N-(5-((aryl or heteroaryl)methyloxy)pentyl)-substituted iminosugars as inhibitors of glucosylceramide synthase
Deoxynojirimycin and deoxygalactonojirimycin derivatives according to the present invention are N-alkylated D-galacto, D-gluco- or L-ido-deoxynojirimycin with a linear methyloxypentyl group bearing various sidegroups and a non-fused bicyclic aromatic group (“X”) on the methyloxy-carbon. Formula (I), Formula (Ia). These compounds display an increased inhibitory potency towards GCS, and/or an increased inhibitory potency towards GBA2, and/or a decreased inhibitory potency towards GBA1, relative to known deoxynojirimycin derivatives of the same (D-gluco, L-ido or D-galacto) configuration. Therefore, compounds of the present invention are effective in the treatment of diseases which are associated with an irregular level of cytosolic or lysosomal glucosylceramide and/or higher glycosphingolipids, such as a lysosomal storage disorder, such as Gaucher disease, Fabry disease, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, Sialidosis, Niemann Pick disease type C and AMRF, or a symptom of one of the diseases collectively classed as metabolic syndrome, such as obesity, insulin resistance, hyperlipidemia, hypercholesterolemia, polycystic kidney disease, type II diabetes and chronic inflammation, or a neurodenegerative disorder, such as Parkinson disease or Lewy-body dementia.
1. A method of inhibiting glucosylceramide synthase (GCS) in a subject having a disorder characterized by glycosphingolipid accumulation, comprising administering to the subject a GCS-inhibiting compound of structure I or Ia:
wherein:
each of R 19 -R 26 is independently selected from H, F, Me or Et;
R 27 and R 28 is independently selected from the group consisting of H, F, CF 3 and C 1 -C 8 linear or branched alkyl;
X is
wherein
Y 1 -Y 5 are independently selected from the group of C and N-atoms provided that not more than two of Y 1 -Y 5 are a N-atom, and provided that if one or two of Y 1 -Y 5 is a N-atom, the R-group attached to that N-atom is void;
Y 6 -Y 9 are independently selected from the group of C-, S-, N- and O-atoms and comprise at least one of an S-, N- or O-atom, provided that Y 6 -Y 9 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, and provided that if one of Y 6 -Y 9 is a S- or O-atom, the R-group attached to any S-, N- and/or O-atom is void, and provided that if none of Y 6 -Y 9 is a S- or O-atom, the R-group attached to any N-atom is selected from the group consisting of H, C 1 -C 8 linear or branched alkyl, IV and V, and provided that O and S-atoms are not concomitantly present;
one of R 1 -R 9 is
and the remaining of R 1 -R 9 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , C 1 -C 8 linear or branched alkyl and C 1 -C 8 linear or branched oxyalkyl;
wherein
Y 10 -Y 14 are independently selected from the group of C- and N-atoms provided that not more than two of Y 10 -Y 14 are a N-atom, and provided that if one or two of Y 10 -Y 14 is a N-atom, the R-group attached to that N-atom is void;
Y 15 -Y 18 are independently selected from the group of C-, S-, N- and O-atoms and Y 19 is selected from the group consisting of a C-atom and a N-atom, provided that Y 15 -Y 19 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, provided that if one of Y 15 -Y 19 is a S- or O-atom, the group attached to any S-, N and/or O-atom is void, and provided that if none of Y 15 -Y 19 is a S- or O-atom, the group attached to any N-atom is selected from the group consisting of H or C 1 -C 8 linear or branched alkyl, and provided that O and S-atoms are not concomitantly present;
R 10 -R 18 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , C 1 -C 8 linear or branched alkyl or C 1 -C 8 linear or branched oxyalkyl, and/or wherein two of R 10 -R 18 form a linear or branched fused alkylene or alkylenedioxy ring on two adjacent atoms of Y 10 -Y 18 ;
or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit GCS in the subject.
2. The method according to claim 1 , wherein X=
wherein each of the group consisting of R 1 -R 4 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , and C 1 -C 8 linear or branched alkyl, and R 10 -R 14 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , and C 1 -C 8 linear or branched alkyl and/or wherein two of the group consisting of R 10 -R 14 form a linear or branched fused alkylene or alkylenedioxy ring on two adjacent atoms.
3. The method according to claim 1 , wherein R 27 is H and R 28 is methyl.
4. The method according to claim 1 , wherein the iminosugar moiety has the L-ido configuration IX:
5. The method according to claim 1 , wherein the iminosugar moiety has the D-gluco configuration XI:
6. The method according to claim 1 , wherein the compound is selected from the group consisting of
7. The method according to claim 1 , wherein the compound is selected from the group consisting of
8. The method according to claim 1 , comprising administering a pharmaceutical composition which comprises the compound in combination with a pharmaceutically acceptable excipient.
9. A method of decreasing the level of glycosphingolipids in a subject having a disorder characterized by glycosphingolipid accumulation, comprising
wherein:
each of R 19 -R 26 is independently selected from H, F, Me or Et;
R 27 and R 28 is independently selected from the group consisting of H, F, CF 3 and C 1 -C 8 linear or branched alkyl;
X is
wherein
Y 1 -Y 5 are independently selected from the group of C and N-atoms provided that not more than two of Y 1 -Y 5 are a N-atom, and provided that if one or two of Y 1 -Y 5 is a N-atom, the R-group attached to that N-atom is void;
Y 6 -Y 9 are independently selected from the group of C-, S-, N- and O-atoms and comprise at least one of an S-, N- or O-atom, provided that Y 6 -Y 9 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, and provided that if one of Y 6 -Y 9 is a S- or O-atom, the R-group attached to any S-, N- and/or O-atom is void, and provided that if none of Y 6 -Y 9 is a S- or O-atom, the R-group attached to any N-atom is selected from the group consisting of H, C 1 -C 8 linear or branched alkyl, IV and V, and provided that O and S-atoms are not concomitantly present;
one of R 1 -R 9 is
and the remaining of R 1 -R 9 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , C 1 -C 8 linear or branched alkyl and C 1 -C 8 linear or branched oxyalkyl;
wherein
Y 10 -Y 14 are independently selected from the group of C- and N-atoms provided that not more than two of Y 10 -Y 14 are a N-atom, and provided that if one or two of Y 10 -Y 14 is a N-atom, the R-group attached to that N-atom is void;
Y 15 -Y 18 are independently selected from the group of C-, S-, N- and O-atoms and Y 19 is selected from the group consisting of a C-atom and a N-atom, provided that Y 15 -Y 19 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, provided that if one of Y 15 -Y 19 is a S- or O-atom, the group attached to any S-, N and/or O-atom is void, and provided that if none of Y 15 -Y 19 is a S- or O-atom, the group attached to any N-atom is selected from the group consisting of H or C 1 -C 8 linear or branched alkyl, and provided that O and S-atoms are not concomitantly present;
R 10 -R 18 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , C 1 -C 8 linear or branched alkyl or C 1 -C 8 linear or branched oxyalkyl, and/or wherein two of R 10 -R 18 form a linear or branched fused alkylene or alkylenedioxy ring on two adjacent atoms of Y 10 -Y 18 ;
or a pharmaceutically acceptable salt thereof, in an amount effective to decrease the level of glycosphingolipids in the subject.
10. The method of claim 9 which comprises decreasing the levels of glucosylceramide in the subject.
11. The method according to claim 9 , wherein X=
wherein each of the group consisting of R 1 -R 4 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , and C 1 -C 8 linear or branched alkyl, and R 10 -R 14 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , and C 1 -C 8 linear or branched alkyl and/or wherein two of the group consisting of R 10 -R 14 form a linear or branched fused alkylene or alkylenedioxy ring on two adjacent atoms.
