JP6457816B2 - アミノ酸脂質 - Google Patents
アミノ酸脂質 Download PDFInfo
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- JP6457816B2 JP6457816B2 JP2014561311A JP2014561311A JP6457816B2 JP 6457816 B2 JP6457816 B2 JP 6457816B2 JP 2014561311 A JP2014561311 A JP 2014561311A JP 2014561311 A JP2014561311 A JP 2014561311A JP 6457816 B2 JP6457816 B2 JP 6457816B2
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- -1 Amino acid lipid Chemical class 0.000 title claims description 95
- 150000001875 compounds Chemical class 0.000 claims description 126
- 239000000203 mixture Substances 0.000 claims description 61
- 125000006850 spacer group Chemical group 0.000 claims description 58
- 125000006239 protecting group Chemical group 0.000 claims description 48
- 239000002105 nanoparticle Substances 0.000 claims description 36
- 230000003213 activating effect Effects 0.000 claims description 32
- 229920001223 polyethylene glycol Polymers 0.000 claims description 26
- 239000002502 liposome Substances 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 239000002202 Polyethylene glycol Substances 0.000 claims description 17
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 239000000693 micelle Substances 0.000 claims description 11
- 239000000427 antigen Substances 0.000 claims description 10
- 108091007433 antigens Proteins 0.000 claims description 10
- 102000036639 antigens Human genes 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 4
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachlorophenol Chemical class OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 150000004891 diazines Chemical class 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 claims description 2
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 claims description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical class OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 claims description 2
- IHDBZCJYSHDCKF-UHFFFAOYSA-N 4,6-dichlorotriazine Chemical compound ClC1=CC(Cl)=NN=N1 IHDBZCJYSHDCKF-UHFFFAOYSA-N 0.000 claims description 2
- ORLGPUVJERIKLW-UHFFFAOYSA-N 5-chlorotriazine Chemical compound ClC1=CN=NN=C1 ORLGPUVJERIKLW-UHFFFAOYSA-N 0.000 claims description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical class C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical class O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 2
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 2
- 238000012377 drug delivery Methods 0.000 claims description 2
