CN103922992A - Anti-cancer active indolone derivate as well as synthesis method and application thereof - Google Patents
Anti-cancer active indolone derivate as well as synthesis method and application thereof Download PDFInfo
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- CN103922992A CN103922992A CN201410169911.7A CN201410169911A CN103922992A CN 103922992 A CN103922992 A CN 103922992A CN 201410169911 A CN201410169911 A CN 201410169911A CN 103922992 A CN103922992 A CN 103922992A
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- formula
- pdcl
- indolone
- compound
- indolone derivatives
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- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 title abstract description 25
- 230000001093 anti-cancer Effects 0.000 title abstract description 6
- FGFUBBNNYLNVLJ-UHFFFAOYSA-N indolone Natural products C1=CC=C2C(=O)C=NC2=C1 FGFUBBNNYLNVLJ-UHFFFAOYSA-N 0.000 title abstract description 4
- 238000001308 synthesis method Methods 0.000 title 1
- 230000000694 effects Effects 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000000654 additive Substances 0.000 claims abstract description 8
- 230000000996 additive effect Effects 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 3
- 150000005624 indolones Chemical class 0.000 claims description 47
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 36
- 101150003085 Pdcl gene Proteins 0.000 claims description 20
- 238000010189 synthetic method Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical group [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 11
- 230000000259 anti-tumor effect Effects 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000011275 oncology therapy Methods 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 17
- 206010017758 gastric cancer Diseases 0.000 abstract description 14
- 201000011549 stomach cancer Diseases 0.000 abstract description 14
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 10
- -1 cyano-indolone compound Chemical class 0.000 abstract description 8
- 238000012360 testing method Methods 0.000 abstract description 7
- 239000003446 ligand Substances 0.000 abstract description 6
- 239000004327 boric acid Substances 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 201000005202 lung cancer Diseases 0.000 abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000004614 tumor growth Effects 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 3
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 150000002475 indoles Chemical class 0.000 description 10
- AQIHMSVIAGNIDM-UHFFFAOYSA-N benzoyl bromide Chemical compound BrC(=O)C1=CC=CC=C1 AQIHMSVIAGNIDM-UHFFFAOYSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 201000005296 lung carcinoma Diseases 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- NVILDTQNJFHJJA-UHFFFAOYSA-N 7-benzoylindol-2-one Chemical compound C=1C=CC2=CC(=O)N=C2C=1C(=O)C1=CC=CC=C1 NVILDTQNJFHJJA-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
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- 125000005843 halogen group Chemical group 0.000 description 5
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- 239000003208 petroleum Substances 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
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- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 0 COc1cc(C(c(cccc2C3)c2N(C=C)C3=[U])=[U])cc(OC)c1* Chemical compound COc1cc(C(c(cccc2C3)c2N(C=C)C3=[U])=[U])cc(OC)c1* 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
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- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- SPXOTSHWBDUUMT-UHFFFAOYSA-N 138-42-1 Chemical compound OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 201000000498 stomach carcinoma Diseases 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 229960002716 bromfenac sodium Drugs 0.000 description 2
- HZFGMQJYAFHESD-UHFFFAOYSA-M bromfenac sodium Chemical compound [Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 HZFGMQJYAFHESD-UHFFFAOYSA-M 0.000 description 2
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- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
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- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
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- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-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-YCRXJPFRSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to an indolone derivate. The derivate can be obtained by virtue of one-step synthesis of a cyano-indolone compound and a boric acid compound in the presence of a catalyst, a ligand and an additive. Meanwhile, the invention discovers that the derivate has favorable anti-cancer activity; discovered by virtue of activity tests, the derivate has a favorable cell tumour growth inhibition effect on a gastric cancer cell line (SGC-7901), a human lung cancer cell line (H446) and a human gastric cancer cell line (HGC-27), can be used as an anti-tumor drug in the field of medicine, and has a favorable medicine research prospect and industrial application value.
Description
Technical field
The present invention relates to a kind of pharmaceutical active compounds, relate to especially a kind of indolone derivatives, preparation method and use with excellent antitumor activity, belong to pharmaceutical chemistry field.
Background technology
Indolone derivatives is the important nitrogenous oxygen-bearing organic matter of a class, in organic and medicine synthesize, has important role and effect.Therefore in medication chemistry, organic synthesis and materials chemistry field, receive much concern.
