JP2021505579A5 - - Google Patents
Download PDFInfo
- Publication number
- JP2021505579A5 JP2021505579A5 JP2020530591A JP2020530591A JP2021505579A5 JP 2021505579 A5 JP2021505579 A5 JP 2021505579A5 JP 2020530591 A JP2020530591 A JP 2020530591A JP 2020530591 A JP2020530591 A JP 2020530591A JP 2021505579 A5 JP2021505579 A5 JP 2021505579A5
- Authority
- JP
- Japan
- Prior art keywords
- salt
- compound
- formula
- item
- tert
- Prior art date
- 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.)
- Granted
Links
- 150000003839 salts Chemical class 0.000 claims description 412
- 238000000034 method Methods 0.000 claims description 258
- 150000001875 compounds Chemical class 0.000 claims description 237
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 92
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 72
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 60
- AJMDMNYTTSGFEL-LURJTMIESA-N (4s)-2,2,4-trimethylpyrrolidine Chemical compound C[C@@H]1CNC(C)(C)C1 AJMDMNYTTSGFEL-LURJTMIESA-N 0.000 claims description 47
- 238000006243 chemical reaction Methods 0.000 claims description 46
- 239000003054 catalyst Substances 0.000 claims description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 42
- JWUXJYZVKZKLTJ-UHFFFAOYSA-N Triacetonamine Chemical compound CC1(C)CC(=O)CC(C)(C)N1 JWUXJYZVKZKLTJ-UHFFFAOYSA-N 0.000 claims description 41
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 29
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 24
- 229910052802 copper Inorganic materials 0.000 claims description 24
- 239000010949 copper Substances 0.000 claims description 24
- -1 copper (I) halide Chemical class 0.000 claims description 23
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 claims description 23
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 22
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 20
- JJXUKXQTFKDOSH-YFKPBYRVSA-N (3S)-3,5,5-trimethylpyrrolidin-2-one Chemical compound C[C@@H]1C(NC(C1)(C)C)=O JJXUKXQTFKDOSH-YFKPBYRVSA-N 0.000 claims description 18
- MWCXFAZRURQVTI-UHFFFAOYSA-N 5,5-dimethyl-3-methylidenepyrrolidin-2-one Chemical compound CC1(C)CC(=C)C(=O)N1 MWCXFAZRURQVTI-UHFFFAOYSA-N 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 16
- DSBILMGLKQKPCU-UHFFFAOYSA-N BrC1=NC(=C(C(=O)N)C=C1)F Chemical compound BrC1=NC(=C(C(=O)N)C=C1)F DSBILMGLKQKPCU-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 15
- 229940127007 Compound 39 Drugs 0.000 claims description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 15
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 14
- 229940125904 compound 1 Drugs 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 13
- WOXLAOFIBHMNKL-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2,2-dimethylpropanoate Chemical compound CCOC(=O)C(C)(C)C(F)(F)F WOXLAOFIBHMNKL-UHFFFAOYSA-N 0.000 claims description 13
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 12
- 238000005984 hydrogenation reaction Methods 0.000 claims description 12
- 239000003446 ligand Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 239000003444 phase transfer catalyst Substances 0.000 claims description 11
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 11
- 235000011009 potassium phosphates Nutrition 0.000 claims description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- PAYVPGRVDMBHHZ-UHFFFAOYSA-N [Si](C)(C)(C(C)(C)C)C(C(C(F)(F)F)(C)C)O Chemical compound [Si](C)(C)(C(C)(C)C)C(C(C(F)(F)F)(C)C)O PAYVPGRVDMBHHZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- OWTCGJRBQMOICX-UHFFFAOYSA-M phenacyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1C(=O)C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 OWTCGJRBQMOICX-UHFFFAOYSA-M 0.000 claims description 10
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 10
- 229940125898 compound 5 Drugs 0.000 claims description 9
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 9
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 8
- JRHPOFJADXHYBR-UHFFFAOYSA-N 1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CNC1CCCCC1NC JRHPOFJADXHYBR-UHFFFAOYSA-N 0.000 claims description 8
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 claims description 8
- ZZOKVYOCRSMTSS-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl carbamate Chemical compound C1=CC=C2C(COC(=O)N)C3=CC=CC=C3C2=C1 ZZOKVYOCRSMTSS-UHFFFAOYSA-N 0.000 claims description 8
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- 229940127573 compound 38 Drugs 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- REWLCYPYZCHYSS-UHFFFAOYSA-N ditert-butyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C(C)(C)C)C(C)(C)C REWLCYPYZCHYSS-UHFFFAOYSA-N 0.000 claims description 8
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- BDAYEPPEDTWVSI-UHFFFAOYSA-N tert-butyl-(1-ethoxy-2-methylprop-1-enoxy)-dimethylsilane Chemical compound CCOC(=C(C)C)O[Si](C)(C)C(C)(C)C BDAYEPPEDTWVSI-UHFFFAOYSA-N 0.000 claims description 8
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 7
- 229940125797 compound 12 Drugs 0.000 claims description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims description 7
- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical class N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 claims description 7
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical class CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 claims description 7
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 6
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 6
- AOZISORLJJDLBQ-UHFFFAOYSA-N butyl(methyl)azanium;chloride Chemical compound Cl.CCCCNC AOZISORLJJDLBQ-UHFFFAOYSA-N 0.000 claims description 6
- 229940125877 compound 31 Drugs 0.000 claims description 6
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 claims description 6
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 6
- 150000003840 hydrochlorides Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 4
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 4
- PFOYYSGBGILOQZ-UHFFFAOYSA-N 2-(2-methylpropanoyl)cyclohexan-1-one Chemical compound CC(C)C(=O)C1CCCCC1=O PFOYYSGBGILOQZ-UHFFFAOYSA-N 0.000 claims description 4
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000005725 8-Hydroxyquinoline Substances 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 4
- 229930182821 L-proline Natural products 0.000 claims description 4
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 4
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 claims description 4
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 4
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical group [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 claims description 4
- 229940127204 compound 29 Drugs 0.000 claims description 4
- 229940125807 compound 37 Drugs 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- DVVDGSKDQGMLPW-UHFFFAOYSA-N ditert-butyl-(1-phenylpyrrol-2-yl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CN1C1=CC=CC=C1 DVVDGSKDQGMLPW-UHFFFAOYSA-N 0.000 claims description 4
- UJONYAVMBYXBJQ-UHFFFAOYSA-N ditert-butyl-[2-(2-methylphenyl)phenyl]phosphane Chemical group CC1=CC=CC=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C UJONYAVMBYXBJQ-UHFFFAOYSA-N 0.000 claims description 4
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 claims description 4
- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229960003540 oxyquinoline Drugs 0.000 claims description 4
- 229960002429 proline Drugs 0.000 claims description 4
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 claims description 4
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 4
- 230000000911 decarboxylating effect Effects 0.000 claims description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 3
- JDNAVZKVTWHWKB-UHFFFAOYSA-N dicyclohexyl-(1-methyl-2,2-diphenylcyclopropyl)phosphane Chemical compound C1CCCCC1P(C1CCCCC1)C1(C)CC1(C=1C=CC=CC=1)C1=CC=CC=C1 JDNAVZKVTWHWKB-UHFFFAOYSA-N 0.000 claims description 3
- QMLPJDVGNRHGJQ-UHFFFAOYSA-N ditert-butyl-(1-methyl-2,2-diphenylcyclopropyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1(C)CC1(C=1C=CC=CC=1)C1=CC=CC=C1 QMLPJDVGNRHGJQ-UHFFFAOYSA-N 0.000 claims description 3
- JALZQSOGOMZLEK-UHFFFAOYSA-N ditert-butyl-[1-(2-methoxyphenyl)pyrrol-2-yl]phosphane Chemical compound COC1=CC=CC=C1N1C(P(C(C)(C)C)C(C)(C)C)=CC=C1 JALZQSOGOMZLEK-UHFFFAOYSA-N 0.000 claims description 3
- PTXJGGGNGMPMBG-UHFFFAOYSA-N ditert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=NN1C1=C(C=2C=CC=CC=2)N(C=2C=CC=CC=2)N=C1C1=CC=CC=C1 PTXJGGGNGMPMBG-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 2
- HWUWODDRROSFEJ-RGMNGODLSA-N (4S)-2,2,4-trimethylpyrrolidine hydrochloride Chemical compound Cl.C[C@@H]1CNC(C)(C)C1 HWUWODDRROSFEJ-RGMNGODLSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000012369 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Substances 0.000 claims description 2
- LZWLLMFYVGUUAL-UHFFFAOYSA-L ditert-butyl(cyclopenta-1,3-dien-1-yl)phosphane;dichloropalladium;iron(2+) Chemical group [Fe+2].Cl[Pd]Cl.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 LZWLLMFYVGUUAL-UHFFFAOYSA-L 0.000 claims description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 2
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 2
- LLLVHTWJGWNRBD-UHFFFAOYSA-N 2-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1F LLLVHTWJGWNRBD-UHFFFAOYSA-N 0.000 claims 1
- 239000007983 Tris buffer Substances 0.000 claims 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 125000000217 alkyl group Chemical group 0.000 description 13
- 239000003960 organic solvent Substances 0.000 description 13
- 0 CC(C)(COc(cc1)n[n]1-c1ccc(C(NSc2c[n](C)nc2C)=O)c(*)n1)C(F)(F)F Chemical compound CC(C)(COc(cc1)n[n]1-c1ccc(C(NSc2c[n](C)nc2C)=O)c(*)n1)C(F)(F)F 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 11
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 10
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 9
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 description 6
- 238000006114 decarboxylation reaction Methods 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 5
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 5
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 5
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 4
- BARUNXKDFNLHEV-UHFFFAOYSA-N [3-diphenylphosphanyl-2-(diphenylphosphanylmethyl)-2-methylpropyl]-diphenylphosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CC(CP(C=1C=CC=CC=1)C=1C=CC=CC=1)(C)CP(C=1C=CC=CC=1)C1=CC=CC=C1 BARUNXKDFNLHEV-UHFFFAOYSA-N 0.000 description 4
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 229940127271 compound 49 Drugs 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 3
- LXYDKYSXJLLCBK-UHFFFAOYSA-N FC(C1(CCOc2n[nH]cc2)CC1)(F)F Chemical compound FC(C1(CCOc2n[nH]cc2)CC1)(F)F LXYDKYSXJLLCBK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 3
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 description 2
- IEQBMVDSUIBLLX-UHFFFAOYSA-N CC(C)(COC)C(F)(F)F Chemical compound CC(C)(COC)C(F)(F)F IEQBMVDSUIBLLX-UHFFFAOYSA-N 0.000 description 2
- GHGZGDGWFWIAQM-UHFFFAOYSA-N Cc1c[n](C)nc1C Chemical compound Cc1c[n](C)nc1C GHGZGDGWFWIAQM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000005604 azodicarboxylate group Chemical group 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 125000006378 chloropyridyl group Chemical group 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical group CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 2
- QPDJILZPDAMLFH-UHFFFAOYSA-N lithium;2-methylbutan-2-olate Chemical compound [Li]OC(C)(C)CC QPDJILZPDAMLFH-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- QBVXKDJEZKEASM-UHFFFAOYSA-M tetraoctylammonium bromide Chemical compound [Br-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC QBVXKDJEZKEASM-UHFFFAOYSA-M 0.000 description 2
- SNNIPOQLGBPXPS-UHFFFAOYSA-M tetraoctylazanium;chloride Chemical compound [Cl-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC SNNIPOQLGBPXPS-UHFFFAOYSA-M 0.000 description 2
- KGPZZJZTFHCXNK-UHFFFAOYSA-M tetraoctylazanium;iodide Chemical compound [I-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC KGPZZJZTFHCXNK-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- LIBASNWCFRYHQB-UHFFFAOYSA-N (2,3-dichlorophenyl)-diphenylphosphane Chemical compound ClC1=CC=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1Cl LIBASNWCFRYHQB-UHFFFAOYSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- STDJRYDBFFDKCR-UHFFFAOYSA-N 1,2,2-trimethylpyrrolidine Chemical compound CN1CCCC1(C)C STDJRYDBFFDKCR-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- LAEJGODWIYHHDW-UHFFFAOYSA-N 2-ethylsulfanyl-n-(2-ethylsulfanylethyl)ethanamine Chemical compound CCSCCNCCSCC LAEJGODWIYHHDW-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- KPZYGCOVQGFZCZ-UHFFFAOYSA-N CC(C)(CC1(C)C)CN1c(nc(cc1)-[n](cc2)nc2OCCC2(CC2)C(F)(F)F)c1C(NS(c1ccccc1)(=O)=O)=O Chemical compound CC(C)(CC1(C)C)CN1c(nc(cc1)-[n](cc2)nc2OCCC2(CC2)C(F)(F)F)c1C(NS(c1ccccc1)(=O)=O)=O KPZYGCOVQGFZCZ-UHFFFAOYSA-N 0.000 description 1
- ISNWWZNXKCBUBX-UHFFFAOYSA-N CC(C)(CC1(C)C)CN1c(nc(cc1)Br)c1C(N)=O Chemical compound CC(C)(CC1(C)C)CN1c(nc(cc1)Br)c1C(N)=O ISNWWZNXKCBUBX-UHFFFAOYSA-N 0.000 description 1
- UVJSCAUSYDTORL-UHFFFAOYSA-N CC(C)(COc1n[nH]cc1C(O)=O)C(F)(F)F Chemical compound CC(C)(COc1n[nH]cc1C(O)=O)C(F)(F)F UVJSCAUSYDTORL-UHFFFAOYSA-N 0.000 description 1
- FZIVTGCLMQWUJT-UHFFFAOYSA-N CC1(C)CNC(C)(C)C1 Chemical compound CC1(C)CNC(C)(C)C1 FZIVTGCLMQWUJT-UHFFFAOYSA-N 0.000 description 1
- TZQLFMOZPOGOHK-UHFFFAOYSA-N CCC(CC1(C)C)CN1c(nc(cc1)-[n](cc2)nc2OCCC2(CC2)C(F)(F)F)c1C(NS(CC)c1ccccc1)=O Chemical compound CCC(CC1(C)C)CN1c(nc(cc1)-[n](cc2)nc2OCCC2(CC2)C(F)(F)F)c1C(NS(CC)c1ccccc1)=O TZQLFMOZPOGOHK-UHFFFAOYSA-N 0.000 description 1
- HLBPDARMNVZKHE-UHFFFAOYSA-N CCOC(c1c[nH]nc1OCCC1(CC1)C(F)(F)F)=O Chemical compound CCOC(c1c[nH]nc1OCCC1(CC1)C(F)(F)F)=O HLBPDARMNVZKHE-UHFFFAOYSA-N 0.000 description 1
- BPKAKJIHHLFACU-UHFFFAOYSA-N CCOC(c1c[n](C2OCCCC2)nc1O)=O Chemical compound CCOC(c1c[n](C2OCCCC2)nc1O)=O BPKAKJIHHLFACU-UHFFFAOYSA-N 0.000 description 1
- XNANEWVIXDXJRA-UHFFFAOYSA-N CS(OCCC1(CC1)C(F)(F)F)(=O)=O Chemical compound CS(OCCC1(CC1)C(F)(F)F)(=O)=O XNANEWVIXDXJRA-UHFFFAOYSA-N 0.000 description 1
- AKVDBLRGWJVDAQ-HNNXBMFYSA-N C[C@@H](CC1(C)C)CN1c(nc(cc1)Br)c1C(NS(C1=CC=CC=CC=C1)(=O)=O)=O Chemical compound C[C@@H](CC1(C)C)CN1c(nc(cc1)Br)c1C(NS(C1=CC=CC=CC=C1)(=O)=O)=O AKVDBLRGWJVDAQ-HNNXBMFYSA-N 0.000 description 1
- MVRHVFSOIWFBTE-INIZCTEOSA-N C[C@@H](CC1(C)C)CN1c1nc(-[n](cc2)nc2OCC(C)(C)C(F)(F)F)ccc1C(NS(c1c[n](C)nc1C)(=O)=O)=O Chemical compound C[C@@H](CC1(C)C)CN1c1nc(-[n](cc2)nc2OCC(C)(C)C(F)(F)F)ccc1C(NS(c1c[n](C)nc1C)(=O)=O)=O MVRHVFSOIWFBTE-INIZCTEOSA-N 0.000 description 1
- LEGZBZOKITXMNO-IENPIDJESA-N C[C@@H]1CNC(C)(C/C=S\C)C1 Chemical compound C[C@@H]1CNC(C)(C/C=S\C)C1 LEGZBZOKITXMNO-IENPIDJESA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- GNLNNQWSFIYXHK-UHFFFAOYSA-N [Ru].C1(=CC=CC=C1)P(CCNCC1=NC=CC=C1)C1=CC=CC=C1.ClC=1C(=C(C=CC1)P(C1=CC=CC=C1)C1=CC=CC=C1)Cl Chemical compound [Ru].C1(=CC=CC=C1)P(CCNCC1=NC=CC=C1)C1=CC=CC=C1.ClC=1C(=C(C=CC1)P(C1=CC=CC=C1)C1=CC=CC=C1)Cl GNLNNQWSFIYXHK-UHFFFAOYSA-N 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 238000005262 decarbonization Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- BJNVYFXBTNBKRU-UHFFFAOYSA-L dichlororuthenium;2-diphenylphosphanylethanamine Chemical compound Cl[Ru]Cl.C=1C=CC=CC=1P(CCN)C1=CC=CC=C1.C=1C=CC=CC=1P(CCN)C1=CC=CC=C1 BJNVYFXBTNBKRU-UHFFFAOYSA-L 0.000 description 1
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- ZUZLIXGTXQBUDC-UHFFFAOYSA-N methyltrioctylammonium Chemical compound CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC ZUZLIXGTXQBUDC-UHFFFAOYSA-N 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical group 0.000 description 1
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 1
- DHAWHVVWUNNONG-UHFFFAOYSA-M tributyl(methyl)azanium;bromide Chemical compound [Br-].CCCC[N+](C)(CCCC)CCCC DHAWHVVWUNNONG-UHFFFAOYSA-M 0.000 description 1
- IPILPUZVTYHGIL-UHFFFAOYSA-M tributyl(methyl)azanium;chloride Chemical group [Cl-].CCCC[N+](C)(CCCC)CCCC IPILPUZVTYHGIL-UHFFFAOYSA-M 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical group ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762596452P | 2017-12-08 | 2017-12-08 | |
| US62/596,452 | 2017-12-08 | ||
| US201862623725P | 2018-01-30 | 2018-01-30 | |
| US62/623,725 | 2018-01-30 | ||
| US201862649970P | 2018-03-29 | 2018-03-29 | |
| US62/649,970 | 2018-03-29 | ||
| PCT/US2018/064522 WO2019113476A2 (en) | 2017-12-08 | 2018-12-07 | Processes for making modulators of cystic fibrosis transmembrane conductance regulator |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2021505579A JP2021505579A (ja) | 2021-02-18 |
| JP2021505579A5 true JP2021505579A5 (enExample) | 2022-01-11 |
| JP7245834B2 JP7245834B2 (ja) | 2023-03-24 |
Family
ID=64902470
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020530591A Active JP7245834B2 (ja) | 2017-12-08 | 2018-12-07 | 嚢胞性線維症膜コンダクタンス制御因子のモジュレーターを作成するためのプロセス |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US11465985B2 (enExample) |
| EP (1) | EP3720849A2 (enExample) |
| JP (1) | JP7245834B2 (enExample) |
| KR (1) | KR102716244B1 (enExample) |
| CN (1) | CN111757874B (enExample) |
| AU (1) | AU2018380426B2 (enExample) |
| CA (1) | CA3085006A1 (enExample) |
| IL (1) | IL275049B2 (enExample) |
| MA (1) | MA51039A (enExample) |
| MX (1) | MX2020005753A (enExample) |
| TW (1) | TWI801465B (enExample) |
| WO (1) | WO2019113476A2 (enExample) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT3203840T (pt) | 2014-10-06 | 2020-10-27 | Vertex Pharma | Moduladores do regulador da condutância transmembranar da fibrose quística |
| LT3519401T (lt) | 2016-09-30 | 2021-11-25 | Vertex Pharmaceuticals Incorporated | Cistinės fibrozės transmembraninio laidumo reguliavimo moduliatorius, farmacinės kompozicijos, gydymo būdai ir moduliatoriaus gamybos būdas |
| MX2021013639A (es) | 2016-12-09 | 2022-09-30 | Vertex Pharma | Forma cristalina del compuesto 1, un modulador del regulador de conductancia transmembrana de fibrosis quística, procesos para su preparación, composiciones farmacéuticas del compuesto 1, y su uso en el tratamiento de fibrosis quística. |
| CA3066084A1 (en) | 2017-06-08 | 2018-12-13 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| AU2018304168B2 (en) | 2017-07-17 | 2023-05-04 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| CN111051280B (zh) | 2017-08-02 | 2023-12-22 | 弗特克斯药品有限公司 | 制备吡咯烷化合物的方法 |
| TWI719349B (zh) | 2017-10-19 | 2021-02-21 | 美商維泰克斯製藥公司 | Ｃｆｔｒ調節劑之結晶形式及組合物 |
| MA51039A (fr) | 2017-12-08 | 2020-10-14 | Vertex Pharma | Procédés pour préparer des modulateurs du régulateur de la conductance transmembranaire de la mucoviscidose |
| TWI810243B (zh) | 2018-02-05 | 2023-08-01 | 美商維泰克斯製藥公司 | 用於治療囊腫纖化症之醫藥組合物 |
| SI3752510T1 (sl) | 2018-02-15 | 2023-03-31 | Vertex Pharmaceuticals Incorporated | Makrocikli kot modulatorji regulatorja transmembranske prevodnosti pri cistični fibrozi, farmacevtski sestavki iz le-teh, njihova uporaba pri zdravljenju cistične fibroze in postopek za njihovo proizvodnjo |
| EP3774825A1 (en) | 2018-04-13 | 2021-02-17 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
| AR118555A1 (es) | 2019-04-03 | 2021-10-20 | Vertex Pharma | Agentes moduladores del regulador de la conductancia transmembrana de la fibrosis quística |
| SI4013741T1 (sl) | 2019-08-14 | 2024-06-28 | Vertex Pharmaceuticals Incorporated | Postopek za izdelavo cftr-modulatorjev |
| CA3150162A1 (en) | 2019-08-14 | 2021-02-18 | Vertex Pharmaceuticals Incorporated | Crystalline forms of cftr modulators |
| TWI867024B (zh) | 2019-08-14 | 2024-12-21 | 美商維泰克斯製藥公司 | 囊腫纖維化跨膜傳導調節蛋白之調節劑 |
| CR20230120A (es) | 2020-08-07 | 2023-09-01 | Vertex Pharma | Moduladores del regulador de la conductancia transmembrana de la fibrosis quística |
| CN111943848B (zh) * | 2020-08-19 | 2023-05-05 | 苏州旺山旺水生物医药有限公司 | 一种elexacaftor中间体的制备方法及其应用 |
| MX2023004074A (es) * | 2020-10-07 | 2023-07-05 | Vertex Pharma | Moduladores del regulador de la conductancia transmembrana de la fibrosis quistica. |
| US12324802B2 (en) | 2020-11-18 | 2025-06-10 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
| EP4259139A1 (en) | 2020-12-10 | 2023-10-18 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| TW202333699A (zh) | 2022-02-03 | 2023-09-01 | 美商維泰克斯製藥公司 | 囊腫纖維化之治療方法 |
| CA3249865A1 (en) | 2022-02-03 | 2023-08-10 | Vertex Pharma | PROCESSES FOR PREPARATION AND CRYSTALLINE FORMS OF (6A,12A)-17-AMINO-12-METHYL-6,15-BIS(TRIFLUOROMETHYL)-13,19-DIOXA-3,4,18-TRIAZATRICYCLO[12,3,1,12,5]NONADECA-1(18),2,4,14,16-PENTAEN-6-OL |
| CN118974059A (zh) | 2022-02-08 | 2024-11-15 | 弗特克斯药品有限公司 | 囊性纤维化跨膜传导调控因子的调节剂 |
| AU2023272562A1 (en) | 2022-05-16 | 2024-11-07 | Vertex Pharmaceuticals Incorporated | Solid forms of a macrocyclic compounds as cftr modulators and their preparation |
| EP4525858A1 (en) | 2022-05-16 | 2025-03-26 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| CN115536493A (zh) * | 2022-10-20 | 2022-12-30 | 海门瑞一医药科技有限公司 | 一种制取3,3,3-三氟甲基-2,2-二甲基丙烷醇的简单方法 |
| WO2025166342A1 (en) | 2024-02-04 | 2025-08-07 | Vertex Pharmaceuticals Incorporated | Combination of vanzacaftor, tezacaftor, deutivacaftor for use in treating cystic fibrosis |
Family Cites Families (235)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB967177A (en) | 1959-10-13 | 1964-08-19 | Rohm & Haas | A method for preparing pyrrolidinones and piperidinones |
| EP0194599A3 (en) | 1985-03-14 | 1988-01-20 | Nissan Chemical Industries Ltd. | Benzamide derivatives, process for producing the same, and soil fungicides containing the same |
| GB9122590D0 (en) | 1991-10-24 | 1991-12-04 | Lilly Industries Ltd | Pharmaceutical compounds |
| DE4410453A1 (de) | 1994-03-25 | 1995-09-28 | Hoechst Ag | Substituierte heterocyclische Carbonsäureamidester, ihre Herstellung und ihre Verwendung als Arzneimittel |
| GB9514160D0 (en) | 1994-07-25 | 1995-09-13 | Zeneca Ltd | Aromatic compounds |
| AU4437296A (en) | 1995-01-19 | 1996-08-07 | Novartis Ag | Herbicidal composition |
| EA001418B1 (ru) | 1995-11-23 | 2001-02-26 | Новартис Аг | Гербицидная композиция |
| EP0873311A1 (en) | 1995-12-15 | 1998-10-28 | Merck Frosst Canada Inc. | Tri-aryl ethane derivatives as pde iv inhibitors |
| WO1998008818A1 (en) | 1996-08-26 | 1998-03-05 | Genetics Institute, Inc. | Inhibitors of phospholipase enzymes |
| JPH10114654A (ja) | 1996-10-09 | 1998-05-06 | Fujisawa Pharmaceut Co Ltd | 新規用途 |
| AU6209098A (en) | 1997-01-15 | 1998-08-07 | Novartis Ag | Herbicidal agent |
| GB9716657D0 (en) | 1997-08-07 | 1997-10-15 | Zeneca Ltd | Chemical compounds |
| DE19742951A1 (de) | 1997-09-29 | 1999-04-15 | Hoechst Schering Agrevo Gmbh | Acylsulfamoylbenzoesäureamide, diese enthaltende nutzpflanzenschützende Mittel und Verfahren zu ihrer Herstellung |
| DE19802697A1 (de) | 1998-01-24 | 1999-07-29 | Bayer Ag | Selektive Herbizide auf Basis von N-Aryl-triazolin(thi)onen und N-Arylsulfonylamino(thio)carbonyltriazolin(thi)onen |
| WO1999041238A1 (en) | 1998-02-13 | 1999-08-19 | Kureha Kagaku Kogyo K.K. | N-(phenylsulfonyl) picolinamide derivatives, process for producing the same, and herbicide |
| EP1070705A4 (en) | 1998-04-06 | 2002-04-17 | Fujisawa Pharmaceutical Co | INDOLE DERIVATIVES |
| CN1156445C (zh) | 1999-06-10 | 2004-07-07 | 沃尼尔·朗伯公司 | 采用二氢异吲哚衍生物抑制淀粉样蛋白聚集和使淀粉样蛋白沉积成像的方法 |
| DE19936438A1 (de) | 1999-08-03 | 2001-02-08 | Aventis Cropscience Gmbh | Kombinationen von Herbiziden und Safenern |
| DE19940860A1 (de) | 1999-08-27 | 2001-03-01 | Bayer Ag | Selektive Herbizide auf Basis eines substituierten Phenylsulfonyl aminocarbonyltriazolinons und Safenern II |
| DE19958381A1 (de) | 1999-12-03 | 2001-06-07 | Bayer Ag | Herbizide auf Basis von N-Aryl-uracilen |
| AU2001286557A1 (en) | 2000-08-23 | 2002-03-04 | Merck Frosst Canada And Co. | Method of treating or preventing urinary incontinence using prostanoid ep1 receptor antagonists |
| AR031130A1 (es) | 2000-09-20 | 2003-09-10 | Abbott Lab | N-acilsulfonamidas promotoras de la apoptosis |
| US20020055631A1 (en) | 2000-09-20 | 2002-05-09 | Augeri David J. | N-acylsulfonamide apoptosis promoters |
| US6720338B2 (en) | 2000-09-20 | 2004-04-13 | Abbott Laboratories | N-acylsulfonamide apoptosis promoters |
| AU2002211901A1 (en) | 2000-10-10 | 2002-04-22 | Smithkline Beecham Corporation | Substituted indoles, pharmaceutical compositions containing such indoles and their use as PPAR-gamma binding agents |
| DE10119721A1 (de) | 2001-04-21 | 2002-10-31 | Bayer Cropscience Gmbh | Herbizide Mittel enthaltend Benzoylcyclohexandione und Safener |
| DK1395566T3 (da) | 2001-05-31 | 2008-01-07 | Vicore Pharma Ab | Tricycliske forbindelser, der er nyttige som angiotensin Il-agonister |
| SI1404653T1 (sl) | 2001-06-28 | 2008-12-31 | Pfizer Prod Inc | S triamidom substituirani indoli, benzofurani in benzotiofeni kot zaviralci mikrosomske prenašalnebeljakovine za trigliceride (MTP) in/ali izločanja apolipoproteina B (APO B) |
| DE10145019A1 (de) | 2001-09-13 | 2003-04-03 | Bayer Cropscience Gmbh | Kombinationen aus Herbiziden und Safenern |
| DE10146873A1 (de) | 2001-09-24 | 2003-04-17 | Bayer Cropscience Gmbh | Heterocyclische Amide und -Iminderivate, Verfahren zu ihrer Herstellung, sie enthaltende Mittel und ihre Verwendung als Schädlingsbekämpfungsmittel |
| MXPA04004657A (es) | 2001-11-14 | 2004-08-13 | Teva Pharma | Formas amorfas y cristalinas de potasio de losartan y proceso para su preparacion. |
| EP1447096A1 (en) | 2001-11-19 | 2004-08-18 | Ono Pharmaceutical Co., Ltd. | Remedies for urinary frequency |
| DE10157545A1 (de) | 2001-11-23 | 2003-06-12 | Bayer Cropscience Gmbh | Herbizide Mittel enthaltend Benzoylpyrazole und Safener |
| EP1497270A4 (en) | 2002-03-27 | 2006-01-04 | Smithkline Beecham Corp | AMID COMPOUNDS AND METHOD FOR THEIR USE |
| GB0212785D0 (en) | 2002-05-31 | 2002-07-10 | Glaxo Group Ltd | Compounds |
| ATE324038T1 (de) | 2002-06-08 | 2006-05-15 | Bayer Cropscience Gmbh | Kombinationen von herbiziden aromatischen carbonsäuren und safener-mitteln |
| DE10237461A1 (de) | 2002-08-16 | 2004-02-26 | Bayer Cropscience Gmbh | Herbizide Mittel enthaltend Benzoylpyrazole und Safener |
| AU2003288901A1 (en) | 2002-09-06 | 2004-03-29 | Merck And Co., Inc. | Treatment of rheumatoid arthritis by inhibition of pde4 |
| WO2004028480A2 (en) | 2002-09-30 | 2004-04-08 | The Regents Of The University Of California | Cystic fibrosis transmembrane conductance regulator protein inhibitors and uses thereof |
| WO2004037798A1 (en) | 2002-10-22 | 2004-05-06 | Merck Frosst Canada & Co. | Nitric oxide releasing selective cyclooxygenase-2 inhibitors |
| GB0225548D0 (en) | 2002-11-01 | 2002-12-11 | Glaxo Group Ltd | Compounds |
| WO2004046141A1 (en) | 2002-11-21 | 2004-06-03 | Vicore Pharma Ab | New tricyclic angiotensin ii agonists |
| CA2505604A1 (en) | 2002-12-20 | 2004-07-08 | Pfizer Products Inc. | Microsomal triglyceride transfer protein inhibitors |
| WO2004056775A1 (en) | 2002-12-20 | 2004-07-08 | Pfizer Products Inc. | Microsomal triglyceride transfer protein inhibitors |
| WO2004078114A2 (en) | 2003-02-28 | 2004-09-16 | Encysive Pharmaceuticals Inc. | Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-ii receptor antagonists. |
| WO2004085420A1 (en) | 2003-03-24 | 2004-10-07 | Vicore Pharma Ab | Bicyclic compounds useful as angiotensin ii agonists |
| ATE440825T1 (de) | 2003-06-06 | 2009-09-15 | Vertex Pharma | Pyrimidin-derivate zur verwendung als modulatoren von atp-bindende kassette transportern |
| WO2005049593A2 (en) | 2003-11-13 | 2005-06-02 | Abbott Laboratories | N-acylsulfonamide apoptosis promoters |
