Methods and compositions for the treatment of cancer using benzopyrone-type PARP inhibitors
First Claim
Patent Images
1. A method of treating a cancer comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
- wherein n=0-10;
R1, R2, R3, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl; and
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen;
wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, Castleman'"'"'s disease, cervical cancer, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
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Abstract
The present invention provides compositions of matter, kits and methods for their use in the treatment of cancer. In particular, the invention provides compositions and methods for treating cancer in a subject by inhibiting a poly-ADP-ribose polymerase, as well as providing formulations and modes of administering such compositions.
116 Citations
248 Claims
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1. A method of treating a cancer comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
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wherein n=0-10;
R1, R2, R3, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl; and
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen;wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, Castleman'"'"'s disease, cervical cancer, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia. - View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)
wherein R5 is selected from the group consisting of hydrogen, carboxyl, amino, nitroso, nitro, hydroxylamino, and hydroxy; and
X is selected from the group consisting of halogen, hydroxy, optionally substituted (C1-C7) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl.
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4. The method of claim 3, wherein X is a halogen selected from the group consisting of F, Cl, Br and I.
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5. The method of claim 3, wherein X is iodine (I) and R5 is nitro, nitroso, hydroxylamino, hydroxyl, or amino.
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6. The method of claim 3, wherein n is 0.
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7. The method of claim 3, wherein the optionally substituted alkyl is substituted with a substituent selected from the group consisting of alkylamine, pyrrole, dihydropyrrole, and pyrrolidene.
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8. The method of claim 3, wherein the compound is of the formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIk, IIIl, IIIm, or IIIn, or one of their pharmaceutically acceptable salts or prodrugs:
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9. The method of claim 8, wherein the compound is 5-iodo-6-nitro-benzopyrone of Formula IIIg, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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10. The method of claim 8, wherein the compound is 5-iodo-6-amino-benzopyrone of Formula IIIk, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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11. The method of claim 8, wherein the compound is 5-iodo-6-nitroso-benzopyrone of Formula IIIl, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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12. The method of claim 8, wherein the compound is 5-iodo-6-hydroxylamino-benzopyrone of Formula IIIm, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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13. The method of claim 3, wherein the optionally substituted (C3-C7) heterocyclic is a five membered heterocyclic ring or a six membered heterocyclic ring.
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14. The method of claim 13, wherein the optionally substituted (C3-C7) heterocyclic contains at least one nitrogen.
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15. The method of claim 13, wherein the optionally substituted (C3-C7) heterocyclic is selected from the group consisting of azeridine, azetidine, pyrrole, dihydropyrrole, pyrrolidene, pyrazole, pyrazoline, pyrazolidine, imidazole, benzimidazole, triazole, tetrazole, oxazole, isoxazole, benzoxazole, oxadiazole, oxazoline, oxazolidine, thiazole, isothiazole, pyridine, dihydropyridine, tetrahydropyridine, quinazoline, pyrazine, pyrimidine, pyridazine, quinoline, isoquinoline, triazine, tetrazine, and piperazine.
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16. The method of claim 13, wherein the optionally substituted (C3-C7) heterocyclic is substituted with a substituent selected from the group consisting of optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, and optionally substituted aryl.
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17. The method of claim 1 or 2 further comprising surgery, radiation therapy, chemotherapy, gene therapy, RNA therapy, immunotherapy, nanotherapy or a combination thereof.
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18. The method of claim 1 or 2 further comprising administering an effective amount of an anti-tumor agent.
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19. The method of claim 1 or 2 further comprising administering an effective amount of an organoplatinum compound.
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20. The method of claim 1 or 2 further comprising administering an effective amount of an anti-metabolite compound.
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21. The method of claim 1 or 2 further comprising administering an effective amount of oxaliplatin (OX).
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22. The method of claim 1 or 2 further comprising administering an effective amount of gemcitabine (GEM).
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23. The method of claim 1 or 2 further comprising administering an effective amount of OX and GEM.
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24. The method of claim 1 or 2 wherein the administration is intravenous or intraperitoneal.
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25. The method of claim 1 or 2 wherein the administration is orally.
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26. The method of claim 1 or 2 wherein a poly-ADP-ribose polymerase (PARP) is inhibited by the compound in the subject.
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27. The method of claim 1 or 2 wherein mono-ADP ribosylation and poly-ADP ribosylation are inhibited.
