JP2009515893A - アスパラギン酸プロテアーゼ抑制剤 - Google Patents
アスパラギン酸プロテアーゼ抑制剤 Download PDFInfo
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- JP2009515893A JP2009515893A JP2008540236A JP2008540236A JP2009515893A JP 2009515893 A JP2009515893 A JP 2009515893A JP 2008540236 A JP2008540236 A JP 2008540236A JP 2008540236 A JP2008540236 A JP 2008540236A JP 2009515893 A JP2009515893 A JP 2009515893A
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- Prior art keywords
- alkyl
- halo
- methyl
- cycloalkyl
- alkoxy
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- 239000003696 aspartic proteinase inhibitor Substances 0.000 title abstract description 78
- 229940092160 Aspartic protease inhibitor Drugs 0.000 title abstract description 49
- OVIFHFRAOKPVPC-UHFFFAOYSA-N aspartic protease inhibitor Natural products CC(N)C(=O)NCC(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(=O)N1CCCC1C(=O)N1C(C(=O)NC(CCC(O)=O)C(O)=O)CCC1 OVIFHFRAOKPVPC-UHFFFAOYSA-N 0.000 title abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 97
- 238000000034 method Methods 0.000 claims abstract description 46
- 108091005502 Aspartic proteases Proteins 0.000 claims abstract description 25
- 102000035101 Aspartic proteases Human genes 0.000 claims abstract description 25
- 230000001404 mediated effect Effects 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 230000003042 antagnostic effect Effects 0.000 claims abstract description 3
- -1 cyano , Hydroxyl Chemical group 0.000 claims description 273
- 239000000460 chlorine Substances 0.000 claims description 176
- 125000005843 halogen group Chemical group 0.000 claims description 161
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 144
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 103
- 150000001875 compounds Chemical class 0.000 claims description 94
- 102000007399 Nuclear hormone receptor Human genes 0.000 claims description 75
- 108020005497 Nuclear hormone receptor Proteins 0.000 claims description 75
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 229910052731 fluorine Inorganic materials 0.000 claims description 63
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 57
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 56
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 56
- 239000011737 fluorine Substances 0.000 claims description 55
- 125000003545 alkoxy group Chemical group 0.000 claims description 53
- 229910052801 chlorine Inorganic materials 0.000 claims description 50
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 48
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 48
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 47
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 35
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 30
- 229910052794 bromium Inorganic materials 0.000 claims description 30
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 30
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 28
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 28
- 101100079984 Caenorhabditis elegans nhr-9 gene Proteins 0.000 claims description 26
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 24
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 24
- 125000000304 alkynyl group Chemical group 0.000 claims description 24
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 claims description 14
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims description 14
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 14
- 239000003112 inhibitor Substances 0.000 claims description 14
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 208000035475 disorder Diseases 0.000 claims description 12
