CN113788809B - 3-site mosaic nitrogen mustard derivative of chromone and application - Google Patents
3-site mosaic nitrogen mustard derivative of chromone and application Download PDFInfo
- Publication number
- CN113788809B CN113788809B CN202111229054.1A CN202111229054A CN113788809B CN 113788809 B CN113788809 B CN 113788809B CN 202111229054 A CN202111229054 A CN 202111229054A CN 113788809 B CN113788809 B CN 113788809B
- Authority
- CN
- China
- Prior art keywords
- mmol
- compound
- reaction
- chromone
- nitrogen mustard
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses 3-site mosaic mustard derivatives of chromone and application thereof, belonging to the field of natural medicines and medicinal chemistry. In particular to a preparation method of a series of chromone 3-site mosaic nitrogen mustard derivatives with anti-tumor activity and new application in anti-tumor drugs. The chromone 3-position split nitrogen mustard derivative and pharmaceutically acceptable salt thereof are shown as a general formula I. Wherein R, n and X are as described in the claims and the description.
Description
Technical Field
The invention belongs to the field of natural medicines and medicinal chemistry, and relates to 3-site mosaic nitrogen mustard derivatives of chromone and application thereof, in particular to a preparation method of a series of chromone 3-site mosaic nitrogen mustard derivatives with anti-tumor activity and application thereof in the aspect of anti-tumor.
Background
Chromone is a class of oxygen-containing heterocyclic compounds with benzo-gamma-pyrone skeletons, and is the core skeleton of some flavonoids. Because of its easy synthesis and various structures, it plays an important role in the field of pharmaceutical chemistry and is an advantageous structure for drug development. Meanwhile, the chromone compound has wide pharmacological activity and exerts certain anti-tumor effect through different action mechanisms. Therefore, the structure of the chromone is modified, and the development of an anti-tumor candidate drug with better activity is promoted.
The nitrogen mustard medicine is one kind of broad spectrum antitumor chemotherapeutic medicine. The action mechanism is that highly active intermediates with electron deficiency or other compounds with active electrophilic groups can be formed in vivo, and then covalent irreversible combination is carried out on the intermediates and biological macromolecules, so that DNA molecules lose activity or are broken. The use of large doses of nitrogen mustard causes serious side effects and drug resistance, and limits the further clinical application of the nitrogen mustard. 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 a chromone 3-site split nitrogen mustard derivative with good anti-tumor activity and pharmaceutically acceptable salts thereof, and further provides a pharmaceutical composition.
In order to solve the technical problems, the invention provides the following technical scheme:
a chromone 3-position split nitrogen mustard 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; n is an integer of 1 to 8; the heteroatom X is N, O, S or Se.
Preferably, R is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms; n is an integer of 1 to 6; 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; n is an integer of 1 to 4; the heteroatom X is N or O.
Further, the following derivatives and pharmaceutically acceptable salts thereof are preferably selected from the following structural formulas a-h:
the derivative of the invention can be prepared by the following method, comprising the following steps:
(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) Melphalan 5 in methanol solvent in the presence of thionyl chloride gives intermediate 6; reacting the intermediate 6 with succinic anhydride in dichloromethane in the presence of 4-dimethylaminopyridine to obtain a compound 7a; or the intermediate 6 reacts with succinic anhydride in dichloromethane in the presence of 4-dimethylaminopyridine to obtain a compound 7b;
(3) Dissolving the compound 3a-b or 4a-b in anhydrous dichloromethane, sequentially adding EDCI, DMAP or HOBt, and reacting with the compound 7a-b at room temperature to obtain target compounds 8a-d and 9a-d.
A pharmaceutical composition, which comprises a therapeutically effective amount of the chromone 3-position split nitrogen mustard derivative shown in the general formula I, and pharmaceutically acceptable salts and pharmaceutically acceptable carriers thereof.
The chromone 3-position split nitrogen mustard derivative shown in the general formula I and the application of the pharmaceutically acceptable salt thereof in preparing the medicine for treating tumor diseases.
Furthermore, the tumor is breast cancer tumor or liver cancer tumor.
The application of the pharmaceutical composition in preparing medicines 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 a class of chromone 3-site split nitrogen mustard derivatives, and tests the biological activity of the synthesized derivatives in the aspect of anti-tumor.
Pharmacological tests prove that the chromone 3-site mosaic nitrogen mustard 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, 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 (R = -CH) 3 )。
(2) 301.3mg of melphalan 5 (0.99 mmol) are dissolved in 10mL of methanol, 287. Mu.L of SOCl are added 2 (3.96 mmol) and then the reaction was refluxed at 65 ℃ for 6h. After the reaction was completed, the reaction solution was spin-dried to obtain intermediate 6.2mg. 448.2mg of intermediate 6 (1.41 mmol), 482.2mg of succinic anhydride (4.23 mmol) and 172.3mg of 4-dimethylaminopyridine (1.41 mmol) are dissolved in 15mL of dichloromethane and stirred at room temperature for 18h. The reaction is completed, dichloromethane is used for extraction for 3 times, saturated salt water is used for washing for 1 time, and the reaction is anhydrousDrying with sodium sulfate, filtering, and concentrating to obtain crude compound. Column chromatography on silica gel (DCM: meOH) afforded compound 7a (n = 2).
(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), 87.8mg of compound 7a (0.21 mmol) were added and reacted at room temperature for 12h. 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 8a. Yellow solid, yield 65.4%. 1 H NMR(CDCl 3 ,400MHz),δ:8.04(1H,s,2-H),8.00(1H,d,J＝2.0Hz,5-H),7.48(1H,dd,J＝8.6,2.0Hz,7-H),7.35(1H,d,J＝8.6Hz,8-H),6.98(2H,d,J＝8.8Hz,Ar-H),6.61(2H,d,J＝8.8Hz,Ar-H),6.11(1H,d,J＝7.8Hz,-NH),5.07(2H,s,-CH 2 ),4.80(1H,m,-CH),3.72(3H,s,-OCH 3 ),3.70(4H,m,-CH 2 ),3.61(4H,m,-CH 2 ),3.04,2.98(each 1H,dd,J＝14.0,5.7Hz,-CH 2 ),2.66(2H,m,-CH 2 ),2.50(2H,t,J＝7.0Hz,-CH 2 ),2.45(3H,s,-CH 3 )； 13 C NMR(CDCl 3 ,100MHz),δ:176.73,172.63,172.06,170.84,155.39,154.76,144.93,135.47,135.19,130.61(2),125.16,123.65,119.17,117.97,112.31(2),58.63,53.61(2),53.01,52.31,40.35(2),36.68,30.79,29.44,20.97；HRMS(ESI)m/z calcd for C 29 H 31 Cl 2 N 2 O 7 [M-H] - 589.1508,found 589.1506。
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 then 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 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, concentration of filtrate to obtain crude product, separation by silica gel column chromatography (DCM: meOH) to obtain compound 3b (R = -OCH) 3 )。
The remaining steps were performed according to the synthetic method of example 1 to prepare compound 8b as a yellow solid with a yield of 62.3%. 1 H NMR(CDCl 3 ,400MHz),δ:8.05(1H,s,2-H),7.58(1H,d,J＝3.1Hz,5-H),7.39(1H,d,J＝9.2Hz,8-H),7.26(1H,dd,J＝9.2,3.1Hz,7-H),6.98(2H,d,J＝8.7Hz,Ar-H),6.62(2H,d,J＝8.7Hz,Ar-H),6.08(1H,d,J＝7.9Hz,-NH),5.08(2H,s,-CH 2 ),4.80(1H,m,-CH),3.89(3H,s,-OCH 3 ),3.72(3H,s,-OCH 3 ),3.70(4H,m,-CH 2 ),3.62(4H,m,-CH 2 ),3.04,2.99(each 1H,m,-CH 2 ),2.67(2H,m,-CH 2 ),2.51(2H,m,-CH 2 )； 13 C NMR(CDCl 3 ,100MHz),δ:176.5,172.6,172.0,170.8,157.1,155.3,151.3,144.9,130.6(2),125.1,124.6,124.0,119.6,118.6,112.4(2),104.9,58.6,55.9,53.7(2),53.3,52.3,40.3(2),36.7,30.8,29.4；HRMS(ESI)m/z calcd for C 29 H 31 Cl 2 N 2 O 8 [M-H] - 605.1457,found 605.1450。
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, 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, and 750. Mu.L of phosphorus tribromide (7.90 mmol) was added dropwise under ice bath to react for 10min, and transferring 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 8a 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), 58.5mg of compound 7a (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 8c.
