EP4114910B1 - Specific organophosphorus compounds as non-neurotoxic anti-wear agents - Google Patents

Description

Technical area

The present invention relates to the technical field of anti-wear additives used in oils, such as oils for lubricating aircraft or aero-derivative turbines or hydraulic oils.

Technology background

Aircraft or aeroderivative turbine engines use synthetic lubricants generally comprising an ester base and a variety of anti-wear additives from the organophosphate family, such as triarylphosphates. The most commercially used anti-wear additive is tricresyl phosphate (TCP), which has singular anti-wear properties that can be considered unique to date. Its triarylphosphate analogues are also valuable anti-wear additives.

Leaks of lubricants, in particular those containing tricresylphosphate or one of its tri-arylphosphate analogues, into the air of aircraft cabins can originate from worn or defective seals, or even under normal conditions of use by passage lubricants in the air for cabin pressurization. These repeated leaks are explained ( Michaelis S et al. Public Health Panorama 2017, 3, 2, p.198-211 ) as being due to pressure variations between the bearing chamber and the air circuit exerted by normal operating conditions (increase in engine power, take-off). In certain circumstances, the leak can become very important, generally following the breakage of a bearing in the turbine, this leading to a smoke event, or white fog visible in the cabin.

Aerotoxic syndrome is a medical condition combining physical and neurological symptoms, caused by the short and long term effects of exposure to aircraft cabin air contaminated with hydraulic oils or engine oils or any other organic pollutant present in the form of gas and/or aerosols. The reported symptoms are generally non-specific, and cabin air quality studies indicate contaminant levels that are below exposure limits and not dangerous to human health, the difficulty being to measure continuously and in service of oil fumes, by definition non-gaseous, conveyed in the air, settling and concentrating, episodically, at different locations in the aircraft ( Kasper Solbu et al. J. About. Monit. 2011, 13, 1393 ).

Symptoms similar to those of aerotoxic syndrome can also be observed in ground environments in the presence of aero-derivative turbines, for example at offshore platforms. Aero-derivative turbines operate identically to that of aircraft turbines and use lubricants of similar composition, particularly in terms of anti-wear agents.

However, a number of studies ( Michaelis, S. et al. Public Health Panorama 2017, 3, 2, p.198-211 ) have demonstrated a relative causal relationship between acute and/or chronic exposure to substances contaminating the air of aircraft cabins and neurological, neurobehavioral and respiratory symptoms.

Conventional organophosphate antiwear additives, such as tricresylphosphate (TCP), especially its isomer tri-ortho-cresylphosphate (ToCP), are known to exhibit a potent neurotoxic effect ( Craig P et al. Journal of Toxicology and Environmental Health Part B: Critical Reviews 1999, 2, 4, p.281-300 ). Beyond the generic toxicity associated with organophosphates widely used in various fields, in particular as insecticides and pesticides, one of the specific and recognized reasons for this neurotoxic effect is the rapid in vivo conversion of tricresylphosphate isomers comprising at least one substitution in ortho to a metabolite called saligenin which is a potent inhibitor of cholinesterases. ToCP poisoning leads to a pathology called organophosphate-induced delayed neuropathy (OPIDN) whose mechanism has been widely studied. Additionally, TCP is also known to be reprotoxic.

Oils comprising, as anti-wear additive, TCP not comprising an ortho isomer have been developed. Nevertheless, despite the absence of ToCP in TCP, the level of cholinesterase inhibition in the serum of TCP-exposed rats is not zero and, although weak, it is persistent ( Mackerer CR et al. J. Toxicol. Approx. Health Part A 1999 57(5):293-328 ). Similarly, older work demonstrates problems of demyelination of the spinal cord following exposure to TCP present in its meta and para forms ( WN Aldridge, Biochemical Journal 1954 56, 185-189 ).

Very recent studies show that tricresylphosphate and its triarylphosphate analogues also act on other biological targets, particularly at the cellular level ( A. V. Terry, Pharmacology and Therapeutics 2012, 134, p.355-365 ; Al Salem et al. Chemosphere 2019, 237, 124519 ).

All these studies and this long history constitute a body of evidence and elements that make tricresylphosphate and its tri-arylphosphate analogues additives of particular concern.

In order to increase the level of safety of hydraulic oils and oils used in aircraft and aeroderivative turbines, it thus seems necessary to develop alternative anti-wear additives to tricresylphosphate and its tri-arylphosphate analogues.

The identification of alternative anti-wear additives to tricresylphosphate and its tri-arylphosphate analogues is an identified problem, even if the need to get rid of tricresylphosphate and its tri-arylphosphate analogues is not unanimous.

To the Applicant's knowledge, no study has enabled the identification of alternative anti-wear additives exhibiting both a satisfactory anti-wear effect and demonstrated non-neurotoxicity. By way of example, recent studies relating to the characterization of the potential neurotoxicity of new organophosphates developed and marketed as next-generation flame retardants are for the vast majority of a level of danger claimed to be equivalent to that of usual substances. like the TCP ( Zhang et al. Neurotoxicology and Teratology 2019, 73, p.54-66 , Ryan et al. Neurotoxicology 2016, 53, 271-281 , Sirenko et al. Toxicologist. Science. 2019, 167, p.58-76 ). The question of the neurotoxicity of organophosphorus compounds remains to this day unresolved and unsolved.

Various solutions have been developed in the prior art.

The patent application US2016/0002565 discloses a tricresylphosphate-free turbine oil that includes at least one base oil, at least one alkylpolyglycoside, and a phenolic derivative such as 3,5-di-tert-butyl-hydroxytoluene. The replacement of tricresylphosphate by the phenolic derivative contributes to the prevention of the aerotoxic syndrome when this oil is used in aircraft turbines. Nevertheless, the use of such an oil in aircraft turbines does not seem to be able to provide the same efficiency as that of the oil containing tricresylphosphate which it is supposed to replace, on the one hand because the formulation described does not includes no agent having an anti-wear effect to replace that of TCP, and on the other hand because the formulation includes alkylpolyglycosides which are heat sensitive.

However, to date, only phosphorus compounds have demonstrated sufficient effectiveness as anti-wear agents in aircraft turbine or aero-derivative oils. Without wishing to be bound by any theory, this may be linked to the fact that phosphorus allows the formation of a protective layer, commonly called tribofilm, even at the high temperatures involved in the intended applications.

The request for patent WO2010/149690 describes the reduced effect on butyrylcholinesterase, compared with TCP in particular, of specific triarylphosphates in which the phenyl groups are substituted by one to three isopropyl or tert-butyl groups. These inhibition results suggest a possible reduction in the neurotoxicity associated with these compounds compared to that observed for TCP. Nevertheless, the simple demonstration of a limited effect on a single cholinesterase does not seem sufficient to guarantee a level of safety sufficient for aviation expectations.

The following documents are also known from the state of the art.

The document US 2019/0277339 describes a zinc-free bearing oil composition for use in the metal industry. This oil composition may comprise, by weight, relative to its total weight, from 0.05% to 2% of a first phosphorus-based ash-free additive.

The document WO 2016/032246 discloses a lubricating composition exhibiting excellent thermo-oxidative stability and color stability. The composition may include a secondary phosphorus antioxidant.

The document US 3,983,046 discloses a composition having good fire resistance and adequate viscosity characteristics. The composition comprises a combination of at least two phosphates, the second phosphate of which may comprise an alkyl diaryl phosphate and at least a combination of two polyalkylene glycol (ester base).

