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 Mdm2 i intermittently. A treatment with the intermittent dosing schedule of a Mdm2 inhibitor can be combined with a daily treatment of the Mdm2 i or with another pharmaceutically acceptable ingredient.

1 . A method of treating cancer comprising a MDM2i, wherein the MDM2i is to be administered to a subject intermittently in at least three consecutive doses and the period between each two consecutive doses is at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks or 60 days, and not longer than 60 days. 
     
     
         2 . The method according to  claim 1 , wherein the MDM2i is to be administered to a subject intermittently and the period between consecutive administrations is at least 3 weeks and not longer than 60 days. 
     
     
         3 . The method according to  claim 1 , wherein the MDM2i is to be administered to a subject intermittently and the period between consecutive administrations is 3 weeks. 
     
     
         4 . The method according to  claim 1 , wherein the MDM2i is to be administered intravenously. 
     
     
         5 . A method of treating cancer comprising a MDM2i, wherein the MDM2i is administered to a subject in a first and a second dose and the first dose is administered on the same day as the second dose, consecutive days or a different day to the second dose, wherein two consecutive administrations of the first dose are administered intermittently at least every 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks or 60 days, and not longer than every 60 days, and the first and the second dose are not the same. 
     
     
         6 . The method according to  claim 5 , wherein the second dose is to be administered daily, optionally with a break. 
     
     
         7 . The method according to  claim 6 , wherein the break is at least 1 day long, 2 days, 3 days, 4 days, 1 week, 2 weeks, or 3 weeks and at most 26 days long. 
     
     
         8 . The method according to  claim 5 , wherein the second dose is to be administered 1 to 14 days after the first dose has been administered. 
     
     
         9 . The method according to  claim 5 , wherein the second dose is administered for two weeks followed by a period of two weeks without treatment and then repeating the cycle. 
     
     
         10 . The method according to  claim 5 , wherein the first dose is higher than the second dose. 
     
     
         11 . The method according to  claim 5 , wherein at least one of the first or the second dose is to be administered intravenously. 
     
     
         12 . The method according to  claim 5 , wherein two consecutive administrations of the first dose are to be administered intermittently at least every 2 weeks. 
     
     
         13 . The method according to  claim 5 , wherein two consecutive administrations of the first dose are to be administered intermittently at least every 3 weeks. 
     
     
         14 . The method according to  claim 1 , wherein the 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. 
     
     
         15 . The method according to  claim 1 , wherein the cancer is melanoma, lung cancer or neuroblastoma. 
     
     
         16 . The method according to  claim 1 , wherein the cancer is melanoma. 
     
     
         17 . (canceled) 
     
     
         18 . A method of treating cancer, wherein MDM2i is administered to a subject in need thereof intermittently in at least three consecutive doses and the period between each two consecutive doses is at least 2 weeks, 3 weeks, at least 4 weeks, at least 6 weeks or 60 days, and not longer than 60 days. 
     
     
         19 . The method of treating cancer according to  claim 18 , wherein the MDM2i is administered to a human. 
     
     
         20 . The method of treating cancer according to  claim 18 , wherein the MDM2i is selected from the group consisting of:
 (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one   (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   (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one   (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one   (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one   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,   (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   4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile   (S)-5-(5-Chloro-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   (S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one,   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and 
         (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxy-d6-pyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one. 
       
     
     
         21 . The method of treating cancer according to  claim 18 , 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 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.   
     
     
         22 . The method of treating cancer according to  claim 18 , 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. 
     
     
         23 . The method of treating cancer according to  claims 18  further comprises another pharmaceutical ingredient which is to be administered to a patient. 
     
     
         24 . The method of treating cancer according to  claim 23 , wherein the another pharmaceutical ingredient is another antineoplastic agent. 
     
     
         25 . The method of treating cancer according to  claim 24 , wherein more than one further antineoplastic agent is to be administered. 
     
     
         26 . The method of treating cancer according to  claim 23 , wherein the MDM2i is to be administered intermittently in at least three consecutive doses and the period between each two consecutive doses is at least 1 week. 
     
     
         27 . The method of treating cancer according to  claim 23 , wherein the MDM2i is to be administered intermittently in at least three consecutive doses and the period between each two consecutive doses is at least 2 weeks. 
     
     
         28 . The method of treating cancer according to  claim 23 , wherein the MDM2i is to be administered intermittently in at least three consecutive doses and the period between each two consecutive doses is at least 3 weeks.