US2019247388A1PendingUtilityA1

Oligomer-opioid agonist conjugates

Assignee: NEKTAR THERAPEUTICSPriority: Mar 12, 2007Filed: Apr 24, 2019Published: Aug 15, 2019
Est. expiryMar 12, 2027(~0.6 yrs left)· nominal 20-yr term from priority
A61P 25/00A61K 31/439A61K 31/402A61K 31/4468A61K 31/485C07D 489/02A61K 47/60A61K 47/10A61K 31/4025
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Claims

Abstract

The invention provides compounds that are chemically modified by covalent attachment of a water-soluble oligomer. A compound of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from those of the compound not attached to the water-soluble oligomer.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A compound comprising a residue of an opioid agonist covalently attached to a water-soluble, non-peptidic oligomer. 
     
     
         2 . The compound of  claim 1 , wherein the opioid agonist is a kappa opioid agonist. 
     
     
         3 . The compound of  claim 1 , wherein the opioid agonist is a mu opioid agonist. 
     
     
         4 . The compound of  claim 1 , having the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is H or OH; 
         R 3  is H or an organic radical; 
         R 4  is H or an organic radical; 
         the dotted line (“---”) represents an optional double bond; 
         Y 1  is O or S; 
         R 5  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       wherein R 6  is an organic radical;
 X is a spacer moiety; 
 POLY is a water-soluble, non-peptidic oligomer. 
 
     
     
         5 . The compound of  claim 1 , having the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or an organic radical; 
         R 2  is H or OH; 
         R 3  is H or an organic radical; 
         R 4  is H or an organic radical; 
         the dotted line (“---”) represents an optional double bond; 
         Y 1  is O or S; 
         X is a spacer moiety; and 
         POLY is a water-soluble, non-peptidic oligomer. 
       
     
     
         6 . The compound of  claim 1 , having the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or an organic radical; 
         R 2  is H or OH; 
         R 3  is H or an organic radical; 
         R 4  is H or an organic radical; 
         Y 1  is O or S; and 
         R 5  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       wherein R 6  is an organic radical;
 X is a spacer moiety; and 
 POLY is a water-soluble, non-peptidic oligomer. 
 
     
     
         7 . The compound of  claim 1 , having the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or an organic radical; 
         R 2  is H or OH; 
         R 3  is H or an organic radical; 
         R 4  is H or an organic radical; 
         the dotted line (“---”) represents an optional double bond; 
         Y 1  is O or S; 
         R 5  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       wherein R 6  is an organic radical;
 X is a spacer moiety; and 
 POLY is a water-soluble, non-peptidic oligomer. 
 
     
     
         8 . The compound of  claim 1 , having the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or an organic radical; 
         R 3  is H or an organic radical; 
         R 4  is H or an organic radical; 
         the dotted line (“---”) represents an optional double bond; 
         Y 1  is O or S; and 
         R 5  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       wherein R 6  is an organic radical;
 X is a spacer moiety; and 
 POLY is a water-soluble, non-peptidic oligomer. 
 
     
     
         9 . The compound of  claim 1 , wherein the opioid agonist is selected from the group consisting of asimadoline, bremazocine, enadoline, ethylketocyclazocine, GR89,696, ICI204448, ICI197067, PD117,302, nalbuphine, pentazocine, quadazocine (WIN 44,441-3), salvinorin A, spiradoline, TRK-820, U50488, and U69593. 
     
     
         10 . A compound corresponding to a structure selected from the group consisting of Formula I-Cb, Formula I-Cc, Formula I-Cd, and Formula I-Ce, wherein
 R 1  is H   R 2  is H or OH;   R 3  is H or an organic radical;   R 4  is H or an organic radical;   R 5  is selected from the group consisting of   
       
         
           
           
               
               
           
         
       
       wherein R 6  is an organic radical;
 the dotted line (“---”) represents an optional double bond; 
 Y 1  is O or S; 
 X is a spacer moiety; and 
 POLY is a water-soluble, non-peptidic oligomer. 
 
     
     
         11 . A compound of  claim 10 , wherein Y is O. 
     
     
         12 . A compound of  claim 10 , wherein R 2  is OH. 
     
     
         13 . A compound of  claim 10 , wherein R 2  is H. 
     
     
         14 . A compound of  claim 10 , wherein R 3  is selected from the group consisting of H, unsubstituted alkyl, cycloalkyl-substituted alkyl, and allyl. 
     
     
         15 . A compound of  claim 10 , wherein R 4  is H. 
     
     
         16 . A compound of  claim 10 , wherein R 5  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound of  claim 10 , wherein the optional double bond is present. 
     
     
         18 . A compound of  claim 10 , wherein the optional double bond is not present. 
     
     
         19 . The compound of  claim 1 , wherein the water-soluble, non-peptidic oligomer is a poly(alkylene oxide). 
     
     
         20 . The compound of  claim 19 , wherein the poly(alkylene oxide) is a poly(ethylene oxide). 
     
     
         21 . The compound of  claim 1 , wherein the water-soluble, non-peptidic oligomer is made of between 1 and 30 monomers. 
     
     
         22 . The compound of  claim 21 , wherein the water-soluble, non-peptidic oligomer is made of between 1 and 10 monomers. 
     
     
         23 . The compound of  claim 19 , wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety. 
     
     
         24 . The compound of  claim 1 , wherein a single water-soluble, non-peptidic oligomer is attached to the residue of the opioid agonist. 
     
     
         25 . The compound of  claim 1 , wherein the residue of the opioid agonist is covalently attached via a stable linkage. 
     
     
         26 . The compound of  claim 1 , wherein the residue of the opioid agonist is covalently attached via a degradable linkage. 
     
     
         27 . The compound of  claim 1 , wherein the linkage is an ether linkage. 
     
     
         28 . A composition comprising a compound comprising a residue of an opioid agonist covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, and optionally, a pharmaceutically acceptable excipient. 
     
     
         29 . A composition of matter comprising a compound comprising a residue of an opioid agonist covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the compound is present in a dosage form. 
     
     
         30 . A method comprising covalently attaching a water-soluble, non-peptidic oligomer to an opioid agonist. 
     
     
         31 . A method comprising administering a compound comprising a residue of an opioid agonist covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer. 
     
     
         32 . A method comprising binding mu opioid receptors, wherein said binding is achieved by administering a compound comprising a residue of an opioid agonist covalently attached to a water-soluble, non-peptidic oligomer. 
     
     
         33 . A method comprising binding kappa opioid receptors, wherein said binding is achieved by administering a compound comprising a residue of an opioid agonist covalently attached to a water-soluble, non-peptidic oligomer.

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