EP4028428A1 - Neue cyclodextrin-dimere und verwendungen davon als chemische scavenger - Google Patents

Neue cyclodextrin-dimere und verwendungen davon als chemische scavenger

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Publication number
EP4028428A1
EP4028428A1 EP20767817.8A EP20767817A EP4028428A1 EP 4028428 A1 EP4028428 A1 EP 4028428A1 EP 20767817 A EP20767817 A EP 20767817A EP 4028428 A1 EP4028428 A1 EP 4028428A1
Authority
EP
European Patent Office
Prior art keywords
formula
medium
compound
μmol
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20767817.8A
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English (en)
French (fr)
Inventor
François ESTOUR
Michaël BOSCO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Direction General pour lArmement DGA
Centre National de la Recherche Scientifique CNRS
Institut National des Sciences Appliquees de Rouen
Universite de Rouen Normandie
Original Assignee
Direction General pour lArmement DGA
Centre National de la Recherche Scientifique CNRS
Institut National des Sciences Appliquees de Rouen
Universite de Rouen Normandie
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Publication of EP4028428A1 publication Critical patent/EP4028428A1/de
Pending legal-status Critical Current

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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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/20—Organic compounds containing oxygen
    • C11D3/22—Carbohydrates or derivatives thereof
    • C11D3/222—Natural or synthetic polysaccharides, e.g. cellulose, starch, gum, alginic acid or cyclodextrin

Definitions

  • TITLE NEW DIMERS OF CYCLODEXTRIN AND THEIR USES AS CHEMICAL SCRUBBERS
  • the present invention relates to novel dimers of cyclodextrin, as well as their preparation processes. It also relates to their uses, in particular as chemical scrubbers.
  • Organophosphate neurotoxicants are irreversible inhibitors of acetylcholinesterases, key enzymes of cholinergic neurotransmission.
  • the most powerful chemical warfare agents and pesticides belong to this family of compounds. In the event of the release of organophosphate neurotoxic agents into the atmosphere, the most urgent thing is to be able to take the necessary measures to protect the civilian or military populations.
  • chemical defense despite recent progress, has undeniable shortcomings.
  • the object of the present invention is therefore to provide new compounds derived from cyclodextrins exhibiting high catalytic activity on chemical warfare agents, in particular soman, sarin, cyclosarin or tabun.
  • Nu corresponds to formula (II) as defined above where R is CO-NH-OH and X is N.
  • the compounds of the invention correspond to formula (I) as defined above, in which R 1 is H and R 2 is -Y-Nu, Y being a linker of formula -O- (CH 2 ) m -, m being 1, 2, or 3, preferably 1 or 3.
  • the compounds of the invention correspond to formula (I) as defined above, in which R 1 is -Y-Nu, Y being a linker of formula -O- (CH 2 ) m -, m being 1, 2, or 3, preferably 1 or 3, and R 2 is H.
  • -Y-Nu meets one of the following formulas (III), (IV) (V), or (VI):
  • R 1 is H and R 2 corresponds to one of formulas (III), (IV) or (V) as defined above .
  • R 1 corresponds to one of the above-mentioned formulas (III), (IV) or (V) and R 2 is H.
  • the compounds of the invention correspond to formula (I) in which R 1 corresponds to formula (VI) and R 2 is H.
  • the aforementioned step is carried out in a solvent chosen from the group consisting of aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, and in particular dimethylsulfoxide (DMSO).
  • aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, and in particular dimethylsulfoxide (DMSO).
  • the aforementioned step is carried out in the presence of a strong base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, and preferably sodium hydroxide.
  • a strong base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, and preferably sodium hydroxide.
  • the aforementioned step is carried out at a temperature of 40 ° C to 60 ° C, and preferably 50 ° C to 55 ° C.
  • the aforementioned step is carried out for a period of from 1 h to 3 h, and preferably from 1 h 45 to 2 h 15.
  • the compound of formula (VIII) mentioned above is subjected to a step of protection of the hydroxyl functions, comprising for example reaction with acetic anhydride (Ac 2 O) in the presence of pyridine at room temperature for 4 days.
