Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
• • 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 present invention relates to new amphiphilic derivatives of cyclodextrins, more precisely of ⁇ -, ⁇ - and ⁇ -cyclodextrins, as well as to their preparation process and to their uses.
• these amphiphilic derivatives show remarkable stability, which makes their manufacture, their conservation and their handling. particularly easy. They are likely to be used in all fields of application of cyclodextrins.
• Cyclodextrins are non-reducing cyclic oligosaccharides, which are obtained industrially by degrading amylose (that is to say the linear form of starch) by cyclodextrin glucosyltransferase, enzyme of origin bacterial.
• the three most frequently encountered cyclodextrins are the oc-, ⁇ - and ⁇ -cyclodextrins which consist respectively of 6, 7 and 8 D-glucopyranosic units, linked together by glycosidic linkages ⁇ (l—> 4).
• the cyclodextrins have a three-dimensional structure in the form of a truncated cone, the wall of which is formed by D-glucopyranosic units, in chair conformation 4 C ⁇ 1,2 and .... delimits a cavity also called "cage".
• the secondary hydroxyl groups of the D-glucopyranosic units are located at the base of the wall of the truncated cone, while the primary hydroxyl groups of these units are located at the top of this wall.
• the outer part of the cyclodextrins is naturally hydrophilic while their inner part, which is lined with hydrogen atoms and interglucosidic oxygen atoms, is hydrophobic.
• This feature makes it possible to include in the cyclodextrin cage hydrophobic molecules to form inclusion complexes soluble in water.
• the biodegradable nature of cyclodextrins predisposes them to important applications in the pharmaceutical and food industries where the ability of cyclodextrins to serve as a "host" molecule makes it possible to protect fragile molecules, to ensure their controlled release or, in the case of hydrophobic molecules, their solubilization in an aqueous medium.
• Pharmaceutical specialties using cyclodextrins are already commercially available.
• amphiphilic derivatives of a-, ⁇ - or ⁇ -cyclodextrin obtained by grafting a derivative steroid, via a spacer arm, on the carbon of the primary hydroxyl group of at least one D-glucopyranosic unit of these cyclodextrins.
• This team was able to obtain, from these derivatives, perfectly spherical micelles, comprising on average 24 monomers and lined on the surface by the cages of these monomers.
• R 4 represent either a hydroxyl group or R 2 except when R 2 is a hydroxypropyl group, or one or more R 4 are identical to R 1 and the other R 4 (s) represent either a group hydroxyl, ie R 2 except when R 2 is a hydroxypropyl group; - n is an integer equal to 5, 6 or 7.
• heteroatom is meant an atom chosen from nitrogen, oxygen, sulfur and halogens (bromine, iodine , chlorine and fluorine).
• residue of an amino acid means the group of atoms which remains of this amino acid when the latter is covalently linked, on the one hand, to the spacer arm E and, on the other hand share in one and / or the other of groups L 1 and L 2 .
• E which serves as a spacer arm, corresponds to formula (III): -CO-XG 1 -, in which X represents an alkylene group forming a bridge and comprising from 1 to 8 carbon atoms, while G 1 represents a group -CO-, -NH- or -NR- in which R is an alkyl group, advantageously Ci to Ce
• X represents, preferably, an alkylene group forming a bridge and comprising from 1 to 4 carbon atoms and, better still, 2 carbon atoms.
• the amino acid is preferably chosen from the twenty amino acids which conventionally enter into the constitution of proteins, namely aspartic acid, glutamic acid , alanine, arginine, asparagine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan and valine.
• it is chosen from aspartic acid, glutamic acid, isoleucine, leucine and phenylalanine, aspartic acid and glutamic acid being particularly preferred.
• this amino acid can also be chosen from rarer amino acids such as, for example, ⁇ -alanine, ⁇ -aminobutyric acid, ⁇ -aminoadipic acid, hydroxyproline, hydroxy-lysine, phenylserine, ⁇ , ⁇ -diaminopimelic acid and ornithine, any amino acid being- a priori likely to be suitable since it comprises, by definition, two functional groups, one carboxylic acid, the other amino, allowing its covalent bond, on the one hand, to the spacer arm E, and, on the other hand, to at least one group L 1 or L 2 .
