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(12) Patent Application Publication (10) Pub. No.: US 2001/0047032 A1 Castillo Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2001/0047032 A1 Castillo Et Al US 20010047032A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2001/0047032 A1 Castillo et al. (43) Pub. Date: Nov. 29, 2001 (54) POLYHYDROXYLATED AROMATIC Related U.S. Application Data COMPOUNDS FOR THE TREATMENT OF AMYLOIDOSIS AND ALPHA-SYNUCLEIN (63) Non-provisional of provisional application No. FBRIL DISEASES 60/173,958, filed on Dec. 30, 1999. (76) Inventors: Gerardo M. Castillo, Seattle, WA Publication Classification (US); Paula Y. Choi, Bothell, WA (US); Alan D. Snow, Lynnwood, WA (51) Int. Cl." ..................... A61K 3177042; A61K 31/70; (US) A61K 31/66 (52) U.S. Cl. ............................ 514/453; 514/456; 514/23; Correspondence Address: 514/643; 514/734; 514/712; HELLER EHRMAN WHITE & MCAULIFFE 514/27; 514/129 LLP 275 MIDDLEFIELD ROAD (57) ABSTRACT MENLO PARK, CA 94025-3506 (US) Polyhydroxylated aromatic compounds, and compositions containing them, are useful for the treatment of amyloidosis, (21) Appl. No.: 09/748,748 especially Alzheimer's disease, and for the treatment of diseases characterized by C-Synuclein fibril formation, espe (22) Filed: Dec. 26, 2000 cially Lewy body disease and Parkinson's disease. US 2001/0047032A1 Nov. 29, 2001 POLYHYDROXYLATED AROMATIC COMPOUNDS circulating precursor protein may result from overproduc FOR THE TREATMENT OF AMYLOIDOSIS AND tion of either intact or aberrant molecules (for example, in ALPHA-SYNUCLEIN FIBRIL DISEASES plasma cell dyscrasias), reduced degradation or excretion (serum amyloid A in Some Secondary amyloid syndromes BACKGROUND OF THE INVENTION and beta-microglobulin in long-term hemodialysis), or genetic abnormalities associated with variant proteins (for 0001) 1. Field of the Invention example, familial amyloidotic polyneuropathy). Proteolysis 0002 This invention relates to the use of certain poly of a larger protein precursor molecule occurs in many types hydroxylated aromatic compounds, and compositions con of amyloidosis, resulting in the production of lower molecu taining them, for the treatment of amyloidosis, especially lar weight fragments that polymerize and assume a beta Alzheimer's disease, and the treatment of diseases charac pleated sheet conformation as tissue deposits, usually in an terized by C-Synuclein fibril formation, especially Lewy extracellular location. The precise mechanisms involved and body disease and Parkinson's disease. the aberrant causes leading to changes in proteolytic pro cessing and/or translational modification are not known in 0003 2. Description of the Related Art most amyloids. 0004 Amyloid and Amyloidosis 0008 Systemic amyloids which include the amyloid 0005 Amyloid is a generic term referring to a group of asSociated with chronic inflammation, various forms of diverse but specific extracellular protein deposits which all malignancy and familial Mediterranean fever (i.e. AA amy have common morphological properties, Staining character loid or inflammation-associated amyloidosis) (Benson and istics, and X-ray diffraction spectra. Regardless of the nature Cohen, Arth. Rheum. 22:36-42, 1979; Kamei et al., Acta of the amyloid protein deposited all amyloids have the Path. Jpn. 32:123-133, 1982; McAdam et al., Lancet 2:572 following characteristics: 1) showing an amorphous appear 573, 1975; Metaxas, Kidney Int. 20:676-685, 1981), and the ance at the light microscopic level, appearing eosinophilic amyloid associated with multiple myeloma and other B-cell using hematoxylin and eosin stains; 2) staining with Congo dyscrasias (i.e. AL amyloid) (Harada et al., J. Histochem. red and demonstrating a red/green birefringence as viewed Cytochem. 19:1-15, 1971), as examples, are known to under polarized light (Puchtler et al., J. Histochem. involve amyloid deposition in a variety of different organs Cytochem. 10:355-364, 1962), 3) containing a predominant and tissues generally lying outside the central nervous beta-pleated sheet Secondary structure, and 4) ultrastructur System. Amyloid deposition in these diseases may occur, for ally consisting of non-branching fibrils of indefinite length example, in liver, heart, Spleen, gastrointestinal tract, kidney, and with a diameter of 7-10 nm. skin, and/or lungs (Johnson et al., N. Engl. J. Med. 321:513 518, 1989). For most of these amyloidoses, there is no 0006 Amyloidoses today are classified according to the apparent cure or effective treatment and the consequences of Specific amyloid protein deposited. The amyloids include, amyloid deposition can be detrimental to the patient. For but are not limited to, the amyloid associated with Alzhe example, amyloid deposition in the kidney may lead to renal imer's disease, Down's Syndrome and hereditary cerebral failure, whereas amyloid deposition in the heart may lead to hemorrhage with amyloidosis of the Dutch type (where the heart failure. For these patients, amyloid accumulation in Specific amyloid is referred to as beta-amyloid protein or Systemic organs leads to eventual death generally within 3-5 Af), the amyloid associated with