Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to use of prodrug of 4,9-dihydroxy-naphtho[2,3-b]furan derivative for circumventing cancer multidrug resistance.
• the present invention also relates to use of prodrug of 4,9-dihydroxy-naphtho[2,3-b]furan derivative for the treatment of various types of cancers exhibiting multidrug resistance phenomenon.
• the present invention further relates to use of the pharmaceutically acceptable composition comprising prodrug of 4,9- dihydroxy-naphtho[2,3-b]furan derivative and methods of using said composition in the treatment of various types of cancers exhibiting multidrug resistance phenomenon.
• Cancer multidrug resistance is defined as the cross-resistance or insensitivity of cancer cells to the cytostatic or cytotoxic actions of various anticancer drugs which are structurally or functionally unrelated and have different molecular targets (Gottesman M. M. Cancer Res, 1993, vol. 53, p747-54).
• the resistance of human tumor to multiple chemotherapeutic drugs has been recognized as a major reason for the failure of cancer therapy (Gottesman M. M., Pastan I. Annu Rev Biochem, 1993, vol. 62, p385-427).
• 4,9-dihydroxy-naphtho[2,3-b]furans are unstable in vitro under aerobic condition, but can be generated in vivo by hydrolyzing esters of 4,9-dihydroxy-naphtho[2,3-b]furans or by reducing naphtho[2,3-b]furan-4,9-diones (PCT application, PCT/CN2011/000357). So esters of 4,9- dihydroxy-naphtho[2,3-b]furans and naphtho[2,3-b]furan-4,9-diones are the prodrugs of 4,9- dihydroxy-naphtho[2,3-b]furans.
• 4,9-dihydroxy-naphtho[2,3-b]furans are active pharmaceutical ingredients for effective treatment of cancer and other diseases, disorders and conditions (PCT application, PCT/CN2011/000357).
• activity of 4,9-dihydroxy-naphtho[2,3-b]furans against multidrug resistance cancer has not been reported.
• the present invention relates to use of prodrug of 4,9-dihydroxy-naphtho[2,3-b]furan derivative for circumventing cancer multidrug resistance (MDR).
• the present invention also relates to use of prodrug of 4,9-dihydroxy-naphtho[2,3-b]furan derivative for the treatment of various types of cancers exhibiting multidrug resistance (MDR) phenomenon.
• the present invention further relates to use of the pharmaceutically acceptable composition comprising prodrug of 4,9-dihydroxy-naphtho[2,3-b]furan derivative and methods of using said composition in the treatment of various types of cancers exhibiting multidrug resistance (MDR) phenomenon.
• aliphatic or "aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
• halogen means F, CI, Br, or I.
• aryl used alone or as part of a larger moiety as in or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
• aryl may be used interchangeably with the term “aryl ring.”
• heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
• heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
• Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
• heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
• administer refers to either directly administering a compound or composition to a patient.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• prodrug means an agent that is converted into the parent drug in vivo.
• a prodrug is easier to administer than a parent drug.
• a prodrug has improved bioavailability by oral administration compared to the parent drug.
• Prodrugs may also have improved stability in pharmaceutical compositions over the parent drug.
• a prodrug has reduced toxicity compared to the parent drug by avoiding unnecessary exposure to unintended target tissues.
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
• systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
• terapéuticaally effective amount means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen.
• treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
• unit dose refers to a physically discrete unit of a formulation appropriate for a subject to be treated. It will be understood, however, that the total daily usage of a formulation of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• An individual who is "suffering from” a disease, disorder, and/or condition has been diagnosed with and/or displays one or more symptoms of the disease, disorder, and/or condition.
• An individual who is "susceptible to" a disease, disorder, and/or condition has not been diagnosed with the disease, disorder, and/or condition.
• 4,9-dihydroxy-naphtho[2,3-b]furans are active pharmaceutical ingredients for effective treatment of cancer and other diseases, disorders and conditions (PCT application, PCT/CN201 1/000357).
• 4,9-dihydroxy-naphtho[2,3-b]furans (I) are unstable in vitro under aerobic condition, but can be generated in vivo by hydrolyzing esters of 4,9-dihydroxy- naphtho[2,3-b]furans (II) or by reducing naphtho[2,3-b]furan-4,9-diones (III), as shown in scheme 1.
