JP2015028474A - Matrix for maldi mass analysis - Google Patents
Matrix for maldi mass analysis Download PDFInfo
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- JP2015028474A JP2015028474A JP2014134965A JP2014134965A JP2015028474A JP 2015028474 A JP2015028474 A JP 2015028474A JP 2014134965 A JP2014134965 A JP 2014134965A JP 2014134965 A JP2014134965 A JP 2014134965A JP 2015028474 A JP2015028474 A JP 2015028474A
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- mass spectrometry
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- amino acid
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- 239000011159 matrix material Substances 0.000 title claims abstract description 104
- 238000004458 analytical method Methods 0.000 title claims abstract description 66
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 claims abstract 4
- 150000001413 amino acids Chemical class 0.000 claims description 90
- 238000004949 mass spectrometry Methods 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 238000001871 ion mobility spectroscopy Methods 0.000 claims description 9
- 125000000129 anionic group Chemical group 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 claims description 6
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 229940000406 drug candidate Drugs 0.000 claims description 4
- 239000003550 marker Substances 0.000 claims description 4
- 238000013513 substance screening Methods 0.000 claims description 3
- 229940024606 amino acid Drugs 0.000 description 90
- 235000001014 amino acid Nutrition 0.000 description 89
- 239000000203 mixture Substances 0.000 description 84
- 239000000243 solution Substances 0.000 description 46
- XJGFWWJLMVZSIG-UHFFFAOYSA-N 9-aminoacridine Chemical compound C1=CC=C2C(N)=C(C=CC=C3)C3=NC2=C1 XJGFWWJLMVZSIG-UHFFFAOYSA-N 0.000 description 40
- 229960001441 aminoacridine Drugs 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 19
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 15
- 239000012298 atmosphere Substances 0.000 description 15
- 229940127271 compound 49 Drugs 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 13
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 229940126545 compound 53 Drugs 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
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- 239000001257 hydrogen Substances 0.000 description 12
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 11
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 11
- 229940126657 Compound 17 Drugs 0.000 description 11
- -1 nitrogen-containing heterocyclic compounds Chemical class 0.000 description 11
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 9
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 9
- 150000002500 ions Chemical class 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 7
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 7
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 7
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 7
- 229940125844 compound 46 Drugs 0.000 description 7
- 235000018417 cysteine Nutrition 0.000 description 7
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 7
- ZHFMVVUVCALAMY-UHFFFAOYSA-N pipecolate Natural products OC1CNC(C(O)=O)C(O)C1O ZHFMVVUVCALAMY-UHFFFAOYSA-N 0.000 description 7
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- XLMJNBAZHRTJED-UHFFFAOYSA-N 1,2,3,4-tetrahydroanthracen-9-amine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=CC2=C1 XLMJNBAZHRTJED-UHFFFAOYSA-N 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000000090 biomarker Substances 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 229940127573 compound 38 Drugs 0.000 description 5
- 238000003795 desorption Methods 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 239000002207 metabolite Substances 0.000 description 5
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 5
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- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 4
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 4
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- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 4
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 4
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 4
- 229940125900 compound 59 Drugs 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 235000013922 glutamic acid Nutrition 0.000 description 4
- 239000004220 glutamic acid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000010948 rhodium Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
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- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 3
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 3
- QSICEHYCBQABMY-UHFFFAOYSA-N 5,6,7,8-tetrahydroanthracen-2-amine Chemical compound C1CCCC2=CC3=CC(N)=CC=C3C=C21 QSICEHYCBQABMY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 3
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- BMRFESVZYWRROS-UHFFFAOYSA-N 1,2,3,4,5,6,7,8-octahydroacridin-9-amine Chemical compound C1CCCC2=C1N=C1CCCCC1=C2N BMRFESVZYWRROS-UHFFFAOYSA-N 0.000 description 2
- IVCGJOSPVGENCT-UHFFFAOYSA-N 1h-pyrrolo[2,3-f]quinoline Chemical class N1=CC=CC2=C(NC=C3)C3=CC=C21 IVCGJOSPVGENCT-UHFFFAOYSA-N 0.000 description 2
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- 238000005684 Liebig rearrangement reaction Methods 0.000 description 2
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- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 2
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 2
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Landscapes
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Abstract
Description
本発明は、マトリックスとして新規な化合物を用いる、マトリックス支援レーザー脱離イオン化（MALDI）質量分析方法に関する。 The present invention relates to a matrix-assisted laser desorption / ionization (MALDI) mass spectrometry method using a novel compound as a matrix.
MALDI（Matrix Assisted Laser Desorption/Ionization、マトリックス支援レーザー脱離イオン化）は、汎用性の高いイオン化法であり、質量分析のためのイオン源として広く利用されている。 MALDI (Matrix Assisted Laser Desorption / Ionization) is a versatile ionization method and is widely used as an ion source for mass spectrometry.
MALDI質量分析では通常、レーザーエネルギーを効率良く吸収するマトリックスと呼ばれる化合物中に分析対象となる分子を均一に分散させた微細結晶を調製し、レーザー光を照射する。この操作により、試料分子をほとんどフラグメント化することなくイオン化し、得られた分子イオンを質量分析に供することができる。MALDI質量分析では多くの場合、対象分子をポジティブイオン化し、ポジティブイオンとして検出するポジティブモードで行われるが、リン酸化または硫酸化されたペプチド類、オリゴヌクレオチド類および酸性オリゴ糖等、プロトンを放出しやすい官能基を有する分子はネガティブイオン化し、ネガティブモードで分析される。 In MALDI mass spectrometry, fine crystals are usually prepared in which molecules to be analyzed are uniformly dispersed in a compound called a matrix that efficiently absorbs laser energy, and laser light is irradiated. By this operation, sample molecules can be ionized with almost no fragmentation, and the obtained molecular ions can be subjected to mass spectrometry. In many cases, MALDI mass spectrometry is performed in a positive mode in which target molecules are positively ionized and detected as positive ions, but they release protons such as phosphorylated or sulfated peptides, oligonucleotides, and acidic oligosaccharides. Molecules with easy functional groups are negatively ionized and analyzed in negative mode.
MALDI質量分析では、分析対象に応じてマトリックスを選択する必要があり、これまで、様々な検討がされてきた。例えば、非特許文献１〜３は、特定の非極性の分子、分子約700〜5000ポリブタジエンまたは低分子粗製油画分等を分析対象とし、anthracene等の非極性分子をマトリックスとして用いるポジティブモードのMALDI質量分析について報告する。また非特許文献４は、gramicidin S、bovine insulin、aprotinin等のタンパク質を分析対象とし、pyridoindole類、pyridylindole類およびpyridylpyridoindole類である含窒素ヘテロ環化合物をマトリックスとして用いるMALDI質量分析について報告する。また非特許文献５は、ネガティブモードのMALDI質量分析における、9-aminoacridineのマトリックスとしての使用について報告する。ここでは、フェノール類、カルボン酸類、スルホン酸エステル類、アミン類およびアルコールのようなプロトンを放出する、分子量の比較的小さい分子、並びにオリゴヌクレオチド、オリゴアミドおよびタンパク質のような高分子を対象として分析を試みている。また、特許文献１は、アミノキノリンのイオンと酸性基含有有機物質のイオンとを含む液体マトリックスを用い、糖、糖ペプチドまたはペプチドを分析対象とするMALDI質量分析法を提案する。 In MALDI mass spectrometry, it is necessary to select a matrix according to an analysis target, and various studies have been made so far. For example, Non-Patent Documents 1 to 3 describe a positive-mode MALDI mass using a specific non-polar molecule, a molecule of about 700 to 5000 polybutadiene or a low-molecular crude oil fraction as an analysis target, and a non-polar molecule such as anthracene as a matrix. Report on the analysis. Non-Patent Document 4 reports MALDI mass spectrometry using proteins such as gramicidin S, bovine insulin, and aprotinin as analysis targets and using nitrogen-containing heterocyclic compounds such as pyridoindoles, pyridylindoles and pyridylpyridoindoles as a matrix. Non-Patent Document 5 reports the use of 9-aminoacridine as a matrix in MALDI mass spectrometry in negative mode. Here, analysis is performed on relatively low molecular weight molecules that release protons such as phenols, carboxylic acids, sulfonate esters, amines, and alcohols, and macromolecules such as oligonucleotides, oligoamides, and proteins. I'm trying. Patent Document 1 proposes a MALDI mass spectrometry method using a liquid matrix containing aminoquinoline ions and acidic group-containing organic substance ions, and analyzing sugars, glycopeptides or peptides.
一方、本発明者らは、アントラセン、フェナントレン、アクリジンまたはキノリン骨格を有するMALDI質量分析用マトリックスを開発している（特許文献２）。そして、9-aminoanthracene（前掲特許文献2中の化合物17）をマトリックスとして、アニオン性生体成分の混合物を分析対象としたネガティブモードのMALDI質量分析に用いたところ、多数の分子が検出可能であることを報告している。 On the other hand, the present inventors have developed a matrix for MALDI mass spectrometry having an anthracene, phenanthrene, acridine or quinoline skeleton (Patent Document 2). When 9-aminoanthracene (compound 17 in the above-mentioned Patent Document 2) is used as a matrix for negative mode MALDI mass spectrometry analysis of a mixture of anionic biological components, a large number of molecules can be detected. Has been reported.
本発明者らは、生体低分子の網羅的な解析を行うことを目的に、約300種の代謝物質を用いたMALDI質量分析を行い、数種のアミノ酸が感度よく検出されることを見出してきた。低分子化合物をネガティブモードで分析するためのマトリックスとしては、上述の9-aminoacridine（9-AA）が汎用されてきたが、9-AAではproline、cysteineおよびpipecolate等を検出できなかった。また、上述の9-aminoanthracene（化合物17）は、アミノ酸検出において比較的有効ではあったが、不安定であり、取扱い上の問題があった。 The present inventors have conducted MALDI mass spectrometry using about 300 kinds of metabolites for the purpose of comprehensive analysis of small biological molecules, and have found that several kinds of amino acids can be detected with high sensitivity. It was. 9-aminoacridine (9-AA) described above has been widely used as a matrix for analyzing low molecular weight compounds in the negative mode, but proline, cysteine, pipecolate, etc. could not be detected with 9-AA. The 9-aminoanthracene (Compound 17) described above was relatively effective in amino acid detection, but was unstable and had a problem in handling.
今般、アミノ酸を高感度で検出するのに有効な、MALDI質量分析用マトリックスを探索した。そして化合物17および9-AAの部分還元体を合成し、数種のアミノ酸混合物を対象としてMALDI質量分析を行った結果、アミノ酸を対象としたネガティブモードMALDI質量分析のための新規なマトリックスを見出し、本発明を完成した。 Recently, we searched for a matrix for MALDI mass spectrometry that is effective in detecting amino acids with high sensitivity. Then, partially reduced forms of compounds 17 and 9-AA were synthesized, and MALDI mass spectrometry was performed on a mixture of several amino acids. As a result, a novel matrix for negative mode MALDI mass spectrometry targeting amino acids was found, The present invention has been completed.
本発明は、下記を提供する。
[１] 次の一般式Ｉまたは式IIで表される化合物、下記化合物56、57、62、63、64、65および66ならびにそれらの塩からなる群より選択される1または複数の化合物を、対象と混合して用いる、MALDI質量分析方法。
The present invention provides the following.
[1] One or more compounds selected from the group consisting of the following compounds represented by the general formula I or II, the following compounds 56, 57, 62, 63, 64, 65 and 66 and salts thereof: MALDI mass spectrometry method used by mixing with the target.
（式I中：
環Cが6員の炭素からなる環であり、かつ環A、BおよびCのうちのいずれか1つまたは2つが非芳香族性であり、残りが芳香族性であるか；または環Cが存在せず、かつ環AおよびBのうちの少なくとも1つが芳香属性であり；かつ
R1、R2およびR3のうち芳香属性の環上の置換基である少なくとも1つがNH2もしくはNHR9であり、このときR9がC1-6アルキルであり、かつ残りがH、F、Cl、BrもしくはIであるか；またはR1が次の式
(In Formula I:
Ring C is a ring composed of 6-membered carbon and any one or two of Rings A, B and C are non-aromatic and the rest are aromatic; or Ring C is Not present and at least one of rings A and B is an aromatic attribute; and
At least one of R 1 , R 2 and R 3 which is a substituent on the aromatic ring is NH 2 or NHR 9 , wherein R 9 is C 1-6 alkyl, and the rest are H, F , Cl, Br or I; or R 1 is of the formula
で表される基であり、R2がHであり、かつR3がNH2もしくはNHR9であり、このときR9がC1-6アルキルであり；かつ
R4がHであるか；または環Bが芳香族性であり、かつR1がNH2もしくはNHR9である（R9は上で定義したとおりである。）とき、R4がF、Cl、BrもしくはIである。）
And R 2 is H and R 3 is NH 2 or NHR 9 wherein R 9 is C 1-6 alkyl; and
When R 4 is H; or ring B is aromatic and R 1 is NH 2 or NHR 9 (R 9 is as defined above), R 4 is F, Cl , Br or I. )
（式II中、
環D、EおよびFが還元されたアクリジン環を構成し；かつ
R5、R6およびR7のうち少なくとも1つがNH2もしくはNHR10であり、このときR10がC1-6アルキルであり、かつ残りがHであるか；またはR5、R6およびR7がHであり；かつ
R8がHまたは存在しない。）
(In Formula II,
Rings D, E and F constitute a reduced acridine ring; and
At least one of R 5 , R 6 and R 7 is NH 2 or NHR 10 , wherein R 10 is C 1-6 alkyl and the remainder is H; or R 5 , R 6 and R 7 is H; and
R 8 is H or absent. )
[２] １または複数の化合物が、下記化合物44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65および66ならびにそれらの塩からなる群より選択される、[１]に記載の方法。 [2] One or more compounds are the following compounds 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, The method according to [1], selected from the group consisting of 63, 64, 65 and 66 and salts thereof.
