CN104586842A - Anti-cancer activity indole derivative, synthesis method and uses thereof - Google Patents

Anti-cancer activity indole derivative, synthesis method and uses thereof Download PDF

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CN104586842A
CN104586842A CN201410171656.XA CN201410171656A CN104586842A CN 104586842 A CN104586842 A CN 104586842A CN 201410171656 A CN201410171656 A CN 201410171656A CN 104586842 A CN104586842 A CN 104586842A
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indole
indole derivatives
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CN104586842B (en
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陈久喜
吴华悦
高文霞
刘妙昌
黄小波
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Wenzhou University
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Abstract

The present invention relates to an indole derivative and uses of the indole derivative in preparation of anti-cancer drugs for tumor inhibition, wherein a cyano indole compound and a boric acid compound can be subjected to one-step synthesis in the presence of a catalyst, a ligand and an additive so as to obtain the derivative. According to the present invention, the derivative has the excellent anti-cancer activity, and results of the activity test show that the derivative provides good tumor cell growth inhibition effects on human gastric cancer cell line (SGC-7901), human lung cancer cell line (H446) and human gastric cancer cell line (HGC-27), such that the derivative can be adopted as the anti-tumor drug in the medicine field and has good medical research prospects and industrial application values.

Description

A kind of active anticancer indole derivatives, preparation method and use
Technical field
The present invention relates to a kind of pharmaceutical active compounds, particularly a kind of indole derivatives, preparation method and use with excellent antitumor activity, belongs to medicinal chemistry art.
Background technology
Indole derivatives is the important nitrogenous oxygen-bearing organic matter of a class, in organic and pharmaceutical synthesis, have important role and effect.Therefore receive much concern in medication chemistry, organic synthesis and technical field of material chemistry.
Up to now, the multiple medical compounds with indole structure is developed.Such as, 7-benzoyl indol-2-one is usually used to synthesis non_steroidal anti_inflammatory drug thing Amfenac sodium (amfenac sodium); And 7-(to benzoyl bromide) indol-2-one is usually used to synthesis non_steroidal anti_inflammatory drug thing Bromfenac sodium (bromfenac sodium):
Just because of this type of important function of indole derivatives, people have synthesized many indole derivativeses, and have carried out large quantity research to its synthesis, such as:
CN102911105A discloses a kind of synthetic method of 3-aroyl benzazolyl compounds; described method is that using mantoquita as catalyst, silver salt is as oxidant with R1-substituted indole and R2-substituted benzene formyl formic acid for raw material; carry out the acylation reaction of decarboxylation in organic solvent, its reaction equation is as follows:
WO0242269A discloses a kind of 3-aroyl indole extremely as CB 2the application of receptor stimulating agent, its structural formula is as follows:
The preparation method of this compound is very loaded down with trivial details, needs just can obtain through multistep reaction, and yield is very low.
CN1136038A discloses a kind of Indoloylguanidine derivatives, and it has following structural formula:
This compound can be prepared into by the following two kinds substance reaction:
EP0221753 reports the new method of synthesis 7-sweet-smelling formacyl indol-2-one analog derivative: adopting bromobenzylcyanide and indoline is raw material, be catalyst with boron chloride and aluminum chloride, carry out Friede-Crafts acylation reaction, generate 7-(to benzoyl bromide) indoline; 7-(to benzoyl bromide) indole is generated again through manganese dioxide reaction.Its reaction equation is as follows:
2003; Medicine Industry Inst., Shandong Prov.'s summer pool is wide waits people's (" synthesis of bromfenac sodium "; " China Medicine University's journal "; 2003; 34:405-406) above-mentioned reaction process is improved; use self-control activated manganese dioxide as oxidant, the yield of its oxidation product 7-(to benzoyl bromide) indole increases.
But up to now, people not yet find that indole derivatives has active anticancer, do not have clear and definite understanding yet for its active target spot and substituent group.But then, because the superior bio of Benzazole compounds is active, therefore, searching has excellent pharmacological or bioactive novel indole derivatives, and seek new synthetic method, be still the research method in current this field and emphasis, this is the basis that is accomplished of the present invention and power place just also.
Summary of the invention
In view of this, in order to seek that there is excellent pharmacological activity and bioactive new indole analog derivative, present inventor has performed further investigation, after paying a large amount of creative work, thus completing the present invention.
The present invention relates to one and there is excellent anti-cancer 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 the indole derivatives of good cell tumour growth inhibited effect, also relate to the preparation method and use of this derivant.
Specifically, first aspect, the present invention relates to indole derivatives shown in a kind of formula (I) with excellent antitumor activity:
Wherein, Ar is by 1-5 identical or different R 1the C replaced 6-12aryl;
R 1be selected from H, C 1-C 6alkyl, C 1-C 6alkoxyl, halogen, halo C 1-C 6alkyl, halo C 1-C 6alkoxyl or phenyl.
In described indole derivatives of the present invention, unless otherwise prescribed, from start to finish, C 6-12aryl refers to the aryl with 6-12 carbon atom, such as, can be phenyl, naphthyl.
In described indole 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, that includes C 1alkyl, C 2alkyl, C 3alkyl, C 4alkyl, C 5alkyl or C 6alkyl, such as can be methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl or n-hexyl etc. in non-limiting manner.
In described indole derivatives of the present invention, unless otherwise prescribed, from start to finish, C 1-C 6alkoxyl refers to " C defined above 1-C 6alkyl " be connected with O atom after group.
In indole derivatives of the present invention, unless otherwise prescribed, from start to finish, the halogen in halogen or halo such as can be F, Cl, Br or I.
In described indole 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 be optionally substituted by halogen 1-C 6alkyl ", be such as trifluoromethyl, pentafluoroethyl group, difluoromethyl, chloromethyl etc. in non-limiting manner.
In described indole derivatives of the present invention, unless otherwise prescribed, from start to finish, halo C 1-C 6the implication of alkoxyl refers to the " C defined above be optionally substituted by halogen 1-C 6alkoxyl ", be such as trifluoromethoxy, five fluorine ethyoxyls, difluoro-methoxy, chlorine methoxyl group etc. in non-limiting manner.
In described indole derivatives of the present invention, formula (I) compound is preferably following formula (II), (III), (VI) or (V) compound:
In described indole derivatives of the present invention, most preferably descend formula V compound:
Second aspect, the present invention relates to the synthetic method of above-mentioned indole derivatives, described method comprises: under the existence of palladium catalyst, part and additive, in solvent, formula (VI) compound and formula (VII) are reacted, thus obtain the indole derivatives of formula (I);
Wherein, Ar as defined above.
In the synthetic method of indole 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 one or multiple mixture; Be preferably palladium trifluoroacetate, acid chloride or PdCl 2; Most preferably be palladium trifluoroacetate.
In the synthetic method of indole derivatives of the present invention, described part is bidentate containing n-donor ligand or Phosphine ligands, such as, any one in L1-L12 that can be following or any multiple mixture:
Wherein, preferred L1-L9, further preferred L1, L2, L3, L8, most preferably L2.
In the synthetic method of indole derivatives of the present invention, described additive is acid, such as, can be trifluoroacetic acid, benzoic acid, trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid, p-nitrophenyl sulfonic acid, methanesulfonic acid, sulphuric acid, hydrochloric acid or potassium bifluoride; Be preferably trifluoroacetic acid, p-methyl benzenesulfonic acid, p-nitrophenyl sulfonic acid or methanesulfonic acid; Most preferably be methanesulfonic acid.
In the synthetic method of indole derivatives of the present invention, described formula (VI) compound can carry out suitable selection with the mol ratio of (VII) compound, such as mol ratio can be 1:1-3, exemplarily such as can be 1:1,1:1.5,1:2,1:2.5 or 1:3.
In the synthetic method of indole derivatives of the present invention, the mol ratio of described formula (VI) compound and catalyst is 1:0.02-0.1, such as, can be 1:0.02,1:0.04,1:0.06,1:0.08 or 1:0.1.
In the synthetic method of indole derivatives of the present invention, the mol ratio of described formula (VI) compound and part is 1:0.05-0.1, such as, can be 1:0.05,1:0.07 or 1:0.1.
In the synthetic method of indole derivatives of the present invention, the mol ratio of described formula (VI) compound and additive is 1:5-15, such as, can be 1:5,1:10 or 1:15.
In the synthetic method of indole derivatives of the present invention, reaction temperature is 60-120 DEG C, such as can be 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C or 120 DEG C in non-limiting manner.
In the synthetic method of indole derivatives of the present invention, described solvent is the mixture of organic solvent and water, wherein said organic solvent such as can be oxolane (THF), 2-methyltetrahydrofuran (2-MeTHF), toluene, dimethylbenzene, dioxane, N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO), isopropyl alcohol, ethanol, n-butyl alcohol, chlorobenzene etc., the volume ratio of organic solvent and water is 1-3:1, such as can be 1:1,2:1 or 3:1, be preferably 2:1.
In the synthetic method of indole derivatives of the present invention, response time, there is no particular limitation, such as by TLC or GC-MS tracing detection object product or raw material residual percentage and determine the suitable response time, it typically is 15-40 hour, is such as 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 non-limiting manner.
In described synthetic method of the present invention, the post processing after reaction terminates can be the combination of any one process means in crystallization, recrystallization, chromatography over CC, extraction etc. or multiple process means.As a kind of exemplary post processing means, such as can be: after reaction terminates, water is added in reactant mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and concentrate is crossed 300-400 order silicagel column, using the mixed liquor of ethyl acetate/petroleum ether as eluant, the wherein volume ratio 1:5-15 of ethyl acetate and petroleum ether, thus obtain target product formula (I) compound.
3rd aspect, the present invention relates to indole derivatives shown in above formula (I) and is used as the novelty teabag of cancer therapy drug.
The present inventor finds, shown in above-mentioned formula (I), indole derivatives has excellent active anticancer, especially to human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446) and human stomach cancer cell line (HGC-27), there is good cell tumour growth inhibited effect, thus antitumor drug can be used as in field of medicaments.
Especially, lower formula V compound has excellent especially, unexpected active anticancer to SGC-7901:
And especially following formula: compound 7-(3,4,5-trimethoxybenzoy) indole has excellent especially, unexpected active anticancer to H446 and HGC-27:
4th aspect, the present invention relates to indole derivatives shown in above formula (I), especially formula (II)-(V) compound or 7-(3,4,5-trimethoxybenzoy) indole are preparing the purposes in cancer therapy drug.
Described (I) indole derivatives especially formula (II)-(V) compound and 7-(3; 4; 5-trimethoxybenzoy) indole has good active anticancer, especially has excellent inhibition to human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446) and human stomach cancer cell line (HGC-27).
5th aspect; the invention still further relates to the pharmaceutical composition of a kind of Therapeutic cancer especially pulmonary carcinoma or gastric cancer; it comprises formula (I) indole derivatives as active component; especially contained (II)-(V) compound or 7-(3; 4,5-trimethoxybenzoy) indole.
Except comprising above-mentioned active ingredient beyond the region of objective existence, described pharmaceutical composition also can comprise pharmaceutically acceptable carrier, excipient and/or auxiliary agent.
In the present invention, " pharmaceutically acceptable carrier " refers to and does not cause significant stimulation also not eliminate the biological activity of used compound and the carrier of characteristic or diluent to organism.Usually, these include 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 compositions, preparation, stability, patient acceptance and bioavailability.
" excipient " or " auxiliary agent " refer to and add in pharmaceutical composition thus contribute to the inert substance used of compound further, and the example is including, but not limited to calcium carbonate, calcium phosphate, multiple sugar and multiple starch, cellulose derivative (comprising microcrystalline Cellulose), gelatin, vegetable oil, Polyethylene Glycol, diluent, granulating agent, lubricant, binding agent, disintegrating agent and analog.
Formula of the present invention (I) indole derivatives, especially formula (II)-(V) compound shows excellent biological activity in anticancer test in vitro, thus has huge potentiality to be exploited and application prospect in the clinical treatment application of tumor disease.
Detailed description of the invention
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 any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Embodiment 1:7-(4-fluoro benzoyl) indole
At room temperature, 100ml solvent (be the mixture of 2-MeTHF and water, both volume ratios are 2:1), 20mmol7-cyanoindole, 40mmol is added to fluorobenzoic boric acid, 1mmol palladium trifluoroacetate, the above-mentioned ligand L 2 of 1.5mmol and 200mmol methanesulfonic acid in reaction vessel; 80 DEG C are warming up under stirring, and insulation reaction 35 hours.
After question response terminates, 100ml water is added in reactant mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and concentrate is crossed 300-400 order silicagel column, using the mixed liquor of ethyl acetate/petroleum ether as eluant, the wherein volume ratio 1:10 of ethyl acetate and petroleum ether, concentrate eluant, obtains the title compound into yellow solid, called after A.Its productive rate is 76.9%, and purity is 98.8% (HPLC).
Fusing point: 101-102 DEG C.
Nuclear magnetic resonance, NMR: 1h NMR (CDCl 3, 500MHz) and δ 10.40 (s, 1H), 7.94 (d, J=7.8Hz, 1H), 7.83-7.80 (m, 2H), 7.58 (d, J=7.5Hz, 1H), 7.40 (s, 1H), 7.22-7.16 (m, 3H), 6.66 (s, 1H);
13C NMR(CDCl 3,125MHz)δ196.7,135.7,131.9,129.6,127.9,127.4,126.5,126.1,125.9,119.7,119.2,118.7,115.5,103.8,102.7。
Embodiment 2:7-(4-chlorobenzene formacyl) indole
At room temperature, 100ml solvent (be the mixture of 2-MeTHF and water, both volume ratios are 2:1), 20mmol7-cyanoindole, 20mmol is added to chlorophenylboronic acid, 0.4mmol palladium trifluoroacetate, the above-mentioned ligand L 2 of 1mmol and 100mmol methanesulfonic acid in reaction vessel; 60 DEG C are warming up under stirring, and insulation reaction 40 hours.
After question response terminates, 100ml water is added in reactant mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and concentrate is crossed 300-400 order silicagel column, using the mixed liquor of ethyl acetate/petroleum ether as eluant, the wherein volume ratio 1:5 of ethyl acetate and petroleum ether, concentrate eluant, obtains the title compound into yellow solid, called after B.Its productive rate is 79.6%, and purity is 99.3% (HPLC).
Fusing point: 149-150 DEG C.
Nuclear magnetic resonance, NMR: 1h NMR (CDCl 3, 500MHz): δ 10.38 (s, 1H), 7.94 (d, J=7.8Hz, 1H), 7.73 (d, J=8.5Hz, 2H), 7.56 (d, J=7.4Hz, 1H), 7.50 (d, J=8.5Hz, 2H), 7.40 (s, 1H), 7.16 (t, J=7.7Hz, 1H), 6.66 (s, 1H);
13C NMR(CDCl 3,125MHz)δ196.8,137.8,137.4,135.6,130.8(2C),129.6,128.6(2C),127.9,127.5,125.9,119.1,118.7,102.7。
Embodiment 3:7-(3,4,5-trimethoxybenzoy) indole
At room temperature, in reaction vessel, add 100ml solvent (is the mixture of 2-MeTHF and water, both volume ratios is 2:1), 20mmol7-cyanoindole, 60mmol3, the above-mentioned ligand L 2 of 4,5-trimethoxy phenylboric acid, 1.5mmol palladium trifluoroacetate, 2mmol and 300mmol methanesulfonic acid; 100 DEG C are warming up under stirring, and insulation reaction 30 hours.
After question response terminates, 100ml water is added in reactant mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and concentrate is crossed 300-400 order silicagel column, using the mixed liquor of ethyl acetate/petroleum ether as eluant, the wherein volume ratio 1:15 of ethyl acetate and petroleum ether, concentrate eluant, obtains the title compound into yellow solid, called after C.Its productive rate is 75.7%, and purity is 98.9% (HPLC).
Fusing point: 112-113 DEG C.
Nuclear magnetic resonance, NMR: 1h NMR (CDCl 3, 500MHz): δ 10.36 (s, 1H), 7.93 (d, J=7.8Hz, 1H), 7.67 (d, J=7.5Hz, 1H), 7.39-7.38 (m, 1H), 7.17 (t, J=7.7Hz, 1H), 7.04 (s, 2H), 6.67-6.65 (m, 1H), 3.95 (s, 3H), 3.90 (s, 6H);
13C NMR(CDCl 3,125MHz)δ197.1,152.9(2C),141.1,135.7,134.2,129.5,127.7,127.1,125.9,119.4,118.6,107.1(2C),102.7,61.0,56.3(2C)。
Embodiment 4:7-(4-anisoyl) indole
At room temperature, 100ml solvent (be the mixture of 2-MeTHF and water, both volume ratios are 2:1), 20mmol7-cyanoindole, 30mmol is added to methoxyphenylboronic acid, 2mmol palladium trifluoroacetate, the above-mentioned ligand L 2 of 1mmol and 150mmol methanesulfonic acid in reaction vessel; 120 DEG C are warming up under stirring, and insulation reaction 25 hours.
After question response terminates, 100ml water is added in reactant mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and concentrate is crossed 300-400 order silicagel column, using the mixed liquor of ethyl acetate/petroleum ether as eluant, the wherein volume ratio 1:7 of ethyl acetate and petroleum ether, concentrate eluant, obtains the title compound into yellow solid, called after D.Its productive rate is 80.7%, and purity is 98.8% (HPLC).
Fusing point: 156-158 DEG C.
Nuclear magnetic resonance, NMR: 1h NMR (CDCl 3, 500MHz) and δ 10.36 (s, 1H), 7.91 (d, J=7.8Hz, 1H), 7.82 (d, J=8.7Hz, 2H), 7.63 (d, J=7.5Hz, 1H), 7.37 (s, 1H), 7.17 (t, J=7.7Hz, 1H), 7.01 (d, J=8.7Hz, 2H), 6.65 (s, 1H), 3.90 (s, 3H);
13C NMR(CDCl 3,125MHz)δ196.8,162.6,135.8,131.9(2C),131.6,129.4,127.6,126.7,125.7,119.8,118.6,113.6,102.5(2C),55.5。
Embodiment 5:7-(3,4-Dimethoxybenzoyl) indole
At room temperature, in reaction vessel, add 100ml solvent (is the mixture of 2-MeTHF and water, both volume ratios is 2:1), the above-mentioned ligand L 2 of 20mmol7-cyanoindole, 45mmol3,4-dimethoxyphenylboronic, 1mmol palladium trifluoroacetate, 1mmol and 200mmol methanesulfonic acid; 70 DEG C are warming up under stirring, and insulation reaction 35 hours.
After question response terminates, 100ml water is added in reactant mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and concentrate is crossed 300-400 order silicagel column, using the mixed liquor of ethyl acetate/petroleum ether as eluant, the wherein volume ratio 1:9 of ethyl acetate and petroleum ether, concentrate eluant, obtains the title compound into yellow solid, called after E.Its productive rate is 84.5%, and purity is 99.1% (HPLC).
Fusing point: 98-100 DEG C.
Nuclear magnetic resonance, NMR: 1h NMR (CDCl 3, 500MHz): δ 10.32 (s, 1H), 7.91 (d, J=7.8Hz, 1H), 7.65 (d, J=7.5Hz, 1H), 7.44-7.42 (m, 2H), 7.37 (s, 1H), 7.16 (t, J=7.7Hz, 1H), 6.95-6.92 (m, 1H), 6.65 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H);
13C NMR(CDCl 3,125MHz)δ196.7,152.3,148.9,135.8,131.6,129.5,127.5,126.7,125.7,124.3,119.2,118.4,112.2,109.9,102.6,56.1,56.1。
Embodiment 6:7-(4-Phenylbenzoyl) indole
At room temperature, 100ml solvent (be the mixture of 2-MeTHF and water, both volume ratios are 2:1), 20mmol7-cyanoindole, 55mmol is added to phenyl phenylboric acid, 0.5mmol palladium trifluoroacetate, the above-mentioned ligand L 2 of 1.5mmol and 250mmol methanesulfonic acid in reaction vessel; 80 DEG C are warming up under stirring, and insulation reaction 30 hours.
After question response terminates, 100ml water is added in reactant mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and concentrate is crossed 300-400 order silicagel column, using the mixed liquor of ethyl acetate/petroleum ether as eluant, the wherein volume ratio 1:11 of ethyl acetate and petroleum ether, concentrate eluant, obtains the title compound into yellow solid, called after F.Its productive rate is 90.8%, and purity is 99.2% (HPLC).
Fusing point: 155-157 DEG C.
Nuclear magnetic resonance, NMR: 1h NMR (CDCl 3, 500MHz): δ 10.48 (s, 1H), 7.96 (d, J=7.8Hz, 1H), 7.88 (d, J=8.4Hz, 2H), 7.75 (d, J=8.3Hz, 2H), 7.70-7.68 (m, 3H), 7.51 (t, J=7.6Hz, 2H), 7.44-7.40 (m, 2H), 7.19 (t, J=7.7Hz, 1H), 6.69 (s, 1H);
13C NMR(CDCl 3,125MHz)δ197.8,144.4,140.2,137.8,135.7,130.1(2C),129.5,129.0,128.1(2C),127.2(2C),126.5(2C),125.9,119.7,119.5,118.7,103.7,102.7。
Embodiment 7:7-(2-naphthyl benzoyl) indole
At room temperature, 100ml solvent (be the mixture of 2-MeTHF and water, both volume ratios are 2:1), 20mmol7-cyanoindole, 25mmol naphthalene-2-ylboronic acid, 1.5mmol palladium trifluoroacetate, the above-mentioned ligand L 2 of 2mmol and 100mmol methanesulfonic acid is added in reaction vessel; 100 DEG C are warming up under stirring, and insulation reaction 25 hours.
After question response terminates, 100ml water is added in reactant mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and concentrate is crossed 300-400 order silicagel column, using the mixed liquor of ethyl acetate/petroleum ether as eluant, the wherein volume ratio 1:13 of ethyl acetate and petroleum ether, concentrate eluant, obtains the title compound into yellow solid, called after G.Its productive rate is 94.6%, and purity is 99.4% (HPLC).
Fusing point: 87-89 DEG C.
Nuclear magnetic resonance, NMR: 1h NMR (CDCl 3, 500MHz): δ 10.48 (s, 1H), 8.27 (s, 1H), 8.00-7.93 (m, 4H), 7.90-7.87 (m, 2H), 7.69 (d, J=8.2Hz, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 7.15-7.20 (m, 2H);
13C NMR(CDCl 3,125MHz)δ198.1,136.3,134.8,132.3,130.5,129.5,129.2,128.2,127.9,127.2,127.0,126.8,126.5,126.4,126.1,125.9,125.8,119.7,118.7。
Comparative example 1-63
Except catalyst palladium trifluoroacetate is wherein replaced with Pd (OAc) respectively 2, PdCl 2, Pd 2(dba) 3, Pd (dba) 2, Pd (pyridine radicals) 2, Pd (NH 3) 4cl 2, two (tri-butyl phosphine) palladium (0), Pd (acac) 2, Pd (PPh 3) 4outward, comparative example 1-9 is implemented in the same manner as example 1 and respectively;
Except catalyst palladium trifluoroacetate is wherein replaced with Pd (OAc) respectively 2, PdCl 2, Pd 2(dba) 3, Pd (dba) 2, Pd (pyridine radicals) 2, Pd (NH 3) 4cl 2, two (tri-butyl phosphine) palladium (0), Pd (acac) 2, Pd (PPh 3) 4outward, comparative example 10-18 is implemented in the same way as in example 2 and respectively;
Except catalyst palladium trifluoroacetate is wherein replaced with Pd (OAc) respectively 2, PdCl 2, Pd 2(dba) 3, Pd (dba) 2, Pd (pyridine radicals) 2, Pd (NH 3) 4cl 2, two (tri-butyl phosphine) palladium (0), Pd (acac) 2, Pd (PPh 3) 4outward, comparative example 19-27 is implemented respectively in the mode identical with embodiment 3;
Except catalyst palladium trifluoroacetate is wherein replaced with Pd (OAc) respectively 2, PdCl 2, Pd 2(dba) 3, Pd (dba) 2, Pd (pyridine radicals) 2, Pd (NH 3) 4cl 2, two (tri-butyl phosphine) palladium (0), Pd (acac) 2, Pd (PPh 3) 4outward, comparative example 28-36 is implemented respectively in the mode identical with embodiment 4.
Except catalyst palladium trifluoroacetate is wherein replaced with Pd (OAc) respectively 2, PdCl 2, Pd 2(dba) 3, Pd (dba) 2, Pd (pyridine radicals) 2, Pd (NH 3) 4cl 2, two (tri-butyl phosphine) palladium (0), Pd (acac) 2, Pd (PPh 3) 4outward, comparative example 37-45 is implemented respectively in the mode identical with embodiment 5.
Except catalyst palladium trifluoroacetate is wherein replaced with Pd (OAc) respectively 2, PdCl 2, Pd 2(dba) 3, Pd (dba) 2, Pd (pyridine radicals) 2, Pd (NH 3) 4cl 2, two (tri-butyl phosphine) palladium (0), Pd (acac) 2, Pd (PPh 3) 4outward, comparative example 46-54 is implemented in the same manner as in example 6 and respectively.
Except catalyst palladium trifluoroacetate is wherein replaced with Pd (OAc) respectively 2, PdCl 2, Pd 2(dba) 3, Pd (dba) 2, Pd (pyridine radicals) 2, Pd (NH 3) 4cl 2, two (tri-butyl phosphine) palladium (0), Pd (acac) 2, Pd (PPh 3) 4outward, comparative example 55-63 is implemented respectively in the mode identical with embodiment 7.
The productive rate of corresponding benzazolyl compounds is as shown in the table.
Comparative example 64-140
L1, L3-L12 is used to implement embodiment 1 and obtain comparative example 64-74 respectively;
L1, L3-L12 is used to implement embodiment 2 and obtain comparative example 75-85 respectively;
L1, L3-L12 is used to implement embodiment 3 and obtain comparative example 86-96 respectively;
L1, L3-L12 is used to implement embodiment 4 and obtain comparative example 97-107 respectively;
L1, L3-L12 is used to implement embodiment 5 and obtain comparative example 108-118 respectively;
L1, L3-L12 is used to implement embodiment 6 and obtain comparative example 119-129 respectively;
L1, L3-L12 is used to implement embodiment 7 and obtain comparative example 130-140 respectively.
The productive rate of corresponding benzazolyl compounds is as shown in the table.
Comparative example 141-148
Except solvent wherein being replaced with following organic solvent/aqueous mixtures (wherein the volume ratio of organic solvent and water is 2:1), implement comparative example 141-148 respectively in the mode identical with embodiment 1-4, the productive rate of its corresponding relation and corresponding methanone compounds is as shown in the table:
The investigation of additive
Except methanesulfonic acid wherein being replaced with except trifluoroacetic acid, acetic acid, benzoic acid, trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid, p-nitrophenyl sulfonic acid, sulphuric acid, hydrochloric acid and potassium bifluoride, the effect of these additives has been investigated respectively according to embodiment 1-7, find when for hydrochloric acid and potassium bifluoride, the reaction of embodiment 1-7 all can not be carried out, and when above-mentioned additive for other, the reaction of embodiment 1-7 all can be carried out, but productive rate has and significantly declines, and usually reduces 25-35%.
Biological activity test
Adopt mtt assay to measure indole derivatives of the present invention and preliminary assessment is carried out to the inhibitory action of growth of tumour cell, 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 cisplatin 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 culture medium: Gibco Products; MTT:Sigma Products, grow directly from seeds Cellular Biotech Co., Ltd.'s subpackage in Shanghai; Hyclone: Gibco Products; Pen .-Strep: Gibco Products; EDTA-trypsinization liquid: Gibco Products; Positive control (cisplatin): Qilu Pharmaceutical Co., Ltd.'s product, batch number: 1010011DC.
Experimental procedure
(1) preparation of sample
Every 1mg test compounds 20 μ L DMSO are dissolved, after getting 2 μ L dissolvings, solution 1000 μ L culture fluid dilute (this culture fluid contains the DMEM culture medium that hyclone mass concentration is 10%), its concentration is made to be 100 μ g/mL, then with identical culture fluid serial dilution to working concentration 1-10 μ g/mL.
(2) preparation of culture medium
Preparation DMEM culture medium, makes the inactivated fetal bovine serum containing 800,000 units of Penicillin, 1.0g streptomycin and 10% quality in every 1000mL DMEM culture medium.
(3) cultivation of cell: in the culture medium respectively above-mentioned tumor cell inoculation prepared in step (2), in 37 DEG C, 5%CO 2cultivate in incubator, 3-5d goes down to posterity.
(4) working sample is to the inhibitory action of growth of tumour cell
By cell human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446), human stomach cancer cell line (HGC-27) respectively with the digestion of EDTA-trypsinization liquid, and be diluted to 1 × 10 by culture medium 5/ mL, is added in 96 porocyte culture plates, and every hole 100 μ L, puts 37 DEG C, 5%CO 2cultivate in incubator.Discard former culture medium after 24 hours, add the culture medium containing test sample, every hole 200 μ L, each concentration adds 3 holes, puts 37 DEG C, 5%CO 2cultivate in incubator, add the MTT of 5mg/mL after 72 hours in cell culture well, every hole 10 μ L, puts 37 DEG C and hatches 4 hours, add DMSO, every hole 150 μ L, and with oscillator vibrates, Shi Jia Za dissolves completely, by microplate reader colorimetric under 570nm wavelength.Respectively with similarity condition with containing sample, containing the culture medium culturing of same concentration DMSO above-mentioned cancer cell in contrast, calculation sample is to the median lethal concentration (IC of 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 G of the present invention has anti-gastric cancer excellent especially and anti-lung cancer activity, its IC 50will far below cisplatin, especially on the inhibit activities of SGC-7901, lower than cisplatin three orders of magnitude, on the inhibit activities of H466 and HGC-27, also significantly lower than cisplatin.
And such indole derivatives of the present inventor's Late Cambrian has significant active anticancer, such as Compound C has excellent inhibit activities to H466 and HGC-27.
Therefore, described indole derivatives of the present invention has huge application potential and clinical value in anticancer medicine.
In sum, the invention provides a kind of active anticancer indole derivatives, find that this compounds has excellent anti-gastric cancer and anti-lung cancer activity simultaneously, this is the Late Cambrian of this purposes for this compounds, thus for the research and development of cancer therapy drug expanded substrate and may, there are huge clinical value and research and development potentiality.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.

Claims (9)

1. indole derivatives shown in following formula (I) is preparing the purposes be used in the cancer therapy drug of Tumor suppression:
Wherein, Ar is by 1-5 identical or different R 1the C replaced 6-12aryl;
R 1be selected from H, C 1-C 6alkyl, C 1-C 6alkoxyl, halogen, halo C 1-C 6alkyl, halo C 1-C 6alkoxyl or phenyl.
2. purposes as claimed in claim 1, is characterized in that: described indole derivatives is following formula (II)-(V) any one compound or 7-(3,4,5-trimethoxybenzoy) indole:
3. purposes as claimed in claim 1 or 2, is characterized in that: described indole derivatives is lower formula V compound or 7-(3,4,5-trimethoxybenzoy) indole:
4. the synthetic method of indole derivatives as described in any one of claim 1-3, described method comprises: under the existence of palladium catalyst, part and additive, in solvent, formula (VI) compound and formula (VII) are reacted, thus obtain the indole derivatives of formula (I);
Wherein, Ar respectively as in claim 1-3 define.
5. method as claimed in claim 4, 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 one or multiple mixture; Be preferably palladium trifluoroacetate, acid chloride or PdCl 2; Most preferably be palladium trifluoroacetate.
6. the method as described in claim 4 or 5, is characterized in that: described part is any one in following formula L1-L12 or any multiple mixture:
Wherein, preferred L1-L9, further preferred L1, L2, L3, L8, most preferably L2.
7. the purposes of the derivatives as anti-cancer agents thing in any one of claim 1-3.
8. the JEG-3 in claim 1-3,7 any one is human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446) or human stomach cancer cell line (HGC-27).
9. pharmaceutical composition, it comprises indole derivatives in any one of claim 1-3 as active component.
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Publication number Priority date Publication date Assignee Title
CN108003085A (en) * 2017-12-19 2018-05-08 张开良 A kind of synthetic method of pharmaceutical intermediate sweet-smelling formacyl indole derivatives
CN113845464A (en) * 2021-10-28 2021-12-28 西安交通大学 Indolylguanidine compound and preparation method and application thereof
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CN115160211A (en) * 2022-06-23 2022-10-11 温州大学 Green synthesis method of isoindolinone compounds
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