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(12) Patent Application Publication (10) Pub. No.: US 2010/0120727 A1 Xu (43) Pub US 20100120727A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0120727 A1 Xu (43) Pub. Date: May 13, 2010 (54) EFLORNITHINE PRODRUGS, CONJUGATES Publication Classification AND SALTS, AND METHODS OF USE (51) Int. Cl. THEREOF A613/60 (2006.01) CD7C 229/26 (2006.01) (75) Inventor: Feng Xu, Palo Alto, CA (US) C07C 315/00 (2006.01) C07C 69/76 (2006.01) Correspondence Address: A 6LX 3L/95 (2006.01) WILSON, SONSINI, GOODRICH & ROSATI C07C 229/00 (2006.01) 650 PAGE MILL ROAD A6II 3L/22 (2006.01) PALO ALTO, CA 94304-1050 (US) A6IP35/04 (2006.01) (52) U.S. Cl. ........... 514/165; 562/561; 562/429; 560/76: (73) Assignee: Kyphia Pharmaceuticals, Inc., 514/564; 560/169; 514/551 Palo Alto, CA (US) (57) ABSTRACT In one aspect, the present invention provides a composition of (21) Appl. No.: 12/617,574 a covalent conjugate of an eflornithine analog with an anti inflammatory drug. In another aspect, the present invention (22) Filed: Nov. 12, 2009 provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, Related U.S. Application Data the present invention provides methods for treating or pre (60) Provisional application No. 61/114,015, filed on Nov. venting cancer using the conjugates or salts of eflornithine 12, 2008. analogs or eflornithine prodrugs. US 2010/01.20727 A1 May 13, 2010 EFLORNITHINE PRODRUGS, CONJUGATES rofecoxib, Salsalate, salicyl salicylate, salicylamide, sodium AND SALTS, AND METHODS OF USE salicylate, Sulindac, tiaprofenic acid, tolfenamic acid, tol THEREOF metin Sodium, and Valdecoxib. In some embodiments, the NSAID is Sulindac. In some embodiments, the NSAID is CROSS-REFERENCE aspirin. In some embodiments, the first and second moieties are linked via a covalent bond selected from the group con 0001. This application claims the benefit of U.S. Provi sisting of an ester bond, an amide bond, an imine bond, a sional Application No. 61/114,015, filed Nov. 12, 2008, carbamate bond, a carbonate bond, a thioester bond, an acy which application is incorporated herein by reference. loxycarbamate bond, an acyloxycarbonate bond, an acylox ythiocarbamate, a phosphate bond, a phosphoramidate and an BACKGROUND OF THE INVENTION acyloxyphosphate bond. In some embodiments, the com 0002 Cancer, also known as malignant neoplasm, is a type pound further comprises a linker that covalently links the first of hyperproliferative disorder characterized by an abnormal moiety to the second moiety. In some embodiments, the linker growth of cells that display uncontrolled cell division, inva is physiologically labile. In some embodiments, the cancer is sion and destruction of adjacent tissues, and sometimes adrenal cortical cancer, anal cancer, aplastic anemia, bile duct metastasis to other locations in the body. There are more than cancer, bladder cancer, bone cancer, bone metastasis, brain 100types of cancer, including breast cancer, skin cancer, lung cancers, central nervous system (CNS) cancers, peripheral cancer, colon cancer, prostate cancer, and lymphoma. Cancer nervous system (PNS) cancers, breast cancer, cervical cancer, may affect people at all ages, even fetuses, but the risk for childhood Non-Hodgkin's lymphoma, colon and rectum can cer, endometrial cancer, esophagus cancer, Ewing's family of most types of cancer increases with age. Cancers can affect all tumors (e.g. Ewing's sarcoma), eye cancer, gallbladder can animals. cer, gastrointestinal carcinoid tumors, gastrointestinal stro 0003 Cancer is influenced by multiple molecular mecha mal tumors, gestational trophoblastic disease, hairy cell leu nisms. Because of the complexity nature of each disease state, kemia, Hodgkin's lymphoma, Kaposi's sarcoma, kidney achieving cures with single agent has often met with limited cancer, laryngeal and hypopharyngeal cancer, acute lympho Success. Thus, combinations of agents have been frequently cytic leukemia, acute myeloid leukemia, children's leukemia, used in the treatment of cancers. It has been reported that there chronic lymphocytic leukemia, chronic myeloid leukemia, is strong correlation between the number of agents adminis liver cancer, lung cancer, lung carcinoid tumors, Non tered and cure rates for cancers such as acute lymphocytic Hodgkin's lymphoma, male breast cancer, malignant leukemia and metastatic colorectal cancer (Frei, et al., Clin. mesothelioma, multiple myeloma, myelodysplastic Syn Cancer Res. 1998, 4, 2027-2037: Fisher, M.D. Clin. Colorec drome, myeloproliferative disorders, nasal cavity and para tal Cancer 2001, 1(2), 85-86). nasal cancer, nasopharyngeal cancer, neuroblastoma, oral 0004 C-Difluoromethylornithine (DFMO) or 2-(difluo cavity and oropharyngeal cancer, osteosarcoma, ovarian can