CN100406461C - 含硫杂环并萘酰亚胺类化合物及其在肿瘤细胞中应用 - Google Patents
含硫杂环并萘酰亚胺类化合物及其在肿瘤细胞中应用 Download PDFInfo
- Publication number
- CN100406461C CN100406461C CNB031167098A CN03116709A CN100406461C CN 100406461 C CN100406461 C CN 100406461C CN B031167098 A CNB031167098 A CN B031167098A CN 03116709 A CN03116709 A CN 03116709A CN 100406461 C CN100406461 C CN 100406461C
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl
- group
- aromatic ring
- replaces
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 naphthalimides compound Chemical class 0.000 title claims abstract description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title abstract description 6
- 125000000623 heterocyclic group Chemical group 0.000 title description 5
- 239000005864 Sulphur Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 239000011593 sulfur Substances 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000005055 alkyl alkoxy group Chemical group 0.000 claims description 2
- 230000001629 suppression Effects 0.000 claims description 2
- 230000004565 tumor cell growth Effects 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- 229920003026 Acene Polymers 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical group C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims 1
- 239000007952 growth promoter Substances 0.000 claims 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 208000032839 leukemia Diseases 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 3
- 201000007270 liver cancer Diseases 0.000 abstract description 3
- 208000014018 liver neoplasm Diseases 0.000 abstract description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 2
- 201000005202 lung cancer Diseases 0.000 abstract description 2
- 208000020816 lung neoplasm Diseases 0.000 abstract description 2
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 1
- 206010017758 gastric cancer Diseases 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 230000035755 proliferation Effects 0.000 abstract 1
- 201000011549 stomach cancer Diseases 0.000 abstract 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 22
- 230000001915 proofreading effect Effects 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 238000004896 high resolution mass spectrometry Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 125000005605 benzo group Chemical group 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- ZHFAXTZGBCAAOL-UHFFFAOYSA-N 6h-thiochromeno[2,3-e]isoindole-1,3-dione Chemical compound C1C2=CC=CC=C2SC2=C1C=CC1=C2C(=O)NC1=O ZHFAXTZGBCAAOL-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- IMUDHTPIFIBORV-UHFFFAOYSA-N aminoethylpiperazine Chemical compound NCCN1CCNCC1 IMUDHTPIFIBORV-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000009830 intercalation Methods 0.000 description 3
- 230000002687 intercalation Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 229940043267 rhodamine b Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000007447 staining method Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 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 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- IPMWIVQWGGRTLD-UHFFFAOYSA-N n'-[2-(propylamino)ethyl]ethane-1,2-diamine Chemical class CCCNCCNCCN IPMWIVQWGGRTLD-UHFFFAOYSA-N 0.000 description 2
- BYVCTYDTPSKPRM-UHFFFAOYSA-N naphthalene-1-carbonyl naphthalene-1-carboxylate Chemical compound C1=CC=C2C(C(OC(=O)C=3C4=CC=CC=C4C=CC=3)=O)=CC=CC2=C1 BYVCTYDTPSKPRM-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- XXVLKDRPHSFIIB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 XXVLKDRPHSFIIB-UHFFFAOYSA-N 0.000 description 1
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 1
- MROVZCRMXJZHCN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-hydroxyethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCO)C=CC=1 MROVZCRMXJZHCN-UHFFFAOYSA-N 0.000 description 1
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 description 1
- MLEPLWCKAQEVNH-UHFFFAOYSA-N 6h-thiochromeno[2,3-e][2]benzofuran-1,3-dione Chemical compound C1C2=CC=CC=C2SC2=C1C=CC1=C2C(=O)OC1=O MLEPLWCKAQEVNH-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 235000014493 Crataegus Nutrition 0.000 description 1
- 241001092040 Crataegus Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GRSMWKLPSNHDHA-UHFFFAOYSA-N Naphthalic anhydride Chemical compound C1=CC(C(=O)OC2=O)=C3C2=CC=CC3=C1 GRSMWKLPSNHDHA-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 229960004701 amonafide Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000002223 garnet Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 229950001745 mitonafide Drugs 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 229920001021 polysulfide Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B57/00—Other synthetic dyes of known constitution
- C09B57/08—Naphthalimide dyes; Phthalimide dyes
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B69/00—Dyes not provided for by a single group of this subclass
- C09B69/10—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds
- C09B69/101—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds containing an anthracene dye
- C09B69/102—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds containing an anthracene dye containing a perylene dye
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B69/00—Dyes not provided for by a single group of this subclass
- C09B69/10—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds
- C09B69/109—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds containing other specific dyes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明公开一类新的含硫杂环并萘酰亚胺化合物的结构及其用途,本发明所说的化合物的特征是萘酰亚胺的共轭平面通过并入的五元(或六元)芳杂环得以扩大,并引入含硫杂原子。这些化合物具有广泛的抗肿瘤活性,尤其是对人肺癌、胃癌、肝癌和白血病等多种不同组织来源的肿瘤细胞的增殖显示出明显的抑制活性,且作用效果呈明显的量效关系。
Description
技术领域
本发明涉及一类新的含硫杂环并萘酰亚胺化合物及其用途。
背景技术
芳环上无并杂环的单萘酰亚胺类化合物是一类有很好抗癌活性的化合物,其中活性最好的amonafide(N-(β-二甲基胺基乙基)-3-胺基-1,8-萘酰亚胺)和mitonafide(N-(β-二甲基胺基乙基)-3-硝基-1,8-萘酰亚胺)已经进入二期临床试验(BranaM.F.Santos A.Roldan C.M.et al.Eur.J.Med.Chem.Chim.Ther.1981,16,207)。这类化合物能够嵌***DNA的碱基对之间,抑制DNA和RNA的合成,并能够抑制拓扑异构酶II,从而达到抑制肿瘤的目的。
如能在芳环上并入杂环及硫杂原子,增大芳香环平面和增强芳香环的平面刚性,提高其对DNA的嵌插能力,从而提高它的抗肿瘤活性。据此,发明人设计合成了一类新型的含硫杂环并萘酰亚胺化合物,试验证明其对体外肿瘤细胞生长表现出很强的抑制能力。
发明内容
本发明所说含硫杂环并萘酰亚胺化合物包括五元(取代)或六元(取代)杂环,具有以下的结构通式:
式中:R2为烷基、N,N-二甲基胺基取代的烷基或含氮饱和杂环取代的烷基;
当X=Y=N时,无取代基R1;
当X=C,Y=N时,R1为(杂)芳环或取代(杂)芳环,芳环上取代基如烷基,烷氧基,羟基,氨基,烷基取代的胺基,卤素,硝基,腈基,酰基,酰氧基,磺酸基和/或三氟甲基;
当X=Y=C时,R1为并(稠)(杂)芳环或取代并(稠)(杂)芳环,芳环上取代基如烷基,烷氧基,羟基,氨基,烷基取代的胺基,卤素,硝基,腈基,酰基,酰氧基,磺酸基和/或三氟甲基;
R3为并(稠)(杂)芳环或取代并(稠)(杂)芳环,芳环上取代基如烷基烷氧基,羟基,氨基,烷基取代的胺基,卤素,硝基,腈基,酰基,酰氧基,磺酸基和/或三氟甲基。
