JP7355801B2 - 1,4-ジエン系の部位特異的同位体標識 - Google Patents
1,4-ジエン系の部位特異的同位体標識 Download PDFInfo
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- JP7355801B2 JP7355801B2 JP2021198937A JP2021198937A JP7355801B2 JP 7355801 B2 JP7355801 B2 JP 7355801B2 JP 2021198937 A JP2021198937 A JP 2021198937A JP 2021198937 A JP2021198937 A JP 2021198937A JP 7355801 B2 JP7355801 B2 JP 7355801B2
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- group
- bis
- polyunsaturated
- alkyl
- allyl
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- 238000001948 isotopic labelling Methods 0.000 title 1
- 150000002632 lipids Chemical class 0.000 claims description 128
- 238000000034 method Methods 0.000 claims description 90
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- -1 fatty acid esters Chemical class 0.000 claims description 63
- 229910052805 deuterium Inorganic materials 0.000 claims description 43
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 37
- 239000003054 catalyst Substances 0.000 claims description 35
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 28
- 229930195729 fatty acid Natural products 0.000 claims description 28
- 239000000194 fatty acid Substances 0.000 claims description 28
- 229910052707 ruthenium Inorganic materials 0.000 claims description 23
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 21
- 230000004048 modification Effects 0.000 claims description 20
- 238000012986 modification Methods 0.000 claims description 20
- 150000004665 fatty acids Chemical class 0.000 claims description 16
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 6
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 110
- 150000001875 compounds Chemical class 0.000 description 96
- 125000003118 aryl group Chemical group 0.000 description 47
- 239000003446 ligand Substances 0.000 description 46
- 229910052723 transition metal Inorganic materials 0.000 description 44
- 150000003624 transition metals Chemical class 0.000 description 44
- 239000000203 mixture Substances 0.000 description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
- 125000001072 heteroaryl group Chemical group 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 28
- 229910052739 hydrogen Inorganic materials 0.000 description 27
- 229910052799 carbon Inorganic materials 0.000 description 25
- 125000000623 heterocyclic group Chemical group 0.000 description 25
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- 230000000155 isotopic effect Effects 0.000 description 23
- 150000001336 alkenes Chemical class 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 22
- JYYFMIOPGOFNPK-AGRJPVHOSA-N ethyl linolenate Chemical group CCOC(=O)CCCCCCC\C=C/C\C=C/C\C=C/CC JYYFMIOPGOFNPK-AGRJPVHOSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 229940090028 ethyl linolenate Drugs 0.000 description 21
- JYYFMIOPGOFNPK-UHFFFAOYSA-N ethyl linolenate Natural products CCOC(=O)CCCCCCCC=CCC=CCC=CCC JYYFMIOPGOFNPK-UHFFFAOYSA-N 0.000 description 21
