IE904047A1 - Novel cephalosporin compounds and processes for preparation¹thereof - Google Patents

Description

Field of the Invention The present invention relates to novel cephalosporin compounds, pharmaceutically acceptable non-toxic salts thereof, and physiologically hydrolyzable esters, hydrates and solvates thereof, which possess potent and broad antibacterial activities. The invention also relates to processes for preparing the saae, and to pharnaceutical coapositions containing the saae as active ingredients.

BactoQund-Qi-ihe...lpyefltiQn Antibiotics of cephalosporin series are widely used in therapy for treatment of diseases which are caused by general pathogenic bacteria in huaan beings and animals. It has been known that such antibiotics are useful for the treatment of diseases caused by bacteria exhibiting the resistance to other antibiotics, e.g. penicillinresistant bacteria, and for treatment of penicillin-sensitive patients.

In most circumstances it is desirable to employ antibiotics showing broad antibacterial activities against both Gram-positive and - 2 Gran-negative bacteria. In this regard, there have been aade aany studies in developing a variety of cephalosporin antibiotics vith broad-spectrua antibiotic activities.

For exaaple, in GB patent No. 1,399,086 there are disclosed aany cephalosporin derivatives which are shovn by the foraula vherein R is hydrogen or an organic group ; R* is an etherifying aonovalent organic group linked to the oxygen atoa through a carbon atoa ; B is -S- or -» 0 ; and P is an organic group.

After the invention of these coapounds, there were aany atteapts to develop antibiotic coapounds having aore iaproved properties, to certain bacteria especially to Gras-negative bacteria.

GB patent No. 1,522,140 discloses cephalosporin antibiotic coapounds of the foraula(B) vhich exist as syn isoaers, or as a aixture of syn and anti isoaers vherein the syn isoaers are present in at least 30%, R’” (B) wherein R' is a furyl or thienyl group ; R is a Cx.4 alkyl, C3~7 cycloalkyl, furylmethyl or thienylmethyl group ; and R' is hydrogen or a carbanoyl, carboxyoethyl, sulfonyl or methyl group.

The foregoing cephalosporin compounds have high antibacterial activities against a range of Gram-positive and Gram-negative bacteria, and particularly high stability to β -lactamases produced by various Graa-negative bacteria. Moreover, they are very stable ia um.

Recently, there have been efforts to prepare new antibiotics having an improved and broadened antibiotic spectrum while showing potent antibiotic activities, especially against Gram-negative bacteria.

Consequently a large number of cephalosporin antibiotics with analogous structures, to those above, have been developed.

As a part of said efforts, an acylamido group has been introduced - 4 into the 7-position of the cephea nucleus as shown in the foregoing formula(B) and certain groups have been introduced into the 3-position thereof.

For example, in BE patent No. 852,427 there are reported a nuaber of cephalosporin coapounds having antibiotic activities which are shown by the foregoing foraula(A) wherein the R is substituted with various organic groups including 2-aainothiazol, the oxygen aton of the oxyiaino group is directly bonded to an aliphatic hydrocarbon group, which aliphatic hydrocarbon group aay itself be substituted with a carboxy group. The substituent in 3-position of such coapounds is an acetoxymethyl, hydroxymethyl, formyl group, or an optionally substituted hetero cyclic thioaethyl group.

Also, in US patent No. 4,390,534 to Psutomu Terachi et al, there are reported new cephem compounds of the formula wherein Bl is aaino or a protected aaino group ; R2 is hydrogen, acyl, substituted or unsubstituted aryl, substituted alkyl, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, cycloalkenyl, or a 0- or S-containing 5-aembered hetero cyclic group ; R3 is hydrogen or alkyl ; R4 is an acyloxyalkyl, acylthioalkyl, substituted or unsubstituted pyridiniuaalkyl, substituted or unsubstituted heterocyclic thioalkyl, alkyl, hydroxy, or a substituted or unsubstitued thiazoliuaalkyl group, or halogen ; Ra is carboxy or a protected carboxy group, wherein Re is COO' when R4 is a substituted or unsubstituted pyridiniuoalkyl group or a substituted or unsubstituted thiazoliuaalkyl group ; and the dotted line ------ represents a single bond or a double bond.

Vhile the P of the aforesaid GB patent No. 1,399,086 or the R4 of the aforesaid OS patent No. 4,390,534 are defined very broadly as an organic group or a substituted or unsubstituted heterocyclic thioalkyl group, respectively, there is not therein mentioned the heart of the present invention, that is a compound having a (l-substituted-4,6diaainopyrimidiniua-2-yl)thiomethyi group introduced into 3-position of the cephea nucleus.

Also. European patent application No. 62,321 discloses cephem compounds of the foraula(D) and pharmaceutically acceptable salts thereof, and their intermediates of the foraula(D') (0) vherein R1 is aaino or a protected aaino group ; R2 is a substituted or unsubstituted lower aliphatic hydrocarbon group, or a cycloalkenyl group ; and - > is a substituted or unsubstituted heterocyclic cation group containing one or aore nitrogen atoas ; wherein R1 and R2 are the saae as defined in the foroula(D), respectively ; R4 is a protected carboxyl group ; and X~ is an acid residue.

In European patent application MO. 74,563, the cephea coapounds of the foraula(E) and their salts are proposed as antibiotic coapounds (E) wherein R1 is aaino or a protected anino group ; R’ is a protected or unprotected lower aliphatic hydrocarbon group, cyclo(lower)alkyl, or cyclo(lower)alkenyl group ; Ra is (lower)alkylaaino, N-protected(lower)alkylaaino, di(lower) alkylaaino, sulfo(lower)alkylaaino, hydroxy(lower)alkylaaino, N-protected hydroxy(lower)alkylaaino, acyloxy(lower)alkyl, (lower)alkoxy(lower)alkoxy(lower)alkyl, di(lower)alkylaaino (lower)alkyl, (lower)alkylthio(lower)alkyl, (lower)alkylthio, (lower)alkoxy(lower)alkoxy, (lower)alkoxy, hydroxy(lower)alkoxy, acyl(lower)alkyl, hydroxy(lower)alkylthio, di(lower)alkylaaino (lower)alkylthio, N-containing unsaturated 5-aeabered heterocyclic group, N-containing unsaturated 5-aeabered heterocyclic thio group, or N-containing unsaturated 5- or 6-aembered heterocyclic (lower)alkyl group which aay be optionally substituted with suitable substituent(s) ; and R4 is hydrogen or a (lower)alkyl group. f IE 904047 There are disclosed cephea conpounds of the foraula(F) and their salts in European patent application Ho.47,977 wherein n is an integer of 0 or 1 ; Aa is aaino or a substituted aaino group ; T is a thiadiazoly aoiety, where one carbon atoa is bonded to Ai and the other carbon atoa is bonded to the group of -C(=N-O-Ra)- ; Ra is hydrogen, a substituted or unsubstituted carbaaoyl group, a cycloalkyl group, or a substituted or unsubstituted carbaaoyl group ; and R1 is a substituted or unsubstituted thiazoliua group, a substituted or unsubstituted pyrazoliua group, a tri(lower)alkyl aaaoniua group or a pyridiniun group of the following foraula R* /=|=\ ροΛ-^R» [wherein.

R“ is (lower)alkyl [which is substituted with a substituent selected from the group consisting of cycloalkyl, methyl, hydroxy, alkoxy, halogen, cyano, carbamoyl, carboxyl and sulfonyl J, (lower)alkenyl or carboxy-substituted (lower)alkenyl, (lower)alkylthio or carboxysubstituted (lower)alkylthio, aaino or mono-substituted aaino (wherein the substituent is selected from the group consisting of (lower) alkyl, (lower)alkanoyl or aminobenzenesulfonyl], di(lower)alkylanino, carbamoyl [which is substituted by (1 over)alkyl, hydroxy(lower)alkyl, (lower)alkoxy, hydroxy or cyano), di(lower)alkylcarbaaoyl, thiocarbanoyl, cycloalkyl, phenyl, hydroxy, (lower)alkoxy, halogen, (lower)alkoxycarbonyl, (lower)alkanoyloxy, (lower)alkanoyl, carboxy, sulfocyano, nitro, or a hydroxysulfo(lower)alkyl group ; Rb is hydrogen, a carbamoyl group, or a group selected from the groups defined for Ra ; and R° is hydrogen or a group selected from the groups as defined in the R“.] As described above, there are a variety of cephea coapounds whose 7positions are substituted by a substituted aainothiadia2ole ring. However, there are no reports about the aost iaportant characteristic of the present invention that is a (l-substituted-4,6-diaainopyrimidiniua-2-yl)thiomethyi group introduced into the 3-position of the cephea nucleus.

SUiaary of the Invention An objective of the present invention is to provide new antibiotic cephalosporin coapounds of the foraula(l), pharaaceutically acceptable non-toxic salts thereof, and aetabolically labile esters and solvates thereof wherein Rl is a Ci-4 alkyl (preferably aethyl or ethyl), C3-4 alkenyl (preferably allyl), Ca-4 alkynyl (preferably propargyl) group, or -C(R*)(Rh)COaH, wherein R* and R”, saae or different, are a hydrogen atoa or a C1-4 alkyl group, or R* and Rb fora a C3.7 cycloalkyl group with the carbon atoa to which they are linked ; .

R is a alkyl (preferably a straight alkyl group such as methyl, ethyl, n-propyl or n-butyl), C^_4 alkenyl (preferably allyl), cycloalkyl, amino or C^_4 alkyl-substituted amino or a phenyl group, cr 2-4- or 6substituted phenyl group with two or less substituents chosen from C^-4 alkyl, alkoxy, halogen and hydroxy (preferably phenyl, 4-hydroxyphenyl, 4-chlorophenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl or 2, 6dimethyoxyphenyl); R’ is hydrogen or a C»-4 alkyl group(preferably methyl or ethyl) ; and Q is N or CH.

Another objective of the present invention is to provide processes for preparing the cephalosporin compounds of formula(I).

A further objective of the present invention is to provide pharmaceutical compositions comprising one or more of the cephalosporin compounds of formula(I ) as active ingredients.

Detailed Description of the Invention The new cephalosporin compounds of the present invention are either io syn isomers or mixtures of syn and anti isomers which contain at least 90% of the sim isoaer and not sore than 10% of the anti isoaer. Also, when the Rl group of formulae I ) compounds is -C(R*)(Rb)COaH. wherein R· and Rb are different the carbon atom to which R· and Rb are linked becomes an asymmetrical center, these compounds being diastereoisomers. ί’ therefore, the present invention also includes such diastereoisomers of cephalosporin compounds of formula (I ), and mixtures thereof.

Also, the solvates including hydrates of the compounds( I ) are included within the scope of the invention. In addition, the compounds ( IE 904047 - 12 of the foraula( I) according to the present invention aay exist in tautoaeric foros and such tautoaers are also included within the scope of the invention.

Naaely, when the Q of the foraula (I ) is a carbon atoa. the aainothiazolyl group undergoes tautoaerisa to fora a iainothiazolinyl group, its tautoaer, as follows : When the Q of the foraula (I ) is a nitrogen atoa. the aainothiadiazolyl group foras iainothiadiazolinyl groups, its tautoaers by tautoaerisa as follows : The coapounds of the foraula ( I ) also include the following resonance structures ( I ') and ( I ’') : (I') (Γ) Suitable pharmaceutically acceptable salts of the object coapounds(I) are conventional non-toxic salts and aay include an inorganic salt, for exaaple, a aetal salt such as an alkali aetal salt(e.g., sodiua salt, potassiua salt, etc.) and an alkaline earth metal salt(e.g., calcium salt, magnesium salt, etc.), ammonium salt, etc.; an organic salt, for example, an organic amine salt(e.g., trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, fi.N'-dibenzylethylene-diamine salt, N-methylglucaaine salt, diethanolamine salt, triethanolamine salt, tris(hydroxyaethylamino) methane salt, phenylethylbenzylamine salt ; dibenzylethylenediamine salt, etc.) etc. ; organic carboxylic or sulfonic acid salt(e.g., formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate etc.); an inorganic acid salt(e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.) ; a salt - 14 with a basic or acidic amino acid(e.g., arginine, aspartic acid, glutamic acid, lysine, etc.) and the like.

The physiologically hydrolyzable esters of the compounds (I) may include, for example, indanyl, phthalidyl, methoxyaethyl, pivaloyloxymethyl, glycyloxynethyl, phenylglycyloxyaethyl or 5-methyl-2-oxo-l,3-dioxolan-4-yl esters, and other physiologically hydrolyzable esters which have been widely used in the technical fields of penicillin and cephalosporin antibiotics. These esters can be prepared in accordance with known methods.

The cephalosporin coapounds of the formulae I) exhibit high antibacterial activities against both Gram-positive and Gram - negative bacteria, and are especially useful in the therapheutic and prophylactic treatment of bacterial infections in human beings and animals.

The present invention also includes within its scope pharmaceutical compositions comprising one or more of the compounds(I) according to the present invention as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives.

The antibiotic coapounds( I ) of the invention may be formulated for administration, which may be presented in unit dose form or in multidose containers. The compositions may take various forms such as solutions, suspensions or emulsions in oily or aqueous vehicles, which can contain conventional additives such as dispersing agents, suspending agents, - 15 stabilizing agents, and the like. Alternatively, the active ingredient ay be foraed into a dried powder that can be normally dissolved in an aqueous solution of sterile, pyrogen-free water, before use. The coipounds(I) iay be also formulated into suppositories containing conventional suppository bases such as cocoa butter or other glycerides.

The pharaaceutical compositions in unit dose fora, preferably coiprise about froa 50 to l,500ag of the active ingredient, depending on the age and body weight of the patient, the nature and the severity of the illness, and so on. In general it has proved advantageous to administer the active coapounds in an aaount of about 500 to 5,000 mg per day in order to achieve the desired results, depending on the routes and frequency of administration. In case of intramuscular or intravenous administrations for adult human treatment, the dose of about 150 to 3,000 ig per day is thought sufficient, but it may be increased in case of treatment for specific infections caused by some strains.

If desired, the compounds( I ) can be administered in combination with other antibiotics such as penicillins or other cephalosporins.

The compounds of the present invention as described above, exhibit potent and broad antibacterial activities against Gram-positive bacteria and a variety of Gram-negative bacteria as well, particulary against Pseudomonas. Also, these compounds have high stability to /?-lactaaases - 16 produced by a nuaber of Graa-negative bcteria.

Examples of especially preferred coapoundsf I) are the coapounds( I -1) and (I -15) of the foraulai I) wherein Rl is -C(CHS)»CO«H, R3 is aethyl or aaino, R9 is hydrogen, and Q is CH, and their pharaaceutically acceptable non-toxic salts. These cnapnimdsf T -I) and ( T —15) possess excellent antibacterial activities, especially against Pseudomonas.

Further exaaples of preferred coapounds( I ) of the present invention are as follows : Rl R* R’ Q -C(CH,),CO«H -CHa B CB -C(CBa)aCOafl -CHaCBa H CB -C(CHs)aCO,H -NHa B CH -C(CH,)«COaH -CHa -CH, CH -CH(CHa)CO«B -CBa H CH -CH(CH,)CO,H -CBaCBa B CH -CH(CH3)CO,B -CHaCHaCHs H CH -C(CHa)CO«fl -NHa H CH -CHaCaCH -CBa H CH -CHaCaCB •CHaCHa H CH -CH,C«CH -NHa H CH -CB.CHa -NHa B CH -CBaCHa -CH, H N -CHaCHa -NBa H N -CHaCOaH -CHa fl CH -CHaCOaB -CHaCBa B CH The cephalosporin coapounds( I), pharmaceutically acceptable non-toxic salts thereof, or physiologically hydrolyzable esters or solvatesiincluding hydrates) thereof aay be prepared by reacting the coapounds of the formula (II) with the coapounds of the foraula(ni) in the presence of a solvent, and then, if necessary, removing the aaino protecting group and/or the carboxyl protecting group and/or reducing the S-oxide Ithat is, S-*(0)n] by a known method, before or after said reaction. This process also constitutes a further aspect of the invention.

Vherein Rx, R*. R3 and Q are the saae as defined above ; a is an integer of 0 or I ; * IE 904047 R* is hydrogen or an aaino protecting group ; R® is a Ci-4 alkyl, C3-4 alkenyl or C«.< alkynyl group, or -C(R“)(Rb)C0t(R°), wherein R· and Rb, saae or different, are a hydrogen atoa or a Ci-4 alkyl group, or R* and Rb aay fora a C3-7 cycioalkyl group with the carbon atoa to which they are linked ; and R° is hydrogen or a carboxyl protecting group ; R® is a hydrogen atoa or a carboxyl protecting group ; and L is a leaving group.

The aaino protecting group aay include acyl, substituted or unsubstituted aryi(lowerJaikyi(e.g. benzyl, diphenyiaetnyi, tnpnenyiaethyi and 4-aethoxybenzyl), halo(lower)alkyl(e.g. trichloroaethyl and trichloroethyl), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted araikylidene or substituted cyclolidene. The acyl group as an aaino protecting group aay include, for exaaple, Ci~e (lower) alkanoyl (e.g. forayl and acetyl), Ca.e alkoxycarbonyl(e.g. aethoxycarbonyl and ethoxycarbonyl), (lower)alkanesulfonyl (e.g. aethanesulfonyl and ethanesulfonyl), or aryl(lower)alkoxycarbonyl(e.g. benzyloxycarbonyl), where the acyl group can be substituted by 1~3 substituent(s) such as halogen, hydroxy, cyano or nitro. In addition, the aaino protecting /J • IE 904047 group may include reaction products obtained from amino groups and silane, boron or phosphorus compounds. c 5 6 The carboxyl protecting group as R of R or R may include for example, (lower)alkylesters (eg. methylester and tbutylester), (lower )alkenylesters (eg. vinylester and allylester), (lower)alkoxy (lower)alkylesters (eg. methoxymethylester), (lower) alkyl thio (lower) alkylesters (eg. methy lthiomethy lester), halo (lewer)alkylesters (eg. 2,2,2trichloroethylester), substituted or unsubstituted aralkytesters (eg. benzylester and p-nitrobenzylester) or silytesters, which can be selected after consideration of the chemical property of the desired ccmpounds (I).

It is desired that the aforementioned amino or carboxyl protecting groups may be readily removed under mild reaction conditions by a known method.

The leaving group L may include, for example, halogen such as chlorine or fluorine, a (lower)alkanoyloxy group such as acetoxy, a (lewer)alkanesulfonyloxy group such as methanesulfonyloxy, an arenesulfonyloxy group such as ptoluenesulfonyloxy, an alkoxycarbonyloxy group and the like.

The term lewer as used hereinabove and elsewhere in this application, for example in reference to lewer alkyl”, encempasses groups having 1 to 6 carbon atoms, eg. 1 to 4 carbon atoms.

The starting materials of the compounds (II) are known as intermediates conventially employed for the preparation of • IE 904047 cephalosporin compounds. The dotted line of the formula! II) represents a single bond or a double bond, and therefore, the compounds of the formula(II) may be the compounds of the formula(II-a), or compounds of the formula (Π-b), or mixtures thereof : (Π-a) (Π-b) wherein n, R*. R®, R®, Q and L are the saae as defined above.

The compounds of the foraula(H) can be prepared by activating the coapounds of the foraula(IV) or their salts with an acylating agent. and reacting with the coapounds of the foraula(V), as follows : / \ ,OR5 N“pC-C-CO2H(Na) R-νηΛ Λ Ο (IV) (Ο)π ♦ Acylation wherein n, R*, Re, R®, Q and L are the saae as defined above ; and the dotted line of the foraula(V) presents a single bond or a double bond, so that the coapounds of the foraula(V) aay be the coapounds of the foraula(V-a), or coapounds of the foraula(V-b), or aixtures thereof n (V-a) (V-b) wherein n, Re and L are the saae as defined above.

In the preparation of the objective compounds! I ), the compounds of the foraula! II) are used preferably in an aaount of froa 1 to 2 equivalent(s) based on 1 equivalent of the coapounds of the foraula(III).

Aaino or acid protecting groups can be readily reaoved by a conventional deprotection aethods which are well known in the field of cephalosporin antibiotics. For exaaple, acid- or basehydrolysis or reduction are generally applicable. For further exaaple. when the protecting group is an aaido group, it is feasible to subject such compounds to iaino-halogenation and iainoetherification, and then, follow by hydrolysis. Acid hydrolysis is preferable applicable to removal of such groups as tri(di)phenylmethyl or alkoxycarbonyl, and is carried out in the presence of an organic acid such as formic acid, trifluoroacetic acid, or p-tolueneacetic acid or an inorganic acid such as hydrochloric acid or the like.

The reaction for introducing the coapounds(HI) into the 3-position of compounds!II) to prepare compounds! I ) is carried out in the presence of a solvent such as water, or a mixed aqueous solvent of water and a water-miscible solvent.In the reaction, the pH of the solvent should range from 5 to 8, but preferably from 6 to 7.5.

An appropriate water-miscible solvent is acetonitrile or acetone.

Also, the reaction may be carried out at 40 * to 100*C, preferably - 24 60 ’ to 80*C.

To stabilize reaction products and tbeir interaediates, one or more salts selected froa the group consisting of sodiua iodide, potassiua iodide, sodiua broaide, potassiua broaide and potassiua thiocyanate can be used as stabilizing agents.

On the other hand, the separation and purification of the compounds! I ) can be carried out using a known Method such as recrystallization, coluan chroaatography over silica gel or ion-exchange chroaatography.

The cephalosporin coapounds! I ) of the present invention, and their non-toxic salts, preferably alkali metal salts, alkaline earth aetal salts, inorganic acid salts or aaino acid salts, show potent antibacterial activities against a variety of general pathogenic bacteria including Graa-negative and Graa-positive bacteria, therefore, they are especially useful in therapy for treataent of bacterial infections in human beings and aniaals.

In order to illustrate the usefulness of the invented conpour.ds. the minimal inhibitory concentrations(KIC) thereof against standard strains and against clinically isolated-strains, were deterained and coapared with Ceftazidiae. a known compound.

Also, the in vitro antibacterial activity was deterained by a twoIE 904047 fold dilution aethod as described below : That is, the two-fold serial dilutions of the compound were made and dispersed in Muller-Hinton agar medium. 2 pi of standard test strain which had the 107 CFU per mfi was inoculated on the medium, and was incubated at 37’C for 20 hours. The results of the MIC tests are shown in Table 1.

The results of the XIC tests against clinically separated-strains are shown in Table 2.

