N-(5-((aryl or heteroaryl)methyloxy)pentyl)-substituted iminosugars as inhibitors of glucosylceramide synthase

Patent metadata

Field	Value
Publication number	US-10189784-B2
Application number	US-201515129815-A
Country	US
Kind code	B2
Filing date	Mar 23, 2015
Priority date	Mar 27, 2014
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

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. 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.

First claim

The invention claimed is:

1. A compound of general 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, ester, hydrate, and/or solvate thereof.

2. A compound 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. A compound according to claim 2 , wherein R 27 is H and R 28 is methyl.

4. A compound according to any of claim 3 , wherein the iminosugar moiety has the L-ido configuration IX:

5. A compound according to any of claim 3 , wherein the iminosugar moiety has the D-gluco configuration XI:

6. A compound according to any of claim 5 , selected from the group consisting of

7. A compound according to any of claim 3 , selected from the group consisting of

8. A pharmaceutical composition comprising a compound according to claim 7 and a pharmaceutically acceptable excipient.

9. A method of making a compound according to claim 7 , comprising alkylation of D-gluco or L-ido deoxynojirimycin or D-galactonojirimycin with an alkyl halide of structure

wherein
Z=bromide, iodide, mesylate, tosylate or triflate;
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 .

10.

Assignees

• Acad Medisch Ct
• Univ Leiden

Inventors

• Overkleeft Herman Steven
• Van Boeckel Stan
• Aerts Johannes Maria Franciscus Gerardus
• Ghisaidoobe Amar
• Van Den Berg Richard

Classifications

• C07D211/40 Primary

  Oxygen atoms · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D211/46 Primary

  having a hydrogen atom as the second substituent in position 4 · CPC title