Treatment of solid tumors with rapamycin derivatives

Abstract

Rapamycin derivatives have interesting effects in the treatment of solid tumours, optionally in combination with a chemotherapeutic agent.

1 . A method for treating solid tumors in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is CH 3  or C 3-6 alkynyl, 
         R 2  is H or —CH 2 —CH 2 —OH, and 
         X is ═O, (H,H) or (H,OH) 
         provided that R 2  is other than H when X is ═O and R 1  is CH 3 . 
       
     
     
         2 . The method of  claim 1 , wherein said compound of formula I is administered concomitantly or sequentially with a co-agent which is a chemotherapeutic agent. 
     
     
         3 . The method of  claim 2  wherein the co-agent is selected from the group consisting of
 i. an aromatase inhibitor, 
 ii. an antiestrogen, an anti-androgen or a gonadorelin agonist, 
 iii. a topoisomerase I inhibitor or a topoisomerase II inhibitor, 
 iv. a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite or a platin compound, 
 v. a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a further anti-angiogenic compound or a compound which induces cell differentiation processes, 
 vi. a bradykinin 1 receptor or an angiotensin II antagonist, 
 vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, a heparanase inhibitor, a biological response modifier, an ubiquitination inhibitor, or an inhibitor which blocks anti-apoptotic pathways, 
 viii. an inhibitor of Ras oncogenic isoforms, 
 ix. a telomerase inhibitor, and 
 x. a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor, or a proteosome inhibitor. 
 
     
     
         4 . A method for treating solid tumor invasiveness or symptoms associated with such tumor growth in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is CH 3  or C 3-6 alkynyl, 
         R 2  is H or —CH 2 —CH 2 —OH, and 
         X is ═O, (H,H) or (H,OH) 
         provided that R 2  is other than H when X is ═O and R 1  is CH 3 . 
       
     
     
         5 . The method of  claim 4 , wherein said compound of formula I is administered concomitantly or sequentially with a co-agent which is a chemotherapeutic agent. 
     
     
         6 . The method of  claim 5 , wherein the co-agent is selected from the group consisting of
 i. an aromatase inhibitor,   ii. an antiestrogen, an anti-androgen or a gonadorelin agonist,   iii. a topoisomerase I inhibitor or a topoisomerase II inhibitor,   iv. a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite or a platin compound,   v. a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a further anti-angiogenic compound or a compound which induces cell differentiation processes,   vi. a bradykinin 1 receptor or an angiotensin II antagonist,   vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, a heparanase inhibitor, a biological response modifier, an ubiquitination inhibitor, or an inhibitor which blocks anti-apoptotic pathways,   viii. an inhibitor of Ras oncogenic isoforms,   ix a telomerase inhibitor, and   x. a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor, or a proteosome inhibitor.   
     
     
         7 . A method for inhibiting or controlling deregulated angiogenesis in a subject in need thereof, comprising administering to said subject a therapeutically affective amount of rapamycin or a rapamycin derivative. 
     
     
         8 . The method of  claim 7 , wherein said rapamycin or rapamycin derivative is administered concomitantly or sequentially with a co-agent which is a chemotherapeutic agent. 
     
     
         9 . The method of  claim 8 , wherein the co-agent is selected from the group consisting of
 i. an aromatase inhibitor,   ii. an antiestrogen, an anti-androgen or a gonadorelin agonist,   iii. a topoisomerase I inhibitor or a topoisomerase II inhibitor,   iv. a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite or a platin compound,   v. a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a further anti-angiogenic compound or a compound which induces cell differentiation processes,   vi. a bradykinin 1 receptor or an angiotensin II antagonist,   vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, a heparanase inhibitor, a biological response modifier, an ubiquitination inhibitor, or an inhibitor which blocks anti-apoptotic pathways,   viii. an inhibitor of Ras oncogenic isoforms,   ix. a telomerase inhibitor, and   x. a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor, or a proteosome inhibitor.   
     
     
         10 . A pharmaceutical composition for use in the treatment of solid tumors comprising a compound of formula I 
       
         
           
           
               
               
           
         
         together with one or more pharmaceutically acceptable diluents or carriers therefor. 
       
     
     
         11 . A pharmaceutical combination comprising a) a compound of Formula I 
       
         
           
           
               
               
           
         
         and b) a co-agent which is a chemotherapeutic agent. 
       
     
     
         12 . The pharmaceutical combination of  claim 11  wherein the co-agent is selected from the group consisting of
 i. an aromatase inhibitor, 
 ii. an antiestrogen, an anti-androgen or a gonadorelin agonist, 
 iii. a topoisomerase I inhibitor or a topoisomerase II inhibitor, 
 iv. a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite or a platin compound, 
 v. a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a further anti-angiogenic compound or a compound which induces cell differentiation processes, 
 vi. a bradykinin 1 receptor or an angiotensin II antagonist, 
 vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, a heparanase inhibitor, a biological response modifier, an ubiquitination inhibitor, or an inhibitor which blocks anti-apoptotic pathways, 
 viii. an inhibitor of Ras oncogenic isoforms, 
 ix. a telomerase inhibitor, and 
 x. a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor, or a proteosome inhibitor. 
 
     
     
         13 . A pharmaceutical composition for use in the inhibition or controlling of deregulated angiogenesis comprising rapamycin or a rapamycin derivative, together with one or more pharmaceutically acceptable diluents or carriers therefor. 
     
     
         14 . A pharmaceutical combination comprising a) rapamycin or rapamycin derivative and b) a co-agent which is a chemotherapeutic agent selected from the group consisting of
 A. an aromatase inhibitor,   B. a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a further anti-angiogenic compound or a compound which induces cell differentiation processes,   C. a bradykinin 1 receptor or an angiotensin II antagonist,   D. a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, a heparanase inhibitor, a biological response modifier, an ubiquitination inhibitor, or an inhibitor which blocks anti-apoptotic pathways,   E. an inhibitor of Ras oncogenic isoforms,   F. a telomerase inhibitor, and   G. a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor, or a proteosome inhibitor.