Oligomer-Phenothiazine Conjugates

Abstract

The invention relates to (among other things) oligomer-phenothiazine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated phenothiazine compounds.

1 . A compound comprising a phenothiazine residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer. 
     
     
         2 . The compound of  claim 1 , having the following structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , and R 4 , each independently are selected from the group consisting of hydrogen, unsubstituted alkyl, and substituted alkyl; or R 3  and R 4  together with the nitrogen form a heterocycle; 
 n is an integer equal to or greater than one; 
 X is a spacer moiety; and 
 POLY is a water-soluble, non-peptidic oligomer. 
 
     
     
         3 . The compound of  claim 1 , having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , and R 3 , each independently are selected from the group consisting of hydrogen, unsubstituted alkyl, and substituted alkyl; 
 n is an integer equal to or greater than one; 
 X is a spacer moiety; and 
 POLY is a water-soluble, non-peptidic oligomer. 
 
     
     
         4 . The compound of  claim 1 , having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , and R 4 , each independently are selected from the group consisting of hydrogen, unsubstituted alkyl, and substituted alkyl; or R 3  and R 4  together with the nitrogen form a heterocycle; 
 n is an integer equal to or greater than one; 
 X is a spacer moiety; and 
 POLY is a water-soluble, non-peptidic oligomer. 
 
     
     
         5 . The compound of  claim 1 , wherein the phenothiazine residue is a residue of a phenothiazine having the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , and R 4 , each independently are selected from the group consisting of hydrogen, unsubstituted alkyl, and substituted alkyl; or R 3  and R 4  together with the nitrogen form a heterocycle; and 
 n is an integer equal to or greater than one. 
 
     
     
         6 . The compound of  claim 1 , wherein the phenothiazine residue is a residue of a phenothiazine having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein the phenothiazine residue is a residue of a phenothiazine having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the phenothiazine residue is selected from the group consisting of mequitazine, promethazine, promezine, and thiazinamium methylsulfate. 
     
     
         9 . The compound of  claim 1 , wherein the water-soluble, non-peptidic oligomer is a poly(alkylene oxide). 
     
     
         10 . The compound of  claim 9 , wherein the poly(alkylene oxide) is a poly(ethylene oxide). 
     
     
         11 . The compound of  claim 1 , wherein the water-soluble, non-peptidic oligomer is made of from about 1 to about 30 monomers. 
     
     
         12 . The compound of  claim 11 , wherein the water-soluble, non-peptidic oligomer is made of from about 1 to about 10 monomers. 
     
     
         13 . The compound of  claim 9 , wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety. 
     
     
         14 . The compound of  claim 1 , wherein a single water-soluble, non-peptidic oligomer is attached to the phenothiazine residue. 
     
     
         15 . The compound of  claim 1 , wherein more than one water-soluble, non-peptidic oligomer is attached to the phenothiazine residue. 
     
     
         16 . The compound of  claim 1 , wherein the phenothiazine residue is covalently attached via a stable linkage. 
     
     
         17 . The compound of  claim 1 , wherein the phenothiazine residue is covalently attached via a degradable linkage. 
     
     
         18 . The compound of  claim 1 , wherein the linkage is an ether linkage. 
     
     
         19 . The compound of  claim 1 , wherein the linkage is an ester linkage. 
     
     
         20 . A composition comprising a compound comprising a phenothiazine residue covalently attached via a stable or degradable linkage to a water-soluble and non-peptidic oligomer, and optionally, a pharmaceutically acceptable excipient. 
     
     
         21 . A composition of matter comprising a compound comprising a phenothiazine residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the compound is present in a dosage form. 
     
     
         22 . A method of making a phenothiazine conjugate, the method comprising covalently attaching a water-soluble, non-peptidic oligomer to a phenothiazine. 
     
     
         23 . A method of treatment comprising administering a compound comprising a phenothiazine residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer to a subject in need thereof.