EP2473506A2 - Composés et compositions pour le traitement du cancer - Google Patents

Composés et compositions pour le traitement du cancer

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Publication number
EP2473506A2
EP2473506A2 EP10814469A EP10814469A EP2473506A2 EP 2473506 A2 EP2473506 A2 EP 2473506A2 EP 10814469 A EP10814469 A EP 10814469A EP 10814469 A EP10814469 A EP 10814469A EP 2473506 A2 EP2473506 A2 EP 2473506A2
Authority
EP
European Patent Office
Prior art keywords
compound
cancer
independently selected
ring
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10814469A
Other languages
German (de)
English (en)
Other versions
EP2473506A4 (fr
Inventor
Michael Andrew Foley
Robert Gould
Peter Elliot
Anna Mandinova
Sam Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
General Hospital Corp
Canthera Therapeutics Inc
Original Assignee
Canthera Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Canthera Therapeutics Inc filed Critical Canthera Therapeutics Inc
Publication of EP2473506A2 publication Critical patent/EP2473506A2/fr
Publication of EP2473506A4 publication Critical patent/EP2473506A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to compounds and composition for the treatment and prevention of cancer.
  • the invention also covers all diseases that may be treated by selective modulation of levels of reactive oxygen species in diseased cells versus normal cells. Methods for the preparation and administration of such compositions are also disclosed.
  • the present invention relates to compounds and compositions for the treatment and prevention of cancer, or decreasing the intensity or duration of cancer.
  • the invention also covers all diseases that may be treated by selective modulation of levels of reactive oxygen species in diseased cells versus normal cells.
  • ROS reactive oxygen species
  • OS oxidative stress
  • Cells are exposed to both endogenous and exogenous sources of ROS.
  • ROS can lead to impaired physiological function through cellular damage of DNA, proteins, lipids, and other macromolecules, which can lead to certain human pathologies including cancers, neurodegenerative disorders, and cardiovascular disease, as well as aging.
  • ROS are important in mediating apoptosis.
  • Selectively increasing levels of ROS in cancer cells and not normal cell may be a safe and effective method for treating cancer.
  • ROS Reducing ROS leads to treatment of neurodegenerative diseases, inflammation and for the treatment of a broad range of disorders including, neurodegenerative diseases, chronic inflammatory diseases, inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure and skin disease.
  • neurodegenerative diseases chronic inflammatory diseases
  • inflammatory bowel disease rheumatoid arthritis
  • psoriasis multiple sclerosis
  • endotoxin shock osteoporosis
  • Alzheimer's disease congestive heart failure and skin disease.
  • the present invention encompasses compounds having the following formula IA, or salts, derivatives, or mixtures thereof:
  • Ring A is selected from the group consisting of one or more monocyclic aryl, one or more heteroaryl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8- 10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated
  • each R 1 , R2 , and R 3 is independently selected from the group consisting of hydrogen, halogen, deuterium, CF 3 , CN, OR, SR, NRR, NRCOR, NRCONRR, NRC0 2 R, COR, C0 2 R, NOR, N0 2, CONRR, OC(0)NRR, S0 2 R, S0 2 NRR, NRS0 2 R, NRS0 2 NRR, C(0)C(0)R, or C(0)CH 2 C(0)R, alkyl, aryl, heteroaryl and morpholino,
  • R 1 and R 2 , or R 2 and R 3 are optionally taken together to form a 4-8 membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R is independently selected from hydrogen or an optionally substituted C C 4 aliphatic moiety, wherein: or alternately, two R moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated, partially unsaturated, or fully unsaturated ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • B is selected from:
  • R4, R5, R6 and R7 are independently selected from a substituted or unsubstituted Ci to C 12 alkyl, a substituted or unsubstituted Ci to C 12 alkenyl or a substituted or unsubstituted Ci to Ci 2 alkynyl;
  • X is O, S;
  • C is a saturated or unsaturated heteroaryl or a saturated or unsaturated CI to C7 heterocyclic containing one or more hetero atoms wherein the heteroatoms are independently selected from N, O or S;
  • any one or more H is optionally replaced by a deuterium.
