Classifications

• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
  • C10M137/00—Lubricating compositions characterised by the additive being an organic non-macromolecular compound containing phosphorus
  • C10M137/02—Lubricating compositions characterised by the additive being an organic non-macromolecular compound containing phosphorus having no phosphorus-to-carbon bond
  • C10M137/04—Phosphate esters
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
  • C10M105/00—Lubricating compositions characterised by the base-material being a non-macromolecular organic compound
  • C10M105/08—Lubricating compositions characterised by the base-material being a non-macromolecular organic compound containing oxygen
  • C10M105/32—Esters
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
  • C10M137/00—Lubricating compositions characterised by the additive being an organic non-macromolecular compound containing phosphorus
  • C10M137/12—Lubricating compositions characterised by the additive being an organic non-macromolecular compound containing phosphorus having a phosphorus-to-carbon bond
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
  • C10M137/00—Lubricating compositions characterised by the additive being an organic non-macromolecular compound containing phosphorus
  • C10M137/16—Lubricating compositions characterised by the additive being an organic non-macromolecular compound containing phosphorus having a phosphorus-to-nitrogen bond
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
  • C10M2207/00—Organic non-macromolecular hydrocarbon compounds containing hydrogen, carbon and oxygen as ingredients in lubricant compositions
  • C10M2207/28—Esters
  • C10M2207/2805—Esters used as base material
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
  • C10M2223/00—Organic non-macromolecular compounds containing phosphorus as ingredients in lubricant compositions
  • C10M2223/02—Organic non-macromolecular compounds containing phosphorus as ingredients in lubricant compositions having no phosphorus-to-carbon bonds
  • C10M2223/04—Phosphate esters
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
  • C10M2223/00—Organic non-macromolecular compounds containing phosphorus as ingredients in lubricant compositions
  • C10M2223/02—Organic non-macromolecular compounds containing phosphorus as ingredients in lubricant compositions having no phosphorus-to-carbon bonds
  • C10M2223/04—Phosphate esters
  • C10M2223/041—Triaryl phosphates
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
  • C10M2223/00—Organic non-macromolecular compounds containing phosphorus as ingredients in lubricant compositions
  • C10M2223/08—Organic non-macromolecular compounds containing phosphorus as ingredients in lubricant compositions having phosphorus-to-nitrogen bonds
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
  • C10N2030/00—Specified physical or chemical properties which is improved by the additive characterising the lubricating composition, e.g. multifunctional additives
  • C10N2030/06—Oiliness; Film-strength; Anti-wear; Resistance to extreme pressure
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
  • C10N2030/00—Specified physical or chemical properties which is improved by the additive characterising the lubricating composition, e.g. multifunctional additives
  • C10N2030/10—Inhibition of oxidation, e.g. anti-oxidants
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
  • C10N2040/00—Specified use or application for which the lubricating composition is intended
  • C10N2040/04—Oil-bath; Gear-boxes; Automatic transmissions; Traction drives
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
  • C10N2040/00—Specified use or application for which the lubricating composition is intended
  • C10N2040/06—Instruments or other precision apparatus, e.g. damping fluids
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
  • C10N2040/00—Specified use or application for which the lubricating composition is intended
  • C10N2040/12—Gas-turbines
• • C—CHEMISTRY; METALLURGY
  • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
  • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
  • C10N2040/00—Specified use or application for which the lubricating composition is intended
  • C10N2040/12—Gas-turbines
  • C10N2040/13—Aircraft turbines

Definitions

• 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.
• Aircraft or aero-derivative 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 widely used antiwear additive commercially is tricresylphosphate (TCP), which has unique antiwear properties that can be considered unique to this day. Its tri-arylphosphates analogues are also valuable antiwear additives.
• Leaks of lubricants, especially those containing tricresylphosphate or one of its tri-arylphosphate analogues, in the air of aircraft cabins can be caused by worn or defective seals, or even under normal conditions of use by passage. lubricants in the air intended 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 conditions. operation (increase in engine power, take-off, etc.). Under certain circumstances, the leak can become very large, generally following a breakage of a bearing in the turbine, which leads to a smoke event, or white fog visible in the cabin.
• Aerotoxic syndrome is a pathological 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 of the above. other organic pollutant present in the form of gas and / or aerosols. Symptoms reported are generally non-specific, and cabin air quality studies indicate levels of contaminants that are below exposure limits and not harmful to human health, the difficulty being to continuously and continuously measure. service of the emanations of oils, by definition non-carbonated, conveyed in the air, settling and concentrating, episodically, at different locations of the aircraft (Kasper Solbu et al. J. Environ. Monit. 2011, 13, 1393 ).
• Aero-derived turbines operate identically to aircraft turbines and use lubricants of similar composition, especially in terms of anti-wear agents.
