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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 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.

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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

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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 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 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, 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. asis, chronic mucocutaneous; Caplan's syndrome; post-myo 0015. If desirable, the compounds and compositions of the cardial infarction syndrome; post-pericardiotomy syndrome; invention can be components of kits. Typically, a kit also carditis; celiac sprue; Chagas's disease; Chediak-Higashi includes instructions for administering the compound or syndrome; Churg-Strauss disease; Cogan's syndrome; cold composition for treating a disease (e.g., a neoplasm or other agglutinin disease: CREST syndrome; Crohn's disease; cryo tumor). globulinemia; cryptogenic fibrosing alveolitis; dermatitis 0016. The compounds, compositions, and kits of the herpetifomis; dermatomyositis; diabetes mellitus; Diamond invention can be employed in methods of treating diseases Blackfan syndrome; DiGeorge syndrome; discoid lupus (e.g., any of the diseases provided herein). In particular, they erythematosus; eosinophilic fascitis; episcleritis: dry thema can be employed in methods of treating cancer or other neo elevatum dilutinum; erythema marginatum, erythema multi plasms. These compounds can also be used to treat hyperc forme; erythema nodosum: familial Mediterranean fever; holesterolemia, autoimmune diseases, diabetes, and viral Felty's syndrome; fibrosis pulmonary; glomerulonephritis, , among others. In a related aspect, the compounds anaphylactoid; glomerulonephritis, autoimmune; glomerulo and compositions of the invention can be used for the manu nephritis, post-Streptococcal; glomerulonephritis, post-trans facture of a medicament for the treatment of any of the fore plantation; glomerulopathy, membranous; Goodpasture's going diseases. Syndrome; graft-vs.-host disease, granulocytopenia, 0017. The invention also features a method for treating a immune-mediated; granuloma annulare; granulomatosis, neoplasm comprising administering to a patient a compound allergic; granulomatous myositis; Grave's disease; Hashimo or combination of compounds that inhibits HMG-CoA reduc to's thyroiditis; hemolytic disease of the newborn: hemochro tase and inhibits uptake of cholesterol into a cell. matosis, idiopathic; Henoch-Schoenlein purpura; hepatitis, 0018 Neoplasms that can be treated according to the chronic active and chronic progressive; histiocytosis X; invention include such as leukemias (e.g., acute leu hypereosinophilic syndrome; idiopathic thrombocytopenic kemia, acute lymphocytic leukemia, acute myelocytic leuke purpura; Job's syndrome; juvenile dermatomyositis; juvenile mia, acute myeloblastic leukemia, acute promyelocytic leu rheumatoid arthritis juvenile chronic arthritis); Kawasaki's kemia, acute myelomonocytic leukemia, acute monocytic disease; keratitis; keratoconjunctivitis sicca; Landry-Guil leukemia, acute erythroleukemia, chronic leukemia, chronic lain-Barre-Strohl syndrome; leprosy, lepromatous: Loeffler's myelocytic leukemia, chronic lymphocytic leukemia), lung syndrome; Lyell's syndrome; Lyme disease; lymphomatoid cancer (e.g., Squamous cell carcinoma, adenocarinoma, or granulomatosis; mastocytosis, systemic; mixed connective large cell carcinoma), colorectal cancer, ovarian cancer (e.g., tissue disease; mononeuritis multiplex: Muckle-Wells syn ovarian adenocarcinoma), , polycythemia drome; mucocutaneous lymph node syndrome; mucocutane Vera, lymphoma (Hodgkin’s disease, non-Hodgkin's dis ous lymph node syndrome; multicentric reticulohistiocyto ease), Waldenstrom's macroglobulinemia, heavy chain dis sis; ; myasthenia gravis; mycosis ease, and tumors such as sarcomas and carcinomas (e.g., fungoides; necrotizing vasculitis, systemic; nephrotic Syn fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, drome; overlap syndrome; panniculitis; paroxysmal cold osteogenic sarcoma, chordoma, angiosarcoma, endotheliosa hemoglobinuria; paroxysmal nocturnal hemoglobinuria; rcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, pemphigoid, pemphigus; pemphigus erythematosus; pem synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, phigus foliaceus; pemphigus Vulgaris; pigeon breeder's dis rhabdomyosarcoma, colon carcinoma, , ease; pneumonitis, hypersensitivity; polyarteritis nodosa; , ovarian cancer, prostate cancer, squamous cell polymyalgia rheumatica; polymyositis; polyneuritis, idio carcinoma, basal cell carcinoma, adenocarcinoma, Sweat pathic; Portuguese familial polyneuropathies; pre-eclampsia/ gland carcinoma, sebaceous gland carcinoma, papillary car eclampsia; primary biliary cirrhosis; progressive systemic cinoma, papillary adenocarcinomas, cystadenocarcinoma, Sclerosis (Scleroderma); psoriasis; psoriatic arthritis; pulmo medullary carcinoma, bronchogenic carcinoma, renal cell nary alveolar proteinosis; pulmonary fibrosis, Raynaud's carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, phenomenon/syndrome; Reidel's thyroiditis; Reiter's syn seminoma, embryonal carcinoma, Wilm's tumor, cervical drome, relapsing polychrondritis; rheumatic fever, rheuma cancer, uterine cancer, testicular cancer, lung carcinoma, toid arthritis; sarcoidosis; Scleritis; Sclerosing cholangitis; Small cell lung carcinoma, bladder carcinoma, epithelial car serum sickness; Sezary syndrome. Sjogren's syndrome; cinoma, glioma, astrocytoma, medulloblastoma, craniophar Stevens-Johnson syndrome: Still's disease; subacute scleros yngioma, ependymoma, pinealoma, hemangioblastoma, ing panencephalitis; sympathetic ophthalmia; systemic lupus acoustic neuroma, oligodendroglioma, Schwannoma, menin erythematosus; transplant rejection; ulcerative colitis; undif gioma, melanoma, neuroblastoma, and retinoblastoma. ferentiated connective tissue disease, urticaria, chronic, urti US 2009/0226431 A1 Sep. 10, 2009

caria, cold: uveitis; vitiligo; Weber-Christian disease; Wege Ed., Vol. 1, pp. 172-178,949-982 (1995). Examples of pro ner's granulomatosis; and Wiskott-Aldrich syndrome. drugs that can be used include, without limitation, esters, thioesters, carbamates, and amides, among others. DEFINITIONS (0021. By “substantially pure' is meant at least 10%, 20%, 0020. By “prodrug is meant any compound of the inven 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or tion further modified in that one or more hydroxyl, sulfhydryl, greater purity of a compound. Additionally, “substantially or amino group of the compound is covalently attached to pure' may refer to a compound of formula (I), where the another molecule via a bond which is cleaved under in vivo compound is present in a composition in a ratio of at least 1.2, conditions to form a free hydroxyl, free amino, or free sulf 1.5, 1.8, 2, 2.5, 3, 5, 10, or greater relative to related com hydryl group, respectively. Thus, “prodrug is intended to pounds with which it naturally occurs, without regard for include any covalently bonded carrier that releases an active other components of the composition. The naturally occur compound of the invention in vivo following administration ring compounds may include cholestane orcholestane deriva to a subject. Prodrugs of the invention can be used, for tives, for example, isomers (e.g., Stereoisomers) of a com example, with the objective(s) of improved chemical stabil pound of formula (I). ity, improved patient acceptance and compliance, improved 0022. By “antiproliferative agent' is meant any antiprolif , prolonged duration of action, improved organ erative agent, including those antiproliferative agents listed in selectivity, improved formulation (e.g., increased hydroSolu Table 1, any of which can be used in combination with a bility), and/or decreased side effects (e.g., ). The pro formula (I) compound to threat the medical conditions recited drug can be readily prepared from the inventive compounds herein. Antiproliferative agents also include organo-platine using methods known in the art, such as those described by derivatives, naphtoquinone and benzoquinone derivatives, Burger's Medicinal Chemistry and Drug Chemistry, Fifth chrysophanic acid and anthroquinone derivatives thereof.

TABLE 1. Alkylating agents hexamethylmelamine phosphate mechlorethamine dacarbazine streptozocin Platinum agents spiroplatin lobaplatin (Aeterna) tetraplatin (Johnson Matthey) ormaplatin BBR-3464 (Hoffmann-La Roche) iproplatin SM-11355 (Sumitomo) ZD-0473 (AnorMED) AP-5280 (Access) azacytidine trimetrexate deoxycoformycin 2-chlorodeoxyadenosine 6- hydroxyurea 6-thioguanine (SuperGen) (Bioenvision) 2-fluorodeoxycytidine irofulven (MGI Pharma) lethotrexate DMDC (Hoffmann-La Roche) tomudex ethynylcytidine (Taiho) meSylate (Daiichi) inhibitors quinamed (ChemGenex) gimatecan (Sigma-Tau) eniposide or diflomotecan (Beaufour-Ipsen) 7-ethyl-10-hydroxy- TAS-103 (Taiho) dexrazoxanet (TopoTarget) (Spectrum) (Novuspharma) J-107088 (Merck & Co) rebeccamycin analogue (Exelixis) BNP-1350 (BioNumerik) BBR-3576 (Novuspharma) CKD-602 (Chong Kun Dang) (SuperGen) KW-2170 (Kyowa Hakko) (CPT-11) hydroxycamptothecin (SN-38) opotecan Antitumor walrubicin azonafide herarubicin anthrapyrazole oxantrazole rubidazone MEN-10755 (Menarini) porfiromycin GPX-100 (Gem Pharmaceuticals) mitoxantrone (novantrone) Epirubicin amonafide mitoxantrone US 2009/0226431 A1 Sep. 10, 2009

TABLE 1-continued Antimitotic colchicine E7010 (Abbott) agents PG-TXL (Cell Therapeutics) IDN 5109 (Bayer) dolastatin 10 (NCI) A 105972 (Abbott) rhizoxin (Fujisawa) A 204197 (Abbott) mivobulin (Warner-Lambert) LU 223651 (BASF) cemadotin (BASF) D 24851 (ASTAMedica) RPR 109881A (Aventis) ER-86526 (Eisai) TXD 258 (Aventis) combretastatin A4 (BMS) B () isohomohalichondrin-B (PharmaMar) T900607 (Tularik) ZD 6126 (AstraZeneca) T 138067 (Tularik) AZ10992 (Asahi) cryptophycin 52 (Eli Lilly) IDN-5109 (Indena) (Fabre) AVLB (Prescient NeuroPharma) auristatin PE (Teikoku Hormone) azaepothilone B (BMS) BMS 247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4 prodrug (OXiGENE) BMS 188797 (BMS) dolastatin-10 (NIH) taxoprexin (Protarga) CA-4 (OXiGENE) SB 408075 (GlaxoSmithKline) Trichostatin A Aromatase aminoglutethimide YM-511 (Yamanouchi) inhibitors (BioMedicines) etrozole anastrazole Thymidylate (Eli Lilly) nolatrexed (Eximias) synthase inhibitors ZD-9331 (BTG) CoFactor TM (Biokeys) DNA antagonists (PharmaMar) edotreotide (Novartis) (Baxter International) (Baxter International) albumin + 32P (Isotope ) apaziquone (Spectrum hymectacin (NewBiotics) Pharmaceuticals) O6 benzyl guanine (Paligent) Farnesyltransferase arglabin (NuOncology Labs) (Johnson & Johnson) inhibitors onafarnib (Schering-Plough) perillyl alcohol (DOR BioPharma) BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) ZOSuquidar trihydrochloride (Eli Lilly) ariquidar (Xenova) biricodar dicitrate (Vertex) MS-209 (Schering AG) Histone acedinaline (Pfizer) pivaloyloxymethylbutyrate (Titan) acetyltransferase SAHA (Aton Pharma) depsipeptide (Fujisawa) inhibitors MS-275 (Schering AG) Metalloproteinase Neovastat (Aeterna Laboratories) CMT-3 (CollaGenex) inhibitors marimastat (British Biotech) BMS-275291 (Celltech) Ribonucleoside gallium maltolate (Titan) tezacitabine (Aventis) reductase inhibitors triapine (Vion) didox (Molecules for Health) TNFalpha virulizin (Lorus Therapeutics) revimid (Celgene) agonistSantagonists CDC-394 (Celgene) Endothelin A (Abbott) YM-598 (Yamanouchi) ZD-4054 (AstraZeneca) Retinoic acid fenretinide (Johnson & Johnson) () receptor LGD-1550 (Ligand) Immuno interferon dexosome therapy (Anosys) modulators oncophage (Antigenics) pentrix (Australian Cancer GMK (Progenics) Technology) adenocarcinoma vaccine (Biomira) ISF-154 (Tragen) CTP-37 (AVI BioPharma) cancer vaccine (Intercell) IRX-2 (Immuno-RX) norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) synchroVax vaccines (CTL Immuno) MGV (Progenics) melanoma vaccine (CTL Immuno) B-alethine (Dovetail) p21 RAS vaccine (GemVax) CLL therapy (Vasogen) Hormonal and dexamethasone antihormonal prednisone agents ethinyl methylprednisolone chlortrianisen prednisolone idenestrol aminoglutethimide hydroxyprogesterone caproate leuprolide medroxyprogesterone octreotide testOSterole propionate; P-04 (Novogen) 2-methoxyestradiol (EntreMed) (Eli Lilly) megestrol toremofine goserelin US 2009/0226431 A1 Sep. 10, 2009