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 21
- 125000003342 alkenyl group Chemical group 0.000 description 20
- 125000000304 alkynyl group Chemical group 0.000 description 20
- 125000004429 atom Chemical group 0.000 description 18
- 239000000126 substance Substances 0.000 description 18
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 17
- 150000002148 esters Chemical class 0.000 description 17
- 125000000753 cycloalkyl group Chemical group 0.000 description 16
- 229910052751 metal Inorganic materials 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 15
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 15
- 125000002947 alkylene group Chemical group 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 15
- 239000002184 metal Substances 0.000 description 15
- 239000000758 substrate Substances 0.000 description 15
- 229910052722 tritium Inorganic materials 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 14
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- ITNKVODZACVXDS-YATCGRJWSA-N ethyl (4e,7e,10e,13e,16e,19e)-docosa-4,7,10,13,16,19-hexaenoate Chemical compound CCOC(=O)CC\C=C\C\C=C\C\C=C\C\C=C\C\C=C\C\C=C\CC ITNKVODZACVXDS-YATCGRJWSA-N 0.000 description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 12
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 11
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 10
- 125000000746 allylic group Chemical group 0.000 description 10
- 229910052782 aluminium Inorganic materials 0.000 description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 229910052697 platinum Inorganic materials 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 235000021342 arachidonic acid Nutrition 0.000 description 9
- 229940114079 arachidonic acid Drugs 0.000 description 9
- 125000004431 deuterium atom Chemical group 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 229910052741 iridium Inorganic materials 0.000 description 9
- 150000002527 isonitriles Chemical class 0.000 description 9
- 229960004488 linolenic acid Drugs 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 230000007246 mechanism Effects 0.000 description 9
- 229910052759 nickel Inorganic materials 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 150000003254 radicals Chemical class 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 8
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 8
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 8
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 description 8
- 229910052735 hafnium Inorganic materials 0.000 description 8
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 description 8
- 150000002466 imines Chemical class 0.000 description 8
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 8
- 229910052703 rhodium Inorganic materials 0.000 description 8
- 239000010948 rhodium Substances 0.000 description 8
