WO2020138389A1 - ナノ粒子、これを含む磁気共鳴イメージング用造影剤及び双性イオンリガンド化合物 - Google Patents
ナノ粒子、これを含む磁気共鳴イメージング用造影剤及び双性イオンリガンド化合物 Download PDFInfo
- Publication number
- WO2020138389A1 WO2020138389A1 PCT/JP2019/051354 JP2019051354W WO2020138389A1 WO 2020138389 A1 WO2020138389 A1 WO 2020138389A1 JP 2019051354 W JP2019051354 W JP 2019051354W WO 2020138389 A1 WO2020138389 A1 WO 2020138389A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- group represented
- alkylene
- zwitterionic
- nanoparticles
- Prior art date
Links
- 239000003446 ligand Substances 0.000 title claims abstract description 195
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 176
- 239000002872 contrast media Substances 0.000 title claims abstract description 138
- 238000002595 magnetic resonance imaging Methods 0.000 title claims abstract description 96
- 150000001875 compounds Chemical class 0.000 title claims abstract description 88
- 239000002245 particle Substances 0.000 claims description 159
- 125000000217 alkyl group Chemical group 0.000 claims description 111
- 239000002923 metal particle Substances 0.000 claims description 102
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 101
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 68
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 65
- 239000005977 Ethylene Substances 0.000 claims description 65
- 229910052736 halogen Inorganic materials 0.000 claims description 61
- 150000002367 halogens Chemical class 0.000 claims description 61
- 125000002947 alkylene group Chemical group 0.000 claims description 55
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- -1 3-{[(2,3-dihydroxyphenyl)methyl](dimethyl)azaniumyl}propyl Chemical group 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 229910052727 yttrium Inorganic materials 0.000 claims description 13
- 125000000656 azaniumyl group Chemical group [H][N+]([H])([H])[*] 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- OQLQBCWYAPAPPJ-UHFFFAOYSA-N 4-[(2,3-dihydroxyphenyl)methyl-dimethylazaniumyl]butane-1-sulfonate Chemical compound C[N+](C)(CCCCS(=O)(=O)[O-])CC1=C(C(=CC=C1)O)O OQLQBCWYAPAPPJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- GEKCMNMENXERRQ-UHFFFAOYSA-N 2-[1-[(2,3-dihydroxyphenyl)methyl]-1-methylpiperidin-1-ium-4-yl]acetate Chemical compound C[N+]1(CCC(CC1)CC(=O)[O-])CC2=C(C(=CC=C2)O)O GEKCMNMENXERRQ-UHFFFAOYSA-N 0.000 claims description 4
- UGVPBAWBJYZFSY-UHFFFAOYSA-N 2-[2-(2,3-dihydroxyphenyl)ethyl-dimethylazaniumyl]ethanesulfonate Chemical compound C[N+](C)(CCC1=C(C(=CC=C1)O)O)CCS(=O)(=O)[O-] UGVPBAWBJYZFSY-UHFFFAOYSA-N 0.000 claims description 4
- RVQYXNYIACWAKI-UHFFFAOYSA-N 3-[(6-fluoro-2,3-dihydroxyphenyl)methyl-dimethylazaniumyl]propane-1-sulfonate Chemical compound C[N+](C)(CCCS(=O)(=O)[O-])CC1=C(C=CC(=C1O)O)F RVQYXNYIACWAKI-UHFFFAOYSA-N 0.000 claims description 4
- UCFSCVXLXHEADF-UHFFFAOYSA-N 4-[2-(2,3-dihydroxyphenyl)ethyl-dimethylazaniumyl]butanoate Chemical compound C[N+](C)(CCCC(=O)[O-])CCC1=C(C(=CC=C1)O)O UCFSCVXLXHEADF-UHFFFAOYSA-N 0.000 claims description 4
- NBHIWKPBVZUHGD-UHFFFAOYSA-N 5-[(2,3-dihydroxyphenyl)methyl-dimethylazaniumyl]pentanoate Chemical compound C[N+](C)(CCCCC(=O)[O-])CC1=C(C(=CC=C1)O)O NBHIWKPBVZUHGD-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 4
- WUSKPRXAWPYPGJ-UHFFFAOYSA-N 1-[(2,3-dihydroxyphenyl)methyl]-1-methylpiperidin-1-ium-4-carboxylate Chemical compound C[N+]1(CCC(CC1)C(=O)[O-])CC2=C(C(=CC=C2)O)O WUSKPRXAWPYPGJ-UHFFFAOYSA-N 0.000 claims description 3
- XORWMRLSKMSIEZ-UHFFFAOYSA-N 3-[(2,3-dihydroxyphenyl)-dimethylazaniumyl]propane-1-sulfonate Chemical compound C[N+](C)(CCCS(=O)(=O)[O-])C1=C(C(=CC=C1)O)O XORWMRLSKMSIEZ-UHFFFAOYSA-N 0.000 claims description 3
- IWQQCTHLCJEPOZ-UHFFFAOYSA-O CCC[N+](C)(C)CC(C(F)=CC=C1O)=C1O Chemical compound CCC[N+](C)(C)CC(C(F)=CC=C1O)=C1O IWQQCTHLCJEPOZ-UHFFFAOYSA-O 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 72
- 238000002405 diagnostic procedure Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 240
- 239000000203 mixture Substances 0.000 description 224
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 130
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 238000000034 method Methods 0.000 description 48
- 239000006228 supernatant Substances 0.000 description 46
- 235000013980 iron oxide Nutrition 0.000 description 45
- 239000000706 filtrate Substances 0.000 description 43
- 239000002904 solvent Substances 0.000 description 41
- 230000002829 reductive effect Effects 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
- 239000012528 membrane Substances 0.000 description 36
- 239000012300 argon atmosphere Substances 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 230000005291 magnetic effect Effects 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 29
- 239000012141 concentrate Substances 0.000 description 28
- 238000005259 measurement Methods 0.000 description 28
- 238000001816 cooling Methods 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000002953 phosphate buffered saline Substances 0.000 description 23
- 241000699666 Mus <mouse, genus> Species 0.000 description 21
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 19
- 210000001519 tissue Anatomy 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 238000005406 washing Methods 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 239000002244 precipitate Substances 0.000 description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 229910052751 metal Inorganic materials 0.000 description 15
- 239000002184 metal Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 238000001542 size-exclusion chromatography Methods 0.000 description 15
- 210000003734 kidney Anatomy 0.000 description 14
- 230000002441 reversible effect Effects 0.000 description 13
- 210000002700 urine Anatomy 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 229940071870 hydroiodic acid Drugs 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 239000003444 phase transfer catalyst Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 230000002209 hydrophobic effect Effects 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 238000004904 shortening Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 238000003384 imaging method Methods 0.000 description 9
- 229940031182 nanoparticles iron oxide Drugs 0.000 description 9
- 210000000056 organ Anatomy 0.000 description 9
- FSSPGSAQUIYDCN-UHFFFAOYSA-N 1,3-Propane sultone Chemical compound O=S1(=O)CCCO1 FSSPGSAQUIYDCN-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 8
- 239000011148 porous material Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 7
- DHABKCYCQGCAFC-UHFFFAOYSA-N 1-(2,3-dimethoxyphenyl)-n,n-dimethylmethanamine Chemical compound COC1=CC=CC(CN(C)C)=C1OC DHABKCYCQGCAFC-UHFFFAOYSA-N 0.000 description 7
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 7
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 7
- 239000002616 MRI contrast agent Substances 0.000 description 7
- 239000005642 Oleic acid Substances 0.000 description 7
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 238000005119 centrifugation Methods 0.000 description 7
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 7
- 230000003907 kidney function Effects 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000010908 decantation Methods 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 150000004665 fatty acids Chemical class 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 210000000244 kidney pelvis Anatomy 0.000 description 6
- 230000005415 magnetization Effects 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229910052742 iron Inorganic materials 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000005408 paramagnetism Effects 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 0 **c(c(*)c(*)c(*)c1O)c1O Chemical compound **c(c(*)c(*)c(*)c1O)c1O 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000011261 inert gas Substances 0.000 description 4
- 239000011572 manganese Substances 0.000 description 4
- 239000008055 phosphate buffer solution Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- HNFOAHXBHLWKNF-UHFFFAOYSA-M sodium;2-bromoethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCBr HNFOAHXBHLWKNF-UHFFFAOYSA-M 0.000 description 4
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- HEZIOZBMPKPOER-UHFFFAOYSA-N 2,3-dimethoxyaniline Chemical compound COC1=CC=CC(N)=C1OC HEZIOZBMPKPOER-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000007771 core particle Substances 0.000 description 3
- 239000011258 core-shell material Substances 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 229910052748 manganese Inorganic materials 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 230000005298 paramagnetic effect Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- KCXFHTAICRTXLI-UHFFFAOYSA-M propane-1-sulfonate Chemical compound CCCS([O-])(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-M 0.000 description 3
- 238000000235 small-angle X-ray scattering Methods 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- RCCGNCVZXDJRJB-UHFFFAOYSA-M (2,3-dimethoxyphenyl)methyl-(5-ethoxy-5-oxopentyl)-dimethylazanium bromide Chemical compound CCOC(=O)CCCC[N+](C)(C)CC1=C(C(=CC=C1)OC)OC.[Br-] RCCGNCVZXDJRJB-UHFFFAOYSA-M 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- SZZAVNHXNDZPOZ-UHFFFAOYSA-N 1-(6-fluoro-2,3-dimethoxyphenyl)-N,N-dimethylmethanamine Chemical compound CN(C)CC1=C(C=CC(=C1OC)OC)F SZZAVNHXNDZPOZ-UHFFFAOYSA-N 0.000 description 2
- MJRVJLUCLPUZER-UHFFFAOYSA-N 1-(chloromethyl)-2,3-dimethoxybenzene Chemical compound COC1=CC=CC(CCl)=C1OC MJRVJLUCLPUZER-UHFFFAOYSA-N 0.000 description 2
- CMUIIRZOUBGDFW-UHFFFAOYSA-N 2-(2,3-dimethoxyphenyl)-N,N-dimethylethanamine Chemical compound COC1=CC=CC(CCN(C)C)=C1OC CMUIIRZOUBGDFW-UHFFFAOYSA-N 0.000 description 2
- ICFKLLYHTRLJTK-UHFFFAOYSA-M 2-(2,3-dimethoxyphenyl)ethyl-(4-ethoxy-4-oxobutyl)-dimethylazanium bromide Chemical compound CCOC(=O)CCC[N+](C)(C)CCC1=C(C(=CC=C1)OC)OC.[Br-] ICFKLLYHTRLJTK-UHFFFAOYSA-M 0.000 description 2
- KIWOMLAKIDDXJK-UHFFFAOYSA-N 2-[2-(2,3-dimethoxyphenyl)ethyl-dimethylazaniumyl]ethanesulfonate Chemical compound C[N+](C)(CCC1=C(C(=CC=C1)OC)OC)CCS(=O)(=O)[O-] KIWOMLAKIDDXJK-UHFFFAOYSA-N 0.000 description 2
- YHBWXWLDOKIVCJ-UHFFFAOYSA-N 2-[2-(2-methoxyethoxy)ethoxy]acetic acid Chemical compound COCCOCCOCC(O)=O YHBWXWLDOKIVCJ-UHFFFAOYSA-N 0.000 description 2
- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 description 2
- FDOWHKRSIOYEFS-UHFFFAOYSA-N 3-(2,3-dimethoxyanilino)propane-1-sulfonic acid Chemical compound COC1=CC=CC(=C1OC)NCCCS(=O)(=O)O FDOWHKRSIOYEFS-UHFFFAOYSA-N 0.000 description 2
- YDXAHAXFYDMTFX-UHFFFAOYSA-N 3-(2-fluoro-4,5-dimethoxyanilino)propane-1-sulfonic acid Chemical compound COC1=C(C=C(C(=C1)NCCCS(=O)(=O)O)F)OC YDXAHAXFYDMTFX-UHFFFAOYSA-N 0.000 description 2
- RFDVYQODBPKRPM-UHFFFAOYSA-N 3-(3,4-dimethoxyanilino)propane-1-sulfonic acid Chemical compound COC=1C=C(NCCCS(=O)(=O)O)C=CC=1OC RFDVYQODBPKRPM-UHFFFAOYSA-N 0.000 description 2
- SHOPFQMHMBEWQL-UHFFFAOYSA-N 3-[(2,3-dihydroxyphenyl)methyl-dimethylazaniumyl]propane-1-sulfonate Chemical compound C[N+](C)(CCCS(=O)(=O)[O-])CC1=C(C(=CC=C1)O)O SHOPFQMHMBEWQL-UHFFFAOYSA-N 0.000 description 2
- KTCRMVKRIRQWLC-UHFFFAOYSA-N 3-[(2,3-dihydroxyphenyl)methyl-dimethylazaniumyl]propyl-hydroxyphosphinate Chemical compound C[N+](C)(CCCP(=O)(O)[O-])CC1=C(C(=CC=C1)O)O KTCRMVKRIRQWLC-UHFFFAOYSA-N 0.000 description 2
- JCXPXGGOLWFSQO-UHFFFAOYSA-N 3-[(2,3-dimethoxyphenyl)-dimethylazaniumyl]propane-1-sulfonate Chemical compound C[N+](C)(CCCS(=O)(=O)[O-])C1=C(C(=CC=C1)OC)OC JCXPXGGOLWFSQO-UHFFFAOYSA-N 0.000 description 2
- CJKYYDPRTILGKW-UHFFFAOYSA-N 3-[(2,3-dimethoxyphenyl)methyl-bis(2-methoxyethyl)azaniumyl]propane-1-sulfonate Chemical compound COCC[N+](CCCS(=O)(=O)[O-])(CCOC)CC1=C(C(=CC=C1)OC)OC CJKYYDPRTILGKW-UHFFFAOYSA-N 0.000 description 2
- OCDTXHJCFVPMTB-UHFFFAOYSA-N 3-[(2,3-dimethoxyphenyl)methyl-dimethylazaniumyl]propane-1-sulfonate Chemical compound C[N+](C)(CCCS(=O)(=O)[O-])CC1=C(C(=CC=C1)OC)OC OCDTXHJCFVPMTB-UHFFFAOYSA-N 0.000 description 2
- DAXHHYDBQWXXDU-UHFFFAOYSA-M 3-diethoxyphosphorylpropyl-[(2,3-dimethoxyphenyl)methyl]-dimethylazanium bromide Chemical compound CCOP(=O)(CCC[N+](C)(C)CC1=C(C(=CC=C1)OC)OC)OCC.[Br-] DAXHHYDBQWXXDU-UHFFFAOYSA-M 0.000 description 2
- JFDPBWWOTIFLDQ-UHFFFAOYSA-N 4-[(2,3-dimethoxyphenyl)methyl-dimethylazaniumyl]butane-1-sulfonate Chemical compound C[N+](C)(CCCCS(=O)(=O)[O-])CC1=C(C(=CC=C1)OC)OC JFDPBWWOTIFLDQ-UHFFFAOYSA-N 0.000 description 2
- MDRWFICNTMXXQK-UHFFFAOYSA-N 7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound C1CNCC2=C(OC)C(OC)=CC=C21 MDRWFICNTMXXQK-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- HFYCGMQNGLGSFV-UHFFFAOYSA-N C[N+](C)(CCCC([O-])=O)CC(C=CC=C1O)=C1O Chemical compound C[N+](C)(CCCC([O-])=O)CC(C=CC=C1O)=C1O HFYCGMQNGLGSFV-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000238366 Cephalopoda Species 0.000 description 2
- PEIKTSJIUKYDPC-UHFFFAOYSA-N Diethyl 3-Bromopropylphosphonate Chemical compound CCOP(=O)(OCC)CCCBr PEIKTSJIUKYDPC-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
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 229910001111 Fine metal Inorganic materials 0.000 description 2
- 229910052688 Gadolinium Inorganic materials 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 108010058846 Ovalbumin Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical class [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 229910001566 austenite Inorganic materials 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical group OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000002059 diagnostic imaging Methods 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 2
- AFRWBGJRWRHQOV-UHFFFAOYSA-N ethyl 5-bromopentanoate Chemical compound CCOC(=O)CCCCBr AFRWBGJRWRHQOV-UHFFFAOYSA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 210000003722 extracellular fluid Anatomy 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 239000005090 green fluorescent protein Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 238000000752 ionisation method Methods 0.000 description 2
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 2
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 2
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 2
- 239000013580 millipore water Substances 0.000 description 2
- 229940055577 oleyl alcohol Drugs 0.000 description 2
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 2
- 229940092253 ovalbumin Drugs 0.000 description 2
- MHYFEEDKONKGEB-UHFFFAOYSA-N oxathiane 2,2-dioxide Chemical compound O=S1(=O)CCCCO1 MHYFEEDKONKGEB-UHFFFAOYSA-N 0.000 description 2
- 229960003330 pentetic acid Drugs 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 229910000859 α-Fe Inorganic materials 0.000 description 2
- NQCOWLGNNSUCND-UHFFFAOYSA-M (2,3-dimethoxyphenyl)methyl-(4-ethoxy-4-oxobutyl)-dimethylazanium bromide Chemical compound CCOC(=O)CCC[N+](C)(C)CC1=C(C(=CC=C1)OC)OC.[Br-] NQCOWLGNNSUCND-UHFFFAOYSA-M 0.000 description 1
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 1
- QGLWBTPVKHMVHM-KTKRTIGZSA-N (z)-octadec-9-en-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCN QGLWBTPVKHMVHM-KTKRTIGZSA-N 0.000 description 1
- ROUYUBHVBIKMQO-UHFFFAOYSA-N 1,4-diiodobutane Chemical compound ICCCCI ROUYUBHVBIKMQO-UHFFFAOYSA-N 0.000 description 1
- YYJQOMKHUBZUGS-UHFFFAOYSA-N 1-(4-fluoro-2,3-dimethoxyphenyl)-N,N-dimethylmethanamine Chemical compound CN(C)CC1=C(C(=C(C=C1)F)OC)OC YYJQOMKHUBZUGS-UHFFFAOYSA-N 0.000 description 1
- VGYQDNXZGBAEJT-UHFFFAOYSA-N 1-[(2,3-dihydroxyphenyl)methyl]-1-methylpiperidin-1-ium-4-carboxylic acid iodide Chemical compound C[N+]1(CCC(CC1)C(=O)O)CC2=C(C(=CC=C2)O)O.[I-] VGYQDNXZGBAEJT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KPOYAONPEKOKDZ-UHFFFAOYSA-N 2-[(2,3-dimethoxyphenyl)methyl-dimethylazaniumyl]ethanesulfonate Chemical compound C[N+](C)(CCS(=O)(=O)[O-])CC1=C(C(=CC=C1)OC)OC KPOYAONPEKOKDZ-UHFFFAOYSA-N 0.000 description 1
- LDYNLRCFVQFFNO-UHFFFAOYSA-N 2-fluoro-4,5-dimethoxyaniline Chemical compound COC1=CC(N)=C(F)C=C1OC LDYNLRCFVQFFNO-UHFFFAOYSA-N 0.000 description 1
- IBZKBSXREAQDTO-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)ethanamine Chemical compound COCCNCCOC IBZKBSXREAQDTO-UHFFFAOYSA-N 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- HRMXRAQWOAJLEQ-UHFFFAOYSA-N 3-(2-chloroethoxy)propane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCOCCCl HRMXRAQWOAJLEQ-UHFFFAOYSA-N 0.000 description 1
- PWVNDWKBBLFDOS-UHFFFAOYSA-N 3-(7,8-dihydroxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium-2-yl)propane-1-sulfonate Chemical compound C[N+]1(CCC2=C(C1)C(=C(C=C2)O)O)CCCS(=O)(=O)[O-] PWVNDWKBBLFDOS-UHFFFAOYSA-N 0.000 description 1
- MIBCOPQFLFQDSQ-UHFFFAOYSA-N 3-[(2-fluoro-4,5-dihydroxyphenyl)-dimethylazaniumyl]propane-1-sulfonate Chemical compound C[N+](C)(CCCS(=O)(=O)[O-])C1=CC(=C(C=C1F)O)O MIBCOPQFLFQDSQ-UHFFFAOYSA-N 0.000 description 1
- AIPMICXJBLQOKW-UHFFFAOYSA-N 3-[(3,4-dihydroxyphenyl)methyl-dimethylazaniumyl]propane-1-sulfonate Chemical compound C[N+](C)(CCCS(=O)(=O)[O-])CC1=CC(=C(C=C1)O)O AIPMICXJBLQOKW-UHFFFAOYSA-N 0.000 description 1
- LGNNWDHHTYLYDR-UHFFFAOYSA-N 3-[(6-fluoro-2,3-dimethoxyphenyl)methyl-dimethylazaniumyl]propane-1-sulfonate Chemical compound C[N+](C)(CCCS(=O)(=O)[O-])CC1=C(C=CC(=C1OC)OC)F LGNNWDHHTYLYDR-UHFFFAOYSA-N 0.000 description 1
- QGSXLDIEVCTBRN-UHFFFAOYSA-N 3-[bis(2-methoxyethyl)amino]propane-1-sulfonic acid Chemical compound COCCN(CCCS(=O)(=O)O)CCOC QGSXLDIEVCTBRN-UHFFFAOYSA-N 0.000 description 1
- FDVVPUVANSFCON-UHFFFAOYSA-N 4-(2,3-dimethoxyanilino)butane-1-sulfonic acid Chemical compound COC1=CC=CC(=C1OC)NCCCCS(=O)(=O)O FDVVPUVANSFCON-UHFFFAOYSA-N 0.000 description 1
- WIXUJZCQKBKJKV-UHFFFAOYSA-N 4-fluoro-2,3-dimethoxybenzaldehyde Chemical compound COC1=C(F)C=CC(C=O)=C1OC WIXUJZCQKBKJKV-UHFFFAOYSA-N 0.000 description 1
- UWAUSMGZOHPBJJ-UHFFFAOYSA-N 4-nitro-1,2,3-benzoxadiazole Chemical compound [O-][N+](=O)C1=CC=CC2=C1N=NO2 UWAUSMGZOHPBJJ-UHFFFAOYSA-N 0.000 description 1
- GDOQJEBNBOJBQX-UHFFFAOYSA-N 6-fluoro-2,3-dimethoxybenzaldehyde Chemical compound COC1=CC=C(F)C(C=O)=C1OC GDOQJEBNBOJBQX-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- LMWFHDQOVQGBDF-UHFFFAOYSA-N C[N+](C)(CCCP([O-])(O)=O)C(C=C1)=CC(O)=C1O Chemical compound C[N+](C)(CCCP([O-])(O)=O)C(C=C1)=CC(O)=C1O LMWFHDQOVQGBDF-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 238000000685 Carr-Purcell-Meiboom-Gill pulse sequence Methods 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 229910005335 FePt Inorganic materials 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- RLPQUDARUQHMKV-UHFFFAOYSA-N N-(3-diethoxyphosphorylpropyl)-3,4-dimethoxyaniline Chemical compound CCOP(=O)(CCCNC1=CC(=C(C=C1)OC)OC)OCC RLPQUDARUQHMKV-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-O Pyrrolidinium ion Chemical compound C1CC[NH2+]C1 RWRDLPDLKQPQOW-UHFFFAOYSA-O 0.000 description 1
- 235000017343 Quebracho blanco Nutrition 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000065615 Schinopsis balansae Species 0.000 description 1
- 239000004115 Sodium Silicate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 238000004279 X-ray Guinier Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- FWLORMQUOWCQPO-UHFFFAOYSA-N benzyl-dimethyl-octadecylazanium Chemical class CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 FWLORMQUOWCQPO-UHFFFAOYSA-N 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229940006460 bromide ion Drugs 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- USLKCMBGQFYUFI-UHFFFAOYSA-N dichloromethane;tribromoborane Chemical compound ClCCl.BrB(Br)Br USLKCMBGQFYUFI-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- JNMAXGXLFFHOOT-UHFFFAOYSA-N ethyl 1-[(2,3-dimethoxyphenyl)methyl]-1-methylpiperidin-1-ium-4-carboxylate Chemical compound CCOC(=O)C1CC[N+](CC1)(C)CC2=C(C(=CC=C2)OC)OC JNMAXGXLFFHOOT-UHFFFAOYSA-N 0.000 description 1
- SQPHCWYJULBRHL-UHFFFAOYSA-N ethyl 1-[(2,3-dimethoxyphenyl)methyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)CCN1CC1=CC=CC(OC)=C1OC SQPHCWYJULBRHL-UHFFFAOYSA-N 0.000 description 1
- NHRYNHBYWJPBTL-UHFFFAOYSA-N ethyl 5-(2,3-dimethoxyanilino)pentanoate Chemical compound CCOC(=O)CCCCNC1=C(C(=CC=C1)OC)OC NHRYNHBYWJPBTL-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229910001448 ferrous ion Inorganic materials 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- HOIQWTMREPWSJY-GNOQXXQHSA-K iron(3+);(z)-octadec-9-enoate Chemical compound [Fe+3].CCCCCCCC\C=C/CCCCCCCC([O-])=O.CCCCCCCC\C=C/CCCCCCCC([O-])=O.CCCCCCCC\C=C/CCCCCCCC([O-])=O HOIQWTMREPWSJY-GNOQXXQHSA-K 0.000 description 1
- DEVYBOZJYUYBMC-KVVVOXFISA-N iron;(z)-octadec-9-enoic acid Chemical compound [Fe].CCCCCCCC\C=C/CCCCCCCC(O)=O DEVYBOZJYUYBMC-KVVVOXFISA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000007769 metal material Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- VJUJFZWCODGJNV-UHFFFAOYSA-N methyl 2-[1-[(2,3-dimethoxyphenyl)methyl]-1-methylpiperidin-1-ium-4-yl]acetate Chemical compound C[N+]1(CCC(CC1)CC(=O)OC)CC2=C(C(=CC=C2)OC)OC VJUJFZWCODGJNV-UHFFFAOYSA-N 0.000 description 1
- KSRDBNKFQBGHOI-UHFFFAOYSA-N methyl 2-[1-[(2,3-dimethoxyphenyl)methyl]piperidin-4-yl]acetate Chemical compound COC1=CC=CC(=C1OC)CN2CCC(CC2)CC(=O)OC KSRDBNKFQBGHOI-UHFFFAOYSA-N 0.000 description 1
- ADBDFGZYGJGDNJ-UHFFFAOYSA-N methyl 2-piperidin-4-ylacetate;hydrochloride Chemical compound Cl.COC(=O)CC1CCNCC1 ADBDFGZYGJGDNJ-UHFFFAOYSA-N 0.000 description 1
- ZUZLIXGTXQBUDC-UHFFFAOYSA-N methyltrioctylammonium Chemical class CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC ZUZLIXGTXQBUDC-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- GSJRUEBQWPLHSN-UHFFFAOYSA-N n-methylmethanamine;oxolane Chemical compound CNC.C1CCOC1 GSJRUEBQWPLHSN-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004767 nitrides Chemical class 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 1
- 238000001208 nuclear magnetic resonance pulse sequence Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- ZPIRTVJRHUMMOI-UHFFFAOYSA-N octoxybenzene Chemical compound CCCCCCCCOC1=CC=CC=C1 ZPIRTVJRHUMMOI-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000005496 phosphonium group Chemical group 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 238000000790 scattering method Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 229910052911 sodium silicate Inorganic materials 0.000 description 1
- 235000019794 sodium silicate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- DAKAQNVUSAGTRS-UHFFFAOYSA-M sodium;1-bromoethanesulfonate Chemical compound [Na+].CC(Br)S([O-])(=O)=O DAKAQNVUSAGTRS-UHFFFAOYSA-M 0.000 description 1
- TZLNJNUWVOGZJU-UHFFFAOYSA-M sodium;3-chloro-2-hydroxypropane-1-sulfonate Chemical compound [Na+].ClCC(O)CS([O-])(=O)=O TZLNJNUWVOGZJU-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000005469 synchrotron radiation Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- UQCWXKSHRQJGPH-UHFFFAOYSA-M tetrabutylazanium;fluoride;hydrate Chemical group O.[F-].CCCC[N+](CCCC)(CCCC)CCCC UQCWXKSHRQJGPH-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000007794 visualization technique Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 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
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3882—Arylalkanephosphonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
- A61K49/1842—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule the small organic molecule being a phosphate or a phosphonate, not being a phospholipid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
- A61K49/1836—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule the small organic molecule being a carboxylic acid having less than 8 carbon atoms in the main chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
- C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
- C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/10—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/07—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/07—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton
- C07C309/08—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton containing hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/07—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton
- C07C309/09—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton containing etherified hydroxy groups bound to the carbon skeleton
- C07C309/10—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton containing etherified hydroxy groups bound to the carbon skeleton with the oxygen atom of at least one of the etherified hydroxy groups further bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/69—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a carbon skeleton substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/03—Monocarboxylic acids
- C07C57/12—Straight chain carboxylic acids containing eighteen carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
- C07C69/58—Esters of straight chain acids with eighteen carbon atoms in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/10—Quaternary compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- 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
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- 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
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- C07F9/3817—Acids containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
-
- 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
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
- C07F9/4009—Esters containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- the present invention relates to a novel nanoparticle, a contrast agent for magnetic resonance imaging containing the same, and a zwitterionic ligand compound used for producing the nanoparticle.
