CN115557890A - Polysubstituted acridone alkyl derivative and preparation method and application thereof - Google Patents
Polysubstituted acridone alkyl derivative and preparation method and application thereof Download PDFInfo
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- CN115557890A CN115557890A CN202211061140.0A CN202211061140A CN115557890A CN 115557890 A CN115557890 A CN 115557890A CN 202211061140 A CN202211061140 A CN 202211061140A CN 115557890 A CN115557890 A CN 115557890A
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- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D219/06—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention discloses a polysubstituted acridone alkyl derivative, a preparation method and application thereof, which are characterized in that the compound is a compound with a structural formula of I, II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein R is 1 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or a linear alkyl group having 2 to 5 carbon atoms, R 2 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or a linear alkyl group having 2 to 5 carbon atoms, R 4 Is NH 2 、NHCH 3 、NHCH 2 CH 3 、OH、COOH、SH，R 5 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 M =0,1 or 2,n =0,1,2,3,4,5,6 or 7, etc., and has the advantage that the compound is effective in selectively inhibiting HDAC isoforms and/or eukaryotic tumor cell proliferation, preventing and/or treating tumors.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a polysubstituted acridone alkyl derivative, and a preparation method and application thereof.
Background
Cancer is the 2 nd leading cause of death worldwide, and the number of deaths and cases increases year by year. The treatment mode is different aiming at different types of cancers, the current clinical cancer treatment mainly comprises surgery and chemotherapy, and the targeted therapy plays an increasingly important role in the cancer treatment by virtue of the specificity and the targeting property.
Studies prove that most of histones are in a low acetylation state in tumor cells, and the imbalance of histone acetylation state caused by the abnormality of histone deacetylase (HDAC for short) is closely related to the occurrence and the development of tumors. The early development of HDAC inhibitors is mostly broad-spectrum inhibitors, lacks selectivity aiming at subtypes, has potential toxic and side effects, and restricts clinical application, so that the development of more HDAC inhibitors with subtype selectivity has important research value.
Disclosure of Invention
The invention aims to provide a polysubstituted acridone alkyl derivative which can effectively inhibit HDAC, inhibit the proliferation of eukaryotic tumor cells and prevent and/or treat tumors, a preparation method and application thereof.
The technical scheme adopted by the invention for solving the technical problems is as follows: a polysubstituted acridone alkyl derivative, the compound is a polysubstituted acridone alkyl derivative with a structural formula I, II or a pharmaceutically acceptable salt of the polysubstituted acridone alkyl derivative with a structural formula I, II,
wherein R is 1 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or straight-chain alkyl with 2-5 carbon atoms; r 2 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、COOH、NO 2 Or linear alkyl, N-dimethyl alkylamine, benzylamine and substituted benzylamine with 2-6 carbon atoms; r is 3 Is an ester group, a carboxylic acid or a substituted amide; r is 4 Is NH 2 、NHCH 3 、NHCH 2 CH 3 、NHCH 2 CH 2 CH 3 OH, COOH or SH; r is 5 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 M =0,1 or 2,n =0,1,2,3,4,5,6 or 7; the pharmaceutically acceptable salt of the compound represented by the formula I, II is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is a salt formed by any one of inorganic acids of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is formed by any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.
The preparation method of the polysubstituted acridone alkyl derivative comprises the following steps:
(1) Reacting the compound shown in the formula III with the compound shown in the formula IV to obtain a compound shown in the formula V;
(2) Reacting the compound shown in the formula V with concentrated sulfuric acid to obtain a compound shown in a formula VI;
(3) Reacting the compound shown as the formula VI with the compound shown as the formula VII in 2-ethoxyethanol for 10-36 hours to obtain R shown as the formula I 3 A compound that is an ester group;
(4) Reacting the compound shown as the formula VI with the compound shown as the formula VII in dichloromethane and anhydrous N, N-dimethylformamide for 10-30 hours by using N, N' -carbonyldiimidazole as a condensing agent to obtain R shown as the formula II 3 A compound that is an ester group;
(5) Let R of formula I or II 3 Reacting the ester-group compound in an aqueous solution containing sodium hydroxide for 1-12 hours, and adjusting the acid-base property of the reaction solution to be neutral by using dilute hydrochloric acid to obtain R shown as formula I or II 3 A compound which is a carboxyl group;
(6) Let R of formula I or II 3 Reacting a carboxyl compound with a compound shown as a formula VIII in the presence of 2- (7-azobenzotriazole) -tetramethylurea hexafluorophosphate serving as a condensing agent and N, N-diisopropylethylamine serving as alkali in dichloromethane and anhydrous N, N-dimethylformamide for 10-30 hours to obtain R shown as a formula I or II 3 A compound that is a benzamide;
wherein R is 1 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or a linear alkyl group having 2 to 5 carbon atoms; r 2 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、COOH、CH 3 、NO 2 Or C2-6 linear alkyl, N-dimethyl alkylamine, benzylamine and substituted benzylamine; r 4 Is NH 2 、NHCH 3 、NHCH 2 CH 3 、NHCH 2 CH 2 CH 3 OH, COOH or SH; r 5 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 Or NO 2 ；R 6 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or a straight chain alkyl group having 2 to 5 carbon atoms, m =0,1 or 2,n =0,1,2,3,4,5,6 or 7.
The step (1) is specifically as follows: and (2) reacting the compound shown in the formula III with the compound shown in the formula IV in anhydrous N, N-dimethylformamide for 1-12 hours at 100-130 ℃ by using copper as a catalyst and potassium carbonate as a base to obtain the compound shown in the formula V.
Furthermore, the mole ratio of the compound shown in the formula III to the compound shown in the formula IV to the N, N-dimethylformamide is (1.1-1.5): 1 (5-25).
The step (2) is specifically as follows: mixing the compound shown in the formula V with concentrated sulfuric acid according to the molar ratio of 1:5-1 of 5363.
The step (3) is specifically as follows: reacting the compound shown in the formula VI with the compound shown in the formula VII in 2-ethoxyethanol at the temperature of between 25 and 135 ℃ for 10 to 36 hours to obtain the R shown in the formula I 3 A compound which is an ester group.
Further, the mole ratio of the compound shown in the formula VI to the compound shown in the formula VII to the 2-ethoxyethanol is 1: (2-5): (5-20).
The step (4) is specifically as follows: reacting the compound shown in the formula VI and the compound shown in the formula VII at the temperature of 10-60 ℃ for 10-30 hours in a solution mixed by dichloromethane and anhydrous N, N-dimethylformamide with the volume ratio of 1:3-1:8 by using N, N' -carbonyldiimidazole as a condensing agent to obtain the compound shown in the formula II 3 A compound which is an ester group.
Further, the molar ratio of the compound shown in the formula VI to the compound shown in the formula VII to the N, N' -carbonyldiimidazole is 1: (1-10): (1-4).
The step (5) is specifically as follows: at 30-100 ℃, enabling R shown as formula I or II 3 Reacting the ester-group compound in an aqueous solution containing sodium hydroxide for 1-12 hours, and adjusting the acid-base property of the reaction solution to be neutral by using dilute hydrochloric acid to obtain R shown in formula I 3 A compound which is a carboxyl group.
Further, R shown as formula I or II 3 The molar ratio of the compound as an ester group to sodium hydroxide is 1:1-1.
The step (6) is specifically as follows: at 10-70 ℃, enabling R shown as formula I or II 3 Reacting a carboxyl compound with a compound shown as a formula VIII in a solution formed by mixing dichloromethane and anhydrous N, N-dimethylformamide with the volume ratio of 1:3-1:8 by taking 2- (7-azobenzotriazole) -tetramethylurea Hexafluorophosphate (HATU) as a condensing agent and N, N-Diisopropylethylamine (DIPEA) as alkali for 10-30 hours to obtain R shown as a formula I or II 3 A compound which is a benzamide.
Further, R shown as formula I or II 3 A carboxyl compound, a compound represented by the formula VIII (1:1-1: (1-10): (1.3-5): (1.5-5).
The application of the acridone derived HDAC inhibitor in preparing a medicament for inhibiting proliferation of eukaryotic tumor cells comprises human chronic myelocytic leukemia cell line K562 cells, human colon cancer cells HCT-116, human myeloblastosis cells HL-60, human acute lymphoblastic leukemia cells CCRF-CEM and human lung cancer cells A549.
The application of the acridone derivative HDAC inhibitor in preparing an HDAC1 and/or HDAC6 activity inhibitor.
The application of the acridone derivative HDAC inhibitor in up-regulating the expression of gamma-H2 AX in HL-60 cells or improving the acetylation level of histone H3.
Compared with the prior art, the invention has the advantages that: the invention relates to a preparation method and application of an acridone derivative HDAC inhibitor, wherein the compound can effectively inhibit HDAC subtype activity, inhibit eukaryotic tumor cell proliferation and prevent and/or treat tumors. The compound provided by the invention is proved to be a potential HDAC inhibitor and an antitumor drug with stronger antitumor cell proliferation activity through a plurality of tumor cell line tests (including blood tumor cells and solid tumor cells), HDAC1 and HDAC6 activity inhibition tests, protein electrophoresis experiments to detect the up-regulation of the expression of a DNA damage marker gamma-H2 AX in cells and the increase of histone H3 acetylation level, apoptosis experiments to detect the induction of tumor cell apoptosis of the compound, and the like. The compound provided by the invention has the advantages of easily-obtained raw materials and relatively simple preparation method, a series of small molecule inhibitors taking HDAC1 or HDAC6 as targets are designed and synthesized, and experiments prove that the compound has good anticancer effect and good application prospect in the field of design and research of antitumor drugs.
Drawings
FIG. 1 shows the results of Western blot analysis tests of Compound 11 and Compound 12 and the quantitative analysis of the relative amounts of the corresponding Western immunoblots proteins, according to one embodiment of the present invention;
figure 2 shows a graph of apoptosis detection of compound 11 and compound 12, according to one embodiment of the present invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. Herein, a "compound of formula N" is also sometimes referred to herein as "compound N", where N is any integer from 1 to 13, e.g., "compound of formula 2" may also be referred to herein as "compound 2".
Detailed description of the preferred embodiment
An HDAC inhibitor of subtype selectivity, which is a pharmaceutically acceptable salt, ester or solvate of a compound having a structural formula of I, II or a compound having a structural formula of I, II,
wherein R is 1 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or straight-chain alkyl with 2-5 carbon atoms; r 2 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、COOH、NO 2 Or linear alkyl, N-dimethyl alkylamine, benzylamine and substituted benzylamine with 2-6 carbon atoms; r 3 Is an ester group, a carboxylic acid or a substituted amide; r 4 Is NH 2 、NHCH 3 、NHCH 2 CH 3 、NHCH 2 CH 2 CH 3 OH, COOH or SH; r 5 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 M =0,1 or 2,n =0,1,2,3,4,5,6 or 7; the pharmaceutically acceptable salt of the compound represented by the formula I, II is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is a salt formed by any one of inorganic acids of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is formed by any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.
The subtype-selective HDAC inhibitor of formula I, II above is preferably any of the following:
the compound can effectively inhibit HDAC subtype activity, inhibit proliferation of eukaryotic tumor cells, and prevent and/or treat tumors. The compound provided by the invention is proved to be a potential HDAC subtype selective inhibitor and an antitumor drug with stronger antitumor cell proliferation activity through various tumor cell line tests (including leukemia cells, lymphoma cells and the like), HDAC (including I type HDAC1 and II type HDAC 6) activity inhibition tests, protein electrophoresis tests for detecting the up-regulation of the expression of a intracellular DNA damage marker gamma-H2 AX and the increase of histone H3 acetylation level, apoptosis test compounds for detecting tumor cell apoptosis and the like.
Detailed description of the invention
The preparation method of the polysubstituted acridone alkyl derivative in the specific embodiment comprises the following steps:
1. reacting the compound shown in the formula III with the compound shown in the formula IV to obtain a compound shown in the formula V; according to the embodiment of the present invention, the conditions for reacting the compound represented by the formula III with the compound represented by the formula IV are not particularly limited, but may be specifically: reacting a compound shown in a formula III with a compound shown in a formula IV in anhydrous N, N-dimethylformamide for 1-12 hours at 100-130 ℃ by using copper as a catalyst and potassium carbonate as a base to obtain a compound shown in a formula V, wherein the molar ratio of the compound shown in the formula III to the compound shown in the formula IV to the N, N-dimethylformamide is (1.1-1.5): 1, (5-25), so that the reaction efficiency is improved, side reactions are reduced, and the yield is improved.
2. Reacting the compound shown in the formula V with concentrated sulfuric acid to obtain a compound shown in a formula VI; the method can also specifically comprise the following steps: mixing the compound shown in the formula V with concentrated sulfuric acid according to the molar ratio of 1:5-1 of 5363. Therefore, the reaction can be carried out under the most appropriate conditions, which is beneficial to improving the reaction efficiency, reducing side reactions and improving the yield.
3. Reacting the compound shown as the formula VI with the compound shown as the formula VII in 2-ethoxyethanol for 10-36 hours to obtain R shown as the formula I 3 A compound that is an ester group; the method specifically comprises the following steps: reacting the compound shown as the formula VI with the compound shown as the formula VII in 2-ethoxyethanol) at the temperature of between 25 and 135 ℃ for 10 to 36 hours to obtain the R shown as the formula I 3 A compound which is an ester group, wherein the molar ratio of the compound represented by the formula VI to the compound represented by the formula VII to the 2-ethoxyethanol is 1: (2-5): (5-20). Therefore, the method is beneficial to improving the reaction efficiency, reducing side reactions and improving the yield.
4. Reacting the compound shown as the formula VI with the compound shown as the formula VII for 10 to 30 hours in dichloromethane and anhydrous N, N-dimethylformamide by using N, N' -carbonyldiimidazole as a condensing agent to obtain R shown as the formula II 3 A compound that is an ester group; the method specifically comprises the following steps: reacting the compound shown in the formula VI and the compound shown in the formula VII at the temperature of 10-60 ℃ for 10-30 hours in a solution mixed by dichloromethane and anhydrous N, N-dimethylformamide with the volume ratio of 1:3-1:8 by using N, N' -carbonyldiimidazole as a condensing agent to obtain the compound shown in the formula II 3 A compound which is an ester group, wherein the molar ratio of the compound of formula VI, the compound of formula VII, and N, N' -carbonyldiimidazole is 1: (1-10): (1-4). Therefore, the method is beneficial to improving the reaction efficiency, reducing side reactions and improving the yield.
5. Reacting R of formula I or II 3 Reacting the ester-group compound in an aqueous solution containing sodium hydroxide for 1-12 hours, and adjusting the acid-base property of the reaction solution to be neutral by using dilute hydrochloric acid to obtain R shown as formula I or II 3 A compound which is a carboxyl group; the method specifically comprises the following steps: at 30-100 ℃, enabling R shown as formula I or II 3 Reacting the ester-group compound in an aqueous solution containing sodium hydroxide for 1-12 hours, and adjusting the acid-base property of the reaction solution to be neutral by using dilute hydrochloric acid to obtain R shown in formula I 3 A compound which is a carboxyl group, wherein R is represented by the formula I or II 3 The molar ratio of the compound as an ester group to sodium hydroxide is 1:1-1.
6. Reacting R of formula I or II 3 Reacting a carboxyl compound with a compound shown as a formula VIII in dichloromethane and anhydrous N, N-dimethylformamide for 10-30 hours by using 2- (7-azobenzotriazol) -tetramethylurea hexafluorophosphate as a condensing agent and N, N-diisopropylethylamine as a base to obtain R shown as a formula I or II 3 Compounds which are benzamides are specifically: at 10-70 ℃, enabling R shown as formula I or II 3 Reacting a carboxyl compound with a compound shown as a formula VIII in a solution formed by mixing dichloromethane and anhydrous N, N-dimethylformamide with the volume ratio of 1:3-1:8 by taking 2- (7-azobenzotriazol) -tetramethylurea Hexafluorophosphate (HATU) as a condensing agent and N, N-Diisopropylethylamine (DIPEA) as a base for 10-30 hours to obtain a compound shown as a formula I or IIShown as R 3 A compound which is a benzamide, wherein R is represented by formula I or II 3 The molar ratio of the compound which is carboxyl, the compound shown in the formula VIII (1:1-1: (1-10): (1.3-5): (1.5-5). Therefore, the reaction can be carried out under the most appropriate conditions, which is beneficial to improving the reaction efficiency, reducing side reactions and improving the yield.
Wherein R is 1 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or a linear alkyl group having 2 to 5 carbon atoms; r 2 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、COOH、CH 3 、NO 2 Or linear alkyl, N-dimethyl alkylamine, benzylamine and substituted benzylamine with 2-6 carbon atoms; r 4 Is NH 2 、NHCH 3 、NHCH 2 CH 3 、NHCH 2 CH 2 CH 3 OH, COOH or SH; r 5 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 Or NO 2 ；R 6 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or a linear alkyl group having 2 to 5 carbon atoms, m =0,1 or 2,n =0,1,2,3,4,5,6 or 7. The compound can be quickly and effectively prepared and obtained by the preparation method, and the method is simple to operate, convenient and quick, and suitable for large-scale production.
Example 1:
preparation of (Compound 1)
1. Preparation of 2- ((5-chloro-2-nitrophenyl) amino) -3-methoxybenzoic acid
A100 mL double-mouth round-bottom flask is taken, and 2-amino-3-methoxybenzoic acid (0.63 mmol) and 2,4-dichloro are sequentially addedNitrobenzene (0.52 mmol), potassium carbonate (1.04 mmol) and copper powder (0.26 mmol) were dissolved in DMF (5 mL) solvent, heated under reflux at 130 ℃ overnight with stirring, and the reaction was terminated by TLC (developing solvent: ethyl acetate/petroleum ether = 1/3). Then cooling the obtained reaction mixture to room temperature, filtering with diatomite, slowly adding the obtained filtrate into 50mL of water, adjusting the pH value of the system to be about 5 by using 2mol/L dilute hydrochloric acid, separating out a large amount of precipitate, performing suction filtration, drying the obtained precipitate to obtain a crude product, heating and washing the crude product with petroleum ether and ethyl acetate for several times to obtain pure powder, namely 2- ((5-chloro-2-nitrophenyl) amino) -3-methoxybenzoic acid, wherein the yield is 71.6%, and the structural data of the compound are characterized as follows: 1 H NMR(600MHz,DMSO-d 6 )δ13.38(s,1H),10.23(s,1H),8.13(d,J＝9.1Hz,1H),7.56(dd,J＝7.6,1.5Hz,1H),7.43–7.36(m,2H),6.92(dd,J＝9.1,2.2Hz,1H),6.46(d,J＝2.2Hz,1H),3.78(s,3H)。
2. preparation of 1-chloro-5-methoxy-4-nitroacridone
Adding the pure compound 2- ((5-chloro-2-nitrophenyl) amino) -3-methoxybenzoic acid (2.48 mmol) obtained in the step 1 into concentrated sulfuric acid (10 mL), refluxing for 3-5 hours under a heating condition of 80 ℃, then cooling the obtained reaction liquid to room temperature, then slowly adding the reaction liquid into an ice-water mixture of about 100-200mL, wherein a large amount of heat is released in the process, and adding ice cubes at any time to control the temperature (if precipitates are directly added into the ice-water mixture, stirring for 30min, then directly filtering, and then washing with clear water for 2-3 times for drying). And (3) if no precipitate is generated, adjusting the pH value of the system to about 7 by using a saturated sodium hydroxide aqueous solution, continuously stirring the mixed solution at room temperature for 30 minutes, directly spin-drying the aqueous solution after the pH adjustment to obtain a solid, and then repeatedly washing and filtering the solid by using dichloromethane and methanol to obtain an organic phase, and directly carrying out the next reaction without purification.
3. Preparation of Compound 1
1-chloro-5-methoxy-4-nitroacridone (0.8 mmol) obtained in step 2 and methyl 7-aminoheptanoate (3.2 mmol) were added to a solution of ethylene glycol ethyl ether (6 mL), followed by dropwise addition of 0.5mL of triethylamine, and stirring at 90-110 ℃ under reflux overnight under nitrogen. TLC (developing solvent: petroleum ether/acetic acid)Ethyl ester = 1:1), adding 20mL of dichloromethane to the reaction solution, extracting 3-4 times with 30mL-50mL of saturated saline, vacuum-drying the obtained organic layer to obtain a crude product, and subjecting the crude product to column chromatography (eluent: petroleum ether/ethyl acetate = 1:1) to obtain pure compound 1, the total yield of the two steps is 40.7%, and the melting point is 160.6-161.2 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,Chloroform-d)δ12.80(s,1H),11.89(s,1H),8.43(d,J＝9.7Hz,1H),7.87(d,J＝8.1Hz,1H),7.28(d,J＝8.0Hz,1H),7.13(d,J＝7.7Hz,1H),6.33(d,J＝9.8Hz,1H),4.08(s,3H),3.67(s,3H),3.41(q,J＝7.0Hz,2H),2.34(t,J＝7.4Hz,2H),1.81(p,J＝7.3Hz,2H),1.68(p,J＝7.5Hz,2H),1.52(p,J＝7.5Hz,2H),1.42(p,J＝7.8Hz,2H). 13 C NMR(151MHz,Chloroform-d)δ178.87,173.08,156.98,146.76,138.63,132.80,128.46,122.20,122.15,120.29,115.86,111.06,103.66,101.15,55.32,50.52,42.10,32.92,27.75,27.61,25.75,23.71；HR-MS(ESI):Calcd for[M+H] + 428.1822；Found:428.1822。
example 2:
preparation of (Compound 2)
Compound 2 was prepared according to the procedure for the implementation of example 1, with the difference that: the 2-amino-3-methoxybenzoic acid in the preparation of 2- ((5-chloro-2-nitrophenyl) amino) -3-methoxybenzoic acid from the preparation of the compound of example 1 was changed to 2-amino-3-methylbenzoic acid and reacted, otherwise, the obtained compound was compound 2, the total yield in the two steps of step 2 and step 3 was 39%, and the melting point was 150.6-153.7 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,Chloroform-d)δ12.76(s,1H),11.92(s,1H),8.43(d,J＝9.8Hz,1H),8.20(d,J＝8.0Hz,1H),7.56(d,J＝7.1Hz,1H),7.29(d,J＝7.7Hz,1H),6.36(d,J＝9.8Hz,1H),3.68(s,3H),3.42(q,J＝7.0Hz,2H),2.61(s,3H),2.34(t,J＝7.4Hz,2H),1.82(p,J＝7.3Hz,2H),1.68(p,J＝7.5Hz,2H),1.53(p,J＝7.4Hz,2H),1.43(p,J＝7.5Hz,2H). 13 C NMR(151MHz,Chloroform-d)δ180.25,174.10,157.99,140.24,137.08,134.40,133.76,125.25,123.84,123.45,122.62,121.17,104.20,102.53,51.55,43.14,33.93,28.76,28.64,26.77,24.73,16.71；HR-MS(ESI):Calcd for[M+H]+412.1872；Found:412.1874。
example 3:
preparation of (Compound 3)
1. Preparation of 2- ((2-carboxy-5-chlorophenyl) amino) -3-methoxybenzoic acid
A100 mL two-necked round bottom flask was taken, and 2-amino-3-methoxybenzoic acid (0.63 mmol), 2,4-dichlorobenzoic acid (0.52 mmol), potassium carbonate (1.04 mmol) and copper powder (0.26 mmol) were added in this order, dissolved in DMF (5 mL), heated under reflux at 130 ℃ overnight with stirring, and the reaction was terminated by TLC (developing solvent: ethyl acetate/petroleum ether = 1/3). Then, cooling the obtained reaction mixture to room temperature, filtering with diatomite, slowly adding the obtained filtrate into 50mL of water, adjusting the pH value of the system to be about 5 by using 2mol/L dilute hydrochloric acid, precipitating a large amount of precipitate, performing suction filtration, drying the obtained precipitate to obtain a crude product, heating and washing the crude product for 3-4 times by using a mixed solution of petroleum ether and ethyl acetate (the volume ratio = 1:1) to obtain pure powder, namely 2- ((2-carboxyl-5-chlorophenyl) amino) -3-nitrobenzoic acid, wherein the yield is 87%, and the structural data of the compound are characterized in that: 1 H NMR(600MHz,DMSO-d 6 )δ13.11(s,2H),10.06(s,1H),7.84(d,J＝8.5Hz,1H),7.47(d,J＝7.5Hz,1H),7.35(d,J＝7.9Hz,1H),7.30(t,J＝7.9Hz,1H),6.76(d,J＝9.7Hz,1H),6.26(s,1H),3.78(s,3H)。
2. preparation of 1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid
Adding the compound 2- ((2-carboxyl-5-chlorphenyl) amino) -3-methoxybenzoic acid (2.49 mmol) obtained in the step 1 into concentrated sulfuric acid (10 mL), refluxing for 3-5 hours under the heating condition of 80 ℃, then cooling the obtained reaction liquid to room temperature, then slowly adding the reaction liquid into an ice-water mixture of about 100-200mL, wherein a large amount of heat is released in the process, adding ice blocks while stirring to control the temperature, adjusting the pH value of the system to about 6 by using a sodium hydroxide solution after the reaction liquid is added, continuously stirring the mixed liquid for 30 minutes at room temperature, performing suction filtration by using a funnel, washing the solid with clear water for 2-3 times, and drying the solid to obtain solid powder, namely 1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid, wherein the next reaction is directly performed without purification.
3. Preparation of Compound 3
The compound 1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid (1.25 mmol) obtained in step 2 was dissolved in a solution of DMF: DCM =4:1 (15 mL), CDI (1.88 mmol) was added thereto and stirred for 30 minutes, and then methyl 7-aminoheptanoate (3.75 mmol) was added to the system and stirring was continued at room temperature overnight. TLC detection (developer: petroleum ether/ethyl acetate = 1:1) reaction is finished, 20mL of dichloromethane is added into reaction liquid, saturated saline solution is used for extraction for 3-4 times by 30mL-50mL, an organic phase is collected and dried in vacuum to obtain a crude product, and the crude product is purified by column chromatography (eluent: petroleum ether/ethyl acetate = 1:1) to obtain a pure product, namely the compound 3, wherein the total yield of the two steps is 24.4%, and the melting point is 165.5-165.8 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,Chloroform-d)δ12.64(s,1H),7.94(d,J＝8.0Hz,1H),7.71–7.62(m,1H),7.18(t,J＝7.8Hz,1H),7.10(d,J＝7.7Hz,1H),7.03(d,J＝4.9Hz,1H),6.73(s,1H),4.07(s,3H),3.66(s,3H),3.53(s,2H),2.33(t,J＝7.4Hz,2H),1.75–1.65(m,4H),1.48–1.37(m,4H). 13 C NMR(151MHz,Chloroform-d)δ177.26,174.23,168.06,147.80,142.45,139.61,130.66,130.61,122.95,122.67,121.80,118.52,117.92,117.12,111.96,56.34,51.57,40.12,33.92,29.22,28.71,26.63,24.74；HR-MS(ESI):Calcd for[M+H]+445.1530；Found:445.1530.
example 4:
preparation of (Compound 4)
1. Methyl 7- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamido) heptanoate is prepared according to the procedure of example 3;
2. preparation of Compound 4
The compound methyl 7- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamido) heptanoate (1.25 mmol) obtained in the above step and N, N-dimethylethylenediamine (5 mmol) were added to a solution of ethylene glycol ether (10 mL), followed by dropwise addition of 0.5mL of triethylamine under nitrogen protection and stirring at 90-110 ℃ under reflux overnight. TLC detection (developing solvent: petroleum ether/ethyl acetate =)1: 1) After the reaction was completed, the reaction mixture was cooled to room temperature, and a large amount of yellow precipitate was precipitated. The precipitate was filtered and washed 2-3 times with ethyl acetate to give pure solid, compound 4, in 35.9% yield and a melting point of 194.2-196.8 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,DMSO-d 6 )δ13.89(s,1H),10.81(t,J＝4.7Hz,1H),8.38(t,J＝5.5Hz,1H),8.05(d,J＝9.0Hz,1H),7.74(d,J＝7.9Hz,1H),7.29(dd,J＝7.9,0.9Hz,1H),7.18(t,J＝8.0Hz,1H),6.32(d,J＝9.1Hz,1H),4.03(s,3H),3.58(s,3H),3.38–3.35(m,2H),3.28(q,J＝6.8Hz,2H),2.58(t,J＝6.1Hz,2H),2.31(t,J＝7.4Hz,2H),2.24(s,6H),1.55(p,J＝7.2Hz,4H),1.32(dd,J＝6.7,3.2Hz,4H). 13 CNMR(151MHz,DMSO-d 6 )δ179.72,173.84,168.94,154.51,147.86,144.09,135.09,130.6,122.12,121.60,116.96,112.58,106.39,101.34,99.84,57.78,56.79,51.63,45.60,40.52,39.39,33.71,29.48,28.73,26.69,24.90；HR-MS(ESI):Calcd for[M+H] + 497.2764；Found:497.2764.
example 5:
preparation of (Compound 5)
1. Methyl 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate was prepared according to the procedure of example 2;
2. preparation of Compound 5
Dissolving the compound methyl 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate (1.22 mmol) obtained in the previous step with a small amount of methanol (0.2 mL), adding the solution into an aqueous solution (10 mL) of sodium hydroxide (1.4 mmol), refluxing for 6h at 80-100 ℃, cooling the reaction solution to room temperature, adjusting the pH to 6-7 with 2mol/L diluted hydrochloric acid, generating a small amount of precipitate, adding less glacial acetic acid, generating a large amount of precipitate, filtering and drying the precipitate, and purifying to obtain the compound 5, wherein the yield is 76.3%, and the melting point is 183.5-190.2 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,DMSO-d 6 )δ12.52(s,1H),12.01(s,1H),11.79(t,J＝5.4Hz,1H),8.34(d,J＝9.8Hz,1H),8.06(d,J＝8.0Hz,1H),7.68(d,J＝8.1Hz,1H),7.34–7.30(m,1H),6.59(d,J＝9.9Hz,1H),3.45(q,J＝6.9Hz,2H),2.53(s,3H),2.23(t,J＝7.4Hz,2H),1.70(p,J＝7.2Hz,2H),1.54(p,J＝7.4Hz,2H),1.44(dt,J＝14.8,7.1Hz,2H),1.37(dt,J＝7.1,3.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ179.56,174.95,157.89,140.16,137.04,134.91,133.79,125.87,123.91,123.65,122.33,120.91,103.96,103.73,42.90,40.51,34.04,28.64,26.61,24.84,16.43；HR-MS(ESI):Calcd for[M+H] + 398.1716；Found:398.1715。
example 6:
preparation of (Compound 6)
1. Methyl 6- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoate was prepared according to the procedure in example 1, except that: the reaction was carried out by replacing methyl 7-aminoheptanoate with methyl 6-aminocaproate, the total yield of the two steps was 37.6%, melting point: 174.4 to 174.5 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,Chloroform-d)δ12.76(s,1H),11.87(s,1H),8.41(d,J＝9.7Hz,1H),7.85(d,J＝8.1Hz,1H),7.29–7.23(m,2H),7.12(d,J＝7.7Hz,1H),6.31(d,J＝9.8Hz,1H),4.07(s,3H),3.67(s,3H),3.40(q,J＝6.6Hz,2H),2.37(t,J＝7.4Hz,2H),1.82(p,J＝7.2Hz,2H),1.73(p,J＝7.5Hz,2H),1.54(p,J＝7.8Hz,2H)。
2. 6- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoic acid was prepared according to step 2 in example 5, except that: the methyl 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate in step 2 in example 5 was exchanged for methyl 6- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoate and reacted without purification to proceed directly to the next step.
3. Preparation of Compound 6
The 6- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoic acid (1.26 mmol) obtained in step 2, HATU (2.26 mmol), DIPEA (1.5 mmol) and a solution (10 mL) in DMF: DCM =4:1 were stirred for 30min at room temperature, o-phenylenediamine (5 mmol) was added and stirring was continued overnight at room temperature, and TLC detection (developing solvent: ethyl acetate/ethanol = 10/1) was performedAnd (6) ending. Adding 30ml of DCM into the reaction solution, repeatedly extracting for 3-5 times by using water, collecting an organic layer, and spin-drying to obtain a crude product. The crude product was purified by column chromatography (eluent: ethyl acetate/ethanol = 10/1) to afford pure compound 6, with an overall yield of 28.1% over the two steps and a melting point of 205.5-206.8 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,DMSO-d 6 )δ12.58(s,1H),11.78(t,J＝5.3Hz,1H),9.13(s,1H),8.31(d,J＝9.8Hz,1H),7.71(d,J＝8.0Hz,1H),7.41–7.37(m,1H),7.33(t,J＝8.0Hz,1H),7.16(dd,J＝7.8,1.3Hz,1H),6.91–6.86(m,1H),6.72(dd,J＝8.0,1.2Hz,1H),6.56(d,J＝9.9Hz,1H),6.52(td,J＝7.7,1.3Hz,1H),4.05(s,3H),3.45(q,J＝6.8Hz,2H),2.37(t,J＝7.4Hz,2H),1.72(dp,J＝29.5,7.3Hz,4H),1.49(p,J＝7.6,7.2Hz,2H). 13 CNMR(151MHz,DMSO-d 6 )δ179.19,171.51,157.90,147.74,142.17,139.58,133.76,129.03,126.17,125.79,124.07,123.99,122.85,120.96,116.73,116.41,113.58,104.14,103.73,57.14,42.87,36.09,28.59,26.56,25.43；HR-MS(ESI):Calcd for[M+H] + 490.2090；Found:490.2090。
example 7:
preparation of (Compound 7)
1. Methyl 7- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate was prepared according to the procedure in example 1.
2. 7- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoic acid is prepared according to step 2 in example 5, except that: the methyl 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate in step 2 in example 5 was converted to methyl 7- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate and reacted without purification and proceeded directly to the next step.
3. Preparation of Compound 7
Compound 7 was prepared according to step 3 in example 6, except that: conversion of 6- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoic acid to 7- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoic acidThe compound 7 is obtained, the total yield of the two steps is 27.7%, and the melting point is 214.8-215.2 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,DMSO-d 6 )δ12.52(s,1H),11.73(t,J＝5.2Hz,1H),9.11(s,1H),8.27(d,J＝9.8Hz,1H),7.67(d,J＝8.0Hz,1H),7.35(d,J＝7.2Hz,1H),7.29(t,J＝8.0Hz,1H),7.15(dd,J＝7.8,1.2Hz,1H),6.88(td,J＝8.1,1.4Hz,1H),6.71(dd,J＝8.0,1.2Hz,1H),6.55–6.49(m,2H),4.82(s,2H),4.03(s,3H),3.43–3.40(m,2H),2.34(t,J＝7.4Hz,2H),1.74–1.68(m,2H),1.64(p,J＝7.5Hz,2H),1.47(dt,J＝14.6,7.0Hz,2H),1.41(q,J＝7.3Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ179.12,171.61,157.84,147.70,142.35,139.51,133.71,128.96,126.18,125.76,124.03,123.94,122.80,120.91,116.70,116.65,116.37,113.50,104.06,103.64,57.10,42.91,36.17,28.79,28.65,26.69,25.67；HR-MS(ESI):Calcd for[M+H] + 504.2247；Found:504.2245。
example 8:
preparation of (Compound 8)
1. Methyl 6- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoate was prepared according to the procedure in example 1, except that: 2-amino-3-methoxybenzoic acid and methyl 7-aminoheptanoate were exchanged for 2-amino-3-methylbenzoic acid and methyl 6-aminocaproate for reaction, the overall yield of the two steps was 41.9%, and the melting point was 158.7-160.2 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,Chloroform-d)δ12.68(s,1H),11.88(s,1H),8.39(d,J＝9.8Hz,1H),8.16(d,J＝8.0Hz,1H),7.53(d,J＝7.1Hz,1H),7.25(d,J＝7.2Hz,1H),6.32(d,J＝9.8Hz,1H),3.68(s,3H),3.41(q,J＝6.8Hz,2H),2.58(s,3H),2.37(t,J＝7.4Hz,2H),1.82(p,J＝7.3Hz,2H),1.73(p,J＝7.5Hz,2H),1.54(p,J＝7.8Hz,2H)。
2. 6- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoic acid was prepared according to step 2 in example 5, except that: the methyl 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate was exchanged for methyl 6- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoate, which was obtained without purification, i.e. 6- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoic acid, and was directly subjected to the next step.
