EP4114910A1 - Specific organophosphorus compounds as non-neurotoxic anti-wear agents - Google Patents
Specific organophosphorus compounds as non-neurotoxic anti-wear agentsInfo
- Publication number
- EP4114910A1 EP4114910A1 EP21725555.3A EP21725555A EP4114910A1 EP 4114910 A1 EP4114910 A1 EP 4114910A1 EP 21725555 A EP21725555 A EP 21725555A EP 4114910 A1 EP4114910 A1 EP 4114910A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- oil
- compound
- group
- formula
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000002903 organophosphorus compounds Chemical class 0.000 title abstract description 4
- 231100000501 nonneurotoxic Toxicity 0.000 title description 13
- 206010029350 Neurotoxicity Diseases 0.000 claims abstract description 48
- 206010044221 Toxic encephalopathy Diseases 0.000 claims abstract description 48
- 231100000228 neurotoxicity Toxicity 0.000 claims abstract description 48
- 230000007135 neurotoxicity Effects 0.000 claims abstract description 48
- 231100000669 Aerotoxic syndrome Toxicity 0.000 claims abstract description 22
- 238000011321 prophylaxis Methods 0.000 claims abstract description 17
- 239000000779 smoke Substances 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 135
- -1 isodecyl group Chemical group 0.000 claims description 43
- 239000003795 chemical substances by application Substances 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 230000000694 effects Effects 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 239000007866 anti-wear additive Substances 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 102100033639 Acetylcholinesterase Human genes 0.000 claims description 13
- 108010022752 Acetylcholinesterase Proteins 0.000 claims description 13
- 229940022698 acetylcholinesterase Drugs 0.000 claims description 13
- 102000004190 Enzymes Human genes 0.000 claims description 12
- 108090000790 Enzymes Proteins 0.000 claims description 12
- 229940088598 enzyme Drugs 0.000 claims description 12
- 108010053652 Butyrylcholinesterase Proteins 0.000 claims description 10
- 102100032404 Cholinesterase Human genes 0.000 claims description 10
- RYUJRXVZSJCHDZ-UHFFFAOYSA-N 8-methylnonyl diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(OCCCCCCCC(C)C)OC1=CC=CC=C1 RYUJRXVZSJCHDZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 230000004071 biological effect Effects 0.000 claims description 6
- 239000003921 oil Substances 0.000 description 94
- YSMRWXYRXBRSND-UHFFFAOYSA-N TOTP Chemical group CC1=CC=CC=C1OP(=O)(OC=1C(=CC=CC=1)C)OC1=CC=CC=C1C YSMRWXYRXBRSND-UHFFFAOYSA-N 0.000 description 42
- 230000002887 neurotoxic effect Effects 0.000 description 26
- 238000004617 QSAR study Methods 0.000 description 24
- 231100000189 neurotoxic Toxicity 0.000 description 24
- 238000012360 testing method Methods 0.000 description 23
- 102000003914 Cholinesterases Human genes 0.000 description 14
- 108090000322 Cholinesterases Proteins 0.000 description 14
- 231100001260 reprotoxic Toxicity 0.000 description 14
- 239000010723 turbine oil Substances 0.000 description 14
- 239000000126 substance Substances 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 12
- 208000024891 symptom Diseases 0.000 description 12
- 229920005862 polyol Polymers 0.000 description 10
- 239000003963 antioxidant agent Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- 231100000419 toxicity Toxicity 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 8
- 229910052698 phosphorus Inorganic materials 0.000 description 8
- 150000003077 polyols Chemical class 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- 230000001154 acute effect Effects 0.000 description 7
- 230000001747 exhibiting effect Effects 0.000 description 7
- 239000010720 hydraulic oil Substances 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 229940059574 pentaerithrityl Drugs 0.000 description 7
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 7
- 239000011574 phosphorus Substances 0.000 description 7
- 150000003018 phosphorus compounds Chemical class 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000012549 training Methods 0.000 description 7
- 238000010200 validation analysis Methods 0.000 description 7
- 239000000654 additive Substances 0.000 description 6
- 150000004982 aromatic amines Chemical class 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 230000001050 lubricating effect Effects 0.000 description 6
- 238000000302 molecular modelling Methods 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- AWBGQVBMGBZGLS-UHFFFAOYSA-N butyrylthiocholine Chemical compound CCCC(=O)SCC[N+](C)(C)C AWBGQVBMGBZGLS-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 210000001428 peripheral nervous system Anatomy 0.000 description 5
- 235000021317 phosphate Nutrition 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 4
- 239000002199 base oil Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- CGSLYBDCEGBZCG-UHFFFAOYSA-N Octicizer Chemical compound C=1C=CC=CC=1OP(=O)(OCC(CC)CCCC)OC1=CC=CC=C1 CGSLYBDCEGBZCG-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940048961 cholinesterase Drugs 0.000 description 3
- 239000013065 commercial product Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 231100001096 no neurotoxicity Toxicity 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- TXBCBTDQIULDIA-UHFFFAOYSA-N 2-[[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC(CO)(CO)CO TXBCBTDQIULDIA-UHFFFAOYSA-N 0.000 description 2
- XFZZDIHCNHYESF-UHFFFAOYSA-N 7-amino-1-bromo-4-phenyl-5,7,8,9-tetrahydrobenzo[7]annulen-6-one Chemical compound C=12CC(=O)C(N)CCC2=C(Br)C=CC=1C1=CC=CC=C1 XFZZDIHCNHYESF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NUPSHWCALHZGOV-UHFFFAOYSA-N Decyl acetate Chemical compound CCCCCCCCCCOC(C)=O NUPSHWCALHZGOV-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OIZXRZCQJDXPFO-UHFFFAOYSA-N Octadecyl acetate Chemical compound CCCCCCCCCCCCCCCCCCOC(C)=O OIZXRZCQJDXPFO-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- HRKAMJBPFPHCSD-UHFFFAOYSA-N Tri-isobutylphosphate Chemical compound CC(C)COP(=O)(OCC(C)C)OCC(C)C HRKAMJBPFPHCSD-UHFFFAOYSA-N 0.000 description 2
- 108010021119 Trichosanthin Proteins 0.000 description 2
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 description 2
- GTVWRXDRKAHEAD-UHFFFAOYSA-N Tris(2-ethylhexyl) phosphate Chemical compound CCCCC(CC)COP(=O)(OCC(CC)CCCC)OCC(CC)CCCC GTVWRXDRKAHEAD-UHFFFAOYSA-N 0.000 description 2
- 239000012445 acidic reagent Substances 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000003063 flame retardant Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- ZAZKJZBWRNNLDS-UHFFFAOYSA-N methyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC ZAZKJZBWRNNLDS-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- YLYBTZIQSIBWLI-UHFFFAOYSA-N octyl acetate Chemical compound CCCCCCCCOC(C)=O YLYBTZIQSIBWLI-UHFFFAOYSA-N 0.000 description 2
- 235000019645 odor Nutrition 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 229920001515 polyalkylene glycol Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000001850 reproductive effect Effects 0.000 description 2
- CQRYARSYNCAZFO-UHFFFAOYSA-N salicyl alcohol Chemical compound OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- XZZNDPSIHUTMOC-UHFFFAOYSA-N triphenyl phosphate Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)(=O)OC1=CC=CC=C1 XZZNDPSIHUTMOC-UHFFFAOYSA-N 0.000 description 2
- BOSMZFBHAYFUBJ-UHFFFAOYSA-N tris(4-methylphenyl) phosphate Chemical compound C1=CC(C)=CC=C1OP(=O)(OC=1C=CC(C)=CC=1)OC1=CC=C(C)C=C1 BOSMZFBHAYFUBJ-UHFFFAOYSA-N 0.000 description 2
- LORSVOJSXMHDHF-UHFFFAOYSA-N tris(4-tert-butylphenyl) phosphate Chemical compound C1=CC(C(C)(C)C)=CC=C1OP(=O)(OC=1C=CC(=CC=1)C(C)(C)C)OC1=CC=C(C(C)(C)C)C=C1 LORSVOJSXMHDHF-UHFFFAOYSA-N 0.000 description 2
- VDIFKDMFGPIVCQ-UHFFFAOYSA-N (2-tert-butylphenyl) diphenyl phosphate Chemical compound CC(C)(C)C1=CC=CC=C1OP(=O)(OC=1C=CC=CC=1)OC1=CC=CC=C1 VDIFKDMFGPIVCQ-UHFFFAOYSA-N 0.000 description 1
- VHYHRNYPVNFGNR-UHFFFAOYSA-N (3,5-ditert-butylphenyl)methanol Chemical compound CC(C)(C)C1=CC(CO)=CC(C(C)(C)C)=C1 VHYHRNYPVNFGNR-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- PIMNDJYXVOQVSP-UHFFFAOYSA-N 1-o-ethyl 10-o-hexyl decanedioate Chemical compound CCCCCCOC(=O)CCCCCCCCC(=O)OCC PIMNDJYXVOQVSP-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- CWPPDTVYIJETDF-UHFFFAOYSA-N 2,2,4-trimethylpentan-1-ol Chemical compound CC(C)CC(C)(C)CO CWPPDTVYIJETDF-UHFFFAOYSA-N 0.000 description 1
- SZSSMFVYZRQGIM-UHFFFAOYSA-N 2-(hydroxymethyl)-2-propylpropane-1,3-diol Chemical compound CCCC(CO)(CO)CO SZSSMFVYZRQGIM-UHFFFAOYSA-N 0.000 description 1
- RWLALWYNXFYRGW-UHFFFAOYSA-N 2-Ethyl-1,3-hexanediol Chemical compound CCCC(O)C(CC)CO RWLALWYNXFYRGW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- PTJWCLYPVFJWMP-UHFFFAOYSA-N 2-[[3-hydroxy-2-[[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC(CO)(CO)COCC(CO)(CO)CO PTJWCLYPVFJWMP-UHFFFAOYSA-N 0.000 description 1
- NTBLZMAMTZXLBP-UHFFFAOYSA-M 2-acetylsulfanylethyl(trimethyl)azanium;iodide Chemical compound [I-].CC(=O)SCC[N+](C)(C)C NTBLZMAMTZXLBP-UHFFFAOYSA-M 0.000 description 1
- WEQAAFZDJROSBF-UHFFFAOYSA-M 2-butanoylsulfanylethyl(trimethyl)azanium;iodide Chemical compound [I-].CCCC(=O)SCC[N+](C)(C)C WEQAAFZDJROSBF-UHFFFAOYSA-M 0.000 description 1
- OTKHZEOSBVSFCJ-UHFFFAOYSA-N 2-butylbutane-1,3-diol Chemical compound CCCCC(CO)C(C)O OTKHZEOSBVSFCJ-UHFFFAOYSA-N 0.000 description 1
- VNAWKNVDKFZFSU-UHFFFAOYSA-N 2-ethyl-2-methylpropane-1,3-diol Chemical compound CCC(C)(CO)CO VNAWKNVDKFZFSU-UHFFFAOYSA-N 0.000 description 1
- SPXWGAHNKXLXAP-UHFFFAOYSA-N 2-methylpentane-1,3-diol Chemical compound CCC(O)C(C)CO SPXWGAHNKXLXAP-UHFFFAOYSA-N 0.000 description 1
- GANZODCWZFAEGN-UHFFFAOYSA-L 2-nitro-5-sulfidobenzoate Chemical compound [O-]C(=O)C1=CC([S-])=CC=C1[N+]([O-])=O GANZODCWZFAEGN-UHFFFAOYSA-L 0.000 description 1
- MBEDWQDNVFZYCN-UHFFFAOYSA-N 4-methylnonane-5,5-diol Chemical compound CCCCC(O)(O)C(C)CCC MBEDWQDNVFZYCN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 239000004604 Blowing Agent Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 206010048650 Cholinesterase inhibition Diseases 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010010947 Coordination abnormal Diseases 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- NEHDRDVHPTWWFG-UHFFFAOYSA-N Dioctyl hexanedioate Chemical compound CCCCCCCCOC(=O)CCCCC(=O)OCCCCCCCC NEHDRDVHPTWWFG-UHFFFAOYSA-N 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical group C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000002430 Multiple chemical sensitivity Diseases 0.000 description 1
- 206010060860 Neurological symptom Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000012545 Psychophysiologic disease Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical group OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- LEKJTGQWLAUGQA-UHFFFAOYSA-N acetyl iodide Chemical compound CC(I)=O LEKJTGQWLAUGQA-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 231100000693 bioaccumulation Toxicity 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- ZDWGXBPVPXVXMQ-UHFFFAOYSA-N bis(2-ethylhexyl) nonanedioate Chemical compound CCCCC(CC)COC(=O)CCCCCCCC(=O)OCC(CC)CCCC ZDWGXBPVPXVXMQ-UHFFFAOYSA-N 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- YRIBGSCJIMXMPJ-UHFFFAOYSA-N butyrylcholine Chemical compound CCCC(=O)OCC[N+](C)(C)C YRIBGSCJIMXMPJ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000004456 color vision Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- DHEMFBSSQAFTOU-UHFFFAOYSA-N dibutyl 2-[bis(2-ethylhexoxy)phosphinothioylsulfanyl]butanedioate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)SP(=S)(OCC(CC)CCCC)OCC(CC)CCCC DHEMFBSSQAFTOU-UHFFFAOYSA-N 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- QYDYPVFESGNLHU-UHFFFAOYSA-N elaidic acid methyl ester Natural products CCCCCCCCC=CCCCCCCCC(=O)OC QYDYPVFESGNLHU-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000005183 environmental health Effects 0.000 description 1
- 231100000584 environmental toxicity Toxicity 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000010696 ester oil Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 210000000609 ganglia Anatomy 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- QWMUDOFWQWBHFI-UHFFFAOYSA-N hydroxy-imino-diphenoxy-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1OP(=O)(N)OC1=CC=CC=C1 QWMUDOFWQWBHFI-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000016290 incoordination Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000018883 loss of balance Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QYDYPVFESGNLHU-KHPPLWFESA-N methyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC QYDYPVFESGNLHU-KHPPLWFESA-N 0.000 description 1
- 229940073769 methyl oleate Drugs 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 230000001095 motoneuron effect Effects 0.000 description 1
- 239000010705 motor oil Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 229940117969 neopentyl glycol Drugs 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000002957 persistent organic pollutant Substances 0.000 description 1
- 208000022821 personality disease Diseases 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 231100000316 potential neurotoxicity Toxicity 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000010731 rolling oil Substances 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QXJQHYBHAIHNGG-UHFFFAOYSA-N trimethylolethane Chemical compound OCC(C)(CO)CO QXJQHYBHAIHNGG-UHFFFAOYSA-N 0.000 description 1
- LLPMAOBOEQFPRE-UHFFFAOYSA-N tris(3,5-dimethylphenyl) phosphate Chemical compound CC1=CC(C)=CC(OP(=O)(OC=2C=C(C)C=C(C)C=2)OC=2C=C(C)C=C(C)C=2)=C1 LLPMAOBOEQFPRE-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- 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
- 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
- C10N2030/40—Low content or no content compositions
-
- 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
- C10N2030/64—Environmental friendly compositions
-
- 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 air-derived turbines or hydraulic oils.
- Aircraft or aero-derivative turbine engines use synthetic lubricants typically 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 the conditions normal operations (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 work the same way to that of aircraft turbines and use lubricants of similar composition, in particular in terms of anti-wear agents.
- organophosphate antiwear additives such as tricresylphosphate (TCP), especially its tri-ortho-cresylphosphate isomer (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).
- TCP tricresylphosphate
- ToCP tri-ortho-cresylphosphate isomer
- OPIDN organophosphate-induced delayed neuropathy
- TCP is also known to be reprotoxic.
- 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.
- Patent application 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. However, the simple demonstration of a limited effect on a single cholinesterase does not seem sufficient to guarantee a level of safety sufficient for the expectations of aviation.
- Document US 2019/0277339 describes a zinc-free rolling oil composition intended for the metallurgical industry.
- This oil composition may comprise, by mass, relative to its total mass, 0.05% to 2% of a first ash-free phosphorus-based additive.
- Document WO 2016/032246 describes a lubricating composition exhibiting excellent thermo-oxidation stability and color stability.
- the composition may include a secondary phosphorus-based antioxidant.
- composition having good fire resistance and suitable viscosity characteristics.
- the composition comprises a combination of at least two phosphates, the second phosphate of which may comprise an alkyl diarylphosphate and at least a combination of two polyalkylene glycols (ester base).