Specific examples of the compounds of formula! I ) provided by this invention are 3hown below : I- 1 : 7-((Z)-2-(2-aeinothiazol-4-y1)-2-(2-carboxylprop-2-oxyiaino)acetaeido ] 3-( 4, S-diaaino-1 -methyl pyr iaidiniua-2-yl)thiomethyl-3-cephem-4^carboxy late .· \ Fy I- 2 : 7-((Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxylprop-2-oxyiaino)acetaBinol3-(4,6-diaaino-l-ethylpyriaidiniua-2-yl)thioaethyl-3-cephea-4-carboxylate I - 3 : 3-(l-allyl-4,6-diaainopyriaidiniua-2-yl)thioaethyl-7-[(Z)-2-{2-aainothiazol4-yl)-2-(2-carboxyprop-2-oxyiHino)acetanido]-3-cephea-4-carboxylate I - 4 : 7-UZ)-2-(2-aai.oothiazol-4-yl)-2-(l-carboxyeth-l-oxyiaino)acetanido]-3(4,5-diaoino-l-aethy'lpyriaidiniiia-2-yl)thioaethyl-3-cephea-4-carboxylate I- 5 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(l-carboxyeth-l-oxyiHino)acetaaido]-3(4,8-diaeino-l-ethylpyriiidiniu>-2-yl)thioaethyl-3-cepheB-4-carboxylate I- 6 : 3-(l-allyl-4,6-diaainopyriaidiniua-2-yl)thioBethyl-7-[(Z)-2-(2-aainothiazol4-yl)-2-(l-carboxyeth-I-oxyiaino)acetaaido)-3-cephea-4-carboxylate I- 7 : 7-[(Z)-2-(2-aainothiazoi-4-yl)-2-(carboxyaethoxyiaino)acetaaido]-3-(4,6diaaino-1-sethylpyriaidiniua-2-yl)thioaethyl-3-cephes-4-carboxyI ate & IE 904047 I - 8 : 7-(iZ}-2-(2-aainothiazoi-4-yl)-2-(carboxyBethoxyiaino)acetanido]-3-(4,ediaiino-I-ethylpyriBidiniun-2-yl)thioBethyl-3~cephes-4-carboxylate I- 9 : 3-(l-allyl-4,6-diaDinopyriBidiniun-2-yl)thioaethyl-7-((Z)-2-aiiinothiazol4-y1)-2-{carboxynethoxyiaino)acetaaidoj-3-cepheB-4-carboxylate NH, λ.Λ N NH.

I CH-CHCH, I - 10 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(aethoxyiaino)acetaaido]-3-(4,6diaaino-1-aethy1pyriaidiniua-2-y1)thioaethyl-3-cephea-4-carboxylate I - 11 : 7-[(Z)-2-(2-aBinothiazol-4-yl)-2-(ethoxyiaino)acetaaido]-3-(4,6diaaino-l-aethylpyriBidiniua-2-yl)thioBethyl-3-cepheB-4-carboxylate I - 12 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(ethoxyiaino)acetaaido)-3-(4,6diaaino-l-ethylpyriaidiniufl-2-yl)thioaethyl-3-cephea-4-carboxylate I - 13 : 7-[(Z)-2-(5-aaino-l,2,4-thiadiazol-3-yl)-2~(2-carboxyprop-2-oxyiaino) acetaaido1-3-(1,4,6-triaiinop}Tiaidiniufl-2-yl)tbioaethyl-3-cepheB-4carboxylate 1-14 : 7-{(Z)-2-(2-aainothiazol-4-yl)-2-(l-carboxyeth-l-oxyiaino)acetaaidol3-(l,4,6-tria«inopyriaidiniua-2-yl)thioiethyl-3-cephei-4-carboxylate I - 15 : 7-((Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop-2-oxyi»ino)acetaaido)3-(l,4,8-triaainopyriaidiniua-2-yl)tbioaethyl-3-cepheH-4-carboxylate I - 15 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(ethoxyiaino)acetaaido]-3-(l,4,6triaainopyrlaidiniua-2-yl)thioaetbyl-3-cephea-4-carboxy late I - 17 : 7-[(Z)-2-(5-aaino-l,2,4-thiadiazol-3-yl)-2-(ethoxyiiino)acetanidoJ3-(1,4,8-triaainopyriaidiniua-2-y1)thioaethy1-3-cephea-4-carboxylate NHj ι NHj NH2 I - 18 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-propyn-l-oxyinino)acetaaido!3-(1,4,6-triaainopyriaidiniua-2-yi)thioaethyl-3-cephea-4-carboxylate I - IS : 7-((Z)-2-(2-aainothiazol-4-yl)-2-(Dethoxyiaino)acetaaido]-3-(l,4.6triaainopyriaidiniua-2-y1)thioaethy1-3-cephea-4-carboxylate I - 20 : 7-{(Z)-2-(5-aaino-l,2,4-thiadiazol-3-yl)-2-(ethoxyiaino)acetaaido]3-(4,8-diaaino-l-aethylpyriaidiniua-2-yl)thioaethyl-3-cephea-4-carboxylate sj NHj tf I CHj NHj I - 21 : 7-[(Z)-2-(5-aaino-l,2.4-thiadiazol-3-yl)-2-(ethoxyiaino)acetaaido]3-(4,8-diaaino-l-ethylpyriaidiniua-2-yl)thioaethyl-3-cephea-4-carboxylate I - 22 : 7-{(Z)-2-(5-aoino-l,2,4-thiadiazol-3-yl)-2-(ethoxyiaino)acetaaidoJ3-(4,6-diaaino-l-propylpyriaidiniua-2-yl) thioaethyl-3-cephea-4-carboxylate - 33 I - 23 : 3-(l-allyl-4,e-diaainopyriaidiniua-2-yl)-7-((2)-2-(5-aaino-1,2,4thiadiazol-3-yl)-2-(ethoxyiaino)acetaaidoI-3-cephea-4-carboxylate I - 24 : 7-((Z)-2-(5-aaino-l,2,4-tbiadiazol-3-yl)-2-(aethoxyiaino)acetaaidol3-(4,6-diaaino-l-aethylpyriaidiniua-2-yl)thioaethyl-3-cephea-4-carboxylate I - 25 : 7-[(Z)-2-(5-aaino-l,2,4-thiadiazol-3-yl)-2-(aethoxyiainci)acetaaidoj3-(4,6-diaaino-l-ethylpyriaidiniua-2-yl)thioaethyl-3-cephea-4-carboxylate I - 26 : 7-[(Z)-2-(5-aaino-l,2.4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyaino)acetanido]3-(4,6-diaeino-l-iethylpyriiidiniua-2-yl)thioaethyl-3-cephen-4-carboxylate I - 27 : 7-((Z)-2-(5-aaino-l,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyiaino)acetaHidoJ3-(4.6-diaaino-l-ethylpyriaidiniua-2-yl)thioaethyl-3-cephea-4-carboxylate I - 28 : 7-l(Z)-2-(5-aaino-l.2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyiBino)acetaaido]3-(4,6-diaiino-l-propylpyrimidiniua-2-yl)thioaethyl-3-cephea-4-c3rboxylate I - 29 : 7-[(Z)-2-(5-aaino-l,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyiaino)acetaaido]3-(l-butyl-4,e-diaainopyriaidiniuB-2-yl)thioaethyl-3-cephea-4-carboxyIate I - 30 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop-2-oxyiaino)acetaBido]-3-(4,ediaaino-l,5-diaethylpyriaidiniua-2-yl)tbioaethyl-3-cepheB-4-carboxylate I - 31 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop’2-oxyiaino)acetanido]-3-(4,6diaaino-5-ethyl-l-oethylpyriBidiniua-2-yl)thiOBethyi-3-cephea-4-carboxyIate I - 32 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop-2-oxyiaino)acetaiidoJ-3-(4,6diaaino-l-ethyl-5-«ethylpyriaidiniua-2-yl)thioaethyl-3-cephei-4-carboxylate 1-33 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop-2-oxyiflino)acetaaido]-3-{4,6diaaino-1.5-diethylpyriaidiniua-2-yl)thionethyl-3-cepbea-4-carboxylate 1-34 : 7-[(Z)-2-(2-aainotbiazol-4-yl)-2-(2-C3rboxyprop-2-oxyiaino)acetaninoJ-3-(5ethyl-l,4,6-trianinopyriBidiniua-2-yl)thioBethyl-3-cephea-4-carboxylate I - 35 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop-2-oxyiaino)acetaaidoJ-3-(4,6diaaino-t-phenylpyriaidiniua-2-yl)thioaethyl-3-cephea-4-carboxylate I - 36 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop-2-oxyiaino)acetaaido]-3-[l-(4hydroxyphenyl)-4,6-diaainopyriaidiniua-2-yl)-thioaethyl-3-cephea-4-carboxylate OH I - 37 ; 7-[(Z)-2-(2-aainothiazol-4-yi)-2-(carboxyaethoxyiaino)acetanidoi-3(4,5-dianino-l-phenylpyriaidiniua-2-yl)thioaethyI-3-cephea-4-carboxylate I - 38 : 7-((Z)-2-(2-aainothiazol-4-yl)-2-(l-carboxyeth-l-oxyiBino)acetaaido]3-(4,6-diaaino-l-phenylpyriaidiniua-2-yl)thioeethyl-3-cephea-4-carboxylate I - 39 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(ethoxyiaino)acetaaidoJ-3-(4,6diaaino-l-phenylpyriaidiniua-2-yl)thioaethyl-3-cephea-4-carboxylate I - 40 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(ethoxyiaino)acetaaido]-3-[l-(4chlorophenyl)-4,6-diaainopyriaidiniua-2-ylIthioaethyl-3-cephea-4-carboxylate I - 41 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop-2-oxyiaino)acetaaido]-3-[4,6diaaino-l-(2,4-diaethylphenyl)-pyriaidiniua-2-ylJthioaethyl-3-cephea-4-carboxylate I - 42 : 7-((Z)-2-(2-aainothiazol-4-yl)-2-(ethoxyiaino)acetaaido]-3-(4,6-diaaino1-(2,4-diaethylphenyD-pyriaidiniufl-2-yl]-thioaethyl-3-cephea-4-carboxylate I - 43 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxjTrop-2-oxyiaino)acetaaidol-3-(4,8-dianincl-(2,6-diaethoxyphenyI)-pyriaidiniua-2-yl]thioaethyl-3-cephen-4-carboxylate (· - 40 I - 44 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop-2-oxyiaino)acetaaido]-3-{4,6diaaino-l-{4-chlorophenyI)-pyriaidiniua-2-yllthioaethyl-3-cephea-4-carboxylate I - 45 : 7-[(Z)-2-{2-aainothiazol-4-yl)-2-(l-carboxyeth-l-oxyiaino)acetaaido]-3[4,6-dianino-l-propylpyriaidiniua-2-yl]thiomethyl-3-cephea-4-carboxylate I - 46 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-propyn-l-oxyiaino)acetaaido]-3-(4,6diamino-l-nethylpyrinidiniua-2-yl)thioaethyl-3-cephea-4-carboxylate • IE 904047 - 41 I - 47 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-propyn-l-oxyiaino)acetaaido]-3(4,6-diaBino-l-ethylpyriaidiniUfl-2-yl)thioaethyl-3-cephea-4-carboxylate I- 48 : 7-[(Z)-2-(2-aainothiazol-4-yi)-2-(2-carboxyprop-2-oxyiaino)acetanidoI3-(l-cyclopropyl-4,8-diaainopyriaidiniua-2-yl)-3-cephea-4-carboxylate I - 49 : 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propen-l-oxyiBino)acetaaido3-3(4,6-diaaino'l-aethylpyriaidiniua-2-yl)'3-cephea-4-carboxylate - 42 I - 50 : 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-propen-l-oxyiaino)acetaaidol3-(4,e-diaaino-l-ethylpyriaidiniua-2-yl)-3-cephea-4-carboxylate Coaparative coapound : Ceftazidine L+7> η r pvivp 'aysufjTiny-rT τηrp>i m ¢0 *4 / \ (ροηιίΓγπιτη f ττρμτι m co by LyAa G TfOTiirjiinA) 1 aiqci m O >1 m <ο ΠΉηιίΓρισ.η •u ^4 Table 2 : Antibacterial Activity against Clinically isolated-^.

Conpound Strains(No. tested) HICtacs/mB)' Range 50% 30 % I -1 Escherichia coli (38) 0.016-0.25 0.0G3 0.13 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.003-0.25 0.063 0.13 aethicillin susceptible(42) Staphylococcus aureus 2—4 2 2 aethicillin resistant. (7) 32— > 128 >128 >128 Pseudoaonas aeruginosa(54) 0.13—64 1 4 I -2 Escherichia coli (38) 0.016-0.25 0.063 0.13 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.031 — 0.25 0.13 0.13 aethicillin susceptible(42) Staphylococcus aureus 1-4 2 2 aethlclllln resistant, (7) 32->120 >128 >128 Pseudoaonas aeruginosa(54) 0.13-64 2 4 I -4 Escherichia coli(38) =0.008-0.25 0.031 0.063 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.031-0.13 0.031 0.13 aethicillin susceptible(42) Staphylococcus aureus 2-4 4 4 ί aethici 11 in resistant!7) >32 >32 \ 0? * v L Pseudoaonas aeruginosa(54) 1— > 128 4 16 I -5 Escherichia coli(38) <=0.008-0.5 0.063 0.13 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.063-0.25 0.063 0.25 I aethicillin susceptible(42) Stapnyiococcus aureus 2-3 4 I 4 1 j aethicillin resistant(7) 64- >123 >128 >123 Pseudoaonas aeruginosa(54) 0.25-648! I -7 Escherichia coli(38) 0.003--0.016 0.016 0.063 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.916-0.063 0.015 C.331 aethicillin susceptible(42) Staphylococcus aureus C-l! 4 4 aethicillin resistant(7) >32 >32 \ O A ' 0 L . Pseudoaonas aeruginosa(54) 0.5' 12S 4 ' 1 ’P ! lu 1 I -H Escherichia coli (33) -0.008 - 0.25 0.0:1 J ( η j 1 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.916 0.063 0.031 1 1 I 0.063 1 aethicillin susceptible(42) Staphylococcus aureus 9.5 44! . J t j 1 aethicillin resistant(7) 4 >123 >128 ' >120, Pseudoaonas aeruginosa(54) 0.25-64 , 1 i I 1 < t 1 1 * Broth eicrodilution test >w H-1 Table Zicantinued) Compound Strains(No. tested) HIC(ncg/mH)~ Range 50% 90% I -19 Escherichia coli(38) 0.016^0.25 0.003 0.13 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.031^0.25 0.13 0.13 aethicillin susceptible(42) Staphylococcus aureus 2'-8 2 4 aethicillin resistant (7) 32—>123 >128 >128 Pseudoaonas a eruginosa (54} 0.25—32 2 8 I -16 Escherichia coli(38) 0.031—0.5 0.13 0.25 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.063—0.25 0.13 0.13 aetbicillin susceptible(42) Staphylococcus aureus 0.25—0.5 0.23 0.25 aethicillin resistant(7) 3~ >32 >32 >32 Pseudoaonas aeruginosa(54) 0.5— 6-4 4 .6 I -17 Escherichia coli(38) 0.063— 1 0.13 0.25 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.13—0.25 0.25 0.25 aethicillin suscept;ble(42) St.ipbylnrnrcus aureus 0.5—1 0.5 1 aethicillin resistant (7) 2--128 10 64 Pseudoaonas aervginosa(54) 0.5- 128 4 8 I -18 Escherichia coli(38) 0.931-1 0.13 ! 0.25 Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.13 0.13 0.13 1 aethicillin susceptible(42) Staphylococcus aureus 0.13— C. 25 0.25 0.25 » ( aethicillin resistant (7) 3~ > 123 j 123 ! >128 ' 1 Pseudoaonas aeruginosa(ai) 0.5~ 16 j3! I -20 Escherichia coli(38) 0.316—0.5 ! 0.063 | 0.25 | Klebsiella pneuaoniae(lO) Staphylococcus aureus 0.063— 0.25 0.13 i 0.12 aethicillin susceptible(12) Staphylococcus aureus 0.25—0.5 t 0.5 0.3 ; aethicillin resistant(7) ; 1—128 16 32 ! ι Pseudoaonas heruginosafSI) 1-64 j ;ej 1 -30 Escherichia coli (38) 0.021 — 0.5 , ., t 0.23 ’ Klebsiella pneuacniae(lO) Staphylococcus aureus 0.063^0.25 0.13 ' I 0.23 1 1 aethici 11 in susceptible!42) Staphylococcus aureus 2--8 1 0 I < ! Ί aethicillin resistant(7) 32-^ > 123 >123 J \ ’ Q ί ’ I Pseudoaonas aeruginosa(54) C. 12—32 Λ ' u 14 I <\'ote> * Broth aicradilution test by Table 2(continued) Compound Strains(No. tested) MIC(ac3/m£)“ Range 50% 30% I -45 Escherichia coli(33) 0.031-0.25 0.13 0.12 I Klebsiella pneumoniae(10) Staphylococcus aureus 0.063-0.25 0.13 0.12 methicillin susceptible(42) Staphylococcus aureus 2-4 2 2 . ^eetbici.ll ’o.regiatoBffV 6.^128 \ 1ιδι I -46 Escherichia coli(38) 0.012-0.5 0.12 0.25 ! Klebsiella pneumoniae(10) Staphylococcus aureus 0.062- 0.25 0.13 0.12 J 1 i methicillin susceptible(42) Staphylococcus aureus 0.12— I 0.25 0.25 I methicillin resistant(7) 4—>32 >32 V « ! VC v Pseudomonas aeruginosa(54) 0.5— 32 4 j 1 3 I I -47 Escherichia coli(38) 0.010—0.3 0.063 0.25 ' Klebsiella pneumoniae(lO) Staphylococcus aureus 0.063-0.25 0.25 0.25 methicillin susceptible(42) Staphylococcus aureus 0.12-0.25 0.25 0.25 methicillin resistant(7) 4- 123 64 64 I Pse9:doior.2S (51' i 0.5-16 Ceftazidiae Escherichia coli(38) 0.003- j 1 0.13 ! 0.13 Klebsiella pneumoniae (10) Staphylococcus aureus 0.062— 0.5 0.302 : 1 η ’ oethicillin suscept:ble(431 Staphylococcus aureus 2- 1631 1 aethici11 in resistant(7) 54—> 12S j 12S; >128 Pseudomonas aeruginosa (541 0.5—’.23 4 ' 1 in * Broth aicrodilution test In-vivo absorbency of the invented compounds! I) was studied in SD rat(S) weighing 220~340g, as follows : The test compound was intravenously administered in a dose of 20ag/kg respectively to 2~5 rats. The blood samples from the femoral vein of the rats were taken every hour after administration, and analyzed by bio-assay(agar well method). The results were shown in Table 3. -«3 o •ή a .3 σ> UJ 1 ►— 135 — ί C3 r— CO UO to CM © : l.C ! uo , 1 ί CM CO CO< i CO | , I” uo CM «—< • j co ! ro CM ro CO co r- uo co cc rf co ΓΟ • • J *— r~ ' ro ί rz co 1 uo co CD CM C5 r— UO co CM • • ί ” i r~ i CM ro CM UO UO _ ro IO OC iO t—- uO «Ο CM —— • — 1 ro CO UO r_- UO CD __ r— CO 1 o CM cC IO co r- — >——* o ΓΟ CO © © xr σ- t- r* CO •r o cc uo CM σ> CM 2 cn CQ ro CO © . uo co uo oo •v co CM © CO 1 jt wr o r~- UO CM • • CM o co CM *r OO IO uo t— Γ— CM © CO *r CO CO CM *”' CO co CO ΓΌ Ci IO — Ci CM OO uo **T CM • • OO «Μ ““ UO 1 *r CM CD CO ro r* CD CO o c— CM © ro •r CM CM •r ro m CO * co •r CO ··* • • • • c— CM ol— «Μ UO ro CM co uo CO IO co CM «*4 • • CM • r— © M , IO UO σ> r* eo 1 UO «»«·« © co CM r* ·»< *“* 2 £ •r-4 UO © o © © © CM 50 UO CM IO CM co *“* ** W O ··* • g CO 1— o s ? o c c o LJ R 2 rt cu TS — ΓΜ U? to o CM ro uo CC CM CM ro Γ'- , UO CM O —r CM ro ί CM CM ro CM CO uo r? CM CM CC — CM ro co uo co co CM CM 00 to β uo ro r~ ro CM 00 — 0 -r = 0 i-5 | ro co ·—· uo CM O UO CM co j CM ί ' uo ro 00 ro CM 0 CO CM cc CO CM —p uo co O co CM CM to O uo CM —r WX CM uo UO CO r- uo CO ro ro CM *r CM CO uo uo CM w>~4 •X ·“* CM CM ro ro CM OO to ro 00 CM •H «X CM c a • FK 0 « => K «< — (0 CM λ CM —“* a Ό e — 0 Oy *=i *0 9 fr— 1- a. O **** & 1 (Λ 0 1 X 0 O 1 L> v *-» rt 0 &> — 1 c U —1 0 rt ω j -c c 1 M T3 Cl. ««χ (X.

CO CO cm CM •3 oc ro QC O (O M CD SJ?~ 0 c a. cm rt 0 »· Ό ζ-> 0J » a> p U5 w S O CJ fr- CD I— z\ • - « IE 904047 The present invention is described in detail by the following Preparations and Exaaples : Preparation 1 : Preparation of 4,8-diaBina-l-aethyl-2(lH)-pyTiaidinethione Sodiua aetal (I.63) wac added to dried ethyl Alcohol (lOOmi). and refluxed for an hour. After N-aethylthiourea (9g) and aalononitrile (6.8g) were added thereto, the reaction aixture was refluxed for 24 hours.

The reaction aixture was cooled to rooa teaperature and neutralized with cone. hydrochloric acid. The precipitates were filtered, washed with water (20m£) and ethyl alcohol (50m2) and dried in vacuo to give the above-indicated coapound (8.lgj in pale yellow solid. b.p, : 185’C'-(decoap.) NMR : δ (DiO + acetone-de) 3.80(s, 3H), 5.39(s, IH).

