JP5645961B2 - ３，４，４ａ，１０ｂ−テトラヒドロ−１Ｈ−チオピラノ−［４，３−ｃ］イソキノリン誘導体 - Google Patents
３，４，４ａ，１０ｂ−テトラヒドロ−１Ｈ−チオピラノ−［４，３−ｃ］イソキノリン誘導体 Download PDFInfo
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- JP5645961B2 JP5645961B2 JP2012543701A JP2012543701A JP5645961B2 JP 5645961 B2 JP5645961 B2 JP 5645961B2 JP 2012543701 A JP2012543701 A JP 2012543701A JP 2012543701 A JP2012543701 A JP 2012543701A JP 5645961 B2 JP5645961 B2 JP 5645961B2
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- Prior art keywords
- methyl
- ethyl
- compound
- oxadiazol
- phenyl
- Prior art date
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- ZQCSTHXMOLTGJA-UHFFFAOYSA-N 3,4,4a,10b-tetrahydro-1h-thiopyrano[4,3-c]isoquinoline Chemical class N1=CC2=CC=CC=C2C2C1CCSC2 ZQCSTHXMOLTGJA-UHFFFAOYSA-N 0.000 title description 6
- -1 pyrazol-4-yl Chemical group 0.000 claims description 823
- 150000001875 compounds Chemical class 0.000 claims description 723
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 167
- 229910052717 sulfur Inorganic materials 0.000 claims description 121
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 95
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 94
- 239000008194 pharmaceutical composition Substances 0.000 claims description 51
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 49
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 48
- 238000011282 treatment Methods 0.000 claims description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 201000010099 disease Diseases 0.000 claims description 42
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 37
- 239000003814 drug Substances 0.000 claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 26
- 239000011737 fluorine Substances 0.000 claims description 26
- 238000004519 manufacturing process Methods 0.000 claims description 26
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 25
- 230000002265 prevention Effects 0.000 claims description 25
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 23
- 229940124597 therapeutic agent Drugs 0.000 claims description 21
- 230000001684 chronic effect Effects 0.000 claims description 20
- 125000001153 fluoro group Chemical group F* 0.000 claims description 17
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 15
- 239000002571 phosphodiesterase inhibitor Substances 0.000 claims description 15
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 208000023504 respiratory system disease Diseases 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 230000001154 acute effect Effects 0.000 claims description 11
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 claims description 11
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 11
- 208000006673 asthma Diseases 0.000 claims description 10
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 claims description 9
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 8
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 8
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 8
- 206010014561 Emphysema Diseases 0.000 claims description 7
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 7
- 239000000048 adrenergic agonist Substances 0.000 claims description 7
- 229940126157 adrenergic receptor agonist Drugs 0.000 claims description 7
- 206010006451 bronchitis Diseases 0.000 claims description 7
- 239000000812 cholinergic antagonist Substances 0.000 claims description 7
- 239000003246 corticosteroid Substances 0.000 claims description 7
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 7
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 6
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 6
- 229940118365 Endothelin receptor antagonist Drugs 0.000 claims description 6
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 6
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 6
- 239000003146 anticoagulant agent Substances 0.000 claims description 6
- 229940127219 anticoagulant drug Drugs 0.000 claims description 6
- 239000002876 beta blocker Substances 0.000 claims description 6
- 229940097320 beta blocking agent Drugs 0.000 claims description 6
- 239000000480 calcium channel blocker Substances 0.000 claims description 6
- 208000007451 chronic bronchitis Diseases 0.000 claims description 6
- 239000002934 diuretic Substances 0.000 claims description 6
- 229940030606 diuretics Drugs 0.000 claims description 6
- 239000003119 guanylate cyclase activator Substances 0.000 claims description 6
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 6
- 239000003580 lung surfactant Substances 0.000 claims description 6
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 229940124125 5 Lipoxygenase inhibitor Drugs 0.000 claims description 5
- 229930003316 Vitamin D Natural products 0.000 claims description 5
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 5
- 229940088710 antibiotic agent Drugs 0.000 claims description 5
- 230000006806 disease prevention Effects 0.000 claims description 5
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 239000000938 histamine H1 antagonist Substances 0.000 claims description 5
- 229960004617 sapropterin Drugs 0.000 claims description 5
- 239000011710 vitamin D Substances 0.000 claims description 5
- 235000019166 vitamin D Nutrition 0.000 claims description 5
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 5
