Sulfated oligosaccharide derivatives
The invention relates to novel compounds that have utility as inhibitors of heparan sulfate-binding proteins; compositions comprising the compounds, and use of the compounds and compositions thereof for the antiangiogenic, antimetastatic, anti-inflammatory, antimicrobial, anticoagulant and/or antithrombotic treatment of a mammalian subject.
1. A compound of the general formula:
[X] n —Y—ZR 1 R 2 I
wherein:
X and Y are each a monosaccharide unit wherein each hydroxyl group not involved in a glycosidic linkage is substituted independently by a group SO 3 M or H, where M is any pharmaceutically acceptable cation;
X and Y are any D - or L -hexose or pentose;
Y is in a cyclic or ring opened form;
Z is O, N, S or C or their higher oxidation states, or a bond, and is linked to the anomeric carbon when Y is a reducing monosaccharide;
R 1 is a linker selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, acyl, aroyl, alkylamido, alkylthioamido, triazolyl, substituted triazolyl, and oxymethyl[1,2,3]-triazole-1-yl linker, or is a bond, wherein if R 1 is substituted triazolyl, the triazolyl is substituted by one or more of: halo, hydroxy, C1-6alkyl, C1-6alkoxy, nitro, amino, C1-6alkylamino, C1-6dialkylamino, halomethyl, halomethoxy or acetyl;
R 2 is a lipophilic moiety selected from the group consisting of: cholestanyl, and propylstearamide, wherein
n is an integer from 0-6; and
the level of sulfation of each compound is between 70 and 100% of the total hydroxyl groups.
2. The compound according to claim 1 wherein R 2 is cholestanyl.
3. The compound according to claim 1 wherein R 2 is propylstearamide.
4. A compound selected from the group consisting of:
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 65);
4-(cholestan-3-yl-oxymethyl)[1,2,3]triazol-1-yl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-1-deoxy-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 70);
4-(cholestan-3β-yl-oxymethyl)[1,2,3]triazol-1-yl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-1-deoxy-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 76);
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 87);
3-stearamidopropyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, decasodium salt (compound 123); and
3-stearamidopropyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, tridecasodium salt (compound 128).
5. A pharmaceutical or veterinary composition for the treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation/thrombosis, raised blood triglyceride levels, microbial infection and/or cardiovascular disease, which composition comprises at least one compound according to claim 1 together with a pharmaceutically or veterinarially acceptable carrier or diluent for at least one said compound.
6. A method for the treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation/thrombosis, raised blood triglyceride levels, microbial infection and/or cardiovascular disease, which method comprises administering to the subject an effective amount of at least one compound according to claim 1 , or a composition comprising said at least one compound.
7. The method of claim 6 wherein the compound is selected from the group consisting of:
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 65);
4-(cholestan-3-yl-oxymethyl)[1,2,3]triazol-1-yl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-1-deoxy-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 70);
4-(cholestan-3β-yl-oxymethyl)[1,2,3]triazol-1-yl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-1-deoxy-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 76);
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 87);
3-stearamidopropyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, decasodium salt (compound 123); and
3-stearamidopropyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, tridecasodium salt (compound 128).
8. The compound according to claim 2 wherein R 1 is an oxymethyl[1,2,3]-triazole-1-yl linker.
9. The compound according to claim 3 wherein R 1 is an oxymethyl[1,2,3]-triazole-1-yl linker.
10. A pharmaceutical or veterinary composition according to claim 5 , selected from the group consisting of:
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 65);
4-(cholestan-3-yl-oxymethyl)[1,2,3]triazol-1-yl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-1-deoxy-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 70);
4-(cholestan-3β-yl-oxymethyl)[1,2,3]triazol-1-yl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-1-deoxy-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 76);
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 87);
3-stearamidopropyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, decasodium salt (compound 123); and
3-stearamidopropyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, tridecasodium salt (compound 128),
together with a pharmaceutically or veterinarially acceptable carrier or diluent for at least one said compound.