  • This step can also be carried out by reaction with acetic anhydride (Ac 2 O) in the presence of 4- (dimethylamino) pyridine (DMAP) or of acetyl chloride (AcCl) in the presence of pyridine.
  • DMAP dimethylamino
  • AcCl acetyl chloride
  • the compound of formula (IX) mentioned above is subjected to a stage of deprotection of the phenol functions, comprising for example the reaction with 1,3-dimethylpyrimidine-2,4,6 (1H, 3H, 5H) - trione and Pd (PPh 3 ) 4 in the presence of THF at reflux for 1 hour.
  • This step makes it possible to transform the compounds of formula (IX) above into compounds of formula (X): in which: - either R ' 4 is H and R' 3 is -OH; - Either R ' 4 is -OH and R' 3 is H.
  • the present invention also relates to the intermediate compounds of formula (X):
  • the intermediate compounds of formula (X) are used to prepare compounds of formula (I) according to the invention.
  • the present invention also relates to a process for preparing compounds of formula (I) as defined above in which R 1 is H and R 2 corresponds to one of the aforementioned formulas (III), (IV) or (V). , from the compound of formula (X-1) above.
  • the present invention therefore relates to a process for preparing compounds of formula (I) as defined above in which R 1 is H and R 2 corresponds to one of the aforementioned formulas (III), (IV) or (V).
  • this step is carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, and preferably potassium carbonate.
  • a base such as sodium carbonate, potassium carbonate, cesium carbonate, and preferably potassium carbonate.
  • this step is carried out in a solvent chosen from the group consisting of aprotic polar solvents such as acetonitrile or acetone, and preferably acetone.
  • this step is carried out at a temperature of from 50 ° C to 70 ° C, and preferably from 55 ° C to 60 ° C.
  • this step is carried out for a period of from 2 p.m. to 6 p.m., and preferably from 3 p.m. to 5 p.m.
  • the compound of formula (XI-1) is subjected to a deprotection step to obtain the compounds of formula (I) mentioned above, and corresponding to the following general sub-formula (XII-1):
  • the present invention also relates to a process for the preparation of compounds of formula (I) as defined above in which R 1 corresponds to one of the above-mentioned formulas (III), (IV) or (V) and R 2 is H , from the compound of formula (X-2) above.
  • the present invention therefore relates to a process for the preparation of compounds of formula (I) as defined above in which R 1 corresponds to one of the above-mentioned formulas (III), (IV) or (V) and R 2 is H , comprising a step of reacting the compound of formula (X-2) above with a reagent selected from methyl 5-bromomethyl-2-iodobenzoate, methyl 4-bromomethyl-2-iodobenzoate or 4- (3-bromopropyl ) Methyl -2-iodobenzoate, to obtain a compound of the following formula (XI-2):
  • this step is carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, and preferably potassium carbonate.
  • this step is carried out in a solvent chosen from the group consisting of aprotic polar solvents such as acetonitrile or acetone, and preferably acetone.
  • this step is carried out at a temperature of from 50 ° C to 70 ° C, and preferably from 55 ° C to 60 ° C.
  • this step is carried out for a period of from 2 p.m. to 6 p.m., and preferably from 3 p.m. to 5 p.m.
  • the compound of formula (XI-2) is subjected to a deprotection step to obtain the compounds of formula (I) mentioned above, and corresponding to the following general sub-formula (XII-2):
  • the present invention also relates to the use of the compound of formula (I) as defined above, as a chemical scrubber in the context of the decontamination of surfaces of materials, of the skin, or of the mucous membranes, contaminated by organophosphate neurotoxic agents. .
  • the present invention also relates to the use of the compound of formula (I) as defined above, for reducing the inhibition of the activity of acetylcholinesterases by organophosphorus neurotoxic agents.
  • organophosphate neurotoxic agents mention may be made, for example, of soman, sarin, cyclosarin or tabun, and agents of the “novitchok” type.
  • the present invention also relates to a method of modifying a textile surface by immobilizing on said surface a compound of formula (I) as defined above, said method comprising a step (a) of bringing said surface into contact.
