Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
  • B01J20/26—Synthetic macromolecular compounds
  • B01J20/262—Synthetic macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. obtained by polycondensation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
  • B01J20/26—Synthetic macromolecular compounds
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
  • B01J20/26—Synthetic macromolecular compounds
  • B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J45/00—Ion-exchange in which a complex or a chelate is formed; Use of material as complex or chelate forming ion-exchangers; Treatment of material for improving the complex or chelate forming ion-exchange properties
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
  • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

• the subject of the present invention is new derivatives of chemically modified per (3, 6-anhydro) cyclodextrins, which can be used to fix metallic elements and more particularly to transport, thanks to chemical modification, such elements to a biological target or eliminate these elements of a target or biological fluid.
• the present invention also relates to cross-linked per (3, 6-anhydro) cyclodextrins, said per (3, 6-anhydro) cyclodextrin derivatives being able to be used to remove metallic elements from a biological fluid.
• the present invention can be applied in particular in the field of diagnosis, of therapy with metallic elements or also in the field of human decontamination in vitro and in vivo.
• Cyclodextrins or cyclomalto-oligosaccharides are compounds of natural origin formed by the cyclic chain of glucose units linked in oc- (1,4). Derivatives thereof can consist of maltose units linked in oc- (1,4).
• the subject of the present invention is new derivatives of peranhydrocyclodextrins in which the substituent in position 2 makes it possible to transport said derivatives towards a biological target. while conferring complexing properties of metallic elements, for example radioactive elements, with a view to possible use of these derivatives in the field of radiodiagnosis, radiotherapy or human decontamination.
• the present invention also relates to derivatives of per (3, 6-anhydro) crosslinked cyclodextrins, which crosslinking gives these new objects a character of insolubility in a biological fluid and allows, thanks to the complexing properties of per (3, 6 -anhydro) cyclodextrins, to purify said biological fluid from toxic metallic elements, in the context for example of dialysis.
• the per (3,6- anhydro) cyclodextrin derivative corresponds to one of the following formulas (I) or (II):
• R 1 represents a radical chosen from peptides, proteins, lipids, oligo- or polynucleotides, oligo- or polysaccharides, biopolymers and any other R 1 , not meeting this definition, represent groups, identical or different, chosen from OH, OR 3 , OM, SH, SR 3 , OCOR 3 , NH 2 , NHR 3 , NR 3 R 4 , CONH 2 , CONHR 3 , CONR 3 R 4 , CN, COOR 3 , OCH 2 COOH, COOH, OS0 2 R 3 , N 3 and R 3 , in which R 3 and R 4 'identical or different, represent a hydrocarbon group, aliphatic or aromatic, saturated or unsaturated, optionally substituted by halogen atoms, which may contain one or more heteroatoms chosen from 0, S and N, and M represents a monovalent cation chosen from alkali metal cations; the R 2 , identical or different, represent groups, identical or different,
• the derivatives of the invention comprise at least one of the groups R 1 representing a radical chosen from peptides, proteins, lipids, oligo- or polynucleotides, oligo- or polysaccharides, biopolymers and optionally
• R 1 groups representing groups, identical or different, chosen from OH, OR 3 , OM, SH, SR 3 , OCOR 3 , NH, NHR 3 , NR 3 R 4 , C0NH 2 ,
• the aliphatic or aromatic hydrocarbon groups capable of being used for R 3 and R 4 can be of various types. They can consist of a carbon chain in which certain carbon atoms can be replaced by one or more heteroatoms such as O, S and N, and they can comprise one or more ethylenic or acetylenic unsaturations. Furthermore, the hydrocarbon group can be substituted by halogen atoms.
• the aromatic hydrocarbon groups capable of being used for R 3 and R 4 may consist of the phenyl group and the tosyl group, optionally substituted, for example, by alkyl groups of 1 to 20 carbon atoms.
• the aliphatic hydrocarbon groups capable of being used to constitute R 3 and R 4 may, in particular, represent an alkyl group, linear or branched, containing from 1 to 20 carbon atoms.
• R 2 can represent a single bond, in particular when the R 1 are groups chosen from OH, OR 3 , OM, SH, SR 3 , OCOR 3 , NH 2 , NHR 3 , NR 3 R 4 , CONH 2 , CONHR 3 , CONR 3 R 4 , CN, COOR 3 , OCH 2 COOH, COOH, OS0 2 R 3 , N 3 and R 3 .
• the R 1 groups are directly covalently linked to the cyclic carbon of the glucose or maltose units.
• R 2 may represent a spacer group, that is to say an organic type group, which is not part of the radicals of peptide, proteinic, lipidic, oligo- or polynucleotide and oligo- or polysaccharide nature.
• This spacer group can be a group chosen, for example, from -NH-, -NR-, -NH- (CH 2 ) m-C0 2 -, -NH- (CH 2 ) m-NH-, -NH-C0 2 -, -NH-CO-, -NH-CO- (CH 2 ) m-COO-, -NH-CO- (CH 2 ) m-CO-NH-,
• At least one of R 1 is a radical chosen from peptides, proteins, lipids, oligo- or polynucleotides, oligo- or polysaccharides, biopolymers.
• peptide is meant, according to the present invention, a molecule consisting of a chain of 2 to 30 amino acids, said amino acids possibly being identical or different, the connection between two consecutive amino acids of the chain being effected by a loss of water between the amino group of an amino acid and the carboxyl group of the neighboring amino acid, to form a bond -CO-NH-.
• protein is meant a molecule formed by the chain of a large number of amino acids, for example, from 30 to 30,000.
• Lipid is understood to mean a molecule consisting of esters of long chain fatty acids, long chain fatty acid amides, straight or branched chain saturated or unsaturated fatty acids, higher aliphatic alcohols, sterols (such as cholesterol), hydrocarbons such as squalene, fat-soluble vitamins, acylglycerols such as 1, 2, 3-triacylglycerol, glycoglycerides, phospholipids.
• oligo- or polynucleotide means a molecule consisting of a nucleotide sequence the number of which varies from one to several tens but less than 100 for oligonucleotides such as oligo [A] (oligoadenylic acid (5 ′)), oligo [I] (oligoinosidic acid (5 ')), oligo [U] (oligouridilic acid (5 f )) and greater than 100 for polynucleotides such as poly [A] (polyadenylic acid (5')), poly [I] (polyinosidic acid (5 ')), poly [U] (polyuridilic acid (5')).
• oligo- or polysaccharide a molecule consisting of a chain of simple saccharide units, identical or different (from 2 to 10 for oligosaccharides (such as glucose, mannose) and greater than 10 for polysaccharides.
• biopolymer a linear or branched chain of identical or different monomers of biological origin (peptides, lipids, proteins, nucleotides, saccharides) such as acid poly-L-glutamic, poly-L-naphthylalanine, poly-L-phenylalanine, poly-L-tryptophan, poly-L-tyrosine, poly-L-histidine, poly-L-lysine.
• biological origin peptides, lipids, proteins, nucleotides, saccharides
• the peranhydrocyclodextrin derivative used corresponding to formula (I) is a derivative in which at least one of R 1 represents a radical of peptide nature, any other R 1 representing - OH, the R 2 linked to R 1 representing a radical of peptide nature represents a spacer group of formula - OCH 2 CO-, the possible R 2 linked to the possible R 1 representing -OH are single bonds, and n is equal to 6 .
• radical of peptide nature can correspond to the formula -NH-CH (CH 3 ) -CO- NH-CHBZ-CO-OCH 3 , Bz corresponding to a benzyl group, that is to say a group of formula :
• the peranhydrocyclodextrin derivative corresponding to formula (I) is a derivative in which at least one of R 1 represents a biopolymer, any other R 1 representing - OH, the R 2 linked to R 1 representing a biopolymer represents a spacer group of formula -OCH 2 CO-, the possible R 2 linked to possible R 1 representing -OH are simple bonds, and n is equal to 6.
• the biopolymer can correspond to a poly-L-lysine.
