CN113717138B - Nitrogen mustard chromone derivatives and application thereof - Google Patents
Nitrogen mustard chromone derivatives and application thereof Download PDFInfo
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Abstract
The invention discloses a nitrogen mustard chromone derivative and application thereof, belonging to the fields of natural medicines and medicinal chemistry. In particular to a preparation method of a series of nitrogen mustard chromone derivatives with anti-tumor activity and new application in anti-tumor drugs. The nitrogen mustard chromone derivative and the pharmaceutically acceptable salt thereof are shown as a general formula I. Wherein R and R 1 And X is as described in the claims and specification.
Description
Technical Field
The invention belongs to the field of natural medicines and medicinal chemistry, relates to nitrogen mustard chromone derivatives and application, and particularly relates to a preparation method of a series of nitrogen mustard chromone derivatives with anti-tumor activity and application of the nitrogen mustard chromone derivatives in the aspect of anti-tumor.
Background
Chromone is a type of oxygen-containing heterocyclic compound with benzo-gamma-pyrone skeleton, which is widely distributed in nature and has various remarkable biological activities. Chromone and derivatives thereof show good antiproliferative activity on breast cancer, liver cancer, lung cancer, leukemia, colon cancer and the like, play a role through multiple mechanisms and have great potential in cancer treatment. However, the further development and application of the compound are limited due to the defects of poor bioavailability, insufficient activity intensity and the like. Therefore, modifications and alterations to the structure of chromones are needed to obtain drug candidates with better activity.
Nitrogen mustards, also known as DNA alkylating agents, belong to the cytotoxic class of drugs. The medicine is widely used clinically, but the toxic and side effects of the medicine are large, the specificity of the effect on cells is lacked, and the treatment effect is not ideal along with the occurrence of tumor drug resistance in recent years. Therefore, the chemical modification of the nitrogen mustard drugs to improve the curative effect thereof has important value.
Disclosure of Invention
The invention aims to solve the technical problem of searching nitrogen mustard chromone derivatives with good antitumor activity and pharmaceutically acceptable salts thereof and further providing a pharmaceutical composition.
In order to solve the technical problems, the invention provides the following technical scheme:
a nitrogen mustard chromone derivative and a pharmaceutically acceptable salt thereof have the following structural general formula I:
wherein R is an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 8 carbon atoms; r 1 Is H, or an alkyl or alkoxy group containing 1 to 10 carbon atoms; the heteroatom X is N, O, S or Se.
Preferably, R is an alkyl group containing 1 to 6 carbon atoms or an alkoxy group containing 1 to 6 carbon atoms; r 1 Is H, or an alkyl or alkoxy group containing 1 to 8 carbon atoms; the heteroatom X is N, O or S.
More preferably, R is an alkyl group containing 1 to 4 carbon atoms or an alkoxy group containing 1 to 4 carbon atoms; r 1 Is H, or an alkyl or alkoxy group containing 1 to 6 carbon atoms; the heteroatom X is N or O.
Further, the following derivatives and pharmaceutically acceptable salts thereof are preferred in the invention, and the structural formulas are shown as a-h:
the derivative of the invention can be prepared by the following method:
(1) Reacting the compound 1a-b with phosphorus oxychloride in N, N-dimethylformamide at room temperature to obtain an intermediate 2a-b; then the intermediate 2a-b is dissolved in isopropanol and alkaline Al is added 2 O 3 Carrying out reflux reaction to obtain a compound 3a-b; dissolving the compounds 3a-b in dichloromethane, dropwise adding phosphorus tribromide under an ice bath condition, transferring to room temperature for reaction, dissolving the treated solid in N, N-dimethylformamide, adding ammonia water, and reacting at room temperature to obtain compounds 4a-b;
(2) Reaction of melphalan 5 with acetic anhydride in formic acid to give compound 6a; or reacting melphalan 5 with di-tert-butyl carbonate in dioxane solvent in the presence of triethylamine to obtain a compound 6b;
(3) Dissolving the compound 3a-b or 4a-b in anhydrous dichloromethane, sequentially adding EDCI, DMAP or HOBt, and reacting with the compound 6a-b at room temperature to obtain target compounds 7a-d and 8a-d.
A pharmaceutical composition, which comprises a therapeutically effective amount of the nitrogen mustard chromone derivative shown in the general formula I and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
The nitrogen mustard chromone derivative shown in the general formula I and the pharmaceutically acceptable salt thereof are applied to the preparation of medicines for treating tumor diseases.
Furthermore, the tumor is breast cancer tumor or liver cancer tumor.
The application of the pharmaceutical composition in preparing medicaments for treating tumor diseases.
Furthermore, the tumor is breast cancer tumor or liver cancer tumor.
The invention takes chromone as a lead compound, designs and synthesizes nitrogen mustard chromone derivatives, and tests the biological activity of the synthesized derivatives in the aspect of anti-tumor.
Pharmacological tests prove that the nitrogen mustard chromone derivative has good anti-tumor cell proliferation effect and can be used for further preparing anti-tumor drugs.
Detailed Description
The following non-limiting examples will allow one of ordinary skill in the art to more fully understand the present invention, but are not intended to limit the invention in any way.
The synthesis route of the derivatives of the embodiment of the invention is as follows:
example 1
(1) 500mg of compound 1a (3.33 mmol) was dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) was added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystal precipitation is carried out, suction filtration and drying are carried out, and intermediate 2a 402.4mg is obtained. 50mg of intermediate 2a (0.27 mmol) are dissolved in 10mL of isopropanol and 1g of basic Al are added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC (TLC) for complete reaction, suction filtration, concentration of the filtrate to obtain crude product, and separation by silica gel column chromatography (DCM: meOH) to obtain compound 3a (R = -CH) 3 )。
(2) 500mg of melphalan 5 (1.64 mmol) are dissolved in 15mL of formic acid, 2mL of acetic anhydride are then added and the reaction is carried out in an oil bath at 50 ℃ for 5h. After the reaction is completed, adding proper amount of water, extracting with dichloromethane for 3 times, washing with saturated saline for 1 time, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain compound 6a (R) 1 ＝-H)。
(3) 50mg of compound 3a (0.26 mmol) was dissolved in 5mL of anhydrous dichloromethane, and 151.6mg of EDCI (0.80 mmol), 16.1mg of DMAP (0.13 mmol), 69.7mg of compound 6a (0.21 mmol) were added and reacted at room temperature for 12h. After the reaction is completed, the reaction solution is poured into waterExtracting with dichloromethane for 3 times, washing with saturated salt water for 1 time, and collecting anhydrous Na 2 SO 4 Drying and concentrating to obtain a crude product. Silica gel column chromatography (DCM: meOH) afforded the title compound 7a. Yellow oil, yield 35.4%. 1 H NMR(CDCl 3 ,400MHz),δ:8.18(1H,s,-CHO),8.04(1H,d,J＝1.8Hz,5-H),7.95(1H,s,-2-H),7.52(1H,dd,J＝8.6,2.0Hz,7-H),7.39(1H,d,J＝8.6Hz,8-H),6.98(2H,d,J＝8.8Hz,Ar-H),6.50(2H,d,J＝8.8Hz,Ar-H),6.07(1H,d,J＝7.7Hz,-NH),5.16,5.06(each 1H,d,J＝12.4Hz,-CH 2 ),4.92(1H,m,-CH),3.62(4H,m,-CH 2 ),3.56(4H,m,-CH 2 ),3.08,3.03(each 1H,dd,J＝14.0,5.5Hz,-CH 2 ),2.47(3H,s,-CH 3 )； 13 C NMR(CDCl 3 ,100MHz),δ:176.54,171.27,160.44,156.03,154.73,145.12,135.77,135.42,130.71(2),125.25,124.22,123.67,118.63,118.00,112.05(2),59.37,53.45(2),52.03,40.29(2),36.66,20.98；HRMS(ESI)m/z calcd for C 25 H 25 Cl 2 N 2 O 5 [M-H] - 503.1141,found 503.1129。
Example 2
Example 1 the procedure for the synthesis of 3a in step (1) was replaced by: 553mg of Compound 1b (3.33 mmol) were dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) were added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystallization is separated out, suction filtration and drying are carried out, and intermediate 2b 410mg is obtained. 55mg of intermediate 2b (0.27 mmol) were dissolved in 10mL of isopropanol and 1g of basic Al was added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completed, suction filtration, filtrate concentration to get crude product, silica gel column chromatography (DCM: meOH) separation to get compound 3b (R = -OCH) 3 )。
The remaining procedure referred to the synthetic method of example 1 yielded compound 7b as a yellow oil in 39.2% yield. 1 H NMR(CDCl 3 ,400MHz),δ:8.18(1H,s,-CHO),7.96(1H,s,2-H),7.60(1H,d,J＝3.1Hz,5-H),7.43(1H,d,J＝9.1Hz,8-H),7.30(1H,dd,J＝9.1,3.1Hz,7-H),6.98(2H,d,J＝8.7Hz,Ar-H),6.50(2H,d,J＝8.7Hz,Ar-H),6.06(1H,d,J＝7.6Hz,-NH),5.16,5.08(each1H,d,J＝12.4Hz,-CH 2 ),4.92(1H,m,-CH),3.91(3H,s,-OCH 3 ),3.63(4H,m,-CH 2 ),3.57(4H,m,-CH 2 ),3.09,3.03(each 1H,m,-CH 2 )； 13 C NMR(CDCl 3 ,100MHz),δ:176.31,171.27,160.45,157.30,155.81,151.28,145.20,130.69(2),124.62,124.21,124.14,119.67,118.02,112.00(2),105.01,59.39,56.00,53.43(2),52.04,40.33(2),36.66；HRMS(ESI)m/z calcd for C 25 H 25 Cl 2 N 2 O 6 [M-H] - 519.1090,found 519.1094。
Example 3
Example 1 the procedure for the synthesis of 3a in step (1) was replaced by: 500mg of compound 1a (3.33 mmol) was dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) was added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystal precipitation is carried out, suction filtration and drying are carried out, and intermediate 2a 402.4mg is obtained. 50mg of intermediate 2a (0.27 mmol) are dissolved in 10mL of isopropanol and 1g of basic Al are added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completion, suction filtration, filtrate concentration to get crude product, silica gel column chromatography (DCM: meOH) separation to get compound 3a 15mg. 500mg of compound 3a (2.62 mmol) was dissolved in 10mL of DCM, 750. Mu.L of phosphorus tribromide (7.90 mmol) was added dropwise under ice bath, reacted for 10min, and transferred to room temperature for reaction for 15h. TLC monitoring, reaction completion, dichloromethane extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 652mg of a yellow solid. The resulting solid was dissolved in 10mL of DMF, and 10mL of aqueous ammonia was added to the solution to react at room temperature overnight. TLC monitoring, complete reaction, ethyl acetate extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. Separating by silica gel column chromatography (DCM: meOH) to obtain compound 4a (R = -CH) 3 )。
Example 1 the procedure for the synthesis of 7a in step (3) was replaced by: 26.4mg of compound 4a (0.14 mmol) was dissolved in 4mL of anhydrous dichloromethane, and 39.9mg of EDCI (0.21 mmol), 22.5mg of HOBt (0.17 mmol), 46.5mg of compound 6a (0.14 mmol) were added and reacted at room temperature for 6h. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane 3 times, washed with saturated brine 1 time, and anhydrous Na 2 SO 4 Drying and concentrating to obtain a crude product. Silica gel column chromatography (DCM: meOH) afforded title compound 7c.
The remaining steps were performed according to example 1 to obtain compound 7c as a white solid with a yield of 61.0%. 1 H NMR(CDCl 3 ,400MHz),δ:8.18(1H,s,-CHO),7.99(1H,s,2-H),7.96(1H,d,J＝2.1Hz,5-H),7.51(1H,dd,J＝8.6,2.1Hz,7-H),7.38(1H,d,J＝6.8Hz,8-H),6.95(2H,d,J＝8.7Hz,Ar-H),6.73(1H,m,-NH),6.44(1H,m,-NH),6.42(2H,J＝8.7Hz,Ar-H),4.68(1H,m,-CH),4.24,4.17(each 1H,dd,J＝14.3,6.5Hz,-CH2),3.54(8H,m,-CH 2 ),3.00,2.90(each 1H,dd,J＝14.0,5.5Hz,-CH 2 ),2.47(3H,s,-CH 3 )； 13 C NMR(CDCl 3 ,100MHz),δ:177.7,170.5,160.6,154.8,154.4,145.0,135.5,135.3,130.6(2),124.9,124.8,123.5,120.4,118.1,112.0(2),53.4(2),53.1,40.3(2),37.6,35.7,21.0；HRMS(ESI)m/z calcd for C 25 H 26 Cl 2 N 3 O 4 [M-H] - 502.1300,found 502.1294。
Example 4
Example 1 the procedure for the synthesis of 3a in step (1) was replaced by: 553mg of Compound 1b (3.33 mmol) were dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) were added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystallization is separated out, suction filtration and drying are carried out, and intermediate 2b 410mg is obtained. 55mg of intermediate 2b (0.27 mmol) were dissolved in 10mL of isopropanol and 1g of basic Al was added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completion, suction filtration and filtrate concentrationThe crude product was condensed and isolated using silica gel column chromatography (DCM: meOH = 300) to give compound 3b 22mg. 540mg of compound 3b (2.62 mmol) was dissolved in 10mL of DCM, 750. Mu.L of phosphorus tribromide (7.90 mmol) was added dropwise in an ice bath, reacted for 10min, and transferred to room temperature for reaction for 15h. TLC monitoring, reaction completion, dichloromethane extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Dried, filtered and concentrated to afford 681mg of a yellow solid. The resulting solid was dissolved in 10mL of DMF, and 10mL of aqueous ammonia was added to the solution to react at room temperature overnight. TLC monitoring, complete reaction, ethyl acetate extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. Separating by silica gel column chromatography (DCM: meOH) to obtain compound 4b (R = -OCH) 3 )。
Example 1 the procedure for the synthesis of 7a in step (3) was replaced by: 28.7mg of compound 4b (0.14 mmol) were dissolved in 4mL of anhydrous dichloromethane, and 39.9mg of EDCI (0.21 mmol), 22.5mg of HOBt (0.17 mmol), 46.5mg of compound 6a (0.14 mmol) were added and reacted at room temperature for 6h. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane 3 times, washed with saturated brine 1 time, and anhydrous Na 2 SO 4 Drying and concentrating to obtain a crude product. Silica gel column chromatography (DCM: meOH) afforded title compound 7d.
The remaining steps were performed according to the synthetic method of example 1 to obtain compound 7d as a white oil with a yield of 51.2%. 1 H NMR(CDCl 3 ,600MHz),δ:8.18(1H,s,-CHO),7.99(1H,s,2-H),7.52(1H,d,J＝2.8Hz,5-H),7.43(1H,d,J＝9.0Hz,8-H),7.30(1H,dd,J＝9.0,2.8Hz,7-H),6.97(2H,d,J＝8.3Hz,Ar-H),6.64(1H,m,-NH),6.44(2H,d,J＝8.3Hz,Ar-H),6.30(1H,d,J＝6.1Hz,-NH),4.66(1H,m,-CH),4.23(2H,m,-CH 2 ),3.90(3H,s,-OCH 3 ),3.55(8H,m,-CH 2 ),3.01,2.91(each 1H,m,-CH 2 )； 13 C NMR(CDCl 3 ,150MHz),δ:117.5,170.5,160.6,157.1,154.1,151.4,145.0,130.6(2),124.7,124.4,124.1,119.8,119.7,112.0(2),104.7,56.0,53.4(2),53.1,40.3(2),37.5,35.7；HRMS(ESI)m/z calcd for C 25 H 26 Cl 2 N 3 O 5 [M-H] - 518.1250,found 518.1246。
Example 5
Example 1 the procedure for the synthesis of 6a in step (2) was replaced by: 100.5mg of melphalan 5 (0.33 mmol) was dissolved in 10mL of dioxane, and then 0.9mL of di-tert-butyl carbonate (3.92 mmol) and 0.59mL of triethylamine (4.26 mmol) were added to the solution, followed by reaction at room temperature for 6 hours. After completion of the reaction, an appropriate amount of water was added, and extraction was performed 3 times with methylene chloride, washing with saturated brine was performed 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 6b (R) 1 ＝-OC(CH 3 ) 3 )。
The remaining steps were performed according to the synthetic method of example 1 to obtain compound 8a as colorless oil in 39.2% yield. 1 H NMR(CDCl 3 ,400MHz),δ:8.03(1H,d,J＝1.8Hz,5-H),7.91(1H,s,2-H),7.51(1H,dd,J＝8.6,1.8Hz,7-H),7.38(1H,d,J＝8.6Hz,8-H),6.97(2H,d,J＝8.7Hz,Ar-H),6.47(2H,d,J＝8.7Hz,Ar-H),5.13,5.04(each 1H,d,J＝12,7Hz,-CH 2 ),4.99(1H,d,J＝7.8Hz,-NH),4.54,(1H,m,-CH),3.62(4H,m,-CH 2 ),3.55(4H,m,-CH 2 ),3.02,2.95(each 1H,m,-CH 2 ),2.46(3H,s,-CH 3 ),1.41(9H,s,t-Bu-H)； 13 C NMR(CDCl 3 ,100MHz),δ:176.51,172.09,155.80,155.13,154.70,144.99,135.63,135.31,130.69(2),125.24,124.77,123.66,118.84,117.95,111.99(2),79.93,58.96,54.63,53.46(2),40.33(2),37.14,28.31(3),20.97；HRMS(ESI)m/z calcd for C 29 H 33 Cl 2 N 2 O 6 [M-H] - 575.1716,found 575.1713。
Example 6
Example 1 the procedure for the synthesis of 3a in step (1) was replaced by: convert 553mg intoCompound 1b (3.33 mmol) was dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) was added dropwise and reacted at room temperature for 12h. TLC monitoring, reaction is almost complete, 15mL water is added, crystallization is separated out, suction filtration and drying are carried out, and intermediate 2b 410mg is obtained. 55mg of intermediate 2b (0.27 mmol) were dissolved in 10mL of isopropanol and 1g of basic Al was added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completed, suction filtration, filtrate concentration to get crude product, silica gel column chromatography (DCM: meOH) separation to get compound 3b (R = -OCH) 3 )。
Example 1 the procedure for the synthesis of 6a in step (2) was replaced by: 100.5mg of melphalan 5 (0.33 mmol) was dissolved in 10mL of dioxane, and then 0.9mL of di-tert-butyl carbonate (3.92 mmol) and 0.59mL of triethylamine (4.26 mmol) were added to the solution, followed by reaction at room temperature for 6 hours. After the reaction was completed, an appropriate amount of water was added, and extracted with dichloromethane 3 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 6b (R) 1 ＝-OC(CH 3 ) 3 )。
The remaining steps were performed as in example 1 to provide compound 8b as a colorless oil in 35.9% yield. 1 H NMR(CDCl 3 ,400MHz),δ:7.91(1H,s,2-H),7.59(1H,d,J＝3.1Hz,5-H),7.41(1H,d,J＝9.2Hz,8-H),7.28(1H,dd,J＝9.2,3.1Hz,7-H),6.97(2H,d,J＝8.7Hz,Ar-H),6.49(2H,d,J＝8.7Hz,Ar-H),5.14,5.05(each 1H,d,J＝12.6Hz,-CH 2 ),5.00(1H,d,J＝8.2Hz,-NH),4.54(1H,m,-CH),3.89(3H,s,-OCH 3 ),3.63(4H,m,-CH 2 ),3.55(4H,m,-CH 2 ),3.01,2.96(each 1H,m,-CH 2 ),1.41(9H,s,t-Bu-H)； 13 C NMR(CDCl 3 ,100MHz),δ:176.26,172.09,157.21,155.58,155.14,151.25,144.97,130.68(2),124.84,124.59,124.10,119.62,118.23,112.04(2),104.99,79.92,58.99,55.97,54.64,53.48(2),40.33(2),37.14,28.31(3)；HRMS(ESI)m/z calcd for C 29 H 33 Cl 2 N 2 O 7 [M-H] - 591.1665,found 591.1677。
Example 7
Example 1 the procedure for the synthesis of 3a in step (1) was replaced by: 500mg of compound 1a (3.33 mmol) was dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) was added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystallization is generated, suction filtration and drying are carried out, and intermediate 2a 402.4mg is obtained. 50mg of intermediate 2a (0.27 mmol) are dissolved in 10mL of isopropanol and 1g of basic Al are added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completion, suction filtration, filtrate concentration to get crude product, silica gel column chromatography (DCM: meOH) separation to get compound 3a 15mg. 500mg of Compound 3a (2.62 mmol) was dissolved in 10mL of DCM, 750. Mu.L of phosphorus tribromide (7.90 mmol) was added dropwise in an ice bath, reacted for 10min, and transferred to room temperature for reaction for 15h. TLC monitoring, reaction completion, dichloromethane extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 652mg of a yellow solid. The resulting solid was dissolved in 10mL of DMF, and 10mL of aqueous ammonia was added to the solution to react at room temperature overnight. TLC monitoring, complete reaction, ethyl acetate extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. Separating by silica gel column chromatography (DCM: meOH) to obtain compound 4a (R = -CH) 3 )。
Example 1 the procedure for the synthesis of 6a in step (2) was replaced by: 100.5mg of melphalan 5 (0.33 mmol) was dissolved in 10mL of dioxane, and then 0.9mL of di-tert-butyl carbonate (3.92 mmol) and 0.59mL of triethylamine (4.26 mmol) were added to the solution, followed by reaction at room temperature for 6 hours. After completion of the reaction, an appropriate amount of water was added, and extraction was performed 3 times with methylene chloride, washing with saturated brine was performed 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 6b (R) 1 ＝-OC(CH 3 ) 3 )。
Example 1 the procedure for the synthesis of 7a in step (3) was replaced by: 26.4mg of compound 4a (0.14 mmol) were dissolved in 4mL of anhydrous dichloromethane, and 39.9mg of EDCI (0.21 mmol), 22.5mg of HOBt (0.17 mmol), 56.6mg of compound 6b (0.14 mmol) were added and reacted at room temperature for 6h. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane 3 times, washed with saturated brine 1 time, and washed with anhydrous Na 2 SO 4 Drying and concentratingAnd (5) condensing to obtain a crude product. Silica gel column chromatography (DCM: meOH) afforded title compound 8c.
The remaining steps were performed as in example 1 to provide compound 8c as a white oil in 49.4% yield. 1 H NMR(CDCl 3 ,400MHz),δ:8.00(1H,s,2-H),7.95(1H,d,J＝2.1Hz,5-H),7.50(1H,dd,J＝8.6,2.1Hz,7-H),7.37(1H,d,J＝8.6Hz,8-H),6.96(2H,d,J＝8.6Hz,Ar-H),6.64(1H,m,-NH),6.43(2H,J＝8.6Hz,Ar-H),5.00(1H,s,-NH),4.2(3H,m,-CH 2 ,-CH),3.55(8H,m,-CH 2 ),2.97,2.88(each 1H,m,-CH 2 ),2.46(3H,s,-CH 3 ),1.39(9H,s,t-Bu-H)； 13 C NMR(CDCl 3 ,100MHz),δ:177.7,171.5,154.8,154.3,144.9,135.3,135.2,130.6(2),125.2,124.9,123.6,120.6,118.0,112.0(2),80.1,55.8,53.4(2),40.3(2),37.6,35.4,29.7,28.3(3),21.0；HRMS(ESI)m/z calcd for C 29 H 34 Cl 2 N 3 O 5 [M-H] - 574.1876,found 574.1889。
Example 8
Example 1 the procedure for the synthesis of 3a in step (1) was replaced by: 553mg of Compound 1b (3.33 mmol) were dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) were added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystallization is separated out, suction filtration and drying are carried out, and intermediate 2b 410mg is obtained. 55mg of intermediate 2b (0.27 mmol) were dissolved in 10mL of isopropanol and 1g of basic Al was added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completion, suction filtration, filtrate concentration to get crude product, silica gel column chromatography (DCM: meOH) separation to get compound 3b 22mg. 540mg of compound 3b (2.62 mmol) was dissolved in 10mL of DCM, 750. Mu.L of phosphorus tribromide (7.90 mmol) was added dropwise in an ice bath, reacted for 10min, and transferred to room temperature for reaction for 15h. TLC monitoring, reaction completion, dichloromethane extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Dried, filtered and concentrated to afford 681mg of a yellow solid. The resulting solid was dissolved in 10mL of DMF, and 10mL of ammonia water was added thereto, and the mixture was cooled in a chamberThe reaction was warmed overnight. TLC monitoring, complete reaction, ethyl acetate extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. Separating by silica gel column chromatography (DCM: meOH) to obtain compound 4b (R = -OCH) 3 )。
Example 1 the procedure for the synthesis of 6a in step (2) was replaced by: after 100.5mg of melphalan 5 (0.33 mmol) was dissolved in 10mL of dioxane, 0.9mL of di-tert-butyl carbonate anhydride (3.92 mmol) and 0.59mL of triethylamine (4.26 mmol) were added and the mixture was reacted at room temperature for 6 hours. After the reaction was completed, an appropriate amount of water was added, and extracted with dichloromethane 3 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 6b (R) 1 ＝-OC(CH 3 ) 3 )。
Example 1 the procedure for the synthesis of 7a in step (3) was replaced by: 28.7mg of compound 4b (0.14 mmol) were dissolved in 4mL of anhydrous dichloromethane, and 39.9mg of EDCI (0.21 mmol), 22.5mg of HOBt (0.17 mmol), 56.6mg of compound 6b (0.14 mmol) were added and reacted at room temperature for 6h. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane 3 times, washed with saturated brine 1 time, and washed with anhydrous Na 2 SO 4 Drying and concentrating to obtain a crude product. Silica gel column chromatography (DCM: meOH) afforded title compound 8d.
The remaining steps were performed according to example 1 to obtain compound 8d as a colorless oil in 34.6% yield. 1 H NMR(CDCl 3 ,400MHz),δ:8.00(1H,s,2-H),7.52(1H,d,J＝3.0Hz,5-H),7.42(1H,d,J＝9.2Hz,8-H),7.28(1H,dd,J＝9.2,3.0Hz,7-H),6.98(2H,d,J＝8.7Hz,Ar-H),6.63(1H,m,-NH),6.46(2H,d,J＝8.7Hz),4.97(1H,s,-NH),4.23(2H,m,-CH 2 ),3.89(3H,s,-OCH 3 ),3.56(8H,m,-CH 2 ),2.96,2.89(each 1H,m,-CH 2 ),1.39(9H,s,t-Bu-H)； 13 C NMR(CDCl 3 ,100MHz),δ:177.5,171.5,157.0,154.1(2),151.4,144.9,130.6(2),125.2,124.5,124.0,120.1,119.7,112.1(2),104.7,55.9(2),53.4(2),40.3(2),37.5,35.4,29.7,28.3(3)；HRMS(ESI)m/z calcd for C 29 H 34 Cl 2 N 3 O 6 [M-H] - 590.1825,found 590.1823。
Example 9
The following are the results of pharmacological experiments with some of the compounds of the invention:
experimental equipment and reagent
Instrument clean bench (Sujing group Antai company)
Constant temperature incubator (Thermo electronic Corporation)
Enzyme-linked immunosorbent assay (BIO-RAD company)
Inverted biological microscope (Chongqing optical instrument factory)
Reagent cell culture Medium RPMI-1640, DMEM (high sugar) (GIBCO Co., ltd.)
Fetal bovine serum (Hangzhou Sijiqing Co., ltd.)
CCK-8 (Biosharp company product)
DMSO (Sigma Co.)
Cell lines of human breast cancer cells MCF-7, human breast cancer cells MDA-MB-231,
Human liver cancer cell HepG2, bel-7402
Experimental methods
Cell inhibitory Activity test method
Cells at 37 deg.C, 5% 2 Culturing in an incubator with saturated humidity. The culture solution is high-glucose DMEM cell culture medium containing 10% heat-inactivated fetal calf serum, penicillin 100U/mL and streptomycin 100U/mL. The culture medium was changed for 48h, and after the cells were attached to the wall, they were digested with 0.25% trypsin for passage. The cells for experiment are all in logarithmic growth phase, and the CCK-8 method shows the cell activity>95％。
Taking a bottle of cells in logarithmic growth phase, adding digestive juice (0.125% trypsin +0.01% EDTA) for digestion, and counting 2-4 × 10 4 cell/mL, preparing cell suspension, inoculating on 96-well plate, 100 μ L/well, and placing in constant temperature CO 2 The culture was carried out in an incubator for 24 hours. The solution was changed, and the test drug was added at 100. Mu.L/well and cultured for 72 hours. CCK-8 was added to 96-well plates at 50. Mu.L/well and incubated in an incubator for 4 hours. The supernatant was aspirated, DMSO was added at 200. Mu.L/well and shaken on a shaker for 10 min. The test substances were examined at 6 concentrations of 0.001 to 100. Mu.M in ten-fold increments, and the cell inhibition rate at each concentration was calculated by measuring the absorbance of each well at a wavelength of 450nm using an enzyme-linked immunosorbent assay.
The inhibition rate calculation method comprises the following steps:
relative OD of drug sensitive wells = absolute OD of drug sensitive wells-absolute OD of blank control wells
Results of the experiment
TABLE 1 examples IC for antiproliferative activity against 2 human breast cancer and 1 human hepatoma cell lines 50 Value (μ M)
Pharmacological tests prove that the target derivative has better anti-breast cancer and anti-liver cancer cell proliferation activity, and can be used for further preparing anti-tumor drugs.
Claims (5)
1. A nitrogen mustard chromone derivative shown in a general formula I and pharmaceutically acceptable salts thereof:
wherein R is methyl or methoxy; r is 1 Is H or tert-butyl oxygen; the heteroatom X is NH or O.
2. A pharmaceutical composition characterized by: the pharmaceutical composition contains a therapeutically effective amount of the nitrogen mustard chromone derivative shown in the general formula I in claim 1 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
3. The use of the nitrogen mustard chromone derivative of the general formula I in claim 1 and the pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment of neoplastic diseases.
4. Use of the pharmaceutical composition of claim 2 for the preparation of a medicament for the treatment of a neoplastic disease.
5. Use according to claim 3 or 4, characterized in that: the tumor is breast cancer tumor or liver cancer tumor.
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