  • textile with the compound of formula (I) and with a bridging agent selected from the group consisting of 1,2,3,4-butanetetracarboxylic acid, succinic acid, citric acid, acid oxalic acid and mixtures thereof, in the presence of a catalyst or of a coupling agent selected from the group consisting of cyanamide, N, N, N ', N'-tetramethyl-O- (N-succinimidyl) uronium tetrafluoroborate, O- [N-succinimidyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), O- (5-norbornene-2,3-dicarboximido) -N, N, N ', N
  • the bridging agent used in the process of the invention is 1,2,3,4-butanetetracarboxylic acid.
  • the catalyst used in the process of the invention is cyanamide.
  • the textile surface is a surface whose textile is chosen from the group consisting of natural or artificial cellulosic fibers. Among these textiles, mention may be made of cotton, linen, hemp, viscose, cellulose acetate and polyvinyl alcohol.
  • the method of the invention comprises an additional step, after step (a) mentioned above, namely a step (b) of rinsing the textile surface on which the dimer of formula (I) is immobilized. .
  • the present invention also relates to a modified textile surface on which is immobilized a cyclodextrin dimer corresponding to formula (I) as defined above.
  • the modified textile surface comprises a textile surface as defined above, on which is immobilized a cyclodextrin dimer as defined above.
  • the present invention also relates to a modified textile surface obtained by the process as defined above.
  • the present invention also relates to the use of a modified textile surface as defined above, for the trapping and degradation of organophosphate neurotoxic agents.
  • the present invention also relates to the use of a modified textile surface as defined above, as a self-decontaminating textile.
  • FIG. 1 represents the monitoring of the hydrolysis kinetics of methyl-paraoxon.
  • Figure 2 shows the relative efficiencies of scrubbers according to the invention against soman (GD).
  • Figure 3 shows the relative efficiencies of scrubbers according to the invention against cyclosarin (GF).
  • Figure 4 shows the relative efficiencies of scrubbers according to the invention against sarin (GB).
  • Figure 5 shows the relative efficiencies of scrubbers according to the invention against tabun (GA).
  • Figure 6 shows the relative efficiencies of scrubbers according to the invention against tabun (GA).
  • FIG. 7 represents the monitoring of the hydrolysis kinetics of dichlorvos by NMR.
  • the medium is heated to 55 ° C., then sodium hydroxide (800 mg, 20 mmol, 20 eq.) Is added to the medium when all the cyclodextrin is dissolved. After half an hour, 1- (allyloxy) - 3,5-bis (bromomethyl) benzene (320 mg, 1 mmol, 1 eq.) Dissolved in 5 mL of anhydrous DMSO is added to the medium dropwise. -drip for five minutes. After two hours of stirring at 55 ° C., the medium is allowed to return to room temperature. The medium is then poured dropwise into 1 L of acetone with vigorous stirring. The precipitate obtained is recovered by filtration on a Buchner funnel.
  • sodium hydroxide 800 mg, 20 mmol, 20 eq.
  • the precipitate is rinsed with 200 ml of acetone.
  • the precipitate is dried under high vacuum (vane pump).
  • vane pump In a 100 mL flask under an argon atmosphere, the dried product is dissolved in freshly distilled pyridine (23.4 mL, 289 mmol). The medium is cooled by an ice bath. Then acetic anhydrous (23.4 mL, 248 mmol) is added dropwise to the medium. The medium is allowed to return to ambient temperature and left under stirring for 4 days. The reaction is stopped by evaporation of the solvents under high vacuum (vane pump). The crude is dissolved in 400 mL of dichloromethane.
  • the organic phase obtained is washed successively with 200 mL of water, 200 mL of a saturated aqueous solution of ammonium chloride, 200 mL of a saturated solution of sodium chloride, then dried over sodium sulfate, filtered and concentrated. under reduced pressure.
  • Rf 0.14 (Acetone / Cyclohexane, 1/1, v / v).
