CN114539195A - Ludartin derivative, pharmaceutical composition thereof, preparation method and application thereof - Google Patents

Ludartin derivative, pharmaceutical composition thereof, preparation method and application thereof Download PDF

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CN114539195A
CN114539195A CN202210213959.8A CN202210213959A CN114539195A CN 114539195 A CN114539195 A CN 114539195A CN 202210213959 A CN202210213959 A CN 202210213959A CN 114539195 A CN114539195 A CN 114539195A
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ludartin
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陈纪军
李天泽
孙金金
王金平
马云保
黄晓燕
耿长安
胡敬
张雪梅
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Kunming Institute of Botany of CAS
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Abstract

The invention provides ludartin derivatives 1-26 shown in a structural formula (I), a pharmaceutical composition thereof, and a preparation method and application thereof. Belongs to the technical field of medicines. The ludartin derivative has obvious cytotoxic activity on HepG2 and Huh7 human liver cancer cell lines, can form a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient, and can be used for preparing anti-liver cancer drugs.

Description

Ludartin derivative, pharmaceutical composition thereof, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to ludartin derivatives (1-26), a pharmaceutical composition taking the ludartin derivatives as active ingredients, a preparation method of the ludartin derivatives, and application of the ludartin derivatives and the pharmaceutical composition thereof in preparation of anti-liver cancer medicines.
Background
Liver cancer is divided into primary and secondary types, is a global disease, and is 90.5 thousands of newly-increased patients in 2020 world, 83 thousands of deaths, and the incidence rate is continuously increased, which is expected to exceed 100 thousands in 2025. Hepatocellular carcinoma accounts for about 90% of primary liver cancer, and the pathogenesis is complex and influenced by a plurality of factors, including nonalcoholic fatty liver, hepatitis B, hemochromatosis or liver cirrhosis caused by primary cholangitis and the like. Currently marketed drugs for treating liver cancer are the tyrosine kinase inhibitors sorafenib, ranvatinib, regorafenib, cabozantinib and ramucirumab, and the PD-1 inhibitors palbociclumab and nivolumizumab. Recently, the national drug administration approved alcaladine for the treatment of hepatocellular carcinoma. The medicine for treating liver cancer has made great progress, but has the defects of obvious toxic and side effects, intolerance, high price and the like, and a novel anti-liver cancer medicine still needs to be developed. Natural products and derivatives thereof play an important role in the development of new drugs due to various structures and biological activities of the natural products and the derivatives thereof, and in recent years, a plurality of reports show that various sesquiterpenes have cytotoxic activity on liver cancer cells.
The guaiane-type sesquiterpenes of the genus Ludartin are isolated from plants such as Artemisia quinquefolia (Artemisia indica), Echinacea angustifolia (Waldheima glabra) and Artemisia carruthii. Recent studies have shown that ludartin has various biological activities, such as gastric cytoprotective effect, aromatase inhibitory activity, cytotoxic activity, and the like. In previous studies by the applicant ludartin was found to have inhibitory effects on HepG2 and Huh7 hepatoma cells. In the prior art, no ludartin derivative 1-26 synthesis method, no compound 1-26 in the preparation of anti-liver cancer drugs, and no pharmaceutical composition containing the compound as an active ingredient are reported.
Disclosure of Invention
The invention aims to provide novel ludartin derivatives 1-26, a preparation and synthesis method thereof, a pharmaceutical composition using the novel ludartin derivatives as an active ingredient, and application of the novel ludartin derivatives as a medicament for treating liver cancer. The invention carries out structural modification on ludartin to synthesize a new derivative, and provides a new anti-liver cancer active compound.
In order to achieve the above object, the present invention provides the following technical solutions:
ludartin derivatives (1-26) represented by structural formula (I) or pharmaceutically acceptable salts thereof,
Figure BDA0003531533320000021
according to the ludartin derivatives 1-26 or the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable salts refer to pharmaceutically acceptable salts and comprise salts formed by organic acids or inorganic acids, wherein the organic acids are citric acid, maleic acid and fumaric acid, and the inorganic acids are hydrochloric acid, sulfuric acid and phosphoric acid.
The invention also provides a method for preparing ludartin derivatives 1-26, which comprises the following steps:
preparation of Compounds 1-2:
methanol is used as a solvent, ludartin is prepared into a compound 1 under the action of concentrated sulfuric acid, and ludartin is subjected to epoxy ring opening under the action of a proper fluorinating reagent to prepare a compound 2, wherein the proper fluorinating reagent comprises hydrofluoric acid and salt thereof or boron trifluoride diethyl etherate.
Preparation of Compounds 3-26:
taking ludartin as a raw material, carrying out epoxy ring opening under the action of perchloric acid aqueous solution to obtain a ludartin glycol derivative, and preparing a compound 3 from glycol under the action of formic acid; preparing a compound 4 from diol under the action of acetic anhydride and 4-dimethylaminopyridine; the diol is subjected to esterification condensation with the corresponding acid under the action of a suitable condensation reagent to obtain the compounds 5-18,20-21,23 and 25-26, wherein the suitable condensation reagent is N, N '-dicyclohexylcarbodiimide or N, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; carrying out amidation reaction on maleic anhydride and dimethylamine under an alkaline condition, and then carrying out esterification condensation on maleic anhydride and diol to obtain a compound 19; carrying out esterification condensation on diol and 4- (tert-butyloxycarbonylamino) benzoic acid, removing tert-butyloxycarbonylamino under an acidic condition, and then condensing with trans-4-dimethylaminocroton to obtain a compound 22; and (3) performing alkylation reaction on the compound 23 and benzyl bromide under an alkaline condition to obtain a compound 24.
The invention also provides application of the Ludartin derivatives (1-26) in preparation of anti-liver cancer drugs.
Further, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the ludartin derivatives (1-26) and a pharmaceutically acceptable carrier.
Meanwhile, a method for preparing a pharmaceutical composition containing effective components of the ludartin derivatives (1-26) is provided, the compound ludartin is taken as a reaction raw material, the ludartin derivatives (1-26) are synthesized, and pharmaceutically acceptable carriers are respectively added.
Also provides the application of the pharmaceutical composition in preparing anti-liver cancer drugs.
When the compound of the present invention is used as a medicament, it may be used as it is or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99%, preferably 0.5-90% of the compound of the present invention, and the balance pharmaceutically acceptable carriers which are non-toxic and inert to humans and animals.
The pharmaceutically acceptable carrier is one or more of solid, semi-solid and liquid diluents, fillers and pharmaceutical adjuvants. The pharmaceutical composition of the present invention is used in the form of a dose per unit body weight. The medicine of the present invention may be administrated through injection and oral taking.
Compared with the prior art, the invention has the following advantages:
1. the present invention provides a series of novel ludartin derivatives 1-26. Fills the blank of the prior art.
2. The invention provides a method for preparing new compounds 1-26, which has the advantages of easily obtained raw materials, short synthetic route, high yield and easy industrial production, and can be separated and extracted from plants in a large amount.
3. The invention provides a pharmaceutical composition with the new compounds 1-26 as effective components, and provides a new drug with better medicinal effect for a new anti-liver cancer drug.
4. The compounds 1-26 of the invention have stronger activity on the cytotoxic activity of three liver cancer cells (HepG2, SK-HEP-1 and Huh 7); the 12 compounds (2-3, 7-9, 13, 16, 20-22 and 24-25) have obviously enhanced cytotoxic activity on HepG2 cells compared with the original compound ludartin, and IC is50The value is between 1.6 and 23.3 mu M; the 14 compounds (2, 8-9, 12-13, 16-22 and 24-25) have remarkably enhanced cytotoxic activity on Huh7 cells, and IC50The value is between 2.0 and 25.1 mu M; in particular, the cytotoxic activity of the compound 25 on HepG2 and Huh7 is improved by 20 times and 17 times compared with ludartin respectively, and is 5 times of that of the positive drug sorafenib.
Ludartin derivatives 1-26 can be used as medicaments for treating liver cancer related diseases.
Drawings
FIG. 1 is a schematic diagram showing the structural formulae of Ludartin derivatives 1-26, i.e., compounds 1-26, according to the present invention.
Detailed Description
In order to better understand the essence of the present invention, the following experimental examples of the present invention will be used to illustrate the synthesis method and pharmacological effect results of ludartin derivatives of the present invention, but the present invention is not limited thereto.
The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Example 1
Preparation of compound 1:
Figure BDA0003531533320000041
in a 10mL round bottom flask at room temperature, ludartin (100mg,0.4mmol) was dissolved in a methanol solution of sulfuric acid (0.1M, 2mL) and reacted at room temperature for 10min, then saturated sodium bicarbonate solution was added to quench the reaction, ethyl acetate (5mL) was extracted three times, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and isolated by silica gel column chromatography (acetone-petroleum ether, 15:85) to give compound 1 in 67% yield.