• This poly-L-lysine can have a molecular weight ranging from 3000 to 300,000, for example a molecular weight equal to
• the derivatives in accordance with the present invention may, in particular, have a greater ability to complex metal elements than that of the basic cyclodextrin from which they are derived, as will be illustrated more fully in the experimental part of this description.
• they have the following advantages:
• the derivatives of the present invention can also be crosslinked, as is emphasized in the previous paragraph.
• crosslinked derivative means a derivative obtained by crosslinking of a derivative comprising at least one R 1 of biopolymer type, said crosslinking being effected by crosslinking of said biopolymer. This crosslinking can be envisaged according to several embodiments.
• the crosslinked derivative of the invention results from the intermolecular crosslinking of at least two separate per (3,6-anhydro) cyclodextrins, said two per (3, 6-anhydro) cyclodextrins being linked by means of a motif forming a bridge between two R 1 representing a radical of biopolymer type.
• the crosslinked derivative according to the invention can result from the intramolecular crosslinking between at least two R 1 of a single per (3, 6-anhydro) cyclodextrin base, said R 1 in question being radicals biopolymer type.
• the resulting crosslinked derivative is in the form of a per (3,6-anhydrocyclodextrin) derivative, of which at least two R 1 of biopolymer type are linked by a bridge-forming unit.
• crosslinked derivatives resulting from the combination of the two abovementioned embodiments, namely a crosslinked derivative resulting from both an intermolecular crosslinking and an intramolecular crosslinking.
• the R 1s of the biopolymer type involved in the intermolecular and / or intramolecular crosslinking comprise, before crosslinking, reactive functions, so that the crosslinking can be done by simple action of a crosslinking agent comprising at at least two reactive functions capable of reacting with said reactive functions carried by the above-mentioned R 1s .
• a particular crosslinked derivative of the invention is a derivative for which the per (3, 6-anhydrocyclodextrin) derivative serving as a basis for crosslinking, is a derivative for which all of the R 1 are radicals of the poly-L-lysine type and the R 2 of the spacer groups of formula -O-CH 2 -C0-, n being equal to 6, at least one of the above-mentioned R 1 being crosslinked by the action of glutaraldehyde in the presence of sodium borohydride.
• R 5 identical or different, represent an OH group or a precursor group of the spacer group R 2 , with a biomolecule chosen from peptides, proteins, lipids, oligo- or polyoligonucleotides, oligo- or polysaccharides, biopolymers, said biomolecule comprising a reactive group capable of reacting with group R 5 as defined above;
• said precursor group of the spacer group R ′ can be a group chosen from -NH 2 , -NHR, -NH- (CH 2 ) m-C0 2 H, -NH- (CH 2 ) m-NH 2 , -NH-C0 2 H, -NH-COX, -NH-CO- (CH 2 ) m-COOH, -NH-CO- (CH) m-CO-NH 2 , -NH-CO- (CH 2 ) m -NH-C0X, -NH-CO-CHR-NH 2 , -OH, -0- (CH 2 ) mX, -O- (CH 2 ) m-COX, -O- (CH 2 ) m-C0 2 H, -O- (CH 2 ) m-NH 2 , -O- (CH 2 ) m-NH-COX, -O- (CH 2 ) m-CO-NH 2 , -0-CO
• the necessary quantity of biomolecules of peptide, protein, lipid, oligo- or polynucleotide, oligo- or polysaccharide or biopolymer nature or the biopolymer is used to suitably modify at least one R 5 group of the starting cyclodextrin.
• step 2) of the process is not to be implemented, when all the R 5 of the starting cyclodextrin represent OH.
• the partially modified peranhydrocyclodextrin can be reacted with during the first step of the process, with an alkali metal hydride in order to transform the -OH functions into -OM function with M representing an alkali metal, then the derivative obtained is reacted with a halide of formula R 3 X in which R 3 has the same meaning given above and X is a halogen atom.
• R 3 and R 4 represent a group of formula SH, SR 3 , NH, NHR 3 NR 3 R 4 , CONR 3 R 4 , CONHR 3 , CONH 2 , CN, COOR 3 , COOH, or R 3 , with R 3 and R 4 having the meanings given above, and n is equal to 6, 7 or 8, it is possible to carry out, starting from a partially modified peranhydrocyclodextrin, that is to say in which at least one of the R-- represents a radical peptide, proteinic, lipidic, oligo- or polynucleotide, oligo- or polysaccharide, or a biopolymer, the other R ⁇ represent OH, the following stages:
• the partially modified per (3, 6-anhydro) cyclodextrin is first transformed into the alcoholate by the action of an alkali metal hydride, then this alcoholate is converted into a derivative comprising a leaving group of formula OS0 2 R 3 , which is then reacted in one or more stages with one or more suitable reagents to replace this leaving group with the desired R - "- group.
• the compound thus obtained called azide can undergo catalytic hydrogenation or be treated in the presence of ammonia NH3, in order to obtain the product where R ⁇ - must represent NH 2 .
• NR 3 R 4 is obtained by reacting the compound defined in
• R ⁇ must represent a hydrocarbon group
• the compound obtained in 2) is reacted with R 3 2 LiCu to give a final compound where R 3 then represents a hydrocarbon group, as defined above.
• the compound where RL represents a halogen can react with CN- to give a final compound where R i will represent CN.
• the compound where R ⁇ represents CN can, by gentle hydrolysis, give a compound where R ⁇ represents CONH 2 .
• the compound where R -'- represents CN can by complete hydrolysis give a compound where R ⁇ will represent COOH.
• R - * - represents COOH
• DCC diclohexylcarbodiimide
• the 3,6-CD can have, preferably, a group terminated by a -NH 2 or -COOH function.
• the acid end of a peptide When the acid end of a peptide is reacted with cyclodextrin (in this case, on an -NH 2 or derivative function), the acid end must be transformed into acid halide, mixed anhydride, azide or ester activated. Once this end activated, it can react directly on the amino function of cyclodextrin to form the peptide bond.
• the acid function can also be reacted with a coupling reagent such as dicyclohexylcarbodiimide.
• the grafting reaction of a protein-based radical can be carried out in a similar manner to that described above.
• this radical (when it corresponds in particular to a fatty acid) on a -NH 2 function, the coupling methods being similar to those described for the coupling of radical of peptide nature or proteinic.
• a DNA sequence containing an amino function can be taken from a terminal phosphate group.
• the coupling methods are similar to those described above.
• the process can also include, after the grafting step and the optional step of transformation of the suitable R 5 into R 1 (or into groups R 2 -R 1 suitable, when R 2 is different from a single bond), a crosslinking step by action of a crosslinking agent, such as glutaraldehyde on the derivative of per (3,6- anhydrocyclodextrins) transformed.
• a crosslinking agent such as glutaraldehyde on the derivative of per (3,6- anhydrocyclodextrins
• the per (3, 6-anhydrocyclodextrin) derivatives in accordance with the invention, have excellent complexing capacities of metallic elements thanks to the presence of the cavity of the per (3, 6-per ( 3, 6-anhydro) cyclodextrin and radicals carried by per (3, 6-anhydrocyclodextrins) in position 2.
• the present invention also relates to complexes of a metallic element with a peranhydrocyclodextrin derivative, as defined above.
• the metallic element forming a complex with a peranhydrocyclodextrin derivative in accordance with the invention, can be chosen from Te, Y, In, Ga, Re, Se, Co, Cu, Ca, Sr, Ag, Au, Sn , Bi, At, Rh, Er, Pm, Sm, Ho, Lu, Dy, Gd, Eu, Mn, Pb, Tl and possibly their radioactive isotopes.
• a particular complex of the invention is a complex of a metallic element chosen from Pb or Er with a peranhydrocyclodextrin derivative, as defined above, with at least one of R 1 being a radical chosen from peptides or biopolymers.
• complexes due to the presence of radicals derived from biomolecules, are capable of being transported to biological targets. Depending on the complexed metallic element, they can therefore be used to treat the target with the metallic element in question or can be used in medical imaging.
• the complexes defined above can enter into the constitution of diagnostic or therapy compositions.
• the invention therefore also relates to diagnostic compositions comprising a complex of a derivative of per (3, 6-anhydro) cyclodextrin and a metallic element as defined above and a pharmaceutically acceptable vehicle .
• the metallic element forming a complex with a peranhydrocyclodextrin derivative according to the invention is preferably a metallic element chosen from the metallic elements emitting ⁇ or ⁇ + radiation, these elements being able to be chosen among Te, In, Ga, Co, Cu, Sm, Ga.
• the invention also relates to therapy compositions comprising a complex of derivative of per (3, 6-anhydro) cyclodextrin and a metallic element as defined above, or a derivative of per (3, 6-anhydro) cylodextrin as defined above and. a pharmaceutically acceptable vehicle.
• compositions comprise a peranhydrocyclodextrin derivative according to the invention, they can be used in particular in the field of decontamination of a target organ or a biological fluid, due to the capacity of the cyclodextrins according to the invention to ability to form complexes with metals.
• compositions comprise a complex of a metallic element, according to the present invention, they are used to convey said complex to a biological target so that the complexed metallic element can exert on this target its therapeutic action.
• such metallic elements can be chosen from metallic elements emitting ⁇ ⁇ and OC radiation, these elements being able to be chosen from Se, Cu, Sr, Y, Rh, Ag, Sn, Pm, Sm, Ho, Lu, Re, Er, Dy, At, Bi, Au, alkaline earth metals such as Ca.
• the subject of the invention is also a method of in-vitro decontamination of a biological medium (target or biological fluid) in at least one metallic element, said method comprising a step consisting in bringing said biological medium into contact with a derivative of per (3, 6-anhydro) cyclodextrin, as defined above, for fixing said elements in the form of a complex with a derivative of per (3,6-anhydro) cyclodextrin according to the invention.
• the metallic elements capable of being fixed or separated by the process of the invention can be of various types.
• these metallic elements can be chosen from Te, Y, In, Ga, Re, Se, Co, Cu, Ca,
• interesting derivatives are derivatives of per (3, 6-anhydro) cyclodextrin corresponding to formula (I) in which an R 1 represents a radical chosen from peptides or biopolymers, the other R 1 representing -OH, R 2 linked to R 1 representing a peptide or biopolymer radical represents a spacer group of formula -OCH 2 CO-, the R 2 linked to R 1 representing -OH are single bonds, and n is equal to 6, and more particularly that with a peptide radical R 1 of formula -NH- CH (CH 3 ) -CO-NH-CHBz-CO- OCH 3 with Bz representing a benzyl group, and that with an R 1 corresponding to a biopolymer of the poly-L-lysine type.
• FIG. 1 represents the NMR spectrum in deuterated water of the crude product (that is to say unpurified) prepared in Example 1, with a part B representing this spectrum in the region from 1 to 7.5 ppm and part A being an enlarged area of the area from 1.2 to 1.6 ppm.
• FIG. 2 represents the NMR spectrum in dimethyl sulfoxide of the crude product (that is to say unpurified) prepared in Example 1, with part A representing this spectrum in the region of 1 to 9 ppm, part B being an enlarged area of this same spectrum between 1 and 1.5 ppm and a part C being an enlarged area of this same spectrum between 7.5 and 9 ppm.
• FIG. 3 represents an NMR spectrum in deuterated water, with part A representing the spectrum of poly-L-lysine and part B representing the spectrum of the product prepared in Example 2.
• FIG. 4 represents a schematic representation of the inverse of the retention factors (1 / Rf) of Pb 2+ and Er 3+ , respectively for the mono-2-O-carboxymethyl-per- (3, 6-anhydro) OC -cyclodextrin (1), the product prepared in Example 1 (2) and the product prepared in Example 2 (3).
• This example corresponds to the preparation of the [(mono-2-O-methylamido) -per (3, 6-anhydro) -OC- cyclodextrin] -L-Ala-L-Phe OMe ester.
