Methods, compounds, and compositions for delivering 1,3-propanedisulfonic acid

Abstract

The invention relates to methods, compounds, and compositions for delivering 1,3-propanedisulfonic acid (1,3PDS) in a subject, preferably a human subject. The invention encompasses compounds that will yield or generate 1,3PDS, either in vitro or in vivo. The invention also relates to sulfonate ester prodrugs of 1,3PDS as well as Gemini dimmers and oligomers of 1,3PDS for the prevention or treatment of associated diseases and conditions.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is selected from OR 3 , —NHC(O)R 5 , —NHC(NH)NHR 5 , —NH(C 5 -C 10 heteroaryl) or a nitrogen atom part of a mono or bicyclic heteroaryl having from 5 to 10 ring members; 
 R 2  is selected from OR 4 , —NHC(O)R 5 , —NHC(NH)NHR 5 , —NH(C 5 -C 10 heteroaryl) or a nitrogen atom part of a mono or bicyclic heteroaryl having from 5 to 10 ring members, or R 1  is a covalent bond and R 2  is selected from O, NH, NC(O)R 5 , NC(NH)NHR 5 , and N(C 5 -C 10 heteroaryl) when R 1  and R 2  are taken together with their adjacent atoms to form a heterocycle; 
 R 3  is selected from hydrogen and a substituted or unsubstituted group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 15 cycloalkyl, C 3 -C 15 heterocycloalkyl, C 6 -C 15 aryl, and C 5 -C 15 heteroaryl; 
 R 4  is a substituted or unsubstituted group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 15 cycloalkyl, C 3 -C 15 heterocycloalkyl, C 6 -C 15 aryl, and C 5 -C 15 heteroaryl; and 
 R 5  is selected from hydrogen and a substituted or unsubstituted group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 15 cycloalkyl, C 3 -C 15 heterocycloalkyl, C 6 -C 15 aryl, and C 5 -C 15 heteroaryl; 
 
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         2 . The compound of  claim 1 , wherein said compound is a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 3  is selected from hydrogen and a substituted or unsubstituted group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 15 cycloalkyl, C 3 -C 15 heterocycloalkyl, C 6 -C 15 aryl, and C 5 -C 15 heteroaryl; and 
 R 4  is a substituted or unsubstituted group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 15 cycloalkyl, C 3 -C 15 heterocycloalkyl, C 6 -C 15 aryl, and C 5 -C 15 heteroaryl; 
 wherein at least one of R 3  and R 4  is a substituted branched C 3 -C 8 alkyl, a substituted or unsubstituted C 6 -C 15 aryl or C 5 -C 15 heteroaryl group, or a group of Formula B: 
 
       
         
           
           
               
               
           
         
       
       wherein,
 R 7  and R 8  are each independently a substituted or unsubstituted croup selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C(O)OH, C(O)OC 1 -C 6 alkyl, NH 2 , NHC(O)OC 1 -C 6 alkyl; and 
 R 22  is a hydrogen atom or a group selected from C 1 -C 6 alkyl, C(O)OH, or C(O)OC 1 -C 6 alkyl; and 
 R 6  is a croup of formula C: 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 9  is absent; 
 X is selected from the group consisting of OH, NO 2 , CN, SH, C(O)OH, C(O)OR 12 , OC(O)OR 12 , SC(O)OR 12 , P(O)(OH) 2 , P(O)(OR 12 ) 2 , P(O)(OR 12 )(OH), OC(O)R 13 , OC(O)NHR 13 , SC(O)R 13 , C(O)R 14 , and NHR 15 ; 
 n is 0; 
 R 12  is a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 6 aryl, C 5 -C 6 heteroaryl, benzyl, CH 2 R 16 , and CH(C 1 -C 6 alkyl)R 16 ; 
 R 13  is a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 6 aryl, C 5 -C 6 heteroaryl, and benzyl; 
 R 14  is the residue of a natural or unnatural N-coupled amino acid having an protected or unprotected carboxyl end; 
 R 15  is the residue of a natural or unnatural C-coupled amino acid having an protected or unprotected amino end; and 
 R 16  is selected from the group consisting of OC(O)C 1 -C 6 alkyl and OC(O)OC 1 -C 6 alkyl; 
 
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         3 . The compound of  claim 2 , wherein R 3  is a substituted or unsubstituted group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 15 cycloalkyl, C 3 -C 15 heterocycloalkyl, C 6 -C 15 aryl, and C 5 -C 15 heteroaryl. 
     
