CN105503745A - 含4-氧代喹唑啉-2-基的查耳酮类似物及其制备方法和用途 - Google Patents
含4-氧代喹唑啉-2-基的查耳酮类似物及其制备方法和用途 Download PDFInfo
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- CN105503745A CN105503745A CN201610009022.3A CN201610009022A CN105503745A CN 105503745 A CN105503745 A CN 105503745A CN 201610009022 A CN201610009022 A CN 201610009022A CN 105503745 A CN105503745 A CN 105503745A
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- Prior art keywords
- compound
- quinazolin
- enyl
- acryloyl
- oxoprop
- Prior art date
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- 150000001788 chalcone derivatives Chemical class 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 6
- 239000001301 oxygen Substances 0.000 title claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 8
- -1 4-oxoquinazolin-2-yl group Chemical group 0.000 claims description 69
- 150000001875 compounds Chemical class 0.000 claims description 64
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- XOXAXLVUISVRJB-ZHACJKMWSA-N 2-[(E)-3-(4-methoxyphenyl)-3-oxoprop-1-enyl]-3H-quinazolin-4-one Chemical compound COC1=CC=C(C=C1)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O XOXAXLVUISVRJB-ZHACJKMWSA-N 0.000 claims description 8
- XFVTYRJIEPULDC-CSKARUKUSA-N 2-[(E)-3-(2,5-dimethoxyphenyl)-3-oxoprop-1-enyl]-3H-quinazolin-4-one Chemical compound COC1=C(C=C(C=C1)OC)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O XFVTYRJIEPULDC-CSKARUKUSA-N 0.000 claims description 7
- UGKWFXKBQWVQHO-MDZDMXLPSA-N 2-[(E)-3-(4-aminophenyl)-3-oxoprop-1-enyl]-3H-quinazolin-4-one Chemical compound NC1=CC=C(C=C1)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O UGKWFXKBQWVQHO-MDZDMXLPSA-N 0.000 claims description 7
- IYUMGEUYTZHFDH-CMDGGOBGSA-N 2-[(E)-3-oxo-3-(2,4,6-trimethoxyphenyl)prop-1-enyl]-3H-quinazolin-4-one Chemical compound COC1=C(C(=CC(=C1)OC)OC)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O IYUMGEUYTZHFDH-CMDGGOBGSA-N 0.000 claims description 7
- BHVINGHDFCPFSJ-CMDGGOBGSA-N 2-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-enyl]-3H-quinazolin-4-one Chemical compound COC=1C=C(C=C(C=1OC)OC)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O BHVINGHDFCPFSJ-CMDGGOBGSA-N 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 5
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000005808 2,4,6-trimethoxyphenyl group Chemical group [H][#6]-1=[#6](-[#8]C([H])([H])[H])-[#6](-*)=[#6](-[#8]C([H])([H])[H])-[#6]([H])=[#6]-1-[#8]C([H])([H])[H] 0.000 claims description 4
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 4
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 4
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 4
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 4
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 3
- 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 claims description 3
- 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 claims description 3
- 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 claims description 3
- 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 claims description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 3
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 3
- 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 claims description 3
- 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 claims description 3
- 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 claims description 3
- 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 claims description 3
- 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 claims description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 3
- 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 claims description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 3
- VWSARCQTVDKURJ-MDZDMXLPSA-N 2-[(E)-3-(2,4-dimethoxyphenyl)-3-oxoprop-1-enyl]-3H-quinazolin-4-one Chemical compound COC1=C(C=CC(=C1)OC)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O VWSARCQTVDKURJ-MDZDMXLPSA-N 0.000 claims description 3
- NTMOCRWTISJBTI-CSKARUKUSA-N 2-[(E)-3-(2,4-dimethoxyphenyl)prop-2-enoyl]-3H-quinazolin-4-one Chemical compound COC1=C(C=CC(=C1)OC)/C=C/C(=O)C1=NC2=CC=CC=C2C(N1)=O NTMOCRWTISJBTI-CSKARUKUSA-N 0.000 claims description 3
- GZVUFAAIFFCJKX-MDZDMXLPSA-N 2-[(E)-3-(2,4-dimethylphenyl)-3-oxoprop-1-enyl]-3H-quinazolin-4-one Chemical compound CC1=C(C=CC(=C1)C)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O GZVUFAAIFFCJKX-MDZDMXLPSA-N 0.000 claims description 3
- ODHKQVAZWLOEAB-ZHACJKMWSA-N 2-[(E)-3-(2-methoxyphenyl)-3-oxoprop-1-enyl]-3H-quinazolin-4-one Chemical compound COC1=C(C=CC=C1)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O ODHKQVAZWLOEAB-ZHACJKMWSA-N 0.000 claims description 3
- CFKOGXDSLQYUQZ-ZHACJKMWSA-N 2-[(E)-3-(2-methoxyphenyl)prop-2-enoyl]-3H-quinazolin-4-one Chemical compound COC1=C(C=CC=C1)/C=C/C(=O)C1=NC2=CC=CC=C2C(N1)=O CFKOGXDSLQYUQZ-ZHACJKMWSA-N 0.000 claims description 3
- QANPVWZFWZYFEA-ZHACJKMWSA-N 2-[(E)-3-(2-methylphenyl)-3-oxoprop-1-enyl]-3H-quinazolin-4-one Chemical compound CC1=C(C=CC=C1)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O QANPVWZFWZYFEA-ZHACJKMWSA-N 0.000 claims description 3
- JSAVFUFZRSEUQM-CMDGGOBGSA-N 2-[(E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl]-3H-quinazolin-4-one Chemical compound COC=1C=C(C=C(C=1OC)OC)/C=C/C(=O)C1=NC2=CC=CC=C2C(N1)=O JSAVFUFZRSEUQM-CMDGGOBGSA-N 0.000 claims description 3
- NFUCXFSUTGMLBM-BQYQJAHWSA-N 2-[(E)-3-(3,4-dichlorophenyl)-3-oxoprop-1-enyl]-3H-quinazolin-4-one Chemical compound ClC=1C=C(C=CC=1Cl)C(/C=C/C1=NC2=CC=CC=C2C(N1)=O)=O NFUCXFSUTGMLBM-BQYQJAHWSA-N 0.000 claims description 3
- ZBZWZLRNNRISID-VQHVLOKHSA-N 2-[(E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]-3H-quinazolin-4-one Chemical compound COC=1C=C(C=CC=1OC)/C=C/C(=O)C1=NC2=CC=CC=C2C(N1)=O ZBZWZLRNNRISID-VQHVLOKHSA-N 0.000 claims description 3
- NIHPGMJRECLZEB-BQYQJAHWSA-N 2-[(E)-3-(3,5-dimethoxyphenyl)prop-2-enoyl]-3H-quinazolin-4-one Chemical compound COC=1C=C(C=C(C=1)OC)/C=C/C(=O)C1=NC2=CC=CC=C2C(N1)=O NIHPGMJRECLZEB-BQYQJAHWSA-N 0.000 claims description 3
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Abstract
本发明公开了通式(I)所示的含4-氧代喹唑啉-2-基的查耳酮类似物，其中，各取代基的定义详见说明书。此外，还公开了上述化合物的制备方法。该通式(I)所示的化合物对人乳腺癌(MFC-7)、人结肠癌(HCT-116)细胞的增殖具有抑制作用，可用作抗肿瘤药物。
