阅读说明：本技术 一种1,4-萘醌衍生物、合成方法及应用 (1, 4-naphthoquinone derivative, and synthesis method and application thereof ) 是由 史大华 秦天 马燕燕 董常娥 王秀军 司鑫鑫 武文龙 冯媛媛 杨顺 苏佳镔 于 2021-09-18 设计创作，主要内容包括：本发明涉及药物合成技术领域,特别涉及一种1,4-萘醌衍生物、合成方法及应用。本发明以式VI所示化合物为起始原料合成得到了式I或式II所示的新的1,4-萘醌衍生物,该1,4-萘醌衍生物具有肿瘤抑制活性。(The invention relates to the technical field of drug synthesis, in particular to a 1, 4-naphthoquinone derivative, a synthesis method and application. The invention takes the compound shown in the formula VI as the initial raw material to synthesize the novel 1, 4-naphthoquinone derivative shown in the formula I or the formula II, and the 1, 4-naphthoquinone derivative has the tumor inhibition activity.)

1. A1, 4-naphthoquinone derivative, wherein the structure of the 1, 4-naphthoquinone derivative is shown as formula I or formula II:

in the structure shown in formula I, R₁Is selected fromOne or more of halogen, C1-C4 alkyl or nitro;

in the structure of formula II, R₂Is selected from one or more of halogen, C1-C4 alkyl or nitro.

2. The 1, 4-naphthoquinone derivative according to claim 1, wherein said R is₁Is halogen,Or nitro monosubstitution; or R₁Is halogen disubstituted or nitro and halogen disubstituted; or R₁Is nitro and halogen trisubstitution or nitro and alkyl trisubstitution of C1-C4;

the R is₂Is mono-substituted with nitro; or R₂Is halogen disubstituted or nitro and halogen disubstituted; or R₂Is nitro and halogen trisubstituent or nitro and alkyl trisubstitution of C1-C4.

3. The 1, 4-naphthoquinone derivative according to claim 2, wherein the 1, 4-naphthoquinone derivative has a structure shown as follows:

。

4. the method for synthesizing the 1, 4-naphthoquinone derivative according to any one of claims 1 to 3, wherein the method comprises the following steps:

(1) reacting the compound shown in the formula VI with HATU or EDCI/HOBT in an alkaline environment;

(2) then adding a compound shown in a formula IV or a formula V for reaction to obtain a compound shown in a formula I or a formula II;

wherein R in the compound shown in the formula VI is selected fromOne or more of halogen, C1-C4 alkyl or nitro.

5. The synthesis method according to claim 4, characterized in that the reaction is carried out in detail by:

(1) reacting the compound shown in the formula VI with HATU or EDCI/HOBT in DCM or DMF solvent at-5 ℃ in a basic environment selected from triethylamine or DIPEA;

(2) then adding a compound shown in formula IV or formula V to react at 15-30 ℃ to obtain a compound shown in formula I or formula II.

6. The synthesis method according to claim 5, wherein the reaction temperature of the step (1) is 0-5 ℃ and the reaction temperature of the step (2) is 20-28 ℃.

7. The method of claim 5, wherein the compound of formula VI, HATU or EDCI, DIPEA or triethylamine is present in a molar ratio of 1: 1.2-1.8: 1.2 to 1.8.

8. The method of claim 4, wherein the compound of formula IV or V is synthesized by the following method:

and reacting the compound shown in the formula III with p-phenylenediamine or m-phenylenediamine to obtain the compound shown in the formula IV or V.

9. Use of the 1, 4-naphthoquinone derivative according to any one of claims 1 to 3 in the preparation of an anti-tumor functional food or medicament.

10. The use according to claim 9, wherein the tumor is selected from liver cancer or pancreatic cancer.

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a 1, 4-naphthoquinone derivative, a synthesis method and application.

