KR20150097660A - Cftr 채널을 억제하기 위한 트리시클릭 화합물 - Google Patents
Cftr 채널을 억제하기 위한 트리시클릭 화합물 Download PDFInfo
- Publication number
- KR20150097660A KR20150097660A KR1020157019061A KR20157019061A KR20150097660A KR 20150097660 A KR20150097660 A KR 20150097660A KR 1020157019061 A KR1020157019061 A KR 1020157019061A KR 20157019061 A KR20157019061 A KR 20157019061A KR 20150097660 A KR20150097660 A KR 20150097660A
- Authority
- KR
- South Korea
- Prior art keywords
- dione
- pyrimido
- pyrrolo
- dimethyl
- alkyl
- 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.)
- Withdrawn
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 350
- 230000002401 inhibitory effect Effects 0.000 title description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 57
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- -1 amino - Chemical class 0.000 claims description 624
- 238000000034 method Methods 0.000 claims description 277
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 108
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 81
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 73
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 68
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 67
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 206010012735 Diarrhoea Diseases 0.000 claims description 30
- 230000015572 biosynthetic process Effects 0.000 claims description 28
- 201000010099 disease Diseases 0.000 claims description 28
- 238000003786 synthesis reaction Methods 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 208000030761 polycystic kidney disease Diseases 0.000 claims description 18
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 16
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4-methylthiazole Chemical compound CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- VFJLUGDGPPHZSJ-UHFFFAOYSA-N 3-[1,3,8,8-tetramethyl-9-(4-methyl-1,3-thiazol-2-yl)-2,4-dioxo-7,9-dihydropyrimido[4,5-a]pyrrolizin-5-yl]benzonitrile Chemical compound CC1=CSC(C2C(CN3C2=C2C(C(N(C)C(=O)N2C)=O)=C3C=2C=C(C=CC=2)C#N)(C)C)=N1 VFJLUGDGPPHZSJ-UHFFFAOYSA-N 0.000 claims description 6
- RLKFROFNVRRLFT-UHFFFAOYSA-N 5-(3-fluorophenyl)-1,3,8,8-tetramethyl-9-(4-methyl-1,3-thiazol-2-yl)-7,9-dihydropyrimido[4,5-a]pyrrolizine-2,4-dione Chemical compound CC1=CSC(C2C(CN3C2=C2C(C(N(C)C(=O)N2C)=O)=C3C=2C=C(F)C=CC=2)(C)C)=N1 RLKFROFNVRRLFT-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 claims description 6
- CXLLNQHZWOYOAT-UHFFFAOYSA-N 3-[1,3-dimethyl-10-(4-methyl-1,3-thiazol-2-yl)-2,4-dioxo-7,8,9,10-tetrahydropyrimido[4,5-a]indolizin-5-yl]benzonitrile Chemical compound CC1=CSC(C2C=3N(C(=C4C(=O)N(C)C(=O)N(C)C4=3)C=3C=C(C=CC=3)C#N)CCC2)=N1 CXLLNQHZWOYOAT-UHFFFAOYSA-N 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- XTAUFYCLOKAISI-UHFFFAOYSA-N 1,2-dihydroazepine-5,7-dione Chemical compound O=C1CC(=O)C=CCN1 XTAUFYCLOKAISI-UHFFFAOYSA-N 0.000 claims description 4
- HMVYYTRDXNKRBQ-UHFFFAOYSA-N 1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC=N1 HMVYYTRDXNKRBQ-UHFFFAOYSA-N 0.000 claims description 4
- QMJHFPIQCRMUCS-UHFFFAOYSA-N 3-[10-(4-chloro-1,3-thiazol-2-yl)-1,3-dimethyl-2,4-dioxo-7,8,9,10-tetrahydropyrimido[4,5-a]indolizin-5-yl]benzonitrile Chemical compound C=12C(=O)N(C)C(=O)N(C)C2=C2C(C=3SC=C(Cl)N=3)CCCN2C=1C1=CC=CC(C#N)=C1 QMJHFPIQCRMUCS-UHFFFAOYSA-N 0.000 claims description 4
- WJPLFRUFLYZVBJ-UHFFFAOYSA-N 3-[9-(4-chloro-1,3-thiazol-2-yl)-1,3-dimethyl-2,4-dioxo-8,9-dihydro-7h-pyrimido[4,5-a]pyrrolizin-5-yl]benzonitrile Chemical compound C=12C(=O)N(C)C(=O)N(C)C2=C2C(C=3SC=C(Cl)N=3)CCN2C=1C1=CC=CC(C#N)=C1 WJPLFRUFLYZVBJ-UHFFFAOYSA-N 0.000 claims description 4
