CEPHALOSPORIN DERIVATIVES, A PROCESS FOR THE MANUFACTURE THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAID DERIVATIVES

Abstract: Compounds of the formula wherein R¹ is hydrogen or a conventional amino-protecting group, R² is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms: allyl, 2-butenyl, 3-butenyl or a group of the formula in which R³ and R⁴ each are independently hydrogen, methyl or ethyl, or R³ 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 R⁵ is hydrogen, amino, (lower)-alkyl, (lower)alkoxy or (lower)alkylthio, and nontoxic pharmaceutically acceptable acid addition salts, physiologically hydrolyzable esters and solvates thereof, as well as processes for their preparation, are disclosed. The compounds in which R¹ is hydrogen are potent antibacterial agents.

Description: Cephalosporin derivatives a a process for the manufacture thereof and pharmaceutical compositions containing said derivatives Summary of the Invention This invention relates to novel cephalosporin derivatives of the formula EMI1.1 wherein R is hydrogen or a conventional amino-protecting group, R2 is a straight or branched chain alkyl group containing from 1 to 4 carbon atorns, allyl, 2-butenyl, 3-butenyl or a group of the formula EMI1.2 in which R3 and RA each are independently hydrogen, methyl or ethyl,. or R3 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 Rs is hydrogen, amino, (lower)- alkyl, (lower) alkoxy or (lower) alkylthio, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof. Processes for their preparation also are described. Description of the Prior Art U.K. Patent Specification No. 1,399,086 contains a generic disclosure encompassing a vast number of cephalosporins of the formula EMI2.1 wherein R is hydrogen or an organic group, Ra is an etherifying monovalent organic group linked to the oxygen through a carbon atom, B is zS or / S+O, and P is an organic group. However, the 2-aminothiazol-4-yl group is not identified as a possible R substituent. Although P may be the group -CH2Y in which Y may be the residue of a nitrogen-containing heterocycle, only pyridinium and 4-carbamoylpyridinium are exemplified, and there is no suggestion that Y may be the 5-thiazolo[4,5-c]pyridinio moiety. U.S. Patent 3,971,778 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 number of cephalosporin derivatives of the formula EMI2.2 in which the variables R1, R2, R3, R41 X and A include generic definitions of the corresponding substituents of the compounds of Formula I claimed herein. Substituent A may be the group -CH2Y in which Y may be the residue of a nucleophilic group (the only heterocyclic rings disclosed for Y are pyridinium, quinolinium and isoquinolinium). In the 20 columns of defined tions of the various substituent groups, the 78 page long table of structural formulae and the 225 examples, there is no disclosure that A may be the 5-thiazolo[4,5-c]pyridinio moiety. United Kingdom Patent Specification No. 1,604,971 is concordant thereto and has a substantially identical disclosure. Published United Kingdom Patent Application NO. 2,028,305 A, although apparently not formally related, contains the same broad generic disclosure but exemplifies A only as hydrogen. U.S. Patent No. 4,278,671 discloses 7-[2-(2-amino- thiazol-4-yl)-2-(syn)-methoxyiminoacetamido] cephalosporin derivatives of the formula EMI3.1 in which R2NH is an optionally protected amino group and R3 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 R "may alternatively be a quaternary ammonium group Only pyridinium, variously substituted pyridinium, quinolinium, picolinium and lutidinium are disclosed as possible quaternary ammonium groups. There is no suggestion that the quaternary ammonium group may be the 5thiazolo[4,5-c]pyridinio moiety. Uaited Kingdom Patent Specification No. 1,581,854 is concordant thereto and has a substantially identical disclosure. Other 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, 4,298,606 and United Kingdom Patent Specification No. 1,536,281. Complete Disclosure This invention relates to novel cephalosporin derivatives of the formula EMI4.1 wherein 1 is hydrogen or a conventional amino-protecting group, 2. R2 is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl, 3-butenyl or a group of the formula EMI4.2 in which R3 and R4 each are independently hydrogen, methyl or 3 ethyl, or R3 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 R5 is hydrogen, amino, (lower)alkyl, (lower) alkoxy or (lower) alkylthio, and nontoxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof, as well as processes for their preparation. 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 2iminothiazolin-4-yl form of the 2-aminothiazol-4-yl moiety. As shown in the structural formula, the compounds of 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 I are "syn" isomers which are essentially free of the corresponding anti" isomers. The nontoxic pharmaceutically acceptable acid addition salts of the compounds of Formula I include, for example, the salts with hydrochloric, hydrobromic, formic, nitric, sulfuric, niethanesulfonic, phosphoric, acetic and trifluoroacetic acids, and other acids which have been used in the penicillin and cephalosporin art. The compounds of Formula I in which R1 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 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 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, pyrogenofree 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. When provided in unit dosage forms the compositions will preferably contain from about 50 to about 1500 mg 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 disease, and is within the discretion of the physician However, the dosage for adult human treatment will usually be in the range of from about 500 to about 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 from about 750 to about 3000 mg per day, in divided 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 R1 is hydrogen, R2 is methyl, ethyl or a group of the formula EMI6.1 in which R3 and R4 each are methyl, or R3 and R4, taken together with the carbon atom to which they are attached, are cyclopropylidene or cyclobutylidene, and R5 is hydrogen or amino. Particularly preferred compounds are those in which RÚ is hydrogen, Rê is methyl, ethyl, 2-carboxyprop-2-oxyimino or l-carboxycyclobut-l-oxyimino, and R5 is hydrogen, methyl or amino. The most preferred compounds of the invention are 1) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-{(5thiazolo[4,5-c]pyridinin)methyl}-3-cephem-4-carboxylate, 2) 7-[ (Z)-2- (2-aminothiazol-4-yl)-2- (2-carboxyprop-2-oxyimino)- acetamido]-3-{(5-thiazolo[4,5-c]pyridinio)methyl}-3-cephem-4carboxylate, 3) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-{(5thiazolo[4,5-c]pyridinio)methyl}-3-cephem-4-carboxylate, 4) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]-3-{(5-thiazolo[4,5-c]pyridinio)methyl}-3 cephem-4-carboxylate, 5) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido}-3 [{5-(2-aminothiazolo[4,5-c]pyridinio)}methyl]-3-cephem-4 carboxylate and 6) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3 [{5-(2-methylthiazolo[4,5-c]pyridinico)}methyl-3-cephem-4 carboxylate. In the primary evaluation of compounds of this invention, the Minimum Inhibitory Concentrations (MIC'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 determined in these tests are shown in Table le Table 1 EMI8.1 <SEP> Geometric <SEP> Mean <SEP> of <SEP> MIC <SEP> (mcq/mL) <tb> Compound <SEP> of <SEP> (G+)-Ia <SEP> (G+)-Ib <SEP> (G+)-Ia <SEP> (G-)-Ib <SEP> (G-)-II <SEP> (G-)-III <tb> Example <SEP> (5 <SEP> strains) <SEP> (5) <SEP> (5) <SEP> (6) <SEP> (5) <SEP> (6) <tb> 1 <SEP> = <SEP> (Ia) <SEP> 0.53 <SEP> 1.2 <SEP> 0.025 <SEP> 0.20 <SEP> 0.40 <SEP> 3.2 <tb> 3 <SEP> = <SEP> (Ib) <SEP> 0.53 <SEP> 1.2 <SEP> 0.044 <SEP> 0.28 <SEP> 0.69 <SEP> 3.2 <tb> 4 <SEP> = <SEP> (Ic) <SEP> 0.46 <SEP> 0.00 <SEP> 0.076 <SEP> 0.63 <SEP> 1.6 <SEP> 5.6 <tb> 5 <SEP> = <SEP> (Id) <SEP> 5.5 <SEP> 11 <SEP> 0.050 <SEP> 0.89 <SEP> 2.4 <SEP> 1.8 <tb> 7 <SEP> = <SEP> (Ie) <SEP> 3.1 <SEP> 6.1 <SEP> 0.033 <SEP> 0.71 <SEP> 1.4 <SEP> 1.8 <tb> 8 <SEP> = <SEP> (If) <SEP> 0.53 <SEP> 1.2 <SEP> 0.017 <SEP> 0.16 <SEP> 0.6 <SEP> 3.2 <tb> 9 <SEP> = <SEP> (Ig) <SEP> 2.7 <SEP> 6.3 <SEP> 0.038 <SEP> 0.79 <SEP> 2.4 <SEP> 2.5 <tb> 10 <SEP> = <SEP> (Ih) <SEP> 0.53 <SEP> 1.2 <SEP> 0.011 <SEP> 0.089 <SEP> 0.46 <SEP> 3.5 <tb> 11 <SEP> = <SEP> (Ii) <SEP> 0.46 <SEP> 0.4 <SEP> 0.05 <SEP> 0.25 <SEP> 1.0 <SEP> 11 <tb> 12 <SEP> = <SEP> (Ij) <SEP> 1.2 <SEP> 1.6 <SEP> 0.066 <SEP> 0.56 <SEP> 1.4 <SEP> 10 <tb> (G+)-Ia : Penicillin-sensitive S. uareus (5 strains) (G+)-Ib : Penicillin-resistant S. aureus (5 etrains) (G-)-Ia : Cephalothin-sensitive E. coli (2 strains), Kl. pneumoniae (1 strain) and Pr. mirabilis (2 strains) (G-)-Ib : Cephalothin-resistant E. coli (3 strains) and Kl. pneumoniae (3 strains) (G-)-II : M. morganii (1 strain), Ent. cloacae (2 strains) and Ser. marcescens (2 strains) (G-)-III : Ps. aeruginosa (6 strains) The absorption of some of the preferred compounds were determined in mice following a single intramuscular injection of the test compound (dissolved in 0.1M 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 Nutrient Agar (pH 606) using E. coli Ess-22-31 as the test organism. The blood levels at various time intervals, the half-life values (t1/2) and the areas under the curve (AUC) are shown in Table 2. Table 2 Mouse Blood Levels EMI9.1 <tb> <SEP> Mouse <SEP> Blood <SEP> Level <SEP> (mcg/mL) <SEP> AUC <tb> <SEP> Minutes <SEP> After <SEP> Administration <SEP> T <SEP> 1/2 <SEP> (mcg* <tb> Compound <SEP> 10 <SEP> 20 <SEP> 30 <SEP> 40 <SEP> 50 <SEP> 60 <SEP> 90 <SEP> 120 <SEP> (min) <SEP> hr/ml) <tb> <SEP> Ia <SEP> 20 <SEP> 15 <SEP> 11 <SEP> 8.6 <SEP> 6.9 <SEP> 6.5 <SEP> 3.1 <SEP> 2.1 <SEP> 35 <SEP> 15 <tb> <SEP> Ib <SEP> 15 <SEP> 12 <SEP> 8.4 <SEP> 6.1 <SEP> 3.8 <SEP> 0.92 <SEP> 0.68 <SEP> 0.43 <SEP> 19 <SEP> 8.4 <tb> <SEP> Ic <SEP> 18 <SEP> 14 <SEP> 10 <SEP> 8.2 <SEP> 5.8 <SEP> 3.6 <SEP> 1.9 <SEP> 1.3 <SEP> 28 <SEP> 12 <tb> <SEP> Id <SEP> 16 <SEP> 14 <SEP> 11 <SEP> 6.1 <SEP> 3.9 <SEP> 2.5 <SEP> 0.72 <SEP> < 0.2 <SEP> 16 <SEP> 9.5 <tb> <SEP> Ie <SEP> 13 <SEP> 12 <SEP> 7.5 <SEP> 4.3 <SEP> 3.0 <SEP> 2.6 <SEP> 0.51 <SEP> 0.15 <SEP> 16 <SEP> 7.9 <tb> <SEP> If <SEP> 14 <SEP> 14 <SEP> 7.6 <SEP> 7.0 <SEP> 4.4 <SEP> 3.9 <SEP> 2.9 <SEP> 1.0 <SEP> 29 <SEP> 11 <tb> <SEP> Ig <SEP> 20 <SEP> 15 <SEP> 8.2 <SEP> 7.2 <SEP> 2.6 <SEP> 1.9 <SEP> 0.78 <SEP> 0.24 <SEP> 17 <SEP> 9.9 <tb> <SEP> Ih <SEP> 16 <SEP> 10 <SEP> 6.9 <SEP> 5.9 <SEP> 4.1 <SEP> 3.0 <SEP> 0.79 <SEP> 0.13 <SEP> 16 <SEP> 8.6 <tb> <SEP> Ii <SEP> 14 <SEP> 10 <SEP> 5.9 <SEP> 4.8 <SEP> 2.4 <SEP> 1.5 <SEP> 0.25 <SEP> < 0.1 <SEP> 13 <SEP> 6.8 <tb> The in vitro activity of some of the preferred compounds against 30 strains of fastidious bacteria was determined by the two-fold serial agar dilution method in Gonococcus agar (GC agar), and the results are shown in Table 3. Table 3 In Vitro Activity of Preferred Compounds Against Fastidious Bacteria EMI10.1 <tb> <SEP> Geometric <SEP> Mean <SEP> of <SEP> MIC <tb> <SEP> Test <SEP> Organism <SEP> (mcg/mL) <tb> <SEP> Ia <SEP> Id <SEP> le <SEP> <tb> S. <SEP> pyogenes <SEP> (5 <SEP> strains) <SEP> 0.0125 <SEP> 0.20 <SEP> 0.20 <SEP> <tb> S. <SEP> pneumoniae <SEP> (5) <SEP> 0.0125 <SEP> 0.20 <SEP> 0.20 <tb> N. <SEP> gonorrhoeae <SEP> (5) <SEP> 0.0125 <SEP> 0.10 <SEP> 0.10 <tb> N. <SEP> meningitidis <SEP> (5) <SEP> 0.0125 <SEP> 0.10 <SEP> 0.10 <tb> B. <SEP> influenzae <SEP> (7) <SEP> 0.0125 <SEP> 0.10 <SEP> 0.10 <SEP> <tb> <SEP> (ampicillin <SEP> sensitive) <tb> H. <SEP> influenzae <SEP> (3) <SEP> 0.0125 <SEP> 0.10 <SEP> 0.10 <tb> <SEP> (ampicillin <SEP> resistant) <tb> The median protective dose (PD50) of some of the preferred compounds against various microorganisms was determined in mice by intramuscular administration of the test compound immediately after an intraperitoneal bacterial challenge. The results are shown in Table 4. Table 4 In Vivo Activity EMI11.1 <tb> <SEP> PD50 <SEP> (mg/kg, <SEP> im) <tb> <SEP> Compound <tb> Microorganism <SEP> Ia <SEP> Ic <SEP> Id <SEP> Ie <SEP> If <tb> S. <SEP> aureus <SEP> Smith <SEP> 0.45 <SEP> 1.1 <SEP> 7.2 <SEP> 3.1 <SEP> 0.62 <tb> S. <SEP> aureus <SEP> BX-1633 <SEP> 0.75 <SEP> - <SEP> 21 <SEP> - <SEP> <tb> E. <SEP> coli <SEP> Juhl <SEP> 0.012 <SEP> 0.048 <SEP> 0.082 <SEP> 0.08 <SEP> 0.015 <tb> P. <SEP> aeruginosa <SEP> A9843 <SEP> 7.2 <SEP> 8.5 <SEP> 4.3 <SEP> 1.8 <SEP> 2 <tb> P. <SEP> aeruginosa <SEP> A21509 <SEP> 6.25 <SEP> - <SEP> 5.0 <SEP> - <SEP> <tb> S. <SEP> pyogenes <SEP> A20201 <SEP> - <SEP> - <SEP> 0.23 <SEP> - <SEP> In another aspect, this invention relates to processes for the preparation of the compounds of Formula I. There are two basic procedures for converting a readily available starting cephalosporin to another cephalosporin having different substituents on the 7- and 3-positions. One may first remove the 7-substituent and replace it with the desired 7-substituent, and then insert the desired 3-substituent. Alternatively, one may first insert the desired 3-substituent and subsequently exchange the 7-substituent. The compounds of Formula I nay be prepared by either procedure and both are included within the scope of this invention, but it is preferred to insert the desired 7-substituent first and then insert the desired 3substituent. The preferred procedure is shown below in Reaction Scheme 1 while the alternative procedure is shown ia Reaction Scheme 2. In each reaction scheme, n nay be 0 or 1. The abbreviation "Tr" represents the trityl (triphenylmethyl) group, which is a preferred amino-protecting group. The abbreviation "Ph" represents the phenyl group. Thus, the -CH(Ph), moiety is the benzhydryl group, which is a preferred carboxyl-protecting group. Reaction Scheme 1 EMI12.1 EMI13.1 Reaction Scheme 2 EMI14.1 EMI14.2 EMI15.1 EMI16.1 Although the above Reaction Schemes show preferred rnulti-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 Reaction Scheme. Thus, the key step in Reaction Scheme 1 is the reaction of Compound VII with the thiazolo[4,5-c]pyridine. Compound VII may itself be prepared by other procedures. Similarly, the key step in Reaction Scheme 2 is the acylation of Compound XII with Compound IV. Both compounds XII and TV may be prepared by other procedures. The present invention provides a process for the preparation of compounds of the formula EMI17.1 wherein R1 is hydrogen or a conventional amino-protecting group, R2is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms. allyl, 2-butenyl, 3-butenyl or a group of the formula EMI17.2 in which R 3 and R4 each are independently hydrogen, methyl or ethyl . or R3 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 R5 is hydrogen, amino, (lower)alkyl, (lower) alkoxy or (lower)alkylthio, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof, which process comprises reacting a compound of the formula EMI18.1 in which R2 is as defined above, B1 is a conventional carboxylprotecting group, B2 is a conventional amino-protecting group and n is O or 1, with a thiazolo[4,5-c]pyridine of the formula EMI18.2 in which is as defined above, to produce a compound of the formula EMI18.3 and; if n is 1, reducing the sulfoxide by conventional means, and subsequently removing all protecting groups by conventional means. The reaction is carried out in a non-aqueous organic solvent such as dimethyl sulfoxide, hexamethylphosphoramide, methylene chloride, chloroform, ethyl ether, hexane, ethyl acetate, tetrahydrofuran, acetonitrile and the like, or mixtures of such solvents. The reaction is conveniently carried out at a temperature of from about -lOeC to about +50 C : we normally prefer to conduct the reaction at room temperature. At least one mole of the tertiary amine should be used per mole of Compound XIV; we normally prefer to utilize from about 50% to 100% excess of the thiazolo tA ,5-c) pyridine. Carboxyl-protecting groups suitable for use as BÚ in the above reaction are well-known to those skilled in the art and include alkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl and diphenylmethyl (benzhydryl); 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 U.K. Patent 1,399,086. We prefer to utilize carboxylprotecting groups which are readily removed by treatment with acid. Particularly preferred carboxyl-protecting groups are the benzhydryl and t-butyl moieties. 2 Amino-protecting groups suitable for use as Bê are also well-known in the art, and include the trityl group and acyl groups such as chloroacetyl, formyl and trichloroethoxy- carbonyl. 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 or the preparation of compounds of the formula EMI19.1 wherein R1 is hydrogen or a conventional amino-protecting group, R2 is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl, 3-butenyl or a group of the formula EMI19.2 in which R3 and R4 each are independently hydrogen, methyl or ethyl, or R3 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 R5 is hydrogen, amino, (lower)alkyl, (lower)alkoxy or (lower)alkylthio, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof, which process comprises acylating a compound of the formula EMI20.1 or an N-silyl derivative thereof, in which BÚ is hydrogen or a conventional carboxyl-protecting group, n or-±=n2Rs is as defined above, with an acylating derivative of an acid of the formula EMI20.2 wherein Bê is a conventional amino-protecting group and R2 is as defined above, to produce a compound of the formula EMI20.3 and, if n is 1, reducing the sulfoxide by conventional means, and subsequently removing all protecting groups. The acylating derivatives of the acid of Formula XVII include the acid halides (and particularly the acid chloride), mlxed acid anhydrides (such as the acid anhydrides formed with pivalic acid or a haloformate 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 in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyl- dimidazole or an isoxazolium salt. As used herein, the term "acylating derivative" of the acid of Formula XVII includes the free acid itself in the presence of a condensing agent such as described above. The preferred acylating derivative of the acid of Formula XVII is the acid chloride, preferably used in the presence of an acid binding agent (and particularly a tertiary gamine acid binding agent such as triethylamine, dimethylaniline 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 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, as well as other conventional solvents such as tetrahydrofuran, acetonitrile and the like. The acylation reaction may be conducted at a temperature of from about -500C to about +500C. However, it is preferably conducted at or below room temperature- and most preferably from about -30 C to about 0 Cr It is usually preferred to acylate the compound of Formula XVI with about a stoichiometric amount of the acylating agent of Formula XVII, although a small excess (e.g. 5-25%) of the acylating agent may be utilized. It is preferable that the compound of Formula XVI be acylated in the form of its N-silyl derivative (when utilizing a non-aqueous reaction medium). This is conveniently done in 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. We prefer to utilize about 3 moles of 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. When substituent R2 of the acylating acid of Formula XVII is a group of the formula EMI22.1 it is preferred that the acylating acid contain a carboxylprotecting group, i.e. that the acylating acid be utilized in the fonn EMI22.2 in which Bê is a conventional amino-protecting group as described above, and B is a conventional carboxyl-protecting group as described above for B1 The acylating acids of Formula XVII (and the corresponding precursor esters), including the carboxyl- and amino protected derivatives [XVIII) thereof, are known in the art or may be prepared by known procedures. Thus, Compounds IIIa, IIIb and Ilic (shown in Preparation No. 1, below) and Compounds Viva, rVb and IVc (shown in Preparation No. 2, below) are described in Tetrahedron, 34, 2233-2243 (1978), in which they were prepared by a different route. Compounds IVd1 and IVe', used as starting materials in Preparation No. 11 and Preparation No. 13, respect ively, were prepared according to the general procedure described in U.S. Patent No. 4,258,041 and published United Kingdom Patent Application No. 2,025,398. The thiazolo[4,5-c]pyridines of the formula EMI23.1 wherein R5 is as described above are known compounds. The preparation of the compounds in which R5 is hydrogen or methyl is described in Pharm. Bull. (Japan), 2, 196-200 (1954) [Chemical Abstracts, 50, 1000i). The preparation of the compound in which no amino is described in Pharm. Bull. (Japan), 2, 34-37 (1954) [Chemical Abstracts, 50, 335h). The compound in which R5 is methylthio is described in J. Heterocyclic Chem., 14, 1045 (1977). When utilizing Reaction Scheme 1 or 2 in which the cephalosporin nucleus is in the form of the l-oxide (n ^ 19, the looxlde is prepared by known procedures such as oxidation with m-chloroperbenzoic acid, peracetic acid, etc. The l-oxide subsequently may be reduced by known procedures, e.g. reduction of the corresponding alkoxysulfonium salt with iodide ion in an aqueous medium. The alkoxysulfonium salt itself is readily prepared by treatment of the 1-oxide with, for example, acetyl chloride. As used herein, the terms "(lower)alkyl" and "(lower)- alkoxy" mean straight or branched chain alkyl and alkoxy groups containing from 1 to 6 carbon atoms, inclusive. Preparation No. 1 EMI24.1 Ethyl (Z)-2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (lIla) A mixture of ethyl (Z)-2-hydroxyimino-2- (2-tritylamino- thiazol-4-yl) acetate (II) (5.00 g, 10.9 mmoles), CH3I (2.04 mL, 32.8 mmoles) and K2CO3 (4.54 g, 32.8 mmoles) in dry dimethylsulfoxide (DMSO) (100 mL) was stirred at room temperature overnight and then poured into water (250 mL). The precipitate which formed was collected by filtration, washed with water and dried to give the title compound (5.15 g, quantitative yield). Mp. 1150C (dec.) : #CDCl3 ppm 1.32 (3H, t), 3.98 (3H, s., 1.30 (2H, g), 6.42 (1H, s), 7.2 (1H, m), 7.25 (15H, s). Compounds IIIb, IIIc, IIId' and IIIe' were prepared by the general procedure set forth above, but replacing the methyl iodide with the appropriate iodide. EMI24.2 <tb> <SEP> Literature <tb> Compound <SEP> R2 <SEP> Yield <SEP> (%) <SEP> Mp <SEP> ( C) <SEP> Mc <SEP> (0C) <tb> <SEP> IIIa <SEP> methyl <SEP> 100 <SEP> 1150 <SEP> (dec.) <SEP> cÅa. <SEP> 120 <SEP> ( ec.) <tb> <SEP> IIIb <SEP> ethyl <SEP> 67 <SEP> 97-980 <SEP> * <tb> <SEP> IIIc <SEP> allyl <SEP> * <SEP> * <SEP> * <tb> <SEP> IvId' <SEP> -C(CH3)2COOtButyl <SEP> 100 <SEP> 125-126 <SEP> 123.5l25(2); <tb> <SEP> 134 <SEP> (3) <tb> <SEP> COOtButyl <SEP> <tb> <SEP> Ille' <SEP> 4 <SEP> 68 <SEP> 81-83 <SEP> not <SEP> reported(3) <tb> *The ester was hydrolyzed without isolation (1) Tetrahedron, 34, 2233 (1978) (2) U.S. Patent 4,258,0,41 (3)u.s. Patent 4,288,434 Preparation No. 2 EMI25.1 (Z)-2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVa) The ethyl ester IIIa prepared in Preparation No. 1 (6.00 g, 12.7 mmoles) in ethanol (120 mL) was treated with 2N NaOH (12.7 mL) at room temperature overnight. The reaction mixture was adjusted to pH 8 by the addition of powdered dry ice and the solvent was evaporated under reduced pressure. The residue was dissolved in water (100 mL) and the solution was acidified with 1N HC1 to pH 2 and then extracted with ethyl acetate (3 x 50 mt). 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 98%) of the title product. Mp. 138-143 C (dec.). NMR : #CDCl3 ppm 3.89 (3H, s), 6.52 (1H, s), 7.2 (15H, s). Compounds IVb, rVc, maw and IVe' were prepared by the general procedure set forth above. EMI25.2 <tb> <SEP> Mp <SEP> (QC, <SEP> Literature <tb> <SEP> oj <tb> tromround <SEP> < <SEP> Yield- <SEP> (8) <SEP> dec.) <SEP> Mp <SEP> (OC, <SEP> dec.) <tb> <SEP> Iva <SEP> methyl <SEP> 98 <SEP> 138-143 <SEP> ca. <SEP> 140(1) <tb> <SEP> 1D <SEP> ethyl <SEP> 85 <SEP> 140-145 <SEP> not <SEP> reportedt <tb> <SEP> z <SEP> allyl <SEP> 66 <SEP> 170-178 <SEP> ca. <SEP> 170(1) <tb> <SEP> IVd' <SEP> -C(CH3)2COOtButyl <SEP> 77 <SEP> 174-175 <SEP> l52l56(2); <SEP> 1got3) <tb> <SEP> CO <SEP> COCtBut <tb> <SEP> 78 <SEP> z <SEP> 78 <SEP> 163-164 <SEP> not <SEP> reported2 <tb> (1) Tetrahedron, 34, 2233 (1978) (2)U.S. Patent 4,258,041 (3)U.S. Patent 4,288,434 Preparation No. 3 Benzhydryl 3-Hydroxymethyl-7-phenylacetamido-3-cephem-4 carboxylate (VIII) 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 mmoles) in one portion. The progress of the reaction was monitored by HPLC until the hydrolysis was complete (5 hours). The suspension was filtered to remove the wheat bran and the filtrate was cooled to 5-100C 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 