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(12) United States Patent (10) Patent No.: US 7,585,859 B2 Ibrahim Et Al

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(12) United States Patent (10) Patent No.: US 7,585,859 B2 Ibrahim Et Al US007585859B2 (12) United States Patent (10) Patent No.: US 7,585,859 B2 Ibrahim et al. (45) Date of Patent: Sep. 8, 2009 (54) PDE4B INHIBITORS AND USES THEREFOR 5,800,992 A 9, 1998 Fodor et al. 5,807,522 A 9, 1998 Brown et al. (75) Inventors: Prabha N. Ibrahim, Mountain View, CA (US); Hanna Cho, Oakland, CA 5,830,645 A 11/1998 Pinkel et al. (US); Bruce England, Hayward, CA 5,840,485 A 11/1998 Leblet al. (US); Sam Gillette, Oakland, CA (US); 5,856,174 A 1/1999 Lipshutz et al. Dean R. Artis, Kensington, CA (US); 5,877,007 A 3/1999 Housey Rebecca Zuckerman, Alameda, CA 5,922,557 A T/1999 Pon (US); Chao Zhang, Moraga, CA (US) 5,959,098 A 9/1999 Goldberg et al. (73) Assignee: Plexxikon, Inc., Berkeley, CA (US) 5,965,452 A 10, 1999 Kovacs 6,013,440 A 1/2000 Lipshutz et al. (*) Notice: Subject to any disclaimer, the term of this 6,022,963 A 2/2000 McGallet al. patent is extended or adjusted under 35 6,025,155 A 2/2000 Hadlacsky et al. U.S.C. 154(b) by 592 days. 6,045,996 A 4/2000 Croninet al. (21) Appl. No.: 11/123,893 6,048,695 A 4/2000 Bradley et al. 6,054,270 A 4/2000 Southern (22) Filed: May 6, 2005 6,090,912 A 7/2000 Leblet al. 6,096,718 A 8, 2000 Weitzman et al. (65) Prior Publication Data 6,107.478 A 8, 2000 Pederson et al. US 2006/OO41 OO6A1 Feb. 23, 2006 6,110,456 A 8/2000 During Related U.S. Application Data 6,110,458 A 8, 2000 Freeman et al. 6,113,913 A 9/2000 Brough et al. (60) Provisional application No. 60/569,435, filed on May 6,117,681 A 9, 2000 SalmonSet al. 6, 2004. 6,178,384 B1 1/2001 Kolossváry (51) Int. Cl. 6,243,980 B1 6/2001 Bronstein et al. A 6LX 3/5.377 (2006.01) 6,258,606 B1 7/2001 Kovacs A6 IK 3L/4525 (2006.01) 6,261,776 B1 7/2001 Pirrung et al. A6 IK 3/422 (2006.01) CO7D 413/14 (2006.01) CO7D 409/4 (2006.01) CO7D 26L/06 (2006.01) (Continued) (52) U.S. Cl. .................... 514/236.8; 514/326; 514/378: 544/137:546/209: 548/248 FOREIGN PATENT DOCUMENTS (58) Field of Classification Search ................. 514/444, EP O154734 9, 1985 514/445, 447, 448, 473, 471, 422, 423, 236.8, 514/326, 378; 549/59, 60, 63, 64, 473, 480; 548/530,517, 248; 54.4/137; 546/209 See application file for complete search history. (Continued) (56) References Cited OTHER PUBLICATIONS U.S. PATENT DOCUMENTS Wolff et al., Burger's Medicinal Chemistry and Drug Discovery, 4,150,949 A 4, 1979 Smith 1994, Wiley-Interscience, Fifth Edition, vol. I: Principles and Prac 4,568,649 A 2/1986 Bertoglio-Matte tice, pp.975-977.* 4,626,513 A 12/1986 Burton et al. 4,861,891 A 8, 1989 Saccomano et al. (Continued) 5,143,854 A 9/1992 Pirrung et al. 5.426,039 A 6, 1995 Wallace et al. Primary Examiner Kamal A Saeed 5.434,049 A 7, 1995 Okano et al. Assistant Examiner—Kristin Bianchi 5.449,614 A 9, 1995 Danos et al. (74) Attorney, Agent, or Firm Foley & Lardner LLP 5,474,935 A 12/1995 Chatterjee et al. 5,556,752 A 9, 1996 Lockhart et al. (57) ABSTRACT 5,580,859 A 12/1996 Felgner et al. 5,631,236 A 5, 1997 Woo et al. 5,632,957 A 5, 1997 Heller et al. 5,658,775 A 8, 1997 Gilboa Compounds active on phosphodiesterase PDE4B are pro 5,700,637 A 12/1997 Southern vided. Also provided herewith are compositions useful for 5,721,118 A 2, 1998 Scheffler treatment of PDE4B-mediated diseases or conditions, and 5,744,305 A 4, 1998 Fodor et al. methods for the use thereof. 5,747,276 A 5, 1998 Hochet al. 5,763,198 A 6, 1998 Hirth et al. 5,770.456 A 6, 1998 Holmes 9 Claims, 5 Drawing Sheets US 7,585,859 B2 Page 2 U.S. PATENT DOCUMENTS Alfthan, "Surface plasmon resonance biosensors as a tool in antibody engineering.” Biosensors & Bioelectronics. 13:653-63 (1998). 6,277,489 B1 8, 2001 Abbott et al. al-Obeidi. “Peptide and Petidomimetic Libraries' Mol Biotechnol 6,277,628 B1 8/2001 Johann et al. 9(3): 205-23 (1998). 6,288,234 B1 9, 2001 Griffin Amersdorfer P. Marks JD., “Phage Libraries for Generation of Anti 6,294,330 B1 9, 2001 Michnicket al. botulinum scFv Antibodies.” Methods in Molecular Biology, 6,500,610 B1 12/2002 Pamukcu et al. 145:219-40 (2001). 6,559,168 B2 5, 2003 Marfat et al. 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Haddad et al., Immunopharmacological potential of selective Bringer, A.T., “Free R value: a novel statistical quantity for assessing phosphodiesterase inhibition. I. Differential regulation of the accuracy of crystal structures.” Nature 355:472-475 (1992). lipopolysaccharide-mediated proinflammatory cytokine Buchschacher, G.L. and Panganiban, A.T., "Human (Interleukin-6 and tumor necrosis factor-O.) Biosynthesis in alveolar Immunodeficiency Virus Vectors for Inducible Expression of Foreign epithelial cells, The Journal of Pharmacology and Experimental Genes,” J. Virol. 66:2731-2739, (1992). Therapeutics, 300:559-566, 2002. Burgers, et al., “Stereochemistry of Hydrolysis of Adenosine 3',5'- Ho et al., Structure of the GAF domain, a ubiquitous signaling motif Cyclic Phosphorothioate by the Cyclic Phosphodiesterase from Beef and a new class of cyclic GMP receptor, The EMBO Journal, Heart.” J. Biol. Chem., 254:9959-9961 (1979). 19(20):5288-5299, 2000. 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