- PCJWLAMUOWWJEG-UHFFFAOYSA-N 3-[9-(4-chloro-1,3-thiazol-2-yl)-7-(hydroxymethyl)-1,3-dimethyl-2,4-dioxo-8,9-dihydro-7h-pyrimido[4,5-a]pyrrolizin-5-yl]benzonitrile Chemical compound C=12C(=O)N(C)C(=O)N(C)C2=C2C(C=3SC=C(Cl)N=3)CC(CO)N2C=1C1=CC=CC(C#N)=C1 PCJWLAMUOWWJEG-UHFFFAOYSA-N 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- ROUYJPQSSQQAHB-UHFFFAOYSA-N 3-(1,3-dimethyl-2,4-dioxo-5-phenyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizin-10-yl)benzonitrile Chemical compound C=12C(=O)N(C)C(=O)N(C)C2=C2C(C=3C=C(C=CC=3)C#N)CCCN2C=1C1=CC=CC=C1 ROUYJPQSSQQAHB-UHFFFAOYSA-N 0.000 claims description 3
- HBEZYXMZZHFYLF-UHFFFAOYSA-N 5-(3-fluorophenyl)-1,3,9-trimethyl-10-(4-methyl-1,3-thiazol-2-yl)-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4-dione Chemical compound CC1CCN(C(=C2C(=O)N(C)C(=O)N(C)C2=2)C=3C=C(F)C=CC=3)C=2C1C1=NC(C)=CS1 HBEZYXMZZHFYLF-UHFFFAOYSA-N 0.000 claims description 3
- GQMRGCWPYIYAMA-UHFFFAOYSA-N 5-(3-fluorophenyl)-1,3-dimethyl-10-(5-methylfuran-2-yl)-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4-dione Chemical compound O1C(C)=CC=C1C1C2=C(N(C)C(=O)N(C)C3=O)C3=C(C=3C=C(F)C=CC=3)N2CCC1 GQMRGCWPYIYAMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 3
- VLWJRCZZLLUQHN-UHFFFAOYSA-N CN1N=C(C=C1)N1C(NC(C=2C1=C1CCCCN1C2)=O)=O Chemical compound CN1N=C(C=C1)N1C(NC(C=2C1=C1CCCCN1C2)=O)=O VLWJRCZZLLUQHN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 3
- 125000006536 (C1-C2)alkoxy group Chemical group 0.000 claims description 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- QENGPZGAWFQWCZ-UHFFFAOYSA-N 3-Methylthiophene Chemical compound CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 claims description 2
- PPVOWBPTODMVJM-UHFFFAOYSA-N 3-[10-(4-chloro-1,3-thiazol-2-yl)-8-(hydroxymethyl)-1,3-dimethyl-2,4-dioxo-8,10-dihydro-7h-pyrimido[1,2]pyrrolo[4,5-a][1,4]thiazin-5-yl]benzonitrile Chemical compound C=12C(=O)N(C)C(=O)N(C)C2=C2C(C=3SC=C(Cl)N=3)SC(CO)CN2C=1C1=CC=CC(C#N)=C1 PPVOWBPTODMVJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000556 agonist Substances 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 102000008371 intracellularly ATP-gated chloride channel activity proteins Human genes 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 239000013543 active substance Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 315
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 277
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 241
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 229
- 239000000203 mixture Substances 0.000 description 226
- 239000000543 intermediate Substances 0.000 description 210
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 159
- 239000000243 solution Substances 0.000 description 153
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 137
- 235000019439 ethyl acetate Nutrition 0.000 description 128
- 238000006243 chemical reaction Methods 0.000 description 96
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 95
- 239000012071 phase Substances 0.000 description 92
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 87
- 238000004808 supercritical fluid chromatography Methods 0.000 description 78
- 238000004587 chromatography analysis Methods 0.000 description 77
- 239000000377 silicon dioxide Substances 0.000 description 76
- 229910052796 boron Inorganic materials 0.000 description 74
- 238000000746 purification Methods 0.000 description 71
- 238000001514 detection method Methods 0.000 description 67
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 62
- 235000011089 carbon dioxide Nutrition 0.000 description 62
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 61
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- 239000011541 reaction mixture Substances 0.000 description 57
- 238000000926 separation method Methods 0.000 description 52
- 239000000284 extract Substances 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
- 230000002209 hydrophobic effect Effects 0.000 description 49
- 229920006395 saturated elastomer Polymers 0.000 description 46
- 239000002904 solvent Substances 0.000 description 43
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 43
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 41
- 238000002360 preparation method Methods 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 239000002585 base Substances 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 36
- 239000007787 solid Substances 0.000 description 36
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 35
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 description 31
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 30
- 239000012267 brine Substances 0.000 description 30
- 230000002829 reductive effect Effects 0.000 description 30
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 29
- 235000019341 magnesium sulphate Nutrition 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 26
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 25
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- 239000000460 chlorine Substances 0.000 description 20
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 20
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 19
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- 229940124597 therapeutic agent Drugs 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 239000007858 starting material Substances 0.000 description 15
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- 208000002551 irritable bowel syndrome Diseases 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 230000029087 digestion Effects 0.000 description 13
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-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 12
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 229910052805 deuterium Inorganic materials 0.000 description 12
- 235000019253 formic acid Nutrition 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 239000012279 sodium borohydride Substances 0.000 description 12
- 229910000033 sodium borohydride Inorganic materials 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- 239000003643 water by type Substances 0.000 description 12
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 239000013058 crude material Substances 0.000 description 11
- 239000003480 eluent Substances 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 229910052763 palladium Inorganic materials 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 11
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
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- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
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- CDMIYIVDILNBIJ-UHFFFAOYSA-N triazinane-4,5,6-trithione Chemical compound SC1=NN=NC(S)=C1S CDMIYIVDILNBIJ-UHFFFAOYSA-N 0.000 description 1
- YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 1
- OTMIHZHASCPXNT-UHFFFAOYSA-N tributyl-(5-methylfuran-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=C(C)O1 OTMIHZHASCPXNT-UHFFFAOYSA-N 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- JQZIKLPHXXBMCA-UHFFFAOYSA-N triphenylmethanethiol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(S)C1=CC=CC=C1 JQZIKLPHXXBMCA-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
