Imidazotetrazine compounds

Abstract

New synthetic methods to provide access to previously unexplored functionality at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.

1 . A method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a salt thereof; 
       wherein
 X is O or S; 
 R 1  is halo, —CN, —NO 2 , —(C 1 -C 6 )alkyl, —C(═O)R a , phenyl, or a 5- or 6-membered heterocycle, wherein R a  is H, halo, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, OR b , SR b , or —NR b R c ; 
 
       wherein
 R b  is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; 
 R c  is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; or 
 when R a  is —NR b R c , Rb and R c  taken together optionally forms a heterocycle; 
 R 2  is —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, phenyl, or a 5- or 6-membered heterocycle; and 
 R 3  is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; 
 wherein each —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, phenyl, and 5- or 6-membered heterocycle are optionally substituted with one or more substituents, and each —(C 1 -C 6 )alkyl is optionally partially or fully unsaturated, and unbranched or optionally branched; 
 wherein the cancer is thereby treated. 
 
     
     
         2 - 25 . (canceled) 
     
     
         26 . The method of  claim 1  wherein R 1  is halo, —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—NH(C 1 -C 6 )alkyl, —C(═O)—N[(C 1 -C 6 )alkyl] 2 , or thiazole. 
     
     
         27 . The method of  claim 26  wherein R 2  is propargyl. 
     
     
         28 . The method of  claim 27  wherein R 3  is H. 
     
     
         29 . The method of  claim 28  wherein X is O. 
     
     
         30 . The method of  claim 1  wherein R 1  is halo, R 2  is propargyl, R 3  is H, and X is O. 
     
     
         31 . The method of  claim 1  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method of  claim 1  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 1  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         34 . The method of  claim 1  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 1  wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient. 
     
     
         36 . The method of  claim 1  wherein the cancer is melanoma, leukemia, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer or brain cancer. 
     
     
         37 . The method of  claim 36  wherein the cancer is brain cancer. 
     
     
         38 . The method of  claim 37  wherein the cancer is glioblastoma (GBM). 
     
     
         39 . The method of  claim 36  wherein a dose of the compound administered is about 0.5 to about 100 mg/kg of body weight per day. 
     
     
         40 . The method of  claim 36  wherein a dose of the compound administered is 5 mg/m 2  to 1000 mg/m 2  of body surface area. 
     
     
         41 . The method of  claim 36  wherein a unit dose of the compound administered is 5 mg to 1000 mg. 
     
     
         42 . The method of  claim 36  wherein a therapeutically effective concentration of the compound reaching the cancer is about 1 nM to about 10 μM. 
     
     
         43 . The method of  claim 36  wherein the composition is administered orally, intravenously, or intracranially. 
     
     
         44 . The method of  claim 36  wherein a dose of the composition is administered once per day. 
     
     
         45 . The compound of  claim 1  wherein R 2  is unbranched —(C 2 -C 6 )alkyl, partially or fully unsaturated. 
     
     
         46 . The compound of  claim 45  wherein R 2  is —CH 2 C≡CH, —CH 2 CH 2 C≡CH, or —CH 2 C≡CCH 3 .