aryi*methyl croup, C _g _ _ln aryl *me thy iεnε group, C _* _- _Q aryi*thio group, substituted siiyi group or 2— C,_- _r! aikoxy-carbonyl-1- methyi-1-ethenyi group .

As "C- _, alkanovl* σrouo" , -there" mav concretely

1-6 ^■* be mentionεd hεre formyi, acεtyl, propionyl, butyryl, valeryl, pivaloyl, succinyl, glutaryl, moncchloro- acetyl, dichloroacetyl, trichloroacetyl, raonofaromoacetyl, monofluoroacetyl, difluoroacetyl, trifluoroacetyl,

monoiodoacetyl, 3-oxobutyry1, 4-chloro-3-oxobutyryl, phenylacetyl, p-chlorophenylacetyl, phenoxyacetyl or p-chlorophεnoxyacεtyl. As "C- - alkenoyl* group", there may concretely be mentioned here acryloyl, crotonoyl, maleoyl, cinnamcyl, p-chlorocinnamoyl or ' S-phεnylcinnamoyi.

As ^r ' ς_m _Q aryi*carbcnyl group", thεre may be mentionεd, for example, bεnzoyl, naphthcyl, p-toluoyl, p-tεrt-butyibenzoyi, p-hydroxybεnzoyi, p-methoxybe zoyl, p-tert-butoxybenzoyl, p-chlorobεnzoyi or p-nitrobεnzoyi.

As the. heterocyclε*carbonyl group, therε may - be mentioned those as dεscribεd hεrεinafter.

As ^' "C ₁ _- aljyi*suifonyl group", there may be mentioned, for example, mεthanεsul onyl or ethane¬ sulfonyl.

As " _g _ ₁₀ aryl*suifonyl group", there may be mεntioned hεre benzenesuifonyl, naphthalεnesulfonyl, p-toluεne- sulfonyl, p-tεrt-butyibenzenesulfonyi, p-mεthoxy- bεnzεnεsulfonyl, p-chicrobεnzεnεsul onyi or p-nitro- bεnzenεsulfonyl, for example.

"Substituted oxvcarbonyl group" means not only the the above-mεntioned one, i.e. C, , alkoxy-carbonyl group, ^C ₆ -10 ^ar yi° ^χ y~carbonyl group or C- ,g aralkyloxycarbonyl group, but includes here one having substituents, and therefore therε may be mεntionεd here methoxycarbonyl, εthoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, cvclonexyloxycarbonyl, norbornyl- oxycarbonyl , phεnoxycarbonyl, naphthyloxycarbonyl,

benzyloxycarbonyl, methoxymethyloxycarbonyl, acetyl- methyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanεsulfonylethoxycarbonyl, 2,2,2-trichloroethoxy- carbonyl, 2-cyanoethoxycarbonyl, p-methylphenoxy- carbonyl, p-methoxyphenoxycarbonyl, p-chlorophenoxy- carbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxy- carbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxy- carbonyl, benzhydryloxycarbonyl, cyclopropyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl, for εxample.

"Carbamoyl* group" is exemplified here by carbamoyl,- N-mathylcarbamoyl, N-εthylcarbamoyl, N, -dimethy1- carbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamαyl, N-acatylcarbamoyl, N-benzoylcarbamoyl or N-(p-methoxy- phεnyl)carbamoyl.

"Carbamoyl*oxy group" is exemplifiεd hεrε by carbamoylox N-mεthylcarbamoyloxy, N,N-dimεthylcarbamoyloxy, N- εthylcarbamoyloxy orN-phεnylcarbamoyloxy.

"Thiocarbamoyl* group" is exemplified here by thio¬ carbamoyl, N-methylthiocarbamoyl or N-phenylthiocarbaaoyl, for example.

"Cg_, _Q aryl*methyl group" is exemplified by benzyl, naphthylmethyl, p-methylbenzyl, p-methoxy- benzyl, p-chlorobenzyl or p-nitrobenzyl.

"Oi-Cg , _Q aryl*methyl group" is exemplified by

benzhydryl or di-(p-tolyl)methyl.

"Tri-Cg_ _1Q aryl*methyl group" is ^' exemplified by trityl or tri-(p-tolyl)methyl.

^' "C _g _, _Q aryl*methylene group" is exemplified by benzyli ^' dene, p-mεthylbεnzylidεne or p-chlorσ- benzylidene.

-!C _g , _Q aryi*thiα group" is exemplified by o-nitrophenylthio.

."Substituted silyl group" means a silyl group, together with the aminc group to be protectεd, rεpresentable by the general formula; R 6R7R8SiNH,

(R ⁶ R ⁷ R ^S Si) T [wherein R ^β , R ⁷ , R ⁸ ,

9 10 9 * 10 '

R , R , R ana R are the same or different and stand for C _j _ _ _g alkyl group or _g , _Q aryl* group , and Z ' stands for C, ₃ alkylene group e. g . methylεne , ethyienε or propylεnε] , which is exemplified by trimethylsilyl , tert-butyldimethylsilyl or -Si (CΞ ₃ ) ₂ CH ₂ CΞ ₂ Si (CΞ ₃ ) ₂ ~ .

The C, _^ , ^. alkoxy-carbonyl group of "2-C, _ _{1 Q} allcoxy- carbonyl-1-methyl-l-ethenyl group" is pref εrably onε of those mentioned in the foregoing. Hence, the 2- _C alkoxv- carbonyl-1-methyl-l-εthenyl group is exemplified by 2-methoxycarbonyl-l-methyl-l-ethenyl , 2-e thoxycarbαnyl-1- methyl-1-ethenyl , 2-tεrt-butoxycarbonyl-l-methyl- 1-ethenyl , 2-cyclohexyloxycarbonyl-l-methyl-l-εthεnyl

_ ^{or 2} ~ ^nor faornyloxycarbonyl-ι-methyl-l-ethenyl.

The symbol B? stands for hydrogen atom or a substituted hydrocarbon residue. The hydrocarbon residue may be exemplified by a C._. alkyl group, C__ _g alkenyl group, C-,_. alkynyl group, ₃ _- _Q cycloalkyl group or C__,- cycloalkenyl group, e≤pεcially preferably, C-_, alkyl group or a substituted C,_. alkyl group. The C, __■ alkyl group is, also here, preferably one of those describεd in the foregoing and may be exemplified by methyl, eώyi, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyi, n-σentyl orn-hexyl, especially preferably, methyl, ethyl and n-propyl. The C- . alkenyl group is, also here, prεf rably one of those described in the foregoi and may be exε piifiεd by vinyl, allyl, isopropenyl, methallyl, 1,1-dimethyiallyi, 2-butanyl or 3-butenyl. The C_ _. alkynyl group may be exemplified by ethyinyi, 1-propynyl, 2-propynyl or propargyl. The C-_, _Q cycloalkyl croup is, also here, preferably the above-mentioned C ₃ -_ _p cycloalkyl group and may be exemplified by cyclopropyi, cyclobutyl, cyclopεntyl, cyclohexyl, cycloheptyl or adamantyl. The C. _. cycloalkenyl group may be exemplified by 2-cyclo- pentenyl, 3-cyclopentεnyl, 2-cyclohεxεnyl, 3-cyclohexεnyI,

- »0 -

cyclopentadienyl or cyclohexadienyl . Substituεnts of thεsε hydrocarbon rεsidues may be one to three groups exemplif ied .by a

hydroxv -l grcuπ , C,— . alkv~l croup~, C-..—o . alkenv - l group ,

C-2-o. alkv-nv-l c-rou-o, C.3.-1,0 _n cv-cicalkv-l crouo, Co-6. cyclo- alkenvl crouo, C. - _π arvl crouo, C- , _a aralkvl croup, heterocy *.ciic c-rouu, C,_ι__ ₀ . aikσxv- c-roup-, C-3—, _nO cvclo- alkαxvloxv- c-rouo-, Co.-,Q. arv-loxv- c-roup-, C-/-1,9 _fl aralkvloxv group, heterocyclε—oxy group, mεrcapto group, C, . alkyithio group, -__ _7α eyeloalkyithio group, C _g ,-, arylthio group, C__ _TQ aralkylthio group, hetεrocyclε- thio crouo, amino σ -rouo, monc-Cl—_ alkvlamino σrouD, di-Cl,-o. alkv-lamino c-rouo, tri-C1,—α. alkvlammonium grαuo, Cj.-1, _n 0 cy- ^■ cloalZ-cv-laminα crouo, C6--1, _n 0 arvlamino group, C__, _g aralkylamino group, hεtεrocyclε-amino group, cyclic amino group, azido group, nitro group, halogεn atom, cyano group, carboxyl group, C,_., _α alkoxy¬ carbonyl group, C. _, _n aryloxy-carbonyl group, C ₇ _, _g aralkyloxy-carbonyl group, C._-, ₀ aryl-acyl ^÷ group, C, alkanov -l c-rouo - , ' Cj.-3. alkanov-l croup- , C_6--1,0 _rt aryl-acyl÷oxy grou

C- ,-. alkanoyloxy group, C-_- alkenoyloxy group, carbamoyl* group, thiocarbamoyl* group, carbamoyl*oxy group, phthalimido group, C, _g alkanoylamino group, ^C ₆ -1 ₀ ^ar yl~acyl+amino group, carboxyamino group, C,_, _Q alkoxy-carboxamido group, C _g , _Q aryloxy-carboxamido

- *1 - ' i

group or C_ , _g aralkyloxy-carboxamido group, and two or three of than, same or different, may be present.

As substituents of the hydrocarbon residues, more specifically stating, theC,_ _g alkyl group stands for the above-mεntioned groups, i.e. methyl _r ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pεntyl or n-hεxv -l, the C _-.—o. alkenv-l grouo stands for the above-mentioned groups, i.e. vinyl, allyl, isopropenyl, methallyl, 1,l-dimethylallyl, 2-butanyl or 3-butenyl, the C-_ _s alkynyl group stands for the above-mεntionεd groups, i.ε. ethynyl, I- propynyl, 2-propynyl or propargyl, the C- , _Q cycloalkyl group stands for the above-mentioned groups, i.ε. cyclopropyi, cyclobutyl, cyclopentyl, cyclohεxyl, cyclohεptyl or adamantyi, the C-_. cycloalkenyl group stands for the above-mentioned groups, i.e. cyclopropenyl, 2-cyclopentenyl, 3-cyclopentεnyl, 2-cyclohεxεnyl, 3-cyclohexenyl, cyclopentadienyl or cyclohexadiεnyl, the C-_, _Q aryl group stands for the above-mentioned groups, i.e. phenyl, naphthyl or biphenylyi, the C _ι _Q aralkyl group stands for the above-mεntionεd groups, i.ε. benzyl, 1-phεnylεthyl, 2-phεnylεthyl, phenylpropyl, naphthylmethyl or benzhydryl, the C ₁ _g alkoxy group stands for the above-mentioned groups, i.e. methoxy.

εthoxy, n-propoxy, isopropoxy, n-butoxy, tεrt-butoxy,

n-pentyloxy or n-hexyloxy, the ₃ _ ₁ o cycloalkyloxy group stands for the above-mentioned groups, i.ε. cyclopropyloxy or cyclohexylαxy, thε C _s __. _Q aryloxy group stands for thε above-mentioned groups, i.e. phεnoxy or naohthyloxy, thε C__, _Q aralkyloxy group stands for thε above- mentioned groups, i.e. benzyloxy, l-phenylεthyloxy, 2-phenylethyloxy or benzhyάryloxy, the C, . alkyithio group stands for the above-mentionεd groups, i.a. methylthio, ethylthio, n-propylthio or n-butylthio, the C- , _Q cycloalkylthio group stands for thε above- mentioned groups, i.e. cyclopropyithio or cyclohεxylthio, thε Cg , _Q a^ryIthio group stands for thε abovε- εntionεd groups, i.e. phenyithio or naphthylthio, the C__ _{1 Q} aralkylthio group stands for the above-mentioned groups, i.e. benzylthio, phenylεthylthio or bεnzhydryIthio, thε mono-C,1-5- alkv-lamino σ-rouD stands for thε above- mentioned groups, i.e. methyla ino, ethylamino, n- propylamino, or n-butylamino, the di-C,_. alkvlamino group stands for the above-mentioned groups, i.e. dimethylamino, diethylamino, methylεthylamino, di-(n- propyl)amino or di-(n-butyl)amino, the tri-C, g alkyl- a monium group stands forthe above-mentioned groups, i.e. trimethylammonium or triethylammonium, the C- __^ _Q cycloalkylamino group stands for the above-mentioned

groups, i.e. cyclopropylamino, eyelopentylamino or eyelohexylamino, the Cg , _Q arylamino group stands for the above-mentioned groups, i.e. anilino or N-methylanilinc, the ₇ ,Q aralkylamino group stands for the above- mεntionεd groups, i.ε. benzylamino, l-phenylε -±ylamino, 2-phεnylethylamino or benzhydrylamino, the cyclic amino group stands for the above-mεntionεd groups, i.e. pyrrolidino, piperidino, piperazino, morpholino or l-?yrrolyl, the halogen atom stands here for fluorine, chlorinε, bromine oriodine, the C, ,« alkoxy-carbonyl group stands forthe above-mεntionεd groups, i.e. methαxycarbonyl, εthoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl , n-butoxycarbonyl, isobutoxycarbonyl, tart-butoxycarbonyl, cyclopεntyloxyσarbonyl, cyclo- hexyioxycarbόnyl ar.norbornyloxycarbonyl, the C*-_- ₀ aryloxy-carbonyl group stands for the above-mεntioned groups, i.e. phenoxycarbonyl or naphthyloxycarbcnyl, thε C__, _g aralkyloxy-carbαnyl group stands for thε abovε-mεntionεd groups, i.e. benzyloxycarbonyl or bεnzhydryloxycarbonyi, thε _g _ _1Q aryl-acyl÷ group stands for the above-mentioned groups, i.e. benzoyl, naphthoyl, phthaloyl orphenylacetyi, the C, _s alkanoyl group stands for the abova-mεntionεd groups, i.ε. formyi acεtyl, propionyl, butyryl, valεryl, pivaloyl, succinyl or glutaryl, the C-_- alkenoyl group stands for the

above- entioned groups, i.ε. acryloyl, crotonoyl or alεoyl, the C _g _, _Q aryl-acyl+oxy group stands for the above-mentioned groups, i.e. benzoyloxy, naphthoyloxy or phenv -lacεtoxv~, the C-—o. alkanov-loxy σ "rouo - stands for the above-mentionεd groups, i.a. acεtoxy, propionyloxy, butyryloxy, valeryloxy or pivaloyloxy, the C-_- alkenoyloxy group stands for the above-mentionεd groups, i.ε. acryloyloxy or crotonoyloxy, the carbamoyl* group stands for the above-mεntionεd groups, i.ε. carbamoyl, N-mεthylcarbamoyl, N-ethylcarbamoyl, N, -dimethylcarbamoyl, N-ethylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-acatylcarbamoyl, N^benzoylcarbamoyl, N-(p-methoxy- phεnyl)carbamoyl and, in addition, pyrrolidinocarbonyl, piparidinocarbonyl, piperazinocarbonyl or mcrpholino- carbonyl, thε thiocarbamoyl* group stands for the above-mentionεd groups, i.e. thiocarbamoyl, N-mεthylthio¬ carbamoyl or N-phεnylthiocarbonyl, tha carbamoyl*oxy group stands for thε abovε-mεntionεd group, i.ε. carbamoyloxy, N-methylcarbamoyloxy, N,N-dimethyl- carbamoyloxy, N-εthylcarbamoyloxy or N-phεnylcarbamoyloxy,

"Cl,-o-. alkanov-lamino c-rouo-" stands for e.c. acetamico, propionamido, butyramido, valeramido or pival- a ido, "C _g , _ aryl-acyl÷amino group" stands for e.g. bεnzamido, naphthoylamido or phthalimido, "C, , _Q alkoxy-carboxamido group" stands for ε.g. methoxy-

carboxa ido (CH OCONΞ-) , ethoxycarboxamido or tert- butoxycarboxamido, "Cg_ _7Q aryloxy-carboxamido group" stands for e.g. phenoxvcarboxamido (C„Ξ_OCONH-) , and

6 5

"C. , ₀ aralkyloxy-carbαxamido group" stands for e.g. benzyloxycarboxamido (C Ξ.CΞ OCOKE-) or bεnzhydryoloxy-

6 3 2 ~ carboxamido. Thε heterocyciic group, heterocyciic groups of hetεrccycle-oxy group, hetεrocycie-thiα group and heterocyclε-amino group ara also harε such groups as formed by removing one hydrogen atom bonding to the carbon atom of the heterocyciic ring. Such a hetεro- cyclic ring as abαvε may bε εxεmplified by a 5- to 8- me bered ring containing onε to sεveral, preferably 1 to 4, hetero atoms such as an oxygen atom or sulfur atom. Such heterocyciic groups may be exεmplifiεd also hεrε by thosε concrεtely mentioned above, including 2-pyrrolyl. Hence, "heterocycle-oxy group" is exεmplifiεd by thiazolyloxy, and "hεtεrocyciε-thio group" is εxεmplifiεd by thiazolyIthio, and "hεterocycle-amino group" is εxe plified by thiazolylamino or thiadiazolylamino.

Preferable substituted hydrocarbon residuεs are C,_ ₃ alkyl groups (C, - alkyl group means methyl, ethyl, n- propyl, isopropyl, etc.) substituted by 1 to 3 groups such as hydrox group, cycloalkyl group, alkoxy group, alkyithio group, amino group, trialkylammonium group, halogen atom, carboxyl group, alkoxycarbonyl group, carbamoyl group, cyano group, azido group or hetεrocyclic group, which may

i

concretεly be mentioned, among many others, cyclopropyl- methyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-hydroxyεthyl, methyl- thiomethyl, 2-ar.inoethyl, 2-(trimethylammonium)ethyl, 2-(triεthyla mcnium) εthyI, fluoromethyl, difluoromethyl, tri luoromethyl, 2- luσroethyl, 2,2-di luoroethyl, chlcromethyl, 2-chloroethyl, 2,2-dichloroεthyI, 2,2,2- trichloroεthyl, 2-bromoe hyl, 2-iodoethyl, 2,2,2- trifluoroεthyl, carboxymethyl, 1-carbcxyεthyl, 2-carboxy- εthyl, 2-carboxyρropyl, 3-carboxypropyl, 1-carboxybutyl, cyanomεthyl, I-carbcxy-i-methylεthyl, mεthoxycarbonyl- mεthyl, εthoxycarbcnylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonyl-l-mεthylεthyl, 1-εthoxycarbonyl-l- methylethyl, 1-tεrt-butcxycarbonyl-l-mεthyl thyl, 1- benzylαxycarbonyl-1-methylethyl, 1-pivaloyloxycarbonyl- 1-mεthylethyl, carbamoylmethyi, 2-azidoethyl, 2- (pyrazolyl)ethyl 2-(imidazoIyl)ethyl, 2-(2-oxopyrrolidin-3- yl)ethyl or 2-amino-4-thiazolylmεthyl. Most prεfεrablε ones among the above-exemplified hydrocarbon residues are straight-chain C,_, alkyl groups, e.g. mεthyl, εthyl and n-propyl ^; s raighfcr as n or branched C _j _ ₃ alkyl gro_ms substituted by 1 to 3 groups such as halogen atom, hydroxyl group, alkoxy group, carboxyl group, alkoxycarbonyl group or cyano group, e.g. 2-fluoroethyl, 2-chloroetiιyl, 2- hydroxyεthyl, 2-methoxyeth l, cyanomethyl, carboxymethyl.

tert-butoxycarbonylmethyl, 1-carboxy-l-methylεth-yl or-

1-tert-butoxycarbonyl-l-mεthylethyl; allyl group and propargyl group. Supposing here that the symbol R 3'

should stand for most preferable hydrocarbon residues exemplified above or a hydrogen atom, the compound [I] of this invention is shown by the following structural formula:

[wherein symbols are of the same meaning as defined above] Preferable examples of the acyl group shown by the formula:

Ό

are

2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-(hydroxyimino)Hcetyl, 2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-(methoxyi ino)acetyl, 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-(ethoxyimino) - acetyl, 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z) -(ethαxy- imino)acetyl, 2-(5-aminc—l,2,4-thiadiazol-3-yl) -2(Z) - [(2-fluoroethyl)oxyimino]acetyl, 2-(5-amino-l,2,4- thiadiazol-3-yi) -2 (Z) -[ (2-chloroethyl)oxyimino]acεtyl, 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z) -(carboxy εthyl- oxyi ino)acetyl, 2-(5-amino-l,2,4-thiadiazol-3-yl) -2(Z) - [ (1-carboxy-l-methylethyl)oxyimino]acetyl, 2-(5-amino- l,2,4-thiadiazol-3-yl)-2(Z) -[ (1-tart-butoxycarbonyi-

1-methylethyi)oxyimino]acetyl. ύ.