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical class F* 0.000 claims description 2
- 229940015043 glyoxal Drugs 0.000 claims description 2
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical class 0.000 claims description 2
- 150000002540 isothiocyanates Chemical class 0.000 claims description 2
- XSDLDLIXLLMXDY-UHFFFAOYSA-N n-methoxyhydroxylamine Chemical class CONO XSDLDLIXLLMXDY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229960002317 succinimide Drugs 0.000 claims description 2
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical class CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims 3
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 claims 1
- CCJXQRNXZKSOGJ-UHFFFAOYSA-N ethylsulfonyl ethanesulfonate Chemical compound CCS(=O)(=O)OS(=O)(=O)CC CCJXQRNXZKSOGJ-UHFFFAOYSA-N 0.000 claims 1
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical class O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 claims 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 150000002632 lipids Chemical class 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 238000000034 method Methods 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 22
- 150000002430 hydrocarbons Chemical group 0.000 description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 17
- 229920005989 resin Polymers 0.000 description 15
- 239000011347 resin Substances 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- 239000002356 single layer Substances 0.000 description 14
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 125000005647 linker group Chemical group 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000012867 bioactive agent Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 230000000087 stabilizing effect Effects 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229910052727 yttrium Inorganic materials 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 235000012000 cholesterol Nutrition 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 229910045601 alloy Inorganic materials 0.000 description 6
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- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
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- 230000001225 therapeutic effect Effects 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 230000030741 antigen processing and presentation Effects 0.000 description 5
- 230000000975 bioactive effect Effects 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
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- 239000001257 hydrogen Substances 0.000 description 5
