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(12) Patent Application Publication (10) Pub. No.: US 2010/0063153 A1 Chatterjee Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0063153 A1 Chatterjee Et Al US 20100063153A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0063153 A1 Chatterjee et al. (43) Pub. Date: Mar. 11, 2010 (54) ANT-CHOLESTEROLEMC COMPOUNDS Related U.S. Application Data AND METHODS OF USE (63) Continuation of application No. PCT/US2007/ (75) Inventors: Subroto Chatterjee, Columbia, 088780, filed on Dec. 24, 2007. MD (US); Mark S. Butler, (60) Provisional application No. 60/876,761, filed on Dec. Brisbane (AU); Brinda 22, 2006, provisional application No. 60/876,599, Somanadhan, Singapore (SG) filed on Dec. 22, 2006, provisional application No. 60/877,753, filed on Dec. 29, 2006, provisional appli Correspondence Address: cation No. 60/877,740, filed on Dec. 29, 2006. EDWARDS ANGELL PALMER & DODGE LLP P.O. BOX SS874 Publication Classification BOSTON, MA 02205 (US) (51) Int. Cl. A63L/92 (2006.01) (73) Assignees: THE JOHNS HOPKINS A6IP 7/00 (2006.01) UNIVERSITY, Baltimore, MD (US); MERLION (52) U.S. Cl. ........................................................ 514/568 PHARMACEUTICAL PTE LTD., (57) ABSTRACT Singapore (CN) The present invention provides novel compounds with hypo (21) Appl. No.: 12/488,965 cholesteremic activity from crude Embilica officinialis (EO) extracts and methods of use. The invention also provides (22) Filed: Jun. 22, 2009 nutraceuticals. Patent Application Publication Mar. 11, 2010 Sheet 1 of 11 US 2010/0063153 A1 HO OH O „(9)91.000HOO HOOOHOOOH OOHHOO QHOOOSLO}} OH HOOOC)HoºOH., HOOOHOOH HO (g)999 HOOH HOOH OOHC) OH H HO HOHO|-?OHOOH HC)OHOH HOOOHHOOOH OHOHOOH HOOHHO Patent Application Publication Mar. 11, 2010 Sheet 2 of 11 US 2010/0063153 A1 HO O HOOC) (z))p?oeo??nqaqo HO O O OH HOOO O O HOOOOH HO HO HO HOOH HOHO OH(??)u?6e||Joo HOHOOHHO HOOH(OL)u??ueue6 (penu??uOO)L’9|- Patent Application Publication Mar. 11, 2010 Sheet 3 of 11 US 2010/0063153 A1 1 OOO 900 -e- Control -O-- fat fed 800 - A-fat + E 700 -A- E alone 600 500 400 300 200 MONTHS FG. 2 -e- Control MONTHS FG. 3 Patent Application Publication Mar. 11, 2010 Sheet 4 of 11 US 2010/0063153 A1 200 10 O MONTHS FG. 4 Patent Application Publication Mar. 11, 2010 Sheet 5 of 11 US 2010/0063153 A1 25O OO 2OO 50 OO 50 ZZZZZ 222ZZZZZZZZZZZ. S Ñ |2222222222 Ñ?ZZZZZZZZZZ) O ZZZZZZZZZZZZZZZZZZZ §22222222 Ñ EZZZZZZZZZZZZZ Š? Š? ZZZZZZZZZZ Š??ZZZZZZZZZZZZZZZZ TC ÑTC TG LDL VLDL HDL apoB apoA- Lp(a) Ñ ÑTGZZZZZZZZZZZZZZZZZZZZ LDL VLDL HDL apoB apoA-I Lp(a) FIG. 5 Patent Application Publication Mar. 11, 2010 Sheet 6 of 11 US 2010/0063153 A1 Cholest, 100 Chol.oleate 80 N N N? - JH-2-F JH-4-M F.G. 6 Patent Application Publication Mar. 11, 2010 Sheet 7 of 11 US 2010/0063153 A1 100 - 7 m-digallic acid Corilaainf 1. .earlil 15 A 1-4 (13) O higher MW i 500 A. 8 c EA." i2 50 seS /Chebulic 9 A \| 3 N 8 S acic (12) NHN 5 S. N O O A. s -\ O 10 2O 30 40 50 SO 70 8O minutes FIG. 7 Patent Application Publication Mar. 11, 2010 Sheet 8 of 11 US 2010/0063153 A1 5 2.5 125 0.62 0.31 5 2.5 125 0.62 0.31 5 2.5 1.25 O.62 0.31 i- r 7-8 Patent Application Publication Mar. 11, 2010 Sheet 9 of 11 US 2010/0063153 A1 140 120 100 O Control LOW 2 3 4 4+1 5 6 7 8 7+8 Compounds FG. 9 10302 O O Low 1 2 3 4 4+1 5 6 7 8 7-8 Compounds FIG 10 Patent Application Publication Mar. 11, 2010 Sheet 10 of 11 US 2010/0063153 A1 2OO 150 10 O 5 O O Control LOW 1 2 3 4 4-1 5 6 7 8 7-8 Compounds FG. 11 Patent Application Publication Mar. 11, 2010 Sheet 11 of 11 US 2010/0063153 A1 400 g i i D Higher molecular wi 2 gallotannins s S 200 S O O minutes F.G. 12 US 2010/0063153 A1 Mar. 11, 2010 ANT-CHOLESTEROLEMC COMPOUNDS cholesterol biosynthesis. Many attempts to use for this pur AND METHODS OF USE pose oxygenated Sterols, which via binding oxysterol recep tors were expected to decrease activity of HMG-CoA reduc RELATED APPLICATIONS tase, did not bring practical results. A series of fungal 0001. This application claims the benefit of U.S. Provi metabolites with very high affinities for HMG-CoA reductase sional Application 60/876,761 filed Dec. 22, 2006, U.S. Pro were found to be highly efficient inhibitors of cholesterol visional Application 60/877,753 filed Dec. 29, 2006, U.S. biosynthesis. These compounds and Some synthetic analogs Provisional Application 60/876,599 filed Dec. 22, 2006 and are commonly known as statins, are available commercially, U.S. Provisional Application 60/877,740 filed Dec. 29, 2006. and are widely used. The entire contents of the aforementioned applications are 0007 Although being relatively safe and efficient in treat hereby incorporated herein by reference. ment and prevention of coronary heart disease, statins have certain limitations in their use because of possible deleterious GOVERNMENT SUPPORT side effects, such as muscle weakness, and renal failure. Sta tin therapy is contra-indicated in pregnant women and 0002 This invention was made with support from the patients with liver disorders. Additionally, there is a signifi United States Government under grant DK-31771 and cant patient population in whom statins are not effective, and DK-31722. The US Government has certain rights in this so the need for an agent that will lower cholesterol extends invention. beyond the number of patients currently taking statins to lower their cholesterol levels. Taking additionally into FIELD OF THE INVENTION account the relatively high costs of Statin therapy, which 0003. The present invention provides novel compounds varies from S20,000 to S40,000 per quality-adjusted life-year with hypocholesteremic activity from Embilica officinalis saved John A. Farmer, Economic Implications of Lipid (EO) extracts and methods of use. The invention provides Lowering Trials: Current Considerations in Selecting a Sta nutraceuticals. The invention relates to the determination of tin, Am J Cardiol 1998: 82:26 M-31M), and the desirability of the biological activity and mechanism of action by which the long-term permanent treatment Terry A. Jacobson, Clinical purified compounds lower cholesterol levels. Context: Current Concepts of Coronary Heart Disease Man agement, Am J Med. 2001; 110 (6A):3S-11S, it is evident BACKGROUND OF THE INVENTION that new agents are needed with similar targeting as the statins but with higher potency, safety, and availability and that will 0004. According to the American Heart Association, an provide significant cost savings. estimated 100,870,000 American adults have total choles 0008 Accordingly, the instant invention provides novel terol levels in the borderline-high risk range of 200 mg/dl to compounds with anticholesterolemic activity, and methods of 239 mg/dl., and there are 40,600,000 American adults living with high-risk cholesterol levels of 240 mg/dl or more. There SC. are many risk factors that can indicate a propensity to have SUMMARY high levels of cholesterol. Such as age, weight, and health conditions such as diabetes, Smoking, gender, race and eth 0009. The present invention relates generally to methods nicity. and compositions for reducing hypercholesteremia in a Sub 0005 Hypercholesterolemia, or elevated blood choles ject. The invention is based on the identification of novel terol levels due to concentration of cholesterol in the cells and compounds from crude Embilica officinialis (EO) extracts. plasma, is an important risk factor definitively connected with The invention relates to the determination of the biological potentially deadly cardiovascular disease, including athero activity and mechanism of action by which the purified com Sclerosis, coronary artery insufficiency, coronary heart dis pounds lower cholesterol levels. The invention provides ease, myocardial infarction and stroke. Millions of people nutraceuticals. around the world suffer from coronary heart disease, and it is 0010. In a first aspect, the invention provides a method for the leading cause of death and morbidity at a productive age, preventing or treating an elevated blood lipid level-related especially in Western Europe and in the United States. disease or disorder in a Subject comprising administering to Accordingly, cardiovascular disease presents a significant the Subject an effective amount of one or more gallic acid drain on healthcare resources in the western world. In the derivatives, thereby preventing or treating an elevated blood United States, total costs (direct and indirect) connected with lipid level-related disease or disorder in the subject. the disease were estimated as about S118 billion in 2000; for 0011. In another aspect, the invention provides a method 1.1 million citizens that experienced myocardial infarction, for preventing or treating inflammation in a Subject compris more than 40% of those died Terry A. Jacobson, Clinical ing administering to the Subject an effective amount of one or Context: Current Concepts of Coronary Heart Disease Man more gallic acid derivatives, thereby preventing or treating agement, Am J. Med. 2001; 110 (6A):3S-11S. In addition, inflammation in the Subject. cardiovascular disease is growing at an alarming rate in Asian 0012. In still another aspect, the invention provides a countries, and in particular among Asian Indians where car method for preventing or treating a stress response in a Sub diovascular disease has reached epidemic proportions 1. ject comprising administering to the Subject an effective 0006 Cholesterol (and its derivatives) biosynthesis under amount of one or more gallic acid derivatives, thereby pre lies cardiovascular disease and, accordingly, inhibitors of venting or treating a stress response in the Subject.
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