Thε substituent R ^" in the compound ^" [I] of this invention stands for hydrogen atom, methoxy group or formamido group (HC0NH-) .

The substituent S." in the.compound [I] of this invention stands for hydrogen atom, methyl group, hydroxyl group or halogen atom. The halogen atom means hεrε fluorine, chlorine, bromine or iodine.

In the compound [I] of this invention, thε substituεnt A ^' stands for imidazolium-1-yl group which forms a condensed ring at 2,3- or 3,4-position. Condensed ring means an imidazole ring having a 5- to 6-mεmbεred aromatic heterocyciic ring condensed therewith, and it may optionally be further condεnsed with another aromatic ring or aromatic heterocyciic ring. The mark 0 attached to the riσht shoulder of the substituent A

mεans that A has a monovalεnt positivε εlectric charge. The optionally substituted imidazolium-1-yl group (j? forming the condensed ring at the 2,3- or 3,4- position is shown by the general formula [A 1] or [A2] ;

wherein B stands for a group forming a 5- to 6-membered aromatic hetεrocyclic ring which may bε condensed with another aromatic ring or aromatic heterocyciic ring,

R stands for hydrogen atom or a substituent (or substituents) en the imidazoie ring andR 12 stands for hydrogen atom or a substituent (or substituents) en the ring which is condensed with the imidazoie ring. B consists of carbon atom, nitrogen atom, oxygen atom and/or sulfur atom, and, among them, a carbon atom combines with one hydrαgεn atom or one substituent, or forms another condensed ring together with an adjacent carbon atom. The A group may be embodiεd as follows, for εxampie;

The A croup may be embodied as follows, ^" for exampr.ie;

Among these groups, espεcially preferable are

) and

In the above-mentionεd formulaε [A. 1] and [A2] as well as m the A 1 groups and A2 groups embodied as above, the positive elεctric chargε J¥t' is a pliεd, for convenience sake, to the nitrogen atom at the 3- position of imidazoie, but there may be a case where the said quaternary nitrogen is that of the nitrogen atom at the 1-position. Further, there may be cases where the monovalent positive electric charge is delocalized at the imidazoie ring, or even delocalizεd

(solid or in solution) of the compound [I] , kinds of solvents, pH, temperature or kinds of substituents.

Accordingly, thε prεsent invεntion includes all the casεs where the positive electric charge is localized at •*- nitrogen atomor is delocalized on the entire condensεd ring. Thε numbεr of the substituents

Rll and Rl2 is preferably one to two.

The substituεnts R11 and R^2 on thε condensed ring A may be exemplified by a hydroxyl grouo, hvdroxy C, . alkyl group, C, . alkvl σroup,

C- . alkenvl group, C- - alkynyl grouo, . alkadienyl group, C, , _n cycloalkyl group, C- . cyclo- alkenyl group, C, , _Q cycloalkyl C, . alkyl group,

Co--i, _Λ O arv*i croup-, C-7,-1,2- aralkv ^■ *l grouo ^• , di-CQ.-1, _n 0 aryl- methyl group, tri-C ₈ , _Q arylmethyi group, hεterocyciic σrouo, Cl,—.o alkoxy ^J g ³ roup-, C,l-o. alkoxy ^■ * ^• C,l-o. alkvl group, C-_ _7Q cycloalkyloxy group, C. _, _Q aryloxy group, C__, _Q aralkyloxy group, mεrcapto group, mεrcapto C, _s alkyl group, sulfo group, sulfo C, . alkyl group,

C ₁ _ _s alkyithio group, C, _. alkyithio C, _g alkyl group,

C,_ _1Q cycioalkylthio group, C _g , _Q arylthio group,

C- , _Q aralkylthio group, amino group, amino C, __,. alkyl group, mono-C,_ _g alkylamino group, di-C, _g alkvlamino crouo, mono-C,l— _o. alkylamino Cl,—o _. .alkyl group, di-Ci,—o,- alkylamino C,. _g alkyl group, C- , _Q cycloalkylamino group, C- , _Q arylamino group, C-__ ^' aralkylamino group, cyclio amino group, cyclic amino C, _g alkyl group, cyclic amino C, _g alkylamino group, azido group, nitro group, halogen atom, halogeno C, _g alkyl group, cyano group, cyano C, _g alkyl group, carboxyl group.

carboxy C, _g alkyl group, C, , _Q alkoxy-carbonyl group, C _1-1Q alkoxy-carbonyl C^_. alkyl group, _g , _Q aryloxy¬ carbonyl group, C- ₁₉ aralkyloxy-carbonyl group, _g , _Q aryi-acyi ^÷ grouo, Cl,—o. alkanov~l σrouo~, C_—o. alkanoyl

C, - alkyl group, C. - alkenoyl group, C _c , _n aryl- acyl÷oxy grouo, C Δ.~Ό. alkancv-icxv— group -, C-Z—,- alkanoyloxy

C, _ _s alkyl group, C__ ₌ alkenoyloxy group, carbamoyl C. _r. alkyl group, carbamoyl* group, thiocarbamoyl* group, carbamoyl*αxy group, carbamoyloxy C,_. alkyl group, C, . alkanoylamino group, C _g _, _Q aryl-acyl+amino group, sulfonamido group, carbcxyamino group, C, , ~ aikoxv-carboxamidc .σrouo, C. , _. arvlcxy-carboxamido group or C-_., _g aralZyioxy-carbcxamido group. Among the above-mentioned substituents, "C . . alkaάienvi grouo" is exεmpiifiεd by 1,3-butadiεnyi, "C ₃ _ _1Q cycloalkyl C-,_. alkyl group" is exemplified by cyclopentylmethyl cr cyclohexylmethyl, anchaiogen atom means hεre fluorine, chlorine or brominε. All thε groups othεr than the above may be exεmpiifiεd as in the foregoing.

Thεsε substituεnts may occur singly or in plurarity, being the same or different ones. And, in A , the 5,6- position of the imidazoie ring may be condensεd with an alicyclic ring, aromatic ring or hεtεrocyclic ring. As thε εxa plas, thε following may be counted:

In the above , 3 and R are of the same significance li

.as afore-defined. The above-mentioned R ~ 'anc R may be further substituted.

In the above compound [I] , the mark Q attached to the right shoulder of the carboxyl substituent (-CQO) means that the carboxyl group is a carboxylate anion and forms internal salt by as in a pair with the positive elecoric charge on the substituent A. Cn thε othεr hand , the compound [I] may be its pharmaceutically acceptable salt, or ester • As the pharmaceutically acceptable salt , there may be mentioned, among others, inorganic base salts , ammonium salt , organic base salts , inorganic acid addition salts , organic acid addition salts and basic amino acid salts . There may be exemplified an alkali metal (e.g. sodium, potassium, etc . ) or an alkaline earth metal (e.g. calcium) as an

inorganic base capable of giving the inorganic base salts; procaine, 2-phanylεthylbεnzylamine, dibenzyl- ethylenediamine, ethanolamine, diethanolamine, tris-hydroxymεthyia inomεthane, poly-hydroxyalkylamine or -methylglucosamine as an organic base capable of giving organic base salts; hydrochloric acid, hydrobrσmic acid, sulfuric acid, nitric acid or phosphoric acid as an inorganic acid capable of giving thε inorganic acid addition salts; p-toluenesulfonic acid, methanεsulfonic acid, formic acid, trifluoro- aoetic acid or malεio acid as an organic acid capable of giving organic acid addition salts; and lysine, arginine, ornithine or histidinε as a basic amino acid capabiε of giving _^ basic amino acid salts.

Among thε≤a salts, basic salts (i.e. inorganic base salts, ammonium salt, organic base salts and basic amino acid salts) εan salts derivable in case there is (are) acidic group(s) e.g. carboxyl group, sulfo group etc. on the substituent Rl, R3 or A of thε compound [I] ^' , and acid addition salts (i.ε. inorganic acid addition salts and organic acid addition salts) mεan salts derivable in case there is (are) basic group (s) e.g. amino group, mono- alkylamino group, dialkylamino group, cycloalkylamino group, arylamino group, aralkylamino group, cyclic amino group, nitrogen-containing heterocyciic group etc. on the substi¬ tuent Rl, R3 _or A of the compound [I]. Incidentally, the acid

- 5Z -

addition salt also includεs an intramolecular salt of the compound [I], i.e. a salt having ^' carboxyl(COOΞ) group at the 4— osition and CΞ-.-^.iT-^ group [wherein vf-' denotes an anion formed by removal of a proton (Ξ^ from inorganic acid or organic acid; such an anion is exemplified by chloride ion, bromide ion, sulfate ion, p-toluenesulfonate ion, methanesuifonatε ion, trifluoroacetate ion] at the 3-position, which is formed through addition of one mole or acid to carboxylate(COO^) group of the 4-pαsιtion and

group of the 3-position of the compound [I] . The estεr dεrivativεs of thε compound [I] mean esters derivablε by εstεrifying thε carboxyl group contained in the molecule, which include esters usable as synthetic inter¬ mediates and bioavailably unstable non-toxic esters. The estεrs usable as synthetic intermediates are exεmpiifiεd by 3. C, _s alkyl* εstεr, C__ _g alkenyl ester, C,_ _1Q cyclo¬ alkyl estεr, C3,-1. _n 0 cv ^■ *cloalkv*l Ci-o. alkv"l aster, Co.-l, _π O aryl* ester, C, , ₂ s÷≥ l* ester, di-C _c _ _1Q aryl- methyl estεr, tri-C ₈ , _Q aryl-methyl estεr or substituted silyl ester. Therε may be exemplified, as "C. ^ alkyl* group"capable of giving C, . alkyl* ester, methyl,

εthyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, n-hexyl, benzyloxymethyl, 2-mεthylsulfonylεthyl, 2-trimethylsilylethyl, 2,2,2-trichioroethyl, 2-iσdoεthyl, acatylmethyi, p—nitrobenzoylmethyl, p-mεsylbεnzoylmεthyi, phthal- imidomethyl, s ccinimidomethyl, benzenesuifonylmethyl, phenyithiαmethyl, dimεthylaminoethyl, pyridine-1-oxido- 2-mεthyl, mεthylsulfinylmεthyl, or 2-cyan.o-l,1- dimethvlethv-l; as C-_;—o. alkenyl group caoablε of σiving

C ₂ _g alkεnyl εster, the afore-mentioned ones, i.e. vinyl, allyl, 1-propenyl, isopropεnyl, 1-butεnyi, 2-butenyl, 3-butenyl, mεthallyl, 1,1-dimεthylallyi or 3-methyl- 3-butεnyl; as C,_, _Q cycloalkyl group capabla of giving C,_- _[Q cycloalkyl ester, the afore-mεntionεd onεs, i.ε. cyclopropyi, cyclobutyl, cyclopεntyl, cycichεxyl, cyclchεptyl, norbornyl or adamantyl; as - , _Q cyclo¬ alkyl C,_- alkyl group capablε of giving C,_T _Q cyclo¬ alkyl C, . alkyl εstεr, thε afora-mentioned onεs, i.ε. cyclαpropylmεthyl, cyclopεntylmεthyl or cyclohexyl- mεthyl; as "Cg_ _1Q aryl* group" capabla of giving Cg_ _1Q aryl* εster, pheny1,α-naphthyl, .-naphthyl, biphenylyl, p-nitrophεnyl or p-chlorophεnyl; as " 7 ι ₂ ^ara 13γl* group" capabla of giving C__ ₁₂ aralkyl* ester, benzyl, 1-phenylethyl, 2-phεnylεthyl, phεnylpropyl, naphthyl- mεthyl, p-nitrobenzyl, p-methoxybεnzyl, 1-indanyl,

phenacyl or 3 ,5-di-tart-butyl-4-hydroxybεnzyl; as ϋ- g_ _Q aryl-mεthyl group capable of giving di- Cg_ _1Q aryl-methyl ester, the aforε-mentioned ones, i.e. benzhydryl or bis(p-methoxyphεnyl)methyl; as tri-C O- — j,„ _π g ary -i-methv -i σ -rouo - ca -oable of c _* ivinσ * tri- ^c g_ _{ι Q} aryl-methyl ester, the afore-mentioned ones, i.e. trityi; and as subsuituted silyl group capable of giving subs -ituted silyl ester, thε afore-menticnεd onεs, i.ε. trimεthyisiiyi, tert-butyld'imεthyisiiyl or -Si(CΞ ₃ ) ₂ CΞ ₂ Ξ ₂ Si(CΞ^) ₂ -. The above esters include esters at the 4-positicn. Such cαrocund having above ester grop at the 4-position forms an intramolecular salt .of [wherein *P' has the same meaning as defined above]! at the 3-pcsiticn.

As thε biovailabiy unstable and ncn-toxic esters, those which have beεn confirmεd as e piσyablε in the fields of penicillin and cephalosporin can conveniently be employed also in the present invention, which may be exεmoiified bv C 2_—Ό . alkano -vioxv - C l-—o . alkv ~l ester, lτ(C l.— _o. alkoxy) C _x _ ₅ alkyl ester ^' ,1-( L_ ₆ alkyithio )C!_ ₆ alkyl ester or l-l _C ^ _g alkoxycarbonyloxy) C_g alkyl estεr. The C ₂ _g alkanoyloxy |_ ₆ alkyl ester is exemplified _b y acetoxvirthyl ester, 1-acetoxyethyl ester, 1-ace _t oxy _b utyl estεr, 2-acεtoxyεthyl ester, propionyloxymet ^h yl ester, pivaloyloxymethyl estεr. Thε l-(C,_ _g alkoxy) C _1-g alkyl εster is εxεmplified by methoxymεthyl εstεr, ethoxymεthyl εster, isopropoxymethyl estεr, 1-methoxyethyl εstεr or 1-ethoxyεthyl εstεr. Thε 1-(C, g alkyithio) C ₁ _ _g alkyl εstεr is exemplified by methyl thiome thy 1 ester or ethylt _h iαtethy _l estεr. The l-GC-^g alkoxycarbonyloxy) C ₁ _ _g alkyl ester is exemplified by 1- (e thoxycar bonyloxy) ethyl ester or 1-

besides the above-mentioned ester derivatives , pharma- ceutically acceptable compounds which are convertible in vivo to the compound [I] . The above-mentioned esters usable as synthetic intermediates and bioavailablv unstable non- toxic esters include esters at the 4-position . Such esters at the 4-position u≤uailv form an intramolecular salt of

CΞ-A^. jβ [wherein hβ has the same meaning as denned aocvei at the 3-position.

When the σαπroound [I] has a hydroxyl group, the hydroxyl group may be protected . Groups usable for protecting the hydroxyl group include those which are usually employed for protecting the hydroxyl group in the field of 3-iactam and organic chemistry , which may be exεmpiified.- by , besides the afore-mentionεd C- . aiJcancyi groups , a substituted oxvcarbonyl group , tart-butyl group , £-._- _* , aralkyl* group , di-Cg_ _{1 Q} aryl-methyl group , tri-Cg_- _Q aryl-methyl group , l- (C _x _g alkoxy) C _χ _g alkyl group , 1- (C ₁ _ ₅ alkyithio ) C ₁ _ ₅ alkyl group and substituted silyl group , acεtal residues e . g . 2-tetrahydro?yranyi or 4-methoxy-4-tεtrahydropyranyi .

When the compound [I] additionally has an amino group other than those mentionεd abcvε , the amino group may also be protected. Groups employablε for protεcting thosε amino groups are exemplified also here by those ref errεd to in thε protεction of thε afore-mentioned amino groups .

The compound {I] of this invention has a broad antibacterial spectrum and can be used for prophylaxis and therapy of various diseases

of men and animals caused by pathogenic bacteria, for example, infections of respiratory tract or of urinary passages. Characteristic features of the antibacterial spectrum of the antibacterial compound [I] are mentioned as follows:

(1) remarkably strong activity against a variety of gram-negative bacteria;

(2) strong activity against gram-positive bacteria (e.g. Staphylococcus aureus or Cornyebacterium diphtariae) ;

(3) remarkably effective against Pseudomonas aeruginosa which are not sεnsitivε to therap -with.con entional cephalosporin-typε antibiotics; and

(4) Strong activity against a variety of . -iactamasε- producing gram-negative bacteria (e.g. the genera Escherichia, Enterobactar, Ξerratia or Proteus) . Especially against bacteria belonging to the genus

Pseudomonas, to which aminoglycoside antibiotics such as A ikacin or Gεntamicin hava been used, the anti¬ bacterial compound [I] shows antibacterial activity comparable to these aminoglycosidεs with remarkably lower toxicity to men and animals, which is countεd as ona of thε great advantages.

Besides, the antibacterial cσπpound [I] of the presεnt invεntion has the following characteristic features,

i.e. excellent stability, high concentration in blood, long duration of effect and remarkably high concentration in tissue.

Among the compounds [I] of this invεntion, the compound having a following structure is preferable:

(1) Ά~ is unsubstituted imidazo [l,2-b]pyridazinium-l-yl group;

(2) is imidazo [l,5-a]pyrιdιmum-2-yl group which is substituted by a C, _s alkyl group, halogen atom, or cyano group; or

(3) R 1 is an amino group, R3 is an optionally substituted

© C-, ₃ alkyl group; and A is an imidazo [l,2-a]pyridinium-l-yl group which is substituted by a fluorinε or cyano group.

How to makε thε compound [I] of this invention, its salt or ester will be describεd in detail as follows. The processes describεd hereafter are all conventional as reactions per se, and analogous ones therεto can also be applied.

! ^• The compound [I] of the present .invention can be produced by conventional methods, which are mεntioned below. Production method (1)

The compound [I] can be synthesized by reacting the 7-amino compound of the formula:

[II]

wherεin thε symbols Z, R , R and ^ arε of the same mean¬ ing as defined above or a salt or estεr thεrεof with carboxylic acid of thε formula:

(this compound may be rreeffeerrrreedd ttoo as "R ^D OH" hereinaftεr)

N-OR

wherεin the symbols R and R are of the samε εaning as dεfinεd above, or a salt or reactive derivative thεrεof.

