IE850866L - Cephalosporins - Google Patents

Abstract

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(substituted)-iminoacetamido]-3 -[3-(quaternaryammonio)-1 - propen-1-yl]-3-cephem-4-carboxylates of the formula <IMAGE> in which R<1> and R<2> are as defined herein and <IMAGE> is a quaternary ammonio group as defined herein, and salts, solvates, hydrates and esters thereof, are potent antibacterial agents. Processes for their preparation and intermediates in such processes are described. [GB2157293A]

Description

8 4 0 '3 o This application relates to 7-[2-(5-amino-lfh4-thiadiazol-3-yl)-2-(substituted)iminoacetamido]-3-[3-(quatemaryammonio)-i-propen-l-vl ]-3--cephem-4-carboxylates of the formula R^HN- / > 1 : CONH \ 2 NOR © CH=CHCH?-N=Q 5 in which R* and R~ are as defined herein and is a quaternary amnionic group as defined herein, and to salts and esters thereof. This invention also relates to processes for the preparation of the compounds of Formula I and pharmaceutical compositions containing at least one compound of Formula I.

A) U.S. Patent 4,390f534, issued June 28, 1983 to Tsutomu Teraji et a_l., discloses cephem and cepham compounds of the £ ormula 5 wherein R^- optionally is ami no or substituted protected amino,- R" is hydrogen, acyl , arylf substituted alkyl, alkenylt. alkyny 1, 4 optionally substituted cycloalkyl, cycloalkenyl or an 0- or S-containing 5-me:nbered heterocyclic ring substituted with ojco 3 4 group(s); R is hydrogen or alkyl; R is hydrogen, acyloxyalky1, acylthioalkyl, optionally substituted pyridinioalkyl, optionally 5 substituted heterocyclylthioalkyl, alkyl, halogen, hydroxy or optionally substituted thiazolioalkyl; and is carboxy or 3 " 4 protected carboxy; provided that R is COO when R' is optionally substituted pyridinioalkvi or optionally substituted thiazolioalkyl; and the dashed line indicates either a single or double bond. 10 European Patent Application No. 13,762, published August 6, 1980 is concordant thereto and has a similar disclosure.

U.S. Patents 4,381,299 (issued April 26, 1983), 4,331,665 (issued May 25, 1982) and 4,332,798 (issued June 1, 1982) each . issued on parent applications of U.S. 4,390,534, and have similar 15 disclosures.

B) European Patent Application No. 62,321, published October 13, 1982, discloses cephem compounds of the formula i ~2 ■ ,, wherein R~ is amino or protected amino; R is an optionally 20 substituted lower aliphatic hydrocarbon group, or cycloalkenyl; and the group of the formula / _ \ N ® i is an optionally substituted heterocyclic cat. j on group containing more than one n;r.:oaen atom; and pharmaceut 1cal ly acceptable salts thei eof. Al.«;-o disclosed are intermediates of the formula 12 4 wherein R and R are as defined above, R is a protected carboxyl croup and X is an acid residue.

C) European Patent Application No. 74,653, published March 23, 1983, discloses cephem compounds of the formula wherein R^" is amino or protected amino; R'" is ?>n optionally substituted lower aliphatic hydrocarbon group, cyclo(lower)alkyl or cvclo(lowerJalkenyl, R^ is (lower)alkylamino, N~protected(1 ower)a 1kylamino , di(lower)alkvlamino, sulfo(lower)alkylamino, hvdr oxy(lower)-alkylairj.no, N-protected hydr oxy (lower ) a 1 ky lam no , acyloxy(lower)-alkyl, (1 ewer)alkoxy(lower)alkoxy(lower)alky1, di(1ower)alkylamino-(lower)a1kyl, (lower )alkylthio(lower)alkyl, (lower)a 1kylth io, 6 (lower ) a 1k oxy, (lower )alkoxy(lower )a 1k oxy, hydroxy(lower )alkoxy, acy 1 (lower)alky 1, hydr oxy(lowerjalkylthio, di(lower)alkylamino- ( 1 ower )a 1 ky 11hio, N-containing unsaturated 5-mernbered heterocyclic group, N-containing unsaturated 5-membered 5 heterocyclicthio, or N-containing unsaturated 5 or 6-membered heterocyclicthio(lower)alky 1 which may be substituted with suitable substituent(s); and 4 R is hydrogen or (1ower)a 1kyl; or a salt thereof.

D) U.S. Patent 4,332 , 800, issifed June 1 , 1982 to Tsutomu Teraji i(i et al . , discloses inter alia compounds of the formula wherein R"^ is amino or protected is hydrogen or carbamoyl.

E) European Patent Application 1982, discloses cephem compounds 2 amino; R is (lower)alkyl and X No. 47,977, published March 24, of the formula (0) Am —T —C CONH- II . N I 0-R_ COO 0 CH2R1 7 wherein m is 0 or 1; Am is optiona liy substituted ami no; T is a thiadiazolyl moiety (attached to the other groups by two of its carbon atoms); R-, is hydrogen, opt ionally substituted alkyl, cycloalkyl or optionally substituted carbamoyl; and is optionally 5 substituted thiazolio, optionally substituted pyrazolio, tri(lower)-alkylammon10 or a pyridinio group of the formula in which R8" is substituted (lower )alkyl [the substituent being cycloalkyl, phenyl, hydroxy, alkoxy, halogen, cyano, carbamoyl 10 ca rboxyl or sulf o], (lower ) alkenyl or carboxy-substituted (lows-r)-alkenyl, (lower)alkylthio or carboxy-substituted (lower)alkylfchio, apino or monosubstituted amino [the substituent being (lower)alkylr (lowerJalkanoyl or aminobenzenesulfonyl], di(lower)alkylamino, substituted carbamoyl (the substituent being (lower) alkyl, 15 hydroxy(lower)alkyl, (lower Jalkoxy, hydroxy or cyano], di(lower)-alkvlcarbamoyl, thiocarbarooyl, cycloalkyl, phenyl, hydroxy, (lower)alkoxy, halogen, (lower)alkoxycarbonyl, (lower)alkanoyloxy, (lower)alkanoy1, carboxylr sulfo, cyano, nitro or hydr oxysulfo-(lower)alkyl; Rb is hydrogen or carbamoyl, or has the same Si C ci 20 meaning as R ; and R is hydrogen or has the same meaning as R ; and salts thereof.

Although not formally related, European Patent Application No. 251017, published March 11,. 1981, has a similar disclosure. 25 F) European Patent Application Ho. 30,630, published June 24, 1981, discloses 3-vinyl cephem compounds of the formula 8 CONH' ❖ 0 R •CH«CH. wherein R~ is an optionally protected amino-subs 11tuted heterocyclic group which may also have halogen, or a group of the formula Rjso2HN 3 5 in which R is (lower)alkyl; R is carboxy or protected carboxy; and A is lower alkylene which may have a substituent selected from amino, protected amino, hydroxy, oxo and a group of the fi. A formula -N~OK'*, wherein R** is hydrogen, cyclo( lower ) alkenyl, (lower)alkynyl, (1ower)alkenyl [optionally substituted by carboxy 10 or protected carboxy],, (lower Jalkyl [optionally substituted by one or more of carboxy, protected carboxy, awino, protected amino, cyano, phosphono, protected phosphono and a heterocyclic group which itself may be substituted]; and salts thereof.

This application specifically discloses compounds of the l5 formula S 0 4 in which OR is methoxyf carboxymethoxy, tert-butoxvcarbonvl-methoxy or 1-tert-butoxycarbonylethoxy.

G) U.K. Patent Specification No. 1,399,086 published June 25, 1975, contains a generic disclosure encompassing a vast number of 5 cephalosporins of the formula R-C-CO-NE * J ^-OR* (J/ COOH wherein H is hydrogen or an organic group, Ra is an etherifying monovalent organic group linked to the oxygen through a carbon, atom, B is or ^S-»0, and P is an organic group. In one 10 embodiment, P may be inter alia a vinyl group of the formula in which R3 and R* independently may be hydrogen, nitrile, (lower Jalkoxycarbonyl, or substituted or unsubstituted aliphatic, cycloaliphatic, araliphatic or aromatic. However, the 5-amino-15 1,2,4"thiadiazol-3-yl group is not identified as a possible R substituent and there is no disclosure or suggestion that P may be a quaternary anunonio-substituted propenyl group. O.S. Patent 3,971,778 and its divisional® Nos. 4,024,133, 4,024,137, 4,064,346, 4,033,950, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 have 20 similar disclosures. 1! 0 / H) European Patent Application No. 88,385, published September 14, 1983, discloses compounds of the formula R' 1 —CONH- 6r2 .! J L i •} xn which R" is (unsubstituted) thiadiazolyl; R~ is carboxy- (lower)alky1 or protected carboxy(lower)alky1; R3 is hydrogen, 4 halogen or (lower)alkenyl; and R is carboxy or protected carboxy Although 1-propenyl is listed as one of the possible meanings of R^, the application only exemplifies compounds where R3 is hydrogen, chloro or vinyl. 1) U.S. Patent No. 4, 307, 233 issued to Daniel Farge et aJL. on December 22, 1981, discloses inter alia, 3-vinylcephalosporin derivatives of the formula CONH CH=CH-N ^,R3 \*4 COOH 5 in which R inter alia may be alkvl, vinyl, cyanomethyl or a 34 protective group such as 2-methoxyprop-2-yl, and R and R" are alkyl groups (optionally substituted by hydroxy, alkoxy, amino, 3 4 alkylamino or dialkylamino) or phenyl groups, or R and R , taken together with the nitrogen to which they are attached, may form a saturated heterocyclic ring of 5 or 6 members,, optionally containing another hetero-atom selected from N, 0 and s, and optionally substituted by an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinyl cephalosporin derivatives. There is no disclosure or suggestion of a 5-amino- J i 1, 2,4-thiadiazol-3-yl moiety in place of the 2-aminothia2:oi-4~yl substituent or of a quaternary ammon10-subs t it ut ed propenyl moiety for the 3-substituent. Published United Kingdom Patent Application No. 2,051,062 is concordant thereto and has a similar 5 disclosure.

J) European Patent Application No. 53,537, published June 9, 1982, discloses, inter alia,-. 3-vinylcephalospor in derivatives of the formula N—r C CONH 1 //\T a J As/ \ c A H2 °>C\b0B5 0 I \r4 5 5 COOR2 10 in which R? and R^ are the same or different and are hydrogen or alkvlp or taken together, form an alkylene group containing 2 or 3 carbon atoms, R^ is an acid protecting group, R, is an acid protecting group such as an ester, and R,, are the same or different and are hydrogen,, alkyl (optionally substituted by 15 hydroxy,, alkoxyp amino, alkylamino or dialkylamino) or phenyl groups, or an° taken together with the nitrogen to which they are attached, m,y form a saturated heterocyclic ring of 5 or 6 members,, optionally containing another hetero-atom selected from N, 0 and S,. and optionally substituted by an alkyl group. 20 The compounds are useful as intermediates in the preparation of 3-thiovinyl cephalosporin derivatives. There is no disclosure or suggestion of a 5-amino-l,2,4-thiadiazol-3-yl moiety in place of the 2-aminothiazol-4-yl substituent or of a quaternary ammonio-substituted propenyl group for the 3-substituent. 25 U.S. 4,423,214 is concordant thereto and has a similar disclosure.

K) European Patent Application No. 53,074, published June 2, 1982, genetically discloses a vast number of 3-vinylcephalosporin derivatives of the formula wherein (in one of several embodiments) may be N - XJ H2 -C-CO- II N in which R^ inter alia may be hydrogen, alkyl, vinyl, cyanomethyl, an oxime-protecting group such as trityl, etc., or a group of the formula -C-COORC, 3 3 in which Ra_ and R*5 are the same or different, and may be hydrogen, alkyl or, taken together,, an alkylene radical of 2 or 3 carbon atoms, and RCg is hydrogen or an acid-protecting radical; R°2a is hydrogen or an acid-protecting radical such as methoxymethyl R° (in one of several embodiments) may be a methyl group substituted by a 5- or 6-membered aromatic heterocyclic ring containing a single hereto atom, such as 2- or 3~pyridyl, 2- or 3-thienyl or 2- or 3-furyl; and 1 li 1*3 is s group of the formula R„SQ,0- 4 2 , in which R. may be alkyl, trihalomethyl or optionally substituted I phenyl. ! I 5 These compounds are stated to be intermediates in the ' preparation of compounds in which the 3-substituent is a group of I the formula R" I ~CH~C~SH ; which are stated to have antibacterial activity. i 0 Although this patent includes the possibility of R° being a methyl group substituted by an N-containing heterocyclic ring, in both the intermediates and final products (thus giving a heterocyclic-substituted propenyl moiety)„ it teaches only that the heterocyclic ring is attached via one of its carbon atoms. Thus, there is no 5 suggestion of a quaternary ammonio-substituted propenyl group. The reference exemplifies R° in the intermediates and final ' products only as methyl. Further, in both the intermediates and final product# the propenyl group must contain a second substituent 4 (-O^SR or -SR, respectively). Also there is no disclosure or 0 suggestion of a 5-amino-l,2,4-thiadiazol-3-yl moiety in place of the 2-aminothiazol~4-yl substituent.

L) European Patent Application No. 53,538, published June 9» 1982, discloses, inter alia, 3-vinylcephalosporin intermediates of the formula 5 in which n is 0 or 1, R is hydrogen, alkvi, vinyl, cyanomethyl 3 or an oxime-protecting group, and R xs halogen. There is no disclosure or suggestion of a 5-amino-l,2,4-thiaciazol-3-yl moiety in place of the 2-aminothiazol-4~yl substituent, and no disclosure or suggestion of a 3-halo-l-propen-l-yl substituent the 3-position.

Complete Disclosure This application relates to novel cephalosporin deriva tives which are potent antibacterial agents. More particularly, it relates to compounds of the formula N- R^KN' I I •C I! N CONH ■ I \ *> OR" © cocP wherein R"5" is hydrogen or a conventional amino-protecting group, R is hydrogen, a straight or branched chain alkyl group contain ing from. 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing from 3 to 6 carbon atoms, or a group of the formula R4 R4 COOH I 3 l 3 \y -C-CH*CH-R , -C-CEC-H , f\ or R5 E5 / ^ A R " C-COOH i5 t 3 in which R is hydrogen, (lower)alkyl or carboxyl, X is halogen, ^ 5 hydroxy or (lower)alkoxyf and R*" and R are each independently 4 S hydrogen „> methyl or ethyl# or R** and R „ taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms,, and 1. 0 is a quaternary ammonio group, end nontoxic pharmaceutically acceptable salts and physiologically hydrolvzable esters thereof. Also included within the scope of the invention ere the solvates arid hydrates of the compounds of Formula t, as we 11 as 5 the tautomeric forms of the compounds of Formula I, e.g. the 2-iminothiazolin~4-vl form of the 2~aminothiazol-4-yl moiety.

In another aspect,, this application relates to a process for the preparation of the compounds of Formula I.

As shown in the structural formula, the compounds of 10 Formula I have the "syn" or "Z" configuration with respect to the alkoxyimino group. Because the compounds are geometric isomers, some of the "anti" isomer may also be present. This invention comprises compounds of Formula I containing at least 90% of the •syn" isomer. Preferably the compounds of Formula 1 are "syn* 15 isomers which are essentially free of the corresponding "'anti® isomers, In addition to geometric isomers possible with respect to the alkoxyimino group, the compounds of Formula 1 (and the intermediates of Formulae viii and IX) also form geometric (cis 20 and trans) isomers about the double bond of the propenyl group. Both the cis (" Z*) and trans ("E") isomers of these compounds are specifically included within the scope of this invention.

The nontoxic pharmaceutically acceptable salts of the compounds of Formula I include salts with mineral acids such as 25 hydr ochlor ic , hydr obromic, phosphoric and sulfur ic, or with organic carboxylic acids or sulfonic acids such as acetic, tr ifluoroacetic, citric# formic,, maleic, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, malic, methane-sulfonic, benzenesulfonic, p-toluenesuIfonic and other acids 30 known and used in the penicillin and cephalosporin arts. Preparation of these acid addition salts is carried out by conventional techniques. 1 7 Examples of physiologically hydrolyzable esters of the corpounds of Formula I include indanyl, phthalidyl, methoxy-methyl, acetoxymethvl, pivaioyloxymethyl, giycyloxymethyl, phenylglycyloxymethyl, 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl and 5 other physiologically hydrolyzable esters known and used in the penicillin and cephalosporin arts. Such esters are prepared by conventional techniques, known in the art.

The compounds of Formula I in which is hydrogen exhibit high antibacterial activity against various Gram-positive 10 £nd Gram-negative bacteria? and are useful in the treatment of bacterial infections in animals, including man. The compounds of Formula I may be formulated for parenteral use in a conventional manner utilizing known pharmaceutical carriers and excipients, and may be presented in unit dosage form or in multi-dosage 15 containers. The compositions may be in the form of solutions, suspensions or emulsions in oily or aqueous vehicles, and may contain conventional dispersing,, suspending or stabilizing agents. The compositions may also be in the form of a dry powder for reconstitution before use, e.g. with sterile, pyrogen-free 2c water. The compounds of Formula I may also be formulated as suppositories utilizing conventional suppository bases such as cocoa butter or other glycerides. The compounds of this invention may, if desired, be administered in combination with other antibiotics such as penicillins or other cephalosporins. 2[> When provided in unit dosage forms the compositions will preferably contain from 50 to 1500 jng of the active ingredient of Formula I. The dosage of the compounds of Formula I is dependent on such factors as the weight and age of the patient as well as the particular nature and severity of the 30 disease, and is within the discretion of the physician. However, the dosage for adult human treatment will usually be in the range of from 500 to 5000 mg per day, depending on the frequency and route of administration. When administered intramuscularly or intravenously to an adult human? a total dosage of 3.-3 from 750 to 3000 mg per day, in divided doses, no rrally will be sufficient, although higher daily doses of some 1 f3 of the compounds may be desirable in the case of Pseudoronas infections.

The quaternary ammonio group of the formula 5 may be acyclic* cyclic, or a combination of the two, and may contain one or more additional hetero atoms selected from nitrogen,- sulfur and oxygen.

An example of an acyclic quaternary ammonio group is a group of the formula 0 6 ©I 7 10 -N-R 1 8 R in which R^, and R® may be the same or different and may, for example, be (lower Jalkyl or substituted (lower)alkyl in which the substituents are, for example, halogen, amino with the provision that the amino group may not be on an a-carbon, hydroxy with the 15 provision that the hydroxy group may not be on an a-carbon, (lower)alkoxy with the provision that the alkoxy group may not be on an e-carhont, (lower)alkylthio, (lower)alkylamino, di(lower)-alkylamino, carbamoyl, (lower)alkenyl, phenyl(lower)alky1, phenyl or substituted phenyl (in which the substituents may be, for 20 example, halogen, hydroxy, amino, (lower)alkylamino, di(lower)-alkylamino, acylamino, (lower)alky1, (lower)alkyIthio, (lower)-alkoxy).

Examples of cyclic quaternary ammon io groups are fully unsaturated monocyclic heterocyclic ring systems, and bicyclic 25 heterocyclic ring systems in which at least one N-containing ring is fully unsaturated. Suitable cyclic quaternary ammonio ring 1 9 systems include, for example, those of the corrnulae «5 »N -K- I -R* ^s-^N^o ■N— I i 0^\ *RM 'N 11 Q —*E" JJ 10 and the like, in which R9 and R10 are the same or different and 2 0 10 fray be, for example, hydrogen, halogen, amino, (1 ower)a 1kyl, (lowe r ) a.i keny 1, (lower )alkvlthio, carboxy, hydroxy, (lower )- alkoxye (lower)alkoxv(lower )alkvl, halo(lower)alkyi, hvdroxv- (lower ) al kyl, amino (lower ) alky1, (1 ower ) al ky lamino (lower ) al ky 1, d i (lower ) al kyl ami no (lower } al ky 1, (lower jalkylammo, di (lower ) - alkylamino, ca rboxy(lower)alky1, car boxy(lower)alkylamino, carboxy (lower Jalkylthio,. carbamoyl, N-(lower )alkylcarbam.oyl, f ormylairino, acylamino, acyloxy, phenyl, pyr idyl, amidino, guanidino . Where the structure of the heterocyclic 9 10 ring permits, R and R" , taken together, may be an alkylene group containing from 3 to 5 carbon atoms, e.g. propylene.

Examples of combined acvclic/cyclic quaternary ammonio groups include, for example, those of the formulae © / 1 1 -R" 1 *? 1 1 •N —4—tc~ 12 1 "> ®r~>c M O _/ ©/~>r' -N S /v_/ R* e N NH .12 © / \ © /Ti N- (lower) alkyl, -n, W —i H. 2 1 and the like, in which R"^ may be, for example, (lower)alkyl, ( lowerJalkoxy(lowerJalkyl, hydroxy(lowerJalkyl with the provision that the hydroxy may not be on an a-csrbon, carboxy(lowerJalkyl, ami. no( lower Jalkyl with the provision that the amino may not be on an c**Cdrbon(lower ) alkenyl, halo( lower ) alkyl, allyl, and R may be, for example, hydrogen, hydroxy, halogen, (lower Jalkylf hydroxy(lower Jalkyl, (lower Jalkoxy(lower Jalkyl, halo (lower J alky 1, amj.no (lower J alky 1, (lower J al koxy £, (lower J-alkyltfcio, (lower Jalkenyl, amino, (lower Jalkylamino, di(lower)-alkylamino, acylamino, acyloxy, "carbamoyl, amidino(lower Jalkyl, phenyl, pyr idyl, amidinoguanidino.

Preferred quaternary-ammonio groups are those of the forrula© R13 ® I 14 -N-R 1 15 R © -H I -4 e -W ) V R" -N e •R 18 (CH_) 4 Ti © and Nf R' 2C 21 wherein R~ , R""* and R"* are the same or different and are (lower Jalkyl, (lower J alkenyl, amino(lower J alky1 with the provision that the amino may not be on an a-carbon, or hydroxy-(lower Jalkyl with the provision that the hydroxy group may not be on an c-carbon; Rl0 is hydrogen, (lower Jalkyl, (lower Jalkoxy, (lower J-alkylthio, amino, (lower J alkylamino, di(lower J alkylamino, formyl-amino, (lower Jalkanoylami.no, carboxy, hydroxy, carboxy (lower J -alky1, carboxy(lowerJalkylthio, hydr oxy(lower J alky1, halo(lower J - vr% rjI H) W alkyl, amino( lower Jalkyl; (lower Jalkoxy (lower ) alkyl, carbamoyl or 1 5 N-(1ower)alkylcarbamoyl# or R~ may represent a divalent alkylene group having 3 to 5 carbon atoms; R17 is (lowerJalkyl, (lower Jalkoxy(lower Jalkyl, halo- 5 (lower)alky 1, allyl, hydroxy(loverJalkyl with the provision that the hydroxy group is not on the a-carbon, amino(lowerJalkyl with the provision that the amino group is not on the a-carbon, or phenyl(lower Jalkyl; 1 O R is hydrogen, (lowerJalkyl, (lowerJalkoxy^ (lowerJ-10 a 1 koxy (lower J alkyl, (lower J alky It hi o, amino, (lower J alkylamino, di(lower Jalkylamino, carboxy, hydroxy, carboxy(lower Jalkyl, hydr oxy(lower J alky1, amino(lower J alkyl, formylamino, (lowerJ-aikanoylamino, carbamoyl or N-(lower Jalkylcarbamoyl; n is an integer of from 1 to 3, inclusive; i Q 15 z is CH. or, when n is 2, Z also may be S, 0 or N-R'", ^ G in which B " is hydrogen or (lowerJalkyl; and 20 2i R and R ~ are the same or different and are hydrogen, (lower J alkyl, (1 ower Jalkoxy, (lower Jalkylthio, amino, (lower J-alkylamino, di(lower Jalkylamino, carboxy, hydroxy, hydroxy-20 ( lower Jalkyl, amino(lower Jalkyl, (lower Jalkoxy(lowerJalkyl, carboxy(lower Jalkyl, carboxy(lower Jalkylamino, (lower Jalkanoylamino,, carboxy(lower J aikanoylamino? carbamoyl or H~(lower Jalkyl-carbamoyl.

Par ticularly preferred quaternary ammon io groups are 25 N~(lowerJalkylpyrrolidinio (and especially N-methylpyrrolidinio), tn (lower )alkylammonio (and especially trimethylammonioJ , pyri-diniOf aminopyrid inio, formylaminopyridinio, carbamoylpyridinio, amino( lower J al ky Ipy r i d in i o carboxypyridinio, hydr oxy (lower J~ a Ikv Ipyr idinio.. N- (lower Jalkylcarbamoylpyr idinio{, (lower J -30 alkylenepyridinio, 2~methylthiazolio and 2-amino~5-thiazolo-(4,5~c Jpyridinio.

In the compounds of Formula I, particularly preferred ? values of R~ are (lover)alkyl (and especially methyl), cycloalkyl containing from 3 to 5 carbon atoms, 1-carboxycycloalk-l-yl containing from 3 to 5 carbon atoms? allyl, propargyl and carboxyllowerJalkyl (and especially 2-carboxyprop~2-yl). The most preferred compounds of the invention are 1) 7-12-(5-amino-l,2,4-thiadiazol~3-yl)-2-methoxyiminoacetamido]-3-( 3 - (tr imethylammonio) -1-propen-l-yl 1-3-ceph em-4-ca rboxyl ate, 2) 7-[2-(5-amino-l,2,4-thiadiezGl-3-yl)-2-methoxyiminoacetamido]-3-13-(l~methylpyrr olidin io)-1-propen-l-ylJ-3-cephem-4-ca rboxy-late, 3) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[3-pyr idinio-1-propen-l-yl]-3-cephem-4-carboxylate, 4) 7-12-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]- 3-[3-(3-aminopyr idinio)-1-propen-l-yl]-3-cephem-4-carboxylate, 5) 7-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido J -3— [ 3— ( 3-formylaminopyridinio)-l-propen-l-yl ]-3-cephem-4- ca rboxylate, 6) 7-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidoJ -3-[3-(3-aminomethyIpyridinio)-1-propen-l-yl3-3-cephem-4- carboxylate, 7) 7-l2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]- 3-[3-(3~carbamoylpyr idinio)-1-propen-l-vl3-3-cephem-4-carboxylate, 8) 7-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-(4-carbamoylpyridinio)-l-propen-l-yl]~3~cephem-4- carboxylate, 9 ) 7—12—(S-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[3-(2~methylthiazolio}-1-propen-l-yl]-3-cephem-4-carboxylate, 10 ) 7- [ 2- (5-ar.ino-l, 2, 4-th iadiazol-3-y 1)-2-me thoxy iminoacetamido J- 3-[3-(2-amino-5-thiazolo[4,5-c3pyridinio)-1-propen-l-yl3-3-cephem-4-ca rboxylate, 11) 7-[2—(5—amino—1,2,4-thiadiazol-3-y1)-2-methoxyiminoacetamido]-3-I3-(4-hydroxymethyIpyridinio)-1-propen-l-yl]-3-cephem-4- ca rboxylate, 12) 7-12-(5-amino-l,2,4-thiadiazol-3-y1)-2-methoxyiminoacetamido 3- 3- [ 3- ( 3-hydroxymethylpyndinio)-l-propen-l-yl ]-3-cephem~ 4-ca rboxylat e , 13) 7-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyinunoacetamido] 3-[3-{4-{N-methylcarbamoyl}pyridinio)-1-propen-l-yl]- 3-cephem-4-ca rboxvlate f 14 ) 7- ( 2- (5-air. in o~l, 2, 4-th iadia2ol~3-yl ) - 2-me thoxy iminoacet ami do ] 3~[3-(2i 3-propylenepyridinio)-1-propen-l~yl]-3-cephem-4-ca rboxvlate f 15) 7-(2-(5-am in o~1 * 2,4-th iadiazol-3-yl)-2-et ho xv iminoacet am. ido ] -3-[3-(4-carbamoylpyr idinio)-T-propen-1-yl]-3-cephem-4-carboxylate, 16) 7-[2-(5-amino-1e 2,4-thiadiasol-3-yl)-2-cvclopen tyloxyiminoacet air. ido]-3~[3-( 4-carbamoyIpvridinio)-1-propen-l-yl }-3~ cephem-4-carboxvlate, 17) 7-[2-(5-amino-1,2,4-thiadia2ol~3~vl)-2-allyloxyimino-acetam.ido ]-3-[3-(4~carbamoyIpyridinio)-l-propen-l~yl]-3-cephem-4-ca rboxylate, 13) 7-(2-(5-amino-1,2,4-th iadiazol-3-y1)-2-propar gyloxyiminoacet amido]~3-[3-(4-carbamoylpyr idinio)-1-propen-l-yl]-3-cephem-4-ca rboxylate, 19) 7-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido] 3-{3-(4-carboxypyridinio)-1-propen-l-yl]-3-cephem-4- ca rboxylate, 20) 7-[2-(S-amino-l,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3—(3—(4-carboxypyr idinio)-2-propen-l-yl]-3~cephem-4~ carboxvlate, 21) 7-[2-(5-amino-l,2, 4-th iadiazol-3-yl)-2-methoxyiminoacetamido] 3-(3-(3-carboxymethyipyridinio)-1-propen-l-yl]~ 3-cephem-4 - carboxylate and 22) 7-[2-(5-amino-l,2e 4-thiadiazol-3-yl)-2-methoxyiminoacetamido] 3—[3 —(4-carboxymethylthiopyridinio)-1-propen-l-yl3-cephem-4 carboxylate.