TABLE 1-continued Leuporelin bicalutamide Photodynamic (Light Sciences) Pd-bacteriopheophorbide (Yeda) agents Theralux (Theratechnologies) lutetium texaphyrin (Pharmacyclics) motexafin (Pharmacyclics) hypericin Kinase Inbibitors imatinib (Novartis) EKB-569 (Wyeth) leflunomide (Sugen Pharmacia) kahalide F (PharmaMar) ZD1839 (AstraZeneca) CEP-701 (Cephalon) erlotinib (Oncogene Science) CEP-751 (Cephalon) canertinib (Pfizer) MLN518 (Millenium) squalamine (Genaera) PKC412 (Novartis) SU5416 (Pharmacia) Phenoxodiol (Novogen) SU6668 (Pharmacia) C225 (ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca) MDX-H210 (Medarex) (Novartis) 2C4 (Genentech) KI166 (Novartis) MDX-447 (Medarex) W2016 (GlaxoSmithKline) ABX-EGF (Abgenix) KB-509 (Wyeth) IMC-1C11 (ImClone) astuzumab (Genentech) Tyrphostins SI-774 (Tarceva TM) Gefitinib (Iressa) -1033 (Pfizer) PTK787 (Novartis) U11248 (Pharmacia) EMD 72000 (Merck) H3 (York Medical) Emodin Radicinol Radicinol Miscellaneous agents SR-27897 (CCKA inhibitor, Sanofi-Synthelabo) ceflatonin (apoptosis promotor, ChemGenex) tocladesine (cyclic AMP , Ribapharm) BCX-1777 (PNP inhibitor, BioCryst) (CDK inhibitor, Aventis) ranpirinase (ribonuclease stimulant, Alfacell) CV-247 (COX-2 inhibitor, Ivy Medical) galarubicin (RNA synthesis inhibitor, Dong-A) P54 (COX-2 inhibitor, Phytopharm) tirapazamine (reducing agent, SRI International) CapCell TM (CYP450 stimulant, Bavarian Nordic) N-acetylcysteine (reducing agent, Zambon) GCS-100 (gal3 antagonist, GlycoGenesys) R-flurbiprofen (NF-kappaB inhibitor, Encore) G17DT immunogen (gastrin inhibitor, Aphton) 3CPA (NF-kappaB inhibitor, Active Biotech) (oxygenator, Allos Therapeutics) Seocalcitol (vitamin D receptor agonist, Leo) PI-88 (heparanase inhibitor, Progen) 131-I-TM-601 (DNA antagonist, tesmilifene ( antagonist, YM TransMolecular) BioSciences) efornithine (ODC inhibitor, ILEX Oncology) histamine (histamine H2 receptor agonist, Maxim) minodronic acid (osteoclast inhibitor, (IMPDH inhibitor, Ribapharm) Yamanouchi) cilengitide (integrin antagonist, Merck KGaA) indisulam ( stimulant, Eisai) SR-31747 (IL-1 antagonist, Sanofi-Synthelabo) aplidine (PPT inhibitor, PharmaMar) CCI-779 (mTOR kinase inhibitor, Wyeth) gemtuzumab (CD33 antibody, Wyeth Ayerst) (PDEV inhibitor, Cell Pathways) PG2 (hematopoiesis enhancer, Pharmagenesis) CP-461 (PDE V inhibitor, Cell Pathways) mmunolTM ( oral rinse, Endo) AG-2037 (GART inhibitor, Pfizer) triacetyluridine (uridine prodrug, Wellstat) WX-UK1 (plasminogen activator inhibitor, Wilex) SN-4071 (sarcoma agent, Signature BioScience) PBI-1402 (PMN stimulant, ProMetic TransMID-107 TM (immunotoxin, KS Biomedix) LifeSciences) PCK-3145 (apoptosis promotor, Procyon) (, Millennium) doranidazole (apoptosis promotor, Pola) SRL-172 (T cell stimulant, SR Pharma) CHS-828 (cytotoxic agent, Leo) TLK-286 (glutathione S transferase inhibitor, trans-retinoic acid (differentiator, NIH) Telik) MX6 (apoptosis promotor, MAXIA) PT-100 (growth factoragonist, Point apomine (apoptosis promotor, ILEX Oncology) Therapeutics) urocidin (apoptosis promotor, Bioniche) idostaurin (PKC inhibitor, Novartis) Ro-31-7453 (apoptosis promotor, La Roche) S.ryostatin-1 (PKC stimulant, GPC Biotech) brostallicin (apoptosis promotor, Pharmacia) DA-II (apoptosis promotor, Everlife) B-lapachone DX-101 (apoptosis promotor, Salmedix) gelonin rituximab (CD20 antibody, Genentech cafestol kahweol Mitoxantrone caffeic acid Tyrphostin AG Absinthin Chrysophanic acid Cesium oxides

0023. By an “antihypercholesterolemia agent' is meant olemia agents include atorvastatin, cerivastatin, fluvastatin, any drug that the lowers cholesterol level of a patient. An lovastatin, pravastatin, rosuvastatin, simvastatin, coleseve antihypercholesterolemia agent may function by reducing the lam, cholestyramine, colestipol, nicotinic acid, gemfibrozil, synthesis of cholesterol in the patient. Antihypercholester probucol, and clofibrate US 2009/0226431 A1 Sep. 10, 2009

0024. By an “antiviral agent' is meant any compound that agonists, dopamine uptake inhibitors, G protein-coupled destroys a virus or that reduces a virus's ability to replicate or receptor modulators, glutamate antagonists, glucagon-like disseminate in vivo. Antiviral agents can be used therapeuti peptide-1 agonists, insulin sensitizers, lipase inhibitors, cally in combination with a formula (I) compound. Examples melanin-concentrating hormone receptor antagonists, nerve of antiviral agents include interferon-C., -f, -y, ribavirin (1BD growth factoragonists, neuropeptide Yagonists, neuropeptide ribofuranosyl-1H-1.2.4 thiazole 3-carboxamide) and its Y antagonists, SNRIs, protein tyrosine phosphatase inhibi tors, and serotonin 20 receptor agonists. derivatives, and the synthetic nucleotide analog lamivudine 0026. By “antiinflammatory agent' is meant any agent ((cis-1-2'-Hydroxymethyl-5'-(1,3-oxathiolanyl)cytosine) that reduces an inflammatory response. Antiinflammatory and its analogs. Other examples of antiviral agents include agents can be used in combination with formula (I) com idoxuridine, vidarabine, trifluridine, acyclovir, famciclovir, pounds for the treatment of autoimmune diseases and other penciclovir, Valacyclovir, ganciclovir, foscarnet, amantadine, inflammatory disorders. Exemplary agents include NSAIDs, rimantadine, cidofovir, Zidovudine, didanosine, Zalcitabine, COX-2 inhibitors (e.g., rofecoxib, , Valdecoxib, and stavudine, nevirapine, delavirdine, saquinavir, ritonavir, indi lumiracoxib), biologics (e.g., inflixamab, adelimumab, etan navir, nelfinavir, adefovir dipivoxil, Suramin, polycytidylic ercept, CDP-870, rituximab, and atlizumab), small molecule acid, 2',3'-dideoxycytidine, or ubenimex. One skilled in the immunomodulators, DMARDs (e.g., , lefluno art would know how to assay the antiviral activity of an agent mide, minocycline, auranofin, gold Sodium thiomalate, using an antiviral assay (e.g., the methods disclosed in e.g., aurothioglucose, and azathioprine), and corticosteroids. Monkarsh et al., Anal. Biochem. 247:434-440, 1997: Grace et 0027. By “corticosteroid' is meant any naturally occur al., J. Interferon Cytokine Res. 21:1103-1115, 2001; Bailonet ring or synthetic compound characterized by a hydrogenated al., Bioconi. Chem. 12:195-202, 2001). Desirably, an “anti cyclopentanoperhydrophenanthrene ring system and having viral agent results in a reduction in viral replication or dis immunosuppressive and/or antiinflammatory activity. Corti semination of for example, at least 10%, 20%, 30%, or 50%. costeroids can be used in combination with formula (I) com In more desirable embodiments, an antiviral agent reduces pounds for the treatment of autoimmune diseases and other viral replication or dissemination, for example, by at least inflammatory disorders. Naturally occurring corticosteroids 70%, 80%, 90%, 95%, or even 99%. are generally produced by the adrenal cortex Synthetic corti 0025 By “antidiabetic agent' is meant any compound that costeroids may be halogenated. may be used to decrease at least one symptom of diabetes. 0028 By “non-steroidal anti-inflammatory drug or Antidiabetic agents can be used in combination with formula “NSAID is meant any non-steroidal agent that decreases (I) compounds for the treatment of diabetes. Exemplary proinflammatory cytokine production or secretion, binds an antidiabetic agents include sulfonylureas, non-sulfonylurea immunophilin, or causes a down regulation of the proinflam Secretagogues, insulin, insulin analogs, glucagon-like pep matory reaction. NSAIDs can be used in combination with tides, exendin-4 polypeptides, beta 3 adrenoceptor agonists, formula (I) compounds for the treatment of autoimmune dis PPAR agonists, dipeptidyl peptidase IV inhibitors, bigu eases and other inflammatory disorders. NSAIDs include cal anides, alpha-glucosidase inhibitors, immunomodulators, cineurin inhibitors, such as cyclosporine, tacrolimus, asco statins and statin-containing combinations, angiotensin con mycin, pimecrolimus, as well as other agents (peptides, Verting inhibitors, adenosine A1 receptor agonists, peptide fragments, chemically modified peptides, or peptide adenosine A2 receptor agonists, antagonists, mimetics) that inhibit the phosphatase activity of calcineurin. alpha 1 adrenoceptor antagonists, alpha 2 adrenoceptor ago NSAIDs also include rapamycin (sirolimus) and everolimus, nists, alpha 2 adrenoceptor agonists, angiotensin receptor which bind to an FK506-binding protein, FKBP-12, and antagonists, antioxidants, ATPase inhibitors, atrial peptide block antigen-induced proliferation of white blood cells and agonists, beta adrenoceptor antagonists, channel cytokine secretion. agonists, calcium channel antagonists, diuretics, dopamine 0029. By “small molecule immunomodulator is meant a D1 receptor agonists, endopeptidase inhibitors, endothelin non-steroidal, non-NSIDI compound that decreases proin receptor antagonists, guanylate cyclase stimulants, phos flammatory cytokine production or secretion, causes a down phodiesterase V inhibitors, protein kinase inhibitors, Cdc2 regulation of the proinflammatory reaction, or otherwise kinase inhibitors, renin inhibitors, thromboxane synthase modulates the immune system in an immunophilin-indepen inhibitors, vasopeptidase inhibitors, vasopressin I antago dent manner. Small molecule immunomodulators can be used nists, vasopressin 2 antagonists, angiogenesis inhibitors, in combination with formula (I) compounds for the treatment advanced glycation end product inhibitors, bile acid binding of autoimmune diseases and other inflammatory disorders. agents, bile acid transport inhibitors, bone formation stimu Exemplary small molecule immunomodulators are p38 MAP lants, apolipoprotein A1 agonists, DNA topoisomerase kinase inhibitors such as VX 702 (Vertex Pharmaceuticals), inhibitors, cholesterol absorption inhibitors, cholesterol SCIO 469 (Scios), doramapimod (Boehringer Ingelheim), antagonists, cholesteryl ester transfer protein antagonists, RO 30201195 (Roche), and SCIO 323 (Scios), TACE inhibi cytokine synthesis inhibitors, DNA polymerase inhibitors, tors such as DPC 333 (Bristol Myers Squibb), ICE inhibitors dopamine D2 receptor agonists, endothelin receptor antago such as pranalcasan (Vertex Pharmaceuticals), and IMPDH nists, growth hormone antagonists, insulin sensitizers, lipase inhibitors such as mycophenolate (Roche) and merimepodib inhibitors, lipid peroxidation inhibitors, lipoprotein A (Vertex Pharmaceuticals). antagonists, microsomal transport protein inhibitors, 0030. The terms “cancer” or “neoplasm' or “neoplastic microsomal triglyceride transfer protein inhibitors, nitric cells' encompass neoplasms, cancers, or neoplastic cells oxide synthase inhibitors, oxidizing agents, phospholipase located at the original site of proliferation (“primary tumor or A2 inhibitors, radical formation agonists, platelet aggrega cancer) and their invasion of other tissues, or organs beyond tion antagonists, prostaglandin synthase stimulants, reverse the primary site (“metastasis). cholesterol transport activators, rho kinase inhibitors, selec 0031. By “inhibits the growth of a neoplasm' is meant tive receptor modulators, squalene epoxidase inhibi measurably slows, stops, or reverses the growth rate of the tors, squalene synthase inhibitors, thromboxane A2 antago neoplasm or neoplastic cells in vitro or in vivo. Desirably, a nists, amylin agonists, cannabinoid receptor antagonists, slowing of the growth rate is by at least 20%, 30%, 50%, or cholecystokinin A agonists, corticotropin-releasing factor even 70%, over a period of treatment of six month is achieved US 2009/0226431 A1 Sep. 10, 2009

