KR102078233B1 - 항바이러스성 화합물 - Google Patents
항바이러스성 화합물 Download PDFInfo
- Publication number
- KR102078233B1 KR102078233B1 KR1020147034784A KR20147034784A KR102078233B1 KR 102078233 B1 KR102078233 B1 KR 102078233B1 KR 1020147034784 A KR1020147034784 A KR 1020147034784A KR 20147034784 A KR20147034784 A KR 20147034784A KR 102078233 B1 KR102078233 B1 KR 102078233B1
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- KR
- South Korea
- Prior art keywords
- mmol
- imidazol
- tert
- naphtho
- butyl
- Prior art date
- 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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- 150000001875 compounds Chemical class 0.000 title claims abstract description 137
- 230000000840 anti-viral effect Effects 0.000 title abstract 2
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 230000001225 therapeutic effect Effects 0.000 claims description 11
- 208000005176 Hepatitis C Diseases 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 7
- 238000011321 prophylaxis Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 abstract description 191
- 238000000034 method Methods 0.000 abstract description 74
- 239000000543 intermediate Substances 0.000 abstract description 40
- 238000002360 preparation method Methods 0.000 abstract description 18
- 230000008569 process Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 437
- 239000000243 solution Substances 0.000 description 317
- -1 -CH 2 CH 2 CH 3 ) Chemical group 0.000 description 310
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 303
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 190
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 184
- 235000019439 ethyl acetate Nutrition 0.000 description 180
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 163
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 142
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 142
- 238000006243 chemical reaction Methods 0.000 description 136
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 129
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- 230000002829 reductive effect Effects 0.000 description 120
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 103
- 239000012267 brine Substances 0.000 description 102
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 102
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- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 91
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 89
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 79
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
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- 238000003786 synthesis reaction Methods 0.000 description 62
- 239000011734 sodium Substances 0.000 description 59
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- 230000015572 biosynthetic process Effects 0.000 description 57
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 48
- 239000013058 crude material Substances 0.000 description 46
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 44
- 239000010410 layer Substances 0.000 description 42
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 40
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- 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 35
- 238000004007 reversed phase HPLC Methods 0.000 description 35
