Derivatives of partially desulphated glycosaminologycans endowed with antiangiogenic activity and devoid of anticogulating effect

Abstract

Partially desulphated glycosaminoglycan derivatives are described, particularly heparin, and more particularly formula (I) compounds, where the U, R and R1 groups have the meanings indicated in the description. Said glycosaminoglycan derivatives are endowed with antiangiogenic activity and are devoid of anticoagulant activity.

Description

[0001] The invention described herein relates to partly desulphated glycosaminoglycan derivatives, particularly heparins, to processes for their preparation, to their use as active ingredients for the preparation of medicaments with an antiangiogenic activity, particularly for the treatment of tumours, such as, for example, the metastatic forms, and to pharmaceutical compositions containing them.[0002] State of the Art[0003] The first molecule possessing antiangiogenic activity was discovered in cartilage by Henry Brem and Judah Folkman in 1975. Since that year more than 300 new molecules capable of inhibiting angiogenesis have been discovered.[0004] In the early `eighties, with the discovery of interferon (.alpha. / .beta.) as an inhibitor of tumour angiogenesis, clinical experimentation was initiated based on this therapeutic approach.[0005] The media caused quite a stir, when on Mar. 3, 1998 the New York Times published the news that two molecules, angiostatin and endostatin, disco...

AI Technical Summary

Benefits of technology

[0073] It is an object of the invention described herein a glycosaminoglycan derivative, particularly desulphated heparin, selectively partially desulphated with a desulphation degree not exceeding 60% of the total uronic units; these desulphation gaps reduce the length of the regular sequences constituted by the succession of disaccharide trisulphate units.

[0080] Advantageously, the compounds according to the invention present reduced, if not non-existent anticoagulant properties, thus avoiding or reducing the side effects typical of the heparins. A further advantage stems from the fact that the compounds according to the invention can be characterised with instrumental analytical techniques, such as NMR spectroscopy, thus allowing process control which is absolutely desirable from the industrial point of view.

Problems solved by technology

Despite the enormous investments and the involvement of large numbers of institutional and private research centres, the cancer problem world-wide is still far from being definitively solved.

Though the prognosis of cancer victims has improved, with survival rates rising over the past 30 years on average from 30 to 50%, and the genetic, cellular and biochemical mechanisms involved in the development of a tumour are now well known, the possibility of defeating or at least limiting this type of pathology is still a problem of keenly felt concern and many aspects are still unsolved, such as the likelihood of recurrence, complete remission and metastatic spread of the primary tumour.

The use of heparin in the treatment of angiogenesis disorders, such as tumours, particularly metastases, is substantially limited by the anticoagulant activity of heparin.

The ability of a primary tumour to generate metastatic cells is perhaps the main problem facing anticancer therapy.

In addition, the inhibition of heparanase reduces the migration ability of tumour cells from the primary tumour to other organs.

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