Pharmaceutical compositions

Abstract

The disclosure relates to a pharmaceutical combination of a mdm2/4 inhibitor, namely (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 or (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, and a cyclin dependent kinase 4/6 (CDK4/6) inhibitor 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide. In addition, the disclosure relates to a pharmaceutical combination product. The disclosure also relates to corresponding pharmaceutical formulations, uses and treatment methods comprising said mdm2/4 inhibitor or a cyclin dependent kinase 4/6 (CDK4/6) inhibitor.

1 . A pharmaceutical combination comprising
 (i) (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 or   (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 a pharmaceutically acceptable salt thereof, and   (ii) 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, or a pharmaceutically acceptable salt thereof.   
     
     
         2 . The pharmaceutical combination according to  claim 1 , wherein the pharmaceutical combination comprises (i) (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 or
 (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 a pharmaceutically acceptable salt thereof, and   (ii) 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, or a pharmaceutically acceptable salt thereof, separately or together.   
     
     
         3 . The pharmaceutical combination according to  claim 1  for simultaneous or sequential use of the (i) (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 or
 (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 a pharmaceutically acceptable salt thereof, and 
 (ii) 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, or a pharmaceutically acceptable salt thereof, as a medicine. 
 
     
     
         4 . The pharmaceutical combination according to  claim 1 , further comprising at least one pharmaceutically acceptable carrier. 
     
     
         5 . The pharmaceutical combination according to  claim 1  in the form of a fixed combination. 
     
     
         6 . The pharmaceutical combination according to  claim 1  in the form of a pharmaceutical composition. 
     
     
         7 . The pharmaceutical combination according to  claim 1  in the form of a kit of parts for the combined administration, wherein the (i) (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 or
 (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 a pharmaceutically acceptable salt thereof, and 
 (ii) 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, or a pharmaceutically acceptable salt thereof, are administered jointly or independently at the same time or separately within time intervals. 
 
     
     
         8 . The pharmaceutical combination according to  claim 1  for use as a medicine. 
     
     
         9 . The pharmaceutical combination according to  claim 1  for use in the treatment of cancer. 
     
     
         10 . The pharmaceutical combination for use in the treatment of cancer according to  claim 9 , wherein the cancer is ER positive breast cancers, melanoma, malignant rhabdoid tumor, neuroblastoma, lymphoma, mantle cell lymphoma or liposarcoma. 
     
     
         11 . The pharmaceutical combination for use in the treatment of cancer according to  claim 9 , wherein the cancer is liposarcoma. 
     
     
         12 . The pharmaceutical combination for use in the treatment of cancer according to  claim 9 , wherein the cancer is well differentiated liposarcoma (WDLPS) or dedifferentiated liposarcoma (DDLPS). 
     
     
         13 . The pharmaceutical combination for use in the treatment of cancer according to  claim 9 , wherein the cancer comprises co-amplified MDM2 and/or CDK4. 
     
     
         14 . The pharmaceutical combination for use in the treatment of cancer according to  claim 9 , wherein the cancer comprises functional p53 or is p53 wild-type. 
     
     
         15 . The pharmaceutical combination according to  claim 1  in the form of a combination product or a pharmaceutical composition. 
     
     
         16 . The pharmaceutical combination according to  claim 1  for the manufacture of a medicament or a pharmaceutical product for the treatment of cancer. 
     
     
         17 . The pharmaceutical combination according to  claim 1 , wherein the pharmaceutical combination comprises
 (i) (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, or a pharmaceutically acceptable salt thereof, and   (ii) 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, or a pharmaceutically acceptable salt thereof.   
     
     
         18 . The pharmaceutical combination according to  claim 1 , wherein the pharmaceutical combination comprises
 (i) (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 a pharmaceutically acceptable salt thereof, and   (ii) 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, or a pharmaceutically acceptable salt thereof.