This is a method of subjεcting a 7-amino compound [II] or a salt or ester thereof (the 7-amino compound [II] , and salt and estεr thereof may simply be abbreviated hereinaftεr as the 7-amino coπpound [H]) to acylation with carboxylic acid ETCH or a salt or reactive derivative thereof. In this method, thε carboxylic acid R~OH in the free form, a salt or reac ivε derivative thereof is used as the acylating agεnt cf thε 7-amino group of the 7-amino

__ compound [II] . More concretely, the frεe acid R OH, or a sal or rεacuive derivative of the free acid R OΞ, such as aninorganic base salt, organic base salt, acid halide, acid azida, acid anhydrida, mixed acid anhydride, active amide, active estεr or ac ivε thicεstεr is used for the acylation. There may be mentioned, among others, as inorganic basε salts, alkali metal salts (e.g. sodium salt, potassium salt, etc.) or alkaline earch metal salts (e.g. calcium salt, etc.); as organic base salts, trimethylamine salt, triethylamine salt, tert-butydimethylaminε salt, dibεnzylmethylamine salt, bεnzyldi ethylamine salt, N,N-dimethyianiline salt, pyridine salt or quinoline salt; as acid halide, acid chloride or acid bromide; as mixed acid anhydride, mono-C,_- alkyl carbonic acid mixed anhydride (e.g. mixed acid anhydride of the free acid HrOH with, for example, monomethyl carbonic acid, monoεthyl carbonic acid, monoisopropyl carbonic acid, monoisobutyl carbonic acid, mono-tεrt-butyl carbonic acid, monobenzyl carbonic acid.

i mono(p-nitrobenzyl)carbonic acid, or monoallvl carbonic acid C, g aliphatic carboxylic acid mixed anhydride (e.g. mixed acid anhydride of the frεe acid R OH with,, for example, acetic acid, trichloroacetic acid, cyanoacεtic acid, prcpiαπic acid, butyric acid, iscbutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoro- acatic acid, trichloroacetic acid or acetoacεtic acid) , C__, ₂ aromatic carboxylic acid ixεd anhydride (e.g. mixed acid anhydride of the freε acid R^OΞ with, for εxampla, bεnzoic acid, p-toluic acid or p-chlorobenzoic acid) , organic sulfonic acid mixed anhydride (e.g. mixεd acid anhydridε of thε free acid RrOΞ with, for example, methanesulfonic acid, εthanεsulfonic acid, benzene≤uifonic acid or p-toluεnεsulfonic acid) ; as activa amide,an amide with a nitrogen-containing heterocyciic compound (e.g. acid amide of the free acid Ε CΕ. with, for examplε, pyrazole, imidazoie or benzo- triazolε, thεsε nitrogεn-containing hεtεrocyclic compounds bεing optionally substitutεd with afore- mεntionεd C, ₆ alkyl group, C, _s alkoxy group, halogen atom, oxo group, thioxo group or C, _g alkyithio group) . As the active estεr, those which can be used for the same purpose in the fields of _. -lactam and peptidε synthεsis can all be used, which are exemplified by, - besides organic phosphoric acid ester (e.g. diεthoxy

phosphoric acid estεr or diphenoxy phosphoric acid) -, p-nitrophenyl ester, 2,4-dinitrophεnyl ester, cyanomεthyl εstεr, pentachlorophenyl ester, N-hydroxysuccinimide εstεr, N-hydroxyphthalimide ester, 1-hydroxybenzotriazαle estεr, β-chloro-1-hydroxybεnzotriazcle ester, 1-hydroxy- lΞ-2-pyridonε ester. The active thioester can be - exεmplifiεd by esters with aromatic heterocyciic thiol compounds (e.g. 2-pyridylthiol ester, 2-bεnzσthiazolyl- thiol estεr, thεse hetεrocyclic rings being substituted with afore-mentioned C, - alkyl group, C, . alkoxy group, halogen atom or C, _g alkyithio group) . On the other hand, the 7-amino compound [II] can bε used as freε base, _{a S£} t or ester thereof. Salts of the 7-amino compound [II] are exemplified by inorganic base salts, ammonium salt , organic base salts, inorganic acid addition salts or organic acid addition salts. There may be mentioned, as inorganic base salts, alkali metal salts (e.g. sodium salts or potassium salts) and alkaline earth metal salts (e.g. calcium salts) ; as organic base salts, for example trimethylamine salts, triethyla ine salts, tert-butyldimethylamine salts, dibenzyI ethylamine salts, benzyldimεthylamine salts, M,N-dimethylaniline salts, pyridine salts or σuinoline salts; as inorganic acid addition salts, for example hydrochlorides, hydrobromides, sulfates, nitrates or

phosphatεs; and as organic acid addition salts, formatεs, acetates, triflucroacatates, methanesulfonatεs, or p-toluenesulfonatεs. As thε εsters of the 7-amino compound [II], esters already referred to as ester derivatives of the compound [I] can also be counted, more concretely, C, __ „ al!<yl* ester, ^C 2- _" alkenyl ester, C, ι _Q cycloalkyl ester, C,_.. cycloalkyl C._- alkyl ester, C-_, _Q aryl* ester, C__,_ aralkyl* ester, di-C ₍ -_, ₀ aryl-methyl ester, tri—C-_- ₀ aryl-methyl ester or ₂ _g alkanoyloxy C._. alkyl ester. The sta ing material R°OΞ as well as salts and reactive derivatives thereof can be easily prepared by kncwn methods or analogous methods thεreto. A reactive derivative of the compound ?. ^* "CH, after isolation from thε reaction mixture, can be allowed to react with a 7-amino compound [II] , or as the reaction mixture containing the reactive derivative of the compound R°0H before the isolation, it can be allowed to react with a 7- amino compound [II] . when the carboxylic acid R~OΞ is used in the state of its free acid or salt, a suitable condensing agent is employed. As the condensing agents, there may be counted N, *-di-substituted carbcdiimides e.g. N,N'-di-cyciohexyIcarbodiimide; azolidεs e.g. N,W- carbonylciimidazole or N,N'-thiocarbonyldiimidazole; dehydrating agents e.g. N-ethoxycarbonyl-2-ethoxy-l,2-

dihydroquinoline, phosphorus oxychloride or alkoxy- acetylene; 2-halogenopyridinium salts e.g. 2-chloro- pyridinium methyl iodide or 2-fluoropyridinium methyl iodide. The reactions where these condensing agents are employed are considered to proceed via reactive ceπvativεs of thε carboxylic acid RbOH. Thεsε reac- ticns are generally conducted in a solvent which does not hamper the reaction. These solvents may be exemplified by ethers such as dioxane, tetra- hydrofuran, diεthyl ether, tert-butyi mεthyl ether, di- isopropyl ether or ethylene- glycol dimethyl ether; esters such as ethyl formate, ethyl acetate or n-butyl acetate; haiogenate hydrocarbons such as dichlσromethane, chloroform, carbon tetrachlσrica, trichlene or 1,2- cichlorcethane; hydrocarbons such as n-hexane, benzene or toluene; amides such as formamide, N,N-dimethyIfσrm- amida or N,N-dimethyiacetamide; ketones such as acetonε, mεthyl ethyl kεtone or methyl isobutyl ketonε; or nitriles such as acetonitrile or propionitrile, and, besides, dimethyl sulfoxide, sulfolane, hexamεthyl- phosphora idε or water, singly or in combination. The amount o acylating agent ( or a salt or reactive derivative thereof) is usually about 1 to 5 mol . , preferably about 1 to 2 πol. , relative to 1 mol. of the 7 -amino compound _[ II ] . The reaction is conducted within the tε peraturε range ^' of about -80 to 80°C, preferably about -40 to 50°C, most preferably

about -30 to 30°C. Thε reaction time varies with kinds of the 7-amino compound [II] and carboxylic acid R OH or a salt or reactivε dεrivativε thεrεof of thε solvent (mixture ratio as well whεn mixture solvents are used) and reaction temperatures, but it is usually within the range from one minute to 72 hours, pre erably from 13 minutes to three hours. When an acid halide is employed as the acylating agent, the reaction can be conducted in the presence of a deacidifying agant for the purpose of eliminating from the rεaction system the hydrogεn halogenide to be liberated. The deacidifying agent may be exemplified by inorganic bases such as sodium carbonate, potassium carbonatε, calcium carbonata or sodium hydrogεn carbonate;, tertiary amines such as triεthylaminε, tri (n-propyl) aminε, tri (n-butyl) amine, diisopropylethyl- amina, cyclohexyldimethylamine, pyridine, lutidine, γ-collidinε, N,N-dimεthylanilinε, N-mεthyipiperidine, N- εthylpyrrolidinε or N-me hyImorpholine; or alkylεnε oxidεs such as propylene oxide or epichlorohydrin.

The 7-amino compound [II] can be synthesized by reacting a compound of the formula;

[ ^τ ,-herein the syrrbcl R ^-1 stands for hydroxyl group, acyicxy group, carbamoyloxy group, substituted carbamoyloxy or halogen atom, and other symbols are of rεspεctivεly the same meanings as dεfinεd above] or a salt or estεr thεreof with an imidazola compound of the formula A* [A' means an optionally substituted imidazolε forming a condensed ring at 2,3- or 3,4- position] or a salt thereof.

The starting compound [IX] or a salt or ester thereof is a compound which can be easily produced by a conventional method or an analogous one thεreto. As salts and esters of the compound [IX] can be also mentio εd here the same ones as those of the compound [II] .

As the acyloxy group represented by the symbol R ⁵ , the abcve-mentionεd acyl+oxy group can be employed also here, e≤pεcially preferablε being acetoxy, chloroacatoxy, propionyloxy, butyryloxy, pivaloyl¬ oxy, 3-oxobutyryloxy, 4-chloro-3-oxobutyryloxy, 3-carboxypropionyloxy, 4-carboxybutyryloxy, 3- εthoxycarbamoylpropionyloxy, benzoyloxy, o-carboxy¬ benzoyloxy, o-(ethoxycarbonylcarbamoyl)benzoyloxy and o-(ethoxycarbonylsulfamoyl)benzoyloxy. As the substituted carbamoyloxy group represεnted by the symbol R ⁵ ,

thε above-mentioned ones can be employed also here, especially preferable being mεtlαylcarbamoyloxy and N,N-dimathylcarbamoyloxy. Ξalogεn atoms represεntεd by thε symbol ^ are preferably chlorine, bromine and iodine. As to the imidazoie compound A' and its salt , detailed description will be given hereafter.

Even in case where the amino group at the 7-position is protectεd, thε above reaction proceeds likewise. When desired, the protεcting group may be removed after the reaction to thereby give a 7-amino compound [II].

The carboxylic acid [R^OH] or a salt or rεaσtivε dεrivative thereof can be easily prepared by a known process or a process analogous thereto. Production method (2)

Furthermore, the compound [I] can be synthesized by reacting a compound of the formula;

[X]

wherein R is hydroxyl group, acyloxy group, carbamoyloxy . group, substituted carbamoyloxy group or halogen atom and other symbols are of the same meaning as defined above or a salt or estεr thεrεof with an imidazolε compound of the formula A* [A ¹ means an optionally substituted imidazoie forming a condεnsεd ring at thε 2,3- or 3,4-position] or a salt thereof .

In this reaction,imidazoie compound A ¹ or a salt therεof is rεactεd with a compound [X] or a salt or εster thereof (the compound [X] , and salt and estεr therof may simply be abbreviated hereinaftεr as the compound [X]) to cause nucleophilic substitution .thereby to give the compound [I] . In thε compound [X] , R" stands for, also hεrε, hydroxyl ^' group, acyloxy group, carbamoyloxy-group, substituted carbamoyloxy group or halogen atom. The compound [X] can be used in the freε statε, or as salts or εstεrs thereof. The salts and esters of the compound [X] are those mentioned as salts and esters of the 7-amino compound [II] in the above Production Method (1) . The compound [X] , or a salt and estεr thereof can be easily prepared by

- 7* -

known methods or analogous ones therεto. On thε other hand, the imidazoie compound A' stands for an optionally substituted imidazoie forming a condensed ring at the 2,3-position or the 3,4-position. The condensed ring means a form of condensation betwεεn the imidazoie ring and the 5- to 6-membered. aromatic heterocyciic ring. Such-condensed ring may be further condensed with another aromatic ring or aromatic heterocyciic ring. The optionally substituted imidazoie (A') forming a condεnsεd ring at thε 2,3-cosition or the 3,4-position l » m naayy bbee represεntεd by thε general formula [A ] or

2 '

[ ^ ] ;

anc the "- group of the compound [I] to bε synthesized by allowing the compound [X] to react with the compound [A" ]or a salt thereof stands for the afore-mentionεd A 1 group , and the A (÷ group of the compound [I] to be synthesized by allowing the compound [X] to react with the compound

₂ » [A ] or a salt thereof stands for the afore-mentioned A^ group. The _ » symbol B in the formulae of condensed imidazoie [A ] and [A 2 ' ] is of the same meaning as that of symbol B

m the [A1] and [A2] groups defined in the above,

1 » Hencε, thε compound [A ] is εxεmplified by

and the compound [A. 2'] is exemplified by

The substituents Rl~ ¹ * and R~ι2 ^* ' on thε lmidazola compound

11 , 12 A.' are those mentioned as the substituents R and R of the group A. And, in the compound [A ] , the 5,6- position of the imidazoie ring may be condensed with an alicyclic ring, aromatic ring or heterocyciic ring, which mav be exεmclified bv

¹² _'

In the above, B and R12' are of the same meaning as defined in the foregoing. The above-mεntionεd substituεnts R 11' and R"i~ ">' may be further substituted.

The imidazoie compound A' may be used as salts thereof, which may be exemplified by inorganic acid addition salts e.g. hydrochloridε, hydrcbro idε, sulfate, nitrate or phosphate, or organic acid addition salts e.g. formate, acetate, tri luoroacetate, methanesuifαnate or p-toluenesulfcnata. The imidazoie compound A' and its salt may be synthesized, in gεnεrai, by known mathods dεscribεd in literature referεncεs cr by analogous mεthods thεrεto.

Thε nucleophilic substitution to the compound [X] with the imidazoie c__πpound A' or a salt thereof is a per se known reaction, which is usually conducted in a solvent, for εxamplε, εthεrs, esters, halogenated hydrocarbons, hydrocarbons, amides, ketonε≤, nitriles or water, which are used in the Production Method (1) . Besides, alcohols such as methane!, ethanol, n-propanol, isopropanol, ethylεne glycol cr 2-methoxyethanol may be used as well. When the imidazoie compound A ¹ or a salt thereof is in liquid state, it may be εcmetimεs used in a large excess amount (e.g. ιo to 200 mol.) relative to the compound

[X] to allow it to act also as the solvent. In this case, use of the above-mεntionεd solvεnts is unnεcεssary.

or the imidazoie A' or a salt thereof may be used as a mixture solvent with any of the above-mεntioned solvents. c The case where R" stands for acy oxy group, carbamcvicxv crouo or a substituted rnamcvicxv ercui

Preferable solvents are water and mixture solvents of water- iscible organic solvents and water. Among thε water-miscible organic solvents, preferable ones are exemplified by acetone, methyl ethyl ketonε and acetonitrile. The amount of the nucleophlic reagent A ¹ or a salt thereof is usually about 1 to 5 moles, preferably about 1 to 3 moles, relative to 1 mole of the compound [X] . The reaction is conducted within a temperature ranging from about 10°C to 100°C, preferably from about 30°C to 80°C. The reaction time depεnds on thε kinds of thε compound [X] and the compound A ¹ or a salt thereof, kinds of solvents (mixture'ratios when mixture solvents are used) , or reaction temperature, and ranges usually from 30 minutes to five days, pref rably from one ^' hour to five hours. The reaction is advantageously conducted at pH 2 to 8, preferably near neutral pH, i.e., pΞ 5 to 8. The reaction readily procεeds usually in thε prεsεncε of 2 to 30 equivalents of an iodide or thiccyanata. These salts are exemplified by sodium iodide, potassium iodide, sodium thiocyanate and potassium thiocyanate. In addition to the above

i ^' εxεmplified salts, a surface-active quaternary ammonium salt such as trimethylbenzylammonium bromide, triethyl- benzylammonium bromide or triethylbenzylammonium hydroxidε may bε so εtimes used for allowing the reac¬ tion to proceed smoothly. The case where R ³ stands for hydroxyl group:

Thε reaction may be conducted in the prεsence of an organic phosphorus compound according to thε annεr dεscribε in, for εxampla, Publicaticn of ϋnexa ined Patent Application (Kokai) in Japan, No. Sho 58-43979. The organic phosphorus compound is exemplified by o- phenylεne phosphcrochloridate, o-phεnyiene phosphoro- fluoridate, methyl c-phenylene phosphate, ethyl o- phεnylεnε phosphate, propyl o-phenylene phosphatε, isopropyl o-phenylene phosphate, butyl o-phenylene phosphate, iscbutyl o-phεnylεne phosphate, sec.-butyl o-phenylene phosphate, cyclchexyl o-phenylene phosphate, phenyl o-phenylεne phosphate, p-chlorophenyl o-phenylεnε phosphata, p-acεtylphεnyl o-phεnylεnε phosphate, 2-chloro- ^' ethyl o-phenylene phosphata, 2,2,2-trichlcroεthyl o- phεnylene phosphata, εthoxycarbonylmεthyl o-phenylenε phosphate, carbamoylmethyl o-phenylene phosphate, 2- cyanoεthyl o-phenylene phosphate, 2-methylsulfonylethyl o-phenylεnε phosphatε, benzyl o-phenylene phosphata, l,l-dimεthyl-2-propenyl o-phenylenε phosphata, 2-propenyl

o-phenylεne phosphate, 3-methyl-2-butenyl o-phenylene- phosphate, 2-thienylmεth l o-phenylene phosphate, 2- furfur lmεthyl o-phenylεnε' phosphate, bis-o-phεnylεnε pyrophcsphatε , 2-phεnyl-l, 3 , 2-bεnzccioxaphosp hcle-2-cxide , 2- (p-chlorophenyl) -1,3, 2-bεnzcdicxaphosphcle-2 -oxide, 2-butyI-I,3 , 2-benzodioxaphosphcie-2 -oxide, 2-aniliro- 1,3, 2-benzcdioxaphosphoIe-2-oxide , 2-ρhenyIthic-I ,2,2- bεnzodioxaphosphole-2-oxid , 2-mεthoxy-5-mεthyI-l, 3 , 2- benzαdicxaphosphole-2-oxide , 2-chlcro-3-ethoxycarbonyl- 1,3, 2-benzodioxaphospholε-2-oxidε , 2-mεthoxy-5-εthoxy- carbonyi-1 , 3 , 2-bεnzodioxaphosphoiε-2-cxid , 5-ethαxy- carbonyI-2-phenyl-l, 3 , 2-benzcdioxaphcsphcIε-2-cxidε, 2 , 5-dichIoro-l , 3 , 2-bεnzodioxaphosphc2a-2-oxida , 4-chlσro- 2-tetho:-Cv--l _Λ 3 ,2-benzodioxaphosphole-2-cxidε, 2-mεthoxy-4- meth^i-l, 3 , 2-benzodioxaphosphoIe-2 -oxide, 2, 2 -naphthalene methyl, phosphate, 5 , β-dimethyl-2-methycxy-l, 3 , 2-benzo- cicxa hcs hoJer-2-oxidε, 2, 2-dihydrα-4, Ξ, 6, 7-tεtrachloro-. 2,2, 2-trimethoxy-l , 3 , 2-benzodioxaphcsthcie, 2 , 2-dihydro- 4,5,ό, 7-tetrachloro-2 , 2 , 2-triphεnoxy-i , 3 , 2-bεnzodioxa- phα≤ hclε, 2, 2-dihydro-2,2-εthylεnεdioxy-2-methoxy-l, 3, 2- benzodiσxaphosphole/ 2, 2-dihydro-benzyI-2, 2-dimethoxy-l, 3 ,2- benzcdioxaphosphole, 2 , 2-dihydro-4 , 5-benzo-2 , 2 , 2-trimethoxy- 1,3, 2-benzodioxaphosphole, 2 , 2-dihydro-2 , 2 , 2-triphenoxy- 1,3,2, -benzodioxaphospholε, 2 , 2-dihydro-2 , 2- (o-phenylenε- dioxy) -2-phεnoxy-l , 3 , 2-bεnzodioxaphosphσla, 2-chrolo-2 , 2 , -