Description
技术领域
本发明涉及药物化学领域，更具体地说涉及4-氧代喹唑啉-2-基的查耳酮类似化合物，及其制备方法和它们在抗肿瘤药物中的应用。
背景技术
喹唑啉是一种重要的含氮杂环母体。在喹唑啉-4(3H)-酮的C5或C6位进行修饰，所得的衍生物表现出良好的抗肿瘤活性，例如雷替曲塞(Raltitrexed,RTX)[Cunningham,D.；Zalcberg,J,；Maroun,J,；James,R.；Clarke,S.；Maughan,T.S.；Vincent,M.；Schulz,J.；Baron,M.G.；Facchini,T.Efficacy,tolerabilityandmanagementraltitrexedmonotheraphyinpatientsadvancedcolorectalcancer-areviewofphaseII/IIItrials.Eur.J.Cancer.2002,38,478–486]和AG337[Webber,S.E.；Bleckman,T.M.；Attard,J.；Deal,J.G.；Kathardekar,V.；Welsh,K.M.；Webber,S；Janson,C.A.；Matthews,D.A.；Smith,W.W.；Freer,S.T.；Jordan,S.R.；Bacquet,R.J.；Howland,E.F.；Booth,C.L.；Ward,R.W.；Hermann,S.M.；White,J.；Morse,C.A.；Hilliard,J.A.；Bartlett,J.A.Designofthymidylatesynthaseinhibitorsusingproteincrystalstructuresthesynthesisandbiologicalevaluationofanovelclassof5-substitutedquinazolinones.J.Med.Chem.1993,36(6),733–746]，它们通过抑制胸苷酸合成酶(Thymidylatesynthetase,TS)而发挥抗肿瘤作用。
研究表明，在喹唑啉-4(3H)-酮的C2位连接不同的基团，所得衍生物可通过不同的机制发挥抗肿瘤活性[Rhee,H.K.；Yoo,J.H.；Lee,E.；Kwon,Y.J.；Seo,H.R.；Lee,Y.S.；Choo,H.Y.P.Synthesisandcytotoxicityof2-phenylquinazolin-4(3H)-onederivatives.Eur.J.Med.Chem.2011,36,3900–3908]。例如，Hour等合成的化合物对微管蛋白的聚合具有明显的抑制作用，IC50值为1.1μM；其对人卵巢癌1A9和人结肠癌HCT-8细胞系也都显示出较好的抗增殖活性，ED50值分别为0.09和0.06g/mL[Hour,M.J.；Huang,L.J.；Kuo,S.C.；Xia,Y.；Bastow,K.；Nakanishi,Y.6-Alkylamino-and2,3-dihydro-3'-methoxy-2-phenyl-4-quinazolinonesandrelatedcompounds:theirsynthesis,cytotoxicity,andinhibitionoftubulinpolymerization.J.Med.Chem.2000,43,4479–4487]。
又如，Ispinesib是一种特异性的纺锤体驱动蛋白(kinesinspindleprotein,KSP)抑制剂，可抑制纺锤体的组装，阻止进一步有丝分裂，从而起到抗肿瘤作用，目前已进入二期临床试验阶段[Lad,L.；Luo,L.；Carson,J.D.；Wood,K.W.；Hartman,J.J.；Copeland,R.A.；Sakowicz,R.MechanismofinhibitionofhumanKSPbyispinesib.Biochemistry2008,47(11),3576–3585.Jennifer,J.；Knox,S.T.；Synold,J.J.；Biagi,P.R.C.N.E.L.PhaseIIandpharmacokineticstudyofSB-715992,inpatientswithmetastatichepatocellularcarcinoma:astudyofthenationalcancerinstituteofcanadaclinicaltrialsgroup.Invest.New.Drugs.2008,26,265–272]。
另一方面，查耳酮(chalcone，1,3-二苯基-2-丙烯-1-酮)广泛存在于天然植物中，是合成黄酮类化合物的重要前体，其本身也具有良好的抗肿瘤、抗菌、抗炎、抗疟疾等生物活性[Singh,P.；Anand,A.；Kumar,V.Recentdevelopmentsinbiologicalactivitiesofchalcones:Aminireview.Eur.J.Med.Chem.2014,85,758–777]。查耳酮由A、B两个苯环通过α,β-不饱和羰基体系连接构成，文献中通常将与羰基相连的苯环称为A环，而与碳-碳双键相连的称为B环[Ivanova,Y.；Momekov,G.；Petrov,O.；Karaivanova,M.；Kalcheva,V.Cytotoxicmannichbasesof6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolones.Eur.J.Med.Chem.2007,42,1382–1387.Lawrence,N.J.；Patterson,R.P.；Ooi,L.L.；Cook,D.；Ducki,S.Effectsofα-substitutionsonstructureandbiologicalactivityofanticancerchalcones.Bioorg.Med.Chem.Lett.2006,16,5844–5848]。
研究者通过在A、B环上引入不同的取代基，或者将A、B环替换成芳杂环，合成了大量具有良好生物活性的查耳酮类似物。例如，Kamal等在A环上引入芳杂环，合成了一系列查耳酮衍生物并测试了其抗肿瘤活性。结果表明，此系列化合物中a对人乳腺癌MCF-7、人结肠癌HT-29和HCT-116细胞系的抗增殖活性最好，其GI50值分别为0.31、0.66、0.33μM。他们还测试了10μM和30μM浓度下，化合物b-d对MCF-7细胞周期的影响。结果发现，当浓度为10μM时，化合物b-d将MCF-7细胞阻滞在G2/M期；而当浓度为30μM时，将MCF-7细胞阻滞在G0/G1期[Kamal,A.；Ramakrishna,G.；Raju,P.；Viswanath,A.；Ramaiah,M.J.；Balakishan,G.；Pal-Bhadra,M.Synthesisandanti-canceractivityofchalconelinkedimidazolones.Bioorg.Med.Chem.Lett.2010,20(16),4865–4869]。
a：R＝3，4，5-triMeO；R1＝phenyl
b：R＝4-OH-3-OMe；R1＝phenyl
c：R＝4-OH-3-OMe；R1＝4-methoxyphen
d：R＝4-OH-3-OMe；R1＝4-chiorophenyl
Wang等分别以连有取代基的苯并吡喃和吲哚环作为A、B环，合成了如下结构的查耳酮类似物，并测试了其对人肝癌HepG2、人前列腺癌PC-3和多药耐药型HCT-8细胞系等10种肿瘤细胞的体外抗增殖活性，其IC50值均在1.8μM以下，其中对HepG2细胞系的IC50值可达0.22μM。该化合物将HepG2细胞阻滞在G2/M期，并能有效抑制微管蛋白的聚合[Wang,G.C.；Li,C.Y.；He,L.；Lei,K.；Wang,F.；Pu,Y.Z.；Yang,Z.；Cao,D.；Ma,L.；Chen,J.Y.；Sang,Y.；Liang,X.L.；Xiang,M.L.；Peng,A.H.；Wei,Y.Q.；Chen,L.J.Design,synthesisandbiologicalevaluationofaseriesofpyranochalconederivativescontainingindolemoietyasnovelanti-tubulinagents.Bioorg.Med.Chem.2014,22(7),2060–2079]。
本课题组曾将2-甲基-4-氧代喹唑啉-6-基分别作为A或B环，合成了如下结构的查耳酮的类似物，其对人结肠癌HCT-116和人乳腺癌MCF-7细胞具有抗增殖作用[曹胜利，许兴智，廖蓟，丁盼盼，马丽，张晶晶，唐雪，含2-甲基-4-氧代喹唑啉-6-基的查耳酮类似物及其制备方法和用途，专利申请号CN201510146525.0]。
发明内容
本发明人将2-甲酰基、2-乙酰基-4-氧代喹唑啉分别与苯乙酮或苯甲醛类化合物反应，合成了新型的查耳酮类似物,该化合物具有抗肿瘤活性。
本发明的目的是提供一种含4-氧代喹唑啉-2-基的查耳酮类似物。
本发明的另一个目的是提供上述含4-氧代喹唑啉-2-基的查耳酮类似物的制备方法。
本发明的另一个目的是提供包含上述4-氧代喹唑啉-2-基的查耳酮类似物的药用组合物。
本发明的另一个目的是提供包含上述含4-氧代喹唑啉-2-基的查耳酮类似物在制备抗癌药物中的用途。
具体地说，本发明提供了一种含4-氧代喹唑啉-2-基的查耳酮类似物，如通式(I)所示：
其中，式(I)中Ar1和Ar2中的一个为4-氧代喹唑啉-2-基，即：
Ar1和Ar2中的另一个为未取代的芳烃基或取代的芳烃基、或者杂环基；
这里，所述未取代的芳烃基为苯基，所述取代的芳烃基为取代的苯基；所述取代的苯基是指苯环被一个或两个以上的C1-4烷基、任意个卤代C1-4烷基、C1-4烷氧基、C1-4烷氧羰酰基、羟基、卤素(例如氟、氯、溴、或碘)、氨基、硝基或氰基所取代，而且在苯环上取代的位置没有限定，或者苯环上相邻的两个碳和与其相连的杂原子、亚烷基一起形成5元或6元杂环，其中杂原子为氮或氧且杂原子个数为2个。更优选地，所述取代的苯基选自2-甲基苯基、4-甲基苯基、2,4-二甲基苯基、4-甲氧基苯基、2-甲氧基苯基、3-甲氧基苯基、4-氨基苯基、4-羟基苯基、4-硝基苯基、4-氰基苯基、4-溴代苯基、4-氯代苯基、4-氟代苯基、3,4-二氯代苯基、2,4-二氯代苯基、2,4-二氟代苯基、4-三氟甲基苯基、4-羟基-3-甲氧基苯基、2,4-二甲氧基苯基、2,5-二甲氧基苯基、3,4-二甲氧基苯基、3,5-二甲氧基苯基、2,4,6-三甲氧基苯基、3,4,5-三甲氧基苯基、或3,4-亚乙基二氧苯基。
所述杂环基选自噻吩基、呋喃基、或吡啶基，更优选地为噻吩-2-基、呋喃-2-基、吡啶-2-基、吡啶-3-基、或吡啶-4-基。
作为一种优选地实施方案，本发明提供的式(I)，其中Ar2为4-氧代喹唑啉-2-基，即为下列式(II)化合物：
其中，式(II)中Ar1为未取代的芳烃基或取代的芳烃基；
这里，所述未取代的芳烃基为苯基，所述取代的芳烃基为取代的苯基；所述取代的苯基是指苯环被一个或两个以上的C1-4烷基、任意个卤代C1-4烷基、C1-4烷氧基、C1-4烷氧羰酰基、羟基、卤素(例如氟、氯、溴、或碘)、氨基、硝基或氰基所取代，而且在苯环上取代的位置没有限定，或者苯环上相邻的两个碳和与其相连的杂原子、亚烷基一起形成5元或6元杂环，其中杂原子为氮或氧且杂原子个数为2个。更优选地，所述取代的苯基选自2-甲基苯基、4-甲基苯基、2,4-二甲基苯基、4-甲氧基苯基、2-甲氧基苯基、3-甲氧基苯基、4-氨基苯基、4-羟基苯基、4-硝基苯基、4-氰基苯基、4-溴代苯基、4-氯代苯基、4-氟代苯基、3,4-二氯代苯基、2,4-二氯代苯基、2,4-二氟代苯基、4-三氟甲基苯基、4-羟基-3-甲氧基苯基、2,4-二甲氧基苯基、2,5-二甲氧基苯基、3,4-二甲氧基苯基、3,5-二甲氧基苯基、2,4,6-三甲氧基苯基、3,4,5-三甲氧基苯基、或3,4-亚乙基二氧苯基。
作为一种优选的实施方案，本发明提供的式(I)，其中Ar1为4-氧代喹唑啉-2-基，即为本发明提供的式(I)为下列式(III)化合物；
其中，式(III)中Ar2为未取代的芳烃基或取代的芳烃基、或者杂环基；
这里，所述未取代的芳烃基为苯基，所述取代的芳烃基为取代的苯基；所述取代的苯基是指苯环被一个或两个以上的C1-4烷基、任意个卤代C1-4烷基、C1-4烷氧基、C1-4烷氧羰酰基、羟基、卤素(例如氟、氯、溴、或碘)、氨基、硝基或氰基所取代，而且在苯环上取代的位置没有限定，或者苯环上相邻的两个碳和与其相连的杂原子、亚烷基一起形成5元或6元杂环，其中杂原子为氮或氧且杂原子个数为2个。更优选地，所述取代的苯基选自2-甲基苯基、4-甲基苯基、2,4-二甲基苯基、4-甲氧基苯基、2-甲氧基苯基、3-甲氧基苯基、4-氨基苯基、4-羟基苯基、4-硝基苯基、4-氰基苯基、4-溴代苯基、4-氯代苯基、4-氟代苯基、3,4-二氯代苯基、2,4-二氯代苯基、2,4-二氟代苯基、4-三氟甲基苯基、4-羟基-3-甲氧基苯基、2,4-二甲氧基苯基、2,5-二甲氧基苯基、3,4-二甲氧基苯基、3,5-二甲氧基苯基、2,4,6-三甲氧基苯基、3,4,5-三甲氧基苯基、或3,4-亚乙基二氧苯基。
所述杂环基选自噻吩基、呋喃基、或吡啶基，更优选地为噻吩-2-基、呋喃-2-基、吡啶-2-基、吡啶-3-基、或吡啶-4-基。
在本发明的一种实施方案中，本发明提供的一种上述通式(I)化合物，其选自下列化合物：
(E)-2-(3-苯基-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物1)
(E)-2-(3-(2-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物2)
(E)-2-(3-(3-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物3)
(E)-2-(3-(4-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物4)
(E)-2-(3-(2,4-二甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物5)
(E)-2-(3-(2,5-二甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物6)
(E)-2-(3-(2,4,6-三甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物7)
(E)-2-(3-(3,4,5-三甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物8)
(E)-2-(3-(4-氨基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物9)
(E)-2-(3-(4-羟基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物10)
(E)-2-(3-(4-羟基-3-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物11)
(E)-2-(3-(2-甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物12)
(E)-2-(3-(4-甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物13)
(E)-2-(3-(2,4-二甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物14)
(E)-2-(3-(4-溴苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物15)
(E)-2-(3-(4-氯苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物16)
(E)-2-(3-(3,4-二氯苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物17)
(E)-2-(3-氧代-3-(4-氟苯基)丙-1-烯基)喹唑啉-4(3H)-酮(化合物18)
(E)-2-(3-(2,4-二氟苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物19)
(E)-2-(3-(4-三氟甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物20)
(E)-2-(3-苯基丙烯酰基)喹唑啉-4(3H)-酮(化合物21)
(E)-2-(3-(2-甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物22)
(E)-2-(3-(3-甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物23)
(E)-2-(3-(4-甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物24)
(E)-2-(3-(2,4-二甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物25)
(E)-2-(3-(3,4-二甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物26)
(E)-2-(3-(3,5-二甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物27)
(E)-2-(3-(3,4-亚乙基二氧苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物28)
(E)-2-(3-(3,4,5-三甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物29)
(E)-2-(3-(4-甲基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物30)
(E)-2-(3-(4-溴苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物31)
(E)-2-(3-(4-氯苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物32)
(E)-2-(3-(2,4-二氯苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物33)
(E)-2-(3-(4-氟苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物34)
(E)-2-(3-(4-氰基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物35)
(E)-2-(3-(4-硝基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物36)
(E)-2-(3-(呋喃-2-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物37)
(E)-2-(3-(噻吩-2-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物38)
(E)-2-(3-(吡啶-2-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物39)
(E)-2-(3-(吡啶-3-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物40)
(E)-2-(3-(吡啶-4-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物41)
另一方面，本发明提供了如通式(I)所示含4-氧代喹唑啉-2-基的查耳酮类似物的制备方法，当Ar2为4-氧代喹唑啉-2-基，即为本发明提供的式(I)为式(II)化合物，包括如下步骤：
中间体(IV)与式(VI)化合物在碱性条件下反应，得到式(II)化合物：
式(II)化合物和式(VI)化合物中的取代基Ar1的定义如式(I)化合物；
或者，
当Ar1为4-氧代喹唑啉-2-基，即为本发明提供的式(I)为式(III)化合物，包括如下步骤：
中间体(V)与式(VII)化合物在碱性条件下反应，得到式(III)化合物；
式(III)化合物和式(VII)化合物中的取代基Ar2的定义如式(I)化合物。
在本发明提供的如通式(I)所示含4-氧代喹唑啉-2-基的查耳酮类似物的制备方法中，其中，所述碱性条件是指在无机碱、有机碱存在下，在水或有机溶剂中，或水和有机溶剂的混合液中反应，例如采用氢氧化钾，在甲醇中反应。
在本发明提供的如通式(I)所示含4-氧代喹唑啉-2-基的查耳酮类似物的制备方法中，其中，中间体(IV)可以通过如下路线合成：
如路线3.1所示，以2-氨基苯甲酸甲酯为起始原料，与原乙酸三乙酯和乙酸铵反应，得到2-甲基喹唑啉-4(3H)-酮(VIII)。参考El-Maghraby等[El-Maghraby,M.A.；Koraiem,A.I.M.；AbdEl-Latif,F.M.E.Synthesis,spectralbehaviourandbiologicalactivityofpyrazolo-pyrimidinecyaninedyes.J.Chem.Tech.Biotechnol.1985,35A,63–72]报道的方法，用二氧化硒氧化VIII中的甲基，制得2-甲酰基喹唑啉-4(3H)-酮(IV)。在碱性条件下，使中间体(IV)与不同的苯乙酮类化合物(VI)发生缩合反应，得到喹唑啉酮作为B环的查耳酮类似物(化合物1-20)。
路线3.1.试剂与反应条件:(a)CH3C(OC2H5)3,AcONH4,回流,30h。(b)SeO2,1,4-二氧六环,回流,2h。(c)苯乙酮类化合物(VI，Ar1COCH3)，CH3OH,30％KOH,室温,24h。
在本发明提供的如通式(I)所示含4-氧代喹唑啉-2-基的查耳酮类似物的制备方法中，其中，中间体V可以通过如下路线合成：
如路线3.2所示，将2-氨基苯甲酸甲酯与原丙酸三乙酯、乙酸铵反应，生成2-乙基喹唑啉-4(3H)-酮(IX)。中间体IX用二氧化硒氧化，得到2-乙酰基喹唑啉-4(3H)-酮(V)。在碱性条件下，将中间体V与不同的芳香醛或芳杂醛(VII)发生缩合反应，得到喹唑啉酮作为A环的查耳酮类似物(化合物21-41)。
路线3.2.试剂与反应条件:(a)C2H5C(OC2H5)3,AcONH4,回流,30h。(b)SeO2,1,4-二氧六环,回流,1h。(c)Ar2CHO(VII)，CH3OH,30％KOH,室温,24h。
核磁共振氢谱(1HNMR)显示，在所合成的查耳酮类似物中，所有的C＝C双键均为单一的几何构型，而且两个双键碳上的氢的耦合常数(couplingconstant)为15.6或16.2Hz，因此均为反式构型(E-configuration)。
另一方面，本发明提供了一种包含上述4-氧代喹唑啉-2-基的查耳酮类似物的药用组合物。该药用组合物包括药理学上有效量的式(I)化合物和药学上可接受的辅料。对于本领域技术人员而言，这些辅料都是已知的，例如，生理盐水，明胶，阿拉伯树胶，乳糖，微晶纤维素，淀粉，改性淀粉，纤维素，改性纤维素，羟乙酸钠，磷酸氢钙，硬脂酸镁，滑石，胶体二氧化硅等。此外，这些组合物还可进一步地包含：稳定剂，润湿剂，乳化剂，甜味剂，香味剂，缓冲剂等。
本发明提供的包含上述4-氧代喹唑啉-2-基的查耳酮类似物的药用组合物，根据需要，能够配制成用于口服给药的固体或液体形式，如片剂、丸剂、口服液等；用于非肠道给药的无菌溶液、悬浮液或乳液形式，喷雾剂等。
例如，片剂配方：
制备方法为：将原辅料过100目筛，然后混合均匀；用90％的乙醇制软材，制粒，整粒，加入硬脂酸镁混匀，压片即得。
注射剂配方：
制备方法：
将甘露醇加入1600mL注射用水中，搅拌溶解；将本发明实施例化合物加入上述溶液，搅拌溶解；4％的磷酸氢二钠溶液调pH值为4.15；加注射用水至2000mL，加入活性炭，50℃保温搅拌20min，过滤脱炭；用0.22μm的微孔滤膜过滤，灌封。121℃，15min高温湿热灭菌。
另一方面，本发明提供了式(I)化合物在制备抗肿瘤药物中的应用。本发明的化合物可用于治疗乳腺癌，结肠癌等。
实验证明，本发明的式(I)的化合物具有抗肿瘤活性，对人乳腺癌(MCF-7)、结肠癌(HCT-116)细胞的增殖具有抑制作用，可作为抗肿瘤药物或作为抗肿瘤活性成分用于抗肿瘤药物组合物。
具体实施方式
以下通过实施例来示例性说明本发明的实施方案，对于本领域的普通技术人员而言，在本发明的教导下，根据现有技术，对本发明实施方案进行的改进，仍属于本发明的保护范围内。
熔点用XT5B或X-4型精密显微熔点仪(控温型)测定，温度未校正。核磁共振氢谱(1HNMR)用VarianNMRsystem600MHz超导核磁共振谱仪测定，TMS为内标。高分辨电喷雾质谱(ESI-HRMS)用ThermoScientific的LTQOrbitrap质谱仪测定。
苯乙酮、4-氨基苯乙酮、4-氯苯乙酮、3,4-二氯苯乙酮、4-氟苯乙酮、2,4-二氟苯乙酮、4-硝基苯乙酮、二氧化硒购自天津陶源素公司；4-羟基苯乙酮、4-甲氧基苯乙酮、3-甲氧基苯乙酮、2-甲基苯乙酮、4-溴苯乙酮、4-三氟甲基苯乙酮、(3,4-亚乙基二氧)苯甲醛购自百灵威试剂公司；2-甲氧基苯乙酮、2,5-二甲氧基苯乙酮购自TCI试剂公司；2,4-二甲氧基苯乙酮、2,4,6-三甲氧基苯乙酮、3,4,5-三甲氧基苯乙酮、4-甲基苯乙酮购自Sigma试剂公司；2,4-二甲基苯乙酮购自Damas-beta试剂公司；其它原料均为市售化学试剂。
实施例中使用的人乳腺癌(MCF-7)和结肠癌(HCT-116)和细胞来自首都师范大学DNA损伤应答北京市重点实验室。所有肿瘤细胞株生长于含有10％胎牛血清、2mM谷氨酸盐和5％盘尼西林的培养基(DMEM)中。抗肿瘤活性实验中所使用的CellTiterAQueous单溶液细胞增殖检测试剂盒(CellTiterAQueousOneSolutionCellProliferationAssay(MTS))购于Promega公司。
缩写词：
Ph＝苯基；
Quin＝喹唑啉-4(3H)-酮
DCM＝二氯甲烷；
m.p.＝熔点；
1HNMR＝核磁共振氢谱；
ESI-HRMS＝电喷雾高分辨质谱；
DMSO-d6＝氘代二甲基亚砜；
MTS＝3-(4,5-二甲基噻唑-2-基)-5-(3-(羧基甲氧基苯基)-2-(4-磺酸基苯基)-2H-四氮唑，内盐
准备例1
4-氧代喹唑啉-2-基作为B环的查耳酮类似物(化合物1-20)的合成
2-甲基喹唑啉-4(3H)-酮(VIII)的制备
在反应瓶中加入2-氨基苯甲酸甲酯(6.04g,40mmol)，乙酸铵(7.7g,100mmol)和原乙酸三乙酯(25mL,275mmol)，加热回流反应30h。冷却至室温，滤集析出的固体，干燥，粗品用乙醇重结晶，得白色针状固体4.86g，收率76％，m.p.226-229℃(文献[Okano,M.；Mito,J.；Maruyama,Y.；Masuda,H.；Niwa,T.；Nakagawa,S.；Nakamura,Y.；Matsuura,A.Discoveryandstructure-activityrelationshipsof4-aminoquinazolinederivatives,anovelclassofopioidreceptorlike-1(ORL1)antagonists.Bioorg.Med.Chem.2009,17(1),119–132]m.p.230-232℃)。1HNMR(600MHz,DMSO-d6)δ:2.61(s,2H,CH3),7.65(t,J＝7.8Hz,1H,Quin6-H),7.83(d,J＝7.8Hz,1H,Quin8-H),7.96(t,J＝7.8Hz,1H,Quin7-H),8.16(d,J＝7.8Hz,1H,Quin5-H).ESI-HRMSm/z:C9H9N2O([M+H]+)计算值:161.0715；实测值:161.0708.
2-甲酰基喹唑啉-4(3H)-酮(IV)的制备
将2-甲基喹唑啉-4(3H)-酮(VIII)(0.48g,3mmol)和二氧化硒(0.66g,6mmol)加入到1,4-二氧六环(50mL)中，加热回流2h。反应液冷却至室温，滤除少量黑色不溶物,滤液用5％碳酸氢钠溶液调节pH至中性。滤除析出的固体,滤液用二氯甲烷萃取(15mL×4)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥过夜。旋转蒸发除去溶剂，粗品用甲醇重结晶，得淡黄色固体0.35g，收率67％，m.p.135-138℃(文献[Khalil,Z.H.；Koraiem,A.I.M.；El-Maghraby,M.A.；Abu-El-Hamd,R.M.Synthesis,spectralbehaviorandbiologicalactivityofbenzoxazonyl(quinoxalonyl)benzofurano(indolo)quinolineapocyaninedyes.J.Chem.Technol.Biot.1986,36(8),379–88]m.p.138-140℃)。1HNMR(600MHz,DMSO-d6)δ:7.69(td,J＝7.8,1.2Hz,1H,Quin6-H),7.89(dd,J＝7.8,1.2Hz,1H,Quin8-H),7.94(td,J＝7.8,1.2Hz,1H,Quin7-H),8.21(dd,J＝7.8,1.2Hz,1H,Quin5-H),9.58(s,1H,CHO),12.66(brs,1H,NH).ESI-HRMSm/z:C9H7N2O2([M+H]+)计算值:175.0508；实测值:175.0502.
化合物1-20的合成通法
在100mL圆底烧瓶中，加入不同的苯乙酮(1.1mmol)和甲醇(10mL)，搅拌下加入30％浓度的KOH溶液(1.0mL)，室温搅拌20min。加入2-甲酰基喹唑啉-4(3H)-酮(IV)(0.17g,1mmol)，室温搅拌反应24h。用6mol/L盐酸调节反应液的pH值至6-7，搅拌20min，滤集析出的固体，晾干。粗品用甲醇重结晶，得目标化合物1-20。
实施例1
(E)-2-(3-苯基-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物1)
收率:41％,白色固体,m.p.231-233℃.1HNMR(600MHz,DMSO-d6)δ:7.34(d,J＝16.2Hz,1H,＝CHCO),7.58(t,J＝7.8Hz,1H,Quin6-H),7.64(t,J＝7.8Hz,2H,Ph3'-H,5'-H),7.74(t,J＝7.8Hz,1H,Ph4'-H),7.78(d,J＝7.8Hz,1H,Quin8-H),7.87(td,J＝7.8,1.2Hz,1H,Quin7-H),8.15(d,J＝7.8Hz,2H,Ph2'-H,6'-H),8.17(dd,J＝7.8,1.2Hz,1H,Quin5-H),8.39(d,J＝16.2Hz,1H,＝CH),12.65(s,1H,NH).ESI-HRMSm/z:C17H13N2O2([M+H]+)计算值:277.0977；实测值:277.0972.
实施例2
(E)-2-(3-(2-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物2)
收率:31％,黄色固体,m.p.225-228℃.1HNMR(600MHz,DMSO-d6)δ:3.91(s,1H,OCH3),7.10(t,J＝7.8Hz,1H,Ph5'-H),7.20(d,J＝15.6Hz,1H,＝CHCO),7.25(d,J＝7.8Hz,1H,Ph3'-H),7.56(t,J＝7.8Hz,1H,Quin6-H),7.58(d,J＝7.8Hz,1H,Ph6'-H),7.62(td,J＝7.8,1.2Hz,1H,Ph4'-H),7.74(d,J＝7.8Hz,1H,Quin8-H),7.85(t,J＝7.8Hz,1H,Quin7-H),7.98(d,J＝15.6Hz,1H,＝CH),8.14(d,J＝7.8Hz,1H,Quin5-H),12.58(s,1H,NH).ESI-HRMSm/z:C18H15N2O3([M+H]+)计算值:307.1083；实测值:307.1080.
实施例3
(E)-2-(3-(3-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物3)
收率:30％,白色固体,m.p.236-238℃.1HNMR(600MHz,DMSO-d6)δ:3.87(s,3H,OCH3),7.32(d,J＝7.8Hz,1H,Ph4'-H),7.33(d,J＝15.6Hz,1H,＝CHCO),7.56(t,J＝7.8Hz,1H,Ph5'-H),7.58(t,J＝7.8Hz,1H,Quin6-H),7.61(s,1H,Ph2'-H),7.76(d,J＝7.8Hz,1H,Quin8-H),7.78(d,J＝7.8Hz,1H,Ph6'-H),7.87(t,J＝7.8Hz,1H,Quin7-H),8.17(d,J＝7.8Hz,1H,Quin5-H),8.36(d,J＝15.6Hz,1H,＝CH),12.63(s,1H,NH).ESI-HRMSm/z:C18H15N2O3([M+H]+)计算值:307.1083；实测值:307.1076.
实施例4
(E)-2-(3-(4-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物4)
收率:35％,黄色固体,m.p.239-243℃.1HNMR(600MHz,DMSO-d6)δ:3.90(s,3H,OCH3),7.14(d,J＝9.0Hz,2H,Ph3'-H,5'-H),7.30(d,J＝15.6Hz,1H,＝CHCO),7.58(t,J＝7.8Hz,1H,Quin6-H),7.77(d,J＝7.8Hz,1H,Quin8-H),7.87(td,J＝7.8,1.2Hz,1H,Quin7-H),8.15(d,J＝9.0Hz,2H,Ph2'-H,6'-H),8.17(dd,J＝7.8,1.2Hz,1H,Quin5-H),8.39(d,J＝15.6Hz,1H,＝CH),12.62(s,1H,NH).ESI-HRMSm/z:C18H15N2O3([M+H]+)计算值:307.1083；实测值:307.1074.
实施例5
(E)-2-(3-(2,4-二甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物5)
收率:18％,黄色固体,m.p.185-188℃.1HNMR(600MHz,DMSO-d6)δ:3.88(s,3H,4'-OCH3),3.94(s,3H,2'-OCH3),6.69(dd,J＝8.4,2.4Hz,1H,Ph5'-H),6.73(d,J＝2.4Hz,1H,Ph3'-H),7.22(d,J＝15.6Hz,1H,＝CHCO),7.56(t,J＝7.8Hz,1H,Quin6-H),7.69(d,J＝8.4Hz,1H,Ph6'-H),7.74(d,J＝7.8Hz,1H,Quin8-H),7.85(td,J＝7.8,1.2Hz,1H,Quin7-H),8.14(d,J＝15.6Hz,1H,＝CH),8.14(dd,J＝7.8,1.2Hz,1H,Quin5-H),12.58(s,1H,NH).ESI-HRMSm/z:C19H17N2O4([M+H]+)计算值:337.1188；实测值:337.1184.
实施例6
(E)-2-(3-(2,5-二甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物6)
收率:41％,黄色固体,m.p.185-188℃.1HNMR(600MHz,DMSO-d6)δ:3.77(s,3H,5'-OCH3),3.86(s,3H,2'-OCH3),7.11(m,1H,Ph3'-H),7.19(m,2H,Ph4'-H,6'-H),7.21(d,J＝15.6Hz,1H,＝CHCO),7.56(td,J＝7.8,1.2Hz,1H,Quin6-H),7.74(d,J＝7.8Hz,1H,Quin8-H),7.85(td,J＝7.8,1.2Hz,1H,Quin7-H),7.99(d,J＝15.6Hz,1H,＝CH),8.14(dd,J＝7.8,1.2Hz,1H,Quin5-H),12.58(s,1H,NH).ESI-HRMSm/z:C19H17N2O4([M+H]+)计算值:337.1188；实测值:337.1184.
实施例7
(E)-2-(3-(2,4,6-三甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物7)
收率:50％,黄色固体,m.p.212-214℃.1HNMR(600MHz,DMSO-d6)δ:3.76(s,6H,2'-OCH3,6'-OCH3),3.86(s,3H,4'-OCH3),6.35(s,2H,Ph3'-H,5'-H),6.99(d,J＝16.2Hz,1H,＝CHCO),7.48(d,J＝16.2Hz,1H,＝CH),7.55(td,J＝7.8,1.2Hz,1H,Quin6-H),7.71(d,J＝7.8Hz,1H,Quin8-H),7.84(td,J＝7.8,1.2Hz,1H,Quin7-H),8.12(dd,J＝7.8,1.2Hz,1H,Quin5-H),12.49(s,1H,NH).ESI-HRMSm/z:C20H19N2O5([M+H]+)计算值:367.1294；实测值:367.1292.
实施例8
(E)-2-(3-(3,4,5-三甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物8)
收率:53％,橙红固体,m.p.223-225℃.1HNMR(600MHz,DMSO-d6)δ:3.80(s,3H,4'-OCH3),3.92(s,6H,3'-OCH3,5'-OCH3),7.33(d,J＝15.6Hz,1H,＝CHCO),7.44(s,2H,Ph2'-H,6'-H),7.59(td,J＝7.8,1.2Hz,1H,Quin6-H),7.78(d,J＝7.8Hz,1H,Quin8-H),7.88(td,J＝7.8,1.2Hz,1H,Quin7-H),8.17(dd,J＝7.8,1.2Hz,1H,Quin5-H),8.35(d,J＝15.6Hz,1H,＝CH),12.60(s,1H,NH).ESI-HRMSm/z:C20H19N2O5([M+H]+)计算值:367.1294；实测值:367.1290.
实施例9
(E)-2-(3-(4-氨基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物9)
收率:14％,橙红色固体,m.p.253-256℃.1HNMR(600MHz,DMSO-d6)δ:6.39(s,2H,4'-NH2),6.66(d,J＝8.4Hz,2H,Ph3'-H,5'-H),7.24(d,J＝15.6Hz,1H,＝CHCO),7.57(t,J＝7.8Hz,1H,Quin6-H),7.76(d,J＝7.8Hz,1H,Quin8-H),7.86(t,J＝7.8Hz,1H,Quin7-H),7.91(d,J＝8.4Hz,2H,Ph2'-H,6'-H),8.16(d,J＝7.8Hz,1H,Quin5-H),8.36(d,J＝15.6Hz,1H,＝CH),12.58(s,1H,NH).ESI-HRMSm/z:C17H14N3O2([M+H]+)计算值:292.1086；实测值:292.1083.
实施例10
(E)-2-(3-(4-羟基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物10)
收率:31％,黄色固体,m.p.280-284℃.1HNMR(600MHz,DMSO-d6)δ:6.95(d,J＝7.8Hz,2H,Ph3'-H,5'-H),7.29(d,J＝15.6Hz,1H,＝CHCO),7.58(t,J＝7.2Hz,1H,Quin6-H),7.77(d,J＝7.2Hz,1H,Quin8-H),7.87(t,J＝7.2Hz,1H,Quin7-H),8.06(d,J＝7.8Hz,2H,Ph2'-H,6'-H),8.16(d,J＝7.2Hz,1H,Quin5-H),8.38(d,J＝15.6Hz,1H,＝CH),10.61(s,1H,4'-OH),12.61(s,1H,NH).ESI-HRMSm/z:C17H13N2O3([M+H]+)计算值:293.0926；实测值:293.0922.
实施例11
(E)-2-(3-(4-羟基-3-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物11)
收率:47％,黄色固体,m.p.244-246℃.1HNMR(600MHz,DMSO-d6)δ:3.90(s,3H,OCH3),6.98(d,J＝8.4Hz,1H,Ph5'-H),7.30(d,J＝15.6Hz,1H,＝CHCO),7.57(t,J＝7.8Hz,1H,Quin6-H),7.61(d,J＝1.8Hz,1H,Ph2'-H),7.76(d,J＝7.8,1H,Quin8-H),7.79(dd,J＝8.4,1.8Hz,1H,Ph6'-H),7.86(td,J＝7.8,1.2Hz,1H,Quin7-H),8.16(dd,J＝7.8,1.2Hz,1H,Quin5-H),8.38(d,J＝15.6Hz,1H,＝CH),10.30(s,1H,4'-OH),12.60(s,1H,NH).ESI-HRMSm/z:C18H15N2O4([M+H]+)计算值:323.1032；实测值:323.1031.
实施例12
(E)-2-(3-(2-甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物12)
收率:48％,浅黄色固体,m.p.198-201℃.1HNMR(600MHz,DMSO-d6)δ:2.44(s,3H,CH3),7.16(d,J＝15.6Hz,1H,＝CHCO),7.39(d,J＝7.8Hz,1H,Ph3'-H),7.41(d,J＝7.8Hz,1H,5'-H),7.52(t,J＝7.8Hz,1H,Ph4'-H),7.57(t,J＝7.8Hz,1H,Quin6-H),7.75(d,J＝7.8Hz,1H,Ph6'-H),7.78(d,J＝7.8Hz,1H,Quin8-H),7.86(t,J＝7.8Hz,1H,Quin7-H),7.95(d,J＝15.6Hz,1H,＝CH),8.15(d,J＝7.8Hz,1H,Quin5-H),12.59(s,1H,NH).ESI-HRMSm/z:C18H15N2O2([M+H]+)计算值:291.1134；实测值:291.1128.
实施例13
(E)-2-(3-(4-甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物13)
收率:62％,白色固体,m.p.246-249℃.1HNMR(600MHz,DMSO-d6)δ:2.43(s,3H,CH3),7.32(d,J＝15.6Hz,1H,＝CHCO),7.44(d,J＝7.8Hz,2H,Ph3'-H,5'-H),7.58(t,J＝7.8Hz,1H,Quin6-H),7.77(d,J＝7.8Hz,1H,Quin8-H),7.87(td,J＝7.8,1.2Hz,1H,Quin7-H),8.06(d,J＝7.8Hz,2H,Ph2'-H,6'-H),8.16(d,J＝7.8Hz,1H,Quin5-H),8.39(d,J＝15.6Hz,1H,＝CH),12.64(s,1H,NH).ESI-HRMSm/z:C18H15N2O2([M+H]+)计算值:291.1134；实测值:291.1129.
实施例14
(E)-2-(3-(2,4-二甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物14)
收率:45％,浅黄色固体,m.p.200-202℃.1HNMR(600MHz,DMSO-d6)δ:2.36(s,3H,4'-CH3),2.44(s,3H,2'-CH3),7.17(d,J＝15.6Hz,1H,＝CHCO),7.20(s,1H,Ph3'-H),7.22(d,J＝7.8Hz,1H,Ph5'-H),7.57(td,J＝7.8,1.2Hz,1H,Quin6-H),7.75(d,J＝7.8Hz,1H,Quin8-H),7.76(d,J＝7.8Hz,1H,Ph6'-H),7.86(td,J＝7.8,1.2Hz,1H,Quin7-H),8.01(d,J＝15.6Hz,1H,＝CH),8.15(dd,J＝7.8,1.2Hz,1H,Quin5-H),12.59(s,1H,NH).ESI-HRMSm/z:C19H17N2O2([M+H]+)计算值:305.1290；实测值:305.1287.
实施例15
(E)-2-(3-(4-溴苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物15)
收率:58％,白色固体,m.p.232-234℃.1HNMR(600MHz,DMSO-d6)δ:7.34(d,J＝15.6Hz,1H,＝CHCO),7.59(t,J＝7.8Hz,1H,Quin6-H),7.77(d,J＝7.8Hz,1H,Quin8-H),7.85(d,J＝8.4Hz,2H,Ph3'-H,5'-H),7.87(t,J＝7.8Hz,1H,Quin7-H),8.07(d,J＝8.4Hz,2H,Ph2'-H,6'-H),8.16(d,J＝7.8Hz,1H,Quin5-H),8.34(d,J＝15.6Hz,1H,＝CH),12.63(s,1H,NH).ESI-HRMSm/z:C17H12BrN2O2([M+H]+)计算值:355.0082,357.0062；实测值:355.0080,357.0059.
实施例16
(E)-2-(3-(4-氯苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物16)
收率:28％,白色固体,m.p.231-233℃.1HNMR(600MHz,DMSO-d6)δ:7.33(d,J＝15.6Hz,1H,＝CHCO),7.59(t,J＝7.8Hz,1H,Quin6-H),7.70(d,J＝8.4Hz,2H,Ph3'-H,5'-H),7.77(d,J＝7.8Hz,1H,Quin8-H),7.87(t,J＝7.8Hz,1H,Quin7-H),8.15(d,J＝8.4Hz,2H,Ph2'-H,6'-H),8.16(d,J＝7.8Hz,1H,Quin5-H),8.36(d,J＝15.6Hz,1H,＝CH),12.63(s,1H,NH).ESI-HRMSm/z:C17H11ClN2O2([M+H]+)计算值:311.0587,313.0558；实测值:311.0585,313.0565.
实施例17
(E)-2-(3-(3,4-二氯苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物17)
收率:35％,白色固体,m.p.229-231℃.1HNMR(600MHz,DMSO-d6)δ:7.33(d,J＝15.6Hz,1H,＝CHCO),7.59(t,J＝7.8Hz,1H,Quin6-H),7.78(d,J＝7.8Hz,1H,Quin8-H),7.87(td,J＝7.8,1.2Hz,1H,Quin7-H),7.90(d,J＝8.4Hz,2H,Ph5'-H),8.08(dd,J＝8.4,1.8Hz,1H,Ph6'-H),8.16(d,J＝7.8Hz,1H,Quin5-H),8.33(d,J＝1.8Hz,1H,Ph2'-H),8.33(d,J＝15.6Hz,1H,＝CH),12.61(s,1H,NH).ESI-HRMSm/z:C17H11Cl2N2O2([M+H]+)计算值:345.0198,347.0168；实测值:345.0195,347.0164.
实施例18
(E)-2-(3-氧代-3-(4-氟苯基)丙-1-烯基)喹唑啉-4(3H)-酮(化合物18)
收率:22％,白色固体,m.p.252-254℃.1HNMR(600MHz,DMSO-d6)δ:7.33(d,J＝15.6Hz,1H,＝CHCO),7.47(d,J＝8.4Hz,2H,Ph3'-H,5'-H),7.59(t,J＝7.8Hz,1H,Quin6-H),7.77(d,J＝7.8Hz,1H,Quin8-H),7.87(t,J＝7.8Hz,1H,Quin7-H),8.16(d,J＝7.8Hz,1H,Quin5-H),8.24(dd,J＝8.4,5.4Hz,2H,Ph2'-H,6'-H),8.38(d,J＝15.6Hz,1H,＝CH),12.63(s,1H,NH).ESI-HRMSm/z:C17H12FN2O2([M+H]+)计算值:295.0883；实测值:295.0877.
实施例19
(E)-2-(3-(2,4-二氟苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物19)
收率:35％,浅黄色固体,m.p.204-207℃.1HNMR(600MHz,DMSO-d6)δ:6.97(dd,J＝8.4,1.8Hz,1H,Ph5'-H),7.03(dd,J＝8.4,1.8Hz,1H,Ph6'-H),7.31(d,J＝15.6Hz,1H,＝CHCO),7.57(t,J＝7.8Hz,1H,Quin6-H),7.76(d,J＝7.8Hz,1H,Quin8-H),7.86(t,J＝7.8Hz,1H,Quin7-H),7.91(t,J＝9.0Hz,1H,Ph3'-H),8.10(d,J＝15.6Hz,1H,＝CH),8.15(d,J＝7.8Hz,1H,Quin5-H),12.63(s,1H,NH).ESI-HRMSm/z:C17H11F2N2O2([M+H]+)计算值:313.0789；实测值:313.0787.
实施例20
(E)-2-(3-(4-三氟甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物20)
收率:41％,白色固体,m.p.234-237℃.1HNMR(600MHz,DMSO-d6)δ:7.37(d,J＝15.6Hz,1H,＝CHCO),7.59(t,J＝7.8Hz,1H,Quin6-H),7.77(d,J＝7.8Hz,1H,Quin8-H),7.87(t,J＝7.8Hz,1H,Quin7-H),8.00(d,J＝8.4Hz,2H,Ph3'-H,5'-H),8.16(d,J＝7.8Hz,1H,Quin5-H),8.31(d,J＝8.4Hz,2H,Ph2'-H,6'-H),8.37(d,J＝15.6Hz,1H,＝CH),12.66(s,1H,NH).ESI-HRMSm/z:C18H12F3N2O2([M+H]+)计算值:345.0851；实测值:345.0849.
准备例2
4-氧代喹唑啉-2-基作为A环的查耳酮类似物(化合物21-41)的合成
2-乙基喹唑啉-4(3H)-酮(IX)的制备
在反应瓶中加入2-氨基苯甲酸甲酯(6.04g,40mmol)、乙酸铵(7.70g,100mmol)和原丙酸三乙酯(25mL)，加热至回流30h。冷却至室温，滤集析出的固体，晾干，用乙醇重结晶，得白色固体5.01g，收率72％，m.p.228-229℃(文献[Xu,W.；Fu,H.Aminoacidsasthenitrogen-containingmotifsincopper-catalyzeddominosynthesisofN-heterocycles.J.Org.Chem.2011,76,3846–3852]m.p.229-231℃)。1HNMR(600MHz,DMSO-d6)δ:1.25(t,J＝7.8Hz,3H,CH2CH3),2.63(q,J＝7.8Hz,2H,CH2CH3),7.46(td,J＝7.8,1.2Hz,1H,Quin6-H),7.60(d,J＝7.8Hz,1H,Quin8-H),7.77(td,J＝7.8,1.2Hz,1H,Quin7-H),8.09(dd,J＝7.8,1.2Hz,1H,Quin5-H),12.16(s,1H,NH).ESI-HRMSm/z:C10H11N2O([M+H]+)计算值:175.0871；实测值:175.0865.
2-乙酰基喹唑啉-4(3H)-酮(V)的制备
将2-乙基喹唑啉-4(3H)-酮(IX)(0.52g,3mmol)、二氧化硒(0.66g,6mmol)和1,4-二氧六环(50mL)的混合物加热至沸，回流反应1h。冷却至室温，滤除少量黑色不溶物，用5％碳酸氢钠溶液将滤液调节pH值至7-8。滤除析出的固体，滤液用二氯甲烷萃取(15mL×4)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥过夜。旋转蒸发除去溶剂，粗品用甲醇重结晶，得棕黄色固体0.34g，收率61％，m.p.174-176℃。1HNMR(600MHz,DMSO-d6)δ:2.64(s,3H,CH3CO),7.66(td,J＝7.8,1.2Hz,1H,Quin6-H),7.85(dd,J＝7.8,1.2Hz,1H,Quin8-H),7.91(td,J＝7.8,1.2Hz,1H,Quin7-H),8.19(dd,J＝7.8,1.2Hz,1H,Quin5-H),12.25(s,1H,NH).ESI-HRMSm/z:C10H9N2O2([M+H]+)计算值:189.0664；实测值:189.0658.
目标化合物21-41的合成通法
将2-乙酰基喹唑啉-4(3H)-酮(V)(0.17g,1.0mmol)与甲醇(10mL)混合，加入30％KOH溶液(1.0mL)，搅拌20min，再加入不同的芳香醛或芳杂醛(1.1mmol)，室温搅拌反应24h。用6mol/L盐酸调节反应液的pH值至6-7，搅拌20min，滤集析出的固体，晾干。粗品用甲醇重结晶，得目标化合物21-41。
实施例21
(E)-2-(3-苯基丙烯酰基)喹唑啉-4(3H)-酮(化合物21)
收率:48％,棕色固体,m.p.171-173℃.1HNMR(600MHz,DMSO-d6)δ:7.52(m,3H,Ph3'-H,4'-H,5'-H),7.69(m,1H,Quin6-H),7.87(m,2H,Ph2'-H,6'-H),7.94(d,J＝16.2Hz,1H,＝CHCO),7.95(m,2H,Quin7-H,8-H),8.12(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.2Hz,1H,Quin5-H),12.42(s,1H,NH).ESI-HRMSm/z:C17H13N2O2([M+H]+)计算值:277.0977；实测值:277.0971.
实施例22
(E)-2-(3-(2-甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物22)
收率:39％,棕色固体,m.p.175-178℃.1HNMR(600MHz,DMSO-d6)δ:3.95(s,1H,OCH3),7.08(t,J＝7.8Hz,1H,Ph5'-H),7.17(d,J＝7.8Hz,1H,Ph3'-H),7.52(t,J＝7.8Hz,1H,Ph4'-H),7.68(m,1H,Quin6-H),7.85(d,J＝7.8Hz,1H,Ph6'-H),7.94(m,2H,Quin7-H,8-H),8.17(s,2H,CH＝CH),8.22(d,J＝7.8Hz,1H,Quin5-H),12.37(s,1H,NH).ESI-HRMSm/z:C18H15N2O3([M+H]+)计算值:307.1083；实测值:307.1082.
实施例23
(E)-2-(3-(3-甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物23)
收率:47％,棕色固体,m.p.169-171℃.1HNMR(600MHz,DMSO-d6)δ:3.85(s,3H,OCH3),7.10(dd,J＝7.8,1.2Hz,1H,Ph4’-H),7.44(m,3H,Ph2'-H,5'-H,6'-H),7.69(td,J＝7.8,1.2Hz,1H,Quin6-H),7.91(d,J＝16.2Hz,1H,＝CHCO),7.94(m,2H,Quin7-H,8-H),8.10(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.8Hz,1H,Quin5-H),12.42(s,1H,NH).ESI-HRMSm/z:C18H15N2O3([M+H]+)计算值:307.1083；实测值:307.1080.
实施例24
(E)-2-(3-(4-甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物24)
收率:43％,黄色固体,m.p.189-192℃.1HNMR(600MHz,DMSO-d6)δ:3.85(s,3H,OCH3),7.07(d,J＝8.4Hz,2H,Ph3'-H,5'-H),7.68(m,1H,Quin6-H),7.84(d,J＝8.4Hz,2H,Ph2'-H,6'-H),7.91(d,J＝16.2Hz,1H,＝CHCO),7.93(m,2H,Quin7-H,Quin8-H),7.98(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.8Hz,1H,Quin5-H),12.35(s,1H,NH).ESI-HRMSm/z:C18H15N2O3([M+H]+)计算值:307.1083；实测值:307.1080.
实施例25
(E)-2-(3-(2,4-二甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物25)
收率:46％,黄色固体,m.p.180-182℃.1HNMR(600MHz,DMSO-d6)δ:3.87(s,3H,4'-OCH3),3.95(s,3H,2'-OCH3),6.67(dd,J＝8.4,2.4Hz,1H,5'-H),6.69(d,J＝2.4Hz,1H,Ph3'-H),7.67(m,1H,Quin6-H),7.81(d,J＝8.4Hz,1H,Ph6'-H),7.93(m,2H,Quin7-H,8-H),8.04(d,J＝16.2Hz,1H,＝CHCO),8.12(d,J＝16.2Hz,1H,＝CH),8.21(d,J＝7.8Hz,1H,Quin5-H),12.28(s,1H,NH).ESI-HRMSm/z:C19H17N2O4([M+H]+)计算值:337.1188；实测值:337.1187.
实施例26
(E)-2-(3-(3,4-二甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物26)
收率51％,黄色固体,m.p.184-186℃.1HNMR(600MHz,DMSO-d6)δ:3.85(s,3H,4'-OCH3),3.88(s,3H,3'-OCH3),7.09(d,J＝8.4Hz,1H,Ph5'-H),(dd,J＝8.4,1.8Hz,1H,6'-H),7.46(J＝1.8Hz,1H,Ph2'-H),7.68(m,1H,Quin6-H),7.90(d,J＝16.2Hz,1H,＝CHCO),7.94(m,2H,Quin7-H,8-H),7.97(d,J＝16.2Hz,1H,＝CH),8.21(d,J＝7.8Hz,1H,Quin5-H),12.36(s,1H,NH).ESI-HRMSm/z:C19H17N2O4([M+H]+)计算值:337.1188；实测值:337.1186.
实施例27
(E)-2-(3-(3,5-二甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物27)
收率:51％,棕色固体,m.p.181-185℃.1HNMR(600MHz,DMSO-d6)δ:3.83(s,6H,2OCH3),6.66(t,J＝1.8Hz,1H,Ph4'-H),7.02(d,J＝1.8Hz,2H,Ph2'-H,6'-H),7.68(td,J＝7.8,1.2Hz,1H,Quin6-H),7.86(d,J＝15.6Hz,1H,＝CHCO),7.93(t,J＝7.8Hz,1H,Quin7-H),7.96(d,J＝7.8Hz,1H,Quin8-H),8.07(d,J＝15.6Hz,1H,＝CH),8.22(d,J＝7.8Hz,1H,Quin5-H),12.42(s,1H,NH).ESI-HRMSm/z:C19H17N2O4([M+H]+)计算值:337.1188；实测值:337.1186.
实施例28
(E)-2-(3-(3,4-亚乙基二氧苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物28)
收率:32％,黄色固体,m.p.193-195℃.1HNMR(600MHz,DMSO-d6)δ:4.32(m,4H,OCH2CH2O),6.98(d,J＝8.4Hz,1H,Ph5'-H),7.39(d,J＝8.4Hz,1H,6'-H),7.40(s,1H,Ph2'-H),7.68(td,J＝7.8,1.8Hz,1H,Quin6-H),7.84(d,J＝16.2Hz,1H,＝CHCO),7.94(m,2H,Quin7-H,Quin8-H),7.95(d,J＝16.2Hz,1H,＝CH),8.21(d,J＝7.8Hz,1H,Quin5-H),12.35(s,1H,NH).ESI-HRMSm/z:C19H15N2O4([M+H]+)计算值:335.1032；实测值:335.1025.
