A four component coupling strategy for the synthesis of D-phenylglycinamide-derived non-covalent factor Xa inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 14, 2003, Pages 2255-2259

  Sheehan, Scott M ^a   Masters, John J ^a   Wiley, Michael R ^a   Young, Stephen C ^b   Liebeschuetz, John W ^b   Jones, Stuart D ^b   Murray, Christopher W ^b   Franciskovich, Jeffrey B ^a   Engel, David B ^a   Weber II, Wayne W ^a   Marimuthu, Jothirajah ^a   Kyle, Jeffrey A ^a   Smallwood, Jeffrey K ^a   Farmen, Mark W ^a   Smith, Gerald F ^a  

^a ELI LILLY AND COMPANY   (United States)

^b Tularik Ltd   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING INHIBITOR; GLYCINAMIDE; ISONITRILE DERIVATIVE; SERINE PROTEINASE;

ANTICOAGULATION; ARTICLE; DRUG SYNTHESIS; METHODOLOGY; STRUCTURE ACTIVITY RELATION;

EID: 12444250679     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00462-1     Document Type: Article

References (27)

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2. (a) Agnelli G., Sonaglia F. Haematologica. 87:2002;757 (b) Zhu B.-Y., Scarborough R.M. Ann. Rep. Med. Chem. 38:2000;83 (c) Turpie A.G. Am. J. Cardiol. 82:1998;11. L (d) Wiley M.R., Fisher M.J. Exp. Opin. Ther. Pat. 7:1997;1265.
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4. (a) Agnelli G., Sonaglia F. Haematologica. 87:2002;757 (b) Zhu B.-Y., Scarborough R.M. Ann. Rep. Med. Chem. 38:2000;83 (c) Turpie A.G. Am. J. Cardiol. 82:1998;11. L (d) Wiley M.R., Fisher M.J. Exp. Opin. Ther. Pat. 7:1997;1265.
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8. (a) Williams, E. C.; Suttie, J. W. In Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology; Verstaete, M., Fuster, V., Topol, E. J., Eds.; Lippincott-Raven: Philadelphia, 1998; pp 285-300. (b) Levine, M. N.; Hirsh, J.; Salzman, E. W. In Hemostasis and Thrombosis: Basic Principles and Clinical Paractice; Colman, R. W., Hirsh, J., Marder, V. J., Salzman, E. W., Eds.; J.B. Lippincott Co.: Philadelphia, 1994; pp 936-955. (c) Hirsh J. N. Engl. J. Med. 324:1991;1865 (d) Amerena J., Mashford M.L., Wallace S. Adverse Drug React. Acute Poisoning Rev. 9:1990;1.
9. (a) Williams, E. C.; Suttie, J. W. In Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology; Verstaete, M., Fuster, V., Topol, E. J., Eds.; Lippincott-Raven: Philadelphia, 1998; pp 285-300. (b) Levine, M. N.; Hirsh, J.; Salzman, E. W. In Hemostasis and Thrombosis: Basic Principles and Clinical Paractice; Colman, R. W., Hirsh, J., Marder, V. J., Salzman, E. W., Eds.; J.B. Lippincott Co.: Philadelphia, 1994; pp 936-955. (c) Hirsh J. N. Engl. J. Med. 324:1991;1865 (d) Amerena J., Mashford M.L., Wallace S. Adverse Drug React. Acute Poisoning Rev. 9:1990;1.
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14. 2 plug was then washed with 3:1 EtOAc:Isopropyl amine to provide 45g of recovered 2.
15. Stored under nitrogen at -20°C in a sealed flask.
16. By the nature of its mechanism, the 4CC reaction as shown provides products in racemic form. Isolation of material enriched in the desired enantiomer requires subsequent separation by chiral HPLC. We have found that the majority of Xa binding affinity results from one enantiomer (unpublished results), and have tested the 4CC products as racemates for expedience.
17. 1H NMR and HPLC analysis.
18. Jones, S. D.; Wiley, M. R.; Masters, J. J.; Young, S. C; Leibeschuetz, J. W.; Murray, C. W.; Richards, S. J.; Webber III, W. W.; Marimuthu, J.; Kyle, J. A.; Sheehan, S. M.; Watson, B. W.; Smallwood, J. K.; Smith G. F. Abstracts of Papers, Part MEDI-231, 225th National Meeting of the American Chemical Society, New Orleans, LA, March 23-27, 2003; American Chemical Society: Washington, DC, 2003.