  • the compounds of the present invention may be produced using piperlongumine as a starting material yet offer numerous advantages over piperlongumine.
  • piperlongumine in the course of the experimental investigations, it was found that more than 0.25 mg/ml of piperlongumine in DMSO was precipitated out when diluted 1: 10 inphosphate buffered saline or water. It was also found that piperlongumine is soluble in water at 0.1 mg/mL.
  • the compounds of the instant invention are highly soluble in water at concentration of at least 25mg/mL facilitating pharmaceutical preparation and delivery.
  • chemotherapeutic agents transiently increase ROS levels in both cancer cells and normal cells.
  • the compounds of the instant invention have a large therapeutic window and do not increase ROS or cause DNA damage in normal cells.
  • the drug is comparable in its effect on net cancer cell growth (melanoma, ovarian, renal, glioblastoma, drug- resistant non-small cell lung cancer cell lines) as a percent of control.
  • FIG. 1 shows the effect of compounds on pancreatic cells
  • FIG. 2 shows viability of normal breast epithelium in the presence of compounds of the invention.
  • FIG. 3 shows the effect of compounds on EJ Bladder Carcinoma cells
  • FIG. 4 shows the effect of compounds on pancreatic cells
  • FIG. 5 shows the effect of SP2007 and SP83 on bladder tumor xenograft-bearing mice
  • alkyl alkenyl, alkoxy, alkylene, alkenylene, alkenyl, alkyl(arylene)", “alkynyl”, and “aryl(alkylene)” include, but are not limited to, linear and branched alkyl, alkenyl, alkoxy, alkylene, alkenylene, alkyl(arylene), and aryl(alkylene) groups, respectively.
  • phrases “pharmaceutically acceptable” refers to compounds or compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a mammal.
  • an “effective amount of compound” means the amount of compound, salt or salts, or (including its solvates, active metabolites, prodrugs, or racemates or enantiomers thereof (assuming the salt has a chiral center)) that, when administered to a mammal for treating or preventing a state, disorder or condition is sufficient to effect such treatment or prevention.
  • the "effective amount” will vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • a therapeutically effective amount of a compound is an amount effective to treat any one of the above mentioned disorders.
  • the compound or its salt or salts may be augmented with a second medication (such as a chemotherapeutic agent, or adjunctive chemotherapeutic agent to treat any of the aforementioned disorders, such as malignancies).
  • an "effective amount of the pharmaceutical formulation” is an amount of the pharmaceutical formulation described which is effective to treat or prevent a condition in a subject to whom it is administered over some period of time, e.g., provides a therapeutic effect during a desired dosing interval.
  • an effective amount of the pharmaceutical formulation includes amounts of compound its salt or salts to treat or prevent the desired condition over a desired period of time.
  • treat includes one or more of the following:
  • treat also includes prophylactically preventing, curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting a condition (e.g., a disease), the symptoms of the condition, or the predisposition toward the condition.
  • a condition e.g., a disease
  • sustained release refers to the release of an active ingredient over an extended period of time leading to lower peak plasma concentrations and a prolonged T max as compared to "immediate release” formulations of the same active ingredient.
  • bioavailability refers to the rate and extent to which the active ingredient (compound its salt or salts) or active moiety is absorbed from a drug product and becomes systematically available.
  • polymorph refers to crystallographically distinct forms of a substance.
  • hydrate as used herein includes, but is not limited to, (i) a substance containing water combined in the molecular form and (ii) a crystalline substance containing one or more molecules of water of crystallization or a crystalline material containing free water.
  • solvate as used herein includes, but is not limited to, a molecular or ionic complex of molecules or ions of a solvent with molecules or ions of a compound or its salt or salts.
