JP7293343B2 - ヘテロアリール化合物及びその使用 - Google Patents
ヘテロアリール化合物及びその使用 Download PDFInfo
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- JP7293343B2 JP7293343B2 JP2021512993A JP2021512993A JP7293343B2 JP 7293343 B2 JP7293343 B2 JP 7293343B2 JP 2021512993 A JP2021512993 A JP 2021512993A JP 2021512993 A JP2021512993 A JP 2021512993A JP 7293343 B2 JP7293343 B2 JP 7293343B2
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- Prior art keywords
- compound
- mmol
- pyridin
- alkyl
- tert
- Prior art date
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- -1 Heteroaryl compound Chemical class 0.000 title claims description 108
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 216
- 125000000217 alkyl group Chemical group 0.000 claims description 129
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 113
- 150000001875 compounds Chemical class 0.000 claims description 110
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 239000012453 solvate Substances 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 16
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 14
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 14
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 10
- 150000004677 hydrates Chemical class 0.000 claims description 10
- 238000000338 in vitro Methods 0.000 claims description 10
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 8
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 8
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 8
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 claims description 8
- 229940127204 compound 29 Drugs 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 6
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 5
- 229910052721 tungsten Inorganic materials 0.000 claims description 5
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 4
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 4
- 229940126639 Compound 33 Drugs 0.000 claims description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125758 compound 15 Drugs 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940125877 compound 31 Drugs 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229940125851 compound 27 Drugs 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 claims 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 claims 2
- 230000002285 radioactive effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 333
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 204
- 239000000203 mixture Substances 0.000 description 186
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 118
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 116
- 239000007787 solid Substances 0.000 description 108
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 106
- 238000000034 method Methods 0.000 description 94
- 239000000243 solution Substances 0.000 description 84
- 238000003818 flash chromatography Methods 0.000 description 69
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 67
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 62
- 239000011541 reaction mixture Substances 0.000 description 56
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 55
- 239000003208 petroleum Substances 0.000 description 53
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 47
- 125000000623 heterocyclic group Chemical group 0.000 description 43
- 239000012267 brine Substances 0.000 description 42
- 230000014759 maintenance of location Effects 0.000 description 42
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 41
- 102000013498 tau Proteins Human genes 0.000 description 41
- 108010026424 tau Proteins Proteins 0.000 description 41
- 239000000706 filtrate Substances 0.000 description 38
- 235000002639 sodium chloride Nutrition 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- 239000012298 atmosphere Substances 0.000 description 31
- 229910001873 dinitrogen Inorganic materials 0.000 description 31
- 238000003384 imaging method Methods 0.000 description 31
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 30
- 238000004440 column chromatography Methods 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 25
- 125000003118 aryl group Chemical group 0.000 description 23
- 235000011181 potassium carbonates Nutrition 0.000 description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
- LBCRWMJTAFCLCL-ZUVMSYQZSA-N 2-[(1e,3e)-4-[6-(methylamino)pyridin-3-yl]buta-1,3-dienyl]-1,3-benzothiazol-6-ol Chemical compound C1=NC(NC)=CC=C1\C=C\C=C\C1=NC2=CC=C(O)C=C2S1 LBCRWMJTAFCLCL-ZUVMSYQZSA-N 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 125000005842 heteroatom Chemical group 0.000 description 17
- 208000024827 Alzheimer disease Diseases 0.000 description 15
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 229910000029 sodium carbonate Inorganic materials 0.000 description 15
- 235000017550 sodium carbonate Nutrition 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 14
- 125000004452 carbocyclyl group Chemical group 0.000 description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- SJXWFNBZBXZDCL-UHFFFAOYSA-N 5-bromo-6-fluoropyridin-2-amine Chemical compound NC1=CC=C(Br)C(F)=N1 SJXWFNBZBXZDCL-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 10
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- 125000001424 substituent group Chemical group 0.000 description 10
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- DUVORGCYSOZZMR-UHFFFAOYSA-N tert-butyl N-[5-(5-bromopyridin-2-yl)pyridin-2-yl]-N-methylcarbamate Chemical compound BrC=1C=CC(=NC=1)C=1C=CC(=NC=1)N(C(OC(C)(C)C)=O)C DUVORGCYSOZZMR-UHFFFAOYSA-N 0.000 description 1
- KMXAFIBNFAGAHR-UHFFFAOYSA-N tert-butyl N-[5-[6-[6-[(3-fluoro-2-hydroxypropyl)amino]-1,3-benzothiazol-2-yl]pyridin-3-yl]pyridin-2-yl]-N-methylcarbamate Chemical compound FCC(CNC1=CC2=C(N=C(S2)C2=CC=C(C=N2)C=2C=CC(=NC=2)N(C(OC(C)(C)C)=O)C)C=C1)O KMXAFIBNFAGAHR-UHFFFAOYSA-N 0.000 description 1
