CN117500813A - 芳基氧膦类化合物 - Google Patents

芳基氧膦类化合物 Download PDF

Info

Publication number: CN117500813A
Authority: CN; China
Prior art keywords: membered; cycloalkyl; heteroaryl; compound; egfr
Prior art date: 2021-06-17
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Pending

Application number

CN202280043087.3A

Other languages

English (en)

Chinese (zh)

Inventor

谢雨礼

吴应鸣

樊后兴

钱立晖

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Wigen Biomedicine Technology Shanghai Co Ltd

Original Assignee

Wigen Biomedicine Technology Shanghai Co Ltd

Priority date (The priority date 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 date listed.)

2021-06-17

Filing date

2022-06-17

Publication date

2024-02-02

2022-06-17 Application filed by Wigen Biomedicine Technology Shanghai Co Ltd filed Critical Wigen Biomedicine Technology Shanghai Co Ltd

2024-02-02 Publication of CN117500813A publication Critical patent/CN117500813A/zh

Status Pending legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 139
150000003839 salts Chemical class 0.000 claims abstract description 22
239000013078 crystal Substances 0.000 claims abstract description 17
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 43
125000001072 heteroaryl group Chemical group 0.000 claims description 38
125000000753 cycloalkyl group Chemical group 0.000 claims description 33
238000000034 method Methods 0.000 claims description 32
125000003118 aryl group Chemical group 0.000 claims description 25
239000012453 solvate Substances 0.000 claims description 18
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 16
229910052736 halogen Inorganic materials 0.000 claims description 15
150000002367 halogens Chemical class 0.000 claims description 15
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 14
125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 14
125000005915 C6-C14 aryl group Chemical group 0.000 claims description 11
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
229910052799 carbon Inorganic materials 0.000 claims description 9
125000001309 chloro group Chemical group Cl* 0.000 claims description 9
239000008194 pharmaceutical composition Substances 0.000 claims description 9
239000000546 pharmaceutical excipient Substances 0.000 claims description 8
239000004480 active ingredient Substances 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 4
125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
125000004093 cyano group Chemical group *C#N 0.000 claims description 4
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
230000008569 process Effects 0.000 claims description 2
YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 abstract description 78
102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 abstract description 77
108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 abstract description 77
-1 aryl phosphine oxide compound Chemical class 0.000 abstract description 25
201000010099 disease Diseases 0.000 abstract description 13
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
206010028980 Neoplasm Diseases 0.000 abstract description 11
239000003814 drug Substances 0.000 abstract description 10
238000002360 preparation method Methods 0.000 abstract description 7
229940121647 egfr inhibitor Drugs 0.000 abstract description 5
238000006243 chemical reaction Methods 0.000 description 52
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
239000000203 mixture Substances 0.000 description 38
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 35
238000003786 synthesis reaction Methods 0.000 description 34
230000015572 biosynthetic process Effects 0.000 description 33
239000007787 solid Substances 0.000 description 29
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 23
239000000047 product Substances 0.000 description 23
230000002829 reductive effect Effects 0.000 description 23
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 22
239000002904 solvent Substances 0.000 description 21
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
230000035772 mutation Effects 0.000 description 20
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
239000000243 solution Substances 0.000 description 18
239000007858 starting material Substances 0.000 description 18
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
239000012074 organic phase Substances 0.000 description 14
229910052786 argon Inorganic materials 0.000 description 13
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
230000000694 effects Effects 0.000 description 12
230000002401 inhibitory effect Effects 0.000 description 12
239000000706 filtrate Substances 0.000 description 11
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
230000005764 inhibitory process Effects 0.000 description 10
125000002950 monocyclic group Chemical group 0.000 description 10
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
238000005481 NMR spectroscopy Methods 0.000 description 9
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
235000019441 ethanol Nutrition 0.000 description 9
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
238000004440 column chromatography Methods 0.000 description 8
230000000052 comparative effect Effects 0.000 description 8
238000010992 reflux Methods 0.000 description 8
238000003756 stirring Methods 0.000 description 8
LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
229940126062 Compound A Drugs 0.000 description 7
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 7
125000004429 atom Chemical group 0.000 description 7
201000011510 cancer Diseases 0.000 description 7
210000004027 cell Anatomy 0.000 description 7
102000004190 Enzymes Human genes 0.000 description 6
108090000790 Enzymes Proteins 0.000 description 6
206010058467 Lung neoplasm malignant Diseases 0.000 description 6
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
239000007864 aqueous solution Substances 0.000 description 6
239000000460 chlorine Substances 0.000 description 6
229940125904 compound 1 Drugs 0.000 description 6
229940079593 drug Drugs 0.000 description 6
238000000605 extraction Methods 0.000 description 6
201000005202 lung cancer Diseases 0.000 description 6
208000020816 lung neoplasm Diseases 0.000 description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
208000024891 symptom Diseases 0.000 description 6
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 description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
241001465754 Metazoa Species 0.000 description 5
229960000583 acetic acid Drugs 0.000 description 5
125000000217 alkyl group Chemical group 0.000 description 5
230000004071 biological effect Effects 0.000 description 5
125000004432 carbon atom Chemical group C* 0.000 description 5
238000001514 detection method Methods 0.000 description 5
125000005842 heteroatom Chemical group 0.000 description 5
238000001727 in vivo Methods 0.000 description 5
239000000463 material Substances 0.000 description 5
239000011259 mixed solution Substances 0.000 description 5
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
230000003287 optical effect Effects 0.000 description 5
125000003367 polycyclic group Chemical group 0.000 description 5
SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
238000002953 preparative HPLC Methods 0.000 description 5
239000000126 substance Substances 0.000 description 5
125000001424 substituent group Chemical group 0.000 description 5
238000004809 thin layer chromatography Methods 0.000 description 5
208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 5
206010059866 Drug resistance Diseases 0.000 description 4
229910004298 SiO 2 Inorganic materials 0.000 description 4
235000011054 acetic acid Nutrition 0.000 description 4
235000019270 ammonium chloride Nutrition 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
239000008346 aqueous phase Substances 0.000 description 4
239000012300 argon atmosphere Substances 0.000 description 4
VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 4
238000002474 experimental method Methods 0.000 description 4
238000004108 freeze drying Methods 0.000 description 4
238000002347 injection Methods 0.000 description 4
239000007924 injection Substances 0.000 description 4
229940098779 methanesulfonic acid Drugs 0.000 description 4
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
229910052757 nitrogen Inorganic materials 0.000 description 4
239000003921 oil Substances 0.000 description 4
235000019198 oils Nutrition 0.000 description 4
YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
229910000160 potassium phosphate Inorganic materials 0.000 description 4
235000011009 potassium phosphates Nutrition 0.000 description 4
238000000746 purification Methods 0.000 description 4
239000000758 substrate Substances 0.000 description 4
229910052717 sulfur Inorganic materials 0.000 description 4
229940121646 third-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 4
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical group C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
SIKXIUWKPGWBBF-UHFFFAOYSA-N 5-bromo-2,4-dichloropyrimidine Chemical compound ClC1=NC=C(Br)C(Cl)=N1 SIKXIUWKPGWBBF-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 3
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
241000699670 Mus sp. Species 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
230000001028 anti-proliverative effect Effects 0.000 description 3
125000002619 bicyclic group Chemical group 0.000 description 3
239000008280 blood Substances 0.000 description 3
210000004369 blood Anatomy 0.000 description 3
239000002775 capsule Substances 0.000 description 3
229910052801 chlorine Inorganic materials 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
125000004122 cyclic group Chemical group 0.000 description 3
239000003085 diluting agent Substances 0.000 description 3
238000010790 dilution Methods 0.000 description 3
239000012895 dilution Substances 0.000 description 3
WQAWEUZTDVWTDB-UHFFFAOYSA-N dimethyl(oxo)phosphanium Chemical compound C[P+](C)=O WQAWEUZTDVWTDB-UHFFFAOYSA-N 0.000 description 3
239000003995 emulsifying agent Substances 0.000 description 3
229940121645 first-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 3
238000003818 flash chromatography Methods 0.000 description 3
229910052731 fluorine Inorganic materials 0.000 description 3
229910052739 hydrogen Inorganic materials 0.000 description 3
239000001257 hydrogen Substances 0.000 description 3
239000007788 liquid Substances 0.000 description 3
YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
229960003278 osimertinib Drugs 0.000 description 3
DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 3
229910052760 oxygen Inorganic materials 0.000 description 3
239000006187 pill Substances 0.000 description 3
229910000027 potassium carbonate Inorganic materials 0.000 description 3
239000000843 powder Substances 0.000 description 3
238000004262 preparative liquid chromatography Methods 0.000 description 3
125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 3
125000004076 pyridyl group Chemical group 0.000 description 3
239000011541 reaction mixture Substances 0.000 description 3
230000004044 response Effects 0.000 description 3
229920006395 saturated elastomer Polymers 0.000 description 3
229940121644 second-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 3
239000007909 solid dosage form Substances 0.000 description 3
239000000725 suspension Substances 0.000 description 3
239000003826 tablet Substances 0.000 description 3
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
230000001225 therapeutic effect Effects 0.000 description 3
125000001544 thienyl group Chemical group 0.000 description 3
239000000080 wetting agent Substances 0.000 description 3
PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
WUIJTQZXUURFQU-UHFFFAOYSA-N 1-methylsulfonylethene Chemical group CS(=O)(=O)C=C WUIJTQZXUURFQU-UHFFFAOYSA-N 0.000 description 2
VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 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
229920001817 Agar Polymers 0.000 description 2
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
229940126657 Compound 17 Drugs 0.000 description 2
FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
206010071975 EGFR gene mutation Diseases 0.000 description 2
101150039808 Egfr gene Proteins 0.000 description 2
KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
108010010803 Gelatin Proteins 0.000 description 2
241000206672 Gelidium Species 0.000 description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
229930195725 Mannitol Natural products 0.000 description 2
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
229920002472 Starch Polymers 0.000 description 2
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
229930006000 Sucrose Natural products 0.000 description 2
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 2
230000002378 acidificating effect Effects 0.000 description 2
235000010419 agar Nutrition 0.000 description 2
235000010443 alginic acid Nutrition 0.000 description 2
229920000615 alginic acid Polymers 0.000 description 2
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
230000037396 body weight Effects 0.000 description 2
OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
230000010261 cell growth Effects 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
229940126142 compound 16 Drugs 0.000 description 2
229940125810 compound 20 Drugs 0.000 description 2
229940126540 compound 41 Drugs 0.000 description 2
239000012043 crude product Substances 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
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 2
NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 2
229910052805 deuterium Inorganic materials 0.000 description 2
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
239000006185 dispersion Substances 0.000 description 2
239000002552 dosage form Substances 0.000 description 2
239000000839 emulsion Substances 0.000 description 2
108700021358 erbB-1 Genes Proteins 0.000 description 2
239000000945 filler Substances 0.000 description 2
238000001914 filtration Methods 0.000 description 2
239000000796 flavoring agent Substances 0.000 description 2
235000019253 formic acid Nutrition 0.000 description 2
150000004675 formic acid derivatives Chemical class 0.000 description 2
239000012634 fragment Substances 0.000 description 2
125000002541 furyl group Chemical group 0.000 description 2
239000008273 gelatin Substances 0.000 description 2
229920000159 gelatin Polymers 0.000 description 2
229940014259 gelatin Drugs 0.000 description 2
235000019322 gelatine Nutrition 0.000 description 2
235000011852 gelatine desserts Nutrition 0.000 description 2
235000011187 glycerol Nutrition 0.000 description 2
239000008187 granular material Substances 0.000 description 2
230000012010 growth Effects 0.000 description 2
JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
125000005843 halogen group Chemical group 0.000 description 2
230000036541 health Effects 0.000 description 2
238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
230000006872 improvement Effects 0.000 description 2
230000005917 in vivo anti-tumor Effects 0.000 description 2
238000011534 incubation Methods 0.000 description 2
239000003701 inert diluent Substances 0.000 description 2
229910052740 iodine Inorganic materials 0.000 description 2
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
125000005647 linker group Chemical group 0.000 description 2
239000008297 liquid dosage form Substances 0.000 description 2
RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 2
239000000314 lubricant Substances 0.000 description 2
238000004020 luminiscence type Methods 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
239000000594 mannitol Substances 0.000 description 2
235000010355 mannitol Nutrition 0.000 description 2
238000004519 manufacturing process Methods 0.000 description 2
238000002156 mixing Methods 0.000 description 2
230000004048 modification Effects 0.000 description 2
238000012986 modification Methods 0.000 description 2
238000012544 monitoring process Methods 0.000 description 2
239000004006 olive oil Substances 0.000 description 2
125000004043 oxo group Chemical group O=* 0.000 description 2
239000001301 oxygen Substances 0.000 description 2
229910052698 phosphorus Inorganic materials 0.000 description 2
239000011574 phosphorus Substances 0.000 description 2
230000026731 phosphorylation Effects 0.000 description 2
238000006366 phosphorylation reaction Methods 0.000 description 2
125000004193 piperazinyl group Chemical group 0.000 description 2
235000011056 potassium acetate Nutrition 0.000 description 2
239000003755 preservative agent Substances 0.000 description 2
235000018102 proteins Nutrition 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
102000004169 proteins and genes Human genes 0.000 description 2
125000000168 pyrrolyl group Chemical group 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
238000011160 research Methods 0.000 description 2
239000008159 sesame oil Substances 0.000 description 2
235000011803 sesame oil Nutrition 0.000 description 2
239000000741 silica gel Substances 0.000 description 2
229910002027 silica gel Inorganic materials 0.000 description 2
235000019333 sodium laurylsulphate Nutrition 0.000 description 2
239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
239000000600 sorbitol Substances 0.000 description 2
235000010356 sorbitol Nutrition 0.000 description 2
125000003003 spiro group Chemical group 0.000 description 2
239000008107 starch Substances 0.000 description 2
235000019698 starch Nutrition 0.000 description 2
239000005720 sucrose Substances 0.000 description 2
239000011593 sulfur Substances 0.000 description 2
239000000375 suspending agent Substances 0.000 description 2
238000010189 synthetic method Methods 0.000 description 2
239000000454 talc Substances 0.000 description 2
229910052623 talc Inorganic materials 0.000 description 2
235000012222 talc Nutrition 0.000 description 2
CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 2
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
210000004881 tumor cell Anatomy 0.000 description 2
229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
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 description 2
JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
229940058015 1,3-butylene glycol Drugs 0.000 description 1
125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
YHIIJNLSGULWAA-UHFFFAOYSA-N 1,4-thiazinane 1-oxide Chemical compound O=S1CCNCC1 YHIIJNLSGULWAA-UHFFFAOYSA-N 0.000 description 1
MYFKLQFBFSHBPA-UHFFFAOYSA-N 1-chloro-2-methylsulfanylethane Chemical compound CSCCCl MYFKLQFBFSHBPA-UHFFFAOYSA-N 0.000 description 1
238000005160 1H NMR spectroscopy Methods 0.000 description 1
BAYAKMPRFGNNFW-UHFFFAOYSA-N 2,4-dimethylpentan-3-ol Chemical compound CC(C)C(O)C(C)C BAYAKMPRFGNNFW-UHFFFAOYSA-N 0.000 description 1
CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
239000005995 Aluminium silicate Substances 0.000 description 1
206010002091 Anaesthesia Diseases 0.000 description 1
235000003276 Apios tuberosa Nutrition 0.000 description 1
244000105624 Arachis hypogaea Species 0.000 description 1
235000010777 Arachis hypogaea Nutrition 0.000 description 1
235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
206010005003 Bladder cancer Diseases 0.000 description 1
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
208000003174 Brain Neoplasms Diseases 0.000 description 1
206010006187 Breast cancer Diseases 0.000 description 1
208000026310 Breast neoplasm Diseases 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
239000004215 Carbon black (E152) Substances 0.000 description 1
206010009944 Colon cancer Diseases 0.000 description 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
235000019739 Dicalciumphosphate Nutrition 0.000 description 1
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
206010061818 Disease progression Diseases 0.000 description 1
241001125671 Eretmochelys imbricata Species 0.000 description 1
239000001856 Ethyl cellulose Substances 0.000 description 1
ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
229920002430 Fibre-reinforced plastic Polymers 0.000 description 1
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
229910004373 HOAc Inorganic materials 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
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
240000007472 Leucaena leucocephala Species 0.000 description 1
235000010643 Leucaena leucocephala Nutrition 0.000 description 1
241000124008 Mammalia Species 0.000 description 1
240000003183 Manihot esculenta Species 0.000 description 1
235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
206010027406 Mesothelioma Diseases 0.000 description 1
208000001145 Metabolic Syndrome Diseases 0.000 description 1
206010027476 Metastases Diseases 0.000 description 1
229920000168 Microcrystalline cellulose Polymers 0.000 description 1
150000001204 N-oxides Chemical class 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
240000007817 Olea europaea Species 0.000 description 1
206010033128 Ovarian cancer Diseases 0.000 description 1
206010061535 Ovarian neoplasm Diseases 0.000 description 1
206010061902 Pancreatic neoplasm Diseases 0.000 description 1
235000019483 Peanut oil Nutrition 0.000 description 1
241000233805 Phoenix Species 0.000 description 1
229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
239000002202 Polyethylene glycol Substances 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
206010060862 Prostate cancer Diseases 0.000 description 1
208000000236 Prostatic Neoplasms Diseases 0.000 description 1
102000001253 Protein Kinase Human genes 0.000 description 1
108020004511 Recombinant DNA Proteins 0.000 description 1
235000004443 Ricinus communis Nutrition 0.000 description 1
244000061456 Solanum tuberosum Species 0.000 description 1
235000002595 Solanum tuberosum Nutrition 0.000 description 1
SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
208000005718 Stomach Neoplasms Diseases 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
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 1
ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
238000002441 X-ray diffraction Methods 0.000 description 1
240000008042 Zea mays Species 0.000 description 1
235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
235000002017 Zea mays subsp mays Nutrition 0.000 description 1
PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 1
SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
239000003655 absorption accelerator Substances 0.000 description 1
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
CXADQLLYLMBGTG-UHFFFAOYSA-N acetonitrile;1,4-dioxane Chemical compound CC#N.C1COCCO1 CXADQLLYLMBGTG-UHFFFAOYSA-N 0.000 description 1
239000002253 acid Substances 0.000 description 1
230000004913 activation Effects 0.000 description 1
239000002671 adjuvant Substances 0.000 description 1
239000003463 adsorbent Substances 0.000 description 1
230000002411 adverse Effects 0.000 description 1
229960001686 afatinib Drugs 0.000 description 1
ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
229940072056 alginate Drugs 0.000 description 1
239000000783 alginic acid Substances 0.000 description 1
229960001126 alginic acid Drugs 0.000 description 1
150000004781 alginic acids Chemical class 0.000 description 1
125000001931 aliphatic group Chemical group 0.000 description 1
125000004450 alkenylene group Chemical group 0.000 description 1
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
235000012211 aluminium silicate Nutrition 0.000 description 1
235000001014 amino acid Nutrition 0.000 description 1
150000001413 amino acids Chemical class 0.000 description 1
230000037005 anaesthesia Effects 0.000 description 1
238000010171 animal model Methods 0.000 description 1
239000002246 antineoplastic agent Substances 0.000 description 1
229940041181 antineoplastic drug Drugs 0.000 description 1
229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
239000003963 antioxidant agent Substances 0.000 description 1
125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
235000003704 aspartic acid Nutrition 0.000 description 1
125000003725 azepanyl group Chemical group 0.000 description 1
XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
125000002393 azetidinyl group Chemical group 0.000 description 1
239000002585 base Substances 0.000 description 1
238000010009 beating Methods 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
125000005605 benzo group Chemical group 0.000 description 1
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
JSMRMEYFZHIPJV-UHFFFAOYSA-N bicyclo[2.1.1]hexane Chemical compound C1C2CC1CC2 JSMRMEYFZHIPJV-UHFFFAOYSA-N 0.000 description 1
239000011230 binding agent Substances 0.000 description 1
229910052796 boron Inorganic materials 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
239000000872 buffer Substances 0.000 description 1
239000006172 buffering agent Substances 0.000 description 1
235000019437 butane-1,3-diol Nutrition 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
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
229910000024 caesium carbonate Inorganic materials 0.000 description 1
229910000019 calcium carbonate Inorganic materials 0.000 description 1
235000010216 calcium carbonate Nutrition 0.000 description 1
239000001506 calcium phosphate Substances 0.000 description 1
CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
235000013539 calcium stearate Nutrition 0.000 description 1
239000008116 calcium stearate Substances 0.000 description 1
150000001721 carbon Chemical group 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
239000001768 carboxy methyl cellulose Substances 0.000 description 1
239000000969 carrier Substances 0.000 description 1
239000004359 castor oil Substances 0.000 description 1
239000001913 cellulose Substances 0.000 description 1
229920002678 cellulose Polymers 0.000 description 1
235000010980 cellulose Nutrition 0.000 description 1
229920002301 cellulose acetate Polymers 0.000 description 1
229960000541 cetyl alcohol Drugs 0.000 description 1
150000005829 chemical entities Chemical class 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
235000015165 citric acid Nutrition 0.000 description 1
238000000576 coating method Methods 0.000 description 1
208000029742 colonic neoplasm Diseases 0.000 description 1
239000003086 colorant Substances 0.000 description 1
239000002131 composite material Substances 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
235000005822 corn Nutrition 0.000 description 1
235000012343 cottonseed oil Nutrition 0.000 description 1
125000000392 cycloalkenyl group Chemical group 0.000 description 1
125000002993 cycloalkylene 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
