CN106674077A - Preparation method and application of 2,3-dihydro-2,3'-biindolyl compound - Google Patents

Preparation method and application of 2,3-dihydro-2,3'-biindolyl compound Download PDF

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Publication number
CN106674077A
CN106674077A CN201510762386.4A CN201510762386A CN106674077A CN 106674077 A CN106674077 A CN 106674077A CN 201510762386 A CN201510762386 A CN 201510762386A CN 106674077 A CN106674077 A CN 106674077A
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dihydro
compound
bis
biindolyl
indole compound
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郭涛
韩书磊
刘钰
朱利敏
赵云辉
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Henan University of Technology
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Henan University of Technology
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    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the field of medicinal chemistry and relates to a preparation method and application of an anti-tumor compund 2,3-dihydro-2,3'-biindolyl derivative. The anti-tumor compund 2,3-dihydro-2,3'-biindolyl derivative is obtained through addition of a polysubstituted compound under the promotion of BiCl3, and has the following structure shown in the specification. The 2,3-dihydro-2,3'-biindolyl compound has excellent anti-tumor activity on multiple tumour cells and can be applied to preparation of anti-tumor medicines as a further developed candidate or lead compound.

Description

One kind 2,3- dihydro -2, the preparation method and applications of 3 '-bis-indole compound
Technical field
The present invention relates to medicinal chemistry art, and in particular to the application of a class 2,3- dihydro -2, the preparation method of 3 '-bis-indole compound, and such compound as the new antineoplastic lead compound of a class.
Background technology
Medically cancer refers to the malignant tumour for originating from epithelial tissue, is body under the effect of various tumorigenesis factors, and local organization cell loses the neoformation for causing paraplasm and differentiation to the normal regulation that it grows and being formed on gene level.Neoformation, not by normal body Physiological effect, destroys normal structure and organ once being formed, and this point is especially apparent in malignant tumour.Malignant growth speed is fast, and bleeding, necrosis, ulcer etc. easily occur, and often has DISTANT METASTASES IN, causes human body to become thin, powerless, anaemia, poor appetite, heating and serious organ function are damaged etc., ultimately cause death.
Liver cancer refers to the malignant tumour for betiding liver, and liver cancer can betide 2 months babies to 80 years old old man, and most age of onset are 40～49 years old.The male sex is multiple, and the ratio of men and women is 6: 1.According to recent statistics, liver cancer patient about 600,000 is newly sent out every year in the whole world, occupy malignant tumour the 5th, China is hepatitis B big country, and the liver cancer of China is more to be developed on the basis of hbv-liver cirrhosis, and hepatitis patient is also gradually increasing, also liver cancer can be developed into after hepatitis B, at present China's number of the infected accounts for the more than half of the whole world, and the people of liver cancer about 110,000 is died from every year, accounts for the 45% of whole world PLC mortality number.Liver cancer has become a big killer of serious threat our people's health and lives, and its danger can not look down upon.Treatment liver cancer is in addition to using operation, bound drug is needed to treat, the new new molecular targeted agents Sorafenib that recent years comes out can delay tumour progression, life cycle can to a certain extent be extended, this time shown by clinical test results both domestic and external, Sorafenib can extend the survival of patients time up to 2-3 month, disease development time is delayed to be 73%, but the drug price is costly, simultaneously may be with diarrhoea, fash, hypertension, the more serious bad reaction such as hand-foot syndrome, effect also needs further evaluation, therefore Devoting Major Efforts To Developing medicines resistant to liver cancer is still needed to.
Biindolyl framework compound is to be widely present in the drug molecule with important physiologically active and natural products, its biologically active such as anti-inflammation, antiallergy etc., representative compound such as Asperazine, GliocladinA, MollenineA, Gliocladin B.In bis-indole compound, 2,3- dihydro -2,3 '-bis-indole derivatives have its unique biologically active value.2014, Cherkasov groups reported 2,3- dihydro -2, and the ability of application and potential treatment prostate gland cancer cell of the 3 '-biindolyl in terms of androgen receptor inhibitor (Chemistry＆Biology 2014,21,1476).But at present for 2; 3- dihydros -2; the study on the synthesis of 3 '-bis-indole derivatives is still less; merely relate to simplest 2; 3- dihydros -2; 3 '-biindolyl (R=H), on indoles substituted base especially electron-withdrawing group such as Cl, F has no document report, and the groups such as Cl, F are introduced in drug molecule would generally increase its pharmaceutically active.2,3- dihydro -2 of design synthesizing new, 3 '-bis-indole derivatives are significant to studying new type antineoplastic medicine, medicine of developing one's own intellectual property.
The content of the invention
It is an object of the invention to provide a kind of new 2,3- dihydro -2,3 '-bis-indole compound, it is characterised in that such compound has structure as shown below,
Wherein R is at least one in different the position of substitution, the alkyl of different numbers, aryl, hydroxyl, alkoxyl, aryloxy group, ester group, halogen, trifluoromethyl and cyano group.
In formula preferably：R is alkyl, alkoxyl, ester group, halogen, trifluoromethyl or the polysubstituted halogen of the mono-substituted C1-C5 of diverse location.
Further object is that providing one kind 2,3- dihydro -2, the preparation method of 3 '-bis-indole compound, it is characterised in that：It is achieved by the steps of：
In organic solvent, add polysubstituted indoles and lewis acid to react, obtain target product.
Organic solvent used is the one kind in dichloromethane, chloroform, toluene, and lewis acid is BiCl3, and at 15 DEG C -30 DEG C, the time is 6-12 hours to reaction temperature.
3rd, it is yet a further object of the present invention to provide application of the compound in antineoplastic is prepared.
Specific embodiment
The specific embodiment of the present invention is described in detail below, it is to be understood that the specific embodiment for saying description herein is merely to illustrate and explains the present invention, is not limited to the present invention.
On the one hand, it is an object of the invention to provide a kind of new 2,3- dihydro -2,3 '-bis-indole compound, it is characterised in that such compound has structure as shown below,
Wherein R is at least one in different the position of substitution, the alkyl of different numbers, aryl, hydroxyl, alkoxyl, aryloxy group, ester group, halogen, trifluoromethyl and cyano group.
In the present invention, alkyl is preferably the alkyl of C1-C5, and alkoxyl is preferably the alkoxyl of C1-C5, and aryloxy group is preferably the aryloxy group of C6-C10, and ester group is preferably the ester group of C1-C5.
2,3- dihydro -2 of the present invention, 3 '-bis-indole compound is more preferably that halogenated compound and double halogenated compounds are as follows, wherein R1、R2For the fluorine of different the position of substitution, chlorine, bromine, iodine.
On the other hand, process provides a kind of 2,3- of convenient synthesis dihydro -2, the method for 3 '-bis-indole compound.Including：
1 by the indoles for replacing and bismuth trichloride are in dichloromethane or chloroform or toluene is stirred, and reaction obtains 2,3- dihydro -2,3 '-bis-indole compound.
In 2 the inventive method, step 1 is also obtained product in addition to using bismuth trichloride using alchlor, butter of tin, but yield is low.
In 3 the inventive method, step 1 reaction condition includes, temperature 15-30 DEG C, and the time is 6-12 hours；The purification such as products therefrom Jing column chromatographies or recrystallization obtains net product；Recrystallization solvent for use is the mixture of the one kind in acetone, ethanol, methyl alcohol, ethyl acetate or two of which.
4 the inventive method can be applicable to gram level above scale and prepare.
Another further aspect, the invention provides such as above-mentioned 2,3- dihydro -2,3 '-bis-indole compound antitumor activity evaluation test result in vitro, for A549 lung carcinoma cells, SMMC7721 liver cancer, MGC803 cancer of the stomach, MDAMB231 breast cancer has obvious inhibiting effect, and the wherein anti tumor activity in vitro of compound 1 is substantially better than 5-fluor-uracil, can be applied to prepare antineoplastic as the candidate of further exploitation or lead compound.
Method is exemplified below：
Prepare following compound：
Compound 1 (5,5 '-two chloro- 2,3- dihydro -2,3 '-biindolyl)
5- chloro-indole (2g, 13mmol), bismuth trichloride (4.1g, 13mmol) with 50mL dichloromethane stirring reaction 10 hours under room temperature in 100mL flasks, subsequently decompression steams most of dichloromethane, add 50mL ethyl acetate, saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate drying are adopted successively.Concentrate, (ethyl acetate/petroleum ether=1: 4) obtains faint yellow solid 1.6g, total recovery 80% to column chromatography.1H NMR (400MHz, CDCl3) δ 3.13 (dd, J=15.6,8.8Hz, 1H), 3.41 (dd, J=15.6,9.2Hz, 1H), 5.19 (t, J=8.8Hz, 1H), 6.56 (d, J=8.4Hz, 1H), 7.01 (dd, J=8.4,2.4Hz, 1H), 7.08-7.16 (m, 3H), 7.27 (d, J=8.4Hz, 1H), 7.56 (d, J=2.0Hz, 1H), 8.1 (s, 1H).13C NMR (100MHz, CDCl3) δ 37.7,56.8,110.0,112.5,118.9,119.1,122.7,122.9,123.5,125.0,125.6,126.9,127.4,130.7,135.2,149.5
Compound 2 (6,6 '-two fluoro- 2,3- dihydro -2,3 '-biindolyl)
Synthetic method is with compound 1, yellow foamy solid, yield 25%.1H NMR (400MHz, CDCl3) δ 3.13 (dd, J=15.2,8.0Hz, 1H), 3.41 (dd, J=15.6,9.2Hz, 1H), 5.25 (t, J=8.4Hz, 1H), 6.34 (dd, J=9.6,2.0Hz, 1H), 6.38-6.43 (m, 1H), 6.82-6.87 (m, 1H), 6.99-7.06 (m, 2H), 7.13 (d, J=2.4Hz, 1H), 7.45 (dd, J=8.4,5.2Hz, 1H), 8.0 (s, 1H).13C NMR (100MHz, CDCl3) for C of δ 37.0,57.3,96.8,97.9,104.6,108.8,119.4,120.4,120.5,121.6,122.3,124.0,125.0,125.1,136.9,152.4,161.4,162.2,164.6.HRMS16H13F2N2 +(M++H)：Calcd.271.1047, found 271.1042
Compound 3 (4,4 '-dicyano -2,3- dihydro -2,3 '-biindolyl)
Synthetic method is with compound 1, yellow liquid, yield 38%.1H NMR (400MHz, DMSO-d6) δ 3.10 (dd, J=16.0,7.6Hz, 1H), 3.67 (dd, J=16.0,9.2Hz, 1H), 5.56 (t, J=8.0Hz, 1H), 6.62 (d, J=0.8Hz, 1H), 6.85 (d, J=7.6Hz, 1H), 6.90 (d, J=7.2Hz, 1H), 7.14 (t, J=7.6Hz, 1H), 7.27 (d, J=7.6Hz, 1H), 7.54-7.56 (m, 2H), 7.75 (d, J=7.2Hz, 1H), 11.6 (s, 1H).13C NMR (100MHz, DMSO-d6) δ 38.1,54.5,100.3,107.5,112.0,117.2,117.3,117.9,119.3,119.5,121.2,124.6,125.6,125.8,128.7,131.9,137.0,152.3
Compound 4 (4,4 '-two (methyl formate base) -2,3- dihydro -2,3 '-biindolyl)
Synthetic method is with compound 1, yellow liquid, yield 40%.1H NMR (400MHz, DMSO-d6) (the dd of δ 3.45, J=17.2, 7.2Hz, 1H), 3.77 (dd, J=17.6, 8.8Hz, 1H), 3.87 (s, 3H), 3.97 (s, 3H), 5.53 (t, J=8.0Hz, 1H), 6.79 (d, J=7.2Hz, 1H), 7.10 (t, J=7.6Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 7.28 (d, J=2.8Hz, 1H), 7.35 (dd, J=8.0, 1.2Hz, 1H), 7.47 (dd, J=7.6, 1.2Hz, 1H), 7.72 (dd, J=7.6, 0.8Hz, 1H), 8.62 (s, 1H).13C NMR (100MHz, DMSO-d6) δ 38.4,51.8,52.3,56.4,113.1,116.0,119.7,119.8,121.2,123.5,123.6,124.0,124.3,126.7,127.5,131.9,138.0,152.1,167.9,169.3
Compound 5 (5,5 '-dimethoxy -2,3- dihydro -2,3 '-biindolyl)
Synthetic method is with compound 1, yellow liquid, yield 70%.1H NMR (400MHz, DMSO-d6) δ 2.95 (dd, J=15.6,8.0Hz, 1H), 3.35 (dd, J=15.6,8.8Hz, 1H), 3.65 (s, 3H), 3.65 (s, 3H), 5.04 (t, J=8.8Hz, 1H), 5.48 (s, 1H), 6.47-6.57 (m, 2H), 6.69-6.75 (m, 2H), 6.91 (s, 1H), 7.20-7.24 (m, 2H), 10.7 (s, 1H).13C NMR (100MHz, DMSO-d6) δ 37.6,55.2,55.5,56.2,101.2,108.5,111.1,111.2,112.0,112.1,118.2,122.7,125.9,129.9,131.9,146.1,152.0,152.8
Compound 6 (4,4 '-dimethoxy -2,3- dihydro -2,3 '-biindolyl)
Synthetic method is with compound 1, yellow solid, yield 90%.1H NMR (400MHz, CDCl3) δ 3.09 (dd, J=16.0,7.6Hz, 1H), 3.56 (dd, J=16.0,8.8Hz, 1H), 4.42 (s, 1H), 5.69 (t, J=8.4Hz, 1H), 6.49 (d, J=7.6Hz, 1H), 6.69 (d, J=8.0Hz, 1H), 6.95 (t, J=8.0Hz, 1H), 7.05-7.10 (m, 3H), 7.14 (dd, J=7.6,1.2Hz, 1H), 8.34 (s, 1H).13C NMR (100MHz, CDCl3) δ 37.2,56.6,107.3,110.3,118.7,119.1,120.7,122.3,122.9,123.4,125.6,127.0,129.0,130.8,138.2,152.0
Compound 7 (5,5 '-dimethoxy -2,3- dihydro -2,3 '-biindolyl)
Synthetic method is with compound 1, yellow solid, yield 85%.1H NMR (400MHz, CDCl3) δ 3.13 (dd, J=15.6,8.8Hz, 1H), 3.41 (dd, J=15.6,8.8Hz, 1H), 5.18 (t, J=8.8Hz, 1H), 6.52 (d, J=8.0Hz, 1H), 7.13-7.17 (m, 2H), 7.21-7.29 (m, 3H), 7.22 (d, J=1.6Hz, 1H), 8.1 (s, 1H).13C NMR (100MHz, CDCl3) δ 37.7,56.8,110.4,110.6,112.9,113.1,118.7,122.2,122.5,125.4,127.6,127.8,130.3,131.2,135.5,150.0
Test case
Choosing compound obtained above 1, compound 2, compound 6, compound 7 carries out following determination of activity
Experiment material：
1 man―machine systems：It is purchased from Chinese Academy of Sciences's Shanghai cell bank.
2 test medicines：After with DMSO dissolvings, 10000 micrograms per millilitre initial concentrations are configured to, it is standby.
3 0.9% physiological saline：Lot number 201521112, specification 250mL：2.25g, Zhengzhou Yonghe Pharmaceutical Co's product.
45 FU 5 fluorouracil parenteral solutions (5-Fu), lot number 140107, specification 10mL：0.25g/, Shanghai Xudong Hipu Medicine Co., Ltd's product.
