Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis

Abstract

The present invention relates to a pharmaceutical combination for the treatment of diseases which involves cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis. The invention also relates to a method for the treatment of said diseases, comprising co-administration of effective amounts of specific active compounds and/or co-treatment with radiation therapy, in a ratio which provides an additive and synergistic effect, and to the combined use of these specific compounds and/or radiotherapy for the manufacture of corresponding pharmaceutical combination preparations.

1 . A method of treating cancer diseases, which method comprises simultaneous, separate or sequential administration of therapeutically effective amounts of:
 (i) (Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof; and   (ii) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or a pharmaceutical acceptable salt the tautomers or the stereoisomers thereof;   in the form of a combined preparation optionally adapted for a co-treatment with radiotherapy or radio-immunotherapy.   
     
     
         2 . The method in accordance with  claim 1  wherein (i) is the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone. 
     
     
         3 . The method in accordance with  claim 1 , wherein (ii) is the quinazoline derivative 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method in accordance with  claim 3 , wherein (ii) is the di-maleic acid salt of the compound 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline. 
     
     
         5 . The method in accordance with  claim 2 , wherein (ii) is the di-maleic acid salt of the compound 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline. 
     
     
         6 . The method in accordance with any of  claims 1  to  5 , wherein the formulation of (i) is for oral administration. 
     
     
         7 . The method in accordance with any one of  claims 1  to  5 , wherein (i) is administered in a daily dosage such that the plasma level of the active substance lies between 10 and 500 ng/ml for at least 12 hours of a 24 hours dosing interval. 
     
     
         8 . The method in accordance with  claim 1  wherein the cancer disease is selected from prostate cancer, renal cell cancers, bladder cancers, ovarian cancers, cervical cancers, endometrial cancers, lung cancer, colorectal cancers, pancreatic cancer, gastric cancer, oesophageal cancers, hepatocellular cancers, cholangiocellular cancers, head and neck cancer, malignant mesothelioma, breast cancer, malignant melanoma or bone and soft tissue sarcomas, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia. 
     
     
         9 . The method in accordance with  claim 5  wherein the cancer disease is selected from prostate cancer, renal cell cancers, bladder cancers, ovarian cancers, cervical cancers, endometrial cancers, lung cancer, colorectal cancers, pancreatic cancer, gastric cancer, oesophageal cancers, hepatocellular cancers, cholangiocellular cancers, head and neck cancer, malignant mesothelioma, breast cancer, malignant melanoma or bone and soft tissue sarcomas, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia. 
     
     
         10 . The method in accordance with  claim 9  wherein (i) is administered in a daily dosage such that the plasma level of the active substance lies between 10 and 500 ng/ml for at least 12 hours of a 24 hours dosing interval. 
     
     
         11 . The method in accordance with  claim 8  or  9 , wherein the cancer disease is selected from colorectal cancers. 
     
     
         12 . The method in accordance with  claim 9 , wherein the cancer disease is selected from colorectal cancers and wherein (i) is administered in a daily dosage such that the plasma level of the active substance lies between 10 and 500 ng/ml for at least 12 hours of a 24 hours dosing interval.