19. For a depiction of the conformational constraint imparted by ortho-substitution in a computationally derived model of an ortho-substituted factor Xa inhibitor from this series docked into the factor Xa active site, see: Sheehan, S. M.; Masters, J. J.; Wiley, M. R.; Young, S. C.; Liebeschuetz, J. W.; Jones, S. D.; Murray, C. W.; Franciskovich, J. B.; Engel, D. B.; Weber, W. W.; Marimuthu, J.; Kyle, J. A.; Smallwood, J. K.; Foster, R. S.; Froelich, L. L.; Gifford-Moore, D. S.; Towner, R. D.; Snyder, D. W.; Chouinard, M. L.; Chastain, M. K.; Johnson, L. M.; Sipes, P. R.; Tluczek, J. P.; Craft, T. J.; Smith, G. F. Abstracts of Papers, Part MEDI-230, 225th National Meeting of the American Chemical Society, New Orleans, LA, March 23-27, 2003; American Chemical Society: Washington, DC, 2003.
20. ass of 0.11 million L/mol.
21. (a) Herron D.K., Goodson T. Jr., Wiley M.R., Weir L.C., Kyle J.A., Yee Y.K., Tebbe A.L., Tinsley J.M., Mendel D., Masters J.J., Franciskovich J.B., Sawyer J.S., Beight D.W., Ratz A.M., Milot G., Hall S.E., Klimkowski V.J., Wikel J.H., Eastwood B.J., Towner R.D., Gifford-Moore D.S., Craft T.J., Smith G.F. J. Med. Chem. 43:2000;859
22. (a) Herron D.K., Goodson T. Jr., Wiley M.R., Weir L.C., Kyle J.A., Yee Y.K., Tebbe A.L., Tinsley J.M., Mendel D., Masters J.J., Franciskovich J.B., Sawyer J.S., Beight D.W., Ratz A.M., Milot G., Hall S.E., Klimkowski V.J., Wikel J.H., Eastwood B.J., Towner R.D., Gifford-Moore D.S., Craft T.J., Smith G.F. J. Med. Chem. 43:2000;859 (b) Smith, G. F.; Gifford-Moore, D. S.; Craft, T. J.; Chirgadze, N. K.; Ruterbories, K. J.; Lindstrom, T. D.; Satterwhite, J. H. in New Anticoagulants for the Cardiovascular Patient; Piffare, R., Ed.; Hanley & Belfus Publishers: Philadelphia, 1997; pp 265-300.
23. ass data generated in this fashion from a single experiment has been determined to have a minimum significant ratio of 2.13(b) Bland, J. M.: Altman, D. G. Lancet 1986, 1, 307. (c) For a description of statistical analysis for precision of a single Kass determination, see ref 11a.
24. For a discussion of this and other bicyclic non-amidine S1 moieties, see: Masters, J. J.; Weber, W. W.; Franciskovich, J. B.; Wiley, M. R.; Halligan, N. G.; Camp, N. P.; Jones, S. D.; Richards, S.; Lyons, A.; Morgan, P.; Liebeschuetz, J. W.; Murray, C. W.; Young, S. C.; Chirgadze, N. Y.; Briggs, S. L.; Craft, T. J.; Towner, R. D.; Smallwood, J. K.; Smith, G. F. Abstracts of Papers, Part MEDI-284, 224th National Meeting of the American Chemical Society, Boston, MA, March 23-27, 2002; American Chemical Society: Washington, DC, 2003.
25. (a) 2XPT is defined as the concentration of test compound required to double the time to clot formation in reconstituted human plasma, using the prothrombin time assay as described in: Wiley M.R., Weir L.C., Briggs S., Bryan N.A., Buben J., Campbell C., Chirgadze N.Y., Conrad R.C., Craft T.J., Ficorilli J.V., Franciskovich J.B., Froelich L.L., Gifford-Moore S.S., Goodson T. Jr., Herron D.K., Klimkowski V.J., Kurz K.D., Kyle J.A., Masters J.J., Ratz A.M., Milot G., Shuman R.T., Smith T., Smith G.F., Tebbe A.L., Tinsley J.M., Towner R.D., Wilson A., Yee Y.K. J. Med. Chem. 43:2000;883 (b) Inhibitor 9 has >1000× selectivity with respect to the following enzymes: Thrombin, Plasmin, Bovine Trypsin, Urokinase, aPC, Kallikrein, and tPA.
26. 6=725.3105; Found=725.3091.
27. Hatanaka M., Ishimaru T. Bull. Chem. Soc. Jpn. 46:1973;3600.