Up to now, people have developed the multiple medical compounds with indolone structure.For example, 7-benzoyl indol-2-one is usually used to synthetic non_steroidal anti_inflammatory drug thing Amfenac sodium (Fenazox); And 7-(to benzoyl bromide) indol-2-one is usually used to synthetic non_steroidal anti_inflammatory drug thing Bromfenac sodium (Bromfenac sodium):
Just because of this type of vital role of indolone derivatives, people synthesize and have carried out large quantity research it, and have developed multiple synthetic method, mainly comprise following several chemical synthesis process:
1979, William J.Welstead, the people such as Jr. have reported the synthetic method shown in following formula, first the method is used N-amino indole-2-ketone is starting raw material, in the mixed solvent of acetic acid and ethanol, with the dehydration condensation of styroyl methyl ketone, generate imine intermediate I; Under acidic conditions, the intramolecular rearrangement of imine intermediate I and ring-closure reaction build the 2-(2-methyl-3-phenyl-7 Indoleacetic ethyl ester intermediate II containing indoles skeleton; Re-use ozone as oxygenant, after oxidation intermediates II, generate the intermediate III after indoles open loop; Finally, intermediate III is carried out intramolecular ring-closure reaction and is obtained target product 7-benzoyl indol-2-one (3a) under acidic conditions.The method need to experience four-step reaction could synthesize 7-benzoyl and indol-2-one, and technique is comparatively complicated, and its total recovery is lower; And in reaction process, used ozone, needed special equipment, complex operation.Its reaction formula is as follows:
1984, the people such as David A.Walsh reported the synthetic method of 7-benzoyl and indol-2-one: first, and at-70 ℃,
tthe lower 2-first ethyl thioglycolate of BuOCl effect generates sulfosalt (IV) with reacting of 2-ADP indolone; Then under alkalescence (as triethylamine) exists, there is rearrangement reaction and generate the 2-ADP indolone intermediate V that 3-replaces; Under acidic conditions, the intramolecular ring-closure reaction of the experience of intermediate V generates 7-benzoyl-3-(first sulfydryl) indol-2-one (VI); Last 7-benzoyl-3-(first sulfydryl) indol-2-one (VI) is reduced and generates target product 7-benzoyl indol-2-one (3a) under Raney's nickel exists.The method also needs to experience four-step reaction could synthesize 7-benzoyl and indol-2-one, and technique is comparatively complicated, and its total recovery is low, and when the first step is reacted, needs (at 70 ℃) at low temperatures to carry out, and reaction conditions is relatively harsh.Its reaction formula is as follows:
1992, R.G.Poser has reported the novel method of synthetic 7-sweet-smelling formacyl indol-2-one analog derivative: adopting is raw material to bromobenzylcyanide and indoline, with boron trichloride and aluminum chloride, it is catalyzer, carry out Friede-Crafts acylation reaction, generate 7-(to benzoyl bromide) indoline (VII); Through Manganse Dioxide oxidizing reaction, generate 7-(to benzoyl bromide) indoles (VIII) again; Then use N-chlorosuccinimide (NCS) to carry out chlorination reaction as chlorination reagent, generate chloro 7-(to benzoyl bromide) indoles (IV); Finally under phosphoric acid exists, carry out acidolysis reaction, generate target product 7-(to benzoyl bromide) indol-2-one (3b).But the method still needs four-step reaction could realize the synthetic of 7-(to benzoyl bromide) indol-2-one (3b), so its total recovery is on the low side, is about 28%.Its reaction formula is as follows:
Recently, Medicine Industry Inst., Shandong Prov.'s summer pool is wide waits people to improve above-mentioned reaction process, use self-control activated manganese dioxide as oxygenant, the yield of its oxidation products 7-(to benzoyl bromide) indoles (VIII) can be increased to 92.4% (document 85%); In addition, also changed chlorination reaction post-treating method, got rid of ether, increased dichloromethane extraction, the yield of chloro 7-(to benzoyl bromide) indoles (IV) is significantly improved to 97.9% (document 64%).Although the method has improved 7-(to benzoyl bromide) indol-2-one (3b) total recovery, but still very low, is about 33%.
But up to now, people not yet find that indolone derivatives has antitumour activity, for its active target spot and substituting group, do not have yet clear and definite understanding.But then, excellent biological activity due to indole ketone compound, therefore, searching has excellent medicine or bioactive novel indolone derivatives, and seek new synthetic method, be still research method and emphasis in current this field, this basis and power place that also the present invention is accomplished just.