The numbering system utilised herein for the various reactantsf intermediates and final products is as follows: [Roman Numeral] ! r Arabic Numeral j i Letter (if appropriate)] (if appropriate) The Roman Numeral designates whether the compound is a final product (l] or an intermediate or other reactant [all other Roman Numerals]. The Arabic Numerals and Letters are not used in those instances where the overall class (genus) of compounds is meant.

The Arabic Numeral designates the particular meaning of 2 ' substituent R . If the particular R group contains a carboxyl group which is protected by a conventional carboxyl-protecting group* a "prime11 (') is used after the Arabic Numeral to indicate this fact. No "prime" is used if the carboxyl group is unpro- 2 tected. A "prime" also is used with the generic R substituent o (i.e. R~ ) when genetically referring to an R" group containing a protected carboxyl group.

The Letter at the end of the compound number refers to the particular meaning of the quaternary ammonio group -N] For convenience, the Arabic Numerals and Letters assigned to some of the preferred R~ groups and quaternary ammon io groups are set forth below.

Arabic Numeral 1 2 3 methyl ethyl allyl propargyl cvclooentyl 0 Letter - n*~~ q A ■ 1-methylpyrrolidinio B * pyridinio C ■ 2-amino-5-thxazolo(4,5-cJpyridinio D « trimethylammonio E s 3-aminopyridinio F - 3-formyiaminopyridinio G s 3-carbamovlpyridinio H « 4~carbamoyIpyridinio r « 3-aminomethylpyridinio j « 2-n»ethyithi£2olio K « 3-hvdroxymethylpyridinio L « 4~hvdroxymethvlpyridinio M « 4-(N-methylcarbamoylJpyridinio N « 4-carboxypyr idin io 0 - 2,3-propylenepyridinio p * 3-carboxymethyIpyridin io ; q = 4-carboxymethylthiopyridinio In the primary evaluation of the compounds of this invention, the Minimum Inhibitory Concentrations (MlC's) of the compounds were determined by the two-fold serial agar dilution method in Mueller-Hinton agar against 32 strains of test organisms in six groups. The geometric means of the MIC's determine in these tests are shown in Table 1.

Table 1 Crrpd Mo.

Conf 3,g . fit double bond Geometric Mean of MIC (meg/ml) (G+)-Ia (G+)-lb (G-)-Ia (G-)-Ib (G-)-II (G-)-i: (5) (5) (5) (5) (5) (7) I-1A :-ia :-ib I-IB I-1C -id i - id :-ie T-1f JL-1G I-1H >11 >1J I-lK X *"■ i Lt I-1M I-1N 1-10 I-2H I-2N -2N I - 3 H J>4H I-5H •-is , A n >1Q E/2-1/1 E/Z*7/l P E / 2 ~ 1 / 4 E E/Z=1/1 E/Z-10/1 E E E E/Z-7/1 E 0.26 0.13 0. 20 0.35 0.10 0, 0, 0, 0, 61 30 20 15 0.20 0. 20 0.80 0.17 0. 35 0. 26 0.35 1. 2 0.17 0. 20 1. 2 1.4 0.23 0.26 0.13 0.8 0.7 0, 0, 0. 0 0, 1, 0, 0 0, 0, 0, 1, 0, 0, 7 0 35 4 0 80 20 A 53 40 40 35 40 6 35 80 I 0.61 0.70 1. 6 0.35 0.40 1 1 40 2 3, 0, 0.. 4 6 0.40 1. 6 0.92 0.05 0.029 0.016 0.05 0.0071 0.10 05 ,0094 0094 0, 0 0, 0 0, 009 4 013 0.10 0.025 0.029 0.029 0.029 0. 013 0.029 0.014 0.016 0. 044 0.057 0.066 0.20 0.013 0.0095 15 ,05 04 4 11 033 2 6 07 6 ,029 033 ,033 043 ,20 07 6 ,044 088 10 06 6 ,033 057 I i i A "f; . 10 1.9 2« y A O X "S! 1 A x^ 2 8 (G +)-1a : Penicillin-sensitive aureus (5 strains) (G-t-)-Ib : Penicillin-resistant S. aureus (5 strains) (G-)-Ia : Cephalothin-sensitive coli (2 strains), K1. pneumoniae (1 strain) and Pr . mi rabi1 is (2 strains) (G-)-Ib : Cephsloth in-resistant coli (3 strains) and K1. pneuiponiae (2 strains) (G-)-II : morganii (1 strain), £nt. cloacae (2 strains) and See. marcescens (2 strains) (G-)-I II : Ps . aeruginosa (7 strains) 10 15 Table 2, below, gives the Protective Do s e <. q (PD^q) .n rrice for a number of the compounds of Formula I against selected micr oorganisms. Table 3 gives blood levels of various compounds of Formula I upon intramuscular administration of the test compounds to mice at a dosage of 20 mg/kg.

Table 2 20 25 S. aureus PD50 (mg/kg) E. coli aer uginosa Cmpd. No.

Smith Juhl A9 84 3A 1-18 0 . 4 4 0.028 7.7 I-IB 0. 65 0.072 NT I-1C 0. 22 0.013 HT X-1G 0.96 0.021 5.92 I-1H 0.39 0.015 3.9 I-1J 0.35 0.029 NT I - IK 0. 53 NT NT I -1M 0. 96 NT NT I-1N 2.0 NT HT I -10 0.26 0.17 NT I-2N 5.0 HT HT 30 NT « Not Tested O I i ^ +9 Table 3 10 15 c rn A « / K AUC max 1/2 Cmpd. Mo. (mcq/m.l) (min ) (mcq hr/ml) I - IB 17 21 11 I-1C 21 32 18 I-1D 20 19 11 I-1H 23 16 14 J-lJ 19 16 9 . 7 I -IK 24 14 14 I-1M 20 23 14 I-IN 24 19 16 1-10 28 32 17 I -2N 22 20 12 X-3H 19 47 25 I-4K 27 22 16 I-5H 22 32 18 In another aspect, this invention relates to processes for the pr eparation of the compounds o f Formula I.

The preferred pr ocedures are shown below in Haa ct ion Sc h em es 1 a, lb and Ic, 20 while an alternative procedure is shown in Reaction Scheme 2.

The abbreviation "Ph" represents the phenyl group. Thus, the -CH(Ph}? moiety is the benzhydryl group, which is a preferred " carboxyl-protecting group. When H~ contains a ca rboxyl group, it is desirable to protect the carboxyl group with a conventional 25 c a rboxyl-protecting group such as the t-butyl moiety, y represents chloro, bromo or iodo.

Reaction Scheme la ■H,N \ / \ 2 O ^ COOCH (Ph) ,N-^ N ? C-COOH i\ 31 >v w N \ 2 OR V 3 0 CONH" X N R" ( CH,C1 COOCH (Ph)«.

Nfil or Kj CON! N "Ndr , CH2I COOCH (Ph).

(Ph) V c ii CONH _/* s \ "> one 0 tr -N 0 H,p(?h) <&> COOCH(Ph)_ base V f N \ *) OR*" ■CONH — S \ 0 N V 4 \^XH=:p(Ph) COOCH (Ph) _ C1CH-CHO N- h2N OK -CONH ch»CHCH2CI COOCH(Ph) 2 N&X or KI H.

N —~- s/J -c- If N CONH- \„_2 OR "M IX J CH*CHCH.

OOCH (Ph) HN R ""V (secondary amine) v \\ W M CO NH &^!l 3 / V\ / a "s OH" COOCH(Ph), B~CBCH,-M ^ Rs R" N/ |Q=N %P V (w^^TTC. iarv ad amine H,N // \\ SI /N*"" \ CONH OR' COOCB(Ph) ~ V O '2"* deblock V /** s X © te»chce,-n: 00 Reaction Scheme la shows two alternate means of going from Compound IX to Compound xii. The direct route, utilizing a tertiary amine (XI), is applicable for the preparation of all 5 compounds of Formula I. The indirect route, via Compound x, utilizes a secondary amine as reactant, and is quaternised in the following step. The secondary amine RH'NH may be acyclic (e.g. dimethylairine) or cyclic (e.g. pyrrolidine), and this indirect procedure therefore is suitable for the preparation of compounds 10 of Formula 1 in which the quaternary ammonio group is acyclic or "mixed® acyclic/cyclic. This indirect route is not suitable for the preparation of compounds of Formula I wherein the quaternary nitrogen is in a fully unsaturated heterocyclic ring (e.g. pyridinio ? thiasolio, 2~amino-5-thiazolol4,5~cJpyridinio). 15 Reaction Scheme lb II 3 3 •ch,en- /S 4 N \^^CH,C1 j 2 COOCH (Ph) ~ Nal or si V ^ ^\-ch=N-t—y*s \ rNv^H.T XIV t 2 COOCH (Ph). ? (ph) // \\ CH=N i ,1 © a— * (Phi 0 | cooch (Ph), Das« v ^ ^>~CH=M |^S X J N ^ 1 cr 6 \^^ch= p (ph) cooch (ph) _ 3 -1 ClCH-jCHO V CH«=N- xv: N X^j£^CH«CHCH,Cl C00CB(Ph), Girard Reagent T or V HC1 H,N- O N XVIII C H=C HC H, C1 I COOCH (Ph) » N—rr—C-COOH A N N 2 ^ 3^ ^ OR as in Scheme la Reaction Scheme lb is a variation of Reaction Scheme la in that the 7-amino group of the starting material (II) is protected as a Schiff base during most of the reaction steps, and 5 the desired 7-side chain acid is added later in the synthesis. Otherwise f the general procedure is similar.

Vi r.; tf jRsaction Scheme Ic ' CH=CH~CH,C1 XV] COOCH(Ph) W Nal or Kj -CH=N • .N. 0 CH=CH-CH,I COOCH(Ph) XIX HN \ R \k (secondary amine) CH=N H=CHCH,-N V COOCH(Ph) R" Y v © Sh- CHCH--ill = Q I 2 COOCH(Ph)0 QSN XI (tertiary amine) 3 fi xxi: © | CH=CHCH,-NSQ © coo N-acylation with III sV N- K5N A ii" N C- II N :onh ^ 2 ob COO \ . © CH-CHCH --N—BQ O Reaction Scheme Ic is a further variation of Reaction Scheme lb. In Reaction Schemes la and lb, auaternization of the 3-side chain is the last step, but in Reaction Scheme Ic the last step is acylation of the 7-amino group. The relationship between Reaction Schemes la, lb and Ic is shown in the following flowchart. 3? A. xv fi T~S m S3 t4- -CONH A COOCH(Ph)2 \ 2 /r~a-N^\CH OK 0 I 2 V U \/ V n~-C— CONH II 1,' N W.

CH,C1 COOCH(Ph) , o XIII H,N S OR vrn 'ST~0 /rVN.,^ o I COOCH(Ph). lb y ic 7- Ib Ouate rti is alios Deblocking Ic Quaceraisa'sien D«bloeking \k Caapou.ad 7-N-Acylation CC0 In Reaction Schernes la, lb and Ic, the benzhydryl group was shown as the preferred carboxyl-protecting group. It will be appreciated by those skilled in the art that other carboxvl-protecting groups, well-known in the art, may be used. The acylating acid III may be used in the form of a derivative such as its acid halide, activated ester, mixed acid anhydride,, all of which are well-known in the act. We prefer to utilize it in the form of its acid chloride, Acylating acid III also may have its amino group protected b*v any of the common amino-protecting groups, e.g. N-trityl, N-formyl. The base used to convert the phosphonium iodide (VI or XV) to give the phosphorylide (VII or XVI) may be NaOH, NajCO^, IRA-410 (OH~) resin, IRAtCO^") resin, or the like, or a mixture thereof. The chloroacetaldehyde used to convert the phosphorylide VII to the. 3-chloropropenyl-3-cephem compound vitt (or compound XVI to Compound xvii) may be the commercially available 40-50% aqueous solution, a distilled solution (e.g. 70%) or the anhydrous aldehyde.

We have found that Compound VIII prepared from Compound VII (Scheme la) typically had a Z:E ratio of about 2:1 at the propenyl double bond. Compound vttj prepared from Compound XVIII (Scheme lb)., on the other hand,, typically was almost exclusively the Z isomer. The difference may not be in the route used, but in the conditions utilized in the Wittig reaction (vil to VIII or XVI to xvii). We have also found that the use of an appropriate silyl reagent such as N*0-bis(trimethylsilyl)acetan»ide in the Wittig reaction (Vil to VIII in Scheme la and XVI to XVII in Scheme lb) caused improvement of the yields and purity of VIII and xvii. The reaction is preferably carried out with 2-5 equivalents of the silyl reagent. When the chloropropenyl cephem (VIII) was reacted with Nal in acetone to give the iodopropenyl cephem (IX).. the double bond in the propenyl group was isomerized from 2 to E during the iodination. A short reaction period retained the configuration of the parent Compound VIII to a large extent, while a long reaction period gave primarily the E isorer of Compound IX. However,, an excessive reaction time at high 3 temperature gives a lower purity compound IX. We find that about 10 minutes at 25SC and 2 hours at 5°C gives pure IX in good yield. When utilizing Reaction Scheme Ic, we have found that, when lod mating compound XIV with Na I, a purer compound is 5 obtained if the acetone solution is diluted with CC1, when 4b iodination is essentially completed, and the isomerization dot1ion of the reaction is conducted in the acetone-CCl, mixture. * *4 When iodination of the ch1oropropeny1 cephem (xvii) to the iodopropenyl cephem (XIX) was performed with KI in DMF, the 10 isomerization of the double bond from z to E proceeded as fast as the iodination did. The whole reaction completed within 45 minutes at room temperature to give pure XIX without dilution with CC1, in the course of the reaction. 4 Compound XII .normally was deblocked without pur if ica-15 tion, and the final product (I) was purified by reverse phase column chromatography utilizing a glass column containing the packing removed from, a Waters' Associates PrepPAK-500/C1 g car -t r idae. 4 0 Reaction Scheme 2 N It c- II n CONH* \ 2 nOR V^^^CH-CH-CH.,! COOCH (Ph) ~ xxi: c ii Ij ! I N — conh" U l| " ■ v R -HBT ^ S"^ OR 0 1 s i COOCH(Ph) xxiv * R~-HN' TP* I '. N CONH- ■ s ^ \ 2 OR X /b\ 4 N •vs^?>^H=CH-CH~NHi Q ^0 i COOCH(Ph) xxv Reduction R--HN i i ^5^ »C' il ■CONH- ^S'\. \ o OR"" ^X^^^CH^CK-C COOCH (Ph) „ 0 1 H,N5Q xxv: 4 1 deblock NK N ■ S2N ■c- II CONH ^OR2 © 'CH«CH2NSQ Reaction Scheme 2, shown in brief outline form above, is similar to Reaction Scheme la except that Compound XXIII (equivalent to Compound IX of Reaction Scheme la) is converted to 5 its S-oxide prior to quaternization. Compound XXV is subsequently reduced, and the remainder of Reaction Scheme 2 is as Reaction Scheme la. In Reaction Scheme 2? it is preferred to protect the amino group of the 7-side chain with a known arnino-protecting group such as the trityl group. io The acylating acids of Formula III herein are either known compounds or are readily prepared by published procedures.

European Patent Specification 7,47 0 published October 12, 1983 (application published February 6, 1980) exemplifies the preparation 2 * of compounds of Formula III wherein R is methyl, ethyl, propyl L5 and isopropyl. U.S. Patent 4,390,534, referred to in the Prior Art section, above, exemplifies the preparation of a wide var iety •) of compounds of Formula III wherein R~ is, for example, cyclopentyl, 2-cyclopenten-l-ylP allyl, 2-propynyl, 1-tert. butyloxycarbonyl-1-methylethyl, l~tert. butyloxyearbony1-1-cyclopentyl, 1-ethoxy-20 carbonyl-l-methylethyl, tect. butyloxycarbonylmethyl, 1-tert. butyloxycarbony1-2-methylpropyl, trityl.

Cor.pcund II herein ( 7-amino- 3-ehlor omethyl-3-cephem-4~ carboxylase) , used as a starting material in Reaction Schemes la, lb and lcf is a known compound.

The tertiary amines of Formula XI (and the secondary amines RR'NH) utilized in preparing the quaternary ammon10 compounds of this invention are either known compounds or are readily prepared by those of ordinary skill in the art. Many of the amines are commercially available.

The present invention also -provides a process for the preparation of compounds of the formula N.

C- ■ CONH* OH* © CE,-N=Q wherein R is hydrogen or a conventional amino-protecting group, 2 R is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing from 3 to 6 carbon atoms, or a group of the formula R* R4 COOH 1 3 '3 -C-CH-CH-R , -C-C—C-R y v or '5 I 5 R R R4 • ca rboxyl-pr otecting group, 3"* is hydrogen or a conventional ami no-protecting g roup,, % is chloro, bromo or iodo, and m is zero or one, with a tertiary amine QSN (or sequentially with a secondary amine RR'NH and a compound of the formula B"Z), and, if m is 1, reducing the sulfoxide by conventional means, and subsequently removing all blocking groups by conventional means.

The present invention also provides a process for the preparation of compounds of the formula 4 -i tf.

RXKN > ■CONK- OJT -r <<> CE»CH-CH,-NSQ cocP wherein R~ is hydrogen or a conventional amino-protecting group, 2 R is hydrogen,, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloaIkenyl ring 5 containing from 3 to 6 carbon atoms, or a group of the formula i -C-COOH in which E is hydrogen,? (lower Jalkyl or carboxyl, X is halogen, 4 5 hydroxy or (lower Jalkoxy, and R and R are each independently AS 10 hydrogen,, methyl or ethyl, or R" and R , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and -N~0 15 is a quaternary ammonio group, and nontoxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof, which process comprises acylating a compound of the formula A 5 4 ■N. 0 © ch-cbch,-nsq © 2 coo with an acid of the formula w B~HN X. w n 'c—cooh n \ 2' OR xxii iii or with an acylating derivative of said acid, wherein R~ is the I ? sane ,as R~ or is a group of the formula COOB" or -C—COOB- s 5 R 4 5 1 in which X, R' and R are as defined above, B~ is a conventional 1 2 carboxyl-protecting group and B is hydrogen or a conventional amino-protecting group™ 10 'The reactions are carried out in a non-aqueous organic l solvent such as dimethyl sulfoxide, hexamethylpfcosphoramide, 1 methylene chloride, chloroform,, ethyl ether,, hexane, ethyl acetate,, tetrahydrofuran, acetonitrile , or mixtures of such solvents. The reactions are conveniently carried out at 15 & temperature of from -10eC to 4-500C; we normally prefer to conduct the reactions at room temperature. During the quaternization step, at least one mole of the tertiary amine should be used per mole of Compound ix, XIX, XXI11 or XXIV; we 4 S normally prefer to utilize froir 25% to 100% excess of the tertiary amine.

Carboxyl-protecting groups suitable for use as B" in the above reactions are well-known to those skilled in the art and 5 include aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobensvl and diphenyImethy1 (benshydrvl); alkyl groups such as t-butyl; haloalkyi groups such as 2,2,2-tnchloroethyl, and other carboxyl protecting groups described in the literature, e.g. in O.K. Patent 1P399,086. *We prefer to utilize 10 carboxyl-protecting groups which are readily removed by treatment with acid. Particularly preferred carboxvl-protecting groups are the benzhydryl and t-butyl moieties. 2 Ami no-protecting groups suitable for use as 8 are also well-known in the art, and include the trityl group and acyl 15 groups such as chloroaeetylg formyl and trichloroethoxvcarbonyl. Amino-protecting groups which are readily removed by treatment with acid, e.g. the trityl group, are preferred.

When the cephalosporin nucleus is utilized in the form of the 1-oxide (m - 1), the 1-oxide is prepared by known procedures 20 such as oxidation with m-chlocoperbenzoic acid, peracetic acid, sodium tungstate . The 1-oxide subsequently may be reduced by known procedures, e.g. reduction of the corresponding alkoxvsulfonium salt with iodide ion in an aqueous medium. The alkoxysulfonium salt itself is readily prepared by treatment of 25 the 1-oxide with, for example, acetyl chloride.

Intermediates useful for the purposes of the present invention notably include compounds of the formula 4 7 N- H2N A W / N •C — CONH-II N \ , OR" I 0 coo:* CH=CHCH2Z xxvii 2 wherein z is chlor o, bromo, or iodof R is hydrogen, a straight or branched chain alkyl group containing front 1 to 4 carbon at oms, a cy cloa Iky 1 or cycloaIk enyl ring containing from 3 to 6 carbon atoms, or a group of the formula R4 R4 COOH I 3 I 3 -C-CH=CH~R , ~C~C~C~R , Oi I Q R- 4 R I •C-COOH '5 R ,3 3 in which R is hydrogen,? (lower Jalkyl or carboxyl, X is halogen, 4 " 5 hydroxy or (lowerJalkoxy, and R" and R are each independently A 5 hydrogen, methyl or ethyl, or R"* and R , taken together with the carbon atom to which they are attached, may be a cycloaIkylidene ring containing from 3 to 5 carbon atoms, and salts and esters thereof. Also included are compounds of Formula XXVIII in which the amino and/or carboxyl groups are protected by conventional amino-protecting or carboxyl-protecting groups.

Intermediates useful for the purposes of the present invention notably include also compounds of the formula 4 8 CH*=N" /-b\ // >'VV^Ss- CH-CHCH o COOR 22 XXIX wherein a22 is hydrogen or a conventional carboxyl-protecting 0 ^ 7 a *>5 group, and R , R"' and E~ are the same or different and are hydrogen„ hydroxy, (lower Jalkyl ot (lower Jalkoxy; or a salt, 5 solvate,, hydrate or ester thereof.

In connection with the intermediates mentioned in the last two preceding paragraphs (i.e. the compounds of the formulae XXVIII and XXIX), we draw attention to our Divisional Application No. /s 0 •aS *■* Intermediates useful for the purposes of the present invention lurther .include, as will be appreciated, compounds of the formula H^N* 0 e e CH^CH.-NSQ COO wherein is a quaternary ammonio group; or a salt, e-ster, solvate or hydrate thereof.

In connection with the intermediates mentioned in the last preceding paragraph (i.e. the compounds of the formula XXII), we draw attention to our Divisional Application 10 No.

As used herein, the terms acylamino and acyloxy refer to an acylated amino or acylated hydroxy group in which the acvl moiety is (lowe; )alkanoyl (e.g., formyl, acetyl, propionyl? butytyl t isobutycyl* isovaleryl ), aroyl (e.g. benzoyl), ]_5 {lower ) al kanes ulf onyl (e.g. mesyl* ethanesulf onyl), or arylsulfonyl (e.g. benzenesulfonyl, tosyl).

As used herein, the terms *{lower)alkyl*, *(lower)alkoxy", to 6 carbon atoms, inclusive. Similarly,, the terms (lower)alkenyl and (1ower)alkynyl mean alkenyl or alkyny1 groups containing from 2 to 6 carbon atoms.

In the Examples section which now follows, procedures are described which either directly illustrate the invention or are of interest in connection with it. " (lower)alkylthio" alkyl, alkoxy, alkylthio mean straight or branched chain groups containing from 1 Example 1 C CONH S "S » I VH ^ N ^Wh-CVNQ 3 iocP / ^ t^t3 Vb> £*=> 2 T-1 A * 7/^=1 /I J. «j^rk «-*/ «*»< «?•/ •*• 7 - [ 2- ( 5-Amino-l ,2,4-thiadiazol-3-yl)-2-methoxyiiT'inoacetan'ido]-3--[ 3-(1-methyIpyr rolidinio)-1-propen-l-yl]-3-cephem-4-carboxviate ( I-IA) To a solution of diphenylmethyl 7-[ 2- ( 5-snino-1, 2, 4-thiadiazol-3-vl)-2-methoxyiminoacetamido]-3-(3-iodo-l-propen-I-y 1)-3-cephem-4-carfc>oxvlate (IX-1) {2/E=2/lf 150 mg, 0.21 mmole) in ethyl acetate (2 ml) was added a solution of 1-methylpyrrolidine (36 mgf 0.42 mmole) in ethyl acetate (I ml) in one portion with stirring. The mixture was stirred for 15 minutes and diluted with isopropyl ether (10 ml) to form a precipitate, which was collected by filtration. A mixture of th solid (130 mg), formic acid (1 ml) and concentrated HC1 (0.1 ml) was stirred at room temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with water (20 ml) and filtered. The aqueous solution was passed through e reverse phase column (the packing of PrepPAK-500/C^g cartridge, 100 ml), eluting with water and 10% CH^OH. The desired fractions were collected,, and concentrated in. vacuo to a small volume and freeze-dried to give 13 mg (12%) of the title compound (I-IA) (Z/E-l/1), melting at >280°C (dec.).

IR vKBr cm"1 3400, 1760, 1660, 1610. max UV : ^Phosphate bur f er (pH 7) nm (£;1% } 236 ( 372), 288 ( 322 ) max 1 cm NMR : no j i zz 6 2 2.31 ( 4H, m, | ), 3.12 (3H, s, N~CH3) , 3.6 (5K PPm H m, 2-H S, N ), 3.79 (1H, s, 2-H), 4.1 (2H, d, J = 6, CH7N), 4.2 (3H, s, OCH3), 5.36 (1H, d, J = <.5, 6-H), 5.95 (3H, m, 7-H & 3-CH=CH), 6.66 (1/2K, d, J = 10, 3-CH cis), 7.0 (1/2H, d, J=16, 3-CH trans).