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28. The method of claim 1 or 2 wherein a tumor cell undergoes apoptosis, cell cycle arrest, and/or necrosis in the subject.
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29. The method of claim 1 or 2 wherein the subject expresses a detectable level of PARP protein.
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30. The method of claim 1 or 2 wherein the subject has a detectable level of mono-ADP ribosylation and poly-ADP ribosylation.
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2. A method of treating a cancer comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
wherein n=0-10;
R1, R2, R3, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl; and
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen;wherein said cancer is a cancer formed at a different site of a body as a result of migration of a cell from a cancer selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, Castleman'"'"'s disease, cervical cancer, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
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31. A method of treating a cancer comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
wherein n=0-10;
R1, R2, R3, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl;
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen; and
wherein at least one of the R1, R2, R3, R4, and R5 substituents is always a substituted cycloalkyl, a substituted heterocyclic, or a substituted phenyl;wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, Castleman'"'"'s Disease, cervical cancer, childhood Non-Hodgkin'"'"'s lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, Kaposi'"'"'s sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin'"'"'s lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia. - View Dependent Claims (32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63)
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46. The method of claim 31, wherein the optionally substituted (C3-C7) heterocyclic is a five membered heterocyclic ring or a six membered heterocyclic ring.
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47. The method of claim 31, wherein the optionally substituted (C3-C7) heterocyclic contains at least one nitrogen.
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48. The method of claim 31, wherein the optionally substituted (C3-C7) heterocyclic is selected from the group consisting of azeridine, azetidine, pyrrole, dihydropyrrole, pyrrolidene, pyrazole, pyrazoline, pyrazolidine, imidazole, benzimidazole, triazole, tetrazole, oxazole, isoxazole, benzoxazole, oxadiazole, oxazoline, oxazolidine, thiazole, isothiazole, pyridine, dihydropyridine, tetrahydropyridine, quinazoline, pyrazine, pyrimidine, pyridazine, quinoline, isoquinoline, triazine, tetrazine, and piperazine.
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49. The method of claim 31, wherein the optionally substituted (C3-C7) heterocyclic is substituted with a substituent selected from the group consisting of optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, and optionally substituted aryl.
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50. The method of claim 31 further comprising surgery, radiation therapy, chemotherapy, gene therapy, RNA therapy, immunotherapy, nanotherapy or a combination thereof.
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51. The method of claim 31 further comprising administering an effective amount of an anti-tumor agent.
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52. The method of claim 31 further comprising administering an effective amount of an organoplatinum compound.
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53. The method of claim 31 further comprising administering an effective amount of an anti-metabolite compound.
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54. The method of claim 31 further comprising administering an effective amount of oxaliplatin (OX).
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55. The method of claim 31 further comprising administering an effective amount of gemcitabine (GEM).
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56. The method of claim 31 further comprising administering an effective amount of OX and GEM.
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57. The method of claim 31, wherein the administration is intravenous or intraperitoneal.
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58. The method of claim 31, wherein the administration is orally.
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59. The method of claim 31, wherein a poly-ADP-ribose polymerase (PARP) is inhibited by the compound in the subject.
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60. The method of claim 31, wherein mono-ADP ribosylation and poly-ADP ribosylation are inhibited.
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61. The method of claim 31, wherein a tumor cell undergoes apoptosis, cell cycle arrest, and/or necrosis in the subject.
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62. The method of claim 31, wherein the subject expresses a detectable level of PARP protein.
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63. The method of claim 31, wherein the subject has a detectable level of mono-ADP ribosylation and poly-ADP ribosylation.
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64. A method of treating a cancer comprising administering to a subject in need thereof an effective amount of a composition comprising an anti-tumor agent and a compound of formula (I), or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
wherein n=0-10;
R1, R2, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl; and
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen.- View Dependent Claims (65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98)
wherein R5 is selected from the group consisting of hydrogen, carboxyl, amino, nitroso, nitro, hydroxylamino, and hydroxy; and
X is selected from the group consisting of halogen, hydroxy, optionally substituted (C1-C7) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl.
