Treprostinil derivatives and compositions and uses thereof

Abstract

The present disclosure provides treprostinil derivatives that can act as prodrugs of treprostinil. The treprostinil derivatives can be used to treat any conditions responsive to treatment with treprostinil, including pulmonary hypertension, such as pulmonary arterial hypertension.

What is claimed is: 
     
         1 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs and stereoisomers thereof. 
     
     
         2 . A pharmaceutical composition comprising a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 —O—Z—CO 2 H is 
 
       
         
           
           
               
               
           
         
       
       —O-heteroalkyl-CO 2 H, —O-cyclyl-CO 2 H, —O—CH 2 -cyclyl-CO 2 H, —O-cyclyl-CH 2 —CO 2 H, or —O—CH 2 -cyclyl-CH 2 —CO 2 H, each of which may optionally be substituted,
 wherein:
 -cyclyl- is -cycloalkyl-, -heterocyclyl-, -aryl- or -heteroaryl-; 
 R 7  and R 8  in each occurrence independently are hydrogen, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, or R 7  and R 8  and the carbon atom to which they are connected form a C 3 -C 6  cycloalkyl ring; and 
 n is an integer from 1 to 10; 
 
 with the proviso that —O—Z—CO 2 H does not contain a sugar moiety; 
 
       or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, and one or more pharmaceutically acceptable excipients or carriers. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein —O—Z—CO 2 H is 
       
         
           
           
               
               
           
         
       
       and wherein:
 R 7  and R 8  are as defined as in  claim 2 ; 
 p is an integer from 1 to 9; and 
 q is an integer from 0 to 8. 
 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein both R 7  and R 8  are hydrogen, and p is an integer from 1 to 9 or from 1 to 5 (or each occurrence of R 7  and R 8  is hydrogen, and q is an integer from 0 to 8 or from 0 to 4). 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein —O—Z—CO 2 H is 
       
         
           
           
               
               
           
         
       
       and p is an integer from 2 to 9 or from 2 to 5. 
     
     
         6 . The pharmaceutical composition of  claim 2 , wherein —O—Z—CO 2 H is —O-heteroalkyl-CO 2 H, and —O-heteroalkyl-CO 2 H is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein r is each of 1, 2 and 3. 
     
     
         7 . The pharmaceutical composition of  claim 2 , wherein —O—Z—CO 2 H is —O-cycloalkyl-CO 2 H, —O—CH 2 -cycloalkyl-CO 2 H, —O-cycloalkyl-CH 2 —CO 2 H, or —O-CH 2 -cycloalkyl-CH 2 —CO 2 H, and for each of the preceding moieties -cycloalkyl- is:
 1,2-cyclopropyl (cis or trans); or 
 1,3-cyclobutyl (cis or trans) or 1,2-cyclobutyl (cis or trans); or 
 1,3-cyclopentyl (cis or trans) or 1,2-cyclopentyl (cis or trans); or 
 1,4-cyclohexyl (cis or trans), 1,3-cyclohexyl (cis or trans), or 1,2-cyclohexyl (cis or trans). 
 
     
     
         8 . The pharmaceutical composition of  claim 2 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs and stereoisomers thereof. 
     
     
         9 . The pharmaceutical composition of  claim 2 , which is configured for transdermal delivery of the compound. 
     
     
         10 . The pharmaceutical composition of  claim 9 , which is configured as a transdermal patch. 
     
     
         11 . A method of treating a medical condition responsive to treatment with treprostinil, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 —O—Z—CO 2 H is 
 
       
         
           
           
               
               
           
         
       
       —O-heteroalkyl-CO 2 H, —O-cyclyl-CO 2 H, —O—CH 2 -cyclyl-CO 2 H, —O-cyclyl-CH 2 —CO 2 H, or —O—CH 2 -cyclyl-CH 2 —CO 2 H, each of which may optionally be substituted,
 wherein:
 -cyclyl- is -cycloalkyl-, -heterocyclyl-, -aryl- or -heteroaryl-; 
 R 7  and R 8  in each occurrence independently are hydrogen, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, or R 7  and R 8  and the carbon atom to which they are connected form a C 3 -C 6  cycloalkyl ring; and 
 n is an integer from 1 to 10; 
 
 with the proviso that —O—Z—CO 2 H does not contain a sugar moiety; or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof. 
 
     
     
         12 . The method of  claim 11 , wherein —O—Z—CO 2 H is 
       
         
           
           
               
               
           
         
       
       and wherein:
 R 7  and R 8  are as defined as in  claim 11 ; 
 p is an integer from 1 to 9; and 
 q is an integer from 0 to 8. 
 
     
     
         13 . The method of  claim 12 , wherein both R 7  and R 8  are hydrogen, and p is an integer from 1 to 9 or from 1 to 5 (or each occurrence of R 7  and R 8  is hydrogen, and q is an integer from 0 to 8 or from 0 to 4). 
     
     
         14 . The method of  claim 12 , wherein —O—Z—CO 2 H is 
       
         
           
           
               
               
           
         
       
       and p is an integer from 2 to 9 or from 2 to 5. 
     
     
         15 . The method of  claim 11 , wherein —O—Z—CO 2 H is —O-heteroalkyl-CO 2 H, and —O-heteroalkyl-CO 2 H is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein r is each of 1, 2 and 3. 
     
     
         16 . The method of  claim 11 , wherein —O—Z—CO 2 H is —O-cycloalkyl-CO 2 H, —O—CH 2 -cycloalkyl-CO 2 H, —O-cycloalkyl-CH 2 —CO 2 H, or —O—CH 2 -cycloalkyl-CH 2 —CO 2 H, and for each of the preceding moieties -cycloalkyl- is:
 1,2-cyclopropyl (cis or trans); or 
 1,3-cyclobutyl (cis or trans) or 1,2-cyclobutyl (cis or trans); or 
 1,3-cyclopentyl (cis or trans) or 1,2-cyclopentyl (cis or trans); or 
 1,4-cyclohexyl (cis or trans), 1,3-cyclohexyl (cis or trans), or 1,2-cyclohexyl (cis or trans). 
 
     
     
         17 . The method of  claim 11 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs and stereoisomers thereof. 
     
     
         18 . The method of  claim 11 , wherein the medical condition is selected from the group consisting of pulmonary hypertension, pulmonary fibrosis, peripheral ischemic lesions on the skin, critical limb ischemia, diabetic neuropathic foot ulcer, kidney malfunction and failure, peripheral vascular disease, atherogenesis, congestive heart failure, tumors, cancers, and pain associated with each of the preceding conditions. 
     
     
         19 . The method of  claim 18 , wherein the medical condition is pulmonary hypertension. 
     
     
         20 . The method of  claim 19 , wherein the medical condition is pulmonary arterial hypertension. 
     
     
         21 . The method of  claim 20 , further comprising administering a vasoactive agent, a diuretic, an anticoagulant or a cardiac glycoside, or any combination thereof. 
     
     
         22 . The method of  claim 11 , wherein the compound is administered transdermally. 
     
     
         23 . The method of  claim 22 , wherein the compound is administered via a transdermal patch.