Ship inhibitors and uses thereof

Abstract

The present invention relates to SHIP inhibitor compounds and methods for using these compounds. In particular, the present invention discloses the following methods: (i) a method of treating graft versus host disease in a subject; (ii) a method of inhibiting a SHIP1 protein in a cell; (iii) a method of selectively inhibiting a SHIP1 protein in a cell; (iv) a method for treating or preventing graft-versus-host disease (GVHD) in a recipient of an organ or tissue transplant; (v) a method of modulating SHIP activity in a cell expressing SHIP1 or SHIP2; (vi) a method of ex vivo or in vitro treatment of transplants; (vii) a method of inhibiting tumor growth and metastasis in a subject; (viii) a method of treating a hematologic malignancy in a subject; (ix) a method of inducing apoptosis of multiple myeloma cells; (x) a method of treating multiple myeloma in a subject; (xi) a method of inhibiting the proliferation of a human breast cancer cell; and (xii) a method of treating breast cancer in a subject.

What is claimed is: 
     
         1 . A SHIP inhibitor compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is as follows: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is methyl; 
 R 2  is methyl; 
 R 3  is hydrogen, hydroxy, amino, or aminomethyl; 
 R 4  is hydrogen, hydroxy, amino, or aminomethyl; 
 R 5  is hydrogen or alkyl; 
 R 13  is hydrogen; 
 X 1  is selected from the group consisting of hydrogen, hydroxy, substituted amino, unsubstituted amino, and aminoalkyl; and 
 the dotted lines represent optional double bonds; 
 wherein if R 3  is a hydrogen, R 4  is a hydrogen, R 5  is a hydrogen, and each dotted line individually represents a single bond, then X 1  is selected from the group consisting of hydrogen, hydroxy, mercapto, alkoxy, aryloxy, alkylthio, arylthio, alkylcarbonamido, alkoxycarbonamido, arylcarbonamido, aryloxycarbonamido, alkylsulfonamido, arylsulfonamido, an unsubstituted amino in beta orientation, and aminoalkyl. 
 
       
     
     
         2 . A SHIP inhibitor compound according to  claim 1 , wherein R 5  is hydrogen. 
     
     
         3 . A SHIP inhibitor compound according to  claim 2 , wherein said compound of formula (I) is a compound of a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt thereof,
 wherein X═NR 2 , NRCOR, NHCONR 2 , OR, SR, OCOR, OCONR 2 , or NHCNHNH 2 , and 
 wherein R═H, alkyl, cycloalkyl, aryl, or benzyl. 
 
     
     
         4 . A SHIP inhibitor compound according to  claim 3 , wherein said compound of formula (I) is a compound of a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . A SHIP inhibitor compound according to  claim 3 , wherein said compound of formula (I) is a compound of Formula 28: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein X═NH 2 . 
       
     
     
         6 . A SHIP inhibitor compound according to  claim 2 , wherein said compound of formula (I) is as follows: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein X═NR 2 , NHR, NHCOH, NRCOH, NHCOR, NRCOR, NHCONR 2 , NHCONH 2 , OR, OH, SR, SH, OCOR, OCOH, OCONR 2 , OCONH 2 , or NHCNHNH 2 , and
 wherein R=alkyl, cycloalkyl, aryl, or benzyl. 
 
     
     
         7 . A compound according to  claim 1 , wherein R 3  is hydrogen. 
     
     
         8 . A compound according to  claim 1 , wherein X 1  is hydroxy. 
     
     
         9 . A compound according to  claim 7 , wherein X 1  is hydroxy. 
     
     
         10 . A SHIP inhibitor compound according to  claim 1 , wherein R 5  is alkyl. 
     
     
         11 . A SHIP inhibitor compound according to  claim 10 , wherein said compound of formula (I) is a compound of a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein X═NR 2 , NRCOR, NHCONR 2 , OR, SR, OCOR, OCONR 2 , or NHCNHNH 2 , and wherein R═H, alkyl, cycloalkyl, aryl, or benzyl. 
     
     
         12 . A compound according to  claim 10 , wherein, wherein R 5  represents a 1, 5-dimethylhexyl group. 
     
     
         13 . A compound according to  claim 10 , wherein X 1  is hydroxy. 
     
     
         14 . A compound according to  claim 10 , wherein R 4  is substituted or unsubstituted amino. 
     
     
         15 . A compound according to  claim 10 , wherein R 5  is methyl. 
     
     
         16 . A SHIP inhibitor compound according to  claim 15 , wherein said compound of formula (I) is as follows: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A SHIP inhibitor compound according to  claim 10 , wherein said compound of formula (I) is as follows: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.