The remaining procedure referred to the synthetic method of example 1 yielded compound 8c as a white oil in 54.4% yield. 1 H NMR(CDCl 3 ,400MHz),δ:8.04(1H,s,2-H),7.96(1H,d,J＝2.1Hz,5-H),7.47(1H,dd,J＝8.6,2.1Hz,7-H),7.33(1H,d,J＝8.6Hz,8-H),6.96(2H,d,J＝8.7Hz,Ar-H),6.77(1H,m,-NH),6.59(2H,d,J＝8.7Hz,Ar-H),6.39(1H,d,J＝7.7Hz,-NH),4.76(1H,m,-CH),4.24(2H,d,J＝6.1Hz,-CH 2 ),3.68(7H,m,-CH2,-OCH 3 ),3.60(4H,m,-CH 2 ),3.00,2.94(each 1H,m,-CH 2 ),2.50(2H,m,-CH 2 ),2.47(2H,m,-CH 2 ),2.44(3H,s,-CH 3 )； 13 C NMR(CDCl 3 ,100MHz),δ:178.1,172.2,172.1,171.7,154.9,154.3,145.1,135.3,135.2,130.5(2),124.9,124.8,123.6,120.8,118.0,112.2(2),53.5(2),53.4,52.2,40.4(2),36.7,35.8,31.4,31.3,20.9；HRMS(ESI)m/z calcd for C 29 H 32 Cl 2 N 3 O 6 [M-H] - 588.1674,found 588.1677。
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 then 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 carried out, suction filtration and drying are carried out, and the 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, reaction was complete, suction filtered and the filtrate was concentrated to give crude product which was isolated using silica gel column chromatography (DCM: meOH = 300. 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 8a 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), 58.5mg of compound 7a (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 the synthetic method of example 1 to obtain compound 8d as a white oil with a yield of 36.5%. 1 H NMR(CDCl 3 ,400MHz),δ:8.06(1H,s,2-H),7.53(1H,d,J＝3.1Hz,5-H),7.37(1H,d,J＝9.1Hz,8-H),7.25(1H,dd,J＝9.1,3.1Hz,7-H),6.95(2H,d,J＝8.6Hz,Ar-H),6.73(1H,m,-NH),6.58(2H,d,J＝8.6Hz,Ar-H),6.34(1H,d,J＝7.7Hz,-NH),4.76(1H,m,-CH),4.25(2H,d,J＝6.0Hz),3.88(3H,s,-OCH 3 ),3.68(7H,m,-OCH 3 ,-CH 2 ),3.60(4H,m,-CH 2 ),3.00,2.94(each 1H,m,-CH 2 ),2.52,2.47(each 2H,m,-CH 2 )； 13 C NMR(CDCl 3 ,100MHz),δ:177.8,172.1,172.1,171.5,157.0,154.1,151.5,145.1,130.5(2),124.8,124.5,124.0,120.2,119.7,112.1(2),104.6,55.9,53.5(2),53.4,52.2,40.4(2),36.7,35.8,31.4,31.3；HRMS(ESI)m/z calcd for C 29 H 32 Cl 2 N 3 O 7 [M-H] - 604.1623,found 604.1627。
Example 5
Example 1 the procedure for the synthesis of 7a in step (2) was replaced by: 448.2mg of intermediate 6 (1.41 mmol), 423.3mg of succinic anhydride (4.23 mmol) and 172.3mg of 4-dimethylaminopyridine (1.41 mmol) are dissolved in 15mL of dichloromethane and stirred at room temperature for 18h. The reaction was completed, extracted with dichloromethane 3 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound. Column chromatography on silica gel (DCM: meOH) afforded compound 7b (n = 3).
