Compositions and methods for treating lysosomal disorders
The present invention provides compositions and methods for treating lysosomal disorders using a class of substituted imidazole derivatives or compounds.
1. A method for treating a lipid storage disease in a subject in need thereof comprising administering to said subject an effective amount of a compound of Formula 1b:
wherein each instance of R a is independently C 1-6 alkyl-amino, di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, or di(substituted C 3-6 alkenyl)amino; and
R b is HO—C 1-6 alkyl-C 2-6 alkenyl, R 7 —O—C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N—C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 7 O—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, or R 7 —C(O)—O—C 1-6 alkyl-C 2-6 alkenyl;
wherein R 6 and R 7 are independently selected from the group consisting of C 1-6 alkyl, phenyl-C 1-6 alkyl, C 1-6 alkoxycarbonylmethyleneoxy, hydroxy-C 2-6 alkyl, C 1-6 alkyloxy-C 2-6 alkyl, amino-C 2-6 alkyl, C 1-6 alkylamino-C 2-6 alkyl, di(C 1-6 alkyl)amino-C 2-6 alkyl, C 1-6 alkylthio-C 2-6 alkyl, substituted C 1-6 alkoxy-C 2-6 alkyl, substituted C 1-6 alkylamino-C 2-6 alkyl, di(substituted C 1-6 alkyl)amino-C 2-6 alkyl, substituted C 1-6 alkylthio-C 2-6 alkyl, wherein the substituents are selected from the group consisting of pyrrolidino, piperidino, morpholino, piperazino, 4-N—C 1-6 alkylpiperazino, 4-N—C 3-6 alkenylpiperazino, 4-N—(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N—(C 1-6 alkoxy-C 3-6 alkenyl)piperazino, 4-N—(C 1-6 alkylamino-C 1-6 alkyl)piperazino, 4-N—(C 1-6 alkylamino-C 3-6 alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; and
R 4 is selected from the group consisting of:
(i) hydrogen;
(ii) substituted C 1-11 alkyl or C 2-11 alkenyl wherein the substituents are independently selected from the group consisting of:
(a) hydrogen, hydroxy, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylamino, phenyl-C 1-6 alkylamino, or C 1-6 alkoxycarbonyl;
(b) substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, or substituted C 3-6 alkenyloxy;
(c) di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, or di(substituted C 3-6 alkenyl)amino; and
(d) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C 1-6 alkylpiperazino, 4-N—C 3-6 alkenylpiperazino, 4-N—(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N—(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N—(C 1-6 alkylamino C 1-6 alkyl)piperazino, or 4-N—(C 1-6 alkylamino C 3-6 alkenyl)piperazino; and
(iii) aryl C 0-11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, and thienyl,
wherein said disease is not Fabry's disease.
2. The method of claim 1 , wherein the compound of Formula 1b has the following formula (Formula 2):
in the form of a free compound or as its pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt.
3. The method of claim 1 wherein the disease is characterized by a defect in glycosphingolipid synthesis.
4. The method of claim 3 , wherein the glycosphingolipid is a neutral glycosphingolipid.
5. The method of claim 1 wherein the disease is characterized by a defect in ceramide synthesis.
6. The method of claim 1 wherein the disease is Gaucher's disease.
7. The method of claim 1 wherein the disease is characterized by a defect in ganglioside synthesis in the subject.
8. The method of claim 7 , wherein the ganglioside is a GM1 ganglioside.
9. The method of claim 7 , wherein the ganglioside is a GM2 ganglioside.
10. The method of claim 9 , wherein the disease is Tay Sach's disease.
11. The method of claim 9 , wherein the disease is Sandhoff's disease.
12. The method of claim 7 , wherein the disease is cystic fibrosis.
13. The method of claim 1 further comprising administering a second compound effective to treat the lipid storage disease.
14. The method of claim 13 wherein the second compound is a glucosylceramide synthase inhibitor.
15. The method of claim 14 , wherein the glucosylceramide synthase inhibitor is miglustat.
16. The method of claim 13 wherein the second compound is an enzyme administered as enzyme replacement therapy.
17. The method of claim 13 wherein the second compound is a pharmacological chaperone which binds to an enzyme and promotes trafficking of the enzyme from the endoplasmic reticulum to the lysosome.
18. The method of claim 1 , wherein R 4 is hydrogen.
19. The method of claim 3 , wherein the compound of Formula 1b has the following formula (Formula 2):
in the form of a free compound or as its pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt.