Pharmaceutical Combinations of Organo-Arsenoxide Compounds and mTOR Inhibitors

Abstract

The present invention relates to synergistic pharmaceutical combinations comprising organic arsenoxide compounds and mTOR inhibitors. Further, the present invention relates to the use of these pharmaceutical combinations in therapy, in particular, treatment of proliferative diseases.

1 . A synergistic pharmaceutical combination comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. 
     
     
         2 . The synergistic pharmaceutical combination of  claim 1 , wherein the organo-arsenoxide compound is a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         the As(OH) 2  group is para- to the N-atom on the phenyl ring; 
         R 1  is selected from hydrogen and C 1-3  alkyl; 
         R 2  and R 3  may be the same or different and are independently selected from hydrogen and optionally substituted C 1-3  alkyl; 
         R 4  and R 5  may be the same or different and are independently selected from hydrogen and optionally substituted C 1-3  alkyl; 
         m is 1; 
         n is 1; 
         * indicates a chiral carbon atom; and 
         wherein each optional substituent is independently C 1-3  alkyl, C 1-3  alkoxy, halo, hydroxyl, or hydroxy(C 1-3 )alkyl; 
         salts, enantiomers and racemates thereof. 
       
     
     
         3 . The synergistic pharmaceutical combination of  claim 2 , wherein R 1  is selected from hydrogen, methyl and ethyl. 
     
     
         4 . The synergistic pharmaceutical combination of  claim 2  or  3 , wherein R 2  and R 3  are independently selected from hydrogen, methyl, ethyl, hydroxymethyl and CF 3 . 
     
     
         5 . The synergistic pharmaceutical combination of any one of  claims 2  to  4 , wherein R 4  and R 5  are independently selected from hydrogen, C 1-3  alkyl, hydroxy-(C 1-3 )alkyl and halo(C 1-3 )alkyl. 
     
     
         6 . The synergistic pharmaceutical combination of  claim 2 , wherein the As(OH) 2  group is para- to the N-atom on the phenyl ring; R 1  is hydrogen or methyl; R 2  and R 3  are independently selected from hydrogen, C 1-3  alkyl, hydroxy(C 1-3 )alkyl and halo(C 1-3 )alkyl; R 4  and R 5  are independently selected from hydrogen, C 1-3  alkyl, hydroxy(C 1-3 )alkyl and halo(C 1-3 )alkyl; in is 1; and n is 1. 
     
     
         7 . The synergistic pharmaceutical combination of any one of  claims 2  to  6  wherein the organo-arsenoxide has the following structural formula: 
       
         
           
           
               
               
           
         
         or a salt, or an enantiomer or racemate thereof. 
       
     
     
         8 . The synergistic pharmaceutical combination of  claim 7 , wherein the stereochemistry at the chiral carbon denoted * is (S), and salts thereof 
     
     
         9 . The synergistic pharmaceutical combination of any one of  claims 1  to  8 , wherein the mTOR inhibitor is a rapalog. 
     
     
         10 . The synergistic pharmaceutical combination of  claim 9 , wherein the rapalog is selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. 
     
     
         11 . The synergistic pharmaceutical combination of  claim 9 , wherein the rapalog is everolimus or temsirolimus. 
     
     
         12 . The synergistic pharmaceutical combination of  claim 1 , wherein the organo-arsenoxide compound is 4-(N—(S-penicllaminylacetyl)amino)phenylarsinous acid (PENAO), or a pharmaceutically acceptable salt thereof, and the mTOR inhibitor is a rapalog. 
     
     
         13 . The synergistic pharmaceutical combination of  claim 1 , wherein the organo-arsenoxide compound is PENAO, or a pharmaceutically acceptable salt thereof, and the mTOR inhibitor is selected from the group consisting of everolimus, temsirolimus and deforolimus. 
     
     
         14 . The synergistic pharmaceutical combination of any one of  claims 1  to  13 , wherein the organo-arsenoxide compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, are present in a single dosage form. 
     
     
         15 . The synergistic pharmaceutical combination of any one of  claims 1  to  13 , wherein the organo-arsenoxide compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, are present in separate dosage forms. 
     
     
         16 . The synergistic pharmaceutical combination of any one of  claims 1  to  15 , wherein the pharmaceutical combination has a combination index (CI) of less than 1. 
     
     
         17 . The synergistic pharmaceutical combination of any one  claims 1  to  16 , wherein the pharmaceutical combination has a CI of less than 0.8. 
     
     
         18 . A pharmaceutical composition comprising an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the organo-arsenoxide compound is PENAO, or a pharmaceutically acceptable salt thereof, and the mTOR inhibitor is a rapalog selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. 
     
     
         20 . A method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of the synergistic pharmaceutical combination of any one of  claims 1  to  17 , or the pharmaceutical composition of  claim 18  or  19 . 
     
     
         21 . The method according to  claim 20 , wherein the proliferative disease is a solid tumour. 
     
     
         22 . A method of inhibiting angiogenesis in a vertebrate, comprising administering to the vertebrate an effective amount of a compound of the synergistic pharmaceutical combination of any one of  claims 1  to  17 , or the pharmaceutical composition of  claim 18  or  19 . 
     
     
         23 . A method of selectively inducing the Mitochondrial Permeability Transition (MPT) in proliferating cells in a vertebrate comprising administering to the vertebrate a therapeutically effective amount a compound of the synergistic pharmaceutical combination of any one of  claims 1  to  17 , or the pharmaceutical composition of  claim 18  or  19 . 
     
     
         24 . A method of inducing apoptosis in proliferating mammalian cells, comprising administering to the mammal an apoptosis-inducing amount of a compound of the synergistic pharmaceutical combination of any one of  claims 1  to  17 , or the pharmaceutical composition of  claim 18  or  19 . 
     
     
         25 . A method of treating a cellular proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of an organo-arsenoxide compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. 
     
     
         26 . The method according to  claim 25 , wherein the organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, are administered simultaneously, separately or sequentially. 
     
     
         27 . The method according to  claim 25 , wherein the organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, are administered simultaneously. 
     
     
         28 . The method according to  claim 25 , wherein the organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, is administered first, followed by the mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. 
     
     
         29 . Use of an organo-arsenoxide compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an mTOR inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of a cellular proliferative disease. 
     
     
         30 . The method of any one of  claims 20  to  28 , or the use of  claim 29 , wherein the organo-arsenoxide compound is PENAO, or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The method of any one of  claim 20  to  28  or  30 , or the use of  claim 29  wherein the mTOR inhibitor is a rapalog, or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method or use of  claim 31 , wherein the rapalog is selected from the group consisting of everolimus, temsirolimus, deforolimus and zotarolimus. 
     
     
         33 . The method or use of  claim 32 , wherein the rapalog is everolimus or temsirolimus. 
     
     
         34 . The method of any one of  claims 25  to  28  or  30  to  33 , or the use of  claim 29 , wherein the proliferative disease is a solid tumour. 
     
     
         35 . The method or use of  claim 35 , wherein the solid tumour is selected from the group consisting of lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; non-Hodgkin's lymphoma; bladder carcinoma; carcinoma of the uterus; glioma, diffuse intrinsic pontine glioma, glioblastoma, medullablastoma, and other tumours of the brain; kidney cancer; cancer of the head and neck; cancer of the stomach; testicular cancer; germ cell tumour; neuroendocrine tumour; cervical cancer; oral cancer, carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumours including sarcomas, fibrosarcomas, haemangioma, angiomatosis, haemangiopericytoma, pseudoangiomatous stromal hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastic tumour, lipoma, angiolipoma, granular cell tumour, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma or a leiomysarcoma.