- LUNKSIJBBADEHG-UHFFFAOYSA-N tert-butyl N-methyl-N-[5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridin-2-yl]carbamate Chemical compound C1(C)(C(C)(C)OB(O1)C1=CC=C(C2=CC=C(N(C(=O)OC(C)(C)C)C)N=C2)C=C1)C LUNKSIJBBADEHG-UHFFFAOYSA-N 0.000 description 1
- CKXAMCSVTNPSCZ-UHFFFAOYSA-N tert-butyl n-(5-bromopyridin-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(Br)C=N1 CKXAMCSVTNPSCZ-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005305 thiadiazolinyl group Chemical group 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000005881 triazolinyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- LVLANIHJQRZTPY-UHFFFAOYSA-N vinyl carbamate Chemical compound NC(=O)OC=C LVLANIHJQRZTPY-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Description
本出願は出願日が2018年5月9日である国際出願番号PCT/CN2018/086144の優先権を主張し、前記出願の全文は、参照により本明細書に組み込まれる。
Rは存在しないか、又はC1-6アルキルであり、前記C1-6アルキルはOH、ハロゲン、C2-6ヘテロシクロアルコキシ、トルエンスルホニルオキシ及びフェニルから選択される置換基で任意に置換され、前記フェニルは、更に、C1-3アルコキシ、OH又はC1-3アルキルで置換され;C2-6ヘテロシクロアルコキシにおけるヘテロ原子は、N、O、Sの一つ又は複数から選択され;前記C2-6ヘテロシクロアルコキシにおけるヘテロ原子の数は1、2、3及び4であり;
R1はH、ハロゲン、OH、NH2、C1-6アルコキシカルボニル、C1-6アルキル、C1-6アルキルアミノ又はC1-6アルコキシであり、前記OH、NH2、C1-6アルコキシカルボニル、C1-6アルキル、C1-6アルキルアミノ又はC1-6アルコキシはハロゲン、OH、C2-6ヘテロシクロアルコキシ及びトルエンスルホニルオキシから選択される一つ又は複数の置換基で任意に置換され;
TはC-R3又はNであり;
R3はH、OH、C1-6アルコキシ又はハロゲンであり;
ZはN又はCHであり;
UはN-R4、S、O又はC-R5であり;
R4は存在しないか、又はH、C1-6アルキル、C1-6アルコキシカルボニル、C1-6アルキルカルボニル又はベンゾイルであり、前記C1-6アルキル、C1-6アルコキシカルボニル、C1-6アルキルカルボニル又はベンゾイルはハロゲン、OH、C1-3アルコキシ、C2-6ヘテロシクロアルコキシ及びトルエンスルホニルオキシから選択される一つ又は複数の置換基で任意に置換され;
R5はH又はC1-6アルキルであり、前記C1-6アルキルはハロゲン及び/又はOHで任意に置換され;
VはCH、N又はNHであり;
QはCH又はNであり;
XはCH又はNであり;
YはCR6又はNであり;
R6はH、NH2及びC1-6アルコキシから選択され、ここで、前記NH2及びC1-6アルコキシはC1-3アルキル、ハロゲン化C1-3アルキル及び/又はハロゲンで任意に置換され;
JはCH又はNであり;
KはCH又はNであり;
ここで、XとYは同時にNではなく、JとYは同時にNではなく;
R´はハロゲン、OH、C1-6アルキル又はC1-6アルコキシであり;
R´´はハロゲン、OH、NH2、C1-6アルコキシ、C1-6アルキルアミノ又はC2-6ヘテロシクロアルキルであり、前記OH、NH2、C1-6アルコキシ、C1-6アルキルアミノ及びC2-6ヘテロシクロアルキルはオキソ、OH、ハロゲン、C3-6シクロアルキル、C1-4アルコキシカルボニル、C2-6ヘテロシクロアルコキシ、トルエンスルホニルオキシ及びフェニルから選択される一つ又は複数で任意に置換され、更に、前記フェニルはOH及び/又はC1-3アルコキシで任意に置換され;
R´´´はH、OH又はハロゲンであり;
mは0、1又は2であり;
nは0、1又は2であり;
UとVが同時にN原子を含む場合、R1及びR3はCF3又はClではない。
構造単位
RaはH、OH、ハロゲン、C1-3アルキル、C1-3アルコキシ、NH2、C1-3アルキルアミノ及びC1-6アルコキシカルボニルから選択され、前記OH、C1-3アルキル、C1-3アルコキシ、NH2、C1-3アルキルアミノ又はC1-6アルコキシカルボニルはOH、ハロゲン、C2-6ヘテロシクロアルコキシ又はトルエンスルホニルオキシで任意に置換され;
RbはH、C1-6アルキル、C1-6アルコキシカルボニル、C1-3アルキルカルボニル、ベンジル及びベンゾイルから選択され、前記C1-6アルキル、C1-6アルコキシカルボニル、C1-3アルキルカルボニル又はベンゾイルはハロゲン、OH、C1-3アルコキシ、C3-6ヘテロシクロアルコキシ又はトルエンスルホニルオキシで任意に置換される。
RaはH、OH、ハロゲン、C1-3アルキル、C1-3アルコキシ、NH2、C1-3アルキルアミノ及びC1-6アルコキシカルボニルから選択され、前記OH、C1-3アルキル、C1-3アルコキシ、NH2、C1-3アルキルアミノ又はC1-6アルコキシカルボニルはOH、ハロゲン、C2-6ヘテロシクロアルコキシ及びトルエンスルホニルオキシで任意に置換され;
RbはH、C1-6アルキル、C1-6アルコキシカルボニル、C1-3アルキルカルボニル、ベンジル及びベンゾイルから選択され、前記C1-6アルキル、C1-6アルコキシカルボニル、C1-3アルキルカルボニル又はベンゾイルはハロゲン、OH、C1-3アルコキシ、C2-6ヘテロシクロアルコキシ又はトルエンスルホニルオキシで任意に置換される。
構造単位
(ii)80℃で、塩基及びPd触媒の存在下でステップ(i)で得られた化合物3と化合物4を有機溶媒の中で反応させるステップを含み;
構造単位
構造単位
i)130℃で、ポリリン酸中で化合物21と化合物22を反応させて化合物23を形成させるステップ;
ii)60℃で、Pd触媒と塩基の存在下でステップi)で得られた化合物23と化合物19をMeCNとH2Oの混合溶媒中で反応させて、化合物25を形成させるステップを含み;
i)室温で、Pd触媒、CuI及び有機塩基の存在下で、化合物26と化合物27を有機溶媒の中で反応させ、化合物28を形成させるステップ;
ii)80℃で、ステップi)で得られた化合物28とDBUをMeOHとH2Oの混合溶媒の中で反応させ、化合物29を形成させるステップ;
iii)80℃で、Pd触媒及び塩基の存在下でステップii)で得られた化合物29と化合物30を有機溶媒の中で反応させ、化合物31を形成させるステップを含み;
i)80℃で、塩基の存在下で化合物32と化合物33をアルコール溶媒の中で反応させ、化合物34を形成させるステップ;
ii)80℃で、塩基及びPd触媒の存在下でステップi)で得られた化合物34と化合物30を有機溶媒の中で反応させるステップを含む。
構造単位
(i)-78℃で、s-ブチルリチウムの存在下で化合物1と化合物2をTHFの中で反応させ、化合物3を形成させるステップ;
(ii)80℃で、Na2CO3及びPd(PPh3)4の存在下でステップi)で得られた化合物3と化合物4をDMFの中で反応させるステップを含み;
構造単位
構造単位
構造単位
構造単位
i)130℃で、化合物21と化合物22をポリリン酸の中で反応させ、化合物23を形成させるステップ;
ii)60℃で、Pd(dppf)Cl2とNa2CO3の存在下でステップi)で得られた化合物23と化合物19をMeCNとH2Oの混合溶媒の中で反応させ、化合物25を形成させるステップを含み;
構造単位
i)室温で、Pd(PPh3)2Cl2、CuI及びトリエタノールアミンの存在下で化合物26と化合物27をDMFの中で反応させて化合物28を形成させるステップ;
ii)80℃で、ステップi)で得られた化合物28とDBUをMeOHとH2Oの混合溶媒の中で反応させ、化合物29を形成させるステップ;
iii)80℃で、Pd(PPh3)4及びNa2CO3の存在下で、ステップii)で得られた化合物29と化合物30をDMFの中で反応させ、化合物31を形成させるステップを含み;
構造単位
i)80℃で、NaHCO3の存在下で化合物32と化合物33をEtOHの中で反応させ、化合物34を形成させるステップ;
ii)80℃で、K2CO3及びPd(PPh3)4の存在下で、ステップi)で得られた化合物34と化合物30をDMFの中でと反応させるステップを含む。
(a)被験対象に有効量の(i)式(I)で表される構造を有するヘテロアリール化合物、又はその薬学的に許容される塩、溶媒化物、水和物、同位体標識誘導体、又は放射性標識誘導体、或は(ii)本発明の医薬組成物を投与するステップ;及び
(b)被験対象の脳に対してイメージングする、ステップを含む、タウイメージングの方法。
具体的な官能基および化学用語の定義を下により詳細に記載する。化学元素はHandbook of Chemistry and Physics, 75th Ed.内表紙の元素周期表CAS版に従って同定され、具体的な官能基はそこに記載の通りに一般的に定義される。加えて、有機化学の一般的な法則、さらには具体的な官能部分および反応性は、Thomas Sorrell、Organic Chemistry、University Science Books、Sausalito、1999; Smith and March、March’s Advanced Organic Chemistry、5th Edition、John Wiley & Sons、Inc.、New York、2001; Larock、Comprehensive Organic Transformations、VCH Publishers、Inc.、New York、1989;及びCarruthers、Some Modern Methods of Organic Synthesis、3rd Edition、Cambridge University Press、Cambridge、1987に記載の通りである。
ほとんどの化学薬品は、Sinopharm Chemical Reagent Co.(SCRC)、Sigma-Aldrich、Alfa又は他のサプライヤーから購入した。
方法A:移動相:A:水(0.01%のTFA)B:CAN(0.01%のTFA);勾配相:1.4分間で5%Bから95%Bに増加し、1.6分内で95%Bに増加(合計実行時間:3分間);流速:2.3mL/min;カラム:SunFire C18、4.6×50mm、3.5μm;カラム温度:50℃である。検出機器:ADC ELSD、DAD(214nm及び254nm)、ES-APIである。
方法B:移動相:A:水(10mMのNH4HCO3)B:アセトニトリル;勾配相:1.5分で5%から95%Bに増加し、1.5分内で95%Bに増加(合計実行時間:3分間);流速:2.0mL/min;カラム:XBridge C18、4.6×50mm、3.5um;カラム温度:40℃である。検出機器:ADC ELSD、DAD(214nm及び254nm)、MSD(ES-API)である。
方法C:移動相:A:水(10mMのNH4HCO3)B:アセトニトリル;勾配相:1.5分で5%から95%Bに増加し、1.5分内で95%Bに増加(合計実行時間:3分間);流速:2.0mL/min;カラム:XBridge C18、4.6×50mm、3.5um;カラム温度:40℃である。検出機器:ADC ELSD、DAD(214nm及び254nm)、MSD(ES-API)である。
工程1:2-[4-(3-アミノフェニル)フェニル]ピロロ[2,3-c]ピリジン-1-カルボン酸tert-ブチル
窒素ガスの雰囲気下で、2-(4-ヨードフェニル)ピロロ[2,3-c]ピリジン-1-カルボン酸tert-ブチル(100mg、0.24mmol)、3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン(156mg、0.71mmol)、炭酸ナトリウム(126mg、1.19mmol)及び1,1-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(18mg、0.02mmol)の1,4-ジオキサン(10mL)及び水(2mL)溶液を、80℃で3時間撹拌した。反応混合物を濃縮して乾燥させた。残留物を酢酸エチル(20mL)に溶解させ、水と食塩水で洗浄し、硫酸ナトリウムで乾燥させ、濃縮した。残留物をフラッシュカラムクロマトグラフィー(ジクロロメタン/メタノール=1%~25%)で精製して、2-[4-(3-アミノフェニル)フェニル]ピロロ[2,3-c]ピリジン-1-カルボン酸tert-ブチル(230mg、収率:75%)を得、茶色の固体であり、精製せず直接的に次の反応に使用した。LCMS(ESI)[M+H]+=386.2。
ピリジン-3,4-ジアミン(200mg、1.83mmol)、4-ヨード安息香酸(500mg、2.02mmol)をPPA(10mL)の中で混合し、130℃で16時間撹拌した。反応混合物を水に注いた。混合物を飽和NaOH溶液でpH9に調整した。沈殿物を濾過し、生成物2-(4-ヨードフェニル)-3H-イミダゾ[4,5-c]ピリジン(560mg、1.74mmol、収率:95.1%)を得、白色の固体であった。LCMS:ESI-MS:m/z:322.0[M+H]+;RT=1.42(方法A)。
Na2CO3(383mg、3.61mmol)、2-(4-ヨードフェニル)-1H-イミダゾ[4,5-c]ピリジン(386mg、1.2mmol)、[6-(ジメチルアミノ)ピリジン-3-イル]ボロン酸(200mg、1.2mmol)及びPd(dppf)Cl2(40mg、0.05mmol)の混合物のMeCN(50mL)及び水(10mL)溶液を60℃で3時間加熱した。反応物を濃縮して乾燥させ、水(20mL)で希釈し、濾過して白色の固体を得た。粗生成物をフラッシュクロマトグラフィー(DCM/MeOH=20/1~10/1)で精製して、5-[4-(1H-イミダゾ[4,5-c]ピリジン-2-イル)フェニル]-N,N-ジメチル-ピリジン-2-アミン(100mg、0.31mmol、収率:26.3%)を得、白色の固体であった。LCMS:ESI-MS:m/z:316.1[M+H]+;RT=1.11(方法B)。
5-[4-(3H-イミダゾ[4,5-c]ピリジン-2-イル)フェニル]-N,N-ジメチル-ピリジン-2-アミン(70mg、0.22mmol)のDMF(2mL)溶液にK2CO3(153mg、1.11mmol)と1-フルオラニル-2-ヨーダニル-エタン(193mg、1.11mmol)を添加した。前記混合物を25℃で2時間撹拌した。反応物を濃縮して乾燥させ、残留物をフラッシュクロマトグラフィー(DCM/MeOH=100/1~30/1で精製して、5-[4-[3-(2-フルオラニルエチル)イミダゾ[4,5-c]ピリジン-2-イル]フェニル]-N,N-ジメチル-ピリジン-2-アミン(40mg、0.11mmol、収率:49.8%)を得、黄色の固体であった。
LCMS:ESI-MS:m/z:362.1[M+H]+;RT=1.68(MethodA);1H NMR(400MHz、DMSO-d6)δ8.94(s、1H)、8.53(d、J=2.4Hz、1H)、8.40(d、J=8.4Hz、2H)、8.09(d、J=6.4Hz、1H)、7.91~7.93(m、1H)、7.72~7.76(m、3H)、6.75(d、J=9.2Hz、1H)、4.96~4.98(m、1H)、4.82~4.86(m、2H)、4.75~4.77(m、1H)、3.08(s、6H)ppm。
LCMS:m/z=383.8(M+H)+、保持時間:2.41分。
LCMS:m/z=320.1(M+H)+、保持時間:1.70分、純度100%(UV254)。
1H NMR (400MHz、DMSO-d6)δ12.10(s、1H)、9.13(d、J=11.0Hz、1H)、8.91~8.78(m、2H)、8.18(dd、J=8.8、2.2Hz、1H)、8.14(d、J=5.4Hz、1H)、7.97(d、J=13.3Hz、1H)、7.56(t、J=10.6Hz、1H)、7.03(s、2H)、6.56(d、J=8.9Hz、1H)、2.88(t、J=17.8Hz、3H)。
LC-MS:m/z=442(M+H)+、純度100%(UV254)、保持時間:2.037分(方法B);1H NMR(400MHz、DMSO-d6)δ8.90(d、J=2.3Hz、1H)、8.76~8.61(m、1H)、8.22(dd、J=9.1、2.4Hz、1H)、8.01(d、J=8.2Hz、1H)、7.80(d、J=8.9Hz、1H)、7.19(d、J=1.9Hz、1H)、7.02~6.90(m、1H)、6.78(d、J=9.2Hz、1H)、6.22(t、J=5.6Hz、1H)、5.73~5.38(m、1H)、5.73~4.17(m、2H)、3.94(d、J=21.0Hz、1H)、3.29~3.18(m、1H)、3.13(s、6H)、2.87~2.82(m、1H)。
LCMS:m/z=453[M+H]+;RT=2.026分(方法B)。
ヒトタウタンパク質の発現及び精製
材料:
pET41a-タウ野生株
OneShot(商標) BL21(DE3) Chemically Competent E. coli (Invitrogen、C600003)
カナマイシン硫酸塩(Sangon Biotech、A506636)
IPTG (Sangon Biotech、A100487)
Pipes 緩衝液(100mMのPipes、pH6.8、1mMのEGTA、1mMのMgSO4)
Hepes 緩衝液(25mMのHepes、pH7.2、0.1mMのEDTA、0.5mMのDTT、100mMのNaCl)
Q-Sepharose Fast Flowカラム(GE Healthcare、17-0510-01)
SP-Sepharose Fast Flowカラム(GE Healthcare、17-0729-01)
タンパク質の発現:
工程1:氷上、30分で1μLの発現プラスミドpET41a-tauwtを1つのOneShot(商標) BL21(DE3)Chemically Competent E.coliに形質転換した。
工程2:42℃で、90秒間熱ショックを与え、次に、氷上に2分間置き、37℃で30分間回復させ、少量をLB(Kan+)寒天プレートに置き、37℃で一晩インキュベートした。
工程3:50μg/mLのカナマイシンで200mLの液体培養物の中の単一コロニーを選択し、再懸濁して種菌培養を製造した。種菌培養に接種し、37℃、200rpmで一晩振とうした。