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 12
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 11
- 125000006715 (C1-C5) alkylthio group Chemical group 0.000 claims description 11
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 108090000783 Renin Proteins 0.000 claims description 9
- 102100028255 Renin Human genes 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 8
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 8
- 125000004450 alkenylene group Chemical group 0.000 claims description 8
- 125000004419 alkynylene group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 7
- 229940125364 angiotensin receptor blocker Drugs 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims description 6
- 108090000028 Neprilysin Proteins 0.000 claims description 6
- 102000003729 Neprilysin Human genes 0.000 claims description 6
- 239000002934 diuretic Substances 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 229940030606 diuretics Drugs 0.000 claims description 5
- 229940123338 Aldosterone synthase inhibitor Drugs 0.000 claims description 4
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 claims description 4
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 claims description 4
- 239000002160 alpha blocker Substances 0.000 claims description 4
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 claims description 4
- 239000002876 beta blocker Substances 0.000 claims description 4
- 229940097320 beta blocking agent Drugs 0.000 claims description 4
- 239000000480 calcium channel blocker Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 230000009977 dual effect Effects 0.000 claims description 4
- 108010020708 plasmepsin Proteins 0.000 claims description 4
- 229940044551 receptor antagonist Drugs 0.000 claims description 4
- 239000002464 receptor antagonist Substances 0.000 claims description 4
- 208000019553 vascular disease Diseases 0.000 claims description 4
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 229940118365 Endothelin receptor antagonist Drugs 0.000 claims description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 229940030600 antihypertensive agent Drugs 0.000 claims description 3
- 239000002220 antihypertensive agent Substances 0.000 claims description 3
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 3
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 2
- 208000006029 Cardiomegaly Diseases 0.000 claims description 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 2
- 208000010412 Glaucoma Diseases 0.000 claims description 2
- 108010010369 HIV Protease Proteins 0.000 claims description 2
- 206010020571 Hyperaldosteronism Diseases 0.000 claims description 2
- 206010062886 Procedural hypertension Diseases 0.000 claims description 2
- 230000002159 abnormal effect Effects 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- 210000004204 blood vessel Anatomy 0.000 claims description 2
- 230000009787 cardiac fibrosis Effects 0.000 claims description 2
- 230000004406 elevated intraocular pressure Effects 0.000 claims description 2
- 201000006370 kidney failure Diseases 0.000 claims description 2
- 230000001452 natriuretic effect Effects 0.000 claims description 2
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 23
- BLHAZQPROGWBQL-ZNFSXRAMSA-N methyl n-[(4s)-4-(3-chloro-5-fluorophenyl)-4-[(3r)-1-[[(2s)-1-cyclohexyl-3-(methylamino)propan-2-yl]carbamoyl]piperidin-3-yl]-4-hydroxybutyl]carbamate Chemical compound C([C@@H](CNC)NC(=O)N1C[C@@H](CCC1)[C@@](O)(CCCNC(=O)OC)C=1C=C(Cl)C=C(F)C=1)C1CCCCC1 BLHAZQPROGWBQL-ZNFSXRAMSA-N 0.000 claims 2