• R 1 , R 2 , R 3 , R 4 , R 5 in scheme 1 are defined as: n is 0-4; each R 1 is independently halogen; -N0 2 ; -CN; -OR; -SR; -N + (R) 3 ; -N(R) 2 ; -C(0)R; -C0 2 R;
• R a and R b are taken together with their intervening atoms to form an optionally substituted 3- to 14-membered heterocycle
• R° is hydrogen; -N(R) 2 ; -OR; -SR; or an optionally substituted group selected from Ci_i 2 aliphatic; 3- to 14-membered carbocyclyl; 3- to 14-membered heterocyclyl; 6- to 14- membered aryl; or 5- to 14-membered heteroaryl;
• Ci_i 2 aliphatic 3- to 14-membered carbocyclyl; 3- to 14-membered heterocyclyl; 6- to 14-membered aryl; or 5- to 14-membered heteroaryl; or:
• R and R are taken together with their intervening atoms to form an optionally substituted ring selected from 3- to 14-membered carbocycle or 3- to 14-membered heterocycle;
• R 4 and R 5 are taken together with their intervening atoms to form an optionally
• substituted ring selected from 3- to 14-membered carbocycle or 3- to 14-membered heterocycle; each R is independently hydrogen or an optionally substituted group selected from C 1-12 aliphatic; 3- to 14-membered carbocyclyl; 3- to 14-membered heterocyclyl; a 6- to 14- membered aryl; or 5- to 14-membered heteroaryl.
• n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
• R 1 is halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -CF 3 . In some embodiments, R 1 is -OH.
• R 4 is hydrogen. In some embodiments, R 4 is other than hydrogen. In some embodiments, R 4 is optionally substituted 6- to 14-membered aryl. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is -N(R) 2 , wherein R is independently an optionally substituted group selected from C 1-12 aliphatic or 6- to 14- membered aryl. In certain embodiments, R 5 is -N0 2 . In some embodiments, R 5 is -C(0)R, wherein R is an optionally substituted group selected from C 1-12 aliphatic or 6- to 14-membered aryl. In some embodiments, R 5 is -C(0)N(R) 2 , wherein each R is independently an optionally substituted group selected from C 1-12 aliphatic or 6- to 14-membered aryl.
• R 4 and R 5 are taken together with their intervening atoms to form an optionally substituted ring selected from 3- to 14-membered carbocycle or 3- to 14-membered heterocycle.
• R 1 is halogen, cyano, or CF 3 ; n is 0, 1, or 2; R 2 and R 3 are each independently hydrogen, isobutyryl, pivaloyl, acetyl, octanoyl, dodecanoyl, or hexanoyl; R 4 is hydrogen or -N(R) 2 ; and R 5 is -C(0)R, wherein R is an optionally substituted group selected from C 1-12 aliphatic or 6- to 14-membered aryl.
• R 1 is halogen or CF 3 ; n is 0, 1, or 2; R z and R J are each independently octanoyl; R is hydrogen; and R is -C(0)R, wherein R is optionally substituted C 1-12 aliphatic.
• compounds I, III, IV, V, and VI can indiscriminately kill regular cancer cell lines and 5-FU or taxol or doxorubicin resistance cancer cell lines.
• 5-FU resistance BEL7404 is also resistant to taxol and doxorubicin;
• Doxorubicin resistance MCF7 is also resistant to 5-FU and taxol;
• Taxol resistance A2780 is also resistant to 5-FU and doxorubicin.
• the present invention relates to, among other things, use of esters of 4,9-dihydroxy- naphtho[2,3-b]furans (II) or use of naphtho[2,3-b]furan-4,9-diones (III) for circumventing cancer multidrug resistance (MDR).
• the present invention also relates to use of esters of 4,9-dihydroxy-naphtho[2,3-b]furans (II) or use of naphtho[2,3-b]furan-4,9-diones (III) for the treatment of various types of cancers exhibiting multidrug resistance (MDR) phenomenon.
• the present invention further relates to use of the pharmaceutically acceptable composition comprising ester of 4,9-dihydroxy-naphtho[2,3-b]furan derivative (II) or naphtho[2,3-b]furan- 4,9-dione derivative (III) and method of using said composition in the treatment of various types of cancers exhibiting multidrug resistance (MDR) phenomenon.
• MDR multidrug resistance
• compositions comprise a compound of formula II or III and at least one pharmaceutically acceptable excipient or carrier or diluent.
• pharmaceutically acceptable excipient or carrier or diluent is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
• the pharmaceutically acceptable excipient or carrier or diluent includes, but not limited to, water, saline solution, dextrose solution, triacetin, human albumin or its derivative, glycerol mono-(or di-)fatty acid esters, lecithin, phospholipids (such as phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, sphingomyelin, and the like), cholesterol, PEG- phospholipids, PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, PEG-glycerol mono-(or di-)fatty acid esters, ethylene glycol mono-fatty acid esters, propylene glycol mono-fatty acid esters, 3-dialkyl(Cl-8)amino-propylene glycol di-fatty acid esters, poly(ethylene glycol) mono-fatty acid esters, stearic acid, sorbitan est
• the bulking agent includes starches or its derivatives, mannitol, lactose, maltitol, maltodextrin, maltose, dextrates, dextrin, dextrose, fructose, sorbitol, glucose, sucrose, carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, ethylcellulose, methylcellulose, other suitable cellulose derivatives, gelatin, alginic acid, and its salt, colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium aluminum silicate, povidone, benzyl phenylformate, chlorobutanol, diethyl phthalate, calcium stearate, glyceryl palmitostearate, magnesium oxide, poloxamer, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, acacia, acrylic and meth
• Formulations of a compound of formula II or III include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
• the formulation may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range, for example, from about 1% to about 99% of active ingredient, from about 5% to about about 70%, from about 10% to about 30%.
• a compound of formula II is formulated as an aqueous nanoparticle suspension prepared according to the method as described in PCT/CN2012/000190.
• the present invention provides a method of treating a subject suffering from or susceptible to a drug resistance cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of formula II or III.
• a drug resistance cancer is resistant to an approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabine, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions
• alkylating drugs
• a drug resistance cancer is resistant to certain cytotoxic or anticancer agent currently in clinical trials and which may ultimately be approved by the FDA (including, but not limited to, epothilones and analogues thereof and geldanamycins and analogues thereof).
• the drug resistance cancer is a hematological malignancy.
• the drug resistance cancer is a solid tumor.
• Exemplary drug resistance cancers that may be treated using compounds of formula II or III include colon cancer, lung cancer, bone cancer, pancreatic cancer, stomach cancer, esophageal cancer, skin cancer, brain cancer, liver cancer, ovarian cancer, cervical cancer, uterine cancer, testicular cancer, prostate cancer, bladder cancer, kidney cancer, neuroendocrine cancer, breast cancer, gastric cancer, eye cancer, nasopharyngeal cancer, gallbladder cancer, laryngeal cancer, oral cancer, penile cancer, glandular tumors, rectal cancer, small intestine cancer, head and neck cancer, multiple myeloma, colorectal carcinoma, kaposi sarcoma, ewing's sarcoma, osteosarcoma, leiomyosarcoma, glioma, meningioma, medulloblastoma, melanoma, urethral cancer, vaginal cancer, to name but a few.
• the drug resistance cancer is a re
• DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
• DMEM Dulbecco's Modified Eagle Medium
• FBS fetal bovine serum
• penicillin/streptomycin/amphotericin B imported from Invitrogen, Carlsbad, CA, USA.
• a compound of formula II or III was added to the wells at the final concentrations of 10 ⁇ , 5 ⁇ , 2.5 ⁇ , 1.25 ⁇ , or ⁇ , 0.75 ⁇ , 0.5 ⁇ and 0.25 ⁇ in complete culture medium; 5-FU was added to the wells at the final concentrations ranged from ⁇ to 10 mM; doxorubicin was added to the wells at the final concentrations ranged from 50 nM to 500 ⁇ ; and taxol was added to the wells at the final concentrations ranged from 15 nM to 40 ⁇ . Each dose level covered 4 equivalent wells.
• Test Results Compounds I, III, IV, V, and VI were tested for their activity against regular cancer cell lines and multidrug resistance (MDR) cancer cell lines, along with 5-FU, taxol, and doxorubicin. The test results are listed in the following tables.

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• 2012
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