Novel combination treatment for acute myeloid leukemia (aml)

Abstract

The present invention relates to a pharmaceutical product comprising a) as a first component an inhibitor of the MDM2-p53 interaction; and b) as a second component cytarabine; as a combined preparation for the sequential or simultaneous use in the treatment of cancer, particularly AML.

1 . A pharmaceutical product comprising a) as a first component an inhibitor of the MDM2-p53 interaction; and b) as a second component cytarabine; as a combined preparation for the sequential or simultaneous use in the treatment of cancer. 
     
     
         2 . The pharmaceutical product according to  claim 1 , wherein the inhibitor of the MDM2-p53 interaction is selected from a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein n is from 3 to 70. 
       
     
     
         3 . The pharmaceutical product according to  claim 2 , wherein n is from 30 to 60. 
     
     
         4 . The pharmaceutical product according to  claim 2 , wherein n is from 40 to 50. 
     
     
         5 . The pharmaceutical product according to  claim 2 , wherein n is 41, 42, 43, 44, 46, 47, 48 or 49. 
     
     
         6 . The pharmaceutical product according to  claim 1 , wherein the inhibitor of the MDM2-p53 interaction is 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-mPEG-carbonyloxy-ethyl ester (mPEG, average MW, ˜2000). 
     
     
         7 . The pharmaceutical product according to  claim 1 , wherein the inhibitor of the MDM2-p53 interaction is 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-mPEG-carbonyloxy-ethyl ester (mPEG, average MW, ˜2200). 
     
     
         8 . The pharmaceutical product according to  claim 1  for the treatment of Acute Myeloid Leukemia (AML). 
     
     
         9 . The pharmaceutical product according to  claim 1  for the treatment of solid tumors. 
     
     
         10 . A method for the treatment of cancer, comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical product according to  claim 1 . 
     
     
         11 . The method according to  claim 10 , wherein the cancer is Acute Myeloid Leukemia (AML). 
     
     
         12 . The method according to  claim 10 , wherein the cancer is a solid tumor. 
     
     
         13 . (canceled) 
     
     
         14 . A pharmaceutical product comprising, a) as a first component a compound of formula (I) according to  claim 2 ; and b) as a second component the compound cytarabine, wherein both components are administered intravenously, as a combined preparation for the simultaneous or sequential use in the treatment of cancer; characterized in that the dose of the compound of formula (I) corresponds to a dose of compound (A) 
       
         
           
           
               
               
           
         
         within the range from about 200 to about 1600 mg/day. 
       
     
     
         15 . The pharmaceutical product according to  claim 14 , wherein the compound of formula (I) is the compound 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-mPEG-carbonyloxy-ethyl ester (mPEG, average MW, ˜2000). 
     
     
         16 . The pharmaceutical product according to  claim 14 , wherein the compound of formula (I) is the compound 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-mPEG-carbonyloxy-ethyl ester (mPEG, average MW, ˜2200). 
     
     
         17 . The pharmaceutical product according to  claim 14 , wherein the compound of formula (I) is administered on days 1 to 5, followed by a 23 days rest period of a 28 days treatment cycle. 
     
     
         18 . The pharmaceutical product according to  claim 17 , wherein the compound of formula (I) is administered once daily (qd) or two times a day (BID). 
     
     
         19 . The pharmaceutical product according to  claim 14 , wherein the cancer is Acute Myeloid Leukemia (AML). 
     
     
         20 . (canceled)