dihydro-2,2-(o-phenylenedioxy) -1,3,2,-benzodioxaphosphole 2,2-dihydro-2-methoxy-2,2-(o-phεnylεnεdioxy)-1,3,2-benzo- dioxaphosphola, 2,2-dihydro-2,2,2-trichloro-l,3,2- benzodioxaphcspholε, ,10-phenanthrεnεdioxytrimethoxy- phαsphorus, o-phenylen phcsphorochloridite, o-phenylene phosphorobromidite, c-phεnylεne phosphcrofluoridite, methyl o-phenylene phcshita, butyl o-phεnylεne phoεthite mεthoxycarbonylmethyi c-thenyiεnε phosphitε, phenyl o-phεnyiεnε phosphite, -chlcro (or p-nitro)phenyl o-phenylεnε phosphite, 2-phenyI-I,3,2-benzodioxaphosphcie, bis-o-phenylεne pyrophosphite, 2-methoxy-5-mεthyI-I,3,2- bεnzodioxaphosphcla, Ξ-acεtyI-2-phεnoxy-l,3,2-benzo- dioxaphospholε, 9,10-phεnanthrenε pho≤phorochloriditε, 2-chloro-4-mεthyI-I,3,2-benzodioxaphosphole,5-ethoxy- carbonyl-2-phεnyI-I,3,2-banzodiαxaphosphole, 2-chloro- 2-thioxo-l,3,2-benzcdicxapho≤phole,2-phenoxy-2-oxo- 1,3,2-bεnzodiazaphcsphcle,2-phenoxy-l, ,2-benzocioxaaza- phcspholε,2,2-dihydro-2-cxo-2-methoxy-4,5-dimethyl-I , 2 . 2- dioxaphosphole,2,2-dihydro-2-oxo-2-chloro-4,5-dimethyI- 1,3,2-dioxaphσsphσie, 2,2-cihydrc-2-oxo-2-(l-imidazolyl) - 4,5-dimεthyl-l,3,2-dioxaphcsphcIe, 2,2-dihydro-2,2-ethyiεne- dioxy-2-mεthoxy-4,5-dimεthyI-l, ,2-dioxaphospholε, 2,2- dihydro-2,2-dimεthoxy-2-phenoxy-4,5-dimethyl-l,3,2- dioxaphosphola,2,2-dihydro-2,2,2-trimεthoxy-4,5-dimεthyl- 1,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-triphenoxy-4,5-

dimethyl-1 , 3 , 2-dioxaphosphole, 2 , 2-dihydro-2 , 2 , 2-tirethoxy- 4 , 5-diphenyl-l , 3 , 2-dioxaphosphole, 2 , 2-dihydro-2 ,2,2- trimethoxy-4 , 5-diphenyl-l , 3 , 2-dioxaphosphole, 2 , 2-dihydro- 2-oxo-2-methcxy-4 , 5-diphenyl-l , 3 , 2-dioxaphosphαle, 2 , 2- dihydro-2 , 2 , 2-trimethoxy-I , 3 , 2-dioxaphospholε, 2 , 2-dihydro- 2,2, 2-trimethoxy-4-phenyl-l , 3 , 2-dioxaphosphole, 2 , 2-dihydro- 2,2,2, -trimethoxy-4-methyI-l , 3 , 2-dioxaphosρhoie , 2 , 2-dihydro- 2,2, 2-trimεthoxy-4-mεthyl-5-phenylcarbamoyI-l ,3,2- dioxaphosphole, 2,2, 4,5, 6, 7 - hexahydro-2,2,2-trimethcxy- 1,3, 2-benzodioxaphosphole, 2,2' -oxybis ( 4 , 5-dimεthyI-2 , 2- dihydro-I,3,2-dioxaphosphole) and 2,2 '-oxybis (4, 5-dimethyI- 2 , 2-dihydro-l , 3 , 2-dioxaphospholε-2-oxidε) . For the reaction, . any solvent can be employεd if only it doεs not hampεr the reaction, and, preferably, the afore- εntionεd ethers, esters, halogenatεd hydrocarbons, hydrocarbons, amidεs, kεtonεs and nitrilεs may bε usεd singly or in a mixtura thereof . Especially, use of dichlorome thane , acetonitrile, formamide, a mixture of fαrmamide and acεtonitrile, or a dichloromethane and acetonitrilε brings about a prεfεrablε result. The amounts of the nucleophilic reagent A ¹ or a salt thereof and the organic phosphorus compound arε rεspεctivεly, relative to I mole of the compound [X] , about 1 to 5 moles and about 1 to 10 moles, more prεferably about 1 to 3 moles and about 1 to 6 moles. The reaction is conductεd within the temperature range from about -80°C to

50°C, prefεrably from about -4Q°C to 40°C. The reaction time is usually within the range of one minute to 15 hours, pre εrablv five minutes to two hours. To the reaction

I system may be added an organic base. ^τϊl ® organic base may be exemplified by amines such as triethylaminε, tri-(n-butyl) amine, di-(n-butyl) amine, diisobutylamine, dicyclohεxyiaminε or 2,ό-lutidine. The amount of the base to be added is preferably about 1 to 5 moles relative to 1 mole of thε compound [X] .

The case where R ⁵ stands for halogen atom:

Preferable solvents are the aforε-mentiσned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, kεtones, nitriles, alcohols and watεr. Thε amount of the nucleophilic reagent A' or a salt thereof to be used is usually, relative to one mole of the compound [X] , about 1 to 5 moles, prεferably about 1 to 3 moles. The reaction is conducted within a tenperature rangε of about 0 to 80°C, preferably about 20 to 60°C.

The reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours. For accelerating the rεaction, the reaction may be conductεd in the presεncε of a dehalogenating agent. As such dehalogεnating agεnts, there may be counted deacidifying agents such as inorganic bases, tertiary amines and alkylεnε oxidεs mεntionεd in thε Production Mεthod (1) , whilε the nucleophilic reagent A ¹ or a salt therεof itself may be allowed to act as the

dehalogenating agent also. In this case, thε compound

A ¹ or a salt thεrεof is usεd in an amount of two molεs or morε rεlative to one mole of the compound [X] . The halogen atom shown by R is exemplified by chlorine, bromine and iodine, and preferably iodine. The compound [X] wherein R ^" stands for iodine can be easily produced in accordance with the method describεd in, for example, Publication of ϋnexaminεd Patεnt Application

(Kokai) in Japan, No. Sho 58-57390 or a method analoσou≤ thereto.

183 PC .JP86. 00_-

The compound [X] can be easily prepared by a known method or a method analogous thereto . Production method (3 )

The compound [I] (wherein R stands for an optionally substituted hydrocarbon residuε) (this compound is re- f erred to as the compound [I ¹ ] or a salt or ester thereof) can also be prepared by, besides the aboye-πjentioned Production Method (1) or ( the Production Method (3 ) to be described below.

The reaction scheme is as follows :

₃ „ t ^l 'I

.wherein the symbol R stands for an optionally sub- stituted hydrocarbon residue, and the symbols Z, R 1, R4,

R and A^re of the same meaning as defined above .

This is a method of synthesizing the compound [I'] or a salt or ester thereof (the compound [I ¹ ],and salt and estεr thereof ma simply be abbreviated hereinafter as the compound [I']) by reacting a compound of the formula : - R 3 " OH or a rεactivε dεrivativε thereof with a hydroxyimino compound [V ^] or a salt or ester thereof (the compound [V] , and salt and este thereof may simply be abbreviated hereinafter as the hydroxyimino com ound V which is a er s known ethe if in reaction.

R " stands for an optionally sub¬ stituted hydrocarbon residue which is the same as that referrεd to in R 3. R "OH may bε employed as it is or as a reactivε derivative therεof.

Rεact ve derivatives of R 3"OE are represented by the formula R" Y, having a croup to be liberated together with the hydrogεn atom of the hydroxyimino compound [V] . The group 1 to be liberated together with a hydrogεn atom may bε exemplified by halogen atom, sulfo group cr mono-substituted sulfonvloxy group. The halogen atom may be exemplified by chlorine, bromine or iodine. The mono-substituted sulfonvloxy group may be I exemplified by C, _g alkylsulfonyloxy and C. , _Q arylsulfonylox groups e.g. methanesulfonyloxy,ethanesul onyloxy, benzene- sulfonyloxy or p-toluenesulfon Icxy. '

When a C, ₄ alkylether dεrivativε of thε compound [V] is intended, there may be used, besides the above- mentioned reaction derivatives, C. _ _<1 diazcalkane such as diazomethane or diazσethana, and di-C, _d alkyl sulfate such as dimethyl sulfate or diethyl sulfatε.

Thε compound [V] can bε prepared by the acylation as mentionεd above in The Production Method (1) or thε nucleophilic substitution as mentioned - above in the Production Method ( 2 ) . The reaction schema are as follows , resoectivelv :

[λiLl (including salt cr reactive derivative) C ]

The starting materials [XII] and [X'] can be easily prepared by a known method cr an analogous one thεrεto.

The compound R 3"OΞ and the reactive derivativε thεrεαr can also be easily prepared by a known method or an analogous one thereto.

The detailed condition of the reaction of the Method

(3) is as follows.

(3-1) The case where R ³ " OH is used:

By using a suitable dehydrating agent the hydroxyimino compound [V] is reacted with the compound R ³ "θH to synthesize the compound [I ¹ ]. The dehydrating agent may be

exemplified by phosphorus oxychloridε, thionyl chloride, dialkyl azodicarboxylate (usally used in the presence of phosphine) or N,N-dicyclohexylcarbodiimide, and prafarably diethyl azαdicarboxylata in thε prεsence of triphenyl phosphine. The rεacticn in which diethyl azodicarboxylate is used in the presence of triphenyl phosphine is usually conducted in an anhydrous solvent such as ethεrs or hydrocarbons mentioned above.

P.elative to 1 olε of the compound [V] , about 1 to 1.5 moles each o tne compound R 3" OH, εthyl azodicarboxylatε and triphenyl phosphine is emplcyεd. The reaction raquirεs l to 4 days at a temperature range of about 0 to 50°C. (3-2) The case where R3"γ is usεd:

Thε rεaction bεtween R" Y and the hydroxyimino compound [V] is a conventional εtherification reaction, which is conducted in a solvent. The solvent is exεmplifiεd also here by those as mentionεd in thε Production Method (1) above, i.e., ethers, esters, hydrogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water or a mixture of any of them, prefεrably a mixture solvent of a water- miscible solvent and water (e.g. aqueous methanol, aqueous ethanol, aqueous acetone and aqueous dimethyl sulfoxide) . Thε rεaction may also be allowed to proceed smoothly in the presencε of a suitablε base. The base may be exemplifiεd by inorganic basεs such as alkali metal salts e.g. sodium carbonate, sodium

hydrogencarbonate or potassium carbonate , or alkali metal hydroxides e . g. sodium hydroxidε or potassium hydroxidε. This rεaction may be conducted in a buffer solution of pH 7.5 to 8.5. The mole numbers of a reagent

R" Y and thε base relative to 1 mole of thε starting compound [V ] are respectively about 1 to 5 and about 1 to 10, prefera about 1 to 3 and about 1 to 5, respectively. The reaction tεrrperaturε is in the rangε from about -30°C to 100°C, preferably, about 0°C to

80 °C. The reaction time ranges from 10 minutes to 15 hours , prεferably from 30 minutes to 5 hours .

(3-3 ) The case where Cχ- ₄ diazoalkane is used :

T' ϋ 1- -Har- ic** mtion is usuallv conducted in a solvent.

As the solvent are εmployεd, for εxampla, the afore¬ mentioned ethers and hydrocarbons. The hydroxyimino compound [V] is dissolved in a solvent, to which is then added a solution of a diazoalkane compound, whereupon the reaction proceeds. The reagent is used, relative to I mole of the compound [V] , in an amount of about 1 to 10 moles, preferably about 1 to 5 moles. The reaction is conductεd at a relatively low temperature range of from about -50°C to 20°C, preferably from about -30°C to 0°C. The reaction time rangεs from 1 minute to 5 hours, preferably 10 minutes to onε hour.

⁽ 3-4 ⁾ - The case where di-C ₁ _ ₄ alkylsulfate is used: The reaction is conducted usually in water or a

mixture solvent of a water-miscible solvent and water. As the mixture solvent are mentioned those mentioned in the Production Method (3-2) . This reaction is usually conducted in the presence of an inorganic base, for example, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxidε. The reagent is used in an amount of about 0.5 to 10 moles, preferably about 1 to 2 moles, relative to 1 mole of the compound [VJ . The reaction tem ^p erature ranges from about 20°C to 100°C, preferably about 50°C to 100°C. The reaction time ranges from 10 minutes to 5 hours, preferably from 30 minutes to 3 hours.

After the above-mεntionεd Production Method (i)-(3), whεn rεquirεd, removal of protecting groups and purification are conducted to obtain the compound [I] of this invention. Methods of removing protecting groups and purification are dascribεc as follows:

Process of removing protecting group: As afore¬ mentioned, in the fields of β-Iactam and peptide syn¬ theses, amino-protecting groups hava baen sufficiently studied, and the method of protecting and deprotecting amino groups has been established. The method of removing the a inc- protecting group has also beεn established, and _r in thε prεsent invention as well, for removing protecting groups, conventional technique can be used as such. For examplε, monohalogenoacetyl group (chloroacatyl, bromoacetyl, etc.) can be removed by using thiourea; alkoxycarbonyl group (methoxycarbσπyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.) can be removed- by using an acid (e.g. hydrochloric acid); aralkyloxycarbσnyl group (e.g. bε zyloxycarbonyl, p-mεthylbεnzyloxycarbcnyl or

p-nitrobenzyloxycarbonyl) can be removed by means catalytic reduction; and 2,2,2-trichloroethoxycarbonyl can be removed by using zinc and an acid (e.g. acetic acid) . On the other hand, in the case when the compound [I] as the intεrmediate has bεεn εstεrified, the ester residuε can bε rεmoved by a per se known procεss or an analogous one thereto. For example, 2-me hylsulfαn l- εthyl ester can be removed by using an alkali; aralkyl estε. (benzyl ester, p-methyoxybenzyl εster, p-nitrobenzyl εster, etc.) can be removed by using an acid (e.g. trifluoroacetie acid) or by means of catalytic reduction; 2,2,2-tri- chloroethyl ester can be removed by using zinc and an acid (e.g. acetic acid) ; and silyl estεr (ε.σ. tri- εthylsilyl εster or tεrt-butyldimεthylsilyl εster) can be removed by using only water.

Process of purifying the compound [II r The compound [I] produced in the reaction mixture by any of the pro¬ cesses described in detail in the foregoing Production Methods (l)-(3) and, upon necessity, followed by removal of protecting groups by conducting the above-mentioned process, can be isolated and purified by a known procεss such as extraction, column-chromatography, precipitation and recrystallization. On the other hand, thε compound [I] thus isolated can be converted

into then desirεd physiologically acceptable salts or bioavailablv unstable non-toxic esters.

The sulfoxide( [I] , Z = S-O) of the cephem compound ( 11 } , 2=5} can be prepared by subjecting thε compound ( fl] , Z=S) to a conventional oxidation. Oxidizing agents suitable for oxidation of the sulfur atom of the cephem ring are exεmplifiεd by oxygen, peracid, hydroperαxide, or hydrogεn peroxide, and the peracid may be made by mixing an acid with a peroxide in the reaction system of the oxidation. As such pεracics, use is often made of peracetic acid, perbenzoic acid cr p-chloroperbεnzoic acid. Thε reaction is usually conducted in a solvent which is exemplified by ethers such as dioxanε or tetrahydrofuran; halogenatad hydrocarbons such as dichloromethane, chloroform or chlcrobεnzene; organic acids such as formic acid, acetic aciά _r trifluoroacetie acid; or amides such as di eth lformamide or dimεthylacatamide. Thε reaction temperature ranges from about -20°C to 80°C, and prεferably a temperature as low as possible, i.e. ranging from about -20°C to 20°C. It is generally known that, when the cephem compound ([I], Z=S) is subjected to oxidation, sulfoxide having an S-configuration is produced. The R- and S-sulfoxide can be separated by utilizing the differεncε in solubilitv between them or the

difference in travelling rate in chromatography. The above-mentioned oxidation to give sulfoxide can be conducted beforε or after the afore-mentioned Production Methods (l)-( ^' 3).

The compound [I] of this ivention can be administerd orally non-orally as injections, capsules, tablets or granules, like known penicillin and cephalosporin preparations. The dosage is Q.5 to 8Q mg/day, preferably 1 to 20 mg/day in

3 to 4 doses relative to one kilogram of the body weight of men and animals infected with pathogenic bacteria as set forth above. Carriers of injectable prεparations are exemplified by distilled water or physiological saline solution-. When usεd as capsula, powder, granule or tablet, the compound [I] is mixed with conventional pharmaceutically acceptable excipients (ε.g. starch, altosε, sucrosε, calcium carbonate or calcium phosphata) , binders (e.g. starch, gum-arabica, carboxyme hyl- cellulose, hydroxypropylcellulose or crystalline cellulose) , lubricants (e.g. magnesium stearate or talc) and disintegrators (e.g. carboxymethyl calcium or talc) .

The presεnt invention will be further explained by the following Reference Examples and Examples, but those Examples are mere εxamplεs and do not restrict

thε prεsent invention in any manner .

Elution in column-ehrcmatography in the Reference

Examples and Examples was conducted undεr observa- tion by means of TLC (Thin-Layer Chromatography) , wherεin were emolαved 6OF-- ,® manufactured bv Ξ. Merck (West Germany ⁾ as

TLC plate, the solvent for elution in the column- chromatography as developing solvent, and a ϋV detεctor as dεtecting means. As silica-gel for the column,

Kiesεlgel 6C>®[ 70-230 mesh ). manufactured by Ξ. Merck (West German was employed. Cephadex^ is a product of Pharmacia

Fine. Chemicals (Sweden) . XAD- 2® resin is a product of Rohm &

Haas Co. (U.S.A) . NMR spectrum was determined by XL-100A

(100 MΞz)-, ΞM2S0 (90 MHz)-, EM360 (SO MHz)- cr

T6_0 _Λ (60 MHz)-tvoe soectromεtεr usinσ tεtramεthvlsilane as internal or external standard, and all the <S values were shewn by pp . The numeral values parenthesized for mixture solvents mean the ratios by volume of each solvent mixed. "%" for solvents means number of grams in 100 ml of each solution. Symbols in the Reference

Examples and Examples have respectively the meanings as follows: s : singlet d : doublet

t : triplet q : quartet

Abq : AB type quartet d. d : double doublet m : multi let br. : broad

J : coupling constant

Hz : Herz mg : milligram g : gram mi : miliiliter

_ or 1.: liter

% : percent

DMSO : dimethylsulfoxide

D ₂ 0 : deuterium oxide

CDC1-: deuterochloroform

Reference Example 1 ^"

7g-[2-(5-tert-3utcxycarbonylaι_ino-l,2, -thiadiazol-3- yl ⁾ -2(Z)-methoxyi inoacetamido]-3-(3-oxobutyryloxy- ethyl) -3—cεphem-4-carbαxylic acid

To 4 ml of dichlαromethane is added 302 mg of 2-(5-tert-butcxycarbonylaminα-l,2,4-thiadiazol-3- yl)-2(Z)-methαsyiiπinoace ic acid, followed by addition of 208 g of phosphorus pentachloride. The mixture is stirred with ice-cooling for 15 minutes. The solvent is then evaporated off under reduced pressure and. hexane is added to the -residue. The mixture is evaporatεd to drynεss under reduced pressure and the residue is dissolved in dichloromethan . The rε≤ulting solution is addεd to a solution of 300 mg of 72-amino-3-(3-αxαbutyloxy methyl)-3-cephem-4-carboxylic acid and 0.6 ml of triethylamin in 5 ml of dimethylacetamida, and the mixture is stirred with ice-cooling for 30 minutes. To the reaction mixture is added a solution of 1 g ofphosphoric acid in 10 ml of water and the resulting mixturε is

extracted with methyl ethyl etone (10 ml) . The extract. ^• is washed with water and driad over magnesium sulfate. The solvent is then evaporated off under reduced pressure. Ethyl acetate is added to the residue and the solvent is evapo ated again to give 390 mg of the above-identified compound.