as determined using a suitable assay for determination of cell 0046 FIGS. 13 and 14 are CT scans showing a non small growth rates (e.g., a cell growth assay described herein). cell lung cancer before treatment (FIG. 13) and the same cut Typically, a reversal of growth rate is accomplished by initi after treatment (FIG. 14) for 9 months using the compound of ating or accelerating necrotic or apoptotic mechanisms of cell formula II. death in the neoplastic cells, resulting in a shrinkage of the 0047 FIGS. 15 and 16 are CT scans showing a non small neoplasm. cell lung cancer metastatic to liver before treatment FIG. 15) 0032. By “an effective amount' is meant the amount of a and after treatment (FIG. 16) for 9 months using the com compound or a combination of compounds required to treat pound of formula II. or prevent a disease in a clinically relevant manner. An effec DETAILED DESCRIPTION tive amount of a compound varies depending upon the disease 0048. The invention features therapeutic uses of a com being treated, the manner of administration, and the age, body pounds of formula (I) (e.g., 24-ethyl-cholestane-3B,5C.6C.- weight, and general health of the patient Ultimately, the pre triol) scribers will decide the appropriate amount and dosage regi men according to good medical practice. 0033. The term “administration' or “administering refers to a method of giving a composition of the invention to a (I) patient, by a route such as inhalation, ocular administration, nasal instillation, parenteral ministration, dermal administra tion, transdermal administration, buccal administration, rec tal administration, Sublingual administration, perilingual administration, nasal administration, topical administration and oral administration. Parenteral administration includes intrathecal, intraarticular, intratumoral, intravenous, intrap eritoneal, Subcutaneous, and intramuscular administration. The optimal method of administration of a drug or drug combination to treat a particular disease can vary depending on various factors, e.g., the oral bioavailability of the drug(s), the anatomical location of the disease tissue, and the severity of disease. 0034. Other features and advantages of the invention will be apparent from the following Detailed Description, the which, either alone or in combination with other therapies, drawings, and the claims. may be used to treat neoplasms and other tumors. Diseases Such as hypercholesterolemia, viral infections, autoimmune BRIEF DESCRIPTION OF THE DRAWINGS disorders, and diabetes may also be treated using a compound of formula (I). Accordingly, the present invention provides 0035 FIG. 1 is the structure of phosphatidylethanolamine. compositions that include a compound of formula (I), meth 0036 FIG. 2 is the structure of phosphatidylcholine. ods for synthesizing a compound of formula (I), uses of and 0037 FIG.3 is a schematic diagram showing the synthesis methods of treatment using a compound of formula (I), and pathway of cholesterol. kits including compounds of formula (I). 0038 FIG. 4 is a schematic diagram showing the role of cholesterol and the sterol regulatory element binding protein Compositions (SREBP) in the regulation of cholesterol synthesis. 0049. The invention provides compositions that include a 0039 FIG.5 is a graph showing a decrease in LDH activity compound of formula (I) or a prodrug (e.g., a prodrug in the blood plasma in diseased mice treated with a compound described herein) of the compound. of formula (I). Preparation of 24-ethyl-cholestane-3?.5C,6C.-triol 0040 FIG. 6 is a graph showing a changes in body weight between diseased, untreated mice and mice treated with a 0050. A compound within formula (I), 24-ethyl-choles compound of formula (I). tane-3,3,5C.6O-triol (formula (II)), shown below, may be syn 0041 FIG. 7 is a photograph showing organs in healthy thesized using the following protocol. mice (right) and in mice with lymphoma (left) treated with a compound of the invention for sixteen days. (II) 0042 FIG. 8 is a photograph showing toxic lesions in the liver of an treated mouse with lymphoma. 0043 FIG. 9 is a photomicrograph (450x) of part of the liver taken from a mouse with experimental lymphoma, showing extensive lymphocytic proliferation and granuloma. 0044 FIG. 10 is a photomicrograph (900x) of part of the liver taken from a mouse with experimental lymphoma, showing extensive lymphocytic granuloma. 0045 FIGS. 11 and 12 are photomicrographs (450x and 900x, respectively) of part of the liver taken from a mouse with experimental lymphoma orally administered 24-ethyl cholestane-33.5C,6C.-triol daily at a dosage of 250 mg/kg. Lymphocytic proliferation is insignificant. US 2009/0226431 A1 Sep. 10, 2009

0051. The starting material is betasitosterol (mp<140°C.) achieved using permanganate or silver iodoacetate according which as isolated is 60% (w/w) and which contains campes to Woodward’s procedure. A variety of synthetic conditions terol (mps 156°C.) and other sterols. The betasitosterol is and oxidizing agents are known to be capable of cis-hydroxy diluted 15-fold in absolute (w/v) at 0°C. and allowed lation of an olefin and may be used in the synthesis of the to separate into a liquid and Solid phase. The liquid phase is compounds of the invention. See, for example, VanRheenen discarded; the remaining Solid phase is dissolved in the same et al., Organic Syntheses, Coll. 6:342 (1988); Vol. 58, p. 43 volume of ethanol at 75° C. (1978). 0052 Liquid and solid phases are again formed, and the 0059 Protection and Deprotection of Reactive Groups solid residue is removed by filtration at 75° C. and discarded. 0060. The synthesis of compounds of the invention may The liquid phase is cooled to room temperature until the include selective protection and deprotection of , appearance of a solid residue. amines, and/or sulfhydryls functional groups. For example, 0053. This solid residue is heated to generate a liquid commonly used protecting groups for amines include car phase (160° C.). The material is very slowly and slightly bamates. Such as tert-butyl, benzyl, 2.2.2-trichloroethyl, cooled until a solid mass forms. The liquid phase is separated 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m-nitro from the solid phase (which is discarded), cooled to room phenyl. Other commonly used protecting groups for amines temperature, and added to pyridine at a ratio to 1/15 (w/v): 0.5 include amides, such as formamides, acetamides, trifluoro grams of osmium tetroxide and 2 times w/v H2O, plus 0.1 acetamides, Sulfonamides, trifluoromethanesulfonyl amides, grams KIO are also added. The is stirred at room trimethylsilylethanesulfonamides, and tert-butylsulfonyl temperature for 12 hours and then heated under pyridine amides. Examples of commonly used protecting groups for reflux for 3 hours. The solution is then cooled to 0° C., alcohols include , such as methyl, methoxymethyl, extracted with , and washed successively with a 5% HCl methoxyethoxymethyl, methylthiomethyl, benzyloxym aqueous solution, water, an aqueous NaCO Solution, and ethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylm water. The organic phase is then dried over MgSO at low ethyl, O-nitrobenzyl, P-nitrobenzyl, P-methoxybenzyl, pressure. 9-phenylxanthyl, trityl (including methoxy-trityls), and silyl 0054 The obtained solid is then dissolved in ethanol and ethers. An acetal can be used to protect the 5-hydroxy and heated until completely dissolved. Water is very slowly added 6-hydroxy positions of an intermediate or compound of the until the appearance of a slight white precipitant, which is invention Examples of commonly used protecting groups for then filtered at the temperature of its formation. The solution Sulfhydryls include many of the same protecting groups used is cooled, dissolved inacetone, and re-crystallized in acetone for hydroxyls. In addition, sulfhydryls can be protected in a water media, filtered and dried under MgSO at low pressure. reduced form (e.g., as disulfides) or an oxidized form (e.g., as 0055 Synthesis of Related Compounds Sulfonic acids, Sulfonic esters, or Sulfonic amides). Protecting 0056 Compounds hydroxylated at positions other than 3, groups can be chosen Such that selective conditions (e.g., 5, and 6 can be prepared by enzymatic oxidation of sitosterol acidic conditions, basic conditions, catalysis by a nucleo or , for example, 24-ethyl-cholestane-3,5,6-triol, phile, catalysis by a lewis acid, or hydrogenation) are required as shown below in Scheme 1. to remove each, exclusive of other protecting groups in a

Scheme 1

sistosterol enzymatic hydroxylation and isolation hydroxylated sistosterol

5,6-cis 5,6-cis dihydroxylation dihydroxylation

24-ethyl hydroxylated 24-ethyl cholestane-3,5,6-triol enzymatic hydroxylation and isolation cholestane-3,5,6-triol

