TWI860279B - 作為hcv rna複製抑制劑之經4'-氟-2'-甲基取代之核苷衍生物 - Google Patents

Info

Publication number

TWI860279B

TWI860279B TW107133372A TW107133372A TWI860279B TW I860279 B TWI860279 B TW I860279B TW 107133372 A TW107133372 A TW 107133372A TW 107133372 A TW107133372 A TW 107133372A TW I860279 B TWI860279 B TW I860279B

Authority

TW

Taiwan

Prior art keywords

formula

amino

compound

methyltetrahydrofuran

difluoro

Prior art date

2017-09-21

Links

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• 239000003112 inhibitor Substances 0.000 title description 27
• 150000003833 nucleoside derivatives Chemical class 0.000 title description 15
• 230000010076 replication Effects 0.000 title description 13
• 150000001875 compounds Chemical class 0.000 claims description 157
• 241000711549 Hepacivirus C Species 0.000 claims description 102
• 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 50
• 150000003839 salts Chemical class 0.000 claims description 23
• 239000003814 drug Substances 0.000 claims description 14
• DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 abstract description 6
• UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 abstract description 4
• UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 abstract description 4
• DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 abstract description 4
• DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 abstract description 4
• 229940045145 uridine Drugs 0.000 abstract description 4
• 230000005764 inhibitory process Effects 0.000 abstract description 3
• 230000002195 synergetic effect Effects 0.000 abstract description 3
• UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 abstract description 2
• 229940127073 nucleoside analogue Drugs 0.000 abstract 2
• -1 cytidine nucleoside Chemical class 0.000 description 101
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 74
• 239000000203 mixture Substances 0.000 description 74
• 125000000217 alkyl group Chemical group 0.000 description 73
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 73
• 238000000034 method Methods 0.000 description 65
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 58
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 44
• 235000019439 ethyl acetate Nutrition 0.000 description 42
• 239000007787 solid Substances 0.000 description 41
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
• 239000011541 reaction mixture Substances 0.000 description 39
• 239000000243 solution Substances 0.000 description 35
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 30
• 229960003767 alanine Drugs 0.000 description 30
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 28
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
• 238000002360 preparation method Methods 0.000 description 27
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 27
• 210000004027 cell Anatomy 0.000 description 26
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
• 239000000460 chlorine Chemical group 0.000 description 23
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
• 230000015572 biosynthetic process Effects 0.000 description 22
• 238000003786 synthesis reaction Methods 0.000 description 22
• HBLLTUPBILQDTQ-MVHNUAHISA-N 4-amino-1-[(2r,3r,4s,5s)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidin-2-one Chemical compound C[C@@]1(F)[C@H](O)[C@@](F)(CO)O[C@H]1N1C(=O)N=C(N)C=C1 HBLLTUPBILQDTQ-MVHNUAHISA-N 0.000 description 21
• 238000011282 treatment Methods 0.000 description 21
• 239000002777 nucleoside Substances 0.000 description 19
• 239000007864 aqueous solution Substances 0.000 description 17
• 239000003921 oil Substances 0.000 description 17
• 235000019198 oils Nutrition 0.000 description 17
• 238000004704 ultra performance liquid chromatography Methods 0.000 description 17
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
• 108091032973 (ribonucleotides)n+m Proteins 0.000 description 15
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
• 229910052757 nitrogen Inorganic materials 0.000 description 15
• 229920006395 saturated elastomer Polymers 0.000 description 15
• 125000001424 substituent group Chemical group 0.000 description 15
• 125000004432 carbon atom Chemical group C* 0.000 description 14
• 125000003545 alkoxy group Chemical group 0.000 description 13
• 239000002585 base Substances 0.000 description 13
• 238000002648 combination therapy Methods 0.000 description 13
• 239000012065 filter cake Substances 0.000 description 13
• 229910052739 hydrogen Inorganic materials 0.000 description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
• 239000012074 organic phase Substances 0.000 description 13
• 239000000047 product Substances 0.000 description 13
• 238000000746 purification Methods 0.000 description 13
• 125000000753 cycloalkyl group Chemical group 0.000 description 12
• 239000000706 filtrate Substances 0.000 description 12
• 229910052736 halogen Inorganic materials 0.000 description 12
• 150000002367 halogens Chemical class 0.000 description 12
• 208000015181 infectious disease Diseases 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• 108010050904 Interferons Proteins 0.000 description 11
• 102000014150 Interferons Human genes 0.000 description 11
• 238000006243 chemical reaction Methods 0.000 description 11
• 239000003795 chemical substances by application Substances 0.000 description 11
• 229940079593 drug Drugs 0.000 description 11
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
• 235000019341 magnesium sulphate Nutrition 0.000 description 11
• MRRCUIBQEZCEAT-NQMVMOMDSA-N 1-[(2r,3r,4r)-3-fluoro-4-hydroxy-3-methyl-5-methylideneoxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@]1(F)[C@H](O)C(=C)O[C@H]1N1C(=O)NC(=O)C=C1 MRRCUIBQEZCEAT-NQMVMOMDSA-N 0.000 description 10
• KIGFOKBYASZURF-MVHNUAHISA-N 1-[(2r,3r,4s,5s)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@]1(F)[C@H](O)[C@@](F)(CO)O[C@H]1N1C(=O)NC(=O)C=C1 KIGFOKBYASZURF-MVHNUAHISA-N 0.000 description 10
