Anti-MRSA cephems. Part 2: C-7 cinnamic acid derivatives

Bioorganic and Medicinal Chemistry

Volumn 11, Issue 2, 2003, Pages 265-279

  Springer, Dane M ^a,b   Luh, Bing Yu ^a   Goodrich, Jason ^a   Bronson, Joanne J ^a  

^a BRISTOL MYERS SQUIBB PHARMACEUTICAL RESEARCH INSTITUTE   (United States)

^b Rib X Pharmaceuticals   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFECTIVE AGENT; AROMATIC COMPOUND; CEPHALOSPORIN DERIVATIVE; CINNAMIC ACID DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG SYNTHESIS; HECK REACTION; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; MINIMUM INHIBITORY CONCENTRATION; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; ANIMAL; CHEMISTRY; DISEASE MODEL; DRUG EFFECT; LD 50; MICROBIOLOGICAL EXAMINATION; MICROBIOLOGY; PATHOGENICITY; PENICILLIN RESISTANCE; STAPHYLOCOCCUS AUREUS; STAPHYLOCOCCUS INFECTION; TOXICITY TESTING;

ACUTE TOXICITY TESTS; ANIMALS; ANTI-BACTERIAL AGENTS; CEPHALOSPORINS; CINNAMATES; DISEASE MODELS, ANIMAL; LETHAL DOSE 50; METHICILLIN RESISTANCE; MICE; MICROBIAL SENSITIVITY TESTS; STAPHYLOCOCCAL INFECTIONS; STAPHYLOCOCCUS AUREUS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0037449350     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0968-0896(02)00336-X     Document Type: Article

References (32)

1. (a) Ayliffe G.A.J. Clinical Infectious Diseases. 24:1997;S74
2. (b) Ehlert K. Curr. Pharm. Des. 5:1999;45.
3. Rotschafer J.C., Petersen M., Hoang A.T.D., Wright D. J. Infect. Dis. Pharm. 3:1998;29.
4. (a) Hiramatsu K., Hanaki H., Ino T., Yabuta K., Oguri T., Tenover F.C. J. Antimicrob. Chemother. 40:1997;135
5. (b) Smith T.L., Pearson M.L., Wilcox K.R., Cruz C., Lancaster M.V., Robinson-Dunn B., Tenover F.C., Zervos M.J., Band J.D., White E., Jarvis W.R. New Eng. J. Med. 340:1999;493.
6. (a) For some recent publications concerning the development of anti-MRSA cephems see: Hecker S.J., Glinka T.W., Cho A., Zhang Z.J., Price M.E., Chamberland S., Griffith D., Lee V.J. J. Antibiot. 53:2000;1272
7. (b) Glinka T.W., Cho A., Zhang Z.J., Ludwikow M., Griffith D., Huie K., Hecker S.J., Dudley M.N., Lee V.J., Chamberland S. J. Antibiot. 53:2000;1045
8. (c) Ishikawa T., Iizawa Y., Okonogi K., Miyake A. J. Antibiot. 53:2000;1053
9. (d) Ishikawa T., Kamiyama K., Matsunaga N., Tawada H., Iizawa Y., Okonogi K., Miyake A. J. Antibiot. 53:2000;1071
10. (e) Tsushima M., Iwamatsu K., Umemura E., Kudo T., Sato Y., Shiokawa S., Takizawa H., Kano Y., Kobayashi K., Ida T., Tamura A., Atsumi K. Bioorg. Med. Chem. 8:2000;2781
11. (f) Pae A.N., Lee J.E., Kim B.H., Cha J.H., Kim H.Y., Cho Y.S., Choi K.I., Koh H.Y., Lee E., Kim J.H. Tetrahedron. 56:2000;5657
12. (g) Yamazaki H., Tsuchida Y., Satoh H., Kawashima S., Hanaki H., Hiramatsu K. J. Antibiot. 53:2000;546
13. (h) Yamazaki H., Tsuchida Y., Satoh H., Kawashima S., Hanaki H., Hiramatsu K. J. Antibiot. 53:2000;551
14. (i). For prior publications from the laboratories of Bristol-Myers Squibb see: Springer D.M., Luh B.-Y., Bronson J.J. Bioorg. Med. Chem. Lett. 11:2001;797
15. (j) D'Andrea S.V., Bonner D., Bronson J.J., Clark J., Denbleyker K., Fung-Tomc J., Hoeft S.E., Hudyma T.W., Matiskella J.D., Miller R.F., Misco P.F., Pucci M., Sterzycki R., Tsai Y., Ueda Y., Wichtowski J.A., Singh J., Kissick T.P., North J.T., Pullockaran A., Humora M., Boyhan B., Vu T., Fritz A., Heikes J., Fox R., Godfrey J.D., Perrone R., Kaplan M., Kronenthal D., Mueller R.H. Tetrahedron. 56:2000;5687
16. (k) Singh J., Kim O.K., Kissick T.P., Natalie K.J., Zhang B., Crispino G.A., Springer D.M., Wichtowski J.A., Zhang Y., Goodrich J., Ueda Y., Luh B.Y., Burke B.D., Brown M., Dutka A.P., Zheng B., Hsieh D.-M., Humora M.J., North J.T., Pullockaran A.J., Livshits J., Swaminathan S., Gao Z., Schierling P., Ermann P., Perrone R.K., Lai M.C., Gougoutas J.Z., DiMarco J.D., Bronson J.J., Heikes J.E., Grosso J.A., Kronenthal D.R., Denzel T.W., Mueller R.H. Org. Process Res. Dev. 4:2000;488
17. (l) Kim O.K., Hudyma T.W., Matiskella J.D., Ueda Y., Bronson J.J., Mansuri M.M. Bioorg. Med. Chem. Lett. 7:1997;2753
18. (m) Kim O.K., Ueda Y., Mansuri M.M., Russell J.W., Bidwell V.W. Bioorg. Med. Chem. Lett. 7:1997;1945.
19. A group from Eli Lilly found that in a series of C-3 acetate cephems, a derivative bearing a 2,5-dichlorothiophenyl acetamide group at C-7 was extremely potent against staphylococcus species. The optimal halogen substitution to maximize anti-staphylococcus activity on the thiophenyl ring was the 2,5-dichloro pattern. In largely unpublished observations, our group at Bristol-Myers Squibb has found this SAR trend at C-7 to be quite general for anti-MRSA activity irrespective of the nature of the C-3 group. For the original work by Lilly, see: Huffman G.W. US Patent 3,907,784, 1975. Chem. Abstr. 84:1975;17395.
20. Kim C.U., Misco P.F., Wichtowski J.A., Ueda Y., Hudyma T.W., Matiskella J.D., D'Andrea S.V., Hoeft S.E., Miller R.F. US Patent 5,567,698, 1996. Chem. Abstr. 126:1996;7903.
21. Compound 1, given at a dose of ∼200 mg/kg, resulted in death to all three mice tested. Compound 2, given at a dose of ∼300 mg/kg, was safe to all three mice tested. See the Experimental details of the acute toxicity assay.
22. For solubility determinations, a known quantity of test compound is dissolved in water, 0.9% saline, or any other buffer and the pH adjusted to the desired point by the addition of min amounts of 1 N NaOH. The solutions are stirred for 2 h, and then filtered through a 0.2-μ filter. The filtrate is then assayed by HPLC and the concentration of dissolved compound determined by comparison to a standard curve.
23. (a) Kwart H., Evans E.R. J. Org. Chem. 31:1966;410
24. (b) Newman M.S., Karnes H.A. J. Org. Chem. 31:1966;3980
25. (c) Sebok P., Timar T., Eszenyi T., Patonay T. J. Org. Chem. 59:1994;6318
26. (d) Robertson D.W., Beedle E.E., Krushinski J.H., Pollock G.D., Wilson H., Wyss V.L., Hayes J.S. J. Med. Chem. 28:1985;717.
27. Chloromethyl cephem amine 10 was purchased from Otsuka Chemical Co., Ltd.
28. Unfortunately, compounds 48 and 49, synthesized towards the end of our MRSA cephem program, remained unevaluated in vivo at the close of our work.
29. Compounds that were found to be inactive in vivo were not generally evaluated in mouse pharmacokinetic or pharmacodynamic studies. Thus, there remain many possible (but unevaluated) explanations for the lack of in vivo activity of many of our cephems. Depending on the nature of the pendant groups on the C-3 thiopyridinium ring, the compounds may have differential metabolic and distribution profiles. One possible common explanation could be that inactive compounds remain localized at the site of intramuscular injection limiting the exposure of the animal to the test drug. This could either be a consequence of low solubility, or poor absorption into the vascular system from the muscle tissue, or both.
30. (a) These compounds were synthesized from the known t-butyl ester of 7-aminocephalosporanic acid by acylation and then TFA deprotection, as described for other derivatives in the experimental section. For syntheses of t-butyl 7-aminocephalosporanate see: Blacklock T.J., Butcher J.W., Sohar P., Lamanec T.R., Grabowski E.J.J. J. Org. Chem. 54:1989;3907
31. (b) Mangia A., Scandroglio A. Org. Prep. Proced. Int. 18:1986;13 For reference purposes, the C-3 acetate derivative with a 2,5-dichlorothiophenyl group at C-7 (no acrylic acid substituent) had an MIC of 2 μg/mL versus MRSA A27223. Thus, with this C-3 group, the inclusion of the acid substituent at C-7 (compare with compound 38) caused no loss of in vitro potency. Usually, a 2-fold loss of in vitro potency is observed by incuding an acid at C-7, while in general an acid placed at C-3 results in a 4-fold loss of activity.
32. These compounds were generally prepared in methanol using the requisite chloromethyl cephem diacid, and the sodium thiolate of the C-3 side-chain group.