- organophosphorus compounds some of which are known as flame retardants, exhibit both satisfactory anti-wear and thermal stability properties, or even improved, and greatly reduced neurotoxicity compared with that.
- 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 aerotoxic syndrome, in particular in the event of a smoke event.
- the present invention relates to the use of at least one compound of formula wherein A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of A and A3 ⁇ 4 is independently an aryl group as an antiwear agent in an oil, preferably a turbine oil, for reduce and / or prevent the neurotoxicity of said oil.
- 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 level of risk in terms of 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 non-reprotoxic.
- the polyphosphorus compounds of formula (I) can thus be used to obtain an oil which is non-neurotoxic or has reduced neurotoxicity.
- the invention also relates to the use of 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 A and A3 ⁇ 4 is independently an aryl group as an antiwear agent in an oil, preferably a turbine oil, for prophylaxis of aerotoxic syndrome, preferably in the event of a smoke event.
- A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms
- each of A and A3 ⁇ 4 is independently an aryl group as an antiwear agent in an oil, preferably a turbine oil, for prophylaxis of aerotoxic syndrome, preferably in the event of a smoke event.
- 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 or cluster 4.
- a first object of the invention is the use of at least one compound of formula (I)
- OAr 2 wherein A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of Ar1 and Ar2 is independently an aryl group as an antiwear agent in an oil 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. oil in which they are included, namely by their presence (generally in the majority), in particular compared to other conventional anti-wear compounds generally neurotoxic, the compound (s) of formula (I) make it possible to lower / reduce the neurotoxicity of an oil and to obtain an oil which is non-neurotoxic or at least of 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
- motor impairment such as weakness, tremors, incoordination, convulsions, etc.
- Neurotoxicity means the ability of a substance or compound to induce adverse effects in the nervous system of a mammal, such as humans.
- the nervous system is divided into the central nervous system (CNS) and the peripheral nervous system (PNS).
- the CNS is located in the cranial box and the spine. It includes the brain, brainstem, and spinal cord. Its role is to receive, record and interpret the signals which 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.
- 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 acid. In physiology, this reaction is necessary to allow cholinergic receptors to return to their resting state after activation.
- neurotoxicity is distinguished from the broader and global notion of “toxicity”.
- 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 to reproduction). on human health and yet be highly neurotoxic (or vice versa).
- 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 OSAR 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 and the activity on an enzyme butyrylcholinesterase, 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.
- 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.
- a value greater than or equal to 15 mg / L for IC50 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; etc.
- the compound (s) of formula (I) belong to Cluster 3 or to 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.
- the compound (s) of formula (I) exhibit a percentage value by QSAR modeling (quantitative structure activity relationship) less than or equal to 0 70 for the measurement of neurotoxicity 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 measurement of reprotoxicity.
- 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, capable of creating pollution in the form of gas and / or aerosol in the cabin.
- the oil is selected from the group consisting of oils for aircraft or aero-derivatives, transmission oils for helicopters and fluids for weapons.
- the oil is an oil for aircraft or air-derived turbines.
- alkyl group of the “A” group denotes a linear or branched saturated hydrocarbon group. The alkyl groups contain from 10 to 32 carbon atoms (C10 to C32).
- the alkyl groups comprise from 10 to 20 carbon atoms (C10 to C20), 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.
- alkyl groups according to the invention, mention may in particular be made of decyl, isodecyl, dodecyl, isododecyl, octadecyl, 2-butyloctyl, 2-hexyldecyl, 2-octyldodedyl and 2-tetradecyloctadecyl groups.
- alkyl group according to the invention can be optionally substituted.
- substituted alkyl group denotes a linear or branched saturated hydrocarbon chain comprising from 10 to 32 carbon atoms (C10 to C32) substituted at the level of one or more of its atoms, by at least one substituent selected from the group consisting of C 1 -C 18 alkyl groups, OH hydroxyl group, NH2 or primary amine group NHR with R alkyl or aryl group, O-phosphate group such as O-diphenylphosphate group, and atoms halogen.
- 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 the desired properties on the compound.
- substitution with halogen atoms could allow an improvement in the extreme pressure and / or antiwear effects of the compounds.
- the "alkyl group” is unsubstituted.
- aryl group denotes a carbon-based monocyclic or polycyclic aromatic group, optionally interrupted by one or more heteroatoms which may in particular be chosen from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
- Each aromatic or polyaromatic ring has 5 to 14 atoms.
- substituent chosen from the group consisting of C 1 to C 18 alkyl groups, preferably a linear or branched C 1 to C 10 alkyl group OR a C1-C18 alkylene group comprising a perfluorinated group, a hydroxyl group OH, a primary NH2 or secondary amine group NHR with R
- 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, preferably C 1 to C 10, alkyl groups, in particular of Ci to C10, typically Ci to C3 .
- halogen atom an atom selected from the group consisting of chlorine, bromine, fluorine and iodine.
- "A" is chosen 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, a 2-butyl 1-octyl group, a 2-hexyl 1-decyl group, a 2-octyl 1 -dodecyl group and a 2-tetradecyl 1 -octadecyl group.
- 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.
- a and A3 ⁇ 4" are independently an unsubstituted phenyl or a substituted phenyl, preferably substituted with at least one ester substituent or an alkyl substituent such as a methyl group, an ethyl group, an isopropyl group or a tert-butyl group.
- a and A3 ⁇ 4 are two unsubstituted phenyls.
- a and A3 ⁇ 4 are two phenyls substituted, preferably with an alkyl substituent such as a methyl group.
- the compound of formula (I) is selected from the group consisting of isodécyldiphenylposphate, n-dodécyldiphenylphosphate, isotrimücyldiphenylphosphate, hexadécyldiphenylphosphate, octadécyldiphenylposphate, 2-octadécyldiphenylphosphate, , 2-hexyl 1-decyldiphenylphosphate, 2-octyl-1-dodécyldiphenylphosphate, 2-tetradecyl 1-octadecyldiphenylphosphate, and any mixture thereof.
- the compound of formula (I) is selected from the group consisting of isodecyldiphenylphosphate, n-dodécyldiphenylphospate, 2-octyl-1-dodécyldiphenylphosphate, and any mixture thereof.
- the compound of formula (I) is isodecyldiphenylphosphate. It can be present in the oil as an antiwear agent in admixture 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 antiwear agent present in the oil.
- the oil in which the compound of formula (I) is used as an antiwear agent preferably does not include tricresylphosphate. In one embodiment, it substantially does not include tricresylphosphate.
- the oil contains as sole (s) antiwear agent (s) the compound (s) of formula (I).
- the antiwear agent according to the invention of general formula (I) represents, by mass, relative to the total mass of the antiwear agents present in the oil, from 50% to 100%, preferably from 80% to 100%, and in particular from 90% to 100% and typically 100%.
- 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.
- the oil in which the compound of formula (I) is used according to the invention substantially does not include, preferably does not include, triarylphosphate antiwear additive.
- the oil in which the compound of formula (I) is used according to the invention substantially does not include, preferably does not include, an organophosphate antiwear additive other than the compound (s) of formula (I).
- the oil in which the compound of formula (I) is used according to the invention substantially does not include, preferably does not include, any antiwear additive other than the compound (s) of formula ( I).
- the oil is preferably an oil for aircraft turbines or aero-derivatives.
- At least one compound of formula (I) as an antiwear 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.
- the compounds of formula (I) exhibit, 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 of reprotoxicity, and are therefore good.
- alternatives to conventional antiwear agents such as tricresylphosphate and its triarylphosphate analogues which are known to be neurotoxic and reprotoxic.
- the use of at least one derivative of formula (I) as an antiwear agent in an oil is for the prophylaxis of aerotoxic syndrome, in particular in the event of a smoke occurrence.
- the use of at least one derivative of formula (I) as an antiwear agent in an oil for the prophylaxis of aerotoxic syndrome in the event of a smoke event can be for lubricating at least one airplane or aeroderivative turbine, for the prophylaxis of aerotoxic syndrome, in particular in smoke event.
- 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 and the activity on an enzyme butyrylcholinesterase, 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.
- 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;
- a value greater than or equal to 15 mg / L for IC50 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;
- the compound (s) of formula (I) belong to Cluster 3 or to Cluster 4, preferentially 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.
- 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% 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 the measurement on reprotoxicity.
- 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.
- aerotoxic syndrome prophylaxis refers to the decrease in the occurrence, or even the near disappearance or the complete disappearance, of several symptoms, preferably all of them. 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 gas and / or aerosols.
- 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.
- an oil not comprising tricresylphosphate is meant an oil in which the amount of tricresylphosphate, regardless of its type of substitution (ortho, meta, para) is less than the detection limit of the usual analysis techniques such as 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.
- 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.
- 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 Ar1 and Ar2 is independently an aryl group, having little or almost no neurotoxicity.
- This oil can also be used for the prophylaxis of aerotoxic syndrome.
- the oil is for its use for the prophylaxis of aerotoxic syndrome in the event of a smoke event.
- the oil for its use in the prophylaxis of aerotoxic syndrome in particular in the event of a smoke event, is an oil for lubricating aircraft or aerodrive turbines.
- composition of the oil suitable for the invention will be described below.
- substantially not denotes amounts 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 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.
- 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 amino antioxidant, and at least one antiwear additive of formula (I).
- the oil 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, metal corrosion inhibitors, passivants, agents improving the viscosity index, detergents or dispersing agents, defoamers, surfactants, blowing agents, tackifiers, stabilizers, bulking agents, stabilizers against hydrolysis, additives suitable for 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) 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 according to the invention, there may be mentioned monoesters of octyl acetate, decyl acetate, octadecyl acetate, methyl myristate, 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 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 to C 30 alkyl groups, or styrene.
- Polymeric aromatic amine antioxidants are the polymerization products of aromatic amine antioxidants as defined above, either with one another or in the presence of a different comonomer.
- Examples of oligomeric or polymeric aromatic amino antioxidants which can be used in 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.
- 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 compound of formula (I) in which A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of A and A3 ⁇ 4 is independently an aryl group and in particular exhibiting a level of risk in terms of neurotoxicity of 0.
- the present invention can thus relate to a method of lubricating a machine / device, such as aircraft turbines or aerodrives, 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 of formula (I) in which A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of A and Ar ⁇ is independently an aryl group and in particular exhibiting a risk level in terms of neurotoxicity of 0,
- Example 1 Toxicity study and in particular neurotoxicity study
- 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, of 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 anti-wear agents 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, 3500 protein units / mg (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.
- Clusters 1 and 2 were defined by similarity, in particular from monophosphate compounds known to be toxic.
- 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 non-toxic training set.
- the validation set was built using compounds from different datasets than those used for the training 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
- the GLM-based QSAR models were then used to study the aryl diphosphorus compounds according to the invention.
- the filtrate was then washed twice with 0.1N HCl solution, twice with 0.1N KOH solution and then with water until neutral pH.
- the organic phase was then dried with MgS0 4 , 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 phosphates thus obtained were characterized by GC or GPC chromatography, by 1 H and 31 P NMR analyzes. The yields obtained vary between 52 and 90%.
- 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.
- ND means not determined.
- Tricresylphosphate (CAS 1330-78-5) corresponds to the commercial product Durad 125 (https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.239.100)
- Compound F Tri (2,6-difluorophenyl) phosphate
- Compound G Tri (4-isopropylbenzoate) phosphate
- Compound H di (p-tertbutylphenyl) phenylphosphate
- Compound 11 tri-phenyl phosphate (CAS 204-112-2) (https://echa.europa.eu/fr/substance- information / - / substanceinfo / 100.003.739)
- Compound I3 Tert-butylphenyl diphenyl phosphate (CAS 700-990-0) corresponds to the commercial product Durad 150B, (https://echa.europa.eu/fr/substance-information/-
- Compound 1 isodécyldiphenylphosphate (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-dodécyldiphenylphosphate (CAS 27460-02-2) (https://echa.europa.eu/en/substance-information/-/substanceinfo/100.103.005)
- compound A (2-ethylhexyldiphenylphosphate) belongs to cluster 1 of neurotoxic and reprotoxic organophosphate molecules
- compound 1, which corresponds to formula (I) according to the invention exhibits high IC50 inhibition values compared to hAChE and eqBuChE cholinesterases.
- modeling via spherical harmonics shows that this molecule belongs to a cluster of molecules different from neurotoxic clusters 1 and 2.
- the semi-empirical QSAR models also indicate a difference in reactivity.
- Compound 1 has a risk level equal to 0, while the compounds of cluster 1 have a risk level of at least 2.
- QSAR modeling also indicates that compound 3, which corresponds to formula (I) according to the invention, belong to a cluster different 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.
- the compounds of formula (I) according to the invention therefore 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 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 according to the invention have a rather deployed and flattened shape approaching 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 tricresylphosphate and its tri-arylphosphate analogues or to the other compounds tested (generally also used as a anti-wear agent in turbine oil) based on phosphorus.
- these intro and modeling tests show that the Applicant has selected, in a non-arbitrary manner, among all the existing phosphorus-based compounds and generally exhibiting an anti-wear action in an oil, a restricted subset of compounds of general formula (I).
- This subset also exhibits a technical effect different from other phosphorus-based compounds.
- 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 of a turbine oil intended for aviation.
- this sub-assembly is suitable / configured for the prophylaxis of aerotoxic syndrome in particular in the event of 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 phosphorus compounds and in particular the other phosphorus compounds used as antiwear 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 known anti-wear compounds comparativative compounds E, 11-3, M, N and P
- the other known anti-wear compounds are neurotoxic.
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Lubricants (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the use of specific organophosphorus compounds as anti-wear agents in an oil so as to prevent and/or reduce the neurotoxicity of said oil and/or provide prophylaxis against aerotoxic syndrome in the instance of a smoke event.
Description
COMPOSES ORGANOPHOSPHORES SPECIFIQUES COMME AGENTS ANTIUSURE SPECIFIC ORGANOPHOSPHORUS COMPOUNDS AS ANTIWEAR AGENTS
NON NEUROTOXIQUES NON NEUROTOXIC
Domaine Technique Technical area
La présente invention concerne le domaine technique des additifs anti-usure utilisés dans des huiles, telles que des huiles pour lubrifier des turbines d’avion ou aérodérivées ou des huiles hydrauliques. The present invention relates to the technical field of anti-wear additives used in oils, such as oils for lubricating aircraft or air-derived turbines or hydraulic oils.
Arrière-plan technologique Technological background
Les moteurs de turbines d’avions ou aérodérivées utilisent des lubrifiants synthétiques comprenant généralement une base ester et une variété d’additifs anti-usure issus de la famille des organophosphates, tels que les triarylphosphates. L’additif anti-usure le plus utilisé commercialement est le tricrésylphosphate (TCP), qui possède des propriétés anti-usure singulières pouvant être considérées comme uniques à ce jour. Ses analogues tri arylphosphates sont également des additifs anti-usure intéressants. Aircraft or aero-derivative turbine engines use synthetic lubricants typically 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.
Des fuites de lubrifiants, notamment ceux contenant du tricrésylphosphate ou un de ses analogues tri-arylphosphates, dans l’air des cabines d’avion peuvent prendre source au niveau de joints usés ou défectueux, ou même dans des conditions normales d’utilisation par passage des lubrifiants dans l’air destiné à la pressurisation de la cabine. Ces fuites répétées sont explicitées (Michaelis S. et al. Public Health Panorama 2017, 3, 2, p.198-211) comme étant dues à des variations de pression entre la chambre de roulements et le circuit d’air exercées par les conditions normales d’opération (augmentation de la puissance moteur, décollage, ...). Dans certaines circonstances, la fuite peut devenir très importante, généralement suite à la casse d’un roulement dans la turbine, celle-ci conduisant à un évènement de fumée, ou brouillard blanc visible en cabine. 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 the conditions normal operations (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.
Le syndrome aérotoxique est un état pathologique mêlant symptômes physiques et neurologiques, causé par les effets à court et à long termes d'une exposition à de l'air de cabine d'avion, contaminé par des huiles hydrauliques ou des huiles de moteurs ou tout autre polluant organique présent sous forme de gaz et/ou d’aérosols. Les symptômes reportés sont généralement non-spécifiques, et les études de qualité de l’air en cabine indiquent des niveaux de contaminants qui sont inférieurs aux limites d’exposition et non dangereux pour la santé humaine, la difficulté étant de mesurer en continu et en service des émanations d’huiles, par définition non gazeuses, véhiculées dans l’air, se déposant et se concentrant, épisodiquement, à différentes localisations de l’avion (Kasper Solbu et al. J. Environ. Monit. 2011 , 13, 1393). 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 ).
Des symptômes similaires à ceux du syndrome aérotoxique peuvent également être observés dans des environnements au sol en présence de turbines aérodérivées, par exemple au niveau de plateformes offshore. Les turbines aérodérivées ont un fonctionnement identique
à celui des turbines d’avions et mettent en œuvre des lubrifiants de composition similaire, notamment en termes d’agents anti-usure. Symptoms similar to those of aerotoxic syndrome can also be observed in ground environments in the presence of aero-derived turbines, for example at offshore platforms. Aero-derived turbines work the same way to that of aircraft turbines and use lubricants of similar composition, in particular in terms of anti-wear agents.
Néanmoins, un certain nombre d’études (Michaelis, S. étal. Public Health Panorama 2017, 3, 2, p.198-211) ont mis en évidence une relative relation de cause à effet entre l’exposition aiguë et/ou chronique à des substances contaminant l’air de cabines d’avion et des symptômes neurologiques, neurocomportementaux et respiratoires. Nevertheless, a certain number of studies (Michaelis, S. etal. Public Health Panorama 2017, 3, 2, p.198-211) have demonstrated a relative cause and effect relationship between acute and / or chronic exposure. substances contaminating the air of aircraft cabins and neurological, neurobehavioural and respiratory symptoms.
Les additifs anti-usure organophosphates classiques, tels que le tricrésylphosphate (TCP), notamment son isomère tri-ortho-crésylphosphate (ToCP), sont connus pour présenter un effet neurotoxique puissant (Craig P. étal. Journal of Toxicology and Environmental Health Part B : Critical Reviews 1999, 2, 4, p.281 -300). Au-delà de la toxicité générique associée aux organophosphates employés très largement dans divers domaines, notamment en tant qu’insecticides et pesticides, une des raisons spécifique et reconnue à cet effet neurotoxique est la conversion rapide in vivo des isomères de tricrésylphosphate comprenant au moins une substitution en ortho en un métabolite nommé saligénine qui est un inhibiteur puissant des cholinestérases. L’empoisonnement au ToCP conduit à une pathologie dénommée neuropathie différée induite par les phosphates organiques (« Organophosphate-induced delayed neuropathy » (OPIDN) en anglais) dont le mécanisme a été largement étudié. En outre, le TCP étant également connu pour être reprotoxique. Conventional organophosphate antiwear additives, such as tricresylphosphate (TCP), especially its tri-ortho-cresylphosphate isomer (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 conversion in vivo of tricresylphosphate isomers comprising at least one ortho substitution for a metabolite called saligenin which is a potent cholinesterase inhibitor. ToCP poisoning leads to a pathology called organophosphate-induced delayed neuropathy (OPIDN), the mechanism of which has been widely studied. In addition, TCP is also known to be reprotoxic.
Des huiles comprenant comme additif anti-usure du TCP ne comprenant pas d’isomère ortho ont été développées. Néanmoins, malgré l’absence de ToCP dans le TCP, le niveau d’inhibition des cholinestérases dans le sérum de rats exposés au TCP n’est pas nul et, bien que faible, il est persistant (Mackerer CR et al. J. Toxicol. Env. Health Part A 1999 57(5) :293-328). De même, des travaux plus anciens démontrent des problèmes de démyélinisation de la moelle épinière faisant suite à une exposition à du TCP présent sous ses formes méta et para (W.N. Aldridge, Biochemical Journal 1954 56, 185-189). Oils comprising as an 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 rats exposed to TCP is not zero and, although low, it is persistent (Mackerer CR et al. J. Toxicol Env. Health Part A 1999 57 (5): 293-328). Likewise, older work demonstrates spinal cord demyelination problems following exposure to TCP present in its meta and para forms (W.N. Aldridge, Biochemical Journal 1954 56, 185-189).
Des études très récentes montrent que le tricrésylphosphate et ses analogues tri- arylphosphates agissent également sur d’autres cibles biologiques, notamment à l’échelle cellulaire (A.V. Terry, Pharmacology and Therapeutics 2012, 134, p.355-365 ; Al Salem étal. Chemosphere 2019, 237, 124519). Very recent studies show that tricresylphosphate and its tri-arylphosphate analogues also act on other biological targets, in particular at the cellular level (AV Terry, Pharmacology and Therapeutics 2012, 134, p.355-365; Al Salem et al. Chemosphere 2019, 237, 124519).
Toutes ces études et ce long historique constituent un faisceau de preuves et d’éléments qui font du tricrésylphosphate et de ses analogues tri-arylphosphates des additifs particulièrement préoccupants. All these studies and this long history constitute a body of evidence and elements which make tricresylphosphate and its tri-arylphosphate analogues additives of particular concern.
Afin d’augmenter le niveau de sécurité des huiles hydrauliques et des huiles utilisées dans les turbines d’avions et aérodérivées, il semble ainsi nécessaire de développer des additifs anti-usure alternatifs au tricrésylphosphate et à ses analogues tri-arylphosphates. In order to increase the level of safety of hydraulic oils and oils used in aircraft and aero-derivative turbines, it therefore seems necessary to develop anti-wear additives alternative to tricresylphosphate and its tri-arylphosphate analogues.
L’identification d’additifs anti-usure alternatifs au tricrésylphosphate et à ses analogues tri-arylphosphates est une problématique identifiée, même si la nécessité de s’affranchir du tricrésylphosphate et de ses analogues tri-arylphosphates ne fait pas l’unanimité.
A la connaissance de la Demanderesse, aucune étude n’a permis l’identification d’additifs anti-usure alternatifs présentant à la fois un effet anti-usure satisfaisant et une non- neurotoxicité démontrée. A titre d’exemple, les études récentes portant sur la caractérisation de la neurotoxicité potentielle des nouveaux organophosphates développés et commercialisés en tant que retardateurs de flamme de nouvelle génération sont pour la grande majorité d’un niveau de danger prétendu équivalent à celui des substances usuelles comme le TCP (Zhang ét al. Neurotoxicology and Teratology 2019, 73, p.54-66, Ryan ét al. Neurotoxicology 2016, 53, 271-281, Sirenko et al. Toxicolog. Sci. 2019, 167, p.58-76). La question de la neurotoxicité des composés organophosphorés reste à ce jour entière et non élucidée. The identification of alternative anti-wear additives to tricresylphosphate and its tri-arylphosphate analogues is an identified problem, even if the need to do away with tricresylphosphate and its tri-arylphosphate analogues is not unanimous. To the knowledge of the Applicant, no study has enabled the identification of alternative anti-wear additives exhibiting both a satisfactory anti-wear effect and demonstrated non-neurotoxicity. For example, recent studies on the characterization of the potential neurotoxicity of new organophosphates developed and marketed as new generation flame retardants are for the great majority of a level of alleged danger equivalent to that of the usual substances. such as TCP (Zhang et al. Neurotoxicology and Teratology 2019, 73, p.54-66, Ryan et al. Neurotoxicology 2016, 53, 271-281, Sirenko et al. Toxicolog. Sci. 2019, 167, p.58- 76). The question of the neurotoxicity of organophosphate compounds remains to this day unresolved and unclear.
Diverses solutions ont été développées dans l’art antérieur. Various solutions have been developed in the prior art.
La demande de brevet US2016/0002565 décrit une huile pour turbine exempte de tricrésylphosphate qui comprend au moins une huile de base, au moins un alkylpolyglycoside et un dérivé phénolique tel que le 3,5-di-tert-butyl-hydroxytoluène. Le remplacement du tricrésylphosphate par le dérivé phénolique contribue à la prévention du syndrome aérotoxique lorsque cette huile est utilisée dans des turbines d’avions. Néanmoins, la mise en œuvre d’une telle huile dans des turbines d’avions ne semble pas pouvoir procurer la même efficacité que celle de l’huile contenant du tricrésylphosphate qu’elle est censée remplacer, d’une part car la formulation décrite ne comprend aucun agent présentant un effet anti-usure permettant de remplacer celui du TCP, et d’autre part car la formulation comprend des alkylpolyglycosides qui sont thermosensibles. 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. 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. 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.
Toutefois, à ce jour, seuls des composés phosphorés ont démontré une efficacité suffisante comme agents anti-usure dans des huiles pour turbines d’avions ou aérodérivées. Sans vouloir être liés par une quelconque théorie, ceci peut être lié au fait que le phosphore permet la formation d’une couche de protection, communément appelée tribofilm, même aux hautes températures impliquées par les applications visées. However, to date, only phosphorus compounds have demonstrated sufficient efficacy as anti-wear agents in oils for aircraft turbines or aero-derivatives. 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 implied by the targeted applications.
La demande de brevet W02010/149690 décrit l’effet diminué sur la butyrylcholinestérase, par rapport au TCP notamment, de triarylphosphates spécifiques dans lesquels les groupements phényles sont substitués par un à trois groupements isopropyles ou tert- butyles. Ces résultats d’inhibition suggèrent une possible réduction de la neurotoxicité associée à ces composés par rapport à celle observée pour le TCP. Néanmoins, la simple démonstration d’un effet limité sur une cholinestérase unique ne semble pas suffisante pour garantir un niveau de sécurité suffisant pour les attentes de l’aviation. Patent application 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. However, the simple demonstration of a limited effect on a single cholinesterase does not seem sufficient to guarantee a level of safety sufficient for the expectations of aviation.
Les documents suivants sont également connus de l’état de la technique. The following documents are also known from the state of the art.
Le document US 2019/0277339 décrit une composition d’huile de roulement sans zinc destinée à l’industrie métallurgique. Cette composition d’huile peut comprendre, en masse, par rapport à sa masse totale 0,05% à 2% d’un premier additif exempt de cendre à base de phosphore.
Le document WO 2016/032246 décrit une composition lubrifiante présentant une excellente stabilité à la thermo-oxydation et une stabilité à la couleur. La composition peut comprendre un antioxydant secondaire à base de phosphore. Document US 2019/0277339 describes a zinc-free rolling oil composition intended for the metallurgical industry. This oil composition may comprise, by mass, relative to its total mass, 0.05% to 2% of a first ash-free phosphorus-based additive. Document WO 2016/032246 describes a lubricating composition exhibiting excellent thermo-oxidation stability and color stability. The composition may include a secondary phosphorus-based antioxidant.
Le document US 3,983,046 décrit une composition ayant une bonne résistance au feu et des caractéristiques de viscosité adéquates. La composition comprend une combinaison d’au moins deux phosphates dont le second phosphate peut comprendre un alkyl diarylphosphate et au moins une combinaison de deux polyalkylène glycol (base ester).Document US Pat. No. 3,983,046 describes a composition having good fire resistance and suitable viscosity characteristics. The composition comprises a combination of at least two phosphates, the second phosphate of which may comprise an alkyl diarylphosphate and at least a combination of two polyalkylene glycols (ester base).
Il existe ainsi un besoin dans l’état de la technique de développer des additifs anti usure alternatifs au tricrésylphosphate et à ses analogues tri-arylphosphates et ce, même si la nécessité de s’affranchir du tricrésylphosphate et de ses analogues tri-arylphosphates ne fait pas l’unanimité. There is thus a need in the state of the art to develop alternative antiwear additives to tricresylphosphate and its tri-arylphosphate analogues, even if the need to do away with tricresylphosphate and its tri-arylphosphate analogues does not exist. not unanimity.
En particulier, il existe un besoin dans l’état de la technique de développer des additifs anti-usure alternatifs présentant à la fois un effet anti-usure satisfaisant et permettant d’augmenter le niveau de sécurité dans l’aviation et autres applications aérodérivées. 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.
Exposé de l’invention Disclosure of the invention
Dans ce cadre, la Demanderesse a démontré que des composés organophosphorés spécifiques, dont certains sont connus comme agents retardateurs de flamme, présentent à la fois des propriétés anti-usure et de stabilité thermique satisfaisantes, voire améliorées et une neurotoxicité fortement réduite au regard de celle des dérivés anti-usure triarylphosphates, tels que le TCP, voire nulle, et peuvent donc être avantageusement utilisés afin de réduire la neurotoxicité des huiles et en particulier des huiles de turbine. In this context, the Applicant has demonstrated that specific organophosphorus compounds, some of which are known as flame retardants, exhibit both satisfactory anti-wear and thermal stability properties, or even improved, and greatly reduced neurotoxicity compared with that. 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.
Ils peuvent également avantageusement être utilisés pour la prophylaxie du syndrome aérotoxique, en particulier en cas d’événement de fumée. They can also advantageously be used for the prophylaxis of aerotoxic syndrome, in particular in the event of a smoke event.
Résumé de l’invention Summary of the invention
Ainsi, la présente invention concerne l’utilisation d’au moins un composé de formule
dans laquelle A est un groupe alkyle linéaire ou ramifié comprenant de 10 à 32 atomes de carbone, et chacun de A et A¾ est indépendamment un groupe aryle 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 a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of A and A¾ is independently an aryl group as an antiwear agent in an oil, preferably a turbine oil, for reduce and / or prevent the neurotoxicity of said oil.
Les composés de formule (I) présentent des propriétés anti-usure intéressantes, qui peuvent être comparables à celles du tricrésylphosphate ou de ses analogues triarylphosphates. Ils présentent également un niveau de risque très faible, voire nul, en
termes de neurotoxicité et réduisent ainsi la neurotocixité de l’huile dans laquelle ils sont intégrés. En effet, comme le montre les essais expérimentaux décrits ci-après, la Demanderesse a découvert, de manière inattendue, que les composés spécifiques de formule (I) ci-dessus sont non toxiques en termes d’action sur les cholinestérases, non neurotoxiques et non reprotoxiques. 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 level of risk in terms of 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 non-reprotoxic.
Les composés polyphosphorés de formule (I) peuvent être ainsi utilisés pour obtenir une huile non-neurotoxique ou ayant une neurotoxicité réduite. The polyphosphorus compounds of formula (I) can thus be used to obtain an oil which is non-neurotoxic or has reduced neurotoxicity.
L’invention concerne également l’utilisation d’une huile comprenant au moins 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 A et A¾ est indépendamment un groupe aryle 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’évènement de fumée. The invention also relates to the use of 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 A and A¾ is independently an aryl group as an antiwear agent in an oil, preferably a turbine oil, for prophylaxis of aerotoxic syndrome, preferably in the event of a smoke event.
Bien entendu, les différentes caractéristiques, variantes et formes de réalisation de l'invention peuvent être associées les unes avec les autres selon diverses combinaisons dans la mesure où elles ne sont pas incompatibles ou exclusives les unes des autres. 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 mutually exclusive.
Brève description des figures Brief description of the figures
[Fig.1 ] présente des molécules issues du travail de modélisation par les harmoniques sphériques : les composés de la ligne supérieure appartiennent au cluster 1, les composés de la ligne inférieure appartiennent au cluster 3 ou au cluster 4. [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 or cluster 4.
Description détaillée detailed description
Un premier objet de l’invention est l’utilisation d’au moins un composé de formule (I) A first object of the invention is the use of at least one compound of formula (I)
O O
A 0 P~-OAr, At 0 P ~ -OAr,
OAr2 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. OAr 2 wherein A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of Ar1 and Ar2 is independently an aryl group as an antiwear agent in an oil to reduce and / or prevent the neurotoxicity of said oil, preferably a turbine oil.
« Par réduire » la neurotoxicité d’une huile, on entend que le ou les composés de formules (I) selon l’invention sont aptes et/ou configuré(s) pour diminuer la neurotoxicité d’une
huile dans laquelle ils sont inclus, à savoir de par leur présence (généralement majoritaire), notamment par rapport à d’autres composés anti-usures classiques généralement neurotoxiques, le ou les composés de formule (I) permettent d’abaisser/diminuer la neurotoxicité d’une huile et d’obtenir une huile non-neurotoxique ou tout au moins à toxicité réduite. “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. oil in which they are included, namely by their presence (generally in the majority), in particular compared to other conventional anti-wear compounds generally neurotoxic, the compound (s) of formula (I) make it possible to lower / reduce the neurotoxicity of an oil and to obtain an oil which is non-neurotoxic or at least of reduced toxicity.