There is thus a need in the state of the art to develop alternative anti-wear additives to tricresylphosphate and its tri-arylphosphate analogues, even if the need to do away with tricresylphosphate and its tri-arylphosphate analogues does not not unanimous.

In particular, there is a need in the state of the art to develop alternative anti-wear additives having both a satisfactory anti-wear effect and making it possible to increase the level of safety in aviation and other aero-derivative applications.

Disclosure of Invention

In this context, the Applicant has demonstrated that specific organophosphorus compounds, some of which are known as flame retardants, have both anti-wear and satisfactory, or even improved, thermal stability properties and a greatly reduced neurotoxicity compared to that of triarylphosphate anti-wear derivatives, such as TCP, or even zero, and can therefore be advantageously used in order to reduce the neurotoxicity of oils and in particular of turbine oils.

They can also advantageously be used for the prophylaxis of the aerotoxic syndrome, in particular in the event of a smoke event.

Summary of the invention

dans laquelle A est un groupe alkyle linéaire ou ramifié, éventuellement substitué, comprenant de 10 à 32 atomes de carbone, et chacun de Ar₁ et Ar₂ est indépendamment un groupe aryle éventuellement substitué en tant qu'agent anti-usure dans une huile, de préférence une huile de turbine, pour réduire et/ou prévenir la neurotoxicité de ladite huile.Thus, the present invention relates to the use of at least one compound of formula

wherein A is an optionally substituted linear or branched alkyl group comprising 10 to 32 carbon atoms, and each of Ar ₁ and Ar ₂ is independently an optionally substituted aryl group as an anti-wear agent in an oil, preferably a turbine oil, to reduce and/or prevent the neurotoxicity of said oil.

The compounds of formula (I) have interesting anti-wear properties, which can be comparable to those of tricresylphosphate or its triarylphosphate analogues. They also present a very low level of risk, if any, in terms of neurotoxicity and thus reduce the neurotocixity of the oil in which they are integrated. Indeed, as shown by the experimental tests described below, the Applicant has discovered, unexpectedly, that the specific compounds of formula (I) above are non-toxic in terms of action on cholinesterases, non-neurotoxic and not reprotoxic.

The polyphosphorus compounds of formula (I) can thus be used to obtain an oil that is non-neurotoxic or has reduced neurotoxicity.

dans laquelle A est un groupe alkyle linéaire ou ramifié, éventuellement substitué, comprenant de 10 à 32 atomes de carbone, et chacun de Ar₁ et Ar₂ est indépendamment un groupe aryle éventuellement substitué en tant qu'agent anti-usure dans une huile, de préférence une huile de turbine, pour la prophylaxie du syndrome aérotoxique, de préférence en cas d'événement de fumée.The invention also relates to the use of an oil comprising at least one compound of formula (I)

wherein A is an optionally substituted linear or branched alkyl group comprising 10 to 32 carbon atoms, and each of Ar ₁ and Ar ₂ is independently an optionally substituted aryl group as an anti-wear agent in an oil, preferably turbine oil, for the prophylaxis of aerotoxic syndrome, preferably in the event of a smoke event.

Of course, the different characteristics, variants and embodiments of the invention can be associated with each other in various combinations insofar as they are not incompatible or exclusive of each other.

Brief description of figures

[ Fig.1 ] presents molecules resulting from the work of modeling by spherical harmonics: the compounds in the upper row belong to cluster 1, the compounds in the lower row belong to cluster 3 or to cluster 4.

detailed description

dans laquelle A est un groupe alkyle linéaire ou ramifié comprenant de 10 à 32 atomes de carbone, et chacun de Ar₁ et Ar₂ est indépendamment un groupe aryle en tant qu'agent anti-usure dans une huile pour réduire et/ou prévenir la neurotoxicité de ladite huile, de préférence une huile de turbine.A first object of the invention is the use of at least one compound of formula (I)

wherein A is a linear or branched alkyl group comprising 10 to 32 carbon atoms, and each of Ar ₁ and Ar ₂ is independently an aryl group as an anti-wear agent in an oil to reduce and/or prevent neurotoxicity of said oil, preferably a turbine oil.

By "reducing" the neurotoxicity of an oil, it is meant that the compound(s) of formula (I) according to the invention are suitable and/or configured to reduce the neurotoxicity of a oil in which they are included, namely by their presence (generally in the majority), in particular compared to other conventional anti-wear compounds which are generally neurotoxic, the compound(s) of formula (I) make it possible to lower/reduce the neurotoxicity of an oil and to obtain a non-neurotoxic oil or at least one with reduced toxicity.

By "preventing" the neurotoxicity of an oil, it is meant that the compound(s) of formula (I) make it possible to prevent the oil from being considered neurotoxic and/or to prevent the appearance of neurotoxic symptoms in a mammal, such as a human being or an animal which would be in contact with said oil; these neurotoxic symptoms can, for example, affect the central nervous system (CNS) and present the following effects: headaches, loss of appetite, drowsiness, mood and personality disorders, cognitive impairment (disorders learning and concentration), or reach the peripheral nervous system (PNS) and present the following effects: motor impairments such as weakness, tremors, incoordination, seizures or sensory impairments such as reduced hearing, color vision, tinnitus , loss of balance; these effects may or may not be reversible depending on the degree of acute or chronic exposure of the mammal.

"Neurotoxicity" means the ability of a substance or compound to induce harmful effects in the nervous system of a mammal, such as a human being. The nervous system is divided into the central nervous system (CNS) and peripheral nervous system (PNS). The CNS is located in the cranium and spine. It includes the brain, brainstem and spinal cord. Its role is to receive, record and interpret the signals that reach it from the periphery. It then organizes the response to be sent. The PNS is made up of nerve ganglia, sensory nerves responsible for transmitting sensations to the brain, such as pain, and motor nerves responsible for movement by stimulating muscles. They circulate information between the CNS and the organs. Thus, according to the invention, a neurotoxic substance or compound usually acts by disturbing or paralyzing nerve impulses, by acting in particular on the synaptic transmitters or receptors or on the enzymes which act on these synaptic transmitters or receptors, such as cholinesterases. In biochemistry, a cholinesterase is an enzyme which catalyzes the hydrolysis reaction of a choline ester (acetylcholine, butyrylcholine) into choline and acetic acid. In physiology, this reaction is necessary to allow cholinergic receptors to return to their resting state after activation.

In particular, "neurotoxicity" is distinguished from the broader and more comprehensive notion of "toxicity".

• la reprotoxicité qui correspond à l'altération de la fertilité ou altération du mammifère à naître),
• la mutagénicité qui est la propension d'une substance à provoquer des mutations génétiques, -
• la toxicité aigüe est la toxicité induite, dans un court laps de temps (ex 24 h), par l'administration d'une dose unique (éventuellement massive) ou de plusieurs doses acquises dans ce laps de temps d'un produit ou mélange toxique (naturel ou chimique),
• l'écotoxicité qui est l'ensemble des déséquilibres ou de nuisances provoqués par une activité industrielle ou la mise en place d'un corps, d'un produit étranger dans un environnement naturel ;
• la neurotoxicité telle que définit ci-dessus.

Indeed, “toxicity” is a fairly broad concept which includes in particular:

• reprotoxicity which corresponds to the alteration of fertility or alteration of the unborn mammal),
• mutagenicity which is the propensity of a substance to cause genetic mutations, -
• acute toxicity is the toxicity induced, in a short period of time (eg 24 hours), by the administration of a single dose (possibly massive) or of several doses acquired in this period of time of a toxic product or mixture (natural or chemical),
• ecotoxicity, which is all the imbalances or nuisances caused by an industrial activity or the placement of a body or a foreign product in a natural environment;
• neurotoxicity as defined above.

However, as the experimental tests demonstrate below, a compound may, for example, not be reprotoxic, show no sign of acute toxicity, or even show no CMR character (carcinogenic, mutagenic, or toxic for reproduction) on human health and yet be highly neurotoxic (or vice versa).

In the present application, the Applicant has demonstrated that, unexpectedly and surprisingly, certain specific phosphorus compounds of formula (I) above and in particular those comprising a diphenylphosphate group exhibited both excellent anti-wear properties suitable particularly in the demanding field of aeronautics, while being weakly or not at all neurotoxic. This last quality thus makes it possible to reduce and/or prevent the neurotoxicity of an oil in which they are integrated,

These tests also show that the compounds of formula (I) selected by the Applicant are not arbitrary and have a different technical effect (namely they make it possible to reduce/prevent the neurotoxicity of an oil) compared to other compounds anti -wear, especially compared to other anti-wear compounds also phosphorus.

For the present invention, the Applicant has demonstrated the non-neurotoxicity of the specific compounds of formula (I) both by in vitro experimental tests relating to cholinesterases and by modeling tests (3D molecular modeling by spherical harmonics and modeling by QSAR for neurotoxicity and for reprotoxicity).

Preferably, the 50% inhibitory concentration of said at least compound of formula (I) on the biological activity of an acetylcholinesterase (AChE) enzyme, called IC ₅₀ hAChE is greater than or equal to 15 mg/L and the activity on a butyrylcholinesterase enzyme, called IC ₅₀ eqBuChE is greater than or equal to 15 mg/L, preferably equal to or greater than 20 mg/L, in particular equal to or greater than 25 mg/L and typically equal to or greater than 30 mg/L.

According to the invention, a value greater than or equal to 15 mg/L for IC ₅₀ hAChE includes the following values and all the intervals between these values: 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30 ; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40.

Also, according to the invention, a value greater than or equal to 15 mg/L for IC ₅₀ eqBuChE includes the following values and all the intervals between these values: 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30 ; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40, ; 45; 50; 55; 60; 65; 70; 75; 80; 85; 90; 95; 100; 105; 110; 115; 120; 125; 130; 135; 140; 145; 150; 155; 160.

Advantageously, the compound(s) of formula (I) belong to Cluster 3 or Cluster 4, in particular to Cluster 4 determined according to molecular modeling by spherical harmonics as described in the publication "Benchmarking of HPCC: A novel 3D molecular representation combining shape and pharmacophoric descriptors for efficient molecular similarity assessments", Karaboga et al. 2013 Journal of Molecular Graphics and Modeling 41; 20-30 .

According to another characteristic of the invention, the compound(s) of formula (I) exhibit a percentage value by QSAR (quantitative structure-activity relationship) modeling (from the English “Quantitative Structure Activity Relationship”) of less than or equal to 0 70 for the neurotoxicity measurement and less than or equal to 1.5, preferably less than or equal to 1.15 and typically less than or equal to 0.7 for the reprotoxicity measurement.

Thus, the compounds of formula (I) according to the invention present a level of risk in terms of neurotoxicity which is very low and which generally corresponds to a score of 0 or to a score of 1 (very low or non-existent risk of neurotoxicity) , preferably a score of 0.

The level of risk as defined above and also illustrated in the experimental part below is very exhaustive and encompasses all the data obtained via the various tests on neurotocixity described above and therefore includes both in-house tests vitro than 3D modeling trials.

• le test in vitro d'inhibition de l'acétylcholinestérase (AChE),
• le test in vitro d'inhibition de la butyrylcholinestérase (BuChE),
• le type de cluster tenant compte de la forme et de la fonctionnalité des harmoniques sphériques (modélisation 3D),
• la prédiction semi-empirique de la neurotoxicité, et
• la prédiction semi-empirique de la reprotoxicité.

In particular, the level of risk takes into account all of the following tests:

• the in vitro acetylcholinesterase (AChE) inhibition test,
• the in vitro butyrylcholinesterase (BuChE) inhibition test,
• the type of cluster taking into account the shape and functionality of the spherical harmonics (3D modeling),
• semi-empirical prediction of neurotoxicity, and
• semi-empirical prediction of reprotoxicity.

By “oil”, is meant in the present invention any organic substance, in particular any hydraulic or turbine oil, capable of creating pollution in the form of gas and/or aerosol in the cabin. In some embodiments, the oil is selected from the group consisting of aircraft or aero-derivative turbine oils, helicopter transmission oils, and weapons fluids. Preferably, in the present invention, the oil is an oil for aircraft or aeroderivative turbines.

By “alkyl group” of the group “A”, is meant a linear or branched saturated hydrocarbon group. The alkyl groups comprise from 10 to 32 carbon atoms (C ₁₀ to C ₃₂ ). According to a first characteristic of the invention, the alkyl groups comprise from 10 to 20 carbon atoms (C ₁₀ to C ₂₀ ), preferably from 10 to 15 carbon atoms and in particular from 10 to 12 carbon atoms. According to another characteristic of the invention, the alkyl groups comprise from 20 to 32 carbon atoms, preferably from 15 to 32 carbon atoms and typically from 16 to 32 carbon atoms. Among the examples of alkyl groups according to the invention, mention may in particular be made of decyl, isodecyl, dodecyl, isododecyl, octadecyl, 2-butyloctyl, 2-hexyldecyl, 2-octyldodedyle and 2-tetradecyloctadecyl groups.

An alkyl group according to the invention can be optionally substituted. By “substituted alkyl group” according to the invention, is meant a linear or branched saturated hydrocarbon chain, comprising from 10 to 32 carbon atoms (C ₁₀ to C ₃₂ ) substituted at one or more of its atoms, by at minus one substituent selected from the group consisting of C ₁ to C ₁₈ alkyl groups, the hydroxyl group OH, an NH ₂ or NHR primary amine group with R alkyl or aryl group, an O-phosphate group such as the O- diphenylphosphate, and halogen atoms.

The substitution of the alkyl or aryl groups in the compounds according to the present invention by each type of substituent makes it possible to confer on the compound desired properties. For example, substitution with halogen atoms could allow an improvement in the extreme pressure and/or anti-wear effects of the compounds.

Preferably, the "alkyl group" is unsubstituted.

The term “aryl group” denotes a monocyclic or polycyclic aromatic carbon group, optionally interrupted by one or more heteroatoms which can in particular be chosen from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Each aromatic or polyaromatic ring comprises 5 to 14 atoms. Each ring may be optionally substituted, at one or more of its atoms, by at least one substituent chosen from the group consisting of C ₁ to C ₁₈ alkyl groups, preferably a linear or branched C ₁ alkyl group to C ₁₀ or a C ₁ to C ₁₈ alkylene group comprising a perfluorinated group, an OH hydroxyl group, an NH ₂ primary or NHR secondary amine group with R alkyl or aryl group, an O-phosphate group such as the O- diphenylphosphate OP(=O)(OPh) ₂ , an ester group and/or halogen atoms.

In general, the aromatic or polyaromatic ring, as described above, is not substituted or is substituted only by one or more linear or branched C ₁ to C ₁₈ alkyl groups, preferably C ₁ to C ₁₀ , in particular from C ₁ to C ₁₀ , typically from C ₁ to C _3. When the aryl group is a polycyclic group in which at least two rings are connected by at least one covalent bond between two distinct atoms each belonging to one of the rings , the covalent bond between the two rings can be interrupted by at least one alkyl group such as a C(CH ₃ ) ₂ group, a carbonyl group or a heteroatom or a heteroatomic group such as an oxygen atom, a sulfur atom, an amine group NH or NR or a sulfite group OS(= O)O.