- Magnetic resonance imaging plays an important role in clinical diagnostic imaging and is also an important tool in the field of biomedical research.
- the image diagnostic method and the contrast agent used for it are technologies used for examining the organs and tissues of living bodies.
- MRI is a technique for creating an elaborate cross-sectional image and three-dimensional image of tissues and organs in a living body based on the magnetic properties of atoms by using a strong magnetic field and a high frequency radio signal.
- MRI is an effective method for obtaining 2D or 3D images of all tissues and organs containing water.
- the contrast agent for MRI changes by mainly shortening the relaxation time (T 1 , T 2 ) of water in living tissue, and enhances the contrast between different tissues, thereby detecting a lesion site, or Refers to drugs that enable investigation of blood flow in blood vessels or the function of each organ.
- the contrast agent for MRI is desired to have a property that a contrast effect is rapidly obtained after administration, it does not adversely affect the living body, and the whole amount is excreted.
- the contrast agent for MRI can be distributed in blood and extracellular fluid by, for example, intravenous administration.
- the half-life of the contrast medium in blood is preferably excreted in the urine transrenally within 3 hours, more preferably within 2 hours.
- the contrast agent distributed in the extracellular fluid is not itself directly imaged by MRI.
- the contrast agent promotes relaxation of protons in the distributed surrounding tissue. This is mainly called the T 1 shortening effect. Due to this effect, the contrast agent exerts a contrast effect on the T 1 -weighted image (signal is enhanced).
- the contrast agent changes the relaxation time of the tissue it occupies.
- the concentration of the contrast agent becomes higher than a certain concentration, the signal is inversely attenuated due to the T 2 and T 2 * shortening effect. Therefore, the optimum concentration for increasing the signal strength differs depending on the purpose of imaging.
- the magnitude of the shortening effect of T 1 and T 2 relaxation of the magnetic substance, that is, the efficiency of shortening the relaxation time of protons is expressed as a relaxation rate (R).
- the relaxation rate per unit concentration is expressed as relaxivity (r)
- r 1 and the transverse relaxivity is represented by r 2 .
- the R 1 /R 2 ratio and the r 1 /r 2 ratio are used as one of the parameters for evaluating the relaxivity of the contrast agent for MRI.
- T 1 shortened contrast agent the one used for the purpose of enhancing the signal on the T 1 -weighted image by utilizing T 1 relaxation is referred to as a T 1 shortened contrast agent or a positive contrast agent.
- a positive contrast agent causes a signal increase in the tissue occupied by the contrast agent.
- a contrast agent used for the purpose of attenuating a signal on a T 2 -weighted image by utilizing T 2 relaxation is called a T 2 shortened contrast agent or a negative contrast agent.
- a negative contrast agent causes a signal reduction in the tissue occupied by the contrast agent.
- T 1 -weighted MRI and T 2 -weighted MRI are standard imaging methods used in medical diagnosis.
- the positive contrast agent in T 1 -weighted MRI is useful in diagnosis because it does not cause tissue loss due to signal reduction and can improve the contrast of lesions without loss of information of normal tissue, as compared with negative contrast agents. Therefore, the use of a positive contrast agent is indispensable for diagnostic imaging.
- the r 1 /r 2 ratio of the contrast agent is an important value for the evaluation of positive contrast agents, and a high r 1 /r 2 as a positive contrast agent results in a T 1 -weighted MR image with good contrast.
- Gadolinium (Gd)-based chelating compounds can be used as positive contrast agents in the clinic and have excellent T 1 contrast with high r 1 and low r 2 (ie high r 1 /r 2 ).
- Gd-based compounds are known to show serious toxicity to elderly patients and patients with reduced renal excretion such as renal insufficiency.
- Non-Patent Document 1 Iron oxides are much less toxic than Gd. Therefore, research and development of iron oxide nanoparticles are underway as a material replacing Gd, which is currently the mainstream in the market (Non-Patent Document 1).
- Nanoparticles have been researched and developed for use in medical purposes such as diagnostic or therapeutic purposes.
- Nanoparticles in which the surface of a core particle made of a metal material is coated with various molecules such as a polymer are known as one of the constitutions of nanoparticles for application to a living body.
- ESIONs iron oxide particles
- PO-PEG polyethylene glycol phosphate
- Non-patent document 3 and Patents. Reference 1 nanoparticles having a structure in which iron oxide nanoparticles are used as core particles and zwitterionic dopamine sulfonate (ZDS) is bonded to the surface of the iron oxide nanoparticles have been reported (Non-patent document 3 and Patents. Reference 1).
- ZDS-SPIONs zwitterionic dopamine sulfonate
- the present invention includes any one of the following aspects. Unless otherwise specified, when a symbol in one chemical formula in this specification is used in another chemical formula, the same symbol has the same meaning. ⁇ 1> Nanoparticles comprising iron oxide-containing metal particles to which one or more zwitterionic ligands of formula (I) are coordinate bonded.
- R 1 and R 2 are a group represented by formula (a) or formula (b), and the other is H, lower alkyl, —O-lower alkyl or halogen, X 1 is a bond or methylene, and when R 1 is a group represented by the formula (a), X 1 may be ethylene, X 2 is C 1-5 alkylene which may be substituted with OH, or —C 1-2 alkylene-O—C 1-3 alkylene-, and R 1 is a group represented by the formula (b).
- X 2 may be a bond
- R a and R b are the same or different and are C 1-3 alkyl, —C 1-3 alkylene-O—C 1-2 alkyl, or R a and R b are attached to each other.
- Y ⁇ is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇
- R 3 and R 4 which may be the same or different from each other, are H, C 1-3 alkyl, —O—C 1-3 alkyl or halogen
- n is an integer of 0 to 2
- R 1 is a group represented by the formula (a) and X 1 is methylene
- R 2 and R a or R b may combine to form ethylene
- R 1 is a group represented by the formula (a) and X 1 is ethylene
- R 2 and R a or R b may together form methylene
- R 2 is a group represented by the formula (a) and X 1 is methylene
- R 3 and R a or R b may together form ethylene.
- R 2 is a group represented by the formula (a), R a and R b are methyl, X 1 is a bond, X 2 is C 1-4 alkylene, and R 1 is When R 3 and R 4 are both H, Y ⁇ is HPO 3 ⁇ or CO 2 ⁇ . ) ⁇ 2> A compound represented by the following formula (I) or a salt thereof.
- R 1 and R 2 are a group represented by the following formula (a) or formula (b), and the other is H, lower alkyl, —O-lower alkyl or halogen, X 1 is a bond or methylene, and when R 1 is a group represented by the formula (a), X 1 may be ethylene, X 2 is C 1-5 alkylene which may be substituted with OH, or —C 1-2 alkylene-O—C 1-3 alkylene-, and R 1 is a group represented by the formula (b).
- X 2 may be a bond
- R a and R b are the same or different and are C 1-3 alkyl, —C 1-3 alkylene-O—C 1-2 alkyl, or R a and R b are attached to each other.
- Y ⁇ is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇
- R 3 and R 4 are the same or different from each other and are H, C 1-3 alkyl, —O—C 1-3 alkyl or halogen
- n is an integer of 0 to 2
- R 1 is a group represented by the formula (a) and X 1 is methylene
- R 2 and R a or R b may combine to form ethylene
- R 1 is a group represented by the formula (a) and X 1 is ethylene
- R 2 and R a or R b may together form methylene
- R 2 is a group represented by the formula (a) and X 1 is methylene
- R 3 and R a or R b may together form ethylene.
- R 2 is a group represented by the formula (a), R a and R b are methyl, X 1 is a bond, X 2 is C 1-4 alkylene, and R 1 is When R 3 and R 4 are both H, Y ⁇ is HPO 3 ⁇ or CO 2 ⁇ . )
- the present invention is expected to exert an effect of providing a novel nanoparticle having good positive contrast ability and showing no cytotoxicity, and a contrast agent for magnetic resonance imaging containing the same.
- (A) is before administration (pre), immediately after administration (post) in the liver of the mouse to which the contrast agent containing the purified 3K particles of Example 6 was administered, 0.5 hours after administration (0.5 hours), 1 hour ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (B) is before administration (pre), immediately after administration (post) in the kidney of the mouse administered with the contrast agent containing the purified 3K particles of Example 6, 0.5 hour (0.5 hour) after administration, and 1 hour ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (C) is before administration (pre), immediately after administration (post) in the bladder of mice to which the contrast agent containing the 3K purified particles of Example 6 was administered, 0.5 hours (0.5 hours), 1 hour after administration ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (A) shows before administration (pre), immediately after administration (post), 0.5 hour (0.5 hour) and 1 hour after administration in the liver of the mouse to which the contrast medium containing the 10K purified particles of Example 6 was administered. The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (B) is before administration (pre), immediately after administration (post) in the kidney of the mouse to which the contrast agent containing the 10K purified particles of Example 6 was administered, 0.5 hour (0.5 hour) after administration, 1 hour ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (C) is before administration (pre), immediately after administration (post) in the bladder of the mouse to which the contrast agent containing the 10K purified particles of Example 6 was administered, 0.5 hours (0.5 hours), 1 hour after administration ( The image of the time-dependent MRI measurement result of 1 hour) and 1.5 hours (1.5 hours) is shown.
- (A) is before administration (pre), immediately after administration (post) in the liver of the mouse administered with the contrast agent containing the purified 3K particles of Example 7, 0.5 hour (0.5 hour) after administration, 1 hour ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (B) is before administration (pre), immediately after administration (post) in the kidney of the mouse administered with the contrast agent containing the 3K purified particles of Example 7, 0.5 hours (0.5 hours) after administration, and 1 hour ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (C) is before administration (pre), immediately after administration (post) in the bladder of the mouse to which the contrast agent containing the purified 3K particles of Example 7 was administered, 0.5 hour (0.5 hour), 1 hour after administration ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (A) is before administration (pre), immediately after administration (post) in the liver of the mouse administered with the contrast agent containing the 10K purified particles of Example 7, 0.5 hours (0.5 hours), 1 hour after administration ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (B) is before administration (pre), immediately after administration (post), 0.5 hour (0.5 hour) after administration, and 1 hour after administration in the kidney of the mouse to which the contrast agent containing the 10K purified particles of Example 7 was administered.
- the images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (C) is before administration (pre), immediately after administration (post) in the bladder of the mouse to which the contrast agent containing the 10K purified particles of Example 7 was administered, 0.5 hour (0.5 hour) after administration, 1 hour ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (A) is before administration (pre), immediately after administration (post) in the liver of the mouse administered with the contrast agent containing the purified 3K particles of Example 25, 0.5 hour (0.5 hour) after administration, 1 hour ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (B) is before administration (pre), immediately after administration (post) in the kidney of the mouse administered with the contrast agent containing the purified 3K particles of Example 25, 0.5 hours after administration (0.5 hours), 1 hour ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (C) is before administration (pre), immediately after administration (post) in the bladder of mice to which the contrast agent containing the 3K purified particles of Example 25 was administered, 0.5 hours (0.5 hours), 1 hour after administration ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (A) is before administration (pre), immediately after administration (post) in the liver of the mouse administered with the contrast medium containing the purified 10K particles of Example 25, 0.5 hour (0.5 hour) after administration, 1 hour ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (B) is before administration (pre), immediately after administration (post) in the kidney of the mouse administered with the contrast agent containing the 10K purified particles of Example 25, 0.5 hours (0.5 hours), 1 hour after administration ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- (C) is before administration (pre), immediately after administration (post) in the bladder of mice to which the contrast agent containing the 10K purified particles of Example 25 was administered, 0.5 hours (0.5 hours), 1 hour after administration ( The images of the T 1 -weighted MRI measurement results for 1 hour) and 1.5 hours (1.5 hours) are shown.
- the magnetic field dependence of the magnetization of the 3K purified particles of Examples 6, 7 and 9 at 300K is shown. It is the graph which plotted the applied magnetic field on the horizontal axis and the magnetization per weight on the vertical axis.
- the “lower alkyl” is a straight-chain or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. In another embodiment, it is C 1-4 alkyl, in yet another embodiment, C 1-3 alkyl, in yet another embodiment, methyl, ethyl, n-propyl, and yet another. An embodiment is methyl. Moreover, one embodiment of “C 1-3 alkyl” is methyl, ethyl or n-propyl, and one embodiment is methyl.
- C 1-5 alkylene is a linear or branched C 1-5 alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, propylene, butylene, methylmethylene, ethylethylene, 1,1- Examples include dimethylethylene, 2,2-dimethylethylene, 1,2-dimethylethylene, 1-methylbutylene and the like. In one embodiment, it is C 1-3 alkylene, in another embodiment it is C 1-2 alkylene, and in yet another embodiment, methylene, ethylene, trimethylene, propylene or butylene. In addition, “C 1-5 alkylene” and “C 1-4 alkylene” are, among the above, C 1-3 or C 1-2 alkylene, respectively, and in one embodiment, methylene or ethylene.
- the “5- or 6-membered nitrogen-containing saturated heterocycle” formed by R a and R b integrally with the quaternary nitrogen atom to which they are bonded means that the quaternary nitrogen atom is contained as a ring-constituting atom and has 5 ring members. Or a non-aromatic heterocycle of 6, that is, a pyrrolidine ring or a piperidine ring.
- Halogen means F, Cl, Br, and I. Another embodiment is F and Cl, yet another embodiment is F, and yet another embodiment is Cl.
- nanoparticle means a particle having a particle size of nanometer scale or less.
- the details of the particle size will be described in the following item of particle size.
- cluster refers to an aggregate in which a plurality of identical or different particles are aggregated into a single mass. In one embodiment, it refers to an assembly of zwitterionic ligands and fine metal particles having a zwitterionic ligand coordinate-bonded thereto.
- the “zwitterionic ligand” or “zwitterionic ligand compound” is a compound having a group having both a positive charge and a negative charge in the molecule, and a group capable of forming a coordinate bond with a metal atom on the surface of a metal particle. Means a compound used as a modifier of the particle surface for stably dispersing metal particles in water.
- the term “zwitterionic ligand” or “zwitterionic ligand compound” is used when the compound is a compound before being coordinate-bonded to the surface of metal particles or after the compound is coordinate-bonded. It means either or both of those having a molecular structure.
- Subject refers to any organism to which the contrast agent for MRI of the present invention, nanoparticles or compositions containing nanoparticles can be administered, eg, for experimental, diagnostic, and/or therapeutic purposes.
- One example is humans.
- the nanoparticles according to the present invention are nanoparticles containing metal particles containing iron oxide in which one or more zwitterionic ligands represented by the formula (I) are coordinate-bonded. Embodiments of the zwitterionic ligand having a coordinate bond will be described in the following sections.
- the nanoparticles according to the present invention are particles formed by coordinatively bonding one or more zwitterionic ligand compounds to the outer surface of iron oxide-containing metal particles. A particle in which the metal particle is covered with a compound.
- the nanoparticles according to the present invention have a metal particle in the center thereof, and one or more zwitterionic ligand compounds are coordinate-bonded to the outer surface of the metal particle.
- the zwitterionic ligand compound has a core-shell structure in which the metal particles are coated with the zwitterionic ligand compound.
- the nanoparticles of the present invention comprise one or more "metal particles containing iron oxide coordinated with one or more zwitterionic ligands" and one or more zwitterionic ligand compounds. Is a complex, which is a particle.
- the nanoparticles according to the present invention comprise two or more zwitterionic ligand compounds and two or more “metal particles containing iron oxide coordinate-bonded with one or more zwitterionic ligand compounds”. Particles that are clusters. In one embodiment, the nanoparticles according to the present invention include two or more zwitterionic ligand compounds and two or more “metal particles containing iron oxide coordinate-bonded with one or more zwitterionic ligand compounds”. Are particles that are irregularly bound clusters.
- the nanoparticles having the zwitterionic ligand compound of the present invention coordinate-bonded prevent the nanoparticles from aggregating, and have stable particle properties even in a solution containing nanoparticles at a high concentration, for example.
- Such nanoparticles can secure a low saturation magnetization, obtain a T 1 -weighted image with clear contrast, and facilitate renal excretion, and thus can be expected to exhibit good renal clearance.
- the metal particles contain iron oxide.
- the metal particles are iron oxide particles containing only iron oxide, and in another example, the metal particles are metal particles containing iron in addition to iron oxide.
- metal particles means “iron oxide nanoparticles” in “iron oxide nanoparticles in which a hydrophobic ligand is coordinate-bonded to the surface" which is a raw material, and the zwitterionic ligand of the present invention is used as metal particles.
- iron oxide-containing metal particles in which some change occurs from the iron oxide nanoparticles as a raw material are included.
- the some change includes, but is not limited to, a structural change from a core-shell structure to a complex or a cluster, a change in particle size, a change in composition, and the like.
- the “metal particles” in the present specification include at least the MEAA method, which is a manufacturing method for coordinating the zwitterionic ligand represented by the formula (I) described herein, with the metal particles, and TMA(OH) described later. ) Method or a phase transfer catalysis method, and all metal particles containing iron oxide are included.
- the metal particles containing iron oxide may further contain at least one kind of metal derivative other than iron oxide. Further, the metal particles may further contain at least one kind of metal element other than iron (Fe). As another metal element, at least one selected from the group consisting of gadolinium (Gd), manganese (Mn), cobalt (Co), nickel (Ni), and zinc (Zn) is optionally used. It can further be included.
- Gd gadolinium
- Mn manganese
- Co cobalt
- Ni nickel
- Zn zinc
- the metal particles may consist solely of iron oxide, or may include ferrite derived from iron oxide.
- Ferrite is an oxide of the formula MFe 2 O 4 , where M is a transition metal preferably selected from Zn, Co, Mn and Ni.
- M may be, for example, Fe, Mn, Ni, Co, Zn, magnesium (Mg), copper (Cu), or a combination thereof.
- the material is magnetite (Fe 3 O 4 )
- the iron oxide is magnetic iron oxide and can be magnetite (Fe 3 O 4 ), maghemite ( ⁇ -Fe 2 O 3 ), or a mixture thereof.
- Such metal particles made of magnetic iron oxide become superparamagnetic nanoparticles.
- each derivative of the metal element may be a different kind of derivative. That is, the iron oxide particles may include oxides and nitrides.
- the core particles may include an iron derivative other than iron oxide (eg, FePt and FeB) having an iron element other than iron oxide.
- the metal particles according to one embodiment may be those produced by a known method such as the method described in the above-mentioned Patent Document 1, Non-Patent Document 2, Non-Patent Document 3 or the like, and are commercially available. It may be. For example, it may be iron oxide particles produced by a coprecipitation method or a reduction method.
- particle size of metal particles refers to the average particle size unless otherwise specified.
- the “particle diameter” of a metal particle is intended to mean, for example, the diameter of the maximum inscribed circle with respect to the two-dimensional shape of the particle when the particle is observed with a transmission electron microscope (TEM).
- TEM transmission electron microscope
- the two-dimensional shape of a particle is substantially circular, the diameter of that circle is intended.
- the shape is substantially elliptical, the minor axis of the ellipse is intended.
- the shape is substantially square, the length of the side of the square is intended, and when the shape is substantially rectangular, the length of the short side of the rectangle is intended.
- the average particle diameter has a value in a predetermined range
- 100 particles are observed with a transmission electron microscope (TEM), and the particle diameter of each particle is measured to obtain 100 particles.
- the average particle size of the particles can be determined.
- the particle size of the metal particles is preferably 5 nm or less, and preferably 4 nm or less when measured by TEM. Is more preferable, 3 nm or less is more preferable, 2 nm or less is further preferable, and 1 nm or less is most preferable.
- a particle diameter of 2 nm or less is more useful as a positive contrast agent for high magnetic field MRI of 3 Tesla (T) or more.
- the particle size is 2 nm or less, preferably 1 nm or less, a higher signal-to-noise ratio can be obtained in use in a high magnetic field MRI of 7 T or more, so that higher spatial resolution and shorter time measurement can be realized. There is a nature.
- the population of nanoparticles included in the MRI contrast agent is as uniform as possible in the characteristics of each nanoparticle. Therefore, it is preferable that the metal particles that are the cores of the nanoparticles have a uniform size and shape. As an example, the metal particles have uniformity within the range of their average particle diameter ⁇ 1 nm. As another example, the average particle size has a uniformity within a range of ⁇ 0.5 nm.
- the nanoparticles contained in the contrast agent for MRI contain a large number of small particles as contained metal particles.
- the number of metal particles having a size of 3 nm or more is 30% or less of the total, preferably 10% or less of the total, and more preferably 5% or less of the total.
- the number ratio of particles having a size of 2 nm or more is 30% or less of the total, preferably 10% or less of the total, and more preferably 5% or less of the total.
- the number ratio of particles having a size of 1 nm or more is 30% or less of the whole, or preferably 10% or less of the whole, and more preferably 5% or less of the whole.
- the population of nanoparticles included in the contrast agent for MRI may have non-uniform properties of each particle, so that the metal particles coordinated with a zwitterionic ligand are non-uniform. It may have a uniform size and shape. As an example, the metal particles may include particles different in size by 1 nm or more from the average particle diameter.
- the particle size of the nanoparticles will be increased by the thickness of the zwitterionic ligand coordinate-bonded to the surface of the metal particles.
- a hydrodynamic diameter (HD) when nanoparticles are used as a solution is used as an index of the size.
- the average HD of the nanoparticles is 10 nm or less, preferably 8 nm or less.
- the average HD of the nanoparticles is 5 nm or less, preferably 4 nm or less, preferably 3 nm or less, preferably 2 nm or less, more preferably 1 nm or less.
- the HD of the nanoparticles can be performed, for example, by observing the particles by an X-ray small angle scattering method (SAXS) and determining the average value of the particle diameters.
- SAXS X-ray small angle scattering method
- a commercially available instrument may be used for measuring SAXS, and it is desirable to use a synchrotron radiation facility such as SPring-8 (BL19B2) or Aichi Synchrotron Light Center.
- SPring-8 BL19B2
- the camera length is set to 3 m
- the sample is irradiated with X-ray of 18 KeV
- the wave number q is observed in the range of about 0.06 to 3 nm -1 .
- a dispersion sample put it in a capillary with a diameter of 2 mm, set the exposure time appropriately so that the scattered radiation is not saturated, and obtain the scattering data.
- the scattering data can be subjected to Guinier analysis or fitting using an appropriate SAXS analysis software to obtain an average particle size.
- SEC size exclusion chromatography
- SEC is an analytical method in which a sample is made to flow through a column packed with a carrier having pores and the size of the sample is estimated by the time until it flows out. Large agglomerates flow out early because they do not enter the pores of the carrier, and small nanoparticles pass through the pores of the carrier, so the route to the outflow is long and flows out slowly. The relative size of the particles can be measured.
- the zwitterionic ligand compound according to the present invention is a compound represented by the following formula (I) or a salt thereof.
- R 1 and R 2 are a group represented by formula (a) or formula (b), and the other is H, lower alkyl, —O-lower alkyl or halogen, X 1 is a bond or methylene, and when R 1 is a group represented by the formula (a), X 1 may be ethylene, X 2 is C 1-5 alkylene which may be substituted with OH, or —C 1-2 alkylene-O—C 1-3 alkylene-, and R 1 is a group represented by the formula (b).
- X 2 may be a bond
- R a and R b are the same or different and are C 1-3 alkyl, —C 1-3 alkylene-O—C 1-2 alkyl, or R a and R b are attached to each other.
- Y ⁇ is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇
- R 3 and R 4 are the same or different from each other and are H, C 1-3 alkyl, —O—C 1-3 alkyl or halogen
- n is an integer of 0 to 2
- R 1 is a group represented by the formula (a) and X 1 is methylene
- R 2 and R a or R b may combine to form ethylene
- R 1 is a group represented by the formula (a) and X 1 is ethylene
- R 2 and R a or R b may together form methylene
- R 2 is a group represented by the formula (a) and X 1 is methylene
- R 3 and R a or R b may together form ethylene.
- R 2 is a group represented by the formula (a), R a and R b are methyl, X 1 is a bond, X 2 is C 1-4 alkylene, and R 1 is When R 3 and R 4 are both H, Y ⁇ is HPO 3 ⁇ or CO 2 ⁇ . )
- a zwitterionic ligand in which one of R 1 and R 2 is a group represented by formula (a) and the other is H, lower alkyl, —O-lower alkyl or halogen.
- the zwitterionic ligand compound according to the present invention is a compound represented by the following formula (o).
- One embodiment of the compounds of formula (o) is a zwitterionic ligand wherein R 2 is H, lower alkyl, —O-lower alkyl or halogen, and in another embodiment R 2 is is H or halogen, X 1 is a bond, or a methylene or ethylene, or when X 1 is methylene, R 2 and the R a or R b may form a ethylene together, X 2 Is a C 2-4 alkylene, R a and R b are both methyl, and R 3 and R 4 are the same or different from each other and are H, C 1-3 alkyl or halogen, a zwitterion.
- R 2 is H or halogen
- X 1 is a bond or methylene, or when X 1 is methylene, R 2 and R a or R b are integrated.
- X 2 is C 2-4 alkylene
- R a and R b are both methyl
- R 3 and R 4 are the same or different from each other
- H A zwitterionic ligand which is C 1-3 alkyl or halogen
- R 2 is H or F
- X 1 is a bond, methylene or ethylene
- X 2 is ethylene or A zwitterionic ligand which is propylene
- R a and R b are both methyl
- R 3 and R 4 are both H
- R 2 is H.
- a zwitterionic ligand wherein X 1 is ethylene, X 2 is ethylene or propylene, R a and R b are both methyl, and R 3 and R 4 are both H.
- R 2 is H or F
- X 1 is a bond or ethylene
- X 2 is an ethylene group or a propylene group
- R a and R b are both methyl
- a zwitterionic ligand in which R 3 and R 4 are both H and Y ⁇ is SO 3 ⁇ or CO 2 ⁇
- R 2 is H or F
- X 1 is methylene
- X 2 is a propylene group or a butylene group
- R a and R b are both methyl
- R 3 and R 4 are both H
- Y ⁇ is A zwitterionic ligand which is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇
- R 2 is H or F and X 1 is
- X 2 is a propylene group or a butylene group
- R a and R b are both methyl
- R 3 and R 4 are both H
- Y ⁇ is SO 3 ⁇ .
- It is a zwitterionic ligand.
- One embodiment is a zwitterionic ligand represented by the following formula (1).
- Another embodiment is a zwitterionic ligand represented by the following formula (2). (The symbol Y ⁇ in the formula is the same as in the formula (I).)
- Another embodiment is a zwitterionic ligand represented by the following formula (3). (The symbol Y ⁇ in the formula is the same as in the formula (I).)
- Another embodiment is a zwitterionic ligand represented by the following formula (4). (The symbol Y ⁇ in the formula is the same as in the formula (I).)
- Another embodiment is a zwitterionic ligand represented by the following formula (5). (The symbol Y ⁇ in the formula is the same as in the formula (I).)
