Decontaminating composition

0001The present invention relates to the decontamination by neutralization of media contaminated with neurotoxic organophosphorus compounds, such as organophosphates and organophosphonates. Neutralization transforms the toxic compound into a harmless compound.

0002Organophosphate cholinesterase inhibitor compounds are used in particular as pesticides and insecticides (for example paraoxon, parathion) in agriculture and also as potential war toxics, which irreversibly block nerve transmission by covalently binding to acetylcholinesterase.

0003The organophosphonates have the following general formula:<chemistry id="chem0001" num="0001"><img file="EP0906773A1_D0001.tif" /></chemistry>

0004BNPP (O, O-bis (4-nitrophenyl) phenylphosphonate) is an example, for which R '= 4-NO₂-ArO, R = Ar, L = 4-NO₂-ArO.

0005War toxics are listed as toxic agents by inhalation (soman, sarin, tabun) or toxic agents V by percutaneous route (VX, VG).

0006For sarin (O-isopropyl methylfluorophosphonate), R '= iPrO, R = CH₃, L = F

0007For soman (O-1,2,2-trimethylpropyl methylfluorophosphonate), R '= OCHCH₃(C (CH₃)₃, R = CH₃, L = F

0008For VX (O-ethyl, S-2- (diisopropylaminoethyl) methyl thiolophosphonate, L = SCH₂CH₂N (iPr)₂, R = CH₃, R '= EtO

0009For VG (O-ethyl, S-2- (diisoethylylaminoethyl) ethoxy thiolophosphonate, L = SCH₂CH₂N (C₂H₅)₂, R = R '= EtO

0010For tabun (dimethylamino ethoxy cyanophosphonate), L = CN, R = EtO, R '= (CH3)₂NOT

0011The threat posed by these toxins since the Second World War has prompted intense research into the neutralization of personnel and materials.

0012This is how many chemical formulations have been proposed for their destruction. Nucleophilic substitution and oxidation are the two chemical pathways used for the destruction of toxic agents at room temperature.

0013Very basic formulations have been used: sodium carbonate, aqueous or alcoholic soda, alcoholic potassium to destroy toxic organophosphorus compounds in phosphonic acids. A formulation developed by the American army, DS2, has the following composition: 70% diethylenetriamine (DETA), 28% ethylene glycol monomethyl ether and 2% sodium hydroxide. These formulations are very aggressive. Other less aggressive formulations have proven effective: hydroxamic acids, phenols and polyphenols, aldehyde hydrates, amines including monoethanolamine. Other authors have looked at oximes, for example 2-PAM in the form of pyridinium chloride 2- [hydroxyimino) methyl] -1-methyl in the article by CD Bedford, M. Miura, JC Bottaro, RA Howd and HW Nolen in J. Med. Chem., 1986, 29, 1689. An oxime synthesized in recent years, known under the name CEB 1574 (3- [4-hydroxyiminomethyl] -1-pylidino propyl 3-methylimidazol), is also effective in neutralizing organophosphate war toxins.

0014Formulations based on the use of highly oxidizing media have also been developed: chloramine B, chlorine, bleach, file chlor (sodium N, N'-dichloroisocyanurate), curox or oxone (triple potassium permonosulfate salt), oxygenated water , tert-butyl hydroperoxide, aryl and aliphatic perborates and peracids in general. These formulations are very suitable for rapid and brutal toxic destruction operations. Very aggressive, these compositions can in no case be used for gentle neutralization actions on humans or animals or even on certain materials for the purpose of reuse.

0015There are other formulations designed with the aim of reconciling efficacy, non-aggressiveness and secondary non-toxicity during operations to neutralize fabrics (clothing), exposed parts of the body or fragile materials.

0016Patent FR 2 676 368 discloses a neutralization composition consisting of an aqueous solution at pH between 7 and 10 of magnesium monoperoxyphthalate hexahydrate (MPPM) containing a surfactant quaternary ammonium salt substituted by alkyl radicals, but this composition turns out to be unstable at pH close to neutral, its preparation having to be done a few minutes before its use.

