Treatment of resistant or refractory cancers with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin

Abstract

A method of treating a resistant or refractory cancer in a mammal includes administering an effective amount of a compound of to the mammal. In preferred aspects, the cancer is resistant or refractory to CPT-11 or CPT therapy.

1 . A method of treating a resistant or refractory cancer in a mammal, comprising: administering an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2 , R 3  and R 4  are independently OH or 
       
       
         
           
           
               
               
           
         
         
           wherein 
           L is a bifunctional linker; 
           m is 0 or a positive integer; and 
           n is a positive integer; 
           provided that R 1 , R 2 , R 3  and R 4  are not all OH; 
         
       
       or a pharmaceutically acceptable salt thereof to said mammal. 
     
     
         2 . The method of  claim 1 , wherein the resistant or refractory cancer is selected from the group consisting of solid tumors, lymphomas, lung cancer, small cell lung cancer, acute lymphocytic leukemia (ALL), breast cancer, pancreatic cancer, glioblastoma, ovarian cancer and gastric cancer. 
     
     
         3 . The method of  claim 1 , wherein the cancer is resistant or refractory to camptothecin or camptothecin analog therapy. 
     
     
         4 . The method of  claim 1 , wherein the cancer is resistant or refractory to CPT-11 therapy. 
     
     
         5 . The method of  claim 1 , wherein the cancer is resistant or refractory to camptothecin therapy. 
     
     
         6 . The method of  claim 1 , wherein L is a residue of an amino acid or amino acid derivative, and the amino acid derivative is selected from the group consisting of 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, beta-aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, piperidinic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4-aminobutyric acid, desmosine, 2,2-diaminopimelic acid, 2,3-diaminopropionic acid, n-ethylglycine, N-ethylasparagine, 3-hydroxyproline, 4-hydroxyproline, isodemosine, allo-isoleucine, N-methylglycine, sarcosine, N-methyl-isoleucine, 6-N-methyl-lysine, N-methylvaline, norvaline, norleucine, and ornithine. 
     
     
         7 . The method of  claim 1 , wherein L is selected from the group consisting of
 —[C(═O)] v (CR 22 R 23 ) t —,   —[C(═O)] v (CR 22 R 23 ) t —O—,   —[C(═O)] v (CR 22 R 23 ) t —NR 26 —,   —[C(═O)] v O(CR 22 R 23 ) t —,   —[C(═O)] v O(CR 22 R 23 ) t —O—,   —[C(═O)] v O(CR 22 R 23 ) t —NR 26 —,   —[C(═O)] v NR 21 (CR 22 R 23 ) t —,   —[C(═O)] v NR 21 (CR 22 R 23 ) t O—,   —[C(═O)] v NR 21 (CR 22 R 23 ) t NR 26 —,   —[C(═O)] v (CR 22 R 23 O) t —,   —[C(═O)] v O(CR 22 R 23 O) t —,   —[C(═O)] v NR 21 (CR 22 R 23 O) t —,   —[C(═O)] v (CR 22 R 23 O) t (CR 24 R 25 ) y —,   —[C(═O)] v O(CR 22 R 23 O) t (CR 24 R 25 ) y —,   —[C(═O)] v NR 21 (CR 22 R 23 O) t (CR 24 R 25 ) y —,   —[C(═O)] v (CR 22 R 23 O) t (CR 24 R 25 ) y O—,   [C(═O)] v (CR 22 R 23 ) t (CR 24 R 25 O) y —,   —[C(═O)] v O(CR 22 R 23 O) t (CR 24 R 25 ) y O—,   —[C(═O)] v O(CR 22 R 23 ) t (CR 24 R 25 O) y —,   —[C(═O)] v NR 21 (CR 22 R 23 O) t (CR 24 R 25 ) y O—,   —[C(═O)] v NR 21 (CR 22 R 23 ) t (CR 24 R 25 O) y —,   [C(═O)] v (CR 22 R 23 ) t O—(CR 28 R 29 ) t′ —,   —[C(═O)] v (CR 22 R 23 ) t NR 26 —(CR 28 R 29 ) t′ —,   —[C(═O)] v (CR 22 R 23 ) t S—(CR 28 R 29 ) t′ —,   —[C(═O)] v O(CR 22 R 23 ) t O—(CR 28 R 29 ) t′ —,   —[C(═O)] v O(CR 22 R 23 ) t NR 26 —(CR 28 R 29 ) t′ —,   —[C(═O)] v O(CR 22 R 23 ) t S—(CR 28 R 29 ) t′ —,   —[C(═O)] v NR 21 (CR 22 R 23 ) t O—(CR 28 R 29 ) t′ —,   —[C(═O)] v NR 21 (CR 22 R 23 ) t NR 26 —(CR 28 R 29 ) t′ —,   —[C (═O)] v NR 21 (CR 22 R 23 ) t S—(CR 28 R 29 ) t′ —,   —[C(═O)] v (CR 22 R 23 CR 28 R 29 O) t NR 26 —,   —[C(═O)] v (CR 22 R 23 CR 28 R 29 O) t —,   —[C(═O)] v O(CR 22 R 23 CR 28 R 29 O) t NR 26 —,   —[C(═O)] v O(CR 22 R 23 CR 28 R 29 O) t —,   —[C(═O)] v NR 21 (CR 22 R 23 CR 28 R 29 O) t NR 26 —,   —[C(═O)] v NR 21 (CR 22 R 23 CR 28 R 29 O) t —,   —[C(═O)] v (CR 22 R 23 CR 28 R 29 O) t CR 24 R 25 ) y —,   —[C(═O)] v O(CR 22 R 23 CR 28 R 29 O) t (CR 24 R 25 ) y —,   —[C(═O)] v NR 21 (CR 22 R 23 CR 28 R 29 O) t (CR 24 R 25 ) y —,   —[C(═O)] v (CR 22 R 23 CR 28 R 29 O) t (CR 24 R 25 ) y O—,   —[C(═O)] v (CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y —,   —[C(═O)] v (CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y NR 26 —,   —[C(═O)] v O(CR 22 R 23 CR 28 R 29 O) t (CR 24 R 25 ) y O—,   —[C(═O)] v O(CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y —,   —[C(═O)] v O(CR 22 R 23 ) t (CR 24 CR 25 CR 28 R 29 O) y NR 26 —,   —[C(O)] v NR 21 (CR 22 R 23 CR 28 R 29 O) t (CR 24 R 25 ) y O—,   —[C(═O)] v NR 21 (CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y —,   —[C(O)] v NR 21 (CR 22 R 23 ) t (CR 24 R 25 CR 28 R 29 O) y NR 26 —,   
       
         
           
           
               
               
           
         
         wherein: 
         R 21 -R 29  are independently selected from the group consisting of hydrogen, amino, substituted amino, azido, carboxy, cyano, halo, hydroxyl, nitro, silyl ether, sulfonyl, mercapto, C 1-6  alkylmercapto, arylmercapto, substituted arylmercapto, substituted C 1-6  alkylthio, C 1-6  alkyls, C 2-6  alkenyl, C 2-6  alkynyl, C 3-19  branched alkyl, C 3-8  cycloalkyl, C 1-6  substituted alkyl, C 2-6  substituted alkenyl, C 2-6  substituted alkynyl, C 3-8  substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1-6  heteroalkyl, substituted C 3-6  heteroalkyl, C 1-6  alkoxy, aryloxy, C 1-6  heteroalkoxy, heteroaryloxy, C 2-6  alkanoyl, arylcarbonyl, C 2-6  alkoxycarbonyl, aryloxycarbonyl, C 2-6  alkanoyloxy, arylcarbonyloxy, C 2-6  substituted alkanoyl, substituted arylcarbonyl, C 2-6  substituted alkanoyloxy, substituted aryloxycarbonyl, C 2-6  substituted alkanoyloxy, substituted and arylcarbonyloxy; 
         (t), (t′) and (y) are independently selected from zero or a positive integer; and 
         (v) is 0 or 1. 
       
     
     
         8 . The method of  claim 1 , wherein m is from about 1 to about 10. 
     
     
         9 . The method of  claim 1 , wherein m is about 1. 
     
     
         10 . The method of  claim 1 , wherein n is from about 28 to about 341. 
     
     
         11 . The method of  claim 1 , wherein n is from about 114 to about 227. 
     
     
         12 . The method of  claim 1 , wherein n is about 227. 
     
     
         13 . The method of  claim 1 , wherein the compound of formula (I) is part of a pharmaceutical composition and the compound of formula (I) included therein has about 3.9 units of 
       
         
           
           
               
               
           
         
       
     
     
         14 . A method of  claim 1 , wherein the compound of formula (I) is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 1 , wherein the compound of formula (I) is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1 , wherein the compound is administered in amounts of from about 0.1 to about 45 mg/m 2 /dose. 
     
     
         17 . The method of  claim 1 , wherein the compound is administered in amounts of from about 1.25 to about 16.5 mg/m 2 /dose. 
     
     
         18 . The method of  claim 1 , wherein the compound is administered in combination with a second chemotherapeutic agent simultaneously or sequentially. 
     
     
         19 . A method of treating a resistant or refractory cancer in a mammal, comprising:
 administering an effective amount of a compound of   
       
         
           
           
               
               
           
         
       
       in amounts from about 1.25 to about 16.5 mg/m 2 /dose,
 wherein n is from about 28 to about 341 
 
       to said mammal.