CN110590806B - 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 - Google Patents
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 Download PDFInfo
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- CN110590806B CN110590806B CN201910925935.3A CN201910925935A CN110590806B CN 110590806 B CN110590806 B CN 110590806B CN 201910925935 A CN201910925935 A CN 201910925935A CN 110590806 B CN110590806 B CN 110590806B
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- Prior art keywords
- thieno
- methyl
- pyrimidin
- oxo
- acryloyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001788 chalcone derivatives Chemical class 0.000 title claims abstract 11
- -1 thieno [2,3-d ] pyrimidine-2-yl Chemical group 0.000 title claims description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
- 230000000259 anti-tumor effect Effects 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- IOZWTNNVPCLNQS-VOTSOKGWSA-N 2-[(E)-3-(4-bromophenyl)-3-oxoprop-1-enyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound BrC1=CC=C(C=C1)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O IOZWTNNVPCLNQS-VOTSOKGWSA-N 0.000 claims description 5
- JYRNCBDKVCGQQI-QPJJXVBHSA-N 2-[(E)-3-(4-bromophenyl)prop-2-enoyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound BrC1=CC=C(C=C1)/C=C/C(=O)C=1NC(C2=C(N=1)SC(=C2)C)=O JYRNCBDKVCGQQI-QPJJXVBHSA-N 0.000 claims description 5
- JRGLONFIKNLPJX-VOTSOKGWSA-N 2-[(E)-3-(4-fluorophenyl)-3-oxoprop-1-enyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound FC1=CC=C(C=C1)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O JRGLONFIKNLPJX-VOTSOKGWSA-N 0.000 claims description 5
- JLXNMACOODBNKE-VOTSOKGWSA-N 6-methyl-2-[(E)-3-(4-nitrophenyl)-3-oxoprop-1-enyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)\C=C\C(=O)C2=CC=C(C=C2)[N+](=O)[O-])S1 JLXNMACOODBNKE-VOTSOKGWSA-N 0.000 claims description 5
- LOFFQCFTGRYXJH-AATRIKPKSA-N 6-methyl-2-[(E)-3-oxo-3-pyridin-2-ylprop-1-enyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)\C=C\C(C2=NC=CC=C2)=O)S1 LOFFQCFTGRYXJH-AATRIKPKSA-N 0.000 claims description 5
- WJNWZOKETVFTQR-SNAWJCMRSA-N 6-methyl-2-[(E)-3-oxo-3-pyridin-3-ylprop-1-enyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)\C=C\C(C=2C=NC=CC=2)=O)S1 WJNWZOKETVFTQR-SNAWJCMRSA-N 0.000 claims description 5
- WCIGWDCZXPJLAR-AATRIKPKSA-N 6-methyl-2-[(E)-3-pyridin-2-ylprop-2-enoyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)C(\C=C\C2=NC=CC=C2)=O)S1 WCIGWDCZXPJLAR-AATRIKPKSA-N 0.000 claims description 5
- MOKANQJRAFMCRV-SNAWJCMRSA-N 6-methyl-2-[(E)-3-pyridin-3-ylprop-2-enoyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)C(\C=C\C=2C=NC=CC=2)=O)S1 MOKANQJRAFMCRV-SNAWJCMRSA-N 0.000 claims description 5
- 239000003814 drug Substances 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
- BYSZXTMMJQOQHE-VOTSOKGWSA-N 2-[(E)-3-(2,4-dimethoxyphenyl)-3-oxoprop-1-enyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound COC1=C(C=CC(=C1)OC)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O BYSZXTMMJQOQHE-VOTSOKGWSA-N 0.000 claims description 4
- RKCDDPIPVWNIGJ-FNORWQNLSA-N 2-[(E)-3-(2,4-dimethoxyphenyl)prop-2-enoyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound COC1=C(C=CC(=C1)OC)/C=C/C(=O)C=1NC(C2=C(N=1)SC(=C2)C)=O RKCDDPIPVWNIGJ-FNORWQNLSA-N 0.000 claims description 4
- FYXKKUPTZJXJQK-QPJJXVBHSA-N 2-[(E)-3-(4-fluorophenyl)prop-2-enoyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound FC1=CC=C(C=C1)/C=C/C(=O)C=1NC(C2=C(N=1)SC(=C2)C)=O FYXKKUPTZJXJQK-QPJJXVBHSA-N 0.000 claims description 4
- DCTZSAVUAVALFC-AATRIKPKSA-N 2-[(E)-3-(4-hydroxy-3-methoxyphenyl)-3-oxoprop-1-enyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound OC1=C(C=C(C=C1)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O)OC DCTZSAVUAVALFC-AATRIKPKSA-N 0.000 claims description 4
- IWWMMTRMGILSSC-GQCTYLIASA-N 2-[(E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound OC1=C(C=C(C=C1)/C=C/C(=O)C=1NC(C2=C(N=1)SC(=C2)C)=O)OC IWWMMTRMGILSSC-GQCTYLIASA-N 0.000 claims description 4
- VOWGMFLXRTVMRO-BQYQJAHWSA-N 2-[(E)-3-(4-methoxyphenyl)-3-oxoprop-1-enyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound COC1=CC=C(C=C1)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O VOWGMFLXRTVMRO-BQYQJAHWSA-N 0.000 claims description 4
- ZFWRXUVQOZIAKW-VMPITWQZSA-N 2-[(E)-3-(4-methoxyphenyl)prop-2-enoyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound COC1=CC=C(C=C1)/C=C/C(=O)C=1NC(C2=C(N=1)SC(=C2)C)=O ZFWRXUVQOZIAKW-VMPITWQZSA-N 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([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
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 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
- 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
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 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
- IFOUURRLFSKRIZ-AATRIKPKSA-N 6-methyl-2-[(E)-3-(2,4,6-trimethoxyphenyl)prop-2-enoyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)C(\C=C\C2=C(C=C(C=C2OC)OC)OC)=O)S1 IFOUURRLFSKRIZ-AATRIKPKSA-N 0.000 claims description 4
- VZUDUBFNFWLBRY-AATRIKPKSA-N 6-methyl-2-[(E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)C(\C=C\C2=CC(=C(C(=C2)OC)OC)OC)=O)S1 VZUDUBFNFWLBRY-AATRIKPKSA-N 0.000 claims description 4
- SEPUNVAIODJRGS-QPJJXVBHSA-N 6-methyl-2-[(E)-3-(4-nitrophenyl)prop-2-enoyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)C(\C=C\C2=CC=C(C=C2)[N+](=O)[O-])=O)S1 SEPUNVAIODJRGS-QPJJXVBHSA-N 0.000 claims description 4
- ICRNVIMBBWCVRK-AATRIKPKSA-N 6-methyl-2-[(E)-3-oxo-3-(2,4,6-trimethoxyphenyl)prop-1-enyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound COC1=C(C(=CC(=C1)OC)OC)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O ICRNVIMBBWCVRK-AATRIKPKSA-N 0.000 claims description 4
- LLENJWUOBDZAOK-AATRIKPKSA-N 6-methyl-2-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-enyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound COC=1C=C(C=C(C=1OC)OC)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O LLENJWUOBDZAOK-AATRIKPKSA-N 0.000 claims description 4
- ICUCQDADJGOXBU-BQYQJAHWSA-N 6-methyl-2-[(E)-3-oxo-3-phenylprop-1-enyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)\C=C\C(C2=CC=CC=C2)=O)S1 ICUCQDADJGOXBU-BQYQJAHWSA-N 0.000 claims description 4
- WOZWQGUCYXTYOI-NSCUHMNNSA-N 6-methyl-2-[(E)-3-oxo-3-pyridin-4-ylprop-1-enyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)\C=C\C(C2=CC=NC=C2)=O)S1 WOZWQGUCYXTYOI-NSCUHMNNSA-N 0.000 claims description 4
- LFOMZCQXMYCROE-NSCUHMNNSA-N 6-methyl-2-[(E)-3-pyridin-4-ylprop-2-enoyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)C(\C=C\C2=CC=NC=C2)=O)S1 LFOMZCQXMYCROE-NSCUHMNNSA-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
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002541 furyl group Chemical group 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
- 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
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- YVSOJBZWCDGAOI-VOTSOKGWSA-N 2-[(E)-3-(4-chlorophenyl)-3-oxoprop-1-enyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound ClC1=CC=C(C=C1)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O YVSOJBZWCDGAOI-VOTSOKGWSA-N 0.000 claims description 3
- DTPUYLRSQONBFU-QPJJXVBHSA-N 2-[(E)-3-(4-chlorophenyl)prop-2-enoyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound ClC1=CC=C(C=C1)/C=C/C(=O)C=1NC(C2=C(N=1)SC(=C2)C)=O DTPUYLRSQONBFU-QPJJXVBHSA-N 0.000 claims description 3
- DNMWIBOJAVLLMW-SNAWJCMRSA-N 2-[(E)-3-(furan-2-yl)-3-oxoprop-1-enyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound O1C(=CC=C1)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O DNMWIBOJAVLLMW-SNAWJCMRSA-N 0.000 claims description 3
- GGDWQSRWAMDAIV-SNAWJCMRSA-N 2-[(E)-3-(furan-2-yl)prop-2-enoyl]-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound O1C(=CC=C1)/C=C/C(=O)C=1NC(C2=C(N=1)SC(=C2)C)=O GGDWQSRWAMDAIV-SNAWJCMRSA-N 0.000 claims description 3
- QQGCQAFOZLYNIR-BQYQJAHWSA-N 6-methyl-2-[(E)-3-(4-methylphenyl)-3-oxoprop-1-enyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC=C(C=C1)C(/C=C/C=1NC(C2=C(N=1)SC(=C2)C)=O)=O QQGCQAFOZLYNIR-BQYQJAHWSA-N 0.000 claims description 3
- AYLBKMFSWXXEJF-BQYQJAHWSA-N 6-methyl-2-[(E)-3-(4-methylphenyl)prop-2-enoyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC=C(C=C1)/C=C/C(=O)C=1NC(C2=C(N=1)SC(=C2)C)=O AYLBKMFSWXXEJF-BQYQJAHWSA-N 0.000 claims description 3
- HFQCZRGXQRLGPS-SNAWJCMRSA-N 6-methyl-2-[(E)-3-oxo-3-thiophen-2-ylprop-1-enyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)\C=C\C(C=2SC=CC=2)=O)S1 HFQCZRGXQRLGPS-SNAWJCMRSA-N 0.000 claims description 3
- GZJAWRKJOTVVCM-SNAWJCMRSA-N 6-methyl-2-[(E)-3-thiophen-2-ylprop-2-enoyl]-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound CC1=CC2=C(N=C(NC2=O)C(\C=C\C=2SC=CC=2)=O)S1 GZJAWRKJOTVVCM-SNAWJCMRSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 230000005764 inhibitory process Effects 0.000 abstract description 8
- 206010006187 Breast cancer Diseases 0.000 abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 6
- 206010009944 Colon cancer Diseases 0.000 abstract description 6
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 6
- 206010008342 Cervix carcinoma Diseases 0.000 abstract description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 abstract description 5
- 201000010881 cervical cancer Diseases 0.000 abstract description 5
- 201000007270 liver cancer Diseases 0.000 abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 4
- 201000005202 lung cancer Diseases 0.000 abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 abstract description 4
- 230000035755 proliferation Effects 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 116
- 210000004027 cell Anatomy 0.000 description 48
- 239000007787 solid Substances 0.000 description 48
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 33
- 150000001789 chalcones Chemical class 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
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- 230000015572 biosynthetic process Effects 0.000 description 12
- 230000001472 cytotoxic effect Effects 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 108010022394 Threonine synthase Proteins 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
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- 235000005513 chalcones Nutrition 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 229930192474 thiophene Natural products 0.000 description 6
- 102000005497 Thymidylate Synthase Human genes 0.000 description 5
- 230000001028 anti-proliverative effect Effects 0.000 description 5
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Abstract
本发明公开了含噻吩并[2,3‑d]嘧啶‑2‑基的查耳酮类似物,如通式(I)所示,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)所示的化合物不仅对人乳腺癌(MFC‑7和MDA‑MB‑231)、人宫颈癌(HeLa)、人结肠癌(HCT‑116和HT‑29)和人肺癌细胞株(A549)细胞的增殖具有抑制作用,而且对人肝癌细胞株(HepG2)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,及其制备方法和它们在抗肿瘤药物中的应用。
背景技术
噻吩并[2,3-d]嘧啶是一个重要的杂环母体,其衍生物在抗肿瘤药物研究中引起了广泛的关注(Aly,A.A.;Ishak,E.A.;Ramadan,M.;Germoush,M.O.;El-Emary,T.I.;Al-Muaikel,N.S.Recent report on thieno[2,3-d]pyrimidines.Their preparationincluding microwave and their utilities in fused heterocycles synthesis.J.Heterocycl.Chem.2013,50,451-472)。在噻吩并[2,3-d]嘧啶的C5或C6位引入侧链,所得衍生物具有叶酸拮抗剂的作用及抗肿瘤活性。例如,Gangjee等合成了在C5位连有L-谷氨酸残基或者疏水性侧链的噻吩并[2,3-d]嘧啶衍生物,并测试了它们作为抗叶酸剂的抗肿瘤活性(Gangjee,A.;Li,W.;Kisliuk,R.L.;Cody,V.;Pace,J.;Piraino,J.;Makin,J.Design,synthesis,and X-ray crystal structure of classical and nonclassical2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylatesynthase and dihydrofolate reductase inhibitors and as potential antitumoragents.J.Med.Chem.2009,52,4892-902)。其中,经典抗叶酸剂I对二氢叶酸还原酶(dihydrofolate reductase,DHFR)和胸苷酸合成酶(thymidylate synthase,TS)的抑制活性较好,IC50值分别为54、19nM,且对人白血病、非小细胞肺癌、黑色素瘤、卵巢癌、肾癌等8种细胞的GI50值均在10nM以下。用芳胺、杂环胺等基团修饰噻吩并[2,3-d]嘧啶的C4位,可得到蛋白激酶抑制剂。Abdelhaleem等将苯基脲或苯基硫脲结构片段与噻吩并[2,3-d]嘧啶的C4位相连接,合成了一系列噻吩并[2,3-d]嘧啶的脲衍生物,其中活性最好的化合物II对MCF-7细胞活性最好(IC50=7.10μM),而且其细胞毒活性与拓扑异构酶II(IC50=9.29μM)和人血管上皮生长因子受体-2(IC50=0.2μM)抑制活性有一定的相关性(Abdelhaleem,E.F.;Abdelhameid,M.K.;Kassab,A.E.;Kandeel,M.M.Design and synthesis ofthienopyrimidine urea derivatives with potential cytotoxic and pro-apoptoticactivity against breast cancer cell line MCF-7.Eur.J.Med.Chem.2018,143,1807-1825)。同时,化合物II能够引起细胞周期中subG1和G2/M期的积累,显著提高p53基因的表达,升高Bax/Bcl-2蛋白水平比例,同时激活caspase-3,从而证实了II可通过线粒体通路诱导细胞凋亡。虽然大部分研究都集中在对C-4、C-5和C-6位进行修饰,但越来越多的证据表明,在噻吩并[2,3-d]嘧啶的C2位引入不同的取代基,也能够得到具有良好抗肿瘤活性的化合物。Amawi等将不同取代的苯环与噻吩并[2,3-d]嘧啶的C2位连接,合成了一系列衍生物(Amawi,H.;Karthikeyan,C.;Pathak,R.;Hussein,N.;Christman,R.;Robey,R.;Ashby,C.R.,Jr.;Trivedi,P.;Malhotra,A.;Tiwari,A.K.Thienopyrimidine derivatives exerttheir anticancer efficacy via apoptosis induction,oxidative stress andmitotic catastrophe.Eur.J.Med.Chem.2017,138,1053-1065)。其中,化合物III能够通过诱导细胞凋亡,同时引发有丝分裂灾难(mitotic catastrophe),从而在5种癌细胞中发挥细胞毒活性。Yang等在噻吩并[2,3-d]嘧啶的C2位引入氨基二硫代甲酸酯,从合成的化合物中筛选出化合物IV,对A549细胞的增殖具有抑制作用(IC50=4.87μM),将细胞阻滞在G2/M期并激活纺锤体装配检验点。本课题组进一步设计、合成了化合物IV的生物素化探针,采用生物素-链霉亲和素亲和纯化技术和生物质谱检测,鉴定出IV的靶蛋白为微管蛋白(tubulin)。此外,IV能够抑制体外微管蛋白的聚合,竞争性结合微管蛋白的紫杉醇位点,并对A549细胞紫杉醇耐药株具有抗增殖活性(Yang,C.R.;Peng,B.;Cao,S.L.;Ren,T.T.;Jiang,W.;Wang,F.C.;Li,Y.S.;Li,Z.;Xu,S.;Liao,J.;Wang,H.L.;Li,J.;Xu,X.Synthesis,cytotoxic evaluation and target identification of thieno[2,3-d]pyrimidine derivatives with a dithiocarbamate side chain atC2position.Eur.J.Med.Chem.2018,154,324-340)。
查耳酮(chalcone)是植物中一类重要的次级代谢产物,也是植物体内合成黄酮(flavonoid)及异黄酮(isoflavonoid)的天然前体。天然存在及合成的查耳酮类似物具有广泛的生物活性,包括抗肿瘤活性。查耳酮由两个苯环以及连接苯环的α,β-不饱和羰基体系构成,通常将与羰基相连的苯环称为A环,与碳碳双键相连的称为B环。近年来,研究者将不同的取代基引入查耳酮的A、B环,或用芳杂环代替查耳酮的A、B环,所得查耳酮类似物可通过不同的机制发挥抗肿瘤作用。Zhang等改变查耳酮上的取代基,合成了43个查耳酮类似物,发现化合物V(IC50=1.4μM in HeLa cells)选择性抑制硫氧还原蛋白还原酶,诱导HeLa细胞产生活性氧(reactive oxygen species,ROS),促进氧化应激介导的细胞凋亡(Zhang,B.;Duan,D.;Ge,C.;Yao,J.;Liu,Y.;Li,X.;Fang,J.Synthesis of Xanthohumolanalogues and discovery of potent thioredoxin reductase inhibitor aspotential anticancer agent.J.Med.Chem.2015,58,1795-1805)。Yan等以3,4,5-三甲氧基苯环、2,2-二甲基苯并吡喃为A环,分别在吲哚环的C4、C5或C3位上与α,β-不饱和羰基体系连接,合成了大量查耳酮类似物,其中化合物VI对A549、HeLa、7402、MCF-7、A2780和HCT-8细胞的IC50值为3-9nM(Yan,J.;Chen,J.;Zhang,S.;Hu,J.;Huang,L.;Li,X.Synthesis,evaluation,and mechanism study of novel indole-chalcone derivatives exertingeffective antitumor activity through microtubule destabilization in vitro andin vivo.J.Med.Chem.2016,59,5264-83)。VI与微管蛋白的秋水仙碱位点结合,抑制微管蛋白的聚合,将A549细胞阻滞在G2/M期;VI可上调Bax、Bad,下调Bcl-2、Bcl-xl等蛋白水平,诱导细胞凋亡。而且,VI对人乳腺细胞MCF-10A、休眠的人脐静脉血管内皮细胞(quiescentHUVECs)、人皮肤成纤维细胞BJ及人胚肺成纤维细胞HLF等正常细胞系的IC50值比对A549细胞的大100-1000倍,具有较高的选择性。Han等设计、合成了喹唑啉-2-基位分别为A、B环的查耳酮类似物VII、VIII,并测试了细胞毒活性。其中,化合物VIIId(R2=2',5'-diOCH3C6H3)对HCT-116细胞的IC50值为3.36μM,对细胞周期分布无明显的影响,但sub G1细胞随着浓度提高而出现明显的积累。VIIId引起线粒体膜电位下降,提高cleaved PARP1、cleavedcaspase 3、cleaved caspase 7和cleaved caspase 9等凋亡相关蛋白的水平,诱导HCT-116细胞凋亡(Han,X.;Peng,B.;Xiao,B.B.;Cao,S.L.;Yang,C.R.;Wang,W.Z.;Wang,F.C.;Li,H.Y.;Yuan,X.L.;Shi,R.;Liao,J.;Wang,H.L.;Li,J.;Xu,X.Synthesis andevaluation of chalcone analogues containing a 4-oxoquinazolin-2-yl group aspotential anti-tumor agents.Eur.J.Med.Chem.2019,162,586-601)。
噻吩并[2,3-d]嘧啶衍生物(I-V)和查耳酮及其类似物(VII-VIII)的结构。
曹胜利等曾将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
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。
本发明人合成了新型的噻吩并[2,3-d]嘧啶-2-基的查耳酮类似物,该化合物具有抗肿瘤活性。
本发明的目的是提供一种含噻吩并[2,3-d]嘧啶-2-基的查耳酮类似物。
本发明的另一个目的是提供上述含噻吩并[2,3-d]嘧啶-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含噻吩并[2,3-d]嘧啶-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噻吩并[2,3-d]嘧啶-2-基的查耳酮类似物在制备抗肿瘤药物中的用途。
在本发明的实施方案中,本发明提供了一种含噻吩并[2,3-d]嘧啶-2-基的查耳酮类似物,如通式(I)所示:
其中,式(I)中Ar1和Ar2中的一个为如式(X)所示的噻吩并[2,3-d]嘧啶基,即:
Ar1和Ar2中的另一个为未取代的芳烃基或取代的芳烃基、或者杂芳基;优选地,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、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;更优选地,所述取代的苯基为4-甲基苯基、4-甲氧基苯基、4-硝基苯基、4-溴代苯基、4-氯代苯基、4-氟代苯基、2,4-二甲氧基苯基、4-羟基-3-甲氧基苯基、2,4,6-三甲氧基苯基、或3,4,5-三甲氧基苯基;所述杂芳基为噻吩基、呋喃基、或吡啶基;更优选地,所述杂芳基为噻吩-2-基、呋喃-2-基、吡啶-2-基、吡啶-3-基、或吡啶-4-基;
式(X)中取代基R1和R2各自独立地为氢或者C1-C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丙基、或叔丁基);优选地,R1为甲基,R2为氢。
在本发明的一些实施方案中,本发明提供的查耳酮类似物,其中,式(I)为下列式(II)化合物:
其中,Ar2为未取代的芳烃基或取代的芳烃基、或者杂芳基;优选地,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、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;更优选地,所述取代的苯基为4-甲基苯基、4-甲氧基苯基、4-硝基苯基、4-溴代苯基、4-氯代苯基、4-氟代苯基、2,4-二甲氧基苯基、4-羟基-3-甲氧基苯基、2,4,6-三甲氧基苯基、或3,4,5-三甲氧基苯基;所述杂芳基为噻吩基、呋喃基、或吡啶基;更优选地,所述杂芳基为噻吩-2-基、呋喃-2-基、吡啶-2-基、吡啶-3-基、或吡啶-4-基;
取代基R1和R2各自独立地为氢或者C1-C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丙基、或叔丁基);优选地,R1为甲基,R2为氢。
在本发明的一些实施方案中,本发明提供的查耳酮类似物,其中,式(I)为下列式(III)化合物:
其中,Ar1为未取代的芳烃基或取代的芳烃基、或者杂芳基;优选地,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、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;更优选地,所述取代的苯基为4-甲基苯基、4-甲氧基苯基、4-硝基苯基、4-溴代苯基、4-氯代苯基、4-氟代苯基、2,4-二甲氧基苯基、4-羟基-3-甲氧基苯基、2,4,6-三甲氧基苯基、或3,4,5-三甲氧基苯基;所述杂芳基为噻吩基、呋喃基、或吡啶基;更优选地,所述杂芳基为噻吩-2-基、呋喃-2-基、吡啶-2-基、吡啶-3-基、或吡啶-4-基;
取代基R1和R2各自独立地为氢或者C1-C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丙基、或叔丁基);优选地,R1为甲基,R2为氢。
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)-6-甲基-2-(3-苯基丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4a);
(E)-6-甲基-2-(3-(4-甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4b);
(E)-6-甲基-2-(3-(2,4-二甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4c);
(E)-6-甲基-2-(3-(2,4,6-三甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4d);
(E)-6-甲基-2-(3-(3,4,5-三甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4e);
(E)-6-甲基-2-(3-(4-羟基-3-甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4f);
(E)-6-甲基-2-(3-(4-甲基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4g);
(E)-6-甲基-2-(3-(4-溴苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4h);
(E)-6-甲基-2-(3-(4-氯苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4i);
(E)-6-甲基-2-(3-(4-氟苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4j);
(E)-6-甲基-2-(3-(4-硝基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4k);
(E)-6-甲基-2-(3-(呋喃-2-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4l);
(E)-6-甲基-2-(3-(噻吩-2-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4m);
(E)-6-甲基-2-(3-(吡啶-2-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4n);
(E)-6-甲基-2-(3-(吡啶-3-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4o);
(E)-6-甲基-2-(3-(吡啶-4-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(4p);
(E)-6-甲基-2-(3-氧代-3-苯基丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8a);
(E)-6-甲基-2-(3-氧代-3-(4-甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8b);
(E)-6-甲基-2-(3-氧代-3-(2,4-二甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8c);
(E)-6-甲基-2-(3-氧代-3-(2,4,6-三甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8d);
(E)-6-甲基-2-(3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8e);
(E)-6-甲基-2-(3-氧代-3-(4-羟基-3-甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8f);
(E)-6-甲基-2-(3-氧代-3-(4-甲基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8g);
(E)-6-甲基-2-(3-氧代-3-(4-溴苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8h);
(E)-6-甲基-2-(3-氧代-3-(4-氯苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8i);
(E)-6-甲基-2-(3-氧代-3-(4-氟苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8j);
(E)-6-甲基-2-(3-氧代-3-(4-硝基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8k);
(E)-6-甲基-2-(3-氧代-3-(呋喃-2-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8l);
(E)-6-甲基-2-(3-氧代-3-(噻吩-2-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8m);
(E)-6-甲基-2-(3-氧代-3-(吡啶-2-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8n);
(E)-6-甲基-2-(3-氧代-3-(吡啶-3-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8o);或
(E)-6-甲基-2-(3-氧代-3-(吡啶-4-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(8p)。
另一方面,本发明提供了如通式(I)所示含噻吩并[2,3-d]嘧啶-2-基的查耳酮类似物的制备方法,当Ar1为式(X),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、式(IV)化合物和式(VI)化合物中的取代基,Ar2、R1和R2的定义如式(I)化合物;
或者,
当Ar2为式(X),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、式(V)化合物和式(VII)化合物中的取代基,Ar1、R1和R2的定义如式(I)化合物。
在本发明提供的如通式(I)所示含噻吩并[2,3-d]嘧啶-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:
首先,以三乙胺为碱,将式(IX)化合物(当R1为甲基,R2为氢时为丙醛)、氰乙酰胺及单质硫在乙醇中50-55℃反应4h,生成式(XI)化合物。将丙酮酸与二氯亚砜在三氯甲烷中回流反应0.5h,生成丙酮酰氯;将式(XI)化合物与丙酮酰氯在四氢呋喃中回流反应2h,生成式(VIII)化合物。式(VIII)化合物在碱存在下,于乙醇中回流1h,生成式(IV)化合物。在碱性条件下,式(IV)化合物分别与苯甲醛类化合物Ar2CHO(VI)在室温下发生缩合反应,生成噻吩并[2,3-d]嘧啶-2-基作为A环的查耳酮类似物(化合物4a-p)。
试剂与反应条件:(a)单质硫,三乙胺,乙醇,50-55℃反应4小时;(b)丙酮酰氯,四氢呋喃,室温反应过夜;(c)i.4%氢氧化钠溶液,乙醇,回流反应2小时;ii.1mol/L盐酸;(d)i.Ar2CHO(VI),30%氢氧化钾溶液或哌啶,甲醇,室温反应过夜;ii.1mol/L盐酸。
在本发明提供的如通式(I)所示含噻吩并[2,3-d]嘧啶-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:
将式(IX)化合物(当R1为甲基,R2为氢时为丙醛)、氰乙酸乙酯、沉降硫、三乙胺和N,N-二甲基甲酰胺的混合物,室温反应4h,生成式(XII)化合物。将式(XII)化合物与氯乙腈溶于1,4-二氧六环,室温下通入干燥的氯化氢气体,生成式(XIII)化合物。在碘化钾存在下,式(XIII)化合物与N-甲基吗啉N-氧化物在四氢呋喃中回流反应,生成式(V)化合物。在室温条件下,式(V)化合物与苯乙酮类化合物(VII,Ar1COCH3)在碱性条件下发生缩合反应,得到噻吩并[2,3-d]嘧啶-2-基作为B环的查耳酮类似物(化合物8a-p)。
试剂与反应条件:(a)单质硫,三乙胺,N,N-二甲基甲酰胺,室温反应4小时;(b)i.氯乙腈,干燥的氯化氢气体,1,4-二氧六环,室温反应5小时;ii.25%氨水;(c)N-甲基吗啉-N-氧化物,碘化钾,干燥的四氢呋喃;(d)i.苯乙酮类化合物(VII,Ar1COCH3),20-50%氢氧化钾溶液,甲醇,室温反应过夜;ii.1mol/L盐酸。
核磁共振氢谱(1H NMR)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(coupling constant)为15.6或16.2Hz,因此均为E-式构型(E-configuration)。
另一方面,本发明提供了一种包含上述噻吩并[2,3-d]嘧啶-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噻吩并[2,3-d]嘧啶-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。
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、肺癌、宫颈癌、或肝癌等。
实验证明,本发明的式(I)的化合物具有抗肿瘤活性,不仅对人乳腺癌(MFC-7和MDA-MB-231)、人宫颈癌(HeLa)、人结肠癌(HCT-116和HT-29)和人肺癌细胞株(A549)细胞的增殖具有抑制作用,而且对人肝癌细胞株(HepG2)具有抑制作用,可用作抗肿瘤药物。
本发明的其它特征和优点将在随后的说明书中阐述,并且,部分地从说明书中变得显而易见,或者通过实施本发明而了解。本发明的目的和其他优点可通过在说明书、权利要求书中所特别指出的结构来实现和获得。
具体实施方式
为使本申请的目的、技术方案和优点更加清楚明白,下文中将对本发明的实施例进行详细说明。需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互任意组合。
熔点用XT5B精密显微熔点仪测定,温度未校正。高效液相色谱(HPLC)用AgilentSeries 1200(色谱柱:C18,4.5×150mm)测定,检测波长238或280nm,流动相为MeOH:H2O=7:3,用于抗肿瘤活性实验的化合物的纯度≥95%。核磁共振氢谱和碳谱(1H NMR、13C NMR)用Varian VNMRS-600核磁共振谱仪,在600MHz或150MHz测定,TMS为内标。电子轰击质谱(MS(EI))用Shimadzu的GCMS-QP2010Plus气相色谱/质谱联用仪测定。高分辨电喷雾质谱(HRMS(ESI))用Thermo Scientific的LTQ Orbitrap质谱仪测定。柱色谱采用200-300目的硅胶填充。
苯乙酮、4-氯苯乙酮、4-氟苯乙酮、4-硝基苯乙酮、苯甲醛、4-甲氧基苯甲醛、2,4-二甲氧基苯甲醛、4-羟基-3-甲氧基苯甲醛购自天津碧橙蓝试剂公司;4-甲氧基苯乙酮、4-溴苯乙酮购自百灵威试剂公司;4-羟基-3-甲氧基苯乙酮、4-氟苯甲醛、3,4,5-三甲氧基苯甲醛、2,4,6-三甲氧基苯甲醛购自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。其它原料均为市售化学试剂。
人肺癌细胞株A549、人结肠癌细胞株HCT-116、HT-29、人乳腺癌细胞株MCF-7、MDA-MB-231、人宫颈癌细胞株HeLa及人肝癌细胞株HepG2均由DNA损伤应答北京市重点实验室提供。DMEM培养基、胎牛血清及0.25%胰酶(Trypsin-EDTA)均购自Hyclone公司。双抗(青霉素-链霉素)购自Gemini公司。体外抗肿瘤活性实验所使用的CellTiter MTS细胞增殖试剂盒购自Promega公司。
缩写词:
PE=石油醚
EtOAc=乙酸乙酯
Ph=苯基;
DCM=二氯甲烷;
m.p.=熔点;
1H NMR=核磁共振氢谱;
13C NMR=核磁共振碳谱;
HRMS(ESI)=高分辨质谱(电喷雾电离);
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
2-氨基-5-甲基噻吩-3-甲酰胺(式(XI)化合物,其中,R1为甲基,R2为氢)的制备
将氰乙酸乙酯(3.4g,30mmol)溶于四氢呋喃(10mL)中,加入浓氨水(15mL),室温搅拌反应24h。反应混合物旋转蒸发除去大部分溶剂,剩余棕色溶液于冰箱中放置过夜。滤集析出的固体,用石油醚洗涤(10mL×3),真空箱中干燥,得到氰乙酸乙酯粗品2.3g直接用于下一步反应。
将氰乙酰胺(0.84g,10mmol)、丙醛(0.58g,10mmol)、沉降硫(0.32g,10mmol)、三乙胺(1.0g,10mmol)与乙醇(30mL)的混合物,于50-55℃搅拌反应4h。旋转蒸发除去部分溶剂,剩余溶液溶于乙酸乙酯(100mL),用饱和食盐水洗涤(100mL×3),无水硫酸钠干燥过夜。滤除干燥剂,滤液旋转蒸发除去溶剂,残余物用硅胶柱色谱法提纯(洗脱液:PE/EtOAc=1:1),得淡黄色固体0.95g,收率71%,mp 119-121℃。1H NMR(600MHz,DMSO-d6)δ:2.17(d,J=1.2Hz,3H,CH3),6.64(br s,1H,1/2CONH2),6.69(d,J=1.2Hz,1H,thiophene 4-H),7.05(brs,3H,1/2CONH2,NH2).EI-MS m/z:156(M+).
5-甲基-2-(2-氧代丙酰基氨基)噻吩-3-甲酰胺(式(VIII)化合物,其中,R1为甲基,R2为氢)的制备
将丙酮酸(0.88g,10mmol)溶于干燥的二氯甲烷(5mL)中,室温下滴加二氯亚砜(1.3g,11mmol)。搅拌5分钟后,升温至回流,继续反应2h。将反应液冷却至室温,旋转蒸发除去溶剂。加入10mL二氯甲烷,旋转蒸发除去,重复2次,把二氯亚砜、氯化氢、二氧化硫等除尽,得到油状液体1g,收率94%,直接用于下一步反应。
将2-氨基-5-甲基噻吩-3-甲酰胺(0.78g,5mmol)和丙酮酰氯(0.64g,6mmol)溶于干燥的四氢呋喃(5mL)中,室温搅拌反应过夜。滤除析出的固体,用四氢呋喃洗涤。合并滤液和洗液,旋转蒸发除去溶剂,残余物混于冷的甲醇(30mL)中,抽滤,得淡黄色固体。粗产物用硅胶柱色谱法提纯(洗脱液:petroleum/ethyl acetate=1:1),得淡黄色固体0.79g,收率70%,mp 211-215℃。1H NMR(600MHz,DMSO-d6)δ:2.38(d,J=1.2Hz,3H,CH3),2.43(s,3H,CH3CO),7.16(d,J=1.2Hz,1H,thiophene 4-H),7.54(br s,1H,1/2CONH2),7.86(br s,1H,1/2CONH2),12.87(s,1H,NH).EI-MS m/z:226(M+).
6-甲基-2-乙酰基-噻吩并[2,3-d]嘧啶-4(3H)-酮(式(IV)化合物,其中,R1为甲基,R2为氢)的制备
将5-甲基-2-(2-氧代丙酰胺基)噻吩-3-甲酰胺(0.23g,1mmol)溶于4%氢氧化钠溶液(4mL)和乙醇(1mL)的混合液中,加热回流2h。冷却至室温,用1mol/L的盐酸调节pH 4-5,有棕色絮状固体析出。滤除析出的固体,滤液用乙酸乙酯萃取(10mL×3),合并有机相,用饱和食盐水洗涤(15mL×3),无水硫酸钠干燥过夜。旋转蒸发除去溶剂,残余物用硅胶柱色谱法提纯(洗脱液:DCM/MeOH=98:2),得淡黄色固体0.12g,收率58%,mp>350℃。1H NMR(600MHz,DMSO-d6)δ:2.33(s,3H,CH3CO),2.46(d,J=1.2Hz,3H,CH3),7.0(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H).EI-MS m/z:208(M+).
化合物4a-p的合成通法
将6-甲基-2-乙酰基-4-氧代噻吩并[2,3-d]嘧啶(式(V)化合物,其中,R1为甲基,R2为氢)(62mg,0.3mmol)和氢氧化钾(56mg,1mmol)配成30%的水溶液(对于化合物4k和4n-p,使用哌啶(0.1mL,1mmol)代替氢氧化钾水溶液)溶于甲醇(1mL)中,加入到反应液中,室温搅拌30min。加入不同的苯甲醛或芳杂醛(0.4mmol),室温搅拌过夜。反应液用1mol/L盐酸调节pH 2-3,滤集析出的固体,用少量甲醇洗涤,晾干。除另有说明外,粗品用甲醇重结晶,得目标化合物4a-p。
实施例1
(E)-6-甲基-2-(3-苯基丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4a)
收率61%,黄色固体,mp 234-237℃。1H NMR(600MHz,DMSO-d6)δ:2.55(d,J=1.2Hz,3H,CH3),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.36(d,J=15.6Hz,1H,COCH=),7.61(t,J=7.8Hz,2H,Ph 3′-H,5′-H),7.73(t,J=7.8Hz,1H,Ph 4′-H),8.13(d,J=7.8Hz,2H,Ph 2′-H,6′-H),8.33(d,J=15.6Hz,1H,CH=),12.82(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.74,119.65,124.85,128.73(2C),129.03(2C),129.85,133.89,134.78,136.64,139.42,149.52,157.34,162.88,188.53.HRMS(ESI)m/z:C16H13N2O2S([M+H]+)理论值:297.0698;实测值:297.0691.
实施例2
(E)-6-甲基-2-(3-(4-甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4b)
收率47%,黄色固体,mp 268-271℃。1H NMR(600MHz,DMSO-d6)δ:2.54(s,3H,CH3),3.89(s,3H,OCH3),7.12(d,J=8.4Hz,2H,Ph 3′-H,5′-H),7.16(s,1H,噻吩并[2,3-d]嘧啶5-H),7.31(d,J=15.6Hz,1H,COCH=),8.13(d,J=8.4Hz,2H,Ph 2′-H,6′-H),8.32(d,J=15.6Hz,1H,CH=),12.75(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.74,55.71,113.89,114.34(2C),119.63,129.64,129.97,130.44,131.25(2C),134.08,139.31,149.67,157.39,163.83,186.54.HRMS(ESI)m/z:C17H15N2O3S([M+H]+)理论值:327.0803;实测值:327.0792.
实施例3
(E)-6-甲基-2-(3-(2,4-二甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4c)
收率70%,黄色固体,mp 246-251℃。1H NMR(600MHz,DMSO-d6)δ:2.54(d,J=1.8Hz,3H,CH3),3.88(s,3H,OCH3),3.91(s,3H,OCH3),6.68(dd,J=9.0,2.4Hz,1H,Ph 5′-H),6.71(d,J=2.4Hz,1H,Ph 3′-H),7.14(d,J=1.8Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.22(d,J=15.6Hz,1H,COCH=),7.67(d,J=9.0Hz,1H,Ph 6′-H),8.03(d,J=15.6Hz,1H,CH=),12.71(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.72,55.60,56.50,113.95,114.08,119.57,119.78,124.67,128.03,133.15,134.19,139.07,149.56,152.46,153.07,157.31,162.99,190.74.HRMS(ESI)m/z:C18H17N2O4S([M+H]+)理论值:357.0909;实测值:357.0894.
实施例4
(E)-6-甲基-2-(3-(2,4,6-三甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4d)
收率56%,黄色固体,mp 233-236℃(DMF重结晶)。1H NMR(600MHz,CDCl3)δ:2.52(d,J=1.2Hz,3H,CH3),3.74(s,6H,2OCH3),3.85(s,3H,OCH3),6.33(s,2H,Ph 3′-H,5′-H),7.0(d,J=15.6Hz,1H,COCH=),7.12(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.38(d,J=15.6Hz,1H,CH=),12.61(s,1H,NH).13C NMR(150MHz,CDCl3)δ:15.69,55.56,55.93(2C),91.10(2C),110.20,119.55,124.61,133.96,135.82,139.08,149.52,157.23,158.48(2C),162.63,162.89,192.04.HRMS(ESI)m/z:C19H19N2O5S([M+H]+)理论值:387.1015;实测值:387.1005.
实施例5
(E)-6-甲基-2-(3-(3,4,5-三甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4e)
收率60%,黄色固体,mp>330℃(DMF重结晶)。1H NMR(600MHz,DMSO-d6)δ:2.55(s,3H,CH3),3.79(s,3H,OCH3),3.91(s,6H,2OCH3),7.18(s,1H,噻吩并[2,3-d]嘧啶5-H),7.35(d,J=15.6Hz,1H,COCH=),7.42(s,2H,Ph2′-H,6′-H),8.30(d,J=15.6Hz,1H,CH=),12.73(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:16.14,56.01,56.38(2C),91.54(2C),110.65,120.0,125.06,134.41,136.26,139.53,149.97,157.68,158.93(2C),163.08,163.34,192.49.HRMS(ESI)m/z:C19H19N2O5S([M+H]+)理论值:387.1015;实测值:387.1006.
实施例6
(E)-6-甲基-2-(3-(4-羟基-3-甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4f)
收率69%,黄色固体,mp>330℃。1H NMR(600MHz,DMSO-d6)δ:2.54(d,J=1.2Hz,3H,CH3),3.88(s,3H,OCH3),6.95(d,J=8.4Hz,1H,Ph 5′-H),7.15(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.29(d,J=15.6Hz,1H,COCH=),7.59(d,J=2.4Hz,1H,Ph 2′-H),7.76(dd,J=8.4,2.4Hz,1H,Ph 6′-H),8.30(d,J=15.6Hz,1H,CH=),10.28(s,1H,OH),12.72(br s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:16.15,56.14,111.94,115.57,120.03,124.82,125.12,129.09,130.38,134.14,139.60,148.45,150.16,153.19,157.82,163.41,186.53.HRMS(ESI)m/z:C17H15N2O4S([M+H]+)理论值:343.0753;实测值:343.0744.
实施例7
(E)-6-甲基-2-(3-(4-甲基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4g)
收率64%,黄色固体,mp 264-267℃。1H NMR(600MHz,DMSO-d6)δ:2.42(s,3H,CH3),2.55(d,J=1.2Hz,3H,CH3),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.33(d,J=15.6Hz,1H,COCH=),7.42(d,J=8.4Hz,2H,Ph3′-H,5′-H),8.05(d,J=8.4Hz,2H,Ph 2′-H,6′-H),8.32(d,J=15.6Hz,1H,CH=),12.77(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.74,21.26,119.63,124.80,128.88(2C),129.61(2C),129.87,134.19,134.49,139.38,144.56,149.57,157.36,162.92,187.85.HRMS(ESI)m/z:C17H15N2O2S([M+H]+)理论值:311.0854;实测值:311.0841.
实施例8
(E)-6-甲基-2-(3-(4-溴苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4h)
收率61%,黄色固体,mp>330℃。1H NMR(600MHz,DMSO-d6)δ:2.59(d,J=1.2Hz,3H,CH3),7.26(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.68(d,J=8.4Hz,2H,Ph 2′-H,6′-H),7.83(d,J=8.4Hz,2H,Ph 3′-H,5′-H),7.86(d,J=16.2Hz,1H,COCH=),8.03(d,J=16.2Hz,1H,CH=),12.54(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.92,120.15,120.20,124.78,127.41,130.98(2C),132.09(2C),133.39,142.18,144.18,147.66,156.70,160.77,181.95.HRMS(ESI)m/z:C16H12BrN2O2S([M+H]+)理论值:374.9803,376.9782;实测值:374.9795,376.9765.
实施例9
(E)-6-甲基-2-(3-(4-氯苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4i)
收率57%,黄色固体,mp 220-223℃。1H NMR(600MHz,DMSO-d6)δ:2.55(d,J=1.2Hz,3H,CH3),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.35(d,J=15.6Hz,1H,COCH=),7.68(d,J=9.0Hz,2H,Ph 2′-H,6′-H),8.15(d,J=9.0Hz,2H,Ph 3′-H,5′-H),8.30(d,J=15.6Hz,1H,CH=),12.78(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.92,120.14,120.17,124.77,127.40,130.96(2C),132.07(2C),133.38,142.16,144.16,147.64,156.69,160.75,181.93.HRMS(ESI)m/z:C16H12ClN2O2S([M+H]+)理论值:331.0308,333.0279;实测值:331.0302,333.0268.
实施例10
(E)-6-甲基-2-(3-(4-氟苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4j)
收率45%,黄色固体,mp 217-219℃。1H NMR(600MHz,DMSO-d6)δ:2.55(s,3H,CH3),7.17(s,1H,噻吩并[2,3-d]嘧啶5-H),7.34(d,J=15.6Hz,1H,COCH=),7.44(t,J=8.4Hz,2H,Ph 3′-H,5′-H),8.23(dd,J=8.4,6.0Hz,2H,Ph2′-H,6′-H),8.31(d,J=15.6Hz,1H,CH=),12.77(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.92,115.96(d,J=21.6Hz,2C),119.87,123.86(d,J=1.8Hz),125.12,130.70(d,J=8.55Hz,2C),131.65,132.71,140.56,158.45,163.14(d,J=247.05Hz),164.67,168.27,189.66.HRMS(ESI)m/z:C16H12FN2O2S([M+H]+)理论值:315.0604;实测值:315.0593.
实施例11
(E)-6-甲基-2-(3-(4-硝基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4k)
收率56%,黄色固体,mp 284-286℃。1H NMR(600MHz,CF3COOD)δ:2.60(s,3H,CH3),7.30(s,1H,噻吩并[2,3-d]嘧啶5-H),7.89(d,J=15.6Hz,1H,COCH=),8.31(d,J=15.6Hz,1H,CH=),8.70(d,J=4.8Hz,2H,Ph 2′-H,6′-H),9.03(d,J=4.8Hz,2H,Ph 3′-H,5′-H).13CNMR(150MHz,CF3COOD)δ:16.21,119.52,121.46,124.36(2C),126.23,129.97(2C),140.23,144.38,145.95,147.52,148.97,161.36(overlapped with CF3COOH),164.38,182.15.HRMS(ESI)m/z:C16H12N3O4S([M+H]+)理论值:342.0549;实测值:342.0538.
实施例12
(E)-6-甲基-2-(3-(呋喃-2-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4l)
收率80%,黄色固体,mp 294-296℃。1H NMR(600MHz,DMSO-d6)δ:2.55(d,J=1.2Hz,3H,CH3),6.84(dd,J=3.6,1.2Hz,1H,furan 4′-H),7.16(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.38(d,J=15.6Hz,1H,COCH=),7.83(d,J=3.6Hz,1H,furan 3′-H),8.08(d,J=15.6Hz,1H,CH=),8.15(d,J=1.2Hz,1H,furan 5′-H),12.74(s,1H,NH).13CNMR(150MHz,DMSO-d6)δ:15.91,113.52,116.21,119.05,120.12,127.27,131.41,142.03,147.21,147.72,150.97,156.68,160.85,181.41.HRMS(ESI)m/z:C14H11N2O3S([M+H]+)理论值:287.0490;实测值:287.0482.
实施例13
(E)-6-甲基-2-(3-(噻吩-2-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4m)
收率61%,黄色固体,mp 308-311℃。1H NMR(600MHz,DMSO-d6)δ:2.59(d,J=1.2Hz,3H,CH3),7.24(dd,J=4.8,3.6Hz,1H,thiophene 4′-H),7.25(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.68(d,J=15.6Hz,1H,COCH=),7.75(d,J=3.6Hz,1H,thiophene3′-H),7.88(d,J=4.8Hz,1H,thiophene 5′-H),8.07(d,J=15.6Hz,1H,CH=),12.49(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.92,117.66,120.13,127.32,129.14,131.68,134.62,138.32,139.55,142.03,147.72,156.69,160.82,181.36.HRMS(ESI)m/z:C14H11N2O2S2([M+H]+)理论值:303.0262;实测值:303.0251.