• TCP is also known to be reprotoxic
• anti-wear additives alternative to tricresylphosphate and its tri-arylphosphate analogues for which an absence of neurotoxicity and reprotoxicity would be established would be advantageous and would allow the level to be increased. safety in aviation and other aero-derivative applications.
• Patent application US2016 / 0002565 describes a tricresylphosphate-free turbine oil which comprises at least one base oil, at least one alkylpolyglycoside and a phenolic derivative such as 3,5-di-tert-butyl-hydroxytoluene.
• Replacing tricresylphosphate with the phenolic derivative contributes to the prevention of aerotoxic syndrome when this oil is used in aircraft turbines.
• 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. comprises no agent exhibiting an anti-wear effect making it possible to replace that of TCP, and on the other hand because the formulation comprises alkylpolyglycosides which are thermosensitive.
• toxicity is a fairly broad concept which includes in particular:
• - acute toxicity is the toxicity induced, in a short period of time (eg 24 h), by the administration of a single dose (possibly massive) or of several doses acquired within this period of time of a product or mixture toxic (natural or chemical),
• 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).
• the present invention relates to the use of at least one anti-wear additive in an oil, said at least anti-wear additive comprising at least one polyphosphorus compound of formula (I) wherein each of R1, R2, R3 and R4 is independently selected from: an alkyl group, an O-alkyl group, an aryl group, an or O-aryl group,
• A is a divalent group selected from a linear alkylene group comprising from 7 to 36 carbon atoms or branched comprising from 6 to 36 carbon atoms, a monocyclic, polycyclic or polyaromatic arylene group or an aralkylene group, each of Xi and X2 is independently a single bond, an oxygen atom or a nitrogen atom, and n is an integer between 1 and 5, to reduce and / or prevent the neurotoxicity of said oil.
• said oil and / or said at least antiwear additive does not comprise tricresylphosphate or one of its triarylphosphate analogues.
• the polyphosphorus compounds of formula (I) can thus be used to obtain an oil which is non-neurotoxic or has reduced neurotoxicity.
• the compounds of formula (I) exhibit valuable anti-wear properties, which can be comparable to those of tricresylphosphate or its triarylphosphate analogues. They also present a very low or even zero risk level in terms of neurotoxicity and thus reduce and / or prevent the neurotocixity of the oil in which they are incorporated.
• the invention also relates to the use of at least one antiwear additive in an oil, said at least antiwear additive comprising at least one polyphosphorus compound of formula (I)
• A is a divalent group selected from an alkyl group comprising from 7 to 36 carbon atoms or branched comprising from 6 to 36 carbon atoms, a monocylic, polycyclic or polyaromatic arylene group or an aralkylene group, each of Xi and X 2 is independently a single bond, an oxygen atom or a nitrogen atom, and n is an integer between 1 and 5, for the prophylaxis of aerotoxic syndrome, preferably in the event of a smoke event.
• the term “include” and its derivatives should be understood as not limiting and not excluding the presence of other components or steps.
• the term “comprising” may be understood as “consisting essentially of” or “consisting of”.
• FIG.1 presents molecules resulting from modeling work using spherical harmonics: the compounds in the upper row belong to cluster 1, the compounds in the lower row belong to cluster 3; and
• a first object of the invention is the use of at least one antiwear additive in an oil, said at least antiwear additive comprising at least one polyphosphorus compound of formula (I) wherein each of R1, R2, R3 and R4 is independently selected from: an alkyl group, an O-alkyl group, an aryl group, an or O-aryl group,
• A is a divalent group selected from an alkylene group comprising from 7 to 36 carbon atoms or branched comprising from 6 to 36 carbon atoms, a monocylic, polycyclic or polyaromatic arylene group or an aralkylene group, each of Xi and X2 is independently a single bond, an oxygen atom or a nitrogen atom, and n is an integer between 1 and 5, to reduce and or prevent the neurotoxicity of said oil, preferably a turbine oil.
• “By reducing” the neurotoxicity of an oil is meant that the compound (s) of formulas (I) according to the invention are suitable and / or configured (s) for reducing the neurotoxicity of an oil in which they are included, namely by their presence (generally in the majority), in particular compared to other generally neurotoxic conventional anti-wear compounds, the compound (s) of formula (I) make it possible to lower / reduce the neurotoxicity of an oil and of obtain a non-neurotoxic oil or at least with reduced toxicity.
• Preventing the neurotoxicity of an oil is understood to mean that the compound (s) of formula (I) make it possible to prevent the oil from being considered as 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, reach the central nervous system (CNS) and present the following effects: headache, loss of appetite, drowsiness, mood and personality disorders, cognitive impairment ( learning and concentration), or affect the peripheral nervous system (PNS) and exhibit the following effects: motor impairment such as weakness, tremors, incoordination, convulsions, etc. or sensory damage, such as hearing loss, color vision, tinnitus, loss of balance, etc. ; these effects may or may not be reversible depending on the degree of acute or chronic exposure of the mammal.