MS(£11 : 156(H*}, 126 IRiKCi, cr') : 3441, 3335(N-H), 1682(C=N), 1095(C=S) Preparation 2 : Preparation of 4,8-diaaino-l-ethyl-2(lH)-pyriiaidinethione Sodiua aetal (4.6g) was added to dried ethyl alcohol (lOOmfi), and refluxed for an hour. After N-ethyI thiourea (10.4g) and malononitrile (6.6g) were added thereto, the obtained reaction mixture was refluxed for 48 hours. The reaction mixture was cooled to room temperature and neutralized with cone, hydrochloric acid. The precipitates were filtered, washed with ethyl alcohol (50mfl), and the filtrate was concentrated under reduced pressure. The residue was chromatographed over silica gel to give the above-indicated compound (8.2g) in yellow solid. b.p, : 197*C > (decoap.) SHE : (DiO + acetone-de) 1.32(t, 3fl), 4.81(q, 2fl), 5.08(s, lfl) Oi : 17O(M*), 142 IKiKCI, πΓι) : 3480, 3200(N-S), 1665(C=N), 1130(C=S) Preparation 3 : Preparation of 4,8-diaaino-l-propyl-2(lH)-pyriaidinethione Sodium aetal (4.8g) was added to dried ethyl alcohol (100,ni), and refluxed for an hour. After N-propylthiourea (11.8g) and aalononitrile (8.6g) were added thereto, the reaction mixture was refluxed for 72 hours, cooled to room teaperature, and neutralized with cone, hydrochloric acid. The precipitates were filtered, washed with ethyl alcohol (50tai), and the filtrate was concentrated under reduced pressure. The residue was chroaatographed over silica gel to give the above-indicated coepound (5.7g) in yellowish brown solid. i.p, : 195’C~ (decoap.) NMR : (D«0 + acetone-de) 0.96(t, 3H), 1.81(a, 2H). 4.51(t, 2H), 5.46(s, IH) US (El) : 184(M·). 142 IR(KC1, cm-1) : 3310, 3200{N-3), 1634(C=N), U50(C=S) Preparation 4 : Preparation of l-butyl-4,0-diaaino-2(IH)-pyriaidinethione Sodiua aetal (4.8g) was added to dried ethyl alcohol (ΙΟΟπί), and refluxed for an hour. After N-butylthiourea (13.2g) and aalononitrile (6.8g) were added thereto, the reaction aixture was refluxed for 72 hours, cooled to rooa teaperature and neutralized with cone, hydrochloric acid.

The precipitates were filtered, washed with ethyl alcohol (50ra£), and the filtrate was concentrated under reduced pressure. The residue was chroaatographed over silica gel to give the above-indicated coapound (4.6g) in brown solid. a.P. : 195’C~ (decoap.) NMR : δ (DzO + acetone-da) 0.88(t, 3H), 1.36(10. 2H), l.B9(m, 211), 4.59(t, 2H), 5.41(s, IH) HS(EI) : 198 MCI, ,CHL21 : 3320, 3200(N-H), 1640(C=N), lllO(OS) Preparation 5 : Preparation of l-allyl-4,6-diamino-2(lH)-pyrimidinethione Sodium netal (4,fig) was added to dried ethyl alcohol (lOOmi), and refluxed for an hour. After N-allylthiourea (ll.Sg) and malononitrile (6.6g) were added thereto, the reaction mixture was refluxed for 72 hours, cooled to room temperature and neutralized with cone. hydrochloric acid. The precipitates were filtered, washed with ethyl alcohol (50mi), and the filtrate was concentrated under reduced pressure. The residue was chromatographed over silica gel to give the above-indicated compound (6.2g) in yellowish brown solid.

BUG : 133°O (decomp. 1 NMR. : <5 (CD3OD) .42(s, IH), 5.16-- 6.11 (π, 5H) MS (El) : 182CC) , 142 Ift(KCl, enr1) : 3310, 3260(0), 1645(C=N), 1012(C=S) Preparation 6 : Preparation of l,4,6~trianiino-2(lH)-pyrimidinethione Sodium metal (4.6g) was added to dried ethyl alcohol (lOOntfl), and refluxed by heating for an hour. After aalononitrile (6.6g) and thioseroicarbazide(9.lg) were added thereto, the reaction mixture was refluxed for 24 hours, cooled to room temperature. The precipitates were filtered, washed with ethyl alcohol (50mfi), and dried under reduced pressure to give the above-indicated compound (8.3g) in white solid. m.p,, : 225’C^ (deconp.) NMR : δ (DsO + acetone-de) .42(s, IH) MS (El) : 157(M”), 126 IR(KC1, cm-1) : 3440, 3420CN-NHJ, 3310, 3250M), 1645(C=N), 1138(C=S) Preparation 7 : Preparation of 4,5-diamino-1,5-dinethy1-2(IH)pyrimidinethione To (±)-2-bronopropionic acid (81.08g) was added water (70m£).

Sodium carbonate (28.32g) was added slowly over an hour and dissolved ( IE 904047 - 59 therein. A solution of potassium cyanide(37.77g) dissolved in water (75rafi) was added and heated to about 50C. Accordingly as the reaction progressed, the temperature of the reaction solution rose to 90’C, The reaction solution was stirred at 90 — 100‘C for an hour, cooled to room temperature, and neutralized with cone. hydrochloric acid (60mfi). Afterwards, the thus neutralized solution was concentrated under reduced pressure, ethyl alcohol(300mi) was added to the concentrated solution. The ethanolic solution was concentrated under reduced pressure again. To the residue was added ethyl alcohol (700m£), followed by filtration. After cone. sulfuric acid(15mfi) was added to the filtrate, the solution was refluxed for 5 hours and distilled to remove about 300mi of ethylalcohol. The solution was concentrated under reduced pressure, and residue was added to sodium carbonate saturated solution (2D0jnil).

After extraction with ether(400mfi), the separated organic layer was washed with a 10% saline solution (SOOmfi) and a saturated saline solution (200m£). and dried over anhydrous magnesium sulfate, filtered and then concentrated. The residue was distilled under reduced pressure to give the colorless above-indicated compound(44.74g) midi : 70 % b.p. : 87-90’C/12 torr - 60 SHR : ί (CDCU) 1.33(t, 3H). 1.60(4. 3H), 3.55(q, IH), 4.28(q, 2H).

L—-toaratipn of (±J_-2-c.vanopropionamide To ethyl (±)-2-cyanopropionate (44.74g) was added cone, aqueous ammonia solution (200m£), The reaction mixture was stirred at room temperature for an hour and concentrated under reduced pressure. After addition of ethyl alcohol (200mfl), the ethanolic solution was concentrated again. The residue was dried in a vacuum oven to give the green above-indicated compound (33.00g).

Yield : 96% W ; ί (DMSO-de) 1.40{d, 3H), 3.74(q, IH). 7.39(bs, IH), 7.82(bs, IB).

C_Preparation of l-aethyljaalQnonltr.ile (±)-2-Cyanopropionamide (33.00g), and phosphorus pentachloride (2S,07g) ground minutely in a mortar were added to a flask equipped with a distillation apparatus. While producing a vacuum using a water pump, the mixture was stirred at SO -IOO’C for 20 minutes to remove hydrogen chloride gas and phosphorus oxychloride, and distilled under reduced pressure in a bath heated to 180Ό to give the above-indicated - 61 compound (15.C7g). This compound was solidified to a white solid state at room temperature.

Yield : 58% b.p, : 86~89°C/12torr nmr ·. 1.63(d, 3H), 4.76(q. Ifl) L- -Preparation of 4.Miamino-l,5-diiBeth.yl-2(lH)-pyriiaidinethione After sodium metal (9.01g) was dissolved in dried ethyl alcohol (ISOmfi) under nitrogen stream, R-raethylthiourea(17.67g) was added thereto and refluxed for an hour. 2-MethyImalononitrile (17.67g) was added to the solution and then refluxed for 15 hours. The reaction mixture was cooled to 40“C and filtered. The filtered solid was washed with cold ethyl alcohol (lOOmfi) and dried to give the pale yellow above-indicated compound(25.20g). in, P,. : 23CTC(decoap.) Held. : 76% TLC : Rf 0.2(MeOH/CHzClz = 1/5) NMR : 2 (DMSO-de) 1.6(5. IH), 3.60(8, 3H), 4.92(bs, 4H) HS(EI) : 170(M*), 156 « IE 904047 - 62 IJUKCL cm’1) : 3480, 3360(N-H), 1623(C=N), 1090(C=S) Preparation 8 : Preparation of 4,6-diamino~l-ethyl-5-nethyl-2(lH)pyriaidinethione After Sodium metal (2.30g) was dissolved in dried ethyl alcohol (50m£), N-ethylthiourea (5.20g) was added and refluxed for an hour. 2-Methylmalononitrile (4.0g) was added to the solution and then refluxed for 15 hours. The reaction mixture was cooled to room temperature, neutralized with cone, hydrochloric acid, and filtered. After water (20mfi) was added to the filtered solid, the mixture was stirred for 10 minutes, and filtered. The filtered solid was dried to give the pale yellow above-indicated compound(3.57g). m.p, : 281’C '-(decomp.) Yield : 39% : δ (DHSO-do) 1.15(t, 3H), 1.75(s, 3H), 4.57(bs. 2H), 0.24(bs, 2fi), 8.08(bs. 2H) MS (cl) : I84(M‘), 156 1R(KC1, era'1) : 3413. 3300(N-H), 1620(C=N), 1105(C=S) - 63 Preparation 9 : Preparation of 5-methyl-l,4,6-triamino-2(lH)pyrimidinethione After sodium metal (2.30g) was dissolved in dried ethyl alcohol (50mfi), thiosemicarbazide (4.55g) was added thereto and refluxed for an hour. 2-Methylmalononitrile (4.0g) was added to the mixture and then refluxed for 15 hours. The reaction mixture was cooled to 40’C, and filtered, washed with ethyl alcohol(50mi), and dried to give the pale yellow above-indicated compound(3.78g). b.p. : 215’C- (decomp.) Yield : 44% ϋϋΚ : <5 (DMSO-de) 1.68(s, 3H) , 3.48(bs, 2H), 5.20(bs. 2K), 5.95(bs, 2H), HS(cI) : 171 (M*), 156 IRCKCI, CT'1) : 3470, 3340(N-H), 1622(C=N), 1060(C=S) Preparation 10 : Preparation of 4,6-diaraino-5-ethy1-1-aethyl-2(111)pyrimidinethione A. Preparation of methyl (±)-2-cyanQbaixrflte To (±)-2-bromobutyric acid(167.Olg) was added water (150m£).

Vi - 64 Sodiua carbonate (54.05g) was added slowly over an hour and dissolved therein. A solution of potassiua cyanide (88.55g) dissolved in water (150tnC) was added, and heated to about 50*C. Accordingly as the reaction progressed, the temperature of the reaction solution rose to 80’C. The reaction solution was stirred at 80—90*C for an hour, coaled to room temperature, and neutralized with cone. hydrochloric acid (120mC). Afterwards, the thus neutralized solution was concentrated under reduced pressure, and ethyl alcohol (SQGmC) was added to the residue. The obtained ethanolic solution was concentrated under reduced pressure again. To the residue was added ethyl alcohol(700nu£), followed by filtration. After cone, sulfuric acid (3δΐί? was added to the filtrate, the solution was refluxed for 5 hours and distilled to remove about 300mfi of ethyl alcohol. The solution was concentrated under reduced prrssure, and the residue was added to sodiua carbonate saturated solution(l00mi}. After extraction with ether (δΟΟιπύ), the separated organic layer was washed with a 10% saline solution (όΟΟιηί) and a saturated saline solution(300mu), dried over anhydrous magnesium sulfate, filtered and then concentrated. The residue solution was distilled under reduced pressure to give the colorless above-indicated compound(49.90g). - 65 Yield : 35% b.p, : 93—36’C/12torr OR : a) 1.14(t, 3H>, 1.34(t, 3ΗΪ, 2.01(a, 2H), 3.47(t, 1H), 4.28(q, 2H) L_Preparation of (±)-2-cyanobutyrnalde.

To ethyl (±)-2-cyanobutyrate (43.sag) was added ethyl alcohol (40m£). After cone, aqueous ammonia solution(200m£) was added thereto over 10 minutes, the solution was stirred at 30~40°C for 30 minutes.

Ether(500m£) was added to the solution and stirred for 10 Minutes.

The precipitates were filtered, and dried to give the colorless aboveindicated compound(31.30g).

Yield : 81% SHR : <5 (DMS0-de) 0.98(t, 3H), 1.83(10, 2Π), 3.Q3(t, IH), 7.43(bs, IH), 7.76(bs, IH) L... Preparation of 2-ethylmaiononitrile (±)-2-Cyanobutyraoide (31.96g), and phosphorus pentachloride (23.85g) ground in a mortar were added to a flask equipped with a distillation apparatus. Vhile producing a vaccina using a water punp, the mixture was stirred at 90—100’C for 20 minutes to remove hydrogen co - 66 chloride gas and phosphorus oxychloride, and distilled under reduced pressure in a bath heated to 180*C to give the above-indicated compound (I9.45g).

YieU : 73% : δ (DMSO-de) 1.2G(t, 3H), 2.10(m, 2H>, 3.73(t, IH) IL_Preparation of 4.6-diaminQ-5Teth.yl-l-methyl-2(in)-p.yriiiiidinethione After sodium metal (2.30g) was dissolved in dried ethyl alcohol (50m2), X-fsetbyithiourea(4.50g) was added thereto and refluxed for an hour. 2-Ethylmalononitrile (4.70g) was added to the solution and then refluxed for 18 hours. The reaction mixture was cooled to 40*C, neutralized with cone, hydrochloric acid, and filtered. To the filtered solid was added water(50m£). The mixture was stirred for 10 minutes, filtered, and dried to give the white above-indicated compound (4.15g). ffl.p., : 259°C'-' (decoap.) field : 45% NMR : S (DMSO-d«j) 0.92(t, 3H), 2.34(q, 2H), 3.S2(s. 3H), 6.78(bs, 2H), 7.06(bs. 2B) MS(El) : 184 (?T), 169, 156 IE 904047 ” _ - 67 IRCKCR-Crr1) : 3410, 3280(N-H), 1645(C=N), 1086(C=S) Preparation 11 : Preparation of 4,6-dianino-1.5-diethyl-2(lH)·* pyrinidinethione After sodium aetal (2.30g) was dissolved in dried ethyl alcohol (50m2), N-ethylthiourea (5.2Cg) was added thereto and refluxed for an hour. 2-Ethylaalononitrile (4.70g) was added to the reflux mixture and then refluxed for 18 hours. The reaction aixture was cooled to 40°C, and the pH adjusted to 5 with a 28* solution of hydrogen chloride dissolved j.rj isopropyl alcohol. The reaction mixture was filtered, io and then water(50n£) was added to the filtered solid. After the solution was stirred for 10 minutes and filtered again, the residue was dried to give the pale yellow above-indicated compound(2.79gj. a.p. : 269’C'-· (decomp.) LLjlU : 28% N,MR : δ (DHSQ-dJ 0.91{t, 3!0, i,16(t, 3H),2.28(q, 2H), 4.57(bs, 2H), 8.45(bs, 2H), 6.70(bs, 2H) MSfgl) : 138(Π, 170 TR(ΖΓi ii : 3380, 332D(N~B), i646(C=N), 1101(0=3) - 68 Preparation 12 : Preparation of 4,6-diaaino-l-phenyl-2(lH)pyrimidinethione Sodium metal (6.6g) was added to dried ethyl alcohol(lOOmi), and refluxed for an hour. After N-pbenylthiourea (9g) and aalononitrile (6.6g) were added thereto, the reaction mixture was refluxed for 72 hours. The reaction mixture was cooled to room temperature and neutralized with cone, hydrochloric acid. The precipitates were filtered, washed with water(20tn£) and ethyl alcohol (50mi), and dried in vacuo to give the above-indicated compound (4.7g) in a pale yellow color. m.p, : 28ΓΟ -(decomp.) NHR : J (acetone-de! .48(s, IH), 5.30(bs, 2H). 6.52(bs, 2H), 6.30—7.70(π. 5H) MS(El) : 218(8·) IR(KC1· cm'1) : 3484, 3400(N-H), 1630(C-N), 1182(C=S) Preparation 13 : Preparation of 1-(4-chloropheny1)-4,6-diamino-2(IH)pyrimidinethione N-(4-Chlorophenyl)-thiourea (Ilg) and aalononitrile (6,6g) were .. J W - 69 reacted in the saae aethod as described in Preparation 12 to give the above-indicated conpound (5.3g). a.p., : 275*C-(decomp.) JiKE. : δ (DMSO-de) .31(s, 1H). 6.38(bs, 2H), 6.87(bs, 2H>, 7.18(d, 2H), 7.55(d, 1H) MU : 252 Or) IJUKC1, or1) : 3460, 3400(N-H), 1630(C=N), 1095(C=S) Preparation 14 ; Preparation of 4,6-diaraino-l-(2,4-diaethylphenyl)-2(lH) pyriaidinethione N-(2,4-Diaethylphenyl)-thiourea (10.8g) and malononitriie (6.6g) were reacted in the same aethod as described in Preparation 12 to give the above-indicated compound (5.7g). : 212*C-(decoap.) : δ (acetone-dQ) 2.08(3, 3H). 2.30(s, 3H), 5.58(s, 1H), 5.91(bs, 2H), 6.80-7.20 (a, 5R) Mil : 246(.r) : 3440» 3300(N-H), 1632(C=N), 1090(C=S) - 70 Preparation 15 : Preparation of 4,8-diaoino-l-(2,6-dinethoxyphenyi)2(lH)-pyriaidinethione N-(2,6-Dimethoxyphenyl)-thiourea (11.5g) and aalononitrile (6.fig) were reacted in the sane aethod as described in Preparation 12 to give the above-indicated compound (6.2g). m.p, ; 207’C- (decomp.) NMR : δ (acetone-do) 3.84(s, 811), 5.44(s, IH). 5.83(bs, 2H), 8.48(bs, 2H), 6.40-7.01 (a. 3H) MS(EI) : 278(M*) IRiKCl, cm'1) ; 3438, 3310(N-H), 1631 (C=N), 1O43 Preparation 16 : Preparation of 4,6-diaaino-l-(4-hydroxyphenyl)-2(lH)pyrimidinethione N-(4-hydroxyphenyi)-thiourea (3.3g) and aalononitrile (6.fig) were reacted in the same method as described in Preparation 12 to give the above-indicated compound (4.1g). m.p. : 282’C— H2UK. : δ (DHSO-do) - 71 5.30(s, IH), 6.19(bs, 2H), 8.78(bs, 2H), 8.84(s, 4H), 9.78(bs, IH) ίϋί£1ϊ · 234 (M*) IRiKCK-cm) t 3480, 3470(N-H), 1640(C=N), 1038(C=S) Preparation 17 : Preparation of l-cyclopropyl-4,6-diaaino-2 (111)pyriaidinethione N-cyclopropylthiourea (6.2g) and aalononitrile(6.6g) were reacted in the same method as described in Preparation 12 to give the pale yellow above-indicated compound(3.7g). a.P- : 242’C^ (decoop.) SHK : (DHSO-de) 0.88^1.52(a, 4H), 2.80'-3.16(m, IH), 5.48(s, IH) mi : 182 m ISiKCl, ca'1) : 1580(C=N), 1015(C=S) Preparation 18 : Preparation of 3-acethoxyaethyl-7-[(Z)-2-(2aainothiazol-4-yl)-2-(fflethoxyiaino)acetaoido]-3cephea-4-carboxylic acid - 72 A. Preparation of ethyl (Z)-2-(inethoxyifflino)-2-[2-(triphenylfflethyl) -aainothiazoI-4-ylIacetate To ethyl (Z)-2-(hydroxyinino)-2-{2-(triphenyioethyl)aainothiazol4-ylJacetate(46g) were added iodo methane(28.4g), potassiua carbonate (27.6g) and dimethylsulfoxide(500mfi), and the mixture was stirred for hours at room temperature. After ethyl ether(2fi) was added to the reaction mixture, the mixture was washed 5 times with distilled water(500mfi). The separated organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated.

The residue was chromatographed over silica gel to give the aboveindicated compound (35.2g) as a pale yellow solid.

B. Preparation of (Z)-2-(methoxyimino)-2-[2-(triphenylmethyl) aminothiazol-4-yllacetic acid After the compound(23.6g) prepared in (A) was dissolved in a mixed solvent of ethyl alcohol(lOOmi) and tetrahydrofuran(50mfi), aqueous 5N-sodiura hydroxide solution (20mfi) was added thereto. The reaction mixture was stirred for 2 hours and neutralized with 5N-hydrochrolic acid (20mfi). After the organic solvent was removed under reduced pressure, ethj'l acetate (lfi) was added to the residue, and then the reaction mixture was washed twice with distilled water(500mfi). - 73 The separated organic layer was dehydrated, and concentrated to give the above-indicated compound(20.7g) as a white solid.

C. Preparation of 3-acetoxymethyi-7-[(Z)-2-(2-aainothiazol-4-yl)-2(raethoxyiniino)ace.ta!iiidol-3-cePheiit-4-carbQj:ylic acidThe compound(4.4g) prepared in (B) was dissolved in S,N-dinethyl acetanide(30m2). To the solution were added triethylamine (3.5m£) and mesityiene sulfonyl chloride(2.3g) at Q°C, and stirred for 20 minutes.

After adding 7-atninocephalosporanic acid (2.9g), the reaction mixture was stirred again for 2 hours. To the mixture was added ethyl acetate (300m£), and it was washed with 1%-hydrochloric acid (10Om£), sodium chloride solutionilOCmi) ana distilled water(200ιω). The separated organic layer was dehydrated, and concentrated. Formic acid (40mi) was added to the residue. After the solution was stirred for 2 hours at room temperature, the precipitates were filtered off.

The filtrate was concentrated under reduced pressure, triturated with ethyl ether(lOOmfi). The solid was filtered, washed, and dried to give the above-indicated compound(4.17g) as a pale yellow solid. : δ (Da0 + NaHCO3) 2.08(s, 3H), 3.52(ABq, 2H), 3.99(s, 3H), 4.41(ABq, 2fl), 5.23 (d, IH), 5.84(d, 1»), 7.01(3, IH) - 74 Preparation 19 : Preparation of 3-acetoxymethyi-7-{(Z)-2-(2-aminothiazol 4-yl)-2-(ethoxyioino)acetamido J-3-cephei»-4-carboxylic acid A. Preparation of ethyl (Z)-2-(ethoxyioino)-2-[2-(triphenyltnethyl) an inothi azo1-4-yl1acetate To ethyl (Z)-2-(hydroxyiaino)-2-(2-(triphenylmethyDaainothiazol4-yljacetate(46g) were added broaoethane(21.8g), potassium carbonate (27.6g) and dlmethyXsulfoxide(500m£), and the solution was stirred for 7 hours at room temperature. After ethyl ether (2jS ) was added thereto, the mixture was washed 5 times with distilled water (500nu?).

The separated organic layer was dehydrated, and concentrated to give the above-indicated compound(41.4g) as a pale yellow solid.

B. Preparation of (Z)-2-(ethoxyimino)-2-[2-(triphenylsiethyl) qiiiinothiazgl-4.-ylIacetic,-a£.id The compound (24,3g) prepared in (A) was dissolved in a nixed solvent of ethyl alcohol(lOOmi) and tetrahydrofuran (50nu2). After aqueous 5N-sodiura hydroxide solution(20m£) was added thereto, the reaction mixture was stirred for 2 hours at room tenperature. The reaction mixture was neutralized with 5N-hydrochloric acid, and the - 75 organic solvent was removed under reduced pressure. To the residue was added ethyl acetate(15), and it was washed twice with distilled water(SOOmfi). The separated organic layer was dehydrated, and concentrated to give the above-indicated compound(19.8g) in white solid.

C. Preparation of 3-acetoxymethyi-7-[ (Z)-2-(2-aminothiazol-4-yl)2-(e,thoxyiniinQ)acetamido 1-3-cephea-j-carboxyIic acid (Z)-2-(ethoxyimino)-2-(2-(triphenylmethyl)aminothiazol-4-yll acetic acid (4.6g) was reacted in the sane method as described in (C) of Preparation 18 to give the above-indicated compound!3.98g) in white solid.

NMR : δ (Dz0 + NaHCO3) 1.31(t, 3H), 2.02(s, 3H), 3.57(ABq, 2H), 4.07(q, 23), 4.52(ABq, ZH), .20(d, IH), 5.81(d, IH). 7.00(s, IH) -J B IE 904047 - 76 Preparation 20 : Preparation of 3-acetoxymethyj~7-{(Z)-2-(2-aminothiazol4-yl)-2-(2-carboxyprop-2-oxyiBino)acetajBido)-3-cephear4carboxylic acid dihydrochloride A. Preparation of ethyl (Z)-2-(2-tert-butoxycarbonylprop-2-oxyimino) -2-(2-(triphenylmethyl )aiPinQthiazo.l-4-yl (acetate . ......,..

To ethyl (Z)-2-(hydroxyimino)-2-(2-(triphenyloethyl)aninothiazoi-4yl]acetate(46g) were added potassium carbonate(27.6g), tert-butyl-2-bromo2-nethylpropionate(24,lg) and dimethylsulfoxide (3G0mi2), and then the solution was stirred for 6 hours at room temperature. Afterwards, distilled water (100m£) was added therein, the solution was stirred again for an hour. The precipitates were filtered, washed with distilled water(500m£), and dried under reduced pressure to give the above-indicated compound(45.lg) as a white solid.

B. Preparation of (2)-2-(2-tert-butoxycarbonylprop-2-oxyinino)-2-(2(triphenyIraeihyI)3idnPt.hiazoI-4-y.Ilacetic acid.

The compound(30g) prepared in (A) was reacted in the same method as described in (B) of Preparation 19. The resultant solid was recrystalized with methyl alcohol(100m£) to give the above-indicated coapound(21g) as a white solid. tE 904047 - 77 C. Preparation of 3-acetoxymethyi-7-((Z)-2-(2-aninothiazol-4-yl)-2(2-carboxyprop-2-oxyimino)acetaaido-3-cepheo-4-carboxylic acid -ditu'drochloride.

(Z) -2-(2-tert-butoxycarbonylprop-2-oxyinino)-2-{2-(triphenylmethyl) aminothiazol-4-yl)acetic acid (5.7g) was dissolved in N.N-dioethylforaaiside (30m£), Triethylamine (3,5mi) and raesitylenesuifonyl chloride(2.3g) were added thereto at O’C, and the obtained solution was stirred for minutes. After 7-aminocephalosporanic acid (2.9g) was added to the solution, the mixture was further stirred for 2 hours.

To the reaction mixture was added ethyl acetate(300πώ), and it was then washed with 1%-hydrochloric acid (iOOmfi), saline solution (lOOmfi), and distilled water (200mi). The separated organic layer was dehydrated, and concentrated. To the residue were added formic acid (40m£) and cone, hydrochloric acid(3m£) at O’C. After stirring for 2 hours, the solid was filtered off. The filtrate was concentrated under reduced pressure, and triturated with ethyl ether.

The solid was filtered, washed, and dried to give the above-indicated compound (3.8?g) in a yellow solid.

NHR : <$ (Acetone-da) 1.5fl(s, 6H>, 2.05(s, 3H), 3.53(ABq, 2H), 4.38(ABq, 20), 5,12(d. IH). .9S(q, 10), 7.0S(s, IH), 7.32(bs. 2H). - 78 Preparation 21 ; Preparation of 3-3cethoxyraethyl-7-[(Z)-2-(2-aminothiazol 4-yl)-2-(l-carboxyeth-l-oxyinino)acetanidoI-3cepheis4-carboxylic acid A. Preparation of ethyl (Z)-2-(l-tert-butoxycarbonyleth-l-oxyiaino)2-f2-(triPhen.ylfflethyl)aiainothiazoI-4-yllacetate After potassium carbonate (27.6g), tert-butyl-Z-bromopiopyonate (23g) and diQethylsulfoxide(300m£) were added to ethyl (Z)-2{hydroxyiHino)-2-{2-(tripheriylaeth.yl)aoinothiazol-4-yl]acetate(16g), the mixture was stirred for 5 hours at room temperature. Ethyl ether (2 2 ) was added thereto, and the mixture washed 5 times with distilled water(SOOmfi). The separated organic layer was dehydrated, and concentrated to give the above-indicated compound (51g) in a pale yellow solid.

B. Preparation of (Z)-2-(l-carboxyeth-l-oxyiaino’2-[2-(triphenylaethyl) aniinothiazol-4-yilacetk-acid ----———---——— The compound(27.9g) prepared in (A) was dissolved in a mixed solvent of ethyl alcohol(ΙΟΟιηώ) and tetrah.ydrofuran(50i7i^). Afterwards, a 5Nsodiua hydroxide aqueous solution (40m£) was added thereto, and the solution was stirred for 2 hours at room temperature.

The reaction w - 79 mixture was neutralized with 5N-hydrochioric acid (40mfi), and the organic solvent was removed under reduced pressure. To the residue was added ethyl acetate(li), and it was washed twice with distilled water (500mfi). The separated organic layer was dehydrated and dried tu give the above-indicated compound(23.lg) in a pale yellow solid; C. Preparation of 3-acetoxymethy]-7~[(Z)-2-(2-aninothiazol-4-yl)2-(1-carboxyeth-l-oxyimino)acetamido J-3-cephem-4-carboxylie acid. ................- — To a solution of (Z)-2-(1-carboxyeth-l-oxyimino)-2-[2-{tripnenyi methyl)aminothiazol-4-yl]acetic acid(5.6g) dissolved in N,N-dimethyl acetamide(30/n£) were added triethylamine (1.4nifi) and mesityiene sulfonylchloride (2.3g) at -10’C. After stirred for 50 minutes, triethylamine(2.8m£) and 7-aminocephalosporanic acid (2,9g) was added thereto. The reaction mixture was stirred again for 2 hours.

After raising the temperature of the reaction mixture to room temperature, ethyl acetate (50Om£) was added thereto. The reaction mixture was washed twice with 1% hydrochloric acid (200m£), saline solution (200m£) and distilled water (200m£). The separated organic layer was dehydrated, and concentrated. To the residue was added formic acid (50ni£). The solution was stirred for 2 hours, and •gap π _ - 80 the obtained solid was filtered off. The filtrate was concentrated udnder reduced pressure, and powder-solidified by addition of ethyl ether. The solid was filtered, washed, and dried to give the above-indicated compound(3.85g).

: S (D80 + NaHCOs) 1.45(d, 311), 2.07(s, 311), 3.54 2H), 5.24{d, 1H), 5.86(dd, 1H), 7.03(s, 1H) Preparation 22 : Preparation of 3-acetoxymethyi-7-f(Z)-2-(2-aminothiazol 4-yl)-2-{l-carboxymethyoxyimiiio)acetaaidol-3-cephea-4 carboxylic acid A. Preparation of ethyl (Z)-2-(butoxycarbonylmethoxyimino)-2-[2Ctriphenylme thy 1) aniflg.thiflZob.i,-xU acetalsTo ethyl (Z)-2-(hydroxyimino)-2-f2-(triphenylmethyl)aainothiazol-4yl]acetate(46g) were added potassium carbonate(27.6g), tert-butyl-2bromopropicnate(20s) and dimethylsul?oxide(3i)0m£). The reaction mixture was stirred for 5 hours at room temperature, followed b.y addition of ethyl ether (2fi). After the reaction mixture was washed 5 times with distilled water(50Gm£), the separated organic layer was dehydrated and concentrated to give the above-indicated fi IE 904047 - 81 compound(47.2g) in a yellow solid.

B. Preparation of (Z)-2-(carboXymethoxyimino)-2-[2-(triphenyJnethyl) -MiJiothwol-j-jyllflcetate..

The compound(27.2g) prepared in (A) was reacted in the same method as described in (B) of Preparation 21 to give the above-indicated compound (21.3g) in a pale yellow solid.

C. Preparation of 3-acetoxymethyi-7-{ (2)-2-(2-aminothiazol-4-yl) -2- (l-carbo.\yiaet.hoxy-l-oxyiinino)acetaiBido]-3-cephee-4-carboxylic acid. . .

To a solution of (Z)-2-(l-carboxymethoxy-l-oxyimino)-2-(2(triphenyImethyl)aroinothinzol-4-yllacetic acid(5.4g) dissolved in N.N-dimethy1 acetamide(30mi) were added triethylamine(1.4m£) and ncsilyiene su 1 f oily 1 ch 1 or ide (2.3g) at -20’C. After stirring for an hour, t.riethylamjiie(2.8inP) and 7-aminocephalosporanic acid(2.9g) were added thereto. The solution was stirred again for 2 hours.

After slowly raising the temperature of the reaction mixture to room temperature, etliyl acetate (5QfimC) was added thereto. The reaction mixture was washed twice with 1% hydrochloric acid (200m£), saline solution (200m£) and distilled water(200m£). jy - 82 The separated organic layer was dehydrated, and concentrated.

To the residue was added foraic acid <50mfl). The solution was » stirred for 2 hours at rooa teaperature and the foraed solid was filtered off. The filtrate was concentrated under reduced pressure, and then triturated with ethyl ether. The solid was filtered, washed, and dried to give the above-indicated coapound (3.32g) in a yellow solid.

NHK : δ (DaO + NaBCO3) 2.06(s, 311), 3.52(ABq, 2H), 4.73{ABq, 2H), 4.82(s, 2H), 5.21 (d, IH), 5.84(d, IH). 7.07(s, IH) Preparation 23 ; Preparation of 3-acetoxymethyi-7-[(Z)-2-(2aninothiazol-4-yl)-2-(2-propen-l-oxyiaino)acetamido] 3-cephem-4-carbox,vlic acid A. Preparation of ethyl (Z)-2-(2-propen-l-oxyimino)-2-(2(trj pheny he 1 haino tktatp k 4-yllac,£t.at gThe above-indicated coapound(39.lg) was prepared in the saae method as described in (A) of Preparation 19, except that 3broaopropyne(24.2g) was used in place of bronoethane. - 83 0. Preparation of (Z)-2-(2-propen-l-oxyinino)-2-[2-(triphenylmethyl) —afllnpthiazpl-4-yllaggt.lc acidThe compound (24.9g) obtained in (A) was reacted in the same method as described in (8) of Preparation 18 to give the above -indicated compound(21.lg).

C. Prc'paration of 3-acetoxymethyi-7-i(Z)-2-(2-aminothiazol-4yl)-2-(2-propen-l-oxyimino)acetamido]-3-cephem-4-carboxylic 3£ld-- --------(Z)-2-(2-propen-l-oxyimino)-2-[2-(triphenylaethyl)aBinothiazol4-yl)acetic aeid(4.7g) was reacted in the same method as described in (C) of Preparation 18 to give the above-indicated compound (4.05g) in a pale yellow solid. : δ (Da0 + NaHCO.i) 2.07(3. 3H). 3.52(ABq, 2H). 4.81(s, 2H), 4.80(A8q. ZH), .23(d. IH), 5.84(d, IH). 5.15-6,24(m. 3H), 5.99(s, IH) Preparation 24 : Preparation of 3-acetoxymethyi-7-((Z)~2-(2~ aminothiazol-4-yl)-2-(2-propen-l-oxyimino) acetamido]-3-cephein-4-carboxylic acid - 84 A. Preparation of ethyl (Z)-2-(2-propyn-l-oxyimino)-2-(2iiriPhenylaethyl)aminolthiazol-4-ylIacetate The above-indicated compound(30.Tg) was prepared in the same method as described in (A) of Preparation 19, except that 3broaopropyne(14.9g) was used in place of brOBOethane.

B. Preparation of (Z)-2-(2-propyn-l-oxyimino)-2-{2-(triphenylfflethyl) Μ1Ω0 thlflAai - 4^Y.llA££ii£Jil£. id..........—. -——-The compound(24.8g) prepared in (A) was reacted in the same method as described in (B) of Preparation 19 to give the above -indicated compound(21.Ig).

C. Preparation of 3-acetoxymethyl-7-[(Z)-2*(2-aminothiazoI-4-yl)_2-(2-prqpyn-l-o.\yiiaino)ac.etaaido.M-:^phem.-A2£arbavlic acid. „.

(Z)-2-(2-propyn-l-oxyimino)-2-(2-(triphenylmethyl)aminothiazol4-yl)acetic acid (4.7s) was reacted in the same method as described in (C) of Preparation 17 to give the above-indicated compound(3.95g) in a yellow solid.

NHR : δ (ΒϊΟ + SaHCO,) 2.06(5. 3H), 2.96(s, IH), 3.56(ABq, 2H), 4.15(ABq, 2H), 4.84 (s, 2H), S.lKd, lfl). 5.84(d. IH). 7.05(3, IH) - 85 Preparation 25 : Preparation of 3-acetoxymethyir7-[(Z)-2-(5-Mino1.2,4-thiadiazol-4~yl)-2-(2-fflethoxyiuino)acetaaidoJ3-oepheia-4-carboxylic acid A...... Preparation of 2-lhydrQxyiaino)walonQnitril£ To a solution of malononitrile(66.Ig) dissolved in water(5Gm£) and acetic acid(50iafi), was added slowly sodium nitrite(69g) dissolved in water(lOOmfi) at 4’C, and then, stirred for 3 hours at room temperature. The reaction mixture was extracted 3 times with ethj'l acetate(respectively, 500mP. 250m£ and 250mP), dried with anhydrous magnesium sulfate, and concentrated in. vacuo. The residue was triturated with ethyl ether to give the above-indicated compound(32.5,g) in a white solid. Β,,.. Preparation of 2-i To a solution of 2-(hydroxylmino)oalononitrile (95g) dissolved in dimethylsulfoxide (ZOO/nfi) were added potassium carbonate (140g) and diraethylsulfatedZC.lg). The reaction mixture was stirred for an hour at room temperature and ethyl ether (700mfi) was added thereto.

After the mixture was washed 5 times with distilled water (1£ ), the separated organic layer was dehydrated, concentrated, and - 86 then, distilled under reduced pressure to give the above-indicated compound(90g) in a pale yellow liquid. b. p. : 60-65‘C/20torr SB : δ (CDCla) 3.90(5, 3H). c. Preparation of 2-cyano-2-(BethoxyiMino)aceta8idiniun .acetate To a mixed solution of ammonium chloride(14,2g) dissolved in ethanol (SOmi) and cone, ammonium hydroxide aqueous solution (I78mfi) was added 2-(methoxyiniino)aalononitrile(29g) at -5—O'C, and the mixture was stirred for 1C hours at these temperatures. The reaction mixture was extracted 3 times with methylene chloride (respectively, 450m£. l00m£ and 100m£), dehydrated, filtered, and concentrated. The residue was dissolved in ethyl acetate, and crystalized with acetic acid to give the above-indicated compound (20.5g) in pale brown.

N.B : δ (DHSO-de) 1.90(5, 3fi), 1.90(s, 3H). 4.18(s, 3H), 7.88(s, 1H) - 87 D. Preparation of 2-(5-aniino-l,2,4-thi&diazol-3-yl)-2-(raethoxyimino) —-acetonitrile To a solution of 2-cyano-2’-(tnethoxyiisino)acetaaidiniuB acetate (12.5g) dissolved in methanol(lOOmfi) was added triethylamine(23.4m2).

Thereafter, bromine (12.9g) was added slowly in saall portions at -15‘C, and the mixture was stirred for 5 minutes at -15-^-10’C.

Potassium thiocyanate(3.7g) dissolved in methanol(55m£) was then added dropwise to the mixture at temperatures of -10 to -o’C, and the mixture was stirred for 2 hours at O’C. The reaction mixture was poured into ice water (1.2.2), and stirred for 30 minutes.

The precipitates were filtered and dried to give the aboveindicated compound (12.2g) in pale brown. v»ff> , t* a ' itiiik · ο \.*/ιΊ^υύβζ 3.30(s. 3H), 8.37 E. Preparation of 2-{5-amino-l,2,4-thiadiazoi-3-yl)-2-(methoxyimino) acetic acid.

A solution of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino) acetonitri 1e(12.2g) dissolved in 4N- sodium hydroxide aqueous solution (250m£) was stirred for 5 hours at temperatures of 50 to 55'C. The reaction mixture was cooled to room temperature and the pH adjusted to.I - 88 with phosphoric acid, followed by extraction with a 3 : 1 (v/v) mixed solvent of ethyl acetate and tetrahydrofuran. After the separated organic layer was dried, filtered and concentrated the residue was triturated with ethyl ether, and the solid was filtered to give the above-indicated compound (11.2g) in pale brown.

NMR : δ (DMSO-do) 3.31(s, 3H), 8.20(s, 2JI).

F. Preparation of 3-acetoxymethyi-7-[(Z)-2-(5-affiino-l,2,4-thiadiazol3-yl)-2-(2-methoxyimino)acetamido 1 -3-cephe3-j-car.box.vlic acid 2-(5-araino-l,Z.4-thiadiazol-3-yl)-2-{nethoxyijiino)acetic acid (2.0g) was dissolved in dried dioethylacetamide{20/n£), and then cooled to -10*C. TriethyIamine(1.5πώ) and mesityiene sulfonyl chloride(2.3g) was added therein, and the mixture was stirred for an hour at -1O’C. After addition of 7-amino-cephalosporanic acid(3.26g) and triethylamine (3mi). the mixture was stirred for 2 hours at room temperature. Vater (lOOmfi) was added to the reaction mixture. The mixture was adjusted topHl with phosphoric acid, and extracted with a 3 : l(v/v) mixed solvent of ethyl acetate and tetrahydrofuran. The reaction mixture was dried, filtered, and concentrated. The residue was triturated with isopropyl ether, and - 89 the solid was filtered to give the above-indicated compound(3.05g) in a clear brown solid.

SHE .· δ WS0-d„) 2.05(s, 3H). 3.2^3.6(ABq, 2H), 3.95(s, 3H), 4.42~5.45 2H), 5.18(d. IH), 5,80(q, IH), 8.20(s, 2fl).

Preparation 26 : Preparation of 3-acetoxymethyi -7-((2)-2-{5-amino1.2,4,-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyinino) acetamido] -3-cephew~4-carboxylic acid A,_Preparation of 2-fethox.yiiaiDp)jitalononitrile 2-(hydroxyinino)nalononitrxle (95gj and diethyisulfate (230mli) were reacted in the same method as described in (8) of Preparation 25 to give the above-indicated compound (97g), b.p. : 65-67C/l3torr SHE. : δ (UUCk) 1.20(t. 311}, 4.2Q(q, 28} L—-P-reparatino of 2-cyanQ-2--J.ethoxyimino)acetamidiniua acetate 2-(ethoxyimino)nalononitrile (15.3g) was reacted in the sane method as described in (C) of Preparation 25 to give the above-indicated - 90 compound (22.4g).

NHE. : δ (DMSO-d») 1.20(t, 3H). 1.90(3, 3H). 4-10(q, 2H), 7.90(s, 4H).

C. Preparation of 2-(5-anino-l,2,4-thiadiazol-3-yl)-2--(ethoxyiBino) acetonitrile . ....... 2-cyano-2-(ethoxyiroino)acetamidinium acetate (13.lg) was reacted in the same method as described in (D) of Preparation 25 to give the above-indicated compound (12.lg), KIR : δ (DMSO-d») 1.37(1. 3K). 4.50 (q, 2H), 8.37 (s, 2H).

D. Preparation of 2-(5-auino-1,2,4-thiadiazol-3-y1)-2-(ethoxyimino) acetic acid. 2-(5-amir.o-l, 2,4-thiadiazol-3-y I) -2-(ethoxyimi.no) acetonitrile (12.lg) was reacted in the same method as described in (E) of Preparation 25 to give the above-indicated compound (10.8g).

NMR : J (DMSC-do) l,20(t, 3H), 4.20(q, 2H), 8.21(s, 2H). - 91 E. Preparation of 3-acetoxymethyl-7-f(Z)-2-(5-araino-1,2,4-thiadiazol ---3-.vB<-.(2rfthpAnjiino)acPtaniidof-3-cePhea-4-carboxyIlc acid 2-{5-amino-l,2,4~thiadiazoI-3-yI)-2-(ethoxyimino)acetic acid (2.Hg) was reacted in the same aethod as described in (f) of Preparation 25 to give the above-indicated compound (3.3lg), XB : J (DMSO-d*; 1.25(1, 3H), 2,95(s, 3H), 3.40-3.80(ABq, 211), 4.22(q, 211), 4.SO 5.48(q, 1H), 8.2S(s, 2H) Preparation 27 : Preparation of 3-acgtoxymethy1-7-[(Z)-Z-(5-anino1,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyinino) acetzuj!idoJ-3-cepheflH4~cafboxylic acid 1_Preparation of 2-ftgr^-huthoxycarbonylprop-Z-oxiTniinoIsaaiononitrile 2-(hydroxyin:ino)n;alononitrile (S5g) and tert-butyl-2-bromo-2-aethyl propionate (2405) were reacted in the same aethod as described in (B) of Preparation 25 to give the above-indicated compound (178g), b.P. : 115-- 12O’C/1O torr BE : J (COCIa) 1.48(s, 9H), 1.63(s, 6H) - 92 B. Preparation of 2-(tert-butoxycarbonylprop-2-oxyimino)-2-cyanoacetamidinium acetate To ammonium acetate (18.5g) dissolved in methanol (IGOmC) was added 2-(tert-butoxycarbonylprop-2-oxyiraino)malononitrile (19g).

