JP2009502845A

JP2009502845A - Ｃ型肝炎ウイルスの大環状インヒビター

Ｃ型肝炎ウイルスの大環状インヒビター Download PDF

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Publication number: JP2009502845A
Authority: JP; Japan
Prior art keywords: alkyl; formula; compound; compounds; mmol
Prior art date: 2005-07-29
Legal status : Pending

Application number

JP2008523260A

Other languages

English (en)

Japanese (ja)

Other versions

JP2009502845A5 (https=

Inventor

ホルスト・ヴェーリング

ベルティル・サムエルソン

Current Assignee

Medivir AB

Original Assignee

Medivir AB

Priority date

2005-07-29

Filing date

2006-07-28

Publication date

2009-01-29

2006-07-28 Application filed by Medivir AB filed Critical Medivir AB

2009-01-29 Publication of JP2009502845A publication Critical patent/JP2009502845A/ja

2009-09-10 Publication of JP2009502845A5 publication Critical patent/JP2009502845A5/ja

Status Pending legal-status Critical Current

Links

241000711549 Hepacivirus C Species 0.000 title description 61
239000003112 inhibitor Substances 0.000 title description 8
125000000217 alkyl group Chemical group 0.000 claims abstract description 118
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 112
239000001257 hydrogen Substances 0.000 claims abstract description 104
125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 83
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 39
150000003839 salts Chemical class 0.000 claims abstract description 34
229920006395 saturated elastomer Polymers 0.000 claims abstract description 28
229910052799 carbon Inorganic materials 0.000 claims abstract description 25
229910003827 NRaRb Inorganic materials 0.000 claims abstract description 23
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 14
150000001204 N-oxides Chemical class 0.000 claims abstract description 13
125000004452 carbocyclyl group Chemical group 0.000 claims abstract description 10
230000002401 inhibitory effect Effects 0.000 claims abstract description 8
NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 5
101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 claims abstract description 3
150000001875 compounds Chemical class 0.000 claims description 427
-1 nitro, hydroxy, mercapto Chemical class 0.000 claims description 230
238000006243 chemical reaction Methods 0.000 claims description 91
238000000034 method Methods 0.000 claims description 73
125000005843 halogen group Chemical group 0.000 claims description 71
125000003118 aryl group Chemical group 0.000 claims description 67
125000003545 alkoxy group Chemical group 0.000 claims description 59
125000001424 substituent group Chemical group 0.000 claims description 52
125000002757 morpholinyl group Chemical group 0.000 claims description 47
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
239000002253 acid Substances 0.000 claims description 43
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
125000004193 piperazinyl group Chemical group 0.000 claims description 38
125000003636 chemical group Chemical group 0.000 claims description 34
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 32
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 29
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 29
239000003814 drug Substances 0.000 claims description 27
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 27
125000001153 fluoro group Chemical group F* 0.000 claims description 26
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
125000000753 cycloalkyl group Chemical group 0.000 claims description 25
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 25
125000001246 bromo group Chemical group Br* 0.000 claims description 23
229940079593 drug Drugs 0.000 claims description 22
229910052757 nitrogen Inorganic materials 0.000 claims description 20
125000004076 pyridyl group Chemical group 0.000 claims description 20
229910052701 rubidium Inorganic materials 0.000 claims description 20
125000003226 pyrazolyl group Chemical group 0.000 claims description 18
230000000694 effects Effects 0.000 claims description 17
125000000335 thiazolyl group Chemical group 0.000 claims description 17
125000001309 chloro group Chemical group Cl* 0.000 claims description 16
239000003795 chemical substances by application Substances 0.000 claims description 15
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 13
238000006751 Mitsunobu reaction Methods 0.000 claims description 13
125000004122 cyclic group Chemical group 0.000 claims description 12
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
238000004519 manufacturing process Methods 0.000 claims description 12
238000005865 alkene metathesis reaction Methods 0.000 claims description 10
150000002678 macrocyclic compounds Chemical class 0.000 claims description 10
125000004043 oxo group Chemical group O=* 0.000 claims description 10
239000008194 pharmaceutical composition Substances 0.000 claims description 10
230000009467 reduction Effects 0.000 claims description 10
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
125000004093 cyano group Chemical group *C#N 0.000 claims description 8
125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 8
241001465754 Metazoa Species 0.000 claims description 6
230000000840 anti-viral effect Effects 0.000 claims description 6
125000004802 cyanophenyl group Chemical group 0.000 claims description 6
125000005059 halophenyl group Chemical group 0.000 claims description 6
125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims description 6
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
125000006383 alkylpyridyl group Chemical group 0.000 claims description 5
125000005842 heteroatom Chemical group 0.000 claims description 5
229910052717 sulfur Inorganic materials 0.000 claims description 5
KWEDUNSJJZVRKR-UHFFFAOYSA-N carbononitridic azide Chemical compound [N-]=[N+]=NC#N KWEDUNSJJZVRKR-UHFFFAOYSA-N 0.000 claims description 4
125000004254 isoquinolin-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C2C(*)=N1 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 claims description 4
241000124008 Mammalia Species 0.000 claims description 3
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
230000008569 process Effects 0.000 claims description 3
125000006413 ring segment Chemical group 0.000 claims description 3
238000006254 arylation reaction Methods 0.000 claims description 2
125000001188 haloalkyl group Chemical group 0.000 claims description 2
230000036961 partial effect Effects 0.000 claims description 2
229910052705 radium Inorganic materials 0.000 claims description 2
229910052727 yttrium Inorganic materials 0.000 claims description 2
QECVIPBZOPUTRD-UHFFFAOYSA-N N=S(=O)=O Chemical compound N=S(=O)=O QECVIPBZOPUTRD-UHFFFAOYSA-N 0.000 claims 2
108010022999 Serine Proteases Proteins 0.000 abstract description 2
102000012479 Serine Proteases Human genes 0.000 abstract description 2
206010054261 Flavivirus infection Diseases 0.000 abstract 1
125000005750 substituted cyclic group Chemical group 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 151
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
239000000203 mixture Substances 0.000 description 113
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 108
239000000243 solution Substances 0.000 description 107
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 54
239000002904 solvent Substances 0.000 description 53
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
125000003386 piperidinyl group Chemical group 0.000 description 46
239000002585 base Substances 0.000 description 45
235000019439 ethyl acetate Nutrition 0.000 description 44
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 40
238000011282 treatment Methods 0.000 description 33
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 32
239000000047 product Substances 0.000 description 32
230000002829 reductive effect Effects 0.000 description 32
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 30
238000005859 coupling reaction Methods 0.000 description 30
125000002887 hydroxy group Chemical group [H]O* 0.000 description 30
239000011541 reaction mixture Substances 0.000 description 30
150000001412 amines Chemical class 0.000 description 29
238000010168 coupling process Methods 0.000 description 29
239000012074 organic phase Substances 0.000 description 29
230000008878 coupling Effects 0.000 description 28
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 28
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
230000015572 biosynthetic process Effects 0.000 description 25
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
238000003818 flash chromatography Methods 0.000 description 24
239000007787 solid Substances 0.000 description 24
125000004568 thiomorpholinyl group Chemical group 0.000 description 24
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 22
239000012267 brine Substances 0.000 description 22
150000002148 esters Chemical class 0.000 description 22
239000000543 intermediate Substances 0.000 description 22
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
239000007821 HATU Substances 0.000 description 21
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
238000003786 synthesis reaction Methods 0.000 description 20
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 18
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
238000002360 preparation method Methods 0.000 description 18
238000000746 purification Methods 0.000 description 18
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 18
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
238000003756 stirring Methods 0.000 description 17
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
0 Cc1c(ccc(*)c2*)c2cc(C2N=C(*)S=C2)n1 Chemical compound Cc1c(ccc(*)c2*)c2cc(C2N=C(*)S=C2)n1 0.000 description 16
AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 16
239000003921 oil Substances 0.000 description 16
150000001408 amides Chemical class 0.000 description 15
125000003277 amino group Chemical class 0.000 description 15
239000007822 coupling agent Substances 0.000 description 15
239000000651 prodrug Substances 0.000 description 15
229940002612 prodrug Drugs 0.000 description 15
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 15
XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 15
125000004169 (C1-C6) alkyl group Chemical group 0.000 description 14
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 14
GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 14
208000015181 infectious disease Diseases 0.000 description 14
238000005160 1H NMR spectroscopy Methods 0.000 description 13
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
150000001721 carbon Chemical group 0.000 description 13
210000004027 cell Anatomy 0.000 description 13
238000005897 peptide coupling reaction Methods 0.000 description 13
239000000725 suspension Substances 0.000 description 13
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
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 12
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
238000004128 high performance liquid chromatography Methods 0.000 description 12
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 12
229910052751 metal Inorganic materials 0.000 description 12
239000002184 metal Chemical class 0.000 description 12
125000002950 monocyclic group Chemical group 0.000 description 12
JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 12
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 12
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 11
150000001413 amino acids Chemical class 0.000 description 11
239000003153 chemical reaction reagent Substances 0.000 description 11
239000000377 silicon dioxide Substances 0.000 description 11
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 10
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
229940024606 amino acid Drugs 0.000 description 10
150000002429 hydrazines Chemical class 0.000 description 10
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
108091032973 (ribonucleotides)n+m Proteins 0.000 description 9
JZVUAOCDNFNSGQ-UHFFFAOYSA-N 7-methoxy-2-phenyl-1h-quinolin-4-one Chemical compound N=1C2=CC(OC)=CC=C2C(O)=CC=1C1=CC=CC=C1 JZVUAOCDNFNSGQ-UHFFFAOYSA-N 0.000 description 9
102000006992 Interferon-alpha Human genes 0.000 description 9
108010047761 Interferon-alpha Proteins 0.000 description 9
125000002619 bicyclic group Chemical group 0.000 description 9
239000012043 crude product Substances 0.000 description 9
239000013078 crystal Substances 0.000 description 9
125000001072 heteroaryl group Chemical group 0.000 description 9
125000006239 protecting group Chemical group 0.000 description 9
238000006722 reduction reaction Methods 0.000 description 9
230000010076 replication Effects 0.000 description 9
238000010898 silica gel chromatography Methods 0.000 description 9
NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 9
UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 9
ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 description 8
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
150000007513 acids Chemical class 0.000 description 8
125000003282 alkyl amino group Chemical group 0.000 description 8
238000003556 assay Methods 0.000 description 8
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
239000003054 catalyst Substances 0.000 description 8
125000006841 cyclic skeleton Chemical group 0.000 description 8
150000004820 halides Chemical class 0.000 description 8
238000001727 in vivo Methods 0.000 description 8
125000002971 oxazolyl group Chemical group 0.000 description 8
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 8
239000002244 precipitate Substances 0.000 description 8
VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 8
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 8
229910052938 sodium sulfate Inorganic materials 0.000 description 8
235000011152 sodium sulphate Nutrition 0.000 description 8
239000007858 starting material Substances 0.000 description 8
PAKOPSLJHAKLPX-JLHYYAGUSA-N tert-butyl n-[(e)-hept-6-enylideneamino]carbamate Chemical compound CC(C)(C)OC(=O)N\N=C\CCCCC=C PAKOPSLJHAKLPX-JLHYYAGUSA-N 0.000 description 8
JKZGKJJRHXYLRI-UHFFFAOYSA-N 1-tert-butyl-3-propan-2-ylthiourea Chemical compound CC(C)NC(=S)NC(C)(C)C JKZGKJJRHXYLRI-UHFFFAOYSA-N 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 7
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
239000005089 Luciferase Substances 0.000 description 7
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 7
208000036142 Viral infection Diseases 0.000 description 7
241000700605 Viruses Species 0.000 description 7
125000004457 alkyl amino carbonyl group Chemical group 0.000 description 7
150000001540 azides Chemical class 0.000 description 7
235000013877 carbamide Nutrition 0.000 description 7
125000002837 carbocyclic group Chemical group 0.000 description 7
238000002648 combination therapy Methods 0.000 description 7
239000003937 drug carrier Substances 0.000 description 7
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 7
239000000843 powder Substances 0.000 description 7
239000002243 precursor Substances 0.000 description 7
125000003831 tetrazolyl group Chemical group 0.000 description 7
230000009385 viral infection Effects 0.000 description 7
108060001084 Luciferase Proteins 0.000 description 6
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
150000001299 aldehydes Chemical class 0.000 description 6
239000004202 carbamide Substances 0.000 description 6
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
239000002552 dosage form Substances 0.000 description 6
NBJXCTLFPNBZSG-UHFFFAOYSA-N ethyl 1-amino-2-ethenylcyclopropane-1-carboxylate Chemical compound CCOC(=O)C1(N)CC1C=C NBJXCTLFPNBZSG-UHFFFAOYSA-N 0.000 description 6
238000001914 filtration Methods 0.000 description 6
239000012634 fragment Substances 0.000 description 6
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 6
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