• This compound corresponds to formula (I), in which an R 1 corresponds to the dipeptide L-Alanyl-L- Phenylalanine-OMe, that is to say corresponds to the formula -NH-CH (CH 3 ) -CO- NH-CH (Bz) -COOCH 3 , the R : associated being a spacer group of formula -0-CH 2 -CO-, the other R 1 correspond to -OH, the R 2 associated representing a single bond and n is equal to 6.
• the solvent is evaporated under vacuum and the evaporation residue taken up in distilled water and filtered on a 0.22 ⁇ m filter (Millex®-SLGS 025 OS) in order to get rid of the dicyclohexylurea.
• the clear solution obtained is lyophilized and characterized by thin layer chromatography and nuclear magnetic resonance of the proton (500 MHz, 298 K).
• Figures 1 and 2 respectively represent the spectra of the crude product (that is to say unpurified) in deuterated water and deuterated dimethylsulfoxide.
• FIG. 1 (that is to say unpurified, or in other words in the presence still of the free dipeptide and of 3,6-basic cyclodextrin) is represented in FIG. 1, in two parts:
• part A representing this spectrum in the zone from 1 to 9 ppm; a part B representing an enlarged area of this same spectrum between 1 and 1.5 ppm; and a part C representing an enlarged area of this same spectrum between 7.5 and 9 ppm.
• This example corresponds to the preparation of [(mono-2- O-methyl- (mono- ⁇ -amido-poly-L-Lysine)] -per- (3, 6-anhydro) - -cyclodextrin.
• This compound corresponds to formula (I) in which an R 1 corresponds to a poly-L-Lysine (PLL), the associated R 2 being a spacer group -0-CH 2 -C0-, said PLL being a commercial PLL of an average molecular mass of 7,500 and the other R 1s correspond to -OH, the associated R 2s representing single bonds, and n is equal to 6.
• PLL poly-L-Lysine
• the solvent is evaporated in vacuo and the evaporation residue is taken up in water.
• the product is then dialyzed against HCl 10 -3 M for 48 hours using a cellulose ester membrane (Spectra / Por® CE, cutoff threshold 1000) and lyophilized.
• the final product is then characterized by thin layer chromatography and by NMR.
• FIG. 3 shows the NMR spectra of the proton (200 MHz, 298 K, D 2 0) of the free PLL (5 mM) (part A) and of the final reaction product (FIG. B), each after dialysis in the same conditions as before.
• the spectrum of part B clearly represents the spectrum of cyclodextrin coupled to PLL, the free 3,6-cyclodextrin having crossed the membrane.
• a simple test confirms the passage of the free 3, 6 -cyclodextrin outside the membrane and the maintenance of the PLL inside the membrane.
• 25-SA-Na (Macherey-Nagel, ref: 80613) loaded with various counterions were used.
• the compound to be tested is introduced onto the plate, which, if it complexes the ions, will be retained on the plate.
• the plates are then developed four times in water, due to the low migration of the cyclodextrin derivatives, then the degree of complexation is determined by the value 1 / Rf, where Rf represents the ratio: (distance traveled by the derivative of cyclodextrin / distance traveled by the solvent).
• FIG. 4 shows that the complexing properties of lead and erbium by the compounds prepared in examples 1 and 2, and in particular of the compound prepared in the context of example 2, are particularly advantageous.
• FIG. 3 shows in particular that the compounds prepared in Example 1 and 2 complex erbium while the uncoupled 3,6-peranhydrocyclodextrin does not complex
• the compounds prepared in the framework of the invention may thus be of interest in human decontamination (in case of lead contamination) and in nuclear medicine, to the extent that the erbium is a ⁇ radiation emitter "used radiotherapy and are particularly interesting because they are biocompatible, due to the presence in their structure of radicals of a peptide or biopolymer nature.

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• 2004
  • 2004-02-06 US US10/544,680 patent/US20070148090A1/en not_active Abandoned
  • 2004-02-06 WO PCT/FR2004/050048 patent/WO2004071639A2/fr active Application Filing
  • 2004-02-06 JP JP2006502174A patent/JP2006522840A/ja active Pending
  • 2004-02-06 EP EP04708796A patent/EP1597284A2/de not_active Withdrawn

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