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WO 2010/075469 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 1 July 2010 (01.07.2010) WO 2010/075469 Al (51) International Patent Classification: (74) Agent: MEARA, Joseph, P.; Foley & Lardner LLP, 150 C07D 455/03 (2006.01) A61K 31/4741 (2006.01) East Gilman Street, Post Office Box 1497, Madison, WI C07D 495/04 (2006.01) A61P 3/06 (2006.01) 53701 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2009/06933 1 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) International Filing Date: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 22 December 2009 (22.12.2009) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (26) Publication Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (30) Priority Data: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 61/140,551 23 December 2008 (23.12.2008) US SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): CVI PHARMACEUTICALS LIMITED [GB/GB]; Scotia (84) Designated States (unless otherwise indicated, for every Centre, 4th Floor, P.O. Box 2804, George Town (KY). kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (72) Inventors; and ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (75) Inventors/Applicants (for US only): LIU, Haiyan TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, [CN/US]; c/o CVI Pharmaceuticals Limited, Scotia Cen ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, tre, 4th Floor, Post Office Box 2804, George Town (KY). MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, LL Gaoping [CN/US]; c/o CVI Pharmaceuticals Limited, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Scotia Centre, 4th Floor, Post Office Box 2804, George ML, MR, NE, SN, TD, TG). Town (KY). WANG, Junbo [CN/CN]; c/o CVI Pharma ceuticals Limited, Scotia Centre, 4th Floor, Post Office Published: Box 2804, George Town (KY). LIU, Jingwen [US/US]; — with international search report (Art. 21(3)) c/o CVI Pharmaceuticals Limited, Scotia Centre, 4th Floor, Post Office Box 2804, George Town (KY). (54) Title: CORYDALINE DERIVATIVES USEFUL FOR REDUCING LIPID LEVELS (57) Abstract: The present technology relates to compounds of Formulas (V) and (VI) and methods of making and using such compounds. Methods of use include prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hep atic steatosis, and metabolic syndrome. Compounds disclosed herein also lower total cholesterol, LDL- cholesterol, and triglyc erides and increase hepatic LDL receptor expression, inhibit PCSK9 expression, and activate AMP-activated potein kinase. CORYDALINΞ DERIVATIVES USEFUL FOR REDUCING LIPID LEVELS RELATED APPLICATIONS [0001] The present application claims priority to U S Provisional Patent Application No 61/140,551 , filed December 23, 2008, the entire contents of which are incorporated by reference herein for all purposes FIELD [0002] The present technology is related to methods, compounds and compositions to treat hyperhpidemia, including hypertriglyceridemia and hypercholesterolemia, as well as hepatic steatosis and metabolic syndrome SUMMARY [0003] In accordance with one aspect, the present technology provides methods of reducing plasma and/or hepatic lipid levels of a subject in need thereof, which comprises administering to the said subject a hpid-loweπng effective amount of a compound, composition or extract described herein The lipid level to be reduced can be one or more of total cholesterol, LDL-cholesterol, triglycerides, and unestenfied long chain fatty acids In another aspect, the present technology provides methods for treating a disease or condition selected from the group consisting of hyperhpidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis and metabolic syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, composition or extract described herein [0004] In one aspect, the present technology provides lipid lowering agents, including hypocholesterolemic and/or hypotriglyceπdermc compounds, and deπvati\es of such compounds, from a variety of plants including Corydahs. Leontice Mahoma Fumana Legnephora Stephama Chehdonium Hunnemannia Coptis Guattena Paihypodanthium, Chasmanthera, Fώrawea, Cheilanthes, Dicranostigma, Glaucium, and Chehdonium In some embodiments, the compounds are obtained from the plant species