• rarer amino acids such as, for example, ⁇ -alanine, ⁇ -aminobutyric acid, ⁇ -aminoadipic acid, hydroxyproline, hydroxy-lysine, phenylserine, ⁇ , ⁇ -diaminopimelic acid and ornithine
• amino acid depends in particular on the value which it is desired to give to p and q in formula (II), insofar as it must contain at least three functional groups so that p and q can be all two equal to 1 (that is, for the two groups L 1 and L 2 to be present), when it suffices - and it is even desirable to simplify the preparation of the cyclodextrin derivative - that it has only two functional groups when one of the integers p and q is equal to 0.
• AA is the remainder of an amino acid belonging to the series L.
• L 1 and / or L 2 correspond to formula (IV): -G 2 -Y in which G 2 represents a group —C0-, -NH - or -NR- where R is an alkyl group, advantageously Ci to Ce, while Y represents a linear Cs to C ⁇ 8 alkyl chain or a cyclic or polycyclic group known to be lipophilic as a steroid group, for example derived from cholesterol, a polyaromatic group, for example derived from naphthalene, dansyl, anthracene or even a group derived from alkaloids.
• - Z represents: • either a covalent bond, in which case R 5 represents a hydrogen atom, a methyl group, the side chain of an amino acid or a group of formula: - (CH 2 ) t _ CO-NH- Y in which t is worth 1 or 2 and Y has the same meaning as above, • or a hydrocarbon group forming a bridge, comprising from 1 to 4 carbon atoms and comprising one or more heteroatoms chosen from 0 and N, in which case R 5 represents a primary amino group or a group of formula: -NH-CO-Y in which Y has the same meaning as above.
• AA represents, in formula (II), the remainder of an amino acid chosen from aspartic acid, glutamic acid, isoleucine, leucine and phenylalanine
• formula (VI) - Z represents a covalent bond
• - Y preferably represents a linear C 8 to C ⁇ 8 and, better still, C 12 to C ⁇ 6 alkyl chain
• - Y preferably represents a linear C 8 to C ⁇ 8 and, better still, C ⁇ 2 to Ci ⁇ alkyl chain;
• cyclodextrin derivatives represent a group of formula: - (CH 2) t -CO-NH-Y, wherein t is 1 or 2 and Y is preferably a linear alkyl chain C 8 C ⁇ 8 and, better still, in C 12 to C ⁇ 6 .
• the cyclodextrin derivatives contain only one substituent R 1 per molecule of derivative. However, it is also possible that one or more or even all of the substituents R 4 are identical to R 1 .
• the cyclodextrin derivatives according to the invention can be derivatives of a-, ⁇ - or ⁇ -cyclodextrin.
• the derivatives are used ⁇ -cyclodextrin, that is to say the derivatives of formula (I) in which n is equal to 6.
• these derivatives can in particular be: - dimethylated, in which case, in the formula ( I), R 2 are methyl groups, R 3 are hydrogen atoms, while R 4 are methoxy groups when they are not identical to R 1 , permethylated, in which case, in formula (I ), all R 2 and R 3 are methyl groups, while R 4 represent methoxy groups when they are not identical to R 1 ,
• the cyclodextrin derivatives of formula (I) can be prepared by conventional coupling processes starting from monoamine derivatives corresponding cyclodextrins. In particular, they can be prepared by a process comprising the coupling of a monoamine derivative of an ⁇ -, ⁇ - or ⁇ -cyclodextrin previously grafted from the spacer arm, with an amino acid previously grafted from the group or groups L 1 and / or L 2. Also, the subject of the invention is also a process for the preparation of cyclodextrin derivatives of formula (I) which comprises a step in which a cyclodextrin derivative of formula (VII) is reacted:
• R 3 represents a hydrogen atom or is identical to R 2 except when R 2 is a hydroxypropyl group
• R 4 represent either a hydroxyl group or R 2 except when R 2 is a hydroxypropyl group, or one or more R 4 represent a group -NH-E 'and the other R or R 4 represent either a hydroxyl group, ie R except when R 2 is a hydroxypropyl group;
• - n is an integer equal to 5, 6 or 7;
• * AA ' represents an amino acid comprising a hydroxyl, amino, carboxylic acid or free thiol group
