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Wo 2008/157537 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 24 December 2008 (24.12.2008) WO 2008/157537 A2 (51) International Patent Classification: (72) Inventors; and C07D 207/22 (2006.01) C07D 403/14 (2006.01) (75) Inventors/Applicants (for US only): CURRIE, Mark C07D 207/34 (2006.01) C07D 413/12 (2006.01) [US/US]; 18 Hall Avenue, Sterling, Massachusetts 01564 C07D 209/24 (2006.01) A61K 31/33 (2006.01) (US). TALLEY, John [US/US]; 96 North Street, #3, C07D 239/42 (2006.01) C07C 59/70 (2006.01) Somerville, Massachusetts 02144 (US). CALI, Brian C07D 257/06 (2006.01) C07C 69/017 (2006.01) [US/US]; 100 Hillside Avenue, Arlington, Massachusetts C07D 263/28 (2006.01) C07C 69/612 (2006.01) 02476 (US). C07D 403/04 (2006.01) C07C 203/00 (2006.01) (74) Agents: BELL, Charles et al.; Heslin Rothenberg Farley C07D 403/12 (2006.01) & Mesiti RC, 5 Columbia Circle, Albany, New York 12203 (US). (21) International Application Number: PCT/US2008/067204 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: 17 June 2008 (17.06.2008) AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (25) Filing Language: English EG, ES, FT, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KR KR, KZ, LA, LC, (26) Publication Language: English LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, (30) Priority Data: SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, 60/944,934 19 June 2007 (19.06.2007) US ZA, ZM, ZW 61/023,744 25 January 2008 (25.0 1.2008) US 61/030,778 22 February 2008 (22.02.2008) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): IRON- GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, WOOD PHARMACEUTICALS, INC [US/US]; 320 ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Bent Street, Cambridge, Massachusetts 02141 (US). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, [Continued on next page] (54) Title: COMPOSITIONS AND METHODS OF USE FOR TREATING OR PREVENTING LIPID RELATED DISORDERS 250 200 150 o 100 50 0 Nane Nai* Vehicle I 10 30 100 compound 1OA (mg/kg) compound 5A (mg/kg) Chow High Fat High Cholesterol Chow * p<0.05 as compared to vehicle only FIG. 1 (57) Abstract: Disclosed herein are novel compositions and methods for treating or preventing a variety of disorders and conditions associated with lipid metabolism. The methods generally include administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising one or more fibric acid or statin derivative compositions alone or in combination with one or more lipid altering agents and/or PDE inhibitors. FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, Published: NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, — without international search report and to be republished CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). upon receipt of that report COMPOSITIONS AND METHODS OF USE FOR TREATING OR PREVENTING LIPID RELATED DISORDERS TECHNICAL FIELD [0001] The subject matter of this application relates to fibric acid and statin derivatives, and pharmaceutical formulations thereof, used alone or in combination with one or more additional agents for treating lipid related disorders and associated conditions. BACKGROUND [0002] Disorders of lipid metabolism or dyslipidemias include various conditions characterized by abnormal concentrations of one or more lipids (i.e., cholesterol and triglycerides), and/or apolipoproteins (i.e., apolipoproteins A, B, C and E), and/or lipoproteins (i.e., the macromolecular complexes formed by the lipid and the apolipoprotein that allow lipids to circulate in blood, such as LDL, VLDL and IDL). Dyslipidemia is a major risk factor for cardiovascular disorders including coronary heart disease. Dyslipidemias were originally classified by Fredrickson according to the combination of alterations mentioned above. The Fredrickson classification includes 6 phenotypes (i.e., I, Ha, lib, III, IV and V) with the most common being the isolated hypercholesterolemia (or type Ha), which is usually accompanied by elevated concentrations of total and LDL cholesterol. A second common form of dyslipidemia is the mixed or combined hyperlipidemia or type lib and III of the Fredrickson classification. This dyslipidemia is often prevalent in patients with type 2 diabetes, obesity and the metabolic syndrome. [0003] The management of dyslipidemia is an important part of the National Cholesterol Education Program Adult Treatment Panel III guidelines. The reduction of low-density lipoprotein cholesterol as the primary target of treatment is recommended. Various lipid altering agents are considered first-line drugs for attaining this goal. However, monotherapy may not always be optimal for patients with significant combined or mixed dyslipidemias (e.g., elevated