After stirring for 2 hours, the mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated, and water (SUUraXt) was added thereto. The obtained mixture was extracted with ethylacetate (SOOrafl). After the extract was dehydrated, filtered, and concentrated, ethyl ether was added thereto, and the nixture stirred for 30 minutes.

The precipitates were filtered to give the above-indicated compound (15g) in pale yellow. iiffi : δ (DMSO-d0) i.40(s, 9H), 1.60(s, 6H), 1.98(s, 3H), T.38(bs, 3H).

C. Preparation of 2-(5-amino-l,2,4-thiadiazol-3-yl)-2-(tertbntox.vcarbojiy torop-2-oxy imino) acntonitriie2-(tert-butoxycarbonyIprop-Z-oxyiaino)-2-cyanoacetamdinium acetate (24.lg) was reacted in the same method as described in (D) of Preparation 25 to give the above-indicated compound (13,7g). m : δ (DMS0-de5 - 93 1.40(8, 9H), 1.58(3, βΗ), 8.43(5, 2H). 0. Preparation of 2-(5-amino-l,2,4,-thiadiazol-3-yi)-2-(2carboxyprop-2-oxyinino)acetic, acid 2-(5-amino-l,2,4-thiadiazol-3-yl)-2-(2-butoxycarbanylprop2-oxyiaino)acetonitrile (13.7g) was reacted in the sane method as described in (E) of Preparation 25 to give the above-indicated compound (10.lg).

BE. = 6 (DMSO-dJ 1.42(s, 6H), 8.22(3, 2H).

E. Preparation of 3-acetoxym0thyi-7-[(Z)-2~(S-aatino-I,2,4thiadiazol-3-yli-2-(2-carboxyprop-2-oxyimino)acetanido)-3cephea-4-carbox.ylic acid 2-(5-aaino-i,2.4-thiadiazol-3-yi)-2-(2-carboxyprop-2-oxyinino) acetic acid (2.93g) was reacted in the sane method as described in (?) of Preparation 25 to give the above-indicated compound (3.42;) BE. · δ (Dz0 + NaHCOa) 1.58(s, 6H). 2.05(3, 3H), 3.10—3.72 (ABq, 2H). 4.80-4.25 (ABq, 2H), 5.14(d, IH), 5.70(d. IH). u, - 94 Exanple 1 : Synthesis of 7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyiaino) acetamido )-3-(4,6-diamino-l-eethylpyrimidinium-2-yl)thioinethyl -3-cephea-4-carboxylate To a solution of 3-acetoxymethyl-7-((Z)-2-(2-aainothiazol-4-yl)2-nethoxyimino) acetamido)-3-cephem-4-carboxylic acid(500mg) suspended in distilled water(5mfi) were added 4,6-diamino-l-methyl-2(lH)-pyrimidinethione (20Qmg) and potassium iodide(SQQrag). While adjusting the pH of the mixture to 7.1-7.2 with a sodium bicarbonate solution, the reaction mixture was heated to 70’C. After stirred for 4 hours, the mixture was cooled to room temperature. The pH was adjusted to 3'-3.5 with 2N hydrochloric acid, and the precipitates were filtered, washed with distilled water(0m£), and chromatographed over silica gel. Elution with a 5 : 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound(320mg) in a pale white solid. m.p. : 157’CG (decomp.) ϋϋΚ : ί (Dz0 * NaHCOa) 3.54 (5, 3H). 3.01 (ABq, ZH), 3.98 (s, 3H), 5.17 (d, IH), 5.65 (s.

IH), 5.78 (d, IH). 7.03 (s, IH). ΗΛ.-1Ϊ : 552 1765 (3-lactao), 1660, 1630, 1550. - 95 Example 2 : Synthesis of 7-((Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyinino) acetamido 1-3-(4,6-diamino-l-niethyl-pyrimidiniuni-2-yl) thiomethyl -3-cephem-4-carboxylate 3-Acetoxymethyl-7-{(Z)-2-<2-aminothiazol-4-yl)-2-{ethoxyimino) acetainido]-3-cephem-4-carboxylic acid (500mg) was reacted in the same manner as described in Example 1 to give the above-indicated compound (310rag) in a white solid. m.p, : 163’CMdecorap.) NMR : δ (Da0 + NaHCOj 1.09 (t. 3H), 3.48 (s, 3H). 3.56 (ABq, 2H), 4.14 (q, 2H), 5.11 (d, 1H). 5.56 (s, 1H), 5.78 (d. 1H), 6.94 (s. IB). ttS.iEAB, H *. 11. : 566 IRfRBr, cm- 1) : 1760 (-lactam), 1660. 1590.

Example 3 : Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyiraino) acetamido 1-3-(4,6-diamino-l-ethylpyrimidinium-2-yI)thiomethyl -3-cephesi-4-carboxylate To a solution of 3-acetoxyaethyl-7-[(2)-2-(2-aainothiazol-4-yl) 2-(ethoxyiaino)acetamido)-3-cephea-4-carboxylic acid (SOOmg) suspended - 96 in distilled water (5πώ) were added 4,6-diamino-l-ethyl-2(lH)pyrimidinethione (200mg) and potassium iodide (lg). With adjusting pH of the mixture to pH 7.1^7.2 with a sodium bicarbonate solution, the reaction mixture was heated to 70C. After being stirred for 5 hours, the mixture was cooled to room temperature. The pH was adjusted to 3~ 3.5 with 2N hydrochloric acid, and the precipitates were filtered, washed with distilled water (5m£), and chromatographed over silica gel.

Elution with a 5 ; 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound(290mg) in a pale white solid. m,p. : 161Ό (decomp.) NHR : z0 + NaHCO3) 1.31 xm. OH), 3.00 (Aoq, 29), 4.13 cm, 4H), 4.43 (Abq, 29}, 5.19 (d, IH), 5.6G (s, IH). 5.84 (d, IH), 6.92 (s, IH). : 580 IRiKBr. cm-1) : 1763 (-lactam), 1680, 1620, 1560.

Example 4 : Synthesis of 3-(l-allyl-4,6-diaminopyrimidinium-2-y’)thiomethy1-7-((2)-2-(2-aiuinothiazol-4-yl)-2-(ethoxyimino) acetamido i-3-cephea-4-cai*boxyl3te To a solution of 3-acetoxymeth.y 1-7-( (Z)-2-(2-aainothiazol-4-yl)-y _ - 97 2-(ethoxyimino)acetaiaidoI-3-cepheni-4-carboxylic acid (SOOmg) suspended in distilled water (5mfi) were added l-allyl-4,6-diamino-2(IH)pyriaidinethione (200mg) and potassium iodide (lg). The pH of the mixture was adjusted to 7.1-^7.2 with a sodium carbonate solution, and acetonitrile (lmfi) was added thereto. After stirring for 4 hours at 7b“C, the mixture was cooled to room temperature. The pH was adjusted to 3-3.5 with 2N hydrochloric acid, and the precipitates were filtered, washed with distilled water (5mfi), and chromatographed over silica gel.

Elution with a 5 : 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound(300mg) in a white solid. m.p, : 165’C -(decomp.) NMR : ¢5 (D20 + NaHCOa) 1.29 (t, 3H), 3.57 (ABq, 2H), 4.17 (q, 2H). 5.16 (d, IH), 5.66 (s, IH). 5.82 (d, IH), 5.09— 6.56 (π, 5H), 6.96 (s, IH).

MS(FAB, M +-1) : 592 IR(KBr, cti~O : 1765 (/?-lactam), 1680. 1630, 1550.

V - 98 Example 5 : Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propen-loxyimino)acetamido]-3-(4,6-diaoino-l-fflethylpyrimidiniun-2-yl) thiomethy1-3-cephem-4-carboxylate A solution of 3-acetoxynethyl-7-l(Z)-2-(2-aainothiazol-4-yl)“2(2-propen-1-oxyimino)acetamido]-3-cephera-4-carboxylic acid (50Oiag) suspended in distilled water (3mf.) was reacted in tbe saae manner as described in Example 1 to give the above-indicated compound (260mg) in a pale white solid, q.p, : 168’C (decamp.) NMR : δ (D20 + acetone-de) 3.60 (ABq, 2K), 3.61 (s. 3H), 4.40 (ABq, 2H), 5.16 (d, IH), 5.88 (s, IH), 5.84 (d, IH). 5.11 -6.25 (m, 5H). 6.36 (s, IH).

MSiFAB, M + 1) : 578 IR(KBr, err1) : 1760 (^-lactam), 1670, 1618, 1522.

Example 6 : Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propen-loxyimino)acetamido]-3-(4,6-diaaino-l-ethylpyrimidinium-2-yl) thiomethy1-3-cephem-4-carboxylate 3-Acetoxyniethy1-7-( (Z)-2-(2-aminothiazol-4-yl)-2-(2-propen-i-oxyimino) v* - 99 acetamido]-3-cephem-l-carboxylic acid (500mg) and 4,6-diaraino-l-eth.yl2(lH)-pyriraidinethione (200mg) were reacted in the same manner as described in Exanple 1 to give the above-indicated compound (290mg). elp. : 165“C (decomp.) NMR : δ (Da0 + acetone-de) 1.41 (I, 3H). 3-57 (ABq, 2H), 4.14 (q, 2H), 4.41 (ABq, 2H), 5.16 (d, 1H). 5.67 (s, Hi), 5.84 (d, 111), 5.05-6.12 (m, 5H), 6.38 (s. IH).

US(FAB, HU) : 592 IRCRBi', cm1) : 1764 (β-lactam), 1765, 1615, 1522.

Example 7 : Synthesis of 3-(1-ally1-4,6-diarainopyrimidinium-2-y1)tiliomethyl -7-[(Z)-2-(2-aminothiazol-4-y 1)-2-(propen-1-oxyiamo) acetamido] -3-cephem-4-carboxylate 3-AfeLoxyiiiethy 1-7-1 (Z)-2-(2-aminothiazol-4-yl)-2-(2-propene-l-oxyimino acetainido]-3-eephem-4-carboxylic acid (SOOmg) and l-allyl-4,S-dianino2(IH)-pyrimidinethione (200mg) were reacted in the sane manner as described in Example 1 to give the above-indicated compound (319®?) NMR : δ (D30 + acetone-do) 3.56 (ABq, 2H), 4.39 (ABq, 2H), 5.16 (d, IH), 3.62 (s, 111), 5.79 (d, IH), 5.08-6.21 (¢, 10H), 7.01 (s, IH). - 100 MS1HLJ4_U1 : 604 IRiKBr, cm-1) : 1770 (^-lactam), 1669, 1620, 1531.

Example 8 : Synthesis of 7-[{Z)-2'(2-aminothiazol-4-yl)-2-(2-propyn-loxyimino)acetamido]-3-(4,6-diamino-l-methylpyrimidiniufl-Z-yl) thiomethyl-3-cephenH-carboxylate To a solution of 3-acetoxyaethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2(2-propyn-l-oxyifflino)acetainido]-3-cepheo-4-carboxylic acid (500mg) suspended in distilled water (5jnC) were added 4,6-diamino-l-methyl-2(IH)pyriaidinethione (2U0ag) and potassium iodide (lg). While adjusting the pH of the mixture to 7.1--- 7.2 with a sodium bicarbonate solution, the reaction mixture was heated to 70'C. After stirring for 4 hours, the mixture was cooled to room tenperature. The pH was adjusted to 3λ· 3.5 with 2N hydrochloric acid, and the precipitates were filtered, washed with distilled water (5mfi), and chromatographed over silica gel.

Elution with a 5 : 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound (300mg) in a pale white solid. hl.?. : 167‘C (decoap.) ,VMR : 20 + acetone-do) 3.01 (s, III), 3.56 (s, 3H), 3.62 (ABq, 2fl), 4.76 (s, 2H). 5.12 (d. - 101 IH), 5.85 (s'. Ill), 5.79 (d, Hi), 6.96 (s, IH).

MS(FAB. H ♦ 1) : 576 IRiKBr, cm-1) : 1766 (0-lactan), 1685, 1632, 1525.

Example 9 : Synthesis of 7-((Z)-2-(2-aminothiazol-4-yl)-2-(2-propyn-loxyiaino)acetamido]-3-(4,8-dianino-l-ethylpyrinidinium-2-yl) thiomethyl-3-cephen-l-carboxylate 2-Acetoxy me thy 1-7-( (Z,'-2-(2-aninothiazol-4-yl}-2-(2-propyn-l-oxyiitino) acetaroido]-3-cephem-4-carboxylic acid (500mg) and 4,6-diaeino-l-ethyl2(lH)-pyriraidinethione(200mg) were reacted in the sane manner as described in Example 1 to give the above-indicated coapound (ZSOng). (b.p. : 163’C'(decomp.) NHR : δ (D20 + acetone-da) 1.41 (t, 3H), 3.03 (s, IH), 3.56 (ABq, 2H), 4.16 (q, 2H), 4.3S (ABq, 2H). 4.31 (s, 2H), 5.16 (d, IH), 5.66 (s, IH), 5.34 (d, IH), 7.00 (s, IH).

MS(FAB, M t 1) : 590 IRiKBr, cm'1) : 1769 (^-lactam), 1781, 1630, 1525. - 102 Example ID : Synthesis of 3-(1-ally1-4,6-diaminopyrimidiniun-Z-yl)thioraethy1Ή (Z)-2-(2-arainothiazol-4-yl)-2-(2-propyn-l-oxyisino)acetaaidol -3-cephera-4-carboxylate 3-Acetoxymethy1-7-( (Z)-2-(2-aainothiazol-4-yl)-2-(2-propyn-l-oxyiHiino) acetaiaidoJ-3-cephem-4-carboxylic acid (500mg) and 1-allyl-4,6-diaoino2(3H)-pyrimidinethione (200®g) were reacted in the 3aae manner as described in Example 1 to give the above-indicated compound (270rag). ϋ,Ρ, : 171’C - (decomp.) NMR : δ (020 + acetone-de) 3.02 (s, IH), 3.57 (AEq, 2H), 4.43 (ABq, 2H), 4.79 (s, 2H). 5.13 (d, IH), 5.63 (s, IH), 5.79 (d, IH), 5.12-6.31 (a, 5H), 6-97 (s, IH).

HS(FAB, M + 1) : 602 IRfKBr, cnT') : 1763 (3-lactam), 1660, 1620, 1530.

Example 11 : Synthesis of 7-[(Z)-2’(2-aminothiazol-i-yl)-2-(2-carbox.yprop2-oxyimino)acetamido )-3-(4,6-diamino-l-fflethyipyrimidinium-2-yl) thiomethyl-3-cephea-4-carboxylate To a solution of 3-acetoxymethyl-7-((Z)-2-(2-aminothiazol-4-j'l)-2 (carboxyprop-2-oxyimino)acetamido]-3-cephem-4-carboxylie acid (SOOrag) - 103 suspended in distilled water (5m$) were added 4,6-dianino-l-nethyi-2(lH) pyrimidinethione (200rafi) and potassiua iodide (l.2g). While adjusting the pH of the mixture to 7.3-7.5 with a sodiua bicarbonate solution, the reaction nixture was heated to 70’C. After stirring for 4 hours, the mixture was cooled to rooa temperature. Insoluble materials were removed by filtration, and the pH of the filtrate was adjusted to 4 with 2N-hydroch!oric acid. The precipitates were filtered, washed with distilled water (5m£), and chromatographed over silica gel. Elution with a 5 : 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound (28Qrag) in a pale white solid. w.n, : 15i*C-(decoap.) SBj δ (Dz0 + NaHCOa) 1.50 (s, 6H), 3.50 (s, 3H), 3.59 (ABq, 2fl), 4.29 (ABq, 2H), 5.17 (d, 1Π), 5.5S (s, 1H), 5.79 (d, 1H), 6.25 (s, 1H).

HS(FAB, H * 1] : 624 IP (KBr,. CT1). : 1761 (β-lactam), I860, 1580, 1550. - 104 Example 12 : Synthesis of 7-l(Z)-2-{2-aminothiazol-4-yl)-2-(2-carboxyprop -2-oxyiaino)acetamido]-3-(4,6-diamino-l-ethylpyrimidinium-2yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethy 1-7-1 (Z)-2-(2-aminothiazol-4-yi)-2-(2-carboxyprop-2oxyirnino)acetamido]-3-cephem-4-carboxylic acid dihydrochloride (500mg) and 4,6-diamino-l-ethyl-2GH)-pyriniidinethione (200mg) were reacted in the sane manner as described in Example 11 to give the above-indicated compound (310mg) in a pale white solid. a.pt : 153*0-(decoap.) NMR,: δ (Dz0 4- SaHCOo) 1.32 (t. 3H), 1.48 (s. 6H). 3.56 (ABq, 2H), 4.04 (q, 2H), 4.31 (ABq, 2H), 5.12 (d, 1H), 5.53 (s. IH), 5.73 (d, IH). 6.92 (s, 1H).

M8(FAB, M + 11 : 638 IRfRBr, cm1) : 1770 (β-lactam). 1680, 1590, 1530.

Example 13 : Synthesis of 7-f(Z)-2-(2-aninothiazol-4-yl)-2-(2-carboxyprop -2-oxyiaino)acetamido]-3-(4,6-diamino-l-propyipyrinidiniuffl-2yi)thiomethyl-3-cephem-4-carboxylate To a solution of 3-acetoxymethyl-7-((Z)-2-(2-aminothiazol-4-yl)- - 105 2-(2-carboxyprop-2-oxyiaino)acetamido1-3-cephem-l-carboxylic acid dihydrochloride (500rag) dissolved in distilled water (lOmfi) were added 4.6-dianino-l-propyl-2(ni)-pyriniidinethione (2Q0mg) and potassium iodide (1.2g). The pH of the mixture was adjusted to 7.3-7.4 with a sodium bicarbonate solution, and acetonitrile (3m£) was added thereto.

After stirring for 5 hours at 73’C, the mixture was cooled to room temperature, and the acetonitrile was removed under reduced pressure.

Insoluble materials were filtered off. and pH of the filtrate was adjusted to 4.5 with 211-hydrochIoric acid. After being concentrated under reduced pressure, the residue was chromatographed over silica gel.

Elution with a 5 : l(v/v) mixture of acetonitrile/distilled water gave the above-indicated compound (210mg) in a pale yellow solid. m.p. : 156’C - (decomp.) MR : 0 (020 + VaHCO,) 3.92 (t, 3H). 1.49 (s, 6H), 1.77 (a. 2H), 3.SI (ABq, 21!). 3.91 (t, 2H), 5.14 (d. IB), 5.54 (s, 1H). 5.77 (d, 1H), 6.92 (s. IB).

MAB, H + 1) : 652 IE(KBr, cm-1 ) : 1765 (0-lactan), 1650, 1596, 1530. - 106 Example 14 : Synthesis of 7-((Z)-2-(2-aoinothiazol-4-yl)-2-(2-carboxyprop -2-oxyiaino)acetamido 1-3-(l-butyl-4,6-diafflinopyrijnidinium-2yl) thionethyl-3-cepheai''4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2oxyiniino)acetamido]-3'cepheni- 1-carboxylic acid dihydrochloride (500rag) and l-butyl-4,B-diamino-l-2(lH)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 13 to give tbe above indicatedcompound (230nig). n),.P, : 16ΓΟ(decomp.) NMR : δ (Dz0 + acetone-de) 0.92 (t, 3H), 1.36 (m, 2H), 1.48 (s, 6H), 1.71 (m, 2H), 3.52 (ABq, 2H), 3.99 (t, 2H). 4.35 (ABq, 2H), 5.14 (d, IH), 5.58 (s, lfi), 5.79 (d, IH). 6.25 (s, lfi), MSfrAB, M > 1) : 666 IRiXBr. cn'1) : 1768 (β-lactam), 1G71, 1625, 1523. - 107 Exanple 15 : Synthesis of 3-(l-allyl-4,B-diaainopyrimidinium-2-y1)thiooethy1 -7-((Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino) acetaaido]-3-cephem-4-carboxylate 3-Acetoxymethyl-7-i(Z,-2-(2-aninothiazol-4-yl)-2-(2-carboxyprop-2oxyimlno)acetanido]-3-cepheiH-4-carboxylic acid dihydrochloride (500ms) and l-allyl-4,6~diamino-2(IH)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 13 to give the above-indicated compound (310rag). m.p,. : IBO’C-- (decomp.) NMR : δ (Dz0 + acetone-do) 1.48 (s, 6H), 3.56 (ABq, 2H), 5.16 (d, IH), 5.61 (s, 1H), 5.79 (d, IH), 5.05--6.51 (m, 5H), 6.96 (s, IH).

MWAB, ni) : 650 IR(KBr, cm-1) : 1765 (/?-lactam), 1670, 1620, 1530.

Example 16 : Synthesis of 7-((Z)-2-(2-aminothiazol-4-yl)-2-(l-carboxyeth -l-oxyimino)acetanido]’3-(4,6-diamino-l-aethylpyriniidiniujD-2yl) thioneth.yl-3-eephem-4-car boxy late To a solution of 3-acetoxjHQthyl-7-[(Z)-2-(2-aoinothiazol-4-y1)-2IE 904047 - 108 (2-carboxyeth-2-oxyimino)acetamidoJ-3-cephem-4-carboxyiic acid (500rag) suspended in distilled water (lOmfi) were added 4,6-diamino-l-methyl-2(lH)pyrimidinethione (200mg) and potassium iodide (1.2g). While adjusting the pH of the mixture to 7.1--7.2 with a sodium bicarbonate solution, the reaction mixture was heated to 70’C. After stirring for 5 hours, the mixture was cooled to room temperature. The pH was adjusted to 4.1 with 2N-hydrochloric acid, and the precipitates were filtered, washed with distilled water (δπώ), and chromatographed over silica gel. Elution with a 5 : 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound (200ag) in a pale white solid. m.p, : 153°C - (decomp.) NMR ,,: tf (D30 + NaHCOo) 1.48 (d, 3H), 3.53 (s, 3H), 3.59 (ABq, 2H), 4.36 (ABq, 2H), 5.17 (d, IH), 5.50 (s, IH), 5.79 (d, IH), 7.01 (s, IH). a&FAB, M t 11 : SIO IRtKBr, cn-1 ) : 1756 (fi - lactam), 1765, 1595, 1525. - 109 Example 17 : Synthesis of 7-((Z)-2~(2~aninothiazol-4-yl)-2-(2-carboxyeth -1-oxyimino)acetamido J-3-(i-ethyl-4,6-diaminopyrimidiniura-2yl)thioBethyl-3-cephem-4-carboxylate 3-Acetoxymethy 1-7-( (Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyeth-loxyimino)acetamido]-3-cephea-4-carboxylic acid (500nig) and 4,6-diaminol-ethyl-2(IH)-pyrinidinethione (2DCrog) were reacted in the sane manner as described in Example 16 to give the above-indicated compound(21Omg). m.p, : 153'C·'(decomp.) NHR : d (DaO + acetone-da) 1.34 (t, 3H), 1.48 (d, 3H), 3.59 (ABq, 2H), 4.04 (q, 2H), 5.15 (d, IH), 5.52 (s. IH), 5.78 (d, IH), 6.96 (s, IH).

