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(10) Patent No.: US 7759518 B2

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(10) Patent No.: US 7759518 B2 USOO7759518B2 (12) United States Patent (10) Patent No.: US 7,759,518 B2 Maderna et al. (45) Date of Patent: *Jul. 20, 2010 (54) DERIVATIVES OF N-(ARYLAMINO) 2004/0171632 A1 9, 2004 Gowan et al. SULFONAMIDESAS INHIBITORS OF MEK 2004/0176418 A1 9/2004 Thiruvengadam et al. 2005, 0004186 A1 1/2005 Barrett et al. (75) Inventors: Andreas Maderna, Stony Point, NY a a (US); Jean-Michel Vernier, San Diego 2005/002697O A1 2/2005 Barrett et al. CA (US). Dinesh Barawkar Foothill s 2005.0054701 A1 3/2005 Wallace et al. Ranch, CA (US), Varaprasad 2006/003061.0 A1 2/2006 Koch et al. Chamakura, Bangalore (IN); Hassan el 2006, O140872 A1 6/2006 Furue et al. Abdellaoui, Jamestown, NC (US); Zhi 2008/005834.0 A1 3/2008 Madeirna et al. Hong, Irvine, CA (US) (73) Assignee: Ardea Biosciences, San Diego, CA (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 EP 239362 A2 9, 1987 U.S.C. 154(b) by 0 days. EP 606046 T 1994 This patent is Subject to a terminal dis- EP T80386 6, 1997 claimer. EP O818.442 A2 1, 1998 EP 93.1788 A2 7, 1999 (21) Appl. No.: 12/323,279 EP O945864 A2 9, 1999 EP 1004578 A2 5, 2000 (22) Filed: Nov. 25, 2008 WO WO-90-05719 A1 5, 1990 (65) Prior Publication Data WO WO-96-27583 A1 3, 1996 WO WO-96-33182 A1 10, 1996 US 2009/OO82457 A1 Mar. 26, 2009 WO WO-98-07697 A1 2/1998 Related U.S. Application Data WO WO-98-30566 A1 7, 1998 WO WO-98-03516 A1 8, 1998 (63) Continuation of application No. 1 1/830,733, filed on WO WO-98-33768 A1 8, 1998 Jul. 30, 2007, which is a continuation-in-part of appli- V V cation No. PCT/US2006/028326, filed on Jul 21, WO WO-98-34.915 A1 8/1998 2006. WO WO-98-34918 A1 8/1998 (60) Provisional application No. 60/701,814, filed on Jul. WO WO-99-07675 A1 2, 1999 21, 2005, provisional application No. 60/706,719, WO WO-99-29667 A1 6, 1999 filed on Aug. 8, 2005, provisional application No. WO WO-99-52889 A1 10, 1999 60/731,633, filed on Oct. 28, 2005, provisional appli- WO WO-99-5291.0 A1 10, 1999 cation No. 607833,886, filed on Jul. 7, 2006. WO WO-00-42003 A1 T 2000 51 Int. Cl WO WO-00-42022 A1 T 2000 (51) y: 307/06 (2006.01) WO WO-00-42029 A1 T 2000 A6 IK3I/63 (2006.01) (52) U.S. Cl. ............................ 564/84; 564/86; 514/601 (58) Field of Classification Search ................... 564/80, (Continued) 564/84, 86; 514/601 See application file for complete search history. OTHER PUBLICATIONS (56) References Cited U.S. Appl. No. 60/148,464, filed Aug. 12, 1999, Noe et al. U.S. PATENT DOCUMENTS (Continued) 5,861,510 A 1/1999 Piscopio et al. 5,863,949 A 1/1999 Robinson et al. Primary Examiner Shailendra Kumar 6,316,462 B1 1 1/2001 Bishop et al. Assistant Examiner Yate K Cutliff 6,440,966 B1 8, 2002 Barrett et al. (74) Attorney, Agent, or Firm Millen, White, Zelano & 6,469,004 B1 10/2002 Barrett et al. Branigan, P.C. 6,545,030 B1 4/2003 Barrett et al. 6,750,217 B2 6, 2004 Barrett et al. (57) ABSTRACT 6,770,778 B2 8, 2004 Barrett et al. 6,780,870 B2 8, 2004 Carter et al. 6,891,066 B2 5, 2005 Rewcastle et al. This invention concerns N-(2-arylamino)aryl Sulfonamides, 7,115,632 B1 10/2006 Bedell et al. which are inhibitors of MEK and are useful in treatment of 2003/0092748 A1 5, 2003 Barrett et al. 2003. O149015 A1 8, 2003 Barrett et al. cancer and other hyperproliferative diseases. 2004.0029898 A1 2/2004 Boyle et al. 2004.0054172 A1 3, 2004 Barrett et al. 4 Claims, No Drawings US 7,759,518 B2 Page 2 FOREIGN PATENT DOCUMENTS Goodson, J. Dental applications. Medical Applications of Controlled Release, vol. 2, Applications and Evaluations. Langer, et al., eds. WO WO-02-06213 A2 1, 2002 (CRC Press, Boca Raton, FL) pp. 115-138, 1984. WO WO-02-06213 A3 1, 2002 Langer, R., “New methods of drug delivery.” Science 249(4976): WO WO-03-077855 A2 9, 2003 1527-33, 1990. WO WO-03-077855 A3 9, 2003 Larsen, et al., “Prodrug forms for the Sulfonamide group. I. Evalua WO WO-03-077914 A1 9, 2003 tion of N-acyl derivative, N-sulfonylamidines, WO WO-2004-083.167 A1 9, 2004 N-sulfonylsulfillimines and Sulfonylureas as possible prodrug deriva WO WO-2005-028426 A1 3, 2005 tives.” IntJ Pharmaceutics 37(1-2): 87-95, 1987. OTHER PUBLICATIONS Larsen et al., “Prodrug forms for the sulfonamide group. II. Water soluble amino acid derivatives of N-methylsulfonamides as possible Berge et al., “Pharmaceutical salts.” J. Pharm. Sci. 66(1): 1-19, 1977. prodrugs.” IntJ Pharmaceutics 47(1-3): 103-10, 1988. Buchwald et al., “Long-term, continuous intravenous heparin admin Lee et al., “The Raf MEK/ERK Signal Transduction Cascade as a istration by an implantable infusion pump in ambulatory patients Target for Chemotherapeutic Intervention in Leukemia. Leukemia with recurrent venous thrombosis.” Surgery 88(4): 507-16, 1980. 16(4):486-507 (2002). Bundgaard, H. Chapter 5: Design and application of prodrugs. A McLeod et al., “A glucocorticoid prodrug facilitates normal mucosal Textbook of Drug Design and Development. Krosgaard-Larsen, et function in rat colitis without adrenal Suppression. Gastroenterology al., eds., pp. 113-191, 1991. 106(2): 405-13, 1994. Bundgaard, H., “Means to enhance penetration: Prodrugs as a means PCT/US06/28326 search report dated Jan. 18, 2008. to improve the delivery of peptide drugs.” Advanced Drug Delivery PCT/US08/71392 Search Report dated Oct. 16, 2008. Reviews 8:1-38, 1992. PCT/US08/71397 Search Report dated Oct. 22, 2008. Cobb et al., “How MAP Kinaes are Regulated.” J. Biol. Chem. Robinson et al., “Discovery of the hemifumarate and (alpha-L- 270(25): 14843-14846 (1995). Fedorak et al., “A novel colon-specific steroid prodrug enhances alanyloxy)methyl ether as prodrugs of an antirheumatic oxindole: sodium chloride absorption in rat colitis.” Am J Physiol 269(2 Pt 1): prodrugs for the enolic OH group.” J Med Chem39(1): 10-8, 1996. G210-8, 1995. Saudek et al., “A preliminary trial of the programmable implantable Fleisher et al., “Improved oral drug delivery: solubility limitations medication system for insulin delivery.” NEnglJMed321 (9): 574-9. overcome by the use of prodrugs.” Advanced Drug Delivery Reviews 1989. 19(2): 115-30, 1996. Sefton, M., “Implantable pumps.” Crit Rev Biomed Eng 14(3): 201 Furniss et al.,ed., Vogel's Textbook of Practical Organic Chemistry, 40, 1987. 5th Ed. Suppl. (Longman Scientific and Technical Ltd, Essex, UK) Sinkula et al., “Rationale for design of biologically reversible drug pp. 809-16, 1991. derivatives: prodrugs.” J Pharm Sci 64(2): 181-210, 1975. Heller, A., “Electrical wiring of redox enzymes.” Acc Chem Res Treat et al., "Liposome encapsulated doxorubicin: Preliminary 23(5): 128-34, 1990. results of phase I and phase II trials.” Liposomes in the Therapy of Hochhaus et al. A selective HPLC/RIA for dexamethasone and its Infectious Diseases and Cancer. Lopez-Bernstein, et al., eds. (Alan R. prodrug dexamethasone-21-sulphobenzoate Sodium in biological Liss, New York) pp. 353–365, 1989. fluids. Biomed Chromatogr. 1992; 6(6):283-286. Widder, K. et al., Method in Enzymology vol.42 (1985), pp.309-396. US 7,759,518 B2 1. 2 DERIVATIVES OF N-(ARYLAMINO) The interaction of Raf and Ras is a key regulatory step in SULFONAMIDESAS INHIBITORS OF MEK the control of cell proliferation. To date, no substrates of MEKother than MAPK have been identified; however, recent CROSS REFERENCE TO RELATED reports indicate that MEK may also be activated by other APPLICATIONS upstream signal proteins such as MEK kinase or MEKK1 and PKC. Activated MAPK translocates and accumulates in the This application is a continuation application of U.S. appli nucleus, where it can phosphorylate and activate transcription cation Ser. No. 1 1/830,733, filed Jul. 30, 2007, incorporated factors such as Elk-1 and Sap1a, leading to the enhanced herein by reference in its entirety, and which is a continua expression of genes Such as that for c-fos. tion-in-part application of International Application Ser. No 10 Once activated, Raf and other kinases phosphorylate MEK PCT/US2006/028326 filed Jul. 21, 2006, which is incorpo on two neighboring serine residues, S' and Sf in the case rated herein by reference in its entirety and to which applica of MEK1. These phosphorylations are required for activation tion we claim priority under 35 USC S120, which claims of MEK as a kinase. In turn, MEK phosphorylates MAP priority to U.S. Provisional Application Ser. No. 60/701,814, kinase on two residues separated by a single amino acid: a filed Jul. 21, 2005; to U.S. Provisional Application Ser. No. 15 tyrosine, Y and a threonine, T. MEKappears to associ 60/706,719, filed Aug. 8, 2005; and to U.S. Provisional Appli ate strongly with MAP kinase prior to phosphorylating it, cation Ser. No. 60/731,633, filed Oct. 28, 2005 all of which suggesting that phosphorylation of MAP kinase by MEK may are hereby incorporated by reference herein in their entirety. require a prior strong interaction between the two proteins.
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