• CNS central nervous system
• PNS peripheral nervous system
• Neurotoxicity means the ability of a substance or compound to induce adverse effects in the nervous system of a mammal, such as humans.
• a neurotoxic substance or compound usually acts by disrupting or paralyzing nerve impulses, in particular by acting on synaptic transmitters or receptors or on the enzymes which act on these synaptic transmitters or receptors, such as cholinesterases.
• a cholinesterase is an enzyme that catalyzes the hydrolysis reaction of an ester of choline (acetylcholine, butyrylcholine) into choline and acetic or butyric acid. In physiology, this reaction is necessary to allow cholinergic receptors to return to their resting state after activation.
• 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).
• the 50% inhibitory concentration of said at least compound of formula (I) on the biological activity of an acetylcholinesterase (AChE) enzyme, called ICsohAChE is greater than or equal to 15 mg / L, preferably greater than or equal to 16 mg / L and the activity on a butyrylcholinesterase enzyme, called IC 50 eqBuChE is greater than or equal to 15 mg / L, in particular greater than or equal to 50 mg / L, preferably equal to or greater than 55 mg / L, in in particular equal to or greater than 60 mg / L and typically equal to or greater than 70 mg / L.
• AChE acetylcholinesterase
• a value greater than or equal to 15 mg / L for ICsohAChE 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, etc.
• the compound (s) of formula (I) exhibit a value in percentage (%) by QSAR modeling (quantitative structure activity relationship) (standing for “Quantitative Structure Activity Relationship”) or equal to 0.70%, preferably less than or equal to 0.50% and typically less than or equal to 0.15% for the measurement of neurotoxicity (neurotoxic QSAR) and less than or equal to 1.5%, preferably less or equal to 1.15% and typically less than or equal to 0.55% for the measurement of reprotoxicity (reprotoxic QSAR).
• a value less than or equal to 0.70% for neurotoxic QSAR modeling includes the following values and all the intervals between these values: 0.70; 0.69 0.68; 0.67; 0.66; 0.65; 0.64; 0.63; 0.62; 0.61; 0.60; 0.59; 0.58; 0.57; 0.56; 0.55; 0.54
• a value less than or equal to 1.50% for reprotoxic QSAR modeling includes the following values and all the intervals between these values: 1.50 1.48; 1.46; 1, 44; 1.42; 1, 40; 1.38; 1.36; 1.34; 1.32; 1.30; 1.28; 1.26; 1.24; 1.22; 1.20
• the compounds of formula (I) according to the invention exhibit 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 no risk of neurotoxicity) , preferably at a score of 0.
• the level of risk as defined above and also illustrated in the experimental part below is very exhaustive and includes all the data obtained via the various tests on neurotocity described above and therefore includes both tests in vitro as 3D modeling tests.
• the risk level takes into account all of the following tests:
• oil denotes any organic substance, in particular any hydraulic or turbine oil, liable to create pollution in the form of gas and / or aerosol in the cabin.
• the oil is selected from the group consisting of aircraft or aero-derivative oils, helicopter transmission oils, and weapon fluids.
• the oil is an oil for aircraft turbines or aero-derivatives.
• the groups R1, R2, R3 and R4 of the polyphosphorus compounds of formula (I) according to the invention is independently chosen from: an alkyl group, an O-alkyl group, an aryl group, a group or O-aryl.
• alkyl group denotes a linear or branched saturated hydrocarbon group comprising (unless otherwise mentioned) from 1 to 36 carbon atoms (C1 to C36), more preferably from 1 to 18 carbon atoms ( Ci to Cie), in particular from 1 to 10 carbon atoms (Ci to C10), and typically from 1 to 4 carbon atoms (Ci to C4).
• alkyl groups according to the invention there may be mentioned in particular the methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl groups.
• substituted alkyl group denotes a linear or branched saturated hydrocarbon chain as defined above and substituted, at the level of one or more of its atoms, by one or more radicals chosen from: a hydroxyl radical OH, an amine NH 2 or primary amine NHR radical with R alkyl or aryl group, preferably an OH hydroxyl radical.
• the alkyl group cannot be substituted with a halogen, such as chlorine.
• O-alkyl group is meant an alkyl group as defined above, connected to the rest of the molecule (here, generally the phosphorus atom) through an oxygen atom.
• a “substituted aryl group” denotes a ring or two fused aromatic hydrocarbon-based rings substituted at the level of one or more of its atoms, by at least one substituent consisting of C 1 -C 18 alkyl groups, the hydroxyl group
• RECTIFIED SHEET (RULE 91) ISA / EP OH, an amine NH2 group or a primary amine NHR with R C1-C6 alkyl group or aryl, preferably by C 1 -C 18 alkyl groups , such as a methyl group, or the hydroxyl group OH.
• O-aryl group is meant an aryl group, as defined above, linked to the rest of the molecule through an oxygen atom.
• each alkyl group is an alkyl group comprising from 1 to 22 carbon atoms (C1 to C22), preferably from 1 to 18 carbon atoms (C1 to Cis), in particular from 1 to 10 carbon atoms. carbon (Ci to C10) and typically from 1 to 4 carbon atoms (Ci to C4).
• At least one of R1, R2, R3 and R4 is aryl or O-aryl.
• at least two of R1, R2, R3 and R4 are aryl or O-aryl groups.
• R1, R2, R3 and R4 are four aryl or O-aryl groups, such as O-phenyl or is a substituted O-aryl group, such as O-dimethylphenyl.
• R1, R2, R3 and R4 are phenyl.
• R1, R2, R3 and R4 are phenyl groups.
• R1, R2, R3 and R4 are unsubstituted phenyl groups or phenyl groups substituted with at least one methyl group, preferably two methyl groups (such as 2,6-dimethylphenyl).
• R1, R2, R3 and R4 are O-phenyl.
• R1, R2, R3 and R4 are O-phenyl groups.
• R1, R2, R3 and R4 are unsubstituted O-phenyl groups or O-phenyl groups substituted with at least one methyl group, preferably substituted with two methyl groups (such as 2,6-dimethylphenyl).
• a of formula (I) according to the invention can be chosen from an alkylene group, an arylene group or an aralkylene group.
• alkylene group denotes a divalent linear saturated hydrocarbon group comprising (unless otherwise stated) from 7 to 36 carbon atoms (C7 to C 36 ), preferably 7 to 22 carbon atoms (C7 to C22), preferably from 7 to 18 carbon atoms (C7 to Cis), or a branched saturated hydrocarbon divalent group comprising (unless otherwise stated) preferably from 6 to 36 carbon atoms (Ob to C 36 ), preferably 6 to 22 carbon atoms (Ob to C 22 ), preferably from 6 to 18 carbon atoms (C 6 to Cis), in particular from 6 to 12 carbon atoms (C 6 to C12).
• substituted alkylene group denotes an alkylene group as defined above substituted at the level of one or more of its atoms, by at least one substituent chosen from the group consisting of the linear or branched C 1 to 4 alkyl group.
• Cis the hydroxyl group OH; an NH2 amine or NHR primary amine group with R alkyl - (as defined above) or aryl (as defined above); an O-phosphate group, such as the O- group
• arylene group denotes a monocyclic or polycyclic aromatic carbon group derived from an aromatic hydrocarbon and including at least two (divalent) anchoring points which are connected to X1 and X2 disposed on the aromatic ring (s) (both anchor points can be on the same ring of the polycyclic group).
• Each aromatic or polyaromatic ring can comprise from 5 to 14 atoms.
• An arylene group can correspond, for example, to an aromatic hydrocarbon ring (such as a phenylene), to two fused aromatic hydrocarbon rings (such as a naphthalene) or to two aromatic hydrocarbon rings linked by a covalent bond between two distinct atoms each belonging to to one of the cycles.
• the aromatic rings can optionally be 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, preferably consisting of by an oxygen atom or a sulfur atom.
• the arylene group does not include a nitrogen atom internal to the monocyclic or polycyclic aromatic carbon group.
• the arylene group cannot correspond, for example, to a pyridine or to a pyrimidine.
• the substituted arylene group may correspond to an O-diphenylphosphate radical may correspond to a 1,3- (5 O- [(diphenyl) phosphate)] phenyl group.
• arylene group is a polycyclic group in which at least two rings are linked by at least one covalent bond between two distinct atoms each belonging to
• X1 and X2 are not in the ortho or meta position unless at least one and preferably all of the groups among R1, R2, R3 and R3 are O-phenyl groups substituted with two groups methyls, in particular in position 2,6. In this case, X1 and X2 can be in the meta position.
• X1 andX2 are not in the ortho or para position (in particular in the 1, 3 position), but can be in the 1,4 or 2,7 position.
• group A does not include electron-withdrawing groups or atoms, such as chlorine, carbonyl functions (aldehyde, carboxylic acid, C (O) -O), one or more internal nitrogen in the monocycle or polycyclic carbon group. (pyridine or pyrimidine). Group A therefore cannot be a pyridine or a pyrimidine.
• polycyclic arylene groups mention may in particular be made of 4,4'-biphenyl, 4,4'-diphenylthioether, 4,4'-diphenylether, 4,4'-diphenylphenylethylidene, 4,4'- dimethyldiphenylmethylidene, 4,4'-diphenylsulfone, 4,4'benzophenone, 2,2'benzophenone, 1,4-naphthalene, 1,3-naphthalene, 2,7-naphthalene, 2,6- anthracene, 9,10-anthracene and phenanthrene.