The characteristics are as follows: white solid
Melting point: 162-164 ℃;
and (3) optical rotation:
Figure BDA0003531533320000051
(c 0.112,CH3OH)；
HRESIMS (+) m/z calculated value C16H23O4([M+H]+)279.1591, Experimental value 279.1596,
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.84-2.74(2H,m,H-2),4.12(1H,d,J＝4.0Hz,H-3),2.30(1H,d,J＝16.3Hz,H-5),4.04(1H,t,J＝10.1Hz,H-6),2.08-2.02(1H,m,H-7),2.71-2.64(1H,m,H-8),1.41-1.31(1H,m,H-8),2.25-2.18(2H,m,H-9),6.15(1H,d,J＝3.2Hz,H-13),5.42(1H,d,J＝2.9Hz,H-13),1.73(3H,s,H-14),1.58(3H,s,H-15),3.26(3H,s,H-16)；13C NMR(100MHz,CDCl3)δ131.6(C,C-1),40.0(CH2,C-2),82.3(CH,C-3),86.7(C,C-4),50.9(CH,C-5),73.9(CH,C-6),55.5(CH,C-7),25.8(CH2,C-8),35.0(CH2,C-9),133.0(C,C-10),139.9(C,C-11),170.8(C,C-12),118.3(CH2,C-13),24.8(CH3,C-14),17.1(CH3,C-15),50.3(CH3,C-16).
example 2
Preparation of compound 2:
Figure BDA0003531533320000052
ludartin (50mg,0.2mmol) was dissolved in dichloromethane (2mL) in a 10mL two-necked flask at room temperature, followed by addition of pyridinium hydrofluoric acid (27 μ L,0.3mmol), reaction at room temperature for 1 hour, quenching with water, extraction three times with ethyl acetate (5mL), combination of organic phases and washing with saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure to remove the solvent, and separation by silica gel column chromatography (acetone-petroleum ether, 15:85) to give compound 2 in 78% yield.
The characteristics are as follows: white solid
Melting point: 190-192 ℃;
and (3) optical rotation:
Figure BDA0003531533320000053
(c 0.109,CH3OH)；
HRESIMS (+) m/z calculated value C15H20O3F([M+H]+)267.1391, Experimental value 267.1408,
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.79-2.70(2H,m,H-2),4.01-3.98(1H,m,H-3),2.39(1H,d,J＝16.9Hz,H-5),3.92(1H,t,J＝10.2Hz,H-6),2.24-2.18(1H,m,H-7),2.32-2.25(1H,m,H-8),1.40-1.30(1H,m,H-8),2.95-2.86(1H,m,H-9),2.10-2.05(1H,m,H-9),6.15(1H,d,J＝3.1Hz,H-13),5.43(1H,d,J＝2.8Hz,H-13),1.75(6H,s,H-14,H-15)；13C NMR(100MHz,CDCl3)δ132.6(C,C-1),39.3(CH2,C-2),81.4(CH,C-3),81.5(C,C-4),51.7(CH,C-5),77.0(CH,C-6),53.3(CH,C-7),25.7(CH2,C-8),34.8(CH2,C-9),133.1(C,C-10),139.5(C,C-11),170.2(C,C-12),118.6(CH2,C-13),24.6(CH3,C-14),20.2(CH3,C-15).
example 3
Preparation of compound 3:
Figure BDA0003531533320000061
in a 250mL round bottom flask at room temperature, ludartin (1g,4.07mmol) was dissolved in ethylene glycol dimethyl ether (50mL), 6% perchloric acid solution (25mL) was added, the reaction was quenched at room temperature for 3h with saturated sodium bicarbonate solution, ethyl acetate (30mL) was extracted three times, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and isolated by silica gel column chromatography (acetone-petroleum ether, 20:80) to give the diol in 87% yield.
Diol (21mg,0.08mmol) was dissolved in 4mL formic acid at room temperature, reacted for 9h at room temperature and quenched by addition of saturated sodium bicarbonate solution, extracted three times with ethyl acetate (5mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and isolated by silica gel column chromatography (acetone-petroleum ether, 15:85) to give compound 3 in 64% yield.
The characteristics are as follows: white solid
Melting point: 180-182 deg.C
And (3) optical rotation:
Figure BDA0003531533320000062
(c 0.130,CH3OH)
HRESIMS (+) m/z calculated value C16H21O5([M+H]+)293.1384, Experimental value 293.1410
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.91-2.87(1H,m,H-2),2.23-2.17(1H,m,H-2),5.04(1H,d,J＝4.5Hz,H-3),2.43(1H,d,J＝17.2Hz,H-5),3.97(1H,t,J＝10.2Hz,H-6),2.12-2.07(1H,m,H-7),2.33-2.25(1H,m,H-8),1.40-1.31(1H,m,H-8),2.82-2.74(2H,m,H-9),6.18(1H,d,J＝3.2Hz,H-13),5.46(1H,d,J＝3.0Hz,H-13),1.72(3H,s,H-14),1.54(3H,s,H-15),7.99(1H,s,H-16)；13C NMR(100MHz,CDCl3)δ132.4(C,C-1),37.1(CH2,C-2),80.6(CH,C-3),82.2(C,C-4),51.2(CH,C-5),82.5(CH,C-6),54.9(CH,C-7),25.7(CH2,C-8),34.5(CH2,C-9),133.2(C,C-10),139.1(C,C-11),169.8(C,C-12),119.0(CH2,C-13),24.2(CH3,C-14),24.0(CH3,C-15),160.2(CH,C-16).
example 4
Preparation of compound 4:
Figure BDA0003531533320000071
diol (21mg,0.08mmol) was dissolved in dichloromethane (1mL) and added to a 10mL round bottom flask at room temperature, acetic anhydride (27. mu.L, 0.24mmol) and 4-dimethylaminopyridine (DMAP,2mg,0.02mmol) were added sequentially, after reaction for 3h at room temperature, a saturated sodium bicarbonate solution was added to quench the reaction, ethyl acetate (3mL) was extracted three times, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and then separated by silica gel column chromatography (acetone-petroleum ether, 10:90) to give compound 4 in 82% yield.
The characteristics are as follows: white powder
Melting point: 138-141 deg.C
And (3) optical rotation:
Figure BDA0003531533320000072
(c 0.109,CH3OH)
HRESIMS (+) m/z calculated value C17H23O5[M+H]+307.1540, Experimental value 307.1555
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.88-2.83(1H,m,H-2),2.28-2.25(1H,m,H-2),4.92(1H,d,J＝4.7Hz,H-3),2.37(1H,d,J＝17.2Hz,H-5),3.98(1H,t,J＝10.2Hz,H-6),2.22-2.16(1H,m,H-7),2.11-2.09(1H,m,H-8),1.40-1.30(1H,m,H-8),2.79-2.73(2H,m,H-9),6.17(1H,d,J＝3.2Hz,H-13),5.46(1H,d,J＝3.0Hz,H-13),1.71(3H,s,H-14),1.51(3H,s,H-15),2.05(3H,s,H-2′)；13C NMR(100MHz,CDCl3)δ132.1(C,C-1),37.3(CH2,C-2),80.9(CH,C-3),82.5(C,C-4),51.2(CH,C-5),82.8(CH,C-6),55.1(CH,C-7),25.9(CH2,C-8),34.6(CH2,C-9),133.6(C,C-10),139.3(C,C-11),170.0(C,C-12),119.1(CH2,C-13),24.4(CH3,C-14),24.0(CH3,C-15),170.4(C,C-1′),21.4(CH3,C-2′)
example 5
Preparation of compound 5:
Figure BDA0003531533320000081
in a 10mL round-bottom flask at room temperature, acrylic acid (0.16mmol) was dissolved in 1mL dichloromethane, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC, 28. mu.L, 0.16mmol), diol (21mg,0.08mmol) and 4-dimethylaminopyridine (DMAP,2mg,0.02mmol) were added in this order, reacted at room temperature for 10 hours, then quenched by the addition of 5% aqueous HCl, extracted three times with ethyl acetate (3mL), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and then isolated by silica gel column chromatography to give Compound 5 in 24% yield.
The characteristics are as follows: white solid
Melting point: 105-107 DEG C
And (3) optical rotation:
Figure BDA0003531533320000082
(c 0.050,acetone)
HRESIMS (+) m/z calculated value C18H23O5[M+H]+319.1540, Experimental value 319.1556
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.92-2.88(1H,m,H-2),2.12-2.07(1H,m,H-2),5.00(1H,d,J＝4.7Hz,H-3),2.43(1H,d,J＝17.2Hz,H-5),4.00(1H,t,J＝10.2Hz,H-6),2.24-2.22(1H,m,H-7),2.33-2.26(1H,m,H-8),1.42-1.32(1H,m,H-8),2.84-2.75(2H,m,H-9),6.19(1H,d,J＝3.2Hz,H-13),5.47(1H,d,J＝3.0Hz,H-13),1.72(3H,s,H-14),1.54(3H,s,H-15),6.11(1H,dd,J＝17.3Hz,J＝10.4Hz,H-2′),5.84(1H,d,J＝10.4Hz,H-3′),6.40(1H,d,J＝17.3Hz,H-3′)；13C NMR(100MHz,CDCl3)δ132.2(C,C-1),37.3(CH2,C-2),81.1(CH,C-3),82.6(C,C-4),51.2(CH,C-5),82.8(CH,C-6),55.2(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.5(C,C-10),139.3(C,C-11),170.0(C,C-12),119.1(CH2,C-13),24.4(CH3,C-14),24.1(CH3,C-15),165.5(C,C-1′),128.6(CH,C-2′),131.2(CH2,C-3′)。
example 6
Preparation of compound 6:
Figure BDA0003531533320000083
the required raw materials, reagents and preparation method were the same as example 5 except that acrylic acid was changed to n-octanoic acid, and the yield was 77%.
The characteristics are as follows: white solid
Melting point: 122-125 DEG C
And (3) optical rotation:
Figure BDA0003531533320000091
(c 0.130,acetone)
HRESIMS (+) m/z calculated value C23H35O5[M+H]+391.2479, Experimental value 391.2495
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.87-2.83(1H,m,H-2),2.22-2.16(1H,m,H-2),4.91(1H,d,J＝4.6Hz,H-3),2.36(1H,d,J＝17.2Hz,H-5),3.98(1H,t,J＝10.2Hz,H-6),2.10-2.07(1H,m,H-7),1.40-1.32(2H,m,H-8),2.79-2.73(2H,m,H-9),6.17(1H,d,J＝3.2Hz,H-13),5.45(1H,d,J＝3.0Hz,H-13),1.70(3H,s,H-14),1.51(3H,s,H-15),6.11(2H,t,J＝7.4Hz,H-2′),1.61-1.57(2H,m,H-3′),1.30-1.24(8H,m,H-4′～7′),0.86(3H,t,J＝6.6Hz)；13C NMR(100MHz,CDCl3)δ132.0(C,C-1),37.4(CH2,C-2),80.7(CH,C-3),82.5(C,C-4),51.2(CH,C-5),82.8(CH,C-6),55.1(CH,C-7),25.9(CH2,C-8),34.6(CH2,C-9),133.6(C,C-10),139.3(C,C-11),170.0(C,C-12),119.0(CH2,C-13),24.3(CH3,C-14),24.0(CH3,C-15),173.1(C,C-1′),34.7(CH2,C-2′),25.1(CH2,C-3′),29.0(CH2,C-4′),29.1(CH2,C-5′),31.8(CH2,C-6′),22.7(CH2,C-7′),14.2(CH3,C-8′).
example 7
Preparation of compound 7:
Figure BDA0003531533320000092
the required raw materials, reagents and preparation method were the same as example 5 except that acrylic acid was replaced with cyclopentanecarboxylic acid, and the yield was 87%.
The characteristics are as follows: colourless solid
Melting point: mp 120-122 deg.C
And (3) optical rotation:
Figure BDA0003531533320000093
(c 0.081,CH3OH)
HRESIMS (+) m/z calculated value C21H29O5[M+H]+361.2010, Experimental value 361.2013
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.88-2.82(1H,m,H-2),2.28-2.25(1H,m,H-2),4.90(1H,d,J＝4.6Hz,H-3),2.34(1H,d,J＝17.3Hz,H-5),3.98(1H,t,J＝10.1Hz,H-6),2.22-2.16(1H,m,H-7),2.72-2.66(1H,m,H-8),1.40-1.30(1H,m,H-8),2.80-2.73(2H,m,H-9),6.17(1H,d,J＝3.1Hz,H-13),5.45(1H,d,J＝2.8Hz,H-13),1.70(3H,s,H-14),1.51(3H,s,H-15),2.11-2.06(1H,m,H-2′),1.90-1.74(4H,m,H-3′,H-6′),1.68-1.54(4H,m,H-4′,H-5′)；13C NMR(100MHz,CDCl3)δ131.9(C,C-1),37.4(CH2,C-2),80.5(CH,C-3),82.5(C,C-4),51.2(CH,C-5),82.8(CH,C-6),55.1(CH,C-7),25.9(CH2,C-8),34.6(CH2,C-9),133.6(C,C-10),139.3(C,C-11),170.0(C,C-12),119.0(CH2,C-13),24.3(CH3,C-14),24.0(CH3,C-15),175.9(C,C-1′),44.1(CH,C-2′),30.3(CH2,C-3′),25.8(CH2,C-4′,C-5′),29.8(CH,C-6′).
example 8
Preparation of compound 8:
Figure BDA0003531533320000101
the required starting materials, reagents and preparation were the same as in example 5 except that acrylic acid was replaced with benzoic acid, and the yield was 83%.
The characteristics are as follows: white powder
Melting point: 88 to 90 DEG C
And (3) optical rotation:
Figure BDA0003531533320000102
(c 0.016,CHCl3)
HRESIMS (+) m/z calculated value C22H25O5[M+H]+369.1697, Experimental value 369.1701
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ3.01-2.91(2H,m,H-2),5.14(1H,d,J＝4.6Hz,H-3),2.53(1H,d,J＝17.2Hz,H-5),4.06(1H,t,J＝10.1Hz,H-6),2.12-2.06(1H,m,H-7),2.34-2.26(1H,m,H-8),1.43-1.33(1H,m,H-8),2.84-2.77(1H,m,H-9),2.24-2.17(1H,m,H-9),6.18(1H,d,J＝3.2Hz,H-13),5.47(1H,d,J＝2.9Hz,H-13),1.70(3H,s,H-14),1.63(3H,s,H-15),8.00-7.97(2H,m,H-3′,H-7′),7.45-7.42(2H,m,H-4′,H-6′),7.57-7.54(1H,m,H-5′)；13C NMR(100MHz,CDCl3)δ132.3(C,C-1),37.4(CH2,C-2),81.6(CH,C-3),82.7(C,C-4),51.2(CH,C-5),82.8(CH,C-6),55.3(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.2(C,C-10),139.3(C,C-11),170.1(C,C-12),119.1(CH2,C-13),24.4(CH3,C-14),24.3(CH3,C-15),165.8(C,C-1′),130.4(C,C-2′),129.7(CH,C-3′,C-7′),128.6(CH,C-4′,C-6′),133.4(CH,C-5′).
example 9
Preparation of compound 9:
Figure BDA0003531533320000111
the desired starting materials, reagents and preparation were the same as in example 5 except that acrylic acid was replaced with p-bromobenzoic acid, giving a yield of 52%.
The characteristics are as follows: white powder
Melting point: 51-53 deg.C
And (3) optical rotation:
Figure BDA0003531533320000112
(c 0.118,CH3OH)
HRESIMS (+) m/z calculated value C22H23O5BrNa[M+Na]+469.0621, Experimental value 469.0628
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.99-2.89(2H,m,H-2),5.12(1H,d,J＝4.6Hz,H-3),2.51(1H,d,J＝17.3Hz,H-5),4.04(1H,t,J＝10.1Hz,H-6),2.84-2.78(1H,m,H-7),2.31-2.29(1H,m,H-8),1.42-1.33(1H,m,H-8),2.23-2.08(2H,m,H-9),6.18(1H,d,J＝3.2Hz,H-13),5.47(1H,d,J＝2.9Hz,H-13),1.70(3H,s,H-14),1.60(3H,s,H-15),7.83(2H,d,J＝8.4Hz,H-3′,H-7′),7.56(2H,d,J＝8.4Hz,H-4′,H-6′)；13C NMR(100MHz,CDCl3)δ132.3(C,C-1),37.4(CH2,C-2),81.9(CH,C-3),82.5(C,C-4),51.1(CH,C-5),82.7(CH,C-6),55.3(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.2(C,C-10),139.2(C,C-11),170.0(C,C-12),119.1(CH2,C-13),24.4(CH3,C-14),24.2(CH3,C-15),165.1(C,C-1′),129.2(C,C-2′),131.9(CH,C-3′,C-7′),131.2(CH,C-4′,C-6′),128.3(C,C-5′).
example 10
Preparation of compound 10:
Figure BDA0003531533320000113
the required starting materials, reagents and preparation were carried out as in example 5, except that acrylic acid was replaced by 2-trifluoromethyl-benzoic acid, giving a yield of 38%.