- the zwitterionic ligand compound according to the present invention is a compound represented by the following formula (6).
- One embodiment is a zwitterionic ligand represented by the following formula (7).
- one of R 1 and R 2 in the above formula (I) is a group represented by the following formula (b-1), and the other is H, lower alkyl, Zwitterionic ligands that are O-lower alkyl or halogen. (The symbols in the formula are the same as in formula (I) above.)
- the zwitterionic ligand compound according to the present invention is a compound represented by the following formula (8).
- One embodiment of the compound of formula (8) is a zwitterionic ligand wherein R 2 is H, lower alkyl, —O-lower alkyl or halogen, and in another embodiment R 2 is H Or halogen, X 1 is a bond or methylene, X 2 is a bond or C 1-3 alkylene, R a is methyl, and R 3 and R 4 are the same or different from each other, H, A zwitterionic ligand which is C 1-3 alkyl or halogen, and in yet another embodiment, R 2 is H or F, X 1 is methylene, X 2 is a bond or methylene, A zwitterionic ligand in which R a is methyl, R 3 and R 4 are both H, and Y ⁇ is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇ , and In another aspect, R 2 is H or F, X 1 is methylene
- a zwitterionic ligand wherein Y ⁇ is CO 2 — , and in yet another embodiment, R 2 is H or halogen, X 1 is a bond or methylene, and X 2 is C 1-5 alkylene or a bond, R a is methyl, and R 3 and R 4 are the same or different from each other, and are H, C 1-3 alkyl, or halogen, and Y ⁇ Is SO 3 ⁇ or CO 2 ⁇ , which is a zwitterionic ligand.
- Another embodiment is a zwitterionic ligand represented by the following formula (9). (The symbols in the formula, Y ⁇ are the same as those in the formula (I).)
- Another embodiment is a zwitterionic ligand represented by the following formula (10). (The symbols in the formula, Y ⁇ are the same as those in the formula (I).)
- the nanoparticles according to the present invention are nanoparticles containing iron oxide-containing metal particles in which one or more zwitterionic ligands represented by the above formula (I) are coordinate-bonded, and the above [2.
- the zwitterionic ligand compound according to each of the embodiments described in (1) to (3) is a coordination-bonded nanoparticle containing iron oxide-containing metal particles. is there.
- the oxygen atoms of the two hydroxyl groups of the zwitterionic ligand compound and the metal atoms on the surface of the metal particles are coordinate-bonded to each other. To form nanoparticles.
- the present invention also includes the use of the zwitterionic ligand compound and the zwitterionic ligand compound itself for producing the nanoparticles of the present invention.
- Each embodiment described in [Zwitterionic ligand compound] is also an embodiment of the zwitterionic ligand compound in these inventions.
- a trisubstituted amino group is substituted with catechol directly or via an alkylene group to form an ammonium cation.
- the zwitterionic ligand of the present invention has a shorter molecular chain and a thinner ligand layer than conventionally known ligands. Further, it is characterized by having a positive charge on the metal particle side and a negative charge on the outer surface side, whereby the nanoparticles of the present invention are expected to exhibit high stability as particles are less likely to aggregate in body fluids. To be done.
- the ligand layer is thin, the distance from the metal atoms becomes short, and it is expected that the excellent contrasting ability due to the increase in the number of water molecules affected by the metal particles will be exhibited.
- the number of zwitterionic ligand molecules (number of zwitterionic ligands) coordinated to the surface of the metal particles changes according to the size and surface area of the metal particles. In one embodiment, the number is 2 to 200 per metal particle, in another embodiment it is 5 to 50, and in yet another embodiment it is 5 to 20.
- the nanoparticles of the present invention may include other than the zwitterionic ligand of the present invention, and in one embodiment, the nanoparticles may be those in which the metal particles themselves have fluorescent properties or fluorescent molecules bound to the surface of the metal particles. Alternatively, it may further contain a molecule such as a dye molecule.
- the nanoparticles can be used not only as a contrast agent for MRI, but also as an optical image contrast agent at the same time, because the metal particles themselves have fluorescent properties or by introducing fluorescent molecules or dye molecules into the nanoparticles. it can.
- the fluorescent or dye molecule may be a ligand covalently bound to the zwitterionic ligand of the invention, the molecule being linked to the iron oxide particle via the zwitterionic ligand. ..
- the fluorescent molecules are present on the surface of the iron oxide particles and can be used for microscopic imaging as well as for examining the localization of the nanoparticles.
- fluorescent molecules and dye molecules include rhodamine, fluorescein, nitrobenzooxadiazole (NBD), cyanine, green fluorescent protein (GFP), coumarin and derivatives thereof.
- it may have at least one substance bound to the surface of the metal particles and may be, without limitation, a peptide, nucleic acid or small molecule.
- a substance bound to the surface of the metal particles may be, without limitation, a peptide, nucleic acid or small molecule.
- a ligand other than the zwitterionic ligand of the present invention may be bound to the surface of the metal particles.
- a ligand having a property of specifically accumulating to a tumor to the metal particles of the present invention, it is possible to impart a tumor-selective binding property.
- contrast agent Granting such tissue specificity to the contrast agent is preferable in order to strengthen the signal at the target site of MRI measurement and to obtain information such as specific pathological conditions.
- the distribution of contrast agents in vivo depends on particle size, charge, surface chemistry, route of administration and route of elimination.
- the nanoparticles of the present invention contain iron oxide as metal particles, they are expected to have low toxicity to living bodies. Therefore, it is expected that it is excellent in safety and has few restrictions on various uses.
- the method for producing the zwitterionic ligand of the formula (I) of the present invention is not particularly limited, and it can be easily produced from a known starting compound using a reaction well known to those skilled in the art. For example, the method described in Wei H. et al., Nano Lett. 12, 22-25, 2012 can be referred to.
- the synthesis method described in the production example is preferably used.
- the metal particles having a hydrophobic or hydrophilic ligand coordinated as a raw material for producing nanoparticles can be produced by a known method. For example, the method described in Byung Hyo Kim et al., J Am. Chem. Soc. 2011, 133, 12624-12631, and Byung Hyo Kim et al., J Am. Chem. Soc. 2013, 135, 2407-2410. Can be done with reference.
- a metal salt is reacted with an alkali metal salt of a fatty acid to form a metal fatty acid complex, and (b) the complex is rapidly heated with a surfactant to a high temperature of 200° C. or higher, and if desired, By reacting at high temperature for a certain period of time, metal particles whose surface is coated with a hydrophobic ligand can be synthesized. Furthermore, (c) metal particles coated with a hydrophobic ligand are coated with [2-(2-Methoxyethoxy)ethoxy]acetic acid (MEAA). It is possible to obtain a metal particle coated with MEAA, which is capable of being converted into a ligand and transformed into a highly polar solvent.
- MEAA [2-(2-Methoxyethoxy)ethoxy]acetic acid
- a metal salt and an alkali metal salt of a fatty acid are dispersed in a solvent.
- the above metal salts iron (III) chloride hexahydrate (FeCl 3 ⁇ 6H 2 O).
- the alkali metal salts of fatty acids sodium oleate, as the solvent ethanol, water, hexane, And mixtures thereof.
- the mixture is stirred under heating, preferably at 70° C., for 1 to 10 hours, preferably 3 to 4 hours, the organic layer is recovered, and the organic layer is washed with water once to plural times, more preferably 3 times. Repeat ⁇ 4 times to obtain metal fatty acid complex.
- the organic layer obtained is dried if desired.
- At least one surface active agent selected from the group consisting of fatty acids, aliphatic alcohols and aliphatic amines is added to the complex obtained in step (a) under an inert gas atmosphere selected from, for example, argon (Ar) and nitrogen.
- the agent and a solvent selected from diphenyl ether and phenyl octyl ether are added.
- the surfactant is oleic acid, oleyl alcohol, oleyl amine or a mixture thereof, and the solvent is diphenyl ether.
- the mixture is then rapidly warmed from room temperature to 180-300° C. and if desired stirred for 10 minutes to several hours. As an example, the temperature is raised from 30° C.
- the temperature is raised from 30° C. to 200° C. at 10° C./min and stirred at 200° C. for 30 minutes.
- the reaction is carried out by stirring at room temperature or under heating, preferably at 25 to 80° C. for about 1 to 15 hours, preferably 5 to 10 hours, for example, stirring at 50° C. for 7 hours. As another example, it is performed by stirring at 70° C. for 10 hours, and as still another example, by stirring at 70° C. for 5 hours.
- reaction solution After cooling the temperature of the reaction solution to room temperature, add a solvent selected from acetone and hexane, centrifuge and remove the supernatant. This operation may be repeated 2 to 3 times, preferably 4 to 5 times. The resulting solution may be dried. As an example, the above operation is repeated three times to obtain metal particles whose surfaces are coated with MEAA.
- the “nanoparticles containing metal particles containing iron oxide in which one or more zwitterionic ligands are coordinate-bonded” of the present invention is a method (MEAA method) via a known metal particle whose surface is coated with MEAA. It can be produced by using a method using TMA(OH) (TMA(OH) method) or a novel synthetic method using a phase transfer catalyst.
- TMA(OH) TMA(OH) method
- A) MEAA Method This production method is a method of obtaining the nanoparticles of the present invention by reacting the metal particles whose surfaces are coated with MEAA with the zwitterionic ligand compound of the present invention.
- the metal particles whose surface is coated with MEAA and the zwitterionic ligand compound of the present invention are heated at room temperature or under heating for 1 to several tens hours in an inert gas atmosphere selected from Ar and nitrogen. It is performed by stirring. As an example, it is performed in an Ar atmosphere.
- the reaction temperature is 25 to 80° C. as an example, and 50 to 70° C. as another example.
- the stirring time is, for example, 5 to 7 hours, and another example is 24 hours. As an example, stir overnight at room temperature.
- the temperature of the reaction solution is lowered to room temperature, a solvent is added and the mixture is centrifuged, and the supernatant is removed to obtain nanoparticles in which one or more zwitterionic ligand compounds of the present invention are coordinate-bonded.
- the solvent is not particularly limited, but is selected from acetone, hexane and the like. Acetone is used as an example.
- the operations of solvent addition, centrifugation, and supernatant removal may be repeated a plurality of times, for example, 4 to 5 times. As an example, this operation is repeated 3 times.
- the resulting solution containing nanoparticles coated with the zwitterionic ligand compound of the present invention may be concentrated using a concentration column such as a centrifugal ultrafiltration filter. This concentration operation may be repeated a plurality of times, and the concentration operation may be repeated by adding a solution such as PBS in the middle.
- TMA(OH) Method Iron oxide particles coated with oleic acid (SNP-OA) were suspended in a hexane solution and mixed with a 1.7% tetramethylammonium hydroxide (TMA(OH)) aqueous solution. Shake vigorously. The aqueous layer is separated from the obtained solution by centrifugation, acetone is added, and the mixture is centrifuged at 8000 to 12000 rpm for 5 to 10 minutes to remove the supernatant. 2 mL of a 0.1% TMA(OH) solution is added to the obtained precipitate to disperse it, and 10 mL of acetone is added again to cause precipitation. This operation may be repeated plural times, preferably 3 to 4 times.
- the resulting solution is dispersed and stored in a 0.1% TMA(OH) solution.
- a solution of the ligand compound prepared to a pH of about 8 to 12 using a 0.1% to 2% TMA(OH) solution is added.
- the obtained solution is stirred at room temperature for 6 to 24 hours, acetone is added to cause precipitation, and the mixture is centrifuged at 8000 to 12000 rpm for 3 to 10 minutes to remove the supernatant.
- the precipitate is dispersed in a phosphate buffer solution, and the solution amount is reduced by centrifuging at 7,000 to 12,000 rpm using a concentration column.
- a phosphate buffer solution is added thereto, and the mixture is centrifuged again at 7,000 to 12,000 rpm for 10 to 20 minutes and concentrated. This operation may be repeated a plurality of times, preferably 3 to 4 times, more preferably 5 to 10 times to obtain nanoparticles in which one or more zwitterionic ligands of the present invention are coordinate-bonded.
- the obtained solution of nanoparticles may be diluted with PBS and stored.
- phase transfer catalyst method The zwitterion of the present invention is used in the presence of a phase transfer catalyst in the presence of a phase transfer catalyst in a bilayer solvent of an organic layer and an aqueous layer in which metal particles having a hydrophobic ligand such as oleic acid coordinate-bonded to the surface thereof.
- the "bilayer solvent of the organic layer and the aqueous layer” is a mixed solvent of the organic solvent and water, which is separated into two layers.
- the organic solvent is an aprotic solvent, and in one embodiment, 2-methyltetrahydrofuran (2-Me-THF), cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), chloroform, toluene, xylene, It is selected from the group consisting of heptane and combinations thereof. In another aspect, it is selected from 2-methyltetrahydrofuran, chloroform and combinations thereof.
- phase transfer catalyst is a phase transfer catalyst selected from salts having a quaternary ammonium and a quaternary phosphonium which are both soluble in an organic solvent and water, and in one embodiment, a quaternary ammonium.
- Salts for example, the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium salt, trioctylmethylammonium salt and benzyldimethyloctadecylammonium salt.
- anion forming a salt here include a halide ion, a hydroxide ion, and a hydrogen sulfate ion.
- the tetrabutylammonium halide salt is selected from tetrabutylammonium bromide (TBAB) and tetrabutylammonium fluoride (TBAF).
- TBAB tetrabutylammonium bromide
- TBAF tetrabutylammonium fluoride
- it is a tetrabutylammonium fluoride hydrate, such as tetrabutylammonium fluoride trihydrate.
- a pH adjuster may be added, and for example, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, ammonium hydrogen carbonate or dipotassium hydrogen phosphate can be used.
- the reaction is carried out by selecting metal particles having a hydrophobic ligand coordinate-bonded to the surface thereof and a zwitterionic ligand compound in a bilayer solvent of an organic layer and an aqueous layer in the presence of a phase transfer catalyst, from nitrogen and argon. Under an inert gas atmosphere, at room temperature or under heating, in one embodiment at room temperature to 80° C., in another embodiment at 30° C. to 60° C. for 1 hour or more, in one embodiment for 1 to 20 hours, in another embodiment. In the above embodiment, the stirring is performed for 1 to 15 hours, and in another embodiment, for 1 to 6 hours.
- the reaction temperature and the reaction time can be appropriately adjusted according to the type of the metal particles used in the reaction and the zwitterionic ligand.
- the zwitterionic ligand can be used in a ratio of 1 to 30 wt (weight ratio), 5 to 20 wt in one aspect, and 6 to 15 wt in another aspect, to the metal particles.
- the phase transfer catalyst is 0.1 to 10 wt with respect to the metal particles, in one embodiment 0.1 wt to 6 wt, in another embodiment 0.1 wt to 5 wt, in another embodiment 0.5 to 6 wt, and in another embodiment. As an aspect, it can be performed by adding in a ratio of 0.5 to 3 wt, and in yet another aspect, 0.5 wt to 2 wt. Further, when a pH adjuster is used, the phase transfer catalyst can be added by adding it to the metal particles in a ratio of 0.1 wt to 5 wt, and in one aspect, 0.5 wt to 2 wt.
- Isolation of nanoparticles from the reaction solution can be performed by using a known method such as centrifugation, ultrafiltration, or liquid separation operation.
- a known method such as centrifugation, ultrafiltration, or liquid separation operation.
- Amicon registered trademark
- Ultracentrifuge filter Merck Millipore
- Agilent Captiva Premium Syringe Filters Regenerated Cellulose, 15 mm
- YMC Duo can be used to repeat filtration using YMC Duo.
- the obtained solution of nanoparticles may be diluted with PBS and stored.
- nanoparticles having a core-shell structure and/or nanoparticles having fine metal particles are obtained.
- one or more zwitterionic ligand compounds are coordinate-bonded to the outer surface of iron oxide-containing metal particles to prepare particles in which the zwitterionic ligand compound covers the metal particles. It In one embodiment, one or more "metal particles containing iron oxide coordinate-bonded with one or more zwitterionic ligand compounds" and one or more zwitterionic ligand compounds as a complex, Particles are produced.
- a cluster of two or more zwitterionic ligand compounds and two or more "metal particles containing iron oxide coordinated with one or more zwitterionic ligand compounds" is prepared.
- the nanoparticles of the present invention can be used as a contrast agent for magnetic resonance imaging.
- One embodiment is the method described in Examples below.
- the present invention also provides a contrast agent for magnetic resonance imaging, which comprises the nanoparticles described above.
- the contrast agent for MRI of the present invention is characterized by containing at least one kind of the nanoparticles described above.
- the MRI contrast agent of the present invention may include a combination of two or more types of the nanoparticles described above.
- the MRI contrast agent may include a solvent and a pharmacologically acceptable additive, if necessary.
- One embodiment of the contrast agent for MRI of the present invention may further include at least one selected from a suitable solvent and/or additives such as a carrier, a vehicle and a complex.
- solvent contained in the contrast agent for MRI examples include water and buffer solution, and examples of the buffer solution include physiological saline, phosphate buffer solution, Tris buffer solution, borate buffer solution, Ringer solution. Etc.
- a preferable solvent is, for example, water, Ringer's solution, physiological saline or the like.
- the contrast agent for MRI according to the present invention may be a solution in which the nanoparticles according to the present invention are suspended in a solution having a desired composition.
- the nanoparticles may be suspended in a buffer solution such as a phosphate buffer solution, a Tris buffer solution, or a borate buffer solution.
- additives such as carriers, complexes and vehicles contained in the contrast agent for MRI include carriers and vehicles generally used in the fields of medicine and biotechnology.
- the carrier include polymers such as polyethylene glycol and metal fine particles
- examples of the complex include diethylenetriamine pentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7. ,10-Tetraacetic acid (DOTA) and the like
- vehicle include lime, soda ash, sodium silicate, starch, glue, gelatin, tannin and quebracho.
- the contrast agent for MRI according to the present invention may further contain an excipient, a lubricant, a wetting agent, an emulsifying agent, a suspending agent, a preservative, a pH adjusting agent, an osmotic pressure adjusting agent and the like.
- the dosage form of the contrast agent for MRI of the present invention is not particularly limited, and can be liquid, solid, semisolid, or semiliquid. These dosage forms can be easily manufactured based on methods known to those skilled in the art.
- the dosage form is a liquid, it may be, for example, a form in which the nanoparticles of the present invention are dispersed, suspended or dissolved in an aqueous solvent.
- the lyophilizing agent may be used by dispersing, suspending or dissolving it when used.
- the concentration of nanoparticles in the contrast agent for MRI is appropriately determined depending on the purpose and the tissue to be imaged. For example, a concentration within a range that has an appropriate contrasting ability and is acceptable for the influence on the living body is selected.
- the nanoparticles of the present invention are less likely to aggregate even at high concentrations and can maintain stability. Therefore, it is expected that a higher MRI contrasting ability will be stably maintained for a long period of time as compared with known nanoparticles.
- the concentration of nanoparticles in the solution is, for example, 0.1 to 1000 mMFe, preferably 1.0 to 500 mMFe when used as a general injection. More preferably, the concentration can be 5.0 to 100 mMFe, in one aspect 10 to 500 mMFe, and in another aspect 5.0 to 50 mMFe.
- the target of administration of the contrast agent according to the present invention includes any non-human organism or human.
- Non-human organisms include mammals (eg, rodents such as mice, rats, rabbits, primates such as monkeys, dogs, cats, sheep, cows, horses, pigs, etc.), birds, reptiles, amphibians, fishes. , But not limited to insects and plants.
- the animal can be a transgenic animal, a genetically engineered animal or a cloned organism.
- the administration target other than the living body may be a tissue sample or a biological material containing cells.
- MRI Contrast Agent As described above, there are two types of contrast agents for MRI, a positive contrast agent and a negative contrast agent.
- the MRI contrast agent of the present invention is a positive contrast agent.
- Another embodiment is a negative contrast agent.
- the present invention also includes an MRI contrasting method using the above MRI contrasting agent. Furthermore, the present invention also relates to a method of imaging various target organs by an MRI apparatus using the contrast agent for MRI. For example, an imaging method of kidney, liver, and cerebral blood vessel can be mentioned. The present invention also relates to a method for diagnosing the presence or absence of lesions and tumors in various target organs using the contrast agent for MRI. For example, it can be suitably used for a method for diagnosing renal function, a method for diagnosing liver tumor, and the like. Furthermore, the present invention also relates to a method for visualizing various target organs by an MRI apparatus, which uses the contrast agent for MRI.
- the diagnostic method or visualization method using the contrast agent of the present invention comprises a step of administering a positive contrast agent to a living subject such as a human being, and an MRI relating to a desired organ of the subject using an MRI apparatus. It includes the step of obtaining an image.
- Paramagnetism is oriented in the same direction as the magnetic field to which a dipole moment was applied, which was in an arbitrary direction when an external magnetic field was applied, and is magnetized in the same direction as the external magnetic field. Such substances bring about a T 1 shortening effect by the interaction between dipoles.
- a superparamagnetic substance also produces a net magnetic moment by a similar mechanism, but the magnetic susceptibility is larger than that of the paramagnetic substance, and the T 2 shortening effect is large.
- This contrast agent is considered to exhibit paramagnetic and superparamagnetic boundaries or paramagnetism, and it is presumed that the relaxation mechanism of both influences depending on the magnetic field strength, resulting in T 1 , T 2 and T 2 * relaxation.
- FIG. 7 shows an example of measurement at 300K.
- the magnetic susceptibility is almost proportional to the magnetic field, and it is considered that the property as superparamagnetism is low. Even though it is a nanoparticle, it has the property of paramagnetism, and an excellent T 1 shortening effect can be expected in the practical magnetic field region. ..
- the contrast agent of the present invention has an imaging ability of r 2 relaxivity of 2.8 to 6.2 mM ⁇ 1 s ⁇ 1 and r 1 relaxivity of 2.5 to 37° C. and a magnetic field of 1.5 T.
- the range is 4.4 mM ⁇ 1 s ⁇ 1 .
- the contrast agent of the present invention has an imaging ability of r 2 relaxivity of 3.0 to 4.2 mM ⁇ 1 s ⁇ 1 and an r 1 relaxivity of 2.7 at 37° C. and a magnetic field of 1.5 T.
- the range is up to 3.9 mM ⁇ 1 s ⁇ 1 .
- Relaxability depends on various factors such as the particle size of metal particles in the contrast agent nanoparticles for MRI, the composition, the charge or property of the particle surface, the particle stability, and the cohesiveness in tissues and the binding property to tissues. Depends on.
- the relaxivity ratio, r 1 /r 2 is commonly used to quantify the type of contrast produced in MRI and can be an indicator of the performance of a contrast agent.
- r 1 / r 2 preferably as the value of r 1 / r 2 is larger in order to improve the diagnostic performance by obtaining a higher positive contrast effect, when the magnetic field is 1.5T r 1 / r
- the value of 2 is, for example, preferably 0.6 or more, more preferably 0.7 or more, and even more preferably 0.8 or more.
- the r 1 /r 2 value is 0.7 or more, the T 1 (positive) effect is excellent, and the MRI measurement in a higher magnetic field has a high resolution and a high contrast effect. From the viewpoint of significantly enhancing the contrast effect and administering a smaller amount of the positive contrast agent for MRI, it is preferably 0.8 or more.
- the molecular chain length of the zwitterionic ligand is shorter than that of known ligands, and the distance between the metal particles and the external water molecule is shortened, so that the relaxation ability can be efficiently derived.
- the contrast for MRI using nanoparticles having a particle size of metal particles is 2 nm or less, and 1 nm or less in one example.
- An agent is included, and the MRI contrast agent can be used as a positive contrast agent in a T 1 -weighted image even with an MRI apparatus of 7T or more.
- it includes a positive contrast agent for MRI for use in an MRI device of 7T or less.
- An example includes a positive contrast agent for MRI for use in an MRI device of 3T or less.
- the contrast agent for MRI of the present invention has high stability of nanoparticles, and the degree of aggregation can be confirmed by the method described in Test Example 3 described later, and the aggregate in a solution at room temperature or 4° C. for a long period of time. It is expected to be storable without. In addition, it is expected to have low toxicity to living organisms and be applicable to long-term and continuous living organisms.
- the present invention includes any one of the following aspects. Unless otherwise specified, when a symbol in one chemical formula in this specification is used in another chemical formula, the same symbol has the same meaning. ⁇ 1> Nanoparticles comprising iron oxide-containing metal particles to which one or more zwitterionic ligands of formula (I) are coordinate bonded.
- R 1 and R 2 are a group represented by formula (a) or formula (b), and the other is H, lower alkyl, —O-lower alkyl or halogen, X 1 is a bond or methylene, and when R 1 is a group represented by the formula (a), X 1 may be ethylene, X 2 is C 1-5 alkylene which may be substituted with OH, or —C 1-2 alkylene-O—C 1-3 alkylene-, and R 1 is a group represented by the formula (b).
- X 2 may be a bond
- R a and R b are the same or different and are C 1-3 alkyl, —C 1-3 alkylene-O—C 1-2 alkyl, or R a and R b are attached to each other.
- Y ⁇ is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇
- R 3 and R 4 are the same or different from each other and are H, C 1-3 alkyl, —O—C 1-3 alkyl or halogen
- n is an integer of 0 to 2
- R 1 is a group represented by the formula (a) and X 1 is methylene
- R 2 and R a or R b may combine to form ethylene
- R 1 is a group represented by the formula (a) and X 1 is ethylene
- R 2 and R a or R b may together form methylene
- R 2 is a group represented by the formula (a) and X 1 is methylene
- R 3 and R a or R b may together form ethylene.
- R 2 is a group represented by the formula (a), R a and R b are methyl, X 1 is a bond, X 2 is C 1-4 alkylene, and R 1 is When R 3 and R 4 are both H, Y ⁇ is HPO 3 ⁇ or CO 2 ⁇ .
- R 1 and R 2 are a group represented by formula (a) or formula (b), and the other is H, lower alkyl or halogen, X 1 is a bond or methylene, and when R 1 is a group represented by the formula (a), X 1 may be ethylene, X 2 is C 1-5 alkylene which may be substituted with OH, or —C 1-2 alkylene-O—C 1-3 alkylene-, and R 1 is a group represented by the formula (b).
- X 2 may be a bond
- R a and R b are the same or different and are C 1-3 alkyl, —C 1-3 alkylene-O—C 1-2 alkyl, or R a and R b are attached to each other.
- Y ⁇ is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇
- R 3 and R 4 are the same or different from each other, and are H, C 1-3 alkyl, or halogen
- n is 1, Furthermore, i) When R 1 is a group represented by the formula (a) and X 1 is methylene, R 2 and R a or R b may be combined together to form ethylene.
- the zwitterionic ligand R 1 is a group represented by formula (a) or formula (b), R 2 is H or halogen, X 1 is a bond or methylene, and when R 1 is a group represented by the formula (a), X 1 may be ethylene, X 2 is C 1-5 alkylene, and when R 1 is a group represented by the formula (b), X 2 may be a bond, R a and R b are both methyl, Y ⁇ is SO 3 ⁇ or CO 2 ⁇ , ⁇ 2> nanoparticles that are zwitterionic ligands.
- the zwitterionic ligand is a zwitterionic ligand in which one of R 1 and R 2 is a group represented by the formula (a) and the other is H, lower alkyl, —O-lower alkyl or halogen ⁇ 1> nanoparticles.
- the zwitterionic ligand 1) a zwitterionic ligand in which R 1 is a group represented by formula (a), and R 2 is H, lower alkyl, —O-lower alkyl or halogen, or 2) R 1 is H, R 2 is a group represented by the formula (a), R 3 is C 1-3 alkyl or halogen, and R 4 is H.
- the zwitterionic ligand is a zwitterionic ligand in which R 1 is a group represented by formula (a), and R 2 is H, lower alkyl, —O-lower alkyl or halogen, ⁇ 5> Nanoparticles.
- the zwitterionic ligand R 2 is H or halogen
- X 1 is a bond, methylene or ethylene
- X 2 is C 2-4 alkylene
- R a and R b are both methyl
- R 3 and R 4 are the same or different from each other and are H, C 1-3 alkyl or halogen
- X 1 is methylene
- R 2 and R a or R b may together form ethylene.
- the zwitterionic ligand R 2 is H or F
- X 2 is ethylene or propylene
- R 3 and R 4 are both H
- the zwitterionic ligand R 2 is H
- X 1 is a bond or ethylene
- the zwitterionic ligand Y ⁇ is SO 3 ⁇ or CO 2 ⁇
- the nanoparticles according to any one of ⁇ 4> to ⁇ 9>, which are zwitterionic ligands.
- the zwitterionic ligand R 1 is a group represented by the following formula (b-1), R 2 is H or halogen, X 1 is a bond or methylene, X 2 is C 1-5 alkylene or a bond, R a is methyl, Y ⁇ is SO 3 ⁇ or CO 2 ⁇ , ⁇ 3> nanoparticles, which are zwitterionic ligands.
- R 1 is a group represented by the following formula (b-1)
- R 2 is H or halogen
- X 1 is a bond or methylene
- X 2 is C 1-5 alkylene or a bond
- R a is methyl
- Y ⁇ is SO 3 ⁇ or CO 2 ⁇
- ⁇ 12> The nanoparticles according to any one of ⁇ 1> to ⁇ 11>, wherein the metal particles containing iron oxide are metal particles containing only iron oxide.
- the nanoparticles are particles formed by one or more zwitterionic ligands coordinate-bonded to the outer surface of the metal particles containing iron oxide, and the metal particles are coated with the zwitterionic ligands.
- Nanoparticles Metal particles containing iron oxide coordinated to one or more zwitterionic ligands, and One or more zwitterionic ligands, The nanoparticle according to any one of ⁇ 1> to ⁇ 12>, which is a composite consisting of: ⁇ 15> Nanoparticles Two or more zwitterionic ligand compounds, and two or more "metal particles containing iron oxide coordinate-bonded with one or more zwitterionic ligand compounds", The nanoparticle according to any one of ⁇ 1> to ⁇ 12>, which is a cluster consisting of ⁇ 16>
- a contrast agent for magnetic resonance imaging which comprises the nanoparticles according to any one of ⁇ 1> to ⁇ 15>.
- ⁇ 18> Use of a zwitterionic ligand compound represented by the following formula (I) for producing nanoparticles of ⁇ 1>.
- R 1 and R 2 is a group represented by the following formula (a) or formula (b), and the other is H, lower alkyl, —O-lower alkyl or halogen, X 1 is a bond or methylene, and when R 1 is a group represented by the formula (a), X 1 may be ethylene, X 2 is C 1-5 alkylene which may be substituted with OH, or —C 1-2 alkylene-O—C 1-3 alkylene-, and R 1 is a group represented by the formula (b).
- X 2 may be a bond
- R a and R b are the same or different and are C 1-3 alkyl, —C 1-3 alkylene-O—C 1-2 alkyl, or R a and R b are attached to each other.
- Y ⁇ is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇
- R 3 and R 4 are the same or different from each other and are H, C 1-3 alkyl, —O—C 1-3 alkyl or halogen
- n is an integer of 0 to 2
- R 1 is a group represented by the formula (a) and X 1 is methylene
- R 2 and R a or R b may combine to form ethylene
- R 1 is a group represented by the formula (a) and X 1 is ethylene
- R 2 and R a or R b may together form methylene
- R 2 is a group represented by the formula (a) and X 1 is methylene
- R 3 and R a or R b may together form ethylene.
- R 2 is a group represented by the formula (a), R a and R b are methyl, X 1 is a bond, X 2 is C 1-4 alkylene, and R 1 is When R 3 and R 4 are both H, Y ⁇ is HPO 3 ⁇ or CO 2 ⁇ . )
- the zwitterionic ligand compound is a zwitterionic ligand compound in which one of R 1 and R 2 is a group represented by the formula (a) and the other is H, lower alkyl, —O-lower alkyl or halogen. Yes, using ⁇ 18>.
- ⁇ 20> A compound represented by the following formula (I) or a salt thereof.
- R 1 and R 2 are a group represented by the following formula (a) or formula (b), and the other is H, lower alkyl, —O-lower alkyl or halogen, X 1 is a bond or methylene, and when R 1 is a group represented by the formula (a), X 1 may be ethylene, X 2 is C 1-5 alkylene which may be substituted with OH, or —C 1-2 alkylene-O—C 1-3 alkylene-, and R 1 is a group represented by the formula (b).
- X 2 may be a bond
- R a and R b are the same or different and are C 1-3 alkyl, —C 1-3 alkylene-O—C 1-2 alkyl, or R a and R b are attached to each other.
- Y ⁇ is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇
- R 3 and R 4 are the same or different from each other and are H, C 1-3 alkyl, —O—C 1-3 alkyl or halogen
- n is an integer of 0 to 2
- R 1 is a group represented by the formula (a) and X 1 is methylene
- R 2 and R a or R b may combine to form ethylene
- R 1 is a group represented by the formula (a) and X 1 is ethylene
- R 2 and R a or R b may together form methylene
- R 2 is a group represented by the formula (a) and X 1 is methylene
- R 3 and R a or R b may together form ethylene.
- R 2 is a group represented by the formula (a), R a and R b are methyl, X 1 is a bond, X 2 is C 1-4 alkylene, and R 1 is When R 3 and R 4 are both H, Y ⁇ is HPO 3 ⁇ or CO 2 ⁇ .
- R 1 and R 2 are a group represented by formula (a) or formula (b), and the other is H, lower alkyl or halogen, X 1 is a bond or methylene, and when R 1 is a group represented by the formula (a), X 1 may be ethylene, X 2 is C 1-5 alkylene which may be substituted with OH, or —C 1-2 alkylene-O—C 1-3 alkylene-, and R 1 is a group represented by the formula (b).
- X 2 may be a bond
- R a and R b are the same or different and are C 1-3 alkyl, —C 1-3 alkylene-O—C 1-2 alkyl, or R a and R b are attached to each other.
- Y ⁇ is SO 3 ⁇ , HPO 3 ⁇ , or CO 2 ⁇
- R 3 and R 4 are the same or different from each other, and are H, C 1-3 alkyl, or halogen
- n is 1, Further, i) when R 1 is a group represented by the formula (a) and X 1 is methylene, R 2 and R a or R b may be combined to form ethylene.
- a compound of ⁇ 20> or a salt thereof is ⁇ 22>
- R 1 is a group represented by formula (a) or formula (b)
- R 2 is H or halogen
- X 1 is a bond or methylene
- R 1 is a group represented by the formula (a)
- X 1 may be ethylene
- X 2 is C 1-5 alkylene
- R 1 is a group represented by the formula (b)
- X 2 may be a bond
- R a and R b are both methyl
- ⁇ 26> 4- ⁇ [(2,3-dihydroxyphenyl)methyl](dimethyl)azaniumyl ⁇ butane-1-sulfonate and 3- ⁇ [(6-fluoro-2,3-dihydroxyphenyl)methyl](dimethyl)azaniumyl ⁇ propane
- the present invention is not limited to the above-described embodiments, but various modifications can be made within the scope of the claims, and embodiments obtained by appropriately combining the technical means disclosed in the different embodiments Is also included in the technical scope of the present invention. Furthermore, new technical features can be formed by combining the technical means disclosed in each of the embodiments.
- APCI/ESI(M+)+ m/z value in mass spectrometry (ionization method APCI and ESI) is shown.
- Production Example 27 shows Mass data of the oleic acid moiety excluding iron ions, and its ESI shows (M-)-.
- Data2 means physicochemical data of Examples, SEC(min) means outflow time of nanoparticles under the conditions described in Test Example 2, and 3K means particles purified by the filter described below. Certain 3K purified particles and 10K mean 10K purified particles which are particles purified by the filter described below.
- THF tetrahydrofuran
- DMF N,N-dimethylformamide
- OA oleic acid
- MEAA [2-(2-methoxyethoxy)ethoxy]acetic acid
- TBAF trihydrate tetrabutylammonium fluoride trihydrate
- PBS Phosphate buffered saline
- iron oxide nanoparticles coordinated with OA or MEAA are referred to as SNP-OA and SNP-MEAA, respectively.
- Br ⁇ represents bromide ion and I ⁇ represents iodide ion.
- a column packed with silica gel whose surface was modified with ODS (octadecylsilyl group) was used for the reverse phase column chromatography.
- Amicon Ultracentrifuge 3K filter used for the purification of iron oxide nanoparticles is referred to as Amicon 3K filter. Further, when the same instrument having different molecular weight cutoffs of 10K, 30K, 50K and 100K is used, it is also referred to as Amicon 10K filter, Amicon 30K filter, Amicon 50K filter and Amicon 100K filter. Particles purified by ultrafiltration with a molecular weight cutoff of 30K, 10K, and 3K are referred to as 30K purified particles, 10K purified particles, and 3K purified particles, respectively.
- Production Example 5 A mixture of 1-(2,3-dimethoxyphenyl)-N,N-dimethylmethanamine (2.00 g), 1,2 ⁇ 6 -oxathian-2,2-dione (1.36 mL) and ethyl acetate (20 mL) was added. After stirring at 50° C. for 3 hours, the mixture was stirred at 70° C. for 24 hours. Further, 1,2 ⁇ 6 -oxathiane-2,2-dione (1.04 mL) was added, and the mixture was stirred at 70° C. for 24 hours.
- Production Example 13 A mixture of diethyl (3-bromopropyl)phosphonate (2.53 g) and 3,4-dimethoxyaniline (3.00 g) was stirred at 95° C. for 6 hours under an argon atmosphere. The mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted once with ethyl acetate. The organic layer was washed once with saturated brine and dried over anhydrous magnesium sulfate.
- Production Example 60 A mixture of 2,3-dimethoxyaniline (5.00 g) and 1,2 ⁇ 6 -oxathiane-2,2-dione (5.78 g) was stirred at 95° C. for 24 hours. This was purified by reverse phase column chromatography (developing solvent: acetonitrile-water). After concentration, the obtained solid was washed with acetonitrile to obtain 4-(2,3-dimethoxyanilino)butane-1-sulfonic acid (4.78 g).
- Example 1 Under an argon atmosphere, a mixture of SNP-OA (100 mg), MEAA (2.5 mL) and methanol (7.5 mL) was stirred at 70° C. for 5 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. Acetone (24 mL) and hexane (96 mL) were added, and the mixture was divided into 6 parts and centrifuged at 10° C. and 7000 rpm for 10 minutes to remove the supernatant. This operation was repeated once more to obtain SNP-MEAA.
- the obtained precipitate was dispersed in PBS and centrifuged at 10° C. and 5800 rpm for 30 minutes using an Amicon 30K filter.
- the obtained filtrate was centrifuged at 5800 rpm at 10° C. for 30 minutes using an Amicon 10K filter. This series of operations was performed three more times. Water was added to the concentrate on the Amicon 30K filter, and the mixture was centrifuged at 5° C. and 10° C. for 30 minutes.
- the obtained filtrate was centrifuged at 5800 rpm at 10° C. for 30 minutes using an Amicon 10K filter. This series of operations was performed twice more. Water was added to the concentrate on the Amicon 10K filter, and the mixture was centrifuged at 5° C. and 10° C.
- the concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 10K purified particles (21.2 mg).
- the filtrate obtained by washing with an Amicon 10K filter was centrifuged at 5°C for 60 minutes at 10°C using an Amicon 3K filter. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes.
- the concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 3K purified particles (41.3 mg).
- Example 2 A mixture of SNP-OA (20 mg), MEAA (0.5 mL) and methanol (1.5 mL) was stirred at 70° C. for 6 hours under an argon atmosphere. After cooling to room temperature, acetone (4 mL) and hexane (16 mL) were added, and the mixture was centrifuged at 10° C. and 7800 rpm for 10 minutes, and the supernatant was removed. This operation was repeated 3 times using acetone (1 mL) and hexane (4 mL) to obtain SNP-MEAA.
- Example 3 A mixture of SNP-OA (20 mg), MEAA (0.5 mL) and methanol (1.5 mL) was stirred at 70° C. for 6 hours under an argon atmosphere. After cooling to room temperature, acetone (4 mL) and hexane (16 mL) were added, and the mixture was centrifuged at 10° C. and 7800 rpm for 10 minutes, and the supernatant was removed. This operation was repeated 3 times using acetone (1 mL) and hexane (4 mL) to obtain SNP-MEAA.
- the obtained precipitate was dispersed in PBS and centrifuged at 10° C. and 5800 rpm for 30 minutes using an Amicon 100K filter.
- the obtained filtrate was centrifuged at 5800 rpm at 10° C. for 30 minutes using an Amicon 10K filter. This series of operations was repeated 3 times later.
- Water was added to the concentrate on the Amicon 10K filter, and the mixture was centrifuged at 5° C. and 10° C. for 30 minutes. This operation was performed twice more.
- the concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 10K purified particles (17.3 mg). After washing with Amicon 10K filter, the filtrate for 3 times was centrifuged at 10° C.
- Example 4 A mixture of SNP-OA (40 mg), MEAA (1 mL) and methanol (3 mL) was stirred at 70° C. for 6 hours under an argon atmosphere. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. Acetone (8 mL) and hexane (32 mL) were added, and the mixture was divided into two and centrifuged at 10° C. and 7,000 rpm for 10 minutes to remove the supernatant. Acetone (6 mL) and hexane (24 mL) were added to this, and this operation was repeated once more to obtain SNP-MEAA.
- the obtained filtrate was centrifuged for 30 minutes at 10° C. and 5800 rpm using an Amicon 30K filter. This series of operations was performed twice more. Water was added to the concentrate on the Amicon 30K filter, and the mixture was centrifuged at 5° C. and 10° C. for 30 minutes. This operation was repeated once. The concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 30K purified particles (2.1 mg). The filtrate obtained by washing with an Amicon 30K filter was centrifuged at 10° C. and 5800 rpm for 30 minutes using an Amicon 10K filter.
- Example 5 A mixture of SNP-OA (20 mg), MEAA (0.5 mL) and methanol (1.5 mL) was stirred at 70° C. for 6 hours under an argon atmosphere. After cooling to room temperature, acetone (8 mL) and hexane (32 mL) were added, and the mixture was divided into two and centrifuged at 10° C. and 7300 rpm for 5 minutes to remove the supernatant. This operation was repeated twice with acetone (6 mL) and hexane (24 mL) to obtain SNP-MEAA.
- the obtained precipitate was dispersed in PBS and centrifuged at 10° C. and 5800 rpm for 10 minutes using an Amicon 50K filter.
- the obtained filtrate was centrifuged at 5800 rpm at 10° C. for 30 minutes using an Amicon 10K filter.
- PBS was added to this, and it centrifuged at 10 degreeC and 5800 rpm for 30 minutes.
- Water was added to this, and it centrifuged at 10 degreeC and 5800 rpm for 30 minutes. This operation was performed 7 more times.
- the concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 10K purified particles (9.3 mg). After washing with Amicon 10K filter, the filtrate for 3 times was centrifuged at 10° C.
- Example 6 Under an argon atmosphere, a mixture of SNP-OA (100 mg), MEAA (2.5 mL) and methanol (7.5 mL) was stirred at 70° C. for 5 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. Acetone (24 mL) and hexane (96 mL) were added, and the mixture was divided into 6 parts and centrifuged at 10° C. and 7000 rpm for 10 minutes, and the supernatant was removed to obtain SNP-MEAA.
- the concentrated liquid was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 10K purified particles (117.7 mg).
- the filtrate obtained by washing with an Amicon 10K filter was sequentially centrifuged using an Amicon 3K filter at 10° C. and 5800 rpm for 60 minutes. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes.
- the concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 3K purified particles (53.2 mg).
- the 3K purified particles were hydrolyzed with hydrochloric acid and analyzed by HPLC.
- Example 7 Under an argon atmosphere, a mixture of SNP-OA (100 mg), MEAA (2.5 mL) and methanol (7.5 mL) was stirred at 70° C. for 5 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. Acetone (24 mL) and hexane (96 mL) were added, and the mixture was divided into 6 parts and centrifuged at 10° C. and 7000 rpm for 10 minutes, and the supernatant was removed to obtain SNP-MEAA.
- the obtained precipitate was dispersed in PBS and centrifuged at 10° C. and 5800 rpm for 30 minutes using an Amicon 30K filter.
- the obtained filtrate was centrifuged at 5800 rpm at 10° C. for 30 minutes using an Amicon 10K filter. This series of operations was performed three more times. Water was added to the concentrate on the Amicon 30K filter, and the mixture was centrifuged at 5° C. and 10° C. for 30 minutes.
- the obtained filtrate was centrifuged at 5800 rpm at 10° C. for 30 minutes using an Amicon 10K filter. This series of operations was performed seven more times. Water was added to the concentrate on the Amicon 10K filter, and the mixture was centrifuged at 5° C.
- the concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 10K purified particles (102.4 mg).
- the filtrate obtained by washing with an Amicon 10K filter was sequentially centrifuged using an Amicon 3K filter at 10° C. and 5800 rpm for 60 minutes. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes.
- the concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 3K purified particles (41.2 mg).
- Example 8 Under an argon atmosphere, a mixture of SNP-OA (20 mg), MEAA (0.5 mL) and methanol (1.5 mL) was stirred at 70° C. for 5 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. Acetone (8 mL) and hexane (32 mL) were added, and the mixture was divided into two and centrifuged at 10° C. and 7000 rpm for 3 minutes to remove the supernatant. This operation was repeated once more to obtain SNP-MEAA.
- Example 9 A mixture of SNP-OA (20 mg), MEAA (0.5 mL) and methanol (1.5 mL) was stirred at 70° C. for 6 hours under an argon atmosphere. After allowing to cool to room temperature, acetone (8 mL) and hexane (32 mL) were added, and the mixture was divided into two and centrifuged at 10° C. and 7,000 rpm for 10 minutes to remove the supernatant. This operation was repeated once with acetone (6 mL) and hexane (24 mL) to obtain SNP-MEAA.
- Example 10 A mixture of SNP-OA (20 mg), MEAA (0.5 mL) and methanol (1.5 mL) was stirred at 70° C. for 6 hours under an argon atmosphere. After allowing to cool to room temperature, acetone (8 mL) and hexane (32 mL) were added, and the mixture was divided into two and centrifuged at 10° C. and 7,000 rpm for 10 minutes to remove the supernatant. This operation was repeated once with acetone (6 mL) and hexane (24 mL) to obtain SNP-MEAA.
- Example 11 Sodium hydrogen carbonate (34 mg) was added to a mixture of 4- ⁇ [(2,3-dihydroxyphenyl)methyl](dimethyl)azaniumyl ⁇ butane-1-sulfonate (275 mg) and water (2.2 mL). This solution was added to a mixture of SNP-OA (20 mg) and chloroform (2.5 mL), then a mixture of TBAF trihydrate (63 mg) and water (300 ⁇ L) was added, and the mixture was stirred at room temperature for 16 hours under an argon atmosphere. did. The aqueous layer was separated, and the chloroform layer was extracted twice with water.
- the aqueous layers were collected, dispersed in PBS, transferred to an Amicon 30K filter, and centrifuged at 10°C and 5800 rpm for 15 minutes.
- the obtained filtrate was centrifuged at 5800 rpm at 10° C. for 30 minutes using an Amicon 10K filter.
- This series of operations was performed three more times. Water was added to the concentrate on the Amicon 30K filter, and the mixture was centrifuged at 5° C. and 10° C. for 15 minutes.
- the obtained filtrate was centrifuged at 5800 rpm at 10° C. for 30 minutes using an Amicon 10K filter. This series of operations was performed twice more.
- Example 12 3- ⁇ [(6-Fluoro-2,3-dihydroxyphenyl)methyl](dimethyl)azaniumyl ⁇ propane-1-sulfonate (280 mg) was dissolved in water (2.2 mL), and sodium hydrogen carbonate (38 mg) was added. .. This solution was added to a solution of SNP-OA (20 mg) in chloroform (2.5 mL), and further a solution of TBAF trihydrate (65 mg) in water (0.3 mL) was added. The mixture was stirred at room temperature under an argon atmosphere for 20 hours. The insoluble material was filtered, the aqueous layer was transferred to an Amicon 30K filter, and the mixture was centrifuged at 5° C. and 10° C.
- the filtrate from 5 times was centrifuged using an Amicon 3K filter at 10° C. and 5800 rpm for 30 to 60 minutes. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes. This operation was performed 9 more times. The concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 3K purified particles (7.3 mg).
- the insoluble matter was filtered, the aqueous layer was transferred to an Amicon 100K filter, and the mixture was centrifuged at 5800 rpm at 10°C for 15 minutes.
- the obtained filtrate was centrifuged at 5800 rpm at 10° C. for 30 minutes using an Amicon 10K filter. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 30 minutes. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes. This operation was performed 8 more times.
- the concentrate was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 10K purified particles (1.0 mg).
- the filtrate obtained by washing the Amicon 10K filter with the first two washings was centrifuged with an Amicon 3K filter at 10° C. and 5800 rpm for 30 to 60 minutes. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes. This operation was performed 7 more times.
- the concentrate was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 3K purified particles (1.4 mg).
- Example 18 Under an argon atmosphere, a mixture of SNP-OA (150 mg), MEAA (3.75 mL) and methanol (11.25 mL) was stirred at 70° C. for 5 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. The solution was divided into 6 centrifuge tubes, and acetone (4 mL) and hexane (16 mL) were added to each tube, followed by centrifugation at 10° C. and 7000 rpm for 10 minutes to remove the supernatant. This operation was repeated once more to obtain SNP-MEAA.
- the obtained precipitate was dispersed in water and centrifuged at 10° C. and 5800 rpm for 30 minutes using an Amicon 30K filter. Water was added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes. This operation was performed twice more.
- the filtrate with an Amicon 30K filter was sequentially centrifuged with an Amicon 10K filter at 10° C. and 5800 rpm for 60 minutes. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes. This operation was performed 8 more times.
- the concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 10K purified particles (16.1 mg).
- the filtrate with an Amicon 10K filter was sequentially centrifuged with an Amicon 3K filter at 10° C. and 5800 rpm for 60 minutes. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes. The concentrated solution was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 3K purified particles (56.0 mg).
- Example 25 Under an argon atmosphere, a mixture of SNP-OA (150 mg), MEAA (3.8 mL) and methanol (11.3 mL) was stirred at 70° C. for 6 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. The tube was divided into four centrifuge tubes with acetone (28 mL), hexane (28 mL) was added to each tube, and the mixture was centrifuged at 10° C. and 7,000 rpm for 10 minutes to remove the supernatant. Acetone (7 mL) and hexane (28 mL) were added to each, and the mixture was centrifuged at 10° C. and 7000 rpm for 10 minutes to remove the supernatant.
- the obtained precipitate was dispersed in water and centrifuged at 10° C. and 5800 rpm for 30 minutes using an Amicon 30K filter. Water was added to the concentrate on the Amicon 30K filter, and the mixture was centrifuged at 5° C. and 10° C. for 30 minutes. This operation was repeated once. Water was added to the concentrate on the Amicon 30K filter, and the mixture was centrifuged at 10° C. and 5800 rpm for 60 minutes. This operation was repeated 4 more times. The obtained filtrate was sequentially transferred to an Amicon 10K filter and centrifuged at 10° C. and 5800 rpm for the first two times for 30 minutes and the subsequent six times for 60 minutes.
- Example 26 Under an argon atmosphere, a mixture of SNP-OA (150 mg), MEAA (3.8 mL) and methanol (11 mL) was stirred at 70° C. for 6 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. The tube was divided into four centrifuge tubes with acetone (28 mL), hexane (28 mL) was added to each tube, and the mixture was centrifuged at 10° C. and 7,000 rpm for 10 minutes to remove the supernatant. Acetone (7 mL) and hexane (28 mL) were added to each, and the mixture was centrifuged at 10° C. and 7000 rpm for 10 minutes to remove the supernatant.
- the obtained precipitate was dispersed in water and centrifuged at 10° C. and 5800 rpm for 30 minutes using an Amicon 30K filter. Water was added to the concentrate on the Amicon 30K filter, and the mixture was centrifuged at 5° C. and 10° C. for 30 minutes. This operation was repeated once. Water was added to the concentrate on the Amicon 30K filter, and the mixture was centrifuged at 10° C. and 5800 rpm for 60 minutes. This operation was repeated 4 more times. The obtained filtrate was sequentially transferred to an Amicon 10K filter and centrifuged at 10° C. and 5800 rpm for the first two times for 30 minutes and the subsequent six times for 60 minutes.
- Example 27 Under an argon atmosphere, a mixture of SNP-OA (150 mg), MEAA (3.75 mL) and methanol (11.25 mL) was stirred at 70° C. for 6 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. The solution was divided into 6 centrifuge tubes, and acetone (4 mL) and hexane (16 mL) were added to each tube, followed by centrifugation at 10° C. and 7000 rpm for 10 minutes to remove the supernatant. This operation was repeated once more to obtain SNP-MEAA.
- the obtained precipitate was dispersed in water and centrifuged at 10° C. and 5800 rpm for 30 minutes using an Amicon 30K filter. Water was added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes. This operation was performed twice more.
- the filtrate with an Amicon 30K filter was sequentially centrifuged with an Amicon 10K filter at 10° C. and 5800 rpm for 60 minutes. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes. This operation was performed 10 more times.
- the concentrate was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 10K purified particles (17.6 mg).
- the filtrate with an Amicon 10K filter was sequentially centrifuged with an Amicon 3K filter at 10° C. and 5800 rpm for 60 minutes. Water was further added to this, and it centrifuged at 10 degreeC and 5800 rpm for 60 minutes. The concentrate was filtered through a membrane (0.2 ⁇ m) and freeze-dried to obtain 3K purified particles (116 mg).
- Test Example 1 Evaluation of MR Relaxability of Nanoparticles Relaxability of the 3K purified particles obtained in each example was evaluated. First, the concentration of nanoparticles was serially diluted in PBS to prepare a test sample. The relaxivity of each sample was measured by 1.5T-NMR.
- T 1 and T 2 were measured under the following conditions. Measuring magnetic field: 1.5T, measuring temperature: 37°C T 1 measurement (reversal recovery method) Recycle Delay (RD): It was set to be 5 times or more of T 1 for each sample and concentration. The number of data points to be acquired was 8 or more, the time of the first inversion pulse (inversion time) was fixed to 5 ms, and the last inversion time was set to be the same as RD.
- T 2 measurement Carr-Purcell-Meiboom-Gill (CPMG) method
- Recycle Delay RD
- ⁇ 0.5 ms and set the number of data points to be acquired so that the number of ⁇ x 2 x data points was almost the same as RD.
- r 1 and r 2 of each sample measure T 1 and T 2 at multiple concentrations respectively, take the concentration on the X axis and the reciprocal of T 1 and T 2 on the Y axis, and calculate the slope with the SLOPE function. Obtained by.
- the values of r 1 /r 2 of the purified 3K particles of Example 6 and Example 11 which were different from each other in the method for producing nanoparticles having the same zwitterionic ligand coordinately bonded were 0.86 to 0.93 and 0.90, respectively.
- the values of r 1 /r 2 of the 3K purified particles of Example 7 and Example 12 are 0.88, respectively.
- the values were ⁇ 0.90 and 0.87 to 0.92. From these results, it was confirmed that nanoparticles having almost the same good relaxivity can be obtained by using any of the production methods.
- the relaxivity r 1 of 3K purified particles of the same zwitterionic ligand obtained by the above-mentioned multiple productions of Example 6 and Example 11 is between 2.74 and 3.76, and the relaxivity r 2 of Values were between 3.06 and 4.18.
- the relaxivity r 1 value of 3K purified particles of the same zwitterionic ligand obtained by multiple productions of Example 7 and Example 12 is between 3.02 and 3.85, and the relaxivity r 2 value is also. Indicates between 3.27 and 4.17.
- the relaxivity r 1 of the 10K purified particles of the same zwitterionic ligand obtained by the multiple productions of Example 6 and Example 11 was between 3.19-4.15, and the relaxivity r 2 was It was between 3.43-4.41 and the value of r 1 /r 2 was between 0.86-0.94.
