CN110964018B - Indole derivative and application thereof - Google Patents

Indole derivative and application thereof Download PDF

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CN110964018B
CN110964018B CN201911217790.8A CN201911217790A CN110964018B CN 110964018 B CN110964018 B CN 110964018B CN 201911217790 A CN201911217790 A CN 201911217790A CN 110964018 B CN110964018 B CN 110964018B
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indole
triazino
hydrazino
ylidene
dihydro
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CN110964018A (en
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马俊杰
倪欣
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Huaqiao University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention discloses an indole derivative which is a derivative containing an indole structure with a novel structure, and the in vitro antitumor activity of the derivative is tested to discover that the compound has a remarkable antitumor effect and can be applied to the preparation of medicines for treating or preventing cancer diseases and other proliferative diseases, so that the treatment or prevention of the cancer diseases and other proliferative diseases is realized, and therefore, the indole derivative has an excellent application prospect in the aspect of developing antitumor drugs.

Description

Indole derivative and application thereof
Technical Field
The invention relates to the technical field of medicine preparation, in particular to indole derivatives, including geometric isomers or pharmaceutically acceptable salts thereof, and application thereof in preparing medicines for treating and/or preventing various cancer diseases.
Background
Tumor is a disease seriously threatening human life and health, and in recent years, the incidence and death rate of tumor have a trend to rise year by year. Cytotoxic drugs can kill tumor cells, but do not kill cancer cells in the dormant stage, which results in extremely high recurrence rate of tumors, so that finding a tumor drug capable of eliminating dormant cells responsible for tumor recurrence is a crucial issue for tumor treatment.
The tumor blood vessel can provide nutrition for tumor tissues, transport metabolites away, contribute to invasion, metastasis and malignant process of tumors, because the over-expression of the angiogenesis promoting factor causes the tumor blood vessel to be abnormal, the tumor blood vessel abnormality can promote the generation of a tissue microenvironment which lacks oxygen and nutrient substances, the microenvironment can effectively protect cells with slow growth and metabolic stress, while cells growing in tissue microenvironments lacking nutrients grow at a much slower rate than cells growing in normal vascularization, even in a quiescent state (dormant tumor cells), and exhibit altered phenotypic characteristics, the phenotypic change of these cells enables them to survive chemotherapy more aggressively and to divide new tumor cells, resulting in tumor recurrence.
Patent WO 2014/046589 discloses a series of indole derivatives, which not only can selectively act on tumor resting cells, but also can induce autophagy of tumor cells. Meanwhile, the growth of malignant proliferated tumor cells can be inhibited, and the metastasis and the diffusion of abnormal cells can be prevented. Among them, VLX-600 is most active.
Studies have shown (DOI:10.1038/ncomms 4295): VLX-600 can induce mitochondrial inactivation in a metabolism-damaged tumor microenvironment to play an anti-tumor role, and can effectively prevent the growth of dormant cells in solid tumors and induce autophagy of the dormant cells. Meanwhile, when the compound is combined with irinotecan, the compound has good anti-solid tumor effect and is in the phase I clinical research stage at present.
Figure BDA0002299964970000021
The inventor designs and synthesizes a series of brand new indole compounds on the basis of reference to a VLX-600 structure and literature reports thereof. In vitro activity screening shows that the compounds have obvious antitumor activity.
Disclosure of Invention
The invention aims to provide indole derivatives which have obvious anti-tumor effect and can be applied to the preparation of medicaments for treating or preventing cancer diseases and other proliferative diseases.
The invention also aims to provide application of the indole derivatives in preparing medicines for treating and/or preventing various cancer diseases.
In order to achieve the above purpose, the solution of the invention is:
an indole derivative, the structural general formula of which is shown as I,
Figure BDA0002299964970000022
wherein X is N or CH, Y is N or CH, N is 0-4 and is an integer, R is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, ester group, sulfonyl, sulfinyl, amido, carbamoyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio and C1-C6 alkyl acyl; .
R1Is a substituent selected from hydrogen, C1-C6 alkyl, unsubstituted or differently substituted benzyl;
R2is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, ester group, sulfonyl, sulfenyl, amido, carbamoyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio and C1-C6 alkylacyl.
Preferably, X and Y are both N, N is 1-2, R is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkylamino; r1Is hydrogen, R2Is hydrogen.
Preferably, the indole derivatives are selected from the following compounds:
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazido [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-methyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-methyl-5H- [1,2,4] triazido [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole.
The indole derivatives include geometric isomers thereof or pharmaceutically acceptable salts thereof, which may be any salt suitable for stabilizing the stable free base of formula i, i.e. acidic salts, such as hydrochloride, nitrate, methanesulfonate, maleate, sulfate and the like, and which may be mono (mono) or di (di) salts, preferably, which may be mono or di, most preferably, which is dihydrochloride.
The indole derivatives can be used for preparing medicines for treating and/or preventing various cancer diseases.
After the technical scheme is adopted, the indole derivatives are widely researched, the methyl group on the VLX-600 original hydrazone structure and the 3-position of a pyridine ring are subjected to ring closing by adopting a ring closing principle, different substituents are introduced on the indole ring at the same time, a series of novel indole structure-containing derivatives are designed and synthesized, and the compounds are found to have remarkable anti-tumor effect by testing the in vitro anti-tumor activity of the derivatives, can be applied to the preparation of medicines for treating or preventing cancer diseases and other proliferative diseases, so that the treatment or prevention of the cancer diseases and other proliferative diseases is realized, and therefore, the indole derivatives have excellent application prospects in the aspect of developing anti-tumor medicines.
Detailed Description
In order to further explain the technical solution of the present invention, the present invention is explained in detail by the following specific examples.
An indole derivative, the structural general formula of which is shown as I,
Figure BDA0002299964970000061
wherein X is N or CH, Y is N or CH, N is 0-4 and is an integer, R is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, ester group, sulfonyl, sulfinyl, amido, carbamoyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio and C1-C6 alkyl acyl; .
R1Is a substituent selected from hydrogen, C1-C6 alkyl, unsubstituted or differently substituted benzyl;
R2is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, ester group, sulfonyl, sulfenyl, amido, carbamoyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio and C1-C6 alkylacyl.
Preferably, X and Y are both N, N is 1-2, R is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkylamino; r1Is hydrogen, R2Is hydrogen.
Preferably, the indole derivatives are selected from the following compounds:
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazido [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-methyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-methyl-5H- [1,2,4] triazido [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-chloro-5H- [1,2,4] triazino [5,6-b ] indole
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole.
Furthermore, the invention also relates to application of the indole derivative in preparing medicaments for treating and/or preventing various cancer diseases.
The present invention will be further described with reference to the following examples.
Synthetic route of indole derivatives
When X and Y are both N, R1And R2All are hydrogen, and the synthetic route is as follows:
Figure BDA0002299964970000091
wherein n is 1 or 2, R is H on the indole ring or one of methyl, fluorine, chlorine, bromine, methoxy and dimethyl substituted on different positions on the indole ring.
Synthesis of di-and indole derivatives
The starting reagents used in the examples were commercially available analytical or chemical grade chemicals, and the NMR spectra of the synthesized compounds were determined using Bruker ARX-400 and the mass spectra were determined using Agilent 1100 LC/MSD.
The structural formulas of the indole derivatives synthesized in examples 1 to 24 are shown in table 1.
TABLE 1 chemical name and structural formula of indole derivatives synthesized in each example
Figure BDA0002299964970000092
Figure BDA0002299964970000101
Figure BDA0002299964970000111
Figure BDA0002299964970000121
Example 1
Step A, preparation of 6-methyl-5H- [1,2,4] triazino [5,6-b ] indole-3-thiol (1 a):
32.2g of 7-methyl-2, 3-indoledione (0.20mol), 20.0g of thiosemicarbazide (0.22mol) and 41.4g of K are added at room temperature2CO3(0.3mol) and 300mL of water are stirred at room temperature for 2h, then the temperature is raised to 100 ℃, the reflux reaction is carried out for 5h, after the reaction is finished, the reaction liquid is cooled to room temperature, the suction filtration is carried out, the pH of the filtrate is adjusted to acidity by acetic acid, a large amount of solid is separated out, the suction filtration, the water washing and the drying are carried out, 43.5g of orange yellow solid is obtained, and the crude product is recrystallized by ethanol, thus obtaining 31.0g of off-white solid product. MS (ESI) M/z (%): 215.1[ M-H]-。
Step B, preparation of 3-hydrazino-6-methyl-5H- [1,2,4] triazino [5,6-B ] indole (2 a):
adding 30.0g of the 6-methyl-5H- [1,2,4] prepared in the step A at room temperature]Triazino [5,6-b]Indole-3-thiol (1a) (0.14mol), adding 150mL 80% hydrazine hydrate, stirring, carrying out oil bath reaction at 120 ℃ for 3h, cooling the reaction solution to room temperature after the reaction is finished, pouring into 500 mL of water, stirring for 10min, precipitating a large amount of solid, carrying out suction filtration, washing a filter cake with water, carrying out rinsing with ethanol, drying to obtain 28.0g of a crude product which is a grey brown solid, and recrystallizing the crude product with ethanol to obtain 27.5g of a yellow white powder product. MS (ESI) M/z (%): 215.0[ M + H]+。
Step C preparation of (E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazino [5,6-b ] indole:
and (3) at room temperature, adding 0.1g of 3-hydrazino-6-methyl-5H- [1,2,4] triazeno [5,6-B ] indole (2a) (0.4mmol) prepared in the step B and 0.07g of 5, 6-dihydro-7H-cyclopenta [ B ] pyridin-7-one (0.44mmol) into absolute ethyl alcohol, adding a drop of glacial acetic acid, carrying out reflux reaction, completing TLC detection reaction, cooling, carrying out suction filtration, washing a filter cake with diethyl ether to obtain a yellow solid, thus obtaining the indole derivatives shown in the structural formula in the table 1, wherein the mass spectrum and the hydrogen spectrum data are shown in the table 2.
Example 2
Referring to the preparation method of example 1, except that 3-hydrazinyl-6-methyl-5H- [1,2,4] triazino [5,6-b ] indole (2a) and 6, 7-dihydro-5H-quinolin-8-one are used as raw materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared, and the mass spectrum and hydrogen spectrum data are shown in Table 2.
Example 3
Referring to step A of example 1, starting from 7-fluoro-2, 3-indoledione, 6-fluoro-5H- [1,2,4] was prepared]Triazino [5,6-b]Indole-3-thiol (1b), MS (ESI) M/z (%). 219.1[ M-H]-。
With reference to step B of example 1, with 6-fluoro-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1b) is used as a raw material to prepare 3-hydrazino-6-fluoro-5H- [1,2,4]Triazino [5,6-b]Indole (2b), MS (ESI) M/z (%): 219.2[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole (2b) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared, and the mass and hydrogen spectra data are shown in Table 2.
Example 4
Referring to the preparation of example 3, except that 3-hydrazino-6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole (2b) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 5
Referring to step A of example 1, starting from 7-chloro-2, 3-indoledione, 6-chloro-5H- [1,2,4] was prepared]Triazino [5,6-b]Indole-3-thiol (1c), MS (ESI) M/z (%): 235.0 [ M-H]-。
With reference to step B of example 1, with 6-chloro-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1c) is used as a raw material to prepare 3-hydrazino-6-chloro-5H- [1,2,4]Triazino [5,6-b]Indole (2c), MS (ESI) m/z (％):235.6[M+H]+。
Referring to step C of example 1, starting from 3-hydrazino-6-chloro-5H- [1,2,4] triazino [5,6-b ] indole (2C) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 6
Referring to the preparation of example 5, except that 3-hydrazino-6-chloro-5H- [1,2,4] triazino [5,6-b ] indole (2C) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 7
Referring to step A of example 1, starting from 7-bromo-2, 3-indoledione, 6-bromo-5H- [1,2,4] was prepared]Triazino [5,6-b]Indole-3-thiol (1d), MS (ESI) M/z (%): 279.0[ M-H]-。
With reference to step B of example 1, with 6-bromo-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1d) is used as a raw material to prepare 3-hydrazino-6-bromine-5H- [1,2,4]Triazino [5,6-b]Indole (2d), MS (ESI) M/z (%): 280.0[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-6-bromo-5H- [1,2,4] triazino [5,6-b ] indole (2d) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared, and the mass and hydrogen spectra data are shown in Table 2.
Example 8
Referring to the preparation of example 7, except that 3-hydrazino-6-bromo-5H- [1,2,4] triazino [5,6-b ] indole (2d) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 9
Referring to step A of example 1, 7-methoxy-2, 3-indoledione was used as a starting material to prepare 6-methoxy-5H- [1,2, 4%]Triazino [5,6-b]Indole-3-thiol (1e), MS (ESI) M/z (%): 231.1[ M-H]-。
With reference to step B of example 1, with 6-methoxy-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1e) is used as a raw material to prepare 3-hydrazino-6-methoxyl-5H- [1,2,4]Triazino [5,6-b]Indole (2e), MS (ESI) M/z (%): 231.1[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole (2e) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 10
Referring to the preparation of example 9, except that 3-hydrazino-6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole (2e) and 6, 7-dihydro-5H-quinolin-8-one were used as raw materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared, and the mass and hydrogen spectra data are shown in Table 2.
Example 11
With reference to step A of example 1,2, 3-indoledione was used as a starting material to prepare 5H- [1,2,4]]Triazino [5,6-b]Indole-3-thiol (1f), MS (ESI) M/z (%): 201.1[ M-H]-。
With reference to step B of example 1, with 5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1f) is used as raw material to prepare 3-hydrazino-5H- [1,2,4]Triazino [5,6-b]Indole (2f), MS (ESI) M/z (%): 201.2[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-5H- [1,2,4] triazino [5,6-b ] indole (2f) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared, the mass and hydrogen spectra data of which are shown in Table 2.
Example 12
Referring to the preparation method of example 11, except that 3-hydrazino-5H- [1,2,4] triazino [5,6-b ] indole (2f) and 6, 7-dihydro-5H-quinolin-8-one are used as raw materials in step C, indole derivatives having the structural formula shown in Table 1 are prepared, and the mass spectrum and hydrogen spectrum data are shown in Table 2.
Example 13
Reference is made to step A in example 1, at 5Preparing 8-methyl-5H- [1,2,4] by using (E) -methyl-2, 3-indole dione as raw material]Triazino [5,6-b]Indole-3-thiol (1g), MS (ESI) M/z (%): 215.1[ M-H]-。
With reference to step B of example 1, with 8-methyl-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1g) is used as raw material to prepare 3-hydrazino-8-methyl-5H- [1,2,4]Triazino [5,6-b]Indole (2g), MS (ESI) M/z (%): 219.2[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-8-methyl-5H- [1,2,4] triazino [5,6-b ] indole (2g) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 14
Referring to the preparation of example 13, except that 3-hydrazino-8-methyl-5H- [1,2,4] triazino [5,6-b ] indole (2g) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 15
Referring to step A of example 1, 5-fluoro-2, 3-indoledione was used as a starting material to prepare 8-fluoro-5H- [1,2, 4%]Triazino [5,6-b]Indole-3-thiol (1H), MS (ESI) M/z (%): 219.1[ M-H]-。
With reference to step B of example 1, with 8-fluoro-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1H) is used as a raw material to prepare 3-hydrazino-8-fluoro-5H- [1,2,4]Triazino [5,6-b]Indole (2H), MS (ESI) M/z (%): 219.1[ M + H]+。
Referring to step C of example 1, starting with 3-hydrazino-8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole (2H) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared with mass and hydrogen spectra data as shown in Table 2.
Example 16
Referring to the preparation of example 15, except that 3-hydrazino-8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole (2H) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 17
Referring to step A of example 1, 5-chloro-2, 3-indoledione was used as a starting material to prepare 8-chloro-5H- [1,2, 4%]Triazino [5,6-b]Indole-3-thiol (1i), MS (ESI) M/z (%): 235.0 [ M-H]-。
With reference to step B of example 1, with 8-chloro-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1i) is used as a raw material to prepare 3-hydrazino-8-chloro-5H- [1,2,4]Triazino [5,6-b]Indole (2i), MS (ESI) M/z (%): 235.6[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-8-chloro-5H- [1,2,4] triazino [5,6-b ] indole (2i) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 18
Referring to the preparation of example 17, except that 3-hydrazino-8-chloro-5H- [1,2,4] triazino [5,6-b ] indole (2i) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 19
Referring to step A of example 1, starting from 5-bromo-2, 3-indoledione, 8-bromo-5H- [1,2,4] was prepared]Triazino [5,6-b]Indole-3-thiol (1j), MS (ESI) M/z (%): 279.5[ M-H]-。
With reference to step B of example 1, with 8-bromo-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1j) is used as a raw material to prepare 3-hydrazino-8-bromine-5H- [1,2,4]Triazino [5,6-b]Indole (2j), MS (ESI) M/z (%): 280.1[ M + H)]+。
Referring to step C of example 1, starting from 3-hydrazino-8-bromo-5H- [1,2,4] triazino [5,6-b ] indole (2j) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared and the mass spectral data are shown in Table 2.
Example 20
Referring to the preparation of example 19, except that 3-hydrazino-8-bromo-5H- [1,2,4] triazino [5,6-b ] indole (2j) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 21
Referring to step A of example 1, 5-methoxy-2, 3-indoledione was used as a starting material to prepare 8-methoxy-5H- [1,2, 4%]Triazino [5,6-b]Indole-3-thiol (1k), MS (ESI) M/z (%): 231.1[ M-H]-。
With reference to step B of example 1, with 8-methoxy-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1k) is used as a raw material to prepare 3-hydrazino-8-methoxyl-5H- [1,2,4]Triazino [5,6-b]Indole (2k), MS (ESI) M/z (%): 231.1[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole (2k) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 22
Referring to the preparation of example 21, except that 3-hydrazino-8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole (2k) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 23
Referring to step A of example 1, 5, 7-dimethyl-2, 3-indoledione was used as a starting material to prepare 6, 8-dimethyl-5H- [1,2,4]]Triazino [5,6-b]Indole-3-thiol (1l), MS (ESI) M/z (%): 229.2[ M-H]-。
With reference to step B of example 1, the reaction mixture was washed with 6, 8-dimethyl-5H- [1,2,4]]Triazino [5,6-b]Indole-3-thiol (1l) is used as raw material to prepare 3-hydrazino-6, 8-dimethyl-5H- [1,2,4]]Triazino [5,6-b]Indole (2l), MS (ESI) M/z (%): 229.2[ M + H)]+。
Referring to step C of example 1, starting from 3-hydrazino-6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole (2l) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 24
Referring to the preparation of example 23, except that 3-hydrazino-6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole (2l) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 25
Preparation of indole derivative hydrochloride ethanol cocrystal:
at room temperature, 100mg of the indole derivative (0.29 mmol) prepared in example 23 was added to 3mL of absolute ethanol, 1.45mmol of ethanol hydrochloride solution was added dropwise, after the addition, stirring was continued at room temperature for 5 hours, and suction filtration was carried out to give 112mg of a pale yellow solid. The hydrogen spectrum data are shown in table 2, confirming that the product is the hydrochloride ethanol co-crystal form.
TABLE 2 Mass and Hydrogen spectra of indole derivatives synthesized in the examples
Figure BDA0002299964970000211
Figure BDA0002299964970000221
Figure BDA0002299964970000231
Figure BDA0002299964970000241
In-vitro anti-tumor activity of indole derivatives
The indole derivatives prepared in examples 1-24 were subjected to in vitro activity tests for inhibiting human non-small cell lung cancer A549, human breast cancer cell MCF-7, human cervical cancer cell Hela and human hepatoma cell HepG-2, and the marketed drugs Sorafenib and VLX-600 were positive control drugs.
The experimental steps are as follows:
(1) plate paving: a549 cells, MCF-7 cells, Hela cells and HepG-2 cells in logarithmic growth phase and good state are taken and inoculated into a 96-well plate by 1.0 x 104 cells/well, wherein the culture medium of the A549 cells, the culture medium of the Hela cells and the culture medium of the HepG-2 cells are RPMI1640, the culture medium of the MCF-7 cells is DMEM, and subsequent experiments are carried out after 24h of culture;
(2) preparing the medicine: taking out each DMSO dissolved compound (including the compound in example 1-24, sorafenib and VLX-600), performing ultrasonic treatment for 20min before use to ensure that the compound is completely dissolved, and respectively diluting the compound with culture medium to 7 concentrations of 0.25. mu.M, 0.5. mu.M, 0.75. mu.M, 1. mu.M, 2. mu.M, 5. mu.M and 10. mu.M;
(3) adding medicine: discarding the culture medium in a 96-well cell plate, adding the culture medium containing the compound, setting a blank control (the concentration of the compound is 0 mu M), setting 3 multiple wells in each group, culturing for 48h in a constant-temperature incubator, wherein each well is 100 microliters;
(4) adding CCK-8 reagent: adding 8 mul of CCK-8 reagent into each hole under the condition of keeping out of the sun, placing the hole in a constant temperature incubator for culture, and observing the color of the liquid in real time;
(5) and (3) testing: after the reaction is sufficient, placing the 96-well plate in an enzyme-labeling instrument to detect the absorbance (A) value of each well under the wavelength of 450nm, and setting the reference wavelength to be 650 nm;
(6) data processing, calculating the median inhibitory concentration, i.e. IC50The value is obtained.
The results are shown in table 3, and it is clear from the results shown in table 3 that the compound of formula i prepared by the present invention generally has significant anti-tumor activity. The compounds of example 1, example 3, example 5, example 7, example 13, example 15, example 17, example 19 and example 23 show outstanding antitumor activity, IC against one or more tumor cells50A value of less than 10. mu. mol, comparable or superior to the antitumor activity of the control drugs sorafenib and VLX-600, wherein the activity of the compounds of examples 5 and 23 is optimal forIC of multiple tumor cell lines50The value is less than 1. mu. mol. Therefore, the compound claimed by the invention has good application prospect in preparing medicines for treating and/or preventing various cancer diseases.
TABLE 3 antitumor Activity of the Compounds in vitro
Figure BDA0002299964970000261
Note: "-" indicates that the activity of the compound was not tested.
The above embodiments are not intended to limit the form and style of the present invention, and any suitable changes or modifications made by those skilled in the art should be considered as not departing from the scope of the present invention.

Claims (2)

1. An indole derivative or a pharmaceutically acceptable salt thereof, wherein: the structural general formula of the indole derivatives is shown as I,
Figure DEST_PATH_IMAGE002
wherein X and Y are both N, N is 1-2, R is hydrogen, halogen, alkyl of C1-C6 or substituent of alkoxy of C1-C6; r1Is hydrogen, R2Is hydrogen.
2. The use of an indole derivative according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of a cancer disease.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104662022A (en) * 2012-09-21 2015-05-27 威沃路克斯股份公司 Means and method for treating solid tumours
CN109651357A (en) * 2017-10-11 2019-04-19 中国科学院上海有机化学研究所 6,7- dihydro -5H- quinoline -8- hydrazone analog derivative iron chelating agents and its purposes for preparing anti-tumor drug

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104662022A (en) * 2012-09-21 2015-05-27 威沃路克斯股份公司 Means and method for treating solid tumours
CN109651357A (en) * 2017-10-11 2019-04-19 中国科学院上海有机化学研究所 6,7- dihydro -5H- quinoline -8- hydrazone analog derivative iron chelating agents and its purposes for preparing anti-tumor drug

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Design, Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives Bearing Semicarbazone Moiety as Antitumor Agents;MA Junjie,et al.,;《Chem. Res. Chin. Univ.》;20151231;第36卷(第6期);第958-963页 *
Design, synthesis, biological evaluation and preliminary mechanism study of novel benzothiazole derivatives bearing indole-based moiety as potent antitumor agents;Junjie Ma,et al.,;《European Journal of Medicinal Chemistry》;20150408;第96卷;第173-186页 *

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