« Par prévenir » la neurotoxicité d’une huile , on entend que le ou les composés de formule (I) permettent d’empêcher l’huile d’être considérée comme neurotoxique et/ou d’empêcher l’apparition de symptômes neurotoxiques chez un mammifère, tel qu’un être humain ou un animal qui serait en contact avec ladite huile ; ces symptômes neurotoxiques pouvant par exemple atteindre le système nerveux central (SNC) et présenter les effets suivants : des maux de tête, une perte d’appétit, une somnolence, des troubles de l’humeur et de la personnalité, des atteintes cognitives (troubles d’apprentissage et de concentration), ou atteindre le système nerveux périphériques (SNP) et présenter les effets suivants : atteintes motrices telles que faiblesse, tremblements, incoordination, convulsions, etc. ou atteintes sensorielles telles que diminution de l’audition, vision des couleurs, acouphènes, pertes d’équilibre, etc. ; ces effets pouvant être réversibles ou non en fonction du degré d’exposition aiguë ou chronique du mammifère. "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.
« Par neurotoxicité », on entend la capacité que possède une substance ou un composé à induire des effets néfastes dans le système nerveux d’un mammifère, tel que l’être humain. Le système nerveux se divise en système nerveux central (SNC) et système nerveux périphérique (SNP). Le SNC est situé dans la boîte crânienne et la colonne vertébrale. Il comprend le cerveau, le tronc cérébral et la moelle épinière. Son rôle est de recevoir, enregistrer et interpréter les signaux qui lui parviennent de la périphérie. Il organise ensuite la réponse à envoyer. Le SNP est formé de ganglions nerveux, de nerfs sensitifs responsables de transmettre les sensations au cerveau, comme la douleur, et de nerfs moteurs responsables du mouvement en stimulant les muscles. Ils font circuler l’information entre le SNC et les organes. Ainsi, selon l’invention une substance ou composé neurotoxique agit habituellement en perturbant ou en paralysant l'influx nerveux, en agissant notamment sur les émetteurs ou les récepteurs synaptiques ou sur les enzymes qui agissent sur ces émetteurs ou ces récepteurs synaptiques, tels que les cholinestérases. En biochimie, une cholinestérase est une enzyme qui catalyse la réaction d'hydrolyse d'un ester de la choline (acétylcholine, butyrylcholine) en choline et en acide acétique. En physiologie, cette réaction est nécessaire pour permettre aux récepteurs cholinergiques de revenir à leur état de repos après activation. "Neurotoxicity" means the ability of a substance or compound to induce adverse effects in the nervous system of a mammal, such as humans. The nervous system is divided into the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS is located in the cranial box and the spine. It includes the brain, brainstem, and spinal cord. Its role is to receive, record and interpret the signals which 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 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. In biochemistry, a cholinesterase is an enzyme that catalyzes the hydrolysis reaction of an ester of choline (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.
En particulier « la neurotoxicité» se distingue de la notion plus large et globale de «toxicité». In particular, “neurotoxicity” is distinguished from the broader and global notion of “toxicity”.
En effet, la « toxicité » est une notion assez large qui inclut notamment : Indeed, “toxicity” is a fairly broad concept which includes in particular:
- 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, -- 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, -
- 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), - 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),
- 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 ; - ecotoxicity, which is all the imbalances or nuisances caused by industrial activity or the establishment of a body or a foreign product in a natural environment;
- la neurotoxicité telle que définit ci-dessus. - neurotoxicity as defined above.
Or, comme les essais expérimentaux le démontrent ci-après, un composé peut, par exemple, ne pas être reprotoxique, ne montrer aucun signe de toxicité aiguë, voire ne montrer aucun caractère CMR (caractère cancérogène, mutagène, ou toxique pour la reproduction) sur la santé humaine et être cependant fortement neurotoxique (ou inversement). 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 to reproduction). on human health and yet be highly neurotoxic (or vice versa).
Dans la présente demande, la Demanderesse a démontré que de manière inattendue et de façon surprenante, certains composés phosphorés spécifiques de formule (I) ci-dessus et en particulier ceux comprenant un groupe diphénylphosphate présentaient à la fois d’excellente propriété anti-usure adaptée notamment au domaine exigeant de l’aéronautique, tout en étant faiblement voire pas du tout neurotoxique. Cette dernière qualité permet ainsi de réduire et/ou prévenir la neurotoxicité d’une huile dans laquelle ils sont intégrés, 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 suitable anti-wear property. especially in the demanding field of aeronautics, while being weakly or not at all neurotoxic. This latter quality thus makes it possible to reduce and / or prevent the neurotoxicity of an oil in which they are integrated,
Ces essais montrent également que les composés de formule (I) sélectionnés par la Demanderesse ne sont pas arbitraires et présentent un effet technique différent (à savoir ils permettent de réduire/prévenir la neurotoxicité d’une huile) par rapport à d’autres composés anti-usure, notamment par rapport à d’autres composés anti-usure également phosphoré. These tests also show that the compounds of formula (I) selected by the Applicant are not arbitrary and exhibit a different technical effect (namely they make it possible to reduce / prevent the neurotoxicity of an oil) compared to other anti-inflammatory compounds. -wear, in particular compared to other anti-wear compounds also phosphorus.
Pour la présente invention, la Demanderesse a démontré la non-neurotoxicité des composés spécifiques de formule (I) à la fois par des essais expérimentaux in vitro portant sur les cholinestérases et par des essais de modélisation (modélisation moléculaire 3D par harmoniques sphériques et modélisation par OSAR pour la neurotoxicité et pour la reprotoxicité). 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 OSAR for neurotoxicity and for reprotoxicity).
De préférence, la concentration inhibitrice à 50% dudit au moins composé de formule (I) sur l’activité biologique d’une enzyme acétylcholinestérase (AChE), nommée ICsohAChE est supérieure ou égale à 15 mg/L et l’activité sur une enzyme butyrylcholinestérase, nommée IC50 eqBuChE est supérieure ou égale à 15 mg/L, de préférence égale ou supérieure à 20 mg/L, en particulier égale ou supérieure à 25 mg/L et typiquement égale ou supérieure à 30 mg/L. Preferably, 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 and the activity on an enzyme butyrylcholinesterase, 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.
Selon l’invention, une valeur supérieure ou égale à 15 mg/L pour ICsohAChE inclut les valeurs suivantes et tous les intervalles entre ces valeurs : 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.
Également, selon l’invention, une valeur supérieure ou égale à 15 mg/L pour IC50 eqBuChE inclut les valeurs suivantes et tous les intervalles entre ces valeurs : 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 ; etc. According to the invention, 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. Also, according to the invention, a value greater than or equal to 15 mg / L for IC50 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; etc.
Avantageusement, le ou les composés de formule (I) appartiennent au Cluster 3 ou au Cluster 4, en particulier au Cluster 4 déterminé selon la modélisation moléculaire par harmoniques sphériques telle que décrite dans la publication « Benchmarking of HPCC: A novel 3D molecular représentation combining shape and pharmacophoric descriptors for efficient molecular similarity assessments », Karaboga et al. 2013 Journal of Molecular Graphics and Modelling 41 ; 20-30. Advantageously, the compound (s) of formula (I) belong to Cluster 3 or to 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.
Selon une autre caractéristique de l’invention, le ou les composés de formule (I) présentent une valeur en pourcentage par modélisation QSAR (relation structure-activité quantitative) (de l’anglais « Quantitative Structure Activity Relationship ») inférieure ou égale à 0,70 pour la mesure de la neurotoxicité et inférieure ou égale à 1,5, de préférence inférieure ou égale à 1,15 et typiquement inférieure ou égale à 0,7 pour la mesure sur la reprotoxicité. According to another characteristic of the invention, the compound (s) of formula (I) exhibit a percentage value by QSAR modeling (quantitative structure activity relationship) less than or equal to 0 70 for the measurement of neurotoxicity 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 measurement of reprotoxicity.
Ainsi, les composés de formule (I) selon l’invention présente un niveau de risque en termes de neurotoxicité qui est très bas et qui correspond généralement à un score de 0 ou à un score de 1 (risque très faible ou inexistant de neurotoxicité), de préférence à un score de 0. Thus, 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.
Le niveau de risque tel que défini ci-dessus et illustré également dans la partie expérimentale ci-après est très exhaustif et englobe l’ensemble des données obtenus via les différents essais sur la neurotocixité décrits ci-dessus et englobe donc aussi bien des essais in vitro que des essais de modélisation 3D. 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.
En particulier, le niveau de risque tient compte de tous les essais suivants : In particular, the risk level takes into account all of the following tests:
- le test in vitro d’inhibition de l’acétylcholinestérase (AChE), - the in vitro acetylcholinesterase (AChE) inhibition test,
- le test in vitro d’inhibition de la butyrylcholinestérase (BuChE), - the in vitro test for inhibition of butyrylcholinesterase (BuChE),
- le type de cluster tenant compte de la forme et de la fonctionnalité des harmoniques sphériques (modélisation 3D), - the type of cluster taking into account the shape and functionality of spherical harmonics (3D modeling),
- la prédiction semi-empirique de la neurotoxicité, et - semi-empirical prediction of neurotoxicity, and
- la prédiction semi-empirique de la reprotoxicité. - the semi-empirical prediction of reprotoxicity.
Par « huile », on désigne dans la présente invention toute substance organique, notamment toute huile hydraulique ou de turbine, susceptible de créer une pollution sous forme de gaz et/ou d’aérosol en cabine. Dans certains modes de réalisation, l’huile est choisie dans le groupe constitué par les huiles pour turbines d’avions ou aérodérivées, les huiles de transmission pour hélicoptère et les fluides pour armes. De préférence, dans la présente invention, l’huile est une huile pour turbines d’avion ou aérodérivées.
Par « groupe alkyle » du groupement « A », on désigne un groupe hydrocarboné saturé linéaire ou ramifié. Les groupes alkyles comprennent de 10 à 32 atomes de carbone (Cio à C32). Selon une première caractéristique de l’invention, les groupes alkyles comprennent de 10 à 20 atomes de carbone (C10 à C20), de préférence de 10 à 15 atomes de carbone et en particulier de 10 à 12 atomes de carbones. Selon une autre caractéristique de l’invention, les groupes alkyles comprennent de 20 à 32 atomes de carbone, de préférence de 15 à 32 atomes de carbone et typiquement de 16 à 32 atomes de carbones. Parmi les exemples de groupes alkyles selon l’invention, on peut citer notamment les groupes décyle, isodécyle, dodécyle, isododécyle, octadécyle, 2-butyloctyle, 2-hexyldécyle, 2-octyldodédyle et 2-tétradécyloctadécyle. In the present invention, the term “oil” denotes 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 oils for aircraft or aero-derivatives, transmission oils for helicopters and fluids for weapons. Preferably, in the present invention, the oil is an oil for aircraft or air-derived turbines. The term “alkyl group” of the “A” group denotes a linear or branched saturated hydrocarbon group. The alkyl groups contain from 10 to 32 carbon atoms (C10 to C32). According to a first characteristic of the invention, the alkyl groups comprise from 10 to 20 carbon atoms (C10 to C20), 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-octyldodedyl and 2-tetradecyloctadecyl groups.
Un groupe alkyle selon l’invention peut être éventuellement substitué. Par « groupe alkyle substitué » selon l’invention, on désigne une chaîne hydrocarboné saturé linéaire ou ramifié, comprennent de 10 à 32 atomes de carbone (C10 à C32) substituée au niveau d’un ou plusieurs de ses atomes, par au moins un substituant choisi dans le groupe constitué par les groupes alkyles en Ci à C18, le groupe hydroxyle OH, un groupe amine NH2 ou primaire NHR avec R groupe alkyle ou aryle, un groupe O-phosphate tel que le groupe O-diphénylphosphate, et les atomes d’halogène. An alkyl group according to the invention can be optionally substituted. The term “substituted alkyl group” according to the invention denotes a linear or branched saturated hydrocarbon chain comprising from 10 to 32 carbon atoms (C10 to C32) substituted at the level of one or more of its atoms, by at least one substituent selected from the group consisting of C 1 -C 18 alkyl groups, OH hydroxyl group, NH2 or primary amine group NHR with R alkyl or aryl group, O-phosphate group such as O-diphenylphosphate group, and atoms halogen.
La substitution des groupes alkyles ou aryles dans les composés selon la présente invention par chaque type de substituant permet de conférer au composé des propriétés souhaitées. Par exemple, la substitution par des atomes d’halogène pourrait permettre une amélioration des effets extrême-pression et/ou anti-usure des composés. 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 the desired properties on the compound. For example, substitution with halogen atoms could allow an improvement in the extreme pressure and / or antiwear effects of the compounds.
De préférence, le « groupe alkyle » n’est pas substitué. Preferably, the "alkyl group" is unsubstituted.
Par « groupe aryle », on désigne un groupe monocyclique ou polycyclique aromatique carboné, éventuellement interrompu par un ou plusieurs hétéroatomes pouvant notamment être choisis dans le groupe constitué par un atome d’azote, un atome d’oxygène, et un atome de soufre. Chaque cycle aromatique ou polyaromatique comprend 5 à 14 atomes. Chaque cycle peut être éventuellement substitué, au niveau d’un ou plusieurs de ses atomes, par au moins un substituant choisi dans le groupe constitué par les groupes alkyles en Ci à C18, de préférence un groupe alkyle linéaire ou ramifié en Ci à C10OU un groupe alkylène en Ci à C18 comprenant un groupe perfluoré, un groupe hydroxyle OH, un groupe amine primaire NH2 ou secondaire NHR avec R groupe alkyle ou aryle, un groupe O-phosphate tel que le groupe O- diphénylphosphate 0-P(=0)(0Ph)2, un groupe ester et/ou des atomes d’halogène. The term “aryl group” denotes a carbon-based monocyclic or polycyclic aromatic group, optionally interrupted by one or more heteroatoms which may in particular be chosen from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Each aromatic or polyaromatic ring has 5 to 14 atoms. Each ring can be optionally substituted, at the level of 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 to C 10 alkyl group OR a C1-C18 alkylene group comprising a perfluorinated group, a hydroxyl group OH, a primary NH2 or secondary amine group NHR with R alkyl or aryl group, an O-phosphate group such as the O-diphenylphosphate group 0-P (= 0) (0Ph) 2 , an ester group and / or halogen atoms.
En général, le cycle aromatique ou polyaromatique, tel que décrit ci-dessus n’est pas substitué ou n’est substitué que par un ou plusieurs groupes alkyles linéaires ou ramifiés en Ci à C18, de préférence en Ci à C10, en particulier de Ci à C10, typiquement en Ci à C3.Lorsque le groupe aryle est un groupe polycyclique dans lequel au moins deux cycles sont reliés par au moins une liaison covalente entre deux atomes distincts appartenant chacun à un des cycles, la liaison covalente entre les deux cycles peut être interrompue par au moins un
groupe alkyle tel qu’un groupe C(CH3)2, un groupe carbonyle ou un hétéroatome ou groupe hétéroatomique tel qu’un atome d’oxygène, un atome de soufre, un groupe amine NH ou NR ou un groupe sulfite 0S(=0)0. 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, preferably C 1 to C 10, alkyl groups, in particular of Ci to C10, typically Ci to C3 . When the aryl 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 one of the rings, the covalent bond between the two rings can be interrupted by at least one alkyl group such as a C (CH3) 2 group, a carbonyl group or a heteroatom or heteroatomic group such as an oxygen atom, a sulfur atom, an NH or NR amine group or an 0S sulfite group (= 0 ) 0.
Parmi les exemples de groupes aryles monocycliques, on peut citer notamment le groupe phényle. Among the examples of monocyclic aryl groups, mention may in particular be made of the phenyl group.
Par « atome d’halogène », on désigne un atome choisi dans le groupe constitué par le chlore, le brome, le fluor et l’iode. By "halogen atom" is meant an atom selected from the group consisting of chlorine, bromine, fluorine and iodine.
Dans un mode de réalisation, « A » est choisi dans le groupe constitué par un groupe isodécyle, un groupe dodécyle, notamment un groupe n-dodécyle, un groupe tridécyle, notamment un groupe iso-tridécyle, un groupe hexadécyle, un groupe octadécyle, un groupe 2-butyl 1-octyle, un groupe 2-hexyl 1-décyle, un groupe 2-octyl 1 -dodécyle et un groupe 2- tétradécyl 1 -octadécyle. In one embodiment, "A" is chosen 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, a 2-butyl 1-octyl group, a 2-hexyl 1-decyl group, a 2-octyl 1 -dodecyl group and a 2-tetradecyl 1 -octadecyl group.
Dans un mode de réalisation particulier, « A » est choisi parmi un groupe isodécyle, un groupe dodécyle, notamment un groupe n-dodécyle, et un groupe 2-octyl 1 -dodécyle. 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 » est de préférence un groupe isodécyle. "A" is preferably an isodecyl group.
Dans un mode de réalisation, « A et A¾ » sont indépendamment un phényle non substitué ou un phényle substitué, de préférence substitué par au moins un substituant ester ou un substituant alkyle tel qu’un groupe méthyle, un groupe éthyle, un groupe isopropyle ou un groupe tert-butyle. De façon préférée, A et A¾ sont deux phényles non substitués. Dans un mode de réalisation alternatif, A et A¾ sont deux phényles substitués, de préférence par un substituant alkyle tel qu’un groupe méthyle. In one embodiment, "A and A¾" are independently an unsubstituted phenyl or a substituted phenyl, preferably substituted with at least one ester substituent or an alkyl substituent such as a methyl group, an ethyl group, an isopropyl group or a tert-butyl group. Preferably, A and A¾ are two unsubstituted phenyls. In an alternative embodiment, A and A¾ are two phenyls substituted, preferably with an alkyl substituent such as a methyl group.
Dans un mode de réalisation, le composé de formule (I) est choisi dans le groupe constitué par l’isodécyldiphénylposphate, le n-dodécyldiphénylphosphate, l’iso- tridécyldiphénylphosphate, l’hexadécyldiphénylphosphate, l’octadécyldiphénylphosphate, le 2-butyl 1-octyldiphénylphosphate, le 2-hexyl 1-décyldiphénylphosphate, le 2-octyl 1- dodécyldiphénylphosphate, le 2-tétradécyl 1-octadécyldiphénylphosphate, et l’un quelconque de leurs mélanges. In one embodiment, the compound of formula (I) is selected from the group consisting of isodécyldiphenylposphate, n-dodécyldiphenylphosphate, isotridécyldiphenylphosphate, hexadécyldiphenylphosphate, octadécyldiphenylposphate, 2-octadécyldiphenylphosphate, , 2-hexyl 1-decyldiphenylphosphate, 2-octyl-1-dodécyldiphenylphosphate, 2-tetradecyl 1-octadecyldiphenylphosphate, and any mixture thereof.
Dans un mode de réalisation, le composé de formule (I) est choisi dans le groupe constitué par l’isodécyldiphénylphosphate, le n-dodécyldiphénylphospate, le 2-octyl 1- dodécyldiphénylphosphate et l’un quelconque de leurs mélanges. In one embodiment, the compound of formula (I) is selected from the group consisting of isodecyldiphenylphosphate, n-dodécyldiphenylphospate, 2-octyl-1-dodécyldiphenylphosphate, and any mixture thereof.
Dans un mode de réalisation, le composé de formule (I) est l’isodécyldiphénylphosphate. Il peut être présent dans l’huile en tant qu’agent anti-usure en mélange avec au moins un autre composé de formule (I). Alternativement, l’isodécyldiphénylphosphate est le seul composé de formule (I) compris dans l’huile. Dans un mode de réalisation, l’isodécyldiphénylphosphate est le seul agent anti-usure présent dans l’huile.
L’huile dans laquelle le composé de formule (I) est utilisé en tant qu’agent anti-usure ne comprend de préférence pas de tricrésylphosphate. Dans un mode de réalisation, elle ne comprend substantiellement pas de tricrésylphosphate. In one embodiment, the compound of formula (I) is isodecyldiphenylphosphate. It can be present in the oil as an antiwear agent in admixture 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 antiwear agent present in the oil. The oil in which the compound of formula (I) is used as an antiwear agent preferably does not include tricresylphosphate. In one embodiment, it substantially does not include tricresylphosphate.
Dans un autre mode de réalisation, l’huile contient comme seul(s) agent(s) anti-usure le ou les composés de formule (I). In another embodiment, the oil contains as sole (s) antiwear agent (s) the compound (s) of formula (I).
En général, l’agent anti-usure selon l’invention de formule générale (I) représente, en masse, par rapport à la masse totale des agents anti-usure présents dans l’huile, de 50% à 100%, de préférence de 80% à 100%, et en particulier de 90% à 100% et typiquement 100%. In general, the antiwear agent according to the invention of general formula (I) represents, by mass, relative to the total mass of the antiwear agents present in the oil, from 50% to 100%, preferably from 80% to 100%, and in particular from 90% to 100% and typically 100%.
Selon l’invention, par « 50% à 100% », on entend les valeurs suivantes ou tout intervalle compris entre ces valeurs : 50 ; 55 ; 60 ; 65 ; 70 ; 75 ; 80 ; 85 ; 90 ; 95 ; 100. According to the invention, by "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.
Dans certains modes de réalisation, l’huile dans laquelle le composé de formule (I) est utilisé selon l’invention ne comprend substantiellement pas, de préférence ne comprend pas, d’additif anti-usure triarylphosphate. In certain embodiments, the oil in which the compound of formula (I) is used according to the invention substantially does not include, preferably does not include, triarylphosphate antiwear additive.
Dans certains modes de réalisation, l’huile dans laquelle le composé de formule (I) est utilisé selon l’invention ne comprend substantiellement pas, de préférence ne comprend pas, d’additif anti-usure organophosphate autre que le ou les composés de formule (I). In some embodiments, the oil in which the compound of formula (I) is used according to the invention substantially does not include, preferably does not include, an organophosphate antiwear additive other than the compound (s) of formula (I).
Dans certains modes de réalisation, l’huile dans laquelle le composé de formule (I) est utilisé selon l’invention ne comprend substantiellement pas, de préférence ne comprend pas, d’autre additif anti-usure que le ou les composés de formule (I). In some embodiments, the oil in which the compound of formula (I) is used according to the invention substantially does not include, preferably does not include, any antiwear additive other than the compound (s) of formula ( I).
L’huile est de préférence une huile pour turbines d’avion ou aérodérivées. The oil is preferably an oil for aircraft turbines or aero-derivatives.
L’utilisation d’au moins un composé de formule (I) en tant qu’agent anti-usure afin de réduire et/ou prévenir et/ou empêcher la neurotoxicité d’une huile est particulièrement avantageuse dans des situations où des individus sont susceptibles d’être exposés à l’huile. En effet, les composés de formule (I) présentent, comme démontré dans la présente invention, un niveau de risque très faible, voire nul, en termes de toxicité, notamment en termes de neurotoxicité, voire même de reprotoxicité, et sont donc de bonnes alternatives aux agents anti-usure classiques, tels que le tricrésylphosphate et ses analogues triarylphosphates qui sont connus pour être neurotoxiques et reprotoxiques. The use of at least one compound of formula (I) as an antiwear 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) exhibit, 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 of reprotoxicity, and are therefore good. alternatives to conventional antiwear agents, such as tricresylphosphate and its triarylphosphate analogues which are known to be neurotoxic and reprotoxic.
Aussi, dans un autre mode de réalisation, l’utilisation du au moins un dérivé de formule (I) en tant qu’agent anti-usure dans une huile est pour la prophylaxie du syndrome aérotoxique, notamment en cas d’évènement de fumée. Also, in another embodiment, the use of at least one derivative of formula (I) as an antiwear agent in an oil is for the prophylaxis of aerotoxic syndrome, in particular in the event of a smoke occurrence.
Dans un mode de réalisation particulier, l’utilisation du au moins un dérivé de formule (I) en tant qu’agent anti-usure dans une huile pour la prophylaxie du syndrome aérotoxique en cas d’évènement de fumée. Par exemple, l’utilisation du au moins un dérivé de formule (I) en tant qu’agent anti-usure dans une huile peut être pour lubrifier au moins une turbine d’avion ou aérodérivée, pour la prophylaxie du syndrome aérotoxique, notamment en cas d’évènement de fumée.
De préférence, la concentration inhibitrice à 50% dudit au moins composé de formule (I) sur l’activité biologique d’une enzyme acétylcholinestérase (AChE), nommée ICsohAChE est supérieure ou égale à 15 mg/L et l’activité sur une enzyme butyrylcholinestérase, nommée IC50 eqBuChE est supérieure ou égale à 15 mg/L, de préférence égale ou supérieure à 20 mg/L, en particulier égale ou supérieure à 25 mg/L et typiquement égale ou supérieure à 30 mg/L. In a particular embodiment, the use of at least one derivative of formula (I) as an antiwear agent in an oil for the prophylaxis of 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 airplane or aeroderivative turbine, for the prophylaxis of aerotoxic syndrome, in particular in smoke event. Preferably, 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 and the activity on an enzyme butyrylcholinesterase, 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.
Selon l’invention, une valeur supérieure ou égale à 15 mg/L pour ICsohAChE inclut les valeurs suivantes et tous les intervalles entre ces valeurs : 15 ; 16 ; 17 ; 18 ; 19 ; 20 ; 21 ; 22 ;According to the invention, 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. 23; 24; 25; 26; 27; 28; 29; 30 ; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40, etc.
Également, selon l’invention, une valeur supérieure ou égale à 15 mg/L pour IC50 eqBuChE inclut les valeurs suivantes et tous les intervalles entre ces valeurs : 15 ; 16 ; 17 ; 18 ; 19 ; 20 ; 21 ; 22 ; 23 ; 24 ; 25 ; 26 ; 27 ; 28 ; 29 ; 30 ; 31 ; 32 ; 33 ; 34 ; 35 ; 36 ; 37 ;Also, according to the invention, a value greater than or equal to 15 mg / L for IC50 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 ;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 ; etc. 125; 130; 135; 140; 145; 150; 155; 160; etc.
Avantageusement, le ou les composés de formule (I) appartiennent au Cluster 3 ou au Cluster 4, préférentiellement au Cluster 3 déterminé selon la modélisation moléculaire par harmoniques sphériques telle que décrite dans la publication « Benchmarking of HPCC: A novel 3D molecular représentation combining shape and pharmacophoric descriptors for efficient molecular similarity assessments », Karaboga et al. 2013 Journal of Molecular Graphics and Modelling 41 ; 20-30. Advantageously, the compound (s) of formula (I) belong to Cluster 3 or to Cluster 4, preferentially 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.
Selon une autre caractéristique de l’invention, le ou les composés de formule (I) présentent une valeur en pourcentage (%) par modélisation QSAR (relation structure-activité quantitative) (de l’anglais « Quantitative Structure Activity Relationship ») inférieure ou égale à 0,70% pour la mesure de la neurotoxicité et inférieure ou égale à 3%, de préférence inférieure ou égale à 1 ,5% et typiquement inférieure ou égale à 0,15%, de préférence inférieure ou égal à 0,7% pour la mesure sur la reprotoxicité. 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) (standing for “Quantitative Structure Activity Relationship”) 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 the measurement on reprotoxicity.
Bien entendu, les différents modes de réalisation décrits ci-avant pour l’utilisation des composés de formule (I) en tant qu’agents anti-usure pour réduire et/ou prévenir la neurotoxicité d’une huile s’appliquent également à l’utilisation de ces composés de formule (I) pour la prophylaxie du syndrome aérotoxique, notamment en cas d’événement de fumée, et à l’huile en tant que telle. Of course, the various embodiments described above for the use of the compounds of formula (I) as antiwear 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 aerotoxic syndrome, in particular in the event of a smoke event, and with oil as such.
Par « prophylaxie du syndrome aérotoxique », on désigne la diminution de l’occurrence et/ou de l’intensité, voire la quasi-disparition ou la disparition totale, d’au moins un symptôme identifié comme étant lié à une exposition aiguë ou chronique des individus à de l’air de cabine d’avion contaminé par des huiles telles que des huiles de turbine ou des huiles hydrauliques sous forme de gaz et/ou d’aérosols. Dans certains modes de réalisation, la prophylaxie du syndrome aérotoxique désigne la diminution de l’occurrence, voire la quasi- disparition ou la disparition totale, de plusieurs symptômes, de préférence de tous les
symptômes, identifiés comme étant liés à une exposition aiguë ou chronique des individus à de l’air de cabine d’avion contaminé par des huiles, telles que des huiles de turbine ou des huiles hydrauliques sous forme de gaz et/ou d’aérosols. By "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. In some embodiments, aerotoxic syndrome prophylaxis refers to the decrease in the occurrence, or even the near disappearance or the complete disappearance, of several symptoms, preferably all of them. 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 gas and / or aerosols.
En particulier, le symptôme peut être un symptôme neurologique, neurocomportemental, neuromoteur et/ou lié à la reproduction. Parmi les symptômes dont l’occurrence et/ou l’intensité peut être diminuée par l’utilisation selon l’invention, on peut citer par exemple des troubles psychologiques ou psychosomatiques, un syndrome de fatigue chronique, des migraines sévères, une sensibilité chimique multiple, des infections virales mystérieuses, des troubles du sommeil, la dépression, le stress et l’anxiété. In particular, the symptom may be a neurological, neurobehavioural, neuromotor and / or reproductive symptom. Among 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.
Par « évènement de fumée », on désigne l’exposition aiguë ou chronique, de préférence aiguë, d’au moins un individu à de l’air de cabine d’avion contaminé par des huiles telles que des huiles de turbine ou des huiles hydrauliques sous forme de gaz et/ou d’aérosol. Un évènement de fumée, s’il est important, peut notamment être détecté par la perception d’une odeur caractéristique désagréable, typique de « chaussettes sales » ou de « chien mouillé ». Dans les cas les plus sévères, par exemple suite à la casse d’un roulement dans la turbine, une fumée ou un épais brouillard blanc pourra être visible. The term “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. 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.
Par « une huile ne comprenant pas de tricrésylphosphate », on désigne une huile dans laquelle la quantité de tricrésylphosphate, quel que soit son type de substitution (ortho, méta, para) est inférieure à la limite de détection des techniques d’analyse usuelles telles que la chromatographie en phase gazeuse couplée à la spectrométrie de masse par exemple. Une technique adaptée pour la détection du tricrésylphosphate dans une huile est décrite par exemple dans De Nola G. ét al. J. Chromatogr. A 2008 ; 1200 (2), p.211-216. By “an oil not comprising tricresylphosphate” is meant an oil in which the amount of tricresylphosphate, regardless of its type of substitution (ortho, meta, para) is less than the detection limit of the usual analysis techniques such as 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.
Dans le cas des turbines aérodérivées, la pathologie désignée par les termes « syndrome aérotoxique » est une pathologie comportant au moins en partie les mêmes symptômes neurologiques et sur la reproduction que ceux observés dans les avions pour le syndrome aérotoxique, mais qui est contracté par exposition aux organophosphates, tels que le tricrésylphosphate dans des installations comportant des turbines industrielles au sol telles que des plateformes offshores. In the case of aero-derived turbines, 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.
L’invention permet ainsi de former une huile comprenant au moins 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, 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 Ar1 and Ar2 is independently an aryl group, having little or almost no neurotoxicity.
Cette huile peut être également utilisée pour la prophylaxie du syndrome aérotoxique.
Dans un autre mode de réalisation, l’huile est pour son utilisation pour la prophylaxie du syndrome aérotoxique en cas d’événement de fumée. 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.
En particulier, l’huile pour son utilisation pour la prophylaxie du syndrome aérotoxique, notamment en cas d’événement de fumée, est une huile pour lubrifier des turbines d’avion ou aérodérivées. In particular, the oil for its use in the prophylaxis of aerotoxic syndrome, in particular in the event of a smoke event, is an oil for lubricating aircraft or aerodrive turbines.
La composition de l’huile convenant pour l’invention va être décrite ci-après. The composition of the oil suitable for the invention will be described below.
Le terme « substantiellement pas » tel qu’utilisé dans la présente invention désigne des quantités inférieures à 0,1% en poids par rapport au poids total de l’huile, de préférence inférieures à 0,05%, en particulier inférieures à la limite de détection des techniques de détection. The term "substantially not" as used in the present invention denotes amounts 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 detection techniques.
Les composés de formule (I) sont présents dans l’huile dans la présente invention en une quantité telle que celles classiquement utilisées dans l’art. Par exemple, ils peuvent être utilisés en une quantité de 0,1 à 10% en poids, de préférence 0,5 à 5% en poids, par rapport au poids total de l’huile. 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.
L’huile selon l’invention comprend de préférence une base ester, au moins un antioxydant aminé, et au moins un additif anti-usure de formule (I). The oil according to the invention preferably comprises an ester base, at least one amino antioxidant, and at least one antiwear additive of formula (I).
Dans certains modes de réalisation, l’huile selon l’invention comprend également au moins un autre additif. L’au moins un autre additif peut notamment être choisi dans le groupe constitué par des agents lubrifiants, d’autres additifs anti-usure, des antioxydants, des inhibiteurs de corrosion de métaux, des passivants, des agents améliorant l’indice de viscosité, des détergents ou agents dispersants, des agents anti-mousse, des tensioactifs, des agents gonflants, des agents tackifiants, des stabilisants, des agents de charge, des agents de stabilisation contre l’hydrolyse, des additifs adaptés aux pressions extrêmes, des pigments et des agents qui masquent les odeurs. De tels additifs et agents sont bien connus de l’homme du métier et sont couramment disponibles dans le commerce. In some embodiments, the oil 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, metal corrosion inhibitors, passivants, agents improving the viscosity index, detergents or dispersing agents, defoamers, surfactants, blowing agents, tackifiers, stabilizers, bulking agents, stabilizers against hydrolysis, additives suitable for 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.
La base ester est une base ester classique, bien connue dans l’art. Il s’agit typiquement d’une huile synthétique qui peut être choisie parmi les esters de mono-alcool ou de polyol, de préférence de polyol, avec un réactif acide mono ou dicarboxylique. 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.
Des polyols particulièrement adaptés sont les néo-polyols tels que le néopentylglycol, le 2-éthyl 2-méthylpropane 1,3-diol, le triméthyloléthane, le triméthylolpropane, le triméthylolbutane et le mono-, di- ou tri-pentaérythritol. 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.
Comme autre polyol adapté, on peut citer n’importe quel polyol de formuleAs another suitable polyol, there may be mentioned any polyol of formula
R(0H)„ dans laquelle R est un groupement hydrocarboné aliphatique linéaire, ramifié ou cyclique éventuellement substitué et p est un entier supérieur ou égal à 2. Le polyol peut être choisi dans le groupe constitué par le 2-éthyl-1,3-hexanediol, le 2-propyl-3,3-heptanediol, le
2-butyl-1 ,3-butanediol, le 2,4-dimethyl-1,3-butanediol, l’éthylène glycol, le propylène glycol et les polyalkylène glycols. R (OH) „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.
Des mono-alcools particulièrement adaptés sont les néo-alcools tels que le 2,2,4- triméthylpentanol et le 2,2-diméthylpropanol. Alternativement, le mono-alcool peut être choisi dans le groupe constitué par les alcools méthylique, butylique, isooctylique et octadécylique. Particularly suitable mono-alcohols are neo-alcohols such as 2,2,4-trimethylpentanol and 2,2-dimethylpropanol. Alternatively, the monoalcohol can be chosen from the group consisting of methyl, butyl, isooctyl and octadecyl alcohols.
Le réactif acide carboxylique utilisé pour former l’ester avec le polyol ou le mono-alcool peut être choisi parmi les acides carboxyliques aliphatiques éventuellement substitués comprenant une ou deux fonctions acides carboxyliques ou un quelconque de leurs mélanges. L’homme du métier saura sélectionner les acides carboxyliques à utiliser en fonction des propriétés désirées pour l’ester et du mono-alcool ou du polyol utilisé. 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.
Parmi les bases esters susceptibles d'être contenues dans une huile selon l'invention, on peut citer les monoesters d'acétate d'octyle, d'acétate de décyle, d'acétate d'octadécyle, de myristate de méthyle, de stéarate de butyle, d'oléate de méthyle, ainsi que les polyesters de phthalate de dibutyle, d'adipate de di-octyle, d'azélate de di-2- éthylhexyle et de sébacate d'ethylhexyle. L'huile de base du type ester de polyol peut être une huile préparée à partir de pentaérythritol technique ou de triméthylol propane et d'un mélange d'acides carboxyliques ayant de 4 à 12 atomes de carbone. Le pentaérythritol technique est un mélange qui comprend environ de 85% à 92% en poids de monopentaérythritol et de 8% à 15% en poids de dipentaérythritol. Among the ester bases which may be contained in an oil according to the invention, there may be mentioned monoesters of octyl acetate, decyl acetate, octadecyl acetate, methyl myristate, 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 from about 85% to 92% by weight of monopentaerythritol and from 8% to 15% by weight of dipentaerythritol.
Un pentaérythritol technique classique du commerce contient environ 88% en poids de monopentaérythritol et environ 12% en poids de dipentaérythritol, par rapport au poids total de ladite huile de base du type ester. Le pentaérythritol technique peut contenir également une certaine quantité de tri- et tétra-pentaérythritols qui sont habituellement formés comme sous-produits au cours de la production du pentaérythritol technique. 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.
Les antioxydants aminés aromatiques sont bien connus dans l’art et peuvent être des antioxydants aminés aromatiques monomériques ou polymériques, appartenant à la famille des amines aromatiques et/ou des composés phénoliques. 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.
Les antioxydants aminés aromatiques monomériques peuvent comprendre notamment au moins une diphénylamine non substituée ou substituée par au moins un groupe hydrocarboné, au moins une naphthylphénylamine non substituée ou substituée par au moins un groupe hydrocarboné, au moins une phénothiazine non substituée ou substituée par au moins un groupe hydrocarboné, ou un mélange quelconque de celles-ci. Les groupes hydrocarbonés substituant les amines sont des groupes alkyles en Ci à C30, ou du styrène. 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 to C 30 alkyl groups, or styrene.
Les antioxydants aminés aromatiques polymériques sont les produits de polymérisation des antioxydants aminés aromatiques tels que définis ci-avant, soit entre eux, soit en présence d’un co-monomère différent. Des exemples d’antioxydants aminés aromatiques oligomériques ou polymériques pouvant être utilisés dans des huiles selon
l’invention sont notamment décrits dans les demandes de brevets FR 2 924 122 et WO 2009/071857. Polymeric aromatic amine antioxidants are the polymerization products of aromatic amine antioxidants as defined above, either with one another or in the presence of a different comonomer. Examples of oligomeric or polymeric aromatic amino antioxidants which can be used in oils according to the invention are described in particular in patent applications FR 2 924 122 and WO 2009/071857.
La présente invention peut ainsi porter sur un procédé de fabrication d’une huile non- neurotoxique ou présentant une neurotoxicité fortement réduite (en comparaison avec des huiles à base de tricrésylphosphate et de ses analogues ou à base d’autres composés phosphorés neurotoxiques) utilisée notamment pour lubrifier des dispositifs/des machines, tels que des turbines d’avions ou aérodérivés, comprenant l’étape suivante : incorporer à une huile de base, telle qu’une huile ester, au moins un agent anti-usure, caractérisé en ce que ledit au moins agent anti-usure est sélectionné parmi au moins 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 A et A¾ est indépendamment un groupe aryle et présentant notamment un niveau de risque en terme de neurotoxicité de 0. 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 compound of formula (I) in which A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of A and A¾ is independently an aryl group and in particular exhibiting a level of risk in terms of neurotoxicity of 0.
Bien entendu, les différents modes de réalisation décrits ci-avant pour l’utilisation des composés de formule (I) pour prévenir et/ou réduire la neurotoxicité d’une huile ou pour la composition d’huile s’appliquent également pour ce procédé de fabrication d’une huile et ne seront pas reprises ci-après. 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.
La présente invention peut ainsi porter sur un procédé de lubrification d’une machine/d’un dispositif, tel(le) que des turbines d’avions ou aérodérivés, comprenant les étapes suivantes : The present invention can thus relate to a method of lubricating a machine / device, such as aircraft turbines or aerodrives, comprising the following steps:
- 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 A et Arå est indépendamment un groupe aryle et présentant notamment un niveau de risque en terme de neurotoxicité de 0, - provide a 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 of formula (I) in which A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of A and Ar å is independently an aryl group and in particular exhibiting a risk level in terms of neurotoxicity of 0,
- appliquer une quantité efficace de ladite huile sur ladite machine/ledit dispositif.- applying an effective amount of said oil to said machine / said device.
Bien entendu, les différents modes de réalisation décrits ci-avant pour l’utilisation des composés polyphosphorés pour prévenir et/ou réduire la neurotoxicité d’une huile ou pour la
composition d’huile s’appliquent également pour ce procédé de lubrification et ne seront pas reprises ci-après. 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.
Exemples Examples
Exemple 1 : Etude de toxicité et en particulier de neurotoxicité Example 1: Toxicity study and in particular neurotoxicity study
Les composés de formule (I) selon l’invention ont été étudiés et comparés à d’autres composés phosphorés, notamment au TCP, en termes d’inhibition de cholinestérases, de modélisation moléculaire 3D par harmoniques sphériques, et en termes de modélisation QSAR pour la neurotoxicité et pour la reprotoxicité. La corrélation des résultats obtenus a permis de déterminer un « niveau de sécurité » pour l’utilisation de ces composés en tant qu’agents anti-usure dans des huiles pour turbines d’avion ou aérodérivées. 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, of 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 anti-wear agents in oils for aircraft turbines or aero-derivatives.
Protocole des différents tests réalisés : Protocol of the various tests carried out:
Mesure des concentrations inhibitrices sur deux cholinestérases : Measurement of inhibitory concentrations on two cholinesterases:
Dans la mesure où l’activité toxique du TCP passe notamment par son action sur les cholinestérases, l’effet des composés utilisés selon l’invention, ainsi que des composés comparatifs, sur deux cholinestérases a été étudié. Les valeurs de concentration nécessaires de chaque composé pour inhiber 50% de l’activité de deux cholinestérases ont été mesurées. Plus la concentration inhibitrice à 50% (IC50) est élevée, moins le composé est neurotoxique puisqu’il a une action plus faible sur la cholinestérase. Insofar as the toxic activity of TCP involves in particular its action on cholinesterases, the effect of the compounds used according to the invention, as well as of the comparative compounds, on two cholinesterases was studied. The concentration values necessary for each compound to inhibit 50% of the activity of two cholinesterases were measured. The higher the 50% inhibitory concentration (IC50), the less neurotoxic the compound is since it has a weaker action on cholinesterase.
La capacité inhibitrice des composés sur l’activité biologique de l’acétylcholinestérase (AChE) et de la butyrylcholinestérase (BuChE) a été évaluée en utilisant la méthode spectrométrique de Ellman (Ellman étal., Biochem. Pharm. 1961, 7, 88-95). 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. Pharm. 1961, 7, 88-95 ).
L’iodure d’acétylthiocholine et de butyrylthiocholine, et l’acide 5,5-dithiobis (2- nitrobenzoïque) (DTNB) ont été achetés auprès de Sigma Aldrich (Steinheim, Allemagne). Acetylthiocholine iodide and butyrylthiocholine, and 5,5-dithiobis (2-nitrobenzoic) acid (DTNB) were purchased from Sigma Aldrich (Steinheim, Germany).
La BuChE lyophilisée à partir de sérum équin (eqBuChE, Sigma Aldrich) a été dissoute dans un tampon phosphate à 0,1M (pH 7,4) pour obtenir des solutions stock d’enzyme avec une activité enzymatique de 2,5 unités/mL. L’AChE d’érythrocytes humains (hAChE, solution tampon aqueuse, ³500 unités/mg de protéine (BCA), Sigma Aldrich) a été diluée dans un tampon HEPES à 20 mM à pH 8 avec 0,1% de Triton X-100 pour obtenir une solution enzymatique avec une activité enzymatique de 0,25 unités/mL. 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, ³500 protein units / mg (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.
Dans la procédure, 100 pL de DTNB à 0,3 mM dissous dans un tampon phosphate à pH 7,4 ont été ajoutés dans les plaques 96-puits, suivis par 50 pL de solution du composé à tester et de 50 pL d’enzyme (0,05 U finale). Après 5 minutes de pré-incubation à 25°C, la réaction a été initiée par injection de 50 pL de solution d’iodure d’acétyl ou de butyrylthiocholine à 0,1 mM. L’hydrolyse de l’acétyl ou de la butyrylthiocholine a été suivie par la formation de l’anion 5-thio 2-nitrobenzoate jaune, en tant que produit de la réaction du DTNB avec la thiocholine relarguée par l’hydrolyse enzymatique de l’acétyl ou de la butyrylthiocholine, à une longueur d’onde de 412 nm, en utilisant un lecteur de microplaques (Synergy 2, Biotek, Colmar, France). Les composés à tester ont été dissous à 5x103M dans
du DMSO de grade analytique. Le Donepezil ou la tacrine ont été utilisés comme standards de référence. Le taux d’augmentation d’absorption à 412 nm a été déterminé 4 minutes après l’ajout de la solution d’iodure d’acétyl ou butyrylthiocholine. Les essais ont été réalisés avec un blanc contenant tous les composés à l’exception de l’acétyl ou butyrylthiocholine, afin de tenir compte des réactions non enzymatiques. 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 injection of 50 μL of 0.1 mM acetyl iodide or butyrylthiocholine solution. The hydrolysis of acetyl or butyrylthiocholine was followed by the formation of the yellow 5-thio 2-nitrobenzoate anion, as a reaction product of DTNB with thiocholine released by enzymatic hydrolysis of 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 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.
Le pourcentage d’inhibition dû à la présence des composés à tester a été calculé par l’expression suivante : The percentage of inhibition due to the presence of the test compounds was calculated by the following expression:
[Math 1] [Math 1]
((v0 - vi) / vO) x 100 dans laquelle v, est le taux calculé en présence de l’inhibiteur, et vo est l’activité enzymatique. ((v0 - vi) / vO) x 100 where v, is the calculated level in the presence of the inhibitor, and vo is the enzyme activity.
Les valeurs d’ICso ont été déterminées graphiquement en traçant le pourcentage d’inhibition en fonction du logarithme de six concentrations d’inhibiteur dans la solution d’essai en utilisant le logiciel GraphPadPrism (version 6.01, GraphPad Software, La Jolla, CA, USA). Toutes les expériences ont été réalisées en n=3. ICso values were determined graphically by plotting percent inhibition versus log of six inhibitor concentrations 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.
Modélisation moléculaire par harmoniques sphériques Molecular modeling by spherical harmonics
La méthode de modélisation 3D employée dans l’invention est décrite dans la publication : « Benchmarking of HPCC: A novel 3D molecular représentation combining shape and pharmacophoric descriptors for efficient molecular similarity assessments », Karaboga étal. 2013 Journal of Molecular Graphics and Modelling 41 ; 20-30. 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.
Deux clusters (clusters 1 et 2) ont été définis par similarité à partir notamment de composés monophosphates connus pour être toxiques. Two clusters (clusters 1 and 2) were defined by similarity, in particular from monophosphate compounds known to be toxic.
L’étude des composés de formule (I) utilisés selon l’invention a mis en évidence leur appartenance à des clusters différents (clusters 3 et 4), associés à des molécules non toxiques. The study of the compounds of formula (I) used according to the invention has shown that they belong to different clusters (clusters 3 and 4), associated with non-toxic molecules.
Modélisation par QSAR QSAR modeling
Les degrés de neurotoxicité et de reprotoxicité de composés utilisés selon l’invention et d’autres composés monophosphates ont été évalués par modélisation QSAR (relation structure-activité quantitative). The degrees of neurotoxicity and reprotoxicity of compounds used according to the invention and of other monophosphate compounds were evaluated by QSAR (quantitative structure-activity relationship) modeling.
Sélection des jeux d’entraînement et de validation Selection of training and validation games
Le jeu d’entraînement a été défini avec des structures chimiques compilées à partir de plusieurs sources publiquement disponibles : HSBD (Hazardous Substances Data Bank), EPA (U. S. Environmental Protection Agency), l’ECHA (European Chemicals Agency) et NTP (National Toxicology Program). 247 composés ont été classifiés comme composés neurotoxiques, 2214 composés ont été classifiés comme composés reprotoxiques, et 1697 composés ont été classifiés comme ni neurotoxiques ni reprotoxiques et formant le jeu d’entraînement non toxique.
Le jeu de validation a été construit en utilisant des composés issus de jeux de données différents de ceux utilisés pour le jeu d’entraînement. Les molécules déjà présentes dans le jeu d’entraînement ont été retirées. Le jeu de validation était composé de 70 composés classifiés comme composés neurotoxiques, 506 composés classifiés comme reprotoxiques et 256 composés classifiés comme ni neurotoxiques ni reprotoxiques et formant le jeu de validation non toxique. 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 non-toxic training set. The validation set was built using compounds from different datasets than those used for the training 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.
Performance du modèle QSAR QSAR model performance
Une méthode de modèle linéaire généralisé (GLM) a été choisie pour réaliser une approche de relation structure/activité quantitative (QSAR). Les modèles GLM ont été entraînés séparément pour discriminer les structures chimiques (i) entre composés neurotoxiques et non-neurotoxiques et (ii) entre composés reprotoxiques et non-reprotoxiques. Cette approche a résulté en un modèle GLM avec 210 descripteurs significatifs au sein des jeux d’entraînement. Pendant l’entraînement, la performance des modèles QSAR a été mesurée par des courbes ROC (Receiver Operator Characteristic) et a donné naissance à des valeurs d’aire sous la courbe (AUC) de 0,90 et plus pour la prédiction de la neurotoxicité et de la reprotoxicité, respectivement. 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. During training, 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.
Pour valider la robustesse des modèles QSAR, ils ont été ensuite utilisés pour prédire (i) les catégories de neurotoxicité des composés du jeu de validation (c’est-à-dire la catégorisation neurotoxiques/non neurotoxiques), (ii) les catégories de reprotoxicité des composés du jeu de validation (c’est-à-dire la catégorisation reprotoxiques/non reprotoxiques). Pendant la validation, la performance des modèles QSAR a été mesurée par des valeurs d’aire sous la courbe (AUC) et a fourni des valeurs significatives de 0,70 et plus pour la prédiction de la neurotoxicité et de la reprotoxicité, respectivement. To validate the robustness of the QSAR models, they 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). During validation, 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.
Les modèles QSAR basés GLM ont été ensuite utilisés pour étudier les composés diphosphorés aryliques selon l’invention. The GLM-based QSAR models were then used to study the aryl diphosphorus compounds according to the invention.
Synthèse des composés de formule (I) Synthesis of the compounds of formula (I)
Dans un ballon tétracol équipé d’un barreau aimanté, d’un réfrigérant, d’une ampoule de coulée, d’une gaine thermométrique et d’un barboteur d’azote ont été introduits 1 équivalent molaire du réactif alcool et 2 équivalents molaires de triéthylamine. Le milieu réactionnel a été dilué avec du toluène, environ 10 volumes par rapport au réactif alcool. Suivant la nature du réactif alcool, le milieu réactionnel a été chauffé entre 25 et 90°C puis, à l’aide de l’ampoule de coulée, 1 équivalent molaire de chlorure de diarylphosphate a été introduit goutte à goutte. A la fin de la réaction, le sel de triéthylamine formé a été éliminé par filtration puis lavé avec 5 volumes d’acétate d'éthyle. Le filtrat a été ensuite lavé deux fois avec une solution de HCl à 0,1 N, deux fois avec une solution de KOH à 0,1 N puis à l’eau jusqu'à pH neutre. La phase organique a ensuite été séchée avec MgS04, filtrée puis concentrée sous pression réduite. Le brut réactionnel ainsi obtenu a été purifié soit par chromatographie sur gel de silice, soit par extraction liquide-liquide, soit par précipitation. Les
phosphates ainsi obtenus ont été caractérisés par chromatographies GC ou GPC, par analyses RMN 1H et 31 P. Les rendements obtenus varient entre 52 et 90%. Into a tetracol flask equipped with a magnetic bar, a condenser, a pouring funnel, a thermometric sheath and a nitrogen bubbler were introduced 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 dropwise. 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 0.1N HCl solution, twice with 0.1N KOH solution and then with water until neutral pH. The organic phase was then dried with MgS0 4 , 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 analyzes. The yields obtained vary between 52 and 90%.
Résultats Results
Les résultats des tests réalisés sont présentés dans le tableau 1 ci-dessous. La dernière colonne correspond à un score de niveau de risque vis-à-vis de la sécurité de ces molécules utilisables dans des huiles telle que des huiles turbine et de leur prétendue toxicité en cabine. Un score de 5 correspond à un risque très élevé en termes de neurotoxicité et/ou reprotoxicité, tandis que des scores de 0 ou 1 correspondent à un niveau de risque très faible ou inexistant. Le niveau de risque est déterminé par la somme des facteurs correspondant à chacun des risques évalués indépendamment basés sur les résultats expérimentaux in vitro d’inhibition (IC50 hAChE et IC50 eqBuChE), de prédiction semi-empirique (modèles QSAR neurotoxicité et QSAR reprotoxicité), et de modélisation moléculaire via les harmoniques sphériques (classement en clusters) et il peut aller de 0 à 5. Une valeur de 0 indique une absence de risque, et une valeur de 5 indique un risque multiple très important. Pour chaque risque, un facteur 0 ou 1 est attribué selon si la valeur est au-dessus ou au-dessous d’un seuil. Les seuils suivants sont appliqués : 15 mg/L pour l’ICso pour hAChE, 15 mg/L pour l’ICso pour eqBuChE, 0,2% pour la neurotoxicité, 3% pour la reprotoxicité. 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 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. 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.
Tableau 1]
Table 1]
ND signifie non déterminé. ND means not determined.
NA signifie non application (cas de mélanges de composés) *PBT : (persistant, Bioaccumulatif et toxique) Les composés sont numérotés comme suit : NA means non application (case of mixtures of compounds) * PBT: (persistent, Bioaccumulative and toxic) The compounds are numbered as follows:
Exemples comparatifs : Comparative examples:
Composé A : 2-éthylhexyldiphénylphosphate (CAS 1241-94-7)Compound A: 2-ethylhexyldiphenylphosphate (CAS 1241-94-7)
(https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.013.625)(https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.013.625)
Composé B : Tri(o/f/70-crésyl)phosphate ToCP Composé C : Tri(mé/a-crésyl)phosphate Composé D : Tri(para-crésyl)phosphate Compound B: Tri (o / f / 70-cresyl) phosphate ToCP Compound C: Tri (me / a-cresyl) phosphate Compound D: Tri (para-cresyl) phosphate
Composé P : Tricrésylphosphate (CAS 1330-78-5) correspond au produit commercial Durad 125 (https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.239.100)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)
Composé E : Trixylylphosphate (CAS 25155-23-1) (https://echa.europa.eu/fr/registration- dossier/-/registered-dossier/2204/7/11/1) Compound E: Trixylylphosphate (CAS 25155-23-1) (https://echa.europa.eu/en/registration- dossier / - / registered-dossier / 2204/7/11/1)
Composé F : Tri(2,6-difluorophényl)phosphate Composé G : Tri(4-isopropylbenzoate)phosphate Composé H: di (p-tertbutylphényl)phénylphosphate
Composé 11 : tri phényl phosphate (CAS 204-112-2) (https://echa.europa.eu/fr/substance- information/-/substanceinfo/100.003.739) Compound F: Tri (2,6-difluorophenyl) phosphate Compound G: Tri (4-isopropylbenzoate) phosphate Compound H: di (p-tertbutylphenyl) phenylphosphate Compound 11: tri-phenyl phosphate (CAS 204-112-2) (https://echa.europa.eu/fr/substance- information / - / substanceinfo / 100.003.739)
Composé I2: Tri(p-tert-butylphényl)phosphate Compound I2: Tri (p-tert-butylphenyl) phosphate
Composé I3 : Tert-butylphényl diphényle phosphate (CAS 700-990-0) correspond au produit commercial Durad 150B, (https://echa.europa.eu/fr/substance-information/-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 /substanceinfo/100.235.046
Composé J: Crésylphosphate de saligénine Compound J: Saligenin cresylphosphate
Composé K: Diphénylphosphoroamidate Compound K: Diphenylphosphoroamidate
Composé Q: isononyldiphénylphosphate Compound Q: isononyldiphenylphosphate
Composé L : Tri(isobutyl)phosphate (CAS 126-71-6) (https://echa.europa.eu/fr/substance- information/-/substanceinfo/100.004.363) Compound L: Tri (isobutyl) phosphate (CAS 126-71-6) (https://echa.europa.eu/en/substance- information / - / substanceinfo / 100.004.363)
Composé M : Tris(2-éthylhexyl)phosphate (CAS 78-42-2)Compound M: Tris (2-ethylhexyl) phosphate (CAS 78-42-2)
(https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.001.015)(https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.001.015)
Composé N : Dibutyl [[bis[(2-ethylhexyl)oxy]phosphinothioyl]thio]succinate (CAS 68413-48- 9) (https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.063.817) Compound N: Dibutyl [[bis [(2-ethylhexyl) oxy] phosphinothioyl] thio] succinate (CAS 68413-48- 9) (https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.063 .817)
Exemples selon l’invention (composés de formules (I)) Examples according to the invention (compounds of formulas (I))
Composé 1 : isodécyldiphénylphosphate (CAS 29761-21-5) correspond au produit commercial Santicizer 148 (https://echa.europa.eu/fr/substance-information/- /substanceinfo/100.045.283) Compound 1: isodécyldiphenylphosphate (CAS 29761-21-5) corresponds to the commercial product Santicizer 148 (https://echa.europa.eu/fr/substance-information/- /substanceinfo/100.045.283)
Composé 2: n-dodécyldiphénylphosphate (CAS 27460-02-2) (https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.103.005)Compound 2: n-dodécyldiphenylphosphate (CAS 27460-02-2) (https://echa.europa.eu/en/substance-information/-/substanceinfo/100.103.005)
Composé 3: 2-octyl 1-dodécyldiphénylphosphate Composé 4 : iso-dodécyldiphénylphosphate Composé 5 : iso- hexadécyldiphénylphosphate (C16), Compound 3: 2-octyl 1-dodécyldiphenylphosphate Compound 4: iso-dodécyldiphenylphosphate Compound 5: iso-hexadécyldiphenylphosphate (C16),
Composé 6 : mélange de n-hexadécyl et n-octadécyl diphénylphosphate (nC16/C18) Composé 7 : iso-C32 diphényl phosphate. Compound 6: mixture of n-hexadecyl and n-octadecyl diphenylphosphate (nC16 / C18) Compound 7: iso-C32 diphenyl phosphate.
Alors que le composé A (2-éthylhexyldiphénylphosphate) appartient au cluster 1 des molécules organophosphorées neurotoxiques et reprotoxiques, le composé 1 , qui répond à la formule (I) selon l’invention, présente en revanche des valeurs d’inhibition IC50 élevées au regard des cholinestérases hAChE et eqBuChE. De façon surprenante, la modélisation via les harmoniques sphériques montre que cette molécule appartient à un cluster de molécules différent des clusters 1 et 2 neurotoxiques. Les modèles semi-empiriques QSAR indiquent également une différence de réactivité. Le composé 1 présente un niveau de risque égal à 0, alors que les composés du cluster 1 présentent un niveau de risque au moins égal à 2.While compound A (2-ethylhexyldiphenylphosphate) belongs to cluster 1 of neurotoxic and reprotoxic organophosphate molecules, compound 1, which corresponds to formula (I) according to the invention, on the other hand exhibits high IC50 inhibition values compared to 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. The semi-empirical QSAR models also indicate a difference in reactivity. Compound 1 has a risk level equal to 0, while the compounds of cluster 1 have a risk level of at least 2.
La modélisation QSAR indique également que le composé 3, qui répond à la formule (I) selon l’invention, appartiennent à un cluster différent des clusters 1 et 2 de composés neurotoxiques, les composés 2 et 4 appartenant au même cluster que le composé 1 (à savoir
le cluster 4), alors que le composé 3 appartient à un autre cluster (à savoir le cluster 3). Ces trois composés (composés 2 à 4) présentent également une neurotoxicité nulle et une reprotoxicité très faible. Le cluster ainsi que la modélisation QSAR n’ont pas été déterminés pour les composés 5 à 7 selon l’invention. Cependant, ces derniers composés 5 à 7 présentent d’excellent résultat in vitro en terme d’ICso de cholinestérases (la concentration inhibitrice à 50% est élevée, supérieure à 18 mg/L pour IC50 hAChE et supérieure à 25mg/L et pouvant même atteindre 127 mg/L pour IC50 eqBuCh). Ces composés 5 à 7 laissent ainsi supposer qu’ils sont non neurotoxiques puisqu’ils ont une action faible sur les cholinestérases testées et doivent certainement présenter de bons résultats aux essais de QSAR, tout en se classant probablement parmi les clusters 3 et 4 selon la modélisation 3D des harmoniques sphériques. On observe que l’allongement de la chaîne alkyle tend vers un cluster de type 3. QSAR modeling also indicates that compound 3, which corresponds to formula (I) according to the invention, belong to a cluster different 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 may even reach 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 present good results in the QSAR tests, while probably ranking among clusters 3 and 4 according to the 3D modeling of spherical harmonics. It is observed that the lengthening of the alkyl chain tends towards a type 3 cluster.
Les composés de formule (I) selon l’invention semblent par conséquent présenter une conformation différente de celle des composés appartenant aux clusters 1 et 2 neurotoxiques, et que leur réactivité diffère également au regard de l’activité biologique des enzymes étudiées. The compounds of formula (I) according to the invention therefore 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.
Les composés du cluster 1 se présentent, selon l’approche de modélisation 3D des harmoniques sphériques, sous la forme d’une « hélice tripale » sur la base de deux plans perpendiculaires au niveau du centre ou du cœur de la molécule alors que les composés selon l’invention présentent une forme plutôt déployée et aplanie s’approchant d’une forme papillon. Les molécules issues du travail de modélisation par les harmoniques sphériques sont représentées sur la figure 1. Ces composés sont donc des alternatives non neurotoxiques et non reprotoxiques au tricrésylphosphate et ses analogues tri-arylphosphates ou aux autres composés testés (généralement utilisés également en tant qu’agent anti-usure dans une huile pour turbine) à base de phosphore. 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 according to the invention have a rather deployed and flattened shape approaching 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 tricresylphosphate and its tri-arylphosphate analogues or to the other compounds tested (generally also used as a anti-wear agent in turbine oil) based on phosphorus.
Les composés 1 à 7, dont le groupement A est un groupe alkyle comprenant 10 à 20 atomes de carbone, sont non neurotoxiques et présentent une très faible reprotoxicité. Comparativement, le composé A et le composé Q, dont le groupement A est un groupe alkyle comprenant respectivement 8 et 9 atomes de carbone, présentent des valeurs de neurotoxicité et de reprotoxicité selon les modèles QSAR nettement plus élevées, et appartiennent au cluster 1 de composés neurotoxiques. 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. In comparison, compound A and compound Q, whose A group is an alkyl group comprising 8 and 9 carbon atoms respectively, exhibit significantly higher neurotoxicity and reprotoxicity values according to QSAR models, and belong to cluster 1 of compounds. neurotoxic.
Ainsi, ces essais intro et de modélisation (3D des harmoniques sphériques ou QSAR) montrent que la Demanderesse a sélectionné, de façon non-arbitraire, parmi tous les composés existants à base de phosphore et présentant généralement une action anti-usure dans une huile, un sous-ensemble restreint de composés de formule générale (I). Ce sous- ensemble présente en outre un effet technique différent des autres composés à base de phosphore. En effet, ce sous-ensemble de composé de formule (I) est au moins non neurotoxique et est apte à et/ou configurer pour réduire et/ou prévenir de la neurotoxicité d’une huile en particulier d’une huile de turbine destinée à l’aviation. De plus, ce sous-ensemble est apte à/ configurer pour la prophylaxie du syndrome aérotoxique en particulier en cas
d’évènement de fumée. Ce sous-ensemble, de par ses caractéristiques, permet de former une huile pour turbine, par exemple pour l’aviation qui est apte à et/ou configurée pour permettre d’augmenter le niveau de sécurité dans l’aviation et dans d’autres applications aérodérivées. Thus, these intro and modeling tests (3D spherical harmonics or QSAR) show that the Applicant has selected, in a non-arbitrary manner, among all the existing phosphorus-based compounds and generally exhibiting an anti-wear action in an oil, a restricted subset of compounds of general formula (I). This subset also exhibits a technical effect different from other phosphorus-based compounds. In fact, 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 of a turbine oil intended for aviation. In addition, this sub-assembly is suitable / configured for the prophylaxis of aerotoxic syndrome in particular in the event of 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.
En outre, aucun indice dans l’état de la technique pouvait permettre un homme du métier à choisir spécifique ce sous-ensemble de composés de formule générale (I) afin de réduire/prévenir la neurotoxicité d’une huile de turbine ou pour la prophylaxie du syndrome aérotoxique. In addition, no index 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 prophylaxis. aerotoxic syndrome.