IR spe-nai . ^K F ^r C3T ^: : 298(1, 2940, 178G, .1715, 1540, 1370,

1245. 1150, 1040, 855 _β NMR specrm (d, - D M S 0 ) £ : l.aδ(δH.s), 2.2 ^Q (3E,s), 3.43 a--.a3.7Q (2H,ABq,J=18Ez), 3.65(2E,s). 4.00(31. s), 4.80 anά5.12 (2E,ABq.J = 12Ez). 5.18CiI.d. J*4.5Iz) . 5.88(lE.d.d, J = 3Hz n 4.5iz). 9.63(iH.d,J = 3Ez) _c

Hefεrεnca Exa pla 2

7β-[2-(5-Jlmino-l,2,4-thiadiazol-3-yl)-2(Z)- e th oxyimino ace ta ido] -3— (3-oxobutyryioxymethyl) -3- cεphεm-4-carboxylic acid

In 200 ml of dichioromethane is suspended 11 g of 7β -aminα-3- (3-αxobutyryloxymethyl) -3-cephem-4-carbox lic acid. To thε suspension is added 14 g of bistrimethyl- silylacet amide and the mixture .is stirred at room temperature until complete dissolution and cooled in an ice-water bath. To this solution, 14 g of 2- (5-amino-l,

2,4-thiadiazol-3-yl)-2(Z)-ethoxy iminαacetyl chloride is added

and the mixture is stirred for a while, to which 6 g of dimethylacetamide is added. The whole mixture is stirred with ice-cooling for 60 minutes. The dichloro- ethane is evaporated off and the residue is dissolved. in methyl ethyl etone. The solution is washed with water and dried. Thε solvent is then evaporated off and. diethyl ethεr is added to the residue to give a finε precipitate, which is collected bv filtration, givinc 12.5 g of the above-identified compound.

I R spec _t um y ^K . ^Br ca' ¹ : 3300. 3000. 1780. 1720. 1820. 1520.

1410. 1260. 1150. 1040= - NMR sn _β c ruπ (d _s -DMS O)ό : 1.25(2E. .J=7Ez). 2.18(3Ξ.s). 3.41an _d 3.63(2S.A3σ.J=l8Sz). 3.82(2E.s}. 4.18(2Ξ.q ^, J=7Ξ ). 4.76 _a n 5.06C2H.ABς.J-13Hz). 5.i4(iΞ.d,j=4.3Ez), 5.82(iE.d.α. j=SHzanά4.8Ez), 8.00C2H.br.). S.48(lE. .J=-3Ez)= Reference Ξxamoie 3

7β-[2-(5-Amino-l,2,4-thiadiazci-2-yi) -2(Z) -(cyano ethoxy- imino) acetamido]-3-(,3-oxobutyrylαxymεthyi)-3-cephem-4- carboxylic acid

A mixturε of 13 g of 2-( _. 5-amino-i,2,4-thiadiazol-3- yl) acεtic acid, 1Q.7 g of salεnium dioxide and 200 mi of dioxane is heated in an oil bath kept at 90°C for 40 minutes with stirring. After cooling, dioxane is evaporatεd off. To. thε rεsiduε is addεd 150 ml of εthvi acetate and,, after

filtration, ethyl acetate is evaporated off under rεducεd prεssurε. To thε residue are added 100 ml of ethanol and than, with stirring, 3.6 g of 0-cyanomathylhydroxylamina. The mixture is then stirred at room temperature for 40 minutes and ethanol is evaporated off under reduced pressure. The residue is dissolved, in 150 ml of ethyl acetate. The ethyl acetate solution is washed once with water and then shaken with 1Q0 ml of 5% aqueous sodium bicarbonate solution. The aqueous phasa is separated, covered with 150 ml of ethyl acetate and acidified with phosphoric acid with εfficiεn stirring. Thε εthyl acεtatε layer is separated and dried over anhydrous magnesium sulfate. Ethyl acetate is evaporated off under reducεd pressure ^' and the residue is dissolved in 30 ml of dichloromethanε. To thε rεsulting solution, is addεd 2.2 g of phosphorus pentachloride undεr ice-cooing. After 20 minutes' stirring at the same temperature, dichloro- methane is evaporated off. The residue is redissolvεd in 5 ml of ^" dichloromethane and the solution is added all at oncε to a solution compositε of 3.1 g of 7β-amino-3-(3- oxobutyryloxy ethyl)-3-cephem-4-carboxylie acid, 6 ml of bistri ethylsilylacεtamide and 60 ml of dichloromethanε and thε mixturε is stirred under ice-cooling for 30 minutes. Dichloromethane is then evaporatεd off and the residue is dissolved in 100 ml of ethyl acatatε. The resulting solution is washed with water and dried over anhydrous magnεsium sulfate and ethyl acetata is than evaporated off under reduced pressure. To the residue is added 10 ml of ice- cooled trifluoroacetie acid and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is addεd 50 ml of εthyl acetate and the solvεnt is then evaporatεd undεr rεducεd prεssurε. Thε residue is trituratεd with ethyl acetate and the insolublε substance is collected by filtration giving 2 g of crudε abovε-idεntifiεd compound. The filtrate is then concentratεd, thε rεsidue treatad with diathyl εth r and insoluble substance is collected by filtration to give 1.4 g of the above-identified compound.

- 10*-

IR spεctrum : 1780, 1700, 1620, 1520, 1400, 1360,

1310, 1140, 1040

NMR spectrum (dg-DMSO) δ : 2..2K3H, s) , 3.44 and 3.68 (2H, A3q, J=I8Hz) , 3.65C2H, s) , 4.79 and 5.10C2H, ABq, =I4Ξzj , 5.11C2Ξ, s) , 5.17 (IE, d, =4.SΞz) , 5.85

QΞ, d, g=4.8 and 3≡z) , 3.15(2Ξ, br. ) , 9.74(1H, d.

_; ιe 4

Imidazo [1,2-a]pyridine derivatives _f imidazo[1,5-a]- pyridine derivatives a imidazo [l,2-b]pyridazine derivatives are prepared according to the known methods described in e.g. -J. Org. Chem. 30_, 4081 (1965), J. Org. Chem. , 30, 4G35 (1965), J. Heterocyciic Cham., 2_, 53 (1965), Tetrahedron, 23_, 387 (1967), Tetrahedron, 2 , 239 (1968), J. Org. Chem., 30_, 2403 (1965), J. ed. Chem., 12_, 122 (1969) and the similar ^' methods

Synthesis of novel imidazo 1,2-a] yridine derivativεs is descrϋεd below.

4-1) 6-Cyanoimidazo[1,2-ajpyridine

A mixture of 2.6 g of 6-carbamcyIimidazo [1,2-a]pyridine and 20 ml of phosphorus oxyohioridε is heated under reflux for IS hours. The excess phosphorus oxychloride is removed under reduced pressure and the residue is poured onto ice. The mixture is neutralized with sodium carbonate and extractεd with ethyl acetate. The organic layer is washed with saturaued aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is thεn evaporated off under rεducεd prεssure to give 2.0 g of thε abovε- identifiεd compound as colorlεss crystals. M.p.: 166-167°C

Elemental analvsis for C ₀ 8Ha.>i-3:

Calcd. C%1: _. C, 67.13; H, 3.52; N, 29.35. Found C%) : C, 67.37; H, 3.62; N, 28.99.

4-2 1 8-Hydroxyimidazo[1,2-a] yridine hydrochlcriάe

In 80 ml of concentrated hydrochloric acid is di≤s< ;_ «='._ 5 g of 8-berzyIoxyimidazo[l,2-ajpyridine, and the sclu-oi¬ ls stirred at rccm temperature for 24 hours and than concan-rausd. After addition of 1-butanol, water is azeotropically removed by distilla icn, and the •aβ - <— ι- -± crysoallized from diethyl ether to give 3.8 g of the ahc identified compound. .p.: 153-I55=C

IR specorum ^ca ^'1 : 1670, 1580, 1520, 1410, 1320, I; _n

NMR specorum (d. α. -DMSO) 5: 7.2-7.4C2H, m) , 8.2SCIΞ, d) ,

8.3-3.5 C2Ξ, m) .

Novel imidazo [1,2-bjpyridazine derivatives are pir-ecarec a follows.

4-3) 6-Ξthoxyimidazo [1,2-bjpyridazine

Sodium metal (0.55 g) is dissolved in 30 ml of ethanol and, to the solution, is added 3 g of 6-chloro- imidazo[1,2-b] yridazine and the mixture is heated under reflux for 3 hours. The solvent is then evaporatεd off under reduced pressure and thε rεsiduε is dissolvεd in water and the mixture is extracted with methylene chloride. The extracts are combined, washed with saturated solution

of sodium chloridε and dried over MgSθ4- The solvent is then evaporatad to give 3.3 g of the title compound as colorless crystals.

M.p.:. 102-103°C

NI'IR spectrum (CDCl ₃ ) δ : 1.45 (3H, t , J=7Hz) , 4 .53 ( 2H , q,

J=7Hz ) , 6 .63 ( 1H , d , J=10Hz ) , 7 .56 ( iΞ , br . s ; ^" . 68

(1Ξ, br.s), 7.74 (1H, d, J=I0Hz) . 4-4) 6-Methylthioimidazo[1,2-b]pyridazine

To a solution of 3.1 g of 6-chlorcimidazo[1,2-b]- pyridazinε in 5 ml of dimεthylformamidε, 13 ml of 15% aqueous solution of sodium methyimεrca uidε arε added and the mixture is heated for 3 hours at 100-105°C with stirring. After cooling, the reaction mixture is diluted with water and extracted with ethεr. Thε extract is washed with water, saturated aqueous solution of sodium chloride and dried over MgS0 ₄ . Evaporation of the solvent under reduced pres¬ sure gives 2.81 g of the title compound as colorless crystals. M.p.: 66-68°C NI-IR spectrum (CDC1.,)5: 2.59 (3H, s) , 6.83 (1Ξ, d, =I0Hz) ,

7.63 (1H, s) , 7.70 (IK, d, J=10Hz) , 7.85 (1H, br.s ⁾ . 4 -5) 6-Dimethylamino [1,2-b] yridazine

6-Chloroimidazo [1,2-b]pyridazine (2.8 g) and 50 ml of dimethylamine solution are placed in a sealed tube and heated for 5 hours at 180°C. After cooling, the solvent is evaporated off and the residue is dissol-.εd in water. Thε mixture is made alkaline with 10% aqueous sodium hvdroxide solution and extracted with ether. The organic

phasε is separated, washed with water and then with saturated sodium chloride solution and dried over MgSO.

Evaporation of the solvent gives 2.61 g of the titlε compound as pale yellow crystals.

M.p.: 83-85°C

NMR spectrum (C Cl,)c: 3.10 (6H, s) , 6.72 (IE, d, J=I0Hz) ,

7.53 (IE, br. s) , 7.68 (IE, br. s) , 7.69 (IE, d,

J=10Ez). 4- ^o 6-(2-Dimethyla inceuhσxy)imidazo[I,2-bjpyridazine

Sodium metal (0.25 g) and 6-chloroimidazo[1,2-b]- pyridazine are added to 25 ml of 2-dimethylaminoethanol and the mixture is heatεd in a sεaled tube for 3 hours at 130°C. After cooling, the solvent is evaporated and the residuε is trεatad with watεr and εxtracted with ethylene chloride. The organic layεr is separated, washed with saturated sodium chloride solution and driεd ovεr MgS0 ₄ . Evaporation of the solven- gives the title com¬ pound as a viscous oil which solidified on standing. The yield is 2.5 g.

NMR spectrum (CDCl- ό: 2.37 (6H, s) , 2.78 (2H, t, J=6Hz) , 4.43 (2E, t, J=6Hz) , 6.75 (IE, d, J=10Hz) , 7.60 (IE, d, J=2Ez) , 7.75 (IE, d, J=2Ξz) , 7.80 (IE, d, J=10Hz) . 4- ^/') 6-(2-Dimethylaminoethylthio) imidazo [1,2-b]pyrid¬ azine To 20 ml of methanol is dissolved 2.8 g of 2-di- ethylaminoεthanethiol. To this, 20 ml of 2 M solution of sodium methoxide in methanol and 3 g of 6-chloroimidazo- [1,2-b]pyridazine are added successively and the mixture is heatεd in a sεaled tubε for 4 hours at 150°C. After cooling, the solvent is evaporated and the residue is treatεd with watεr. Thε mixture is then extractεd with mεthylene chloridε. Thε organic layεr is sεparatεd, washed with saturated aqueous solution of sodium chloride and dried over gS0 ₄ . Evaporation of the solvent gives 2.5 g of the title compound as pale yellow crystals.

M. p . : 52-54 °C

NMR spεctrum (CDC1 ) <5 : 2.34 (6E, s) , 2.70 (2H, t, J=7Ez) , 3.37 (2H, t, J=7Hz) , 6.83 (IE, d, J=10Ez) , 7.68 (IB, br. s) , 7.74 (1H, d, J=10Hz) , 7.81 (IE, br. s).

4-8 ⁾ 6-Fluoroi iάazo [1,2-b] yridazine

(1) A mixture of 3,6-difluσropyricazire (7.8 g) and 25 ml of concentrated ammonium hydroxide solution is heat¬ ed in a sealed tube for 2 hours at 70°C. After cooling, the crystals separated are filtered and washed with water to give 4 g of 3-amino-6-fluoropyridazinε.

NMR spectrum (d _g -DMSO)o: 6.23 (2E, br. s) , 7-7.2 (2Ξ, ).

(2) A mixture of 16.6 g of bromoacεtaldehydε diethyl- acetal, 7 ml of concentratεd EBr solution and 7 ml of water is heatεd one hour at 100°C. After cooling, the mixture is diluted with 100 ml of ethanol and neutralized with NaECO, . Insoluble material is removed by filtration and to the filtrate is added 5 g of 3-aminc-6-flucro- pyridazine and the mixture is stirred overnight at room temperature. Crystals separated are filtered, washed with ether and dissolved in water. The solution is made alkaline by addition of sodium carbonate and extracted with methylene chloride. The organic layer is washed with water saturated with sodium chloride and dried over MgSO.. Evaporation of the solvent gives 1.7 g of the title compound as pale yellow crystals.

NMR spectrum (CDCl ₃ )δ: 6.90 (IE, d, J=10Ξz) , 7.83 (IE, s) , 7.88 (IE, s) , 7.95 (IE, d, J=10Hz) .

': . I

Rεference Example 5

73-(t-Butoxycarbonylamino)-3-(3-oxobutyryloxymethyl)-3- cephem-4-carboxylic acid.

To a mixture of 200 g of 7β-amino-3-(3-oxobutyryloxymethyl)- 3-cephem-4-carboxylic acid in 500 ml of di ethylsulfoxide is added 129 g of triethylamine with stirring, followed by stirring at room temperature for 20 minutes. Then to the mixture is added 200 g of di-t-butyl dicarbonatε at room temperature, followed by stirring at room temperature for 16 hours.

To the mixture are added 200 g of ice, 2 Lof water, and

1 1. of ethyl acetate, and the aqueous layer is separated. To the aqueous solution, are added 1 1. of ethyl acetate and 129 g of phosphoric acid.

After vigorous stirring, the ethyl acetate layer is separated and thε aqueous layer is extracted with 1 1. of ethyl acetate. The extracts are combined, washed with

2 I. of ice water (twice) and saturated aqueous sodium chloride solution in thau order and dried over magnesium sulfate.

The ethyl acetate solution is concentrated under reduced pressure, followed by adding 100 ml of ethylene chloride

(this procedure is repeated three times) .

Resulting residue is dried over phosphorus pentoxide under reduced pressure to give 194 g of the title compound.

Yield: 74 %.

Elemental analy ^J sis for •0.5B2-0

Calcd. (%) : C, 48.22; E, 5.47; N, 6.62. Found (%) : C, 48.16; H, 5.30; N, 6.32.

IR ^υ πax ^cιa ~ ^{1: 1780} ' ¹⁷² °, 1520, 1370, 1320

NMR (DMSO-dg)ό: 1.42 (9E, s) , 2.18 (3E, s) , 3.41 &

3.62(2E, AB , J=18Ez) , 3.62(2E, s) , 4.78 & 5.06 (2E, ABq, J=14Ez) , 5.03 (IE, d, J=5Ez) , 5.45 (IE, dd, J=5 & 8Ez) , 7.83 (IE, d, J=8Kz) .

Reference Example 6

7β-Amino-3-[ (imidazo [l,2-b]pyridazinium-l-yl) - methyl]-3-cephem-4-carboxylate hydrochloride.

(1) 7β-[D-5-Carboxy-5-phenoxycarbonylaminovaleramido]-3- hydroxymethyl-3-cephem-4-carboxylic acid di-(tri-butylamine ⁾ salt (25.9 g) and imidazo [1,2-b]pyridazine (7.15 g) are dissolved in 150 ml of methylene chloride.

The solution is cooled to -50°C and to this, 20 ml of 2M solution of ethyl O-phenylenεphosphata in methylεne chloridε is addεd. The mixture is maintained at -50 to -40°C for two minutes and then warmed up gradually up to 5°C ever 2 hours. A prεcipitatε separates. Ethyl acetate

(450 ml) is added to the reaction mixture and is filtered and washed twice with each 100 ml of methylεnε chloride and then three times with ethyl acetate to give 17.8 g of 73-[D-5-carboxy-5-phenoxycarbonylaminovaIεramidoj-3-

[ (imidazo[1,2-b]pyridazinium-1-yl) ethyl]-3-qεphεm-4- carbo ylate.

Yield:100 %.

TLC (Silica gel, Merck, Art 5715; Solvent: acetonitrile: water=4:l): Rf=0.19.

IR soectrum v ^K3r cm ^"1 - 1780, 1720, 1625, 1520, 1435, max

1380, 1200.

(2) The compound (5.95 g) obtained above is pulverized and added to 150 ml of methylene chloride. To this, under ice-cooling, 5.94 ml of tributylamine and 12.7 ml of dimethylaniline are added. Then, the resulting solution is cooled to -30°C and to this is added 8.7 ml of propionyl chloride. After being stirred for 15 minutes at -20°C to -10°C, the mixture is cooled to -60°C. To this, 7.29 g of phosphorus pentachlorida is added all at once and the mixture is stirred for 50 minutes at -55°C to -50°C. Then, 30 ml of isobutanol is added to the reaction mixture maintaining the inner temperature at -55°C to -45°C. After completion of the addition, the reaction mixture is warmed up from -50°C to 20°C over about one hour and then

- Il l -

stirred for half an hour at 20°C and for one hour at 0°C. The precipitatε separated is collected by filtration and washed three times with each 10 ml of ethylene chloridε and dried giving 2.87 g of the title compound. Yield: 81 %.

TLC (Silica gel, Merck, Art 571Ξ; Solvent: acεtonitriie: water=4:l) :Rf=0.14

IR spectrum ^ ccmm .-1: 1780, 1720, 162Ξ, 1485, 1380,

1200,

Reference Example 7

7β-Amino-3-[ (imidazo[1,2-b]pyridazinium-l-yl)methyl]- 3-cephεm-4-carboxylate hydrochloride.

73-[D-5-Carboxy-5-phenoxycarbonylaminovalεramido]-3- hydroxymethyl-3-cephem-4-carboxylic acid di- (tributylamine) salt (51.8 g) and imidazo[1,2-b] yridazine (14.3 g) are dissolved in 300 ml of methylene chloride and the resulting solution is cooled to -50°C. To this, is added 24.Og of ethyl O-phenylenεphosphate and the mixture is stirred for two minutes at -50° to -40°C. Then, the mixture is warmed up from -40°C to 10°C over 2 hours. A precipitate separates. To the reaction mixture, 600 ml of methylene chloride and 28.6 ml of tributylamine are added at 0°C to redissolve the precipitate and then, after addition of 76 ml of dimethyl- aniline, cooled to -30°C. To this is added 52.1 ml of propionyl chloride and the mixture is stirred for 15 minutes at -20°C to -10°C and then cooled to -55°C. To this, 43.7 g of phosphorus pentachloridε is addεd all at oncε and thε ixturε is stirred for 50 minutes at -55 ³ C to -50°C. Then, 180 ml of isobutanol is added, maintaining the inner temperature between -55° to -45°C. After completion of the addition, the mixture is warmed up from -50°C to 20°C over about one hour and then stirred for 30 minutes at 20°C and for one hour at 0°C. The precipitate separated is collected by filtration and washed three times with each 50 ml of methylenε chloride and dried to give 20.0 g of the title compound.

Yield : 94 . 2 % .

TLC ⁽ Silica gel, Merck, Art 5715; Solvent: acetonitrile: water=4:l): Rf=0.14.

Reference Examole 8

7S-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)- methoxyiminoacetamido]-3- (3-oxobutyryloxymethyl)-3- cephem-4-carbcxylic acid

In 240 ml of dichloromethane is suspended 9.06 g of 7£-amino-3-(Ξ-oxobutyryloxymethyl)-3-cephεm-4-carboxyiic acid. To thε suspension is added 28.9 g of bistrimethyi- silylacetamide and the mixture ^' is stirred at room tempεrature until complete dissolution and cooled in an ice-water bath. To this solution, 2-(5-aminσ-l,2,4- thiadiazol-3-yI)-2(Z)-methoxyiminoacetyl chloridε hydrochloridε prepared from 5.83 g of 2- (5-amino-l,2,4- thiadiazol-3-yl)-2 (Z)-methoximinoacetic acid and 6.02 g of phosphorus pentachloride in 90 ml of dichloromethane is added and the mixture is stirred for a while. The whole mixture is stirred with ice-cooling for 60 minutes. The dichloromethane .is evaporated off and thε residuε is dissolved in methyl ethyl ketone. The solution is washed with watεr and dried. The solvent is then evaporated off and diethyl ether is added to the residue to give a fine precipitate, which is collected by filtration, giving II.8 (82% yield) g of the title compound.

IR spectrum vi ^K n ^B CLΛ ^r cm ^"1 : 3300, 3000, 1770, 1710, 1620,

1520, 1400, 1260, 1150, 1040.

NMR spectrum (d _g -DMSO) <5: 2.19 (3E,s), 3.40 and 3.65

(2E,ABq,J=18Ez) , 3.63 (2E,s), 3.95(3E,s), 4.73 and

5.09 (2E,ABq,J=14Ez) , 5.14 (lE,d,J=4.8Ez) ,

5.84(lE,d,d,J=8Ez and 4.8Ez), 8.11(2E,br.) ,

9.59(lE,d,J=8Ez) .

Examolε 1

73-[2- ⁽ 5-.-mino-l,2,4-thiadiazol-3-yl)-2(Z)-εthoxy- iminoacetamido]-3- [(6-cyanoimidazo[1,2-aj yridinium-l- yi) εthyl]-3-ca _? hem-4-carboxylaue

In 30 ml of a 1:1 mixture of acetonitrile and water are dissolved 2.2 g of 7S-[2- (5-amino-1,2,4-thiaάiazol-

3-yl)-2 (Z)-ethoxyiminoaceta ido]-3-(3-oxσbutyryioxy- ethyl) -3-cephem-4-carbo: Iic acid, 1.79 g cf β-cyano- i idazc [1,2-a yridine and 2.2 g of potassium icdife, and the mixture is stirred at 60-70°C for 1.5 hours.

The solvent is then evaporated off under reduced pressure and the residue is solidified by addition of 100 ml of acetonitrile. The resulting powder is collected by filtration and then subjected to silica gel column chromatocraphy. The acetonitriie-water (7:3)-el ted fraction is concentrated under reduced pressure and the residuε is lyophilizεd. A solid obtained is dissolved in 5 ml of water and chromatographed on a column of MCI GEL CΞ?20P^

(150-300 mashεs; Mitsubishi Chemical Industries, Ltd.,

Japan), with water-ethanol.

-11*

The water-ethanbl (85 : 15) - eluted fraction is concentrated under reducεd pressure and the residuε lyophilize to civε 0.27 σ of the above-identified comoound.

C lcd.

-. -. -. /'fl/ . -"5 19. ZZ . 5Λ. \T 12 : ! o

NMR (d ₃ -DMS O)o : 1.19(3E.t. J = 7Ξ ), 2.33 --. 3.44C2Ξ.iΞq.J=18Ez), 4.12 (2S.q, J = 7Sz) , 5. OO .iS.d, J = =Hz) . 5.1-S.SC2E.πO. 3.68(lE.d.d. J = SEz ^& 8Ξz) . 8.10(2E. br.s) ^, 3.2-9.G GΞ.π . =.42(iE.d. J = 3Ξz), 3.78C1Ξ. br.s),

Example 2

73- [2- (5-Aminσ-l,2,4- thiadiazoi-3-yi) -2 (Z) - ethoxy- iminoacetamico]-3- [ (imidazo [l,2-a]pyridinium-l- yl) me -chyi] -3-cephem-4-car boxviata

ϋ Three grams of 7β-[2-(3-tsrt-butoxyca. 1, 2,4-thiadiazol-3-yl)-2(Z)-methcxyimincacataridoj—3—(3— cxcbutyryicxy ethyl)-3-ceρhεm-4-carboxyiic ac: potassi m iodide and 3 g of imidazo[i,2-a]pyr: are reacted as in Example 1.

The reaction mixture is t en washed with e h l acetaue, and the aσueous laver is seoarated and uo XA -2 ®^eclumn chromatography using waue '.as eluenu. The reaction-' product .elvited is suijec: to silica gel column chromatography [silica e eiuεnt: acetone-water (6:4)] to give 290 mg of identifiεd compound.

Elsaencal analysis for C _J OH NJO _S S: ' 4 HzO :

Calcd. (%): c. 40.95; H, 4.47; N. 19.10.

Εaτ-Zmά 0&): c. 41.15: K. 4.23; N, 18.54 _β

I R nβc a v ^C a ^"1 : 1770, 1620, 1530. 1390, 1045, 770 _β πax

NMR 5=2 -3= (d _s -DMSO)o : 2.96 ^' &3. 2(21, ABq,J = 18Hz) .

3.8S _. 3E,s), 4.S8ClK,d = 4.8Ez), 5.26 & 5.48(2E.ABq. J=14£z),

5.S2CH.d.d.J = 8Hz& 4.8Hz), 7.40-7.60 (lΞ.t) , 7.86-8.20 (3E,m) , 8. ^" 34-3.76(3Ξ,m) , 8.86-9.00 (lE,d)/ ?.43 (lH,d,J=3Hz ⁾ .

Further,- another re≤cticn product eluted frαa the XnD- ,©^^^ ccoolliumn chro atography using 50% ethanol as eluεnt is again subjected to silica, gel column chromatography [silica gel: 40g; eiuentr acetone-water (6:4)] to give 240 mg of 7. - [2- (5-tert-butoxycarόonylamino-l , 2 , 4-thiadiazol- 3-yl) -2(S)-mεthσxyiminoacetamido]-3- [ (imidazo [1,2-a]- pyridinium-1-yi) me hyll -3-caphεm-4-carboxγlate .

I R s- _s c^^ i/ ca ^_1 : 1775. 1520. 1530, 1380. 1150. 1045.

770 ^' . R spectr-ia (D ₂ 0)<5: 1.50(9H.s). 3.15&3.55

C2H.A3q.J=18Hz). 4.0δ(3H.s). 5.23(lE.d. J = 4,8Ez). 5.32.2E. s). 5.85Clfl.d.J = 4.8Ez). .09-8.20(7H.m ). 8.63ClE.d. J = 8Hz) _c

ii) 76-[2-(5-tεrt-Butoxycarbonyla ino-l,2,4- thiadiazol-3-yl)-2(Z)-me hoxyiminσacetamido]-3- [(imidazo[1,2-a]pyridinium-1-yl) ethyl]-3-cephem-4- carbcxylata (240 mg) obtained in the above procedure i) is trea εd with 2 ml of trifluorcacet_Lc acid under ice- cooline. Then, the r~fiτ-if<τ bath-is rsscved.and the reaction mxure is stirred at room temperature for 40 minutes,- followed by the addition of ethyl acetate. The mixture is evaporated to dryness under reduced pressure. The residue is dissolved in water, and the .solution is _^ neutralized-'.with sodiu hydrogen carbonate under ice—cooling and then subjected to XϊlD-2 column chromatography using 20% C^HgOΞ as the eluent. Thε eluted •fraction is further subjected to silica gel column chromatography [silica gel: 40 g; εluεnt: acetonε-watεr (6:4)]. Fractions containing the desired product is concentrated and lyophilizeά to give 310 mg of the above-idεntifiεd compound. Example 3

7. -[2-(5-Amino-l,2,4-t iadiazol-S-ylJ^tSj-εtuioxy- iminσacatamidσ]-3-[(imidazo[1,2-a]pyridinϊum-l-yl)mεthyl ]- 3-cephem-4-carboxylatε

7. -[2-(5-Amino-l,2,4-thiadiazol-3-yl)- 2 ⁽ Z ⁾ -εthoxyiminoaceta ido]-3-(3-oxobutyryloxymethyl).-3- ce?hem-4-carboxylic acid and imidazo[1,2-a]pyridine, are reacted ^' in a manner as in Example 1 to give the above—idεntified compound.

Ξleπeπτ_3l analysis for C:ιE:<ι jOsS: ^• 4.H ₂ 0 :

Calcd. (%); C. 42.00; H. 4.70; N, 18.66 _* round; (%): C. 42.25; H. 4.23; N, 18.44 _*

I Rs ecrum y ^KBr cm" ¹ : 1770. 1610, 1530. 1390, 1360. 1040. max

T:: i u we

NMR spectrum (ά _s - D M S 0 ) δ : 1.20 C3Ξ.t. J=7Ez), 3.02 a 3.44C2E.ABq,J=18E _∑ ), 4.12 (2E.q, J = 7Sz) . 5.0.Clϊ.d, J = 4.8ΞΞ) . 5.42C2E Γ.S). 5.6O(1E. d.d, J = 8EΞ &4.8HZ), 7.50(t. J = 7Ez) ^, 8.00(t.] = 7Ez), 8.40-7.00 (m) and 8.98 (ά,J=7Ez ^{) (} total 6Ξ ⁾ , 9.42(lE.d.J = 8Sz). 8.16(2E.s)«

Example 4

7 S- [2- (5-Smino-l , 2 , -thiadiazol-3-yl) -2 ( S) -ethoxy- iminoacatamido]-3- [ (6-chlorσ imidazo [1,2-aJpyridinium- 1-yl ⁾ methyl] -3-cephem-4-carboxylatε

7S-[2-(5-Amino-l,2,4-thiadiazol-3-yl)- 2(2)-ethoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)- -caphεm-4-carboxylic acid and β-chloroimidazo[1,2-a]- pyridine are reacted in a manner as in . - _ : Ξxampla 1 tα give the above-identified compound.

Calcd. (%) _r c. 40.88; K. 4.08; N. 18.16, Fα-= C%J: C. 40.85: H. 3.97; N. 18.01.

IR sps uπ. ι, ^KBr ca~ ^l : 3300. 3150, 1780. 1S30. 1S20, 1520.

-max

1330, 104!

NMR spec— a Cd*-D S O)5: 1.11(3B, t. J = 7Ez) . 2.99 an ^d 3.44(2E.ABq.J = LSEz), 4.13(2£,q, J= 7Sz) , 5. OOClE.d. J = 4.8Ez) , 5.27&-Ξ.43C25.AE .J = 14Sz). 5.6δ(lE.d.d. J = 8Ez &4.8Ez) . 8.00

-3.85 (m) and 9. 0 (s) (total 5Ξ) , 9.42 (lΞ,d, J=3Ξz) .

Example 5

75- [2- C5-Ssino-l, 2 , 4-thiadiazol-3-yl) -2(2) -ethoxy¬ iminoacetamido] -3- [ 3- ( dime thy laminomε thy 1) imidazo [1,2-a] pyridinium-1-yl) methyl] -3-cεphεm-4-carboxylate

73-[2-(5-Anino-l,2,4-thiadiazol-3-yl)- 2 (Z) -ethoxyiminoacεtamido]-3-(3-oxobutyryloxymεthyl) - 3-cεphεm-4-carbcxyiic acid and 3-(dimethyiaminome h i)- imidazo [1,2-a] yridine are reacted in a manner as in Ξxa pie 1 to give the above-identified compound.

~— '"3 is vz C ;÷ ~- : 7 s 05 i ; :-: = o _\ --c J . m. , 4-J.IJW , n u- . - J N, IS. Ti

- - — — - ,a J . -* , ΪU . iδ, 4.- , 1 N

; -. s a z -a > ^• ca ⁴ : l/.-u, lacu, LZ-.Z, ι5ou-

_EX rx -vi ■_. s sc-i --s (Q ₃ — D iVi S 0 _. c : I . i o . -J- , , j = / -.Z) , i . s ^• - . ^OU . S _. , ^.sc _. ai.sj. 4.1/ v.2 ;.C, J = lύZ; , z. us .in. u..S. , _u -.i:-. ⁱ -.--- J = 4.5Ξz). 5.S3αi.d.d.J = 4.5Ξ sSΞz). S.95-7.55(2E._), 7.: -7.75ClZ. _fl i), 7.84-3.GQCiE._). 8.10C2Ξ. br.s) . 8.78-3.00 (IE, .), S.4SC1H. d. J 3 r .

Example 6

7 _. -[2-(5-.Amino-l,2,4-thiadiazol-3-yl)-2(Z)-methoxy- iminoacetamido]-3-[ (imidazo[l,2-b]pyridaziniu -l-yl)- methyl]-3-cεphεm-4-carboxylatε hydrochloride.

To a solution of 73-[2-(5-amino-l,2,4-thiadia .ol-

3-yi)-2 (Z)-methoxyiminoacetamido]-3-[ (imidazo [1,2-b]pyri- dazinium-1-yl) ethyl]-3-cephem-4-carboxylate (130 g) in 0.4 ml of water, 200 1 of IN hydrochloric acid is added. To this, 20 ml of acetonε is added and thε mixture is stirred for 5 minutes. The precipitate separated is collected by filtration, washed with small amount of acetone and dried to give the title compound.

IR soectru v ^KBr cm ^"1 : 1780, 1675, 1620, 1520, 1450, max

1380, 1220.

Example 7 78-[2-(.5-Amino-l,2,4-thiadiazol-3-yi) -2(Z) -cya cmεthylcxy- iminoacetamido]-3-[ (imidazo [1,2-a]pyridini m-1-y1)methyl]- 3-cephem-4-carboxvlatε

Two grams of the 7β-[2-(5-amino-l,2,4-thiadiazol-

3-yl) -2(Z) - cyanomethoxyiminoacetamido]-3-(3-oxobutyryloxy- methyi)-3-cephem-4-carboxylic acid obtainεd in Rεfεrεnca

Example 3, 2 g of imidazo [1,2-a]pyridine and 2 g of sodium iodide are mixed in a mixture of 20 ml each of acetonitrile and water and the mixture is heated in an oil bau kept at

73 ³ C for 60 minutes with suirring and then allowed to cool.

To the reaction mix-cure, 50 ml of ethyl acetate is added and, after shaking, the aqueous layer is separated and conce trated. The rεsiduε is thεn placεd on a XAD-2 column and eluted first with water, thεn with 20% ethanol in water. Fractions containing the objective compound are concentrated and filtered to remove some insoluble materials.

The filtrauε is lyophiiized and the product obtained is dissolved in small amount of water and subjεctεd to chromatography on a column of silica gεl. Thε column is washed with acetone and then the desired product is eluted with acetone:watεr=7: . Fractions containing the objective compound are concentrated and the residue is lyophiiized to give thε above—idenuified. coiπpound.

I?, soεctrum vm ^KΞ ax ^r cm ^"i : 3100, 1760, 1605, 1520, 1380, 1040,

1010, 760. NI-S. ≤pεcur

C1Ξ, d , 7. 0-7.SO, 7.90-8.30 and 8.60-8.80 (6Ξ, m) . <-*-_.: -m*i _; O

7S- [2- C5-.-mino-l , 2 , 4-thiadiazol-3-yl) -2 ( Z) -ethoxy iminσ- acεta iάo ] -3- [ (3-cyanoimidazo [l , 2-a] pyridinium-l-yl) - methvi] -3-ceohεm-4-carboxvlata

7g-[2-(5-.-mino-l,2,4-thiadiazαl-3-yl) -2 (Z) -e_.hoxyii.inc- acatamido]-3-C3-oxobutyryloxymethyl) -3-cεphεm-4-carbox lic acid and 3-cyanoimidazo[1,2-a]pyridinε arε rεactεd in a manner as in Example 1 to give the above- identified compound.

Elemental analysis for C ,-Ξ- _Q _-T ₃ 0_S_•3Ξ.,0:

Caicd. C%): C, 43.4?; ≡, 4.15? N, 20.45. F un.d C%) : C, 43.53; Ξ, 3.59; N, 20.38. I?, spectrum ^ ^r cm~- _: 2245, 1770, 1630, 1640, 1610, 1510.

NMR soectrum ?d,-DMΞC) £: 1.20 (.3Ξ, t, J=7Ξz) , 3.0K1Ξ, b

.-3CX-/2, J=lSΞo; , 4.12C2H, d, J=7Ξz) , 4.98(1Ξ, d, J=4.5Ξz), 5.33 and 5.53 (2K, ABς, J=14Ξz) , 5.65 (1H, d.d, J=4.5Ξz and 8Ξz), 7.64-7.88 (1Ξ, m) , 8.04(2Ξ, br.s) , 8.00- S.4SC1H, m) , 8.92-9.12{2Ξ, ) , 9.42UH, d, J=3Hz) , 9.47C1Ξ, s) . ΞxamDle 9

75_ F2- Ξ-Aminc-1, 2, 4-thiadiazci-2-yl) -2 (Z) -cyancmethoxy- imincacetamidc]-3- [ (.6-cyanσ imi azo [1,2- j yridinium-l-yD - mεthvi] -3-ceuhem-4-carbσxvia-:e

The compound obtained in F.efεrεnce Example 3 and 6- cyanoimidazo[1,2-a]pvricine are reacued in a manner

as in Example 1 to give the above-idεntified compound.

Elemεntal analvsis for C 23-E1,-7N _Q 905-S2-.4.-5H-20:

Calcd. (_%) : C, 42.85; E, 4.07; N, 19.56.

Found C ) Ϊ C, 42.63; H, 4.01; N, 19.51.

I?, spεctrum vm ³ ax ^r cm~ ^± : 3400, 2250, 1760, 1670, 1653, 1510,

1530.

NMR spacurum Cd.-DM≤0)S _: 2.96 and 2.46 (2E, A3ς, C ^" =16Ξn; , o

5.01 1H, d, =5Ξz) , 5.Q2C2Ξ, s) , 5.27 and 5.52C2H ^, λBc, =15Ez) , 5.64C1H, ά.ά, u=5Hz and 3Hz) , 8.2-9.0 L4Ξ, m) , S.22C2E, br.s) , 9.66 1Ξ, d, J=3Ez) , 9.77C1H, br.s) .

Ξxam la 10

7S-[2-(5-._minc-l,2,4-thiadiazci-3-yl)-2CZ) -mεthoxyimino- acetamido]-3-[(6-cyanoimidazo[1,2-ai yridinium-l-yi)mεthyl]-

3-cεohεm-4-carboxvlatε

Thε compound obtained in Rεfεrεr.cε ixampiε 1 an 6- cyancimidazoFi,2-a]pyridine are reacted in a manner as in Example 2 to give the above-ide tified compound.

