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3-​Chloromethyl oxacephem as a 5-oxa-1-azabicyclo[4.2.0]oct-2-en-8-one heterocycle displayed the potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Importantly, it can be used as a starting material to synthesize Latamoxef and Flomoxef. However, the industrial route of 3-​chloromethyl oxacephem is trival and low yielding. Therefore, discovery a Simple and productive synthetic method is very necessary. The inexpensive 6-Aminopenicillanic acid was used to obtain the 3-​chloromethyl oxacephem in our group.

A series of 1-oxacephem analogs were synthesized and their antibacterial properties against five strains of Gram-positive and Gram-negative bacteria were evaluated in vitro while ceftazidine was selected as control. Some of the tested compounds, compound 12c in particular, showed more active against three selected strains than the standard.

Metallo-beta-lactamases (mbetals) are zinc-dependent enzymes that hydrolyze a wide range of beta-lactam antibiotics. The mbetal active site features an invariant Asp-120 that ligates one of the two metal ions (Zn2) and a metal-bridging water/hydroxide (Wat1). Previous studies show that substitutions at Asp-120 dramatically affect mbetal activity, but no consensus exists as to its role in beta-lactam turnover. Here we present crystal structures of the Asn and Cys mutants of Asp-120 of the L1 mbetal from Stenotrophomonas maltophilia. Both mutants retain a dinuclear zinc center with Wat1 present. In the essentially inactive Cys enzyme Zn2 is displaced to a more buried position relative to that in the wild-type enzyme. In the catalytically impaired Asn enzyme the coordination of Zn2 is altered, neither it nor Wat1 is coordinated by Asn-120, and the N-terminal 19 amino acids, important to cooperative interactions between subunits in the wild-type enzyme, are disordered. Comparison with the structure of L1 complexed with the hydrolyzed oxacephem moxalactam suggests that in the Cys mutant Zn2 can no longer make stabilizing interactions with anionic nitrogen species formed in the hydrolytic reaction. The diminished activity of the Asn mutant arises from a combination of loss of intersubunit interactions and impaired proton transfer to, and reduced interaction of Zn2 with, the substrate amide nitrogen. We conclude that, while interactions of Asp-120 with active site water molecules are important to proton transfer and possibly nucleophilic attack by Wat1, its primary role is to optimally position Zn2 for catalytically important interactions with the charged amide nitrogen of substrate.

All four trans -stereoisomers of 7-(1-hydroxyethyl)-2- iso -oxacephem-4-carboxylic acids, which are the 2- iso -oxacephem analogues of Thienamycin , have been synthesized. (α R ,6 R ,7 R )- and (α S ,6 S ,7 S )-7-(1-hydroxyethyl)-3-methyl-2- iso -oxacephem-4-carboxylic acids have been prepared starting from l - and d -threonine, the configuration at the α-position was inverted by using Mitsunobu reactions providing the (α S ,6 R ,7 R )- and (α R ,6 S ,7 S )-diastereomers of the compounds above. A synthetic route to the cis -annelated analogues was also worked out.

While hospitalized for pneumonia with ventilator-dependent respiratory failure, a 45-year-old man on continuous ambulatory peritoneal dialysis (CAPD) had nosocomial peritonitis secondary to infection by expanded spectrum beta-lactamase producing Klebsiella pneumoniae (ESBL-Kp). He was treated successfully with a 3-week course of intraperitoneal (IP) flomoxef therapy without subsequent relapse, loss of peritoneal catheter, ultrafiltration failure, or dialysis inadequacy. The International Consensus Panel recommends IP ceftazidime as the treatment of choice for CAPD patients suffering Klebsiella species-related peritonitis. However, the most appropriate form of IP antibiotic therapy and the outcomes for expanded-spectrum beta-lactamase (ESBL)-producing bacteria-related peritonitis for CAPD patients have not been established yet. Further, the ability to correctly report minimal inhibitory concentrations (MICs) of ceftazidime for ESBL bacteria in the resistant range varies between laboratories, making the diagnosis of ESBL-Kp-related CAPD peritonitis more complex and difficult. Thus, it appears reasonable to suggest that its incidence is probably underestimated and its significance ignored. The authors suggest that a 3-week IP treatment with flomoxef, a synthesized oxacephem, with loading and maintenance doses of 250 and 125 mg/L, respectively, is effective and safe for ESBL-Kp-related peritonitis in these patients. ESBL producing bacterial infection should be considered as a possible cause of overt CAPD-related peritonitis. Early detection of ESBLB pathogens and institution of effective antibiotic treatment may improve the prognosis.

Tripropeptin C (TPPC) is a natural calcium-ion-dependent lipopeptide antibiotic that inhibits peptidoglycan biosynthesis by binding to prenyl pyrophosphate. It displays very potent antimicrobial activity both in vitro and in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) septicemia. The combination of TPPC with all classes of beta-lactams tested (including penam, carbapenem, cephem and oxacephem) showed highly synergistic (SYN) effects against MRSA strains, but not against methicillin-sensitive S. aureus strains. These SYN effects were observed with both a checkerboard methodology and a time-kill analysis. The TPPC analog, bis-methyl ester-TPPC, which has neither antimicrobial activity nor the ability to bind prenyl pyrophosphate, also potentiated the activity of beta-lactams. This result indicates that the mechanism of the SYN activity of TPPC is independent of its binding to prenyl pyrophosphate. Therefore, synergistically enhancing the anti-MRSA activities of TPPC and beta-lactams by combining them is a novel and potentially powerful therapeutic strategy for MRSA infections.

[2+2]Cycloaddition of chlorosulfonyl isocyanate to 3-O-vinyl ethers derived from D-glucose and D-glucuronolactone proceeded with an excellent stereoselectivity to provide azetidin-2-ones with (R) configuration at C-4′. Intramolecular N-alkylation afforded 1-oxabicyclic-β-lactams having six- or seven-membered ring fused to the four-membered one.

General methods have been developed for the synthesis of 7-amino-2-iso-oxacephem-4-carboxylic acid esters 21a,b; 35b. Clayfen [Fe(III) nitrate supported by montmorillonite] was used for the preparation of benzyl 2,3-dioxobutyrate (3). The latter readily reacted with N(1)-unsubstituted β-lactams (9a, 28) to give products formed by addition reaction on the middle carbonyl-C atom. These intermediates furnished the corresponding acetoacetic esters 10, 29 which gave by ring closure the O-mono- and the O,N-diprotected-2-iso-oxacephems (11, 30). Intermolecular carbene insertion was used for the synthesis of tert-butyl 2-(2-oxoazetidin-1-yl)acetoacetates 19a,b whose ring closure led to the tert-butyl 2-iso-oxa-cephem-4-carboxylates 20a,b. The O-protecting tert-butyl group could be removed without decomposition of the 2-isooxacephem moiety to give 2-iso-oxacephem-4-carboxylic acids 2a,b which exhibit antibacterial activity against Grampositive microorganisms.

2,4,6-Tri-O-benzyl-D-galactal (1) was transformed into a 1-oxacephem skeleton. The sequence of reaction involved: [2+2]cycloaddition, N-alkylation, glycolic cleavage of the vic-diol grouping, reduction of dialdehyde and cyclization to the title skeleton.

This paper reports the first attempt to characterize the penicillin-binding proteins (PBPs) of Shigella dysenteriae, an important human pathogen. The PBP pattern of the membranes of S. dysenteriae closely resembles that of Escherichia coli membranes. A 38 kDa PBP which is an important target for the penem SCH34343, the cephamycin cefoxitin and the oxacephem moxalactam, has been purified. This PBP is immunologically related to a PBP of similar molecular mass in E. coli and is present at high levels in stationary-phase cells of S. dysenteriae.

The effect of flomoxef as empiric therapy for surgical infections of the digestive organs was analyzed in 103 patients, most of whom (94.2%) had intra-abdominal infections. Surgical procedures were performed on 73 patients contemporaneously with the flomoxef therapy. Flomoxef is an oxacephem and has a potent and broad bactericidal spectrum against aerobes and anaerobes. It provokes fewer adverse reactions than latamoxef such as vitamin K deficiency and platelet dysfunction. Flomoxef was administered intravenously at a dose 1-4g/day for more than 3 days without any other antimicrobial agent. The clinical response was classified into 3 groups; cured, improved and failed, and both the cured and improved responses were defined as satisfactory. A satisfactory response was obtained in 99 patients (96.1%). Regarding bacteriological response, the overall eradication rate was 81.3%. Adverse reactions including abnormal laboratory data occurred in only two patients. One had abdominal pain, and the other had a mild elevation of transaminases, and both were mild and easily reversible. Therefore, flomoxef is considered to have the potential of becoming one of the most effective agents in empiric therapy for surgical infections of the digestive organs.

The therapeutic perspectives of flomoxef, SCE 2787, cefpirome, cefepime, latamoxef, cefotaxime and of piperacillin plus tazobactam were comparatively evaluated by theirin vitro activity against 1119 clinical isolates of 83 bacterial species.Escherichia coli, Klebsiella spp.Enterobacter sakazakii, Proteus spp. andShigella spp. were about equally susceptible to the cephalosporins (MIC90: 0.06 to 0.5 mg/l), while the MIC90 for piperacillin plus tazobactam was between 2 and 16 mg/l.Enterobacter cloacae, Enterobacter aerogenes andSerratia spp. were most susceptible to SCE 2787, cefpirome and cefepime (MIC90: 0.06 to 2 mg/l) followed by latamoxef, cefotaxime, flomoxef and piperacillin plus tazobactam. ForCitrobacter spp.,Providencia spp. andYersinia enterocolitica MIC90 were between 0.06 and 0.5 mg/l. Flomoxef was between 2 to 4 log2 less active against these species but more active than piperacillin plus tazobactam (MIC90: 2 and 8 mg/l).Morganella morganii andHafnia alvei were most susceptible to cefepime, cefpirome and latamoxef (MIC90: 0.13 to 0.5 mg/l) while cefotaxime (MIC90: 8 mg/l) and piperacillin plus tazobactam (MIC90: 8 and > 64 mg/l) were the least active compounds. SCE 2787, cefepime and cefpirome were the most potent beta-lactams against the majority of the 13 species of non-fermentative bacilli (NFB) investigated (MIC90: 0.5 to 16 mg/l). The oxacephems were the least active compounds against NFB. Cefepime was the most active of the compounds included againstPseudomonas aeruginosa (MIC90: 16 mg/l).Haemophilus spp.,Neisseria gonorrhoeae andBordetella pertussis were most susceptible to cefotaxime (MIC90: 0.03 to 0.06 mg/l). Latamoxef had the lowest activity of all compounds against gram-positive cocci. Flomoxef was the most active compound against penicillinase producingStaphylococcus aureus and about equally active as the other betalactams against methicillin susceptible staphylococci of other staphylococcal species. Non-enterococcal streptococci had MIC90 between 0.03 und 0.5 mg/l for all.Streptococcus pneumoniae with MICs for penicillin equal to or above 1 mg/l were between 16 and 64 times less susceptible (MIC90: between 0.5 and 4 mg/l) than penicillin-susceptible organisms (MIC90: between 0.03 and 0.13 mg/l). Flomoxef and piperacillin plus tazobactam were the most active of the compounds against anaerobic organisms. The oxacephem flomoxef was the most stable of the compounds included against novel extended broad spectrum beta-lactamases (TEM-3 to TEM-7, SHV-2 to SHV 5, CMY-1, CTX-M-1) followed by latamoxef. However, both oxacephamycins are hydrolysed by cephamycinases while SCE 2787, cefepime and cefpirome are stable against cephamycinases. Progress in antibacterial activity of parenteral cephalosporins was achieved both by structural modifications (of latamoxef or cefotaxime) and combination of piperacillin with taxobactam. Flomoxef in comparison with latamoxef extended its spectrum to include staphylococci and increased activity against non-enterococcal streptococci 16 to 32 times. The various structural modifications of cefotaxime at position 3 of the cephalosporin ring improved the antibacterial profile of SCE 2787, cefepime and cefpirome in very much the same way (enhanced activity mainly against organisms producing chromosomal cephalosporinases, e. g.Enterobacter spp.,Serratia spp.,H. alvei, M. morganii and non-fermentative bacilli). Tazobactam protects piperacillin against plasmidic beta-lactamases, however, this was achieved to an even higher extent by the structural modifications of aminothiazole-methoximino cephalosporins (SCE 2787, cefepime and cefpirome) and in particular of flomoxef.

A pioneering work in the field of oxacephem antibiotics which had been carried out in our research laboratories is reviewed. Our research of beta-lactam antibiotics was started in 1974 with the policy to make chemical modification at the nuclei but not the side chain of the existing beta-lactam antibiotics, with an expectation to discover a new type of antibiotics. After the success in establishing an efficient synthetic method for 3'-norcephalosporin, we started oxacephem research in 1975. We succeeded in developing three synthetic methods starting from penicillins which efficiently served to prepare numerous oxacephem (1-oxa-1-dethia-cephalosporin) derivatives. It turned out that the oxacephem nucleus was much more distorted with an increased ring strain, resulting in reduction of the beta-lactam amide resonance to a greater extent than the cephalosporin nucleus. This physicochemical properties conferred an increased chemical reactivity on the nucleus as evidenced by an increased hydrolysis rate as compared with the corresponding 1-thia counterpart. This increased chemical reactivity coupled with the reduced hydrophobicity of the oxacephem nucleus as evidenced by the lower distribution constant in a water-octanol system, characterized unique biological properties of oxacephem derivatives. These include (1) 2-16 times increase in antibacterial activity with emphasis against gram-negative bacteria; (2) increased protecting effect in vivo parallel to the increased in vitro activity; (3) reduction of the stability to beta-lactamases leading to decreased antibacterial activity against the beta-lactamase producing strains; (4) 1.6-3.2 times increase in penetrability through the outer membrane of certain gram-negative bacteria, the increase being due to the increased hydrophilicity of the oxacephem nucleus; (5) remarkably reduced binding to human serum albumin improving the efficacy of the oxacephems in the blood; (6) a remarkable change in the excretion pattern, i.e. recovery in the bile reduced and that in the urine increased. These biological characteristics are generally favorable for antibacterial agents against pathogenic diseases except for the reduced stability to beta-lactamases. This unfavorable property of the oxacephem nucleus was the only barrier for developing a new agent of the oxacephem nucleus. However, this problem was relatively easily solved by introduction of (1) the methoxy group at 7 alpha and (2) appropriately alpha-substituted acyl amide chain at 7 beta; the former and the latter substituent effectively stabilized the oxacephems to various kinds of penicillinases and cephalosporinases, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Methicillin- and cephem-resistant Staphylococcus aureus (MRSA) strains were found to be unable to grow in sputum from patients treated with a beta-lactam antibiotic. Sputum containing no beta-lactams also exhibited bactericidal activity when the MRSA strain was pretreated with a subinhibitory concentration of a beta-lactam; however, lysozyme-free sputum was inactive. Peptidoglycan of MRSA grown in the presence of cefazolin was susceptible to lysis by respiratory mucus. Hen albumen lysozyme contained the same activity against beta-lactam-treated MRSA. The median minimum inhibitory concentration of cefazolin for 45 S. aureus strains (including 20 MRSA strains) shifted from approximately 50 micrograms/ml to approximately 0.78 microgram/ml by addition of 1 mg/ml of hen albumen lysozyme to susceptibility-testing media. Such lysozyme-dependent antistaphylococcal activity was manifested specifically with beta-lactams (9 penicillins, 10 cephalosporins, 3 cephamycins, 1 oxacephem, and 1 carbapenem).

A convenient synthesis of precursors of bicyclic β-lactam compounds from 4-acetoxy-1-(bistrimethylsilylmethyl)azetidin-2-ones prepared in few steps from the acid chloride-imine approach is described. A novel method to construct a bicyclic β-lactam ring system through an intramolecular Peterson type alkenation catalyzed by fluoride ion is also made.

Summary: 1. Assay methods to detect drug interaction in toxicological samples were established by determining cytochrome P450 content and its activity in liver samples. The O-dealkylation reaction of 7-alkoxycoumarin was indicated to reflect changes in the molecular forms of P450s, and the enzyme induction or inhibition in the toxicological samples was easily detected by using the established methods. 2. During toxicological studies of 450191-S or the sleep inducer rilmazafone, a phenobarbital type-induction of hepatic drug metabolizing enzymes was observed in animals, and the doses required for the induction differed markedly between rats and dogs. Enzyme induction was caused by some specific metabolites of 450191-S, and the plasma concentrations of these metabolites were comparable when the enzyme induction was developed in both animals. 3. A nonsteroidal antiinflammatory compound 480156-S showed a slight or no effect on microsomal drug metabolizing activity in rats. On the other hand, repeated administration of this compound to humans resulted in a marked decrease in the oxidative metabolism of 480156-S, followed by a marked increase in the plasma concentrations of the compound. When volunteers were given 480156-S followed by several drugs, such as tolubutamide, the plasma clearance was delayed remarkably, indicating a severe drug interaction. 4. Cytochrome P450 belonging to the CYP2C family was indicated to participate in the oxidative metabolism of 480156-S in both rat and human liver microsomes. The preincubation of microsomes with 480156-S caused a concentration-dependent inhibition of CYP2C-dependent tolubutamide hydroxylation reaction in both rats and humans. There was a marked species difference in the susceptibility to the inhibitory effect of 480156-S, and the concentration required to inhibit rat CYP2C was almost 10 times higher than that required in humans. 5. The cephem antibiotics having N-methyltetrazolethiol (NMTT) at the 3' -position substituent were demonstrated to inhibit mitochondrial low K m aldehyde dehydrogenase (ALDH), and produced disulfiram-like (Antabuse) reaction during alcohol metabolism. Pharmacokinetic studies indicated that NMTT released from the antibiotics in bile duct or intestine cause the inhibitory action followed by the development of disulfiram-like reaction. 6. Attempts had been made to develop new cephem antibiotics lacking the disulfiram-like reaction by changing the chemical structure of 3'-position substituents, and a hydroxyethyltetrazolethiol was found not to inhibit the enzyme. Based on this result, together with the antibacterial activity, we have developed a new oxacephem antibiotic flomoxef (6315-S). Flomoxef showed no disulfiram-like reaction both in rats and human.

We previously reported that the biliary excretion of flomoxef, an oxacephem antibiotic, was greater after dosing at 21:00 than at 09:00 h in diurnally active human subjects. The present study was undertaken to examine whether the biliary excretion of flomoxef is also dependent on its dosing time in rats. Adult male Wistar rats were housed under light on at 07:00 h and off at 19:00 h. Bile fluid was completely drained through a polyethylene catheter from conscious animals. Flomoxef (20 mg/kg) was injected into the tail vein at 09:00 or 21:00 h by a cross-over design, and drained bile fluid was collected for 8 h after each dosing. The maximum concentration of biliary flomoxef was significantly greater and its total excretion tended to be greater after dosing at 09:00 than 21:00 h. These results suggest the biliary excretion of flomoxef is enhanced after dosing at the beginning of the rest period in rats, as it is in humans.

1-Oxacephem derivatives were synthesized and evaluated as a novel series of chymase inhibitors. Structure-activity relationship studies of 1-oxacephems led to compound 34, which exhibited 6 nM inhibition of human chymase and high selectivity for human chymase compared to other serine enzymes.

1-Oxacephem derivatives were evaluated as a novel series of chymase inhibitors. The structure-activity relationship studies of 1-oxacephems led to compounds 15, which exhibited 27 nM inhibition of human chymase and improvement of stability in human plasma (t 1/2 1.5 h).

1-Oxacephem derivatives were synthesized and evaluated as a novel series of chymase inhibitors. Structure-activity relationship studies of 1-oxacephems led to compound 34, which exhibited 6 nM inhibition of human chymase and high selectivity for human chymase compared to other serine enzymes.

1-Oxacephem derivatives were evaluated as a novel series of chymase inhibitors. The structure-activity relationship studies of 1-oxacephems led to compounds 15, which exhibited 27 nM inhibition of human chymase and improvement of stability in human plasma (t 1/2 1.5 h).

The in vivo antibacterial activities of 7alpha-methoxy-cephems or 7alpha-methoxy-1-oxacephems and their demethoxy congeners after oral administration were compared in a mouse model of gastric infection with Helicobacter felis. The MICs of all four pairs of compounds with and without the 7alpha-methoxy substituent were within one two-fold dilution for H. felis and Helicobacter pylori, but the 7alpha-methoxy compounds were at least four-fold more active at bacterial eradication than their demethoxy congeners. Since these compounds are not absorbed after oral administration, they are likely to have gained direct access to the bacteria from the gastric cavity. Thus the 7alpha-methoxy substituent may enhance in vivo activity by promoting the gastric mucus permeability of the compounds or by allowing the compounds to remain longer in the gastric cavity.

Flomoxef is a new oxacephem of broad antibacterial activity. The compound is mainly excreted through the kidneys. Two dose finding studies in patients with various degrees of renal insufficiency revealed that the dosage of flomoxef has to be reduced exactly according to the renal function. Although the N-methylthiotetrazole group has been replaced by a hydroxyethyl group, an inhibitory effect of flomoxef on vitamin K metabolism persisted. This effect was, however, less pronounced than with latamoxef. Only patients with low vitamin K stores are endangered. For those in whom low vitamin K stores are suspected repeated controls of prothrombin time are advised during the treatment. In contrast to latamoxef the platelet system was not affected by flomoxef. With the exception of loose stools in some patients no other clinical side effects during treatment were observed.

1-Oxacephem antibiotics, in which the 1-sulfur atom in cephalosporins is replaced by oxygen, show marked enhancement in their antibacterial activity. This finding led to intensive efforts toward establishing a stereocontrolled and industrially feasible method for their production. One method along a synthetic route involving epi-oxazoline (46), allylic alcohol (47), its cyclized 3-methylene-1- oxacepham (48) and 7α-methoxy-7β-amino-1-oxacephem (41) was found to be the most efficient for producing 1-oxacephamycin-type antibiotics, such as latamoxef (11a), flomoxef (11b), and 2355-S (11c).

The stereoselective syntheses of 3-substituted 2α- and 2β-methyl-1-oxacephems have been achieved through the intramolecular Wittig condensations of 4-(1-methylpropoxy)azetidinones

The 2α- and 2β-methyl-1-oxacephems were synthesized stereoselectively starting from (3R,4S)-oxazolinoazetidinone by reaction with chiral alcohols followed by intramolecular carbene insertion of α-diazo-β-keto intermediates

A series of 7 alpha-hydroxyethyl-1-oxacephems (1) was synthesized. The main focus of this study was to investigate biological activity relationships between 1-oxacephems (1) and the corresponding cephems (2). Replacement of the sulfur atom of 2 by the oxygen atom caused an enhancement of antibacterial activity, although the antibacterial activity of 1 was not high enough. Additionally 1 showed beta-lactamase inhibitory activity, especially against cephalosporinase. However, the potency was lower than that of 2.

The MIC values of 99 isolates of Enterobacteriaceae to 11 of the newer beta-lactam antibiotics, and 25 isolates of Pseudomonas aeruginosa to 9 of these drugs were compared with representatives of the established beta-lactam antibiotics and gentamicin. The MIC values for the newer agents were significantly lower in comparison with the older reference compounds. The potential clinical use of these newer antibiotics is discussed.

The thioformimidate 4, which may be obtained by S-methylation of 5 reacts with chloroacetyl chloride/triethylamine to yield the trans-2-azetidinone 7. 7 is dehalogenated to 8. Removal of the protective group leads to 9, which undergoes ring closure by the action with mercuric chloride/ mercuric oxide. Chlorolysis of 8 and the subsequent reaction with hydrofluoric acid/acetonitrile yields 12. The treatment of 12 with silver tetrafluoroborate/silver oxide gives also the title compound 10

The stability of sodium latamoxef (Shiomarin; LMOX) in aqueous solution, a newly developed oxacephem antibiotic for injection, was tested at 5°, room temperature (20±5°), and 37°. Decomposition products were studied with thin-layer chromatography, bioautography and spectrophotometry. Furthermore, the residual potency was determined by a microbiological assay (cylinder-plate method). The results were as follows:1) LMOX (1g (potenty)/10ml) aqueous solution showed changes in color, without any variation in pH after 7 days. Its residual potency after 7 days was 95.1%. The residual potencies after 24 hours were 99.0% at 5° with increased color intensity, 96.5% at 20° and 82.6% at 37°. 2) Aqueous solution of LMOX showed no color change at pH 3.60, but developed a light brown color at pH 8.00 and a light blue color at pH 10.00. No decrease in potency was observed after 24 hours at pH 3.60-10.10 at 5° or pH 3.60-9.00 at 20° and after 6 hours at pH 3.60-10.00 at 37°.

Triethyl phosphite-induced cyclisation of 1-oxalyl-4-(alkylthio-thionocarbonylthiomethyl or -oxymethyl)-2-azetidinones provides novel 3-alkylthio isocephems and isooxacephems.

The synthesis of tert-butyl 3-benzyl-1-oxa-Δ3-cephem-4-carboxylate (16) and other bicyclic β-lactams is described.

Reaction of penicillin sulfoxides with a tervalent phosphorous compound in the presence of a catalytic amount of squaric acid gave oxazolinoazetidinones, potential intermediates for synthesis of 1-oxacephems, in good yields.2β-Chloromethyl- and 6α-methoxypenicillin sulfoxides also undergo this reaction. The reaction contrasts with the well-known Cooper reaction which usually gives thiazolinoazetidinones.

6315-S, a novel difluoromethyl thioacetamido oxacephem, had in vitro activity comparable to that of cefotaxime and moxalactam against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Klebsiella oxytoca, Citrobacter diversus, Salmonella spp., and Shigella spp., inhibiting 90% at less than or equal to 0.25 microgram/ml. It inhibited piperacillin- and cefoperazone-resistant isolates in these species. 6315-S did not inhibit cefotaxime- or moxalactam-resistant Citrobacter freundii, Enterobacter aerogenes, or Enterobacter cloacae (MICs for 90% of the strains tested were greater than or equal to 16 micrograms/ml). Proteus vulgaris resistant to cefotaxime was inhibited. Pseudomonas species and Acinetobacter species were resistant (MICs greater than 64 micrograms/ml). MICs for 90% of the Staphylococcus aureus and S. epidermidis isolates were 4 micrograms/ml. 6315-S was highly active against anaerobic species of Clostridium, Fusobacterium, Bacteroides, and peptostreptococci and was superior to other agents against these organisms. 6315-S was not hydrolyzed by the major plasmid and chromosomal beta-lactamases, but it induced chromosomal beta-lactamases in Enterobacter cloacae and Pseudomonas aeruginosa.

1-Oxacephem skeletons were constructed in a convergent manner starting from building blocks B and C , which were easily prepared from penicillin and diketene, respectively, followed by intramolecular carbene insertion reaction of the resulting intermediate A .

The susceptibility of 113 strains of pathogenic Nocardia, N. asteroides, N. farcinica, N. nova, N. brasiliensis and N. otitidiscaviarum to a new oxacephem antibiotic flomoxef was determined by an agar dilution method in comparison with those of 13 other cephalosporins. Flomoxef was two to 50 times more active against these pathogenic Nocardia than other cephalopsorins tested. However, there were differences in susceptibility to this antibiotic among these Nocardia strains. N. asteroides was the most sensitive species, followed by N. farcinica and N. nova. N. brasiliensis was moderately sensitive and N. otitidiscaviarum was resistant.

The synthesis and in vitro activity of 7 beta-difluoromethylthioacetamido-7 alpha-methoxy-3-[[1-(hydroxyethyl)-1H- tetrazol-5-yl]thiomethyl]-1-oxa-3-cephem-4-carboxylic acid sodium salt, 6315-S, are described. 6315-S shows good antibacterial activity against Gram-positive and Gram-negative bacteria, being especially highly active against clinical isolates of Staphylococcus aureus resistant to either ampicillin or methicillin. The structure-activity relationship of related 1-oxa and 1-thia cephems is also presented.

Latamoxef, 1-S replaced and/or decarboxylated derivatives of latamoxef, compounds possessing a partial structure of latamoxef, and a beta-lactam ring-opened derivative of latamoxef were examined for their effects on human platelet aggregation in vitro. Latamoxef produced a dose-dependent inhibition of ADP-induced platelet aggregation at high concentrations over about 2000 micrograms/ml (or 4 mM), and the potency was similar to that produced by cefotaxime, carbenicillin or ceftizoxime. Replacement of the oxygen atom in the oxacephem ring with a sulfur atom caused no significant change in the potency. The decarboxylated derivatives of latamoxef and the 1-S replaced analogue of latamoxef showed stronger inhibition for both ADP- and collagen-induced aggregation than the parent compounds. The effects of the compounds possessing a partial structure of latamoxef were weaker than that of latamoxef, but the effect of the beta-lactam ring-opened compound was about 3-fold stronger than that of latamoxef. These data suggest that neither the oxygen atom in the oxacephem ring nor the carboxyl group in the amide side chain is responsible for the inhibitory effect of latamoxef on platelet aggregation.

A number of new optically active 1-oxacephem compounds were synthesized and tested for antibacterial activity. Various 7 alpha-unsubstituted 1-oxacephem nuclei 2a approximately 3 and a 7 alpha-methoxy-1-oxacephem nucleus 3, reported previously, were converted into the corresponding phenylacetylamino-, 2-thienylacetylamino-, D-mandelylamino-, D-phenylglycylamino-, and arylmalonylamino-1-oxacephem carboxylic acids. All the compounds except for the phenylglycylamine derivatives exhibited four-to sixteen-fold enhanced antibacterial activity compared with that of the corresponding cephalosporins. A combination of the 7 alpha-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-oxacephem nucleus and a 7 beta-arylmalonylamino side chain, as represented by compound 1 (disodium salt of 33), produced the highest efficacy among them: high antibacterial activity with a widely expanded spectrum against Gram-negative bacteria including resistant strains and Pseudomonas aeruginosa was observed.

Progress in synthetic studies on 1-oxacephems is reviewed. Antibacterial activity of this new class of compounds is also discussed briefly. Earlier syntheses, rather lengthy but quite pioneering, provided us with valuable information of the interesting biological activity of 1-oxacephems. Several improved synthesis have appeared, enabling to prepare a variety of derivatives and examine their antibacterial activity. Thus, syntheses and antibacterial activity of some interesting 1-oxacephems and 7α-methoxy-1-oxacephems, such as, arylmalonamido-, α-acylureidophenylacetamido-, and α-aminothiazolyl-α-methoxyiminoacetamido derivatives with representative 3'-substituents are described. A compound 6059-S 98 discovered in Shionogi Research Laboratories, proved to have excellent antibacterial activity, spectrum, and other pharmacological properties and, therefore, is currently under clinical studies. An industrially feasible synthetic method for its nucleus 88 a as well as 7α-methoxy-1-oxacephem nuclei with a variety of substituents at the 3'-position in general was established after extensive studies.