JP2020517668A - ニラパリブの製造方法 - Google Patents
ニラパリブの製造方法 Download PDFInfo
- Publication number
- JP2020517668A JP2020517668A JP2019557567A JP2019557567A JP2020517668A JP 2020517668 A JP2020517668 A JP 2020517668A JP 2019557567 A JP2019557567 A JP 2019557567A JP 2019557567 A JP2019557567 A JP 2019557567A JP 2020517668 A JP2020517668 A JP 2020517668A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- acid
- salt
- compound
- contacting
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 238
- 238000000034 method Methods 0.000 claims abstract description 230
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 31
- 229950011068 niraparib Drugs 0.000 claims abstract description 17
- -1 9-fluorenylmethyloxycarbonyl Chemical group 0.000 claims description 280
- 150000001875 compounds Chemical class 0.000 claims description 210
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 204
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 163
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 161
- 239000000203 mixture Substances 0.000 claims description 130
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 123
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 102
- 125000000217 alkyl group Chemical group 0.000 claims description 98
- 229910052736 halogen Inorganic materials 0.000 claims description 98
- 150000002367 halogens Chemical class 0.000 claims description 97
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 92
- 239000002904 solvent Substances 0.000 claims description 79
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 75
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 72
- 125000006242 amine protecting group Chemical group 0.000 claims description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 66
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 62
- 125000003118 aryl group Chemical group 0.000 claims description 57
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 239000002253 acid Substances 0.000 claims description 49
- 150000004682 monohydrates Chemical class 0.000 claims description 49
- 239000003446 ligand Substances 0.000 claims description 47
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 44
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 41
- 239000003054 catalyst Substances 0.000 claims description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 38
- 125000001188 haloalkyl group Chemical group 0.000 claims description 38
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 35
- 229910052751 metal Inorganic materials 0.000 claims description 35
- 239000002184 metal Substances 0.000 claims description 35
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 34
- 150000001768 cations Chemical class 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 33
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 33
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 30
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 25
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 24
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 22
- 239000002585 base Substances 0.000 claims description 21
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 21
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 20
- 229910052783 alkali metal Inorganic materials 0.000 claims description 20
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 20
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 18
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 17
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 17
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 17
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 17
- LUZDYPLAQQGJEA-UHFFFAOYSA-N 2-Methoxynaphthalene Chemical compound C1=CC=CC2=CC(OC)=CC=C21 LUZDYPLAQQGJEA-UHFFFAOYSA-N 0.000 claims description 16
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 16
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 16
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 16
- GPKUICFDWYEPTK-UHFFFAOYSA-N methoxycyclohexatriene Chemical compound COC1=CC=C=C[CH]1 GPKUICFDWYEPTK-UHFFFAOYSA-N 0.000 claims description 16
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 16
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 15
- 239000010949 copper Substances 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 235000011054 acetic acid Nutrition 0.000 claims description 13
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 12
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 11
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 claims description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 11
- 235000019253 formic acid Nutrition 0.000 claims description 11
- 229940006487 lithium cation Drugs 0.000 claims description 11
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 10
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 10
- 235000015165 citric acid Nutrition 0.000 claims description 10
- 229910017604 nitric acid Inorganic materials 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 10
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 9
- 239000005711 Benzoic acid Substances 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 9
- 239000000908 ammonium hydroxide Substances 0.000 claims description 9
- 235000010233 benzoic acid Nutrition 0.000 claims description 9
- 239000004310 lactic acid Substances 0.000 claims description 9
- 235000014655 lactic acid Nutrition 0.000 claims description 9
- 235000006408 oxalic acid Nutrition 0.000 claims description 9
- 235000019260 propionic acid Nutrition 0.000 claims description 9
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 9
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 8
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 8
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims description 8
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims description 8
- 150000001447 alkali salts Chemical class 0.000 claims description 8
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 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
- 239000001630 malic acid Substances 0.000 claims description 8
- 235000011090 malic acid Nutrition 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 229960003080 taurine Drugs 0.000 claims description 8
- 229940116269 uric acid Drugs 0.000 claims description 8
- 229940005605 valeric acid Drugs 0.000 claims description 8
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 8
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 238000000137 annealing Methods 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- 239000010948 rhodium Substances 0.000 claims description 7
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 6
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical group [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 6
- 229910052742 iron Inorganic materials 0.000 claims description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 238000001238 wet grinding Methods 0.000 claims description 6
- 229910052725 zinc Inorganic materials 0.000 claims description 6
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 5
- 229910052759 nickel Inorganic materials 0.000 claims description 5
- 150000002894 organic compounds Chemical class 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 229910052719 titanium Inorganic materials 0.000 claims description 5
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 claims description 4
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 4
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 241001530392 Aphos Species 0.000 claims description 4
- 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 claims description 4
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 claims description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001879 copper Chemical class 0.000 claims description 4
- LCSNDSFWVKMJCT-UHFFFAOYSA-N dicyclohexyl-(2-phenylphenyl)phosphane Chemical compound C1CCCCC1P(C=1C(=CC=CC=1)C=1C=CC=CC=1)C1CCCCC1 LCSNDSFWVKMJCT-UHFFFAOYSA-N 0.000 claims description 4
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 claims description 4
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound 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
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 4
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 4
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims description 4
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 claims description 3
- 150000004820 halides Chemical group 0.000 claims description 3
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 3
- 150000004692 metal hydroxides Chemical class 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- 239000007821 HATU Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- DWYMPOCYEZONEA-UHFFFAOYSA-L fluoridophosphate Chemical compound [O-]P([O-])(F)=O DWYMPOCYEZONEA-UHFFFAOYSA-L 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 11
- VNJOEUSYAMPBAK-UHFFFAOYSA-N 2-methylbenzenesulfonic acid;hydrate Chemical compound O.CC1=CC=CC=C1S(O)(=O)=O VNJOEUSYAMPBAK-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 32
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 71