Among the examples of monocyclic aryl groups, mention may in particular be made of the phenyl group.

The term “halogen atom” denotes an atom chosen from the group consisting of chlorine, bromine, fluorine and iodine.

In one embodiment, "A" is selected from the group consisting of an isodecyl group, a dodecyl group, in particular an n-dodecyl group, a tridecyl group, in particular an iso-tridecyl group, a hexadecyl group, an octadecyl group, 2-butyl 1-octyl group, 2-hexyl 1-decyl group, 2-octyl 1-dodecyl group and 2-tetradecyl 1-octadecyl group.

In a particular embodiment, "A" is chosen from an isodecyl group, a dodecyl group, in particular an n-dodecyl group, and a 2-octyl 1-dodecyl group.

"A" is preferably an isodecyl group.

In one embodiment, "Ar ₁ and Ar ₂ " are independently unsubstituted phenyl or substituted phenyl, preferably substituted with at least one ester substituent or an alkyl substituent such as a methyl group, an ethyl group, a isopropyl or a tert-butyl group. Preferably, Ar ₁ and Ar ₂ are two unsubstituted phenyls. In an alternative embodiment, Ar ₁ and Ar ₂ are two substituted phenyls, preferably with an alkyl substituent such as a methyl group.

In one embodiment, the compound of formula (I) is selected from the group consisting of isodecyldiphenylphosphate, n-dodecyldiphenylphosphate, iso-tridecyldiphenylphosphate, hexadecyldiphenylphosphate, octadecyldiphenylphosphate, 2-butyl 1-octyldiphenylphosphate , 2-hexyl 1-decyldiphenylphosphate, 2-octyl 1-dodecyldiphenylphosphate, 2-tetradecyl 1-octadecyldiphenylphosphate, and any mixture thereof.

In one embodiment, the compound of formula (I) is selected from the group consisting of isodecyldiphenylphosphate, n-dodecyldiphenylphosphate, 2-octyl 1-dodecyldiphenylphosphate and any of their mixtures.

In one embodiment, the compound of formula (I) is isodecyldiphenylphosphate. It may be present in the oil as an anti-wear agent mixed with at least one other compound of formula (I). Alternatively, isodecyldiphenylphosphate is the only compound of formula (I) included in the oil. In one embodiment, isodecyldiphenylphosphate is the only anti-wear agent present in the oil.

The oil in which the compound of formula (I) is used as anti-wear agent preferably does not comprise tricresylphosphate. In one embodiment, it comprises substantially no tricresylphosphate.

In another embodiment, the oil contains as sole anti-wear agent(s) the compound(s) of formula (I).

In general, the anti-wear agent according to the invention of general formula (I) represents, by mass, relative to the total mass of the anti-wear agents present in the oil, from 50% to 100%, preferably from 80% to 100%, and in particular from 90% to 100% and typically 100%.

According to the invention, “50% to 100%” means the following values or any interval between these values: 50; 55; 60; 65; 70; 75; 80; 85; 90; 95; 100.

In certain embodiments, the oil in which the compound of formula (I) is used according to the invention substantially does not comprise, preferably does not comprise, any triarylphosphate anti-wear additive.

In certain embodiments, the oil in which the compound of formula (I) is used according to the invention substantially does not comprise, preferably does not comprise, any organophosphate anti-wear additive other than the compound or compounds of formula (I).

In certain embodiments, the oil in which the compound of formula (I) is used according to the invention substantially does not comprise, preferably does not comprise, any anti-wear additive other than the compound(s) of formula ( I).

The oil is preferably an oil for aircraft or aeroderivative turbines.

The use of at least one compound of formula (I) as an anti-wear agent in order to reduce and/or prevent and/or prevent the neurotoxicity of an oil is particularly advantageous in situations where individuals are susceptible to be exposed to oil. Indeed, the compounds of formula (I) have, as demonstrated in the present invention, a very low level of risk, or even zero, in terms of toxicity, in particular in terms of neurotoxicity, or even reprotoxicity, and are therefore good alternatives to conventional anti-wear agents, such as tricresylphosphate and its triarylphosphate analogues which are known to be neurotoxic and reprotoxic.

Also, in another embodiment, the use of at least one derivative of formula (I) as an anti-wear agent in an oil is for the prophylaxis of the aerotoxic syndrome, in particular in the event of a smoke event.

In a particular embodiment, the use of at least one derivative of formula (I) as an anti-wear agent in an oil for the prophylaxis of the aerotoxic syndrome in the event of a smoke event. For example, the use of at least one derivative of formula (I) as an anti-wear agent in an oil can be for lubricating at least one aircraft or aero-derivative turbine, for the prophylaxis of aerotoxic syndrome, in particular in smoke event case.

Preferably, the 50% inhibitory concentration of said at least compound of formula (I) on the biological activity of an acetylcholinesterase (AChE) enzyme, called IC ₅₀ hAChE is greater than or equal to 15 mg/L and the activity on a butyrylcholinesterase enzyme, called IC ₅₀ eqBuChE is greater than or equal to 15 mg/L, preferably equal to or greater than 20 mg/L, in particular equal to or greater than 25 mg/L and typically equal to or greater than 30 mg/L.

According to the invention, a value greater than or equal to 15 mg/L for IC ₅₀ hAChE includes the following values and all the intervals between these values: 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30 ; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40.

Also, according to the invention, a value greater than or equal to 15 mg/L for IC ₅₀ eqBuChE includes the following values and all the intervals between these values: 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30 ; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40, ; 45; 50; 55; 60; 65; 70; 75; 80; 85; 90; 95; 100; 105; 110; 115; 120; 125; 130; 135; 140; 145; 150; 155; 160.

Advantageously, the compound(s) of formula (I) belong to Cluster 3 or Cluster 4, preferably to Cluster 3 determined according to molecular modeling by spherical harmonics as described in the publication "Benchmarking of HPCC: A novel 3D molecular representation combining shape and pharmacophoric descriptors for efficient molecular similarity assessments", Karaboga et al. 2013 Journal of Molecular Graphics and Modeling 41; 20-30 .

According to another characteristic of the invention, the compound(s) of formula (I) exhibit a value in percentage (%) by QSAR modeling (quantitative structure-activity relationship) that is lower or equal to 0.70% for the measurement of neurotoxicity and less than or equal to 3%, preferably less than or equal to 1.5% and typically less than or equal to 0.15%, preferably less than or equal to 0.7 % for reprotoxicity measurement.

Of course, the various embodiments described above for the use of the compounds of formula (I) as anti-wear agents for reducing and/or preventing the neurotoxicity of an oil also apply to the use of these compounds of formula (I) for the prophylaxis of the aerotoxic syndrome, in particular in the event of a smoke event, and with the oil as such.

By “aerotoxic syndrome prophylaxis”, is meant the reduction in the occurrence and/or intensity, or even the virtual disappearance or total disappearance, of at least one symptom identified as being linked to an acute or chronic exposure. individuals to aircraft cabin air contaminated with oils such as turbine oils or hydraulic oils in the form of gases and/or aerosols. In certain embodiments, the prophylaxis of the aerotoxic syndrome designates the reduction in the occurrence, or even the virtual disappearance or the total disappearance, of several symptoms, preferably of all the symptoms, identified as being related to acute or chronic exposure of individuals to aircraft cabin air contaminated with oils, such as turbine oils or hydraulic oils in gaseous and/or aerosol form.

In particular, the symptom may be a neurological, neurobehavioral, neuromotor and/or reproductive related symptom. Among the symptoms whose occurrence and/or intensity can be reduced by the use according to the invention, mention may be made, for example, of psychological or psychosomatic disorders, chronic fatigue syndrome, severe migraines, multiple chemical sensitivity , mysterious viral infections, sleep disturbances, depression, stress and anxiety.

By “smoke event”, is meant the acute or chronic exposure, preferably acute, of at least one individual to air in an aircraft cabin contaminated by oils such as turbine oils or hydraulic oils. in gas and/or aerosol form. A smoke event, if significant, can in particular be detected by the perception of an unpleasant characteristic odor, typical of “dirty socks” or “wet dog”. In the most severe cases, for example following the breakage of a bearing in the turbine, smoke or a thick white mist may be visible.

By "an oil not comprising tricresylphosphate", is meant an oil in which the quantity of tricresylphosphate, whatever its type of substitution (ortho, meta, para) is below the detection limit of the usual analysis techniques such as gas chromatography coupled with mass spectrometry, for example. A suitable technique for the detection of tricresylphosphate in an oil is described for example in De Nola G et al. J. Chromatogr. In 2008; 1200 (2), p.211-216 .

In the case of aero-derivative turbines, the pathology referred to as "aerotoxic syndrome" is a pathology comprising at least in part the same neurological and reproductive symptoms as those observed in airplanes for aerotoxic syndrome, but which is contracted by exposure to organophosphates, such as tricresylphosphate in installations comprising industrial turbines on the ground such as offshore platforms.

dans laquelle A est un groupe alkyle linéaire ou ramifié comprenant de 10 à 32 atomes de carbone, et chacun de Ar₁ et Ar₂ est indépendamment un groupe aryle, ayant une faible, voire quasi nulle neurotoxicité.The invention thus makes it possible to form an oil comprising at least one compound of formula (I)

wherein A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of Ar ₁ and Ar ₂ is independently an aryl group, having little or almost no neurotoxicity.

This oil can also be used for the prophylaxis of aerotoxic syndrome.

In another embodiment, the oil is for its use for the prophylaxis of aerotoxic syndrome in the event of a smoke event.

In particular, the oil for its use for the prophylaxis of the aerotoxic syndrome, in particular in the event of a smoke event, is an oil for lubricating aircraft or aeroderivative turbines.

The composition of the oil suitable for the invention will be described below.

The term "substantially not" as used in the present invention denotes quantities of less than 0.1% by weight relative to the total weight of the oil, preferably less than 0.05%, in particular less than the limit detection of detection techniques.

The compounds of formula (I) are present in the oil in the present invention in an amount such as those conventionally used in the art. For example, they can be used in an amount of 0.1 to 10% by weight, preferably 0.5 to 5% by weight, based on the total weight of the oil.

The oil according to the invention preferably comprises an ester base, at least one amine antioxidant, and at least one anti-wear additive of formula (I).

In certain embodiments, the oil according to the invention also comprises at least one other additive. The at least one other additive may in particular be chosen from the group consisting of lubricating agents, other anti-wear additives, antioxidants, metal corrosion inhibitors, passivators, viscosity index improvers, detergents or dispersing agents, anti-foaming agents, surfactants, swelling agents, tackifying agents, stabilizers, bulking agents, hydrolysis stabilizers, extreme pressure additives, pigments and odor masking agents. Such additives and agents are well known to those skilled in the art and are commonly available commercially.

The ester base is a conventional ester base, well known in the art. It is typically a synthetic oil which can be chosen from esters of mono-alcohol or polyol, preferably polyol, with a mono or dicarboxylic acid reactant.

Particularly suitable polyols are neo-polyols such as neopentylglycol, 2-ethyl 2-methylpropane 1,3-diol, trimethylolethane, trimethylolpropane, trimethylolbutane and mono-, di- or tri-pentaerythritol.

As another suitable polyol, mention may be made of any polyol of formula

R(OH) _p

in which R is an optionally substituted linear, branched or cyclic aliphatic hydrocarbon group and p is an integer greater than or equal to 2. The polyol can be chosen from the group consisting of 2-ethyl-1,3-hexanediol, 2- propyl-3,3-heptanediol, the 2-butyl-1,3-butanediol, 2,4-dimethyl-1,3-butanediol, ethylene glycol, propylene glycol and polyalkylene glycols.

Particularly suitable mono-alcohols are neo-alcohols such as 2,2,4-trimethylpentanol and 2,2-dimethylpropanol. Alternatively, the mono-alcohol can be selected from the group consisting of methyl, butyl, isooctyl and octadecyl alcohols.

The carboxylic acid reactant used to form the ester with the polyol or the mono-alcohol can be chosen from optionally substituted aliphatic carboxylic acids comprising one or two carboxylic acid functions or any of their mixtures. A person skilled in the art will know how to select the carboxylic acids to be used depending on the properties desired for the ester and the mono-alcohol or polyol used.

Among the ester bases which may be contained in an oil according to the invention, mention may be made of the monoesters of octyl acetate, of decyl acetate, of octadecyl acetate, of methyl myristate, of stearate of butyl, methyl oleate, as well as the polyesters of dibutyl phthalate, di-octyl adipate, di-2-ethylhexyl azelate and ethylhexyl sebacate. The polyol ester base oil can be an oil prepared from technical pentaerythritol or trimethylol propane and a mixture of carboxylic acids having 4 to 12 carbon atoms. Technical pentaerythritol is a mixture which comprises approximately 85% to 92% by weight of monopentaerythritol and 8% to 15% by weight of dipentaerythritol.

A typical commercial technical pentaerythritol contains about 88% by weight monopentaerythritol and about 12% by weight dipentaerythritol, based on the total weight of said ester base oil. Technical pentaerythritol may also contain a certain amount of tri- and tetra-pentaerythritols which are usually formed as by-products during the production of technical pentaerythritol.

Aromatic amine antioxidants are well known in the art and can be monomeric or polymeric aromatic amine antioxidants, belonging to the family of aromatic amines and/or phenolic compounds.

The monomeric aromatic amine antioxidants may comprise in particular at least one diphenylamine which is unsubstituted or substituted by at least one hydrocarbon group, at least one naphthylphenylamine which is unsubstituted or substituted by at least one hydrocarbon group, at least one phenothiazine which is unsubstituted or substituted by at least one hydrocarbon group, or any mixture thereof. The hydrocarbon groups substituting the amines are C ₁ to C ₃₀ alkyl groups, or styrene.

Polymeric aromatic amine antioxidants are the products of polymerization of aromatic amine antioxidants as defined above, either with each other or in the presence of a different comonomer. Examples of oligomeric or polymeric aromatic amino antioxidants that can be used in oils according to the invention are described in particular in the applications for patents FR 2 924 122 And WO 2009/071857 .

dans laquelle A est un groupe alkyle linéaire ou ramifié comprenant de 10 à 32 atomes de carbone, et chacun de Ar₁ et Ar₂ est indépendamment un groupe aryle et présentant notamment un niveau de risque en terme de neurotoxicité de 0.The present invention may thus relate to a process for the manufacture of a non-neurotoxic oil or one having a greatly reduced neurotoxicity (compared to oils based on tricresylphosphate and its analogues or based on other neurotoxic phosphorus compounds) used in particular for lubricating devices/machines, such as aircraft turbines or aero derivatives, comprising the following step: incorporating into a base oil, such as an ester oil, at least one anti-wear agent, characterized in that said at least one anti-wear agent is selected from at least one compound of formula (I)

in which A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of Ar ₁ and Ar ₂ is independently an aryl group and in particular presenting a level of risk in terms of neurotoxicity of 0.

Of course, the various embodiments described above for the use of the compounds of formula (I) for preventing and/or reducing the neurotoxicity of an oil or for the oil composition also apply for this method of manufacture of an oil and will not be repeated below.

• fournir une huile non-neurotoxique ou à toxicité très réduite (niveau de risque à un score de 0), de préférence exempte de tricrésyl phosphate et/ou de ses analogues, ladite huile comprenant au moins un agent anti-usure sélectionné parmi un composé de formule (I)
  
  dans laquelle A est un groupe alkyle linéaire ou ramifié comprenant de 10 à 32 atomes de carbone, et chacun de Ar₁ et Ar₂ est indépendamment un groupe aryle et présentant notamment un niveau de risque en terme de neurotoxicité de 0,
• appliquer une quantité efficace de ladite huile sur ladite machine/ledit dispositif.

The present invention may thus relate to a method for lubricating a machine/device, such as aircraft turbines or aeroderivatives, comprising the following steps:

• providing a non-neurotoxic oil or one with very reduced toxicity (level of risk at a score of 0), preferably free of tricresyl phosphate and/or its analogues, said oil comprising at least one anti-wear agent selected from a compound of formula (I)
  
  in which A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of Ar ₁ and Ar ₂ is independently an aryl group and in particular presenting a level of risk in terms of neurotoxicity of 0,
• applying an effective amount of said oil to said machine/device.

Of course, the various embodiments described above for the use of polyphosphorus compounds to prevent and/or reduce the neurotoxicity of an oil or for the oil composition also apply for this lubrication process and will not be repeated below.

Examples Example 1: Study of toxicity and in particular of neurotoxicity

The compounds of formula (I) according to the invention were studied and compared with other phosphorus compounds, in particular with TCP, in terms of inhibition of cholinesterases, 3D molecular modeling by spherical harmonics, and in terms of QSAR modeling for neurotoxicity and for reprotoxicity. The correlation of the results obtained made it possible to determine a “safety level” for the use of these compounds as anti-wear agents in oils for aircraft turbines or aero-derivatives.

Protocol of the various tests carried out: Measurement of inhibitory concentrations on two cholinesterases:

Insofar as the toxic activity of TCP passes in particular through its action on cholinesterases, the effect of the compounds used according to the invention, as well as comparative compounds, on two cholinesterases was studied. The necessary concentration values of each compound to inhibit 50% of the activity of two cholinesterases were measured. The higher the 50% inhibitory concentration (IC ₅₀ ), the less the compound is neurotoxic since it has a weaker action on cholinesterase.

The inhibitory capacity of the compounds on the biological activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was evaluated using the spectrometric method of Ellman ( Ellman et al., Biochem. Pharma. 1961, 7, 88-95 ).

Acetylthiocholine and butyrylthiocholine iodide, and 5,5-dithiobis(2-nitrobenzoic) acid (DTNB) were purchased from Sigma Aldrich (Steinheim, Germany).

Freeze-dried BuChE from equine serum (eqBuChE, Sigma Aldrich) was dissolved in 0.1M phosphate buffer (pH 7.4) to obtain enzyme stock solutions with an enzyme activity of 2.5 units/mL . AChE from human erythrocytes (hAChE, aqueous buffer solution, ≥500 units/mg protein (BCA), Sigma Aldrich) was diluted in 20 mM HEPES buffer pH 8 with 0.1% Triton X- 100 to obtain an enzyme solution with an enzyme activity of 0.25 units/mL.

In the procedure, 100 µL of 0.3 mM DTNB dissolved in pH 7.4 phosphate buffer was added to the 96-well plates, followed by 50 µL of test compound solution and 50 µL of enzyme (0.05 U final). After 5 minutes of pre-incubation at 25° C., the reaction was initiated by injecting 50 μl of 0.1 mM acetyl iodide or butyrylthiocholine solution. Hydrolysis of acetyl or butyrylthiocholine was followed by the formation of the anion 5-thio 2-nitrobenzoate yellow, as a reaction product of DTNB with thiocholine salted out by the enzymatic hydrolysis of the acetyl or butyrylthiocholine, at a wavelength of 412 nm, using a microplate reader (Synergy 2, Biotek, Colmar, France). The compounds to be tested were dissolved at 5×10 ^-3 M in analytical grade DMSO. Donepezil or tacrine were used as reference standards. The rate of increase in absorption at 412 nm was determined 4 minutes after the addition of the acetyl or butyrylthiocholine iodide solution. The tests were carried out with a blank containing all the compounds with the exception of acetyl or butyrylthiocholine, in order to take account of the non-enzymatic reactions.

dans laquelle v_i est le taux calculé en présence de l'inhibiteur, et v₀ est l'activité enzymatique.The percentage inhibition due to the presence of the compounds to be tested was calculated by the following expression: $$\left(\left(v0-\mathit{vi}\right)/v0\right)\times 100$$

in which v _i is the level calculated in the presence of the inhibitor, and v ₀ is the enzymatic activity.

IC ₅₀ values were determined graphically by plotting percent inhibition against the logarithm of six concentrations of inhibitor in the test solution using GraphPadPrism software (version 6.01, GraphPad Software, La Jolla, CA, USA). All the experiments were carried out in n=3.

Molecular modeling by spherical harmonics

The 3D modeling method used in the invention is described in the publication: "Benchmarking of HPCC: A novel 3D molecular representation combining shape and pharmacophoric descriptors for efficient molecular similarity assessments", Karaboga et al. 2013 Journal of Molecular Graphics and Modeling 41; 20-30 .

Two clusters (clusters 1 and 2) were defined by similarity based in particular on monophosphate compounds known to be toxic.

The study of the compounds of formula (I) used according to the invention has demonstrated their belonging to different clusters (clusters 3 and 4), associated with non-toxic molecules.

Modeling by QSAR

The degrees of neurotoxicity and reprotoxicity of compounds used according to the invention and of other monophosphate compounds were evaluated by QSAR modeling (quantitative structure-activity relationship).

Selection of training and validation sets

The training set was defined with chemical structures compiled from several publicly available sources: HSBD (Hazardous Substances Data Bank), EPA (US Environmental Protection Agency), ECHA (European Chemicals Agency), and NTP (National Toxicology program). 247 compounds were classified as neurotoxic compounds, 2214 compounds were classified as reprotoxic compounds, and 1697 compounds were classified as neither neurotoxic nor reprotoxic and forming the nontoxic training set.

The validation set was built using compounds from different datasets than those used for the training set. Molecules already present in the training set have been removed. The validation set was composed of 70 compounds classified as neurotoxic compounds, 506 compounds classified as reprotoxic and 256 compounds classified as neither neurotoxic nor reprotoxic and forming the non-toxic validation set.

QSAR model performance

A generalized linear model (GLM) method was chosen to perform a quantitative structure-activity relationship (QSAR) approach. The GLM models were trained separately to discriminate the chemical structures (i) between neurotoxic and non-neurotoxic compounds and (ii) between reprotoxic and non-reprotoxic compounds. This approach resulted in a GLM model with 210 significant descriptors within the training sets. During training, the performance of QSAR models was measured by Receiver Operator Characteristic (ROC) curves and resulted in area under the curve (AUC) values of 0.90 and greater for the prediction of neurotoxicity and reprotoxicity, respectively.