[３] 分析が、ネガティブモードで行われる、[１]または[２]に記載の方法。
[４] MALDI-TOF質量分析方法である、[１]〜[３]のいずれか一に記載の方法。
[５] 対象が、一または複数の分子量1000以下のアニオン種を含む試料である、[１]〜[４]のいずれか一に記載の方法。
[６] 分子量1000以下のアニオン種が、アミノ酸である、[５]に記載の方法。
[７] イメージング質量分析、メタボローム解析、疾患マーカー解析または医薬候補物質のスクリーニングのために行われる、[１]〜[６]のいずれか一に記載の方法。
[８] [１]に定義された一般式Iまたは式IIで表される化合物およびそれらの塩からなる群より選択される1または複数の化合物を含む、MALDI質量分析用マトリックス。
[９] １または複数の化合物が、[２]に定義された群より選択される、[７]に記載のマトリックス。
[１０] [８]または[９]に記載のマトリックスを含む、MALDI質量分析用キット。
[１１] 次の一般式I-1で表される化合物またはその塩。
[3] The method according to [1] or [2], wherein the analysis is performed in a negative mode.
[4] The method according to any one of [1] to [3], which is a MALDI-TOF mass spectrometry method.
[5] The method according to any one of [1] to [4], wherein the object is a sample containing one or more anionic species having a molecular weight of 1000 or less.
[6] The method according to [5], wherein the anionic species having a molecular weight of 1000 or less is an amino acid.
[7] The method according to any one of [1] to [6], which is performed for imaging mass spectrometry, metabolome analysis, disease marker analysis, or drug candidate substance screening.
[8] A matrix for MALDI mass spectrometry, comprising one or more compounds selected from the group consisting of compounds represented by the general formula I or formula II defined in [1] and salts thereof.
[9] The matrix according to [7], wherein the one or more compounds are selected from the group defined in [2].
[10] A MALDI mass spectrometry kit comprising the matrix according to [8] or [9].
[11] A compound represented by the following general formula I-1 or a salt thereof:
（式I-1中：
R1がNH2またはNHR9であり、かつR2およびR3がHであり；かつ
R4がF、Cl、BrもしくはIである。）
[１２] 化合物が下記のいずれかである、[１１]に記載の化合物またはその塩。
(In Formula I-1:
R 1 is NH 2 or NHR 9 and R 2 and R 3 are H; and
R 4 is F, Cl, Br or I. )
[12] The compound or salt thereof according to [11], wherein the compound is any of the following:
[１３] 下記のいずれかの化合物またはその塩。 [13] Any of the following compounds or salts thereof:
本発明はまた、下記を提供する。
[１] 次の一般式Ｉまたは式IIで表される化合物およびそれらの塩からなる群より選択される1または複数の化合物を、対象と混合して用いる、MALDI質量分析方法。
The present invention also provides the following.
[1] A MALDI mass spectrometric method using one or more compounds selected from the group consisting of the following compounds represented by general formula I or formula II and salts thereof in a mixture with a subject.
（式I中：
環Cが6員の炭素からなる環であり、かつ環A、BおよびCのうちのいずれか1つまたは2つが非芳香族性であり、残りが芳香族性であるか；または環Cが存在せず、かつ環AおよびBのうちの少なくとも1つが芳香属性であり；かつ
R1、R2およびR3のうち芳香属性の環上の置換基である少なくとも1つがNH2もしくはNHR9であり、このときR9がC1-6アルキルであり、かつ残りがHであるか；またはR1が次の式
(In Formula I:
Ring C is a ring composed of 6-membered carbon and any one or two of Rings A, B and C are non-aromatic and the rest are aromatic; or Ring C is Not present and at least one of rings A and B is an aromatic attribute; and
At least one of the substituents on the aromatic ring in R 1 , R 2 and R 3 is NH 2 or NHR 9 , where R 9 is C 1-6 alkyl and the rest is H Or R 1 is
で表される基であり、R2がHであり、かつR3がNH2もしくはNHR9であり、このときR9がC1-6アルキルであり；かつ
R4がHであるか；または環Bが芳香族性であり、かつR1がNH2もしくはNHR9である（R9は上で定義したとおりである。）とき、R4がF、Cl、BrもしくはIである。）
And R 2 is H and R 3 is NH 2 or NHR 9 wherein R 9 is C 1-6 alkyl; and
When R 4 is H; or ring B is aromatic and R 1 is NH 2 or NHR 9 (R 9 is as defined above), R 4 is F, Cl , Br or I. )
（式II中、
環D、EおよびFが還元されたアクリジン環を構成し；かつ
R5、R6およびR7のうち少なくとも1つがNH2もしくはNHR10であり、このときR10がC1-6アルキルであり、かつ残りがHであるか；またはR5、R6およびR7がHであり；かつ
R8がHまたは存在しない。）
[２] １または複数の化合物が、下記化合物44、45、46、47、48、49、50、51、52、53および54ならびにそれらの塩からなる群より選択される、[１]に記載の方法。
(In Formula II,
Rings D, E and F constitute a reduced acridine ring; and
At least one of R 5 , R 6 and R 7 is NH 2 or NHR 10 , wherein R 10 is C 1-6 alkyl and the remainder is H; or R 5 , R 6 and R 7 is H; and
R 8 is H or absent. )
[2] The compound or compounds described in [1], wherein the one or more compounds are selected from the group consisting of the following compounds 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 and 54 and salts thereof the method of.
[３] 分析が、ネガティブモードで行われる、[１]または[２]に記載の方法。
[４] MALDI-TOF質量分析方法である、[１]〜[３]のいずれか一に記載の方法。
[５] 対象が、一または複数の分子量1000以下のアニオン種を含む試料である、[１]〜[４]のいずれか一に記載の方法。
[６] 分子量1000以下のアニオン種が、アミノ酸である、[５]に記載の方法。
[７] イメージング質量分析、メタボローム解析、疾患マーカー解析または医薬候補物質のスクリーニングのために行われる、[１]〜[６]のいずれか一に記載の方法。
[８] [１]に定義された一般式Iまたは式IIで表される化合物およびそれらの塩からなる群より選択される1または複数の化合物を含む、MALDI質量分析用マトリックス。
[９] １または複数の化合物が、[２]に定義された群より選択される、[７]に記載のマトリックス。
[１０] [８]または[９]に記載のマトリックスを含む、MALDI質量分析用キット。
[１１] 次の一般式I-1で表される化合物またはその塩。
[3] The method according to [1] or [2], wherein the analysis is performed in a negative mode.
[4] The method according to any one of [1] to [3], which is a MALDI-TOF mass spectrometry method.
[5] The method according to any one of [1] to [4], wherein the object is a sample containing one or more anionic species having a molecular weight of 1000 or less.
[6] The method according to [5], wherein the anionic species having a molecular weight of 1000 or less is an amino acid.
[7] The method according to any one of [1] to [6], which is performed for imaging mass spectrometry, metabolome analysis, disease marker analysis, or drug candidate substance screening.
[8] A matrix for MALDI mass spectrometry, comprising one or more compounds selected from the group consisting of compounds represented by the general formula I or formula II defined in [1] and salts thereof.
[9] The matrix according to [7], wherein the one or more compounds are selected from the group defined in [2].
[10] A MALDI mass spectrometry kit comprising the matrix according to [8] or [9].
[11] A compound represented by the following general formula I-1 or a salt thereof:
（式I-1中：
R1がNH2またはNHR9であり、かつR2およびR3がHであり；かつ
R4がF、Cl、BrもしくはIである。）
[１２] 下式で表される、[１１]に記載の化合物またはその塩。
(In Formula I-1:
R 1 is NH 2 or NHR 9 and R 2 and R 3 are H; and
R 4 is F, Cl, Br or I. )
[12] The compound according to [11] or a salt thereof represented by the following formula:
[１３]
下式で表される化合物またはその塩。
[13]
A compound represented by the following formula or a salt thereof.
〔MALDI質量分析用マトリックス〕
本発明のMALDI質量分析においては、9-aminoacridine（9-AA）または9-aminoanthracene（化合物17）を還元した構造を有する化合物およびそれらの塩からなる群より選択される1または複数の化合物を、マトリックスとして用いる。具体的には、次の一般式Ｉまたは式IIで表される化合物、下記化合物56、57、62、63、64、65および66ならびにそれらの塩からなる群より選択される1または複数の化合物を、マトリックスとして用いる。
[Matrix for MALDI mass spectrometry]
In the MALDI mass spectrometry of the present invention, one or more compounds selected from the group consisting of compounds having a structure obtained by reducing 9-aminoacridine (9-AA) or 9-aminoanthracene (Compound 17) and salts thereof, Used as a matrix. Specifically, one or more compounds selected from the group consisting of compounds represented by the following general formula I or formula II, the following compounds 56, 57, 62, 63, 64, 65 and 66 and salts thereof Is used as a matrix.
式I中：
環Cが、環Bと共通する炭素を含めて6員の炭素からなる環であり、かつ環A、BおよびCのうちのいずれか1つまたは2つが非芳香族性であり、残りが芳香族性であるか；または環Cが存在せず、かつ環AおよびBのうちの少なくとも1つが芳香属性であり；かつ
R1、R2およびR3のうち芳香属性の環上の置換基である少なくとも1つがNH2もしくはNHR9であり、このときR9がC1-6アルキルであり、かつ残りがH、F、Cl、BrもしくはIであるか；またはR1が次の式
In formula I:
Ring C is a ring composed of 6-membered carbon including carbon in common with ring B, and any one or two of rings A, B and C are non-aromatic and the rest is aromatic Or ring C is absent and at least one of rings A and B is aromatic in nature; and
At least one of R 1 , R 2 and R 3 which is a substituent on the aromatic ring is NH 2 or NHR 9 , wherein R 9 is C 1-6 alkyl, and the rest are H, F , Cl, Br or I; or R 1 is of the formula
で表される基であり、R2がHであり、かつR3がNH2もしくはNHR9であり、このときR9がC1-6アルキルであり（好ましくはR9がC1-3アルキルであり、より好ましくはR9がCH3である。）；かつ
R4がHであるか；または環Bが芳香族性であり、かつR1がNH2もしくはNHR9である（R9は上で定義したとおりである。）とき、R4がF、Cl、BrもしくはIである。
Wherein R 2 is H and R 3 is NH 2 or NHR 9 , wherein R 9 is C 1-6 alkyl (preferably R 9 is C 1-3 alkyl) And more preferably R 9 is CH 3 );
When R 4 is H; or ring B is aromatic and R 1 is NH 2 or NHR 9 (R 9 is as defined above), R 4 is F, Cl , Br or I.
式II中、
環D、EおよびFが還元されたアクリジン環を構成し；かつ
R5、R6およびR7のうち少なくとも1つがNH2もしくはNHR10（このときR10がC1-6アルキルである。）であり、かつ残りがHであるか；またはR5、R6およびR7がHであり；かつ
R8がHまたは存在しない。
Rings D, E and F constitute a reduced acridine ring; and
At least one of R 5 , R 6 and R 7 is NH 2 or NHR 10 (where R 10 is C 1-6 alkyl) and the remainder is H; or R 5 , R 6 And R 7 is H; and
R 8 is H or absent.
式Iで表される化合物またはその塩のうち、9-AAでは測定不能なproline、cysteineおよびpipecolateのうち少なくとも1つ（好ましくは2つ以上、より好ましくはすべて）を検出でき、かつより多くのアミノ酸（例えば10種類以上、好ましくは20種類以上、さらに好ましくは25種類以上のアミノ酸）を検出できるとの観点からは、次の式で表される化合物またはその塩であることが好ましい。 Among compounds represented by Formula I or salts thereof, at least one (preferably two or more, more preferably all) of proline, cysteine and pipecolate that cannot be measured by 9-AA can be detected, and more From the standpoint that amino acids (for example, 10 or more, preferably 20 or more, more preferably 25 or more amino acids) can be detected, a compound represented by the following formula or a salt thereof is preferable.
各式中、
環A、BおよびCのうちのいずれか1つまたは2つが非芳香族性であり、残りが芳香族性であり；かつ
R1、R2およびR3のうち芳香属性の環上の置換基である少なくとも1つ（好ましくはいずれか1つ）がNH2もしくはNHR9であり、このときR9がC1-6アルキルであり（好ましくはR9がC1-3アルキルであり、より好ましくはR9がCH3である。）、かつ残りがH、F、Cl、BrもしくはIであり；かつ
R4がHであるか；または環Bが芳香族性であり、かつR1がNH2もしくはNHR9であるとき、R4がF、Cl、BrもしくはIである。
In each formula,
Any one or two of rings A, B and C are non-aromatic and the rest are aromatic; and
At least one (preferably any one) of R 1 , R 2 and R 3 which is a substituent on the aromatic ring is NH 2 or NHR 9 , wherein R 9 is C 1-6 alkyl (Preferably R 9 is C 1-3 alkyl, more preferably R 9 is CH 3 ), and the remainder is H, F, Cl, Br or I; and
R 4 is H; or when ring B is aromatic and R 1 is NH 2 or NHR 9 , R 4 is F, Cl, Br or I.
式I-1〜4で特定された化合物またはその塩のうち、さらに特定された好ましい例は、下記の化合物またはその塩である。 Among the compounds identified by the formulas I-1 to I-4 or salts thereof, further preferred specific examples are the following compounds or salts thereof.
式Iで表される化合物またはその塩のうち、9-AAでは測定不能なproline、cysteineおよびpipecolateのうち少なくとも1つ（好ましくは2つ以上、より好ましくはすべて）を検出できる他の例は、環Cが6員の炭素からなる環であり、かつ環A、BおよびCのうちのいずれか1つまたは2つが非芳香族性であり、残りが芳香族性であり；かつ
R1が次の式
Other examples in which at least one (preferably two or more, more preferably all) of proline, cysteine, and pipecolate that are not measurable by 9-AA among compounds represented by Formula I or salts thereof can be detected are: Ring C is a 6-membered carbon ring and any one or two of Rings A, B and C are non-aromatic and the rest are aromatic; and
R 1 is
で表される基であり、R2がHであり、かつR3がNH2もしくはNHR9であり、このときR9がC1-6アルキルであり（好ましくはR9がC1-3アルキルであり、より好ましくはR9がCH3である。）；かつ
R4がHであるものである。
Wherein R 2 is H and R 3 is NH 2 or NHR 9 , wherein R 9 is C 1-6 alkyl (preferably R 9 is C 1-3 alkyl) And more preferably R 9 is CH 3 );
R 4 is H.
上で特定された化合物またはその塩のうち、さらに特定された好ましい例は、下記の化合物またはその塩である。 Among the compounds specified above or salts thereof, preferred specific examples further specified are the following compounds or salts thereof.
式Iで表される化合物またはその塩のうち、9-AAでは測定不能なproline、cysteineおよびpipecolateのうち少なくとも1つ（好ましくは2つ以上、より好ましくはすべて）を検出できる他の例は、式Iにおいて、環Cが存在せず、かつ環AおよびBのうちの少なくとも1つが芳香属性（1つが芳香族性で、他方が非芳香族性である場合と、2つが芳香族性である場合とを含む。）であるものである。さらに特定すると、次の式で表される化合物またはその塩である。 Other examples in which at least one (preferably two or more, more preferably all) of proline, cysteine, and pipecolate that are not measurable by 9-AA among compounds represented by Formula I or salts thereof can be detected are: In formula I, ring C is absent and at least one of rings A and B is aromatic (one is aromatic and the other is non-aromatic and two are aromatic Including the case.) More specifically, it is a compound represented by the following formula or a salt thereof.
各式中、R1、R2、R3およびR4は、式Iに関して定義した場合と同じである。 In each formula, R 1 , R 2 , R 3 and R 4 are the same as defined for formula I.
式I-5で特定された化合物またはその塩のうち、さらに特定された好ましい例は、下記の化合物またはその塩である。 Among the compounds identified by the formula I-5 or salts thereof, further preferred specific examples are the following compounds or salts thereof.
9-AAでは測定不能なproline、cysteineおよびpipecolateのうち少なくとも1つ（好ましくは2つ以上、より好ましくはすべて）を検出できる他の例は、化合物54、化合物55、化合物56、化合物58、化合物59、化合物60、化合物62、化合物63、化合物64、化合物65および化合物66である。これらの内、proline、cysteineおよびpipecolateのすべてを検出できるとの観点からの特に好ましい例は、化合物55、化合物58、化合物59、化合物60、化合物62、化合物65および化合物66である。 Other examples that can detect at least one (preferably two or more, more preferably all) of proline, cysteine and pipecolate that cannot be measured by 9-AA are Compound 54, Compound 55, Compound 56, Compound 58, Compound 59, Compound 60, Compound 62, Compound 63, Compound 64, Compound 65 and Compound 66. Among these, particularly preferred examples from the viewpoint that all of proline, cysteine and pipecolate can be detected are Compound 55, Compound 58, Compound 59, Compound 60, Compound 62, Compound 65 and Compound 66.
式Iで表される化合物のうち、検出可能なアミノ酸が多いという観点からは、化合物53、化合物50、化合物49、化合物47、化合物48が好ましく、化合物53、化合物50、化合物49、化合物47および化合物48がより好ましく、化合物53、化合物50、化合物49および化合物47がより好ましく、化合物53、化合物50および化合物49がより好ましく、化合物53および化合物50がより好ましく、化合物53がさらに好ましい。式Iで表される化合物のうち、バックグラウンドピークが少ないとの観点からは、化合物47、化合物48、化合物49、化合物50および化合物53が好ましく、化合物47、化合物48および化合物49がより好ましく、化合物47および化合物48がより好ましく、化合物47がさらに好ましい。 Of the compounds represented by formula I, from the viewpoint that there are many detectable amino acids, compound 53, compound 50, compound 49, compound 47, and compound 48 are preferred, and compound 53, compound 50, compound 49, compound 47 and Compound 48 is more preferred, Compound 53, Compound 50, Compound 49 and Compound 47 are more preferred, Compound 53, Compound 50 and Compound 49 are more preferred, Compound 53 and Compound 50 are more preferred, and Compound 53 is even more preferred. Of the compounds represented by formula I, from the viewpoint that the background peak is small, Compound 47, Compound 48, Compound 49, Compound 50 and Compound 53 are preferred, Compound 47, Compound 48 and Compound 49 are more preferred, Compound 47 and compound 48 are more preferable, and compound 47 is more preferable.
検出可能なアミノ酸が多い他の例は、化合物55、化合物58、化合物59、化合物62、化合物63、化合物65および化合物66である。これらの内、より多くのアミノ酸が検出できるとの観点からは、化合物55、化合物58、化合物59、化合物60、化合物62、化合物65および化合物66である Other examples with many detectable amino acids are Compound 55, Compound 58, Compound 59, Compound 62, Compound 63, Compound 65 and Compound 66. Among these, from the viewpoint that more amino acids can be detected, they are Compound 55, Compound 58, Compound 59, Compound 60, Compound 62, Compound 65, and Compound 66.
式IIで表される化合物またはその塩のうち、より多くのアミノ酸（例えば10種類以上、好ましくは20種類以上、さらに好ましくは25種類以上のアミノ酸）を検出できるとの観点からは、R5、R6およびR7のうち少なくとも1つ（好ましくはいずれか1つ）がNH2もしくはNHR10（このときR10がC1-6アルキルであり、好ましくはR10がC1-3アルキルであり、より好ましくはR10がCH3である。）であり、残りがHであり、かつR8がHまたは存在しない化合物またはその塩である。より特定された好ましい例は、環D、EおよびFが、環Dおよび環Fのうち少なくとも1つの環において還元されたアクリジン環（例えば、環Dまたは環Fにおいて還元されたテトラヒドロアクリジン環、環Dおよび環Fにおいて還元されたオクタヒドロアクリジン環）を構成し；かつR5、R6およびR7のうち還元されていない環上の少なくとも1つがNH2もしくはNHR10（このときR10がC1-6アルキルである。）であり、かつ残りがHであり；かつR8が存在しない化合物またはその塩である。
さらに特定された好ましい例は、下記の化合物またはその塩である。
From the viewpoint that more amino acids (for example, 10 or more, preferably 20 or more, more preferably 25 or more amino acids) can be detected in the compound represented by Formula II or a salt thereof, R 5 , At least one (preferably any one) of R 6 and R 7 is NH 2 or NHR 10 (where R 10 is C 1-6 alkyl, preferably R 10 is C 1-3 alkyl) More preferably, R 10 is CH 3 ), the remainder is H, and R 8 is H or a non-existing compound or a salt thereof. More specific preferred examples include acridine rings wherein rings D, E and F are reduced in at least one of ring D and ring F (eg, tetrahydroacridine rings reduced in ring D or ring F, rings Constituting a reduced octahydroacridine ring at D and ring F); and at least one of R 5 , R 6 and R 7 on the unreduced ring is NH 2 or NHR 10 (where R 10 is C 1-6 alkyl) and the remainder is H; and R 8 is not present or a salt thereof.
Further preferred specific examples are the following compounds or salts thereof.
式IIで表される化合物またはその塩のうち、9-AAでは測定不能なprolineを検出できるとの観点からは、好ましい例は、下記の化合物またはその塩である。 Of the compounds represented by the formula II or salts thereof, from the viewpoint that proline that cannot be measured by 9-AA can be detected, preferred examples are the following compounds or salts thereof.
本発明者らの検討によると、本発明により提供される化合物は、化合物17と比較して安定性は改善されているといえる。化合物17は、冷凍庫（約-20℃）保存中にですら分解し、変色・変質するが、化合物44〜53は、冷凍庫（約4℃）で少なくとも1ヶ月は保存でき、分解せず、安定であることが確認されている。また、本発明により提供される化合物は、窒素レーザー（波長 337nm）を用いるMALDI質量分析に特に適している。吸光度測定を行うと、9-AAは337nm付近の波長の光をほとんど吸収しないのに対し、化合物47は比較的よく吸収することが確認されている。 According to the study by the present inventors, it can be said that the compound provided by the present invention has improved stability as compared with the compound 17. Compound 17 decomposes even when stored in a freezer (approximately -20 ° C), and discolors and changes in quality, but compounds 44 to 53 can be stored in the freezer (approximately 4 ° C) for at least one month, do not decompose, and are stable It has been confirmed that. In addition, the compounds provided by the present invention are particularly suitable for MALDI mass spectrometry using a nitrogen laser (wavelength 337 nm). As a result of the absorbance measurement, it has been confirmed that 9-AA hardly absorbs light having a wavelength around 337 nm, whereas compound 47 absorbs relatively well.
本発明で、「マトリックス」というときは、一の化合物を指す場合と、二以上の化合物の混合物を指す場合とがある。また一の化合物または二以上の化合物の混合物は、MALDI質量分析のために適した適切な溶媒に、例えばメタノールに、溶解された状態であってもよい。マトリックスは、そのような溶液である場合を含む。本発明でマトリックスとして使用される化合物に関し、「その塩」というときは、MALDI質量分析に際してアミノ酸測定の障害とならず、またMALDI質量分析のために適した適切な溶媒に、例えばメタノールに、溶解可能なものであることが好ましい。このような塩の例は、例えば、低分子（例えば、分子量100以下）の酸との塩であり、より具体的には、塩酸塩、硫酸塩および酢酸塩である。なお、本発明で「n〜m」または「n-m」で範囲を表す際は、その範囲は両端の値mおよびnを含む。 In the present invention, the term “matrix” may refer to one compound or a mixture of two or more compounds. One compound or a mixture of two or more compounds may also be dissolved in a suitable solvent suitable for MALDI mass spectrometry, such as methanol. The matrix includes cases where it is such a solution. Regarding the compound used as a matrix in the present invention, the term “salt thereof” does not interfere with amino acid measurement in MALDI mass spectrometry, and is dissolved in an appropriate solvent suitable for MALDI mass spectrometry, for example, methanol. Preferably it is possible. Examples of such salts are, for example, salts with acids of low molecular weight (for example, molecular weight of 100 or less), and more specifically, hydrochlorides, sulfates and acetates. In addition, when the range is expressed by “n to m” or “n−m” in the present invention, the range includes the values m and n at both ends.
〔MALDI質量分析の対象〕
本発明により提供されるマトリックスを用いるMALDI質量分析の測定対象は、分子量１０００以下のアニオン種（アニオンを生じさせる化合物）であり得る。測定対象は、好ましくは、アミノ酸（αアミノ酸、βアミノ酸、γアミノ酸、プロリン、L-アミノ酸、D-アミノ酸を含む。）である。
[Target of MALDI mass spectrometry]
The measurement target of MALDI mass spectrometry using the matrix provided by the present invention may be an anionic species (compound that generates an anion) having a molecular weight of 1000 or less. The measurement target is preferably an amino acid (including α-amino acid, β-amino acid, γ-amino acid, proline, L-amino acid, and D-amino acid).
本発明により検出可能なアミノ酸は、alanine、serine、N-acetylglycine、asparagine、anthranilate、glutamine、histidine、1-Aminocyclopropane-1-carboxylate、ornithine、lysine、N-acetylproline、N-acetylcysteine、3-methylhistidine、beta-alanine、proline、cysteine、pipecolate、L-Homocystein、glutamate、phenylalanine、5-Aminolevulinate、4-Aminobenzoate、methionine、D-Alanyl-D-alanine、N-acetylleucine、tyrosine、xanthurenate、5-aminovalerate、isoleucine、O-Acetyl-L-Homoserine、homocitrulline、phenylacetylglycine、tryptophan、sarcosine (N-Methylglycine)、L-Homoserine、L-Hydroxyproline、N-acetylglutamate、N-acetylmethionine、N-acetylphenylalanine、leucine、acetylcarnitine、N-acetyl-aspartyl-glutamate (NAAG)、cysteine-glutathione disulfide、Folate、5-methyltetrahydrofolate (5MeTHF)、glutathione, oxidized (GSSG)、glycine、2-aminobutyrate、threonine、5-oxoproline、aspartate、Nicotinurate、glutathione, reduced (GSH)、arginine、およびvalineからなる群より選択されるアミノ酸またはそのエナンチオマーもしくはジアステレオマーのいずれかである。 Amino acids detectable by the present invention include alanine, serine, N-acetylglycine, asparagine, anthranilate, glutamine, histidine, 1-Aminocyclopropane-1-carboxylate, ornithine, lysine, N-acetylproline, N-acetylcysteine, 3-methylhistidine, beta -alanine, proline, cysteine, pipecolate, L-Homocystein, glutamate, phenylalanine, 5-Aminolevulinate, 4-Aminobenzoate, methionine, D-Alanyl-D-alanine, N-acetylleucine, tyrosine, xanthurenate, 5-aminovalerate, isoleucine, O -Acetyl-L-Homoserine, homocitrulline, phenylacetylglycine, tryptophan, sarcosine (N-Methylglycine), L-Homoserine, L-Hydroxyproline, N-acetylglutamate, N-acetylmethionine, N-acetylphenylalanine, leucine, acetylcarnitine, N-acetyl-aspartyl- glutamate (NAAG), cysteine-glutathione disulfide, Folate, 5-methyltetrahydrofolate (5MeTHF), glutathione, oxidized (GSSG), glycine, 2-aminobutyrate, threonine, 5-oxoproline, aspartate, Nicotinurate, glutathione, reduced (GSH), arginine , Amino acid selected from the group consisting of finely valine or of any of the enantiomers or diastereomers.
分析対象であるアミノ酸は、微生物、植物、動物（細胞、組織切片、血液、体液および排泄物を含む。）または食品等の種々の源に由来するサンプル中に含まれていてもよい。 The amino acid to be analyzed may be contained in samples derived from various sources such as microorganisms, plants, animals (including cells, tissue sections, blood, body fluids and excreta) or foods.
本発明においては、MALDI質量分析に際し、マトリックスを溶媒に溶解して用いてもよい。溶媒として、揮発性のものを選択することができる。当業者であれば、選択したマトリックス化合物（またはその塩）に応じ、適切な溶媒を適宜決定することができる。溶媒の具体的な例は、メタノール、アセトニトリルおよびテトラヒドロフラン（THF）である。 In the present invention, the matrix may be dissolved in a solvent for MALDI mass spectrometry. A volatile solvent can be selected as the solvent. A person skilled in the art can appropriately determine an appropriate solvent according to the selected matrix compound (or a salt thereof). Specific examples of solvents are methanol, acetonitrile and tetrahydrofuran (THF).
本発明においては、MALDI質量分析に際し、マトリックスが対象と「混合」して用いられる。ここでいう「混合」は、例えばアミノ酸水溶液にメタノールに溶解したマトリックスを添加する場合（またはその逆）のように、液状の両者を混ぜ合わせる場合のほか、例えば動物組織由来の切片に、メタノールに溶解したマトリックスを噴霧する場合のように、固体状のサンプルに対してマトリックスを添加する場合を含む。当業者であれば、サンプルの状態に応じ、適宜マトリックスの用法を決定することができる。 In the present invention, in MALDI mass spectrometry, a matrix is used as “mixed” with an object. “Mixing” as used herein refers to, for example, adding a liquid solution such as when adding a matrix dissolved in methanol to an aqueous amino acid solution (or vice versa), for example, in a section derived from animal tissue, This includes the case where the matrix is added to the solid sample as in the case of spraying the dissolved matrix. A person skilled in the art can appropriately determine how to use the matrix according to the state of the sample.
またマトリックスの使用量は、サンプルの量またはサンプル中に含まれるであろう分析対象の量等に応じて、当業者であれば適宜決定できる。通常、対象物の量に比較して、多い量のマトリックスが使用される。例えば、サンプル1重量部に対して10〜100,000重量部または100〜10,000重量部の、マトリックス化合物（複数のマトリックス化合物を用いる場合は、各マトリックス化合物の総量として）を用いることができる。 The amount of the matrix used can be appropriately determined by those skilled in the art according to the amount of the sample or the amount of the analyte to be contained in the sample. Usually a large amount of matrix is used compared to the amount of object. For example, 10 to 100,000 parts by weight or 100 to 10,000 parts by weight of a matrix compound (when a plurality of matrix compounds are used, the total amount of each matrix compound) can be used with respect to 1 part by weight of the sample.
〔MALDI質量分析方法〕
本発明により提供されるマトリックスを使用したMALDI質量分析においては、窒素レーザー（波長337 nm）を利用するものが好ましい。また、分析計として、種々のものが選択しうる。例えば、本発明のMALDI質量分析と組み合わせて使用可能な分析計には、飛行時間型（TOF）、イオントラップ型（IT）、磁場型（Sector）、四重極型（Q-pole）およびフーリエ変換イオンサイクロトロン共鳴型（FT-ICR）が含まれる。適用できるサンプルの種類が多く、簡便であるとの観点からは、TOF型が好ましい。
[MALDI mass spectrometry method]
In MALDI mass spectrometry using the matrix provided by the present invention, those utilizing a nitrogen laser (wavelength 337 nm) are preferred. Various analyzers can be selected. For example, analyzers that can be used in combination with MALDI mass spectrometry of the present invention include time-of-flight (TOF), ion trap (IT), magnetic field (Sector), quadrupole (Q-pole) and Fourier Converted ion cyclotron resonance type (FT-ICR) is included. The TOF type is preferable from the viewpoint that there are many types of samples that can be applied and it is simple.
本発明によるMALDI質量分析は、ネガティブモードで行われることが好ましい。アミノ酸はプロトンを放出しやすい官能基を有するが、本発明により提供されるマトリックスは、ネガティブモードでアミノ酸を分析するのに特に適している。 MALDI mass spectrometry according to the present invention is preferably performed in negative mode. Although amino acids have functional groups that readily release protons, the matrix provided by the present invention is particularly suitable for analyzing amino acids in a negative mode.
〔MALDI質量分析の用途〕
本発明によるMALDI質量分析方法（以下、単に「本発明の方法」ということがある。）は、イメージング質量分析のために用いることができる。イメージング質量分析は、生体組織切片などのサンプル上の位置情報を残したまま、一または複数の生体分子や代謝物を対象として質量分析計で解析する技術である。測定から得られた位置情報と質量スペクトル中の特定イオンの信号強度に基づき、検出された対象分子の二次元分布図を画像化する（MSイメージング）。
[Use of MALDI mass spectrometry]
The MALDI mass spectrometry method according to the present invention (hereinafter sometimes simply referred to as “the method of the present invention”) can be used for imaging mass spectrometry. Imaging mass spectrometry is a technique for analyzing one or a plurality of biomolecules and metabolites with a mass spectrometer while keeping position information on a sample such as a biological tissue section. Based on the positional information obtained from the measurement and the signal intensity of specific ions in the mass spectrum, a two-dimensional distribution map of the detected target molecule is imaged (MS imaging).
本発明の方法を、イメージング質量分析として行う際には、本発明のマトリックスは、例えば、適切な溶媒に溶解した溶液とし、生体組織切片等のサンプル表面にスプレーして用いることができる。溶液におけるマトリックスの濃度は、当業者であれば適宜決定できるが、例えば、0.5〜50mg/mlとすることができる。スプレーするに際しては、市販されている専用デバイスを用いることができる。マトリックスが添加されたサンプルは、MALDI装置内で一定間隔でレーザー光が照射され、サンプル上のイオンが連続して検出される。イメージング質量分析のための装置、および得られる膨大なデータを処理するためのソフトウェアが市販されており、本発明の方法にも適用できる。 When the method of the present invention is performed as imaging mass spectrometry, the matrix of the present invention can be used, for example, as a solution dissolved in an appropriate solvent and sprayed onto a sample surface such as a biological tissue section. The concentration of the matrix in the solution can be appropriately determined by those skilled in the art, and can be, for example, 0.5 to 50 mg / ml. When spraying, a commercially available dedicated device can be used. The sample to which the matrix is added is irradiated with laser light at regular intervals in the MALDI apparatus, and ions on the sample are continuously detected. An apparatus for imaging mass spectrometry and software for processing a large amount of obtained data are commercially available and can be applied to the method of the present invention.
本発明に基づくイメージング質量分析は、バイオマーカーの探索、投与した薬物またはその代謝物の局在等を評価するために用いることができる。また、異なる組織から得られた複数のサンプルの結果を比較することで、組織による差異を画像として比較することができる。 Imaging mass spectrometry based on the present invention can be used to search for biomarkers, evaluate the location of administered drugs or their metabolites, and the like. Moreover, the difference by a structure | tissue can be compared as an image by comparing the result of the several sample obtained from a different structure | tissue.
本発明の方法は、メタボローム解析（生体低分子の網羅的解析）のために用いることができる。これまで分析の対象とされてきた、糖および有機酸に加えて、本発明によりアミノ酸の高感度・迅速な検出が可能となった。メタボローム解析は、医療分野では、細胞や組織に存在する様々なバイオマーカーを探索する強力な手段となり得る。また他の分野では、例えば、有用物質を産生する微生物について、通常時と有用物質酸性時の細胞内代謝物質を網羅的に測定することにより、有用物質を生産するメカニズムの解明、関連する遺伝子の特定、効率的な生産への応用が期待できる。さらに、ストレスに曝した植物や羅病した植物のメタボローム解析により、ストレスや病害に強い農作物の開発等にも寄与しうる。また、メタボローム解析は、食品に含まれる機能成分の探索にも用いることができる。 The method of the present invention can be used for metabolome analysis (exhaustive analysis of small biological molecules). In addition to sugars and organic acids, which have been the subject of analysis so far, the present invention enables highly sensitive and rapid detection of amino acids. Metabolome analysis can be a powerful means of searching for various biomarkers present in cells and tissues in the medical field. In other fields, for example, for microorganisms that produce useful substances, by comprehensively measuring intracellular metabolites during normal and acidic conditions of useful substances, elucidation of the mechanisms that produce useful substances, and related genes Application to specific and efficient production can be expected. Furthermore, metabolomic analysis of plants exposed to stress and diseased plants can contribute to the development of crops that are resistant to stress and disease. Metabolome analysis can also be used to search for functional components contained in food.
本発明に基づくメタボローム解析は、ゲノミクス、トランスクリプトミクス、プロテオミクス等と組み合わせることができる。それにより、代謝調節メカニズムの解明、遺伝子およびタンパク質の機能解明、薬物の作用のメカニズムの解明、バイオマーカー探索、食品に含まれる機能成分の探索、生物の育種等の、さらに幅広い分野への利用が期待できる。 Metabolomic analysis according to the present invention can be combined with genomics, transcriptomics, proteomics and the like. As a result, elucidation of metabolic regulation mechanisms, elucidation of gene and protein functions, elucidation of drug action mechanisms, search for biomarkers, search for functional components contained in food, breeding of organisms, etc. I can expect.
本発明の方法、または本発明の方法を組み合わせた解析は特に、疾患マーカーの探索のために有用であろう。一般に、多くの病気で代謝経路の一部が活性化または不活性化されるので、代謝物等を数値化することで特定の病気のマーカーとすることができる。疾患マーカーには、診断用バイオマーカー、疾患段階を判断するバイオマーカー、疾患予後バイオマーカー、治療処置に対する反応を見る目的のモニター用バイオマーカーが含まれる。 The method of the present invention, or an analysis combining the methods of the present invention, will be particularly useful for the search for disease markers. In general, a part of the metabolic pathway is activated or inactivated in many diseases, and therefore, a metabolite or the like can be expressed as a marker for a specific disease. Disease markers include diagnostic biomarkers, biomarkers that determine disease stage, disease prognostic biomarkers, and monitoring biomarkers for the purpose of viewing responses to therapeutic treatment.
本発明の方法は、または本発明の方法を組み合わせた解析は特に、医薬候補物質のスクリーニングのために有用であろう。 The method of the present invention or an analysis combining the methods of the present invention will be particularly useful for screening drug candidates.
〔新規化合物〕
本発明は、新規化合物を提供する。具体的には、次の一般式I-1で表される化合物またはその塩を提供する。
[New compound]
The present invention provides novel compounds. Specifically, a compound represented by the following general formula I-1 or a salt thereof is provided.
式I-1中：
R1がNH2またはNHR9であり、かつR2およびR3Hであり；かつ
R4がF、Cl、BrもしくはIである。
In formula I-1:
R 1 is NH 2 or NHR 9 and R 2 and R 3 H; and
R 4 is F, Cl, Br or I.
式I-1で表される化合物またはその塩の特に好ましい例は、下記の化合物またはその塩である。 Particularly preferred examples of the compound represented by the formula I-1 or a salt thereof are the following compounds or salts thereof.
この化合物は、例えば次の方法で製造することができる。
出発物質として9-Amino-1,2,3,4-tetrahydroanthracene (化合物47。この製法は本明細書の実施例の項を参考にすることができる。)を用い、この溶液に、臭素源（例えば、N-ブロモスクシンイミド（NBS））を加え、アルゴン雰囲気下、環境温度で数十分間、反応させる。必要に応じ、ろ過、溶媒除去、再結晶を行う。
当業者であれは、式I-1に包含される化合物54以外の化合物を、上記の方法を参考にして適宜製造することができる。
This compound can be produced, for example, by the following method.
Using 9-Amino-1,2,3,4-tetrahydroanthracene (Compound 47. For the preparation, reference can be made to the Examples section of this specification) as a starting material, a bromine source ( For example, N-bromosuccinimide (NBS)) is added and allowed to react for several tens of minutes at ambient temperature in an argon atmosphere. If necessary, filtration, solvent removal, and recrystallization are performed.
A person skilled in the art can appropriately prepare compounds other than the compound 54 included in the formula I-1 with reference to the above method.
本発明はまた、別の新規化合物を提供する。具体的には、下式で表される化合物またはその塩を提供する。 The present invention also provides another novel compound. Specifically, a compound represented by the following formula or a salt thereof is provided.
この化合物は、例えば次の方法で製造することができる。
出発物質として2-Aminoanthrathene（化合物38。この化合物は市販されている。）の溶液に、Rh-Al2O3等の適切な触媒加え、水素雰囲気下、環境温度で数時間〜数日間反応させる。反応液を濾過後、水酸化ナトリウム溶液を加え、酢酸エチルで抽出し、有機溶剤相を洗浄後、必要に応じ、乾燥、溶媒除去、再結晶を行う。
This compound can be produced, for example, by the following method.
An appropriate catalyst such as Rh-Al 2 O 3 is added to a solution of 2-Aminoanthrathene (compound 38. This compound is commercially available) as a starting material and allowed to react for several hours to several days at ambient temperature in a hydrogen atmosphere. . The reaction solution is filtered, a sodium hydroxide solution is added, and the mixture is extracted with ethyl acetate. After washing the organic solvent phase, drying, solvent removal, and recrystallization are performed as necessary.
〔化合物の製造方法〕
本発明はまた、化合物47およびその塩の、新規な製造方法を提供する。本発明の方法は、出発物質を化合物17とし、それを還元することにより化合物47を製造する。具体的には、化合物17の溶液に、パラジウム触媒を加え、水素雰囲気下、環境温度で数時間反応する。必要に応じ、反応液について、濾過、溶媒除去、再結晶等の操作を行う。
[Method for producing compound]
The present invention also provides a novel method for producing Compound 47 and salts thereof. The process of the present invention produces compound 47 by starting with compound 17 and reducing it. Specifically, a palladium catalyst is added to the solution of compound 17 and reacted at ambient temperature for several hours in a hydrogen atmosphere. If necessary, the reaction solution is subjected to operations such as filtration, solvent removal, and recrystallization.
出発物質である化合物17は、Adams, H.; Bawa, R. A.; McMillan, K. G.; Jones, S. Tetrahedron: Asymmetry, 2007, 18, 1003−1012または前掲特許文献2に記載されている。 Compound 17, which is the starting material, is described in Adams, H .; Bawa, R. A .; McMillan, K. G .; Jones, S. Tetrahedron: Asymmetry, 2007, 18, 1003-1012 or the above-mentioned Patent Document 2.
本発明はまた、化合物49およびその塩の、新規な製造方法を提供する。本発明の方法は、出発物質を化合物40とし、それを還元することにより化合物49を製造するものである。具体的には、1-aminoanthracene（化合物40。この化合物は市販されている。）の溶液に、Rh-Al2O3等の適切な触媒加え、水素雰囲気下、数時間反応する。必要に応じ、反応液について、濾過、溶媒除去、再結晶等の操作を行う。 The present invention also provides a novel method for producing compound 49 and salts thereof. In the method of the present invention, Compound 49 is produced by reducing Compound 40 as the starting material. Specifically, an appropriate catalyst such as Rh-Al 2 O 3 is added to a solution of 1-aminoanthracene (compound 40. This compound is commercially available), and reacted for several hours in a hydrogen atmosphere. If necessary, the reaction solution is subjected to operations such as filtration, solvent removal, and recrystallization.
以下、本発明を実施例を例に説明する。 Hereinafter, the present invention will be described by way of examples.
＜MALDI質量分析＞
下表に示したアミノ酸5〜7種類を等重量含む混合物を８種類作成し、これらについて負イオンモードでMALDI質量分析を行い、各アニオン性化合物のイオン化能、ピーク強度に及ぼすマトリックスの効果を評価した。
<MALDI mass spectrometry>
Eight kinds of mixtures containing the same weight of 5-7 amino acids shown in the table below were prepared, and these were subjected to MALDI mass spectrometry in negative ion mode to evaluate the effect of the matrix on the ionization ability and peak intensity of each anionic compound. did.
さらに下表に示したアミノ酸混合物を２種類を追加作成し、これらについて負イオンモードでMALDI質量分析を行い、各アニオン性化合物のイオン化能、ピーク強度に及ぼすマトリックスの効果を評価した。 Furthermore, two types of amino acid mixtures shown in the table below were additionally prepared, and these were subjected to MALDI mass spectrometry in the negative ion mode to evaluate the effect of the matrix on the ionization ability and peak intensity of each anionic compound.
1. 方法
アミノ酸水溶液（100μg/ml）を用いて混合溶液を調製した後に純水で希釈し、サンプルとした（各アミノ酸の濃度10μg/ml）。マトリックス候補化合物（化合物44〜53、および化合物55〜66）をメタノールに溶解し、マトリックス溶液を作成した（マトリックス濃度10 mg/ml）。96 well plate上で、サンプル5μl、マトリックス候補化合物溶液5μlを混合した（各アミノ酸の終濃度5μg/ml、化合物終濃度5mg/ml）。サンプルプレートを真空乾燥した。レーザーショット1210/wellまたは605/wellの条件で、MALDI質量分析装置（島津製作所製 MALDI-TOF-MS: AXIMA,Performance）で測定した。
1. Method A mixed solution was prepared using an aqueous amino acid solution (100 μg / ml) and then diluted with pure water to prepare a sample (concentration of each amino acid 10 μg / ml). Matrix candidate compounds (compounds 44 to 53 and compounds 55 to 66) were dissolved in methanol to prepare a matrix solution (matrix concentration 10 mg / ml). On a 96-well plate, 5 μl of sample and 5 μl of matrix candidate compound solution were mixed (final concentration of each amino acid 5 μg / ml, final compound concentration 5 mg / ml). The sample plate was vacuum dried. Measurement was performed with a MALDI mass spectrometer (MALDI-TOF-MS: AXIMA, Performance, manufactured by Shimadzu Corporation) under the conditions of laser shot 1210 / well or 605 / well.
2. 結果
アミノ酸混合物としてMix3を用いた場合の、化合物44の結果を図1に、化合物45の結果を図2に、化合物46の結果を図3に、化合物47の結果を図4に、化合物48の結果を図5に、化合物49の結果を図6に、化合物50の結果を図7に、化合物51の結果を図8に、化合物52の結果を図9に、化合物53の結果を図10に示した。Mix8を用いた場合の、化合物44の結果を図11に、化合物45の結果を図12に、化合物46の結果を図13に、化合物47の結果を図14に、化合物48の結果を図15に、化合物49の結果を図16に、化合物50の結果を図17に、化合物51の結果を図18に、化合物52の結果を図19に、化合物53の結果を図20に示した。また、結果を下表にまとめた。
2. Results When Mix3 is used as the amino acid mixture, the result of Compound 44 is shown in FIG. 1, the result of Compound 45 is shown in FIG. 2, the result of Compound 46 is shown in FIG. 3, the result of Compound 47 is shown in FIG. Fig. 5 shows the results of 48, Fig. 6 shows the results of Compound 49, Fig. 7 shows the results of Compound 50, Fig. 8 shows the results of Compound 51, Fig. 9 shows the results of Compound 52, and Fig. 9 shows the results of Compound 53. Shown in 10. FIG. 11 shows the results of Compound 44, FIG. 12 shows the results of Compound 45, FIG. 13 shows the results of Compound 46, FIG. 14 shows the results of Compound 47, and FIG. FIG. 16 shows the results of Compound 49, FIG. 17 shows the results of Compound 50, FIG. 18 shows the results of Compound 51, FIG. 19 shows the results of Compound 52, and FIG. The results are summarized in the table below.
化合物38: 2-aminoanthrathene
Compound 38: 2-aminoanthrathene
＜マトリックスを用いたイメージング質量分析＞
方法：化合物51をmethanolにて5 mg/mLの濃度に溶解し、エアブラシを用いたスプレーコーティング法により、マウス脳切片に適量塗布した。マトリックスを塗布した脳切片は、AXIMA Confidence（島津製作所）を用い、50-1000 m/zを測定範囲としてネガティブモードにて質量分析イメージングに供した。得られたスペクトルデータはSIMedit（島津製作所）総イオン強度にて標準化を行った後、BioMap(http://www.MALDI-msi.org)により画像化した。
<Imaging mass spectrometry using matrix>
Method: Compound 51 was dissolved in methanol at a concentration of 5 mg / mL, and an appropriate amount was applied to a mouse brain slice by spray coating using an airbrush. The brain slices coated with the matrix were subjected to mass spectrometry imaging in negative mode using AXIMA Confidence (Shimadzu Corporation) with a measurement range of 50-1000 m / z. The obtained spectral data was standardized with SIMedit (Shimadzu Corporation) total ionic strength, and then imaged with BioMap (http://www.MALDI-msi.org).
グルタミンの分布画像を図21に、グルタミン酸の分布画像を図22に、グルタミン/グルタミン酸の強度比画像を図23に示した。 A distribution image of glutamine is shown in FIG. 21, a distribution image of glutamic acid is shown in FIG. 22, and an intensity ratio image of glutamine / glutamic acid is shown in FIG.
＜化合物の合成＞
化合物44〜48を、以下の方法で合成した。
<Synthesis of compounds>
Compounds 44 to 48 were synthesized by the following method.
〔No.44 (9,10-dihydroacridine)の合成〕 (Synthesis of No. 44 (9,10-dihydroacridine))
9-Aminoacridine (9-AA, 300 mg, 1.54 mmol)のEtOH (15 ml)溶液に、PtO2 (70 mg, 0.31 mmol, 0.20 equiv.)を加え、水素雰囲気下、室温で攪拌した。15時間後、PtO2 (70 mg, 0.31 mmol, 0.20 equiv.)を追加し、さらに23時間攪拌した。反応液をセライト濾過した後、溶剤を減圧下で留去して、粗生成物を得た。これをシリカゲルクロマトグラフィーにより精製し、化合物44を163 mg (収率55%)で得た。EtOHから再結晶を行い、白色針状結晶(融点171-172℃)を得た。CAS番号[92-81-9] 、参考文献: Matesic, L. et al. Tetrahedron 2012, 68, 6810-6819. To a solution of 9-Aminoacridine (9-AA, 300 mg, 1.54 mmol) in EtOH (15 ml) was added PtO 2 (70 mg, 0.31 mmol, 0.20 equiv.), And the mixture was stirred at room temperature in a hydrogen atmosphere. After 15 hours, PtO 2 (70 mg, 0.31 mmol, 0.20 equiv.) Was added, and the mixture was further stirred for 23 hours. The reaction solution was filtered through Celite, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel chromatography to obtain 163 mg (yield 55%) of compound 44. Recrystallization from EtOH gave white needle crystals (melting point 171-172 ° C). CAS number [92-81-9], reference: Matesic, L. et al. Tetrahedron 2012, 68, 6810-6819.
colorless needles (mp. 171-172℃, lit: 171-172℃). 1H-NMR (400 MHz, CDCl3) δ: 4.06 (s, 2H), 5.94 (brs, 1H), 6.63-6.69 (m, 2H), 6.81-6.89 (m, 2H), 7.04-7.14 (m, 4H). colorless needles (mp. 171-172 ° C, lit: 171-172 ° C). 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.06 (s, 2H), 5.94 (brs, 1H), 6.63-6.69 (m , 2H), 6.81-6.89 (m, 2H), 7.04-7.14 (m, 4H).
〔No.45 (9-amino-1,2,3,4-tetrahydroacridine)の合成〕 (Synthesis of No. 45 (9-amino-1,2,3,4-tetrahydroacridine))
Tacrine hydrochloride（235 mg, 1.00 mmol）のCHCl3 (20 ml)溶液に、1M水酸化ナトリウム溶液 (10 ml)を加え、室温で10分間攪拌した。反応液をCHCl3で抽出し、得られた有機溶剤層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶剤を減圧下で留去して粗生成物を得た。benzeneから再結晶を行い、化合物45を白色針状結晶(融点179-181℃)として116 mg (収率59%)を得た。CAS番号[321-64-2] 、参考文献: McKenna, M. T. et al. J. Med. Chem. 1997, 40, 3516-3523. To a solution of Tacrine hydrochloride (235 mg, 1.00 mmol) in CHCl 3 (20 ml) was added 1M sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was extracted with CHCl 3 , and the obtained organic solvent layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. Recrystallization from benzene gave 116 mg (yield 59%) of compound 45 as white needle crystals (melting point: 179-181 ° C.). CAS number [321-64-2], reference:... M c Kenna, MT et al J. Med Chem 1997, 40, 3516-3523.
colorless needles (mp. 179-181℃, lit: 178-180℃). 1H-NMR (400 MHz, CDCl3) δ: 1.85-2.05 (m, 4H), 2.60-2.75 (2H, m), 2.95-3.10 (m, 2H), 4.63 (brs, 2H), 7.32-7.41 (m, 1H), 7.52-7.65 (m, 1H), 7.66-7.74 (m, 1H), 7.85-7.93 (m, 1H). colorless needles (mp. 179-181 ° C, lit: 178-180 ° C). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.85-2.05 (m, 4H), 2.60-2.75 (2H, m), 2.95 -3.10 (m, 2H), 4.63 (brs, 2H), 7.32-7.41 (m, 1H), 7.52-7.65 (m, 1H), 7.66-7.74 (m, 1H), 7.85-7.93 (m, 1H) .
〔No.46 (9-amino-1,2,3,4,5,6,7,8-octahydroacridine)の合成〕 (Synthesis of No. 46 (9-amino-1,2,3,4,5,6,7,8-octahydroacridine))
9-Aminoacridine (9-AA, 300 mg, 1.54 mmol)のEtOH(15 ml)溶液に、5% Rh-Al2O3 (350 mg, 0.17 mmol, 0.11 equiv.)を加え、水素雰囲気下、室温で38時間攪拌した。反応液をセライト濾過した後、溶剤を減圧下で留去して、粗生成物を得た。MeOH-H2O (1:2)から再結晶を行い、化合物46を白色針状結晶(融点213-216℃)として48 mg (収率15%)を得た。CAS番号[13415-07-1]、参考文献: [1] Goncharenko, S. B.; Kaganskii, M. M.; Portnov, Y. N.; Granik, V. G. Pharmaceutical Chemistry Journal 1992, 26, 769-772. [2] Potmischil, F. et al. Magn. Reson. Chem. 2009, 47, 1031-1035. To a solution of 9-Aminoacridine (9-AA, 300 mg, 1.54 mmol) in EtOH (15 ml), add 5% Rh-Al 2 O 3 (350 mg, 0.17 mmol, 0.11 equiv.), Under a hydrogen atmosphere at room temperature For 38 hours. The reaction solution was filtered through Celite, and then the solvent was distilled off under reduced pressure to obtain a crude product. Recrystallization from MeOH—H 2 O (1: 2) yielded 48 mg (yield 15%) of Compound 46 as white needle crystals (melting point 213-216 ° C.). CAS Number [13415-07-1], References: [1] Goncharenko, SB; Kaganskii, MM; Portnov, YN; Granik, VG Pharmaceutical Chemistry Journal 1992, 26, 769-772. [2] Potmischil, F. et al. Magn. Reson. Chem. 2009, 47, 1031-1035.
colorless needles (mp. 213-216℃, lit: 218-220℃). 1H-NMR (400 MHz, CDCl3) δ: 1.78-1.90 (m, 8H), 2.38-2.44 (4H, m), 2.76-2.82 (m, 4H). colorless needles (mp. 213-216 ° C, lit: 218-220 ° C). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.90 (m, 8H), 2.38-2.44 (4H, m), 2.76 -2.82 (m, 4H).
〔No.47 (9-amino-1,2,3,4-tetrahydroanthracene)の合成〕 (Synthesis of No. 47 (9-amino-1,2,3,4-tetrahydroanthracene))
化合物17（500 mg, 2.59 mmol）のEtOH (26 ml)溶液に、10% Pd-C (154 mg, 0.15 mmol, 0.056 equiv.)を加え、水素雰囲気下、室温で6時間攪拌した。反応液をセライト濾過した後、溶剤を減圧下で留去して、粗生成物を得た。これをEtOHから再結晶を行い、化合物47を白色針状結晶(融点99-101℃)として284 mg (収率56%)を得た。SciFinder [1348473-64-2]、化合物17についての参考文献：Adams, H.; Bawa, R. A.; McMillan, K. G.; Jones, S. Tetrahedron: Asymmetry, 2007, 18, 1003-1012、および前掲特許文献2 10% Pd-C (154 mg, 0.15 mmol, 0.056 equiv.) Was added to a solution of compound 17 (500 mg, 2.59 mmol) in EtOH (26 ml), and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was recrystallized from EtOH to obtain 284 mg (yield 56%) of Compound 47 as white needle crystals (melting point 99-101 ° C.). SciFinder [1348473-64-2], References for Compound 17: Adams, H .; Bawa, R. A .; McMillan, K. G .; Jones, S. Tetrahedron: Asymmetry, 2007, 18, 1003-1012, and supra Patent Document 2
colorless needles (mp. 99-101℃). 1H-NMR (400 MHz, CDCl3) δ: 1.78-1.86 (m, 2H), 1.92-2.00 (m, 2H), 2.68 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 6.8 Hz, 2H), 4.12 (brs, 2H), 7.08 (s, 1H), 7.32-7.38 (m, 2H), 7.65-7.76 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ: 22.9 (t), 23.4 (t), 24.7 (t), 30.8 (t), 116.7 (s), 117.5 (d), 120.0 (d), 121.6 (s), 123.8 (d), 124.9 (d), 127.7 (d), 132.4 (s), 136.6 (s), 138.6 (s). IR (KBr): 3339, 2931, 1630, 1506 cm-1. MS (EI) m/z 197 (M+, 100%). Anal. Calcd for C14H15N: C, 85.24; H, 7.66; N, 7.10, found: C, 85.09; H, 7.66; N, 7.06. colorless needles (mp. 99-101 ℃). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.86 (m, 2H), 1.92-2.00 (m, 2H), 2.68 (t, J = 6.8 Hz , 2H), 2.94 (t, J = 6.8 Hz, 2H), 4.12 (brs, 2H), 7.08 (s, 1H), 7.32-7.38 (m, 2H), 7.65-7.76 (m, 2H). 13 C -NMR (100 MHz, CDCl 3 ) δ: 22.9 (t), 23.4 (t), 24.7 (t), 30.8 (t), 116.7 (s), 117.5 (d), 120.0 (d), 121.6 (s) , 123.8 (d), 124.9 (d), 127.7 (d), 132.4 (s), 136.6 (s), 138.6 (s) .IR (KBr): 3339, 2931, 1630, 1506 cm -1 .MS (EI ) m / z 197 (M + , 100%). Anal.Calcd for C 14 H 15 N: C, 85.24; H, 7.66; N, 7.10, found: C, 85.09; H, 7.66; N, 7.06.
〔No.48 (9-amino-1,2,3,4,5,6,7,8-octahydroanthracene)の合成〕 (Synthesis of No. 48 (9-amino-1,2,3,4,5,6,7,8-octahydroanthracene))
化合物17 (250 mg, 1.29 mmol)のEtOH (13 ml)溶液に、5% Rh-Al2O3 (293 mg, 0.14 mmol, 0.11 equiv.)を加え、水素雰囲気下、室温で14時間攪拌した。反応液をセライト濾過した後、溶剤を減圧下で留去して、粗生成物を得た。これをMeOHから再結晶を行い、化合物48を白色針状結晶(融点83-84℃)として106 mg (収率41%)を得た。CAS番号[25911-42-6]、参考文献: Dewar, M. J. S.; Michl, J. Tetrahedron 1970, 26, 375-384. 5% Rh-Al 2 O 3 (293 mg, 0.14 mmol, 0.11 equiv.) Was added to a solution of compound 17 (250 mg, 1.29 mmol) in EtOH (13 ml), and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. . The reaction solution was filtered through Celite, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was recrystallized from MeOH to obtain 106 mg (yield 41%) of compound 48 as white needle crystals (melting point 83-84 ° C.). CAS number [25911-42-6], reference: Dewar, MJS; Michl, J. Tetrahedron 1970, 26, 375-384.
Colorless needles (mp. 83-84℃, lit: 84.5-85.0℃). 1H-NMR (400 MHz, CDCl3) δ: 1.70-1.77 (m, 4H), 1.82-1.90 (m, 4H), 2.44 (t, J = 6.4 Hz, 4H), 2.69 (t, J = 6.4 Hz, 2H), 3.54 (brs, 2H), 6.37 (s, 1H). Anal. Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96, found: C, 83.19; H, 9.40; N, 6.90. Colorless needles (mp. 83-84 ℃, lit: 84.5-85.0 ℃). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.70-1.77 (m, 4H), 1.82-1.90 (m, 4H), 2.44 (t, J = 6.4 Hz, 4H), 2.69 (t, J = 6.4 Hz, 2H), 3.54 (brs, 2H), 6.37 (s, 1H). Anal. Calcd for C 14 H 19 N: C, 83.53 ; H, 9.51; N, 6.96, found: C, 83.19; H, 9.40; N, 6.90.
化合物49〜52を、以下の方法で合成した。 Compounds 49 to 52 were synthesized by the following method.
〔No.49 (5-Amino-1,2,3,4-tetrahydroanthracene)の合成〕 (Synthesis of No. 49 (5-Amino-1,2,3,4-tetrahydroanthracene))
1-Aminoanthracene（化合物40, 224 mg, 1.16 mmol）のEtOH (10 ml)溶液に、5% Rh-Al2O3 (264 mg, 0.13 mmol, 0.11 equiv.)を加え、水素雰囲気(3 atm)下、室温で12時間攪拌した。反応液をセライト濾過した後、溶剤を減圧下で留去して、粗生成物を得た。これをシリカゲルクロマトグラフィーにより精製し、化合物49を124 mg (収率54%)で得た。Hexaneから再結晶を行い、褐色針状結晶(融点95-96度)を得た。SciFinder [1379367-47-1] To a solution of 1-Aminoanthracene (compound 40, 224 mg, 1.16 mmol) in EtOH (10 ml), add 5% Rh-Al 2 O 3 (264 mg, 0.13 mmol, 0.11 equiv.) And hydrogen atmosphere (3 atm) The mixture was stirred at room temperature for 12 hours. The reaction solution was filtered through Celite, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel chromatography to obtain Compound 49 (124 mg, yield 54%). Recrystallization from Hexane gave brown needles (melting point 95-96 degrees). SciFinder [1379367-47-1]
Pale brown needles (mp. 95-96℃). 1H-NMR (400 MHz, CDCl3) δ: 1.82-1.90 (m, 4H), 2.92-3.02 (m, 4H), 4.06 (brs, 2H), 6.67 (dd, J = 1.6, 6.8 Hz, 1H), 7.12-7.22 (m, 2H), 7.49 (s, 1H), 7.52 (s, 1H). MS (EI) m/z 197 (M+, 100%). Anal. Calcd for C14H15N: C, 85.24; H, 7.66; N, 7.10, found: C, 85.11; H, 7.60; N, 7.16. Pale brown needles (mp. 95-96 ℃). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.82-1.90 (m, 4H), 2.92-3.02 (m, 4H), 4.06 (brs, 2H), 6.67 (dd, J = 1.6, 6.8 Hz, 1H), 7.12-7.22 (m, 2H), 7.49 (s, 1H), 7.52 (s, 1H) .MS (EI) m / z 197 (M + , 100 Anal.Calcd for C 14 H 15 N: C, 85.24; H, 7.66; N, 7.10, found: C, 85.11; H, 7.60; N, 7.16.
〔No.50 (6-amino-1,2,3,4-tetrahydroanthracene)の合成〕 (Synthesis of No. 50 (6-amino-1,2,3,4-tetrahydroanthracene))
2-Aminoanthrathene（化合物38, 250 mg, 1.30 mmol）のEtOH (13 ml)溶液に、5% Rh-Al2O3 (259 mg, 0.13 mmol, 0.10 equiv.)を加え、水素雰囲気下、室温で22時間攪拌した。反応液をセライト濾過した後、溶剤を減圧下で留去して、粗生成物を得た。これをシリカゲルクロマトグラフィーにより精製し、化合物50を109 mg (収率43%)で得た。MeCNから再結晶を行い、褐色針状結晶(融点149-150度)を得た。CAS番号[160555-08-8] 、参考文献: v. Braun, J.; Bayer, O. Justus Liebigs Annalen der Chemie 1929, 472, 90-121. To a solution of 2-Aminoanthrathene (compound 38, 250 mg, 1.30 mmol) in EtOH (13 ml), add 5% Rh-Al 2 O 3 (259 mg, 0.13 mmol, 0.10 equiv.) And at room temperature under a hydrogen atmosphere. Stir for 22 hours. The reaction solution was filtered through Celite, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel chromatography to obtain 109 mg (yield 43%) of compound 50. Recrystallization from MeCN gave brown needles (melting point: 149-150 degrees). CAS number [160555-08-8], reference: v. Braun, J .; Bayer, O. Justus Liebigs Annalen der Chemie 1929, 472, 90-121.
Pale brown needles (mp. 149-150℃, lit.: 154℃). 1H-NMR (400 MHz, CDCl3) δ: 1.78-1.88 (m, 4H), 2.82-2.94 (m, 4H), 3.72 (brs, 2H), 6.84 (dd, J = 2.0, 8.4 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 7.29 (s, 1H), 7.39 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H). MS (EI) m/z 197 (M+, 100%). Pale brown needles (mp. 149-150 ℃, lit .: 154 ℃). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.88 (m, 4H), 2.82-2.94 (m, 4H), 3.72 (brs, 2H), 6.84 (dd, J = 2.0, 8.4 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 7.29 (s, 1H), 7.39 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H) .MS (EI) m / z 197 (M + , 100%).
〔No.51 (1,1',2,2',3,3',4,4',-octahydro-9,9'-bianthracene-7,7'-diamine)の合成〕 (Synthesis of No. 51 (1,1 ', 2,2', 3,3 ', 4,4',-octahydro-9,9'-bianthracene-7,7'-diamine))
2-Aminoanthrathene（化合物38, 250 mg, 1.30 mmol）のトリフルオロ酢酸 (13 ml)溶液に、5% Rh-Al2O3 (290 mg, 0.15 mmol, 0.11 equiv.)を加え、水素雰囲気(3 atm)下、室温で6日間攪拌した。反応液をセライト濾過した後、3 M水酸化ナトリウム溶液を加え、AcOEtで抽出した。有機溶剤相を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、溶剤を減圧下で留去して、粗生成物を得た。これをシリカゲルクロマトグラフィーにより精製し、化合物51を134 mg (収率53%)で得た。HPLC精製により無色油状物を得た。 To a solution of 2-Aminoanthrathene (compound 38, 250 mg, 1.30 mmol) in trifluoroacetic acid (13 ml), add 5% Rh-Al 2 O 3 (290 mg, 0.15 mmol, 0.11 equiv.) And hydrogen atmosphere (3 The mixture was stirred at room temperature for 6 days. The reaction mixture was filtered through celite, 3 M sodium hydroxide solution was added, and the mixture was extracted with AcOEt. The organic solvent phase was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel chromatography to obtain 134 mg (yield 53%) of compound 51. A colorless oil was obtained by HPLC purification.
Colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 1.65-1.84 (m, 8H), 2.58-2.74 (m, 4H), 2.91 (t, J = 6.4 Hz, 4H), 3.54 (brs, 4H), 6.82 (s, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.50 (s, 2H), 7.67 (d, J = 8.8 Hz, 2H). MS (EI) m/z 392 (M+, 100%) Colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.65-1.84 (m, 8H), 2.58-2.74 (m, 4H), 2.91 (t, J = 6.4 Hz, 4H), 3.54 (brs, 4H), 6.82 (s, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.50 (s, 2H), 7.67 (d, J = 8.8 Hz, 2H) .MS (EI) m / z 392 ( (M + , 100%)
他の化合物は、以下の方法で合成した。なお、以下に合成方法の記載のない化合物は、上述のMALDI質量分析等では、市販の化合物を購入して試験した。 Other compounds were synthesized by the following method. In addition, the compound without description of the synthesis method below purchased and tested the commercially available compound in the above-mentioned MALDI mass spectrometry etc.
〔No.53 (2-amino-9,10-dihydroanthracene)の合成〕 (Synthesis of No. 53 (2-amino-9,10-dihydroanthracene))
2-Aminoanthrathene（化合物38, 50 mg, 0.26 mmol）のEtOH (2.6 ml)溶液に、10% Pd-C (16 mg, 0.015 mmol, 0.050 equiv.)を加え、水素雰囲気(3 atm)下、室温で29時間攪拌した。反応液をセライト濾過した後、溶剤を減圧下で留去して、粗生成物を得た。これをシリカゲルクロマトグラフィーにより精製し、化合物53を28 mg (収率54%)で得た。Hexaneから再結晶を行い、黄色針状結晶(融点85-86度)を得た。CAS番号[871879-54-8] 、参考文献: v. Braun, J.; Bayer, O. Justus Liebigs Annalen der Chemie 1929, 472, 90-121. To a solution of 2-Aminoanthrathene (compound 38, 50 mg, 0.26 mmol) in EtOH (2.6 ml), add 10% Pd-C (16 mg, 0.015 mmol, 0.050 equiv.), And hydrogen atmosphere (3 atm) at room temperature For 29 hours. The reaction solution was filtered through Celite, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel chromatography to obtain Compound 53 in 28 mg (yield 54%). Recrystallization from Hexane gave yellow needles (melting point 85-86 degrees). CAS number [871879-54-8], reference: v. Braun, J .; Bayer, O. Justus Liebigs Annalen der Chemie 1929, 472, 90-121.
Yellow needles (mp. 85-86℃, lit.: 88-90℃). 1H-NMR (400 MHz, CDCl3) δ: 3.56 (brs, 2H), 3.84 (s, 4H), 6.55 (dd, J = 2.4, 8.0 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.14-7.7.19 (m, 2H), 7.22-7.29 (m, 2H). MS (EI) m/z 195 (M+), 194 (100%). Anal. Calcd for C14H13N: C, 86.12; H, 6.71; N, 7.17, found: C, 85.79; H, 6.66; N, 7.24. Yellow needles (mp. 85-86 ° C, lit .: 88-90 ° C). 1 H-NMR (400 MHz, CDCl 3 ) δ: 3.56 (brs, 2H), 3.84 (s, 4H), 6.55 (dd, J = 2.4, 8.0 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.14-7.7.19 (m, 2H), 7.22-7.29 (m MS (EI) m / z 195 (M + ), 194 (100%). Anal.Calcd for C 14 H 13 N: C, 86.12; H, 6.71; N, 7.17, found: C, 85.79 ; H, 6.66; N, 7.24.
〔No.54 (9-amino-10-bromo-1,2,3,4-tetrahydroanthracene)の合成〕 (Synthesis of No. 54 (9-amino-10-bromo-1,2,3,4-tetrahydroanthracene))
9-Amino-1,2,3,4-tetrahydroanthracene (化合物47, 40 mg, 0.20 mmol)のCH2Cl2 (2 ml)溶液に、NBS (36 mg, 0.20 mmol, 1.0 equiv.)を加え、アルゴン雰囲気下、室温で30分間攪拌した。反応液をセライト濾過した後、溶剤を減圧下で留去して、粗生成物を得た。これをシリカゲルクロマトグラフィーにより精製し、化合物54を32 mg (収率58%)で得た。MeOHから再結晶を行い、褐色針状結晶(分解点98度)を得た。 Add NBS (36 mg, 0.20 mmol, 1.0 equiv.) To a CH2Cl2 (2 ml) solution of 9-Amino-1,2,3,4-tetrahydroanthracene (compound 47, 40 mg, 0.20 mmol) under an argon atmosphere. And stirred at room temperature for 30 minutes. The reaction solution was filtered through Celite, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel chromatography to obtain Compound 54 (32 mg, yield 58%). Recrystallization from MeOH gave brown needle crystals (decomposition point 98 degrees).
Pale brown needles (98度分解). 1H-NMR (400 MHz, CDCl3) δ: 1.76-1.82 (m, 4H), 2.67 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 8.27 (d, J =8.0 Hz, 1H). MS (EI) m/z 275 (M+, 100%), 277 (M++2). Pale brown needles (98 degree resolution). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.76-1.82 (m, 4H), 2.67 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H) .MS (EI) m / z 275 (M + , 100%), 277 (M + +2).
〔No.55(9,10-dihydroanthracen-1-amine)の合成〕 (Synthesis of No. 55 (9,10-dihydroanthracen-1-amine))
1-aminoanthracene（578 mg, 3 mmol）のEtOH (30 ml)溶液に、10% Pd/ C (159 mg, 0.15 mmol, 0.050 equiv.)を加え、水素雰囲気(1 atm)下、室温で44時間攪拌した。反応液をセライト濾過した後、溶剤を減圧下で留去して、粗生成物を得た。これをシリカゲルクロマトグラフィー(eluent: Hex/EA = 8: 2)により精製し、黄色針状結晶402 mg (収率68%)で得た。Hexaneから再結晶を行い、黄色針状結晶を得た。 10% Pd / C (159 mg, 0.15 mmol, 0.050 equiv.) Was added to a solution of 1-aminoanthracene (578 mg, 3 mmol) in EtOH (30 ml), and 44 hours at room temperature under a hydrogen atmosphere (1 atm). Stir. The reaction solution was filtered through Celite, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel chromatography (eluent: Hex / EA = 8: 2) to obtain 402 mg of yellow needle crystals (68% yield). Recrystallization from Hexane gave yellow needle crystals.
〔No.57(2-aminotetradecahydroanthracene)の合成〕 (Synthesis of No. 57 (2-aminotetradecahydroanthracene))
2-aminoanthracene（50 mg, 0.26 mmol）をトリフルオロ酢酸2.6ｍLに溶かし５％ロジウムアルミナ（58 mg）を加え水素ガスで0.3 MPaに加圧し4日間反応させた。反応液をセタイトでろ過したのち３M水酸化ナトリウム水溶液で反応液をpH>8とした。これを酢酸エチルで抽出し、その有機層を飽和食塩水で洗浄後、減圧濃縮しシリカゲルカラムクロマトグラフィーで生成し立体異性体の混合物として得た。
2-aminoanthracene (50 mg, 0.26 mmol) was dissolved in 2.6 mL of trifluoroacetic acid, 5% rhodium alumina (58 mg) was added, and the mixture was pressurized to 0.3 MPa with hydrogen gas and reacted for 4 days. The reaction solution was filtered through cetite, and the reaction solution was adjusted to pH> 8 with 3M aqueous sodium hydroxide solution. This was extracted with ethyl acetate, and the organic layer was washed with saturated brine, concentrated under reduced pressure, and produced by silica gel column chromatography to obtain a mixture of stereoisomers.
〔No.58(chloro-1,2,3,4-tetrahydroanthracen-9-amine)の合成〕 (Synthesis of No. 58 (chloro-1,2,3,4-tetrahydroanthracen-9-amine))
1,2,3,4-tetrahydroanthracen-9-amine (78.9 mg, 0.40 mmol)にCH2Cl2 (4 ml)を加え、NCS (53.4 mg, 0.40 mmol)を加えた後、室温空気雰囲気下で撹拌した。15分後、TLCで原料の消失を確認した後、CH2Cl2で洗いながら吸引濾過を行い、濃縮した。これをシリカゲルカラムクロマトグラフィー(10% →20% EtOAc/Hexane)にて単離した。No.58が収量70 mg, 76%で得られた。その後、EtOHで再結晶を行い、白色針状結晶を得た。 Add CH 2 Cl 2 (4 ml) to 1,2,3,4-tetrahydroanthracen-9-amine (78.9 mg, 0.40 mmol), add NCS (53.4 mg, 0.40 mmol), and then at room temperature under air atmosphere Stir. After 15 minutes, the disappearance of the raw material was confirmed by TLC, and then suction filtration was performed while washing with CH 2 Cl 2 , followed by concentration. This was isolated by silica gel column chromatography (10% → 20% EtOAc / Hexane). No. 58 was obtained in a yield of 70 mg, 76%. Thereafter, recrystallization was performed with EtOH to obtain white needle crystals.
colorless needles: mp 94.6-95.2 (EtOH); 1H-NMR (400 MHz, CDCl3) δ: 1.78-1.92 (m, 4H), 2.61 (t, J = 6.2 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H), 4.05 (s, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ: 22.6 (t), 25.3 (t), 28.9 (t), 117.6 (s), 120.2 (d), 120.7 (s), 122.4 (s), 124.5 (d), 124.6 (d), 125.9 (d), 129.5 (s), 134.0 (s), 137.6 (s); EI-MS m/z 231 (M+), 233 (M++2) ; IR (KBr) 3383, 3462 cm-1 (NH2); Anal. calcd for C14H14ClN: C, 72.57; H, 6.09; N, 6.04. found: C, 72.65; H, 6.09; N, 6.01. colorless needles: mp 94.6-95.2 (EtOH); 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.92 (m, 4H), 2.61 (t, J = 6.2 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H), 4.05 (s, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ) δ: 22.6 (t), 25.3 (t), 28.9 (t), 117.6 (s), 120.2 (d), 120.7 (s), 122.4 (s), 124.5 (d), 124.6 (d), 125.9 (d), 129.5 (s), 134.0 (s), 137.6 (s); EI-MS m / z 231 (M + ), 233 (M + +2); IR (KBr) 3383, 3462 cm -1 (NH 2 ); Anal.calcd for C 14 H 14 ClN: C, 72.57; H, 6.09; N, 6.04.found: C , 72.65; H, 6.09; N, 6.01.
〔No.59(1,1',2,2',3,3',4,4'-octahydro-[9,9'-bianthracene]-10,10'-diamine)の合成〕 [Synthesis of No.59 (1,1 ', 2,2', 3,3 ', 4,4'-octahydro- [9,9'-bianthracene] -10,10'-diamine)]
1,2,3,4-tetrahydroanthracen-9-amine (168 mg, 0.85 mmol)にRh/C (5%) (88 mg, 0.043 mmol)を加え、さらにTFA (4 ml)を加えた後、室温空気雰囲気下で撹拌した。1.5時間後、TLCで原料の消失を確認した後、氷浴にて冷やしつつ塩基性になるまで3N NaOH aqを加えた。EtOAcで洗いながら吸引濾過を行った。EtOAcにて抽出した後、飽和食塩水で洗浄、Na2SO4を用いて脱水した後、濃縮した。これをシリカゲルカラムクロマトグラフィー(20% EtOAc/Hexane)で単離した。No.59が収量144 mg, 86%で得られた。 Rh / C (5%) (88 mg, 0.043 mmol) was added to 1,2,3,4-tetrahydroanthracen-9-amine (168 mg, 0.85 mmol), and TFA (4 ml) was added. Stir in an air atmosphere. After 1.5 hours, the disappearance of the raw materials was confirmed by TLC, and then 3N NaOH aq was added until it became basic while cooling in an ice bath. Suction filtration was performed while washing with EtOAc. The mixture was extracted with EtOAc, washed with saturated brine, dried over Na 2 SO 4 , and concentrated. This was isolated by silica gel column chromatography (20% EtOAc / Hexane). No. 59 was obtained in a yield of 144 mg, 86%.
1H-NMR (400 MHz, CDCl3)δ: 1.52-1.69 (m, 4H), 1.81-1.95 (m, 4H), 2.16-2.3
5 (m, 4H), 2.70-2.85 (m, 4H), 4.19 (s, 4H), 7.03 (d, J = 8.8 Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ: 23.0 (t), 23.1 (t), 25
.5 (t), 28.6 (t), 117.0 (s), 120.0 (d)., 121.8 (s), 123.7 (d), 124.9 (d), 126.2 (s), 126.2 (d), 131.8 (s), 135.3 (s), 137.8 (s) ; IR (KBr) 3379, 3466 cm-1 (NH2); MALDI-MS- m/z calcd for C28H27N2 391.21797 (M-). found 391.21744.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52-1.69 (m, 4H), 1.81-1.95 (m, 4H), 2.16-2.3
5 (m, 4H), 2.70-2.85 (m, 4H), 4.19 (s, 4H), 7.03 (d, J = 8.8 Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 7.33 (t , J = 7.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ) δ: 23.0 (t), 23.1 (t), 25
.5 (t), 28.6 (t), 117.0 (s), 120.0 (d)., 121.8 (s), 123.7 (d), 124.9 (d), 126.2 (s), 126.2 (d), 131.8 (s ), 135.3 (s), 137.8 (s); IR (KBr) 3379, 3466 cm -1 (NH 2);. MALDI-MS - m / z calcd for C 28 H 27 N 2 391.21797 (M -) found 391.21744 .
