Sulfated oligosaccharide derivatives
The invention relates to compounds which are polysulfated oligosaccharide derivatives having activity as inhibitors of heparan sulfate-binding proteins and inhibitors of the enzyme heparanase; methods for the preparation of the compounds; compositions comprising the compounds, and use of the compounds and compositions thereof for the antiangiogenic, antimetastatic, anti-inflammatory, antimicrobial, anticoagulant and/or antithrombotic treatment, lowering of blood triglyceride levels and inhibition of cardiovascular disease of a mammalian subject.
1. A compound of the general formula:
X—[Y] n —Z—UR 1
wherein:
X, Y and Z are each the same monosaccharide unit with a group UR bonded via a single or multiple bond to each non-linking carbon of X, Y and Z, except carbon-1 of monosaccharide Z which bears UR 1 bonded via a single or multiple bond;
n is an integer having a value of 0-6;
each U is independently C, N, S O CO, COO, NO, NO 2 , S(O), or S(O)O;
each R is independently SO 3 M or H, where M is any pharmaceutically acceptable cation, or is any alkyl, aryl, acyl, aroyl, alkyl sulfonyl, aryl sulfonyl, PEG, an alkoxy PEG, H or the group
where independently in each AB group, A is O or NH, and B is H, or M where M is any pharmaceutically acceptable cation, an alkyl, an aryl group, or R together with U is N 3 ; and
R 1 is SO 3 M, H, aryl, acyl, aroyl, alkyl sulfonyl, aryl sulfonyl, PEG or an alkoxy PEG, or R 1 together with U is N 3 or a substituted triazole, or a substituted tetrazole, or a substituted aryl, or a substituted heteroaryl;
with the provisos that:
at least one UR is N 3 ; and
at least 50% of the R groups are SO 3 M.
2. The compound of claim 1 , wherein M is sodium.
3. The compound of claim 1 , wherein n is 3.
4. The compound of claim 1 , wherein 70 to 100% of the R groups comprise SO 3 M.
5. A pharmaceutical or veterinary composition for the treatment in a mammalian subject of a disorder resulting from one or more of: angiogenesis, metastasis, inflammation, coagulation, thrombosis, raised blood triglyceride levels, proliferative retinopathy, or solid tumor, HSV-1 infection, 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 said at least one compound.
6. The composition according to claim 5 which further includes a pharmaceutically or veterinarially acceptable excipient, buffer, stabiliser, isotonicising agent, preservative or antioxidant.
7. The composition according to claim 5 , wherein said compound is present therein as an ester, a free acid or base, or having one or more lipid substituents.
8. A method for the treatment in a mammalian subject of a disorder resulting from one or more of: angiogenesis, metastasis, inflammation, coagulation, thrombosis, raised blood triglyceride levels, proliferative retinopathy, or solid tumor, HSV-1 infection, 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.
9. The method according to claim 8 wherein said mammalian subject is a human subject.
10. The method according to claim 8 , wherein said disorder resulting from angiogenesis is a proliferative retinopathy or angiogenesis resulting from the growth of a solid tumour.
11. The method according to claim 8 , wherein said disorder resulting from inflammation is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, allograft rejection or chronic asthma.
12. The method according to claim 8 , wherein said disorder resulting from coagulation or thrombosis is deep venous thrombosis, pulmonary embolism, thrombotic stroke, peripheral arterial thrombosis, unstable angina or myocardial infarction.
13. A compound of the general formula:
wherein:
n is an integer having a value of 0-6;
U is C, N, S O, CO, COO, NO, NO 2 , S(O), or S(O)O;
each R is independently SO 3 M or H, where M is any pharmaceutically acceptable cation or is any alkyl, aryl, acyl, aroyl, alkyl sulfonyl, aryl sulfonyl, PEG, an alkoxy PEG, H or the group
where independently in each AB group, A is O or NH, and B is H, or M where M is any pharmaceutically acceptable cation, an alkyl, aryl group or or R together with U is N 3 ; and
R 1 is SO 3 M, H, alkyl, aryl, acyl, aroyl, alkyl sulfonyl, aryl sulfonyl, PEG or an alkoxy PEG, or R 1 together with U is N 3 or a substituted triazole, or a substituted tetrazole, or a substituted aryl, or a substituted heteroaryl;
with the provisos that:
at least one R is N 3 ; and
at least 50% of the R groups are SO 3 M.
14. The compound of claim 13 , wherein M is sodium.
15. The compound of claim 13 , wherein n is 3.
16. The compound of claim 13 , wherein R 1 is n-octyl.
17. The compound of claim 13 , wherein 70 to 100% of the R groups comprise SO 3 M.
18. A pharmaceutical or veterinary composition for the treatment in a mammalian subject of a disorder resulting from one or more of: angiogenesis, metastasis, inflammation, coagulation, thrombosis, raised blood triglyceride levels, proliferative retinopathy, or solid tumor, HSV-1 infection, or cardiovascular disease, which composition comprises at least one compound according to claim 13 together with a pharmaceutically or veterinarially acceptable carrier or diluent for said at least one compound.
19. The composition according to claim 18 which further includes a pharmaceutically or veterinarially acceptable excipient, buffer, stabiliser, isotonicising agent, preservative or antioxidant.
20. The composition according to claim 18 , wherein said compound is present therein as an ester, a free acid or base, or having one or more lipid substituents.
21. A method for the treatment in a mammalian subject of a disorder resulting from one or more of: angiogenesis, metastasis, inflammation, coagulation, thrombosis, raised blood triglyceride levels, proliferative retinopathy, or solid tumor, HSV-1 infection, or cardiovascular disease, which method comprises administering to the subject an effective amount of at least one compound according to claim 13 , or a composition comprising said at least one compound.
22. The method according to claim 21 wherein said mammalian subject is a human subject.
23. The method according to claim 21 , wherein said disorder resulting from angiogenesis is a proliferative retinopathy or angiogenesis resulting from the growth of a solid tumour.
24. The method according to claim 21 , wherein said disorder resulting from inflammation is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, allograft rejection or chronic asthma.
25. The method according to claim 21 , wherein said disorder resulting from coagulation or thrombosis is deep venous thrombosis, pulmonary embolism, thrombotic stroke, peripheral arterial thrombosis, unstable angina or myocardial infarction.
26. A pharmaceutical or veterinary composition for the treatment in a mammalian subject of a disorder resulting from one or more of: angiogenesis, metastasis, inflammation, coagulation, thrombosis, raised blood triglyceride levels, proliferative retinopathy, or solid tumor, HSV-1 infection, or cardiovascular disease, which composition comprises at least one compound of the general formula:
X—[Y] n —Z—UR 1
wherein:
X, Y and Z are each the same monosaccharide unit with a group UR bonded via a single or multiple bond to each non-linking carbon of X, Y and Z, except carbon-1 of monosaccharide Z which bears UR 1 bonded via a single or multiple bond;
n is an integer having a value of 0-6;
each U is independently C, N, S or O, CO, COO, NO, NO 2 , S(O), S(O)O;
each R is independently SO 3 M, where M is any pharmaceutically acceptable cation, or is any alkyl, aryl, acyl, aroyl, alkyl sulfonyl, aryl sulfonyl, PEG, an alkoxy PEG, H or the group
where independently in each AB group, A is O or NH, and B is H, or M where M is any pharmaceutically acceptable cation, an alkyl, an aryl group or R together with U is N 3 ;
R 1 is alkyl;
with the proviso that at least 50% of the R groups are SO 3 M.
27. The composition according to claim 26 which further includes a pharmaceutically or veterinarially acceptable excipient, buffer, stabiliser, isotonicising agent, preservative or antioxidant.
28. The composition according to claim 26 , wherein said compound is present therein as an ester, a free acid or base, having one or more lipid substituents.
29. A method for the treatment in a mammalian subject of a disorder resulting from one or more of: angiogenesis, metastasis, inflammation, coagulation, thrombosis, raised blood triglyceride levels, proliferative retinopathy, solid tumor, HSV-1 infection, or cardiovascular disease, which method comprises administering to the subject an effective amount of at least one compound of the general formula:
X—[Y] n —Z—UR 1
wherein:
X, Y and Z are each the same monosaccharide unit with a group UR bonded via a single or multiple bond to each non-linking carbon of X, Y and Z, except carbon-1 of monosaccharide Z which bears UR 1 bonded via a single or multiple bond;
n is an integer having a value of 0-6;
each U is independently C, N, S or O, CO, COO, NO, NO 2 , S(O), S(O)O;
each R is independently SO 3 M, where M is any pharmaceutically acceptable cation, or is any alkyl, aryl, acyl, aroyl, alkyl sulfonyl, aryl sulfonyl, PEG, an alkoxy PEG, H or the group
where independently in each AB group, A is O or NH, and B is H, or M where M is any pharmaceutically acceptable cation, an alkyl, an aryl group or R together with U is N 3 ;
R 1 is alkyl;
with the proviso that at least 50% of the R groups are SO 3 M; or a composition comprising said at least one compound.
30. The method according to claim 29 wherein said mammalian subject is a human subject.
31. The method according to claim 29 , wherein said disorder resulting from angiogenesis is a proliferative retinopathy or angiogenesis resulting from the growth of a solid tumour.
32. The method according to claim 29 , wherein said disorder resulting from inflammation is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, allograft rejection or chronic asthma.
33. The method according to claim 29 , wherein said disorder resulting from coagulation or thrombosis is deep venous thrombosis, pulmonary embolism, thrombotic stroke, peripheral arterial thrombosis, unstable angina or myocardial infarction.
34. A compound, wherein said compound is PG505: 2,3,4,6-Tetra-O-sulfono-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfono-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfono-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfono-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfono-α-D-glucopyranosyl-(1→4)-1-azido-2,3,6-tri-O-sulfono-α-D-glucopyranose, hexadecasodium salt.
35. A compound according to claim 2 , wherein said compound is PG515: Benzyl (6-Azido-6-deoxy-2,3,4-tri-O-sulfono-α-D-mannopyranoside)-(1,3)-(2,4,6-tri-O-sulfono-α-D-mannopyranoside)-(1,3)-(2,4,6-tri-O-sulfono-α-D-mannopyranoside)-(1,2)-3,4,6-tri-O-sulfono-α-D-mannopyranoside, dodecasodium salt.