Summary of the invention
In view of this, in order to seek to have excellent pharmaceutical activity and bioactive new indole ketones derivant, the inventor conducts in-depth research, and after paying a large amount of creative works, thereby has completed the present invention.
The present invention relates to a kind of excellent antitumour activity that has, especially human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446) and human stomach cancer cell line (HGC-27) are there is the indolone derivatives of good cell tumour growth-inhibiting effect, also relate to the preparation method and use of this derivative.
Particularly, first aspect, the present invention relates to indolone derivatives shown in a kind of formula (I) with excellent antitumor activity:
R
1be selected from independently of one another H, C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
N is the integer of 0-5 independently.
Preferably, described indolone derivatives is preferably following formula (II) compound:
Wherein, R
1there is above-mentioned identical definition with n.
In described indolone derivatives of the present invention, unless otherwise prescribed, from start to finish, C
1-C
6the implication of alkyl refers to the straight or branched alkyl with 1-6 carbon atom, and it has comprised C
1alkyl, C
2alkyl, C
3alkyl, C
4alkyl, C
5alkyl or C
6alkyl, indefiniteness ground is such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or n-hexyl etc.
In described indolone derivatives of the present invention, unless otherwise prescribed, from start to finish, C
1-C
6alkoxyl group refers to " C defined above
1-C
6alkyl " group after being connected with O atom.
In indolone derivatives of the present invention, unless otherwise prescribed, from start to finish, the halogen in halogen or halo for example can be F, Cl, Br or I.
In described indolone derivatives of the present invention, unless otherwise prescribed, from start to finish, halo C
1-C
6the implication of alkyl refers to the " C defined above being replaced by halogen
1-C
6alkyl ", indefiniteness ground is such as being trifluoromethyl, pentafluoroethyl group, difluoromethyl, chloromethyl etc.
In described indolone derivatives of the present invention, unless otherwise prescribed, from start to finish, halo C
1-C
6the implication of alkoxyl group refers to the " C defined above being replaced by halogen
1-C
6alkoxyl group ", indefiniteness ground is such as being trifluoromethoxy, five fluorine oxyethyl groups, difluoro-methoxy, chlorine methoxyl group etc.
In described indolone derivatives of the present invention, the integer that n is 0-5, for example, can be 0,1,2,3,4 or 5, and phenyl ring can be by 0,1,2,3,4 or 5 identical or different R separately
1institute replaces.
In described indolone derivatives of the present invention, preferred R
1for C
1-C
6alkoxyl group, most preferably is methoxyl group.
In described indolone derivatives of the present invention, the integer that preferably n is 1-3, most preferably is 3.
In described indolone derivatives of the present invention, formula (I) compound is preferably following formula (III), (VI) or (V) compound:
In described indolone derivatives of the present invention, formula (I) compound most preferably is lower formula V compound:
Second aspect, the present invention relates to the synthetic method of above-mentioned indolone derivatives, described method comprises: under the existence of palladium catalyst, part and additive, in solvent, formula (VI) compound reacts with formula (VII), thus the indolone derivatives of the formula of obtaining (I);
Wherein, R
1, n as defined above.
In the synthetic method of indolone derivatives of the present invention, when formula (VI) is following formula (VIII), just can obtain formula (II) compound:
In the synthetic method of indolone derivatives of the present invention, described palladium catalyst is palladium trifluoroacetate (Pd (O
2cCF
3)
2), acid chloride (Pd (OAc)
2), PdCl
2, PdCl
2(PPh
3)
2, PdCl
2(dppf)
2, PdCl
2(dppe), PdCl
2(cod), PdCl
2(py)
2, PdCl
2(MeCN)
2, Pd (acac)
2, Pd (PPh
3)
4, Pd
2(dba)
3, Pd
2(dba)
2in any or multiple mixture; Be preferably palladium trifluoroacetate, acid chloride or PdCl
2; Most preferably be palladium trifluoroacetate.
In the synthetic method of indolone derivatives of the present invention, described part is bidentate containing n-donor ligand or phosphine part, for example, any or any multiple mixture in L1-L12 that can be following:
Wherein, preferred L1-L9, further preferred L1, L2, L3, L8, most preferably L2.
In the synthetic method of indolone derivatives of the present invention, described additive is acid, for example, can be trifluoroacetic acid, phenylformic acid, trifluoromethanesulfonic acid, tosic acid, p-nitrophenyl sulfonic acid, methylsulfonic acid, sulfuric acid, hydrochloric acid or potassium bifluoride; Be preferably trifluoroacetic acid, tosic acid, p-nitrophenyl sulfonic acid or methylsulfonic acid; Most preferably be methylsulfonic acid.
In the synthetic method of indolone derivatives of the present invention, described formula (VI) compound and (VII) mol ratio of compound can be carried out suitable selection, for example mol ratio can be 1:1-3, exemplarily for example can be 1:1,1:1.5,1:2,1:2.5 or 1:3.
In the synthetic method of indolone derivatives of the present invention, the mol ratio of described formula (VI) compound and catalyzer is 1:0.02-0.1, for example, can be 1:0.02,1:0.04,1:0.06,1:0.08 or 1:0.1.
In the synthetic method of indolone derivatives of the present invention, the mol ratio of described formula (VI) compound and part is 1:0.05-0.1, for example, can be 1:0.05,1:0.07 or 1:0.1.
In the synthetic method of indolone derivatives of the present invention, the mol ratio of described formula (VI) compound and additive is 1:5-15, for example, can be 1:5,1:10 or 1:15.
In the synthetic method of indolone derivatives of the present invention, temperature of reaction is 60-120 ℃, for example can be to indefiniteness 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃ or 120 ℃.
In the synthetic method of indolone derivatives of the present invention, described solvent is the mixture of organic solvent and water, wherein said organic solvent for example can be tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran (2-MeTHF), toluene, dimethylbenzene, dioxane, N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), Virahol, ethanol, propyl carbinol, chlorobenzene etc., the volume ratio of organic solvent and water is 1-3:1, for example can be 1:1,2:1 or 3:1, be preferably 2:1.
In the synthetic method of indolone derivatives of the present invention, reaction times there is no special restriction, for example can determine the suitable reaction times by the residual per-cent of TLC or GC-MS tracking testing goal product or raw material, it typically is 15-40 hour, is indefiniteness for example 15 hours, 17 hours, 19 hours, 21 hours, 23 hours, 25 hours, 27 hours, 29 hours, 30 hours, 32 hours, 34 hours, 36 hours, 38 hours or 40 hours.
In described synthetic method of the present invention, the aftertreatment of reaction after finishing can be any processing means in crystallization, recrystallization, column chromatography purification, extraction etc. or the combination of multiple processing means.As a kind of exemplary aftertreatment means, for example can be: after reaction finishes, in reaction mixture, add water, use extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation is removed ether and is concentrated, and enriched material is crossed to 300-400 order silicagel column, usings the mixed solution of ethyl acetate/petroleum ether as eluent, the volume ratio 1:5-15 of ethyl acetate and sherwood oil wherein, thus target product formula (I) compound obtained.
The 3rd aspect, the present invention relates to indolone derivatives shown in above formula (I) as the new purposes of cancer therapy drug.
The inventor finds, shown in above-mentioned formula (I), indolone derivatives has excellent antitumour activity, especially human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446) and human stomach cancer cell line (HGC-27) are had to good cell tumour growth-inhibiting effect, thereby can in field of medicaments, be used as antitumor drug.
Wherein, lower formula V compound has most preferred antitumour activity:
The 4th aspect, the present invention relates to the purposes of compound in preparing cancer therapy drug of indolone derivatives, especially formula (III) shown in above formula (I)-(V).
Especially formula (III)-(V) compound has good antitumour activity to described (I) indolone derivatives, especially human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446) and human stomach cancer cell line (HGC-27) is had to good inhibition.
The 5th aspect, the invention still further relates to a kind of especially pharmaceutical composition of lung cancer or cancer of the stomach of cancer for the treatment of, and formula (I) indolone derivatives that it comprises as activeconstituents especially comprises the compound of formula (III)-(V).
Except comprising above-mentioned active ingredient beyond the region of objective existence, described pharmaceutical composition also can comprise pharmaceutically acceptable carrier, vehicle and/or auxiliary agent.
In the present invention, " pharmaceutically acceptable carrier " refers to organism do not caused to significant stimulation do not eliminate the biological activity of used compound and the carrier of characteristic or thinner yet.Conventionally, these have comprised the consideration of patient for pharmacology/toxicology aspect, and pharmaceutical chemistry man thinks acceptable characteristic and/or material for the consideration of the physical/chemical aspect of composition, preparation, stability, patient's acceptance and bioavailability.
" vehicle " or " auxiliary agent " thus refer to and add the inert substance of using that further contributes to compound in pharmaceutical composition to, the example is including, but not limited to calcium carbonate, calcium phosphate, multiple sugar and multiple starch, derivatived cellulose (comprising Microcrystalline Cellulose), gelatin, vegetables oil, polyoxyethylene glycol, thinner, granulating agent, lubricant, binding agent, disintegrating agent and analogue.
Formula of the present invention (I) indolone derivatives, especially formula (III)-(V) compound shows good biological activity in anticancer test in vitro, thereby has huge potentiality to be exploited and application prospect in the clinical treatment application of tumor disease.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not real protection scope of the present invention is formed to any type of any restriction, more non-protection scope of the present invention is confined to this.
Embodiment 1:7-(4-benzoyl bromide)-indol-2-one
At room temperature, in reaction vessel, add 100ml solvent (be the mixture of 2-MeTHF and water, both volume ratios are 2:1), 20mmol7-cyano group-indol-2-one, 40mmol to bromobenzene boric acid, 1mmol palladium trifluoroacetate, the above-mentioned ligand L 2 of 1.5mmol and 200mmol methylsulfonic acid; Under stirring, be warming up to 80 ℃, and insulation reaction 35 hours.
After question response finishes, in reaction mixture, add 100ml water, use extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation is removed ether and is concentrated, and enriched material is crossed to 300-400 order silicagel column, usings the mixed solution of ethyl acetate/petroleum ether as eluent, the volume ratio 1:10 of ethyl acetate and sherwood oil wherein, concentrate eluant, obtains the title compound into yellow solid, called after A.Its productive rate is 74.8%, and purity is 98.9% (HPLC).
Fusing point: 195-196 ℃.
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 9.49 (s, 1H), 7.65 (d, J=8.6Hz, 2H), 7.59 (d, J=8.5Hz, 2H), 7.49 (d, J=8.1Hz, 1H), 7.43 (d, J=7.3Hz, 1H), 7.04 (t, J=7.7Hz, 1H), 3.57 (s, 2H);
13C?NMR(CDCl
3,125MHz)δ195.6,176.4,145.7,136.7,131.7(2C),130.9(2C),130.7,129.2,127.2,121.1,117.6,112.0,35.1。
Embodiment 2:7-(3-anisoyl)-indol-2-one
At room temperature, in reaction vessel, add 100ml solvent (be the mixture of 2-MeTHF and water, both volume ratios are 2:1), 20mmol7-cyano group-indol-2-one, 20mmol meta-methoxy phenylo boric acid, 0.4mmol palladium trifluoroacetate, the above-mentioned ligand L 2 of 1mmol and 100mmol methylsulfonic acid; Under stirring, be warming up to 60 ℃, and insulation reaction 40 hours.
After question response finishes, in reaction mixture, add 100ml water, use extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation is removed ether and is concentrated, and enriched material is crossed to 300-400 order silicagel column, usings the mixed solution of ethyl acetate/petroleum ether as eluent, the volume ratio 1:5 of ethyl acetate and sherwood oil wherein, concentrate eluant, obtains the title compound into yellow solid, called after B.Its productive rate is 81.9%, and purity is 99.2% (HPLC).
Fusing point: 131-133 ℃.
Nucleus magnetic resonance:
1hNMR (CDCl
3, 500MHz) δ 9.69 (s, 1H), 7.56 (d, J=8.1Hz, 1H), 7.43-7.38 (m, 2H), 7.29-7.26 (m, 2H), 7.14-7.12 (m, 1H), 7.04 (t, J=7.7Hz, 1H), 3.85 (s, 3H), 3.57 (s, 2H);
13C?NMR(CDCl
3,125MHz)δ196.4,176.8,159.6,145.5,139.2,131.0,129.3,129.0,127.0,121.9,121.0,118.3,118.0,114.0,55.5,35.1。
Embodiment 3:7-(3,4-dimethoxy benzoyl)-indol-2-one
At room temperature, to adding 100ml solvent in reaction vessel, (be the mixture of 2-MeTHF and water, both volume ratios are 2:1), 20mmol7-cyano group-indol-2-one, 60mmol3,4-dimethoxy phenylo boric acid, 1.5mmol palladium trifluoroacetate, the above-mentioned ligand L 2 of 2mmol and 300mmol methylsulfonic acid; Under stirring, be warming up to 100 ℃, and insulation reaction 30 hours.
After question response finishes, in reaction mixture, add 100ml water, use extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation is removed ether and is concentrated, and enriched material is crossed to 300-400 order silicagel column, usings the mixed solution of ethyl acetate/petroleum ether as eluent, the volume ratio 1:15 of ethyl acetate and sherwood oil wherein, concentrate eluant, obtains the title compound into yellow solid, called after C.Its productive rate is 88.7%, and purity is 98.6% (HPLC).
Fusing point: 154-156 ℃.
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz): δ 9.36 (s, 1H), 7.57 (d, J=8.8Hz, 1H), 7.40 (d, J=7.3Hz, 1H), 7.36-7.34 (m, 2H), 7.04 (t, J=7.7Hz, 1H), 6.92 (d, J=8.0Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.56 (s, 2H);
13C?NMR(CDCl
3,125MHz)δ195.1,176.5,152.9,149.1,145.3,130.6,130.5,128.5,127.0,124.5,120.8,118.4,112.0,109.9,56.1,56.1,35.3。
Embodiment 4:7-(3,4,5-trimethoxy benzoyl)-indol-2-one
At room temperature, to adding 100ml solvent in reaction vessel, (be the mixture of 2-MeTHF and water, both volume ratios are 2:1), 20mmol7-cyano group-indol-2-one, 30mmol3,4,5-trimethoxy phenylo boric acid, 2mmol palladium trifluoroacetate, the above-mentioned ligand L 2 of 1mmol and 150mmol methylsulfonic acid; Under stirring, be warming up to 120 ℃, and insulation reaction 25 hours.
After question response finishes, in reaction mixture, add 100ml water, use extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation is removed ether and is concentrated, and enriched material is crossed to 300-400 order silicagel column, usings the mixed solution of ethyl acetate/petroleum ether as eluent, the volume ratio 1:7 of ethyl acetate and sherwood oil wherein, concentrate eluant, obtains the title compound into yellow solid, called after D.Its productive rate is 62.8%, and purity is 98.5% (HPLC).
Fusing point: 156-158 ℃.
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz): δ 9.45 (s, 1H), 7.59 (d, J=8.1Hz, 1H), 7.43 (d, J=7.3Hz, 1H), 7.05 (t, J=7.4Hz, 1H), 6.97 (s, 2H), 3.93 (s, 3H), 3.88 (s, 6H), 3.58 (s, 2H);
13C?NMR(CDCl
3,125MHz)δ195.7,176.5,153.0(2C),145.5,141.8,133.0,130.7,128.9,127.1,120.9,118.0,107.1(2C),61.0,56.3(2C),35.2。
Comparative example 1-36
Except catalyzer palladium trifluoroacetate is wherein replaced with respectively to Pd (OAc)
2, PdCl
2, Pd
2(dba)
3, Pd (dba)
2, Pd (pyridyl)
2, Pd (NH
3)
4cl
2, two (tri-butyl phosphine) palladium (0), Pd (acac)
2, Pd (PPh
3)
4in the mode identical with embodiment 1, implemented respectively comparative example 1-9 outward;
Except catalyzer palladium trifluoroacetate is wherein replaced with respectively to Pd (OAc)
2, PdCl
2, Pd
2(dba)
3, Pd (dba)
2, Pd (pyridyl)
2, Pd (NH
3)
4cl
2, two (tri-butyl phosphine) palladium (0), Pd (acac)
2, Pd (PPh
3)
4in the mode identical with embodiment 2, implemented respectively comparative example 10-18 outward;
Except catalyzer palladium trifluoroacetate is wherein replaced with respectively to Pd (OAc)
2, PdCl
2, Pd
2(dba)
3, Pd (dba)
2, Pd (pyridyl)
2, Pd (NH
3)
4cl
2, two (tri-butyl phosphine) palladium (0), Pd (acac)
2, Pd (PPh
3)
4in the mode identical with embodiment 3, implemented respectively comparative example 19-27 outward;
Except catalyzer palladium trifluoroacetate is wherein replaced with respectively to Pd (OAc)
2, PdCl
2, Pd
2(dba)
3, Pd (dba)
2, Pd (pyridyl)
2, Pd (NH
3)
4cl
2, two (tri-butyl phosphine) palladium (0), Pd (acac)
2, Pd (PPh
3)
4in the mode identical with embodiment 4, implemented respectively comparative example 28-36 outward.
The productive rate of corresponding oxindole compounds is as shown in the table.
Comparative example 37-80
Use respectively L1, L3-L12 to implement embodiment 1 and obtain comparative example 37-47;
Use respectively L1, L3-L12 to implement embodiment 2 and obtain comparative example 48-58;
Use respectively L1, L3-L12 to implement embodiment 3 and obtain comparative example 59-69;
Use respectively L1, L3-L12 to implement embodiment 4 and obtain comparative example 70-80.
The productive rate of corresponding oxindole compounds is as shown in the table.
Comparative example 81-88
Except being following organic solvent/water mixture (wherein the volume ratio of organic solvent and water is 2:1) by solvent replacing wherein, in the mode identical with embodiment 1-4, implemented respectively comparative example 81-88, the productive rate of its corresponding relation and corresponding methanone compounds is as shown in the table:
The investigation of additive
Except methylsulfonic acid wherein being replaced with trifluoroacetic acid, acetic acid, phenylformic acid, trifluoromethanesulfonic acid, tosic acid, p-nitrophenyl sulfonic acid, sulfuric acid, hydrochloric acid and potassium bifluoride, according to embodiment 1-4, investigated respectively the effect of these additives, find when for hydrochloric acid and potassium bifluoride, the reaction of embodiment 1-4 all can not be carried out, and when above-mentioned additive for other, the reaction of embodiment 1-4 all can be carried out, but productive rate has significantly decline, conventionally reduces 25-35%.
Biological activity test
Adopt mtt assay to measure indolone derivatives of the present invention the restraining effect of growth of tumour cell is carried out to preliminary assessment, subject cell comprises human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446) and human stomach cancer cell line (HGC-27), and anticarcinogen cis-platinum is as positive control drug.
Active testing material
Cell: SGC-7901: human stomach cancer cell line; H446: human lung carcinoma cell line; HGC-27: human stomach cancer cell line; Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank.
Reagent: DMEM substratum: Gibco company product; MTT:Sigma company product, Shanghai Cellular Biotech Co., Ltd.'s packing of growing directly from seeds; Foetal calf serum: Gibco company product; Penicillin-Streptomycin sulphate: Gibco company product; EDTA-trysinization liquid: Gibco company product; Positive control (cis-platinum): Qilu Pharmaceutical Co., Ltd.'s product, lot identification mark: 1010011DC.
Experimental procedure
(1) preparation of sample
Every 1mg test compounds is dissolved with 20 μ L DMSO, after getting 2 μ L dissolvings, solution dilutes (the DMEM substratum that this nutrient solution is is 10% containing foetal calf serum mass concentration) with 1000 μ L nutrient solutions, making its concentration is 100 μ g/mL, then uses identical nutrient solution serial dilution to working concentration 1-10 μ g/mL.
(2) preparation of substratum
Prepare DMEM substratum, make to contain in every 1000mL DMEM substratum the inactivated fetal bovine serum of 80Wan unit's penicillin, 1.0g Streptomycin sulphate and 10% quality.
(3) cultivation of cell: in the substratum of respectively above-mentioned tumor cell inoculation being prepared in step (2), in 37 ℃, 5%CO
2in incubator, cultivate, 3-5d goes down to posterity.
(4) restraining effect of working sample to growth of tumour cell
Cell human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446), human stomach cancer cell line (HGC-27) are digested with EDTA-trysinization liquid respectively, and be diluted to 1 * 10 with substratum
5/ mL, is added in 96 porocyte culture plates, and every hole 100 μ L, put 37 ℃, 5%CO
2in incubator, cultivate.After 24 hours, discard former substratum, add the substratum containing test sample, every hole 200 μ L, each concentration adds 3 holes, puts 37 ℃, 5%CO
2in incubator, cultivate, add the MTT of 5mg/mL after 72 hours in cell cultures hole, every hole 10 μ L, put 37 ℃ and hatch 4 hours, add DMSO, every hole 150 μ L, and with vibrator vibration, Shi Jia Za dissolves completely, by microplate reader colorimetric under 570nm wavelength.Respectively with similarity condition with containing sample, containing the above-mentioned cancer cell of the culture medium culturing of same concentration DMSO in contrast, the median lethal concentration (IC of calculation sample to growth of tumour cell
50).
After above-mentioned steps is measured, the IC of the compounds of this invention
50as shown in the table:
As seen from the above table, Compound D of the present invention has excellent especially anti-cancer of the stomach and anti-lung cancer activity, its IC
50will be far below cis-platinum, especially in the inhibition activity for H446, than cis-platinum low three orders of magnitude, in the inhibition activity for SGC-7901 and HGC-27, also than cis-platinum low two orders of magnitude, thereby in anticancer medicine, there is huge application potential and clinical value.
In sum, the invention provides a kind of antitumour activity indolone derivatives, find that this compounds has good anti-cancer of the stomach and anti-lung cancer activity simultaneously, this is the discovery first for this purposes of this compounds, thereby for the research and development of cancer therapy drug, expanded substrate and possibility, there are huge clinical value and research and development potentiality.
The purposes that should be appreciated that these embodiment only limits the scope of the invention for the present invention being described but not being intended to.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various changes, modification and/or modification to the present invention, within these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. indolone derivatives shown in a formula (I) with antitumour activity:
Wherein, R
1be selected from independently of one another H, C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
N is the integer of 0-5 independently.
2. derivative as claimed in claim 1, is characterized in that: described indolone derivatives is following formula (II) compound:
Wherein, R
1there is the identical definition in claim 1 with n.
3. derivative as claimed in claim 1 or 2, is characterized in that: described indolone derivatives is following formula (III), (VI) or (V) compound:
。
4. derivative claimed in claim 3, is characterized in that: described indolone derivatives is lower formula V compound:
5. the synthetic method of indolone derivatives as described in claim 1-4 any one, described method comprises: under the existence of palladium catalyst, part and additive, in solvent, formula (VI) compound reacts with formula (VII), thus the indolone derivatives of the formula of obtaining (I);
Wherein, R
1, n is respectively as defined in claim 1-4.
6. method as claimed in claim 5, is characterized in that: described palladium catalyst is palladium trifluoroacetate (Pd (O
2cCF
3)
2), acid chloride (Pd (OAc)
2), PdCl
2, PdCl
2(PPh
3)
2, PdCl
2(dppf)
2, PdCl
2(dppe), PdCl
2(cod), PdCl
2(py)
2, PdCl
2(MeCN)
2, Pd (acac)
2, Pd (PPh
3)
4, Pd
2(dba)
3, Pd
2(dba)
2in any or multiple mixture; Be preferably palladium trifluoroacetate, acid chloride or PdCl
2; Most preferably be palladium trifluoroacetate.
7. the method as described in claim 5 or 6, is characterized in that: described part is any or any multiple mixture in following formula L1-L12:
Wherein, preferred L1-L9, further preferred L1, L2, L3, L8, most preferably L2.
8. the purposes of the derivatives as anti-cancer agents thing in claim 1-4 any one.
9. the purposes of the derivative in claim 1-4 any one in preparing cancer therapy drug.
10. pharmaceutical composition, it comprises as indolone derivatives in the claim 1-4 any one of activeconstituents, especially comprises formula (IV) or (V) compound.
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CN108003085A (en) * | 2017-12-19 | 2018-05-08 | 张开良 | A kind of synthetic method of pharmaceutical intermediate sweet-smelling formacyl indole derivatives |
CN109608380A (en) * | 2018-12-04 | 2019-04-12 | 温州大学 | The synthetic method of general sieve nanogram intermediate 7- (to benzoyl bromide) indol-2-one |
CN110172036A (en) * | 2018-02-19 | 2019-08-27 | 齐鲁制药有限公司 | A kind of preparation method of bromfenac sodium intermediate |
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CN104402762A (en) * | 2014-12-26 | 2015-03-11 | 桂林理工大学 | Synthesis and application of 3,5-dichloralicyl aldolase-2-amino-2-methyl-1,3-propanediol Schiff base with anti-cancer activity |
CN104402762B (en) * | 2014-12-26 | 2016-09-28 | 桂林理工大学 | The synthesis of with anticancer activity 3,5-dichloro-salicylaldehyde's contracting AMPD schiff bases and application |
CN108003085A (en) * | 2017-12-19 | 2018-05-08 | 张开良 | A kind of synthetic method of pharmaceutical intermediate sweet-smelling formacyl indole derivatives |
CN110172036A (en) * | 2018-02-19 | 2019-08-27 | 齐鲁制药有限公司 | A kind of preparation method of bromfenac sodium intermediate |
CN110172036B (en) * | 2018-02-19 | 2022-03-04 | 齐鲁制药有限公司 | Preparation method of bromfenac sodium intermediate |
CN109608380A (en) * | 2018-12-04 | 2019-04-12 | 温州大学 | The synthetic method of general sieve nanogram intermediate 7- (to benzoyl bromide) indol-2-one |
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