ES2910367T3 - Derivados de tiazina y oxazina bicíclicos como inhibidores de beta-secretasa y métodos de uso - Google Patents

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Publication number

ES2910367T3

ES2910367T3 ES17822986T ES17822986T ES2910367T3 ES 2910367 T3 ES2910367 T3 ES 2910367T3 ES 17822986 T ES17822986 T ES 17822986T ES 17822986 T ES17822986 T ES 17822986T ES 2910367 T3 ES2910367 T3 ES 2910367T3

Authority

ES

Spain

Prior art keywords

thiazin

fluoro

fluorophenyl

amino

fluorovinyl

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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• 238000000034 method Methods 0.000 title description 55
• AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 title description 4
• 239000002439 beta secretase inhibitor Substances 0.000 title description 2
• 125000002619 bicyclic group Chemical group 0.000 title description 2
• 150000004893 oxazines Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 355
• 150000003839 salts Chemical class 0.000 claims abstract description 76
• -1 2-propynyloxy Chemical group 0.000 claims abstract description 64
• 125000001424 substituent group Chemical group 0.000 claims abstract description 24
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
• 150000002367 halogens Chemical class 0.000 claims abstract description 17
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 13
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 8
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 8
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
• 125000005843 halogen group Chemical group 0.000 claims abstract 2
• 208000024827 Alzheimer disease Diseases 0.000 claims description 65
• WADGHWKXQZVKFK-UHFFFAOYSA-N thiazin-2-amine Chemical compound NN1SC=CC=C1 WADGHWKXQZVKFK-UHFFFAOYSA-N 0.000 claims description 50
• 125000000217 alkyl group Chemical group 0.000 claims description 45
• 239000008194 pharmaceutical composition Substances 0.000 claims description 33
• 210000004556 brain Anatomy 0.000 claims description 28
• 238000011282 treatment Methods 0.000 claims description 27
• 125000003545 alkoxy group Chemical group 0.000 claims description 23
• 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 23
• GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims description 20
• 206010012289 Dementia Diseases 0.000 claims description 18
• 208000010877 cognitive disease Diseases 0.000 claims description 17
• 229910052799 carbon Inorganic materials 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
• ZFFHULOAPNORBL-XKMNTDACSA-N (4aS,5S,7aS)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-(5-fluoropyridin-2-yl)ethenyl]phenyl]-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound NC1=N[C@]2(CO[C@@H]([C@H]2CS1)C(F)(F)F)C1=C(F)C=CC(\C=C(/F)C2=NC=C(F)C=C2)=C1 ZFFHULOAPNORBL-XKMNTDACSA-N 0.000 claims description 10
• 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 10
• 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 10
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 10
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
• BUJQZBNDSOLLBU-QFWLKESYSA-N 5-[(Z)-2-[3-[(4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyrazine-2-carbonitrile Chemical compound NC1=N[C@]2(CO[C@@H]([C@H]2CS1)C(F)(F)F)C1=C(F)C=CC(\C=C(/F)C2=NC=C(N=C2)C#N)=C1 BUJQZBNDSOLLBU-QFWLKESYSA-N 0.000 claims description 9
• GWEZIKZYIWTLEB-ANUQTDGMSA-N 6-[(Z)-2-[3-[(4aS,5S,7aS)-2-amino-5-(fluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC=1SC[C@H]2[C@@](N=1)(CO[C@@H]2CF)C=1C=C(C=CC=1F)\C=C(/F)\C1=NC=C(C#N)C=C1 GWEZIKZYIWTLEB-ANUQTDGMSA-N 0.000 claims description 9
• 230000007505 plaque formation Effects 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
• ATYAWJWVHNUXQF-DAISNLPVSA-N 6-[(Z)-2-[3-[(4aR,7aS)-2-amino-6-(5-fluoro-4-methoxypyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound COC1=C(F)C=NC(=N1)N1C[C@H]2CSC(N)=N[C@]2(C1)C1=C(F)C=CC(\C=C(/F)C2=CC=C(C=N2)C#N)=C1 ATYAWJWVHNUXQF-DAISNLPVSA-N 0.000 claims description 8
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 8
• 208000028698 Cognitive impairment Diseases 0.000 claims description 8
• WHIUBCKUVNJKKI-LETVZAPESA-N 6-[(Z)-2-[3-[(4aS,5S,7aS)-2-amino-5-(difluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC=1SC[C@H]2[C@@](N=1)(CO[C@@H]2C(F)F)C=1C=C(C=CC=1F)\C=C(/F)\C1=NC=C(C#N)C=C1 WHIUBCKUVNJKKI-LETVZAPESA-N 0.000 claims description 7
• WYLKDBUCNHBXCP-XOYQDKGISA-N 6-[(Z)-2-[3-[(4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC1=N[C@]2(CO[C@@H]([C@H]2CS1)C(F)(F)F)c1cc(\C=C(/F)c2ccc(cn2)C#N)ccc1F WYLKDBUCNHBXCP-XOYQDKGISA-N 0.000 claims description 7
• HENFIGCJZYPGHN-ZVSUQRSESA-N (4aR,7aS)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-(5-prop-2-ynoxypyrazin-2-yl)ethenyl]phenyl]-6-pyrimidin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine Chemical compound NC1=N[C@]2(CN(C[C@H]2CS1)C1=NC=CC=N1)C1=C(F)C=CC(\C=C(/F)C2=CN=C(OCC#C)C=N2)=C1 HENFIGCJZYPGHN-ZVSUQRSESA-N 0.000 claims description 6
• GKKLJUXLRFAZSA-NZEFLHGSSA-N (4aR,7aS)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-[5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl]ethenyl]phenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine Chemical compound FC1=C(C=C(C=C1)\C=C(\C1=NC=C(N=C1)OCC(C(F)F)(F)F)/F)[C@@]12N=C(SC[C@@H]1CN(C2)C1=NC=C(C=N1)F)N GKKLJUXLRFAZSA-NZEFLHGSSA-N 0.000 claims description 6
• CDTWUVDFDJGSJB-KJPUCCIKSA-N (4aR,7aS)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-[5-[(2S)-1-methoxypropan-2-yl]oxypyrazin-2-yl]ethenyl]phenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine Chemical compound COC[C@H](C)OC1=NC=C(N=C1)C(\F)=C\C1=CC(=C(F)C=C1)[C@]12CN(C[C@H]1CSC(N)=N2)C1=NC=C(F)C=N1 CDTWUVDFDJGSJB-KJPUCCIKSA-N 0.000 claims description 6
• GGJSTTRLUUKPRS-YYEWTLSSSA-N (4aR,7aS)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-[5-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]pyrazin-2-yl]ethenyl]phenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine Chemical compound CC1=NOC(COC2=NC=C(N=C2)C(\F)=C\C2=CC(=C(F)C=C2)[C@]23CN(C[C@H]2CSC(N)=N3)C2=NC=C(F)C=N2)=N1 GGJSTTRLUUKPRS-YYEWTLSSSA-N 0.000 claims description 6
• OHBAMRDCYITIKZ-ZAULRJFKSA-N (4aR,7aS)-7a-[5-[(Z)-2-(5-but-2-ynoxypyrazin-2-yl)-2-fluoroethenyl]-2-fluorophenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine Chemical compound CC#CCOC1=NC=C(N=C1)C(\F)=C\C1=CC(=C(F)C=C1)[C@]12CN(C[C@H]1CSC(N)=N2)C1=NC=C(F)C=N1 OHBAMRDCYITIKZ-ZAULRJFKSA-N 0.000 claims description 6
• KRDTZIZUJNTCAC-PFXPYRGJSA-N (4aS,5S,7aS)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-(5-methoxypyrazin-2-yl)ethenyl]phenyl]-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound COC1=NC=C(N=C1)C(\F)=C\C1=CC(=C(F)C=C1)[C@]12CO[C@@H]([C@H]1CSC(N)=N2)C(F)(F)F KRDTZIZUJNTCAC-PFXPYRGJSA-N 0.000 claims description 6
• YIQUYGRGOCRWFL-QFMRXCROSA-N 5-[(Z)-2-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyrazine-2-carbonitrile Chemical compound NC1=N[C@]2(CN(C[C@H]2CS1)C1=NC=C(F)C=N1)C1=C(F)C=CC(\C=C(/F)C2=NC=C(N=C2)C#N)=C1 YIQUYGRGOCRWFL-QFMRXCROSA-N 0.000 claims description 6
• WYLKDBUCNHBXCP-YIHKTLQQSA-N 6-[(Z)-2-[3-[(4aR,5R,7aR)-2-amino-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC1=N[C@@]2(CO[C@H]([C@@H]2CS1)C(F)(F)F)c1cc(\C=C(/F)c2ccc(cn2)C#N)ccc1F WYLKDBUCNHBXCP-YIHKTLQQSA-N 0.000 claims description 6
• BCOHSRWZBPAAFJ-XOYQDKGISA-N 6-[(Z)-2-[3-[(4aR,5S,7aS)-2-amino-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]oxazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC=1OC[C@H]2[C@@](N=1)(CO[C@@H]2C(F)(F)F)C=1C=C(C=CC=1F)\C=C(/F)\C1=NC=C(C#N)C=C1 BCOHSRWZBPAAFJ-XOYQDKGISA-N 0.000 claims description 6
• LDFGUJZWAPTGJN-NJQKEIMISA-N 6-[(Z)-2-[3-[(4aR,7aR)-2-amino-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC1=N[C@@]2(COC[C@@H]2CS1)C1=C(F)C=CC(\C=C(/F)C2=CC=C(C=N2)C#N)=C1 LDFGUJZWAPTGJN-NJQKEIMISA-N 0.000 claims description 6
• ZOLASYMXTWTSAU-AIELCWNPSA-N 6-[(Z)-2-[3-[(4aR,7aS)-2-amino-6-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound COC1=C(F)C(C)=NC(=N1)N1C[C@H]2CSC(N)=N[C@]2(C1)C1=C(F)C=CC(\C=C(/F)C2=CC=C(C=N2)C#N)=C1 ZOLASYMXTWTSAU-AIELCWNPSA-N 0.000 claims description 6
• ULUVFLUZTKOQFK-GQGWRHQGSA-N 6-[(Z)-2-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC1=N[C@]2(CN(C[C@H]2CS1)C1=NC=C(F)C=N1)C1=C(F)C=CC(\C=C(/F)C2=CC=C(C=N2)C#N)=C1 ULUVFLUZTKOQFK-GQGWRHQGSA-N 0.000 claims description 6
• QXCNRVRFOLSHHN-NETAFIBYSA-N 6-[(Z)-2-[3-[(4aR,7aS)-2-amino-6-pyrimidin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC1=N[C@]2(CN(C[C@H]2CS1)C1=NC=CC=N1)C1=C(F)C=CC(\C=C(/F)C2=CC=C(C=N2)C#N)=C1 QXCNRVRFOLSHHN-NETAFIBYSA-N 0.000 claims description 6
• LKKOUIIDFVHOOT-ZZKGRASYSA-N 6-[(Z)-2-[3-[(4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]-5-chloropyridine-3-carbonitrile Chemical compound NC=1SC[C@H]2[C@@](N=1)(CO[C@@H]2C(F)(F)F)C=1C=C(C=CC=1F)\C=C(/F)\C1=NC=C(C#N)C=C1Cl LKKOUIIDFVHOOT-ZZKGRASYSA-N 0.000 claims description 6
• GRUTXYOBHJITRJ-BCUMICGMSA-N 6-[(Z)-2-[3-[(4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]-5-methylpyridine-3-carbonitrile Chemical compound CC1=C(N=CC(=C1)C#N)C(\F)=C\C1=CC(=C(F)C=C1)[C@]12CO[C@@H]([C@H]1CSC(N)=N2)C(F)(F)F GRUTXYOBHJITRJ-BCUMICGMSA-N 0.000 claims description 6
• ULUVFLUZTKOQFK-OFNIGGJOSA-N 6-[(Z)-2-[3-[(4aS,7aR)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC1=N[C@@]2(CN(C[C@@H]2CS1)C1=NC=C(F)C=N1)C1=C(F)C=CC(\C=C(/F)C2=CC=C(C=N2)C#N)=C1 ULUVFLUZTKOQFK-OFNIGGJOSA-N 0.000 claims description 6
• LDFGUJZWAPTGJN-HHOPTJALSA-N 6-[(Z)-2-[3-[(4aS,7aS)-2-amino-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC=1SC[C@H]2[C@@](N=1)(COC2)C=1C=C(C=CC=1F)\C=C(/F)\C1=NC=C(C#N)C=C1 LDFGUJZWAPTGJN-HHOPTJALSA-N 0.000 claims description 6
• 208000012902 Nervous system disease Diseases 0.000 claims description 6
• NVNVYXHMZVSSEQ-WUXFZBHOSA-N (4aS,5S,7aS)-7a-[5-[(Z)-2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-fluoroethenyl]-2-fluorophenyl]-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound NC1=N[C@]2(CO[C@@H]([C@H]2CS1)C(F)(F)F)c1cc(\C=C(/F)c2ncc(cc2Cl)C(F)(F)F)ccc1F NVNVYXHMZVSSEQ-WUXFZBHOSA-N 0.000 claims description 5
• GWEZIKZYIWTLEB-WJDPGPTFSA-N 6-[(Z)-2-[3-[(4aR,5R,7aR)-2-amino-5-(fluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC1=N[C@@]2(CO[C@@H](CF)[C@@H]2CS1)C1=C(F)C=CC(\C=C(/F)C2=CC=C(C=N2)C#N)=C1 GWEZIKZYIWTLEB-WJDPGPTFSA-N 0.000 claims description 5
• BCOHSRWZBPAAFJ-YIHKTLQQSA-N 6-[(Z)-2-[3-[(4aS,5R,7aR)-2-amino-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]oxazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile Chemical compound NC=1OC[C@@H]2[C@](N=1)(CO[C@H]2C(F)(F)F)C=1C=C(C=CC=1F)\C=C(/F)\C1=NC=C(C#N)C=C1 BCOHSRWZBPAAFJ-YIHKTLQQSA-N 0.000 claims description 5
• 208000018282 ACys amyloidosis Diseases 0.000 claims description 5
• 201000010374 Down Syndrome Diseases 0.000 claims description 5
• 208000007487 Familial Cerebral Amyloid Angiopathy Diseases 0.000 claims description 5
• 208000032849 Hereditary cerebral hemorrhage with amyloidosis Diseases 0.000 claims description 5
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
• 206010048327 Supranuclear palsy Diseases 0.000 claims description 4
• 230000001054 cortical effect Effects 0.000 claims description 4
• 230000007850 degeneration Effects 0.000 claims description 4
• 230000003412 degenerative effect Effects 0.000 claims description 4
• 210000004558 lewy body Anatomy 0.000 claims description 4
• ZJVSZNABCFISIE-WURPYDPGSA-N (4aS,7aS)-7a-[5-[(Z)-2-(5-chloropyridin-2-yl)-2-fluoroethenyl]-2-fluorophenyl]-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound NC1=N[C@]2(COC[C@H]2CS1)C1=C(F)C=CC(\C=C(/F)C2=NC=C(Cl)C=C2)=C1 ZJVSZNABCFISIE-WURPYDPGSA-N 0.000 claims description 3
• 208000018737 Parkinson disease Diseases 0.000 claims description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
• FSZBZCCCGRRZMK-ULGVCQJVSA-N (4aR,7aS)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-(5-prop-2-ynoxypyrazin-2-yl)ethenyl]phenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine Chemical compound FC1=C(C=C(C=C1)\C=C(\C1=NC=C(N=C1)OCC#C)/F)[C@@]12N=C(SC[C@@H]1CN(C2)C1=NC=C(C=N1)F)N FSZBZCCCGRRZMK-ULGVCQJVSA-N 0.000 claims description 2
• OCOWEWOMRYUXLY-NZEFLHGSSA-N (4aR,7aS)-7a-[5-[(Z)-2-[5-(2,2-difluoroethoxy)pyrazin-2-yl]-2-fluoroethenyl]-2-fluorophenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine Chemical compound NC1=N[C@]2(CN(C[C@H]2CS1)C1=NC=C(F)C=N1)C1=C(F)C=CC(\C=C(/F)C2=CN=C(OCC(F)F)C=N2)=C1 OCOWEWOMRYUXLY-NZEFLHGSSA-N 0.000 claims description 2
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 9
• 125000004093 cyano group Chemical group *C#N 0.000 abstract description 5
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 394
• 235000019439 ethyl acetate Nutrition 0.000 description 187
• 239000000243 solution Substances 0.000 description 141
• 239000000203 mixture Substances 0.000 description 140
• 150000002500 ions Chemical class 0.000 description 136
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
• 239000007787 solid Substances 0.000 description 112
• 238000005160 1H NMR spectroscopy Methods 0.000 description 107
• 238000002360 preparation method Methods 0.000 description 101
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 99
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 93
• 239000011541 reaction mixture Substances 0.000 description 84
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 76
• 238000010898 silica gel chromatography Methods 0.000 description 76
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
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