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 229910052719 titanium Inorganic materials 0.000 description 8
- 239000010936 titanium Substances 0.000 description 8
- 229910052726 zirconium Inorganic materials 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 125000001183 hydrocarbyl group Chemical group 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 7
- 238000011068 loading method Methods 0.000 description 7
- 150000002825 nitriles Chemical class 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 230000004792 oxidative damage Effects 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 150000002978 peroxides Chemical class 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- BPEVHDGLPIIAGH-UHFFFAOYSA-N ruthenium(3+) Chemical compound [Ru+3] BPEVHDGLPIIAGH-UHFFFAOYSA-N 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 7
- UBEIMDKGOYBUKT-FLIQGJDUSA-N 1,2,3-trilinolenoylglycerol Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/C\C=C/C\C=C/CC)COC(=O)CCCCCCC\C=C/C\C=C/C\C=C/CC UBEIMDKGOYBUKT-FLIQGJDUSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- 125000004452 carbocyclyl group Chemical group 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 238000007697 cis-trans-isomerization reaction Methods 0.000 description 6
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 6
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 6
- 230000037353 metabolic pathway Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 150000001451 organic peroxides Chemical class 0.000 description 6
- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical compound NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 150000001975 deuterium Chemical group 0.000 description 5
- 150000004985 diamines Chemical class 0.000 description 5
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 5
- 125000004475 heteroaralkyl group Chemical group 0.000 description 5
- 235000020778 linoleic acid Nutrition 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 150000005846 sugar alcohols Polymers 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 150000003568 thioethers Chemical class 0.000 description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 4
- 239000005062 Polybutadiene Substances 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 150000001345 alkine derivatives Chemical class 0.000 description 4
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 239000000306 component Substances 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 4
- 229940012843 omega-3 fatty acid Drugs 0.000 description 4
- 229940033080 omega-6 fatty acid Drugs 0.000 description 4
- 235000020665 omega-6 fatty acid Nutrition 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229920002857 polybutadiene Polymers 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- YNWSXIWHOSSPCO-UHFFFAOYSA-N rhodium(2+) Chemical compound [Rh+2] YNWSXIWHOSSPCO-UHFFFAOYSA-N 0.000 description 4