To validate the robustness of the QSAR models, they were then used to predict (i) the neurotoxicity categories of the compounds in the validation set (i.e. the neurotoxic/non-neurotoxic categorization), (ii) the reprotoxicity of the compounds in the validation set (i.e. reprotoxic/non-reprotoxic categorization). During validation, the performance of QSAR models was measured by area under the curve (AUC) values and provided significant values of 0.70 and above for the prediction of neurotoxicity and reprotoxicity, respectively.

The GLM-based QSAR models were then used to study the aryl diphosphorus compounds according to the invention.

Synthesis of compounds of formula (I)

1 molar equivalent of the alcohol reagent and 2 molar equivalents of triethylamine. The reaction medium was diluted with toluene, approximately 10 volumes relative to the alcohol reagent. Depending on the nature of the alcohol reagent, the reaction medium was heated between 25 and 90° C. then, using the dropping funnel, 1 molar equivalent of diarylphosphate chloride was introduced drop by drop. At the end of the reaction, the triethylamine salt formed was removed by filtration and then washed with 5 volumes of ethyl acetate. The filtrate was then washed twice with a 0.1 N HCl solution, twice with a 0.1 N KOH solution and then with water until neutral pH. The organic phase was then dried with MgSOa, filtered and then concentrated under reduced pressure. The reaction crude thus obtained was purified either by chromatography on silica gel, or by liquid-liquid extraction, or by precipitation. THE The phosphates thus obtained were characterized by GC or GPC chromatography, by ¹ H and ³¹ P NMR analyses. The yields obtained vary between 52 and 90%.

Results

The results of the tests carried out are presented in Table 1 below. The last column corresponds to a risk level score with respect to the safety of these molecules that can be used in oils such as turbine oils and their alleged toxicity in the cabin. A score of 5 corresponds to a very high risk in terms of neurotoxicity and/or reprotoxicity, while scores of 0 or 1 correspond to a very low or non-existent level of risk. The level of risk is determined by the sum of the factors corresponding to each of the risks assessed independently based on the in vitro experimental results of inhibition (IC ₅₀ hAChE and IC ₅₀ eqBuChE), semi-empirical prediction (QSAR neurotoxicity and QSAR reprotoxicity), and molecular modeling via spherical harmonics (classification in clusters) and it can range from 0 to 5. A value of 0 indicates an absence of risk, and a value of 5 indicates a very significant multiple risk. For each risk, a factor of 0 or 1 is assigned depending on whether the value is above or below a threshold. The following thresholds are applied: 15 mg/L for ICso for hAChE, 15 mg/L for ICso for eqBuChE, 0.2% for neurotoxicity, 3% for reprotoxicity.

The compounds are numbered as follows:

Comparative examples :

• Compound A: 2-ethylhexyldiphenylphosphate ( CAS 1241-94-7 ) (https://echa.europa.eu/en/substance-information/-/substanceinfo/100.013.625)
• Compound B: Tri(ortho-cresyl)phosphate ToCP
• Compound C: Tri(meta-cresyl)phosphate
• Compound D: Tri(para-cresyl)phosphate
• Compound P: Tricresylphosphate ( CAS 1330-78-5 ) corresponds to the commercial product Durad 125 (https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.239.100)
• Compound E: Trixylylphosphate ( CAS 25155-23-1 ) (https://echa.europa.eu/fr/registration-dossier/-/registered-dossier/2204/7/11/1)
• Compound F: Tri(2,6-difluorophenyl)phosphate
• Compound G : Tri(4-isopropylbenzoate)phosphate
• Compound H: di(p-tertbutylphenyl)phenylphosphate
• Compound I1 : tri phenyl phosphate ( CAS 204-112-2 ) (https://echa.europa.eu/en/substance-information/-/substanceinfo/100.003.739)
• Compound I2: Tri(p-tert-butylphenyl)phosphate
• Compound I3 : Tert-butylphenyl diphenyl phosphate ( CAS 700-990-0 ) corresponds to the commercial product Durad 150B, (https://echa.europa.eu/fr/substance-information/- /substanceinfo/100.235.046
• Compound J: Saligenin cresylphosphate
• Compound K: Diphenylphosphoroamidate
• Compound Q: isononyldiphenylphosphate
• Compound L: Tri(isobutyl)phosphate ( CAS 126-71-6 ) (https://echa.europa.eu/en/substance-information/-/substanceinfo/100.004.363)
• Compound M : Tris(2-ethylhexyl)phosphate ( CAS 78-42-2 ) (https://echa.europa.eu/en/substance-information/-/substanceinfo/100.001.015)
• Compound N : Dibutyl [[bis[(2-ethylhexyl)oxy]phosphinothioyl]thio]succinate ( CAS 68413-48-9 ) (https://echa.europa.eu/en/substance-information/-/substanceinfo/100.063.817)

Examples according to the invention (compounds of formulas (I))

• Compound 1 : isodecyldiphenylphosphate 28 CAS 29761-21-5 ) corresponds to the commercial product Santicizer 148 (https://echa.europa.eu/fr/substance-information/- /substanceinfo/100.045.283)
• Compound 2: n-dodecyldiphenylphosphate ( CAS 27460-02-2 ) (https://echa.europa.eu/en/substance-information/-/substanceinfo/100.103.005)
• Compound 3: 2-octyl 1-dodecyldiphenylphosphate
• Compound 4: iso-dodecyldiphenylphosphate
• Compound 5: iso-hexadecyldiphenylphosphate (C16),
• Compound 6: mixture of n-hexadecyl and n-octadecyl diphenylphosphate (nC16/C18)
• Compound 7: iso-C32 diphenyl phosphate.

While compound A (2-ethylhexyldiphenylphosphate) belongs to cluster 1 of neurotoxic and reprotoxic organophosphorus molecules, compound 1, which corresponds to formula (I) according to the invention, on the other hand, exhibits high IC ₅₀ inhibition values at hAChE and eqBuChE cholinesterases. Surprisingly, modeling via spherical harmonics shows that this molecule belongs to a cluster of molecules different from neurotoxic clusters 1 and 2. Semi-empirical QSAR models also indicate a difference in responsiveness. Compound 1 presents a level of risk equal to 0, while the compounds of cluster 1 present a level of risk at least equal to 2.

The QSAR modeling also indicates that compound 3, which corresponds to formula (I) according to the invention, belongs to a different cluster from clusters 1 and 2 of neurotoxic compounds, compounds 2 and 4 belonging to the same cluster as compound 1 (to know cluster 4), while compound 3 belongs to another cluster (namely cluster 3). These three compounds (compounds 2 to 4) also exhibit zero neurotoxicity and very low reprotoxicity. The cluster as well as the QSAR modeling have not been determined for compounds 5 to 7 according to the invention. However, these latter compounds 5 to 7 show excellent results in vitro in terms of IC ₅₀ of cholinesterases (the inhibitory concentration at 50% is high, greater than 18 mg/L for IC ₅₀ hAChE and greater than 25 mg/L and even reaching 127 mg/L for IC ₅₀ eqBuCh). These compounds 5 to 7 thus suggest that they are non-neurotoxic since they have a weak action on the cholinesterases tested and must certainly show good results in QSAR tests, while probably classifying among clusters 3 and 4 according to the 3D modeling of spherical harmonics. It is observed that the elongation of the alkyl chain tends towards a type 3 cluster.

The compounds of formula (I) according to the invention consequently seem to have a different conformation from that of the compounds belonging to neurotoxic clusters 1 and 2, and that their reactivity also differs with regard to the biological activity of the enzymes studied.

