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Wo 2010/065069 A2 (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 10 June 2010 (10.06.2010) WO 2010/065069 A2 (51) International Patent Classification: (74) Agent: SCHULMAN, Aaron, B.; STITES & HARBI A61K 31/382 (2006.01) A61K 31/4184 (2006.01) SON PLLC, 1199 North Fairfax Street, Suite 900, A61K 31/385 (2006.01) A61K 9/22 (2006.01) Alexandria, VA 223 14 (US). A61K 31/195 (2006.01) A61P 9/12 (2006.01) (81) Designated States (unless otherwise indicated, for every A61K 31/41 (2006.01) A61P 3/10 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/41 78 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US2009/006247 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 23 November 2009 (23.1 1.2009) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (26) Publication Language: English TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/1 18,724 1 December 2008 (01 .12.2008) US kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): IN GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, VASC THERAPEUTICS, INC. [US/US]; 3562 Haber- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, sham At Northlake, Bldg. J, Suite, Tucker, GA 30084 TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, (US). ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, (72) Inventors; and TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (75) Inventors/Applicants (for US only): KHAN, Bobby, V. ML, MR, NE, SN, TD, TG). [US/US]; c/o In Vase Therapeutics, Inc., 3562 Habersham At Northlake, Bldg. J, Suite, Tucker, GA 30084 (US). Published: PARTHASARATHY, Sam [US/US]; c/o In Vase Thera — without international search report and to be republished peutics, Inc., 3562 Habersham At Northlake, Bldg. J. upon receipt of that report (Rule 48.2(g)) Suite, Tucker, GA 30084 (US). (54) Title: COMPOSITIONS COMPRISING RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM INHIBITORS AND LIPOIC ACID COMPOUNDS, AND THE USE THEREOF FOR THE TREATMENT OF RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM RELATED DISORDERS (57) Abstract: Compositions are provided which can be useful in treating a renin-angiotensin aldosterone system-related disorder. These compositions include renin-angiotensin aldosterone system inhibitors and lipoic acid compounds, as well as other therapeu- tic agents, and are useful in treating hypertension, stroke, metabolic syndrome, or other renin-angiotensin aldosterone system-re- lated disorders in a subject. The compositions are also useful in improving vasodilation, reducing proteinuria, and reducing insulin resistance in a subject. Pharmaceutical compositions and methods of treatment using the compositions are further provided. COMPOSITIONS COMPRISING RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM INHIBITORS AND LIPOIC ACID COMPOUNDS, AND THE USE THEREOF FOR THE TREATMENT OF RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM- RELATED DISORDERS CROSS-Reference TO RELATED APPLICATIONS The present application claims the benefit of U.S. Provisional Application Serial No. 61/1 18,724, filed December 1, 2008, the entire disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to compositions and methods for the treatment of a renin-angiotensin aldosterone system (RAAS)-related disorder. In particular, the present invention relates to compositions including a RAAS inhibitor and a lipoic acid compound that are useful in the treatment of RAAS-related disorders, such as hypertension, diabetes mellitus, target organ damage related to diabetes mellitus, atherosclerosis, coronary heart disease, angina, stroke, renal disorders, Reynaud's disease, metabolic syndrome, obesity, impaired glucose tolerance, and dyslipidemia. In addition, the present invention relates to the use of a composition including a RAAS inhibitor and a lipoic acid compound in improving vasodilation, reducing proteinuria, and reducing insulin resistance in subjects in need of such treatment. BACKGROUND OF THE INVENTION In the United States and other countries, hypertension, stroke, and other disorders related to the renin-angiotensin aldosterone system (RAAS) are a major cause of widespread morbidity and mortality, causing great hardship and economic loss to millions of people throughout the world. It has been estimated that nearly 600 million people worldwide are affected with hypertension, with nearly 50 million of those individuals residing in the United States. Furthermore, it has also been estimated that hypertension alone resulted in an annual expenditure of $66.4 billion in the United States alone in 2007. Despite the widespread hardship and economic consequences associated with hypertension and other RAAS-related disorders, adequate and appropriate treatment of these disorders has still remained elusive for many individuals as the etiology of these disorders is