CN109160914B - Synthesis method of bis-indolopyridine derivative and application of bis-indolopyridine derivative in tumor resistance - Google Patents

Synthesis method of bis-indolopyridine derivative and application of bis-indolopyridine derivative in tumor resistance Download PDF

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CN109160914B
CN109160914B CN201811369810.9A CN201811369810A CN109160914B CN 109160914 B CN109160914 B CN 109160914B CN 201811369810 A CN201811369810 A CN 201811369810A CN 109160914 B CN109160914 B CN 109160914B
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dihydropyrido
diindole
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indolopyridine
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徐志刚
陈中祝
张亚军
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Chongqing University of Arts and Sciences
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Abstract

The invention relates to a simple preparation method and application of a bis-indolopyridine derivative, wherein the bis-indolopyridine derivative is synthesized by using three-component reaction as a basis, using methanol as a solvent and performing a microwave-assisted reaction to close a ring under an acidic condition, has an anti-tumor activity, and particularly has a strong inhibition effect on colon cancer tumor cells HCT 116.

Description

Synthesis method of bis-indolopyridine derivative and application of bis-indolopyridine derivative in tumor resistance
Technical Field
The application relates to the field of drug synthesis, in particular to a rapid preparation method of a bisindolopyridine derivative and application of the bisindolopyridine derivative in antitumor drugs.
Background
The indolopyridine derivatives have very wide biological and pharmaceutical activities and good therapeutic characteristics, and can be used for preparing novel compounds for inhibiting the activity of protein kinases; drugs for the treatment of diabetes, hypertension, hyperlipidemia, hypercholesterolemia, and cardiovascular complications; compounds that are also useful as kinase inhibitors; medicine for improving cellular immunity, resisting virus, bacteria and microbe, and treating tumor or psychosis.
Common pyridine compounds include imidazopyridine, benzopyridine, pyridopyridine, thienopyridine, pyrazolopyridine, furopyridine, indolopyridine and the like, especially the indolopyridine compounds can be directly used for preparing an intermediate for inhibiting angiotensin, can be used for reducing blood pressure, and can also be used for preparing other drug intermediates, such as therapeutic agents or preventive agents of gastric ulcer or duodenal drugs. The research on the compounds is more and more, the synthesis and the biological activity of related compounds are also reported, and the patent does not adopt the traditional synthetic steps, but uses multi-component reaction to construct the parent structure of the compounds by one step to complete the integral framework. However, the multicomponent reaction of the compounds with similar structures has not been reported much, and much attention and research are urgently needed.
Disclosure of Invention
The invention aims to provide a rapid preparation method of bis-indolopyridine derivatives. The application uses multi-component reaction, under the catalysis of perchloric acid, the bis-indolopyridine derivative can be synthesized in one step through microblog assistance, and the bis-indolopyridine derivative can be used for antitumor activity research and preparation of antitumor drugs.
The purpose of the invention is realized by the following technical scheme:
a bis-indolopyridine derivative is characterized in that the structural general formula of the derivative is as follows:
Figure 707134DEST_PATH_IMAGE001
。
wherein R is1Is C1-10Alkyl chains, aryl and heteroaryl, R2Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano, R3Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano.
Further, the compound is 6-phenyl-7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6-cyclohexyl-7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6- (4-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6-butyl-7, 12-dihydropyrido [3, 2-B: 5,4-B' ] diindole.
Further, the compound is 6- (4-chlorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6- (4-fluorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6- (4-nitrophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6- (3-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6- (3, 4-dichlorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6- (4-methoxyphenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6- (p-tolyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6- (2-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
Further, the compound is 6-phenethyl-7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole.
The bis-indolopyridine derivative is characterized in that the synthetic route is as follows:
Figure 724769DEST_PATH_IMAGE002
wherein R is1Is C1-10Alkyl chains, aryl and heteroaryl, R2Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano, R3Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano.
Moreover, the bis-indolopyridine derivative can be used as an antitumor drug. The invention has the advantages and positive effects that:
(1) the invention takes substituted benzyl isonitrile and substituted 1H-indole-3-amine as raw materials, and the bis-indolopyridine derivative is obtained by ring closure under microwave-assisted conditions through three-component reaction. The derivative with anti-tumor activity is synthesized by a multi-component reaction mode for the first time, has stronger inhibition effect on tumor cells HCT116, and can be used for preparing anti-tumor drugs.
(2) The synthetic route of the invention has the advantages of simple operation process, short synthetic route, simple post-treatment, low cost and the like.
Drawings
FIG. 1 is a structural formula, wherein R is1Is C1-10Alkyl chains, aryl and heteroaryl, R2Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano, R3Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano.
FIG. 2 is a schematic representation of the structure of 6-phenyl-7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 3 is a schematic representation of the 6-cyclohexyl-7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 4 is a schematic representation of 6- (4-bromophenyl) -7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 5 is a schematic representation of 6-butyl-7, 12-dihydropyrido [3, 2-B: nuclear magnetic spectrum of 5,4-B' ] diindole.
FIG. 6 is a schematic representation of 6- (4-chlorophenyl) -7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 7 is a schematic representation of 6- (4-fluorophenyl) -7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 8 is a schematic representation of 6- (4-nitrophenyl) -7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 9 is a schematic representation of 6- (3-bromophenyl) -7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
Fig. 10 is a schematic representation of 6- (3, 4-dichlorophenyl) -7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 11 is a schematic representation of 6- (4-methoxyphenyl) -7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 12 is a schematic representation of 6- (p-tolyl) -7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 13 is a schematic representation of 6- (2-bromophenyl) -7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
FIG. 14 is a schematic representation of the structure of 6-phenethyl-7, 12-dihydropyrido [3, 2-b: nuclear magnetic spectrum of 5,4-b' ] diindole.
Detailed Description
For understanding the invention, the invention is further illustrated below with reference to examples of embodiment: the following examples are illustrative and not intended to be limiting, and are not intended to limit the scope of the invention.
The structural general formula of the bis-indolopyridine derivative is as follows:
Figure 547232DEST_PATH_IMAGE001
。
wherein R is1Is C1-10Alkyl chains, aryl and heteroarylRadical, R2Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano, R3Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano.
The specific synthetic route of the bis-indolopyridine derivative is as follows:
Figure 283106DEST_PATH_IMAGE003
。
wherein R is1Is C1-10Alkyl chains, aryl and heteroaryl, R2Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano, R3Is hydrogen atom, halogen, methoxy, C1-3Alkyl, nitro, cyano.
The synthesis process is specifically illustrated by the following examples.
Example 1.
Wherein R is1Is phenyl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6-phenyl-7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
0.5 mmol of benzaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol in a 5 mL microwave reaction tube, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20 to 80%) to obtain the target compound 6-phenyl-7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, yield 76%.
1H NMR (400 MHz, DMSO-d 6 ) δ 12.95 (s, 1H), 12.48 (s, 1H), 8.96 (d,J=8.0 Hz, 1H), 8.57 (d,J= 7.6 Hz, 1H), 8.08 (d,J= 6.8 Hz, 2H), 7.89 – 7.76(m, 6H), 7.67 (t,J= 7.5 Hz, 1H), 7.57 (t,J= 7.3 Hz, 1H), 7.45 (t,J= 7.5Hz, 1H).13C NMR (100 MHz, DMSO-d 6 ) δ 139.48, 130.68, 129.48, 128.74, 127.22,123.11, 120.61, 120.35, 118.15, 112.37, 111.89. HRMS (ESI) m/z calcd forC23H16N3 +(M+H)+334.13442, found 334.13437。
Example 2.
Wherein R is1Is alkyl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6-cyclohexyl-7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of cyclohexylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20 to 80%) to obtain the target compound 6-cyclohexyl-7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, yield 72%.
1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.59 (s, 1H), 8.41 (d,J= 7.7Hz, 1H), 8.23 (d,J= 7.8 Hz, 1H), 7.63 (d,J= 8.2 Hz, 1H), 7.56 (t,J= 7.4Hz, 2H), 7.43 – 7.35 (m, 2H), 7.30 (t,J= 7.4 Hz, 1H), 3.28 – 3.20 (m, 1H),2.06 – 1.95 (m, 3H), 1.84 – 1.78 (m, 4H), 1.56 – 1.41 (m, 3H).13C NMR (100MHz, CDCl3) δ 142.63, 138.12, 132.21, 131.14, 125.88, 125.12, 124.04, 122.82,121.00, 120.05, 119.21, 118.88, 111.94, 110.55, 109.97, 52.39, 42.04, 30.93,25.91, 25.22. HRMS (ESI) m/z calcd for C23H22N3 +(M+H)+340.18137, found340.18198。
Example 3.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6- (4-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']the synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of 4-bromophenylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20-80%) to obtain the target compound 6- (4-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, yield 83%.
1H NMR (400 MHz, DMSO-d 6 ) δ 12.09 (s, 1H), 11.69 (s, 1H), 8.77 (d,J=7.9 Hz, 1H), 8.23 (d,J= 7.7 Hz, 1H), 8.05 (d,J= 8.5 Hz, 2H), 7.83 (d,J=8.5 Hz, 2H), 7.74 – 7.69 (m, 2H), 7.59 (t,J= 7.6 Hz, 1H), 7.51 – 7.45 (m,1H), 7.41 (t,J= 7.4 Hz, 1H), 7.29 (t,J= 7.4 Hz, 1H).13C NMR (100 MHz,DMSO-d 6 ) δ 140.55, 140.29, 138.87, 135.24, 133.03, 132.51, 132.09, 131.07,127.40, 125.68, 123.33, 122.97, 121.54, 120.33, 119.48, 113.47, 112.76,112.15. HRMS (ESI) m/z calcd for C23H15BrN3 +(M+H)+412.04494, found 412.04498。
Example 4.
Wherein R is1Is alkyl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6-butyl-7, 12-dihydropyrido [3, 2-B: 5,4-B']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of n-butylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction is finished, the reaction solution is cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and salt water are poured into the reaction solution for washing, and the organic phase is washed by anhydrous sodium bicarbonateDried over sodium sulfate, concentrated, and eluted with ethyl acetate/n-hexane (20-80%) in a gradient to give the desired compound 6-butyl-7, 12-dihydropyrido [3, 2-B: 5,4-B']Diindole, yield 65%.
1H NMR (400 MHz, DMSO-d 6 ) δ 11.85 (s, 1H), 11.72 (s, 1H), 8.70 (d,J=7.9 Hz, 1H), 8.15 (d,J= 7.7 Hz, 1H), 7.69 (d,J= 8.2 Hz, 1H), 7.64 (d,J=8.0 Hz, 1H), 7.57 (d,J= 7.3 Hz, 1H), 7.42 – 7.33 (m, 2H), 7.23 (t,J= 7.1Hz, 1H), 3.28 – 3.23 (m, 2H), 1.93 – 1.85 (m, 2H), 1.52 – 1.47 (m, 2H), 0.98(t,J= 7.4 Hz, 3H).13C NMR (100MHz, DMSO-d 6 ) δ 138.81, 138.66,138.50,132.26, 130.70, 125.90, 125.22, 123.74, 122.28, 121.96, 119.52, 118.64,118.12, 111.19, 110.81, 32.89, 30.43, 21.71, 13.42. HRMS (ESI) m/z calcd forC21H20N3 +(M+H)+314.16572, found 314.16443。
Example 5.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6- (4-chlorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of 4-chlorophenylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20 to 80%) to obtain the objective compound 6- (4-chlorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, 62% yield.
1H NMR (400 MHz, DMSO-d 6 ) δ 12.07 (s, 1H), 11.67 (s, 1H), 8.77 (d,J=7.9 Hz, 1H), 8.22 (d,J= 7.7 Hz, 1H), 8.14 – 8.08 (m, 2H), 7.74 – 7.68(m,4H), 7.62 – 7.56 (m, 1H), 7.49 – 7.45 (m,1H), 7.43 – 7.37 (m, 1H), 7.31 –7.27 (m, 1H).13C NMR (100 MHz, DMSO-d 6 ) δ 139.45, 139.18, 137.42, 134.11,131.85, 131.43, 129.68, 128.09, 126.32, 126.08, 124.59, 122.23, 121.90,119.23, 119.07, 118.40, 112.36, 111.68, 111.07. HRMS (ESI) m/z calcd forC23H15ClN3 +(M+H)+368.09545, found 368.09561。
Example 6.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6- (4-fluorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of 4-fluorophenylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the resulting product was subjected to gradient elution with ethyl acetate/n-hexane (20 to 80%) to obtain the target compound 6- (4-fluorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, 62% yield.
1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.65 (s, 1H), 8.46 (d,J= 7.8Hz, 1H), 8.27 (d,J= 7.8 Hz, 1H), 8.05 – 7.98 (m, 2H), 7.62 – 7.59 (m, 3H),7.49 (t,J= 7.6 Hz, 1H), 7.43 – 7.39 (m, 1H), 7.36 (t,J= 7.4 Hz, 1H),7.30– 7.28 (m, 2H).13C NMR (100 MHz, CDCl3) δ 139.44, 136.33, 135.78, 134.21,132.36, 130.25, 127.39, 126.88, 125.78, 123.62, 122.11, 120.80, 120.68,120.57, 120.12, 116.30, 116.09, 111.72, 111.17. HRMS (ESI) m/z calcd forC23H15FN3 +(M+H)+352.12500, found 352.12415。
Example 7.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6- (4-nitrophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of 4-nitrophenylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by the addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20 to 80%) to obtain the target compound 6- (4-nitrophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, 75% yield.
1H NMR (400 MHz, DMSO-d 6 ) δ 12.29 (s, 1H), 11.92 (s, 1H), 8.83 (d,J=7.9 Hz, 1H), 8.49 (d,J= 8.8 Hz, 2H), 8.41 (d,J= 8.9 Hz, 2H), 8.26 (d,J=7.7 Hz, 1H), 7.77 – 7.72 (m, 2H), 7.62 (t,J= 7.3 Hz, 1H), 7.50 (t,J= 7.6Hz, 1H), 7.43 (t,J= 7.4 Hz, 1H), 7.31 (t,J= 7.3 Hz, 1H).13C NMR (100 MHz,DMSO-d 6 ) δ 147.00, 146.12, 140.64, 133.59, 132.89, 129.95, 127.73, 126.07,124.39, 123.18, 120.37, 120.23, 119.62, 113.66, 112.79, 112.31. HRMS (ESI) m/z calcd for C23H15N4O2 +(M+H)+379.11950, found 379.11948。
Example 8.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6- (3-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of 3-bromophenylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing in microwaveIn reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20-80%) to obtain the target compound 6- (3-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, yield 76%.
1H NMR (400 MHz, DMSO-d 6 ) δ 12.11 (s, 1H), 11.76 (s, 1H), 8.78 (d,J=7.9 Hz, 1H), 8.27 – 8.20 (m, 2H), 8.10 (d,J= 7.7 Hz, 1H), 7.76 – 7.69 (m,3H), 7.63 – 7.58 (m, 2H), 7.48 (t,J= 7.5 Hz, 1H), 7.41 (t,J= 7.5 Hz, 1H),7.30 (t,J= 7.4 Hz, 1H).13C NMR (100 MHz, DMSO-d 6 ) δ 140.96, 139.51, 139.26,133.62, 132.00, 131.46, 130.40, 129.93, 126.88, 126.22, 124.68, 122.23,121.90, 121.54, 119.25, 119.10, 118.49, 112.45, 111.73, 111.09. HRMS (ESI) m/z calcd for C23H15BrN3 +(M+H)+412.04494, found 412.04431。
Example 9.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6- (3, 4-dichlorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of 3, 4-dichlorophenyl aldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20 to 80%) to obtain the target compound 6- (3, 4-dichlorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, yield 81%.
1H NMR (400 MHz, DMSO-d 6 ) δ 12.13 (s, 1H), 11.79 (s, 1H), 8.78 (d,J=7.9 Hz, 1H), 8.28 – 8.24 (m, 2H), 8.10 – 8.07 (m, 1H), 7.89 (d,J= 8.3 Hz,1H), 7.76 – 7.70 (m, 2H), 7.61 (t,J= 7.5 Hz, 1H), 7.49 (t,J= 7.6 Hz, 1H),7.42 (t,J= 7.4 Hz, 1H), 7.30 (t,J= 7.4 Hz, 1H).13C NMR (100 MHz, DMSO-d 6 )δ 140.59, 140.37, 140.24, 133.67, 133.14, 132.54, 131.94, 131.32, 130.80,130.63, 129.16, 127.55, 125.87, 123.21, 123.02, 120.29, 119.60, 113.57,112.76, 112.20. HRMS (ESI) m/z calcd for C23H14Cl2N3 +(M+H)+402.05648, found402.05615。
Example 10.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6- (4-methoxyphenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of 4-methoxyphenylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20 to 80%) to obtain the target compound 6- (4-methoxyphenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, yield 71%.
1H NMR (400 MHz, DMSO-d 6 ) δ 11.06 (s, 2H), 8.30 (d,J= 7.7 Hz, 2H),7.81 (d,J= 8.6 Hz, 2H), 7.55 (d,J= 8.1 Hz, 2H), 7.44 (t,J= 7.5 Hz, 2H),7.31 – 7.22 (m, 4H), 3.92 (s, 3H).13C NMR (100MHz, DMSO-d 6 ) δ 158.77,140.76, 136.55, 130.14, 129.90, 125.47, 124.66, 121.58, 118.95, 118.39,114.34, 112.13, 111.01, 54.80. HRMS (ESI) m/z calcd for C24H18N3O+(M+H)+364.14499, found 364.14474。
Example 11.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6- (p-tolyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of p-methylphenylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20 to 80%) to obtain the desired compound, i.e., 6- (p-tolyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, yield 68%.
1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.65 (s, 1H), 8.48 (d,J= 7.8Hz, 1H), 8.28 (d,J= 7.8 Hz, 1H), 7.95 (d,J= 7.9 Hz, 2H), 7.63 – 7.59 (m,3H), 7.48 (d,J= 8.0 Hz, 1H), 7.45 – 7.42 (m, 3H), 7.37 (t,J= 7.4 Hz, 1H),2.49 (s, 3H).13C NMR (100 MHz, CDCl3) δ 139.36, 138.74, 129.98, 128.57,128.34, 127.39, 127.24, 125.80, 125.61, 123.19, 122.07, 120.74, 120.59,120.44, 120.20, 118.40, 111.67, 111.09, 21.40. HRMS (ESI) m/z calcd forC24H18N3 +(M+H)+348.15007, found 348.15018。
Example 12.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6- (2-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of 2-bromophenylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by0.05mmol perchloric acid and 0.5 mmol benzylisonitrile were added, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction, the reaction mixture was cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine were poured into the reaction mixture, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the mixture was subjected to gradient elution with ethyl acetate/n-hexane (20-80%) to obtain the target compound, i.e., 6- (2-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, yield 85%.
1H NMR (400 MHz, DMSO-d 6 ) δ 12.09 (s, 1H), 11.40 (s, 1H), 8.76 (d,J=7.9 Hz, 1H), 8.16 (d,J= 7.7 Hz, 1H), 7.88 (d,J= 7.8 Hz, 1H), 7.70 (d,J=8.1 Hz, 1H), 7.67 – 7.59 (m, 3H), 7.57 – 7.49 (m, 2H), 7.46 (t,J= 7.2 Hz,1H), 7.38 (t,J= 7.4 Hz, 1H), 7.27 (t,J= 7.4 Hz, 1H).13C NMR (100 MHz,DMSO-d 6 ) δ 139.29, 138.94, 136.02, 132.12, 131.93, 131.72, 131.03, 129.55,127.24, 126.16, 124.39, 122.83, 122.25, 121.96, 119.17, 118.97, 118.81,118.36, 111.42, 110.99. HRMS (ESI) m/z calcd for C23H15BrN3 +(M+H)+412.04494,found 412.04407。
Example 13.
Wherein R is1Is aryl, R2Is a hydrogen atom, R3Is a hydrogen atom, i.e., 6-phenethyl-7, 12-dihydropyrido [3, 2-b: 5,4-b']The synthesis of diindole comprises the following specific steps:
in a 5 mL microwave reaction tube, 0.5 mmol of phenethylaldehyde and 0.5 mmol of Boc-protected indoleamine were dissolved in 2mL of methanol, and the reaction was stirred at room temperature for 5 minutes, followed by addition of 0.05mmol of perchloric acid and 0.5 mmol of benzylisonitrile, respectively. Then placing the mixture in a microwave reactor 100oC, reacting for 10 minutes. After the reaction is finished, the reaction solution is cooled to room temperature, 15 mL of ethyl acetate, saturated sodium bicarbonate and brine are poured into the reaction solution, an organic phase is dried by anhydrous sodium sulfate and then concentrated, and the mixture is subjected to gradient elution and separation by ethyl acetate/n-hexane (20-80%) to obtain a target compound of 6-phenethyl-7, 12-dihydropyrido [3, 2-b: 5,4-b']Diindole, 66% yield.
1H NMR (400 MHz, DMSO-d 6 ) δ 11.90 (s, 1H), 11.81 (s, 1H), 8.72 (d,J=7.9 Hz, 1H), 8.20 (d,J= 7.7 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.57 (t,J= 7.4Hz, 1H), 7.46 (d,J= 7.4 Hz, 2H), 7.36 – 7.31 (m, 4H), 7.26 – 7.21 (m, 2H),3.58 – 3.54 (m, 2H), 3.29 – 3.24 (m, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 141.53,138.83, 138.53, 137.53, 132.21, 130.72, 127.95, 127.61, 125.98, 125.33,125.19, 123.83, 122.24, 121.99, 119.50, 118.72, 118.17, 111.19, 110.84,34.76, 33.67. HRMS (ESI) m/z calcd for C25H20N3 +(M+H)+362.16572, found362.16550。
The tested tumor cells HCT116 were cultured under standard conditions (37 ℃ C. and 5% CO)210% fetal bovine serum) with 100 UI/mL penicillin and 100 mg/L streptomycin. Cells 2000-8000 cells/well were seeded in 96-well multi-well plates (Castar) and various concentrations of the example compounds 1-13 were added after 12 hours. After 48 hours of incubation, the cells were washed twice with PBS and 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) was added at a concentration of 0.5 mg/mL. The 96-well plate was incubated at 37 ℃ for 4 hours. Finally, the blue precipitate was dissolved in 0.2mL of dimethyl sulfoxide (DMSO). The samples were read on a plate reader (Bio Tek staining TM 5) at a wavelength of 570 nm. All MTT assays were repeated at least three times using five samples per assay.
TABLE 1 biological Activity data for Compounds
Figure 685269DEST_PATH_IMAGE005

Claims (4)

1. A bis-indolopyridine derivative is characterized in that: the structural general formula of the derivative is as follows:
Figure FDA0002455918640000011
wherein R is1Is one of phenyl, cyclohexyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, butyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, phenethyl, 3, 4-dichlorophenyl, 4-methoxyphenyl and p-tolyl, R is2Is a hydrogen atom, R3Is a hydrogen atom.
2. The bis-indolopyridine derivative of claim 1 wherein the derivative is 6-phenyl-7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole, 6-cyclohexyl-7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole, 6- (4-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-B' ] diindole, 6-butyl-7, 12-dihydropyrido [3, 2-B: 5,4-B' ] bisindole, 6- (4-chlorophenyl) -7, 12-dihydropyrido [3, 2-B: 5,4-b' ] diindole, 6- (4-fluorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole, 6- (4-nitrophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole, 6- (3-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] bisindole, 6- (3, 4-dichlorophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole, 6- (4-methoxyphenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole, 6- (p-tolyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole, 6- (2-bromophenyl) -7, 12-dihydropyrido [3, 2-b: 5,4-b' ] diindole, 6-phenethyl-7, 12-dihydropyrido [3, 2-b: 5,4-b' ] di-indole.
3. The bis-indolopyridine derivative of claim 1, wherein the derivative is synthesized by the following steps:
Figure FDA0002455918640000012
4. the bis-indolopyridine derivative of claim 1 for use in preparing an antitumor drug.
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