HSfFAB, H + 1) : 624 IR(KBr, cur1) : 1765 (£-lactan), 1765, 1590, 1530.

Exaaple 18 : Synthesis of 7-( (Z)-2-(2-aminothiazol-4-yI)-2-(2-carbox.veth -l-oxyimino)acetaaido]-3-(4,6-diamino-l-propylpyrimidiniun-2yl)thiomethyl-3-cepheni-4-carboxylate 3-Acetoxymethyl-7-((Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyeth-loxyimino)acetamido)-3-cepben-4-carboxylic acid (SOCmg) and 4,6-dianiino/1 φ — - 110 l-propyl-2(lH)-pyrimidinethione (200rag) were reacted in the same manner as described in Example 16 to give the above-indicated compound (170mg). m,p, ; 154‘C-^ (decomp.) NMJS : δ (Da0 + NailCOa) 0.95 (t, 311). 1.-10 (d. 3H), 1.65 (a, 211). 3.56 (ABq, 2H), 3.91 (t. ZH). .17 (d, IH), 5.50 (s, IH). 5.77 (d, 1H), 6.96 (s, IH).

MS (FAB, X + ,1) : 638 IR(KBr. era'1) : 1760 (β-lactam), 1671, 159Q, 1525.

Example 19 : Synthesis of 3-(l-allyl-4,6-diaainopyriaidiniua-2-yl)thiomethyl -7-i(Z)-2-(2-aainotniazoi-4-yi)-2-icarDoxyeth-2-oxj'iBino; acetasiido]-3-cephera-4-carboxylate 3-Aceto.\ywethyl-7-[(Z)-2-(2-aminothiazol'4-yl)-2-(2-carboxyeth-loxyiaino)acetamido]-3-cephem-4-carbox.ylic acid (500mg) and l-all:-'l-4,5diamino-2(Ill)-pyrimidinethione (200 mg) were reacted in the saae manner as described in Example 16 to give the above-indicated compound (2300 · m.p, : 155Τ'j (decoap.) NMR : δ (Dz0 + acetone-d0) 1.44 (d, 3H), 3.52 (ABq, 2H), 5.16 (d, IH), 5.59 (s. Ill), 5.76 (d, - Ill 1H), 5.07—6.51 (β. 5B), 6.99 (s. 1H).

MAE, ft ». 1). : 636 IRiKBr, cm1) : 1765 (β-lactam), 1680, 1600. 1530.

Example 20 ; Synthesis of 7-((Z)-2-(2-aminothiazol-4-yl)-2-(l-carboxymethoxyimino)acetamido]-3-(4,B-diaraino-l-methylpyrimidiniua-S-yl) thioniethyl'3-ccphein-l-carboxylate To a solution of3-acetoxjTaethyl-7-((Z)-2-(2-aninothiazoI-4-yl)-2(2-carboxyoethoxyimino)aceta»ido]-3-cepheB-4-carboxylic acid (SOOrag) suspended in distilled water (10m£) were added 4,8-dianiino-l-aethj’l-2(lH)pyrimidinethione (SOOrag) and potassium iodide (1.2s). With the adjusting of the pH of the mixture to 7.2 with a sodium bicarbonate solution, the reaction mixture was stirred for 5 hours at 70’C.

After the mixture cooled to rooa tenperature, insoluble aaterials were filtered off, and the pH of the filtrate was adjusted to 4.1 with, 2N~hydrochioric acid. After being concentrated under reduced pressure, the residue was chromatographed over silica gel. Elution with a 4 : 1 (v/v) mixture of acetonitrile/distilled water gave aboveindicated compound(350mg) in a white solid. m.p. : 167*0- (decomp.) - 112 δ (Da0 + NaHCOa) 3,49 (s, 3H), 3.52 (ABq, 2H), 4.34 (ABq, 2fl), 4.60 (s, 2fl), 5.16 (d, IH), 5.56 (s, IH), 5.78 (d. IH), 6.98 (s. IH).

MAExJLUA : 596 IR(KBr. cm:1) : 1760 (β-lactam), 1670, 1600, 1550.

Example 21 : Synthesis of 7-[(Z)-2-(2-aniinothiazQl~4-yl)-2-(carboxyiJiethoxyimino)acetamido]-3-(4,6-diamino-l-ethylpyrimidiniuni-2yl)thiomethyi-3-cephea-4-carboxylate 3-Acetoxymethyl-7-l(Z)-2-(2-aminothiazoI-4-yl)-2-(2-carboxymethoxyifflino) acetamido]-3-cephea-4-carboxylic acid (500 mg) and 4,6-diamino-1-ethy12(lH)'pyrimidinethione (200 mg) were reacted in the same manner as described in Example 20 to give the above-indicated compound(280mg). m.p.. : 165’C - (decoap.) WL·- δ (D20 + NaHCO3) 1,32 (t, 3H), 3.62 (ABq, 2H), 3.38 (q, 2H), 4.50 (s. 211). 3.17 (d.

HI). 5.58 (s, IH), 5.80 (d. IH), 7.01 (s. IH).

M5(FAB, H +· 1) : 610 IR(KBr, cnT1) : 1765 (/?-lactam), 1870, 1600, 1520. - 113 Example 22 : Synthesis of 7-((Z)-2-(2-aflinothiazol-4-yl)-2-(carboxyniethoxyiraino)acetamido 1-3-(4,6-dianino-l-propylpyrimidiniua-2yl)thiomethyl-3-cephem-4-carboxyIate 3-Acetoxyraethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxynethoxyinino) acetajnidoJ-3-cephem-4-carboxylic acid (SOQiag) and 4,6-diamino-l-propyl2(1 'll-pyriaidinethione (200mg) were reacted in the sane manner as described in Example 20 to give the above-indicated compound (2lOmg). m.p. : 16970 (decamp.) NMR : δ (Dz0 + NaHCO3) 0.93 (t. 3H), 1.73 (m, 2H), 3.56 (ABq, 2H), 3.32 (t, 2H). 4.58 (s, 2H). 5.15 (d, IH), 5.56 (s, IH), 5.78 (d, IH), 6.98 (s, IH).

MS(FAB, M f 1) : 624 IR(KB.r, cm-1) : 1763 (β-lac tarn), 1670, 1610, 1525.

Example 23 : Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-3-(l-butyi-4,6-diaminopyriaidinium-2yl)thioaethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxymethoxyiaino) acetamido]-3-cephem-4-carboxylic acid (50Gntg) and l-but.yl-4,8-diaminoi , - 114 2(lH)-pyrinidinethione (200mg) were reacted in the saae wanner as described in Example 20 to give the above-indicated compound(240rag). b.p, : 167’C— (decomp.) BK_: zO 4 NaHCOa) 0.92 (t, 3H), 1.32 (a, 2H), 1.66 (a, 2S), 3.60 (ABq. 2H), 3.96 (t, 2H), 4.57 (s, 211), 5.15 (d, Hi), 5.58 (s, 1H), 5.78 (d, IH), 7.01 (s.

HI).

MS(FAB, *) + 1) : 638 fRCKBr, cm-1) : 1765 ((3-lactam), 1670, 1610. 1530.

Example 24 ; Synthesis of 3-(1-allyi-4,S-diaaiinopyriaiidiniua-2-yl)thioaiethyl -?-{(Z)-2-(2-amincthiazol-4-yl)-2-(2-carboxyiiethoxyiaino)acetanido ] -3-cephem-4-carboxylate 3-Acetoxymethy1-7-{(Z)-2-(2-aminothiazo1-4-yl)-2-(2-carboxymethoxyimino) acetamido]-3-cephem-4-carboxylic acid (500mg) and l-allyl-4,6-diainino2(IH)-pyrimidinetbione (200mg) were reacted in the same manner as described in Example 20 to give the above-indicated compound(220mg). m.p. : 165’C - (deconp.) SiiiL: δ (0a0 4 NaliC03) 3.56 (ABq, 2H), 4.56 (s. 2H), 5.12 (d. IH), 5,63 (s, UI), 5.79 (d, - 115 IH), 5,07--6.51 (a, 5H). 7.00 (s. IH). dSlfALJLLli : 622 IR(KBr, αιτυ : 1770 (tf-lactaa), 1660, 1600, 1535.

Example 25 : Synthesis of 7-[(Z)“2-(2-aminothiazol-4-yl)-Z-(nethoxyifflino) acetamido ]-3-(1,4,6-triaininopyriniidini un-2-yl) thicaethy 1-3cephem-4-carboxylate To a solution of 3-acetox.ymethyl-7-[(Z)-2-(2-aainothiazol-4-yl)-2(methoxyimino)acetamido]-3-cephem-4-carboxylic acid (500mg) suspended in distilled water (5m£) were added l,4,6-triamino-2(lH)-pyrimidinethione (200mg) and potassium iodide (8UUmgj. With adjusting of the pH of the mixture to 7.1-7.2 with a sodium bicarbonate solution, the reaction mixture was heated to 70’C. After stirring for 4 hours, the mixture was cooled to room temperature. The pH was adjusted to 3- 3.5 with 2S-hydrochloric acid, and the precipitates were filtered, washed with distilled water (5m£), and chromatographed over silica gel. Elution with a 5 : 1(v/v) mixture of acetonitrile/distilled water gave the above-indicated compound (300mg) in a pale white solid, m.p. : 156’C-- (decomp.) NMR, : δ (Da0 + acetone-de) - 116 3.58 (ABq, 211), 3.81 (s, 3H), 4.33 (ABq, 2H), 5.12 (d, IH), 5.61 (s, IH). 5.83 (d. IH), 6.91 (s, IB).

M&lfAB, K..+ 1) : 553 IRCKBr. cur*) : 1765 (β-lactam), 1670, 1620, 1560.

Example 26 : Synthesis of 7-( (Z)-2-(2-aiainothiazol-4-yl)-2-(ethoxyiniino) acetamido (-3-( 1,4,6-tr ianinopyriBidinium-2-yl) thioniethyl-3-* cephem-4-carboxylate 3-Acetoxymethy1-7-((Z)-2-(2-aainothiazol-4-y1)-2-(ethoxyimino)acetanido] 3-cephem-4-carboxylic acid (500<) was reacted in the same manner as described in Example 25 to give the above-indicated compound (2S0mg) in a pale white solid. m.p, : 165’C'-' (decoap.) NHR : δ (Da0 + acetone-dj 1.29 (t, ZH). 3.57 (ABq, 2H), 4.24 (q, 2H), 4.35 (ABq, 2H), 5.16 (d, IH), 5.52 (s, IH), 6.31 (s, IH).

MSCF.IB, K + II : 567 IRfKDr, cm' 1) : 1765 (^-lactam), 1680, 1590. - 117 Example 27 : Synthesis of 7-((Z)-2-(2-aminothiazol-4-yl)-2-(2-propyn -l-oxyifflinQ)acetaoidoJ-3-(l,4,6-triaminopyriraidinium-2-yl) thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-((Z)-2-(2-aninothiazol-*4-yl)-2-(2-propyn-l-oxyimino) acetamidoj-3-cephem-4-carboxylic acid (5000 was reacted in the same manner as described in Example 25 to give the above-indicated compound (350rag) in a pale yellow solid. a.P, : 167°C -(decomp.) NHR : δ (D20 + acetone-de) 3.06 (t, IH), 3.56 (ABq, 2H), 4.41 (ABq, 2H), 4.80 (d, 2H). 5.12 (d, IH), 5.62 (s. IH), 5.80 (d, IH), 6.96 (s, IH).

MS(FAB, M + 1) : 577 IRiXBr, cm-1) : 1765 (β -lactam), 1690, 1580.

Example 28 : Synthesis of 7-[(Z)-2-(5-ajjiino-l,2,4-thiadiazol-3-yi)’2(ethoxy imino) acetamido ]-3-(1,4,6-triaainopyriiaidiniun-Z'-yl) thiomethyl-3-cephea-4-carboxylate 3-Acetoxymethyl-7-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyiaino) acetamido]-3-cephem-4-carboxylic acid (5000 was reacted in the same - 118 manner as described in Example 25 to give the above-indicated compound (280nig) in a yellow solid. m.p, : 169*C—(decomp.) NMR : tf (DgO + acetone-de) 1.52 (t, 3H), 3.57 (ABq, 2H), 4.26 (ABq. 2H), 4.36 (q, 2H), 5.14 (d.

IH), 5.58 (s, IH), 5.84 (d. IH).

IR(KBr, cm-1) : 1769 (^-lactam), 1020, 1630.

Example 29 : Synthesis of 7-[(Z)-2-{2-aminothiazol-4-yl)-2-(carboxyprop2-oxyimino)acetamido )-3-(1, 4,6-triaainopyrinidinium-2-yl) thiomethyl-3-cephem-4-carbo.xylate To a solution of 3-acetoxynethyl-7-[(Z)-(:-arainothiazol-4-y!)-2(2-carboxyprop-2-oxyiaiino)acetamidoj-3-cephem-4-carboxylie acid (SCOtng) suspended in distilled water (10m£) were added 1,4,S-triamino-2-{IH)pyriiaidinethione (200mg) and potassium iodide (1.2g). The pH of the reaction mixture was adjusted to 7.1 —7.3 with a sodium bicarbonate solution, and the reaction mixture was beared for 4 hours to 70’C.

After cooling to room temperature, insoluble materials were filtered off, and the pH of the filtrate was adjusted to 4. After being concentrated under reduced pressure, the residue was chromatographed over silica gel. - 119 Elution with a 4 : 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound (310ag) in a pale white solid. m.p, : 155‘C-(decoap.) NMR : ί (D20 + NaHCOs) 1.49 (s, 6H), 3.58 (ABq, 2H), 4.22 (ABq, 2H), 5.16 (d. 1H), 5.56 (s, 1H), 5.77 (d. 1H). 6.94 (s. 1H).

HS(FAB, Μ ί 1) : 825 IRiKBr, cnT1) : 1770 (β-lactam), 1690, 1610. 1570.

Example 30 : Synthesis of 7-{(Z)-2-(2-aainothiazol-4-yl)-2-(l-carboxyeth1-oxyimino)acetamido]-3-(1,4,6-triaainopyriwidinium-2-yl) thiomethyl-3-cephea-4-carboxyiate 3-Acetoxynethyl-7-t(Z)-2-(2-aainothiazol-4-yl)-2-(l-carboxyeth-loxyimino)acetamido1-3-cephea-J-carboxylic acid (500mg) was reacted in the same manner as described in Example 29 to give the above-indicated compound (Z30mg) in a pale yellow solid. m.p. : 1G7’C(decomp.) NMR : δ (DzO t acetone-da) 1.44 (d, 3H), 3.55 (ABq, 2H), 4.21 (ABq, 2H), 5.17 (d, IB), 5.54 (s. IH). 5.76 (d, 1H), 6.97 (s, HI). - 120 IE 904047 MS (FAB, HH) ; 611 IRiKBr, an-1) : 17C5 (β -lactam), 1660. 1590. 1540.

Example 31 : Synthesis of 7-((Z)-2-(5-aaino-l,2,4-thiadiazol-3-yl)-2-(2carboxyprop-2-oxyiniino)acetamido )-3-(1,4,6-triaminopyriraidinium -2-yl)thioBethyl-3-cephem-l-carboxylate 3-Acetoxymethy1-7-((Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-(2carboxyprop-2-oxyimino)acetamidc)-3-cephem-4-carbo,xylic acid (500ng) was reacted in the same manner as described in Exaaple 29 to give the aboveindicated compound (280mg) in a pale white solid. m.p. : 173’C- (deccap.) NMR : (020 + NaHCQa) 1.52 (s, 6H). 3.52 (ABq, 20), 4.23 (ABq, 2H), 5.16 (d, IH), 5.54 (S. 1H), 5.81 (d, IH).

IRiKBr, ciTT1) ; 1760 (^-lactam), 1690, 1610, 1570. - 121 Example 32 : Synthesis of 7-[(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2(nethoxyiaino)acetaBido]-3-(4,6-diaaino-l-Bethylpyriaidiniu· -2-yl)thioBethyl-3-cepheig-4-carboxylate To a solution of 3-acetoxymethyl-7-[(Z)-(5~aaino-l,2,4-thiadiazol -3-yl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid (500mg) suspended in distilled water were added 4,6-diamino-l'raethyl2(lH)-pyrioidinethione (2C0mg) and potassium iodide (800mg), With adjusting of the pH of the mixture to 7.1-7.2 with a sodium bicarbonate solution, the reaction mixture was heated to 70*C.

After stirring for 4 hours, the mixture was cooled to room temperature.

The pH was adjusted to 3--3.5 with 2N-hydrochloric acid, and the resultant precipitates were filtered, washed with distilled water (5mi), and chromatographed over silica gel. Elution with a 5 : l(v/v) mixture of acetonitrile/distilled water gave the above-incicated compound(SOOng) in a pale white solid. m.p. : 161’C -- (decomp.) NMR : δ (D20 + acetone-de) 3.62 (s, 3H), 3.66 (ABq, 2H), 4.05 (s, 3H), 4.45 (ABq, 2H). 5,15 (d. IH), 5.62 (s, IH), 5.81 (d, 1H).

IR(KBr, cm-1) : 1765 (tf-lactam), 1680, 1630, 1570. - 122 Example 33 : Synthesis of 7-((2)-2-(5-aaino-l,2,4-thiadiazol-3-yl)-2(nethoxyimino)acetajnido]-3-(4,6-diamino-l-ethylpyriniidiniua -2-yl)thiomethyl-3-cephea-4-carboxylate 3-Acetoxymethy 1-7- {(2) -2- (5-amino-l. 2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido]-3-cephem-4-carboxylic acid (500mg) and 4,6-diamino-l-ethyl2(IH)-pyriaidinethione (200®g) were reacted in the same manner as described in Example 32 to give the above-indicated compound (230mg). m.p, : 169aC -(decomp.) NMR : tf (Da0 + acetone-de) 3.60 (q, 211). 3.60 (ABq, 2H), 4.05 (s, 3H), 4.55 (ABq, 2H), 5.11 (d. IH), 5.68 (s, IH), 5.82 (d, IH).

IB(KBr, cm-1) .· 1770 (^-lactam), 1690, 1630, 1580.

Example 34 : Synthesis of 7-[(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2(methoxyimino)acetamido]-3-(4,S-diamino-l-propylpyrimidinium -2-yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-(methoxyimino) acetamido]-3-cephem-4-carboxylic acid (500mg) and 4,6-diamino-l-propyl2(lH)-pyrimidinethione (200rag) were reacted in the sane manner as r x' - 123 described in Example 32 to give the above-indicated compound (250mg). clp. : 67*C— (decomp.) NHR ? d(DZQ + acetone-de, 1.05 (t, 3115. 1.80 (», 2H), 3.52 (ABq, 2H). 3.80 (t. 2H). 4.05 (s, 3H), 4.55 (ABq, 2H), 5,16 (d, IH), 5.65 (s. IH), 5.84 (d, IH).

IRiKBr, cm1) : 1765 (^-lactam), 1695, 1640, 1580.

Example 35 : Synthesis of 7-[(Z)-2-(5-amino-I,2,4-thiadiazoI-3-yl)-2(methoxyimino)acetamido]-3-(l-allyl-4,6-diarainopyrimidinium -2-yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethy1-7-((Z)-2-(5-amino-1,2,4-thiadiazoI-3-yl)-2-(aethoxyimino) acetamido]-3-cephem-4-carboxylic acid (5Q0ag) and l-allyl-4,6-diamino-2(IH)pyrinidinethione (200ag) were reacted in the saae manner as described in Example 32 to give the above-indicated coapound(170rag). m.p, : 158°C·-' (decomp.) NMR : d (D2C + acetone-do) 3.56 (A3q, 2H), 4.05 (s. 3H). 4.42 (ABq, 2H), 5.16 (d, IH), 5.70 (S, IH), 5.85 (d, IH), 5.05—6.51 (ra, 5H).

IRiKBr, cm-1) : 1760 (£-lactam), 1700, 1650, 1590.

Example 36 : Synthesis of 7-[(Z)-2-(5-amina-l,2,4-thiadiazal.-3-yl)-Z(ethoxyiaino}acetamido]-3-(4,6-diaDino-l-oethylpyriisidiniUffl -2-yl) thiomethy l-3-'Cephen-4-carboxylate 3-Acetcxymethyl-7-[(Z)-2-(5-amino-l. 2,4-1hi adiazo1-3-y1)-2-(ethoxyimino) acetamidoj-3-cephen-4-carboxylic acid (SOOmg) and 4,6-diaraino-l-methyl~ 2(lH)-pyrimidinethione (200rag) were reacted in the sane manner as described in Example 32 to give the above-indicated compound (280mg). mp, : 163’C^ (decomp.) NMR : δ (DaO + acetone-de) 1.30 (t, 3H), 3.90 (S, 3H), 3.56 (ABq, 2H), 4.30 (q, 2H), 4.40 (ABq. ZH), 5.13 (d, IH), 5.62 (s. IH). 5.84 (d, IH).

IR(KBr, cm-1). : 1768 (/7-lactaa), 1690, 1630, 1580.