• 229910004298 SiO 2 Inorganic materials 0.000 description 10
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
• 150000002148 esters Chemical class 0.000 description 10
• 239000000377 silicon dioxide Substances 0.000 description 10
• 125000003118 aryl group Chemical group 0.000 description 9
• 230000000694 effects Effects 0.000 description 9
• 125000004494 ethyl ester group Chemical group 0.000 description 9
• 238000003818 flash chromatography Methods 0.000 description 9
• 229910052731 fluorine Inorganic materials 0.000 description 9
• 239000000543 intermediate Substances 0.000 description 9
• VOWPVJACXJNHBC-UHFFFAOYSA-N methyl diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(OC)OC1=CC=CC=C1 VOWPVJACXJNHBC-UHFFFAOYSA-N 0.000 description 9
• 229910052760 oxygen Inorganic materials 0.000 description 9
• 229910052717 sulfur Inorganic materials 0.000 description 9
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
• ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 8
• UXRDAJMOOGEIAQ-CKOZHMEPSA-N [(8r,9s,10r,13s,14s,17r)-17-acetyl-10,13-dimethyl-16-methylidene-3-oxo-1,2,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(=C)[C@](OC(=O)C)(C(C)=O)[C@@]1(C)CC2 UXRDAJMOOGEIAQ-CKOZHMEPSA-N 0.000 description 8
• 239000003443 antiviral agent Substances 0.000 description 8
• 239000012267 brine Substances 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 125000004093 cyano group Chemical group *C#N 0.000 description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
• 125000001624 naphthyl group Chemical group 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
• 239000012258 stirred mixture Substances 0.000 description 8
• XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 7
• JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 7
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
• 125000000304 alkynyl group Chemical group 0.000 description 7
• 238000004458 analytical method Methods 0.000 description 7
• 229910052799 carbon Inorganic materials 0.000 description 7
• 239000012043 crude product Substances 0.000 description 7
• BYAGYQXRLBVKTP-ZETCQYMHSA-N cyclohexyl (2s)-2-aminopropanoate Chemical compound C[C@H](N)C(=O)OC1CCCCC1 BYAGYQXRLBVKTP-ZETCQYMHSA-N 0.000 description 7
• 238000001914 filtration Methods 0.000 description 7
• 238000009472 formulation Methods 0.000 description 7
• 239000001257 hydrogen Substances 0.000 description 7
• 229940079322 interferon Drugs 0.000 description 7
• IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 7
• 239000000546 pharmaceutical excipient Substances 0.000 description 7
• 239000012071 phase Substances 0.000 description 7
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
• MAMMVUWCKMOLSG-UHFFFAOYSA-N Cyclohexyl propionate Chemical compound CCC(=O)OC1CCCCC1 MAMMVUWCKMOLSG-UHFFFAOYSA-N 0.000 description 6
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• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
• IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
• ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
• 125000003342 alkenyl group Chemical group 0.000 description 6
• 235000019270 ammonium chloride Nutrition 0.000 description 6
• 229910052681 coesite Inorganic materials 0.000 description 6
• 229910052906 cristobalite Inorganic materials 0.000 description 6
• ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
• XRDRKVPNHIWTBX-UHFFFAOYSA-N methyl 3-chlorobenzoate Chemical compound COC(=O)C1=CC=CC(Cl)=C1 XRDRKVPNHIWTBX-UHFFFAOYSA-N 0.000 description 6
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
• 235000012239 silicon dioxide Nutrition 0.000 description 6
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• 238000004809 thin layer chromatography Methods 0.000 description 6
• 229910052905 tridymite Inorganic materials 0.000 description 6
• BLAOQYUKUBIXCF-UHFFFAOYSA-N 1-dichlorophosphoryloxynaphthalene Chemical compound C1=CC=C2C(OP(Cl)(=O)Cl)=CC=CC2=C1 BLAOQYUKUBIXCF-UHFFFAOYSA-N 0.000 description 5
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
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• 125000002252 acyl group Chemical group 0.000 description 5
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• 230000000840 anti-viral effect Effects 0.000 description 5
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• 125000004663 dialkyl amino group Chemical group 0.000 description 5
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• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
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• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
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• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
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• HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 5
• 235000017557 sodium bicarbonate Nutrition 0.000 description 5
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• 239000002904 solvent Substances 0.000 description 5
• 239000007858 starting material Substances 0.000 description 5
• 125000000547 substituted alkyl group Chemical group 0.000 description 5
• ZDTANFBJNPQQJG-MVHNUAHISA-N 1-[(2r,3r,4s,5r)-3,5-difluoro-4-hydroxy-5-(iodomethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@]1(F)[C@H](O)[C@@](F)(CI)O[C@H]1N1C(=O)NC(=O)C=C1 ZDTANFBJNPQQJG-MVHNUAHISA-N 0.000 description 4
• 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 description 4
• OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
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• 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 4
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
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• LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
• 230000009467 reduction Effects 0.000 description 4
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• 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 4
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