| CA2545719A1 (en) | 2003-11-14 | 2005-06-02 | Vertex Pharmaceuticals Incorporated | Thiazoles and oxazoles useful as modulators of atp-binding cassette transporters |
| GB0328024D0 (en) | 2003-12-03 | 2004-01-07 | Glaxo Group Ltd | Compounds |
| AU2005207037A1 (en) | 2004-01-22 | 2005-08-04 | Nitromed, Inc. | Nitrosated and/or nitrosylated compounds, compositions and methods of use |
| WO2005075435A1 (en) | 2004-01-30 | 2005-08-18 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
| US7977322B2 (en) | 2004-08-20 | 2011-07-12 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
| WO2005080373A1 (en) | 2004-02-04 | 2005-09-01 | Pfizer Products Inc. | Substituted quinoline compounds |
| WO2005082414A2 (en) | 2004-03-02 | 2005-09-09 | Astellas Pharma Inc. | Concomitant drugs of a sulfonamide and another therapeutic agent |
| CN1930136B (zh) | 2004-03-05 | 2012-02-08 | 日产化学工业株式会社 | 异*唑啉取代苯甲酰胺化合物及有害生物防除剂 |
| WO2005099705A2 (en) | 2004-03-24 | 2005-10-27 | Bayer Pharmaceuticals Corporation | Preparation of imidazole derivatives and methods of use |
| CA2561560A1 (en) | 2004-03-30 | 2005-10-13 | The Regents Of The University Of California | Hydrazide-containing cftr inhibitor compounds and uses thereof |
| GB0410121D0 (en) | 2004-05-06 | 2004-06-09 | Glaxo Group Ltd | Compounds |
| US8354427B2 (en) | 2004-06-24 | 2013-01-15 | Vertex Pharmaceutical Incorporated | Modulators of ATP-binding cassette transporters |
| PL2489659T3 (pl) | 2004-06-24 | 2018-06-29 | Vertex Pharma | Modulatory transporterów posiadających kasetę wiążącą atp |
| US7550463B2 (en) | 2004-09-15 | 2009-06-23 | Shionogi & Co., Ltd. | Carbamoylpyridone derivatives having inhibitory activity against HIV integrase |
| BRPI0516181A (pt) | 2004-09-29 | 2008-08-26 | Portola Pharm Inc | composto e sais farmaceuticamente aceitáveis do mesmo, composição farmacêutica, e, métodos para tratar trombose em um indivìduo e para prevenir a ocorrência de um evento isquêmico secundário |
| US20080287399A1 (en) | 2004-12-14 | 2008-11-20 | Astrazeneca Ab | Substituted Aminopyridines and Uses Thereof |
| US8101770B2 (en) | 2004-12-16 | 2012-01-24 | Vertex Pharmaceuticals Incorporated | Pyridones useful as inhibitors of kinases |
| GB0428173D0 (en) | 2004-12-23 | 2005-01-26 | Astrazeneca Ab | Compounds |
| EA200801909A1 (ru) | 2004-12-23 | 2009-06-30 | Глэксо Груп Лимитед | Соединения пиридина для лечения заболеваний, опосредованных действием простагландина |
| ATE533749T1 (de) | 2005-05-24 | 2011-12-15 | Vertex Pharma | Modulatoren von atp-bindenden kassettentransportern |
| WO2007019397A2 (en) | 2005-08-05 | 2007-02-15 | Genelabs Technologies, Inc. | 6-membered aryl and heteroaryl derivatives for the treatment of hepatitis c virus |
| KR20080053297A (ko) | 2005-08-11 | 2008-06-12 | 버텍스 파마슈티칼스 인코포레이티드 | 낭포성 섬유종 트랜스막 전도도 조정자의 조절자 |
| WO2007053641A2 (en) | 2005-11-01 | 2007-05-10 | Mars, Incorporated | A-type procyanidins and inflammation |
| DK2774925T3 (en) | 2005-11-08 | 2017-02-27 | Vertex Pharma | Heterocyclic modulators of ATP binding cassette transporters |
| EP1974212A1 (en) | 2005-12-27 | 2008-10-01 | Vertex Pharmaceuticals Incorporated | Compounds useful in cftr assays and methods therewith |
| US7671221B2 (en) | 2005-12-28 | 2010-03-02 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette transporters |
| NZ569327A (en) | 2005-12-28 | 2011-09-30 | Vertex Pharma | 1-(benzo [d] [1,3] dioxol-5-yl) -n- (phenyl) cyclopropane- carboxamide derivatives and related compounds as modulators of ATP-binding cassette transporters for the treatment of cystic fibrosis |
| PT1993360T (pt) | 2005-12-28 | 2017-05-25 | Vertex Pharma | Formas sólidas de n-[2,4-bis(1,1-dimetiletil)-5-hidroxifenil]-1,4-di-hidro-4-oxoquinolina-3-carboxamida |
| WO2007113327A2 (en) | 2006-04-05 | 2007-10-11 | Bayer Cropscience Sa | Fungicide n-cyclopropyl-sulfonylamide derivatives |
| ES2882684T3 (es) | 2006-04-07 | 2021-12-02 | Vertex Pharma | Preparación de moduladores de transportadores del casete de unión a ATP |
| JP2009536969A (ja) | 2006-05-12 | 2009-10-22 | バーテックス ファーマシューティカルズ インコーポレイテッド | Ｎ−［２，４−ビス（１，１−ジメチルエチル）−５−ヒドロキシフェニル］−１，４−ジヒドロ−４−オキソキノリン−３−カルボキサミド組成物 |
| JP5642963B2 (ja) | 2006-06-30 | 2014-12-17 | スネシス ファーマシューティカルズ，インコーポレイティド | ピリジノニルｐｄｋ１阻害剤 |
| EP2826778B1 (en) | 2006-11-03 | 2017-09-20 | Vertex Pharmaceuticals Incorporated | Azaindole derivatives as CFTR modulators |
| US7754739B2 (en) | 2007-05-09 | 2010-07-13 | Vertex Pharmaceuticals Incorporated | Modulators of CFTR |
| AU2008216382A1 (en) | 2007-02-12 | 2008-08-21 | Array Biopharma, Inc. | Novel inhibitors hepatitis C virus replication |
| WO2008141385A1 (en) | 2007-05-21 | 2008-11-27 | Biota Scientific Management Pty Ltd | Viral polymerase inhibitors |
| US8058299B2 (en) | 2007-05-22 | 2011-11-15 | Via Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
| CA2687608C (en) * | 2007-05-25 | 2013-07-02 | Amgen Inc. | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
| TW200901991A (en) * | 2007-05-25 | 2009-01-16 | Amgen Inc | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
| GB0716532D0 (en) | 2007-08-24 | 2007-10-03 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| PE20090995A1 (es) | 2007-08-29 | 2009-08-03 | Schering Corp | Derivados indolicos 2,3-sustituidos como inhibidores del virus de la hepatitis c (vhc) |
| BRPI0816345A2 (pt) | 2007-09-14 | 2015-02-24 | Vertex Pharma | Formas sólidas de n-[2,4-bis-(1,1-dimetiletil)-5-hidroxifenil]-1,4-diidro-4-o xoquinolin-3-carboxamida |
| WO2009064848A1 (en) | 2007-11-16 | 2009-05-22 | Schering Corporation | 3-heterocyclic substituted indole derivatives and methods of use thereof |
| AU2013231151B2 (en) | 2007-11-16 | 2015-06-25 | Vertex Pharmaceuticals Incorporated | Isoquinoline modulators of ATP-Binding Cassette transporters |
| GB0723794D0 (en) | 2007-12-05 | 2008-01-16 | Lectus Therapeutics Ltd | Potassium ion channel modulators and uses thereof |
| CN103626744B (zh) | 2007-12-07 | 2016-05-11 | 沃泰克斯药物股份有限公司 | 3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的固体形式 |
| AU2008335440B2 (en) | 2007-12-07 | 2013-11-07 | Vertex Pharmaceuticals Incorporated | Processes for producing cycloalkylcarboxamido-pyridine benzoic acids |
| AU2013270464B2 (en) | 2008-03-31 | 2016-05-26 | Vertex Pharmaceuticals Incorporated | Pyridyl derivatives as CFTR modulators |
| JP2011520785A (ja) | 2008-04-16 | 2011-07-21 | バイオリポックス エービー | 薬剤としての使用のためのビスアリール化合物 |
| US20110112193A1 (en) | 2008-05-14 | 2011-05-12 | Peter Nilsson | Bis-aryl compounds for use as medicaments |
| EP2145537A1 (en) | 2008-07-09 | 2010-01-20 | Bayer CropScience AG | Plant growth regulator |
| UY31982A (es) | 2008-07-16 | 2010-02-26 | Boehringer Ingelheim Int | Derivados de 1,2-dihidropiridin-3-carboxamidas n-sustituidas |
| US20100074949A1 (en) | 2008-08-13 | 2010-03-25 | William Rowe | Pharmaceutical composition and administration thereof |
| KR20110042356A (ko) | 2008-08-13 | 2011-04-26 | 버텍스 파마슈티칼스 인코포레이티드 | 제약 조성물 및 그의 투여 |
