Synthesis and evaluation of acylguanidine FXa inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 16, 2008, Pages 4696-4699

  O'Connor, Stephen P ^a   Atwal, Karnail ^a   Li, Chi ^a   Liu, Eddie C K ^a   Seiler, Steven M ^a   Shi, Mengxiao ^a   Shi, Yan ^a   Stein, Philip D ^a   Wang, Ying ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

Coagulation; Factor Xa; Serine protease

Indexed keywords

BLOOD CLOTTING FACTOR 10A INHIBITOR; CARBOXYLIC ACID DERIVATIVE; GUANIDINE DERIVATIVE; IMIDAZOLE DERIVATIVE; REAGENT;

ACYLATION; ARTICLE; DRUG PURIFICATION; DRUG SCREENING; DRUG SYNTHESIS; IC 50;

ANTICOAGULANTS; ANTITHROMBIN III; BLOOD COAGULATION; CARBOXYLIC ACIDS; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; FACTOR XA; GUANIDINES; GUANINE; HUMANS; IMIDAZOLES; INHIBITORY CONCENTRATION 50; MODELS, CHEMICAL; MOLECULAR STRUCTURE;

EID: 48649097169     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.07.004     Document Type: Article

References (42)

1. Ruef J., and Katus H.A. Expert Opin. Investig. Drugs 12 (2003) 781
2. Hirsh J. Thromb. Res. 109 (2003) S1
3. Bisacchi G.S. In: Abraham D. (Ed). Burger's Medicinal Chemistry and Drug Discovery Vol. 3 (2003), John Wiley 283-338
4. Walenga J.M., Jeske W.P., Hopensteadt D., and Fareed J. Curr. Opin. Investig. Drugs 4 (2003) 272
5. Betz A. Expert Opin. Ther. Patents 11 (2001) 1007
6. Steinmetzer T., Hauptmann J., and Sturzebacher J. Expert Opin. Investig. Drugs 10 (2001) 845
7. Sanderson P.E.J. In: Doherty A.N. (Ed). Annu. Rep. Med. Chem. Vol. 36 (2001), Academic Press, San Diego 79-88
8. Sanderson P.E.J. Med. Res. Rev. 19 (1999) 179
9. Lassen M.R., Davidson B.L., Gallus A., Pineo G., Ansell J., and Deitchman D. J. Thromb. Haemost. 5 (2007) 2368
10. Wong P.C., Crain E.J., Watson C.A., Wexler R.R., and Knabb R.M. J. Pharmacol. Exp. Ther. 303 (2002) 993
11. Walenga J.M., Jeske W.P., Samama M.M., Frapaise F.X., Bick R.L., and Fareed J. Expert Opin. Investig. Drugs 11 (2002) 397
12. Shimbo D., Osende J., Chen J., Robbins J., Shimoto Y., Kunitada S., Fuster V., and Badimon J.J. Thromb. Haemost. 88 (2002) 733
13. Lam P.Y.S., Clark C.G., Li R., Pinto D.J.P., Orwat M.J., Galemmo R.A., Fevig J.M., Teleha C.A., Alexander R.S., Smallwood A.M., Rossi K.A., Wright M.R., Bai S.A., He K., Luettgen J.M., Wong P.C., Knabb R.M., and Wexler R.R. J. Med. Chem. 46 (2003) 4405
14. Hirayama F., Koshio H., Katayama N., Kurihara H., Taniuchi Y., Sato K., Hisamichi N., Sakai-Moritani Y., Kawasaki T., Matsumoto Y., and Yanagisawa I. Bioorg. Med. Chem. Lett. 10 (2002) 1509
15. Choi-Sledeski Y.M., Kearney R., Poli G., Pauls H., Gardner C., Gong Y., Becker M., Davis R., Spada A., Liang G., Chu V., Brown K., Collussi D., Leadley Jr. R., Rebello S., Moxey P., Morgan S., Bentley R., Kasiewski C., Maignan S., Guilloteau J.-P., and Mikol V. J. Med. Chem. 46 (2003) 681
16. Phillips G.A., Buckman B.O., Davey D.D., Eagen K.A., Guilford W.J., Hinchman J., Ho E., Koovakkat S., Liang A., Light D.R., Mohan R., Ng H.P., Post J.M., Shaw K.J., Smith D., Subramanyam B., Sullivan M.E., Trinh L., Vergona R., Walters J., White K., Whitlow M., Wu S., Xu W., and Morrissey M.M. J. Med. Chem. 41 (1998) 3557
17. Samama M.M., and Gerotziafas G.T. Thromb. Res. 109 (2003) 1
18. Quan M.L., Lam P.Y.S., Han Q., Pinto D.J.P., He M.Y., Li R., Ellis C.D., Clark C.G., Teleha C.A., Sun J.-H., Alexander R.S., Bai S., Luettgen J.M., Knabb R.M., Wong P.C., and Wexler R.R. J. Med. Chem. 48 (2005) 1729
19. Pinto D.J.P., Orwat M.J., Koch S., Rossi K.A., Alexander R.S., Smallwood A., Wong P.C., Rendina A., Luettgen J.M., Knabb R.M., He K., Xin B., Wexler R.R., and Lam P.Y.S. J. Med. Chem. 50 (2007) 5339
20. Straub A., Pohlmann J., Lampe T., Pernerstorfer J., Schlemmer K.-H., Reinemer P., Perzborn E., and Roehrig S. J. Med. Chem. 48 (2005) 5900
21. Eriksson B.L., Borris L., Dahl O.E., Haas S., Huisman M.V., and Kakkar A.K. J. Thromb. Haemost. 4 (2006) 121
22. Liebeschuetz J.W., Jones S.D., Wiley M.E., and Young S.C. Struct. Based Drug Des. (2006) 173
23. Hampton T. JAMA 295 (2006) 743
24. Bisacchi G.S., Stein P.D., Gougoutas J.Z., Hartl K.S., Lawrence R.M., Liu E., Pudzianowski A., Schumacher W.A., Sitkoff D., Steinbacher T.E., Sutton J., and Seiler S.M. Lett. Drug Des. Discov. 2 (2005) 563
25. Shi Y., Zhang J., Stein P.D., Shi M., O'Connor S.P., Bisaha S.N., Li C., Atwal K.S., Bisacchi G.S., Sitkoff D., Pudzianowski A.T., Liu E.C., Hartl K.S., Seiler S.M., Youssef S., Steinbacher W.A., Rendina A.R., Bozarth J.M., Peterson T.L., Zhang G., and Zahler R. Bioorg. Med. Chem. Lett. 15 (2005) 5453
26. Adam W., Ahrweiler M., Saha-Moller C.R., Sauter M., Schonberger A., Epe B., Muller E., Schiffmann D., Stopper H., and Wild D. Toxicol. Lett. 67 (1993) 41
27. Kim S., and Yi K.Y. J. Org. Chem. 51 (1986) 2613
28. Wiggall K.J., and Richardson S.K. J. Heterocy. Chem. 32 (1995) 867
29. Multiple acylation products were observed with benzoyl chloride and we experienced difficulty in separating the PyBop-derived phosphoryl triamide by-products from the desired acylguanidines without resorting to preparative HPLC.
30. Ahmad S., Doweyko L.M., Dugar S., Grazier N., Ngu K., Wu S.C., Yost K.J., Chen B.-C., Gougoutas J.Z., DiMarco J.D., Lan S.-J., Gavin B.J., Chen A.Y., Dorso C.R., Serafino R., Kirby M., and Atwal K.S. J. Med. Chem. 44 (2001) 3302
31. Ahmad, S.; Wu, S. C.; Atwal, K. S.; Dugar, S. U.S. Patent 6,011,059, 2000.
32. Kitano, M.; Nakano, K.; Ohashi, N. WO 2000044707, 2000.
33. Owens A.H., Goehring R.R., Lampe J.W., Erhardt P.W., Lumma Jr. W.C., and Wiggins J. Eur. J. Med. Chem. 23 (1988) 295
34. Lide D.R. CRC Handbook of Chemistry and Physics. 78th ed. (1997-1998), CRC Press, Boca Raton
35. a 6.95) was problematic. This contaminant co-eluted with product from both types of ion-exchange cartridges. In addition, silica gel did not provide a general method of purification as the products had a range of polarities and required tedious adjustment of the solvent composition for efficient elution.
36. The conditions for LC analysis were either (a) or (b): (a) YMC S5 ODS 4.6 × 50 mm column; gradient from 10% MeOH/0.1% aqueous TFA to 90% MeOH/0.1% aqueous TFA over 4 min; flow rate = 4 mL/min; 220 nM detection.
37. 4 over 4 min; flow rate = 4 mL/min; 220 nM detection.
38. An excess of benzoic acid and CDI was used to drive all of the guanidines to product ensuring that the reaction mixture would contain, after an aqueous quench, only the fast eluting benzoic acid and imidazole along with the less polar product.
39. 13C NMR, and co-eluted on LC, LC-MS, and TLC with compound 1 produced by the alternative method shown in Scheme 1.
40. The cartridges were first washed sequentially with 4-5 vol each of methanol then water. Reaction mixtures were loaded onto the cartridges under water. We have achieved comparable results using Varian 2 g MegaBondElut C18 HF cartridges (cat. #14256015), United Chemical Technologies 2.5 g Endcapped C-18 cartridges (cat. #CEC181(2500)6), or cartridges prepared with 2 g of J.T. Baker Bakerbond C-18 40 μM Prep LC Packing (cat. #7025-01).
41. A modification of the reaction conditions described above was made when synthesizing multiple acylguanidines simultaneously: the carboxylic acid (1.5 equiv) and CDI (1.5 equiv) were combined and allowed to react for 2 h. The guanidine (1.0 equiv) was then added and the reaction mixture was stirred for 16 h.
42. We viewed this as an 'on-off' cartridge purification strategy whereby the product would remain 'on' the C-18 packing with a high concentration of water, while the undesired components would elute 'off'. The concentration of the organic component in the solvent could then be increased to elute the product.