125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 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
125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
230000003111 delayed effect Effects 0.000 description 1
230000002939 deleterious effect Effects 0.000 description 1
238000012217 deletion Methods 0.000 description 1
230000037430 deletion Effects 0.000 description 1
238000011161 development Methods 0.000 description 1
230000018109 developmental process Effects 0.000 description 1
NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
229940038472 dicalcium phosphate Drugs 0.000 description 1
229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
125000003963 dichloro group Chemical group Cl* 0.000 description 1
125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
125000005879 dioxolanyl group Chemical group 0.000 description 1
230000005750 disease progression Effects 0.000 description 1
239000007884 disintegrant Substances 0.000 description 1
CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 1
239000008298 dragée Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
239000003480 eluent Substances 0.000 description 1
238000010828 elution Methods 0.000 description 1
230000001804 emulsifying effect Effects 0.000 description 1
230000002708 enhancing effect Effects 0.000 description 1
239000002702 enteric coating Substances 0.000 description 1
238000009505 enteric coating Methods 0.000 description 1
229960001433 erlotinib Drugs 0.000 description 1
AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
235000019325 ethyl cellulose Nutrition 0.000 description 1
229920001249 ethyl cellulose Polymers 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
239000011151 fibre-reinforced plastic Substances 0.000 description 1
239000012065 filter cake Substances 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
235000013355 food flavoring agent Nutrition 0.000 description 1
238000009472 formulation Methods 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
125000000524 functional group Chemical group 0.000 description 1
206010017758 gastric cancer Diseases 0.000 description 1
210000001035 gastrointestinal tract Anatomy 0.000 description 1
238000003304 gavage Methods 0.000 description 1
229960002584 gefitinib Drugs 0.000 description 1
XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
239000000499 gel Substances 0.000 description 1
238000007429 general method Methods 0.000 description 1
239000012362 glacial acetic acid Substances 0.000 description 1
239000008103 glucose Substances 0.000 description 1
235000001727 glucose Nutrition 0.000 description 1
239000004220 glutamic acid Substances 0.000 description 1
235000013922 glutamic acid Nutrition 0.000 description 1
YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
229940093915 gynecological organic acid Drugs 0.000 description 1
201000010536 head and neck cancer Diseases 0.000 description 1
208000014829 head and neck neoplasm Diseases 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
239000003906 humectant Substances 0.000 description 1
WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
229940091173 hydantoin Drugs 0.000 description 1
150000004677 hydrates Chemical class 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
229910000041 hydrogen chloride Inorganic materials 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 1
229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
125000002883 imidazolyl group Chemical group 0.000 description 1
238000000338 in vitro Methods 0.000 description 1
125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
125000001041 indolyl group Chemical group 0.000 description 1
230000001939 inductive effect Effects 0.000 description 1
238000002329 infrared spectrum Methods 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
239000011630 iodine Substances 0.000 description 1
229940044173 iodine-125 Drugs 0.000 description 1
230000007794 irritation Effects 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
125000001786 isothiazolyl group Chemical group 0.000 description 1
230000000155 isotopic effect Effects 0.000 description 1
125000000842 isoxazolyl group Chemical group 0.000 description 1
NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
239000008101 lactose Substances 0.000 description 1
239000003446 ligand Substances 0.000 description 1
BYRPTKZOXNFFDB-UHFFFAOYSA-N lithium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Li+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C BYRPTKZOXNFFDB-UHFFFAOYSA-N 0.000 description 1
231100000053 low toxicity Toxicity 0.000 description 1
150000002678 macrocyclic compounds Chemical class 0.000 description 1
HSSGNVITVKZRHD-UHFFFAOYSA-L magnesium octadecanoate octadecanoic acid Chemical compound [Mg++].CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HSSGNVITVKZRHD-UHFFFAOYSA-L 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
238000004949 mass spectrometry Methods 0.000 description 1
238000001819 mass spectrum Methods 0.000 description 1
238000005259 measurement Methods 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
230000001404 mediated effect Effects 0.000 description 1
238000002844 melting Methods 0.000 description 1
230000008018 melting Effects 0.000 description 1
QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
229910052753 mercury Inorganic materials 0.000 description 1
230000009401 metastasis Effects 0.000 description 1
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
239000003094 microcapsule Substances 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
230000002297 mitogenic effect Effects 0.000 description 1
239000012046 mixed solvent Substances 0.000 description 1
230000009456 molecular mechanism Effects 0.000 description 1
239000002808 molecular sieve Substances 0.000 description 1
CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
239000002105 nanoparticle Substances 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
125000006574 non-aromatic ring group Chemical group 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
230000005311 nuclear magnetism Effects 0.000 description 1
239000002674 ointment Substances 0.000 description 1
235000008390 olive oil Nutrition 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
235000006408 oxalic acid Nutrition 0.000 description 1
125000002971 oxazolyl group Chemical group 0.000 description 1
125000004430 oxygen atom Chemical group O* 0.000 description 1
MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
201000002528 pancreatic cancer Diseases 0.000 description 1
208000008443 pancreatic carcinoma Diseases 0.000 description 1
239000012188 paraffin wax Substances 0.000 description 1
230000036961 partial effect Effects 0.000 description 1
239000000312 peanut oil Substances 0.000 description 1
239000002304 perfume Substances 0.000 description 1
125000005561 phenanthryl group Chemical group 0.000 description 1
125000005544 phthalimido group Chemical group 0.000 description 1
230000006461 physiological response Effects 0.000 description 1
OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
125000003386 piperidinyl group Chemical group 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
229920001223 polyethylene glycol Polymers 0.000 description 1
229920005862 polyol Polymers 0.000 description 1
150000003077 polyols Chemical class 0.000 description 1
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
239000001267 polyvinylpyrrolidone Substances 0.000 description 1
229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000000651 prodrug Substances 0.000 description 1
229940002612 prodrug Drugs 0.000 description 1
239000003380 propellant Substances 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
235000013772 propylene glycol Nutrition 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
108060006633 protein kinase Proteins 0.000 description 1
239000003909 protein kinase inhibitor Substances 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
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
125000005494 pyridonyl 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
238000010791 quenching Methods 0.000 description 1
230000000171 quenching effect Effects 0.000 description 1
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 description 1
125000003410 quininyl group Chemical group 0.000 description 1
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
230000002285 radioactive effect Effects 0.000 description 1
239000000376 reactant Substances 0.000 description 1
230000008261 resistance mechanism Effects 0.000 description 1
238000000926 separation method Methods 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
150000004760 silicates Chemical class 0.000 description 1
RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
235000012239 silicon dioxide Nutrition 0.000 description 1
239000011734 sodium Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
235000019345 sodium thiosulphate Nutrition 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
239000012265 solid product Substances 0.000 description 1
239000003549 soybean oil Substances 0.000 description 1
235000012424 soybean oil Nutrition 0.000 description 1
239000007921 spray Substances 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
201000011549 stomach cancer Diseases 0.000 description 1
238000003860 storage Methods 0.000 description 1
125000000547 substituted alkyl group Chemical group 0.000 description 1
150000005846 sugar alcohols Polymers 0.000 description 1
125000001174 sulfone group Chemical group 0.000 description 1
150000003457 sulfones Chemical class 0.000 description 1
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
230000002459 sustained effect Effects 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
230000002194 synthesizing effect Effects 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
238000004885 tandem mass spectrometry Methods 0.000 description 1
230000008685 targeting Effects 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
238000012360 testing method Methods 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
125000000335 thiazolyl group Chemical group 0.000 description 1
125000004568 thiomorpholinyl group Chemical group 0.000 description 1
125000000464 thioxo group Chemical group S=* 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
206010044412 transitional cell carcinoma Diseases 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
229910052722 tritium Inorganic materials 0.000 description 1
230000005748 tumor development Effects 0.000 description 1
125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
201000005112 urinary bladder cancer Diseases 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
210000003462 vein Anatomy 0.000 description 1
239000001993 wax Substances 0.000 description 1

Classifications

- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Medicinal Chemistry (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Molecular Biology (AREA)
Biochemistry (AREA)
Epidemiology (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CN202280043087.3A 2021-06-17 2022-06-17 芳基氧膦类化合物 Pending CN117500813A (zh)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
CN2021106722336		2021-06-17
CN202110672233		2021-06-17
PCT/CN2022/099503 WO2022262857A1 (fr)	2021-06-17	2022-06-17	Composés oxydes d'arylphosphine

Publications (1)

Publication Number	Publication Date
CN117500813A true CN117500813A (zh)	2024-02-02

Family

ID=84526924

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CN202280043087.3A Pending CN117500813A (zh)	2021-06-17	2022-06-17	芳基氧膦类化合物

Country Status (2)

Country	Link
CN (1)	CN117500813A (fr)
WO (1)	WO2022262857A1 (fr)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
ES2645689T3 (es) *	2008-05-21	2017-12-07	Ariad Pharmaceuticals, Inc.	Derivados de fósforo como inhibidores de quinasas
CN106883213B (zh) *	2015-12-15	2021-04-20	合肥中科普瑞昇生物医药科技有限公司	一种egfr和alk激酶的双重抑制剂
WO2019007293A1 (fr) *	2017-07-01	2019-01-10	浙江同源康医药股份有限公司	Composé utilisé comme inhibiteur de la kinase alk et son utilisation
CN113480575A (zh) *	2017-07-19	2021-10-08	正大天晴药业集团股份有限公司	作为egfr激酶抑制剂的芳基磷氧化合物
CN109593102B (zh) *	2018-01-04	2022-02-08	深圳市塔吉瑞生物医药有限公司	一种氘代二苯氨基嘧啶类化合物的制备方法及其晶型
CN110467638A (zh) *	2018-05-09	2019-11-19	北京赛特明强医药科技有限公司	一种含有间氯苯胺类取代基的双氨基氯代嘧啶类化合物、制备方法及其应用
CN112538072B (zh) *	2019-09-21	2024-02-06	齐鲁制药有限公司	氨基嘧啶类egfr抑制剂
CN114728932A (zh) *	2019-11-29	2022-07-08	江苏先声药业有限公司	作为egfr激酶抑制剂的多芳基化合物

2022
- 2022-06-17 WO PCT/CN2022/099503 patent/WO2022262857A1/fr active Application Filing
- 2022-06-17 CN CN202280043087.3A patent/CN117500813A/zh active Pending

Also Published As

Publication number	Publication date
WO2022262857A1 (fr)	2022-12-22

Legal Events

Date	Code	Title
2024-02-02	PB01	Publication
2024-02-02	PB01	Publication
2024-02-23	SE01	Entry into force of request for substantive examination
2024-02-23	SE01	Entry into force of request for substantive examination

Publication	Publication Date	Title
CN115335379B (zh)	2024-03-29	含螺环的喹唑啉化合物
CN113767103B (zh)	2024-03-29	新型螺环类K-Ras G12C抑制剂
CN117279916A (zh)	2023-12-22	含哌嗪结构的parp抑制剂、其制备方法及医药用途
CN115315427B (zh)	2024-03-29	Hpk1抑制剂及其制备方法和用途
CN116390728B (zh)	2024-03-29	喹唑啉衍生物及其制备方法和用途
CN117751116A (zh)	2024-03-22	作为KRas G12D抑制剂的稠环化合物
CN118076586A (zh)	2024-05-24	Kif18a抑制剂
CN115785068A (zh)	2023-03-14	Kif18a抑制剂
CN116867787A (zh)	2023-10-10	吡唑并[3,4-d]嘧啶-3-酮衍生物
CN115867542A (zh)	2023-03-28	新型苯并咪唑化合物
WO2022174765A1 (fr)	2022-08-25	Composé cyclique fusionné utilisé comme inhibiteur de wee-1
CN117500813A (zh)	2024-02-02	芳基氧膦类化合物
CN116323617A (zh)	2023-06-23	5,6-二氢吡嗪并[2,3-c]异喹啉化合物
EP4159731A1 (fr)	2023-04-05	Nouveau composé de pyrazine
CN117295743A (zh)	2023-12-26	作为Wee-1抑制剂的吡咯并嘧啶衍生物
CN117412971A (zh)	2024-01-16	含吡嗪结构的吡咯并嘧啶衍生物
CN118119622A (zh)	2024-05-31	作为shp2抑制剂的稠环化合物
CN117222648A (zh)	2023-12-12	作为Wee-1抑制剂的稠环化合物及其制备方法和用途
WO2023143344A1 (fr)	2023-08-03	Nouvel inhibiteur d'egfr
CN117222649A (zh)	2023-12-12	吡咯并嘧啶衍生物及其制备方法和用途
CN117751123A (zh)	2024-03-22	作为Wee-1抑制剂的5-氟-7H-吡咯并[2,3-d]嘧啶类化合物
CN116783194A (zh)	2023-09-19	含螺环的喹唑啉衍生物
CN116888109A (zh)	2023-10-13	作为Wee-1抑制剂的嘧啶化合物
CN116848117A (zh)	2023-10-03	作为Wee-1抑制剂的稠环化合物
CN117940430A (zh)	2024-04-26	作为Wee-1抑制剂的1,2-二氢-3H-吡唑[3,4-d]嘧啶-3-酮化合物