IE830455L

IE830455L - Cephalosporin derivatives

Info

Publication number: IE830455L
Application number: IE830455A
Authority: IE
Original assignee: Bristol Myers Squibb Co
Priority date: 1982-03-04
Filing date: 1983-03-03
Publication date: 1983-09-04
Also published as: EG15934A; KR840004118A; BE896086A; NL193284C; ATA228285A; FI830689L; MY8700943A; ES8403919A1; PH18002A; PT76330B; DK86283A; FI830689A0; ES526397A0; ES8507557A1; YU149685A; FR2522659B1; SE8301178D0; CA1213882A; CH654313A5; AU1130483A

Abstract

Novel cephalosporin derivatives of the formula <IMAGE> wherein R<1> is hydrogen or a conventional amino-protecting group, and R<2> is a straight or branched alkyl group containing from 1 to 4 carbon atoms, allyl, 2- butenyl or 3-butenyl, or is a group <IMAGE> wherein R<3> and R<4> each are independently hydrogen, methyl or ethyl, or R<3> and R<4>, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof exhibit potent antibacterial activity and can be incorporated into pharmaceutical compositions. [GB2116180A]

Description

6 6 4 7 2 This invention relates to novel cepnaiosporin derivatives of tne formula wherein K1 is hydrogen or a conventional ainino-protecting group, ami is a straight or branched alkyl group containing lrom 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a jjroup r3—c—r4 I cooh 3 4 wherein K and K each are independently hydrogen, methyl or 3 4 ethyl, or k and k , taken together with the carbon atom to which tney are attached, may be a cycloalkylidene ring containing from 3 to carbon atoms, and nontoxic pharmaceutical^ acceptable salts, physiologically hydrolyzable esters and solvates thereof. Processes for their preparation are also described. 3 Patent Specification No. 38172 contains a generic disclosure encompassing a vast number of cephalosporins of the formula wherein K is hydrogen or an organic group, Ka is an etherifying 5 monovalent organic group linked to the oxygen through a carbon atom, b is or and P is an organic group. However, the 2-aminothiazol-4-y1 group is not identified as an K substituent and there is no suggestion that P may be N-methylpyrrolidiniummethyl (or any other fully saturated nitrogen-containing ring which is attached lO to the 3-methyl moiety via its nitrogen atom and which contains an additional substituent t>n its nitrogen atom). U.S. Patent 5,971,778 and its divisionals 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 similar disclosures.

U.S. 4,278,793 contains a generic disclosure encompassing a vast 15 number of cephalosporin derivatives of the fprmula tt tt in which the variables Kj, K^, Kj, K^, X and A include generic definitions of the corresponding substituents of the compounds of Formula I claimed herein. However, in the 20 columns of definitions of the various substituent groups, the 78 page long table of structural formulae and the 22S examples, there is no disclosure that A may be N-methylpyrrolidiniuminethyl (or any other fully saturated nitrogen-containing heterocyclic ring) which is attached to the 3-methyl moiety via its nitrogen atom and which contains an additional substituent on its nitrogen atom. United Kingdom Patent Specification No. 1,604,971 is concordant thereto and has a substantially identical disclosure. Published United Kingdom Patent Application No. 2,028,3nS A, although apparently not formally related, contains the same broad generic disclosure but exemplifies A only as hydrogen.

West German ULS 2,805,655 discloses 7-[2-(2-aminothiazol-4-yl) -2-IsynjinethoxyiminoacetamidoJcephalosporin acid derivatives of the formula COOR 1 2 in which K NH is an optionally protected amino group, K is halogen or an optionally substituted hydroxyl, thiol or amino group, and CUOR is an optionally esterified carboxyl group. It is also 7 disclosed that, when K . is an amino group, it may be disubstituted and the suDstituents, taken together with the N atom, may form inter alia a pyrrolidino group. However, there is no disclosure of an N-mcthyl-pyrrolidiniuinmethyl group (or of any other quaternary ammonium group) and substituent cannot be connected to the 3-position via a methylene group.

U.S. Patent No. 4,278,1)71 discloses 7-[2-(2-aminothiazol-1-4-y1) -2 -( synJ-mcthoxyiminoacetamido]cephalosporin derivatives of the formula in which K^NH is an optionally protected amino group and Rj is hydrogen or "the residue of a nucleophilic compound". The term "the residue of a nucleophilic compound" is broadly defined and it is then stated that K3 "may alternatively be a quaternary ammonium group". Pyridinium, variously substituted pyridinium, quinoliniura, picoliniun and lutidinium are disclosed as quaternary ammonium groups. There is no suggestion that the quaternary ammonium group may consist of a fully saturated nitrogen-containing heterocyclic ring system which is bound via its nitrogen atom and which contains an additional substituent on its nitrogen atom. United Kingdom Patent Specification No. 1,581,854 is concordant thereto and has a substantially identical disclosure. Uther patents to the same patentee, which are not formally related but which have similar disclosures, include U.S. Patent 4,098,888 and its divisionals U.S. Patents 4,203,899, 4,205,180 and 4,298,606, and United Kingdom Patent Specification No. 1,556,281. 6 U.S. Patent No. 4,168,309 discloses cephalosporin derivatives of the formula R-C-C-NH- J « 0(CH2)m-9-(CH2)nCOO« Iw a K R and K are independently wherein R is phenyl, thienyl or furyl; hydrogen, alkyl, cycloalkyl, phenyl, naphthyl, thienyl, furyl, a K carboxy, alkoxycarbonyl or cyano, or R and R , taken together with the carbon atom to which they are attached, form a cycloalkylidene or cycloalkenylidene ring; m and n are each 0 or 1 such that the sum of m and n is 0 or 1; and R1, together with the 10 nitrogen atom to which it is attached, is broadly defined but may not inter alia be a saturated 5-membered ring. The compound having the formula *3 COOH 'O-C-COOH CH, L. 3 is exemplified in Example 5 thereof. United Kingdom Patent 15 Specification No. 1,591,439 is concordant thereto and has a substantially identical disclosure. There is no suggestion in this patent that the R substituent may be the 2-aminothiazol-4-yl moiety or that the iinino substituent not contain a carboxyl group. 7 This invention relates to cephalosporin derivatives of the furmula wherein K is hydrogen or a conventional amino-protecting group, ana K2 is a straight or branched chain alkyl group containing from 1 to 5 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group R3—C—R4 I COOH 3 4 wherein K and K each are independently hydrogen, methyl or 3 4 ethyl, or k and K , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to lo 5 carbon atoms, and nontoxic pharmaceutical^ acceptable salts and physiologically hydrolyzable esters thereof. Also included within the scope of this invention are the solvates (including hydrates) of the compounds of Formula I, as well as the tautomeric forms of the compounds of Formula I, e.g. the 2-iminothiazolin-4-yl form of the 15 2-aminothiazol-4-yl moiety.

As shown in the structural formula, the compounds of Formula 1 have the "syn" or "i" configuration with respect to the alkoxyimino (or alkenyloxyimino) group or the carboxy-substituted alkoxyimino group, because the compounds are geometric isomers, some of the 2o "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 I are "syn" isomers which are essentially free of the corresponding "anti" isomers. 8 The pharmaceutically acceptable salts of the compounds of Formula I include the inorganic base salts such as the alkali metal salts (e.g. the sodium and potassium salts) and the alkaline earth metal salts (e.g. the calcium salts), ammonium salts, organic base salts 5 (e.g. with triethylamine, procaine, phenethylbenzylamine, dibenzylethylenediamine and other organic bases which have been used in the penicillin and cephalosporin art), and the acid addition salts (e.g. the salts with hydrochloric, hydrobromic, formic, nitric, sulfuric, methanesulfonic, phosphoric, acetic or trifluoroacetic acid) lO and other acids which have been used in the penicillin and cephalosporin art. The physiologically hydrolyzable esters include the acyloxyalkyl esters, e.g. (lower)alkanoyl(lower)alky1 esters such as, for example, acetoxymethyl, acetoxyethyl and pivaloyloxymethvl. The base salts and the esters may be formed with either of the carboxyl groups 15 of the compounds of Formula I.

The compounds of Formula 1 in which is hydrogen exhibit high antibacterial activity against various Gram positive and Gram negative bacteria, and are useful in the treatment of bacterial infections in animals, including man. The compounds of Formula I may be formulated 20 for parenteral use in a conventional manner utilizing known pharmaceutical carriers and excipients, and may.be presented in unit dosage form or in multi-disage 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 25 stabilizing agents. The compositions may also be in the form of a dry powder for reconstitution before use, e.g. with sterile, pyrogen-free water. The compounds of Formula 1 may also be formulated as suppositories utilizing conventional suppository bases such as cocoa butter or other glycerides. The compounds of this invention may, if 30 desired, be administered in combination with other antibiotics such as penicillins or other cephalosporins.

When provided in unit dosage forms the compositions will preferably contain from about SO to about 1500 mg of the active ingredient of Formula 1. The dosage for adult human treatment will » 9 preferably be in the range of from about SOU to about 5000 iiik per day, depending on the frequency and route of administration. When administered intramuscularly or intravenously to an adult human, a total dosage of l'rom about 750 to about 3000 mg per day, in divided 5 doses, normally will be sufficient, although higher daily doses of some of the compounds may be desirable in the case of Pseudomonas infections.

The preferred compounds of Formula I are those in which R* is 2 3 4 hydrogen and R is methyl or ethyl or R and R each are independently hydrogen or methyl. In the most preferred compounds, 2 3 4 R is methyl or R and K each are methyl. In the primary evaluation of the compounds of this invention, the Minimum Inhibitory Concentrations (MIC'sJ of the compounds and two reference compounds (cefotaxime and ceftazidime) 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 determined in this test are shown in Tables 1 and 4.

(Cefotaxime; Comparison Compound) (Ceftazidime; Comparison Compounds) It may be seen that all of the test compounds were more active than cefotaxime against the (G-)-Il and (G-)-IIl groups of test organisms, with the most preferred Compound la being markedly more active. All of the test compounds were more active than ceftazidime against the 5 (G+)-la and (U+)-lb groups of test organisms, with the most preferred Compound la being markedly more active than ceftazidime against all groups of test organisms except (G~)-1II, which was somewhat more susceptible to ceftazidime.

The absorption of the most preferred Compound la and of reference 10 compounds (cefotaxime and ceftazidime) were determined in mice following a single intramuscular injection of the test compound (dissolved in p.lM phosphate buffer; pH 7) at a dosage of 20 mg/kg. Blood samples were collected from the orbital sinuses into heparinized capillary tubes and assayed in Mueller-Hinton medium using Morganella 15 Mor^ani i A9695 as the test organism. The blood levels at various time intervals, the half-life values and the areas under the curve IaUC) are shown in Table 2.

Tests to identify organisms resistant to the preferred compound of Formula la, cefotaxime and ceftazidime were also conducted. The 2o MIC's of these three compounds against 240 strains of tinterobacteriaceae were determined in Mueller-Hinton medium, and an MIC of equal to or greater than 8 for at least one of the test compounds was arbitrarily taken as indicating a resistant organism. l)f the 240 strains, 27 were found to be resistant to at least one of 25 the test compounds. The results, showing 3 organisms resistant to Compound la, 15 organisms resistant to ceftazidime and 18 organisms resistant to cefotaxime, are given in Table 3.

Geometric Mean of MIC (mcg/mL) Compound (G+J-Ia (5 strains) (G+)-Ib (5) (G-)-Ia (5) (G-)-Ib (6) IG-J-II (5) (G-)-III (6) la? R^=mathyl lbs R2=ethyl 2 let R =isopropyi Id; R2=allyl Cefotaxime'a' Ceftazidime * 1.2 1.4 1.4 1.8 1.0 .1 3ol 3 = 1 3.6 3.6 2.2 12 0.025 0.087 0.35 0.53 0.015 0.070 0.13 0.32 1.3 1.1 0.35 1,7 0.33 1.0 3.2 2.4 4.1 2.6 2.8 5.6 13 22 1.8 ►3 Dl tr (G"S)-Ia (G-)-Xa Peniciilin-sensitiv® S;_ aureus (5 strains) Penicillin-ires is tan t S^_ aureus (5 strains) Csphalothin-sensitive Ro_ coli (2 strains), Kl. pneumoniae (1 strain) and Pr. mlrabilis (2 strains) Cephalothin-resistant coli (3 strains) and Kl. pneumonias (3 strains) Pr. morganii (1 strain), Ent. cloacae (2 strains) and Ser. roarcsscens (2 strains) Pa. aeruginosa (S strains) (G-)-Ifa (G-)-lI JG-)-XZX (a) Mean of five experiments Table 2 Blood Levels After Intrajnuscular Administration to Mice (20 mg/kg) Compound Blood Levels (mcg/mL) Minutes After Administration 4l 1/2 (minutes) AUC (meg•hour/ml) 45 60 90 la? S2=msthyl^a' :s£otaxime^ (c) Ceftazidime .7 27.8 21.5 19.6 19.3 18.4 13.6 13 14.9 8.8 9.1 8.7 4 . 4.6 4a4 M).9 1.2 MK8 17 15 17 13.5 14.9 13.8 r-o (a) average of 2 tests (b) 1 test (c) average of 3 tests 13 Table 3 Resistance (MIC = >8 jig/ml) to One or More Test Compounds Among 240 Strains of Enfcerobacteriaceae in Mueller-Hinton Medium Geometric Mean MIC (jjg/ml) Organism No o o£ .

Strains la Ceftazidime Cefotaxime Escherichia coli 1 0.25 32 S Escherichia coli 1 4 0.5 8 Klebsiella pneumoniae 1 2 16 0.13 Enterobacter aerogenes 3 0„2S 32 13 Enterobacter aerogenes 1 4 8 32 Enterobacter cloacae X 0.13 j!) cd 8 Enterobacter cloacae 3 0.5 40 50 Rnterobacter cloacae 3 1.6 >63 >63 Enterobacter cloacae 1 >32 >63 >63 ritrobacter freundii 2 0.35 45 32 :itrobacter species 1 0.03 >63 32 Proteus vulgaris 1 0 "06 8 8 'lorqanella morganii 1 o c o 32 32 Serrafcia snarcescens 1 i 1 16 Serratia marccscens 1 2 8 16 14 Table 3 - con:.

Geometric Mean MIC (vg/ml) Organism Wo„ of Strains Xa Ceftazidime Cefotaxime 5erratia marcescens 2 2,8 2 11 Serratia" marcescens 1 4 8 63 Serratia marcescens 1 8 16 8 Serratia marcescens 1 32 >63 >63 Total Number of Resistant Strains 27 3 18 (Test Compound) Table 4 Geometric Mean of MIC (mcg/mLJ Compound Test Compound f a ) [ a ] Organisms Ie Cefotaxime Ceftazidime (G+)- la (5 strains) 14 1.0 .1 (G+)-lb (5) 33 2.2 12 (G-)-Ia (5) 0.066 0.015 0.070 (G-)-Ib (6) 0.79 0.35 1.7 (G-)-Il (5) 1.2 4.1 2.6 (G-)-IlI (6) 4.0 22 1.8 : Penicillin-sensitive S. aureus (5 strains) : Penicillin-resistant S. aureus (5 strains) : Cephalothin-sensitive E. coli (2 strains), Kl. pneumoniae (1 strain) and Pr. mirabilis (2 strains) : Cephalothin-resistant E. coli (3 strains) and Kl. pneumoniae (3 strains) : Pr. moreani (1 strain), Ent. cloacae (2 strains) and Ser. Marcescens (2 strains) Ps. aeruginosa (6 strains) five experiments (G+)-Ia (l>+)-Ib (G-)-Ia (G-)-Ib (G-)-II (G-)-III (a) Mean of 16 1? 133y 6>e seen shot compound Je hss raore active than ceJotaaiae Kigaiasi the (C-)-ll group tesi os-$asiasas and giar&edly more active sh®n csffotwJiiQe Bjasnsi She (G-J-331 group of test organisms (?s, aeruginosa). 1$ fe>as taore ective shan eslaaisidjfne against all groups 5 el Gyaisii-negatiwe sest ejgsasBBis escftpt (G-J-I3J (Ps. leyueiaosa). which Has some what mora susceptible so cef £Mifi arae.

The following forms of medication are Included within the present invention:- (i) Medication comprising an antibacterially 10 effective amount of at least one compound of this invention, for use in a method of combatting bacterial infection in a warm-blooded animal. (ii) Medication comprising an antibacterially effective amount of 7-I[(Z)-2-methoxylniino-2-(2-aminothiazol-4-yl) 15 aceteunido]-3-£( l-methyl-l-pyrrolidinium)methyl] -3-cephem-4-carboxylate or a nontoxic pharmaceutical^ acceptable salt or solvate thereof, for use in a method of combatting bacterial infection in a warm-blooded animal. (iii) Medication comprising an antibacterially 20 effective amount of at least one compound-of this invention, wherein R* is as hereinbefore defined and R3 and 4 R each are independently hydrogen, methyl or ethyl, or 3 4 R and R , taken together with the carbon atom to which they are attached may be a cycloalkylidene ring containing 25 from 3 to 5 carbon atoms or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, for use in a method of combatting Gram-negative bacterial infection in a warm-blooded animal, (iv) Medication comprising an antibacterially 30 effective amount of 7-£2-(2-aminothiazol-4-yl)-(Z)-2-(2-carboxyprop-2-oxyimino)-acetamldo3-3-[(1-methy1-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutical^ acceptable salt, physiologically hydrolyzable ester or solvate thereof, for use in a method of 35 combatting Gram-negative bacterial infection in a warmblooded animal. 1/ Also, the following antibacterial compositions are included within the scope of the present invention (a) An antibacterial composition active against Gram-negative bacteria comprising an antibacterially effective amount of at least one compound of this invention wherein R1 is as hereinbefore defined and R3 and R4 each are independently hydrogen, methyl or ethyl, or •a a R and R , taken together with the carbon atom to which they are attached may be a cycloalkylidene ring containing 10 from 3 to 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, and an inert pharmaceutical carrier. (b) The composition of "(a)" above wherein the compound of this invention is 7-£2-(2-aminothiazol-4-yl)- (Z)-2-( 2-carboxyprop-2-oxy imino) ace tamidoj -3- [,(1 -me thy 1 - 3—X< l-methyl-l-pyrrolidinium)methyl3 -3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. (c) An antibacterial composition active against 20 Gram-negative bacteria in unit dosage form comprising from about 50 mg to about 1500 mg of at least one compound of this invention wherein R1 is as hereinbefore 3 4 defined and R and R each are independently hydrogen, 3 4 methyl or ethyl, or R and R , taken together with the 25 carbon atom to which they are attached, may be a cyclo-alkylidene ring containing from 3 to 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, and an inert pharmaceutical carrier. (d) The composition of "(c)" above wherein the compound of this invention is 7-[2-(2-aminothiazol-4-yl)-( Z)-2-(2-carboxyprop-2-oxyimino)acetamido]-3- [(1-methy1-1-pyrrolidinium)methyl3-3-cephem-4-carboxylate , or a nontoxic pharmaceutically acceptable salt, physiologically hydroly-35 zable ester or solvate thereof. 18 la another Aspect, this Invention relates to processes for the preparation of She compounds of Porraula 1. There are two basic procedures for converting m ?isadily Mailable starting cephalosporin to another cephalosporin having different substituents en the ?- and ^-positions. One may first resaove the 7-subsijtucni and replace it with the desired 7"sa&ssstuent„ and then lasers the desired J'substisuent. Alternatively,, on® aay first insert She desired 3°a«bsvivuesit sad subsequently sschange She 7-substituent. The compounds of Formula J my be prepared by either procedure and both arts included uithin the scope of this invention but is is preferred to insert the desired 7°substisueas first sand then insert the desired 3-substituent. The preferred procedure is shows below in Reaction Scheme 1 while the alternative procedure is shown in Reaction Scheme 2. The abbreviation "Ty" represents the trityl (triphenylraetbyl) group, which is a preferred anino-protecting group. The abbreviation.

"Ph" represents the phenyl group. Thus, the -CHlPh^ aoiety as tS>e b«n*hyd?yl group, which is a preferred carbostyl-protecting group.

Reaction Schemes 3 and 4 shoia the preparation of Compound (Is) in 1 5 4 whieh 8 is hydrogen and H aad a axe eseh methyl. 19 Reaction Scheme 1 N —x-C COOC2H5 // \ TrHN' •S uH R2X N T-C COOC2H5 // TtKN'\s/ \,„2 OH N -r—C-COOH XVK TriW^\s/ \r2 TrHN N C CONH" - Ilia' ■c-cooh ill TrHW^\s/ \ O H,cicH, 'i 3 ooc(ch3)3 H,N- 0, ch,c1 COOCH(Ph). ^1) dicyclohexyl- carbodiimide (DCC) 1) bis(trimethyl-silyl)acetamide (BSA) 2) Ilia' 4- PClc TrHN conh" ooc(ch3)3 N\Ah2C: COOCH(Ph).

Va Nal si/ TrHN N C CONH - '/ \IL 24 h3ccch3 cooc(chj) 3 ✓XX COOCH(Ph)_ Via k3C-0 n \— c ■ AM — conh TrHN H3C]CH3 iooc(cH3)3 v Vila deblock /S V n-- tt-c conh 1 f h2n h3cCch3 cooh Reaction Scheme 4 Ie PhCJ^CONH JY1 cooch(Ph).

VIII pci5 pyridine PhCHjCONH- / ,C1 COOCH(Ph)2 PhCH^CONH Nal \S/ COOCH{Ph)2 H3C"0 26 X© c»2—p OOCH(Ph)2 \ 3 XII Ilia' DCC conh- /s\ 1 P H3cicH3 COOCH (Ph),V^ Vila ioOC(CH3)3 ch, Nk deblock conh- h3ccch3 cooh Ie r"i>Y 71 Although the above Keaction Schemes show preferred multi-step procedures for the preparation of the compounds of Formula I, it will be appreciated that other starting materials and procedures may be utilized to prepare the intermediates used in the key step of each Keaction Scheme. Thus, the key step in Keaction Scheme 1 is the reaction of Compound VII with N-methylpyrrolidine. Compound VII may itself be prepared by other procedures. Similarly, the key step in Keaction Scheme 2 is the acylation of Compound XII with Compound IV. both compounds XII and IV may be prepared by other procedures.

The key step in Keaction Scheme 3 is the reaction of Compound Via with N-methylpyrrolidine. Compound Via may itself be prepared by other procedures. Similarly, the key step in reaction Scheme 4 is the acylation of Compound XII with Compound Ilia'. Both Compounds XII and Ilia'may be prepared by other procedures.

The present invention provides a process for the preparation of compounds of the formula wherein K^ is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group R3—C— I COOH 28 3 4 wherein K and K each are independently hydrogen, methyl or 3 4 etnyl, or K and K , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to S carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof which process comprises reacting a compound of the formula XIV COOB in which K2 is as defined above, B1 is a conventional 2 carboxyl-protecting group and B is a conventional ammo-protecting 10 group, with N-methylpyrrolidine to produce a compound of the formula N r-c C NH-i J0 COOB"" fa XV and subsequently removing all protecting groups by conventional means or which comprises reacting a compound of the formula COOB XlVa amino-protecting group, with N-methylpyrrolidine to produce a compound of the formula and subsequently removing all protecting groups by conventional means.

The reaction is carried out in a non-aqueous organic solvent such as, for example, methylene chloride, chloroform, ethyl ether, hexane ethyl acetate, tetrahydrofuran and acetonitrile or mixtures of such solvents. The reaction is conveniently carried out at a temperature of from about -10°C to +50°C; we normally prefer to conduct the reaction at room temperature. At least one mole of N-methylpyrrolidine should be used per mole of Compound XIV or XlVa; we normally prefer to utilize from about 50* to 100* excess of N-methylpyrrolidine.

Carboxyl-protecting groups suitable for use as B* and B^ in the above reaction are well-known to those skilled in the art and include aralkyl groups such as benzyl, p-methoxybenzy1, p-nitroben:y1 and dipehnylmethyl (benezhydryl); alkyl groups such as t-butyl; haloalkyl groups such as 2,2,2-trichloroethyl, and other carboxyl-protecting groups described in the literature, e.g. in Patent Specification No. 38172. We prefer to utilize carboxyl-protecting groups which are readily removed by treatment with acid. Particularly preferred carboxyl-protecting groups are the benzhydryl and t-butyl moities.

I S XVa Amino-protecting groups suitable for use as are also well-known in the art, and include the trityl group and acyl groups such as chloroacety1. Amino-protecting groups which are readily removed by treatment with acid, e.g. the trityl group, are preferred.

The present invention also provides a process for the preparation of compounds of the formula 2 wherein K is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group COOH wherein k3 and R4 each are independently hydrogen, methyl or ethyl, or K3 and R4, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof, which process comprises acylating a compound of the formula 31 or .111 N-silyl derivative thereof, ill which B is hydrogen or a conventional c;irboxyl-protecting group, with an acylating derivative of an acid of the formula N r-C-COOH B HH XVII wherein B^ is a conventional amino-protecting group and is as defined above, to produce a compound of the formula XV and subsequently removing all protecting groups or acylating compound XVI or an N-Silyl derivative thereof with an acylating derivative of 10 an acid of the formula C-COOH N—rr-c-co , /X B HN C XVI la COOBJ 2 3 wherein B is a conventional amino-protecting group, B is a 3 4 conventional carboxyl-protecting group and R and R each are 3 4 independently hydrogen, methyl or ethyl, or R and R , taken together with the carbon atom to which they are attached, inay be a cyeloalkenylidene ring containing from 3 to 5 carbon atoms, to produce a compound of the formula O H— r-C i! NU-1 S >Ssi fp\ -JjK A/.-4Q R3-C-R4 COOB1 / ' 3 COOB XVa 32 and subsequently removing all protecting groups.

The acylating derivatives of the acid of Formula XVII or XVIIa include the acid halides (and particularly the acid chloride), mixed acid anhydrides (such as the acid anhydrides formed with pivalic acH 5 or a haloforinute such as ethyl chloroformate), and activated esters (such as may be formed with N-hydroxybenztriazole in the presence of a condensing agent such as dicyclohexylcarbodiimide.). The acylation may also be effected by use of the free acid of Formula XVII or XVIIa in the presence of a condensing agent such as dicyclohexylcarbodiimide, 10 carbonyldiimidazole or an isoxazolium salt. As used herein, the term "acylating derivative" of the acid of Formula XVII or XVIIa includes tne free acid itself in the presence of a condensing agent such as described above. The preferred acylating derivative of the acid of Formula XVII or XVIIa is the acid chloride, preferably used in the 15 presence of an acid oinding agent (and particularly a tertiary amine acid binding agent such as triethylamine, dimethylani1ine or pyridine).

When the acylation is conducted with an acid halide it is possible to utilize an aqueous reaction medium, but a non-aqueous medium is preferred. When acid anhydrides, activated esters, or the 20 free acid in the presence of a condensing agent, are used for the acylation, the reaction medium should be non-aqueous. Particularly preferred solvents for the acylation reaction are halogenated hydrocarbons such as methylene chloride and chloroform, but tertiary amides such as dimethylacetamide or dimethylformamide may be utilized, 25 as well as other conventional solvents such as , for example, tetra-hydrofuran and acetonitrile.

The acylation reaction may be conducted at a temperature of from about -50°C to +50°C. However, it is preferably conducted at or below room temperature and most preferably from about -30°C to 30 0°C. It is usually preferred to acylate the compound of Formula XVI 33 with about a stoichiometric amount of the acylating agent of Formula XVII or XVIIa, although a small excess (e.g. 5-25*) of the acylating agent may be utilized.