• L 1 and L 2 identical or different, represent a hydrocarbon group, linear, branched and / or cyclic, saturated or unsaturated, comprising from 6 to 24 carbon atoms and optionally comprising one or more heteroatoms;
• Leaving groups are, for example, halogens, tosylates, mesylates and other sulfonates.
• the monoamine cyclodextrin derivative of formula (IX) can itself be prepared by subjecting the monoazide derivative of cyclodextrin corresponding to a Staudinger reaction, using triphosphine and ammonia, as described in reference [1].
• this grafting is carried out in a single step by reacting the amino acid with a precursor compound which is the same for the two groups, while, in the case where it is desired to graft on the amino acid two different groups L 1 and L 2 , this grafting is carried out in two successive stages: a first stage in which the acid is reacted amine with one of the precursor compounds of groups L 1 and L 2 after having protected the functional group of the amino acid intended to react with the other of these compounds, and a second step in which, after deprotection of said functional group, the amino acid is reacted with the other of said precursor compounds.
• the free functional group of the precursor compounds of groups L 1 and L 2 may in particular be a carboxylic acid group, a group derived from carboxylic acid, a primary or secondary amino group or a leaving group, depending on the nature of the functional group. of the amino acid with which it must react.
• the group E 'precursor compound is preferably an acid anhydride of formula (X):
• amphiphilic cyclodextrin derivatives according to the invention have many advantages, including in particular that of having both a very high affinity with respect to organized surfactant systems and a remarkable stability, which makes them very easy to handle.
• these compounds are stable in the solid state for several months at room temperature and in the light. They are also stable for several weeks in aqueous or organic solution, which is not the case for lipid derivatives of the phospholipid type which are only stable at -80 ° C. They are in . furthermore, relatively simple to prepare, essentially because their synthesis can be carried out by conventional peptide coupling methods.
• the invention also relates to inclusion complexes of cyclodextrin derivatives of formula (I) with hydrophobic compounds.
• cyclodextrin derivatives of formula (I) can be of different types: thus, they can in particular be principles drug active ingredients (steroids, neurotropes, antivirals, bacteriostats, vitamins, etc.), molecules useful in cosmetology, contrast agents for medical imaging, or compounds useful in proteomics such as, for example, detergents suitable for destroy the lipid layers of cell membranes without affecting the membrane proteins.
• inclusion complexes can be prepared by conventional methods, for example by adding to a solution or a suspension of a cyclodextrin derivative of formula (I), a solution of the hydrophobic compound in a suitable organic solvent, for example the acetone.
• the invention also relates to organized surfactant systems comprising a cyclodextrin derivative of formula (I) or an inclusion complex of this derivative.
• the surfactants capable of forming such organized systems can be of different types. By way of example, mention may be made of phospholipids corresponding to the general formula below:
• R 3 represents CH 3 - (CH 2 ) p-CO, p being an integer from 6 to 18.
• R 3 represents CH 3 - (CH 2 ) p-CO, p being an integer from 6 to 18.
• the invention will be better understood in the light of the additional description, which refers to exemplary embodiments of amphiphilic cyclodextrin derivatives according to the invention and which is given by way of illustration and not by way of limitation.
• ESI-HRMS high resolution with detection in positive mode: m / z measured at 1683.8441 [M + H] + , calculated at 1683, 8441 for C 74 Hi 3 iN 4 ⁇ 38 (deviation: 0 ppm); m / z measured at 1705.8169 [M + Na] + , calculated at 1705.8261 for C 74 Hi 3 c ⁇ N 4 0 38 Na (deviation: 5.4 ppm)
• H-4 II_VII CD 4.19 (H- ⁇ 'cD); 4.06 (H- ⁇ ⁇ co); 3.99-4.14 (m, H-2 II "VII CD ); 3.91 (dd, 1H, H-2 I CD ); 3.81 (t, 1H, H-4 I CD ); 3 , 36, 3.31 (2m, 4H, H-l ⁇ , H-l ⁇ ); 3.12 (d, 1H, H- ⁇ ); 3.07 (d, 1H, H- ⁇ '); 2.5 -3.0 (m, 4H, Hb / Hc); 1.53, 1.46 (2m, 4H, H-2 ⁇ , H-2 ⁇ ); 1.20, 1.18 (H-30C, H-3 ⁇ ); 1.13 (H-ll ⁇ / H-ll ⁇ ); 1.05-1.25 (m,
