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US 10,239,830 B2Granted
Benzenesulfonamide upregulators of NPC1 for Neimann-Pick disease and other lysosomal storage disorders
AssigneesIcahn School of Medicine at Mount Sinai, The United States of America, as represented by the Secretary, Depart. of Health and Human Services
InventorsSamarjit Patnaik, Mercedes Taylor, Raul Rolando Calvo, Juan Jose Marugan, Noel Southall, Wei Zheng, Marc Ferrer-Alegre, Seameen Dehdasthi, Patricia Dranchak, Fannie Chen, Yiannis Ioannou
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Abstract
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:
Claims28
A method of treating a lysosomal storage disorder comprising administering a compound of formula I
- wherein
- R1 is selected from hydrogen and (C1-C6)alkyl;
- R2 is selected from (C1-C6)alkyl, optionally substituted benzyl, meta-substituted phenyl and para-substituted phenyl, wherein substituents on the benzyl or phenyl are selected from (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, (C1-C6)alkoxy, and cyano;
- or
- R1 and R2, together with the nitrogen to which they are attached, form an optionally substituted and/or fused heterocycle;
- R3, R4, R5 and R6 are independently selected from hydrogen, (C1-C6)alkyl, halogen, hydroxy, cyano, nitro, amino, halo(C1-C6)alkyl, (C1-C6)alkoxy, and (C1-C6)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 R2 is (C1-C6)alkyl, Cy is not unsubstituted aryl or heteroaryl.
4 more elements
A compound of formula:
- wherein:
- (A) Cy is a substituted pyridine, wherein the substituents on the pyridine are (C1-C7)hydrocarbon, (C1-C6)acyl, halo(C1-C6)alkyl, or (C1-C10)oxaalkyl;
- R1 is hydrogen;
- R2 is para-substituted phenyl, wherein the substituents on the phenyl are selected from (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, (C1-C6)alkoxy, and cyano, provided that a para substituent on the phenyl is bromo;
- and
- R3 is cyano, halo(C1-C6)alkyl, (C1-C6)alkoxy, or (C1-C6)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 (C1-C7)hydrocarbon, (C1-C6)acyl, halo(C1-C6)alkyl, (C1-C10)oxaalkyl and halogen
- R1 is selected from hydrogen and (C1-C6)alkyl;
- R2 is selected from optionally substituted (C1-C6)alkyl, benzyl, meta-substituted phenyl and para-substituted phenyl, wherein substituents on the benzyl or phenyl are selected from (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, (C1-C6)alkoxy, and cyano;
- and
- R3 is selected from (C1-C6)alkyl, halogen, hydroxyl, cyano, amino, halo(C1-C6)alkyl, (C1-C6)alkoxy, and (C1-C6)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 (C1-C2)alkyl, (C1-C6)acyl, halo(C1-C6)alkyl, (C1-C10)oxaalkyl and halogen;
- R1 and R2, together with the nitrogen to which they are attached, form an optionally substituted and/or fused heterocycle;
- and
- R3 is selected from (C1-C6)alkyl, halogen, hydroxyl, cyano, amino, halo(C1-C6)alkyl, (C1-C6)alkoxy, and (C1-C6)alkoxy substituted with an amine or saturated nitrogen heterocycle.
14 more elements
A compound of formula:
- wherein:
- R1 is selected from hydrogen and (C1-C6)alkyl;
- R2 is selected from optionally substituted (C1-C6)alkyl, benzyl, meta-substituted phenyl and para-substituted phenyl, wherein substituents on the benzyl or phenyl are selected from (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, (C1-C6)alkoxy, and cyano;
- or
- R1 and R2, together with the nitrogen to which they are attached, form an optionally substituted and/or fused heterocycle;
- R3 is selected from (C1-C6)alkyl, halogen, hydroxyl, cyano, amino, halo(C1-C6)alkyl, (C1-C6)alkoxy, and (C1-C6)alkoxy substituted with an amine or saturated nitrogen heterocycle.
3 more elements
Dependencies are inferred from the claim text.