- 239000002077 nanosphere Substances 0.000 description 5
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
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- 206010028980 Neoplasm Diseases 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
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- MIJXPIIDXCVPFW-UHFFFAOYSA-N n-tetradecoxypropan-1-amine Chemical compound CCCCCCCCCCCCCCONCCC MIJXPIIDXCVPFW-UHFFFAOYSA-N 0.000 description 4
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- DXFRUMODOJLITQ-MUUNZHRXSA-N tert-butyl (3r)-3-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[2-[(4-methoxybenzoyl)amino]ethylamino]-4-oxobutanoate Chemical compound C1=CC(OC)=CC=C1C(=O)NCCNC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 DXFRUMODOJLITQ-MUUNZHRXSA-N 0.000 description 4
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- KWVJHCQQUFDPLU-YEUCEMRASA-N 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KWVJHCQQUFDPLU-YEUCEMRASA-N 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
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- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 3
- 102000001301 EGF receptor Human genes 0.000 description 3
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- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 3
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- 229910010272 inorganic material Inorganic materials 0.000 description 3
- 125000005645 linoleyl group Chemical group 0.000 description 3
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- MVDTXHHGMXWCRJ-UHFFFAOYSA-N n-(2-aminoethyl)-4-methoxybenzamide Chemical compound COC1=CC=C(C(=O)NCCN)C=C1 MVDTXHHGMXWCRJ-UHFFFAOYSA-N 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
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- 239000004530 micro-emulsion Substances 0.000 description 1
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- 238000003801 milling Methods 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
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- 239000002159 nanocrystal Substances 0.000 description 1
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- 239000002073 nanorod Substances 0.000 description 1
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- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000002469 tricosyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、新種の脂質、さらに詳細には極性の頭部基を有するエーテル−脂質、およびこれらの脂質を含む小胞、これらの調製方法、ならびにこれらの医療用途における使用を対象にする。