chronic inflammation, years. Other amyloidoses may affect a single organ or tissue various forms of malignancy and familial Mediterranean such as observed with the AP amyloid deposits found in the fever (where the specific amyloid is referred to as AA brains of patients with Alzheimer's disease and Down's amyloid or inflammation-associated amyloid), the amyloid syndrome: the PrP amyloid deposits found in the brains of asSociated with multiple myeloma and other B-cell dyscra patients with Creutzfeldt-Jakob disease, Gerstmann-Straus sias (where the specific amyloid is referred to as AL amy sler Syndrome, and kuru; the islet amyloid (amylin) deposits loid), the amyloid associated with type II diabetes (where the found in the islets of Langerhans in the pancreas of 90% of Specific amyloid is referred to as amylin or islet amyloid), patients with type II diabetes (Johnson et al., N. Engl. J. Med. the amyloid associated with the prion diseases including 321:513-518, 1989; Lab. Invest. 66:522 535, 1992); the Creutzfeldt-Jakob disease, Gerstmann-Straussler Syndrome, beta-microglobulin amyloid deposits in the medial nerve kuru, and Scrapie (where the specific amnyloid is referred to leading to carpal tunnel Syndrome as observed in patients as PrP amyloid), the amyloid associated with long-term undergoing long-term hemodialysis (Geyjo et al, Biochem. hemodialysis and carpal tunnel Syndrome (where the spe Biophys. Res. Comm. 129:701-706, 1985; Kidney Int. cific amyloid is referred to as beta-microglobulin amyloid), 30:385-390, 1986); the-prealbumin/transthyretin amyloid the amyloid associated with Senile cardiac amyloid and observed in the hearts of patients with Senile cardiac amy familial amyloidotic polyneuropathy (where the specific loid; and the prealbumin/transthyretin amyloid observed in amyloid is referred to as prealbumin or transthyretin amy peripheral nerves of patients who have familial amyloidotic loid), and the amyloid associated with endocrine tumors polyneuropathy (Skinner and Cohen, Biochem. Biophys. Such as medullary carcinoma of the thyroid (where the Res. Comm. 99:1326-1332, 1981; Saraiva et al., J. Lab. Clin. Specific amyloid is referred to as variants of procalcitonin). Med. 102:590-603, 1983; J. Clin. Invest. 74: 104-119, 1984; 0007 Although amyloid deposits in clinical conditions Tawara et al., J. Lab. Clin. Med. 98:811-822, 1989). share common physical properties relating to the presence of a beta-pleated sheet conformation, it is now clear that many 0009 Alzheimer's Disease and the Aging Population different chemical types exist and additional ones are likely 0010 Alzheimer's disease is a leading cause of dementia to be described in the future. It is currently thought that there in the elderly, affecting 5-10% of the population over the age are Several common pathogenetic mechanisms that may be of 65 years (A Guide to Understanding Alzheimer's Disease operating in amyloidosis in general. In many cases, a and Related Disorders, Jorm, ed., New York University US 2001/0047032A1 Nov. 29, 2001 Press, New York, 1987). In Alzheimer's disease, the parts of patients with Alzheimer's disease. In addition, Alzheimer's the brain essential for cognitive processes Such as memory, disease is characterized by the presence of numerous neu attention, language, and reasoning degenerate, robbing Vic rofibrillary "tangles', consisting of paired helical filaments tims of much that makes us human, including independence. which abnormally accumulate in the neuronal cytoplasm In Some inherited forms of Alzheimer's disease, onset is in (Grundke-Iqbal et al., Proc. Natl. Acad. Sci. USA 83:4913 middle age, but more commonly, Symptoms appear from the 4917, 1986; Kosik et al., Proc. Natl. Acad. Sci. USA mid-60's onward. Alzheimer's disease today affects 4-5 83:4044-4048, 1986; Lee et al., Science 251:675-678, 1991). million Americans, with slightly more than half of these The pathological hallmark of Alzheimer's disease is there people receiving care at home, while the others are in many fore the presence of "plaques' and "tangles', with amyloid different health care institutions. The prevalence of Aizhe imer's disease and other dementias doubles every 5 years being deposited in the central core of the plaques. The other beyond the age of 65, and recent Studies indicate that nearly major type of lesion found in the Alzheimer's disease brain 50% of all people age 85 and older have symptoms of is the accumulation of amyloid in the walls of blood vessels, Alzheimer's disease (1999 Progress Report On Alzheimer's both within the brain parenchyma and in the walls of Disease, National Institute on Aging/National Institute of meningeal vessels which lie outside the brain. The amyloid Health). 13% (33 million people) of the total population of deposits localized to the walls of blood vessels are referred the United States are age 65 and older, and this percentage to as cerebrovascular amyloid or congophilic angiopathy will climb to 20% by the year 2025 (1999 Progress Report (Mandybur, J. Neuropath. Exp. Neurol. 45:79-90, 1986; On Alzheimer's Disease). Pardridge et al., J. Neurochem. 49:1394-1401, 1987).
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