Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-11-28
2003-05-06
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S103000, C536S124000
Reexamination Certificate
active
06559135
ABSTRACT:
This application is the national stage entry of PCT/FR01/00923, filed Mar. 27, 2001.
TECHNICAL FIELD
The present invention concerns new derivatives of per-(3,6-anhydro)-cyclodextrin, which may be used, in particular, for fixing and separating ions, such as ions of cobalt, the lanthanides and uranyl.
It may, in particular, be applied to the field of environmental decontamination, and human decontamination, of these polluting ions.
STATE OF THE PRIOR ART
Cyclodextrins or cyclo-malto-oligosaccharides are compounds that occur naturally, formed from chains of &agr;-linked (1,4) glucose groups.
Extensive studies have shown that these compounds are capable of forming inclusion complexes with hydrophobic molecules, which allow them to be rendered soluble in aqueous media. Numerous applications have been proposed to take advantage of this phenomenon, particularly in the pharmaceutical field, as described by D. Duchêne in “Pharmaceutical application of cyclodextrins” in “Cyclodextrins and their industrial uses”. D. Duchêne, Ed., Editions de Santé, Paris, 1987, pages 213-257 (I).
Pharmaceutical specialities have already been commercialised in Japan, in Italy and, more recently, in France, in the form of complexes in cyclodextrins. In France, the first active ingredient marketed in the form of an inclusion complex in a cyclodextrin is Piroxicam, an anti-inflammatory sold by Pierre Fabre Médicament, under the trade name BREXIN®. Amongst the very many modified derivatives of these cyclodextrins, those in which the cavity is turned round itself have interesting properties, even though their ability to include organic molecules is lost or very limited. Compounds of this type are per-(3,6-anhydro)-cyclodextrins.
The synthesis of these per-anhydro-cyclodextrins was initially described in 1991 in document (2): A. Gadelle and J. Defaye, Angew. Chem. Int. Ed. Engl., (1991), 30, pages 78-79; and document (3): P. R. Ashton, P. Ellwood, I. Staton and J. F. Stoddart, Angew. Chem. Int. Ed. Engl., (1991), 30, pages 80-81, and it has been demonstrated that these derivatives have favourable solubility in water as well as in organic solvents. Some later studies (document (4): H. Yamamura and K. Fujita, Chem. Pharm. Bull., (1991), 39, pages 2505-2508; document (5): H. Yamamura, T. Ezuka, Y. Kawase, M. Kawai, Y. Butsugan and K. Fujita, J. Chem. Soc., Chem. Com., (1993), pages 636-637; and document (6): H. Yamamura, H. Nagaoka, M. Kawai and Y. Butsugan, Tetrahedron Lett. (1995), 36, pages 1093-1094) have, moreover, shown that these per-anhydro derivatives can complex alkaline ions with quite significant selectivity.
Document FR-A-2 744 127 (7) and document FR-A-2 764 525 (8) describe other derivatives of per-(3,6-anhydro)-cyclodextrins substituted in position 2, which are useful for the separation of different ions, and in particular potassium and caesium in the case of document (7), thanks to the presence of an acetyl substituent, or lead in the case of document (8), thanks to the presence of a methyl substituent.
However, it is not possible to obtain satisfactory separation by complexation of ions of cobalt, uranyl and the lanthanides, such as dysprosium, which pollute the environment, with the derivatives described in these documents.
Moreover, the lanthanide ions are toxic to living organisms because they disrupt calcium and sodium ionic exchanges. Thus, lanthane, which is the same size as calcium but which does not have the same valency, disrupts exchanges, as described by C. H. Evans in “Interactions of Lanthanides with Tissues, Cells and Cellular Organelles” in Biochemistry of the Lanthanides, C. H. Evans Ad., Plenum Press, New York, 1990, pp. 211-283 (9).
DESCRIPTION OF THE INVENTION
The present invention precisely concerns new derivatives of per-anhydro-cyclodextrins in which the substituent in the 2 position is selected to provide them with properties for complexing polluting ions such as Co
2+
, UO
2
2+
and the lanthanide ions such as Dy
3+
and Eu
3+
.
According to the invention, the derivative of per-(3,6-anhydro)-cyclodextrin corresponds to one of the following formulae:
in which at least one of the R
1
groups represents the group —OCH
2
COOH and the other R
1
groups, which may be identical or different, represent a group that corresponds to one of the following formulae: OH, OR
2
, SH, SR
2
, OCOR
2
, NH
2
, NHR
2
, NR
2
R
3
, CONH
2
, CONHR
2
, CONR
2
R
3
, CN, COOR
2
, COOH and R
2
, in which R
2
and R
3
, which may be identical or different, represent an aliphatic or aromatic hydrocarbon group, either saturated or unsaturated, which may include one or several hetero-atoms comprising O, S and N, and n is equal to 6, 7 or 8.
In the cyclodextrin derivative with formula (I) or (II), the aliphatic or aromatic hydrocarbon groups that may be used for R
2
and R
3
may be different types. They are composed of a carbon chain in which certain carbon atoms may be replaced by one or several hetero-atoms such as O, S and N, and they can include one or several ethylenic or acetylenic unsaturated groups. Furthermore, the hydrocarbon group may comprise various substituents, in particular functional groups or halogen atoms. The aromatic hydrocarbon groups may be composed of a phenyl or a tosyl group, which may be substituted, for example by alkyl groups with between 1 and 20 carbon atoms.
R
2
and R
3
may, in particular, represent a linear or branched alkyl group with between 1 and 20 carbon atoms.
According to a preferred embodiment of the invention, the derivative of per-(3,6-anhydro)-cyclodextrin is a derivative of &agr;-cyclodextrin, in other words, where n=6 in the formulae (I) and (II) given above.
Even more preferably, the derivative used corresponds to formula (I), in which all of the R
1
groups represent the group —OCH
2
COOH and n is equal to 6.
The cyclodextrin derivatives according to the invention may be prepared by various procedures.
When the cyclodextrin derivative corresponds to formulae (I) or (II) given above, in which at least one of the R
1
groups represents the group —OCH
2
COOH and the other R
1
groups represent OH or another group and n is equal to 6, 7 and 8, these may be prepared by a procedure comprising the following stages:
1) reacting a per-anhydro-cyclodextrin, which corresponds to one of the formulae:
(III) or (IV)
in which n is equal to 6, 7 or 8, with a alkali metal hydride, in order to convert the OH group(s) into OM group(s), where M represents an alkali metal;
2) reacting, in an alkaline medium, the modified per-anhydro-cyclodextrin obtained in 1) with a halide with the formula XCH
2
COOR
4
, in which X represents a halogen atom such as Cl, and R
4
represents H, Si(CH
3
)
3
or an alkali metal, in sufficient quantity to ensure that at least one of the OM group(s) is converted into a —CH
2
COOR
4
group;
3) reacting, in the case where all of the OM groups have not been converted into —OCH
2
COOR
4
groups, the remaining OM groups with one or several reagents in order to convert them into R
1
groups that are intentionally different to —OCH
2
COOH; and
4) treating the derivative of per-anhydro-cyclodextrin obtained in 3) with an alcohol, water or a slightly acid medium in order to convert the —OCH
2
COOR
4
groups into —OCH
2
COOH groups.
In order to carry out stage 2), sufficient XCH
2
COOR
4
is used to modify one or several of the OH groups in the cyclodextrin.
In stage 4), when R
4
represents M, the —OCH
2
COOR
4
groups are converted into —OCH
2
COOH groups through the action of an alcohol such as methanol. Water may also be used, but the reaction is more violent.
When R
4
represents Si(CH
3
)
3
, a slightly acid medium is used to regenerate the acid function.
When the cyclodextrin derivative corresponds to formulae (I) or (II) given above, in which the other R
1
groups represent OR
2
, where R
2
has the signification given above, the same procedure described previously is followed in order to introduce the —OCH
2
COOM groups, then the derivative is reacted with a halide with the formula R
2
X, in which R
2
has the significat
Debouzy Jean-Claude
Fauvelle Florence
Gadelle Andree
Commissariat a l'Energie Atomique
Fonda Kathleen K.
Maier Leigh C.
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