En effet, d’une part, les autres composés phosphorés et notamment les autres composés phosphorés utilisés en tant qu’agent anti-usure dans une huile et connus de l’art antérieur ne présentent cet effet technique nouveau (i.e. : réduire et/ou prévenir la neurotoxicité d’une huile ou pour la prophylaxie du syndrome aérotoxique). Au contraire, les autres composés anti-usures connus (composés comparatifs E, 11-3, M, N et P) et notamment utilisés en tant qu’agent anti-usure dans une huile, sont neurotoxiques. In fact, on the one hand, the other phosphorus compounds and in particular the other phosphorus compounds used as antiwear 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). On the contrary, the other known anti-wear compounds (comparative compounds E, 11-3, M, N and P) and in particular used as an anti-wear agent in an oil, are neurotoxic.
D’autre part, avant les essais réalisés par la Demanderesse, la plupart des autres composés phosphorés commerciaux et enregistrés, notamment connus en tant qu’agent antiusure, comme par exemple les composés A, 11-13, L, M et N sont reconnus notamment par le site officiel de l’ECHA (Agence Européenne des produits chimiques, de l’anglais « European Chemical Agency ») comme ne présentant pas de danger grave de toxicité aiguë ou grave (caractère CMR). L’agence ECHA est une autorité compétente pour statuer sur la toxicité des produits chimiques enregistrés pour le marché européen. Elle publie des données scientifiques publiques et reconnues. Le composé 13 est notamment utilisé dans le domaine des lubrifiants en remplacement du TCP ou de ses analogues. Or, les essais de la Demanderesse via les essais in vitro IC50 ou les essais de modélisation 3D ou QSAR montre, au contraire, que ces composés sont fortement neurotoxiques. Par exemple, d’après le site de l’ECHA, ce composé ne présenterait pas de signes de toxicité vis-à-vis de la santé humaine. Or le tableau 1 ci-dessus montre que ce composé I3 est un mélange de composés neurotoxiques incluant le triphénylphosphate et le tri(p-tertbutylphényle)phosphate. Un homme du métier n’aurait donc pas été incité ou encouragé à sélectionner le sous-ensemble formé par les composés de formule générale (I) afin de réduire et/ou prévenir la neurotoxicité d’une huile ou pour la prophylaxie du syndrome aérotoxique.
Exemple 2 : Performances anti-usure des composés selon l’invention La performance anti-usure des huiles selon l’invention a été mesurée en utilisant le test d’usure à 4 billes selon la norme ASTM D4172. Les résultats obtenus sont présentés dans le tableau 2 ci-dessous. [Tableau 2]
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 antiwear agent, such as for example compounds A, 11-13, L, M and N are recognized in particular by the official site of the ECHA (European Chemicals Agency, from the English "European Chemical Agency") as not presenting a serious danger of acute or serious toxicity (CMR character). The ECHA agency is the competent authority to rule on the toxicity of chemicals registered for the European market. It publishes public and recognized scientific data. Compound 13 is used in particular in the field of lubricants as a replacement for TCP or its analogues. However, the tests of the Applicant via the IC50 in vitro 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 signs of toxicity to human health. Now, 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 encouraged 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 aerotoxic syndrome. Example 2 Anti-Wear Performance 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 presented in Table 2 below. [Table 2]
Les résultats confirment que les composés de formule (I) utilisés selon l’invention possèdent des propriétés anti-usure intéressantes et potentiellement analogues à celles du TCP, donc qu’ils sont compatibles avec une utilisation efficace en tant qu’agent anti-usure, notamment dans des huiles pour turbines d’avions ou aérodérivées. Bien entendu, diverses autres modifications peuvent être apportées à l’invention dans le cadre des revendications annexées.
The results confirm that the compounds of formula (I) used according to the invention have advantageous anti-wear properties and potentially similar to those of TCP, therefore they are compatible with effective use as an anti-wear agent, in particular in oils for aircraft turbines or aero-derivatives. Of course, various other modifications can be made to the invention within the scope of the appended claims.
Claims
1. Utilisation d’au moins un composé de formule (I) o 1. Use of at least one compound of formula (I) o
A 0 p" OAr, At 0 p " OAr,
OA r2 dans laquelle A est un groupe alkyle linéaire ou ramifié comprenant de 10 à 32 atomes de carbone, et chacun de A et A¾ est indépendamment un groupe aryle en tant qu’agent anti usure dans une huile pour réduire et/ou prévenir la neurotoxicité de ladite huile. OA r 2 in which A is a linear or branched alkyl group comprising from 10 to 32 carbon atoms, and each of A and A¾ is independently an aryl group as an antiwear agent in an oil for reducing and / or preventing the neurotoxicity of said oil.
2. Utilisation selon la revendication 1, dans laquelle la concentration inhibitrice à 50% dudit au moins composé de formule (I) sur l’activité biologique d’une enzyme acétylcholinestérase (AChE), nommée ICsohAChE est supérieure ou égale à 15 mg/L et l’activité sur une enzyme butyrylcholinestérase, nommée IC50 eqBuChE est supérieure ou égale à 15 mg/L, de préférence égale ou supérieure à 20 mg/L, en particulier égale ou supérieure à 25 mg/L et typiquement égale ou supérieure à 30 mg/L. 2. Use according to claim 1, wherein 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. 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.
3. Utilisation selon la revendication 1 ou 2, dans laquelle A est choisi dans le groupe constitué par un groupe isodécyle, un groupe n-dodécyle et un groupe 2-octyl 1-dodécyle. 3. Use according to claim 1 or 2, wherein A is selected from the group consisting of an isodecyl group, an n-dodecyl group and a 2-octyl 1-dodecyl group.
4. Utilisation selon l’une quelconque des revendications précédentes, dans laquelle A et Ar2 sont des phényles. 4. Use according to any one of the preceding claims, wherein A and Ar2 are phenyls.
5. Utilisation selon l’une quelconque des revendications 1 à 4, dans laquelle le composé de formule (I) est choisi dans le groupe constitué par l’isodécyldiphénylphosphate, le n- dodécyldiphénylphospate, le 2-octyl 1-dodécyldiphénylphosphate et l’un quelconque de leurs mélanges. 5. Use according to any one of claims 1 to 4, wherein the compound of formula (I) is selected from the group consisting of isodécyldiphenylphosphate, n-dodécyldiphenylphospate, 2-octyl 1-dodécyldiphenylphosphate and un any of their mixtures.
6. Utilisation selon la revendication 5, dans laquelle le composé de formule (I) est l’isodécyldiphénylphosphate. 6. Use according to claim 5, wherein the compound of formula (I) is isodecyldiphenylphosphate.
7. Utilisation selon l’une quelconque des revendications 1 à 6, dans laquelle l’huile ne comprend pas d’additif anti-usure triarylphosphate. 7. Use according to any one of claims 1 to 6, wherein the oil does not include an anti-wear additive triarylphosphate.
8. Utilisation selon l’une quelconque des revendications 1 à 7, dans laquelle l’huile contient comme seul(s) agent(s) anti-usure seulement le ou les composés de formule (I). 8. Use according to any one of claims 1 to 7, wherein the oil contains as sole (s) antiwear agent (s) only the compound (s) of formula (I).
9. Utilisation d’au moins 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 A et A¾ est indépendamment un groupe aryle en tant qu’agent anti usure dans une huile pour la prophylaxie du syndrome aérotoxique en cas d’événement de fumée.
9. Use of 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 A and A¾ is independently an aryl group as an antiwear agent in an oil for the prophylaxis of aerotoxic syndrome in the event of smoke event.
10. Utilisation selon la revendication 9, dans laquelle la concentration inhibitrice à 50% dudit au moins composé de formule (I) sur l’activité biologique d’une enzyme acétylcholinestérase (AChE), nommée ICsohAChE est supérieure ou égale à 15 mg/L et l’activité sur une enzyme butyrylcholinestérase, nommée IC50 eqBuChE est supérieure ou égale à 15 mg/L, de préférence égale ou supérieure à 20 mg/L, en particulier égale ou supérieure à 20 et typiquement égale ou supérieure à 30 mg/L. 10. Use according to claim 9, wherein 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. 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 20 and typically equal to or greater than 30 mg / L THE.
11. Utilisation selon la revendication 9 ou 10, dans laquelle A est choisi dans le groupe constitué par un groupe isodécyle, un groupe n-dodécyle et un groupe 2-octyl 1-dodécyle. 11. Use according to claim 9 or 10, wherein A is selected from the group consisting of an isodecyl group, an n-dodecyl group and a 2-octyl 1-dodecyl group.
12. Utilisation selon l’une quelconque des revendications 9 à 11, dans laquelle A et A¾ sont des phényles. 12. Use according to any one of claims 9 to 11, wherein A and A¾ are phenyls.
13. Utilisation selon l’une quelconque des revendications 9 à 12, dans laquelle le composé de formule (I) est choisi dans le groupe constitué par l’isodécyldiphénylphosphate, le n- dodécyldiphénylphospate, le 2-octyl 1-dodécyldiphénylphosphate et l’un quelconque de leurs mélanges. 13. Use according to any one of claims 9 to 12, wherein the compound of formula (I) is selected from the group consisting of isodécyldiphenylphosphate, n-dodécyldiphenylphospate, 2-octyl 1-dodécyldiphenylphosphate and un any of their mixtures.
14. Utilisation selon la revendication 13, dans laquelle le composé de formule (I) est l’isodécyldiphénylphosphate. 14. Use according to claim 13, wherein the compound of formula (I) is isodecyldiphenylphosphate.
15. Utilisation selon l’une quelconque des revendications 9 à 14, dans laquelle l’huile ne comprend pas d’additif anti-usure triarylphosphate ou dans laquelle l’huile contient comme seul(s) agent(s) anti-usure seulement le ou les composés de formule (I).
15. Use according to any one of claims 9 to 14, in which the oil does not comprise an anti-wear additive triarylphosphate or in which the oil contains as sole (s) anti-wear agent (s) only the or the compounds of formula (I).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR2005251A FR3110594B1 (en) | 2020-05-20 | 2020-05-20 | Specific organophosphorus compounds as non-neurotoxic antiwear agents |
| PCT/EP2021/063201 WO2021233947A1 (en) | 2020-05-20 | 2021-05-18 | Specific organophosphorus compounds as non-neurotoxic anti-wear agents |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| EP4114910A1 true EP4114910A1 (en) | 2023-01-11 |
| EP4114910C0 EP4114910C0 (en) | 2023-07-19 |
| EP4114910B1 EP4114910B1 (en) | 2023-07-19 |
Family
ID=72088308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP21725555.3A Active EP4114910B1 (en) | 2020-05-20 | 2021-05-18 | Specific organophosphorus compounds as non-neurotoxic anti-wear agents |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20230183592A1 (en) |
| EP (1) | EP4114910B1 (en) |
| FR (1) | FR3110594B1 (en) |
| WO (1) | WO2021233947A1 (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3951837A (en) * | 1973-09-24 | 1976-04-20 | Mcdonnell Douglas Corporation | Functional fluid compositions |
| FR2924122B1 (en) | 2007-11-28 | 2009-12-25 | Nyco Sa | ANTI-OXIDANT AND / OR ANTI-CORROSION AGENT, LUBRICATING COMPOSITION CONTAINING SAID AGENT AND PROCESS FOR PREPARING THE SAME |
| FR2946983B1 (en) * | 2009-06-23 | 2011-12-23 | Nyco | ANTI-WEAR AGENTS WITH REDUCED NEUROTOXICITY |
| DE102013003282B4 (en) | 2013-02-27 | 2016-09-29 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Tricresyl phosphate-free oil and its use |
| WO2016032246A1 (en) * | 2014-08-27 | 2016-03-03 | Sk Innovation Co., Ltd. | Lubricant composition for improving thermo-oxidation stability and color stability |
| US11242893B2 (en) * | 2018-03-06 | 2022-02-08 | Indian Oil Corporation Limited | Composition of high performance bearing oil for steel plants |
-
2020
- 2020-05-20 FR FR2005251A patent/FR3110594B1/en active Active
-
2021
- 2021-05-18 US US17/926,218 patent/US20230183592A1/en active Pending
- 2021-05-18 WO PCT/EP2021/063201 patent/WO2021233947A1/en unknown
- 2021-05-18 EP EP21725555.3A patent/EP4114910B1/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021233947A1 (en) | 2021-11-25 |
| EP4114910C0 (en) | 2023-07-19 |
| FR3110594B1 (en) | 2022-09-23 |
| FR3110594A1 (en) | 2021-11-26 |
| US20230183592A1 (en) | 2023-06-15 |
| EP4114910B1 (en) | 2023-07-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Abou-Donia et al. | Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review | |
| Liyasova et al. | Exposure to tri-o-cresyl phosphate detected in jet airplane passengers | |
| Haraguchi et al. | Alkaloidal components in the poisonous plant, Ipomoea carnea (Convolvulaceae) | |
| Colovic et al. | Acetylcholinesterase inhibitors: pharmacology and toxicology | |
| Jokanović et al. | Organophosphate induced delayed polyneuropathy in man: an overview | |
| Mangas et al. | Neurotoxic effects associated with current uses of organophosphorus compounds | |
| EP2446005B1 (en) | Anti-wear agents with a reduced neurotoxicity | |
| Facanha et al. | Evaluation of antioxidant properties of a phosphorated cardanol compound on mineral oils (NH10 and NH20) | |
| JP3165279B2 (en) | Oil-soluble antioxidant containing 3-acylated catechin | |
| EP4114910B1 (en) | Specific organophosphorus compounds as non-neurotoxic anti-wear agents | |
| Gupta et al. | Toxicity of organophosphates and carbamates | |
| EP3938478B1 (en) | Use of oils comprising non-neurotoxic anti-wear additives | |
| Krátký et al. | Salicylanilide diethyl phosphates as cholinesterases inhibitors | |
| EP3085369B1 (en) | Therapeutic and/or preventive agent comprising 1-indansulfamide derivative for pain | |
| Pandelides et al. | Transcriptomic changes and the roles of cannabinoid receptors and PPARγ in developmental toxicities following exposure to δ9-tetrahydrocannabinol and cannabidiol | |
| FR3110593A1 (en) | Use of oils comprising non-neurotoxic anti-wear additives | |
| US11230683B2 (en) | Use of oils comprising non-neurotoxic anti-wear additives | |
| Chelliah et al. | Inhibition of cholinesterase activity by tetrahydroaminoacridine and the hemisuccinate esters of tocopherol and cholesterol | |
| OKINO et al. | Biological evaluation and molecular docking of Indonesian Gracilaria salicornia as antioxidant agents. | |
| WO2023209038A1 (en) | Use of an antioxidant for reducing and/or preventing the toxicity of a lubricant composition | |
| US20070082946A1 (en) | Methods of treating mental diseases, inflammation and pain | |
| Hartwig et al. | Tricresyl phosphate, sum of all ortho isomers | |
| US20050113445A1 (en) | Methods of treating mental diseases, inflammation and pain | |
| Lauria | THE ENDOCANNABINOID ENZYME MONOACYLGLYCEROL LIPASE: DEVELOPMENT OF A NEW FLUORESCENT ASSAY AND NOVEL INHIBITORS | |
| PT105914A (en) | USE OF AN ABSTRACT OF OLIVE OIL INHIBITOR OF ACETILCOLINESTERASE IN THE TREATMENT OF COLINERGIC DISTURBATIONS |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
| 17P | Request for examination filed |
Effective date: 20210809 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
| GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
| DAV | Request for validation of the european patent (deleted) | ||
| DAX | Request for extension of the european patent (deleted) | ||
| INTG | Intention to grant announced |
Effective date: 20230217 |
|
| GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
| GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
| AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
| REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D Free format text: NOT ENGLISH |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
| REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602021003634 Country of ref document: DE |
|
| REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D Free format text: LANGUAGE OF EP DOCUMENT: FRENCH |
|
| U01 | Request for unitary effect filed |
Effective date: 20230817 |
|
| U07 | Unitary effect registered |
Designated state(s): AT BE BG DE DK EE FI FR IT LT LU LV MT NL PT SE SI Effective date: 20230824 |
|
| REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG9D |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20231020 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20231119 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20230719 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20231019 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20231119 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20230719 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20231020 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20230719 |
|
| U20 | Renewal fee paid [unitary effect] |
Year of fee payment: 4 Effective date: 20240301 |
|
| REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602021003634 Country of ref document: DE |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20230719 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20230719 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20230719 Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20230719 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20230719 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20230719 |
|
| PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |