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WO 2013/112809 A2 1 August 2013 (01.08.2013) P O P C T

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WO 2013/112809 A2 1 August 2013 (01.08.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/112809 A2 1 August 2013 (01.08.2013) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/4745 (2006.01) C07D 491/22 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US201 3/023 110 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 25 January 20 13 (25.01 .2013) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (26) Publication Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (30) Priority Data: ZM, ZW. 61/590,5 16 25 January 2012 (25.01.2012) US (84) Designated States (unless otherwise indicated, for every (71) Applicants: SALIX PHARMACEUTICALS, LTD kind of regional protection available): ARIPO (BW, GH, [US/US]; 85 10 Colonnade Center Dr., Raleigh, NC 27615 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (US). ALFA WASSERMANN S.P.A. [ΓΓ/ΙΤ]; Via UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Ragazzi del'99,5, 1-40133 Bologna (ΓΓ). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventors: GOLDEN, Pam; 5 Fontana C , Durham, NC MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 2771 3 (US). KABIR, Mohammed, A.; 703 Unison Ct., TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cary, NC 2751 9 (US). VISCOMI, Giuseppe, Claudio; ML, MR, NE, SN, TD, TG). Via Ragazzi del '99, 5, 1-40133 Bologna (IT). CAM- PANA, Manuela; Via Ragazzi del '99, 5, 1-40133 Bologna Published: (IT). CONFORTINI, Donatella; Via Ragazzi del '99, 5, 1- — without international search report and to be republished 40133 Bologna (IT). BARBANTI, Miriam; Via Ragazzi upon receipt of that report (Rule 48.2(g)) del'99, 5, 1-40133 Bologna (IT). (74) Agents: SPARKS, Jonathan M. et al; McCarter & Eng lish LLP, 265 Franklin Street, Boston, MA 021 10 (US). (54) Title: RIFAXIMIN DERIVATIVE AND USES THEREOF (57) Abstract: 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof is provided. Methods of treatment of bowl re lated disorders using isolated and/or purified 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof are also provided. RIFAXIMIN DERIVATIVE AND USES THEREOF RELATED APPLICATIONS This application claims the benefit of US Provisional Application No. 61/590,516 filed January 25, 2012, the entire contents of which are expressly incorporated herein by reference. BACKGROUND The number of species and strains of bacteria resistant to antibiotics and the number of antibiotics to which they are resistant has increased world-wide. As a result, infections that had been readily treatable by antibiotics may no longer be so. Increased resistance of bacterial infections to antibiotic treatment has now become a generally recognized medical problem. Throughout the developed world there is public and governmental concern about the increasing prevalence of antimicrobial resistance to antibiotic therapy in bacteria that cause diseases in humans. Many pathogens exist for which there are few effective treatments, and the number of strains resistant to available drugs is continually increasing. New antimicrobial agents and improved methods are thus needed for the treatment and prevention of infections by such pathogens. SUMMARY Provided herein is a 25-desacetyl rifaximin and methods of using the same for the treatment of at least one bowel related disorder. Bowel related disorders, include, for example, irritable bowel syndrome, travelers' diarrhea, small intestinal bacterial overgrowth, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, hepatic encephalopathy, pouchitis, enteritis and colitis (including, ulcerative colitis) and other related conditions. In certain embodiments, the 25-desacetyl rifaximin is isolated and/or purified. Embodiments relate to a purified and/or isolated 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof. Embodiments also relate to a purified and/or isolated 25-desacetyl rifaximin having the formula: Embodiments are directed to pharmaceutical compositions comprising 25- desacetyl rifaximin or a pharmaceutically acceptable salt thereof. In some embodiments, 25-desacetyl rifaximin is 50% - 99.9% pure or purified. In some embodiments, 25-desacetyl rifaximin is 90% pure or purified. In some embodiments, 25-desacetyl rifaximin is 95% pure or purified. In some embodiments, 25-desacetyl rifaximin is from between about 50% to about 99.9% pure or purified. In some embodiments, a 25-desacetyl rifaximin composition is formulated as one or more of a tablet, caplet, capsule, or liquid dosage form. Embodiments are directed to methods for treating or preventing one or more bowel related disorders, comprising administering to a subject in need thereof a therapeutically effective amount of 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more bowel related disorders comprise irritable bowel syndrome, travelers' diarrhea, small intestinal bacterial overgrowth, Crohn's disease, pancreatitis, pancreatic insufficiency, peritonitis, hepatic encephalopathy, pouchitis, infectious diarrhea, inflammatory bowel disease, diverticular disease, Clostridium, C. difficile disease, H. pylori infection, enteritis, colitis, ulcerative colitis, and bacterial periodontal conditions. In some embodiments, the traveler's diarrhea is caused by exposure to one or more enteric pathogens. In some embodiments, the one or more enteric pathogens comprise Salmonella spp., Shigella spp., Campylobacter spp., Aeromonas, Plesiomonas, Vibro spp., Yersinia entercolitica, E. coli, Enterotoxigenic Escherichia coli (ETEC), E. coli 0157:H7, C. difficile or H. pylori. In some embodiments, the enteric pathogens comprise one or more of a gram-postive bacteria, a gram-negative bacteria, an aerobic bacteria or an anaerobic bacteria. In some embodiments, E. coli comprises enterotoxigenic and/or enteroaggregative strains. In some embodiments, the methods further comprise administering rehydration therapy (RT) to the subject. In some embodiments, the RT is administered before, during and/or after the administration of the 25-desacetyl rifaximin. In some embodiments, the RT comprises one or more of oral rehydration therapy or intravenous rehydration therapy. Embodiments relate to methods for alleviating the symptoms of bloating, abdominal pain, gas or flatulence in a subject comprising administering to a subject in need thereof a therapeutically effective amount of 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof. Embodiments are also directed to methods of treating disorders caused by abnormal GI flora comprising administering to a subject in need thereof a therapeutically effective amount of 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof. In some embodiments, the abnormal GI flora comprises one or more of enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), Shigella spp., Salmonella spp., Campylobacter spp., Vibrio, H. pylori, Staphylococcus spp., and C. difficile. Embodiments are directed to kits comprising 25-desacetyl rifaximin and instructions for use. Embodiments are also directed to methods for treating or preventing traveler's diarrhea in a subject comprising administering to a subject in need thereof a therapeutically effective amount of 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof. In particular aspects, the traveler's diarrhea to be treated is caused by exposure to E. coli. Embodiments relate to methods for treating or preventing hepatic encephalopathy in a subject comprising administering to a subject in need thereof a therapeutically effective amount of 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof. Embodiments also relate to methods for alleviating the symptoms of bloating, gas or flatulence in a subject comprising administering to a subject in need thereof a therapeutically effective amount of 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof. Embodiments are directed to methods for treating irritable bowel syndrome in a subject comprising administering to a subject in need thereof a therapeutically effective amount of 25-desacetyl rifaximin or a pharmaceutically acceptable salt thereof. In some embodiments, the 25-desacetyl rifaximin or pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the 25- desacetyl rifaximin or pharmaceutically acceptable salt thereof is administered topically. In some embodiments, the topically administered 25-desacetyl rifaximin or pharmaceutically acceptable salt thereof is administered in a cream, enema, ointment, lotion, or gel. Embodiments are also directed to the use of 25-desacetyl rifaximin as a metabolite of rifaximin. In some embodiments, rifaximin is administered to a subject in need of treatment for a bacterial infection in an amount that results in a therapeutically effective amount of 25-desacetyl rifaximin
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