Heterodimer compositions and methods for the treatment of ocular disorders

Abstract

Described herein are processable compositions comprising at least one moiety that is processable in its free form. Also described herein are compositions and methods for the treatment of ocular diseases or disorders including glaucoma, blepharitis, ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration (e.g., wet macular degeneration (AMD) or dry AMD), post-cataract surgery, and retinal vein occlusion. Said compositions and methods comprise steroids and prostaglandins which demonstrate anti-inflammatory activity, intraocular pressure (IOP) lowering, and/or other desirable activities. Injection of said compositions in the eye provides therapeutic benefit to patients suffering from ocular disorders.

We claim: 
     
         1 . A compound represented by the structure of Formula (VI-C): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein,
 L is a linker; and 
 PG is selected from the group consisting of: 
 
         (i) a prostaglandin radical represented by a structure of Formula (VII): 
       
       
         
           
           
               
               
           
         
         wherein 
            is a single bond or a double bond; 
         G is OH and Y 1  is hydrogen; or G together with Y 1  form —O—CH 2 —; 
         Y 2  is a bond or —CH 2 —; 
         g is 1 or 2; 
         Z is —O— or —CH 2 —; 
         R 6  and R 6′  are each independently hydrogen, halogen, OH, or L of Formula (VI-C); 
         R 11  is OR 13 , NR 13′ R 13″ , or L of Formula (VI-C); 
         each R 12  is independently halogen or haloalkyl; 
         R 13 , R 13′  and R 13″  are each independently hydrogen or C 1 -C 3  alkyl; and 
         u is 0-5; and 
         (ii) a radical of a prostaglandin, wherein the prostaglandin is selected from the group consisting of latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, bimatoprost acid, sepetaprost, and sepetaprost acid. 
       
     
     
         2 . The compound of  claim 1 , wherein PG is a prostaglandin radical represented by a structure of Formula (VII). 
     
     
         3 . The compound of  claim 2 , wherein R 6  and R 6′  are each independently fluoro. 
     
     
         4 . The compound of  claim 2 , wherein R 6  is OH and R 6′  is hydrogen. 
     
     
         5 . The compound of  claim 2 , wherein Z is —O—. 
     
     
         6 . The compound of  claim 2 , wherein Z is —CH 2 —. 
     
     
         7 . The compound of  claim 2 , wherein R 12  is F and u is 2. 
     
     
         8 . The compound of  claim 2 , wherein R 12  is CF 3  and u is 1. 
     
     
         9 . The compound of  claim 2 , wherein u is 0. 
     
     
         10 . The compound of  claim 2 , wherein R 6  is L of Formula (VI-C) and R 6′  is hydrogen. 
     
     
         11 . The compound of  claim 2 , wherein R 11  is OH, —NHCH 2 CH 3 , or —OCH(CH 3 ) 2 . 
     
     
         12 . The compound of  claim 2 , wherein R 11  L of Formula (VI-C). 
     
     
         13 . The compound of  claim 1 , wherein PG is a prostaglandin radical represented by a structure of Formula (VII-A): 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein PG is a prostaglandin radical represented by the structure of Formula (VII-B) 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , wherein PG is a radical of latanoprost. 
     
     
         16 . The compound of  claim 1 , wherein PG is a radical of bimatoprost. 
     
     
         17 . The compound of  claim 1 , wherein L is a bond. 
     
     
         18 . The compound of  claim 1 , wherein L is alkylene, cycloalkylene, or C═O. 
     
     
         19 . The compound of  claim 1 , wherein L comprises one or more linker groups, each linker group being independently selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, and alkoxy, wherein the alkyl, cycloalkyl, heteroalkyl, or alkoxy is optionally substituted. 
     
     
         20 . A pharmaceutical implant comprising at least 50 wt. % of the compound of  claim 1 . 
     
     
         21 . A method of treating an ophthalmic disease or disorder in an individual in need thereof, the method comprising administering to the individual a compound or  claim 1  or a pharmaceutically acceptable salt thereof, or an implant, article, or composition comprising the compound of  claim 1 .