The characteristics are as follows: white powder
Melting point: 154-156 DEG C
And (3) optical rotation:
Figure BDA0003531533320000121
(c 0.079,CHCl3)
HRESIMS (+) m/z calculated value C23H23O5F3Na[M+Na]+459.1390, Experimental value 459.1396
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.82-2.73(2H,m,H-2),5.14(1H,d,J＝4.5Hz,H-3),2.61(1H,d,J＝17.2Hz,H-5),4.00(1H,t,J＝10.2Hz,H-6),2.98-2.92(1H,m,H-7),2.31-2.25(1H,m,H-8),1.42-1.32(1H,m,H-8),2.23-2.10(2H,m,H-9),6.18(1H,d,J＝3.2Hz,H-13),5.46(1H,d,J＝3.0Hz,H-13),1.74(3H,s,H-14),1.59(3H,s,H-15),7.75-7.72(2H,m,H-3′,H-6′),7.65-7.58(2H,m,H-4′,H-5′)；13C NMR(100MHz,CDCl3)δ132.3(C,C-1),36.9(CH2,C-2),82.7(CH,C-3),82.5(C,C-4),51.5(CH,C-5),83.0(CH,C-6),55.0(CH,C-7),25.9(CH2,C-8),34.5(CH2,C-9),133.4(C,C-10),139.3(C,C-11),170.0(C,C-12),119.0(CH2,C-13),24.2(CH3,C-14),24.1(CH3,C-15),166.3(C,C-1′),126.9(C,C-2′),130.3(CH,C-3′),131.3(C,C-4′),132.0(CH,C-5′),126.8(CH,C-6′),131.5(CH,C-7′),124.8(C,CF3).
example 11
Preparation of compound 11:
Figure BDA0003531533320000122
the required starting materials, reagents and preparation were as in example 5 except that acrylic acid was replaced with 3-trifluoromethyl-benzoic acid, and the yield was 42%.
The characteristics are as follows: white solid
Melting point: 65-67 deg.C
And (3) optical rotation:
Figure BDA0003531533320000123
(c 0.136,CH3OH)
HRESIMS (+) m/z calculated value C23H24O5F3[M+H]+437.1570, Experimental value 437.1585
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ3.02-2.92(2H,m,H-2),5.17(1H,d,J＝4.6Hz,H-3),2.55(1H,d,J＝17.4Hz,H-5),4.05(1H,t,J＝10.1Hz,H-6),2.87-2.81(1H,m,H-7),2.36-2.29(1H,m,H-8),1.43-1.34(1H,m,H-8),2.21-2.09(2H,m,H-9),6.20(1H,d,J＝3.2Hz,H-13),5.49(1H,d,J＝2.9Hz,H-13),1.72(3H,s,H-14),1.63(3H,s,H-15),8.23(1H,s,H-3′),8.17(1H,d,J＝7.8Hz,H-5′),7.59(1H,t,J＝7.8Hz,H-6′),7.82(1H,d,J＝7.7Hz,H-7′)；13C NMR(100MHz,CDCl3)δ132.5(C,C-1),37.4(CH2,C-2),82.3(CH,C-3),82.6(C,C-4),51.1(CH,C-5),82.7(CH,C-6),55.3(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.2(C,C-10),139.2(C,C-11),169.9(C,C-12),119.2(CH2,C-13),24.4(CH3,C-14),24.3(CH3,C-15),164.6(C,C-1′),131.1(C,C-2′),126.6(CH,C-3′),131.5(C,C-4′),129.7(CH,C-5′),129.3(CH,C-6′),132.9(CH,C-7′),131.1(CF3).
example 12
Preparation of compound 12:
Figure BDA0003531533320000131
the required starting materials, reagents and preparation were as in example 5 except that acrylic acid was replaced with 4-trifluoromethyl-benzoic acid, and the yield was 41%.
The characteristics are as follows: white solid
Melting point: 82-84 DEG C
And (3) optical rotation:
Figure BDA0003531533320000132
(c 0.079,CHCl3)
HRESIMS(+)m/zcalculated value C23H24O5F3[M+H]+437.1570, Experimental value 437.1595
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ3.03-2.91(2H,m,H-2),5.16(1H,d,J＝4.6Hz,H-3),2.54(1H,d,J＝17.3Hz,H-5),4.05(1H,t,J＝10.1Hz,H-6),2.85-2.79(1H,m,H-7),2.31-2.27(1H,m,H-8),1.44-1.34(1H,m,H-8),2.25-2.08(2H,m,H-9),6.19(1H,d,J＝3.2Hz,H-13),5.48(1H,d,J＝2.9Hz,H-13),1.71(3H,s,H-14),1.62(3H,s,H-15),8.09(2H,d,J＝8.1Hz,H-3′,H-7′),7.70(2H,d,J＝8.1Hz,H-4′,H-6′)；13C NMR(100MHz,CDCl3)δ132.5(C,C-1),37.4(CH2,C-2),82.3(CH,C-3),82.5(C,C-4),51.2(CH,C-5),82.7(CH,C-6),55.3(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.1(C,C-10),139.2(C,C-11),170.0(C,C-12),119.2(CH2,C-13),24.4(CH3,C-14),24.2(CH3,C-15),164.6(C,C-1′),134.5(C,C-2′),130.1(CH,C-3′,C-7′),125.6(CH,C-4′,C-6′),134.9(C,C-5′),133.6(CF3).
example 13
Preparation of compound 13:
Figure BDA0003531533320000141
the required starting materials, reagents and preparation were the same as in example 5 except that acrylic acid was replaced with pentafluorobenzoic acid, and the yield was 32%.
The characteristics are as follows: white solid
Melting point: 40-42 DEG C
And (3) optical rotation:
Figure BDA0003531533320000142
(c 0.160,CH3OH)
HRESIMS (+) m/z calculated value C22H20O5F5[M+H]+459.1225, Experimental value 459.1235
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.84-2.76(2H,m,H-2),5.20(1H,d,J＝4.6Hz,H-3),2.54(1H,d,J＝17.4Hz,H-5),3.99(1H,t,J＝10.2Hz,H-6),2.99-2.95(1H,m,H-7),2.30-2.25(1H,m,H-8),1.40-1.34(1H,m,H-8),2.23-2.19(1H,m,H-9),2.12-2.08(1H,m,H-9),6.19(1H,d,J＝3.3Hz,H-13),5.47(1H,d,J＝3.1Hz,H-13),1.73(3H,s,H-14),1.62(3H,s,H-15)；13C NMR(100MHz,CDCl3)δ132.7(C,C-1),37.2(CH2,C-2),82.6(CH,C-3),82.3(C,C-4),51.3(CH,C-5),83.7(CH,C-6),55.0(CH,C-7),25.8(CH2,C-8),34.6(CH2,C-9),132.9(C,C-10),139.1(C,C-11),169.9(C,C-12),119.2(CH2,C-13),24.3(CH3,C-14),24.1(CH3,C-15),158.3(C,C-1′).
example 14
Preparation of compound 14:
Figure BDA0003531533320000143
the required raw materials, reagents and preparation method were the same as example 5 except that acrylic acid was changed to nicotinic acid, and the yield was 90%.
The characteristics are as follows: white powder
Melting point: 167-169 ℃ C
And (3) optical rotation:
Figure BDA0003531533320000151
(c 0.085,CH3OH)
HRESIMS (+) m/z calculated value C21H24NO5[M+H]+370.1649, Experimental value 370.1650
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ3.01-2.96(1H,m,H-2),2.24-2.18(1H,m,H-2),5.17(1H,d,J＝4.3Hz,H-3),2.53(1H,d,J＝17.2Hz,H-5),4.04(1H,t,J＝10.1Hz,H-6),2.14-2.08(1H,m,H-7),2.36-2.29(1H,m,H-8),1.43-1.33(1H,m,H-8),2.94-2.91(1H,m,H-9),2.86-2.80(1H,m,H-9),6.18(1H,d,J＝2.9Hz,H-13),5.48(1H,d,J＝2.5Hz,H-13),1.71(3H,s,H-14),1.61(3H,s,H-15),8.31-8.29(1H,m,H-3′),7.47-7.43(1H,m,H-4′),8.85-8.78(1H,m,H-5′),9.24-9.18(1H,m,H-6′)；13C NMR(100MHz,CDCl3)δ132.6(C,C-1),37.3(CH2,C-2),82.3(CH,C-3),82.4(C,C-4),51.1(CH,C-5),82.7(CH,C-6),55.3(CH,C-7),25.8(CH2,C-8),34.7(CH2,C-9),133.0(C,C-10),139.2(C,C-11),170.0(C,C-12),119.2(CH2,C-13),24.4(CH3,C-14),24.2(CH3,C-15),164.2(C,C-1′),123.8(C,C-2′),137.8(CH,C-3′,C-4′),153.4(CH,C-5′),150.8(CH,C-6′).
example 15
Preparation of compound 15:
Figure BDA0003531533320000152
the required raw materials, reagents and preparation method were the same as example 5 except that acrylic acid was changed to cinnamic acid, and the yield was 71%.
The characteristics are as follows: white solid
Melting point: 87 to 89 DEG C
And (3) optical rotation:
Figure BDA0003531533320000153
(c 0.084,CH3OH)
HRESIMS (+) m/z calculated value C24H27O5[M+H]+395.1853, Experimental value 395.1859
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.96-2.86(2H,m,H-2),5.06(1H,d,J＝4.6Hz,H-3),2.47(1H,d,J＝17.2Hz,H-5),4.02(1H,t,J＝10.1Hz,H-6),2.82-2.76(1H,m,H-7),2.35-2.27(1H,m,H-8),1.42-1.32(1H,m,H-8),2.24-2.19(1H,m,H-9),2.13-2.08(1H,m,H-9),6.19(1H,d,J＝3.2Hz,H-13),5.47(1H,d,J＝3.0Hz,H-13),1.73(3H,s,H-14),1.58(3H,s,H-15),6.42(1H,d,J＝16.0Hz,H-2′),7.67(1H,d,J＝16.0Hz,H-3′),7.53-7.51(2H,m,H-5′,H-9′),7.38-7.36(3H,m,H-6′,H-7′,H-8′)；13C NMR(100MHz,CDCl3)δ132.1(C,C-1),37.5(CH2,C-2),81.0(CH,C-3),82.6(C,C-4),51.2(CH,C-5),82.8(CH,C-6),55.2(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.6(C,C-10),139.3(C,C-11),170.0(C,C-12),119.0(CH2,C-13),24.4(CH3,C-14),24.1(CH3,C-15),166.3(C,C-1′),118.2(CH,C-2′),145.3(CH,C-3′),134.4(C,C-4′),128.2(CH,C-5′,C-9′),129.0(CH,C-6′,C-8′),130.5(CH,C-7′).
example 16
Preparation of compound 16:
Figure BDA0003531533320000161
the required raw materials, reagents and preparation method were the same as example 5 except that acrylic acid was changed to 3- (4-pyridyl) acrylic acid, and the yield was 51%.
The characteristics are as follows: white solid
Melting point: 123 to 125 DEG C
And (3) optical rotation:
Figure BDA0003531533320000162
(c 0.100,CH3OH)
HRESIMS (+) m/z calculated value C23H26NO5[M+H]+396.1805, Experimental value 396.1814.
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.98-2.91(1H,m,H-2),2.32-2.27(1H,m,H-2),5.07(1H,d,J＝4.6Hz,H-3),2.47(1H,d,J＝17.3Hz,H-5),4.02(1H,t,J＝10.2Hz,H-6),2.14-2.08(1H,m,H-7),2.25-2.19(1H,m,H-8),1.43-1.33(1H,m,H-8),2.88-2.76(2H,m,H-9),6.19(1H,d,J＝3.2Hz,H-13),5.48(1H,d,J＝2.9Hz,H-13),1.73(3H,s,H-14),1.58(3H,s,H-15),6.59(1H,d,J＝16.0Hz,H-2′),7.58(1H,d,J＝16.0Hz,H-3′),7.40-7.37(2H,m,H-5′,H-8′),8.68-8.65(2H,m,H-6′,H-7′)；13C NMR(100MHz,CDCl3)δ132.4(C,C-1),37.4(CH2,C-2),81.6(CH,C-3),82.5(C,C-4),51.3(CH,C-5),82.7(CH,C-6),55.2(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.4(C,C-10),139.2(C,C-11),170.0(C,C-12),119.2(CH2,C-13),24.4(CH3,C-14),24.1(CH3,C-15),165.3(C,C-1′),122.1(CH,C-2′),142.3(CH,C-3′),141.9(C,C-4′),123.1(CH,C-5′,C-8′),150.6(CH,C-6′,C-7′).
example 17
Preparation of compound 17:
Figure BDA0003531533320000171
the required starting materials, reagents and preparation were the same as in example 5 except that acrylic acid was replaced with quinoline-6-carboxylic acid, and the yield was 95%.
The characteristics are as follows: white solid
Melting point: 98-100 DEG C
And (3) optical rotation:
Figure BDA0003531533320000172
(c 0.101,CHCl3)
HRESIMS (+) m/z calculated value C25H26NO5[M+H]+420.1805, Experimental value 420.1809
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ3.05-2.97(2H,m,H-2),5.21(1H,d,J＝4.5Hz,H-3),2.57(1H,d,J＝17.3Hz,H-5),4.10(1H,t,J＝10.1Hz,H-6),2.87-2.83(1H,m,H-7),2.35-2.29(1H,m,H-8),1.43-1.33(1H,m,H-8),2.24-2.18(1H,m,H-9),2.12-2.07(1H,m,H-9),6.17(1H,d,J＝3.1Hz,H-13),5.46(1H,d,J＝2.8Hz,H-13),1.71(3H,s,H-14),1.67(3H,s,H-15),8.52(1H,s,H-3′),8.28-8.21(2H,m,H-5′,H-10′),7.48-7.45(1H,m,H-6′),8.99-8.98(1H,m,H-7′),8.15-8.13(1H,m,H-9′)；13C NMR(100MHz,CDCl3)δ132.3(C,C-1),37.5(CH2,C-2),82.1(CH,C-3),82.4(C,C-4),51.0(CH,C-5),82.7(CH,C-6),55.4(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.1(C,C-10),139.3(C,C-11),170.0(C,C-12),119.0(CH2,C-13),24.4(CH3,C-14),24.1(CH3,C-15),165.3(C,C-1′),128.3(C,C-2′),131.1(CH,C-3′),127.5(C,C-4′),137.5(CH,C-5′),122.0(CH,C-6′),152.6(CH,C-7′),150.1(C,C-8′),128.9(CH,C-9′),129.9(CH,C-10′).
example 18
Preparation of compound 18:
Figure BDA0003531533320000173
the required starting materials, reagents and preparation were the same as in example 5 except that acrylic acid was replaced with quinaldinic acid, and the yield was 87%.
The characteristics are as follows: white solid
Melting point: 90-92 DEG C
And (3) optical rotation:
Figure BDA0003531533320000181
(c 0.165,CHCl3)
HRESIMS (+) m/z calculated value C25H25NO5Na[M+Na]+442.1625, Experimental value 442.1629
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ3.07-2.99(2H,m,H-2),5.26(1H,d,J＝4.5Hz,H-3),2.64(1H,d,J＝17.4Hz,H-5),4.06(1H,t,J＝10.2Hz,H-6),2.84-2.78(1H,m,H-7),2.32-2.26(1H,m,H-8),1.42-1.32(1H,m,H-8),2.22-2.17(1H,m,H-9),2.12-2.06(1H,m,H-9),6.18(1H,d,J＝3.2Hz,H-13),5.46(1H,d,J＝2.9Hz,H-13),1.70(6H,s,H-14,H-15),8.04-8.02(1H,m,H-4′),7.79-7.74(1H,m,H-5′),7.87-7.85(1H,m,H-6′),8.29-8.26(2H,m,H-7′,H-9′),7.64-7.61(1H,m,H-10′)；13C NMR(100MHz,CDCl3)δ132.3(C,C-1),37.4(CH2,C-2),82.6(CH,C-3),82.7(C,C-4),51.0(CH,C-5),82.7(CH,C-6),55.3(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.2(C,C-10),139.3(C,C-11),170.0(C,C-12),119.1(CH2,C-13),24.4(CH3,C-14),24.2(CH3,C-15),164.4(C,C-1′),148.0(C,C-2′),147.9(C,C-3′),130.4(CH,C-4′),131.0(CH,C-5′),128.7(CH,C-6′),127.5(CH,C-7′),129.3(C,C-8′),137.3(CH,C-9′),120.9(CH,C-10′).
example 19
Preparation of compound 19:
Figure BDA0003531533320000182
maleic anhydride (49mg,0.5mmol) was dissolved in dichloromethane (2mL) at room temperature, dimethylamine (250. mu.L, 0.5mmol,2.0M in THF) and 4-dimethylaminopyridine (DMAP,7mg,0.06mmol) were added sequentially and reacted for 1h at room temperature, after which the solvent was removed by concentration under reduced pressure. The crude product was dissolved in dichloromethane (2mL) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC, 86. mu.L, 0.5mmol) and diol (26mg,0.1mmol) were added. After the reaction at room temperature overnight, water was added to quench the reaction, extracted three times with ethyl acetate (3mL), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and isolated by silica gel column chromatography (acetone-petroleum ether, 25:75) to give compound 19 in 89% yield.
The characteristics are as follows: white solid
Melting point: 92-94 DEG C
And (3) optical rotation:
Figure BDA0003531533320000183
(c 0.080,CH3OH)
HRESIMS (+) m/z calculated value C21H28NO6[M+H]+390.1911, Experimental value 390.1922
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.81-2.74(2H,m,H-2),4.98(1H,d,J＝4.5Hz,H-3),2.40(1H,d,J＝17.2Hz,H-5),3.97(1H,t,J＝10.1Hz,H-6),2.92-2.85(1H,m,H-7),2.10-2.05(1H,m,H-8),1.38-1.29(1H,m,H-8),2.27-2.19(2H,m,H-9),6.15(1H,d,J＝3.2Hz,H-13),5.45(1H,d,J＝3.0Hz,H-13),1.69(3H,s,H-14),1.51(3H,s,H-15),6.74(2H,d,J＝15.3Hz,H-2′),7.39(2H,d,J＝15.3Hz,H-3′),3.01(1H,s,H-5′),3.11(1H,s,H-6′)；13C NMR(100MHz,CDCl3)δ132.3(C,C-1),37.2(CH2,C-2),81.7(CH,C-3),82.3(C,C-4),51.2(CH,C-5),82.7(CH,C-6),55.0(CH,C-7),25.8(CH2,C-8),34.6(CH2,C-9),133.2(C,C-10),139.2(C,C-11),170.0(C,C-12),119.0(CH2,C-13),24.3(CH3,C-14),24.0(CH3,C-15),165.1(C,C-1′),131.1(CH,C-2′),134.5(CH,C-3′),164.7(CH,C-4′),35.9(CH,C-5′),37.7(CH,C-6′).
example 20
Preparation of compound 20:
Figure BDA0003531533320000191
4-acrylamidobenzoic acid (38mg,0.2mmol) was dissolved in dichloromethane (1mL) at room temperature, and N, N' -dicyclohexylcarbodiimide (DCC,41mg,0.2mmol), diol (26mg,0.1mmol), and 4-dimethylaminopyridine (DMAP,2mg,0.02mmol) were added in this order. After overnight reaction at room temperature, water was added to quench the reaction, extracted three times with ethyl acetate (3mL), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and isolated by silica gel column chromatography (acetone-petroleum ether, 10:90) to give compound 20 in 56% yield.
The characteristics are as follows: white solid
Melting point: 120-122 deg.C
And (3) optical rotation:
Figure BDA0003531533320000192
(c 0.092,CH3OH)
HRESIMS (+) m/z calculated value C25H28NO6[M+H]+438.1911, Experimental value 438.1918
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.99-2.92(2H,m,H-2),5.11(1H,d,J＝4.4Hz,H-3),2.53(1H,d,J＝17.2Hz,H-5),4.05(1H,t,J＝10.1Hz,H-6),2.86-2.81(1H,m,H-7),2.13-2.09(1H,m,H-8),1.42-1.37(1H,m,H-8),2.31-2.23(2H,m,H-9),6.19(1H,d,J＝3.1Hz,H-13),5.49(1H,d,J＝2.8Hz,H-13),1.71(3H,s,H-14),1.60(3H,s,H-15),7.96-7.94(2H,m,H-3′,H-7′),7.71-7.69(2H,m,H-4′,H-6′),6.31(1H,dd,J＝16.8,10.2Hz H-9′),6.47(1H,d,J＝16.8Hz,H-10′),5.80(1H,d,J＝10.2Hz,H-10′)；13C NMR(100MHz,CDCl3)δ132.3(C,C-1),37.5(CH2,C-2),81.5(CH,C-3),82.7(C,C-4),51.1(CH,C-5),82.9(CH,C-6),55.3(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.3(C,C-10),139.3(C,C-11),170.2(C,C-12),119.2(CH2,C-13),24.4(CH3,C-14),24.3(CH3,C-15),163.9(C,C-1′),125.9(C,C-2′),131.0(CH,C-3′,C-4′,C-6′,C-7′),142.5(C,C-5′),165.3(C,C-8′),119.3(CH,C-9′),128.9(CH2,C-10′).
example 21
Preparation of compound 21:
Figure BDA0003531533320000201
the required raw materials, reagents and preparation method were the same as example 20 except that 4-acrylamidobenzoic acid was changed to 3-acrylamidobenzoic acid, and the yield was 88%.
The characteristics are as follows: white solid
Melting point: 111-113 deg.C
And (3) optical rotation:
Figure BDA0003531533320000202
(c 0.103,CH3OH)
HRESIMS (+) m/z calculated value C25H28NO6[M+H]+438.1911, Experimental value 438.1917
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.97-2.86(2H,m,H-2),5.06(1H,d,J＝4.5Hz,H-3),2.49(1H,d,J＝17.2Hz,H-5),4.05(1H,t,J＝10.1Hz,H-6),2.74-2.71(1H,m,H-7),2.07-2.03(1H,m,H-8),1.39-1.29(1H,m,H-8),2.29-2.14(2H,m,H-9),6.15(1H,d,J＝2.9Hz,H-13),5.45(1H,d,J＝2.5Hz,H-13),1.67(3H,s,H-14),1.55(3H,s,H-15),8.04(1H,s,H-3′),7.68-7.66(1H,m,H-5′),7.38-7.34(1H,m,H-6′),8.12-8.10(1H,m,H-7′),5.73-5.70(1H,m,H-9′),6.43-6.30(1H,m,H-10′)；13C NMR(100MHz,CDCl3)δ132.2(C,C-1),37.3(CH2,C-2),81.9(CH,C-3),82.3(C,C-4),50.7(CH,C-5),82.8(CH,C-6),55.1(CH,C-7),25.7(CH2,C-8),34.6(CH2,C-9),132.8(C,C-10),139.2(C,C-11),170.5(C,C-12),119.2(CH2,C-13),24.4(CH3,C-14),23.9(CH3,C-15),164.2(C,C-1′),130.8(C,C-2′),120.9(CH,C-3′),138.6(C,C-4′),125.2(CH,C-5′),129.2(CH,C-6′),124.9(CH,C-7′),165.6(C,C-8′),131.1(CH,C-9′),128.2(CH2,C-10′).
example 22
Preparation of compound 22:
Figure BDA0003531533320000211
4- (tert-Butoxycarbonylamino) benzoic acid (355mg,1.5mmol) was dissolved in dichloromethane (5mL), and N, N' -dicyclohexylcarbodiimide (DCC,309mg,1.5mmol), diol (264mg,1.0mmol) and 4-dimethylaminopyridine (DMAP,25mg,0.2mmol) were added in this order. After overnight reaction at room temperature, the reaction was quenched with water, extracted three times with ethyl acetate (10mL), the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and isolated by silica gel column chromatography (acetone-petroleum ether, 20:80) to yield 263mg of intermediate S1 (white solid, 54% yield). Compound S1(240mg,0.7mmol) was dissolved in dichloromethane (5mL) at room temperature, trifluoroacetic acid (1mL) was added, the reaction was quenched by addition of saturated sodium bicarbonate solution for 4h, extracted three times with ethyl acetate (10mL), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and isolated by silica gel column chromatography (acetone-petroleum ether, 20:80) to give 247mg of Compound S2 (white solid, 92% yield). Trans-4-dimethylaminocrotonate (83mg,0.5mmol) was dissolved in tetrahydrofuran (2mL) at room temperature, oxalyl chloride (85. mu.L, 1.0mmol) and DMF (5. mu.L, 0.06mmol) were added sequentially, reacted for 2h and the solvent was removed by concentration under reduced pressure. The crude product was dissolved in dichloromethane (3mL), compound S2(23mg,0.06mmol) and triethylamine (138. mu.L, 1.0mmol) were added, the reaction was quenched with water at room temperature for 4h, extracted three times with ethyl acetate (10mL), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and isolated by silica gel column chromatography (acetone-petroleum ether, 20:80) to give compound 22.
The characteristics are as follows: white solid
Melting point: 130-132 deg.C
And (3) optical rotation:
Figure BDA0003531533320000212
(c 0.097,CH3OH)
HRESIMS (+) m/z calculated value C28H35N2O6[M+H]+495.2490, Experimental value 495.2494
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.98-2.90(2H,m,H-2),5.09(1H,d,J＝4.4Hz,H-3),2.50(1H,d,J＝17.2Hz,H-5),4.06(1H,t,J＝10.1Hz,H-6),2.84-2.79(1H,m,H-7),1.42-1.33(2H,m,H-8),2.19-2.07(2H,m,H-9),6.20-6.15(2H,m,H-13,H-9′),5.45(1H,d,J＝2.7Hz,H-13),1.70(3H,s,H-14),1.58(3H,s,H-15),7.92(2H,d,J＝8.3Hz,H-3′,H-7′),7.69(2H,d,J＝8.4Hz,H-4′,H-6′),7.01-6.94(1H,m,H-10′),3.09-3.07(2H,m,H-11′),2.25(6H,s,H-12′,H-13′)；13C NMR(100MHz,CDCl3)δ132.2(C,C-1),37.5(CH2,C-2),81.6(CH,C-3),82.5(C,C-4),51.1(CH,C-5),82.9(CH,C-6),55.3(CH,C-7),25.9(CH2,C-8),34.7(CH2,C-9),133.3(C,C-10),139.3(C,C-11),170.4(C,C-12),119.2(CH2,C-13),24.5(CH3,C-14),24.1(CH3,C-15),164.0(C,C-1′),125.6(C,C-2′),130.9(CH,C-3′,C-4′,C-6′,C-7′),142.8(C,C-5′),165.5(C,C-8′),125.8(CH,C-9′),143.2(CH,C-10′),60.3(CH2,C-11′),45.6(CH3,C-12′,C-13′)
example 23
Preparation of compound 23:
Figure BDA0003531533320000221
the required starting materials, reagents and preparation were the same as in example 5 except that acrylic acid was replaced with 2, 4-dioxo-5-fluoro-3, 4-dihydro-1 (2H) -pyrimidineacetic acid, and the yield was 77%.
The characteristics are as follows: white solid
Melting point: 121 to 123 DEG C
HRESIMS (+) m/z calculated value C21H24N2O7F[M+H]+435.1562, Experimental value 435.1564
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.29-2.16(2H,m,H-2),5.00(1H,br.s,H-3),2.36(1H,d,J＝17.2Hz,H-5),3.97(1H,t,J＝10.1Hz,H-6),2.89-2.85(1H,m,H-7),2.08-2.05(1H,m,H-8),1.37-1.28(1H,m,H-8),2.77-2.68(2H,m,H-9),6.14(1H,s,H-13),5.45(1H,s,H-13),1.69(3H,s,H-14),1.46(3H,s,H-15),4.51-4.39(2H,m,H-2′),7.35-7.33(1H,m,H-6′)；13C NMR(100MHz,CDCl3)δ132.6(C,C-1),37.1(CH2,C-2),82.1(CH,C-3),82.6(C,C-4),51.1(CH,C-5),82.9(CH,C-6),54.9(CH,C-7),25.7(CH2,C-8),34.6(CH2,C-9),132.7(C,C-10),139.2(C,C-11),170.4(C,C-12),119.2(CH2,C-13),24.4(CH3,C-14),23.7(CH3,C-15),166.6(C,C-1′),49.3(CH2,C-2′),149.9(C,C-3′),157.5(C,C-4′),141.7(C,C-5′),129.3(CH,C-6′).
example 24
Preparation of compound 24:
Figure BDA0003531533320000231
compound 23(22mg,0.05mmol) was dissolved in N, N-dimethylformamide (DMF,1mL) and added to a 10mL round bottom flask at room temperature, benzyl bromide (12 μ L,0.1mmol) and potassium carbonate (28mg,0.2mmol) were added in this order, reacted at room temperature for 10h, quenched by addition of 5% aqueous HCl, extracted three times with ethyl acetate (3mL), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and isolated by silica gel column chromatography (acetone-petroleum ether, 25:75) to give compound 24 in 73% yield.
The characteristics are as follows: white solid
Melting point: 93-95 DEG C
And (3) optical rotation:
Figure BDA0003531533320000232
(c 0.094,CH3OH)
HRESIMS (+) m/z calculated value C28H30N2O7F[M+H]+525.2032, Experimental value 525.2038
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.91-2.85(1H,m,H-2),2.62-2.59(1H,m,H-2),5.01(1H,d,J＝4.4Hz,H-3),2.38(1H,d,J＝17.2Hz,H-5),3.92(1H,t,J＝10.1Hz,H-6),2.10-2.04(1H,m,H-7),2.68-2.63(1H,m,H-8),1.38-1.30(1H,m,H-8),2.21-2.19(2H,m,H-9),6.18(1H,d,J＝3.2Hz,H-13),5.47(1H,d,J＝3.0Hz,H-13),1.72(3H,s,H-14),1.46(3H,s,H-15),5.16-5.08(2H,m,H-2′),7.32-7.26(3H,m,H-6′,H-9′,H-13′),4.53(1H,d,J＝17.4Hz,H-7′),4.34(1H,d,J＝17.4Hz,H-7′),7.48-7.46(2H,m,H-10′,H-12′),7.20-7.18(1H,m,H-11′)；13C NMR(100MHz,CDCl3)δ132.8(C,C-1),37.1(CH2,C-2),82.4(CH,C-3),82.2(C,C-4),51.3(CH,C-5),82.8(CH,C-6),54.9(CH,C-7),25.7(CH2,C-8),34.5(CH2,C-9),132.9(C,C-10),139.1(C,C-11),169.9(C,C-12),119.2(CH2,C-13),24.3(CH3,C-14),24.0(CH3,C-15),166.4(C,C-1′),50.1(CH2,C-2′),157.1(C,C-3′),157.4(C,C-4′),150.1(C,C-5′),127.0(CH,C-6′),45.4(CH2,C-7′),135.9(C,C-8′),128.7(CH,C-9′,C-13′),129.4(CH,C-10′,C-12′).
example 25
Preparation of compound 25:
Figure BDA0003531533320000241
terephthalic acid (17mg,0.1mmol) was dissolved in dichloromethane (2mL) and added to a 10mL round bottom flask at room temperature, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC, 70. mu.L, 0.4mmol), diol (53mg,0.2mmol) and 4-dimethylaminopyridine (DMAP,5mg,0.04mmol) were added in this order, reacted for 10h at room temperature, quenched by addition of 5% aqueous HCl, extracted three times with dichloromethane (3mL), the organic phases were combined and washed with saturated anhydrous brine, dried over sodium sulfate, concentrated under reduced pressure to remove the solvent and isolated by silica gel column chromatography (acetone-petroleum ether, 10:90) to give compound 25 in 15% yield.
The characteristics are as follows: white solid
Melting point: 138-140 deg.C
And (3) optical rotation:
Figure BDA0003531533320000242
(c 0.117,CH3OH)
HRESIMS (+) m/z calculated value C38H43O10[M+H]+659.2851, Experimental value 659.2861
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ3.01-2.97(2H,m,H-2,H-2′),2.24-2.20(2H,m,H-2,H-2′),5.16(2H,d,J＝4.5Hz,H-3,H-3′),2.55(2H,d,J＝17.2Hz,H-5,H-5′),4.04(2H,t,J＝10.1Hz,H-6,H-6′),2.93-2.90(2H,m,H-7,H-7′),2.34-2.27(2H,m,H-8,H-8′),1.44-1.34(2H,m,H-8,H-8′),2.83-2.78(2H,m,H-9,H-9′),2.13-2.11(2H,m,H-9,H-9′),6.21(2H,d,J＝3.2Hz,H-13,H-13′),5.49(2H,d,J＝2.9Hz,H-13,H-13′),1.72(6H,s,H-14,H-14′),1.62(6H,s,H-15,H-15′),8.06(4H,s,H-18,H-18′,H-19,H-19′)；13C NMR(100MHz,CDCl3)δ132.5(C,C-1,C-1′),37.4(CH2,C-2,C-2′),82.1(CH,C-3,C-3′),82.6(C,C-4,C-4′),51.3(CH,C-5,C-5′),82.7(CH,C-6,C-6′),55.4(CH,C-7,C-7′),25.9(CH2,C-8,C-8′),34.7(CH2,C-9,C-9′),133.2(C,C-10,C-10′),139.2(C,C-11,C-11′),170.0(C,C-12,C-12′),119.3(CH2,C-13,C-13′),24.4(CH3,C-14,C-14′),24.3(CH3,C-15,C-15′),164.9(C,C-16,C-16′),134.3(C,C-17,C-17′),129.8(CH,C-18,C-18′,C-19,C-19′).
example 26
Preparation of compound 26:
Figure BDA0003531533320000251
the required raw materials, reagents and preparation were the same as in example 25 except that terephthalic acid was changed to succinic acid, and the yield was 48%.
The characteristics are as follows: white solid
Melting point: 97-99 deg.C
And (3) optical rotation:
Figure BDA0003531533320000252
(c 0.012,CHCl3)
HRESIMS (+) m/z calculated value C34H42O10Na[M+Na]+633.2670, Experimental value 633.2678
1H-NMR and13C-NMR data:1H NMR(400MHz,CDCl3)δ2.88-2.84(2H,m,H-2,H-2′),2.22-2.17(2H,m,H-2,H-2′),4.94(2H,d,J＝4.6Hz,H-3,H-3′),2.37(2H,d,J＝17.2Hz,H-5,H-5′),3.97(2H,t,J＝10.1Hz,H-6,H-6′),2.11-2.09(2H,m,H-7,H-7′),2.53-2.26(2H,m,H-8,H-8′),1.40-1.31(2H,m,H-8,H-8′),2.80-2.74(4H,m,H-9,H-9′),6.18(2H,d,J＝3.2Hz,H-13,H-13′),5.47(2H,d,J＝2.9Hz,H-13,H-13′),1.71(6H,s,H-14,H-14′),1.51(6H,s,H-15,H-15′),2.61(4H,s,H-17,H-17′)；13C NMR(100MHz,CDCl3)δ132.2(C,C-1,C-1′),37.3(CH2,C-2,C-2′),81.2(CH,C-3,C-3′),82.5(C,C-4,C-4′),51.2(CH,C-5,C-5′),82.7(CH,C-6,C-6′),55.1(CH,C-7,C-7′),25.9(CH2,C-8,C-8′),34.7(CH2,C-9,C-9′),133.4(C,C-10,C-10′),139.2(C,C-11,C-11′),170.0(C,C-12,C-12′),119.2(CH2,C-13,C-13′),24.4(CH3,C-14,C-14′),24.1(CH3,C-15,C-15′),171.5(C,C-16,C-16′),29.5(C,C-17,C-17′).
example 27:
ludartin derivatives 1-26 cytotoxic activity against HepG2 and Huh7 hepatoma cells.
1. Materials and methods
1.1 materials
The HepG2 cell line was awarded by the Kunming plant research institute, China academy of sciences, and the Huh7 cell line was purchased from Shanghai Jinning Biotech, Inc.; medium (Dulbecco's Modified Eagle Medium, DMEM) was purchased from Thermo Fisher Scientific, Suzhou, China; serum (total bone serum, FBS) was purchased from Life Technologies (NY, USA); RPMI-1640 was purchased from ThermoFisher Biochemical Products (Beijing, China).
1.2 instruments
Flex Station 3 desktop multifunctional microplate reader (Bio-RAD 680, USA); analytical balance (AG135, Metler Toledo, china); incubator (DHP-9082, Shanghai).
1.3 Experimental procedures
1) Taking the liver cancer cells growing in the logarithmic phase, removing the old culture medium, washing twice by using PBS, and removing the PBS;
2) digesting the cells by 0.25% of trypsin, and quickly absorbing the trypsin when the cell contour deepens and tends to become round under a microscope;
3) the digestion was stopped with 10% FBS-containing DMEM complete medium and the cells were resuspended, 10. mu.L of the cell suspension was taken, counted with a cell counter, and the cell concentration was adjusted to 1X 10 with the medium4Perml, seeded in 96-well plates, 100. mu.L of cell suspension per well, 5% CO at 37 ℃2The culture box is incubated for 24 hours to ensure that the cells adhere to the wall;
4) the culture medium is aspirated, the diluted sample is added into the plate, 100 μ L of the diluted sample is added into each well, 3 multiple wells are set for each concentration, and the incubation is continued in the incubator for 48 h;
5) the culture medium is aspirated, the prepared MTT solution (1mg/mL) is added, 100 mu L of the MTT solution is added into each hole, and the mixture is incubated in an incubator for 4 hours;
6) the MTT solution is aspirated, DMSO is added, 100 mu L of DMSO is added into each hole, and the mixture is incubated in an incubator for 10 min;
7) measuring absorbance values using a microplate reader at 490nm wavelength by the formula: the cell inhibition rate was calculated as (negative-experimental group)/(negative-blank group) × 100%, and IC was calculated using statistical software GraphPad prism 550The experiment was repeated 3 times.
2. Results
Cytotoxic activity against HepG2 and Huh7 hepatoma cells, IC thereof, was evaluated on all derivatives50The values are shown in Table 1. The synthesized compounds all have certain cytotoxic activity on HepG2 and Huh7, whereinThe 12 compounds (2-3, 7-9, 13, 16, 20-22, 24-25) have remarkably enhanced cytotoxic activity on HepG2 cells compared with the original compound ludartin, and IC is50The value is between 1.6 and 23.3 mu M; the 14 compounds (2, 8-9, 12-13, 16-22, 24-25) have remarkably enhanced cytotoxic activity on Huh7 cells, and IC50The value is between 2.0 and 25.1 mu M; particularly, the cytotoxic activity of the compound 25 on HepG2 and Huh7 is improved by 20 times and 17 times compared with ludartin respectively, and is 5 times of that of the positive medicament sorafenib.
TABLE 1 cytotoxic Activity of derivatives 1-26 against HepG2 and Huh7 hepatoma cells
Figure BDA0003531533320000271
aActivity data are expressed as mean ± SD (n ═ 3);bsorafenib as a positive control
3. Conclusion
The 12 compounds (2-3, 7-9, 13, 16, 20-22, 24-25) have remarkably enhanced cytotoxic activity on HepG2 cells compared with the original compound ludartin, and IC is50The value is between 1.6 and 23.3 mu M; the 14 compounds (2, 8-9, 12-13, 16-22, 24-25) have remarkably enhanced cytotoxic activity on Huh7 cells, and IC50The value is between 2.0 and 25.1 mu M; particularly, the cytotoxic activity of the compound 25 on HepG2 and Huh7 is improved by 20 times and 17 times compared with ludartin respectively, and is 5 times of that of the positive medicament sorafenib. The results show that ludartin derivatives 1-26 can be used as medicines for liver cancer related diseases.
Formulation examples:
in the following application examples, conventional reagents were selected and the preparation was carried out according to the conventional methods, and this application example embodies that only at least one of the compounds 1 to 26 of the present invention can be prepared into various preparations, and the specific reagents and operations are not particularly limited:
1. dissolving at least one of the compounds 1-26 in DMSO, adding water for injection by conventional method, fine filtering, bottling, and sterilizing to obtain injection with concentration of 0.5-5 mg/mL.
2. Dissolving at least one of compounds 1-26 in DMSO, dissolving in sterile water for injection, stirring to dissolve, filtering with sterile suction filter funnel, sterile fine filtering, packaging in ampoule, freeze drying at low temperature, and sealing by aseptic melting to obtain powder for injection.
3. Adding excipient into at least one of the compounds 1-26 at a mass ratio of 9:1 to the excipient, and making into powder.
4. Adding excipient into at least one of the compounds 1-26 according to the mass ratio of the compound to the excipient of 5:1, granulating and tabletting.
5. Making at least one of compounds 1-26 into oral liquid by conventional oral liquid preparation method.
6. Adding excipient into at least one of the compounds 1-26 at a mass ratio of 5:1 to the excipient, and making into capsule.
7. Adding excipient into at least one of compounds 1-26 at a weight ratio of 5:1 to excipient, and making into granule.
From the above embodiments, the invention provides a ludartin derivative, a preparation method and application thereof, a pharmaceutical composition and application thereof. The 26 ludartin derivatives provided by the invention have cytotoxic activities with different degrees on HepG2 and Huh7 liver cancer cells, can form a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient, and can be used for preparing anti-liver cancer drugs.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (7)

1. Ludartin derivatives 1-26 shown in structural formula (I) or medicinal salts thereof,
Figure FDA0003531533310000011
2. the ludartin derivative 1-26 or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt, and comprises a salt formed by an organic acid or an inorganic acid, wherein the organic acid is citric acid, maleic acid or fumaric acid, and the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid.
3. Use of ludartin derivatives 1-26 of formula (I) as claimed in claim 1 or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of liver cancer.
4. A process for the preparation of ludartin derivatives 1-26 of formula (I) according to claim 1, characterized in that: the method comprises the following steps:
preparation of Compounds 1-2: taking methanol as a solvent, preparing a compound 1 from ludartin under the action of concentrated sulfuric acid, and preparing a compound 2 from ludartin through epoxy ring-opening under the action of a proper fluorinating reagent, wherein the proper fluorinating reagent comprises hydrofluoric acid and salt thereof or boron trifluoride diethyl etherate;
preparation of Compounds 3-26: taking ludartin as a raw material, carrying out epoxy ring opening under the action of perchloric acid aqueous solution to obtain a ludartin glycol derivative, and preparing a compound 3 from glycol under the action of formic acid; preparing a compound 4 from diol under the action of acetic anhydride and 4-dimethylaminopyridine; the diol is subjected to esterification condensation with the corresponding acid under the action of a suitable condensation reagent to obtain the compounds 5-18,20-21,23 and 25-26, wherein the suitable condensation reagent is N, N '-dicyclohexylcarbodiimide or N, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; carrying out amidation reaction on maleic anhydride and dimethylamine under an alkaline condition, and then carrying out esterification condensation on maleic anhydride and diol to obtain a compound 19; carrying out esterification condensation on diol and 4- (tert-butyloxycarbonylamino) benzoic acid, removing tert-butyloxycarbonylamino under an acidic condition, and then condensing with trans-4-dimethylaminocroton to obtain a compound 22; alkylation reaction of the compound 23 and benzyl bromide under alkaline conditions is carried out to obtain a compound 24.
5. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of at least one ludartin derivative 1-26 of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. The use of the pharmaceutical composition of claim 5 for the preparation of a medicament against liver cancer.
7. A process for preparing a pharmaceutical composition according to claim 5, characterized in that: the method comprises the following steps:
preparation of Compounds 1-2: taking methanol as a solvent, preparing ludartin under the action of concentrated sulfuric acid to obtain a compound 1, and preparing ludartin under the action of a proper fluorinating reagent for epoxy ring opening to obtain a compound 2, wherein the proper fluorinating reagent comprises hydrofluoric acid and salt thereof or boron trifluoride diethyl etherate;
preparation of Compounds 3-26: taking ludartin as a raw material, carrying out epoxy ring opening under the action of perchloric acid aqueous solution to obtain a ludartin glycol derivative, and preparing a compound 3 from glycol under the action of formic acid; preparing a compound 4 from diol under the action of acetic anhydride and 4-dimethylaminopyridine; the diol is subjected to esterification condensation with the corresponding acid under the action of a suitable condensation reagent to obtain the compounds 5-18,20-21,23 and 25-26, wherein the suitable condensation reagent is N, N '-dicyclohexylcarbodiimide or N, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; carrying out amidation reaction on maleic anhydride and dimethylamine under an alkaline condition, and then carrying out esterification condensation on maleic anhydride and diol to obtain a compound 19; carrying out esterification condensation on diol and 4- (tert-butyloxycarbonylamino) benzoic acid, removing tert-butyloxycarbonylamino under an acidic condition, and then condensing with trans-4-dimethylaminocroton to obtain a compound 22; performing alkylation reaction on the compound 23 and benzyl bromide under an alkaline condition to obtain a compound 24;
then, at least one of the compounds 1 to 26 obtained as described above is added to a pharmaceutically acceptable carrier.
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