CN107880029A - Design, synthesis and the application of a kind of indole derivatives antitumoral compounds containing pyrazol framework - Google Patents
Design, synthesis and the application of a kind of indole derivatives antitumoral compounds containing pyrazol framework Download PDFInfo
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- CN107880029A CN107880029A CN201610877391.4A CN201610877391A CN107880029A CN 107880029 A CN107880029 A CN 107880029A CN 201610877391 A CN201610877391 A CN 201610877391A CN 107880029 A CN107880029 A CN 107880029A
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- 150000002475 indoles Chemical class 0.000 title claims abstract description 21
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229940054051 antipsychotic indole derivative Drugs 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 title claims description 41
- 238000013461 design Methods 0.000 title description 4
- 230000000259 anti-tumor effect Effects 0.000 title description 2
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims abstract description 37
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 66
- 239000007787 solid Substances 0.000 claims description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 48
- 239000000376 reactant Substances 0.000 claims description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000012074 organic phase Substances 0.000 claims description 22
- 230000004044 response Effects 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 16
- 238000001704 evaporation Methods 0.000 claims description 14
- 230000008020 evaporation Effects 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- 230000006837 decompression Effects 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 235000002639 sodium chloride Nutrition 0.000 claims description 10
- 239000011780 sodium chloride Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 5
- 150000003217 pyrazoles Chemical class 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- 239000005725 8-Hydroxyquinoline Substances 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- QXAUTQFAWKKNLM-UHFFFAOYSA-N methyl indole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)=CNC2=C1 QXAUTQFAWKKNLM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002480 mineral oil Substances 0.000 claims description 4
- 235000010446 mineral oil Nutrition 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- 229960003540 oxyquinoline Drugs 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229940126062 Compound A Drugs 0.000 claims description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 238000004458 analytical method Methods 0.000 claims description 2
- -1 and finally Substances 0.000 claims description 2
- 238000011275 oncology therapy Methods 0.000 claims 2
- 239000000284 extract Substances 0.000 claims 1
- 238000009834 vaporization Methods 0.000 claims 1
- 230000008016 vaporization Effects 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
- 206010028980 Neoplasm Diseases 0.000 description 8
- 230000006907 apoptotic process Effects 0.000 description 6
- 235000015097 nutrients Nutrition 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
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- 206010009944 Colon cancer Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000003041 virtual screening Methods 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- XJYIPDKSWROWBM-UHFFFAOYSA-N 1-(4-methylphenyl)pyrazole Chemical class C1=CC(C)=CC=C1N1N=CC=C1 XJYIPDKSWROWBM-UHFFFAOYSA-N 0.000 description 2
- AKQAJYLKBCWJBV-UHFFFAOYSA-N 1-benzylpyrazole Chemical class C1=CC=NN1CC1=CC=CC=C1 AKQAJYLKBCWJBV-UHFFFAOYSA-N 0.000 description 2
- UHQHFXKJFJHBAE-UHFFFAOYSA-N 1-methylindole-3-carboxamide Chemical class C1=CC=C2N(C)C=C(C(N)=O)C2=C1 UHQHFXKJFJHBAE-UHFFFAOYSA-N 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- 108010040476 FITC-annexin A5 Proteins 0.000 description 2
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 2
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
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- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- FLNMQGISZVYIIK-UHFFFAOYSA-N 1-ethylpyrazole Chemical class CCN1C=CC=N1 FLNMQGISZVYIIK-UHFFFAOYSA-N 0.000 description 1
- WITMXBRCQWOZPX-UHFFFAOYSA-N 1-phenylpyrazole Chemical class C1=CC=NN1C1=CC=CC=C1 WITMXBRCQWOZPX-UHFFFAOYSA-N 0.000 description 1
- 125000002528 4-isopropyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- FBYDJZXWEGXWIQ-UHFFFAOYSA-N Cc(cc1)ccc1-[n]1ncc(NC(c2c[nH]c3ccccc23)=O)c1 Chemical compound Cc(cc1)ccc1-[n]1ncc(NC(c2c[nH]c3ccccc23)=O)c1 FBYDJZXWEGXWIQ-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
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- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
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- 108091000080 Phosphotransferase Proteins 0.000 description 1
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- 102000001253 Protein Kinase Human genes 0.000 description 1
- QTENRWWVYAAPBI-YZTFXSNBSA-N Streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O QTENRWWVYAAPBI-YZTFXSNBSA-N 0.000 description 1
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- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
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- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
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- 238000012827 research and development Methods 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
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- 230000004083 survival effect Effects 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses indole derivatives of the one kind containing pyrazol framework, its preparation method and application, the structure of the indole derivatives containing pyrazol framework as shown in formula,Wherein, R1Selected from H, CH3;R2Selected from CH3、‑CH2CH3、
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to indole derivatives containing pyrazol framework, its preparation method and
Using.
Background technology
In recent years, with from cell, molecular level to the further understanding of Tumorigenesis, some produce in tumour and
The large biological molecule such as the key signal path and membrane receptor that are played a significant role in development, kinases is disclosed so that for this
A little efficient antineoplastics of tumor-specific molecule drone design low toxicity are possibly realized.Mitogen original activated protein kinase
(MAPK) signal transduction pathway is one of intracellular most important signal path, and BRAF is the key members in path MAPK, greatly
About 8% human tumor is found with V600E mutation BRAF (BRAFV600E), so as to cause downstream MEK-ERK signal paths to be held
Continuous abnormal activation, the growth, propagation, invasion and attack and transfer to tumour are most important.Therefore, BRAFV600EIt is current antineoplastic
The popular target of research and development.
High flux virtual screening technology is the screening technique being commonly used.High flux virtual screening technology is by target protein
The computational screening technology that high-resolution crystal structure is carried out as template.First, using high flux virtual screening technology with
BRAFV600EAlbumen is that template filter comes out molecule of the skeleton.Then, using Discovery Studio softwares by molecule of the skeleton and
BRAFV600EAlbumen carries out molecular docking, and corresponding modification transformation is carried out to it, obtains best molecule of the skeleton.
The content of the invention
It is an object of the invention to provide one kind to be used as BRAFV600EThe indoles containing pyrazol framework of target spot inhibitor derive
Thing, its preparation method and its application in tumour medicine.
Technical scheme:A kind of indole derivatives containing pyrazol framework, its structure as shown in formula,
Wherein, R1Selected from H ,-CH3;R2Selected from-CH3、-CH2CH3、
A kind of method for preparing the indole derivatives containing pyrazol framework, the indole derivatives containing pyrazol framework
Structure as shown in formula,
Wherein, R1Selected from H ,-CH3;R2Selected from-CH3、-CH2CH3、
Preparation method comprises the following steps,
Step 1. is dissolved into dry DMF (350mL) at 0 DEG C, by indole -3-carboxylic acid methyl ester (25.00g, 142.7mmol)
In, sodium hydride (60%, be stored in mineral oil, 8.26g, a 214mmol) part part is added to above-mentioned mixing
In thing.After all addition terminates sodium hydride, iodomethane (44.4mL, 713.5mmol) is added in solution, then will be whole
Reaction system is placed in stirring reaction 15 minutes in 0 DEG C, and reaction system finally is slowly ramped into room temperature, and stirring reaction is overnight.Treat
After reaction terminates, addition water is quenched in reaction solution.Obtained reactant mixture water and ethyl acetate (30mL × 3) extraction
Take, organic phase uses saturated aqueous common salt and washing successively, and is removed water organic phase using anhydrous magnesium sulfate.Finally, by organic phase
Vacuum decompression evaporation drying obtains crude product, and carries out separating-purifying to it using silica gel column chromatography, obtains structural formula as indicated at a
Compound.Appropriate potassium hydroxide is dissolved in water, then obtained compound A is added in above-mentioned solution, is added suitable
The methanol of amount, whole reaction system is then placed in stirring reaction 2 hours in 60 DEG C.After question response terminates, by reactant mixture
Vacuum decompression evaporation drying removes the methanol in reaction system, then adds dilute hydrochloric acid solution and adjusts Ph values to 5-6, has big
White solid is measured to separate out.The white solid of precipitation is separated by filtration, finally obtained solid is dried, obtains structural formula such as B institutes
The compound shown.
Pyrazoles (14g, 205.64mmol) is dissolved in the concentrated sulfuric acid (50mL), then by concentrated nitric acid by step 2. at 0 DEG C
(9.2Ml, 226.20mmol) is added dropwise, and adds after terminating whole reaction system temperature is heated slowly into 60 while stirring
℃.Whole reactant mixture agitating and heating is reacted into 1.5h.After question response terminates, reactant mixture is added to mixture of ice and water
In (600g).After standing a period of time, reactant mixture has white solid precipitation, is then separated by filtration white solid, will
The white solid separated is dried after washing again, obtains the compound of a part of structural formula as shown at c.By the filter after filtering
Liquid is extracted with ethyl acetate (100mL × 3), obtains organic phase.Sodium bicarbonate solution (100mL) of the organic phase with 1%, water
(100mL) and saturated aqueous common salt (100mL) rinse successively.Finally, the ethyl acetate anhydrous sodium sulfate drying after will be treated
And vacuum decompression evaporation drying obtains the compound of another part structural formula as shown at c.
Compound (7.14mmol), structural formula compound as shown atd of the step 3. by structural formula as shown at c
(7.14mmol), 8-hydroxyquinoline (0.18g, 1.23mmol), potassium carbonate (1.8g, 13.02mmol) are dissolved in anhydrous dimethyl Asia
In sulfone (9mL), the container where reactant mixture is then poured into argon gas, adds cuprous iodide (0.135g, 0.69mmol).
Whole reaction system is heated to 130 DEG C, then agitating and heating reaction 20h.Suitable quantity of water is added to reaction by question response after terminating
In system, a large amount of solids can be produced.Solid is separated by filtration and dries and separating-purifying is carried out to it using silica gel column chromatography, is obtained
Compound of the structural formula as shown in E.
Compound (4mmol) of the structural formula as shown in E is dissolved in absolute ethyl alcohol (4mL) by step 4., is then added
80% hydrazine hydrate solution (2mL), 10% palladium carbon hydrogenation catalyst (0.08g).Then the temperature of reactant mixture is heated
To 80 DEG C, reaction system is heated while stirring and reacted 10 minutes.After question response terminates, reactant mixture is filtered, collects filter
Liquid.Finally, filter vacuum is evaporated under reduced pressure and is dried to obtain compound of the structural formula as shown in F.
Step 5. is by compound (0.25mmol) of the structural formula as shown in B, EDC (0.25mmol), HOBT (0.25mmol)
It is dissolved in dry DMF (5mL), reactant mixture is then positioned over stirring reaction 30 minutes under normal temperature., will after 30 minutes
Compound (0.25mmol) of the structural formula as shown in F, DMAP (0.25mmol), triethylamine (1mL) are added in reactant mixture,
Then reaction is stayed overnight while stirring at normal temperatures for whole reaction.After question response terminates, obtained reactant mixture saturated common salt
Water and ethyl acetate (100mL × 3) extraction, finally, obtain crude product, and utilize silica gel by organic phase vacuum decompression evaporation drying
Column chromatography carries out separating-purifying to it, obtains compound of the final structural formula as shown in G.
In formula A~G, R1Selected from H ,-CH3;R2Selected from-CH3、-CH2CH3、
Embodiment
In some specific embodiment, the structural formula of preparation process of the invention and associated products is as described below:
A kind of method for preparing the above-mentioned indole derivatives containing pyrazol framework, it comprises the following steps:
Step 1. is dissolved into dry DMF (350mL) at 0 DEG C, by indole -3-carboxylic acid methyl ester (25.00g, 142.7mmol)
In, sodium hydride (60%, be stored in mineral oil, 8.26g, a 214mmol) part part is added to above-mentioned mixing
In thing.After all addition terminates sodium hydride, iodomethane (44.4mL, 713.5mmol) is added in solution, then will be whole
Reaction system is placed in stirring reaction 15 minutes in 0 DEG C, and reaction system finally is slowly ramped into room temperature, and stirring reaction is overnight.Treat
After reaction terminates, addition water is quenched in reaction solution.Obtained reactant mixture water and ethyl acetate (30mL × 3) extraction
Take, organic phase uses saturated aqueous common salt and washing successively, and is removed water organic phase using anhydrous magnesium sulfate.Finally, by organic phase
Vacuum decompression evaporation drying obtains crude product, and carries out separating-purifying to it using silica gel column chromatography, obtains structural formula as indicated at a
Compound.Appropriate potassium hydroxide is dissolved in water, then obtained compound A is added in above-mentioned solution, is added suitable
The methanol of amount, whole reaction system is then placed in stirring reaction 2 hours in 60 DEG C.After question response terminates, by reactant mixture
Vacuum decompression evaporation drying removes the methanol in reaction system, then adds dilute hydrochloric acid solution and adjusts ph values to 5-6, has big
White solid is measured to separate out.The white solid of precipitation is separated by filtration, finally obtained solid is dried, obtains structural formula such as B institutes
The compound shown.
Pyrazoles (14g, 205.64mmol) is dissolved in the concentrated sulfuric acid (50mL), then by concentrated nitric acid by step 2. at 0 DEG C
(9.2Ml, 226.20mmol) is added dropwise, and adds after terminating whole reaction system temperature is heated slowly into 60 while stirring
℃.Whole reactant mixture agitating and heating is reacted into 1.5h.After question response terminates, reactant mixture is added to mixture of ice and water
In (600g).After standing a period of time, reactant mixture has white solid precipitation, is then separated by filtration white solid, will
The white solid separated is dried after washing again, obtains the compound of a part of structural formula as shown at c.By the filter after filtering
Liquid is extracted with ethyl acetate (100mL × 3), obtains organic phase.Sodium bicarbonate solution (100mL) of the organic phase with 1%, water
(100mL) and saturated aqueous common salt (100mL) rinse successively.Finally, the ethyl acetate anhydrous sodium sulfate drying after will be treated
And vacuum decompression evaporation drying obtains the compound of another part structural formula as shown at c.
Compound (7.14mmol), structural formula compound as shown atd of the step 3. by structural formula as shown at c
(7.14mmol), 8-hydroxyquinoline (0.18g, 1.23mmol), potassium carbonate (1.8g, 13.02mmol) are dissolved in anhydrous dimethyl Asia
In sulfone (9mL), the container where reactant mixture is then poured into argon gas, adds cuprous iodide (0.135g, 0.69mmol).
Whole reaction system is heated to 130 DEG C, then agitating and heating reaction 20h.Suitable quantity of water is added to reaction by question response after terminating
In system, a large amount of solids can be produced.Solid is separated by filtration and dries and separating-purifying is carried out to it using silica gel column chromatography, is obtained
Compound of the structural formula as shown in E.
Compound (4mmol) of the structural formula as shown in E is dissolved in absolute ethyl alcohol (4mL) by step 4., is then added
80% hydrazine hydrate solution (2mL), 10% palladium carbon hydrogenation catalyst (0.08g).Then the temperature of reactant mixture is heated
To 80 DEG C, reaction system is heated while stirring and reacted 10 minutes.After question response terminates, reactant mixture is filtered, collects filter
Liquid.Finally, filter vacuum is evaporated under reduced pressure and is dried to obtain compound of the structural formula as shown in F.
Step 5. is by compound (0.25mmol) of the structural formula as shown in B, EDC (0.25mmol), HOBT (0.25mmol)
It is dissolved in dry DMF (5mL), reactant mixture is then positioned over stirring reaction 30 minutes under normal temperature., will after 30 minutes
Compound (0.25mmol) of the structural formula as shown in F, DMAP (0.25mmol), triethylamine (1mL) are added in reactant mixture,
Then reaction is stayed overnight while stirring at normal temperatures for whole reaction.After question response terminates, obtained reactant mixture saturated common salt
Water and ethyl acetate (100mL × 3) extraction, finally, obtain crude product, and utilize silica gel by organic phase vacuum decompression evaporation drying
Column chromatography carries out separating-purifying to it, obtains compound of the final structural formula as shown in G.