- 229940046008 vitamin d Drugs 0.000 claims description 5
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 4
- 229960001334 corticosteroids Drugs 0.000 claims description 4
- 229940082657 digitalis glycosides Drugs 0.000 claims description 4
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 claims description 4
- 229960001123 epoprostenol Drugs 0.000 claims description 4
- 229960003073 pirfenidone Drugs 0.000 claims description 4
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims description 4
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 claims description 4
- 239000000021 stimulant Substances 0.000 claims description 4
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 claims description 3
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims description 3
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims description 3
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims description 3
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 3
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 3
- 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 3
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims description 2
- SUCDHPJUXCCMDN-UHFFFAOYSA-N 2-ethyl-1,3-oxazole Chemical group CCC1=NC=CO1 SUCDHPJUXCCMDN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 2
- 230000036039 immunity Effects 0.000 claims 2
- 125000004515 1,2,4-thiadiazol-3-yl group Chemical group S1N=C(N=C1)* 0.000 claims 1
- 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 528
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 186
- 239000007787 solid Substances 0.000 description 178
- 239000000243 solution Substances 0.000 description 169
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 132
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 105
- 238000006243 chemical reaction Methods 0.000 description 102
- 238000000034 method Methods 0.000 description 102
- 239000000203 mixture Substances 0.000 description 101
- 239000000741 silica gel Substances 0.000 description 100
- 229910002027 silica gel Inorganic materials 0.000 description 100
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 96
- 238000003818 flash chromatography Methods 0.000 description 95
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 92
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 87
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 69
- 238000010828 elution Methods 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- 239000011541 reaction mixture Substances 0.000 description 63
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 62
- 238000000746 purification Methods 0.000 description 61
- 239000002904 solvent Substances 0.000 description 61
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 58
- 239000012071 phase Substances 0.000 description 57
- 239000000725 suspension Substances 0.000 description 57
- UZKBSZSTDQSMDR-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-UHFFFAOYSA-N 0.000 description 53
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 49
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 229910000027 potassium carbonate Inorganic materials 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 42
- 230000002829 reductive effect Effects 0.000 description 42
- 239000003480 eluent Substances 0.000 description 40
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
- 238000002953 preparative HPLC Methods 0.000 description 31
- UXIZVOHYPKZDGA-QZTJIDSGSA-N 4-[(4ar,10br)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1h-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid Chemical compound N([C@@H]1CCSC[C@@H]1C=1C=C(C(=CC=11)OC)OCC)=C1C1=CC=C(C(O)=O)C=C1 UXIZVOHYPKZDGA-QZTJIDSGSA-N 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 30
- 238000003756 stirring Methods 0.000 description 29
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 28
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 11
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- AHIUOMGSUBQPIJ-QZTJIDSGSA-N 3-[(4ar,10br)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1h-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid Chemical compound N([C@@H]1CCSC[C@@H]1C=1C=C(C(=CC=11)OC)OCC)=C1C1=CC=CC(C(O)=O)=C1 AHIUOMGSUBQPIJ-QZTJIDSGSA-N 0.000 description 10
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- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 description 8
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- 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 8
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| MD20150071A2 (ro) | 2013-02-19 | 2016-02-29 | Pfizer Inc. | Compuşi azabenzimidazolici ca inhibitori ai PDE4 izoenzimelor pentru tratamentul tulburărilor SNC şi altor afecţiuni |
| WO2016012896A1 (en) | 2014-07-24 | 2016-01-28 | Pfizer Inc. | Pyrazolopyrimidine compounds |
| EA031201B1 (ru) | 2014-08-06 | 2018-11-30 | Пфайзер Инк. | Соединения имидазопиридазина |
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| US12383547B2 (en) | 2020-07-01 | 2025-08-12 | Vanderbilt University | Methods of treatment for a kidney disease |
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| DE602005027866D1 (de) * | 2004-09-08 | 2011-06-16 | Nycomed Gmbh | 3-oxa-10-aza-phenanthrene als pde4- oder pde3/4-inhibitoren |
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2012
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