Core 2 GlcNAc-T inhibitors
View Patent ↗A method of treating a subject in need of therapy for a condition involving detrimental activity of the enzyme core 2 GlcNAc-T is provided, comprising administration of a therapeutically effective amount of an inhibitor of core 2 GlcNAc-T of formula I to a patient in need thereof wherein: R 1 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 -alkoxy-C 1-6 -alkyl; R 2 is H, —OH or C 1-6 alkoxy; S 1 and S 2 are independently selected saccharide moieties; and Z is a steroid moiety; or a pharmaceutically acceptable salt, ether or ester thereof.
1. A method of treating a subject in need of therapy for a condition involving detrimental activity of the enzyme core 2 GlcNAc-T comprising administering, to a patient having a condition involving detrimental activity of the enzyme core 2 GlcNAc-T selected from the group consisting of vascular diseases, autoimmune and inflammatory conditions, a therapeutically effective amount of an inhibitor of core 2 GlcNAc-T of formula I to a patient in need thereof
wherein:
R 1 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 -alkoxy-C 1-6 -alkyl;
R 2 is H, —OH or C 1-6 alkoxy;
Sac 1 and Sac 2 are independently selected saccharide moieties; and
Z is a steroid moiety;
or a pharmaceutically acceptable salt, ether or ester thereof.
2. A method according to claim 1 in which R 1 is —H, —CH 3 or —CH 2 OH.
3. A method according to claim 1 in which R 1 is —CH 2 OH.
4. A method according to claim 1 in which R 1 is —CH 2 OH and a ring in the structure of formula I is a glucose moiety.
5. A method according to claim 1 in which R 2 is —OH.
6. A method according to claim 1 in which Sac 1 and Sac 2 are monosaccharides.
7. A method according to claim 1 in which Sac 1 is a pentose or an aldohexose.
8. A method according to claim 1 in which Sac 1 is an aldohexose.
9. A method according to claim 1 in which Sac 1 is glucose.
10. A method according to claim 1 in which Sac 2 is selected from the group consisting of a tetrose a pentose and a hexose moiety.
11. A method according to claims 1 in which Sac 2 is rhamnose.
12. A method according to claim 1 in which the compound of the formula I is
13. A method according to claims 1 in which the steroid moiety Z is a Compound of the formula:
which steroid moiety Z may further incorporate a further group selected from the groups consisting of groups VI(a) to VI(e):
wherein:
R 3 , R 10 and R 18 are independently selected from H and —OH;
R 4 and R 25 are independently selected from C 1-6 alkyl;
R 5 , R 7 and R 12 are independently selected from H and C 1-6 alkyl;
R 6 is H or —OH or the H normally also present is absent and R 6 is ═;
R 8 is H, —OH or C 1-6 acyl or a group selected from VII a or VII b.
R 9 is H.
R 11 is H, C 1-6 alkyl or —OH or R 9 and R 11 taken together form a —CH 2 —CH 2 — group;
R 13 is H, C 1-6 alkyl or C 1-6 hydroxyalkyl;
R 14 , R 19 , R 23 and R 29 are independently selected from C 1-6 alkyl;
R 15 is H or —OH;
R 16 is H, —OH or C 1-6 alkoxy or R 15 and R 16 taken together represent the second bond of a double bond joining adjacent carbon atoms;
R 17 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or a C 1-6 alkyl group substituted by one or more groups selected from the group consisting of —OH, C 1-6 alkoxy and Sac 3 ;
R 20 is H or —OH;
R 21 is C 1-6 alkyl, C 1-6 hydroxyalkyl or ═CH 2 ;
R 22 is —OH; R 24 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 26 is C 1-6 hydroxyalkyl;
R 27 is C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 alkyl substituted by Sac 4 ;
R 28 is C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl;
R 30 is C 1-6 hydroxyalkyl or C 1-6 alkyl substituted by Sac 5 ;
R 31 is C 1-6 alkyl;
Sac 3 and Sac 5 are independently selected saccharide moieties;
Sac 4 is a saccharide;
X is either O or NH; and
Represents either a single bond or a double bond.
14. A method according to claims 13 in which R 17 is C 2-6 alkenyl or a C 1-6 alkyl group substituted by one or more groups selected from the group consisting of —OH, —OCH 3 and Sac 3 .
15. A method according to claim 13 in which R 17 is selected from the group comprising 3-methyl but-2-eneyl, 2-methyl-prop-2-enyl, 3-methylbutanyl substituted at the 4-position by Sac 3 , 1-hydroxy-3-methylbutanyl substituted at the 4-position by Sac 3 or 1-methoxy-3-methylbutanyl substituted at the 4-position by Sac 3 .
16. A method according to claim 13 in which R 21 is —CH 3 , —CH 2 OH or ═CH 2 .
17. A method according to claim 13 in which R 24 is C 2-6 alkenyl.
18. A method according to claims 13 in which R 27 is —CH 3 or —CH 2 -Sac 4 .
19. A method according to claim 13 in which Sac 4 is glucose.
20. A method according to claim 13 in which R 28 is C 1-8 alkyl or C 2-8 alkenyl.
21. A method according to claim 13 in which R 28 is 3-ethyl-4-methyl-pentanyl or 5-methyl-hex-4-enyl.
22. A method according to claim 13 in which R 30 is —CH 2 -Sac 5 .
23. A method according to claim 13 in which Sac 5 is glucose.
24. A method according to claim 13 in which X is O.
25. A method according to claim 1 in which the compound is selected from the group consisting of:
Protogracillin protoneogracillin methylprotogracillin methylprotoneogracillin, pseudoprotogracillin, dracenoside Q, dioscoreside E dracenoside P tuberoside C, icogenin, gracillin, collettiside IV, 17-OH gracillin, dracaenoside H dracaenoside L, dracaenoside I, lilioglycoside H, lilioglycoside I, dracaenoside D, neoalsoside A, neoalsoside C, hoduloside V, Lotoside II, compound 17, compound 21 and compound 25.