Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-09-05
2003-03-04
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S025000, C536S118000, C536S123100, C536S124000, C536S122000, C536S120000, C536S121000, C536S004100
Reexamination Certificate
active
06528497
ABSTRACT:
The present invention relates to novel synthetic polysaccharides which have the anticoagulant and antithrombotic pharmacological activities of heparin.
Heparin belongs to the family of glycosaminoglycans (GAGs), which are heterogeneous natural sulphated polysaccharides.
Heparin preparations are mixtures of chains comprising a number of monosaccharide units ranging from 10 up to 100 or more. This molecular size heterogeneity is accompanied by a structural heterogeneity as regards not only the nature of the constituent monosaccharides but also the substituents they bear (L. Rodén in: “The Biochemistry of Glycoproteins and Glycosaminoglycans”, edited by Lennarz W. J., Plenum Press, New York and London, 267-371, 1980).
Each family of natural GAGs generally has a range of pharmacological activities. All are combined in the preparations which can be obtained from natural products. Thus, for example, heparins and heparan sulphates have an antithrombotic activity which is associated with simultaneous action on several coagulation factors.
Heparin catalyses—in particular via antithrombin III (AT III)—the inhibition of two enzymes which are involved in the blood coagulation cascade, i.e. factor Xa and factor IIa (or thrombin). Preparations of low molecular weight heparins (LMWHs) contain chains formed of 4 to 30 monosaccharides and have the property of acting more selectively on factor Xa than on thrombin.
Certain synthetic oligosaccharides, in particular those described in EP 84999, have the property of selectively inhibiting, via antithrombin III, factor Xa without any activity on thrombin.
It is known that the inhibition of factor Xa requires the binding of heparin to AT III via the antithrombin binding domain (ABD), and that the inhibition of factor IIa (thrombin) requires binding to AT III, via the ABD, as well as to thrombin via a less well defined binding domain (TBD).
Synthetic oligosaccharides corresponding to the ABD of heparin are known and show antithrombotic activity in venous thrombosis. These compounds are described in EP 529,715 and EP 621,282 and in patent CA 2,040,905.
The efficacy of these oligosaccharides in the prevention of arterial thrombosis is nevertheless frustrated by their inability to inhibit thrombin.
A synthesis of heparin-type glycosaminoglycans capable of inhibiting thrombin via activation of AT III is described in patent application PCT/FR 97/01344.
That patent application describes novel biologically active polysaccharide derivatives. In particular, they are anticoagulant and antithrombotic. Furthermore, since these polysaccharides are obtained by synthesis, it is possible to selectively modify their structure, and in particular to remove unwanted sulphate substituents involved in interaction with certain basic proteins such as platelet factor 4 (PF4), which is released during the activation of the platelets, leading to considerable neutralization of heparin in the region of the clot. Thus, polysaccharides can be obtained which are powerful antithrombotic and anticoagulant agents and which, furthermore, can escape in vivo the action of proteins such as PF4, which neutralize the effect of heparin in particular on thrombin.
It has been shown in particular that these sulphated and alkylated polysaccharides can be powerful antithrombotic and anticoagulant agents depending on the arrangement of the alkyl groups and of the sulphate groups borne by the carbohydrate skeleton.
It has been found, more generally, that by making polysaccharide sequences, it is possible to accurately modify the GAG-type activities in order to obtain very active products which have the properties of heparin.
However, the use in human therapy of certain products described in patent application PCT/FR 97/01344 can prove to be difficult, in particular if these products have a long half-life. In the field of preventing or treating thrombosis with the above products, the fluidity of the blood must be re-established or maintained while at the same time avoiding the induction of a haemorrhage. The vital nature of the functions associated herewith is such that it is preferable to use, in order to obtain this equilibrium, only compounds which have a short half-life, which are easier to work with.
The reason for this is that it is well known that a haemorrhage can be triggered in a patient under treatment, due to any accidental cause whatsoever. It may also be necessary to perform surgery on a patient under antithrombotic treatment. For these various reasons also, it is preferred to use compounds with a short half-life.
The half-life of the synthetic polysaccharides of the invention was determined in rats, in which it was observed, unexpectedly, that it is influenced by the structure of the molecule and in particular of the ABD, of the TBD (thrombin binding domain) and of the spacer.
Thus, the present invention relates to novel synthetic polysaccharides, which are similar in structure to that of the compounds of patent application PCT/FR 97/01344, but which have specific properties. The reason for this is that these compounds unexpectedly have a half-life of removal, evaluated after intravenous administration to rats, by means of the anti-Xa activity, of less than one and a half hours.
These compounds are hexadecasaccharides comprising three distinct sequences: a sulphated pentasaccharide sequence DEFGH, a non-sulphated heptasaccharide sequence Z(MN)
3
and a sulphated tetrasaccharide sequence VWXY.
The compounds according to the present invention are synthetic polysaccharides in acidic form and the pharmaceutically acceptable salts thereof with pharmaceutically acceptable cations, the anionic form of which corresponds to one of the formulae (I), (II), (III), (IV) and (V) below:
The invention encompasses the polysaccharides in their acidic form or in the form of any of the pharmaceutically acceptable salts thereof. In the acidic form, the —COO
−
and —SO
3
−
functions are in —COOH and —SO
3
H form, respectively.
The expression “pharmaceutically acceptable salt of the polysaccharides of the invention” is intended to refer to a polysaccharide in which one or more of the —COO
−
and/or —SO
3
−
functions are ionically bonded to a pharmaceutically acceptable metal cation. The preferred salts according to the invention are those in which the cation is chosen from alkali metal cations, and even more preferably those in which the cation is Na
+
or K
+
.
The present invention also relates to a process for preparing the polysaccharides of the invention.
In its principle, this process uses di- or oligosaccharide synthons prepared as reported previously in the literature. Reference will be made in particular to EP 300,099, EP 529,715, EP 621,282 and EP 649,854, as well as to C. van Boeckel, M. Petitou, Angew. Chem. Int. Ed. Engl., 1993, 32, 1671-1690. These synthons are then coupled together so as to give a fully protected precursor of a hexadecasaccharide according to the invention, which is then selectively deprotected and sulphated to give the hexadecasaccharide of the invention.
In the coupling reactions mentioned above, a “donor” di- or oligosaccharide, activated on its anomeric carbon, reacts with an “acceptor” di- or oligosaccharide, containing a free hydroxyl.
The hexadecasaccharides of the invention can be synthesized according to the following sequence of operations, which refer to the saccharide units as represented in formula (I) above.
A protected precursor of GH, pGH, which has an alcohol function in position 4′, and a protected precursor of EF, pEF, whose anomeric carbon is activated, are first prepared. The intermediates pGH and pEF react together to give EFGH. Position 4 of the non-reductive end unit is then deprotected to give a precursor pEFGH.
In parallel, a precursor of the portion YZ(MN)
3
D, whose anomeric carbon is activated, pYZ(MN)
3
D, is prepared according to the same strategy.
The tetrasaccharide pEFGH then reacts with pYZ(MN)
3
D to give YZ(MN)
3
DEFGH. The non-reducing end unit is deprotected to give a precursor pYZ(MN)
3
DEFGH.
Basten Johannes
Dreef-Tromp Cornelia
Driguez Pierre Alexandre
Duchaussoy Philippe
Herbert Jean Marc
Alexander Michael D.
Barts Samuel
Dupont Paul E.
Henry Michael G.
Sanofi-Synthelabo
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