Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-02-24
2001-09-18
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S025000, C536S004100
Reexamination Certificate
active
06291433
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention concerns, as new industrial products, the derivatives of &agr;-D-xylose defined by formula I below. It also concerns the process for the preparation of these compounds, as well as the therapeutic compositions containing them as active ingredients.
Derivatives of &bgr;-D-xyose, in particular derivatives of benzoyl- or &agr;-hydroxy-benzyl-phenyl &bgr;-xylosides, recommended in therapeutics for the treatment of venous thromboses, are already known, for example, according to EP-A0051023.
Derivatives of benzyl-phenyl &bgr;-D-xylosides, exhibiting a hypocholesterolemiant and/or hypolipidemiant activity, are also known according to EP-A-0133103.
Derivatives of the type &bgr;-D-phenylthioxylosides, used for their antithrombotic activity, are also known according to EP-A0365397, EP-A-0290321, EP-A-0133103 and EP-A-0051023.
The antithrombotic activity of a certain number of derivatives of &bgr;-xylose has also been reported and studied in the article of J. Med. Chem, 1993, 36, (no. 7) pages 898903. Research carried out in the laboratory has shown that these derivatives of &bgr;-D-xylose are good substrates of galactosyl transferase I. For this reason, these compounds, active when taken orally, initiate the synthesis of glycosaminoglycanes (GAGs). After administration of the compounds orally, the circulation rates of GAGs are appreciably increased and approximately 20% of the latter display an activity of the dermatan-sulphate type capable of inhibiting thrombin, via HC II (Heparin Cofactor II), this initiation of the biosynthesis of GAGs probably being responsible for the antithrombotic activity observed experimentally for the compounds mentioned previously. In correlation with the potential of these compounds to reduce the formation of venous thromboses, only the &bgr; configuration derivatives of D-xylose increase the synthesis of GAGs. The other derivatives of the glycopyranoside type have proved to be inactive in this area, both from the biological standpoint on the synthesis of GAGs, as well as from the pharmacological standpoint on the reduction or prevention of venous thromboses.
The activity of certain derivatives of &bgr;-D-xylose, in particular estradiol &bgr;-D-xyloside, has been studied in the publication Journal of Biological Chemistry, 1991, 266, (No. 11) pages 6674-6677 and the authors establish a relationship between this compound and the biosynthesis of heparane sulphate, as well as an inflator role of &bgr;-D-xyloside in the synthesis of chondroitin sulphate. These studies confirm the benefit of derivatives of &bgr;-D-xylose for the treatment or the prevention of venous thromboses.
According to the invention, it is proposed to provide a new technical solution making it possible to arrive at new products that are biologically beneficial with respect to arterial atheromatous platelets.
SUMMARY OF THE INVENTION
According to the new technical solution of the invention, use is made of products of the type &agr;-D-xylose or &agr;-D-thioxylose.
It has in fact been found, in a surprising manner, that derivatives of D-xylose or of 5-thio-D-xylose no longer displaying the &bgr; configuration, but the a configuration on the anomeric carbon, possess a particularly beneficial activity for the prevention or the regression of arterial atheromatous platelets.
The new products according to the invention, which are compounds of &agr;-D-xylose, are characterised in that they are selected from the compounds of the general formula I:
wherein
X and Y represent, independently of one another, an oxygen atom or a sulphur atom,
R
1
represents a CN, CF
3
or SO
2
CH
3
group, and
R represents a hydrogen atom or an aliphatic acyl group containing 2 to 5 carbon atoms.
According to another aspect of the invention, a composition is provided that is characterised in that it contains, in association with a physiologically acceptable excipient, a therapeutically effective quantity of at least one compound of the formula I.
It is also recommended to use the compound of the formula I as an antiatheromatous drug.
DETAILED DESCRIPTION OF THE INVENTION
As presented in formula I above, the compounds according to the invention are derivatives of &agr;-D-xylose or &agr;-D-thioxylose, substituted on the anomeric carbon in the a position by a substituted benzophenone group.
The hydroxyl functions of D-xylose or D-thioxylose can be free or substituted by an acyl group containing 2 to 5 carbon atoms, preferably the acetyl group.
Aliphatic acyl group containing 2 to 5 carbon atoms is understood here to mean an acyl group with a straight, branched or cyclised chain, such as in particular CH
3
CO, CH
3
CH
2
CO, (CH
3
)
2
CHCO, (CH
3
)
3
CCO, or cyclopropyl-carbonyl.
The compounds of the formula I can be prepared according to a method known per se by using conventional reactive mechanisms. According to a preferred operating method, a benzophenone of the formula II is reacted (according to a coupling reaction):
wherein Y is the oxygen atom or the sulphur atom and R
1
represents CN, CF
3
or SO
2
CH
3
, with a compound of D-ylose (or of 5-thio-D-xylose) of the formula III:
where
represents a bond of indeterminate configuration (&agr;, &bgr; or &agr;/&bgr; mixture), X is an oxygen atom or a sulphur atom, Ac represents the acetyl group, Z represents an acetyl group or a trichloromethylimino group [—C(═NH)—CCl
3
], the reaction being conducted in a solvent and in the presence of a Lewis acid, in order to obtain a compound of the formula I after purification:
wherein
X, Y and R
1
retain the same significance as in the starting products and R represents an acetyl group.
The compounds of the formula I in which R is a hydrogen atom can be obtained from the preceding compounds, in which R is the acetyl group, by the action of a base such as for example sodium methylate or ammonia which permit the acetyl group to be replaced by a hydrogen atom.
The compounds of the formula I in which R is a C
2
-C
5
acyl group, such as defined above, can be obtained from compounds with formula I in which R is a hydrogen atom, by the action of chloride or acid anhydride corresponding to the desired C
2
-C
5
acyl group, in the presence of an aprotic base such as for example triethylamine or pyridine, and in a solvent such as for example dichloromethane.
Briefly, the process of preparation according to the invention comprises (a) the II+III coupling reaction and the purification of the compound I (R=Ac) thus obtained, (b) if necessary the hydrolysis (saponification) of said compound of the formula I (R=Ac) so as to obtain the deacetylated compound with formula I (R=H), and (c) if necessary the esterification of said compound of the formula I (R=H) so as to obtain any other esterified compound of the formula I (R=acyl, in particular an acyl group different from Ac).
The compounds of the formula I are useful in therapeutics as active principles of drugs intended for the treatment or prevention of atherosclerosis.
According to the invention, it is recommended to use a product selected from the group consisting of the compounds of the formula I above for the preparation of an antiatheromatous drug intended for use in therapeutics with respect to atherosclerosis.
The preferred products according to the invention, in view of the beneficial properties with respect to atherosclerosis, are the compounds of the formula I where R
1
is CN
1
, and among the latter the products in which X=Y=S or X=Y=O.
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patent: 4598068 (1986-07-01), Samreth et al.
patent: 4877808 (1989-10-01), Samreth et al.
patent: 5101048 (1992-03-01), Bajgrowicz et al.
patent: 0 051 023 (1982-05-01), None
patent: 0 133 103 (1985-02-01), None
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Bellamy et al., “Glycosylated Derivatives of Benzophenone, Benzhydrol, and Benzhydril as Potential Venous Antithrombotic Agents”,J. Med. Chem., vol. 36, 1993, pp. 898-903.
Lugemwa et al.,
Barberousse Veronique
Edgar Alan Dunlap
Legendre Christiane
Samreth Soth
Crowell & Moring LLP
Fournier Industrie et Sante
Geist Gary
Maier Leigh C.
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