Aquaporin modulators and methods of using them for the treatment of edema and fluid imbalance

Abstract

Compounds, including 3-carboxy aryl sulfonamide compounds, which agonize or antagonize aquaporin channels and methods of using them to treat disorders or diseases mediated by aquaporins.

1 . A compound of any one of formulas (I)-(IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein: 
 B is —OH, —OR, —OCHR 1 OCOR 2 , or NR 1 R 2 ; 
 X, Y, and Z are, independently, selected from the group consisting of hydrogen, halogen, —OH, —OR, —NHR, —NHCOR, —NHSO 2 R, —SR, —SOR, or —SO 2 R;
 wherein R is one member of the group consisting of 
 (a) a linear or branched C1 to C6 alkyl; 
 (b) aryl or aryl C1 to C6 alkyl, unsubstituted or substituted with at least one member of the group consisting of halogen, trihalomethane, hydroxy, alkoxy, aryloxy, amino, N-alkylamino, N,N-dialkylamino, alkylcarbamoyl, arylcarbamoyl, aminocarbamoyl, N-alkyl- or N,N-dialkylaminocarbamoyl, alkylsulfonylamino, arylsulfonylamino, carboxy, carboxyalkyl, N-alkylcarboxamido, N,N-dialkylcarboxamido, alkylthio, alkylsulfinyl, alkylsulfonyl, trifluoromethylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, hydroxyalkyl, alkoxyalkyl, aryloxalkyl, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, alkylcarbamoylalkyl, arylcarbamoylalkyl, aminocarbamoylalkyl, N-alkylaminocarbamoylalkyl N,N-dialkylaminocarbamoylalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, 
 (c) heteroaryl or heteroaryl C1 to C6 alkyl, unsubstituted or substituted with at least one member of the group consisting of halogen, trihalomethane, hydroxy, alkoxy, aryloxy, amino, N-alkylamino, N,N-dialkylamino, alkylcarbamoyl, arylcarbamoyl, aminocarbamoyl, N-alkyl- or N,N-dialkylaminocarbamoyl, alkylsulfonylamino, arylsulfonylamino, carboxy, carboxyalkyl, N-alkylcarboxamido, N,N-dialkylcarboxamido, alkylthio, alkylsulfinyl, alkylsulfonyl, trifluoromethylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, hydroxyalkyl, alkoxyalkyl, aryloxalkyl, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, alkylcarbamoylalkyl, arylcarbamoylalkyl, aminocarbamoylalkyl, N-alkylaminocarbamoylalkyl N,N-dialkylaminocarbamoylalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, alkylcarboxy, alkylcarboxyalkyl, N-alkylcarboxamindoalkyl, N,N-dialkylcarboxamindoalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, trifluoromethylsulfonylaminoalkyl, arylthioalkyl, arylsulfinylalkyl, and arylsulfonylalkyl; and 
 
 R 1  and R 2  are: 
 (a) independently hydrogen or an optionally substituted linear or branched C 1 -C 6  alkyl; 
 (b) a group of the formula —(CH 2 ) n CHR-Q or —CHR(CH 2 ) n -Q where n=0-2 and Q is taken from aryl, heteroaryl, —CF 3 , —CH 2 OH, —OR 3 , —CH 2 NHCOR 3 , —CH 2 NHS(O) 2 R 3 , —SR 3 , —S(O)R 3 , —S(O) 2 R 3 ; and R 3  may be either H, C1-C6 linear or branched alkyl, aryl C0-C3 alkyl-, heteroaryl C0-C3 alkyl-, 
 (c) a group of the formula —CH 2 CHR-Q or —CHRCH 2 -Q where n=0-2 and Q is —NHCONR 3 R 4  or —NR 3 R 4 , where R 3  and R 4  are independently H, C 1 -C 6  linear or branched alkyl, aryl, heteroaryl, aryl C1-C3 alkyl, heteroaryl C 1 -C 3  alkyl, or when taken together form a ring of: 
 
       
         
           
           
               
               
           
         
         wherein 
         A is selected from the group consisting of —(CH 2 ) n —, —CH═CH— —(CH 2 ) n CO—, —(CH 2 ) n O—, —(CH 2 ) n SO m —, or —(CH 2 ) n NR—, and —NRCO—, n and m are independently integers between 0 and 2, and R is as defined above, 
         D is —(CH 2 ) n — and n is an integer between 0 and 2, 
         E and F are, independently, —(CH 2 ) n — wherein n is an integer between 0 and 2; or a substituted or unsubstituted adjacently attached aryl- or heteroaryl-ring system; 
         (d) when taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5 to 7-membered heterocycloalkyl which may contain a heteroatom containing group, such as —O—, —S—, —SO—, —SO 2 —, —NH—, —NR—, —NCOR—, —NSO 2 R—, internal to the ring system and is optionally fused to a substituted or unsubstituted aryl or heteroaryl group and R is as defined above; and where W in formula (IV) is S, O, NR, wherein R is H, alkyl, or aryl alkyl. 
       
     
     
         2 : The compound in  claim 1  having formula (I) where X is hydrogen. 
     
     
         3 : The compound in  claim 2  having formula (I) where Y is —NHR. 
     
     
         4 : The compound in  claim 3  where Z is OR. 
     
     
         5 : The compound in  claim 4  where R 1  and R 2  are hydrogen. 
     
     
         6 : The compound in  claim 5  where B is —OR, wherein R is optionally —CHR 1 —O—COR 2  or is —NH(CH 2 ) 2 -Morpholino. 
     
     
         7 : The compound in  claim 5  where B is —NR 1 R 2 . 
     
     
         8 : The compound in  claim 1  where X is —OR. 
     
     
         9 : The compound in  claim 8  where Y is hydrogen. 
     
     
         10 : The compound in  claim 9  where Z is halogen. 
     
     
         11 : The compound in  claim 10  where R 1  and R 2  are hydrogen. 
     
     
         12 : The compound in  claim 11  where B is —OR. 
     
     
         13 : The compound in  claim 11  where B is —NR 1 R 2 . 
     
     
         14 : The compound of  claim 1 , which has formula (I). 
     
     
         15 : The compound of  claim 1 , which has formula (II). 
     
     
         16 : The compound of  claim 1 , which has formula (III). 
     
     
         17 : The compound of  claim 1 , which has formula (IV). 
     
     
         18 : A composition comprising the compound of  claim 1  and a pharmacologically acceptable diluent, carrier, or excipient. 
     
     
         19 : A method of treating a patient suffering from a disease or disorder mediated by an aquaporin or by abnormal expression of an aquaporin comprising administering to a subject in need thereof an effective amount of the compound of  claim 1  in an amount effective to reduce the edema or to modulate fluid imbalance. 
     
     
         20 : The method of  claim 19 , wherein said disease or disorder is selected from the group consisting of edema, brain trauma, head trauma, eye disorder, pulmonary disorder, lung disease, vascular disease, kidney disease, heavy metal toxicity, Alzheimer's disease, tumor, and cancer.