EA021113B1 - Хиназолины в качестве ингибиторов калиевых каналов - Google Patents
Хиназолины в качестве ингибиторов калиевых каналов Download PDFInfo
- Publication number
- EA021113B1 EA021113B1 EA201270378A EA201270378A EA021113B1 EA 021113 B1 EA021113 B1 EA 021113B1 EA 201270378 A EA201270378 A EA 201270378A EA 201270378 A EA201270378 A EA 201270378A EA 021113 B1 EA021113 B1 EA 021113B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- pyridin
- case
- alkyl
- quinazolin
- phenyl
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title claims description 19
- 102000004257 Potassium Channel Human genes 0.000 title description 4
- 108020001213 potassium channel Proteins 0.000 title description 4
- 150000003246 quinazolines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 150000003839 salts Chemical class 0.000 claims abstract description 83
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 9
- 230000006793 arrhythmia Effects 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 308
- 125000000217 alkyl group Chemical group 0.000 claims description 192
- 229910052739 hydrogen Inorganic materials 0.000 claims description 168
- -1 (5- (5-phenyl-4- (pyridin-2-ylmethylamino) quinazolin-2-yl) pyridin-3yl) methyl Chemical group 0.000 claims description 142
- 229910052799 carbon Inorganic materials 0.000 claims description 83
- 125000003545 alkoxy group Chemical group 0.000 claims description 76
- 125000001072 heteroaryl group Chemical group 0.000 claims description 76
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 61
- 239000001257 hydrogen Substances 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 49
- 229910052794 bromium Inorganic materials 0.000 claims description 47
- 229910052740 iodine Inorganic materials 0.000 claims description 44
- 125000003342 alkenyl group Chemical group 0.000 claims description 41
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 37
- 229910052698 phosphorus Inorganic materials 0.000 claims description 36
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000004122 cyclic group Chemical group 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 16
- 125000002971 oxazolyl group Chemical group 0.000 claims description 16
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 16
- 125000000335 thiazolyl group Chemical group 0.000 claims description 16
- 125000001425 triazolyl group Chemical group 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 15
- 229940124530 sulfonamide Drugs 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 239000003146 anticoagulant agent Substances 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000002757 morpholinyl group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- FVMLHPCDJCQAPK-UHFFFAOYSA-N 2-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]acetonitrile Chemical compound N#CCC1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 FVMLHPCDJCQAPK-UHFFFAOYSA-N 0.000 claims description 7
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- AGBLAKRVOJGRKT-UHFFFAOYSA-N [5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]methanol Chemical compound OCC1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 AGBLAKRVOJGRKT-UHFFFAOYSA-N 0.000 claims description 5
- 230000002785 anti-thrombosis Effects 0.000 claims description 5
- 229940127219 anticoagulant drug Drugs 0.000 claims description 5
- 229940125708 antidiabetic agent Drugs 0.000 claims description 5
- 239000003472 antidiabetic agent Substances 0.000 claims description 5
- 239000002220 antihypertensive agent Substances 0.000 claims description 5
- 229940030600 antihypertensive agent Drugs 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- NSQNJIOTYOYVPJ-UHFFFAOYSA-N methyl 5-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]-1,3,4-oxadiazole-2-carboxylate Chemical compound O1C(C(=O)OC)=NN=C1C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 NSQNJIOTYOYVPJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 210000001685 thyroid gland Anatomy 0.000 claims description 5
- CSRQWQAFGUGBMQ-UHFFFAOYSA-N 2-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]propane-1,3-diol Chemical compound OCC(CO)C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 CSRQWQAFGUGBMQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 claims description 4
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 4
- 229940127218 antiplatelet drug Drugs 0.000 claims description 4
- 239000000480 calcium channel blocker Substances 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 4
- 239000010802 sludge Substances 0.000 claims description 4
- KCMPNIHDCHNBLR-UHFFFAOYSA-N 1-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl]butan-1-one Chemical compound C1C(C(=O)CCC)=NOC1C1=NC(NCC=2N=CC=CC=2)=C(C(=CC=C2)C=3C=CC=CC=3)C2=N1 KCMPNIHDCHNBLR-UHFFFAOYSA-N 0.000 claims description 3
- CFIPTVYHUSQTPE-UHFFFAOYSA-N 1-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]cyclopropane-1-carbonitrile Chemical compound C=1N=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=CC=1C1(C#N)CC1 CFIPTVYHUSQTPE-UHFFFAOYSA-N 0.000 claims description 3
- YFHBVPJJSPKCBC-UHFFFAOYSA-N 1-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]ethanol Chemical compound CC(O)C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 YFHBVPJJSPKCBC-UHFFFAOYSA-N 0.000 claims description 3
- WRQMKFLJGNZAMX-UHFFFAOYSA-N 1-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]cyclopropane-1-carbonitrile Chemical compound N=1C(NCC=2N=CC=CC=2)=C2C(C=3C=CC=CC=3)=CC=CC2=NC=1C1(C#N)CC1 WRQMKFLJGNZAMX-UHFFFAOYSA-N 0.000 claims description 3
- IZKJBTRAWREWFD-UHFFFAOYSA-N 2-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]acetamide Chemical compound NC(=O)CC1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 IZKJBTRAWREWFD-UHFFFAOYSA-N 0.000 claims description 3
- DCZRNAOHORCJCS-UHFFFAOYSA-N 2-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]ethanesulfonamide Chemical compound NS(=O)(=O)CCC1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 DCZRNAOHORCJCS-UHFFFAOYSA-N 0.000 claims description 3
- ORAPDKIAZMXQNT-UHFFFAOYSA-N 2-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]propan-2-ol Chemical compound CC(C)(O)C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 ORAPDKIAZMXQNT-UHFFFAOYSA-N 0.000 claims description 3
- VPKRECDQVAXWPK-UHFFFAOYSA-N 2-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]propanamide Chemical compound NC(=O)C(C)C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 VPKRECDQVAXWPK-UHFFFAOYSA-N 0.000 claims description 3
- PDIQUSOLRPLOGI-UHFFFAOYSA-N 2-[[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]methylsulfonyl]acetamide Chemical compound NC(=O)CS(=O)(=O)CC1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 PDIQUSOLRPLOGI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
- AIWGUQUXNSMXNH-UHFFFAOYSA-N 2-methyl-1-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]propan-1-ol Chemical compound CC(C)C(O)C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 AIWGUQUXNSMXNH-UHFFFAOYSA-N 0.000 claims description 3
- DQDWIXDURRTWQQ-UHFFFAOYSA-N 2-methyl-2-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]propanenitrile Chemical compound N#CC(C)(C)C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 DQDWIXDURRTWQQ-UHFFFAOYSA-N 0.000 claims description 3
- VKGUZDMOYVPPLI-UHFFFAOYSA-N 2-methyl-2-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]propane-1,3-diol Chemical compound C=12C(C=3C=CC=CC=3)=CC=CC2=NC(C(CO)(CO)C)=NC=1NCC1=CC=CC=N1 VKGUZDMOYVPPLI-UHFFFAOYSA-N 0.000 claims description 3
- ZDRPFFAIGWCFRK-UHFFFAOYSA-N 3-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]-1,2,4-oxadiazole-5-carboxamide Chemical compound O1C(C(=O)N)=NC(C=2C=C(C=NC=2)C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=N1 ZDRPFFAIGWCFRK-UHFFFAOYSA-N 0.000 claims description 3
- CRBPVOYQPCSBGD-UHFFFAOYSA-N 3-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]propanamide Chemical compound NC(=O)CCC1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 CRBPVOYQPCSBGD-UHFFFAOYSA-N 0.000 claims description 3
- WNSUHLRXJPCQQL-UHFFFAOYSA-N 4-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 WNSUHLRXJPCQQL-UHFFFAOYSA-N 0.000 claims description 3
- MJJFPHTURAZWKX-UHFFFAOYSA-N 5-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]-1,3,4-oxadiazol-2-amine Chemical compound O1C(N)=NN=C1C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 MJJFPHTURAZWKX-UHFFFAOYSA-N 0.000 claims description 3
- DTWBCZCMEULUNG-UHFFFAOYSA-N 5-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]-1,3,4-oxadiazole-2-carboxamide Chemical compound O1C(C(=O)N)=NN=C1C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 DTWBCZCMEULUNG-UHFFFAOYSA-N 0.000 claims description 3
- KITYXUGKWPDMSJ-UHFFFAOYSA-N 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]-1h-pyridin-2-one Chemical compound N1C(=O)C=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 KITYXUGKWPDMSJ-UHFFFAOYSA-N 0.000 claims description 3
- HEDAUIXNFZMILW-UHFFFAOYSA-N 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyrimidine-2-carbonitrile Chemical compound C1=NC(C#N)=NC=C1C1=NC(NCC=2N=CC=CC=2)=C(C(=CC=C2)C=3C=CC=CC=3)C2=N1 HEDAUIXNFZMILW-UHFFFAOYSA-N 0.000 claims description 3
- USSODORNBVBVFT-UHFFFAOYSA-N [5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]urea Chemical compound NC(=O)NC1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 USSODORNBVBVFT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- OMRSYQIZCBMGGX-UHFFFAOYSA-N methyl 3-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]propanoate Chemical compound C=12C(C=3C=CC=CC=3)=CC=CC2=NC(CCC(=O)OC)=NC=1NCC1=CC=CC=N1 OMRSYQIZCBMGGX-UHFFFAOYSA-N 0.000 claims description 3
- 229940127015 mineralocorticoid receptor agonist Drugs 0.000 claims description 3
- 125000006546 (C4-C10) cycloalkyl group Chemical group 0.000 claims description 2
- BJMGXMYXAHQFBO-UHFFFAOYSA-N 1-methyl-2-oxo-5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide Chemical compound C1=C(S(N)(=O)=O)C(=O)N(C)C=C1C1=NC(NCC=2N=CC=CC=2)=C(C(=CC=C2)C=3C=CC=CC=3)C2=N1 BJMGXMYXAHQFBO-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000013256 coordination polymer Substances 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 2
- BKTVVVVSDQVHEI-UHFFFAOYSA-N methyl 3-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]propanoate Chemical compound COC(=O)CCC1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 BKTVVVVSDQVHEI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 claims 1
- BZCOASIWPFVBQZ-UHFFFAOYSA-N 5-methyl-1-(4-pyrrolidin-1-ylbut-2-ynyl)pyrrolidin-2-one Chemical compound CC1CCC(=O)N1CC#CCN1CCCC1 BZCOASIWPFVBQZ-UHFFFAOYSA-N 0.000 claims 1
- QPZKONBYBJXIFG-UHFFFAOYSA-N 5-phenyl-4-(pyridin-2-ylmethylamino)-2-[1-[(sulfamoylamino)methyl]cyclopropyl]quinazoline Chemical compound N=1C(NCC=2N=CC=CC=2)=C2C(C=3C=CC=CC=3)=CC=CC2=NC=1C1(CNS(=O)(=O)N)CC1 QPZKONBYBJXIFG-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 125000005347 halocycloalkyl group Chemical group 0.000 claims 1
- JQUHYGFWCNJOLE-UHFFFAOYSA-N n-[[1-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]cyclopropyl]methyl]methanesulfonamide Chemical compound N=1C(NCC=2N=CC=CC=2)=C2C(C=3C=CC=CC=3)=CC=CC2=NC=1C1(CNS(=O)(=O)C)CC1 JQUHYGFWCNJOLE-UHFFFAOYSA-N 0.000 claims 1
- SVEUVITYHIHZQE-UHFFFAOYSA-N n-methylpyridin-2-amine Chemical compound CNC1=CC=CC=N1 SVEUVITYHIHZQE-UHFFFAOYSA-N 0.000 claims 1
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- 125000004260 quinazolin-2-yl group Chemical group [H]C1=NC(*)=NC2=C1C([H])=C([H])C([H])=C2[H] 0.000 claims 1
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 claims 1
- 229940044601 receptor agonist Drugs 0.000 claims 1
- 239000000018 receptor agonist Substances 0.000 claims 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 11
- 230000002265 prevention Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 369
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 369
- 239000011541 reaction mixture Substances 0.000 description 358
- 230000014759 maintenance of location Effects 0.000 description 242
- 239000000243 solution Substances 0.000 description 222
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 204
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 198
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 192
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 181
- 239000000203 mixture Substances 0.000 description 159
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 152
- 230000002829 reductive effect Effects 0.000 description 150
- 239000007787 solid Substances 0.000 description 112
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 103
- 238000004128 high performance liquid chromatography Methods 0.000 description 101
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 99
- 229910052757 nitrogen Inorganic materials 0.000 description 96
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 239000002904 solvent Substances 0.000 description 67
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 65
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 63
- 238000010898 silica gel chromatography Methods 0.000 description 56
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 54
- 239000012044 organic layer Substances 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 42
- 238000000746 purification Methods 0.000 description 42
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 42
- 239000012267 brine Substances 0.000 description 40
- 239000010410 layer Substances 0.000 description 39
- 239000000706 filtrate Substances 0.000 description 37
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 37
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 36
- 239000012071 phase Substances 0.000 description 31
- 229910000027 potassium carbonate Inorganic materials 0.000 description 31
- 239000012299 nitrogen atmosphere Substances 0.000 description 30
- 239000012047 saturated solution Substances 0.000 description 30
- 229910052763 palladium Inorganic materials 0.000 description 28
- 239000003480 eluent Substances 0.000 description 27
- 238000003818 flash chromatography Methods 0.000 description 26
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- 150000003892 tartrate salts Chemical class 0.000 description 1
- SULLUMQUIHDZSE-BMRADRMJSA-N tert-butyl n-[(e)-2-[5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-yl]ethenyl]sulfonylcarbamate Chemical compound CC(C)(C)OC(=O)NS(=O)(=O)\C=C\C1=CN=CC(C=2N=C3C=CC=C(C3=C(NCC=3N=CC=CC=3)N=2)C=2C=CC=CC=2)=C1 SULLUMQUIHDZSE-BMRADRMJSA-N 0.000 description 1
- GAIZFMKSOHADOV-UHFFFAOYSA-N tert-butyl n-methylsulfonylcarbamate Chemical compound CC(C)(C)OC(=O)NS(C)(=O)=O GAIZFMKSOHADOV-UHFFFAOYSA-N 0.000 description 1
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- OSXXGBUMRXAAFP-UHFFFAOYSA-N tetramethylazanium;cyanide Chemical compound N#[C-].C[N+](C)(C)C OSXXGBUMRXAAFP-UHFFFAOYSA-N 0.000 description 1
- UTYXJYFJPBYDKY-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] UTYXJYFJPBYDKY-UHFFFAOYSA-N 0.000 description 1
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- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
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- 238000002054 transplantation Methods 0.000 description 1
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- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
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- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07D401/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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| ES2900504T3 (es) * | 2009-09-03 | 2022-03-17 | Bristol Myers Squibb Co | Quinazolinas como inhibidores de los canales iónicos de potasio |
| AR079814A1 (es) * | 2009-12-31 | 2012-02-22 | Otsuka Pharma Co Ltd | Compuestos heterociclicos, composiciones farmaceuticas que los contienen y sus usos |
| KR20140048216A (ko) * | 2011-06-29 | 2014-04-23 | 오츠카 세이야쿠 가부시키가이샤 | 치료 화합물로서의 퀴나졸린 및 관련된 사용 방법 |
| JP6121658B2 (ja) * | 2011-06-29 | 2017-04-26 | 大塚製薬株式会社 | 治療用化合物、及び関連する使用の方法 |
| CN103360382B (zh) * | 2012-03-26 | 2016-04-27 | 中国科学院福建物质结构研究所 | 喹唑啉衍生物及其用途 |
| SI2858987T1 (en) * | 2012-06-11 | 2018-06-29 | Bristol-Myers Squibb Company | PREPARATION OF 5-PHENYL-4- (PYRIDIN-2-ILLETHYLAMINO) -CHUINAZOLIN-2-YL) -PIRIDIN-3-SULPHONAMIDE PHOSPHORAMIDIC ACID |
| WO2014133059A1 (ja) | 2013-02-28 | 2014-09-04 | 武田薬品工業株式会社 | スルホニルクロライド化合物の製造法 |
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| EP2970199A1 (en) | 2013-03-11 | 2016-01-20 | Bristol-Myers Squibb Company | Isoquinolines as potassium ion channel inhibitors |
| JP6386527B2 (ja) * | 2013-03-11 | 2018-09-05 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | カリウムイオンチャネル阻害剤としてのピロロピリダジン |
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| US9050345B2 (en) * | 2013-03-11 | 2015-06-09 | Bristol-Myers Squibb Company | Pyrrolotriazines as potassium ion channel inhibitors |
| BR112016008406B1 (pt) * | 2013-10-17 | 2021-02-23 | Sumitomo Chemical Company, Limited | composto de tetrazolinona e aplicação do mesmo |
| CA2951784C (en) | 2014-06-10 | 2022-05-31 | Ube Industries, Ltd. | N-substituted sulfonamide compound and method for producing same |
| CN106458903B (zh) | 2014-06-10 | 2021-02-05 | 宇部兴产株式会社 | 杂芳族磺酰胺化合物的制造方法 |
| US10774072B2 (en) | 2014-06-10 | 2020-09-15 | Ube Industries, Ltd. | Crystal of N-substituted sulfonamide compound |
| CA2969839A1 (en) * | 2014-12-05 | 2016-06-09 | Subramaniam Ananthan | Heterocyclic compounds as biogenic amine transport modulators |
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| CN106432067B (zh) * | 2016-09-18 | 2019-04-19 | 北京天弘天达医药科技有限公司 | 一种3-吡啶磺酰氯的绿色化学合成方法 |
| EP3700891A1 (en) * | 2017-10-29 | 2020-09-02 | Bayer Aktiengesellschaft | Aromatic sulfonamide derivatives for the treatment of ischemic stroke |
| EP3820861A1 (en) * | 2018-04-20 | 2021-05-19 | Bayer Aktiengesellschaft | Heteroaryl-triazole and heteroaryl-tetrazole compounds as pesticides |
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