| EP2326178A4 (en) | 2008-08-21 | 2012-10-24 | Glaxosmithkline Llc | INHIBITORS OF PROLYL-HYDROXYLASE |
| KR101724161B1 (ko) | 2008-08-27 | 2017-04-06 | 칼시메디카, 인크 | 세포내 칼슘을 조절하는 화합물 |
| UA104147C2 (uk) | 2008-09-10 | 2014-01-10 | Новартис Аг | Похідна піролідиндикарбонової кислоти та її застосування у лікуванні проліферативних захворювань |
| SI2349263T1 (sl) | 2008-10-23 | 2014-09-30 | Vertex Pharmaceuticals Incorporated | Modulatorji cistiäśno-fibroznega transmembranskega regulatorja prevodnosti |
| UA104876C2 (uk) | 2008-11-06 | 2014-03-25 | Вертекс Фармасьютікалз Інкорпорейтед | Модулятори atф-зв'язувальних касетних транспортерів |
| KR20160013251A (ko) | 2008-11-06 | 2016-02-03 | 버텍스 파마슈티칼스 인코포레이티드 | Ａｔｐ-결합 카세트 수송자의 조절자 |
| US20100160322A1 (en) | 2008-12-04 | 2010-06-24 | Abbott Laboratories | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
| UA108193C2 (uk) | 2008-12-04 | 2015-04-10 | Апоптозіндукуючий засіб для лікування раку і імунних і аутоімунних захворювань | |
| WO2010078103A1 (en) | 2008-12-30 | 2010-07-08 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
| NZ593593A (en) | 2009-01-19 | 2013-11-29 | Abbvie Inc | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
| BRPI1008949B1 (pt) | 2009-03-11 | 2018-07-10 | Bayer Intellectual Property Gmbh | Cetoenóis haloalquilmetilenóxi-fenil-substituídos e seu uso, composição, seu uso e seu método de produção, métodos para combate de pestes animais e/ou crescimento de plantas indesejadas |
| ES2683633T3 (es) | 2009-03-20 | 2018-09-27 | Vertex Pharmaceuticals Incorporated | Moduladores de regulador de conductancia transmembrana de la fibrosis quística |
| EP3330255B1 (en) | 2009-03-20 | 2020-12-09 | Vertex Pharmaceuticals Incorporated | Process for making modulators of cystic fibrosis transmembrane conductance regulator |
| WO2010110231A1 (ja) | 2009-03-26 | 2010-09-30 | 塩野義製薬株式会社 | 置換された３－ヒドロキシ－４－ピリドン誘導体 |
| WO2010123822A1 (en) | 2009-04-20 | 2010-10-28 | Institute For Oneworld Health | Compounds, compositions and methods comprising pyridazine sulfonamide derivatives |
| UY32668A (es) | 2009-05-26 | 2010-12-31 | Abbott Lab | Agentes inductores de la apoptosis para el tratamiento del cáncer y de enfermedades inmunes y autoinmunes |
| WO2011102514A1 (ja) | 2010-02-22 | 2011-08-25 | 武田薬品工業株式会社 | 芳香環化合物 |
| AU2011227021A1 (en) | 2010-03-19 | 2012-10-18 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
| US8247436B2 (en) | 2010-03-19 | 2012-08-21 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
| ES2845449T3 (es) | 2010-03-25 | 2021-07-26 | Vertex Pharma | Dispersión sólida de forma amorfa de (R)-1(2,2-difluorobenzo[d][1,3]dioxol-5-il)-N-(1-(2,3-dihidroxipropil)-6-fluoro-2(1-hidroxi-2-metilpropan-2-il)-1h-indol-5il)-ciclopropanocarboxamida |
| AR081069A1 (es) | 2010-04-07 | 2012-06-06 | Vertex Pharma | Formas solidas del acido 3-(6-(1-(2,2-difluorbenzo[d][1,3]dioxol-5-il)ciclopropancarboxamido)-3-metilpiridin-2-il)benzoico |
| EP2555755B2 (en) | 2010-04-07 | 2019-07-10 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyriodin-2-yl)benzoic acid and administration thereof |
| US8344137B2 (en) | 2010-04-14 | 2013-01-01 | Hoffman-La Roche Inc. | 3,3-dimethyl tetrahydroquinoline derivatives |
| AU2011242452A1 (en) | 2010-04-22 | 2012-11-08 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions and administrations thereof |
| RU2569678C2 (ru) | 2010-04-22 | 2015-11-27 | Вертекс Фармасьютикалз Инкорпорейтед | Способ получения циклоалкилкарбоксамидо-индольных соединений |
| TWI520960B (zh) | 2010-05-26 | 2016-02-11 | 艾伯維有限公司 | 用於治療癌症及免疫及自體免疫疾病之細胞凋亡誘導劑 |
| US8563593B2 (en) | 2010-06-08 | 2013-10-22 | Vertex Pharmaceuticals Incorporated | Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide |
| CA2808501A1 (en) | 2010-08-23 | 2012-03-01 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition of (r)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxy propyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide and administration therof |
| RU2013113627A (ru) | 2010-08-27 | 2014-10-10 | Вертекс Фармасьютикалз Инкорпорейтед | Фармацевтическая композиция и ее введения |
| WO2012052540A1 (en) | 2010-10-21 | 2012-04-26 | Universitaet Des Saarlandes | Selective cyp11b1 inhibitors for the treatment of cortisol dependent diseases |
| WO2012087938A1 (en) | 2010-12-20 | 2012-06-28 | Glaxosmithkline Llc | Quinazolinone derivatives as antiviral agents |
| EP2471363A1 (de) | 2010-12-30 | 2012-07-04 | Bayer CropScience AG | Verwendung von Aryl-, Heteroaryl- und Benzylsulfonamidocarbonsäuren, -carbonsäureestern, -carbonsäureamiden und -carbonitrilen oder deren Salze zur Steigerung der Stresstoleranz in Pflanzen |
| JPWO2012102297A1 (ja) | 2011-01-26 | 2014-06-30 | 杏林製薬株式会社 | ピラゾロピリジン誘導体、またはその薬理学的に許容される塩 |
| BR112013021021A2 (pt) | 2011-02-17 | 2016-08-02 | Bayer Ip Gmbh | 3- (bifenil - 3 - il) - 8, 8 - difluoro - 4 - hidroxi - 1 - azaspiro [4, 5] dec - 3 - eno - 2 - onas substituídas para terapia e cetoenóis espirocíclicos substituídos com halogéneo |
| AU2012222517B2 (en) | 2011-03-01 | 2016-09-22 | Bayer Intellectual Property Gmbh | 2-acyloxy-pyrrolin-4-ones |
| AR085585A1 (es) | 2011-04-15 | 2013-10-09 | Bayer Cropscience Ag | Vinil- y alquinilciclohexanoles sustituidos como principios activos contra estres abiotico de plantas |
| ME03652B (me) | 2011-05-18 | 2020-07-20 | Vertex Pharmaceuticals Europe Ltd | Deuterisani derivati ivakaftora |
| EP2714680B1 (en) | 2011-05-27 | 2015-11-25 | Amira Pharmaceuticals, Inc. | Heterocyclic autotaxin inhibitors and uses thereof |
| AU2012284127A1 (en) | 2011-07-18 | 2013-05-02 | Adolor Corporation | Processes for the preparation of peripheral opioid antagonist compounds and intermediates thereto |
| CA2844521A1 (en) | 2011-08-30 | 2013-03-07 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
| WO2013037955A1 (en) | 2011-09-16 | 2013-03-21 | Bayer Intellectual Property Gmbh | Use of acylsulfonamides for improving plant yield |
| WO2013038373A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
| US9034879B2 (en) | 2011-09-16 | 2015-05-19 | Novartis Ag | Heterocyclic compounds for the treatment of CF |
| BR112014006940A2 (pt) | 2011-09-23 | 2017-04-04 | Bayer Ip Gmbh | uso de derivados de ácido 1-fenilpirazol-3-carboxílico 4-substituído como agentes contra estresse abiótico em plantas |
| US9254291B2 (en) | 2011-11-08 | 2016-02-09 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
| US8426450B1 (en) | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
| SMT201900451T1 (it) | 2012-01-25 | 2019-11-13 | Vertex Pharma | Formulazioni di acido 3-(6-(1-(2,2-difluorobenzo[d][1,3]diossol-5-il) ciclopropancarbossammido)-3-metilpiridin-2-il)benzoico |
| JP2015083542A (ja) | 2012-02-08 | 2015-04-30 | 大日本住友製薬株式会社 | ３位置換プロリン誘導体 |
| IL311180A (en) | 2012-02-27 | 2024-04-01 | Vertex Pharma | Pharmaceutical preparations containing a solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and uses thereof |
| US8889730B2 (en) | 2012-04-10 | 2014-11-18 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
| EP2838882A1 (en) | 2012-04-20 | 2015-02-25 | Vertex Pharmaceuticals Incorporated | Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
| KR101719893B1 (ko) | 2012-05-22 | 2017-03-24 | 제넨테크, 인크. | Ｎ-치환된 벤즈아미드 및 통증의 치료에서 이들의 용도 |
| CA2874851A1 (en) | 2012-06-08 | 2013-12-12 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions for the treatment of cftr-mediated disorders |
| WO2013185202A1 (en) | 2012-06-14 | 2013-12-19 | Beta Pharma Canada Inc | Apoptosis inducers |
| JP6309519B2 (ja) | 2012-07-06 | 2018-04-11 | ジェネンテック， インコーポレイテッド | Ｎ置換ベンズアミド及びその使用方法 |
| US9012496B2 (en) | 2012-07-16 | 2015-04-21 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide and administration thereof |
| JP2015178458A (ja) | 2012-07-25 | 2015-10-08 | 杏林製薬株式会社 | ベンゼン環縮合含窒素５員複素環式化合物、またはその薬理学的に許容される塩 |
| JP6225187B2 (ja) | 2012-08-13 | 2017-11-01 | アッヴィ・インコーポレイテッド | アポトーシス誘発剤 |
| CA2881357C (en) | 2012-08-21 | 2020-12-08 | Peter Maccallum Cancer Institute | Perforin inhibiting benzenesulfonamide compounds, preparation and uses thereof |
| WO2014039714A2 (en) | 2012-09-06 | 2014-03-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| WO2014047427A2 (en) | 2012-09-21 | 2014-03-27 | Vanderbilt University | Substituted benzofuran, benzothiophene and indole mcl-1 inhibitors |
| WO2014071247A1 (en) | 2012-11-02 | 2014-05-08 | Dana-Farber Cancer Institute, Inc. | Pyrrol-1 -yl benzoic acid derivates useful as myc inhibitors |
| TWI736768B (zh) | 2012-11-02 | 2021-08-21 | 美商維泰克斯製藥公司 | 治療cftr介導疾病之醫藥組合物 |
| WO2014071378A1 (en) | 2012-11-05 | 2014-05-08 | Nant Holdings Ip, Llc | Substituted indol-5-ol derivatives and their therapeutical applications |
| WO2014086751A1 (de) | 2012-12-05 | 2014-06-12 | Bayer Cropscience Ag | Verwendung substituierter 1-(arylethinyl)-, 1-(heteroarylethinyl)-, 1-(heterocyclylethinyl)- und 1-(cyloalkenylethinyl)-cyclohexanole als wirkstoffe gegen abiotischen pflanzenstress |
| BR112015013056A2 (pt) | 2012-12-05 | 2017-07-11 | Bayer Cropscience Ag | uso de 1-(ariletinil)-, 1-(heteroariletinil)-, 1-(heterocicliletinil)- substituídos e 1-(cicloalqueniletinil)-bicicloalcanóis como agentes ativos contra o estresse abiótico da planta |
| UA115576C2 (uk) | 2012-12-06 | 2017-11-27 | Байєр Фарма Акцієнгезелльшафт | Похідні бензимідазолу як антагоністи ер4 |
| GB201223265D0 (en) | 2012-12-21 | 2013-02-06 | Selvita Sa | Novel benzimidazole derivatives as kinase inhibitors |
| WO2014109858A1 (en) | 2013-01-14 | 2014-07-17 | Amgen Inc. | Methods of using cell-cycle inhibitors to modulate one or more properties of a cell culture |
| US10273243B2 (en) | 2013-03-14 | 2019-04-30 | The Trustees Of Columbia University In The City Of New York | 4-phenylpiperidines, their preparation and use |
| EP2968303B1 (en) | 2013-03-14 | 2018-07-04 | The Trustees of Columbia University in the City of New York | Octahydrocyclopentapyrroles, their preparation and use |
| RS59981B1 (sr) | 2013-03-15 | 2020-03-31 | Cyclerion Therapeutics Inc | Sgc stimulatori |
| CN105492433B (zh) | 2013-03-29 | 2018-11-23 | 武田药品工业株式会社 | 6-(5-羟基-1h-吡唑-1-基)烟碱酰胺衍生物和其作为phd抑制剂的用途 |
| US9382254B2 (en) | 2013-05-07 | 2016-07-05 | Galapagos Nv | Compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis |
| WO2014181287A1 (en) | 2013-05-09 | 2014-11-13 | Piramal Enterprises Limited | Heterocyclyl compounds and uses thereof |
| EP3000073B1 (en) | 2013-05-21 | 2017-07-12 | Sicpa Holding SA | Identifying one- or two-dimensional bar codes via weighted image data combination |
| EP3004083A4 (en) | 2013-05-24 | 2016-11-16 | California Inst Biomedical Res | COMPOUNDS FOR THE TREATMENT OF DRUG-RESISTANT AND PERSISTENT TUBERCULOSIS |
| WO2015010832A1 (en) | 2013-07-22 | 2015-01-29 | Syngenta Participations Ag | Microbiocidal heterocyclic derivatives |
| US10005728B2 (en) | 2013-08-28 | 2018-06-26 | Vanderbilt University | Substituted indole Mcl-1 inhibitors |
| US9663508B2 (en) | 2013-10-01 | 2017-05-30 | Amgen Inc. | Biaryl acyl-sulfonamide compounds as sodium channel inhibitors |
| CA2917193A1 (en) * | 2013-10-11 | 2015-04-16 | F. Hoffmann-La Roche Ag | Substituted heterocyclic sulfonamide compounds useful as trpa1 modulators |
| WO2015069287A1 (en) | 2013-11-08 | 2015-05-14 | Allergan, Inc. | Compounds as tyrosine kinase modulators |
| HRP20210516T2 (hr) | 2013-11-12 | 2021-10-01 | Vertex Pharmaceuticals Incorporated | Postupak proizvodnje farmaceutskih pripravaka za liječenje bolesti koje su posredovane putem cftr |
| PT3131582T (pt) | 2014-04-15 | 2018-10-08 | Vertex Pharma | Composições farmacêuticas para o tratamento de doenças mediadas pelo regulador de condutância transmembranar da fibrose quística |
| PT3203840T (pt) | 2014-10-06 | 2020-10-27 | Vertex Pharma | Moduladores do regulador da condutância transmembranar da fibrose quística |
| CN107250113B (zh) | 2014-10-07 | 2019-03-29 | 弗特克斯药品有限公司 | 囊性纤维化跨膜传导调节蛋白的调节剂的共晶 |
| DK3221692T3 (da) | 2014-11-18 | 2021-08-23 | Vertex Pharma | Fremgangsmåde til udførsel af tests med høj kapacitet ved hjælp af højtryksvæskekromatografi |
| MA41253A (fr) | 2014-12-23 | 2017-10-31 | Proteostasis Therapeutics Inc | Composés, compositions et procédés pour augmenter l'activité du cftr |
| US10738011B2 (en) | 2014-12-23 | 2020-08-11 | Proteostasis Therapeutics, Inc. | Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis |
| CN107922392B (zh) | 2015-02-15 | 2020-07-21 | 豪夫迈·罗氏有限公司 | 1-(杂)芳基磺酰基-(吡咯烷或哌啶)-2-甲酰胺衍生物及其用途 |
| US10196384B2 (en) | 2015-03-31 | 2019-02-05 | Vertex Pharmaceuticals (Europe) Limited | Deuterated CFTR modulators |
| EP3352757B1 (en) | 2015-09-21 | 2023-08-16 | Vertex Pharmaceuticals (Europe) Limited | Administration of deuterated cftr potentiators |
| US10766858B2 (en) | 2016-03-30 | 2020-09-08 | Genentech, Inc. | Substituted benzamides and methods of use thereof |
| US10738030B2 (en) | 2016-03-31 | 2020-08-11 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
| SG11201808682XA (en) | 2016-04-07 | 2018-11-29 | Proteostasis Therapeutics Inc | Silicone atoms containing ivacaftor analogues |
| BR112018072047A2 (pt) | 2016-04-26 | 2019-02-12 | AbbVie S.à.r.l. | moduladores da proteína reguladora de condutância transmembranar de fibrose cística |
| US10138227B2 (en) | 2016-06-03 | 2018-11-27 | Abbvie S.Á.R.L. | Heteroaryl substituted pyridines and methods of use |
| CA3028966A1 (en) | 2016-06-21 | 2017-12-28 | Proteostasis Therapeutics, Inc. | Substituted phenyl-isoxazole-carboxamide compounds and use thereof for increasing cftr activity |
| LT3519401T (lt) | 2016-09-30 | 2021-11-25 | Vertex Pharmaceuticals Incorporated | Cistinės fibrozės transmembraninio laidumo reguliavimo moduliatorius, farmacinės kompozicijos, gydymo būdai ir moduliatoriaus gamybos būdas |
| US10399940B2 (en) | 2016-10-07 | 2019-09-03 | Abbvie S.Á.R.L. | Substituted pyrrolidines and methods of use |
