AU2010332955B8 - 3,4,4a,10b-tetrahydro-1H-thiopyrano-[4, 3-c] isoquinoline derivatives - Google Patents

Info

Publication number

AU2010332955B8

AU2010332955B8 AU2010332955A AU2010332955A AU2010332955B8 AU 2010332955 B8 AU2010332955 B8 AU 2010332955B8 AU 2010332955 A AU2010332955 A AU 2010332955A AU 2010332955 A AU2010332955 A AU 2010332955A AU 2010332955 B8 AU2010332955 B8 AU 2010332955B8

Authority

AU

Australia

Prior art keywords

methyl

ethyl

compound

oxadiazol

phenyl

Prior art date

2009-12-18

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.)

Ceased

Links

• Espacenet
• Global Dossier
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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
• 150000001875 compounds Chemical class 0.000 claims description 706
• -1 pyrazol-4-yl Chemical group 0.000 claims description 631
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 175
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 172
• 238000000034 method Methods 0.000 claims description 116
• 229910052717 sulfur Inorganic materials 0.000 claims description 65
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 55
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 52
• 201000010099 disease Diseases 0.000 claims description 47
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 38
• 238000011282 treatment Methods 0.000 claims description 38
• ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 30
• 239000008194 pharmaceutical composition Substances 0.000 claims description 30
• CIGMXKHMLLBHRM-UHFFFAOYSA-N 1-phenylthieno[3,2-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C=2SC=CC=2N1C1=CC=CC=C1 CIGMXKHMLLBHRM-UHFFFAOYSA-N 0.000 claims description 26
• 239000011737 fluorine Substances 0.000 claims description 26
• 229910052731 fluorine Inorganic materials 0.000 claims description 26
• 125000001153 fluoro group Chemical group F* 0.000 claims description 26
• 230000001684 chronic effect Effects 0.000 claims description 25
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 23
• 238000011321 prophylaxis Methods 0.000 claims description 23
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 23
• 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims description 18
• 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims description 18
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 16
• 230000001154 acute effect Effects 0.000 claims description 16
• 208000005069 pulmonary fibrosis Diseases 0.000 claims description 16
• 208000023504 respiratory system disease Diseases 0.000 claims description 14
• 238000004519 manufacturing process Methods 0.000 claims description 13
• 230000005764 inhibitory process Effects 0.000 claims description 11
• 208000006673 asthma Diseases 0.000 claims description 10
• 125000000623 heterocyclic group Chemical group 0.000 claims description 10
• 239000002571 phosphodiesterase inhibitor Substances 0.000 claims description 10
• 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 claims description 9
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 8
• 208000029523 Interstitial Lung disease Diseases 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 206010014561 Emphysema Diseases 0.000 claims description 7
• ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 claims description 7
• 206010006451 bronchitis Diseases 0.000 claims description 7
• 206010006458 Bronchitis chronic Diseases 0.000 claims description 6
• 208000007451 chronic bronchitis Diseases 0.000 claims description 6
• 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 6
• 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 6
• 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 claims description 5
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
• 229910052736 halogen Inorganic materials 0.000 claims description 5
• 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims description 4
• 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims description 4
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
• 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims description 3
• 125000004515 1,2,4-thiadiazol-3-yl group Chemical group S1N=C(N=C1)* 0.000 claims description 3
• 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 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
• 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=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
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 3
• 150000002617 leukotrienes Chemical class 0.000 claims description 3
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
• 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 3
• 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
• CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 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
• 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 2
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 22
• 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 8
• 239000003119 guanylate cyclase activator Substances 0.000 claims 6
• 229940044551 receptor antagonist Drugs 0.000 claims 5
• 239000002464 receptor antagonist Substances 0.000 claims 5
• 229940127291 Calcium channel antagonist Drugs 0.000 claims 4
• 229940118365 Endothelin receptor antagonist Drugs 0.000 claims 4
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims 4
• 102000003834 Histamine H1 Receptors Human genes 0.000 claims 4
• 108090000110 Histamine H1 Receptors Proteins 0.000 claims 4
• 239000000867 Lipoxygenase Inhibitor Substances 0.000 claims 4
• 229930003316 Vitamin D Natural products 0.000 claims 4
• 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 4
• 239000000556 agonist Substances 0.000 claims 4
• 239000003242 anti bacterial agent Substances 0.000 claims 4
• 229940088710 antibiotic agent Drugs 0.000 claims 4
• 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims 4
• 239000003146 anticoagulant agent Substances 0.000 claims 4
• 229940127219 anticoagulant drug Drugs 0.000 claims 4
• 239000002876 beta blocker Substances 0.000 claims 4
• 229940097320 beta blocking agent Drugs 0.000 claims 4
• 239000000480 calcium channel blocker Substances 0.000 claims 4
• 239000000812 cholinergic antagonist Substances 0.000 claims 4
• 239000003246 corticosteroid Substances 0.000 claims 4
• 229960001334 corticosteroids Drugs 0.000 claims 4
• 229940082657 digitalis glycosides Drugs 0.000 claims 4
• 239000002934 diuretic Substances 0.000 claims 4
• 229940030606 diuretics Drugs 0.000 claims 4
• 239000002308 endothelin receptor antagonist Substances 0.000 claims 4
• 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims 4
• 229960003444 immunosuppressant agent Drugs 0.000 claims 4
• 239000003018 immunosuppressive agent Substances 0.000 claims 4
• 239000003580 lung surfactant Substances 0.000 claims 4
• 229940066294 lung surfactant Drugs 0.000 claims 4
• 229960003073 pirfenidone Drugs 0.000 claims 4
• ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims 4
• 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 claims 4
• 229960004617 sapropterin Drugs 0.000 claims 4
• 229940124597 therapeutic agent Drugs 0.000 claims 4
• 235000019166 vitamin D Nutrition 0.000 claims 4
• 239000011710 vitamin D Substances 0.000 claims 4
• 150000003710 vitamin D derivatives Chemical class 0.000 claims 4
• 229940046008 vitamin d Drugs 0.000 claims 4
• 229940065725 leukotriene receptor antagonists for obstructive airway diseases Drugs 0.000 claims 3
• 239000003199 leukotriene receptor blocking agent Substances 0.000 claims 3
• 125000005843 halogen group Chemical group 0.000 claims 2
• 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims 2
• YVCCESYQJQHEIA-UHFFFAOYSA-N 1-[(2-ethyltetrazol-5-yl)methyl]-6-phenylthieno[3,2-d]pyrimidine-2,4-dione Chemical compound C(C)N1N=C(N=N1)CN1C(NC(C2=C1C=C(S2)C1=CC=CC=C1)=O)=O YVCCESYQJQHEIA-UHFFFAOYSA-N 0.000 claims 1
• 108010078321 Guanylate Cyclase Proteins 0.000 claims 1
• 102000014469 Guanylate cyclase Human genes 0.000 claims 1
• 239000012190 activator Substances 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 523
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 290
• 239000000243 solution Substances 0.000 description 204
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 198
• 239000007787 solid Substances 0.000 description 177
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 150
• 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 106
• 239000000741 silica gel Substances 0.000 description 99
• 229910002027 silica gel Inorganic materials 0.000 description 99
• 238000003818 flash chromatography Methods 0.000 description 91
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 90
• 239000000203 mixture Substances 0.000 description 89
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 85
• 238000006243 chemical reaction Methods 0.000 description 78
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 76
• 239000011541 reaction mixture Substances 0.000 description 64
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 59
• 239000012071 phase Substances 0.000 description 59
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 55
• 238000000746 purification Methods 0.000 description 54
• 239000002904 solvent Substances 0.000 description 54
• 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 52
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
• 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 50
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 50
• 239000000725 suspension Substances 0.000 description 50
• 229910000027 potassium carbonate Inorganic materials 0.000 description 45
• 229940093956 potassium carbonate Drugs 0.000 description 45
• 235000011181 potassium carbonates Nutrition 0.000 description 45
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 45
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 44
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
• 239000003480 eluent Substances 0.000 description 41
• 230000002829 reductive effect Effects 0.000 description 39
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
• BQWXYSKVNGRGHR-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-6-phenyl-1h-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)C(SC(=C2)C=3C=CC=CC=3)=C2NC1=O BQWXYSKVNGRGHR-UHFFFAOYSA-N 0.000 description 33
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• 238000002953 preparative HPLC Methods 0.000 description 30
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• 239000012044 organic layer Substances 0.000 description 26
• 238000003756 stirring Methods 0.000 description 26
• 239000012074 organic phase Substances 0.000 description 25
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
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• 238000002360 preparation method Methods 0.000 description 21
• 229920006395 saturated elastomer Polymers 0.000 description 21
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• 238000007792 addition Methods 0.000 description 19
• 239000007864 aqueous solution Substances 0.000 description 19
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• 235000011152 sodium sulphate Nutrition 0.000 description 19
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 18
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
• 235000017557 sodium bicarbonate Nutrition 0.000 description 17
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 17
• QAFVXBQPQCSSLI-UHFFFAOYSA-N 1h-thieno[3,2-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)NC2=C1SC=C2 QAFVXBQPQCSSLI-UHFFFAOYSA-N 0.000 description 16
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• 239000000463 material Substances 0.000 description 16
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• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 14
• 239000002253 acid Substances 0.000 description 14
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• 210000004072 lung Anatomy 0.000 description 8
• 239000012299 nitrogen atmosphere Substances 0.000 description 8
• 238000012746 preparative thin layer chromatography Methods 0.000 description 8
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• 238000003786 synthesis reaction Methods 0.000 description 8
• 238000004809 thin layer chromatography Methods 0.000 description 8
• 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
• NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 7
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• YPVGGQKNWAKOPX-UHFFFAOYSA-N Nifekalant hydrochloride Chemical compound Cl.O=C1N(C)C(=O)N(C)C(NCCN(CCO)CCCC=2C=CC(=CC=2)[N+]([O-])=O)=C1 YPVGGQKNWAKOPX-UHFFFAOYSA-N 0.000 description 7
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