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United States Patent (10) Patent No.: US 7,351,739 B2 H0 Et Al

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United States Patent (10) Patent No.: US 7,351,739 B2 H0 Et Al US00735.1739B2 (12) United States Patent (10) Patent No.: US 7,351,739 B2 H0 et al. (45) Date of Patent: Apr. 1, 2008 (54) BIOACTIVE COMPOUNDS AND METHODS 5,354,556. A 10/1994 Sparks et al. OF USES THEREOF 5,360,716 A 1 1/1994 Ohmoto et al. 5,426,181 A 6/1995 Lee et al. (75) Inventors: Chi-Tang Ho, East Brunswick, NJ 5,436,154 A 7/1995 Barbanti et al. (US); Naisheng Bai, Highland Park, NJ 36 A 1. Rht (US); Zigang Dong, Rochester, MN I - w uosianu (US); Ann M. Bode, Cannon Falls, MN 5,523,209 A 6/1996 Ginsberg et al. s s s 5,578,704 A 11/1996 Kim et al. (US); Slavik Dushenkov, Fort Lee, NJ 5,589,570 A 12/1996 At al. (US) 5,591,767 A 1/1997 Mohr et al. 5,610,279 A 3, 1997 Brockhaus et al. (73) Assignees: Wellgen, Inc., New Brunswick, NJ 5,639,476 A 6/1997 OShlack et al. (US); The Regents of the University 5,644,034 A 7/1997 Rathjen et al. of Minnesota, Minneapolis, MN (US); 5,652,109 A 7, 1997 Kim et al. Rutgers, the State University of New 3. g 3. it al. Jersey, New Brunswick, NJ (US) 5,658,746W - W A 8/1997 CoanC. C. eta. al. (*) Notice: Subject to any disclaimer, the term of this 5,665,393 A 9, 1997 Chen et al. patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 11/118,915 EP O 555 880 8, 1993 (22) Filed: Apr. 29, 2005 (Continued) (65) Prior Publication Data OTHER PUBLICATIONS US 2006/OO52438 A1 Mar. 9, 2006 Egyal- Chemical & pharmaceutical Bulletin, 1975, vol. 23, pp. Related U.S. Application Data (Continued) (60) Eyal application No. 60/567.340, filed on Apr. Primary Examiner Margaret D. Seaman s Assistant Examiner Niloofar Rahmani (51) Int. Cl. (74) Attorney, Agent, or Firm Jones Day AOIN 43/20 (2006.01) 57 ABSTRACT AOIN 43/24 (2006.01) (57) A6 IK3I/335 (2006.01) In one aspect, the present invention provides compounds C ey 3:08: having formula I or IV as shown below: (52) U.S. Cl. ....................................... 514/475; 549/332 I (58) Field of Classification Search ................ 549/332; 514/475 See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 3,536,809 A 10/1970 AppleZweig et al. 3,598,123 A 8, 1971 Zaffaroni et al. 3,845,770 A 11/1974 Theeuwes et al. 3,916,899 A 11/1975 Theeuwes et al. IV 4,008,719 A 2f1977 Theeuwes et al. 4,658,019 A 4, 1987 Kung et al. 5,017,691 A 5, 1991 Lee et al. 5,059,595 A 10, 1991 Le Grazie 5,073,543 A 12/1991 Marshall et al. 5, 120,548 A 6, 1992 McClelland et al. 5,136,021 A 8, 1992 Dembinski et al. 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Dong et al., 1994, "Differential transformation efficiency but not 5,733,566 A 3, 1998 Lewis AP-1 induction under anchorage-dependent and—independent con 5,736,138 A 4, 1998 Pfizenmaier et al. ditions.” Carcinogenesis 15:1001-1004. 5,741,488 A 4, 1998 Feldman et al. 5,753,230 A 5, 1998 Brooks et al. Fodde & Smits, “Disease model: familial adenomatous polyposis.” 5,767,071 A 6, 1998 Palladino et al. 2001, Trends Mol Med 7(8):369-73. 5,770,565 A 6/1998 Cheng et al. Ghaneh et al., 2001, “Adenovirus-mediated transfer of p53 and 5,780,426 A 7, 1998 Palladino et al. p16(INK4a) results in pancreatic cancer regression in vitro and in 5,808,029 A 9, 1998 Brockhaus et al. vivo.” Gene Ther 8(3):199-208. 5,817.457 A 10, 1998 Bird et al. Goodson et al., 1994. "High-Affinity Urokinase Receptor Antago 5,830,678 A 11/1998 Carter nists Identified with Bacteriophage Peptide Display” Proc. Natl. 5,849,692 A 12/1998 Jonczyk et al. Acad. Sci., USA 91:7129-7133 5,919,452 A 7, 1999 Le et al. Hamburger et al., “Supercritical carbon dioxide extraction of 5,955,269 A 9, 1999 Ghai et al. Selected medicinal plants—effects of high pressure and added 5,955,572 A 9, 1999 Ruoslahti et al. ethanol on yield of extracted Substances.” Phytochemical Analysis 5,958,412 A 9, 1999 Welt et al. (2004), 15(1), 46-54. 5,959,087 A 9/1999 Rathjen et al. Han et al., 2003, “Ent-kaurane Diterpenoids from Isodon rubescens 5,968,741 A 10/1999 Plevy et al. var: lushanensis” Chem. Pharm. Bull. 51(7): 790-793. 5,985,278 A 11/1999 Mitjans et al. Han et al., 2003a, 2003, “Eng-Kaurane Diterpenoids from Isodon 5,994,510 A 11/1999 Adair et al. rubescensvar. Lushiensis.” Heterocycles, 60(4): 933-938. 6,036,978 A 3, 2000 Gombotz et al. Han et al., 2003b, “Two Novel ent-Kaurene Diterpenoids from 6,048,861 A 4/2000 Askew et al. Isodon rubescens” Helvetica Chimica Acta, 86(3): 773-777. 6,090,944 A 7/2000 Hutchinson Han et al., 2004, “Two novel tricyclic diterpenoids from Isodon 6,096,707 A 8, 2000 Heino et al. rubescens var. taihangensis.” Tetrahedron 60: 2373-2377. 6,114,517 A 9, 2000 Monia et al. Han et al., 2004a, “Novel ent-kaurane dimers from Isodon 6,130,231 A 10/2000 Wityak et al. rubescens var, rubescens.” Tetrahedron Letters 45(13): 2833-2837. 6,153,628 A 11/2000 Jin et al. Han et al., 2003, “Synthesis of Poly(aryl ether) Dendrimers and 6, 160,099 A 12/2000 Jonak et al. Studies on the In-tramolecular Photosensitization' Huaxue Xuebao 6,162,432 A 12/2000 Wallner et al. (Acta Chimica Sinica) 61(7): 1077-1082. 6,171,588 B1 1/2001 Carron et al. Han et al., 2003, “New ent-Kaurane Diterpenoids from Isodon 6,171,787 B1 1/2001 Wiley rubescens.’ Youji Huaxue 23(3): 270-273. 6,498,195 B2 12/2002 Rosen et al. Herber et al., 1996, "Squamous epithelial hyperplasia and carci 6,627,623 B2 9, 2003 Ho et al. noma in mice transgenic for the human papillomavirus type 16 E7 6,790,869 B2 9, 2004 Ghai et al. oncogene” J. Virol 70(3): 1873-81. 2003.0035851 A1 2/2003 Chen Hosokawa et al., 2001, “In vivo analysis of mammary and non mammary tumorigenesis in MMTV-cyclin D1 transgenic mice FOREIGN PATENT DOCUMENTS deficient in p53” Transgenic Res 10(5):471-8). WO WO 93,08656 4f1993 Hou et al., 2001, “Cytotoxic 7, 20-epoxy ent-kauranoids from WO WO95/22543 8, 1995 Isodon xerophilus' Phytochemistry 58: 179-183. WO WO 98.33919 8, 1998 Hough et al., 1998, “A model for spontaneous B-lineage lymphomas WO WO 98.40488 9, 1998 in IgE-HOXII transgenic mice” Proc Natl Acad Sci USA WO WO 98.46264 10, 1998 95(23): 13853-8. WO WOOO,31248 6, 2000 IkeZoe et al., 2003, “Oridonin induces growth inhibition and WO WOOO,78815 12/2000 apoptosis of a variety of human cancer cells.” International Journal WO WO O1,21137 3, 2001 of Oncology, 23(4): 1187-1193. WO WO O2,39956 6, 2002 Kado et al., 2001, “Intestinal microflora are necessary for develop WO WO O2/O7OOO7 9, 2002 ment of spontaneous adenocarcinoma of the large intestine in T-cell WO PCT/USO5, 1528O 12/2006 receptor beta chain and p53 double-knockout mice.” Cancer Res 61(6):2395-8. OTHER PUBLICATIONS Kohno et al., 1990, “A Second Tumor Necrosis Factor Receptor Gene Product can Shed a Naturally Occurring Tumor Necrosis Ashkenazi et al., 1991, “Protection Against Endotoxic Shock by a Factor Inhibitor Proc. Natl. Acad. Sci., USA 87:8331-8335. Tumor Necrosis Factor Receptor Immunoadhesin' Proc. Natl. Acad. Kuraguchi et al., 2000, "Tumor-associated Apc mutations in Sci. USA 88:10535-10539. M1h1-/- Apc1638N mice reveal a mutational signature of M1h1 Bai et al., Abstracts of Papers, 223rd ACS National Meeting, deficiency.” Oncogene 19(50):5755-63. Orlando, FL, United States, Apr. 7-11, 2002: AGFD-093. Bryant et al., 2000, “Development of Intermediate-Grade (Mantle Liet al., 2000a, “ent-Kaurene diterpenoids from Isodon rubescens.” Cell) and Low-Grade (Small Lymphocytic and Marginal Zone) Phytochemistry 53(8): 855-859.
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