Benzenesulfonamide upregulators of NPC1 for Neimann-Pick disease and other lysosomal storage disorders
Methods and compositions for treating lysosomal storage disorders are disclosed. The methods involve administering a genus of benzenesulfonamides, particularly N-[3-(aminosulfonyl)phenyl]-benzamides and heteroarylamides. A genus of suitable compounds is shown in formula 1:
1. A method of treating a lysosomal storage disorder comprising administering a compound of formula I
wherein
R 1 is selected from hydrogen and (C 1 -C 6 )alkyl;
R 2 is selected from (C 1 -C 6 )alkyl, optionally substituted benzyl, meta-substituted phenyl and para-substituted phenyl, wherein substituents on the benzyl or phenyl are selected from (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and cyano; or
R 1 and R 2 , together with the nitrogen to which they are attached, form an optionally substituted and/or fused heterocycle;
R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, (C 1 -C 6 )alkyl, halogen, hydroxy, cyano, nitro, amino, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkoxy substituted with an amine or saturated nitrogen heterocycle;
Cy is chosen from adamantyl, optionally substituted monocyclic aryl, and optionally substituted monocyclic heteroaryl, with the proviso that when R 2 is (C 1 -C 6 )alkyl, Cy is not unsubstituted aryl or heteroaryl.
2. A method according to claim 1 wherein said disorder is chosen from sphingolipidoses and mucopolysaccharidoses.
3. A method according to claim 1 wherein said disorder is chosen from Niemann-Pick C, Niemann-Pick A/B, Fabry Disease, Farber Disease, Wolman Disease, Gaucher's Disease, Krabbe Disease, MPS VII (mucopolysaccharidosis VII), Neuronal Ceroid Lipofuscinosis Type 2 (CLN 2), and Glycogen Storage Type II (Pompe Disease).
4. A method according to claim 1 wherein Cy is an optionally substituted ring selected from optionally substituted pyrazole, pyrrole, thiazole, imidazole, oxazole, pyridine, pyridazine, pyrimidine, thiophene, furan, and phenyl.
5. A method according to claim 4 wherein Cy is a ring selected from substituted pyrrole, ortho-substituted phenyl, meta-substituted phenyl, and optionally substituted pyridine or imidazole, wherein the substituents on the ring are selected from (C 1 -C 7 )hydrocarbon, (C 1 -C 6 )acyl, halo(C 1 -C 6 )alkyl, (C 1 -C 10 )oxaalkyl and halogen.
6. A method according to claim 1 wherein R 1 is selected from hydrogen and (C 1 -C 6 )alkyl.
7. A method according to claim 6 wherein R 2 is selected from meta- and para-substituted phenyl.
8. A method according to claim 7 wherein said meta and para substituents are chosen from bromo, chloro, cyano and acetyl.
9. A method according to claim 1 wherein R 1 is (C 1 -C 6 )alkyl and R 2 is (C 1 -C 6 )alkyl.
10. A method according to claim 1 wherein R 1 and R 2 , together with the nitrogen to which they are attached, form an optionally substituted monocyclic heterocycle.
11. A method according to claim 10 wherein said optionally substituted heterocycle is chosen from pyrrolidine, piperidine, azepine, morpholine and piperazine.
12. A method according to claim 1 wherein R 1 and R 2 , together with the nitrogen to which they are attached, form an optionally substituted fused heterocycle.
13. A method according to claim 12 wherein said optionally substituted fused heterocycle is chosen from tetrahydrobenzoazepine, tetrahydroquinoline, tetrahydroisoquinoline, indoline and isoindoline.
14. A method according to claim 1 wherein R 3 is selected from hydrogen, (C 1 -C 6 )alkyl, halogen, hydroxy, cyano, nitro, amino, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkoxy substituted with an amine or saturated nitrogen heterocycle; and R 4 , R 5 and R 6 are independently selected from hydrogen and fluorine.
15. A method according to claim 14 wherein R 3 is selected from hydrogen, methyl, ethyl, methoxy, dimethylaminopropoxy, and hydroxy; R 4 and R 6 are hydrogen; and R 5 is hydrogen or fluorine.
16. A compound of formula:
wherein:
(A) Cy is a substituted pyridine, wherein the substituents on the pyridine are (C 1 -C 7 )hydrocarbon, (C 1 -C 6 )acyl, halo(C 1 -C 6 )alkyl, or (C 1 -C 10 )oxaalkyl;
R 1 is hydrogen;
R 2 is para-substituted phenyl, wherein the substituents on the phenyl are selected from (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and cyano, provided that a para substituent on the phenyl is bromo; and
R 3 is cyano, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )alkoxy substituted with an amine or saturated nitrogen heterocycle;
or
(B) Cy is an optionally substituted imidazole, wherein the substituents on the imidazole ring are independently selected from (C 1 -C 7 )hydrocarbon, (C 1 -C 6 )acyl, halo(C 1 -C 6 )alkyl, (C 1 -C 10 )oxaalkyl and halogen
R 1 is selected from hydrogen and (C 1 -C 6 )alkyl;
R 2 is selected from optionally substituted (C 1 -C 6 )alkyl, benzyl, meta-substituted phenyl and para-substituted phenyl, wherein substituents on the benzyl or phenyl are selected from (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and cyano; and
R 3 is selected from (C 1 -C 6 )alkyl, halogen, hydroxyl, cyano, amino, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkoxy substituted with an amine or saturated nitrogen heterocycle;
or
(C) Cy is an optionally substituted imidazole, wherein the substituents on the imidazole ring are independently selected from (C 1 -C 2 )alkyl, (C 1 -C 6 )acyl, halo(C 1 -C 6 )alkyl, (C 1 -C 10 )oxaalkyl and halogen;
R 1 and R 2 , together with the nitrogen to which they are attached, form an optionally substituted and/or fused heterocycle; and
R 3 is selected from (C 1 -C 6 )alkyl, halogen, hydroxyl, cyano, amino, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkoxy substituted with an amine or saturated nitrogen heterocycle.
17. A compound according to claim 16 wherein R 3 is methoxy or ethyl.
18. A compound according to claim 16 wherein Cy is unsubstituted imidazolyl.
19. A compound according to claim 16 wherein Cy is substituted imidazole.
20. A compound according to claim 19 wherein Cy is an imidazole substituted with a substituent selected from trifluoromethyl, chloro, methyl, and ethyl.
21. A compound according to claim 16 wherein Cy is substituted or unsubstituted imidazole; R 1 is hydrogen; and R 2 is para-substituted phenyl, wherein the substituents on the phenyl are selected from (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and cyano, provided that the para substituent on the phenyl is bromo.
22. A compound according to claim 16 wherein Cy is an optionally substituted imidazole and R 1 and R 2 , together with the nitrogen to which they are attached, form an optionally substituted and/or fused heterocycle.
23. A compound of formula:
wherein:
R 1 is selected from hydrogen and (C 1 -C 6 )alkyl;
R 2 is selected from optionally substituted (C 1 -C 6 )alkyl, benzyl, meta-substituted phenyl and para-substituted phenyl, wherein substituents on the benzyl or phenyl are selected from (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and cyano; or
R 1 and R 2 , together with the nitrogen to which they are attached, form an optionally substituted and/or fused heterocycle;
R 3 is selected from (C 1 -C 6 )alkyl, halogen, hydroxyl, cyano, amino, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkoxy substituted with an amine or saturated nitrogen heterocycle.
24. A compound according to claim 23 wherein R 3 is methoxy or ethyl.
25. A compound according to claim 24 wherein R 1 is hydrogen; and
R 2 is para-substituted phenyl, wherein the substituents on the phenyl are selected from (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and cyano, provided that the para substituent on the phenyl is bromo.
26. A compound according to claim 16 wherein Cy is chosen from 4-methylpyridin-3-yl, imidazole-4-yl, and 2-phenylimidazole-4-yl.
27. A compound according to claim 16 of formula
28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 16 .