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(12) STANDARD PATENT (11) Application No. AU 2002245022 B8 (19) AUSTRALIAN PATENT OFFICE

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(12) STANDARD PATENT (11) Application No. AU 2002245022 B8 (19) AUSTRALIAN PATENT OFFICE (12) STANDARD PATENT (11) Application No. AU 2002245022 B8 (19) AUSTRALIAN PATENT OFFICE (54) Title Inhibition of NF-kappaB by triterpene compositions (51) International Patent Classification(s) A61K 31/00 (2006.01) (21) Application No: 2002245022 (22) Date of Filing: 2001.11.19 (87) WIPO No: W002/055016 Priority Data (31) Number (32) Date (33) Country 60/249,710 2000.11.17 US 60/322,859 2001.09.17 US (43) Publication Date: 2002.07.24 (43) Publication Journal Date: 2003.02.06 (44) Accepted Journal Date: 2006.09.21 (48) Corrigenda Journal Date: 2006.10.12 (71) Applicant(s) Research Development Foundation (72) Inventor(s) Haridas, Valsala;Gutterman, Jordan, U. (74) Agent Attorney Callinan Lawrie, 711 High Street, Kew, VIC, 3101 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau 11111111111111IIIII I11 UlII I I1111111111IIII H11111111111111111111iiI I iii (43) International Publication Date (10) International Publication Number 18 July 2002 (18.07.2002) PCT WO 02/055016 A2 7 (51) International Patent Classification A61K (81) Designated States (national): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, (21) International Application Number: PCT/US01/43286 CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, (22) International Filing Date: LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, 19 November 2001 (19.11.2001) MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG UZ, VN, YU, Filing Language: English ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (regional): ARIPO patent (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW), Priority Data: Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 60/249,710 17 November 2000 (17.11.2000) US European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, 60/322,859 17 September 2001 (17.09.2001) US GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, ML, MR, (71) Applicant: RESEARCH DEVELOPMENT FOUNDA- NE, SN, TD, TG). TION [US/US]: 402 North Division Street, Carson City, NV 89703 (US) Published: (72) Inventors: GUTTERMAN, Jordan, 1701 Hermann without international search report and to be republished G, Houston, TX 77004 HARIDAS, Valsala; upon receipt of that report 2120 El Pasco Street #1802, Houston, TX 77054 (US). For two-letter codes and other abbreviations, refer to the "Guid- (74) Agent: WEILER, James, F; Suite 1560, 1 Riverway, ance Notes on Codes andAbbreviations appearingat the begin- Iouston, TX 77056 (US). ning of each regularissue of the PCT Gazette. ID In (54) Title: INHIBITION OF NR-KB BY TRITERPENE COMPOSITIONS (57) Abstract: The invention provides methods for the inhibition of inflammation by providing, to a cell, in need thereof, monoter- pene compositions that inhibit NF-KB. These compositions may also contain a carrier moiety that renders the monoterpene composi- Stion membrane permeable. The carrier may include triterpenoid moieties, sugars, lipids, or even additional monoterpenoid moieties. The composition can also contain additional chemical functionalites. Methods for using these compounds to prevent and treat a wide range of inflammatory conditions, especially, premalignant inflammatory conditions are described. WO 02/055016 PCT/US01/43286 INHIBITION OF NF-KB BY TRITERPENE COMPOSITIONS BACKGROUND OF THE INVENTION This application claims the priority of U.S. Provisional Application Ser. No. 60/249,710, filed November 17, 2000, and U.S. Provisional Application Ser. No. 60/322,859, filed September 17, 2001, both of which disclosures are specifically incorporated herein by reference in their entirety. 1. Field of the Invention The present invention relates generally to the field of medicine. More specifically, the invention relates to methods of inhibiting inflammation using monoterpene compositions that inhibit NF-KB. 2. Description of Related Art Plants and animals especially, marine animals, are valuable sources for the identification of novel biologically active molecules. One diverse class of molecules which has been identified in plants is the class of saponins. Saponins are high molecular weight compounds comprising glycosides with a sugar moiety linked to a triterpene or steroid aglycone. Triterpene saponins particularly have been the subject of much interest because of their biological properties. Pharmacological and biological properties of triterpene saponins from different plant species have been studied, including fungicidal, anti-viral, anti-mutagenic, spermicidal or contraceptive, cardiovascular, and anti-inflammatory activities (Hostettmann et al., 1995). Saponins are