Latamoxef

Latamoxef
Systematic (IUPAC) name
(6R,7R)-7-{[carboxy(4-hydroxyphenyl)acetyl]amino}-7-methoxy-3-{[(1-methyl-1H-tetrazol-5-yl)thio]methyl}-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration		 Intramuscular, intravenous
Pharmacokinetic data
Protein binding 35 to 50%
Metabolism Nil
Biological half-life 2 hours
Excretion Mostly renal, unchanged; also biliary
Identifiers
CAS Number 64952-97-2 YesY
ATC code J01DD06 (WHO)
PubChem CID 47499
DrugBank DB04570 N
ChemSpider 43215 YesY
UNII VUF6C936Z3 YesY
KEGG D08109 YesY
ChEBI CHEBI:599928 N
ChEMBL CHEMBL74632 YesY
Chemical data
Formula C20H20N6O9S
Molar mass 520.474 g/mol
 NYesY (what is this?)  (verify)

Latamoxef (or moxalactam) is an oxacephem antibiotic usually grouped with the cephalosporins. In oxacephems such as latamoxef, the sulfur atom of the cephalosporin core is replaced with an oxygen atom.

Latamoxef has been associated with prolonged bleeding time, and several cases of coagulopathy, some fatal, were reported during the 1980s.[1][2] Latamoxef is no longer available in the United States. As with other cephalosporins with a methylthiotetrazole side chain, latamoxef causes an antabuse reaction when mixed with alcohol. Additionally, the methylthiotetrazole side chain inhibits γ-carboxylation of glutamic acid; this can interfere with the actions of vitamin K.

It has been described as a third-generation cephalosporin.[3]

Synthesis

Oxa-substituted third generation cephalosporin antibiotic (oxacephalosporin).

Moxalactam synthesis:[4][5][6][7] (excerpt from Lednicer book 3)

The benzhydrol ester of 6-Aminopenicillanic acid (6-APA) is S-chlorinated and treated with base whereupon the intermediate sulfenyl chloride fragments (to 2). Next, displacement with propargyl alcohol in the presence of zinc chloride gives predominanntly the stereochemistry represented by diastereoisomer 3. The side chain is protected as the phenylacetylamide; the triple bond is partially reduced with a 5% Pd-CaCO3 (Lindlar catalyst) and then epoxidized with mCPBA to give 4. The epoxide is opened at the least hindered end with 1-methyl-1H-tetrazole-5-thiol to put in place the future C-3 side chain and give intermediate 5. Jones oxidation followed in turn by ozonolysis (reductive work-up with zinc-AcOH) and reaction with SOCl2 and pyridine give halide 6. The stage is now wet for intramolecular Wittig reaction. Displacement with PPh3 and Wittig olefination gives 1-oxacephem 7. Next a sequence is undertaken of side chain exchange and introduction of a 7-methoxyl group analogous to that which is present in cephamycins and gives them the enhanced beta-lactamase stability. First 7 is converted to the imino chloride with PCl5 and then to the imino methyl ether (with methanol) and next hydrolyzed to the free amine (8). Imine formation with 3,5-di-t-butyl-4-hydroxybenzaldehyde is next carried out leading to 9. Oxidation with nickel peroxide gives iminoquinone methide 10, to which methanol is added in a conjugate sense and in the sterechemistry represented by formula 11. The imine is exchanged with Girard's reagent T to give 12, and this is acylated by a suitable protected arylmalonate, as the hemiester hemiacid chloride so as to give 11. Deblocking with aluminium chloride and anisole gives moxalactam 14.

References

  1. ↑ Weitekamp MR, Aber RC (1983). "Prolonged bleeding times and bleeding diathesis associated with moxalactam administration". JAMA 249 (1): 69–71. doi:10.1001/jama.249.1.69. PMID 6217353.
  2. ↑ Brown RB, Klar J, Lemeshow S, Teres D, Pastides H, Sands M (1986). "Enhanced bleeding with cefoxitin or moxalactam. Statistical analysis within a defined population of 1493 patients". Arch Intern Med 146 (11): 2159–64. doi:10.1001/archinte.146.11.2159. PMID 3778044.
  3. ↑ Salem RR, McIndoe A, Matkin JA, Lidou AC, Clarke A, Wood CB (June 1987). "The hematologic effects of latamoxef sodium when used as a prophylaxis during surgical treatment". Surg Gynecol Obstet 164 (6): 525–9. PMID 3296254.
  4. ↑ M. Narisada, W. Nagata, DE 2713370; eidem, U.S. Patent 4,138,486 (1977, 1979 both to Shionogi).
  5. ↑ Narisada, Masayuki; Yoshida, Tadashi; Onoue, Hiroshi; Ohtani, Mitsuaki; Okada, Tetsuo; Tsuji, Teruji; Kikkawa, Ikuo; Haga, Nobuhiro; Satoh, Hisashi; et al. (1979). "Synthetic studies on β-lactam antibiotics. Part 10. Synthesis of 7β-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7.alpha.-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt (6059-S) and its related 1-oxacephems". Journal of Medicinal Chemistry 22 (7): 757–9. doi:10.1021/jm00193a001. PMID 448673. delete character in |title= at position 129 (help)
  6. ↑ Otsuka, H.; Nagata, W.; Yoshioka, M.; Narisada, M.; Yoshida, T.; Harada, Y.; Yamada, H. (1981). "Discovery and development of moxalactam (6059-S): The chemistry and biology of 1-oxacephems". Medicinal Research Reviews 1 (3): 217. doi:10.1002/med.2610010302. PMID 6213825.
  7. ↑ Narisada, Masayuki; Onoue, Hiroshi; Nagata, Wataru (1977). "Synthetic Studies on b-Lactam Antibiotics. Part 5. A Synthesis of 7b-Acylamino-3-methyl-1-oxadethia-3-cephem-4-carboxylic Acids". Heterocycles 7 (2): 839. doi:10.3987/S-1977-02-0839.
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