Methods and compounds for treatment of lymphocyte-related diseases and conditions

Abstract

Methods for treatment of lymphocyte-related diseases and conditions, such as cancer and automimmune diseases, are provided. The methods comprise administration of an effective amount of an oligomer to a patient in need thereof, wherein the oligomer comprises, inter alia, at least one intersubunit linkage having the following structure:wherein R1, L1, X, Y and Z are as defined herein.

1 . A method for treatment of a lymphocyte-related disease or condition, the method comprising administering an effective amount of an oligomer to a patient in need thereof, wherein the oligomer comprises a backbone having a sequence of morpholino ring structures joined by intersubunit linkages, the intersubunit linkages joining a 3′-end of one morpholino ring structure to a 5′-end of an adjacent morpholino ring structure, wherein each morpholino ring structure is bound to a base-pairing moiety, such that the oligomer can bind in a sequence-specific manner to a target nucleic acid, wherein at least one of the intersubunit linkages has the following structure (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
 R 1  is guanidinyl, alkylguanidinyl or alkylaminyl; 
 L 1  is absent or present, and when present is selected from alkylene, aminoalkylene, oxyalkylene and thioalkylene; 
 X is, at each occurrence, independently S or O; 
 Y is, at each occurrence, independently —O— or —NH—; and 
 Z is an optionally substituted 5, 6 or 7-membered heterocyclic ring. 
 
       
     
     
         2 . The method of  claim 1 , wherein the morpholino ring structures have the following structure (i): 
       
         
           
           
               
               
           
         
         wherein B is, at each occurrence, independently a base-pairing moiety. 
       
     
     
         3 . The method of any one of  claims 1 - 2 , wherein Z is an optionally substituted 5 or 6-membered heterocyclic ring. 
     
     
         4 . The method of  claim 3 , wherein Z is pyrrolidinyl, or piperidinyl. 
     
     
         5 . The method of  claim 4 , wherein Z is piperidinyl. 
     
     
         6 . The method of  claim 4 , wherein Z has one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 6 , wherein Z has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 7 , wherein Z has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of any one of  claims 1 - 8 , wherein R 1  is guanidinyl. 
     
     
         10 . The method of any one of  claims 1 - 8 , wherein R 1  is alkylguanidinyl. 
     
     
         11 . The method of  claim 10 , wherein alkylguanidinyl has the following structure: 
       
         
           
           
               
               
           
         
         wherein R′ is C 1 -C 6 alkyl. 
       
     
     
         12 . The method of  claim 11 , wherein R′ is methyl. 
     
     
         13 . The method of any one of  claims 1 - 8 , wherein R 1  is alkylaminyl. 
     
     
         14 . The method of  claim 13 , wherein alkylaminyl is —NHR″, where R″ is C 1 -C 6 alkyl. 
     
     
         15 . The method of  claim 14 , wherein R″ is methyl. 
     
     
         16 . The method of any one of  claim 1 - 15 , wherein L 1  is absent. 
     
     
         17 . The method of any one of  claims 1 - 16 , wherein X is O. 
     
     
         18 . The method of any one of  claims 1 - 17 , wherein Y is —O—. 
     
     
         19 . The method of any one of  claims 1 - 13 , wherein at least one of the intersubunit linkages has the following structure (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
 R 2  and R 3  are each independently H or C 1 -C 6 alkyl, 
 X′ is S or O; and 
 Y′ is —O— or —NH—. 
 
       
     
     
         20 . The method of  claim 19 , wherein R 2  and R 3  are each methyl. 
     
     
         21 . The method of  claim 19  or  20  wherein X′ is O. 
     
     
         22 . The method of any one of  claims 19 - 21 , wherein Y′ is —O—. 
     
     
         23 . The method of  claim 1 , wherein at least one of the intersubunit linkages has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of  claim 1 , wherein at least one of the intersubunit linkages has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 1 , wherein at least one of the intersubunit linkages has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The method of any one of  claims 1 - 25 , wherein the lymphocyte-related disease or condition is a T-cell-related disease or condition. 
     
     
         27 . The method of  claim 26 , wherein the T-cell is an activated T-cell. 
     
     
         28 . The method of  claim 26 , wherein the T-cell is a CD4 or CD8 cell. 
     
     
         29 . The method of any one of  claims 1 - 28 , wherein the disease or condition is cancer or an autoimmune disease or condition. 
     
     
         30 . A method for treatment of a T-cell related disease or condition, the method comprising contacting activated T-cells with an oligomer comprising a backbone having a sequence of morpholino ring structures joined by intersubunit linkages, the intersubunit linkages joining a 3′-end of one morpholino ring structure to a 5′-end of an adjacent morpholino ring structure, wherein each morpholino ring structure is bound to a base-pairing moiety, such that the oligomer can bind in a sequence-specific manner to a target nucleic acid, wherein at least one of the intersubunit linkages has the following structure (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
 R 1  is guanidinyl, alkylguanidinyl or alkylaminyl; 
 L 1  is absent or present, and when present is selected from alkylene, aminoalkylene, oxyalkylene, oxoalkylene and thioalkylene; 
 X is, at each occurrence, independently S or O; 
 Y is, at each occurrence, independently —O— or —NH—; and 
 Z is an optionally substituted 5, 6 or 7-membered heterocyclic ring. 
 
       
     
     
         31 . Use of an oligomer comprising a backbone having a sequence of morpholino ring structures joined by intersubunit linkages, the intersubunit linkages joining a 3′-end of one morpholino ring structure to a 5′-end of an adjacent morpholino ring structure, wherein each morpholino ring structure is bound to a base-pairing moiety, such that the oligomer can bind in a sequence-specific manner to a target nucleic acid, wherein at least one of the intersubunit linkages has the following structure (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
 R 1  is guanidinyl, alkylguanidinyl or alkylaminyl; 
 L 1  is absent or present, and when present is selected from alkylene, aminoalkylene, oxyalkylene, oxoalkylene and thioalkylene; 
 X is, at each occurrence, independently S or O; 
 Y is, at each occurrence, independently —O— or —NH—; and 
 Z is an optionally substituted 5, 6 or 7-membered heterocyclic ring, for preparation of a pharmaceutical composition for treatment of a lymphocyte-related disease or condition.