12. The method according to claim 9 , wherein R 27 is H and R 28 is methyl.
13. The method according to claim 9 , wherein the iminosugar moiety has the L-ido configuration IX:
14. The method according to claim 9 , wherein the iminosugar moiety has the D-gluco configuration XI:
15. The method according to claim 9 , wherein the compound is selected from the group consisting of
16. The method according to claim 9 , wherein the compound is selected from the group consisting of
17. The method according to claim 9 comprising administering a pharmaceutical composition which comprises the compound in combination with a pharmaceutically acceptable excipient.
18. A method of inhibiting neutral glucosylceramidase (GBA2) in a subject having a disorder characterized by glycosphingolipid accumulation and over-activity of GBA2, comprising administering to the subject a GBA2-inhibiting compound of structure I or Ia:
wherein:
each of R 19 -R 26 is independently selected from H, F, Me or Et;
R 27 and R 28 is independently selected from the group consisting of H, F, CF 3 and C 1 -C 8 linear or branched alkyl;
X is
wherein
Y 1 -Y 5 are independently selected from the group of C and N-atoms provided that not more than two of Y 1 -Y 5 are a N-atom, and provided that if one or two of Y 1 -Y 5 is a N-atom, the R-group attached to that N-atom is void;
Y 6 -Y 9 are independently selected from the group of C-, S-, N- and O-atoms and comprise at least one of an S-, N- or O-atom, provided that Y 6 -Y 9 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, and provided that if one of Y 6 -Y 9 is a S- or O-atom, the R-group attached to any S-, N- and/or O-atom is void, and provided that if none of Y 6 -Y 9 is a S- or O-atom, the R-group attached to any N-atom is selected from the group consisting of H, C 1 -C 8 linear or branched alkyl, IV and V, and provided that 0 and S-atoms are not concomitantly present;
one of R 1 -R 9 is
and the remaining of R 1 -R 9 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , C 1 -C 8 linear or branched alkyl and C 1 -C 8 linear or branched oxyalkyl;
wherein
Y 10 -Y 14 are independently selected from the group of C- and N-atoms provided that not more than two of Y 10 -Y 14 are a N-atom, and provided that if one or two of Y 10 -Y 14 is a N-atom, the R-group attached to that N-atom is void;
Y 15 -Y 18 are independently selected from the group of C-, S-, N- and O-atoms and Y 19 is selected from the group consisting of a C-atom and a N-atom, provided that Y 15 -Y 19 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, provided that if one of Y 15 -Y 19 is a S- or O-atom, the group attached to any S-, N and/or O-atom is void, and provided that if none of Y 15 -Y 19 is a S- or O-atom, the group attached to any N-atom is selected from the group consisting of H or C 1 -C 8 linear or branched alkyl, and provided that O and S-atoms are not concomitantly present;
R 10 -R 18 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , C 1 -C 8 linear or branched alkyl or C 1 -C 8 linear or branched oxyalkyl, and/or wherein two of R 10 -R 18 form a linear or branched fused alkylene or alkylenedioxy ring on two adjacent atoms of Y 10 -Y 18 ;
or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit GBA2 in the subject.
19. The method according to claim 18 , wherein X=
wherein each of the group consisting of R 1 -R 4 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , and C 1 -C 8 linear or branched alkyl, and R 10 -R 14 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , and C 1 -C 8 linear or branched alkyl and/or wherein two of the group consisting of R 10 -R 14 form a linear or branched fused alkylene or alkylenedioxy ring on two adjacent atoms.
20. The method according to claim 18 , wherein R 27 is H and R 28 is methyl.
21. The method according to claim 18 , wherein the iminosugar moiety has the L-ido configuration IX:
22. The method according to claim 18 , wherein the iminosugar moiety has the D-gluco configuration XI:
23. The method according to claim 18 , wherein the compound is selected from the group consisting of
24. The method according to claim 18 , wherein the compound is selected from the group consisting of
25. The method according to claim 18 , comprising administering a pharmaceutical composition which comprises the compound in combination with a pharmaceutically acceptable excipient.