CN104586842B - Anti-cancer activity indole derivative, synthesis method and uses thereof - Google Patents
Anti-cancer activity indole derivative, synthesis method and uses thereof Download PDFInfo
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- CN104586842B CN104586842B CN201410171656.XA CN201410171656A CN104586842B CN 104586842 B CN104586842 B CN 104586842B CN 201410171656 A CN201410171656 A CN 201410171656A CN 104586842 B CN104586842 B CN 104586842B
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- 150000002475 indoles Chemical class 0.000 title claims abstract description 62
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- 238000001308 synthesis method Methods 0.000 title 1
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- 230000000996 additive effect Effects 0.000 claims abstract description 7
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- 229940054051 antipsychotic indole derivative Drugs 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
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- 238000010189 synthetic method Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 12
- 229910052763 palladium Inorganic materials 0.000 claims description 11
- 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 11
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- QAKJXJZBXCVFLX-UHFFFAOYSA-N n-(diaminomethylidene)-1h-indole-2-carboxamide Chemical class C1=CC=C2NC(C(=O)N=C(N)N)=CC2=C1 QAKJXJZBXCVFLX-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KPTRDYONBVUWPD-UHFFFAOYSA-N naphthalen-2-ylboronic acid Chemical class C1=CC=CC2=CC(B(O)O)=CC=C21 KPTRDYONBVUWPD-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 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
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000001953 recrystallisation 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000012549 training Methods 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
- 230000004614 tumor growth Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Landscapes
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
Technical field
The present invention relates to a kind of pharmaceutical active compounds, particularly a kind of indoles with excellent antitumor activity is derivative
Thing, preparation method and use, belong to medicinal chemistry art.
Background technology
Indole derivatives is the important nitrogenous oxygen-bearing organic matter of a class, has important role in organic and pharmaceutical synthesis
And effect.Therefore receive much concern in medication chemistry, organic synthesis and technical field of material chemistry.
So far, various medical compounds with indole structure are developed.For example, 7- benzoyls Yin
Diindyl -2- ketone is usually used to synthesis non_steroidal anti_inflammatory drug thing Amfenac sodium (amfenac sodium)；And 7- is (to bromobenzene first
Acyl group) indol-2-one be usually used to synthesis non_steroidal anti_inflammatory drug thing Bromfenac sodium (bromfenac sodium)：
Just because of such important function of indole derivatives, people have synthesized many indole derivativeses, and it is synthesized
Numerous studies are carried out, for example：
CN102911105A discloses a kind of synthetic method of 3- aroyls benzazolyl compounds, and methods described is taken with R1-
Be raw material for indoles and R2- substituted benzene formyls formic acid, using mantoquita as catalyst, silver salt as oxidant, in organic solvent
The acylation reaction of decarboxylation is carried out, its reaction equation is as follows：
WO0242269A discloses a kind of 3- aroyls indoles extremely as CB2The application of receptor stimulating agent, its structural formula
It is as follows：
The preparation method of the compound is very loaded down with trivial details, needs just to be obtained through multistep reaction, and yield is very low.
CN1136038A discloses a kind of Indoloylguanidine derivatives, and it has following structural formula：
The 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 derivatives:Using to bromobenzylcyanide
It is raw material with indoline, is catalyst with boron chloride and alchlor, carry out Friede-Crafts acylation reactions, generates 7-
(to benzoyl bromide) indoline；Jing manganese dioxides reaction again generates 7- (to benzoyl bromide) indoles.Its reaction equation is such as
Under：
2003, Medicine Industry Inst., Shandong Prov.'s summer pool width et al. (" synthesis of bromfenac sodium ",《China Medicine University
Journal》, 2003,34:405-406) above-mentioned reaction process is improved, using self-control activated manganese dioxide as oxidant,
The yield of its oxidation product 7- (to benzoyl bromide) indoles increases.
But so far, people not yet have found that indole derivatives has active anticancer, for its active target spot and substituent
There is not clearly understanding yet.But then, due to the superior bio activity of Benzazole compounds, therefore, find with excellent
The novel indole derivatives of medicine or biologically active, and new synthetic method is sought, it is still the research side in the current field
Method and emphasis, this basis and power that also exactly the present invention is accomplished are located.
The content of the invention
In view of this, it is of the invention in order to seek the new indole analog derivative with excellent pharmacological activity and biologically active
People has made intensive studies, after a large amount of creative works are paid, so as to complete the present invention.
The present invention relates to a kind of have excellent anti-cancer activity, especially to human stomach cancer cell line (SGC-7901), human lung cancer
Cell line (H446) and human stomach cancer cell line (HGC-27) have the indole derivatives of good cell tumour growth inhibition effect,
Further relate to the preparation method and use of the derivative.
Specifically, one side, the present invention relates to indoles shown in a kind of formula (I) with excellent antitumor activity derives
Thing：
Wherein, Ar is by 1-5 identical or different R1Substituted C6-12Aryl；
R1Selected from H, C1-C6Alkyl, C1-C6Alkoxyl, halogen, halo C1-C6Alkyl, halo C1-C6Alkoxyl or phenyl.
In the indole derivatives of the present invention, unless otherwise prescribed, from start to finish, C6-12Aryl is referred to 6-12
The aryl of individual carbon atom, for example, can be phenyl, naphthyl.
In the indole derivatives of the present invention, unless otherwise prescribed, from start to finish, C1-C6The implication of alkyl refers to tool
There is the straight or branched alkyl of 1-6 carbon atom, that includes C1Alkyl, C2Alkyl, C3Alkyl, C4Alkyl, C5Alkyl or C6Alkane
Base, in non-limiting manner for example can for methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, positive penta
Base, isopentyl or n-hexyl etc..
In the indole derivatives of the present invention, unless otherwise prescribed, from start to finish, C1-C6Alkoxyl refers to above-mentioned fixed
" the C of justice1-C6Alkyl " be connected with O atom after group.
In the indole derivatives of the present invention, unless otherwise prescribed, from start to finish, the halogen in halogen or halo for example may be used
For F, Cl, Br or I.
In the indole derivatives of the present invention, unless otherwise prescribed, from start to finish, halo C1-C6Alkyl is meant that
" the C defined above that finger is optionally substituted by halogen1-C6Alkyl ", in non-limiting manner for example, trifluoromethyl, pentafluoroethyl group, difluoro first
Base, chloromethyl etc..
In the indole derivatives of the present invention, unless otherwise prescribed, from start to finish, halo C1-C6The implication of alkoxyl
Refer to " the C defined above being optionally substituted by halogen1-C6Alkoxyl ", in non-limiting manner for example, trifluoromethoxy, five fluorine ethyoxyls,
Difluoro-methoxy, chloromethane epoxide etc..
In the indole derivatives of the present invention, formula (I) compound preferably lower formula (II), (III), (VI) or (V)
Compound：
In the indole derivatives of the present invention, formula (V) compound is most preferably descended：
Second aspect, the present invention relates to the synthetic method of above-mentioned indole derivatives, methods described includes：In palladium chtalyst
In the presence of agent, part and additive, in solvent, formula (VI) compound is reacted with formula (VII), so as to obtain formula (I)
Indole derivatives；
Wherein, Ar is as defined above.
In the synthetic method of the indole derivatives of the present invention, the palladium catalyst is palladium trifluoroacetate (Pd
(O2CCF3)2), acid chloride (Pd (OAc)2)、PdCl2、PdCl2(PPh3)2、PdCl2(dppf)2、PdCl2(dppe)、PdCl2
(cod)、PdCl2(py)2、PdCl2(MeCN)2、Pd(acac)2、Pd(PPh3)4、Pd2(dba)3、Pd2(dba)2Any one of
Or various mixtures；Preferably palladium trifluoroacetate, acid chloride or PdCl2；Most preferably palladium trifluoroacetate.
In the synthetic method of the indole derivatives of the present invention, the part is bidentate containing n-donor ligand or Phosphine ligands, for example
Any one of L1-L12 that can be following or any various mixtures：
Wherein, preferred L1-L9, most preferably further preferred L1, L2, L3, L8, L2.
In the synthetic method of the indole derivatives of the present invention, the additive is acid, for example, can be trifluoroacetic acid, benzene first
Acid, TFMS, p-methyl benzenesulfonic acid, p-nitrophenyl sulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid or potassium bifluoride；Preferably trifluoro second
Acid, p-methyl benzenesulfonic acid, p-nitrophenyl sulfonic acid or methanesulfonic acid；Most preferably methanesulfonic acid.
In the synthetic method of the indole derivatives of the present invention, formula (VI) compound and (VII) compound mole
Than can suitably be selected, such as mol ratio can be 1:1-3, for example can be exemplarily 1:1、1:1.5、1:2、1:2.5 or
1:3。
In the synthetic method of the indole derivatives of the present invention, formula (VI) compound is 1 with the mol ratio of catalyst:
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 the indole derivatives of the present invention, formula (VI) compound is 1 with the mol ratio of part:
0.05-0.1, for example, can be 1:0.05、1:0.07 or 1:0.1.
In the synthetic method of the indole derivatives of the present invention, formula (VI) compound is 1 with the mol ratio of additive:
5-15, for example, can be 1:5、1:10 or 1:15.
In the synthetic method of the indole derivatives of the present invention, reaction temperature is 60-120 DEG C, for example may be used in non-limiting manner
For 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C or 120 DEG C.
In the synthetic method of the indole derivatives of the present invention, the solvent is the mixture of organic solvent and water, wherein
The organic solvent for example can be tetrahydrofuran (THF), 2- methyltetrahydrofurans (2-MeTHF), toluene, dimethylbenzene, dioxy six
Ring, DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO), isopropanol, ethanol, n-butanol, chlorobenzene etc., organic solvent
It is 1-3 with the volume ratio of water:1, for example can be 1:1、2:1 or 3:1, preferably 2:1.
In the synthetic method of the indole derivatives of the present invention, the reaction time, there is no particular limitation, for example, can pass through TLC
Or GC-MS tracing detections purpose product or raw material residual percentage and determine the suitable reaction time, it typically is 15-40 little
When, for example, 15 hours in non-limiting manner, 17 hours, 19 hours, 21 hours, 23 hours, 25 hours, 27 hours, 29 hours, 30
Hour, 32 hours, 34 hours, 36 hours, 38 hours or 40 hours.
In the synthetic method of the present invention, the post processing after reaction terminates can be carried for crystallization, recrystallization, column chromatography
The combination of any one of pure, extraction etc. processing means or various processing means.As a kind of exemplary post processing means,
For example can be：After reaction terminates, water is added in reactant mixture, extracted 2-4 time with ether, combined ether layer, and with anhydrous
Sodium sulphate is dried, and evaporation after filtration removes ether and concentrated, and concentrate is crossed into 300-400 mesh silicagel columns, with ethyl acetate/stone
The mixed liquor of oily ether is used as eluant, eluent, the wherein volume ratio 1 of ethyl acetate and petroleum ether:5-15, so as to obtain target product formula
(I) compound.
3rd aspect, the present invention relates to indole derivatives shown in upper formula (I) is used as the new application of cancer therapy drug.
The inventors discovered that, indole derivatives shown in above-mentioned formula (I) has excellent active anticancer, especially to human gastric cancer
There is good cell tumour to give birth to for cell line (SGC-7901), human lung carcinoma cell line (H446) and human stomach cancer cell line (HGC-27)
Long inhibitory action, such that it is able to be used as antineoplastic in field of medicaments.
Especially, lower formula (V) compound has especially excellent, unexpected active anticancer to SGC-7901：
And, especially following formula: compound 7- (3,4,5- trimethoxybenzoy) indoles has to H446 and HGC-27
Especially excellent, unexpected active anticancer：
4th aspect, the present invention relates to indole derivatives shown in upper formula (I), especially formula (II)-(V) compound or 7-
(3,4,5- trimethoxybenzoys) purposes of indoles in cancer therapy drug is prepared.
(I) indole derivatives especially formula (II)-(V) compound and 7- (3,4,5- trimethoxybenzoys)
Indoles has good active anticancer, especially to human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446) and people
Stomach cancer cell line (HGC-27) has excellent inhibition.
5th aspect, the invention further relates to the pharmaceutical composition of a kind for the treatment of cancer especially lung cancer or cancer of the stomach, its bag
Containing formula (I) indole derivatives as active component, especially comprising formula (II)-(V) compound or 7- (3,4,5- trimethoxies
Benzoyl) indoles.
Except comprising above-mentioned active ingredient beyond the region of objective existence, described pharmaceutical composition can also include pharmaceutically acceptable carrier, figuration
Agent and/or auxiliary agent.
In the present invention, " pharmaceutically acceptable carrier " refers to that not causing significant stimulation also not eliminate organism is applied
The biologically active of compound and the carrier of characteristic or diluent.Generally, these include patient for pharmacology/toxicology side
The consideration in face, and pharmaceutical chemistry man is for the physics/change of composition, preparation, stability, patient acceptance and bioavilability
Consideration in terms of is considered acceptable characteristic and/or material.
" excipient " or " auxiliary agent " is referred to and is added in pharmaceutical composition so as to further help in the administration of compound
Inert substance, the example is included but is not limited to：Calcium carbonate, calcium phosphate, various sugared and various starch, cellulose derivative (bag
Include microcrystalline cellulose), gelatin, vegetable oil, polyethylene glycol, diluent, granulating agent, lubricant, binding agent, disintegrant and similar
Thing.
Formula (I) indole derivatives of the present invention, especially formula (II)-(V) compound show in vitro during anticancer is tested
Excellent biologically active, so as to have huge potentiality to be exploited and application prospect in the clinical treatment application of tumor disease.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not constitutes any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Embodiment 1：7- (4- fluoro benzoyls) indoles
At room temperature, 100ml solvents are added in reaction vessel, and (for 2-MeTHF and the mixture of water, both are at volume ratio
2:1), 20mmol7- cyanoindoles, 40mmol are to fluorobenzoic boric acid, 1mmol palladium trifluoroacetates, the above-mentioned and of ligand L 2 of 1.5mmol
200mmol methanesulfonic acids；It is warming up to 80 DEG C under stirring, and insulation reaction 35 hours.
After question response terminates, 100ml water is added in reactant mixture, extracted 2-4 time with ether, combined ether layer, and
With anhydrous sodium sulfate drying, evaporation removing ether is concentrated after filtration, concentrate is crossed into 300-400 mesh silicagel columns, with acetic acid
The mixed liquor of ethyl ester/petroleum ether is used as eluant, eluent, the wherein volume ratio 1 of ethyl acetate and petroleum ether:10, concentrate eluant is obtained
To the title compound for yellow solid, A is named as.Its yield is 76.9%, and purity is 98.8% (HPLC).
Fusing point：101-102℃.
Nuclear magnetic resonance：1H NMR(CDCl3, 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(CDCl3,125MHz)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 formacyls) indoles
At room temperature, 100ml solvents are added in reaction vessel, and (for 2-MeTHF and the mixture of water, both are at volume ratio
2:1), 20mmol7- cyanoindoles, 20mmol are to chlorophenylboronic acid, 0.4mmol palladium trifluoroacetates, the above-mentioned and of ligand L 2 of 1mmol
100mmol methanesulfonic acids；It is warming up to 60 DEG C under stirring, and insulation reaction 40 hours.
After question response terminates, 100ml water is added in reactant mixture, extracted 2-4 time with ether, combined ether layer, and
With anhydrous sodium sulfate drying, evaporation removing ether is concentrated after filtration, concentrate is crossed into 300-400 mesh silicagel columns, with acetic acid
The mixed liquor of ethyl ester/petroleum ether is used as eluant, eluent, the wherein volume ratio 1 of ethyl acetate and petroleum ether:5, concentrate eluant is obtained
For the title compound of yellow solid, B is named as.Its yield is 79.6%, and purity is 99.3% (HPLC).
Fusing point：149-150℃.
Nuclear magnetic resonance：1H NMR(CDCl3,500MHz):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(CDCl3,125MHz)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- trimethoxybenzoys) indoles
At room temperature, 100ml solvents are added in reaction vessel, and (for 2-MeTHF and the mixture of water, both are at volume ratio
2:1), 20mmol7- cyanoindoles, 60mmol3,4,5- trimethoxy phenyl boric acids, 1.5mmol palladium trifluoroacetates, 2mmol are above-mentioned
Ligand L 2 and 300mmol methanesulfonic acids；It is warming up to 100 DEG C under stirring, and insulation reaction 30 hours.
After question response terminates, 100ml water is added in reactant mixture, extracted 2-4 time with ether, combined ether layer, and
With anhydrous sodium sulfate drying, evaporation removing ether is concentrated after filtration, concentrate is crossed into 300-400 mesh silicagel columns, with acetic acid
The mixed liquor of ethyl ester/petroleum ether is used as eluant, eluent, the wherein volume ratio 1 of ethyl acetate and petroleum ether:15, concentrate eluant is obtained
To the title compound for yellow solid, C is named as.Its yield is 75.7%, and purity is 98.9% (HPLC).
Fusing point：112-113℃.
Nuclear magnetic resonance：1H NMR(CDCl3,500MHz):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(CDCl3,125MHz)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- methoxybenzoyl bases) indoles
At room temperature, 100ml solvents are added in reaction vessel, and (for 2-MeTHF and the mixture of water, both are at volume ratio
2:1), 20mmol7- cyanoindoles, 30mmol are to methoxyphenylboronic acid, 2mmol palladium trifluoroacetates, the above-mentioned and of ligand L 2 of 1mmol
150mmol methanesulfonic acids；It is warming up to 120 DEG C under stirring, and insulation reaction 25 hours.
After question response terminates, 100ml water is added in reactant mixture, extracted 2-4 time with ether, combined ether layer, and
With anhydrous sodium sulfate drying, evaporation removing ether is concentrated after filtration, concentrate is crossed into 300-400 mesh silicagel columns, with acetic acid
The mixed liquor of ethyl ester/petroleum ether is used as eluant, eluent, the wherein volume ratio 1 of ethyl acetate and petroleum ether:7, concentrate eluant is obtained
For the title compound of yellow solid, D is named as.Its yield is 80.7%, and purity is 98.8% (HPLC).
Fusing point：156-158℃.
Nuclear magnetic resonance：1H NMR(CDCl3, 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(CDCl3,125MHz)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- Dimethoxybenzoyls) indoles
At room temperature, 100ml solvents are added in reaction vessel, and (for 2-MeTHF and the mixture of water, both are at volume ratio
2:1), 20mmol7- cyanoindoles, 45mmol3,4- dimethoxyphenylboronics, 1mmol palladium trifluoroacetates, the above-mentioned parts of 1mmol
L2 and 200mmol methanesulfonic acids；It is warming up to 70 DEG C under stirring, and insulation reaction 35 hours.
After question response terminates, 100ml water is added in reactant mixture, extracted 2-4 time with ether, combined ether layer, and
With anhydrous sodium sulfate drying, evaporation removing ether is concentrated after filtration, concentrate is crossed into 300-400 mesh silicagel columns, with acetic acid
The mixed liquor of ethyl ester/petroleum ether is used as eluant, eluent, the wherein volume ratio 1 of ethyl acetate and petroleum ether:9, concentrate eluant is obtained
For the title compound of yellow solid, E is named as.Its yield is 84.5%, and purity is 99.1% (HPLC).
Fusing point：98-100℃.
Nuclear magnetic resonance：1H NMR(CDCl3,500MHz):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(CDCl3,125MHz)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- Phenylbenzoyls) indoles
At room temperature, 100ml solvents are added in reaction vessel, and (for 2-MeTHF and the mixture of water, both are at volume ratio
2:1), 20mmol7- cyanoindoles, 55mmol are to phenyl phenyl boric acid, 0.5mmol palladium trifluoroacetates, the above-mentioned ligand Ls 2 of 1.5mmol
With 250mmol methanesulfonic acids；It is warming up to 80 DEG C under stirring, and insulation reaction 30 hours.
After question response terminates, 100ml water is added in reactant mixture, extracted 2-4 time with ether, combined ether layer, and
With anhydrous sodium sulfate drying, evaporation removing ether is concentrated after filtration, concentrate is crossed into 300-400 mesh silicagel columns, with acetic acid
The mixed liquor of ethyl ester/petroleum ether is used as eluant, eluent, the wherein volume ratio 1 of ethyl acetate and petroleum ether:11, concentrate eluant is obtained
To the title compound for yellow solid, F is named as.Its yield is 90.8%, and purity is 99.2% (HPLC).
Fusing point：155-157℃.
Nuclear magnetic resonance：1H NMR(CDCl3,500MHz):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(CDCl3,125MHz)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 benzoyls) indoles
At room temperature, 100ml solvents are added in reaction vessel, and (for 2-MeTHF and the mixture of water, both are at volume ratio
2:1), 20mmol7- cyanoindoles, 25mmol naphthalene -2- ylboronic acids, 1.5mmol palladium trifluoroacetates, the above-mentioned and of ligand L 2 of 2mmol
100mmol methanesulfonic acids；It is warming up to 100 DEG C under stirring, and insulation reaction 25 hours.
After question response terminates, 100ml water is added in reactant mixture, extracted 2-4 time with ether, combined ether layer, and
With anhydrous sodium sulfate drying, evaporation removing ether is concentrated after filtration, concentrate is crossed into 300-400 mesh silicagel columns, with acetic acid
The mixed liquor of ethyl ester/petroleum ether is used as eluant, eluent, the wherein volume ratio 1 of ethyl acetate and petroleum ether:13, concentrate eluant is obtained
To the title compound for yellow solid, G is named as.Its yield is 94.6%, and purity is 99.4% (HPLC).
Fusing point：87-89℃.
Nuclear magnetic resonance：1H NMR(CDCl3,500MHz):δ10.48(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(CDCl3,125MHz)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 therein is replaced with respectively into Pd (OAc)2、PdCl2、Pd2(dba)3、Pd(dba)2、
Pd (pyridine radicals)2、Pd(NH3)4Cl2, double (tri-butyl phosphine) palladiums (0), Pd (acac)2、Pd(PPh3)4Outward, with the phase of embodiment 1
With mode and implement comparative example 1-9 respectively；
Except catalyst palladium trifluoroacetate therein is replaced with respectively into Pd (OAc)2、PdCl2、Pd2(dba)3、Pd(dba)2、
Pd (pyridine radicals)2、Pd(NH3)4Cl2, double (tri-butyl phosphine) palladiums (0), Pd (acac)2、Pd(PPh3)4Outward, with the phase of embodiment 2
With mode and implement comparative example 10-18 respectively；
Except catalyst palladium trifluoroacetate therein is replaced with respectively into Pd (OAc)2、PdCl2、Pd2(dba)3、Pd(dba)2、
Pd (pyridine radicals)2、Pd(NH3)4Cl2, double (tri-butyl phosphine) palladiums (0), Pd (acac)2、Pd(PPh3)4Outward, with the phase of embodiment 3
With mode and implement comparative example 19-27 respectively；
Except catalyst palladium trifluoroacetate therein is replaced with respectively into Pd (OAc)2、PdCl2、Pd2(dba)3、Pd(dba)2、
Pd (pyridine radicals)2、Pd(NH3)4Cl2, double (tri-butyl phosphine) palladiums (0), Pd (acac)2、Pd(PPh3)4Outward, with the phase of embodiment 4
With mode and implement comparative example 28-36 respectively.
Except catalyst palladium trifluoroacetate therein is replaced with respectively into Pd (OAc)2、PdCl2、Pd2(dba)3、Pd(dba)2、
Pd (pyridine radicals)2、Pd(NH3)4Cl2, double (tri-butyl phosphine) palladiums (0), Pd (acac)2、Pd(PPh3)4Outward, with the phase of embodiment 5
With mode and implement comparative example 37-45 respectively.
Except catalyst palladium trifluoroacetate therein is replaced with respectively into Pd (OAc)2、PdCl2、Pd2(dba)3、Pd(dba)2、
Pd (pyridine radicals)2、Pd(NH3)4Cl2, double (tri-butyl phosphine) palladiums (0), Pd (acac)2、Pd(PPh3)4Outward, with the phase of embodiment 6
With mode and implement comparative example 46-54 respectively.
Except catalyst palladium trifluoroacetate therein is replaced with respectively into Pd (OAc)2、PdCl2、Pd2(dba)3、Pd(dba)2、
Pd (pyridine radicals)2、Pd(NH3)4Cl2, double (tri-butyl phosphine) palladiums (0), Pd (acac)2、Pd(PPh3)4Outward, with the phase of embodiment 7
With mode and implement comparative example 55-63 respectively.
The yield of corresponding benzazolyl compounds is as shown in the table.
Comparative example 64-140
Implement embodiment 1 using L1, L3-L12 respectively and obtain comparative example 64-74；
Implement embodiment 2 using L1, L3-L12 respectively and obtain comparative example 75-85；
Implement embodiment 3 using L1, L3-L12 respectively and obtain comparative example 86-96；
Implement embodiment 4 using L1, L3-L12 respectively and obtain comparative example 97-107；
Implement embodiment 5 using L1, L3-L12 respectively and obtain comparative example 108-118；
Implement embodiment 6 using L1, L3-L12 respectively and obtain comparative example 119-129；
Implement embodiment 7 using L1, L3-L12 respectively and obtain comparative example 130-140.
The yield of corresponding benzazolyl compounds is as shown in the table.
Comparative example 141-148
Except solvent therein is replaced with into following organic solvent/aqueous mixtures, (wherein organic solvent is with the volume ratio of water
2:1) outward, to implement comparative example 141-148 respectively with embodiment 1-4 identical mode, its corresponding relation and corresponding ketone
The yield of compound is as shown in the table：
The investigation of additive
Except by methanesulfonic acid therein replace with trifluoroacetic acid, acetic acid, benzoic acid, TFMS, p-methyl benzenesulfonic acid, to nitre
Outside base benzene sulfonic acid, sulfuric acid, hydrochloric acid and potassium bifluoride, the effect of these additives has been investigated according to embodiment 1-7 respectively, find to work as
For hydrochloric acid and potassium bifluoride when, the reaction of embodiment 1-7 can not be carried out, and when for other above-mentioned additives when, embodiment
The reaction of 1-7 can be carried out, but yield has and significantly declines, and generally reduces 25-35%.
Biological activity test
Determine indole derivatives of the present invention using mtt assay carries out preliminary assessment to the inhibitory action of growth of tumour cell, receives
Examination cell includes human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (H446) and human stomach cancer cell line (HGC-27), resists
Cancer medicine cis-platinum is used 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；It is 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 mediums：Gibco Products；MTT：Sigma Products, grow directly from seeds cellular biological technique in Shanghai
Co., Ltd dispenses；Hyclone：Gibco Products；Pen .- Strep：Gibco Products；EDTA- pancreatin digests
Liquid：Gibco Products；Positive control (cis-platinum)：Qilu Pharmaceutical Co., Ltd.'s product, batch number：1010011DC.
Experimental procedure
(1) preparation of sample
To be dissolved with 20 μ L DMSO per 1mg test compounds, and take 1000 μ L nutrient solutions of solution after 2 μ L dissolvings and dilute (this
Nutrient solution is the DMEM culture mediums that mass concentration containing hyclone is 10%) so as to concentration is 100 μ g/mL, then is trained with identical
Nutrient solution serial dilution is to concentration 1-10 μ g/mL.
(2) preparation of culture medium
Prepare DMEM culture mediums so that in per 1000mL DMEM culture mediums containing 800,000 units of Penicillin, 1.0g streptomysins and
The inactivated fetal bovine serum of 10% mass.
(3) culture of cell：Respectively by above-mentioned tumor cell inoculation in the culture medium that step (2) is prepared, in 37 DEG C,
5%CO2Cultivate in incubator, 3-5d is passed on.
(4) inhibitory action of the determination sample to 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)
Digested with EDTA- pancreatin digestive juice respectively, and 1 × 10 is diluted to culture medium5/ mL, in being added to 96 porocyte culture plates, per hole
100 μ L, put 37 DEG C, 5%CO2Cultivate in incubator.Former culture medium is discarded after 24 hours, the culture medium containing test sample is added,
Per the μ L of hole 200, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Cultivate in incubator, add in cell culture well after 72 hours
The MTT of 5mg/mL, per the μ L of hole 10, puts 37 DEG C and is incubated 4 hours, adds DMSO, per the μ L of hole 150, is vibrated with oscillator, and Shi Jia Za is complete
CL, with ELIASA under 570nm wavelength colorimetric.Respectively with similarity condition with without sample, the training containing same concentration DMSO
The above-mentioned cancer cell of foster base culture calculates LC50 (IC of the sample to growth of tumour cell as control50)。
After above-mentioned steps measurement, the IC of the compounds of this invention50It is as shown in the table：
As seen from the above table, compound G of the invention has especially excellent anti-gastric cancer and anti-lung cancer activity, its IC50It is remote
Less than cis-platinum, especially in the inhibitory activity of SGC-7901, lower than cis-platinum three orders of magnitude, for H466 and HGC-27
Inhibitory activity on, also significantly be less than cis-platinum.
And, the present inventor has found that first such indole derivatives has significant active anticancer, such as compound C pair
H466 and HGC-27 have excellent inhibitory activity.
Therefore, the indole derivatives of the invention has huge application potential and clinical valency in anticancer medicine
Value.
In sum, the invention provides a kind of active anticancer indole derivatives, while it is excellent to find that such compound has
Good anti-gastric cancer and anti-lung cancer activity, this is the discovery first of the purposes for such compound, so as to for cancer therapy drug
Substrate and possibility have been expanded in research and development, with huge clinical value and research and development potentiality.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the protection model of the present invention
Enclose.Additionally, it will also be appreciated that after the technology contents for having read the present invention, those skilled in the art can make each to the present invention
Plant and change, change and/or modification, all these equivalent form of value equally falls within the guarantor that the application appended claims are limited
Within the scope of shield.
Claims (3)
1. the synthetic method of indole derivatives shown in formula (I) is descended,
Methods described includes：In the presence of palladium catalyst, part and additive, in solvent, formula (VI) compound and formula
(VII) reacted, so as to obtain the indole derivatives of formula (I)；
Wherein, Ar is by 1-5 identical or different R1Substituted C6- 12 aryl；
R1Selected from H, C1-C6Alkyl, C1-C6Alkoxyl, halogen, halo C1-C6Alkyl, halo C1-C6Alkoxyl or phenyl；
The palladium catalyst is palladium trifluoroacetate；
The part is following formula L2：
The additive is methanesulfonic acid；
The solvent is the mixture of organic solvent and water, wherein the organic solvent is 2- methyltetrahydrofurans, it is described organic
Solvent is 1-3 with the volume ratio of water:1.
2. the method for claim 1, it is characterised in that：The indole derivatives is lower formula (II)-(V) any one chemical combination
Thing or 7- (3,4,5- trimethoxybenzoys) indoles：
3. method as claimed in claim 1 or 2, it is characterised in that：The indole derivatives is lower formula (V) compound or 7-
(3,4,5- trimethoxybenzoys) indoles：
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