Studies on β-lactam antibiotics, synthesis and antibacterial activity of novel 1β-methylcarbapenems related to FR21818: 5-membered ring analogs

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 11, 1997, Pages 1409-1414

  Azami, Hidenori ^a   Barrett, David ^a   Tanaka, Akira ^a   Sasaki, Hiroshi ^a   Matsuda, Keiji ^a   Sakurai, Minora ^a   Matsumoto, Yoshimi ^a   Tawara, Shuichi ^a   Chiba, Toshiyuki ^a   Sakane, Kazuo ^a  

^a ASTELLAS PHARMA INC   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

BIAPENEM; CARBAPENEM DERIVATIVE; CILASTATIN PLUS IMIPENEM; FR 21818; MEROPENEM; UNCLASSIFIED DRUG; VANCOMYCIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBACTERIAL ACTIVITY; ARTICLE; BACTERIAL INFECTION; CONTROLLED STUDY; DRUG ACTIVITY; DRUG STABILITY; DRUG SYNTHESIS; GRAM NEGATIVE BACTERIUM; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; SUBCUTANEOUS DRUG ADMINISTRATION;

EID: 0030924639     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00230-8     Document Type: Article

References (11)

1. For a recent review on the chemistry and biology of carbapenems, see: Coulton, S.; Hunt, E. in Progress in Medicinal Chemistry, Vol. 33, pp 99-145 (1996); Eds. Ellis, G.P.; Luscombe, G.K., Elsevier.
2. Clinical experience with the Imipenem-Cilastatin combination was reviewed recently, see: Buckley, M.M.; Brogden, R.N.; Barradell, L.B.; Goa, K.L. Drugs 1992, 44, 408.
3. Azami, H.; Barrett, D.; Tanaka, A.; Sasaki, H.; Matsuda, K.; Chiba, T.; Matsumoto, Y.; Matsumoto, S.; Morinaga, C.; Ishiguro, K.; Tawara, S.; Sakane, K.; Takasugi, H. Bioorg. Med. Chem. Lett. 1995, 5, 2199.
4. Azami, H.; Barrett, D.; Chiba, T.; Fujikawa, A.; Sakane, K.; Shirai, F. Chem. Pharm. Bull. 1997, 45, 209.
5. We developed an alternative synthesis of the thiols required for 1g and 1j, illustrated below for the 5-pyrazole series, employing quaternary salt formation prior to carbapenem coupling. Coupling in the standard way, followed by Pd-catalyzed deprotection afforded the final compounds. Trace amounts (<10%) of the carboxylic acid derivatives, arising from competing ester hydrolysis, were carried through to the final antibacterial agents and separated at the final stage by preparative HPLC, to give carbapenems 1h and 1k. (equation presented)
6. 8d The same compound was more conveniently obtained on a large scale by coupling of 6a with the anion derived from 7g, and treatment of the crude worked-up product with AcOH-MeOH to effect desilylation.
7. The key thiobenzoate intermediate for carbapenem Is was not obtained by application of the general method. Instead, the pyrazole ring was constructed by the multi-step sequence outlined below, involving condensation of methylhydrazine with an alkynone intermediate obtained from an aldehyde. A regioisomeric mixture of pyrazoles was obtained from this process, with the separated major isomer being carried forward to the final stage, although the same final carbapenem product would be also be produced from the minor isomer. (equation presented)
8. (a) Olofson, R.A.; Kendall, R.V. J. Org. Chem. 1970, 35, 2246.
9. (b) Pedersen, C. Acta Chem. Scand. 1959, 13, 888.
10. (c) Hüttel, R.; Wagner, H.; Jochum, P. Liebigs Ann. Chem. 1955, 593, 179.
11. (d) Ohta, S.; Yamamoto, T.; Kawasaki, I.; Yamashita, M.; Katsuma, H.; Nasako, R.; Kobayashi, K.; Ogawa, K. Chem. Pharm. Bull. 1992, 40, 2681.