Phosphoramidate nucleoside derivatives as anticancer agents

Abstract

This invention relates to derivatives of cladribine. The compounds are phosphoramidate derivatives in which the phosphoramidate moiety is situated on the 3′-hydroxyl group of cladribine. The invention also relates to pharmaceutical formulations of the cladribine derivatives and their use in methods of treatment. The compounds are useful in the treatment of cancer.

1 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is aryl; 
 R 2  is selected from the group consisting of C 1 -C 24 -alkyl, C 3 -C 24 -alkenyl, C 3 -C 24 -alkynyl, C 0 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, and C 0 -C 4 -alkylene-aryl; 
 R 3  and R 4  are each independently selected from the group consisting of H, C 1 -C 6 -alkyl and C 1 -C 3 -alkylene-R 9 ; or wherein R 3  and R 4  together with the atom to which they are attached form a C 3 -C 6 -cycloalkyl or 3- to 6-membered heterocycloalkyl group, wherein said heterocycloalkyl group comprises at least one heteroatom selected from O, N, or S; 
 R 5  and R 7  are each independently selected from the group consisting of H and C 1 -C 4 -alkyl; 
 R 6  is independently selected from the group consisting of H and C(O)R 10 ; 
 R 8  is independently selected from the group consisting of H, C(O)OR 10  and C(O)R 10 ; 
 R 9  is independently selected from the group consisting of aryl, imidazole, indole, SR a , OR a , CO 2 R a , CO 2 NR a R a , NR a R b  and NH(═NH)NH 2 ; 
 R 10  is independently at each occurrence selected from the group consisting of C 1 -C 24 -alkyl, C 3 -C 24 -alkenyl, C 3 -C 24 -alkynyl, C 0 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, and C 0 -C 4 -alkylene-aryl; 
 wherein any aryl group is selected from the group consisting of phenyl, naphthyl, and tetrahydronaphthyl and wherein any phenyl, alkyl, alkyne, alkene, alkylene, cycloalkyl, naphthyl or tetrahydronaphthyl group is optionally substituted with from 1 to 4 substituents selected from: halo, nitro, cyano, NR a R a , NR a S(O) 2 R a , NR a C(O)R a , NR a CONR a R a , NR a CO 2 R a , OR a , SR a , SOR a , SO 3 R a , SO 2 R a , SO 2 NR a R a , CO 2 R a C(O)R a , CONR a R a , CR a R a NR a R a , C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and C 1 -C 4 -haloalkyl; 
 wherein R a  is independently at each occurrence selected from the group consisting of: H and C 1 -C 4 -alkyl; and R b  is independently at each occurrence selected from the group consisting of: H, C 1 -C 4 -alkyl, C(O)—C 1 -C 4 -alkyl, and S(O) 2 —C 1 -C 4 -alkyl. 
 
     
     
         2 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein R 1  is substituted or unsubstituted phenyl. 
     
     
         4 . The method of  claim 3 , wherein R 1  is unsubstituted phenyl. 
     
     
         5 . The method of  claim 1 , wherein R 1  is substituted or unsubstituted 1-naphthyl. 
     
     
         6 . The method of  claim 5 , wherein R 1  is unsubstituted 1-naphthyl. 
     
     
         7 . The method of  claim 1 , wherein R 2  is C 4 -C 8 -alkyl. 
     
     
         8 . The method of  claim 7 , wherein R 2  is selected from the group consisting of iso-butyl, tert-butyl, n-butyl, n-pentyl, CH 2 C(Me) 3 , and n-hexyl. 
     
     
         9 . The method of  claim 1 , wherein R 2  is C 5 -C 7 -cycloalkyl. 
     
     
         10 . The method of  claim 9 , wherein R 2  is unsubstituted cyclohexyl. 
     
     
         11 . The method of  claim 1 , wherein R 2  is CHR 11 -phenyl; wherein R 11  is selected from the group consisting of H and C 1 -C 4 -alkyl. 
     
     
         12 . The method of  claim 11 , wherein R 2  is unsubstituted benzyl. 
     
     
         13 . The method of  claim 1 , wherein one of R 3  and R 4  is H and the other is selected from the group consisting of: H, Me, isopropyl, isobutyl, and benzyl. 
     
     
         14 . The method of  claim 13 , wherein R 4  is H and R 3  is selected from the group consisting of: H, Me, isopropyl, isobutyl, and benzyl. 
     
     
         15 . The method of  claim 14 , wherein R 4  is H and R 3  is Me. 
     
     
         16 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 - 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the cancer is selected from the group consisting of leukaemia, multiple myeloma, lung cancer, liver cancer, breast cancer, head and neck cancer, neuroblastoma, thyroid carcinoma, skin cancer, oral squamous cell carcinoma, urinary bladder cancer, Leydig cell tumour, colon cancer, colorectal cancer, and gynaecological cancers. 
     
     
         20 . The method of  claim 1 , wherein the subject has mycoplasma infected cells. 
     
     
         21 . The method of  claim 1 , wherein the method targets cancer stem cells. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein the cancer is leukaemia, and the leukaemia is selected from the group consisting of myeloid leukaemia, multiple myeloma, chronic myelogenous leukaemia, acute myelogenous leukaemia, and acute lymphocytic leukaemia. 
     
     
         24 . The method of  claim 1 , wherein the cancer is lymphoma, and the lymphoma is selected from the group consisting of Hodgkin Lymphoma and non-Hodgkin Lymphoma.