The compounds of cluster 1 are presented, according to the 3D modeling approach of spherical harmonics, in the form of a "three-bladed helix" on the basis of two perpendicular planes at the level of the center or the core of the molecule, whereas the compounds according to the invention have a rather deployed and flattened shape approaching a butterfly shape. The molecules resulting from the work of modeling by the spherical harmonics are represented on the figure 1 . These compounds are therefore non-neurotoxic and non-reprotoxic alternatives to tricresylphosphate and its tri-arylphosphate analogues or to the other compounds tested (generally also used as an anti-wear agent in turbine oil) based on phosphorus.

Compounds 1 to 7, in which the group A is an alkyl group comprising 10 to 20 carbon atoms, are non-neurotoxic and exhibit very low reprotoxicity. Comparatively, compound A and compound Q, whose group A is an alkyl group comprising respectively 8 and 9 carbon atoms, show markedly higher neurotoxicity and reprotoxicity values according to the QSAR models, and belong to cluster 1 of compounds neurotoxic.

Thus, these intro and modeling tests (3D of spherical harmonics or QSAR) show that the Applicant has selected, in a non-arbitrary manner, from all the existing compounds based on phosphorus and generally having an anti-wear action in an oil, a restricted subset of compounds of general formula (I). This subset further exhibits a technical effect different from other phosphorus-based compounds. Indeed, this subset of compound of formula (I) is at least non-neurotoxic and is capable of and/or configuring to reduce and/or prevent the neurotoxicity of an oil, in particular a turbine oil intended for aviation. In addition, this subset is suitable to / configure for the prophylaxis of the aerotoxic syndrome in particular in case of smoke event. This subassembly, by virtue of its characteristics, makes it possible to form a turbine oil, for example for aviation, which is suitable for and/or configured to make it possible to increase the level of safety in aviation and in other aero-derivative applications.

Furthermore, no indication in the state of the art could allow a person skilled in the art to specifically choose this subset of compounds of general formula (I) in order to reduce/prevent the neurotoxicity of a turbine oil or for the prophylaxis aerotoxic syndrome.

Indeed, on the one hand, the other phosphorus compounds and in particular the other phosphorus compounds used as an anti-wear agent in an oil and known from the prior art do not exhibit this new technical effect (i.e.: reducing and/or prevent the neurotoxicity of an oil or for the prophylaxis of the aerotoxic syndrome). On the contrary, the other known anti-wear compounds (comparative compounds E, I1-3, M, N and P) and in particular used as anti-wear agent in an oil, are neurotoxic.

On the other hand, before the tests carried out by the Applicant, most of the other commercial and registered phosphorus compounds, in particular known as anti-wear agents, such as, for example, compounds A,!1-!3,L,M and N are recognized in particular by the official website of the ECHA (European Chemicals Agency) as not presenting a serious danger of acute or serious toxicity (CMR character). The ECHA agency is a competent authority to rule on the toxicity of chemicals registered for the European market. It publishes public and recognized scientific data. Compound I3 is used in particular in the field of lubricants as a replacement for TCP or its analogs. However, the Applicant's tests via the in vitro IC50 tests or the 3D or QSAR modeling tests show, on the contrary, that these compounds are highly neurotoxic. For example, according to the ECHA website, this compound does not show any signs of toxicity with respect to human health. However, Table 1 above shows that this compound I3 is a mixture of neurotoxic compounds including triphenylphosphate and tri(p-tertbutylphenyl)phosphate. A person skilled in the art would therefore not have been incited or encouraged to select the subset formed by the compounds of general formula (I) in order to reduce and/or prevent the neurotoxicity of an oil or for the prophylaxis of the aerotoxic syndrome.

Example 2: Anti-wear performances of the compounds according to the invention

The anti-wear performance of the oils according to the invention was measured using the 4-ball wear test according to the ASTM D4172 standard. The results obtained are shown in Table 2 below. [Table 2] Anti-wear compound formulated in aviation finished oil Wear 4 balls (in mm) Without anti-wear compound 0.83 TCP 0.46 Isodecyldiphenylphosphate 0.45 n-dodecyldiphenylphosphate 0.45 2-octyl 1-dodecyldiphenylphosphate 0.45

The results confirm that the compounds of formula (I) used according to the invention have interesting anti-wear properties and potentially analogous to those of TCP, therefore that they are compatible with an effective use as an anti-wear agent, in particular in oils for aircraft or aeroderivative turbines.

Of course, various other modifications may be made to the invention within the scope of the appended claims.

Claims (15)

1. Use of at least one compound of formula (I)

   

   wherein A is a linear or branched alkyl group, optionally substituted, comprising 10 to 32 carbon atoms, and each of Ar₁ and Ar₂ is independently an aryl group, optionally substituted, as an anti-wear agent in an oil to reduce and/or prevent the neurotoxicity of said oil.
2. The use according to claim 1, wherein the 50% inhibitory concentration of said at least one compound of formula (I) on the biological activity of an acetylcholinesterase (AChE) enzyme, called IC₅₀ hAChE is greater than or equal to 15 mg/L, and the activity on a butyrylcholinesterase enzyme, called IC₅₀ eqBuChE is greater than or equal to 15 mg/L, preferably equal to or greater than 20 mg/L, in particular equal to or greater than 25 mg/L and typically equal to or greater than 30 mg/L.
3. The use according to claim 1 or 2, wherein A is selected from the group consisting of isodecyl, n-dodecyl and 2-octyl 1-dodecyl group.
4. The use according to any one of the preceding claims, wherein Ar₁ and Ar₂ are phenyls.
5. The use according to any one of claims 1 to 4, wherein the compound of formula (I) is selected from the group consisting of isodecyl diphenylphosphate, n-dodecyl diphenylphospate, 2-octyl 1-dodecyl diphenylphosphate, and any mixtures thereof.
6. The use according to claim 5, wherein the compound of formula (I) is isodecyl diphenylphosphate.
7. The use according to any one of the claims 1 to 6, wherein the oil does not comprise triaryl phosphate anti-wear additive.
8. The use according any one of claims 1 to 7, wherein the oil only contains the compound(s) of formula (I) as single anti-wear agent(s).
9. An use of at least one compound of formula (I)

   

   wherein A is a linear or branched alkyl group, optionally substituted, comprising 10 to 32 carbon atoms, and each of Ar₁ and Ar₂ is independently an aryl group, optionally substituted, as an anti-wear agent in an for the aerotoxic syndrome prophylaxis in case of fume event.
10. The use according to claim 9, wherein the 50% inhibitory concentration of said at least one compound of formula (I) on the biological activity of an acetylcholinesterase (AChE) enzyme, called IC₅₀ hAChE is greater than or equal to 15 mg/L, and the activity on a butyrylcholinesterase enzyme, called IC₅₀ eqBuChE is greater than or equal to 15 mg/L, preferably equal to or greater than 20 mg/L, in particular equal to or greater than 20, and typically equal to or greater than 30 mg/L.
11. The use according to claim 9 or 10, wherein A is selected from the group consisting of isodecyl, n-dodecyl and 2-octyl 1-dodecyl group.
12. The use according to any one of claims 9 to 11, wherein Ar₁ and Ar₂ are phenyls.
13. The use according to any one of claims 9 to 12, wherein the compound of formula (I) is selected from the group consisting of isodecyl diphenylphosphate, n-dodecyl diphenylphospate, 2-octyl 1-dodecyl diphenylphosphate, and any mixtures thereof.
14. The use according to claim 13, wherein the compound of formula (I) is isodecyl diphenylphosphate.
15. The use according to any one of the claims 9 to 14, wherein the oil does not comprise triaryl phosphate anti-wear additive or wherein the oil only contains the compound(s) of formula (I) as single anti-wear agent(s).

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