本发明所述的化合物与现有的化合物相比,由于其在芳香环上并入杂环及或引入硫杂原子,提高其对DNA的嵌插能力,从而增强它对肿瘤细胞生长的抑制能力。
具体实施方法
下面通过实施例对本发明作进一步的说明,其目的是为更好理解本发明的内容,但所举的实施例并不限制本发明的保护范围:
实施例1
N-(N’,N’-二甲基胺基乙基)-4H,6H-9-间硝基苯基-苯并[de]噻唑并[5,4-g]异喹啉-4,6-二酮(化合物1)的合成:
(1)Na2S·9H2O(0.009摩尔)与硫磺(0.018摩尔)在水中混合,加热(不超过40℃),直至硫磺全部溶解,得到多硫化钠的水溶液.然后加入4-溴-3-硝基-1,8萘酐(0.0025摩尔)(4)(J.Soc.Dyers Colourists 1974,90,153),回流8小时,降至室温后,用冰浴冰却约30分钟,然后过滤得暗红色滤液。在冰醋酸中加入间硝基苯甲醛0.00275摩尔,于50℃保温并通氩气30分钟,然后缓慢滴加上述滤液。回流反应4个小时,降至室温反应4个小时,反应液倒入冰水中,析出沉淀,过滤,滤饼用氢氧化钠溶液溶解,过滤,滤去不溶物后,滤液加盐酸酸析,所得固体抽干放置,称量固体为0.520克,产率为55%。
(2)称取0.52克由步骤(1)合成的产物,加入无水乙醇中,再向加入0.239毫升N,N-二甲基乙二胺。升温,回流,薄板层析跟踪反应,直至反应完全,过滤,所得固体经柱层析分离,得纯品目标产物(化合物1)0.17克,产率28%,熔点229-230℃(未校正)。
1H-NMR(d6-DMSO)δ(ppm):2.27(s,6H),2.59(s,2H),4.21(s,2H),7.91(d,1H,J=5.55),8.00(m,1H),8.44(m,1H),8.53(m,2H),8.62(m,1H),8.80(m,1H),8.89(m,1H)。
IR(KBr):2970,2800,2750,1700,1660,1525,1340,780cm-1。
EI-MS;m/z(%)446.0(M+)(1.47),388.0(1.05),358.0(1.79),342(1.10),258.0(1.62),157.0(1.98),71.1(41.03),58.1(100)。
元素分析C23H18N4O4S:计算值:C61.87,H4.06,N12.55;试验值:C62.03,H4.31,N12.79。
实施例2
N-(N’,N’-二甲基胺基乙基)-4H,6H-9-苯基-苯并[de]噻唑并[5,4-g]异喹啉-4,6-二酮(化合物2)的合成:
除用苯甲醛代替间硝基苯甲醛外,其它合成及提纯方法同实施例1。所得产物(化合物2),熔点220-221℃(未校正)。
1H-NMR(d6-DMSO)δ(ppm):2.25(s,8H),4.20(s,2H),7.66(d,J=4.54Hz,3H),8.03(t,J1=7.79,J2=7.57,1H),8.21(m,2H),8.56(d,J=6.97,1H),8.67(d,J=7.49,1H),8.95(s,1H)。
IR(KBr):2960,2800,1700,1660,1320,780cm-1。
HR-MS;C23H19N3O2S计算值:401.1198;试验值:401.1186;m/z(%)401(M+)(5.46),343(5.73),313(8.58),285(9.97),157(7.56),71(41.4),58(100)。
元素分析C23H19N3O2S:计算值:C68.81,H4.77,N 10.47;试验值:C68.54,H4.89,N10.51。
实施例3
N-(N’,N’-二甲基胺基乙基)-4H,6H-9-对甲基苯基-苯并[de]噻唑并[5,4-g]异喹啉-4,6-二酮(化合物3)的合成:
除用对甲苯甲醛代替间硝基苯甲醛外,其它合成及提纯方法同实施例1,所得产物(化合物3),熔点202-203℃(未校正)。
1H-NMR(d6-DMSO)δ(ppm):2.31(s,6H),2.43(s,5H),4.22(s,2H),7.46(d,J=7.91Hz,2H),8.03(t,J1=7.81,J2=7.83,1H),8.10(d,J=7.85Hz,2H),8.57(d,J=7.19,1H),8.66(d,J=8.11,1H),8.94(s,1H)。
IR(KBr):2960,2820,1700,1660,1325,790cm-1。
EI-MS:m/z(%)415.1(M+)(15.48),371(3.51),327(5.66),299(6.45),157(6.50),71(71.0),58(100)。
元素分析C24H21N3O2S:计算值:C69.38,H5.09,N 10.11;试验值:C69.30,H4.71,N10.25。
实施例4
N-(N’,N’-二甲基胺基乙基)-4H,6H-9-对甲氧基苯基-苯并[de]噻唑并[5,4-g]异喹啉-4,6-二酮(化合物4)的合成:
除用对甲氧基苯甲醛代替间硝基苯甲醛外,其它合成及提纯方法同实施例1,所得产物(化合物4)熔点216-217℃(未校正)。
1H-NMR(d6-DMSO)δ(ppm):2.27(s,6H),2.61(s,2H),3.89(s,3H),4.21(t,2H,J1=6.56,J2=6.64),7.19(d,J=8.66Hz,2H),8.01(t,J1=7.77,J2=7.77,1H),8.15(d,J=8.50Hz,2H),8.55(d,J=7.28,1H),8.63(d,J=8.18,1H),8.91(s,1H)。
IR(KBr):2970,2810,1700,1665,1330,780cm-1。
HR-MS;C24H21N3O3S计算值:431.1304;试验值:431.1311;m/z(%)431.1311(M+)(3.39),386.0719(2.49),343.0533(1.70),246.0349(1.69),157.0111(1.75),71.0732(73.67),58.0622(100)。
元素分析C24H21N3O3S:计算值:C66.80,H4.91,N 9.74;试验值:C66.94,H4.73,N10.03。
实施例5
N-(N’,N’-二甲基胺基乙基)-4H,6H-9-邻氯苯基-苯并[de]噻唑并[5,4-g]异喹啉-4,6-二酮(化合物5)的合成:
除用邻氯苯甲醛代替间硝基苯甲醛外,其它合成及提纯方法同实施例1。所得产物(化合物5)熔点235-237℃(未校正)。
1H-NMR(d6-DMSO)δ(ppm):2.28(s,6H),2.62(d,2H,J=1.44),4.19(t,2H,J1=6.78,J2=6.81),7.63(m,2H),7.76(m,1H),7.99(t,J1=7.74,J2=7.75,1H),8.38(dd,J1=1.78,J2=7.50,1H),8.54(d,J=7.32,1H),8.70(d,J=8.17,1H),8.94(s,1H)。
IR(KBr):2980,2800,1700,1660,1340,780cm-1。
HR-MS;C23H18ClN3O2S计算值:435.0808;试验值:435.0792;m/z(%)435.0792(M+)(5.06),377.0117(2.45),347.0052(4.14),319.0059(4.03),259.0427(1.14),157.0104(7.16),71.0733(67.76),58.0610(100)。
元素分析C23H18ClN3O2S:计算值:C63.37,H4.16,N 9.64;试验值:C63.42,H4.43,N9.35。
实施例6
N-(N’,N’-二甲基胺基乙基)-4H,6H-9-邻羟基苯基-苯并[de]噻唑并[5,4-g]异喹啉-4,6-二酮(化合物6)的合成:
除用邻羟基苯甲醛代替间硝基苯甲醛外,其它合成及提纯方法同实施例1。所得产物(化合物6)熔点240-241℃(未校正)。
1H-NMR(d6-DMSO)δ(ppm):2.27(s,6H),2.60(s,2H),4.21(t,2H,J1=6.88,J2=6.95,),7.07(t,1H,J1=7.39,J2=7.32),7.15(d,1H,J=8.21),7.47(m,1H),7.99(t,J1=7.76,J2=7.81,1H),8.30(dd,J1=1.46,J2=8.11,1H),8.53(d,J=7.25,1H,8.71(d,J=8.10,1H),8.94(s,1H)。
IR(KBr):2980,2800,2500(Br),1700,1660,1330,780cm-1。
HR-MS;C23H19N3O3S计算值:417.1147;试验值:417.0342;m/z(%)417.0342(M+)(6.20),372.9947(2.65),358.9714(3.38),300.9830(4.03),259.0427(4.62),156.9798(8.19),71.0554(100),58.0452(88.55)。
元素分析C23H19N3O3S:计算值:C66.17,H4.59,N10.07;试验值:C66.34,H4.78,N9.89。
实施例7
5-(N’,N’-二甲基胺乙基)-4H,6H-苯并[de]-1,2,3,-噻二唑并[5,4-g]异喹啉-4,6-二酮(化合物7)的合成:
(1)4-苄巯基-3-硝基-1,8-萘酐
4-溴-3-硝基-1,8-萘酐(0.0072摩尔)(4)于100毫升三口烧瓶中,加入45毫升DMF将其溶解,得黄色液体,再加入K2CO3(0.0036摩尔),苄硫醇(0.0072摩尔),80℃左右反应8小时,TLC跟踪至无原料,将反应液倒入冰水中,加盐盐析,搅拌,析出黄色沉淀,抽滤,水洗,烘干得土黄色滤饼2.47克,产率93%,m.p.188~193℃(未校正)。
(2)4-苄巯基-3-氨基-1,8-萘酐
100毫升三口烧瓶中加入4-苄疏基-3-硝基-1,8-萘酐(0.0068mol),7.6克SnCl2·2H2O,31毫升浓盐酸,90℃下搅拌反应2小时,反应中间补加10~20ml浓盐酸,TLC跟踪至原料消失,倒入冰水中,抽滤,烘干,得黄色固体2.85g,产率126%(可能产物中含有SnCl1),m.p.171~185℃(未校正)。
(3)1,2,3-噻二唑并-1,8-萘二甲酸酐
在250毫升三口烧瓶中加入4-苄巯基-3-氨基-1,8-萘酐(0.0044摩尔),57毫升冰醋酸,7毫升水,8.5毫升浓盐酸,室温下搅拌30分钟,得黄绿色液体,冰盐浴冷却至-10℃左右,滴加10毫升的NaNO2水溶液,剧烈搅拌,溶液变为红色,维持此温度搅拌30分钟,然后在冰水浴中反应3.5小时,接着在15~20℃水浴中反应3.5小时左右,TLC跟踪显示原料已消耗完,抽滤,滤饼用1%NaHCO3溶液洗至中性,抽干,得黄绿色固体0.97g,产率86%。
(4)5-(N’,N’-二甲基胺乙基)-4H,6H-苯并[de]-1,2,3,-噻二唑并[5,4-g]异喹啉-4,6-二酮的合成
将0.28克1,2,3-噻二唑并-1,8-萘二甲酸酐放入50毫升单口烧瓶中,加入20毫升无水乙醇,加入0.189毫升N,N-二甲基乙二胺,回流2小时左右,TLC跟踪至无原料,降温,蒸干溶剂得固体,经柱层析分离,得到淡黄色目标化合物(化合物7)0.25克,产率70%。熔点:178~179℃(未校正)。
1H NMR(d6-DMSO)δ(ppm):2.25(s,6H),2.57(t,J1=6.87Hz,J2=6.97Hz,2H),4.19(t,J1=6.86Hz,J2=6.99Hz,2H),8.06(t,J1=8.06Hz,J2=7.72Hz,1H),8.64(d,J=7.44Hz,1H),8.85(d,J=8.04Hz,1H),9.38(d,J=1.52Hz,1H)
IR(KBr压片):2940,2870,1700,1660,1300cm-1
HR-MS:C16H14N4O2S计算值:326.0837,试验值:326.0788。MS:m/z(%)326.0788(M+)(25.29),254.0261(14.92),209.9968(39.54),182.0024(45.43),155.9992(42.73),71.0683(84.29),58.0493(82.70)。
元素分析:C16H14N4O2S计算值:C58.88,H4.32,N17.17;实验值:C58.69,H4.17,N17.05。
实施例8
5-(N’,N’-二甲基胺丙基)-4H,6H-苯并[de]-1,2,3,-噻二唑并[5,4-g]异喹啉-4,6-二酮(化合物8)的合成:
除用N,N-二甲基丙二胺替代N,N-二甲基乙二胺外,其它合成及提纯方法同实施例7,得目标化合物8,熔点:101~102℃(未校正)。
1H NMR(CDCl3)δ(ppm):1.9(m,2H),2.22(s,6H),2.43(t,J1=7.16,J2=7.27,2H),4.23(t,J1=7.49,J2=7.66,2H),7.91(t,J1=7.74,J2=7.75,1H),8.4(t,J1=7.86,J2=0.86,1H),8.73(t,J1=7.16,J2=0.81,1H),9.58(s,1H)。
IR(KBr):2960,2870,1710,1670,1300cm-1。
HR-MS(m/z,%)C17H16N4O2S计算值:340.0994;实验值:340.0991。MS:m/z(%):340.0991(M+)(10.41),240.0145(2.96),210.0064(10.85),157.0130(5.39),84.0832(71.88),58.0655(100)。
元素分析:C17H16N4O2S计算值:C59.98,H4.74,N16.46;实验值:C59.74,H4.48,N16.65。
实施例9
5-丁基-4H,6H-苯并[de]-1,2,3,-噻二唑并[5,4-g]异喹啉-4,6-二酮(化合物9)的合成:
除用正丁胺替代N,N-二甲基乙二胺外,其它合成及提纯方法同实施例7,得目标化合物9,其熔点:177~179℃(未校正)。
1H NMR(d6-DMSO)δ(ppm):0.94(t,J1=7.33,J2=7.39,3H),1.38(m,2H),1.64(m,2H),4.05(t,J1=7.44,J2=7.54,2H),8.03(t,J1=7.78,J2=7.75,1H),8.62(d,J=7.11,1H),8.82(t,J1=0.70,J2=7.97,1H),9.32(s,1H)。
IR(KBr):2950,2870,1710,1660,1300cm-1。
HR-MS:C16H13N3O2S 计算值:311.0728;实验值:311.0728。MS:m/z(%):311.0728(M+)(17.00),283.0705(100.00),266.0659(27.86),241.0200(28.75),227.0069(89.84),157.0128(23.66)。
元素分析:C16H13N3O2S计算值:C 61.72,H 4.21,N 13.50;实验值:C61.59,H4.41,N13.62。
实施例10
5-(2’-哌嗪基乙基)-4H,6H-苯并[de]-1,2,3,-噻二唑并[5,4-g]异喹啉-4,6-二酮(化合物10)的合成:
除用1-(2-氨基乙基)哌嗪替代N,N-二甲基乙二胺外,其它合成及提纯方法同实施例7,得化合物10,其熔点:145~146℃(未校正)。
1H-NMR(CDCl3)δ(ppm):2.54(s,4H),2.67(t,J1=6.95,J2=6.94,2H),2.81(t,J1=4.76,J2=4.79,4H),4.34(t,J1=6.93,J2=7.01,2H),7.92(t,J1=7.8,J2=7.840,1H),8.41(d,J=7.96,1H),8.73(d,J=7.35,1H),9.58(s,1H)。
IR(KBr):3310,1710,1670,1300cm-1。
HR-MS:C18H17N5O2S计算值:367.1103;实验值:367.1095。MS(m/z,%):367.1095(M+,5.33),325.0751(6.87),282.0327(4.27),254.0289(8.85),182.0091(4.53),157.0128(2.36)99.0940(100)。
元素分析:C18H17N5O2S计算值:C 58.84,H 4.66,N 19.06;实验值:C58.75,H4.92,N18.86。
实施例11
N-(N’,N’-二甲基胺乙基)苯并[b]噻吩并[2,1-c]萘酰亚胺(化合物11)的合成:
将0.1123克苯并[b]噻吩并[2,1-c]萘二甲酸酐(Tetrahedron Lett.2002,43,2995-2998)放入50毫升单口烧瓶,加入20毫升无水乙醇,加入0.05毫升N,N-二甲基乙二胺,回流2小时左右,TLC跟踪至无原料,降温,过滤得产品(化合物11)0.1257克,产率91%。熔点:171~173℃(未校正)。
1H NMR(d6-DMSO)δ(ppm):2.3(s,6H),2.6(m,2H,),4.21(t,J1=6.55Hz,J2=6.62Hz,2H),7.65(m,2H),7.96(t,J1=7.74Hz,J2=7.82Hz,1H),8.23(m,1H),8.64(d,J=7.27Hz,1H),8.66(m,2H),9.28(s,1H)
IR(KBr压片):2940,2870,1700,1660,1330cm-1
HR-MS:C22H18N2O2S计算值:374.1089,实验值:374.1081。MS:m/z(%)374.1081(M+)(21.50),330.0558(6.48),260.0351(4.55),232.0327(14.95),71.0696(47.90),58.0623(100)
元素分析:C22H18N2O2S计算值:C 70.57,H 4.85,N 7.48;实验值:C70.41,H4.97,N7.68。
实施例12
N-(N’,N’-二甲基胺丙基)苯并[b]噻吩并[2,1-c]萘酰亚胺(化合物12)的合成:
除用N,N-二甲基丙二胺替代N,N-二甲基乙二胺外,其它合成及分离方法同实施例11,的目标化合物12,熔点:168-170℃(未校正)。
1H NMR(d6-DMSO)δ(ppm):1.95(m,2H),2.24(s,6H),2.45(m,2H),4.2(t,J1=7.38,J2=7.69,2H),7.54(m,2H),7.81(dd,J1=7.86,J2=7.82,1H),7.96(m,1H),8.33(m,1H),8.44(d,J=7.99,1H),8.59(d,J=6.96,1H),9.35(s,1H)。
IR(KBr压片):2940,2880,1700,1665,1330cm-1。
HR-MS:C23H20N2O2S计算值:388.1246,实验值:388.1253。MS:m/z(%)388.1253(M+)(20.62),330.0517(7.80),317.0350(10.03),303.0277(34.29),277.0735(50.50),246.0314(20.90),84.0779(100),58.0644(69.84)。
元素分析:C23H20N2O2S计算值:C 71.11,H 5.19,N 7.21;实验值:C71.01,H5.45,N7.46。
实施例13
N-(2’-哌嗪基乙基)苯并[b]噻吩并[2,1-c]萘酰亚胺(化合物13)的合成:
除用1-(2-氨基乙基)哌嗪替代N,N-二甲基乙二胺外,其它合成及分离方法同实施例11,得化合物13,熔点:226-228℃(未校正)。
1H NMR(d6-DMSO)δ(ppm):2.6(m,6H),3.34(s,4H),4.2(t,J1=6.47,J2=6.51,2H),7.65(m,2H),7.96(t,J1=7.75,J2=7.82,1H),8.2(m,1H),8.54(d,J=7.27,1H),8.64(m,2H),9.25(s,1H)。
IR(KBr压片):2950,2820,1700,1670,1330cm-1。
HR-MS:C24H21N3O2S计算值:415.1354,实验值:415.1349。MS:m/z(%)415.1349(M+)(8.30),373.1020(81.83),330.0602(44.08),304.0417(17.40),286.0309(19.16),259.0407(16.70),99.0890(100.0),70.0631(8.10)。
元素分析:C24H21N3O2S计算值:C 69.38,H 5.09,N 10.11;实验值:C69.49,H5.37,N10.32。
实施例14
N-丁基苯并[b]噻吩并[2,1-c]萘酰亚胺(化合物14)的合成:
除用正丁胺替代N,N-二甲基乙二胺外,其它合成及分离方法同实施例11,得化合物14,熔点:226-228℃(未校正)。
1H NMR(d6-DMSO)δ(ppm):0.94(t,J1=7.36,J2=7.36,3H),1.43(m,2H),1.71(m,2H),4.18(t,J1=7.57,J2=7.62,2H),7.54(m,2H),7.79(t,J1=7.78,J2=7.66,1H),7.95(m,1H),8.31(m,1H),8.42(m,1H),8.59(dd,J1=6.43,J2=0.89,1H)9.22(s,1H)。
IR(KBr压片):2990,2830,1700,1650,1330cm-1。
HR-MS:C22H17NO2S计算值:359.0980,实验值:359.0992。MS:m/z(%)359.0992(M+)(85.25),342.1040(45.10),317.0563(65.21),303.0304(100.0),286.0356(18.72),259.0480(19.09),232.0359(16.20)。
元素分析:C22H17NO2S计算值:C 73.51,H4.77,N 3.90;实验值:C73.46,H5.01,N3.18。
实施例15
N-(N’,N’-二甲基胺乙基)苯并[k,1]噻吨-3,4-二甲酰亚胺(化合物15)的合成:
将0.3克苯并[k,1]噻吨-3,4-二甲酸酐(Tetrahedron Lett.2002,43,2995-2998)放入50毫升单口烧瓶中,加入20毫升无水乙醇,加入0.162毫升N,N-二甲基乙二胺,回流2小时,TLC跟踪至无原料,降温,蒸干溶剂得固体,经柱层析分离(洗脱液为三氯甲烷∶丙酮=1∶1),得到目标化合物(化合物15)0.314克,产率85%。熔点:212-213℃(未校正)。
1H NMR(CDCl3)δ(ppm):1.27(m,8H),4.42(t,J1=6.78Hz,J2=6.65Hz,2H),7.39(m,3H),7.48(d,J=7.99,1H),8.18(m,2H),8.40(d,J=7.98Hz,1H),8.59(d,J=8.12,1H)
IR(KBr压片):2950,2870,1695,1660,1560,1380cm-1
MS:m/z(%)374(M+)(1.62),304(23.30),303(29.64),71(29.58),58(100),56(9.81),43(12.49)
元素分析:C22H18N2O2S计算值:C 70.57,H 4.85,N 7.48,S 8.56;实验值:C 70.46,H 4.98,N 7.35,S 8.83。
实施例16
N-(2’-哌嗪基乙基)苯并[k,1]噻吨-3,4-二甲酰亚胺(化合物16)的合成:
除用1-(2-氨基乙基)哌嗪替代N,N-二甲基乙二胺外,其它合成及提纯方法同实施例15,得化合物16,熔点:286-287℃(未校正)。
1H NMR(d6-DMSO)δ(ppm):2.80(t,J1=5.96,J2=6.00,2H),2.89(s,4H),3.14(s,4H)4.32(t,J1=6.08,J2=5.88,2H),7.41(m,3H),7.54(d,J=8.06,1H),8.24(m,2H),8.42(d,J=8.01,1H),8.62(d,J=8.18,1H)。
IR(KBr压片):3410,2970,2840,1690,1640,1330cm-1。
MS:m/z(%)415(M+)(5.45),373(39.42),330(35.98),303(27.95),99(100.0),70(27.95),56(42.09),42(21.07)。
元素分析:C24H21N3O2S计算值:C 69.38,H5.09,N 10.11;实验值:C69.56,H5.23,N9.96。
体外抑制肿瘤细胞生长活性测定:
分别用四氮唑盐(microculture tetrozolium,MTT)还原法对P388小鼠白血病细胞和磺酰罗丹明B(Sulforhodamine B,SRB)蛋白染色法对A-549人肺腺癌细胞进行抑制试验。
四氮唑盐(MTT)还原法的具体操作是:按不同肿瘤生长速率,将一定数量处于对数生长期的肿瘤细胞90μl/孔接种于96孔微量培养板内,培养24h后加入药液10μl/孔,对每个细胞株,每个浓度均为三个复孔。另设无细胞调零孔、如果药物有颜色要做相应药物浓度无细胞调零孔。肿瘤细胞在37℃、5%CO2条件下培养48小时后,加MTT(Sigma)液5mg/ml用生理盐水配制20μl/孔;继续培养4小时后,加入三联液(10%SDS-5%异丁醇-0.01mol/lHCl)50μl/孔,于CO2培养箱中过夜。然后用酶标仪测OD570值。按下列公式计算被测物对癌细胞生长的抑制率:肿瘤抑制率=(对照组OD值-治疗组OD值)/对照组OD值×100%。
磺酰罗丹明B(Sulforhodamine B,SRB)蛋白染色法的具体操作如下:根据细胞生长速率,将处于对数生长期的肿瘤细胞以90μl/孔接种于96孔培养板,贴壁生长24小时再加药10μl/孔。每个浓度设三复孔。并设相应浓度的生理盐水溶媒对照及无细胞调零孔。肿瘤细胞在37℃、5%CO2条件下培养72小时,然后倾去培养液,用10%冷TCA固定细胞,4℃放置1小时后用蒸馏水洗涤5次,空气中自然干燥。然后加入由1%冰醋酸配制的SRB(Sigma)4mg/ml溶液100μl/孔,室温中染色15分钟,去上清液,用1%醋酸洗涤5次,空气干燥。最后加入150μl/孔的Tris溶液,酶标仪520nm波长下测定A值。按下列公式计算被测物对癌细胞生长的抑制率:肿瘤抑制率=(A540对照孔-A540 给药孔)/A540对照孔×100%。
筛选方法:磺酰罗丹明B(Sulforhodamine B,SRB)蛋白染色法
四氮唑盐(microculture tetrozolium,MTT)还原法*
细胞株:P388小鼠白血病*MOLT-4人白血病*
A-549人肺腺癌SGC-7901人胃癌
BEL-7402人肝癌WI-38人胚胎成纤维细胞
作用时间:48h*-72h
对化合物1-16以及N-(N’,N’-二甲基胺丙基)苯并[k,l]噻吨-3,4-二甲酰亚胺(化合物17)、N-丁基苯并[k,l]噻吨-3,4-二甲酰亚胺(化合物18)的体外生测结果如下:
化合物对A-549生长的抑制率%
化合物对MOLt-4的生长抑制率%
化合物对SGC-7901生长的抑制率%
化合物对BEL-7402生长的抑制率%
化合物对P388生长的抑制率%
以上化合物具有广泛的抗肿瘤活性,尤其是对人肺癌、胃癌、肝癌和白血病等多种不同组织来源的肿瘤细胞的增殖显示出明显的抑制活性,且作用效果呈明显的量效关系。
Claims (8)
1.一种含硫杂环并萘酰亚胺类化合物,其特征在于,所述的化合物具有以下的结构通式:
式中:R2为烷基、N,N-二甲基胺基取代的烷基或含氮饱和杂环取代的烷基;
当X=Y=N时,无取代基R1;
当X=C,Y=N时,R1为芳环或取代芳环,芳环上取代基如烷基,烷氧基,羟基,氨基,烷基取代的胺基,卤素,硝基,腈基,酰基,酰氧基,磺酸基和/或三氟甲基;
当X=Y=C时,R1为并芳环或取代并芳环,芳环上取代基如烷基,烷氧基,羟基,氨基烷基取代的胺基,卤素,硝基,腈基,酰基,酰氧基,磺酸基和/或三氟甲基;
R3为并芳环或取代并芳环,芳环上取代基如烷基烷氧基,羟基,氨基,烷基取代的胺基,卤素,硝基,腈基,酰基,酰氧基,磺酸基和/或三氟甲基。
2.如权利要求1所述的化合物,其特征在于,其中X,Y均为氮。
3.如权利要求2所述的化合物,其特征在于,R2为烷基、N,N-二甲基胺基取代的烷基或2’-哌嗪基乙基。
4.如权利要求1所述的化合物,其特征在于,其中X为碳,Y为氮。
5.如权利要求4所述的化合物,其特征在于,R1为苯、甲苯、硝基苯、甲氧基苯、氯苯或邻羟基苯;R2为烷基、N,N-二甲基胺基取代的烷基或2’-哌嗪基乙基。
6.如权利要求1所述的化合物,其特征在于,其中X,Y均为碳。
7.如权利要求6所述的化合物,其特征在于,R1为并苯,R2为烷基、N,N-二甲基胺基取代的烷基或2’-哌嗪基乙基。
8.权利要求1-7所述的任意一种化合物在体外抑制肿瘤细胞生长剂方面的应用。
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB031167098A CN100406461C (zh) | 2003-04-30 | 2003-04-30 | 含硫杂环并萘酰亚胺类化合物及其在肿瘤细胞中应用 |
PCT/CN2004/000442 WO2004101570A1 (fr) | 2003-04-30 | 2004-04-30 | Derives de naphthoylimide contenant du soufre |
DE602004024386T DE602004024386D1 (de) | 2003-04-30 | 2004-04-30 | Schwefelhaltige naphthoylimidderivate |
EP04730460A EP1626050B1 (en) | 2003-04-30 | 2004-04-30 | Sulfur-containing naphthoylimide derivatives |
US11/263,591 US7541463B2 (en) | 2003-04-30 | 2005-10-31 | Sulfur-containing naphthalimide derivatives |
US12/116,452 US20080234287A1 (en) | 2003-04-30 | 2008-05-07 | Sulfur-containing naphthalimide derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB031167098A CN100406461C (zh) | 2003-04-30 | 2003-04-30 | 含硫杂环并萘酰亚胺类化合物及其在肿瘤细胞中应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1542011A CN1542011A (zh) | 2004-11-03 |
CN100406461C true CN100406461C (zh) | 2008-07-30 |
Family
ID=33438158
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB031167098A Expired - Fee Related CN100406461C (zh) | 2003-04-30 | 2003-04-30 | 含硫杂环并萘酰亚胺类化合物及其在肿瘤细胞中应用 |
Country Status (5)
Country | Link |
---|---|
US (2) | US7541463B2 (zh) |
EP (1) | EP1626050B1 (zh) |
CN (1) | CN100406461C (zh) |
DE (1) | DE602004024386D1 (zh) |
WO (1) | WO2004101570A1 (zh) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1786003B (zh) * | 2004-12-10 | 2011-05-11 | 华东理工大学 | 硫、氮杂环并萘酰亚胺类化合物及其在肿瘤细胞中应用 |
CN100406458C (zh) * | 2005-06-15 | 2008-07-30 | 华东理工大学 | 萘酰亚胺衍生物及其用途 |
CN100364536C (zh) * | 2006-03-03 | 2008-01-30 | 大连理工大学 | 甲基异硫脲阳离子作为连接基的脱氧核糖核酸双嵌入剂 |
CN101941984B (zh) * | 2010-09-10 | 2012-07-25 | 大连理工大学 | 一类2,1,3-噻二唑并萘酰亚胺化合物及其在肿瘤细胞中的应用 |
CN102304128B (zh) * | 2011-07-01 | 2013-03-20 | 北京大学 | 杂环并萘酰亚胺衍生物及其制备方法和用途 |
AU2013217282B2 (en) * | 2012-02-09 | 2016-07-28 | Basf Se | Rylene monoimide derivatives and use thereof as photosentizers in solar cells and photodetectors |
CN102617573B (zh) * | 2012-02-23 | 2014-09-17 | 北京大学 | 9-取代三氮唑并萘酰亚胺衍生物及其制备方法和用途 |
US9751789B2 (en) * | 2012-12-28 | 2017-09-05 | Ecolab Usa Inc. | Fluorescent monomers and tagged treatment polymers containing same for use in industrial water systems |
CN104945414A (zh) * | 2015-06-08 | 2015-09-30 | 浙江工业大学 | 苯并硫杂蒽类衍生物及其制备方法与应用 |
CN105153173B (zh) * | 2015-08-31 | 2017-11-07 | 浙江工业大学 | 一种苯并[k,l]呫吨‑3,4‑二甲酰亚胺衍生物及其制备方法和应用 |
US9885863B2 (en) * | 2015-12-31 | 2018-02-06 | Amazon Technologies, Inc. | Dye compounds for an electrowetting element |
CN107603269B (zh) * | 2016-07-11 | 2019-12-20 | 华东理工大学 | 一类基于萘酰亚胺的荧光染料、其制备方法及应用 |
KR102345008B1 (ko) * | 2019-05-24 | 2021-12-30 | 주식회사 키텍바이오 | 화합물, 상기 화합물을 포함하는 조성물, 및 상기 조성물을 이용하여 종양 세포를 비활성화 또는 사멸시키는 광역학 치료방법 |
CN111635754A (zh) * | 2020-06-22 | 2020-09-08 | 浙江工业大学 | 苯并硫杂蒽类衍生物的应用 |
CN114702509B (zh) * | 2022-04-18 | 2023-07-25 | 浙江工业大学 | 一种苯并噻吩并萘酰亚胺衍生物及其合成工艺和应用 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1391324U (zh) | ||||
DE1297259B (de) * | 1964-08-07 | 1969-06-12 | Hoechst Ag | Verfahren zur Herstellung von Farbstoffen |
DE1720618B2 (de) | 1967-02-10 | 1976-05-20 | Hoechst Ag, 6000 Frankfurt | Herstellung farbiger polystyrolschaeume aus expandierbaren perlen |
US3888863A (en) * | 1970-04-14 | 1975-06-10 | Hoechst Ag | Benzoxanthene and benzothioxanthene dyestuffs and process for their manufacture |
DE2238457A1 (de) | 1972-08-04 | 1974-02-14 | Hoechst Ag | Verfahren zum faerben von synthetischen fasermaterialien aus organischen loesemitteln |
DE2353639C2 (de) * | 1973-10-26 | 1983-08-04 | Hoechst Ag, 6230 Frankfurt | Elektrophotographisches Aufzeichnungsmaterial |
US4254109A (en) * | 1979-11-08 | 1981-03-03 | Ayerst, Mckenna & Harrison Inc. | 1H-Benz[de]isoquinoline-2(3H)-acetic acid derivatives |
US4499266A (en) * | 1983-04-01 | 1985-02-12 | Warner-Lambert Company | 3,6-Dinitro-1,8-naphthalimides |
JPS60221403A (ja) * | 1984-04-18 | 1985-11-06 | Nippon Kayaku Co Ltd | 重合性樹脂組成物 |
US6462128B1 (en) * | 2000-07-14 | 2002-10-08 | Clariant International Ltd. | Process of making finely divided opaque particles |
ES2191532B1 (es) * | 2001-05-28 | 2005-02-16 | Fundacion Universitaria San Pablo - Ceu | Derivados de naftalimidas heterociclicas como agentes antiproliferativos. |
GB0116677D0 (en) * | 2001-07-09 | 2001-08-29 | Clariant Int Ltd | Thermoplastic fluorescent pigment |
JP3732166B2 (ja) | 2002-08-22 | 2006-01-05 | 株式会社シマノ | 自転車用ハブ |
CN1239512C (zh) * | 2003-09-17 | 2006-02-01 | 大连理工大学 | 光敏芳香杂环化合物高效快速降解基因组dna |
-
2003
- 2003-04-30 CN CNB031167098A patent/CN100406461C/zh not_active Expired - Fee Related
-
2004
- 2004-04-30 EP EP04730460A patent/EP1626050B1/en not_active Expired - Lifetime
- 2004-04-30 WO PCT/CN2004/000442 patent/WO2004101570A1/zh active Application Filing
- 2004-04-30 DE DE602004024386T patent/DE602004024386D1/de not_active Expired - Lifetime
-
2005
- 2005-10-31 US US11/263,591 patent/US7541463B2/en not_active Expired - Fee Related
-
2008
- 2008-05-07 US US12/116,452 patent/US20080234287A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO2004101570A1 (fr) | 2004-11-25 |
CN1542011A (zh) | 2004-11-03 |
US7541463B2 (en) | 2009-06-02 |
EP1626050A1 (en) | 2006-02-15 |
EP1626050A4 (en) | 2008-03-05 |
DE602004024386D1 (de) | 2010-01-14 |
EP1626050B1 (en) | 2009-12-02 |
US20060111367A1 (en) | 2006-05-25 |
US20080234287A1 (en) | 2008-09-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100406461C (zh) | 含硫杂环并萘酰亚胺类化合物及其在肿瘤细胞中应用 | |
EP1802306A2 (en) | Quinolone analog as cell proliferation inhibitors | |
CN102206203A (zh) | 含有苯并咪唑的萘酰亚胺衍生物的合成及其在抗肿瘤上的应用 | |
CN110698474B (zh) | 一种α位取代四氢-γ-咔啉类化合物及其制备方法和应用 | |
CA2535370C (en) | Isothiazoloquinolones and related compounds as anti-infective agents | |
CA2597930A1 (en) | New isothiazoloquinolones and related compounds as anti-infective agents | |
CN112538079B (zh) | 一种香豆素类衍生物及其合成方法与应用 | |
CN108530343A (zh) | 一种大黄酸特定基团修饰的有机化合物、其芳基金属配合物、及其制备方法和应用 | |
CN101717411A (zh) | 去甲基斑蝥素衍生物磷酸二钠盐及其合成方法与用途 | |
CN104072493A (zh) | 一类含2-巯基苯并噻唑和***杂环的萘酰亚胺化合物,其制备方法及其应用 | |
CN100465177C (zh) | 氧、氮杂环并萘酰亚胺类化合物及其生物应用 | |
JP5469604B2 (ja) | 新規テトラヒドロ融合ピリジン | |
CN102731493B (zh) | 一类抗肿瘤含苯并噻唑杂环结构的化合物及其应用 | |
CN1786003B (zh) | 硫、氮杂环并萘酰亚胺类化合物及其在肿瘤细胞中应用 | |
CN114702509B (zh) | 一种苯并噻吩并萘酰亚胺衍生物及其合成工艺和应用 | |
CN109053725A (zh) | 一种2-(四氢喹啉-6-基)-四氢-1,8-萘啶类化合物及其制备方法与应用 | |
CN112174958B (zh) | 一种吡啶并[2,3-d]嘧啶类化合物及其制备方法和用途 | |
Helali et al. | Utility of activated nitriles in the synthesis of some new pyridine and fused pyridine derivatives with anticancer activity | |
CN104059062A (zh) | 含苯并噻唑和***双杂环的稠环化合物及其应用 | |
JP2782823B2 (ja) | ニコチン酸アミド化合物 | |
Burch | Nitrofuryl heterocycles. VII. 4-Amino-6-(5-nitro-2-furyl)-1H-pyrazolo [3, 4-d] pyrimidines | |
Elliott | Reactions of benzothiohydrazide as a bidentate nucleophile | |
CN108864110B (zh) | 萘醌并吡喃衍生物及其合成方法与应用 | |
Bátori et al. | Selective dimerizations of substituted N-aminopyridinium salts and their benzologs | |
Fan et al. | Studies of in vitro anti-prostate cancer potential of newer 1, 2, 4-triazolo-1, 3, 4-thiadiazines with different heteroaromatics |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080730 Termination date: 20150430 |
|
EXPY | Termination of patent right or utility model |