WO2009113543A1 - ホスフィン化合物、その製造方法およびそれを用いた過酸化物捕捉剤 - Google Patents
ホスフィン化合物、その製造方法およびそれを用いた過酸化物捕捉剤 Download PDFInfo
- Publication number
- WO2009113543A1 WO2009113543A1 PCT/JP2009/054551 JP2009054551W WO2009113543A1 WO 2009113543 A1 WO2009113543 A1 WO 2009113543A1 JP 2009054551 W JP2009054551 W JP 2009054551W WO 2009113543 A1 WO2009113543 A1 WO 2009113543A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- groups
- phosphine
- cyclic
- Prior art date
Links
- -1 Phosphine compound Chemical class 0.000 title claims abstract description 229
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 66
- 150000002978 peroxides Chemical class 0.000 title claims abstract description 34
- 239000002516 radical scavenger Substances 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims description 13
- 230000008569 process Effects 0.000 title description 2
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 56
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052797 bismuth Inorganic materials 0.000 claims abstract description 5
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 5
- 239000011574 phosphorus Substances 0.000 claims abstract description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000004585 polycyclic heterocycle group Chemical group 0.000 claims description 42
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 37
- 125000003367 polycyclic group Chemical group 0.000 claims description 27
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 21
- 125000000169 tricyclic heterocycle group Chemical group 0.000 claims description 19
- 229910000085 borane Inorganic materials 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000000732 arylene group Chemical group 0.000 claims description 10
- 125000002619 bicyclic group Chemical group 0.000 claims description 9
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 6
- 230000001335 demethylating effect Effects 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 claims description 6
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 5
- 125000003828 azulenyl group Chemical group 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 5
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000002676 chrysenyl group Chemical group C1(=CC=CC=2C3=CC=C4C=CC=CC4=C3C=CC12)* 0.000 claims description 5
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 5
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 5
- 125000003933 pentacenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC5=CC=CC=C5C=C4C=C3C=C12)* 0.000 claims description 5
- 125000001828 phenalenyl group Chemical group C1(C=CC2=CC=CC3=CC=CC1=C23)* 0.000 claims description 5
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 claims description 5
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 claims description 5
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims description 5
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001388 picenyl group Chemical group C1(=CC=CC2=CC=C3C4=CC=C5C=CC=CC5=C4C=CC3=C21)* 0.000 claims description 5
- 125000005936 piperidyl group Chemical group 0.000 claims description 5
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 5
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 5
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000001725 pyrenyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 claims description 5
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000004306 triazinyl group Chemical group 0.000 claims description 5
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 claims description 5
- 125000003336 coronenyl group Chemical group C1(=CC2=CC=C3C=CC4=CC=C5C=CC6=CC=C1C1=C6C5=C4C3=C21)* 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 3
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 25
- FZICDBOJOMQACG-UHFFFAOYSA-N benzo[h]isoquinoline Chemical compound C1=NC=C2C3=CC=CC=C3C=CC2=C1 FZICDBOJOMQACG-UHFFFAOYSA-N 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 239000003642 reactive oxygen metabolite Substances 0.000 claims 1
- 210000003470 mitochondria Anatomy 0.000 abstract description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 9
- 239000001301 oxygen Substances 0.000 abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 abstract description 6
- 230000001590 oxidative effect Effects 0.000 abstract description 2
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical group CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- 150000002430 hydrocarbons Chemical group 0.000 description 67
- 238000005481 NMR spectroscopy Methods 0.000 description 55
- 238000006243 chemical reaction Methods 0.000 description 37
- 239000002904 solvent Substances 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 28
- 239000013078 crystal Substances 0.000 description 28
- 239000000243 solution Substances 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000007254 oxidation reaction Methods 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 230000003647 oxidation Effects 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 230000036542 oxidative stress Effects 0.000 description 12
- 230000035484 reaction time Effects 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- QKGHIIWSVAHAFD-UHFFFAOYSA-N 1-[(4-methoxyphenyl)-phenylphosphoryl]pyrene Chemical compound C1=CC(OC)=CC=C1P(=O)(C=1C2=CC=C3C=CC=C4C=CC(C2=C43)=CC=1)C1=CC=CC=C1 QKGHIIWSVAHAFD-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003963 antioxidant agent Substances 0.000 description 7
- 230000003078 antioxidant effect Effects 0.000 description 7
- 235000006708 antioxidants Nutrition 0.000 description 7
- 235000010323 ascorbic acid Nutrition 0.000 description 7
- 229960005070 ascorbic acid Drugs 0.000 description 7
- 239000011668 ascorbic acid Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000012351 deprotecting agent Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000002438 mitochondrial effect Effects 0.000 description 6
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- BWJRMVLPCQPWGR-UHFFFAOYSA-N boron;phosphane Chemical compound [B].P BWJRMVLPCQPWGR-UHFFFAOYSA-N 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 4
- JTMRUHFSMJUTNZ-UHFFFAOYSA-M 3-[(4-phenoxyphenyl)phosphanyl-pyren-1-ylphosphanyl]propyl-triphenylphosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CCCP(C=1C2=CC=C3C=CC=C4C=CC(C2=C43)=CC=1)PC(C=C1)=CC=C1OC1=CC=CC=C1 JTMRUHFSMJUTNZ-UHFFFAOYSA-M 0.000 description 4
- OEFVXSHVPUVBIX-UHFFFAOYSA-N 4-[perylen-1-yl(phenyl)phosphoryl]phenol Chemical compound C1=CC(O)=CC=C1P(=O)(C=1C=2C=3C=CC=C4C=CC=C(C=34)C3=CC=CC(C=23)=CC=1)C1=CC=CC=C1 OEFVXSHVPUVBIX-UHFFFAOYSA-N 0.000 description 4
- LXEKPEMOWBOYRF-QDBORUFSSA-N AAPH Chemical compound Cl.Cl.NC(=N)C(C)(C)\N=N\C(C)(C)C(N)=N LXEKPEMOWBOYRF-QDBORUFSSA-N 0.000 description 4
- ZHKMBFRYHQKQEH-UHFFFAOYSA-N B.Oc1ccc(cc1)P(c1ccccc1)c1ccc2cccc3c4cccc5cccc(c1c23)c45 Chemical compound B.Oc1ccc(cc1)P(c1ccccc1)c1ccc2cccc3c4cccc5cccc(c1c23)c45 ZHKMBFRYHQKQEH-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- 150000001450 anions Chemical group 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- IMDXZWRLUZPMDH-UHFFFAOYSA-N dichlorophenylphosphine Chemical compound ClP(Cl)C1=CC=CC=C1 IMDXZWRLUZPMDH-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- GAZSZCWRMSVQPJ-UHFFFAOYSA-N (4-methoxyphenyl)-diphenylphosphane Chemical compound C1=CC(OC)=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 GAZSZCWRMSVQPJ-UHFFFAOYSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- PFELMVYZHLNZBW-UHFFFAOYSA-N 1-[(4-methoxyphenyl)-phenylphosphoryl]perylene Chemical compound C1=CC(OC)=CC=C1P(=O)(C=1C=2C=3C=CC=C4C=CC=C(C=34)C3=CC=CC(C=23)=CC=1)C1=CC=CC=C1 PFELMVYZHLNZBW-UHFFFAOYSA-N 0.000 description 3
- HYGLETVERPVXOS-UHFFFAOYSA-N 1-bromopyrene Chemical compound C1=C2C(Br)=CC=C(C=C3)C2=C2C3=CC=CC2=C1 HYGLETVERPVXOS-UHFFFAOYSA-N 0.000 description 3
- SIUKFPNPKPRVNS-UHFFFAOYSA-N B.Oc1ccc(cc1)P(c1ccccc1)c1ccc2ccc3cccc4ccc1c2c34 Chemical compound B.Oc1ccc(cc1)P(c1ccccc1)c1ccc2ccc3cccc4ccc1c2c34 SIUKFPNPKPRVNS-UHFFFAOYSA-N 0.000 description 3
- XCNQSMOOHQLJID-UHFFFAOYSA-N C[O-].[Mg+]c1ccccc1 Chemical compound C[O-].[Mg+]c1ccccc1 XCNQSMOOHQLJID-UHFFFAOYSA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical group [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- RBWRWAUAVRMBAC-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=[C-]C=C1 RBWRWAUAVRMBAC-UHFFFAOYSA-M 0.000 description 3
- 239000010453 quartz Substances 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- PMOXSKHPSYNZNS-UHFFFAOYSA-N (4-methoxyphenyl)-phenyl-pyren-1-ylphosphane Chemical compound C1=CC(OC)=CC=C1P(C=1C2=CC=C3C=CC=C4C=CC(C2=C43)=CC=1)C1=CC=CC=C1 PMOXSKHPSYNZNS-UHFFFAOYSA-N 0.000 description 2
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 150000000996 L-ascorbic acids Chemical class 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 238000006664 bond formation reaction Methods 0.000 description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 2
- DSYGKYCYNVHCNQ-UHFFFAOYSA-N diphenyl(pyren-1-yl)phosphane Chemical compound C1=CC=CC=C1P(C=1C2=CC=C3C=CC=C4C=CC(C2=C43)=CC=1)C1=CC=CC=C1 DSYGKYCYNVHCNQ-UHFFFAOYSA-N 0.000 description 2
- MIZGHTIFZNEFGR-UHFFFAOYSA-N diphenyl(pyren-1-yl)phosphanium iodide Chemical compound [I-].C1(=CC=CC=C1)[PH+](C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C34)C3=CC=CC=C3 MIZGHTIFZNEFGR-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- IFTVAQUNDKGWDD-UHFFFAOYSA-M mitoTracker Green FM Chemical compound [Cl-].O1C2=CC=CC=C2N(C)C1=CC=CC(=[N+](C1=CC(Cl)=C(Cl)C=C11)C=2C=CC(CCl)=CC=2)N1C1=CC=C(CCl)C=C1 IFTVAQUNDKGWDD-UHFFFAOYSA-M 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- WARQTKYZIGTZOB-UHFFFAOYSA-N perylene hydrobromide Chemical compound Br.C1=CC(C2=CC=CC=3C2=C2C=CC=3)=C3C2=CC=CC3=C1 WARQTKYZIGTZOB-UHFFFAOYSA-N 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- XFAPMHUAOSDUAJ-UHFFFAOYSA-N pyrene hydrobromide Chemical compound Br.C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 XFAPMHUAOSDUAJ-UHFFFAOYSA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 2
- 239000005052 trichlorosilane Substances 0.000 description 2
- POXSDSRWVJZWCN-UHFFFAOYSA-N triphenylphosphanium;iodide Chemical compound I.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 POXSDSRWVJZWCN-UHFFFAOYSA-N 0.000 description 2
- AZUCPFMKPGFGTB-UHFFFAOYSA-N 2,2-diiodopropane Chemical compound CC(C)(I)I AZUCPFMKPGFGTB-UHFFFAOYSA-N 0.000 description 1
- LRLQQERNMXHASR-UHFFFAOYSA-N 2-diphenylphosphanylpropan-2-yl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 LRLQQERNMXHASR-UHFFFAOYSA-N 0.000 description 1
- YMATWZPXVGZJLT-UHFFFAOYSA-N 3-iodopropylphosphanium;iodide Chemical compound [I-].[PH3+]CCCI YMATWZPXVGZJLT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- JOGHFNRWGSNDFS-MHTLYPKNSA-N [(2s)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethyl] acetate Chemical compound CC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O JOGHFNRWGSNDFS-MHTLYPKNSA-N 0.000 description 1
- NEUVABJQBCZBNZ-WRWORJQWSA-N [(2s)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethyl] hexanoate Chemical compound CCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O NEUVABJQBCZBNZ-WRWORJQWSA-N 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- XCEUHXVTRJQJSR-UHFFFAOYSA-N bromo(phenyl)phosphane Chemical compound BrPC1=CC=CC=C1 XCEUHXVTRJQJSR-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- YYDZNOUMWKJXMG-UHFFFAOYSA-N chloro(phenyl)phosphane Chemical compound ClPC1=CC=CC=C1 YYDZNOUMWKJXMG-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- SDJKREQSNPYHJT-UHFFFAOYSA-N dibromo(phenyl)phosphane Chemical compound BrP(Br)C1=CC=CC=C1 SDJKREQSNPYHJT-UHFFFAOYSA-N 0.000 description 1
- UOGKRVUAVNCBRS-UHFFFAOYSA-N diiodo(phenyl)phosphane Chemical compound IP(I)C1=CC=CC=C1 UOGKRVUAVNCBRS-UHFFFAOYSA-N 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- PUNYGFAPYLHNLV-UHFFFAOYSA-N iodo(phenyl)phosphane Chemical compound IPC1=CC=CC=C1 PUNYGFAPYLHNLV-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- QCFRAUYDPLRPCI-UHFFFAOYSA-M magnesium;1-methanidyl-4-methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C([CH2-])C=C1 QCFRAUYDPLRPCI-UHFFFAOYSA-M 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000005787 mitochondrial ATP synthesis coupled electron transport Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- CSHWQDPOILHKBI-UHFFFAOYSA-N peryrene Natural products C1=CC(C2=CC=CC=3C2=C2C=CC=3)=C3C2=CC=CC3=C1 CSHWQDPOILHKBI-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 125000005628 tolylene group Chemical group 0.000 description 1
- 238000001926 trapping method Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
Definitions
- the present invention relates to a phosphine compound and a peroxide scavenger using the phosphine compound, and more specifically, the present invention relates to a phosphine compound and a peroxide scavenger using the same, which are localized in mitochondria. It relates to a peroxide scavenger.
