Chemically Modified Dendrimers

Abstract

Dendrimers comprising N-acyl urea terminal moieties are described herein. The dendrimers can be used, for example, in the treatment of arthritis.

1 . (canceled) 
     
     
         2 . A method of inhibiting a matrix metalloprotease (MMP) or inhibiting production of a matrix metalloprotease (MMP), the method comprising administering to a subject an effective amount of a dendrimer, said dendrimer comprising a plurality of branched repeating units radiating out from a central atom, multifunctional moiety, or cluster of atoms, wherein each repeating unit comprises a terminal moiety, and wherein at least about 5% of the terminal moieties include a urea of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         each R 1  and R 2  is independently C 1 -C 6  alkyl, C 1 -C 6  alkenyl, cyclyl, aryl, heterocyclyl, heteroaryl, cyclylalkyl, arylalkyl, or heterocyclylalkyl, heteroarylalkyl; any of which are optionally substituted by C 1 -C 6  alkyl, amino, C 1 -C 6  alkylamino, C 1 -C 6  dialkylamino, hydroxy, C 1 -C 6  alkoxy, and wherein either of R 1  or R 2  independently optionally have a net charge; 
            indicates the point of attachment of the terminal moiety of formula (I) to the dendrimer; and 
         wherein less than about 12% of the terminal moieties are covalently bound to a saccharide moiety. 
       
     
     
         3 . The method of  claim 2 , wherein less than about 10% of the terminal moieties are covalently bound to a saccharide moiety. 
     
     
         4 . The method of  claim 2 , wherein either of R 1  or R 2  has a net positive charge. 
     
     
         5 . The method of  claim 2 , wherein R 1  and R 2  are both cyclohexyl. 
     
     
         6 . The method of  claim 2 , wherein R 1  and R 2  are both isopropyl. 
     
     
         7 . The method of  claim 2 , wherein one of R 1  and R 2  is ethyl and the other of R 1  and R 2  is dimethylaminopropyl. 
     
     
         8 . The method of  claim 2 , wherein one of R 1  and R 2  is cyclohexyl and the other of R 1  and R 2  is morpholinoethyl. 
     
     
         9 . The method of  claim 2 , wherein each of R 1  and R 2  is independently C 1 -C 6  alkyl, and one of R 1  and R 2  is substituted by C 1 -C 6  dialkylamino and has a positive net charge. 
     
     
         10 . The method of  claim 2 , wherein a terminal moiety includes a urea of formula (I′) 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 2 , wherein a terminal moiety includes a urea of formula (I″) 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 2 , wherein at least about 5% of the terminal moieties include a urea of formula (I′), formula (I″), or a combination thereof. 
     
     
         13 . The method of  claim 2 , wherein the dendrimer is selected from the group consisting of a polyamidoamine dendrimer, a polypropylene dendrimer, a polyethyleneimine dendrimer, a carbohydrate based dendrimer, a peptide based dendrimer, a glycopeptide dendrimer, a metal containing dendrimer, a poly aryl amine dendrimer, a polyamide dendrimer, a poly (alkyl amine) dendrimer, a polyamido alcohol dendrimer, a cyano dendrimer, a polyether dendrimer, a polythioether dendrimer, a polysiloxane dendrimer, a dendritic aryl ester, a perchlorinated dendrimer, a catalytic center containing dendrimer, a silicon containing dendrimer, a phosphorus containing dendrimer, and a hydrocarbon dendrimer. 
     
     
         14 . The method of  claim 13 , wherein the dendrimer is a polyamidoamine dendrimer. 
     
     
         15 . The method of  claim 2 , wherein at least about 80% of the terminal moieties are terminated with a carboxylate. 
     
     
         16 . The method of  claim 15 , wherein the dendrimer is a polyamidoamine dendrimer. 
     
     
         17 . The method of  claim 2 , wherein the dendrimer is a polyamidoamine dendrimer, and wherein at least about 50% of the terminal moieties are terminated with a carboxylate group. 
     
     
         18 . The method of  claim 2 , wherein the dendrimer is a polyamidoamine dendrimer of generation 0.5, 1.5, 2.5, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5, or 9.5. 
     
     
         19 . The method of  claim 2 , wherein the dendrimer is a polyamidoamine dendrimer of generation 0.5, 1.5, 2.5, or 3.5 with a carboxylate terminal moiety. 
     
     
         20 . The method of  claim 2 , wherein the dendrimer of formula (I) is made by reacting one or more terminal moieties of a starting dendrimer with a carbodiimide of formula (II) R 1 —N═C═N—R 2 , wherein R 1  and R 2  are defined as in  claim 1 , to provide the dendrimer of  claim 1  formula (I). 
     
     
         21 . The method of  claim 2 , wherein the matrix metalloprotease (MMP) is selected from the group consisting of MMP-1, MMP-3 and MMP-13.