CN108191719A - 一种含砜类取代的查尔酮类似物、其制备方法及其医药用途 - Google Patents
一种含砜类取代的查尔酮类似物、其制备方法及其医药用途 Download PDFInfo
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- CN108191719A CN108191719A CN201810075456.2A CN201810075456A CN108191719A CN 108191719 A CN108191719 A CN 108191719A CN 201810075456 A CN201810075456 A CN 201810075456A CN 108191719 A CN108191719 A CN 108191719A
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- Prior art keywords
- compound
- trimethoxyphenyl
- sulfuryl
- vinyl
- indoles
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- 150000003457 sulfones Chemical class 0.000 title claims abstract description 12
- 238000006467 substitution reaction Methods 0.000 title claims description 11
- 150000001788 chalcone derivatives Chemical class 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- -1 methoxyl group Chemical group 0.000 claims description 140
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 32
- 229920002554 vinyl polymer Polymers 0.000 claims description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 15
- 150000003462 sulfoxides Chemical class 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000004215 Carbon black (E152) Substances 0.000 claims description 10
- 229930195733 hydrocarbon Natural products 0.000 claims description 10
- 150000002430 hydrocarbons Chemical class 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000012188 paraffin wax Substances 0.000 claims description 10
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 150000002475 indoles Chemical class 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 150000008131 glucosides 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
- BVBLWWZTZWLTHF-UHFFFAOYSA-N 1-(2-fluoroethenyl)-4-methoxybenzene Chemical class COC1=CC=C(C=CF)C=C1 BVBLWWZTZWLTHF-UHFFFAOYSA-N 0.000 claims description 3
- UAJRSHJHFRVGMG-UHFFFAOYSA-N 1-ethenyl-4-methoxybenzene Chemical class COC1=CC=C(C=C)C=C1 UAJRSHJHFRVGMG-UHFFFAOYSA-N 0.000 claims description 3
- JLBJTVDPSNHSKJ-UHFFFAOYSA-N 4-Methylstyrene Chemical class CC1=CC=C(C=C)C=C1 JLBJTVDPSNHSKJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 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 claims description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 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 claims description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 2
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 claims description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 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 claims description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 claims description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 claims description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 claims description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 2
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- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 2
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 2
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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Abstract
本发明涉及药物化学领域,具体涉及一类新的砜类查尔酮类似物及其制备方法。本发明还公开了含有所属化合物的药用组合物和所述化合物在治疗肿瘤以及通过抑制微管蛋白活性来治疗其他疾病或病症中的应用。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类新的砜类查尔酮类似物及其制备方法。本发明还公开了含有所属化合物的药用组合物和所述化合物在治疗肿瘤以及通过抑制微管蛋白活性来治疗其他疾病或病症中的应用。
背景技术
微管是细胞骨架的主要组成部分,在维持细胞形态、细胞分裂、信号转导等过程中起着重要作用,因此,微管蛋白是一个非常有前景的新型化疗药物的靶标。微管蛋白抑制剂能阻止肿瘤细胞的过度增殖,是一类重要的抗肿瘤治疗药物。目前,临床上应用的微管抑制剂主要有以紫杉醇为代表的抑制微管蛋白解聚药物及以长春碱类为代表的抑制微管蛋白聚集药物。而这些药物存在毒副作用大、合成难度大、水溶性差、易产生耐药性等缺点。而秋水仙碱结合位点是目前对微管蛋白研究较多的一个位点,作用于该位点的抑制剂通常结构较简单,如秋水仙碱、 Combretastatin A-4等。此外,作用于该位点的抑制剂还能破坏肿瘤组织的血管,因此,对作用于秋水仙碱位点的微管蛋白抑制剂的研究已成为当今抗肿瘤研究的热点。
查尔酮类化合物是一类重要的微管蛋白抑制剂。Sylvie Ducki等人于1998 年在《Bioorganic & Medicinal Chemistry Letters》第8期1051-1056页发表了“Potentantimitotic and cell growth inhibitory properties of substituted chalcones”,该文发现了一种查尔酮化合物具有很高的抗增殖活性,并证实它具有抗微管蛋白聚集的作用。后来,该课题组又发表了多篇同类型研究,证明该类化合物是典型的作用于秋水仙碱结合位点的微管蛋白抑制剂。
而Jun Yan等人与2016年在《Journal of Medicinal Chemistry》杂志第59期5264-5283页发表了“Synthesis,Evaluation,and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity ThroughMicrotubule Destabilization in Vitro and in Vivo”,发现含有吲哚结构的查尔酮化合物同样具有很高的抗增殖活性,其在体内抗肿瘤模型上显示出较好的抗肿瘤活性。
这些研究表明,具有α,β不饱和酮取代的查尔酮类化合物是一类重要的微管蛋白抑制剂。而乙烯基砜及亚砜作为迈克尔受体,其结构与α,β不饱和酮类似,因此,通过生物电子等排替换,我们设计合成了一类新型的含乙烯基砜及亚砜的类查尔酮化合物,并通过抗肿瘤活性测试,发现了一类活性好,毒性小,具有抗肿瘤细胞耐药性的新型微管蛋白抑制剂。
发明内容
本发明的目的旨在寻找活性好,毒性小,对耐药肿瘤有效的乙烯基砜类微管蛋白抑制剂,并提供该类化合物的制备方法及用途。
为实现上述目的,本发明提供如下技术方案:
一种乙烯基砜及亚砜类小分子微管蛋白抑制剂,及其可药用盐,具有通式I及通式II所示的结构:
其中:
X代表硫、砜、亚砜;
R1代表氢、低级烷烃、甲氧基、卤素、氰基、酯基、酰胺基,羧基;
R2代表氢、低级烷烃;
R3,R4,R5可以是下列基团中的任意一个:氢、低级烷烃、甲氧基、卤素、氰基、酯基、酰胺基,羟基,氨基,硝基,二甲氨基,硼酸基,糖苷基团,氨基酸,磺酰胺,磷酸二钠盐;
R6代表氢、低级烷烃,羟基,甲氧基,磷酸二钠盐,糖苷,(CH2)1-6OH;
R7代表氢、低级烷烃,甲氧基,醛基,酰胺基,氰基,羟甲基,乙烯基, -CH=NHOH,-CH2OAc;
通式II中,烯基取代的位置可在吲哚3位,4位,5位,6位,7位;
通式II中,烯基取代吲哚环或烯基取代二氢吲哚环。
本发明通式I与II的微管蛋白抑制剂,其中:
X优选砜、亚砜;
R1优选氢、甲基、氯、氟、甲氧基;
R2优选氢;
R3优选氢、羟基、氨基、氟、磷酸二钠盐、氨基酸;
R4优选氟、甲氧基、羟基、甲基、二甲氨基、硝基;
R5优选氢;
R6优选氢、甲基、磷酸二钠盐;
R7优选氢、醛基;
通式II中,烯基取代优先在吲哚环的3,4,5位。
本发明的部分优选化合物为:
化合物1:(E)-1,2,3-三甲氧基-5-(苯乙烯基砜基)苯;
化合物2:(E)-5-((4-氟苯乙烯基)砜基)-1,2,3-三甲氧基苯;
化合物3:(E)-N,N-二二甲基-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯胺;
化合物4:(E)-1,2,3-三甲氧基-5-((4-甲基苯乙烯基)砜基)苯;
化合物5:(E)-1,2,3-三甲氧基-5-((4-硝基苯乙烯基)砜基)苯;
化合物6:(E)-1,2,3-三甲氧基-5-((4-甲氧基苯乙烯基)砜基)苯;
化合物7:(E)-5-((3,4-二甲氧基苯乙烯基)砜基)-1,2,3-三甲氧基苯;
化合物8:(E)-1,2,3-三甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯;
化合物9:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯酚;
化合物10:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯基-1,2-二酚;
化合物11:(E)-5-((3-氟-4-甲氧基苯乙烯基)砜基)-1,2,3-三甲氧基苯;
化合物12:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯酚;
化合物13:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基-1-丙烯基苯酚;
化合物14:(E)-5-(2-氟-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-2-甲氧基苯酚;
化合物15:(E)-3-(3-羟基-4-甲氧基苯基)-2-((3,4,5-三甲氧基苯基)砜基)丙烯腈;
化合物16:(Z)-5-(2-氯-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-2-甲氧基苯酚;
化合物17:((E)-2-甲氧基-5-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)烯基)苯酚;
化合物18:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)烯基)苯胺;
化合物19:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基-1-丙烯基苯胺;
化合物20:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)苯酚;
化合物21:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)亚砜基-1-丙烯基苯酚;
化合物22:(E)-3-(3-羟基-4-甲氧基苯基)-2-((3,4,5-三甲氧基苯基)亚砜基)丙烯腈;
化合物23:(Z)-5-(2-氯-2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-2-甲氧基苯酚;
化合物24:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)亚砜基)烯基)苯胺;
化合物25:(E)-3-(3-羟基-4-甲氧基苯基)-2-((3,4,5-三甲氧基苯基)砜基)丙烯酸乙酯;
化合物26:(E)-5-甲氧基-3-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物27:(E)-6-甲氧基-3-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物28:(E)-5-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物29:(E)-6-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物30:(E)-7-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物31:(E)-3-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物32:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物33:(E)-5-(2-((3,4,5-三甲氧基苯基)砜基)-1-丙烯基)-1H-吲哚;
化合物34:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)-1-丙烯基)-1H-吲哚;
化合物35:(E)-4-(2-氟-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物36:(E)-3-(1H-吲哚-4-基)-2-((3,4,5-三甲氧基苯基)砜基)丙烯腈;
化合物37:(E)-4-(2-氯-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物38:(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物39:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)二氢吲哚;
化合物40:(E)-1-甲基-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物41:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚-3-甲醛;
化合物42:(E)-5-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物43:(E)-4-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物44:(E)-4-(2-((3,4,5-三甲氧基苯基)亚砜基)-1-丙烯基)-1H-吲哚;
化合物45:(E)-4-(2-氯-2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物46:(E)-3-(1H-吲哚-4-基)-2-((3,4,5-三甲氧基苯基)亚砜基)丙烯腈;
化合物47:(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物48:(E)-1-甲基-4-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物49:(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚-3- 甲醇;
化合物50:(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚-3- 甲腈;
化合物51:(E)-(2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)烯基)苯基)甘氨酸钠盐酸盐;
化合物52:(E)-4-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚磷酸二钠盐。
本发明通式I与II的化合物可用下列方法制备得到:
反应1
反应2
反应3
A.反应式解1合成步骤如下:
以三甲氧基苯胺1为起始原料,经重氮反应制成重氮盐,然后与乙基黄原酸钾反应,在碱性条件下水解可得三甲氧基苯硫酚3;三甲氧基苯硫酚与对甲苯磺酰氧甲基膦酸二乙酯4在碳酸钾/乙腈条件下反应可得磷酸酯中间体5;该中间体与N-氯丁二酰亚胺反应可得氯代的磷酸酯中间体6,然后在甲醇中回流得到甲氧基取代的磷酸酯7;磷酸酯中间体在-78度经正丁基锂拔氢,与碘甲烷反应可得甲基取代的中间体8。
B.反应式解2的合成步骤如下:
磷酸酯中间体5-8在间氯过氧苯甲酸的选择性氧化下可得含砜的磷酸酯 5a-8a及含亚砜的磷酸酯5b-8b,然后再与醛经wittig-hornor反应可得目标产物。氟取代的目标产物合成如下:含砜的磷酸酯9在钠氢条件下拔氢,然后与 Selectflor反应可得氟取代的磷酸酯9a,然后再与醛经wittig-hornor反应可得目标产物;氰基取代的目标产物合成如下:三甲氧基苯硫酚3与溴乙腈在碳酸钾/ 乙腈条件下反应,然后再在间氯过氧苯甲酸的选择性氧化下可得含砜的磷酸酯 10a及含亚砜的磷酸酯10b,然后与醛发生克脑文格尔反应,可得氰基取代的目标产物。
C.反应式解2的合成步骤如下:
含砜或亚砜的目标产物在11氰基硼氢化钠/醋酸条件下还原可得到二氢吲哚的目标产物12;经Vilsmeier反应可在吲哚3位上醛基可得到13,该醛基可被还原为羟甲基14;醛基的目标产物与盐酸羟肟缩合、醋酐/吡啶条件脱水可得吲哚 3位氰基取代的目标产物16。
下面是本发明部分化合物的药理实验结果:
抗增殖实验
1.实验方法
2.细胞消化、计数、制成浓度为5×104个/mL的细胞悬液,96孔板中每孔加入100μl细胞悬液(每孔5×103个细胞);
3. 96孔板置于37℃,5%CO2培养箱中培养24小时;
4.用完全培养基稀释药物至所需浓度,每孔加入100μL相应的含药培养基;
5. 96孔板置于37℃,5%CO2培养箱中培养72小时;
6.MTT法:
1)将96孔板进行MTT染色,λ=490nm,测定OD值。
2)每孔加入20μL MTT(5mg/mL),在培养箱继续培养4小时;
3)弃去培养基,每孔加入150μL DMSO溶解,摇床10分钟轻轻混匀;λ=490nm,酶标仪读出每孔的OD值。
6.计算抑制率。
2.实验结果
表1 通式I中的实施例对3种人类癌细胞株抗增殖活性的IC50值(μM)
化合物编号 | HepG2 | A549 | K562 |
1 | 18.12 | 26.32 | 18.67 |
2 | 17.79 | 25.75 | 17.74 |
3 | 2.75 | 4.78 | 2.75 |
4 | 3.78 | 5.75 | 2.75 |
5 | 6.86 | 10.64 | 5.75 |
6 | 3.67 | 6.43 | 2.86 |
7 | 4.63 | 5.78 | 3.74 |
8 | 12.78 | 20.53 | 10.86 |
9 | 1.56 | 4.45 | 1.57 |
10 | 0.75 | 3.45 | 0.84 |
11 | 1.41 | 3.64 | 1.66 |
12 | 0.21 | 2.83 | 0.23 |
13 | 0.83 | 2.97 | 0.52 |
14 | 0.52 | 1.43 | 0.45 |
15 | 10.64 | 20.65 | 8.64 |
16 | 2.34 | 5.34 | 2.13 |
17 | 0.52 | 2.91 | 0.19 |
18 | 0.22 | 0.61 | 0.12 |
19 | 0.82 | 2.24 | 0.67 |
20 | 0.29 | 1.50 | 0.24 |
21 | 3.24 | 5.37 | 2.64 |
22 | 10.84 | 15.37 | 8.63 |
23 | 0.24 | 1.172 | 0.19 |
24 | 0.75 | 2.57 | 0.71 |
25 | 8.93 | 15.37 | 7.72 |
顺铂 | 3.56 | 3.89 | 2.76 |
表2 通式II中的实施例对3种人类癌细胞株抗增殖活性的IC50值(μM)
化合物编号 | HepG2 | A549 | K562 |
26 | 12.35 | 16.32 | 10.38 |
27 | 11.86 | 17.38 | 9.73 |
28 | 2.75 | 4.72 | 2.77 |
29 | 10.37 | 18.73 | 12.75 |
30 | 16.86 | 20.64 | 15.73 |
31 | 0.34 | 2.10 | 0.33 |
32 | 0.08 | 0.26 | 0.07 |
33 | 3.47 | 8.36 | 3.27 |
34 | 0.28 | 1.41 | 0.51 |
35 | 0.20 | 1.16 | 0.10 |
36 | 10.27 | 17.27 | 9.87 |
37 | 0.18 | 1.80 | 0.13 |
38 | 5.29 | 8.16 | 3.28 |
39 | 0.68 | 3.22 | 0.60 |
40 | 0.32 | 1.73 | 0.29 |
41 | 3.29 | 5.23 | 2.97 |
42 | 3.97 | 4.09 | 2.98 |
43 | 0.09 | 0.56 | 0.15 |
44 | 0.31 | 1.15 | 0.21 |
45 | 0.33 | 1.93 | 0.28 |
46 | 5.23 | 8.38 | 4.23 |
47 | 2.49 | 4.23 | 2.94 |
48 | 0.26 | 0.80 | 0.22 |
49 | 2.98 | 3.49 | 1.97 |
50 | 1.98 | 2.97 | 1.72 |
51 | 0.52 | 1.59 | 0.32 |
52 | 0.17 | 0.59 | 0.17 |
顺铂 | 3.56 | 3.89 | 2.76 |
下面是部分化合物的体外抗微观蛋白聚集的实验
1.实验方法
化合物按照相应要求配置成母液,按照倍数稀释成终浓度后用于后续试验。浓度设置为5个,每个浓度生物学重复3次。将2mg/mL微管蛋白(细胞骨架) 的量重新悬浮于PEM缓冲液[80mM PIPES(pH6.9),0.5mM EGTA,2mM MgCl2和15%甘油]中,然后在冰上与化合物或溶剂DMSO预孵育5分钟。在检测微管蛋白聚合反应之前,加入含有GTP的PEG至终浓度为3mg/mL。通过Berthold LB941微孔板式多功能酶标仪,30分钟后在340nm检测吸光度。通过设置空白对照组,Graphpad计算得出不同化合物的IC50,结果以μM为单位。
2.实验结果
表3 本发明部分化合物的体外微管蛋白聚集的药理实验结果:
化合物编号 | 抑制微管蛋白聚集IC50 |
12 | 8.23 |
13 | 7.89 |
14 | 8.29 |
17 | 6.34 |
18 | 4.25 |
19 | 4.87 |
20 | 7.17 |
23 | 3.99 |
31 | 4.87 |
32 | 3.83 |
34 | 5.98 |
35 | 5.39 |
37 | 6.98 |
43 | 6.76 |
CA-4 | 2.17 |
下面是部分化合物的体内抗肿瘤实验
1.实验方法
由上海斯莱克实验动物有限责任公司提供,周龄为3周,体重12-16g的雌性Balb/c裸鼠70只。收集培养的肝癌H22细胞,计数、调整使细胞悬液浓度为 1.5×107个/ml,于裸小鼠右侧腋窝皮下每只接种0.1ml。用游标卡尺测量裸鼠移植瘤的直径,接种肿瘤细胞7天后,肿瘤长至50-75mm3时,每组10只将裸鼠随机分为7组。衍生物溶于DMSO,再滴入poloxamer母液,最后加生理盐水至所需剂量。DMSO终浓度为1%,poloxamer终浓度为2%。各组裸鼠给药,模型组腹腔注射等量溶媒,每天注射1次,持续21天;阳性对照组尾静脉注射 30mg/kg顺铂,每天注射1次,持续21天;实验组静脉注射30mg/kg化合物17, 18,19,20,31,32,34,35,37。每天注射1次,持续21天;给药21天结束后处死裸鼠,通过手术剥取瘤块,称重。计算肿瘤生长抑制率(%),用SPSS 17.0对结果进行分析,组间用t检验进行统计学分析处理,其计算公式如下:
2.实验结果
表4 部分实施例的体内抗肿瘤活性
具体实施方式
以下通过实施例形式展示具体的实施方式,对本发明内容进行进一步的详细说明,但不应当将此理解为本发明上述主题的范围仅限于以下的实施例,凡是基于本发明上述内容在本领域内所能实现的技术均应属于本发明的内容。
实施例1
(E)-1,2,3-三甲氧基-5-(苯乙烯基砜基)苯
(a)将三甲氧基苯胺(2g,10.9mmol)溶于甲醇(5mL)与10%稀盐酸(5ml)的混合液中,0度下缓慢滴入亚硝酸钠(1g,14.4mmol)的水溶液(20ml),搅拌15分钟后,滴入乙基黄原酸钾(3.4g,21.2mmol)的水溶液,65度搅拌30分钟,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析(PE/EA 15∶1,10∶1)得油状1.73g,产率55.8%。
(b)将a的产物(100mg,0.35mmol)溶于5ml甲醇中,加入5ml 10%的氢氧化钠水溶液,室温反应30分钟,旋掉甲醇,10%稀盐酸调至中性,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩得64mg油状三甲氧基苯硫酚。
(c)将三甲氧基苯硫酚(5.6g,28mmol)溶于乙腈中(50.0mL),加入碳酸钾(4.6g,33.6mmol)搅拌十分钟,再加入对甲苯磺酰氧甲基膦酸二乙酯,50度反应两小时,反应结束后旋掉乙腈,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析(DCM/CH3OH 200∶1)得无色油状6.2g,产率63%。
(d)将c的产物(1g,2.85mmol)溶于干燥的二氯甲烷中,加入75%含量的间氯过氧苯甲酸(1.3g,5.65mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析(DCM/CH3OH 100∶1)得黄色油状600mg,产率55%。
(e)将d的产物(50mg,0.13mmol)溶于干燥的四氢呋喃中,氮气保护下加入60%含量的钠氢(7.8mg,0.195mmol),0度下搅拌15分钟后,加入苯甲醛(16mg, 0.156mmol),室温反应1小时,反应结束后旋掉THF,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析(PE/EA 5∶1)得白色固体33mg,产率76.7%。1H NMR(300MHz,CDCl3)δ 7.65(d,J=15.4Hz,1H),7.45-7.17(m, 5H),7.17(s,2H),6.87(d,J=15.4Hz,1H),3.92(s,9H);13C NMR(75MHz,CDCl3) δ 153.63,141.86,135.25,132.43,131.16,129.09,128.55,127.47,105.04,58.98, 56.51;HR-MS(ESI)m/z:calcd for C17H17FO5S[M+H]+353.0853,found335.0945.
实施例2
(E)-5-((4-氟苯乙烯基)砜基)-1,2,3-三甲氧基苯
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 7.61(d,J=15.4Hz, 1H),7.52-7.47(m,2H),7.12-7.06(m,2H),6.83-6.77(d,J=15.4Hz,1H),5.32- 4.90(m,1H),3.91(s,J=5.3Hz,9H);13C NMR(75MHz,CDCl3)δ 153.14,140.02, 134.62,130.13,130.01,128.16,126.73,115.97,115.68,104.51,60.44,56.01.
实施例3
(E)-N,N-二甲基-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯胺
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 7.56(d,J=15.2Hz, 1H),7.37(d,J=8.8Hz,2H),7.15(s,2H),6.64(d,J=8.8Hz,2H),6.58(d,J=15.2 Hz,1H),3.91(s,9H),3.01(s,6H);13C NMR(75MHz,CDCl3)δ 170.65,153.49, 152.28,147.69,142.75,141.85,136.59,130.37,120.81,119.25,111.73,104,68, 60.91,56.47,40.03;HR-MS(ESI)m/z:calcd for C19H23NO5S[M+H]+378.1370, found 378.1366.
实施例4
(E)-1,2,3-三甲氧基-5-((4-甲基苯乙烯基)砜基)苯
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 7.62(d,J=15.4Hz, 1H),7.39(d,J=7.9Hz,2H),7.20(d,J=8.1Hz,2H),7.16(s,2H),6.81(d,J=15.4 Hz,1H),3.91(s,6H),3.90(s,3H),2.37(s,3H);13C NMR(75MHz,CDCl3)δ 153.10, 141.76,141.45,141.33,134.98,129.31,129.18,128.07,125.72,104.45,60.43,56.00, 20.98;HR-MS(ESI)m/z:calcd for C18H20O5S[M+H]+349.1104,found 349.1103.
实施例5
(E)-1,2,3-三甲氧基-5-((4-硝基苯乙烯基)砜基)苯
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 8.17(d,J=8.6Hz, 2H),7.72-7.37(m,3H),7.09(s,2H),6.95(d,J=15.5Hz,1H),3.85(s,6H),3.84(s, 3H);13C NMR(75MHz,CDCl3)δ 153.75,148.99,142.83,138.58,138.46,134.11, 131.83,129.22,124.26,105.25,60.98,56.55;HR-MS(ESI)m/z:calcd for C17H17NO7S[M+NH4]+397.1064,found 397.1067.
实施例6
(E)-1,2,3-三甲氧基-5-((4-甲氧基苯乙烯基)砜基)苯
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 7.57(d,J=15.3Hz, 1H),7.44(d,J=8.5Hz,2H),7.16(s,2H),6.87(d,J=8.4Hz,2H),6.72(d,J=15.3 Hz,1H),3.91(s,6H),3.89(s,3H),3.83(s,3H);13C NMR(75MHz,CDCl3)δ 162.09, 153.57,142.18,141.63,131.74,130.30,125.02,124.55,114.47,104.75,77.46,77.04,76.62,60.92,56.49,55.43;HR-MS(ESI)m/z:calcd for C18H20O6S[M+H]+365.1053, found 365.1053.
实施例7
(E)-5-((3,4-二甲氧基苯乙烯基)砜基)-1,2,3-三甲氧基苯
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 7.68(d,J=15.3Hz, 1H),7.17(s,2H),7.09(d,J=8.3Hz,1H),6.99(s,1H),6.87(d,J=8.3Hz,1H), 6.73(d,J=15.3Hz,1H),3.92(s,6H),3.90(s,3H),3.89(s,3H);13C NMR(75MHz, CDCl3)δ 153.09,151.41,148.90,141.72,141.45,135.15,124.76,124.31,122.91, 110.66,109.63,104.43,60.43,56.00,55.49,55.47;HR-MS(ESI)m/z:calcd for C19H22O7S[M+H]+395.1159,found395.1165.
实施例8
(E)-1,2,3-三甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 7.56(d,J=15.3Hz, 1H),7.17(s,2H),6.79(d,J=15.3Hz,1H),6.72(s,2H),3.92(s,6H),3.90(s,3H), 3.87(s,9H);13CNMR(75MHz,CDCl3)δ 153.09,153.06,141.85,141.65,140.46, 134.81,127.22,125.94,105.45,104.51,60.46,56.01,55.75;HR-MS(ESI)m/z:calcd for C20H24O8S[M+H]+425.1265,found 425.1269.
实施例9
(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯酚
(a)将对羟基苯甲醛(500mg,4.09mmol)溶于二氯甲烷中,滴入三乙胺(681μL,4.9mmol),再缓慢滴入醋酐(681μL,4.9mmol),反应一小时,二氯甲烷稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩得602mg白色固体,产率90.0%。
(b)将实施例一中d的产物(70mg,0.18mmol)溶于干燥的四氢呋喃中,氮气保护下加入60%含量的钠氢(11mg,0.275mmol),0度下搅拌15分钟后,加入a 的产物(33mg,0.20mmol),室温反应1小时,反应结束后旋掉THF,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后溶于5ml甲醇,加入5ml 10%氢氧化钠水溶液,室温搅拌三十分钟,反应结束后,旋掉甲醇,稀盐酸酸化,二氯甲烷稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA 4∶1),得57mg绿色固体,产率89.0%。1H NMR(300MHz,DMSO)δ 10.12(s,1H), 7.55(d,J=7.9Hz,2H),7.51(d,J=15.6Hz,1H),7.31(d,J=15.6Hz,1H),7.15(s,1H),6.79(d,J=7.6Hz,2H),3.85(s,3H),3.72(s,3H),3.35(s,3H);13C NMR(75 MHz,DMSO)δ160.83,153.66,142.12,141.80,136.67,131.45,124.26,123.90, 116.32,104.85,60.67,56.81;HR-MS(ESI)m/z:calcd for C20H24O8S[M+H]+ 351.0902,found 351.0905.
实施例10
(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯基-1,2-二酚
参照实施例1的合成方法。1H NMR(300MHz,DMSO)δ 7.42(d,J=15.3Hz, 1H),7.26(d,J=15.2Hz,1H),7.20(s,2H),7.08(d,J=1.7Hz,1H),7.04(dd,J=1.8 Hz,8.3Hz,1H),6.79(d,J=8.1Hz,1H),3.88(s,6H),3.75(s,3H);13C NMR(75 MHz,DMSO)δ 153.13,148.94,145.62,142.00,141.25,136.24,123.96,123.83, 122.05,115.68,115.48,104.35,60.16,56.31;HR-MS(ESI)m/z:calcd for C17H18O7S [M+H]+367.0846,found 367.0845.
实施例11
(E)-5-((3-氟-4-甲氧基苯乙烯基)砜基)-1,2,3-三甲氧基苯
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 7.54(d,J=15.2Hz, 1H),7.25-7.21(m,2H),7.16(s,2H),6.96(t,J=8.3Hz,1H),6.73(d,J=15.3Hz, 1H),3.92(s,12H);13C NMR(75MHz,CDCl3)δ 154.02,153.62,150.73,140.50, 135.31,126.20,126.13,126.09,115.28,115.03,113.32,104.95,60.92,56.49,56.28; HR-MS(ESI)m/z:calcdforC18H19FO6S[M+H]+383.0959,found 383.0963.
实施例12
(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯酚
参照实施例1的合成方法。1H NMR(300MHz,DMSO)δ 9.20(s,1H),7.45(d, J=15.3Hz,1H),7.33(d,J=15.3Hz,1H),7.17(s,2H),7.15-7.09(m,2H),6.97(d, J=8.3Hz,1H),3.86(s,6H),3.81(s,3H),3.73(s,3H);13C NMR(75MHz,DMSO) δ 153.65,151.02,147.18,142.12,141.84,136.52,125.73,125.62,122.47,115.33, 112.40,104.92,60.67,56.82,56.16;HR-MS(ESI)m/z:calcd for C18H20O7S [M+H]+381.1003,found 381.1004.
实施例13
(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基-1-丙烯基苯酚
(a)将实施例1中c的产物(1g,2.86mmol)溶于无水四氢呋喃中,零下78度下缓慢滴入2.5mol/L的正丁基锂的正己烷溶液(1.5ml,3.4mmol),保持该温度搅拌30分钟,再滴入碘甲烷(212μL,3.1mmol)的四氢呋喃溶液,升至室温反应,TLC 检测,反应结束后,旋掉四氢呋喃,二氯甲烷稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(DCM/CH3OH 200∶1),得500mg油状,产率48.0%。
(b)将a的产物(1g,2.74mmol)溶于干燥的二氯甲烷中,加入75%含量的间氯过氧苯甲酸(1.3g,5.65mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析(DCM/CH3OH 100∶1)得黄色油状809mg,产率76%。
(e)将b的产物(72mg,0.18mmol)溶于干燥的四氢呋喃中,氮气保护下加入60%含量的钠氢(11mg,0.27mmol),0度下搅拌15分钟后,加入乙酰基保护的异香兰素(42mg,0.22mmol),室温反应1小时,反应结束后旋掉THF,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后溶于5ml甲醇,加入5ml 10%氢氧化钠水溶液,室温搅拌三十分钟,反应结束后,旋掉甲醇,稀盐酸酸化,二氯甲烷稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA4∶1),得27mg绿色固体,两步产率37.5%。1H NMR(300MHz,DMSO)δ 9.21(s,1H), 7.53(s,1H),7.06(s,2H),6.95(s,3H),3.81(s,6H),3.76(s,3H),3.70(s,3H),2.04(s, 3H);13C NMR(75MHz,DMSO)δ 153.68,149.56,146.94,142.00,137.32,134.57,134.51,126.59,122.85,117.11,112.54,105.63,60.68,56.87,56.08,13.64;HR-MS (ESI)m/z:calcd for C19H22O7S[M+H]+395.1159,found 395.1158.
实施例14
(E)-5-(2-氟-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-2-甲氧基苯酚
(a)将实施例1中d的产物(500mg,1.3lmmol)溶于干燥的四氢呋喃中,0度下滴入Selectflor(510mg,1.44mmol)的DMF溶液,TLC监控反应,结束后旋掉THF,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析 (DCM/CH3OH 150∶1)得黄色油状270mg,产率51.6%。
(b)参照实施例13中e的合成方法。1H NMR(300MHz,CDCl3)δ 7.22(d,J=1.9 Hz,1H),7.20(d,2H),7.10(dd,J=8.3,1.8Hz,1H),7.98-6.84(d,J=42Hz,1H),6.87(s,1H),5.66(s,1H),3.93(s,6H),3.92(s,6H);13C NMR(75MHz,CDCl3)δ 153.53,147.51,145.10,142.08,128.86,123.07,122.74,122.12,115.42,115.36, 114.74,110.09,105.25,103.67,60.54,56.04,55.74;HR-MS(ESI)m/z:calcd for C18H19FO7S[M+NH4]+416.1174,found 416.1177.
实施例15
(E)-3-(3-羟基-4-甲氧基苯基)-2-((3,4,5-三甲氧基苯基)砜基)丙烯腈(
(a)三甲氧基苯硫酚(750mg,3.75mmol)溶于乙腈中,加入碳酸钾(62lmg,4.5mmol),搅拌十分钟后滴入溴乙腈(313μL,4.5mmol),室温反应1小时后,旋掉乙腈,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩得灰色固体820mg,产率91.5%。
(b)将a的产物(600mg,2.51mmol)溶于干燥的二氯甲烷中,加入75%含量的间氯过氧苯甲酸(1.27g,5.52mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩灰色固体620mg,产率91.2%。
(c)将b的产物(80mg,0.3mmol)溶于无水甲苯中,加入乙酰基保护的异香兰素(63mg,0.33mmol),滴入催化量的哌啶(5μL)和醋酸(5μL),回流反应,TLC 监控反应结束后,旋掉甲苯,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后溶于5ml甲醇,加入5ml 10%氢氧化钠水溶液,室温搅拌三十分钟,反应结束后,旋掉甲醇,稀盐酸酸化,二氯甲烷稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA4∶1),得37mg黄色固体,两步产率31.1%。
1H NMR(300MHz,CDCl3)δ 7.95(s,1H),7.48(d,J=2.1Hz,1H),7.38(dd,J=8.5,2.1Hz,1H),7.12(s,2H),6.85(d,J=8.5Hz,1H),3.88(s,3H),3.85(s,6H),3.84(s, 3H);13CNMR(75MHz,CDCl3)δ 153.13,151.24,150.31,145.83,142.21,132.16, 125.71,123.07,115.47,113.28,110.73,110.59,105.17,60.53,56.06,55.74;HR-MS (ESI)m/z:calcd forC19H19NO7S[M+NH4]+423.1220,found 423.1223.
实施例16
(z)-5-(2-氯-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-2-甲氧基苯酚
(a)将实施例1中c的产物(1.9g,5.43mmol)溶于四氯化碳中,加入N-氯丁二酰亚胺(863mg,6.52mmol),室温反应2h,抽滤除去丁二酰亚胺,旋干滤液,柱层析(DCM/CH3OH 200∶1)得1.52g无色油状,产率72%。
(b)将a的产物(387mg,1.01mmol)溶于干燥的二氯甲烷中,加入75%含量的间氯过氧苯甲酸(509mg,2.03mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩柱层析(DCM/CH3OH 200∶1) 得无色油状352mg,产率84%。
(c)参照实施例13中e的合成方法。1H NMR(300MHz,CDCl3)δ 7.83(s,1H),7.45 (d,J=1.8Hz,1H),7.29-7.20(m,2H),7.11(s,2H),6.81(d,J=8.5Hz,1H),3.85(s, 3H),3.85(s,9H);13C NMR(75MHz,CDCl3)δ 152.87,148.52,145.11,142.84, 133.90,131.43,128.29,127.62,124.10,124.06,115.36,109.97,105.72,60.68,60.51, 57.47;HR-MS(ESI)m/z:calcd for C18H19ClO7S[M+H]+415.0613,found 415.0623.
实施例17
(E)-2-甲氧基-5-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)烯基)苯酚
(a)将实施例16中a的产物(500mg,1.42mmol)溶于甲醇中,回流反应30min,旋掉甲醇得488mg油状,产率90%。
(b)将a的产物(350mg,0.92mmol)溶于干燥的二氯甲烷中,加入75%含量的间氯过氧苯甲酸(423mg,1.85mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩柱层析(DCM/CH3OH 200∶1) 得无色油状332mg,产率87.6%。
(c)参照实施例13中e的合成方法。1H NMR(300MHz,CDCl3)δ 7.32(d,J=2.0 Hz,1H),7.18(s,2H),7.13(dd,J=8.4Hz,2.1Hz,1H),7.11(s,1H),6.86(d,J=8.4 Hz,1H),3.92(s,9H),3.90(s,3H),3.89(s,3H);13C NMR(75MHz,CDCl3)δ 152.89, 151.36,147.53,145.26,141.10,133.19,124.22,122.86,122.03,114.86,110.06, 105.01,61.34,60.62,55.97,55.70;HR-MS(ESI)m/z:calcd for C19H22O8S[M+H]+ 411.1108,found 411.1111.
实施例18
(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)烯基)苯胺
将实施例1中d的产物(50mg,0.13mmol)溶于干燥的四氢呋喃中,氮气保护下加入60%含量的钠氢(7.8mg,0.20mmol),0度下搅拌15分钟后,加入3-氨基-4-甲氧基苯甲醛(24mg,0.16mmol),室温反应1小时,反应结束后旋掉THF,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析(PE/EA 4∶1) 得黄色固体30mg,产率60%。1H NMR(300MHz,CDCl3)δ 7.52(d,J=15.3Hz,1H), 7.14(s,2H),6.89(dd,J=8.2,2.0Hz,1H),6.84(d,J=2.0Hz,1H),6.76(d,J=8.3 Hz,1H),6.65(d,J=15.3Hz,1H),3.87-3.91(m,12H);13C NMR(75MHz,CDCl3)δ 153.02,149.43,141.97,141.42,124.81,123.56,120.41,12.65,109.63,104.17,60.47, 55.96,55.12;HR-MS(ESI)m/z:calcd for C18H21NO6S[M+H]+380.1162,found 380.1167.
实施例19
(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基-1-丙烯基苯胺
将实施例13中b的产物(50mg,0.13mmol)溶于干燥的四氢呋喃中,氮气保护下加入60%含量的钠氢(7.8mg,0.20mmol),0度下搅拌15分钟后,加入 3-氨基-4-甲氧基苯甲醛(24mg,0.16mmol),室温反应1小时,反应结束后旋掉THF,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析 (PE/EA4∶1)得黄色固体28mg,产率56.5%。1H NMR(300MHz,CDCl3)δ 7.66 (s,1H),7.11(s,2H),6.87-6.79(m,3H),3.91(s,9H),3.88(s,3H),2.14(d,J=1.0 Hz,3H);13C NMR(75MHz,CDCl3)δ 152.93,147.46,136.33,135.84,133.90,126.16,124.41,120.62,115.22109.62,104.81,60.49,58.61,55.99,12.94;HR-MS (ESI)m/z:calcd for C19H23NO6S[M+H]+394.1319,found 394.1317.
实施例20
(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)苯酚
(a)将实施例1中c的产物(240mg,0.69mmol)溶于干燥的二氯甲烷中,0度下分批加入75%含量的间氯过氧苯甲酸(126mg,0.55mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析(DCM/CH3OH 100∶1)得黄色油状195mg,产率77.7%。
(b)将a的产物(50mg,0.14mmol)溶于干燥的四氢呋喃中,氮气保护下加入60%含量的钠氢(8mg,0.2mmol),0度下搅拌15分钟后,加入乙酰基保护得异香兰素(29mg,0.15mmol),室温反应1小时,反应结束后旋掉THF,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后溶于5ml甲醇,加入5ml 10%氢氧化钠水溶液,室温搅拌三十分钟,反应结束后,旋掉甲醇,稀盐酸酸化,二氯甲烷稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA 3∶2),得17mg反式构型产物,产率28.6%。1H NMR(300MHz,CDCl3)δ 7.25(d,J= 15.8Hz,1H),7.06(d,J=1.8Hz,1H),6.97(dd,J=8.3,1.8Hz,1H),6.90(s,2H),6.83(d,J=8.3Hz,1H),6.68(d,J=15.5Hz,1H),6.04(s,1H),3.90(s,9H),3.87(s, 3H);13CNMR(75MHz,CDCl3)δ 153.59,147.82,145.50,139.23,138.17,136.66, 130.20,126.14,120.78,112.54,110.13,100.84,60.23,55.88,55.61;HR-MS(ESI) m/z:calcd forC18H20O6S[M+H]+365.1053,found 365.1054.
实施例21
(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)亚砜基-1-丙烯基苯酚
(a)将实施例13中a的产物(508mg,1.39mmol)溶于干燥的二氯甲烷中,0度下分批加入75%含量的间氯过氧苯甲酸(273mg,1.19mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析(DCM/CH3OH 100∶1)得黄色油状300mg,产率56.6%。
(b)参照实施例二十中b的合成方法,得产物为顺反异构体1∶1,ESI-MS m/z 378.1[M+H]+379.1。
实施例22
(E)-3-(3-羟基-4-甲氧基苯基)-2-((3,4,5-三甲氧基苯基)亚砜基)丙烯腈
(a)将实施例15中a的产物(600mg,2.5lmmol)溶于干燥的二氯甲烷中,加入75%含量的间氯过氧苯甲酸(262mg,2.13mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩灰色固体364mg,产率56.9%。
(b)参照实施例十五的合成方法。1H NMR(300MHz,CDCl3)δ 7.69(s,1H),7.51 (d,J=2.0Hz,1H),7.43(dd,J=8.5,2.0Hz,1H),6.96(s,2H),6.91(d,J=8.5Hz, 1H),3.95(s,3H),3.91(s,6H),3.89(s,3H);13C NMR(75MHz,CDCl3)δ 153.64, 149.94,147.70,145.54,144.05,140.60,135.70,124.37,123.90,115.03,114.23, 113.19,110.25,101.19,60.48,55.97,55.65;HR-MS(ESI)m/z:calcd for C19H19NO6S[M+H]+390.1011,found 390.1012.
实施例23
(Z)-5-(2-氯-2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-2-甲氧基苯酚
(a)将实施例16中a的产物(407mg,1.06mmol)溶于干燥的二氯甲烷中,0度下分批加入75%含量的间氯过氧苯甲酸(207mg,0.90mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩后柱层析(DCM/CH3OH 100∶1)得黄色油状310mg,产率73.1%。
(b)参照实施例二十中b的合成方法。1H NMR(300MHz,CDCl3)δ 7.24(s,1H), 7.15(d,J=2.0Hz,1H),7.07-7.04(dd,J=2.1Hz,8.5Hz,1H),7.91(d,J=8.3Hz, 1H),6.82(s,2H),5.97(s,1H),3.79(s,9H),3.70(s,3H);13C NMR(75MHz,CDCl3) δ 153.36,147.90,145.36,139.82,137.85,137.68,135.50,125.27,121.87,114.99, 110.20,101.05,60.47,55.65,55.53;HR-MS(ESI)m/z:calcd for C18H19ClO6S [M+H]+390.0669,found 399.0660.
实施例24
(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)亚砜基)烯基)苯胺
将实施例20中a的产物(100mg,0.27mmol)溶于干燥的四氢呋喃中,氮气保护下加入60%含量的钠氢(18mg,0.4mmol),0度下搅拌15分钟后,加入3- 氨基-4-甲氧基苯甲醛(42mg,0.28mmol),室温反应1小时,反应结束后旋掉THF,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩柱层析(PE/EA 1∶1) 得黄色固体45mg,产率45.5%。1H NMR(300MHz,CDCl3)δ 7.23(d,J=15.6Hz, 1H),6.89(s,2H),6.83(s,2H),6.75(d,J=8.1Hz,1H),6.64(d,J=15.5Hz,1H), 3.90(s,6H),3.87(s,6H);13C NMR(75MHz,CDCl3)δ 153.55,148.53,139.36, 138.70,137.49,136.08,129.58,126.17,119.18,112.40,109.64,100.78,60.43,55.88, 55.24;HR-MS(ESI)m/z:calcd for C18H21NO5S[M+H]+364.1213,found 364.1212.
实施例25
(E)-3-(3-羟基-4-甲氧基苯基)-2-((3,4,5-三甲氧基苯基)砜基)丙烯酸乙酯
(a)三甲氧基苯硫酚(200mg,lmmol)溶于乙腈中,加入碳酸钾(207mg,1.5mmol),搅拌十分钟后滴入溴乙酸乙酯(133μL,1.2mmol),室温反应1小时后,旋掉乙腈,乙酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩得固体250mg,产率87.4%。
(b)将a的产物(50mg,0.17mmol)溶于干燥的二氯甲烷中,加入75%含量的间氯过氧苯甲酸(80mg,0.34mmol),反应结束后用二氯甲烷稀释,饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水Na2SO4干燥,浓缩灰色固体38mg,产率69.1%。
(c)将b的产物(50mg,0.16mmol)溶于无水甲苯中,加入乙酰基保护的异香兰素(33mg,0.17mmol),滴入催化量的哌啶(5μL)和醋酸(5μL),回流反应, TLC监控反应结束后,旋掉甲苯,乙酸乙酯稀释,水洗,饱和食盐水洗,无水 Na2SO4干燥,浓缩后溶于5ml甲醇,加入5ml 10%氢氧化钠水溶液,室温搅拌三十分钟,反应结束后,旋掉甲醇,稀盐酸酸化,二氯甲烷稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA 4∶1),得43mg黄色油状,两步产率60.6%。1H NMR(300MHz,DMSO)δ 9.49(s,1H),7.78(s,1H),7.16(s,2H),7.11-7.03(m,1H),7.01(d,J=8.5Hz,1H),6.91(d,J=1.9Hz,1H),4.27(q,J=1.7 Hz,2H),3.84(s,6H),3.81(s,3H),3.74(s,3H),2.50(t,J=1.7Hz,3H);13C NMR (75MHz,DMSO)δ163.87,153.09,151.41,148.90,141.72,141.45,135.15,124.76, 124.31,122.91,110.66,109.63,104.43,60.43,56.00,55.49,55.47,14.32;HR-MS (ESI)m/z:calcd forC19H22O7S[M+H]+453.1214,found 395.1216.
实施例26
(E)-5-甲氧基-3-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
(a)5-甲氧基吲哚(200mg,1.36mmol)溶于无水DMF中,滴入新制备的Vilsmeier 试剂,室温反应一小时,结束后倒入冰水中,抽滤,干燥得黄色固体150mg,产率63%。
(b)参照实施例1的合成方法。δ 1H NMR(300MHz,DMSO)δ 11.77(s,1H),7.97 (d,J=2.7Hz,1H),7.87-7.73(d,J=15.4Hz,1H),7.38(d,J=8.8Hz,2H),7.26(s, 1H),7.23-7.18(s,J=15.4Hz,1H),6.94-6.81(m,1H),3.89(s,6H),3.85(s,3H),3.74(s,3H);13C NMR(75MHz,DMSO)δ 155.04,153.08,140.93,137.47,136.17, 133.29,132.21,125.29,119.43,113.08,112.44,109.83,104.20,102.42,60.14,56.32, 55.74;ESI-MS m/z 403.1[M+H]+404.1.
实施例27
(E)-6-甲氧基-3-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
参照实施例26的合成方法。1H NMR(300MHz,DMSO)δ 11.69(s,1H),7.89 -7.86(m,2H),7.78-7.73(d,J=15.3Hz,1H),7.24(s,2H),7.17(d,J=15.6Hz,1H), 6.98(s,1H),6.83(d,J=6Hz,1H),3.89(s,6H),3.80(s,3H),3.74(s,3H);13C NMR (75MHz,DMSO)δ156.35,153.08,140.95,138.39,137.28,135.98,132.46,120.80, 119.71,118.55,110.80,110.10,104.22,95.51,60.13,56.30,55.19.ESI-MS m/z 403.1 [M+H]+404.1.
实施例28
(E)-5-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
参照实施例1的合成方法。1H NMR(300MHz,DMSO)δ 11.21(s,1H),7.83 (s,1H),7.58(d,J=15.3Hz,1H),7.47-7.22(m,4H),7.10(s,2H),6.40(s,1H),3.78 (s,6H),3.64(s,3H);13C NMR(75MHz,DMSO)δ 153.65,144.03,141.68,137.90, 136.87,128.28,127.38,124.38,123.98,123.60,121.66,112.54,104.78,102.61, 60.66,56.79.ESI-MS m/z373.10[M+H]+374.10.
实施例29
(E)-6-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 8.70(s,1H),7.79(d, J=15.3Hz,1H),7.68-7.50(m,2H),7.34-7.31(m,1H),7.29(d,J=1.3Hz,1H), 7.17(s,2H),6.85(d,J=15.3Hz,1H),6.60(dd,J=18.5,5.2Hz,1H),3.89(s,9H);13C NMR(75MHz,CDCl3)δ 153.06,143.33,141.47,135.34,135.24,130.00,126.74, 125.57,123.67,120.81,118.91,112.74,104.18,102.69,60.49,55.95;ESI-MS m/z 373.10[M+H]+374.10.
实施例30
(E)-7-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 9.47(s,1H),8.21(d, J=15.4Hz,1H),7.72(d,J=7.8Hz,1H),7.38(d,J=7.4Hz,1H),7.30-7.18(m, 3H),7.17-7.06(m,2H),6.57(d,J=1.8Hz,1H),3.88(s,3H),3.85(s,6H);13C NMR(75MHz,CDCl3)δ 153.67,142.25,139.16,135.18,134.48,129.30,125.95, 125.47,124.61,122.60,119.94,116.02,104.71,103.19,61.01,56.48;ESI-MS m/z 373.10[M+H]+374.10.
实施例31
(E)-3-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
参照实施例26的合成方法。1H NMR(300MHz,CDCl3)δ 9.11(s,1H),7.90(d, J=15.3Hz,1H),7.77(d,J=7.1Hz,1H),7.55(d,J=2.8Hz,1H),7.43(dd,J=10.8, 3.6Hz,1H),7.28-7.21(m,2H),7.19(s,2H),6.81(d,J=15.3Hz,1H),3.91(s,6H), 3.89(s,3H);13CNMR(75MHz,CDCl3)δ 153.50,141.71,137.18,136.59,136.20, 130.63,124.87,123.68,121.88,120.98,120.07,112.19,111.37,104.53,60.99,56.47; ESI-MS m/z 373.10[M+H]+374.10.
实施例32
(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 9.06(s,1H),7.76(d, J=15.5Hz,1H),7.43(d,J=7.9Hz,1H),7.35-7.20(m,2H),7.15(t,J=7.6Hz, 1H),7.00(d,J=16.5Hz,1H),6.86(s,2H),6.72(s,1H),3.87(s,9H);13C NMR(75 MHz,CDCl3)δ 154.14,140.20,139.01,136.71,136.44,132.57,126.61,125.85, 125.59,121.79,120.20,113.27,101.73,100.72,60.91,56.41;ESI-MS m/z 373.10 [M+H]+374.10.
实施例33
(E)-5-(2-((3,4,5-三甲氧基苯基)砜基)-1-丙烯基)-1H-吲哚
参照实施例13的合成方法。1H NMR(300MHz,CDCl3)δ 8.45(s,1H),7.94(s, 1H),7.75(s,1H),7.44(d,J=8.3Hz,1H),7.27(s,2H),7.15(s,2H),6.59(s,1H), 3.91(s,9H),2.23(s,3H);13C NMR(75MHz,DMSO)δ 153.67,141.85,139.18, 136.81,134.80,133.36,128.26,127.21,124.77,123.77,123.28,112.20,105.52, 102.44,60.67,56.85,13.83;ESI-MS m/z 387.1[M+H]+388.1.
实施例34
(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)-1-丙烯基)-1H-吲哚
参照实施例13的合成方法。1H NMR(300MHz,CDCl3)δ 8.57(s,1H),8.21(s, 1H),7.42(d,J=9.7Hz,1H),7.31(s,1H),7.28-7.09(m,4H),6.61(s,1H),3.91(s,9H),2.17(s,3H);13C NMR(75MHz,CDCl3)δ 152.98,141.47,136.54,135.35, 135.20,133.44,127.20,125.13,124.82,121.22,119.85,111.98,104.87,100.49, 60.53,55.99,13.21;ESI-MS m/z 387.1[M+H]+388.1.
实施例35
(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)-1-丙烯基)-1H-吲哚
参照实施例14的合成方法。1H NMR(300MHz,CDCl3)δ 8.57(s,1H),7.58- 7.47(d,J=32.25Hz,1H),7.55(d,J=1.47Hz,1H),7.44(d,J=4.23Hz,1H),7.33(t, J=2.7Hz,1H),7.25(s,2H),7.21(t,J=7.9Hz,1H),6.73(s,1H),3.92(s,3H),3.92 (s,6H);13C NMR(75MHz,CDCl3)δ 154.69,153.10,150.67,142.49,135.42,131.54, 127.63,125.21,121.64,121.51,121.35,120.40,113.03,113.00,112.53,105.32, 100.26,60.56,56.04;ESI-MS m/z 391.1[M+H]+392.1.
实施例36
(E)-3-(1H-吲哚-4-基)-2-((3,4,5-三甲氧基苯基)砜基)丙烯腈
参照实施例15的合成方法。1H NMR(300MHz,CDCl3)δ 8.70(s,1H),8.58(s, 1H),8.04(d,J=7.7Hz,1H),7.56(d,J=8.1Hz,1H),7.37(d,J=2.8Hz,1H),7.19 (d,J=1.3Hz,1H),7.17(s,2H),6.74(s,1H),3.85(s,9H);13C NMR(75MHz, CDCl3)δ 153.17,147.80,142.55,135.66,132.09,129.58,126.89,121.74,121.05, 120.65,116.85,113.67,112.10,105.30,99.92,60.59,56.09;ESI-MS m/z 398.1 [M+H]+399.1.
实施例37
(E)-4-(2-氯-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
参照实施例16的合成方法。1H NMR(300MHz,CDCl3)δ 8.60(s,1H),8.51(s, 1H),7.89(d,J=7.6Hz,1H),7.52(d,J=7.5Hz,1H),7.36(m,1H),7.28-7.17(m, 4H),6.74(m,1H),3.93(s,3H),3.92(s,6H);13C NMR(75MHz,CDCl3)δ 152.91, 142.20,135.35,131.99,131.48,129.20,128.37,125.34,122.25,121.27,120.17, 113.61,105.76,100.19,60.56,56.04;ESI-MS m/z 407.1[M+H]+408.1.
实施例38
(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
参照实施例17的合成方法。1H NMR(300MHz,CDCl3)δ 8.59(s,1H),7.68(s, 1H),7.66(d,J=7.5Hz,1H),7.45(d,J=8.1Hz,1H),7.36-7.32(m,1H),7.23(s, 2H),7.20(d,J=7.9Hz,1H),6.75(m,1H),3.93-3.88(m,9H),3.83(d,J=7.2Hz, 3H);13C NMR(75MHz,CDCl3)δ 152.91,152.33,141.81,135.42,133.18,127.56, 124.96,122.42,121.64,120.46,119.22,112.41,105.12,100.56,61.40,60.51,55.98; ESI-MS m/z 403.1[M+H]+404.1.
实施例39
(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)二氢吲哚
实施例32的产物(50mg,0.13mmol)溶于醋酸中,加入氰基硼氢化钠(17mg,0.26mmol),室温反应2h,旋掉醋酸,乙酸乙酯稀释,饱和NaHCO3水溶液洗,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA2∶1)过柱得产物30mg,产率59.7%。1H NMR(300MHz,CDCl3)δ 7.59(d,J=15.4Hz,1H),7.04(s,2H), 6.95(t,J=7.7Hz,1H),6.74(d,J=8.0Hz,1H),6.69(d,J=15.5Hz,1H),6.58(d,J =7.7Hz,1H),3.84(s,6H),3.83(s,3H),3.53(t,J=8.4Hz,2H),3.09(t,J=8.4Hz, 2H);13C NMR(75MHz,CDCl3)δ 153.58,152.49,142.14,140.04,135.33,130.18, 128.74,128.08,127.67,117.41,111.24,104.83,61.00,56.50,47.03,29.02;ESI-MS m/z 375.1[M+H]+376.1.
实施例40
(E)-1-甲基-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚
参照实施例32的合成方法。1H NMR(300MHz,CDCl3)δ 8.03(d,J=15.4Hz, 1H),7.41(d,J=8.0Hz,1H),7.33(d,J=7.2Hz,1H),7.24(d,J=7.8Hz,1H),7.20- 7.19(m,3H),7.02(d,J=15.4Hz,1H),6.70(d,J=3.1Hz,1H),3.92(s,6H),3.89(s, 3H),3.83(s,3H);13CNMR(75MHz,CDCl3)δ 153.06,141.49,140.64,136.68, 135.29,130.25,127.01,126.14,123.85,120.97,120.74,111.94,104.30,98.92,60.49, 55.99,32.64.ESI-MS m/z 387.1[M+H]+387.1.
实施例41
(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚-3-甲醛
实施例32的产物(50mg,0.13mmol)溶于无水DMF中,滴入新制备的 Vilsmeier试剂,室温反应一小时,EA稀释,水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,浓缩后柱层析(PE/EA 1∶1)过柱得白色粉末20mg,产率74.3%。1H NMR(300MHz,DMSO)δ 12.55(s,1H),9.83(s,1H),9.32(d,J=15.4Hz,1H), 8.52(s,1H),7.68(d,J=7.6Hz,1H),7.62(d,J=8.0Hz,1H),7.46(d,J=15.4Hz, 1H),7.35(d,J=7.8Hz,1H),7.28(s,2H),3.87(s,6H),3.72(s,3H);13C NMR(75 MHz,DMSO)δ 184.11,153.12,143.83,143.60,141.18,138.71,136.23,127.68, 126.14,123.85,123.30,121.09,119.08,115.21,104.40,60.14,56.19;ESI-MS m/z 401.1[M+H]+402.1.
实施例42
(E)-5-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚
参照实施例1的合成方法。1H NMR(300MHz,CDCl3)δ 8.77(s,1H),7.66(s, 1H),7.40(d,J=15.5Hz,1H),7.29(d,J=8.5Hz,1H),7.23-7.20(m,1H),7.17- 7.11(m,1H),6.85(s,2H),6.70(d,J=15.5Hz,1H),6.46(s,1H),3.80(s,6H),3.80 (s,3H);13C NMR(75MHz,CDCl3)δ 154.08,140.17,139.37,139.23,136.92,129.36, 128.15,125.64,125.51,121.92,121.30,111.74,103.21,101.44,60.92,56.39; ESI-MS m/z 357.1[M+H]+358.1.
实施例43
(E)-4-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚
参照实施例20的合成方法。1H NMR(300MHz,CDCl3)δ 9.06(s,1H),7.76(d, J=15.5Hz,1H),7.43(d,J=7.9Hz,1H),7.27-7.25(m,2H),7.15(t,J=7.6Hz, 1H),7.00(d,J=16.5Hz,1H),6.96(s,2H),6.72(s,1H),3.87(s,9H);13C NMR(75 MHz,CDCl3)δ 154.14,140.20,139.01,136.71,136.44,132.57,126.61,125.85, 125.59,121.79,120.20,113.27,101.73,100.72,60.91,56.41;ESI-MS m/z 357.1 [M+H]+358.1.
实施例44
(E)-4-(2-((3,4,5-三甲氧基苯基)亚砜基)-1-丙烯基)-1H-吲哚
参照实施例21的合成方法。1H NMR(300MHz,CDCl3)δ 8.82(s,1H),7.73(s, 1H),7.34(d,J=7.7Hz,1H),7.22(t,J=2.5Hz,1H),7.14-7.05(m,2H),6.86(s, 2H),6.53(s,1H),3.81(s,3H),3.80(s,6H),1.88(d,J=1.1Hz,3H);13C NMR(75 MHz,CDCl3)δ 153.89,142.36,139.74,137.75,135.96,131.71,127.51,126.41, 125.19,121.66,120.13,111.93,101.80,100.81,56.36,31.94,29.71;ESI-MS m/z 371.1[M+H]+372.1.
实施例45
(E)-4-(2-氯-2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚
参照实施例23的合成方法。1H NMR(300MHz,CDCl3)δ 8.74(s,1H),7.69 (s,1H),7.49(d,J=8.0Hz,1H),7.37-7.32(m,2H),7.29-7.24(m,1H),6.74(s,2H),6.62(s,1H),3.86(s,3H),3.77(s,6H);13C NMR(75MHz,CDCl3)δ 153.27, 140.03,136.12,135.82,135.38,126.40,125.05,124.14,121.39,120.48,119.88, 112.18,101.00,100.36,60.45,55.76;ESI-MS m/z391.1[M+H]+392.1.
实施例46
(E)-3-(1H-吲哚-4-基)-2-((3,4,5-三甲氧基苯基)亚砜基)丙烯腈
参照实施例22的合成方法。1H NMR(300MHz,CDCl3)δ 8.77(s,1H),8.26(s, 1H),7.95(d,J=7.6Hz,1H),7.49(d,J=8.1Hz,1H),7.32(s,1H),7.20-7.15(m,2H),6.94(s,1H),6.74(s,1H),3.83(s,9H);13C NMR(75MHz,CDCl3)δ 154.17,142.80,136.27,136.21,129.09,126.74,122.80,122.14,120.37,116.39,115.85, 113.98,101.80,100.34,100.33,61.02,56.47;ESI-MS m/z 382.1[M+H]+383.1.
实施例47
(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚
参照实施例20的合成方法。1H NMR(300MHz,CDCl3)δ 8.59(s,1H),7.68- 7.64(m,2H),7.45(d,J=8.1Hz,1H),7.33(t,J=2.7Hz,1H),7.23(s,2H),7.21- 7.10(m,1H),6.75(m,1H),3.91(s,9H),3.81(s,3H);13C NMR(75MHz,CDCl3)δ 152.91,152.33,141.81,135.42,133.18,127,56,124.96,122.42,121.64,120.46, 119.22,112.41,105.12,100.56,61.40,60.51,55.98;ESI-MS m/z 387.1[M+H]+ 388.1.
实施例48
(E)-1-甲基-4-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚
参照实施例20的合成方法。1H NMR(300MHz,CDCl3)δ 7.67(d,J=15.6Hz, 1H),7.28(d,J=7.9Hz,1H),7.25-7.13(m,2H),7.08(d,J=3.1Hz,1H),6.92(d,J =15.6Hz,1H),6.87(s,2H),6.62(d,J=2.9Hz,1H),,3.82(s,6H),3.80(s,3H),3.74 (s,3H);13C NMR(75MHz,CDCl3)δ 153.59,139.48,138.63,136.66,135.77,132.36, 129.73,126.65,125.29,121.02,119.32,110.66,101.02,98.88,60.44,55.90,32.59; ESI-MS m/z 371.1[M+H]+372.1.
实施例49
(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚-3-甲醇
实施例41的产物(50mg,0.12mmol)溶于甲醇中,加入硼氢化钠(5mg, 0.13mmol),室温反应30min,氯化铵淬灭,旋掉甲醇,乙酸乙酯稀释,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA2∶1)过柱得产物33mg,产率 66%。1H NMR(300MHz,CDCl3)δ 9.06(s,1H),7.76(d,J=15.5Hz,1H),7.43(d,J =7.9Hz,1H),7.35-7.20(m,2H),7.10(t,J=7.6Hz,1H),7.02(d,J=16.5Hz,1H), 6.85(s,2H),6.63(s,1H),4.48(s,2H),3.87(s,9H);13C NMR(75MHz,CDCl3)δ 154.14,140.20,139.01,136.71,136.44,132.57,126.61,125.85,125.59,121.79, 120.20,113.27,101.73,100.72,60.91,57.2,56.41;ESI-MS m/z 403.1[M+H]+404.1.
实施例50
(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚-3-甲腈
(a)实施例41的产物(100mg,0.24mmol)溶于甲醇中,分别加入盐酸羟胺(26mg,0.36mmol)与醋酸钠(30mg,0.36mmol),室温反应2h,旋掉甲醇,乙酸乙酯稀释,饱和食盐水洗,无水硫酸钠干燥,浓缩得56mg黄色固体。将该产物溶于1ml 吡啶中,加入1ml醋酐,室温反应2h,结束后用10%稀盐酸洗去吡啶,10%NaOH 水溶液洗,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA 1∶1)过柱得产物28mg,两步产率28.3%。1H NMR(300MHz,CDCl3)δ9.05(s,1H),7.81(d, J=15.5Hz,1H),7.42(d,J=7.9Hz,1H),7.38-7.25(m,2H),7.10(s,1H),7.02(d, J=16.5Hz,1H),6.85(s,2H),6.63(s,1H),3.89(s,3H)3.87(s,6H);13C NMR(75 MHz,CDCl3)δ 155.24,143.25,138.01,135.81,133.44,132.57,125.61,125.86,125.49,121.00,120.10,116.50,114.27,101.79,100.72,57.2,56.41;ESI-MS m/z 398.1[M+H]+399.1.
实施例51
(E)-(2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)烯基)苯基)甘氨酸盐酸盐
将实施例18中的产物(500mg,1.32mmol)溶于二氯甲烷中,分别加入1- 羟基苯丙三氮唑(214mg,1.58mmol),EDCI(505mg,2.64mmol),甘氨酸(119mg, 1.58mmol),室温反应2h,反应结束后用二氯甲烷稀释,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA 1∶1)过柱得产物450mg。将该产物加入到氯化氢的乙酸乙酯溶液中,搅拌30min,抽滤得到白色固体390mg,产率80%。 ESI-MS m/z 472.0[M-Cl]+437.1.
实施例51
(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚磷酸二钠盐
将实施例43的产物(357mg,1mmol)溶于无水四氢呋喃中,-78度下缓慢滴入二(三甲基硅基)氨基钠(2.3ml,2.3mmol)的四氢呋喃溶液,搅拌30min,滴入二苄基磷酰基氯(740mg,2.5mmol)的二氯甲烷溶液,反应5h,旋掉溶剂,乙酸乙酯稀释,,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析(PE/EA 2∶1) 得产物580mg。将该产物(580mg,0.94mmol)溶于无水乙腈中,氮气保护下,加入TMSBr(10mmol,1.5ml),0度搅拌5h,旋掉TMSBr,再加入9ml乙腈和 1ml水,浓缩后加入5ml二氯甲烷及5ml正己烷,过滤得固体200mg。将该固体溶于甲醇中,加入40mg氢氧化钠的甲醇溶液,试问搅拌30min后,浓缩,再加入3ml乙腈与1ml水的混合溶剂,过滤得到白色固体86mg,总产率17.8%。1H NMR(300MHz,DMSO)δ 8.16(d,J=15.5Hz,1H),7.43(d,J=7.9Hz,1H),7.27- 7.25(m,2H),7.15(t,J=7.6Hz,1H),7.00(d,J=16.5Hz,1H),6.96(s,2H),6.72(s, 1H),3.87(s,9H);13C NMR(75MHz,CDCl3)δ 154.14,140.20,139.01,136.71, 136.44,132.57,126.61,125.85,125.59,121.79,120.20,113.27,101.73,100.72,60.91,56.41;ESI-MSm/z481.0[M+H]+482.0。
Claims (5)
1.一种乙烯基砜及亚砜类小分子微管蛋白抑制剂,及其可药用盐,具有通式I及通式II所示的结构:
其中:
X代表硫、砜、亚砜;
R1代表氢、低级烷烃、甲氧基、卤素、氰基、酯基、酰胺基,羧基;
R2代表氢、低级烷烃;
R3,R4,R5可以是下列基团中的任意一个:氢、低级烷烃、甲氧基、卤素、氰基、酯基、酰胺基,羟基,氨基,硝基,二甲氨基,硼酸基,糖苷基团,氨基酸,磺酰胺,磷酸二钠盐;
R6代表氢、低级烷烃,羟基,甲氧基,磷酸二钠盐,糖苷,(CH2)1-6OH;
R7代表氢、低级烷烃,甲氧基,醛基,酰胺基,氰基,羟甲基,乙烯基,-CH=NHOH,-CH2OAc;
通式II中,烯基取代的位置可在吲哚3位,4位,5位,6位,7位;
通式II中,烯基取代吲哚环或烯基取代二氢吲哚环。
2.权利要求1的乙烯基砜及亚砜类小分子微管蛋白抑制剂,及其可药用盐,其中:
X优选砜、亚砜;
R1优选氢、甲基、氯、氟、甲氧基;
R2优选氢;
R3优选氢、羟基、氨基、氟、磷酸二钠盐、氨基酸;
R4优选氟、甲氧基、羟基、甲基、二甲氨基、硝基;
R5优选氢;
R6优选氢、甲基、磷酸二钠盐;
R7优选氢、醛基;
通式II中,烯基取代优先在吲哚环的3,4,5位。
3.权利要求2中的部分优选化合物为:
化合物1:(E)-1,2,3-三甲氧基-5-(苯乙烯基砜基)苯;
化合物2:(E)-5-((4-氟苯乙烯基)砜基)-1,2,3-三甲氧基苯;
化合物3:(E)-N,N-二甲基-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯胺;
化合物4:(E)-1,2,3-三甲氧基-5-((4-甲基苯乙烯基)砜基)苯;
化合物5:(E)-1,2,3-三甲氧基-5-((4-硝基苯乙烯基)砜基)苯;
化合物6:(E)-1,2,3-三甲氧基-5-((4-甲氧基苯乙烯基)砜基)苯;
化合物7:(E)-5-((3,4-二甲氧基苯乙烯基)砜基)-1,2,3-三甲氧基苯;
化合物8:(E)-1,2,3-三甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯;
化合物9:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯酚;
化合物10:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯基-1,2-二酚;
化合物11:(E)-5-((3-氟-4-甲氧基苯乙烯基)砜基)-1,2,3-三甲氧基苯;
化合物12:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)苯酚;
化合物13:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基-1-丙烯基苯酚;
化合物14:(E)-5-(2-氟-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-2-甲氧基苯酚;
化合物15:(E)-3-(3-羟基-4-甲氧基苯基)-2-((3,4,5-三甲氧基苯基)砜基)丙烯腈;
化合物16:(Z)-5-(2-氯-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-2-甲氧基苯酚;
化合物17:(E)-2-甲氧基-5-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)烯基)苯酚;
化合物18:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)烯基)苯胺;
化合物19:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基-1-丙烯基苯胺;
化合物20:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)苯酚;
化合物21:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)亚砜基-1-丙烯基苯酚;
化合物22:(E)-3-(3-羟基-4-甲氧基苯基)-2-((3,4,5-三甲氧基苯基)亚砜基)丙烯腈;
化合物23:(Z)-5-(2-氯-2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-2-甲氧基苯酚;
化合物24:(E)-2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)亚砜基)烯基)苯胺;
化合物25:(E)-3-(3-羟基-4-甲氧基苯基)-2-((3,4,5-三甲氧基苯基)砜基)丙烯酸乙酯;
化合物26:(E)-5-甲氧基-3-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物27:(E)-6-甲氧基-3-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物28:(E)-5-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物29:(E)-6-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物30:(E)-7-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物31:(E)-3-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物32:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物33:(E)-5-(2-((3,4,5-三甲氧基苯基)砜基)-1-丙烯基)-1H-吲哚;
化合物34:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)-1-丙烯基)-1H-吲哚;
化合物35:(E)-4-(2-氟-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物36:(E)-3-(1H-吲哚-4-基)-2-((3,4,5-三甲氧基苯基)砜基)丙烯腈;
化合物37:(E)-4-(2-氯-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物38:(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物39:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)二氢吲哚;
化合物40:(E)-1-甲基-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚;
化合物41:(E)-4-(2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚-3-甲醛;
化合物42:(E)-5-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物43:(E)-4-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物44:(E)-4-(2-((3,4,5-三甲氧基苯基)亚砜基)-1-丙烯基)-1H-吲哚;
化合物45:(E)-4-(2-氯-2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物46:(E)-3-(1H-吲哚-4-基)-2-((3,4,5-三甲氧基苯基)亚砜基)丙烯腈;
化合物47:(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物48:(E)-1-甲基-4-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚;
化合物49:(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚-3-甲醇;
化合物50:(E)-4-(2-甲氧基-2-((3,4,5-三甲氧基苯基)砜基)乙烯基)-1H-吲哚-3-甲腈;
化合物51:(E)-(2-甲氧基-5-(2-((3,4,5-三甲氧基苯基)砜基)烯基)苯基)甘氨酸钠盐酸盐;
化合物52:(E)-4-(2-((3,4,5-三甲氧基苯基)亚砜基)乙烯基)-1H-吲哚磷酸二钠盐。
4.一种药物组合物,其中含有治疗有效量的权利要求1的通式(I)的化合物及药学上可接受的载体。
5.权利要求1的化合物或其盐在制备治疗肿瘤疾病药物中的应用。
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CN109535068A (zh) * | 2018-12-26 | 2019-03-29 | 中国药科大学 | 吡啶取代查尔酮类化合物或其可药用的盐及其制备方法和用途 |
CN109535068B (zh) * | 2018-12-26 | 2022-07-29 | 中国药科大学 | 吡啶取代查尔酮类化合物或其可药用的盐及其制备方法和用途 |
CN109678815A (zh) * | 2019-01-09 | 2019-04-26 | 中国药科大学 | N-苄基苯甲酰胺类衍生物及其制备方法与制药用途 |
CN109678815B (zh) * | 2019-01-09 | 2022-11-29 | 中国药科大学 | N-苄基苯甲酰胺类衍生物及其制备方法与制药用途 |
CN116332802A (zh) * | 2023-05-30 | 2023-06-27 | 中国药科大学 | 一种微管蛋白和nrp1双靶点化合物及其制法与应用 |
CN116332802B (zh) * | 2023-05-30 | 2023-08-22 | 中国药科大学 | 一种微管蛋白和nrp1双靶点化合物及其制法与应用 |
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