low-density lipoprotein cholesterol plus hypertriglyceridemia) or with concomitant conditions that increase the patient's level of risk (e.g., type 2 diabetes or the metabolic syndrome). Accordingly, combination drug therapy, which utilizes complementary mechanisms of action to alter levels of one or more lipoproteins may be useful. [0004] It would be desirable to develop an effective treatment for management of lipid related disorders using fibric acid and statin derivatives that can be administered alone or in combination with one or more lipid altering agents. Lipid altering agents encompass several classes of drugs that include HMG CoA reductase inhibitors (statins), fibric acid derivatives (fibrates), cholesterol-ester-transfer-protein ("CETP") inhibitors, squalene synthase inhibitors, microsomal-triglyceride-transfer-protein ("MTTP") inhibitors, cholesterol absorption inhibitors ("CAIs"), soluble guanylate cyclase modulators ("sGC modulators"), bile acid sequestrants, nicotinic acid, thyroid receptor agonists, liver X- receptor (LXR) modulators, antisense inhibitors of apoB-100 or C reactive protein, and probucol and derivatives thereof (e.g. AGI- 1067). These drugs differ with respect to mechanism of action and to the degree and type of lipid modulation. Thus, the indications for a particular drug are influenced by the underlying lipid abnormality. Monotherapy with statins, which competitively inhibit the intracellular rate-limiting enzyme for cholesterol biosynthesis, and bile acid sequestrants, which reduce terminal ileal bile acid absorption, primarily lower plasma low-density lipoprotein (LDL) cholesterol by enhancing hepatic LDL-receptor activity. Monotherapy with fibrates, which serve as ligands for peroxisome proliferator-activated receptor α, a transcription factor influencing gene expression in lipid metabolism, reduces plasma very-low-density lipoprotein (VLDL) cholesterol and triglycerides, and also increases high-density lipoprotein (HDL) cholesterol. SUMMARY [0005] Briefly, the present application discloses compositions of fibric acid and statin derivatives and their use in methods of prevention and/or treatment of various lipid related disorders, wherein the administration of such compositions is to a subject in need thereof. The application also discloses pharmaceutical formulations comprising fibric acid and statin derivatives alone or in combination with one or more lipid altering agents. [0006] In accordance with the above, the present application discloses methods to prevent and/or treat lipid related disorders such as dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, and fatty liver disease, by administering a therapeutically effective dose of at least one fibric acid or statin derivative described herein, alone or in combination with another therapeutic agent such as a lipid altering agent or a PDE inhibitor. [0007] In a first aspect, compounds represented by the structure of Formula I or II: (I) (H) wherein R1 is chosen from H and halogen; R2 is chosen from H, halogen, cycloalkyl substituted with from 1 to 3 halogens, 3 3 COR , and (CH2)mNHOR ; R3 is phenyl substituted with from one to three halogen groups; Z is chosen from O and (CH2)nO; X is chosen from direct bond, O, NH, and an amino acid residue; R4 is chosen from OH, NO, NO , an amino acid residue, a fϊbric acid residue, guanidine, tetrazolyl, agmatine, an amino-containing compound; lower alkyl terminating in ONO, (ONO )P, or guanidine; a resveratrol residue; and an imidazoline receptor agonist residue; wherein m, n, and p are independently chosen from 1 to 3; and R5 is chosen from a residue of a statin are provided herein. [0008] In certain embodiments, the compositions can include therapeutically effective amounts of the compounds represented by Formula (I), which include, but are not limited to, any of the compounds for which the synthesis is shown in Examples 1-35. In other embodiments, the compositions can include therapeutically effective amounts of the compounds represented by Formula (II), which include, but are not limited to, any of the compounds for which the synthesis is shown in Examples 36-1 15. In still other embodiments, the present disclosure provides compounds comprising a fϊbric acid or statin derivative in the form of a salt, wherein a fϊ bric acid or statin residue is a cation or anion, and another molecule is presented as a counterion to the fϊbric acid or statin residue. In some embodiments, the counterion includes, but is not limited to, a NOS substrate or an amino-tetrazole compound. Synthesis of particular fϊbric acid or statin derivative salt compounds is shown in Examples 116-139, although any fϊbric acid or statin compound can be used.
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