〔No.60(1-bromo-5,6,7,8-tetrahydroanthracen-2-amine)の合成〕 (Synthesis of No. 60 (1-bromo-5,6,7,8-tetrahydroanthracen-2-amine))
5,6,7,8-tetrahydroanthracen-2-amine (162 mg, 0.82 mmol)にCH2Cl2 (8.2 ml)を加え、NBS (146 mg, 0.82 mmol)を加えた後、室温空気雰囲気下で撹拌した。5分後、TLCで原料の消失を確認した後、CH2Cl2で洗いながら吸引濾過を行い、濃縮した。その後、シリカゲルカラムクロマトグラフィー(50% CH2Cl2/Hexane)を行い単離した。No.60が収量111 mg, 49%で得られた。更に、シリカゲルカラムクロマトグラフィー(100% Hexane)を行い、Hexaneで再結晶を行うことで、純粋な白色針状結晶を得た。 Add CH 2 Cl 2 (8.2 ml) to 5,6,7,8-tetrahydroanthracen-2-amine (162 mg, 0.82 mmol) and NBS (146 mg, 0.82 mmol). Stir. After 5 minutes, the disappearance of the raw material was confirmed by TLC, and then suction filtration was performed while washing with CH 2 Cl 2 , followed by concentration. Thereafter, the product was isolated by silica gel column chromatography (50% CH 2 Cl 2 / Hexane). No. 60 was obtained in a yield of 111 mg, 49%. Further, silica gel column chromatography (100% Hexane) was performed, and recrystallization was performed with Hexane to obtain pure white needle crystals.
colorless needles: mp 91.0-92 (hexane); 1H-NMR (400 MHz, CDCl3) δ: 1.80-1.90 (m, 4H), 2.87-2.95 (m, 2H), 2.95-3.02 (m, 2H), 4.27 (s, 2H), 6.90 (d, J = 4.4, 1H), 7.39 (s, 1H), 7.49 (d, J = 4.4 Hz, 1H), 7.72 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ: 23.4 (t), 23.4 (t), 29.1(t), 30.0 (t), 103.3 (s), 11
7.0 (d), 123.9 (d), 127.0 (d), 127.3 (s), 127.7 (d), 131.4 (s), 133.0 (s), 138.1 (s), 141.1 (s); EI-MS m/z 275 (M+), 277 (M++2) ; IR (KBr) 3308, 3416 cm-1 (NH2); Anal. calcd for C14H14BrN: C, 60.89; H, 5.11; N, 5.07. found: C, 60.85; H, 5.05; N, 5.03.
colorless needles: mp 91.0-92 (hexane); 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.80-1.90 (m, 4H), 2.87-2.95 (m, 2H), 2.95-3.02 (m, 2H) , 4.27 (s, 2H), 6.90 (d, J = 4.4, 1H), 7.39 (s, 1H), 7.49 (d, J = 4.4 Hz, 1H), 7.72 (s, 1H); 13 C-NMR ( 100 MHz, CDCl 3 ) δ: 23.4 (t), 23.4 (t), 29.1 (t), 30.0 (t), 103.3 (s), 11
7.0 (d), 123.9 (d), 127.0 (d), 127.3 (s), 127.7 (d), 131.4 (s), 133.0 (s), 138.1 (s), 141.1 (s); EI-MS m / z 275 (M + ), 277 (M + +2); IR (KBr) 3308, 3416 cm -1 (NH 2 ); Anal.calcd for C 14 H 14 BrN: C, 60.89; H, 5.11; N, Found: C, 60.85; H, 5.05; N, 5.03.
〔No.61(1-chloro-5,6,7,8-tetrahydroanthracen-2-amine)の合成〕 (Synthesis of No. 61 (1-chloro-5,6,7,8-tetrahydroanthracen-2-amine))
5,6,7,8-tetrahydroanthracen-2-amine (133 mg 0.67 mmol)にCH2Cl2(13.5 ml)を加え、NCS(90 mg 0.67 mmol)を加えた後、室温空気雰囲気下で撹拌した。5分後、TLCで原料の消失を確認した後、CH2Cl2で洗いながら吸引濾過を行い、濃縮した。その後、シリカゲルカラムクロマトグラフィー(30% → 50% CH2Cl2/Hexane)で単離した。No.61が収量116 mg, 75%で得られた。更に、シリカゲルカラムクロマトグラフィー(100% Hexane)を行い、Hexaneで再結晶を行うことで、純粋な白色針状結晶を得た。 CH 2 Cl 2 (13.5 ml) was added to 5,6,7,8-tetrahydroanthracen-2-amine (133 mg 0.67 mmol), NCS (90 mg 0.67 mmol) was added, and the mixture was stirred in an air atmosphere at room temperature. . After 5 minutes, the disappearance of the raw material was confirmed by TLC, and then suction filtration was performed while washing with CH 2 Cl 2 , followed by concentration. Then, it was isolated by silica gel column chromatography (30% → 50% CH 2 Cl 2 / Hexane). No. 61 was obtained in a yield of 116 mg, 75%. Further, silica gel column chromatography (100% Hexane) was performed, and recrystallization was performed with Hexane to obtain pure white needle crystals.
colorless needles: mp 74.9-75.5 (hexane); 1H-NMR (400 MHz, CDCl3) δ: 1.79-1.90 (m, 4H), 2.85-2.96 (m, 2H), 2.96-3.03 (m, 2H), 4.23 (s, 2H), 6.91 (d, J = 4.4, 1H), 7.40 (s, 1H), 7.47 (d, J = 4.4 Hz, 1H), 7.74 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ: 23.3 (t), 23.4 (t), 29.2 (t), 30.0 (t), 110.8 (s),
117.0 (d), 121.3 (d), 126.8 (d), 127.0 (d), 127.2(s), 130.1 (s), 133.0 (s), 137.8 (s), 139.4 (s); EI-MS m/z 231 (M+), 233 (M++2) ; IR (KBr) 3310, 3422 cm-1 (NH2); Anal. calcd for C14H14ClN: C, 72.57; H, 6.09; N, 6.04. found: C, 72.56; H, 6.03; N, 6.00.
colorless needles: mp 74.9-75.5 (hexane); 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.79-1.90 (m, 4H), 2.85-2.96 (m, 2H), 2.96-3.03 (m, 2H) , 4.23 (s, 2H), 6.91 (d, J = 4.4, 1H), 7.40 (s, 1H), 7.47 (d, J = 4.4 Hz, 1H), 7.74 (s, 1H); 13 C-NMR ( 100 MHz, CDCl 3 ) δ: 23.3 (t), 23.4 (t), 29.2 (t), 30.0 (t), 110.8 (s),
117.0 (d), 121.3 (d), 126.8 (d), 127.0 (d), 127.2 (s), 130.1 (s), 133.0 (s), 137.8 (s), 139.4 (s); EI-MS m / z 231 (M + ), 233 (M + +2); IR (KBr) 3310, 3422 cm -1 (NH 2 ); Anal.calcd for C 14 H 14 ClN: C, 72.57; H, 6.09; N, 6.04.found: C, 72.56; H, 6.03; N, 6.00.
〔No.62([1,1'-bianthracene]-2,2'-diamine)の合成〕 [Synthesis of No.62 ([1,1'-bianthracene] -2,2'-diamine)]
2-aminoanthracene（50 mg, 0.26 mmol）のトリフルオロ酢酸 (2.6 ml)溶液に、5% Rh/ C (11 mg, 0.0052 mmol, 0.02 equiv.)を加え、室温で2時間攪拌した。反応液に、3 M水酸化ナトリウム溶液(20 ml)を加え、EA(10×3 ml)で抽出した。有機溶剤相を飽和食塩水で洗浄後、Na2SO4で乾燥し、溶剤を減圧下で留去して、粗生成物を得た。これをシリカゲルクロマトグラフィー（eluent: CHCl3）で精製し、黄色固体を50 mg (収率100%)で得た。 5% Rh / C (11 mg, 0.0052 mmol, 0.02 equiv.) Was added to a solution of 2-aminoanthracene (50 mg, 0.26 mmol) in trifluoroacetic acid (2.6 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 3 M sodium hydroxide solution (20 ml), and the mixture was extracted with EA (10 × 3 ml). The organic solvent phase was washed with saturated brine, dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel chromatography (eluent: CHCl 3 ) to obtain 50 mg (yield 100%) of a yellow solid.
〔No.63(8H-dinaphtho[2,3-c:2',3'-g]carbazole)の合成〕 (Synthesis of No. 63 (8H-dinaphtho [2,3-c: 2 ', 3'-g] carbazole))
2-aminoanthrathene（50 mg, 0.26 mmol）の1,1,1,3,3,3-Hexafluoro-2-propanol(2.6 ml)溶液に、5% Rh/ C (27 mg, 0.015 mmol, 0.05 equiv.)を加え、室温で6時間攪拌した。反応液に、3 M水酸化ナトリウム溶液(20 ml)を加え、EA(10×3 ml)で抽出した。有機溶剤相を飽和食塩水で洗浄後、Na2SO4で乾燥し、溶剤を減圧下で留去して、粗生成物を得た。これをシリカゲルクロマトグラフィー（eluent: Hex/CHCl3 ＝ 1/4）で精製し、黄色固体を36 mg (収率76%)で得た。 To a 1,1,1,3,3,3-Hexafluoro-2-propanol (2.6 ml) solution of 2-aminoanthrathene (50 mg, 0.26 mmol), 5% Rh / C (27 mg, 0.015 mmol, 0.05 equiv. ) Was added and stirred at room temperature for 6 hours. To the reaction solution was added 3 M sodium hydroxide solution (20 ml), and the mixture was extracted with EA (10 × 3 ml). The organic solvent phase was washed with saturated brine, dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel chromatography (eluent: Hex / CHCl 3 = 1/4) to obtain a yellow solid in 36 mg (yield 76%).
Claims (13)
環Cが6員の炭素からなる環であり、かつ環A、BおよびCのうちのいずれか1つまたは2つが非芳香族性であり、残りが芳香族性であるか；または環Cが存在せず、かつ環AおよびBのうちの少なくとも1つが芳香属性であり；かつ
R1、R2およびR3のうち芳香属性の環上の置換基である少なくとも1つがNH2もしくはNHR9であり、このときR9がC1-6アルキルであり、かつ残りがH、F、Cl、BrもしくはIであるか；またはR1が次の式
R4がHであるか；または環Bが芳香族性であり、かつR1がNH2もしくはNHR9である（R9は上で定義したとおりである。）とき、R4がF、Cl、BrもしくはIである。）
環D、EおよびFが還元されたアクリジン環を構成し；かつ
R5、R6およびR7のうち少なくとも1つがNH2もしくはNHR10であり、このときR10がC1-6アルキルであり、かつ残りがHであるか；またはR5、R6およびR7がHであり；かつ
R8がHまたは存在しない。）
Ring C is a ring composed of 6-membered carbon and any one or two of Rings A, B and C are non-aromatic and the rest are aromatic; or Ring C is Not present and at least one of rings A and B is an aromatic attribute; and
At least one of R 1 , R 2 and R 3 which is a substituent on the aromatic ring is NH 2 or NHR 9 , wherein R 9 is C 1-6 alkyl, and the rest are H, F , Cl, Br or I; or R 1 is of the formula
When R 4 is H; or ring B is aromatic and R 1 is NH 2 or NHR 9 (R 9 is as defined above), R 4 is F, Cl , Br or I. )
Rings D, E and F constitute a reduced acridine ring; and
At least one of R 5 , R 6 and R 7 is NH 2 or NHR 10 , wherein R 10 is C 1-6 alkyl and the remainder is H; or R 5 , R 6 and R 7 is H; and
R 8 is H or absent. )
R1がNH2またはNHR9であり、かつR2およびR3がHであり；かつ
R4がF、Cl、BrもしくはIである。） A compound represented by the following general formula I-1 or a salt thereof:
R 1 is NH 2 or NHR 9 and R 2 and R 3 are H; and
R 4 is F, Cl, Br or I. )
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| US11120980B2 (en) | 2019-12-06 | 2021-09-14 | Lg Chem, Ltd. | Method of preparing specimen of poorly water-soluble material for MALDI mass spectrometry and sample plate used therein |
| US11282684B2 (en) | 2018-09-11 | 2022-03-22 | Lg Chem, Ltd. | Method for producing test pieces of water-insoluble material for MALDI mass spectrometry and method for quantitative analysis of water-insoluble material using MALDI mass spectrometry |
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| JP2019211441A (en) * | 2018-06-08 | 2019-12-12 | 株式会社島津製作所 | Analysis method, matrix additive, mass spectrometry kit, sugar chain analysis matrix additive and sugar chain mass spectrometry kit |
| JP7305926B2 (en) | 2018-06-08 | 2023-07-11 | 株式会社島津製作所 | Analysis method, mass spectrometry sample preparation material, mass spectrometry kit, sugar chain analysis material, and sugar chain mass spectrometry kit |
| US11282684B2 (en) | 2018-09-11 | 2022-03-22 | Lg Chem, Ltd. | Method for producing test pieces of water-insoluble material for MALDI mass spectrometry and method for quantitative analysis of water-insoluble material using MALDI mass spectrometry |
| US11120980B2 (en) | 2019-12-06 | 2021-09-14 | Lg Chem, Ltd. | Method of preparing specimen of poorly water-soluble material for MALDI mass spectrometry and sample plate used therein |
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