CN103601722B - 新型抗肿瘤化合物 - Google Patents
新型抗肿瘤化合物 Download PDFInfo
- Publication number
- CN103601722B CN103601722B CN201310416151.0A CN201310416151A CN103601722B CN 103601722 B CN103601722 B CN 103601722B CN 201310416151 A CN201310416151 A CN 201310416151A CN 103601722 B CN103601722 B CN 103601722B
- Authority
- CN
- China
- Prior art keywords
- compound
- carbon atoms
- pharmaceutically acceptable
- group
- acceptable salt
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 52
- 230000000259 anti-tumor effect Effects 0.000 title description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- -1 phenylthiazolyl Chemical group 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229910052757 nitrogen Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 239000012453 solvate Substances 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 235000011114 ammonium hydroxide Nutrition 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000009471 action Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000011161 development Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 229940125807 compound 37 Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 4
- 0 CC*=CC=C(C)C*C([C@](C1)C(N(CC2)CCN2NCC)=NN)=CC(OC)=C1OC(C)(C)C(C)CN1[C@@](*)C(*)*C(*I)C1* Chemical compound CC*=CC=C(C)C*C([C@](C1)C(N(CC2)CCN2NCC)=NN)=CC(OC)=C1OC(C)(C)C(C)CN1[C@@](*)C(*)*C(*I)C1* 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 108091008605 VEGF receptors Proteins 0.000 description 4
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- BVWTXUYLKBHMOX-UHFFFAOYSA-N methyl vanillate Chemical compound COC(=O)C1=CC=C(O)C(OC)=C1 BVWTXUYLKBHMOX-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 229940125851 compound 27 Drugs 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 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 3
- 229960002584 gefitinib Drugs 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 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
- PVRDAVSDHWPSOF-UHFFFAOYSA-N Vanillic acid methyl ester Natural products COC(=O)C(=O)C1=CC=C(O)C(OC)=C1 PVRDAVSDHWPSOF-UHFFFAOYSA-N 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 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
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 2
- 229950000578 vatalanib Drugs 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- 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 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- MOQCFMZWVKQBAP-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)benzoyl]-n-(4-chlorophenyl)piperidine-3-carboxamide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C(=O)N2CC(CCC2)C(=O)NC=2C=CC(Cl)=CC=2)=C1 MOQCFMZWVKQBAP-UHFFFAOYSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- NGZSKKYBWMJLTI-UHFFFAOYSA-N CCCN(CC)c1ccc2[o]c(C(C#C)=O)cc2c1 Chemical compound CCCN(CC)c1ccc2[o]c(C(C#C)=O)cc2c1 NGZSKKYBWMJLTI-UHFFFAOYSA-N 0.000 description 1
- 206010055114 Colon cancer metastatic Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 150000002691 malonic acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical group 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 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229940108949 paclitaxel injection Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
Classifications
-
- 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
- C07D405/14—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 three or more hetero rings
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals
-
- 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
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon 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
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种式(I)所示的化合物，其药学上可接受的盐或其溶剂合物以及上述化合物应用于肿瘤及其他与肿瘤相关的疾病的预防和/或治疗。其中式(I)中各取代基的定义同说明书中的定义相同。
Description
技术领域
本领域属于药物化学技术领域，具体涉及一种新的抗肿瘤化合物及其用于治疗或预防肿瘤等疾病以及与肿瘤相关的疾病的用途。
背景技术
目前，肿瘤仍是当今世界直接危及人类生命的一种最常见、最严重的疾病。肿瘤化疗取得了一定的进展，明显延长了患者的生存时间，但仍没有取得令人满意的疗效。近年来，人们对肿瘤学和肿瘤病灶部位分子水平研究的深入及许多新的治疗靶点的发现，为新型抗肿瘤药的开发提供了可能。随着对肿瘤细胞信号转导途径研究的不断深入，新型抗肿瘤药物的设计与研究越来越受到关注。
吉非替尼是由英国Astra-Zeneca公司开发的抗肿瘤药物，化学名为N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉-4-丙氧基)喹唑啉-4-胺，结构式如式1所示。它可竞争细胞表面的表皮生长因子受体酪氨酸激酶(EGFR-TK)催化区域上Mg-ATP结合位点，属于EGFR-TK抑制剂并通过阻断细胞表面EGFR信号传导通路，阻碍肿瘤的生长、转移和血管生成，并可诱导肿瘤细胞的凋亡。目前已被FDA批准用于晚期非小细胞肺癌(NSCLC)患者经化疗后继续恶化的单用疗法，吉非替尼的上市为临床实体瘤治疗提供了一种全新的方法。
瓦他拉尼是由诺华和先灵制药公司联合开发的用于治疗转移性结肠癌的药物，化学名为N-(4-氯苯基)-4-(4-吡啶甲基)-1-酞嗪胺，结构如式2所示。瓦他拉尼可有效地抑制血管内皮生长因子受体(VEGFR)家族成员、血小板衍生生长因子受体p(PDGFR13)及c-Kit受体激酶，且口服生物利用度良好。体外激酶抑制试验显示，瓦他拉尼可抑制包括VEGFR.1/Fh-1.、VEGFR-2/KDR和VEGFR-3/FLT.4在内的所有已知的血管内皮生长因子受体家族成员。这些受体能够调控血管和淋巴管的生成以及肿瘤细胞的运动性，对肿瘤的发生起着重要作用。
在一系列抗肿瘤药物中，还有很多待深入研究的新化合物。文献(SynthesisandCytotoxicEvaluationofSomeNewPhthalazinylpiperazineDerivatives.Arch.Pharm.Chem.LifeSci.2012，345，287-293)将瓦他拉尼分子结构引入哌嗪基，并将取代苯基通过乙酰基与之相连，制备得到一系列具有潜在抗肿瘤效果的化合物，其结构如式3所示。
发明内容
本发明的目的是提供一种新型的抗肿瘤化合物。
本发明的另一目的是提供上述化合物应用于肿瘤及其他与肿瘤相关的疾病的预防和/或治疗。
本发明的目的可以通过以下措施达到：
一类式(I)所示的化合物，其药学上可接受的盐或其溶剂合物：
其中，
n为1-4的整数；
W选自H、
X选自氧原子或NR5R6；
Y选自碳原子或氮原子；
Z1选自烷基、环烷基、杂环烷基、取代或非取代的苯基；
Z2、Z3和Z4分别独立地选自取代或非取代的苯基；
M为芳基、杂芳基或杂环烷基；
R1、R2、R3、R4、R5、R6分别独立地选自氢，或者取代的或非取代的烷基、亚烷基、环烷基、杂环烷基；
m、p和q分别为0-4的任意整数。
在一种方案中，M是任选的被取代的苯基、吲哚基、苯并噻吩基、苯并呋喃基、苯并噻唑基、喹啉基、苯基噻唑基、吡啶噻唑基、苯基呋喃基或吡啶呋喃基；
在一种方案中，R1、R2、R3、R4、R5和R6分别独立地选自氢、C1-C8烷基、C3-C8环烷基或C3-C8杂环烷基。
优选地，R1、R2、R3、R4分别为氢。
在一种方案中，Z1选自甲基、乙基、
在一种优选的方案中，Z2、Z3和Z4分别独立地选自选自
本发明的化合物的举例性的，非限制性的具体实例如下：
或其药学上可接受的盐或其溶剂合物。
“药学上可接受的盐”是包含式(I)的化合物与有机酸或无机酸形成的盐。
含有本发明化合物的药物组合物，该药物组合物包含治疗有效量的游离形式或可药用盐形式的符合通式(I)的化合物作为活性成分；一种或多种药用载体物质和／或稀释剂。
本发明还提供了式(I)的化合物的制备方法(其中n、X、Y、R1、R2的定义与说明书上文相同)，但不仅限于下列方法，其方案如下所示：
路线(一)以香草酸甲酯(化合物1)为起始原料，与化合物2在碳酸钾的作用下反应制备得到化合物3；化合物3的反应液可直接进行下一步反应，与化合物4在碳酸钾和碘化钾的作用下反应，制备得到化合物5；将化合物5在无机碱的作用下皂化反应生成化合物6；化合物6在强酸的作用下生成化合物7；将化合物7在酸的作用下与甲醛水溶液反应生成化合物8；化合物8与化合物12在强碱的催化作用下反应生成化合物9；将化合物9与水合肼反应生成化合物10；将化合物10在三氯氧磷等氯化试剂的作用下反应生成化合物11，进一步以化合物11为原料制备得到一系列符合式(I)的化合物。
当式(I)中W为H或时，其制备方法可采用路线一的方案，但不仅限于此方案。路线一将化合物11与无水哌嗪或化合物21在有机碱的催化下反应，分别得到化合物13和化合物20。
当式(I)中W为(M的定义与说明书上文相同)时，其制备方法可采用路线二的方案，但不仅限于此方案。路线二将化合物13与化合物15在催化剂作用下进行酰胺反应，制备得到化合物14。
当式(I)中W为(Z1和Z2的定义与说明书上文相同)时，其制备方法可采用路线三的方案，但不仅限于此方案。路线三将化合物13与化合物16在催化剂作用下进行酰胺反应，制备得到化合物17。
当式(I)中W为(p和Z4的定义与说明书上文相同)时，其制备方法可采用路线四的方案，但不仅限于此方案。路线四将化合物13与化合物18在碱催化作用下进行反应，制备得到化合物19。
当式(I)中W为(q和Z3的定义与说明书上文相同)时，其制备方法可采用路线五的方案，但不仅限于此方案。路线五将化合物13与化合物20在有机碱的催化作用下进行反应，制备得到化合物21。
除非另有说明，下列用在权利要求书和说明书中的术语有如下含义：
“烷基”，表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团(本申请书中提到的数字范围，例如“1-20”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括20个碳原子)。含1-4个碳原子的烷基称为低级烷基。当低级烷基没有取代基时，称其为未取代的低级烷基。更优选的是，烷基是有1-10个碳原子的中等大小的烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。最好是，烷基为有1-3个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。
本发明中的“亚烷基”，表示1-20个碳原子的饱和的脂烃基，其两端或两个碳原子分别与其他基团相连，包括直链和支链基团(本申请书中提到的数字范围，例如“1-20”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括20个碳原子)。更优选的是，亚烷基是有1-10个碳原子的中等大小的烷基，例如亚甲基、亚乙基、亚丙基、2-亚丙基、亚正丁基、亚异丁基、亚叔丁基、亚戊基等。
本发明中的“环烷基”表示全部为碳的单环或稠合的环(“稠合”环意味着系统中的每个环与系统中的其它环共享毗邻的一对碳原子)基团，其中一个或多个环不具有完全连接的π电子系统，其一般具有3-10个碳原子，环烷基的实例(不局限于)为环丙烷、环丁烷、环戊烷、环戊烯、环己烷、金刚烷、环己二烯、环庚烷和环庚三烯。环烷基可为取代的和未取代的。
本发明中的“杂环烷基”表示至少含有一个杂原子的单环或稠合的饱和环(“稠合”环意味着系统中的每个环与系统中的其它环共享毗邻的一对碳原子)基团，其中一个或多个不不具有完全连接的π电子系统，其一般具有3-10个碳原子。“杂环烷基”可以是取代的或未取代的。
本发明中的“芳基”表示6至12个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳基的非限制性实例有苯基、萘基和蒽基。芳基可以是取代的或未取代的。
本发明中的“杂芳基”表示5至12个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。未取代的杂芳基地非限制性实例有吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、嘧啶、喹啉、异喹啉、嘌呤、四唑、三嗪和咔唑。杂芳基可以是取代的或未取代的。
“药学上可接受的盐”“药学上可接受的盐”是包含式(I)的化合物与有机酸或无机酸形成的盐，表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸例如(但不限于)盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸例如(但不限于)乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属离子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药用组合物”指的是在此描述的一种或多种化合物或者它们的药学上可接受的盐和前药与其它的化学成分，例如药学上可接受的载体和赋形剂的混合物。药用组合物的目的是促进化合物对生物体的给药。
“溶剂合物”是本发明的符合通式(I)特征的化合物化合物或其盐，其还包含由非共价分子间力结合的化学计算量或非化学计算量的溶剂。当所述溶剂是水时，所述溶剂合物是水合物。
“水合物”是指本发明的符合通式(I)特征的化合物与水相互作用过程中形成的固态结晶物质。
本发明的化合物具有新型结构，可应用于制备预防和/或治疗肿瘤药物或其他与肿瘤相关疾病的药物。
具体实施方式
以下实施例进一步描述本发明，但是，这些实施例仅是用于说明本发明，而不是对本发明范围的限制。
一、非市售中间体的制备实施例
实施例1
取化合物22香草酸甲酯(73g，0.4mol)与1-溴-3-氯丙烷(94g，0.6mol)混合加入1L三口圆底烧瓶中，量取500ml的N,N-甲基甲酰胺(DMF)搅拌溶解，加入80g碳酸钾40℃加热搅拌，TLC检测(石油醚：乙酸乙酯＝2：1，紫外显色)反应进程，4～5小时基本反应完全，得到化合物23的反应液，可直接用于下一步反应。
取30g碳酸钾、20g碘化钾和70g吗啉直接加入化合物23的反应液中，75℃加热搅拌过夜，TLC检测(石油醚：乙酸乙酯=2：1，紫外显色)原料基本反应完全后过滤，去除不溶物，滤饼用二氯甲烷洗涤，滤液浓缩去除大部分DMF，加入约800ml水稀释，用300mL*2二氯甲烷(洗涤液)萃取两遍，合并有机相，500mL*2水洗涤后滴加稀盐酸调节pH至3～4，分出水相，用500mL*2二氯甲烷洗涤后再用浓氨水调节pH至8～9，用300mL*3二氯甲烷萃取后合并有机相，500mL*2饱和食盐水洗涤后浓缩得到化合物24粗品，不用提纯可直接用于下一步反应。
将上述实验所得化合物24粗品直接加入32g氢氧化钠，用400ml甲醇溶解，65℃加热搅拌，皂化反应过夜，得到钠盐化合物25，继续通过TLC检测(二氯甲烷：甲醇：氨水＝15：1：0.2，紫外显色)原料反应进程，皂化完全后冰水浴降温，缓慢滴加浓盐酸酸化后浓缩去除甲醇，得到化合物26粗品，不用提纯可直接用于下一步反应。
将上述实验所得化合物26粗品直接加入400mL的37％甲醛水溶液和400mL浓盐酸溶解，60℃加热搅拌48小时左右，浓缩去除大部分甲醛和浓盐酸，加入500mL水稀释后滴加浓氨水调节pH至8～9，用300mL*3二氯甲烷萃取后合并有机相，有机相用500mL*2饱和食盐水洗涤后无水硫酸钠干燥，浓缩得到约60g灰白色固体，柱层析(二氯甲烷：甲醇＝100：1～30：1，加少量氨水)收集得到41g化合物27，MS：m/z308[M+H]+。
称取0.11mol化合物27与24g4-吡啶甲醛混合，加入250mL丙酸乙酯搅拌均匀，部分不溶，将24.5g甲醇钠用200mL甲醇溶解冷却后缓慢加入化合物27的反应液中，85℃加热搅拌，TLC监测(二氯甲烷：甲醇：氨水＝10：1：0.2)反应进程，约6小时原料反应完全，得到化合物28的反应液，室温冷却，浓缩去除溶剂，加入500mL水溶解，分别用200mL*2二氯甲烷和200mL*2乙酸乙酯洗涤，去除有机相，向水相中缓慢滴加冰乙酸调节pH至中性，析出大量固体，过滤去除大部分滤液，滤饼用300mL80％水合肼100℃加热搅拌，溶液逐渐变成红棕色澄清液，过夜反应有固体生成，冷却过滤，滤饼用少量乙醇漂洗后放入烘箱50℃减压干燥，得到7.5g化合物29，MS：m/z411[M+H]+。
量取25mL乙腈与7.5g化合物29混合，滴入3滴N，N-二甲基甲酰胺，搅拌均匀，缓慢滴加50mL三氯氧磷，升温至90℃加热搅拌，约3小时反应完全，室温冷却，浓缩去除溶剂，加入约150mL水，滴加浓氨水调节pH呈碱性，用100mL*3二氯甲烷萃取后合并有机相，用100mL*2饱和食盐水洗涤后无水硫酸钠干燥，浓缩，得到6.5g棕黄色固体，即化合物30。MS：m/z429[M+H]+。
化合物30的衍生物、类似结构单元的其他化合物或者出现在所伴随的反应流程中的其它中间体制备，参照实施例1的程序进行。其测试结果如下表1所示。
表1
二、新化合物实施例
实施例7
称取0.2g化合物30与0.23g化合物35混合，用约50mL无水乙醇溶解，加入0.07g三乙胺，0.02gKI80℃加热搅拌，反应72h，TCL监测(二氯甲烷：甲醇：氨水=10：1：0.1)至反应结束，通过柱层析提纯得0.09g化合物36。
MSm/z(ESI)：638[M+H]+1；H-NMR(500MHz，氘代DMSO：δ：8.45(d.2H),8.26(m.1H)，7.92(m.1H)，7.38(m.2H)4.62(s.2H)，4.21(t.2H)，4.01(s.3H)，3.61～3.70(m.4H)，3.58(m.2H)，2.83(t.2H)，2.46～2.48(t.4H)，1.96(m.2H)。
实施例8
称取2.7g化合物30与4g无水哌嗪混合，用约50mL无水乙醇溶解，加入1g三乙胺，0.2g碘化钾80℃加热搅拌，反应48h，TCL监测(二氯甲烷：甲醇：氨水＝10：1：0.1)至反应结束，后浓缩去除乙醇，加入100mL水，用50mL*3二氯甲烷萃取后合并有机相，有机相用100mL*2饱和氯化铵溶液洗涤后再用100mL*2水洗两遍，无水硫酸钠干燥，浓缩得到1.5g化合物37。
MSm/z(ESI)：464；
1H-NMR(500MHz，氘代DMSO：δ：8.45(d.2H)，8.26(m.1H)，7.92(m.1H)，7.38(m.2H)，4.62(s.2H)，4.21(t.2H)，4.01(s.3H)，3.61(t.2H)，3.29(t.2H)，2.83(t.2H)，2.46～2.48(t.4H)。
化合物38、化合物39、化合物40、化合物42、化合物43及化合物44具有化合物37或化合物38类似的结构单元，其制备程序参照实施例7或实施例8的方案进行。化合物测试结果如下表2所示。
表2
实施例16
称取0.12g化合物37与0.06g化合物46混合，用约30mL的DMF溶解，加入0.08g三乙胺和0.19g苯并三氮唑-N，N，N′，N′-四甲基脲六氟磷酸盐(HBTU)，室温搅拌1h，TCL监测(二氯甲烷：甲醇：氨水=10：1：0.1)至反应结束，通过柱层析得到约50mg化合物47。
MSm/z(ESI)：[M+H]+683；
1H-NMR(500MHz，氘代DMSO：δ：8.45(d.2H)，8.26(m.1H)，7.92-7.45(m.4H)，7.40-7.12(m.5H)，4.62(s.2H)，4.21(t.2H)，4.01(s.3H)，3.61(t.2H)，3.29(t.2H)，2.83-2.61(m.4H)，2.46～2.48(t.4H)，1.01(t，3H)。
实施例17---24的制备流程参照实施例15的程序方案进行。其测试结果如下表3所示。
表3
实施案例25
称取0.1g化合物37与0.05g化合物56混合，用30mLDMF溶解，加入0.06g三乙胺和0.15g苯并三氮唑-N,N,N′，N′-四甲基脲六氟磷酸盐(HBTU)，室温搅拌1h，TCL监测(二氯甲烷：甲醇：氨水=10：1：0.1)至反应结束，通过柱层析得到约60mg化合物57。
实施例26---30分别选用以化合物45为反应原料，他们的制备流程参照实施例25的程序方案进行。其测试结果如下表4所示。
表4
实施案例31
称取0.1g化合物37与0.17g化合物63混合，用30mL二氯甲烷溶解，滴入0.1g三乙胺，45℃加热搅拌3h左右，TCL监测(二氯甲烷：甲醇：氨水=10：1：0.1)至反应结束，分别用50mL水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩拌样过柱收集得到25mg化合物64。
MSm/z(ESI)：708[M+H]+；
1H-NMR(500MHz，氘代DMSO)：δ：10.12(s，1H)，8.19m,1H)，8.11(m，1H)，8.06(d，1H)，7.92(m,2H)，7.67m,1H)，7.45(d，1H)，7.29(m,4H)，7.18(m,1H)，4.62(s.2H)，4.21(t.2H)，4.01(s.3H)，3.61(t.2H)，3.29-3.26(m，4H)，2.83(t.2H)，2.46～2.48(t.4H)。
实施例32--41的制备流程参照实施例31的程序方案进行。其测试结果如下表表5所示。
表5
实施例43
称取2.33g4-溴-2-氟苯胺用15mL二氯甲烷溶解，加入1.61g三乙胺搅拌均匀，缓慢滴加1.5g草酰氯甲酯/10mL二氯甲烷稀释液，防止二氯甲烷暴沸，滴加完毕后室温搅拌过夜，TLC检测(PE：EA=3：1，紫外显色)原料大部分反应，加入50mL水搅拌分液，有机相用50mL饱和食盐水洗涤后直接浓缩得到3.2g淡黄色固体，即化合物87粗品，直接用于下一步反应；
加入150mL甲醇溶解化合物87，称取1.8g氢氧化钠加入反应液中，65℃加热搅拌2h左右，TLC检测(PE：EA=3：1，紫外显色)造化完全，室温冷却，浓缩去除甲醇，加入300mL水搅拌，乳化物大部分不溶，滴加浓盐酸调节pH至4左右，固体逐渐溶解，用300mL乙酸乙酯萃取后无水硫酸钠干燥，浓缩得到2.1g类白色固体，即化合物76；
依次称取0.2g化合物37、0.12g化合物76和0.32g苯并三氮唑-N，N，N′，N′-四甲基脲六氟磷酸盐(HBTU)加入100mL圆底烧瓶中，加入15mLDMF溶解搅拌均匀，滴入0.13g三乙胺，室温搅拌过夜，TLC检测(二氯甲烷：甲醇=10：1，少量氨水，紫外显色)，原料基本反应完全，加入200mL水稀释，分别用200mL、100mL二氯甲烷萃取后合并有机相，有机相用200mL饱和食盐水洗涤后无水硫酸钠干燥，浓缩拌样过柱得到20mg化合物77。
MSm/z(ESI)：722[M+H]+；
1H-NMR(500MHz，氘代DMSO：δ：10.12(s,1H)，8.17(m，1H)，8.12(m，1H),8.06(d，1H)，7.93(m,2H)，7.67(m，1H)，7.45(d，1H)，7.28(m,4H)，7.17(m，1H)，4.62(s.2H)，4.21(t.2H)，4.01(s.3H)，3.61(t.2H)，3.29-3.26(m，4H)，2.83(t.2H)，2.46～2.48(t.4H)。
实施例44--54的制备流程参照实施例43的程序方案进行。其测试结果如下表6所示。
表6
三、生物学测试例：
下面的实验应用MTT细胞增殖检测法测定本发明化合物以及吉非替尼和瓦他拉尼对人癌细胞体外增殖的影响，对比发现，本发明化合物对人癌细胞增殖具有较好的抑制作用。其中母液浓度为100mM，4℃保存备用。对照药品为紫杉醇注射液。
1、材料
(1)细胞株：
细胞株由南京凯基生物科技发展有限公司提供。
表7细胞株及培养条件
(2)实验设备与试剂：
表8实验设备与仪器
3、实验方法：
(1)细胞消化、计数、配制成浓度为3～5×104个/mL的细胞悬液，96孔细胞培养板中每孔加入100μL细胞悬液(每孔3～5×103个细胞)；
(2)96孔细胞培养板置于37℃，5％CO2培养箱中培养24小时；
(3)用完全培养基稀释药物至所需浓度，每孔加入100μL相应的含药培养基，同时设立阴性对照组，阳性对照组；
(4)96孔细胞培养板置于37℃，5％CO2培养箱中培养72小时；
(5)将96孔板进行MTT染色，λ＝490nm，测定OD值；
1)每孔加入20μLMTT(5mg/mL)，在培养箱继续培养4小时；
2)弃去培养基，每孔加入150μLDMSO溶解，摇床10分钟轻轻地混匀；
3)λ＝490nm，酶标仪读出每孔的OD值，计算抑制率。
(6)计算各组别抑制率(InhibitiveRate)。
4、实验结果
本发明化合物对各细胞株的体外增殖的IC50值如下表9所示(化合物的编号及具体结构见说明书中各化合物的制备实施例)：
表9
Claims (7)
1.式(I)所示的化合物，其药学上可接受的盐：
其中，n为1-4的整数；
W选自H、
X选自氧原子或NR5R6；
Y选自碳原子或氮原子；
Z1选自1-10个碳原子的烷基、3-10个碳原子的环烷基、3-10个碳原子的杂环烷基、苯基；
Z2、Z3和Z4分别独立地选自
M为6至12个碳原子的芳基、5至12个环原子的杂芳基或3-10个碳原子的杂环烷基，所述的杂芳基为含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统；
R1、R2、R3、R4、R5、R6分别独立地选自氢、C1-C8烷基、C3-C8环烷基或C3-C8杂环烷基；m、p和q分别为0-4的整数。
2.根据权利要求1所述的化合物，其特征在于M是任选的被取代的苯基、吲哚基、苯并噻吩基、苯并呋喃基、苯并噻唑基、喹啉基、苯基噻唑基、吡啶噻唑基、苯基呋喃基或吡啶呋喃基。
3.根据权利要求1所述的化合物，其特征在于Z1选自甲基、乙基、
4.根据权利要求1所述的化合物，其特征在于化合物选自：
或其药学上可接受的盐。
5.根据权利要求1中所述的化合物，其特征在于“药学上可接受的盐”是包含式(Ⅰ)的化合物与有机酸或无机酸形成的盐。
6.一种药物组合物，该药物组合物包含游离形式或可药用盐形式的权利要求1至5中任意一项所定义的化合物作为活性成分；一种或多种药用载体物质和/或稀释剂。
7.权利要求6中的药物组合物，其为肿瘤疾病的预防和/或治疗药物。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310416151.0A CN103601722B (zh) | 2013-09-13 | 2013-09-13 | 新型抗肿瘤化合物 |
| PCT/CN2014/085756 WO2015035866A1 (zh) | 2013-09-13 | 2014-09-02 | 新型抗肿瘤化合物、药物组合物及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310416151.0A CN103601722B (zh) | 2013-09-13 | 2013-09-13 | 新型抗肿瘤化合物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103601722A CN103601722A (zh) | 2014-02-26 |
| CN103601722B true CN103601722B (zh) | 2016-03-02 |
Family
ID=50120003
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310416151.0A Active CN103601722B (zh) | 2013-09-13 | 2013-09-13 | 新型抗肿瘤化合物 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN103601722B (zh) |
| WO (1) | WO2015035866A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601722B (zh) * | 2013-09-13 | 2016-03-02 | 南京华威医药科技开发有限公司 | 新型抗肿瘤化合物 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1208404A (zh) * | 1996-10-01 | 1999-02-17 | 协和发酵工业株式会社 | 含氮杂环化合物 |
| US20040023992A1 (en) * | 2002-05-20 | 2004-02-05 | Jagabandhu Das | Pyrazolo-pyrimidine aniline compounds useful as kinase inhibitors |
| CN1662509A (zh) * | 2002-04-23 | 2005-08-31 | 布里斯托尔-迈尔斯斯奎布公司 | 可用作激酶抑制剂的吡咯并三嗪苯胺化合物 |
| CN101821258A (zh) * | 2007-08-13 | 2010-09-01 | 贝林格尔.英格海姆国际有限公司 | 新的制备方法 |
| CN102108078A (zh) * | 2009-12-24 | 2011-06-29 | 沈阳药科大学 | 1,4-取代酞嗪类化合物及其制备方法和用途 |
| US8067589B2 (en) * | 2007-02-26 | 2011-11-29 | Pfizer Inc | Heterocyclic compounds useful in treating diseases and conditions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601722B (zh) * | 2013-09-13 | 2016-03-02 | 南京华威医药科技开发有限公司 | 新型抗肿瘤化合物 |
-
2013
- 2013-09-13 CN CN201310416151.0A patent/CN103601722B/zh active Active
-
2014
- 2014-09-02 WO PCT/CN2014/085756 patent/WO2015035866A1/zh not_active Ceased
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1208404A (zh) * | 1996-10-01 | 1999-02-17 | 协和发酵工业株式会社 | 含氮杂环化合物 |
| CN1662509A (zh) * | 2002-04-23 | 2005-08-31 | 布里斯托尔-迈尔斯斯奎布公司 | 可用作激酶抑制剂的吡咯并三嗪苯胺化合物 |
| CN102093363A (zh) * | 2002-04-23 | 2011-06-15 | 布里斯托尔-迈尔斯斯奎布公司 | 可用作激酶抑制剂的吡咯并三嗪苯胺化合物 |
| US20040023992A1 (en) * | 2002-05-20 | 2004-02-05 | Jagabandhu Das | Pyrazolo-pyrimidine aniline compounds useful as kinase inhibitors |
| US8067589B2 (en) * | 2007-02-26 | 2011-11-29 | Pfizer Inc | Heterocyclic compounds useful in treating diseases and conditions |
| CN101821258A (zh) * | 2007-08-13 | 2010-09-01 | 贝林格尔.英格海姆国际有限公司 | 新的制备方法 |
| CN102108078A (zh) * | 2009-12-24 | 2011-06-29 | 沈阳药科大学 | 1,4-取代酞嗪类化合物及其制备方法和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103601722A (zh) | 2014-02-26 |
| WO2015035866A1 (zh) | 2015-03-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6621486B2 (ja) | ピリド−アザヘテロサイクリック化合物及びその製造方法と用途 | |
| CN109983016B (zh) | 嘧啶并[5,4-b]吲嗪或嘧啶并[5,4-b]吡呤化合物、其制备方法及用途 | |
| CN112300153B (zh) | 一种杂环化合物、药物组合物和用途 | |
| WO2001083456A1 (en) | Condensed heteroaryl derivatives | |
| CN114656482A (zh) | 作为egfr抑制剂的大环杂环类化合物及其应用 | |
| CN116143805A (zh) | 一类含氮杂环联芳基类化合物、制备方法和用途 | |
| WO2016208592A1 (ja) | 二環性複素環アミド誘導体 | |
| WO2022222871A1 (en) | Heterocyclic compounds as kras g12c inhibitors | |
| WO2013178021A1 (zh) | 吡咯并[2，1—f][1，2，4]三嗪衍生物及其抗肿瘤用途 | |
| JP7041821B2 (ja) | アミノ置換窒素含有縮合環化合物、その調製方法及び使用 | |
| CN110857292A (zh) | 一种egfr激酶抑制剂及其制备方法和应用 | |
| CN105503863A (zh) | 新型抗肿瘤化合物 | |
| JP2022509076A (ja) | 芳香環結合ジオキシノ－キナゾリンまたはジオキシノ－キノリン系化合物、組成物およびその使用 | |
| CN108558865B (zh) | 一种以吡啶并[2,3-d]嘧啶结构为母核的衍生物及其制备方法和应用 | |
| CN113087671A (zh) | 一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用 | |
| CN108358894B (zh) | 一种抑制组蛋白乙酰转移酶的化合物及其制备方法与应用 | |
| CN109476649B (zh) | 五元杂环类化合物及其制备方法、药物组合物和用途 | |
| CN103601722B (zh) | 新型抗肿瘤化合物 | |
| CN110577546B (zh) | Vegfr抑制剂及其制备方法和应用 | |
| WO2024235289A1 (zh) | 用于egfr蛋白降解的化合物及其用途 | |
| EP4442684A1 (en) | A class of pyrimidine compounds, and preparation method therefor and use thereof | |
| TWI535724B (zh) | 埃克替尼磷酸鹽的新晶型及其用途 | |
| EP4063361A1 (en) | Crystal forms of fused ring compound, and composition thereof, preparation method therefor and application thereof | |
| CN115894486B (zh) | 一种氢化吡啶并喹唑啉类化合物、组合物及其应用 | |
| CN107056754B (zh) | 内嵌脲类结构的wnt通路抑制剂 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Address after: Cheng Wei Road Nanjing city Jiangsu province 210046 Xianlin University No. 9 Applicant after: Nanjing Huawe Medical Science & Technology Development Co., Ltd. Address before: Cheng Wei Road Nanjing city Jiangsu province 210012 Xianlin University No. 9 Applicant before: Nanjing Huawe Medical Science & Technology Development Co., Ltd. |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 210012 NANJING, JIANGSU PROVINCE TO: 210046 NANJING, JIANGSU PROVINCE |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Cheng Wei Road Nanjing city Jiangsu province 210046 Xianlin University No. 9 Patentee after: Nanjing Huawei Medicine Technology Group Co Ltd Address before: Cheng Wei Road Nanjing city Jiangsu province 210046 Xianlin University No. 9 Patentee before: Nanjing Huawe Medical Science & Technology Development Co., Ltd. |
|
| CP01 | Change in the name or title of a patent holder |