  • the medium is degassed for ten minutes under a stream of argon. Then tetrakis (triphenylphosphine) palladium (36 mg, 31 ⁇ mol, 0.3 eq.) And dimethylbarbituric acid (161 mg, 1.03 mmol, 10 eq.) Are added to the medium. The medium is then brought to reflux. After stirring for one hour at 75 ° C., the medium is allowed to return to ambient temperature and the reaction is stopped by adding 7.5 ml of a saturated aqueous solution of sodium bicarbonate. The medium is extracted with 100 mL of ethyl acetate.
  • the medium is left under stirring at 45 ° C. for 19 h.
  • the middle is then diluted in 5 mL of MilliQ water. It is then extracted three times with 25 mL of ethyl acetate.
  • the organic phases are combined, washed with 30 mL of a saturated aqueous solution of sodium bicarbonate, 30 mL of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude obtained is suspended in 10 mL of MilliQ water.
  • sodium hydroxide (84.4 mg, 2.11 mmol, 57 eq.) Is added to the suspension.
  • the reaction medium is left under stirring at room temperature for 16 h (solution pH 10-11).
  • the reaction is stopped by adding glacial acetic acid (pH brought to 7).
  • the medium is diluted with 10 mL of a 25 mM aqueous solution of ammonium hydrogencarbonate.
  • the solution obtained is deposited on 4.5 g of ZEOPREP C18 silica gel.
  • the column is eluted with a gradient of a 25 mM aqueous solution of ammonium hydrogencarbonate and acetonitrile (50 mL fraction, 1/0, 95/5, 9/1, 85/15, 8/2, 75/25, 7/3, v / v).
  • the medium is left under stirring at 45 ° C. for 19 h.
  • the medium is then diluted in 5 mL of MilliQ water. It is then extracted three times with 25 mL of ethyl acetate.
  • the organic phases are combined, washed with 30 mL of a saturated aqueous solution of sodium bicarbonate, 30 mL of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude product obtained is purified on silica gel (20 mL) using as eluent a mixture of cyclohexane and acetone (from 4/1 to 0/1, v / v) to give a partially deacetylated white product.
  • the column is eluted with a gradient of a 25 mM aqueous solution of ammonium hydrogencarbonate and acetonitrile (50 mL fraction, 1/0, 95/5, 9/1, 85/15, 8/2, 75/25, 7/3, v / v).
  • the medium is left under stirring at 45 ° C. for 19 h.
  • the medium is then diluted in 5 mL of MilliQ water. It is then extracted three times with 25 mL of ethyl acetate.
  • the organic phases are combined, washed with 30 mL of a saturated aqueous solution of sodium bicarbonate, 30 mL of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude obtained is suspended in 10 mL of MilliQ water.
  • sodium hydroxide (82.3 mg, 2.05 mmol, 57 eq.) Is added to the suspension.
  • the reaction medium is left under stirring at room temperature for 16 h (solution pH 10-11).
  • the reaction is stopped by adding glacial acetic acid (pH brought to 7).
  • the medium is diluted with 10 mL of an aqueous solution 25 mM ammonium hydrogencarbonate.
  • the solution obtained is deposited on 4.5 g of ZEOPREP C18 silica gel.
  • the column is eluted with a gradient of a 25 mM aqueous solution of ammonium hydrogencarbonate and acetonitrile (50 mL fraction, 1/0, 95/5, 9/1, 85/15, 8/2, 75/25, 7/3, v / v).
  • Example 2 Synthesis of different cyclodextrin dimers as scavengers - Synthesis of the compounds “NORD” (N1-3) 1- (Allyloxy) -2,6-bis (2 ' A - ⁇ 3' A , 6 ' A -di-O-acetyl-hexakis- [2 ', 3', 6'-tri-O-acetyl] - cyclomalto-heptaosoxy ⁇ -methyl) -benzene N5: In a 100 ml flask under an argon atmosphere, the b-cyclodextrin (2.27 g, 2 mmol, 2 eq.) Is dissolved in 30 ml of anhydrous DMSO.
