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 having 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, 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, M where M is any pharmaceutically acceptable cation, an alkyl, or an aryl group; 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, or a substituted tetrazole or, or a substituted aryl or derivative, or a substituted heteroaryl or;
with the provisos that:
at least one of UR 1 or UR is not OSO 3 M, NSO 3 M, OH or OPO 3 M 2 , and
at least 50% of the R groups are SO 3 M.
2. A compound having 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, 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, or an aryl group; 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, or a substituted tetrazole or derivative, or a substituted aryl or derivative, or a substituted heteroaryl or;
with the provisos that:
when U is O or N, at least one of R 1 or R is not SO 3 M, H or PO 3 M 2 , and
at least 50% of the R groups are SO 3 M.
3. The compound of claim 1 or claim 2 , wherein M is sodium.
4. The compound of claim 1 or claim 2 , wherein n is 3.
5. The compound of claim 2 , wherein R 1 is n-octyl.
6. The compound of claim 1 or claim 2 , wherein 70 to 100% of the R groups comprise SO 3 M.
7. A compound according to claim 2 , wherein said compound is PG500, PG501, PG502, PG503, PG504, PG506, PG508, PG509, PG510, PG511, PG512, PG513, or PG514.
8. 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 or claim 2 together with a pharmaceutically or veterinarially acceptable carrier or diluent for said at least one compound.
9. The composition according to claim 8 which further includes a pharmaceutically or veterinarially acceptable excipient, buffer, stabiliser, isotonicising agent, preservative or antioxidant.
10. The composition according to claim 8 , wherein said compound is present therein as an ester, a free acid or base, a, or having one or more lipid substituents.
11. 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 according to claim 1 or claim 2 , or a composition comprising an effective amount of said at least one compound.
12. The method according to claim 11 wherein said mammalian subject is a human subject.
13. The method according to claim 11 , wherein said disorder resulting from angiogenesis is a proliferative retinopathy or angiogenesis resulting from the growth of a solid tumor.
14. The method according to claim 11 , wherein said disorder resulting from coagulation or thrombosis is deep venous thrombosis, pulmonary embolism, thrombotic stroke, peripheral arterial thrombosis, unstable angina, or myocardial infarction.