Pharmaceutical uses and synthesis of diketopiperazines

Abstract

The synthesis of novel diketopiperazines, their use in inhibiting cellular events such as those involving NFK-α, NFK-β and in the treatment of inflammation events, a combinatorial library of diverse diketopiperazines and process for their synthesis as a library and as individual compounds. In particular novel diketopiperazines are disclosed including their synthesis and use in cellular events such as activation of the transcription factor, nuclear factor, TNF-α, TNF-β and also apoptosis.

1 . A compound of the structure (I):  
       
         
           
           
               
               
           
         
         as an isolated isomer, disastereomer, or enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof; where, independently at each location:  
         R 1  is a heteroaryl ring;  
         R 2  and R 3  are selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring, and heterocycle aliphatic ring;  
         n is 3;  
         R 4  is selected from —OR 5  and —NR 6 R 7 ,  
         R 5  is selected from alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring and heterocycle aliphatic ring; and  
         R 6  and R are independently selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring and heterocycle aliphatic ring or R 6  and R taken together with the nitrogen atom to which they are attached form a heterocycle aliphatic ring.  
       
     
     
         2 . The compound of  claim 1  wherein R 1  is phenyl and the phenyl is substituted with 1-4 substituents independently selected at each occurrence from alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring, heterocycle aliphatic ring.  
     
     
         3 . The compound of  claim 2  wherein R 1  is phenyl having a substituent at the position para to the site of attachment to the piperazine ring.  
     
     
         4 . The compound of  claim 3  wherein R 1  is phenyl having a substituent at the position para to the site of attachment to the piperazine ring, and the substituent has the formula R 10 —R 9 —R 8 —, wherein R 8  is selected from direct bond, alkylene and haloalkylene; R 9  is selected from direct bond and carbonyl, and R 10  is selected from hydrogen, R 11 —O—, (R 11 ) 2 N— and R 11 —(C═O)—NH—, wherein R 11  is selected from hydrogen and organic groups having 1-20 carbons and optionally containing 1-4 heteroatoms selected from oxygen and nitrogen.  
     
     
         5 . The compound of  claim 4  wherein R 8  is methylene; R 9  is carbonyl, and R 10  is (R 11 ) 2 N— wherein R 11  is selected from hydrogen and organic groups having 1-20 carbons and optionally containing 1-4 heteroatoms selected from oxygen and nitrogen.  
     
     
         6 . The compound of  claim 3  wherein R 1  is phenyl having a substituent at the position para to the site of attachment to the piperazine ring, and the substituent has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 12  is selected from hydrogen and organic groups having 1-20 carbons and optionally containing 1-4 heteroatoms selected from oxygen and nitrogen.  
     
     
         7 . The compound of  claim 6  wherein R 12  is selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring and heterocycle aliphatic ring.  
     
     
         8 . The compound of  claim 7  wherein R 12  is selected from  
       
         
           
                 
               
                     
                 
                     
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         9 . The compound of  claim 1  wherein R 1  is phenyl.  
     
     
         10 . (canceled)  
     
     
         11 . The compound of  claim 1  wherein R 2  and R 3  are independently selected from groups of the formula R 10 —R 9 —R 8 —, wherein R 8  is selected from direct bond, alkylene and haloalkylene; R 9  is selected from direct bond and carbonyl, and R 10  is selected from hydrogen, R 11 —O—, (R 11 ) 2 N— and R 11 —(C═O)—NH—, wherein R 11  is selected from hydrogen and organic groups having 1-20 carbons and optionally containing 1-4 heteroatoms selected from oxygen and nitrogen, with the proviso that two R 11  groups bonded to the same nitrogen may be bonded together so as to form a heterocyclic ring with the common nitrogen.  
     
     
         12 . The compound of  claim 11  wherein R 8  is methylene; R 9  is selected carbonyl, and R 10  is (R 11 ) 2 N— 
     
     
         13 . A compound of  claim 12  wherein R 10  is selected from:  
       
         
           
                 
               
                     
                 
                     
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         14 . The compound of  claim 1  wherein R 4  is —OR 5 .  
     
     
         15 . The compound of  claim 9  wherein R 5  is alkyl.  
     
     
         16 . The compound of  claim 1  wherein R 4  is —NR 6 R 7 .  
     
     
         17 . The compound of  claim 16  wherein R 6  is hydrogen and R 7  is R 13 —C(═O)— where R 13  is selected from:  
       
         
           
                 
               
                     
                 
                     
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         18 . A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable adjuvant, carrier, diluent or excipient.  
     
     
         19 . A method of treating inflammation comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         20 . A method for inhibiting a TNF-α mediated processes, comprising administering to a patient in need thereof, through a therapeutically or prophylactically acceptable manner, a therapeutically or pharmaceutically effective amount of a composition comprising a compound of  claim 1 .  
     
     
         21 . A method for inhibiting a TNF-α mediated processes, comprising administering to a patient in need thereof, through a therapeutically or prophylactically acceptable manner, a therapeutically or pharmaceutically effective amount of a composition comprising a compound of  claim 1 , wherein the administering is selected from transdermal, oral, intravenous, intramuscular, vaginal, rectal, pulmonary, subcutaneous, sublingual and transmucosal administration.  
     
     
         22 . A method for inhibiting a TNF-α mediated processes, comprising administering to a patient in need thereof, through a therapeutically or prophylactically acceptable manner, a therapeutically or pharmaceutically effective amount of a composition comprising a compound of  claim 1 .  
     
     
         23 . A method for treating a condition associated with an elevated level of NFκB activity in a subject, comprising administering to a subject in need thereof an amount of a compound effective to lower the NFκB activity, wherein the compound is a compound of  claim 1 .  
     
     
         24 . (canceled)  
     
     
         25 . A method of inhibiting IL-8 production in a subject in need thereof comprising administering to the subject an effective amount of a compound of  claim 1 .  
     
     
         26 . A method of inhibiting GRO-α production in a subject in need thereof comprising administering to the subject an effective amount of a compound of  claim 1 .  
     
     
         27 . A method for inhibiting a CXCR1 and/or CXCR2 mediated processes, comprising administering to a patient in need thereof, through a therapeutically or prophylactically acceptable manner, a therapeutically or pharmaceutically effective amount of a composition comprising a compound of  claim 1 .  
     
     
         28 . The method of  claim 27  wherein the method inhibits a CXCR1 mediated processes.  
     
     
         29 . The method of  claim 27  wherein the method inhibits a CXCR2 mediated processes.  
     
     
         30 . The method according to  claim 27  wherein the administering is selected from transdermal, oral, intravenous, intramuscular, vaginal, rectal, pulmonary, subcutaneous, sublingual and transmucosal administration.  
     
     
         31 . A method for treating an inflammation event, comprising administering to a patient in need thereof, through a therapeutically or prophylactically acceptable manner, a therapeutically or pharmaceutically effective amount of a composition comprising a compound of  claim 1 .  
     
     
         32 . The method according to  claim 31  wherein the administering is selected from transdermal, oral, intravenous, intramuscular, vaginal, rectal, pulmonary, subcutaneous, sublingual and transmucosal administration.  
     
     
         33 . A method for identifying a binding partner to a compound of  claim 1:   immobilizing proteins known to be involved in the TNF-α signaling pathway onto a suitable carrier; and    passing a solution of said compounds in isolation or mixture over said proteins and analyzing for compound:protein complex formation using surface plasmon resonance (SPR).    
     
     
         34 . A method for identifying a binding partner to a compound of  claim 1  wherein said method comprises: 
 providing said compound(s) bound to a solid support to provide solid phase compound(s);    contacting a cell or cell components containing said binding partner with said solid phase compound(s) in isolation or mixture to form a binding partner:solid phase compound(s) complex;    removing uncomplexed cell or cell component material, from said binding partner:solid phase compound(s) complex; and    recovering said binding partner from the binding partner:solid phase compound(s) complex.