Example 37 : Synthesis of 7-[(Z)-2~(5-anino-l,2,l-thiadiazol-3-yl}-2(ethoxyimino)acetamidoJ-3-(4,6-diamino-l-ethylpyrimidiniun -2-yl)thioisethyl-3-cephes-4-carboxyiate 3-Acetoxymethyl-7-[(Z)-2-(5-aoino-l,2,I-thiadia2ol-3-yl)-2-(ethoxyimino) acetamido)-3~cephem-4-carboxylic acid (500mg) and 4,6-diamino-l-ethyl2(1H)-pyrioidinethione (200mg) were reacted in the same manner as - 125 described in Example 32 to give the above-indicated conpound(270mg). m ,.2.,. : 165Ό (decomp.) NHR : δ (DsO + acetone-de) 1.18 (t. 3H). 1.30 (t, 3H), 3.80 (q, 2H), 3.58 (ABq, 2H), 4.30 (q, 2H), 4.10 (ABq, 2H), 5.18 (d, IH), 5.71 (s, IH). 5.84 (d, IH).

IliKBr, cm-1) : 1765 (/?-lactam), 1695, 1630. 1570.

Example 38 : Synthesis of 7-[(Z)-2-(5-aaino-l,2,4-thiadiazol-3-yi)-2(ethoxyiaiino)acetamidoJ-3-(4,6-diamino-l-propylpyriaidinium -2-yl)thioraethyl-3-cephem-4-carboxylate 3-Acetoxynethyi-7-l(Z)-2-(5-amino-1,2,4-thiaciazoi-3-yi)-2-(ethoxyimino; acetamido]-3-cephem-4-carboxylic acid (500mg) and 4,8-diamino-l-propyl2(1H)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 32 to give the above-indicated compound(230mg). m.p. : 158’C (decomp.) NHR : 0) 1.05 (t, 3H), 1.30 (t, 3H), 1.30 (ο. 211), 3.54 (ABq, 2«), 4.0 (t, 28). 4.32 (q, 2H), 4.58 (ABq, 2H), 5.18 (d. Hi), 5.89 (s, IH). .84 (d, IH). : 1770 (x?-lactam), 1690. 1640, 1580. j - 126 Example 39 ; Synthesis of 7-{(Z)-2-(5-anino-l,2,4-thiadiazol-3-yl)-2(ethoxyimino)acetanido1-3-(1-allyl-4,6-diaminopyriraidinium -2-yl)thioraethyI-3-cephem-4-carboxylate 3-Acetoxymethy 1-7-( (Z)-2-(5-amino-l, 2,4-thiadiazoI-3-yl)-2-(ethomoino) acetamido]-3-cephera-1-carboxylic acid (SOOmg) and l-allyl-4,6-diamino2{lH)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 32 to give the above-indicated compound(210ag). m.p. ; 159’C—(decomp.) NMR : δ (Da0 + acetone-do) 1.31 (t, 3H), 3.80 (ABq, 2H), 4.32 (q, 2H), 4.42 (AEq, 2H), 5.16 (d, IH), 5.68 (s. IH), 5.82 (d, IH), 5.05-6.51 (is, 5H).

IRiKBr, cm-1) : 1769( ^-lactam), 1095, 1630, 1570.

Exaaple 40 ; Synthesis of 7-((Z)-2-(5-amino-l12,4-thiadiazol-3-''lj-2(2-carboxyprop-2-oxyimino)acetamido J-3-(4,6-diarainc-lmethylpyrimidinium-Z-yl)thiomethyl-3-cephem-4-carbox.v late To a solution of 3-aeetoxymethyl-7-[(Z)-2-(5-amino-l,2,4-thiadiazol -3-y1)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-ccphem-4-carboxylie acid (500rag) suspended in distilled water (lOmf) were added 4,S-diamino-lJ - 127 nethy1-2(IH)-pyrimidinethione (2Q0mg) and potassium iodide (l,2g).

After adjusting the pH of the reaction mixture to 7.3-7.5 with a sodium bicarbonate solution, the reaction mixture was stirred for 4 hours at 70‘C. The mixture was cooled to room temperature, and insoluble materials were filtered off, and pH of the filtrate was adjusted to i. After concentration under reduced pressure, the residue was chromatographed over silica gel. Elution with a 4 : 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound (200mg) in a pale white solid. m.p. : 154’Ο- (decomp.) NMR : δ (D20 + acetone-de) 1.52 (s, 6H), 3.51 (s, 3H), 3.58 (ABq, ZH), 4.40 (ABq, 2H), 5.18 (d, IH), 5.60 (s, IH). 5.81 (d. IH).

IRfKBr, cm-1) : 1769 (^-lactam), 1700, 1650, 1590.

Example 41 : Synthesis of 7-[(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2(carboxyprop-2-oxyiraino)acetamido )-2-(4,6-diamino-IethylpyrimidiniUB-2-yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-{(Z)-2-(5-aieino-l,2,4-thiadiazol-3-yl)-2-(2carboxyprop-2-oxyiaino)acetaniido]-3-cepheni-4-carboxylic acid (500rag) w - 128 and 4,6-diamino-l-ethyl-2(lH)-pyrimidinethione (200 rag) were reacted in the sane manner as described in Example 40 to give the aboveindicated conpound(250mg). m.p. : 161’C—(decomp.) NMR : J (DgO + acetone-d0) 1.32 (t, 3H), 1.58 (s, 6H), 3.55 (ABq, 2H), 4.02 (q, 2H), 4.43 (ABq, 2H), 5.18 (d. IB), 5.58 (s, 111), 5.81 (d, IB).

IRiKBr, err1) : 1767 {/?-lactara), 1695, 1640, 1580.

Example 42 : Synthesis of 7-[(Z)-2-{5-aaino-l,2,4-thiadiazol-3-yl)-2(2-carboxyprop-2-oxy’iaino)acetaraidoI-3-(4,6-diamino-lpropylpyriniidiniun-2-yl)thionethyl-3-c3phea-4-carboxyiate 3-Acetoxyraethyl-7-[(Z)-2-(5-araino-l,2,4-thiadiazol-3-yl)-2-(2carboxyprop-2-oxyimino)acetamidoJ-3-cephem-4-carboxylic acid(500mg' and 4,6-diaraino-l-propyl-2(lH)-pyriflidinethione (200mg) were reacted in the same manner as described in Example 40 to give the aboveindicated compound(190ng). m.p, : 159’C’·(decomp.) NMR : δ (DzO + acetone-de) 1.02 (ί. 3H). 1.52 (s, 6H), 1.53 (a. 2H), 2.60 (ABq, 2H), 3.98 (t. - 129 2H), 4.45 (ABq, 2H), 5.18 (d, HI). 5-58 (s, IH). 5.81 (d, IH).

IRiKBr, cur1). : 1765 {£-lactam), 1690, 1630, 1570.

Example 43 : Synthesis of 7-i(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)~2(2-carboxyprop-2-oxyimino)acetamido]-3-(l-butyl-4,6-diamino pyriiaidinium-2-yi)thiomethyi-3-cephem-4-carboxylate 3-acetoxymethy1-7-((Z)-2-(5-aaino-l,2,4-thiadiazoI-3-yi)-2-(2carboxyprop-2-oxyifflino)acetamido]-3-cspnea-4-carboxylic acid(500mg) and l-butyl-4,S-diamino-2(IH)-pyrinidinethione (200ms) were reacted in the same manner as described in Example 40 to give the aboveindicated compound(160mg). a,p. : 163’C (decomp.) NMR : δ (D20 + acetone-d*) 0.98 (t. 3H), 1.50 (m, 4f.), 1.54 (s. 611), 3.30 (ABq, 211). 3.35 (t, 211), 4.46 (ABq, 2H), 5.18 (d, IH), 5.5S(s. Ifl), 5,31 (d, IH).

IRiKBr, cm'1) : 1770 (β-lactam), 1890, 1620, 1550. t - X30 Example 44 : Synthesis of 7-l(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2(2-cjrboxyprop-2-oxyiBino)acetamido]-3-(l-allyl-4,6-diaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethy1-7-1(Z)-2-(5-amino-l,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyinino)acetaBido]-3-cephera-4-carboxylic acid (500mg) and l-allyl-4,G-djaciino-2(lH)-pyriBidinethione (200rag) were reacted in the same manner as described in Example 40 to give the above-indicated compound (210mg). m,.p, : 156*0- (decomp.) MR : ί (Dc0 + acetone-de) 1.53 (s, 6H), 3.60 (ABq, 2H), 3.71 (d, 2K). 4.45 (ABq, 2H), 5.18 (d, IK), 5.00 (s, IK). 5.31 (d, ill), 5.01-6.31 (m, 3H).

IRiXBr, cm-1) : 1760 (β -lactam). 1630, 1620, 1570.

Example 45 : Synthesis of 7-[(Z)-2-(2-ar»inothiazol-4-yl)-2-(2-carboxyprop -2-oxyimino)acetamidoJ-3-{4,6-diamino-1,5-dinethylpyrinidiniuai -2-yl)thiomethyl-3-cephem-4-carboxylate To 3-acetoxynethyl-7-[(Z)-2-(2-asinothiazol-4-yl)-2-(2-carboxypropl-oxyimino)acetamidoJ-3-cephea-4-earboxylic acid (SOOrag) were added 4,6IE 904047 - 131 diamino-1,5-dimethyl-2(lH)-pyrimidinethione (200mg) obtained in Preparation 7, potassiua iodide (800rag) and distilled water (30ml!), With adjusting of the pH of the mixture to 7.0-7.5 with a saturated aqueous sodium bicarbonate solution, the reaction mixture was stirred for 4 hours at 70-75*C. After the mixture was cooled to room temperature, the pH of the mixture was adjusted to 4.5-5.0 with 2N-hydrochloric acid.

The precipitates were collected by filtration and chromatographed over silica gel. Elution with a 7 : 1 (v/v) mixture of acetonitrile/ distilled water gave the above-indicated compound (128mg) in a pale yellow solid.

BL£x_ : 174'C(decoap.) NMR..: tf (Dz0 + NaHCO3) 1.48 (s, 6H), 2.21 (s, 3H), 3.33 and 3.73 (ABq, 2H), 3.49 (s, 3H), 3.89 and 4.72 (ABq, 2H), 5.18 (d, IH), 5.78 (d, IH), 5.92 (s, IH). t H + 1) : 638 IR(KBr, cm-1-' : 177C (/J-lactam), 1701, 1530. 1527.

Example 46 : Synthesis of 7-((Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop -2-oxyimino)acetamido )-3-(4,S-diaaino-5-eth.vl-l-methyIpyrimidinium-2-yl)thioaethyl-3-cephea-ί-carboxy late - 132 The above-indicated compound (13Qrag) in a pale white solid was prepared in the same method as described in Example 45 except for using 4,6-dianino-l-ethyl-5-aiethyl-2(lH)-pyrimidinethione (200mg) obtained in Preparation 10 in place of 4,6-diamino-l,5-dimethyl-2(lH)-pyriraidinethione ifljPj. : 178’Ο' (decomp.) NHE_: d(DMSO-de) 0.93 (t. 3H), 1.42 (d, 6H), 2.38 (q, 2H). 3.19 and 3.54 (ABq, 2H), 3.49 (s, 3H), 3.85 and 4.80 (ABq, 211), 4.96 (d, 111), 5.68 (dd, IH). 6.75 (s, IH), 7.20 (s, 2d) , 7.71 (bs. 4H), 11.42 (bs. ill). KSiFAU.!,, 1) : G52 TR(KBr. cm~ I \ : 1709 (/3- -lad Lara), 1685, 1632. 1580.

Example 47 : Synthesis of 7-[(Z)-2-(2-aminothiazol-l-yl)-2-(2-carbcxyprop -2-oxyimino)acetaoidcI-3'(4,S-dianino-i-ethj'l-0-methylpyrimidinium-2-yl)thiomethyl-3-cephen-4-carboxylate The above-indicated compound (150,mg) in a yellow solid was prepared in the same method as described in Example 45 except for using 4,5-iiaminol-ethyl-5-aethyI-2(IH)-pyriraidinethione (20Cmg) obtained in Preparation 8 in place of 4,6-diamino-l,5-diaethyl-2(IH)-pyriraidinethione. m. ρ, : ISO °C · (decomp.) W si — - 133 NMR. : i(DMS0-de) 1.22 (t, 3H). 1.42 (d, 611), 1.90 (s, 3H), 3.20 and 3.55 (ABq, 2H), 3.89 and 4.78 (ABq, 2H), 4.10 (q, 211), 4.98 (d, IH), 5.70 (dd, IH). 6.79 (s, IH). 7.22 (s, 2H), 7.78 (bs, 411), 11.24 (bs, IB). 1) : 652 IRfKBr, cm-1) : 1765 (;?-lactam), 1685, 1630. 1580.

Example 48 : Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop -2-axy im ino)acetamido]-3-(4,6-di amiπο-I,5-diethylpyrimidiniiie -2-yl)thioBethyl-3-cephem-4-carboxylate The above-indicated compound (140rag) in a Pale yellow solid was prepared in the same method as described in Example 45 except for using 4,6-diamino-l.5-diethyl-2(IB)-pyrimidinethione (200 rag) obtained in Preparation 11 in place of 4,G-diaatino-1,5-dimettiy 1-2(IH)-pyrimidinethione. ra.P, : 168*C—(decomp.) NMR : 0) 0.37 (t, 3H), 1.22 (t, 3H), 1.43 (d, 6H), 2.40 (q, 2H), 3.20 and 3.56 (ABq, 2H), 3.84 and 4.81 (ABq, 2H), 4.08 (q, 2K), 4.98 (d, IH), 5.70 (dd, 111), 6.74 (s. IB), 7.20 (s, 2H), 7.71 (bs. 4H), 11.45 (bs, IH).

MS.(FAB, L· I) : 666 - 134 IRfliBr, cm'1) : 1766 (/J-lactaa), 1640, 1600.

Example 49 : Synthesis of 7-((Z)-2-(2-aminothiazo{-4-yl)~2-(2-carboxyprop -2-oxyimino)acetamido J-3-(5-methyl-1,4,6-triarainopyrimidinium -2-yl) thiomethyl-3-cephem-4-carboxylate The above-indicated compound (l?0mg) in a Pale yellow solid was prepared m the same method as described in Example 45 except for using -melhyl-l,4,6-triamino-2(lK5-pyrimidinethione (20Dmg) obtained in Preparation 9 in place of 4,S-diamino-l,0-dimethyl-2(lH)-pyriaidinethione. a.a, : 17S4C(decoap.) tf (DMSO-dJ 1.43 (ri, 6K), 1.S3 (s, 3H), 3.19 and 3.48 (AEq, 2H). 3.72 and 4.52 (ABq, 2H), 4.39 (d, IH), 5.68 (dd, IH), 6,. 11 (s, 2S), 6.73 (s, IH). 7.22 (s, 2H), 7.70 (bs, 4H), 11.31 (bs. IH).

MS (FAB, Μ 4- l) ; 633 IRiKftTx ca-1) : 1765 (β-lactam), 1628, 15S0.

Example 50 : Synthesis of 7-[(Z)-2-(2-aainothiazol-4-yl)-2-(2-carboxyprop -2-oxyiaino)acetaaidol-3-(l-cyclopropyl'4,6-diaiiinopyrinidiniuB! -2-yl) thiomethy l-3-cephern-4-carboxylate To a solution of 3-acetoxyiaethyl-7-[(Z)-2-(2-amino‘hiazol-4-yl)-2(carboxyprop-2-oxyimino)acetamidoJ-3-cephem-l-earboxylie acid dihydrochloride (500<) suspended in distilled water (lCmfi) were added 1cyclopropyl-4,S-diamino-Z(IH)-pyrinidinethione (200mg) and potassium iodide (1.2s). With adjusting of the pH of the reaction mixture to 7.3--7.5 with a sodium bicarbonate solution, the reaction mixture was stirred for 4 hours at 70*C. After the mixture was cooled to room temperature, insoluble materials were filtered off. and the pH of the filtrate was adjusted to 4. After being concentrated under reduced pressure, the residue was chromatographed over silica gel. Elution with a 4 : 1 (v/v) mixture of acetonitrile/disriI led water gave the above-indicated compound (laOmg) in a pale yellow solid. m. ο. : 194’C--(decontp.) NMR : δ (DzO * .'iaHCOJ 1.13(31, 2H), 1.44 (s, 6H), 1.5fl(a, 2ΙΪ). 3.0Q(m. IH), 2.41 (A3q, 2H), 4.32 (ABq. 2H), 5.11 (d, IH). 3.66(s, IH), 5.71 (d, IH!, 6.92 (s, IH).

O', - 136 WALJL±_1L .· 650 IRiKBr. -.orl) : 1768 (,3-lactam), 1645, 1600.

Example 51 : Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yi)-2-(2-carboxyprop -2-oxyimino)acetamidoJ-3-[l-(4-chlorophenyl)-4,6-diaminopyriai dinium-2-yl)thiomethyl-3-cephem-l-carboxylate 3-Acetoxyraethy1-7-[(Z)-2-(2-aminothiazo1-4-yl)-2-(2-carfcoxyprop-2-oxyiraino)acetamido]-2-cephera-4-carboxylic acid (500mg) and 1-(4-chlprophenyl) -4,0-diamino-2(lH)-pyriaidinethione (2C0ragj were reacted in the same manner as described in Example 50 tc give the above-indicated compound (170mg). m,n.t : 182’C - (decomp.) MIR : δ (D20 + NaHCC3) 1.43 (s. 611), 3.42 (ABq, 211), 4.35 (ABq, 2H), 5.3S (d. IH), 5.64 (s.

Ill), 5.66 (d. IH), 6.54 (s. IH) , 7.26--7.52 (m. 4H).

MS (FAB, Hl) : 720 IRiKBr, cm'1) : 1768 (/?-lactam), 1643, 1600. - 137 Example 52 : Synthesis of 7-l(Z}-Z-(2~aninothiazol-4-yl)-2-(2-carboxynethoxyimino)acetamido]-3-(4,6-diamino-l-phenylpyriniidiniun-2yl)thioaethyl-3-cephera-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(2-aminotbiazol-4-yl)-2-(2-carboxymethoxyimino) acetamido]-3-cephem-4-carboxylic acid (SOQmg) and 4,6-diamino-l-phenyl-2(lH) -pyrimidinethione (200mg) were reacted in the same manner as described in E.xample 50 to give the above-indicated compound (190mg). m.p. : !87'C (decomp.) NHR : d (D»0 + NaHCOj 3.48 (ABq, 2H), 4.42 (ABq, 2H), 4.59 is, 2H), 5.08 (d. IK), 5.33 (s, IB), 5.71 (d, 1H), 6.38 is, IH), 7.41-7.32 (m, 5K).

MS(FAB, Hl) : 858 IRiKBr, cm-1) : 1766 (4-lactan), 1655, 1600, 1533.

Example 53 : Synthesis of 7-[(Z)-2-(2-aainothiazoi-4-yl)-2-{l-carbox.veth -1-oxyimino)acetamido]-3-{4,6-1lamino-1-pheny1pyrimidinium-2-yl) thioaethyl-3-cephea-4-carboxy late 3-Acetoxymethyl-7-((Z)-2-(2-aminothiacol-4-yl)-2-(2-carbox.yetb-l-cxyimino)acetanido)-3-cephem-4-carboxyiic acid (5C0mg) and 4,8-diamino-!-phenyI - 138 -2(IH)-pyrimidinethione (200wg) were reacted in the same Banner as described in Example 50 to give the above-indicated compound (210iag). : 156’C—(decomp.) NHIL: δ (D20 + NaiICOs) 1.48 (d, 3H), 3.48 (ABq, 2H), 4.49 (ABq, 2H), 5.16 (d, IH). 5.76 (s, Hi). 5.73 (d, IH), 6.97 (s, IH), 7.48- 7.83 (a, 5H). iLSlfAL MM) : 672 IRiKBr, cm-») : 17G5 (β-lactam), 1655, 1598, 1515.

Example 54 : Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino) acetamido]-3-(4,6-diamino-1-phenylpyrimidinium-2-yl)thiomethyl -3-Ctfphem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(aminothiazol-4-y])·2 - (cthoxyimino)acetamido] -3-eephea-4-carboxy)ic acid (500mg) and 1,6-diaaiino-1 -pheny 1-2(If!)-pyrjmidinethione (200rag) were reacted in the same partner as described in Example 50 to give the abo\c-indirated ci.mpotaid () 30r;ig). m.P, : 182’C -· (decor;-,) N.HR : S (M v NaHCih) 1.28 (t. 3K). 2.52 (\Bq. 2H>, 4.20 (q, 2H). 4.31 (ABq, 2H), 5.16 (d, iii). 5.75 (s, 151), 5.81 (d, IH), 6.88 (s, IH), 7.48-7.82 (m, 5H) - 139 mmidp, a.ui 623 FKtKOr, cm'’) : 1768 (3-lactan), 1643, 1612, 1600, 1515.

Example 55 : Synthesis of 7-((Z)-2-(2-aainothiazol-4-yi)-2-(ethoxyiBino) acetaraido]-3-[l-(4-chlorophenyi)-4,6-diaeino-l-phenylpyriaidiiuum-2-yl) thioraethyl-3-cephen-4-carboxylate 3-Acctoxyeethy1-7-((Z)-2-(2-arainothiazol-4-y1)-2 -(ethoxyimino)acetamido] -3-cepheai-4'carboxylic acid (500rag) and l-(4-chlorophenyl-4,6-diaBino2(lH)-pyriaidinethione (200mg) were reacted in the saae Banner as described in Example 50 to give the above-indicated compound (170mg), a.P._ : 177‘C—(decorap.) NMR .: δ (D20 + acetone-da) 1.28 (t, 3H), 3.48 (ABq, 2H) , 4.21 (q, 211), 4.32 (ABq, 211), 5.12 (d, 111), 5.73 (s, IH), 5.80 (d. IH), 0.87 (s, IH), 7.52- 7.79 (a, 4H).

MS(FAB..M * j) ; 662 IRfKBr, cm-1) : 1665 (S3-lactam) , 1643, 1610, 1530. .:.7, - 140 Example 56 : Synthesis of 7-[(Z)-2-(2-aninothiazol-4-yl)-2-(2-carboxyprop2-oxyimino)acetaBido}-3-i4,6-diaaino-l-(2,4-diiBethylphenyl)pyrimidiniua-2-ylJthioniethyl-3-cepheD-i-carboxylate 3-acetoxyraethy1-7-[(Z)-2-(2-aninothiazo1-4-yl)-2-(2-carboxyprop-2-oxyiaino)acetaniidoJ-3-cepheiD-4-carboxylic acid (500mg) and 4,6-diamino-l(2.4-dimethylphenyl)-2(l!l)~pyrinidinethione (200sg) were reacted in the same manner as described in Example 50 to give the above-indicated compound (180mg). m.p. : 189C (decump.) NMR : tf (Da0 t NailCOo) 1.44 (s, BH), 2.02 (s, 3H), 2.34 (s. 3H), 3.36 (ABq, 2K), 4.27 (ABq. 2H). 5.06 (d, IH). 5.68 (s, IH), 5.71 (d. IH). 6.S8 (s. IH), 7.087.35 (ra, 3H).

