2'-halogenated-4'-thio-2'-deoxy-5-azacytidine analogs and use thereof

Abstract

Halogenated analogs of 5-aza-2′-deoxycytidine, such as halogenated analogs of 5-aza-4′-thio-2′-deoxycytidine (5-aza-T-dCyd) are described. Pharmaceutical compositions including a halogenated analog and methods of using the halogenated analogs to inhibit neoplasia are described. In some examples, the halogenated analogs have a structure according to formula Ia, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

1 . A compound according to formula Ia, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       where X is halo;
 Y is hydrogen, halo, or deuterium; 
 each R independently is hydrogen or deuterium; and 
 R a  is hydrogen, deuterium, alkyl, alkoxy, amino, or halo. 
 
     
     
         2 . The compound of  claim 1 , wherein:
 (i) X is F; or   (ii) Y is hydrogen or F; or   (iii) each R is hydrogen; or   (iv) R a  is hydrogen; or   (v) any combination of (i), (ii), (iii), and (iv).   
     
     
         3 . The compound of  claim 1  having a stereochemistry according to any one of formulas IIa-Va or any combination thereof 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or any combination thereof. 
     
     
         5 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or any combination thereof. 
     
     
         6 . The compound of  claim 1 , wherein the compound is 4-amino-1-((2R,3S,4S,5R)-3-fluoro-4-hydro-5-(hydroxymethyl)tetrahydrothiophen-2-yl)-1,3,5-triazin-2(1H)-one: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the pharmaceutical composition is formulated for intravenous, oral, intraperitoneal, subcutaneous, rectal, or buccal administration. 
     
     
         9 . A method of inhibiting a neoplasia, comprising:
 contacting neoplastic cells with an effective amount of a compound according to  claim 1 .   
     
     
         10 . The method of  claim 9 , wherein contacting the neoplastic cells with the effective amount of the compound reduces proliferation of the neoplastic cells. 
     
     
         11 . The method of  claim 9 , wherein the compound is 4-amino-1-((2R,3S,4S,5S)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrothiophen-2-yl-1,3,5-triazin-2(1H)-one: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 9 , wherein contacting the neoplastic cells with the effective amount of the compound comprises administering a therapeutically effective amount of the compound to a subject having or suspected of having a disease characterized at least in part by presence of neoplastic cells. 
     
     
         13 . The method of  claim 12 , wherein the disease is a cancer. 
     
     
         14 . The method of  claim 13 , wherein the cancer is a cancer of the kidney, bladder, breast, colon, endometrium, skin, blood, pancreas, prostate, bone, liver, lung, esophagus, or central nervous system. 
     
     
         15 . The method of  claim 12 , wherein administering the therapeutically effective amount of the compound to the subject reduces a sign or symptom of the disease. 
     
     
         16 . The method of  claim 15 , wherein:
 the sign or symptom of the disease is a solid tumor and administering the therapeutically effective amount of the compound to the subject reduces growth of the solid tumor, reduces a volume of the solid tumor, reduces metastasis of the solid tumor, or any combination thereof; or   the sign or symptom of the disease is an abnormal complete blood count and administering the therapeutically effective amount of the compound to the subject at least partially normalizes the complete blood count.   
     
     
         17 . The method of  claim 12 , wherein administering the therapeutically effective amount of the compound comprises administering a pharmaceutical composition comprising the therapeutically effective amount of the compound to the subject. 
     
     
         18 . The method of  claim 12 , wherein administering comprises intravenous, oral, intraperitoneal, subcutaneous, rectal, or buccal administration. 
     
     
         19 . The method of  claim 12 , further comprising administering a second active agent to the subject. 
     
     
         20 . The method of  claim 19 , wherein the second active agent is an anti-cancer agent, an anti-inflammatory agent, an antimicrobial agent, an antiviral agent, an anesthetic agent, or any combination thereof.