     
         4 . The compound of  claim 2 , wherein said compound is a compound of Formula II-A 
       
         
           
           
               
               
           
         
       
       wherein,
 R 4  is a substituted branched C 3 -C 8 alkyl, or a substituted or unsubstituted C 6 -C 15 aryl or C 5 -C 15 heteroaryl; 
 or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         5 - 10 . (canceled) 
     
     
         11 . The compound of  claim 2 , wherein at least one of R 3  and R 4  is a group of Formula D: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 17  in each occurrence is each independently a hydrogen atom or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, an electron-withdrawing group or a substituent selected from the group consisting of amino, amido, hydroxyl, alkoxy, acyloxy, alkoxycabonyloxy, and the like; and 
 m is an integer from 1 to 5. 
 
     
     
         12 - 13 . (canceled) 
     
     
         14 . The compound of  claim 2 , wherein said compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         15 . (canceled) 
     
     
         16 . The compound of  1 , wherein said compound is selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         17 - 23 . (canceled) 
     
     
         24 . The compound of  claim 1 , wherein said compound is a compound of Formula IV: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 18  is selected from OR 3 , NH 2 , —NHC(O)R 5 , —NHC(NH)NHR 5 , —NH(C 5 -C 10 heteroaryl), —NR 20 R 21 , R 14 , and —NHR 15 ; 
 R 19  is selected from NH 2 , —NHC(O)R 5 , —NHC(NH)NHR 5 , —NH(C 5 -C 10 heteroaryl), —NR 20 R 21 , R 14 , and —NHR 15 ; 
 R 3 , R 5 , R 14 , and R 15  are as defined in any one of the preceding claims; and 
 R 20  and R 21  are taken together with their adjacent nitrogen atom to form a mono or bicyclic heteroaryl having from 5 to 10 ring members; 
 
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         25 . The compound of  claim 24 , wherein:
 R 18  is selected from OR 3 , —NHC(O)R 5 , —NHC(NH)NHR 5 , —NH(C 5 -C 10 heteroaryl) and —NR 20 R 21 ;   R 19  is selected from —NHC(O)R 5 , —NHC(NH)NHR 5 , —NH(C 5 -C 10 heteroaryl) and —NR 20 R 21 ;   R 3  and R 5  are as defined in any one of the preceding claims; and   R 20  and R 21  are taken together with their adjacent nitrogen atom to form a mono or bicyclic heteroaryl having from 5 to 10 ring members;   
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         26 . The compound of  claim 24 , wherein said compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         27 - 28 . (canceled) 
     
     
         29 . A pharmaceutical composition comprising a compound according to  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         30 - 42 . (canceled) 
     
     
         43 . A method for treating AA amyloidosis or diabetic naphropathy, comprising the step of administering to a subject in need thereof, a therapeutically effective amount of a compound of  claim 1  such that said AA amyloidosis or diabetic naphropathy is treated. 
     
     
         44 . A method for treating a renal disorder, comprising the step of administering to a subject in need thereof, a therapeutically effective amount of a compound of  claim 1 , such that said renal disorder is treated. 
     
     
         45 . The method of  claim 43 , wherein diabetic nephropathy is treated. 
     
     
         46 . A method for the treatment of metabolic syndrome, hyperglycemia, or diabetes mellitus, comprising the step of administering to a subject in need thereof, a therapeutically effective amount of a compound of  claim 1 , such that said metabolic syndrome, hyperglycemia, or diabetes mellitus is treated. 
     
     
         47 - 48 . (canceled) 
     
     
         49 . The method of  claim 46 , wherein said diabetes mellitus is type 1 diabetes. 
     
     
         50 . The method of  claim 46 , wherein said diabetes mellitus is type 2 diabetes. 
     
     
         51 . The method of  claim 50 , wherein said diabetes mellitus is type 2 diabetes with features of metabolic syndrome. 
     
     
         52 . A method for increasing insulin levels circulating in blood in response to food, decreasing resistance to insulin and/or increasing insulin sensitivity in selected tissues, increasing insulin secretion by pancreatic cells, increasing beta-cells and/or islets of Langerhans neogenesis and/or regeneration of islets of Langerhans or preventing their destruction by apoptosis, preventing apoptosis in beta-cells, and stabilizing, restoring, and/or improving beta-cells size, growth and/or function, or delaying the requirement for treating a diabetic patient with exogenous insulin, comprising administering a therapeutically effective amount of a compound of  claim 1  to a subject in need thereof. 
     
     
         53 . (canceled) 
     
     
         54 . The method of  claim 43 , wherein AA amyloidosis is treated. 
     
     
         55 - 62 . (canceled)