- the relaxivity r 1 values of 10K purified particles of the same zwitterionic ligand obtained by multiple productions of Example 7 and Example 12 are between 3.38 and 4.84, and the relaxivity r 2 values. was between 3.77 and 6.14, and the value of r 1 /r 2 was between 0.71 and 0.94.
- the relaxivity r 1 value was 2.52
- the relaxivity r 2 value was 3.02
- the r 1 /r 2 value was 0.83. It was
- the relaxivity r 1 thereof was between 2.93 and 2.94, and the relaxivity r 2 thereof was between 3.13 and 4.09.
- the relaxivity r 1 thereof was between 3.18 and 3.43, and the relaxivity r 2 thereof was between 3.30 and 3.52.
- Test example 2 Evaluation test of particle size of nanoparticles The relative size of the nanoparticles was measured using size exclusion chromatography (SEC).
- SEC is an analytical method in which a sample is made to flow through a column packed with a carrier having pores and the size of the sample is estimated by the time until it flows out. Large aggregates do not enter the pores of the carrier and flow out quickly, and small nanoparticles pass through the pores of the carrier, so the route to the outflow is long, and the particles flow out slowly. Size can be measured.
- the purified nanoparticles and the 10K purified nanoparticles were measured twice under the following SEC conditions.
- the outflow time of the standard ovalbumin is between 9.4 and 10.2 minutes.
- nanoparticles with almost the same particle size could be obtained from the SEC outflow time even when different manufacturing methods were used. Also, it was confirmed from the outflow time and the ratio with the standard ovalbumin (particle size: 6.1 nm) that the obtained nanoparticles had a relatively small particle size.
- Test example 3 Stability evaluation test In order for contrast agents using nanoparticles to exhibit the expected performance, they must be stably dispersed in the solution, and maintain dispersibility even at high concentration for a long period of time. Is desirable.
- the dispersion stability of nanoparticles can be evaluated using size exclusion chromatography (SEC).
- the nanoparticles obtained in the examples were freeze-dried and then dispersed in PBS so that the Fe ion concentration was about 100 mM.
- test samples -20°C, 4°C and It is allowed to stand at room temperature (20° C.) and subjected to SEC after 2 weeks, 1 month and 3 months to confirm the degree of aggregation.
- the SEC measurement conditions are the same as the conditions described in Test Example 2.
- Test example 4 MRI Contrast Using Mouse i
- the contrast agent containing the nanoparticles obtained in the example was administered to each mouse, and a T 1 -weighted image was acquired with a 1 tesla MRI apparatus.
- the conditions at the time of measurement are shown below.
- Magnetic field strength 1T Imaging method: T 1 emphasis (Figs.
- a contrast agent containing nanoparticles was made into a 20 mM solution and 100 ⁇ L per 20 g of the mouse body weight was intravenously administered, and images were taken at each time point and followed for 1.5 hours. ..
- Example 7 in FIG. 3 In the mice to which the contrast agent containing the purified 3K particles of Example 7 in FIG. 3 was administered, it was observed that the signal increased in both renal pelvis and renal cortex immediately after the administration, and urine containing the contrast agent was accumulated. From this, it was shown that the contrast medium is excreted in the urine via the kidney. In addition, it was suggested that the contrast medium could be used for renal function tests by following the signal changes.
- Example 7 in FIG. 4 In the mice to which the contrast agent containing the purified 10K particles of Example 7 in FIG. 4 was administered, it was observed that the signal increased in both renal pelvis and renal cortex immediately after the administration, and urine containing the contrast agent was accumulated. From this, it was shown that the contrast medium is excreted in the urine via the kidney. In addition, it was suggested that the contrast medium could be used for renal function tests by following the signal changes.
- Example 25 in FIG. 6 In the mouse to which the contrast agent containing the 10K purified particles of Example 25 in FIG. 6 was administered, it was observed that the signal increased in both renal pelvis and renal cortex immediately after the administration, and urine containing the contrast agent was accumulated. From this, it was shown that the contrast medium is excreted in the urine via the kidney. In addition, it was suggested that the contrast medium could be used for renal function tests by following the signal changes.
- Test example 5 Measurement of Magnetic Field Dependence of Magnetization (MH Curve)
- the 3K purified particles obtained in each of Examples 6, 7 and 9 were inserted into the SQUID device, and the applied magnetic field was 3T at an interval of 1000 to 5000 Oe at a temperature of 300K.
- the magnetization of the particles at each point was measured while changing in the order of -3T to 3T.
- the measurement results are shown in FIG. 7.
- the magnetic susceptibility is almost proportional to the magnetic field, and the properties as superparamagnetism are considered to be low.
- the nanoparticles have paramagnetic properties even though they are nanoparticles, and an excellent T 1 shortening effect can be expected in the practical magnetic field region It was a result.
- the contrast agent for MRI of the present invention can be suitably used as a contrast agent for MRI in the medical field.
- the nanoparticles and zwitterionic ligand compounds of the present invention can be applied to various pharmaceutical compositions containing a contrast agent for MRI, and in various fields such as diagnostic methods and test reagents, in the fields of medicine and biotechnology, etc. It can be widely used.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nanotechnology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
造影剤が占める組織に信号上昇をもたらす。またT2緩和を利用し、T2強調画像上での信号を減衰する目的で使用される造影剤をT2短縮造影剤又は陰性造影剤(negative contrast agent)と呼ぶ。陰性造影剤は、当該造影剤が占める組織に信号減少をもたらす。
T1強調MRIとT2強調MRIは医療の診断において標準的に用いられる画像法である。T1強調MRIにおける陽性造影剤は、陰性造影剤と比較して、信号減少による組織の欠損が生じず、正常組織の情報を欠損することなく病変のコントラストを向上させることができるため診断における有用性が高く、画像診断において陽性造影剤の使用が不可欠である。
なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。
<1>
1つ以上の式(I)で表される双性イオンリガンドが配位結合した、酸化鉄を含有する金属粒子を含むナノ粒子。
R1及びR2の一方は、式(a)又は式(b)で示される基であり、他方は、H、低級アルキル、-O-低級アルキル又はハロゲンであり、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となって5又は6員含窒素飽和ヘテロ環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、-O-C1-3アルキル又はハロゲンであり、
nは0~2の整数であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよく、
ii)R1が式(a)で示される基であり、且つ、X1がエチレンであるとき、R2とRaまたはRbとが一体となってメチレンを形成してもよく、及び
iii)R2が式(a)で示される基であり、且つ、X1がメチレンであるとき、R3とRaまたはRbとが一体となってエチレンを形成してもよい、
但し、R2が式(a)で示される基であり、Ra及びRbがメチルであり、X1が結合であり、X2が、C1-4アルキレンであり、且つ、R1、R3及びR4がいずれもHであるとき、Y-はHPO3 -、又は、CO2 -である。)
<2>
下式(I)で表される化合物又はその塩。
R1及びR2の一方は、下式(a)又は式(b)で示される基であり、他方は、H、低級アルキル、-O-低級アルキル又はハロゲンであり、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となって5又は6員含窒素飽和ヘテロ環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、-O-C1-3アルキル又はハロゲンであり、
nは0~2の整数であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよく、
ii)R1が式(a)で示される基であり、且つ、X1がエチレンであるとき、R2とRaまたはRbとが一体となってメチレンを形成してもよく、及び
iii)R2が式(a)で示される基であり、且つ、X1がメチレンであるとき、R3とRaまたはRbとが一体となってエチレンを形成してもよい、
但し、R2が式(a)で示される基であり、Ra及びRbがメチルであり、X1が結合であり、X2が、C1-4アルキレンであり、且つ、R1、R3及びR4がいずれもHであるとき、Y-はHPO3 -、又は、CO2 -である。)
「低級アルキル」とは、直鎖又は分枝状の炭素数が1から6(以後、C1-6と略す)のアルキル、例えばメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、n-ヘキシル等である。別の態様としては、C1-4アルキルであり、さらに別の態様としては、C1-3アルキルであり、さらに別の態様としては、メチル、エチル、n-プロピルであり、またさらに別の態様としては、メチルである。また、「C1-3アルキル」のある態様としては、メチル、エチル又はn-プロピルであり、ある態様としては、メチルである。
本発明に係るナノ粒子は、前記式(I)で表される双性イオンリガンドが1つ以上配位結合した、酸化鉄を含有する金属粒子を含む、ナノ粒子である。配位結合している双性イオンリガンドの実施態様については次項以降で説明する。
一態様としては、本発明に係るナノ粒子は、酸化鉄を含有する金属粒子の外表面に双性イオンリガンド化合物が1つ以上配位結合して形成された粒子であり、該双性イオンリガンド化合物によって当該金属粒子が被覆されている、粒子である。
一態様としては、本発明に係るナノ粒子は、その中心部(コア)に金属粒子を有しており、当該金属粒子の外表面に双性イオンリガンド化合物が1つ以上配位結合することによって、当該双性イオンリガンド化合物が当該金属粒子を被覆したコア-シェル構造を有する、粒子である。
一態様としては、本発明に係るナノ粒子は、1以上の「1つ以上の双性イオンリガンドが配位結合した酸化鉄を含有する金属粒子」、及び、1以上の双性イオンリガンド化合物からなる複合体である、粒子である。
一態様としては、本発明に係るナノ粒子は、2以上の双性イオンリガンド化合物と、2以上の「1つ以上の双性イオンリガンド化合物が配位結合した酸化鉄を含有する金属粒子」からなるクラスターである、粒子である。
一態様としては、本発明に係るナノ粒子は、2以上の双性イオンリガンド化合物と、2以上の「1つ以上の双性イオンリガンド化合物が配位結合した酸化鉄を含有する金属粒子」とが不規則に結合したクラスターである、粒子である。
金属粒子は、酸化鉄を含有する。一実施形態では、金属粒子は、酸化鉄のみを含有する酸化鉄粒子であり、別の一例としては、金属粒子は、酸化鉄に加え鉄を含有する金属粒子である。本願明細書における「金属粒子」は、原料である「表面に疎水性リガンドが配位結合した酸化鉄ナノ粒子」における「酸化鉄ナノ粒子」、並びに、本発明の双性イオンリガンドを金属粒子に配位結合させる製造法、例えば後述のMEAA法を実施した結果、原料の酸化鉄ナノ粒子から何らかの変化が生じた、「酸化鉄を含有する金属粒子」を包含する。ここで、何らかの変化とはコア-シェル構造から複合体やクラスターへの構造的な変化、粒子径の変化、組成の変化等が挙げられるが、これらに限定されない。即ち、本願明細書における「金属粒子」は、少なくとも、本明細書に記載の式(I)で示される双性イオンリガンドを金属粒子に配位させる製造法であるMEAA法や後述のTMA(OH)法又は相間移動触媒法によって得られる、酸化鉄を含有する金属粒子を全て包含する。
本明細書において、粒子径という場合は、特に記載をしていない場合は平均粒子径を指す。
ナノ粒子の粒子径は、上記金属粒子表面に配位結合している双性イオンリガンドの厚さの分大きくなると推定される。通常、ナノ粒子を溶液とした場合の流体力学的直径(hydrodynamic diameter、HD)がその大きさの指標とされる。一例としては、ナノ粒子の平均HDは10nm以下、好ましくは、8nm以下である。更に別の一例としては、ナノ粒子の平均HDは5nm以下、好ましくは4nm以下、好ましくは3nm以下、好ましくは2nm以下、更に好ましくは1nm以下である。
SAXSの測定には、市販の機器を用いても良く、更にはSPring-8(BL19B2)やあいちシンクロトロン光センターのような放射光施設を用いるのが望ましい。例えばSPring-8(BL19B2)を用いた場合、カメラ長を3mに設定し、18KeVのX線を試料に照射し、波数qを約 0.06~3 nm-1の範囲で観測する。
本発明に係る双性イオンリガンド化合物は、下式(I)で表される化合物又はその塩である。
R1及びR2の一方は、式(a)又は式(b)で示される基であり、他方は、H、低級アルキル、-O-低級アルキル又はハロゲンであり、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となって5又は6員含窒素飽和ヘテロ環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、-O-C1-3アルキル又はハロゲンであり、
nは0~2の整数であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよく、
ii)R1が式(a)で示される基であり、且つ、X1がエチレンであるとき、R2とRaまたはRbとが一体となってメチレンを形成してもよく、及び
iii)R2が式(a)で示される基であり、且つ、X1がメチレンであるとき、R3とRaまたはRbとが一体となってエチレンを形成してもよい、
但し、R2が式(a)で示される基であり、Ra及びRbがメチルであり、X1が結合であり、X2が、C1-4アルキレンであり、且つ、R1、R3及びR4がいずれもHであるとき、Y-はHPO3 -、又は、CO2 -である。)
式(o)に示される化合物の一実施態様としては、R2がH、低級アルキル、-O-低級アルキル又はハロゲンである、双性イオンリガンドであり、別の実施態様としては、R2がH又はハロゲンであり、X1が結合、メチレン又はエチレンであるか、またはX1がメチレンのとき、R2とRaもしくはRbとが一体となってエチレンを形成してもよく、X2がC2-4アルキレンであり、Ra及びRbがいずれもメチルであり、且つ、R3及びR4が同一又は互いに異なって、H、C1-3アルキル又はハロゲンである、双性イオンリガンドであり、更に別の実施態様としては、R2がH又はハロゲンであり、X1が結合又はメチレンであるか、またはX1がメチレンのとき、R2とRaもしくはRbとが一体となってエチレンを形成してもよく、X2がC2-4アルキレンであり、Ra及びRbがいずれもメチルであり、且つ、R3及びR4が同一又は互いに異なって、H、C1-3アルキル又はハロゲンである、双性イオンリガンドであり、更に別の実施態様としては、R2がH又はFであり、X1が結合、メチレン又はエチレンであり、X2がエチレン又はプロピレンであり、Ra及びRbがいずれもメチルであり、且つ、R3及びR4がいずれもHである、双性イオンリガンドであり、更に別の実施態様としては、R2がHであり、X1がエチレンであり、X2がエチレン又はプロピレンであり、Ra及びRbがいずれもメチルであり、且つ、R3及びR4がいずれもHである、双性イオンリガンドであり、更に別の実施態様としては、R2がH又はFであり、X1が結合又はエチレンであり、X2がエチレン基又はプロピレン基であり、Ra及びRbがいずれもメチルであり、且つ、R3及びR4がいずれもHであり、且つ、Y-がSO3 -又はCO2 -である、双性イオンリガンドであり、更に別の実施態様としては、R2がHまたはFであり、X1がメチレンであり、X2がプロピレン基又はブチレン基であり、Ra及びRbがいずれもメチルであり、R3及びR4がいずれもHであり、且つ、Y-がSO3 -、HPO3 -、又は、CO2 -である、双性イオンリガンドであり、更に別の実施態様としては、R2がH又はFであり、X1がメチレンであり、X2がプロピレン基またはブチレン基であり、Ra及びRbがいずれもメチルであり、R3及びR4がいずれもHであり、且つ、Y-がSO3 -である、双性イオンリガンドである。
ある実施態様としては、下記式(1)で示される双性イオンリガンドである。
式(8)に示される化合物の一実施態様としては、R2がH、低級アルキル、-O-低級アルキル又はハロゲンである双性イオンリガンドであり、別の実施態様としては、R2がH又はハロゲンであり、X1が結合又はメチレンであり、X2が結合又はC1-3アルキレンであり、Raがメチルであり、且つ、R3及びR4が同一又は互いに異なって、H、C1-3アルキル又はハロゲンである、双性イオンリガンドであり、更に別の実施態様としては、R2がH又はFであり、X1がメチレンであり、X2が結合又はメチレンであり、Raがメチルであり、且つ、R3及びR4がいずれもHであり、且つ、Y-がSO3 -、HPO3 -、又は、CO2 -である、双性イオンリガンドであり、更に別の態様としては、R2がH又はFであり、X1がメチレンであり、X2が結合又はメチレンであり、Raがメチルであり、且つ、R3及びR4がいずれもHであり、且つ、Y-がCO2 -である、双性イオンリガンドであり、また更に別の実施態様としては、R2がH又はハロゲンであり、X1が結合又はメチレンであり、X2がC1-5アルキレン又は結合であり、Raがメチルであり、且つ、R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、又は、ハロゲンであり、且つ、Y-がSO3 -、又は、CO2 -である、双性イオンリガンドである。
本発明のナノ粒子は、本発明の双性イオンリガンド以外を含んでいてもよく、一実施形態においてナノ粒子は、金属粒子そのものが蛍光特性を持つか、金属粒子の表面に結合された蛍光分子又は色素分子等の分子をさらに含んでいてもよい。金属粒子そのものが蛍光特性を持つか、蛍光分子又は色素分子をナノ粒子に導入することによって、ナノ粒子は、MRI用の造影剤としてのみならず、同時に、光学画像造影剤としても使用することができる。別の一実施形態として、蛍光分子又は色素分子が本発明の双性イオンリガンドと共有結合により結合したリガンドであってもよく、当該分子は酸化鉄粒子と双性イオンリガンドを介し連結されている。体内にナノ粒子が注入された後にも、蛍光分子は酸化鉄粒子の表面に存在することによって、顕微鏡イメージングならびにナノ粒子の局在化を調べるのに利用することができる。蛍光分子及び色素分子としては、ローダミン、フルオレセイン、ニトロベンゾオキサジアゾール(NBD)、シアニン、緑色蛍光タンパク質(GFP)、クマリン及びこれらの誘導体が挙げられる。
本発明の式(I)の双性イオンリガンドの製造方法は特に限定されず、当業者に周知の反応を用いて公知原料化合物から容易に製造することができる。例えば、Wei H. et al., Nano Lett. 12, 22-25, 2012に記載の方法を参考にすることができる。
次に、ナノ粒子の製造方法について説明する。
(原料となる疎水性リガンド又は親水性リガンドが配位結合した金属粒子の製造)
ナノ粒子の製造原料となる疎水性リガンド又は親水性リガンドが配位結合した金属粒子は、公知の方法を用いて製造することができる。例えば、Byung Hyo Kim et al., J Am. Chem. Soc. 2011, 133, 12624-12631、及びByung Hyo Kim et al., J Am. Chem. Soc. 2013, 135, 2407-2410に記載の方法を参考に行うことができる。
以下、各工程について詳細に説明する。
金属塩及び、脂肪酸のアルカリ金属塩を溶媒に分散させる。ここで、上記金属塩としては、塩化鉄(III)六水和物(FeCl3・6H2O)が、脂肪酸のアルカリ金属塩としては、オレイン酸ナトリウムが、溶媒としてはエタノール、水、ヘキサン、及びこれらの混合物が挙げられる。続いて、加温下、好ましくは70℃で、1~10時間、好ましくは3~4時間撹拌し、有機層を回収し、該有機層の水による洗浄を1~複数回、より好ましくは3~4回繰り返し、金属脂肪酸錯体を得る。所望により得られた有機層を乾燥する。
例えばアルゴン(Ar)及び窒素から選択される不活性ガス雰囲気下で、工程(a)で得られた錯体に、脂肪酸、脂肪族アルコール及び脂肪族アミンからなる群から選択される少なくとも1つの界面活性剤、及びジフェニルエーテル及びフェニルオクチルエーテルから選択される溶媒を添加する。一例として、界面活性剤がオレイン酸、オレイルアルコール、オレイルアミン又はこれらの混合物であり、溶媒はジフェニルエーテルが挙げられる。次に、この混合物を室温から180~300℃まで急速に昇温し、所望により、そのまま10分から数時間撹拌する。一例として、30℃から250℃まで10℃/minで昇温し、250℃で30分間撹拌する。別の一例として、30℃から200℃まで10℃/minで昇温し、200℃で30分間撹拌する。
Ar及び窒素から選択される不活性ガス雰囲気下で、疎水性リガンドで被覆されたナノ粒子を溶媒に分散させた後に、MEAAを添加して反応させる。溶媒としてはメタノールが好適である。
本発明の「双性イオンリガンドが1つ以上配位結合した酸化鉄を含有する金属粒子を含む、ナノ粒子」は公知のMEAAで表面が被覆された金属粒子を経由する方法(MEAA法)、TMA(OH)を用いた方法(TMA(OH)法)、あるいは、相間移動触媒を用いた新規な合成方法を用いることによって製造することができる。
A)MEAA法
本製法は、MEAAで表面が被覆された金属粒子と、本発明の双性イオンリガンド化合物とを反応させて本発明のナノ粒子を得る方法である。反応は、MEAAで表面が被覆された金属粒子と、本発明の双性イオンリガンド化合物とを、Ar及び窒素から選択される不活性ガス雰囲気下で、室温もしくは加温下で1~数十時間撹拌することにより行われる。一例としてAr雰囲気下で行われる。反応温度は一例として25~80℃であり、別の一例として50~70℃である。撹拌時間は、一例として5~7時間、別の一例として24時間である。一例として、室温で終夜撹拌する。続いて、反応溶液の温度を室温まで低下させ、溶媒を添加して遠心し、上清を除去して、本発明の双性イオンリガンド化合物が1つ以上配位結合したナノ粒子を得る。溶媒は特に限定されないが、アセトン、ヘキサン等から選択される。一例としてアセトンを用いる。またこの溶媒添加、遠心及び上清除去の操作は複数回繰り返してもよく、例えば4~5回繰り返してもよい。一例としてこの操作を3回繰り返す。続いて得られた本発明の双性イオンリガンド化合物が被覆したナノ粒子を含む溶液を、遠心式限外ろ過フィルター等の濃縮カラム等を用いて濃縮してもよい。この濃縮操作は複数回繰り返してもよく、途中でPBS等の溶液を添加して濃縮操作を繰り返してもよい。
オレイン酸で被覆された酸化鉄粒子(SNP-OA)をヘキサン溶液中に懸濁させ、1.7%テトラメチルアンモニウムヒドロキシド(TMA(OH))水溶液と混合して激しく振盪する。得られた溶液から遠心分離によって水層を分離し、アセトンを加え、8000~12000rpmで5~10分間遠心し、上澄みを取り除く。得られた沈殿に対し0.1%TMA(OH)溶液2mLを加え分散させ、再び10mLのアセトンを加えて沈殿させる。この操作を複数回繰り返してもよく、好ましくは3~4回繰り返す。得られた溶液を、0.1%TMA(OH)溶液に分散させて保存する。
上記の手順で作成した0.1%TMA(OH)溶液に0.1%~2%のTMA(OH)溶液を用いてpH8~12程度に調製したリガンド化合物の溶液を加える。得られた溶液を室温で6~24時間撹拌し、アセトンを加えて沈殿させ8000~12000rpmで3~10分間遠心し、上澄みを取り除く。この沈殿をリン酸緩衝液に分散させ、濃縮カラムを用い7000~12000rpmで遠心することにより溶液量を減少させる。そこにリン酸緩衝液を加え再び7000~12000rpmで10~20分遠心し濃縮する。この操作を複数回繰り返してもよく、好ましくは3~4回、より好ましくは5~10回繰り返して、本発明の双性イオンリガンドが1つ以上配位結合したナノ粒子を得る。得られたナノ粒子の溶液を、PBSで希釈し、保存してもよい。
表面にオレイン酸等の疎水性リガンドが配位結合した金属粒子を有機層と水層との二層系溶媒中、相間移動触媒の存在下で、本発明の双性イオンリガンド化合物とを接触させて、本発明の双性イオンリガンドが1つ以上配位結合したナノ粒子を製造する方法である。
「有機層と水層の二層系溶媒」としては、有機溶媒と水の混合溶媒であって、二層に分離するものある。有機溶媒としては、非プロトン性溶媒であり、一実施態様では、2-メチルテトラヒドロフラン(2-Me-THF)、シクロペンチルメチルエーテル(CPME)、メチルtert-ブチルエーテル(MTBE)、クロロホルム、トルエン、キシレン、ヘプタン及びこれらの組み合わせからなる群から選択される。別の態様としては、2-メチルテトラヒドロフラン、クロロホルム及びこれらの組み合わせから選択される。
本反応において、双性イオンリガンドは、金属粒子に対して1~30wt(重量比)、ある態様としては5~20wt、別の態様としては、6~15wtの比率で用いることができる。相関移動触媒は、金属粒子に対して0.1~10wt、ある態様としては0.1wt~6wt、別の態様としては0.1wt~5wt、別の態様としては0.5~6wt、別の態様としては0.5~3wt、更に別の態様としては0.5wt~2wtの比率で加えることによって行うことができる。更にpH調整剤を用いる場合は、相関移動触媒は、金属粒子に対して0.1wt~5wt、ある態様としては0.5wt~2wtの比率で加えることによって行うことができる。
一実施態様としては、酸化鉄を含有する金属粒子の外表面に双性イオンリガンド化合物が1つ以上配位結合して、該双性イオンリガンド化合物によって当該金属粒子が被覆された粒子が製造される。
一実施態様としては、1以上の「1つ以上の双性イオンリガンド化合物が配位結合した酸化鉄を含有する金属粒子」と、1以上の双性イオンリガンド化合物からなる複合体として、微小な粒子が製造される。
一実施態様としては、2以上の双性イオンリガンド化合物と、2以上の「1つ以上の双性イオンリガンド化合物が配位結合した酸化鉄を含有する金属粒子」からなるクラスターが製造される。
いずれの形態であっても、本発明のナノ粒子は磁気共鳴イメージング用造影剤として使用できる。
一実施態様としては後記実施例に記載の方法である。
本発明は、上述のナノ粒子を含む、磁気共鳴イメージング用造影剤も提供する。
i)ナノ粒子
一実施形態において、本発明のMRI用造影剤は、上述したナノ粒子を、少なくとも1種類含んでいることを特徴とする。別の実施形態において、本発明のMRI用造影剤は、上述したナノ粒子の2種類以上の組み合わせを含んでいてもよい。
MRI用造影剤に含まれる溶媒としては、水、緩衝液等が挙げられ、緩衝液としては、さらに、生理食塩水、リン酸緩衝液、トリス緩衝液、ホウ酸緩衝液、リンガー溶液等が挙げられる。剤型が注射剤である場合の好ましい溶媒は、例えば水、リンガー溶液、生理食塩水等である。
MRI用造影剤に含まれる担体、錯体、ビヒクル等の添加剤としては、医薬分野及び生命工学分野において一般的に使用される担体、ビヒクル等が挙げられる。担体の例としては、ポリエチレングリコール等のポリマー、金属微粒子等が挙げられ、錯体の例としては、ジエチレントリアミン5酢酸(DTPA)、1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラ酢酸(DOTA)、等が挙げられ、ビヒクルの例としては、石灰、ソーダ灰、ケイ酸ソーダ、デンプン、膠、ゼラチン、タンニン及びケブラチョが挙げられる。
本発明のMRI用造影剤の剤型は特に限定されず、液体、固体又は半固体若しくは半液体とすることができる。これらの剤型は、当業者に公知の方法に基づき、容易に製造することができる。剤型が液体の場合は例えば水性の溶媒に本発明に係るナノ粒子を分散、懸濁又は溶解して含有させた形態であり得る。また凍結乾燥剤の形態として、使用する際に分散、懸濁又は溶解して用いるものであってもよい。
MRI用造影剤中のナノ粒子の濃度は目的及び造影対象組織等に応じて適宜決定される。例えば、適当な造影能を有し且つ生体への影響が許容できる範囲の濃度が選択される。
本発明に係る造影剤の投与の対象としては任意のヒト以外の生物又はヒトが挙げられる。ヒト以外の生物としては、哺乳類(例えば、マウス、ラット、ウサギなどのげっ歯類、サルなどの霊長類、イヌ、ネコ、ヒツジ、ウシ、ウマ、及びブタ等)、鳥類、爬虫類、両生類、魚類、昆虫及び植物を含むが、これらに限定されない。ある態様において、動物は、トランスジェニック動物、遺伝子操作された動物又はクローン生物であり得る。また、生体以外の投与対象としては、組織試料又は細胞を含む生物学的材料であり得る。
MRI用造影剤には、前記の通り陽性造影剤及び陰性造影剤の2種類が存在している。
常磁性と超常磁性の境界内又は常磁性を示すことは、超電導量子干渉計(SQUID)を用いて磁化の磁場依存性を測定することにより、確認することが出来る。図7に300Kにおける測定例を示した。磁化率は磁場に対してほぼ比例関係にあり、超常磁性としての性質は低いと考えられ、ナノ粒子でありながら常磁性の性質を有し、実用磁場領域において優れたT1短縮効果が期待できる。
一実施形態において、本発明に係る造影剤の造影能は、37℃及び1.5Tの磁場で、r2緩和能が2.8~6.2mM-1s-1であり、r1緩和能は2.5~4.4mM-1s-1の範囲である。別の実施形態において、本発明に係る造影剤の造影能は、37℃及び1.5Tの磁場で、r2緩和能が3.0~4.2mM-1s-1であり、r1緩和能は2.7~3.9mM-1s-1の範囲である。
本発明のMRI用造影剤は、ナノ粒子の安定性が高く、後記試験例3に記載の方法によって凝集の度合いの確認が可能であり、溶液中において、室温又は4℃で長期間凝集することなく保存可能であることが期待される。また生物に対して毒性が低く、長期的かつ連続的な生体への適用も可能であることが期待される。
上記の課題を解決するために、本発明は、以下の何れかの一態様を包含する。
なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。
<1>
1つ以上の式(I)で表される双性イオンリガンドが配位結合した、酸化鉄を含有する金属粒子を含むナノ粒子。
R1及びR2の一方は、式(a)又は式(b)で示される基であり、他方は、H、低級アルキル、-O-低級アルキル又はハロゲンであり、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となって5又は6員含窒素飽和ヘテロ環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、-O-C1-3アルキル又はハロゲンであり、
nは0~2の整数であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよく、
ii)R1が式(a)で示される基であり、且つ、X1がエチレンであるとき、R2とRaまたはRbとが一体となってメチレンを形成してもよく、及び
iii)R2が式(a)で示される基であり、且つ、X1がメチレンであるとき、R3とRaまたはRbとが一体となってエチレンを形成してもよい、
但し、R2が式(a)で示される基であり、Ra及びRbがメチルであり、X1が結合であり、X2が、C1-4アルキレンであり、且つ、R1、R3及びR4がいずれもHであるとき、Y-はHPO3 -、又は、CO2 -である。)
<2>
双性イオンリガンドが、
R1及びR2の一方が、式(a)又は式(b)で示される基であり、他方が、H、低級アルキル又はハロゲンであり、
X1は、結合又はメチレンであり、更にR1が式(a)で示される基のときX1はエチレンであってもよく、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となってピロリジン環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、又はハロゲンであり、
nは1であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよい、
双性イオンリガンドである<1>のナノ粒子。
<3>
双性イオンリガンドが、
R1が、式(a)又は式(b)で示される基であり、R2が、H又はハロゲンであり、
X1は、結合又はメチレンであり、更にR1が式(a)で示される基のときX1はエチレンであってもよく、
X2は、C1-5アルキレンであり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、いずれもメチルであり、
Y-は、SO3 -又は、CO2 -である、
双性イオンリガンドである<2>のナノ粒子。
<4>
双性イオンリガンドが、R1及びR2の一方が式(a)で示される基であり、他方が、H、低級アルキル、-O-低級アルキル又はハロゲンである、双性イオンリガンドである<1>のナノ粒子。
<5>
双性イオンリガンドが、
1)R1が式(a)で示される基であり、且つ、R2がH、低級アルキル、-O-低級アルキル又はハロゲンである双性イオンリガンドであるか、又は、
2)R1がHであり、R2が式(a)で示される基であり、R3がC1-3アルキル又はハロゲンであり、且つ、R4がHである、
双性イオンリガンドである、<4>のナノ粒子。
<6>
双性イオンリガンドが、R1が式(a)で示される基であり、且つ、R2がH、低級アルキル、-O-低級アルキル又はハロゲンである、双性イオンリガンドである、<5>のナノ粒子。
<7>
双性イオンリガンドが、
R2がH又はハロゲンであり、
X1が結合、メチレン又はエチレンであり、
X2がC2-4アルキレンであり、
Ra及びRbがいずれもメチルであり、
R3及びR4が同一又は互いに異なって、H、C1-3アルキル又はハロゲンであり、
更に、X1がメチレンであるとき、R2とRaもしくはRbとが一体となってエチレンを形成してもよい、
双性イオンリガンドである、<6>のナノ粒子。
<8>
双性イオンリガンドが、
R2がHまたはFであり、
X2がエチレン又はプロピレンであり、
R3及びR4がいずれもHである、
双性イオンリガンドである、<7>のナノ粒子。
<9>
双性イオンリガンドが、
R2がHであり、
X1が結合又はエチレンであり、
双性イオンリガンドである、<8>のナノ粒子。
<10>
双性イオンリガンドが、
Y-がSO3 -又はCO2 -である、
双性イオンリガンドである、<4>~<9>のいずれかに記載のナノ粒子。
<11>
双性イオンリガンドが、
R1が、下式(b-1)で示される基であり、
X1は、結合又はメチレンであり、
X2は、C1-5アルキレン又は結合であり、
Raがメチルであり、
Y-がSO3 -、又は、CO2 -である、
双性イオンリガンドである、<3>のナノ粒子。
<12>
酸化鉄を含有する金属粒子が、酸化鉄のみを含有する金属粒子である、<1>~<11>のいずれかに記載のナノ粒子。
<13>
ナノ粒子が、酸化鉄を含有する金属粒子の外表面に双性イオンリガンドが1つ以上配位結合して形成された粒子であり、該双性イオンリガンドによって当該金属粒子が被覆されている、ナノ粒子である<1>~<12>のいずれかに記載のナノ粒子。
<14>
ナノ粒子が、
1つ以上の双性イオンリガンドが配位結合した酸化鉄を含有する金属粒子、及び、
1つ以上の双性イオンリガンド、
からなる複合体である、<1>~<12>のいずれかに記載のナノ粒子。
<15>
ナノ粒子が、
2以上の双性イオンリガンド化合物、及び
2以上の「1つ以上の双性イオンリガンド化合物が配位結合した酸化鉄を含有する金属粒子」、
からなるクラスターである、<1>~<12>のいずれかに記載のナノ粒子。
<16>
<1>~<15>のいずれかに記載のナノ粒子を含む、磁気共鳴イメージング用造影剤。
<17>
陽性造影剤である、<16>の磁気共鳴イメージング用造影剤。
<18>
<1>のナノ粒子を製造するための、下式(I)で表される双性イオンリガンド化合物の使用。
R1及びR2の一方は、下式(a)又は式(b)で示される基であり、他方は、H、低級アルキル、-O-低級アルキル又はハロゲンであり、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となって5又は6員含窒素飽和ヘテロ環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、-O-C1-3アルキル又はハロゲンであり、
nは0~2の整数であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよく、
ii)R1が式(a)で示される基であり、且つ、X1がエチレンであるとき、R2とRaまたはRbとが一体となってメチレンを形成してもよく、及び
iii)R2が式(a)で示される基であり、且つ、X1がメチレンであるとき、R3とRaまたはRbとが一体となってエチレンを形成してもよい、
但し、R2が式(a)で示される基であり、Ra及びRbがメチルであり、X1が結合であり、X2が、C1-4アルキレンであり、且つ、R1、R3及びR4がいずれもHであるとき、Y-はHPO3 -、又は、CO2 -である。)
<19>
双性イオンリガンド化合物が、R1及びR2の一方が、式(a)で示される基であり、他方が、H、低級アルキル、-O-低級アルキル又はハロゲンである双性イオンリガンド化合物である、<18>の使用。
<20>
下式(I)で表される化合物又はその塩。
R1及びR2の一方は、下式(a)又は式(b)で示される基であり、他方は、H、低級アルキル、-O-低級アルキル又はハロゲンであり、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となって5又は6員含窒素飽和ヘテロ環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、-O-C1-3アルキル又はハロゲンであり、
nは0~2の整数であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよく、
ii)R1が式(a)で示される基であり、且つ、X1がエチレンであるとき、R2とRaまたはRbとが一体となってメチレンを形成してもよく、及び
iii)R2が式(a)で示される基であり、且つ、X1がメチレンであるとき、R3とRaまたはRbとが一体となってエチレンを形成してもよい、
但し、R2が式(a)で示される基であり、Ra及びRbがメチルであり、X1が結合であり、X2が、C1-4アルキレンであり、且つ、R1、R3及びR4がいずれもHであるとき、Y-はHPO3 -、又は、CO2 -である。)
<21>
R1及びR2の一方が、式(a)又は式(b)で示される基であり、他方が、H、低級アルキル又はハロゲンであり、
X1は、結合又はメチレンであり、更にR1が式(a)で示される基のときX1はエチレンであってもよく、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となってピロリジン環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、又はハロゲンであり、
nは1であり、
更に、i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよい、
<20>の化合物又はその塩。
<22>
R1が、式(a)又は式(b)で示される基であり、R2が、H又はハロゲンであり、
X1は、結合又はメチレンであり、更にR1が式(a)で示される基のときX1はエチレンであってもよく、
X2は、C1-5アルキレンであり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、いずれもメチルであり、
Y-は、SO3 -又は、CO2 -である、<21>の化合物又はその塩。
<23>
R1及びR2の一方が、式(a)で示される基であり、他方が、H、低級アルキル、-O-低級アルキル又はハロゲンである、<20>の化合物又はその塩。
<24>
4-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナート、
3-{[(6-フルオロ-2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート、
ヒドロゲン=(3-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロピル)ホスホナート、
5-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ペンタノアート
{1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム-4-イル}アセタート、
1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム-4-カルボキシラート、
4-{[2-(2,3-ジヒドロキシフェニル)エチル](ジメチル)アザニウムイル}ブタノアート、
2-{[2-(2,3-ジヒドロキシフェニル)エチル](ジメチル)アザニウムイル}エタン-1-スルホナート、及び
3-[(2,3-ジヒドロキシフェニル)(ジメチル)アザニウムイル]プロパン-1-スルホナート
からなる群から選択される<20>の化合物又はその塩。
<25>
{1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム-4-イル}アセタート、及び
2-{[2-(2,3-ジヒドロキシフェニル)エチル](ジメチル)アザニウムイル}エタン-1-スルホナート
からなる群から選択される<24>の化合物又はその塩。
<26>
4-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナート、及び
3-{[(6-フルオロ-2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート
からなる群から選択される<24>の化合物又はその塩。
本発明は上述した各実施形態に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、異なる実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。さらに、各実施形態にそれぞれ開示された技術的手段を組み合わせることにより、新しい技術的特徴を形成することができる。
また、実施例、製造例及び後記表中において、以下の略号を用いることがある。
Agilent Captiva Premium Syringe Filters(Regenerated Cellulose、15mm、ポアサイズ:0.2μm)やYMC Duo-Filter(XQUO15ポアサイズ0.2μm)を用いた粒子の濾過操作は、メンブレン(0.2μm)濾過と記す。
また後記実施例表中の破線は、金属粒子表面の金属原子との配位結合を表す。
なお、双性イオンリガンド化合物、鉄オレイン酸錯体及びオレイン酸で被覆された酸化鉄ナノ粒子(SNP-OA)の製造実施例を製造例に、SNP-OAから直接又はSNP-MEAAを経由した、双性イオンリガンド化合物が配位結合したナノ粒子の製造例を実施例に記載した。
6-フルオロ-2,3-ジメトキシベンズアルデヒド(2.50g)に9.5mol/Lジメチルアミン水溶液(7.1mL)を加え、室温で15時間撹拌した。これに水浴下、水素化ホウ素ナトリウム(514mg)を加え、室温で2時間撹拌した。氷浴下、濃塩酸を加えた(pH1-2)。水層をジクロロメタンで二回洗浄した。この水層に1mol/L水酸化ナトリウム水溶液を加えた(pH>11)。これをジクロロメタンで三回抽出し、無水硫酸ナトリウムで乾燥した。濾過後、濃縮し、1-(6-フルオロ-2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(2.46g)を得た。
4-フルオロ-2,3-ジメトキシベンズアルデヒド(2.50g)、ジクロロメタン(75mL)、2mol/LジメチルアミンTHF溶液(13.6mL)の混合物に、水浴下、トリアセトキシ水素化ホウ素ナトリウム(3.74g)を加え、室温で1時間撹拌した。塩基性シリカゲルを加え、減圧下濃縮した。塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン-クロロホルム)で精製し、1-(4-フルオロ-2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(2.81g)を得た。
1-(2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(3.82g)、1,2λ6-オキサチオラン-2,2-ジオン(1.89mL)、酢酸エチル(38.2mL)の混合物を室温で7日間撹拌した。更に1,2λ6-オキサチオラン-2,2-ジオン(515μL)を追加して50℃で4時間撹拌した。室温まで放冷後、固体を濾取し、酢酸エチルで洗浄し、減圧乾燥して、3-{[(2,3-ジメトキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(5.41g)を得た。
1-(2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(3.00g)、炭酸ナトリウム(1.63g)、2-ブロモエタン-1-スルホン酸ナトリウム(3.24g)、水(6mL)、エタノール(30mL)の混合物を75℃で3日間撹拌した。更に2-ブロモエタン-1-スルホン酸ナトリウム(3.24g)を追加して80℃で2日間撹拌した。更に2-ブロモエタン-1-スルホン酸ナトリウム(3.24g)を追加して80℃で2日間撹拌した。室温まで放冷後、減圧濃縮した。水を加えて逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、2-{[(2,3-ジメトキシフェニル)メチル](ジメチル)アザニウムイル}エタン-1-スルホナート(3.50g)を得た。
1-(2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(2.00g)、1,2λ6-オキサチアン-2,2-ジオン(1.36mL)、酢酸エチル(20mL)の混合物を50℃で3時間撹拌した後、70℃で24時間撹拌した。更に1,2λ6-オキサチアン-2,2-ジオン(1.04mL)を追加して70℃で24時間撹拌した。室温まで放冷後、固体を濾取し、酢酸エチルで洗浄し、減圧乾燥して、4-{[(2,3-ジメトキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナート(2.28g)を得た。
2-フルオロ-4,5-ジメトキシアニリン(2.50g)、1,2λ6-オキサチオラン-2,2-ジオン(1.54mL)、アセトニトリル(63mL)の混合物を115℃で8時間撹拌した。更に1,2λ6-オキサチオラン-2,2-ジオン(0.64mL)を追加して115℃で8時間撹拌した。室温まで放冷後、固体を濾取し、アセトニトリルで洗浄し、50℃で減圧乾燥して、3-(2-フルオロ-4,5-ジメトキシアニリノ)プロパン-1-スルホン酸(4.00g)を得た。
3-(2-クロロエトキシ)プロパン-1-スルホン酸(1.46g)、ジオキサン(22mL)、水(11mL)の混合物に、3,4-ジメトキシアニリン(1.66g)、ヨウ化カリウム(1.79g)、炭酸カリウム(2.49g)を加え、100℃で、終夜撹拌した。反応液を室温まで放冷後、濃縮し、逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、凍結乾燥することにより、3-[2-(3,4-ジメトキシアニリノ)エトキシ]プロパン-1-スルホン酸(532mg)を得た。
2-メトキシ-N-(2-メトキシエチル)エタン-1-アミン(3.0mL)、1,2λ6-オキサチオラン-2,2-ジオン(2.0mL)、アセトニトリル(27mL)の混合物を80℃で4時間撹拌した。室温まで放冷後、濃縮し、ジエチルエーテルを加え、室温で2時間撹拌後、固体を濾取し、室温で減圧乾燥することにより、3-[ビス(2-メトキシエチル)アミノ]プロパン-1-スルホン酸(5.00g)を得た。
1-(2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(1.70g)、3-クロロ-2-ヒドロキシプロパン-1-スルホン酸ナトリウム(3.42g)、ヨウ化カリウム(1.73g)、エタノール(26mL)、水(7.7mL)の混合物を80℃で終夜撹拌した。室温まで放冷後、濃縮し、逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、凍結乾燥することにより、3-{[(2,3-ジメトキシフェニル)メチル](ジメチル)アザニウムイル}-2-ヒドロキシプロパン-1-スルホナート(2.17g)を得た。
7,8-ジメトキシ-1,2,3,4-テトラヒドロイソキノリン(1.80g)、1,2λ6-オキサチオラン-2,2-ジオン(0.98mL)、炭酸カリウム(1.29g)、アセトニトリル(45mL)の混合物を100℃で8時間撹拌した。室温まで放冷後、水を加え、濃縮し、逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、凍結乾燥することにより、3-(7,8-ジメトキシ-3,4-ジヒドロイソキノリン-2(1H)-イル)プロパン-1-スルホン酸(1.79g)を得た。
1-(2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(1.30g)、(3-ブロモプロピル)ホスホン酸ジエチル(1.66mL)、エタノール(6.50mL)の混合物を80℃で6時間撹拌した。室温まで放冷後、濃縮し、逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、3-(ジエトキシホスホリル)-N-[(2,3-ジメトキシフェニル)メチル]-N,N-ジメチルプロパン-1-アミニウム=ブロミド(2.70g)を得た。
3-[ビス(2-メトキシエチル)アミノ]プロパン-1-スルホン酸(3.00g)、1-(クロロメチル)-2,3-ジメトキシベンゼン(4.39g)、炭酸カリウム(1.95g)、エタノール(45mL)の混合物を80℃で終夜撹拌した。室温まで放冷後、濃縮し、逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、凍結乾燥することにより、3-{[(2,3-ジメトキシフェニル)メチル]ビス(2-メトキシエチル)アザニウムイル}プロパン-1-スルホナート(3.09g)を得た。
(3-ブロモプロピル)ホスホン酸ジエチル(2.53g)、3,4-ジメトキシアニリン(3.00g)の混合物をアルゴン雰囲気下95℃で6時間攪拌した。室温まで放冷し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで一回抽出した。有機層を飽和食塩水で一回洗浄し、無水硫酸マグネシウムで乾燥した。濾過後、濃縮し、シリカゲルカラムクロマトグラフィー(展開溶媒; ヘキサン-酢酸エチル、ついで酢酸エチル-メタノール)で精製することにより[3-(3,4-ジメトキシアニリノ)プロピル]ホスホン酸ジエチル(1.74g)を得た。
1-(2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(2.00g)と4-ブロモブタン酸エチル(2.60g)の混合物を80℃で3時間攪拌した。これを逆相カラムクロマトグラフィー(展開溶媒; 水-アセトニトリル)で精製することによりN-[(2,3-ジメトキシフェニル)メチル]-4-エトキシ-N,N-ジメチル-4-オキソブタン-1-アミニウム=ブロミド(3.93g)を得た。
1-(6-フルオロ-2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(1.20g)、1,2λ6-オキサチオラン-2,2-ジオン(990μL)、酢酸エチル(12mL)の混合物を50℃で18時間撹拌した。室温まで放冷後、固体を濾取し、酢酸エチルで洗浄し、減圧乾燥して、3-{[(6-フルオロ-2,3-ジメトキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(1.79g)を得た。
1-(2,3-ジメトキシフェニル)-N,N-ジメチルメタンアミン(2.00g)と5-ブロモペンタン酸エチル(2.79g)の混合物を80℃で3時間攪拌した。これを逆相カラムクロマトグラフィー(展開溶媒; 水-アセトニトリル)で精製することにより、N-[(2,3-ジメトキシフェニル)メチル]-5-エトキシ-N,N-ジメチル-5-オキソペンタン-1-アミニウム=ブロミド(3.91g)を得た。
3-(2-フルオロ-4,5-ジメトキシアニリノ)プロパン-1-スルホン酸(4.00g)、炭酸カリウム(4.52g)、ヨウ化メチル(7.7mL)、メタノール(60mL)の混合物を50℃で終夜撹拌した。室温まで放冷後、濃縮し、逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、凍結乾燥することにより、3-[(2-フルオロ-4,5-ジメトキシフェニル)(ジメチル)アザニウムイル]プロパン-1-スルホナート(4.34g)を得た。
3-(3,4-ジメトキシアニリノ)プロパン-1-スルホン酸(2.00g)、1,4-ジヨードブタン(1.04mL)、炭酸カリウム(2.21g)、ジオキサン(30mL)、水(15mL)の混合物を100℃で終夜撹拌した。室温まで放冷後、濃縮し、逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、凍結乾燥することにより、3-[1-(3,4-ジメトキシフェニル)ピロリジン-1-イウム-1-イル]プロパン-1-スルホナート(2.37g)を得た。
3-(3,4-ジメトキシアニリノ)プロパン-1-スルホン酸(2.00g)、ヨウ化エチル(2.94mL)、炭酸カリウム(2.41g)、メタノール(30mL)の混合物を50℃で終夜撹拌した。ヨウ化メチル(4.1mL)を加え、引き続き50℃で終夜撹拌した。室温まで放冷後、濃縮し、逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、凍結乾燥することにより、3-[(3,4-ジメトキシフェニル)(エチル)(メチル)アザニウムイル]プロパン-1-スルホナート(2.14g)を得た。
3-{[(2,3-ジメトキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(5.41g)、57%ヨウ化水素酸(24mL)の混合物を110℃で15時間撹拌した。室温まで放冷後、水(30mL)を加え減圧下濃縮した。この操作をもう一度繰り返した。これに水(6mL)を加え溶解させた後、アセトン(100mL)を加え、氷浴下3分間攪拌した。静置した後、上澄みをデカンテーションで除去した。さらに水(6mL)、アセトン(75mL)を加え、もう一度同様の操作を行った。これに水(6mL)、アセトン(75mL)を加え、氷浴下3分間攪拌した後、固体を濾取しアセトンで洗浄し、減圧乾燥して、3-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(5.02g)を得た。
アルゴン雰囲気下、ドライアイスーアセトンバス冷却下、3-{[(2,3-ジメトキシフェニル)メチル]ビス(2-メトキシエチル)アザニウムイル}プロパン-1-スルホナート(2.59g)、ジクロロメタン(52mL)の混合物に、1mol/L三臭化ホウ素ジクロロメタン溶液(19.2mL)を滴下し、ゆっくり3時間かけて室温まで昇温し、室温で2時間撹拌した。氷冷下メタノールを加え、室温で30分間撹拌し減圧下濃縮した。残渣にメタノールを加えて再び減圧下濃縮した。この操作を後2回行い、逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製し、凍結乾燥することにより、3-{[(2,3-ジヒドロキシフェニル)メチル]ビス(2-メトキシエチル)アザニウムイル}プロパン-1-スルホナート(674mg)を得た。
4-{[(2,3-ジメトキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナート(2.28g)、57%ヨウ化水素酸(9.6mL)の混合物を110℃で4時間撹拌した。室温まで放冷後、水を加え減圧下濃縮した。この操作をもう一度繰り返した。これに水(4mL)を加え溶解させた後、アセトン(80mL)を加え、攪拌、静置した後、上澄みをデカンテーションで除去した。さらにミリポア水(4mL)、アセトン(60mL)を加え、同様の操作を行った。これにミリポア水(4mL)、アセトン(60mL)を加え、攪拌した後、固体を濾取し、アセトンで洗浄し、減圧乾燥して、4-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナート(2.45g)を得た。
3-{[(6-フルオロ-2,3-ジメトキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(1.79g)、57%ヨウ化水素酸(7.5mL)の混合物を110℃で6時間撹拌した。室温まで放冷後、水を加え減圧下濃縮した。この操作をもう一度繰り返した。これにアセトン(70mL)を加え、氷冷下攪拌した。一晩静置し固体を析出させた後、氷冷下1時間攪拌した。静置した後、上澄みをデカンテーションで除去した。これにアセトンを加えた後、固体を濾取し、アセトンで洗浄し、減圧乾燥して、3-{[(6-フルオロ-2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(1.58g)を得た。
3-(ジエトキシホスホリル)-N-[(2,3-ジメトキシフェニル)メチル]-N,N-ジメチルプロパン-1-アミニウム=ブロミド(2.80g)、57%ヨウ化水素酸(8mL)の混合物を100℃で18時間撹拌した。室温まで放冷後、水とアセトンを加え、減圧下濃縮した。これに水を加え、減圧下濃縮した。これに水を加え、不溶物を濾別し、濾液を減圧下濃縮した。これにアセトンを加え、生じた固体を濾過した。これをアセトンで洗浄し、減圧乾燥して、N-[(2,3-ジヒドロキシフェニル)メチル]-N,N-ジメチル-3-ホスホノプロパン-1-アミニウム=ヨージド(571mg)を得た。
N-[(2,3-ジメトキシフェニル)メチル]-4-エトキシ-N,N-ジメチル-4-オキソブタン-1-アミニウム=ブロミド(3.91g)、57%ヨウ化水素酸(22.5g)の混合物を110℃で15時間撹拌した。濃縮し、得られた残渣に水を加え、減圧下濃縮した。この操作をもう1回繰り返した。これにアセトンを加え、氷浴下冷却し、上澄みを除去した。これにアセトンを加え、氷浴下冷却し、生じた固体を濾過した。これをアセトンで洗浄し、3-カルボキシ-N-[(2,3-ジヒドロキシフェニル)メチル]-N,N-ジメチルプロパン-1-アミニウム=ヨージド(2.13g)を得た。
N-[(2,3-ジメトキシフェニル)メチル]-5-エトキシ-N,N-ジメチル-5-オキソペンタン-1-アミニウム=ブロミド(3.90g)、57%ヨウ化水素酸(22.0g)の混合物を110℃で16時間撹拌した。濃縮し、得られた残渣に水を加え、減圧下濃縮した。この操作をもう1回繰り返した。これにアセトンを加え、氷浴下冷却し、上澄みを除去した。これにアセトンを加え、氷浴下冷却し、生じた固体を濾過した。これをアセトンで洗浄し、4-カルボキシ-N-[(2,3-ジヒドロキシフェニル)メチル]-N,N-ジメチルブタン-1-アミニウム=ヨージド(1.33g)を得た。濾液をすべて濃縮し、得られた残渣を逆相カラムクロマトグラフィー(展開溶媒; 水-アセトニトリル)で精製した。濃縮して生じた固体にアセトンを加え、濾過した。これをアセトンで洗浄し、4-カルボキシ-N-[(2,3-ジヒドロキシフェニル)メチル]-N,N-ジメチルブタン-1-アミニウム=ヨージド(1.29g)を得た。
塩化鉄(III)六水和物(5.80g)、オレイン酸ナトリウム(19.5g)、エタノール(43mL)、水(33mL)、ヘキサン(75mL)を混合し、アルゴン雰囲気下70℃で4時間加熱還流した。放冷後、分液漏斗に移し、水層を除去した。50mLの水を加えて洗浄し、有機層を回収した。この操作をあと2度繰り返した(2回目は50%メタノール水を使用)。得られた有機層を硫酸ナトリウムで乾燥し、減圧下濃縮してオレイン酸鉄錯体(FeOA3、19.2g)を得た。
FeOA3(6.53g)、オレイルアルコール(11.7g)、ジフェニルエーテル(36.4g)の混合物を、減圧下90℃で2時間撹拌した。その後アルゴンで常圧に戻し、バス温213℃まで16分かけて昇温し、内温200℃を超えてから30分間攪拌した。室温まで放冷後、ヘキサン(5mL)、アセトン(150mL)を加え、10℃、8000rpmで10分間遠心分離し、上澄みを除去した。得られた沈殿にヘキサンを加え(24mL)、さらにアセトン(150mL)を加えた後、10℃、8000rpmで10分間遠心分離し上澄みを除去した。この操作をもう一度繰り返し、得られた沈殿を減圧乾燥して、表面にオレイン酸が配位結合した酸化鉄ナノ粒子(SNP-OA、992mg)を得た。
2-(2,3-ジメトキシフェニル)-N,N-ジメチルエタン-1-アミン(7.71g)、水(15.4mL)、エタノール(77mL)の混合物に炭酸ナトリウム(15.6g)、2-ブロモエタン-1-スルホン酸ナトリウム(23.3g)を加え、80℃で18時間攪拌した。2-ブロモエタン-1-スルホン酸ナトリウム(11.7g)、炭酸ナトリウム(7.81g)、エタノール(20mL)、水(4mL)を加え、80℃で1日間攪拌した。濃縮後、逆相カラムクロマトグラフィー(展開溶媒; 水-アセトニトリル)で精製することにより2-{[2-(2,3-ジメトキシフェニル)エチル](ジメチル)アザニウムイル}エタン-1-スルホナート(9.00g)を得た。
2,3-ジメトキシアニリン(5.61g)、1,2λ6-オキサチオラン-2,2-ジオン(5.83g)、アセトニトリル(140mL)の混合物を8時間還流した。室温まで放冷後、氷浴下攪拌した。固体を濾取し、冷アセトニトリルで洗浄し、3-(2,3-ジメトキシアニリノ)プロパン-1-スルホン酸(5.59g)を得た。
3-(2,3-ジメトキシアニリノ)プロパン-1-スルホン酸(5.58g)、炭酸カリウム(6.72g)、ヨウ化メチル(11.4mL)、メタノール(85mL)の混合物を50℃で8時間撹拌した。ヨウ化メチル(11.4mL)を加え、50℃で24時間撹拌した。不溶物を濾過後、濃縮し、セパビーズ(登録商標)SP207SSにて精製した。濃縮し、得られた固体をエタノールに加温下溶解させた。これを室温まで放冷し、ついで氷浴下攪拌した。固体を濾過し、冷エタノールで洗浄し、3-[(2,3-ジメトキシフェニル)(ジメチル)アザニウムイル]プロパン-1-スルホナート(5.40g)を得た。
3-[(2,3-ジメトキシフェニル)(ジメチル)アザニウムイル]プロパン-1-スルホナート(5.40g)、57%ヨウ化水素酸(40g)の混合物を8時間還流した。室温まで放冷後、水を加えて減圧下濃縮した。この操作をもう二回繰り返した。これに水(3mL)を加え溶解させた後、アセトン(50mL)を加え、氷浴下30分間攪拌した。静置した後、上澄みをデカンテーションで除去した。さらに水(3mL)、アセトン(40mL)を加え、もう一度同様の操作を行った。これに水(3mL)、アセトン(40mL)を加え、氷浴下30分間攪拌し、固体を濾過、アセトンで洗浄し、3-[(2,3-ジヒドロキシフェニル)(ジメチル)アザニウムイル]プロパン-1-スルホナート(4.35g)を得た。
2-{[2-(2,3-ジメトキシフェニル)エチル](ジメチル)アザニウムイル}エタン-1-スルホナート(9.00g)、57%ヨウ化水素酸(40mL)の混合物を100℃で15時間撹拌した。濃縮し、アセトンを加え、氷浴下5分間攪拌した。生じた固体を濾過し、アセトンで洗浄し、2-{[2-(2,3-ジヒドロキシフェニル)エチル](ジメチル)アザニウムイル}エタン-1-スルホナート(3.40g)を得た。
(ピペリジン-4-イル)酢酸メチル一塩酸塩(5.00g)、1-(クロロメチル)-2,3-ジメトキシベンゼン(5.78g)、炭酸カリウム(4.64g)、アセトニトリル(50mL)の混合物を室温で終夜攪拌した。反応混合物を濾過し、濾液を濃縮し、塩基性シリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン-酢酸エチル)で精製することにより{1-[(2,3-ジメトキシフェニル)メチル]ピペリジン-4-イル}酢酸メチル(4.90g)を得た。
2-(2,3-ジメトキシフェニル)-N,N-ジメチルエタン-1-アミン(10.9g)と4-ブロモブタン酸エチル(8.28mL)の混合物を80℃で3時間攪拌した。これを逆相カラムクロマトグラフィー(展開溶媒; 水-アセトニトリル)で精製することによりN-[2-(2,3-ジメトキシフェニル)エチル]-4-エトキシ-N,N-ジメチル-4-オキソブタン-1-アミニウム=ブロミド(15.7g)を得た。
2,3-ジメトキシアニリン(5.00g)、1,2λ6-オキサチアン-2,2-ジオン(5.78g)の混合物を95℃で24時間撹拌した。これを逆相カラムクロマトグラフィー(展開溶媒:アセトニトリル-水)で精製した。濃縮し、得られた固体をアセトニトリルで洗浄し、4-(2,3-ジメトキシアニリノ)ブタン-1-スルホン酸(4.78g)を得た。
2,3-ジメトキシアニリン(5.00g)、5-ブロモペンタン酸エチル(8.19g)、トリエチルアミン(3.96g)の混合物を室温で5日間撹拌した。水を加え、酢酸エチルで一回抽出した。有機層を飽和食塩水で一回洗浄し、無水硫酸マグネシウムで乾燥した。濾過後、濃縮し、シリカゲルカラムクロマトグラフィー(展開溶媒; 一回目:ヘキサン-酢酸エチル、二回目:クロロホルム-酢酸エチル)で精製することにより5-(2,3-ジメトキシアニリノ)ペンタン酸エチル(6.26g)を得た。
{1-[(2,3-ジメトキシフェニル)メチル]ピペリジン-4-イル}酢酸メチル(4.90g)、ヨウ化メチル(5.0mL)、メタノール(74mL)の混合物を50℃で4時間撹拌した。室温まで放冷後、濃縮し、逆相シリカゲルカラムクロマトグラフィー(展開溶媒;水-アセトニトリル)で精製することにより1-[(2,3-ジメトキシフェニル)メチル]-4-(2-メトキシ-2-オキソエチル)-1-メチルピペリジン-1-イウム=ヨージド(6.54g)を得た。
1-[(2,3-ジメトキシフェニル)メチル]ピペリジン-4-カルボン酸エチル(18.8g)、ヨウ化メチル(19.1mL)、エタノール(188mL)の混合物を50℃で4時間撹拌した。室温まで放冷後、濃縮し、逆相シリカゲルカラムクロマトグラフィー(展開溶媒;水-アセトニトリル)で精製することにより1-[(2,3-ジメトキシフェニル)メチル]-4-(エトキシカルボニル)-1-メチルピペリジン-1-イウム=ヨージド(25.9g)を得た。