Elemental analvsis for C- 21,Ξ J,._/N _n 9Q 3-Ξ ._..2Ξ -..O:

Calcd. (.%) : C, 42.49; H, 3.91; , 21.24. Found C%) : C, 42.55; E, 3.67; N, 21.01

7 -- -1 i -j e— ac— — ••—[ j

^"' ■ "- max ~: 3450, 2250, 1760, 1600, 15!

NMR Cdg-DMSOJo: 2.98 and 3.46(2E, A3σ, J=16Ξz) , 3.36(3H, s) , 5.00 1Ξ, d, J=5Ez) , 5.28 and 5.54(2E, AB , J=15Hz)

5.64C1S, d.d, J= 5 Hz and 8Hz) _, , 8.1K2Ξ, br.s) , 8.2-9.0 5E, m) , 9.44C1E, d, J=8Ξz) , 9.78(1E, br.s) .

Example 11

7β- [2- C5-.-mino-l, 2, 4-thiadiazol-3-yl) -2 (Z) -carbox mεthoxy- iminoacatamido] ^' -3-[ (6-cyanoimidazo [l,2-a]pyridinium-l-yl ⁾ - mathyl]-2-caphem-4-carboxyiatε monosodium salt

CCΞ .CCC a

Onε gram of 7.S- [2- (5-≤minc-i, 2 , - thiadiazol-3-yi -2 (Z) -carboxy- acid obtained . in Exaiπple 12 (iii) , 1 g of 6-cyanoimidazo [1,2-a] - pyridine and 1 g of sodium iodide are added in a mixture of 15 ml of acetonitrile and 15 mi of water and the mixture is heated in an oil bath keen an 70-75 =C for 1.5 hours with stirring. The reaction mixture is shaken with eohyl acetate and the aqueous layer is separated, concentrated under reduced pressure and chromatographed on a silica gel column wiuh aceuone anc then acetone :water= : 2. Fractions contain¬ ing thε objectivε compound are concentrated and thε residue is lyophiiized to give the above-identified compound. Elemental analvsis for C ._Ξ- _C N_G .5,Na- 5Ξ-0 Calcd. (. ) : C, 37. SS; Ξ, 2.77; N, 13.12. Found (%) : C, 33.13; Ξ, 2.23; l. , 17.15. IR soacurum v^^c ^"1 : 2240, 1760, 1600, 1520, 1400, 1360,

1045. NMR spectrum D ₂ 0) δ : 3.15 and 2.59(2E, ABq, J=18Hz) , 5.24

C1Ξ, d, J=4.8Ez) , 5.38(2Ξ, br.s) , 5.86CLH, d, J=4.8Hz) , S.2-3.0C4H, m) , 9.8(1Ξ, br.s) .

Examplε 12

7 ^β -[2-(5-Amino-l,2,4-thiaάiazαl-3-yl)-2(Z)-carboxymeth σxy- iminoacetamido]-3-[ (imidazo[1,2-aJpyridinium-1-yl)mεthyl]-

3-cephem-4-carboxyiate

i ⁾ To- a solution of 2-(5-tεrt-butcxycarbcnyiamirc-i,2,4- thiadia∑oi-3-yl)-2-cxoacetic acid in ethanol (100 mi) , prepared from 13 g of 2-(5-amino-i,2,4-thiadiazoi-2-yi - acatic acid and 10.7 g of saiεnium dioxide in a manner as in Reference Example 3, is added, under ice-cooling, 6.2 g of O-tart-butoxycarbonylmathylhydroxvl- aminε(prepared from 14 g of -tert-butoxycarbcr.yimεthcxy- phthaiimide and 2.3 g of methyihydrazine) and the mixture is stirred at room temperature for 4 hours. E hane! is then evaporated off and the residue is shaken with ethyl acauate and water. The organic layer is separated and extracted with an aqueous sodium bicarbonate solution. The aqueous extract is made acid with I -HCI and extracted with εu yl acεtatε. Thε εxtract is driεd over anhydrous magnesium sulfate. The solvent is then evaporated off and the residue is crystallized from hexane t give, after filtration and drying, 11 g of 2-(Ξ-tert-butoxycarbcnylamino-i,2,4-thiadiaool- 3-yi) -2 (Z) -(tert-butoxycarbonyl εthoxyimino) cetic acid. mp 128°C (decomposition)

NMR spectrum (CDCl δ: 1.43(9H, s) , 1.55(9H, s) ,4.73 (2H,s) .

ii) To a solution of 13 g of 2-(tert-butoxycarbonylamino-

1,2,4-thiadiazol-3-yl)-2 (Z)-(tert-butoxycarbonylmethoxy- i ino) acetic acid in 100 ml of dichloromethana, 7 g of phosphorus pentachloride is added and the mixturε is stirrrεd for 20 minutes under ice-cooling. The reaction mixture is evaporated to dryness and to thε rεsidue is added hexane and the solvent is evaporated off again. The residue is dissolved in 5 ml of dichloromethane and the solution is added under ice-cooling to a solution preparεά by allowing

10 g of 73-amino-3-(3-oxαbutyryloxymεthyl)-3-cεphεm-4- carboxylic acid and IS g of N,0-bistrimεthylsiiyiacεtamidε to rεact in 200 ml of dichloromεthanε at room temperature for one hour. The mixture is stirred at the same temperature for one hour and the solvεnt is then evaporated under rεducεd pressure. The residuε is dissolvεd in 300 ml of εthyl acεtate and the solution is washed with water and then driεd ovεr anhydrous magnesium sulfate. Thεn, thε solvεnt is εvaporatεd off and thε rεsiduε is triturated with hexane.

Insoluble substance is collεctεd by filtration to givε

23 g of 7. -[2-(5-tεrt-butαxycarbσnylamino-l,2,4-thiadiazol-

3-yl)-2(Z) -(tert-butoxycarbonylmethoxyimino)acetamido]-3-

(3-oxobutyryloxymεthyl)-3-cephem-4-carboxylic acid.

IR soεctrum vm ^KB ax ^r cm ^_1 : 3250, 2960, 1780, 1715, 1540, 1370,

1205, 1150, 1060. NMR spectrum(dg-DMSO) δ: 1.43 (9Ξ, s) , 1.50 (9Ξ, s) , 2.18

(3Ξ, s) , 3.41 and 3.65 (2Ξ, AΞq, J=18Ez) , 3.62(2Ξ, s) , 4.66(2Ξ, s) , 4.78 and 5.06(2H, ABq, J=12Ξz) , 5.15 (1Ξ, d, J=4.8Ez) , 5.86 (1H, d.d, J=4.8Hz and SΞz) , 9.56 (1Ξ, d, J=3Ez) . iii) The wholε amount of the compound obtained in ii) is added to 50 ml of trifluoroacetie acid under ice-rcooling. Thεn, thε cooling-bath is removed and the rεaction mixturε is stirred at room tεmpεraturε for 1.5 hours. Aftεr being diluted with ethyl acetate , the reaction mixture is evaporated off to dryness and the rεsiduε is trituratεd with εthyl acetate. Insoluble substance is collected by

filtration to give 12 g of 7. -[2-(5-amino-l,2,4-thiadiazol- 3-yl)-2(Z)-carboxymethoxyiminoacetamido]-3-(3-oxobutyryloxy- ethyl)-3-cephem-4-carboxylic acid. From the filtrate, after evaporation to dryness, addition of diethyl ethεr to the residue and filtration of'insoluble matarial, 5 g of the same objective compound is recovεrad.

IR spectrum z 1760, 1720, 1630, 1520, 1400, 1310,

1130, 1145.

NM spectru (Dg-D SQ) δ: 2.20(3E, s),3.41 and 3.65(2Ξ, AEσ,

J=18Ξz) , 3.63 (2E, s), 4.65 (2Ξ,s) , 4.78 and 5.07 (2Ξ,

AEq, J=12Ξz) , 5.15(lE, d, J=4.SΞz), 5.85(1E, d.d,

J=4.8Ξz and 8Ξz) , 8.10 (2Ξ, br.), 9.48 (IE, d, J=3Ez) . iv) One gram of 7β-[2-(5-amino-l,2,4-thiadiazol-3-yl)-

2(Z) -carboxymethoxyiminoacetamido]-3-(3-oxobutyryloxymεthyl) -

3-cephem-4-carboxylie acid, 1 g of imidazo[1,2-a]pyridine and 1 g of sodium iodide are added to a mixύure of 10 ml of acetonitrila and 10 ml of water and heated in an oil bath kept at 70-75°C for 1.5 hours. Thε rεacticn mixturε is worked up as in. Examplε 1 to givε thε abovε-idεntifiεd compound.

Elεmεntal analysis for C- ₁ E ₁₇ g0 ₇ S ₂ a-5E20:

Calcd. (%) : C, 42.79; Ξ, 3.08; N, 19.01

Found (%) : C, 42.88; E, 3.64; N, 17.55

IR soεctru vm ^K3 ax ^r cm ^_1 : 1760, 1600, 1520, 1400, 1305, 1050.

NMR spεctrum(D ₂ 0) δ: 3.16 and 3.53 (2Ξ, AΞq, J=13Ξz) , 5.22(1Ξ, d, J=4.8Ξz), 5.32(2Ξ, br.s) ,5.-56 (IE, d, J=4.8Ξz), 7.40-8.80 (6Ξ, m) .

Example 13

76- [2-(5-Amino-l,2,4-thiadiazol-3-yl)-2 (Z) -methoxy- i inoacatamido]-3-[ (imidazo [1,2-b]pyridazinium-l-yl)me hyl]- 3-cephem-4-carboxylate

73- [2-(5-.-mino-l,2,4-thiadiazoi-2-yl)-2 (Z) -methoxy- iminoacatamido]-3-(3-oxobutyryioxymeth l) -3-cephεm-4- carboxyiic acid (1.1 g) , imidazo [1,2-b] yridazine (1.0 g) and pouassium iodide (1.1 g) are dissolved in 30 ml of 50% aqueous acetonitrile and the mixture is heated for 2 hours at 6Q-70°C. After cooling, the reaction mixuurε is chrom uographed on a column of silica gel with acetone and thεn wiuh aqueous acetone, successively. Fractions con-ain- ing the objective compound are combined and concenrraued undεr reduced pressure. The residue is then chromatocraohεd on a column of MCI gεl CEP20?^ resin (Mitsubishi Kasei,Japan) with water and then with aqueous alcohol. Fractions containing thε object: compound are combined and concen¬ trated and the residue is lyophiiized to give the title compound.

Elemental analysis for: C 1 ₉ H _l7 a 0 ₅ S ₂ ^• 3 H ^■ >0 Caicd.(%): C.40.07; H.4.07; N.22.13. Found (%):C .39.75; H.3.51; N ,21.89.

I R spectrum . ^K m ^B a^x cm ^"1 : 1765, 1660. 1610.

1520.

XMR spectru aiCdβ- DMS 0) δ : 3.03& 3.44(2H. ABq.J = 18Hz). 3.86(3H,s), 4.99(lH,d.J =4.5Hz). 5.27 & 5.51(2 H. ABq. J = 14Hz) ,- 5.33(1H, d. d. J = 4.5 Hz &8Hz), 7.8-3.32(1H,_), 8.12C2H.br. s). 8.76(2H.s) , 9.04(iH.d.i = ⁱ Hz), 9.31(lH.d.J = SKz). 9.44(1H,

Ixample 14

73- [2- (5-.-mino-l,2,4-thiadiazoi-3-yl) -2 (Z • -ethoxy- imxnc acetamido] -3- [ (imidazo [1 , 2-b] yridasinium-i-yl) ethyl] hsm-4-carboxviata

73-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-ethoxy- iminoaceta ido]-3- (oxobutyryioxymethyl)-3-cephem-4- carboxylic acid is made to react with imidazo [1,2-b] pyridazine by the procedure of Examplε 1 to give the title comoound.

Ilementai analysis for: C ₂₀ H ι ₃ X ₃ 0 ₅ S ; 4 π . cj

US !3: H.4.52: N.20.95.

^? ound C%) r ,4U n X.20. _ 00_ ,

I R spectrum max :m ^"L : 1770, 1670, 1610 i -j i υ .

XMR spectr mCdβ-DMS 0)o : ^■ 1.20(3H, t , J = 7

- ^■ - - " 3J. f0l3. 4.l3(2H,q,J = 7Hz). 4.99(lH,d.J = 4.5Hz. . 5.28& 5.52.2H. ABq. J =

Hz) _, 5.65(lH _, d.d.J=4.5Hz&8Hz), 7.8-8.2(lH.m) ^, δ.75(2H.s), 9.05(lH.d,J=4Hz). 9.28(lH.s). 9.43 (lH.d,J=8Hz).

Example 15

76- [2- (5-Amino-l,2,4-thiadiazoi-3 iminoacetamido]-3- [ (8-methylimidazo [1, 2 -oj ovr: .nil yl)mεthyl]-3-cephem-4-carhoxylatε

By thε procedure of Example 1, 73- [2- (5-amino-l, 2 , 4- thiadiazol-3-yl) -2 (Z) -methoxyiminσace "aπidoj -3- (3-oxo- butyryloxymethyl) -3-cεphem-4-carboxylic acid is reacted with 8-methylimidazo [1, 2-b] pyridazine to give thε title compound.

Elemental analysis for: C _!0 H ₁₃ X ₃ 0. S i • 4 K _: 0 Calcd. (%):C ,39.34: H.4.^2: S. ^" ..... Found (%): C ,39.43; H.4. 2; X.:;. ^' 4.

I R spectrum :

1520. ^■ . M R spectrum (d ₆ - D >.I S 0 ^""■ o : .1 ^{" '} SΞ. s ^" . 3.90(3H, s) , 3.06& 3.39(2H. A3ς. J= liHz!- , 3. S .In. d,J = 4.5Hz). 5.50(2H.br.s). 5. Ti lΞ.ά.d. J = 4.5Hz &8Hz), 7.68(lH,d,J = 5Hz), 7.9?.; Ξ. br.s) . 8.32- 8.52(1H,_), 8.56-S.66(lH,_), 8. S4(lH.d, j = 5Hz) . 9.47(lH,d,J = 8Hz).

05183

132-

Example 16

7β- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2 (Z) -ethoxy- iminoacetamido] -3- [ ( 5 -meth l midazo [1 , 5-a] ρyridinium-2- yl) methyl] -3-cephem-4-carboxylate

By the procedure of Example i, 76- [2- (5-amino-l,2,4- thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamido] -3- (3-oxobutyryl oxymethyl)-3-cephem-4-carboxylic acid is reacted with 5- methylimidazo [1, 5-a] pyridine to give the title compound -

Elemental analysis for: C ₂₂ H πKs 0. S ₂ * 2H ₂ O Calcd. (2 :C,45.67; H.4.5-3: N-,19.37. Found (%):C,45.31; H.5.00; N.19.21.

I R spectrum max 1760, 1660, 1640,

1510. 1390, 1350. NMR spectrum (dβ-D. MS 0) (5 : 1.20(3H,t,J = 7Hz), 2.66C3H,s), 3.17(2HX 1/2, ABq, J = 18Hz) , 4.12(2H,q,J = 17Hz). 5. OSClH.d. J = 5Hz), 5.06& 5.54(2H,ABq,J = 14Hz). 5.67(lH.d.d, J = 5Hz&8Hz), 6.9-7.4(2H,m), 7.79(lH,d, J = 8Hz), 8.09(1H, br.s) , 8.63C1H.S), 9.39ClH,d.J = 8Hz), 9.93(lH.s).

Example 17

73- [2-(5-Amino-l,2,4-thiadiazol-3-yl) -2 (Z) - ethoxy- iminoacetamido]-3-[ (6-methylimidazo [l,2-b]pyridazinium-l- yl)methyl]-3-cephem-4-carboxylate

3y the procedure of Example 1, 7S- [2-(5-amino-i,2,4- thiadiazol-3-yl)-2(Z)-methoxyi inoacetamido]-3-(3-oxo- butyryloxymethyl) -3-cephem-4-carbcxylic acid is reacted with 6-methylimiάazo [1,2-b] yridazine to give the title compound.

Elemental analysis for C„Ξ, _Q N _Q 0-S,-5H,0:

Calcd. (%) : C, 33.77; H, 4.72; N, 20.34 Found(%) : C, 33.94; H, 4.69; N _. 20.32

IR spectrum v^ j cm ^"1 : 1765, 1660, 1605, 1520

NMR spectrum (d.-DMSC) c: 2.99 & 3.43 (2H,ABσ,J=18Hz) ,

2.67 (2H,s) , 3.36(3Ξ,s), 4. 7 (lH,d,J=4.5Hz) , 5.24 & 5.40 (2H,AΞq,J=14Hz) , 5.61(lH,d. ,J=4.5Hz & SHz) , 7.36 (1H,a, J=9Ez) , 3.10 (2Ξ,br.s) , 8.53-3.76 (2H,m) , 9.20 (lH,d,J=9Hz) 9.43 (iH,d,u=3Hz) .

By the procedure of Example 1, compounds of the fol¬ lowing Examples 18-24 can be prepared by reacting 7«_ _[ 2-

(5-amino-l,2,4-thiaciazol-3-yl) -2 (Z) -methoxyiminoacet¬ amido]-3-(3-oxobutyryioxymethyl) -3-cephem-4-carboxylic acid with various imidazo [1,2-b]pyridazines.

- 13*

Example 18

73-[2-(5-Aπino-l,2,4-thiadiazol-3-yl)-2 (S) -methox ininc- acetamido]-3-[(6-ethoxyimidazo[1,2-b]pyridazinium-1-yl) methyl]-3-cephem-4-carboxylate

OCH ₃

Elemental analysis for C ₂₁ H ₂ -. _a OgS ₂ *3H ₂ 0:

Calcd. (%) : C, 41.11; H, 4.43; N, 20.54 Found (%) : C, 40.95; H, 4.56; N, 20.32.

IR spectrum 00.

NMR spectrum , 2.98 &

3.42 (2H, ABq, J=18Hz) , 3.87 (3H, s) , 4.46 (2E. q, J=7Hz) , 4.98 (1H, d, J=4.5Hz), 5.20 όi 5.50 (2E, ABq, J=14Hz) , 5.60 (1H, d.d, J=4.5Ξz S. 3Hz), ".57 (2H, d, J=14Hz) , 8.04 (2H, br. s) , 8.46 (1H, d, J=2Hz) , 8.64 (1H, d, J=2Hz) , 9.24 (IΞ, d, J=10Ξz) , 9.40 (1H, d, J=8Hz) .

Example 19 '

7β-[2-(5-Amino-l,2,4-thiadiazol-3-yl) -2.(Z)-methoxyimi- noacetamido]-3-[(6-methylthioimidazo[l,2-b]ρyridazinium-l- yl) ethyl]-3-cephem-4-carboxylate

Elemental analysis for C _2Q E, _g NgO _g S ₃ -7/2 H ₂ 0:

Calcd. (%) : C, 38.45; H, 4.20; N, 20.18. Found (%) : C, 38.40, H, 4.25; N, 20.11.

IR spectrum ^ cm ^"1 : 1770, 1670, 1600, 1520.

N2ϊR soectrum (d o. -DMSC)δ: 2.66 (3H, s) , 3.01 (2H x 1/2,

A3q x 1/2, J=lSEz) , 3.86 (3E, s) , 4.9S (IE, d, J=4. 5Iϊz) 5.22 S 5.50 (2Ξ, d, J=14Ez) , 5.63 (IE, d.d, J= 4.5E2 & 3Sz) , 7.91 (IE, d, J=10Ez) , 8.10 (2H, br. s) _/ O _• 3 J.— 3.74 (2E, ) , 9.22 (IE, d, J=10Ez) , 9.44 (1H, d, J=

Example 20

75- [2-(5-Amino-l,2,4-thiadiazol-3-yl) -2 (Z) - ethoxyi; r.oacs oamido] -3-[ (6-chloroimidazo [1, 2-b] yridazinium-1-yl) - me ohy ] -3-oephem-4-carboxylate

Elemental analysis for C, _α E- _g Cl _a O-S ₂ -4H .0:

Calcd. (%) : C, 36.69; H, 3.39; N, 20.27.

Found (%) : C, 36.80; S, 3.12; N. 20.09.

IR s ectru v m^ ^B ax ^r cm ^_i : 1775, 1670, 1610, 1520

NMR soectrum (d 0. -DMSO) δ 2.98 & 3.42 (2Ξ, A3c, J=18Ez) , 3.86 (3E, s) , 4.98 (1H, d, J=4.5Bz), 5.24 & 5.55 (2E, ABq, J=14Ez) , 5.59 (IB, d.d, J=4.5Hz & SΞz) , 8.09 (2Ξ, br. s) , 8.17 (IB, d, J=9Bz) , 8.73-3.90 (2B, m) , 9.42 (IE, d, =8Bz) , 9.48 (IE, d, J=9Ez) .

Example 21

73-[2-(5-Amino-l,2,4-thiadiazol-3-yi) -2 (Ξ)- ethoxy- iminoacetamido]-3—[(6-methoxyimidazo[1,2-bj yridazini m-1- yi]-3-cephem-4-carboxyiate

Elemental analysis for C _2Q B, _{Q g} OgS ₂ -9/2 B ₂ <D:

Calcd. (%) : C, 38.34; Ξ, 4.50; N, 20.12. Found (%) : C, 38.39; E, 4.54; N, 20.02.

IR spectrum v> ^ cm ^"1 : 1770, 1670, 1610, 1510.

NI1R spectrum (dg-DMSO)δ: 2,98 & 3.43 (2B, ABq, J=18Ez) , 3.86 (3S, s) , 4.06 (3B, s) , 4.97 (IB, d, J=4.5Bz) , 5.20 & 5.50 (2B, ABq, J=14Ez) , 5.62 (IE, d.d, J= 4.5BZ & 8Ez) , 7.62 (IB, d, J=9Ez) , 8.04 (2B, br. s) ,

8.38-8.68 (2E, m) , 9.22 (IB, d, J=9Hz) , 9.42 (IB, d, J=8Ez) . Example 22

73-2- ( 5-Amino-l , 2 , 4-thiadiazol-3-yl) -2 ( Z ) -methoxy- iminoaceta ido] -3- [ ( 6-methylimidazo [1 , 2-b] pyridazini m-l-yi)- methyl]-3-cephem-4-carboxyiate

Elemental analysis for C^E, _Q N _g O_S. '5E-0:

Calcd. (%) : C, 38.77; E, 4.72; N, 20.34. Found (%) : C, 38.94; E, 4.69; N, 20.32.

IR soectrum 3r ^-1 : 1765, 1660, 1605, 1520 max

NMR soectrum (do. -DMSO) δ: 2.99 & 3.43 (2Ξ ABq,. 3Ξz)

2.67 (3E, s) , 3.86 (3E, s) , 4.97 (IE, ri. I ,

5.24 & 5.40 (2B, ABq, J=14Ez) , ^' 5.61 (IE, d.d, J=4.5Ez

6 SEs) , 7.36 (IE, d, J=9Ez) , 3.10 (2Ξ, br. s) , 3.58- 3.76 (2E, m) , 9.20 (IE, d, J=9Ez) , 9.43 (IE, d, J ⁼ 3Bz) .

Example 23

73-[2- (5-Amino-i,2,4-thiadiazoi-3-yl) -2 (Ξ) -methoxy- iminoacetamido] -3- [ (6-dimethylaminoimidazo [l,2-b]pyridaziniu^ 1-yl)meohyl] -3-cephem-4-carboxyla -a

Elemental analysis for C ₂ ,Ξ ₂₂ N, _Q 0 ₅ S ₂ '4S ₂ 0:

Calcd. (%) : C, 39.99; B, 4.79; N, 22.21. Found (%) : C, 40.26; B, 3.90; N, 22.07.

IR spectrum (KBr) cm ^"1 : 1775, 1670, 1610, 1590, 1510.

NMR spectrum (d _g -DMSO) c : 3.04 (2B, br. s) , 3.14 (6E, s) , 3.86 (3B, s) , 4.95 (IE, d, J=4.5Ez), 5.15 & 5.43 (2E, ABq, J=14Ez: , 3.57 (IE, d.d, J=4.5Ez &. 8Ξz) , 7.68 (IB, d, J=10Ξz) , 3.07 (2B, br. s) , 8.24 (IE, br. s) , 8.39 (IE, br. s) , 8.96 (1H, d, J=10Ez) , 9.40 (IE, d, J=SΞz) .

Example 24

73-2-(5-Amino-l,2,4-thiadiazol-3-yi) -2(Z) -methoxy- iminoaceta ido]-3-[(6-fluoroimidazo[1,2-b]pyridazinium-1- yl)methyl]-3-cephem-4-carboxylate

Elemental analysis for C, gE. ,- _g Q_S ₂ F-4Ξ ₂ 0:

Calcd cr 3.99; N, 20.82, Found ( . ) C, 33.03; E, 3.89; N, 20.55.

IR spectrum '* .Z ^~ . cm ^"' : 1770, 1570, 1610, 1520

NMR spectrum (d.-DMSO)δ: 3.00 (2Ξ x 1/2, ABq x 1/2,

J=18Ez) , 3.86 (3E, s), 4.98 (IB, d, J=4.5Ξz), 5.26 &

5.59 (2E, ABq, J=_ .62 (IB, d.d, J=4.5Ez & 8Ez)

7.9-8.24 (3Ξ, ... ); ,. 3.62-3.36 (2E, m) , 9.41 (IE, d,

J=8Ez) , 9.48-S.74 (IE, ) .

Example 25

73-[2-(5-Amino-l,2,4-thiadiazol-3-yl-2 (Z) -carboxy¬ methoxyiminoacetamido]-3-[ (imidazo[l,2-b]pyridazinium-l- yl)methyl]-3-cephem-4-carboxylate*mono-sodium salt

By the procedure of Example 1, 72-[2-(5-amino-l,2,4- thiadiazol-3-yl) -2 (Z)-carboxymethoxyiminoacetamido]-3- (3- oxobutyryioxymethyl)-3-cephem-4-carboxylic acid is made to ^' react with imidazo[1,2-b]pyridazine to give the title compound. Elemental analysis for C^B^N _Q O.^ _Q •3/2E.,0:

Calcd. (%) : C, 34.38; E, 4.18; N, 18.04.

Found (%) : C, 34.48; B, 3.64; N, 17.54. KBr 1 IR spectrum υ max ^{cm : 177} °- 1600, 1520.

NMR spectrum (d _g -DMSO-D ₂ 0) : 3.52 & 3.72 (IE, AΞq, J=

18Ez) , 4.34 (2E, s) , 4.98 (IE, d, J=4.5Ez), 5.34 δ

5.50 (2E, ABq, J=14Ez) , 5.68 (IE, d, J=4.ΞΞz) , 7.90

(IB, d.d, J=5Bz & 10EZ) , 8.17 (IE, a, =10Ez) .

- 1*0 -

Example 26

73-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)-methoxy- iminoacetamido]-3- [ [6-(2-dimethylaminoethyIthio) imidazo- [1,2-b]pyridazinium-i-yl]methyl]-3-cephem-4-carboxylate• dihvdrochloride

73-[2-C5-anino-l,2,4-thiadiazoi-3-yl)-2(Z)-methoxyimino- acetamido]-3-C3-oxcbutyryloxγmethyi)-3-cephem-4-carboxylic acid

(1.5 g) , 6-(2-d ^' imethyiaminoethylthio) imidazo[1,2-b]- pyridazine (1.5 g) and potassium iodide (1.5 g) are dis¬ solved in a mixoure of 5 ml of IN hydrochloric acid, 5 ml of water and 10 mi of acetonitrile and the solution is heated for 2 hours at 60-70°C with stirring. The aceto¬ nitrile is evaporated under reduced pressure and thε residue is chromatographe on a column of high porous polymer MCI gel

CE?20P^- (Mitsubishi Kasei,Japan) with 0.0IN hydrochloric acid. Fractions containing the object compound are combined and concentrated under reduced pressure and the residue is lyophiiized to give 0.13 g of the title compound.

Elemental analysis for C^E^ ., _Q 0-S., ^■ 2E .0-ii/2S ₂ 0:

Calcd. (%) : C, 35.03; Ξ, 4.73; N, 17.76.

Found (%) : C, 35.15, E, 4.46; N, 17.66.

IR spectrum v ^K m ^c =. cm ^"1 : 1770, 1675, 1625, 1510.

NMR spectrum (d _g -DMSO-D ₂ 0) δ: 2.90 (6B, s) , 3.3-3.85 (6E, m) , 4.08 (3B, s) , 5.18 (IB, d, J=4.5Bz), 5.46 (2B, br. s) , 5.82 (IE, d, J=4.5Ez), 7.97 (IB, d, J=10Bz) , 8.27 (IB, br. s) , 8.73 (IB, d, J=10Bz) , 8.79 (IB, br. s) .

, _/ .. .

Example 27

73-[2-(5-Amino-l,2,4-thiadiazol-3-yl) -2(Z) - methoxyiminoacetamido]-3- [(7-methylimidazo[l,2-b]pyridazi- nium-1-yl)methyl]-3-cephem-4-carboxylate

By the procedure of Example 1, 7£-2-(5-amino-i,2,4- thiadiazol-3-yl) -2(Z) -methoxyiminoacetamido]-3-(3-oxo- butyryloxymethyl)-3-cephem-4-carboxylic acid is made to react with 7-methyiimidazo [1 ,2-b] yridazine to give the title compound. Elemental analysis for C _n H, _Q N 3_S_•3E_0:

Calcd. (%) : C, 33.77; Ξ, 4.72; N, 20.34. Found (%) : C, 38.82; E, 4.75; N, 20.32. IR spectrum '. ^• _~ ^~ cm : 1760, 1563, 1510, 1520. NMR spectrum (d _g -DMSO) δ : 2.56 (3Ξ, s) , 3.00 (2E x 1/2,

ABq x 1/2, J=18Bz) , 3.86 (3B, s) , 4.99 (IE, d, J=4.3 Ez) , 5.20 & 5.43 (2Ξ, ABq, J=14Ξz) , 5.52 (IE, d.d, J=4.5Ez & 8Bz) , 8.09 (2Ξ, br. s) , 8.53-3.74 (2E, m) , 8.97 (IB, br. s) , 9.08 (IB, br. s) , 9.42 (IE, d, J=3Ez) .

Example 28

73-[2-(5-Amino-l,2,4-thiadiazol-3-yl) -2(Z) - methoxyiminoacetamido]-3-[(imidazo[1,2-b]pyridazinium-1- yl) ethyl]-3-cephem-4-carboxylate

(11 73-tert-Butoxycarbonylamino-3-(3-oxobutyryloxymethyl) - 3-cephem-4-carboxylic acid (4.14 g) , imidazo [1,2-b yri¬ dazine (4.14 g) and sodium iodide (3.28 g) are added to a mixture of 20 ml of water and 20 mi of aceoonitriie and the mixture is heated for 2 hours at 70°C with stirring. After being allowed to cool to room tempera-cure, the reac¬ tion mixture is subjected to silica gel (100 g) column chromatography. The column is washed with acetone and 95% acetone-water and then the product is eluted with 75% acetone-water. Fractions containing the object compound are combined and concentrated and -he residue is lyophiiized to give 1.14 g of 73-tert-b toxycarbonviamino- 3-1 Cimidazo[l,2-b]pyridazinium-l-yi/methyi]-3-cephem-4- carboxylate as a _. powder.

IR spectrum ^' cm ^'- ; 1760, 1710, 1610, 1520, 1385, 1370. NMR spectrum (d _g -DMSO)δ: 1.39 (9Ξ, s) , 3.08 & 3.43 (2Ξ

ABq, J=18Bz) , 4.91 (IE, d, =6Ez) , 5.1-5.6 (3Ξ, m) , 7.6-8.2 (2E, ) , 8.78 (2E, br. s) , 9.07 (IE, d, J= 4Ez) , 9.31 (lB,d, J=10Ez) . TLC (Merck, Art 5715; solvent: cetonitrile: ater = 4:1) ,

Rf=0.4. (2) 7g-(tert-Butoxycarbonylamino)-3- [(imidazo [1,2-b]- pyridazinium-1-yl)methyl]-3-oephεm-4-carboxyiare (1.45 g) is dissolved in 20 ml of trifi-ioroacetic acid and the solution is stirred at room temperao re for 30 minutes. The reaction mixture is concentrated under reduced pres¬ sure and the residue is treated with 100 ml of ether with stirring. Precipitate separated is collected by filtration and washed with ether to give 1.42 g of 73-amino-3-

[ ⁽ imidazo [1,2-b]pyridazinium-1-yl) ethyl- 3-ceρhem-4- carboxylate trifluoroacetate

- 1*3 -

The yield : 95 % .

IR spectrum v ° ^* _ cm : 1780, 1680, 1525, 1410, 1380. NMR spectrum (CF ₃ COOD)δ: 3.50 & 3.80 (2E, ABq, J=18Bz) , 5.51 (2B, br. s) , 5.58 & 6.09 (2B, ABq, J=14Ez) , 7.96 (IB, d.d, J=5Bz & lOEz) , 8.26 (IB, d, J=2Ξz) , 8.40 (IB, d, J=2Sz) , 8.71 (IB, d, J=10Ez) , 9.0 (IE, d, J=ΞEz) . TLC (Merck, Art 5715; solvent:acetonitrile .formic acid: water = 3:1:1), Rf=0.5. (3) To 20 ml of dichloromethane, are added 2-(5-amino- 1,2,4-ohiadiazol-3-yl)-2(Z) -2-methoxyiminoacetic acid (202 mg) , N-hydroxybenztriazole (153 mg) and dicyclohexyl- carbodiimide (206 mg) and the suspension obtained is stirred for 60 minutes at room temperature. Insoluble material is filtered off and the filtrate is added to a solution of 445 mg of73-amino-3-[(imidazo[1,2-b] ^■ pyridazini m-1-yl)methyl]-3-σephem-4-carboxylate trifiuoro- aceta- e in 8 ml of dimethylacetamide and the mixture is s-irred for 16 hours at room temperature. To thε reac ion mixturε is added 30 ml of ether. After the erhεr layer is removed bv decantation, the residue is dissolved in water and subjectεd to chromatography on a column of X E—2^' The column is developed with ether and then wioh 20% thanol-watεr. Thε eluate containing thε objεcr ccmpcur.ά is concεntratεd and the residue is lyophiiized o give 0.2 g of thε titlε compound.

I.R. spεctrum of thε compound is the same as ohat in Examplε 13.

Example 29

73-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2(Z)- methoxyi inoacetamidoj-3-[ (imidazo[1,2-b]pyridazinium-1- yl)methyl]-3-cephem-4-carboxyl e.

CD To a solution of 218 mg of phosphorus pentachloride in 3 ml of methylene chloride, 202 mg of 2-(5-amino- 1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid is added under cooling at-20°Cwith stirring and the mixture is stirred for half an hour at -20°C and for two hours at -5°C. The reaction mixture is concentrated under reduced pressure and the residue is triturated with 10 ml of hexane. The precipitate is collected by filtration to give 2- (5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetyl chloride hydrochloride.

(2) 73-Amino-3-[ (imidazo[1,2-b]pyridazinium-1-yl)methyl]- 3-cephεm-4-carboxylate hydrochloride (354 mg) is dissolved in a mixture of 10 ml each of acetone and water under ice-cooling. After addition of 504 mg of sodium bicarbonate and one minute's stirring, the whole amount of 2-(5- amino-l,2,4-thiadiaZ"ol-3-yl)-2(Z)-mεthoxyiminoacetyl chloride hydrochloride obtained above is added and thε mixture is stirred enεrgetically for 20 minutes under ice-cooling.

To the reaction mixturε is addεd 20 ml of ethyl acetate and the upper layer is removεd and the lower layer is washed twice with each 20 ml of ethyl acetate. The aqueous layer is separated and acidified with concentrated hydrochloric acid to pE 1 and washed with a mixture of 20 ml of mεthyl ethyl ketone and 10 ml of ethyl acetatε and then with a mixture of each 10 ml of mεthyl ethyl ketone and ethyl acetate. Then, the aqueous layer is adjusted to p nd chromatographed on a column of MCI gel, CBP (Mitsubishi asei, Japan) , first, with watεr and thεn with aquεous acεtonitrilε. Fractions containing thε objεct compound arε combinεd and concentrated and the residuε is lyophiiized to give the title compound.

86/ 5183 . , ψ ₅ _

TLC (Silica gel, Merck, Art 5715; Solvent: acetonitrile: water = 4:1): Rf=0.26 IR spectrum v H ^K I ^B -ΞL ^r .2cm ^'1 : 1765, 1660, 1610, 1520

Example 30

73-[2-(5-4_mino-l,2,4-thiadiazol-3-yl)-2(Z)-methoxy- iminoacεtamido]-3-[ (imidazo[1,2-b]pyridazinium-1-yl)methyl]- 3-cephem-4-carboxylate.

30-1) By the procedure of Example 29 but using 606 mg of triethylamine instead of the 504 mg of sodium bicarbonate, the title compound is obtained and identified as such by comparing its IR-, NMR-spectra, Rf-value in TLC and retentio time in BPLC with those of the product obtained in Example 29.

30-2) By the procedure of Example 29 but using tetra- hydrofuran instead of the acetone, the title compound is obtained.

30-3) By the procedure of Example 29 but using acetonitrile instead of the acetonε, the title compound is obtained. Example 31

73-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2 (Z)-methoxy- iminoacεtamido]-3-[(imidazo[1,2-b]pyridazinium-1-yl)mεthyl ]- 3-cεphεm-4-carboxylatε

73-Amino-3-[(imidazo[l,2-b]ρyridazinium-l-yl)methyl]- 3-cephem-4-carboxylate hydrochloride (354 mg) is dissolved in a mixture of 4 ml of dimethylfor a idε and 1.11 g of tributylaminε and the solution is cooled to -20°C. To this, 2- (5-amino-l,2,4-thiadiazol-3-yl)-2 (Z)-methoxy- iminoacetyl chloridε hydrochloride (the whole amount of it preparεd as in Examplε 29 using the same amounts of the starting matεrial and rεagents) is added and the mixture is stirred for ten minutes at -20° to -10°C and thεn for anothεr ten minutes at -10° to -0°C. The reaction mixture is diluted with 60 ml of ethyl acetate and then treated with 2 ml of 4N solution of hydrogen chloride in ether. The precipitatε sεparatεd is collected by filtration.

washed with 10 ml of ethyl acetate and 20 ml of methylεne chloride and then suspended in 5 ml of water. The mixture is adjusted to pE 3 and chromatographed on a column of MCI gel, CBP-20P® (Mitsubishi-Kasei, Japan) . The column is developed first with water and then with aqueous aceto¬ nitrile and fractions containing the object compound are combined and concentrated and the residue is lyophiiized to give the title compound.

The produce obtained showed identical IR ^' -, NMR- spectra, RF-value in TLC and rεtεntion time in BPLC with those of the product obtained in Example 29. Example 32

73-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2 (Z)-methoxy- iminoaceta ido]-3-[ (imidazo[1,2-b]pyridazinium-1-yl)methyl]- 3-cephεm-4-carboxylat .

32-1) By the procedurε of Examplε 31 but using dimethyl- acεta idε instεad of the dimethyIformamide, the title compound is obtained and identified with it by means of physico-chemical measurements.

32-2) By the procedurε of Examplε 31 but using triethyl- a inε instead of the tributylamine, the title compound is obtained.