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Sk&F 59962 (Cefazaflur) VOL. XXIX NO. 9 THE JOURNAL OF ANTIBIOTICS 973 Communications to the editor SYNTHESIS AND IN VITRO more successful when applied to analogs having ANTIBACTERIAL ACTIVITY OF at the 3 position substituents other than methyl- 7-TR I FL UO RO M ETH YLTHI OACETA M I D O tetrazolethiomethyl, the 7cc-methoxycephalospo- CEPHAMYCINS RELATED TO rins 4 and 5, as well as 6, were synthesized by SK&F 59962 (CEFAZAFLUR) coupling the appropriate tert-butyl 7-amino-7a- methoxy-3-cephem-4-carboxylates (1, 2 and 3) to Sir: trifluoromethylthioacetic acid with DCC. Inter- Various 7a-methoxycephalosporins (cepha- mediate 1 was prepared from 7-ADCA tert-butyl mycins) have been reported to show enhanced ester by thiomethylation of its benzaldehyde antibacterial activity against certain gram-nega- SCHIFF base followed by mercury-catalyzed me- tive organisms relative to their unmethoxylated thoxy exchange.') Compound 2 was obtained by analogs.',') Consequently, several synthetic direct methoxylation of the p-nitrobenzylcarba- methods have been developed for producing mate of 7-ACA tert-butyl ester with lithium cephamycin analogs by introducing a 7a-methoxy methoxide and tert-butyl hypochlorite.e) The group into the cephalosporin structure.' -7) This previously unreported 3 was synthesized from enables one to determine whether the introduc- tert-butyl -7- amino -3- (1-methyl-1 H-tetrazol -5-yl- tion of a 7a-methoxy group into an already pro- thiomethyl)-3-cephem-4-carboxylatee) by a pro- mising cephalosporin molecule would improve cedure analogous to that used to obtain 1. The its antimicrobial profile. Previously we reported tert-butyl esters were cleaved by treatment with the broad-spectrum antibacterial activities of 7- trifluoroacetic acid and the cephamycins, 4, 5 and trifluoromethylthioacetamido-3-(1-methyl-1 H-tet- 6, were converted to their sodium salts with 30 razol-5-ylthiomethyi)-3-cephem-4-carboxylic acid sodium 2-ethylhexanoate in isopropyl alcohol. (cefazaflur, compound 9) and some closely The ir, nmr and elemental analyses of all final related analogs.8) We have extended this work products were consistent with their structure. to several of the corresponding 7a-methoxy ana- The in vitro antibacterial activities of the three logs. The synthesis and in vitro antibacterial cephamycins (4, 5 and 6) as well as the corres- activities of these derivatives are reported here. ponding cephalosporins (7, 8 and 9) are presented Cephalosporins 7, 8 and 9 were prepared by in Table 1. Inspection of these data reveals sev- acylation of the appropriate 7-amino-3-cephem- eral distinct differences in the spectrum of activi- 4-carboxylic acids with the N-hydroxysuccinimide ties of the methoxylated versus unmethoxylated ester of trifluoromethylthioacetic acid as describ- analogs. Insertion of the methoxyl group into the ed previously.8) Attempts to introduce the 7a- 7-ADCA derivative 7 results in a compound (4) methoxy group directly into 9 by treatment of its which is devoid of antibacterial activity. This tert-butyl ester with lithium methoxide and tert- agrees with previously reported results for the butyl hypochloriteb) were unsuccessful. Since it 7-thienylacetamido -7a- methoxydesacetoxycepha- appeared unlikely that this procedure would be losporanic acid.') For the analogs which Scheme 1. Synthesis of 7-trifluoromethylthioacetamido cephamycins 974 THE JOURNAL OF ANTIBIOTICS SEPT. 1976 Table 1. In vitro activities of 7-trifluoromethylthioacetamido cephalosporins and cephamycins Minimum inhibitory concentration (pg/ml)* Compound Y X 10 1 2 3 4 5 6 7 8 9 Pr.nt. S.a.(R) S.a.