• aralkylene group is meant an alkyl group covalently bonded to an aryl group and comprising two (divalent) anchor points located on the alkyl group and / or on the aryl group.
• an “aralkylene” group may or may not be substituted.
• substituted aralkylene denotes an aralkylene group as defined above substituted, at the level of a
• aralkylene groups mention may in particular be made of the 4,4'- [diphenyl (dimethyl) methylidene] group and the 4,4'-diphenylhexafluoropropane group.
• A is selected from the group consisting of a 1,4-phenyl group, a 4,4'-biphenyl group, a 4,4'-diphenylthioether group, a 4,4'-diphenyl ether group, a 1,3- (5 0 - [(diphenyl) phosphate)] phenyl group, 1,3- (2-ethyl 2-butyl) propyl group, 1,3- (2-ethyl 2- [methyl 0- diphenylphosphate]) propyl, a 4,4'- [diphenyl (dimethyl) methylidene] group, a 2,2'-benzophenone group, a 2,7-naphthalene group, a 1,2-ethyl group, a 4,4 group '- [diphenylphenylethylidene], a 4,4'-diphenylsulfone group, a 4,4'-diphenylhexafluoropropane group
• A is selected from the group consisting of a 1,4-phenyl group, a 4,4'-biphenyl group, a 4,4'-diphenylthioether group, a 4,4'-diphenyl ether group, a 1,3- (5 0 - [(diphenyl) phosphate)] phenyl group, a 1,3- (2-ethyl 2-butyl) propyl group, a 1,3- (2-ethyl 2- [methyl 0 -diphenylphosphate]) propyl, a 4,4'- [diphenyl (dimethyl) methylidene] group, a 2,2'-benzophenone group, a 2,7-naphthalene group and a 1,2-ethyl group.
• A is selected from the group consisting of a 1,4-phenyl group, a 4,4'-biphenyl group, a 4,4'-diphenylthioether group, a 4,4'-diphenyl ether group. , a 1, 3- (5 0 - [(diphenyl) phosphate)] phenyl group, a 1, 3- (2-ethyl 2-butyl) propyl group, a 1,3- (2-ethyl 2- [methyl 0-diphenylphosphate]) propyl
• A is an optionally substituted alkylene group, a substituted monocyclic arylene group or a polycyclic arylene group in which at least two rings are linked by at least one covalent bond between two distinct atoms each belonging to one of the rings, the covalent bond between the two rings being interrupted by at least one heteroatom or heteroatomic group.
• Xi or X 2 is a nitrogen atom, it may be in the form of an NH group or an NR group, R being an alkyl or aryl group.
• N is an integer between 1 and 5.
• n can in particular be equal to 1, 2, 3, 4 or 5.
• “n” is equal to 1.
• a polyphosphorus compound denotes at least one among the oligomers comprising 1 to 5 units -XI-AX 2 -P (O) R4-, or any mixture of at least two of these.
• it may be a mixture of oligomers comprising 1 to 3 units -XI-AX 2 -P (0) R4-
• n 1.
• the polyphosphorus compounds used according to the invention are aryl diphosphates, that is to say they are such that Xi and X 2 are two oxygen atoms, and each of R1, R2, R3 and R4 is an O-aryl group (as defined above), optionally substituted for example by two methyl groups
• said oil and / or said at least antiwear additive does not comprise tricresylphosphate or one of its triarylphosphate analogues.
• an oil or anti-wear agent not comprising tricresylphosphate is meant an oil or an anti-wear agent in which / in which the amount of tricresylphosphate, regardless of its type of substitution (ortho, meta, para) is lower than the detection limit of conventional 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; 7200 (2), p.211-216.
• the oil used according to the invention or the antiwear agent used according to the invention substantially does not include, preferably does not include, any aryl monophosphate antiwear additive, whatever. 'it be. In some embodiments, the oil used according to the invention or the antiwear agent used according to the invention substantially does not include, preferably does not include, an organophosphate antiwear additive other than the additive (s). polyphosphorus compounds.
• the oil used according to the invention or the antiwear agent used according to the invention substantially does not include, preferably does not include, any antiwear additive other than the compound additive (s). polyphosphorus.
• 50% to 100% is meant the following values or any interval between these values: 50; 55; 60; 65; 70; 75; 80; 85; 90; 95; 100.
• polyphosphorus compound present in the oil used according to the invention is chosen from the group consisting of:
• DPP diphenylphosphate
• polyphosphorus compound present in the oil used according to the invention is chosen from the group consisting of:
• polyphosphorus compound present in the oil used according to the invention is chosen from the group consisting of:
• polyphosphorus compound present in the oil used according to the invention is chosen from the group consisting of:
• Polyphosphorus compounds are present in the oil used 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 used according to the invention can include all of the conventional constituents and additives known in the art for this type of oil.
• the oil used according to the invention preferably comprises an ester base, at least one amino antioxidant, and at least one polyphosphorus anti-wear additive of formula (I).
• the oil used according to the invention also includes at least one other additive.
• the at least one other additive can in particular be chosen from the group consisting of lubricating agents, other anti-wear additives, antioxidants, inhibitors
• RECTIFIED SHEET (RULE 91) ISA / EP corrosion agents, passivators, viscosity index improvers, detergents or dispersing agents, anti-foaming agents, surfactants, blowing agents, tackifying agents, stabilizers, bulking agents, agents stabilization against hydrolysis, additives adapted to extreme pressures, pigments and agents that mask odors.
• 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 monoalcohol or polyol, preferably polyol, with a mono or dicarboxylic acid reagent.
• 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.
• neo-polyols such as neopentylglycol, 2-ethyl 2-methylpropane 1,3-diol, trimethylolethane, trimethylolpropane, trimethylolbutane and mono-, di- or tri-pentaerythritol.
• 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, 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.
• the monoalcohol can be chosen from the group consisting of methyl, butyl, isooctyl and octadecyl alcohols.
• the carboxylic acid reagent used to form the ester with the polyol or the monoalcohol can be chosen from optionally substituted aliphatic carboxylic acids comprising one or two carboxylic acid functions or any of their mixtures. Those 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 monoalcohol or polyol used.
• ester bases which may be contained in an oil used according to the invention, mention may be made of monoesters of octyl acetate, decyl acetate, octadecyl acetate, methyl myristate or stearate. of butyl, of 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 from about 85% to 92% by weight of monopentaerythritol and from 8% to 15% by weight of dipentaerythritol.
• a conventional commercial technical pentaerythritol contains about 88% by weight of monopentaerythritol and about 12% by weight of dipentaerythritol, based on the total weight of said base oil of the ester type.
• Technical pentaerythritol may also contain some 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 can comprise in particular at least one diphenylamine which is unsubstituted or substituted with at least one hydrocarbon group, at least one naphthylphenylamine which is unsubstituted or substituted with at least one hydrocarbon group, at least one phenothiazine which is unsubstituted or substituted with at least one. hydrocarbon group, or any mixture thereof.
• the hydrocarbon groups substituting for the amines are C 1 -C 30 alkyl groups, or styrene.
• Polymeric aromatic amine antioxidants are the polymerization products 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 amine antioxidants which can be used in turbine oils according to the invention are described in particular in patent applications FR 2 924 122 and WO 2009/071857.
• the present invention can thus relate to a process for the manufacture of a non-neurotoxic oil or one exhibiting greatly reduced neurotoxicity (in comparison with 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 air-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 antiwear agent is selected from at least one polyphosphorus compound of formula (I) wherein each of R1, R2, R3 and R4 is independently selected from: an alkyl group, an O-alkyl group, an aryl group, an or O-aryl group,
• A is a divalent group selected from a linear alkylene group comprising from 7 to 36 carbon atoms or branched comprising from 6 to 36 carbon atoms, a monocyclic, polycyclic or polyaromatic arylene group or an aralkylene group, each of X and X is independently a single bond, an oxygen atom or a nitrogen atom, and
• ISA / EP n is an integer between 1 and 5, and presenting in particular a level of risk in terms of neurotoxicity of 0.
• Another subject of the invention relates to the use of at least one anti-wear additive in an oil, said at least anti-wear additive comprising at least one polyphosphorus compound of formula (I) wherein each of R1, R2, R3 and R4 is independently selected from: an alkyl group, an O-alkyl group, an aryl group, an or O-aryl group,
• A is a divalent group selected from an alkylene group comprising from 7 to 36 carbon atoms or branched comprising from 6 to 36 carbon atoms, a monocylic, polycyclic or polyaromatic arylene group or an aralkylene group, each of Xi and X2 is independently a single bond, an oxygen atom or a nitrogen atom, and n is an integer between 1 and 5, for the prophylaxis of aerotoxic syndrome, preferably in the event of a smoke event.
• the pathology designated by the terms "aerotoxic syndrome” is a pathology comprising at least in part the same neurological and reproductive symptoms as those observed in airplanes for the aerotoxic syndrome, but which is contracted by exposure.
• organophosphates such as tricresylphosphate in installations comprising industrial turbines on the ground such as offshore platforms.
• prophylaxis of the aerotoxic syndrome is meant the decrease in the occurrence and / or the intensity, or even the virtual disappearance or the 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 gas and / or aerosols.