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical class [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- PRBHEGAFLDMLAL-XQRVVYSFSA-N (4z)-hexa-1,4-diene Chemical compound C\C=C/CC=C PRBHEGAFLDMLAL-XQRVVYSFSA-N 0.000 description 3
- 239000001149 (9Z,12Z)-octadeca-9,12-dienoate Substances 0.000 description 3
- WTTJVINHCBCLGX-UHFFFAOYSA-N (9trans,12cis)-methyl linoleate Natural products CCCCCC=CCC=CCCCCCCCC(=O)OC WTTJVINHCBCLGX-UHFFFAOYSA-N 0.000 description 3
- MQFYRUGXOJAUQK-UHFFFAOYSA-N 2-[2-[2-(2-octadecanoyloxyethoxy)ethoxy]ethoxy]ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOC(=O)CCCCCCCCCCCCCCCCC MQFYRUGXOJAUQK-UHFFFAOYSA-N 0.000 description 3
- LNJCGNRKWOHFFV-UHFFFAOYSA-N 3-(2-hydroxyethylsulfanyl)propanenitrile Chemical compound OCCSCCC#N LNJCGNRKWOHFFV-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PKIXXJPMNDDDOS-UHFFFAOYSA-N Methyl linoleate Natural products CCCCC=CCCC=CCCCCCCCC(=O)OC PKIXXJPMNDDDOS-UHFFFAOYSA-N 0.000 description 3
- DJEQZVQFEPKLOY-UHFFFAOYSA-N N,N-dimethylbutylamine Chemical compound CCCCN(C)C DJEQZVQFEPKLOY-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 3
- 125000005263 alkylenediamine group Chemical group 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 239000013522 chelant Substances 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000006911 enzymatic reaction Methods 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000006317 isomerization reaction Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 235000021315 omega 9 monounsaturated fatty acids Nutrition 0.000 description 3
- 239000006014 omega-3 oil Substances 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 230000036542 oxidative stress Effects 0.000 description 3
- 229950006768 phenylethanolamine Drugs 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
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Description
出願データシートにおいて特定されたいずれかのおよびすべての優先権主張またはそれらに対する任意の補正が、参照により本明細書に援用される。本願は、2015年11月23日に出願された米国仮出願第62/258,993号の利益を主張する。上述の出願は、その全体が参照により本明細書中に援用され、明確に本明細書の一部を成す。
いくつかの実施形態は、以下の態様を含む。
[1]
多価不飽和脂質を同位体で部位特異的に修飾するための方法であって、該方法は、
遷移金属系触媒の存在下で多価不飽和脂質を同位体含有物質と反応させることによって、1つ以上のモノ-アリル部位またはビス-アリル部位に該同位体を有する同位体的に修飾された多価不飽和脂質を得る工程を含み、該同位体含有物質は、ジュウテリウム、トリチウムおよびそれらの組み合わせからなる群より選択される少なくとも1種の同位体を含む、方法。
[2]
前記多価不飽和脂質が、脂肪酸、脂肪酸エステル、脂肪酸チオエステル、脂肪酸アミド、脂肪酸模倣物および脂肪酸プロドラッグからなる群より選択される、[1]に記載の方法。
[3]
前記多価不飽和脂質が、2つ以上の炭素-炭素二重結合を有する、[1]又は[2]に記載の方法。
[4]
前記多価不飽和脂質が、少なくとも3つの炭素-炭素二重結合を有する、[1]~[3]のいずれか1に記載の方法。
[5]
前記多価不飽和脂肪酸が、式(IA):
R1は、HおよびC1-10アルキルからなる群より選択され;
R2は、-OH、-OR3、-SR3、ホスフェートおよび-N(R3)2からなる群より選択され;
各R3は、独立して、C1-10アルキル、C2-10アルケン、C2-10アルキン、C3-10シクロアルキル、C6-10アリール、4~10員のヘテロアリールおよび3~10員の複素環式環からなる群より選択され、各R3は、置換されるか、または非置換であり;
nは、1~10の整数であり;
pは、1~10の整数である)
に記載の構造を有する、[1]~[4]のいずれか1に記載の方法。
[6]
前記多価不飽和脂質が、オメガ-3脂肪酸、オメガ-6脂肪酸およびオメガ-9脂肪酸からなる群より選択される、[1]~[5]のいずれか1に記載の方法。
[7]
前記多価不飽和脂質が、リノール酸およびリノレン酸からなる群より選択される、[1]~[5]のいずれか1に記載の方法。
[8]
前記多価不飽和脂質が、ガンマリノレン酸、ジホモガンマリノレン酸、アラキドン酸およびドコサテトラエン酸からなる群より選択される、[1]~[5]のいずれか1に記載の方法。
[9]