The remaining steps were performed according to the synthetic method of example 1 to obtain compound 9a as a white oil in 46.7% yield. 1 H NMR(CDCl 3 ,400MHz),δ:8.05(1H,s,2-H),8.01(1H,d,J＝2.0Hz,5-H),7.49(1H,dd,J＝8.6,2.0Hz,7-H),7.37(1H,d,J＝8.6Hz,8-H),6.98(2H,d,J＝8.7Hz,Ar-H),6.61(2H,d,J＝8.7Hz,Ar-H),6.19(1H,d,J＝8.0Hz,-NH),5.03(2H,s,-CH 2 ),4.82(1H,m,-CH),3.71(3H,s,-OCH 3 ),3.69(4H,m,-CH 2 ),3.60(4H,m,-CH 2 ),3.05,2.95(each 1H,dd,J＝13.9,5.7Hz,-CH 2 ),2.45(3H,s,-CH 3 ),2.24(2H,t,J＝7.1Hz,-CH 2 ),1.92(2H,m,-CH 2 )； 13 C NMR(CDCl 3 ,100MHz),δ:176.92,173.13,172.22,171.81,155.65,154.79,144.77,135.57,135.29,130.56(2),125.21,123.71,119.21,118.01,112.44(2),58.50,53.67(2),53.16,52.29,40.30(2),36.82,35.09,33.10,20.97,20.89；HRMS(ESI)m/z calcd for C 30 H 33 Cl 2 N 2 O 7 [M-H] - 603.1665,found 603.1667。
Example 6
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 then 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 carried out, suction filtration and drying are carried out, and the 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 7a in step (2) was replaced by: 448.2mg of intermediate 6 (1.41 mmol), 423.3mg of succinic anhydride (4.23 mmol) and 172.3mg of 4-dimethylaminopyridine (1.41 mmol) were dissolved in 15mL of dichloromethane and stirred at room temperature for 18 hours. The reaction was completed, extracted with dichloromethane 3 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound. Column chromatography on silica gel (DCM: meOH) afforded compound 7b (n = 3).
The remaining steps were performed according to the synthetic method of example 1 to obtain compound 9b as colorless oil with a yield of 64.7%. 1 H NMR(CDCl 3 ,400MHz),δ:8.07(1H,s,2-H),7.60(1H,d,J＝3.1Hz,5-H),7.41(1H,d,J＝9.1Hz,8-H),7.28(1H,dd,J＝9.1,3.1Hz,7-H),6.98(2H,d,J＝8.7Hz,Ar-H),6.61(2H,d,J＝8.7Hz,Ar-H),6.17(1H,d,J＝7.9Hz,-NH),5.05(2H,s,-CH 2 ),4.82(1H,m,-CH),3.89(3H,s,-OCH 3 ),3.71(3H,s,-OCH 3 ),3.68(4H,m,-CH 2 ),3.61(4H,m,-CH 2 ),3.06,2.96(each 1H,m,-CH 2 ),2.36(2H,m,-CH 2 ),2.25(2H,m,-CH 2 ),1.93(2H,m,-CH 2 )； 13 C NMR(CDCl 3 ,100MHz),δ:176.7,173.1,172.2,171.8,157.2,155.5,151.4,144.9,130.5(2),125.2,124.7,124.1,119.7,118.6,112.4(2),105.0,58.5,56.0,53.6,53.1(2),52.3,40.3(2),36.8,35.1,33.1,20.9；HRMS(ESI)m/z calcd for C 30 H 33 Cl 2 N 2 O 8 [M-H] - 619.1614,found 619.1616。
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, 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 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 7a in step (2) was replaced by: 448.2mg of intermediate 6 (1.41 mmol), 423.3mg of succinic anhydride (4.23 mmol) and 172.3mg of 4-dimethylaminopyridine (1.41 mmol) were dissolved in 15mL of dichloromethane and stirred at room temperature for 18 hours. The reaction was completed, extracted with dichloromethane 3 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound. Column chromatography on silica gel (DCM: meOH) afforded compound 7b (n = 3).
Example 1 the procedure for the synthesis of 8a 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), 60.5mg of compound 7b (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 9c.
The remaining steps were performed according to the synthetic method of example 1 to prepare compound 9c as a white solid with a yield of 37.3%. 1 H NMR(CDCl 3 ,400MHz),δ:8.14(1H,s,2-H),7.99(1H,d,J＝2.0Hz,5-H),7.51(1H,dd,J＝8.6,2.1Hz,7-H),7.39(1H,d,J＝8.6Hz,8-H),7.22(1H,m,-NH),7.17(2H,d,J＝8.7Hz,Ar-H),6.87(1H,d,J＝8.2Hz,-NH),6.64(2H,d,J＝8.7Hz,Ar-H),4.84(1H,m,-CH),4.23,4.13(each 1H,m,-CH 2 ),3.76(3H,s,-OCH 3 ),3.71(4H,m,-CH 2 ),3.62(4H,m,-CH 2 ),3.16,3.10(each 1H,m,-CH 2 ),2.48(3H,s,-CH 3 ),2.10(2H,m,-CH 2 ),1.95(2H,m,-CH 2 ),1.83(2H,m,-CH 2 )； 13 C NMR(CDCl 3 ,100MHz),δ:178.6,173.7,173.1,172.6,155.3,155.0,145.1,135.4,135.3,130.4(2),125.6,124.8,123.7,120.7,118.2,112.1(2),53.6(2),52.5,40.4(2),36.5,36.3,34.7,34.4,29.7,22.0,21.1；HRMS(ESI)m/z calcd for C 30 H 34 Cl 2 N 3 O 6 [M-H] - 602.1830,found 602.1837。
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, room temperatureThe reaction is carried out 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 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 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 (2) was replaced by: 448.2mg of intermediate 6 (1.41 mmol), 423.3mg of succinic anhydride (4.23 mmol) and 172.3mg of 4-dimethylaminopyridine (1.41 mmol) were dissolved in 15mL of dichloromethane and stirred at room temperature for 18 hours. The reaction was completed, extracted with dichloromethane 3 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound. Column chromatography on silica gel (DCM: meOH) afforded compound 7b (n = 3).
Example 1 the procedure for the synthesis of 8a in step (3) was replaced by: 28.7mg of compound 4b (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), 60.5mg of compound 7b (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 9d.
The remaining steps were performed according to the synthetic method of example 1 to obtain compound 9d as a white oil with a yield of 42.9%. 1 H NMR(CDCl 3 ,400MHz),δ:8.12(1H,s,2-H),7.56(1H,d,J＝3.1Hz,5-H),7.43(1H,d,J＝9.2Hz,8-H),7.30(1H,dd,J＝9.2,3.1Hz,7-H),7.12(2H,d,J＝8.7Hz,Ar-H),6.90(1H,d,J＝8.2Hz,-NH),6.62(2H,d,J＝8.2Hz,Ar-H),4.83(1H,m,-CH),4.24,4.15(each 1H,m,-CH 2 ),3.89(3H,s,-OCH 3 ),3.73(3H,s,-OCH 3 ),3.70(4H,m,-CH 2 ),3.60(4H,m,-CH 2 ),3.14,3.07(each 1H,m,-CH 2 ),2.11(2H,m,-CH 2 ),1.99(2H,m,-CH 2 ),1.84(2H,m,-CH 2 )； 13 C NMR(CDCl 3 ,100MHz),δ:178.3,173.5,173.4,172.7,157.1,155.2,151.6,145.1,130.4(2),125.5,124.6,123.9,119.9,119.8,112.2(2),104.8,55.9,53.5(2),52.5,40.4(2),36.5,36.3,34.7,34.5,29.7,21.9；HRMS(ESI)m/z calcd for C 30 H 34 Cl 2 N 3 O 7 [M-H] - 618.1774,found 618.1776。
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 cell MCF-7, human breast cancer cell MDA-MB-231,
Human liver cancer cell HepG2, bel-7402
Experimental method
Cell inhibitory activity test method
Cells at 37 deg.C, 5% 2 Culturing in an incubator with saturated humidity. The culture medium contains 10% heat-inactivated fetal calf serum, and penicillin 100U-mL and streptomycin 100U/mL high glucose DMEM cell culture medium. 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, 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 for 6 concentrations of 0.001 to 100. Mu.M in ten-fold increasing concentrations, and the absorbance of each well was measured at a wavelength of 450nm using an enzyme-linked immunosorbent assay to calculate the cell inhibitory rate at each concentration.
The inhibition rate calculation method comprises the following steps:
relative OD value of drug sensitive wells = absolute OD value of drug sensitive wells-absolute OD value of blank control wells
Results of the experiment
TABLE 1 IC for antiproliferative activity of examples on 2 human breast cancers and 1 human hepatoma cell lines 50 Value (μ M)
Pharmacological tests prove that the target derivative has certain anti-breast cancer and anti-liver cancer cell proliferation activity, and can be used for further preparing anti-tumor drugs.
Claims (5)
1. A chromone 3-position split nitrogen mustard derivative shown in a general formula I and pharmaceutically acceptable salts thereof:
wherein R is methyl or methoxy; n is 2 or 3; the heteroatom X is NH or O.
2. A pharmaceutical composition characterized by: the pharmaceutical composition comprises a therapeutically effective amount of the chromone 3-split nitrogen mustard derivative shown in the general formula I in claim 1 and pharmaceutically acceptable salts and carriers thereof.
3. The use of the chromone 3-position split nitrogen mustard derivative shown in the general formula I and the pharmaceutically acceptable salt thereof in the claim 1 for preparing the medicine for treating tumor 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111229054.1A CN113788809B (en) | 2021-10-21 | 2021-10-21 | 3-site mosaic nitrogen mustard derivative of chromone and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111229054.1A CN113788809B (en) | 2021-10-21 | 2021-10-21 | 3-site mosaic nitrogen mustard derivative of chromone and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113788809A CN113788809A (en) | 2021-12-14 |
| CN113788809B true CN113788809B (en) | 2023-02-28 |
Family
ID=79185186
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111229054.1A Active CN113788809B (en) | 2021-10-21 | 2021-10-21 | 3-site mosaic nitrogen mustard derivative of chromone and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113788809B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0374789A1 (en) * | 1988-12-19 | 1990-06-27 | Kyowa Hakko Kogyo Co., Ltd. | 5- Aminoflavone derivatives |
| CN102993148A (en) * | 2011-09-13 | 2013-03-27 | 复旦大学 | Quercetin derivatives or analogs thereof, and application thereof |
| CN106566276A (en) * | 2016-10-23 | 2017-04-19 | 深圳大学 | Low toxicity washing-free biological fluorescent dye, preparation method and application thereof |
| CN108864024A (en) * | 2018-08-10 | 2018-11-23 | 沈阳药科大学 | A kind of Scutellarein mustargen analog derivative and its preparation method and application |
| CN109134487A (en) * | 2018-08-10 | 2019-01-04 | 沈阳药科大学 | Compound and its preparation method and application of the one kind containing benzoic acid nitrogen mustard segment |
| CN113416189A (en) * | 2021-07-14 | 2021-09-21 | 沈阳药科大学 | Beta-cabbagine mustard derivative, preparation method and anti-tumor application |
-
2021
- 2021-10-21 CN CN202111229054.1A patent/CN113788809B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0374789A1 (en) * | 1988-12-19 | 1990-06-27 | Kyowa Hakko Kogyo Co., Ltd. | 5- Aminoflavone derivatives |
| CN102993148A (en) * | 2011-09-13 | 2013-03-27 | 复旦大学 | Quercetin derivatives or analogs thereof, and application thereof |
| CN106566276A (en) * | 2016-10-23 | 2017-04-19 | 深圳大学 | Low toxicity washing-free biological fluorescent dye, preparation method and application thereof |
| CN108864024A (en) * | 2018-08-10 | 2018-11-23 | 沈阳药科大学 | A kind of Scutellarein mustargen analog derivative and its preparation method and application |
| CN109134487A (en) * | 2018-08-10 | 2019-01-04 | 沈阳药科大学 | Compound and its preparation method and application of the one kind containing benzoic acid nitrogen mustard segment |
| CN113416189A (en) * | 2021-07-14 | 2021-09-21 | 沈阳药科大学 | Beta-cabbagine mustard derivative, preparation method and anti-tumor application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113788809A (en) | 2021-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108864024B (en) | Scutellarin aglycone nitrogen mustard derivative and preparation method and application thereof | |
| CN104072493A (en) | Naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, preparation method and application thereof | |
| CN113416189B (en) | Beta-carbopol Lin Dangai derivative, preparation method and anti-tumor application | |
| CN111072682A (en) | Chelidonine furazan nitric oxide donor derivative and preparation method and application thereof | |
| CN113717138B (en) | Nitrogen mustard chromone derivatives and application thereof | |
| CN110981882B (en) | Chelidonium nitric oxide donor derivatives, and preparation method and application thereof | |
| CN110981881B (en) | Chelidonine nitric oxide donor derivative and preparation method and application thereof | |
| CN113788809B (en) | 3-site mosaic nitrogen mustard derivative of chromone and application | |
| CN108276424B (en) | Plectranthin type kaurane diterpene assembled nitrogen mustard derivative and preparation method and application thereof | |
| CN106928293A (en) | One class has furazan NO donator type scutellarin derivatives of antitumor activity and its production and use | |
| CN110964033B (en) | Oridonin 14-position hydrogen sulfide donor derivative and preparation method and application thereof | |
| CN113788810B (en) | Chromone nitrogen mustard derivative and anti-tumor application | |
| CN113563330B (en) | 3-position derivative of beta-carbopol as well as preparation method and application thereof | |
| CN110759961B (en) | Ursolic acid indolyquinone amide derivatives and preparation method and application thereof | |
| CN106883277A (en) | One class has furazan class NO donator type scutellarin derivatives of antitumor activity and its production and use | |
| CN110950883A (en) | 1-site oxidation oridonin hydrogen sulfide donor derivative and application thereof | |
| CN109810119B (en) | Isodon japonicus type diterpene derivative and preparation method and application thereof | |
| CN113563331B (en) | Nitrogen mustard beta-carbopol derivative and preparation method and application thereof | |
| CN112745310B (en) | Chromone 2-piperazine linked furazan derivative and preparation method and application thereof | |
| CN111635396B (en) | Spirolactone type diterpene split hydrogen sulfide donor derivative and preparation method and application thereof | |
| CN109336901B (en) | Plectranthin type diterpene 6, 14-position split hydrogen sulfide donor derivative | |
| CN113651867B (en) | Sulfonamide 18 beta-glycyrrhetinic acid derivative and preparation method and application thereof | |
| CN111635395B (en) | Spirolactone type diterpene derivative, preparation method and anti-tumor application thereof | |
| CN110981886A (en) | Hydrogen sulfide donor derivative of diterpene dimer and preparation method and application thereof | |
| CN109776411B (en) | Nitrogen mustard carbostyril derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |