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United States Patent (19) (11) 4,436,912 Wheeler 45) Mar United States Patent (19) (11) 4,436,912 Wheeler 45) Mar. 13, 1984 54) 7-(2-(2-AMINOOXAZOL-4-YL)-2-(OX (56) References Cited MINO)ACETAMIDO CEPHALOSPORIN ANTBOTCS AND INTERMEDIATES U.S. PATENT DOCUMENTS THEREFOR 4,152,432 5/1979 Iteymes et al. ...................... 424/246 (75) Inventor: William J. Wheeler, Indianapolis, 4,258,041 3/1981 O'Callaghan et al............... 424/246 Ind. Primary Examiner-Donald G. Daus Assignee: Eli Lilly and Company, Indianapolis, Assistant Examiner-G. Hendricks (73) Attorney, Agent, or Firm-Paul C. Steinhardt; Arthur R. Ind. Whale; William B. Scanlon (21) Appl. No.: 417,242 57 ABSTRACT Filed: Sep. 13, 1982 22) Cephalosporin broad spectrum antibiotics possessing a Related U.S. Application Data 7A-2-(2-aminooxazol)-4-yl)-2-(substituted OX iminolacetamido side chain and a variety of substituents (62) Division of Ser. No. 300,140, Sep. 8, 1981. at the 3-position of the cephalosporins are claimed. Also (51) Int. Cl............................................. CO7D 263/30 claimed are intermediates in the synthesis of the above (52) U.S. Cl. .................................... 548/233; 548/236; cephalosporin antibiotics. 548/257; 548/473; 544/25; 544/21; 424/246. (58) Field of Search ........................ 548/233,236, 257 25 Claims, No Drawings 4,436,912 1. 2 7-2-(2-AMINOOXAZOL-4-yl)-2-(OX MINOACETAMDO CEPHALOSPORIN O A ANTIBOTCS AND INTERMEDIATES O HN THEREFOR 5 2 t S This application is a division of application Ser. No. 300,140 filed Sept. 8, 1981. YN i?- N BACKGROUND OF THE INVENTION O N / R3 This invention relates to cephalosporin antibiotic OR compounds and intermediates in the synthesis thereof. COOR2 In particular, it relates to cephalosporin compounds substituted in the 7-position with a 2-(2-aminooxazol-4- wherein R1 can be hydrogen, C1 to C4 alkyl or a group yl)-2-(substituted-oximino)acetamido group and in the 15 of the formula 3-position with a variety of substituents, such as fluoro, chloro, bromo, hydroxy, acyloxymethyl, carbamoyl al methyl, substituted and unsubstituted methyl pyridin ium groups and heterocyclic thiomethyl groups con --CH)-cor taining 5- and 6-membered heterocyclic rings. 20 b In recent years, much research has been done in the area of cephalosporins containing a 7-2-(2-amino wherein R' can be, e.g., hydroxy, alkoxy, amino, substi thiazol-4-yl)-2-(substituted oximino)acetamido side tuted amino and m is 0 to 3, R2 can be hydrogen, a chain, with a wide variety of substitutents in the 3-posi pharmaceutically acceptable, non-toxic salt, the hy tion of the cephalosporin. Two of the most notable 25 drates of said salt, or the non-toxic metabolically labile examples of such compounds are the potent antibiotics esters thereof; R3 can be hydrogen, halo, hydroxy, me (a) sodium 7-2-(2-aminothiazol-4-yl)-2-methox thoxy, lowr acyloxyoxymethyl, a group of the formula iminoacetamido)-3-acetoxy-3-cephem-4-carboxylate disclosed by Heymes, et al. in U.S. Pat. No. 4,152,432 and (b) the compound of the formula 30 S O H2N H N S N 6B A N O N CH3 N COOe o–-cooh CH3 50 O 55 a methyl pyridinium group of the formula disclosed by O'Callahan et al. in U.S. Pat. No. T 4,258,041. a M The cephalosporin antibiotics of the instant invention possess excellent antibiotic activity while differing in structure from the aforementioned compounds and other compounds previously disclosed. or a heterocyclic thiomethyl group, wherein the hetero cyclic ring can be a 5- or 6-membered ring at least one SUMMARY OF THE INVENTION 65 nitrogen and up to 3 other heteroatoms chosen from The cephalosporin antibiotics and cephalosporin in nitrogen, sulfur or oxygen. termediates of this invention are represented by the A second aspect of this invention is an intermediate following general formula A. oxime side chain of the general formula B 4,436,912 4. is referred to as the “Z” or "syn' isomer, while the B opposite isomer, represented by the following partial formula O R8-N 10 4K N ^ wherein R1 is the same as in general formula A; G is N chloro, bromo, hydroxy, lower alkoxy, phenoxy, a / group of the formula -O-J wherein J is the residue of RO a group forming an activated ester, or a group of the 15 formula -Oe M6B wherein MGB is a monovalent cation is referred to as the 'E' or "anti' isomer. and R8 is hydrogen or an amino protecting group. It will be understood that since the cephalosporins and the oxime sidechain intermediates of this invention DETALED DESCRIPTION OF THE are geometrical isomers, some admixture between the Z. INVENTION 20 isomer and the corresponding E isomer may occur. This invention is directed to cephalosporin com The cephalosporin compounds of this invention are pounds of the following general formula represented by the following general formula I O I 25 O O O H2N H 1 H2N H N S N S N 7 6 2 N 30 N /85 N 3 N - N N O R3 N O R3 OR1 4. OR1 COOR2 COOR2 35 This invention is also directed to an intermediate used in wherein: the synthesis of the above cephalosporin compounds. R1 is hydrogen, C1 to C4 alkyl, a carboxy-substituted The intermediate compound has the general formula alkyl or carboxy-substituted cycloalkyl group repre 1 40 sented by the formula O H 5 O 3. RsN- - --(CH)- COR' b N G 45 3 N N wherein m is 0 to 3, a and b when taken separately are OR independently hydrogen or C1 to C3 alkyl, or when taken together with the carbon to which they are at and for convenience sake will be referred to in the in tached form a C3 to C7 carbocyclic ring; R is hydroxy, stant application as the "oxime sidechain'. amino, C1 to C4 alkoxy, or -OR', where R' is a car In the formulas contained in this application, the boxy protecting group; or R1 is a secondary amido mark 'a' indicates the b-configuration and the hash line “I” indicates the a-configuration. Also, in the group of the formula formulas contained in this application the geometrical 55 isomer of the oxime function indicated by the following O partial formula -C-NHR'. - O wherein R' is C to C4 alkyl, phenyl or C1 to C3 alkyl 60 substituted by phenyl; R2 is hydrogen, a carboxy pro H RN tecting group or a pharmaceutically acceptable, non toxic salt thereof, the hydrates of said salt, or the non toxic metabolically labile esters thereof; R3 is N J (a) hydrogen, fluoro, brono, chloro, hydroxy, or N 65 N methoxy; or OR (b) (C2 to C4 acyloxy)methyl; or (c) a methyl carbamate group of the formula 4,436,912 5 6 -continued N-N N R7 -CH-O-C-NH-R" 5 X. /X, R7, wherein R' is hydrogen or C1 to C4 alkyl; or R7. / N (d) a methyl pyridinium group of the formula S N R7 re- T 10 69 -CH-N H t / N / o N. / lo wherein T is 15 N / / / / (i) hydrogen, trifluoromethyl, C1 to C4alkyl, C1 to C4 N N O N O alkoxy, hydroxy, cyano, halo or hydroxymethyl; H Or R (ii) carboxy, C1-C4 alkoxycarbonyl, C1 to C4alkanoyl O or C1 to C4 alkanoyloxy; or 20 (iii) an amido group of the formula R7Y^ N N OH N / CH3 / /N \ /N or M N -CON 25 O N N N N N d O wherein c is hydrogen, methyl, ethyl or cyclopro wherein pyl and d is hydrogen, methyl or ethyl; or 30 R5 is hydrogen, C1 to C4 alkyl, -CH2COOH, or (iv) a group of the formula -CH2SO3H; R6 is hydrogen, C1 to C4 alkyl, phenyl or amino; and R7 is hydrogen or C1 to C4 alkyl; provided that, when R2 is hydrogen, R3 is not hy -C-NH-(CH2)-OH 35 droxy. In the foregoing definitions of the cephalosporin wherein p is 2 to 4; provided that: (a) when the compounds, the term "C1 to C4 alky' means methyl, pyridinium ring is substituted with the above sub ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl. stituents in (iv), the pyridinium ring is additionally The term "C1 to C3 alkyl' means methyl, ethyl, pro substituted with R4, wherein R4 is hydrogen or C1 pylor iso-propyl. to C4 alkyl; and (b) when T is hydroxy or halo T is The term "C1 to C4 alkoxy' refers to methoxy, eth only bonded to the 3-position of the pyridinium oxy, n-propoxy, iso-propoxy, sec-butoxy, n-butoxy and ring; or the like. (e) a heterocyclic thiomethyl group of the formula With respect to the term R1 in Formula I, the car -CH2-S-Y, wherein Y is 45 boxy-substituted alkyl group (R' is hydroxy) repre sented by the formula N N N N- N / S. M. M. R. 50 3. N S R6 O R6 --CH)-corb k is illustrated by carboxymethyl, 2-carboxyethyl, 1-car R boxyethyl, 3-carboxypropyl, 2-carboxypropyl, 4-car boxybutyl, 3-carboxypentyl, 4-carboxyheptyl, 2-car N - it is 55 boxybutyl, and the like. When a and b are taken to M N s N s N gether, examples of the carboxy-substituted C3-C7 car S S O bocyclic rings are 1-carboxycycloprop-1-yl, 1-carbox 60 ycyclobut-1-yl, 1-carboxymethylcyclobut-1-yl, 1-car boxycyclopent-1-yl, 1-carboxycyclohex-1-yl, 1-carbox R /\ ycyclohep-1-yl, 1-carboxyethylcyclopent-1-yl, 1-car boxypropylcyclohex-1-yl, and the like.
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