(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) CORRECTED VERSION (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 3 April 2008 (03.04.2008) PCT WO 2008/040002 A9 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/095 (2006.01) A61P 9/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 33/04 (2006.01) A61P 11/00 (2006.01) AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, AOlN 1/00 (2006.01) A61P 41/00 (2006.01) CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, A61P 7/00 (2006.01) A61P 43/00 (2006.01) ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KR KR, KZ, LA, LC, LK, (21) International Application Number: LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, PCT/US2007/079948 MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, (22) International Filing Date: TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 28 September 2007 (28.09.2007) ZM, ZW (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (30) Priority Data: ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 60/827,337 28 September 2006 (28.09.2006) US European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (71) US): Applicant (for all designated States except FRED PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, HUTCHINSON CANCER RESEARCH CENTER GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). [US/US]; 1100 Fairway Avenue North, C2m-027, Ro. Box 19024, Seattle, WA 98109-1024 (US). Published: (72) Inventors; and — without international search report and to be republished (75) Inventors/Applicants (for US only): ROTH, Mark, B. upon receipt of that report [US/US] ; 1100 Fairway Avenue North, C2m-027, Ro. Box — with information concerning authorization of rectification 19024, Seattle, WA 98109-1024 (US). BUDDE, Mark of an obvious mistake under Rule 91.1 [US/US]; 1100 Fairway Avenue North, C2m-027, P.O. Box 19024, Seattle, WA 98109-1024 (US). (48) Date of publication of this corrected version: 16 April 2009 (74) Agent: SHISHIMA, Gina, N.; FULBRIGHT & JA- WORSKI L.L.R, 600 Congress Avenue, Suite 2400, (15) Information about Correction: Austin, TX 78701 (US). see Notice of 16 April 2009 (54) Title: METHODS, COMPOSITIONS AND ARTICLES OF MANUFACTURE FOR HIF MODULATING COMPOUNDS (57) Abstract: The present invention generally relates to the modulation of hypoxia- inducible factor (HIF) using the compounds and methods disclosed herein. These compounds and methods can be applied to the prevention, pretreatment, and/or treatment of conditions or states associated with HIF, such as hypoxia- and ischemia-related conditions and the induction of stasis. DESCRIPTION METHODS, COMPOSITIONS AND ARTICLES OF MANUFACTURE FOR HIF MODULATING COMPOUNDS BACKGROUND OF THE INVENTION This application claims priority to U.S. provisional patent application 60/827,337 filed on September 28, 2006, which is hereby incorporated by reference in its entirety. This invention was made with government support under grant number GM048435 from the National Institute of General Medical Sciences (NIGMS). The government has certain rights in the invention. I. Field of the Invention The present invention relates generally to the field of cell biology and physiology. More particularly, it concerns methods, compositions and apparatuses for enhancing survivability of and/or reducing damage to cells, tissues, organs, and organisms, particularly under adverse conditions, including but not limited to hypoxic or ischemic states, using one or more substances, including those that compete with oxygen. In certain embodiments, the present invention includes methods, compositions and apparatuses for treating, preventing, and diagnosing diseases and conditions by exposing a subject to a compound, such as an oxygen antagonist, protective metabolic agent, or other chemical compound discussed herein, or a precursor thereof, that can achieve its stated goal (collectively referred to as "Effective Compounds"). More broadly, the methods, compositions and apparatuses of the present invention relate to the modulation of the α-subunt of hypoxia inducible factor (HIF), an oxygen-responsive transcriptional activator. II. Description of Related Art As discussed herein, hypoxia and ischemia are two physiological states characterized by reductions in oxygen and blood flow, respectively. Typically, hypoxic and ischemic states are unfavorable, and treatments exist to combat these states and their related conditions, such as anemia, myocardial infarction, stroke and occlusive arterial disease. However, situations may exist wherein hypoxic and/or ischemic states may be preferable, such as during organ transplantation or prior to the inducement of trauma. Currently, treatment of ischemic and hypoxic disorders is focused on relief of symptoms and treatment of causative disorders. For example, treatments for myocardial infarction include nitroglycerin and analgesics to control pain and relieve the workload of the heart. Other medications, including digoxin, diuretics, amrinone, β-blockers, lipid-lowering agents and angiotensin-converting enzyme inhibitors, are used to stabilize the condition, but none of these therapies directly address the tissue damage produced by the ischemia and hypoxia. Due to deficiencies in current treatments, there remains a need for compounds that are effective in treating hypoxia- and ischemia-related conditions. For example, there is a need for compounds that are effective in treating erythropoietin-associated conditions, which can be categorized as hypoxia-related conditions, such as anemia, including anemia associated with diabetes, ulcers, kidney failure, cancer, infection, dialysis, surgery, and chemotherapy. Other conditions involving ischemia and hypoxia include, for example, occlusive arterial disease, angina pectoris, intestinal infarctions, pulmonary infarctions, cerebral ischemia, and myocardial infarction. There is also a need for compounds that are effective in the prevention of tissue damage caused by these conditions. One oxygen-regulated protein involved in hypoxia and ischemia is hypoxia inducible factor (HIF), a protein comprised of two subunits, the α-subunit of which is oxygen-regulated. As described in more detail herein, under normoxic conditions, HIFα is hydroxylated and degraded but under hypoxic conditions, HIFα is not degraded and forms a complex with HIFβ. HIFα/β then regulates the expression of certain genes, such as erythropoeitin (EPO). Since the accumulation of HIFα is associated with hypoxic and ischemic conditions, HIFα presents itself as a viable target for treatment of deleterious hypoxic and ischemic conditions as well as for the intentional inducement of such conditions that may be beneficial for a tissue, organ or organism. Indeed, compounds have been found that can modulate these conditions via HIF regulation. See, e.g., U.S. Pat. Appln. 2003/0176317; U.S. Pat. Appln. 2004/0254215, each of which is incorporated herein by reference in its entirety. Stasis is another physiological state that may be associated with reductions in oxygen and blood flow. As described herein, in "stasis" or "suspended animation," a cell, tissue or organ, or organism (collectively referred to as "biological material") is living, but cellular functions necessary for cell division, developmental progression, and/or metabolic state are slowed or even stopped. This state is desirable in a number of contexts. Stasis can be used as a method of preservation by itself, or it may be induced as part of a cryopreservation regimen. For example, biological materials may be preserved for research use, for transportation, for transplantation, for therapeutic treatment (such as ex vivo therapy), and to prevent the onset of trauma. In another example, tissue culture cells are often stored for periods of time in tanks that hold liquid nitrogen; however, these tanks frequently require that the liquid nitrogen in the unit be periodically replaced, otherwise it becomes depleted and the temperature is not maintained. Furthermore, damage to cells and tissue occurs as a result of the freeze/thaw process. Thus, improved techniques are needed. Stasis with respect to entire organisms has similar uses. For instance, transportation of organisms could be facilitated if they had entered stasis. This might reduce physical and physiological damage to the organism by reducing or eliminating stress or physical injury. Stasis may be beneficial by decreasing the need of the biological material for oxygen and, therefore, bloodflow. Moreover, the lack of ability to control cellular and physiologic metabolism in whole organisms subjected to traumas such as amputation and hypothermia is a key shortcoming in the medical field. On the other hand, the anecdotal evidence discussed above and herein strongly suggests that if properly understood and regulated, it is possible to induce stasis in cells, tissues and whole organisms. Thus, there is a great need for improved methods for controlling metabolic processes particularly under traumatic conditions. As with the HIFα-related conditions described above, compounds have been found that can modulate stasis. See, e.g., U.S. Appln. 11/408,734, incorporated herein by reference in its entirety. As discussed, the conditions of hypoxia, ischemia and stasis all involve reductions in physiological aspects such as oxygen, blood flow and metabolic rates. Thus far, no intercorrelation between each of these conditions and HIF has been suggested or detected. If such a connection could be found, the physiology of these conditions as related to HIF behavior would become clearer, and application and treatment options could be expanded. For example, compounds used in the treatment of one condition, such as a hypoxia-related condition, may prove useful for the inducement of stasis as well.