Derivatives of partially desulphated glycosaminoglycans endowed with antiangiogenic activity and devoid of anticoagulating effect

a glycosaminoglycan and partially desulphated technology, applied in the direction of antinoxious agents, drug compositions, metabolic disorders, etc., can solve the problems of many aspects still unsolved, defeating or at least limiting this type of pathology, and achieving non-existent anticoagulant properties, avoiding or reducing side effects, and reducing the effect of anticoagulant properties

Inactive Publication Date: 2005-05-19
SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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.

Method used

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  • Derivatives of partially desulphated glycosaminoglycans endowed with antiangiogenic activity and devoid of anticoagulating effect
  • Derivatives of partially desulphated glycosaminoglycans endowed with antiangiogenic activity and devoid of anticoagulating effect
  • Derivatives of partially desulphated glycosaminoglycans endowed with antiangiogenic activity and devoid of anticoagulating effect

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0160] 1 g of heparin is dissolved in 12.5 ml of NaOH 1N. The solution is heated and stirred at 60° C. for 45 minutes. The reaction is blocked by rapid cooling and neutralisation. The solution is then heated at 70° C. at pH 7 until the epoxide ring is completely open (the reaction trend is controlled by NMR). The desulphated sample (here called G2999H) is dissolved in 20 ml of water and cooled to 4° C. After the addition of 20 ml of a solution of NaIO4 0.2 M, the solution is left to stir in the dark for 20 hours, and the reaction is stopped by adding ethylene glycol and the salts are eliminated by tangential ultrafiltration. 400 mg of NaBH4, subdivided into several portions, are added to the desalted solution (30-40 ml). The solution is left to stir for 3 hours at ambient temperature, then neutralised with diluted HCl and desalted by tangential ultrafiltration. 710 mg of product, here called ST1514, are obtained.

[0161] Molecular weight (MW): 11200 D, polydispersion index D 1.3, des...

examples 2-4

[0162] Adopting the same procedure as in example 1, with the exception that the basic solution was heated for 15, 30 and 60 minutes, respectively, compounds with the following characteristics were obtained: [0163] ST1513: molecular weight (MW) 12900 D, polydispersion index D 1.5, desulphation degree 2.05 (expressed as SO3—:COO— molar ratio), percentage of modified uronic acids compared to total uronic acids: 5% epoxide groups, 29% oxidated and reduced (split) uronic residues; [0164] ST1516: molecular weight (MW) 12900 D, polydispersion index D 1.5, desulphation degree 1.8 (expressed as SO3—:COO— molar ratio), percentage of modified uronic acids compared to total uronic acids: 5% epoxide groups, 29% oxidated and reduced (split) uronic residues; [0165] ST1515: molecular weight (MW) 9200 D, polydispersion index D 1.5, percentage of modified uronic acids compared to total uronic acids: 11% epoxide groups, 27.5% oxidated and reduced (split) uronic residues.

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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. The 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. STATE OF THE ART [0002] 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. [0003] In the early 'eighties, with the discovery of interferon (α / β) as an inhibitor of tumour angiogenesis, clinical experimentation was initiated based on this therapeutic approach. [0004] The media caused quite a stir, when on 3 Mar. 1998 the New York Times published the news that two molecules, angiostatin and endostatin, discovered in J. Fol...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12P19/04A61K31/7024A61K31/726A61K31/727A61P3/10A61P9/08A61P17/06A61P27/02A61P35/00C07H11/00C08B37/00C08B37/10
CPCC08B37/0075A61P17/06A61P27/02A61P35/00A61P35/04A61P39/00A61P9/08A61P3/10A61K31/727
Inventor BANITO, CASUGIANGIACOMO, TORRIANNA MARIA, NAGGIGINSEPPE, GIAONINICLAUDIO, PISANOSERGIO, PENCO
Owner SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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