Embodiment one:N- (1- (4- methoxyphenyls) -1H- pyrazoles -4- bases) -1- Methyl-1H-indole -3- formamides
The preparation of (5a)
At 0 DEG C, indole -3-carboxylic acid methyl ester (25.00g, 142.7mmol) is dissolved into dry DMF (350mL), by hydrogen
Change being added in said mixture for sodium (60%, be stored in mineral oil, 8.26g, a 214mmol) part part.When
After sodium hydride whole addition terminates, iodomethane (44.4mL, 713.5mmol) is added in solution, then by whole reactant
System is placed in stirring reaction 15 minutes in 0 DEG C, reaction system finally is slowly ramped into room temperature, stirring reaction is overnight.Question response knot
Shu Hou, addition water is quenched in reaction solution.Obtained reactant mixture water and ethyl acetate (30mL × 3) extraction, has
Machine mutually uses saturated aqueous common salt and washing successively, and is removed water organic phase using anhydrous magnesium sulfate.Finally, organic phase vacuum is subtracted
Pressure evaporation drying obtains crude product, and carries out separating-purifying to it using silica gel column chromatography, obtains white solid.By appropriate hydrogen-oxygen
Change potassium to be dissolved in water, then obtained white solid is added in above-mentioned solution, adds appropriate methanol, then will be whole
Reaction system is placed in stirring reaction 2 hours in 60 DEG C.After question response terminates, reactant mixture vacuum decompression evaporation drying is removed
Methanol in reaction system, then add dilute hydrochloric acid solution and adjust ph values to 5-6, have a large amount of white solids and separate out.Will analysis
The white solid gone out is separated by filtration, and is finally dried obtained solid, is obtained compound 1a.At 0 DEG C, by pyrazoles (14g,
205.64mmol) it is dissolved in the concentrated sulfuric acid (50mL), then concentrated nitric acid (9.2Ml, 226.20mmol) is added dropwise, adds
Temperature is heated slowly to 60 DEG C by whole reaction system while stirring after end.Whole reactant mixture agitating and heating is reacted
1.5h.After question response terminates, reactant mixture is added in mixture of ice and water (600g).After standing a period of time, reaction is mixed
Compound has white solid precipitation, is then separated by filtration white solid, is dried after the white solid separated is washed again,
Obtain a part of compound 2a.Filtrate after filtering is extracted with ethyl acetate (100mL × 3), obtains organic phase.Organic
Mutually rinsed successively with 1% sodium bicarbonate solution (100mL), water (100mL) and saturated aqueous common salt (100mL).Finally, will handle
Later ethyl acetate obtains another part compound 2a with anhydrous sodium sulfate drying and vacuum decompression evaporation drying.It will change
Compound 2a (7.14mmol), to methoxyl group iodobenzene (7.14mmol), 8-hydroxyquinoline (0.18g, 1.23mmol), potassium carbonate
(1.8g, 13.02mmol) is dissolved in anhydrous dimethyl sulfoxide (9mL), and the container where reactant mixture then is poured into argon gas,
Add cuprous iodide (0.135g, 0.69mmol).Whole reaction system is heated to 130 DEG C, then agitating and heating is reacted
20h.Suitable quantity of water is added in reaction system by question response after terminating, and can produce a large amount of solids.Solid is separated by filtration and dried simultaneously
Separating-purifying is carried out to it using silica gel column chromatography, obtains compound 3a.Compound 3a (4mmol) is dissolved in absolute ethyl alcohol
In (4mL), 80% hydrazine hydrate solution (2mL), 10% palladium carbon hydrogenation catalyst (0.08g) are then added.Then will reaction
The temperature of mixture is heated to 80 DEG C, and reaction system is heated while stirring and reacted 10 minutes.It is after question response terminates, reaction is mixed
Compound filters, and collects filtrate.Finally, filter vacuum is evaporated under reduced pressure and is dried to obtain compound 4a.By compound 1a
(0.25mmol), EDC (0.25mmol), HOBT (0.25mmol) are dissolved in dry DMF (5mL), then by reactant mixture
It is positioned over stirring reaction 30 minutes under normal temperature.Is by compound 4a (0.25mmol), DMAP (0.25mmol), three after 30 minutes
Ethamine (1mL) is added in reactant mixture, and then reaction is stayed overnight while stirring at normal temperatures for whole reaction.Question response terminates
Afterwards, reactant mixture saturated aqueous common salt and ethyl acetate (100mL × 3) extraction obtained, finally, by organic phase vacuum decompression
Evaporation drying obtains crude product, and carries out separating-purifying to it using silica gel column chromatography, obtains final compound 5a.Obtain white
Color solid powder, yield 82.4%, m.p.236.5~238.7 DEG C;1H NMR(DMSO-d6, 400MHz) and δ:10.12 (s, 1H,
NH), 8.59 (s, 1H, ArH), 8.40-8.10 (m, 2H, CH), 7.78 (d, J=32.9Hz, 3H, ArH), 7.55 (d, J=
7.0Hz, 1H, CH), 7.44-6.79 (m, 4H, ArH), 3.85 (d, J=34.1Hz, 6H, CH3).MS EI+:346.39
(C20H18N4O2, [M]+).
Embodiment two:The preparation of N- (1- benzyl -1H- pyrazoles -4- bases) -1- Methyl-1H-indole -3- formamides (5b)
Preparation method reference implementation example one.Obtain white solid powder, yield 80.2%, m.p.191~192 DEG C;1H
NMR(DMSO-d6, 400MHz) and δ:9.98 (s, 1H, NH), 8.22 (d, J=7.9Hz, 1H, ArH), 8.13 (d, J=10.6Hz,
2H, CH), 7.63-7.48 (m, 2H, ArH), 7.39-7.22 (m, 6H, ArH), 7.19 (t, J=7.4Hz, 1H, CH), 5.32 (s,
2H, CH2), 3.87 (s, 3H, CH3).MS EI+:330.39(C20H18N4O, [M]+).
Embodiment three:The preparation of 1- methyl-N- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- indoles -3- formamides (5c)
Preparation method reference implementation example one.Obtain white solid powder, yield 79.5%, m.p.190.2~192.7
℃;1H NMR(DMSO-d6, 400MHz) and δ:9.90 (s, 1H, NH), 8.22 (d, J=7.8Hz, 1H, ArH), 8.12 (s, 1H,
CH), 8.01 (s, 1H, CH), 7.52 (t, J=4.0Hz, 2H, ArH), 7.25 (t, J=7.5Hz, 1H, ArH), 7.19 (t, J=
7.4Hz, 1H, CH), 3.85 (d, J=17.4Hz, 6H, CH3).MS EI+:254.29(C14H14N4O, [M]+).
Example IV:The preparation of N- (1- ethyl -1H- pyrazoles -4- bases) -1- Methyl-1H-indole -3- formamides (5d)
Preparation method reference implementation example one.Obtain white solid powder, yield 84.6%, m.p.174.8~175.6
℃;1H NMR(DMSO-d6, 400MHz) and δ:9.91 (s, 1H, NH), 8.22 (d, J=7.7Hz, 1H, ArH), 8.12 (s.1H,
CH), 8.04 (s, 1H, CH), 7.52 (d, J=8.2Hz, 2H, ArH), 7.25 (t, J=7.5Hz, 1H, ArH), 7.19 (t, J=
7.4Hz, 1H, CH), 4.11 (q, J=7.2Hz, 2H, CH2), 3.87 (s, 3H, CH3), 1.37 (t, J=7.3Hz, 3H, CH3).MS
EI+:268.32(C15H16N4O, [M]+).
Embodiment five:The preparation of 1- methyl-N- (1- phenyl -1H- pyrazoles -4- bases) -1H- indoles -3- formamides (5e)
Preparation method reference implementation example one.Obtain white solid powder, yield 81.3%, m.p.182.4~184.4
℃;1H NMR(DMSO-d6, 400MHz) and δ:10.15 (s, 1H, NH), 8.69 (s, 1H, ArH), 8.26 (d, J=7.7Hz, 1H,
CH), 8.18 (s, 1H, CH), 7.88 (s, 1H, CH), 7.84 (d, J=7.9Hz, 2H, ArH), 7.56-7.48 (m, 3H, ArH),
7.29 (q, J=7.8Hz, 2H, ArH), 7.21 (t, J=7.4Hz, 1H, ArH), 3.90 (s, 3H, CH3).MS EI+:316.36
(C19H16N4O, [M]+).
Embodiment six:1- methyl-N- (1- (p-methylphenyl) -1H- pyrazoles -4- bases) -1H- indoles -3- formamides (5f)
Prepare
Preparation method reference implementation example one.Obtain white solid powder, yield 79.4%, m.p.180.8~183.2
℃;1H NMR(DMSO-d6, 400MHz) and δ:10.13 (s, 1H, NH), 8.64 (s, 1H, ArH), 8.25 (d, J=7.7Hz, 1H,
CH), 8.17 (s, 1H, CH), 7.84 (s, 1H, CH), 7.71 (d, J=8.4Hz, 2H, ArH), 7.32-7.18 (m, 5H, ArH),
3.89 (s, 3H, CH3), 2.34 (s, 3H, CH3).MS EI+:330.39(C20H18N4O, [M]+).
Embodiment seven:1-N- methyl-N- (1- (4- methyl-benzyls) -1H- pyrazoles -4- bases) -1H- indoles -3- formamides
The preparation of (5g)
Preparation method reference implementation example one.Obtain white solid powder, yield 83.2%, m.p.188.3~190.3
℃;1H NMR(DMSO-d6, 400MHz) and δ:9.94 (s, 1H, NH), 8.20 (d, J=7.8Hz, 1H, ArH), 8.10 (d, J=
7.9Hz, 2H, CH), 7.60-7.48 (m, 2H, ArH), 7.25 (t, J=7.4Hz, 1H, CH), 7.17 (s, 5H, ArH), 5.25
(s, 2H, CH2), 3.86 (s, 3H, CH3), 2.28 (s, 3H, CH3).MS EI+:344.42(C21H20N4O, [M]+).
Embodiment eight:N- (1- (4- isopropyl benzyls) -1H- pyrazoles -4- bases) -1- Methyl-1H-indole -3- formamides
The preparation of (5h)
Preparation method reference implementation example one.Obtain white solid powder, yield 84.7%, m.p.208.3~211 DEG C;1H NMR(DMSO-d6, 400MHz) and δ:9.94 (s, 1H, NH), 8.21 (d, J=7.5Hz, 1H, ArH), 8.11 (s, 2H, CH),
7.55 (d, J=4.7Hz, 1H, ArH), 7.52 (d, J=8.0Hz, 1H, CH), 7.22 (s, 6H, ArH), 5.26 (s, 2H, CH2),
3.86 (d, J=4.5Hz, 3H, CH3), 2.86 (d, J=5.6Hz, 1H, CH), 1.22-1.13 (m, 6H, CH3).MS EI+:
372.47(C23H24N4O, [M]+).
Embodiment nine:N- (1- (3- methoxyphenyls) -1H- pyrazoles -4- bases) -1- Methyl-1H-indole -3- formamides
The preparation of (5i)
Preparation method reference implementation example one.Obtain white solid powder, yield 79.4%, m.p.167.4~170 DEG C;1H NMR(DMSO-d6, 400MHz) and δ:10.15 (s, 1H, NH), 8.70 (s, 1H, ArH), 8.26 (d, J=7.7Hz, 1H, CH),
8.18 (s, 1H, CH), 7.87 (s, 1H, CH), 7.55 (d, J=8.1Hz, 1H, ArH), 7.45-7.38 (m, 3H, ArH), 7.27
(t, J=7.5Hz, 1H, ArH), 7.21 (t, J=7.4Hz, 1H, ArH), 6.87 (dt, J=5.5,2.9Hz, 1H, ArH), 3.87
(d, J=16.8Hz, 6H, CH3).MS EI+:346.39(C20H18N4O2, [M]+).
Embodiment ten:N- (1- (2- ((4- methoxyphenyls) amino) -2- oxoethyls) -1H- pyrazoles -4- bases) -1- first
The preparation of base -1H- indoles -3- formamides (5j)
Preparation method reference implementation example one.Obtain bright yellow solid powder, yield 71.5%, m.p.223~225 DEG C;1H NMR(DMSO-d6, 600MHz) and δ:10.16 (s, 1H, NH), 9.95 (s, 1H, NH), 8.23 (d, J=7.9Hz, 1H, ArH),
8.12 (s, 2H, CH), 7.60 (s, 1H, ArH), 7.53 (d, J=9.0Hz, 3H, ArH), 7.27-7.24 (m, 1H, ArH), 7.19
(t, J=7.4Hz, 1H, CH), 6.91 (d, J=9.1Hz, 2H, ArH), 4.97 (s, 2H, CH2), 3.88 (s, 3H, CH3), 3.73
(s, 3H, CH3).MS EI+:403.44(C22H21N5O3, [M]+).
Embodiment 11:N- (1- (2- ((3- methoxyphenyls) amino) -2- oxoethyls) -1H- pyrazoles -4- bases) -1-
The preparation of Methyl-1H-indole -3- formamides (5k)
Preparation method reference implementation example one.Obtain pink solid powder, yield 71.9%, m.p.217~219 DEG C;1H NMR(DMSO-d6, 600MHz) and δ:10.30 (s, 1H, NH), 9.95 (s, 1H, NH), 8.23 (d, J=7.9Hz, 1H, ArH),
8.13 (s, 2H, CH), 7.60 (s, 1H, ArH), 7.53 (d, J=8.2Hz, 1H, ArH), 7.33 (s, 1H, ArH), 7.25 (q, J
=8.7,8.2Hz, 2H, ArH), 7.19 (t, J=7.9Hz, 1H, CH), 7.13 (d, J=8.1Hz, 1H, ArH), 6.67 (d, J=
8.2Hz, 1H, ArH), 5.00 (s, 2H, CH2), 3.88 (s, 3H, CH3), 3.73 (s, 3H, CH3).MS EI+:403.44(C22H2]
N5O3, [M]+).
Embodiment 12:The preparation of N- (1- benzyl -1H- pyrazoles -4- bases) -1H- indoles -3- formamides (5l)
Preparation method reference implementation example one.Obtain white solid powder, yield 82.8%, m.p.221~224 DEG C;1H
NMR(DMSO-d6, 400MHz) and δ 11.68 (s, 1H, NH), 9.93 (s, 1H, NH), 8.20 (d, J=7.7Hz, 1H, ArH), 8.15
(d, J=2.9Hz, 1H, CH), 8.14 (s, 1H, CH), 7.58 (s, 1H, ArH), 7.46 (d, J=7.8Hz, 1H, ArH), 7.36
(t, J=7.2Hz, 2H, ArH), 7.29 (dd, J=15.9,7.1Hz, 3H, ArH), 7.16 (dt, J=18.6,7.0Hz, 2H,
ArH), 5.32 (s, 2H, CH2).MS EI+:316.36(C19H16N4O, [M]+).
Embodiment 13:The preparation of N- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- indoles -3- formamides (5m)
Preparation method reference implementation example one.Obtain yellow solid powder, yield 74.3%, m.p.202~204 DEG C;1H
NMR(DMSO-d6, 600MHz) and δ:11.65 (s, 1H, NH), 9.87 (s, 1H, NH), 8.21 (d, J=7.8Hz, 1H, ArH),
8.16 (d, J=2.9Hz, 1H, CH), 8.01 (s, 1H, CH), 7.52 (s, 1H, ArH), 7.46 (d, J=8.0Hz, 1H, ArH),
7.18 (t, J=6.9Hz, 1H, ArH), 7.14 (t, J=7.4Hz, 1H, CH), 3.83 (s, 3H, CH3).MS EI+:240.27
(C13H12N4O, [M]+).
Embodiment 14:The preparation of N- (1- (p-methylphenyl) -1H- pyrazoles -4- bases) -1H- indoles -3- formamides (5n)
Preparation method reference implementation example one.Obtain white solid powder, yield 75%, m.p.217~219.5 DEG C;1H
NMR(DMSO-d6, 600MHz) and δ:11.72 (s, 1H, NH), 10.09 (s, 1H, NH), 8.65 (s, 1H, ArH), 8.25 (d, J=
7.7Hz, 1H, CH), 8.22 (s, 1H, CH), 7.85 (s, 1H, CH), 7.71 (d, J=8.4Hz, 2H, ArH), 7.49 (d, J=
8.2Hz, 1H, ArH), 7.30 (d, J=8.4Hz, 2H, ArH), 7.18 (dt, J=22.2,7.1Hz, 2H, ArH), 2.34 (s,
3H, CH3).MS EI+:316.36(C19H16N4O, [M]+).
Embodiment 15:The system of N- (1- (4- methoxyphenyls) -1H- pyrazoles -4- bases) -1H- indoles -3- formamides (5o)
It is standby
Preparation method reference implementation example one.Obtain pink solid powder, yield 74.8%, m.p.212~215 DEG C;1H NMR(DMSO-d6, 400MHz) and δ:11.72 (s, 1H, NH), 10.07 (s, 1H, NH), 8.59 (s, 1H, ArH), 8.27-8.19
(m, 2H, CH), 7.82 (s, 1H, ArH), 7.74 (d, J=9.0Hz, 2H, ArH), 7.49 (d, J=8.0Hz, 1H, CH), 7.23-
7.12 (m, 2H, ArH), 7.05 (d, J=9.1Hz, 2H, ArH), 3.80 (s, 3H, CH3).MS EI+:332.36(C19H16N4O2,
[M]+).
Embodiment 16:N- (1- (2- ((4- methoxyphenyls) amino) -2- oxoethyls) -1H- pyrazoles -4- bases) -1H-
The preparation of indoles -3- formamides (5p)
Preparation method reference implementation example one.Obtain white solid powder, yield 78.6%, m.p.268.5~271.5
℃;1H NMR(DMSO-d6, 600MHz) and δ:11.66 (s, 1H, NH), 10.16 (s, 1H, NH), 9.92 (s, 1H, NH), 8.22 (d,
J=7.8Hz, 1H, ArH), 8.17 (s, 1H, CH), 8.12 (s, 1H, CH), 7.60 (s, 1H, ArH), 7.52 (d, J=8.9Hz,
2H, ArH), 7.47 (d, J=8.0Hz, 1H, ArH), 7.19 (t, J=7.4Hz, 1H, CH), 7.14 (t, J=7.4Hz, 1H,
ArH), 6.91 (d, J=8.9Hz, 2H, ArH), 4.97 (s, 2H, CH2), 3.73 (s, 3H, CH3).MS EI+:389.42
(C21H19N5O3, [M]+).
Embodiment 17:The Anticancer Activity in vitro progress of indole derivatives containing pyrazol framework
Bone containing pyrazoles is determined using MTT [3- (4,5)-bis- methyl -2- thiazoles-(2,5)-phenyl bromination tetrazole is blue] methods
The indole derivatives of frame are to Human colorectal cancer cells (HT-29), and people's malignant melanoma cell (A375), Humanmachine tumour is thin
The inhibiting rate of born of the same parents' (WM1361 cells) reaches drug concentration (half maximal inhibitory when 50%
Concentration, IC50)。
(1) preparation of nutrient solution:DMEM (basal medium) 89%, hyclone 10%, Penicillin Streptomycin Solution
(10000IU/mL, 10000 μ g/mL) 1%.
The culture of (2) three kinds of adherent cancer cells:Using above-mentioned nutrient solution, (nutrient solution volume is about the 1/ of blake bottle capacity
10), at 37 DEG C, 5%CO2Cultivated in incubator, judge the generation time according to the growth conditions of cancer cell.
(3) preparation of various concentrations medicine:Storing solution, every hole after dosing are prepared using tri-distilled water (a small amount of DMSO hydrotropies)
DMSO final concentration is usually no more than 0.05%-0.1% in cell suspension;Storing solution is diluted to four concentration ladders with tri-distilled water
Spend (100 μm of ol, 10 μm of ol, 1 μm of ol, 0.1 μm of ol);It is stored in standby in -20 DEG C of refrigerators.
(4) cell incubation:Take the logarithm growth period tumour cell, tune concentration of cell suspension is 1-1.5 × 105/mL, after mixing
(100 μ L/ holes) is added in 96 well culture plates, at 37 DEG C, 5%CO224h is cultivated in incubator.
(5) dosing:The medicine of the various concentrations gradient diluted is added separately in 96 well culture plates, each concentration ladder
Degree sets 3 flat hole, continues to cultivate 48h.Experiment is divided into experimental group (nutrient solution, cell, medicine), control group (nutrient solution and cell)
With blank group (only nutrient solution).
(6) survivaling cell detects:In 96 orifice plates after having cultivated 48h, add the μ L/ holes of MTT (5mg/mL) 10;Put at 37 DEG C
After putting 4h, supernatant is removed, adds the μ L/ holes of DMSO 150, vibrated to formazan and crystallize all dissolvings;Existed using automatic ELIASA
The optical density (OD values) in each hole is detected at 570nm wavelength.
The calculating of inhibiting rate:
Growth inhibition ratio=(1- survival rates) × 100%=[1- (OD experiment-OD blank)/(OD control-OD blank)] ×
100% (OD experiments represent the average optical density of experimental group, and OD controls represent the average optical density of control group, and OD blank represents empty
The average optical density organized in vain).
According to the standard curve of drug concentration-inhibitory rate of cell growth, its IC is sought50。
Suppression IC of the listed indole derivatives containing pyrazol framework to tumour cell of the invention50Value (μm ol/mL) is seen below
Table
It was found from above-mentioned experiment:The present invention is to Human colorectal cancer cells (HT-29), people's malignant melanoma cell
(A375), human melanoma cell (WM1361 cells) has obvious inhibitory action, and activity is preferably.
Embodiment 18:The external evoked apoptosis recent progress in experimental study of indole derivatives containing pyrazol framework
The indole derivatives containing pyrazol framework are detected to HT-29 cells using the double dye methods of Annexin V-FITC/PI
Apoptosis is tested.
(1) suspension cell centrifugation (2000rpm centrifuges 5min) is collected;Attached cell uses the pancreatin digestion without EDTA to receive
Collection;
(2) wash cell secondary (2000rpm centrifuges 5min) with PBS and collect cell;
(3) 500 μ L Binding Buffer suspension cells are added;
(4) after adding 5 μ L Annexin V-FITC mixings, 5 μ L PI is added, is mixed;
(5) room temperature, lucifuge, reaction 5 to 15min;
(6) in one hour, the observation and detection of flow cytometer are carried out.
The listed indole derivatives containing pyrazol framework of the invention are to tumor cell induction apoptosis as in Figure of description
Shown in Fig. 1, Fig. 2.
It was found from above-mentioned experiment:The present invention has the work of obvious inducing cell apoptosis to Human colorectal cancer cells (HT-29)
With activity is preferably.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of equivalents can be carried out to technical scheme, this
A little equivalents belong to protection scope of the present invention.It is further to note that described in above-mentioned embodiment
Each particular technique feature, in the case of reconcilable, can be combined by any suitable means.In order to avoid not
Necessary repetition, the present invention no longer separately illustrate to various combinations of possible ways.In addition, a variety of implementations of the present invention
It can also be combined between mode, as long as it without prejudice to the thought of the present invention, it is public that it should equally be considered as institute of the invention
The content opened.
Brief description of the drawings
Fig. 1, the medicine are to the concentration dependant figure of HT-29 cells apoptosis
Fig. 2, the medicine are to the Time Dependent figure of HT-29 cells apoptosis.
Claims (4)
1. a kind of indole derivatives containing pyrazol framework, its structure as shown in formula,
Wherein, R1Selected from H ,-CH3;R2Selected from-CH3、-CH2CH3、
2. a kind of method for preparing the indole derivatives containing pyrazol framework, the knot of the indole derivatives containing pyrazol framework
Structure as shown in formula,
Wherein, R1Selected from H ,-CH3;R2Selected from-CH3、-CH2CH3、
Preparation method comprises the following steps,
Indole -3-carboxylic acid methyl ester (25.00g, 142.7mmol) is dissolved into dry DMF (350mL) by step 1. at 0 DEG C, will
Sodium hydride (60%, be stored in mineral oil, 8.26g, a 214mmol) part part is added in said mixture.
After all addition terminates sodium hydride, iodomethane (44.4mL, 713.5mmol) is added in solution, then will entirely be reacted
System is placed in stirring reaction 15 minutes in 0 DEG C, and reaction system finally is slowly ramped into room temperature, and stirring reaction is overnight.Question response
After end, addition water is quenched in reaction solution.Obtained reactant mixture water and ethyl acetate (30mL × 3) extraction,
Organic phase uses saturated aqueous common salt and washing successively, and is removed water organic phase using anhydrous magnesium sulfate.Finally, by organic phase vacuum
Reduction vaporization is dried to obtain crude product, and carries out separating-purifying to it using silica gel column chromatography, obtains the change of structural formula as indicated at a
Compound.Appropriate potassium hydroxide is dissolved in water, then obtained compound A is added in above-mentioned solution, added appropriate
Methanol, whole reaction system is then placed in stirring reaction 2 hours in 60 DEG C.After question response terminates, by reactant mixture vacuum
The methanol dried and removed in reaction system is evaporated under reduced pressure, then adds dilute hydrochloric acid solution and adjusts ph values to 5-6, has a large amount of white
Color solid separates out.The white solid of precipitation is separated by filtration, finally obtained solid is dried, obtains structural formula as shown in B
Compound.
Pyrazoles (14g, 205.64mmol) is dissolved in the concentrated sulfuric acid (50mL), then by concentrated nitric acid by step 2. at 0 DEG C
(9.2mL, 226.20mmol) is added dropwise, and adds after terminating whole reaction system temperature is heated slowly into 60 while stirring
℃.Whole reactant mixture agitating and heating is reacted into 1.5h.After question response terminates, reactant mixture is added to mixture of ice and water
In (600g).After standing a period of time, reactant mixture has white solid precipitation, is then separated by filtration white solid, will
The white solid separated is dried after washing again, obtains the compound of a part of structural formula as shown at c.By the filter after filtering
Liquid is extracted with ethyl acetate (100mL × 3), obtains organic phase.Sodium bicarbonate solution (100mL) of the organic phase with 1%, water
(100mL) and saturated aqueous common salt (100mL) rinse successively.Finally, the ethyl acetate anhydrous sodium sulfate drying after will be treated
And vacuum decompression evaporation drying obtains the compound of another part structural formula as shown at c.
Step 3. by structural formula compound (7.14mmol) as shown at c, structural formula compound (7.14mmol) as shown atd,
8-hydroxyquinoline (0.18g, 1.23mmol), potassium carbonate (1.8g, 13.02mmol) are dissolved in anhydrous dimethyl sulfoxide (9mL), so
The container where reactant mixture is poured into argon gas afterwards, adds cuprous iodide (0.135g, 0.69mmol).By whole reactant
System is heated to 130 DEG C, then agitating and heating reaction 20h.Suitable quantity of water is added in reaction system by question response after terminating, and can be produced
A large amount of solids.Solid is separated by filtration and dries and separating-purifying is carried out to it using silica gel column chromatography, obtains structural formula as shown in E
Compound.
Compound (4mmol) of the structural formula as shown in E is dissolved in absolute ethyl alcohol (4mL) by step 4., then adds 80%
Hydrazine hydrate solution (2mL), 10% palladium carbon hydrogenation catalyst (0.08g).Then the temperature of reactant mixture is heated to 80 DEG C,
Reaction system is heated while stirring and reacted 10 minutes.After question response terminates, reactant mixture is filtered, collects filtrate.Finally,
Filter vacuum is evaporated under reduced pressure and is dried to obtain compound of the structural formula as shown in F.
Step 5. dissolves compound (0.25mmol) of the structural formula as shown in B, EDC (0.25mmol), HOBT (0.25mmol)
In dry DMF (5mL), reactant mixture is then positioned over stirring reaction 30 minutes under normal temperature.After 30 minutes, by structure
Compound (0.25mmol) of the formula as shown in F, DMAP (0.25mmol), triethylamine (1mL) are added in reactant mixture, then
Whole reaction reaction while stirring at normal temperatures is overnight.After question response terminates, obtained reactant mixture saturated aqueous common salt and
Ethyl acetate (100mL × 3) extracts, and finally, organic phase vacuum decompression evaporation drying is obtained into crude product, and utilize silica gel column layer
Analysis carries out separating-purifying to it, obtains compound of the final structural formula as shown in G.
Wherein, R1Selected from H ,-CH3;R2Selected from-CH3、-CH2CH3、
3. application of the indole derivatives containing pyrazol framework in cancer therapy drug is prepared, it is characterised in that its structure such as formula institute
Show
Wherein, R1Selected from H ,-CH3;R2Selected from-CH3、-CH2CH3、
A kind of 4. cancer therapy drug, it is characterised in that including compound of the structure as shown in formula and medically acceptable carrier,
Wherein, R1Selected from H ,-CH3;R2Selected from-CH3、-CH2CH3、
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Cited By (2)
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CN111100116A (en) * | 2019-11-14 | 2020-05-05 | 南京大学 | Preparation method and application of novel aniline derivative containing methylindole and taking pyrazoline as skeleton |
WO2022251533A1 (en) * | 2021-05-27 | 2022-12-01 | Protego Biopharma, Inc. | Heteroaryl diamide ire1/xbp1s activators |
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WO2008007113A2 (en) * | 2006-07-14 | 2008-01-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
WO2008079277A1 (en) * | 2006-12-22 | 2008-07-03 | Millennium Pharmaceuticals, Inc. | Certain pyrazoline derivatives with kinase inhibitory activity |
CN102015639A (en) * | 2008-05-07 | 2011-04-13 | 医学研究委员会 | Compounds for use in stabilizing p53 mutants |
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- 2016-09-30 CN CN201610877391.4A patent/CN107880029A/en active Pending
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2008007113A2 (en) * | 2006-07-14 | 2008-01-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
WO2008079277A1 (en) * | 2006-12-22 | 2008-07-03 | Millennium Pharmaceuticals, Inc. | Certain pyrazoline derivatives with kinase inhibitory activity |
CN102015639A (en) * | 2008-05-07 | 2011-04-13 | 医学研究委员会 | Compounds for use in stabilizing p53 mutants |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN111100116A (en) * | 2019-11-14 | 2020-05-05 | 南京大学 | Preparation method and application of novel aniline derivative containing methylindole and taking pyrazoline as skeleton |
WO2022251533A1 (en) * | 2021-05-27 | 2022-12-01 | Protego Biopharma, Inc. | Heteroaryl diamide ire1/xbp1s activators |
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