  • the medium is heated to 55 ° C., then sodium hydroxide (800 mg, 20 mmol, 20 eq.) Is added to the medium when all the cyclodextrin is dissolved. After half an hour, 1- (allyloxy) - 2,6-bis (bromomethyl) benzene (320 mg, 1 mmol, 1 eq.) Dissolved in 10 mL of anhydrous DMSO is added to the medium dropwise. -drip for five minutes. After two hours of stirring at 55 ° C., the medium is allowed to return to room temperature. The medium is then poured dropwise into 1 L of acetone with vigorous stirring. The precipitate obtained is recovered by filtration on a Buchner funnel.
  • sodium hydroxide 800 mg, 20 mmol, 20 eq.
  • the precipitate is rinsed with 200 ml of acetone.
  • the precipitate is dried under high vacuum (vane pump).
  • vane pump In a 100 mL flask under an argon atmosphere, the dried product is dissolved in freshly distilled pyridine (23.4 mL, 289 mmol). The medium is cooled by an ice bath. Then acetic anhydrous (23.4 mL, 248 mmol) is added dropwise to the medium. The medium is allowed to return to ambient temperature and left under stirring for 4 days. The reaction is stopped by evaporation of the solvents under high vacuum (vane pump). The crude is dissolved in 400 mL of dichloromethane.
  • the organic phase obtained is washed successively with 200 mL of water, 200 mL of a saturated aqueous solution of ammonium chloride, 200 mL of a saturated solution of sodium chloride, then dried over sodium sulfate, filtered and concentrated. under reduced pressure.
  • the residue is purified on 600 mL of silica gel using as eluent a mixture of cyclohexane and acetone (1/1, 10/11, 5/6 v / v) to give the product in the form of a solid.
  • Rf 0.41 (Acetone / Cyclohexane, 1/1, v / v).
  • the medium is degassed for 10 minutes under a stream of argon. Then tetrakis (triphenylphosphine) palladium (78.3 mg, 68 ⁇ mol, 0.3 eq.) And dimethylbarbituric acid (351 mg, 2 .25 mmol, 10 eq.) are added in the middle. The medium is then brought to reflux. After stirring for one hour at 75 ° C., the medium is allowed to return to ambient temperature and the reaction is stopped by adding 12.5 ml of a saturated aqueous solution of sodium bicarbonate. The medium is extracted with 170 mL of ethyl acetate.
  • methyl 4- (bromomethyl) - 2-iodobenzoate (42 mg, 118 ⁇ mol, 2 eq.) Is added to the medium, followed by potassium carbonate (32.6 mg, 236 ⁇ mol).
  • the medium is left under stirring at 45 ° C. for 19 h.
  • the medium is then diluted in 5 mL of MilliQ water. It is then extracted three times with 25 mL of ethyl acetate.
  • the organic phases are combined, washed with 30 mL of a saturated aqueous solution of sodium bicarbonate, 30 mL of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude product obtained is purified on silica gel (20 mL) using as eluent a mixture of cyclohexane and acetone (from 4/1 to 0/1, v / v) to give a partially deacetylated white product.
  • the column is eluted with a gradient of a 25 mM aqueous solution of ammonium hydrogencarbonate and acetonitrile (50 mL fraction, 1/0, 95/5, 9/1, 85/15, 8/2, 75/25, 7/3, v / v).
  • the medium is left under stirring at 45 ° C. for 19 h.
  • the medium is then diluted in 5 mL of MilliQ water. It is then extracted three times with 25 mL of ethyl acetate.
  • the organic phases are combined, washed with 30 mL of a saturated aqueous solution of sodium bicarbonate, 30 mL of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude product obtained is purified on silica gel (20 mL) using a mixture of cyclohexane and acetone (from 5/6 to 0/1, v / v) as eluent to give a partially deacetylated white product.
  • the column is eluted with a gradient of a 25 mM aqueous solution of ammonium hydrogencarbonate and acetonitrile (50 mL fraction, 1/0, 95/5, 9/1, 85/15, 8/2, 75/25, 7/3, v / v).
  • the medium is left under stirring at 45 ° C. for 19 h.
  • the medium is then diluted in 5 mL of MilliQ water. It is then extracted three times with 25 mL of ethyl acetate.
  • the organic phases are combined, washed with 30 mL of a solution. saturated aqueous sodium bicarbonate solution, 30 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude obtained is suspended in 10 mL of MilliQ water.
  • sodium hydroxide (89 mg, 2.22 mmol, 57 eq.) Is added to the suspension.
  • the reaction medium is left under stirring at room temperature for 16 h (solution pH 10-11).
  • the reaction is stopped by adding glacial acetic acid (pH brought to 7).
  • the medium is diluted with 10 mL of a 25 mM aqueous solution of ammonium hydrogencarbonate.
  • the solution obtained is deposited on 4.5 g of ZEOPREP C18 silica gel.
  • the column is eluted with a gradient of a 25 mM aqueous solution of ammonium hydrogencarbonate and acetonitrile (50 mL fraction, 1/0, 95/5, 9/1, 85/15, 8/2, 75/25, 7/3, v / v).
  • the medium is heated to 55 ° C. then sodium hydroxide (0.65 g, 16.25 mmol, 20 eq.) Is added to the medium when all the cyclodextrin is dissolved.
  • sodium hydroxide (0.65 g, 16.25 mmol, 20 eq.)
  • 1- (azoturomethyl) -3,5-bis (bromomethyl) benzene (260 mg, 812 mmol, 1 eq.) Dissolved in 8 mL of anhydrous DMSO is added to the medium dropwise for five minutes.
  • the medium is left under stirring at 55 ° C. for two hours. After allowing the medium to return to ambient temperature, it is poured dropwise into 1.65 L of acetone with vigorous stirring. The precipitate obtained is recovered by filtration on a Buchner funnel.
  • the precipitate is washed twice with 300 ml of acetone.
  • the precipitate is dried under high vacuum (vane pump).
  • vane pump In a 100 mL flask under an argon atmosphere, the dried product is dissolved in anhydrous pyridine (23.4 mL, 289 mmol). The medium is cooled by an ice bath. Then acetic anhydrous (23.4 mL, 248 mmol) is added dropwise to the medium. It is left to return to ambient temperature and left under stirring for 4 days. The solvents are evaporated off under high vacuum (vane pump). The medium is dissolved in 200 mL of ethyl acetate and 100 mL of water.
  • the organic phase is recovered and the aqueous phase is extracted with 2 x 100 mL of ethyl acetate.
  • the organic phases are combined, washed with 100 ml of a saturated solution of salmiac, 100 ml of brine, dried over sodium sulphate, filtered and concentrated under reduced pressure.
  • Rf 0.14 (Acetone / Cyclohexane, 1/1, v / v).
  • the reaction medium After having purged the medium again with argon, the reaction medium is purged three times with hydrogen. After 16 h of stirring at room temperature, the reaction is stopped by purging with argon. The medium is filtered through Celite ⁇ which is rinsed with 20 mL of methanol. The filtrate is concentrated under reduced pressure to give the hydrogenation product (189 mg, 46.2 ⁇ mol, 95%) in the form of a white solid.
  • 6- ((benzyloxy) carbamoyl) picolinic acid 28 mg, 95 ⁇ mol
  • chlorotripyrrolidinophosphonium hexafluorophosphate 52 mg, 123 ⁇ mol
  • diisopropylethylamine 40 ⁇ L, 229 ⁇ mol
  • the hydrogenation product 185 mg, 45 ⁇ mol
  • diisopropylethylamine 23 ⁇ L, 136 ⁇ mol
  • the medium is purged with argon then the palladium on carbon (10% by mass, 127 mg, 120 ⁇ mol, 2 eq.) Is added to the medium.
  • the medium is purged again with argon and then three times with hydrogen.
  • the reaction is stopped by purging with argon.
  • the reaction medium is filtered through Celite ⁇ which is rinsed with a mixture of dichloromethane and methanol. The filtrate is concentrated under reduced pressure.
  • the reaction is stopped by adding glacial acetic acid (pH brought to 7).
  • the medium is then diluted with 10 mL of a 25 mM aqueous solution of ammonium hydrogencarbonate (0.988 mg in 0.5 L of MilliQ water).
  • the medium is deposited on 3.6 g of ZEOPREP C18 silica gel.
  • the column is eluted with a gradient of a 25 mM aqueous solution of ammonium hydrogencarbonate and acetonitrile (50 mL fraction, 1/0, 95/5, 9/1, 85/15, 8/2, 75/25, 7/3).
  • the product 43 mg, 16.7 ⁇ mol, 67%) is obtained in the form of a white solid after lyophilization.
  • a 13.4 mM cetyltrimethylammonium chloride solution containing 3% v / v dimethylsulfoxide in a phosphate buffer solution is prepared by dissolving 2.144 g of the product in 200 mL of the solution prepared in (1), then adding 15 mL of dimethylsulfoxide. The volume is made up to 500 mL with the solution prepared in (1).
  • a solution of methyl paraoxon at a concentration of 16.67 mM in methanol is prepared by dissolving 41.18 mg of methyl paraoxon in 10 ml of anhydrous methanol. This solution is kept in a sealed bottle and stored at - 20 ° C.
  • Solutions of the cyclodextrin derivatives at a concentration of 2.5 mM in a phosphate buffer solution were prepared by dissolving 10 ⁇ mol of each compound in 4 mL of the solution prepared in (2).
  • Monitoring of the hydrolysis kinetics of methyl paraoxon The hydrolysis hydrolysis monitoring of methyl paraoxon was carried out on a Varian® Cary 50 single-beam UV-visible spectrophotometer thermostated at 25 ° C.
  • a solution of cyclodextrin derivative at a concentration of 1 mM in a phosphate buffer solution was made by diluting 1.6 mL of the solution prepared in (4) in 2.4 mL of the solution prepared in ( 2).
  • a solution of cyclodextrin derivative at a concentration of 0.5 mM in a phosphate buffer solution was made by diluting 0.8 mL of the solution prepared in (4) in 3.2 mL of the solution prepared in 2).
  • a solution of cyclodextrin derivative at a concentration of 0.25 mM in a phosphate buffer solution was made by diluting 0.4 mL of the solution prepared in (4) in 3.6 mL of the solution prepared in 2).
  • (8) 30 ⁇ L of the solution prepared in (3) are added to 970 ⁇ L of the solution prepared in (5).
  • the final concentrations of cyclodextrin derivative and methyl paraoxon were 1mM and 0.5mM, respectively.
  • the final concentrations of cyclodextrin derivative and methyl paraoxon were 0.25mM and 0.5mM, respectively.
  • the rate of degradation of the pesticide depends on the length of the spacer arm between the benzene ring and the ⁇ -nucleophilic group, the flexibility of the spacer arm promoting better positioning towards the substrate.
  • the compound AH8 weakly accelerates the hydrolysis of methyl paraoxon.
  • concentration of the scrubber was halved for S3 (0.25 mM)
  • its efficiency was almost identical to that of S1 used at a higher concentration (0.5 mM).
  • doubling the S3 concentration (1 mM) resulted in limited improvement due to the inclusion of para-nitrophenol (hydrolysis product of methyl paraoxon) in the cyclodextrin cavity.
  • Example 5 Relative efficiency of different scrubbers by monitoring hydrolysis of dichlorvos by 31 P NMR.
  • a buffer solution of 109.9 mM tris-hydroxymethylmethylammonium chloride (TRIS.HCl) and cetyltrimethylammonium chloride (CTAC) 14.29 mM in deuterated water is carried out by dissolving 259.80 mg of TRIS.HCl and 68.50 mg of CTAC in 15 mL of deuterated water.
  • the pH is adjusted to 7.65 with a solution of hydrochloric acid diluted in deuterated water and checked with a pH meter.
  • a solution of 16.67 mM of dichlorvos in anhydrous methanol is prepared by dissolving 36.77 mg of dichlorvos in 10 mL of anhydrous methanol. This solution is kept in a sealed vial and stored at -20 ° C.
  • the final concentrations of cyclodextrin derivative and dichlorvos were 1.5 mM.
  • the hydrolysis of dichlorvos is measured every 30 minutes. Each NMR acquisition consists of 64 scans. The NMR tubes containing the hydrolysis experiments are stored in a thermostated bath at 25 ° C. Each experiment was carried out three times. The signal at -3.23 ppm is that of 31 P in dichlorvos, the signal at 3.25 ppm is that of dimethylphosphate (product of phosphorus hydrolysis) .Analysis of the commercial source of dichlorvos used in ur assays showed a single signal at 3.25 ppm in Tris-HCl buffer in D 2 O (pH 7.65, 25 ° C).
  • Example 6 Relative efficacy of different scrubbers on different chemical warfare agents G (Soman, Tabun, Cyclosarin, Sarin).
  • the efficacy of each cyclodextrin derivative is evaluated by indirect assay of the organophosphorus substrate via an enzymatic method based on the activity of the acetylcholinesterase enzyme.
  • the addition of a cyclodextrin derivative causes a partial lifting of the inhibition of acetylcholinesterase by said organophosphorus substrate.
  • acetylcholinesterase can hydrolyze acetylthiocholine into thiocholine and acetic acid.
  • the released thiocholine is assayed with Ellman's reagent (DTNB: 5,5'-dithio-bis- (2-nitrobenzoic acid)) by UV-visible spectrophotometry at 412 nm.
  • Ellman's reagent Ellman's reagent (DTNB: 5,5'-dithio-bis- (2-nitrobenzoic acid)
  • UV-visible spectrophotometry at 412 nm.
  • the method consists, first of all, in bringing the organophosphorus substrate into contact with the cyclodextrin derivative for different incubation times (respectively 10, 20, 30, 40, 50 and 60 minutes) at 37 ° C.
  • the organophosphorus substrate is placed in the presence of the acetylcholinesterase enzyme for 3 min at 37 ° C.
  • the activity of the acetylcholinesterase enzyme is evaluated according to the DGAMNRBC 200574 S-SAT procedure.
  • the cyclodextrin derivative N2 exhibits significant catalytic activity because it reduces the inhibition of acetylcholinesterases by soman to 50% from the first minute of contact and at 95% from 10 minutes.
  • the N1 and S2 derivatives are also very active since they make it possible to reduce the inhibition of acetylcholinesterases by soman to 90% after 10 and 20 minutes of contact respectively.
  • the activity of AH8 is less rapid, because it reduces the inhibition of acetylcholinesterases by soman after 30 minutes of contact with the toxicant.
  • the N2 derivative reduced by 95% the inhibition of acetylcholinesterases by cyclosarin after only 1 minute of contact with the toxicant. It therefore has a very strong catalytic power in the degradation of cyclosarin.
  • the N1 and S2 derivatives have good catalytic activity because they make it possible to reduce the inhibition of acetylcholinesterases by cyclosarin by 95% after only 10 and 20 minutes respectively of contact with the toxicant.
  • AH8 reduced inhibition by cyclosarin by more than 95% after 20 minutes of contact with the toxicant. According to FIG.
  • the N2 derivative has a catalytic activity to decrease the inhibition of acetylcholinesterases by soman, cyclosarin and tabun, with a very rapid action on soman and cyclosarin. It is the most effective derivative of the compounds tested.
  • the N1 derivative however remains particularly active on soman and cyclosarin.
  • Compounds N1 and S2 have less activity on tabun, with an advantage for derivative S2.
  • the compound AH8 is itself always less effective than N2 and S2 whatever the toxicant used.

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EP20767817.8A 2019-09-11 2020-09-09 Neue cyclodextrin-dimere und verwendungen davon als chemische scavenger Pending EP4028428A1 (de)

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FR1910022A FR3100541B1 (fr) 2019-09-11 2019-09-11 Nouveaux dimères de cyclodextrine et leurs utilisations comme épurateurs chimiques
PCT/EP2020/075204 WO2021048208A1 (fr) 2019-09-11 2020-09-09 Nouveaux dimères de cyclodextrine et leurs utilisations comme épurateurs chimiques

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