工程4:100倍に希釈したスターターを新鮮な培地(Kan+)に添加し、OD600=0.8になるまで37℃、200rpmで振とうした。
工程5:IPTG(最終濃度:1mM)を添加し、タンパク質を3時間発現させた。
工程6:細胞ペレットを収集し、更に精製するために-80℃で保存した。
工程1:細胞ペレットをPipes緩衝液に再懸濁させた。
工程2:超音波で振とうし、遠心分離(15,000rpm、4℃で15分)した。
工程3:上澄みを沸騰水浴に20分間入れ、次に、遠心分離した。上澄みの熱安定性タンパク質をQ-SepharoseFast Flowカラム(20mL)にロードした。
工程4:タウを含む通過液をSP-Sepharose Fast Flowカラム(10mL)にロードし、0.2MのNaClを含むPipes緩衝液で溶出させた。
工程6:タウを含む部分を合わせ、濃縮し、Hepes緩衝液で透析し、-80℃で保存した。
工程7:SP-FlowをQ-SepharoseFast Flowカラム(20mL)とSP-Sepharose Fast Flowカラム(10mL)に再度ロードし、0.2MのNaClを含むPipes緩衝液で溶出させた。
工程8:タウを含む部分をプールし、濃縮し、Hepes緩衝液で透析し、-80℃で保存した。工程6~7を2回繰り返し、すべての溶出生成物を収集して濃縮した。
体外での蛍光定量的タウ結合テスト
2μMの組換えタウタンパク質と15μMのヘパリンを30mMのTris(pH7.5)緩衝液で、37℃で一晩インキュベートすることにより繊維化させた。次に、30mMのTris緩衝液(pH7.5)で希釈した0.04μMの組換えタウタンパク質と試験化合物(1%のDMSOを含む)を1時間反応させた。飽和曲線を作成し、Prismソフトウェア(GraphPad)を使用し、パラメーター推定法を使用して蛍光測定データを読み取った。各試験化合物のKd値を測定した。表Aには、例示的な試験化合物のKd値を示した。
前記記載に従い、体外での蛍光競合結合テストを実施した1。アルツハイマー病患者の側頭皮質に由来する凍結組織を、プロテアーゼ阻害剤混合物(cOmpleteTM、EDTAフリー、Roche)を含む50mMのTris-HCl緩衝液(pH7.4)の中で均質化させ、分析のために-80℃で保存した。放射性リガンドの同種または異種遮断への結合を測定するために、PBB3の非存在下または非標識下で、これらのホモジネート(100μg組織)を5nMの[11C]PBB3(モル放射能:100~150GBq/mol)を10-11~10-6Mの濃度で、10%エタノールを含むTris-HCl緩衝液の中で、pH7.4で、室温で30分間インキュベートした。5×10-7M PBB3の存在下で[11C]PBB3の非特異的結合を測定した。サンプルは1回のみ測定し、特異的放射性リガンド結合はpmol/g組織で測定した。非線形回帰を使用して阻害定数(Ki)と変位率を測定し、GraphPad Prism 6.0(GraphPad Software)を使用し、Cheng-Prusoff方程式により、濃度結合グラフに適合する単位点および2部位結合モデルを取得し、モデル選択のためのF検定を行った。単一サイトの相同ブロッキングモデルでは、当該函数を使用して、相同競合結合から解離定数(Kd)を計算した:
Kd=Ki=IC50-放射性リガンド
ここで、IC50と[放射性リガンド]は、それぞれ50%の阻害と放射性リガンド濃度を誘発する競合者の濃度を表す。[11C]PBB3及び非標識PBB3の実験は、化合物の光変換を回避するために、薄暗い条件で行われた。表Bは、例示的な試験化合物のKi値を表した。
前記記載に従い、蛍光結合の評価を実施した1。PBB3と試験化合物を利用した蛍光標識に対して、AD脳の脱パラフィンされた側頭葉皮質を切片し、0.001%(W/V)PBB3または試験化合物を含む50%エタノールの中で室温で30分間インキュベートした。サンプルを50%のエタノールで5分間洗浄し、蒸留水に2回3分間浸し、非蛍光封入剤(VECTASHIELD; Vector Laboratories)にロードした。PBB3用のカスタムフィルターキューブを備えたDM4000顕微鏡(Leica)を使用して蛍光画像をキャプチャした(励起バンドパスは391~437nmの通過、阻害ローパスは458nmの通過)。蛍光結合評価では、化合物とタウ凝集体との反応性は「0」(標識なし)、「1」(かすかな標識)、「2」(PBB3より弱い)、「3」(PBB3以上)として半定量的に評価され。「0.5」スコアは、2つの整数スコア0及び1の中間条件を表した。「1.5」スコアは、2つの整数スコア1及び2の中間条件を表した。「2.5」スコアは、2つの整数スコ2及び3の中間条件を表した。表Cは、例示的な試験化合物のスコアを表した。
前記に記載の通り、覚醒している動物のリアルタイムイメージングは、2光子レーザー走査顕微鏡を使用して実行した2。頭蓋窓を配置するために、生後6~13か月のrTg4510タウトランスジェニックマウス3を、空気、酸素、及びイソフルラン(誘導用に3~5%、手術用に2%を使用)の混合物を含むマスクで麻酔し、「Seylaz-Tomita法」4に従って、頭蓋窓(直径3~4mm)を左体性感覚皮質に配置し、中心をブレグマの1.8mm、ブレグマの外側の2.5mmにした。頭蓋骨の窓の上の中心にある直径7mmの穴を通して、カスタマイズされた金属プレートを頭蓋骨に固定した。Takuwa et al.5に詳述されている慢性頭蓋窓を製造する方法を使用した。すべてのイメージング実験は、頭蓋窓の製造から少なくとも2週間後に実行された。血管及び病理学的タウ含有物は、それぞれ、スルホローダミン101(SR101; MP Biomedicals、Irvine、CA)及びPBB3又は試験化合物で蛍光標識された。SR101を塩水に5mMまで溶解させ、PBB3又は試験化合物をDMSO(和光):塩水=1:1溶液に0.05%(W/V)まで溶解させた。イメージング実験を開始する直前に、2種の溶液100μLをマウスの腹腔内に注射した。注:同じ実験グループ(それぞれ、試験化合物及びPBB3実験からなる)の実験は、同じrTg4510タウトランスジェニックマウスに約1週間の間隔で順次的に実施された。イメージング期間では、覚醒している動物を前記に記載のカスタマイズされた装置に配置した5。簡単に言うと、動物のヘッドの金属板をカスタマイズされた立体定位固定装置にねじ込み、次に、空気流を利用して浮かんでいる発泡スチロールのボールの上に動物を置き、動物をボールの上で自由に運動できるようにし、動物のヘッドを装置に固定した。ヘッドを固定した後、励起波長900nmの2光子レーザー走査顕微鏡(TCS-SP5 MP、Leica Microsystems GmbH、Wetzlar、ドイツ)でリアルタイムのイメージングを実行した。ビームスプリッター(560/10nm)で発光信号を分離し、同時にSR101(610/75nm)及びPBB3(525/50nm)のバンドパスフィルターで検出した。単一の画像平面は1024×1024ピクセルで構成され、面内ピクセルサイズは0.45μmであった。ボリューム画像が得られ、その最大深度は、皮質表面から0.3~0.5mmで、z方向は2.5μmであった。同じrTg4510タウトランスジェニックマウスで実施された各グループの実験は、対照(PBB3)実験の結果に基づいて、相応する豊富で明確な蛍光標識されたタウ病理の参照画像平面を示し、比較のために元のボリューム画像から関連するすべての実験の同等物を抽出した。各イメージング結果では、ImageJによってランダムに選択した10個の蛍光標識された病態の蛍光強度を測定し、バックグラウンド正規化後に平均値を計算した。ランダムに選択された10個の領域における蛍光強度の平均によって各画像のバックグラウンド強度を取得したことに注意されたい。図1は、PBB3と比較した化合物J及び化合物Wの2光子レーザー蛍光顕微鏡の結果を示している。図2は、PBB3と比較した化合物Jの2光子イメージングをrTg4510マウスに使用して生成させた画像(上)、及び経時的な緑色蛍光シグナルの定量化(下)を示している。
1. Ono M、Sahara N、Kumata K、et al. Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies. Brain. 2017;140(3):764-780. doi:10.1093/brain/aww339
2. Maruyama M、Shimada H、Suhara T、et al. Imaging of Tau Pathology in a Tauopathy Mouse Model and in Alzheimer Patients Compared to Normal Controls. Neuron. 2013;79(6):1094-1108. doi:10.1016/J.NEURON.2013.07.037
3. Santacruz K、Lewis J、Spires T、et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005;309(5733):476-481. doi:10.1126/science.1113694
4. Tomita Y、Kubis N、Calando Y、et al. Long-Term in Vivo Investigation of Mouse Cerebral Microcirculation by Fluorescence Confocal Microscopy in the Area of Focal Ischemia. J Cereb Blood Flow Metab. 2005;25(7):858-867. doi:10.1038/sj.jcbfm.9600077
5. Takuwa H、Tajima Y、Kokuryo D、et al. Hemodynamic changes during neural deactivation in awake mice: A measurement by laser-Doppler flowmetry in crossed cerebellar diaschisis. Brain Res. 2013;1537:350-355. doi:10.1016/J.BRAINRES.2013.09.023
Claims (12)
- 式(II)で表される構造を有するヘテロアリール化合物、又はその薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物又はその放射性標識化合物であって、
構造単位
ここで、式I-(c)において、UはO又はSであり;WはCH又はNであり;
RaはH、OH、ハロゲン、C1-3アルキル、C1-3アルコキシ、NH2、C1-3アルキルアミノまたはC1-6アルコキシカルボニルであって、前記C 1-3アルキル、C1-3アルコキシ、NH2、C1-3アルキルアミノ又はC1-6アルコキシカルボニルはOH、ハロゲン、C3-6ヘテロシクロアルコキシ及びトルエンスルホニルオキシで任意に置換され;
RbはH、C1-6アルキル、C1-6アルコキシカルボニル、C1-3アルキルカルボニル、ベンジルまたはベンゾイルであって、前記C1-6アルキル、C1-6アルコキシカルボニル、C1-3アルキルカルボニル又はベンゾイルはハロゲン、OH、C1-3アルコキシ、C3-6ヘテロシクロアルコキシ又はトルエンスルホニルオキシで任意に置換され、
R´はハロゲン、OH、C1-6アルキルは又はC1-6アルコキシであり;
R´´はBr、I、OH、
Bocはtert-ブトキシカルボニルであり、
mは0、1または2であり;
nは1または2である、
ヘテロアリール化合物、又はその薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物又はその放射性標識化合物。 - R´はF、C1-3アルキル又はC1-3アルコキシである、請求項1に記載の式(II)で表される構造を有するヘテロアリール化合物、又はその薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物又はその放射性標識化合物。
- 式I-(c)において、WはCHであり、UはS又はOである、請求項1に記載の式(II)で表される構造を有するヘテロアリール化合物、又はその薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物又はその放射性標識化合物。
- 前記RaはH、OH、F、Cl、メチル、エチル、メトキシ、エトキシ、n-プロポキシ、NH2、N-メチルアミノ、N-エチルアミノ、N-n-プロピルアミノ、N,N-ジメチルアミノ、メチルエチルアミノ、メトキシカルボニルまたはtert-ブトキシカルボニルであって、前記メチル、エチル、メトキシ、エトキシ、n-プロポキシ、NH2、N-メチルアミノ、N-エチルアミノ、N-n-プロピルアミノ、N,N-ジメチルアミノ、メチルエチルアミノ、メトキシカルボニルもしくはtert-ブトキシカルボニルはOH、F、Cl、C3-5ヘテロシクロアルコキシ又はトルエンスルホニルオキシで任意に置換され;
及び/又は、前記RbはH、C1-3アルキル、C1-4アルコキシカルボニル、C1-3アルキルカルボニル、ベンジル又はベンゾイルであり、前記C1-3アルキル、C1-4アルコキシカルボニル、C1-3アルキルカルボニル又はベンゾイルはF、Cl、OH、C1-3アルコキシ、C3-5ヘテロシクロアルコキシ又はトルエンスルホニルオキシで任意に置換される、請求項1に記載の式(II)で表される構造を有するヘテロアリール化合物、又はその薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物又はその放射性標識化合物。 - R´はF、OH、メチル又はメトキシである、請求項1に記載の式(II)で表される構造を有するヘテロアリール化合物、又はその薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物又はその放射性標識化合物。
- 請求項1~6のいずれか一項に記載の式(II)で表される構造を有するヘテロアリール化合物、又はそれらの薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物又はその放射性標識化合物の製造方法であって、
以下のステップにおける化合物中のQはCHであり;
構造単位
(i)-78℃で、塩基の存在下で化合物1と化合物2を有機溶媒の中で反応させ、化合物3を形成させるステップ;
(ii)80℃で、塩基及びPd触媒の存在下でステップ(i)で得られた化合物3と化合物4を有機溶媒の中で反応させるステップを含み;
構造単位
構造単位
i)室温で、Pd触媒、CuI及び有機塩基の存在下で、化合物26と化合物27を有機溶媒の中で反応させ、化合物28を形成させるステップ;
ii)80℃で、ステップi)で得られた化合物28と1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エンをMeOHとH2Oの混合溶媒の中で反応させ、化合物29を形成させるステップ;
iii)80℃、Pd触媒及び塩基の存在下でステップii)で得られた化合物29と化合物30を有機溶媒の中で反応させ、化合物31を形成させるステップを含み、以下の式中の化合物26および28におけるBocはtert-ブトキシカルボニルであり;
i)80℃で、塩基の存在下で化合物32と化合物33をアルコール溶媒の中で反応させ、化合物34を形成させるステップ;
ii)80℃で、塩基及びPd触媒の存在下でステップi)で得られた化合物34と化合物30を有機溶媒の中で反応させるステップを含む;
- 構造単位
(i)-78℃で、s-ブチルリチウムの存在下で化合物1と化合物2をTHFの中で反応させ、化合物3を形成させるステップ;
(ii)80℃で、Na2CO3及びPd(PPh3)4の存在下でステップi)で得られた化合物3と化合物4をDMFの中で反応させるステップを含み;
構造単位
構造単位
構造単位
構造単位
構造単位
i)室温で、Pd(PPh3)2Cl2、CuI及びトリエタノールアミンの存在下で、化合物26と化合物27をDMFの中で反応させて化合物28を形成させるステップ;
ii)80℃で、ステップi)で得られた化合物28と1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エンをMeOHとH2Oの混合溶媒の中で反応させ、化合物29を形成させるステップ;
iii)80℃で、Pd(PPh3)4及びNa2CO3の存在下でステップii)で得られた化合物29と化合物30をDMFの中で反応させ、化合物31を形成させるステップを含み;
構造単位
i)80℃で、NaHCO3の存在下で化合物32と化合物33をEtOHの中で反応させ、化合物34を形成させるステップ;
ii)80℃で、K2CO3及びPd(PPh3)4の存在下でステップi)で得られた化合物34と化合物30をDMFの中でと反応させるステップを含む、請求項8に記載の製造方法。 - 請求項1~7のいずれか1項に記載のヘテロアリール化合物、その薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物、又は放射性標識化合物、並びに任意に選択される薬学的に許容される賦形剤を含む、医薬組成物。
- 試験管内、体外及び生体内でのタウ凝集体の検出に用いる、請求項1~7のいずれか1項に記載のヘテロアリール化合物、その薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物、又は放射性標識化合物。
- タウ凝集体造影剤の製造における、請求項1~7のいずれか1項に記載のヘテロアリール化合物、その薬学的に許容される塩、溶媒化物、水和物、その同位体標識化合物、又は放射性標識化合物の使用。
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CN112384517B (zh) | 2023-07-14 |
US20230047178A1 (en) | 2023-02-16 |
IL278579A (en) | 2020-12-31 |
KR102572014B1 (ko) | 2023-08-29 |
CN112384517A (zh) | 2021-02-19 |
EP3790883A4 (en) | 2022-08-24 |
JP2021523231A (ja) | 2021-09-02 |
WO2019214681A1 (en) | 2019-11-14 |
AU2019265346A1 (en) | 2021-01-07 |
AU2019265346B2 (en) | 2022-06-16 |
ZA202007547B (en) | 2022-07-27 |
IL278579B1 (en) | 2024-05-01 |
MX2020011959A (es) | 2021-02-17 |
US20230374006A1 (en) | 2023-11-23 |
CA3099318C (en) | 2024-02-13 |
BR112020022741A2 (pt) | 2021-02-02 |
KR20210008049A (ko) | 2021-01-20 |
SG11202010946YA (en) | 2020-12-30 |
CA3099318A1 (en) | 2019-11-14 |
EP3790883A1 (en) | 2021-03-17 |
US20210253569A1 (en) | 2021-08-19 |
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