实施例29
(E)-2-(3-(3,4,5-三甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物29)
收率:33％,黄色固体,m.p.189-193℃.1HNMR(600MHz,DMSO-d6)δ:3.74(s,3H,4'-OCH3),3.89(s,6H,3'-OCH3,5'-OCH3),7.21(s,2H,Ph2'-H,6'-H),7.68(t,J＝7.8Hz,1H,Quin6-H),7.89(d,J＝15.6Hz,1H,＝CHCO),7.94(m,2H,Quin7-H,8-H),8.01(d,J＝15.6Hz,1H,＝CH),8.22(d,J＝7.8,1H,Quin5-H),12.39(s,1H,NH).ESI-HRMSm/z:C20H19N2O5([M+H]+)计算值:367.1294；实测值:367.1291.
实施例30
(E)-2-(3-(4-甲基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物30)
收率:39％,橙色固体,m.p.186-189℃.1HNMR(600MHz,DMSO-d6)δ:2.38(s,3H,CH3),7.33(d,J＝7.8Hz,2H,Ph3'-H,5'-H),7.68(m,1H,Quin6-H),7.96(d,J＝7.8Hz,2H,Ph2'-H,6'-H),7.91(d,J＝16.2Hz,1H,＝CHCO),7.94(m,2H,Quin7-H,8-H),8.07(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.8,1H,Quin5-H),12.39(s,1H,NH).ESI-HRMSm/z:C18H15N2O2([M+H]+)计算值:291.1134；实测值:291.1132.
实施例31
(E)-2-(3-(4-溴苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物31)
收率:68％,浅黄色固体,m.p.202-205℃.1HNMR(600MHz,DMSO-d6)δ:7.69(m,1H,Quin6-H),7.71(d,J＝8.4Hz,2H,Ph3'-H,5'-H),7.83(d,J＝8.4Hz,2H,Ph2'-H,6'-H),7.91(d,J＝16.2Hz,1H,＝CHCO),7.94(m,2H,Quin7-H,8-H),8.12(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.8,1H,Quin5-H),12.43(s,1H,NH).ESI-HRMSm/z:C17H12BrN2O2([M+H]+)计算值:355.0082,357.0062；实测值:355.0076,357.0060.
实施例32
(E)-2-(3-(4-氯苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物32)
收率:46％,浅黄色固体,m.p.198-201℃.1HNMR(600MHz,DMSO-d6)δ:7.57(d,J＝8.4Hz,2H,Ph3'-H,5'-H),7.69(m,1H,Quin6-H),7.91(d,J＝8.4Hz,2H,Ph2'-H,6'-H),7.92(m,3H,Quin7-H,8-H,＝CHCO),8.11(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.8,1H,Quin5-H),12.43(s,1H,NH).ESI-HRMSm/z:C17H12ClN2O2([M+H]+)计算值:311.0587,313.0558；实测值:311.0587,313.0569.
实施例33
(E)-2-(3-(2,4-二氯苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物33)
收率:69％,粉色固体,m.p.200-202℃.1HNMR(600MHz,DMSO-d6)δ:7.58(dd,J＝8.4,1.8Hz,1H,Ph5'-H),7.69(td,J＝7.8,1.2Hz,1H,Quin6-H),7.82(d,J＝1.8Hz,1H,Ph3'-H),7.92(d,J＝7.8Hz,1H,Quin8-H),7.94(td,J＝7.8,1.2Hz,1H,Quin7-H),8.12(d,J＝16.2Hz,1H,＝CHCO),8.13(d,J＝8.4Hz,1H,Ph6’-H),8.17(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.8,1H,Quin5-H),12.49(s,1H,NH).ESI-HRMSm/z:C17H11Cl2N2O2([M+H]+)计算值:345.1884,347.0168；实测值:345.0193,347.0165.
实施例34
(E)-2-(3-(4-氟苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物34)
收率:31％,粉色固体,m.p.189-193℃.1HNMR(600MHz,DMSO-d6)δ:7.35(d,J＝8.4Hz,2H,Ph3'-H,5'-H),7.68(m,1H,Quin6-H),7.94(d,J＝16.2Hz,1H,＝CHCO),7.95(m,4H,Ph2'-H,6'-H,Quin7-H,8-H),8.06(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.8Hz,1H,Quin5-H),12.41(s,1H,NH).ESI-HRMSm/z:C17H12FN2O2([M+H]+)计算值:295.0883；实测值:295.0882.
实施例35
(E)-2-(3-(4-氰基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物35)
收率:61％,粉色固体,m.p.200-202℃.1HNMR(600MHz,DMSO-d6)δ:7.69(m,1H,Quin6-H),7.95(m,3H,＝CHCO,Quin7-H,8-H),7.96(d,J＝7.8Hz,2H,Ph2'-H,6'-H),8.06(d,J＝7.8Hz,2H,Ph3'-H,5'-H),8.21(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.8Hz,1H,Quin5-H),12.48(s,1H,NH).ESI-HRMSm/z:C18H12N3O2([M+H]+)计算值:302.0930；实测值:302.0926.
实施例36
(E)-2-(3-(4-硝基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物36)
收率:69％,浅黄色固体,m.p.206-209℃.1HNMR(600MHz,DMSO-d6)δ:7.70(m,1H,Quin6-H),7.95(m,2H,Quin7-H,8-H),8.01(d,J＝16.2Hz,1H,＝CHCO),8.15(d,J＝8.4Hz,2H,Ph2'-H,6'-H),8.23(d,J＝8.4,1H,Quin5-H),8.25(d,J＝16.2Hz,1H,＝CH),8.32(d,J＝8.4Hz,2H,Ph3'-H,5'-H),12.50(s,1H,NH).ESI-HRMSm/z:C17H12N3O4([M+H]+)计算值:322.0828；实测值:322.0826.
实施例37
(E)-2-(3-(呋喃-2-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物37)
收率:65％,黄色固体,m.p.187-190℃.1HNMR(600MHz,DMSO-d6)δ:6.75(dd,J＝6.0,1.8Hz,1H,furan-2-yl4'-H),7.20(d,J＝5.4Hz,1H,furan-2-yl3'-H),7.68(td,J＝7.8,1.8Hz,1H,Quin6-H),7.73(d,J＝15.6Hz,1H,＝CHCO),7.87(d,J＝15.6Hz,1H,＝CH),7.93(m,2H,Quin7-H,8-H),8.01(d,J＝1.2Hz,1H,furan-2-yl5'-H),8.21(d,J＝7.8,1H,Quin5-H),12.36(s,1H,NH).ESI-HRMSm/z:C15H11N2O3([M+H]+)计算值:267.0770；实测值:267.0764.
实施例38
(E)-2-(3-(噻吩-2-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物38)
收率:37％,棕色固体,m.p.174-177℃.1HNMR(600MHz,DMSO-d6)δ:7.25(dd,J＝4.8,3.6Hz,1H,thiophen-2-yl4'-H),7.67(m,1H,Quin6-H),7.76(d,J＝4.8Hz,1H,thiophen-2-yl3'-H),7.80(d,J＝15.6Hz,1H,＝CHCO),7.88(d,J＝5.4Hz,1H,thiophen-2-yl5'-H),7.93(m,2H,Quin7-H,8-H),8.12(d,J＝15.6Hz,1H,＝CH),8.21(d,J＝7.8,1H,Quin5-H),12.38(s,1H,NH).ESI-HRMSm/z:C15H11N2O2S([M+H]+)计算值:283.0541；实测值:283.0537.
实施例39
(E)-2-(3-(吡啶-2-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物39)
收率:28％,橙色固体,m.p.190-192℃.1HNMR(600MHz,DMSO-d6)δ:7.50(dd,J＝7.8,4.8Hz,1H,pyridin-2-yl5'-H),7.69(td,J＝7.8,1.2Hz,1H,Quin6-H),7.85(d,J＝7.8Hz,1H,pyridin-2-yl3'-H),7.91(d,J＝15.6Hz,1H,＝CHCO),7.94(m,2H,Quin7-H,8-H),7.96(m,1H,pyridin-2-yl4'-H),8.22(d,J＝7.8,1H,Quin5-H),8.51(d,J＝15.6Hz,1H,＝CH),8.75(d,J＝4.8Hz,1H,pyridin-2-yl6'-H),12.44(s,1H,NH).ESI-HRMSm/z:C16H12N3O2([M+H]+)计算值:278.0930；实测值:278.0925.
实施例40
(E)-2-(3-(吡啶-3-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物40)
收率:48％,棕色固体,m.p.197-200℃.1HNMR(600MHz,DMSO-d6)δ:7.54(t,J＝6.0Hz,1H,pyridin-3-yl5'-H),7.69(m,1H,Quin6-H),7.94(m,2H,Quin7-H,8-H),7.97(d,J＝16.2Hz,1H,＝CHCO),8.21(d,J＝16.2Hz,1H,＝CH),8.22(d,J＝7.8,1H,Quin5-H),8.34(d,J＝7.8Hz,1H,pyridin-3-yl6'-H),8.67(d,J＝4.2Hz,1H,pyridin-3-yl4'-H),9.01(s,1H,pyridin-3-yl2'-H),12.47(s,1H,NH).ESI-HRMSm/z:C16H12N3O2([M+H]+)计算值:278.0930；实测值:278.0927.
实施例41
(E)-2-(3-(吡啶-4-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物41)
收率:19％,棕色固体,m.p.218-220℃.1HNMR(600MHz,DMSO-d6)δ:7.70(m,1H,Quin6-H),7.81(d,J＝6.0Hz,2H,pyridin-4-yl2'-H,6'-H),7.88(d,J＝16.2Hz,1H,＝CHCO),7.95(m,2H,Quin7-H,8-H),8.23(d,J＝7.8,1H,Quin5-H),8.28(d,J＝16.2Hz,1H,＝CH),8.72(d,J＝6.0Hz,2H,pyridin-4-yl3'-H,5'-H),12.51(s,1H,NH).ESI-HRMSm/z:C16H12N3O2([M+H]+)计算值:278.0930；实测值:278.0927.
试验例
抗增殖活性
采用下述的MTS比色法测定了本发明式(I)化合物对人结肠癌HCT-116和人乳腺癌MCF-7细胞增殖的半抑制浓度(IC50)，5-氟尿嘧啶(5-FU)做为阳性对照。
所有肿瘤细胞株生长于含有10％胎牛血清、2mM谷氨酸盐和5％盘尼西林的培养基(DMEM)中。
选用指数生长期的贴壁肿瘤细胞，经胰蛋白酶消化后，用含10％小牛血清的RPMI1640培养液配成5×104～10×104个细胞/mL的细胞悬液，接种在96孔培养板所设的实验孔中，每孔加入90μL，同时设置本底孔(即加入90μL培养液)。于37℃，5％CO2环境下培养24h。配制样品溶液时，将各化合物用培养液配制为不同浓度的溶液，对照组为含2％DMSO的培养液。于样品孔中加入10μL样品溶液，对照孔中加入10μL含2％DMSO的培养液，本底孔中加入10μL培养液，每孔设置3个复孔，于37℃，5％CO2下培养72h。向各孔中加入20μLMTS溶液(Promega公司的CellTiterAQueous单溶液细胞增殖检测试剂盒)，37℃继续培养2h。用酶联免疫检测仪测定各孔在波长492nm处的光密度(OD)值。按如下公式计算细胞增殖抑制率(InhibitionRate，IR％)，然后用SPSS数理统计软件求出半数抑制浓度(IC50值)，结果见表1和表2。以同样方法获得5-氟尿嘧啶的IC50值，数值列在表1和2中。
IR％＝[1－(OD样品组－OD本底组)/(OD对照组－OD本底组)]×100％
表1.本发明化合物(II)对HCT-116和MCF-7细胞的抗增殖活性(IC50,μM)
表2.化合物(III)对HCT-116和MCF-7细胞的抗增殖活性(IC50,μM)
在喹唑啉的C5或C6位进行修饰，所得衍生物主要通过抑制叶酸依赖性酶(如胸苷酸合成酶、二氢叶酸还原酶等)，干扰细胞的叶酸代谢和一碳代谢，从而发挥抗肿瘤活性，代表药物有甲氨蝶呤、雷替曲塞和AG337等。它们可看作是叶酸的类似物，起到细胞还原叶酸辅酶的拮抗剂的作用，也称为抗叶酸剂(antifolates)。根据喹唑啉侧链结构是否还有L-谷氨酸残基，可分为经典型抗叶酸剂和非经典型抗叶酸剂。
本发明化合物在喹唑啉的C2位进行结构修饰和衍化，所得到的含4-氧代喹唑啉-2-基的查耳酮类似物，并非通过抑制胸苷酸合成酶、二氢叶酸还原酶活性而发挥抗增殖作用。细胞生物学、分子生物学实验和微管蛋白聚合试验(Tublinpolymerizationassay，Cat.#BK006P,Versinon1.2，1/7/2011,www.cytoskeleton.com)结果表明，本发明化合物的作用靶点为微管蛋白聚合，通过干扰细胞有丝分裂而产生细胞毒活性。而且，本发明的化合物不仅对MCF-7和HCT-116细胞具有抗增殖活性，对耐药的肿瘤细胞株也具有抗增殖活性。
综上所述，以上仅为本发明的较佳实施例而已，并非用于限定本发明的保护范围，因此，凡在本发明的精神和原则之内所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.含4-氧代喹唑啉-2-基的查耳酮类似物，如通式(I)所示：
其中，式(I)中Ar1和Ar2中的一个为4-氧代喹唑啉-2-基，即：
Ar1和Ar2中的另一个为未取代的芳烃基或取代的芳烃基、或者杂环基。
2.根据权利要求1所述的查耳酮类似物，其中，式(I)为下列式(II)化合物：
其中，式(II)中Ar1的定义如权利要求1式(I)化合物。
3.根据权利要求1所述的查耳酮类似物，其中，式(I)为下列式(III)化合物：
其中，式(III)中Ar2的定义如权利要求1式(I)化合物。
4.根据权利要求1至3中任一权利要求所述的查耳酮类似物，其中，所述未取代的芳烃基为苯基，所述取代的芳烃基为取代的苯基；所述取代的苯基是指苯环被一个或两个以上的C1-4烷基、任意个卤代C1-4烷基、C1-4烷氧基、C1-4烷氧羰酰基、羟基、卤素(例如氟、氯、溴、或碘)、氨基、单C1-4烷基取代的氨基、双C1-4烷基取代的氨基、硝基或氰基所取代，而且在苯环上取代的位置没有限定，或者苯环上相邻的两个碳和与其相连的杂原子、亚烷基一起形成5元或6元杂环，其中杂原子为氮或氧且杂原子个数为2个。
5.根据权利要求4所述的查耳酮类似物，其中，所述取代的苯基选自2-甲基苯基、4-甲基苯基、2,4-二甲基苯基、4-甲氧基苯基、2-甲氧基苯基、3-甲氧基苯基、4-氨基苯基、4-羟基苯基、4-硝基苯基、4-氰基苯基、4-溴代苯基、4-氯代苯基、4-氟代苯基、4-二甲胺基苯基、2-氟代苯基、4-乙氧酰苯基、4-羧基苯基、3,4-二氯代苯基、2,4-二氯代苯基、2,4-二氟代苯基、2,3,4,5,6-五氟苯基、4-三氟甲基苯基、4-羟基-3-甲氧基苯基、2,4-二甲氧基苯基、2,5-二甲氧基苯基、3,4-二甲氧基苯基、3,5-二甲氧基苯基、2,4,6-三甲氧基苯基、3,4,5-三甲氧基苯基、或3,4-亚乙基二氧苯基。
6.根据权利要求1至3中任一权利要求所述的查耳酮类似物，其中，所述杂环基选自噻吩基、呋喃基、或吡啶基。
7.根据权利要求6所述的查耳酮类似物，其中，所述杂环基选自噻吩-2-基、呋喃-2-基、吡啶-2-基、吡啶-3-基、或吡啶-4-基。
8.如权利要求1所述的查耳酮类似物，选自化合物中的一种：
(E)-2-(3-苯基-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物1)
(E)-2-(3-(2-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物2)
(E)-2-(3-(3-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物3)
(E)-2-(3-(4-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物4)
(E)-2-(3-(2,4-二甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物5)
(E)-2-(3-(2,5-二甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物6)
(E)-2-(3-(2,4,6-三甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物7)
(E)-2-(3-(3,4,5-三甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物8)
(E)-2-(3-(4-氨基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物9)
(E)-2-(3-(4-羟基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物10)
(E)-2-(3-(4-羟基-3-甲氧基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物11)
(E)-2-(3-(2-甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物12)
(E)-2-(3-(4-甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物13)
(E)-2-(3-(2,4-二甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物14)
(E)-2-(3-(4-溴苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物15)
(E)-2-(3-(4-氯苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物16)
(E)-2-(3-(3,4-二氯苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物17)
(E)-2-(3-氧代-3-(4-氟苯基)丙-1-烯基)喹唑啉-4(3H)-酮(化合物18)
(E)-2-(3-(2,4-二氟苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物19)
(E)-2-(3-(4-三氟甲基苯基)-3-氧代丙-1-烯基)喹唑啉-4(3H)-酮(化合物20)
(E)-2-(3-苯基丙烯酰基)喹唑啉-4(3H)-酮(化合物21)
(E)-2-(3-(2-甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物22)
(E)-2-(3-(3-甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物23)
(E)-2-(3-(4-甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物24)
(E)-2-(3-(2,4-二甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物25)
(E)-2-(3-(3,4-二甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物26)
(E)-2-(3-(3,5-二甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物27)
(E)-2-(3-(3,4-亚乙基二氧苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物28)
(E)-2-(3-(3,4,5-三甲氧基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物29)
(E)-2-(3-(4-甲基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物30)
(E)-2-(3-(4-溴苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物31)
(E)-2-(3-(4-氯苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物32)
(E)-2-(3-(2,4-二氯苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物33)
(E)-2-(3-(4-氟苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物34)
(E)-2-(3-(4-氰基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物35)
(E)-2-(3-(4-硝基苯基)丙烯酰基)喹唑啉-4(3H)-酮(化合物36)
(E)-2-(3-(呋喃-2-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物37)
(E)-2-(3-(噻吩-2-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物38)
(E)-2-(3-(吡啶-2-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物39)
(E)-2-(3-(吡啶-3-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物40)
(E)-2-(3-(吡啶-4-基)丙烯酰基)喹唑啉-4(3H)-酮(化合物41)。
9.一种包含权利要求1至8中任一权利要求所述查耳酮类似物的药用组合物。
10.如权利要求1至8中任一权利要求所述的查耳酮类似物或如权利要求9所述的药用组合物在制备抗癌药物中的应用。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590806A (zh) * | 2019-09-27 | 2019-12-20 | 深圳大学 | 含噻吩并[2,3-d]嘧啶-2-基的查耳酮类似物及其制备方法和用途 |
| CN116410184A (zh) * | 2023-04-07 | 2023-07-11 | 西南大学 | 喹唑酮烯酮唑类化合物及其制备方法和应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1964946A (zh) * | 2004-04-12 | 2007-05-16 | 托伦脱药品有限公司 | 作为hsp 70诱导物的2－丙烯－1－酮 |
| WO2007132945A1 (ja) * | 2006-05-17 | 2007-11-22 | Sumitomo Chemical Company, Limited | シンナモイル化合物及びその用途 |
| CN104803927A (zh) * | 2015-03-31 | 2015-07-29 | 首都师范大学 | 含2-甲基-4-氧代喹唑啉-6-基的查耳酮类似物及其制备方法和用途 |
-
2016
- 2016-01-07 CN CN201610009022.3A patent/CN105503745B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1964946A (zh) * | 2004-04-12 | 2007-05-16 | 托伦脱药品有限公司 | 作为hsp 70诱导物的2－丙烯－1－酮 |
| WO2007132945A1 (ja) * | 2006-05-17 | 2007-11-22 | Sumitomo Chemical Company, Limited | シンナモイル化合物及びその用途 |
| CN104803927A (zh) * | 2015-03-31 | 2015-07-29 | 首都师范大学 | 含2-甲基-4-氧代喹唑啉-6-基的查耳酮类似物及其制备方法和用途 |
Non-Patent Citations (4)
| Title |
|---|
| ACS: "CAS RN：107833-51-2", 《STN-REGISTRY数据库》 * |
| ACS: "CAS RN：234103-64-1", 《STN-REGISTRY数据库》 * |
| ALY, A. A.: "Synthesis of novel quinazoline derivatives as antimicrobial agents", 《CHINESE JOURNAL OF CHEMISTRY》 * |
| 曹胜利，等: "4(3H)-喹唑啉酮芳胺衍生物的合成及其抗肿瘤活性评价", 《应用化学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590806A (zh) * | 2019-09-27 | 2019-12-20 | 深圳大学 | 含噻吩并[2,3-d]嘧啶-2-基的查耳酮类似物及其制备方法和用途 |
| CN116410184A (zh) * | 2023-04-07 | 2023-07-11 | 西南大学 | 喹唑酮烯酮唑类化合物及其制备方法和应用 |
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