- 125000002947 alkylene group Chemical group 0.000 description 38
- 125000004432 carbon atom Chemical group C* 0.000 description 35
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 22
- 125000000623 heterocyclic group Chemical group 0.000 description 22
- 239000000047 product Substances 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 125000001072 heteroaryl group Chemical group 0.000 description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 16
- 125000004452 carbocyclyl group Chemical group 0.000 description 15
- 150000003254 radicals Chemical class 0.000 description 15
- 125000003710 aryl alkyl group Chemical group 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 14
- 239000001257 hydrogen Substances 0.000 description 14
- 125000003709 fluoroalkyl group Chemical group 0.000 description 13
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 13
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
- 238000007792 addition Methods 0.000 description 12
- 125000004122 cyclic group Chemical group 0.000 description 12
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 125000004450 alkenylene group Chemical group 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 125000000304 alkynyl group Chemical group 0.000 description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 229910052741 iridium Inorganic materials 0.000 description 9
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 125000005884 carbocyclylalkyl group Chemical group 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- CPRMKOQKXYSDML-UHFFFAOYSA-M rubidium hydroxide Chemical compound [OH-].[Rb+] CPRMKOQKXYSDML-UHFFFAOYSA-M 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 239000011651 chromium Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 239000010936 titanium Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- GHWSWLZMLAMQTK-UHFFFAOYSA-J [OH-].[OH-].[OH-].[OH-].[Pu+4] Chemical compound [OH-].[OH-].[OH-].[OH-].[Pu+4] GHWSWLZMLAMQTK-UHFFFAOYSA-J 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 229910052738 indium Inorganic materials 0.000 description 6
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- 238000005292 vacuum distillation Methods 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000005909 Kieselgur Substances 0.000 description 5
- 239000012661 PARP inhibitor Substances 0.000 description 5
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000010926 purge Methods 0.000 description 5
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 102000036365 BRCA1 Human genes 0.000 description 4
- 108700020463 BRCA1 Proteins 0.000 description 4
- 101150072950 BRCA1 gene Proteins 0.000 description 4
- 102000052609 BRCA2 Human genes 0.000 description 4
- 108700020462 BRCA2 Proteins 0.000 description 4
- 101150008921 Brca2 gene Proteins 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 150000001767 cationic compounds Chemical class 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 4
- 239000010931 gold Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000011572 manganese Substances 0.000 description 4
- IPJKJLXEVHOKSE-UHFFFAOYSA-L manganese dihydroxide Chemical compound [OH-].[OH-].[Mn+2] IPJKJLXEVHOKSE-UHFFFAOYSA-L 0.000 description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 4
- 239000010955 niobium Substances 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 150000002892 organic cations Chemical class 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229910052703 rhodium Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 3
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 description 3
- 230000033616 DNA repair Effects 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 3
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 3
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 3
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 3
- QKDGGEBMABOMMW-UHFFFAOYSA-I [OH-].[OH-].[OH-].[OH-].[OH-].[V+5] Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[V+5] QKDGGEBMABOMMW-UHFFFAOYSA-I 0.000 description 3
- 125000004419 alkynylene group Chemical group 0.000 description 3
- 150000005840 aryl radicals Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229910052793 cadmium Inorganic materials 0.000 description 3
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052804 chromium Inorganic materials 0.000 description 3
- 229910017052 cobalt Inorganic materials 0.000 description 3
- 239000010941 cobalt Substances 0.000 description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 3
- 229910052737 gold Inorganic materials 0.000 description 3
- 229910052735 hafnium Inorganic materials 0.000 description 3
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 description 3
- 229910021473 hassium Inorganic materials 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 229910003002 lithium salt Inorganic materials 0.000 description 3
- 159000000002 lithium salts Chemical class 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 3
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 3
- 229910052753 mercury Inorganic materials 0.000 description 3
- NSLOBVGASZUPDO-UHFFFAOYSA-N methyl 3-formyl-2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC(C=O)=C1[N+]([O-])=O NSLOBVGASZUPDO-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229910052750 molybdenum Inorganic materials 0.000 description 3
- 239000011733 molybdenum Substances 0.000 description 3
- RAVWHRINPHQUMU-UHFFFAOYSA-N n-(4-bromophenyl)benzamide Chemical compound C1=CC(Br)=CC=C1NC(=O)C1=CC=CC=C1 RAVWHRINPHQUMU-UHFFFAOYSA-N 0.000 description 3
- 229910052758 niobium Inorganic materials 0.000 description 3
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 229910052762 osmium Inorganic materials 0.000 description 3
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 3
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 229910052702 rhenium Inorganic materials 0.000 description 3
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 3
- 229910052707 ruthenium Inorganic materials 0.000 description 3
- 229910021481 rutherfordium Inorganic materials 0.000 description 3
- YGPLJIIQQIDVFJ-UHFFFAOYSA-N rutherfordium atom Chemical compound [Rf] YGPLJIIQQIDVFJ-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910052706 scandium Inorganic materials 0.000 description 3
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical group [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 3
- 229910021477 seaborgium Inorganic materials 0.000 description 3
- 229910052709 silver Inorganic materials 0.000 description 3
- 239000004332 silver Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 229910052715 tantalum Inorganic materials 0.000 description 3
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 3
- 229910052713 technetium Inorganic materials 0.000 description 3
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 3
- PGGWMBHXTKXROX-UHFFFAOYSA-N tert-butyl 5-(4-benzamidophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound C(C1=CC=CC=C1)(=O)NC1=CC=C(C=C1)C1=CCCN(C1)C(=O)OC(C)(C)C PGGWMBHXTKXROX-UHFFFAOYSA-N 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 125000000464 thioxo group Chemical group S=* 0.000 description 3
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 3
- 229910052721 tungsten Inorganic materials 0.000 description 3
- 239000010937 tungsten Substances 0.000 description 3
- 229910052720 vanadium Inorganic materials 0.000 description 3
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 3
- 229910052727 yttrium Inorganic materials 0.000 description 3
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 3
- 229910052726 zirconium Inorganic materials 0.000 description 3
- FWZVIUZIYYIKRK-UHFFFAOYSA-N (4-benzamidophenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1NC(=O)C1=CC=CC=C1 FWZVIUZIYYIKRK-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 229910018661 Ni(OH) Inorganic materials 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 229910020282 Pb(OH) Inorganic materials 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 2
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 2
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- NCMHKCKGHRPLCM-UHFFFAOYSA-N caesium(1+) Chemical compound [Cs+] NCMHKCKGHRPLCM-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229940006165 cesium cation Drugs 0.000 description 2
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 2
- VQWFNAGFNGABOH-UHFFFAOYSA-K chromium(iii) hydroxide Chemical compound [OH-].[OH-].[OH-].[Cr+3] VQWFNAGFNGABOH-UHFFFAOYSA-K 0.000 description 2
- PKSIZOUDEUREFF-UHFFFAOYSA-N cobalt;dihydrate Chemical compound O.O.[Co] PKSIZOUDEUREFF-UHFFFAOYSA-N 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- 235000011180 diphosphates Nutrition 0.000 description 2
- NKBXHKCTSZBQNE-BTQNPOSSSA-N ethanesulfonate [4-[(3S)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-3-yl]phenyl]azanium Chemical compound CCS([O-])(=O)=O.CC(C)(C)OC(=O)N1CCC[C@H](C1)c1ccc([NH3+])cc1 NKBXHKCTSZBQNE-BTQNPOSSSA-N 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- OCABHVDKBUNYTK-UHFFFAOYSA-N francium(1+) Chemical compound [Fr+] OCABHVDKBUNYTK-UHFFFAOYSA-N 0.000 description 2
