| Use of epothilone d in treating tau-associated diseases including alzheimer's disease -> Monitor Keywords |
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Use of epothilone d in treating tau-associated diseases including alzheimer's diseaseUse of epothilone d in treating tau-associated diseases including alzheimer's disease description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20090270465, Use of epothilone d in treating tau-associated diseases including alzheimer's disease. Brief Patent Description - Full Patent Description - Patent Application Claims
This invention relates generally to the treatment of Tau-associated diseases using epothilone D, and more specifically, to the treatment of Alzheimer\'s Disease using epothilone D. Alzheimer\'s disease (AD) is the most common form of dementia, affecting an estimated 27 million people worldwide in 2006. Age is the greatest known risk factor for AD with an incidence of 25-50% in people aged 85 years or older. As the average age of the population increases, the number of patients with AD is expected to rise exponentially. AD is the fifth leading cause of death in people aged 65 and older, and most patients eventually need nursing home care. Consequently, AD has an enormous economic impact, e.g., estimated direct and indirect costs for 2005 in the US only were $148 billion. Besides the economic costs, AD has a devastating impact upon patients and their family members, causing severe emotional distress and turmoil. Patients are diagnosed with probable AD based on the presence of dementia with progressive worsening of memory and other cognitive functions and with the exclusion of other causes of dementia. A diagnosis of AD can only be confirmed post-mortem as the clinical diagnosis is based on brain neuropathology, specifically, the diagnosis requires an evaluation of brain tissue, including the existence and concentration of extracellular plaques in the brain, intracellular tangles, and brain neurodegeneration. Dementia is also a required part of the diagnosis, since plaques and tangles are observed in cognitively normal adults, although usually to a lesser extent. Two classes of medications, cholinesterase inhibitors and an N-methyl-D-aspartic acid (NMDA) antagonist, are currently approved for AD. Although these two classes of therapeutics show some clinical benefit, many patients do not respond, and these drugs only ameliorate the symptoms of AD (e.g., cognitive function) with little or no modification of disease progression. For these reasons, identification of disease-modifying therapeutics for this devastating disease is a major focus of the pharmaceutical industry. Microtubule stabilizers have been suggested as therapies to treat tauopathies including AD. See, e.g., Lee et al. (references list, infra). In U.S. Pat. No. 5,580,898, filed May 1994 and granted Dec. 3, 1996, Trojanowski et al. suggest use of paclitaxel (TAXOL®) to treat AD patients by stabilizing microtubules. Paclitaxel has proven highly effective as a microtubule-stabilizing agent in treating cancer patients; however, it presents brain-penetration and peripheral neuropathy issues when considered for AD (further described below), and has not emerged as a viable therapy to treat AD. In 1995, epothilone B was reported to exert microtubule-stabilizing effects similar to paclitaxel (Bollag et al. 1995). Epothilone A and epothilone B are naturally-occurring compounds that were isolated by Hofle et al. from fermentation products of the microorganism Sorangium cellulosum (e.g., WO 93/10121). Hofle et al. also discovered 37 natural epothilone variants and related compounds produced by S. cellulosum and modified strains, including epothilones C, D, E, F and other isomers and variants (e.g., U.S. Pat. No. 6,624,310). Unique characteristics of the natural epothilones generated much interest in their exploration as potential anti-cancer drugs. Now, nearly twenty years have passed since the first discovery of the natural epothilones A and B. Hundreds of epothilone analogs have been discovered and described in various patent applications, and abundant literature has published under the rubric, “epothilones” (See, e.g., Altmann et al., references list, infra, at 396-423). The assignee of the current application has developed ixabepilone, a semi-synthetic analog of epothilone B, for treatment of cancer. Ixabepilone has the structural formula:
The chemical name for ixabepilone is (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0] heptadecane-5,9-dione. See also U.S. Pat. No. 6,605,599, assigned to the current assignee, Bristol-Myers Squibb Company (BMS). Ixabepilone is a microtubule-stabilizing agent that has been approved by the FDA for treatment of metastatic breast cancer and is sold by BMS under the tradename IXEMPRA®. Ixabepilone can be prepared as described in U.S. Pat. No. 6,605,599 or 7,172,884, incorporated herein by reference. Other natural epothilones and analogs are in advanced clinical trials for treatment of cancer including epothilone B (a/k/a patupilone, or EPO-906), in Phase III trials by Novartis Pharma AG, for treatment of ovarian cancer, and sagopilone (or ZK-EPO), a benzothiazolyl-7-propenyl synthetic analog of epothilone B, in Phase II trials by Bayer Schering AG for treatment of various cancers including tumors of the ovary, breast, lung, prostate and melanoma. In 2007, a Phase II trial with sagopilone was initiated in the US for treatment of brain metastases from breast cancer. Additionally, an epothilone D analog, KOS-1584, had advanced to Phase II clinical trials by Kosan Biosciences, Inc. (now a wholly-owned subsidiary of BMS) for treatment of non-small-cell lung cancer and solid tumors, and epothilone D had advanced to Phase II clinical trials for treatment of cancer by Kosan in collaboration with Hoffmann-La Roche, Inc.; however, the clinical trials with epothilone D for treating cancer were discontinued in 2007. The structure for epothilone D can be represented by the following formula:
The epothilone D compound is claimed, as composition of matter, in U.S. patent application Ser. No. 09/313,524 to Hofle et al., and described in U.S. Pat. Nos. 6,242,469 and 6,284,781 to Danishefsky et al., which application and patents were the subject of Interference No. 105,298, before the USPTO Board of Patent Appeals and Interferences. The assignee of the current application also has clinically evaluated BMS-310705 (Compound II herein), for cancer therapy. BMS-310705 was pursued through Phase I clinical trials for treatment of ovarian cancer; it is an amino-epothilone F analog and has the chemical structure:
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