Intermittent dosing of mdm2 inhibitor

Abstract

The present disclosure relates to mdm2 inhibitors for use in specific dosing schedules. It was found that if sufficiently potent or, in alternative, sufficiently high dose of a Mdm2 inhibitor is used, it can cause antineoplastic effect by triggering much longer lasting antiproliferative mechanism in cells. The long lasting effect can sustain for several weeks after a single dose, which eliminates the need for daily treatment and allows administering the Mdm2i intermittently. A treatment with the intermittent dosing schedule of a Mdm2 inhibitor can be combined with a daily treatment of the Mdm2i or with another pharmaceutically acceptable ingredient.

1 . A method of treatment for cancer with a MDM2i, wherein said MDM2i is to be administered once every 3 weeks (q3w) and the MDM2i is selected from (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one or (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. 
     
     
         2 . The method of treatment according to  claim 1 , wherein the MDM2i is (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one. 
     
     
         3 . The method of treatment according to  claim 1 , wherein said MDM2i is (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one is administered between 100 and 800 mg once every 3 weeks per os. 
     
     
         4 . The method of treatment according to  claim 1 , wherein said MDM2i is (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one the MDM2i is administered between 500 and 4000 mg once every 3 weeks per os. 
     
     
         5 . The method of treatment according to  claim 1 , wherein said cancer is bladder, breast, brain, head and neck, liver, oral, biliary tract, acute and chronic lymphoid leukemia, acute and chronic myeloid leukemia, chronic myelomonocytic leukemia, colorectal, gastric, gastrointestinal stromal, hepatocellular, glioma, lymphoma, melanoma, multiple myeloma, myeloproliferative disease, neuroendocrine, lung, non-small cell lung, pancreatic, ovarian, prostate, renal cell, sarcoma, liposarcoma or thyroid cancer. 
     
     
         6 . The method of treatment according to  claim 5 , wherein the cancer is melanoma, lung cancer or neuroblastoma. 
     
     
         7 . The method of treatment according to  claim 6 , wherein the cancer is melanoma. 
     
     
         8 . The method of treatment according to  claim 1 , wherein said MDM2i comprises a pharmaceutical ingredient which is to be administered to a patient. 
     
     
         9 . The method of treatment according to  claim 8 , wherein said pharmaceutical ingredient is an antineoplastic agent.