0017Hydrolysis or solvolysis by a toxic nucleophile Nu takes place according to the following reaction (I):<chemistry id="chem0002" num="0002"><img file="EP0906773A1_D0002.tif" /></chemistry>

0018For a good nucleophilic catalysis of hydrolysis or solvolysis, most of the formulations proposed for mild neutralization are based on the use of basic reagents with pKa greater than or equal to 9, such as various phenate, hydroxamate, oximate or even ions. alcoholate introduced in the form of alkaline salts. As a result, the pH of the formulations is on average 2 to 3 units above the physiological pH. Some of them even use non-aqueous solvents or co-solvents or ingredients (chelating agents, surfactants, macrocycles) whose intrinsic properties are by their nature intended to reinforce the basicity of the reagents. Even if the pH conditions described appear acceptable with regard to the priority objective sought, they therefore remain significant side effects, especially as the basic reagents used are not devoid of aggressiveness or even toxicity (phenate ions ). In addition, the use of organic solvents and complexing agents such as those described in US Patents 4,874,532, US 5,075,297, GB 2,239,598A complicates the formulations while constituting an additional source of harmfulness. The prohibitive cost of certain ingredients also appears to be incompatible with large-scale formulation.

0019The object of the present invention is to propose a simple but very effective formulation for the destruction under very mild conditions (pH = 7, non-aggressive reagents) of type G (sarin, soman) or type V chemical warfare agents ( VX), which is particularly suitable for neutralizing the skin or even the mucous membranes of living beings, and which is stable.

0020The subject of the invention is therefore a composition for decontamination by neutralization of media contaminated with organophosphorus toxic agents, in particular of type G or V, characterized in that it comprises an oxime / oximate buffer solution of pK_at between 7.5 and 8.6.

0021Preferably, the concentration of oxime is equal to the concentration of oximate.

0022It is based on the demonstration of the fact that the nucleophilic reactivity of the oximate function〉 C = NO^- vis-à-vis phosphorus-containing electrophilic centers is practically maximum as soon as a basicity of pKa of the order of 8.3 - 8.6 is reached. Beyond that, nucleophilia appears at best constant or even decreases at basicities of the order of pKa = 10. In terms of nucleophilic efficiency, to carry out the hydrolysis of organophosphorus compounds according to reaction (I), there is therefore a priori no advantage in using alkali salts of oximes (or phenols) of greater or equal pKa to 8.6, such as those conventionally used: acetophenone oxime (pKa = 11.80) or 2,3-butanedione oxime (pKa = 9.3).

0023This behavior is illustrated in FIGS. 1a and 1b, which are Brönsted graphs (log of the speed constant as a function of pKa) describing the results obtained by studying hydrolysis reactions catalyzed by various oximate reagents in aqueous solution. Figure concerns a toxic G, soman, and figure 1b BNPP. As can be seen, there is only a very small difference in reactivity (less than a factor of 2) between the pKa oximes of the order of 8, strongly ionized at physiological pH and the pKa oximes greater than 9 whose ionization occurs only at fairly basic pHs and for which the saturation effect is at its maximum.

0024FIGS. 1 a and 1 b also illustrate the fact that all the phenate anions have a clearly lower nucleophilic reactivity than that of the oximate reagents of the same basicity. Also, because of this extra-reactivity, the alkaline oximates of pKa of the order of 8 have, at physiological pH conditions, a nucleophilic potential greater than or equal to that of all the alkali oxime or phenol salts used. until now.

0025The nucleophilic behavior of the oximate anion is superior to that of the phenates, and increases to a maximum reached in the range of pH 7.5 to 8.6, which remains unchanged with an increase in the basicity of the medium. This behavior had already been observed with respect to a carbon-center electrophile (paranitrophenyl acetate or PNPA) by F. Terrier, P. MacCormack, E. Kizilian, JC. Hallé, P. Demerseman, F. Guir, C. Lion in J. Chem. Soc. Perkin Trans. 2, 1991, 153, but nothing suggested that it could also concern electrophiles with a phosphorus center.

0026As demonstrated by the tests described below in the examples, the action of simple buffering compositions of oximes (oxime / oximate) obtained by semi-neutralization with a strong base of a neutral oxime, makes it possible to destroy with efficiency and rapidity toxins like sarin, soman and even VX. The buffer solutions can use oximes in aqueous solution such as 2-pyridinium aldoxime (2-PAM) in the form of contrathion or methyl sulfate and pyridinium 2- [hydroxyimino) methyl] -1-methyl from pK_at^H2O = 7.75, or a carbaldoxime such as CEB 1574 from pK_at^H2O = 8.05 or alternatively a dioxime as described in patent FR 2 605 631.

EXAMPLE 1 DESTRUCTION OF SALIN AND SOMAN BY 2-PYRIDINIUM ALDOXIME OXIMATE

0027A 2-PAM buffer solution (oxime / oximate) is used for the destruction of sarin and soman under the following conditions:<ul id="ul0001" list-style="none" compact="compact"><li>temperature of 25 ° C,</li><li>total concentration of 2-PAM = 2x10^-2 mole / liter with equal concentrations for oxime (OxH) and oximate (Ox^-) (10^-2 mole / liter)</li><li>toxic agent concentration = 10^-3 mole / liter</li><li>ionic strength 0.16 mole / liter (NaCl), pH = 7.75.</li></ul>

0028The speed of the overall hydrolysis reaction is too high (half-reaction time less than 10 seconds) so that the destruction of toxins can be studied kinetically by following the appearance of F ions^- released by a potentiometric assay method using a fluorine indicating electrode.

0029The rapidity of the hydrolysis was confirmed by measuring the rate constants k of the reactions under experimental conditions making it possible to obtain lower rates. By fixing the pH via non-nucleophilic external buffers such as HEPES (N-2-hydroxyethylpiperazine-N'-ethane-2-sulfonic acid) at a value of 7.49, the concentration of ion oximate, forms active formulations, can be reduced, which slows down hydrolysis.

0030The concentrations of HEPES, sarin and 2-PAM are respectively 10^-1 mole / liter, 10^-3 mole / liter, 4 x 10^-3 mole / liter. By potentiometric monitoring of the concentrations of F-ions released, the rate constant k has been determined per unit of concentration (mole / l): 5.3 mol^-1 ls^-1 as well as the half-reaction time in HEPES: 170 seconds. The speed constant and therefore the half-reaction time corresponding to the pseudo-first order experimental conditions brought into play in the proposed formulation (large excess of oximate ion compared to sarin), were calculated and are respectively 5.3 x 10^-2 s^-1 and 13 s.

0031The concentrations of HEPES, soman and 2-PAM are respectively 10^-1 mole / liter, 10^-3 mole / liter, 4 x 10^-3 mole / liter. By potentiometric monitoring of the concentrations of F-ions released, the rate constant k has been determined per unit of concentration (mole / l): 1.5 mol^-1 1 sec^-1 as well as the half-reaction time in HEPES: 500 s. The speed constant and therefore the half-reaction time corresponding to the pseudo-first order experimental conditions brought into play in the proposed formulation (large excess of oximate ion with respect to soman), were calculated and are respectively 1.5 x 10^-2 s^-1 and 46 s.

0032The half-reaction times are very short and involve rapid destruction of the toxins.

EXAMPLE 2: DESTRUCTION OF SALIN AND SOMAN BY THE OXIMATE OF CEB 1574

0033A CEB 1574 buffer solution is used for the destruction of sarin and soman under the following conditions:<ul id="ul0002" list-style="none" compact="compact"><li>temperature of 25 ° C,</li><li>total CEB 1574 concentration = 2x10^-2 mole / liter with equal concentrations for oxime and oximate (10^-2 mole / liter)</li><li>Toxic agent concentration = 10^-3 mole / liter</li><li>Ionic strength 0.16 mole / liter (NaCI), pH = 8.05.</li></ul>

0034The speed of hydrolysis has also been confirmed here by measuring the rate constant k of the reactions under experimental conditions allowing lower rates to be obtained. By fixing the pH by means of non-nucleophilic external buffers such as TAPS or 3- [tris (hydroxymethyl) methylamino] -1-propane sulfonic acid at a value of 8.30, the concentration of oximate ion, the active form of formulations, can be reduced, which slows down hydrolysis.

0035The concentrations of TAPS, sarin and CEB 1574 are respectively 10^-1 mole / liter, 10^-3 mole / liter, 2 x 10^-3 mole / liter.

0036By potentiometric monitoring of the F-ion concentrations released, the rate constant k has been determined per concentration unit (mole / l): 8.2 mol^-1 ls^-1 as well as the half-reaction time in the TAPS: 100 s.

0037The speed constant and therefore the half-reaction time corresponding to the pseudo-first order experimental conditions brought into play in the proposed formulation (large excess of oximate ion compared to sarin), were calculated and are respectively 8.2 x 10^-2 s^-1 and 8.4 s.

0038The TAPS, soman and CEB 1574 concentrations are 10 respectively^-1 mole / liter, 10^-3 mole / liter, 2 x 10^-3 mole / liter.

0039By potentiometric monitoring of the concentrations of F-ions released, the speed constant k has been determined per unit of concentration (mole / l): 2 mol^-1 1 sec^-1 as well as the half-reaction time in the TAPS: 300 s.

0040The speed constant and therefore the half-reaction time corresponding to the pseudo-first order experimental conditions brought into play in the proposed formulation (large excess of oximate ion with respect to soman), have been calculated and are respectively 2 x 10^-2 s^-1 and 34.6 s.

0041The half-reaction times are very short and involve rapid destruction of the toxins.

EXAMPLE 3: DESTRUCTION OF VX BY 2-PYRIDINIUM ALDOXIME OXIMATE

0042For reasons of solubility, the tests were carried out in a 50-50 H2O-methanol medium by volume. In the absence of a leaving group allowing either spectrophotometric monitoring or fluorimetric monitoring of the reaction, the degradation of the VX according to the equation was studied by NMR³¹P.

0043A 2-PAM buffer solution (oxime / oximate) is used under the following conditions:<ul id="ul0003" list-style="none" compact="compact"><li>temperature of 25 ° C,</li><li>total concentration of 2-PAM = 0.5 mole / liter with equal concentrations for oxime and oximate (0.25 mole / liter)</li><li>VX concentration = 0.05 mole / liter</li><li>non-constant ionic strength, pH of the order of 8.</li></ul>

0044The reaction is rapid (half-reaction time of the order of 120 s) and the efficiency of the formulation is greater than that involving the oxidizing reagent MPPM under similar concentration and pH conditions. In addition, the use of MPPM requires an external buffer, for example KHCO₃/ KOH in equimolar mixture. The MPPM concentration is 1.4 mole / l for a VX concentration of 0.14 mole / l.

0045The major advantage of the proposed formulations is the rapid destruction of the toxins under mild conditions suitable for effective neutralization of physiological tissues, without generating products which in turn have significant toxicity.

0046Efficiency can be increased by increasing the concentration of oximate used as a buffer.

0047Any other pKa oxime between 7.5 and 8.5 can be substituted for 2-PAM or CEB 1574 without compromising efficiency.

0048Oximes of 2-propanal oxo (CH₃COCH = NOH), 2-oxo-methylsulfinyl-3 propanal (CH₃SOCH₂COCH = NOH), 2-methyl-3-propanal oxo (CH₃SCH₂COCH = NOH), 4-pyridiniumaldoxime in the form of pyridinium iodide 2- (hydroxyimino) methyl] -1-methyl, have pKa in aqueous solution in the range 7.5 to 8.6 and are equally effective .

0049The dioximes described in patent FR 2 605 631 such as toxogonin (1,3-bis [4- (hydroxyimino) methyl-1-pyridino] -2-oxopropane) in the form of dichloride, TMB 4 (1,3-bis [ 4- (hydroxyimino) methyl-1-pyridino] propane) in the form of dibromide. Dioxime known as R-665 (1,5-bis [2-hydroxyiminomethyl 1-methyl] -3-pyridino-1,5dioxopentane) is also suitable as iodide.

0050This possibility is important for a possible extension of the therapeutic use of reactivation of acetylcholinesterase. To this end, it is in fact advisable to choose oximes having both a good affinity for the enzyme and a good ability to cross the blood-brain barrier.

0051In addition, the kinetic measurements are simple because no organic co-solvent or additive promoting complexation is involved, and the cost of implementation is low.

0052The formulation according to the invention also allows the neutralization of other organophosphorus compounds, including parathion and DFP (diisopropylphosphorofluoridate).