Background

Cancer, i.e., a malignant tumor, remains a medical problem in the world today. Any part of the human body can be possibly diseased and have a tumor, and the main harm is that the tumor invades adjacent tissues or is transferred to a far-end organ, and finally the body dies down. Cancer development is primarily characterized by uncontrolled division or apoptotic regulation of normal cells. Cancers are largely classified according to histological origin into epithelial cancers (originating from epithelial cells), sarcomas (originating from connective tissue, bone, muscle, etc.) and hematologic tumors. As the development speed of various cancers is fast, most cancer patients are found to be in an advanced stage from the current clinical practice, the treatment difficulty is high, and the treatment result is not ideal. Research has shown that the mechanism of cancer development is mainly characterized by the following features: dysregulation of cellular metabolism, uncontrolled regulation of apoptosis, genomic instability or mutation, induction of angiogenesis, activation of invasion and metastasis, promotion of inflammatory response of tumors, unlimited proliferation, immune escape, and release of contact inhibition.

Currently, the treatment of cancer is a major problem facing the global medical community. The traditional treatment methods comprise surgical excision, and chemotherapy with drugs in combination with radiotherapy, immunotherapy, etc. The traditional chemotherapy drugs are mainly cytotoxic antitumor drugs, such as various alkylating agents (cyclophosphamide and cisplatin), antimetabolites (methotrexate and fluorouracil), and antitumor antibiotics (mitomycin and adriamycin). After the nineties of the twentieth century, some new chemotherapeutics, such as noviban, taxol, and the like, appeared in succession. The chemotherapy drugs have important functions in modern tumor treatment, and most of the chemotherapy drugs are still used as a first-line drug in clinic. However, these chemotherapeutic drugs have indiscriminate inhibitory or killing effects on tumor cells and normal cells, and further have side effects such as bone marrow suppression, immune function reduction, gastrointestinal reactions, alopecia, and the like. Most patients have to use these chemotherapeutic drugs to last life, but the quality of life of the patients does not improve fundamentally because of the side effects of chemotherapy. Therefore, the search for low-toxic and highly effective antitumor drugs has become an important research topic for cancer treatment.

Disclosure of Invention

The invention aims to provide a novel 1, 4-naphthoquinone derivative, an efficient synthesis method of a novel compound and application of the novel compound in preparation of antitumor drugs.

In order to achieve the purpose, the invention specifically adopts the following technical scheme:

a1, 4-naphthoquinone derivative, wherein the structure of the 1, 4-naphthoquinone derivative is shown as a formula I or a formula II:

in the structure shown in formula I, R₁Is selected fromOne or more of halogen, C1-C4 alkyl or nitro;

in the structure of formula II, R₂Is selected from one or more of halogen, C1-C4 alkyl or nitro.

Preferably, said R is₁Is halogen,Or nitro monosubstitution; or R₁Is halogen disubstituted or nitro and halogen disubstituted; or R₁Is nitro and halogen trisubstitution or nitro and alkyl trisubstitution of C1-C4; the R is₂Is mono-substituted with nitro; or R₂Is halogen disubstituted or nitro and halogen disubstitutedGeneration; or R₂Is nitro and halogen trisubstituent or nitro and alkyl trisubstitution of C1-C4. Here "or R₁The expression "trisubstituted with nitro and halogen or with nitro and alkyl of C1 to C4" means that R is₁There are an additional three substituents on the phenyl group, the three substituents being selected from nitro and halo; or a nitro group and a C1-C4 alkyl group, such as a compound represented by formula 3 or formula 11.

Preferably, the 1, 4-naphthoquinone derivative has the following structure:

the synthesis method of the 1, 4-naphthoquinone derivative comprises the following steps:

(1) reacting the compound shown in the formula VI with HATU or EDCI/HOBT in an alkaline environment; (2) then adding a compound shown in a formula IV or a formula V for reaction to obtain a compound shown in a formula I or a formula II;

wherein R in the compound shown in the formula VI is selected fromOne or more of halogen, C1-C4 alkyl or nitro.

Preferably, the specific operation of the reaction is as follows:

(1) reacting the compound shown in the formula VI with HATU or EDCI/HOBT in DCM or DMF solvent at-5 ℃ under the alkaline condition, wherein the alkaline environment is selected from triethylamine or DIPEA;

(2) then adding a compound shown in formula IV or formula V to react at 15-30 ℃ to obtain a compound shown in formula I or formula II.

More preferably, the reaction temperature in the step (1) is 0 to 5 ℃, and the reaction temperature in the step (2) is 20 to 28 ℃.

Preferably, the compound of formula VI, HATU or EDCI, DIPEA or triethylamine is present in a molar ratio of 1: 1.2-1.8: 1.2 to 1.8.

Preferably, the compound shown in formula IV or formula V is synthesized by the following method:

and reacting the compound shown in the formula III with p-phenylenediamine or m-phenylenediamine to obtain the compound shown in the formula IV or V.

The 1, 4-naphthoquinone derivative is applied to preparing anti-tumor functional food or drugs. Preferably, the tumor is selected from liver cancer or pancreatic cancer.

Advantageous effects

The invention provides a novel 1, 4-naphthoquinone derivative.

The invention provides a novel synthesis method of 1, 4-naphthoquinone derivatives, which is simple and safe to operate, and has fewer reaction byproducts, higher yield and easier separation and purification of products when HATU is used as a condensing agent.

The 1, 4-naphthoquinone derivative has strong inhibition activity on tumor cells, the IC50 of the derivative reaches 5.545 mu M with the strongest activity, and the derivative has wide application prospect in the aspect of preparing anti-tumor drugs.

Drawings

FIGS. 1-2 shows the hydrogen and carbon spectra of the compound of example 1 of formula IV; FIGS. 3 to 4 shows the hydrogen and carbon spectra of the compound of example 2 of formula V; 5-7, hydrogen spectrogram, carbon spectrogram and mass spectrogram of the target product 1 obtained in example 3; 8-10 hydrogen, carbon and mass spectrograms of the product 2 obtained in example 4; FIGS. 11 to 12 shows the hydrogen and carbon spectra of the product 3 obtained in example 5; FIGS. 13 to 14 shows the hydrogen and carbon spectra of the product 4 obtained in example 6; FIGS. 15 to 16 shows the hydrogen and carbon spectra of the product 5 obtained in example 7; 17-18 hydrogen and carbon spectra of product 6 from example 8; FIGS. 19 to 20 shows the hydrogen and carbon spectra of the product 7 obtained in example 9; FIGS. 21 to 22 shows the hydrogen and carbon spectra of the product 8 obtained in example 10; FIGS. 23 to 24 shows the hydrogen and carbon spectra of the product 9 obtained in example 11; FIGS. 25 to 26 shows the hydrogen and carbon spectra of the product 10 obtained in example 12; FIGS. 27 to 28 shows the hydrogen and carbon spectra of the product 11 obtained in example 13; FIGS. 29 to 30 shows the hydrogen and carbon spectra of the product 12 obtained in example 14; FIGS. 31 to 32 shows the hydrogen and carbon spectra of the product 13 obtained in example 15; FIGS. 33-35 shows a hydrogen, carbon and infrared spectrum of the product 14 of example 16; FIGS. 36-37 shows the hydrogen and carbon spectra of the product 15 obtained in example 17; FIGS. 38-39 hydrogen and carbon spectra of product 16 from example 18; FIGS. 40-41 hydrogen and carbon spectra of product 17 from example 19; FIGS. 42-43 hydrogen and carbon spectra of product 18 from example 20; FIGS. 44-45 shows the hydrogen and carbon spectra of product 19 from example 21; FIGS. 46-47 hydrogen and carbon spectra of product 20 from example 22; FIGS. 48 to 49 shows a hydrogen spectrum and a carbon spectrum of the product 21 obtained in example 23; FIGS. 50-51 the hydrogen and carbon spectra of product 22 from example 24.

Detailed Description

The following will clearly and completely describe the technical solutions in the specific embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

Wherein the terms in the present specification have the following meanings:

C1-C4 alkyl: refers to an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl; HATU: 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate; DIPEA: n, N-diisopropylethylamine.

The present invention will be described in detail with reference to examples below to facilitate understanding of the present invention by those skilled in the art. The products obtained in examples 3 to 24 described below were subjected to detection of hydrogen spectrum, carbon spectrum, infrared spectrum and mass spectrum to confirm the structure.

EXAMPLE 1 preparation of 2- ((4-aminophenyl) amino) naphthalene-1, 4-dione, a Compound of formula IV

Dissolving 0.0126mol of 1, 4-naphthoquinone shown in the formula III in 20mL of absolute ethanol, adding p-phenylenediamine, and reacting for 8 hours at 25 ℃ by magnetic stirring. The mol ratio of the 1, 4-naphthoquinone to the p-phenylenediamine is 1:1. after the reaction is finished, carrying out suction filtration, and washing a filter cake by using cold ethanol to obtain a mauve solid 2- ((4-aminophenyl) amino) naphthalene-1, 4-diketone. Yield: 90%, melting point: 216 ℃ and 218 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 1-2, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₁₆H₁₂N₂O₂265.0899,found265.0969.

Example 2 preparation of the compound 2- ((3-aminophenyl) amino) naphthalene-1, 4-dione, of formula V.

0.0126mol of 1, 4-naphthoquinone shown in formula III is dissolved in 20mL of absolute ethanol, and then m-phenylenediamine is added. The mixture was reacted at 25 ℃ for 8 hours with magnetic stirring. The molar ratio of the 1, 4-naphthoquinone to the m-phenylenediamine is 1:1. after the reaction is finished, carrying out suction filtration, and washing a filter cake by using cold ethanol to obtain2- ((3-aminophenyl) amino) naphthalene-1, 4-dione as an orange-yellow solid. Yield: 92 percent. Melting point: 216 ℃ and 218 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 3-4, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₁₆H₁₂N₂O₂265.0899,found265.0971。

Example 3N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide (object product 1)

Iminic acid 0.00185mol was dissolved in 20mL of dichloromethane, then HATU was added and DIPEA was stirred for 2 hours at 5 ℃ in an ice bath. Then, 2- ((4-aminophenyl) amino) naphthalene-1, 4-dione, a compound represented by the formula IV, was added thereto and the reaction was stirred at 25 ℃ for 12 hours. And after the reaction is finished, carrying out reduced pressure distillation and column chromatography to obtain the dark purple solid N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalene-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide. Yield: 67%, melting point: 226-228 ℃. Wherein the molar ratio of 2- ((4-aminophenyl) amino) naphthalene-1, 4-dione to imaric acid, HATU and DIPEA is 1:1: 1.5: 1.5. the hydrogen spectrogram, the carbon spectrogram and the mass spectrogram of the obtained product are respectively shown in figures 5-7, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcdfor C₂₉H₂₈N₄O₃481.2161,found481.2263。

Example 42-chloro-N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4-nitrobenzamide (target product 2)

The imma acid in example 3 was changed to 2-chloro-4-nitrobenzoic acid, and the other reaction conditions were unchanged to give 2-chloro-N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4-nitrobenzamide as a red-brown solid, the desired product 2. Yield: 93%, melting point: 260 ℃ and 262 ℃. The hydrogen spectrogram, the carbon spectrogram and the mass spectrogram of the obtained product are respectively shown in figures 8-10, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄ClN₃O₅448.0622,found448.0701。

Example 5N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-methyl-3, 5-dinitrobenzamide (target product 3)

The imma acid in example 3 was changed to 2-methyl-3, 5-dinitrobenzoic acid, and the other reaction conditions were not changed to obtain N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-methyl-3, 5-dinitrobenzamide as a red solid, i.e., the objective product 3. Yield: 91%, melting point: 260 ℃ and 262 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 11-12, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₄H₁₆N₄O₇473.1019,found473.1092。

Example 6N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4, 5-difluoro-2-nitrobenzamide (target product 4)

The imate acid from example 3 was changed to 4, 5-difluoro-2-nitrobenzoic acid, and the other reaction conditions were unchanged to give N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4, 5-difluoro-2-nitrobenzamide as a tan solid. Yield: 90%, melting point: 273 and 275 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 13-14, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcdfor C₂₃H₁₃F₂N₃O₅450.0823,found450.0903。

Example 7N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-fluoro-5-nitrobenzamide (product of interest 5)

The imate in example 3 is changed to 2-fluoro-5-nitrobenzoic acid, and other reaction conditions are not changed, so that a dark red solid, namely the target product 5, is obtained. Yield: 85%, melting point: 260 ℃ and 262 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 15-16, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcdfor C₂₃H₁₄FN₃O₅432.0917,found432.0989。

Example 82-chloro-N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4-fluorobenzamide (object product 6)

The imate in example 3 was changed to 2-chloro-4-fluorobenzoic acid, and the other reaction conditions were not changed to obtain a crimson solid, which was the target product 6. Yield of: 81%, melting point: 250 ℃ and 252 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 17-18, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄ClFN₂O₃421.0677,found421.0755。

Example 92, 5-dibromo-N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) benzamide (target product 7)

The imate in example 3 was changed to 2, 5-dibromobenzoic acid and the other reaction conditions were unchanged to give a reddish-brown solid. Yield: 74%, melting point: 267-. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 19-20, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄Br₂N₂O₃524.9371,found 524.9456。

Example 10N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -3-fluoro-4-nitrobenzamide (product of interest 8)

The imate in example 3 was changed to 3-fluoro-4-nitrobenzoic acid, and the other reaction conditions were unchanged to give N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -3-fluoro-4-nitrobenzamide as a dark purple solid. Yield: 92%, melting point: 270 ℃ and 272 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 21-22, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄FN₃O₅432.0917,found432.0995。

Example 11N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-fluoro-4-nitrobenzamide (product of interest 9)

The imate in example 3 was changed to 2-fluoro-4-nitrobenzoic acid, and the other reaction conditions were unchanged to give N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-fluoro-4-nitrobenzamide as a dark purple solid. Yield: 82%, melting point: 275 ℃ and 277 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 23-24, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄FN₃O₅432.0917,found432.0988。

Example 12N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -3-nitrobenzamide (product of interest 10)

The imate in example 3 was changed to m-nitrobenzoic acid, and the other reaction conditions were unchanged to give a dark red solid. Yield: 88%, melting point: 275 ℃ and 277 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 25-26, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₅N₃O₅414.1012,found414.1082。

Example 134-chloro-N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -3, 5-dinitrobenzamide (object product 11)

The imate from example 3 was changed to 3, 5-dinitro-4-chlorobenzoic acid and the other reaction conditions were unchanged to give 4-chloro-N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -3, 5-dinitrobenzamide as a dark red solid. Yield: 90%, melting point: 280 ℃ and 282 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 27-28, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcdfor C₂₃H₁₃ClN₄O₇493.0473,found 493.0550。

Example 14N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2, 4-difluorobenzamide (object product 12)

The imate in example 3 was changed to 2, 4-difluorobenzoic acid and the other reaction conditions were unchanged to give N- (4- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2, 4-difluorobenzamide as a red-brown solid. Yield: 85%, melting point: 250 ℃ and 252 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 29-30, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄F₂N₂O₃405.0972,found405.1050。

Example 154-chloro-N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) benzamide (target product 13)

The imma acid in the example 3 is changed into p-chlorobenzoic acid, other reaction conditions are not changed,the brownish red solid 4-chloro-N- (4- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) benzamide is obtained. Yield: 88%, melting point: 275 ℃ and 277 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 31-32, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₅ClN₂O₃403.0771,found403.0840。

Example 16N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -3-fluoro-4-nitrobenzamide (product of interest 14)

0.00185mol of 3-fluoro-4-nitrobenzoic acid was dissolved in 20mL of dichloromethane, then HATU was added and DIPEA was stirred for 2 hours at 5 ℃ in an ice bath. Then 2- ((3-aminophenyl) amino) naphthalene-1, 4-dione was added thereto and the reaction was stirred at 25 ℃ for 12 hours. After the reaction is finished, carrying out reduced pressure distillation and column chromatography to obtain the deep red solid N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalene-2-yl) amino) phenyl) -3-fluoro-4-nitrobenzamide. Yield: 79%, melting point: 260 ℃ and 262 ℃. Wherein the molar ratio of 2- ((3-aminophenyl) amino) naphthalene-1, 4-dione to 3-fluoro-4-nitrobenzoic acid, HATU, DIPEA is 1:1: 1.5: 1.5. the hydrogen spectrogram, the carbon spectrogram and the infrared spectrogram of the obtained product are respectively shown in figures 33-35, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄FN₃O₅432.0917,found432.0993。

Example 17N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-fluoro-4-nitrobenzamide (product of interest 15)

The 3-fluoro-4-nitrobenzoic acid from example 16 was replaced with 2-fluoro-4-nitrobenzoic acid, and the other reaction conditions were unchanged to give N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-fluoro-4-nitrobenzamide as a reddish-brown solid. Yield: 85%, melting point: 258 ℃ and 260 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 36-37, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄FN₃O₅432.0917,found 432.0994。

Example 18N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-fluoro-5-nitrobenzamide (product of interest 16)

The 3-fluoro-4-nitrobenzoic acid from example 16 was replaced with 2-fluoro-5-nitrobenzoic acid, and the other reaction conditions were unchanged to give a violet-black solid. Yield: 84%, melting point: 186 ℃ and 188 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 38-39, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄FN₃O₅432.0917,found432.0993。

Example 19N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4, 5-difluoro-2-nitrobenzamide (product of interest 17)

The 3-fluoro-4-nitrobenzoic acid from example 16 was replaced with 4, 5-difluoro-2-nitrobenzoic acid, and the other reaction conditions were unchanged to give N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4, 5-difluoro-2-nitrobenzamide as a dark red solid. Yield: 86%, melting point: 149 ℃ and 151 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 40-41, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₃F₂N₃O₅450.0823,found 450.0916。

Example 202, 5-dibromo-N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) benzamide (object product 18)

The 3-fluoro-4-nitrobenzoic acid from example 16 was replaced with 2, 5-dibromobenzoic acid and the other reaction conditions were unchanged to give 2, 5-dibromo-N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) benzamide as a reddish-brown solid. Yield: 74%, melting point: 140 ℃ and 142 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 42-43, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄Br₂N₂O₃524.9371,found 524.9452。

Example 212-chloro-N- (3- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4-nitrobenzamide (target product 19)

The 3-fluoro-4-nitrobenzoic acid from example 16 was replaced by 2-chloro-4-nitrobenzoic acid, and the other reaction conditions were unchanged, giving a reddish-brown solid2-chloro-N- (3- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4-nitrobenzamide. Yield: 93%, melting point: 218-22 ℃ below zero. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 44-45, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₄ClN₃O₅448.0622,found 448.0693。

Example 22N- (3- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -3-nitrobenzamide (title product 20)

The 3-fluoro-4-nitrobenzoic acid from example 16 was exchanged for m-nitrobenzoic acid, and the other reaction conditions were unchanged to give N- (3- ((1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -3-nitrobenzamide as a dark red solid. Yield: 90%, melting point: 225 ℃ and 227 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in figures 46-47, and the related detection data are as follows: HRMS (ESI, M/z) [ M + H ]]⁺calcd for C₂₃H₁₅N₃O₅414.1012,found414.1091。

Example 23N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -4-nitrobenzamide (product 21)

The 3-fluoro-4-nitrobenzoic acid from example 16 was replaced by p-nitrobenzoic acid, and the other reaction conditions were unchanged to give a colored solid. Yield: 67%, melting point: 215 ℃ and 217 ℃. The obtained product has hydrogen spectrogram and carbon spectrogram shown in FIGS. 48-49, respectively, and related detection data as follows HRMS (ESI, M/z): [ M + H ]]+calcd for C₂₃H₁₅N₃O₅414.1012,found414.1088。

Example 24N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-methyl-3, 5-dinitrobenzamide (object product 22)

The 3-fluoro-4-nitrobenzoic acid from example 16 was exchanged for 2-methyl-3, 5-dinitrobenzoic acid, and the other reaction conditions were unchanged to give N- (3- ((1, 4-dioxy-1, 4-dihydronaphthalen-2-yl) amino) phenyl) -2-methyl-3, 5-dinitrobenzamide as an orange solid. Yield: 85%, melting point: 285 ℃ 287 ℃. The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in the figures 50-51, and the related detection data are as follows: HRMS (ESI, m/z)):[M+H]+calcd for C₂₄H₁₆N₄O₇473.1019,found 473.1097。

EXAMPLE 25 inhibitory Activity of the aforementioned 22 1, 4-naphthoquinone derivatives against human hepatoma cell Bel-7402 and human pancreatic cancer cell SW 1990.

The invention tests the tumor inhibition activity of 22 1, 4-naphthoquinone derivatives. After counting the activation of Bel-7402 human hepatoma cells/SW 1990 human pancreatic cancer cells, they were plated in 96-well plates at 2000/well. The test was divided into three groups, blank control group, experimental group (1. mu.g/mL) and cis-platinum positive control group (4. mu.g/mL), each group having 5 duplicate wells. After the cells are plated and grown overnight, the benzoic acid-containing phenylenediamine 1, 4-naphthoquinone derivative DMSO solution is added, after 48 hours, CCK-8 is added for incubation for 2 hours, and the absorbance value at 450nmol is measured. The cytotoxic activity of the 1, 4-naphthoquinone derivative of the present invention against in vitro cells was measured by the CCK-8 method (colorimetric method) against human hepatoma cells 7402/human pancreatic cancer cells SW 1990. Cell survival after compound treatment was determined using Cell Counting Kit-8. Cells were seeded in 96-well plates at a density of 5X 103 cells/well in 5% CO₂Incubators were incubated at 37 ℃ for 24 hours and replaced with solvent (DMSO) and the desired concentration of compound for 48 h. Then, 10ul of CCK-8 solution was added to each well at 37 ℃ with 5% CO₂Incubate for 2h in an incubator. Finally, absorbance at 450nm was measured using a microplate reader. Calculation of cell viability, IC₅₀Values were calculated from IBM SPSS Statistics 23, taking the average of three independent experiments. The optical density of the wells without the compound is taken as 100%, and the optical density of the measured wells with the compound is compared with the optical density, and the reduction percentage is the tumor cell inhibition rate. Measuring the inhibitory activity of at least 5 concentration gradients per compound on acetylcholinesterase, and plotting the logarithm of compound concentration against the inhibition rate to obtain IC₅₀Value (concentration of compound that inhibits 50% of tumor cell activity). The series of compounds have strong tumor inhibiting activity, and can inhibit highest IC of human liver cancer cell₅₀The value was 8.642. + -. 3.097. mu.M.

In the above table, the detection result without contents, which is drawn by the horizontal line, indicates that no corresponding experiment is performed, and thus no result is obtained. The inhibition ratio in the above table is the inhibitory activity of the compound at a 1, 4-naphthoquinone derivative concentration of 50. mu.M.

Example 26 the compound of formula VI was dissolved in 20ml DMF and then EDCI, HOBT, triethylamine were added and stirred for 2 hours at 5 ℃ in an ice bath. Then, the compound represented by formula IV or formula V is added and the reaction is stirred at 25 ℃ for 12 hours. After the reaction, the reaction solution was extracted in an ethyl acetate-distilled water system to remove DMF. And finally, carrying out reduced pressure distillation and column chromatography on the organic phase to obtain a corresponding product. The molar ratio of the compound shown in the formula VI, the compound shown in the formula IV or the formula V, triethylamine, EDCI and HOBT is 1:1:1.2:1.2: 1.2.

The target products 1 to 5 are synthesized again by adopting the method, and the yield of the finally obtained products is lower than 30 percent and is about 20 to 30 percent. And the solvent DMF was very difficult to remove.

Example 27 substitution of the R substituent for ethyl in the compound of formula VI; or tert-butyl substitution; or methyl substitution, the reaction conditions were otherwise the same as in example 3, and the reaction yields were 23%, 21%, and 25%.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.