PARP INHIBITORS FOR THE TREATMENT OF CIPN
The present invention relates to the method of treating chemotherapy-induced neuropathy in a subject in need thereof with the use of a poly(ADP-ribose)polymerase (PARP) inhibitor.
1 . A method for treating chemotherapy-induced peripheral neuropathy in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)
or a pharmaceutically acceptable salt or solvate 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, (NR C R D )sulfonyl, and oxo; and
R A , R B , R C , and R D are independently selected from the group consisting of hydrogen, alkyl, and alkycarbonyl.
2 . The method of claim 1 , wherein the treatment is prophylactic treatment.
3 . The method of claim 1 , wherein A is selected from the group consisting of
4 . The method of claim 1 , wherein R 1 , R 2 , and R 3 are independently hydrogen or halogen;
R 6 is hydrogen; and
n is 0.
5 . The method of claim 1 , wherein the compound of formula (I) is 2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide.
6 . The method of claim 1 , wherein the compound of formula (I) is 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide.
7 . The method of claim 1 , wherein the compound of formula (I) is 2-[(2S)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide.
8 . The method of claim 1 , further comprising administering one or more chemotherapeutic agents.
9 . The method of claim 8 , wherein the chemotherapeutic agent or agents is utilized for the treatment of cancer.
10 . The method of claim 8 , wherein the chemotherapeutic agent is selected from the group consisting of bortezomib, carboplatin, cisplatin, gemcitabine, misonidazole, oxaliplatin, procarbazine, thalidomide, docetaxel, hexamethylmelamine, paclitaxel, vincristine, vinblastine, or vinorelbine.
11 . The method of claim 10 , wherein the chemotherapeutic agent is carboplatin.
12 . The method of claim 10 , wherein the chemotherapeutic agent is cisplatin.
13 . The method of claim 10 , wherein the chemotherapeutic agent is paclitaxel.
14 . The method of claim 10 , wherein the chemotherapeutic agent is vinorelbine.
15 . The method of claim 10 , wherein the chemotherapeutic agents are cisplatin and docetaxel.
16 . The method of claim 10 , wherein the chemotherapeutic agents are carboplatin and docetaxel.
17 . The method of claim 10 , wherein the chemotherapeutic agents are cisplatin and gemcitabine.
18 . The method of claim 10 , wherein the chemotherapeutic agents are carboplatin and gemcitabine.
19 . The method of claim 9 , wherein the cancer is selected from the group consisting of ovarian cancer, cervical cancer, colorectal cancer, prostate cancer, breast cancer, testicular cancer, leukemia, neuroblastoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and non-small cell lung cancer.
20 . The method of claim 9 , wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, and non-small cell lung cancer.
21 . The method of claim 8 , wherein the compound of formula (I) is administered before the administration of the chemotherapeutic agent.
22 . The method of claim 8 , wherein the compound of formula (I) is administered during the administration of the chemotherapeutic agent.
23 . The method of claim 8 , wherein the compound of formula (I) is administered after the administration of the chemotherapeutic agent.