受容体−リガンド(receptor Ligand)、抗原−抗体、DNA−タンパク質、糖質−レクチン、RNA−リボソーム間などの分子認識は、多くの生物系を支える重要な原理であり、医療用途において、例えば、重合ビーズ、小胞型脂質(vesicular lipid)、マイクロエマルションなどを含めた人工の(マイクロ−またはナノ−)微粒子系などにおいて使用するために人工的に創出される多くの生物系に応用されている。
Yは、O、N、Sまたは共有結合を表し、
P1は、H、Y保護基もしくはY活性化基またはスペーサー基を表し、
P2、P3は、互いに独立して、H、アミノ保護基もしくはスペーサー基を表し、またはP2とP3はそれらが結合しているNと一緒になって、環構造を形成し、
Lは、式(a)の基であり:
R1は、Hまたは式−(CH2)2−ORb1の基を表し、
R1’は、Hまたは式−(CH2)2−ORb2の基を表し、
R2は、Hまたは式−CH2−ORcの基を表し、
R2’は、Hまたは式−ORdもしくは−CH2−ORdの基を表す。)、
R3は、Hまたは式−(CH2)2−OReもしくは−(CH2)3−OReの基を表し、
Ra、Rb1、Rb2、Rc、Rd、Reは、互いに独立して、飽和または不飽和で直鎖または分枝状の炭化水素鎖を表し、
mは、1、2または3であり、
ただし、R1、R1’、R2、R2’、R3の少なくとも1つはHではない。)。
P1、P2、P3、Y、Ra、Reおよびmは、式Iの基について上記に定義される通りである)。
Yは、O、N、Sまたは共有結合を表し、
P1は、H、Y保護基もしくはY活性化基またはスペーサー基を表し、
P2、P3は、互いに独立して、H、アミノ保護基もしくはスペーサー基を表し、またはP2とP3はそれらが結合しているNと一緒になって、環構造を形成し、
Lは、式(a)の基であり:
R1は、Hまたは式−(CH2)2−ORb1の基を表し、
R1’は、Hまたは式−(CH2)2−ORb2の基を表し、
R2は、Hまたは式−CH2−ORcの基を表し、
R2’は、Hまたは式−ORdもしくは−CH2−ORdの基を表す。)、
R3は、Hまたは式−(CH2)2−OReもしくは−(CH2)3−OReの基を表し、
Ra、Rb1、Rb2、Rc、Rd、Reは、互いに独立して、飽和または不飽和で直鎖または分枝状の炭化水素鎖を表し、
mは、1、2または3であり、
ただし、R1、R1’、R2、R2’、R3の少なくとも1つはHでない。)。
Ra、RcおよびRdは互いに独立して、飽和または不飽和で直鎖または分枝状の炭化水素鎖である)。
P1、P2、P3、Y、Ra、Reおよびmは、式Iの基について上記に定義される通りである)。
YはO、N、Sまたは共有結合を表し、
P1は、H、Y保護基もしくはY活性化基またはスペーサー基を表し、
P2、P3は、互いに独立して、H、アミノ保護基もしくはスペーサー基を表し、またはP2とP3はそれらが結合しているNと一緒になって、環構造を形成し、
R1は、Hまたは式−(CH2)2−ORb1の基を表し、
R1’は、Hまたは式−(CH2)2−ORb2の基を表し、
R2は、Hまたは式−CH2−ORcの基を表し、
R2’は、Hまたは式−ORdもしくは−CH2−ORdの基を表し、
Ra、Rb1、Rb2、Rc、Rdは、互いに独立して、飽和または不飽和で直鎖または分枝状の炭化水素鎖を表し、
mは、1、2または3であり、
ただし、式IIにおいて、R2およびR2’の1つはHでなく、式IIIにおいて、R1およびR1’の1つはHではない。)。
Yは、O、N、Sまたは共有結合を表し、
P1は、H、Y保護基もしくはY活性化基またはスペーサー基を表し、
P2、P3は、互いに独立して、H、アミノ保護基もしくはスペーサー基を表し、またはP2とP3はそれらが結合しているNと一緒になって、環構造を形成し、
Ra、Rc、Rdは、互いに独立して、飽和または不飽和で直鎖または分枝状の炭化水素鎖を表し、
mは1、2または3である)。
YはO、N、Sまたは共有結合を表し、
P1はH、Y保護基もしくはY活性化基またはスペーサー基を表し、
P2、P3は互いに独立して、H、アミノ保護基もしくはスペーサー基を表し、またはP2とP3はそれらが結合しているNと一緒になって、環構造を形成し、
Ra、Rb1、Rb2は互いに独立して、飽和または不飽和で直鎖または分枝状の炭化水素鎖を表し、
mは1、2または3である)。
YはO、N、Sまたは共有結合を表し、
P1はH、Y保護基もしくはY活性化基またはスペーサー基を表し、
P2、P3は互いに独立して、H、アミノ保護基もしくはスペーサー基を表し、またはP2とP3はそれらが結合しているNと一緒になって、環構造を形成し、
Ra、Reは互いに独立して、飽和または不飽和で直鎖または分枝状の炭化水素鎖を表し、
mは1、2または3である)。
YはO、N、Sまたは共有結合を表し、
P1はH、Y保護基もしくはY活性化基またはスペーサー基を表し、
P2、P3は互いに独立して、H、アミノ保護基もしくはスペーサー基を表し、またはP2とP3はそれらが結合しているNと一緒になって、環構造を形成し、
p1、q1、p2、q2、p3、q3は互いに独立して、1〜23であり、ただし、p1およびq1、p2およびq2、p3およびq3の合計が12〜24であることを条件とする)。
材料:コレステロールおよびPOPCは、Avanti Polar Lipids社(Alabaster、AL)から購入する。保護アミノ酸はすべて、Novabiochem社から入手する。ジフェニルジアゾメタン樹脂D−2230はBachem AG社から入手する。他の化学薬品および溶媒はすべて、A.R.グレード以上である。
(a)N−(2−アミノエチル)−4−メトキシベンズアミドの合成