MS(FAB, M t 1) : 714 IRiKBr, cm-1) : 17S8 (β -lactam), 1641, 1600. 1552.

Example 57 : Synthesis of 7-((Z)-2-(2-aninothiazoI-4-yl)-2-(etho.\yiniino) acetamido )-3-( (4.6-diamino-1- (2,4-diaethylphenyl)-p;· rimidiniun -2-yl Jthiomethyl-3-cepheai-4-carboxy late 141 3-Acctoxyraethyl-7-((Z)-2-<2-aminothiazol-4-y1)-2-(ethoxyimino)acetamido] -3-cephem-4-carboxylic acid (500mg) and 4,6-diamino-I-(2,4-dimethylphenyl) -2(lH)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 50 to give the above-indicated compound (lSOmg). m.p,. : 176’C(decomp.) NMR : <5 (DaO + acetone-de) 1.29 (t. 3H), 2.12 (s, 3H), 2.40 (s, 3H), 3.51 (ABq, 2H), 4.21(q, 211), 4.26 (ABq, 2H), 5.OS (d, IH), 5.76 (s. IH), 5.31 (d. IK). 6.50 (s, IH), 7.23--7.41 (ra, 3H).

HSiFAB. M + 1) : 656 ISCKBr, cm'1) : 1770 (^-lactam), 1643, 1610. 1540.

Example 53 : Synthesis cf 7-((Z)-2-(2-aminothiazcl-4-yl)-2-(2-carbox.yprop -2-oxyimino)acetamido]-3-(4,6-diamino-1-(2,6-diaethcxyphen.vl) -pyriraidiniua-2-yl]thiomethyl-3-cephen-ΐ-carboxy;ate 3-Acetoxymethy1-7-((Z)-2-(2-aminothiazol-4-yl)-2-ί -ear: -_-oxyimino)acetauidoJ-3-cephera-4-carboxylic acid (SOOrag) and 4,5-diaraino-1-(2, 6-diaethoxyphenyl)-2(lH)-pyrijnidinethione (BOGrag) were reacted in the same manner as described in Example 50 to give the above-indicated compound (210mg). - 142 m.p., : 1C4*C- (docoap.) SUL· <5* (D20 + NaliCOj 1.46 (s, 69), 3.40 (ABq, 2H). 3.73 (s, 6Π), 4.29 (ABq, 2Ii), 5.12 (d, 111), 5.67 MB(FAB. M ? 1) : 746 IRiKBr, cm'1) : 1766 (/7-lactaa). 1641. 1600. 1550.

Example 59 : Synthesis of 7-((Z)-2-(2-aninothiazol-4-yl)-2-(2-carboxyprop -2-oxyimino)acetanidoJ-3-((4.δ-dianino-l-(4-hydroxyphenyl)PjTinidiniuai-2-ylIthioaethyl-3-cephen-4-carboxylate 3-Acetcxynie thy 1-7-( (Z) -2-(2-aminothiazol-4-y 1)-2-(2-earhox:,/prcp-2-oxyinino)acetainido)-3-cephea-4-carboxylic acid (500mg) and 4,S-diaaino-l-(4hydroxypheny1)-2(III)-pyrimidinethione (ZOOng) were reacted in the saae manner as described In Example 50 to give the above-indicated compound (22O.mg). a.P, : 171’C- (decomp.) V!R : £ (D-0 * NaliCOa) 1.47 (s, 611), 3,39 (ACq, 2H). 4.27 (ABq, 2H), 5.06 (d. 19), .64 (s, 19). 5.74 (d, IH), 6.91 (s, 19), 6,90-7.32 (a, 49).

MLAO, 1 + 1) : 702 IF. (KBr, ca'1) : 1768 (/3- lactam). 1641, 1600, 1525.

Claims (45)

1. I I.A cephalosporin conpound of the formula (I) wherein is a alkyl, C^_ 4 alkenyl, C^_ 4 alkynyl group or -C(R a )(R^)CO2H, wherein R a and R b are the same or different, and each is a hydrogen atom or a C^_4 alkyl group, or R a and R b form a C^_ 7 cycloalkyl group with the carbon atom to which they are linked; R is a C^_ 4 alkyl, C^_ 4 alkenyl or C^_ 4 cycloalkyl group, an amino or C- 1 _ 4 alkyl-substituted amino group, phenyl, or 2-, 4-, or 6-substituted phenyl with two or less substituents selected from C^_ 4 alkyl, C^_ 3 alkoxy, halogen and hydroxy; R 1 is hydrogen or a C^ 4 alkyl group; and Q is N or CH; or a pharmaceutically acceptable non-toxic salt thereof, or a physiologically hydrolyzable ester or solvate thereof. - 144 2. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazoI4-yI)-2-(2-carboxylprop-2-oxyimino)acetamido]-3-(4,6-diamino-1-methyIpyriaidinium

2. -yl)thiomethyl~3-cephem-4-carboxylate.

3. The compound according to Claim 1 which is 7-((Z)-2-(2-aminothiazol4-yl)-2-(2-carho.\ylprop-2-oxyimino)acetamino]-3-(4,6-diamino-l-ethylpyriaidinium2-yl)thiomethyl-3-cephem-4-carboxylate.

4. The compound according to Claim 1 which is 3-(l-aiiyl-4,6diaminopyrimidiniua-2-yi)thio!iiethyl-7’[(Z)-2-(2-aainothiazol-4-yl)“2-(2carboxyprop-2-oxyimino)acetamido]-3-cephem-4-carboxy lata. icmpouad according to Claim 1 which is T-i(Z)· 2-(2-aminothiazoi4-yl)-2-(1-carboxy?th-1-oxyirair.o)acetamido!-3-(4,

5. -diamino-1-methylpyrimidinium2-yl)thioaethy1-3-cephem-l-carboxylain.

6. The compound according to Claim 1 which is 7-( {2)-2-(2-rainothiazol4-yl)-2-(l-carboxyeth-1-oxyimino)acetamido]-3-(4, S-dlamino-l-ethylpyriraidinrjo2-y1)thiomethyl-3-cephem-i-carboxylate.

7. The compound according to Claim i which is 3-(l-allyl-4,SI? - 145 diaainopyrimidiniuni-2-y1)thiomethyl-7-[(Z)-2-(2-aainothiazol-4-y1)-2-(1carboxyeth-1-oxyimino)acetamido)-3-cephem-4-carboxylate.

8. The compound according to Claim 1 which is 7-i(Z)-2-(2-aminothiazol4-y!)-2'(carboxyraetho.\yimino)acetamido3-3’(4,8-diamino-l-fl!ethylpyrinidinium 2-yl)thioraethyl-2-cephem-4-carboxyiate. 2. The compound accnrdin? to Claim 1 which is 7-{(Z)-2-(2-aminothiazol4-yl)-2-(carboxynethoxyiraino)acetaisidol-3-(i,6-diamino-l-ethylpyriaidiniuffl2-yl)thiomethyl-3-cephem-4-carboxylate.

9. 10. The compound according to Claim i which is 3-(l-allyl-4,3diaainopyriniidinium-2-yl)thiofflethyl-7-1(Z)-2-aainothiazol-4~yl)-2(carboxymethoxyi«ino) acetamido]-3-cephem-4-carboxylate.

10. 11. The compound according to Claim 1 which is 7-i(Z)-2-(2-aninothio:ol4-y1)-2-(methoxyimine)acetamido]-3-(4,3-diamino-l-methylpyrimidinium-C-yl) thioraethyl-3-cephem-4-carboxylate.

11. 12. The compound according to Claim 1 which is 7-[(Z)-3-(2-aminothia2ol4-y1)-2-(ethoxyimino)acetamido]-3-(4,6-diaoino-1-methylpit imidiniun-2-yl) •_x - 146 thionethyI-3-cephem-4-carboxylate.

12. 13. The compound according to Claim 1 which is 7-[(Z)-2-(2-aaincthiazol4-y1)-2-(ethoxyimino)acetamido]-3-(4,6-dianino-l-ethylpyriraidiniun-2-yl) thionethyl-3-cephem-4-carboxylate.

13. 14. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-l,£,4thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(l,4,3triaminopyrimidiniuia-2-yl) thiomethyl-3-cephero-4-car boxy lace.

14. 15. The compound according to Claim 1 which is 7-[ (2)-2-(2-aminotiiiazoi4-y1)-2-(I-carboxyeth-l-oxyimino)acetamido)-3-(1,4.3-triaainopyriiaidiniura2-y1)thiomethy i-2-cephem-4-carboxylate. IG. The compound according to Claim ’ which is 7-[(Z)-2-(2-aminothiazol4-y!)-2-(2-carboxyprop-2-oxyiaino)acstaniido]-3’{l,4.S-triaaincpyriaidin;um2-yl) thionethyl-3-c3phetn-4-carboxylate. 17. The compound according to Claim 1 which is ininoi.aiazol4 -y I) -2- (ethoxyimino)acetamido]-3-(1,4,3-triaminopyrimidiniuo-2-vl)thioaeth.vI' 3-c2pheiB-4-carboxylaie. - 147 IS. The compound according to Claim I which is 7-[{Z)-2-(5-amino-l,2,4thiadiazol-3-yl)-2-(ethoxyinino)acetamidoJ-3-(1,4,6-trianinopyrinidiniuin2-yl)thioaethyi-3-cephea-4-carboxylate.

15. 19. The coapound according to Claim 1 which is 7-[(Z)-2-(2-aainothiazol4-yl)-2-(2-propyn-l-o.xyimino)acetamido]-3-(l,4,8-trianinopyrinidiniun-2yl)thicraethyl-3-cepheni-4-carbox.vIate.

16. 20. The compound .according to Claim 1 which is 7-((Z)-2-(2-aainoihiazol4-y 1)-2- (me t hoxy imino) acetamido )-3-(1.4. S-trianiinopyriniidinium-Z-yl) thiome thy1-3-cephea-4-carboxy1a t e.

17. 21. The compound according to Claim 1 which is' 7-[(Z)-2-(5-amino-l,2,4thiadiazo1-3-yl)-2-(ethoxyimino)acetamido )-3-(4,6-dianino-l-aethylpyrlaidinium 2-y1)thiomethyl-3-cepheo-4-carboxylate.

18. 22. The compound according to Claim 1 which is 7-((i)-2-(0-aaino-l,2.4thiad iazo 1-3-yl)-2-(ethoxyimino) acetamido]-3-(4,3-diaraino-1-e ·, hylpyriai Jiniust2-yl)thiomethyl-o-cephea-i-carboxylate. 22. The compound according to Claim 1 which is 7-i(Z)-2-(0-amino-1.2,4thiadiazol-3-y 11-2-(ethoxyiaino)acstafflido)-3-(4,S-diaaLno-l-propylpyrlaidinium· rj - 146 2-yl)thiomethyl-3-cepheB-4-carboxylate,

19. 24, The compound according to Ciain 1 which ::-, 3-(I-allyl-4,5diaminopyriraidiniuni-2-yl)-7-((Z)-2-(5-anino-l,2, l-thiadiazol-3-yl)-2(ethoxyimino)acetaniido]-3-cepheni-4-carboxyiate.

20. 25. The compound according to Claim 1 which is 7-((Z)-'2'(5-araino-1.2,4thiadiazol-3-yl)-2-(methoxy iiaino) acetamido ]-2- !, G-dianinc-l-nethyipyrimidiniun 2-yl)thiomethyl-3-cephen-4-carboxylate. 25. The compound according to Claim 1 which is 7“((Z'-2-{5-aaino-l,2,4th iadiazo 1-3-yl)-2-(me thoxyiisino) acetamido ]-3-(4,3-diaaino-l-ethyipyr iaiair.iua2-yl)thiomethyl-3-cephea-4-carboxylato. The compound according to Claim ’ which is 7-( (Z)-2-(5-amino-l.2,4thiadiazol-3-yl)-2-(2-carbcxyprop-2-oxyaino)acetaaido]-3-(4,3-dianinc-laethyIpyrinidinium-2-yI)thionethy1-3-cephem-4-carboxylate. 25. The compound according to Claim 1 which is 7-( (2)-2-(5-aainc-l, 2,4thiadiazoi-3-yl)-2-(2-carboxyprop-2-oxyinino)acetaaido]-2-(4,3-iiaaino1-ethylpyriraidmium-2-yl)thiomethy1-3-cephes-4-carboxylate. - 149 29. The compound according to Claim 1 which is 7-[(Z)-2-(5-a»ino-l,2,4thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyinino)acetaaidol-3-(4,8-dianiino1-propylpyrimidiniura-2-yl)thiomethyl-3-cephen-4-carboxylate.

21. 30. The compound according to Claim 1 which is 7-((Z)-2-(S-aaino-l,2.4thiadiazo1-3-y1)-2-(2-carboxyprop-2-oxyijiino)acetamido]-3-(1-butyl-4,3diaminopyrimidinium-2-yl)thiomethyl-3-cephea-4-carboxyIate.

22. 31. The compound according to Claim 1 which is 7-{(Z)-2-(2-aminothiazcl· 4-yl)-2-(2-carbox,yprop-2-oxyimino)acetaBido]-3-(4,6-diamino-l,5diaethylpyriaiidiniuia-2-yl) thiomethy l-3-cephem-4-carboxylate. The compound according to Claim 1 which ia 7-((Z)-2-(2-aninothiazol 4-yl]-2-(2-carboxyprop-2-cxyiaino)acetamidoJ-3-(4,S-liamino-S-ethy1-1me thy Ipyriaidiniun-2-yl) thiomethyl-O-cephem^-carboxyiaie. T ii e c o mpounu according a c. □ i r i w h i c n is 1-,7. . (- am 1 .η n.. ± * 4-yl'-2-(2-carhoxyprop-2-oxyimino)acetamido]-3-(4,5-diamino-1-ethy;-i methylpyriaidiniym-2-yl)thiomethy1-3-eephea-4-carboxylate.

23. 34. The compound according to Claim which i (Z)-2-(2-aminoth;azol - 150 4-yl)-2-{2-carboxyprop-2-oxyimino)acetamidoJ-3-(4.6-diaiaino-l,5diethylpyrimidiniua-2-yl) thiomethy 1-3-cephen—1-carboxylate. The compound according to Ziaisi 1 which is 7-[(Z)-2-(2-aninothiazo[4-yl)-2-(2-earboxyprop-2-oxyiinino)acetanino]-3-(5-aethyl-l,4,3trianinopyriraidin iua-2-y1)thiomethy1-O-esphem-A-carboxyla ta. The compound according to Claim 1 which is ?-((2)-2-(2-aminothiazci4-y 1)-2-(2-carboxypr op-2-cxy imino) acetamido]-3- (i.S-diaairo-lphenylpyriinidiniuni-2-yl) thiomethy l-3-cephem-4-carboxylate.

24. 37. The corar-curti according tc Ciaia i which is 7-[(Z)-;-{2-arainotkiazol4-; 1)-2-(2-carfcoxyprop-2-0xyiaino)acetamido]-3-[1-(4-hydroxyphsnyi)-4.2diaminopyriraidiniua-Z-yl ]-thiomethy I-3-cephe!a-4’car boxy late.

25. 38. The ?oap.’>!jr,d according to Claim 1 which is 7-( (2)-2-(2-anincthi,izoi4-y 1) -2- (carboxymethoxj’imino)acetamidoj-3- (4,S-diamino-1-pheny · pyr lai-dini: 2-yI)thioaethyt-3-cephem-4-carboxylate. The compound according to Claim 1 which is ?-((Z)-2-(2-anmothiazoi4-y!} - 2- (i -carcoxyeth-1-oxyimino)acetamido I-3- (4.6-diaaino-IIE 904047 - 151 phenylpyrimidiniuat-2-yl) thiooethyl-3-cephem-4-carboxylate.

26. 40. The compound according to Claim 1 which is 7-( (Z)-2-(2-aniinothiazol4-yl)-2-(ethoxyiraino)acetamido]-3-(4,6-diamino-1-phenylpyriaidiniua-2-yl) thiomethyl-3-cephein-4-carboxy late.

27. 41. The compound according to Claim 1 which is ?-i(Z)-2-(2-aainothiazol1- y l)-Z-(ethoxyiainc)acetamido]-2-(l-(4-chiorophsny1)-4,3-dianinopyrimidiniua 2- yljthicmethy1-3-cephem-4-carbo.xylate. The compound ac 4-y1)-2-{2-carboxypr ding to Claim 1 which is 7-( (Z)-2-(2-aainothiazoi-i-oxyimino;acetamidcj-3-(4,3-dianino-1-(2,4diraeihylphenyl) -pyri.Tiidiniuai-2-yl ] thiooethy l-2-cephea-4-carboxyIate.

28. 43, The coopouno according to Claim 1 which is 7-((2)-2-(2-aminothiazolI-yl)-2-(ethoxyini no)acetamido]-3- (4,5-diamino-1-(2,1-dime Mviphenyl )pyrimidiniua-2-yί!thioaethyl-3-ccphea-4-carhoxylate. 41. The compound according to Claim 1 which is 7-[ (Z)-2-(2-ammothiaco 1 4-y 1) -2- (2-carboxy pro p-2-oxy iaino) ace tarn i.doj-2-(4,6-diataino-1-(2,6dimethoxyphenyl)-p.vrlaidiniua-2-yl]thiomethyl-O-cephea-l-carboxy]ate. t - 152 15. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol4-y1)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-[4.6-diamino-1-(4chlorophenyl)-pyriflidinium-Z-yl]thioraethyl-3-cephem-4-carboxylatc.

29. 46. The compound according to Claim 1 which is 7-[(Z)-2-(2-aoinothiazol4-yI)-2-(l-carboxyeth-l-oxyimino)acetamido]-3-(4,8-diaainc-lpropylpyrimidinium-2-yl]thioaethy1-3-cephem-4-carbcxylate.

30. 47. The compound according to Claim 1 which is 7-((Z)-2-{2-aminothiazol4-yl)-2-(2-propyn-1-oxyiniino)acetamido]-3-(4,8-diaraino-l-aethylpyrimidinium 2-yl) thioaethyl-3-c ephe«-4-carbox.y late.

31. 48. The coapound according to Claim 1 which is {C-aminotiiiazol4-yl)-2-(2-propyn-l-oxyimino)acetamido J-3iamino-1-? thylpyriaiciniua2-yllthiomethyl-3-cepheffl-4-carboxylate.

32. 49. The coapound according to Claim l which is 7-iiZ;-2-i2-amino:hiacoi4-yl)-2-(2-carboxyprop-2-oxyinnno)acetamido]-3-(1-cyclopropy1- !, Jdiaoinopyrimidinium-2-yl)-3-cephea-4-carbcxylate. - 153

33. 50. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol~ 4-yl)-2-(2-propen-l-oxyimino)acetamido]-3-(4,0-diamino-l-methylpyritsidinium2-yl)-3-cephem-4“carboxylate.

34. 51. The compound according to Claim I which is 7-[(Z)-2-(2-aminothiazol4-yi)-2-(2-propen-i.Oxyimino) acetamido j-3-(4, S-diamino-l-ethylpyriinidinium2-yl )-3-eephea-4-carbox.y late.

35. 52. A process for preparing the cephalosporin coapounds of formula! I ), pharmaceutically acceptable non-toxic salts thereof, or physiologically hydrolyzable esters or solvates thereof, which comprises reacting the compounds of the formula! II) with tbe coapounds of the formulaiHi) in th? presence of a solvent ι - 154 wherein R l , R 2 , R 3 and Q are the same as defined in Claim 1 ; n is an integer of 0 or 1 ; R 4 is a hydrogen atom or an amino-protecting group ; R 6 is a C x .4 alkyl, C 3 ~« alkenyl or C a . 4 alkynyl group, or -C(R R )(R b )CO 2 (R c ), wherein R a and R b are the same cr different, and each is a hydrogen atom or a C1.4 alkyl group, or R and R b form a C.·,.? cycloalkyl group with the carbon atom to which they are linked ; and R c is a hydrogen atom or a carboxyl-protecting group ; R fl is a hydrogen or a carboxyl-protecting group ; and L is a leaving group.

36. 53. The process according to Claim 52 wherein the solvent is water, or a mixed solvent of water and a water-miscible solvent.

37. 54. The process according to Claim 53 wherein the water-miscible solvent is acetonitrile or acetone.

38. 55. The process according to Claim 52 wherein the solvent has a pH of from 5 to 8. »£» - 155

39. 56. The process according to Claim 52 wherein the compounds!II) are used in an amount of from 1 to 2 equivalent(s) based on 1 equivalent of the compounds(ΙΠ).

40. 57. The process according to Claim 52 which is carried out in the presence of one or more stabilizing agents. The process according to Claim 57 wherein the stabilizing agent is sleeted from the group consisting of sodium iodide, potassium iodide, sodium bromide, potassium bromide and potassium thiocyanate. 53. The process according to data 52 which further comprises removing the amino protecting group and/or the carboxyl protecting group and/' or reducing the S-oxide, before or after reacting the compoundsί 'I) and the compounds (III). GO. A pharmaceutical composition which comprises a therapeutically effective amount of one or more of the cephalosporin compounds of formula (I) recited in Claim 1, pharmaceutically acceptable non-toxic salts thereof, or physiologically hydrolyzable esters or solvates thereof as active ingredients, in association with a pharmaceutically /J lb» - 156 acceptable carrier, excipient or other additive therefor.

41. 61. A compound of the formula (1) as defined in any one of Claims 1 to 51 for use in medicine.

42. 62. A ccmpound of the formula (I) as defined in any one of Claims 1 to 51 for use as an antibiotic.

43. 63. The use of a ccmpound of the formula (I) as defined in any one of Claims 1 to 51 for the manufacture of a medicament for antibiotic use.

44. 64. A process for preparing compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof, or physiologically hydrolyzable esters or solvates thereof, substantially as hereinbefore described by way of Example.

45. 65. Compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof, or physiologically hydrolyzable esters or solvates thereof, whenever prepared by a process as claimed in Claim 52 or 64.