CN101094840B - 抑制癌细胞生长的喹唑啉衍生物和制备其的方法 - Google Patents
抑制癌细胞生长的喹唑啉衍生物和制备其的方法 Download PDFInfo
- Publication number
- CN101094840B CN101094840B CN2005800455133A CN200580045513A CN101094840B CN 101094840 B CN101094840 B CN 101094840B CN 2005800455133 A CN2005800455133 A CN 2005800455133A CN 200580045513 A CN200580045513 A CN 200580045513A CN 101094840 B CN101094840 B CN 101094840B
- Authority
- CN
- China
- Prior art keywords
- quinazoline
- chloro
- phenyl amino
- fluoro
- pyridine
- 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.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims description 346
- 238000000034 method Methods 0.000 title claims description 23
- 206010028980 Neoplasm Diseases 0.000 title claims description 10
- 201000011510 cancer Diseases 0.000 title claims description 9
- 230000002401 inhibitory effect Effects 0.000 title abstract description 3
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract 2
- 230000010261 cell growth Effects 0.000 title description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 647
- 238000006243 chemical reaction Methods 0.000 claims description 186
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 146
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 143
- -1 4Be hydrogen Chemical class 0.000 claims description 117
- 239000002253 acid Substances 0.000 claims description 73
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 16
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 241001597008 Nomeidae Species 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 238000006482 condensation reaction Methods 0.000 claims description 13
- BCVKHLNENRXHTC-UHFFFAOYSA-N 1-prop-2-enoylazetidine-2-carboxylic acid Chemical compound OC(=O)C1CCN1C(=O)C=C BCVKHLNENRXHTC-UHFFFAOYSA-N 0.000 claims description 12
- 125000003368 amide group Chemical group 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 230000012010 growth Effects 0.000 claims description 10
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- CUHNIWKJWIPCER-UHFFFAOYSA-N 1-prop-2-enoylazetidine-3-carboxylic acid Chemical compound OC(=O)C1CN(C(=O)C=C)C1 CUHNIWKJWIPCER-UHFFFAOYSA-N 0.000 claims description 6
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 6
- 230000001093 anti-cancer Effects 0.000 claims description 6
- 230000003327 cancerostatic effect Effects 0.000 claims description 6
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 239000002512 suppressor factor Substances 0.000 claims description 4
- OFDFPXXXMAPNCC-ZETCQYMHSA-N (2s)-4-methyl-2-(prop-2-enoylamino)pentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)C=C OFDFPXXXMAPNCC-ZETCQYMHSA-N 0.000 claims description 3
- AVMHMVJVHYGDOO-UHFFFAOYSA-N 1-bromobut-2-ene Chemical compound CC=CCBr AVMHMVJVHYGDOO-UHFFFAOYSA-N 0.000 claims description 3
- MDMLQWGTZCCSHA-UHFFFAOYSA-N 1-but-2-enyl-4-methylpiperazine Chemical compound CC=CCN1CCN(C)CC1 MDMLQWGTZCCSHA-UHFFFAOYSA-N 0.000 claims description 3
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 3
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- YXNSGXMTJQQMNT-UHFFFAOYSA-N CC=CCN(C)CCO Chemical compound CC=CCN(C)CCO YXNSGXMTJQQMNT-UHFFFAOYSA-N 0.000 claims description 3
- AZRWEQBJWQJEIC-UHFFFAOYSA-N CS(=O)(=O)CCNCC=CC Chemical compound CS(=O)(=O)CCNCC=CC AZRWEQBJWQJEIC-UHFFFAOYSA-N 0.000 claims description 3
- 102000009024 Epidermal Growth Factor Human genes 0.000 claims description 3
- 102000009465 Growth Factor Receptors Human genes 0.000 claims description 3
- 108010009202 Growth Factor Receptors Proteins 0.000 claims description 3
- 150000001348 alkyl chlorides Chemical class 0.000 claims description 3
- 125000006242 amine protecting group Chemical group 0.000 claims description 3
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- YEZFZWKMYVDWFK-UHFFFAOYSA-N n,n-dimethylbut-2-en-1-amine Chemical compound CC=CCN(C)C YEZFZWKMYVDWFK-UHFFFAOYSA-N 0.000 claims description 3
- IBGCXOFOCKCBNQ-UHFFFAOYSA-N nitro cyanate Chemical group [O-][N+](=O)OC#N IBGCXOFOCKCBNQ-UHFFFAOYSA-N 0.000 claims description 3
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 claims description 3
- 125000004806 1-methylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000004807 2-methylethylene group Chemical group [H]C([H])([H])C([H])([*:2])C([H])([H])[*:1] 0.000 claims description 2
- 229940123587 Cell cycle inhibitor Drugs 0.000 claims description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 2
- 229940121849 Mitotic inhibitor Drugs 0.000 claims description 2
