Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00

Definitions

• the present invention relates to a process for the preparation of oligomers or polymers of cyclodextrins.
• the invention also relates to the oligomers or polymers of cyclodextrins obtained and their uses.
• Cyclodextrins, or cyclomaltooligosaccharides are cyclic oligosaccharides which have a frustoconical structure, with a hydrophilic outer surface and a relatively hydrophobic inner surface. Because of this particular structure, cyclodextrins have many properties, the most notable being their ability to include in their cavity, various molecular structures, preferably of the hydrophobic type, to form water-soluble inclusion complexes. This specificity has given rise to applications in many fields, especially in pharmacy, particularly for the transport of drugs, agrochemicals, cosmetics, the perfume and aroma industry and the environment.
• oligomers or polymers of cyclodextrins consist of several cyclodextrin molecules that are coupled or crosslinked together covalently to allow cooperative complexation with one or more guest molecule (s).
• An oligomer of cyclodextrins is defined as a molecule consisting of a small, finite number of cyclodextrin monomers coupled or crosslinked together covalently.
• a cyclodextrin polymer is defined as a molecule consisting of an infinity of cyclodextrin monomers coupled or crosslinked together covalently.
• oligomers or polymers of cyclodextrins are structures of choice for many applications, in particular for the solubilization of pharmacologically active substances in aqueous medium which are difficult to complex with simple cyclodextrins.
• EP-1.689.789 mentions processes for the preparation of cyclodextrin dimers capable of complexing and solubilizing anticancer agents of the taxoid family. These compounds may contain carbohydrate substituents which confer on the dimer a particular affinity for certain biological sites.
• the present invention provides by proposing a process for the preparation of oligomers or polymers of cyclodextrins, the cyclodextrin molecules being coupled together covalently via a spacer arm, based on a coupling reaction between an alkyne and an azide resulting in the formation of an aromatic heterocyclic bridge between the coupled units. More particularly, the present invention provides a process that is flexible and simple to implement, which uses the 1,3-dipolar cycloaddition reaction of Huisgen.
• cyclodextrin means any natural or modified cyclodextrin.
• spacer arm refers to any multiplication element with several branches on which azide or alkyne functions can be integrated.
• the cyclodextrins used for the preparation of the same oligomer or cyclodextrin polymer may be identical or different.
• cyclodextrins used for the preparation of an oligomer or polymer according to the invention have the following formula:
• n an integer equal to 5, 6 or 7, and
• the groups R which may be identical or different, represent a hydrogen atom or an acyl, alkyl, hydroxyalkyl or sulphoalkyl group of 1 to 16 carbon atoms.
• the spacer arm (s) are chosen from hydrocarbon groups, peptides, proteins, oligonucleotides, polynucleotides, oligosaccharides, polysaccharides, or biopolymers.
• the hydrocarbon groups may be aliphatic or aromatic, saturated or unsaturated, optionally substituted with heteroatoms chosen from 0.5 or N.
• the spacer arm (s) are glycols, diethylene glycols, triethylene glycols or molecules of 1,1,1- tris (hydroxymethyl) ethylene, 1,1,1-tris (hydroxymethyl) ⁇ minomethene or pentaerythritol.
• the ⁇ -functional functions used according to the present invention may be mono- or di-substituted, symmetrical or asymmetric.
• the present invention relates to a process for the preparation of oligomers or polymers of cyclodextrins, the cyclodextrin molecules being covalently coupled to one another via a spacer arm, comprising at least:
• Step of integration of alkyne and azide functions on each cyclodextrin and / or on each spacer arm This step consists in integrating:
• the azide or acetylenic cyclodextrins formed may undergo other chemical transformations such as alkylation, halogenation, esterification, etc., without resorting to any additional protection step and / or protection.
• the process for preparing oligomers or cyclodextrin polymers according to the invention may also comprise a step of chemical transformation of the azide or acetylenic cyclodextrins before the step of creating bonds between the spacer arms and the cyclodextrins.
• the method according to the invention provides a step of creating bonds between the spacer arm (s) and the cyclodextrins in the form of rings.
• 1,2,3-triazole by coupling reaction between alkynes and azides.
• the reaction that occurs also called Huisgen's 1,3-dipolar cycloaddition reaction, is as follows:
• This reaction allows for simple and reliable chemical transformations. It is an efficient and highly versatile reaction that allows the construction of a wide variety of multivalent structures.
• This coupling reaction can be carried out in an aqueous medium, with relatively short reaction times and high yields.
• the process for preparing oligomers or cyclodextrin polymers according to the invention is simple to implement. This process can be carried out in an aqueous medium under mild reaction conditions.
• the method according to the invention can be used for any cyclodextrin, without having to find the appropriate functional groups and to set up chemical methods adapted to each type of cyclodextrin.
• Another advantage of the present invention is its synthetic flexibility.
• the preparation method according to the invention makes it possible to envisage the synthesis of oligomers or polymers of cyclodextrins with varying lengths of spacer arms in order to adapt the geometry of the oligomer or polymer of cyclodextrins for complexation. effective, or even optimal, of one or more specific guest molecule (s).
• - CD identical or different, represent a cyclodextrin, linked by its secondary or primary side
• X identical or different, represent an amine (-NH-), ether (-O-), thioether (-S-), disulphide (S-S-), carbamate (-NHCO-O-;
• T represents a 1,2,3-triazole ring
• B represents:
• branches comprising at least one biological recognition group, or at least one
• n an integer greater than or equal to 1.
• multi-branching multiplication element is meant a functionalized symmetric or asymmetric compound, comprising at least two branches, for example an ethylene glycol chain, polyethylene glycol or a molecule of TRIS (tris (hydroxymethyl) aminomethane or tris (hydroxymethyl) ethane). ) or pentaerythritol.
• a “biological recognition group” is a molecular structure complementary to a biological receptor, capable of being recognized by this last and lead to a specific response such as for example the induction and regulation of the biosynthesis of an enzyme, the inhibition of the enzymatic activity of an enzyme by binding to its active site, the induction of an immune response following a bacterial infection, or the inhibition of an inflammatory process by blocking the active site.
• fluorescent or radioactive visualization or detection probe designates any molecular structure allowing the detection of a system by a physicochemical technique, such as fluorescence or radioactivity.
• the oligomers or polymers of cyclodextrins obtained according to the invention may be symmetrical or unsymmetrical.
• the groups CD, A, X and T are respectively identical on either side of the group B.
• the groups CD, A, X and T are respectively identical on either side of the group B.
• the groups CD, A, X and T are respectively identical on either side of the group B.
• CD, A, X or T are different on both sides of the group B.
• the cyclodextrins may be identical or different.
• the cyclodextrins CD have the following formula:
• n an integer equal to 5, 6 or 7, and
• the groups R which may be identical or different, represent a hydrogen atom or an acyl, alkyl, hydroxyalkyl or sulphoalkyl group of 1 to 16 carbon atoms.
• the oligomers or polymers according to the invention comprise triazole rings which contribute to improving the complexation of oligomers or polymers with guest molecules.
• triazole rings are resistant to hydrolysis and oxidation, and are capable of easily associating with biological targets through dipolar interactions and hydrogen bonds.
• the oligomers or polymers of cyclodextrins can be used for cooperative complexation with one or more guest molecules.
• the oligomers or polymers of cyclodextrins according to the invention can be used to solubilize and vectorize in an aqueous medium one or more hydrophobic chemical compound (s), in particular one or more substance (s) pharmacologically and / or or cosmetologically active (s).
• the oligomers or polymers of cyclodextrins according to the invention can be used for the efficient and selective transport of one or more pharmacologically active substance (s) to one or more target organ (s).
• the pharmacologically active substance (s) may be selected from anti-cancer drugs, anti-tumor drugs, anti-fungal drugs, antibacterial drugs, antiviral drugs, cardiovascular drugs, neurological drugs, alkaloids, antibiotics, bioactive peptides, steroids, steroid hormones, polypeptide hormones, interferons, interleukins, narcotics, prostaglandins, purines, pyrimidines, anti-protozoal drugs, barbiturates or drugs pest Control.