romethyl)-DL-ornithine, also known as eflornithine, is an cer, pancreatic cancer, penile cancer, pituitary tumor, prostate inhibitor of ornithine decarboxylase (ODC), the rate limiting cancer, retinoblastoma, rhabdomyosarcoma, salivary gland enzyme of the polyamine biosynthetic pathway. As a result of cancer, sarcomas, melanoma skin cancer, non-melanoma this inhibition of polyamine synthesis, the compound is effec skin cancers, stomach cancer, testicular cancer, thymus can tive in preventing cancer formation in many organ systems, cer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), inhibiting cancer growth, and reducing tumor size. It also has transitional cell carcinoma, vaginal cancer, Vulvar cancer, synergistic action with other antineoplastic agents. mesothelioma, squamous cell or epidermoid carcinoma, bronchial adenoma, choriocarinoma, head and neck cancers, teratocarcinoma, or Waldenstrom's macroglobulinemia. In SUMMARY OF THE INVENTION Some embodiments, the cancer is a Ki-ras-dependent cancer. 0005. In one aspect, the present invention provides a com In some embodiments, the compound further comprises a pound for treating or preventing cancer, the compound com third moiety that is ionically or covalently linked to the first prising a first moiety and a second moiety, the first moiety moiety or second moiety of the compound. In some embodi being covalently linked to the second moiety, wherein the first ments, the compound can be used in combination with at least moiety is eflornithine or an analog or derivative of eflorni one other therapeutic agent. In some embodiments, the other thine, and the second moiety is a non-steroidal anti-inflam therapeutic agent is an antitumor alkylating agent, antitumor matory drug (NSAID). In some embodiments, the first moiety antimetabolite, antitumor antibiotics, plant-derived antitu is eflornithine. In some embodiments, the second moiety is mor agent, antitumor organoplatinum compound, antitumor selected from the group consisting of aspirin, aceclofenac, campthotecin derivative, antitumor tyrosine kinase inhibitor, acemethacin, alclofenac, amoxiprin, ampyrone, azapropa monoclonal antibody, interferon, biological response modi Zone, benorylate, bromfenac, choline and magnesium salicy fier, hormonal anti-tumor agent, angiogenesis inhibitor, dif lates, choline Salicylate, celecoxib, clofeZone, diclofenac ferentiating agent, or a pharmaceutically acceptable salt potassium, diclofenac sodium, diclofenac sodium with miso thereof. In some embodiments, compound can be used in prostol, diflunisal, droxicam, lornoxicam, meloxicam, combination with Surgery, radiation therapy, chemotherapy, tenoxicam, ethenZamide, etodolac, fenoprofen calcium, fais gene therapy, RNA therapy, adjuvant therapy, immuno lamine, flurbiprofen, flufenamic acid, ibuprofen, ibuproxam, therapy, nanotherapy or a combination thereof. indoprofen, alminoprofen, carprofen, dexibuprofen, dexketo 0006. In some embodiments, the present invention pro profen, fenbufen, flunoxaprofen, indomethacin, ketoprofen, vides a pharmaceutical composition for treating or preventing ketorolac, kebuZone, loxoprofen, magnesium salicylate, cancer, comprising the compound of claim 1 and a pharma meclofenamate Sodium, metamizole, mofebutaZone, ceutically acceptable carrier. In some embodiments, the oxyphenbutaZone, phenaZone, Sulfinpyrazone, mefenamic present invention provides a kit for treating or preventing acid, meloxicam, methyl salicylate, nabumetone, naproxen, cancer in a Subject, the kit comprising the compound of the naproxen Sodium, nebumetone, oxaprozin, oxametacin, phe invention or the pharmaceutical composition of the invention, nylbutaZone, proglumetacin, piroxicam, pirprofen, Suprofen, and instructions for using the kit. In some embodiments, the US 2010/0120727 A1 May 13, 2010 subject is an animal, preferably a human. In some embodi skin cancers, stomach cancer, testicular cancer, thymus can ments, the kit further comprises at least one other agent for cer, thyroid cancer, uterine cancer (e.g. uterine sarcoma). use in the treatment of cancer, for reducing side effects transitional cell carcinoma, vaginal cancer, Vulvar cancer, induced by the compound of the invention, and/or for enhanc mesothelioma, squamous cell or epidermoid carcinoma, ing the therapeutic efficacy of the compound of the invention. bronchial adenoma, choriocarinoma, head and neck cancers, teratocarcinoma, or Waldenstrom's macroglobulinemia. In 0007. In another aspect, the present invention provides a some embodiments, the cancer is a Ki-ras-dependent cancer. method of treating or preventing cancer, the method compris In some embodiments, the compound further comprises a ing administering to a subject in need thereof
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