KR20150097660A - Cftr 채널을 억제하기 위한 트리시클릭 화합물 - Google Patents

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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

2012-12-19

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Withdrawn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
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• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
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• 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
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• 239000003921 oil Substances 0.000 description 17
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• 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
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• 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
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