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| image = Latamoxef.svg
| image = Latamoxef.svg
<!--Clinical data-->
<!--Clinical data-->
| tradename =
| tradename =
| Drugs.com = {{drugs.com|international|latamoxef}}
| Drugs.com = {{drugs.com|international|latamoxef}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status =
| legal_status =
| routes_of_administration = [[Intramuscular injection|Intramuscular]], [[intravenous therapy|intravenous]]
| routes_of_administration = [[Intramuscular injection|Intramuscular]], [[intravenous therapy|intravenous]]
<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability =
| bioavailability =
| protein_bound = 35 to 50%
| protein_bound = 35 to 50%
| metabolism = Nil
| metabolism = Nil
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It has been described as a third-generation cephalosporin.<ref name="pmid3296254">{{cite journal |author=Salem RR, McIndoe A, Matkin JA, Lidou AC, Clarke A, Wood CB |title=The hematologic effects of latamoxef sodium when used as a prophylaxis during surgical treatment |journal=Surg Gynecol Obstet |volume=164 |issue=6 |pages=525–9 |date=June 1987 |pmid=3296254 |doi= |url=}}</ref>
It has been described as a third-generation cephalosporin.<ref name="pmid3296254">{{cite journal |author=Salem RR, McIndoe A, Matkin JA, Lidou AC, Clarke A, Wood CB |title=The hematologic effects of latamoxef sodium when used as a prophylaxis during surgical treatment |journal=Surg Gynecol Obstet |volume=164 |issue=6 |pages=525–9 |date=June 1987 |pmid=3296254 |doi= |url=}}</ref>
==Synthesis==
==Synthesis==
Oxa-substituted third generation cephalosporin antibiotic (oxacephalosporin).
Oxa-substituted third generation cephalosporin antibiotic (oxacephalosporin).
[[File:Moxalactam synthesis.svg|thumb|center|700px|Moxalactam synthesis:<ref>M. Narisada, W. Nagata, {{Cite patent|DE|2713370}}; eidem, {{US patent|4138486}} (1977, 1979 both to [[Shionogi]]).</ref><ref>{{Cite journal|doi=10.1021/jm00193a001}}</ref><ref>{{Cite journal|doi=10.1002/med.2610010302}}</ref><ref>{{Cite journal|doi=10.3987/S-1977-02-0839}}</ref> (excerpt from Lednicer book 3)]]
[[File:Moxalactam synthesis.svg|thumb|center|700px|Moxalactam synthesis:<ref>M. Narisada, W. Nagata, {{Cite patent|DE|2713370}}; eidem, {{US patent|4138486}} (1977, 1979 both to [[Shionogi]]).</ref><ref>{{Cite journal|doi=10.1021/jm00193a001|pmid=448673|title=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=Journal of Medicinal Chemistry|volume=22|issue=7|pages=757–9|year=1979|last1=Narisada|first1=Masayuki|last2=Yoshida|first2=Tadashi|last3=Onoue|first3=Hiroshi|last4=Ohtani|first4=Mitsuaki|last5=Okada|first5=Tetsuo|last6=Tsuji|first6=Teruji|last7=Kikkawa|first7=Ikuo|last8=Haga|first8=Nobuhiro|last9=Satoh|first9=Hisashi|last10=Itani|first10=H|last11=Nagata|first11=W|display-authors=9}}</ref><ref>{{Cite journal|doi=10.1002/med.2610010302|pmid=6213825|title=Discovery and development of moxalactam (6059-S): The chemistry and biology of 1-oxacephems|journal=Medicinal Research Reviews|volume=1|issue=3|pages=217|year=1981|last1=Otsuka|first1=H.|last2=Nagata|first2=W.|last3=Yoshioka|first3=M.|last4=Narisada|first4=M.|last5=Yoshida|first5=T.|last6=Harada|first6=Y.|last7=Yamada|first7=H.}}</ref><ref>{{Cite journal|doi=10.3987/S-1977-02-0839|title=Synthetic Studies on b-Lactam Antibiotics. Part 5. A Synthesis of 7b-Acylamino-3-methyl-1-oxadethia-3-cephem-4-carboxylic Acids|journal=Heterocycles|volume=7|issue=2|pages=839|year=1977|last1=Narisada|first1=Masayuki|last2=Onoue|first2=Hiroshi|last3=Nagata|first3=Wataru}}</ref> (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-1''H''-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'''.
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-1''H''-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'''.


Revision as of 03:35, 22 September 2015

Latamoxef
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Intramuscular, intravenous
ATC code
Pharmacokinetic data
Protein binding35 to 50%
MetabolismNil
Elimination half-life2 hours
ExcretionMostly renal, unchanged; also biliary
Identifiers
  • (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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.059.334 Edit this at Wikidata
Chemical and physical data
FormulaC20H20N6O9S
Molar mass520.474 g/mol g·mol−1
3D model (JSmol)
  • O=C2N1/C(=C(\CO[C@@H]1[C@]2(OC)NC(=O)C(c3ccc(O)cc3)C(=O)O)CSc4nnnn4C)C(=O)O
  • InChI=1S/C20H20N6O9S/c1-25-19(22-23-24-25)36-8-10-7-35-18-20(34-2,17(33)26(18)13(10)16(31)32)21-14(28)12(15(29)30)9-3-5-11(27)6-4-9/h3-6,12,18,27H,7-8H2,1-2H3,(H,21,28)(H,29,30)(H,31,32)/t12?,18-,20+/m1/s1 checkY
  • Key:JWCSIUVGFCSJCK-CAVRMKNVSA-N checkY
 ☒NcheckY (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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ M. Narisada, W. Nagata, DE 2713370 ; eidem, U.S. patent 4,138,486 (1977, 1979 both to Shionogi).
  5. ^ {{Cite journal|doi=10.1021/jm00193a001|pmid=448673|title=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=Journal of Medicinal Chemistry|volume=22|issue=7|pages=757–9|year=1979|last1=Narisada|first1=Masayuki|last2=Yoshida|first2=Tadashi|last3=Onoue|first3=Hiroshi|last4=Ohtani|first4=Mitsuaki|last5=Okada|first5=Tetsuo|last6=Tsuji|first6=Teruji|last7=Kikkawa|first7=Ikuo|last8=Haga|first8=Nobuhiro|last9=Satoh|first9=Hisashi|last10=Itani|first10=H|last11=Nagata|first11=W|display-authors=9}}
  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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