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US 20090226431A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0226431 A1 Habib (43) Pub. Date: Sep. 10, 2009 (54) TREATMENT OF CANCER AND OTHER Publication Classification DISEASES (51) Int. Cl. A 6LX 3/575 (2006.01) (76)76) InventorInventor: Nabilabil Habib,Habib. Beirut (LB(LB) C07J 9/00 (2006.01) Correspondence Address: A 6LX 39/395 (2006.01) 101 FEDERAL STREET A6IP 29/00 (2006.01) A6IP35/00 (2006.01) (21) Appl. No.: 12/085,892 A6IP37/00 (2006.01) 1-1. (52) U.S. Cl. ...................... 424/133.1:552/551; 514/182: (22) PCT Filed: Nov.30, 2006 514/171 (86). PCT No.: PCT/US2O06/045665 (57) ABSTRACT .."St. Mar. 6, 2009 The present invention relates to a novel compound (e.g., 24-ethyl-cholestane-3B.5C,6C.-triol), its production, its use, and to methods of treating neoplasms and other tumors as Related U.S. Application Data well as other diseases including hypercholesterolemia, (60) Provisional application No. 60/741,725, filed on Dec. autoimmune diseases, viral diseases (e.g., hepatitis B, hepa 2, 2005. titis C, or HIV), and diabetes. F2: . - 2 . : F2z "..., . Cz: ".. .. 2. , tie - . 2 2. , "Sphagoshgelin , , re Cls Phosphatidiglethanolamine * - 2 .- . t - r y ... CBs .. A . - . Patent Application Publication Sep. 10, 2009 Sheet 1 of 16 US 2009/0226431 A1 E. e'' . Phosphatidylcholine. " . Ez'.. C.2 . Phosphatidylserias. * . - A. z' C. w E. a...2 .". is 2 - - " - B 2. Sphingoshgelin . Cls Phosphatidglethanglamine Figure 1 Patent Application Publication Sep. 10, 2009 Sheet 2 of 16 US 2009/0226431 A1 Chile Phosphater Glycerol Phosphatidylcholine E. E. E. - : : .. Fatty acids . : Figure 2 Patent Application Publication Sep. 10, 2009 Sheet 3 of 16 US 2009/0226431 A1 O O Acetoacetyl-CoA CH3-C-CH2- C- S-CoA O CH3-C- SCOA.s, Acetyl-CoA --"s HMG-CoASynthase HSCOA ge?' OH CH3 N / C M. N. CH2 CH2- C-S-CoA N HMG-CoA CO O O Y 2NADPH "is HMG-CoA 2NADP+ HscoAg"? 41 reductase OH CH3 N / C / N. CH2 CH2 - CH2- OH N A. c=o ar 2. ps) OH CH3 Y^ O O / N. O CH2 CH2 - CH2-O-P - O - P - O Ye Se O O - O / Spyrophosphonevalonate O *rts g fe AP CO2 gaf . Ys, asses ADP + P. CH3 Z N ch? CH2 - CH2-O-P - O - P - O --> militar Witania D. O O isopentenylpyrophosphate Figure 3 Patent Application Publication Sep. 10, 2009 Sheet 4 of 16 US 2009/0226431 A1 slashasa assasasas ar SSSSSSSSSSSSSSSSSS . ; RSSSSSS: y 6SSSSSS EE2Si2 seasessessessel Sile:Cels essessiest Figure 4 Patent Application Publication Sep. 10, 2009 Sheet 5 of 16 US 2009/0226431 A1 ?j? as a 5 ab 18 Aeth Figure 5 Patent Application Publication Sep. 10, 2009 Sheet 6 of 16 US 2009/0226431 A1 est 5 as es 1aels Eacete Figure 6 Patent Application Publication Sep. 10, 2009 Sheet 7 of 16 US 2009/0226431 A1 Figure 7 Patent Application Publication Sep. 10, 2009 Sheet 8 of 16 US 2009/0226431 A1 Figure 8 Patent Application Publication Sep. 10, 2009 Sheet 9 of 16 US 2009/0226431 A1 Figure 9 Patent Application Publication Sep. 10, 2009 Sheet 10 of 16 US 2009/0226431 A1 Figure 10 Patent Application Publication Sep. 10, 2009 Sheet 11 of 16 US 2009/0226431 A1 Figure 11 Patent Application Publication Sep. 10, 2009 Sheet 12 of 16 US 2009/0226431 A1 Figure 12 Patent Application Publication Sep. 10, 2009 Sheet 13 of 16 US 2009/0226431 A1 g Figure 13 Patent Application Publication Sep. 10, 2009 Sheet 14 of 16 US 2009/0226431 A1 Figure 14 Patent Application Publication Sep. 10, 2009 Sheet 15 of 16 US 2009/0226431 A1 Patent Application Publication Sep. 10, 2009 Sheet 16 of 16 US 2009/0226431 A1 SR 85 s s wi. S. s his SR 3 Figure 16 US 2009/0226431 A1 Sep. 10, 2009 TREATMENT OF CANCER AND OTHER 0008. By contrast, endogenous synthesis requires substan DISEASES tial energy. The synthesis of sterols (cholestane, Vitamin D, and cholesterol) starts with squalene. Typically, cholesterol BACKGROUND OF THE INVENTION synthesis takes place in the cytoplasm of liver and intestinal cells through hydroxymethylglutaryl-CoA reductase (HMG 0001. The invention relates to the treatment of neoplasms CoA reductase). or other tumors as well as other diseases including hypercho 0009. During the last three decades, cancer treatment was lesterolemia, autoimmune diseases, a viral diseases (e.g., mainly focused on using cytotoxic products attacking both hepatitis B, hepatitis C, or HIV), and diabetes. tumor and normal cells. There is therefore a need to finding 0002 Throughout the world there are public and govern additional targeted therapies to treat cancer with fewer side ment concerns about the increasing prevalence cancer. Many effects as compared to conventional therapies. treatments exist but severe side effects and limited survival rate are pushing the research community into new approaches SUMMARY OF THE INVENTION for treatments. 