US2023192750A1PendingUtilityA1

Salts of diphosphate phosphoramidate of nucleosides as anticancer compounds

Assignee: NuCana plcPriority: Dec 5, 2017Filed: Dec 16, 2022Published: Jun 22, 2023
Est. expiryDec 5, 2037(~11.4 yrs left)· nominal 20-yr term from priority
C07H 19/10A61P 35/02C07H 19/207A61P 35/00A61K 31/7052C07H 19/20A61K 31/7068A61K 31/7076
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Claims

Abstract

The present invention relates to compounds comprising a salt of a diphosphate phosphoramidate of a nucleoside drug, e.g., clofarabine. The compounds are useful in the treatment of cancer, e.g., leukemia.

Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from: C 1 -C 24 -alkyl, C 0 -C 4 -alkylene-C 3 -C 8 -cycloalkyl and C 0 -C 4 -alkylene-aryl; 
         R 2  and R 3  are independently selected from H, C 1 -C 6 -alkyl and C 1 -C 3 -alkylene-R 7 ; 
         R 4  is H; 
         R 5  is aryl; 
         R 6  is 
       
       
         
           
           
               
               
           
         
         R 7  is selected from 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 ; 
         Z 1  is 0; 
         X is at each occurrence a pharmaceutically acceptable cation; 
         wherein each aryl is either phenyl or naphthyl; 
         wherein where any of R 1 , R 2 , R 3 , R 5  or R 7  is an alkyl, cycloalkyl, or aryl, that alkyl, cycloalkyl, or aryl 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 , SO3R 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: H and C 1 -C 4 -alkyl; and R b  is independently at each occurrence selected from: H, and C 1 -C 4 -alkyl and C(O)—C 1 -C 4 -alkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is selected from C 5 -C 7 -cycloalkyl, C 1 -C 8 -alkyl, and benzyl. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is selected such that it comprises five or more carbon atoms. 
     
     
         4 . The compound of  claim 2 , wherein R 1  is benzyl. 
     
     
         5 . The compound of  claim 4 , wherein R 1  is unsubstituted benzyl. 
     
     
         6 . The compound of  claim 2 , wherein R 1  is C 1 -C 8 -alkyl. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is H 
     
     
         8 . The compound of  claim 1 , wherein R 2  is selected from C 1 -C 6 -alkyl and C 1 -C 3 -alkylene-R 7 . 
     
     
         9 . The compound of  claim 8 , wherein R 2  is C 1 -C 4 -alkyl. 
     
     
         10 . The compound of  claim 1 , wherein R 2  is H. 
     
     
         11 . The compound of  claim 1 , wherein R 5  is phenyl. 
     
     
         12 . The compound of  claim 11 , wherein R 5  is unsubstituted phenyl. 
     
     
         13 . The compound of  claim 1 , wherein R 5  is naphthyl. 
     
     
         14 . The compound of  claim 13 , wherein R 5  is 1-naphthyl. 
     
     
         15 . The compound of  claim 13 , wherein R 5  is unsubstituted naphthyl. 
     
     
         16 . The compound of  claim 15 , wherein R 5  is unsubstituted 1-naphthyl. 
     
     
         17 . A method for treating cancer, comprising administering to a patient in need thereof a compound of  claim 1 , wherein the cancer is a leukemia or a lymphoma. 
     
     
         18 . The method of  claim 17 , wherein the cancer is a leukemia selected from the group consisting of acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CIVIL), chronic lymphoid leukemia (CLL) and biphenotypic acute leukemia (BAL). 
     
     
         19 . The method of  claim 17 , wherein the cancer is a lymphoma selected from the group consisting of Hodgkin's lymphoma and non-hodgkin's lymphoma. 
     
     
         20 . A pharmaceutical composition comprising the compound of  claim 1 , and at least one pharmaceutically acceptable excipient.

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