JP2022514303A - 置換されているオキソピリジン誘導体 - Google Patents

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Publication number

JP2022514303A

JP2022514303A JP2021535063A JP2021535063A JP2022514303A JP 2022514303 A JP2022514303 A JP 2022514303A JP 2021535063 A JP2021535063 A JP 2021535063A JP 2021535063 A JP2021535063 A JP 2021535063A JP 2022514303 A JP2022514303 A JP 2022514303A

Authority

JP

Japan

Prior art keywords

mmol

methyl

mixture

formula

minutes

Prior art date

2018-12-21

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.)

Pending

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• 238000000034 method Methods 0.000 claims abstract description 116
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 53
• 229940079593 drug Drugs 0.000 claims abstract description 21
• 239000003814 drug Substances 0.000 claims abstract description 21
• 201000010099 disease Diseases 0.000 claims abstract description 20
• 230000001732 thrombotic effect Effects 0.000 claims abstract description 16
• 208000007536 Thrombosis Diseases 0.000 claims abstract description 15
• 150000001875 compounds Chemical class 0.000 claims description 224
• -1 Here Chemical group 0.000 claims description 98
• 229910052739 hydrogen Inorganic materials 0.000 claims description 94
• 239000001257 hydrogen Substances 0.000 claims description 94
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 92
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 78
• 150000003839 salts Chemical class 0.000 claims description 36
• 239000012453 solvate Substances 0.000 claims description 32
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
• 125000001424 substituent group Chemical group 0.000 claims description 29
• 229910052731 fluorine Inorganic materials 0.000 claims description 28
• 239000011737 fluorine Substances 0.000 claims description 28
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 24
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 22
• 229910052757 nitrogen Inorganic materials 0.000 claims description 15
• 208000001435 Thromboembolism Diseases 0.000 claims description 13
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
• 239000000126 substance Substances 0.000 claims description 13
• 208000006011 Stroke Diseases 0.000 claims description 12
• 239000000460 chlorine Substances 0.000 claims description 12
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 11
• 229910052801 chlorine Inorganic materials 0.000 claims description 11
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
• 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 claims description 10
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 8
• 150000002431 hydrogen Chemical class 0.000 claims description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
• 206010014498 Embolic stroke Diseases 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
• 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 claims description 7
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 206010000891 acute myocardial infarction Diseases 0.000 claims description 5
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims description 5
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
• 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 4
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• 206010038563 Reocclusion Diseases 0.000 claims description 4
• 238000002399 angioplasty Methods 0.000 claims description 4
• 230000000747 cardiac effect Effects 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 208000037803 restenosis Diseases 0.000 claims description 4
• 238000002054 transplantation Methods 0.000 claims description 4
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
• 206010003658 Atrial Fibrillation Diseases 0.000 claims description 3
• 208000032382 Ischaemic stroke Diseases 0.000 claims description 3
• 241001465754 Metazoa Species 0.000 claims description 3
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• 206010008118 cerebral infarction Diseases 0.000 claims description 3
• 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
• 210000002216 heart Anatomy 0.000 claims description 3
• 229910052740 iodine Inorganic materials 0.000 claims description 3
• 239000011630 iodine Substances 0.000 claims description 3
• 231100000252 nontoxic Toxicity 0.000 claims description 3
• 230000003000 nontoxic effect Effects 0.000 claims description 3
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• 206010002388 Angina unstable Diseases 0.000 claims description 2
• 208000025494 Aortic disease Diseases 0.000 claims description 2
• 208000031104 Arterial Occlusive disease Diseases 0.000 claims description 2
• 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 2
• 208000007718 Stable Angina Diseases 0.000 claims description 2
• 208000007814 Unstable Angina Diseases 0.000 claims description 2
• 238000002266 amputation Methods 0.000 claims description 2
• 208000021328 arterial occlusion Diseases 0.000 claims description 2
• 230000002490 cerebral effect Effects 0.000 claims description 2
• 210000004351 coronary vessel Anatomy 0.000 claims description 2
• 239000012024 dehydrating agents‎ Substances 0.000 claims description 2
• 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 2
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
• 201000002818 limb ischemia Diseases 0.000 claims description 2
• 210000003141 lower extremity Anatomy 0.000 claims description 2
• 238000005580 one pot reaction Methods 0.000 claims description 2
• 230000002093 peripheral effect Effects 0.000 claims description 2
• 230000001052 transient effect Effects 0.000 claims description 2
• 208000006117 ST-elevation myocardial infarction Diseases 0.000 claims 2
• 208000038006 embolic stroke of undetermined source Diseases 0.000 claims 1
• 230000000302 ischemic effect Effects 0.000 claims 1
• 230000009424 thromboembolic effect Effects 0.000 abstract description 17
• 238000011282 treatment Methods 0.000 abstract description 14
• 230000002265 prevention Effects 0.000 abstract description 9
• 206010059245 Angiopathy Diseases 0.000 abstract description 4
• 230000003073 embolic effect Effects 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 482
• 239000000203 mixture Substances 0.000 description 278
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 254
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 216
• 230000002829 reductive effect Effects 0.000 description 167
• 239000000243 solution Substances 0.000 description 167
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 165
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 165
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 164
• 239000003480 eluent Substances 0.000 description 155
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 119
• 239000011541 reaction mixture Substances 0.000 description 112
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 107
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 106
• 238000003756 stirring Methods 0.000 description 88
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 84
• 238000005160 1H NMR spectroscopy Methods 0.000 description 83
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
• 239000000741 silica gel Substances 0.000 description 70
• 229910002027 silica gel Inorganic materials 0.000 description 70
• 238000004440 column chromatography Methods 0.000 description 69
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 68
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 56
• 239000012267 brine Substances 0.000 description 53
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 53
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 50
• 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 47
• 239000012043 crude product Substances 0.000 description 46
• 229920006395 saturated elastomer Polymers 0.000 description 44
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 42
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 42
• 238000000746 purification Methods 0.000 description 41
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 40
• 239000012074 organic phase Substances 0.000 description 39
• 238000000825 ultraviolet detection Methods 0.000 description 39
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
• 238000006243 chemical reaction Methods 0.000 description 38
• 239000003208 petroleum Substances 0.000 description 37
• 239000012044 organic layer Substances 0.000 description 34
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 34
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
• 208000035475 disorder Diseases 0.000 description 31
• 239000000706 filtrate Substances 0.000 description 31
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 29
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 29
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
• 238000007429 general method Methods 0.000 description 29
• 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 28
• 235000019253 formic acid Nutrition 0.000 description 28
• 239000000725 suspension Substances 0.000 description 27
• 239000012300 argon atmosphere Substances 0.000 description 26
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• 238000002360 preparation method Methods 0.000 description 26
• 239000002904 solvent Substances 0.000 description 26
• 239000007864 aqueous solution Substances 0.000 description 25
• 230000015271 coagulation Effects 0.000 description 25
• 238000005345 coagulation Methods 0.000 description 25
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
• 239000008346 aqueous phase Substances 0.000 description 24
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 24
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• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
• 239000002585 base Substances 0.000 description 21
• 239000001569 carbon dioxide Substances 0.000 description 21
• 229910002092 carbon dioxide Inorganic materials 0.000 description 21
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 21
• 235000017557 sodium bicarbonate Nutrition 0.000 description 21
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 20
• 235000019270 ammonium chloride Nutrition 0.000 description 20
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 20
• 230000002441 reversible effect Effects 0.000 description 19
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• 238000005481 NMR spectroscopy Methods 0.000 description 8
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• 239000002244 precipitate Substances 0.000 description 8
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