Pharmaceutical formulations comprising substituted pyrazolo[5,1-c]pyrido[4,3-e][1,2,4]triazines for treating lysosomal storage disorders
This disclosure provides compounds, such as compounds of Formula I: pharmaceutical formulations thereof, and related methods of use for the treatment of defects of cholesterol homeostasis including lysosomal storage disorders such as Niemann-Pick Type C disease.
1. A method for treating a lysosomal storage disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —(C 2 -C 6 alkylidene)-NR 6 R 7 , —(C 2 -C 6 alkylidene)-X 1 —(C 2 -C 6 alkylidene)-NR 6 R 7 , or —(C 3 -C 6 cycloalkylidene)-NR 6 R 7 , each of which is optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, —OH, alkoxy, —NO 2 , amino, —CN, —COOH, —COOR 8 , and amido;
R 2 , R 3 , R 4 , and R 5 are independently selected from H, halogen, —CN, amino, —NO 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, alkoxy, —(C 1 -C 6 alkylidene)-X 2 —(C 1 -C 6 alkyl), aryl, heterocyclyl, heteroaryl, aralkyl, heteroarylalkyl, and heterocyclylalkyl, wherein the amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, alkoxy, —(C 1 -C 6 alkylidene)-X 2 —(C 1 -C 6 alkyl), aryl, heterocyclyl, heteroaryl, aralkyl, heteroarylalkyl, and heterocyclylalkyl are optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, —OH, -alkoxy, —NO 2 , amino, —CN, —COOH, —COOR 9 , and amido;
X 1 and X 2 are independently selected from null, —O—, —S—, —SO 2 —, —(C═O)—, —N(R 11 )—, and —C(O)N(R 12 )—;
R 6 and R 7 are independently selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; or R 6 , R 7 , and the nitrogen to which they are attached join together to form a heterocyclic ring;
R 8 and R 9 are independently selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; and
R 11 and R 12 are independently selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl are optionally substituted with one or more groups independently selected from halogen, —OH, amino, alkoxy, —CN, and —NO 2 ;
and wherein the lysosomal storage disorder is Niemann Pick type A disease, Niemann Pick type C disease, Gaucher type 1 disease, or Gaucher type 2 disease.
2. The method of claim 1 , wherein the method further comprises administering to the subject a therapeutically effective amount of cyclodextrin.
3. The method of claim 1 , wherein the lysosomal storage disorder is Niemann Pick type C disease.