Wehave studied an ester prodrug of a carbapenem to develop a potent orally active /Mactam antibiotic. A variety of l/?-methylcarbapenem derivatives have been synthesized. We have found that some derivatives having an amide group in the C-2 side chain show potent and well balanced antibacterial activities as well as high stability against dehydropeptidase-I. Oral absorption of derivatives has been optimized by modifying the C-3 ester promoiety. Pivaloyloxymethyl (li?,5S,6S)-6-[(JR)-l-hydroxyethyl]-l-methyl-2-[(jR)-5-oxopyrrolidin-3-ylthio]-l-carbapen-2-em-3-carboxylate, CS-834, has been selected as the most promising compound for further evaluation. An orally active antibiotic with potent activity is of much interest in the clinical realm because oral administration and lower dosage are advantageous for patients. Carbapenems are the most potent jS-lactam antibiotics which have a broad antibacterial spectrum and potent bactericidal activities against both Gram-positive and-negative organisms.1>2) They are highly resistant to hydrolysis by a variety of /Mactamases. So far, imipenem,3) panipenem4) and meropenem5)have been launched on the market, and several compounds are currently under clinical evaluation.6~8) However, most compoundshave been developed for parenteral use, and none for the practical purpose of oral administration. Currently, tricyclic /Mactam antibiotics, GV-1 04326 and its ester GV-118819, have been developed. GV-118819 is now under clinical study as an oral antiinfective drug.9-ll)

N,N′-Disubstituted phenylpropiolamidines were synthesized from phenylacetylene and carbodiimides. They were inert toward nucleophiles in a neutral or basic medium, but reactive in an acidic one. They reacted in the presence of hydrogen chloride with hydroxylamine, hydrazine, and arylhydrazines to give 5-N-substituted amino-3-phenylisoxazoles, 5-N-substituted amino-3-phenylpyrazole and 5-N-substituted amino-1-aryl-3-phenylpyrazoles, respectively, by nucleophilic addition followed by cyclization. The reaction mechanism is discussed on the basis of the structures of these heterocyclic compounds.

The synthesis and in vitro antimicrobial activity of a new penem antibiotic, sodium (5R, 6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-carboxylate (1), are reported. The MIC values of 1 are compared with those of some related 2-halcalkylthio penems prepared in this work, and also Sch 29482 and thienamycin. Nonclassical 13-lactam antibiotics, penems and carbapenems have received extensive attention since the pioneering synthetic work Of WOODWARD2) and the discovery of thienamycin (THM)3~6) Among penems, Sch 294827) and FCE 221018) have been reported to be potent broad-spectrum antibiotics. From the viewpoint of molecular modification, new penem derivatives having the fluoroal-kylthio group at 2-position were of particular interest to us since the introduction of fluorine atom does influence biological properties such as antimicrobial activity, pharmacokinetics and metabolism of those penems9,10). As a result of extensive syntheses of 2-fluoroalkylthio penems, we ultimately obtained a new penem, sodium (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-car-boxylate (1), having potent in vitro and in vivo activity against wide range of bacteria. Synthesis For the synthesis of 1, we utilized thioxopenam which was developed by MIYADERA et al. in our research laboratories11). Alkylation reaction of p-nitrobenzyl (5S,6S)-6-[(lR)-1-tert-butyldimethyl-silyloxyethyl]-2-thioxopenam-3-carboxylate (2) with 1-bromo-2-fluoroethane was carried out in nitromethane in the presence of triethylamine at room temperature for 3 days to give cis 2-fluoroethyl-thio penem 3 in 23 % yield as shown in Chart 2. The cis penem 3 isomerized to the trans penem 4 by heating in xylene containing a small amount of hydroquinone at 135°C for 3 hours and reached equilibrium in which the ratio of 3:4 was ca. 1: 2.6. After separation of 3 and 4 by chromatography through a Lobar column, 4 was subjected to equilibration again and eventually 4 was obtained in 75 % yield. Presumably, this equilibrium would occur via betaine intermediate 6. The deprotection of tert-butyldimethylsilyl group with tetrabutylammonium fluoride in THE furnished the hydroxy penem 5 in 81 % yield. The conversion of 5 into 1 was achieved by hydrogenolysis over 10 % Pd-C in THF-phosphate buffer in 90% yield. Other structurally related 2-haloalkylthio penems 7-12 were prepared by alkylation reactions of the thioxopenam 2 with halogen substituted alkylhalide, modified MITSUNORU reactions12) of 2 with alcohols, and intramolecular Wittig-type reactions between phosphoranes and trithiocarbonates which were developed by WOODWARD et al.13). The details of t See ref 1. tt Present address:

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