  • adjunctive chemotherapeutic agent includes agents which treat, alleviate, relieve, or amelliorate the side effects of chemo therapeutic agents. Such agents include those which modify blood cell growth and maturation. Examples of adjunctive chemotherapeutic agents include, but are not limited to, filgrastim and erythropoietin.
  • salt includes compound salt or salts, complexes and active metabolites, prodrugs, racemates, enantiomers, and hydrates thereof.
  • chemotherapeutic agent includes any agent which treats, prevents, cures, heals, alleviates, relieves, alters, remedies, ameliorates, improves, or affects malignancies and their metastasis. Examples of such agents (also known as statin), doxifen, doxifen, doxifen, doxifen, doxifen, doxifen, doxifen, doxifen, doxifen, doxifen, doxa, doxedoxe, doxe, doxe, doxe, remedies, ameliorates, improves, or affects malignancies and their metastasis. Examples of such agents (also known as
  • anti-plastic agents include, but are not limited to, prednisone, fluorouracil (e.g., 5- fluorouracil (5-FU)), anastrozole, bicalutamide, carboplatin, cisplatin, chlorambucil, docetaxel, doxorubicin, flutamide, interferon-alpha, letrozole, leuprolide, megestrol, mitomycin, paclitaxel, plicamycin (Mithracin.TM.), tamoxifen, thiotepa, topotecan, valrubicin, vinvlastin, vincristine, and any combination of any of the foregoing. Further examples are provided herein.
  • 'Hydrogen or “H” includes any form of hydrogen, including deuterium.
  • the present invention provides compounds and compositions which treat and prevent cancer.
  • Compounds of the present invention include those having the following formula
  • Ring A is selected from the group consisting of one or more monocyclic aryl, one or more heteroaryl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8 10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R 1 , R2 , and R 3 is independently selected from the group consisting of hydrogen, halogen, deuterium, CF 3 , CN, OR, SR, NRR, NRCOR,
  • R 1 and R 2 , or R 2 and R 3 are optionally taken together to form a 4-8 membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently selected from hydrogen or an optionally substituted C C 4 aliphatic moiety (i.e. alkyl, alkenyl, or alkynyl), wherein:
  • two R moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated, partially unsaturated, or fully unsaturated ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • B is selected from:
  • R4, R5, R6 and R7 are independently selected from a substituted or unsubstituted Ci to C 12 alkyl, a substituted or unsubstituted Ci to C 12 alkenyl or a substituted or unsubstituted Ci to Ci 2 alkynyl;
  • X is O, S;
  • C is a saturated or unsaturated heteroaryl or a saturated or unsaturated CI to C7 heterocyclic containing one or more hetero atoms wherein the heteroatoms are independently selected from N, O or S;
  • any one or more H is optionally replaced by a deuterium.
  • the compounds of the invention are compounds of Formula I above wherein ring A is selected from:
  • ring carries Rl, R2 and R3 as defined above; wherein Y is N, O or S; and
  • C is selected from:
  • R 10 and R 11 are independently selected from a substituted or unsubstituted Ci to C 12 alkyl, a substituted or unsubstituted Ci to C 12 alkenyl or a substituted or unsubstituted Ci to C 12 alkynyl, an ether, a thioether, aryl, n is 1, 2 or 3;
  • Xi is O or S
  • the compound of formula I is represented by the following compounds:
  • the compounds of the present invention interact with proteins to increase ROS in cancer cells but not in normal cells. In one embodiment, the compounds of the present invention increase phosphor- JNK levels. In one embodiment, the compounds of the present invention increase p53 activity. In one embodiment, the compounds of the present invention increase p21 activity. In one embodiment, the compounds of the present invention decrease pro- survival gene activity. In one embodiment, the compounds of the present invention induce apoptosis in cancer cell lines.
  • the one or more compounds of the instant invention are used to treat cancer.
  • Another embodiment includes a method for increasing apoptosis by administering a compound of the instant invention.
  • Another embodiment includes a method for increasing p53 activity by administering one or more compounds of the instant invention.
  • Another embodiment includes a method for increasing p21 activity by administering one or more compounds of the instant invention.
  • Another embodiment includes a method of preferentially inducing DNA damage in cancer cells by
  • Another embodiment is a method of suppressing DNA damage in normal cells by administering one or more compounds of the instant invention.
  • the invention provides a method for improving the expression of proteins associated with normal cell survival. In another embodiment, the invention provides for a method of sparing normal cells while killing cancer cells.
  • the invention provides a method of administering a compound of the instant invention at a dose of about lOOmg/kg to about 3000mg/kg. In another embodiment the invention provides a method of administering a compound of the instant invention at a dose of about 2.5 mg/kg to about lOmg/kg. In some embodiments, a therapeutically effective amount is less than 50 mg/kg, such as less than 45 mg/kg, less than 40 mg/kg, less than 35 mg/kg, less than 30 mg/kg, less than 25 mg/kg, less than 20 mg/kg or less than 15 mg/kg.
  • a therapeutically effective amount is less than 10 mg/kg, such as less than 9 mg/kg, less than 8 mg/kg, less than 7 mg/kg, less than 6 mg/kg, less than 5 mg/kg, less than 4 mg/kg, less than 3 mg/kg or less than 2 mg/kg.
  • a therapeutically effective amount is less than 1.5 mg/kg, such as less than 1.4 mg/kg, less than 1.3 mg/kg, less than 1.2 mg/kg, less than 1.1 mg/kg, less than 1 mg/kg, less than 0.9 mg/kg, less than 0.8 mg/kg, less than 0.7 mg/kg, less than 0.6 mg/kg, less than 0.5 mg/kg, less than 0.4 mg/kg, less than 0.3 mg/kg, less than 0.2mg/kg or less than 0.1 mg/kg.
  • the invention provides a method for inhibiting cell proliferation.
  • the method for inhibiting cell proliferation comprises contacting a cell with an effective amount of a composition comprising a compound of the invention to inhibit the proliferation of the cell.
  • the method further comprises contacting the cells with a compound of the invention and a chemotherapeutic agent.
  • the invention provides a method for increasing apoptosis of a cell or in a population of cells.
  • the method for increasing apoptosis of a cell or in a population of cells the method comprises contacting the cell or population of cells with an effective amount of a composition comprising a compound of the invention to increase apoptosis in the cell or population of cells.
  • the number of apoptotic cells in a population of cells is increased by at least two-fold. In some embodiments, the number of apoptotic cells in a population of cells is increased by at least five-fold. In some embodiments, the number of apoptotic cells in a population of cells is increased by at least ten-fold. In some embodiments, the method further comprises contacting the cells with a compound of the invention and a chemotherapeutic agent.
  • one or more compounds of the instant invention are administered with one or more chemotherapeutic agent. In another embodiment, one or more compounds of the instant invention are administered prior to one or more chemotherapeutic agents. In another embodiment, one or more compounds of the instant invention are administered following one or more chemotherapeutic agents.
  • Chemotherapeutic agents include, but are not limited to an agent which is administered to a subject for the purpose of treating a cancer.
  • Chemotherapeutic agents include, but are not limited to antiproliferative compounds, anti-neoplastic compounds, anti-cancer supplementary potentiating agents and radioactive agents.
  • One of ordinary skill in the art is familiar with a variety of chemotherapeutic agents, or can find those agents in the routine art, which are used in the medical arts to treat cancer.
  • Chemotherapeutic agents include, but are not limited to, the following sub-classes of compounds: Antineoplastic agents such as: Acivicin; Aclarubicin; Acodazole
  • Droloxifene Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate;
  • Eflornithine Hydrochloride Elsamitrucin; Enloplatin; Enpromate; Epipropidine;
  • Idarubicin Hydrochloride Ifosfamide; Ilmofosine; Interferon Alfa-2a; Interferon Alfa- 2b; Interferon Alfa-nl; Interferon Alfa-n3; Interferon Beta-la; Interferon Gamma-lb;
  • Liarozole Hydrochloride 5 Lometrexol Sodium; Lomustine; Losoxantrone
  • Mitogillin Mitomalcin; Mitomycin,. Mitosper; Mitotane; Mitoxantrone Hydrochloride;
  • Spirogermanium Hydrochloride Spiromustine; Spiroplatin; Streptonigrin; Streptozocin;
  • Testolactone Thiamiprine; Thioguanine; Thiotepa; Thymitaq; Tiazofurin; Tirapazamine;
  • Vinblastine Sulfate Vincristine; Vincristine Sulfate, Vindesine; Vindesine Sulfate;
  • Vinepidine Sulfate Vinglycinate Sulfate; Vinleursine Sulfate; Vinorelbine Tartrate;
  • Anti-neoplastic compounds include, but are not limited to 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclanibicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antogonists; altretamine; ambamustine; amidox;
  • amifostine aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
  • benzochlorins benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene;
  • bisaziridinylspermine bisnafide; bistratene A; bizelesin; breflate; bropirimine;
  • clomifene analogues clotrimazole; collismycin A; collismycin 13; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;
  • cryptophycin A derivatives curacin A; cyclopentanthraquinones; cycloplatam;
  • cypemycin cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab;
  • decitabine dehydrodidemnin 10 deslorelin; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol; dioxamycin; diphenyl spiromustine; discodermolide; docosanol; dolasetron;
  • edelfosine edrecolomab; eflornithine; elemene; emitefur; epirubicin; epothilones; epithilones; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide; etoposide 4'-phosphate (etopofos); exemestane; fadrozole;
  • isohomohalicondrin B isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone;
  • leuprorelin leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine;
  • lometrexol lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
  • masoprocol maspin
  • matrilysin inhibitors maspin
  • matrix metalloproteinase inhibitors masoprocol inhibitors
  • menogaril menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor;
  • mifepristone miltefosine; mirimostim; mismatched double stranded RNA; mithracin; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone;mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin;monophosphoryl lipid A + myobacterium cell wall sk; mopidamol; multiple drug resistancegene inhibitor, multiple tumor suppressor 1 -based therapy; mustard anticancer agent;15 mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline;N-substituted benzamides; nafarelin; nagrestip; naloxone
  • oxaliplatin oxaunomycin
  • paclitaxel analogues paclitaxel derivatives
  • palauamine oxaliplatin
  • palmitoylrhizoxin pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;
  • perflubron perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
  • placetin B plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; podophyllotoxin; porfimer sodium; porfiromycin; propyl bis- acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
  • pyrazoloacridine pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; Sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran;
  • sobuzoxane sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; 5 sparfosic acid; spicamycin D; spiromustine; splenopentin;
  • spongistatin 1 squalamine
  • stem cell inhibitor stem-cell division inhibitors
  • stipiamide stromelysin inhibitors
  • sulfinosine superactive vasoactive intestinal peptide antagonist
  • suradista suramin
  • swainsonine synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium;
  • telomerase inhibitors temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thalidomide; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene dichloride; topotecan;
  • topsentin toremifene; totipotent stem cell factor; translation inhibitors; tretinoin;
  • triacetyluridine triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine;
  • vinxaltine vitaxin
  • vorozole zanoterone
  • zeniplatin zilascorb
  • zinostatin stimalamer
  • Anti-cancer supplementary potentiating agents include, but are not limited to, Tricyclic anti-depressant drugs (e.g., imipramine, desipramine, amitryptyline, clomipramine, trimipramine, doxepin, nortriptyline, pro trip tyline, amoxapine and maprotiline); non- tricyclic anti-depressant drugs (e.g., sertraline, trazodone and citalopram); Ca2+ antagonists (e.g., verapamil, nifedipine, nitrendipine and caroverine); Calmodulin inhibitor (e.g. prenylamine, trifluoroperazine and clomipramine); Amphotericin B; Triparanol analogues (e.g. tamoxifen); antiarrhythmic drugs (e.g., quinidine);
  • Tricyclic anti-depressant drugs e.g., imipramine, desi
  • antihypertensive drugs e.g. reserpine
  • Thiol depleters e.g., buthionine and sulfoximine
  • Multiple Drug Resistance reducing agents such as Cremaphor EL.
  • the compounds of the invention also can be administered with cytokines such as granulocyte colony stimulating factor.
  • Radioactive agents include but are not limited to Fibrinogen 1 125;
  • the compounds of the instant invention are efficacious in the treatment and/or prevention of a broad range of cancers.
  • cancers include but are not limited to lung cancer, bladder cancer, melanoma, bladder carcinoma, pancreatic cancer, breast cancer.
  • the invention provides methods for the treatment of cancer.
  • Carcinomas are malignant cancers that arise from epithelial cells and include adenocarcinoma and squamous cell carcinoma.
  • Sarcomas are cancer of the connective or supportive tissue and include osteosarcoma, chondrosarcoma and gastrointestinal stromal tumor.
  • Hematopoietic cancers such as leukemia, are able to outcompete the normal hematopoietic
  • cancer includes the following types of cancer, breast cancer, biliary tract cancer; bladder cancer; brain cancer including glioblastomas and
  • meduUoblastomas cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric cancer; hematological neoplasms including acute lymphocytic and myelogenous leukemia; T-cell acute lymphoblastic leukemia/lymphoma; hairy cell leukemia; chromic myelogenous leukemia, multiple myeloma; AIDS-associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms including Bowen's disease and Paget's disease; liver cancer; lung cancer; lymphomas including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer including squamous cell carcinoma; ovarian cancer including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate cancer; rectal cancer; sarcomas including leiomyosar
  • the compounds may be in the form of the carboxylic acid and/or their salts.
  • Salts include but are not limited to organic and inorganic salts, for example alkali-metal salts, such as sodium, potassium and lithium; alkaline-earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids such as lysine or arginine; and organic amines, such as dimethylamine or pyridine.
  • the salts are tartrate and will be hydrochloride salts.
  • the salts may be mono- or multi-valent salts, such as monosodium salts and di-sodium salts.
  • the salts may also be solvates including ethanol solvates.
  • the compounds described herein can be readily prepared synthetically by methods described herein.
  • the compounds may be prepared as in Example 1.
  • Other methods of preparation are known to those skilled in the art and are found, for example in Synthesis of diverse analogues of Oenostacin and their antibacterial activities (Vandana, Bioorganic & Medicinal Chemistry 15 (2007) 518-525); A Simple Regio selective Demethylation of p-Aryl Methyl Ethers Using Aluminum Chloride- Dichloromethane System (Negi, Synthetic Communications, 35: 15-21, 2005); Antiplatelet Activities of Newly Synthesized Derivatives of Pipeiiongumine (Park, Phytother, Res.
  • Salts of the present compound may be made by methods known in the art. For example, sodium salts may be made by dissolving the compound in ethanol and adding aqueous sodium hydroxide. Hydrochloride and Tartrate salts are prepared as described in Examples 1 and 2.
  • Scheme I represents the preparation of Compound 1 and its tartaric acid salt.
  • the compounds of the present invention exert their therapeutic effect by reducing oxidative stress and thereby reducing damage to DNA in normal cells while increasing ROS levels in cancer cells.
  • ROS Reactive oxygen species
  • GSTPl inhibits JNK phosphorylation by sequestering the JNK-c-JUN complex. Stressor triggers oligomeraization of GSTPl and results in dissociation of the JNK-c-JUN complex. JNK can then become phosphorylated and activate downstream kinase and transcription factors.
  • ROS Reactive oxygen species
  • EJ Bladder Carcinoma cells have been shown to be increased in, for example, EJ Bladder Carcinoma cells, Breast Carcinoma cells, and removal of GSTJI has been shown to block the increase in ROS.
  • SP2007 has been shown to increase ROS in cancer cells and causes apoptosis.
  • Other compounds of this invention have been shown to be efficacious in vivo against pancreatic cancer cells, breast epithelium and EJ Bladder cancer cells.
  • compounds of the instant invention are superior to the traditional Piper longum parent molecule in that the compounds are highly soluble.
  • the parent Piper longum can dissolve only in quantities of 0.1 mg/ml in water, much larger quantities of compounds of the present invention are soluble in water.
  • the tartrate salt of compound one of the present invention is soluble at lOOmg/ml of water.
  • the administration compositions may alternately be in the form of a solid, such as a tablet, capsule or particle, such as a powder or sachet.
  • Solid dosage forms may be prepared by mixing the solid form of the compound with the solid form of the active agent. Alternately, a solid may be obtained from a solution of compound and active agent by methods known in the art, such as freeze drying, precipitation, crystallization and solid dispersion.
  • the amount of compound used in an administration composition of the present invention is an amount effective to accomplish the purpose of the particular compound. However, the amount can be less than that amount when the composition is used in a dosage unit form because the dosage unit form may contain a plurality of compound compositions or may contain a divided pharmacologically, biologically, therapeutically, or chemically effective amount. The total effective amount can then be administered in cumulative units containing, in total, an effective amount of the active agent.
  • the total amount of compound to be used can be determined by methods known to those skilled in the art.
  • the presently disclosed compounds may be in any dosage form known to those skilled in the art, particularly suitable for oral, intranasal, sublingual, intraduodenal, subcutaneous, buccal, intracolonic, rectal, vaginal, mucosal, pulmonary, transdermal, intradermal, parenteral, intravenous, intramuscular, intrathecal, intraperitoneal and ocular administrations, as well as traversing the blood-brain barrier.
  • the compounds may also be prepared for injections, either by infusion into a vein or artery or injected into the peritoneum, bladder, or directly into tumors. Topical preparations such as creams, ointments, gels, lotions or transdermal patches are contemplated dosage forms.
  • Dosage unit forms can also include any one or combination of excipients, diluents, disintegrants, lubricants, plasticizers, colorants, flavorants, taste-masking agents, sugars, sweeteners, salts, and dosing vehicles, including, but not limited to, water, 1,2- propane diol, ethanol, olive oil, or any combination thereof.
  • the compounds and compositions of the subject invention are useful for administering biologically or chemically active agents to any animals, including but not limited to birds such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and particularly humans; and insects.
  • the compounds of the invention can be administered to animal and man, directly or together with a vehicle commonly used.
  • the dose form is not particularly limited, and is selected appropriately as needed on use, including oral drugs such as tablets, capsules, granules, grains and powder, or non-oral drugs such as injection and suppository.
  • the oral drugs are prepared by ordinary methods, using starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, or inorganic salts.
  • a binder In the drugs of this type, use can be made of a binder, a disintegrator, a surfactant, a lubricant, a fluidity-promoting agent, a flavor, a tinction, a perfume and the like, in addition to the vehicle mentioned above.
  • a disintegrator In the drugs of this type, use can be made of a binder, a disintegrator, a surfactant, a lubricant, a fluidity-promoting agent, a flavor, a tinction, a perfume and the like, in addition to the vehicle mentioned above.
  • a surfactant In the vehicles of this type, use can be made of a binder, a disintegrator, a surfactant, a lubricant, a fluidity-promoting agent, a flavor, a tinction, a perfume and the like, in addition to the vehicle mentioned above.
  • a fluidity-promoting agent a flavor, a tinction, a perfume and the like
  • Binder Starch, dextrin, powdered acasia, gelatin, hydroxypropylstarch, methylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, and macrogol.
  • Disintegrator Starch, hydroxypropylstarch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, and low-substituted
  • Surfactant Sodium laurylsulfate, soybean lecithin, succharose fatty acid ester, and polysorbate 80.
  • Lubricant Talc, waxes, hydrogenated vegetable oil, succharose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol.
  • Fluidity-Promoting Agent Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
  • the compounds of the present invention can also be administered in the form of suspension, emulsion, syrup or elixir.
  • These forms of drugs may also contain flavor, perfume and tinction.
  • the non-oral drugs can be prepared by ordinary methods, and use may be made of an attenuant such as distilled water for injection, physiological saline, aqueous solution of glucose, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, or polyethylene glycol. If necessary, germicide, preservative, and stabilizer may be added.
  • the non-oral drugs can be filled in a vial or the like and frozen, and then be removed of water by the ordinary freeze-dry technique. A liquid drug can be reformulated from the freeze-dried drug immediately before administration. Further, an isotonic, a stabilizer, a preservative, an antiseptic, a sedative, and the like may be added.
  • compositions comprising the compounds have utility in the treatment of cancer.
  • the Intermediate was prepared as in Example 1 and the procedure for the de-boc step to form the by product is as follows. To a solution of BPS-02085 (about 35 mg) in menthol (5.0ml) was bubled HCl(g) for 15 minutes at room temperature (20° C). The solvent was removed in vacuo and the residue was purified by TLC
  • Figures 1-4 show in-vivo efficacy of the compounds against pancreatic cancers cells, breast epithelium and EJ Bladder Cancer Cells.
  • mice Four nude/nude mice weighing approximately 0.02 Kg were fasted overnight and anestatized with Avertin (2,2,2, Tribromoethanol), 250mg/kg, body weight; IP injection. A total 2 x 106 EJ cells (acquired from Japanese cellbank) were implanted

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Abstract

L'invention concerne des composés et une composition pour le traitement et la prévention contre le cancer. L'invention recouvre également toutes les maladies qui peuvent être traitées par modulation sélective de niveaux d'espèces réactives de l'oxygène dans des cellules malades par rapport à des cellules normales. L'invention concerne également des procédés pour la préparation et l'administration de telles compositions.
EP10814469A 2009-09-02 2010-09-02 Composés et compositions pour le traitement du cancer Withdrawn EP2473506A4 (fr)

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GB201715008D0 (en) * 2017-09-18 2017-11-01 Inst De Medicina Molecular Faculdade De Medicina Univ De Lisboa TRPV2 Antagonists
KR20200081633A (ko) 2018-12-27 2020-07-08 주식회사 티에스디라이프사이언스 피퍼롱구민을 함유하는 담도폐쇄증 치료 또는 예방용 의약 조성물
CN110002987B (zh) * 2019-03-22 2020-09-15 南通大学 苯基亚烯丙基环己烯酮衍生物及制备方法和用途

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HUANG: "A facile and highly stereoselective synthesis of (2E)-, (2E,4E)-unsaturated amides and related natural products", TETRAHEDRON LETTERS, vol. 28, no. 19, 1 January 1987 (1987-01-01), pages 2159-2162, XP055050870, DOI: 10.1016/S0040-4039(00)96069-6 *
See also references of WO2011028860A2 *

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CA2772614A1 (fr) 2011-03-10
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CN102625805A (zh) 2012-08-01
KR20120104165A (ko) 2012-09-20
WO2011028860A2 (fr) 2011-03-10
JP2013503888A (ja) 2013-02-04
AU2010289493A1 (en) 2012-04-19
EP2473506A4 (fr) 2013-03-06

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