3. Preparation of Compound 8
Compound 8 was prepared according to step 3 in example 6, except that: 6- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoic acid is changed into 6- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoic acid to react, and then the compound 8 is obtained. The total yield of the two steps is 25.4 percent, and the melting point is 148.9-150.1 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,DMSO-d 6 )δ12.34(s,1H),11.68(t,J＝5.2Hz,1H),9.11(s,1H),8.23(d,J＝9.8Hz,1H),7.96(d,J＝8.0Hz,1H),7.60(d,J＝7.1Hz,1H),7.25(t,J＝7.6Hz,1H),7.16(dd,J＝7.8,1.3Hz,1H),6.88(td,J＝8.0,1.4Hz,1H),6.70(dd,J＝8.0,1.2Hz,1H),6.53–6.47(m,2H),4.83(s,2H),3.40(q,J＝6.7Hz,2H),2.44(s,3H),2.37(t,J＝7.4Hz,2H),1.71(dp,J＝15.3,7.4Hz,4H),1.49(p,J＝7.7,7.3Hz,2H). 13 CNMR(151MHz,DMSO-d 6 )δ178.23,170.40,156.61,156.59,141.27,138.79,135.73,133.66,132.46,125.08,124.70,124.62,122.89,122.70,122.42,121.08,119.68,115.49,115.22,102.76,102.42,41.80,35.01,27.49,25.49,24.36,15.27；HR-MS(ESI):Calcd for[M+H] + 474.2141；Found:474.2141。
example 9:
preparation of (Compound 9)
1. 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoic acid is prepared according to the procedure in example 5.
2. Preparation of Compound 9
Compound 9 was prepared according to step 3 in example 6, except that: the compound 9 is obtained by the reaction of 6- ((5-methoxy-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) hexanoic acid with 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoic acid, the total yield of the two steps is 22.9%, and the melting point is 169.4-173.5 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,DMSO-d 6 )δ12.35(s,1H),11.68(t,J＝5.1Hz,1H),9.11(s,1H),8.23(d,J＝9.8Hz,1H),7.96(d,J＝8.0Hz,1H),7.60(d,J＝7.1Hz,1H),7.25(t,J＝7.6Hz,1H),7.16(d,J＝7.8Hz,1H),6.89(t,J＝8.2Hz,1H),6.71(d,J＝8.0Hz,1H),6.55–6.51(m,1H),6.48(d,J＝9.9Hz,1H),4.82(s,2H),3.39(q,J＝6.7Hz,2H),2.44(s,3H),2.35(t,J＝7.4Hz,2H),1.68(dp,J＝29.8,7.2Hz,4H),1.45(ddt,J＝33.8,13.9,8.0Hz,4H). 13 C NMR(151MHz,DMSO-d 6 )δ178.25,170.49,156.60,141.27,138.79,135.73,133.66,132.47,125.07,124.66,124.62,122.94,122.69,122.43,121.08,119.69,115.54,115.26,102.73,102.43,41.84,35.09,27.72,27.56,25.63,24.59,15.27；HR-MS(ESI):Calcd for[M+H] + 488.2298；Found:488.2289。
example 10:
preparation of (Compound 10)
1. Methyl 4- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamido) butanoate was prepared according to the procedure of example 3, except that: the methyl 7-aminoheptanoate in step 3 in example 3 was replaced with methyl 4-butanoate.
2. 4- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamido) butanoic acid is prepared according to step 2 in example 5, except that: the methyl 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate in step 2 of example 5 was converted to methyl 4- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridin-4-carboxamido) butanoate and reacted without purification in the next step.
3. Preparation of Compound 10
example 11:
preparation of (Compound 11)
1. Methyl 6- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamido) hexanoate was prepared according to the procedure of example 3, except that: the reaction was carried out by replacing methyl 7-aminoheptanoate with methyl 6-aminocaproate in step 3 of example 3.
2. 6- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamido) hexanoic acid was prepared according to step 2 in example 5, except that: the methyl 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate in step 2 of example 5 was exchanged for methyl 6- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridin-4-carboxamido) hexanoate and reacted without purification to proceed directly to the next step.
3. Preparation of Compound 11
example 12:
preparation of (Compound 12)
1. Methyl 7- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamido) heptanoate is prepared according to the procedure of example 3.
2. 7- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamido) heptanoic acid is prepared according to step 2 in example 5, except that: the methyl 7- ((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl) amino) heptanoate in step 2 of example 5 was exchanged for methyl 7- (1-chloro-5-methoxy-9-oxo-9,10-dihydroacridin-4-carboxamido) heptanoate and reacted without purification for the next step.
3. Preparation of Compound 12
example 13:
preparation of (Compound 13)
Compound 13 was prepared according to the procedure for example 12, except that: the o-phenylenediamine was replaced with 4-fluorophenylenediamine in step 3 of example 12. The resulting compound 13 was a yellow solid with a total yield of 44.8% over the two steps and a melting point of 218.7-218.9 ℃. Compound structural data are characterized as: 1 H NMR(600MHz,DMSO-d 6 )δ13.26(s,1H),9.01(d,J＝8.4Hz,2H),8.17(d,J＝8.3Hz,1H),7.73(d,J＝8.1Hz,1H),7.34(dd,J＝16.4,8.0Hz,2H),7.23(t,J＝8.0Hz,1H),7.08(dd,J＝8.6,6.4Hz,1H),6.48(dd,J＝11.2,2.9Hz,1H),6.29(td,J＝8.5,2.8Hz,1H),5.13(s,2H),4.03(s,3H),3.38–3.34(m,2H),2.31(t,J＝7.4Hz,2H),1.61(h,J＝7.0Hz,4H),1.42–1.35(m,4H). 13 C NMR(151MHz,DMSO-d 6 )δ176.07,171.85,167.76,160.92(d,J＝238.4Hz),147.97,144.70(d,J＝11.7Hz),142.88,137.91,132.96,130.45,127.52(d,J＝10.2Hz),123.18,122.62,122.35,120.04,117.94,117.47,117.13,113.29,102.35(d,J＝22.3Hz),101.92–101.71(m),56.95,40.51,36.10,29.15,28.94,26.81,25.67.HR-MS(ESI):Calcd for[M+H] + 539.1861；Found:539.1858。
detailed description of the preferred embodiment
Use of a compound prepared according to the above embodiment one or embodiment two in the manufacture of a medicament. The medicine is a potential HDAC inhibitor, and can be used for effectively inhibiting HDAC subtype activity, inhibiting eukaryotic tumor cell proliferation and preventing and/or treating tumors.
The above eukaryote is a mammal; the tumor cell is a cancer cell; the cancer cells are leukemia cells, lymphoma cells, breast cancer cells, liver cancer cells, pancreatic cancer cells, lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, stomach cancer cells, nasopharyngeal cancer cells, colon cancer cells, bladder cancer cells or rectal cancer cells, wherein the leukemia cells are preferably human chronic myelogenous leukemia cells and human acute lymphocytic leukemia cells, and the lymphoma cells are preferably human histiocytic lymphoma cells.
It is to be noted that the above-mentioned drug of the present invention can be introduced into the body, such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue, by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or can be mixed or coated with other materials and introduced into body. If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field. In addition, the medicine of the invention can be prepared into various forms such as injection, tablets, powder, granules, capsules, oral liquid, ointment, cream and the like. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
Example 1
Screening of cell proliferation inhibitory Activity by MTT method
The tested cells were selected from the human chronic myelocytic leukemia cell line K562 cells (suspension cells, 8000/well), human colon cancer cells HCT-116 (adherent cells, 5000/well), human promyelocytic leukemia cells HL-60 (suspension cells, 10000/well), human acute lymphoblastic leukemia cells CCRF-CEM (suspension cells, 10000/well), human normal liver cells L-O2 (adherent cells, 5000/well) and human lung cancer cells a549 (adherent cells, 5000/well) in logarithmic growth phase by MTT method, and the compounds screened for anti-proliferative activity in vitro were 13 target compounds. Wherein, the positive pairThe medicine preparation is as follows: the HDAC subtype selective inhibitor cidalimide. The specific steps of the cell proliferation inhibition activity test are as follows: (1) The test compounds were prepared as solutions of 5mM in the initial concentration with DMSO reagents, respectively, and then the obtained solutions of the initial concentrations were subjected to gradient dilution to obtain 2.5mM,1mM,0.5mM,0.25mM, 0.1mM,0.01mM compound solutions; (2) Tumor cells (suspension cells or adherent cells) were seeded in 96-well plates (99. Mu.L per well), respectively, and then a compound solution (1. Mu.L per well) was added to give final concentrations of the compounds of 0.1. Mu.M, 1. Mu.M, 2.5. Mu.M, 5. Mu.M, 10. Mu.M, 25. Mu.M and 50. Mu.M, respectively. When solid tumor cells are used, the cells are cultured at 37 deg.C in RPIM-1640 culture medium containing 10% fetal calf serum and 5% CO 2 And (4) performing routine culture, and adding compound solutions with different concentrations into the cells after the cells are attached. Each concentration of compound was provided with 3 multiple wells. In addition, a blank was set in the 96-well plate, and DMSO (1 μ L per well) was added to the blank; (3) After culturing a 96-well plate in an incubator for 72h, adding MTT solution (10 mu L per well), then continuing culturing for 4h, taking out, placing in a 4 ℃ incubator, cooling, and centrifuging for 5 min (adherent cells do not need to be centrifuged in the process). The supernatant was aspirated off, and DMSO (100 μ L per well) was added, followed by shaking the 96-well plate with a micro-shaker for about 3-5 minutes; (4) Finally, OD was measured at 490nm using a microplate reader, and the inhibition rate of cell proliferation (IR%) was calculated. The calculation formula is as follows: IR% = (positive control OD-drug sample OD)/(positive control OD-blank OD) × 100%. The results are shown in Table 1.
TABLE 1 screening results for antiproliferative Activity of Compounds 1-13
Note: IC (integrated circuit) 50 The median inhibitory concentration is indicated.
As can be seen from Table 1, when the ester group long chain is inserted into the benzamide sheetAfter the period, the antiproliferative activity of the compound on leukemia HL-60 cells is obviously improved, and when the acridone mother nucleus R is adopted 1 The substituent in position 5 being-OCH 3 When compared with other substituents at position 5 (e.g., -CH) 3 、-NO 2 ) The inhibition activity is stronger; simultaneously influenced by the length of the connecting chain, wherein the inhibitory activity is relatively stronger when n = 5; in the case of identical substituents and identical chain length, R 5 The inhibiting activity is stronger when the substituent is H than when the substituent is F, and the IC of the compound 11 50 A value of 0.56 was slightly better than that of xidapamide. Secondly, the compound 4 is found to have more N, N-dimethylethylenediamine at the 1-position compared with other ester-based compounds, but shows better anticancer activity, and can be seen to have relatively best inhibition effect on leukemia K562 cells. In addition, for HCT-116 cells, R can be seen from compounds 7 and 9 1 Substituent 5-OCH 3 Ratio of 5-CH 3 The inhibition effect is better; for A549 adenocarcinoma cells, the inhibitory activity of the compound 12 is improved to a greater extent than that of the cydariamine.
Example 2
Inhibition assay for in vitro Activity of Histone deacetylase (HDAC 1 and HDAC 6)
The experiment detects the inhibition effect of the compounds 1-13 on the activity of HDAC1 and HDAC6, and the specific steps are carried out according to the instruction of the HDAC1 and HDAC6 activity inhibition detection kit. The method comprises the following steps: the test compound was added to Tris buffer, 15 μ L of HDAC1 or HDAC6 enzyme solution was added, and after incubation for 15 minutes at room temperature, 10 μ L of substrate buffer solution containing trypsin and acetylated fluorescent protein was added, gently mixed and incubated for 1 hour at room temperature. Detecting the fluorescence signal intensity at 355nM (excitation wavelength) and 460nM (emission wavelength) by a Synergy MX instrument, calculating the inhibition rate of the compound on HDAC1 and HDAC6, and obtaining IC according to a concentration-inhibition rate curve 50 The value is obtained. The positive control drug is selected from a subtype selective HDAC inhibitor of cidalimide. The results are shown in Table 2.
As can be seen from Table 2, compounds 6, 7, 8, 9, 11, 12, 13 have significant HDAC1 inhibitory activity, IC 50 The value is 87nM-358nM, and compared with the positive control drug of Sidamine, the compound 12 has better activity; compounds 1,23,4,5 have significant HDAC6 inhibitory activity, IC 50 Values were between 28nM and 294 nM. Thus, the series of compounds reported in this patent are a class of HDAC1 or HDAC6 subtype selective inhibitors.
TABLE 2 inhibition of HDAC1/6 target Activity of Compounds 1-13 screening results
Note: IC (integrated circuit) 50 The median inhibitory concentration is indicated.
Example 3
Western blot analysis experiment
The ribozyme related target inhibitor can cause DNA chain breakage in tumor cells, cause DNA damage and further induce apoptosis. When DNA damage occurs, intracellular histone H2AX is promoted to phosphorylate to form γ -H2AX, so γ -H2AX is considered to be an important biomarker of DNA damage. In order to verify whether compounds are effective in causing DNA damage in HL-60 cells, the present inventors performed Western blot analysis experiments with compound 11 and compound 12 selected as test samples. As can be seen from FIG. 1, the expression of γ -H2AX in HL-60 cells was significantly up-regulated as the concentration of compound 11 was increased from 0.1. Mu.M to 0.5. Mu.M and the concentration of compound 12 was increased from 0.2. Mu.M to 1. Mu.M, indicating that compounds 11 and 12 indeed induced DNA damage by inhibiting the activity of the nuclease target in leukemia HL-60 cells.
In addition, this experiment further explored the effect of compound 11 and compound 12 on histone acetylation at the cellular level. Acetylation of lysine residues of histone H3 can promote relaxation and activation of chromatin, thereby facilitating binding of transcription factors to promoters of cancer suppressor genes. We tested the change in histone H3 acetylation levels after 48 hours of treatment of HL-60 cells with different concentrations of compound 11 and compound 12. The results are shown in figure 1, and Ac-H3 acetylation levels are significantly increased with increasing concentrations of compounds 11 and 12, which further verifies that compounds 11 and 12 are potent HDAC subtype selective inhibitors.
Example 4
Apoptosis detection
To further verify whether compounds 11 and 12 were effective in inducing apoptosis in cancer cells, this experiment was analyzed by flow cytometry. Results as shown in fig. 2, when the concentration of compound 11 (fig. 2A) was increased from 0.1 μ M to 2.5 μ M, early and late apoptosis of HL-60 cells was significantly induced in a dose-dependent manner, with the proportion of apoptosis rising from 9.74% to 85.8% of the control cell group. In addition, when compound 12 (fig. 2B) concentration was increased from 0.2 μ M by 5 μ M, early and late apoptosis of HL-60 cells was significantly induced in a dose-dependent manner, with the apoptosis ratio rising from 13.17% to 70.3% of the cell control group. Thus, it was further shown that compounds 11 and 12 significantly induced apoptosis in cancer cells.
The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Those skilled in the art should also realize that changes, modifications, additions and substitutions can be made without departing from the true spirit and scope of the invention.
Claims (10)
1. A polysubstituted acridone alkyl derivative characterized by: the compound is a pharmaceutically acceptable salt of a polysubstituted acridone alkyl derivative with a structural formula of I, II or a polysubstituted acridone alkyl derivative with a structural formula of I, II,
wherein R is 1 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or a linear alkyl group having 2 to 5 carbon atoms; r is 2 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、COOH、NO 2 Or linear alkyl, N-dimethyl alkylamine, benzylamine and substituted benzylamine with 2-6 carbon atoms; r 3 Is an ester group, a carboxylic acid or a substituted amide; r is 4 Is NH 2 、NHCH 3 、NHCH 2 CH 3 、NHCH 2 CH 2 CH 3 OH, COOH or SH; r is 5 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 M =0,1 or 2,n =0,1,2,3,4,5,6 or 7; the pharmaceutically acceptable salt of the compound represented by the formula I, II is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is a salt formed by any one of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is formed by any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.
2. A method for producing a polysubstituted acridone alkyl derivative according to claim 1, which comprises the steps of:
(1) Reacting the compound shown in the formula III with the compound shown in the formula IV to obtain a compound shown in the formula V;
(2) Reacting the compound shown in the formula V with concentrated sulfuric acid to obtain a compound shown in a formula VI;
(3) Reacting the compound shown as the formula VI with the compound shown as the formula VII in 2-ethoxyethanol for 10-36 hours to obtain R shown as the formula I 3 A compound that is an ester group;
(4) Reacting the compound shown as the formula VI with the compound shown as the formula VII in dichloromethane and anhydrous N, N-dimethylformamide for 10-30 hours by using N, N' -carbonyldiimidazole as a condensing agent to obtain R shown as the formula II 3 A compound that is an ester group;
(5) Reacting R of formula I or II 3 Reacting the ester-group compound in an aqueous solution containing sodium hydroxide for 1-12 hours, and adjusting the acid-base property of the reaction solution to be neutral by using dilute hydrochloric acid to obtain R shown as formula I or II 3 A compound which is a carboxyl group;
(6) Reacting R of formula I or II 3 Reacting a carboxyl compound with a compound shown as a formula VIII in dichloromethane and anhydrous N, N-dimethylformamide for 10-30 hours by using 2- (7-azobenzotriazol) -tetramethylurea hexafluorophosphate as a condensing agent and N, N-diisopropylethylamine as a base to obtain R shown as a formula I or II 3 A compound that is a benzamide;
wherein R is 1 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or a linear alkyl group having 2 to 5 carbon atoms; r is 2 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、COOH、CH 3 、NO 2 Or linear alkyl, N-dimethyl alkylamine, benzylamine and substituted benzylamine with 2-6 carbon atoms; r 4 Is NH 2 、NHCH 3 、NHCH 2 CH 3 、NHCH 2 CH 2 CH 3 OH, COOH or SH; r 5 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 Or NO 2 ；R 6 Is H, OCH 3 、OCH 2 CH 3 、F、Cl、Br、CH 3 、NO 2 Or a linear alkyl group having 2 to 5 carbon atoms, m =0,1 or 2,n =0,1,2,3,4,5,6 or 7.
3. The method for preparing a polysubstituted acridone alkyl derivative according to claim 2, wherein the step (1) is specifically as follows: the step (1) is specifically as follows: reacting a compound shown in a formula III with a compound shown in a formula IV in anhydrous N, N-dimethylformamide for 1-12 hours at 100-130 ℃ by using copper as a catalyst and potassium carbonate as a base to obtain a compound shown in a formula V, wherein the molar ratio of the compound shown in the formula III to the compound shown in the formula IV to the N, N-dimethylformamide is (1.1-1.5): 1 (5-25); specifically, the step (2) is to mix the compound shown in the formula V and concentrated sulfuric acid according to the molar ratio of 1:5-1 to 20 at 50-100 ℃ and then react for 1-5 hours to obtain the compound shown in the formula VI.
4. The method for preparing a polysubstituted acridone alkyl derivative according to claim 2, wherein the step (3) is specifically as follows: reacting a compound of formula VI with a compound of formula VII at 25-135 deg.CThe compound is reacted in 2-ethoxy ethanol for 10 to 36 hours to obtain R shown in formula I 3 A compound that is an ester group, wherein the molar ratio of said compound of formula VI, said compound of formula VII, and said 2-ethoxyethanol is 1: (2-5): (5-20).
5. The method for preparing polysubstituted acridone alkyl derivatives according to claim 2, wherein the step (4) is specifically: reacting the compound shown in the formula VI and the compound shown in the formula VII at the temperature of 10-60 ℃ for 10-30 hours in a solution mixed by dichloromethane and anhydrous N, N-dimethylformamide with the volume ratio of 1:3-1:8 by using N, N' -carbonyldiimidazole as a condensing agent to obtain the compound shown in the formula II 3 A compound that is an ester group, wherein the molar ratio of said compound of formula VI, said compound of formula VII, and said N, N' -carbonyldiimidazole is 1: (1-10): (1-4).
6. The method for preparing a polysubstituted acridone alkyl derivative according to claim 2, wherein the step (5) is specifically: at 30-100 ℃, enabling R shown as formula I or II to react 3 Reacting the ester-group compound in an aqueous solution containing sodium hydroxide for 1-12 hours, and adjusting the acid-base property of the reaction solution to be neutral by using dilute hydrochloric acid to obtain R shown in formula I 3 A compound which is a carboxyl group, wherein R is represented by formula I or II 3 The molar ratio of the compound as an ester group to sodium hydroxide is 1:1-1.
7. The method for preparing a polysubstituted acridone alkyl derivative according to claim 2, wherein the step (6) is specifically: at 10-70 ℃, enabling R shown as formula I or II 3 Reacting a carboxyl compound and a compound shown in a formula VIII in a solution formed by mixing dichloromethane and anhydrous N, N-dimethylformamide with the volume ratio of 1:3-1:8 by taking 2- (7-azobenzotriazol) -tetramethylurea hexafluorophosphate as a condensing agent and N, N-diisopropylethylamine as base for 10-30 hours to obtain a compound shown in a formula I or II R 3 A compound which is a benzamide, wherein said formula I or IR is shown as I 3 A carboxyl compound, a compound represented by the formula VIII (1:1-1: (1-10): (1.3-5): (1.5-5).
8. Use of polysubstituted acridone alkyl derivatives according to any one of claims 1 to 7 for the preparation of a medicament for inhibiting the proliferation of eukaryotic tumor cells, characterized in that: the tumor cells comprise human chronic myelocytic leukemia cell line K562 cells, human colon cancer cells HCT-116, human myeloblastosis cells HL-60, human acute lymphoblastic leukemia cells CCRF-CEM and human lung cancer cells A549.
9. Use of a polysubstituted acridone alkyl derivative of any one of claims 1 to 7 for the preparation of an inhibitor of HDAC1 and/or HDAC6 activity.
10. Use of a polysubstituted acridone alkyl derivative of any one of claims 1 to 7 for upregulating the expression of γ -H2AX in HL-60 cells or for increasing the level of histone H3 acetylation.
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