It is preferable that the compound of Formula XVI by acylated in the form of its N-silyl derivative (when utilizing a non-aqueous reaction medium.). This is conveniently done jhr) situ by simply adding a suitable silylating agent (e.g.N.O-bistrimethylsilylacetamide) to the solution of compound XVI prior to the addition of the acylating agent of Formula XVII or XVIIa. We prefer to utilize about 3 moles of lO silylating agent per mole of Compound XVI although this is not critical. The silyl compound is readily removed after acylation by the addition of water.

The acylating acids of Formula XVII or XVIIa including carboxyl-and amino protected derivatives thereof, are known in the art or may be prepared by known procedures. This, (Z)-2-(2-t-butoxycarbonylprop-2 15 -oxyimino)-2-(2-tritylamino-thiazol-4-yl)acetic acid (Ilia) was prepared by the general procedure described in U.S. Patent 4,258,041 and Patent Specification No. 49172. The melting point reported therein was 152-156°C (decomp.) but, in our hands this compound melted at 174-175°C decomp.) Preparation No. 1 Ethyl (Z)-2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (Ilia) A mixture of ethyl (Z)-2-hydroxyimino-2-(2-tritylamino-thia:ol-4-yl) acetate (II) (5.DO g, 10.9 mmolesj, CHjI (2.04 mL, 32.8 mmoles) and I^CU^ (4.54 g, 32.8 mmoles) in dry dimethyl-sulfoxide 34 (1)MS Compounds 111b, IIIc and 111d were prepared by the general procedure set forth above, but replacing the methyl iodide with the appropriate iodide.

Literature Compound Yield (*) Mp (°C) Mp (°C) Ilia methyl 100 115° (dec.) ca. 120" (dec.) IHb ethyl 67 97-98° * IIIc isopropyl 26 51-55° B nid allyl * e ■ ® The ester was hydrolyzed without isolation (1JTetrahedrom, 34, 2233 (1978) Preparation No. 2 COOH JTJV ^ \or2 IV (2)-2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVa) The ethyl ester Ilia prepared in Preparation No. 1 (6.00 g, 12.7 minoles) in ethanol (120 mL) was treated with 2N NaUH (12.7 mL) at room temperature overnight. The reaction mixture was adjusted to pll 8 by the addition of powdered dry ice and the solvent was evaporated under 5 reduced pressure. The residue was dissolved in water (100 mL) and the solution was acidified with IN HCl to pH 2 and then extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with a saturated aqueous NaCl solution, dried and evaporated. The residue was crystallized from ethyl acetate-hexane to afford 5.56 g (yield lO 98*) of the title product. Mp. 138-143°C (dec.).

MMK : SCDC13 ppm 3.89 (3H, s), 6.52 (1H, s), 7.2 (15H, s).

Compounds lVb, IVc and IVd were prepared by the general procedure set forth above.

Literature Compound R2 Yield (*) Mp (°C,dec.) Mp (°C dec.) IVa methyl 98 138-143 ca. 140 lVb ethyl 85 140-145 not reported IVc isopropyl 85 166-169 ca. 170 Hid allyl 66 170-178 ca. 170 (1J Tetrahedrom, 34, 2233 (1978) Preparation No. 3 Benzhydryl 3-Hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxvlatP (VI11J 36 To a stirred suspension of phosphate buffer (pH 7, 162.5 ml.) and wheat bran (20 g, dry) at room temperature was added 7-phenylacetamidocephalosporanic acid sodium salt (5 gm, 12.1 minoles) in one portion. The progress of the reaction was monitored by HPLC 5 until the hydrolysis was complete (5 hours). The suspension was filtered to remove the wheat bran and the filtrate was cooled to 5-10°C for extractive esterification. To the cooled solution was added methylene chloride (32 mL) followed by a 0.5M solution of diphenyldiazomethane in methylene chloride (24 mL). The pH was then 10 adjusted to 3.0 with 28t phosphoric acid. After 1 hour the reaction mixture was allowed to rise to 20°C. Heptane (56 mL) was slowly auded and the resulting crystalline title product was recovered by filtration. Yield of the title product was 3.0 gm (50*).

Preparation No. 4 Benzhydryl 7-Amino-3-chloromethyl-3-cephem-4-carboxylate (V) To a slurry of PClj (8.3 g, 40 mmoles) in CH^Cl^ (100 mL) was added pyridine (3.2 g, 40 mmoles) and the mixture was stirred for 20 minutes at 20°C. To the mixture was added benzhydryl 20 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate prepared in Preparation No. 3 (5.1 g, 10 mmoles) with stirring at -40°C, in one portion. The mixture was stirred at -10°C for 15 minutes and allowed to stand at -10°C to -15°C for 7 hours. To the cooled solution (-20°C) was added propane-l,3-diol (10 mL) and the mixture was allowed 25 to stand at -20°C for 16 hours and then at room temperature for 20 minutes with stirring. The resulting solution was washed with ice-water (2 x 20 mL) and saturated aqueous NaCl (10 mL), dried over MgSU^ and concentrated in vacuo. The gummy residue (12 g) was dissolved in a mixture of CHClj and n-hexane (2:1), and subjected to 30 chromatography using a silica gel column (200 g) and the same solvent as eluant. Fractions containing the title compound were evaporated in vacuo and the residue triturated with n-hexane to give the title product (2.1 g, 51*), melting at >110°C (dec.). 37 1K : vKBr 3400, 2800, 1785, 1725 cm"1.

UV : x tt0" 265 nm (E1* 160). max 1cm NMK : l>MSU-d6 ♦ C1)C13 3>69 l2H> sJ> 4>4J (2))> sJe s>09 (1)i> d> P1>m J = 4.5Hz), 5.24 (1H, d, J = 4.5Hz), 6.87 (1H, s), 7.3 (10, m).

Example 1 7-t(2 J-2-Methoxyimino-2-(2-aminothiazol-4-y1)acetamido)- 3-[(1-methy1-1-pyrrolidiniuinjmethyl]-3-cephem-4-carboxylate (la) lO A. Benzhydryl 3-Chloromethyl-7-[(2)-2-methoxyimino-2-(2-tritylamino-thiazol-4-ylJacetamido]-3-cephem-4-carboxylate (Via') Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate prepared in Preparation No. 4 (2.29 g, 5.52 mmoles) in CH^CN (57 mL) was treated with bis(trimethylsilyl)acetamide (BSA, 4.09 mL, 16.6 15 mmoles) at room temperature for 50 minutes to give a clear solution. To the solution was added an acid chloride solution, which was prepared from (Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acet ic acid (IVa) (2.04 g, 4.60 mmoles) and PCI,. (1.15 g, 5.52 mmoles) in methylene chloride (20 mL). The mixture was stirred at room 2o temperature for 30 minutes, poured into cold water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts ucre washed with aqueous NaCl, dried and evaporated. The residual syrup (4 g) was chroinatographed on a silica gel (150 g) column by eluting with 10:1 and 3:1 mixtures of toluene and ethyl acetate successively. The 25 fractions containing the desired compound were combined and evaporated to afford 2.61 g (68t) of Via' as an amorphous powder. 38 NMK : «CUC13 3.50 (2H, s) , 4.02 (3H, s), 4.33 (2H, s), 4.98 (1H, d), 5.87 (1H, q), 6.65 (1H, s), 6.90 (1H, s), 7.3 (25H, mj.

B. Benzhydryl 3-lodomethyl-7-[IZ)-2-methoxyimino-2-(2-tritylamino-5 thiazol-4-yl)acetamido]-3-cephem-4-carboxylate (Vila') A mixture of the 3-chloroinethyl derivative (Via'} (1.50 g, 1.79 mmoles) and Nal (1.34 g, 8.93 mmoles) in methyl ethyl ketone (30 mL) was stirred at room temperature for 1 hour. After evaporation of the solvent the residue was dissolved in ethyl acetate (100 mL) and washed 10 with water, aqueous Na2S20j and aqueous NaCl, dried and evaporated to give the title compound Vila' (1.47 g, 894) as an amorphous powder.

NMK : 6CI)C13 ppm 3.55 (2H, ABq), 4.00 (3H, s), 4.25 (2H, s). 4.97 (1H, d), 5.80 (1H, q), 6.65 (1H, s), 15 6.90 (1H, s), 7.3 (25H, m).

C. 7-1(2)-2-Methoxyimi no-2-(2-aininothiazol-4-yl)acetamidol-3-|(l-inetny1-1-pyrrolidinium)methyll-3-cephem-4-carboxylate (la) A mixture of Vila' (4.5 g, 4.83 mmoles) and N-methylpyrrolidinc (0.65 mL, 6.28 minoles) in (45 mLJ was stirred at room temperature for 20 minutes, fcther (300 mL) was added to the mixture to separate the quaternary salt of the blocked cephalosporin, which was collected by filtration and treated with 90* trifluoroacetic acid (TFA) (40 mL) at room temperature for 1 hour. The mixture was then evaporated under reduced pressure below 20°C. The residue was 25 triturated with ether to give the TFA salt of la (2.40 g), which was dissolved in methanol (5 mL) and treated with 1M solution of sodium-2-ethylhexoate (SfcH) in ethyl acetate (8 mL) at room temperature for 30 minutes. After the addition of ethyl acetate (100 mL), the precipitate (1.94 g) formed was collected by filtration. HPLC 39 analysis showed that the crude product was 7* pure with a 1:8 ratio cf 3 2 the a isomer to the a isomer. Purification of the product by ilPLC was repeated three times (Lichrosorb RP-18, 8 x 300mm, eluted with St aqueous CHjOH or 0.01M ammonium phosphate buffer (pH 7.2} containing St CH^OH to give 35 mg (1.5*} of the title product as a colorless powder. Estimated purity (by HPLC} 90*. Mp. 150°C (dec.}.

