Derivatives of partially desulphated glycosaminoglycans as heparanase inhibitors, endowed with antiangiogenic activity and devoid of anticoagulating effect
Partially desulphated glycosaminoglycan derivatives are described, particularly heparin, and more particularly a compound of formula (I) where the U, R and R 1 groups have the meanings indicated in the description. These glycosaminoglycan derivatives have antiangiogenic and heparanase-inhibiting activity and are devoid of anticoagulant activity.
1. A compound of formula (I)
where the U ring has the following meaning
R and R 1 are an acetyl residue;
n and m, which can be the same or different, may vary from 1 to 40; the sum of m+n ranges from 6 to 40; the m:n ratio ranges from 10:2 to 1:1, the symbol indicates that units marked m and n are statistically distributed along the polysaccharide chain and are not necessarily in sequence.
2. A compound according to claim 1 , which is 100% desulphated and N-reacetylated heparin with a molecular weight MW=20.2 kDa.
3. A pharmaceutical composition containing the compound of claim 1 as an active ingredient in admixture with pharmaceutically acceptable vehicles and excipients.
4. A method of inhibiting heparanase and/or inhibiting FGF growth factor comprising administering to a subject in need of said inhibition an effective amount of the compound of claim 1 .
5. The method of claim 4 , wherein said compound has antiangiogenic activity.
6. The method of claim 4 , wherein said method is useful for the treatment of an inflammation.
7. The method of claim 4 , wherein said method is useful for the treatment of a disease selected from primary tumours, metastases, diabetic rethinopathy, psoriasis, retrolenticular fibroplasia, arthritis, allograft rejection, cardiovascular diseases, fibro-proliferative disease, diseases elicited by abnormal platelet aggregation, proliferative rethinopathies, insulin dependent diabetes, inflammatory bowel disease.
8. The method according to claim 7 , wherein said inflammatory bowel disease is selected from the group consisting of ulcerative colitis, and Crohn's disease.
9. The method of claim 4 , wherein said method is useful for the treatment of a disease selected from the group consisting of: diseases elicited by smooth muscle proliferation, Goodpasture syndrome, acute glomerulonephritis, neonatal pulmonary hypertension, asthma, congestive heart failure, adult pulmonary hypertension, renal vascular hypertension.
10. The method of claim 4 , wherein said method is useful for the treatment of restenosis after angioplasty or coronary by-pass.