rat). The pH was then adjusted to 3.0 with 28% phosphoric acid. After 1 hour the reaction mixture was allowed to rise to 200C. Heptane (56 mL) was slowly added 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 PCl5 (8.3 g, 40 mmoles) in ClI2C12 (100 mL) was added pyridine (3.2 g, 40 mmoles) and the mixture was stirred for 20 minutes at 200C. To the mixture was added benzhydryl 3-hydroxymethyl-7-phenylacetamido-3-.cephem-4carboxylate prepared in Preparation No. 3 (5.1 g, 10 mmoles) with stirring at -400C, in one portion. The mixture was stirred at -100C for 15 minutes and allowed to stand at -100C to -150C for 7 hours. To the cooled solution (-20 C) was added propane-1,3-diol (10 mL) and the mixture was allowed to stand at -2CtC 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 MsSOA a.d concentrated in vacua. The gummy residue (12 g) was dissolved in a mixture of CHC13 and n-hexane (2:1), and subjected to 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.). IR : vKBr 3400, 2800, 1785, 1725 cm-1. UV : #max EtOH 265 nm (E1cm 1% 160). NMR : #ppm DMSO-d# + CDCl3 3.69 (2H, s), 4.43 (2H, s), 5.09 (1H, d, J = 4,5Hz), 5.24 (1H, d, J = 4.5Hz), 6.87 (lH, s), 7.3 (10H, m). Preparation No. S Benzhydryl 3-Chloromethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate (Vla) Benzhydryl 7-amino-3-chloromethyl-3-cephem-4carboxylate prepared in Preparation No. 4 (2.29 g, 5.52 mmoles) in CH3CN (57 mL) was treated with bis (trimethylsilyl)acetamide (BSA, 4.09 mL, 16.6 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-methoxyimino2-(2-tritylaminothiazol-4-yl)acetic acid (IVa) (2.04 g, 4.60 mmoles) and PCl5 (1.15 g, 5.52 mmoles) in methylene chloride (20 mL). The mixture was stirred at room temperature for 30 minutes, poured into cold water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with aqueous NaCl, dried and evaporated. The residual syrup (4 g) was chromatographed on a silica gel (150 g) column by eluting with 10:1 and 3:1 mixtures of toluene and ethyl acetate successively. The fractions containing the desired compound verve combined and evaporated to afford 2.61 g (68%) of Via as an amorphous powder. NMR : #CDCl3 ppm 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 (lH, s), 7.3 (25H, m). Preparation No. 6 Benzhydryl 3-Iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VIIa) A mixture of the 3-chioromethyl derivative prepared in Preparation No. 5 (VIa) (1.50 g, 1.79 mmoles) and NaI (1.34 g, 8.93 moles) 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 with water, aqueous Na2S2O3 and aqueous NaCl, dried and evaporated to give the title compound VIla (1.47 g, 89%) as an amorphous powder. NMR : CDC13 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), 6.90 (1H, s), 7.3 (25H, m). Preparation No. 7 Ben zhvdryl 3-Chloromethvl-7-l(Z)-2-eçhoxsrimino-2-t2-tritvlamino- thiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VIb) To a solution of (Z)-2-ethoxyimino-2-(2-tritylamino- thiazol-4-yl)acetic acid (IVb) (1.095 g, 2.4 mmoles) in dichloron.ethane (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 ice-cooled solution of Compound V (1.083 g, 2.4 mmoles) and BSA (1 mL) in dichloromethane (20 mL). After stirring for 0.5 hour the reaction mixture was poured into 101 aqueous NaHCO3 (200 mL) and extracted with CHCl3 (100 mL). The extract was washed with water, dried over MgSO4, and evaporated under reduced pressure. The residue was chroma- tographed on a silica gel column. Elution with CHCl3 gave VIb as an amorphous powder, 1.76 g (86^). NMR : #CDCl3 ppm 1.40 (3H, t, CH2CH3), 3.53 (2H, ABq, 2-CH2), 4.37 (2H, s, -CH2Cl), 4.60 (2H, q, -CH2C133), 4.90 (1H, d, 6-H), 5.89 (1H, d, 7-H), 6.88 (1H, s, thiazole-H), 6.91 (1H, s, benzhydryl CH). Preparation No. 8 Diphenylmethyl 7-[(Z)-2-Ethoxyimino-2-(2-tritylaminothiazol-4 yl)acetamido]-3-iodomethyl-3-ce::hem-4-carboxylate (VIIb) A mixture of VIb prepared in Preparation No. 7 (1.07 g, 1.25 mmoles) and NaI (562 mg, 2.75 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 Na2S203, water and saturated aqueous NaCl, dried over MgSO4 and evaporated to give 1.04 g (89%) of Compound VIIb. : #CDCl3 ppm 3.55 (2H, q, 2-CH2), 4.27 (2H, s, CH2I), 5.02 (1H, d, 6-H), 5.87 (1H, d, 7-H), 6.68 (1H, s, thiazole ring H), 6.93 (1H, s, benzhydryl-CH). Preparation No. 9 Benzhydryl 7-[(Z)-2-Allyloxyimino-2-(2-tritylaminothiazol-4-yl) acetamido]-3-chloromethyl-3-cephem-4-carboxylate (VIc) To a suspension of Compound V (1.35 g, 3 mmoles) in methylene chloride (20 mL) was added BSA (1.1 ml, 4.5 mmoles), and the mixture was stirred for 30 minutes at room temperature to become a clear solution. A mixture of (Z)-2-allyloxyimino2-(2-tritylaminothiazol-4-yl)acetic acid (IVc) (1.40 g, 3.0 mmoles) and phosphorus pentachloride (690 mg, 3.3 mmoles) in methylene chloride (20 mL) 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 acetate (200 mL), washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wako-gel, C-200, 30 g). The column was eluted with chloroform and the fractions containing the desired product were combined. Enzaporation under reduced pressure afforded the title compound (VIc) as an amorphous powder, yield 2.32 g (89%). ttp. 100115 C (dec.). IR : #max KBr cm-1 3390, 1790, 1730, 1680, 1530, 1380, 1250, 1160, 1020. NMR : #CDCl3 pp:n 3.50 (2H, 2-H), 4.32 (2E, s, 3-CE2), 4.6 6.1 (7H, m, CH2CH=CH2 and 6,7-H), 6.70 (1H, s, thiazole-H), 6.90 (1H, s, Ph2CH), 7.1-7.6 (30H, m, phenyl protons). Anal. Calc'd. for C48H40N5O5S2Cl.1/3CHCl3 : C, 64.05; H, 4.45; N, 7.73 : 5, 7.08 ; Cl, 7.82. Found: C, 64.13, 63.99; E, 4.61, 4.64; N, 7.50, 7.30; S, 6.85, 6.85 ; Cl, 7.55, 7.46. Preparation No. 10 Benzhydryl 7-[(Z)-2-Allyloxyimino-2-(tritylaminothiazol)-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VIIc) A mixture of Compound VIc (2.30 g, 2.65 mmoles) and sodium iodide (2 o, 13.3 mmoles) in acetone (15 mL) was stirred for l 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% sodium thiosulfate and water, evaporated under reduced pressure to afford Compound VIIc as an amorphous powder, which was used in the subsequent step without further purification. Yield 2.52 g (99%). Preparation No. 11 Benzhydryl 3-Chloromethyl-7-[(Z)-2-(2-t-butoxycarbonylprop-2 oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4 carboxylate (VId') Procedure 1 A mixture of (Z)-2-(2-t-butoxycarbonylprop-2- oxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IVd') (1.94 g, 3.6 mmoles) DCC (742 mg, 3.6 mmoles) and N-hydroxybenztriazole (486 mg, 3.6 mmoles) in 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 dissolved in CHCl3 (20 rat), washed with saturated aqueous NaHC03 and saturated aqueous NaCl, dried over DSgSO4 and evaporated to dryness. The residue t3.9 g) was dissolved in n-hexane:CHCl2 (X:2) and passed through a silica gel column (40 g) using the same solvent system. Fractions containing the title compound were evaporated in vacuo to give 1.3 g (39%) of VId' melting at > 100 C (dec.). IR : #max KBr cm-1 3390, 1790, 1715, 1690. UV : #max EtOH nm 240 (E1cm 1% 280), 265 (E1cm 1% 190). : : CDC13 ppm 1.45 (9H, s), 1.63 & 1.66 (H, each s), 3.49 (2H, broad s), 4.34 (2H, s), 4.96 (lH, d, J=4.5Hz), 5.90 (1H, d-d, J=4.5 # 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 CH3CN (46.5 mL) was 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 chloride solution which had been prepared from IVd' (2.56 g, 4.49 mmoles) and PC15 (1.12 g, 5.38 mmoles) in methylene chloride (26 mL). The mixture was stirred at room temperature for 30 minutes, poured into cold water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with aqueous NaCl, dried and evaporated. The residual syrup (5 g) was chromatographed 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 VId1. Preparation No. 12 Benzhydryl 7-[(Z)-2-(2-t-Butoxycarbonylprop-2-oxyimino]-2-(2tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4carboxylate (VIId') A mixture of VId' (500 mg, 0.53 mmole) and Nal (240 ma, 1.6 mmoles) in acetone (3 mL) was stirred for 2 hours at room temperature and then evaporated in vacuc. To the residue ere added CH2Cl2 (20 mL) and water (10 mL). The organic layer was washed with 10% w/v sodium thiosulfate (5 mL) and aqueous N2C1 (5 mL), dried over MgSO4, and evaporated to dryness to give 540 mg (99%) of VIId' as an amorphous powder melting at 106 C (dec.). IR : #max