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(12) Patent Application Publication (10) Pub. No.: US 2010/0160351A1 UENKNS Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0160351A1 UENKNS Et Al US 2010.0160351A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0160351A1 UENKNS et al. (43) Pub. Date: Jun. 24, 2010 (54) PHARMACEUTICAL COMPOSITIONS AND sional application No. 61/232,344, filed on Aug. 7, METHODS FOR TREATING 2009, provisional application No. 61/139,415, filed on HYPERURCEMIA AND RELATED Dec. 19, 2008. DSORDERS Publication Classification (75) Inventors: Helen JENKINS, Foster City, CA (51) Int. Cl. (US); Michael KITT, Mountain A 6LX 3/59 (2006.01) View, CA (US); Rodney A6II 3/426 (2006.01) PEARLMAN, El Granada, CA A6II 3/196 (2006.01) (US); Tito SERAFINI, Belmont, A6IP 9/06 (2006.01) CA (US); Eugene THORSETT, Half Moon Bay, CA (US) (52) U.S. Cl. ....................... 514/262.1; 514/365: 514/563 (57) ABSTRACT Correspondence Address: COOLEY GODWARD KRONISH LLP Disclosed is a pharmaceutical composition comprising (a) a ATTN: Patent Group first therapeutic agent, wherein the first therapeutic agent is a Suite 1100, 777 - 6th Street, NW compound of formula II: WASHINGTON, DC 20001 (US) (73) Assignee: NUON THERAPEUTICS, INC., (II) San Diego, CA (US) Appl. No.: 12/642,802 (21) RI N CO2H (22) Filed: Dec. 19, 2009 44 R: (X), Related U.S. Application Data (60) Provisional application No. 61/140,802, filed on Dec. or a pharmaceutically acceptable salt thereof, wherein R', 24, 2008, provisional application No. 61/161,754, R. R. R. X and n are as defined herein; (b) a second filed on Mar. 19, 2009, provisional application No. therapeutic agent, wherein the second therapeutic agent 61/165,114, filed on Mar. 31, 2009, provisional appli is a uric acid synthesis inhibitor or a uricosuric agent; cation No. 61/242,354, filed on Sep. 14, 2009, provi and (c) a pharmaceutically acceptable diluent or carrier. Patent Application Publication Jun. 24, 2010 US 2010/0160351A1 PRESTO hyperuricemia data 28.0 mg/dL at baseline -- placebo -á- 300 ring BD month A-300 mg BD 3 month --459 trig BD month O-450 mg BID 3 month FIGURE 1 US 2010/01 60351 A1 Jun. 24, 2010 PHARMACEUTICAL COMPOSITIONS AND the upper limit of solubility of uric acid (also called urate) in METHODS FOR TREATING extracellular fluids. However, hyperuricemia also has been HYPERURCEMIA AND RELATED associated with other levels of serum uric acid depending on DISORDERS factors such as gender and age, for example. Hyperuricemia leads to gout when urate crystals are formed from Supersatu RELATED APPLICATIONS rated body fluids and deposited in joints, tophi, and paren 0001. This application claims the benefit of U.S. Provi chymal organs. sional Application No. 61/139,415, filed Dec. 19, 2008, U.S. 0004. In addition to gout, other disorders related to Provisional Application No. 61/140,802, filed Dec. 24, 2008, elevated serum uric acid levels include gout-associated U.S. Provisional Application No. 61/161,754, filed Mar. 19, inflammation, renal disorders, cardiovascular disease, aber 2009, U.S. Provisional Application No. 61/165,114, filed rant metabolic conditions, fatty liver disease, kidney Stones, Mar. 31, 2009, U.S. Provisional Application No. 61/242,354, cognitive impairment and dementia. Elevated serum uric acid filed Sep. 14, 2009, and U.S. Provisional Application No. levels have been identified as an independent risk factor for 61/242,344, filed Sep. 14, 2009, each of which is hereby chronic kidney disease, cardiovascular disease and hyperten incorporated be reference in its entirety. sion. Edwards, N. L., Clev. Clin. J. Med., Vol. 75, Suppl. 5, July 2008, S13-16. With respect to cardiovascular disease, BACKGROUND OF THE INVENTION hyperuricemia has been identified as an independent risk 0002 Gout, which is sometimes called podagre, affects 3 factor for atherSclerotic disease in general and for coronary to 5 million individuals in the United States and continues to artery disease in particular. Edwards, N. L., Curr. Opin. increase in incidence. Gout includes a group of disorders Rheum., 2009, 21:132-137. It also has been identified as an including painful attacks of acute, monarticular, inflamma independent risk factor for heart failure. Krishnan, E., Circ. tory arthritis due to uric acid crystals, deposition of urate Heart Fail., 2009, 2:556-562. Hyperuricemia independent of crystals in joints, deposition ofurate crystals in renal paren crystal deposition also may play a pathogenetic role in aber chyma, urolithiasis (formation of calculus in the urinary rant metabolic states, such as hypertriglyceridemia, obesity, tract), and nephrolithiasis (formation of kidney Stones). insulin resistance, diabetes and metabolic syndrome. Beck, Gouty arthritis is usually an extremely painful attack of gout M. A., et. al. Rheum Dis. Clin. Am., 32 (2006), 275-293. In with a rapid onset of joint inflammation. The joint inflamma addition, hyperuricemia has been linked to cerebral vascular tion is precipitated by deposits ofuric-acid crystals in the joint disease. Edwards, N. L., Curr. Opin. Rheum., 2009, 21:132 fluid (synovial fluid) and joint lining (synovial lining). 