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- 238000003818 flash chromatography Methods 0.000 description 33
- 239000007787 solid Substances 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
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- 239000012044 organic layer Substances 0.000 description 32
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 31
- 229910052786 argon Inorganic materials 0.000 description 31
- GOJLQSAREKTKPT-MRVPVSSYSA-N (2r)-2-(methoxycarbonylamino)-2-phenylacetic acid Chemical compound COC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 GOJLQSAREKTKPT-MRVPVSSYSA-N 0.000 description 29
- 125000006239 protecting group Chemical group 0.000 description 29
- OGUYUCIDLVQIDE-UHFFFAOYSA-N N-(1-methoxyethenyl)-3-methylbutanamide Chemical compound COC(=C)NC(CC(C)C)=O OGUYUCIDLVQIDE-UHFFFAOYSA-N 0.000 description 28
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 28
- 229940002612 prodrug Drugs 0.000 description 27
- 239000000651 prodrug Substances 0.000 description 27
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 27
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000002253 acid Substances 0.000 description 22
- 239000003112 inhibitor Substances 0.000 description 22
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- CEFVHPDFGLDQKU-YFKPBYRVSA-N (2s)-2-(methoxycarbonylamino)-3-methylbutanoic acid Chemical compound COC(=O)N[C@@H](C(C)C)C(O)=O CEFVHPDFGLDQKU-YFKPBYRVSA-N 0.000 description 20
- 125000003118 aryl group Chemical group 0.000 description 20
- 239000000463 material Substances 0.000 description 19
- 239000002244 precipitate Substances 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
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- 239000003814 drug Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
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- 125000000623 heterocyclic group Chemical group 0.000 description 17
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- 238000001816 cooling Methods 0.000 description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
- 125000006626 methoxycarbonylamino group Chemical group 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 13
- 108010050904 Interferons Proteins 0.000 description 12
- 102000014150 Interferons Human genes 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
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- 229910052763 palladium Inorganic materials 0.000 description 12
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 239000002002 slurry Substances 0.000 description 12
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical group 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 11
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 11
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 10
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- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 5
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- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
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- 229960002510 mandelic acid Drugs 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
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- 238000013160 medical therapy Methods 0.000 description 1
- 229950003168 merimepodib Drugs 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UQFFIZLZYFWZDM-FWTWSYJPSA-N methyl N-[(1R)-2-[(2S,4S)-2-[17-[2-[(2S)-1-[(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]-21-oxa-5,7-diazapentacyclo[11.8.0.03,11.04,8.014,19]henicosa-1(13),2,4(8),5,9,11,14(19),15,17-nonaen-6-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl]carbamate Chemical compound C1([C@@H](NC(=O)OC)C(=O)N2[C@@H](C[C@@H](C2)COC)C=2NC3=C(C4=CC5=C(C6=CC=C(C=C6CO5)C=5NC(=NC=5)[C@H]5N(CCC5)C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C=C4C=C3)N=2)=CC=CC=C1 UQFFIZLZYFWZDM-FWTWSYJPSA-N 0.000 description 1
- JQVHZKVXNPFJJW-DANLSDFQSA-N methyl N-[(2S,3R)-3-methoxy-1-[(2S,4S)-2-[5-[6-[(2S,4S)-1-[(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoyl]-4-(methoxymethyl)pyrrolidin-2-yl]-21-oxa-5,7-diazapentacyclo[11.8.0.03,11.04,8.014,19]henicosa-1(13),2,4(8),5,9,11,14(19),15,17-nonaen-17-yl]-1H-imidazol-2-yl]-4-methylpyrrolidin-1-yl]-1-oxobutan-2-yl]carbamate Chemical compound COC(=O)N[C@@H]([C@@H](C)OC)C(=O)N1C[C@@H](COC)C[C@H]1C(N1)=NC(C2=C3)=C1C=CC2=CC1=C3OCC2=CC(C=3NC(=NC=3)[C@H]3N(C[C@@H](C)C3)C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)=CC=C12 JQVHZKVXNPFJJW-DANLSDFQSA-N 0.000 description 1
- ZWLRIFNDJTYUOL-OQTVQIBGSA-N methyl N-[(2S,3S)-1-[(2S,4S)-2-[5-[6-[(2S,5S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-5-methylpyrrolidin-2-yl]-21-oxa-5,7-diazapentacyclo[11.8.0.03,11.04,8.014,19]henicosa-1(13),2,4(8),5,9,11,14(19),15,17-nonaen-17-yl]-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H]([C@@H](C)CC)C(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N([C@@H](C)CC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)N1 ZWLRIFNDJTYUOL-OQTVQIBGSA-N 0.000 description 1
- YFFYYVAPSDAVFG-OQTVQIBGSA-N methyl N-[(2S,3S)-1-[(2S,5S)-2-[5-[6-[(2S,4S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-4-(methoxymethyl)pyrrolidin-2-yl]-21-oxa-5,7-diazapentacyclo[11.8.0.03,11.04,8.014,19]henicosa-1(13),2,4(8),5,9,11,14(19),15,17-nonaen-17-yl]-1H-imidazol-2-yl]-5-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](C)CC[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N(C[C@@H](COC)C3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)N1 YFFYYVAPSDAVFG-OQTVQIBGSA-N 0.000 description 1
- NANRTICORMTVPZ-IJWSHSPWSA-N methyl [(2s)-3-methyl-1-{(2s,4s)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1C[C@@H](C)C[C@H]1C1=NC2=CC=C(C=C3C4=CC=C(C=C4COC3=C3)B4OC(C)(C)C(C)(C)O4)C3=C2N1 NANRTICORMTVPZ-IJWSHSPWSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- ZZOIZIXLSKHYCP-GMOBBJLQSA-N methyl n-[(2s)-1-[(1s,3s,5s)-3-(5-bromo-1h-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound C1([C@@H]2C[C@@H]3C[C@@H]3N2C(=O)[C@H](C(C)C)NC(=O)OC)=NC=C(Br)N1 ZZOIZIXLSKHYCP-GMOBBJLQSA-N 0.000 description 1
- VMVOGALUTOHLRC-GJZGRUSLSA-N methyl n-[(2s)-1-[(2s)-2-(6-bromo-1h-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC2=CC(Br)=CC=C2N1 VMVOGALUTOHLRC-GJZGRUSLSA-N 0.000 description 1
- XXIGDZWPZXEBKF-GVXVVHGQSA-N methyl n-[(2s)-1-[(2s,4s)-2-(5-bromo-1h-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(Br)N1 XXIGDZWPZXEBKF-GVXVVHGQSA-N 0.000 description 1
- BKOIBDBRKSOXEO-ZPFDUUQYSA-N methyl n-[(2s,3s)-1-[(2s,5s)-2-(5-iodo-1h-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](C)CC[C@H]1C1=NC=C(I)N1 BKOIBDBRKSOXEO-ZPFDUUQYSA-N 0.000 description 1
- UWHWNFVVODLFIQ-UHFFFAOYSA-N methyl pyrrolidine-1-carboxylate Chemical compound COC(=O)N1CCCC1 UWHWNFVVODLFIQ-UHFFFAOYSA-N 0.000 description 1
- FPHWBSRFAUYMNX-LBJGZVHDSA-N methyl {(1r)-2-[(2s)-2-(5-{2-[(2s,4s)-1-{(2s)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1h-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1C[C@@H](COC)C[C@H]1C(N1)=NC(C2=C3)=C1C=CC2=CC1=C3OCC2=CC(C=3NC(=NC=3)[C@H]3N(CCC3)C(=O)[C@H](NC(=O)OC)C=3C=CC=CC=3)=CC=C12 FPHWBSRFAUYMNX-LBJGZVHDSA-N 0.000 description 1
- LRJIODVRAPCLKX-FWTWSYJPSA-N methyl {(1r)-2-[(2s)-2-(9-{2-[(2s,4s)-1-[n-(methoxycarbonyl)-o-methyl-l-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1h-imidazol-5-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate Chemical compound COC(=O)N[C@@H]([C@@H](C)OC)C(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N(CCC3)C(=O)[C@H](NC(=O)OC)C=3C=CC=CC=3)=CC=2)N1 LRJIODVRAPCLKX-FWTWSYJPSA-N 0.000 description 1
- HATMSDOEOSQUMN-ZBQZKQBYSA-N methyl {(1r)-2-[(2s,4s)-2-(9-{2-[(2s,4s)-1-{(2s)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(trifluoromethyl)pyrrolidin-2-yl]-1h-imidazol-5-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-ph Chemical compound C1([C@@H](NC(=O)OC)C(=O)N2[C@@H](C[C@@H](C2)COC)C=2NC3=C(C4=CC5=C(C6=CC=C(C=C6CO5)C=5NC(=NC=5)[C@H]5N(C[C@H](C5)C(F)(F)F)C(=O)[C@@H](NC(=O)OC)C(C)C)C=C4C=C3)N=2)=CC=CC=C1 HATMSDOEOSQUMN-ZBQZKQBYSA-N 0.000 description 1
- ROPGIFQVPODFQL-YDDOYHJCSA-N methyl {(1r)-2-[(2s,4s)-2-(9-{2-[(2s,5s)-1-{(2s,3s)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-5-methylpyrrolidin-2-yl]-1h-imidazol-5-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenyleth Chemical compound COC(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](C)CC[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N(C[C@@H](COC)C3)C(=O)[C@H](NC(=O)OC)C=3C=CC=CC=3)=CC=2)N1 ROPGIFQVPODFQL-YDDOYHJCSA-N 0.000 description 1
- LIIRDVGFTREQMZ-VXGVJOLYSA-N methyl {(2s)-1-[(2s)-2-(5-{2-[(2s,4s)-1-[(2r)-2-amino-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1h-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate Chemical compound C1([C@@H](N)C(=O)N2[C@@H](C[C@@H](C2)COC)C=2NC3=C(C4=CC5=C(C6=CC=C(C=C6CO5)C=5NC(=NC=5)[C@H]5N(CCC5)C(=O)[C@@H](NC(=O)OC)C(C)C)C=C4C=C3)N=2)=CC=CC=C1 LIIRDVGFTREQMZ-VXGVJOLYSA-N 0.000 description 1
- OYOYKGOPADEAFH-VXGVJOLYSA-N methyl {(2s)-1-[(2s)-2-(9-{2-[(2s,4s)-1-[(2r)-2-amino-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1h-imidazol-5-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate Chemical compound C1([C@@H](N)C(=O)N2[C@@H](C[C@@H](C2)COC)C=2NC(=CN=2)C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)=CC=CC=C1 OYOYKGOPADEAFH-VXGVJOLYSA-N 0.000 description 1
- LKJQZTMAZIZPSB-LBJGZVHDSA-N methyl {(2s)-1-[(2s,4s)-2-(5-{2-[(2s)-1-{(2r)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1h-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N(CCC3)C(=O)[C@H](NC(=O)OC)C=3C=CC=CC=3)=CC=2)N1 LKJQZTMAZIZPSB-LBJGZVHDSA-N 0.000 description 1
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- UFFDRVRCFRQJKL-MYYSICFRSA-N tert-butyl (2s)-2-(5-{2-[(2s,4s)-1-[n-(methoxycarbonyl)-o-methyl-l-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1h-imidazol-2-yl)pyrrolidine-1-carboxylate Chemical compound COC(=O)N[C@@H]([C@@H](C)OC)C(=O)N1C[C@@H](COC)C[C@H]1C(N1)=NC(C2=C3)=C1C=CC2=CC1=C3OCC2=CC(C=3NC(=NC=3)[C@H]3N(CCC3)C(=O)OC(C)(C)C)=CC=C12 UFFDRVRCFRQJKL-MYYSICFRSA-N 0.000 description 1
- NQSKLMWKPPMQJN-QFIPXVFZSA-N tert-butyl (2s)-2-(9-chloro-3,4,5,7-tetrahydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(N1)=NC2=C1CCC1=C(OCC=3C4=CC=C(Cl)C=3)C4=CC=C21 NQSKLMWKPPMQJN-QFIPXVFZSA-N 0.000 description 1
- RGHVFSNDNVEKSR-DXCXKBQZSA-N tert-butyl (2s,4 s)-2-[5-(2-{(2s,4 s)-1-[n-(methoxycarbonyl)-l-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1h-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1C[C@@H](C)C[C@H]1C(N1)=NC(C2=C3)=C1C=CC2=CC1=C3OCC2=CC(C=3NC(=NC=3)[C@H]3N(C[C@@H](C)C3)C(=O)OC(C)(C)C)=CC=C12 RGHVFSNDNVEKSR-DXCXKBQZSA-N 0.000 description 1
- XKHZZLNMGWQCNJ-UWVGGRQHSA-N tert-butyl (2s,4s)-2-(1h-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](C)C[C@H]1C1=NC=CN1 XKHZZLNMGWQCNJ-UWVGGRQHSA-N 0.000 description 1
- ZOTSCPHMAPKCRS-WFJFNWOVSA-N tert-butyl (2s,4s)-2-(5-{2-[(2s,4s)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1h-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N(C[C@@H](COC)C3)C(=O)OC(C)(C)C)=CC=2)N1 ZOTSCPHMAPKCRS-WFJFNWOVSA-N 0.000 description 1
- LWRMUSROCRYDJN-CYFREDJKSA-N tert-butyl (2s,4s)-2-(9-chloro-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](OCC)C[C@H]1C1=NC2=CC=C(C=C3C4=CC=C(Cl)C=C4COC3=C3)C3=C2N1 LWRMUSROCRYDJN-CYFREDJKSA-N 0.000 description 1
- PCSQCDXLBXEGFM-CTYDWQPISA-N tert-butyl (2s,4s)-2-(9-{2-[(2s,4s)-1-[n-(methoxycarbonyl)-l-valyl]-4-(trifluoromethyl)pyrrolidin-2-yl]-1h-imidazol-5-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C(N1)=NC(C2=C3)=C1C=CC2=CC1=C3OCC2=CC(C=3NC(=NC=3)[C@H]3N(C[C@H](C3)C(F)(F)F)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=C12 PCSQCDXLBXEGFM-CTYDWQPISA-N 0.000 description 1
- XIBAKIQYNFINQU-GILITBBJSA-N tert-butyl (2s,4s)-2-[5-(2-{(2s)-1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1h-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6N=C(NC6=C5C=C4OC3)[C@H]3N(CCC3)C(=O)OCC=3C=CC=CC=3)=CC=2)N1 XIBAKIQYNFINQU-GILITBBJSA-N 0.000 description 1
- RCGAYQZCZRSTGT-BZLVROSRSA-N tert-butyl (2s,4s)-2-[5-(2-{(2s)-1-[n-(methoxycarbonyl)-l-valyl]pyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1h-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC=5CCC=6NC(=NC=6C=5C=C4OC3)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)N1 RCGAYQZCZRSTGT-BZLVROSRSA-N 0.000 description 1
- QKGGUNXXQZFEGI-FABOOFKTSA-N tert-butyl (2s,4s)-2-[5-(2-{(2s,4s)-1-[n-(methoxycarbonyl)-l-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1h-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N(C[C@@H](C)C3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)N1 QKGGUNXXQZFEGI-FABOOFKTSA-N 0.000 description 1
- RYDUAIDTLDYCSU-JQUGNBNZSA-N tert-butyl (2s,4s)-2-[5-(2-{(2s,5s)-1-[(benzyloxy)carbonyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1h-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N([C@@H](C)CC3)C(=O)OCC=3C=CC=CC=3)=CC=2)N1 RYDUAIDTLDYCSU-JQUGNBNZSA-N 0.000 description 1
- ZSRKEYPLXWCMMZ-MYYSICFRSA-N tert-butyl (2s,4s)-2-[9-(2-{(2s)-1-[n-(methoxycarbonyl)-o-methyl-l-threonyl]pyrrolidin-2-yl}-1h-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C(N1)=NC(C2=C3)=C1C=CC2=CC1=C3OCC2=CC(C=3NC(=NC=3)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)=CC=C12 ZSRKEYPLXWCMMZ-MYYSICFRSA-N 0.000 description 1
- SSGYJFSKVBKTAW-FABOOFKTSA-N tert-butyl (2s,4s)-2-[9-(2-{(2s,4s)-1-[n-(methoxycarbonyl)-l-valyl]-4-methylpyrrolidin-2-yl}-1h-imidazol-5-yl)-3,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C(N1)=NC(C2=C3)=C1C=CC2=CC1=C3OCC2=CC(C=3NC(=NC=3)[C@H]3N(C[C@@H](C)C3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=C12 SSGYJFSKVBKTAW-FABOOFKTSA-N 0.000 description 1