• prophylaxis of aerotoxic syndrome refers to the decrease in occurrence, or even virtual disappearance or complete disappearance
• RECTIFIED SHEET (RULE 91) ISA / EP multiple symptoms, preferably all 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 the form of gases, products dispersed in the air, aerosol types.
• the symptom may be a neurological, neurobehavioural, neuromotor and / or reproductive symptom.
• the symptoms whose occurrence and / or intensity can be reduced by the use according to the invention, there may be mentioned, for example, psychological or psychosomatic disorders, chronic fatigue syndrome, severe migraines, multiple chemical sensitivity. , mysterious viral infections, sleep disturbances, depression, stress and anxiety.
• smoke event denotes the acute or chronic, preferably acute, exposure of at least one individual to aircraft cabin air contaminated with oils such as turbine oils or hydraulic oils. in the form of gas and / or aerosol.
• oils such as turbine oils or hydraulic oils. in the form of gas and / or aerosol.
• a smoke event if significant, can be detected in particular by the perception of a characteristic unpleasant 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.
• the present invention can thus relate to a method of lubricating a machine / device, such as aircraft or air-derivative turbines, comprising the following steps:
• non-neurotoxic or very low toxicity oil (risk level at a score of 0), preferably free of tricresyl phosphate and / or its analogues, said oil comprising at least one antiwear agent selected from a compound polyphosphorus of formula (I) wherein each of R1, R2, R3 and R4 is independently selected from: an alkyl group, an O-alkyl group, an aryl group, an or O-aryl group,
• A is a divalent group selected from a linear alkylene group comprising from 7 to 36 carbon atoms or branched from 6 to 36 carbon atoms, a monocyclic, polycyclic or polyaromatic arylene group or an aralkylene group, each of Xi and X ⁇ is independently a single bond, an oxygen atom or a nitrogen atom, and n is an integer between 1 and 5,
• Example 1 Toxicity study and in particular neurotoxicity study
• the polyphosphorus compounds according to the invention were studied and compared with other phosphorus compounds, in particular with TCP, in terms of cholinesterase inhibition, 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 "level of safety" for the use of these compounds as an anti-wear agent in oils for aircraft turbines or aero-derivatives.
• Acetylthiocholine iodide and butyrylthiocholine, and 5,5-dithiobis (2-nitrobenzoic) acid (DTNB) were purchased from Sigma Aldrich (Steinheim, Germany).
• Lyophilized BuChE from equine serum (eqBuChE, Sigma Aldrich) was dissolved in 0.1M phosphate buffer (pH 7.4) to obtain enzyme stock solutions with an enzymatic activity of 2.5 units / mL .
• Human erythrocyte AChE (hAChE, aqueous buffer solution,> 500 units / mg protein (BCA), Sigma Aldrich) was diluted in 20 mM HEPES buffer at pH 8 with 0.1% Triton X- 100 to obtain an enzyme solution with an enzyme activity of 0.25 units / mL.
• RECTIFIED SHEET (RULE 91) ISA / EP using a microplate reader (Synergy 2, Biotek, Colmar, France).
• the compounds to be tested were dissolved to 5x10 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 except acetyl or butyrylthiocholine, in order to take account of non-enzymatic reactions.
• Clusters 1 and 2 Two clusters (clusters 1 and 2) were defined by similarity from in particular monophosphate compounds known to be neurotoxic and reprotoxic such as ir ⁇ (ortho-cresyl) phosphate ToCP, tri (mefa-cresyl) phosphate, tri (para- cresyl) phosphate, trixylylphosphate and cresyl phosphate of saligenin.
• monophosphate compounds known to be neurotoxic and reprotoxic such as ir ⁇ (ortho-cresyl) phosphate ToCP, tri (mefa-cresyl) phosphate, tri (para- cresyl) phosphate, trixylylphosphate and cresyl phosphate of saligenin.
• cluster 5 A third cluster of probably toxic compounds has been identified (cluster 5), including in particular a CMR reprotoxic mutagenic mutagenic compound such as tri (n-butylphosphate).
• the degrees of neurotoxicity and reprotoxicity of the various compounds used according to the invention and of other monophosphate compounds were evaluated by QSAR (quantitative structure-activity relationship) modeling.
• the training set was defined with chemical structures compiled from several publicly available sources: HSBD (Hazardous Substances Data Bank), EPA (U. S. Environmental Protection Agency), ECHA (European Chemicals Agency) and NTP (National
• the validation set was constructed using compounds from different datasets than those used for the practice set. The molecules already present in the training set have been removed.
• the validation set consisted 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.
• a generalized linear model (GLM) method was chosen to perform a quantitative structure / activity relationship (QSAR) approach.
• 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 meaningful descriptors within training games.
• the performance of the QSAR models was measured by Receiver Operator Characteristic (ROC) curves and resulted in area under the curve (AUC) values of 0.90 and above for the prediction of neurotoxicity. and reprotoxicity, respectively.
• ROC Receiver Operator Characteristic
• the QSAR models were then used to predict (i) the categories of neurotoxicity of the compounds in the validation set (i.e. the neurotoxic / non-neurotoxic categorization), (ii) the categories of reprotoxicity of compounds in the validation set (i.e. reprotoxic / non-reprotoxic categorization).
• the performance of the QSAR models was measured by area under the curve (AUC) values and provided significant values of 0.70 and greater for the prediction of neurotoxicity and reprotoxicity, respectively.
• AUC area under the curve
• GLM-based QSAR models were then used to study the polyphosphorus compounds according to the invention.
• reagent A dialcohol, diamine, or aminoalcohol
• reagent A dialcohol, diamine, or aminoalcohol
• the reaction medium is diluted with toluene, approximately 10 volumes relative to reagent A.
• the reaction medium is heated between 25-110 ° C then using the dropping funnel, 2.2 molar equivalents of phosphate chloride are introduced dropwise.
• the triethylamine salt formed is removed by filtration and then washed with 5 volumes of ethyl acetate.
• the filtrate is then washed twice with 0.1 N HCl solution, twice with 0.1 N KOH solution and then with water until neutral pH.
• the organic phase is then dried with MgSQ4, filtered and then concentrated under reduced pressure.
• ISA / EP obtained is purified either by chromatography on silica gel, or by liquid-liquid extraction, or by precipitation.
• the products thus obtained are characterized by GC (gas chromatography) or GPC (gel permeation chromatography) chromatography, by 1 H and / or 31 P NMR analyzes. The yields obtained vary between 15 and 75%.
• the results of the tests carried out are shown in Fig. 2. to 9.
• the penultimate column corresponds to a risk level score with respect to the safety of these molecules which 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 no 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 models ), and molecular modeling via spherical harmonics (cluster classification) and it can range from 0 to 5.
• a value of 0 indicates no risk, and a value of 5 indicates a very high multiple 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.
• 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-
• Compound M tri (n-butylphosphate) (CAS 126-73-8) https://echa.europa.eu/en/registration- dossier / - / registered-dossier / 13548
• Compound N tris (chloroethyl) phosphate (CAS 115-96-8) https://echa.europa.eu/en/substance- information / - / substanceinfo / 100.003.744
• the compounds of the triarylphosphates type (TCP family) entirely belong to cluster 1 presenting a level of risk varying from 2 to 5 with an average of 3.6 out of the 8 molecules presenting complete characteristics.
• the compounds of cluster 1 appear, 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 heart of the molecule while the compounds of cluster 3 have a rather deployed and flattened shape resembling a butterfly shape.
• the molecules resulting from the modeling work by spherical harmonics are represented in FIG. 1. These compounds are therefore non-neurotoxic and non-reprotoxic alternatives to tricresyl phosphate and its tri-arylphosphates analogues.
• compound I2 described in patent application WO2010 / 149690, exhibits reduced inhibition on butyrylcholinesterase, but is found to be active with respect to acetylcholinesterase. Modeling classifies the latter as part of cluster 1, which confirms the experimental result on acetylcholinesterase.
• this sub-assembly is suitable for / configured for the prophylaxis of aerotoxic syndrome in particular in the event of a smoke event.
• This sub-assembly 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.
• the other polyphosphorus compounds and in particular the other polyphosphorus compounds used as anti-wear agent in an oil and known from the prior art do not exhibit this new technical effect (ie: reduce and / or prevent neurotoxicity of an oil or for the prophylaxis of aerotoxic syndrome).
• the other compounds do not exhibit this new technical effect (ie: reduce and / or prevent neurotoxicity of an oil or for the prophylaxis of aerotoxic syndrome).
• the other compounds do not exhibit this new technical effect (ie: reduce and / or prevent neurotoxicity of an oil or for the prophylaxis of aerotoxic syndrome).
• ISA / EP anti-wear and other organophosphorus compounds known and used in the field of lubricants and aircraft oils T are neurotoxic (such as compounds E, P, 11-3, L, R and M, the latter being used in hydraulic fluids of the 'aviation).
• compound 13 does not show signs of toxicity to human health.
• the table in FIG. 5 shows that this compound 13 is a mixture of neurotoxic compounds belonging to cluster 1 including triphenylphosphate and tri (p-tertbutylphenyl) phosphate.
• compound A which according to the ECHA website does not show any sign of neurotoxicity, and yet presents a risk level 4.
• a person skilled in the art would therefore not have been encouraged or encouraged. in selecting the subset formed by the compounds of general formula (I) (in particular from known and public generic toxicity data) in order to reduce and / or prevent the neurotoxicity of an oil or for the prophylaxis of aerotoxic syndrome.

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