| US9981910B2 (en) | 2016-10-07 | 2018-05-29 | Abbvie S.Á.R.L. | Substituted pyrrolidines and methods of use |
| US20190256474A1 (en) | 2016-10-26 | 2019-08-22 | Proteostasis Therapeutics, Inc. | N-phenyl-2-(3-phenyl-6-oxo-1,6-dihydropyridazin-1-yl)acetamide derivatives for treating cystic fibrosis |
| AU2017348183A1 (en) | 2016-10-26 | 2019-05-16 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for modulating CFTR |
| US20190248765A1 (en) | 2016-10-26 | 2019-08-15 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing cftr activity |
| UA125400C2 (uk) | 2016-11-18 | 2022-03-02 | Цистік Фіброзис Фаундейшн | Піролопіримідин як потенціатор трансмембранної провідності при муковісцидозі (cftr) |
| MX2021013639A (es) * | 2016-12-09 | 2022-09-30 | Vertex Pharma | Forma cristalina del compuesto 1, un modulador del regulador de conductancia transmembrana de fibrosis quística, procesos para su preparación, composiciones farmacéuticas del compuesto 1, y su uso en el tratamiento de fibrosis quística. |
| RU2753056C2 (ru) | 2016-12-16 | 2021-08-11 | Систик Файбросис Фаундейшн | Бициклические гетероарильные производные в качестве стимуляторов cftr |
| WO2018116185A1 (en) | 2016-12-20 | 2018-06-28 | AbbVie S.à.r.l. | Deuterated cftr modulators and methods of use |
| US11053239B2 (en) | 2017-01-07 | 2021-07-06 | Fochon Pharmaceuticals, Ltd. | Compounds as BLC-2-selective apoptosis-inducing agents |
| TW201831471A (zh) | 2017-02-24 | 2018-09-01 | 盧森堡商艾伯維公司 | 囊腫纖化症跨膜傳導調節蛋白的調節劑及其使用方法 |
| US20180280349A1 (en) | 2017-03-28 | 2018-10-04 | Vertex Pharmaceuticals Incorporated | Methods of treating cystic fibrosis in patients with residual function mutations |
| CA3061476A1 (en) | 2017-04-28 | 2018-11-01 | Proteostasis Therapeutics, Inc. | 4-sulfonylaminocarbonylquinoline derivatives for increasing cftr activity |
| CA3066084A1 (en) | 2017-06-08 | 2018-12-13 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| US20210069174A1 (en) | 2017-07-01 | 2021-03-11 | Vertex Pharmaceuticals Incorporated | Compositions and methods for treatment of cystic fibrosis |
| US20200171015A1 (en) | 2017-07-17 | 2020-06-04 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| AU2018304168B2 (en) | 2017-07-17 | 2023-05-04 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| WO2019026075A1 (en) | 2017-07-31 | 2019-02-07 | Technion Research & Development Foundation Limited | METHODS OF DETECTING MODIFIED AND UN-MODIFIED DNA |
| CN111051280B (zh) | 2017-08-02 | 2023-12-22 | 弗特克斯药品有限公司 | 制备吡咯烷化合物的方法 |
| US10988454B2 (en) | 2017-09-14 | 2021-04-27 | Abbvie Overseas S.À.R.L. | Modulators of the cystic fibrosis transmembrane conductance regulator protein and methods of use |
| WO2019071078A1 (en) | 2017-10-06 | 2019-04-11 | Proteostasis Therapeutics, Inc. | COMPOUNDS, COMPOSITIONS AND METHODS FOR INCREASING CFTR ACTIVITY |
| TWI719349B (zh) | 2017-10-19 | 2021-02-21 | 美商維泰克斯製藥公司 | Ｃｆｔｒ調節劑之結晶形式及組合物 |
| US20210228489A1 (en) | 2017-12-04 | 2021-07-29 | Vertex Pharmaceuticals Incorporated | Compositions for treating cystic fibrosis |
| MA51039A (fr) | 2017-12-08 | 2020-10-14 | Vertex Pharma | Procédés pour préparer des modulateurs du régulateur de la conductance transmembranaire de la mucoviscidose |
| TWI810243B (zh) | 2018-02-05 | 2023-08-01 | 美商維泰克斯製藥公司 | 用於治療囊腫纖化症之醫藥組合物 |
| WO2019191620A1 (en) | 2018-03-30 | 2019-10-03 | Vertex Pharmaceuticals Incorporated | Crystalline forms of modulators of cftr |
| WO2019195739A1 (en) | 2018-04-05 | 2019-10-10 | Alexander Russell Abela | Modulators of cystic fibrosis transmembrane conductance regulator |
| EP3774825A1 (en) | 2018-04-13 | 2021-02-17 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
| WO2020214921A1 (en) | 2019-04-17 | 2020-10-22 | Vertex Pharmaceuticals Incorporated | Solid forms of modulators of cftr |
| WO2020242935A1 (en) | 2019-05-29 | 2020-12-03 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| CA3150162A1 (en) | 2019-08-14 | 2021-02-18 | Vertex Pharmaceuticals Incorporated | Crystalline forms of cftr modulators |
| SI4013741T1 (sl) | 2019-08-14 | 2024-06-28 | Vertex Pharmaceuticals Incorporated | Postopek za izdelavo cftr-modulatorjev |
| BR112022002606A2 (pt) | 2019-08-14 | 2022-05-03 | Vertex Pharma | Moduladores do regulador de condutância transmembrana da fibrose cística |
| TWI867024B (zh) | 2019-08-14 | 2024-12-21 | 美商維泰克斯製藥公司 | 囊腫纖維化跨膜傳導調節蛋白之調節劑 |
-
2018
- 2018-12-07 MA MA051039A patent/MA51039A/fr unknown
- 2018-12-07 WO PCT/US2018/064522 patent/WO2019113476A2/en not_active Ceased
- 2018-12-07 KR KR1020207019376A patent/KR102716244B1/ko active Active
- 2018-12-07 MX MX2020005753A patent/MX2020005753A/es unknown
- 2018-12-07 US US16/769,047 patent/US11465985B2/en active Active
- 2018-12-07 EP EP18829637.0A patent/EP3720849A2/en active Pending
- 2018-12-07 CN CN201880088848.0A patent/CN111757874B/zh active Active
- 2018-12-07 AU AU2018380426A patent/AU2018380426B2/en active Active
- 2018-12-07 CA CA3085006A patent/CA3085006A1/en active Pending
- 2018-12-07 JP JP2020530591A patent/JP7245834B2/ja active Active
- 2018-12-10 TW TW107144317A patent/TWI801465B/zh active
-
2020
- 2020-06-01 IL IL275049A patent/IL275049B2/en unknown
-
2022
- 2022-08-31 US US17/899,672 patent/US12415798B2/en active Active
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2021505579A5 (enExample) | ||
| IL275049B2 (en) | Processes for preparing modulators to regulate cystic fibrosis transmembrane conductance | |
| JP7113023B2 (ja) | ６－（シクロプロパンアミド）－４－（（２－メトキシ－３－（１－メチル－１ｈ－１，２，４－トリアゾール－３－イル）フェニル）アミノ）－ｎ－（メチル－ｄ３）ピリダジン－３－カルボキシアミドの製造方法 | |
| JP2020529414A5 (enExample) | ||
| ES2564175T3 (es) | Procedimiento para la preparación de biarilos | |
| CN105392791A (zh) | 制备氯代酰联苯胺和联苯胺的改进方法 | |
| RU2015106019A (ru) | Способ получения 4-амино-5-фтор-3-галоген-6-(замещенных)пиколинатов | |
| JP2015518892A5 (enExample) | ||
| TWI690520B (zh) | 製備二芳基硫尿囊素化合物之方法 | |
| CN103342663B (zh) | 一种阿那曲唑关键中间体的制备方法 | |
| WO2012049688A1 (en) | An improved process for the preparation of racemic 6, 6- dimethyl-3-azabicyclo-[3.1.0]-hexane and its salts, a key raw material for hcv inhibitor. | |
| CN102015625B (zh) | 取代联苯胺的制备方法 | |
| NZ730843A (en) | Synthesis of copanlisib and its dihydrochloride salt | |
| AU2018260728A1 (en) | Process for the preparation of deuterated ethanol from D2 | |
| JP7703547B2 (ja) | ６－メチル－ｎ１－（４－（ピリジン－３－イル）ピリミジン－２－イル）ベンゼン－１，３－ジアミンの合成 | |
| KR101613679B1 (ko) | 아미노페닐피리미디닐알코올 유도체의 제조 방법 및 그 합성 중간체 | |
| IL292707A (en) | Process and intermediates for the preparation of oxetane-2-ylmethanamine | |
| WO2017076213A1 (zh) | 苯并咪唑类化合物、其制备方法及用途 | |
| CN107892699B (zh) | 一种吡啶-4-硼酸的合成工艺 | |
| JP2007210923A (ja) | ４−トリフルオロメチルニコチン酸又はその塩の製造方法 | |
| NZ765171B2 (en) | Processes for making modulators of cystic fibrosis transmembrane conductance regulator | |
| JP2024509995A (ja) | リスジプラムを調製するための方法 | |
| CN102060719A (zh) | 盐酸米多君中间体1-(2,5-二甲氧基苯基)-2-氨基乙醇的制备方法 | |
| JPWO2022259222A5 (enExample) | ||
| CN110526866B (zh) | 一种2-喹啉酮类化合物的合成方法 |