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66. The method of claim 65, wherein the compound is of the formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIk, IIIl, IIIm, or IIIn, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
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67. The method of claim 66, wherein the compound is 5-iodo-6-nitro-benzopyrone of Formula IIIg, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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68. The method of claim 66, wherein the compound is 5-iodo-6-amino-benzopyrone of Formula IIIk, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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69. The method of claim 66, wherein the compound is 5-iodo-6-nitroso-benzopyrone of Formula IIIl, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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70. The method of claim 66, wherein the compound is 5-iodo-6-hydroxylamino-benzopyrone of Formula IIIm, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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71. The method of claim 64, wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, Castleman'"'"'s Disease, cervical cancer, childhood Non-Hodgkin'"'"'s lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, Kaposi'"'"'s sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin'"'"'s lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
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72. The method of claim 64, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, brain cancer, skin cancer, colon cancer, or a cancer derived from cancer stem cells.
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73. The method of claim 64, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2.
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74. The method of claim 64, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2; and
wherein the breast cancer is positive for at least one of ER, PR or HER2.
- ER, PR or HER2; and
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75. The method of claim 64, wherein the breast cancer is negative for two of:
- ER, PR or HER2.
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76. The method of claim 64, wherein the breast cancer is ER-negative and PR-negative.
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77. The method of claim 64, wherein the breast cancer is ER-negative and HER2-negative.
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78. The method of claim 64, wherein the breast cancer is PR-negative and HER2-negative.
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79. The method of claim 64, wherein the breast cancer is an ER-negative breast cancer.
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80. The method of claim 64, wherein the breast cancer is an HER2-negative breast cancer.
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81. The method of claim 64, wherein the anti-tumor agent is selected from the group consisting of antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor organoplatinum compounds, antitumor campthotecin derivatives, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other agents having antitumor activities, or a pharmaceutically acceptable salt thereof.
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82. The method of claim 81, wherein the antitumor alkylating agents are nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, and carmustine;
- the antitumor antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium;
the antitumor antibiotics are actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, and valrubicin;
the plant-derived antitumor agents are vincristine, vinblastine, vindeshine, etoposide, sobuzoxane, docetaxel, paclitaxel, and vinorelbine;
the antitumor platinum-complex compounds are cisplatin, carboplatin, nedaplatin, and oxaliplatin;
the antitumor campthotecin derivatives are irinotecan, topotecan, and campthotecin;
the antitumor tyrosine kinase inhibitors are gefitinib, imatinib, and erlotinib;
the monoclonal antibodies are abciximab, adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, daclizumab, eculizumab, efalizumab, ibritumomab, tiuxetan, infliximab, muromonab-CD3, natalizumab, omalizumab, palivizumab, panitumumab, ranibizumab, gemtuzumab ozogamicin, rituximab, tositumomab, and trastuzumab;
the interferons are interferon α
, interferon α
-2a, interferon α
-2b, interferon β
, interferon γ
-1a, and interferon γ
-n1, the biological response modifiers are krestin, lentinan, sizofuran, picibanil, or ubenimex, and the other antitumor agents are mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoetin alfa, anastrozole, exemestane, bicalutamide, leuprorelin, flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox, aldesleukin, thyrotropin alfa, arsenic trioxide, bortezomib, capecitabine, and goserelin.
- the antitumor antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium;
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83. The method of claim 64, wherein the anti-tumor agent is an organoplatinum compound.
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84. The method of claim 83, wherein the anti-tumor agent is oxaliplatin (OX), cisplatin, or carboplatin.
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85. The method of claim 84, wherein the anti-tumor agent oxaliplatin (OX).
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86. The method of claim 64, wherein the anti-tumor agent is an anti-metabolite agent.
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87. The method of claim 86, wherein the anti-tumor agent is gemcitabine (GEM).
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88. The method of claim 64 further comprising more than one anti-tumor agent.
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89. The method of claim 88, wherein the anti-tumor agents are an organoplatinum compound and an anti-metabolite agent.
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90. The method of claim 88, wherein the anti-tumor agents are OX and GEM.
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91. The method of claim 64 further comprising surgery, radiation therapy, gene therapy, immunotherapy, RNA therapy, nanotherapy or a combination thereof.
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92. The method of claim 64, wherein the administration is intravenous or intraperitoneal.
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93. The method of claim 64, wherein the administration is orally.
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94. The method of claim 64, wherein a poly-ADP-ribose polymerase (PARP) is inhibited by the compound in the subject.
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95. The method of claim 64, wherein mono-ADP ribosylation and poly-ADP ribosylation are inhibited.
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96. The method of claim 64, wherein a tumor cell undergoes apoptosis, cell cycle arrest, and/or necrosis in the subject.