- 229910021513 gallium hydroxide Inorganic materials 0.000 description 2
- DNUARHPNFXVKEI-UHFFFAOYSA-K gallium(iii) hydroxide Chemical compound [OH-].[OH-].[OH-].[Ga+3] DNUARHPNFXVKEI-UHFFFAOYSA-K 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical compound FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical group C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 235000014413 iron hydroxide Nutrition 0.000 description 2
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 229910021514 lead(II) hydroxide Inorganic materials 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 2
- 125000005341 metaphosphate group Chemical group 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 229940095102 methyl benzoate Drugs 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 108020004707 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229940049953 phenylacetate Drugs 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 229920002477 rna polymer Polymers 0.000 description 2
- NCCSSGKUIKYAJD-UHFFFAOYSA-N rubidium(1+) Chemical compound [Rb+] NCCSSGKUIKYAJD-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229940116351 sebacate Drugs 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 229910052717 sulfur Chemical group 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- SWUANUQBXJNXGP-CYBMUJFWSA-N tert-butyl (3s)-3-(4-aminophenyl)piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC[C@H]1C1=CC=C(N)C=C1 SWUANUQBXJNXGP-CYBMUJFWSA-N 0.000 description 2
- STWZKMWVLCYCRB-UHFFFAOYSA-N tert-butyl 5-(4-methylphenyl)sulfonyloxy-3,4-dihydro-2H-pyridine-1-carboxylate Chemical compound Cc1ccc(cc1)S(=O)(=O)OC1=CN(CCC1)C(=O)OC(C)(C)C STWZKMWVLCYCRB-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 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 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 1
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000005877 1,4-benzodioxanyl group Chemical group 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- IVORCBKUUYGUOL-UHFFFAOYSA-N 1-ethynyl-2,4-dimethoxybenzene Chemical compound COC1=CC=C(C#C)C(OC)=C1 IVORCBKUUYGUOL-UHFFFAOYSA-N 0.000 description 1
- 125000005987 1-oxo-thiomorpholinyl group Chemical group 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000006088 2-oxoazepinyl group Chemical group 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- RCYIWFITYHZCIW-UHFFFAOYSA-N 4-methoxybut-1-yne Chemical compound COCCC#C RCYIWFITYHZCIW-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- SIVHJLZWCUWTSH-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)NC1=CC=C(C=C1)C=1CCC=NC1 Chemical compound C(C1=CC=CC=C1)(=O)NC1=CC=C(C=C1)C=1CCC=NC1 SIVHJLZWCUWTSH-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229910021503 Cobalt(II) hydroxide Inorganic materials 0.000 description 1
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical class [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 241001125671 Eretmochelys imbricata Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 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
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910019440 Mg(OH) Inorganic materials 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MXRIRQGCELJRSN-UHFFFAOYSA-N O.O.O.[Al] Chemical compound O.O.O.[Al] MXRIRQGCELJRSN-UHFFFAOYSA-N 0.000 description 1
- NSUCHOAKLRYREQ-UHFFFAOYSA-N O.O.O.[AsH3] Chemical compound O.O.O.[AsH3] NSUCHOAKLRYREQ-UHFFFAOYSA-N 0.000 description 1
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 1
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 229910003514 Sr(OH) Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- MTAGIWZLHXMRFR-UHFFFAOYSA-M [Hg]O Chemical compound [Hg]O MTAGIWZLHXMRFR-UHFFFAOYSA-M 0.000 description 1
- OSOVKCSKTAIGGF-UHFFFAOYSA-N [Ni].OOO Chemical compound [Ni].OOO OSOVKCSKTAIGGF-UHFFFAOYSA-N 0.000 description 1
- FTHTZFKPEWFFJQ-UHFFFAOYSA-I [OH-].[Cr+5].[OH-].[OH-].[OH-].[OH-] Chemical compound [OH-].[Cr+5].[OH-].[OH-].[OH-].[OH-] FTHTZFKPEWFFJQ-UHFFFAOYSA-I 0.000 description 1
- KYVKDXLYFWMRNL-UHFFFAOYSA-L [OH-].[OH-].[In++] Chemical compound [OH-].[OH-].[In++] KYVKDXLYFWMRNL-UHFFFAOYSA-L 0.000 description 1
- RJEYBEFNKVLVMQ-UHFFFAOYSA-J [OH-].[OH-].[OH-].[OH-].[Mn+4] Chemical compound [OH-].[OH-].[OH-].[OH-].[Mn+4] RJEYBEFNKVLVMQ-UHFFFAOYSA-J 0.000 description 1
- ARVNHJBMBBFPCP-UHFFFAOYSA-L [OH-].[OH-].[Ra+2] Chemical compound [OH-].[OH-].[Ra+2] ARVNHJBMBBFPCP-UHFFFAOYSA-L 0.000 description 1
- FVNVPZWLJJBDNX-UHFFFAOYSA-L [OH-].[OH-].[Tc++] Chemical compound [OH-].[OH-].[Tc++] FVNVPZWLJJBDNX-UHFFFAOYSA-L 0.000 description 1
- PDKXJKWLFFZPPF-UHFFFAOYSA-N [dimethylamino-(3-oxidotriazolo[4,5-b]pyridin-3-ium-1-yl)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(C(N(C)C)=[N+](C)C)N=[N+]([O-])C2=N1 PDKXJKWLFFZPPF-UHFFFAOYSA-N 0.000 description 1
- YTIVTFGABIZHHX-UHFFFAOYSA-L acetylenedicarboxylate(2-) Chemical compound [O-]C(=O)C#CC([O-])=O YTIVTFGABIZHHX-UHFFFAOYSA-L 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000005600 alkyl phosphonate group Chemical group 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- OQXNIFCDVQIYRG-UHFFFAOYSA-N aniline;ethanesulfonic acid Chemical compound CCS(O)(=O)=O.NC1=CC=CC=C1 OQXNIFCDVQIYRG-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229910052789 astatine Inorganic materials 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 230000033590 base-excision repair Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005870 benzindolyl group Chemical group 0.000 description 1
- 125000005875 benzo[b][1,4]dioxepinyl group Chemical group 0.000 description 1
- 125000005876 benzo[b][1,4]oxazinyl group Chemical group 0.000 description 1
- 125000005873 benzo[d]thiazolyl group Chemical group 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WPJWIROQQFWMMK-UHFFFAOYSA-L beryllium dihydroxide Chemical compound [Be+2].[OH-].[OH-] WPJWIROQQFWMMK-UHFFFAOYSA-L 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 description 1
- IAQAJTTVJUUIQJ-UHFFFAOYSA-N bismuth;trihydrate Chemical compound O.O.O.[Bi] IAQAJTTVJUUIQJ-UHFFFAOYSA-N 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- PLLZRTNVEXYBNA-UHFFFAOYSA-L cadmium hydroxide Chemical compound [OH-].[OH-].[Cd+2] PLLZRTNVEXYBNA-UHFFFAOYSA-L 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- UNJPQTDTZAKTFK-UHFFFAOYSA-K cerium(iii) hydroxide Chemical compound [OH-].[OH-].[OH-].[Ce+3] UNJPQTDTZAKTFK-UHFFFAOYSA-K 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 229940005991 chloric acid Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 description 1
- 229940077239 chlorous acid Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Chemical compound O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- RXCXTWLPFKKEMF-UHFFFAOYSA-H chromium(6+);hexahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Cr+6] RXCXTWLPFKKEMF-UHFFFAOYSA-H 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- AEJIMXVJZFYIHN-UHFFFAOYSA-N copper;dihydrate Chemical compound O.O.[Cu] AEJIMXVJZFYIHN-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000005507 decahydroisoquinolyl group Chemical group 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 125000002720 diazolyl group Chemical group 0.000 description 1
- 125000005509 dibenzothiophenyl group Chemical group 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical group C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000003844 furanonyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229910021505 gold(III) hydroxide Inorganic materials 0.000 description 1
- WDZVNNYQBQRJRX-UHFFFAOYSA-K gold(iii) hydroxide Chemical compound O[Au](O)O WDZVNNYQBQRJRX-UHFFFAOYSA-K 0.000 description 1
- MPOKJOWFCMDRKP-UHFFFAOYSA-N gold;hydrate Chemical compound O.[Au] MPOKJOWFCMDRKP-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000000232 haloalkynyl group Chemical group 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- KKLGDUSGQMHBPB-UHFFFAOYSA-N hex-2-ynedioic acid Chemical compound OC(=O)CCC#CC(O)=O KKLGDUSGQMHBPB-UHFFFAOYSA-N 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- PIPQOOWEMLRYEJ-UHFFFAOYSA-N indium(1+) Chemical compound [In+] PIPQOOWEMLRYEJ-UHFFFAOYSA-N 0.000 description 1
- IGUXCTSQIGAGSV-UHFFFAOYSA-K indium(iii) hydroxide Chemical compound [OH-].[OH-].[OH-].[In+3] IGUXCTSQIGAGSV-UHFFFAOYSA-K 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- IUJMNDNTFMJNEL-UHFFFAOYSA-K iridium(3+);trihydroxide Chemical compound [OH-].[OH-].[OH-].[Ir+3] IUJMNDNTFMJNEL-UHFFFAOYSA-K 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- YXEUGTSPQFTXTR-UHFFFAOYSA-K lanthanum(3+);trihydroxide Chemical compound [OH-].[OH-].[OH-].[La+3] YXEUGTSPQFTXTR-UHFFFAOYSA-K 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- JSNLGRZEIWJZTP-UNTBIKODSA-M lithium 2-[4-[(3S)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-3-yl]phenyl]indazole-7-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C[C@@H](CCC1)C1=CC=C(C=C1)N1N=C2C(=CC=CC2=C1)C(=O)[O-].[Li+] JSNLGRZEIWJZTP-UNTBIKODSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229910021507 mercury(II) hydroxide Inorganic materials 0.000 description 1
- VLKKXDVIWIBHHS-UHFFFAOYSA-L mercury(ii) hydroxide Chemical compound [OH-].[OH-].[Hg+2] VLKKXDVIWIBHHS-UHFFFAOYSA-L 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- FJJWGNGAAZZGKW-UHFFFAOYSA-N methyl 2-azido-3-formylbenzoate Chemical compound COC(=O)c1cccc(C=O)c1N=[N+]=[N-] FJJWGNGAAZZGKW-UHFFFAOYSA-N 0.000 description 1
- PPCHVJGFXSDKDO-UHFFFAOYSA-N methyl 3-[2-(dimethylamino)ethenyl]-2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC(C=CN(C)C)=C1[N+]([O-])=O PPCHVJGFXSDKDO-UHFFFAOYSA-N 0.000 description 1
- NJHDBIXFFZVJGZ-UHFFFAOYSA-N methyl 3-methyl-2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC(C)=C1[N+]([O-])=O NJHDBIXFFZVJGZ-UHFFFAOYSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- GDXTWKJNMJAERW-UHFFFAOYSA-J molybdenum(4+);tetrahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[Mo+4] GDXTWKJNMJAERW-UHFFFAOYSA-J 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- NOUUUQMKVOUUNR-UHFFFAOYSA-N n,n'-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1NCCNC1=CC=CC=C1 NOUUUQMKVOUUNR-UHFFFAOYSA-N 0.000 description 1
- QPJSUIGXIBEQAC-UHFFFAOYSA-N n-(2,4-dichloro-5-propan-2-yloxyphenyl)acetamide Chemical compound CC(C)OC1=CC(NC(C)=O)=C(Cl)C=C1Cl QPJSUIGXIBEQAC-UHFFFAOYSA-N 0.000 description 1
- BRERQYZGASSZJR-UHFFFAOYSA-N n-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzamide Chemical compound O1C(C)(C)C(C)(C)OB1C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 BRERQYZGASSZJR-UHFFFAOYSA-N 0.000 description 1
- ILCQYORZHHFLNL-UHFFFAOYSA-N n-bromoaniline Chemical compound BrNC1=CC=CC=C1 ILCQYORZHHFLNL-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- BFDHFSHZJLFAMC-UHFFFAOYSA-L nickel(ii) hydroxide Chemical compound [OH-].[OH-].[Ni+2] BFDHFSHZJLFAMC-UHFFFAOYSA-L 0.000 description 1
- UMTMDKJVZSXFNJ-UHFFFAOYSA-N nickel;trihydrate Chemical compound O.O.O.[Ni] UMTMDKJVZSXFNJ-UHFFFAOYSA-N 0.000 description 1
- WPCMRGJTLPITMF-UHFFFAOYSA-I niobium(5+);pentahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[Nb+5] WPCMRGJTLPITMF-UHFFFAOYSA-I 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Chemical group C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- CDCFKVCOZYCTBR-UHFFFAOYSA-J osmium(4+);tetrahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[Os+4] CDCFKVCOZYCTBR-UHFFFAOYSA-J 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Chemical group 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- NFOHLBHARAZXFQ-UHFFFAOYSA-L platinum(2+);dihydroxide Chemical compound O[Pt]O NFOHLBHARAZXFQ-UHFFFAOYSA-L 0.000 description 1
- JTAFSELAEYLDJR-UHFFFAOYSA-J platinum(4+);tetrahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[Pt+4] JTAFSELAEYLDJR-UHFFFAOYSA-J 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920000172 poly(styrenesulfonic acid) Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 229940005642 polystyrene sulfonic acid Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006578 reductive coupling reaction Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- VDRDGQXTSLSKKY-UHFFFAOYSA-K ruthenium(3+);trihydroxide Chemical compound [OH-].[OH-].[OH-].[Ru+3] VDRDGQXTSLSKKY-UHFFFAOYSA-K 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- LQPWUWOODZHKKW-UHFFFAOYSA-K scandium(3+);trihydroxide Chemical compound [OH-].[OH-].[OH-].[Sc+3] LQPWUWOODZHKKW-UHFFFAOYSA-K 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- UKHWJBVVWVYFEY-UHFFFAOYSA-M silver;hydroxide Chemical compound [OH-].[Ag+] UKHWJBVVWVYFEY-UHFFFAOYSA-M 0.000 description 1
- 230000033443 single strand break repair Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 description 1
- 229910001866 strontium hydroxide Inorganic materials 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ZIRLXLUNCURZTP-UHFFFAOYSA-I tantalum(5+);pentahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[Ta+5] ZIRLXLUNCURZTP-UHFFFAOYSA-I 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- RUNXZBCDKGKTNK-LJQANCHMSA-N tert-butyl (3S)-3-(4-benzamidophenyl)piperidine-1-carboxylate Chemical compound C1=C(C=CC=C1)C(=O)NC1=CC=C([C@H]2CN(CCC2)C(=O)OC(C)(C)C)C=C1 RUNXZBCDKGKTNK-LJQANCHMSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- UIJXHKXIOCDSEB-UHFFFAOYSA-N tert-butyl 3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(O)C1 UIJXHKXIOCDSEB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229910021515 thallium hydroxide Inorganic materials 0.000 description 1
- 229910021516 thallium(I) hydroxide Inorganic materials 0.000 description 1
- 229910021517 thallium(III) hydroxide Inorganic materials 0.000 description 1
- QGYXCSSUHCHXHB-UHFFFAOYSA-M thallium(i) hydroxide Chemical compound [OH-].[Tl+] QGYXCSSUHCHXHB-UHFFFAOYSA-M 0.000 description 1
- GEPJDKDOADVEKE-UHFFFAOYSA-K thallium(iii) hydroxide Chemical compound O[Tl](O)O GEPJDKDOADVEKE-UHFFFAOYSA-K 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- SFKTYEXKZXBQRQ-UHFFFAOYSA-J thorium(4+);tetrahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[Th+4] SFKTYEXKZXBQRQ-UHFFFAOYSA-J 0.000 description 1
- FBGKGORFGWHADY-UHFFFAOYSA-L tin(2+);dihydroxide Chemical compound O[Sn]O FBGKGORFGWHADY-UHFFFAOYSA-L 0.000 description 1
- CVNKFOIOZXAFBO-UHFFFAOYSA-J tin(4+);tetrahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[Sn+4] CVNKFOIOZXAFBO-UHFFFAOYSA-J 0.000 description 1
- 229910021509 tin(II) hydroxide Inorganic materials 0.000 description 1
- LLZRNZOLAXHGLL-UHFFFAOYSA-J titanic acid Chemical compound O[Ti](O)(O)O LLZRNZOLAXHGLL-UHFFFAOYSA-J 0.000 description 1
- MDENFZQQDNYWMM-UHFFFAOYSA-N titanium trihydrate Chemical compound O.O.O.[Ti] MDENFZQQDNYWMM-UHFFFAOYSA-N 0.000 description 1
- RCFVAODLMSHDAW-UHFFFAOYSA-L titanium(2+);dihydroxide Chemical compound O[Ti]O RCFVAODLMSHDAW-UHFFFAOYSA-L 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229960004319 trichloroacetic acid Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- SPDGFQQVHZEUOP-UHFFFAOYSA-L tungsten(2+);dihydroxide Chemical compound [OH-].[OH-].[W+2] SPDGFQQVHZEUOP-UHFFFAOYSA-L 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 229910021510 uranyl hydroxide Inorganic materials 0.000 description 1
- VWIQIIGYDAPONF-UHFFFAOYSA-L uranyl hydroxide Chemical compound O[U](O)(=O)=O VWIQIIGYDAPONF-UHFFFAOYSA-L 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- SJHMKWQYVBZNLZ-UHFFFAOYSA-K ytterbium(3+);trihydroxide Chemical compound [OH-].[OH-].[OH-].[Yb+3] SJHMKWQYVBZNLZ-UHFFFAOYSA-K 0.000 description 1
- GFDKELMFCRQUSG-UHFFFAOYSA-N yttrium;trihydrate Chemical compound O.O.O.[Y] GFDKELMFCRQUSG-UHFFFAOYSA-N 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本明細書に記載されている総ての刊行物、特許、および特許出願は、各個の刊行物、特許、または特許出願が具体的かつ個々に引用することにより本明細書の一部とされることが示されている場合と同程度に引用することにより本明細書の一部とされる。
本明細書では、式(1):
[式中、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールである]
が開示される。
本明細書では、式(5):
[式中、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールである]
が開示される。
本明細書では、式(7):
[式中、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
Aは、陽イオンである]
が開示される。
本明細書では、式(9):
[式中、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
Aは、陽イオンである]
が開示される。
本明細書では、式(11):
[式中、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールである]
が開示される。
本明細書では、式(12):
a) トシル酸(R)−ニラパリブ一水和物およびトシル酸(S)−ニラパリブ一水和物を含んでなる混合物を、水および第1の有機溶媒と接触させること;
b) 濾過により混合物からトシル酸(S)−ニラパリブ一水和物を分離して、エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物を形成させること;ならびに
c) エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物を、第2の有機溶媒、水、またはその任意の組合せと接触させて、エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物の結晶形を形成させること、
を含んでなる方法が開示される。
a) 式(13):
b) 式(15):
c) 式(14)の化合物を式(16)の化合物およびTFAと接触させて、式(4):
d) 式(4)の化合物をトリフルオロメタンスルホン酸銅(II)(Cu(OTf)2)、THFおよびトルエンと接触させて、式(6):
e) 式(6)の化合物を水酸化リチウムおよびエタノールと接触させて、式(8):
f) 式(8)の塩をCDI、TFA、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、および水酸化アンモニウムと接触させて、式(10):
g) 式(10)の化合物をp−トルエンスルホン酸一水和物(pTSA・H2O)およびTHFと接触させて、式(12):
h) 式(12)のトシル酸(S)−ニラパリブ一水和物をアセトニトリルおよび水と接触させて、混合物を形成させること;
i) 濾過により混合物からトシル酸(S)−ニラパリブ一水和物を分離して、エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物を形成させること;ならびに
j) エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物をDMSOおよび水と接触させて、エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物の結晶形を形成させること、
を含んでなる方法が開示される。
本明細書では、式(7):
[式中、
R1は、Hまたはアミン保護基であり;
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
Aは、陽イオンである]
が開示される。
本明細書では、式(17):
本明細書では、式(20):
本明細書では、式(23):
[式中、各R5は、独立に、HまたはC1−3アルキルである]
が開示される。
本明細書では、式(20):
本明細書では、式(25):
本明細書では、式(14):
式(25)
本明細書では、式(13):
本明細書では、式(21):
式(29)の化合物またはその塩をp−トルエンスルホン酸無水物と接触させること、を含んでなる方法が開示される。いくつかの実施態様では、酸化剤は2,2,6,6−テトラメチルピペリジン−1−オキシル(TEMPO)である。
本明細書では、式(30):
[式中、
各R1は、独立に、Hまたはアミン保護基であり;かつ
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールである]
が開示される。
実施例1は、化合物3−ホルミル−2−ニトロ安息香酸メチル(アルデヒドA)の合成を説明する(図1も参照)。
実施例2は、化合物(S)−4−(1−(tert−ブトキシカルボニル)ピペリジン−3−イル)ベンゼンアミニウムエタンスルホン酸塩(アニリンESA塩)の合成を説明する(図2も参照)。
076, 125.560, 124.867, 124.0634, 122.847, 122.505, 120.383, 120.281, 115.818, 81.054,80.893, 42.293, 41.265, 28.527, 28.367, 24.174, 23.788, 21.710; HRMS m/z: [M + H]+ C23H27N2O3についての計算値:379.2016; 実測値: 379.2016.
粗不飽和アニリン誘導体(5−(4−ベンズアミドフェニル)−3,6−ジヒドロピリジン−1(2H)−カルボン酸tert−ブチルおよび5−(4−ベンズアミドフェニル)−3,4−ジヒドロピリジン−1(2H)−カルボン酸tert−ブチル、100g)を反応器に投入した後、アセトニトリル(CAN、316g)を投入した。混合物を75℃で1時間撹拌した後、アセトニトリル(143mL)を加えた。水(291g)を75℃で徐々に加えた。混合物を75℃で2時間撹拌した後、6時間かけて4℃まで徐々に冷却し、4℃でさらに5時間維持した。生成物を濾過により単離し、濾過ケーキをアセトニトリル:水(2:1、75g)に次いで水(100g)で洗浄した。湿ケーキを45℃にて真空下で48時間乾燥させ、精製生成物(96.0g、96%)を得た。
11; HRMS m/z: [M +H]+ C12H17N2O2についての計算値:221.1285; 実測値:221.1282.
実施例3は、化合物トシル酸ニラパリブ一水和物の合成を説明する(図3も参照)。
Claims (194)
- 式(1)の化合物またはその塩を製造する方法であって、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールである]。 - 前記接触が水分子の形成をもたらす、請求項1に記載の方法。
- 前記接触が酸の存在下で行われる、請求項1または2に記載の方法。
- 前記酸が、ギ酸、酢酸、プロピオン酸、酪酸、吉草酸、カプロン酸、シュウ酸、乳酸、リンゴ酸、クエン酸、安息香酸、炭酸、尿酸、タウリン、p−トルエンスルホン酸、トリフルオロメタンスルホン酸、アミノメチルホスホン酸、トリフルオロ酢酸(TFA)、ホスホン酸、硫酸、硝酸、リン酸、塩酸、エタンスルホン酸(ESA)、またはその任意の組合せである、請求項3に記載の方法。
- 前記酸がTFAである、請求項4に記載の方法。
- R1がアミン保護基である、請求項1〜5のいずれか一項に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル(Boc)、9−フルオレニルメチルオキシカルボニル(Fmoc)、カルボキシベンジル基(Cbz)、p−メトキシベンジルカルボニル(Moz)、アセチル(Ac)、ベンゾイル(Bz)、p−メトキシベンジル(PMB)、3,4−ジメトキシベンジル(DMPM)、p−メトキシフェニル(PMP)、2−ナフチルメチルエーテル(Nap)、トシル(Ts)、またはクロロギ酸トリクロロエチル(Troc)である、請求項6に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル基(Boc)である、請求項7に記載の方法。
- R2がC1−10アルキルである、請求項1〜8のいずれか一項に記載の方法。
- R2がメチルである、請求項9に記載の方法。
- 各R3がHである、請求項1〜10のいずれか一項に記載の方法。
- 前記式(1)の化合物またはその塩が、式(4):
- 前記式(1)の化合物またはその塩が、式(4):
- 式(5)の化合物またはその塩を製造する方法であって、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールである]。 - 前記触媒が、ルイス酸、またはその溶媒和物を含んでなる、請求項14に記載の方法。
- 前記ルイス酸が式MXnを有し、ここで、Mは、Cu、Zn、B、Ti、Fe、Ni、Co、Al、またはAgであり、ここで、Xは、ハロゲン化物、トリフラート、リン酸塩、フルオロリン酸塩、または酢酸塩であり、ここで、nは、1、2、3、または4である、請求項15に記載の方法。
- 前記MがCuである、請求項16に記載の方法。
- 前記ルイス酸が銅塩である、請求項16に記載の方法。
- 前記銅塩がトリフルオロメタンスルホン酸銅(II)(Cu(OTf)2)である、請求項18に記載の方法。
- 前記接触が溶媒の存在下で行われる、請求項14〜19のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項20に記載の方法。
- 前記溶媒がTHFを含んでなる、請求項21に記載の方法。
- R1がアミン保護基である、請求項14〜22のいずれか一項に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル(Boc)、9−フルオレニルメチルオキシカルボニル(Fmoc)、カルボキシベンジル基(Cbz)、p−メトキシベンジルカルボニル(Moz)、アセチル(Ac)、ベンゾイル(Bz)、p−メトキシベンジル(PMB)、3,4−ジメトキシベンジル(DMPM)、p−メトキシフェニル(PMP)、2−ナフチルメチルエーテル(Nap)、トシル(Ts)、またはクロロギ酸トリクロロエチル(Troc)である、請求項23に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル基(Boc)である、請求項24に記載の方法。
- R2がC1−10アルキルである、請求項14〜25のいずれか一項に記載の方法。
- R2がメチルである、請求項26に記載の方法。
- 各R3がHである、請求項14〜27のいずれか一項に記載の方法。
- 前記式(5)の化合物またはその塩が、式(6):
- 前記式(5)の化合物が、式(6):
- 式(7)の塩を製造する方法であって、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
Aは、陽イオンである]。 - 前記陽イオンがアルカリ金属陽イオンである、請求項31に記載の方法。
- 前記アルカリ金属陽イオンがリチウム陽イオンである、請求項32に記載の方法。
- R1がアミン保護基である、請求項31〜33のいずれか一項に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル(Boc)、9−フルオレニルメチルオキシカルボニル(Fmoc)、カルボキシベンジル基(Cbz)、p−メトキシベンジルカルボニル(Moz)、アセチル(Ac)、ベンゾイル(Bz)、p−メトキシベンジル(PMB)、3,4−ジメトキシベンジル(DMPM)、p−メトキシフェニル(PMP)、2−ナフチルメチルエーテル(Nap)、トシル(Ts)、またはクロロギ酸トリクロロエチル(Troc)である、請求項34に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル基(Boc)である、請求項35に記載の方法。
- R2がC1−10アルキルである、請求項31〜36のいずれか一項に記載の方法。
- R2がメチルである、請求項37に記載の方法。
- 各R3がHである、請求項31〜38のいずれか一項に記載の方法。
- 前記式(7)の塩が、式(8):
- 式(9)の化合物またはその塩を製造する方法であって、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
Aは、陽イオンである]。 - 前記陽イオンがアルカリ金属陽イオンである、請求項41に記載の方法。
- 前記アルカリ金属陽イオンがリチウム陽イオンである、請求項42に記載の方法。
- 前記接触が溶媒の存在下で行われる、請求項41〜43のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項44に記載の方法。
- 前記溶媒がDMFを含んでなる、請求項45に記載の方法。
- 前記接触が酸の存在下で行われる、請求項41〜46に記載の方法。
- 前記酸が、ギ酸、酢酸、プロピオン酸、酪酸、吉草酸、カプロン酸、シュウ酸、乳酸、リンゴ酸、クエン酸、安息香酸、炭酸、尿酸、タウリン、p−トルエンスルホン酸、トリフルオロメタンスルホン酸、アミノメチルホスホン酸、トリフルオロ酢酸(TFA)、ホスホン酸、硫酸、硝酸、リン酸、塩酸、エタンスルホン酸(ESA)、またはその任意の組合せである、請求項47に記載の方法。
- 前記酸がトリフルオロ酢酸(TFA)である、請求項48に記載の方法。
- 前記カップリング試薬が、カルボニルジイミダゾール(CDI)、N,N’−ジシクロヘキシルカルボジイミド(DCC)、3−(ジエトキシホスホリルオキシ)−1,2,3−ベンゾトリアジン−4(3H)−オン(DEPBT)、N,N’−ジイソプロピルカルボジイミド、1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム3−オキシドヘキサフルオロホスファート(HATU)、2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスファート(HBTU)、1−ヒドロキシ−7−アザベンゾトリアゾール(HOAt)、ヒドロキシベンゾトリアゾール(HOBt)、7−アザベンゾトリアゾール−1−イルオキシ)トリピロリジノホスホニウムヘキサフルオロホスファート(PyAOP)、またはベンゾトリアゾール−1−イル−オキシトリピロリジノホスホニウムヘキサフルオロホスファート(PyBOP)である、請求項41〜49のいずれか一項に記載の方法。
- 前記カップリング試薬がCDIである、請求項50に記載の方法。
- R1がアミン保護基である、請求項41〜51のいずれか一項に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル(Boc)、9−フルオレニルメチルオキシカルボニル(Fmoc)、カルボキシベンジル基(Cbz)、p−メトキシベンジルカルボニル(Moz)、アセチル(Ac)、ベンゾイル(Bz)、p−メトキシベンジル(PMB)、3,4−ジメトキシベンジル(DMPM)、p−メトキシフェニル(PMP)、2−ナフチルメチルエーテル(Nap)、トシル(Ts)、またはクロロギ酸トリクロロエチル(Troc)である、請求項52に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル基(Boc)である、請求項53に記載の方法。
- R2がC1−10アルキルである、請求項41〜54のいずれか一項に記載の方法。
- R2がメチルである、請求項55に記載の方法。
- 各R3がHである、請求項41〜56のいずれか一項に記載の方法。
- 前記式(9)の化合物またはその塩が、式(10):
- 前記式(9)の化合物が、式(10):
- 式(11)の塩を製造する方法であって、
R1は、Hまたはアミン保護基であり;
R2は、H、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールである]。 - 前記接触が酸の存在下で行われる、請求項60に記載の方法。
- 前記酸が、ギ酸、酢酸、プロピオン酸、酪酸、吉草酸、カプロン酸、シュウ酸、乳酸、リンゴ酸、クエン酸、安息香酸、炭酸、尿酸、タウリン、p−トルエンスルホン酸、トリフルオロメタンスルホン酸、アミノメチルホスホン酸、トリフルオロ酢酸(TFA)、ホスホン酸、硫酸、硝酸、リン酸、塩酸、エタンスルホン酸(ESA)、またはその任意の組合せである、請求項61に記載の方法。
- 前記酸がトリフルオロ酢酸(TFA)である、請求項62に記載の方法。
- 前記接触が溶媒の存在下で行われる、請求項60〜63のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項64に記載の方法。
- 前記溶媒がTHFを含んでなる、請求項65に記載の方法。
- R1がアミン保護基である、請求項60〜66のいずれか一項に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル(Boc)、9−フルオレニルメチルオキシカルボニル(Fmoc)、カルボキシベンジル基(Cbz)、p−メトキシベンジルカルボニル(Moz)、アセチル(Ac)、ベンゾイル(Bz)、p−メトキシベンジル(PMB)、3,4−ジメトキシベンジル(DMPM)、p−メトキシフェニル(PMP)、2−ナフチルメチルエーテル(Nap)、トシル(Ts)、またはクロロギ酸トリクロロエチル(Troc)である、請求項67に記載の方法。
- 前記アミン保護基が、tert−ブチルオキシカルボニル基(Boc)である、請求項68に記載の方法。
- R2がC1−10アルキルである、請求項60〜69のいずれか一項に記載の方法。
- R2がメチルである、請求項70に記載の方法。
- 各R3がHである、請求項60〜71のいずれか一項に記載の方法。
- 前記式(11)の塩が、式(12):
- 式(12)のエナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物を製造する方法であって、
b) 濾過により前記混合物からトシル酸(S)−ニラパリブ一水和物を分離して、エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物を形成させること;ならびに
c) 前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物を、第2の有機溶媒、水、またはその任意の組合せと接触させて、前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物の結晶形を形成させること、
を含んでなる、方法。 - 前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物の結晶形を湿式粉砕することをさらに含んでなる、請求項74に記載の方法。
- 1以上の温度サイクルを用いて、前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物をアニーリングすることをさらに含んでなる、請求項74または75に記載の方法。
- 前記第1の有機溶媒がアセトニトリルを含んでなる、請求項74〜76のいずれか一項に記載の方法。
- 約200:1〜約1:200の水:第1の有機溶媒比(v/v)が前記接触に用いられる、請求項74〜77のいずれか一項に記載の方法。
- 前記水:第1の有機溶媒比(v/v)が約5:1〜約1:5である、請求項78に記載の方法。
- 前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物が、前記濾過後の濾液部分に存在する、請求項74〜79のいずれか一項に記載の方法。
- 前記第2の有機溶媒がDMSOを含んでなる、請求項74〜80のいずれか一項に記載の方法。
- 前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物をジメチルスルホキシド(DMSO)および水と接触させることを含んでなる、請求項81に記載の方法。
- 約200:1〜約1:200の水:DMSO比(v/v)が前記接触に用いられる、請求項81または82に記載の方法。
- 前記水:DMSO比(v/v)が約5:1〜約1:5である、請求項83に記載の方法。
- 式(12)のエナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物を製造する方法であって、
i) 濾過により前記混合物からトシル酸(S)−ニラパリブ一水和物を分離して、エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物を形成させること;ならびに
j) 前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物をDMSOおよび水と接触させて、前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物の結晶形を形成させること、
を含んでなる、方法。 - 前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物の結晶形を湿式粉砕することをさらに含んでなる、請求項85に記載の方法。
- 1以上の温度サイクルを用いて、前記エナンチオマー豊富化トシル酸(S)−ニラパリブ一水和物をアニーリングすることをさらに含んでなる、請求項85に記載の方法。
- 式(7)の塩:
R1は、Hまたはアミン保護基であり;
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールであり;かつ
Aは、陽イオンである]。 - 前記陽イオンがアルカリ金属陽イオンである、請求項88に記載の塩。
- 前記アルカリ金属陽イオンがリチウム陽イオンである、請求項89に記載の塩。
- R1がアミン保護基である、請求項88〜90のいずれか一項に記載の塩。
- 前記アミン保護基が、tert−ブチルオキシカルボニル(Boc)、9−フルオレニルメチルオキシカルボニル(Fmoc)、カルボキシベンジル基(Cbz)、p−メトキシベンジルカルボニル(Moz)、アセチル(Ac)、ベンゾイル(Bz)、p−メトキシベンジル(PMB)、3,4−ジメトキシベンジル(DMPM)、p−メトキシフェニル(PMP)、2−ナフチルメチルエーテル(Nap)、トシル(Ts)、またはクロロギ酸トリクロロエチル(Troc)である、請求項91に記載の塩。
- 前記アミン保護基が、tert−ブチルオキシカルボニル基(Boc)である、請求項92に記載の塩。
- 各R3がHである、請求項88〜93のいずれか一項に記載の塩。
- 前記式(7)の塩が、式(8):
- 式(17)の化合物またはその塩を製造する方法であって、
- 式(19)の化合物またはその塩を塩化ベンゾイルおよび有機化合物と接触させて、式(18)の化合物またはその塩を形成させることを含んでなる、請求項96に記載の方法:
- 前記有機化合物がトリエチルアミン(trimethylamine)(TEA)またはトリメチルアミン(TMA)である、請求項97に記載の方法。
- R4がBrである、請求項96〜98のいずれか一項に記載の方法。
- 前記接触が溶媒の存在下で行われる、請求項96〜99のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項100に記載の方法。
- 前記溶媒がTHFを含んでなる、請求項101に記載の方法。
- 式(20)の化合物またはその塩を製造する方法であって、
- 前記式(17)の化合物またはその塩の接触が、式(22):
- 前記式(21)の塩および前記式(22)の塩が、約50:1〜約1:50の比(w/w)を有する、請求項104に記載の方法。
- 前記比(w/w)が約7:1である、請求項105に記載の方法。
- 前記接触が配位子の存在下で行われる、請求項103〜106のいずれか一項に記載の方法。
- 前記配位子がホスフィン配位子を含んでなる、請求項107に記載の方法。
- 前記ホスフィン配位子が、DavePhos、XantPhos、JohnPhos、SPhos、XPhos、tBuXPhos、APhos、CyJohnPhos、またはその任意の組合せを含んでなる、請求項108に記載の方法。
- 前記ホスフィン配位子がXPhosを含んでなる、請求項109に記載の方法。
- 前記触媒が金属触媒を含んでなる、請求項103〜110のいずれか一項に記載の方法。
- 前記金属触媒がパラジウムを含んでなる、請求項111に記載の方法。
- 前記金属触媒が酢酸パラジウム(II)を含んでなる、請求項112に記載の方法。
- 前記接触が塩基の存在下で行われる、請求項103〜113のいずれか一項に記載の方法。
- 前記塩基がアルカリ塩を含んでなる、請求項114に記載の方法。
- 前記アルカリ塩が、Cs2CO3、CsHCO3K3PO4、K2HPO4、KH2PO4、K2CO3、KHCO3、NaHCO3、Na2CO3、またはその任意の組合せを含んでなる、請求項115に記載の方法。
- 前記接触が溶媒の存在下で行われる、請求項103〜116のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項117に記載の方法。
- 前記溶媒がTHFを含んでなる、請求項118に記載の方法。
- 前記式(20)の化合物またはその塩をアセトニトリルと接触させることをさらに含んでなる、請求項103〜119のいずれか一項に記載の方法。
- 式(23)の化合物またはその塩を製造する方法であって、
- 各R5が独立にC1−3アルキルである、請求項121に記載の方法。
- 各R5がメチルである、請求項122に記載の方法。
- 前記式(23)の化合物またはその塩が、式(24):
- 前記接触が溶媒の存在下で行われる、請求項121〜124のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項125に記載の方法。
- 前記溶媒がTHFを含んでなる、請求項126に記載の方法。
- 式(20)の化合物またはその塩を製造する方法であって、
- 前記式(23)の化合物またはその塩の接触が、式(22):
- 前記式(21)の塩および前記式(22)の塩が、約50:1〜約1:50の比(w/w)を有する、請求項129に記載の方法。
- 前記比(w/w)が約7:1である、請求項130に記載の方法。
- 前記接触が配位子の存在下で行われる、請求項128〜131のいずれか一項に記載の方法。
- 前記配位子がホスフィン配位子を含んでなる、請求項132に記載の方法。
- 前記ホスフィン配位子が、DavePhos、XantPhos、JohnPhos、SPhos、XPhos、tBuXPhos、APhos、CyJohnPhos、またはその任意の組合せを含んでなる、請求項133に記載の方法。
- 前記ホスフィン配位子がXPhosを含んでなる、請求項134に記載の方法。
- 前記触媒が金属触媒を含んでなる、請求項128〜135のいずれか一項に記載の方法。
- 前記金属触媒がパラジウムを含んでなる、請求項136に記載の方法。
- 前記金属触媒が酢酸パラジウム(II)を含んでなる、請求項137に記載の方法。
- 前記接触が塩基の存在下で行われる、請求項128〜138のいずれか一項に記載の方法。
- 前記塩基がアルカリ塩を含んでなる、請求項139に記載の方法。
- 前記アルカリ塩が、Cs2CO3、CsHCO3K3PO4、K2HPO4、KH2PO4、K2CO3、KHCO3、NaHCO3、Na2CO3、またはその任意の組合せを含んでなる、請求項140に記載の方法。
- 前記接触が溶媒の存在下で行われる、請求項128〜141のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項142に記載の方法。
- 前記溶媒がTHFを含んでなる、請求項143に記載の方法。
- 前記式(20)の化合物またはその塩をアセトニトリルと接触させることをさらに含んでなる、請求項128〜144のいずれか一項に記載の方法。
- 式(25)の化合物またはその塩を製造する方法であって、
- 式(26)の化合物またはその塩を前記配位子と接触させることをさらに含んでなる、請求項146に記載の方法。
- 前記配位子がキラル配位子を含んでなる、請求項147に記載の方法。
- 前記キラル配位子がJosiphos配位子を含んでなる、請求項148に記載の方法。
- 前記Josiphos配位子が、Josiphos SL−J505−2、Josiphos SL−J013、Josiphos SL−J212、Josiphos SL−J011、Josiphos SL−N012、またはその任意の組合せを含んでなる、請求項149に記載の方法。
- 前記接触が金属塩の存在下で行われる、請求項146〜150のいずれか一項に記載の方法。
- 前記金属塩が、テトラフルオロホウ酸ビス(ノルボルエナジン)ロジウム(I)(Rh(nbd)2BF4)を含んでなる、請求項151に記載の方法。
- 前記接触が溶媒の存在下で行われる、請求項146〜152のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項153に記載の方法。
- 前記溶媒がDCMを含んでなる、請求項154に記載の方法。
- 式(14)の化合物またはその塩を製造する方法であって、
- 前記塩基が水酸化アルカリを含んでなる、請求項156に記載の方法。
- 前記水酸化アルカリが水酸化ナトリウムを含んでなる、請求項157に記載の方法。
- 前記接触が溶媒の存在下で行われる、請求項156〜158のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項159に記載の方法。
- 前記溶媒がエタノールを含んでなる、請求項160に記載の方法。
- 式(13)の塩を製造する方法であって、
- 前記酸が、ギ酸、酢酸、プロピオン酸、酪酸、吉草酸、カプロン酸、シュウ酸、乳酸、リンゴ酸、クエン酸、安息香酸、炭酸、尿酸、タウリン、p−トルエンスルホン酸、トリフルオロメタンスルホン酸、アミノメチルホスホン酸、トリフルオロ酢酸(TFA)、ホスホン酸、硫酸、硝酸、リン酸、塩酸、エタンスルホン酸(ESA)、またはその任意の組合せである、請求項162に記載の方法。
- 前記酸がESAである、請求項163に記載の方法。
- 前記接触が溶媒の存在下で行われる、請求項162〜164のいずれか一項に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項165に記載の方法。
- 前記溶媒が、アセトニトリル、メタノール、DCM、またはその任意の組合せを含んでなる、請求項166に記載の方法。
- 前記溶媒がアセトニトリルおよびメタノールを含んでなる、請求項167に記載の方法。
- 前記溶媒が、1%〜50%(v/v)のメタノール:アセトニトリル比を有する、請求項168に記載の方法。
- 前記溶媒がアセトニトリルおよびDCMを含んでなる、請求項167に記載の方法。
- 前記溶媒が、1%〜50%(v/v)のDCM:アセトニトリル比を有する、請求項170に記載の方法。
- 式(21):
a) 式(28):
b) 前記式(29)の化合物またはその塩をp−トルエンスルホン酸無水物と接触させること、
を含んでなる、方法。 - 前記酸化剤が2,2,6,6−テトラメチルピペリジン−1−オキシル(TEMPO)である、請求項172に記載の方法。
- 前記酸化または接触が溶媒の存在下で行われる、請求項173に記載の方法。
- 前記溶媒が、N,N−ジメチルホルムアミド(dimethylformide)(DMF)、t−ブタノール、ジメトキシエタン(DME)、アセトニトリル、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、2−メチルテトラヒドロフラン(ME−THF)、イソプロピルアルコール、メタノール、エタノール、またはその任意の組合せを含んでなる、請求項174に記載の方法。
- 前記溶媒がDCMを含んでなる、請求項175に記載の方法。
- 前記式(28):
- 前記式(29)の化合物またはその塩の接触が、トリエチルアミン(trimethylamine)(TEA)、水、イソプロピルアルコール、アジ化ナトリウム、またはその任意の組合せの存在下で行われる、請求項172〜177のいずれか一項に記載の方法。
- 前記式(29)の化合物またはその塩の接触が、前記式(21):
- 式(30)の組成物またはその塩:
各R1は、独立に、Hまたはアミン保護基であり;かつ
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールである]。 - 各R1が独立にアミン保護基である、請求項180に記載の組成物またはその塩。
- 前記アミン保護基が、tert−ブチルオキシカルボニル(Boc)、9−フルオレニルメチルオキシカルボニル(Fmoc)、カルボキシベンジル基(Cbz)、p−メトキシベンジルカルボニル(Moz)、アセチル(Ac)、ベンゾイル(Bz)、p−メトキシベンジル(PMB)、3,4−ジメトキシベンジル(DMPM)、p−メトキシフェニル(PMP)、2−ナフチルメチルエーテル(Nap)、トシル(Ts)、またはクロロギ酸トリクロロエチル(Troc)である、請求項181に記載の組成物またはその塩。
- 前記アミン保護基が、tert−ブチルオキシカルボニル基(Boc)またはベンゾイル(Bz)である、請求項182に記載の組成物またはその塩。
- 各R3がHである、請求項180〜183のいずれか一項に記載の組成物。
- 化合物またはその塩が、式(25):
- 化合物が、式(25):
- 式(31)もしくは(32)の組成物またはその塩:
各R1は、独立に、Hまたはアミン保護基であり;かつ
各R3は、独立に、H、ハロゲン、C1−10アルキル、C1−10ハロアルキル、またはアリールである]。 - 各R1が独立にアミン保護基である、請求項187に記載の組成物またはその塩。
- 前記アミン保護基が、tert−ブチルオキシカルボニル(Boc)、9−フルオレニルメチルオキシカルボニル(Fmoc)、カルボキシベンジル基(Cbz)、p−メトキシベンジルカルボニル(Moz)、アセチル(Ac)、ベンゾイル(Bz)、p−メトキシベンジル(PMB)、3,4−ジメトキシベンジル(DMPM)、p−メトキシフェニル(PMP)、2−ナフチルメチルエーテル(Nap)、トシル(Ts)、またはクロロギ酸トリクロロエチル(Troc)である、請求項188に記載の組成物またはその塩。
- 前記アミン保護基が、tert−ブチルオキシカルボニル基(Boc)またはベンゾイル(Bz)である、請求項189に記載の組成物またはその塩。
- 各R3がHである、請求項187〜190のいずれか一項に記載の組成物。
- 化合物またはその塩が、式(20)または(26):
- 化合物が、式(20):
- 化合物が、式(26):
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762489387P | 2017-04-24 | 2017-04-24 | |
US201762489415P | 2017-04-24 | 2017-04-24 | |
US62/489,415 | 2017-04-24 | ||
US62/489,387 | 2017-04-24 | ||
PCT/US2018/029131 WO2018200517A1 (en) | 2017-04-24 | 2018-04-24 | Methods of manufacturing of niraparib |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2020517668A true JP2020517668A (ja) | 2020-06-18 |
JP2020517668A5 JP2020517668A5 (ja) | 2021-06-17 |
JP7179014B2 JP7179014B2 (ja) | 2022-11-28 |
Family
ID=63919973
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019557567A Active JP7179014B2 (ja) | 2017-04-24 | 2018-04-24 | ニラパリブの製造方法 |
Country Status (15)
Country | Link |
---|---|
US (2) | US11161834B2 (ja) |
EP (1) | EP3615513B1 (ja) |
JP (1) | JP7179014B2 (ja) |
KR (1) | KR102582624B1 (ja) |
CN (1) | CN110753684A (ja) |
AU (2) | AU2018258274C1 (ja) |
BR (1) | BR112019022320A2 (ja) |
CA (1) | CA3060715A1 (ja) |
ES (1) | ES2926255T3 (ja) |
IL (1) | IL270068B (ja) |
MA (1) | MA48475A (ja) |
SG (1) | SG11201909807TA (ja) |
TW (1) | TWI783993B (ja) |
WO (1) | WO2018200517A1 (ja) |
ZA (1) | ZA201906944B (ja) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020512350A (ja) | 2017-03-27 | 2020-04-23 | テサロ, インコーポレイテッド | ニラパリブ組成物 |
CA3060715A1 (en) | 2017-04-24 | 2018-11-01 | Tesaro, Inc. | Methods of manufacturing of niraparib |
CA3063715A1 (en) | 2017-05-18 | 2018-11-22 | Tesaro, Inc. | Combination therapies for treating cancer |
BR112020006039A2 (pt) | 2017-09-26 | 2020-10-06 | Tesaro, Inc. | formulações de niraparibe |
KR20200086664A (ko) | 2017-09-30 | 2020-07-17 | 테사로, 인코포레이티드 | 암을 치료하기 위한 조합 요법 |
WO2019071123A1 (en) | 2017-10-06 | 2019-04-11 | Tesaro, Inc. | POLYRHEERAPIES AND USES THEREOF |
CN112300074B (zh) * | 2019-08-02 | 2023-12-29 | 北京盈科瑞创新药物研究有限公司 | 一种吲唑甲酰胺类化合物及其制备方法和应用 |
WO2023159066A1 (en) | 2022-02-15 | 2023-08-24 | Tesaro, Inc. | Use of niraparib for the treatment of brain cancer |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010515715A (ja) * | 2007-01-10 | 2010-05-13 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | ポリ(adp−リボース)ポリメラーゼ(parp)阻害剤としてのアミド置換インダゾール |
JP2011509252A (ja) * | 2008-01-08 | 2011-03-24 | メルク シャープ エンド ドーム リミテッド | 2−{4−[(3s)−ピペリジン−3−イル]フェニル}−2h−インダゾール−7−カルボキサミドの薬学的に許容される塩 |
WO2014088983A1 (en) * | 2012-12-07 | 2014-06-12 | Merck Sharp & Dohme Corp. | Regioselective n-2 arylation of indazoles |
Family Cites Families (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5605793A (en) | 1994-02-17 | 1997-02-25 | Affymax Technologies N.V. | Methods for in vitro recombination |
US6335160B1 (en) | 1995-02-17 | 2002-01-01 | Maxygen, Inc. | Methods and compositions for polypeptide engineering |
US5837458A (en) | 1994-02-17 | 1998-11-17 | Maxygen, Inc. | Methods and compositions for cellular and metabolic engineering |
FI104465B (fi) | 1995-06-14 | 2000-02-15 | Valio Oy | Proteiinihydrolysaatteja allergioiden hoitamiseksi tai estämiseksi, niiden valmistus ja käyttö |
DE69841075D1 (de) | 1997-04-23 | 2009-10-01 | Kaneka Corp | Deoxynukleinsäure welche ein Polypeptid mit stereoselektiver Transaminase Aktivität kodiert, sowie die Deoxynukleinsäure enthaltende Transformanden |
KR20010032861A (ko) | 1997-12-08 | 2001-04-25 | 캘리포니아 인스티튜트 오브 테크놀로지 | 폴리뉴클레오티드 및 폴리펩티드 서열을 형성하는 방법 |
JP4221100B2 (ja) | 1999-01-13 | 2009-02-12 | エルピーダメモリ株式会社 | 半導体装置 |
GB0004297D0 (en) | 2000-02-23 | 2000-04-12 | Ucb Sa | 2-oxo-1 pyrrolidine derivatives process for preparing them and their uses |
EP1272967A2 (en) | 2000-03-30 | 2003-01-08 | Maxygen, Inc. | In silico cross-over site selection |
DK2272813T3 (en) | 2001-04-24 | 2017-02-27 | Massachusetts Inst Of Tech (Mit) | COPPER CATALYST CREATION OF CARBON OXYGEN COMPOUNDS |
US7199147B2 (en) | 2001-06-12 | 2007-04-03 | Dainippon Sumitomo Pharma Co., Ltd. | Rho kinase inhibitors |
JP5186213B2 (ja) | 2004-09-29 | 2013-04-17 | 田辺三菱製薬株式会社 | タウプロテインキナーゼ1阻害剤としての6−ピリジニル−4−ピリミドン誘導体 |
CA2647545C (en) | 2006-04-03 | 2016-02-23 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Amide substituted indazole and benzotriazole derivatives as poly(adp-ribose)polymerase (parp) inhibitors |
JP2010502617A (ja) | 2006-08-31 | 2010-01-28 | シェーリング コーポレイション | 抗菌物質として有用なヒダントイン誘導体 |
EP2132322A4 (en) | 2007-03-02 | 2013-02-20 | Richmond Chemical Corp | METHOD FOR INCREASING YIELD AND IMPROVING PURIFICATION OF PRODUCTS FROM REACTIONS WITH TRANSAMINASE |
PE20081889A1 (es) * | 2007-03-23 | 2009-03-05 | Smithkline Beecham Corp | Indol carboxamidas como inhibidores de ikk2 |
EP2152262A2 (en) | 2007-04-27 | 2010-02-17 | UCB Pharma, S.A. | New heterocyclic derivatives useful for the treatment of cns disorders |
JP5707344B2 (ja) | 2009-02-26 | 2015-04-30 | コデクシス, インコーポレイテッド | トランスアミナーゼ生体触媒 |
JP2010269667A (ja) | 2009-05-20 | 2010-12-02 | Alps Electric Co Ltd | 多回転角度検出装置 |
EP2606139B1 (en) | 2010-08-16 | 2015-07-15 | Codexis, Inc. | Biocatalysts and methods for the synthesis of (1r,2r)-2-(3,4-dimethoxyphenethoxy)cyclohexanamine |
EP2649062B1 (en) | 2010-11-30 | 2015-04-08 | Takeda Pharmaceutical Company Limited | Bicyclic compounds as inhibitors of acetyl-coa carboxylase (acc) |
CN104744370A (zh) | 2011-02-08 | 2015-07-01 | 辉瑞大药厂 | 胰高血糖素受体调节剂 |
US8802673B2 (en) | 2011-03-24 | 2014-08-12 | Hoffmann-La Roche Inc | Heterocyclic amine derivatives |
US9073911B2 (en) | 2011-06-09 | 2015-07-07 | Hoffmann-La Roche Inc. | Pyrazole derivatives |
ES2672328T3 (es) | 2012-12-07 | 2018-06-13 | Merck Sharp & Dohme Corp. | Proceso de transaminación biocatalítica |
WO2016094391A1 (en) | 2014-12-08 | 2016-06-16 | Myriad Genetics, Inc. | Methods and materials for predicting response to niraparib |
NZ749413A (en) | 2016-06-29 | 2023-05-26 | Tesaro Inc | Methods of treating ovarian cancer |
CN106496187A (zh) * | 2016-09-14 | 2017-03-15 | 陕西科技大学 | 一种制备PARP抑制剂Niraparib的合成方法 |
CN106432056A (zh) * | 2016-09-17 | 2017-02-22 | 青岛辰达生物科技有限公司 | 一种尼拉帕布中间体(3s)‑3‑(4‑氨基苯基)哌啶‑1‑甲酸叔丁酯的制备方法 |
CN106432057A (zh) * | 2016-09-17 | 2017-02-22 | 青岛云天生物技术有限公司 | 一种制备(3s)‑3‑(4‑氨基苯基)哌啶‑1‑甲酸叔丁酯的方法 |
CN106432055A (zh) * | 2016-09-17 | 2017-02-22 | 青岛辰达生物科技有限公司 | 一种尼拉帕布中间体4‑(哌啶‑3‑基)苯胺的制备方法 |
WO2018183349A1 (en) | 2017-03-27 | 2018-10-04 | Tesaro, Inc. | Niraparib formulations |
JP2020512350A (ja) | 2017-03-27 | 2020-04-23 | テサロ, インコーポレイテッド | ニラパリブ組成物 |
CA3060715A1 (en) | 2017-04-24 | 2018-11-01 | Tesaro, Inc. | Methods of manufacturing of niraparib |
US20200289493A1 (en) | 2017-05-09 | 2020-09-17 | Tesaro, Inc. | Combination therapies for treating cancer |
CA3063715A1 (en) | 2017-05-18 | 2018-11-22 | Tesaro, Inc. | Combination therapies for treating cancer |
BR112020006039A2 (pt) | 2017-09-26 | 2020-10-06 | Tesaro, Inc. | formulações de niraparibe |
KR20200086664A (ko) | 2017-09-30 | 2020-07-17 | 테사로, 인코포레이티드 | 암을 치료하기 위한 조합 요법 |
WO2019071123A1 (en) | 2017-10-06 | 2019-04-11 | Tesaro, Inc. | POLYRHEERAPIES AND USES THEREOF |
KR20200105862A (ko) | 2017-12-27 | 2020-09-09 | 테사로, 인코포레이티드 | 암을 치료하는 방법 |
KR20200118117A (ko) | 2018-02-05 | 2020-10-14 | 테사로, 인코포레이티드 | 소아용 니라파립 제제 및 소아용 치료 방법 |
-
2018
- 2018-04-24 CA CA3060715A patent/CA3060715A1/en active Pending
- 2018-04-24 TW TW107113922A patent/TWI783993B/zh active
- 2018-04-24 CN CN201880040321.0A patent/CN110753684A/zh active Pending
- 2018-04-24 KR KR1020197034673A patent/KR102582624B1/ko active IP Right Grant
- 2018-04-24 JP JP2019557567A patent/JP7179014B2/ja active Active
- 2018-04-24 EP EP18790167.3A patent/EP3615513B1/en active Active
- 2018-04-24 WO PCT/US2018/029131 patent/WO2018200517A1/en unknown
- 2018-04-24 BR BR112019022320-7A patent/BR112019022320A2/pt unknown
- 2018-04-24 ES ES18790167T patent/ES2926255T3/es active Active
- 2018-04-24 IL IL270068A patent/IL270068B/en unknown
- 2018-04-24 US US16/608,059 patent/US11161834B2/en active Active
- 2018-04-24 MA MA048475A patent/MA48475A/fr unknown
- 2018-04-24 AU AU2018258274A patent/AU2018258274C1/en active Active
- 2018-04-24 SG SG11201909807T patent/SG11201909807TA/en unknown
-
2019
- 2019-10-22 ZA ZA2019/06944A patent/ZA201906944B/en unknown
-
2021
- 2021-08-09 AU AU2021215116A patent/AU2021215116B2/en active Active
- 2021-10-29 US US17/452,928 patent/US11629137B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010515715A (ja) * | 2007-01-10 | 2010-05-13 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | ポリ(adp−リボース)ポリメラーゼ(parp)阻害剤としてのアミド置換インダゾール |
JP2011509252A (ja) * | 2008-01-08 | 2011-03-24 | メルク シャープ エンド ドーム リミテッド | 2−{4−[(3s)−ピペリジン−3−イル]フェニル}−2h−インダゾール−7−カルボキサミドの薬学的に許容される塩 |
WO2014088983A1 (en) * | 2012-12-07 | 2014-06-12 | Merck Sharp & Dohme Corp. | Regioselective n-2 arylation of indazoles |
Non-Patent Citations (2)
Title |
---|
CHUNG, CHEOL K.: "Process Development of C-N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymme", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 18(1),, JPN7022001167, 2014, pages 215 - 227, ISSN: 0004727302 * |
WALLACE, DEBRA J.: "Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 15(4),, JPN7022001168, 2011, pages 831 - 840, ISSN: 0004727303 * |
Also Published As
Publication number | Publication date |
---|---|
KR20200021456A (ko) | 2020-02-28 |
AU2021215116A1 (en) | 2021-08-26 |
SG11201909807TA (en) | 2019-11-28 |
ES2926255T3 (es) | 2022-10-24 |
IL270068B (en) | 2022-06-01 |
AU2018258274C1 (en) | 2021-12-02 |
JP7179014B2 (ja) | 2022-11-28 |
AU2021215116B2 (en) | 2022-12-01 |
MA48475A (fr) | 2020-03-04 |
US20220041575A1 (en) | 2022-02-10 |
US11629137B2 (en) | 2023-04-18 |
AU2018258274B2 (en) | 2021-05-13 |
EP3615513A1 (en) | 2020-03-04 |
CN110753684A (zh) | 2020-02-04 |
AU2018258274A1 (en) | 2019-11-14 |
US20200055837A1 (en) | 2020-02-20 |
ZA201906944B (en) | 2023-03-29 |
TW201841889A (zh) | 2018-12-01 |
WO2018200517A1 (en) | 2018-11-01 |
EP3615513B1 (en) | 2022-07-20 |
KR102582624B1 (ko) | 2023-09-22 |
BR112019022320A2 (pt) | 2020-05-26 |
TWI783993B (zh) | 2022-11-21 |
CA3060715A1 (en) | 2018-11-01 |
EP3615513A4 (en) | 2020-12-09 |
US11161834B2 (en) | 2021-11-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7179014B2 (ja) | ニラパリブの製造方法 | |
KR102040382B1 (ko) | Ask1 억제제의 제조 방법 | |
US10781211B2 (en) | Spirocycle compounds and methods of making and using same | |
WO2016203112A1 (en) | Spiro[cyclobutane-1,3'-indolin]-2'-one derivatives as bromodomain inhibitors | |
AU2011360550A1 (en) | Novel compounds as Histamine H3 receptor ligands | |
JP7237010B2 (ja) | Hdac6選択的阻害剤およびその製造方法と使用 | |
WO2022192781A1 (en) | Phenalkylamines and methods of making and using the same | |
JP7399846B2 (ja) | (s)-tert-ブチル4,5-ジアミノ-5-オキソペンタノエートの調製プロセス | |
JP2019522059A (ja) | S1p1アゴニスト及びその応用 | |
JP5606440B2 (ja) | チアベンゾアズレンプロピオン酸誘導体の製造法 | |
EA044378B1 (ru) | Способы изготовления нирапариба | |
US11739088B2 (en) | Synthesis of heterocyclic compounds | |
WO2022271557A1 (en) | Processes for the preparation of (s)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl) methyl)benzyl) amino)isoindoline-1,3-dione | |
CN105777616A (zh) | 色瑞替尼的合成中间体及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210426 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210426 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220310 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220315 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220615 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20221018 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20221115 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7179014 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |