CN109160914A - A kind of synthetic method of double trypoline analog derivatives and the application in antitumor - Google Patents
A kind of synthetic method of double trypoline analog derivatives and the application in antitumor Download PDFInfo
- Publication number
- CN109160914A CN109160914A CN201811369810.9A CN201811369810A CN109160914A CN 109160914 A CN109160914 A CN 109160914A CN 201811369810 A CN201811369810 A CN 201811369810A CN 109160914 A CN109160914 A CN 109160914A
- Authority
- CN
- China
- Prior art keywords
- indoles
- hydrogen atom
- dihydro pyrido
- trypoline
- double
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
The present invention relates to a kind of simple preparation method of double trypoline analog derivatives and its applications, the present invention is based on three component reactions, in acid condition, it the use of methanol is solvent, such double trypoline analog derivative is synthesized by microwave-assisted reaction cyclization, and there is anti-tumor activity, especially there is stronger inhibiting effect to colon cancer tumours cell HCT116.
Description
Technical field
This application involves pharmaceutical synthesis field, the fast preparation method of especially a kind of double trypoline analog derivatives and
Its application in anti-tumor drug.
Background technique
Trypoline analog derivative is a kind of very extensive biological and pharmacoligical activities, and good treatment characteristic can be used
Inhibit the new compound of protein kinase activity in preparation；Treat diabetes, hypertension, hyperlipemia, high-cholesterol disease with
And the drug of cardiovascular complication；It can also be used for the compound of kinase inhibitor；Improvement cellular immunity, antiviral, antibacterium,
Antimicrobial acivity treats the drug of tumour or mental disease.
Common pyridine compounds and their has imidazopyridine, benzo pyridine, pyridopyridine, thienopyridine, pyrazolo
The types such as pyridine, furopyridine and trypoline, especially trypoline class compound can be directly used for preparation suppression
The intermediate of angiotensin processed can be used for reducing blood pressure, it can also be used to the preparation of other drugs intermediate, such as gastric ulcer or
The therapeutic agent or prophylactic of duodenum drug.People are more and more to the research of such compound, the conjunction of related compound
It is also had been reported that at bioactivity, this patent does not use traditional synthesis step, but uses multi-component reaction, a step construction
The precursor structure of such compound completes whole frame.But the multi-component reaction of similar structural compound, there are no very much
Report, be badly in need of more concerns and research.
Summary of the invention
The purpose of the present invention is to provide a kind of fast preparation methods of double trypoline analog derivatives.The application uses
Multi-component reaction under perchloric acid catalysis, is assisted by microblogging, and a step can synthesize double trypoline analog derivatives, such can
For use as antitumor activity, it is used to prepare anti-tumor drug.
The purpose of the present invention is what is be achieved through the following technical solutions:
A kind of double trypoline analog derivatives, which is characterized in that the general structure of derivative is as follows:
。
The wherein R1For C1-10Alkyl chain, aryl and heteroaryl, R2For hydrogen atom, halogen, methoxyl group, C1-3Alkyl,
Nitro, cyano, R3For hydrogen atom, halogen, methoxyl group, C1-3Alkyl, nitro, cyano.
Moreover, the compound is two indoles of 6- phenyl -7,12- dihydro pyrido [3,2-b:5,4-b'].
Moreover, the compound is two indoles of 6- cyclohexyl -7,12- dihydro pyrido [3,2-b:5,4-b'].
Moreover, the compound is 6-(4- bromophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles.
Moreover, the compound is two indoles of 6- butyl -7,12- dihydro pyrido [3,2-B:5,4-B'].
Moreover, the compound is 6-(4- chlorphenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles.
Moreover, the compound is 6-(4- fluorophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles.
Moreover, the compound is 6-(4- nitrobenzophenone) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles.
Moreover, the compound is 6-(3- bromophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles.
Moreover, the compound is 6-(3,4- dichlorophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two Yin
Diindyl.
Moreover, the compound is 6-(4- methoxyphenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two Yin
Diindyl.
Moreover, the compound is 6-(p-methylphenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles.
Moreover, the compound is 6-(2- bromophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles.
Moreover, the compound is two indoles of 6- phenethyl -7,12- dihydro pyrido [3,2-b:5,4-b'].
Double trypoline analog derivatives, which is characterized in that synthetic route is as follows:
The wherein R1For C1-10Alkyl chain, aryl and heteroaryl, R2For hydrogen atom, halogen, methoxyl group, C1-3Alkyl, nitro,
Cyano, R3For hydrogen atom, halogen, methoxyl group, C1-3Alkyl, nitro, cyano.
Moreover, double trypoline analog derivatives can be used as anti-tumor drug.The advantages and positive effects of the present invention:
(1) present invention with the benzyl isonitrile replaced and substituted 1H- indoles -3- amine for raw material therein, by three component reactions,
Cyclization under the conditions of microwave-assisted obtains double trypoline analog derivatives.The multi-component reactive mode of first passage synthesizes
Derivative with anti-tumor activity, to tumour cell HCT116 shows stronger inhibitory effect, and it is anti-swollen to can be used as preparation
Tumor medicine.
(2) synthetic route of the present invention has many advantages, such as that operating procedure is simple, synthetic route is short, post-processes simple, at low cost.
Detailed description of the invention
Fig. 1 is general structure, wherein the R1For C1-10Alkyl chain, aryl and heteroaryl, R2For hydrogen atom, halogen, first
Oxygroup, C1-3Alkyl, nitro, cyano, R3For hydrogen atom, halogen, methoxyl group, C1-3Alkyl, nitro, cyano.
Fig. 2 is the nuclear magnetic spectrogram of two indoles of 6- phenyl -7,12- dihydro pyrido [3,2-b:5,4-b'].
Fig. 3 is the nuclear magnetic spectrogram of two indoles of 6- cyclohexyl -7,12- dihydro pyrido [3,2-b:5,4-b'].
Fig. 4 be 6-(4- bromophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'] two indoles nuclear magnetic spectrogram.
Fig. 5 is the nuclear magnetic spectrogram of two indoles of 6- butyl -7,12- dihydro pyrido [3,2-B:5,4-B'].
Fig. 6 be 6-(4- chlorphenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'] two indoles nuclear magnetic spectrogram.
Fig. 7 be 6-(4- fluorophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'] two indoles nuclear magnetic spectrogram.
Fig. 8 be 6-(4- nitrobenzophenone) -7,12- dihydro pyrido [3,2-b:5,4-b'] two indoles nuclear magnetic spectrogram.
Fig. 9 be 6-(3- bromophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'] two indoles nuclear magnetic spectrogram.
Figure 10 be 6-(3,4- dichlorophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'] two indoles nuclear magnetic spectrogram.
Figure 11 be 6-(4- methoxyphenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'] two indoles nuclear magnetic spectrogram.
Figure 12 be 6-(p-methylphenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'] two indoles nuclear magnetic spectrogram.
Figure 13 be 6-(2- bromophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'] two indoles nuclear magnetic spectrogram.
Figure 14 is the nuclear magnetic spectrogram of two indoles of 6- phenethyl -7,12- dihydro pyrido [3,2-b:5,4-b'].
Specific embodiment
In order to understand the present invention, below with reference to examples of implementation, the invention will be further described: following examples of implementation are to say
Bright property, it is not restrictive, cannot be limited the scope of protection of the present invention with following embodiments.
The general structure of double trypoline analog derivatives of the present invention is as follows:
。
The wherein R1For C1-10Alkyl chain, aryl and heteroaryl, R2For hydrogen atom, halogen, methoxyl group, C1-3Alkyl,
Nitro, cyano, R3For hydrogen atom, halogen, methoxyl group, C1-3Alkyl, nitro, cyano.
Double specific synthetic routes of trypoline analog derivative are as follows:
。
The wherein R1For C1-10Alkyl chain, aryl and heteroaryl, R2For hydrogen atom, halogen, methoxyl group, C1-3Alkyl,
Nitro, cyano, R3For hydrogen atom, halogen, methoxyl group, C1-3Alkyl, nitro, cyano.
Synthesis process is illustrated below by examples of implementation.
Embodiment 1.
Wherein R1For phenyl, R2For hydrogen atom, R3For hydrogen atom, i.e. 6- phenyl -7,12- dihydro pyrido [3,2-b:5,4-
B'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the benzaldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, is dissolved in 2 mL
Methanol is stirred at room temperature reaction 5 minutes, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.It is subsequently placed in
100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL ethyl acetate, saturation
Sodium bicarbonate and salt washing are concentrated, with ethyl acetate/n-hexane (20-80%) gradient after organic phase anhydrous sodium sulfate drying
Elute isolated two indoles of target compound 6- phenyl -7,12- dihydro pyrido [3,2-b:5,4-b'], 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 = 7.5
Hz, 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 for
C23H16N3 +(M+H)+ 334.13442, found 334.13437。
Embodiment 2.
Wherein R1For alkyl, R2For hydrogen atom, R3For hydrogen atom, i.e., 6- cyclohexyl -7,12- dihydro pyrido [3,2-b:5,
4-b'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the cyclohexyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, is dissolved in 2
ML methanol is stirred at room temperature reaction 5 minutes, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.Then it sets
100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL ethyl acetate, satisfies
It washes, is concentrated after organic phase anhydrous sodium sulfate drying, with ethyl acetate/n-hexane (20-80%) ladder with sodium bicarbonate and salt
Degree elutes isolated two indoles of target compound 6- cyclohexyl -7,12- dihydro pyrido [3,2-b:5,4-b'], yield 72%.
1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.59 (s, 1H), 8.41 (d, J = 7.7
Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.56 (t, J = 7.4
Hz, 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 (100
MHz, 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, found
340.18198。
Embodiment 3.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, i.e. 6-(4- bromophenyl) -7,12- dihydro pyrido [3,2-
B:5,4-b'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the 4- bromophenyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, is dissolved in 2
ML methanol is stirred at room temperature reaction 5 minutes, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.Then it sets
100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL ethyl acetate, satisfies
It washes, is concentrated after organic phase anhydrous sodium sulfate drying, with ethyl acetate/n-hexane (20-80%) ladder with sodium bicarbonate and salt
Degree elutes isolated target compound 6-(4- bromophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles, 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。
Embodiment 4.
Wherein R1For alkyl, R2For hydrogen atom, R3For hydrogen atom, i.e. 6- butyl -7,12- dihydro pyrido [3,2-B:5,4-
B'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the normal-butyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, is dissolved in 2
ML methanol is stirred at room temperature reaction 5 minutes, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.Then it sets
100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL ethyl acetate, satisfies
It washes, is concentrated after organic phase anhydrous sodium sulfate drying, with ethyl acetate/n-hexane (20-80%) ladder with sodium bicarbonate and salt
Degree elutes isolated two indoles of target compound 6- butyl -7,12- dihydro pyrido [3,2-B:5,4-B'], 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 = 7.1
Hz, 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 for
C21H20N3 +(M+H)+ 314.16572, found 314.16443。
Embodiment 5.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, i.e. 6-(4- chlorphenyl) -7,12- dihydro pyrido [3,2-
B:5,4-b'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the 4- chlorphenyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, is dissolved in 2
ML methanol is stirred at room temperature reaction 5 minutes, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.Then it sets
100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL ethyl acetate, satisfies
It washes, is concentrated after organic phase anhydrous sodium sulfate drying, with ethyl acetate/n-hexane (20-80%) ladder with sodium bicarbonate and salt
Degree elutes isolated target compound 6-(4- chlorphenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles, yield
62%。
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 for
C23H15ClN3 +(M+H)+ 368.09545, found 368.09561。
Embodiment 6.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, i.e. 6-(4- fluorophenyl) -7,12- dihydro pyrido [3,2-
B:5,4-b'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the 4- fluorophenyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, is dissolved in 2
ML methanol is stirred at room temperature reaction 5 minutes, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.Then it sets
100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL ethyl acetate, satisfies
It washes, is concentrated after organic phase anhydrous sodium sulfate drying, with ethyl acetate/n-hexane (20-80%) ladder with sodium bicarbonate and salt
Degree elutes isolated target compound 6-(4- fluorophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles, yield
62%。
1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.65 (s, 1H), 8.46 (d, J = 7.8
Hz, 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 for
C23H15FN3 +(M+H)+ 352.12500, found 352.12415。
Embodiment 7.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, i.e. 6-(4- nitrobenzophenone) -7,12- dihydro pyrido [3,
2-b:5,4-b'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the 4- nitrobenzophenone aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, it is molten
In 2 mL methanol, reaction 5 minutes is stirred at room temperature, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.So
It is placed on 100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL acetic acid second
Ester, saturated sodium bicarbonate and salt washing are concentrated, with ethyl acetate/n-hexane (20- after organic phase anhydrous sodium sulfate drying
80%) the isolated target compound 6-(4- nitrobenzophenone of gradient elution) -7,12- dihydro pyrido [3,2-b:5,4-b'] two
Indoles, yield 75%.
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 = 7.6
Hz, 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。
Embodiment 8.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, i.e. 6-(3- bromophenyl) -7,12- dihydro pyrido [3,2-
B:5,4-b'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the 3- bromophenyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, is dissolved in 2
ML methanol is stirred at room temperature reaction 5 minutes, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.Then it sets
100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL ethyl acetate, satisfies
It washes, is concentrated after organic phase anhydrous sodium sulfate drying, with ethyl acetate/n-hexane (20-80%) ladder with sodium bicarbonate and salt
Degree elutes isolated target compound 6-(3- bromophenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles, 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。
Embodiment 9.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, i.e. 6-(3,4- dichlorophenyl) -7,12- dihydro pyrido
The synthesis of [3,2-b:5,4-b'] two indoles, the specific steps are as follows:
The indoles amine for protecting 3, the 4- dichlorophenyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL,
2 mL methanol are dissolved in, reaction 5 minutes is stirred at room temperature, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.
It is subsequently placed in 100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL acetic acid
Ethyl ester, saturated sodium bicarbonate and salt washing are concentrated, with ethyl acetate/n-hexane after organic phase anhydrous sodium sulfate drying
The isolated target compound 6-(3,4- dichlorophenyl of (20-80%) gradient elution) -7,12- dihydro pyrido [3,2-b:5,4-
B'] two indoles, 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, found
402.05615。
Embodiment 10.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, i.e. 6-(4- methoxyphenyl) -7,12- dihydro pyrido
The synthesis of [3,2-b:5,4-b'] two indoles, the specific steps are as follows:
The indoles amine for protecting the 4- methoxyphenyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL,
2 mL methanol are dissolved in, reaction 5 minutes is stirred at room temperature, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.
It is subsequently placed in 100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL acetic acid
Ethyl ester, saturated sodium bicarbonate and salt washing are concentrated, with ethyl acetate/n-hexane after organic phase anhydrous sodium sulfate drying
The isolated target compound 6-(4- methoxyphenyl of (20-80%) gradient elution) -7,12- dihydro pyrido [3,2-b:5,4-
B'] two indoles, 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 (100 MHz, 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。
Embodiment 11.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, as 6-(p-methylphenyl) -7,12- dihydro pyrido [3,
2-b:5,4-b'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the p-methylphenyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, it is molten
In 2 mL methanol, reaction 5 minutes is stirred at room temperature, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.So
It is placed on 100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL acetic acid second
Ester, saturated sodium bicarbonate and salt washing are concentrated, with ethyl acetate/n-hexane (20- after organic phase anhydrous sodium sulfate drying
80%) the isolated target compound of gradient elution is 6-(p-methylphenyl) -7,12- dihydro pyrido [3,2-b:5,4-b'] two
Indoles, yield 68%.
1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.65 (s, 1H), 8.48 (d, J = 7.8
Hz, 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 for
C24H18N3 +(M+H)+ 348.15007, found 348.15018。
Embodiment 12.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, as 6-(2- bromophenyl) -7,12- dihydro pyrido [3,
2-b:5,4-b'] two indoles synthesis, the specific steps are as follows:
The indoles amine for protecting the 2- bromophenyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, is dissolved in 2
ML methanol is stirred at room temperature reaction 5 minutes, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.Then it sets
100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL ethyl acetate, satisfies
It washes, is concentrated after organic phase anhydrous sodium sulfate drying, with ethyl acetate/n-hexane (20-80%) ladder with sodium bicarbonate and salt
It is 6-(2- bromophenyl that degree, which elutes isolated target compound) -7,12- dihydro pyrido [3,2-b:5,4-b'], two indoles, it produces
Rate 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。
Embodiment 13.
Wherein R1For aryl, R2For hydrogen atom, R3For hydrogen atom, as 6- phenethyl -7,12- dihydro pyrido [3,2-b:
5,4-b'] synthesis of two indoles, the specific steps are as follows:
The indoles amine for protecting the phenethyl aldehyde of 0.5 mmol and 0.5 mmolBoc in the microwave reaction pipe of 5 mL, is dissolved in 2
ML methanol is stirred at room temperature reaction 5 minutes, is then respectively adding 0.05mmol perchloric acid and 0.5 mmol benzyl isonitrile.Then it sets
100 in microwave reactoroC reacts 10 minutes.It is cooled to room temperature after the reaction was completed, reaction solution pours into 15 mL ethyl acetate, satisfies
It washes, is concentrated after organic phase anhydrous sodium sulfate drying, with ethyl acetate/n-hexane (20-80%) ladder with sodium bicarbonate and salt
It is two indoles of 6- phenethyl -7,12- dihydro pyrido [3,2-b:5,4-b'], yield that degree, which elutes isolated target compound,
66%。
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 = 7.4
Hz, 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, found
362.16550。
By the tumour cell HCT116 of test under Standard culture conditions, (37 DEG C and 5%CO2, the spy of 10% fetal calf serum
Determine culture medium) in culture, be furnished with 100 UI/mL penicillin and 100 mg/L streptomysin.It is thin by 2000-8000, cell
Born of the same parents/hole is seeded in 96 hole porous plates (Castar), and the Compound of Example 1-13 of various concentration is added after 12 hours.It is small to incubate 48
Shi Hou washs cell twice with PBS, and bromination 3-(4,5- dimethylthiazole -2- base is added) -2,5- diphenyltetrazoliumbromide (MTT) is dense
Degree is 0.5mg/mL.96 orifice plates are incubated for 4 hours at 37 DEG C.Finally, it is sub- that blue precipitate is dissolved in 0.2mL dimethyl
In sulfone (DMSO).On plate reader (Bio Tek CytationTM 5), and wavelength is that sample is read at 570nm.It is logical
Measurement every time is crossed using five samples, all MTT measurements repeat at least three times.
The biologically active data of 1. compound of table
Claims (6)
1. a kind of double trypoline analog derivatives, it is characterised in that: the general structure of derivative is as follows:
The wherein R1For C1-10Alkyl chain, aryl and heteroaryl, R2For hydrogen atom, halogen, methoxyl group, C1-3Alkyl, nitro,
Cyano, R3For hydrogen atom, halogen, methoxyl group, C1-3Alkyl, nitro, cyano.
2. indazole analog derivative according to claim 1, it is characterised in that: the R1For C1-10Alkyl chain, aryl and miscellaneous
Aryl.
3. indazole analog derivative according to claim 1, it is characterised in that: R2For hydrogen atom, halogen, methoxyl group, C1-3Alkane
Base, nitro, cyano.
4. indazole analog derivative according to claim 1, it is characterised in that: the R2For hydrogen atom, halogen, methoxyl group,
C1-3Alkyl, nitro, cyano.
5. double trypoline analog derivatives according to claim 1, which is characterized in that synthetic route is as follows:
。
6. double trypoline analog derivatives as described in claim 1 are applied in the preparation of antitumor drugs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811369810.9A CN109160914B (en) | 2018-11-17 | 2018-11-17 | Synthesis method of bis-indolopyridine derivative and application of bis-indolopyridine derivative in tumor resistance |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811369810.9A CN109160914B (en) | 2018-11-17 | 2018-11-17 | Synthesis method of bis-indolopyridine derivative and application of bis-indolopyridine derivative in tumor resistance |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109160914A true CN109160914A (en) | 2019-01-08 |
| CN109160914B CN109160914B (en) | 2020-06-16 |
Family
ID=64877114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811369810.9A Active CN109160914B (en) | 2018-11-17 | 2018-11-17 | Synthesis method of bis-indolopyridine derivative and application of bis-indolopyridine derivative in tumor resistance |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109160914B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114437095A (en) * | 2022-01-21 | 2022-05-06 | 上海八亿时空先进材料有限公司 | Heterocyclic compound, organic electroluminescent material and device |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389628A (en) * | 2006-02-22 | 2009-03-18 | 4Sc股份公司 | Indolopyridines as EG5 kinesin modulators |
| CN106083830A (en) * | 2016-06-01 | 2016-11-09 | 中国海洋大学 | Bisindole maleimide derivant and its production and use |
| CN108864089A (en) * | 2018-08-01 | 2018-11-23 | 河南湾流生物科技有限公司 | A kind of new indole and pyridone drug molecule and its preparation method and application |
-
2018
- 2018-11-17 CN CN201811369810.9A patent/CN109160914B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389628A (en) * | 2006-02-22 | 2009-03-18 | 4Sc股份公司 | Indolopyridines as EG5 kinesin modulators |
| CN106083830A (en) * | 2016-06-01 | 2016-11-09 | 中国海洋大学 | Bisindole maleimide derivant and its production and use |
| CN108864089A (en) * | 2018-08-01 | 2018-11-23 | 河南湾流生物科技有限公司 | A kind of new indole and pyridone drug molecule and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| MARK L. TRUDELL ET AL.: "Synthesis of Substituted 7,12-Dihydropyrido[3,2-b:5,4-b’]diindoIes: Rigid Planar Benzodiazepine Receptor Ligands with Inverse Agonist/Antagonist Properties", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114437095A (en) * | 2022-01-21 | 2022-05-06 | 上海八亿时空先进材料有限公司 | Heterocyclic compound, organic electroluminescent material and device |
| WO2023138254A1 (en) * | 2022-01-21 | 2023-07-27 | 上海八亿时空先进材料有限公司 | Heterocyclic compound, and organic electroluminescent material and element |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109160914B (en) | 2020-06-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102288281B1 (en) | FGFR4 inhibitors, methods for their preparation and pharmaceutical applications | |
| CN110563703B (en) | Compound for inducing PARP-1 degradation based on CRBN ligand, preparation method and application | |
| CN106220641B (en) | Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure | |
| CN107652308A (en) | A kind of JAK3 inhibitor | |
| Zhang et al. | Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative | |
| CN107235902A (en) | The licochalcone A pyrazoline analog derivative and its synthetic method of one class tool antitumor activity | |
| CN104072493A (en) | Naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, preparation method and application thereof | |
| CN109160914A (en) | A kind of synthetic method of double trypoline analog derivatives and the application in antitumor | |
| CN108530436B (en) | Pyrazole compound and preparation method and application thereof | |
| CN115477639B (en) | Polysubstituted pyrimidine compound with FGFR1 as target point, and preparation method and application thereof | |
| CN110804059A (en) | Carbamate compound, pharmaceutical composition and application thereof | |
| CN113045567B (en) | Phosphatase recruitment chimera (PHORCs) compound based on protein phosphatase 5, preparation method and medical application thereof | |
| CN109232703A (en) | Containing 16- (1 '-aromatic radical -1 ', 2 ', 3 '-triazoles) methylene-androstane -17- ketone derivatives | |
| CN109336890A (en) | A kind of synthetic method and antitumor application thereof of indazole analog derivative | |
| CN110054577B (en) | Compound containing urea and thiourea structure, synthetic method and application thereof | |
| CN112174958A (en) | Pyrido [2,3-d ] pyrimidine compound and preparation method and application thereof | |
| CN110041239B (en) | N- (benzoyl) -L-cysteine methyl ester derivative and preparation method and application thereof | |
| CN107353287B (en) | A kind of quinoxaline and heterocyclic fourth ketone compounds and its application in antitumor | |
| CN109879875A (en) | Isoquinoline class derivate and synthetic method and antitumor application thereof | |
| CN107857766B (en) | Synthetic method and application of spiroindole compound based on phenylalanine and polycarbonyl cyclic ketone compound | |
| CN106928224B (en) | Indoles Sophoridine derivative and preparation method thereof | |
| CN109369658B (en) | Synthesis method of spiro [ pyrrolidine-3, 3' -oxindole ] ring systems | |
| CN115322192B (en) | Pyrrolo [3,4-b ] pyridine derivative and synthetic method and application thereof | |
| CN114349760B (en) | Spiro indoline compound and preparation method and application thereof | |
| CN107973810B (en) | A kind of synthetic method and its application of the spiral Benzazole compounds based on proline analog derivative and more carbonyl class cyclic ketone compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |