EP0906773A1 - Decontaminating composition - Google Patents

Abstract

A decontaminating composition to neutralize toxic organo-phosphorus materials, especially type G and type V chemical warfare agents, comprises a buffered oxime/oximate solution at pKa = 7.5 to 8.6. A decontaminating composition to neutralize toxic organo-phosphorus materials, especially type G and type V chemical warfare agents, such as soman, sarin, tabun, VX or VG, as well as pesticides and insecticides such as paraoxon and parathion, comprises a buffered oxime/oximate solution at pKa = 7.5 to 8.6, the concentration of oxime and oximate preferably being the same.

Description

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

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

The organophosphonates have the following general formula:

BNPP (O, O-bis (4-nitrophenyl) phenylphosphonate) is an example, for which R '= 4-NO ₂ -ArO, R = Ar, L = 4-NO ₂ -ArO.

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

For sarin (O-isopropyl methylfluorophosphonate), R '= iPrO, R = CH ₃ , L = F

For soman (O-1,2,2-trimethylpropyl methylfluorophosphonate), R '= OCHCH ₃ (C (CH ₃ ) ₃ , R = CH ₃ , L = F

For VX (O-ethyl, S-2- (diisopropylaminoethyl) methyl thiolophosphonate, L = SCH ₂ CH ₂ N (iPr) ₂ , R = CH ₃ , R '= EtO

For VG (O-ethyl, S-2- (diisoethylylaminoethyl) ethoxy thiolophosphonate, L = SCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ , R = R '= EtO

For tabun (dimethylamino ethoxy cyanophosphonate), L = CN, R = EtO, R '= (CH3) ₂ N

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

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

Very basic formulations were used: sodium carbonate, soda aqueous or alcoholic, alcoholic potash to destroy compounds organophosphates toxic to phosphonic acids. A formulation developed by the American army, DS2, has the following composition: 70% diethylenetriamine (DETA), 28% monomethyl ether of ethylene glycol and 2% sodium hydroxide. These formulations are very aggressive. Other less aggressive formulations have proven effective: hydroxamic acids, phenols and polyphenols, hydrates aldehyde, amines including monoethanolamine. Other authors have been interested in oximes, for example 2-PAM in the form of pyridinium chloride 2- [hydroxyimino) methyl] -1-methyl in the article by C.D. Bedford, M. Miura, J.C. Bottaro, R.A. Howd and H.W. 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 neutralization of organophosphate war toxicants.

Formulations based on the use of highly oxidizing media have also been developed: chloramine B, chlorine, bleach, Fichlor (sodium N, N'-dichloroisocyanurate), curox or oxone (triple potassium permonosulfate salt), water oxygenated, tert-butyl hydroperoxide, perborates and aryl peracids and aliphatics in general. These formulations are very suitable for operations rapid and brutal destruction of toxic substances. Very aggressive, these compositions do not can in no case be used for gentle neutralization actions on humans or animals or even on certain materials for the purpose of reuse.

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

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

Hydrolysis or solvolysis by a toxic Nucleucleile takes place according to the following reaction (I):

For a good nucleophilic catalysis of hydrolysis or solvolysis, the 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 ions phenate, hydroxamate, oximate or even alcoholate introduced in the form of salts alkaline. As a result, the pH of the formulations is on average 2 to 3 units above physiological pH. Some of them even use solvents or non-aqueous cosolvents or ingredients (chelating agents, surfactants, macrocycles) whose intrinsic properties are by their nature intended to strengthen the basicity of reagents. Even if the pH conditions described appear acceptable at with regard to the priority objective sought, they therefore carry side effects not negligible 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 formulations while constituting a source additional harmfulness. The prohibitive cost of certain ingredients also appears hardly compatible with a large-scale formulation.

The object of the present invention is to propose a simple but very effective for destruction under very mild conditions (pH = 7, reagents not aggressive) type G (sarin, soman) or type V (VX) chemical warfare agents, particularly suitable for neutralizing the skin or even mucous membranes of living things, and that is stable.

The 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 _a between 7.5 and 8.6.

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

It is based on the demonstration of the fact that the nucleophilic reactivity of the oximate function C = NO ^- with respect to phosphorus-containing electrophilic centers is practically maximum as soon as a basicity of pKa of the order of 8 is reached. , 3 - 8.6. Beyond that, nucleophilia appears at best constant or even decreases to 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 alkaline salts of oximes (or phenols) of pKa greater than or equal to 8.6, such as those conventionally used: acetophenone oxime (pKa = 11.80) or 2,3-butanedione oxime (pKa = 9.3).

This behavior is illustrated in Figures la and 1b, which are graphs of Brönsted (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 la concerns a toxic G, soman, and Figure 1b the BNPP. As we can see, 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 pKa oximes greater than 9, the ionization of which only occurs fairly basic pH and for which the saturation effect is at its maximum.

Figures la and 1b also illustrate the fact that all phenate anions have a significantly lower nucleophilic reactivity than that of the reagents oximates of the same basicity. Also, due to this extra-reactivity, the oximates alkalines of pKa of the order of 8 have, at physiological pH conditions, a potential nucleophile greater than or equal to that of all alkali metal oxime or phenol salts used so far.

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

As demonstrated by the tests described below in the examples, the action of simple oxime buffer compositions (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 methyl contrathion or sulphate and pyridinium 2- [hydroxyimino) methyl] -1-methyl from pK _to ^H2O = 7.75, or a carbaldoxime such as CEB 1574 of pK _a ^H2O = 8.05 or alternatively a dioxime as described in patent FR 2 605 631.

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

température de 25 °C,

concentration totale en 2-PAM = 2x10^-2 mole/litre avec des concentrations égales pour l'oxime(OxH) et l'oximate (Ox^-) (10^-2 mole/litre)

concentration en agent toxique = 10^-3 mole/litre

force ionique 0,16 mole/litre (NaCI), pH = 7,75.

A 2-PAM buffer solution (oxime / oximate) is used for the destruction of sarin and soman under the following conditions:

temperature of 25 ° C,

total concentration in 2-PAM = 2x10 ^-2 mole / liter with equal concentrations for oxime (OxH) and oximate (Ox ^- ) (10 ^-2 mole / liter)

toxic agent concentration = 10 ^-3 mole / liter

ionic strength 0.16 mole / liter (NaCl), pH = 7.75.

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

The rapidity of hydrolysis was confirmed by measuring the rate constants k of reactions under experimental conditions allowing to get lower speeds. By setting the pH through buffers non-nucleophilic exteriors 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 hydrolysis.

The 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 experimental pseudo-first order 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.

The 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 F-ion concentrations released, the rate constant k has been determined per unit of concentration (mole / l): 1.5 mol ^-1 1 s ^{-1 as} well as the half-reaction time in HEPES : 500 s. The speed constant and therefore the half-reaction time corresponding to the experimental pseudo-first order 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.

The half-reaction times are very short and involve destruction fast toxic.

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

température de 25 °C,

concentration totale en CEB 1574 = 2x10^-2 mole/litre avec des concentrations égales pour l'oxime et l'oximate (10^-2 mole/litre)

Concentration en agent toxique = 10^-3 mole/litre

Force ionique 0,16 mole/litre (NaCI), pH = 8,05.

A CEB 1574 buffer solution is used for the destruction of sarin and soman under the following conditions:

temperature of 25 ° C,

total concentration of CEB 1574 = 2x10 ^-2 mole / liter with equal concentrations for oxime and oximate (10 ^-2 mole / liter)

Toxic agent concentration = 10 ^-3 mole / liter

Ionic strength 0.16 mole / liter (NaCI), pH = 8.05.

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

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

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

The speed constant and therefore the half-reaction time corresponding to the experimental pseudo-first order 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.

The concentrations of TAPS, soman and CEB 1574 are respectively 10 ^-1 mole / liter, 10 ^-3 mole / liter, 2 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): 2 mol ^-1 1 s ^{-1 as} well as the half-reaction time in the TAPS: 300 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), have been calculated and are respectively 2 x 10 ^{- 2} s ^- 1 and 34.6 s.

The half-reaction times are very short and involve destruction fast toxic.

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

For 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 ³¹ P NMR.

température de 25 °C,

concentration totale en 2-PAM = 0,5 mole/litre avec des concentrations égales pour l'oxime et l'oximate ( 0,25 mole/litre)

concentration en VX = 0,05 mole/litre

force ionique non constante, pH de l'ordre de 8.

A 2-PAM buffer solution (oxime / oximate) is used under the following conditions:

temperature of 25 ° C,

total concentration of 2-PAM = 0.5 mole / liter with equal concentrations for oxime and oximate (0.25 mole / liter)

VX concentration = 0.05 mole / liter

non-constant ionic strength, pH of the order of 8.

The 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 KHCO ₃ / KOH in equimolar mixture. The MPPM concentration is 1.4 mole / l for a VX concentration of 0.14 mole / l.

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

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

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

The oximes of oxo-2 propanal (CH ₃ COCH = NOH), of oxo-2methylsulfinyl-3 propanal (CH ₃ SOCH ₂ COCH = NOH), of oxo-2methylthio-3 propanal (CH ₃ SCH ₂ COCH = 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 .

The 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) also suitable as iodide.

This possibility is important for a possible extension of the use in therapeutic reactivation of acetylcholinesterase. For this purpose, it is indeed appropriate to choose oximes having both a good affinity for the enzyme and a good ability to cross the blood-brain barrier.

In addition, the kinetic measurements are simple because no organic co-solvent or additive promoting complexation is not involved, and the cost of implementation is low.

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

Claims (12)

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 _a between 7.5 and 8.6. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim 1, characterized in that the oxime concentration is equal to the oximate concentration. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim 1 or 2, characterized in that it comprises a buffer solution of 2-pyridinium aldoxime ,. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim 1 or 2, characterized in that it comprises a buffer solution of CEB 1574. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim 1 or 2, characterized in that it comprises a buffer solution of the oxo-2 propanal oxime. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim 1 or 2, characterized in that it comprises a buffer solution of 2-oxo-methylsulfinyl-3 propanal oxime. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim 1 or 2, characterized in that it comprises a buffer solution of the oxime of 2-oxo-methyl-3-propanal. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim 1 or 2, characterized in that it comprises a buffer solution of 4-pyridinium aldoxime. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim 1 or 2, characterized in that it comprises a buffer solution of toxogonin. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim lou 2, characterized in that it comprises a TMB buffer solution 4. Composition of decontamination by neutralization of contaminated media by organophosphorus toxic agents, in particular of type G or V, according to the claim 1 or 2, characterized in that it comprises a buffer solution of R-665. Application of the composition according to one of claims 1 to 11 to the decontamination of the skin or even the mucous membranes of living beings.

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