- 101710183280 Topoisomerase Proteins 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 230000002280 anti-androgenic effect Effects 0.000 claims description 2
- 230000003388 anti-hormonal effect Effects 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 239000000051 antiandrogen Substances 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- 230000005754 cellular signaling Effects 0.000 claims description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 2
- 239000002532 enzyme inhibitor Substances 0.000 claims description 2
- 229940125532 enzyme inhibitor Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- 101800003838 Epidermal growth factor Proteins 0.000 claims 1
- 229940116977 epidermal growth factor Drugs 0.000 claims 1
- 150000003949 imides Chemical class 0.000 claims 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 claims 1
- 230000005907 cancer growth Effects 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000002585 base Substances 0.000 description 313
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 279
- 238000005160 1H NMR spectroscopy Methods 0.000 description 277
- 239000000243 solution Substances 0.000 description 167
- 230000002829 reductive effect Effects 0.000 description 131
- 238000004821 distillation Methods 0.000 description 105
- 238000004440 column chromatography Methods 0.000 description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 72
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 48
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 44
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 32
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 30
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 29
- 238000001035 drying Methods 0.000 description 29
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 29
- 229920006395 saturated elastomer Polymers 0.000 description 29
- 239000012266 salt solution Substances 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 26
- 238000005406 washing Methods 0.000 description 26
- 238000003810 ethyl acetate extraction Methods 0.000 description 25
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 24
- 230000006837 decompression Effects 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 239000012153 distilled water Substances 0.000 description 19
- 238000000605 extraction Methods 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- SMQSMQUBQPWGAO-UHFFFAOYSA-N methylsulfonyl acetate Chemical compound CC(=O)OS(C)(=O)=O SMQSMQUBQPWGAO-UHFFFAOYSA-N 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 16
- 125000001072 heteroaryl group Chemical group 0.000 description 16
- 239000007858 starting material Substances 0.000 description 16
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 15
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000003513 alkali Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 13
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 150000003222 pyridines Chemical class 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 9
- 238000007865 diluting Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000003102 growth factor Substances 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 5
- XNERWVPQCYSMLC-UHFFFAOYSA-N phenylpropiolic acid Chemical compound OC(=O)C#CC1=CC=CC=C1 XNERWVPQCYSMLC-UHFFFAOYSA-N 0.000 description 5
- 229910052727 yttrium Inorganic materials 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 4
- 206010011224 Cough Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000000370 acceptor Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000002919 epithelial cell Anatomy 0.000 description 4
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 4
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 4
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000638 solvent extraction Methods 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- JWJVSDZKYYXDDN-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]azetidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC1C(O)=O JWJVSDZKYYXDDN-UHFFFAOYSA-N 0.000 description 3
- MXWMFBYWXMXRPD-UHFFFAOYSA-N 2-azaniumyl-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoate Chemical compound CC(C)(C)OC(=O)CC(N)C(O)=O MXWMFBYWXMXRPD-UHFFFAOYSA-N 0.000 description 3
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 3
- HDJJMNPRPZFGJG-UHFFFAOYSA-N 3-[(2-methylsulfonylacetyl)amino]-n-[4-(1-phenylethylamino)quinazolin-6-yl]propanamide Chemical compound N=1C=NC2=CC=C(NC(=O)CCNC(=O)CS(C)(=O)=O)C=C2C=1NC(C)C1=CC=CC=C1 HDJJMNPRPZFGJG-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 3
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RZMZBHSKPLVQCP-UHFFFAOYSA-N ethyl 2-amino-2-oxoacetate Chemical compound CCOC(=O)C(N)=O RZMZBHSKPLVQCP-UHFFFAOYSA-N 0.000 description 3
- 238000002875 fluorescence polarization Methods 0.000 description 3
- 150000002240 furans Chemical class 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- JUPZOYPYWRYPCM-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]-3-[(2-methylsulfonylacetyl)amino]propanamide Chemical compound C12=CC(NC(=O)CCNC(=O)CS(=O)(=O)C)=CC=C2N=CN=C1NC1=CC=C(F)C(Cl)=C1 JUPZOYPYWRYPCM-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 229940005605 valeric acid Drugs 0.000 description 3
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 description 2
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 description 2
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 description 2
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- NCADHSLPNSTDMJ-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]azetidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC(C(O)=O)C1 NCADHSLPNSTDMJ-UHFFFAOYSA-N 0.000 description 2
- SHVBIOFGBGRZTB-UHFFFAOYSA-N 3-acetamido-n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]propanamide Chemical compound C12=CC(NC(=O)CCNC(=O)C)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 SHVBIOFGBGRZTB-UHFFFAOYSA-N 0.000 description 2
- OKARIZQJWNQURA-UHFFFAOYSA-N 5-[(2-methylsulfonylacetyl)amino]pentanoic acid Chemical compound CS(=O)(=O)CC(=O)NCCCCC(O)=O OKARIZQJWNQURA-UHFFFAOYSA-N 0.000 description 2
- JJMDCOVWQOJGCB-UHFFFAOYSA-N 5-aminopentanoic acid Chemical compound [NH3+]CCCCC([O-])=O JJMDCOVWQOJGCB-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-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
- 239000001828 Gelatine Substances 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 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 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 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 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-M ethanimidate Chemical compound CC([O-])=N DLFVBJFMPXGRIB-UHFFFAOYSA-M 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 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 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 229910052738 indium Inorganic materials 0.000 description 2
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BZTMBGOLCXLKEK-UHFFFAOYSA-N n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]quinazolin-6-yl]-3-[(2-methylsulfonylacetyl)amino]propanamide Chemical compound C12=CC(NC(=O)CCNC(=O)CS(=O)(=O)C)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 BZTMBGOLCXLKEK-UHFFFAOYSA-N 0.000 description 2
- VLBCMDXBYSODKH-UHFFFAOYSA-N n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-2-methyl-3-[(2-methylsulfonylacetyl)amino]propanamide Chemical compound C12=CC(NC(=O)C(CNC(=O)CS(C)(=O)=O)C)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 VLBCMDXBYSODKH-UHFFFAOYSA-N 0.000 description 2
- RYHQFYVAMAXRFN-UHFFFAOYSA-N n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-3-[(2-methylsulfonylacetyl)amino]-3-phenylpropanamide Chemical compound C=1C=CC=CC=1C(NC(=O)CS(=O)(=O)C)CC(=O)NC(C=C12)=CC=C1N=CN=C2NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 RYHQFYVAMAXRFN-UHFFFAOYSA-N 0.000 description 2
- AJNVXFDXWJEUDD-UHFFFAOYSA-N n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-3-[(2-methylsulfonylacetyl)amino]propanamide Chemical compound C12=CC(NC(=O)CCNC(=O)CS(=O)(=O)C)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 AJNVXFDXWJEUDD-UHFFFAOYSA-N 0.000 description 2
- RQLNADVMCINRSZ-UHFFFAOYSA-N n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-3-[[2-(2-methylsulfonylethylamino)acetyl]amino]propanamide Chemical compound C12=CC(NC(=O)CCNC(=O)CNCCS(=O)(=O)C)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 RQLNADVMCINRSZ-UHFFFAOYSA-N 0.000 description 2
- UBAACUHVTIRXQF-UHFFFAOYSA-N n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-3-[[2-(4-methylpiperazin-1-yl)acetyl]amino]propanamide Chemical compound C1CN(C)CCN1CC(=O)NCCC(=O)NC1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 UBAACUHVTIRXQF-UHFFFAOYSA-N 0.000 description 2
- ITXSZXTWKDQFDN-UHFFFAOYSA-N n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-3-[[2-(dimethylamino)acetyl]amino]propanamide Chemical compound C12=CC(NC(=O)CCNC(=O)CN(C)C)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 ITXSZXTWKDQFDN-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003246 quinazolines Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000002769 thiazolinyl group Chemical group 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 2
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 1
- VLHQXRIIQSTJCQ-ZCFIWIBFSA-N (2r)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound OC(=O)[C@@H](C)N(C)C(=O)OC(C)(C)C VLHQXRIIQSTJCQ-ZCFIWIBFSA-N 0.000 description 1
- BLZVRFJABGJEEO-MRVPVSSYSA-N (2r)-2-amino-2-methyl-3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoic acid Chemical compound CC(C)(C)OC(=O)[C@](C)(N)C(O)=O BLZVRFJABGJEEO-MRVPVSSYSA-N 0.000 description 1
- GFJATYWLXLZSCZ-ZETCQYMHSA-N (2s)-2-[ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)N(CC)C(=O)OC(C)(C)C GFJATYWLXLZSCZ-ZETCQYMHSA-N 0.000 description 1
- BLZVRFJABGJEEO-QMMMGPOBSA-N (2s)-2-amino-2-methyl-3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoic acid Chemical compound CC(C)(C)OC(=O)[C@@](C)(N)C(O)=O BLZVRFJABGJEEO-QMMMGPOBSA-N 0.000 description 1
- BHWHELTTXYXJMN-KRWDZBQOSA-N (2s)-2-amino-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-7-(3-methoxypropoxy)quinazolin-6-yl]propanamide Chemical compound C=12C=C(NC(=O)[C@H](C)N)C(OCCCOC)=CC2=NC=NC=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 BHWHELTTXYXJMN-KRWDZBQOSA-N 0.000 description 1
- BYZBKAVGLRXARV-INIZCTEOSA-N (2s)-2-amino-n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-7-(2-methoxyethoxy)quinazolin-6-yl]propanamide Chemical compound C=12C=C(NC(=O)[C@H](C)N)C(OCCOC)=CC2=NC=NC=1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 BYZBKAVGLRXARV-INIZCTEOSA-N 0.000 description 1
- 125000006595 (C1-C3) alkylsulfinyl group Chemical group 0.000 description 1
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 1
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- DGHHQBMTXTWTJV-BQAIUKQQSA-N 119413-54-6 Chemical compound Cl.C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 DGHHQBMTXTWTJV-BQAIUKQQSA-N 0.000 description 1
- BMVLUKFWZSVSOB-UHFFFAOYSA-N 2-amino-n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]acetamide Chemical compound C12=CC(NC(=O)CN)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 BMVLUKFWZSVSOB-UHFFFAOYSA-N 0.000 description 1
- JRMAQQQTXDJDNC-UHFFFAOYSA-N 2-ethoxy-2-oxoacetic acid Chemical compound CCOC(=O)C(O)=O JRMAQQQTXDJDNC-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- FFJLSBFLTYYWII-UHFFFAOYSA-N 3-(methylamino)propanamide Chemical compound CNCCC(N)=O FFJLSBFLTYYWII-UHFFFAOYSA-N 0.000 description 1
- CQUBAECEWHOKRS-UHFFFAOYSA-N 3-amino-n-[4-(1-phenylethylamino)quinazolin-6-yl]propanamide Chemical compound N=1C=NC2=CC=C(NC(=O)CCN)C=C2C=1NC(C)C1=CC=CC=C1 CQUBAECEWHOKRS-UHFFFAOYSA-N 0.000 description 1
- SQWWZMJOTNNEMV-UHFFFAOYSA-N 3-amino-n-[4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]propanamide Chemical compound C12=CC(NC(=O)CCN)=CC=C2N=CN=C1NC1=CC=C(F)C(Cl)=C1 SQWWZMJOTNNEMV-UHFFFAOYSA-N 0.000 description 1
- QNXBWZIJILRVDH-UHFFFAOYSA-N 3-amino-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]quinazolin-6-yl]propanamide Chemical compound C12=CC(NC(=O)CCN)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 QNXBWZIJILRVDH-UHFFFAOYSA-N 0.000 description 1
- BNVUJHCXWYBUHL-UHFFFAOYSA-N 3-amino-n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-2-methylpropanamide Chemical compound C12=CC(NC(=O)C(CN)C)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 BNVUJHCXWYBUHL-UHFFFAOYSA-N 0.000 description 1
- GICFHPSVCDZDJR-UHFFFAOYSA-N 3-amino-n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-3-phenylpropanamide Chemical compound C=1C=CC=CC=1C(N)CC(=O)NC(C=C12)=CC=C1N=CN=C2NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 GICFHPSVCDZDJR-UHFFFAOYSA-N 0.000 description 1
- VSJSGUTYXNBZKZ-UHFFFAOYSA-N 3-amino-n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-n-methylpropanamide Chemical compound C12=CC(N(C(=O)CCN)C)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 VSJSGUTYXNBZKZ-UHFFFAOYSA-N 0.000 description 1
- UKDBLLUTWQUIGV-UHFFFAOYSA-N 3-amino-n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]propanamide Chemical compound C12=CC(NC(=O)CCN)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 UKDBLLUTWQUIGV-UHFFFAOYSA-N 0.000 description 1
- AYPFEYDGZDPAPE-UHFFFAOYSA-N 3-chloro-4-[(3-fluorophenyl)methoxy]aniline Chemical compound ClC1=CC(N)=CC=C1OCC1=CC=CC(F)=C1 AYPFEYDGZDPAPE-UHFFFAOYSA-N 0.000 description 1
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- IJVSXIKXYCJKTB-UHFFFAOYSA-N 4-[3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl]-1H-quinazoline-4,6-diamine Chemical group ClC=1C=C(C=CC1OCC1=NC(=CC=C1)C)C1(NC=NC2=CC=C(C=C12)N)N IJVSXIKXYCJKTB-UHFFFAOYSA-N 0.000 description 1
- QEUSEKYHDPJEEK-UHFFFAOYSA-N 4-chloro-6-nitroquinazoline;hydrochloride Chemical compound Cl.N1=CN=C(Cl)C2=CC([N+](=O)[O-])=CC=C21 QEUSEKYHDPJEEK-UHFFFAOYSA-N 0.000 description 1
- UYQMNEZWVKRWMS-UHFFFAOYSA-N 4-chloro-7-fluoro-6-nitroquinazoline Chemical compound N1=CN=C2C=C(F)C([N+](=O)[O-])=CC2=C1Cl UYQMNEZWVKRWMS-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- RUCHWTKMOWXHLU-UHFFFAOYSA-N 5-nitroanthranilic acid Chemical compound NC1=CC=C([N+]([O-])=O)C=C1C(O)=O RUCHWTKMOWXHLU-UHFFFAOYSA-N 0.000 description 1
- MOBNCKURXDGQCB-UHFFFAOYSA-N 6-nitro-1h-quinazolin-4-one Chemical compound N1C=NC(=O)C2=CC([N+](=O)[O-])=CC=C21 MOBNCKURXDGQCB-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BMBGGFJJHPYJKU-UHFFFAOYSA-N C(C)(C)(C)OC(=O)CC(C(=O)O)(F)N Chemical compound C(C)(C)(C)OC(=O)CC(C(=O)O)(F)N BMBGGFJJHPYJKU-UHFFFAOYSA-N 0.000 description 1
- CPVQKJNEJHGION-UHFFFAOYSA-N COC(CSOCCC)(OC)OCC Chemical compound COC(CSOCCC)(OC)OCC CPVQKJNEJHGION-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 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 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 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
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101001031591 Mus musculus Heart- and neural crest derivatives-expressed protein 2 Proteins 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- MVZGYPSXNDCANY-UHFFFAOYSA-N N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide Chemical compound FC1=CC=CC(COC=2C(=CC(NC=3C4=CC(NC(=O)C=C)=CC=C4N=CN=3)=CC=2)Cl)=C1 MVZGYPSXNDCANY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 235000007244 Zea mays Nutrition 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- OMOZGSRMZAYUCI-UHFFFAOYSA-N amino cyanate Chemical compound NOC#N OMOZGSRMZAYUCI-UHFFFAOYSA-N 0.000 description 1
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 description 1
- 125000002431 aminoalkoxy group Chemical group 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 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
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 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
- LUEHNHVFDCZTGL-UHFFFAOYSA-N but-2-ynoic acid Chemical compound CC#CC(O)=O LUEHNHVFDCZTGL-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 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
- 244000309466 calf Species 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- HDRXZJPWHTXQRI-BHDTVMLSSA-N diltiazem hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC[NH+](C)C)C2=CC=CC=C2S1 HDRXZJPWHTXQRI-BHDTVMLSSA-N 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 150000002194 fatty esters Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 1
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 125000004836 hexamethylene group Chemical class [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 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
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical class CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- DATVKWYPAUBOHE-UHFFFAOYSA-N n-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6-nitroquinazolin-4-amine Chemical compound C12=CC([N+](=O)[O-])=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 DATVKWYPAUBOHE-UHFFFAOYSA-N 0.000 description 1
- KEWDZRBUFXTLGZ-UHFFFAOYSA-N n-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-fluoro-6-nitroquinazolin-4-amine Chemical compound N1=CN=C2C=C(F)C([N+](=O)[O-])=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 KEWDZRBUFXTLGZ-UHFFFAOYSA-N 0.000 description 1
- KVOOOHQGXSBFFV-UHFFFAOYSA-N n-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-nitroquinazolin-4-amine;hydrochloride Chemical compound Cl.C12=CC([N+](=O)[O-])=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 KVOOOHQGXSBFFV-UHFFFAOYSA-N 0.000 description 1
- SFEZOUWJJIYUFD-UHFFFAOYSA-N n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-3-(dimethylamino)propanamide Chemical compound C12=CC(NC(=O)CCN(C)C)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 SFEZOUWJJIYUFD-UHFFFAOYSA-N 0.000 description 1
- XRSYXWKQTUODOD-UHFFFAOYSA-N n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-3-(methylamino)propanamide Chemical compound C12=CC(NC(=O)CCNC)=CC=C2N=CN=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC(F)=C1 XRSYXWKQTUODOD-UHFFFAOYSA-N 0.000 description 1
- XTFSPXGZPDPJNB-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine;pyridine Chemical compound C1=CC=NC=C1.CCN(C(C)C)C(C)C XTFSPXGZPDPJNB-UHFFFAOYSA-N 0.000 description 1
- ABMDIECEEGFXNC-UHFFFAOYSA-N n-ethylpropanamide Chemical compound CCNC(=O)CC ABMDIECEEGFXNC-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- UBZJXAQDXUGXIZ-UHFFFAOYSA-N quinazoline;quinoline Chemical compound N1=CC=CC2=CC=CC=C21.N1=CN=CC2=CC=CC=C21 UBZJXAQDXUGXIZ-UHFFFAOYSA-N 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000005389 trialkylsiloxy group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims (12)
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020040114839 | 2004-12-29 | ||
KR10-2004-0114839 | 2004-12-29 | ||
KR20040114839 | 2004-12-29 | ||
KR10-2005-0111724 | 2005-11-22 | ||
KR1020050111724A KR100735639B1 (ko) | 2004-12-29 | 2005-11-22 | 암세포 성장 억제 효과를 갖는 퀴나졸린 유도체 및 이의제조방법 |
KR1020050111724 | 2005-11-22 | ||
PCT/KR2005/004395 WO2006071017A1 (en) | 2004-12-29 | 2005-12-20 | Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101094840A CN101094840A (zh) | 2007-12-26 |
CN101094840B true CN101094840B (zh) | 2012-10-31 |
Family
ID=36615106
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2005800455133A Expired - Fee Related CN101094840B (zh) | 2004-12-29 | 2005-12-20 | 抑制癌细胞生长的喹唑啉衍生物和制备其的方法 |
Country Status (15)
Country | Link |
---|---|
US (1) | US8003658B2 (zh) |
EP (1) | EP1844022B1 (zh) |
JP (1) | JP4914372B2 (zh) |
KR (2) | KR100735639B1 (zh) |
CN (1) | CN101094840B (zh) |
AU (1) | AU2005320472B2 (zh) |
BR (1) | BRPI0519474A2 (zh) |
CA (1) | CA2592286C (zh) |
ES (1) | ES2427445T3 (zh) |
IL (1) | IL183583A (zh) |
MX (1) | MX2007007458A (zh) |
NO (1) | NO20073959L (zh) |
NZ (1) | NZ556773A (zh) |
RU (1) | RU2362773C2 (zh) |
WO (1) | WO2006071017A1 (zh) |
Families Citing this family (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2399427T3 (es) | 2003-08-14 | 2013-04-01 | Array Biopharma, Inc. | Análogos de quinazolina como inhibidores de los receptores de la tirosina-quinasa |
US7501427B2 (en) | 2003-08-14 | 2009-03-10 | Array Biopharma, Inc. | Quinazoline analogs as receptor tyrosine kinase inhibitors |
JP2008542356A (ja) * | 2005-06-03 | 2008-11-27 | ファイザー・プロダクツ・インク | 異常な細胞増殖の治療用の二環式誘導体 |
PT2090575E (pt) | 2005-11-15 | 2011-06-06 | Array Biopharma Inc | Inibidores de erbb |
CN101003514A (zh) | 2006-01-20 | 2007-07-25 | 上海艾力斯医药科技有限公司 | 喹唑啉衍生物、其制备方法及用途 |
KR100929146B1 (ko) * | 2006-06-28 | 2009-12-01 | 한미약품 주식회사 | 암세포 성장 억제 효과를 갖는 퀴나졸린 유도체 |
US7547781B2 (en) | 2006-09-11 | 2009-06-16 | Curis, Inc. | Quinazoline based EGFR inhibitors containing a zinc binding moiety |
SG174774A1 (en) * | 2006-09-11 | 2011-10-28 | Curis Inc | Quinazoline based egfr inhibitors containing a zinc binding moiety |
EP2061772A4 (en) * | 2006-09-11 | 2011-06-29 | Curis Inc | MULTIFUNCTIONAL SMALL MOLECULES AS PROLIFERATION-ACTIVE ACTIVE SUBSTANCES |
CN101245050A (zh) | 2007-02-14 | 2008-08-20 | 上海艾力斯医药科技有限公司 | 4-苯胺喹唑啉衍生物的盐 |
US8148532B2 (en) * | 2007-03-14 | 2012-04-03 | Guoqing Paul Chen | Spiro substituted compounds as angiogenesis inhibitors |
US8163923B2 (en) | 2007-03-14 | 2012-04-24 | Advenchen Laboratories, Llc | Spiro substituted compounds as angiogenesis inhibitors |
US20120101114A1 (en) | 2007-03-28 | 2012-04-26 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
US20120065201A1 (en) * | 2007-03-28 | 2012-03-15 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
PL2154967T3 (pl) | 2007-04-16 | 2014-08-29 | Hutchison Medipharma Entpr Ltd | Pochodne pirymidyny |
KR101397523B1 (ko) * | 2007-04-27 | 2014-05-30 | 한미약품 주식회사 | 다중저해제로서의 퀴나졸린 유도체 |
CN101348466B (zh) * | 2007-07-20 | 2012-06-20 | 江苏艾力斯生物医药有限公司 | N-{4-[3-氯-4-(3-氟-苄氧基)-苯胺基]-喹唑啉-6-基}-丙烯酰胺的制备方法 |
CN101357905B (zh) * | 2007-08-01 | 2012-06-20 | 江苏艾力斯生物医药有限公司 | 4-[3-氯-4-(3-氟-苄氧基)-苯胺基]-6-取代胺基-喹唑啉衍生物的制备方法 |
CN101544609A (zh) | 2008-03-25 | 2009-09-30 | 上海艾力斯医药科技有限公司 | 4-苯胺喹唑啉衍生物的结晶形式 |
US7829574B2 (en) | 2008-05-09 | 2010-11-09 | Hutchison Medipharma Enterprises Limited | Substituted quinazoline compounds and their use in treating angiogenesis-related diseases |
CN101584696A (zh) | 2008-05-21 | 2009-11-25 | 上海艾力斯医药科技有限公司 | 包含喹唑啉衍生物的组合物及制备方法、用途 |
US8426430B2 (en) * | 2008-06-30 | 2013-04-23 | Hutchison Medipharma Enterprises Limited | Quinazoline derivatives |
US7737157B2 (en) | 2008-08-29 | 2010-06-15 | Hutchison Medipharma Enterprises Limited | Pyrimidine compounds |
ITMI20082336A1 (it) * | 2008-12-29 | 2010-06-30 | Univ Parma | Composti inibitori irreversibili di egfr con attivita' antiproliferativa |
US8575203B2 (en) | 2010-04-21 | 2013-11-05 | Boehringer Ingelheim International Gmbh | Chemical compounds |
NZ789041A (en) | 2010-06-03 | 2023-09-29 | Pharmacyclics Llc | The use of inhibitors of bruton’s tyrosine kinase (btk) |
CN102311438A (zh) * | 2010-06-30 | 2012-01-11 | 和记黄埔医药(上海)有限公司 | 喹唑啉化合物 |
CN102906086B (zh) * | 2010-06-30 | 2014-02-12 | 和记黄埔医药(上海)有限公司 | 喹唑啉化合物 |
CN102485735B (zh) * | 2010-12-02 | 2014-09-24 | 东莞南方医大代谢医学研发有限公司 | 6-果糖氨-4-芳胺基喹唑啉衍生物及其用途 |
EA201490265A1 (ru) | 2011-07-13 | 2014-12-30 | Фармасайкликс, Инк. | Ингибиторы тирозинкиназы брутона |
CN102898386B (zh) | 2011-07-27 | 2015-07-29 | 上海医药集团股份有限公司 | 喹唑啉衍生物、其制备方法、中间体、组合物及其应用 |
US8377946B1 (en) | 2011-12-30 | 2013-02-19 | Pharmacyclics, Inc. | Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors |
CN103360382B (zh) * | 2012-03-26 | 2016-04-27 | 中国科学院福建物质结构研究所 | 喹唑啉衍生物及其用途 |
EP2752413B1 (en) * | 2012-03-26 | 2016-03-23 | Fujian Institute Of Research On The Structure Of Matter, Chinese Academy Of Sciences | Quinazoline derivative and application thereof |
EP2877598A1 (en) | 2012-07-24 | 2015-06-03 | Pharmacyclics, Inc. | Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk) |
CN103102315B (zh) * | 2012-11-01 | 2016-01-20 | 云南大学 | 一种喹唑啉类芳基脲及其制备方法和用途 |
CN102942561A (zh) * | 2012-11-06 | 2013-02-27 | 深圳海王药业有限公司 | 4-氨基喹唑啉杂环化合物及其用途 |
CN103275018B (zh) * | 2013-04-26 | 2016-03-02 | 浙江工业大学 | 4-[3-氯-4-取代苯胺基]-6-取代甲酰氨基喹唑啉类化合物及制备和应用 |
CN103288758B (zh) * | 2013-05-16 | 2015-01-21 | 苏州明锐医药科技有限公司 | 一种达克米替尼的制备方法 |
US9624224B2 (en) | 2013-09-30 | 2017-04-18 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase |
CN103570692A (zh) * | 2013-10-31 | 2014-02-12 | 浙江大学 | 含吖丙啶环侧链的喹唑啉衍生物及制备和应用 |
WO2015120820A1 (zh) * | 2014-02-17 | 2015-08-20 | 李勤耕 | 一类羧酸衍生物及其在制备前药中的用途 |
WO2015120821A1 (zh) * | 2014-02-17 | 2015-08-20 | 江苏恩华络康药物研发有限公司 | 一类水溶性丙泊酚衍生物及其用途 |
WO2015143400A1 (en) | 2014-03-20 | 2015-09-24 | Pharmacyclics, Inc. | Phospholipase c gamma 2 and resistance associated mutations |
CA3081443A1 (en) | 2014-12-15 | 2016-06-23 | The Regents Of The University Of Michigan | Small molecule inhibitors of egfr and pi3k |
CN106117182B (zh) * | 2016-06-20 | 2019-08-30 | 中国药科大学 | 喹唑啉-n-苯乙基四氢异喹啉类化合物及其制备方法和应用 |
JP2020023441A (ja) * | 2016-11-02 | 2020-02-13 | 国立大学法人九州大学 | Egfr阻害及び腫瘍治療に有用な新規化合物 |
CN112770758A (zh) * | 2018-09-14 | 2021-05-07 | 光谱制药有限公司 | 用于治疗癌症的试剂盒和方法 |
KR20230155422A (ko) | 2020-12-22 | 2023-11-10 | 메카니스틱 테라퓨틱스 엘엘씨 | Egfr 및/또는 pi3k 억제제로서의 치환된 아미노벤질헤테로아릴 화합물 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999009016A1 (en) * | 1997-08-01 | 1999-02-25 | American Cyanamid Company | Substituted quinazoline derivatives and their use as tyrosine kinase inhibitors |
CN1211240A (zh) * | 1996-02-14 | 1999-03-17 | 曾尼卡有限公司 | 作为抗肿瘤剂的喹唑啉衍生物 |
WO2002068396A1 (en) * | 2001-02-26 | 2002-09-06 | Mcgill University | Combi-molecules having signal transduction inhibitory properties and dna damaging properties |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9323290D0 (en) | 1992-12-10 | 1994-01-05 | Zeneca Ltd | Quinazoline derivatives |
SI20582A (sl) * | 2000-05-05 | 2001-12-31 | Univerza V Ljubljani | Novi inhibitorji trombina, njihova priprava in uporaba |
MXPA02012870A (es) | 2000-06-22 | 2003-05-14 | Pfizer Prod Inc | Derivados biciclicos sustituidos para el tratamiento del crecimiento celular anormal. |
US20020082270A1 (en) | 2000-08-26 | 2002-06-27 | Frank Himmelsbach | Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases |
PE20040945A1 (es) * | 2003-02-05 | 2004-12-14 | Warner Lambert Co | Preparacion de quinazolinas substituidas |
CA2565812C (en) | 2004-05-06 | 2012-03-13 | Warner-Lambert Company Llc | 4-phenylamino-quinazolin-6-yl-amides |
-
2005
- 2005-11-22 KR KR1020050111724A patent/KR100735639B1/ko active IP Right Grant
- 2005-12-20 AU AU2005320472A patent/AU2005320472B2/en not_active Ceased
- 2005-12-20 EP EP05819138.8A patent/EP1844022B1/en not_active Not-in-force
- 2005-12-20 CN CN2005800455133A patent/CN101094840B/zh not_active Expired - Fee Related
- 2005-12-20 CA CA2592286A patent/CA2592286C/en not_active Expired - Fee Related
- 2005-12-20 US US11/722,096 patent/US8003658B2/en not_active Expired - Fee Related
- 2005-12-20 RU RU2007128920/04A patent/RU2362773C2/ru not_active IP Right Cessation
- 2005-12-20 JP JP2007549242A patent/JP4914372B2/ja not_active Expired - Fee Related
- 2005-12-20 MX MX2007007458A patent/MX2007007458A/es active IP Right Grant
- 2005-12-20 WO PCT/KR2005/004395 patent/WO2006071017A1/en active Application Filing
- 2005-12-20 ES ES05819138T patent/ES2427445T3/es active Active
- 2005-12-20 NZ NZ556773A patent/NZ556773A/en not_active IP Right Cessation
- 2005-12-20 BR BRPI0519474-1A patent/BRPI0519474A2/pt not_active IP Right Cessation
- 2005-12-22 KR KR1020050127660A patent/KR100658891B1/ko active IP Right Grant
-
2007
- 2007-05-31 IL IL183583A patent/IL183583A/en not_active IP Right Cessation
- 2007-07-27 NO NO20073959A patent/NO20073959L/no unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1211240A (zh) * | 1996-02-14 | 1999-03-17 | 曾尼卡有限公司 | 作为抗肿瘤剂的喹唑啉衍生物 |
WO1999009016A1 (en) * | 1997-08-01 | 1999-02-25 | American Cyanamid Company | Substituted quinazoline derivatives and their use as tyrosine kinase inhibitors |
WO2002068396A1 (en) * | 2001-02-26 | 2002-09-06 | Mcgill University | Combi-molecules having signal transduction inhibitory properties and dna damaging properties |
Also Published As
Publication number | Publication date |
---|---|
MX2007007458A (es) | 2007-08-15 |
WO2006071017A1 (en) | 2006-07-06 |
KR100658891B1 (ko) | 2006-12-15 |
US8003658B2 (en) | 2011-08-23 |
IL183583A0 (en) | 2007-09-20 |
KR20060076210A (ko) | 2006-07-04 |
CA2592286A1 (en) | 2006-07-06 |
EP1844022B1 (en) | 2013-08-14 |
NZ556773A (en) | 2010-10-29 |
RU2362773C2 (ru) | 2009-07-27 |
CA2592286C (en) | 2012-05-29 |
EP1844022A4 (en) | 2009-10-28 |
US20080009509A1 (en) | 2008-01-10 |
BRPI0519474A2 (pt) | 2009-01-27 |
KR20060076186A (ko) | 2006-07-04 |
RU2007128920A (ru) | 2009-02-10 |
EP1844022A1 (en) | 2007-10-17 |
KR100735639B1 (ko) | 2007-07-04 |
CN101094840A (zh) | 2007-12-26 |
NO20073959L (no) | 2007-09-27 |
JP2008525522A (ja) | 2008-07-17 |
JP4914372B2 (ja) | 2012-04-11 |
AU2005320472B2 (en) | 2009-02-26 |
ES2427445T3 (es) | 2013-10-30 |
AU2005320472A1 (en) | 2006-07-06 |
IL183583A (en) | 2015-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101094840B (zh) | 抑制癌细胞生长的喹唑啉衍生物和制备其的方法 | |
CN101304978B (zh) | 作为多元抑制剂的喹唑啉衍生物、药物组合物及用途 | |
JP5236664B2 (ja) | 心血管疾患を予防および治療するための化合物 | |
CN100457726C (zh) | 取代的磺酰胺化合物、其制备方法及其作为治疗cns疾病、肥胖和ⅱ型糖尿病的药物的应用 | |
KR102426138B1 (ko) | PI3K, mTOR 저해제로서 융합된 퀴놀린 화합물 | |
RU2505534C2 (ru) | Производные хиназолина, ингибирующие активность egfr | |
WO2015043515A1 (zh) | 喹唑啉衍生物及其制备方法 | |
CN103270023A (zh) | 作为用于治疗疾病诸如癌症的nampt 抑制剂的4-{[(吡啶-3-基-甲基)氨基羰基]氨基}苯-砜衍生物 | |
ES2277098T3 (es) | Derivados de quinolina y aza-indol y su uso como ligandos para 5-ht6. | |
JP7186761B2 (ja) | 新規な化合物、それらの調製及びそれらの使用 | |
TW201620882A (zh) | 作為egfr抑制劑的苯基取代的三嗪類化合物及其應用 | |
WO2014079232A1 (zh) | 7-氧代吡啶并嘧啶类化合物及其药用组合物和应用 | |
US20020025968A1 (en) | Method for inhibiting neoplastic cells and related conditions by exposure to 4-aminoquinazoline derivatives | |
US10730878B2 (en) | Fused quinoline compounds as PI3K/mTOR inhibitors | |
CN102149678A (zh) | 用于治疗癌症的新型邻氨基酰苯胺类 | |
JP2020512327A (ja) | 熱ショックタンパク質90阻害剤 | |
TW202233604A (zh) | 嘧啶化合物、組合物及其醫藥應用 | |
TW201240666A (en) | Piperazinedione compounds | |
WO2014190872A1 (zh) | 一种含硒化合物及其医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
ASS | Succession or assignment of patent right |
Owner name: HANMI PHARMACEUTICAL INDUSTRIAL CO., LTD. Free format text: FORMER OWNER: HANMI PHARM. CO., LTD. Effective date: 20110310 |
|
C41 | Transfer of patent application or patent right or utility model | ||
COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: GYEONGGI, SOUTH KOREA TO: SEOUL, SOUTH KOREA |
|
TA01 | Transfer of patent application right |
Effective date of registration: 20110310 Address after: Seoul, South Kerean Applicant after: Hanmi Pharm Ind Co.,Ltd. Address before: Gyeonggi Do, South Korea Applicant before: Hanmi Pharm. Co., Ltd. |
|
C53 | Correction of patent of invention or patent application | ||
CB02 | Change of applicant information |
Address after: Gyeonggi Do, South Korea Applicant after: Hanmi Holdings Co., Ltd. Address before: Seoul, South Kerean Applicant before: Hanmi Pharm Ind Co.,Ltd. |
|
COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: HANMI HOLDINGS CO., LTD. TO: HANMI SCIENCE CO., LTD. |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20121031 Termination date: 20161220 |
|
CF01 | Termination of patent right due to non-payment of annual fee |