Benzenesulfonamide upregulators of NPC1 for Neimann-Pick disease and other lysosomal storage disorders

Patent metadata

Field	Value
Publication number	US-10239830-B2
Application number	US-201615549743-A
Country	US
Kind code	B2
Filing date	Feb 11, 2016
Priority date	Feb 11, 2015
Publication date	Mar 26, 2019
Grant date	Mar 26, 2019

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:

First claim

The invention claimed is:

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 (

Assignees

• Icahn School Med Mount Sinai
• Us Health
• The Us Secretary Depart Of Health And Human Services

Inventors

• Patnaik Samarjit
• Taylor Mercedes
• Calvo Raul Rolando
• Marugan Juan Jose
• Southall Noel
• Zheng Wei
• Ferrer-Alegre Marc
• Dehdasthi Seameen
• Dranchak Patricia
• Chen Fannie
• Ioannou Yiannis

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title