1-[(2,3-ジメトキシフェニル)メチル]-4-(2-メトキシ-2-オキソエチル)-1-メチルピペリジン-1-イウム=ヨージド(6.54g)、57%ヨウ化水素酸(19mL)の混合物を100℃で6時間攪拌した。室温まで放冷後、水を加え減圧下濃縮した。この操作をもう2回繰り返した。これにアセトン(30mL)を加え、室温で攪拌後、氷浴下冷却、静置し、上澄みをデカンテーションで除去した。さらにアセトンを加え、もう二回同様の操作を行った。これにアセトン(30mL)を加え、室温で攪拌後、氷浴下冷却し、固体を濾取し、4-(カルボキシメチル)-1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム=ヨージド(4.49g)を得た。
1-[(2,3-ジメトキシフェニル)メチル]-4-(エトキシカルボニル)-1-メチルピペリジン-1-イウム=ヨージド(25.9g)、57%ヨウ化水素酸(76mL)の混合物を100℃で終夜攪拌した。室温まで放冷後、水を加え減圧下濃縮した。この操作をもう2回繰り返した。これにアセトンを加え、室温で攪拌後、氷浴下冷却、静置し、上澄みをデカンテーションで除去した。さらにアセトンを加え、もう一回同様の操作を行った。これにアセトンを加え、室温で攪拌後、氷浴下冷却し、固体を濾取し、4-カルボキシ-1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム=ヨージド(10.8g)を得た。また濾液を濃縮し、逆相シリカゲルカラムクロマトグラフィー(展開溶媒;水-アセトニトリル)で精製することにより、4-カルボキシ-1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム=ヨージド(12.0g)を得た。
N-[2-(2,3-ジメトキシフェニル)エチル]-4-エトキシ-N,N-ジメチル-4-オキソブタン-1-アミニウム=ブロミド(15.7g)、57%ヨウ化水素酸(52mL)の混合物を100℃で18時間撹拌した。濃縮し、得られた残渣に水を加え、減圧下濃縮した。これにアセトニトリルを加えた。氷浴下冷却し、固体を析出させた後、濃縮した。これにアセトンを加え、室温で10分間攪拌した後、固体を濾過し、3-カルボキシ-N-[2-(2,3-ジヒドロキシフェニル)エチル]-N,N-ジメチルプロパン-1-アミニウム=ヨージド(14.8g)を得た。
アルゴン雰囲気下、SNP-OA(100mg)、MEAA(2.5mL)とメタノール(7.5mL)の混合物を、70℃で5時間攪拌した。室温まで放冷後、減圧下濃縮した。アセトン(24mL)、ヘキサン(96mL)を加え、6つに分け、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。この操作をもう1回繰り返し、SNP-MEAAを得た。
3-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(1.19g)、DMF(25mL)、水(17mL)の混合物を加熱下溶解し、炭酸水素ナトリウム(700mg)を加えた。これに先のSNP-MEAAのDMF(8mL)溶液を加え、アルゴン雰囲気下、室温で16時間攪拌した。反応混合物を水(3mL)を用いて、6つに分け、それぞれにアセトン(30mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを除去した。得られた沈殿をPBSに分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作をあと3回行った。Amicon 30K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作をあと2回行った。Amicon 10K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をあと7回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、10K精製粒子(21.2mg)を得た。Amicon 10K filterによる洗浄の濾液をAmicon 3K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、3K精製粒子(41.3mg)を得た。
アルゴン雰囲気下、SNP-OA(20mg)、MEAA(0.5mL)とメタノール(1.5mL)の混合物を、70℃で6時間攪拌した。
室温まで放冷後、アセトン(4mL)、ヘキサン(16mL)を加え、10℃、7800rpmで10分間遠心分離し上澄みを取り除いた。この操作をアセトン(1mL)、ヘキサン(4mL)を用いて3回繰り返し、SNP-MEAAを得た。
3-[(2-フルオロ-4,5-ジヒドロキシフェニル)(ジメチル)アザニウムイル]プロパン-1-スルホナート(266mg)、水(3.3mL)の混合物に、炭酸水素ナトリウム(53mg)を加えた。これに先のSNP-MEAAのDMF(6.6mL)溶液を加え、アルゴン雰囲気下、室温で15時間撹拌した。反応混合物を水(1.5mL)を用いて、2つに分け、それぞれにアセトン(30mL)を加え、10℃、7800rpmで10分間遠心分離し上澄みを取り除いた。
得られた沈殿をPBSに分散させ、Amicon 100K filterを用い、10℃、5800rpmで30分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作を後3回繰り返した。Amicon 10K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をあと2回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、10K精製粒子(9.9mg)を得た。Amicon 10K filterによる洗浄のはじめ3回分の濾液をAmicon 3K filterを用い、10℃、5800rpmで1時間遠心分離した。これに更に水を加え、10℃、5800rpmで1時間遠心分離した。この操作をあと7回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、3K精製粒子(3.2mg)を得た。
アルゴン雰囲気下、SNP-OA(20mg)、MEAA(0.5mL)とメタノール(1.5mL)の混合物を、70℃で6時間攪拌した。
室温まで放冷後、アセトン(4mL)、ヘキサン(16mL)を加え、10℃、7800rpmで10分間遠心分離し上澄みを取り除いた。この操作をアセトン(1mL)、ヘキサン(4mL)を用いて3回繰り返し、SNP-MEAAを得た。
3-(7,8-ジヒドロキシ-2-メチル-3,4-ジヒドロイソキノリン-2-イウム-2(1H)-イル)プロパン-1-スルホナート(274mg)、水(6.6mL)の混合物に、炭酸水素ナトリウム(53mg)を加えた。これに先のSNP-MEAAのDMF(13.2mL)溶液を加え、アルゴン雰囲気下、50℃で17時間撹拌した。
反応混合物を水(3mL)を用いて、4つに分け、それぞれにアセトン(30mL)を加え、10℃、7800rpmで10分間遠心分離し上澄みを取り除いた。
得られた沈殿をPBSに分散させ、Amicon 100K filterを用い、10℃、5800rpmで30分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作を後3回繰り返した。Amicon 10K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をあと2回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、10K精製粒子(17.3mg)を得た。Amicon 10K filterによる洗浄のはじめ3回分の濾液をAmicon 3K filterを用い、10℃、5800rpmで1時間遠心分離した。これに更に水を加え、10℃、5800rpmで1時間遠心分離した。この操作をあと7回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、3K精製粒子(11.1mg)を得た。
アルゴン雰囲気下、SNP-OA(40mg)、MEAA(1mL)とメタノール(3mL)の混合物を、70℃で6時間攪拌した。室温まで放冷後、減圧下濃縮した。アセトン(8mL)、ヘキサン(32mL)を加え、2つに分け、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。これにアセトン(6mL)、ヘキサン(24mL)を加えこの操作をもう1回繰り返し、SNP-MEAAを得た。
3-[(2,3-ジヒドロキシフェニル)(ジメチル)アザニウムイル]プロパン-1-スルホナート(500mg)、水(14.7mL)の混合物を加熱下溶解し、炭酸水素ナトリウム(130mg)を加えた。これに先のSNP-MEAAのDMF(2mL)溶液を加え、アルゴン雰囲気下、室温で16時間攪拌した。反応混合物を水(2mL)を用いて、4つに分け、それぞれにアセトン(30mL)を加え、10℃、7000rpmで3分間遠心分離し上澄みを除去した。得られた沈殿をPBSに分散させ、Amicon 50K filterを用い、10℃、5800rpmで10分間遠心分離した。得られた濾液をAmicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作をあと2回行った。Amicon 30K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をもう一度繰り返した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、30K精製粒子(2.1mg)を得た。Amicon 30K filterによる洗浄の濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。これに更に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をあと6回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、10K精製粒子(1.9mg)を得た。Amicon 10K filterによる洗浄の濾液をAmicon 3K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと5回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、3K精製粒子(5.0mg)を得た。
アルゴン雰囲気下、SNP-OA(20mg)、MEAA(0.5mL)とメタノール(1.5mL)の混合物を、70℃で6時間攪拌した。室温まで放冷後、アセトン(8mL)、ヘキサン(32mL)を加え、2つに分け、10℃、7300rpmで5分間遠心分離し上澄みを取り除いた。この操作をアセトン(6mL)、ヘキサン(24mL)を用いて2回繰り返し、SNP-MEAAを得た。
3-{[(3,4-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(250mg)のDMF(5mL)と水(3.3mL)の溶液を加熱下溶解し、炭酸水素ナトリウム(50mg)を加えた。これに先のSNP-MEAAのDMF(1.7mL)溶液を加え、アルゴン雰囲気下、室温で21.5時間攪拌した。反応混合物を水(3mL)を用いて、2つに分け、それぞれにアセトン(30mL)を加え、10℃、7300rpmで10分間遠心分離し上澄みを取り除いた。得られた沈殿をPBSに分散させ、Amicon 50K filterを用い、10℃、5800rpmで10分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。これにPBSを加え、10℃、5800rpmで30分間遠心分離した。これに水を加え、10℃、5800rpmで30分間遠心分離した。この操作をあと7回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して10K精製粒子(9.3mg)を得た。Amicon 10K filterによる洗浄のはじめ3回分の濾液をAmicon 3K filterを用い、10℃、5800rpmで30分間遠心分離した。これに更に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をあと5回行った。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して3K精製粒子(2.6mg)を得た。
アルゴン雰囲気下、SNP-OA(100mg)、MEAA(2.5mL)とメタノール(7.5mL)の混合物を、70℃で5時間攪拌した。室温まで放冷後、減圧下濃縮した。アセトン(24mL)、ヘキサン(96mL)を加え、6つに分け、10℃、7000rpmで10分間遠心分離し上澄みを取り除き、SNP-MEAAを得た。
4-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナート(1.31g)、水(40mL)の混合物に炭酸水素ナトリウム(900mg)を加えた。これに先のSNP-MEAAのDMF(8mL)溶液を加え、アルゴン雰囲気下、室温で16時間攪拌した。反応混合物を水(3mL)を用いて、6つに分け、それぞれにアセトン(30mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。得られた沈殿をPBSに分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作をあと3回行った。Amicon 30K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作をあと6回行った。Amicon 10K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をあと7回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、10K精製粒子(117.7mg)を得た。Amicon 10K filterによる洗浄の濾液を順次Amicon 3K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、3K精製粒子(53.2mg)を得た。なお、当該3K精製粒子を塩酸を用いて酸加水分解し、HPLCにて分析した結果、双性イオンリガンド、4-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナートの存在が確認されたことから、当該3K精製粒子には該双性イオンリガンドが配位結合していたことが確認された。
HPLC条件を以下に示す。
カラム:YMC Triart C18
溶離液:10mM リン酸水素二カリウム (pH6.0)/アセトニトリル (98 : 2)
アルゴン雰囲気下、SNP-OA(100mg)、MEAA(2.5mL)とメタノール(7.5mL)の混合物を、70℃で5時間攪拌した。室温まで放冷後、減圧下濃縮した。アセトン(24mL)、ヘキサン(96mL)を加え、6つに分け、10℃、7000rpmで10分間遠心分離し上澄みを取り除き、SNP-MEAAを得た。
3-{[(6-フルオロ-2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(1.32g)、水(40mL)の混合物に炭酸水素ナトリウム(650mg)を加えた。これに先のSNP-MEAAのDMF(8mL)溶液を加え、アルゴン雰囲気下、室温で16時間攪拌した。反応混合物を水(3mL)を用いて、6つに分け、それぞれにアセトン(30mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。得られた沈殿をPBSに分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作をあと3回行った。Amicon 30K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作をあと7回行った。Amicon 10K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をあと4回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、10K精製粒子(102.4mg)を得た。Amicon 10K filterによる洗浄の濾液を順次Amicon 3K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、3K精製粒子(41.2mg)を得た。
アルゴン雰囲気下、SNP-OA(20mg)、MEAA(0.5mL)とメタノール(1.5mL)の混合物を、70℃で5時間攪拌した。室温まで放冷後、減圧下濃縮した。アセトン(8mL)、ヘキサン(32mL)を加え、2つに分け、10℃、7000rpmで3分間遠心分離し上澄みを取り除いた。この操作をもう1回繰り返し、SNP-MEAAを得た。
N-[(2,3-ジヒドロキシフェニル)メチル]-N,N-ジメチル-3-ホスホノプロパン-1-アミニウム=ヨージド(263mg)、水(9.5mL)の混合物に炭酸水素ナトリウム(50mg)を加えた。これに先のSNP-MEAAのDMF(0.5mL)溶液を加え、アルゴン雰囲気下、室温で18時間攪拌した。反応混合物をPBSに分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで60分間遠心分離した。この一連の操作をあと3回行った。Amicon 10K filter上の濃縮液に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと2回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、10K精製粒子(3.0mg)を得た。Amicon 10K filterによる洗浄の濾液をAmicon 3K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと2回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、3K精製粒子(6.0mg)を得た。
アルゴン雰囲気下、SNP-OA(20mg)、MEAA(0.5mL)とメタノール(1.5mL)の混合物を、70℃で6時間攪拌した。室温まで放冷後、アセトン(8mL)、ヘキサン(32mL)を加え、2つに分け、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。この操作をアセトン(6mL)、ヘキサン(24mL)を用いて1回繰り返し、SNP-MEAAを得た。
3-カルボキシ-N-[(2,3-ジヒドロキシフェニル)メチル]-N,N-ジメチルプロパン-1-アミニウム=ヨージド(347mg)の水(8mL)溶液に炭酸水素ナトリウム(122mg)を加えた。これに先のSNP-MEAAのDMF(2mL)溶液を加え、アルゴン雰囲気下、室温で17時間攪拌した。反応混合物を水(1mL)を用いて、2つに分け、それぞれにアセトン(30mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。得られた沈殿をPBSに分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。これにPBSを加え、10℃、5800rpmで30分間遠心分離した。この操作をあと1回行った。Amicon 30K filterによる濾液を順次Amicon 10K filterを用い、10℃、5800rpmで30-60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと14回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して10K精製粒子(23.2mg)を得た。Amicon 10K filterによる洗浄のはじめ3回分の濾液をAmicon 3K filterを用い、10℃、5800rpmで30-60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと13回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して3K精製粒子(7.2mg)を得た。
アルゴン雰囲気下、SNP-OA(20mg)、MEAA(0.5mL)とメタノール(1.5mL)の混合物を、70℃で6時間攪拌した。室温まで放冷後、アセトン(8mL)、ヘキサン(32mL)を加え、2つに分け、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。この操作をアセトン(6mL)、ヘキサン(24mL)を用いて1回繰り返し、SNP-MEAAを得た。
4-カルボキシ-N-[(2,3-ジヒドロキシフェニル)メチル]-N,N-ジメチルブタン-1-アミニウム=ヨージド(359mg)の水(8mL)溶液に炭酸水素ナトリウム(123mg)を加えた。これに先のSNP-MEAAのDMF(2mL)溶液を加え、アルゴン雰囲気下、室温で20時間攪拌した。反応混合物を水(1mL)を用いて、2つに分け、それぞれにアセトン(30mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。得られた沈殿をPBSに分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。これにPBSを加え、10℃、5800rpmで30分間遠心分離した。この操作をあと1回行った。Amicon 30K filterによる濾液を順次Amicon 10K filterを用い、10℃、5800rpmで30-60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと13回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して10K精製粒子(24.2mg)を得た。Amicon 10K filterによる洗浄のはじめ4回分の濾液をAmicon 3K filterを用い、10℃、5800rpmで30-60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと11回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して3K精製粒子(8.8mg)を得た。
4-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナート(275mg)、水(2.2mL)の混合物に炭酸水素ナトリウム(34mg)を加えた。この溶液をSNP-OA(20mg)、クロロホルム(2.5mL)の混合物に加えた後、TBAF三水和物(63mg)、水(300μL)の混合物を加え、アルゴン雰囲気下、室温で16時間攪拌した。水層を分離し、クロロホルム層を水で2回抽出した。水層を集め、PBSに分散させ、Amicon 30K filterに移し、10℃、5800rpmで15分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作をあと3回行った。Amicon 30K filter上の濃縮液に水を加え、10℃、5800rpmで15分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。この一連の操作をあと2回行った。Amicon 10K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をあと5回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、10K精製粒子(30.3mg)を得た。Amicon 10K filterによる洗浄の濾液を順次Amicon 3K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥することにより、3K精製粒子(17.8mg)を得た。
3-{[(6-フルオロ-2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート(280mg)を水(2.2mL)に溶かし、炭酸水素ナトリウム(38mg)を加えた。SNP-OA(20mg)のクロロホルム(2.5mL)溶液にこの溶液を加え、さらにTBAF三水和物(65mg)の水(0.3mL)溶液を加えた。この混合物をアルゴン雰囲気下室温で20時間攪拌した。不溶物を濾過し、水層をAmicon 30K filterに移し、10℃、5800rpmで30分間遠心分離した。これにPBSを加え、10℃、5800rpmで30分間遠心分離した。Amicon 30K filterによる洗浄のはじめ2回分の濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。これに更に水を加え、10℃、5800rpmで30分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと12回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して10K精製粒子(13.5mg)を得た。Amicon 10K filterによる洗浄のはじめ5回分の濾液をAmicon 3K filterを用い、10℃、5800rpmで30-60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと9回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して3K精製粒子(7.3mg)を得た。
3,4-ジヒドロキシ-N,N-ジメチル-N-(3-ホスホノプロピル)アニリニウム=ヨージド(265mg)を水(2.4mL)に溶かした。この水溶液に炭酸水素ナトリウム(100mg),TBAF三水和物(67mg)の水(0.3mL)溶液を加えた。SNP-OA(20mg)のクロロホルム(2.5mL)溶液にこの溶液を加え、水(0.6mL)で洗いこんだ。この混合物をアルゴン雰囲気下室温で18時間攪拌した。不溶物を濾過し、水層をAmicon 100K filterに移し、10℃、5800rpmで15分間遠心分離した。得られた濾液をAmicon 10K filterを用い、10℃、5800rpmで30分間遠心分離した。これに更に水を加え、10℃、5800rpmで30分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと8回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して10K精製粒子(1.0mg)を得た。Amicon 10K filterによる洗浄のはじめ2回分の濾液をAmicon 3K filterを用い、10℃、5800rpmで30-60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと7回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して3K精製粒子(1.4mg)を得た。
アルゴン雰囲気下、SNP-OA(150mg)、MEAA(3.75mL)とメタノール(11.25mL)の混合物を、70℃で5時間攪拌した。室温まで放冷後、減圧下濃縮した。遠沈管6本に分け、それぞれにアセトン(4mL)、ヘキサン(16mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。この操作をもう1回繰り返し、SNP-MEAAを得た。
2-{[2-(2,3-ジヒドロキシフェニル)エチル](ジメチル)アザニウムイル}エタン-1-スルホナート(1.97g)、水(25mL)、炭酸水素ナトリウム(370mg)の混合物を室温で攪拌した。これに先のSNP-MEAAのDMF(12.5mL)溶液を加え、アルゴン雰囲気下、室温で16時間攪拌した。反応混合物を水(3mL)を用いて、遠沈管6本に分け、それぞれにアセトン(30mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを除去した。得られた沈殿を水に分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。これに水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと2回行った。Amicon 30K filterによる濾液を順次Amicon 10K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと8回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して10K精製粒子(16.1mg)を得た。Amicon 10K filterによる濾液を順次Amicon 3K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して3K精製粒子(56.0mg)を得た。
アルゴン雰囲気下、SNP-OA(150mg)、MEAA(3.8mL)とメタノール(11.3mL)の混合物を、70℃で6時間攪拌した。室温まで放冷後、減圧下濃縮した。アセトン(28mL)で遠沈管4本に分け、それぞれにヘキサン(28mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。それぞれにアセトン(7mL)、ヘキサン(28mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。この操作をもう1回繰り返し、SNP-MEAAを得た。
4-(カルボキシメチル)-1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム=ヨージド(2.77g)、水(60mL)の混合物を加熱下溶解し、炭酸水素ナトリウム(1.39g)を加えた。これに先のSNP-MEAAのDMF(15mL)溶液を加え、アルゴン雰囲気下、室温で42時間攪拌した。反応混合物を水(3mL)を用いて、遠沈管12本に分け、それぞれにアセトン(40mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを除去した。得られた沈殿を水に分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。Amicon 30K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をもう1回繰り返した。Amicon 30K filter上の濃縮液に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をもう4回繰り返した。得られた濾液を順次Amicon 10K filterに移し、10℃、5800rpmで最初の2回は30分間、その後の6回は60分間遠心分離した。さらにこのAmicon 10K filter上の濃縮液に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をもう14回繰り返した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して10K精製粒子(96.0mg)を得た。Amicon 10K filterを用いて得られた濾液を順次Amicon 3K filterに移し、10℃、5800rpmで最初の1回は30分間、その後の13回は60分間遠心分離した。さらにこのAmicon 3K filter上の濃縮液に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をもう7回繰り返した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して3K精製粒子(121mg)を得た。
アルゴン雰囲気下、SNP-OA(150mg)、MEAA(3.8mL)とメタノール(11mL)の混合物を、70℃で6時間攪拌した。室温まで放冷後、減圧下濃縮した。アセトン(28mL)で遠沈管4本に分け、それぞれにヘキサン(28mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。それぞれにアセトン(7mL)、ヘキサン(28mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。この操作をもう1回繰り返し、SNP-MEAAを得た。
4-カルボキシ-1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム=ヨージド(2.68g)、水(60mL)の混合物を加熱下溶解し、炭酸水素ナトリウム(832mg)を加えた。これに先のSNP-MEAAのDMF(15mL)溶液を加え、アルゴン雰囲気下、室温で42時間攪拌した。反応混合物を水(3mL)を用いて、遠沈管12本に分け、それぞれにアセトン(40mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを除去した。得られた沈殿を水に分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。Amicon 30K filter上の濃縮液に水を加え、10℃、5800rpmで30分間遠心分離した。この操作をもう1回繰り返した。Amicon 30K filter上の濃縮液に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をもう4回繰り返した。得られた濾液を順次Amicon 10K filterに移し、10℃、5800rpmで最初の2回は30分間、その後の6回は60分間遠心分離した。さらにこのAmicon 10K filter上の濃縮液に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をもう14回繰り返した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して10K精製粒子(62.5mg)を得た。Amicon 10K filterを用いて得られた濾液を順次Amicon 3K filterに移し、10℃、5800rpmで最初の1回は30分間、その後の13回は60分間遠心分離した。さらにこのAmicon 3K filter上の濃縮液に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をもう7回繰り返した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して3K精製粒子(74.1mg)を得た。
アルゴン雰囲気下、SNP-OA(150mg)、MEAA(3.75mL)とメタノール(11.25mL)の混合物を、70℃で6時間攪拌した。室温まで放冷後、減圧下濃縮した。遠沈管6本に分け、それぞれにアセトン(4mL)、ヘキサン(16mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを取り除いた。この操作をもう1回繰り返し、SNP-MEAAを得た。
3-カルボキシ-N-[2-(2,3-ジヒドロキシフェニル)エチル]-N,N-ジメチルプロパン-1-アミニウム=ヨージド(2.69g)、水(25mL)、炭酸水素ナトリウム(1.24g)の混合物を室温で5分間攪拌した。これに先のSNP-MEAAのDMF(12.5mL)溶液を加え、アルゴン雰囲気下、室温で41時間攪拌した。反応混合物を水(3mL)を用いて、遠沈管6本に分け、それぞれにアセトン(30mL)を加え、10℃、7000rpmで10分間遠心分離し上澄みを除去した。得られた沈殿を水に分散させ、Amicon 30K filterを用い、10℃、5800rpmで30分間遠心分離した。これに水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと2回行った。Amicon 30K filterによる濾液を順次Amicon 10K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。この操作をあと10回行った。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して10K精製粒子(17.6mg)を得た。Amicon 10K filterによる濾液を順次Amicon 3K filterを用い、10℃、5800rpmで60分間遠心分離した。これに更に水を加え、10℃、5800rpmで60分間遠心分離した。濃縮液をメンブレン(0.2μm)濾過し、凍結乾燥して3K精製粒子(116mg)を得た。
各実施例で得られた3K精製粒子の緩和能を評価した。
まず、PBS中でナノ粒子の濃度を系列的に希釈し、試験試料とした。各試料について1.5T-NMRにおいて緩和能を計測した。
測定磁場:1.5T、測定温度:37℃
T1測定(反転回復法)
Recycle Delay (RD):サンプル及び濃度毎にT1の5倍以上となるよう設定した。取得するデータ点の数は8以上、最初の反転パルスの時間(反転時間)は5msに固定し、最後の反転時間はRDと同一に設定した。
T2測定(Carr-Purcell-Meiboom-Gill(CPMG)法)
Recycle Delay (RD):T1のRDと同一に設定。τ = 0.5msとし、取得するデータ点の数は τ x 2 xデータ点の数がほぼRDと同一となるように設定した。
各サンプルのr1、r2は、複数濃度におけるT1、T2をそれぞれ測定し、濃度をX軸、T1、T2の逆数をY軸に取り、その傾きをSLOPE関数で算出することにより得た。
サイズ排除クロマトグラフィー(Size Exclusion Chromatography、SEC)を用いて、ナノ粒子の相対的な大きさを測定した。
<SEC条件>
流速:0.3mL/min
溶離液:PBS(pH 7.4)
カラム:Shodex KW403-4F(4.6 x 300 mm)
検出器:UV 280nm
ナノ粒子を用いた造影剤が期待された性能を発揮するためには、それらが溶液中に安定に分散している必要があり、長い期間、高濃度な状態でも分散性を維持していることが望ましい。
i)実施例で得られたナノ粒子を含有する造影剤をそれぞれマウスに投与し、1テスラのMRI装置においてT1強調画像を取得した。測定時の条件を以下に示す。
動物:C57BL/6j jms mouse 雄、体重約25g
投与ナノ粒子濃度:20mM
投与量:体重20gあたり100μL
磁場強度:1T
撮影法:T1強調(図1~図6)、使用装置:Bruker社製ICON
<Bruker社製ICON>
T1強調画像
Pulse sequence : MSME (Multi Slice Multi Echo), Slice Orientation = Axial, TE/TR = 10.464 / 400 msec, Field of view = 40 × 40 mm2, matrix size = 256 × 256, Number of Slice = 15, Slice thickness = 1 mm, Slice Gap = 2 mm, Number of averages = 8, Scan Time = 13 min 39 sec
図1の実施例6の3K精製粒子を含有する造影剤を投与したマウスにおいて、投与直後から、腎盂及び腎皮質の両方で信号が上昇し、造影剤を含む尿が溜まっていくのが観察されたことから、本造影剤は、腎臓を介して尿排泄されていることが示された。また、その信号変化を追うことで、本造影剤は、腎機能検査に利用できる可能性が示唆された。
SQUID装置に実施例6、7又は9でそれぞれ得られた3K精製粒子を挿入し、温度300Kにて印加磁場を1000~5000 Oe の間隔で3T~-3T~3Tの順に変化させ、各ポイントでの粒子の磁化を測定した。
Claims (26)
- 1つ以上の式(I)で表される双性イオンリガンドが配位結合した、酸化鉄を含有する金属粒子を含むナノ粒子。
R1及びR2の一方は、式(a)又は式(b)で示される基であり、他方は、H、低級アルキル、-O-低級アルキル又はハロゲンであり、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となって5又は6員含窒素飽和ヘテロ環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、-O-C1-3アルキル又はハロゲンであり、
nは0~2の整数であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよく、
ii)R1が式(a)で示される基であり、且つ、X1がエチレンであるとき、R2とRaまたはRbとが一体となってメチレンを形成してもよく、及び
iii)R2が式(a)で示される基であり、且つ、X1がメチレンであるとき、R3とRaまたはRbとが一体となってエチレンを形成してもよい、
但し、R2が式(a)で示される基であり、Ra及びRbがメチルであり、X1が結合であり、X2が、C1-4アルキレンであり、且つ、R1、R3及びR4がいずれもHであるとき、Y-はHPO3 -、又は、CO2 -である。) - 双性イオンリガンドが、
R1及びR2の一方が、式(a)又は式(b)で示される基であり、他方が、H、低級アルキル又はハロゲンであり、
X1は、結合又はメチレンであり、更にR1が式(a)で示される基のときX1はエチレンであってもよく、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となってピロリジン環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、又はハロゲンであり、
nは1であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよい、
双性イオンリガンドである請求項1記載のナノ粒子。 - 双性イオンリガンドが、
R1が、式(a)又は式(b)で示される基であり、R2が、H又はハロゲンであり、
X1は、結合又はメチレンであり、更にR1が式(a)で示される基のときX1はエチレンであってもよく、
X2は、C1-5アルキレンであり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、いずれもメチルであり、
Y-は、SO3 -又は、CO2 -である、
双性イオンリガンドである請求項2記載のナノ粒子。 - 双性イオンリガンドが、R1及びR2の一方が式(a)で示される基であり、他方が、H、低級アルキル、-O-低級アルキル又はハロゲンである、双性イオンリガンドである請求項1記載のナノ粒子。
- 双性イオンリガンドが、
1)R1が式(a)で示される基であり、且つ、R2がH、低級アルキル、-O-低級アルキル又はハロゲンである双性イオンリガンドであるか、又は、
2)R1がHであり、R2が式(a)で示される基であり、R3がC1-3アルキル又はハロゲンであり、且つ、R4がHである、
双性イオンリガンドである、請求項4記載のナノ粒子。 - 双性イオンリガンドが、R1が式(a)で示される基であり、且つ、R2がH、低級アルキル、-O-低級アルキル又はハロゲンである、双性イオンリガンドである、請求項5記載のナノ粒子。
- 双性イオンリガンドが、
R2がH又はハロゲンであり、
X1が結合、メチレン又はエチレンであり、
X2がC2-4アルキレンであり、
Ra及びRbがいずれもメチルであり、
R3及びR4が同一又は互いに異なって、H、C1-3アルキル又はハロゲンであり、
更に、X1がメチレンであるとき、R2とRaもしくはRbとが一体となってエチレンを形成してもよい、
双性イオンリガンドである、請求項6記載のナノ粒子。 - 双性イオンリガンドが、
R2がHまたはFであり、
X2がエチレン又はプロピレンであり、
R3及びR4がいずれもHである、
双性イオンリガンドである、請求項7記載のナノ粒子。 - 双性イオンリガンドが、
R2がHであり、
X1が結合又はエチレンであり、
双性イオンリガンドである、請求項8記載のナノ粒子。 - 双性イオンリガンドが、
Y-がSO3 -又はCO2 -である、
双性イオンリガンドである、請求項4~9のいずれか1項に記載のナノ粒子。 - 酸化鉄を含有する金属粒子が、酸化鉄のみを含有する金属粒子である、請求項1~11のいずれか1項に記載のナノ粒子。
- ナノ粒子が、酸化鉄を含有する金属粒子の外表面に双性イオンリガンドが1つ以上配位結合して形成された粒子であり、該双性イオンリガンドによって当該金属粒子が被覆されている、ナノ粒子である請求項1~12のいずれか1項に記載のナノ粒子。
- ナノ粒子が、1つ以上の双性イオンリガンドが配位結合した酸化鉄を含有する金属粒子、及び、1つ以上の双性イオンリガンド、からなる複合体である、請求項1~12のいずれか1項に記載のナノ粒子。
- ナノ粒子が、
2以上の双性イオンリガンド化合物、及び、2以上の「1つ以上の双性イオンリガンド化合物が配位結合した酸化鉄を含有する金属粒子」、からなるクラスターである、請求項1~12のいずれか1項に記載のナノ粒子。 - 請求項1~15のいずれか1項に記載のナノ粒子を含む、磁気共鳴イメージング用造影剤。
- 陽性造影剤である、請求項16記載の磁気共鳴イメージング用造影剤。
- 請求項1記載のナノ粒子を製造するための、下式(I)で表される双性イオンリガンド化合物の使用。
R1及びR2の一方は、下式(a)又は式(b)で示される基であり、他方は、H、低級アルキル、-O-低級アルキル又はハロゲンであり、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となって5又は6員含窒素飽和ヘテロ環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、-O-C1-3アルキル又はハロゲンであり、
nは0~2の整数であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよく、
ii)R1が式(a)で示される基であり、且つ、X1がエチレンであるとき、R2とRaまたはRbとが一体となってメチレンを形成してもよく、及び
iii)R2が式(a)で示される基であり、且つ、X1がメチレンであるとき、R3とRaまたはRbとが一体となってエチレンを形成してもよい、
但し、R2が式(a)で示される基であり、Ra及びRbがメチルであり、X1が結合であり、X2が、C1-4アルキレンであり、且つ、R1、R3及びR4がいずれもHであるとき、Y-はHPO3 -、又は、CO2 -である。) - 双性イオンリガンド化合物が、R1及びR2の一方が、式(a)で示される基であり、他方が、H、低級アルキル、-O-低級アルキル又はハロゲンである双性イオンリガンド化合物である、請求項18に記載の使用。
- 下式(I)で表される化合物又はその塩。
R1及びR2の一方は、下式(a)又は式(b)で示される基であり、他方は、H、低級アルキル、-O-低級アルキル又はハロゲンであり、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となって5又は6員含窒素飽和ヘテロ環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、-O-C1-3アルキル又はハロゲンであり、
nは0~2の整数であり、
更に、
i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよく、
ii)R1が式(a)で示される基であり、且つ、X1がエチレンであるとき、R2とRaまたはRbとが一体となってメチレンを形成してもよく、及び
iii)R2が式(a)で示される基であり、且つ、X1がメチレンであるとき、R3とRaまたはRbとが一体となってエチレンを形成してもよい、
但し、R2が式(a)で示される基であり、Ra及びRbがメチルであり、X1が結合であり、X2が、C1-4アルキレンであり、且つ、R1、R3及びR4がいずれもHであるとき、Y-はHPO3 -、又は、CO2 -である。) - R1及びR2の一方が、式(a)又は式(b)で示される基であり、他方が、H、低級アルキル又はハロゲンであり、
X1は、結合又はメチレンであり、更にR1が式(a)で示される基のときX1はエチレンであってもよく、
X2は、OHで置換されていてもよいC1-5アルキレン、又は、-C1-2アルキレン-O-C1-3アルキレン-であり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、同一又は互いに異なって、C1-3アルキル、-C1-3アルキレン-O-C1-2アルキルであるか、又は、Ra及びRbは、それらが結合する4級窒素原子と一体となってピロリジン環を形成し、
Y-は、SO3 -、HPO3 -、又は、CO2 -であり、
R3及びR4は、同一又は互いに異なって、H、C1-3アルキル、又はハロゲンであり、
nは1であり、
更に、i)R1が式(a)で示される基であり、且つ、X1がメチレンであるとき、R2とRaまたはRbとが一体となってエチレンを形成してもよい、
請求項20記載の化合物又はその塩。 - R1が、式(a)又は式(b)で示される基であり、R2が、H又はハロゲンであり、
X1は、結合又はメチレンであり、更にR1が式(a)で示される基のときX1はエチレンであってもよく、
X2は、C1-5アルキレンであり、更にR1が式(b)で示される基のときX2は結合であってもよく、
Ra及びRbは、いずれもメチルであり、
Y-は、SO3 -又は、CO2 -である、請求項21記載の化合物又はその塩。 - R1及びR2の一方が、式(a)で示される基であり、他方が、H、低級アルキル、-O-低級アルキル又はハロゲンである、請求項20記載の化合物又はその塩。
- 4-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナート、
3-{[(6-フルオロ-2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート、
ヒドロゲン=(3-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロピル)ホスホナート、
5-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ペンタノアート、
{1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム-4-イル}アセタート、
1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム-4-カルボキシラート、
4-{[2-(2,3-ジヒドロキシフェニル)エチル](ジメチル)アザニウムイル}ブタノアート、
2-{[2-(2,3-ジヒドロキシフェニル)エチル](ジメチル)アザニウムイル}エタン-1-スルホナート、及び
3-[(2,3-ジヒドロキシフェニル)(ジメチル)アザニウムイル]プロパン-1-スルホナート
からなる群から選択される請求項20記載の化合物又はその塩。 - {1-[(2,3-ジヒドロキシフェニル)メチル]-1-メチルピペリジン-1-イウム-4-イル}アセタート、及び
2-{[2-(2,3-ジヒドロキシフェニル)エチル](ジメチル)アザニウムイル}エタン-1-スルホナート
からなる群から選択される請求項24記載の化合物又はその塩。 - 4-{[(2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}ブタン-1-スルホナート、及び
3-{[(6-フルオロ-2,3-ジヒドロキシフェニル)メチル](ジメチル)アザニウムイル}プロパン-1-スルホナート
からなる群から選択される請求項24記載の化合物又はその塩。
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020217023570A KR20210109574A (ko) | 2018-12-27 | 2019-12-27 | 나노 입자, 이를 함유하는 자기 공명 영상용 조영제 및 양쪽성 이온 리간드 화합물 |
EP19903140.2A EP3904331A4 (en) | 2018-12-27 | 2019-12-27 | NANOPARTICLES, CONTRAST AGENT FOR MAGNETIC RESONANCE IMAGING WITH THEM AND ZZITTERIONIC LIGAND COMPOUND |
BR112021012694-5A BR112021012694A2 (pt) | 2018-12-27 | 2019-12-27 | Nanopartícula, agente de contraste para imagem de ressonância magnética compreendendo a mesma e composto de ligante zwitteriônico |
JOP/2021/0162A JOP20210162A1 (ar) | 2018-12-27 | 2019-12-27 | جسيم نانوي، وعامل تباين للتصوير بالرنين المغناطيسي يشتمل على الجسيم النانوي، ومركب ترابطي ثنائي القطب |
MX2021007731A MX2021007731A (es) | 2018-12-27 | 2019-12-27 | Nanoparticula, agente de contraste para formacion de imagenes por resonancia magnetica que comprende la misma y un compuesto de ligando zwitterionico. |
CA3124757A CA3124757A1 (en) | 2018-12-27 | 2019-12-27 | Nanoparticle, contrast agent for magnetic resonance imaging comprising same and zwitterionic ligand compound |
SG11202107083SA SG11202107083SA (en) | 2018-12-27 | 2019-12-27 | Nanoparticle, contrast agent for magnetic resonance imaging comprising same and zwitterionic ligand compound |
CN201980086467.3A CN113227040A (zh) | 2018-12-27 | 2019-12-27 | 纳米颗粒、包含该纳米颗粒的核磁共振成像造影剂及两性离子配体化合物 |
JP2020562470A JP7360577B2 (ja) | 2018-12-27 | 2019-12-27 | ナノ粒子、これを含む磁気共鳴イメージング用造影剤及び双性イオンリガンド化合物 |
AU2019415375A AU2019415375A1 (en) | 2018-12-27 | 2019-12-27 | Nanoparticle, contrast agent for magnetic resonance imaging comprising same and zwitterionic ligand compound |
US17/418,142 US20220184236A1 (en) | 2018-12-27 | 2019-12-27 | Nanoparticle, contrast agent for magnetic resonance imaging comprising same and zwitterionic ligand compound |
IL284383A IL284383A (en) | 2018-12-27 | 2021-06-24 | A nanoparticle, a magnetic resonance imaging contrast agent containing it, and a zwitterionic ligand |
PH12021551522A PH12021551522A1 (en) | 2018-12-27 | 2021-06-25 | Nanoparticle, contrast agent for magnetic resonance imaging comprising same and zwitterionic ligand compound |
ZA2021/04733A ZA202104733B (en) | 2018-12-27 | 2021-07-07 | Nanoparticle, contrast agent for magnetic resonance imaging comprising same and zwitterionic ligand compound |
CONC2021/0009388A CO2021009388A2 (es) | 2018-12-27 | 2021-07-19 | Nanopartícula, agente de contraste para formación de imágenes por resonancia magnética que comprende la misma y un compuesto de ligando zwitteriónico |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018245927 | 2018-12-27 | ||
JP2018-245927 | 2018-12-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020138389A1 true WO2020138389A1 (ja) | 2020-07-02 |
Family
ID=71129084
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2019/051354 WO2020138389A1 (ja) | 2018-12-27 | 2019-12-27 | ナノ粒子、これを含む磁気共鳴イメージング用造影剤及び双性イオンリガンド化合物 |
Country Status (16)
Country | Link |
---|---|
US (1) | US20220184236A1 (ja) |
EP (1) | EP3904331A4 (ja) |
JP (1) | JP7360577B2 (ja) |
KR (1) | KR20210109574A (ja) |
CN (1) | CN113227040A (ja) |
AU (1) | AU2019415375A1 (ja) |
BR (1) | BR112021012694A2 (ja) |
CA (1) | CA3124757A1 (ja) |
CO (1) | CO2021009388A2 (ja) |
IL (1) | IL284383A (ja) |
JO (1) | JOP20210162A1 (ja) |
MX (1) | MX2021007731A (ja) |
PH (1) | PH12021551522A1 (ja) |
SG (1) | SG11202107083SA (ja) |
WO (1) | WO2020138389A1 (ja) |
ZA (1) | ZA202104733B (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115636761A (zh) * | 2021-07-20 | 2023-01-24 | 中国石油天然气股份有限公司 | 一种油溶性表面活性剂、驱油剂及其应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013090601A2 (en) | 2011-12-16 | 2013-06-20 | Massachusetts Institute Of Technology | Compact nanoparticles for biological applications |
WO2016044068A2 (en) | 2014-09-15 | 2016-03-24 | Massachusetts Institute Of Technology | Nanoparticles for magnetic resonance imaging applications |
WO2019004297A1 (ja) * | 2017-06-28 | 2019-01-03 | 国立研究開発法人理化学研究所 | ナノ粒子、これを含む磁気共鳴イメージング用造影剤及びリガンド化合物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101311295B1 (ko) | 2011-07-13 | 2013-09-25 | 주식회사 유진로봇 | 이동 로봇의 휠 조립체 |
-
2019
- 2019-12-27 EP EP19903140.2A patent/EP3904331A4/en active Pending
- 2019-12-27 CA CA3124757A patent/CA3124757A1/en active Pending
- 2019-12-27 WO PCT/JP2019/051354 patent/WO2020138389A1/ja unknown
- 2019-12-27 AU AU2019415375A patent/AU2019415375A1/en not_active Abandoned
- 2019-12-27 KR KR1020217023570A patent/KR20210109574A/ko not_active Application Discontinuation
- 2019-12-27 JO JOP/2021/0162A patent/JOP20210162A1/ar unknown
- 2019-12-27 US US17/418,142 patent/US20220184236A1/en active Pending
- 2019-12-27 SG SG11202107083SA patent/SG11202107083SA/en unknown
- 2019-12-27 CN CN201980086467.3A patent/CN113227040A/zh active Pending
- 2019-12-27 JP JP2020562470A patent/JP7360577B2/ja active Active
- 2019-12-27 MX MX2021007731A patent/MX2021007731A/es unknown
- 2019-12-27 BR BR112021012694-5A patent/BR112021012694A2/pt not_active Application Discontinuation
-
2021
- 2021-06-24 IL IL284383A patent/IL284383A/en unknown
- 2021-06-25 PH PH12021551522A patent/PH12021551522A1/en unknown
- 2021-07-07 ZA ZA2021/04733A patent/ZA202104733B/en unknown
- 2021-07-19 CO CONC2021/0009388A patent/CO2021009388A2/es unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013090601A2 (en) | 2011-12-16 | 2013-06-20 | Massachusetts Institute Of Technology | Compact nanoparticles for biological applications |
WO2016044068A2 (en) | 2014-09-15 | 2016-03-24 | Massachusetts Institute Of Technology | Nanoparticles for magnetic resonance imaging applications |
JP2017529156A (ja) * | 2014-09-15 | 2017-10-05 | マサチューセッツ インスティテュート オブ テクノロジー | 磁気共鳴画像法用途のためのナノ粒子 |
WO2019004297A1 (ja) * | 2017-06-28 | 2019-01-03 | 国立研究開発法人理化学研究所 | ナノ粒子、これを含む磁気共鳴イメージング用造影剤及びリガンド化合物 |
Non-Patent Citations (7)
Title |
---|
BYUNG HYO KIM ET AL., J AM. CHEM. SCI., vol. 133, 2011, pages 12624 - 12631 |
BYUNG HYO KIM ET AL., J AM. CHEM. SOC., vol. 133, 2011, pages 12624 - 12631 |
BYUNG HYO KIM ET AL., J AM. CHEM. SOC., vol. 135, 2013, pages 2407 - 2410 |
COROT ET AL., ADVANCED DRUG DELIVERY REVIEWS, vol. 58, 2006, pages 1471 - 1504 |
HE WEI ET AL., INTEGR. BIOL., vol. 5, 2013, pages 108 - 114 |
HE WEI ET AL., PROC. NATR. ACAD. SCI., vol. 114, no. 9, 2017, pages 2325 - 2330 |
WEI H. ET AL., NANO LETT, vol. 12, 2012, pages 22 - 25 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115636761A (zh) * | 2021-07-20 | 2023-01-24 | 中国石油天然气股份有限公司 | 一种油溶性表面活性剂、驱油剂及其应用 |
Also Published As
Publication number | Publication date |
---|---|
EP3904331A1 (en) | 2021-11-03 |
EP3904331A4 (en) | 2022-10-05 |
ZA202104733B (en) | 2022-09-28 |
PH12021551522A1 (en) | 2022-02-28 |
BR112021012694A2 (pt) | 2021-10-05 |
JP7360577B2 (ja) | 2023-10-13 |
AU2019415375A1 (en) | 2021-07-29 |
JPWO2020138389A1 (ja) | 2021-11-04 |
SG11202107083SA (en) | 2021-07-29 |
US20220184236A1 (en) | 2022-06-16 |
MX2021007731A (es) | 2021-08-05 |
CN113227040A (zh) | 2021-08-06 |
CO2021009388A2 (es) | 2021-07-30 |
KR20210109574A (ko) | 2021-09-06 |
JOP20210162A1 (ar) | 2023-01-30 |
CA3124757A1 (en) | 2020-07-02 |
IL284383A (en) | 2021-08-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Zhang et al. | Ultrasmall ferrite nanoparticles synthesized via dynamic simultaneous thermal decomposition for high-performance and multifunctional T 1 magnetic resonance imaging contrast agent | |
Dumont et al. | Biofunctionalized gadolinium-containing prussian blue nanoparticles as multimodal molecular imaging agents | |
US20090317327A1 (en) | Aqueous Dispersion of Superparamagnetic Single-Domain Particles, Production and Use Thereof in Diagnosis and Therapy | |
JP2010516760A (ja) | 酸化マンガンナノ粒子を含む磁気共鳴映像t1造影剤 | |
KR20120101362A (ko) | 친수성 알파-히드록시포스폰산 접합체를 사용한 수불용성 나노입자의 처리법, 이로써 개질된 나노입자 및 조영제로서의 그의 용도 | |
CN101757642A (zh) | 一种含钆纳米粒子的制备方法 | |
JP7360577B2 (ja) | ナノ粒子、これを含む磁気共鳴イメージング用造影剤及び双性イオンリガンド化合物 | |
JP7107532B2 (ja) | ナノ粒子、これを含む磁気共鳴イメージング用造影剤及びリガンド化合物 | |
EP3922271A1 (en) | Ultrafine iron oxide nanoparticle-based magnetic resonance imaging t1 contrast agent | |
WO1995019185A1 (en) | Functionalized aza-macrobicyclic ligands for imaging applications | |
Liu et al. | Biocompatible KMnF3 nanoparticular contrast agent with proper plasma retention time for in vivo magnetic resonance imaging | |
RU2799760C2 (ru) | Наночастица, содержащее ее контрастное вещество для магнитно-резонансной томографии и цвиттер-ионное лигандное соединение | |
Hao et al. | Chelating ligand-bridged IO-Gd nanoparticles with enhanced contrast performance for dual-mode MRI | |
RU2794613C1 (ru) | Контрастное вещество т1 на основе ультратонких наночастиц оксида железа для магнитно-резонансной визуализации | |
US20210052749A1 (en) | Amphiphilic polymer nano micelle containing poly-3,4-dihydroxyphenylalanine chelated ferric ions | |
KR101010061B1 (ko) | 양친매성 포르피린 유도체 및 그 제조방법 | |
US5869026A (en) | Tripodal carboxamide ligands for MRI contrast agents | |
KR20080071472A (ko) | 산화망간 나노입자를 포함하는 자기공명영상 티1 조영제 | |
Lynn | Synthesis of silica and gold coated gadolinium oxide nanoparticles for magnetic resonance imaging | |
BR102015013031B1 (pt) | Nanopartículas e seu uso como agente de contraste em imagem por ressonância magnética |
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: 19903140 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2020562470 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 3124757 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112021012694 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 20217023570 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2019415375 Country of ref document: AU Date of ref document: 20191227 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2019903140 Country of ref document: EP Effective date: 20210727 |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01E Ref document number: 112021012694 Country of ref document: BR Free format text: APRESENTE AS TRADUCAO SIMPLES DA FOLHA DE ROSTO DA CERTIDAO DE DEPOSITO DA PRIORIDADE 27/12/2018 JP 2018-245927 ; OU DECLARACAO DE QUE OS DADOS DO PEDIDO INTERNACIONAL ESTAO FIELMENTE CONTIDOS NA PRIORIDADE REIVINDICADA, CONTENDO TODOS OS DADOS IDENTIFICADORES DESTA (TITULARES, NUMERO DE REGISTRO, DATA E TITULO), CONFORME O PARAGRAFO UNICO DO ART. 25 DA RESOLUCAO 77/2013. CABE SALIENTAR QUE NAO FOI POSSIVEL IDENTIFICAR OS TITULARES DO PEDIDO NOS DOCUMENTOS JUNTADOS AO PROCESSO, TAMPOUCO NOS APRESENTADOS NA OMPI, POIS SE ENCONTRAM EM JAPONES. |
|
ENP | Entry into the national phase |
Ref document number: 112021012694 Country of ref document: BR Kind code of ref document: A2 Effective date: 20210625 |