- BZWFFDIHCRNIEM-QLOIWQOISA-N C([C@@H](CNC)NC(=O)N1C[C@@H](CCC1)[C@@](O)(CCCNC(=O)OC)C=1C(=C(Cl)C=CC=1)F)[C@H]1CC[C@H](F)CC1 Chemical compound C([C@@H](CNC)NC(=O)N1C[C@@H](CCC1)[C@@](O)(CCCNC(=O)OC)C=1C(=C(Cl)C=CC=1)F)[C@H]1CC[C@H](F)CC1 BZWFFDIHCRNIEM-QLOIWQOISA-N 0.000 claims 1
- 208000028698 Cognitive impairment Diseases 0.000 claims 1
- 108010059378 Endopeptidases Proteins 0.000 claims 1
- 102000005593 Endopeptidases Human genes 0.000 claims 1
- 206010061216 Infarction Diseases 0.000 claims 1
- 208000012902 Nervous system disease Diseases 0.000 claims 1
- 208000025966 Neurological disease Diseases 0.000 claims 1
- 238000002399 angioplasty Methods 0.000 claims 1
- 208000010877 cognitive disease Diseases 0.000 claims 1
- 208000017169 kidney disease Diseases 0.000 claims 1
- JYRUULJWQJQTCT-YHZWXPKMSA-N methyl n-[(4s)-4-(3-chlorophenyl)-4-[(3r)-1-[[(2s)-1-cyclohexyl-3-(methylamino)propan-2-yl]carbamoyl]piperidin-3-yl]-4-(propanoylamino)butyl]carbamate Chemical compound C([C@@H](CNC)NC(=O)N1CCC[C@H](C1)[C@](CCCNC(=O)OC)(NC(=O)CC)C=1C=C(Cl)C=CC=1)C1CCCCC1 JYRUULJWQJQTCT-YHZWXPKMSA-N 0.000 claims 1
- WLSZRWKNFJAKEI-FKIGELJASA-N methyl n-[(4s)-4-(3-chlorophenyl)-4-[(3r)-1-[[(2s)-1-cyclohexyl-3-(methylamino)propan-2-yl]carbamoyl]piperidin-3-yl]-4-hydroxybutyl]carbamate Chemical compound C([C@@H](CNC)NC(=O)N1C[C@@H](CCC1)[C@@](O)(CCCNC(=O)OC)C=1C=C(Cl)C=CC=1)C1CCCCC1 WLSZRWKNFJAKEI-FKIGELJASA-N 0.000 claims 1
- JQRFWBUMHAMLAJ-VJTSUQJLSA-N methyl n-[2-[(r)-(3-chlorophenyl)-[(3r)-1-[[(2s)-1-cyclohexyl-3-(methylamino)propan-2-yl]carbamoyl]piperidin-3-yl]methoxy]ethyl]carbamate Chemical compound C([C@@H](CNC)NC(=O)N1C[C@@H](CCC1)[C@@H](OCCNC(=O)OC)C=1C=C(Cl)C=CC=1)C1CCCCC1 JQRFWBUMHAMLAJ-VJTSUQJLSA-N 0.000 claims 1
- UDBBEGCXNKSBEV-NHTMILBNSA-N methyl n-[2-[(r)-[(3r)-1-[[(2s)-1-amino-3-cyclohexylpropan-2-yl]carbamoyl]piperidin-3-yl]-(3-chlorophenyl)methoxy]ethyl]carbamate Chemical compound C([C@@H](CN)NC(=O)N1CCC[C@H](C1)[C@@H](OCCNC(=O)OC)C=1C=C(Cl)C=CC=1)C1CCCCC1 UDBBEGCXNKSBEV-NHTMILBNSA-N 0.000 claims 1
- XAAODCDZXIITSC-VJTSUQJLSA-N methyl n-[2-[(r)-[(3r)-1-[[(2s)-1-cyclohexyl-3-(methylamino)propan-2-yl]carbamoyl]piperidin-3-yl]-(3-fluorophenyl)methoxy]ethyl]carbamate Chemical compound C([C@@H](CNC)NC(=O)N1C[C@@H](CCC1)[C@@H](OCCNC(=O)OC)C=1C=C(F)C=CC=1)C1CCCCC1 XAAODCDZXIITSC-VJTSUQJLSA-N 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 claims 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims 1
- 230000002792 vascular Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 258
- 239000000243 solution Substances 0.000 description 246
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 245
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 224
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 146
- 239000011734 sodium Substances 0.000 description 135
- 235000019439 ethyl acetate Nutrition 0.000 description 110
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 107
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 103
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 99
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 98
- 239000002904 solvent Substances 0.000 description 89
- 239000011541 reaction mixture Substances 0.000 description 85
- 238000005481 NMR spectroscopy Methods 0.000 description 80
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 80
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- 238000006243 chemical reaction Methods 0.000 description 72
- 239000012044 organic layer Substances 0.000 description 70
- 238000000746 purification Methods 0.000 description 68
