JP7149272B2 - β－セクレターゼ阻害剤としてのチアジン誘導体および使用方法 - Google Patents

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Publication number

JP7149272B2

JP7149272B2 JP2019531722A JP2019531722A JP7149272B2 JP 7149272 B2 JP7149272 B2 JP 7149272B2 JP 2019531722 A JP2019531722 A JP 2019531722A JP 2019531722 A JP2019531722 A JP 2019531722A JP 7149272 B2 JP7149272 B2 JP 7149272B2

Authority

JP

Japan

Prior art keywords

compound

tautomer

amino

dihydro

methyl

Prior art date

2016-12-15

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 239000002439 beta secretase inhibitor Substances 0.000 title 1
• 150000004897 thiazines Chemical class 0.000 title 1
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• 150000003839 salts Chemical class 0.000 claims description 69
• 125000000217 alkyl group Chemical group 0.000 claims description 38
• 238000002360 preparation method Methods 0.000 claims description 38
• -1 2-propynyloxy Chemical group 0.000 claims description 36
• 239000008194 pharmaceutical composition Substances 0.000 claims description 36
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• DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 claims description 26
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• IRLAUZMPCLFJAE-PXNMLYILSA-N 2-amino-4-[5-[(Z)-2-(5-cyanopyridin-2-yl)-2-fluoroethenyl]-2-fluorophenyl]-4,6-dimethyl-5H-1,3-thiazine-6-carboxylic acid Chemical compound CC1(CC(C)(N=C(N)S1)c1cc(\C=C(/F)c2ccc(cn2)C#N)ccc1F)C(O)=O IRLAUZMPCLFJAE-PXNMLYILSA-N 0.000 claims description 12
• 229910052731 fluorine Inorganic materials 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 230000009467 reduction Effects 0.000 claims description 11
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• DUXJJGZUZXKWAW-WJFVXKAHSA-N (4S,6S)-2-amino-4-[2-fluoro-5-[(Z)-2-fluoro-2-(5-prop-2-ynoxypyrazin-2-yl)ethenyl]phenyl]-N,4,6-trimethyl-5H-1,3-thiazine-6-carboxamide Chemical compound NC=1S[C@@](C[C@@](N=1)(C)C1=C(C=CC(=C1)\C=C(\C1=NC=C(N=C1)OCC#C)/F)F)(C(=O)NC)C DUXJJGZUZXKWAW-WJFVXKAHSA-N 0.000 claims description 9
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• GDBAWUOZQRRHNL-NVNXTCNLSA-N 2-amino-4-[5-[(Z)-2-(5-chloropyridin-2-yl)-2-fluoroethenyl]-2-fluorophenyl]-4,6-dimethyl-5H-1,3-thiazine-6-carboxylic acid Chemical compound CC1(CC(C)(N=C(N)S1)c1cc(\C=C(/F)c2ccc(Cl)cn2)ccc1F)C(O)=O GDBAWUOZQRRHNL-NVNXTCNLSA-N 0.000 claims description 8
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• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
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• GSHVIWQGAADYSD-AUWJEWJLSA-N 2-amino-4-[5-[(Z)-2-(5-chloropyridin-2-yl)-2-fluoroethenyl]-2-fluorophenyl]-4-methyl-5,6-dihydro-1,3-thiazine-6-carboxylic acid Chemical compound CC1(CC(SC(N)=N1)C(O)=O)c1cc(\C=C(/F)c2ccc(Cl)cn2)ccc1F GSHVIWQGAADYSD-AUWJEWJLSA-N 0.000 claims description 5
• WKOIVUXVVOAIDL-QHVUTBCBSA-N 6-[(Z)-2-[3-[(4S)-2-amino-4-methyl-1,3-thiazin-4-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC=1SC=C[C@@](N=1)(C)C=1C=C(C=CC=1F)\C=C(/F)\C1=NC=C(C#N)C=C1 WKOIVUXVVOAIDL-QHVUTBCBSA-N 0.000 claims description 5
• OEEHPGXMFVJORU-QHVUTBCBSA-N 6-[(Z)-2-[3-[(4S)-2-amino-4-methyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound C[C@]1(CCSC(N)=N1)C1=C(F)C=CC(\C=C(/F)C2=CC=C(C=N2)C#N)=C1 OEEHPGXMFVJORU-QHVUTBCBSA-N 0.000 claims description 5
• QBRVMFURZXJSCP-PQLPFPTISA-N 6-[(Z)-2-[3-[(4S,6S)-2-amino-4,6-dimethyl-6-(morpholine-4-carbonyl)-5H-1,3-thiazin-4-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound C[C@]1(C[C@](C)(N=C(N)S1)C1=C(F)C=CC(\C=C(/F)C2=CC=C(C=N2)C#N)=C1)C(=O)N1CCOCC1 QBRVMFURZXJSCP-PQLPFPTISA-N 0.000 claims description 5
• 206010048327 Supranuclear palsy Diseases 0.000 claims description 5
• 125000001072 heteroaryl group Chemical group 0.000 claims description 5
• LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 claims description 5
• QBRVMFURZXJSCP-QKYCXKCASA-N 6-[(Z)-2-[3-[(4S,6R)-2-amino-4,6-dimethyl-6-(morpholine-4-carbonyl)-5H-1,3-thiazin-4-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound C[C@@]1(C[C@](C)(N=C(N)S1)c1cc(\C=C(/F)c2ccc(cn2)C#N)ccc1F)C(=O)N1CCOCC1 QBRVMFURZXJSCP-QKYCXKCASA-N 0.000 claims description 4
• ADMYTHHAGLTLOW-UHFFFAOYSA-N C1C=C(SC=N1)C(=O)N Chemical class C1C=C(SC=N1)C(=O)N ADMYTHHAGLTLOW-UHFFFAOYSA-N 0.000 claims description 4
• 208000011990 Corticobasal Degeneration Diseases 0.000 claims description 4
• 125000001153 fluoro group Chemical group F* 0.000 claims description 4
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 4
• SUXMDOZZNWAJIB-YHTSIIMFSA-N (4S)-4-[5-[(Z)-2-(5-chloropyridin-2-yl)-2-fluoroethenyl]-2-fluorophenyl]-4-methyl-5,6-dihydro-1,3-thiazin-2-amine Chemical compound C[C@]1(CCSC(N)=N1)C1=C(F)C=CC(\C=C(/F)C2=NC=C(Cl)C=C2)=C1 SUXMDOZZNWAJIB-YHTSIIMFSA-N 0.000 claims description 3
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• 150000002500 ions Chemical class 0.000 description 36
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