KBr cm-1 3350, 1790, 1690. UV : #max EtOH nm 240 (E1cm 1% 270), 265 (E1cm 1% 190). NMR : #CDCl3 ppm 1.44 (9H, s), 1.65 (6H, s), 3.54 (2H, ABq), 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). Preparation No. 13 Diphenylmethyl 7-[(Z)-2-(1-t-Butoxycarbonylcyclobut-1-oxyimino) 2- (2-tritylaminothiazoi-4-yl) acetamido)-3-chloromethyl-3 Cephem-4-carboxylate (VIe') Phosphorus pentachloride (1.46 g, 7 mmoles) was added to a suspension of (Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyin@@@ 2-(2-tritylaminothiazol-4-yl)acetic acid [IVe'] (4.09 g, 7 mmoles) in 70 nw of dry methylene culoride, and the mixture was. stirred for 1 hour at room temperature. The acid chloride solution was added at -20 C to a solution of silylated 7-ACA ester, which was prepared by adding BSA (5.6 s, 21 mmoles) to a stirred suspension of benzhydryl 7-amino-3-chloromethyl-3- cephem-4-carboxylate hydrochloride [V] (3.16 g, 7 mmoles) in dry methylene chloride (70 mL). The mixture was stirred for 2B minutes at -10 C and then at room temperature for 40 minutes. The reaction mixture was evaporated and diluted with ethyl acetate (300 mL), and the organic layer was washed with 5% aqueous sodium bicarbonate, water and a saturated sodium chloride solution. After drying over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (Wako gel C-200, 60 g); elution with chloroform. The fractions containing the desired product were combined and evaporated to obtain 5.88 g (86%) of VIe' as a yellow powder. IR : #max KBr cm-1 1790, 1725, 1690, 1525. UV : #max EtOH nm 254 nm (E1cm 1% = 214). Preparation No. 14 Diphenylmethyl 7-[(Z)-2-(1-t-Butoxycarbonylcyclobut-1-oxyimino) 2- (2-tritylaminothiazol-4-yl) acetamido) -3-iodomethyl-3-cephem- 4-carboxylate (VIIe') To a stirred solution of VIe' (5.4 g, 5.5 mmoles) in acetone (108 mL) was added sodium iodide (2.48 g, 16.5 mmoles), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then filtered and evaporated to dryness, and the residue was dissolved in ethyl acetate (200 mL). The solution was washed with water (100 mL), 10% w/v sodium thiosulfate (40 mL) and saturated sodium chloride (3 x 70 mL). After drying over magnesium sulfate, the solvent was removed under reduced pressure to give 5.38 g (958) of VIIe' as a yellow powder. IR : #max KBr cm-1 1790, 1725, 1690, 1525. UV : #max EtOH nm 254 (E1cm 1% = 184). NMR : CDC13 ppm 1.45 (9H, s), 1.8-2.8 (6H, m), 3.52 (2H, ABq), 4.25 (2H, s), 4.98 (1H, d, 3 = 5.3Hz), 5.87 (1H, d, J = 9 & 5.3Hz), 6.70 (1H, s), 6.88 (1H, s), -6.90 (1H, s), 7.28 (25H, s), 8.41 (1H, d, J = 9Hz). Example 1 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3 {(5-thiazolo[4,5-c]pyridinio)methyl}-3-cephem-4-carboxylate (Ia) A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4carboxylate [VIIa] (1.50 g, 1.61 mmoles) and thiazolo[4,5-c]pyridine (300 mg, 2.20 mmoles) in dry dimethylsulfoxide (DMSO) (7.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (5 mL), dried and evaporated to dryness. To a solution of the residue in CHC13 (5 mL) was added ether (50 mL) to give the quaternized blocked cephalosporin [XIIIa] (1.7 g), which was collected by filtration and treated with 90% trifluoroacetic acid [TFA] (17 mL) at room temperature for 1 hour. After evaporation of the solvent, the residue was triturated with ether, filtered and dissolved in CH3OH (2 mL). The solution was treated with 1M sodium 2-ethylhexanoate [SEH] in ethyl acetate (3.2 mL) at room temperature. for 30 minutes to afford 774 mg of the crude title compound (Ia), which was purified by HPLC (Column, Lichrosorb RP-18, 8 x 300 mm; eluted with 0.01M ammonium phosphate buffer, pE 7.2 - 15% CH3OH) and HP-20 column chromatography (3 x 30 Cm, washed with 1L of water and eluted with 70û mL of 30% CH3OH). The fractions containing the desired product were collected, concentrated and lyophilized to afford 180 mg (22%) of the title compound (Ia) as a colorless powder, mp 165 C (dec.). IR : #max KBr cm-1 3400, 1770, 1615. UV : #max phosphate buffer, pH 7 nm (#) 225 (43400), 261 (21000). D O NMR : #D2O ppm 3.53 (2H, ABq), 4.03 (3H, s), 5.36 (1H, d, J = 4.8 Hz), 5.88 (1H, d), 6.94 (1H, s), 8.9 (2H, m), 9.81 (1H, s), 9.88 (1H, s). Example 2 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3 {(5-thiazolo[4,5-c]pyridinio)methyl}-3-cephem-4-carboxylate (Ia) A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxy- imino-2 - (2-tritylaminothia zol-4 -yl) acetamido) -3-cephem-4- carboxylate [VIIa] (18.6 g, 0.02 mole) and thiazolo[4,5-c)- pyridine (3.54 g, 0.026 mole) in 60 mL of dry DMSO was stirred at room temperature for one hour. The reaction mixture was diluted with 300 mL of chloroform, washed with 200 mL of water and dried over anhydrous MgSO4. The chloroform solution was treated with active carbon (2 g) and filtered. The filtrate was concentrated to 30 mL and diluted with 1L of ether. The resulting precipitate was collected by filtration and washed with ether to give 23 g of the blocked cephalosporin [XIIIa), which was deblocked by stirring with 100 mL of 908 trifluoroacetic acid at room temperature for one hour. The mixture was concentrated to 10 mL below 300C and poured into 1L of ether. The resuiting solid was collected by. filtration and dissolved in 50 mL of methanol. Insolubles were removed by filtration. To the filtrate was added 40 mL (0.04 mole) of SEH in ethyl acetate with shaking and the mixture was diluted with 1L of ethyl acetate. The precipitate which separated was collected by filtration, washed with ethyl acetate and dried in vacuo over P205 to give 11 g of crude title compound (Ia). The crude product was dissolved in 1500 mL of water and insoluble material (4.2 g) was removed by filtration. The filtrate was evaporated to dryness to give an oily residue which was dissolved in 300 mL of water at 30-350C. The solution was filtered, concentrated to 50 mL and lyophilized to give an amorphous powder, which was dissolved in 30 mL of 5% methanol and chromatographed by preparative HPLC (Waters System 500, PrepPAK-500/C18). Fractions containing the desired product were collected and concentrated to 30 nL and lyophilized to give 3.64 g (34%) of the purified title compound (Ia). Mp ca. 1700C (gradually dec.). A more soluble form of Compound Ia was prepared as follows. A stirred mixture of Compound Ia prepared in the above procedure (250 mg) and distilled water (1.0 mL) was not completely soluble (indicated pH was 4.3). Powdered NaHCO3 was added in small portions, with stirring. A clear solution was obtained after adding 5.0 mg of NaHCO3 and the indicated pH then was 6.0. After filtration through a Millipore membrane filter to remove any insoluble impurities, the filtrate was lyophilized to give 245 mg of a water-soluble form of Compound Ia, mp 1650C. Estimated purity 80% (by HPlC). The sample was completely soluble in water to give a 25% solution. IR : #max KBr cm-1 3400, 1770, 1615. UV : #max phosphate buffer, pH 7 nm(#) 225 (44200),.260 (21600). Anal. Calc'd for C20H17N7O5S3.3H2O : C, 41.02 ; H, 3.96, N, 16.74. Found : C, 40.92 ; H, 3.18 ; N, 16.61. Example 3 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-{(5thiazolo[4,5-c]pyridinio)methyl}-3-cephem-4-carboxylate (Ib) A mixture of benzhydryl 7-[(Z)-2-ethoxyimino-2-(2- tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4carboxylate [VIIb] (517 mg, 0.5 mmole) and thiazolo [4,5-c]pyridine (88 mg, 0.65 mmole) in DMSO (5 mL) was stirred for 1 hour at room temperature. The reaction mixture was diluted with CHCl3 (40 mL), washed with water and dried over MgS04. The filtrate was evaporated in vacuo and the residue was washed with ether and dissolved in 90% aqueous TFA. After standing for 1 hour at room temperature, the reaction mixture was concentrated in vacuo- The addition of ether to the concentrate resulted in separation of the product, which was collected by filtration and dissolved in a small amount of CH30H. The solution was chromatox graphed on an H:P-20 column (50 m-) by eluting with 30% aqueous CH30H. The eluate was lyophilized to give 133 mg (47%) of the title compound (Ib) as an amorphous powder. Mp > 1600C (dec.). W : phosphate buffer, pH 7 nm(#) 226 (44000), 258 (20000). NMR : D20 ppm 1.38 (3H, t), 3.57 (2H, q), 4.32 (2H, q), 5.37 (1H, d), 5.70 (2H, d), 5.93 (1H, d), 6.98 (1H, s), 8.70-9.0 (2H, m), 9.80-9.92 (2H, m). Example 4 7-[(Z)-2-Allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-{(5thiazolo[4,5-c]pyridinio)methyl}-3-cephem-4-carboxylate (Ic) A mixture of benzhydryl 7-[ (Z)-2-allyloxyimino-2- (2- tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4carboxylate [VIIc] (478 mg, 0.5 mmole) and thiazolo[4,5-c]- pyridine (108 mg, 0.8 mmole) in DMSO (1 mL) was stirred for 50 minutes at.room temperature. The mixture was diluted with chloroform (100 mL), washed with water and evaporated under reduced pressure. The oily residue was triturated with ether and collected by filtration (610 mg). A mixture of this material and TFA (3 mL) was allowed to stand at room temperature for 2 hours and diluted with ether to precipitate the trifluoroacetate of the title compound (465 mg), which was collected by filtration and chromatographed on a column of HP-20 (1.8 x 15 cm). The column was eluted with water (1L) and 30% aqueous methanol (1L). The methanolic eluate was evaporated under reduced pressure and the residue was lyophilized to give the crude title compound (58 mg), which was purified by HPLC column, Lichrosorb RP-18; Mobile phase, 0.01M NH4H2PO4 (pH 7) : CH3OH = 75:25]. The eluate of the HPLC was chromatographed on a column of HP-20 (1.8 x 10 cm). The column was eluted with water (500 mL) and 50% aqueous methanol (500 mL). The methanolic eluate was evaporated under reduced pressure and the residue was lyophilized to give 31 mg (118) of the title compound (Ic) as a pale yellow powder. Mp > 1600C (dec.). IR : #max cm-1 3600-3000, 1770, 1660, 1535. UV : #max phosphate buffer, pH 7 nm(#) 225 (44000), 260 (21300). NMR : #D2O + NaHCO3 ppm 3.50 (1H, d, 18Hz, 2-H), 3.85 (1H, d, 18Hz, 2-H), 5.95 (1H, d, 4Hz, 7-H), 7.00 (1H, s, thiazole-H), 8.90 (2H, m, thiazolopyridine-H), 9.85 (1H, s, thiazolopyridine-H), 9.93 (1H, s, thiazolopyridine-H). Example 5 7- F (Z) -2- (2-Aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido]-3-{(5-thiazolo[4,5-c]pyridinio)methyl}-3-cephem-4carboxylate (Id) To a stirred solution of diphenylmethyl 7-[(Z)-2-tbutoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIId'] (700 mg, 0.66 mmole) in 3 mL of DMSO, was added thiazolo[4,5-c]pyridine (115 mg, 0.84 mmole) in two portions and the mixture was stirred for 1.25 hours at room temperature. The reaction mixture was diluted with ether (150 mL) to separate an oily product, which was washed again with ether. The residue was dissolved in methylene chloride (100 mL) and the solution was filtered and evaporated to give 655 mg of the blocked product [XIIId']. The yellow product (630 mg) was suspended in anisole (1 mL) and, with ice cooling, was treated with a mixture of TFA (10 mL) and water (0.5 mL). The mixture was stirred for 20 minutes with ice cooling and then for 1 hour at room temperature. After evapora- tion of the mixture below 30 C, the residue was triturated with isopropyl ether (50 mL). The precipitate was collected by filtration, and dried under reduced pressure to obtain 485 mg of crude title compound as a yellow powder. The crude product (480 mg) was dissolved in a small volume of aqueous sodium bicarbonate and purified by HPLC (Column, Lichrosorb RP-18; mobile phase, water). The desired fractions were combined (ca. 90 mL) and acidified to pH 2 with dilute hydrochloric acid. The acidified solution was passed through an HP-20 column (50 mL) and washed with water (200 mL). The fractions eluted with 40% methanol were combined, concentrated and lyophilized to afford 154 mg of pale yellow amorphous powder, which was slightly soluble in water. Microanalysis showed that this was the free acid of the title compound (Id). Mp > 180 C (dec.). IR : #max KBr cm-1 1770, 1660, 1610, 1540. UV : #max phosphate buffer, pH 7 nm(#) 225 (45900), 260 (22200). NMR : #DMSO-d6 ppm 1.40 (6H, s), 5.10 (1H, d, J = 4Hz), 5.33 (1H, br, s), 5.70 (1H, br, s), 5.80 (1H, m), 6.66 (1H, s), 9.14 (2H, ABq), 9.88 (1H, s), 10.33 (1H, br, s). Anal. Calc'd for C23H21N7O7S3.2.5H2O : C, 42.59 ; H, 4.04 ; N, 15.11 ; S, 14.83. Found: C, 42.69, 42. v8 H, 3.49, 3.47; N, 15.15, 15.08; S, 15.01. Atomic absorption analysis: a, 0,01. The free acid of Compound Id (100 mg) was dissolved in a small volume of aqueous sodium bicarbonate and subjected to HPLC (Column, Lichrosorb RP-18; mobile phase, water). The eluate containing the desired product which was concentrated and lyophilized to give 30 mg of the sodium salt of Id as a pale yellow amorphous powder, which was more than 25% soluble in water. Mp 178-196 C (dec.). IR : #max KBR cm-1 1770, 1605, 1540. UV : #max phosphate buffer, pH 7 nm (#) 225 (42400), 260 (21000). NMR : #D2O ppm 1.57 (6H, s), 3.55 (2H, ABq), 5.38 (1H, d, J = 4.5Hz), 5.70 (2H, ABq), 5.93 (1H, d, J = 4.5Hz), 6.94 (1H, s), 8.89 (2H, ABq), 9.83 (1H, s), 9.92 (1H, s). Anal. Calc'd for C23H20N7O7S3Na.3H2O : C, 40.64 ; H, 3.86 ; N, 14.43; S, 14.15; Na, 3.38. Found: C, 40.54, 40.65; H, 3.52, 3.48 ; N, 14.35, 14.41; S, 14.16; Na, 3.35. Example 6 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-{(5-thiazolo[4,5-c]pyridinio)methyl}-3-cephem-4 carboxylate (Id) A solution of diphenylmethyl 7-[(Z)-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]3-iodomethyl-3-cephem-4-carboxylate [VIId'] (9.0 g, 8.5 mmoles) and thiazolo[4,5-c]pyridine (1.5 g, 11 mmoles) in dimethyl sulfoxide (38 mL) ) was stirred at room temperature for 1 hour. -The reaction mixture was poured into ether (500 mL) and, after decantation, the oily precipitate was dissolved in chloroform (300 mL). The solution was washed with water (2 x 250 mL), dried over Na2SO4 and evaporated in vacuo. The oily residue was triturated with ether to give a yellow solid (8.5 g) which was treated with a mixture of anisole (4.3 mL), water (2.2 mL) and TFA (43 mL) at OOC for 5 minutes and then at room temperature =or 1 hour. The reaction mixture was evaporated and the oily residue was triturated with isopropyl ether to give 7.49 g of the crude title product (estimated purity 426), The product was dissolved in aqueous NaHCO3 and purified by HPLC (Waters System 500, prepPack-S-500/C18, mobile phase H2O), yielding 1.55 -g (36%) of the title compound (Id) as its Na salt, which was more than 25% soluble in water. Mp > 180 C (dec.). IR : #max KBr cm-1 3400, 1770, 1660, 1610, 1540, 1480, 1400, 1360, 1190, 1550, 1120, 1085, 1040, 970, 920, 840, 790, 71 UV : #max phosphate buffer, pH 7 nm(#) 225 (45700), 260 (22000). DO : #D2O ppm 1.47 (6H, s), 3.20 & 3.70 (1H each, d, J = 17Hz), 5.26 (1H, d, J = 4.5Hz), 6.40 & 5.75 (1H each, d, J = 15Hz), 5.78 (1H, d, J = 4.5Hz), 6.68 (1H, s), 8.68 (1H, d, J = 7.5Hz), 8.88 (1H, d, J = 7.5Hz), 9.68 (1H, s), 9.84 (1H, s). Example 7 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]-3-{(5-thiazolo[4,5-c]pyridinio)methyl}-3-cephen 4-carboxylate (Ie) To a solution of diphenylmethyl 7-( (Z)-2-(l-t-butoxy- carbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIe'] (482 mg, 0.45 mmole) in 2 mL of DMSO was added thiazolo[4,5-c] pyridine (68 mg, 0.5 mmole) in one portion. The mixture was stirred for 45 minutes at room temperture. The reaction mixture was then diluted with ether (50 nL) and the precipitated oil was triturated in ether (4 x 50 nL). The precipitate was mixed with anisole (0.5 mL), trifluoroacetic acid (; mL) and water (0.5 nL), and the mixture was stirred with ice cooling for 30 ninutes and at room temperature for 1 hour, and then was concentrated under reduced pressure ( < 300C). The residue was triturated with isopropyl ether (100 mL), and the restting precipitate was collected by filtration to afford 395 mg of crude title compound, as a yellow powder. The crude product (387 mg) was purified on an HP-20 column (100 mL). The eluate containing desired product, which was eluted with 50% methanol, was concentrated and lyophilized to give 80 mg (31%) of the title product (Ie) as a pale yellow amorphous powder. Mp > 170 C (dec.). IR : #max KBr cm-1 1775, 1663, 1620, 1540. UV : #max phosphate buffer, pH 7 nm(#) 224.5 (46000), 259 (22500). NMR: . #D2O(NaHCO3), ppm 1.8-2.7 (6H, m), 3.56 (2H, ABq), 5.42 (1H, d, 3 = 4.5Hz), 5.70 (2H, ABq), 5.94 (1H, d, J = 4.5Hz), 6.93 (1H, s), 8.90 (2H, ABq), 9.82 (1H, s), 9.94 (1H, s). Example 8 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[{5 (2-aminothiazolo[4,5-c]pyridinio)}methyl]-3-cephem-4carboxylate (If) To a stirred solution of benzhydryl 3-iodomethyl-7 [(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3cephem-4-carboxylate [VIIa] (466 mg, 0.5 mmole) in 3 mL of DMSO, was added 2-aminothiazolo[4,5-c]pyridine (100 mg, 0.66 mmole). The mixture was stirred at room temperature for 1.2 hours and diluted with ether (50 mL). The deposited oil was triturated with ether and the solvent was decanted. This procedure was repeated another three times. A solution of the residual precipitate in 50 mL of CHCl3-CH3OH (4:1) was filtered and concentrated in vacuo. The residue was triturated in isopropyl ether (50 mL). The precipitate (602 mg) was collected by filtration and treated with anisole (0.5 mL) and 90% TFA with cooling in an ice-water bath. After one hour stirring at room temperature, the mixture was evaporated in vacuo and the residue was triturated with isopropyl ether (50 mL). The precipitate was collected by filtration to give 414 mg of crude If as a tan powder, which was purified by column chromatography on HP-20 resin (100 mL), eluting with water and 30% CE30H successively. The desired fractions which were eluted with 30% CH3OH, were combined, concentrated and lyophilized to obtain 36 mg (13%) of the title compound (If) as a pale yellow amorphous powder. Estimated purity 60% (by HPLC). IR vXBr : 1 1770, 1640, 1610, 1540. UV : #max phosphate buffer pH 7 nm(#) 246 (43600). NMR : #DMSO-d6(D2O) ppm 3.78 (3H,s), 5.07 (1H, d, J=4), 5.67 (1H, d, J=4), 6.67 (1H, s), 8.57 (2H, ABq), 9.25 (1H, s). Example 9 7-[(z)-2-(2-Aminothiazol-4-yl)-2-(2-c2rboxyprob2-oxyimino)- acetamido]-3-[{5-(2-aminothiazolo[4,5-c]pyridinio)}methyl]-3cephem-4-carboxylate (Ig) A mixture of diphenylmethyl 7-1 (Z)-2-t-butoxycarbonyl- prop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3 iodomethyl-3-cephem-4-carboxylate [VIld') (455 mg, 0.43 mmole) and 2-aminothiazolo[4,5-c]pyridine (75 mg, 0.5 mmole) in 2.5 mL of DMSO was stirred for 1.5 hours at room temperature and then treated with ether (50 mL) to separate an oily precipitate, which was triturated with ether. The ether layer was removed by decantation. This procedure was repeated another three times. A solution of the residual precipitate in 30 mL of CHC13-CH30H (4:1) was filtered, the filtrate was evaporated and the residue was triturated with isopropyl ether. The precipitate (349 mg) was collected by filtration and treated with anisole (0.3 mL) and 90% TFA (3 mL) with ice cooling. The mixture was stirred at room temperature for 1.5 hours and evaporated in vacuo, and the residue was triturated with isopropyl ether (50 mL) to give 280 mg of crude Ig as a yellow powder, which was purified by HP-20 resin column chromatography (40 mL). The column was eluted with water and subsequently with 30% aqueous CE3OH. The desired fractions, eluted with 30% CH3OH, were combined, concentrated and lyophilized to afford 19 mg (7%) of the title compound (Ig) as a pale yellow amorphous powder. Estimated purity 60% (by HPLC). IR : #max cm-1 1770, 1660sh, 1635, 1540. UV : #max phosphate buffer pH 7 nm(#) 247 (41700). : #DMSO-d6(D2O) ppm 1.42 (6H, s), 5.10 (1H, d, J-4), 5.75 (1H, d, J=4), 6.66 (1H, s). 8.54 (2H, ABq), 9.23 (1H, s). Example 10 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3 [{5-(2-methylthiazolo[4,5-c]pyridinio)}methyl]-3-cephem-4carboxylate (Ih) A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4 carboxylate [VIIa] (466 mg, g,5 mmole) and 2-methylthiazolo- [4,5-c]pyridine (100 mg, 0.67 mmole) in 2.5 mL of DMSO was stirred at room temperature for an hour and diluted with ether (150 ml.). The resulting oil was triturated with ether and the solvent was decanted. This s procedure was repeated another three times. A solution of the residual precipitate in 50 mL of CHCl3-CH3OH (4:1) was filtered and evaporated, and the residue was triturated with isopropyl ether (50 ml,) to afford 558 mg of the quaternized blocked cephalosporin (vKBr cm-1 : 1785, 1720, 1670, 1625, 1525, 1030), which was treated with anisole (0.5 mL) and 90% TFA (5 mL) with cooling in an ice-water bath. The mixture was stirred at room temperature for 1.5 hours and evaporated below 400C. The residue was triturated with isopropyl ether (30 mL) to give 395 mg of a yellow powder. The crude powder was dissolved in a mixture of 98% formic acid (2 mL) and concentrated hydrochloric acid (0.1 mL), and the solution was allowed to stand at room temperature for 30 minutes. The resulting mixture was chromatographed on a column of HP-20 resin (100 mL) by eluting with water and 30% CH3OH successively. The fractions containing the desired product were combined, concentrated and lyophilized to give 161 mg (59%) of the title compound (Ih) as a yellow amorphous powder. Estimated purity 65% (by HPLC). IR : #max KBrcm-1 1770, 1660, 1620, 1535. UV : #max phosphate buffer pH 7 nm(#) 228 (50300), 260 (22000). NMR : #D2O ppm 3.06 (3H, s), 3.51 (2H, ABq), 4.04 (3H,s), 5.36 (1H, d, J=4), 5.61 (2H, ABq), 5.84 (1H, d, J=4), 6.75 (IH, s), 8.72 (2H, ABq), 9.68 (1H, s). Example 11 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3 [{5-(2-methylthiothiaozlo[4,5-c]pyridinio)}methyl]-3-cephem-4carboxylate (Ii) A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxy- imino-2- (2-tritylaminothiazol-4-yl) acetamido) -3-cephem-4- carboxylate [VIIa] (470 mg, 0.51 mmole) and 2-methylthiothiazolo[4,5-c]pyridine (121 mg, 0.66 mmole) in 3 mL of dry DMSO was allowed to stand for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (3 x 20 mL) and aqueous NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was treated with ethyl ether and filtered to give 475 mg of the quaternized blocked cephalosporin, which was dissolved in 3 mL of TFA (99%) and allowed to stand for 1.5 hours at ambient temperature. Removal of the solvent followed by trituration with isopropyl ether (30 mL) gave 360 mg of the TFA salt of Ii as a powder. The TFA salt was chromatographed en a column of HP-20 resin and eluted with water (300 mL), 10% CH3OH-H2O (300 mL) and 30% CH3OH-H2O (300 mL), successively. Fractions eluted with 30% CH30H-H20 were combined, concentrated in vacuo and lyophilized to afford 136 mg (25%) of the title compound (Ii). Estimated purity 50% (by HPLC). IR : vmax cm-1 1770, 1660, 1615, 1530. UV : #max phosphate buffer pH 7 nm (#) 262 (36900), 294 (16500). NMR : #D2O ppm 2.91 (3H,-s, -SCH3), 3.50 (2H, m, 2-CH2), 4.09 (3H, s, =N-OCH3), 5.37 (1H, d, J=5, 6-H), 5.71 (2H, ABq, 3-CH2), 5.87 (1H, d, J=5, 7-H), 6.86 (1H, , thiazole-5-H), 8.55 (1H, d, J=6, thiazolopyridinio-7'-H), 8.81 (1H, d, J=6, thiazolopyridinio-6'-H), 9.50 (1H, s, thiazolopyridinio-4'-H). Example 12 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido)-3-[{5 (2-aminothiazolo[4,5-c]pyridinio)}methyl]-3-cephem-4-carboxylate (Ij) To a stirred solution of benzhydryl 7-[(Z)-2-ethoxy- imino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3cephem-4-carboxylate [VIIb] (600 mg, 0.64 mmole) in 4 mL of DMSO, was added 2-aminothiazolo[4,5-c]pyridine (128 mg, 0.85 : :nmole). The mixture was stirred at room temperature for 40 minutes and then diluted with ether (100 mL) The oily precipitate which separated was triturated with ethyl ether and the solvent was decanted. This procedure was repeated another four times. A solution of the residual precipitate in 50 mL of CHCl3-CH3OH (4:1) was filtered and the filtrate was concentrated to give an oily residue, which was triturated with isopropyl ether (50 mL). The solid thus obtained was collected by filtration to give 675 mg of the quaternized blocked cephalosporin as yellow powder0 The powder was treated with anisole (2 mt) and go TFA (11 mL) with ice cooling. The mixture was stirred at room temperature for 1.5 hours and evaporated in vacuo. The residue was triturated with isopropyl ether (50 mL) and collected by filtration to give 490 mg of crude Ij, which was purified by column chromatography using EP-20 resin (100 mL). The column was eluted with water and 30% aqueous methanol successively. The desired fractions which were obtained by elution with 30% CH3 OH were combined, concentrated and lyophilized to afford 44 mg (13t) of the title compound (Ij) as a yellow amorphous powder. Estimated purity 30% (by HPLC). IR : #max KBr cm-1 1750, 1655sh, 1600, 1520. UV : #phosphate buffer pH 7 nm(#) 246 (26800).

Claims: CLAIMS 1. Compounds of the general formula I: EMI49.1 wherein R1 is hydrogen or a conventional amino-protecting group, R2is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl, 3-butenyl or a group of the formula EMI49.2 in which R3 and R4 each are independently hydrogen, methyl or ethyl, or R 3 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 R5 is hydrogen, amino, (lower)-alkyl, (lower)alkoxy or (lower)alkylthio: or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. 2. Compounds of Claim 1 wherein R1 is hydrogen and R2 is methyl, ethyl, allyl, 2-carboxyprop-2-yl, l-car boxycycloprop-1-ylidene or 1-carboxycyclobut-1-yli dene, and R5 is hydrogen, amino, methyl or methylthio; or a nontoxic pharmaceutically acceptable salt, phy siologically hydrolyzable ester or solvate thereof. 3. Compounds of Claim 1 namely: 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido] 3- 5-thiazoloF4,5-c]pyridinio)methyl} -3-cephem-4- carboxylate; 7-F (Z)-2-( 2-aminothiazol-4-yl)-2-ethoxyiminoacetamido)- 3-{(5-thiazolo[4,5-c]pyridinio)methyl}-3-cephem-4 carboxylate; 7-[(Z)-2-(2-allyloxyimino-2-(2-aminothiazol-4-yl) acetamido]-3-{(5-thiazolo[4,5-c]pyridinio)methyl} 3-cephem-4-carboxylate ; 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2 oxyimino)-acetamido]-3-{(5-thiazolo[4,5-c]pyridinio) methyl}-3-cephem-4-carboxylate ; 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-cÅarboxycyclobut- 1-oxyimino)-acetamido]-3-{(5-thiazolo[4,5-c]pyridinio) methyl}-3-cephem-4-carboxyalte ; ; 7-F (Z )-2-( 2-aminothiazol-4-yl)-2-methoxyirninoacetamido )- 3-[{5-(2-aminothiazolo[4,5-c]pyridinio)}methyl]-3 cephem-4-carboxylate ; 7-l(z)-2-(2-amirlothiazol-4-yl)-2-ethoxyiminoacetamidol- 3-[{5-(2-aminothiazolo[4,5-c]pyridinio)]methyl]-3-cephem 4-carboxylate; 7-F (Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino) acetamido]-3-[{5-2-aminothiazolo[4,5-c]pyridinio)}methyl]3-cephem-4-carboxylate ; 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido- 3-[{5-(2-methylthiothiazolo[4,5-c]-pyridinio)}methyl] 3-cephem-4-carboxylate; ; and 7-[ (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido3-[{5-(2-methylthiazolo[4,5-c]pyridinio]}methyl]-3-cephem4-carboxylate, or a nontoxic pharmaceutically acceptable salt a physiologically hydrolyzable ester or solvate thereof. 4. Pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of Claims 1 to 3 and an inert pharmaceutical carrier. 5. Composition according to claim 4, wherein the compound of Claims 1 to 3 is selected from the group consisting of a) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino-aceta mido]-3-{(5-thiazolo[4,5-c]pyridinio)methyl}-3 cephem-4 -carboxylate, b) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop 2-oxyimino)acetamido]-3-{(5-thiazolo[4,5-c]pyridi nio )methylcl -3-cephem-4-carboxylate, c) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoaceta mido]-3-{(5-thiazolo[4,5-c]pyridinio)methyl]-3 cephem-4-carboxylate, d) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclo but-1-oxyimino)acetamido]-3-{(5-thiazolo[4,5-c] pyridinio)methyl}-3-cephem-4-carboxylate, e) 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetamido]-3-[{5-(2-aminothiazolo[4,5-c]pyridinio)} methyl] -3-cephem-4-carboxylate, f) 7-F (z)-2-( 2-aminothiazol-4-yl)-2-inethoxyiminoaceta- mido]-3-[{5-(2-methylthiazolo[4,5-c]pyridinio)} methyl-3-cephem-4-carboxylate, and the nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates of said compounds. 6. An antibacterial composition in unit dosage form comprising from about 50 mg to about 1500 mg of- at least one compound of Claims 1 to 3 and an inert pharma ceutical carrier. 7. Composition according to claim 6 wherein the compound of claims 1 to 3 is selected from the group as stated in claim 5. 8. Process for the manufacture of the compounds of Claims 1 to 3, characterized in that a compound of the general formula II: EMI53.1 in which Rê is as defined above, B is a conventional carboxyl-protecting, B2 is a conventional amino-protecting group, n is O or 1, is reacted with a thiazolo [4,5-c1pyridine of the formula III: EMI53.2 in which R5 is as defined above, to produce a compound of the formula IV: : EMI53.3 in which R , R5 , B1, B2 and n are as defined above and, if n is 1, the sulfoxide is reduced by conventional means, and subsequently all protecting groups are removed by conventional means to give compounds of formula I, wherein R is hydrogen or the protecting group B1 is removed to give compounds of formula I, wherein R is a conventional amino-protecting group and/or if desired compounds of formula I are converted to their nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters' and solvates thereof. 9. Process for the manufacture of compounds of Claims 1 to 3, characterized in that a compound of the formu la V: EMI54.1 or an N-silyl derivative thereof, in which B1 is hydrogen or a conventional carboxyl-protecting group, n is O or 1 and R5 is as defined above, is acylated with an acylating derivative of an acid of the formula VI or VI I EMI54.2 EMI55.1 in which Rê, R , R4 are as defined above, Bê is a conventional amino-protecting group, and B is a conventional carboxyl-protecting group, to produce a compound of the formula VIII: : EMI55.2 in which Rê, R5, BÚ, Bê and are as defined above and, if n is 1, the sulfoxide is reduced by conventional means , and subsequently ail protecting groups are removed to produce compounds of formula I, wherein RÚ is hydrogen or the protecting groups BÚ and B3 are removed to give compounds of formula I, wherein R is a conventional amino-protecting group and/or if desired the compounds of formula I are converted to their nontoxic pharmaceutically acceptable salt a physiologically hydrolyzable esters and solvates thereof.

Inventors: ABURAKI, SHIMPEI, IMAE, KIYOTO, NAITO, TAKAYUKI, NARITA, YUKIO, OKUMURA, JUN
Applicants: BRISTOL-MYERS COMPANY
Application year: 1983
Main classification: C07D501
IPC codes: C07D501, C07D519, A61K31, C07D277, A61P31