often multi-factorial. For example, pro-inflammatory mechanisms are thought to be a hallmark of many RAAS-related disorders, such as hypertension and diabetes; however, those findings of inflammation are often exacerbated by the increasing prevalence of obesity worldwide. As another example, metabolic syndrome, a RAAS-related disorder that has reached epidemic proportions over the last decade, often includes multiple components such as abnormal glucose levels, blood pressure, and lipid metabolism (12,46). Further, it has also been observed that individuals displaying multiple components of the metabolic syndrome are at a considerable risk for developing other RAAS-related disorders, including a 2 to 4 fold increased risk of stroke, a 2 to 3 fold increased risk of end-stage renal disease, and a 3 to 4 fold increased risk of myocardial infarction (12). Additionally, recent evidence has indicated that there is a relationship between the etiology of many RAAS-related disorders and oxidative stress and inflammation. To date, however, and regardless of the increasing amount of evidence that oxidative stress and inflammation play a significant role in the development and pathology of RAAS-related disorders, angiotensin-converting enzyme (ACE) inhibitors and angiotensin Il receptor blockers (ARBs) continue to be regarded as preferred agents for the treatment of RAAS-related disorders. It has been known for a number of years that ACE cleaves a C-terminal histidine-leucine dipeptide from the 10 amino acid angiotensin I to generate angiotensin II, which is then able to mediate a variety of physiological responses by binding to an angiotensin Il receptor. For example, in addition to the common vasoconstrictive action of angiotensin II, which can lead to increased blood pressure and hypertension, the physiologic effects of angiotensin Il also include: ventricular remodeling of the heart, which may lead to ventricular hypertrophy and congestive heart failure; increased free radical generation in blood vessels; stimulation of the adrenal cortex to release aldosterone, which subsequently leads to increases in blood volume and increases in blood pressure; and, stimulation of the posterior pituitary to release vasopressin (also known as anti-diuretic hormone, ADH) which acts on the kidneys to increase water retention. Further, angiotensin Il has also been implicated as having multiple effects on inflammation, as well as atherosclerotic plaque development and progression (33, 35, 36). In light of these wide-ranging effects, the RAAS has thus been implicated extensively in the pathogenesis of many disorders including hypertension, diabetes mellitus, target organ damage related to diabetes mellitus, atherosclerosis, coronary heart disease, angina, stroke, renal disorders, Reynaud's disease, metabolic syndrome, obesity, impaired glucose tolerance, and dyslipidemia. In this regard, recent evidence also suggests that the activation of the RAAS within adipose tissue may represent a link between glucose tolerance, hypertension, and obesity ( 13). Accordingly, and because angiotensin Il is thought to mediate many of the symptoms observed in these disorders, blocking the ability of angiotensin Il to bind to its receptors or inhibiting ACE activity thus has great therapeutic potential for the treatment of these disorders. Indeed, ACE inhibitors are currently approved for the treatment of high blood pressure (hypertension) and are also widely prescribed for the treatment of diabetes with target organ damage, systolic heart failure, acute coronary syndrome, and for treatment following a heart attack. The use of ACE inhibitors in these clinical conditions is considered necessary to meet the standard of care as they have been shown to improve clinical outcomes, independent of their blood pressure-lowering effects. However, prescription of ACE inhibitors, or ARBs, for the treatment of these various disorders still largely ignores the underlying oxidative stress and inflammation that accompanies many, if not all, of these disorders. As such, individuals diagnosed with RAAS-related disorders must rely on additional medications to treat the underlying inflammation and oxidative stress. Currently, a number of anti-inflammatory agents and antioxidants are available, or are naturally-occurring, and are capable of reducing the amount of oxidative stress or inflammation in patients. In plants and animals, one such agent is alpha lipoic acid. Alpha lipoic acid, also known as thioctic acid, is a naturally- occurring 8-carbon fatty acid that is synthesized by plants and animals, including humans, and serves several important functions in the body. Alpha lipoic acid contains two sulfur atoms that are normally found in an oxidized, disulphide form, but which can be reduced to form thiols.
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