COMPOUNDS AND METHODS FOR TREATING CHEMOTHERAPY-INDUCED PAIN
Disclosed herein are methods and compositions for treating, managing, and preventing chemotherapy-induced pain in a patient in need thereof. Particular methods and compositions utilize an adaptor associated kinase 1 inhibitor of Formula I:
1 . A method of treating, managing, or preventing chemotherapy-induced peripheral neuropathy (CIPN), which comprises administering a therapeutically or prophylactically effective amount of an adaptor associated kinase 1 (AAK1) inhibitor to a patient in need thereof, wherein the AAK1 inhibitor is a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from
wherein “ ” denotes the point of attachment to B;
B is selected from
wherein “*” indicates the point of attachment to R 5 and “**” indicates the point of attachment to ring A;
R 1 is selected from hydrogen, amino, —CO 2 H, difluoromethyl, ethyl, halo, hydroxymethyl, methoxy, methyl, —NHC(O)CH 3 , —NHCO 2 CH 3 , trifluoromethoxy, and trifluoromethyl;
R 2 is selected from hydrogen, cyano, —CH 2 OH, halo, and methyl;
R 3 is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, methylsulfonyl, trifluoromethoxy, trifluoromethyl, —CH 2 N(CH 3 ) 2 , and a five-membered aromatic ring containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur;
R 4 is selected from hydrogen, halo, and methyl;
R 5 is selected from
R 6 is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl; and
R 7 is methyl.
2 . The method of claim 1 , wherein the AAK1 inhibitor is (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl) oxy)-2,4-dimethylpentan-2-amine:
or a pharmaceutically acceptable salt thereof.
3 . The method of claim 2 , wherein the CIPN is chronic.
4 . The method of claim 2 , wherein the CIPN is acute.
5 . The method of claim 2 , wherein the patient is undergoing chemotherapy, which chemotherapy comprises administering to the patient a chemotherapeutic agent.
6 . The method of claim 5 , wherein the AAK1 inhibitor is administered to the patient before the administration of the chemotherapeutic agent.
7 . The method of claim 5 , wherein the AAK1 inhibitor and chemotherapeutic agent are administered concurrently to the patient.
8 . The method of claim 5 , wherein the AAK1 inhibitor is administered to the patient after the administration of the chemotherapeutic agent.
9 . The method of claim 5 , wherein the chemotherapeutic agent and the AAK1 inhibitor are administered to the patient by the same route of administration.
10 . (canceled)
11 . (canceled)
12 . (canceled)
13 . (canceled)
14 . (canceled)
15 . The method of claim 5 , wherein the patient is undergoing chemotherapy for the treatment of cancer, wherein the cancer is colorectal cancer, neuroblastoma, biliary adenocarcinoma, leukemia, esophageal cancer, gastric cancer, neuroendocrine tumors, non-Hodgkin lymphoma, pancreatic cancer, ovarian cancer, or testicular cancer.
16 . The method of claim 15 , wherein the cancer is colorectal cancer.
17 . The method of claim 5 , wherein the chemotherapeutic agent is chelated platinum, a taxane, a proteosome inhibitor, a vinca alkaloid, or an immunomodulatory drug.
18 . The method of claim 17 , wherein the chemotherapeutic agent is 5-fluorouracil, capecitabine, cisplatin, cytarabine, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, gemcitabine, ifosfamide, irinotecan, leucovorin, oxaliplatin, paclitaxel, or rituximab.
19 . The method of claim 17 , wherein the chemotherapeutic agent is chelated platinum.
20 - 54 . (canceled)