- the present invention also relates to a novel phosphine compound localized in mitochondria, a method for producing the same, and a method for capturing peroxide using the same. Furthermore, this invention relates to the phosphinyl compound which is an oxidation product of a phosphine compound.
- Oxidative stress is defined as the difference between the oxidative damage potential of the active oxygen group generated in vivo and the antioxidant potential of the antioxidant system in vivo.
- the active oxygen group is originally useful for energy production, invading foreign body attack, unnecessary cell processing, cell information transmission, and the like.
- excessive reactive oxygen groups are generated that cannot be captured by the in vivo antioxidant system, lipids, proteins, enzymes that carry the structure and functions of living organisms, and genetic DNA that carries genetic information are oxidized and damaged. It disturbs the structure and function of the living body, causes diseases such as cancer and lifestyle-related diseases, and accelerates aging (Non-patent Document 1).
- mitochondria are a source of active oxygen, they are one of the microorgans most susceptible to oxidative stress. Therefore, analyzing the state of oxidative stress in mitochondria greatly assists in elucidating the mechanism of many diseases caused by oxidative stress. Therefore, it is extremely useful to generate functional molecules that visualize the degree of mitochondrial oxidative stress.
- Non-patent Document 2 Japan Antioxidant Society website (http://www.jsa-site.com/sanka_storesu.htm) Suzuki, B., Et al., Bioorg. Med. Chem. Lett. 2007, 2055-2058 Okimoto, Y., Et al., FEBS Lett., 2000, 474, 137-140
- the present inventors have introduced a new peroxide scavenger that introduces a diphenylmonopyrenylphosphine compound, which is a substituent localized in mitochondria, as a fluorescent probe that captures only peroxide.
- a new peroxide scavenger that introduces a diphenylmonopyrenylphosphine compound, which is a substituent localized in mitochondria, as a fluorescent probe that captures only peroxide.
- an object of the present invention is to provide a phosphine compound represented by the following general formula [I] and a method for producing the same as one embodiment.
- Another object of the present invention is to provide a novel peroxide scavenger wherein the peroxide scavenger is a phosphine compound [I] and a method for using the same.
- the present invention provides, as another form, the following general formula [I ′], which is an oxidation product generated by oxidation of a novel peroxide scavenger that is a phosphine compound represented by the following general formula [I].
- the object is to provide the phosphinyl compounds represented.
- Z 1 and Z 2 are both cyclic groups, Ar means an arylene group, R means an aliphatic hydrocarbon group; Y means phosphorus (P), nitrogen (N) or bismuth (Bi), R 1 , R 2 and R 3 all represent a cyclic group)
- the phosphine compound represented by these is provided.
- any of the cyclic groups represented by Z 1 and Z 2 is an unsubstituted or substituted monocyclic hydrocarbon group or polycyclic hydrocarbon group, A heteromonocyclic or heteropolycyclic group;
- the arylene group represented by Ar is an unsubstituted or substituted monocyclic hydrocarbon group or bicyclic hydrocarbon group;
- the aliphatic hydrocarbon group represented by R is a linear or branched divalent aliphatic hydrocarbon group having 1 to 8 carbon atoms,
- the cyclic groups represented by R 1 , R 2 and R 3 may be the same or different from each other, and are unsubstituted or substituted monocyclic hydrocarbon group, polycyclic hydrocarbon group or heteromonocyclic Group or heteropolycyclic group, Provided that one of the cyclic groups Z 1 and Z 2 is a monocyclic hydrocarbon group or a heteromonocyclic group, and the other cyclic group is a polycyclic group
- R 1 , R 2 and R 3 is a monocyclic hydrocarbon group or a heteromonocyclic group, and the other cyclic group is a polycyclic hydrocarbon group or A heteropolycyclic group, A phosphine compound is provided.
- any one of the cyclic groups Z 1 and Z 2 is a polycyclic hydrocarbon group or a heteropolycyclic group.
- the other monocyclic group is a monocyclic hydrocarbon group or a heteromonocyclic group, and all the cyclic groups of R 1 , R 2 and R 3 are monocyclic hydrocarbon groups or heteromonocyclic groups Or all cyclic groups of Z 1 and Z 2 are monocyclic groups are monocyclic hydrocarbon groups or heteromonocyclic groups, and any one ring of R 1 , R 2 and R 3
- the formula group is a polycyclic hydrocarbon group or a heteropolycyclic group, and it is to provide a phosphine compound in which the other cyclic group is a monocyclic hydrocarbon group or a heteromonocyclic group.
- the present invention provides a phosphine compound represented by the above general formula [I], wherein among the cyclic groups represented by Z 1 and Z 2 , a monocyclic hydrocarbon group is For example, a phenyl group, etc .; as a polycyclic hydrocarbon group, a bicyclic hydrocarbon group includes, for example, an indanyl group, an indenyl group, a pentarenyl group, an azulenyl group, a naphthyl group, a tetrahydronaphthyl group, etc .;
- the hydrocarbon group is, for example, anthracenyl group, fluorenyl group, phenalenyl group, phenanthrenyl group, etc .;
- the tetracyclic hydrocarbon group is, for example, pyrenyl group, naphthacenyl group, chrysenyl group, etc .
- the pentacyclic hydrocarbon group is, for example
- heterocyclic polycyclic group includes, for example, an N-containing heterocyclic polycyclic group such as indolyl group, indolinyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, quinoxalinyl group, N-containing heterobicyclic groups such as naphthyridinyl group, pteridinyl group, purinyl group; acridinyl group, carbazolyl group, phenanthridinyl group, phenazini
- An N-containing heterotricyclic group such as a benzoisoquinolinyl group
- O-containing heteropolycyclic group such as a benzofur
- the arylene group represented by Ar is a phenylene group, a tolylene group or a naphthalene group;
- the linear or branched divalent aliphatic hydrocarbon group having 1 to 8 carbon atoms represented by R is a methylene group, an ethylene group, a propylene group, an isopropylene group, a butylene group or a methylbutylene group. ;
- the monocyclic hydrocarbon group is, for example, a phenyl group; a polycyclic hydrocarbon group For example, an indanyl group, an indenyl group, a pentarenyl group, an azulenyl group, a naphthyl group, a tetrahydronaphthyl group, and the like; a tricyclic hydrocarbon group such as an anthracenyl group, a fluorenyl group, a phenalenyl group, and the like.
- tetracyclic hydrocarbon group for example, pyrenyl group, naphthacenyl group, chrysenyl group, etc .
- pentacyclic hydrocarbon group for example, perylenyl group, picenyl group, pentacenyl group, etc .
- a hydrogen group is, for example, a naphthobirenyl group
- a seven-ring hydrocarbon group is, for example, a coronenyl group
- N-containing heteromonocyclic group is, for example, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, piperidyl group, triazinyl group, etc .
- O-containing heteromonocyclic group is, for example, furanyl group, pyranyl group, etc .
- S-containing heteropolycyclic group for example, thiopolycyclic group, for example,
- the O-containing heteropolycyclic group is, for example, an O-containing heterobicyclic group such as a benzofuranyl group, a chromanyl group, a chromenyl group, or an isochromanyl group, an O-containing heterotricyclic group such as a xanthenyl group; S-containing heteropolycyclic groups such as S-containing heterotricyclic groups such as containing heterotricyclic groups and thiantenyl groups; pyridooxazolyl groups, thienofuranyl groups, phenoxazinyl groups, phenothiazinyl groups, pyrazolooxazolyls N / O / S-containing heteropolycyclic groups such as a group; examples of the substituent include lower aliphatic groups having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, and an isopropyl group
- a phosphine compound
- the phosphine compound represented by the general formula [I] is in a cation state, the phosphine compound may be bonded to an anion as represented by the following general formula [I].
- Such cations include, for example, halogen atom ions such as chlorine, bromine or iodine ions.
- compounds in a state of binding to anions are also one embodiment of the present invention.
- X means a halogen atom
- This invention provides the manufacturing method of the phosphine compound represented by general formula [I] as another form. More specifically, the phosphine compound [I] of the present invention has the general formula [II]: (Wherein Z 1 represents a cyclic group, and X 1 represents a halogen atom) A halide compound represented by:
- the hydroxyarylphosphine borane compound [VIII] obtained in the above step 4 is represented by the general formula [IX]: (Wherein X 5 represents a halogen atom, R means an aliphatic hydrocarbon group; Y means phosphorus (P), nitrogen (N) or bismuth (Bi), R 1 , R 2 and R 3 all represent a cyclic group) And a halide compound [IX] represented by
- Step 3 in which the methoxyaryl phosphine oxide compound [VI] obtained in the above step 1b is demethylated with a demethylating reagent to obtain a hydroxyaryl phosphine oxide compound [VII];
- the halo compound [XVI] obtained in the step 8 is converted into the general formula [VIII] obtained in the step 4:
- a step 10 of obtaining a phosphine compound [I] represented by: Provides a method for producing a phosphine compound comprising producing a phosphine compound [I].
- the present invention provides a peroxide scavenger containing a phosphine compound represented by the general formula [I] and a method for using the same.
- the present invention provides a peroxide trapping method comprising trapping a peroxide using a phosphine compound represented by the general formula [I].
- the present invention provides a peroxide trap, wherein the peroxide is, for example, a radical species such as superoxide or hydroxy radical, or a non-radical species such as hydrogen peroxide or singlet oxygen.
- the peroxide is, for example, a radical species such as superoxide or hydroxy radical, or a non-radical species such as hydrogen peroxide or singlet oxygen.
- the present invention provides, as another form, an oxidation product produced by oxidation of the phosphine compound represented by the general formula [I]. Specifically, the present invention provides an oxidation product obtained by oxidizing the phosphine compound represented by the general formula [I].
- the phosphinyl compound represented by these is provided.
- the phosphine compound according to the present invention is a source of active oxygen, it generates a functional molecule that can visualize the state of oxidative stress in mitochondria, which is one of the microorgans most susceptible to oxidative stress. There is an advantage that the mechanism of many diseases caused by oxidative stress can be elucidated.
- FIG. 1 is a graph showing the change over time in the fluorescence intensity of the oxidation reaction of MitoDPPP with hydrogen peroxide.
- FIG. 2 is a diagram showing the introduction of MitoDPPP into Hep G2 cells.
- FIG. 3 is a diagram showing introduction of MitoDPPP into Hep2G2 cells and oxidation by tert-butoxyhydroperoxide (tBHP) stimulation.
- FIG. 4 is a diagram showing the results of comparison of oxidation of Hep G2 intracellular MitoDPPP by hydrogen peroxide and tBHP.
- FIG. 5 is a graph showing the change in fluorescence intensity with time in an aqueous solution of MitoDPPP.
- FIG. 6 is a graph showing changes in fluorescence intensity over time due to oxidation of MitoDPPP in cells in the presence of ascorbic acid.
- the present invention provides the following general formula [I]: (Wherein, Z 1 and Z 2 are both cyclic groups, Ar means an arylene group, R means an aliphatic hydrocarbon group; Y means phosphorus (P), nitrogen (N) or bismuth (Bi), R 1 , R 2 and R 3 all represent a cyclic group) It is related with the phosphine compound represented by these.
- each of the cyclic groups represented by Z 1 and Z 2 is an unsubstituted or substituted monocyclic hydrocarbon group, polycyclic hydrocarbon group, or heteromonocyclic A group or a heteropolycyclic group;
- the arylene group represented by Ar is an unsubstituted or substituted monocyclic hydrocarbon group or bicyclic hydrocarbon group;
- the aliphatic hydrocarbon group represented by R is a linear or branched divalent aliphatic hydrocarbon group having 1 to 8 carbon atoms,
- the cyclic groups represented by R 1 , R 2 and R 3 may be the same or different from each other, and are unsubstituted or substituted monocyclic hydrocarbon group, polycyclic hydrocarbon group or heteromonocyclic Group represents a heterocyclic group or a heterocyclic polycyclic group),
- one of the cyclic groups Z 1 and Z 2 is a monocyclic hydrocarbon group or a heteromonocyclic group, and the
- R 1 , R 2 and R 3 is a monocyclic hydrocarbon group or a heteromonocyclic group, and the other cyclic group is a polycyclic hydrocarbon group or Heteropolycyclic group.
- any one of the cyclic groups Z 1 and Z 2 is a polycyclic hydrocarbon group or a heteropolycyclic group.
- the other monocyclic group is a monocyclic hydrocarbon group or a heteromonocyclic group, and all the cyclic groups of R 1 , R 2 and R 3 are monocyclic hydrocarbon groups or heteromonocyclic groups.
- all cyclic groups of Z 1 and Z 2 are monocyclic groups wherein the monocyclic group is a monocyclic hydrocarbon group or a heteromonocyclic group, and any one ring of R 1 , R 2 and R 3
- the formula group may be a polycyclic hydrocarbon group or a heteropolycyclic group, and the other cyclic group may be a monocyclic hydrocarbon group or a heteromonocyclic group.
- the monocyclic hydrocarbon group is, for example, a phenyl group
- the polycyclic hydrocarbon group is, for example, an indanyl group, an indenyl group, a pentarenyl group, an azulenyl group, a naphthyl group, a tetrahydronaphthyl group, or the like;
- a tricyclic hydrocarbon group is For example, anthracenyl group, fluorenyl group, phenalenyl group, phenanthrenyl group, etc .;
- a tetracyclic hydrocarbon group for example, a pyrenyl group, a naphthacenyl group, a chrysenyl group, etc .;
- a pentacyclic hydrocarbon group for example, a perylenyl group, a picenyl group
- heteropolycyclic group includes, for example, an indolyl group, indolinyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, quinoxalinyl group, naphthyridinyl group, pteridinyl group, purinyl group N-containing heterobicyclic groups such as groups; acridinyl group, carbazolyl group, phenanthridinyl group, phenazinyl group, benzoisoquinolini N-containing heterotricyclic groups such as ruthenium groups;
- O-containing heteropolycyclic groups include, for example, O-containing heterobicyclic groups such as benzofuranyl group, chromanyl group, chromenyl group, isochromanyl group, and xanthenyl group.
- S-containing heterotricyclic group such as dithianaphthyl group, S-containing heteropolycyclic group such as S-containing heterotricyclic group such as thiantenyl group; pyridooxazolyl group, thienofuranyl group N / O / S-containing heteropolycyclic groups such as a phenoxazinyl group, a phenothiazinyl group, and a pyrazolooxazolyl group.
- these cyclic groups may have, for example, a lower aliphatic hydrocarbon group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, and an isopropyl group as a substituent. Good.
- the arylene group represented by Ar is a phenylene group, a naphthalene group, or the like, and the linear or branched divalent aliphatic hydrocarbon group represented by R is a methylene group, an ethylene group, a propylene group, or an isopropylene group. , Butylene group or methylbutylene group.
- the monocyclic hydrocarbon group is, for example, a phenyl group; a polycyclic hydrocarbon group
- the bicyclic hydrocarbon group for example, an indanyl group, an indenyl group, a pentarenyl group, an azulenyl group, a naphthyl group, a tetrahydronaphthyl group, and the like
- a tricyclic hydrocarbon group includes, for example, an anthracenyl group, a fluorenyl group, a phenalenyl group, and the like.
- tetracyclic hydrocarbon groups are, for example, pyrenyl groups, naphthacenyl groups, chrysenyl groups, etc .
- pentacyclic hydrocarbon groups are, for example, perylenyl groups, picenyl groups, pentacenyl groups, etc .
- the hydrogen group is, for example, a naphthobirenyl group
- the seven-ring hydrocarbon group is, for example, a coronenyl group
- the heterocyclic monocyclic group of a heterocyclic group N-containing heteromonocyclic group is, for example, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, piperidyl group, triazinyl group, etc .
- O-containing heteromonocyclic group is, for example, furanyl group, pyranyl group, etc .
- S-containing heteropolycyclic groups include, for example,
- the O-containing heteropolycyclic group includes, for example, an O-containing heterobicyclic group such as a benzofuranyl group, a chromanyl group, a chromenyl group, and an isochromanyl group, an O-containing heterotricyclic group such as a xanthenyl group, and the like; S-containing heteropolycyclic groups such as S-containing heterotricyclic groups such as containing heterotricyclic groups and thiantenyl groups; pyridooxazolyl groups, thienofuranyl groups, phenoxazinyl groups, phenothiazinyl groups, pyrazolooxazolyls N / O / S-containing heteropolycyclic groups such as groups.
- an O-containing heterobicyclic group such as a benzofuranyl group, a chromanyl group, a chromenyl group, and an isochromanyl group, an O-containing heterotricyclic
- these cyclic groups may have, for example, a lower aliphatic hydrocarbon group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, and an isopropyl group as a substituent. Good.
- the phosphine compound represented by the above general formula [I] is in a cation state, it is preferable that the phosphine compound be bonded to an anion.
- Such cations include, for example, halogen atom ions such as chlorine, bromine or iodine ions.
- compounds in a bonded state with anions are also one form included in the present invention.
- the phosphine compound [I] according to the present invention can be produced by a method known per se in the art. The production method will be described in more detail according to the following reaction steps.
- step 1a the halide compound [II], the dihalophosphine compound [III], and the methoxyaryl metal magnesium halide [IV] are reacted to give the methoxyarylphosphine compound [V].
- the halogen atom of the halide compound [II] used in Step 1 include bromine, iodine, chlorine and the like.
- the halide compound [II] include phenyl bromide, tolyl chloride, naphthyl bromide, anthrace. Examples include nyl bromide, pyrenyl bromide, and perylenyl bromide.
- Examples of the dihalophosphine compound [III] include dichlorophenylphosphine, dibromophenylphosphine, diiodophenylphosphine, and the like.
- Examples of the substituent of the dihalophosphine compound [III] include an aliphatic hydrocarbon group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as a methyl group, an ethyl group, and a propyl group. And isopropyl group.
- Examples of the methoxyaryl metal magnesium halide [IV] include methoxyphenylmagnesium chloride, methoxyphenylmagnesium bromide, methoxyphenylmagnesium iodide and the like.
- Examples of the substituent include 1 to 6 carbon atoms, preferably Includes an aliphatic hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, and an isopropyl group. Further, the number and position of the substituents are not particularly limited, and may be arbitrary as long as the reaction is not hindered.
- the reaction in Step 1 is preferably performed in a solvent, and examples of the solvent include ethers such as diethyl ether and tetrahydrofuran.
- the reaction temperature is, for example, 0 ° C to -100 ° C, preferably -40 ° C to -80 ° C, and the reaction time is, for example, about 1 to 24 hours, preferably about 5 to 15 hours. Good.
- Step 2 is an oxidation reaction of the methoxyaryl phosphine compound [V] obtained in Step 1a and is a step for obtaining a methoxyaryl phosphine oxide compound [VI].
- This oxidation reaction can be performed using an oxidizing agent in a solvent.
- the oxidizing agent examples include hydrogen peroxide and potassium hydrogenated monosulfate.
- the solvent an organic solvent such as dichloromethane and alkyl halides such as chloroform can be used.
- the reaction temperature is from room temperature to about 60 ° C., preferably 40 ° C. to 45 ° C., and the reaction time is about 10 minutes to 1 hour, preferably about 15 minutes to 25 minutes.
- the methoxyaryl phosphine oxide compound [VI] can also be produced by the step 1b as shown in the above reaction step. That is, it can also be produced by reacting the halide compound [II] with methoxyaryl phosphine oxide [XI].
- the reaction of step 1b is preferably carried out in a solvent such as dimethylsulfone oxide or dimethylformamide in the presence of a palladium compound such as palladium acetate and an amine such as 1.3-bis (diphenylphosphino) propane and diisopropylethylamine. .
- the reaction temperature is under heating, for example, room temperature to 160 ° C., preferably 150 ° C., and the reaction time is about 10 to 24 hours, preferably 12 to 18 hours.
- Step 3 is a deprotection reaction of the protecting group of the methoxyaryl phosphine oxide compound [VI] obtained in Step 2, and is a step for obtaining the hydroxyaryl phosphine oxide compound [VII].
- the methoxy group of the methoxyphenyl group in the methoxyarylphosphine oxide compound [VI] can be deprotected and converted to a hydroxy group.
- This deprotection reaction is preferably carried out in a solvent using a deprotecting agent.
- a deprotecting agent for example, a demethylating reagent such as borane tribromide can be used.
- an aprotic solvent such as an alkyl halide such as dichloromethane, dichloroethane or chloroform can be used.
- the reaction temperature is about ⁇ 50 ° C. to 0 ° C., preferably about ⁇ 20 ° C. to ⁇ 10 ° C., and the reaction time is about 1 hour to 24 hours, preferably about 10 hours to 20 hours.
- Step 4 is a step of reacting the hydroxyarylphosphine oxide compound [VII] obtained in Step 3 above with a protective reagent to introduce a protecting group to obtain a hydroxyarylphosphine borane compound [VIII].
- the dicyclic group-substituted hydroxyarylphosphine oxide compound [VII] is reacted with a protecting agent in a solvent to introduce a borane protecting group.
- protective agents that can be used in this step include borohydride compounds such as monoborane.
- the solvent for example, alkylamines such as triethylamine and tributylamine can be used.
- the reaction temperature is about -50 ° C to 200 ° C, preferably about -20 ° C to 150 ° C, and the reaction time is about 10 minutes to 24 hours, preferably about 30 minutes to 20 hours.
- Step 5 is an alkylation step in which the hydroxyarylphosphine borane compound [VIII] obtained in Step 4 is reacted with a substituted alkyl halide [IX] to obtain a phosphine borane compound [X].
- This ether bond formation reaction is carried out in an organic solvent such as formamide such as dimethylformamide in the presence of a base such as sodium hydride at a reaction temperature of about ⁇ 50 ° C. to 0 ° C., preferably about ⁇ 20 ° C. to 0 ° C. for 10 minutes to The reaction time is about 24 hours, preferably about 30 minutes to 20 hours.
- Step 6 is a step in which the borane protecting group of the tri-substituted phosphine borane compound [X] obtained in Step 5 is deprotected to obtain the phosphine compound [I].
- This deprotection reaction is preferably carried out in a solvent using a deprotecting agent.
- a deprotecting agent for example, a deboraneation reagent such as diethylamine or diisopropylethylamine can be used.
- aprotic solvents such as alkyl halides such as dichloromethane and dichloroethane can be used.
- the reaction temperature is about 0 ° C. to 60 ° C., preferably about 30 ° C. to 40 ° C., and the reaction time is about 1 hour to 24 hours, preferably about 10 hours to 15 hours.
- the phosphine compound [I] according to the present invention can also be produced by a method comprising the following steps.
- the phosphine compound [I] is represented by the general formula [XVIII].
- Step 7 is a step in which the halide compound [XII] and the monohalophosphine compound [XIII] are reacted in the presence of alkyllithium, for example, butyllithium, to obtain the triarylphosphine compound [XIV].
- alkyllithium for example, butyllithium
- the halogen atom of halide [XII] used in Step 7 include bromine, iodine, chlorine and the like
- examples of the halide compound [XII] include phenyl bromide, tolyl chloride, naphthyl bromide, anthracenyl. Examples include bromide, pyrenyl bromide, and perylenyl bromide.
- Examples of the monohalophosphine compound [XIII] include chlorophenylphosphine, bromophenylphosphine, iodophenylphosphine, and the like.
- the substituent of the halophosphine compound [XIII] for example, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as a methyl group, an ethyl group, a propyl group, An isopropyl group etc. are mentioned. Further, the number and position of the substituents are not particularly limited, and may be arbitrary as long as the reaction is not hindered.
- the reaction in step 7 is preferably performed in a solvent, and examples of the solvent include ethers such as diethyl ether and tetrahydrofuran.
- the reaction temperature is, for example, 0 ° C to -100 ° C, preferably -40 ° C to -80 ° C, and the reaction time is, for example, about 1 to 24 hours, preferably about 5 to 15 hours. Good.
- Step 8 is a step of reacting alkyl dihalide [XVI] with triarylphosphine [XIV] to obtain substituted alkyl halide [XVI].
- This alkylation reaction is carried out in an organic solvent such as an aromatic hydrocarbon such as toluene at a reaction temperature of about ⁇ 50 ° C. to 200 ° C., preferably about ⁇ 20 ° C. to 150 ° C. for about 10 minutes to 24 hours, preferably 30
- the reaction time is preferably about 20 minutes to 20 minutes.
- Step 9 is an alkylation step in which the hydroxyarylphosphine borane compound [VIII] obtained in the above Step 1a, Step 2, Step 3 and Step 4 is reacted with a substituted alkyl halide [XVI] to obtain a phosphine borane compound [XVII]. It is.
- This ether bond formation reaction is carried out in an organic solvent such as formamide such as dimethylformamide in the presence of a base such as sodium hydride at a reaction temperature of about ⁇ 50 ° C. to 0 ° C., preferably about ⁇ 20 ° C. to 0 ° C.
- the reaction time is preferably about minutes to 24 hours, preferably about 30 minutes to 20 hours.
- Step 10 is a step of obtaining the phosphine compound [XVIII] by deprotecting the borane protecting group of the tri-substituted phosphine borane compound [XVII] obtained in Step 9.
- This deprotection reaction is preferably carried out in a solvent using a deprotecting agent.
- a deprotecting agent for example, a deboraneation reagent such as diethylamine or diisopropylethylamine can be used.
- the solvent aprotic solvents such as alkyl halides such as dichloromethane and dichloroethane can be used.
- the reaction temperature is about 0 ° C. to 60 ° C., preferably about 30 ° C. to 40 ° C., and the reaction time is about 1 hour to 24 hours, preferably about 10 hours to 15 hours.
- the phosphine compound [I] according to the present invention When the phosphine compound [I] is oxidized, it quickly becomes a phosphonium oxide salt [I ′] and increases the fluorescence intensity. Double staining of the phosphonium oxide salt [I ′] and the mitochondrial fluorescent marker confirmed that the phosphonium oxide salt [I ′] was localized in the mitochondria.
- the phosphine compound [I] was oxidized with hydrogen peroxide and tert-butoxyhydroperoxide (tBHP) in an aqueous solution, an increase in fluorescence intensity was confirmed with either oxidizing agent.
- tBHP tert-butoxyhydroperoxide
- the phosphine compound [I] is oxidized to a phosphonium oxide salt [I ′] as shown above. That is, the phosphonium oxide salt [I ′] has the general formula [I ′]: (In the formula, Z 1 ′ and Z 2 ′ have the same meaning as Z 1 and Z 2 , respectively, provided that all of R 1 , R 2 and R 3 are monocyclic hydrocarbon groups. Is a cyclic group other than a monocyclic hydrocarbon group, and when Z 1 ′ and Z 2 ′ are both monocyclic hydrocarbon groups, R 1 , R 2 and One of R 3 means a cyclic group other than a monocyclic hydrocarbon group) It is a compound represented by these.
- the phosphine compound [I] of the present invention is capable of capturing peroxides such as active oxygen that are localized in living cells, particularly mitochondria, and are generated in mitochondria. Accordingly, the phosphine compound [I] of the present invention can be used as a mitochondrial peroxide scavenger because it can localize in mitochondria and capture peroxides.
- Step 1c Synthesis of 4-methoxyphenylphenylpyrenylphosphine [Va] Pyrene bromide [IIa] (3.28 g, 15 mmol) was dissolved in 70 mL of THF and n-BuLi (6.11 mL, 2.7 M, 16.5 mmol, 1.1 eq) was added dropwise for 15 minutes and stirred for 3 hours.
- This reaction is THF
- dichlorophenylphosphine [IIIa] (2.03 mL, 15 mmol, 1 eq) dissolved in 6 mL ( ⁇ 78 ° C.) for 15 minutes.
- Step 2a Synthesis of 4-methoxyphenylphenylpyrenylphosphine oxide [VIa] Pyrenyl-phenyl-4-methoxyphenylphosphine [Va] (1.68 g, 4.03 mmol) is dissolved in 25 mL of chloroform, and 5 mL of hydrogen peroxide is slowly added dropwise. To do. Stir for 5 minutes and quench with 25 mL of 10% sodium thiosulfate. Extraction was performed with chloroform (20 mL ⁇ 3). The organic layer was dried over sodium sulfate and concentrated with an evaporator to obtain white crystals with a yield of 97%. The white crystals obtained were identified by 1 H-NMR, 31 P-NMR and 13 C-NMR.
- Step 3a Synthesis of 4-methoxyphenylphenylpyrenylphosphine oxide [VIIa] Pyrenyl-phenyl-4-methoxyphenylphosphine oxide [VIa] (1.7 g, 3.9 mmol) was dissolved in 100 mL of dichloromethane, and the solution was dissolved at -78 ° C. Bromide (11 mL, 11 mmol, 4 eq) was added dropwise. After stirring for 18 hours, it was quenched with 40 mL of H 2 O. The white precipitate formed at that time was suction filtered. The obtained crystals were dried with a pistol overnight to obtain white crystals with a yield of 94%. The obtained white crystals were identified by 1 H-NMR and 31 P-NMR.
- Step 4a Synthesis of 4-hydroxyphenylphenylpyrenylphosphine borane [VIIIa] Pyrenyl-phenyl-4-methoxyphenylphosphine oxide [VIIa] (1.2 g, 3.1 mmol) dissolved in 100 mL of toluene and triethylamine (1.79 mL, 13 mmol, 4 eq) is added dropwise and stirred in ice. Trichlorosilane (1.2mL, 12 mmol, 4 eq) is added dropwise for 10 minutes and refluxed at 110 ° C. After stirring for 18 hours, borane THF complex (3.00mL, 3.1 mmol, 1 eq) is added dropwise for 10 minutes.
- VIIIa Pyrenyl-phenyl-4-methoxyphenylphosphine oxide
- Step 5a Synthesis of phosphine borane [Xa] Sodium hydride [VIIIa] (192 mg, 2.9 mmol, 1.1 eq) was washed with hexane (1 mL ⁇ 3) in a glow box, 5 mL of DMF was added dropwise and stirred for 10 minutes. To do. Pyrenyl-phenyl-4-phenoxyphosphine borane (1.14 g, dissolved in 5 mL DMF) 2.7 mmol, 1 eq) is added dropwise for 5 minutes.
- iodine propane triphenylphosphonium iodide [IXa] (1.51 g, 2.7 mmol, 1 eq) dissolved in 5 mL of DMF was added dropwise at -15 ° C. for 5 minutes. After stirring for 6 hours, the reaction solution turned from an orange turbid solution to a clear yellow solution. At that time, the reaction was quenched with 5 mL of saturated aqueous ammonium chloride solution. Extraction was performed with dichloromethane (10 mL ⁇ 3), and the organic layer was dried over sodium sulfate. Concentration with an evaporator gave a yellow oil.
- the obtained yellow crystals were dissolved in a small amount of dichloromethane, and ethyl acetate was added to precipitate a white precipitate.
- the upper layer was removed by decantation, and when an oil pump was pulled, white crystals were obtained in a yield of 33%.
- the obtained white crystals were identified by 1 H-NMR, 31 P-NMR and ESI-MS.
- Step 6a Synthesis of [3- (4-Phenoxyphenylphosphinopyrenylphosphino) bropyl] triphenylphosphonium iodide [Ia] [Pyrenyl-phenyl-4-phenoxyphosphineborane] triphenylphosphonium dye [Xa] ( 167 mg, 0.21 mmol) was dissolved in 1 mL of chloroform, and diethylamine (102 ⁇ L, 0.84 mmol, 4 eq) was added dropwise. The mixture was stirred overnight at 40 ° C. in a water bath.
- Example 2 is a method for synthesizing MitoPeDPP.
- Diiodopropane (0.6mmol, 175 mg) was dissolved in toluene (1 mL) and refluxed, and the resulting dipyrenylphosphine (0.6 mmol, A solution of 232 mg, 1 eq) dissolved in toluene (1 mL) was slowly added dropwise. The mixture was allowed to stir overnight, and the deposited yellow precipitate was taken out by suction filtration and washed with hot toluene three times. The crystals were dried to obtain iodopropanediphenylpyrenylphosphonium iodide (yield 63%). They were identified by 1 H-NMR, 31 P-NMR, 13 C-NMR, ESI-MS, IR, and elemental analysis.
- Diphenylphosphine chloride (5 mmol, 0.92 ml) was dissolved in THF (25 ml) and cooled to 0 ° C. 4-methoxyphenylmagnesium bromide (6.5 mmol, 19 ml, 1.3 eq) was added dropwise for 20 minutes. The mixture was stirred for 3 hours and allowed to return to room temperature. After further stirring for 5 hours, the reaction was terminated with saturated NH 4 Cl (20 ml). Inorganic salts were removed by suction filtration, and the filtrate was extracted with dichloromethane (40 ml ⁇ 3). It was dried with sodium sulfate and concentrated using an evaporator and an oil pump to obtain diphenyl-4-methoxyphenylphosphine.
- FIG. 2 (a) is a view stained with a mitochondrial fluorescent stain Mito Tracker Green FM, and the right side is an enlarged view of the left circle.
- FIG. 2 (b) is a view stained with MitoDPPP, and the right side is an enlarged view of the left circle.
- ascorbic acid (25 ⁇ M) solution 6-O-acetylascorbic acid (25 ⁇ M) solution, 6-O-hexanoylascorbic acid (25 ⁇ M) solution, 5,6-O-isopropylidene-L-asukorubinic acid 2 mL of each (25 ⁇ M) solution was prepared, poured into a petri dish, and incubated at 37 ° C. for 30 minutes. After loading, the solution was removed and washed twice with 1 mL of PBS. 1980 ⁇ L of DPBS heated to 37 ° C.
- MitoDPPP is oxidized using AAPH which is a radical initiator.
- AAPH a radical initiator.
- Ascorbic acid and its derivatives are added during the reaction, an increase in fluorescence intensity is suppressed. This degree of inhibition becomes the antioxidant power of ascorbic acid and its derivatives.
- FIG. 5 shows the change over time of the fluorescence intensity in the aqueous solution.
- ascorbic acid and the synthesized fat-soluble derivatives were compared in antioxidant activity in HepG2 cells.
- HepG2 cells are cultured on a glass plate, the autofluorescence of the cells on the plate is measured, then MitoDPPP and an ascorbic acid derivative are introduced, and then AAPH is introduced to initiate the reaction.
- the increase in fluorescence intensity was normalized by dividing the measured fluorescence intensity by autofluorescence.
- FIG. 6 shows time-dependent changes in fluorescence intensity due to oxidation of MitoDPPP in cells in the presence of ascorbic acid.
- the phosphine compound according to the present invention is capable of capturing peroxides localized in mitochondria that are particularly susceptible to oxidative stress, and also causes the disorder of mitochondrial membrane function and causes the degree of oxidative stress to cause apoptosis. Since it can be visualized by a probe, it is useful as a mitochondrial peroxide scavenger.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Toxicology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
体内では、呼吸で取り入れた酸素をミトコンドリアの電子伝達系で使用してH2Oが生成されるときに産生する活性酸素などの過酸化物は、酸化ストレスを増加させると考えられている。ミトコンドリアは、ATPを構成し細胞の生命を維持するだけでなく、アボトーシス(細胞死)に中心的な役割を果たしている。なお、酸化LDL、酸化RLPなどは血管内皮細胞の酸化ストレスを増加させることが知られている。
日本抗酸化学会ホームページ(http://www.jsa-site.com/sanka_storesu.htm) Suzuki,B., et al., Bioorg. Med. Chem. Lett. 2007, 2055-2058 Okimoto,Y., et al., FEBS Lett., 2000, 474, 137-140
Arはアリレン基を意味し、
Rは脂肪族炭化水素基を意味し、
Yはリン(P)、窒素(N)またはビスマス(Bi)を意味し、
R1、R2およびR3はいずれも環式基を意味する)
で表されるホスフィン化合物を提供する。
Arで表されるアリレン基は、非置換もしくは置換の単環式炭化水素基または2環式炭化水素基であり;
Rで表される脂肪族炭化水素基は、炭素原子数が1~8個の直鎖状または分岐状の2価脂肪族炭化水素基であり、
R1、R2およびR3で表される環式基がそれぞれ、同一かまたは異なっていてもよく、非置換もしくは置換の単環式炭化水素基もしくは多環式炭化水素基または複素単環式基もしくは複素多環式基を意味し、
ただし、Z1およびZ2のいずれか一方の環式基は単環式炭化水素基または複素単環式基であり、他方の環式基は多環式炭化水素基または複素多環式基であり、および/またはR1、R2およびR3のいずれか一方の環式基は単環式炭化水素基または複素単環式基であり、他方の環式基は多環式炭化水素基または複素多環式基である、
ホスフィン化合物を提供する。
Rで表される炭素原子数が1~8個の直鎖状または分岐状の2価脂肪族炭化水素基がメチレン基、エチレン基、プロピレン基、イソプロピレン基、ブチレン基またはメチルブチレン基であり;
で表されるハライド化合物と、
で表されるメトキシアリールホスフィンオキシド化合物を得る工程2と;
で表されるヒドロキシアリールホスフィンオキシド化合物を得る工程3と;
で表されるヒドロキシアリールホスフィンボラン化合物を得る工程4と;
Rは脂肪族炭化水素基を意味し、
Yはリン(P)、窒素(N)またはビスマス(Bi)を意味し、
R1、R2およびR3はいずれも環式基を意味する)
で表されるハライド化合物[IX]と反応させて、
で表されるメトキシアリールホスフィンオキシド化合物と反応させて、一般式[VI]で表されるメトキシアリールホスフィンオキシド化合物を得る工程1bと;
で表されるホスフィンボラン化合物を得る工程9と;
工程9で得られたホスフィンボラン化合物[XVII]を脱保護することによって一般式[XVIII]:
で表されるホスフィン化合物[I]を得る工程10と、からなる方法;
によってホスフィン化合物[I]を製造することからなるホスフィン化合物の製造方法を提供する。
Arはアリレン基を意味し、
Rは脂肪族炭化水素基を意味し、
Yはリン(P)、窒素(N)またはビスマス(Bi)を意味し、
R1、R2およびR3はいずれも環式基を意味する)
で表されるホスフィン化合物に関するものである。
Arで表されるアリレン基は、非置換もしくは置換の単環式炭化水素基または2環式炭化水素基であり;
Rで表される脂肪族炭化水素基は、炭素原子数が1~8個の直鎖状または分岐状の2価脂肪族炭化水素基であり、
R1、R2およびR3で表される環式基がそれぞれ、同一かまたは異なっていてもよく、非置換もしくは置換の単環式炭化水素基もしくは多環式炭化水素基または複素単環式基もしくは複素多環式基を意味する)で表されるカチオン基であり、
ただし、Z1およびZ2のいずれか一方の環式基は単環式炭化水素基または複素単環式基であり、他方の環式基は多環式炭化水素基または複素多環式基であり、および/またはR1、R2およびR3のいずれか一方の環式基は単環式炭化水素基または複素単環式基であり、他方の環式基は多環式炭化水素基または複素多環式基である。
工程1で使用されるハライド化合物[II]のハロゲン原子としては、例えば、臭素、ヨウ素、塩素などが挙げられ、ハライド化合物[II]としては、例えば、フェニルブロミド、トリルクロリド、ナフチルブロミド、アントラセニルブロミド、ピレニルブロミド、ペリレニルブロミドなどが挙げられる。
ジハロホスフィン化合物[III]としては、例えば、ジクロロフェニルホスフィン、ジブロモフェニルホスフィン、ジヨードフェニルホスフィンなどが挙げられる。ジハロホスフィン化合物[III]の置換基としては、例えば、炭素原子数が1から6個、好ましくは炭素原子数が1から3個の脂肪族炭化水素基、例えばメチル基、エチル基、プロピル基、イソプロピル基などが挙げられる。
メトキシアリール金属マグネシウムハライド[IV]としては、例えば、メトキシフェニルマグネシウムクロライド、メトキシフェニルマグネシウムブロマイド、メトキシフェニルマグネシウムヨーダイドなどが挙げられ、置換基としては、例えば、炭素原子数が1から6個、好ましくは炭素原子数が1から6個の脂肪族炭化水素基、例えばメチル基、エチル基、プロピル基、イソプロピル基などが挙げられる。また、置換基の数および位置は特に限定されるものではなく、反応に支障がない限り任意であってよい。
工程7で使用されるハライド[XII]のハロゲン原子としては、例えば、臭素、ヨウ素、塩素などが挙げられ、ハライド化合物[XII]としては、例えば、フェニルブロミド、トリルクロリド、ナフチルブロミド、アントラセニルブロミド、ピレニルブロミド、ペリレニルブロミドなどが挙げられる。
モノハロホスフィン化合物[XIII]としては、例えば、クロロフェニルホスフィン、ブロモフェニルホスフィン、ヨードフェニルホスフィンなどが挙げられる。ハロホスフィン化合物[XIII]の置換基としては、例えば、炭素原子数が1から6個、好ましくは炭素原子数が1から3個の脂肪族炭化水素基、例えばメチル基、エチル基、プロピル基、イソプロピル基などが挙げられる。また、置換基の数および位置は特に限定されるものではなく、反応に支障がない限り任意であってよい。
工程7における反応は溶媒中で行うのがよく、溶媒としては、例えば、ジエチルエーテルやテトラヒドロフラン等のエーテルなどを使用することができる。また、反応温度は、例えば、0℃~-100℃、好ましくは-40℃~-80℃であって、反応時間は、例えば、1~24時間、好ましくは5~15時間程度であるのがよい。
で表される化合物である。
工程1c:4-メトキシフェニルフェニルピレニルホスフィン[Va]の合成
ピレンブロミド[IIa](3.28g, 15mmol)を70mLのTHFに溶かし、-78℃でn-BuLi(6.11mL, 2.7M,
16.5mmol, 1.1eq)を15分間滴下し、3時間撹拌した。この反応物をTHF
6mLに溶かしたジクロロフェニルホスフィン[IIIa](2.03mL, 15mmol, 1eq)へ15分間滴下した(-78℃)。一晩撹拌した後、4-メトキシフェニルマグネシウムブロミド[IVa](45mL, 0.5M, 22.5mmol, 1.5eq)を-78℃にて15分間滴下した。6時間撹拌した後、50mLの飽和塩化アンモニウム水溶液にてクエンチした。その際生じた無機塩を吸引ろ過にて除去し、ジクロロメタン(100mL×3)にて抽出した。有機層を硫酸ナトリウムにて乾燥後、エバポレーターにて濃縮した。精製はカラムクロマトグラフィーを展開溶媒(ジクロロメタン:へキサン=1:2)にて行った。得られた淡黄色の結晶が収率32%で得られた。得られた淡黄色の結晶は1H-NMR、31P-NMR、13C-NMR、H-H COSYおよびC-H COSYにて同定した。
3.78 (s, 3H), 6.89 (d, J = 8.8 Hz,2H), 7.28-7.34 (m, 7H), 7.54 (dd, J = 8.0, 4.4 Hz, 1H), 7.98-8.10 (m, 5H), 8.17-8.20 (m,
2H), 8.73 (dd, 8.0, 4.4 Hz, 1H). 31P NMR
(CDCl3, 162 MHz) δ -14.23. 13C NMR (CDCl3, 100 Hz) δ
114.36, 114.38, 114.62, 114.71, 124.78, 124.80, 124.88, 124.93, 124.99, 125.54,
125.60, 125.74, 125.81, 126.29, 127.29, 127.36, 127.64, 127.95, 127.98, 128.29,
128.49、128.55,
128.78, 128.83, 128.49, 130.98, 131.09, 131.55, 131.94, 132.26, 132.41, 132.43,
133.94, 134.03, 134.13, 134.26, 134.76, 134.97, 136.07, 136.29, 137.68, 137.78,
160.69.
ピレニル-フェニル-4-メトキシフェニルホスフィン[Va](1.68g, 4.03mmol)をクロロホルム25mLに溶かし、5mLの過酸化水素をゆっくり滴下する。5分間撹拌し、10%チオ硫酸ナトリウム25mLにてクエンチする。クロロホルム(20mL×3)にて抽出した。有機層を硫酸ナトリウムにて乾燥し、エバポレーターにて濃縮して白色結晶を収率97%で得た。得られた白色結晶は1H-NMR、31P-NMRおよび13C-NMRにて同定した。
2H), 7.52-7.56 (m, 1H), 7.60-7.78 (m, 5H), 8.00-8.08 (m, 4H), 8.15-8.23 (m,
3H), 8.94 (d, J = 9.6 Hz, 1H). 31P NMR (CDCl3, 162 MHz) δ
33.93. 13C NMR (CDCl3, 100 Hz) δ
114.37, 114.50, 123.68, 123.82, 124.03, 124.43, 125.14, 125.27, 125.32, 125.37,
126.35, 126.59, 126.67, 127.36, 128.74, 128.86, 129.06, 130.01, 130.66, 131.24,
131.35, 131.48, 131.98, 132.01, 132.33, 132.43, 133.51, 134.24, 134.28, 134.35,
134.38, 134.55, 162.66, 162.69.
ピレニル-フェニル-4-メトキシフェニルホスフィンオキシド[VIa](1.7g, 3.9mmol)をジクロロメタン100mLに溶かし、-78℃にてボラントリブロミド(11mL, 11mmol, 4eq)を滴下した。18時間撹拌後、40mLのH2Oにてクエンチした。そのとき生じた白色の沈殿物を吸引ろ過した。得られた結晶を一晩ピストル乾燥して白色結晶を収率94%で得た。得られた白色結晶は1H-NMRおよび31P-NMRにて同定した。
(d, J = 10.8 Hz, 2H), 7.40-7.45 (m, 2H), 7.52-7.61 (m, 5H), 7.69 (dd, J = 12.0, 7.6 Hz, 1H), 8.11-8.40 (m, 7H), 8.83 (d, J =
9.2 Hz, 1H), 10.34 (br). 31P NMR (DMSO-d6,
162 MHz) δ31.10.
ピレニル-フェニル-4-メトキシフェニルホスフィンオキシド[VIIa](1.2g, 3.1 mmol)にトルエン100mLに溶かしトリエチルアミン(1.79mL,
13mmol, 4eq)を滴下し、氷溶中にて撹拌する。トリクロロシラン(1.2mL,
12mmol, 4eq)を10分間滴下し110℃で還流する。18時間撹拌後、氷溶中にてボランTHFコンプレックス(3.00mL,
3.1mmol, 1eq)を10分間滴下する。15分間撹拌後、5mLのメタノールにてクエンチした。白色の沈殿物を吸引ろ過し、ろ液をエバポレーターにて濃縮して淡黄色の結晶を収率88%で得た。得られた淡黄色の結晶を展開溶媒(酢酸エチル:へキサン=1:2)にてカラムクロマトグラフィーを行って淡黄色の結晶を得た。得られた淡黄色の結晶は1H-NMRおよび31P-NMRにて同定した。
6.88 (d, 8.4 Hz,2H),7.40-7.44 (m, 2H), 7.49-7.58 (m, 3H), 7.65-7.74 (m, 3H),
7.96-8.06 (m, 4H), 8.11-8.24 (m, 3H), 8.40 (d, J = 9.2 Hz, 1H). 31P
NMR (CDCl3, 162 MHz) δ 20.40 (br). 13C
NMR (CDCl3, 100 Hz) δ 116.41, 116.51, 119.96, 120.58, 122.39, 122.94, 124.38,
124.42, 124.53, 125.36, 125.44, 126.37, 126.61, 126.67, 126.72, 127.35, 128.35,
129.13, 129.24, 129.74, 130.02, 130.55, 130.61, 131.27, 131.45, 131.47, 131.96,
13204, 133.43, 133.48, 133.53, 133.57, 133.96, 133.98, 135.69, 135.79, 158.66,
158.68. IR 830.91, 1102.58, 1175.52, 1435.70, 1500.34, 1580.50, 2375.59,
3405.33.
グローボックス内にてナトリウムハイドライド[VIIIa](192mg, 2.9mmol, 1.1eq)をヘキサン(1mL×3)にて洗浄し、5mLのDMFを滴下し10分間撹拌する。5mLのDMFに溶かしたピレニル-フェニル-4-フェノキシホスフィンボラン(1.14g,
2.7mmol, 1eq)を5分間滴下する。3時間撹拌後、-15℃にて5mLのDMFに溶かしたヨ-ドプロパントリフェニルホスホニウムヨ-ダイド[IXa](1.51g, 2.7mmol, 1eq)を5分間滴下した。6時間撹拌後、反応溶液はオレンジ色の混濁液から黄色の透明溶液になった。そのとき飽和塩化アンモニウム水溶液5mLにてクエンチした。ジクロロメタン(10mL×3)にて抽出し、有機層を硫酸ナトリウムにて乾燥した。エバポレーターにて濃縮し、黄色のオイルが得られた。この黄色のオイルを展開溶媒(ジクロロメタン:酢酸エチル=3:7)を用いてカラムクロマトグラフィーで精製した。得られた黄色の結晶を少量のジクロロメタンに溶かし、酢酸エチルを加えると白色の沈殿物が沈降した。上層をデカンテーションにて取り除き、オイルポンプを引くと白色の結晶を収率33%で得た。得られた白色結晶は1H-NMR、31P-NMRおよびESI-MSにて同定した。
MHz) δ 2.16-2.18 (m, 2H), 4.05-4.13 (m, 2H) 4.38-4.41 (m, 2H), 6.92 (d, J = 8.0
Hz, 2H), 7.27-7.44 (m, 2H), 7.49-7.57 (m, 3H), 7.65-7.86 (m, 18H), 7.95-8.08
(m, 4H), 8.12-8.22 (m, 3H), 8.39 (d, J = 9.2 Hz, 1H),31P NMR (CDCl3,
162 MHz) δ 20.26 (br), 25.90 13C NMR (CDCl3,
100 Hz) δ 19.95 (d, JCP = 52.60 Hz), 23.01 (s), 66.99 (d, JCP = 16.80 Hz),
115.48, 115.59, 117.87, 118.73, 120.13, 120.76, 122.41, 122.96, 124.38, 124.49,
124.59, 125.32, 125.41, 126.35, 126.56, 126.61, 126.68, 127.41, 128.31, 129.13,
129.23, 129.69, 129.93, 130.51, 130.67, 130.80, 131.26, 131.45, 131.47, 132.01,
132.10, 133.36, 133.43, 133.52, 133.87, 133.97, 135.32, 135.35, 135.41, 135.51,
160.97, 160.99. IR 688.37, 738.36, 1105.66, 1247.54, 1435.83, 1498.61, 1592.29,
2377.83. ESI-MS (C49H42BOP2 +) : 計算値:719; 測定値:721.
元素分析(C49H42BIOP2);計算値:C, 69.52; H, 5.00; 測定値: C, 69.37; H, 5.28.
[ピレニル-フェニル-4-フェノキシホスフィンボラン]トリフェニルホスホニウムダイド[Xa](167mg, 0.21mmol)をクロロホルム1mLに溶かし、ジエチルアミン(102μL, 0.84mmol, 4eq)を滴下した。水浴にて40℃で一晩撹拌した。溶媒をエバポレーターにて濃縮し、展開溶媒(ジクロロメタン:メタノール=13:1)を用いてカラムクロマトグラフィーで精製すると、白色の結晶が収率51%で得られた。この白色結晶は1H-NMRおよび31P-NMRにて同定した。
MHz) δ 2.15-2.19(m, 2H), 4.08-4.15 (m, 2H), 4.34 (t, J = 5.6 Hz, 2H), 6.82 (d,
J = 8.8 Hz, 2H), 7.21-7.33 (m, 7H), 7.52 (dd, J =
7.6, 4.4 Hz, 1H), 7.63-7.87 (m, 15H), 7.97-8.09 (m, 5H), 8.16-8.19 (m, 2H),
8.71 (dd, J = 9.2 Hz, 4.4 Hz, 1H). 31P NMR
(CDCl3, 162 MHz) δ -13.76, 26.07. 13C NMR (CDCl3,
100 Hz) δ 19.96 (d, JCP = 51.9 Hz), 23.15 (s), 66.75 (d, JCP = 16.0 Hz),
115.22, 115.31, 118.05, 118.90, 124.76, 124.84, 124.89, 125.06, 125.50, 125.58,
125.70, 125.77, 126.26, 127.68, 127.74, 127.81, 127.90, 127.933, 128.25,
128.78, 128.85, 130.62, 130.74, 131.01, 131.06, 131.54, 131.91, 132.20, 132.34,
133.91, 134.01, 134.09, 134.18, 135.22, 135.25, 136.09, 136.30, 137.48, 137.58,
159.29. IR 687.78, 1110.48, 1241.25, 1434.81, 1588.94. ESI-MS for C49H39OP2 +:
計算値:705; 測定値: 705
ペリレン3.0g(11mmol)をジクロロメタン700mLに溶かし5分間攪拌した。そこへ、N-ブロモサクシンイミド2.11g(12mmol,
1.1eq)を室温でゆっくり滴下し一晩攪拌した。反応溶液を展開溶媒ジクロロメタン:ヘキサン=1:1に調整したシリカゲルカラムクロマトグラフィーにより精製し、N-ブロモサクシンイミドを取り除いた。溶媒を濃縮後、黄色の結晶(収率90%)を得た。化合物の同定は1H-NMR、ESI-MSより行った。
MHz) δ 7.46-7.51
(m, 2H), 7.59 (t, J = 4.4 Hz,1H), 7.68-7.72 (m, 2H), 7.78-7.80 (m, 1H),
7.98-8.04 (m, 1H), 8.09-8.14 (m, 1H), 8.17-8.28 (m, 3H). ESI-MS (C20H11Br):計算値:330.00;
測定値: 331.9.
ヘキサン30mlにピリジン3.2mL(40mmol, 2eq)を加え、そこへジクロロフェニルホスフィン2.7mL(20mmol)をゆっくり滴下した。そこへジエチルアミン4.18mL(40mmol, 2eq)をゆっくり滴下後、3時間還流した。溶媒を除去後、淡黄色の油状物質(収率60%)を得た。
ペリレンブロミド780mg(2.35mmol)とアニシルフェニルホスフィンオキシド1.1g(4.7mmol, 2eq)と酢酸パラジウム53mg(0.24mmol, 0.05eq)と1.3-ビス(ジフェニルホスフィノ)プロパン99mg(0.24mmol,
0.05eq)の混合物に17mLのDMSOに溶かしたジイソプロピルエチルアミン1.2g(9.4
mmol, 4eq)を滴下した。反応温度を150℃に上げ一晩撹拌する。TLCにて反応を確認後、酢酸エチル50mLを加えて薄め、H2O、飽和NaCl水溶液にて3回洗浄した(30ml×3回)。有機層を硫酸ナトリウムにて乾燥し、溶媒を除去後、淡黄色の結晶を得た。精製はシリカゲルカラムクロマトグラフィー(ジクロロメタン:エチルアセテート=1:1)により行った(収率70%)。化合物の同定は1H-NMR、31P-NMR、13C-NMR、IR、ESI-MS、UVより行なった。
MHz) δ 3.86 (s,
3H), 6.99 (d, J = 4.4 Hz, 2H), 7.24-7.29 (m, 1H), 7.30-8.06 (m, 12H), 8.08 (d,
J = 2 Hz, 1H), 8.20-8.24 (m, 3H), 8.49 (d, J = 4.2 Hz, 1H). 31P NMR
(CDCl3, 162 MHz) δ
33.60. 13C NMR (CDCl3, 100 Hz) δ 55.59, 114.43, 114.56, 118.52,
118.67, 121.03, 121.19, 121.84, 124.32, 126.81, 127.09, 127.77, 127.83, 127.94,
128.44, 128.57, 128.67, 128.79, 128.91, 129.57, 130.37, 131.13, 131.83, 132.11,
132.29, 132.38, 133.78, 134.20, 134.32, 134.50, 134.61, 134.68, 135.61, 135.97,
162.78. IR 758.72, 809.70, 117.79, 1170.46, 1254.81, 1501.34, 1595.92, 3048.39.
ESI-MS (C33H23O2P+H):計算値:483.15;
測定値: 483.11;UV 427 nm, 453 nm.
4-メトキシフェニルフェニルペリレニルホスフィンオキシド(400mg,
0.83mmol)をジクロロメタン30mLに溶かし、-78℃にてボラントリブロミド(2.5mL,
2.5mmol, 4eq)を滴下する。18時間撹拌後、10mLのH2Oを加えて反応を終了した。そのとき生じた赤褐色の沈殿物を吸引ろ過した。得られた結晶を一晩ピストル乾燥して赤褐色の結晶(収率77%)を得た。得られた結晶は1H-NMR、31P-NMR、IR、ESI-MS、UVにて同定した。
MHz) δ 6.92 (d, J
= 3.6 Hz, 2H), 7.21 (dd, J = 3.8, 15 Hz, 1H),
7.41-7.63 (m, 10H), 7.84-7.90 (m, 2H), 8.35-8.42 (d, J = 2 Hz, 5H), 10.24 (br, 1H). 31P NMR (CDCl3, 162 MHz) δ 30.59. IR 757.64, 805.41, 118.60,
114.94, 1292.26, 1437.65, 1505.70, 1579.50, 3050.38. ESI-MS (C32H21O2P+K):計算値:509.09;
測定値:: 509.12;UV 427 nm, 453 nm.
4-ヒドロキシフェニルフェニルペリレニルホスフィンオキシド(293mg,
0.63mmol)にトルエン20mLに溶かし、トリエチルアミン(900μL, 6.26mmol, 8eq)を滴下し、氷溶中にて撹拌する。トリクロロシラン(780μL, 7.8mmol, 12eq)を10min滴下し110℃で還流する。18時間撹拌後、氷溶中にてボランTHFコンプレツクス(1.23mL, 1.2mmol, 2eq)を10分間滴下する。15分間撹拌後、10mLのメタノールを加えて反応を終了させた。黄色の沈殿物を吸引ろ過し、ろ液をエバポレーターにて濃縮した。得られた赤褐色の結晶を展開溶媒(ジクロロメタン)にてカラムクロマトグラフィーを行って淡黄色の結晶(収率83%)を得た。得られた結晶は1H-NMR、31P-NMR、13C-NMR、IR、UVにて同定した。
MHz) δ 6.92 (d, J = 3.6 Hz, 2H), 7.20-7.23 (m, 1H), 7.37 (t, J = 8.2 Hz, 1H),
7.45-7.76 (m, 11H), 7.99-8.07 (m, 2H), 8.16-8.20 (m, 3H). 31P NMR
(CDCl3, 162 MHz) δ 20.12 (br). 13C
NMR (CDCl3, 100 Hz) δ116.45, 116.56, 116.63, 119.15, 119.27, 119.76,
120.90, 121.09, 121.63, 125.05, 125.60, 126.79, 126.98, 127.12, 127.80, 127.87,
128.40, 129.10, 129.20, 129.33, 129.41, 129.48, 129.53, 130.11, 130.25, 130.95,
131.44, 131.93, 132.84, 132.94, 133.44, 133.54, 134.56, 134.93, 134.99, 135.09,
135.24, 135.35, 135.63, 135.74, 158.94.IR 810.14, 1100.33, 1170.57, 1253.73,
1498.76, 1595.37, 2927.87, 3050.72;UV
428 nm, 454 nm.
ナトリウムハイドライド38.4mg(1.1eq,
0.58mmol)をグローブボックス内でヘキサン(1mL)を用いて3回洗浄した。残ったヘキサンをオイルポンプを用いて乾燥後、DMF
2mLを加え室温で10分間撹拌した。その混合溶液に4-ヒドロキシフェニルフェニルペリレニルホスフィンボラン245mg(0.52mmol)のDMF(2mL)溶液をゆっくり滴下し、2.5時間室温で撹拌した。反応溶液は次第に深赤色の混濁液になり、同時に気泡が発生した。この反応溶液をアイスバスにより-15℃に冷やし、ヨードプロピルホスホニウムヨーダイド290mg(1eq, 0.52mmol)のDMF(1mL)溶液をゆっくり滴下した。徐々に室温に戻し、一晩撹拌した。薄層クロマトグラフィーにより反応の進行を確認後、飽和塩化アンモニウム水溶液を5mLゆっくり滴下した。ジクロロメタンにより抽出後、硫酸ナトリウムにより乾燥した。溶媒を除去し深赤色のオイルを得た。精製はシリカゲルカラムクロマトグラフィー(ジクロロメタン:エチルアセテート=3:7)により行なった(収率41%)。得られた化合物の同定は1H-NMR、31P-NMR、IR、ESI-MS、元素分析より行なった。
2.22 (m, 2H), 4.04 (m, 2H), 4.41 (m, 2H), 6.95 (d, J = 3.4 Hz, 2H), 7.35 (t, J
= 4 Hz, 1H), 7.39-7.59 (m, 8H), 7.65-7.87 (m, 22H), 8.01 (d, J = 4.2 Hz, 1H),
8.10 (d, J = 3.8 Hz, 1H), 8.20 (d, J = 3.6 Hz, 3H). 13C NMR (CDCl3,
100 Hz) δ20.24,Jcp = 43.722.98, 67.01 (d, Jcp = 8.4), 115.50, 115.62, 117.60, 118.46, 119.27, 119.38,
119.71, 120.34, 120.90, 121.11, 121.71, 124.98, 125.54, 126.86, 126.99, 127.13,
127.71, 127.79, 128.38, 128.44, 129.14, 129.24, 129.35, 129.48, 129.95, 130.22,
130.77, 130.90, 131.54, 131.96, 133.40, 133.50, 133.86, 133.97, 134.54, 134.96,
135.07, 135.24, 135.38, 135.49, 160.97. 31P NMR (CDCl3,
162 MHz) δ 19.94 (br),
25.91. IR 687.41, 737.06, 1105.67, 1253.35, 1435.94, 1498.13, 1590.88, 2380.33.
ESI-MS for C53H41O2P2:
計算値:755.26; 測定値: 755.29;元素分析(C53H44BIOP2・2H2O):計算値:C, 68.26. H, 5.19; 測定値:C, 68.21. H, 5.07.
MitoPeDPPB(60mg,
0.067mmol)をクロロホルム1mLに溶かし、ジエチルアミン(52μL,
0.52mmol, 8eq)を滴下する。ウォーターバスにて40℃で一晩撹拌した。溶媒をエバポレーターにて濃縮した。精製は展開溶媒(ジクロロメタン:メタノール=20:1)にてシリカゲルカラムクロマトグラフィーを行った。溶媒を濃縮し、赤褐色の結晶(収率62%)を得た。化合物の同定は1H-NMR、31P-NMR、13C-NMR、IR、ESI-MS、UVより行った。
3.92-3.99 (m, 2H), 4.31 (m, 2H), 6.84 (d, J = 4.2 Hz, 2H), 6.93-7.00 (m, 1H),
7.11-7.53 (m, 12H), 7.63-7.83 (m, 21H), 8.02 (d, J = 3.8 Hz, 1H), 8.10 (d, J =
3.8 Hz, 1H), 8.14-8.23 (m, 3H). 31P NMR (CDCl3, 162 MHz)
δ-13.85, 25.78 13C NMR (CDCl3, 100 Hz) δ20.20Jcp = 26.3
Hz 23.08, 66.84, 115.31, 115.39, 117.74, 118.60, 120.72, 120.83, 126.08,
126.35, 126.87, 127.04, 128.20, 128.47, 128.65, 128.86, 128.93, 129.18, 130.71,
130.84, 131.06, 131.35, 131.86, 132.45, 132.80, 133.88, 133.98, 134.21, 134.77,
135.41, 136.15, 136.36, 136.68, 159.48 IR 686.99, 810.59, 1109.21, 1239.95,
1434.91, 1494.37, 1588.13, 3048.96. ESI-MS (C53H41O2P2):計算値: 755.26; 測定値:755.36;UV 433 nm,
463 nm
1.41g)を入れTHF(25ml)に溶かした。これを-78℃に冷やしておき、ここにn-BuLi(5.5mmol, 2.08ml, 2.64M, 1.1eq)をゆっくり滴下し2時間攪拌し、ジフェニルホスフィンクロリド(5mmol,
0.92ml, 1eq)をゆっくり滴下し、一晩攪拌した。飽和NH4Cl(10mL)を加え、THF層と水層を分け、水層をジクロロメタン(50mL×3)で抽出し、有機層とTHF層を混ぜ、硫酸ナトリウムを用いて乾燥させた。エバポレーターを用いて濃縮した。精製はシリカゲルカラムクロマトグラフィー(展開溶媒、ジクロロメタン:ヘキサン=1:3)によって行った。これより白黄色の結晶であるジフェニルピレニルホスフィン(DPPP)を得た(収率39%)。この結晶の同定は1H-NMR、31P-NMRにて行った。
7.8 Hz, 1H), 7.98-8.10 (m, 5H), 8.17-8.20 (m, 2H), 8.75-8.78 (dd, J = 7.9Hz, 1H) 31P NMR (CDCl3,
162 MHz) δ-12.84
175mg)をトルエン(1mL)に溶かし還留させ、そこに得られたジピレニルホスフィン(0.6mmol,
232mg, 1eq)をトルエン(1mL)に溶かしたものをゆっくり滴下した。一晩攪拌させ、析出した黄色い沈殿物を吸引ろ過によってとりだし、熱トルエンで3回洗浄した。この結晶を乾燥させヨードプロパンジフェニルピレニルホスホニウムヨーダイドを得た(収率63%)。1H-NMR、31P-NMR、13C-NMR、ESI-MS、IR、元素分析にて同定した。
(m, 2H), 3.38-3.41 (t, J = 3.2 Hz, 2H), 3.82-3.83 (m, 2H), 7.77-7.79 (m, 4H),
7.89-7.97 (m, 7H), 8.21-8.33 (m, 3H), 8.43-8.45 (d, J = 7.6 Mz,
1H), 8.47-8.53 (m, 4H) 31P NMR (CD3OD, 162 MHz) δ24.06. 13C
NMR (DMSO-d6, 100MHz) δ6.40-6.61,
24.79-25.30, 28.06, 108.40, 109.25, 119.44, 120.28, 123.51, 124.34, 126.12, 126.25,
127.81, 128.44, 128.79, 128.91, 130.02, 131.15, 131.28, 131.54, 132.48, 13367,
133.93, 134.12, 134.22, 135.70, 136.70. IR 481.80, 2878.23, 3039.23, 3398.25.
ESI-MS (C31H25IP):計算値:555.41;
測定値:555.03. 元素分析(C31H25IP):計算値:C, 54.57 H, 3.69、測定値:C,
54.50 H, 4.06.
まず、ジフェニル-4-メトキシフェニルホスフィンを下記のように合成した。
19ml, 1.3eq)を20分間滴下した。3時間攪拌させ室温に戻し、さらに5時間攪拌後飽和NH4Cl(20ml)で反応を終了させた。無機塩を吸引ろ過で除去し、ろ液をジクロロメタン(40ml×3)で抽出した。硫酸ナトリウムで乾燥させ、エバポレーター、オイルポンプを用いて濃縮しジフェニル-4-メトキシフェニルホスフィンを得た。
NMR (CDCl3, 400 MHz)δ
2.23-2.24 (d, J = 5.2, 2H), 4.29-4.30 (dd, 3.6, 2H),
4.40-4.42 (m, 2H), 6.88-6.90 (d, J = 8.8, 2H), 7.39-7.55 (m, 12H), 7.65-7.70
(m, 4H), 7.77-7.80 (m, 2H), 7.93-7.98 (m, 5H), 8.15-8.23 (m, 3H), 8.34-8.43 (m,
5H) 31P NMR (CDCl3, 162 MHz) δ 19.98, 25.68. ESI-MS (C49H42BIOP2):計算値:706.52 測定値:706.15.
0.02mmol)をCHCl3(2ml)に溶か、CHCl3(1ml)に溶かしたDABCO(2mg, 0.02mmol, 1eq)を滴下した。40℃で一晩攪拌させた。溶媒をエバポレーター、オイルポンプで濃縮した。精製はカラムクロマトグラフィー(展開溶媒:ジクロロメタン:メタノール=40:1)にて行った(収率10%)。同定は1H-NMR、31P-NMRにて同定した。
MHz) δ2.22 (s, 2H), 4.28-4.29 (d, J = 3.6, 2H), 4.32-4.33 (d, J = 5.2, 2H),
6.80-6.82 (d, J = 8.4, 2H), 7.18-7.23 (t, J = 10, 2H), 7.30-7.60 (m, 10H),
7.67-7.70 (m, 4H), 7.76-7.78 (m, 2H), 7.94-7.99 (m, 5H), 8.15-8.23 (m, 3H),
8.34-8.43 (m, 5H) 31P NMR (CDCl3, 162 MHz) δ -5.96, 25.71.
MitoDPPP(16μM)のジメチルスルホキシド溶液に10mM H2O2を滴下して、蛍光波長380nmの蛍光強度を10分間測定した。その結果を図1に示す。図1に示すように、MitoDPPPが徐々に酸化されてその蛍光強度が増加していることが分かる。
次に、HepG2細胞を表面に培養したガラスプレートを石英セルの中心に斜めに固定し、DPBS
3mLを加え、自家蛍光(励起波長:281nm、蛍光波長:340nm付近)を測定した。自家蛍光を測定したプレートをシャーレに移し、PBS
1mLで2回洗浄し、MitoDPPP(16μM)溶液2mLをシャーレに注ぎ、37℃で20分間インキュベートした。その後、溶液を取り除きDPBS 1mLで2回洗浄した。次いで、アスコルビン酸(25μM)の溶液、6-O-アセチルアスコルビン酸(25μM)の溶液、6-O-ヘキサノイルアスコルビン酸(25μM)の溶液、5,6-O-イソプロピリデン-L-asukorubin酸(25μM)の溶液をそれぞれ2mL調整し、シャーレに注ぎ37℃で30分間インキュベートした。ロード後、溶液を取り除きPBS 1mLで2回洗浄した。石英セルに37℃に加温したDPBS 1980μLを注ぎ、マグネットを用いて石英セルの中心にプレートを立て蛍光強度(励起波長:353nm、蛍光波長:380nm)を測定した。AAPH(25μM)をDPBS 1mLに溶かし冷やしておいた溶液20μL(最終濃度250μM)を加え、37℃に加温し蛍光分光計にて蛍光強度の増加を追跡した。その結果を図5および図6に示す。
まず、ラジカル開始剤であるAAPHを用いてMitoDPPPを酸化する。その反応中にアスコルビン酸およびその誘導体を加えると、蛍光強度の増大が抑制される。この抑制の度合いがアスコルビン酸およびその誘導体の抗酸化力となる。図5は水溶液での蛍光強度の経時変化を示す。
Claims (9)
- 請求項1に記載のホスフィン化合物であって、Z1およびZ2で表される環式基がいずれも、非置換または置換の単環式炭化水素基もしくは多環式炭化水素基または複素単環式基もしくは複素多環式基であり;
Arで表されるアリレン基は、非置換または置換の単環式炭化水素基または2環式炭化水素基であり;
Rで表される脂肪族炭化水素基は、炭素原子数が1~8個の直鎖状または分岐状の2価脂肪族炭化水素基であり、
R1、R2およびR3で表される環式基がそれぞれ、同一かまたは異なっていてもよく、非置換または置換の単環式炭化水素基もしくは多環式炭化水素基または複素単環式基もしくは複素多環式基を意味する)で表されるカチオン基であり、
ただし、Z1およびZ2のいずれか一方の環式基は単環式炭化水素基または複素単環式基であり、他方の環式基は多環式炭化水素基または複素多環式基であり、および/またはR1、R2およびR3のいずれか一方の環式基は単環式炭化水素基または複素単環式基であり、他方の環式基は多環式炭化水素基または複素多環式基である、
ことを特徴とするホスフィン化合物。 - 請求項2に記載のホスフィン化合物であって、Z1およびZ2のいずれか一つの環式基が多環式炭化水素基または複素多環式基であり、他方の単環式基が単環式炭化水素基または複素単環式基であり、R1、R2およびR3の全ての環式基は単環式炭化水素基または複素単環式基である、またはZ1およびZ2の全ての環式基が単環式基が単環式炭化水素基または複素単環式基であり、R1、R2およびR3のいずれか一つの環式基は多環式炭化水素基または複素多環式基であり、他の環式基が単環式炭化水素基または複素単環式基であることを特徴とするホスフィン化合物。
- 請求項2または3に記載のホスフィン化合物であって、
Z1、Z2、R1、R2およびR3でいずれも表される環式基が、フェニル基等の単環式炭化水素基;インダニル基、インデニル基、ペンタレニル基、アズレニル基、ナフチル基、テトラヒドロナフチル基等の2環式炭化水素基;アントラセニル基、フルオレニル基、フェナレニル基、フェナントレニル基等の3環式炭化水素基;ピレニル基、ナフタセニル基、クリセニル基などの4環式炭化水素基;ペリレニル基、ピセニル基、ペンタセニル基等の5環式炭化水素基;ナフトビレニル基等の6環式炭化水素基;コロネニル基等の7環式炭化水素基などであり;複素環式基が、ピロリル基、イミダゾリル基、ピラゾリル基、ピリジル基、ピペリジル基、トリアジニル基等のN含有複素単環式基、フラニル基、ピラニル基等のO含有複素単環式基、チオフェニル基等のS含有複素多環式基、オキサゾリル基、チアゾリル基、モルホリニル基等のN/O/S含有複素単環式基などの複素単環式基;インドリル基、インドリニル基、キノリニル基、イソキノリニル基、キナゾリニル基、キノキサリニル基、ナフチリジニル基、プテリジニル基、プリニル基等のN含有複素2環式基、アクリジニル基、カルバゾリル基、フェナントリジニル基、フェナジニル基、ベンゾイソキノリニル基等のN含有複素3環式基などのN含有複素多環式基、ベンゾフラニル基、クロマニル基、クロメニル基、イソクロマニル基等のO含有複素2環式基、キサンテニル基等のO含有複素3環式基などのO含有複素多環式基;ジチアナフチル基等のS含有複素3環式基、チアントレニル基等のS含有複素3環式基等のS含有複素多環式基;ピリドオキサゾリル基、チエノフラニル基、フェノキサジニル基、フェノチアジニル基、ピラゾロオキサゾリル基等のN/O/S含有複素多環式基などの複素多環式基であり;置換基はメチル基、エチル基、プロピル基、イソプロピル基等の炭素原子数が1~6個の低級脂肪族炭化水素基であり;
Arで表されるアリレン基がフェニレン基、ナフタレン基であり;
Rで表される直鎖状または分岐状の2価脂肪族炭化水素基がメチレン基、エチレン基、プロピレン基、イソプロピレン基、ブチレン基またはメチルブチレン基である、
ことを特徴とするホスフィン化合物。 - ハライド化合物[II]と、ジハロホスフィン化合物[III]と、メトキシアリール金属マグネシウムハライド[IV]を反応させて、メトキシアリールホスフィン化合物[V]を得る工程1aと、上記工程1aで得られたメトキシアリールホスフィン化合物[V]を酸化剤と反応させてメトキシアリールホスフィンオキシド化合物[VI]を得る工程2と、上記工程2で得られたメトキシアリールホスフィンオキシド化合物[VI]を脱メチル化試薬で脱メチル化してヒドロキシアリールホスフィンオキシド化合物[VII]を得る工程3と、上記工程3で得られたヒドロキシアリールホスフィンオキシド化合物[VII]をボラン化合物と反応させてヒドロキシアリールホスフィンボラン化合物[VIII]を得る工程4と、上記工程4で得られたジ環式基置換ヒドロキシメトキシアリールホスフィンボラン化合物[VII]をハライド化合物[IX]と反応させてホスフィンボラン化合物[X]を得る工程5と、上記工程5で得られたホスフィンボラン化合物[X]の保護基を脱保護して一般式[I]で表されるホスフィン化合物を得る工程6とからなる方法;または
ハライド化合物[II]をメトキシアリールホスフィンオキシド化合物[XI]と反応させて、一般式で表されるジ環式基置換メトキシアリールホスフィンオキシド化合物[VI]を得る工程1bと、上記工程1bで得られたメトキシアリールホスフィンオキシド化合物[VI]を脱メチル化試薬で脱メチル化してヒドロキシアリールホスフィンオキシド化合物[VII]を得る工程3と、上記工程3で得られたヒドロキシアリールホスフィンオキシド化合物[VII]をボラン化合物と反応させてヒドロキシアリールホスフィンボラン化合物[VIII]を得る工程4と、上記工程4で得られたヒドロキシアリールホスフィンボラン化合物[VIII]をハライド化合物[IX]と反応させてホスフィンボラン化合物[X]を得る工程5と、上記工程5で得られたホスフィンボラン化合物[X]の保護基を脱保護して一般式[I]で表されるホスフィン化合物を得る工程6と、からなる方法;または
ハライド化合物[XII]と、ハライド化合物[XIII]を反応させて化合物[XIV]を得る工程7と、上記工程7で得られた上記化合物[XIV]と、ジハロ化合物[XV]を反応させてハロ化合物[XVI]を得る工程8と、上記工程8で得られた上記ハロ化合物[XVI]と、上記工程4で得られたヒドロキシアリールホスフィンボラン化合物[VIII]を置換アルキルハライド[XVI]と反応させてホスフィンボラン化合物[XVII] を得る工程で9と、上記工程9で得られたホスフィンボラン化合物[VI]を脱保護することによってホスフィン化合物[XVIII]または[I]を得る工程10と、からなる方法;
によってホスフィン化合物[I]または[XVIII]をえることを特徴とするホスフィン化合物の製造方法。 - 一般式[I]で表されるホスフィン化合物を含む過酸化物捕捉剤。
- 一般式[I]で表されるホスフィン化合物を用いて過酸化物を捕捉することを特徴とする過酸化物捕捉方法。
- 請求項6に記載の過酸化捕捉方法であって、前記過酸化物が、過酸化脂質、1重項酸素などの活性酸素種などであることを特徴とする過酸化物捕捉方法。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010502833A JP5668924B2 (ja) | 2008-03-11 | 2009-03-10 | ホスフィン化合物、その製造方法およびそれを用いた過酸化物捕捉剤 |
CA2717943A CA2717943C (en) | 2008-03-11 | 2009-03-10 | Phosphine compound, process for producing the same, and peroxide scavenger using the same |
US12/921,967 US8420865B2 (en) | 2008-03-11 | 2009-03-10 | Phosphine compound, process for producing the same, and peroxide scavenger using the same |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008060715 | 2008-03-11 | ||
JP2008-060715 | 2008-03-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009113543A1 true WO2009113543A1 (ja) | 2009-09-17 |
Family
ID=41065211
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2009/054551 WO2009113543A1 (ja) | 2008-03-11 | 2009-03-10 | ホスフィン化合物、その製造方法およびそれを用いた過酸化物捕捉剤 |
Country Status (4)
Country | Link |
---|---|
US (1) | US8420865B2 (ja) |
JP (2) | JP5668924B2 (ja) |
CA (1) | CA2717943C (ja) |
WO (1) | WO2009113543A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6887688B2 (ja) * | 2019-02-07 | 2021-06-16 | 株式会社高純度化学研究所 | 蒸発原料用容器、及びその蒸発原料用容器を用いた固体気化供給システム |
JP6901153B2 (ja) | 2019-02-07 | 2021-07-14 | 株式会社高純度化学研究所 | 薄膜形成用金属ハロゲン化合物の固体気化供給システム。 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5202493A (en) * | 1991-04-26 | 1993-04-13 | E. I. Du Pont De Nemours And Company | Chiral tridentate bis(phospholane) ligands |
CN1096315A (zh) * | 1992-11-24 | 1994-12-14 | 联邦科学及工业研究组织 | 除氧组合物 |
JP3830180B2 (ja) * | 1995-07-27 | 2006-10-04 | 高砂香料工業株式会社 | 新規ホスフィン−ホスフィナイト化合物およびそれを用いた4−[(r)−1’−ホルミルエチル]アゼチジン−2−オン誘導体の製造方法 |
US20030216599A1 (en) * | 2000-05-31 | 2003-11-20 | Hillhouse John Henry | Synthesis of diphosphinoarenes |
EP1341799B1 (en) * | 2000-12-13 | 2005-03-16 | Warner-Lambert Company LLC | P-chirale bisphospholane ligands, their transition metal complexes |
JP4005800B2 (ja) * | 2001-12-10 | 2007-11-14 | 高砂香料工業株式会社 | 新規不斉ホスフィン配位子 |
JP2004210672A (ja) * | 2002-12-27 | 2004-07-29 | Nippon Chem Ind Co Ltd | ビスホスホニウム塩化合物及びその製造方法 |
-
2009
- 2009-03-10 CA CA2717943A patent/CA2717943C/en active Active
- 2009-03-10 US US12/921,967 patent/US8420865B2/en active Active
- 2009-03-10 WO PCT/JP2009/054551 patent/WO2009113543A1/ja active Application Filing
- 2009-03-10 JP JP2010502833A patent/JP5668924B2/ja active Active
-
2014
- 2014-08-27 JP JP2014172278A patent/JP5794506B2/ja active Active
Non-Patent Citations (2)
Title |
---|
BAN, S. ET AL.: "Novel mitochondria-localizing TEMPO derivative for measurement of cellular oxidative stress in mitochondria.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, 2007, pages 2055 - 2058 * |
OKIMOTO, Y. ET AL.: "A novel fluorescent probe diphenyl-1-pyrenylphosphine to follow lipid peroxidation in cell membranes", FEBS LETTERS, vol. 474, 2000, pages 137 - 140 * |
Also Published As
Publication number | Publication date |
---|---|
US8420865B2 (en) | 2013-04-16 |
JP2015007095A (ja) | 2015-01-15 |
JP5794506B2 (ja) | 2015-10-14 |
US20110015440A1 (en) | 2011-01-20 |
JP5668924B2 (ja) | 2015-02-12 |
JPWO2009113543A1 (ja) | 2011-07-21 |
CA2717943A1 (en) | 2009-09-17 |
CA2717943C (en) | 2014-01-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Shavaleev et al. | Near-infrared luminescence of nine-coordinate neodymium complexes with benzimidazole-substituted 8-hydroxyquinolines | |
CA2642747A1 (en) | Phosphonylated fluorescent dyes and conjugates | |
US20020013306A1 (en) | Terpyridine-platinum(ii) complexes | |
Arm et al. | Synthesis and pH-sensitive luminescence of bis-terpyridyl iridium (III) complexes incorporating pendent pyridyl groups | |
WO2016133218A1 (ja) | ホスファフルオレセイン化合物若しくはその塩、又はそれを用いた蛍光色素 | |
JP5794506B2 (ja) | ホスフィン化合物、その製造方法およびそれを用いた過酸化物捕捉剤 | |
Butler et al. | Utility of tris (4-bromopyridyl) europium complexes as versatile intermediates in the divergent synthesis of emissive chiral probes | |
Makarov et al. | Methylenebisphosphonates with dienone pharmacophore: synthesis, structure, antitumor and fluorescent properties | |
Qi et al. | Synthesis and hydrolysis of 4-chloro-PyMTA and 4-iodo-PyMTA esters and their oxidative degradation with Cu (I/II) and oxygen | |
EP0647223A1 (en) | Ion-sensitive bipyridine complexes | |
CN104903335B (zh) | 用于制造ecl-标记物的新型双-铱-配合物 | |
JP6165065B2 (ja) | 蛍光プローブ | |
EP2683714A1 (en) | Ii (pi)-conjugated fluoroionophores and method for determining an alkali ion | |
Rockstroh et al. | Structural properties of ruthenium biimidazole complexes determining the stability of their supramolecular aggregates | |
Bansal et al. | Substitution of 2‐phosphaindolizines by bromine and by chlorophosphines | |
EP3590919B1 (en) | Enamine compound and use thereof | |
Gamonal et al. | Pd cross-coupling reactions in the access to bis-pyrazole and bis-indazole pyridine-based nona-coordinated ligands. Luminescence properties of their lanthanide complexes | |
RU2620265C1 (ru) | Ди(3-сульфофенилфосфинил)производные 2,2'-бипиридила, 1,10-фенантролина и пиридина и способ их получения | |
EP3992182A1 (en) | Europium(iii) complexes as ph sensors | |
KR101255255B1 (ko) | 로다민 유도체 및 이의 제조방법 | |
JP4903565B2 (ja) | ランタニド錯体、調製及びその使用方法 | |
RU2012574C1 (ru) | 18(15)-краун-6(5)-содержащие стириловые красители в качестве селективных реагентов на катионы аммония, щелочных или щелочноземельных металлов и способ их получения | |
Schoemaker | Dipyrazolylphosphanes in Condensation and P–N/P–P Bond Metathesis Reactions | |
CN115448952A (zh) | 一种具有荧光性质的五配位磷杂环化合物及其合成方法 | |
CN116283737A (zh) | 一种吡啶盐类有机光敏剂及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09718709 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2717943 Country of ref document: CA Ref document number: 2010502833 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12921967 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 09718709 Country of ref document: EP Kind code of ref document: A1 |