3.85gのジフェニルジアゾメタン樹脂(3.3mmol)を100mlのSPPS反応器中30mlのDCMで2回洗浄し、30mlのDCM中4.2gの(2S)−2−(((9H−フルオレン−9−イル)メトキシ)カルボニルアミノ)−グルタミン酸−γ−2,3−ビス(テトラデシルオキシ)プロピル−アミド(例2を参照、1.5当量、5.0mmol)溶液で終夜処理する。溶液を濾取し、残渣をDCMで4回洗浄する。最終的に未反応のジフェニルジアゾメタンを破壊するために、残渣を30mlのDCM中125μlの酢酸(0.5当量、2.2mmol)で15分間処理し、その後30mlのジメチルホルムアミドおよびイソプロパノールで交互に3回洗浄する。残渣をジイソプロピルエーテルで2回洗浄し、真空で終夜乾燥する。所望の生成物が6.7g得られる(>理論値の100%、理論上の収量6.5g)。残渣の負荷量をFmoc切断生成物の304nmにおけるUV測定により0.49mmol/gに決定する(理論上の最大負荷量0.51mmol/g)。
H−Glu−OtBu−NH−PEG11−Glu(DMA)−ジフェニルメチル樹脂は、通常の固相合成により以下の反応順序で得られる:
1)DMF中ピペリジンによるFmoc−Glu(DMA)−OtBu樹脂のFmoc基の切断
(2)DMFおよびDIPEA中HTBUを使用するFmoc−NH−PEG11−COOHとの縮合
(3)DMF中ピペリジンによるFmoc−NH−PEG11−Glu(DMA)−OtBu樹脂のFmoc基の切断
(c)H−Glu−OtBu−NH−PEG11−Glu(DMA)−ジフェニルメチル樹脂の切断および脱保護:
所望の化合物は、樹脂からの切断、例えばトリフルオロ酢酸(Trifluaroacetic acid)およびトリイソプロピルシランでの処理によって得ることができる。
470mgのPOPC、60mgのCholおよび13.5mgのアニスアミド脂質(実施例4を参照)を55℃で750μlのエタノール(96%)に溶解し、4.25mLのPBS(pH7.4)に注入する。脂質の使用モル比は77.99:18.83:1.02:0.27である。100nmのポリカルボナート膜を通して押し出した後、リポソームの平均サイズは110nmであり、PDIは0.068である。HPLC分析によれば、アニスアミド脂質含有量は理論値の72%である。
(b)NH2−PEG8−PA−Glu(DMA)−Sieber樹脂の合成:
NH2−PEG8−PA−Glu(DMA)−Sieber樹脂は、通常の固相合成により以下の反応順序で得られる:
(1)DMF中ピペリジンによるFmoc−Glu(DMA)−Sieber樹脂のFmoc基の切断
(2)DMFおよびDIPEA中HTBUを使用するFmoc−NH−PEG8−PAとの縮合、最後に
(3)DMF中ピペリジンによるFmoc−NH−PEG8−PA−Glu(DMA)−Sieber樹脂のFmoc基の切断
(c)NH2−PEG8−PA−Glu(DMA)−アミドの合成:
生成物は、ジクロロメタン中トリフルオロ酢酸を使用してNH2−PEG8−PA−Glu(DMA)−Sieber樹脂から切断される。ESI−MS:モノアイソトピックMw(計算値)=1034.8、Mw[M+H]+=1035.9。
Claims (16)
- 一般式Iの化合物:
Yは、O、NH、または共有結合を表し、
P1は、Y保護基もしくはY活性化基、またはスペーサー基を表し(但し、Yが共有結合の場合はP 1 はY活性化基またはスペーサー基を表し)、
P2、P3は、互いに独立して、H、アミノ保護基もしくはスペーサー基を表し、または、 P2とP3は、それらが結合しているNと一緒になって、環構造を形成し、
YがOの場合のY保護基は、ベンズヒドリル、ベンジル、o−ニトロベンジル、p−ニトロベンジル、p−メトキシベンジル、メチル、t−ブチル、4−ピリジルメチル、2−ナフチルメチル、2,2−トリクロロエチル、2−トリメチルシリル、t−ブチルジメチルシリル、t−ブチルジフェニルシリル、2−(トリメチルシリル)エチル、オルト酢酸トリメチル、オルト酢酸トリエチル、オキサゾリン、アリル、2−クロロアリル、フェナシル、アセトニル、及びp−メトキシフェニルから選ばれ、
YがNHの場合のY保護基、及びP2、P3におけるアミノ保護基は、Boc(t−ブチルオキシカルボニル)、Cbz(ベンジルオキシカルボニル)、Fmoc(フルオレニルメチルオキシカルボニル)、alloc(アリルオキシカルボニル)、トリチル、ベンジル、ベンジリデン、トシル、スクシンイミド、フタルイミド、ホルミル、アセチル、ベンゾイル、t−ブチルジメチルシリル、及びトリイソプロピルシリルから選ばれ、
Y活性化基は、アルキル、アリール、アラルキル、ヘテロアリール、ヘテロシクリル、アルキルカルボニル、アリールカルボニル、アラルキルカルボニル、ヘテロアリールカルボニル、ヘテロシクリルカルボニル、C(S)O−アリール、C(S)O−アルキル、シリル、置換アルキルカルボニル、ペンタハロフェニル、アセチル、トリフルオロアセチル、カルボキシル置換アルキルカルボニル、フルオロ、クロロ、ブロモ、ヨード、ヒドロキシベンゾトリアゾール、イミダゾール、ニトロフェノール、ペンタクロロフェノール、N−ヒドロキシスクシンイミド、ジシクロヘキシルカルボジイミド、N−ヒドロキシ−N−メトキシアミン、酢酸無水物、ギ酸無水物、スルホン酸無水物、メタンスルホン酸無水物、エタンスルホン酸無水物、ベンゼンスルホン酸無水物、p−トリルスルホン酸無水物、酸塩化物、酸臭化物、酸ヨウ化物、イソチオシアネート、イソシアナート、モノクロロトリアジン、ジクロロトリアジン、モノハロゲン置換ピリジン、ジハロゲン置換ピリジン、モノハロ置換ジアジン、ジハロ置換ジアジン、マレイミド、アジリジン、スルホニルハロゲン化物、酸ハロゲン化物、ヒドロキシスクシンイミドエステル、ヒドロキシスルホスクシンイミドエステル、イミドエステル、ヒドラジン、アジドニトロフェニル、アジ化物、3−(2−ピリジルジチオ)プロピオンアミド(3-(2-pyridyl dithio)proprionamide)、グリオキサール、及びアルデヒドから選ばれ、
P1、P2、P3におけるスペーサー基は、ポリエチレングリコールまたはエンドキャップされたポリエチレングリコールから選択され、
Lは、式(a)の基であり:
破線は、Nへの結合を表し、
R1は、Hまたは式−(CH2)2−ORb1の基を表し、
R1'は、Hまたは式−(CH2)2−ORb2の基を表し、
R2は、Hまたは式−CH2−ORcの基を表し、
R2'は、Hまたは式−ORdまたは−CH2−ORdの基を表す)
R3は、Hまたは式−(CH2)2−OReもしくは−(CH2)3−OReの基を表し、
Ra、Rb1、Rb2、Rc、Rd、Reは、互いに独立して、直鎖または分枝状のC(10〜22)アルキル、C(10〜22)一不飽和または多不飽和のアルケニルまたは一不飽和または多不飽和のC(10〜22)アルキニルを表し、
mは、1、2または3であり、
ただし、
R1、R1'、R2、R2'、R3の少なくとも1つは、Hでないことを条件とする)。 - R1、R1'、R2、R2'が、Hであり、
R3が、式−(CH2)2−OReまたは−(CH2)3−OReの基であり、
P1、P2、P3、Y、Ra、Reおよびmが、請求項1に記載の通りであることを特徴とする、請求項1に記載の化合物。 - 式IIまたはIIIを有する:
Yは、O、NH、または共有結合を表し、
P1は、Y保護基もしくはY活性化基、またはスペーサー基を表し(但し、Yが共有結合の場合はP 1 はY活性化基またはスペーサー基を表し)、
P2、P3は、互いに独立して、H、アミノ保護基、もしくはスペーサー基を表し、または、
P2とP3は、それらが結合しているNと一緒になって、環構造を形成し、
R1は、Hまたは式−(CH2)2−ORb1の基を表し、
R1'は、Hまたは式−(CH2)2−ORb2の基を表し、
R2は、Hまたは式−CH2−ORcの基を表し、
R2'は、Hまたは式−ORdもしくは−CH2−ORdの基を表し、
Ra、Rb1、Rb2、Rc、Rdは、互いに独立して、直鎖または分枝状のC(10〜22)アルキル、C(10〜22)一不飽和または多不飽和のアルケニルまたは一不飽和または多不飽和のC(10〜22)アルキニルを表し、
mは、1、2または3であり、
ただし、
式IIにおいて、R2およびR2'の1つは、Hでなく、
式IIIにおいて、R1およびR1'の1つは、Hでないことを条件とする)
ことを特徴とする、請求項1に記載の化合物。 - 式IIa、IIb、IIcまたはIIdを有する:
Yは、O、NH、または共有結合を表し、
P1は、Y保護基もしくはY活性化基、またはスペーサー基を表し(但し、Yが共有結合の場合はP 1 はY活性化基またはスペーサー基を表し)、
P2、P3は、互いに独立して、H、アミノ保護基、もしくはスペーサー基を表し、または、
P2とP3は、それらが結合しているNと一緒になって、環構造を形成し、
Ra、Rc、Rdは、互いに独立して、直鎖または分枝状のC(10〜22)アルキル、C(10〜22)一不飽和または多不飽和のアルケニルまたは一不飽和または多不飽和のC(10〜22)アルキニルを表し、
mは、1、2または3である)ことを特徴とする、請求項6に記載の化合物。 - 式IIIaまたはIIIbを有する:
Yは、O、NH、または共有結合を表し、
P1は、Y保護基もしくはY活性化基、またはスペーサー基を表し(但し、Yが共有結合の場合はP 1 はY活性化基またはスペーサー基を表し)、
P2、P3は、互いに独立して、H、アミノ保護基、もしくはスペーサー基を表し、または、
P2とP3は、それらが結合しているNと一緒になって、環構造を形成し、
Ra、Rb1、Rb2は、互いに独立して、直鎖または分枝状のC(10〜22)アルキル、C(10〜22)一不飽和または多不飽和のアルケニルまたは一不飽和または多不飽和のC(10〜22)アルキニルを表し、
mは、1、2または3である)ことを特徴とする、請求項6に記載の化合物。 - 式IVaまたはIVbを有する:
Yは、O、NH、または共有結合を表し、
P1は、Y保護基もしくはY活性化基、またはスペーサー基を表し(但し、Yが共有結合の場合はP 1 はY活性化基またはスペーサー基を表し)、
P2、P3は、互いに独立して、H、アミノ保護基、もしくはスペーサー基を表し、または、
P2とP3は、それらが結合しているNと一緒になって、環構造を形成し、
Ra、Reは、互いに独立して、直鎖または分枝状のC(10〜22)アルキル、C(10〜22)一不飽和または多不飽和のアルケニルまたは一不飽和または多不飽和のC(10〜22)アルキニルを表し、
mは、1、2または3である)ことを特徴とする、請求項1に記載の化合物。 - C(10〜22)一不飽和または多不飽和のアルケニルおよびC(10〜22)一不飽和または多不飽和のアルキニルは、1、2、3または4個の不飽和結合を有することを特徴とする、請求項1〜9のいずれか一項に記載の化合物。
- C(10〜22)一不飽和または多不飽和のアルケニルおよびC(10〜22)一不飽和または多不飽和のアルキニルは、1または2個の不飽和結合を有することを特徴とする、請求項1〜9のいずれか一項に記載の化合物。
- P1、P2、P3の少なくとも1つが、スペーサー基であることを特徴とする、請求項1〜11のいずれか一項に記載の化合物。
- 式Iの請求項1〜12のいずれか一項に記載の少なくとも1つの化合物を、任意選択で1つまたは複数の他の小胞形成性化合物と混合して、含む、小胞型組成物。
- 薬物送達系用、または抗原表示系用である請求項13に記載の小胞型組成物。
- 前記小胞型組成物は、リポソーム、ミセルまたはナノ粒子であることを特徴とする、請求項13または14に記載の小胞型組成物。
- 請求項1〜12のいずれか一項に記載の化合物、または請求項13〜15のいずれか一項に記載の小胞型組成物を含むキット。
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KR20200036033A (ko) * | 2012-03-16 | 2020-04-06 | 메르크 파텐트 게엠베하 | 표적화 아미노산 지질 |
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US10232050B1 (en) | 2014-12-12 | 2019-03-19 | Clemson University | Multi-functional particles and methods of using the same |
US11633355B2 (en) | 2014-12-12 | 2023-04-25 | Clemson University Research Foundation | Multi-functional particles and methods of using the same |
CN108136449B (zh) * | 2015-11-11 | 2019-06-07 | 横滨橡胶株式会社 | 轮胎的内表面的清洗系统 |
CN106083637B (zh) * | 2016-06-06 | 2018-11-23 | 大连民族大学 | 味精类脂、味精脂质体的合成方法及其应用 |
MX2018015236A (es) * | 2016-06-24 | 2019-04-11 | Eisai R&D Man Co Ltd | Lipido cationico. |
JP2019524781A (ja) * | 2016-08-03 | 2019-09-05 | ニューロポア セラピーズ インコーポレイテッド | Tlr2二量体化調節剤としての脂質置換アミノ1,2−ジオール化合物および脂質置換アミノ1,3−ジオール化合物 |
TWI801477B (zh) | 2017-12-27 | 2023-05-11 | 日商衛材R&D企管股份有限公司 | 陽離子性脂質 |
AU2020269626A1 (en) * | 2019-05-07 | 2021-10-28 | Universidade Do Minho | Method for production of liposomes |
CN112010995A (zh) * | 2019-05-30 | 2020-12-01 | 株式会社大赛璐 | 壳聚糖衍生物及光学异构体用分离剂 |
CN114177136B (zh) * | 2020-09-12 | 2023-08-01 | 苏州优诺康医药科技有限公司 | 一种可注射用的两亲性嵌段共聚物纳米载药胶束 |
CN117460711A (zh) * | 2022-06-02 | 2024-01-26 | 厦门赛诺邦格生物科技股份有限公司 | 一种含有不饱和键的氨基酸阳离子脂质 |
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CN104168887B (zh) | 2018-09-04 |
CA2867184A1 (en) | 2013-09-19 |
AU2013231819A1 (en) | 2014-10-30 |
WO2013135360A1 (en) | 2013-09-19 |
CA2867184C (en) | 2020-09-01 |
NZ630990A (en) | 2016-04-29 |
CN104168887A (zh) | 2014-11-26 |
HK1199819A1 (en) | 2015-07-24 |
KR20140135832A (ko) | 2014-11-26 |
ZA201407491B (en) | 2015-12-23 |
MX2014010810A (es) | 2014-12-08 |
PT2825157T (pt) | 2018-12-14 |
ES2700742T3 (es) | 2019-02-19 |
TWI606030B (zh) | 2017-11-21 |
AU2013231819B2 (en) | 2017-07-20 |
BR112014022847A2 (ja) | 2017-06-20 |
KR102081046B1 (ko) | 2020-02-25 |
RU2670618C2 (ru) | 2018-10-24 |
SI2825157T1 (sl) | 2019-01-31 |
US20150030670A1 (en) | 2015-01-29 |
EP2825157A1 (en) | 2015-01-21 |
RU2014141547A (ru) | 2016-05-10 |
PL2825157T3 (pl) | 2019-05-31 |
US9796666B2 (en) | 2017-10-24 |
JP2015514692A (ja) | 2015-05-21 |
MX359736B (es) | 2018-10-09 |
DK2825157T3 (da) | 2019-01-02 |
TW201343615A (zh) | 2013-11-01 |
HUE040256T2 (hu) | 2019-02-28 |
SG11201405536YA (en) | 2014-10-30 |
BR112014022847B1 (pt) | 2022-08-23 |
EP2825157B1 (en) | 2018-09-05 |
SG10201610402VA (en) | 2017-02-27 |
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