Diazabenzo[de] anthracen-3-one compounds and methods for inhibiting PARP
The present invention relates to diazabenzo[de]anthracen-3-one compounds which inhibit poly(ADP-ribose) polymerase (“PARP”), compositions containing these compounds and methods for using these PARP inhibitors to treat, prevent and/or ameliorate the effects of the conditions described herein.
1. A maleate salt of the compound
2. A pharmaceutical composition comprising:
i) a therapeutically acceptable amount of the maleate salt of claim 1 , and
ii) optionally a pharmaceutically acceptable carrier, diluent or excipient.
3. The pharmaceutical composition of claim 2 , further comprising a therapeutically effective amount of at least one chemotherapeutic agent, wherein the chemotherapeutic agent is selected from a taxoid, temozolomide, adriamycin, camptothecin, carboplatin, cisplatin, dactinomycin, danorubicin, docetaxel, doxorubicin, 4′-deoxydoxorubicin, bleomycin, pilcamycin, mitomycin, neomycin and gentamycin, etoposide, 4-OH cyclophosphamide, a platinum coordination complex, interferon (alpha, beta, gamma), interleukin 2, irinotecan, paclitaxel, topotecan, therapeutically effective analogs and derivatives of the same and mixtures thereof.
4. The pharmaceutical composition of claim 3 wherein the chemotherapeutic agent is temozolomide.
5. A method of radiosensitizing tumor cells in a mammal in need of radiation therapy comprising administering to said mammal the maleate salt of claim 1 , wherein the amount of the maleate salt is sufficient to sensitize the tumor cells to the effects of the radiation therapy.
6. The method of claim 5 wherein the tumor cells are selected from the group consisting of ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and/or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovary (germ cell) cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva and Wilm's tumor.
7. A method of chemosensitizing tumor cells in a mammal in need of chemotherapy comprising administering to said mammal the maleate salt of claim 1 , wherein the amount of the maleate salt is sufficient to sensitize the tumor cells to the effects of at least one chemotherapeutic agent.
8. The method of claim 7 , wherein said at least one chemotherapeutic agent is selected from a taxoid, temozolomide, adriamycin, camptothecin, carboplatin, cisplatin, dactinomycin, danorubicin, docetaxel, doxorubicin, 4′-deoxydoxorubicin, bleomycin, pilcamycin, mitomycin, neomycin and gentamycin, etoposide, 4-OH cyclophosphamide, a platinum coordination complex, interferon (alpha, beta, gamma), interleukin 2, irinotecan, paclitaxel, topotecan, therapeutically effective analogs and derivatives of the same and mixtures thereof.
9. The method of claim 7 , wherein the chemotherapeutic agent is temozolomide.
10. The method of claim 7 , further comprising:
(a) first: allowing a time period following administration of the maleate salt to provide an effective amount of chemosensitization, and,
(b) second: administering to the mammal a pharmaceutically effective dose of said at least one chemotherapeutic agent.
11. The method of claim 7 , wherein the maleate salt and said at least one chemotherapeutic agent are administered essentially simultaneously.
12. The method of claim 7 , wherein the maleate salt is administered in a pharmaceutical composition comprising the maleate salt and a pharmaceutically acceptable carrier, diluent, or excipient.
13. The method of claim 7 , wherein the tumor cells are selected from the group consisting of ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chrome lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head & neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and/or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, lymphoma, glioblastoma multiforme, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovary (germ cell) cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva and Wilm's tumor.
14. The method of claim 13 , wherein the tumor cells are selected from melanoma, lymphoma, ovarian cancer and breast cancer.
15. The method of claim 6 , wherein the tumor cells are selected from melanoma, lymphoma, ovarian cancer and breast cancer.
16. The method of claim 14 , wherein the cancer cells are melanoma located at a site in the central nervous system.
17. The method of any one of claims 5 and 7 , wherein the mammal is human.