• Compound 20 is prepared by following the same experimental protocol as that described for the preparation of compound 19 in Example 1 above, but using: - 5.89 g (16.0 mmol; 1 eq.) Of compound 18 - 7.4 mL (47.8 mmol; 3 eq.) of DIC - 6.47 g (47.9 mmol; 3 eq.) Of HOBT - 8.87 g (47.9 mmol; 3 eq.) Of dodecylamine. 9.29 g (13.2 mmol) of compound 20 are thus obtained.
• H _ 6 II- V H CD H _ 6 II- V H CD
• 4.28-4.53 m, II-VII C D
• 4.41 H-5 J CD
• 4.14-4.27 m, H-4 II-VII CD
• 4.19 H- ⁇ ⁇
• 4.06 H-6 ,]: C D
• 3.98-4.13 m, H-2 II "V1I CD ); 3.92 (dd, 1H, H-2 ⁇ CD); 3.80 (t, 1H, H-4 I CD); 3 , 35, 3.30 (m, 4H, H-l ⁇ , H-l ⁇ ); 2.6-3.0 (m, Hb / Hc); 2.61 (m, H- ⁇ / H- ⁇ ') ; 2.61 (m, H- ⁇ ); 2.34 (m, 1H, H- ⁇ '); 1.50, 1.47 (m, 4H, H-2 ⁇ , H-2 ⁇ ); 1.18 (H-3 ⁇ / H-3 ⁇ ); 1.05-1.25 (m,
• the residual solid from the decantation is taken up with dichloromethane (3 X 100 mL) and then filtered.
• the organic phases are combined, washed with a saturated aqueous sodium chloride solution (3 X 130 mL), then with water (3 x 130 mL), dried over sodium sulfate and concentrated in a rotary evaporator (40 ° C) until a residual oil is obtained.
• This residue is precipitated in 250 ml of hexane with stirring.
• the precipitate is filtered, washed with hexane and dried in a vacuum oven.
• H-b / H-c 2.46 (m, 1H, H- ⁇ ); 2.29 (m, 1H, H- ⁇ '); 2.08 (m, 1H, H- ⁇ ); 1.99 (m, 1H, H- ⁇ '); 1.49 (m, 4H,
• the solution is then concentrated on a rotary evaporator (40 ° C) and the oily residue is taken up in 140 ml of water.
• the white precipitate formed (mixture of triphenylphosphine and triphenylphosphine oxide) is filtered and washed (2 x 20 ml of water).
• the precipitate is recovered by centrifugation (10,000 rpm, 20 min).
• the solid is dried, then a final stage of recrystallization from methanol (dissolution in a minimum of boiling methanol, filtration of the insoluble materials in the hot state and recrystallization at 4 ° C.) makes it possible to isolate by filtration, and after drying overnight at l vacuum oven, 196 mg (0.37 mmol) of compound 32 in the form of a white powdery powder.
• H- ⁇ ' 1.48 (m, 4H, H-2 ⁇ / H-2 ⁇ ); 1.24-1.32 (m, 44 H, H-3 ⁇ to H-11 ⁇ / H-3 ⁇ to H-15 ⁇ ); 0.88 (t, 6H, H-12 ⁇ / H-16 ⁇ )
• Hio / Hi ⁇ 2.6 (m, 2H, H ⁇ , H ⁇ ; 1.6-1.1 (m, H 2 ⁇ to H ⁇ 6 ⁇ / H 2 ⁇ to Hig ⁇ ); 0.87 (t, 6H, H ⁇ g ⁇ / H ⁇ g ⁇ )
• the compound 21a is prepared by following the same experimental protocol as that described for the preparation of 21 in Example 1 above but using 8.2 g (16.6 mmol, 1 eq.) Of the compound 19a. 3.6 g (13.3 mmol, 80% yield) of compound 21a are thus obtained.
• reaction medium is left at room temperature for 72 hours then the reaction is stopped with 6 ml of water.
• the precipitate formed is filtered and washed with DMF.
• the filtrate is concentrated on a rotary evaporator.
• the pasty residue is taken up in water and extracted with chloroform (5 x 50 mL).
• the organic phase is washed with water (3 x 100 mL).
• the organic phases are combined, dried over Na 2 S ⁇ 4, filtered and then evaporated.
• the residue is taken up a last time in water and left to settle overnight to remove the fat containing sodium hydride. After evaporation and lyophilization, compound 3a is obtained with a quantitative yield.
• the thin layer chromatographies were carried out on aluminum plates (5 ⁇ 7.5 cm) coated with silica gel 60 F 254 (Merck).
• the melting points were determined using a ⁇ fler bench requiring calibration with reference products from Merck Eurolab.

Applications Claiming Priority (2)

Publications (1)

Family

ID=34400926

Family Applications (1)

Country Status (5)

Families Citing this family (14)

Family Cites Families (8)

• 2003
  • 2003-10-24 FR FR0350736A patent/FR2861396B1/fr not_active Expired - Fee Related
• 2004
  • 2004-10-21 US US10/576,346 patent/US7812152B2/en not_active Expired - Fee Related
  • 2004-10-21 JP JP2006536144A patent/JP2007509218A/ja active Pending
  • 2004-10-21 WO PCT/FR2004/050519 patent/WO2005042590A2/fr active Application Filing
  • 2004-10-21 EP EP04805762A patent/EP1675876A2/de not_active Withdrawn

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events