11. A compound selected from the group consisting of:
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→2)-3,4,6-tri-O-sodium sulfonato-α- D -mannopyranoside (compound 20);
3-stearamidopropyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→2)-3,4,6-tri-O-sodium sulfonato-α- D -mannopyranoside (compound 24);
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→2)-3,4,6-tri-O-sodium sulfonato-α- D -mannopyranoside (compound 27);
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -mannopyranosyl-(1→2)-3,4,6-tri-O-sodium sulfonato-α- D -mannopyranoside (compound 33);
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→2)-3,4,6-tri-O-sodium sulfonato-α- D -mannopyranoside (compound 39);
3-stearamidopropyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→2)-3,4,6-tri-O-sodium sulfonato-α- D -mannopyranoside (compound 44);
3-{4-(cholestan-3β-yl-oxymethyl)-[1,2,3]triazol-1-yl}propyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→2)-3,4,6-tri-O-sodium sulfonato-α- D -mannopyranoside (compound 48);
3′-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-3,4,6-tri-O-sodium sulfonato-α- D -mannopyranoside (compound 56);
3-{4-(cholestan-3β-yl-oxymethyl)-[1,2,3]triazol-1-yl}propyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-2,4,6-tri-O-sodium sulfonato-α- D -mannopyranosyl-(1→3)-3,4,6-tri-O-sodium sulfonato-α- D -mannopyranoside (compound 60);
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 65);
4-(cholestan-3-yl-oxymethyl)[1,2,3]triazol-1-yl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-1-deoxy-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 70);
4-(cholestan-3β-yl-oxymethyl)[1,2,3]triazol-1-yl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-1-deoxy-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 76);
3β-cholestanyl-2,3,4,6-tetra-O-sulfonato-α- D -mannopyranoside tetrasodium salt (compound 79);
3β-cholestanyl-2,3,4,6-tetra-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sodium sulfonato-β- D -glucopyranoside (compound 87);
4-(cholestan-3β-yl-oxymethyl)[1,2,3]triazol-1-yl-2,3,4,6-tetra-O-sulfo-β- D -galactopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, heptasodium salt (compound 93);
4-(cholestan-3β-yl-oxymethyl)[1,2,3]triazol-1-yl 2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, heptasodium salt (compound 97);
3′-cholestanyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, heptasodium salt (compound 102);
3′-cholestanyl-2,3,4,6-tetra-O-sulfo-β- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, heptasodium salt (compound 107);
3′-cholestanyl-2,3,4,6-tetra-O-sulfo-β- D -galactopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, heptasodium salt (compound 112);
3′-cholestanyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranosyl-(1→6)-2,3,4-tri-O-sulfo-α- D -mannopyranoside, tridecasodium salt (compound 119);
3-stearamidopropyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, decasodium salt (compound 123);
3-stearamidopropyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, tridecasodium salt (compound 128);
2-(cholestan-3-yloxy)acetamido-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside, decasodium salt (compound 134);
1-[(cholestan-3-yloxy)propyl]-3-[2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β- D -glucopyranoside]thiourea, decasodium salt (compound 139); and
3′-cholestanyl-2,3,4,6-tetra-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α- D -glucopyranosyl-(1→4)-((1-pyridinium-1-yl)-2,3,5,6-tetra-O-sulfo- D -glucoside, tridecasodium salt (compound 140).
12. The compound according to claim 2 , wherein R 1 is a bond.
13. The compound according to claim 12 , wherein each X is a D-hexose, and Y is a D-hexose.
14. The compound according to claim 13 , wherein n is 3.
15. A pharmaceutical or veterinary composition for the treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation/thrombosis, raised blood triglyceride levels, microbial infection and/or cardiovascular disease, which composition comprises at least one compound according to claim 11 together with a pharmaceutically or veterinarially acceptable carrier or diluent for at least one said compound.
16. A method for the treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation/thrombosis, raised blood triglyceride levels, microbial infection and/or cardiovascular disease, which method comprises administering to the subject an effective amount of at least one compound according to claim 11 , or a composition comprising said at least one compound.
17. A compound of the general formula:
[X] n —Y—ZR 1 R 2 I
wherein:
X and Y are each a monosaccharide unit wherein each hydroxyl group not involved in a glycosidic linkage is substituted independently by a group SO 3 M or H, where M is any pharmaceutically acceptable cation;
X and Y are any D- or L-hexose or pentose;
Y is in a cyclic or ring opened form;
Z is O, N, S or C or their higher oxidation states, or a bond, and is linked to the anomeric carbon when Y is a reducing monosaccharide;
R 1 is an oxymethyl[1,2,3]-triazole-1-yl linker;
R 2 is a lipophilic moiety selected from the group consisting of: cholesteryl, cholestanyl, cholate, deoxycholate, glycyrrhetinyl, C9 to C18 straight chain alkyl, C9 to C18 substituted alkyl, alkylamido, substituted alkylamido, and propylstearamide, straight chain acyl, branched acyl, and —C(O)-alkyl or —C(O)-aryl, in which the alkyl or aryl groups are optionally substituted by one or more of halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, nitro, amino, C 1-6 alkylamino, C 1-6 dialkylamino, halomethyl, halomethoxy or acetyl, wherein
if R 2 is substituted alkyl or substituted alkylamido, the group is substituted by one or more of: halo, hydroxy, C 1-6 alkoxy, nitro, amino, C 1-6 alkylamino, C 1-6 dialkylamino, halomethyl, halomethoxy or acetyl;
n is an integer from 0-6; and
the level of sulfation of each compound is between 70 and 100% of the total hydroxyl groups.
18. A pharmaceutical or veterinary composition for the treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation/thrombosis, raised blood triglyceride levels, microbial infection and/or cardiovascular disease, which composition comprises at least one compound according to claim 17 together with a pharmaceutically or veterinarially acceptable carrier or diluent for at least one said compound.
19. A method for the treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation/thrombosis, raised blood triglyceride levels, microbial infection and/or cardiovascular disease, which method comprises administering to the subject an effective amount of at least one compound according to claim 17 , or a composition comprising said at least one compound.