Example 2 N- H,N" 11 11 11 N .N \ CONH OCH.

CH-CH,-N.

I-IB 7 - [ 2-(5-Amino-l, 2, 4-thiadiazoI-3-yl)-2-methoxyiminoacetamido ] -3-[3~pyr idinio-1-propen-l-yl]-3-cephem-4-carboxylate (1-13) a mixture of diphenylmethyl 7-12-(5-amino-l,2,4-thi adiazol-3-yl)-2-methoxyiminoacetamido3-3-(3-iodo-l-propen-l-yl)-3~cephem-4-carboxylate (ix-l) (E, 716 mg„ 1 mmole), pyridine (158 mg, 2 mmoles) in dimethylsulfoxide (DMSO) (1 ml) was stirre for 1 hour at room temperature. To the mixture was added ethyl acetate (20 ml) to precipitate a solid (620 mg), which was added to formic acid (6 ml) containing sodium bisulfite (60 mg). The mixture was stirred for 30 minutes at 400C and concentrated to dryness. The residue was dissolved in h,0 (40 ml) and some insolubles were removed. The aqueous solution was charged on a column of reverse phase (preppak-50 0/c^g, 100 ml) eluting with H^O (300 ml) and 5% aqueous CH^OH (800 ml), and the eluate was monitored by uv (254 nm) and HPLC. The fractions (51 aqueous CH^OH) containing the desired product were combined, concentrated to a snail volume and lyophilized to yield 40 mg (8%) of the title compound (I-IB), melting at >200°C (dec.).

KSr - 1 IR : v*D- cm " 3350, 1760, 1650, 1600. nici x uv ^Phosphate butfer (pH /) nm ( £U } 240 (352), 258 (366), maX 1 Cm 267 (279), 290 (469).

NMH : 6D2CHDMSO-d6 3 . 74 (2H, br-s, 2-H), 4.20 (3H, s, OCE 3) , P?rn 5.92 (1H, d, J=4 » 5, 7—H) , 6.15 (1H, m, 3-CHcCH), 7.04 (1H, d, J»16, 3-CH trans), 8.2 (2H, m, Py-H3 $), 8.62 (1H, m, Py-H^), 8.97 (2H, m, Py-fl, g).

Example 3 N H2N X ll 11 A N N S X CONH- OCH, O V N /a " vS7 // CH«CH-CH--N 1' ' W -IB !2;/E=4/j 7-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[ 3-pyridinio-l-propen-l-yl]-3-cephem~4-carboxylate (1-13) The chloroDroDenyl compound, diohenvlmethvl 7~[2~(5~ & « Go " <>« 40 #4 '' * amino-l»2,4~thiadiazol~3~yl)-2-methoxviminoacetamido]-3-(3-ch loro-1-propen-l-yl) - 3-ceph em - 4-ca rboxyl ate (Vin-1) (z, 937 mg, 1.5 mmoles) was added to a stirred solution of pyridine (237 mg, 3 mmoles) in DMSO (3 mi) containing Nal (11 mg, 0.0/5 mmole) . The mixture was allowed to stand overnight at room temperature xn the dark. The mixture was diluted with ethyl acetate (30 ml) to separate the precipitate which was then collected by filtration, washed with ethyl acetate (10 ml) and dried to give 350 mg of the blocked product. The precipitate was treated with formic acid (3.4 ml) containing sodium bisulfite (34 mg) for 30 minutes at 40°C. After removal of the formic acid, the residue was purified by reverse phase column chromatography (packing of PrepPAK-500/C^g cartridge, 100 ml) by eluting with 5% aqueous CH^OH. The fractions containing the desired product were combined on the basis or HPLC analysis, evaporated under reduced pressure and lyophilized to give 41 mg (5.5%) of the title compound (I- IB) (Z/E = 4/l) . Mp . >200°C (dec.).

IR : vKBr cm-1 33 00 j, 1760, 1660, 1600. max UV Phosphate buffer (pH 7) max nm (E~ ) 1 cm 237 (386), 250 (377), 258 (369), 265 (347), 280 (311). dD2° PPm 3.45 & 3.76 (each 1H, d, J=16, 2-H), 4.18 (3H, s, OCH3), 5.34 ( 3H s m, CH*CH-CH, h 6-H) , 5.92 (1H, d, JM.5, 7-H), 6.58 (4/5H, d, J«ll, 3-CH cis), 7.03 (1/5H, d, J=16, 3-CH trans), 8.12 (2H, m, Py-H3 5), 8.56 (1H/ m, Py-H.)„ 8.82 (2H, m, Py-H. -). fif «£ f O Example 4 N- H,N •CONH- "\ OCH.

I-IC 7-[2-(5-Ami no-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[ 3-(2-amino-5-thia2olo[4,5-c]pyridinio)-1-propen-l-yl]-3-cephem-4-ccrboxylate (I-IC) A stirred solution of diphenylmethyl 7-[2-(5-amino-1, 2,4-thiadiazol~3~yl)-2-methoxyiminoacetamido]-3-(3-iodo-l-propen-l-yl)-3~cephem-4-carboxvlate (IX-1) (E isomer, 714 mg, 1 mir.ole), 2-aninothia2olol4,5-c]pyridine [prepared according to the procedure of T= Takahashi et al., Pharm. Bull (Japan), 2, 34 (1954)] and dry DMSO (1 ml) was kept for 1 hour at room temperature. To the reaction mixture was added ethyl acetate (20 ml) to give a yellow powder (710 mg). Formic acid (7 ml) and sodium bisulfite (70 mg) were added to the powder (700 mg), and the mixture was stirred for 30 minutes at 40-45#C. After evaporation, the residue was triturated with H^O (40 ml). Insolubles were filtered off, and the filtrate was chromatographed over a reverse phase column (PrepPAK-500/C.,g, 100 ml), with H^O and 10% CK^OH as eluant. The fractions containing the desired product were combined, and the solvent was removed under reduced pressure . Lyophilization gave the desired product (I-IC) as a colorless amorphous powder of the E isomer. Yield 110 mg (19%). Hp. >2009C (dec. ). 5 IR : vKBr cm"1 3300, 1760, 1660, 1630, 1600. max UV : xPhosphate burfer (pH /) nm (£1% } 245 (499), 285 (286) max 1 cm N MP. 6DMS0-d6 + D20 3 _ g g (3H, s, OCH3), 4.98 (1H, d, J = 4.5, ppm 6-H), 5.2 (2H, m, CH-CH-CH2), 5.57 (1H, m, 3-CB*CH), 5.96 (1H, m, 7-H) , 7.16 (IK, d, J«16„ 3-CH trans), 8.36 & 6.4 5 (each 1H, c, J = 7, Py-H), 8.92 (1H, s, Py-H). 10 Example 5 N- -C-II N CONH- ^ \ ^S\ <^~ 1Vl\£^CH^CH-CH2^N(CH3) © h9n* ^ s OCH.

I 0 coo^ 3' 3 I ~1D * 2 /E s 1/1 7-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetami do]-3-(3-tr imethylammon io-l-propen-l-yl)-3-cephem-4-ca rboxvlat e (I-ID) To a solution of diphenylmethyl 7-(2-(5-amino-l,2,4-15 thiadi azol-3-yl)-2-methoxyiminoacetamido J-3-(3-iodo-l-pr open-1-yl )-3-cephejn~4-carboxylate (IX-l) (Z/E=2/l, 490 mg, 0.68 mmole) in ethyl acetate (14 ml) was added a 0.1 M trimethylamine solution in ether (13.6 ml) in one portion. The mixture was stirred for 10 minutes and evaporated to dryness, and the residue 20 W£S triturated with ether (20 ml). The resulting solid (490 mg) was added to trifluoroacetic acid (0.2 ml) containing one drop of anisole. After 1.5 hours' stirring,, the mixture was evaporated to dryness under reduced pressure and the residual oil was triturated with ether (20 ml). The resulting precipitate was 25 collected by filtration and dissolved in K,0 (20 ml). Some insolubles were removed, and the aqueous solution was eluted on a 5 7 10 Cg reverse phase column (the packing of PrepPAK-50 0/C^g cartridge, Waters' 30 ml) using water as eluant. Fractions containing the desired compound were combined and concentrated to a srr.all volume and lyophi 1 ized to afford 30 mg (9.2%) of the title compound (I-1D) (Z/E * 1/1) as a colorless amorphous powder, melting at >150°C (dec.).

IR : vKBr cm'1 3300, 1770, 1670, 1605. max UV : phate buffet (pH 7) nm (_1S j (3M)_ 2_7 {)uj max 1 cm NMjR : 6D2° 3.45 & 3.7 (1H, d, J = 16, 2-H), 3.81 (1H, s, 2-H), ppm 0 4.1 (2H, d, J=8, -CH,N), 4.21 (3H, s, OCH3), 5.39 (1H, d, J=4.5, 6-H), 5.95 (2H, m, 3-CH«CH & 7-H), 15 6.61 (1/2H, d, J=il, 3-CH cis), 7.05 (1/2H, c, J~16 , 3-CH trans).

Ex am.pl e 6 -O—-CONH Jj ll \ HjN OCH3 O mw 6 ^ The mixture was stirred for 1 hour and diluted with ethyl acetate (20 ml). The resulting precipitate was collected by filtration, washed with ethyl acetate and dried to give 520 mg of yellow powder. A mixture of the powder (500 mg), formic acid (5 ml) and sodium bisulfite (50 mg) was stirred for 30 minutes at 40°C. The mixture was concentrated i_n vacuo, dissolved in H.O (40 ml) and filtered to remove insolubles. The aqueous solution was chromatographed on a column of reverse phase (packing of Prep?AK-500/C^g, 100 ml), with 7.5% aqueous CH^OH elution. The fractions containing the desired compound were evaporated and lyophilized to give the title compound (1-1E) (7 mg, 1.4%), melting at >185°C (dec.).

IR : vKBr cm'1 3400, 1765, 1675, 162C, 1600. max UV : ^Phosphate burrer (pH 7) njp (£1% } 246 ( 403), 290 (465 ). max 1cm KMR : 6° 2° 3.72 (2H, m, 2-H), 4.14 (3H, s, OCH 3) , 5.35 (3H, m, ppm 6-H S, CH = CH-CH2) , 5.9 (1H, d, JM.5, 7~H) , 6.1 CH, m, 3-CH=CH), 7.05 (1H, a, J=16, 3-CH, trans), 6.1 (1H, m, Py-H5), 8.54 (1H, br-s, Py-Kg), 8.68 (1H, m, Py-«4), 9.4 (1H, m, Py-H2).

Treatment of IX-l (716 mg, 1 mmoie) with 3-t~butoxy~ ca rbonylaminopyridine ( 324 mg, 2 mmoles) by a procedure similar to that described above gave 12 mg (2.3%) of I-1E. 5 0 Example 7 N C- |l '] -conb- T I n NH.

\H, ^^^CH-chch,?,// < CO 160°C (dec.). 8 0 IR vKBr cm"1 3 4 00,. 1755, 1675, 1620, 1600 max UV . .Phosphate buffer (PH 7) nm (£U } 244 (434)> ^ (,.3) max cm , 4.14 (3H, s, OCH3), 5.35 ( 3H , m„ 6-H & CH=CH-CH2), 6.0 (2H, m, 7-H 6 ,DMSO~d,h-D.O -> T-> /il, < NKR : 6 6 2 3.7 3 (2H, m) PPm 3 - CH <= CH ) , 6.6 (1/2H , d, J«ll, 3-CH cis), 7.05 (1/2H, d, J«16, 3-CH trans), 8.08 (IK, m, Py-H5), 8.6 (2H, m, Py-H4 g), 9.4 (1H, jr., Pv-H,).

N r- C i H2N ^ S' OCH.

CONH cck£) H=CHCH2~ NHCHO I-IF 7 - [ 2- ( 5-Ami no-1,2,4-thiadiazol-3-yl) - 2-me thoxy iminoacet ar.i do j - 3-[.3- (3-for my laminopyr idinio) -1-propen-l-yl ] -3-cephem-4-ca rboxvl ate ( I-IF) A mixture of diphenylmethyl 7-[2-(5-amino-l,2,4-thiadia2ol-3-vl)-2-methoxviminoacetamido J-3-(3-iodo-l-propen-i~ y1)-3-cephem-4-ca rboxylate (IX-l) IE, 716 mg, 1 mmole) and 3~ formylaminopyridine [prepared according to the procedure of N. Enomoto et al., Bull. Chem. Soc. Japan, 45, 2665 (1972)] (244 mg, 2 mmoles) in DMSO (2 ml) was stirred at room temperature for 1 hour* and poured into ethyl acetate ( 200 ml). The precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt ( 500 nig) and sodium bisulfite (50 nig) in HCOOH (5 ml) was stirred at 40-50°C for 80 minutes and evaporated to dryness in vacuo. The residue was 6 I dissolved in water (40 ml), neutralized with NaHCO^ and then filtered to remove insoluble material. The clear filtrate was chromatographed on a reverse phase column, PrepPAK-500/C1g (100 ml), with water and 5% CH-jOH, 10% Ci^OH, 20% CHjOH and 30% CH3OH The fractions containing the desired compound were combined, concentrated in vacuo and lyophilized to give 16 mg (2.9%) of th title compound (I — IF) (E) as a tan powder. Hp. >170°C (dec.).

IR ; vKBr cm"1 3340(br ), 1760, 1670, 1620(br), 1590. max uv . ^Phosphate buffer (pH 7) max nm (E1 % ) 1 cm 216 (428), 248 (362) 290 (474).

,D,(>+NaHCO, NKi-. : 6 2 3 ppm 3.68 (2H, br t 2-H), 4.15 (3E, s, OCE^), 5.91 (1H, d, J = 4 . 5, 7-H), 6.25 (1H, m, CH*CH-CH-,) 6.98 (1H, d, J*16, 3-CH trans), 8.8-7.9 (4*H, m, Py-H), 9.35 (1H, br, NKCHO).

Example 9 C CONH-, fS > N\ J N * © /7~C 2 XOCH, ^ Vy^CH-CHCHj-l^' ^ cocP I-lG *E 7 - [ 2- ( 5-Amino-l, 2,4-thiadiazol-3~yl) - 2-me thoxy lmm pace t ami do ) ~3~ [ 3- ( 3-carbarnoy Ipyr idinio) -1-propen-l-yl ]-3~cephem~ 4-carboxy late (I-1G) To a solution of diphenylmethyl 7-[2-(5-amino-l,2#4-thi adiazol~3-yl)-2-methoxviminoacetamido 3-3-(3-iodo-1-propen-l-yl )-3-cephem-4-carboxylate (IK-1) (Ef 716 mg, 1 mmole) in DMSO (2 ml) was added nicotinamide (244 mg, 2 mmoles), and the mixture was stirred at ambient temperature for 1.5 hours and poured into N- 1 ^ H2N"**^ S-"" 62 ethyl acetate (200 ml) with stirring. The resulting precipitate was collected by filtration. The quaternized salt (500 mg) was dissolved in HCOOH (5 ml) in the presence of sodium bisulfite (50 mg;, and the mixture was heated at 40- 50°C for 40 minutes, with stirring, and evaporated to dryness. The residue was dissolved in water (40 ml) and an insoluble solid was filtered off and washed with a small amount of water. The filtrate and wash were combined and chromatographed on a reverse phase column, PrepPAK- 50C/C,o (100 ml). After elution with water and 5%, 10% and 20% 18 aqueous CH^OH, successively, the fractions containing the desired material were combined, concentrated i_n vacuo and f reez e-dr led to yield 21 mg (3.8%) of the title compound (I-lG) (E) as a yellow powder. Hp. >175°C (dec,).

IR : vK3r cm"1 334C(br), 1760, 1670, 1600. max UV .Phosphate buffer (pH 7) nJJX (£1 % ) 23f> ( 326)/ 274 {sh/ max 1 cm 405), 290 (446 i ,'MS : 6D2O+NaHC03 3>68 (2H, br, 2-H), 4.15 (3H, s, OCH3) , 5.32 PPrc (1H, d, J~4.5, 6-H), 5.45 (IK, d, J=7, CH-CH-CH,), 5.88 (1H, d, J=4.5, 7-H), 6.15 (1H, d-t, J=16 & 7, 3-CH=CH), 7.00 (IK, d, J = 161 3-CH trans), 8.23 (1H, m, Pv-H5) , 9. (2H, m, Py-H4£(6), 9.34 (1H, s, Py~H2). 6 3 Example 10 .1 H 7 - [ 2 - ( 5-Ami no-1, 2, 4-thiadiazol-3-yl)~2~methoxyiminoacetamido]-3- [ 3- ( 4-carbamoylpyridinio)--l~prop8n-l-yl)-3-ceph.err-4-carboxylate (I-IK) To a. stirred solution of diphenylmethyl 7-[ 2-( 5-amin o-l,2,4-thiadiazol-3-yl) - 2-me thoxy iminoacet air ido ]-3-(3~iodo-l-propen-l-vl)"3-cephem-4-carboxylate (IX-l) (E, 716 mg, 1 mmole) in dry DMSO (2 ml) was added isonicotinamiae (244 mg, 2 mmoles). The mixture was stirred at room temperature for 1 hour and then poured into ethyl acetate (200 ml). The resulting precipitate was collected by filtration, washed well with ethyl acetate and dried. A stirred mixture of the quaternized material (400 mg) and sodium bisulfite (40 mg) in HCOOH (4 ml) was heated at 40-50°C for 1 hour, and evaporated to dryness under reduced pressure. The crude solid was dissolved in water (40 ml). Af te filtration of an insoluble material, the filtrate was chromato-graphed on a reverse phase column (packing of PrepPAK/C^g, 100 ml) using water and 5%, 10%? 20% and 30% aqueous CH^OH as eluant The fractions containing the desired compound were combined, evaporated and lyophilized to give 21 mg (3.8%) of the title compound (I-1H) (E) as a pale yellow powder. Hp. >180°C (dec.).

IR : vKBr cm"1 3340(br ) , 1760, 1670, 1600. max UV : .Phosphate buffer (pH 7) ^ (E1% ) 222 (352), 285 (452) max 1 cm ,D_CHNaHCO. N MR 6 2 PPm 3.68 (2H, br, 2-H), 4.15 (3H, s, OCH3), 5.33 (1H, d, J=«4.5f 6 — H) j 5.46 (2H, d, J~7 f CH-CH-CH2)„ 5.90 (1H, d, J = 4.5, 7-H) , 6.17 (1H, d-t, J®16 & 7, 3-CH=CH), 7.02 (1H, d, JsI6 Example 11 CONH- S \ CKjNH, ,N S/K XOCH3 IR : vKBr cm"1 3380(br), 1760, 1650(sh), 1620(sh). max uv : ^Phosphate buffer (pH 7) njB (U% } 235 ^ 2,Q) ^ ,86 max 1 cm (37q ) .

N MR : 6D2°+NaHC°3 3.68 ( 2H, br, 2-H), 4.16 (3H, s, OCH3), 6.9-8 PPm (1Hd, J=16, 3-CH trans), 8.05 (1H, m, Pv-H,), 8.50 (IB, m, Py-H,), 8.80 (2H, m, D ** Py~H_ ,). 2,0 Example 12 w- ,N I s / C-II ■ CONI SL ! \ OCH.

^ ^ // \\ CH-CHCS* I (i« -CONH. 7- [ 2-(5-Amino-l, 2,4--fchiadiazol-3-yl)-2-methoxyiminoacetamido3-3-|3-(4-ca rbamovlpyri dinio)-1-propen-l-yl]-3-cephem-4-carboxyl ate (I-1H) A mixture of diphenylmethyl 7-[2-(5-amino-l„2, 4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-l-yl) -3-cephem-4-carboxylate (IX-l) (E isomer, 4.1 g, 5.7 mmoles) and isonicotinamide (1.4 g, II mmoles) in dry DMSO (6 ml) was (5 t) stirred for 2 hours at room temperature while monitoring by TLC (silica gel plate, CHCl^:CH^OH * 3:1). The reaction mixture was diluted with ethyl acetate (100 ml) to separate a yellow gum, which was treated with formic acid (40 ml) and sodium bisulfite 5 (390 mg) at 45°C for 30 minutes. The resulting solution was concentrated to dryness. The residue was dissolved in H^O (100 ml) and insolubles were removed by filtration. The combined filtrate and water wash was applied to the top of a column containing reverse phase packing (PrepPAK-500/C^g, 120 ml). The 10 column was eluted with H-,0. The eluate was collected in 300 ml fractions and monitored by uv (254 nm) and HPLC (Lichrosorh RP-18, 4 x 300 mm., 0.01 M ammonium phosphate buffer, pH 7.2 containing 20% CH^OH). Fraction Nos. 4 and 5 were combined and concentrated to a small volume. Lyophilizat ion gave 25.0 mg 15 (6.1%) of the title compound I-1H, melting at >180 °C (dec.).

The spectra indicated that the product was identical to that obtained in Example 10.

Preparation of the hydrochloride - To a suspension of Compound I-1H (98 mg, 0.18 mir.ole) in CH^OH (1 ml) was added 10% 20 HCl (0.1 ml), and the mixture was stirred for 5 minutes. To the resulting yellow solution was added acetone (100 ml) to give a precipitate, which was collected by filtration, washed with acetone (2 x 10 ml) and dried in_ vacuo to give the hydrochloride salt of I~1H as a colorless powder. Yield 88 mg (79%). Hp. 25 > 19 0 0 C (dec.). 67 IR vKBr cm-1 3300, 1770, 1680, 1520. max uv : xPhosphate bufrer (pH 7) ^ {£ x% ) 227 ( 385), 286 maX 1 Cm (374).

N MR 6D2° ppm 2.32 (1H, st, acetone-H), 3.79 (2H, br-s, 2-H), 4.17 3H, S, OCH3), 5.34 (1H, d, J=4.5, 6-H) , 5.49 (2K, d, J = 7, CH=CH-CH2), 5.93 (1H, d, J«4.5, 7~H)f 6.28 (1H, d-t t, J=16 h 7, 3-CH-CH), 7.15 (1H, d, J*16, 3-CH), 8.4 3 & 9.1 (each 2H, dr J«7, Py-H). 10 Example 13 n- IT) CONH" f OCH. ch«chch,-n coov H in "X 3 S i-1j 7-[2-(5°Ami no-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[3-(2-methylthiazolio)-1-propen-l-yl3-cephem-4-carboxylate (i-1j) 15 To a mixture of diphenylmethyl 7-[2-(5-amino-l,2,4- thiadiazol-3-vl)-2-methoxyiminoacetamido]- 3-(3-iodo-1-propen-l- yl )-3-cephem-4-carboxylate (IX-l) (E, 714 mg, 1 mmola) and 2- methylthiazole [prepared according to the procedure of R. P.

Kur k jy, E. v. Br own, J. Am. Chem. Soc., 7 4, 5778 (1952)] (198 mg, 20 2 rrjnoles) in dry CH2C12 (10 ml) was added AgBF^ (90% pure, 217 mg, 1 mmole) at ~20°C. The mixture was stirred for 30 minutes at room temperature and filtered- The precipitate was extracted with 10% CH,0H-CHC1, (3 x 20 ml). The combined extracts were 3 3 washed with brine (2 x 5 ml), dried over MgSO„ and evaporated to ®a * 25 dryness to give a yellow residuef which was triturated with isopropyl ether and filtered to yield 350 mg of the quaternized 6 3 product. A irixture of this solid, sodium bisulfite (35 mg) and formic acid (3.5 ml) was stirred at 40°C for 30 minutes. The irixture was concentrated to remove the formic acid, and the residue was diluted with H^O (40 ml). Some insolubles were 5 removed by filtration. The filtrate was placed on a reverse phase column (PrepPAK-500/C^g, 100 ml). The column was eluted with H^O (200 ml), 5% aqueous CH^OH (400 ml) and 10% aqueous CH-jOH (300 ml), successively. The fractions containing the desired product were pooled on the basis of HPLC analysis 10 (Lichrosorb RP-18, 4 x 300 mm, 0.01 M ammonium phosphate buffer pH 7.2, containing 20% CH^OH). The combined solution was concentrated to a small volume and lyophilized to give 40 mg (7.7%) of the title compound (1-1J) (E). Hp. >195°C (dec.).

IR vKBc cm 1 3300, 1760, 1660, 1600. 1 5 max UV ^Phosphate buffer (pH 7) max nm (E1% ) 238 (442), 292 (421). 1 cm.

NMR 6D,O+DMS0-d ppm 6 3.06 (3H, s, thiazole-CH^), 3.74 (2H, br-s 2-H), 4.19 (3H, s, OCH3), 5.92 ( 1H, d, J-4.5, 7-H), 6.1 (1H, m, 3-CH=CH), 6.8 (1H, d, J=16, 3-CH trans), 8.04 & 8.23 (each 1H, d, J = 4, thiazole-H). 20 Example 14 S H « N"* 5 »" OCH CONH 3 1-11 * e 7-[2-(5- Ami no -1, 2, 4-th iadiazoI-3-yl)-2-me thoxy iminoacet arr.ido]-3-[ 3- ( 4-hydr ox vine thy Ipyr id inic , -1-propen-l-yl ] - 3-ceph em-4-ca r box vl-ate (I -1L) 3-yl)-2-methoxyiminoacetamido ] — 3 —{3-ioao-l-ptopen-l-vl)-3-cephem- 4-carboxylate (IX-l) (E isomer,1.07 g, 1.5 mmole), 4-hydroxy-methylpyridine (818 mg, 7.5 mmole) in CH^CN (4.5 ml) and CH^OH (3 ml) was stirred at room temperature under atmosphere for one hour. After removal of the solvents by evaporation, the residual oil was triturated with isopropyl ether, collected by filtration, and washed with a mixture of isopropyl ether and methanol (3:1, 10 ml) to give 1.28 g of the quaternized cephem ester as a yellow powder. A solution of the qusterni zed ester (1.25 g) and sodium bisulfite (600 mg) in 85 % HCOOH (10 ml) was stirred at room temperature under Nj atmosphere for one hour. After the addition of 85 % HCOOH (5 ml), the mixture was stirred under the same conditions for an additional hour. Toluene was added and the reaction mixture was evaporated azeotropically under reduced pressure. The residue was triturated with acetone to yield 1.17 g of the crude formate of the title compound. A suspension of this compound (1,15 g) in water (100 ml) was filtered to remove insolubles, which were washed with water (10 ml x 2). The filtrate and the washes were combined and subjected to reverse phase column chromatography. The column,, which was packed with the packing taken out of a prepPAK-500/C^g cartridge column A mixture of diphenyl 7-[2-(5-amino-l,2,4-thiaaiazol- (Waters) 60 ml),, was developed with vatsr, 5 % methanol and 10 t methanol,, successively. The fractions containing the desired coir pound were combined, concentrated under reduced pressure,, and precipitated by the addition of acetone to give 100 wg of the title compound (I-lU&s a pale yellow powder. To a suspension of the powder (90 n\g) in methanol (9 ml) was added 1 H HCl in CK^OH (0.5 ml) a,nd the mixture was stirred at room temperature and concentrated i_n vacuo. To the concentrate was added isopcopanol to precipitate 77 mg of the hydrochloride of the title compound. Pale yellow powder. M. p. >190"C(dec.).

