Glucoimidazole and polyhydroxycyclohexenyl amine derivatives to treat gaucher disease
The present invention provides glucoimidazole (GIZ) and polyhydroxycyclohexenyl amine (PHCA) derivatives, methods of making them, and methods of use where the GIZ and PHCA derivatives have a short, flexible linker emanating from the corresponding position of the ring oxygen in a pyranose; and a lipophilic moiety connected to the linker and pharmaceutically acceptable salts thereof. More particularly, the present invention further provides a method for treating individuals having Gaucher disease by administering the novel GIZ or PHCA derivatives as “active-site specific chaperones” for the mutant glucocerebrosidase associated with the disease.
1 . A compound of the Formula I:
wherein B is hydrogen, hydroxy, N-acetamino, or halogen;
R 1 and R 2 are optionally present, are flexible linkers with a linear length of about 6 Å to about 12 Å;
L 1 and L 2 are lipophilic groups having 3-12 carbon atoms comprising a substituted or unsubstituted: alkyl, alkenyl, alkynyl; cycloalkyl, cycloalkenyl; aryl; arylalkyl; heteroaryl; heterocyclic; heterocycloalkyl; or heteroarylalkyl; and
R 5 is a hydrogen, hydroxy, or hydroxymethyl.
2 . A compound of the Formula I:
wherein B is hydrogen, hydroxy, N-acetamino, or halogen;
R 1 and R 2 are independently C 2 -C 6 substituted or unsubstituted: alkyl, alkenyl, or alkynyl, which are optionally interrupted by one or more moieties chosen from the group consisting of NH, NHCOO, NHCONH, NHCSO, NHCSNH, CONH, NHCO, NR 3 , O, S, S(O) m and —S(O) m NR 3 ;
L 1 and L 2 are lipophilic groups having 3-12 carbon atoms comprising a substituted or unsubstituted: alkyl, alkenyl, alkynyl; cycloalkyl, cycloalkenyl; aryl; arylalkyl; heteroaryl; heterocyclic; heterocycloalkyl; or heteroarylalkyl;
wherein R 1 -L 1 or R 2 -L 2 can be a hydrogen, if either R 2 -L 2 or R 1 -L 1 is other than a hydrogen;
R 3 is independently selected from each occurrence a hydrogen, or a substituted or unsubstituted: alkyl, alkenyl; alknyl; cycloalkyl, cycloalkenyl; aryl; arylalkyl; heteroaryl; heterocyclic; heterocyclyalkyl; or heteroarylalkyl, or —C(O) attached to a C 1 -C 6 substituted or unsubstituted alkyl;
m is 1 or 2; and
R 5 is a hydrogen, hydroxy, or hydroxymethyl;
and pharmaceutically acceptable salts and prodrugs thereof.
3 . A method for synthesizing a compound of the Formula III:
wherein R 1 and R 2 are independently C 2 -C 6 substituted or unsubstituted: alkyl, alkenyl, or alkynyl, which are optionally interrupted by one or more moieties chosen from the group consisting of NH, NHCOO, NHCONH, NHCSO, NHCSNH, CONH, NHCO, NR 3 , O, S, S(O) m and —S(O) m NR 3 ;
L 1 and L 2 are lipophilic groups having 3-12 carbon atoms comprising a substituted or unsubstituted: alkyl, alkenyl, alkynyl; cycloalkyl, cycloalkenyl; aryl; arylalkyl; heteroaryl; heterocyclic; heterocycloalkyl; or heteroarylalkyl;
wherein R 1 -L 1 or R 2 -L 2 can be a hydrogen, if either R 2 -L 2 or R 1 -L 1 is other than a hydrogen;
R 3 is independently selected from each occurrence a hydrogen, or a substituted or unsubstituted: alkyl, alkenyl; alknyl; cycloalkyl, cycloalkenyl; aryl; arylalkyl; heteroaryl; heterocyclic; heterocyclyalkyl; or heteroarylalkyl, or —C(O) attached to a C 1 -C 6 substituted or unsubstituted alkyl;
m is 1 or 2; and pharmaceutically acceptable salts and prodrugs thereof; and
comprising the steps of:
a) reacting a compound of the Formula IV:
wherein P 1 , P 2 , P 3 and P 4 are O-protection groups, with N-iodo-succinimide in a polar aprotic solvent or additional reactions for selective removal of 3-iodo group from Formula VI to yield compounds of the Formula V, VI, or VII:
b) reacting a compound of the Formula V, VI or VII with a compound of the Formula VIII or IX:
wherein L is a L 1 or L 2 and R is R 1 or R 2 ,
in the presence of palladium catalyst in a polar aprotic solvent to yield a compound of the Formula X:
deprotecting the O-protection groups to yield formula III:
4 . The compound according to claim 2 wherein R 2 -L 2 is hydrogen.
5 . The compound according to claim 2 wherein B is hydroxy.
6 . The compound according to claim 2 wherein R 5 is hydroxy.
7 . The compound according to claim 2 wherein R 5 is hydroxymethyl.
8 . The compound according to claim 4 wherein R 1 -L 1 is unsubstituted C 1 -C 12 alkyl.
9 . The compound according to claim 8 wherein R 1 -L 1 is unsubstituted C 6 -C 12 alkyl.
10 . The compound according to claim 9 wherein R 1 -L 1 is unsubstituted C 8 alkyl.
11 . The compound according to claim 8 wherein and R 1 -L 1 is unsubstituted branched C 3-12 alkyl.
12 . The compound according to claim 11 wherein R 1 -L 1 is unsubstituted branched C 6-12 alkyl.
13 . The compound according to claim 12 wherein R 1 -L 1 is unsubstituted branched C 6 alkyl.
14 . The compound according to claim 4 wherein R 1 -L 1 is 3,3-dimethylbutyl.
15 . A compound according to claim 2 comprising (5R,6R,7S,8S)-5-hydroxymethyl-2-octyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
16 . A compound according to claim 2 comprising (5R,6R,7S,8S)-5-hydroxymethyl-2-(3,3-dimethylbutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
17 . A compound of the Formula II:
wherein B is hydrogen, hydroxy, N-acetamino, or halogen;
R 1 is a hydrogen, substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, heterocyclyalkyl, or heteroarylalkyl; —C(O)R 3 or —S(O) m R 3 ;
R 2 optionally present, is a flexible linker with a linear length of about 6 Å to about 12 Å;
L is a lipophilic group having 3-12 carbon atoms comprising a substituted or unsubstituted: alkyl, alkenyl, alkynyl; cycloalkyl, cycloalkenyl; aryl; arylalkyl; heteroaryl; heterocyclic; heterocycloalkyl; or heteroarylalkyl;
R 3 is independently selected from each occurrence a hydrogen, or a substituted or unsubstituted: alkyl, alkenyl; alknyl; cycloalkyl, cycloalkenyl; aryl; arylalkyl; heteroaryl; heterocyclic; heterocyclyalkyl; or heteroarylalkyl, or —C(O) attached to a C 1 -C 6 substituted or unsubstituted alkyl;
m is 1 or 2; and
R 5 is a hydrogen, hydroxy, or hydroxymethyl,
and pharmaceutically acceptable salts and prodrugs thereof.
18 . A compound of the Formula II:
wherein B is hydrogen, hydroxy, N-acetamino, or halogen;
R 1 is a hydrogen, substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, heterocyclyalkyl, or heteroarylalkyl; —C(O)R 3 or —S(O) m R 3 ;
R 2, optionally present, is a C 2 -C 6 substituted or unsubstituted: alkyl, alkenyl, or alkynyl, which is optionally interrupted by one or more moieties chosen from the group consisting of NH, NHCOO, NHCONH, NHCSO, NHCSNH, CONH, NHCO, NR 3 , O, S, S(O) m and —S(O) m NR 3 ;
L is a lipophilic group having 3-12 carbon atoms comprising a substituted or unsubstituted: alkyl, alkenyl, alkynyl; cycloalkyl, cycloalkenyl; aryl; arylalkyl;
heteroaryl; heterocyclic; heterocycloalkyl; or heteroarylalkyl;
R 3 is independently selected from each occurrence a hydrogen, or a substituted or unsubstituted: alkyl, alkenyl; alknyl; cycloalkyl, cycloalkenyl; aryl; arylalkyl; heteroaryl; heterocyclic; heterocyclyalkyl; or heteroarylalkyl, or —C(O) attached to a C 1 -C 6 substituted or unsubstituted alkyl;
m is 1 or 2; and
R 5 is a hydrogen, hydroxy, or hydroxymethyl; and
pharmaceutically acceptable salts and prodrugs thereof.
19 . The compound according to claim 18 wherein R 5 is hydroxy.
20 . A method of inhibiting glucocerebrosidase, comprising contacting a glucocerebrosidase with a compound as set forth in claim 1 , in an amount effective to inhibit the glucocerebrosidase.
21 . The method of claim 20 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-octyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
22 . The method of claim 20 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-(3,3-dimethylbutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
23 . The method of 20 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
24 . The method of claim 20 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-phenethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
25 . A method of inhibiting glucocerebrosidase comprising contacting glucocerebrosidase with a compound as set forth in claim 18 , in an amount effective to inhibit the glucocerebrosidase.
26 . A method of inhibiting glucocerebrosidase in a mammalian cell comprising contacting the cell with an inhibitory amount of a compound as set forth in claim 1 .
27 . The method of claim 26 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-octyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
28 . The method of claim 26 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-(3,3-dimethylbutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
29 . The method of claim 26 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
30 . The method of claim 26 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-phenethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
31 . A method of inhibiting glucocerebrosidase in a mammalian cell comprising contacting the cell with an inhibitory amount of a compound as set forth in claim 18 .
32 . A method of enhancing in a mammalian cell the activity of glucocerebrosidase, comprising contacting the cell with a compound as set forth in claim 1 in an amount effective to enhance the activity of glucocerebrosidase, and wherein the effective amount does not inhibit glucocerebrosidase activity.
33 . The method of claim 32 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-octyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
34 . A method of enhancing in a mammalian cell the activity of glucocerebrosidase, comprising contacting the cell with a compound as set forth in claim 18 in an amount effective to enhance the activity of glucocerebrosidase, and wherein the effective amount does not inhibit glucocerebrosidase activity.
35 . A method of stabilizing glucocerebrosidase, comprising contacting the glucocerebrosidase with a compound as set forth in claim 1 , wherein the compound binds reversibly to the glucocerebrosidase, in an amount effective to stabilize the glucocerebrosidase.
36 . The method of claim 35 , wherein the compound is (5R,6R,7S,8S)-5-Hydroxymethyl-2-octyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
37 . The method of claim 35 , wherein the compound is (5R,6R,7S,8S)-5-Hydroxymethyl-2-(3,3-dimethylbutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
38 . The method of claim 35 , wherein the compound is (5R,6R,7S,8S)-5-Hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
39 . The method of claim 35 , wherein the compound is (5R,6R,7S,8S)-5-Hydroxymethyl-2-phenethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
40 . A method of stabilizing glucocerebrosidase, comprising contacting the glucocerebrosidase with a compound as set forth in claim 18 , wherein the compound binds reversibly to the glucocerebrosidase, in an amount effective to stabilize the glucocerebrosidase.
41 . A pharmaceutical composition comprising a compound as set forth in claim 1 and a pharmaceutically acceptable carrier.
42 . The method of claim 41 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-octyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
43 . The method of claim 41 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-(3,3-dimethylbutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
44 . The method of claim 41 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
45 . The method of claim 41 , wherein the compound is (5R,6R,7S,8S)-5-hydroxymethyl-2-phenethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol.
46 . A pharmaceutical composition comprising a compound as set forth claim 18 and a pharmaceutically acceptable carrier.
47 . A method of inhibiting a β-glucosidase, comprising contacting the β-glucosidase with a compound as set forth in claim 1 , wherein the compound binds reversibly to the 13-glucosidase, in an amount effective to inhibit the β-glucosidase.
48 . A method of inhibiting a β-glucosidase, comprising contacting the β-glucosidase with a compound as set forth in claim 18 , wherein the compound binds reversibly to the β-glucosidase, in an amount effective to inhibit the β-glucosidase.
49 . A method for treating Gaucher disease comprising administering to an individual in need of such treatment a pharmaceutical composition as set forth in claim 1 in an amount effective to enhance the activity of glucocerebrosidase.
50 . The method of claim 49 , wherein the treatment further comprises administering to the individual a functional glucocerebrosidase enzyme.
51 . The method of claim 49 , wherein the treatment further comprises administering to the individual a vector functional glucocerebrosidase gene.
52 . A method for treating Gaucher disease comprising administering to an individual in need of such treatment a pharmaceutical composition as set forth in claim 18 in an amount effective to enhance the activity of glucocerebrosidase.
53 . The method of claim 52 , wherein the treatment further comprises administering to the individual a functional glucocerebrosidase enzyme.
54 . The method of claim 52 , wherein the treatment further comprises administering to the individual a vector functional glucocerebrosidase gene.
55 . A glucoimidazole derivative having a short flexible linker emanating from the corresponding ring oxygen position in a pyranose and a lipophilic moiety connected to the linker; and pharmaceutically acceptable salts of such derivatives.
56 . A polyhydroxycyclohexyl amine derivatives having a short flexible linker emanating from the corresponding ring oxygen position in a pyranose and a lipophilic moiety connected to the linker; and pharmaceutically acceptable salts of such derivatives.