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97. The method of claim 64, wherein the subject expresses a detectable level of PARP protein.
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98. The method of claim 64, wherein the subject has a detectable level of mono-ADP ribosylation and poly-ADP ribosylation.
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99. A method of treating a cancer comprising administering to a subject in need thereof an effective amount of a composition comprising an organoplatinum compound and a compound of formula (I), or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
wherein n=0-10;
R1, R2, R3, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl; and
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen.- View Dependent Claims (100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128)
wherein R5 is selected from the group consisting of hydrogen, carboxyl, amino, nitroso, nitro, hydroxylamino, and hydroxy; and
X is selected from the group consisting of halogen, hydroxy, optionally substituted (C1-C7) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl.
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101. The method of claim 100, wherein the compound is of the formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIk, IIIl, IIIm, or IIIn, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
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102. The method of claim 101, wherein the compound is 5-iodo-6-nitro-benzopyrone of Formula IIIg, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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103. The method of claim 101, wherein the compound is 5-iodo-6-amino-benzopyrone of Formula IIIk, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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104. The method of claim 101, wherein the compound is 5-iodo-6-nitroso-benzopyrone of Formula IIIl, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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105. The method of claim 101, wherein the compound is 5-iodo-6-hydroxylamino-benzopyrone of Formula IIIm, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
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106. The method of claim 99, wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, Castleman'"'"'s Disease, cervical cancer, childhood Non-Hodgkin'"'"'s lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, Kaposi'"'"'s sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin'"'"'s lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
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107. The method of claim 99, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, brain cancer, skin cancer, colon cancer, or a cancer derived from cancer stem cells.
-
108. The method of claim 99, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2.
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109. The method of claim 99, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2; and
wherein the breast cancer is positive for at least one of ER, PR or HER2.
- ER, PR or HER2; and
-
110. The method of claim 99, wherein the breast cancer is negative for two of:
- ER, PR or HER2.
-
111. The method of claim 99, wherein the breast cancer is ER-negative and PR-negative.
-
112. The method of claim 99, wherein the breast cancer is ER-negative and HER2-negative.
-
113. The method of claim 99, wherein the breast cancer is PR-negative and HER2-negative.
-
114. The method of claim 99, wherein the breast cancer is an ER-negative breast cancer.
-
115. The method of claim 99, wherein the breast cancer is an HER2-negative breast cancer.
-
116. The method of claim 99, wherein the organoplatinum compound is oxaliplatin (OX).
-
117. The method of claim 99 further comprising administering an effective amount of OX and 5-iodo-6-nitro-benzopyrone (IIIg).
-
118. The method of claim 99 further comprising administering an effective amount of OX and 5-iodo-6-amino-benzopyrone (IIIk).
-
119. The method of claim 99 further comprising administering an effective amount of an anti-metabolite.
-
120. The method of claim 99 further comprising administering an effective amount of gemcitabine (GEM).
-
121. The method of claim 99 further comprising surgery, radiation therapy, gene therapy, immunotherapy, RNA therapy, nanotherapy or a combination thereof.
-
122. The method of claim 99, wherein the administration is intravenous or intraperitoneal.
-
123. The method of claim 99, wherein the administration is orally.
-
124. The method of claim 99, wherein a poly-ADP-ribose polymerase (PARP) is inhibited by the compound in the subject.
-
125. The method of claim 99, wherein mono-ADP ribosylation and poly-ADP ribosylation are inhibited.
-
126. The method of claim 99, wherein a tumor cell undergoes apoptosis, cell cycle arrest, and/or necrosis in the subject.
-
127. The method of claim 99, wherein the subject expresses a detectable level of PARP protein.
-
128. The method of claim 99, wherein the subject has a detectable level of mono-ADP ribosylation and poly-ADP ribosylation.
-
129. A method of treating a cancer comprising administering to a subject in need thereof an effective amount of a composition comprising an anti-metabolite agent and a compound of formula (I), or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
wherein n=0-10;
R1, R2, R3, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl; and
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen.- View Dependent Claims (130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158)
wherein R5 is selected from the group consisting of hydrogen, carboxyl, amino, nitroso, nitro, hydroxylamino, and hydroxy; and
X is selected from the group consisting of halogen, hydroxy, optionally substituted (C1-C7) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl.
-
-
131. The method of claim 130, wherein the compound is of the formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIk, IIIl, IIIm, or IIIn, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
132. The method of claim 131, wherein the compound is 5-iodo-6-nitro-benzopyrone of Formula IIIg, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
133. The method of claim 131, wherein the compound is 5-iodo-6-amino-benzopyrone of Formula IIIk, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
134. The method of claim 131, wherein the compound is 5-iodo-6-nitroso-benzopyrone of Formula IIIl, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
135. The method of claim 131, wherein the compound is 5-iodo-6-hydroxylamino-benzopyrone of Formula IIIm, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
136. The method of claim 129, wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, Castleman'"'"'s Disease, cervical cancer, childhood Non-Hodgkin'"'"'s lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, Kaposi'"'"'s sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin'"'"'s lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
-
137. The method of claim 129, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, brain cancer, skin cancer, colon cancer, or a cancer derived from cancer stem cells.
-
138. The method of claim 129, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2.
-
139. The method of claim 129, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2; and
wherein the breast cancer is positive for at least one of ER, PR or HER2.
- ER, PR or HER2; and
-
140. The method of claim 129, wherein the breast cancer is negative for two of:
- ER, PR or HER2.
-
141. The method of claim 129, wherein the breast cancer is ER-negative and PR-negative.
-
142. The method of claim 129, wherein the breast cancer is ER-negative and HER2-negative.
-
143. The method of claim 129, wherein the breast cancer is PR-negative and HER2-negative.
-
144. The method of claim 129, wherein the breast cancer is an ER-negative breast cancer.
-
145. The method of claim 129, wherein the breast cancer is an HER2-negative breast cancer.
-
146. The method of claim 129 wherein the anti-metabolite agent is gemcitabine (GEM).
-
147. The method of claim 129 further comprising administering an effective amount of GEM and 5-iodo-6-nitro-benzopyrone (IIIg).
-
148. The method of claim 129 further comprising administering an effective amount of GEM and 5-iodo-6-amino-benzopyrone (IIIk).
-
149. The method of claim 129 further comprising administering an effective amount of an organoplatinum compound.
-
150. The method of claim 129 further comprising administering an effective amount of oxaliplatin (OX).
-
151. The method of claim 129 further comprising surgery, radiation therapy, gene therapy, immunotherapy, RNA therapy, nanotherapy or a combination thereof.
-
152. The method of claim 129, wherein the administration is intravenous or intraperitoneal.
-
153. The method of claim 129, wherein the administration is orally.
-
154. The method of claim 129, wherein a poly-ADP-ribose polymerase (PARP) is inhibited by the compound in the subject.
-
155. The method of claim 129, wherein mono-ADP ribosylation and poly-ADP ribosylation are inhibited.
-
156. The method of claim 129, wherein a tumor cell undergoes apoptosis, cell cycle arrest, and/or necrosis in the subject.
-
157. The method of claim 129, wherein the subject expresses a detectable level of PARP protein.
-
158. The method of claim 129, wherein the subject has a detectable level of mono-ADP ribosylation and poly-ADP ribosylation.
-
159. A method of treating a cancer comprising administering to a subject in need thereof an effective amount of a composition comprising an organoplatinum compound and an anti-metabolite agent, and a compound of formula (I), or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
wherein n=0-10;
R1, R2, R3, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl; and
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen.- View Dependent Claims (160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187)
wherein R5 is selected from the group consisting of hydrogen, carboxyl, amino, nitroso, nitro, hydroxylamino, and hydroxy; and
X is selected from the group consisting of halogen, hydroxy, optionally substituted (C1-C7) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl.
-
-
161. The method of claim 160, wherein the compound is of the formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIk, IIIl, IIIm, or IIIn, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
162. The method of claim 161, wherein the compound is 5-iodo-6-nitro-benzopyrone of Formula IIIg, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
163. The method of claim 161, wherein the compound is 5-iodo-6-amino-benzopyrone of Formula IIIk, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
164. The method of claim 161, wherein the compound is 5-iodo-6-nitroso-benzopyrone of Formula IIIl, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
165. The method of claim 161, wherein the compound is 5-iodo-6-hydroxylamino-benzopyrone of Formula IIIm, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
166. The method of claim 159, wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, Castleman'"'"'s Disease, cervical cancer, childhood Non-Hodgkin'"'"'s lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, Kaposi'"'"'s sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin'"'"'s lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
-
167. The method of claim 159, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, brain cancer, skin cancer, colon cancer, or a cancer derived from cancer stem cells.
-
168. The method of claim 159, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2.
-
169. The method of claim 159, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2; and
wherein the breast cancer is positive for at least one of ER, PR or HER2.
- ER, PR or HER2; and
-
170. The method of claim 159, wherein the breast cancer is negative for two of:
- ER, PR or HER2.
-
171. The method of claim 159, wherein the breast cancer is ER-negative and PR-negative.
-
172. The method of claim 159, wherein the breast cancer is ER-negative and HER2-negative.
-
173. The method of claim 159, wherein the breast cancer is PR-negative and HER2-negative.
-
174. The method of claim 159, wherein the breast cancer is an ER-negative breast cancer.
-
175. The method of claim 159, wherein the breast cancer is an HER2-negative breast cancer.
-
176. The method of claim 159, wherein the organoplatinum compound is OX.
-
177. The method of claim 159, wherein the anti-metabolite agent is GEM.
-
178. The method of claim 159 further comprising administering an effective amount of OX, GEM and 5-iodo-6-nitro-benzopyrone (IIIg).
-
179. The method of claim 159 further comprising administering an effective amount of OX, GEM and 5-iodo-6-amino-benzopyrone (IIIk).
-
180. The method of claim 159 further comprising surgery, radiation therapy, gene therapy, immunotherapy, RNA therapy, nanotherapy or a combination thereof.
-
181. The method of claim 159, wherein the administration is intravenous or intraperitoneal.
-
182. The method of claim 159, wherein the administration is orally.
-
183. The method of claim 159, wherein a poly-ADP-ribose polymerase (PARP) is inhibited by the compound in the subject.
-
184. The method of claim 159, wherein mono-ADP ribosylation and poly-ADP ribosylation are inhibited.
-
185. The method of claim 159, wherein a tumor cell undergoes apoptosis, cell cycle arrest, and/or necrosis in the subject.
-
186. The method of claim 159, wherein the subject expresses a detectable level of PARP protein.
-
187. The method of claim 159, wherein the subject has a detectable level of mono-ADP ribosylation and poly-ADP ribosylation.
-
188. A composition for the treatment of a cancer, the composition comprising compound of formula I, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
wherein n=0-10;
R1, R2, R3, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl; and
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen; andwherein the compound is not one of the following; - View Dependent Claims (189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216)
-
-
190. The composition of claim 188, wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, Castleman'"'"'s Disease, cervical cancer, childhood Non-Hodgkin'"'"'s lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, Kaposi'"'"'s sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin'"'"'s lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
-
191. The composition of claim 188, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, brain cancer, skin cancer, colon cancer, or a cancer derived from cancer stem cells.
-
192. The composition of claim 188, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2.
-
193. The composition of claim 188, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2; and
wherein the breast cancer is positive for at least one of ER, PR or HER2.
- ER, PR or HER2; and
-
194. The composition of claim 188, wherein the breast cancer is negative for two of:
- ER, PR or HER2.
-
195. The composition of claim 188, wherein the breast cancer is ER-negative and PR-negative.
-
196. The composition of claim 188, wherein the breast cancer is ER-negative and HER2-negative.
-
197. The composition of claim 188, wherein the breast cancer is PR-negative and HER2-negative.
-
198. The composition of claim 188, wherein the breast cancer is an ER-negative breast cancer.
-
199. The composition of claim 188, wherein the breast cancer is an HER2-negative breast cancer.
-
200. The composition of claim 188 further comprises an anti-tumor agent.
-
201. The composition of claim 200, wherein the anti-tumor agent is selected from the group consisting of antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor organoplatinum compounds, antitumor campthotecin derivatives, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other agents having antitumor activities, or a pharmaceutically acceptable salt thereof
-
202. The composition of claim 201, wherein the antitumor alkylating agents are nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, and carmustine;
- the antitumor antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium;
the antitumor antibiotics are actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, and valrubicin;
the plant-derived antitumor agents are vincristine, vinblastine, vindeshine, etoposide, sobuzoxane, docetaxel, paclitaxel, and vinorelbine;
the antitumor platinum-complex compounds are cisplatin, carboplatin, nedaplatin, and oxaliplatin;
the antitumor campthotecin derivatives are irinotecan, topotecan, and campthotecin;
the antitumor tyrosine kinase inhibitors are gefitinib, imatinib, and erlotinib;
the monoclonal antibodies are abciximab, adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, daclizumab, eculizumab, efalizumab, ibritumomab, tiuxetan, infliximab, muromonab-CD3, natalizumab, omalizumab, palivizumab, panitumumab, ranibizumab, gemtuzumab ozogamicin, rituximab, tositumomab, and trastuzumab;
the interferons are interferon α
, interferon α
-2a, interferon α
-2b, interferon β
, interferon γ
-1a, and interferon γ
-n1, the biological response modifiers are krestin, lentinan, sizofuran, picibanil, or ubenimex, and the other antitumor agents are mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoetin alfa, anastrozole, exemestane, bicalutamide, leuprorelin, flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox, aldesleukin, thyrotropin alfa, arsenic trioxide, bortezomib, capecitabine, and goserelin.
- the antitumor antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium;
-
203. The composition of claim 200, wherein the anti-tumor agent is an organoplatinum compound.
-
204. The composition of claim 203, wherein the anti-tumor agent is oxaliplatin (OX), cisplatin, or carboplatin.
-
205. The composition of claim 200, wherein the anti-tumor agent is an anti-metabolite agent.
-
206. The composition of claim 205, wherein the anti-tumor agent is gemcitabine (GEM).
-
207. The composition of claim 188 further comprising more than one anti-tumor agent.
-
208. The composition of claim 188, wherein the anti-tumor agents are an organoplatinum compound and an anti-metabolite agent.
-
209. The composition of claim 188, wherein the anti-tumor agents are OX and GEM.
-
210. The composition of claim 188 may be used in combination with surgery, radiation therapy, gene therapy, immunotherapy, RNA therapy, nanotherapy or a combination thereof.
-
211. The composition of claim 188, wherein a poly-ADP-ribose polymerase (PARP) is inhibited by the compound of formula (I).
-
212. The composition of claim 188, wherein mono-ADP ribosylation and poly-ADP ribosylation are inhibited.
-
213. The composition of claim 188, wherein a cancer cell expresses a detectable level of PARP protein.
-
214. The composition of claim 188, wherein the subject has a detectable level of mono-ADP ribosylation and poly-ADP ribosylation.
-
215. A kit for the treatment of a cancer, the kit comprising an effective amount of a composition of claim 188, or a pharmaceutically acceptable salt or prodrug thereof.
-
216. The kit of claim 215, wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, Castleman'"'"'s disease, cervical cancer, childhood Non-Hodgkin'"'"'s lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, Kaposi'"'"'s sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin'"'"'s lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
-
217. A composition for the treatment of a cancer, the composition comprising a combination of an anti-tumor agent and a compound of formula I, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
wherein n=0-10;
R1, R2, R3, R4, R5 and X are independently selected from the group consisting of hydrogen, hydroxy, optionally substituted amine, amino, carboxyl, ester, nitroso, nitro, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl; and
wherein at least two of the R1, R2, R3, R4, and R5 substituents are always hydrogen.- View Dependent Claims (218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248)
wherein R5 is selected from the group consisting of hydrogen, carboxyl, amino, nitroso, nitro, hydroxylamino, and hydroxy; and
X is selected from the group consisting of halogen, hydroxy, optionally substituted (C1-C7) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocyclic, phenyl, and optionally substituted aryl.
-
-
219. The composition of claim 218, wherein the compound is of the formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIk, IIIl, IIIm, or IIIn, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof:
-
220. The composition of claim 219, wherein the compound of formula (I) is 5-iodo-6-nitro-benzopyrone of Formula IIIg, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
221. The composition of claim 219, wherein the compound of formula (I) is 5-iodo-6-amino-benzopyrone of Formula IIIk, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
222. The composition of claim 219, wherein the compound is 5-iodo-6-nitroso-benzopyrone of Formula IIIl, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
223. The composition of claim 219, wherein the compound is 5-iodo-6-hydroxylamino-benzopyrone of Formula IIIm, or a metabolite, a pharmaceutically acceptable salt or prodrug thereof.
-
224. The composition of claim 217, wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, Castleman'"'"'s disease, cervical cancer, childhood Non-Hodgkin'"'"'s lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, Kaposi'"'"'s sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin'"'"'s lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
-
225. The composition of claim 217, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, brain cancer, skin cancer, colon cancer, or a cancer derived from cancer stem cells.
-
226. The composition of claim 217, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2.
-
227. The composition of claim 217, wherein the breast cancer is negative for at least one of:
- ER, PR or HER2; and
wherein the breast cancer is positive for at least one of ER, PR or HER2.
- ER, PR or HER2; and
-
228. The composition of claim 217, wherein the breast cancer is negative for two of:
- ER, PR or HER2.
-
229. The composition of claim 217, wherein the breast cancer is ER-negative and PR-negative.
-
230. The composition of claim 217, wherein the breast cancer is ER-negative and HER2-negative.
-
231. The composition of claim 217, wherein the breast cancer is PR-negative and HER2-negative.
-
232. The composition of claim 217, wherein the breast cancer is an ER-negative breast cancer.
-
233. The composition of claim 217, wherein the breast cancer is an HER2-negative breast cancer.
-
234. The composition of claim 217, wherein the anti-tumor agent is selected from the group consisting of antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor organoplatinum compounds, antitumor campthotecin derivatives, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other agents having antitumor activities, or a pharmaceutically acceptable salt thereof.
-
235. The composition of claim 234, wherein the antitumor alkylating agents are nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, and carmustine;
- the antitumor antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium;
the antitumor antibiotics are actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, and valrubicin;
the plant-derived antitumor agents are vincristine, vinblastine, vindeshine, etoposide, sobuzoxane, docetaxel, paclitaxel, and vinorelbine;
the antitumor platinum-complex compounds are cisplatin, carboplatin, nedaplatin, and oxaliplatin;
the antitumor campthotecin derivatives are irinotecan, topotecan, and campthotecin;
the antitumor tyrosine kinase inhibitors are gefitinib, imatinib, and erlotinib;
the monoclonal antibodies are abciximab, adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, daclizumab, eculizumab, efalizumab, ibritumomab, tiuxetan, infliximab, muromonab-CD3, natalizumab, omalizumab, palivizumab, panitumumab, ranibizumab, gemtuzumab ozogamicin, rituximab, tositumomab, and trastuzumab;
the interferons are interferon α
, interferon α
-2a, interferon α
-2b, interferon β
, interferon γ
-1a, and interferon γ
-n1, the biological response modifiers are krestin, lentinan, sizofuran, picibanil, or ubenimex, and the other antitumor agents are mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoetin alfa, anastrozole, exemestane, bicalutamide, leuprorelin, flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox, aldesleukin, thyrotropin alfa, arsenic trioxide, bortezomib, capecitabine, and goserelin.
- the antitumor antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium;
-
236. The composition of claim 217, wherein the anti-tumor agent is an organoplatinum compound.
-
237. The composition of claim 236, wherein the anti-tumor agent is oxaliplatin (OX), cisplatin, or carboplatin.
-
238. The composition of claim 217, wherein the anti-tumor agent is an anti-metabolite agent.
-
239. The composition of claim 238, wherein the anti-tumor agent is gemcitabine (GEM).
-
240. The composition of claim 217 further comprising more than one anti-tumor agent.
-
241. The composition of claim 217, wherein the anti-tumor agents are an organoplatinum compound and an anti-metabolite agent.
-
242. The composition of claim 217, wherein the anti-tumor agents are OX and GEM.
-
243. The composition of claim 217, wherein a poly-ADP-ribose polymerase (PARP) is inhibited by the compound of formula (I).
-
244. The composition of claim 217, wherein mono-ADP ribosylation and poly-ADP ribosylation are inhibited.
-
245. The composition of claim 217, wherein a cancer cell expresses a detectable level of PARP protein.
-
246. The composition of claim 217, wherein the subject has a detectable level of mono-ADP ribosylation and poly-ADP ribosylation.
-
247. A kit for the treatment of a cancer, the kit comprising an effective amount of a composition of claim 217, or a pharmaceutically acceptable salt or prodrug thereof.
-
248. The kit of claim 247, wherein the cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, central nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, breast cancer, Castleman'"'"'s disease, cervical cancer, childhood Non-Hodgkin'"'"'s lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing'"'"'s family of tumors (e.g. Ewing'"'"'s sarcoma), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, hairy cell leukemia, Hodgkin'"'"'s disease, Kaposi'"'"'s sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children'"'"'s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin'"'"'s lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, and Waldenstrom'"'"'s macroglobulinemia.
Specification