KBr IR : v w cm"1, 1775, 1670, 1635, 1530, max Phosphate buffer (pH7) UV : X max nm (e) , 230 (22600), 264. (sh, 163*00) NMR ; 6D2° ppir 3.83 ( 2H, br . 2-CH) , 4.17 ( 3H, s, ) , 5.06 (2H, S, CH?OH) , 5.36 (1H, d, J«4.5 Hzt 6-H), 5.41 (2H, d, J«7 Hz, CH-CH-CH,), 5.9 4 (1H, d„ J-4.5 Hz, 7-H) , 6,36 (1H, d-t, OCH3 J-16 and 7 Hz, CH*CHCK2), 7.13 (1H» d, J=16 Hz, CH^CH-CH,), 8.08 and 8.83 (each 2H, d, J-7 fl2, Py-H). 7 1 Example 15 N •CONH' h2N \ S oc,h5 ./ \ I ^ N V^^CH-CHCH,- i Q 2 cocP :onh.

I» 2 H * £ 7- [ 2 - ( 5-Ami no -1,2,4-fchiadiazol-3-yl)~2-ethoxyiirinoacetannclo]-3- i 3 - ( 4-ca rbamoy Ipyr idinio )•-1-propen-l-yl ]-3-ceph eir.-4-c a r boxy late (I-2H) To a solution of 200 mg of 7-amino~3- [ 3- ( 4-ca r bamoyl-pyrioinio)- 1-propen-l-yl]-3-cephem-4-carboxylate hydrochloride (£ isomer) in 5 ml of 50 % aqueous acetone was added poctionwise 190 mg of 2-ethoxyimino~2~(5-amino-le2,4-thiadiazol-3-yl)acetyl chloride hydrochloride [prepared according to the procedure described in published Japan patent application (Kokai) 57-24389 (2/8/82)3? and the mixture was adjusted to pH 6.5-7.0 with 2 N Ma^CO^ (about 1 ml). The reaction mixture was stirred at 10 °C for an hour, acidified to pH 2 with 1 N HCl and evaporated in vacuo. The residue was filtered and the filtrate was chromatographed on a column of HP-20, which was eluted with 500 ml of water and 25 % aqueous isopropanol, successively. Fractions containing the desired product were combined and evaporated under reduced pressure. The oily residue was treated with isopropanol (20 ml) to give 263 mg (93 1) of the title compound (I-2H). H. p. 170 "C (dec. ).

To a stirred suspension of 225 mg (0.40 mmole) of the above zwitterion in 10 ml of methanol was added 1 ml of 1 N HCl in CH^OH and the mixture was stirred at room temperature for 30 minutes. The solution was filtered and concentrated under rj i reduced pressure. To the residue was added 15 mi of isopropyl alcohol, and the resulting precipitate was collected by filtration and dried in vacuo to give the tit.le compound as its hydrochloride. Yield 146 mg (57 %). M. p. 160 °C (dec.). Estimated purity 65 %.

KBr IK •* v _ cm"1, 3300, 1780, 1680, 1620. max UV .Phosphate buffer (pH7) om . , a - nm (e), 22 / max (22300), 288 (22800). 10 NMR : 6D2° 1.44 ( 3H f t, J«7 Hz, OCH^-Cj^) , ppm 3,74 (2H, br. s, 2-H) 4.45 (2H, q, J=7 Hz, OCH2-CH3), 5.36 (1H, d, J»4. 5 Hz, 6-H), 5.46 (2H, d, J«7 He, 3~CH = CH-CH2),5.92 (1H, d, J=4.5 Hz, 7-H), 6.20 (1H, m, 3-CH=CK), 7.04 (1H, d, l5 J=16 Hz, 3-CH-CH), 8.43 (2H, d, J=7 He, Py-HA), 9.10 (2H, d, J~ 7 Hz, Py-Hg).

Example 16 7-[ 2- ( 5-Amino-l, 2, 4-thiadia2Ql-3-yl )~2-me thoxy iminoacet arr ido] - 3-[3-(4-carbamoylpyridinio)-l-propen-l-yl)-3-cephem-4-carboxylace 20 (I-1H) (E isomer) This Example shows the preparation of Compound I-1H via the last few steps of Reaction Scheme la oc lb, wherein the intermediate benzhydryl 7—[2—(5-amino-l,2, 4-thiadia20l-3~yl)-2-methoxyiminoacetamido 3-3-1 3-(4-carbamoylpyridinio)-1-propen-1-25 yl]»3-cephem-4~earboxylate formate (XXVJX-1H) is isolated.

A . Benzhydryl 7 — [ 2 — ( 5-Ami no-1 ,2,4-thiadia2ol--3-yl)-2-mgthoxy-imnoacetamido]-3~[3-(4-carbairovl-i-pyridinio)-l-propen-l-yl]-3-c ephem-4-carboxylate Formate (£ isomer) (XXVII-IH) A solution of XII-IH (Y® » , E isomer) (34 g, 75% pu:e) in a mixture of acetone and CH,OH (1/1, 20u ml) was placed 3 on a column of Amber lite IRA-410 (formate form 340 ml). The column was sluted with the same solvent system. The first fraction (1 L) was evaporated to about 100 ml of the volume and the brown residue was triturated with isopropyl ether (400 ml). The resulting powder was collected by filtration and dried under vacuum to afford 29 g (75% pure by HPLC) of the title compound XXVII-1H (£ isomer) as a brown powder melting at >150#C (dec.).

IR : vKBr cm"1 3300, 1780, 1680, 1530, 1600. ma x UV : XEt0H nm (E1% ) 282 (186). ma x 1cm -acetone-d^/CH^OH-d, (1/1) „ n , , r o- (1, - : 0 o 3 4 4 . 0 ( 3H, s, OCh ^) , 5. 2o, (lh, a, ppm. J= 4.5 Hz, 6-H) , 5.4 3 (2H, d, J=7 Hz, CU^~), 5.99 (1H, d, J»4.5 Hz, 7-H), 6.5 (1H, m, 3-CH«CH), 6. 92 (1H, s, CHPhj), 7.1 (1H, d, J~16 Hz, 3-CH) , 7. 35 (10H, m, Ph-H), 8.36 (1H, st HCOO), 8.46 & 9.12 (2H each, d, J=8 HZ, Py-H).

B. 7-[2-(5-Amino-l,2,4-thiadiazol-3-vl)~2"inethoxyin,.inoacet-amido ) — 3— [ 3-( 4-carbairoyl-l-pyr idinio)-1-propen-l-yl ]-3-cephem-4- ca rboxylate (I~ih) (e isomer) A mixture of XXVII-1H (E isomer) from Step A (29 g, 75% pure) and 85% formic acid (290 ml) was stirred for 2 hours at room, temperature. Evaporation of the mixture gave a brown oil which was triturated with acetone (500 ml). The powder was collected by filtration, washed with acetone (2 x 100 ml) and 7 '' dried in vacuo to give 24 g (50% pu re by HPLC) of the crude title compound. The brown solid was treated twice with 2 N HCl (1 L and 0.5 L). The aqueous extracts were combined and placed on a column packed with Diaion HP-20 (1.5 L). The column was washed 5 wath water (8 L) and eluted with 30% CH^OH (5 L). The fraction containing the desired product was evaporated to about 30 ml. The concentrate was treated with acetone (200 ml) to give a precipitate, which was collected by filtration and dried ijn vacuo to give 10.1 g (85% pure) of the title compound (zwitterion form) 10 as a yellow powder. To a suspension of this product in CH^OH (100 ml) was added N HCl in CH^OH (55 ml) at room temperature and the mixture was stirred for 30 minutes. The resulting clear solution was filtered to remove insolubles, concentrated to about 50 ml of the volume and precipitated with isopropanol (200 ml). 15 The resulting powder was collected, washed with isopropanol (50 ml) and dried i_n vacuo to give 10.5 g (85% pure) of the title compound I-IH (E isomer) (HCl salt), melting at >180°C (dec.). Pale yellow powder.

Example 17 7-j 2-(5-Amino-1,2,4-thiadia2ol-3-yl)-2-methoxyiminoacetamido]-3-( 3 - ( 4-ca rbair.oylpy r idin io) -1-propen-l-yl ] - 3-ceph em- 4-ca rboxyl at 8 (I-IH) (E isomer) This example shows the preparation of Compound I-IH via the last few steps of Reaction Scheme la or lb, wherein inter-25 mediate XXVii-lH (the formate) is not isolated.

A solution of IX-l (E isomer) (27.6 g, 38.5 mmole) and isonicotinamide (22.8 g* 187 imnole) in a mixture of CH^CN (120 ml) and CH^OH (100 ml) was stirred at room temperature for 1 hour under a nitrogen atmosphere. After evaporation of the organic 30 solvents,, the oily residue was triturated with isopropyl ether to give 50.5 g of a mixture of the quaternized salt and isonieotin-amide. A solution of the mixture (50.3 g) and sodium bisulfite (16 g) in 85% HCOOH (160 ml) was stirred at room temperature for 40 minutes and subsequently at 40°C for 1 hour under . The mixture was evaporated ijn vacuo. The residual oil was mixed with toluene (50 mi), evaporated azeotropically and triturated with acetone (400 ml) to give 27.8 g of the crude title compound.

This material was treated twice with 2 N HCl (1 L and 0.5 L). The acid extracts were combined and placed on a column of HP-20 resin (1.5 L). The column was eluted with, water (9 L) and 30% methanol (10L). The fractions containing the desired compound were combined and concentrated to give a yellow oil, which was triturated with acetone (300 ml) to yield 9.35 g of the zwitterion form, of the title compound.

To a suspension of the product (9.3 g) in CH^OK (180 ml) was added 1 N HCl in CB,OH (55 ml) to obtain a clear — 3 solution. The solution was concentrated to about 100 ml and diluted with isopropanol to precipitate 9.50 g (purity 75%) of the title compound I-IH (E isomer) as its hydr ochloride. Pale-yellow amorphous powder. M.p. >195°C (dec.).

Example 18 7-[2~(5-Amino-l>2>4-thiadia2ol-3~yl)-2-methoxyiminoacetamido]-3-[ 3-(4-ca rbamoylpyri dinio)-1-propen-l-yl]-3-ceph em-4-ca rboxylate (I-IH) (E isomer) This example shows the preparation of Compound I-IH via the last step (7-N-acylation) of Reaction Scheme Ic, To an ice-chilled suspension of the 7-amino-cephem. hydrochloride XXII-H (E isomer) (5.0 g, 12.6 mmole) in 50% aqueous acetone (10 0 ml) was added sodium bicarbonate in small portions. The pH of the mixture was monitored by a pH meter throughout the reaction. To the cold neutralized solution (pH about 7) was added 2~(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl chloride hydrochloride (4.02 g, 15.6 mmole) in small portions over a period of an hour, and the pH of the reaction mixture was maintained in the range of 6.8-7.5 by occasional additions of sodium bicarbonate. The reaction was also monitored by tic. After all of Compound XXII-H had been 7 6 consumed, the mixture was acidified to pH 3 by the addition of 2 N hydrochloric acid. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with acetone (400 ml) to separate the precipitate, which was 5 collected by filtration to afford 9.59 g of the crude title compound as a light yellow powder. Estimated purity 40% by HPLC. A suspension of the crude product (9.5 g) in 2 N hydrochloric acid (150 ml) was filtered, and the filtrate was adsorbed on a column of HP-20 resin (500 ml). After washing with water (1.5 10 L), the column was eluted with 25% aqueous isopropyl alcohol and the eluate was collected in 100~ml fractions. The desired fractions were pooled, acidified with 2 N hydrochloric acid (10 ml) and concentrated. The residual oil was triturated with isopropyl alcohol (200 ml), and the precipitate was collected by 15 filtration. After drying over phosphorus pentoxide, 5.18 g of the title compound I-IH (E isomer) hydrochloride was obtained as a yellow amorphous powder. M.p. >190°C (dec.). Estimated purity 75% .

Example 19 20 Purification and crystallization of Compound I-IH (E isomer) Compound 1-1H hydrochloride obtained in Example 16 was a pale yellow amorphous powder of 85% purity.

Procedure 1 Six grams of the 851 purity hydrochloride was dissolved 25 in 20 ml of H-,0 and filtered through a celite pad. The amber- colored filtrate (pH 2) was passed through a reverse phase column (the packing of prepPAK-500/C^g cartridge, Waters; 120 ml), which was eluted with water. The eluate was collected in 120-m.l fr actions with monitoring by HPLC*. Fraction No. 3 through 30 fraction No. 5 were combined and concentrated to about 10 ml, and precipitated by acetone (100 ml) to give 3.3 g of the zwitterion form of I-IH (pale yellow amorohous oowde r; estimated ourity W ft A * # 95%) . 77 To a suspension of the 951 purity powder (3.2 g) in CH ,0H (32 ml) was added N HCl in CH-OH (18 mi), and the mixture j — J was stirred at room temperature until a clear solution was obtained. The solution was filtered and the filtrate was concentrated to about 10 ml. To the concentrate was added isopropanol (100 ml) to separate a pale yellow precipitate, which was collected by filtration, washed with isopropanol (5 ml) and dried to yield 2.6 g of the HCl salt (amorphous powder; estimated purity 95%).

A solution of the 95% purity hydrochloride (1 g) in water (4 ml) was adjusted to pH 6.5 with NaHCO^ (200 mg) and stirred for 30 minutes. The crystals which separated during stirring were collected by filtration, washed with water (2 x 5 ml) and dried i_n vacuo to give 710 mg of I-IH (zwitterion form) as pale yellow prisms. H.p. >185°C (dec.). Microanalysis showed it to be the trihydrate.

IR % vKBr cm"1 1780, 1695, 1660, 1630, 1610. max UV : xPhosphate butfer (pH7) nm (e) 227 (22000), 290 (23000). max 3.45 (2H, br, s, 2-H), 3.9 (3H, s, OCHj), 4.99 (1H, d, J-4.5 Hz, 6-H), 5.16 (2H, d, J«7 H2, CH2N+), 5.61 (1H, d, J = 4 . 5 Hz, 7-H) , 5.8 (1H, d-t, J*16 & 7 Hz, 3-CH-CH), 6.93 C1H, d, J»16 Hz, 3-CH)f 8.18 & 8.89 (each 2E( d, J=7 Hz, Py-H). ,.„r .DMS0-d,+D-0 N MR : 6 o 2 ppm Anal'. Calc'd for C,, H,0»8O6S2' 3H,Q: C, 42.14? H, 4. 38; N, 18.72; S, 10.71.

Found: C, 42.41; H, 4.35? N, 18.86; S, 11.00.

* Column, Lichrosorb RP-18, 4x300 mm: Mobile phase, 0.01 M 7 3 phosphate buffer (pH 7.2)/CH^OH * 85/15: Detection, uv (25 4 nm).

Procedure 2 Once crystalline 1-1H had been obtained from Procedure 5 1, it was possible to obtain the crystalline zwitterion form of I-IH directly from the crude I-IH hydrochloride by seeding with § few crystals of the pure 1-1H.

A solution of the 85% pure hydrochloride (250 mg) in water (1 ml) was treated with charcoal. The solution was 10 ad 3 usted to pH 6.5 with NaHCO^ (60 mg) and decolorized with charcoal. The filtrate was seeded with a few pieces of the crystals obtained from Procedure 1 and stirred overnight at room temperature. The separated crystals were collected by. filtration, washed with water (2 x 2 ml) and dried under reduced 15 pressure to give 170 mg (80% recovery) of pale yellow prisms of I-IH (zwitterion form), melting at >185°C (dec.), which was identical with that obtained by Procedure 1, (as shown by IR, UV, N MR J .

The crystalline zwitterion form, of Compound I-1K was 20 slightly soluble in water (6 mg/ml in saline at 23°C).

Example 20 N r-C CONH- |i ila H2N ^ S ^ OCH3 O I-1K *E 7 - [ 2 - ( 5-Ami no-1,2, 4-th iadia2ol-3-yl)- 2-me thoxy innoacetai?ido ]-3-[ 3- ( 3-hyd r oxymethyIpyr id in io) -1 -propenyl ]- 3-ceph err -4-ca rboxv late - IK ) (E i somer ) A . Diphenylmethyl 7- [ 2- ( 5-Amino-1 , 2,4~thiadiazol-3-yl)-2- methoxyiminoacetamido ] -3- [ 3- ( 3-hydroxyme thy Ipyr idinio)-!-propeny1]-3-cephem-4-ca rboxylate iodide (B~isomer) (XII-1K) To a solution of IX-l (E-isomer f 1.79 gf 2.5 mmoles) in 2.5 ml of CH^OH and 7.5 ml of CK^CN was added 3-hydroxymethvl-pyn dine (545 mg, 5 mmoles)„ and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ethyl acetate (100 ml) with vigorous stirring. The resulting precipitate was collected by filtration? washed with a small volume of ethyl acetate and dried to give 2.06 g (100%) of the title compound XII-IK as a tan powder. Mp. 170-130°C (dec.), IR : v (KBr) in cm"1 1780, 1725, 1675, 1615, 1530, 1385, 1225, 1040, 750, 700.

UV : A (C,H5OH) in nm (E1% ) 290 (196). 1 cm.

CH=CH-CH H_,OH 8 N MR : 6 (DMSO + D20) in DC rs 3.7 ( 2H, br.s, 2-H), 3.91 (3H, s, OCH3), 4.70 (2H, s, Py-CH2-OH), 5.28 ( 2H, m, CH2~N+ ) , 5.23 (1H, d, J-5H2, 6-H), 5.90 (1H, d, J=5Hz, 7-H ) , 6.34 (1H, m, 3-CH-CH) , 6.66 (1H, d, J«16Hz, 3-CH), 6.8 9 (1H, s, CHPh _,) , 7.35 (10H, m, Ph-H), 7.9-8.9 (4H, m, Py-H).

B. 7-[2-(5~Ami no-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacet a jri do ] - 3- [ 3- ( 3-hydr oxymethylpyri danio)-I-propenylJ-3-ceph err-4-car boxy late (I-1K) (E isomer) A mixture cif XII-IK (E isomer, 2.0 g, 2.4 mmoles) ana sodium bisulfite (1 g) in 85% HCOOH (10 ml) was stirred for 2 hours at room temperature. The reaction mixture was concentrated 15 to ca. 5 ml under reduced pressure. The oily residue was poured into acetone (100 ml) with vigorous stirring. The precipitate was collected by filtration, washed with a small amount of acetone and dried to give 1.1 g of a tan powder, which was purified by column chromatography [using the packing of a 20 PreppAK-500/C1q cartridge (Waters)) to give 283 mg (22%) of I-1K as an amorphous powder- The powder was crystallized from 4N £2S04 and acetone to give 144 mg of the title compound I~1K as colorless needles. Mp„ 185-188°C (dec.).

IR : v (K3r) in cm-1 1775, 1680sh, 1660, 1630, 1225, 1045, max 25 850. 1 fit UV : ^■max (Phosphate buffer, pH 7) in nm (E ) 236.5 ( 283), 1 cm) 275 sh (280) , 292.5 (330).

NMJR : 6 (D^O) in ppm 3.75 (2Hf s, 2-H), 4.18 (3H, s, OCH^), 4.97 (2H„ s t Py-CH2OH), 5.35 (1H, d, J«4Hz, 6-H ) , 5.43 ( 2H, d, J«=6. 5Hz, CH^-N*), 5.92 (1H, d, J«4Hz, 7-H), 6.18 (IB, d-t, J*16H 2, J = 6.5Hz, 3-CH»CH-), 6.9 7 (1H, d, J - i 6 H z , 3-CH), 8.13 {1H, d-d, J«8Hz, J«6Hz, Py-H), 8.60 (1I-I, d, J = 8Hz, Py-H), 8.84 (1H, d, J=6Hz, Py-H), 8.90 (1H, s, Py-H).

Example 21 7 - [ 2 - ( 5-AiT.ino-l, 2,4-thiadiazol-3-yl)-2-(2) -me thoxy i mi no-ac etamido ] -3- [ 3- ( 4~N~roethylcarbamoylpy r idin io ) -1-propenyl ]-3-c eph em-4-car boxvlate (I-1M) (E isomer) A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-l-pcopenyl)- 3-cephem-4-carboxylate (IX-l) (E isomer, 450 mg, 0.62 mmole) and 4-N-methylcarbamoylpyridine {prepared according to the procedure of M. Same 3 i ma, Yakugaku Zasshi, 8_0, 1706 ( 1960) J (215 mg, 1.58 mmoles) in acetonitrile (2 ml) was stirred under nitrogen atmosphere for 5 hours at room temperature. The mixture was evaporated under reduced pressure and the residue was triturated with ether to give 530 mg of the quaternary salt. A mixture of the solid and sodium bisulfite (150 mg) in 85% formic acid (2 ml) was stirred for 4 hours and then heated at 40°C for 30 minutes. The mixture was evaporated under reduced pressure. The residue was triturated with acetone and the crude product was collected by filtration. The crude product was chromatographed on a column of HP-20 (1.5 x 18 cm) and the column was eluted with water and 30% aqueous methanol. The methanolic eluate was evaporated under 8 2 reduced pressure and the residue was freeze-dr ied to give 140 mg of an amorphous powder„ which was further purified by HPLC (Column: Lichr osorb RP~18s, Solvent: 15% CH^OH) and the eluate of KPLC was freeze-dried to give 60 mg (18%) of the title product 5 I-1M. Mp. 180-183°C (dec.). Estimated purity: 80%.

IR : v (KBr) in cm ~ 1760, 1660, 1600. max UV ; X (Phosphate buffer, pH 7) in nm (e) 230 (22100), 266 max (22100).

NMR : 6 (D,0) in ppm 3.08 (3H, s, CONHCH3), 3.72 (2H, s, 2-H), 10 4.16 (3H, s f OCH3), 5.35 (1H, d, J=4.5Hz, 6-H), 5.95 (1H, d, J=4.5Hz, 7-H), 7.00 (1H, d, J=16Hz, 3-CH) ; 8.35 (2H, d, J-6Hz , pyridine-H), 9.05 (2H, d, J=16K2T pyridine-H). 15 Example 22 H.

N pp X J k S' OCH, I-1N CONH- ./s X & N * © CH=CH-CH- ccxP ■o 00 h *E/Z * 7/1 7- [ 2- ( 5-Amino-l, 2,4~thi3diazol-3-yl)- 2-methoxyiminoacetamido]-3-[3-(4-ca rboxypvri dinio)-1-propenyl3-3-cephem-4-ca rboxylat e (I-IN) 20 To a stirred suspension of isonicotinic acid (340 mg, 2.8 mmoles) in dry DMF (3.5 ml) was added N,0-bis(trimethyl-silyl)acetamide (0.7 ml, 2.8 mmoles) under nitrogen atmosphere. To the resulting clear solution was added diphenylmethyl 7-[2-(5-amino-l2,4-fchia<3iasol-3-y1)-2-methoxyiminoacetamido3-3-(3-25 iodo-l-pcopenyl)-3~cephem-4-carboxylate (IX-l) (E isomer, 720 mg, 1 mmole) in one port1 onand the red solution was stirred foe 1.5 hours at room temperature. The reaction mixture was added 8 3 dropwise to a stirred saturated sodium chloride solution (50 ml) containing sodium thiosulfate (ISO mg). The yellow precipitate vas collected by filtration, washed with water e and dried to obtain 722 mg of a pale yellow powder. The powder (700 mg) end 5 sodium bisulfite (70 mg) were dissolved in 85% formic acid (5 nl), and the solution was allowed to stand at room temperature for 1.5 hours. The mixture was suspended in toluene (50 ml) and concentrated. The residue was triturated with acetone (70 ml), and the precipitate was isolated by filtration to afford 421 mg 10 cf a yellow powder. This crude powder (400 mg) was suspended in water (2 ml) and to the suspension was added sodium bicarbonate. The resulting dark solution was adsorbed on a column of the packing (50 ml) of a PrepPAK/C^g cartridge (Water's System 500), and the column was eluted by water (200 ml). The eluent was '.5 fractionated into 10 fractions (20 ml of each), and the desired fractions (Fractions Nos. 4-7) were combined, acidified to pH 3 with 2H hydrochloric acid, and concentrated. The residue was triturated with acetone (30 ml) and the precipitate was collected by filtration to give 201 mg (37%) of the title compound I-1N as 20 a yellow powder. E/Z = 7/1; 80% pure. Mp. >189°C (dec.).

IR : v (RBr) in cm ~ 1770, 1665, 1600. nva x UV : X (Phosphate buffer, dH 7) in nm (e) 227 (22500), max 290 (22100).

NMR : 6 (D,0 + NaHCO^) in ppm 3.7 (2H, br.s)P 4.15 (3H, s), 2 5 5.32 (1H, d, J=4Hz), 5.39 (2H, d, J-6Bz)f 6.14 (1H, d-t, J=15.5 and 6Hz), 7.03 (1H, d, J = 15 . 5Hz ) <. 8.31 (2H, dt, J=7Hz), 8.94 (2H, d, J=7Hz).

Example 23 CONH H,N 3 I-10 7-(2"(5-Aff.ino-I/2,4~thiadiazol~3-yl)"2--(Z)-methoxyimino-acetamido]-3"[3-(2,3~cyclopgntenopyridinio)-1-propeny13 - 3-cephem-4-carboxylafce (1-10) (£ Isomer) thiadiazol~3-yl) ~2-m€thoxyiminoacetamido ]-3- ( 3-iodo- 1-pr openy 1) -3-cephe?n-4-carboxylate (IX-l) (E isomer, 450 mg, 0.62 mmole) and 2, j-cyclopentenopyridine (217 mg, 1.83 mmole) in acetorii tr lie (2 ml) was stirred under nitrogen atmosphere for 4 hours at room temperature. After evaporation under reduced pressure, the mixture was triturated with ether to give 560 mg of the quaternary salt. A mixture of the solid and 65% formic acid (2 ml) was stirred under nitrogen for 3 hours at room temperature and then heated at 40°C for 30 minutes. The mixture was evaporated under reduced pressure and trituration of the residue afforded 391 mg of the crude product, which was purified by chromatography on a column of HP-20 (1.5 jc 18 cm). The column was eluted with water and 30% aqueous methanol. Evaporation of the methanolic eluate under reduced pressure, followed by freaze-drying afforded 160 mg of an amorphous powder, which was further purified by HPLC (Column: Lichrosorb, Solvent: 10% CH^OH). The eluate of HPLC was freeze-dried to give 50 mg (15%) of the title product 2-10. Hp. > 19 00 C (dec.). Estimated purity 7 5%.

A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4- IR v max (KB™) in cm * 1765f 1670, 1600.

UV : X (Phosphate buffer, oH 7) in nm (e) 235 (20000), 283 mdx (25000). 8 5 N'MR : 6 (D20 + NesHC03) in ppm 2.2-2.6 ( 2H, m, -CH2~) , 3.1-3.6 (4H, m, -CH2-), 3.72 (2H, s, 2-H), 4.17 (3H, OCH3)f 5.33 (1H, d, J * 4 . 5 H z , 6-H), 5.90 (1H, d, J = 4.5Hz, 7-H), 6.75 (1H, d, J = 16Hz, 3-CH) , 7.65-8.2 (3K, rr, pyridine-H).

Example 24 CONH- I-2N COO® CH=CH-CH,-N J/ \\ -N ' \\JT 00 h 7 - [ 2 - ( 5-Air.ino~l ,2,4-thiadiazol-3-yl)-2~(2)-ethoxyimino-acetarridoj-3-[ 3-( 4-ca r boxy pyr idinio) -1-pr openv 1 ] - 3-ceph eir- 4-car'boxylate (I-2N, E isomer) and 7- [ 2- ( 5-Air.i no-1,2,4~th.iadiazol~3-yl)-2-(z)-ethoxyimino-acetamido) — 3— ( 3— (4-carboxypyridinio) -1-propenyl ]- 3-ceph.eir-4- carboxylate (I-2N, Z isomer) To a chilled mixture of BSA (1.0 ml, 4.12 mmoles) and isonicotinic acid (506 mg, 4.12 mmoles) was added IX-2 (from Preparation No. 21) (1.0 g, 1.37 mmoles), and the mixture was stirred under nitrogen at room temperature for 2 hours. The mixture was poured into 10% Ha 2S703 (20 ml) to precipitate 1.3 g of the quaternary salt, which was collected by filtration, washed with water and dried. a mixture of the solid and sodium bisulfite (0.3 g) in formic acid (98%, 5 ml) was heated at 40°C for 1 hour and evaporated under reduced pressure. The residue was triturated with acetone and filtered to give 900 mg of the crude product (E-propenyl isomer:Z-propenyl isomer * 2:1). Separation of the isomers was carried out by HPLC (Column: 8 0 L ichrosorb, Solvent: 154 CH^OH). The faster moving fractions o HPLC were collected, evaporated under reduced pressure and treeze-dried to give the E-propeny1 isomer of I-2N (44 mg, yield 6%). The slower moving fractions gave the Z-propenyl isomer of I-2N (32 mg, yield 4%) in a similar procedure.

I-2N, £ isomer Hp.: >200°C (dec. ) . v (KBr) in cm ~ 1765, 1660, 1620, 1380. ma x X (Water) in nm (e) 228 (22200), 291 (23600). max 6 (DjO) in ppm 1.45 ( 3H, t, J = 6Hz, CH-jCH^), 3.72 ( 2H, s, 2-H), 4.45 ( 2H, q, CH2CH3), 5. 40 ( 1H, d J = 4 H z , 6-H) , 5.90 (1H, d, J=4Hz, 7-H), 7.05 (1H, d, J=15Hz, 3-CH), 8.30 (2H, d, J=6Hz, Py-H), 8.95 (2H, d, J=6Hz, Py-H).

I-2N, Z isomer Hp.: >200°C (dec, ) .

IB : v (KBr) in cm ^ 1760, 1660(sh), 1620, 13 70. nva x UV : X (Phosohate buffer, pH 7) in nm (e) 225 (22400) , 275 ni a v * ** (sh, 16000).

NMR : 6 (D,0) in ppm 1.45 (3H, t, J=7Hz, CH,CH3), 3.50 (1H, d, J«17Hz, 2-H), 3.75 (1H, d, J»17Hz, 2-H), 5,38 (1H, d, J=4Hz, 6-H), 5.95 (1H, d, J*4HZ, 7-H), 6.62 (1H, d, J^l1Hz, 3-CH), 8.35 (2H, d, J-6H2, Py-H), 8.92 (2H, d, IP. uv : N mr : Example 25 N j—C II fl i com ch»ch-ch2 conh, 7-- [ 2 - (Amino-l, 2, 4~thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetarr.ido ] -3- [ 3- (4-car bamoyl pyr idinio ) -1-pr openy 1 ] -3-cephem-4-carboxylate (I-3H) (E isomer) To a solution of 35 mg (0.08 mole) of 7-amino-3-[ 3- (-flea r bamoylpyr idinio) -1- ( E)-propenyl]-3-cephem-4-carboxylafee hydrochloride in 2 ml of 50% aqueous acetone was added 52 mg of 2-[ 5-amino-l,2,4-thiadiazol-3-yl)3-2- (propen-3-yloxyimino)acetyl chloride hydrochloride (from Preparation Ho. 25) and the mixture was adjusted to pH 6.5-7.0 with 2N Na^CO^. The mixture was stirred at room temperature for 1 hour? acidified to pH 2 with 1 HCl and concentrated under reduced pressure. The residue was chromatographed on a column of HP-20 resin which was eluted with 300 ml of water and 30% CH»0H-H50. Fractions containing the product were combined and evaporated under reduced pressure. Th residue? 73 mg, was purified by a column of reverse phase carrie which was taken out of a PrepPAK-500/C^g cartridge (Waters, 30 ml). The column was eluted with water, 5% CH^OH, 10% CH^OH and 20% CH^OHf successively. Fractions containing the product were combined and lyophilized to afford 26 mg (62%) of the title product I-3H. Hp. 160°C (dec.).

IH : vm»y (KBrJ in cm~1 3400" 1765< 1680, 1605, 1400.

UV : X (Phosphate buffer? dH 7) in nm (e) 226 (24600) , 288 max ( 22800) . 8 3 NMR : 6 (D20) in ppm 3.75 (2H, s, 2-H), 5.41 (1H, d, J« 5Hz, 6-h) , 5.50 (4h, m, £ ch-ch2) , 5.96 (IB, d, j-5h2, 7-H), 6.20 (1h, m, 3-CH-CH), 7.09 (1H, d, J«17Hz, 3-CH), 8.50 (2h, d, J«7Hz, Py-H), 9.16 (2h, d, j«7hz, Py-H).

Example 26 n« k2N" ■3^ 11 'A. conh ■ L™ f CH i-4h co-cP H-CH-CH ?0- CONH, 1- . 2-( 5-AJtr.ino-l ,2,4-thiadiazol~3-yl) -2-proparqyl oxyimino - l o ac atami do 3-3-[3-(4-carbamoylpyridin io)-1-propeny1]-3-ceohem-4-carboxvlate (I-4H) (E isomer) To a solution of 86 mg (0.19 mmole) of 7~amino~3~[3-(4-carbamoyIpyridinio)-l-(E)-propenyl)-3-cephem-4-carboxylace hydrochloride (XXIX-H) in 2 ml of 50% aqueous acetone was added 15 63 mg of 2-propargvloxyimino-2~(5-amino-l,2, 4-chiadiazol-3-y1)-acetyl chloride hydrochloride (from Preparation No. 26). The suspension was maintained at pH 6.5-7.0 with 2N h^CO^ and then stirred at room temperature for 1 hour. The reaction mixture was acidified to pH 2 with IN HCl and concentrated _in vacuo. The 20 residue was diluted with 30 ml of water, neutralized with NaHCO^ and filtered. The filtrate was transferred on the top of a coiunvn which was packed with reverse phase carrier (30 ml) taken from a PrepPAK-500/C1g cartridge (Maters). The column was eluted with water,. 5% CH^OH, 10% CH^OH and 20% CH^OH, successively. 25 Fractions containing the product were combined and lyophilized to afford 13 mg (12%) of the title product I-4H. Estimated purity 70%. Hp. 1608C.

IR : v (KBr) in cm"1 3400, 2120, 1765, 1680, 1610.

O Q.

KJ/ K.V UV : A (Phosphate buffer, pH 7) in nm (c) 229 (24000), Si\<& X 288 (21200).

N MR : 6 (D20) in ppm 3.78 (2H, s, 2~K) , 5.15 (2H, d, J*lHz, -CH,-CSCH), 5.40 (1H, d, J«5Bzf 6-H), 5.50 (2H, m, CH-N+), 5.98 (1H, d, J=5Kz, 7-H) , 6.20 (1H, m, 3-CH = CH), 7.05 (1H, c, J*17Hz, 3-CH) , 8.50 (2H, d, J=7Hz, Py-H), 9.16 (2H „ d, J*7Hz, Py-H).

Example 27 10 n- u »> i2h S X' \0 o CONH ch--ch-ch. *0- CONH. 1-5! * p 7-[2-(5~Amino~l,2,4"thiadiazol-3-yl)-2-cvclopentvloxyirr.ino-ac etamido]-3-[3-(4-carbamoylpyridinio)-1-propeny1] - 3-cephem-4-carboxylate (I-5H) (£ isomer) To a stirred solution of 139 mg (0.31 mmole) of 7-amino-15 3- [ 3- ( 4-carbamoyIpyridinio)-1-propeny1]-3-cephem-4-carboxylate hydrochloride in 3.5 ml of 50% aqueous acetone in an ice-cooling bath was added portionwise 120 mg (0.44 mmole) of 2-(5-amino-1,2,4-thiadiazol-3-vl)-2-cvclopentyloxyiminoacetyl chloride hydrochloride (from Preparation No. 27). The mixture was 2o adjusted to pB 6.5-/.0 with 2N Na2C03 (0.9 ml) and stirred for 1 hour at 10°C. The reaction mixture was acidified to pH 2 with IN HCl and evaporated under reduced pressure. The residue was chromatographed on a column of HP-20 resin (20 ml) and was eluted with 300 ml of water and 30% CH^OH-H^O, successively, fractions 25 containing the product were combined and concentrated in_ vacuo. The residue was treated with 60 ml of acetone to give 111 mg (63%) of the title compound I-5H. Hp. 160°C (dec.). Estimated purity 70%. 9 0 IR : si < KBr) cm'1 3400, 1770, 1680, 1605, 1530. itio x UV : Xm>„ (Phosphate buffer, pH 7) in nm (e) 224 (23300), max 28 6 (24600). 5 N Mr- : 6 (DMSO-dg) in ppm 1.70 (8H, br.s, ), 4.68 (IH, H br . s, XJ ) , 5. 05 ( IH, d, J * 5 H z , 6-H) , 5.30 ( 2H, it., CH2N^), 5.67 (IH, d-d, J = 5Hz & 7Hz, 7-H), 6.20 (IH, m, 3-CH»CH), 7.08 (IH, d, J=17Hz, 3-CH), 10 8.34 (2H, d, J=7Hz, Py-H), 9.11 (2H, d, J-7Hz, Py-H), 9.38 (IH, d, J=7Hz, 7-NH).

N- K0N* 11 i CONH OCH, H=CH~CH. cocP CH^COOH I-1P *E 15 7-[ 2" ( S-Araino-l, 2, 4-thiadia2ol-3~yl)-2-methoxyiminoacetan>ido]~3-[ 3- ( 3~ca rboxymethvlpy r idinio) -1-pr openy 13 -3-cephem- 4-ca rboxyl ate (I-1P) (E isomer) A. Diphenylmethyl 7-[2-(5-Amino-1,2P4-thiadia2ol-3-yl)~2-~ me thoxy iminoac etamido)- 3- [ 3- (3-carboxymeth.y Ipyr idinio) -1-20 propenyl]-3-cephem-4-carboxylate (XII-1P, iodide, E isomer) To a suspension of 3-carboxymethyIpyr idine hydrochloride (0.89 g, 5 mmoles) in 10 ml of CH?C1, was added N,0-ois(trimethylsilylJacetamide (4.97 ml, 18 mmoles), and the mixture was stirred at room temperature until a clear solution 25 wes obtained. To the solution was added IX-l (1.79 g, 2.5 mmoles)„ and the mixture was allowed to stand at room 9 1 temperature. After 3 Scours? 3 ml of CH^OH was added to the cooled mixture and the solution was evaporated ijn vacuo to give an oil which was triturated with ethyl acetate to afford 2.28 g of the title compound XI I-IP as a tan powder. Hp. 161°C (dec.) IR : v {KBr ) in cm"1 1780, 1720, 1675, 1630, 1530 , 1385, ma x 1225, 10 45,- 755, 700. tr.7 : \ „ (C-H _ OH) in nm (E1% ) 295 ( 188) max 2 5 1 cm N\"-R : 6 (OMSO 4- D2O) in ppm 3.70 (2H, br.s, 2-H), 3.90 (5H, s, OCH3 & Py-CE.CO), 5.25 (3H, m, -CH2N+ h 6-H), 5.92 (IH, d, 4.5Hz, 7-H), 6.35 (IH, m, 3~CH=CH-), 6.90 (IH, d, J=16Hz, 3-CH), 6.92 (IH, S, CHPh,), 7.35 (10K, m, Ph-H)f 8.8-9.0 (4H, m, Py-H). 3 . 7 - [ 2- ( 5-Am.ino-l, 2,4-thiadiazol-3-yl) - 2-me thoxy iminoacet ami do ] - 3- [ 3- ( 3-ca rboxyirethylpyr idinio ) -1-pr openy 1 ] ~3-cephem-4-carboxylate (I-1P) (E isomer) A mixture of XII-1P (iodide) (2.28 g) and sodium bisulfite (1.1 g) in 85% HCOOH (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to ca. 5 ml under reduced pressure. The oily residue was triturated with acetone (100 ml) to give 1.22 g of the crude product, which was purified by column chromatography (HP-20, 420 ml) to afford 533 mg of the title compound I-1P (38%, from IX-l) as a pale yellow amorphous powder, Hp. 165®C (dec.).

IR : v (KBr) in cm"1 1770, 1570, 1600, 1530, 1385, 1140, ih3: x 10 40 .

Ct o uv : X (Phosphate buffer, pH S.2) in nm (E1% ) 234 (374), In ci X . 2 7 7 s h (390) , 29 0 (402).

NKR : 6 (DjO + NaHCO-j) in ppm 3.78 (2H, s, 2-H), 3.92 (2K, s, 5 Py-CH2CO), 4.22 (3H, s, OCH3), 5.40 (IH, d, J«4Hz, 6-H), 5.44 (2H, d, J«6.5Hz, -CH,-N+), 5.97 (IH, d, J=4Hz, 7-H), 6.20 (IH, d-t, J«16 & 6.5H2, 3-CH«CH), 10 7.08 (IH, d, J=16Hz, 3-CH), 8.11 (IH, d-d, J«8 & 7Hz, Pv-Hc), 8.53 J (IH, d, J = 8 H z, Py-H4), 8.82 (IH, d, J=7Hz, Py-H6), 8.86 (IK, s, Py-H2). 15 Example 29 I-1q *E 7 - [ 2- ( 5~Ajrsino-l ,2,4-thiadiaaol-3~yl )-2~iae thoxy imi no acetate i do ] -3-[3-(4-carboxymethylthiopyridinio)-1-propenyl]-3-cephem-4-carboxylate (I~ 1Q) (E isomer) 20 A• Diphenylmethyl 7-[2-(5~Amino-l,2,4-thiadiazol-3-yl)-2" methoxyiminoacetamido3-3-[3-(4-earboxymethylthiopyridini o)-1-propenyl]-3~cephem-4~carboxylate (XII-1Q, iodide, E i somer) To a suspension of 4-carboxymethylthiopvridine (0.88 g, 25 5 mmoles) in 10 ml of CH?C1., was added N,O-bis(trimefchylsily1)-acetamide (5 ml, 18 mmoles)„ and the mixture was stirred at room temperature until a clear solution was obtained. To the solution was added IX-l (S isomer 1.79 g, 2.5 mmoles), and the mixture was 9 3 20 30 allowed to stand at room temperature. After 3 hours, 3 mi of CH-.OH was added to the cold mixture and the solution was evaporated i_n vacuo to give oily residue which was triturated with ethyl acetate to give 2.43 g of the title compound XII-1Q (iodide) as a tan powder. Mp. 155°C (dec.).

IR : v v (KBr) in cm"1 1780, 1720, 1670, 1625, 1525, 1365, max 12 25, 1115, 1040, 755, 700, UV : >, v (C0H,OH) in nm (E1% ) 312 (29 9). m ci x 2 5 1 cm 10 N MP. : 6 (DMSO-dg + pp,T' 70 (2K„ br.s, 2-H), 3.93 (3H, s, OCH3), 5.07 (2H, m, CH2-N+), 5.23 (IK, d, J«5Hz, 6-H), 5.90 (IH, 6, J=5Hz, 7-H), 6.29 (IH, m, 3~CH~CB), 6.87 (IH, 15 d, J=16Kz, 3-CH), 6.91 (IH, s, CHPh2) , 7.35 (1 OK, ir., Ph-K), 7.88 & 8.58 (each 2H, d, J = 6 H z , Py-H). 3 . 7-[2-(5-Afrino~l,2,4~thiadia2ol-3-yl) -2-meth oxy iminoacet ami do]-3-[3-(4-ca rboxymethylthiopyridinio)-!-pcopenyl]-3-cephem-4-cacboxylate (I-1Q) (£ isomer) A mixture of XII-1Q (iodide, 2.43 g) and sodium bisulfite (1.1 g) in 85% HCOOH (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated 25 to ca. 5 ml under reduced pressure. The oily residue was triturated with acetone (100 ml) f filtered and dried to give a crude product (1.39 g), which was purified by column chromatography (HP-20, 20 ml) to afford 57 7 mg of the title compound I-1Q (39% from IX-l) as a pale yellow amorphous powder. Mp. 108®C (dec. ).

I?: : v (KBr) in cm"1 176 5, 1670? 1625, 1530, 1380, 1110, ma x 1035 . 9 4 UV : X (Phosphate buffer, pH 6.2) in nm (E~ * ) 23 4 (459), fUeaX . 1 310(678).

NMR 10 6 (°2° + NaHC03 ) in ppm 3.79 (2H, br.s, 2-H), 4.10 (2H, s, S-CH,), 4.23 (3H, s, OCH ) , 5. 25 ( 2H, d, J=» 6 . 5Hz , CH^-n"), 5.39 (IH, d, J«4.0H2, 6-H), 5.97 (IH, d, J«4Hz, 7-H), 6 o18 (IH, d-t, J ■« 15 , 5 H z & 6.5Hz, 3-CH = CK), 7.05 (IH, d, J= 15.5Kz, 3-CH), 7.84 & 8.55 (each 2H, d, J*7Hz, Py-H).

Example 30 15 I I us och.

■CONH—j j" r * H3CSS©/ *ch»ch-ch7-n cocP I-IA *E/Z - 7/1 7-[2- ( 5-Am.ino-l, 2, 4-thiadia20l~3-yl )-2-methoxyiirinoacetairido]-3 - [ 3- (l-methylpyrrolidinio)-l-propenyl 3-3-cepherp.-4-carboxylate sulfate (1-1A, sulfate) A. Diphenylmethyl 7-(2-(5-Amino-1,2,4~thiadiazol-3-yl)~2-methoxyiminoacetamido]-3-[3-(l-methylpyrrolidinio)-1~ propenyl]-3-cephem-4-carboxylate (XII-IA, iodide) 20 To a cold solution of diphenylmethyl 7-[2~(5-amino- l,2,4-thiadiazol-3-yl)~2~methoxyiminoacetamido3-3-(3-iodopropenyl )-3-cephem-4-carboxylate (IX-l) (from Preparation No. 14) (21.5 q, 30 mmoles) in ethyl acetate (300 ml) was added dropwise a solution of l-methylpyrrolidine (2.55 q, 30 mmoles) in ethyl 25 acetate (30 ml) over a period of 1 hour at -5 to 0°C, with stirring. After stirring for an additional 10 minutes, the resulting precipitate was collected by filtration and washed with 9 5 chloroform (200 ml) to give 23.0 g (95.8%) of the title compound (IX-1A, iodide), melting at >175°c (dec.).

If: ; v (KBr) in cm"1 3300, 1780, 17 30, 1685, 16 15. max UV : X aw (C0H,OH) in nm (E1% ) 218 (435), 295 (188). 5 max 2 5 i B . Diphenylmethyl 7~[ 2- ( 5-Ami no-1, 2, <-thiadi a.zol~ 3-yl) -2~ ir.ethoxyirr.inoacetairido]-3-[3-( l-methylpyr r ol idin i o) -1-pr openy 1 ] - 3-ceph. em- 4-ca rboxyl ate (KII-1A, chloride) The compound (XII-1A, iodide) (23 g, 28.7 mmoles) was 10 dissolved in a mixture of acetone and methanol (1:1, 230 ml) and applied on an Amber lite IRA-410 (chloride form, 230 ml) column which was pretreated with the same mixed solvent. The column was developed with the solvent and the fractions containing the desired compound were combined and concentrated to an oily 15 residue, which was triturated with ethyl acetate (300 ml) to yield 17.9 g (87=7%) of the title compound (XII-1A, chloride), melting at 190°C (dec.).

IR : v (K3r) in cnf1 3380, 1780, 1680, 1620. ma x 20 uv : Xmax (c?Hs0H) in nm ' 290 ( 232) . 9 $ C. 7-12"(5-Amino-I,2,4-thiadiazol-3-~yl)~2-methoxyirr.ino-acetamido)-3"[3-(I-n>ethylpyrroIidinio)-I-propenyl]-3-cephem-4-carboxylate sulfate (I-1Af sulfate) A mixture of the compound (XII-1A, chloride) (17.8 g, 5 25 rrmoles) in 85% formic acid (178 ml) was stirred at room temperature for 2 hours under & nitrogen atmosphere. The mixture was evaporated i_n vacuo and the oily residue was triturated with acetone to give 9.80 g of crude I-IA. Concentration of the filtrate and the acetone washings yielded additional 2.95 g of 10 cruce I-IA. Two crops of the crude material wer e combined and extracted with 2N HCl (1 L and 0.5 L). The combined extracts were adsorbed on a Diaion HP-20 resin (1.5 L column), which was eluted with water and 30% aqueous methanol. The desired fractions were collected and evaporated in vacuo to an oily 15 residue, which was triturated with isopropanol (200 ml) and acetone (200 ml), successively, to yield 7.09 g of a light yellow powcer. This material (6.80 g) was dissolved in water (20 ml) and then subjected to coluinn chromatography over the packing of PrepPAK-500/C1g cartridge (90 ml), using water and 10% aqueous 2o methanol as an eluent. The eluate was collected in 20-ml fractions with monitoring by HPLC. [Column, Nucleocil SSC-ODS-262, 8 x 100 nun? Mobile phase, 0.01M phosphate buffer (pH 7.2)/CH^OH « 90:10,- Detection, UV ( 254 nm)]. Fraction Mo. 4 through Fraction No. 10 were combined,, evaporated under reduced 25 pressure and lyophilized to give 2.28 g of a yellow powder (E/Z « 7/1, 70% pure) (Crop 1], Fraction Mo. 11 through Fraction No. 85 were worked up in the same manner as described above to give 3.27 g of yellow powder (E/S ■ 5/1, 70% pure) (Crop 2]. A portion of Crop 1 (1.0 g) was purified by rechromatography on the packing of 30 PrepPAK-50 0/Cla cartridge (90 ml). The column was eluted with water and 5% aqueous methanol# successively. The eluate containing the desired compound was concentrated and lyophilized to yield 638 mg (E/Z » 7/1, 80% pure) of yellow powder. Another portion of Crop 1 (1.14 g) was worked up the same way to give 880 35 mg (E/Z * 7/1, 801 pure) of yellow powder. The two purified samples were combined and a portion (1.45 g) dissolved in IN sulfuric acid (5 ml). The solution was diluted with acetone (315 9 7 rri), with stirring. The creamy precipitate was collected by filtration to obtain 1.48 g of the title compound (I-IA, sulfate) (E/Z « 7/1, 80% pure),, melting at >185°C (dec.).

IR : v (KBr) in cm"1 3380, 3000, 1765, 1675, 1630, 1535, ma x 5 1390, 1115.

UV : X (Phosohate buffer, rra x NMR : o (D„0 + NaHCO, ) in oorn d J 10 15 pH 7) in nm (e) 236 (19900), 291.5 (22500).

"S.$ /— I) 5 • conh \ och. ch»ch-ch,-n (ch, ) - <*■ J j-ld l/l .0/1 7 - j 2- ( 5-Ami no-1, 2»4~ thiadiazol-3-yl)-2-me thoxy iminoacet arrido]-3-[3-trimethy1ammonio-1-propeny1)-3-cephem-4-carboxylate (I— IP) A. Diphenylmethyl 7—12—(5-amino-1,2,4~thiadiazol~3-yl)~2~ methoxyiminoacetamido]-3- ( 3-tr ime thy lammon io-1-pr ope~nyl) 3-cephem-4-ca rboxylate (XII-ID, iodide) To a solution of 13.0 g (19 mmoles) of diphenylmethyl 7-[2-(5-amino-le2,4-thiadia2ol-3-yl)-2-methoxyiminoacetamido]-3-l0 (3-iodopropenyl)-3-cephem~4-carboxylate (IX-l, from Preparation No. 10) in 38 ml of dry ethyl acetate was added 1.75 ml (19.1 mmoles) of 1. IN tcimethylam.ine in ethyl acetate at -50CP and the mixture was stirred for 1 hour at -5°C. The resulting precipitate was filtered off, washed well with chcl^ and dried to L5 give 12.5 g (88%) of the title compound (X1I-1D) as the iodide.

IR : v„ (KBr) in cm"1 3300, 1765, 1720, 1665. rP3 K UV : X (C.HrOH) in nm (e) 300 (18400). x 2 b B. Diphenylmethyl 7-[2-(5-Amino-1^2,4-thiadia2ol-3-yl)-2-20 methoxyiminoacetamido)-3-(3-tr imethylammonio-l-propenyl)- 3-cephem-4-carboxylate (XII-1D, chloride) The iodide (XII-1D, 12.5 g) was dissolved in 60 ml of CH^OH-acetone (1:1) and passed through a column of ion-exchange resin IIRA-410 (CI ), 125 ml]. The column was eluted with 300 ml 25 of CH^OH-acetone (1; 1) t. and the eluate was evaporated in, vacuo and triturated with 300 ml of isopropyl-ether to afford 10.4 g (91%) of the quaternary salt (XII-1D, chloride). 9 9 IR : v , (KBr) in cm"1 3300, 1765, 1710, 1S65. ff>3 X UV : X , (CnHcOH) in nm (e) 298 (151G0). max 2 5 C. 7-[2"(5-Ajr.ino-l,2,4-thiadia2ol-3-yl)--2-n'ethoxyiirino- acetairido)-3-[ 3-t r imethyl ammon io- 1-pr openyl ] - 3-ceph err-5 4-carboxylate (I-1D, sulfate, E isomer) A solution of 10.4 g (16.0 mmoles) of XJI-1D (chloride) in 20.8 ml of 85% formic acid was allowed to stand for 3 hours at room, temperature and concentrated iri vacuo. The residue was treated with 210 ml of isopropanol and the precipitate was 10 filtered off. The solid (10.1 g) was triturated with 210 ml of water and neutralized with sodium bicarbonate. The suspension was filtered off and the filtrate was chromatographed on a column of HP-20 (300 ml) which was eluted with water (1000 ml), 10% CH^OH (200 ml) and 30% CH^OH (150 ml), successively. Fractions 15 containing the desired product were combined and concentrated under reduced pressure. The residue was purified by reverse phase chromatography. The column was packed with a packing obtained from a PrepPAK-500/C^ g cartridge (Waters, 200 ml). Elution with water (600 ml) and 30% CH^OH (200 ml), successively, 2o followed by concentration of fractions containing the desired product gave 2.52 g (18%) of the title compound. A solution of the zwitterionic oroduct (1.5 g) in IN H.S04 (5 ml) was added * ~ A Sr jportionwise to 300 ml of acetone and the resulting precipitate was filtered and dried. Yield of I-lD sulfate was 1.42 g (80%). 25 The ratio of E/Z was approximately 10/1 based on HPLC.

IR • v „(KBr) in cm-1 3380,, 1765e 1665, iiW> (Phosphate buffer, pH 7) in nffl (e) 237 (19500), IT. G 293 (22400). 10 0 NMR : & (D?0) in ppm 3.25 (9H, s, N+-CH3), 3.94 (2H, s, 2-H); 4.14 (2H, d, J * 7 H 2, CH,N+), 4.23 ( 3H, s, 0-CH3), 5.42 (IH, d,~J«4.5Hz, 6-H), 6.00 (IH, d, J-4.5Hz, 7-H), 6.2 3 (IH, d-t, J«7 & 16Hz, 3-CH=CH), 7.23 (IE, d, J-16H2, 3-CH).

Example 32 I-IH *E 7- [ 2 - ( 5-Amino-1,2,4-bhiadia2 0l~3-yl)-2-methoxyiminoacetamidoJ~ 10 3- [ 3- ( 4-carbaiP.oylpyridinio)-l-propenyl ]-3~cephem-4-carboxylate (I-IH, E isomer) To a mixture of 7-amino~3-[3-(4~carbamoylpyridinio)-I-(E)-propenyl]-3-cephem-4-carboxylic acid hydrochloride (XXII-H, 39 7 mg, 1 mmole) end NaHCO^ (168 mg, 2 mmoles) in aqueous DMF 15 (water, 3.5 ml and DMF, 7.5 ml) was added benzotriazol-l-yl-2-(5-amino-l,2,4-thiadiazol~3-yl)~2-methoxyiminoacetate (479 mg, 1.5 mmoles) (from Preparation Ho. 23). The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was adjusted to pH 3-4 with 3N HCl and diluted with 200 ml of acetone 20 to give a precipitate, which was collected by filtration. The crude product was dissolved in a small volume of aqueous THF and the solution was adjusted to ?H 6.8 with NaHCO^, treated with decolorising carbon, concentrated to ca. 1 ml and seeded with a few pieces of crystalline I-IH. After stirring overnight, the 25 crystalline precipitate was collected by filtration to afford the title compound I-IH (zwitterion form). Yield 83 mg (16%). Mp. >1850C (dec.). Physico-chemical data of this product were identical to those of the compound in Example 10. preparation No. 1 DiphenvInethyl 7-[2-(5~Ami no-1,2,4-thladiazol-3-yl)- 2 -irethoxyinunoacet?rrido )-3~chlorOinethyl-3-cephem-4-carboxylate (IV-1) To a stirred suspension of 2-(5-amino-l,2,4-thiadiaaol-3-y 1) - 2~methoxy iminoacetic acid (111-1) (2.1 g, 10 mmole ) in dry CH2C12 (50 ml) was added PC15 (2.09 g, 10 mmole) at -30°C, and the mixture was stirred for 20 minutes at -15 to -20 ®C. To the above acid chloride solution was added a solution of diphenyl-p.e thyl 7-amino- 3-ch loromethyl-3-cephem-4-carbojcylate hydrochloride (II) (4.5 g, 10 mmole) in CH,C1, (50 ml) containing N,0-bis-(trimethylsilyl)acetamide (10 g, 50 mmole) at -30 "C, After stirring at -10 °C for 1 hour, the mixture was cancan tr a t-ad to remove the CH^Cl^ and diluted with ethyl acetate (200 ml). The mixture was washed with 10 % aqueous NaHCO^ (2 x 40 ml), H,0 (2 x 20 ml) and brine (10 ml) „ successively,, and dried over MgSO^o The solvent was evaporated ijn vacuo and the resulting oily residue (10 g) was dissolved in CHCl^ (20 ml) and chromafco-gtaphed on a silica gel (Wake gel C-200, 100 g containing 10 ml of 1/1.5 M pH 7 phosphate buffer) using 1 - 3 % CH30H~CHC13. Fractions containing the title compound were evaporated to give 5.7 g (95 D of IV-1 as a yellow amorphous powder. M. p. >140 9C (dec . ).

IR : vKBrcnf1 3300 j. 1780, 1720, 1680, 1620, ma x UV ; XEc0Hnm (c) 245 (1800), 280 (9900). max nmr : ^dmso-dg 3 53 (2e, abq, 2-h), 3.94 (3h, sr och-j), 4.42 ppm (2H, St 3-CH2), 5.22 (IH, d, J-4.5, 6-H), 5.92 (IH, d-d, J«4.5 & 6, 7-H), 6.93 (IH, s, CHPh,), 7.36 (10H, m, Ph-H), 8.1 (28, br-s, NH7), 9.38 (IH, d, J«6, 7-NH). 1 0 Preparation No. 2 Diphenylmethyl 7-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetanudo)-3-iodomethyl-3-ceph em- 4-ca rboxyl at e (V -1) A mixture of IV-1 from. Preparation No. 1 {5.7 g, 9.5 mmole) and Nal (4.3 g 29 mmole) in dry acetone (50 ml) was stirred for 5 minutes at room temperature. The mixture was concentrated under reduced pressure and the resulting oil was shaken with a mixture of ethyl acetate (100 ml) and H^O (10 ml). The organic layer was separated and washed with 10 % w/v sodium thiosulfate and brine, successively. After drying, the ethyl acetate was removed _in vacuo to give 6.1 g (93 %) of the title compound (V-l) as a yellow amorphous powder melting at > 120 °C (cec . ).

IR : vKBccm~1 3300, 1780, 1725, 1680, 1620 max UV : XEt0Hnm (e) 245 (17000), 282 (12000). max NMS : 6DMSO-d6 3.72 ( 2H, ABa, 2-H), 3.94 (3H# S, OCH^, 4.23 ?pm (2H, s, 3-CH2), 5.21 (IH, d, J=4.5, 6-H), 5.89 (IH, d-d, J=4„5 6 6, 7-H), 6.94 (IE, s, CHPh2), 7.35 (10H, m, Ph-H), 8.12 (2H, br-s, NH-,), 9.65 (IH, d, J=6, 7-NH) .

Preparation No. 3 Diphenylmethyl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-triphenylphosphon iomethy1-3-cephem-4-carboxylate iodide (VI-1) A mixture of V-l from Preparation No. 2 (690 mg, 1 mmole) and triphenylphosphine (786 mg, 3 mmole) in ethyl acetate (20 ml) was stirred overnight at room temperature. The solid which separated was collected, washed with ethyl acetate (2 x 10 103 ml) and dried to give 950 mg (100 %) of the phosphonium iodide VI-1. M. p. 186 °C (dec.). vn r 1 IR : v cm " 3300, 1780, 1710, 1680, 1610. max IP *■* O W uv : X L nm (e) 266 ( 15000), 275 ( 13000 ), 300 ( 7300 ). ma x NMR ; oDHSO-d6 3.52 (2H„ br-s, 2H)» 3.94 (3H, s, OCH3) , 5.34 ppm (IH, d, J*4.5, 6-H), 5.9 (IH, m, 7-H), 6.3 (IH, s), 7.3 (10H, m, Ph-H), 7.8 (15H, m, Ph-K).

L0 Pre pa r at ion No . 4 Dphen ylme thyl 7 - [ 2 - ( 5 - Ami no-1,2,4-thiadiazol-3-yl)-2~methoxy-ir'inoacetarrido]-3--I (triphenvlphosphoranvlidene)methyl}-3-c»-phem-4-carboxylate (VII-1) A mixture of VI-1 from Preparation No. 3 (952 mg, 1 5 rr.nole), Amberlite IRA-410 (OH form, 500 mg) and N NaOH (4 ml) in C:-;7C17 (10 ml) was stirred for 1 hour at room temperature. The mixture was filtered and the separated organic layer was dried over MgSO„ and concentrated under diminished pressure. The resulting oil was triturated with ethyl acetate and the resulting !0 yellow precipitate was collected by filtration to give 740 mg (90%) of the title compound VII-1. M.p. >180cC (dec.).

I?. : vK3r cm"1 3400, 1750, 1630 . max UV : XEt0H nm (e) 268 (12000), 276 (10000), 384 (23000). 5 max i 0 4 Preparation No. 5 Diphenylmethyl 7-[2-(5-&min0-l,2,4-thiadiaz0l-3-yl)~2-meth03cy-iminoacetamido]»3-( 3-ch Ioro-1-propen-1-vI) - 3-ceph em- 4-ca rboxylate (v: 11 -1) To a solution of VII-1 from Preparation No. 4 (6.9 g, 8.4 mmole) were added MgSO, (3 g) and 40% chloroacetaldehyde (610 mg, 8.4 mmole). The mixture was stirred for 1.5 hours at rooir. temperature and then filtered. The filtrate was eluted on silica gel (Wakogel C-200, 100 g containing 10 ml of 1/1.5 H phosphate buffer) column by using CHCl^, and CHCl^ containing CH^OH. fractions containing the desired product (0.5 - 1% CH^OH-CKCl^) were evaporated ui vacuo to give 1.6 g (30%) of the title compound VI11-1 as a yellow amorphous powder, which was a mixture of the 2 and E isomers with respect to the chloropropenyl moiety (Z/E = 2/l, by nmr). M.p. >130°C (dec.). i IR : vK3r cm"1 3300, 1780, 1725, 1680, 1620. max UV : xEt0H nm (e) 240 (20000), 286 (12000). max NMR * 6DMSO~d6+D?° 3-56 h 3-8 2-H), 3.94 (3H, s, OCHj), ppm 4.16 (d, J=7.5, CH?C1), 5.26 (IH, d, J=4.5, 6-H), 5.87 (IH, d, J*4.5, 7-H), 6.28 (2/3H, d, J-ll, 3-CH cis-H), 6.72 (1/3H t, d, J»16, 3-CH trans-H), 6.81 (2/3H, S, CHPh , ) , 6.92 (1/3H, S, CHPh 2), 7.4 (10H, m, Ph-H). '' j. 0 s Pr eparation Mo. 6 D ipheny Imethy 1 7-Senzylideneamino-3-[(triphenylphosphoranyli-dene ) methyl ]-3-cephem-4-carboxylate (XVI) To a solution of diphenylmethyl 7-henzyl ideneamino-3-5 [ (triphenylphosphonio)methyl]-3-cephem-4-carboxylate iodide (XV) [prepared according to the procedure of Japan published patent application (Kokai) 56-86187 (7/31/81 )] (60 ge 70 mmole) in CKjCl, ( 350 ml) were added N NaOH (140 ml) and Amber lite IRA-410 (OH" form, 35 g) at 5°C, The mixture was stirred for 1 hour at 10 5eC and filtered. The organic layer was separated,, dried over M g S 0 „, concentrated to ca. 100 ml of volume and precipitated with *3 «•* * . ethyl acetate (500 ml). The resulting yellow solid was collected by filtration and dried i_n vacuo to afford 48 g (94%) of the title compound XVI, melting at 195~6eC (dec.). i 15 IR : vK3r cm-1 1770, 1620. max Preparation Mo. 7 Diphenylmethyl 7-Benzylideneamino-3- (3-ch. lor o-1-pr open-1-yl) -3-cephem-4-carboxylate (XVII) 20 To a stirred solution of XVI from Preparation No. 6 (2.9 g, 4 mmole) in a mixture of CH?C19 (40 ml) and I-^O (10 ml), v/as added anhydrous chloroacetaldehyde (800 mg) at room tempera-ture. To the mixture was added additional 800 mg of chloro-acetaldehyde in three portions over a period of 1 hour, while the 25 pH of the mixture was kept between 6 to 9 by addition of N NaOH.

After 15 minutes, the aqueous layer was removed and the organic layer was dried over MgSO,. Evaporation of the solvent gave a red oil which was dissolved in a mixture of ethyl acetate and isopropyl ether (1/2 s 80 ml). The solution was washed with 30 saturated aqueous NaHCO^ (10 ml) and H^O (10 ml), successively.

After drying over MgS04, removal of the solvent afforded 3.3 g of yellow oil. A solution of the oil in CH^Cl, (50 ml) was filtered 1 0 6 wxth aid of silica gel (12 g, Wakogel C-200) containing 1/1.5 M phosphate buffer (1.2 mlf pH 6.4) and the silica gel was washed with CH^Cl, (50 ml). The filtrate and washing were combined and evaporated to dryness. The residue was triturated with n-hexane to give 1.7 g (80%) of the title compound (XVII) as a yellow powder. The nmr spectrum indicated that the chloropropenyl moiety had the Z configuration. M.p. >50°C (dec.).

IR : vKBr cm"1 3400, 17 /5, 1720, 1630. max uv : XEt0H nm (e) 253 (11000), 258 (11000), 265 (10000), 273 max (8300)? 261 (7000), 290 (6300).

NKR : 6DMSO_d6 3.63 (20, br-s, 2-H) , 4.0 (2H, m, CH,-C1), 5.42 ppm (2H, m, 6-H & 3-CH=CH) , 5.72 (IH, d, J-4.5, 7-H), 6.27 (IH, d, J=ll, 3-CH), 6.85 (IH, s, CHPh,), 7.33 (10B, m, Ph-H).

Preparation of anhydrous chloroacetaldehyde Anhydrous calcium chloride was added to a chilled solution of 50% aqueous chloroacetaldehyde (50 ml), with stirring, to separate it into two layers. The chloroacetaldehvde hydrate layer ^ (the upper layer) was separated and diluted with CHC1^ (100 ml), mixed with MgSO^ (20 g), heated to reflux for 5 minutes, and filtered. The solvent and water were removed azeo- i •>) tropically (b.o. 56~64°C) , and the residue was distilled to give anhydrous chloroacetaldehyde ^^, b.p. 70-82°C/760 mm.

IR : vfllm cm"1 1720. max (1) R.P. Kurkjy, S» v. Brown, J. Amer. Chem. Soc. , 7_4' 5778 (1952). (2) S. Trippett, D. M. Walker, J. Chem. Soc., 1961 1266. i 0 7 (3) H. 0. House,, v. k . Jones , G. A. Frank, J. Org. Chem. , 29, 3327 (1964).

Preparation Wo. 8 Diphenylmethyl 7-* Ami no-3- ( 3-chloro-1-propen-l-yl) - 3-ceph err-4-carboxylate (XVIII) A solution of XVII from Preparation Ho. 7 (180 mg, 0.3 4 mmole) in ethyl acetate (10 ml) was added to a solution of Girard Reagent T [ (carboxymethyl )trimethylammoniuro chloride hydra2ide) (251 mg, 1.5 mmole) in CH^OH (10 sal) containing acetic acid (0.25 ml), at 5®C. After stirring for 30 minutes at 5#C, the mixture was concentrated to remove the CH^OH and then ethyl acetate (20 ml) was added. The ethyl acetate solution was washed with HjO I 2 x 5 ml), saturated aqueous Nah'CO^ (5 ml) and brine (5 ml), successively and dried over MgSO^. Evaporation of the solvent gave 145 mg (97%) of the title compound XVIII (2 isomer) as a yellow powder. M.p. >100°C (dec.).

IR : vKBr cm"1 34 00, 1770, 1720. max UV : XEt0H nm (e) 252 (3700), 258 (3800), 260 (4000), 274 max (4000), 285 (4000).

Preparation No. 9 Diphenylmethyl 7 — t 2 —(5-Amino-l,2,4-thiadiazol~3-yl)-2-methoxy-i minoacetamido]-3-(3-chloro-l-propen~l-yl) 3-ceph em-4- carboxylate (VIII-l) A mixture of 2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid (lll-l) (10.1 g, 50 mmole) and PCIj (10.4 g, 50 mmole) in dry CH^Cl, (100 ml) was stirred at -7 to -15°C for 2 hours. The clear solution was poured into n-hexane (500 ml) to give a precipitate. The organic layer was discarded by 10 8 decantation and the remaining solid was triturated with n-hexane (100 ml). The yellow precipitate was collected by filtration and dried juri vacuo to give 12.5 g (99%) of the acid chloride, melting at 80°C (dec.). 5 ir : ynuj°i cm~i 1770 . mas The acid chloride (25 mg, 0.1 mmole) was added to a solution of xvixi (2 isomet) from Preparation No. 8 (44 mg, 0.1 indole) in dry CH->Cl, (5 ml) at room temperature, with stirring. 10 After 30 minutes# the mixture was concentrated under reduced pressure and diluted with ethyl acetate (20 ml) and saturated aqueous NaHCO^ (5 ml). The organic layer was washed with saturated aqueous MaHCO^ (5 ml) * brine (5 ml) , 10% HCl (S ml) and brine (5 ml). The solvent was dried over MgSO^ and then 15 evaporated to dryness to give the product as a yellow foam. The foam was purified by silica gel (Wakogel C-200* 1 g, containing 0.1 ml of 1/1.5 M phosphate buffer »H 6.4) column chromatography by elution with CH?C1,-CH^OH (100 : 1), to give 31 mg (50%) of the title compound VHl-1 U isomer) as a yellow powder. M.p. 20 >150°C (dec.).

IR : vKBr cm"1 3400, 1775, 1720, 1675, 1630. max UV : XEt0H nm U) 240 (17000)., 280 (10000). max 25 NMR : 6DMSO~d6 3.6 (2H, m# 2-H), 3.92 (3H, s, 0-CH3), 4.0 (2H, ppm m, CH,C1), 5.27 (2H, m, 6-H b 3~CH=CH), 5.83 (IB, d-d, J«4.5 & 10, 7-H), 6.25 (IH, d, J-ll, 3-CH), 6.03 (1H,s, CHPh0), 7.33 (10H, m, Ph-H), 8.0 (2H, br-s, NH2), 9.57 (1H, d, J»10, 7-NH). i 0 9 Preparation No. 10 Diphenylmethyl 7-[2-(5-Amino-1s2,4~thiadia2ol-3-yl)-2-methoxy-iminoacetarrido ] -3- (3-iodo-l-oropen-l-yl) -3~cephem-4-carboxyl ate (IX-l) 5 A solution of ¥111-1 from Preparation No. 5 (Z/E-2/1, 430 mg, 0.77 mmole) in dry acetone (10 ml) containing Nal (346 mg, 2.3 mrr.ole) was stirred for 30 minutes at ambient temperature, The reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between ethyl acetate (50 ml) and 10 water (10 ml). The UDoer laver washed with 10% w/v aoueous sodium thiosulfate solution (10 ml) and brine (10 ml) successively, and dried over MgSO^. Evaporation of the solvent gave 540 mg (98%) of the title compound IX-l (Z/E=l/1) as a reddish amorphous solid? melting at >120°C (dec.). 15 IR : vK3r cm"1 3300, 1780, 1720, 1680, 1620. max UV : xEc0H nm (c) 240 (21000), 290 (12000). max NMR : 6DMSO+D2° 3.67 (2Hr m, 2«H), 5.29 (IH, d, J-4.5, 6-H), 20 ppm 5.95 (IH, d, J»4.5, 7-H), 6. 27 (1/2H, d, Jail, 3-CH cis), 6.72 (1/2H, d, J«16, 3-CH trans), S.87 & 6.96 (each 1/2H, s, CHPh,), 7.4 (10Hr m, Ph-H). 110 Preparation Ho. 11 Diphenylmethyl 7- ( 2- ( S-Amino-'l,. 2g 4-thladia2ol~3~yl)-2-methoxy-ii'ninoacetan)ido)-3~( 3~iodo-1-propen-l-yl) - 3-ceph em-4-ca rboxylate (IX-l) 5 A mixture of VIII-1 (2 isomer) from Preparation No. 9 (5.6 g, 9 mmole) and Me,I (4 g, 27 mmole) in dry acetone (100 ml) was stirred for 1.5 hours at room temperature. The mixture was evaporated and the resulting oil was diluted with ethyl acetate (90 ml). The ethyl acetate layer was washed with 10% w/v aqueous 10 sodium thiosulfate solution (10 ml) and H^O (10 ml). Removal of the dried (HgSO^) solvent gave a yellow oi1f which was solidified by trituration with isopropyl ether. Filtration of the precipitate gave 4.3 g 167%) of the title compound IX-l as the E isomer. M.p. >165°C (dec.), 15 IH : vK3r cm"1 3400, 1780, 1725, 1680, 1610. max UV : xEt0H nm (e) 240 (18000), 297 (11000). max NMR : 6DMSO~d6+D2° 3.90 (3H, s, OCH3), 5.25 (IH, m, 6-H), 5.95 20 ppm (IH, m, 7-H), 6.72 (d, J*16, 3-CH trans), 6.96 (IH, s, CH-Ph2), 7.4 (10H, m, Ph-H). preparation Ho. 12 Benzhydryl 7-Amino-3-[3-chloro-l-oropen-l-yl)~3-cephem-4~ carboxylate (2-isomer) (XVIII) 25 ' Compound XVin is the common intermediate utilised in Reaction Schemes lb and Ic.

A. Ben zhydr yl 7-Benzyl ideneamino- 3-tr iphenylph.osphon iomethyl-3-ceph.em-4- c arboxylate ch lor id a (XV) 1 ^ 1 To a suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (II hydrochloride) (200 g, 0.44 mole) in CH^Cl^ (940 ml) was added 1 N NaOH (440 ml) at room temperature. The mixture was shaken for 10 minutes and the 5 organic layer was separated. To the organic layer were added MgSO,, (75 g) and benzaldehyde (51 g, 0.48 mole) and the mixture was allowed to stand for 3 hours. The reaction mixture was filtered and the insolubles were washed with CH^Cl^ (200 ml). To t.^e combined filtrate and washings was added tr iphenylphosphine 10 (126 g, 0.46 mole). The mixture was concentrated to about 400 ml and allowed to stand for 4 days. The resulting viscous oil was diluted with ethyl acetate (1 L) and triturated to separate the title compound XV a pale yellow crystalline powder which was collected by filtration and dried _in vacuo. Yield 322 g (96%). 15 M-P- 185-190°C (dec.).

IR : vK3r cm"1 1780, 1720, 1630. max UV : XCH2C12 nm (e) 260 (24100). max 20 3 * Benzhydryl 7-Benzvlideneamino-3-[(tr iphenylphosphoran- y lidene )ir.ethyl ]-3~cephem-4-carbosiyIate (XVI) A mixture of JO/ (322 g, 0.42 mole) and 5 N NajCO^ (252 ml) in CH^Cl, (1.6 L) was stirred vigorously for 15 minutes at room temperature. The organic layer was separated, dried over 25 MgSO. and concentrated to about 500 ml of volume. The concentrate was added to acetone (1 L), with stirring, to give a light yellow crystalline powder which was collected by filtration to yield 237 g (78%) of XVI, melting at 19 5~198°C (dec.). t t 2 IR : vKBt cm"1 1770, 1620 max UV : ACH2C12 nm (e) 254 (23000), 389 (22000). max 5 NHR : 6CDC13 2.56 & 3.15 (2H, ABq), 5.00 (IH, d, J=4 Hz), 5.23 ppm. ( IH, d, J«=4 Hz), 5.47 (IH, d, J*22 Hz), 6.95 (IH, s), 7.2-7.8 (30H, m), 8.55 (IH, s).

C. Ben z hydr yl 7-Ajmino-3~fchloro-l~propen"l-yl) - 3-ceph em~ 4-catboxylate hydrochloride (Z isomer) (XVIII Hydrochloride) 10 To a refluxing solution of XVI (214 g, 0.294 mole) and N,O-bis-(trimethylsilyl)acetamide (40 ml, 0.15 mole) in dry CH ^C1^ (2.9 L) was added dropwi se, with stirring, a 50% solution of chloroacetaldehyde (93 gt 0.59 mole) in CHC1^ over a period of 15 minutes. After standing for 30 minutes, the mixture was 15 concentrated to dryness. To the residual oil were added CH~C17 (1.5 L), Girard Reagent T (99 g, 0.59 mole) and 10% aqueous HCl (300 ml), and the mixture was stirred for 1 hour at room temperature. The organic layer was washed with water (200 ml) and a saturated KaCl solution (200 ml), dried over MgSO., treated with 20 charcoal (5 g) and filtered. The filtrate was cooled to -10°C and treated with 1 N HCl in CH^OH (300 ml). The mixture was stirred for 30 minutes at room temperature and concentrated to about 300 ml. The concentrate was diluted with ethyl acetate (400 ml) and seeded with a few crystals of XVIII hydrochloride. 25 After 2 hours the separated crystals were collected by filtration, washed with ethyl acetate (200 ml) and dried i_n vacuo to give 74 g (53%) of the title compound XVII1 as its hydrochloride, melting at >185°C (dec.). Pale yellow needles. 113 IR : vK0r cm"1 2030, 1780, 1720 maK uv : xEt0H nm (e) 286 (8800). ma x 5 NMR : 6DMSO~d6 3. 73 ( 2H, br, s, 2-H), 3.97 (2H, m, CH^Cl) , 5.22 ppm (IH, d, J ■ 4 . 5 Hz, 6-H), 5.37 (IH, d, J*4.5 Hz, 7-H) , 5.77 (IH, m, 3-CH»CH), 6.45 (IH, d, JN11 Hz, 3-CH) , 6.88 (IH, S, CHPhj), 7.33 (10H, br, s ,• Ph-H). 10 Anal. CalC'd for C,3H21 N^SCl'HCl: C, 57.67; H, 4.65; N, 5.87; S, 6.72; CI, 14.85.

Found: C, 57.62; H, 4 . 53 ; N„ 5.70? S, 6.64; ^5 CI,14.89.

Preparation Wo. 13 Ben zhydr yl 7-[2-(5-Ajr.ino~l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido ]-3~ [3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate (2 isomer) (VII1-1) 20 To a stirred solution of XVIII (z isomer) (20 g, 42 mmole) in CHjCl, (420 ml) containing N,O-bis(trimethylsilyl)- acetamide (34 mlf 12 5 mmole) was added 2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl chloride hydrochloride (15.2 g, 59 mmole) in three portions over a period of 30 minutes 25 at -10 to 0®C, The mixture was stirred for 30 minutes at 0-5*0 and concentrated under reduced pressure. The residual brown oil was dissolved in ethyl acetate (420 al) and the solution was washed successively with saturated aqueous NaHCOj (3 x 15 ml), saturated aqueous NaCl (15 ml), 10% HCl (15 ml) and saturated 30 aqueous NaCl (15 ml), and concentrated to about 50 ml of the volume. To the concentrate was added n-heptane (200 ml) to give 1 I 4 28. S g (90% pure) of the title compound Vlli-i (Z-isomer) as a colorless powder. M.p. »150°C (dec.).

IR : \>K3t cm"1 3400# 1780, 1720, 1680, 1620. max uv ; XEt0H nm (e) 240 (20000), 283 (12000). max NMR ; 6aCet0ne"d6 3.6 (2H, m, 2-H) , 3..95 (3H, s, OCH3), 4.0 ppm (2H, m, CHjCl), 5.32 (IH, d, J=4.5 Hz, 6-H), 5.62 (IH, m, 3-CH=CH), 6.03 (IH, d, J*4.5 HE, 7-H), 6,32 (IK, d, J = ll Hz, 3-CH), 6.87 (IH, s, CBPh2), 7.33 (10H, br, s, Ph-H).

Preparation No. 14 Ben zhydryl 7-[2-(5-Amino-l,2,4-th iadiazol-3-yl)-2-methoxyiminoacet am jdo)-3-[ 3 -i odo- 1-propen-l-yl)-3-ceph. em-4-ca rboxylate (£ isomer) (IX-l) A mixture of VUI-1 (2 isomer) (28,5 g, 90% pure) and sodium iodide (19 g) in dry acetone (420 ml) was stirred for 10 minutes at room temperature and allowed to stand at 5*C for 2 hours. The mixture was concentrated under reduced pressure. To the residue were added ethyl acetate (420 ml) and 10% w/v aqueous sodium thiosulfate solution (30 ml), and the mixture was shaken. The organic layer was washed with water (30 ml), dried over MgSO^ and evaporated to about 50 sal of volume. The concentrate was diluted with n-heptane (200 ml) to yield 30.6 g (95% pure) of the title compound IX-l IE isomer) as a yellow powder, melting at >120°C (dec.). 115 KB r - 1 IH : cm - 3400, 1780, 1725, 1680, 1620. max uv : XEt0H nm (e) 306 (15000). max 3.71 (2H, m, 2-H), 3.97 (3K, s, OCH3), 4.0 (2H, d, J«8 Hzf CH,I), 5.25 (IH, d, J*4.5 Hz, 6-H) , 6.03 (IH, d-d, «J«=4 . 5 & 8 Hz, changed to doublet J-4.5 Ez by D,0, 7-H), 6.32 (IB, d-t, J-15 & 8 Hz, 3~CH«CH), 6.79 (IH, d, J-15 Hz, 3-CH), 6.98 (IH, s, CHPh2), 7.35 (10H, m, Ph-H), 7.63 (2H, br, s, disappeared by D^O, NH2), 8.52 (IH, d, J~8 Hz, disappeared by D,0, 7-NH) .

Preparation Wo. 15 Ben zhydryl 7-[2"(5-Amino-l,2,4-th iadiazol-3-y1)-2-methoxvimino-acetair.ido 3-3 - [ 3 -( 4-carbaff.oyl-l-pyr idinio) -1-pcopen-1-yl 3-3-ceohem-4-carboxvlate Iodide (E isomer) (XII-IH) . . a.. . . .. -.^c— . , , To © suspension of IX-l (S isomer) (30.5 g) and isonicotinamide (26 g, 212 mmole) in CH^CN (120 ml) was added CHjOH (100 ml) until the mixture became clear. The solution was stirred for 2 hours under nitrogen atmosphere at room temperature and concentrated to about 100 ml under reduced pressure. The residual semi-solid was triturated with isopropyl ether (200 ml). The solvent was removed by decantation and the residual yellow powder was washed with a mixture of isopropyl ether and CH^OH (3/1, 120 ml). The powder was collected by filtration and dried in vacuo to give 36 g (75% pure estimated by HPLC) of the title compound XII-IH (E isomer) as a light yellow powder melting at >1506C (dec.).

NMS : 6»«tone-d6 ppm IR : vKSc cm_i 33 00, 1780, 1720, 1680, 1620. max UV : ^Et0H nm (E1%H ) 282 (170 ). 1 err 3.72 (2H, m, 2-H), 3.90 (3H, s, OCHj), 5.25 (3H, m, 6-H h CH,N+), 5.9 (IH, d-d, J«4.5 b 8 Hz, changed to a doublet J*4.5 Hz by D^O addition, 7-H), 6.35 (IH, in, 3-CH-CH), 6.89 (IH, s, CHPh,), 6.9 (IH, d, J«16 Hz, 3-CH), 7.35 (10H, m, Ph-H), 8.06 (2H, br, s, disappeared by D90, ), 8.21 (2H, be, s, disappeared by D^O addition, NH^) «■ 8.36 h 9.07 (each 2H, d, J«6 Hz, Py-H), 9.57 (IH, d, J=6 Hz, di sappeared by D90 addition, 7-NH).

Preparation Ho. 16 Benzhydryl 7-Benzylideneamino-3-[3-chloro-1-propen-l-yl3-3-cephesr-4-ca rboxyl ate (XVII) (2 isomer) To an ice-cooled mixture of the crystalline 7-amino-cephem intermediate XVXJI (z isomer) (13.4 g f 28 mmole) and benzaldehyde (3.3 g, 31 mmole) in ethyl acetate (150 ml) was added dropwise 0.5 N sodium hydroxide (56 ml, 28 mmole) over a period of 20 minutes, to maintain the temperature of the reaction mixture below io°C. The mixture was stirred with cooling for another 15 minutes, and the organic layer was separated, washed with saturated aqueous sodium bicarbonate (100 ml x 2) and dried over magnesium sulfate. To the dried solution was added a small amount of charcoal and the mixture was filtered. The filtrate was concentrated to dryness. The residual oil was dissolved in ca rbon tetrachloride (50 ml), and concentrated again. This procedure was repeated 3 times, and the mixture was monitored by reverse phase tic to confirm that all of the starting 7-amino- max M.<0 -DMSO-d, N i-iR : 0 o PPrc 117 c ephalospor in was converted to the Schiff's base. Removing the solvent i_n vacuo gave 16.45 g of the title compound XVI: (2 i sorer) as a pale yellow powder (estimated purity 85%; M.p. 74°C (dec. ), which was used for the next step without purification.

IR : vKBr cm"1 1780, 1725, 1635, max UV : XCH2C12 nm (E1% ) 257 (400). max 1 cm NMR : 6CDC13 6.18 (IH, d, J-ll @2). opm Preparation No. 17 Ben zhydryl 7-Benzylideneamino-3-[3-(4-carbamoyl-1-pyridinio)-1-oropen-l-yl ]-3-cepheir.-4-carboxylate Iodide (XXI-H) (£ isomer) To a chilled mixture of the 3-chloropropenylcephem xv:i (2 isomer) (16.4 g) in acetone (5 ml), was added dropwise a solution of sodium iodide (6.3 gf. 42 mmole) in acetone (30 ml) over 10 minutes under nitrogen atmosphere, and the mixture was stirred at room temperature. The reaction was monitored by the i % i % ratio of uv absorption [E" " (255 nm)/E* (320 nm)]. When 1 cm 1 cir. the ratio reached below 1.30 (after 45 minutes), the mixture was diluted with carbon tetrachloride ( 400 ml), and allowed to stand at room temperature. When the ratio came to below 1.10 (after 3 hours), the mixture was concentrated to a half its volume. The concentrate was treated with a small amount of charcoal and diatomaceous earth# and filtered. The filter cake was washed with a 1:1 mixture (100 ml) of methylene chloride and carbon tetrachloride. To the combined solution of the filtrate and washings, was added a solution of isonicotinamide (3.5 g, 28.7 mmole) in dimethylformamide (20 ml) and the mixture was concentrated under reduced pressure. The concentrate was allowed to stand at room temperature for 1.5 hours and washed with isopropyl 1 1 8 ether (100 ml x 3). The residual brown semi-solid was dissolved in methylene chloride (50 ml) and the solution was added dropwise, with stirring, to ethyl acetate (1.5 L). The resulting precipitate was collected by filtration and washed with ethyl 5 acetate (200 ml). After drying over phosphorous pentox ide in vacuo, 17 g of the title compound XXI-H (£ isomer) was obtained. Yellow amorphous powder. M.p, 150-155°C (dec.). Estimated purity 80% by nmr.

IH : vKBr cm"1 1775, 1725, 1690, 1635. 10 ma x UV : XCH2C12 nm (E1% ) 258 (335)» 298 (255). 1 cm 3.4-3.8 (2H, br.), 5.35 (2H, br. ), 5.41 (IH, d, J=4 Hz), 5.73 (IH, d, J~4 Hz), 6.93 (IH, s), 6.97 (IH, d, J=15 Hz), 7.3-7.5 (15H, br . s) , 8.40 (2Ht d, J~6.5 Hz), 9.15 (2H, df J«6.5 Hz).

Preparation No. 18 7-Amino-3- [ 3 - ( 4-carbamoyl-1-pyr idinio) -1-propen-l-vl ]-3-cepheir.~4-20 ca rboxylate (XXII-H) (£ isomer) To a suspension of the auaternized cephem XXI-H (17 g) in 85% formic acid (25 snl) was added dropvise concentrated hydrochloric acid (5 ml), and the mixture was stirred at room temperature for 1.5 hours and treated with a small amount of 25 charcoal. The mixture was filtered and washed with 85% formic acid (5 ml). The filtrate was combined with the wash and poured into acetone (1 L), with stirring. The resulting precipitate was collected by filtration to give 9.52 g of yellow-colored crude product. To a suspension of the crude material (9.5 g) in water 30 (50 ml) was added a small amount of charcoal, and the mixture was filtered. The filtrate was added dropvise, with stirring, to isopropyl alcohol (700 ml). The resulting precipitate was max NKR : 6DMSO~d6 PP* 15 1 1 9 collected by filtration, washed with a small amount of methanol (30 ml), and dried to give 7.53 g of the title compound XXII-h" (E isomer) as the hydrochloride. Light yellow powder. Estimated purity 85% by UV. M.p. 173-188*C (dec.).

KBr -1 5 IR : v cm - 1795, 1680, 1620, 1575, 1540. wax UV : ^Phosphate butter (pH 7) n?n (£1 % ) 294 (457 )t max 1 cm 3.82 (2H, s), 5.17 (IH, d, J*5 Hz), 5.33 (2H, d, J=7 HZ), 5.43 (IH, d, J=5 Hz), 6.37 (IB, d-t, J«16 & 7 He), 7.23 (IH, d, J«16 Hz), 8.34 (2Ht dt J-l Hz), 9.00 (2H, d, J = 7 Hz).

Preparation No. 19 15 2-( 5-Amino-l,2,4--thiadiazol-3-yl)-2-methoxyiminoacetyl Chloride Hydrochloride (11X—1 as its acid chloride hydrochloride) A. 2-Cyano-2-methoxyiwinpacetamide To a stirred mixture of a-cyanpacetamide (252 g, 3 mole) and sodium nitrite (414 g, 6 mole) in water (600 ml) was 20 added acetic acid (371 ml, 10 mole) at 5-10®C over 1.5 hours. The mixture was allowed to stir for another 1.5 hours and adjusted to pH 8.5 with 6 N NaOH. To the mixture was added dimethyl sulfate (568 ml, 6 mole) at 15-20°C and the mixture was stirred at 45°C for 1.5 hours. . The reaction mixture was adjusted 25 to pH 8.5 with 6 N .NaOH and allowed to stand at 5#C overnight to separate the precipitate, which was collected by filtration, washed with cold water and air-dried to give 292 g (77%) of the title compound as brown needles melting at 170-172®C.

NMH : l»20*DC1 io ppm 12 0 SfSf .1 IR : v cm * 34 00; 3180, 1720(sh), 1715, 1690, maX 1615, 1570.

UV : XH2° nm (e) 238.S (8290), 268 (sh, 3870). max 5 NMR: &DMS0~d6 4 . 20 (3H, s, OCH-j), 7.85 (2H, br. NH,) P?m Anal. Calc'd. for C,H,N,0o: C, 37.80; H, 3.97; N( 33.06 ^ J J 4 Found: C, 37.43; H, 3.75; N, 32.51, B. 2-Methoxyiminopropenedini trile 10 A stirred mixture of 2-cvano-2-methoxyiminoacetamide (88.9 g, 0.7 mole), sodium chloride (70 g) and phosphorus oxv-chlor ide (97 ml, 1.05 mole) in dry 1,2-dichlor oethane ( 350 ml) was refluxed for 16 hours. The insolubles were filtered off through a dicalite pad and washed with dichloroethane, The 15 filtrate and the wash were combined? and poured into stirred ice-water (1.5 L) to decompose the excess of phosphorus oxychloride. The organic phase was washed with 10% NaHCO^ (500 ml), water (500 ml x 3) and a saturated NaCl solution (500 ml), and dried over MgSO„. The filtrate was distilled under *$> 20 diminished pressure to give 61.5 g (81%) of the title compound boiling at 620C/24 mm Hg. (Lit.,, b.p. 47-480C/12 mm Hg).

IR : vLiqUld Fllm cm"1 3020, 2960, 224.5, 2020, 1530, 1455, ms. x cdc NMR: 6V w3 2 5 pp"* 1080, 4.35 (3Hi be ochj). 1 2 1 10 C. 2 "Cyano- 2-meth oxy iminoacet am idin i urn Acetate To a solution of ammon ium chloride (28.4 g 0.53 mole) in 28% aqueous ammonia (355 ml) and ethanol (180 ml) was added dropwise a solution of 2-methoxyiminopropanedinitrile (58.0 g, 0.53 mole) in ethanol (120 ml) at -15 to -10°C over a period of 30 minutes, with stirring. The mixture was stirred at -10®c overnight and then at ambient temperature (20~25°C) for one day. The reaction mixture was partitioned between water ( 350 snl) and CK^Cl-j (350 ml) „ and the aqueous phase was saturated with sodium chloride,, and extracted again with CH^Cl7 ( 300 ml). The organic extracts were combined, dried over MgSO^ and evaporated in vacuo. A solution of the residue in ethyl acetate (1.6 L) was adjusted to pH 3-4 with acetic acid to precipitate the title compound as crystals,, which were collected by filtration and washed with 15 ethyl acetate. Yield 67.5 g (69%). M.p. 152-4°C (dec.). [Lit , m.p, 150-155°C (dec.)].

IR : vKBr cm"1 3160, 2900, 2360, 2235, 2000, 1665, 1555, maX 1495, 1415. uv : XEt0E nm (e) 243 (8500), 265 (sh, 5380), 305 (sh, 1400). 2o ma x Mvra. -DMSO-d.

NMR: 6 o ppW! 1.88 (3H f s j) CH3COOH) r 4.15 (3Kf s, OCH3), 7.60 (4H, br.).

Anal. Calc'd for C4HgN40-CHjCOOH: Cf 38.71? H, 5.41; N, 30.09 25 Found: C, 38.71; H, 5.59; N, 29.51.

D. 2-(5-Amino-!t2e4~thiadlazol-3-yi)-2-methoxyimino-acetonitrile 30 To a suspension of 2~cyano-2-methoxyinunoacetami<3inium acetate (125 g, 0.672 mole) in CH^OH (1.25 L) were added dropwise trlethylamine (234 ml, 1.68 mole) at -10eC, and subsequently Br, II 9 r> (41.6 ml, 0.806 mole) over 20 minutes at -15 to ~10°C, and the mixture was stirred for 20 minutes. To the mixture was added dropwise a solution of KSCN (78.3 g# 0.806 mole) in CH^OH (550 ml) over 1 hour at -15 to -10°C. After stirring at 0-5°C for 1 5 hour, the mixture was poured into ice-water (12 L) to form a crystalline precipitate, which was collected by filtration, washed with water and air-dried to give 120 g (98%) of the title compound. M.p. 263-S°C (dec.). The m.p. of the compound prepared by us is higher by about 60#C than that given in the 10 literature* [m.p. 210-15°C (dec.)], but our spectral and microanalytical data ate consistent for the structure.

IR : vKBr cm"1 3435, 3260, 3120, 2960, 2245, 2020, 1630; maX 1545, 1455, 1415.

Pf HH uv : X nm U) 248 (13300), 310 (3470). 15 max Mf_ , DMSO-d , N MR: 6 o ppm 4.21 (3H, s, OCH3), 8.30 (2H, br. NH,).

Anal. Calc6 d for CgHgNj-OS: C, 32.78; H, 2.75; N, 38.23; S# 17.50 Found: C, 32.76; H, 2.51; N, 38.02; 20 S, 17.50. £. 2~ (5-Amino-l# 2,4-thiadia2ol-3-yl) - 2-me thoxy iminoacet ic Ac id (III-l) A mixture of 2- (5-amino-l#2,4-fchiadiazol~3~yl-2-methoxyiminoacetonitrile (18.3 g, 0.1 mole) in 4 N NaOH (250 ml) 25 was heated at 50-55°C with stirring for 3 hours. The reaction mixture was adjusted to pH 1 with H^PO^# and washed with ethyl acetate (100 ml) # saturated with NaCl# and extracted three times with a mixture of ethyl acetate and tetrahydrofuran (3:1# 300 ml x 2e and 200 ml x 1). The extracts were combined, dried over 30 MgSO^ and concentrated under reduced pressure. The residue was triturated with isopropyl ether to afford pale yellow crystals of jL ^ the title acid. Yield 16.8 g (83%). M.p. 184-5eC (dec.) (Lit.*, m.p. 180-182 KBf -1 IR : v cm 3460, 3260, 3140, 1725, 1620, 1605, 1545. max UV : XH2° nm (c) 234 ( 13200), 288 (sh, 3620) max F . 2- (5-Amino-l, 2, 4-th iadiagol-3-vl) - 2-me thoxy iminoacet yl Chloride Hydrochloride ■ i i .

To a suspension of 2-(5-amino-l,2,4-thiadiazol-3~yl)-2-10 me thoxyiminoaceti c acid (111-1) (40.4 g, 0.2 mole) in dry CH^Cl, (400 ml) was added PC1P (41.6 gf 0«2 mole) in one portion at -50°C. The mixture was stirred for 4 hours at -20 to -5°C, and poured into a mixture of n-heptane and isopropyl ether (2 ; 1, 2 LK The yellow precipitate was collected by filtration, washed 15 with the same solvent mixture, and dried with KOH under reduced pressure to give 46.0 g (90%) of the title acid chloride.

Nuiol -1 IR : v J cm 1 /7s. max 20 * Japan Kokai 57-158769 published September 30, (Brit. appl., 3/6/81) 1982, to Fujisawa 12-1 're vat at ion No. 20 H^N il C 81 N ■ CONH \ f j— C M V A iwi r-" 2 5 COOCH(Ph) VIIi-2 *2 Diphenylmethyl 1-[2-(5-Ami no-1,2g4"thiadiazol~3-yl)~2-(2)-ethoxyiminoacetamido]°3-|3-chloro-l-propenyl ]- 3-cepham-4-5 carboxylase (VIII-2/ 1 ispmer) Tp a mixture of N,0~bis(trimethylsilyl)acetamide (2.3 ml, 9 mmoles) and crystalline diphenylmethyl 7-amino-3-[3-chloro~l-(2)-oropen-l-ylJ-3-cephem-4-carboxylate hydrochloride (XVIII) ( 1.338 g# 2.8 mmoles) (from Preparation No. 12.) in 10 methylene chloride (10 ml) was added 2-(5-amino-l/2,4- thiadiazol-3-yl)-2-(Z)~ethoxyiminoacetyl chlor ids hydrochlor ide (800 mg, 2.95 mmoles) port ion wise,, with stirring, at -100 C and the mixture was allowed to stand at 0#C for 2 hours. The mixture was diluted with ethyl acetate (200 ml), washed with water and 15 evaporated under reduced pressure. Trituration of the residue with isopropyl ether afforded the title product vni-2 as an amorphous powder. Yield 1.70 g (95%). Mp. >150°C (dec.). 20 IH UV NMR u , (KBr) in cm max 3300, 1780, 17 2 0, 1690, 1380, 1220, X (C,HcOH) in nm (e) 285 (11000) . ma x 2 5 6 (DMSO-d.) in ppm 1.26 (3H, t, J=7Hz, CH,CH,), 4.25 0 " UV k (CnHcOH) in nm (E max 2 5 1% 1 cm ) 304 (199). 120 Pre par at ion Mo. 2 2 3© CH«CH-CH^?// \N COOCH (Ph).

:ONH- XXI-H Iodide *E Diphenylmethyl T-Benzylidenearnino-S-[ ( £)-3-( 4-carfaamoyl-pvridinio)-l-propenyl ]-3-ceph em--8-carboxyl ate (XXI-H iodide) (B isomer) To a chilled solution of the 3~chlor opropeny1cephem (XVII, 1 isomer? 42.8 g, 90 mmoles) (from Preparation No. 16) in cry DMF (80 ml), was added KI (20 g, 120 mmoles) in one portion., and the mixture was stirred at room, temperature. The .reaction i % 10 was monitored by the ratio of UV absorption [E~ (255 nm)/ 1 cm 1 & E (320 nm)]. When the ratio became below l.io (after 45 1 cm minutes), the mixture was diluted with 800 ml of methylene chloride, treated with active carbon (4 g), and filtered. The 15 filter cake was washed with 100 ml of CH2C10. To the combined filtrate and washings was added isonicotinair.ide (14.64 g), and the mixture was concentrated under reduced pressure. The concentrate was kept at room temperature for 1.5 hours and washed with a mixture of toluene and n-heptane (1:1, 600 ml). The 20 residual brown semi-solid was dissolved in CH^Cl, (100 ml) and the solution was added dropwise to ethyl acetate (3 L) with vigorous stirring. After drying over i_n vacuo, 57. 37 g (88%) of the quaternized title product XXI-H was obtained as the iodide. Yellow amorphous powder. Mp. 150-155°C (dec.). This 25 product was identical to that obtained by iodination with Nal (Preparation No. 17). -!! vy .i. "J P r e oa r a t i on No . 2 3 HCl i - LjN* ■X" CH»CK-CH,-C: II 2 COOCH(Ph)™ XVIII *% Diphenylmethyl 7-Air.ino~3-( 3-chloro-l-propenyl)-3-cephem-4- ca rboxyl ate hydrochloride (2 isomer ) (XVIII, Hydr och. lor ide) A 25% solution of chloroacetaldehyde (69 gf 0.22 mrroles) in CHC1 ^ was added to a solution of XVI (80 g, 0.11 mole) in CHjCl, (1.1 h) containing N, O-bis (tr imethylsilyl )ac;etamide (16.2 mlt 0.06 mole) at -10#C in one portion, and the mixture was allowed to stand overnight at 5°C. The mixture was concentrated to ca. 0.3 L, diluted with a mixed solvent of ethyl acetate and isopropyl ether (1/20.6 L), treated with silica gel (Wakogel C-100, 60 g) and filtered through a dicalite pad. The filter cake was washed with the same solvent system (0.2 L). The combined filtrate and washing were concentrated to ca. 0.2 L, treated with Girard Reagent T (60 g, 0.26 mole) and 4W HCl (220 ip.l), and seeded with a few crystals of XVIII hydrochloride.

After stirring for 3 hours, the resulting crystals were collected by filtration, washed with water (0.5 L) and ethyl acetate (0.5 L) and dried irs vacuo to give 37 g (70%) of the title compound xviil hydrochloride,- melting at >185°C (dec.). Pale yellow needles. This product was identical to that obtained in Preparation No. 12. 128 Pre pa ration No. 24 XVIII *% Diphenylmethyl 7-Amino-3-(3~chloro-l-propenyl)-3-cephem-4-carhoxvlate hydrochloride (Z isomer) (XVIII, Hydrochloride) 5 To a solution of chloroacetaldehyde (25% solution in CHC1^i 628 mg, 2 mmoles) in CH ?C10 (10 ml) were added N, O-bis-(trimethylsilvl)acetamide (0.135 ml, 0.5 mmole) and XVI (728 mg, 1 mmole), successively, at 5°C. The mixture was allowed to stand overnight at 5°C. The mixture was evaporated and diluted with a 10 mixture of ethyl acetate and isopropyl ether (1/2, 10 ml).

Insolubles were removed by filtration and the filtrate was concentrated to ca. 5 ml. The concentrate was treated with 4N HCl (2 ml), seeded with XVIII hydrochloride and stirred for 1 hour at room temperature. The crystals were collected by 15 filtration, washed with ethyl acetate (10 ml) and water (10 ml) and dried iri vacuo to give 384 mg (80%) of the title compound XVIII hydrochloride, melting at >185°C (dec.). Pale yellow needles. This product was identical to that obtained by Preparation No. 12.

Preparation No. 25 20 2-( 5-Amino-l, 2, 4-thiadiagol-3~yl)~2~(propen-3*-yIoxyimino)-' acetyl chloride hydrochloride (111 — 3 as its acid chloride hydrochloride A. Methyl 2-(5-t-butoxycarbonylamino-1,2,4-thiadiazol-3~yl)-nr 2- (propen-3-yloxyimino)aceta te A mixture of 68 5 mg (3.37 mmoles) of N-(propen-3-yloxy)phthalimide (prepared according to the procedure of E. 12 9 G rochosak i & J. Ju rczak, Synthesis 1976 682 ] and 175 mg (3.35 mmoles) of hydrazine hydrate in 5 ml of C^H^OH was stirred for 1 hour at room temperature. The resulting precipitate was filtered off and the filtrate and washings were combined. To the solution 5 was added 967 mg (3.37 mmoles) of methyl 2-(5-t-butoxycarbonyl-srrino-l, 2, 4-thiadiazol-3-yl)-2-oxoacetate, and the mixture was allowed to stand for 1 hour at room temperature and concentrated by a rotary evaporator. The residue was purified by silica gel chromatography. The column was eluted with n-hexane/ethyl 10 acetate (4:1) and fractions containing the major product were combined and evaporated under reduced pressure. Yield 514 mg (46%). Mp. 8 3-86®C.

IR : v v (KBr) in cm"1 3100, 1745, 1710, 1610.

JiWS A UV : kav (C,H,OH) in nm (c) 223 (9700), 242 (10000). max i D 15 NKR : 5 (CDC13) in ppm 1.55 (9H, S, BOC-B), 4.40 (2H, d, J= 5Hz t 0-CH2), 5.21 (2H, m, CH,=CK), 5.90 (IH, m, -CH=CH,), 9.50 (IH, br.s, NH) .

B. 2-(5-t-Butoxvcarbonylamino-l„2,4-thiadiazol-3-yl)-2~ 20 (propen-3-yloxvimi.no ) acetic acid1^ A solution of 770 mg (2.3 mmoles) of methyl 2-(5-t-butoxycarbonylamino-1,2, 4-thiadiazol-3-yl)-2~(propen-3-yloxy-i mi no) acetate and 3.5 ml of 2N Ha OH solution (7.0 mmoles) in 15 ml of CHjOH was refluxed for 30 minutes. The reaction mixture 25 was concentrated in vacuo and diluted with 10 ml of ethyl acetate-HjO (1:1). The water layer was separated, acidified to pH 2 with 6N HCl and extracted with ethyl acetate (10 ml v. 2). The ethyl acetate solution was dried over MgSO^ and concentrated by a rotary evaporator to afford 59S mg (81%) of the title 30 compound. Hp. 134-135°C (lit1*: mp. 135-136°C.

IR : v v (Nujol) in cm"1 3150, 1745, 1710, 1550. iTVS X 130 uv : Xm.v (CoH,0H) in nm (e) 223 (11000), 242 (11300). ma x 2 5 NMlR : 6 (DMSO-dg) in ppm 1.55 ( 9H, s, BOC-H) , 4.77 ( 2H, d, J= 5Hz f 0~CH2), 5.22 (2H, m, CH,*CH), 6.0 (IH, m, CH«CH,). 5 1)1. Csendes, et a1., J. Antibiotics, 36, 1020 ( 1983).

C. 2~(5-Amino~l,2,4-thiadiazol-3-yl)-2-{propen-3~yloxyimino)-acetic acid (111-3)1^ A solution of 57 0 mg (1.74 mmoles) of 2-(5-t-butoxy-carbonylamino-1„2,4-thiadiazol-3-yl)-2™(or open-3-yloxyimino)- 10 acetic acid in 6 ml of trifluoroacetic acid was allowed to stand for 1 hour at ambient temperature. Evaporation followed by trituration with 30 ml of isopropyl ether gave 376 mg (95%) of. the title compound. Hp. 109°C (dec.).

IR : w (Nujol) in cm"1 3180, 1710, 1545, 1460. ma x 15 UV : \ (C" OH) in nm (e) 245 (13500).

JiiS X D NMR : o (DMSO-dg) in ppm 4.77 (2He. d, J=5Hz, O-CH^), 5.20 (2H, m, CH«*CH), 6.0 (IH, ST., CH=CH,) . 1) Japan Kokai 57-112396 (7/13/82, Fujisawa) Brit. appl. 7935538 (10/12/79). 20 D. 2-(5-Amino-l,2,4-thiadia2ol-3-yl)-2-(propen-3-yloxyimino)-acetyl chloride hydrochloride A solution of 350 mg (1.54 mmoles) of III-3 and 410 mg (1.97 mmoles) of phosphorous pentachloride in dichloromethane (5 ml) was stirred for 1 hour at 25#C. The reaction mixture was 25 poured into 60 ml of n-hexane and the precipitate was filtered off. Yield 323 mg.

IR : wm£„ (Nujol) in cm"1 1765. 13 1 Preparation Mo. 26 2~( 5-Amino-l, 2, 4-thiadiazol-3-yl )-2-proparqyloxyin'.inoacetyl chloride hydrochloride (II1-4 as its acid chloride hydrochloride) i A. Methyl 2- ( 5-t-Butoxycar bonylairino-1, 2>4-thiadiazol-3-yl)-5 2-propargyloxyiminoacetate A suspension of 87 0 mg (4.32 mmoles) of N-propargyl-i ) oxyphthalimide and 200 mg (4.0 mmoles) of hydrazine hydrate in 5 ml of ethanol was stirred afc 25°C for 1 hour and filtered. To the combined filtrate and washings was added 1.0 g (3.86 mmoles) 10 of methyl 2-(5-t-butoxycarbonylamino-l,2,4-thiadiazol-3-yl)-2~ oxoacetate"^. The solution was allowed to stand for 1 hour and concentrated under reduced pressure. Purification by silica gel chromatography followed by evaporation afforded 319 mg (27%) of. the title product, Mp. 72-75°C. 15 IH : v_ (KBr) in crrT1 3200, 2380, 1 /45, 1710, 1610. n\ci x uv : X (C-HcOH) in nm (e) 235 (12200). m.cs x 2 5 UMR : 6 (DMSO-dg) in ppm 1.56 (9H, s, BOC-H), 3.55 (IH, t, J-2Hz, C==CH), 4.85 (2H, d, J=2Hz, b* -CH-,-C= CH) , 8.9 (IH, br.s, HE). 1) Commercially available, Aldrich, 2) I. Csendes et al., J. Antibiotics 36, 1020 (1983).

B. 2-(5-t-3utoxycarbonylamino-l,2,4~thiadiazol~3-yl)-2-propargyloxyiminoacetic acid A solution of 490 mg (1.4 mmoles) of methyl 2-(5-t-butoxycarbonylamino-l ,2,4-thiadiazol-3-yl)-2-propergyloxyimino-acetate and 2.2 ml of 2N aqueous NaOH solution (4.4 mmoles) in 14 ml of CH^OH was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure and 10 ml of ethyl I. qji> acecate-H^O (1:1) was added to the solution. The separated water layer was acidified to pH 2 with 6N HCl and extracted with ethyl acetate (2 x 10 ml). Drying over MgSO^ followed by evaporation of the organic layer gave 149 mg (89%) of the title product. Hp. 5 135°C (dec.), IR : v (Nuiol) in cm 1 3350, 17 20, 1670, 1550. ms x uv : X (C-H,OH) in nm (e) 233 (11500). ma x 2 5 1.55 (9H, s, BOC-H), 3.55 (IH, t, J=2Hz, C—CH), 4.89 (2H, d, J*2Hz, CH2C=CH) , 9.0 (IH, s, NH) .

C. 2-(5-Amino-1,2,4-thiadiazol~3-vl)-2-proparqvloxvimino- — acetic acid (111-4) A solution of 410 mg (1.26 mmoles) of 2-(5-t-hutoxy-carbony1 amino-1,2,4-thiadiazol~3-yl)-2-propargyloxyiminoacetic 15 acid in 5 ml of trifluocoacetic acid was allowed to stand for 1 hour at 25°C. Evaporation followed by trituration of the residue with 25 ml of isopropyl ether gave 204 mg (72%) of the title compound. Mp. 156-158°C (dec.).

IR : v (Nujol) in cm"1 3300, 2480, 1730, 1610. max 20 UV : X < C_HcOH) in nm (e) 234 (12000).

Tfla X X D NMR : 6 (DMSO-d,) in ppm 3,52 (IH, t, J«2Hz, CSCH)s 4.86 e (2H, d, J=2Hz, CH2"CSTH) , 8.10 (2H, br.s, NH0).

NMR : 6 (DMSO-d,) in ppm o 10 133 3) Japan Kokai 57-112396 (7/13/82- Fujxsava) Brit. appl. 7935538 (10/12/79).

D . 2-(S-Aifi no-1, 2/4- thiadiazol-3-yl) -2-pr opargyloxyirrino-acetyl chloride hydrochloride 5 A mixture of 175 mg (0.0/ mmole) of IIJ-4 and 182 mg (0.68 mmole) of phosphorous pentachloride in dichloromethane (2 ml) was stirred for 1 hour at -5°C. The reaction mixture was poured into 30 ml of n-hexane and the precipitate was filtered off. Yield 65 mg (34%), 10 IR : v ... (Nujol) in cm-1 1770.

Hi q X Preparation No. 27 2-(5-Amino-1,2,4~thiadiazol-3-yl)-2-cyclopentyloximinoacetyl chloride hydrochloride (III-5 as its acid chloride hydrochloride) A. Methyl 2-(5-t-butoxycarbony1amino-1„2,4-thiadiazol-3-yl)-2- 15 cyclopentyloxyiminoacetate A suspension of 860 mg (3.7 mmoles) of N-(cyclo-pentyloxy)phthaiimide1* and 185 mg (3.7 mmoles) of hydrazine hydrate in 5 ml of C^H^OH was stirred for 1 hour at ambient temperature and filtered. The filtrate and washings were 20 combined and added to 1.06 g (3.7 mmoles) of methyl 2-(5-t- i) butoxycarbonylamino-1,2f4~thiadiazol-3-yl)-2-oxoacetate . The solution was allowed to stand for 1 hour at room temperature and concentrated jji vacuo. The residue was purified by silica gel column chromatography. Elution with n~hexane-ethyl acetate (4:1) 25 followed by evaporation cave the title product™ Yield 90S mg l 61%). Mp. 115~118°C.

IR : v w (KBr) in cm"1 3200, 1745, 1710, 1550. nUs X UV i X (C,H,OH) in nm (e) 217 (1800), 252 (7600). it 4 x <4 j f 3 4 NMR : 6 (CDC13) in ppm 1.51 (9H, s, BOC-H), 1.60 (8H, br.se •C '■ (3H, s, OCH3), 4.90 (IH, H m br.s, V ), 8.70 (IH, br.s, NH). o — 1) U.S. Patent 3,971,778 (7/27/76; Glaxo), Brit, appl. 49255 5 (10/25/72). 2) I. Csendes et al., J. Antibiotics 36.« 1020 (1983 ) „ B. 2-(5»t~Butoxycarbonylamino-1,2,4-thiadiazol-3-yl)~2-cyclo- pentyloxyiminoacetic acid A solution of 500 mg (1.34 mmoles) of methyl 2- (5-1-10 butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxy- iir.inoacetate and 2N NaOH solution (2 ml, 4 mmoles) in 15 n1.! of CH^OH was rsfluxed for 30 minutes. The reaction mixture was evaporated and 10 ml of ethyl acetate~H,0 (1:1) was added to the solution. The water layer was separated,, acidified to pH 2 with 15 6N HCl and extracted with ethyl acetate (10 ml x 2). The organic lever was washed with brine, dried over MgSO^ and concentrated under reduced pressure to give 37/ mg (78%) of the title compound. Mp. 185 °C (dec.).

IR : v (KBr) in cm"1 3160, 1710, 1550. 20 uv : X (C,Hc0H) in nm (e) 238 (13300). u ma x 2 3 NMR : 6 (DMSO) in ppm 1.51 (9H, s, BOC-H), 1.70 (8H, br.s., H -C >■ 4.82 (IH, m, ) O C . 2- (5-Amino-l, 2, 4-thiadiazol~3-yl)-2-cvclopentyloxyiinino-acetic acid (111 — 5, 2 isomer ) ^ 25 A solution of 348 mg (0.97 mmoles) of 2-(5-t-hutoxy- ca r bony lamin o-l». 2, 4-thiadiazol-3-yl) -2-cycl open tyloxy iminoacet ic 1 3 5 acid in 2 mi of trifluoroacetic acid was allowed to stand for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was triturated with 5 ml of isopropyl ether and 10 ml of hexane to give 215 mg (86%) of the 5 title compound. Mp. 162-16 5°C (dec.) (lit^: mp. 160-165°C (dec.)].

IR : v (Nujol) in cm"1 3290, 3200, 1710, 1615, 1600. ma x UV : X (C-.Hj.QH) in nm (e) 238 (13300). ma x 2 5 NMR : o (DMSO-dg) in ppm 1.17-2.10 (8H, m) , 4.60-4. 98 (IH, •^g m), 8. 22 ( 2H, s ) „ 3) Japan Kokai 57-1567 69 (9/30/82, Fu^isawa) Brit, appl. 8107134 (3/6/81).

D. 2- (5-Air.ino-l, 2, 4-th iadi azol-3-yl)-2-cycl open tyloxy imino-acetyl chloride hydrochloride 15 A solution of 190 mg (0./4 mmole) of II1-5 and 219 mc (1.0 mmole) of phosphorous pentachlor ide in dichloromethane (5 ml) was stirred for 1 hour at room temperature. The reaction mixture was poured into 50 ml of n-hexane. The resulting precipitate was collected by filtration. Yield 122 mg (60%). 20 IH : v „ (Nujol) in cm"1 1760. ma A Preparation Ho. 28 Benzotriazol-l-yl~2-(5-amino-l,2,4-thiadiazol~3~yl)-2-methoxy-iminoacetate A mixture of 1-hydroxybenzotr iazole (2.7 gf 20 mmoles) 25 and dicyclohexylcarbodiimide (4.12 gP 20 mmoles) in 65 ml of DMF was stirred at room temperature. After 15 minutes, III-l (4.04 g, 20 mmoles) was added to the stirring mixture at 0°C, and stirring was continued for 3 hours. The reaction mixture was 1 3 6 filtered to remove the insoluble urea, and the filter cake was washed with a small volume of DMf. The filtrate and washings were combined and poured into 800 ml of ica water. The precipitate was collected by filtration to give 5.24 g (82%) of the title compound as a light grey powder. Mp. 189-192°C (dec.

IR v max (KBr) in cm"1 1815, 1620,, 1540, 1415, 1090, 1060 1005, 945, 865, 740.

UV X max (C-jK^OH) in nm (E 1% ) 246 (580) , 28 3sh ( 228) 1 cm In the claims which now follow,, the word "solvate" is to be understood as not including a "hydrate". «s rf o «

Claims (5)

CLAIMS A compound of the formula N r-C CONH ii ll N R HK ii u 'v 3* \. 2 Ndr © H-CH-CH2-N^Q COC^ 1 wherein E~ is hydrogen or a conventional amino-pr otect mg group, R^ is hydrogen, a straight or branched chain alkyl group contain ing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing from 3 to 6 carbon atoms, or a group of the formula R4 R4 COOH -C-CI-3 = CH-R3 , -C-CSC-R3 , f\ or 1 5, 15 / \ \/ I X R4 I -C-COOH I 5 R 3 in which R is hydrogen,, (lower Jalkyl or carboxyl, X is halogen, 4 5 hydroxy or (lower)alkoxyr and R and R are each independently 4 5 hydrogen,, methyl or ethyl# or R ' and R , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and :Q is a quaternary ammon io group,* or a nontoxic pharmaceutically acceptable salt, solvate,, hydrate or physiologically hydrolyzabl 13 8 2 . A compound of Claim 1 wherein is selected fr on R13 i15 © N- 11 -16 w .16 R I -N 17 -R 18 ,17 © ,18 > / and wherein R13, R14 .15 and R~ are the same or different and are 5 {lowerJalkylf {lower)alkenyl, amino(lower)alkyl with the provision that the amino may not be on an a-carbon, or hydroxy-(lowerJalkyl with the provision that the hydroxy group may not be on an a-carbon? R16 is hydrogen,, (lower Jalkyl, {lower Jalkoxy, (lowerj-10 alkvlthio, amino# (lowerJalkylamino, di(lower J alkylamino, formyl-amino, (lowerJalkanoylanii.no, carboxy, hydroxy, carboxy (lower J -alkyl, carboxy(lowerJalkylthio, hydroxy(lowerJal kyl, halo(lower Jalkyl, amino(lower J alkyl, (lower Jalkoxy(lower Jalkyl, carbamoyl or N~(lower Jalkylcarbamoyl, or R~^ may represent a 15 divalent alkylene group having 3 to 5 carbon atoms; 1 7 R~ is (lowerJalkvl, (lowerJalkoxy(lowerJalkyl, halo-(lowerJalkyl„ allyl, hydroxy(lowerJalkyl with the provision that the hydroxy group is not on the a-carbon, amino(lowerJalkyl with the provision that the amino group is not on the a-carbon* or 20 phenyl(lowerJalkyl; 25 18 R is hydrogen, (lower Jalkyl, (lower Jalkoxy., (lower J-alkoxy(lowerJalkyl, (lower J alkylthio, amino, (lowerJalkylamino, di(lower Jalkylamino, carboxy, hydroxy,'carboxy(lowerJalkyl, hycroxydower Jalkyl, amino( lower )alky 1, formylamino, (lowerJ-alkanoylamino, carbamoyl or N-(lower Jalkylearbamoyl; 1 3 9 n is an integer of from 1 to 3, inclusive; 1Q Z is CH, or, when n is 2, Z also may be S, 0 or N-R "* 1° in which H ' is hydrogen or (lower Jalkyland R2^1 and R21 are the same or different and are hydrogen, 5 (lower ) alkyl, (lower ) alkoxy,, (lower ) alkylthio, amino,, (lower J-alkyla mino* di(lower Jalkylamino* carboxy* hydroxy* hydroxy-(lower)alkyl, amino (lower)alkyl, (lower)alkoxy(lower)alkyl, carboxy(lower Jalkyl, carboxy(lower}alkylamino, (lower Jalkanovl-amino, carboxy(lower)alkanoylamino, carbamoyl or N-(lower)alkyl-10 carbamoyl. 2 3, The compounds of claims 1 or 2 wherein R is (lower Jalkyl, cvcloalkyl of 3 to 5 carbon atoms, 1-carboxvcycloaIk-l~yl of 3 to 5 carbon atoms, allyl* propargvl or carboxy(lowerJalkyl. 4. 7-[2-(5-amino-l*2,4-15 thiadiazol-3-ylJ-2-methoxyiminoacetamido]-3-[3-(tr imethyl- ammonioJ-1-propen-l-yll-3~cephem-4~carboxyiate* or a nontoxic pharmaceutically acceptable salt,, solvate,, hydrate or physiologically hydrolyzable ester thereof. 5. 7-[2-(5-amino-l,2,4-20 thiadiazol-3-ylJ-2-methoxyiminoacetamido1-3-(3-(1-methyl- pyrrolidinio)-1-propen-l-yl3-3-cephem-4-carboxylate* or a nontoxic pha rmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 6. 2-(5-amino-l* 2,4-25 thiadiazol-3-yl)-2~methoxyiminoacetamidol-3-l3~pyridinio-l- propen-l-yl1-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 7. 7-[2-(5-amino-l,2,4-30 thiadiazol-3-ylJ-2-me thoxyiminoacetamido]-3-[3-(3-amino- I. 4 0 pyrid inio)-1-propen-X-yl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate,, hydrate or physiologically hydrolyzable ester thereof. 8. 7~[2-(5-amino-l,2,4~ 5 thiadie;zol-3-yi)-• 2™me thoxy iminoacetamido]-3- [ 3- (3-forroylarr.ino- pvridinio)-1-propen-l-yl]-3-cephem-4~carboxylate, or a nontoxic pharmaceutically acceptable salt,, solvate., hydrate or physiologically hydrolyzable ester thereof. 9. 7-[2-(5-amino-l,2,4-10 thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[3-(3-aminomethyl- pyridinio)-l-propen-l-yl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate? hydrate or physiologically hydrolyzable ester thereof. 10. 7-[2-(5-amino-l,2,4- 15 thi adiasol-3-yl)-2-methoxyiminoacetamido ] - 3 - [ 3 - (3-carbamoyl- pyridinio)-l-propen-l~yl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 11. 7-[2-(5-amino-l,2 20 thiadiazol-3-yl) - 2-me thoxy irni no ace tarn i do ] -3 - [ 3-( 4-carbamoyl-pvridinio)-1-propen-l-yl]-3-cephem-4~carbo*ylate, or a nontoxic pharmaceutically acceptable -salt, solvate, hydrate or physiologically hydrolyzable ester thereof.. 12. 7-1 2-(5-amino-l,2,4-25 thiadiazol-3-yl)-2-methoxyiminoacetamidoJ-3-1 3-(2-mcthyl- thiazolio)-1-propen-l-ylJ-3~cephem~4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 13. 7-(2-(5-amino-1,2,4-30 chiadia2ol-3-yl)-2-me thoxyiminoacecamido]-3-[3-(2-amino-5- 1 4 I tfriazolof 4f 5-c ]pvridinio)-1-propen-l-yl ]~3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 14. 7-[2-(5-amino-l,2,4-5 thiadiazol-3-vl)-2-methoxyiminoacetamido] — 3—[3—(4-hydroxymethyl- pyridinioJ-l-propen-l-ylj-O-cephem-^-ca rboxyiat€f or a nontoxic pha rmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 15. 7—[2—(5-amino-l, 2,4-10 thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[3-(3-hvdr oxymethvl- pyridinio)-1-propen-l-yl1-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt,, solvate, hydrate or physiologically hydrolyzable ester thereof. 16. 7-[2~(5-amino-l,2, 4- 15 thiadiaEol-3-yi)-2 -methoxviminoacetamido]-3-[3-(4-(N-methyl- ca rbamoyl}pyridinio)-1-propen-l-yl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 17. 7-[2-(5-amino-l? 2?4-20 thiadiazol-3-yl)-2-me thoxy iminoacet ainido 1-3-13-(2,3-propylene- pyridinio)-1-propen-l-ylJ-3-cephem-4-carboxylate, or & nontoxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 18. 7-{2-(5-amino-l,2,4» 2 5 thiadiazol-3-yl) -2-ethoxyiminoacetainido 1-3-[3-(4-carbamoyl- pyridinio)-1-propen-l-yl1-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 19. 7-[2-(5-amino-l,2,4- 30 thiadiazol-3-yl)"2-cyclopentyloxyiminoacetamido]~3-[3~(4» 11 4 2 carbamoyIpyridinio)-1-propen-1-vl )-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt,, solvate,, hydrate or physiologically hydrolyzable ester thereof. 20. 7~[2-(5-amino-l,2,4- 5 thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[3-(4-cacbamovl-pyridinio)-l-propen-l-yl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt,, solvate,, hydrate or physiologically hydrolyzable ester thereof. 21. 7~[2~(5-air>i no-1/2,4-10 thiadiazol-3-y1)-2~propargyloxyiminoacetamido3-3-[3-(4~ carbamoylpyridinio)-1-propen-l-yl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 22. 7-[2-{5-amino-l,2,4~ 15 thiadiazol-3-yl)-2-methoxyiminoacetamido]-3~[3-(--carboxy- pyridinio)-l-propen-l-vl]-3-cephem~4-carboxylate, or a nontoxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 23. 7-[2-(5-amino-l,2,4-20 thiadiazol-3-y1)-2-ethoxyiminoacetamido]-3-1 3-(4-carboxy- pyridinio)-2-propen-l-yl]-3-cephem-4~carboxylafce, or a nontoxic pharmaceutically acceptable salt, solvate,, hydrate or physiologically hydrolyzable ester thereof. 24» 7-[ 2-( 5-amino-l, 2, 4- 2 5 thiadiazol-3~yl)-2-methoxyiminoacetamido1-3-[ 3- ( 3-carboxymethyl-pyridinio)-1-propen-l-yl)-3-cephem-4-carboxylate, or a. nontoxic pharmaceutically acceptable salt, solvate,, hydrate or physiologically hydrolyzable estes thereof. 2 5. 7-12-(5-amino-l,2,4- 30 th iadi azol-3-v 1) - 2-me thoxy iminoacet amido ] -3- ( 3- ( 4-ca rboxymethyl-thicpyridinio)-1-propen-1-vl]-3-cephem-4-carboxylata, or a nontoxic pharmaceutically acceptable salt, solvate, hydrate or Ii 4 3 physiologically hydrolyzable ester thereof. 26. A process for the preparation o£ compounds of the formula »■ J rfj C0M5- OP* rr E-CH»CH2»H~0 COu wherein R is hydrogen or a conventional aaino-protectxng group, R*" is hydrogen, a straight- br branched chain alkyl group containing froa X to 4 carbon atoms,, a cycloa Iky 1 or cycloalkenyl ring containing from'3 to 6 carbon atoms, or a group of the formula R4 COOH -C-CH-CH-H*3 , -C-C=OR3 y v ©r is j,5 H H 4 R ! •C-coos 8S E 0 10 which R" is hydrogen, (lowerlalkyl or carboxyl, X is halogen, 4 hydroxy or ( lower) alkoxy, and R" and H"' are each independently 4 5 hydrogen, nethyl or ethyl, or R and E , taken together with the carbon atoa to which they are attached® aay be a cyclo-alkylidene ring containing fros 3 to 5 carbon atoas, and 14 4 is a quaternary anmonio group, and nontoxic pharmaceutically acceptable salts and. physiologically hydrolyzable esters thereof, which process comprises reacting a compound of the forasiula

1. ) 7~[2~(5-amino-l,2,4-thiadiazol~3-yl)-2-methoxyiminoacetamido]-3~[3-( trisethylammonio)-1-propen-l-yl ]-3~ce!pheffl-4-carboxylate, 2) 7~[2-(5-amino-l, 2e 4-thiadiazol-3-yl) -2~iaethoxyiainoacetaaido]-3-C3-(1-nethylpyrrolidinio)-1-propen-l-yl3-3-cephea-4-

2. 0 carboxylate, 3) 7-[2-( 5-amino-l,2,4-thiadiazol~3-vl)-2-methoxviminoacetamido]-3-C3-pyridinio-l-propen~l-yl]-3-cephea-4-carboxylate, 4) 7-C2- (5-amino-l«, 2,4-tMadiazol~3-yl )~2~ae thoxy iminoacet amido 3-3-C 3-(3-awinopyr idinio) -l~propen-l-yl3-3-cepheB-4-carboxylate, 15 5) 7-[2~(5-amino-l „2,4-thiadiazol~3~yl)-2-methoxyininoacetamido3-3-[3-( 3-foraylaiainopyridinio)-1-propen-l-yl]-3-cephem-4-carboxvlate, 6) 7—C 2—(5-aaino-l, 2,4~fchiadiaaol-3-yl)~2-nethoxyiminoacetaaido3- 3-[ 3- (3-aainomethylpyridinio) -l-propen-l-yl3-3-cephen-4- 20 carboxylate, 7) 7-C 2- C 5-aaino-I, 2,4-thiadiazol-3-yl )-2-nethoxyiBinoacetaaido3-3-[3-( 3-carbaaoyIpyridinio)-1-propen-l-yl3-3-cephea-4-carboxylate, 8) 7-C2-C 5~aaino~l«2,4-thiadiasol-3-yl I -2-Bethoxyiainoacetaaido3- 25 3-£3-( 4-carba®oyIpyr idinio J-l-prope^"l»yl 3-3-eephes-4- carboxylate, 9) 7-[2-(5-aaino-l,2,4-thiadiasol-3~yl)~2-aethoxyiminoacetamido3-3-C 3™ (2-ae thy 1th iazolio) -1-propen-l-yl 3-3-cephen-4-carboxy late s 10) 7-[2-(5-amino-l,2,4~thiadiazol~3~yl)-2-methoxyiminoacetaaido3~ 30 3-[3-(2-amino~5-thiazolo[4,5-c]pyridinio)-1-propen-l-yl]-3- cephea-4-carboxylate, i 4 8 11) 7-£2-( 5-aaino-l, 2,4-thiadiazol-3-yl)-2~aethoxyininoacetaaido3-3~[3-(4-hydroxyaethyIpyridinio)-1-propen-l-yl3-3-cephem-4- carboxylate, 12) 7-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-aethoxyiainoacetamido3-5 3-13-(3-hydroxy»ethyIpyr idinio)-1-propen-l-yl3-3-cephea-4- c&rboxylate, 13) 7-C2~(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiainoacetaaido3- 3-C3-(4- N-methylcarbaraoy1 pyridinio)-l-propen-l-yl3-3-cephem- 4-carboxylate, 10 14) 7-[2-{5-amino-l,2,4-thiadiazol-3-yl)-2-aethoxyiainoacetamido]-3-|[3~{ 2, 3-propylenepvridinio)-1-propen-l-yl3-3-cephem-4-carboxylate, 15) 7-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2~ethoxyiminoacetaaido3— 3~[3-(4-carbanoylpyridinio)-1-propen-l-yl3-3~cephem-4- 15 carboxylate# 16) 7-[2-(S-amino-1,2,4-tniadiazol-3-yl)-2~cyciopentyioxyiminoacet anido]-3-[3-J4-carbaaoyIpyridinio)-1-propen-l-yl3~3-cephea-4-carboxvlate, 17) 7-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-allyloxyimino- 20 acetaraido3-3-[3~{4-carbamoylpyridinio)-1-propen-l-yl]-3- cephem-4-carboxylate, 18) 7— C2— (5-aaino-l, 2,4-thiadiazol~3-yl)-2-propargyloxyiaino-acetaaido3-3-[3-(4-carbaaoylpvridinio)-1-propen-l-yl3-3-cephea-4-carboxylate, 25 19) 7-C2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methQxyiainoacetaaido3-3-C 3-(4-carboxypyr idinio)-1-propen-l-yl 3-3-cephesa-4-cffi.rboxyla.te, 20| 7-£2-C 5-aaino-l,2,4-thiadiasol-3~yl1-2-ethoxyiminoacetamido]-3~C3-(4-carboxypyr idinio |-2-prop«en-l-yl]-3-cephea-4-30 carboxylate, 21) 7-[2-{5-aaino-l,2,4-thiadiazol-3-yl)-2-aethoxyiainoacetamido3-3~C3-(4-carhoxyaefchylpvridinio)-l-propea-l-yl3-3-cephea~4-carboxylate, and I 4 9 22) 7-[2-S 5-amino-l, 2, 4-thiad iatol-3-yl )-2-oicthoxyiminoacetaaido]

3. -C 3 - (

4. -carboxyae thy ithiopyr idinio) -1-propen-l-yl 3-3-ceph«ai-4 carboxylate. 29. A pharmaceutical composition which comprises 5 an effective antibacterial amount of at least one compound of formula I, or a salt, hydrate or solvate thereof, plus a pharmaceutically acceptable carrier. 30. Medication comprising an effective antibacterial amount of at least one compound of formula I, 10 or a saltv hydrate or solvate thereof, in a pharmaceutically acceptable carrier, for use in a method of treating bacterial infections in a warmblooded mammal (including man) in need thereof. 31. The process of claim 26, substantially as 15 described in any of the foregoing Examples. 32. The process of claim 27, substantially as described in any of the foregoing Examples. 33. A compound of claim 1, prepared by a process as claimed in claim 26, 27. 28, 31 or 32. 20 34. A pharmaceutical composition which comprises a compound as claimed in any of claims 1 to 25, or claim 33, plus a pharmaceutically acceptable carrier or excipient. 3

5. Use of a compound as claimed in any one of Claims 25 1 to 25 for treating bacterial infections in a warm-blooded mammal (including man). F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.