0003 Cancer is a disease marked by the uncontrolled 0010. The invention features a substantially pure prepara growth of abnormal cells. Cancer cells have overcome the tion of a compound described by the formula (I) barriers imposed on normal cells, which have a finite lifespan, to grow indefinitely. As the growth of cancer cells continue, genetic alterations may persist until the cancerous cell has (I) manifested itself to pursue a more aggressive growth pheno type. If left untreated, metastasis, the spread of cancer cells to distant areas of the body by way of the lymph system or bloodstream, may ensue, destroying healthy tissue. 0004. According to a recent American Cancer Society study, approximately 1,268,000 new cancer cases were expected to be diagnosed in the United States in the year 2001 alone. Lung cancer is the most common cancer-related cause of death among men and women, accounting for over 28% of all cancer-related deaths. It is the second most commonly occurring cancer among men and women; it has been esti mated that there were more than 169,000 new cases of lung cancer in the U.S. in the year 2001, accounting for 13% of all new cancer diagnoses. While the rate of lung cancer cases is or a prodrug thereof. declining among men in the U.S., it continues to increase I0011. In formula (I), each of Rs. Rs, and R is, indepen among women. According to the American Cancer Society, dently, selected from OH, SH, and NH; the stereochemistry an estimated 157,400 Americans were expected to die due to at positions 3, 5, and 6 is either 3C, 53, 6(3 or 3 B, 5C, 6C.: each lung cancer in 2001. of R-7, Rs. Rs. R. R. R. and Rs is, independently, selected from H, OH, SH, and NH2. In one embodiment, each Cholesterol in Cell Membrane Activity of Rs. Rs, and R is OH. An exemplary compound of formula (I) has the structure: 0005 Cells require a flexible, permeable, fluid, active membrane. The cell membrane, which defines the cell and boundaries of cell organelles, is generally composed of lipid (II) cholesterol, phospholipids, sphingolipids, proteins, and car bohydrates. Cholesterol plays an important role in the flex ibility, the fluidity, and the permeability of the membrane and the maintenance of these properties across a range of tem peratures. Cholesterol Synthesis and Uptake 0006 Mammalian cells receive cholesterol through uptake of exogenic cholesterol and endogenous synthesis. 0007 Exogenic uptake is mediated by specific receptors on the membrane itself: cholesterol is adsorbed from body H fluids in contact with the cell. This uptake occurs through endocytosis of lipoprotein particles that contain cholesterol. 0012. The compound can be part of a composition also The isomerization process of the phosphatidylcholine (FIG. including a pharmaceutically acceptable carrier and be Suit 2) CC double bond cis/trans allow phospholipids with low able for oral, intravenous, topical, Subcutaneous, buccal, density lipoprotein to contain specific receptors for choles intramuscular, inhalation, intrathecal, intraarticular, intratu terol adsorption. Most animal cells acquire cholesterol by moral, or rectal administration. When formulated for oral receptor-mediated endocytosis of low density lipoproteins administration, the compound can be present, for example, in that contain cholesterol to form endosomes which migrate to an amount between 0.005 mg and 500 mg, more desirably lysosomes for degradation and release of cholesterol into the between 1 mg and 100 mg (e.g., 1, 5, 10, 20, 25, 30, 50, 75, or cell. 100 mg). US 2009/0226431 A1 Sep. 10, 2009 0013 The composition can further another agent, such as 0019 Autoimmune diseases that can be treated according an antiproliferative agent, an cholesterol-reducing agent, an to the invention include allergic bronchopulmonary antidiabetic agent, an antiinflammatory agent, or an antiviral aspergillosis; autoimmune hemolytic anemia; acanthosis nig agent. Exemplary agents are provided herein. ricans; allergic contact dermatitis. Addison's disease; atopic 0014. The invention also features a process for preparing dermatitis; alopecia greata; alopecia universalis; amyloido 24-ethyl cholestane 3,5,6 triol comprising the step of oxidiz sis; anaphylactoid purpura; anaphylactoid reaction, aplastic ing sitosterol. Using this process, for example, 24-ethyl anemia; angioedema, hereditary; angioedema, idiopathic; cholestane 3 B.5C,6O. triol can be prepared from B-sitosterol, ankylosing spondylitis; arteritis, cranial; arteritis, giant cell; and 24-ethyl cholestane 3C.5 B.6? triol can be prepared from arteritis, Takayasu’s; arteritis, temporal; asthma; a-telang C-sitosterol. There are many methods by which the sitosterol iectasia; autoimmune oophoritis; autoimmune orchitis; can be oxidized to prepare 24-ethyl cholestane 3,5,6 triol. In autoimmune polyendocrine failure; Behcet’s disease; Berg one such method, sitosterol is oxidized by reaction with er's disease; Buerger's disease; bullous pemphigus, candidi periodate in the presence of osmium tetroxide.
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