• the oligomers or polymers of cyclodextrins obtained according to the invention can also be used for the design of materials to based on cyclodextrins immobilized on porous supports, such as silicas or resins for example. They can also be used for fixing and separating various substances, in particular by chromatographic techniques for example.
• cyclodextrin dimers according to the invention are obtained from monoazide- ⁇ -cyclodextrins for the examples DM1, DM2 and DM3, and monoazide- ⁇ -cyclodextrins alkylated for DM4.
• the monoazide- ⁇ -cyclodextrin is synthesized as follows: selective monotosylation of ⁇ -cyclodextrin in the presence of tosyl chloride (TsCl) in an aqueous alkaline solution, and
• alkylated monoazide- ⁇ -cyclodextrin is synthesized as follows:
• TsCl tosyl chloride
• cyclodextrin dimers according to the invention are obtained with spacer arms of different lengths for the examples DM1, DM2 and
• Spacer arms are formed from glycol and polyethylene glycol chains, chosen for their chemical stability and biological compatibility. They are functionalized at their ends by alkynes.
• the spacer arms are synthesized in the presence of propargyl bromide and sodium hydride at room temperature in tetrahydrofuran (THF).
• the 1,3-dipolar cycloaddition is carried out in the presence of a pair of catalysts which allows the exclusive formation of the product 1,4 triazole.
• Catalysts commonly used are copper sulphate or copper bromide, combined with bases of the type L-ascorbate sodium (L-asc.) Or diisopropylethylamine (DIPEA).
• L-asc. L-ascorbate sodium
• DIPEA diisopropylethylamine
• the copper sulfate pair L-asc is used. in an aqueous medium.
• the ⁇ -cyclodextrin monotosyl is solubilized slowly in DMF (dimethylformamide), previously dried on a molecular sieve.
• DMF dimethylformamide
• Sodium azide is added and the mixture is stirred at 60 ° C. under an inert atmosphere.
• the DMF is evaporated and the residue taken up in ethanol: a white precipitate appears.
• the white precipitate is filtered on sintered glass and washed with ethanol. A white powder is obtained which is dried under high vacuum.
• the monoazide- ⁇ -cyclodextrin obtained can be used without further purification for the production of DM1, DM2 or DM3.
• Barium hydroxide and barium oxide are added to the reaction mixture.
• the reaction mixture is heated at 70 ° C. for two hours, then the solvents are evaporated.
• the residue is taken up in dichloromethane, the precipitate formed is filtered on sintered glass porosity 3 and washed with dichloromethane.
• the filtrate is recovered and then extracted with water and brine.
• the white precipitate obtained is filtered, washed with methanol and then dried under high vacuum.
• the alkylated monoazide- ⁇ -cyclodextrin obtained can be used without further purification for producing DM4 dimer and TMl trimer.
• the monoazide ⁇ -cyclodextrin obtained in 1 is solubilized in anhydrous DMF.
• the mixture is cooled to 0 ° C. and methyl iodide is added slowly.
• the reaction is kept at room temperature for 24 hours.
• reaction medium When the reaction is complete, the reaction medium is filtered and the filtrate is concentrated in vacuo. The oily residue is taken up in a minimum of water and then extracted with dichloromethane.
• the collected organic phase is washed with water, with brine, and is dried over anhydrous sodium sulphate. After evaporation of the solvent in vacuo, the oily residue is taken up in a minimum of water, the insolubles are filtered and the solution is freeze-dried. After filtration and evaporation, the crude product is dried under high vacuum. The residue is covered with methanol and then placed at 60 ° C. The product is obtained in the form of a white powder.
• the alkylated monoazide- ⁇ -cyclodextrin obtained can be used without additional purification for producing the DM5 dimer.
• glycol chain (glycol, diethylene glycol or triethylene glycol) is solubilized in THF (tetrahydrofuran or 1,4-epoxybutane).
• reaction mixture is cooled to 0 ° C. in an ice-water bath and propargyl bromide is added dropwise.
• distilled water is added to the reaction medium in order to hydrolyze the excess propargyl bromide.
• the solvents are evaporated and the oil obtained is taken up in ethyl acetate and then washed with water.
• the organic phase is recovered, dried with sodium sulphate and then filtered.
• the ethyl acetate is evaporated and the residue obtained is purified on a column of silica gel with a pentane / ether mixture as the eluent phase.
• the product obtained is in the form of a yellow oil.
• 1,1,1-tris (hydroxymethyl) ethane is solubilized in THF.
• Sodium hydride is added and the mixture is stirred for a few minutes under an inert atmosphere.
• reaction mixture is cooled to 0 ° C. in an ice-water bath and propargyl bromide is added dropwise.
• distilled water is added to the reaction medium in order to hydrolyze the excess propargyl bromide.
• the organic phase is recovered, dried with sodium sulphate and then filtered.
• the ethyl acetate is evaporated and the residue obtained is purified on a column of silica gel with a pentane / ether mixture as the eluent phase.
• the product obtained is in the form of a yellow oil.
• Triethylamine is then added.
• the flask is immersed in an ice bath and propargyl bromide solubilized in THF is added dropwise. After 24 hours of reaction, the salts formed are filtered and the filtrate is taken up in water and then stirred for one hour to hydrolyze the excess propargyl bromide.
• the organic phase is recovered, dried over anhydrous sodium sulphate and then filtered.
• the product is purified on a column of silica gel.
• ⁇ -cyclodextrin precursors are used:
• dialkyne glycol as synthesized in 3.1 for DM1, DM4 and DM5
• dialkyne diethylene glycol as synthesized in 3.1 for DM2
• dialyne triethylene glycol as synthesized in 3.1 for DM3, and
• the cyclodextrin azide precursors are solubilized in distilled water. L-asc. and copper sulfate pentahydrate are then added.
• glycol derivative solubilized in ethanol
• a precipitate is formed which is filtered and rinsed.
• the colored powder obtained is solubilized in distilled water and then placed in the presence of Amberlite 200.
• dimers DM1, DM2, DM3, DM4, DM5 and trimer TM1 are obtained in the form of a slightly colored powder, which does not require additional purification.
• a branched cyclodextrin monoazide is synthesized from alkylated monoazide- ⁇ -cyclodextrins as synthesized in 2.1 and tert-butyl [3- (di-prop-2-ynylamino) -propyl] -carbamate. as synthesized in 3.3.
• the reaction scheme is as follows:
• An ⁇ -alkylated ⁇ -cyclodextrin mono ⁇ zide- ⁇ as synthesized in 2.1. is solubilized in a water / ethanol mixture with L-ascorbate, copper sulfate and tert-butyl [3- (di-prop-2-ynyl-amino) -propyl] -carbamate as synthesized in 3.3.
• the reaction medium is heated to 50 ° C. When the reaction is complete, the ethanol is evaporated.
• the aqueous solution is extracted with dichloromethane.
• the organic phase is then washed with a dilute hydrochloric acid solution and then brine.
• the organic phase is recovered, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum.
• the residue obtained is purified on a column of silica gel and then used to synthesize DM6 dimer.
• DM6 is obtained by coupling a folic acid on the branched cyclodextrin monoazide obtained previously.
• the reaction scheme is as follows:
• the branched cyclodextrin monoazide is solubilized in dichloromethane and then TFA (trifluoroacetic acid) is added.
• the reaction is stirred for 20 hours.
• the solution is washed with water, with dilute sodium hydroxide solution and then with brine solution.
• the organic phase is dried and then evaporated under vacuum and the product is dried under high vacuum.
• the resulting residue is placed in a balloon protected from light then solubilized in DMF.
• folic acid N, N'-Dicyclohexylcarbodiimide
• pyridine a catalytic amount of pyridine.
• the reaction is complete, the DMF is evaporated under vacuum and the residue is taken up in dichloromethane.
• the solution is washed with water, dilute sodium hydroxide solution and brine.
• the organic phase is dried over anhydrous sodium sulphate, filtered and evaporated.
• the product is purified on a column of silica gel.
• dimers prepared according to the invention make it possible to significantly increase the solubility of the active agents tested.
• the invention is obviously not limited to the examples shown and described above, but on the contrary covers all the variants, particularly with regard to the nature of the cyclodextrins and spacer arms, as well as the uses of the oligomers or cyclodextrin polymers obtained.

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