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

1. A compound of formulas (I):

or a pharmaceutically acceptable salt thereof;

wherein:

B is NR′ 1 R′ 2 ;

X is selected from the group consisting of hydrogen, halogen, —OH, —OR, —NHR, —NHCOR, —NHSO 2 R, —SR, —SOR, or —SO 2 R;

Y is selected from the group consisting of —NHR, —NHCOR, and —NHSO 2 R;

Z is selected from the group consisting of —OH, —OR, SR, —SOR, or —SO 2 R;

wherein R is:

(a) a linear or branched C 1 to C 6 alkyl;

(b) aryl or aryl C 1 to C 6 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, or

(c) heteroaryl or heteroaryl C 1 to C 6 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-alkylaminocarbarnoylalkyl N,N-dialkylaminocarbamoylalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, alkylcarboxy, alkylcarboxyalkyl, N-alkylcarboxamindoalkyl, N,N-dialkylcarboxamindoalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, trifluoromethylsulfonylaminoalkyl, arylthioalkyl, arylsulfinylalkyl, and arylsulfonylalkyl;

R 1 and R 2 are independently hydrogen or an optionally substituted linear or branched C 1 -C 6 alkyl; 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, C 1 -C 6 linear or branched alkyl, aryl C 0 -C 3 alkyl-, heteroaryl C 0 -C 3 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 C 1 -C 3 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 — wherein 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; or

(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 —O—, —S—, —SO—, —SO 2 —, —NH—, —NR—, —NCOR—, —NSO 2 R—, or another heteroatom containing group internal to the ring system and which is optionally fused to a substituted or unsubstituted aryl or heteroaryl group wherein R is as defined above;

with the proviso that when R is phenyl, then Z is not —OR.

2. The compound in claim 1 , where X is hydrogen.

3. The compound in claim 2 , 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 1 , wherein B is —NR′ 1 R′ 2 , wherein at least one of R′ 1 R′ 2 is optionally substituted linear or branched C 1 -C 6 alkyl.

7. The compound in claim 5 , wherein B is —NR′ 1 R′ 2 , and R′ 1 and R′ 2 are each hydrogen.

8. The compound in claim 1 , where X is —OR.

9. A composition comprising at least one compound of claim 1 and a pharmacologically acceptable diluent, carrier, or excipient.

10. A method of treating a subject 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 the compound of claim 1 in an amount effective to reduce edema or to modulate fluid imbalance;

wherein said disease or disorder is selected from the group consisting of head trauma, brain trauma, brain tumor, glaucoma, macular degeneration, pulmonary disorder, lung disease, vascular disease, kidney disease, and heavy metal toxicity.

11. The compound of claim 1 ,

where R 1 and R 2 are hydrogen, and

where B is NR′ 1 R′ 2 , wherein R′ 1 is hydrogen, and R′ 2 is aryl.

12. The compound of claim 11 , wherein Y is —NHR,

where R a linear or branched C 1 to C 6 alkyl, and

where Z is OR, where R is aryl.

13. The compound of claim 1 , wherein B is NR′ 1 R′ 2 and R′ 1 and R′ 2 are each hydrogen.

14. The compound of claim 1 , wherein X is halogen or —OH.

15. The compound of claim 1 , wherein X is —NHR, —NHCOR, or —NHSO 2 R.

16. The compound of claim 1 , wherein X is —SR, —SOR, or —SO 2 R.

17. The compound of claim 1 , wherein Y is —NHCOR.

18. The compound of claim 1 , wherein Y is —NHSO 2 R.

19. The compound of claim 1 , wherein Z is —OH or —OR.

20. The compound of claim 1 , wherein Z is SR, —SOR, or —SO 2 R.

21. The compound of claim 1 , wherein R 1 and R 2 are each hydrogen.

22. The compound of claim 1 , wherein at least one of R 1 and R 2 is an optionally substituted linear or branched C 1 -C 6 alkyl.

23. A method for treating edema comprising administering to a subject in need thereof an effective amount of at least one compound of claim 1 .

24. The method of claim 23 , wherein said edema is brain edema.

25. The method of claim 23 , wherein said edema is pulmonary edema.

26. The method of claim 23 , wherein said compound is administered orally.

27. The method of claim 23 , wherein said compound is administered parenterally.