selected from the group consisting of Corydahs (amhigua bulbosa cava chaerophylla pallida ϊohda thahctrifoha tuberosa turtschanmowu Besser), Leontice (leontopetalum) Mahonia (aqmfolmm) Fumana (yaillantii) Legnephυra (moorn) Stephania (glabra letranda) Chelidomum (majus) Hunnemanma (fumartaefolia) Coptis (groenlandica) Guattena (discolor) Pachypodantkium (staudtu), Chasmanthera (dependens), Fibraurea (chloroleuta) , Cheilanthes (meifoha), Dicranosligma (leptopodum), Glaucium (vitelhnum), Corydahs yan hu suo, and Corydalis Xiar Ri Wu [0005] In certain embodiments the lipid lowering agent is lsoquinolmyl-containing alkaloid from e g , a Corydalis extract or a derivative of a Corydalis compound, such as a compound of Formulae I, II, III, or IV as shown herein Exemplary lipid lowering agents include substantially pure corlumidin (CLMD), (+)-corlumidin, (+)-CLMD, corypalmme (CRPM), 14R-(+)-corypalmine (14R (+)-CRPM), tetrahydropalmatine (THP), 14R-(+)- tetrahydropalmatine (14R-(+) THP), corydalme (CRDL), 14R,13S (+)-corydalme (14R,13S (+)-CRDL), bicuculline (BCCL), d-(+)-bicuculline (d-(+)-BCCL), and Egemne (EGN), (+)-egemne ((+)-EGN) [0006] For compounds of either Formula I or Formula II, Ri, R2, R3, R4, R5, and R< are selected (independently collectively, or in any combination) from H, halogen, hydroxy Ci- C alkyl, alkoxy, nitro, amino armnoalkyi, tπfluoromethyl, tπfluoromethoxy, cycloalkyl alkanoyl, alkanoyloxy, nitπle, dialkylamino, alkenyl, hydroxyalkyl, alkylaminoalkyl, aminoalkyl, dialkylammoalkyl, haloalkyl, carboxyalkyl, alkoxyalkyl, carboxy, alkanoylammo, carbonylamino, carbamoyl, alkylsulfonylammo, and heterocyclyl groups Preferably, Ri, R2, R3, R4, R5, and R are not halogen when halogen would be covalently bonded to oxygen In one aspect, the compounds of the present technology can also compose one or more halogens as substituents at any position of Formula I or Formula II In some embodiments, compounds ot Formula I have the 14R-(+) stereochemical configuration In some embodiments, compounds of Formula I have the 14S-(-) stereochemical configuration [0007] In some embodiments, the lipid lowering agents that may be used in methods described herein include compounds of Formula III and Formula IV Formula III or stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof, wherein R i and R2 are independently -H, -(CH2)0 (,COOR', -C(O)R", or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, or R and R2 together are a methylene group, R3 and R g are independently -H, -OH, -Cl, -Br, -F, -I, -CN. -NH2, -C(O)NH2, -COOH, or a substituted or unsubstituted alkyl, alkoxy, alkenyl, or aralkyl group, R3' is H, or R3 and R ' together are an oxo group, 1 R4 is -H, halogen, -OR , -OSO2R' , -OC(O)R", -OC(O)OR", -OC(O)NRR", -O- π alkylene-NR'R', -O-alkyle e-OSO2R", -O-alkylene-S(O)0 2R", -O-alkylene-NR'SO2R", -O-alkylene-N(R )C(0)R' or a substituted or unsubstituted alkyl group, R and R<, are independently -H, halogen, -OH, or a substituted or unsubstituted alkoxy group; or R4 and Rs together are a methylenedioxy group, or R and R together are a methylenedioxy group; R7 is H, halogen, OH, or a substituted or unsubstituted alkyl or alkoxy group; R9 is H or a substituted or unsubstituted alkyl group, each R' is independently a hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, alkenyl. cycloalkyl, cycloalkylalkyl, aryl. aralkyl, heteroaryl. heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group. [0008] In other embodiments, there are provided a second group of compounds of Formula III: stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof; wherein Ri and R2 are independently -H, -(CH2)o-6COOR', -C(O)R", or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group; or Ri and R2 together are a methylene group; R3 and R8 are independently -H, -OH, -Cl. -Br. -F, -I, -CN. -NH2, -C(O)NH2, -COOH, or a substituted or unsubstituted alkyl, alkenyl, alkoxy or aralkyl group; R ' is -H, or R3 and Ra' together are an oxo group, R4 is -H, halogen, -OR', -OSO2R", -OC(O)R", -OC(O)OR", -OC(O)NRR", -O- 1 alkylene-NR'R , -O-alkylene-OSO2R", -0-alkylene-S(0)o 2R", -O-alkylene-NR'SO2R", -O-alkylene-N(R')C(O)R', or a substituted or unsubstituted alkyl group, Rs and Rf, are independently -H, halogen,
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