Thiadiazolidinone Derivatives

Abstract

The present invention relates to compounds of the formulae herein, their acceptable salts, solvates, hydrates and polymorphs thereof. The compounds of this invention are useful in treatment of disease, particularly leukemia. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating disease, disorders, or symptoms thereof in a subject.

What is claimed is: 
     
         1 . A method for treating leukemia in a subject comprising administration to the subject of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt thereof; or a prodrug or a salt of a prodrug thereof; or a hydrate, solvate or polymorph thereof; wherein:
 A is —C(R 1 ) 2 —, —O— or —NR 1 —; E is —NR 1 — or —CR 1 R 2 — and the substituent R 2  is absent if - - - is a second bond between E and G; G is —S—, —NR 1 — or —CR 1 R 2 — and the substituent R 2  is absent if - - - is a second bond between E and G; - - - may be a second bond between E and G where the nature of E and G permits and E with G optionally then forms a fused aryl group; R 1  and R 2  are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, —(Z) n -aryl, heteroaryl, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —(Z) n —C(O)OR 3  and —S(O) t — or as indicated R 2  can be such that E with G then form a fused aryl group; Z is independently selected from —C(R 3 )(R 4 )—, —C(O)—, —O—, —C(═NR 3 )—, —S(O) t — and N(R 3 )—; n is zero, one or two; t is zero, one or two; R 3  and R 4  are each independently selected from hydrogen, alkyl, aryl and heterocyclic; and X and Y are each independently selected from ═O, ═S, ═N(R 3 ) and ═C(R 1 )(R 2 ). 
 
     
     
         2 . A method for treating leukemia in a subject comprising administration to the subject of a compound of Formula (I) in  claim 1  capable of causing cell death of leukemia tumor cells. 
     
     
         3 . A method for treating leukemia in a subject comprising administration to the subject of a compound of Formula (I) in  claim 1  capable of causing cell death of the rare leukemia stem cell subpopulation. 
     
     
         4 . A method for treating leukemia in a subject comprising causing the cell death of leukemia stem cells in a subject by administration to the subject of a compound of Formula (I) in  claim 1 . 
     
     
         5 . A method for treating leukemia in a subject comprising administration to the subject of a compound of Formula (I) in  claim 1  capable of permeabilization of cell membranes and inducing oxidative stress. 
     
     
         6 . A method for treating leukemia in a subject comprising administration to the subject of a compound of Formula (I) in  claim 1  capable of causing cell death of both leukemia cells and leukemia stem cells. 
     
     
         7 . A method for treating a blood disease in a subject comprising administration to the subject of a compound of Formula (I) in  claim 1 . 
     
     
         8 . A method for treating leukemia in a subject comprising administration to the subject of a compound of Formula (I) in  claim 1  and an additional therapeutic agent. 
     
     
         9 . The method of  claim 1 , wherein the leukemia is acute myelogenus leukemia (AML), blast crisis leukemia (CML, both lymphoid and meloid forms of the disorder), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL). 
     
     
         10 . A method of treating a disorder in a subject, wherein the disorder is cancer cell growth; lymphoma, multiple myeloma, leukemia cell growth; proliferative diseases; blood cancers; hematologic malignancies, or disorders such as acute myelogenus leukemia (AML), blast crisis leukemia (CML, both lymphoid and meloid forms of the disorder), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL), comprising administration of a compound of Formula (I) in  claim 1 . 
     
     
         11 . The method of  claim 1  wherein A is —NR 1 — and E is —NR 1 —. 
     
     
         12 . The method of  claim 1  wherein G is —S—, A is —NR 1 — and E is —NR 1 —. 
     
     
         13 . The method of  claim 12  wherein X and Y are O. 
     
     
         14 . The method of  claim 13  wherein the compound is 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). 
     
     
         15 . Use of a compound of Formula (I) in  claim 1  for the manufacture of a medicament for use in treatment or prevention of leukemia. 
     
     
         16 . A composition for use in treatment or prevention of leukemia in a subject comprising a compound of Formula (I) in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . An article of manufacture comprising separate dosage forms of a composition comprising a compound of Formula I in  claim 1 , or a pharmaceutically acceptable salt thereof; or a prodrug, or a pharmaceutically acceptable salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; and an acceptable carrier; and a second therapeutic agent, wherein both dosage forms are in a single container. 
     
     
         18 . A method for treating leukemia in a subject comprising administration to the subject of a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein:
 each R 1  and R 2  are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, —(Z) n -aryl, heteroaryl, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —(Z) n —C(O)OR 3  and —S(O) t — or as indicated R 2  can be such that E with G then form a fused aryl group; Z is independently selected from —C(R 3 )(R 4 )—, —C(O)—, —O—, —C(═NR 3 )—, —S(O) t — and N(R 3 )—; n is zero, one or two; t is zero, one or two; R 3  and R 4  are each independently selected from hydrogen, alkyl, aryl and heterocyclic; and X and Y are each independently selected from ═O, ═S, ═N(R 3 ) and ═C(R 1 )(R 2 ). 
 
     
     
         19 . The method of  claim 18 , wherein each R 1  is independently alkyl or arylalkyl. 
     
     
         20 . The method of  claim 18 , wherein one R 1  is independently alkyl and the other R 1  is independently arylalkyl. 
     
     
         21 . A method of treating a kinase-mediated disease or disorder in a subject comprising administration to the subject of a compound of Formula (I) in  claim 1 . 
     
     
         22 . The method of  claim 21 , wherein the kinase is AKT1 (PKB alpha), CHEK1 (CHK1), DYRK3, FLT3, GSK3B, KDR (VEGFR2), MAP4K4 (HGK), MAPK14 (p38 alpha), MAPKAPK2, MET (cMet), PHKG2, PIM1, PRKCA (PKC alpha), PRKCB1 (PKC beta1), PRKCB2 (PKC beta2), PRKCD (PKC delta), PRKCE (PKC epsilon), PRKG (PKC gamma), PRKCH (PKC eta), PRKCI (PKC iota), PRKCN (PKD3), PRKCQ (PKC theta), PRKCZ (PKC zeta), PRKCD1 (PKC mu), ROCK1, RPS6KA3 (RSK2), STK6 (Aurora A), or SYK.