Experimental technique
Cell routine is inoculated in complete medium, 37 DEG C of Jing, 5% CO2Saturated humidity culture, amplification.After cell is with 0.25% Trypsin Induced, plus nutrient solution is diluted to 1 × 105/mL tumor cell suspensions (tire expects blue dyeing, the equal ＞ 95% of viable count), is for experiment.Negative control hole and Positive control wells, test sample variable concentrations hole are set on 96 hole sterile culture plates, concentration is set as 64,32,16,8,4,2,1,0.5 micrograms per millilitre, while each concentration sets 3 multiple holes.By the cell suspension inoculation for preparing in 96 hole sterile culture plates, the compound that variable concentrations are added after 24h is cultivated.The nutrient solution of equivalent is added in negative control hole, is inserted in incubator and is cultivated.Take out after 72h, the μ L of MTT 20 are added per hole, continue to cultivate 4h, be centrifuged after taking-up, supernatant is abandoned in suction.DMSO150 μ L, concussion is added to be completely dissolved the crystallization of hyacinthine first a ceremonial jade-ladle, used in libation per hole.The OD values in each hole are determined with ELIASA, its IC is calculated by SPSS50。
Experimental result
Antitumor activity evaluation data of the above-claimed cpd to four kinds of human tumor cells
Test result indicate that：This several compound shows excellent antitumor activity, especially to SMMC7721 HCCs, compound 1 shows excellent activity, show broad-spectrum anti-tumor activity simultaneously, 5-fluor-uracil is superior to the activity of first three tumour cell, can be applied to prepare cancer therapy drug as the candidate of further exploitation or lead compound.

Claims (4)

1. one kind 2,3- dihydro -2,3 '-bis-indole compound, it has structure as shown below, and wherein R is at least one in different the position of substitution, the alkyl of different numbers, aryl, hydroxyl, alkoxyl, aryloxy group, ester group, halogen, trifluoromethyl and cyano group.
2. 2,3- dihydro -2 as claimed in claim 1,3 '-bis-indole compound, it is characterised in that preferably：R is alkyl, alkoxyl, ester group, halogen, trifluoromethyl or the polysubstituted halogen of the mono-substituted C1-C5 of diverse location.
3. one kind 2,3- dihydro -2, the preparation method of 3 '-bis-indole compound, it is characterised in that：It is achieved by the steps of：
In organic solvent, add polysubstituted indoles and lewis acid stirring to react, obtain following target product,
Organic solvent used is the one kind in dichloromethane, chloroform, toluene, and lewis acid is BiCl3, at 15 DEG C -30 DEG C, the time is 6-12 hours to reaction temperature.
4. 2,3- dihydro -2 in claim 1-2 described in any one, application of the 3 '-bis-indole compound in medicine is prepared, it is characterised in that as active component, are prepared into anti-lung cancer, liver cancer, cancer of the stomach, breast cancer medicines.
CN201510762386.4A 2015-11-11 2015-11-11 Preparation method and application of 2,3-dihydro-2,3'-biindolyl compound Pending CN106674077A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114349759A (en) * 2022-01-25 2022-04-15 曲阜师范大学 Fused ring 3, 3' -biindole derivative and synthesis method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3697553A (en) * 1970-01-19 1972-10-10 Mead John & Co 2-(3-indolyl)-1(1-iminomethyl)-indolines and process for their preparation
WO2015154169A1 (en) * 2014-04-09 2015-10-15 The University Of British Columbia Binding function3 (bf3) site compounds as therapeutics and methods for their use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3697553A (en) * 1970-01-19 1972-10-10 Mead John & Co 2-(3-indolyl)-1(1-iminomethyl)-indolines and process for their preparation
WO2015154169A1 (en) * 2014-04-09 2015-10-15 The University Of British Columbia Binding function3 (bf3) site compounds as therapeutics and methods for their use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114349759A (en) * 2022-01-25 2022-04-15 曲阜师范大学 Fused ring 3, 3' -biindole derivative and synthesis method thereof

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