- FETOJCJHSSAFED-UWVGGRQHSA-N tert-butyl (2s,4s)-2-[methoxy(methyl)carbamoyl]-4-methylpyrrolidine-1-carboxylate Chemical compound CON(C)C(=O)[C@@H]1C[C@H](C)CN1C(=O)OC(C)(C)C FETOJCJHSSAFED-UWVGGRQHSA-N 0.000 description 1
- NHTWEENRSIZMME-IJWSHSPWSA-N tert-butyl (2s,4s)-4-(methoxymethyl)-2-(5-{2-[(2s)-pyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1h-imidazol-2-yl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6N=C(NC6=C5C=C4OC3)[C@H]3NCCC3)=CC=2)N1 NHTWEENRSIZMME-IJWSHSPWSA-N 0.000 description 1
- BMYFIQBMHHPFGB-NLTVXIILSA-N tert-butyl (2s,4s)-4-(methoxymethyl)-2-(5-{2-[(2s,5s)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1h-imidazol-2-yl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](COC)C[C@H]1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6N=C(NC6=C5C=C4OC3)[C@H]3N[C@@H](C)CC3)=CC=2)N1 BMYFIQBMHHPFGB-NLTVXIILSA-N 0.000 description 1
- PFNJNVYZGBQEAP-UWVGGRQHSA-N tert-butyl (2s,5s)-2-(1h-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1[C@@H](C)CC[C@H]1C1=NC=CN1 PFNJNVYZGBQEAP-UWVGGRQHSA-N 0.000 description 1
- HDAQUNKNGXXELE-QCRNIGCCSA-N tert-butyl (2s,5s)-2-(9-{2-[(2s,5s)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1h-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1[C@@H](C)CC[C@H]1C1=NC=C(C=2C=C3C(C4=CC=5CCC=6NC(=NC=6C=5C=C4OC3)[C@H]3N([C@@H](C)CC3)C(=O)OC(C)(C)C)=CC=2)N1 HDAQUNKNGXXELE-QCRNIGCCSA-N 0.000 description 1
- GKESNQIGBAUQBL-LPSDWCEBSA-N tert-butyl 2-[5-(2-{1-[n-(methoxycarbonyl)valyl]-4-(methoxymethyl)pyrrolidin-2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1h-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CC(COC)CC1C1=NC2=CC=C(C=C3C4=CC=C(C=C4COC3=C3)C=4NC(=NC=4)C4N(CC(C)C4)C(=O)OC(C)(C)C)C3=C2N1 GKESNQIGBAUQBL-LPSDWCEBSA-N 0.000 description 1
- UKOUKOXPIIEUQW-OGEBGHDTSA-N tert-butyl 2-[9-(2-{1-[n-(methoxycarbonyl)valyl]pyrrolidin-2-yl}-1h-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCCC1C1=NC=C(C=2C=C3C(C4=CC5=CC=C6N=C(NC6=C5C=C4OC3)C3N(CCC3)C(=O)OC(C)(C)C)=CC=2)N1 UKOUKOXPIIEUQW-OGEBGHDTSA-N 0.000 description 1
- ZQVFCJHLFVZZSE-UHFFFAOYSA-N tert-butyl 4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4',3': 6,7]-naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(COC)CC1C1=NC2=CC=C(C=C3C4=CC=C(C=C4COC3=C3)B4OC(C)(C)C(C)(C)O4)C3=C2N1 ZQVFCJHLFVZZSE-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- IYWRCNFZPNEADN-CXODAYGWSA-N tert-butyl n-[(2s)-1-[(2s,4r)-2-[[(1r,2s)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]carbamoyl]-4-(6-methoxyisoquinolin-1-yl)oxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC=1C2=CC=C(C=C2C=CN=1)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C IYWRCNFZPNEADN-CXODAYGWSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000004927 thianaphthalenyl group Chemical group S1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000583 toxicological profile Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000004306 triazinyl 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
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229950002810 valopicitabine Drugs 0.000 description 1
- 125000002114 valyl group Chemical group 0.000 description 1
- HPAPGONEMPZXMM-CMWVUSIZSA-N vaniprevir Chemical compound O=C([C@H]1C[C@@H]2OC(=O)N3CC=4C=CC=C(C=4C3)CCCCC(C)(C)COC(=O)N[C@@H](C(N1C2)=O)C(C)(C)C)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C HPAPGONEMPZXMM-CMWVUSIZSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- FHCUMDQMBHQXKK-CDIODLITSA-N velpatasvir Chemical compound C1([C@@H](NC(=O)OC)C(=O)N2[C@@H](C[C@@H](C2)COC)C=2NC(=CN=2)C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N([C@@H](C)CC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)=CC=CC=C1 FHCUMDQMBHQXKK-CDIODLITSA-N 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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| EP2640719B1 (en) | 2010-11-17 | 2017-05-10 | Gilead Pharmasset LLC | Antiviral compounds |
| MD4403C1 (ro) | 2011-11-16 | 2016-09-30 | Gilead Pharmasset Llc. | Compuşi antivirali în bază de dihidroxiizocromen-naftoimidazoli condensaţi |
| US20130309196A1 (en) | 2012-05-16 | 2013-11-21 | Gilead Sciences, Inc. | Antiviral compounds |
| US9233974B2 (en) * | 2012-12-21 | 2016-01-12 | Gilead Sciences, Inc. | Antiviral compounds |
| WO2015030854A1 (en) * | 2013-08-27 | 2015-03-05 | Gilead Pharmasset Llc | Solid dispersion formulation of an antiviral compound |
| SG11201600919UA (en) | 2013-08-27 | 2016-03-30 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
| TWI679203B (zh) * | 2014-06-11 | 2019-12-11 | 美商基利法瑪席特有限責任公司 | 製備抗病毒化合物之方法 |
| TWI721947B (zh) | 2014-06-11 | 2021-03-21 | 美商基利法瑪席特有限責任公司 | 抗病毒化合物的固態形式 |
| WO2016004166A1 (en) * | 2014-07-02 | 2016-01-07 | Xavier University Of Louisiana | Boron-based prodrug strategy for increased bioavailability and lower-dosage requirements for drug molecules containing at least one phenol (or aromatic hydroxyl) group |
| LT3236972T (lt) | 2014-12-26 | 2021-11-10 | Emory University | Antivirusiniai n4-hidroksicitidino dariniai |
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| WO2017191546A1 (en) * | 2016-05-05 | 2017-11-09 | Laurus Labs Private Ltd. | Process for the preparation of intermediates useful in the preparation of hepatitis c virus (hcv) inhibitors |
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| WO2018006811A1 (zh) * | 2016-07-08 | 2018-01-11 | 深圳市塔吉瑞生物医药有限公司 | 一种取代的咪唑基化合物及其药物组合物 |
| CN106220639A (zh) * | 2016-07-22 | 2016-12-14 | 上海众强药业有限公司 | 一种维帕他韦中间体新晶型 |
| CN110698489B (zh) * | 2016-11-30 | 2022-02-22 | 上海新礼泰药业有限公司 | 维帕他韦中间体、制备方法及应用 |
| CN111263586B (zh) | 2017-08-28 | 2021-12-03 | 英安塔制药有限公司 | 乙型肝炎抗病毒剂 |
| CN107501280A (zh) * | 2017-09-05 | 2017-12-22 | 安徽华昌高科药业有限公司 | 一种维帕他韦的合成方法 |
| HRP20241620T1 (hr) | 2017-12-07 | 2025-01-31 | Emory University | N4-hidroksi-citidin i derivati i antivirusna uporaba s njima povezana |
| CN113271946A (zh) | 2018-11-21 | 2021-08-17 | 英安塔制药有限公司 | 官能化杂环化合物作为抗病毒剂 |
| CN111018870B (zh) * | 2019-11-29 | 2021-07-23 | 南京正济医药研究有限公司 | 一种维帕他韦中间体的制备方法 |
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| WO2022040058A1 (en) * | 2020-08-18 | 2022-02-24 | Merck Sharp & Dohme Corp. | Cyclopentapyrrole orexin receptor agonists |
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Patent Citations (3)
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| WO2012068234A2 (en) | 2010-11-17 | 2012-05-24 | Gilead Sciences, Inc. | Antiviral compounds |
| KR101835474B1 (ko) | 2010-11-17 | 2018-03-08 | 길리애드 파마셋 엘엘씨 | 항바이러스 화합물 |
| KR101890400B1 (ko) * | 2011-11-16 | 2018-08-21 | 길리애드 파마셋 엘엘씨 | 항바이러스성 화합물로서의 축합된 이미다졸릴이미다졸 |
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