0057 Enzymatic hydroxylations can be achieved, for molecule. The conditions required for the addition of protect example, by enzymatic oxidation using the P450 enzyme ing groups to amine, alcohol, and Sulfhydryl functionalities CYP3A4 (Research Diagnostics, Inc., product number RDI and the conditions required for their removal are provided in CYP3A4). Either the commercially available enzyme can be detail in “T. W. Green and P. G. M. Wuts: Protective Groups used or the sitosterol or 24-ethyl-cholestane-3,5,6-triol can be in Organic Synthesis” (2" ed., 1991, John Wiley & Sons) and incubated in liver microsomes or fermented in a microbial “P. J. Kocienski: Protecting Groups'' (1994 Georg Thieme culture. See, for example, Ambrus et al., 60:621 Verlag); each of which is hereby incorporated by reference. (1995); Aringer L., J. Biol. Chem. 257:13720 (1982); Mahato 0061 Synthesis of Sulfhydryl and Amine Derivatives et al., Biochem.J. 196:629 (1981); Aringer et al., J. Lipid Res. 0062 An unprotected hydroxyl in a compound of the 17:263 (1976); and Aringeret al., J. Lipid Res. 14:563 (1973). invention can be activated using standard techniques (e.g., 0.058. The reaction of an olefin with osmium tetroxide, conversion to a tosylate, brosylate, mesylate, triflate or other described above, is the most reliable method for cis-dihy reactive leaving group see, for example, J. March, Advanced droxylation of a double bond, particularly for preparation of Organic Chemistry: Reactions, Mechanisms and Structure, cis-diols. Cis-dihydroxylation of olefins may also be John Wiley & Sons, Inc. pp. 352-354, 1992). The conversion US 2009/0226431 A1 Sep. 10, 2009

of the activated alcohol to a sulfhydryl group can be achieved kg/day). For example, a dose of 0.01, 0.05, 0.1, 0.2,0.25, 0.3, by either addition of sulfide (e.g., NASH, NaS), addition of 0.4,0.5,0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3, 4, 5, 8, 10, 25, disulfide (e.g., NaS) followed by reduction of the disulfide 50, 100,250, 500, 750, 1000, 1250, 1500, or 1750 mg/kg/day to a Sulfhydryl group, or transesterification of the activated may be provided to the patient. Typically, a patient Suffering alcohol with thioacetate followed by hydrolysis to the Sulf from a neoplasm is given 1 mg/kg/day initially. Once a 50% hydryl with sodium acetate. The conversion of the activated remission of the neoplasm is achieved, the dosage may be alcohol to an amino group can be achieved by either addition reduced to 0.5 mg/kg/day. Further six months following the of an amine or addition of azide followed by reduction to the 50% remission, the dose may be further decreased to 0.25 amino group. mg/kg/day. This treatment may be continued indefinitely, or may be discontinued if it appears the neoplasm has been Formulation of Pharmaceutical Compositions successfully treated. If a patient does not achieve a 50% 0063. The compositions including a compound of formula remission, or is at an advanced stage of disease, the initial (I) are formulated such that an effective amount of compound dose may be doubled to 2 mg/kg/day until 50% remission is reaches the target region (e.g., a neoplasm). The compound achieved. Dosages are typically given orally. In one embodi may be contained in any appropriate amount in any Suitable ment, capsules each contain 10 mg of the compound. To carrier Substance, and is generally present in an amount of achieve a 1 mg/kg/day dosing, a 60 kg individual may take 6 1-95% by weight of the total weight of the composition. The capsules each containing 10 mg of the compound each day, composition may be provided in a dosage form that is Suitable where one capsule is taken at time intervals spaced through for oral, parenteral (e.g., intrathecally, intraarticularly, intra out the day. tumorally, intravenously, intramuscularly), rectal, cutaneous, 0068. The dosage of each compound or agent of the nasal, vaginal, inhalant, skin (patch), or ocular administration claimed compositions may additionally depend on other fac rOute. tors, including: the administration method, the disease (e.g., a 0064. Thus, the composition may be in the form of, e.g., neoplasm or other tumor, hypercholesterolemia, a viral infec tablets, capsules, pills, powders, granulates, Suspensions, tion, an autoimmune disease) to be treated, the severity of the emulsions, Solutions, gels including hydrogels, pastes, oint disease, whether the disease is to be treated or prevented, site ments, creams, plasters, drenches, osmotic delivery devices, of the diseased tissue (e.g., a tumor), and the race, gender, age, Suppositories, enemas, injectables, implants, sprays, or aero weight, and health of the patient to be treated. Ultimately Sols. The pharmaceutical compositions may be formulated dosing will be determined by a physician or other prescriber according to conventional pharmaceutical practice (see, e.g., of treatment based on these factors. Dosages may be altered Remington: The Science and Practice of Pharmacy, 20th (e.g., lowered) where a compound of the invention is admin edition, 2000, ed. A R Gennaro, Lippincott Williams & istered in combination with a second therapeutic. For Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical example, in the case of treating a patient with a neoplasm or Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, other tumor, a lower dose of a compound of the invention may Marcel Dekker, New York). be provided when given in conjunction with a chemothera 0065 For compositions that include combinations of com peutic agent (e.g., an antiproliferative described herein). pounds, each compound of the combination may be formu lated in any variety of ways that are known in the art. For Therapy example, the first and second agents may be formulated together or separately. Desirably, the first and second agents 0069 Compounds of formula (I) and compositions are formulated together for the simultaneous or near simul including compounds of formula (I) are administered to a taneous administration of the agents. Such co-formulated patient for the treatment of a neoplasm such as cancer. Other compositions can include the compound of formula (I) and, diseases that may be treated by the methods of the invention for example, an antiproliferative agent formulated together in include hypercholesterolemia, a viral Such as hepa the same pill, capsule, liquid, etc. titis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, or 0066. The individually or separately formulated agents hepatitis E) or HIV, an autoimmune disorder (e.g., psoriasis or can be packaged together as in a kit. Non limiting examples other diseases described herein), and diabetes, in particular, include kits that contain, e.g., two pills, a pill and a powder, a type II diabetes. Suppository and a liquid in a vial, two topical creams, among 0070 Any composition or formulation including a com others. The kit can include optional components that aid in the pound of formula (I) and any mode of delivery may be used to administration of the unit dose to patients, such as vials for provide treat the patient including oral, intrathecal, intraar reconstituting powder forms, Syringes for injection, custom ticular, intratumoral, parenteral (e.g., intravenously, intra ized IV delivery systems, inhalers, among others. Addition muscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin ally, the unit dose kit can contain instructions for preparation (patch), or ocular administration. Therapeutic compositions and administration of the compositions. The kit may be may be administered to patients who exhibit at least one manufactured as a single use unit dose for one patient, mul symptom of a disease, to prevent the development of disease, tiple uses for a particular patient (at a constant dose or in or to maintain a reduction of disease achieved by administra which the individual compounds may vary in potency as tion of a compound of the invention or another therapy. therapy progresses); or the kit may contain multiple doses 0071 Compounds of formula (I) or compositions com suitable for administration to multiple patients (“bulk pack prising a compound of formula (I) and another therapeutic or aging). The kit components may be assembled in cartons, therapeutics may be administered together. For example, blister packs, bottles, tubes, and the like. treatment of a neoplasm, an autoimmune disorder, or a viral infection may include administration of a compound of for Dosages mula (I) together with an antiproliferative agent, an antiin 0067 Dosages of a compound of the invention may range flammatory agent, or an antiviral agent respectively. The from 0.005 mg/kg to 2000 mg/kg body weight per day (mg/ combination administered may include one or more com US 2009/0226431 A1 Sep. 10, 2009

pounds in a Subtherapeutically effective amount as deter for treating many retroviral infections. Formula (I) com mined separately for each compound. pounds may be combined with other antivirals. 0072. In one example, a compound of formula (I) with an 0083. Autoimmune Disorders additional therapeutic agent are administered to a patient. I0084. A formula (I) compound may be administered to a After symptoms of the disease have decreased, administra patient Suffering from an autoimmune disorder Such as pso tion of the additional agent is discontinued. The administra riasis, rheumatoid arthritis, or any other Such disease listed tion of a compound of formula (I) is then used to maintain the herein. Administration of a compound of the invention may improved state of the patient following Successful treatment be further include administration of an antiinflammatory with the combination of therapies. Such an approach may be agent, Such as those described herein. particularly advantageous in cases where the additional agent 0085 Diabetes has undesired side effects. I0086 A formula (I) compound may be administered to a 0073 Neoplasms and Other Tumors patient Suffering from diabetes. This administration may fur 0074. A formula (I) compound may be administered to ther include administration of an antidiabetic compound, treat a patient who has, or has an increased propensity to such as those described herein. develop, a cancer or other neoplasm. Administration of the compound may be performed alone or in combination with Mode of Action—Antineoplastic Activity existing therapies for neoplasms, such as , I0087 Ibelieve that formula (I) compounds both inhibit the radiation therapy, Surgery, or a personalized vaccine. activity of HMG-CoA reducatase, and competitively bind 0075 Chemotherapy employs chemical agents to treat receptors involved in exogenous cholesterol adsorption. Inhi neoplasms. Exemplary chemotherapeutic (e.g., antiprolifera bition of HMG-CoA reductase occurs in both normal cells tive) agents are shown in Table 1. As with radiation therapy, and neoplastic cells; however, neoplastic cells are addition chemotherapy typically targets rapidly dividing cells, which ally rendered unable to adsorb exogenous cholesterol follow include neoplastic cells. ing administration of a formula (I) compound. This selectiv 0076 Radiation therapy uses isotopes (e.g., cesium ity for neoplastic cells occurs for two reasons. First, tumors (''Cs) cobalt ('Co) (''I), phosphorus (P) gold are poorly vascularized, which leads to a reduced supply of (Au) iridium ('Ir) yttrium (Y, or palladium ('Pd)) to available exogenous cholesterol. Second, the reduced vascu treat cancer. The radioactivity selectively kills rapidly divid larization additionally leads to hypoxia, thereby increasing ing cells that include neoplastic cells. Methods of adminis the concentration of anaerobic metabolic products, including tration include brachytherapy Such as seed implants, where a , pyruvic acid and carbon dioxide. Further, poor radioactive Substance in implanted in the body at or near the vascularization decreases the rate of carbon dioxide removal location of the neoplasm, radioactivity from external sources from the tumor tissue. Increased levels of carbon dioxide, in Such as external beam radiation therapy. turn, leads to increased levels of carbonic acid, the formation 0077. A common approach used to treat cancer is surgery. of which is catalyzed by carbonic anhydrase. These factors Once a tumor has been identified, a Surgeon can physically reduce the pH of the environment surrounding the cells from remove the tumor or a portion thereof from the patient. a pH of 7.3–7.4 found in normal cells to pH 6.4-6.8. 0078 Personalized vaccines employ antibodies directed I0088. The lower pH environment in neoplastic cells toward a tumor found in the individual cancer patient. Such causes the administered formula (I) compound, e.g., vaccines may be prepared as described in Hockertz, Toxicol 24-ethyl-cholestane-3?.5C,6C.-triol, to migrate towards inter ogy. 214:151-161, 2005 and Morse et al., Nat Clin Pract cellular interstitial acidic fluid, and also increases the affinity Oncol. 2005 2:108-113, 2005 and references cited therein. To of 24-ethyl-cholestane-3,3,5C.6O-triol for the cholesterol prepare Such a vaccine, a sample containing either all or part receptors. This increased affinity, in combination with the of the tumor is removed from the patient using Surgical tech reduced cholesterol concentration present in the fluid sur niques, and cells or proteins are isolated from the tumor. rounding tumor cells, leads to specific, irreversible binding of Isolated proteins are preferably expressed preferentially in the compound to the receptor. In the case of 24-ethyl-choles tumor cells as compared to normal cells. These cells or pro tane-3,3,5C.6O-triol, binding is mediated by the three highly teins, in conjunction with an adjuvant that increases immune hydrophilic hydroxyl groups interacting with carbonyl reactivity, are injected into the patient. This induces an groups of the receptor. The positions 3 B, 5C, 6O. hydroxides immune response to the injected cells or proteins, a response further provoke distortion of the membrane layers, and the which is targeted to the tumor composed of these cells or ethyl group at position 24 plays the role of a “check valve.” targeted to tumor cells that contain these proteins. fixing the hydrophobic tail between the two lipidic layers. 0079 Hypercholesterolemia I0089. In addition to binding the receptors directly, 0080 A formula (I) compound may also be administered 24-ethyl-cholestane-3?.5C,6C.-triol alters the three-dimen to a patient Suffering from hypercholesterolemia. The com sional structure of remaining unbound cholesterol receptors pound can block synthesis of cholesterol through HMG-CoA through distortion of the lipid bilayer. This alteration is suf reductase inhibition, thereby reducing cholesterol levels, thus ficient to prevent adsorption of cholesterol molecules. The decreasing the risk of diseases including arteriosclerosis, distortion of the lipid bilayer has other effects as well. The heart disease, and heart attacks. Formula (I) compounds may permeability and the fluidity of the bilayer membrane is also be combined with other antihypercholesterolemia agents. reduced, thus decreasing passive, mediated, and active diffu 0081 Viral Infections sion across the membrane. This alteration can further 0082 Administration of a formula (I) compound has been decrease nutrition level of tumor cells. shown to be effective in treating a patient having a viral (0090 Feedback Down-Regulation of Cholesterol Synthe infection such as HIV, hepatitis B, and hepatitis C. As the sis in Tumor Cells appears to be inhibition of reverse tran 0091 Sterol feedback control, mediated by sterol regula Scription, a formula (I) compound the invention may be useful tory element binding proteins (SREBPs) exerts the primary US 2009/0226431 A1 Sep. 10, 2009 regulation on HMG-CoA reductase activity at the transcrip reference, the results in mice having experimentally induced tional level. Secondary regulation and non sterol isoprenoid large B-cell lymphoma and healthy mice are shown in Table mediated fine tuning of reductase activity occurs at the levels 2 of reductase translation and degradation. Reductase activity in tumors is elevated and resistant to sterol feedback regula TABLE 2 tion to aberrant SREBPs activity. Tumor reductase remains sensitive to 24-ethyl-cholestane-3B.5C,6C.-triol post-tran Student's Scriptional down-regulation. Group of animals coefficient Treating a Neoplasm by Inhibition of HMG-coA Reductase Parameter Lymphoma Healthy (P) and Specific Inhibition of Cholesterol Uptake into Neoplastic Erythrocytes|CO 12/1 10.02 127 10.65 - 0.99 0.22 Cells. Leukocytes 10°/L 12.9 - 2.06 9.34 - 0.66 0.0003 0092. The invention also provides a method of treating a Hematocrit, LL O34 O.O16 O34 - 0.011 O.67 neoplasm by administering to a patient a compound or com Color 1210.18 1.4 - 0.11 O.OO38 Hemoglobin g/L 149.4 - 7.94 166.6 7.45 O.OOO1 bination of compounds that inhibits HMG-CoA reductase Lymphocytes, 10°/L 9.03 - 1.45 6.54 - 0.46 OOOO32 and prevents uptake of cholesterol into neoplastic cells. Com Total protein g/L 52.91.96 56.2 + 2.36 OOO19 pounds that inhibit HMG-CoA reductase are known in the art LDH, UL 1228.9 - 139.8 444.1 - 48.9 OOOOOOOO23 and include atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. An exemplary compound that 0.095 As is seen from Table 2, statistically important dif inhibits cholesterol uptake is 7-ketocholesterol. ferences (P<0.05) between animals with lymphoma and 0093. The following examples are intended to illustrate, healthy animals were marked by the amount of leukocytes, rather than limit, the invention. hemoglobin, by color indication, the absolute number of lym EXAMPLES phocytes in blood, as well as the content of total protein in the blood serum and the LDH activity in blood plasma. These Example 1 changes characterize the presence of disorders in the lym phoid component of blood formation, indicate the presence of Assessment of the Therapeutic Efficacy of 24-ethyl intensive cytolysis in the process of carcinogenesis (due to cholestane-3?.5C.6C.-triol in Mice Having Experi increased LDH), and show the presence of processes Sup mentally Induced Large B-Cell Lymphoma pressing biosynthesis of protein. 0094. Investigations were carried out on immunocompro I0096. The dynamics of therapeutic measures with the use mised laboratory mice with experimentally-induced large of 24-ethyl-cholestane-3?.5C.6O-triol showed significant B-cell lymphoma using hematological, immunological, bio changes in chosen parameters (Table 3). The total content of chemical, anatomical, and cytological methods. Two groups protein in the blood serum and the hemoglobin concentration of 15 mice were employed. In the first group, 24-ethyl-choles are increased. At the same time, a decrease in LDH activity in tane-3B.5C.6O-triol was administered orally daily at a dosage the blood plasma and in the number of lymphocytes was of 5 mg/kg. The second group served as the control. The observed (FIG. 5). LDH activity in blood plasma in diseased following parameters of therapeutic efficacy were compared: mice treated with 24-ethyl-cholestane-3?.5C.6O-triol dynamics of LDH activity in the blood plasma, content of decreased 42.3% by the sixteenth day of treatment and, in total protein, and general clinical blood test results. As a some animals, LDH reached the level of healthy animals.

TABLE 3

BLOOD TEST RESULTS Animal group Animal JVp erythrocytes, 1012/1 nieukocytes, 109/I rhematocryte, III thrombocytes|O/I

Healthy 1 O.68 8.6 O.336 329 2 2.90 10.3 O.345 368 3 1.26 8.9 O.349 376 4 9.68 9.2 0.355 365 5 9.85 1O.S O.329 348 6 O.S9 9.6 O.336 398 7 1.25 9.7 O.348 406 8 9.53 8.6 O.329 337 9 0.27 8.8 O.333 326 10 1.30 8.9 O.352 415 11 9.89 9.6 O.329 361 M O.65 9.34 O.34 366 l O.99 O.66 O.O10 3O.S P 0.5079 O4516 O.2O3S 0.3655 Lymphoma 1 O.32 14.8 O.339 289 2 9.58 12.6 O.356 386 3 8.96 9.3 0.327 361 4 1.28 11.9 O.338 326 5 O.S3 12.8 O.328 298 6 8.53 16.5 O.346 295 7 2.02 12.9 O.345 3O2 8 1.25 10.7 O.338 329 9 9.52 12.9 0.337 338

US 2009/0226431 A1 Sep. 10, 2009 14

TABLE 3-continued

BLOOD TEST RESULTS Lymphoma 1 2 3 5 76 5th day of 2 1 2 7 78 observation 3 3 2 22 70 M 2.00 2.33 8.OO 74.67 l 1.00 O.S8 3.61 4.16 P O.S808337 0.5599.376 O.8.192365 O.6957082 Lymphoma 10th 1 2 1 8 75 day of 2 2 3 5 76 observation 3 1 3 8 75 M 1.67 2.33 7.OO 75.33 l O.S8 1.15 1.73 O.S8 P 0.1571958 0.7377.703 0.3519747 O.1996.915 15th day of 1 3 3 3 77 2 2 2 5 75 3 1 2 8 74 4 1 1 8 76 M 1.75 2.OO 6.OO 75.50 l O.96 O.82 2.45 1.79 P O.30 0.27 O.18 O.19 Segment rod Animal group Animal JVp neutrophiles% Lymphocytes % monocytes % neutrophiles%

Healthy 1 23 70 2 25 2 27 66 3 30 3 24 69 3 25 4 27 65 3 30 5 17 71 5 21 Q 27 65 3 30 7 25 68 4. 26 8 23 69 3 25 9 26 67 3 29 10 25 66 3 28 11 26 65 3 30 M 24.SS 67.36 3.18 27.18 l 2.91 2.16 0.75 2.99 P Lymphoma 1 6 76 3 19 2 21 72 2 24 3 2O 69 4 24 4 2 79 3 14 5 8 75 3 19 6 6 76 2 19 7 21 73 2 23 8 27 66 3 30 9 6 78 3 18 10 9 71 4 22 M 8.60 73.50 2.90 21.20 l 4.06 4.09 O.74 4.39 P O.OO O.OO O40 O.OO Lymphoma 1 5 76 4 8 5th day of 2 7 78 2 9 observation 3 9 70 6 21 M 7.OO 74.67 4.OO 9.33 l 2.OO 4.16 2.00 1.53 P O.383.1484 O.6957082 O4424511 O.2824.126 Lymphoma 10th 1 6 23 8 7 day of 2 5 71 9 8 observation 3 4 75 7 7 M S.OO 73.00 8.00 7.33 l 1.OO 2.00 1.00 O.S8 P O.O26685 O.7808126 O.OOS6274 O.O221896 15th day of 1 3 77 4 6 2 5 75 6 7 3 8 68 11 2O 4 7 72 9 8 M 5.75 73.00 7.50 7.75 l 2.22 3.92 3.11 1.71 P O.12 O.84 O.O6 O.O6 US 2009/0226431 A1 Sep. 10, 2009 15

TABLE 3-continued

BLOOD TEST RESULTS Young Nuclear rod Animal group Animal No Eosinophiles% metamyelocytes % neutrophiles% neutrophiles, % Lymphoma + G 2 2 18 75 145th day of observation 2 3 19 71 1 2 26 69 1.67 2.33 21.00 71.67 O.S8 O.S8 4.36 3.06 0.1571958 0.5599.376 O4S56646 O44463O1 Lymphoma + G 1 3 72 1410th day of observation 2 3 25 66 2 2 26 68 1.67 2.67 23.67 68.67 O.577 0.577 3.214 3.055 0.1571958 O.882O888 O.O8SS304 O.O84890S Lymphoma + G 2 2 24 68 14th day of 2 2 27 66 observation 3 3 19 73 4 3 25 65 2.75 2.5 23.75 68.0 0.957 0.577 3.403 3.56 0.561758 O.805340 O.O48093 O.O44O19 Segment rod Animal group Animal No neutrophiles% Lymphocytes, 96 monocytes % neutrophiles%

Lymphoma + G 3 75 8 15 145th day of observation 6 71 8 19 23 69 5 25 7.33 71.67 7.00 19.67 5.13 3.06 1.73 5.03 0.72279 O44463O1 O.O4807SS 0.6667086 Lymphoma + G 5 72 9 18 1410th day of observation 66 9 23 9 68 9 21 8.01 68.7 9.0 20.7 2.645 3.05 O 2.52 0.775.2258 O.O84890S 8.462E-10 0.7993,774 Lymphoma + G 2O 68 8 22 14th day of 9 66 11 21 observation 6 73 5 19 23 65 5 26 9.5 68.0 7.25 22.O 2.89 3.56 2.872 2.94 0.653.787 O.O44O19 O.OS4445 0.702377

neutrophiles/ Total Animal group Animal JVp lymphocytes protein; gl LDH, UL Body weight, g lymphocytes, 10°/n

SflopoBbie 1 60.3 370 6.02 2 56.8 519 7.21 3 60.3 487 6.23 4 54.2 467 6.44 5 53.9 469 7.35 6 56.5 423 6.72 7 56.3 487 6.79 8 55.2 387 6.02 9 54.8 472 6.16 10 56.7 406 6.23 11 53.2 398 6.72 56.2O 444 6.54 l 2.36 48 O46 P gol 1 O.25 52.8 984 18.06 10.36 Hanano onbixa 2 O.33 51.5 1298 18.15 8.82 3 O3S 54.8 1147 18.27 6.51 4 O.18 S2.6 1289 1929 8.33 5 O.25 55.1 1157 18.57 8.96 6 O.25 52.3 1079 1986 11.55 7 O.32 49.7 1457 1851 9.03 8 O45 54.8 1287 18.23 7.49 US 2009/0226431 A1 Sep. 10, 2009 16

TABLE 3-continued

BLOOD TEST RESULTS

9 O.23 53.2 229 8.27 9.03 10 O.31 53.1 362 8.51 1022 M O.29 52.99 228.90 8.57 9.03 l O.08 1.66 139.77 0.57 1.45 P O.OO O.OO1908O O.OOOOOOO2S #if: O.OOO32 sacolas ABS 1 O.24 48.9 364 8.06 10.64 is?iusFat 2 O.24 53.4 147 8.04 8.26 3 O.30 55.6 O78 8.12 9.52 M O.26 S2.63 196.33 8.07 9.473.333 l O.O3 3.42 149.25 O.04 1.190686 P O.3396658 O.8754870 0.7578670 O.O220475 O433866 not 1 O.23 48.7 285 7.89 7.14 HaSalf 2 O.25 S1.6 197 8.15 9.73 3 O.23 53.5 307 8.24 11.34 M O.24 51.27 263.OO 8.09 9.40 l O.O1 2.42 58.21 O.18 2.12 P O.OS956.33 O.3430529 O.SS44.08O O.0431143 O.796312 6a 1 O.21 53.8 256 8.O2 8.96 2 O.23 46.5 2O3 7.34 1162 3 O.29 S1.6 115 8.16 9.73 4 O.25 SO.4 382 8.23 10.43 M O.24 50.58 239 7.94 10.19 l O.04 3.06 87.48 O41 1.13 P O.15 O.21 O.48 O.OS O.15 Total Body, Lymphocytes, Animal group Anumal No neutrophiles lymphocytes proteing LDH, UL Weight, g 10%

boat 1 O.2O 51.5 1056 8.27 1O.O1 GSB 2 0.27 S2.6 974 7.86 9.1 statists 3 O.36 56.8 856 8.OO 8.33 M O.28 S3.63 962.OO 8.04 9.15 l O.O8 2.80 100.54 O.21 O.84 P 0.7875676 O.73S282O O.O16646S O.O3SOO3 O.866805 A f 1 O.25 S2.9 698 8.28 8.295 Glads, 2 O.35 54.5 753 8.36 7.112 Hastine Hi 3 O.31 56.8 798 7.97 7.16.1 M O.3024.361 54.733333 749.66666 8.2O3333 7.522667 l O.O49SS21 19604421 SO.O83264 O.205993S O.669309 P 0.79587 0.2589797 3.684E-06 0.11848.78 O.O3S816 so- 1 O.32 56.5 759 8.53 7.413 46;e 2 O.32 57.8 583 8.12 7.182 air relei 3 O.26 59.7 697 8.26 6.65 4 O40 56.5 653 8.60 8.61 M O.3254963 57.625 673 8.3775 7.46375 l 0.0573356 1.5129992 74.099.032 0.2257,395 O.828259 P O.404205 O.002249 OOOOOO2 O.3784OO O.O296S

Notes 1) M - (function <> - appendix Exel for MsOffice XP; 4) # - Student's reliability coefficient has not been counted as parameters values equal to 0 (metamyelocytes, young neu trophiles and basophiles might not be found in leukogramma made by counting of 200 cells per Smear, but this is quite a norm for white mice). 5) P - fljia >KMBOTHbix c nuMdpoMoilipacchMTbieanacb no KomponbHoi?irpynne; P - f|Ljin XMBOTHbix c muMdpo MOM+ mpenapai Libanus cedra G 14 paccEMTbiBanocb no rpynne ca/MCPOMOil

0097. By day 16 of the study, significant differences in Example 2 body weight of animals between the groups were observed; in mice treated with 24-ethyl-cholestane-3B.5C.6O-triol, there Assessment of the Therapeutic Efficacy of 24-ethyl cholestane-3?.5C.6C.-triol on Human Tumor Cell was a tendency to a gain in mass (FIG. 6). Lines in Mice 0098. An autopsy investigation revealed no differences between animals with lymphoma treated with 24-ethyl 0099 Immunocompromised mice were used for this cholestane-3?.5C,6C.-triol and healthy mice. Liver, kidney, experiment. Mice were inbred in a sterile environment and and spleen tissues showed no differences (FIG. 7). In contrast, fed ad libitum. Four groups of 40 mice, weighing approxi in three animals receiving no displayed macro mately 20 g each (range: 17-25 g), were used for each tumor scopic morphological changes (FIG. 8). type. The human tumor cell lines used were the following: US 2009/0226431 A1 Sep. 10, 2009

large B-cell lymphoma; squamous-cell carcinoma of the tumor in the left kidney associated with multiple bilateral lung; ductal carcinoma breast; and adenocarcinoma of the lung metastases (1.5-2 cm size). Pathology revealed a sarco lung. A Suspension of tumor cells was injected in the perito matoid renal cell carcinoma (grade 4/4). A left nephrectomy neum of immunocompromised mice. Following this, mice was performed, followed by interferon therapy for 6 weeks. were examined and weighed daily. After 6-8 days, we Two months later, a chest CT scan reveals persistence of one observed the development of abdominal carcinomatosis and metastatic deposit 1 cm in size in both lungs. At this point, the ascitis. At day 18, we observed the development of an abun patient is administered 24-ethyl-cholestane-3B.5C.6O-triol dant ascitis, which increased the weight of the mice by (80 mg/day). Six weeks later, a chest CT scan reveals a approximately 20 g. At that time, mice were divided into four disappearance of the left lung metastasis. Eight months later, groups of 10. One group of 10 mice was used as control and another chest CT scan revealed one 1 mm nodule in the right did not receive any medication. The other three groups were lower lobe. One year after commencing therapy, the chest CT treated respectively with 4, 2 and 0.8 mg/kg/day of 24-ethyl scan appeared normal. cholestane-3?.5C,6C.-triol administered orally for 10 days. Assessment of tumor cell concentration in the asciitis and Example 4 abdominal metastases were measured on day 18 and every 2 days thereafter. Treatment of Hormone Resistant Metastatic Prostate 0100. In all mice, prior to treatment, we observed an Cancer with 24-ethyl-cholestane-3,3,5C.6O-triol increase in LDH ESR (>100) and a decrease in the hemat ocrit. Control (untreated) mice all died between day 21 and 0104. A 75-year old male patient presented with hormone day 25 in all tumor types. Dead mice were examined and resistant metastatic prostate cancer. He had previously been showed abdominal carcinoinatosis associated with lymph treated with three courses of chemotherapy (Navelbine-- nodes and liver metastases. Taxotere, but his PSA was still increasing. Administration of 0101 Our observations of treated mice are summarized in 24-ethyl-cholestane-3?.5C,6C.-triol was commenced (70 Table 4. mg/day). 0105. The patient's PSA history is shown in Table 5. TABLE 4 TABLE 5 Squamous Breast CA Lymphoma lung Adenocarcinonia PSA Complete 60% 80% SO% 40% Day 0 (prior to 1958 (nl < 4) Remission treatment) Partial 20% 10% 30% 20% Day 13 1590 Remission Day 15 1142 Stable Disease 20% 10% 20% 30% Day 67 802 Progressive O% O% O% 10% Day 110 772 Disease Symptomatic 100% 100% 100% 100% Response The patient died in May 2005 due to a severe pneumonia unrelated to his cancer. Complete response: Weight (and ascetic) loss and the disap pearance of all abdominal metastatic nodules and tumor cells. Example 5 Partial response: Weight (and ascitic) loss and at least 25% decrease of tumor cell in the ascitis with at least 25% decrease Treatment of Breast Carcinoma with 24-ethyl in measured abdominal metastatic nodules. cholestane-3?.5C,6C.-triol Stable disease: When tumor regression and or tumor cells in 0106. A 46YO female patient with a past medical history the ascitic fluid did not regress by at least 25%. of anemia and mild chronic renal failure due to retroperito Progressive disease: When we observed an increase in ascitis neal fibrosis presented with a stage IV poorly differentiated or tumor volume or death of the animal. lobular carcinoma of the right breast and liver, spleen and Symptomatic response: Improvement in the general condi bone metastases. After many hormonal treatments with tion of mice with decrease in LDH, normalization of ESR and tamoxifen, Zoladex and arimidex, she had a liver progression. of hematocrit level. Treatment with 24-ethyl-cholestane-3?.5C.6O-triol was 0102. Furthermore we observed in most of the treated commenced (60 mg/day). Three days after treatment, we mice: (1) a rapid response to therapy (asciitic regression observed a decrease in LDH level from 450 to 204. Five within 1-2 days); (2) a total clearance of tumor cells associ months after treatment commenced, liver including ated with an important tumor lysis; (3) a normalization of LDH returned to normal and her markers decreased as shown hematological abnormalities; and (4) an improvement in the in Table 6: general condition. Additionally, we observed a three month survival without recurrence in mice that exhibited a complete TABLE 6 response. CA 15-3 CA 12S Example 3 Before LC 237 125 Treatment of a Metastatic Renal Cell Carcinoma After LC 86 69 with 24-ethyl-cholestane-3?.6C.-triol 0103) A 45-year old male patient presented with a meta Her spleen metastasis has regressed on CT scan and the static renal cell carcinoma (stage IV), including an 8 cm primitive breast mass has also regressed on ultrasound from 5 US 2009/0226431 A1 Sep. 10, 2009

to 3 cm. Renal failure and anemia both improved, and a total More than a year after commencement of therapy, the Body MRI showed a complete liver and spleen response. patient's CT scans show a decrease in number and size of previous masses seen in the lungs and liver (FIGS. 13-16). Example 6 Example 9 Treatment of Uterine Cancer with 24-ethyl-choles tane-3?.5C.6O-triol Treatment of Breast Cancer with 24-ethyl-choles 0107 A49 year-old female patient presented with uterine tane-3,3,5C.6O-triol cancer stage IIB. She previously received cisplatin-based 0111. A 36 year-old female patient presented with breast chemotherapy and radiotherapy. A pelvic MRI showed a cancer stage IV with lung and bone metastases. She previ recurrent 3.2 cm pelvic mass+retroperitoneal lymph nodes. A ously underwent a left radical mastectomy for a stage 2 col cervical biopsy confirms the recurrence. loidal mucinous adenocarcinoma Hormone receptors and 0108) Administration with 24-ethyl-cholestane-3?.5C. c-erbB were negative. She received adjuvant chemotherapy 6O-triol was commenced (60 mg/day). Within three months, (FAC) followed by radiotherapy. Later, a sternal bone the tumor had disappeared on clinical exam and abdomino metastasis appeared and was resected. The pathology pelvic CT scan. revealed an adenocarcinoma with positive hormone recep tors. She also developed lung metastases up to 4 cm size. She Example 7 received chemotherapy with taxotere, navelbine, and pamidr onate, followed by tamoxifen. This treatment gave an almost Treatment of Squamous Cell Lung Carcinoma with complete response in the lungs. Tamoxifen was replaced by 24-ethyl-cholestane-3?.5C.6C.-triol Femara. The patient received radiotherapy on the spine (T4 0109. A 67 year-old female patient with presented with a and T1 2) and Zometa is administered along with Femara. left Squamous-cell carcinoma of the lung. She commenced However, there is progression of bone metastases on bone therapy with 24-ethyl-cholestane-3?.5C.6O-triol (50 Scan, and a chest CT scan reveals stable lung metastases. mg/day) and experienced a drastic and rapid improvement in 0112 Therapy with 24-ethyl-cholestane-3?.5C.6C.-triol is her general condition. Seven months later the patient received commenced (60 mg/day), when the CA 15-3 marker was at radiotherapy to the left lung. Nine months after commencing 227 U. Zometa and Femara were continued and Decapeptyl treatment, the patient has considerable improvement and sig was added to the treatment. nificant regression of the left lung opacity, with a persistence 0113. The course of CA 15-3 is shown in Table 8. of a small stellate image around the left Superior bronchus. Fourteen months after therapy commenced, the patient TABLE 8 fibroscopy is normal, and the dose of 24-ethyl-cholestane-3?, Month O (prior to treatment) 277 (nl & 35) 5C,6C.-triol is reduced to 30 mg/day. A fibroscopy later that Month 5 1S6 year shows a compression on the left Superior lobular bron Month 6 85 chus, and the dose of 24-ethyl-cholestane-3?.5C.6C.-triol is Month 6 52 Month 14 24 increased to 50 mg/day. Nearly five years after commence Month 16 19.5 ment of therapy, there is recurrence of the left lung tumor. The patient undergoes a left pneumonectomy and drug therapy is stopped, but the tumor recurs and the patient dies. Two weeks after the beginning of LC, the patient was totally asymptomatic. Example 8 Example 10 Treatment of Lung Large-cell Adenocarcinoma with 24-ethyl-cholestane-3?.5C.6C.-triol Treatment of Pancreatic Cancer with 24-ethyl cholestane-3?.5C,6C.-triol 0110 A 26 year-old male patient was diagnosed with a lung large-cell adenocarcinoma metastatic to liver. He 0114. A 68 year-old diabetic and insulin dependent male received chemotherapy with no Success. The patient was patient with a past history of lymphoma presented with a 3 cm administered 24-ethyl-cholestane-3?.5C.6O-triol (70 tumor in the head of pancreas and a Suspicion of hepatic mg/day). He also had frequent hemoptysis and elevated LDH, metastasis. An open biopsy of the pancreas revealed a mod GGT, and bilirubin. The course of the patient's biologic erately differentiated adenocarcinoma. Therapy with parameters during treatment are depicted in Table 7. In addi 24-ethyl-cholestane-3?.5C,6C.-triol was commenced (50 tion to these data, GGT also fell to 31. mg/day). The course of CA19-9 is shown in Table 9.

TABLE 7 TABLE 9 Day 0 (prior to 884 (nl < 37) LDH Total Bilirubin treatment) Day 0 2560 (nl < 480) 1.9 (nl < 1) Day 1 793 (prior to Day 32 675 treatment) Day 59 1127 Day 11 2264 ND Day 128 545 Day 30 283 ND Day 63 118 O42 Day 85 230 0.37 On Day 59, the dose of 24-ethyl-cholestane-3?.5C.6O-triol was increased to 60 mg/day because CA19-9 levels were increasing. A CT scan of the abdomen performed on Day 200 US 2009/0226431 A1 Sep. 10, 2009 of therapy revealed an atrophic pancreas with no masses seen, 4. The preparation of claim 3, wherein said compound is a normal liver, and multiples lymph nodes in the peri-aortic described by the formula: and mesenteric areas.

Example 11 (II) Histological Analysis of Therapeutic Efficacy of 24-ethyl-cholestane-33.5C.6O-triol in Mice with Experimental Lymphoma 0115 Parenchymatous organs liver and kidneys received from mice with experimental lymphoma on the 15th day of observation and from mice treated with 24-ethyl-cholestane 3f.5C.6O-triol were taken for the histological analysis. Micropreparations were stained with hematoxilin and examined by microscopy (FIGS. 9, 10, 11, and 12).

Other Embodiments 5. The preparation of claim 1 admixed with a pharmaceu tically acceptable carrier to form a therapeutic composition. 0116. All publications, patent applications including U.S. 6. The composition of claim 5, wherein said composition is Patent Application No. 60/741,725, filed Dec. 2, 2005, and suitable for oral administration. patents cited in this specification are incorporated herein by 7. The composition of claim 6, wherein said composition is reference as if each individual publication or patent were in unit dosage form. specifically and individually indicated to be incorporated by 8. The composition of claim 7, wherein said compound is reference. Although the foregoing invention has been present in said unit dosage form in an amount between 0.005 described in some detail by way of illustration and example mg and 500 mg. for purposes of clarity of understanding, it will be readily 9. The composition of claim 5, wherein said composition is apparent to those of ordinary skill in the art in light of the Suitable for intrathecal, intraarticular, intratumoral, intrave teachings of this invention that certain changes and modifi nous, topical, Subcutaneous, buccal, intramuscular, inhala cations may be made thereto without departing from the spirit tion, or rectal administration. or scope of the appended claims. 10. The composition of claim 5, wherein said compound is present in an effective amount for treating a neoplasm, hyper cholesterolemia, diabetes, an autoimmune disease, or a viral What is claimed is: infection. 11. The composition of claim 5, further comprising an 1. A substantially pure preparation of a compound antiproliferative agent, an antidiabetic agent, an antiinflam described by the formula (I) matory agent, or an antiviral agent. 12. A process for preparing 24-ethyl cholestane 3,5,6 triol comprising the step of oxidizing sitosterol. (I) 13. The process of claim 12, wherein 24-ethylcholestane 3f.5C.6C. triol is prepared from B-sitosterol. 14. The process of claim 12, wherein 24-ethylcholestane 3C,53.63 triol is prepared from C-sitosterol. 15. The process of claim 12, wherein sitosterol is oxidized by reaction with periodate in the presence of osmium tetroX ide. 16-33. (canceled) 34. A kit comprising (a) a compound of formula (I); and (b) instructions for administering said compound of for mula (I) to a patient diagnosed with or at risk of devel oping a neoplasm, hypercholesterolemia, an autoim wherein mune disease, diabetes, or a viral infection. 35. A kit comprising each of Rs. Rs, and R is, independently, selected from OH. (a) a compound of formula (I); SH, and NH; the stereochemistry at positions 3, 5, and (b) an antiproliferative agent; and 6 is either 3C, 5 B, 6B or 3B, 5C, 6o: (c) instructions for administering said compound of for each of R7, Rs. Rs. R16, R22, R2, and R2s is, indepen mula (I) and said antiproliferative agent to a patient dently, selected from H, OH, SH, and NH; or a prodrug diagnosed with or at risk of developing a neoplasm. thereof. 36. A kit comprising: 2. The preparation of claim 1, wherein each of R. Rs, and (a) a compound of formula (I); and R is OH. (b) instructions for administering said compound of for 3. The preparation of claim 2, wherein the stereochemistry mula (I) and an antiproliferative agent to a patient diag at positions 3, 5, and 6 is nosed with or at risk of developing a neoplasm. US 2009/0226431 A1 Sep. 10, 2009 20

37. A kit comprising darabine, raltitrexed, amsacrine, epirubicin, etoposide, (a) a compound of formula (I); or mitoxantrone, 7-ethyl-10-hydroxy-camptoth (b) an antidiabetic agent; and ecin, dexraZOxanet (TopoTarget), pixantrone (Novusp (c) instructions for administering said compound of for harma), rebeccamycin analogue (Exelixis), BBR-3576 (No mula (I) and said antidiabetic agent to a patient diag Vuspharma), rubitecan (SuperGen), irinotecan (CPT-11), nosed with or at risk of developing diabetes. , , therarubicin, idarubicin, rubidaZone, 38. A kit comprising: plicamycin, porfiromycin, mitoxantrone (novantrone), (a) a compound of formula (I); and amonafide, colchicine, vinblastine, Vindesine, dolastatin 10 (b) instructions for administering said compound of for (NCI), rhizoxin (Fujisawa), mivobulin (Warner-Lambert), mula (I) and an antidiabetic agent to a patient diagnosed cemadotin (BASF), RPR 109881A (Aventis), TXD 258 with or at risk of developing diabetes. (Aventis), epothilone B (Novartis), T 900607 (Tularik), T 39. A kit comprising 138067 (Tularik), cryptophycin 52 (Eli Lilly), vinflumine (a) a compound of formula (I); (Fabre), auristatin PE (Teikoku Hormone), BMS 247550 (b) an antiinflammatory agent; and (BMS), BMS 184476 (BMS), BMS 188797 (BMS), taxo (c) instructions for administering said compound of for prexin (Protarga), SB 408075 (GlaxoSmithKline), Vinorel mula (I) and said antiinflammatory agent to a patient bine, Trichostatin A, aminoglutethimide, atamestane (Bio diagnosed with or at risk of developing a autoimmune Medicines), letrozole, anastrazole, pemetrexed (Eli Lilly), disease. ZD-9331 (BTG), trabectedin (PharmaMar), glufosfamide 40. A kit comprising: (Baxter International), albumin-i-32P (Isotope Solutions), (a) a compound of formula (I); and thymectacin (NewBiotics), arglabin (NuOncology Labs), (b) instructions for administering said compound of for lonafarnib (Schering-Plough), BAY-43-9006 (Bayer), CBT-1 mula (I) and an antiinflammatory agent to a patient diag (CBA Pharma), tariquidar (Xenova), MS-209 (Schering AG), nosed with or at risk of developing an autoimmune dis tacedinaline (Pfizer), SAHA (Aton Pharma), MS-275 (Scher CaSC. ing AG), Neovastat (Aeterna Laboratories), marimastat (Brit 41. A kit comprising ish Biotech), gallium maltolate (Titan), triapine (Vion), viru (a) a compound of formula (I); lizin (Lorus Therapeutics), CDC-394 (Celgene), atrasentan (b) an antiviral agent; and (Abbott), ZD-4054 (AstraZeneca), fenretinide (Johnson & (c) instructions for administering said compound of for Johnson), LGD-1550 (Ligand), interferon, oncophage (Anti mula (I) and said antiviral agent to a patient diagnosed genics), GMK (Progenics), adenocarcinoma vaccine with or at risk of developing a viral infection. (Biomira), CTP-37 (AVI BioPharma), IRX-2 (Immuno-RX), 42. A kit comprising: PEP-005 (Peplin Biotech), synchrovax vaccines (CTL (a) a compound of formula (I); and Immuno), melanoma vaccine (CTL (b) instructions for administering said compound of for Immuno), p21 RAS vaccine (GemVax), estrogens, conju mula (I) and an antiproliferative agent to a patient diag gated estrogens, ethinyl estradiol, chlortrianisen, nosed with or at risk of developing a viral infection. idenestrol, hydroxyprogesterone caproate, medroX 43. A kit comprising yprogesterone, testosterone, ; (a) a compound of formula (I); fluoxymesterone, methyltestosterone, diethylstilbestrol, (b) a cholesterol reducing agent; and megestrol, bicalutamide, flutamide, nilutamide, talapor (c) instructions for administering said compound of for fin (Light Sciences). TheraluX (Theratechnologies), mula (I) and said cholesterol reducing agent to a patient motexafin gadolinium (Pharmacyclics), imatinib (No diagnosed with or at risk of developing hypercholester vartis), leflunomide (Sugen/Pharmacia), ZD1839 (As olemia. traZeneca), erlotinib (Oncogene Science), canertinib 44. A kit comprising: (Pfizer), squalamine (Genaera), SU5416 (Pharmacia), (a) a compound of formula (I); and SU6668 (Pharmacia), ZD4190 (AstraZeneca), ZD6474 (b) instructions for administering said compound of for (AstraZeneca), Vatalanib (Novartis), PKI166 (Novartis), mula (I) and a cholesterol reducing agent to a patient GW2016 (GlaxoSmithKline), EKB-509 (Wyeth), tras diagnosed with or at risk of developing hypercholester tuzumab (Genentech), OSI-774 (TarcevaTM), CI-11033 olemia. (Pfizer), SU11248 (Pharmacia), RH3 (York Medical), 45. A method of treating a neoplasm, said method com Genistein, Radicinol, Chlorambucil, procarbazine, prising administering a neoplasm-treating amount of a prepa altretamine, , mechlorethamine, ration of claim 1 to a patient with or at risk of developing a streptozocin, temozolomide, Semustine, lobaplatin neoplasm. (Aeterna), satraplatin (Johnson Matthey), BBR-3464 46. The method of claim 45, further comprising adminis (Hoffmann-La Roche), SM-11355 (Sumitomo), tering to said patient an antiproliferative agent, wherein said AP-5280 (Access), cisplatin, trimetrexate, deoxycofor preparation and said antiproliferative agent are administered mycin, pentostatin, hydroxyurea, decitabine (Super simultaneously or within 28 days of each other. Gen), clofarabine (Bioenvision), irofulven (MGI 47. The method of claim 46, wherein said antiproliferative Pharma), DMDC (Hoffiann-La Roche), ethynylcytidine agent is selected from the group consisting of BuSulfan, dac (Taiho), gemcitabine, capecitabine, exatecan meSylate arbazine, ifosfamide, hexamethylmelamine, thiotepa, dacar (Daiichi), quinamed (ChemGenex), gimatecan (Sigma bazine, lomustine, cyclophosphamide, Spiroplatin, tetrapl Tau), diflomotecan (Beaufour-Ipsen), TAS-103 (Taiho), atin, ormaplatin, iproplatin, ZD-0473 (AnorMED), elsamitrucin (Spectrum), J-107088 (Merck & Co), oxaliplatin, carboplatin, azacytidine, Floxuridine, 2-chloro BNP-1350 (BioNumerik), CKD-602 (Chong Kun deoxyadenosine, 6-mercaptopurine, 6-thioguanine, cytara Dang), KW-2170 (Kyowa Hakko), hydroxycamptoth bine, 2-fluorodeoxy cytidine, methotrexate, tomudex, flu ecin (SN-38), azonafide, anthrapyrazole, oxantrazole, US 2009/0226431 A1 Sep. 10, 2009 21

losoxantrone, MEN-10755 (Menarini), GPX-100 (Gem motor. Everlife), SDX-101 (apoptosis promotor, Salme Pharmaceuticals), Epirubicin, mitoxantrone, doxorubi dix), rituximab (CD20 antibody, Genentech, carmus cin, E7010 (Abbott), PG-TXL (Cell Therapeutics), IDN tine, Mitoxantrone, Bleomycin, Absinthin, 5109 (Bayer), A 105972 (Abbott), A204197 (Abbott), Chrysophanic acid, Cesium oxides, ceflatonin (apopto LU 223651 (BASF), D 24851 (ASTAMedica), sis promotor, ChemGenex), BCX-1777 (PNP inhibitor, ER-86526 (Eisai), combretastatin A4 (BMS), isohomo BioCryst), ranpirinase (ribonuclease stimulant, Alfa cell), galarubicin (RNA synthesis inhibitor, Dong-A), halichondrin-B (PharmaMar), ZD 6126 (AstraZeneca), tirapazamine (reducing agent, SRI International), AZ10992 (Asahi), IDN-5109 (Indena), AVLB (Pre N-acetylcysteine (reducing agent, Zambon), R-flurbi scient NeuroPharma), azaepothilone B (BMS), BNP profen (NF-kappaB inhibitor, Encore), 3CPA (NF-kap 7787 (BioNumerik), CA-4 prodrug (OXiGENE), dola paB inhibitor, Active Biotech), seocalcitol (vitamin D statin-10 (NIH), CA-4 (OXiGENE), docetaxel, receptoragonist, Leo), 131-I-TM-601 (DNA antagonist, Vincristine, paclitaxel, YM-511 (Yamanouchi), formes TransMolecular), efornithine (ODC inhibitor, ILEX tane, exemestane, nolatrexed (Eximias), CoFactorTM Oncology), minodronic acid (osteoclast inhibitor, (Biokeys), edotreotide (Novartis), mafosfamide (Baxter Yamanouchi), indisulam (p53 stimulant, Eisai), aplidine International), apaziquone (Spectrum Pharmaceuticals), (PPT inhibitor, PharmaMar), gemtuzumab (CD33 anti O6 benzyl guanine (Paligent), tipifarnib (Johnson & body, Wyeth Ayerst), PG2 (hematopoiesis enhancer, Johnson), perillyl alcohol (DOR BioPharma), Zosudui Pharmagenesis), ImmunolTM (triclosan oral rinse, dar trihydrochloride (Eli Lilly), biricodar dicitrate (Ver Endo), triacetyluridine (uridine prodrug, Wellstat), tex), pivaloyloxymethylbutyrate (Titan), depsipeptide SN-4071 (sarcoma agent, Signature BioScience), Trans (Fujisawa), CMT-3 (CollaGenex), BMS-275291 MID-107TM (immunotoxin, KS Biomedix), PCK-3145 (Celltech), tezacitabine (Aventis), didox (Molecules for (apoptosis promotor, Procyon), doranidazole (apoptosis Health), revimid (Celgene), YM-598 (Yamanouchi), ali promotor, Pola), CHS-828 (cytotoxic agent, Leo), trans (Ligand), dexosome therapy (Anosys), pentrix retinoic acid (differentiator, NIH), MX6 (apoptosis pro (Australian Cancer Technology), ISF-154 (Tragen), motor, MAXIA), apomine (apoptosis promotor, ILEX cancer vaccine (Intercell), norelin (Biostar), BLP-25 Oncology), urocidin (apoptosis promotor, Bioniche), (Biomira), MGV (Progenics), B-alethine (Dovetail), CLL therapy (Vasogen), dexamethasone, prednisone, Ro-31-7453 (apoptosis promotor, La Roche), brostalli methylprednisolone, prednisolone, aminoglutethimide, cin (apoptosis promotor, Pharmacia), B-lapachone, leuprolide, octreotide, mitotane, P-04 (Novogen), gelonin, cafestol, kahweol, caffeic acid, and Tyrphostin 2-methoxyestradiol (EntreMed), arzoxifene (Eli Lilly), AG. tamoxifen, toremofine, goserelin, Leuporelin, bicaluta 48. A method of treating a treating diabetes, said method mide, Pd-bacteriopheophorbide (Yeda), lutetium texa comprising administering a diabetes-treating amount of a phyrin (Pharmacyclics), hypericin, EKB-569 (Wyeth), preparation of claim 1 to a patient with or at risk of developing kahalide F (PharmaMar), CEP-701 (Cephalon), CEP diabetes. 751 (Cephalon), MLN518 (Millenium), PKC412 (No 49. The method of claim 48, further comprising adminis vartis), Phenoxodiol (Novogen), C225 (ImClone), rhu tering to said patient an antidiabetic agent, wherein said Mab (Genentech), MDX-H210 (Medarex), 2C4 preparation and said antidiabetic agent are administered (Genentech), MDX-447 (Medarex), ABX-EGF (Ab simultaneously or within 28 days of each other. genix), IMC-1C11 (ImClone), Tyrphostins, Gefitinib 50. The method of claim 49, wherein said antidiabetic (Iressa), PTK787 (Novartis), EMD 72000 (Merck), agent is selected from the group consisting of Sulfonylureas, Emodin, SR-27897 (CCK A inhibitor, Sanofi-Syn non-Sulfonylurea secretagogues, insulin, insulin analogs, thelabo), tocladesine (cyclic AMP agonist, Ribapharm), glucagon-like peptides, exendin-4 polypeptides, beta 3 alvocidib (CDK inhibitor, Aventis), CV-247 (COX-2 adrenoceptor agonists, PPAR agonists, dipeptidyl peptidase inhibitor, Ivy Medical), P54 (COX-2 inhibitor, Phytop IV inhibitors, , alpha-glucosidase inhibitors, harm), CapCellTM (CYP450 stimulant, Bavarian Nor immunomodulators, statins and statin-containing combina dic), GCS-100 (ga13 antagonist, GlycoGenesys), tions, angiotensin converting enzyme inhibitors, adenosine G17DT immunogen (gastrin inhibitor, Aphton), A1 receptor agonists, adenosine A2 receptor agonists, aldos efaproxiral (oxygenator, Allos Therapeutics), PI-88 terone antagonists, alpha 1 adrenoceptor antagonists, alpha 2 (heparanase inhibitor, Progen), tesmilifene (histamine adrenoceptoragonists, alpha 2 adrenoceptor agonists, angio antagonist, YM BioSciences), histamine (histamine H2 tensin receptor antagonists, antioxidants, ATPase inhibitors, receptoragonist, Maxim), tiazofurin (IMPDH inhibitor, atrial peptide agonists, beta adrenoceptor antagonists, cal Ribapharm), cilengitide (integrin antagonist, Merck cium channel agonists, calcium channel antagonists, diuret KGaA), SR-31747 (IL-1 antagonist, Sanofi-Syn ics, dopamine D1 receptor agonists, endopeptidase inhibi thelabo), CCI-779 (mTOR kinase inhibitor, Wyeth), tors, endothelin receptor antagonists, guanylate cyclase exisulind (PDE V inhibitor, Cell Pathways), CP-461 stimulants, phosphodiesterase V inhibitors, protein kinase (PDE V inhibitor, Cell Pathways), AG-2037 (GART inhibitors, Cdc2 kinase inhibitors, renin inhibitors, throm inhibitor, Pfizer), WX-UK1 (plasminogen activator boxane synthase inhibitors, vasopeptidase inhibitors, vaso inhibitor, Wilex), PBI-1402 (PMN stimulant, ProMetic pressin Iantagonists, Vasopressin2 antagonists, angiogenesis LifeSciences), bortezomib (proteasome inhibitor, Mil inhibitors, advanced glycation end product inhibitors, bile lennium), SRL-172 (T cell stimulant, SR Pharma), acid binding agents, bile acid transport inhibitors, bone for TLK-286 (glutathione S transferase inhibitor, Telik), mation stimulants, apolipoprotein A1 agonists, DNA topoi PT-100 (growth factor agonist, Point Therapeutics), somerase inhibitors, cholesterol absorption inhibitors, cho midostaurin (PKC inhibitor, Novartis), bryostatin-1 lesterol antagonists, cholesteryl ester transfer protein (PKC stimulant, GPC Biotech), CDA-II (apoptosis pro antagonists, cytokine synthesis inhibitors, DNA polymerase US 2009/0226431 A1 Sep. 10, 2009 22 inhibitors, dopamine D2 receptoragonists, endothelin recep a COX-2 inhibitor, a biologic, a small molecule immuno tor antagonists, growth hormone antagonists, insulin sensi modulator, a DMARD, and a corticosteroid. tizers, lipase inhibitors, lipid peroxidation inhibitors, lipopro 54. A method of treating a viral infection, said method tein A antagonists, microsomal transport protein inhibitors, comprising administering a viral infection-treating amount of microsomal triglyceride transfer protein inhibitors, nitric a preparation of claim 1 to a patient with or at risk of devel oxide synthase inhibitors, oxidizing agents, phospholipase oping a viral infection. A2 inhibitors, radical formation agonists, platelet aggrega 55. The method of claim 54, further comprising adminis tion antagonists, prostaglandin synthase stimulants, reverse tering to said patient an antiviral agent, wherein said prepa cholesterol transport activators, rho kinase inhibitors, selec ration and said antiviral agent are administered simulta tive modulators, squalene epoxidase inhibi neously or within 28 days of each other. tors, squalene synthase inhibitors, thromboxane A2 antago nists, amylin agonists, cannabinoid receptor antagonists, 56. The method of claim 55, wherein said antiviral agent is cholecystokinin A agonists, corticotropin-releasing factor selected from the group consisting of interferon-C, -f, -y, agonists, dopamine uptake inhibitors, G protein-coupled ribavirin (13-D ribofuranosyl-1H-1.2.4 triazole 3-carboxam receptor modulators, glutamate antagonists, glucagon-like ide), lamivudine ((cis-1-2'-Hydroxymethyl-5'-(1,3-oxathi peptide-1 agonists, insulin sensitizers, lipase inhibitors, olanyl)cytosine), idoxuridine, Vidarabine, trifluridine, acy melanin-concentrating hormone receptor antagonists, nerve clovir, famciclovir, penciclovir, Valacyclovir, ganciclovir, growth factor agonists, neuropeptide Yagonists, neuropep foscarnet, amantadine, rimantadine, cidofovir, Zidovudine, tide Y antagonists, SNRIs, protein tyrosine phosphatase didanosine, Zalcitabine, stavudine, nevirapine, delavirdine, inhibitors, and serotonin 2C receptor agonists. saquinavir, ritonavir, indinavir, nelfinavir, adefovir dipivoxil, 51. A method of treating an autoimmune disease, said Suramin, polycytidylic acid, 2',3'-dideoxycytidine, and ube method comprising administering an autoimmune disease nimex. treating amount of a preparation of claim 1 to a patient with or 57. A method of treating a neoplasm comprising adminis at risk of developing an autoimmune disease. tering to a patient a compound or combination of compounds 52. The method of claim 51, further comprising adminis that tering to said patient an antiinflammatory agent, wherein said (i) inhibits HMG-CoA reductase; and preparation and said antiinflammatory agent are administered (ii) specifically inhibits uptake of cholesterol into a neo simultaneously or within 28 days of each other. cell, thereby treating said neoplasm. 53. The method of claim 52, wherein said antiinflamma tory agent is selected from the group consisting of an NSAID, c c c c c