137. Elevated serum uric acid also has been independently Intense joint inflammation occurs as white blood cells engulf associated with non-alcoholic fatty liver disease (NAFLD). the uric-acid crystals and release chemicals of inflammation, Lee, Y-J., et. al. Clin. Chem. Lab. Med., 2010, 48(2). Elevated causing pain, heat, and redness of the joint tissues. Chronic serum uric acid also has been identified as a strong risk factor gout can lead to deposits of hard lumps of uric acid in and for myocardial infarction and stroke. Bos, M.J., et al., Stroke, around the joints, kidney Stones, and blockage of the kidney 2006, 37, 1503-1507. In addition, normal but mildly elevated filtering tubules with uric-acid crystals, leading to kidney serum uric acid levels have been linked to cognitive impair failure. ment and dementia. Schretlen, D.J., et al., Neuropsychology, 0003. The underlying metabolic aberration in gout is 2007, Vol. 21, No. 1, 1.36-140. hyperuricemia. Hyperuricemia has been associated with a 0005. The biosynthesis pathway for uric acid is represent serum uric acid (suA) level of 6.8 mg/dL or greater, which is in the following Scheme I: Scheme I NH O O O a N AMP N N N Nls y -surdeaminase HN y N- N N- N oz n N1 N oan N1 N ribose-5-phosphate ribose-5-phosphate H ribose-5-phosphate H ribose-5-phosphate AMP IMP XMP GMP setts setts cells adenosine deaminase Adenosine He- Inosine Xanthosine Guanosine purine nucleotide purine nucleotide phosphorylase (PNP) phosphorylase (PNP) Xanthine oxidase guanine deaminase Hypoxanthine He Xanthine a Guanine utile oxidase US 2010/01 60351 A1 Jun. 24, 2010 -continued O HN , O1. N N O H Uric Acid 0006 Scheme I. Purines are converted to hypoxanthine, ora pharmaceutically acceptable salt thereof, wherein each of then Xanthine and finally urate via sequential oxidation by the R" and R is independently selected from a hydrogenatom or enzyme Xanthine oxidase. a C-C alkyl group, R and Rare each hydrogen atoms or 0007 Hyperuricemia can result from increased produc together form another chemical bond, each X is indepen tion or decreased excretion of uric acid, or from a combina tion of the two processes. Urate is the end product of purine dently selected from a hydroxyl group, a halogen atom, a metabolism in humans, shown above in Scheme I. C-C alkyl group or a C-C alkoxy group, or when two X 0008 Known methods for treating gout include the use of groups are alkyl or alkoxy groups, they may be connected uric acid synthesis inhibitors to inhibit the accumulation of together to form a ring, and n is an integer from 1 to 3; (b) a uric acid in the body. These compounds function by inhibiting second therapeutic agent, wherein said second therapeutic an enzyme involved in uric acid synthesis. In fact, it may be agent is a uric acid synthesis inhibitor or a uricosuric agent; possible to inhibit uric acid synthesis by inhibiting any one of and (c) a pharmaceutically acceptable diluent or carrier. several enzymes shown above to be involved in uric acid 0013. In another aspect the present invention provides a synthesis. For example, Xanthine oxidase inhibitors, such as method of treating a condition associated with an elevated febuxostat and allopurinol, reduce serum uric acid levels by serum uric acid level comprising administering to a subject in inhibiting the enzyme Xanthine oxidase. Known methods also need thereof a pharmaceutical composition comprising (a) a include introduction of a recombinant, non-human uricase first therapeutic agent, wherein said first therapeutic agent is enzyme into the body, Such as rasburicase or pegloticase. a compound of formula II, or a pharmaceutically acceptable 0009. Another known method for treating gout involves salt thereof; (b) a second therapeutic agent, wherein said the use of uric acid excretion promoters These compounds second therapeutic agent is auric acid synthesis inhibitor or a accelerate the rapid excretion ofuric acid accumulated in the uricoSuric agent; and (c) a pharmaceutically acceptable dilu body. Probenecid, sulfinpyrazone and benzbromarone are examples ofuric acid excretion promoters. These compounds ent or carrier. prevent the reuptake ofurate back into the bloodstream in the 0014. In another aspect the present invention provides a kidney, leading to a net increase in excretion. Interleukin-6 method of treating a condition associated with an elevated (IL-6) has been proposed for use in the treatment of gout as a serum uric acid level comprising administering to a subject in serum uric acid decreasing agent (see U.S. Pat. No. 6,007, need thereof of a pharmaceutically effective amount of com 804). In addition, non-steroidal anti-inflammatory drugs pound of formula II, or a pharmaceutically acceptable salt (NSAIDs), corticosteroids and colchicine have been used to thereof.
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