Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-09-07
2003-03-18
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000, C536S017200, C536S021000
Reexamination Certificate
active
06534481
ABSTRACT:
This application is the U.S. National Stage entry under 35 U.S.C. §371 of PCT/FR97/01344, filed Jul. 8, 1997.
The present invention relates to novel synthetic polysaccharides possessing 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 to 100 and more. In addition to this size heterogeneity there is a structural heterogeneity, as regards the nature of the constituent monosaccharides and also as regards the substituents which they bear (L. Rodén in: The Biochemistry of Glycoproteins and Glycosaminoglycans, Ed by Lennarz W. J., Plenum Press, New York and London, 267-371, 1980).
Each family of natural GAGs generally possesses a wide range of pharmacological activities. All are combined in the preparations which may be obtained from natural products. Thus, for example, the heparin and heparan sulphates possess an antithrombotic activity which is associated with the simultaneous action of several coagulation factors.
Heparin catalyses, in particular via antithrombin III (AT III), the inhibition of two enzymes involved in the blood coagulation cascade, namely factor Xa and factor IIa (or thrombin). Low molecular weight heparin (LMWH) preparations 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 84,999, have the property of selectively inhibiting, via antithrombin III, factor Xa without having any activity on thrombin.
It is known that the inhibition of factor Xa requires binding of the heparin to AT III via the antithrombin-binding region (ABR), and that the inhibition of factor IIa (thrombin) requires binding to AT (III), via ABR, as well as to thrombin via a less well-defined binding region (TBR).
The synthetic oligosaccharides corresponding to the ABR region of heparin are known and manifest an antithrombotic activity in venous thrombosis. These compounds are described in EP 529,715 and EP 621,282 and in Canadian patent 2,040,905.
The efficacy of these oligosaccharides in the prevention of arterial thrombosis is, nevertheless, hampered by their inability to inhibit thrombin.
A synthesis of glycoaminoglycans of heparin type which are capable of inhibiting thrombin via the AT (III) activator presents great difficulties and, indeed, this has never been achieved.
With the aim of rediscovering the activity of thrombin-inhibitor and factor Xa-inhibitor products, in EP-A-0,649,854 it has been proposed to connect two small oligosaccharides (an ABR and a TBR) by a species (“spacer”) which is not involved in the biological activity.
It has now been found that novel polysaccharide derivatives may be synthesized relatively simply and are biologically active. They are, in particular, anticoagulant and antithrombotic. Furthermore, on account of the production of these polysaccharides by synthesis, it is possible to selectively modify their structure, and in particular to remove unwanted sulphate substituents involved in the interaction with certain proteins. Thus, polysaccharides may be obtained which are powerful antithrombotic and anticoagulant agents and which may furthermore escape in vivo the action of proteins such as platelet factor 4 (PF4), which neutralize the effect of heparin in particular on thrombin.
Thus, it has been found, surprisingly, that sulphated and alkylated polysaccharides may be powerful antithrombotic and anticoagulant agents depending on the arrangement of the alkyl and sulphate groups borne by the carbohydrate skeleton.
More generally, it has been found that by preparing polysaccharide sequences, it is possible to modify with precision the GAG-type activities in order to obtain very active products which have the properties of heparin.
Thus, according to one of its aspects, the present invention relates to a novel synthetic polysaccharide comprising an antithrombin III-binding region consisting of a sequence of five monosaccharides bearing in total two carboxylic acid functions and at least four sulphate groups, this region being bound directly at its non-reducing end by a thrombin-binding region comprising a sequence of 10 to 25 monosaccharide units chosen from hexoses, pentoses or deoxy sugars in which all the hydroxyl groups are, independently, etherified with a (C
1
-C
6
)alkyl group or esterified in the form of sulphate groups, as well as its salts, in particular its pharmaceutically acceptable salts.
Preferably, the invention relates to a polysaccharide as defined above, characterized in that all its hydroxyl groups are etherified with a methyl or are esterified in the form of a sulpho group and its salts, in particular its pharmaceutically acceptable salts.
The products of the present invention are, in particular, polysaccharides represented by the following formula:
in which
the wavy line denotes a bond either below or above the plane of the pyranose ring,
denotes a polysaccharide Po containing n identical or different monosaccharide units, which is linked via its anomeric carbon to Pe,
is a diagrammatic representation of a monosaccharide unit of pyranose structure chosen from hexoses, pentoses and the corresponding deoxy sugars, this unit being linked via its anomeric carbon to another monosaccharide unit, and the hydroxyl groups of this unit being substituted with identical or different groups —X, the groups X being chosen from (C
1
-C
6
)alkyl groups and sulpho groups,
n is an integer from 10 to 25,
Pe represents a pentasaccharide of structure:
in which
R represents a (C
1
-C
6
)alkyl or a sulpho group,
R
1
a represents R
1
or constitutes, with the oxygen atom to which it is attached and the carbon atom bearing the carboxylic function on the same ring, a group
C—CH
2
—O,
R represents a (C
1
-C
6
)alkyl,
W represents an oxygen atom or a methylene group,
or one of their salts, in particular a salt which is pharmaceutically acceptable.
It will be noted in general in the present description that a wavy line denotes a bond either below or above the plane of the pyranose ring.
The monosaccharides contained in Po may be identical to or different from each other, and the interglycoside linkages may be of the &agr; or &bgr; type.
These monosaccharides are advantageously chosen from the D or L hexoses allose, altrose, glucose, mannose, galose, idose, galactose and talose (in this case h=3) or from the D or L pentoses ribose, arabinose, xylose and lyxose (in this case h=2). Other monosaccharides such as, for example, deoxy sugars may also be used (h=1 and/or —CH
2
OX═CH
3
).
When, in the pentasaccharides Pe, the unit W represents an oxygen atom and R
1
a is as defined for R, these pentasaccharides constitute known compounds described in particular in patents EP 300,099, EP 529,715, EP 621,282 and EP 649,854 as well as in the literature. They are obtained from synthons which are also described in the literature by C. van Boeckel and M. Petitou, Angew. Chem. Int. Ed. Engl., 1993, 32, 1671-1690.
When, in the pentasaccharides Pe, R
1
a is other than R
1
and/or W represents a carbon atom, these pentasaccharides are prepared using novel synthons which constitute a further aspect of the invention.
When, in the pentasaccharides Pe, the unit of L-iduronic acid type is replaced with a unit whose conformation is locked by a bridge, these pentasaccharides are prepared using novel synthons which constitute a further aspect of the invention.
Thus, according to another of its aspects, the present invention relates to novel intermediates which are useful for the preparation of compounds (I).
The polysaccharide part Po may consist of 10 to 25 alkylated and di- or trisulphated monosaccharide units.
The polysaccharide part Po may consist of 10 to 25 alkylated and mono- or disulphated monosaccharide units.
The polysaccharide part Po may consist of 1
Basten Johannes
Dreef-Tromp Cornelia
Driguez Pierre Alexandre
Duchaussoy Philippe
Grootenhuis Peter
Alexander Michael D.
Dupont Paul E.
Fonda Kathleen K.
Sanofi-Synthelabo
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