NOVEL AMPHIPHILIC CYCLODEXTRIN DERIVATIVES

• US 20100093662A1
• Filed: 07/20/2007
• Published: 04/15/2010
• Est. Priority Date: 07/21/2006
• Status: Abandoned Application

• Current Assignee: Centre National De La Recherche Scientifique
• Original Assignee: Centre National De La Recherche Scientifique
• Inventors: Defaye, Jacques, Vierling, Pierre, Diaz Moscoso, Alejandro, Balbuena, Patricia, Geze, Annabelle, Benito, Juan M., Wouessidjewe, Denis, Garcia Fernandez, Jose, Gomez Garcia, Marta, Ortiz Mellet, Carmen, Di Giorgio, Christophe
• Application Number:
  US12/374,211
• Publication Number:
  US 20100093662A1
• Time in Patent Office: Days
• US Class Current: 514/58
• CPC Class Codes: A23L 29/30 containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin products from apiculture A23L21/20; artificial sweetening agents A23L27/30
• CPC Class Codes: A23L 5/00 Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
• CPC Class Codes: A61K 2800/413 Nanosized, i.e. having sizes below 100 nm
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 8/11 Encapsulated compositions
• CPC Class Codes: A61K 8/738 Cyclodextrins
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08B 37/0012 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
• CPC Class Codes: C08B 37/0015 Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
• CPC Class Codes: C08L 5/16 Cyclodextrin; Derivatives thereof

Abstract

The present invention relates to cyclodextrins having the following formula (I): to nanostructures comprising them, to processes for preparing them, to the use thereof, and also to compositions comprising them.

Claims

1. A cyclodextrin having the following Formula (I):

2. A cyclodextrin according to claim 1, in which R², R³ and/or R⁴ are chosen among the benzyl, phenyl, allyl, methyl, ethyl, propyl, butyl, pentyl, hexyl groups or superior homologues comprising up to 12 linear, branched or cyclic, saturated or unsaturated carbon atoms, groups that may comprise other neutral or charged functional groups.

3. A cyclodextrin according to claim 2 in which R² and/or R⁴ are chosen among the acetyl, propionyl, butyroyl, pentanoyl, hexanoyl groups or homologues comprising up to 22 linear, branched or cyclic, saturated or unsaturated carbon atoms, these groups may bear other neutral or charged functional groups.

4. A cyclodextrin according to any one of claims 1 to 3, in which all of the R¹ radicals are identical and represent halogen atoms, in particular chosen among iodine or bromine.

5. A cyclodextrin according to any one of claims 1 to 3, complying with the following Formula (III):

6. A cyclodextrin according to any one of claims 1 to 3, complying with the following Formula (IV):

7. A cyclodextrin according to claim 6, in which n=2 and R represent the tert-butoxycarbonylamino (NHBoc) group or NH₂.

8. A cyclodextrin according to any one of claims 1 to 3, in which the R¹ radicals are identical complying with the following Formula (V):

9. A cyclodextrin according to claim 8, in which n=2, Q represents a sulphur atom, Z and T represent a hydrogen atom and W represents the methyl group.

10. A cyclodextrin according to claim 8, in which m=6, n=2, Q represents a sulphur atom, Z and T represent a hydrogen atom and W represents a group chosen among 2-hydroxyethyl, 2-(tert-butoxycarbonylamino)ethyl, 2-aminoethyl, possibly protonated, 2-(α

-D-mannopyranosyloxy)ethyl, 2-[2-azidoethyl-2′

-(tert-butoxycarbonylamino)ethyl]aminoethyl, 2,2-bis[2-(tert-butoxycarbonylamino)ethyl]aminoethyl.

11. A cyclodextrin according to claim 8, in which m=6, n=2, Q represents a sulphur atom, Z represents a hydrogen atom, T and W are identical and represent the 2-(tert-butoxycarbonylamino)ethyl group.

12. A cyclodextrin according to claim 8, in which m=6, n=2, Q=S, Z=H, T represents the 2-azidoethyl group and W represents the 2-(tert-butoxycarbonylamino)ethyl group.

13. A cyclodextrin according to claim 8, in which all of the R² radicals represent a hexanoyl group.

14. A cyclodextrin according to claim 1 in which m=6 and all of the R² radicals represent the hexanoyl group and/or the tetradecanoyl (myristoyl) group.