前記多価不飽和脂肪酸エステルが、トリグリセリド、ジグリセリドおよびモノグリセリドからなる群より選択される、[1]~[5]のいずれか1に記載の方法。
[10]
前記脂肪酸エステルが、エチルエステルである、[1]~[5]のいずれか1に記載の方法。
[11]
前記同位体的に修飾された多価不飽和脂質が、1つ以上のビス-アリル部位にジュウテリウムを有する重水素化多価不飽和脂質である、[1]~[10]のいずれか1に記載の方法。
[12]
前記同位体的に修飾された多価不飽和脂質が、すべてのビス-アリル部位にジュウテリウムを有する重水素化多価不飽和脂質である、[1]~[11]のいずれか1に記載の方法。
[13]
前記同位体的に修飾された多価不飽和脂質が、1つ以上のモノ-アリル部位にジュウテリウムを有する重水素化多価不飽和脂質である、[1]~[12]のいずれか1に記載の方法。
[14]
前記同位体的に修飾された多価不飽和脂質が、ビス-アリル部位に50%を超える重水素化度を有する重水素化多価不飽和脂質である、[1]~[13]のいずれか1に記載の方法。
[15]
前記同位体的に修飾された多価不飽和脂質が、モノ-アリル部位に30%より低い重水素化度を有する重水素化多価不飽和脂質である、[1]~[14]のいずれか1に記載の方法。
[16]
前記遷移金属系触媒が、ロジウム、イリジウム、ニッケル、白金、パラジウム、アルミニウム、チタン、ジルコニウム、ハフニウム、ルテニウムおよびそれらの組み合わせからなる群より選択される遷移金属を含む、[1]~[15]のいずれか1に記載の方法。
[17]
前記遷移金属系触媒が、ルテニウム触媒である、[16]に記載の方法。
[18]
前記遷移金属系触媒が、式(IIA)
[ML1(L2)m]Qn (IIA)
(式中、
Mは、ロジウム、イリジウム、ニッケル、白金、パラジウム、アルミニウム、チタン、ジルコニウム、ハフニウムおよびルテニウムからなる群より選択され;
L1は、C3-10シクロアルキル、C6-10アリール、4~10員のヘテロアリールおよび3~10員の複素環式環からなる群より選択され、L1は、置換されるか、または非置換であり;
各L2は、独立して、アミン、イミン、カルベン、アルケン、ニトリル、イソニトリル、アセトニトリル、エーテル、チオエーテル、ホスフィン、ピリジン、置換C3-10シクロアルキル、非置換C3-10シクロアルキル、置換C6-10アリール、4~10員の置換ヘテロアリール、非置換C6-10アリール、4~10員の非置換ヘテロアリール、3~10員の置換複素環式環、3~10員の非置換複素環式環およびそれらの任意の組み合わせからなる群より選択され;
mは、1~3の整数であり;
Qは、単一電荷を有するアニオンであり、
nは、0または1である)
に記載の構造を有する、[16]に記載の方法。
[19]
Mが、ルテニウムである、[1]~[18]のいずれか1に記載の方法。
[20]
L2が、-P(R4)3であり、各R4が、独立して、水素、C1-15アルキル、C3-8シクロアルキル、4~10員のヘテロアリール、C6-15アリールからなる群より選択され、各々が、C1-15アルキル、C2-15アルケン、C2-15アルキン、OH、ハロゲン、シアノ、アルコキシ、C3-8シクロアルキル、4~10員のヘテロアリールおよびC6-15アリールで必要に応じて置換される、[1]~[18]のいずれか1に記載の方法。
[21]
前記同位体含有物質が、D2O、DO-C1-10アルキル、T2OおよびTO-C1-10アルキルからなる群より選択される、[1]~[20]のいずれか1に記載の方法。
[22]
多価不飽和脂質混合物を同位体で部位特異的に修飾するための方法であって、該方法は、
遷移金属系触媒の存在下で該多価不飽和脂質混合物を同位体含有物質と反応させることによって、1つ以上のモノ-アリル部位またはビス-アリル部位に該同位体を有する同位体的に修飾された多価不飽和脂質混合物を得る工程を含み、該同位体含有物質は、ジュウテリウム、トリチウムおよびそれらの組み合わせからなる群より選択される少なくとも1種の同位体を含む、方法。
[23]
主に1つ以上のアリル部位に同位体を有する1つ以上の同位体的に修飾された多価不飽和脂質を含む組成物であって、該同位体は、ジュウテリウム、トリチウムおよびそれらの組み合わせからなる群より選択される、組成物。
[24]
前記同位体的に修飾された多価不飽和脂質が、[1]~[22]のいずれか1に記載の方法に従って調製される、[23]に記載の組成物。
本明細書中で用いられる項の見出しは、単に構成上の目的のものであって、説明されている主題を限定すると解釈されるべきでない。
ALA アルファ-リノレン酸
LIN リノレエート
LNN リノレネート
ARA アラキドネート
cap カプロラクタメート
D- 負に帯電したジュウテリウムイオン
T- 負に帯電したトリチウムイオン
DHA ドコサヘキサエン酸
DNA デオキシリボ核酸
EPA エイコサペンタエン酸
HPLC 高速液体クロマトグラフィー
IR 赤外
LA リノール酸
LC/MS 液体クロマトグラフィー/質量分析
mg ミリグラム
mmol ミリモル
NMR 核磁気共鳴
PUFA 多価不飽和脂肪酸
Rf 保持因子
ROS 活性酸素種
TBHP tert-ブチルヒドロペルオキシド
TLC 薄層クロマトグラフィー
UV 紫外線
Cp シクロペンタジエニル
修飾されていない1,4-ジエン系から「直接交換」合成経路を介してビス-アリル位において同位体的に修飾された1,4-ジエン系を調製することが、ビス-アリル位に同位体修飾を有する化合物を調製するための効率的な方法である。しかしながら、塩基を用いてビス-アリル水素を引き抜き、得られたラジカルをD2Oでクエンチし、次いで、このプロセスを繰り返して、第2のビス-アリル水素を置換すると、ビス-アリル位からの水素引き抜きの際に共役1,3-ジエンに再配列する1,4-ジエン系の固有の傾向に起因して、必然的に二重結合がシフトしてしまう。ゆえに、二重結合の再配列をもたらさない「より穏やかな」方法が必要とされる。
「直接交換」合成経路を介した修飾されていないPUFAからの同位体的に修飾されたPUFAの調製は、図1~3において、上に記載されたように達成され得る。いくつかの実施形態において、式1の化合物は、以下の化合物のうちのいずれか1つ以上から選択される:
D-PUFAは、単純なフラグメントを段階的な様式で化学的にアセンブルして所望の誘導体を生成する全合成によって製造され得る。その単純なD-PUFAであるD2-リノール酸(D2-Lin)は、このアプローチを用いて生成され得る。しかしながら、二重結合の数が増加するにつれて、その合成は、より複雑かつ高価になり、収率は低下し、不純物のレベルが上がる。2より多い二重結合の数を有するD-PUFA、例えば、リノレン酸(LNN)、アラキドン酸(ARA)、エイコサペンタエン酸(EPA)およびデコサヘキサエン酸(decosahexaenoic)(DHA)は、ますます生成するのが困難である。精製工程を必要としない合成法が、非常に望ましい。しかし、2より多い二重結合数のために、D-PUFAは、高価で時間のかかるクロマトグラフィー精製工程を必要とし得る。4を超える二重結合の数を有するD-PUFAの場合、硝酸銀含浸シリカゲルクロマトグラフィーに基づく精製が、いっそう非効率的であることから、全合成の製造アプローチが本質的に不適切となる。本明細書中に記載される方法は、より少ない反応工程で選択的かつ効率的な同位体修飾を達成するだけでなく、高価で時間のかかる精製工程を回避する。
R1は、HおよびC1-10アルキルからなる群より選択され;
R2は、-OH、-OR3、-SR3、ホスフェートおよび-N(R3)2からなる群より選択され;
各R3は、独立して、C1-10アルキル、C2-10アルケン、C2-10アルキン、C3-10シクロアルキル、C6-10アリール、4~10員のヘテロアリールおよび3~10員の複素環式環からなる群より選択され、各R3は、置換されるか、または非置換であり;
nは、1~10の整数であり;
pは、1~10の整数である)
に記載の構造を有する。
[ML1(L2)m]Qn (IIA)
(式中、
Mは、ロジウム、イリジウム、ニッケル、白金、パラジウム、アルミニウム、チタン、ジルコニウム、ハフニウムおよびルテニウムからなる群より選択され;
L1は、C3-10シクロアルキル、C6-10アリール、4~10員のヘテロアリールおよび3~10員の複素環式環からなる群より選択され、L1は、置換されるか、または非置換であり;
各L2は、独立して、アミン、イミン、カルベン、アルケン、ニトリル、イソニトリル、アセトニトリル、エーテル、チオエーテル、ホスフィン、ピリジン、非置換C3-10シクロアルキル、置換C3-10シクロアルキル、置換C6-10アリール、4~10員の置換ヘテロアリール、非置換C6-10アリール、4~10員の非置換ヘテロアリール、3~10員の置換複素環式環、3~10員の非置換複素環式環およびそれらの任意の組み合わせからなる群より選択され;
mは、1~3の整数であり、
Qは、単一電荷を有するアニオンであり、
nは、0または1である)
に記載の構造を有する。
いくつかの実施形態は、主に1つ以上のアリル部位に同位体を有する1つ以上の同位体的に修飾された多価不飽和脂質を含む組成物に関し、その同位体は、ジュウテリウム、トリチウムおよびそれらの組み合わせからなる群より選択される。いくつかの実施形態において、同位体は、ジュウテリウムである。いくつかの実施形態において、同位体は、トリチウムである。
J Young NMRチューブに、PUFAを投入した後、D2Oおよびアセトン-d6を投入し、その後、まず、1H NMRスペクトルを取得した。次いで、グローブボックス内において、PUFA溶液を、それぞれのルテニウム錯体を含むシンチレーションバイアルに移した。得られた溶液を十分に混合し、NMRチューブに戻した。反応の進行を、最初の12時間は1時間ごとの1H NMRスキャン、その後は、毎日のスキャンによってモニターした。
グローブボックス内において、2本のシンチレーションバイアルに、それぞれPUFAおよび錯体4を投入した。両方を、それぞれ3つの0.5mlのアセトンを用いて2つの別個のSchlenkフラスコに移した。PUFAを含むフラスコにD2Oを加えた後、同種の溶液を形成するのに必要な量のアセトンを加えた。次いで、錯体4を含むアセトンの溶液を、カニューレを介してPUFAの溶液に加え、反応物を室温において撹拌したまま放置した。反応が完了したら、過剰量の2N HCl(反応混合物の5倍以上の体積)を加え、その混合物を15分間、激しく撹拌した。その生成物を100mlのヘキサンで抽出し、次いで、その溶液を飽和NaHCO3およびNaCl溶液で洗浄し、無水NaSO4で乾燥させた。その溶液を濾過し、活性炭を加えた。さらに15分間撹拌し、濾過して、真空中で揮発性物質を除去することにより、所望の生成物を得た。
一般手順Bの後、100mgのE-Lnn(0.326mmol)、1.18mlのD2O(65.40mmol)および1.42mgの錯体4(1%、3.26μmol)を含む10mlのアセトンを共に混合し、1時間撹拌して、所望の重水素化された生成物を無色透明の油状物として得た(101.06mg、99.6%収率)。
一般手順Bの後、100mgのE-Ara(0.301mmol)、1.63mlのD2O(90.22mmol)および1.31mgの錯体4(1%、3.01μmol)を含む12.5mlのアセトンを共に混合し、24時間撹拌して、所望の重水素化された生成物を無色透明の油状物として得た(101.36mg、99.5%収率)。
一般手順Bの後、100mgのE-DHA(0.280mmol)、2.53mlのD2O(0.14mol)および2.44mgの錯体4(2%、5.61μmol)を含む15mlのアセトンを共に混合し、18時間撹拌して、所望の重水素化された生成物を無色透明の油状物として得た(101.96mg、99.8%収率)。
一般手順Bの後、100mgのT-Lnn(0.115mmol)、1.24mlのD2O(68.70mmol)および0.50mgの錯体4(1%、1.15mmol)を含む20mlのアセトンを共に混合し、7時間撹拌して、所望の重水素化された生成物を無色透明の油状物として得た(101.34mg、99.7%収率)。
本開示は、図面および前述の説明において詳細に例証され、記載されてきたが、そのような例証および説明は、例証的または例示的であって、限定的でないと見なされるべきである。本開示は、開示された実施形態に限定されない。特許請求される開示を実施する際、図面、本開示および添付の請求項を検討することによって、開示された実施形態に対するバリエーションが当業者によって理解され得、実施され得る。
Claims (5)
- ジュウテリウムで多価不飽和脂質を部位特異的に修飾するための方法であって、
下記式から選択されるルテニウム触媒の存在下で多価不飽和脂質をD 2 O又はDO-C 1-10 アルキルと反応させることによって、
- 前記ルテニウム触媒が、置換又は非置換シクロペンタジエニルを含む、請求項1に記載の方法。
- 前記ルテニウム触媒が、非置換シクロペンタジエニルを含む、請求項1に記載の方法。
- 前記ルテニウム触媒が、下記式で表される、請求項1に記載の方法。
- 前記多価不飽和脂質が、脂肪酸、脂肪酸エステル、脂肪酸チオエステル及び脂肪酸アミドからなる群より選択される、請求項1に記載の方法。
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