IK : vKBr cm"1 1770, 1660, 1620. max uv ^phosphate buffer, pH 7 m(c } 235 (16200Jf 258 (15400}. max NMK :«U2° ppm 2.31 (4H, m}, 3.08 (3H, s}, 3.63 (4H, m), 4.09 (3H, s}, 5.43 (1H, d, J - 4.8 Hz}, 5.93 (1H, dj, 7.08 (1H, s}.

Example 2 7-1(L)- 2-Methoxyimino-2-(2-aminothiazol-4-yl}acetami do]-3-[ (1-methyl-l-pyrrolidiniuin}methylJ -5-cephem-4-carboxylate (la} To a stirred solution of 20.4 g (21.9 mmoles} of Vila' in 150 mL of dry methylene chloride was added 2.42 g (28.5 mmoles} of 1-methylpyrrolidine in one portion at room temperature. The mixture was stirred for 5 minutes and poured into 1000 mL of ether with vigorous stirring to form a precipitate, which was filtered, washed with ether (5 x 30 mL} and dried in vacuo to give 19.3 g of the blocked product as a pale yellow powder.

IK : uKBr cm"1 3400, 1780 (s}, 1740, 1675, 1530. max TLC : solvent ethanol-CHCl^ (1:3), Rf=0.30 (Rf=0.95 for Vila1). 40 The solid was dissolved in 185 mL of trifluroacetic acid-water (99:1J, stirred for 1 hour at room temperature and concentrated to ca. 3U mL below 10®C. The concentrate was poured into 1U0U mL of ether with vigorous stirring to form a precipitate, which was filtered, 5 washed with ether 15 x 40 mLJ and dried under vacuum to yield 10.6 g of pale yellow powder. The powder was dissolved in 20 mL of methanol and the solution was filtered. To the filtrate was added 45 mL of 0.8M SEH in ethyl acetate. The resultant suspension was poured to 400 inL of ethyl acetate and filtered to give 8.08 g of a solid which was a 10 mixture of the title compound and the corresponding i2 isomer (A^/a2 = 1:8J as shown by HPLC analysis (Lichrosorb kP-18, 10-151 methanol in 0.01M phosphate buffer, pH 7J. A second run from 28.y g (31.0 minolesj of Vila' gave 16.0 g of the crude product (a 3/a 2 = 1:8J. Isolation of the desired A3 isomer from the combined crude 15 product (24.08 gj by using preparative HPLC (System 500, haters Associates, PrepPAN 500/C^g, 5-10t CHjOHJ afforded 769 mg of Compound la.

Example 3 7 - I(LJ- 2-Methoxyimino-2-(2-(2-aminothiazol-4-ylJacetamido]-5-[(l-20 methyl-1-pyrrolidiniuinjmethy 1]-3-cephem-4-carboxylate (laJ A series of experiments were conducted to determine the effect of solvent, amount of solvent and reaction time on the yield of Compound 7 2 la and the a /a ratio in tne reaction product. The general procedure was as follows: To a suspension of the 3-iodomethyl derivative Vila' (45 mg, 0.048 mmolej in the indicated amount of the indicated solvent was added a solution of N-methylpyrrolidine (0.01 inL, 0.097 mmolej in ether 10.1 mLJ and the mixture was stirred at room temperature for the indicated period. The reaction mixture was diluted with ether (5 inL J and the resulting precipitate was collected by filtration and mixco a 41 with 90* TFA. The mixture was stirred for one hour and evaporated to dryness under reduced pressure below 20°C to give the product. The ratio of a^/&2 in the product was determined by HPLC (Lichrosorb RP-18; mobile phase, 0.01 M ammonium phosphate buffer (pH 7.2) 3 2 containing 15* CH,OH;,retention time, A 6.60 minutes, S.S6 3 2 minutes.). Yield of the product and the ratio of a /a isomers for each experiment are given below.

Ratio of Vila' hxperi-ment No Solvent (in gms.J to Solvent (in mLJ Reaction Time (Min.J Yield UJ Ra1- io a j/a 2 1 Cri2C12 1 73 1/8 2 CH2Cl2-tther tJl/10J 1 100 4/1 3 tthyl acetate tther (1/10J 1 100 27 4/1 4 Ethyl acetate-tther (1/10 J 1 100 60 64 2/1 Ether 1 100 31 6/1 6 Ether 1 100 60 62 3/1 7 tther 1 60 55 3.5/1 8 Ether 1 60 60 82 1/1 Example 4 7-[(Z J -2-hthoxyimino-2-(2-aminothiazol-4-yIJ acetami do]-3-[(l-methyl-l-pyrrolidiniumjmethyl]-3-cephem-4-carboxylate (lbJ 2 5 A. Benzhydryl 3-Chloromethyl-7-[(Zj-2-ethoxyimino-2-(2-tritylamino-thiazul-4-yl)acetamido]-3-cephem-4-carboxylate (VIbJ 42 To a solution of (Z)-2-ethoxyimino-2-(2-tritylamjnothiazol-4-yl1 acetic acid (lVb) (1.095 g, 2.4 mmoles) in dichloroinethane (20 mL) was added phosphorus pentachloride (500 mg). After stirring for 1 hour at room temperature, the mixture was added in one portion to an 5 ice-cooled solution of Compound V (1.083 g, 2.4 mmoles) and BSA (1 mL) in dichloroinethane (20 mL). After stirring for 0.5 hour the reaction mixture was poured into 10* aqueous NaHCOj (200 mL) and extracted with CHClj (100 mL). The extract was washed with water, dried over MgSt>4, and evaporated under reduced pressure.

The residue was chromatographed on a silica gel column. Elution with CHClj gave VIb as an amorphous powder, 1.76 g (86t).

NMK : 6 CUC13 ppm 1.40 (3H, t, Ct-^CHj), 3.53 (2H, ABq, 2-CH2), 4.37 (2H, s, -CH2C1), 4.60 (21), q, -CH2CH3), 4.90 (1H, d, 6-H), 5.89 (1H, d, 7-H), 6.88 (1H, s), thiazole-H), 6.91 (1H, s, benzhydryl- CH. ) tt. Uiphenylmethy1 7-[(2)-2-Ethoxyimino-2-(2-tritylaminothiazol-4-yl) acetamido1 - 3-iodomethy1-3-cephem-4-carboxylate (VI lb) A mixture of VIb (1.07 g, 1.25 mmoles) and Nal (562 mg, 2.75 20 mmoles) in acetone (20 mL) was stirred for 1 hour. The mixture was filtered and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 5* aqueous Na2S2 NMK : 6 CUC13 ppm 3.55 (2H, q, 2-CH2), 4.27 (21), s, CH,-I), .02 (1H, d, 6-H), 5.87 (1H, d, 7-H), 6.68 (1H, s, thiazole ring H), 6.93 (1H, s, benzhydryl-CH).

A 43 C. 7-l(Z)-2-Ethoxyimino-2-(2-aminothiazol-4-yl)acetamidol-3-[(l-methy1-1-pyrrolidiniumJ methyl 1 -3-cephem-4-carboxylate (Ib) A mixture Vllb (333 mg, 0.35 mmole) and N-methylpyrrolidine (CO mg, 0.7 mmole in Cll^Ci^ (5 mL) was stirred for 0.5 hour at room temperature and then evaporated in vacuo. The residue was washed with ether and dissolved in 90* aqueous TFA. After standing for 0.5 hour at room temperature the mixture was concentrated under reduced pressure. Ether was added to the concentrate to separate the quaternized product, which was collected by filtration and dissolved lO in a small amount of methanol. The solution was chromatographed on an HP-2- column (40 mL). Elution with 301 aqueous CH.OH followed by 2 3 lyophi1ization afforded 0.062 g of a mixture of the & and A isomer (a2:a3 » 5:1). The mixture was purified by HPLC (Lichrosorb RP-18, 8 x 300 mm, 15* methanol) and the desired a3 15 isomer (lb) was isolated as pale yellow powder, 4.9 mg (2.7*). uv . phosphate buffer, Ph 7 max NMK 6D2U ppm 1.43 (3H, t), 3.64 (4H, m), 5.95 (1H, d), nm(c ) 235 (15000), 258 (14000). 2.33 (4H, m), 3.10 (3H, s, 4.36 (2H, q), 5.44 (1H, d), 7.08 (1H, s).

Example 5 7-[(Z)-2-(2-PropoxyiminoJ-2-(2-aminothiazol-4-ylJacetamido 1-3-1 time thy 1 -1-pyrrol id iniumjmethyl ]-3-cephem-4-carboxylate (Ic) A. Pi phenylmethyl 3-Chloromethyl-7-[(Z)-2-(2-propoxyimino)-2-(2-tritylaminothiazol-4-ylJacetainido]-3-cephem-4-carboxylate (Vic) 4 A mixture of (Z)-2-(2-propoxyiminoJ-2-(2-tritylamino-thiazol-4-y1J acetic acid (IVcJ (707) mg, 1.5 minoles) and phosphorus pentachloridc (344 mg, 1.65 mmoles} in dichloroinethane (14 mLJ was stirred at room temperature for 1 hour and poured into a solution of Compound V (677 5 mg, 1.5 mmolesj and BSA (1.1 mL, 4.5 ramolesJ in dichloroinethane (15 mLJ. The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 mLJ, and water (3 x 1U0 mLJ, dried over sodium sulfate and evaporated to give 1.4 g (100$) of Compound Vic. ik : vKBrcm"1 3360, 3020, 3060, 2960, 1785, 1725, 1680, 1520, maX 1500, 1450, 1375, 1300, 1250, 1160, 1090, 1060, 1010, 990, 840, 740, 700.

UV : xEt0Hnin(eJ 240 (24600J, 260 (20700J. max NMK : {CUC13 ppm 1.35 (6H, d, J=6HzJ, 3.50 (2H, sJ, 4.35 15 2H, sJ, 4.58 (1H, m, J=6Hz), 5.00 (1H, d, J=4. 5Hz J, 5.91 (1H, d-d, J = 4.S 5 9Hz ; d by U,U, J-4.5HzJ, 6.68 (1H, sJ, 6.88 (1H, s), 7.25 (25H, sJ.

B. Ui phenylmethyl 3-Iodometliyl-7-[(Z) - 2-(2-propoxyiminoJ- 2-(2-20 tritylaminot hiazol-4-ylacetami do]-3-cephem-4-carboxylate (VI1c J A mixture of Compound Vic (500 mg, 0.55 mmole) and sodium iodide (248 mg, 1.66 mmolesj in acetone (10 mLJ was stirred at room temperature for 50 minutes. After evaporation, the residue was dissolved in ethyl acetate (15 mLJ, washed successively with 10* 25 aqueous sodium thiosulfate (10 mL), water (10 mL) and aqueous NaCl (10 mL), dried over sodium sulfate and evaporated to yield 494 ing (90*) of the title compound (Vile). 45 IK : uKBrcm"1 3360, 3040, 3020, 2960, 1785, 1720, 1680, raaX 1600, 1520, 1500, 1450, 1370, 1300, 1230, 1150, 1115, 1080, 990, 900, 840, 750, 700.

UV : atty" nm(c) 240 (24900J, 260 (19400J.

NMR : SCUC13 ppm 1.30 (6H, d, J=6HzJ, 3.37 5 3.70 (1H each, d, J=16Hz J, 4.22 (2H, s), 4.55 (1H, m, J=6HzJ, 4.95 (1H, d, J=4.5HzJ, 5.83 (1H, d-d, J-4.5 $ 9Hz; d by 020), 6.66 (1H, sJ, 6.87 (1H, si, 7.25 (25H, sJ.

C. 7^ [(I J-2-(2-PropoxyiminoJ- 2-(2-aminothiazol-4-ylJ acetami do 1-3-(11-methy1-1-pyrrolidiniumjmethyl]-3-cephem-4-carboxylate (Ic) A mixture of the Compound VIIc (545 mg, 0.55 mmole) and 1-methylpyrrolidine (70 mg, 0,82 mmolej in dichloromethane (10 mLJ was stirred at room temperature for 30 minutes and diluted with ether (100 mLJ. The resulting precipitate was collected by filtration. A solution of the precipitate in 90% TFA (4.5 mLJ was stirred at room temperature for 30 minutes and evaporated i_n vacuo. The residue was triturated with ether to give 317 mg of the crude product, which was chromatographed on an Hl>-20 column (50 mLJ, eluted with water (500 nLJ and 304 CH.OH (500 mLJ. The 30* CH.UH eluate was concentrated and 2 3 lyophilized to yield 109 mg ot a mixture of the A and A isomers (a2/a3 = 6/1J, 100 mg of which was purified by HPLC (Lichrosorb KP-18, 154 MeOHJ to give 5 mg (34J of the desired title Compound Ic.

UV : xP" 7 buffer nm(e) 236 (15100), 252 (14600J. max NMK : «lJ20ppm 1.42 (6H, d, J=6HzJ, 2.33 (4H, sJ, 3.10 (3H, sJ, 3.65 (4H, sJ, 3.83 5 4.23 (1H each, d, J=17!UJ, 5.45 (1H, d, J-4.5HzJ, 5.95 (1H, d, J=4.5HzJ, 7.05 (1H, sJ.

Example 6 7-[(LJ-2-Allyloxyjmino-2-(2-aminothiazol-4-yl)acetamidol-3-[(l-metWl-1-pyrrolidiniumJmethyl]-3-cepliem-4-carboxylate (Id J A. Benzhydryl 7-[(2J-2-Allyloxyimino-2-(2-tritylaminothiazol-4-ylJ acetamidol-3-chloromethy1-3-cephem-4-carboxylate CVId) To a suspension of Compound V (1.35 g, 3 mmolesj in methylene chloride (20 mLJ was added BSA (1.1 mL, 4.5 mmolesj, and the mixture was stirred for 30 minutes at room temperature to become a clear solution. A mixture of lZ)-2-allyloxyimino-2-( 2-tritylaminothiazol-4-ylJacetic acid (IVdJ (1.40 g, 3.0 mmolesj and phosphorus pentachloride (690 mg, 3.3 mmolesj in methylene chloride (20 mLJ was stirred for 15 minutes at room temperature and poured in one portion into the solution of the trimethylsilylated Compound V. The mixture was stirred for 20 minutes at room temperature and diluted with ethyl acetdte (200 mLJ, washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified oy silica gel column chromatography (Wako-gel, C-200, 30 gJ. The column was eluted with chloroform and the fractions containing the desired product were combined. Evaporation under reduced pressure afforded the title compound (VIdJ as an amorphous powder, yield 2.32 g (89t J. Mp. 100-115 °C (dec.J.

IR : vKBrcm"1 3990, 1790, 1730, 1680, 1530, 1380, 1250, max 1160, 1020.

NMK : 5C0C13 ppm 3.50 (2H, 2-HJ, 4.32 (2H, s. 3-CH2J, 4.6- 6.1 (7H, m, CH2CH=CH2 and 6,7-HJ, 6.70 (1H, s, thiazole-HJ, 6.90 (1H, s, Ph2CHJ, 7.1-7.6 (30H, m, phenyl protonsj. 47 Anal. Calc'd. tor C48H40NS05S2C1.1/3CHC13: C, 64.05; H, 4.45; N, 7.73; S, 7.08; CI, 7.82.

Found: C, 64.13, 63.99; H, 4.61, 4.64; N, 7.50, 7.30; S, 6.85, 6.85; CI, 7.55, 7.46.

B. Benzhydryl 7 -[(L)- 2-Allyloxyimino-2 -(tritylaminothiazol) -4-y1J lo acetami do]-3-iodomethyl-3-cephem-4-carboxylate (VI Id) A mixture of Compound VId (2.30 g, 2.65 mmoles) and sodium iodide (2 g, 13.3 mmoles) in acetone (15 mL) was stirred for 1 hour at room temperature and then evaporated under reduced pressure. A solution of the oily residue in ethyl acetate (200 mL) was washed with 10* sodiuir, 15 thiosulfate and water, evaporated under reduced pressure to afford Compound VI Id as an amorphous powder, which was used in the next step without further purification. Yield 2.52 g (99t).

C. 7-l(Zj-2-Allyloxyimino-2-t2-aniinothiazol-4-yl)acetamidol-3-[(l-methyl-1-pyrrolidinium)methy1]-3-cephem-4-carboxylate (Id) 2o A mixture of Compound VI Id (478 mg, 0.5 mmole) and N-methyl pyrrolidine (0.05 mL, 0.5 mmole) in methylene chloride (5 mL) was stirred for 20 minutes at room temperature and diluted with ether (50 mL) to precipitate the quaternized product (yield 500 mg). A mixture of the quaternized product and TFA (2 mL) was allowed to stand at room temperature for 1.5 hours and diluted with ether to precipitate the crude TFa salt of the product (yield 265 mg), which was chromatographed on a column of HP-20 (1.8 x 18 cm). The column was eluted with water and 30* aqueous methanol. The methanolic eluate was evaporated under reduced pressure and the residue was freeze-dried to give an amorphous powder (yield 124 ing), which contained the desired 48 product (174) and the corresponding a 2 isomer (83*). The mixture was purified by HPLC (Lichrosorb KP-18; 0.01M NH^I^PU^ (pH 7) :CHjOH=85:15). The eluate was acidified to pH 3 with dilute HCl and chromatographed on a column of HP-20 (1.8 x 10 cm). The column was eluted with water and then with 30* aqueous methanol. The methanolic eluate was evaporated under reduced pressure and the residue was freeze-dried to afford the title compound (Id) as an amorphous powder (yield 13 mg, 5.1*). Mp. 155°C (dec).

IK : vKBr cm"1 3600-2800, 1770, 1670, 1610, 1530, 1200.

UV : aPH 7 buf£er nmU) 235 (16600), 253 (15600). max NMK 4^20 ppm 2.1-2.5 (4H, m, pyrrolidine-H), 3-10 (3H, s, iMCHj), 3.4-3.8 (4H, m, pyrrolidine-H), 5.95 (1H, d, 4Hz, ~-H), 7.10 (1H, s, thiazole-H).

Example 7 7-[2-(2-Aminothiazol-4-y1)-(Lj-2-(2-carboxyprop-2-oxyimino)- acetamido 1 - 3-K1-methy1-1- pyrrol idinium)methyl 1-3-cephem-4-carboxylate (Ie) A. benzhydryl 3-Chloroinethy1-7-[(I)-2-(2-t-butoxycarbonylprop-2-oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (Va) b Procedure 1 49 A mixture of (1)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-( 2-tritylaminothiuzol-4-yl)acetic acid (Ilia') (1.94 g, 3.6 mmolesj UDC (742 mg, 3.6 mmoles) and N-hydroxybenztriazole (486 mg, 3.6 minoles) in 5 tetrahydrofuran (THF) (45 mL) was stirred at room temperature for 45 minutes, during which dicyclohexylurea separated. The dicyclohexylurea was removed by filtration and the filtrate was mixed with V (1.5 g, 3.6 mmoles). The mixture was stirred overnight at room temperature and then evaporated in vacuo. The residual oil was lO dissolved in CHCl^ (20 inL), washed with saturated aqueous NaHCO^ and saturated aqueous NaCl, dried over MgS04 and evaporated to dryness. The residue (3.9 g) was dissolved in n-hexane:CHClj (1:2) and passed through a silica gel column (40 g) using the same solvent system. Fractions containing the title compound were evaporated j_n 15 vacuo to give 1.3 g (39%) of Va melting at >100"C (dec.).

IK : vKBr cm"1 3990, 1790, 1715, 1690.

UV : xtt0H 240 IE1* 280), 265 (E1* 190). max 1 cm 1 cm NMK : «CUC13 ppm 1.45 (9H, s), 1.63 5 1.66 (6H, each s), 3.49 (2H, broad s), 4.34 (2H, s), 4.96 (1H, d, 20 J=4.5Hz), 5.90 (lri, d-d, J=4.5 5 7.5), 6.66 (1H, s), 6.86 (1H, s), 7.0-7.5 (25H, m), 8.23 (1H, d, J-7.5HZ).

Procedure 2 A solution of V (1.86 g, 4.49 mmoles) in CH.CN (46.5 mL) was 25 treated with BSA (3.33 mL, 13.5 mmoles) at room temperature for 50 minutes to give a clear solution. To the solution was added an acid 50 chloride solution which had been prepared from Ilia' (2.56 g, 4.49 mmolesj and PCl^ (1.12 g, 5.38 mmolesj in methylene chloride (26 mLJ. The mixture was stirred at room temperature for 30 minutes, poured into cold water (100 mLJ and extracted with ethyl acetate (3 x 5 50 mLJ. The combined extracts were washed with aqueous NaCl, dried and evaporated. The residual syrup (5 gj was chromatographcd on a silica gel (100 g) column by eluting with 10:1 mixture of toluene and ethyl acetate. The fractions containing the desired compound were combined and evaporated to afford 2.84 g (65%) of Va. lO u. Benzhydryl 7-[(2)-2-(2-t-Butoxycarbonylprop-l-oxyimino)-2-(2-tritylaminothiazol-4-y1Jacetamidol-3-iodomethyl-3-cephem-4-carboxylate (VlaJ A mixture of Va (500 mg, 0.53 mmolej and Nal (240 mg, 1.6 mmoles) in acetone (3 mLJ was stirred for 2 hours at room temperature and then 15 evaporated m vacuo. To the residue were added Ch^Cl^ (20 mL) and water (10 mL). The organic layer was washed with 10% s/v sodium thiosulfate (5 mL) and aqueous NaCl (5 mL), dried over MgSO^ and evaporated to dryness to give 540 ing (90%) of Via as an amorphous powder melting at 106°C (dec.).

IK : „KBr cm*1 3350' 1790' 169°* UV xEtUH nm 240 (E1* 270), 265 (EU 190). max 1 cm 1 cm NMK : 6CUC13 ppm 1.44 (9H, sJ, 1.65 (6H, s), 3.54 (1H, 4.28 (2H, s), 4.98 (1H, d, J=4.5Hz), 5.85 (1H, d-d, J=4.5 § 7.5Hz), 6.70 (1H, s), 6.90 (1H, s), 7.1-7.5 (25H, m).

A 51 C. 7-I 2-(2-Aminothiazol-4-ylJ-(l.J-2-(2-carboxyprop-2-oxyimino J -acutainido]-3-[(l-niethyI-l-pyrrolidiniumJmethyl]-3-cephem-4-carboxylatc (IeJ A mixture of the iodomethyl derivative Via (S38 mg, 0.51 mmole) 5 and N-methylpyrrolidine (0.079 mL, 0.076 mmolej in CH^C^ (10.8 mLJ was allowed to stand at room temperature for 30 minutes and then diluted with ether (80 mLJ. The precipitate which formed was collected by filtration and washed with ether to give 420 mg of the quaternized product (Ih) which was deblocked with 90'.*. trif luoroacetic 10 acid (TFAJ (4.2 mLJ at room temperature for 1 hour. The reaction mixture was then evaporated to dryness. To the residue was added either to give crude TFA salt of la (245 mg, quantitativeJ, which »as a 1:4 mixture of the ^ and A2 isomers. The crude was subjected to HPLC purification [Lichrosorb RP-18, 4 x 300 mm, eluted with 0.01 M 15 ammonium phosphate buffer (pH 7.0J containing 10* CHjUH]. The fraction containing the desired product was collected and evaporated to a small volume. The concentrate was adjusted to pH ca. 2 by adding 1 M HCl and passed througn an liP-20 column (2 x 15 cmj to remove the inorganic salt. The column was washed with H^O (1000 mLJ and eluted 20 with 30* CHjUH. The eluant was evaporated and lyophilized to afford 21 mg (10*J of the title product (IeJ as a colorless powder. Mp. 160°C (dec.J.

IK : vKBr cm"1 3400, 1775, 1610. max uv phosphate buffer. pH 7 nm(E j 237 (15700J, 257 (155500J. max NMK : sD2° ppm l.b5 (6H, sJ, 2.3 (4H, mj, 3.09 (5H, sJ, 3.6 (4H, mj, 4.0 (2H, mj, 5.44 (1H, d, J-4.8Hz), 5.94 (1H, dj, 7.15 (1H, sJ.

A 4 52 Example 8 The general procedure of Example 7 is followed except that the (I)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-C2-tritylaminothiazol-4-yl) acetic acid is replaced by an equimolar amount of (Z)-2-(t-butoxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-ylJacetic acid, t (Z)- 2-11-t-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl) acetic acid, 4 (Z J - 2-(2-t-butoxycarbony1but-2-oxyiminoJ-2-(2-tritylaminothiazo1-4-y1-lO acetic acid, IL)-2-(3-t-butoxycarbonylpent-3-oxyiminoJ-1-(2-tritylaminothiazol-4-yl) acetic acid, (Z J - 2 -11-1-butoxycarbonylcycloprop-l-oxyiminoJ-2-(2-tritylaminothiazol-4-yl)acetic acid, (Z)- 2 -(1-t-butoxycarbonyIcyclobut-1-oxyimino)-2-(2-tritylaminothia:ol--;-yljacetic acid and (Z) - 2-(1-t-butoxycarbonylcyclopent-1-oxyimino)- 2-(2-tritylaminothiaiol-1 -yljacetic acid, respectively, and there is thereby produced 7-[2-(2-aminothiazol-4-ylJ-(ZJ-2-(carboxymethoxyimino)acetamido1-3-111-methyl-1-pyrrolidinium)methylJ-3-cephem-4-carboxylate, 7-[2-(2-aminothiazol-4-ylJ-(ZJ-2-(l-carboxyethoxyiinino)acetamido ] - 3-[ (1-inethy 1-1-pyrrol id in iunijmet hy 1 ] - 3-cephem-4 - carboxylate, A 53 7-l2-(2-aminothiazol-4-yl)-(Z)-2-(2-carboxybut-2-oxyiminoJ -acetamido]-3-I(1-methyl-1-pyrrolidiniumjmethyl]-3-cephera-4-carboxylate, 7-l2-(2-aminothiazol-4-yl.)-{Z)-2-( 3-carboxypent- 3- oxy imi no J - acet limit- - J -3-1 (1 - mot Ity 1- 1 -py rrol idi niuin J methyl ] - 3- ccphum- 4 -carboxylate, 7-12-(2-ami nothiazol-4-y1J-IZJ-2-(1-carboxyeyeloprop-1-oxyimino J -ace-tami do J-3-[(1-methyl-1-pyrrolidiniumjmethyl]-3-cephem-4-carboxylate, 7-l2-(2-aminothiazol-4-ylJ-lZJ-2-(1-carboxycyclobut-1-oxyiminoJ ace-tamidoJ--3-l(1-methyl-1-pyrrolidiniumjmethy1]-3-cephem-4-carboxylate and 7-12-I 2-ami nothi azol-4-ylJ -(ZJ - 2-(1-carboxycyclopent-1-oxyimi no) acetamido J-3-[(1-methyl-l-pyrrolidinium)methyl]-3-cephem-4-car boxy-late, respectively.

In the claims which follow (cf. Claim 21), as also in the foregoing description (cf. Procedure 1), "DCC" is to be understood as 15 standing for "dicyclohexylcarbodiimide", as indicated in the foregoing Reaction Scheme 3. 54

Claims

1. A compound of the formula „ j 51;1 - s v 2y wherein K1 is hydrogen or a conventional amino-protecting group, and 7 R is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl or is a group RJ—C—R* I COOH wherein R^ and R4 each are independently hydrogen, methyl or 3 4 ethyl, or R and R , taken together with the carbon atom to which 10 they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable esters or solvate thereof.

2. The compound of Claim 1 which is 7-[(Z)-2-methoxyimino-2-(2 - amiro-thiazol-4-ylJacetamidoJ-3-[ll-methyl-l-pyrrolidiniuinJ-methyl]-3-cephem- 15 4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof.

3. The compound of Claim 1 which is 7-[(Z)-2-ethoxyimino-2-(2-amino-thiazol-4-ylJacetamido]-3-(1-methy 1-1-pyrrolidinium)-methyl]-3-ceptiem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate 20 thereof. i* i 55

4. The compound of Claim 1 which is 7-[(L)-2-(2-propoxyiminoJ-2-(2-aininothiazol-4-ylacetamido]-3-(1-methyl-1-pyrrolidinium)methyl]- 3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof.

5. S. The compound of Claim 1 which is 7-[(Z)-2-Allyloxyimino-2-(2-aminothiazol-4-ylJacetamido]-3-(l-methyl-l-pyrrolidiniumJmethyl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof.

6. Medication comprising an antibacterially effective amount of lO at least one compound of Claim 1, for use in a method of combatting bacterial infection in a warm-blooded animal.

7. Medication comprising an antibacterially effective amount of 7- [

8. An antibacterial composition comprising an antibacterially effective amount of at least one compound of Claim 1 and an inert pharmaceutical carrier. 20 y.

9. The composition of Claim 8 wherein the compound of Claim 1 is 7-[(Z J-2-inethoxyimino-2-(2-aminothiazol-4-yl)-acetamido J-5-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt or solvate thereof.

10. An antibacterial composition in unit dosage form comprising from 25 about 50 mg to lbOO mg of at least one compound of Claim 1 and an inert pharmaceutical carrier. i. %

11. The composition of Claim 10, wherein the compound of Claim 1 is 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-[(1-methyl-l-pyrrolldinium)methyl-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt 5 or solvate thereof.

12. The compound of Claim 1 which is 7-[2-(2-aminothiazol- 4-yl)-(Z)-2-(carboxyprop-2-oxyimino)acetamido]-3-[(1-methyl- 1 1-pyrrolidinium) methyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable 10 ester or solvate thereof. "

13. Medication comprising an antibacterially effective amount of at least one compound of claim 1, wherein R1 3 4 is as defined in Claim 1 and R and R each are independently 3 4 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 or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, for use in a method of combatting Gram-negative bacterial infection in a warm-blooded animal.

14. Medication comprising an antibacterially effective amount of 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(2-carboxyprop- 2-oxyimino)-acetamido]-3-[(1-methyl-l-pyrrolidinium)methyl]- 3-cephem-4-carboxylate or a nontoxic pharmaceutically 25 acceptable salt, physiologically hydrolyzable ester or solvate thereof, for use in a method of combatting Gram-negative bacterial infection in a warm-blooded

15. An antibacterial composition active against Gram-negative bacteria comprising an antibacterially effective amount of at least one compound of Claim 1 wherein R1 is as defined 3 4 in Claim 1 and R and R each are Independently hydrogen, 3 4 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 or a nontoxic r pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof and an inert pharmaceutical carrier. A 15 20 30 35 1ST

16. The composition of Claim IS wherein the compound of Claim 1 is 7-[2-(2-aminothiazol-4-yl}-(Z)-2-(2-carboxyprop-2-oxyimino)acetainidol-3-[(l-methyl-3-[(1-methyl-.l-pyrrol idiniumJmethyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt, physiologically 5 hydrolyzable ester or solvate thereof.

17. An antibacterial composition active against Gram-negative bacteria in unit dosage form comprising from 50 mg to 1500 mg of at least one compound of Claim 1 wherein K* is as defined in claim 1 and k^ and each are independently hydrogen, methyl or 3 4 lo ethyl, or k 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 or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof and an inert pharmaceutical carrier. 15

18. The composition of Claim 17 wherein the compound of Claim 1 is 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(2 -carboxyprop-2-oxyimino}acetamido ] -3-I (1-methyl-1-pyrrolidiniumjmethyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. 20

19. A process for the preparation of compounds of the formula coc^ <4 wherein k1 is hydrogen or a conventional amino-protecting group, and R2 is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3- butenyl, or is a group 25 R3—C—R^ I cooh k. 33 3 4 wherein K and K each are independently hydrogen, methyl or ethyl, or and R4, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable esters or solvate thereof, which comprises acylating a compound of the formula xvi or an N-silyl derivative thereof, in which B1 is hydrogen or a 10 conventional-protecting group, with an acylating derivative of an acid of the formulae n r— . £>K- B HN XS OR' c-cooii 2 cooh XVII or 2 / \ B^HN nO -|:-r4 COOB3 XVIIa 2 3 wherein B is a conventional amino-protecting group, B is a conventional carboxyl-protecting group and R^ and R4 are as defined above, to produce a compound of the formulae 15 coob1 ^ XV or coob1 /h, ^ p 3"h coobj XVa ss and subsequently removing all protecting group.

20. A process for the preparation of compounds of the formula N r— \or2 o .a- NH-t—r 1 CO(P yVJ CH, wherein K is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group lO R3- -C I COOH A 3 4 wherein K and K each are independently hydrogen, methyl or 3 4 ethyl, or K and K , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof, which process comprises reacting a compound of the formulae B2HN //" Wfi u I- \>R2 XIV COOB -NH- S" ? & R 4 3 XlVa H2* COOB COOB"1 © 0 wherein K2, and k'® are as defined above, B* and are conventional carboxyl-protecting groups, B2 is a conventional ainino-protecting group, with N-raethylpyrrolidine to produce a compound of the formulae 2 b h or l cW XV b2h & ^ h,-n VvJ XVa CH3 and subsequently removing all protecting groups by conventional means.

21. The process of claim 19 or 20, for the preparation of 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(2-carboxyprop-2-oxyimino)-acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (Ie) or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, which comprises reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate, (Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2(2-tritylaminothiazol-4-yl) acetic acid, DCC, N-hydroxybenztriazole in an organic solvent to give benzhydryl 3-chloromethyl- 7-[C Z)-2-(2-t-butoxycarbony1prop-2 -oxyimino)-2-(2-tritylami nothiazol-4-yl)acetamidoJ-3-cephem-4-carboxylate (If) or alternatively reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate and bis(trimethylsilylj acetamide with an acid chloride of (Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid to give (If), then reacting (If) with iodide salt to give benzhydryl 7-[(Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylami nothiazol-4-yl) Si acetamido]-j-iodanctliyl-3-cephem-4-carboxylate (Via), then further reacting (Via) with N-mcthylpyrrolidine in an organic solvent to give a quaternized product (Ih), and finally deblocking CIhJ to give the title compound (Ie), melting at 160°C (decj and/or if desired optionally converting (IeJ to 5 its nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof.

22. The process of claim 19 or 20, for the preparation of compounds of the formula allyl, or a nontoxic pharmaceutically acceptable salt or solvate thereof, which comprises reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate and bis(trimethyl-silylJ acetamide with an acid chloride of (Z)-2-methoxyimino-2-(2-15 tritylaminothiazol-4-ylJ acetic acid or (Z)-2-ethoxyimino-2-(2-tritylamino-thiazol-4-yl) acetic acid or (ZJ-2-(2-propoxyimino)-2-(2-tritylamino-thiazol-4-ylJacetic acid or (Z)-2-allyloxyimino-2-(2-tritylaminothiazol-4-ylJ acetic acid to give the corresponding condensed derivative containing 2-methoxyimino or 2-ethoxyimino or 20 2-propoxyimino or 2-allyloxyimino group, then reacting said condensed derivative with iodide salt to give the corresponding 3-iodomethyl derivative, then further reacting said 3-iodomethyl derivative with N-inethyl-pyrrolidine in an organic solvent or a mixture of organic solvents to give the corresponding pyrrolidinium derivative and 25 finally deblocking said pyrrolidinium derivative to give -7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-ylJacetamido]-3-[(1-methy 1-1-pyrrolidinium)-methyl]-3-cephem-4-carboxylate, or 7-[(Z)-2-ethoxyimino -2-1 2-aminothiazol-4-yl)acetamidoJ-3-[(1-methyl-1-pyrrolidiniuin)-methvl| * t 62 -3-cephem-4-carboxylate, or 7-[(Z)-2-(2-propoxyiminoJ-2-{2-aminothiazol -4-ylJacetainido]-3-{l-methyl-l-pyrrolidiniumjmethyl]-3-cephem-«-carboxylate, or 7-[(Z)-2-allyloxyimino-2-(2-aminothiazol-4-yl) acetamido]-3-I(l-methyl-l-pyrrolidiniumJmethyl]-3-cephem-4-carboxylate, 5 and/or if desired converting said deblocked derivatives to nontoxic pharmaceutically acceptable salt or solvate thereof.

23. A method of combating bacterial infection in a warm-blooded, non-human animal in need of such treatment comprising administering 4 to said animal an antibacterially effective amount of at least one 10 compound according to any one of Claims 1 to 5.

24. A process according to Claim 19 or 20, substantially as ' described in any of the foregoing Examples 1 to 8.

25. A compound according to Claim 1, whenever prepared by a process as claimed in any one of Claims 19 to 22 or 24. 15

26. Use of an antibacterially effective amount of at least one compound according to any one of Claims 1 to 5 in a method of combating bacterial infection in warm-blooded, human or non-human animal. F. R. KELLY & CO. AGENTS FOR THE APPLICANTS * J /