15. A cyclodextrin according to any of claims 1 to 3 complying with Formula (VI):

16. A cyclodextrin according to claim 1 to 3, complying with the following Formula (VII):

in which m, R¹ and R² are as defined according to any of claims 1 to 3.

17. A cyclodextrin according to claim 16, in which the R¹ radical represents the 2-(tert-butoxycarbonylamino)ethylthio, 2-aminoethylthio group or 2-[N′

-(2-α

-p-mannopyranosyloxyethyl)thioureidol]ethylthio.

18. A cyclodextrin according to claim 16, in which m=6 and all of the R² radicals represent the hexanoyl group.

19. A cyclodextrin according to claim 18 comprising at least one host molecule, in particular forming an inclusion complex.

20. A method for the preparation of cyclodextrin as defined according to claim 1, comprising steps consisting in:

(i) introducing at least one group on at least one of the carbons bearing the primary hydroxyl or protecting at least one of the primary hydroxyls of the starting compound, in particular a cyclodextrin;

(ii) introducing at least one R² group on at least one secondary hydroxyl carried by carbon in position 3 of the monomers forming a cyclodextrin;

(iii) recovering at least one cyclodextrin as defined according to any of claims 1 to 19.

21. A method according to claim 20, to prepare a cyclodextrin that complies with Formula (I) in which all R¹ groups represent a halogen atom, in Formula (III) or Formula (IV) in which R represents NHY, Y represents a carbamate group or R^a—

C(=0)- in which R^a represents an alkyl radical in C₁ or C₂ to C₁₂ or aryl in C₆ to C₂₀ and the R² radical represents an R^a—

C(=0)- group in which R^a represents an alkyl radical in C₁ or C₂ to C₂₁, or aryl in C₆ to C₂₀,

in which a selectively halogenated, azidated or functionalised cyclodextrin derivative with NHY groups in primary alcohol position with an acid anhydride, in particular in N,N-dimethylformamide, in the presence of a base, preferably N,N-dimethylaminopyridine;

where each of the aforementioned alkyl radicals may be linear, branched or cyclic, saturated or non saturated;

and each of the aforementioned aryl radicals is possibly substituted.

22. A process according to claim 20, to prepare a cyclodextrin that complies with Formula (III) as defined in claim 5, in which a halogenated cyclodextrin derivative as defined in claim 2 is made to react with an azide anion.

23. A process according to claim 20, to prepare a cyclodextrin as defined in claim 6, in which a halogenated cyclodextrin derivative as defined in claim 2 is made to react with cysteamine, a ω

-aminothiol, or one of their derivatives, in the presence of a base, such as triethylamine or cesium carbonate.

24. A process according to claim 20, to prepare a cyclodextrin as defined in claim 6 in which R represents a primary amine group (NH₂) in which the carbamate group is hydrolysed in a percursor as defined in claim 7 in which R represents an NHBoc group.

25. A process according to claim 20, to prepare a cyclodextrin that complies with Formula (V) as defined in claim 8 in which a precursor of Formula (IV) as defined in claim 6 in which R represents NHY, where Y represents a hydrogen atom or an alkyl substituent in C₁ or C₂ to C₁₂ or aryl in C₆ to C₂₀, is made to react with an isocyanate or an isothiocyanate of general formula W—

NCQ, Q represents an oxygen atom or a sulphur atom and W has the meaning indicated in claim 8;

where each of the aforementioned alkyl radicals may be linear, branched or cyclic, saturated or non saturated;

and each of the aforementioned aryl radicals is possibly substituted.

26. A process according to claim 20, to prepare a cyclodextrin that complies with Formula (IV) in which R represents a primary amine group (NH₂) consisting in hydrolysing the carbamate group in a precursor of Formula (IV) in which R represents an NHBoc group.

27. A process according to claim 20, to prepare a cyclodextrin of Formula (V) in which Q=S and Z=H, as defined in claim 7, in which a precursor as defined in claim 15 is made to react with an amine of general formula WNHT, W and T having the meaning indicated in claim 8.

28. A process according to claim 20, to prepare a cyclodextrin that complies with Formula (VII) in which one of the R¹ radicals is different from the hydroxyl and the others represent OH, consisting in:

(i) selectively introducing a functional group on one of the primary positions of the cyclodextrin;

(ii) protecting the other primary hydroxyls with a protector group, in particular in silylether form;

(iii) then introducing the substituents on the primary hydroxyls; and

(iv) possibly hydrolysing the protector groups.

29. A nanostructure comprising at least one of the cyclodextrins according to claim 1.

30. A nanostructure according to claim 29, incorporating, comprising, being associated or forming a complex, with at least one host molecule.

31. A nanostructure according to claim 29 or 30 coming in the form of nanospheres, nanocapsules or nanoparticles.

32. Nanostructures, in particular nanospheres and/or nanocapsules according to claim 31, also comprising at least one host molecule, in particular at least one pharmacologically active molecule.

33. A nanocapsule according to claim 31, enclosing or containing an organic phase, in particular such as Miglyol 812 (trade mark).

34. Nanoparticles according to claim 31 also comprising at least one nucleic acid, in particular selected from the group containing DNA (linear or plasma), RNA (and in particular interfering RNA -RNAi- or even (<

silencing >

>

-RNAsi-, micro-RNA), modified nucleic acids, such as the ribonucleotides or desoxyribonucleotides presenting a sugar group or a modified carbon group, or even synthetic analogs of nucleotides.

39. A method for the preparation of nanostructures, in particular nanospheres and/or nanocapsules, comprising at least one host molecule, in which the nanostructures are as defined in claim 32, comprising the following steps:

(i) the introduction of at least one organic phase containing a water-miscible solvent, such as acetone, a cyclodextrin derivative, or, alternatively, several preparations comprising cyclodextrins complying with Formula (I) of different chemical formulae in variable proportions, and the active ingredient, in an aqueous phase, possibly with a surfactant, in particular a non ionic hydrophilic surfactant, while shaking,

(ii) then after nanoprecipitation, i.e. the formation of nanocapsules or nanospheres, the elimination of the organic solvent.

40. A cosmetic, food and/or pharmaceutical, composition comprising at least one cyclodextrin according to claim 1 and/or one nanostructure according to claim 29 and an active compound.

41. A pharmaceutical composition according to claim 40, containing per unit dose from 50 mg to 500 mg of cyclodextrin according to claim 1 and/or nanostructures according to claim 29 and a pharmacologically active host molecule in a molar proportion of cyclodextrin derivative/host molecule that may range from 50:

1 to 1;

500, in particular from 25;

1 to 1;

10, in particular from 20;

1 to 1;

1, or even 10;

1 to 1, 5;

1.

35. A method for the preparation of nanostructures, and in particular nanospheres, comprising steps consisting of:

(i) the addition of at least one water-miscible organic solvent containing at least one compound of Formula (I) of identical or different chemical formula, with an aqueous solution, the volume of water varying in particular from one to two times the volume of organic solvent, under stirring;

(ii) then after nanoprecipitation, i.e. the formation of nanostructres, the elimination of the organic solvent.

36. Method according to claim 35, in which, in step (i), at least two organic solutions are added, in variable proportion, containing cyclodextrins of Formula (I) of different chemical formulae respectively.

37. A method for the preparation of nanostructures, in particular nanocapsules, comprising the following steps:

(i) the preparation of an acetone phase containing a small fraction of triglycerides, preferably an acetone;

triglyceride proportion ranging from 1,000;

1 to 10;

1, a preparation of amphiphilic cyclodextrin of Formula (I) of identical chemical formula, at least one non ionic lipophilic surfactant, and a hydrophilic phase containing distilled water and at least one non ionic hydrophilic surfactant;

(ii) the introduction of the organic phase in the hydrophilic phase under magnetic stirring;

(iii) then after nanoprecipitation, i.e. the formation of nanocapsules, the elimination of the organic solvent.

38. A method according to claim 37, in which in step (i), at least two cyclodextrin preparations are added, in variable proportion, containing cyclodextrins of Formula (I) of different chemical formulae respectively.

42. (canceled)

43. (canceled)

44. An in vitro method for the transfer of host molecules in cells, in particular eukaryote cells consisting in:

(i) putting in contact the nanostructure/host molecule complex and/or cyclodextrin/other host molecule complex with cells;

(ii) leaving in contact the cells with the nanostructure/host molecule complex and/or cyclodextrin/host molecule complex for a time T preferably between 4 and 72 hours;

(iii) removing the culture medium and washing the cells.