COMBINATION THERAPY WITH PARP INHIBITORS
The present invention describes benzimidazole derivatives of Formula (I) which constitute potent PARP inhibitors in combination with radiotherapy or in combination with other chemotherapeutic agents.
1 .- 10 . (canceled)
11 . A method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I):
or a therapeutically acceptable salt thereof, wherein
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR A R B , and (NR A R B )carbonyl;
A is a nonaromatic 4, 5, 6, 7, or 8-membered ring that contains 1 or 2 nitrogen atoms and, optionally, one sulfur or oxygen atom, wherein the nonaromatic ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NR C R D , (NR C R D )alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, and (NR C R D )sulfonyl; and
R A , R B , R C , and R D are independently selected from the group consisting of hydrogen, alkyl, and alkycarbonyl or a therapeutically acceptable salt thereof,
and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan.
12 . The method of claim 11 , wherein the compound of formula (I) is 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide.
13 . The method of claim 11 , wherein the cancer is leukemia.
14 . The method of claim 11 , wherein the cancer is a CNS tumor.
15 . The method of claim 14 , wherein the compound of formula (I) is 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide and the cytotoxic agent is temozolomide.
16 . The method of claim 15 , wherein the cancer is glioma.
17 . The method of claim 15 , wherein the cancer is medulloblastoma.
18 . The method of claim 11 , wherein the compound of formula (I) is 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, the cytotoxic agent is temozolomide, and the cancer is melanoma.
19 . The method of claim 11 , wherein the compound of formula (I) is 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, the cytotoxic agent selected from the group consisting of cisplatan and carboplatin, and the cancer is breast cancer.