- UOCLRXFKRLRMKV-UHFFFAOYSA-N trolnitrate phosphate Chemical class OP(O)(O)=O.OP(O)(O)=O.[O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O UOCLRXFKRLRMKV-UHFFFAOYSA-N 0.000 description 1
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- 238000009736 wetting Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
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| US201261739335P | 2012-12-19 | 2012-12-19 | |
| US61/739,335 | 2012-12-19 | ||
| US201361906141P | 2013-11-19 | 2013-11-19 | |
| US61/906,141 | 2013-11-19 | ||
| PCT/IB2013/061043 WO2014097148A1 (en) | 2012-12-19 | 2013-12-17 | Tricyclic compounds for inhibiting the cftr channel |
Publications (1)
| Publication Number | Publication Date |
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| KR20150097660A true KR20150097660A (ko) | 2015-08-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1020157019061A Withdrawn KR20150097660A (ko) | 2012-12-19 | 2013-12-17 | Cftr 채널을 억제하기 위한 트리시클릭 화합물 |
Country Status (25)
| Country | Link |
|---|---|
| US (2) | US20140171417A1 (enExample) |
| EP (1) | EP2935278B1 (enExample) |
| JP (1) | JP6284546B2 (enExample) |
| KR (1) | KR20150097660A (enExample) |
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| AR (1) | AR094122A1 (enExample) |
| AU (1) | AU2013365739A1 (enExample) |
| BR (1) | BR112015014292A2 (enExample) |
| CA (1) | CA2895660A1 (enExample) |
| CL (1) | CL2015001730A1 (enExample) |
| CR (1) | CR20150325A (enExample) |
| CU (1) | CU20150066A7 (enExample) |
| EA (1) | EA201591177A1 (enExample) |
| ES (1) | ES2628369T3 (enExample) |
| HK (1) | HK1209741A1 (enExample) |
| IL (1) | IL239389A0 (enExample) |
| MX (1) | MX2015007939A (enExample) |
| PE (1) | PE20151055A1 (enExample) |
| PH (1) | PH12015501386A1 (enExample) |
| SG (1) | SG11201504594QA (enExample) |
| TN (1) | TN2015000279A1 (enExample) |
| TW (1) | TW201429974A (enExample) |
| UY (1) | UY35211A (enExample) |
| WO (1) | WO2014097148A1 (enExample) |
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| EP2755652B1 (en) | 2011-09-16 | 2021-06-02 | Novartis AG | N-substituted heterocyclyl carboxamides |
| CN105143230B (zh) | 2012-12-19 | 2017-06-09 | 诺华股份有限公司 | 用于抑制cftr通道的三环化合物 |
| EA201591175A1 (ru) * | 2012-12-19 | 2015-11-30 | Новартис Аг | Трициклические соединения в качестве ингибиторов cftr |
| TWI686429B (zh) | 2014-09-19 | 2020-03-01 | 美商摩曼帝夫特性材料公司 | 用於經控制之矽氧烷交聯的鉑(ii)二烯錯合物 |
| HUE054399T2 (hu) * | 2015-04-23 | 2021-09-28 | Trevi Therapeutics Inc | Vegyületek viszketéses állapotok kezelésére |
| CN106478558B (zh) * | 2016-10-17 | 2019-03-29 | 天津雅奥科技发展有限公司 | 一种4-羟甲基-二氢-呋喃-2(3h)-酮的合成方法 |
| EP3911649A1 (en) * | 2019-01-17 | 2021-11-24 | F. Hoffmann-La Roche AG | A process for the preparation of tetrahydropyridopyrimidines |
| JP7669295B2 (ja) * | 2019-06-12 | 2025-04-28 | ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア | 胆汁酸性下痢を治療する方法 |
| WO2022232634A1 (en) | 2021-04-29 | 2022-11-03 | Novartis Ag | Deubiquitinase-targeting chimeras and related methods |
| CN117654560B (zh) * | 2023-12-01 | 2024-06-04 | 安徽泽升科技股份有限公司 | 一种通过氧化氨基连续化制备硝基化合物的方法 |
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| JP2002255967A (ja) | 2001-02-27 | 2002-09-11 | Banyu Pharmaceut Co Ltd | イソインドール誘導体を有効成分とする糖尿病の治療剤、糖尿病の慢性合併症の予防剤又は肥満の治療剤。 |
| WO2004078163A2 (en) | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
| KR20090087487A (ko) | 2006-12-12 | 2009-08-17 | 쉐링 코포레이션 | 아스파르틸 프로테아제 억제제 |
| US20110015137A1 (en) * | 2007-07-05 | 2011-01-20 | Trustees Of Boston University | Reca inhibitors and their uses as microbial inhibitors or potentiators of antibiotic activity |
| US8642660B2 (en) | 2007-12-21 | 2014-02-04 | The University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
| WO2011019737A1 (en) * | 2009-08-10 | 2011-02-17 | The Regents Of The University Of California | Pyrimido-pyrrolo-quinoxalinedione inhibitors of cystic fibrosis transmembrane conductance regulator protein and uses therefor |
| WO2012166658A1 (en) * | 2011-05-27 | 2012-12-06 | The Regents Of The University Of California | Pyrimido-pyrrolo-oxazine-dione compound inhibitors of the cystic fibrosis transmembrane conductance regulator protein and uses therefor |
| CN105143230B (zh) | 2012-12-19 | 2017-06-09 | 诺华股份有限公司 | 用于抑制cftr通道的三环化合物 |
| EA201591175A1 (ru) * | 2012-12-19 | 2015-11-30 | Новартис Аг | Трициклические соединения в качестве ингибиторов cftr |
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2013
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- 2013-12-17 SG SG11201504594QA patent/SG11201504594QA/en unknown
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- 2013-12-17 JP JP2015548837A patent/JP6284546B2/ja not_active Expired - Fee Related
- 2013-12-17 HK HK15110599.7A patent/HK1209741A1/xx unknown
- 2013-12-17 AU AU2013365739A patent/AU2013365739A1/en not_active Abandoned
- 2013-12-17 US US14/109,922 patent/US20140171417A1/en not_active Abandoned
- 2013-12-17 ES ES13826625.9T patent/ES2628369T3/es active Active
- 2013-12-17 AP AP2015008539A patent/AP2015008539A0/xx unknown
- 2013-12-17 US US14/653,084 patent/US9359381B2/en active Active
- 2013-12-17 EA EA201591177A patent/EA201591177A1/ru unknown
- 2013-12-17 CA CA2895660A patent/CA2895660A1/en not_active Abandoned
- 2013-12-17 MX MX2015007939A patent/MX2015007939A/es unknown
- 2013-12-17 WO PCT/IB2013/061043 patent/WO2014097148A1/en not_active Ceased
- 2013-12-17 PE PE2015001056A patent/PE20151055A1/es not_active Application Discontinuation
- 2013-12-17 EP EP13826625.9A patent/EP2935278B1/en active Active
- 2013-12-17 KR KR1020157019061A patent/KR20150097660A/ko not_active Withdrawn
- 2013-12-18 TW TW102147023A patent/TW201429974A/zh unknown
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2015
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- 2015-06-16 TN TNP2015000279A patent/TN2015000279A1/fr unknown
- 2015-06-17 PH PH12015501386A patent/PH12015501386A1/en unknown
- 2015-06-18 CL CL2015001730A patent/CL2015001730A1/es unknown
- 2015-06-19 CU CUP2015000066A patent/CU20150066A7/es unknown
- 2015-06-19 CR CR20150325A patent/CR20150325A/es unknown
Also Published As
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|---|---|
| WO2014097148A1 (en) | 2014-06-26 |
| CN105143230B (zh) | 2017-06-09 |
| UY35211A (es) | 2014-07-31 |
| PH12015501386A1 (en) | 2015-09-02 |
| CR20150325A (es) | 2015-08-10 |
| IL239389A0 (en) | 2015-07-30 |
| CN105143230A (zh) | 2015-12-09 |
| SG11201504594QA (en) | 2015-07-30 |
| HK1209741A1 (en) | 2016-04-08 |
| EP2935278B1 (en) | 2017-03-15 |
| EA201591177A1 (ru) | 2015-11-30 |
| CU20150066A7 (es) | 2015-11-27 |
| JP6284546B2 (ja) | 2018-02-28 |
| ES2628369T3 (es) | 2017-08-02 |
| BR112015014292A2 (pt) | 2017-07-11 |
| AP2015008539A0 (en) | 2015-06-30 |
| WO2014097148A9 (en) | 2015-02-19 |
| PE20151055A1 (es) | 2015-08-05 |
| AU2013365739A1 (en) | 2015-07-09 |
| MX2015007939A (es) | 2016-03-11 |
| TN2015000279A1 (en) | 2016-10-03 |
| US20150336986A1 (en) | 2015-11-26 |
| CL2015001730A1 (es) | 2015-08-28 |
| JP2016509579A (ja) | 2016-03-31 |
| TW201429974A (zh) | 2014-08-01 |
| US9359381B2 (en) | 2016-06-07 |
| CA2895660A1 (en) | 2014-06-26 |
| AR094122A1 (es) | 2015-07-08 |
| US20140171417A1 (en) | 2014-06-19 |
| EP2935278A1 (en) | 2015-10-28 |
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