(S) E.c. K.p. Sal. p. Slt. p. Ent.a. Ent.c. Ser.nt. (+) 4 > 200 > 200 > 200 > 200 > 200 > 200 > 200 > 200 > 200 > 200 5 1.6 3.1 6.3 6.3 3.1 1.6 12.5 6.3 12.5 12.5 6 0.8 1.6 3.1 1.6 1.6 1.6 6.3 1.6 6.3 3.1 7 6.3 6.3 25 25 25 50 200 50 > 200 NT 8 0.4 0.4 1.6 1.6 0.4 3.1 3.1 3.1 > 200 200 9 0.4 0.2 0.4 0.4 0.8 0.8 1.6 1.6 200 50 Cephalothin 0.4 0.2 3.1 1.6 0.8 1.6 12.5 6.3 > 200 > 200 Cefoxitin 1.6 3.1 6.3 12.5 6.3 3.1 200 25 25 25 The in vitro antibacterial activities are reported as minimum inhibitory concentrations (MIC) in ,ug/ml. The MICs were determined by the twofold agar dilution method on Trypticase soy agar buffered to pH 6.0. Organisms selected for inclusion in this table are: S.a. (R), Staphylococcus aureus HH 127 (penicillin G resistant); S.a. (S), Staphylococcus aureus 23390 (Smith); Ex., Escherichia coli 12140; K.p., Klebsiella pnetanoniae 4200; Sal.p., Salmonella paratyphi ATCC 12176; Sh.p., Shigella paradrsenteriae HH 117; Ent.a., Enterobacter aerogenes ATCC 13048; Ent. c., Enterobacter cloacae HH 31254; Ser.m., Serratia marcescens ATCC 13880: Pr.m. (T), Proteus morganii 179 (indole-positive). NT=not tested. Cefazaflur, SK&F 59962. have acetoxymethyl or methyltetrazolethiomethyl cefoxitin calls for further biological studies of at the 3 position, the gram-positive activities this cephalnycin analog. (organisms 1 and 2) of the cephamycins are lower than those of the corresponding cephalosporins. Aclnowledgement This is also true for the activity against those We wish to thank Dr. G. L. DuNN and Dr. J. R. E. gram-negative bacteria (organisms 3-8) which HOOVER for their advice and assistance during the are usually sensitive to cephalosporins. On the course of this work and in the preparation of the final other hand, these cephamycins are more active manuscript. against gram-negative organisms 9 and 10 which are relatively insensitive to cephalosporins. Jo R. M. DEMARINIS vitro activities of cephamycins 5 and 6 compare J. V. URI favorably with those of cefoxitin10,rr° through- J. A. WEISBACH out the entire spectrum studied. Based on these data, compound 9 (cefazaflur) still appears to Smith Kline & French Laboratories provide the most advantageous combination of 1500 Spring Garden Street, Philadelphia, gram-positive and gram-negative activities. How- Pennsylvania 19101, U.S.A. ever, the favorable broad-spectrum antibacterial activity of compound 6 as compared to that of (Received July 12, 1976) VOL. XXIX NO. 9 THE JOURNAL OF ANTIBIOTICS 975 References by methoxylation of 7/3-(p-nitrobenzyloxycar- boxamido) cephalosporanic acid. Tetrahedron 1) NAGARAJAN, R.; L. D. BOECK, M. GORMAN, R. Lett. 1974: 1311-1313, 1974 L. HAMILL,C. E. HIGGENS,M. M. HOEHN,W. 7) YANAGISAWA, H.; M. FUKUSHIMA, A. ANDO & M. STARK& J. G. WHITNEY:/3-Lactam anti- H. NAKAO: A novel general method synthesiz- biotics from Streptomyces. J. Am. Chem. Soc. ing for 7a-methoxycephalosporins. Tetrahedron 93: 2308-2310, 1971 Lett. 1975: 2705-2708, 1975, and references 2) STAPLEY, E. 0.; M. JACKSON, S. HERNANDEZ, therein. S. B. ZIMMERMAN,S. A. CURRIE,S. MOCHALES, 8) DEMARINIS, R. M.; J. R. E. HOOVER, G. L. J. M. MATA,H. B. WOODRUFF& D. HENDLIN: DUNN, P. ACTOR,J. V. URIL & J. A. WEISBACH: Cephamycins, a new family of /3-lactam antibio- A new parenteral cephalosporin, SK&F 59962: tics. I. Production by Actinomycetes, including 7-Trifluoromethylthioacetamido-3-(1-methyl-1 H Streptomyces lactamdurans nov. sp. Antimicr. -tetrazol-5ylthiomethyl)1-3-cephem-4-carboxylic Agents & Chemoth. 2: 122-131, 1972 acid. Chemistry and structure-activity relation- 3) CAMA, L. D.; W. J. LEANZA, T. R. BEATTIE & ships. J. Antibiotics 28: 463470, 1975 B. G. CHRISTENSEN: Substituted penicillin and 9) DEMARINIS, R. M.; J. R. E. HOOVER, L. L. LAM, cephalosporin derivatives. I. Stereospecific in- J. V. URI, J. R. GUARINI, L. PHILLIPS, P. ACTOR troduction of the C-6(7) methoxy group. J. Am. & J. A. WEISBACH: Semisynthetic cephalo- Chem. Soc. 94: 1408-1410, 1972 sporins. Synthesis and structure-activity rela- 4) JEN, T.; J. FRAZEE & J. R. E. HOOVER: A tionships of 7-sulfonylacetamido-3-cephem-4- stereospecific synthesis of Cg(7) methoxy- carboxylic acids. J. Med. Chem. 19:754-759,1976 penicillin and -cephalosporin derivatives. J. Org. 10) WALLICK, H. & D. HENDLIN: Cefoxitin, a Chem. 38: 2857-2859, 1973 semisynthetic cephamycin antibiotic: suscepti- 5) KOPPEL, G. A. & R. E. KOEHLER: Functionali- bility studies. Antimicr. Agents & Chemoth. 5: zation of Cg(7) of penicillins and cephalosporins. 2532, 1974 A one-step stereoselective synthesis of 7a- 11) HAMILTON-MILLER, J. M. T. & W. BRUMFITT: methoxycephalosporin C. J. Am. Chem. Soc. Cephamycins: A review, prospects and some 95: 2403-2404, 1973 original observations. Infection 3 : 183-188, 6) LUNN, W. H. W. & E. V. MASON: The synthesis 1975 of 7a-methoxy-7/3-amidocephalosporanicacids .
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