known to form complexes with cholesterol by binding plasma lipids, thereby altering cholesterol metabolism (Oakenfull et al., 1983). Triterpene glycosides given in feed also have been shown to decrease the amount of cholesterol in the blood and tissues of experimental animals (Cheeke, 1971). Saponins have been found to be constituents of many folk medicine remedies and some of the more recently developed plant drugs. The triterpene glycyrrhetinic acid, and certain derivatives thereof, are known to have anti-ulcer, anti-inflammatory, anti-allergic, anti-hepatitis and antiviral actions. For instance, certain glycyrrhetinic acid derivatives can prevent or heal gastric ulcers (Doll et al., 1962). WO 02/055016 PCT/US01/43286 Among such compounds known in the art are carbenoxolone Patent No. 3,070,623), glycyrrhetinic acid ester derivatives having substituents at the 3' position Patent No. 3,070,624), amino acid salts of glycyrrhetinic acid (Japanese Patent Publication JP-A-44-32798), amide derivatives of glycyrrhetinic acid (Belgian Patent No. 753773), and amide derivatives of 11-deoxoglycyrrhetinic acid (British Patent No. 1346871). Glycyrrhetinic acid has been shown to inhibit enzymes involved in leukotriene biosynthesis, including 5-lipoxygenase activity, and this is thought to be responsible for the reported anti-inflammatory activity (Inoue et al., 1986). Betulinic acid, a pentacyclic triterpene, is reported to be a selective inhibitor of human melanoma tumor growth in nude mouse xenograft models and was shown to cause cytotoxicity by inducing apoptosis (Pisha et al., 1995). A triterpene saponin from a Chinese medicinal plant in the Cucurbitaceae family has demonstrated anti-tumor activity (Kong et al., 1993). Monoglycosides of triterpenes have been shown to exhibit potent and selective cytotoxicity against MOLT-4 human leukemia cells (Kasiwada et al., 1992) and certain triterpene glycosides of the Iridaceae family inhibited the growth of tumors and increased the life span of mice implanted with Ehrlich ascites carcinoma (Nagamoto et al., 1988). A saponin preparation from the plant Dolichosfalcatus,which belongs to the Leguminosae family, has been reported to be effective against sarcoma-37 cells in vitro and in vivo (Huang et al., 1982). Soya saponin, also from the Leguminosae family, has been shown to be effective against a number of tumors (Tomas-Barbaren et al., 1988). Oleanolic acid and gypsogenin glycosides exhibiting haemolytic and molluscicidal activity have been isolated from the ground fruit pods of Swartzia madagascariensis(Leguminosae) (Borel and Hostettmann, 1987). Genistein, a naturally occurring isoflavonoid isolated from soy products, is a tyrosine kinase inhibitor that has been shown to inhibit the proliferation of estrogen-positive and estrogen-negative breast cancer cell lines (Akiyama et al., 1987). Inositol hexaphosphate (phytic acid), which is abundant in the plant kingdom and is a natural dietary ingredient of cereals and legumes, has been shown to cause terminal differentiation of a colon carcinoma cell line. Phytic acid also exhibits anti-tumor activity against experimental colon and mammary carcinogenesis in vivo (Yang et al., 1995). Some triterpene aglycones also have been demonstrated to have cytotoxic or cytostatic properties, stem bark from the plant Crossopteiyx febrifuga WO 02/055016 PCT/US01/43286 (Rubiaceae) was shown to be cytostatic against Co-115 human colon carcinoma cell line in the ng/ml range (Tomas-Barbaren et al., 1988). While the previous reports have identified triterpene compounds which have any of a number of uses, there still is a great need in the art for the identification of novel biologically active triterpene compounds. Many of these compounds are toxic to normal mammalian cells. Still further, the biological activities of previously identified triterpenes vary widely and many posses limited or varying degrees of efficacy in the treatment of any given human or mammalian condition. The great diversity of different triterpenes which have been identified and the great range of differences and unpredictability in the biological activities observed among even closely related triterpene compounds, underscores the difficulties which have been encountered in obtaining triterpenes which are potential therapeutic agents. Achieving the difficult goal of identifying novel triterpenes with beneficial biological activities could provide entirely new avenues of treatment for a diverse set of human ailments in which therapeutic options currently are limited. NF-KB, is a ubiquitous transcription factor and regulates the transcription of a number of genes involved in immune and inflammatory pathways such as various pro-inflammatory cytokines, adhesion molecules, and apoptosis
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