HYDROXY PIPERIDINE DERIVATIVES TO TREAT GAUCHER DISEASE
The present invention provides novel hydroxy piperidine (HP) derivatives having (i) a positive charge at the position corresponding to the anomeric position of a pyranose ring; (ii) a short, flexible linker emanating from the corresponding position of the ring oxygen in a pyranose; and (iii) a lipophilic moiety connected to the linker and pharmaceutically acceptable salts thereof. The linker can be absent if the lipophilic moiety corresponds to a hydrocarbon chain with a linear length of 6 or more carbons. The present invention further provides a method for treating individuals having Gaucher disease by administering the novel HP derivative as “active-site specific chaperones” for the mutant glucocerebrosidase associated with the disease.
1 - 70 . (canceled)
71 . A method for treating Gaucher disease comprising administering to an individual in need of such treatment a pharmaceutical composition in an amount effective to enhance the activity of glucocerebrosidase, wherein the treatment comprises a compound according to Formula I and pharmaceutically acceptable salts and drugs thereof:
wherein A is a carbon;
B is a hydrogen, hydroxyl, N-acetamide or a halogen;
R 1 is a hydrogen;
R 2 is an optional C 1 -C 6 alkyl;
R 5 is hydroxymethyl; and
L is alkyl or benzyl, wherein R 2 and L together have at least 4 carbon atoms.
72 . The method of claim 71 , wherein the treatment further comprises administering to the individual a functional glucocerebrosidase enzyme.
73 . The method of claim 71 , wherein the treatment further comprises administering to the individual a vector functional glucocerebrosidase gene.
74 - 75 . (canceled)
76 . The method of claim 71 , wherein the compound is (3R,4R,5R,6S)-5-(hydroxymethyl)-6-n-butyl-3,4-dihydroxypiperidine.
77 . The method of claim 71 , wherein the compound is (3R,4R,5R,6S)-5-(hydroxymethyl)-6-n-hexyl-3,4-dihydroxypiperidine.
78 . The method of claim 71 , wherein the compound is (3R,4R,5R,6S)-5-(hydroxymethyl)-6-n-heptyl-3,4-dihydroxypiperidine.
79 . The method of claim 71 , wherein the compound is (3R,4R,5R,6S)-5-(hydroxymethyl)-6-n-octyl-3,4-dihydroxypiperidine.
80 . The method of claim 71 , wherein the compound is (3R,4R,5R,6S)-5-(hydroxymethyl)-6-n-nonyl-3,4-dihydroxypiperidine.
81 . The method of claim 71 , wherein the effective amount does not significantly inhibit lysosomal glucocerebrosidase activity