实施例14
(E)-6-甲基-2-(3-(吡啶-2-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4n)
收率56%,黄色固体,mp>330℃。1H NMR(600MHz,DMSO-d6)δ:2.60(d,J=1.2Hz,3H,CH3),7.27(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.48(ddd,J=7.8,4.8,1.2Hz,1H,吡啶4′-H),7.85(d,J=7.8Hz,1H,吡啶6′-H),7.87(d,J=15.6Hz,1H,COCH=),7.92(td,J=7.8,1.8Hz,1H,吡啶5′-H),8.41(d,J=15.6Hz,1H,CH=),8.73(d,J=4.8Hz,1H,吡啶3′-H),12.57(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.94,120.20,122.80,125.38,126.29,127.45,137.42,142.33,143.86,147.67,150.27,152.08,156.73,160.80,182.31.HRMS(ESI)m/z:C15H12N3O2S([M+H]+)理论值:298.0650;实测值:298.0641.
实施例15
(E)-6-甲基-2-(3-(吡啶-3-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4o)
收率76%,黄色固体,mp 221-224℃。1H NMR(600MHz,DMSO-d6)δ:2.59(s,3H,CH3),7.27(s,1H,噻吩并[2,3-d]嘧啶5-H),7.51(dd,J=7.8,4.8Hz,1H,吡啶5′-H),7.92(d,J=16.2Hz,1H,COCH=),8.13(d,J=16.2Hz,1H,CH=),8.36(d,J=7.8Hz,1H,吡啶4′-H),8.65(d,J=4.8Hz,1H,吡啶6′-H),9.0(s,1H,吡啶2′-H),12.58(s,1H,NH).13C NMR(150MHz,CF3COOD)δ:16.26,120.98,126.05,128.15,128.76,130.09,134.80,138.84,143.17,143.61,145.53,147.94,157.54,161.63,182.67.HRMS(ESI)m/z:C15H12N3O2S([M+H]+)理论值:298.0650;实测值:298.0642.
实施例16
(E)-6-甲基-2-(3-(吡啶-4-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物4p)
收率80%,黄色固体,mp 221-224℃。1H NMR(600MHz,DMSO-d6)δ:2.60(d,J=1.2Hz,3H,CH3),7.27(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.81(d,J=6.0Hz,2H,吡啶2′-H,6′-H),7.83(d,J=16.2Hz,1H,COCH=),8.19(d,J=16.2Hz,1H,CH=),8.70(d,J=6.0Hz,2H,吡啶3′-H,5′-H),12.63(s,1H).13C NMR(150MHz,CF3COOD)δ:16.06,120.56,126.16(2C),128.14,129.53,139.01,142.69(2C),143.17,147.48,151.01,156.94,160.86,182.10.HRMS(ESI)m/z:C15H12N3O2S([M+H]+)理论值:298.0650;实测值:298.0642.
准备例2
2-氨基-5-甲基噻吩-3-甲酸乙酯(式(XII)化合物,其中,R1为甲基,R2为氢)的制备
将氰乙酸乙酯(5.6g,50mmol)、沉降硫(1.6g,50mmol)及三乙胺(5.0g,50mmol)与N,N-二甲基甲酰胺(20mL)混合,加热至50-55℃,搅拌30min。保持温度,向混合物中滴加丙醛(2.9g,50mmol)。滴加完毕,室温搅拌3h。将反应液倾入蒸馏水(200mL)中,混匀,用乙酸乙酯萃取(100mL×3)。合并有机相,无水硫酸钠干燥过夜。旋转蒸发除去溶剂,残余物用硅胶柱色谱法提纯(洗脱液:PE/EtOAc=4:1),得淡黄色固体6.0g,收率65%,m.p.46-49℃(文献值:45-47℃)。
6-甲基-2-氯甲基噻吩并[2,3-d]嘧啶-4(3H)-酮(式(XIII)化合物,其中,R1为甲基,R2为氢)的制备
将2-氨基-5-甲基噻吩-3-甲酸乙酯(14.0g,75mmol)和氯乙腈(6.8g,90mmol)溶于1,4-二氧六环(50mL)中,室温搅拌下,持续通入干燥的氯化氢气体5h。旋转蒸发除去溶剂,残余物用浓盐酸调节pH 3-4,室温搅拌1h后有大量固体析出。滤集析出的固体,用少量二氯甲烷洗涤,晾干。粗品用1,4-二氧六环重结晶,得到类白色固体11.0g,收率69%,m.p.211-214℃.1H NMR(600MHz,DMSO-d6)δ:2.51(d,J=1.2Hz,3H,CH3),4.56(s,2H,CH2Cl),7.11(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),12.73(s,1H,NH).EI-MS m/z:214,216(M+)。
6-甲基-4-氧代噻吩并[2,3-d]嘧啶-2-甲醛(式(V)化合物,其中,R1为甲基,R2为氢)的制备
将6-甲基-2-氯甲基-4-氧代噻吩并[2,3-d]嘧啶(1.1g,5mmol)、N-甲基吗啉N-氧化物(1.2g,10mmol)和碘化钾(1.1g,6.5mmol)与干燥的四氢呋喃(10mL)混合,加热回流2h。冷却至室温,滤除不溶物,固体用10mL四氢呋喃洗涤。滤液旋转蒸发除去溶剂,残余物用硅胶柱色谱法提纯(洗脱液:DCM/MeOH=98:2),得类白色固体0.56g,收率58%,m.p.190-192℃.1H NMR(600MHz,DMSO-d6)δ:2.57(d,J=1.2Hz,3H,CH3),7.24(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),9.50(s,1H,CHO),12.80(s,1H,NH).EI-MS m/z:194(M+)。
化合物8a-p的合成通法
将不同的苯乙酮、杂环乙酮(0.55mmol)溶于甲醇(2mL)中,将氢氧化钾(84mg,1.5mmol)配成15%(8k,8n-p)、30%(8a-e,8g-j)或50%(8f,8l,8m)的水溶液,加入到反应液中,室温搅拌30min。加入6-甲基-4-氧代噻吩并[2,3-d]嘧啶-2-甲醛(97mg,0.5mmol),室温反应过夜。反应液用1mol/L盐酸调pH 2-3,滤集析出的固体,用少量甲醇洗涤,晾干。除另有说明外,粗品用甲醇重结晶,得目标化合物8a-p。
实施例17
(E)-6-甲基-2-(3-氧代-3-苯基丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8a)
收率47%,黄色固体,mp 200-205℃。1H NMR(600MHz,DMSO-d6)δ:2.55(d,J=1.2Hz,3H,CH3),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.36(d,J=15.6Hz,1H,COCH=),7.62(t,J=7.8Hz,2H,Ph 3′-H,5′-H),7.73(t,J=7.8Hz,1H,Ph 4′-H),8.14(d,J=7.8Hz,2H,Ph 2′-H,6′-H),8.33(d,J=15.6Hz,1H,CH=),12.81(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.74,119.65,124.85,128.73(2C),129.03(2C),129.85,133.89,134.78,136.64,139.42,149.52,157.34,162.88,188.54.HRMS(ESI)m/z:C16H13N2O2S([M+H]+)理论值:297.0698;实测值:297.0688.
实施例18
(E)-6-甲基-2-(3-氧代-3-(4-甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8b)
收率46%,黄色固体,mp 245-248℃。1H NMR(600MHz,DMSO-d6)δ:2.55(d,J=0.6Hz,3H,CH3),3.89(s,3H,OCH3),7.13(d,J=9.0Hz,2H,Ph 3′-H,5′-H),7.16(d,J=0.6Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.31(d,J=15.6Hz,1H,COCH=),8.14(d,J=9.0Hz,2H,Ph 2′-H,6′-H),8.33(d,J=15.6Hz,1H,CH=),12.75(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.73,55.69,114.32(2C),119.61,124.74,129.63,129.95,131.23(2C),134.06,139.28,149.66,157.37,162.94,163.82,186.52.HRMS(ESI)m/z:C17H15N2O3S([M+H]+)理论值:327.0803;实测值:327.0794.
实施例19
(E)-6-甲基-2-(3-氧代-3-(2,4-二甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8c)
收率51%,黄色固体,mp 220-223℃。1H NMR(600MHz,DMSO-d6)δ:2.54(s,3H,CH3),3.87(s,3H,OCH3),3.91(s,3H,OCH3),6.67(d,J=9.0Hz,1H,Ph 5′-H),6.71(s,1H,Ph 3′-H),7.14(s,1H,噻吩并[2,3-d]嘧啶5-H),7.22(d,J=15.6Hz,1H,COCH=),7.67(d,J=9.0Hz,1H,Ph 6′-H),8.03(d,J=15.6Hz,1H,CH=),12.71(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.71,55.73,56.17,98.64,106.42,119.53,120.40,124.52,131.90,132.42,134.86,138.81,149.84,157.38,160.81,163.12,164.75,188.16.HRMS(ESI)m/z:C18H17N2O4S([M+H]+)理论值:357.0909;实测值:357.0899.
实施例20
(E)-6-甲基-2-(3-氧代-3-(2,4,6-三甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8d)
收率35%,黄色固体,mp 233-237℃(DMF重结晶)。1H NMR(600MHz,DMSO-d6)δ:2.52(d,J=1.2Hz,3H,CH3),3.74(s,6H,2OCH3),3.85(s,3H,OCH3),6.33(s,2H,Ph 3′-H,5′-H),7.0(d,J=16.2Hz,1H,COCH=),7.13(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.38(d,J=16.2Hz,1H,CH=),12.61(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.69,55.56,55.93(2C),91.10(2C),110.20,119.55,124.61,133.96,135.82,139.08,149.52,157.23,158.48(2C),162.63,162.89,192.04.HRMS(ESI)m/z:C19H19N2O5S([M+H]+)理论值:387.1015;实测值:387.1005.
实施例21
(E)-6-甲基-2-(3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8e)
收率52%,黄色固体,mp 211-213℃(DMF重结晶)。1H NMR(600MHz,DMSO-d6)δ:2.55(d,J=1.2Hz,3H,CH3),3.79(s,3H,OCH3),3.91(s,6H,2OCH3),7.18(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.34(d,J=15.6Hz,1H,COCH=),7.42(s,2H,Ph 2′-H,6′-H),8.30(d,J=15.6Hz,1H,CH=),12.73(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.74,56.28(2C),60.25,106.50(2C),119.64,124.82,129.75,131.96,134.86,139.46,142.67,149.53,153.01(2C),157.36,162.89,187.31.HRMS(ESI)m/z:C19H19N2O5S([M+H]+)理论值:387.1015;实测值:387.1005.
实施例22
(E)-6-甲基-2-(3-氧代-3-(4-羟基-3-甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8f)
收率47%,黄色固体,mp 256-260℃。1H NMR(600MHz,DMSO-d6)δ:2.54(d,J=1.2Hz,3H,CH3),3.88(s,3H,OCH3),6.95(d,J=8.4Hz,1H,Ph5′-H),7.15(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.29(d,J=15.6Hz,1H,COCH=),7.58(d,J=1.8Hz,1H,Ph 2′-H),7.76(dd,J=8.4,1.8Hz,1H,Ph 6′-H),8.30(d,J=15.6Hz,1H,CH=),10.27(s,1H,OH),12.72(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.71,55.70,111.50,115.13,119.59,124.38,124.68,128.65,129.95,133.69,139.15,148.01,149.72,152.75,157.37,162.97,186.09.HRMS(ESI)m/z:C17H15N2O4S([M+H]+)理论值:343.0753;实测值:343.0745.
实施例23
(E)-6-甲基-2-(3-氧代-3-(4-甲基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8g)
收率60%,黄色固体,mp 248-249℃。1H NMR(600MHz,DMSO-d6)δ:2.42(s,3H,CH3),2.55(d,J=1.2Hz,3H,CH3),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.33(d,J=15.6Hz,1H,COCH=),7.42(d,J=8.4Hz,2H,Ph3′-H,5′-H),8.04(d,J=8.4Hz,2H,Ph 2′-H,6′-H),8.32(d,J=15.6Hz,1H,CH=),12.77(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.75,21.27,119.64,124.81,128.89(2C),129.61(2C),129.87,134.20,134.49,139.39,144.57,149.58,157.36,162.92,187.85.HRMS(ESI)m/z:C17H15N2O2S([M+H]+)理论值:311.0854;实测值:311.0845.
实施例24
(E)-6-甲基-2-(3-氧代-3-(4-溴苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8h)
收率68%,黄色固体,mp 230-234℃。1H NMR(600MHz,DMSO-d6)δ:2.55(s,3H,CH3),7.17(s,1H,噻吩并[2,3-d]嘧啶5-H),7.35(d,J=15.6Hz,1H,COCH=),7.83(d,J=8.4Hz,2H,ph 3′-H,5′-H),8.06(d,J=8.4Hz,2H,Ph 2′-H,6′-H),8.28(d,J=15.6Hz,1H,CH=),12.78(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.75,119.66,124.90,128.15,129.45,130.70(2C),132.11(2C),135.09,135.63,139.55,149.41,157.32,162.86,187.67.HRMS(ESI)m/z:C16H12BrN2O2S([M+H]+)理论值:374.9803,376.9782;实测值:374.9797,376.9770.
实施25
(E)-6-甲基-2-(3-氧代-3-(4-氯苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8i)
收率39%,黄色固体,mp 236-240℃。1H NMR(600MHz,CF3COOD)δ:2.55(s 3H,CH3),7.17(s,1H,噻吩并[2,3-d]嘧啶5-H),7.35(d,J=15.6Hz,1H,COCH=),7.68(d,J=9.0Hz,2H,Ph 3′-H,5′-H),8.15(d,J=9.0Hz,2H,Ph 2′-H,6′-H),8.30(d,J=15.6Hz,1H,CH=),12.78(s,1H,NH).13C NMR(150MHz,CF3COOD)δ:13.88,119.21,125.03,128.78,129.46(2C),130.60(2C),133.15,134.59,143.61,146.53,149.35,158.32,162.10(与CF3COOH重叠),189.35.HRMS(ESI)m/z:C16H12ClN2O2S([M+H]+)理论值:331.0308,333.0279;实测值:331.0301,333.0268.
实施例26
(E)-6-甲基-2-(3-氧代-3-(4-氟苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8j)
收率57%,黄色固体,mp 243-246℃。1H NMR(600MHz,CF3COOD)δ:2.55(d,J=1.2Hz,3H,CH3),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.34(d,J=15.6Hz,1H,COCH=),7.44(t,J=9.0Hz,2H,Ph 3′-H,5′-H),8.23(dd,J=9.0,5.4Hz,2H,Ph 2′-H,6′-H),8.31(d,J=15.6Hz,1H,CH=),12.77(s,1H,NH).13C NMR(150MHz,CF3COOD)δ:13.86,116.35(d,J=22.65Hz,2C),119.24,125.07,128.31(d,J=3.75Hz),131.30,132.54(d,J=10.35Hz,2C),135.01,146.55,149.46,158.17,162.08(与CF3COOH重叠),167.98(d,J=259.8Hz),188.84.HRMS(ESI)m/z:C16H12FN2O2S([M+H]+)理论值:315.0604;实测值:315.0594.
实施例27
(E)-6-甲基-2-(3-氧代-3-(4-硝基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8k)
收率41%,黄色固体,mp 236-238℃。1H NMR(600MHz,DMSO-d6)δ:2.55(d,J=1.2Hz,3H,CH3),7.18(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.35(d,J=15.6Hz,1H,COCH=),7.68(d,J=8.4Hz,2H,Ph 2′-H,6′-H),8.15(d,J=8.4Hz,2H,Ph 3′-H,5′-H),8.30(d,J=15.6Hz,1H,CH=),12.78(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.50,119.0,123.51,123.83(2C),124.03,129.51(2C),130.11,136.91,141.29,149.94,157.49,158.02,162.90,196.91.HRMS(ESI)m/z:C16H12N3O4S([M+H]+)理论值:342.0549;实测值:342.0540.
实施例28
(E)-6-甲基-2-(3-氧代-3-(呋喃-2-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8l)
收率60%,黄色固体,mp 255-259℃(柱色谱提纯,洗脱液:DCM/MeOH=98:2)。1HNMR(600MHz,DMSO-d6)δ:2.55(d,J=1.2Hz,3H,CH3),6.84(dd,J=3.6,1.8Hz,1H,furan 4′-H),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.39(d,J=15.6Hz,1H,COCH=),7.83(d,J=3.6Hz,1H,furan 3′-H),8.08(d,J=15.6Hz,1H,CH=),8.15(d,J=1.8Hz,1H,furan5′-H),12.74(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.73,113.20,119.61,120.97,124.82,129.75,133.73,139.37,149.39,152.43,157.30,162.27,162.89,175.47.HRMS(ESI)m/z:C14H11N2O3S([M+H]+)理论值:287.0490;实测值:287.0481.
实施例29
(E)-6-甲基-2-(3-氧代-3-(噻吩-2-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8m)
收率66%,黄色固体,mp 201-204℃(DMF/H2O=3:1重结晶)。1H NMR(600MHz,DMSO-d6)δ:2.55(d,J=1.2Hz,3H,CH3),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.35(dd,J=4.8,4.2Hz,1H,thiophene 4′-H),7.35(d,J=15.6Hz,1H,COCH=),8.16(dd,J=4.8,1.2Hz,1H,thiophene 3′-H),8.22(d,J=15.6Hz,1H,CH=),8.28(dd,J=4.2,1.2Hz,1H,thiophene 5′-H),12.74(s,1H,NH).13C NMR(150MHz,DMSO-d6)δ:15.75,119.64,124.86,129.26,129.71,134.09,134.82,136.96,139.47,144.47,149.36,157.33,162.88,180.70.HRMS(ESI)m/z:C14H11N2O2S2([M+H]+)理论值:303.0262;实测值:303.0253.
实施例30
(E)-6-甲基-2-(3-氧代-3-(吡啶-2-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8n)
收率67%,黄色固体,mp 206-209℃。1H NMR(600MHz,DMSO-d6/CF3COOD=2:1)δ:2.55(s,3H,CH3),7.16(s,1H,噻吩并[2,3-d]嘧啶5-H),7.52(d,J=15.6Hz,1H,COCH=),7.75(t,J=4.8Hz,1H,吡啶5′-H),8.09(t,J=7.2Hz,1H,吡啶4′-H),8.13(d,J=7.2Hz,1H,吡啶3′-H),8.75(d,J=15.6Hz,1H,CH=),8.84(d,J=3.0Hz,1H,吡啶6′-H),12.84(br s,1H,NH).13C NMR(150MHz,DMSO-d6/CF3COOD)δ:16.07,113.78,116.75,119.22,120.53,127.86,131.92,142.50,147.43,148.04,151.58,157.12,158.31(与CF3COOH重叠),161.51,181.95.HRMS(ESI)m/z:C15H12N3O2S([M+H]+)理论值:298.0650;实测值:298.0642.
实施例31
(E)-6-甲基-2-(3-氧代-3-(吡啶-3-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8o)
收率59%,黄色固体,mp 239-241℃。1H NMR(600MHz,CF3COOD)δ:2.55(d,J=1.2Hz,3H,CH3),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.37(d,J=15.6Hz,1H,COCH=),7.64(ddd,J=7.8,4.8,0.6Hz,1H,吡啶5′-H),8.30(d,J=15.6Hz,1H,CH=),8.45(dt,J=7.8,1.8Hz,1H,吡啶4′-H),8.86(dd,J=4.8,1.8Hz,1H,吡啶6′-H),9.28(d,J=1.8Hz,1H,吡啶2′-H),12.78(br s,1H,NH).13C NMR(150MHz,CF3COOD)δ:14.26,118.87,124.91,127.66,127.82,135.46,136.75,141.89,142.28,144.60,145.23,148.21,158.78,163.93,184.47.HRMS(ESI)m/z:C15H12N3O2S([M+H]+)理论值:298.0650;实测值:298.0641.
实施例32
(E)-6-甲基-2-(3-氧代-3-(吡啶-4-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮(化合物8p)
收率66%,黄色固体,mp 238-239℃。1H NMR(600MHz,DMSO-d6/CF3COOD=2:1)δ:2.55(s,3H,CH3),7.17(d,J=1.2Hz,1H,噻吩并[2,3-d]嘧啶5-H),7.38(d,J=15.6Hz,1H,COCH=),7.96(dd,J=4.8,1.8Hz,2H,吡啶3′-H,5′-H),8.22(d,J=15.6Hz,1H,CH=),8.88(dd,J=4.8,1.8Hz,2H,吡啶2′-H,6′-H),12.79(s,1H,NH).13C NMR(150MHz,DMSO-d6/CF3COOD)δ:15.95,120.21,125.61(2C),125.86,129.07(2C),137.67,140.60,144.94,149.41,149.66,157.79,163.39,187.38.HRMS(ESI)m/z:C15H12N3O2S([M+H]+)理论值:298.0650;实测值:298.0642.
试验例
所有肿瘤细胞均在37℃ 5%CO2细胞培养箱中培养。待细胞铺满培养皿底部约80-90%后,吸除原培养基,沿培养皿侧边缓慢加入约5mL的1×PBS缓冲液润洗细胞。吸除PBS,加入1mL 0.25%胰蛋白酶,轻摇培养皿使其铺满整个皿底并与细胞充分接触,吸除胰蛋白酶。将培养皿置于培养箱中,消化2-3min。加入合适体积的新培养基终止细胞消化,轻轻吹打细胞,使细胞在培养基中单个悬浮分散。吸取1mL细胞悬液传至新的培养皿中,补齐培养皿中培养基到10mL。轻摇培养皿使细胞分散均匀,放入培养箱中培养。
细胞增殖抑制实验
参照文献(Cao,S.L.;Han,Y.;Yuan,C.Z.;Wang,Y.;Xiahou,Z.K.;Liao,J.;Gao,R.T.;Mao,B.B.;Zhao,B.L.;Li,Z.F.;Xu,X.Synthesis and antiproliferative activityof 4-substituted-piperazine-1-carbodithioate derivatives of2,4-diaminoquinazoline.Eur.J.Med.Chem.2013,64,401-409)的方法,使用CellTiter AQueous OneSolution Cell Proliferation Assay试剂盒(Promega)。待测化合物事先配成104μM的DMSO溶液,-20℃保存,解冻后使用,用培养基稀释至所需浓度。实验数据均为三次独立平行实验计算所得。
按上述细胞传代方法制得细胞悬液,5×103/well的密度接种于96孔培养板中,留出两个孔作为空白,其余每孔加入90μL细胞悬液。在培养箱中培养24h后,吸除旧培养基,空白及本底孔加入100μL新培养基,其余孔加入配好的待测化合物的培养基溶液,放入培养箱中继续培养72h。预先将冷冻保存的MTS溶液在室温下解冻,向96孔培养板每孔加入20μLMTS溶液,放入培养箱2h,使用酶标仪(Molecular Devices SpectraMax M5)检测492nm波长处各孔的光密度(optical density,OD)。按如下公式计算细胞增殖抑制率:
细胞增殖抑制率(%)=[1-(OD试验组-OD本底组)/(OD空白组-OD本底组)]×100%
其中OD试验组、OD空白组、OD本底组分别代表在492nm波长下试验组、空白组以及本底组的光密度。通过SPSS 20for Windows软件绘制抑制率的S型曲线,计算化合物的半抑制浓度(IC50)。
表1.化合物4a-p对A549和HCT-116细胞的IC50值
如表1所示,噻吩并[2,3-d]嘧啶作为A环时的,8个化合物(4b-c、4e、4g-j和4l)对A549细胞有细胞毒活性(IC50<20μM),其中化合物4h、4j和4l活性较好(IC50<10μM)。10个化合物(4a、4e、4g-j、4l-m和4o-p)对HCT-116细胞有细胞毒活性(IC50<20μM),其中化合物4b、4g、4h和4l活性较好(IC50<10μM)。化合物4h和4l同时对A549和HCT-116细胞均有较好的活性,其IC50值分别为8.93、8.66μM和9.40、7.87μM。
表2.化合物8a-p对A549和HCT-116细胞的IC50值
如表2所示,噻吩并[2,3-d]嘧啶为B环时,9个化合物对A549细胞具有细胞毒活性,其中5个化合物活性较好;12个化合物对HCT-116细胞具有细胞毒活性,其中5个化合物活性较好。在苯环上连有卤素原子或4-硝基,或用杂环代替A环时,所得化合物的活性与母体化合物8a相近或降低,只有含噻吩环化合物8m活性好于8a。在苯环引入给电子基团时,除化合物8c外,其余化合物对A549和HCT-116细胞系的活性都提高了。4个化合物(8d-g)对两种细胞的的活性最好,其中化合物8d-f对HCT-116细胞的IC50值均小于5.00μM,与阳性对照5-FU活性相近。总的来说,当噻吩并[2,3-d]嘧啶作为B环时,大部分化合物的抗增殖活性要优于作为A环时化合物的活性。只有B环为4-溴、4-氟取代的苯环,或为呋喃-2-基时,所得化合物4h、4j和4l的抗增殖活性,比相应取代的化合物8h、8j和8l要好。相比于A549细胞,两系列化合物对HCT-116细胞的抗增殖活性普遍要更高一些。
表3化合物8d-f对MCF-7、MDA-MB-231、HeLa、HT-29以及MCF-10A细胞的IC50值.
进一步测试了化合物8d-f,对人乳腺癌MCF-7,MDA-MB-231、人宫颈癌HeLa人结肠癌HT-29、人肝癌HepG2细胞,以及人乳腺上皮细胞MCF-10A的细胞毒活性(表3)。化合物8d-f对测试的所有癌细胞系均有活性。但是,它们对正常细胞MCF-10A也有细胞毒性。与A549和HCT-116细胞类似,化合物8d对MCF-7、MD-MBA-231、HeLa、HT-29和HepG2细胞的IC50值也相对较低。
表4化合物4a-p、8a-p和化合物VIIa-s、VIIIa-s活性对比
Han等曾合成了以喹唑啉分别作为A、B环的查耳酮类似物VIIa-s和VIIIa-s。如表4所示,含有4-甲氧基、4-甲基、4-溴、4-氯、4-氟或呋喃-2-基的化合物4b、4g、4h、4i、4j、4l,其对HCT-116细胞的活性要优于含相同取代基的化合物VIId、VIIi、VIIj、VIIk、VIIl、VIIo。含有2,4,6-三甲氧基、3,4,5-三甲氧基或4-羟基-3-甲氧基的化合物8d-f,其对MCF-7和HCT-116细胞的活性均优于含相同取代基的化合物VIIIg、VIIIh、VIIIk。此外,8d-f还对HepG2细胞表现出较好的细胞毒活性,而化合物VIIa-s和VIIIa-s则均未能对HepG2细胞表现出任何活性。
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
虽然本申请所揭露的实施方式如上,但所述的内容仅为便于理解本申请而采用的实施方式,并非用以限定本申请。任何本申请所属领域内的技术人员,在不脱离本申请所揭露的精神和范围的前提下,可以在实施的形式及细节上进行任何的修改与变化,但本申请的专利保护范围,仍须以所附的权利要求书所界定的范围为准。
Claims (9)
1.含噻吩并[2,3-d]嘧啶-2-基的查耳酮类似物,如通式(I)所示:
其中,式(I)中Ar1和Ar2中的一个为如式(X)所示的噻吩并[2,3-d]嘧啶基,即:
Ar1和Ar2中的另一个为未取代的芳烃基或取代的芳烃基、或者杂芳基;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如下基团所取代:C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C1-4烷氧羰酰基、羟基、卤素、氨基、单C1-4烷基取代的氨基、双C1-4烷基取代的氨基、硝基和氰基,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;所述杂芳基为噻吩基、呋喃基、或吡啶基;
式(X)中取代基R1和R2各自独立地选自氢或者C1-C4烷基。
2.根据权利要求1所述的查耳酮类似物,其中,式(I)中R1为甲基,R2为氢。
5.根据权利要求1至4中任一项所述的查耳酮类似物,其中,所述取代的苯基为4-甲基苯基、4-甲氧基苯基、4-硝基苯基、4-溴代苯基、4-氯代苯基、4-氟代苯基、2,4-二甲氧基苯基、4-羟基-3-甲氧基苯基、2,4,6-三甲氧基苯基、或3,4,5-三甲氧基苯基。
6.根据权利要求1至4中任一项所述的查耳酮类似物,其中,所述杂芳基为噻吩-2-基、呋喃-2-基、吡啶-2-基、吡啶-3-基、或吡啶-4-基。
7.如权利要求1所述的查耳酮类似物,选自如下化合物中的一种:
(E)-6-甲基-2-(3-苯基丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(4-甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(2,4-二甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(2,4,6-三甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(3,4,5-三甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(4-羟基-3-甲氧基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(4-甲基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(4-溴苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(4-氯苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(4-氟苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(4-硝基苯基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(呋喃-2-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(噻吩-2-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(吡啶-2-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(吡啶-3-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-(吡啶-4-基)丙烯酰)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-苯基丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(4-甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(2,4-二甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(2,4,6-三甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(4-羟基-3-甲氧基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(4-甲基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(4-溴苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(4-氯苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(4-氟苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(4-硝基苯基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(呋喃-2-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(噻吩-2-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(吡啶-2-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;
(E)-6-甲基-2-(3-氧代-3-(吡啶-3-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮;和
(E)-6-甲基-2-(3-氧代-3-(吡啶-4-基)丙-1-烯-1-基)噻吩并[2,3-d]嘧啶-4(3H)-酮。
8.一种包含权利要求1至7中任一权利要求所述查耳酮类似物的药用组合物。
9.如权利要求1至7中任一权利要求所述的查耳酮类似物或如权利要求8所述的药用组合物在制备抗肿瘤药物中的应用。
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