- 229920006395 saturated elastomer Polymers 0.000 description 62
- 238000004519 manufacturing process Methods 0.000 description 60
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 30
- 239000003921 oil Substances 0.000 description 29
- 235000019198 oils Nutrition 0.000 description 29
- 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 29
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 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 13
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 238000004007 reversed phase HPLC Methods 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 11
- 238000002953 preparative HPLC Methods 0.000 description 11
- NQGXVXHYGRAABB-SNVBAGLBSA-N tert-butyl (3r)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate Chemical compound CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1 NQGXVXHYGRAABB-SNVBAGLBSA-N 0.000 description 11
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
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Classifications
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2010503682A (ja) * | 2006-09-18 | 2010-02-04 | ビテ ファーマシューティカルズ, インコーポレイテッド | レニン阻害剤としてのピペリジン誘導体 |
| JP2010503684A (ja) * | 2006-09-18 | 2010-02-04 | ビテ ファーマシューティカルズ, インコーポレイテッド | レニン阻害剤 |
| WO2012081582A1 (ja) * | 2010-12-15 | 2012-06-21 | 国立大学法人北海道大学 | ジアステレオ選択的にアルコール化合物を製造する方法及びルテニウム化合物 |
| WO2012081585A1 (ja) * | 2010-12-15 | 2012-06-21 | 国立大学法人北海道大学 | 光学活性アルコール化合物の製造方法 |
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| JP5067968B2 (ja) | 2004-10-07 | 2012-11-07 | ビテ ファーマシューティカルズ, インコーポレイテッド | ジアミノアルカンアスパラギン酸プロテアーゼ阻害剤 |
| EP2010488A2 (en) * | 2006-04-05 | 2009-01-07 | Vitae Pharmaceuticals, Inc. | Renin inhibitors |
| US20090275581A1 (en) * | 2006-04-05 | 2009-11-05 | Baldwin John J | Renin inhibitors |
| US7858624B2 (en) * | 2006-04-05 | 2010-12-28 | Vitae Pharmaceuticals, Inc. | Piperidine and morpholine renin inhibitors |
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| US8242290B2 (en) | 2007-09-17 | 2012-08-14 | Vitae Pharmaceuticals, Inc. | Process for the preparation of renin inhibitors |
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| US7741327B2 (en) | 2008-04-16 | 2010-06-22 | Hoffmann-La Roche Inc. | Pyrrolidinone glucokinase activators |
| US20100010228A1 (en) * | 2008-06-26 | 2010-01-14 | Vitae Pharmaceuticals, Inc. | Process for the asymmetric reduction of 3-benzoylpiperidines |
| AU2009262319A1 (en) * | 2008-06-26 | 2009-12-30 | Vitae Pharmaceuticals, Inc. | Salts of methyl 2-((R))-(3-chlorophenyl) ((R)-1-((S)-2- (methylamino)-3((R)-tetrahydro-2H-pyran-3-yl) propylcarbamoyl) piperidin-3-yl)methoxy)ethylcarbamate |
| NZ590688A (en) | 2008-08-05 | 2012-09-28 | Daiichi Sankyo Co Ltd | imidazo[4,5-b]pyridin-2-one derivatives |
| WO2010111634A2 (en) * | 2009-03-26 | 2010-09-30 | Takeda Pharmaceutical Company Limited | Renin inhibitors |
| US20110021570A1 (en) | 2009-07-23 | 2011-01-27 | Nancy-Ellen Haynes | Pyridone glucokinase activators |
| AR077692A1 (es) | 2009-08-06 | 2011-09-14 | Vitae Pharmaceuticals Inc | Sales de 2-((r)-(3-clorofenil) ((r)-1-((s) -2-(metilamino)-3-((r)-tetrahidro-2h-piran-3-il) propilcarbamoil) piperidin -3-il) metoxi) etilcarbamato de metilo |
| US8178689B2 (en) | 2010-06-17 | 2012-05-15 | Hoffman-La Roche Inc. | Tricyclic compounds |
| BR112015003393A2 (pt) | 2012-08-16 | 2017-07-04 | Janssen Pharmaceutica Nv | pirazóis substituídos como bloqueadores de canal de cálcio de tipo-n |
| US9453002B2 (en) | 2013-08-16 | 2016-09-27 | Janssen Pharmaceutica Nv | Substituted imidazoles as N-type calcium channel blockers |
| GB201706102D0 (en) | 2017-04-18 | 2017-05-31 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| CA3173676A1 (en) * | 2020-04-24 | 2021-10-28 | Guangzhou Kangrui Biological Pharmaceutical Technology Co., Ltd. | A formulation for treating ophthalmic conditions |
| US12083099B2 (en) | 2020-10-28 | 2024-09-10 | Accencio LLC | Methods of treating symptoms of coronavirus infection with viral protease inhibitors |
| TW202300150A (zh) | 2021-03-18 | 2023-01-01 | 美商薛定諤公司 | 環狀化合物及其使用方法 |
| AR129265A1 (es) | 2022-05-12 | 2024-08-07 | Syngenta Crop Protection Ag | Compuestos de alcoxi-heteroaril-carboxamida o tioamida |
| WO2024033374A1 (en) | 2022-08-11 | 2024-02-15 | Syngenta Crop Protection Ag | Novel arylcarboxamide or arylthioamide compounds |
| EP4634152A1 (en) | 2022-12-15 | 2025-10-22 | Syngenta Crop Protection AG | Novel bicyclic-carboxamide compounds useful as pesticides |
| CN116987090B (zh) * | 2023-07-25 | 2025-06-27 | 乳源东阳光药业有限公司 | (4aR,7aS)-6-(2,2-二乙氧基乙基)六氢-5H-[1,4]二恶烷并[2,3-c]吡咯的合成方法 |
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-
2006
- 2006-10-31 TW TW095140163A patent/TWI411607B/zh not_active IP Right Cessation
- 2006-11-13 BR BRPI0618585-1A patent/BRPI0618585A2/pt not_active IP Right Cessation
- 2006-11-13 SG SG201101062-6A patent/SG169983A1/en unknown
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- 2006-11-13 NZ NZ568042A patent/NZ568042A/en not_active IP Right Cessation
- 2006-11-13 AU AU2006325322A patent/AU2006325322B2/en not_active Ceased
- 2006-11-13 US US12/084,928 patent/US8487108B2/en not_active Expired - Fee Related
- 2006-11-13 JP JP2008540236A patent/JP2009515893A/ja not_active Withdrawn
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- 2006-11-13 KR KR1020087014407A patent/KR101379663B1/ko not_active Expired - Fee Related
- 2006-11-13 WO PCT/US2006/043920 patent/WO2007070201A1/en not_active Ceased
- 2006-11-13 PE PE2006001432A patent/PE20070804A1/es not_active Application Discontinuation
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2008
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2010
- 2010-08-06 PE PE2010000496A patent/PE20120229A1/es not_active Application Discontinuation
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010503682A (ja) * | 2006-09-18 | 2010-02-04 | ビテ ファーマシューティカルズ, インコーポレイテッド | レニン阻害剤としてのピペリジン誘導体 |
| JP2010503684A (ja) * | 2006-09-18 | 2010-02-04 | ビテ ファーマシューティカルズ, インコーポレイテッド | レニン阻害剤 |
| WO2012081582A1 (ja) * | 2010-12-15 | 2012-06-21 | 国立大学法人北海道大学 | ジアステレオ選択的にアルコール化合物を製造する方法及びルテニウム化合物 |
| WO2012081585A1 (ja) * | 2010-12-15 | 2012-06-21 | 国立大学法人北海道大学 | 光学活性アルコール化合物の製造方法 |
| JP5616976B2 (ja) * | 2010-12-15 | 2014-10-29 | 国立大学法人北海道大学 | ジアステレオ選択的にアルコール化合物を製造する方法及びルテニウム化合物 |
| JP5616977B2 (ja) * | 2010-12-15 | 2014-10-29 | 国立大学法人北海道大学 | 光学活性アルコール化合物の製造方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20082108L (no) | 2008-08-06 |
| AR057890A1 (es) | 2007-12-26 |
| WO2007070201A1 (en) | 2007-06-21 |
| BRPI0618585A2 (pt) | 2011-09-27 |
| EP1966139B1 (en) | 2011-12-21 |
| US8487108B2 (en) | 2013-07-16 |
| HK1121459A1 (en) | 2009-04-24 |
| TWI411607B (zh) | 2013-10-11 |
| CA2628952A1 (en) | 2007-06-21 |
| SG169983A1 (en) | 2011-04-29 |
| ATE538092T1 (de) | 2012-01-15 |
| KR20080069685A (ko) | 2008-07-28 |
| AU2006325322A1 (en) | 2007-06-21 |
| AU2006325322B2 (en) | 2011-08-04 |
| PE20120229A1 (es) | 2012-04-04 |
| KR101379663B1 (ko) | 2014-04-14 |
| TW200800893A (en) | 2008-01-01 |
| CA2628952C (en) | 2014-04-01 |
| EP1966139A1 (en) | 2008-09-10 |
| PE20070804A1 (es) | 2007-09-06 |
| NZ568042A (en) | 2010-12-24 |
| US20100048636A1 (en) | 2010-02-25 |
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