CN109369649A - Matrine amide derivatives and its preparation method and application - Google Patents

Matrine amide derivatives and its preparation method and application Download PDF

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CN109369649A
CN109369649A CN201811578871.6A CN201811578871A CN109369649A CN 109369649 A CN109369649 A CN 109369649A CN 201811578871 A CN201811578871 A CN 201811578871A CN 109369649 A CN109369649 A CN 109369649A
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matrine
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CN109369649B (en
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陈新
胡莉娟
周晓鹰
江欣育
赵帅
宋爽
杜银端
范玲玲
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Changzhou University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses matrine amide derivatives and its preparation method and application, belong to field of medicinal chemistry.A series of noval chemical compounds that the present invention synthesizes have anticancer activity, and this method is using matrine as raw material, alkaline condition hydrolysis, and by esterification, hydrolysis, amide coupling reaction finally obtains a series of new matrine derivatives.Since matrine itself has certain pharmacological action, the present invention carries out anticancer activity test with new derivative of the MTT colorimetric method to synthesis, and new derivative anticancer activity is substantially better than matrine.

Description

Matrine amide derivatives and its preparation method and application
Technical field
The present invention relates to the synthesis of a series of matrine new amide derivative, and it is living to carry out biology to synthesized compound Property test, belong to field of medicinal chemistry.
Background technique
Tumour is current clinical common disease, the intractable recurrence and transfer for being that tumour of tumour, and tumor neogenetic The generation of blood vessel is one of the essential condition of tumor recurrence and transfer.Therefore it is generated by inhibiting tumor vascular thus to control The development of tumor disease has become the hot spot of current antineoplaston.Matrine (Matrine, formula 1) is from traditional medicinal A kind of active constituent isolated in plant kuh-seng, due to its extensive bioactivity, such as it is antitumor, anti-inflammatory, antiviral and It is concerned.In China, matrine injection is clinically used to treat hepatitis and liver cancer, and Radix Sophorae Flavescentis Suppositoria can treat vaginitis and chronic Cervicitis.However, up to the present, because its medium anti-tumor activity, matrine derivative or the like become not yet Anticancer drug.Therefore this method synthesizes a series of derivative to the structural modification of matrine, becomes candidate to have found that it is likely that The compound of drug.This method is that the precursor structure based on matrine is transformed modification.
Open loop forms kuh-seng acid to matrine under alkaline condition, then carries out benzyl protection to 16 N with benzyl, then again Hydrolysis, obtains N- benzyl kuh-seng acid, and last carboxyl is coupled by linking group and NO donor furans oxynitrides, is obtained NO donator type matrine derivative 13 (formula 2), anticancer activity are superior to matrine (L.Q.He, et al., Chinese Chemical Letters, 2010,381-384).
Nineteen fifty-seven, Tsuda et al. (K.Tsuda, et al., J.Org.Chem., 1958,23 (8), 1179-1183) will be bitter Ginseng alkali hydrolyzes in potassium hydroxide obtains kuh-seng acid potassium salt；Matrine obtains kuh-seng by lithium aluminium hydride reduction or catalytic hydrogen reduction Then alkali carries out methylation reaction to the two respectively, be prepared for the quaternary ammonium salt (formula 3) of two kinds of matrine derivatives, but activity is not It appears in the newspapers.
Summary of the invention
The present invention has synthesized a series of matrine amides by matrine hydrolysis, esterification and amide coupling reaction Class new derivative, and anticancer activity test is carried out to these compounds, synthesized matrine amide derivatives are living with anticancer Property, it can be used to inhibit cancer cell multiplication.
The structural formula of matrine amide derivatives are as follows:
Wherein, formula R1For 3- fluorophenyl, 3- chlorphenyl, 3- bromophenyl, 3- aminomethyl phenyl, 3- methoxyphenyl, 3- Nitrobenzophenone, 2- naphthalene or 2- pyridine.
The synthetic route of matrine new amide derivative is as follows:
The synthetic method of matrine amide derivatives, specific synthesis step are as follows:
(1) under alkali effect, matrine is added in solvent, heating reflux reaction, post-processing obtains product Compound 2； The alkali is sodium hydroxide or potassium hydroxide；The solvent is tetrahydrofuran or water.
(2) thionyl chloride is added in solvent, low temperature is stirred to react, then compound 2 is added thereto, and is added after low temperature stirring Heat reflux, post-processing obtain product Compound 3；Solvent is methanol, methylene chloride, chloroform or tetrahydrofuran；The low temperature Whipping temp is -20-0 DEG C；Reflux temperature is 50-70 DEG C.
(3) compound 3 and 4-dimethylaminopyridine are added in dichloromethane solution, reaction are stirred at room temperature, then It is added thereto after di-tert-butyl dicarbonate is dissolved in dichloromethane solution, reaction is stirred at room temperature, obtain 16-Boc kuh-seng acid methyl esters, Compound 4；16 N are protected with tertbutyloxycarbonyl first, then carry out amide coupling reaction, reaction selectivity can be effectively improved, made Carboxyl in coupling reaction preferentially with 16-Boc kuh-seng acid reacts；Then de- Boc reaction is carried out, operation is easy, System side reaction is less.
(4) under alkaline condition, 16-Boc kuh-seng acid methyl esters is added in solvent, reaction is stirred at room temperature, obtains compound 5；Step (4) solvent is water, tetrahydrofuran or methanol.
(5) compound 5 and amide coupling agent are dissolved in n,N-Dimethylformamide, are added under ice bath after being stirred at room temperature Enter n,N-diisopropylethylamine, continue thereafter with and be stirred at room temperature, aromatic amine compound is added, 18h is stirred at room temperature, obtains amide Compound 6.
The amide coupling agent be O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester (TBTU), six Fluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetra- One of methylurea hexafluorophosphoric acid ester (HATU) or O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU).Preferably 2- (7- aoxidize benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) are used as amide coupling agent, be by In the reaction when HATU is as coupling reagent, system side reaction is less, and yield is higher.
(6) amide compound 6 is dissolved in methylene chloride, acid is added, is stirred to react, obtains kuh-seng acid amide compound 7； The acid is hydrogen chloride gas or trifluoroacetic acid.
(7) compound 7 is dissolved in methylene chloride, alkali is added, chlorobenzoyl chloride is then added dropwise, reaction is stirred at room temperature, be concentrated, Column chromatographic purifying obtains matrine amide derivatives 8a；The alkali is triethylamine, ethylenediamine or potassium hydroxide.
Or compound 7 and triethylamine are dissolved in solvent, benzaldehyde is added dropwise, after being stirred at reflux reaction, then will reduction Agent is slowly added portionwise in reaction solution, continues to flow back, be cooled to room temperature, and concentration extraction, column chromatographic purifying obtains matrine amide and spreads out Biological 8b.The solvent is 1,2- dichloroethanes or methylene chloride；The reducing agent is sodium triacetoxy borohydride or boron hydrogen Change sodium.
The invention has the benefit that
This method have the advantage that: a series of completely new matrine new amide derivatives are prepared for, and biology is carried out to it Activity determination the result shows that, new derivative anticancer activity is substantially better than matrine.
Specific embodiment
Presently in connection with example, the present invention is described further.
Step 1: the preparation of 4- (decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base) butyric acid (compound 2)
Embodiment 1: compound 1 (20g, 80.5mmol) is dissolved in water (456mL), continuously add sodium hydroxide (9.1g, It 228mmol) dissolves, at 90 DEG C, is heated to reflux 12h.End of reaction, with 2N hydrochloric acid solution tune pH 5-7, by solvent concentration, then 460mL ethyl alcohol is added, 30min is stirred at room temperature, filters to obtain white solid 21g, yield 99%.1H NMR(300MHz,D2O):δ 1.61-1.80(m,9H),1.83-2.01(m,4H),2.16-2.20(t,1H),2.26-2.34(m,4H),2.90-2.97(q, J1=12.6Hz, J2=4.5Hz, 1H), 2.71 (s, 1H), 3.23-3.31 (t, J=12.9Hz, 1H), 3.37-3.41 (q, 1H) .13C NMR(75MHz,D2O):δ22.00,22.26,23.16,27.27,28.33,32.52,35.32,39.68,40.25, 46.18,58.64,58.70,64.32.HRMS(ESI):m/z[M-H]-calcd for C15H25N2O2:265.1922；found: 265.1924.
Embodiment 2: other conditions change into potassium hydroxide by sodium hydroxide with embodiment 1, by alkali used, products therefrom Yield is 70%.
Embodiment 3: other conditions are changed to tetrahydrofuran by water with embodiment 1, by reaction dissolvent, and the yield of products therefrom is 70%.
Step 2: the preparation of 4- (decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base) methyl butyrate (compound 3)
At 4:0 DEG C of embodiment, by SOCl2(29.5mL, 40.7mmol) is dissolved in MeOH (336mL), stirs 1h.After will be molten It is added thereto in the mixture of the compound 2 (13g, 48.8mmol) of MeOH (168mL), ice bath reacts 2h, and flow back 3h afterwards.Reaction Terminate, be cooled to room temperature, 356mL CHCl is added3, 50g NaHCO3, 0.5h is stirred at room temperature, filters, mother liquor concentrations.It is white to obtain 9g Color solid, yield 66%.1H NMR(300MHz,CD3OD):δ1.44-1.64(m,5H),1.71-1.64(m,5H),1.74- 1.80(m,3H),1.91-1.94(d,1H),2.00-2.08(m,3H),2.26(s,1H),2.26(s,1H),2.41-2.37(m, 2H),2.37-2.41(m,2H),2.94-2.98(dd,J1=6.2Hz, J2=2.1Hz, 1H), 3.40-3.46 (t, J= 12.8Hz,1H),3.54-3.60(m,1H),3.65-3.63(d,3H).13CNMR(75MHz,CD3OD):δ20.44,20.63, 25.63,26.66,30.47,33.68,33.90,38.51,44.51,48.15,49.85,49.85,53.92,57.27, 62.93,175.06.HRMS(ESI):m/z[M+Na]+calcd for C16H28O2Na:303.2043；found:303.2039.
Embodiment 5: other conditions are changed to methylene chloride, the yield of products therefrom by methanol with embodiment 4, by reaction dissolvent It is 50%.
Embodiment 6: other conditions are changed to tetrahydrofuran, the yield of products therefrom by methanol with embodiment 4, by reaction dissolvent It is 55%.
Embodiment 7: other conditions are changed to -10 DEG C by 0 DEG C with embodiment 4, by reaction temperature, and the yield of products therefrom is 45%.
Embodiment 8: other conditions are changed to -20 DEG C by 0 DEG C with embodiment 4, by reaction temperature, and the yield of products therefrom is 54%.
Embodiment 9: other conditions are changed to 50 DEG C by 70 DEG C with embodiment 4, by reflux temperature, and the yield of products therefrom is 48%.
Step 3: tert-butyl -1- (4- methoxyl group -4- oxo butyl) octahydro -1H, 4H- pyrido [1,6] benzodiazine -2 The preparation of (3H)-carboxylic acid (compound 4)
Embodiment 10: compound 3 (6.5g, 23.2mmol) and 4-dimethylaminopyridine (650mg) are dissolved in methylene chloride In (116mL), after methylene chloride (23mL) solution of di-tert-butyl dicarbonate (7.6g, 34.8mmol) is dissolved in wherein, room temperature It is stirred to react 16h.TLC monitoring reaction, concentration.Methylene chloride: methanol=50:1 column chromatography obtains 7.3g yellow, viscous liquid Body, yield 83%.1H NMR(300MHz,CDCl3):δ1.42-1.34(m,3H),1.45(s,11H),1.61-1.58(m, 2H), 1.83-1.63 (m, 9H), 1.96-1.95 (t, J=4.1Hz, 1H), 2.31-2.38 (m, 2H), 2.67-2.71 (t, J= 6.8Hz,2H),3.26-3.33(dd,J1=9.8Hz, J2=18.2Hz, 1H), 3.50-3.55 (dd, 1H, J1=10.9Hz, J2 =18.0Hz), 3.65 (s, 3H), 3.78-3.86 (m, 1H)13C NMR(75MHz,CDCl3):δ20.81,20.97,21.67, 27.95,28.22,28.90,31.15,33.50,34.70,40.14,43.89,51.04,53.81,56.48,56.67, 63.01,78.53,155.45,173.71.HRMS(ESI):m/z[M+H]+calcd for C21H37N2O4:381.2748； found:381.2749.
Step 4: 4- ((3aS, 3a1S, 10aR) -2- (tert-butoxycarbonyl) decahydro -1H, 4H- pyrido [1,6] naphthyridines - 1- yl) butyric acid (compound 5) preparation
Embodiment 11: compound 4 (5g, 13.1mmol) is dissolved in methanol (59mL), and 4N sodium hydroxide solution is added Reaction 4h is stirred at room temperature in (13.2mL).TLC monitoring, concentration.Methylene chloride: methanol=10:1 crosses column, obtains white solid 4g, Yield 85%.1H NMR(400MHz,CDCl3):δ1.26-1.22(m,1H),1.30(s,10H),1.36(m,2H),1.40- 1.52 (m, 5H), 1.66-1.68 (m, 2H), 1.75-1.78 (d, 3H), 1.91 (s, 1H), 2.02-2.07 (t, J=5.9Hz, 2H), 2.18-2.20 (m, 1H), 2.30 (m, 1H), 2.48 (s, 1H), 3.12-3.20 (q, J=11.2Hz, 2H), 3.27-3.34 (m,1H),3.51-3.55(dd,J1=5.0Hz, J2=6.8Hz, 1H), 3.66-3.73 (m, 1H)13C NMR(100MHz, CDCl3)δ19.90,20.19,21.93,26.47,27.37,28.56,29.45,34.51,35.92,39.60,47.72, 54.89,56.09,56.20,65.28,79.75,156.12,177.82.HRMS(ESI):m/z[M+H]+calcd for C20H35N2O4:367.2591；found:367.2593.
Embodiment 12: other conditions are changed to water, yield 54% with embodiment 11, by reaction dissolvent.
Embodiment 13: other conditions are changed to tetrahydrofuran, yield 32% with embodiment 11, by reaction dissolvent.
Step 5: the preparation of 16-Boc matrine derivative (compound 6)
Embodiment 14: tert-butyl (1R, 3aS, 3a1S, 10aR) -1- (4- ((3- fluorophenyl) amino) -4- oxo butyl) eight The preparation of hydrogen -1H, 4H- pyrido [1,6] naphthyridines -2 (3H)-carboxylic acid tert-butyl ester (6a)
By compound 5 (100mg, 0.27mmol) and HATU (124mg), 30min is stirred at room temperature.Then under condition of ice bath, It is added DIEA (67 μ L), 1h is stirred at room temperature, be added 3- fluoroaniline (32 μ L), 18h is stirred at room temperature.TLC monitoring reaction, evaporating column layer Analysis.Obtain 110mg white solid, yield 88%.1H NMR(300MHz,CD3OD): δ 1.19-1.24 (t, 1H, J= 7.0Hz), 1.32 (s, 1H), 1.52 (s, 9H), 1.66-1.78 (m, 4H), 1.85-1.88 (t, 5H, J=3.7Hz), 1.91 (s, 1H),2.05(S,1H),2.33-2.34(d,1H),2.44-2.49(m,2H),3.38(s,1H),3.44-3.50(m,3H), 3.81-3.88(dd,1H,J1=13.0Hz, J2=6.8Hz), 6.80-6.87 (m, 1H), 7.24-7.36 (m, 2H), 7.55- 7.60(dd,1H,J1=11.4Hz, J2=2.1Hz)13C NMR(75MHz,CD3OD)δ19.81,20.28,23.46,26.77, 27.92,28.60,32.50,34.33,37.38,42.27,54.86,56.05,56.36,64.14,82.30,107.80, 108.15,111.15,111.43,116.32,116.36,129.66,130.57,131.07,131.20,141.56,141.70, 151.70,157.28,162.60,165.82,174.12.HRMS(ESI):m/z[M+H]+calcd for C26H39FN3O3: 460.2970；found:460.2973.
Embodiment 15: tert-butyl (1R, 3aS, 3a1S, 10aR) -1- (4- ((3- chlorphenyl) amino) -4- oxo butyl) eight The preparation of hydrogen -1H, 4H- pyrido [1,6] naphthyridines -2 (3H)-carboxylic acid tert-butyl ester (6b)
Other conditions are changed to 3- chloroaniline, yield 78% with embodiment 14, by 3- fluoroaniline.1H NMR(300MHz, CD3OD):δ1.29-1.32(d,1H),1.49(s,9H),1.59-1.76(m,4H),1.81-1.94(m,8H),2.03(s, 1H), 2.28 (s, 1H), 2.44-2.48 (t, 2H, J=6.9Hz), 2.87-3.03 (m, 3H), 3.37 (s, 1H), 3.44-3.47 (t, 1H, J=3.8Hz), 3.49-3.50 (d, 1 1H), 3.52-3.53 (d, 1H), 3.83-3.90 (m, 1H), 7.07-7.11 (m, 1H), 7.26-7.31 (t, 1H, J=8.1Hz), 7.42-7.46 (m, 1H), 7.81-7.82 (t, 1H, J=2.0Hz)13C NMR(75MHz,CD3OD)δ19.86,20.18,23.35,26.71,27.52,28.61,32.17,33.49,37.20,39.01, 43.41,54.99,56.12,56.44,64.47,82.18,119.00,120.79,124.76,131.07,135.28, 141.31,157.29,174.19.HRMS(ESI):m/z[M+H]+calcd for C26H39ClN3O3:476.2674；found: 476.2678.
Embodiment 16: tert-butyl (1R, 3aS, 3a1S, 10aR) -1- (4- ((3- bromophenyl) amino) -4- oxo butyl) eight The preparation of hydrogen -1H, 4H- pyrido [1,6] naphthyridines -2 (3H)-carboxylic acid tert-butyl ester (6c)
For other conditions with embodiment 14, it is 85% that 3- fluoroaniline, which is changed to 3- bromaniline yield,.1H NMR(300MHz, CD3OD):δ1.49(s,9H),1.56-1.87(m,12H),1.95(s,2H),2.23(s,1H),2.42-2.47(m,2H), 2.78-2.86(m,2H),3.23(s,2H),3.26(s,1H),3.45-3.48(d,2H),3.81-3.88(m,1H),7.22- 7.24(m,2H),7.45-7.49(m,1H),7.95-7.99(m,1H).13C NMR(75MHz,CD3OD)δ20.12,20.51, 23.44,17.19,27.98,28.64,33.14,33.83,37.32,39.28,42.95,54.92,56.29,56.55, 64.22,81.99,119.43,123.21,123.70,127.75,141.41,157.28,174.17.HRMS(ESI):m/z[M+ H]+calcd for C26H39BrN3O3:520.2169；found:520.2164.
Embodiment 17: tert-butyl (1R, 3aS, 3a1S, 10aR) -1- (4- ((3- methoxyphenyl) amino) -4- oxo fourth Base) octahydro -1H, 4H- pyrido [1,6] naphthyridines -2 (3H)-carboxylic acid tert-butyl ester (6d) preparation
Other conditions are changed to 3- aminoanisole, yield 88% with embodiment 14, by 3- fluoroaniline.1H NMR (400MHz,CD3OD):δ1.47(s,9H),1.52-1.59(m,1H),1.67-1.89(m,9H),1.94-2.01(m,3H), 2.16(s,1H),2.41-2.54(m,2H),2.92-3.00(dd,2H,J1=20.8Hz, J2=9.4Hz), 2.32-3.36 (m, 2H),3.47(s,1H),3.51-3.64(m,2H),3.77(s,3H),3.90-3.96(dd,1H,J1=15.0Hz, J2= 9.0Hz),6.64-6.67(m,1H),7.16-7.22(m,2H),7.38(s,1H).13C NMR(100MHz,CD3OD)δ19.92, 19.95,23.23,26.53,26.68,31.85,34.41,36.99,39.19,45.55,55.16,55.70,56.23, 56.55,65.07,81.85,106.97,11.39,113.25,130.49,141.05,157.23,161.32,174.06.HRMS (ESI):m/z[M+H]+calcd for C27H42N3O4:472.3170；found:472.3171.
Embodiment 18: tert-butyl (1R, 3aS, 3a1S, 10aR) -1- (4- ((3- aminomethyl phenyl) amino) -4- oxo butyl) The preparation of octahydro -1H, 4H- pyrido [1,6] naphthyridines -2 (3H)-carboxylic acid tert-butyl ester (6e)
Other conditions are changed to 3- methylaniline, yield 95% with embodiment 14, by 3- fluoroaniline.1H NMR(300MHz, CDCl3):δ1.20-1.24(d,1H),1.29-1.34(m,1H),1.42(s,9H),1.62-1.65(d,7H),1.77-1.80 (d,2H),1.87(s,2H),1.96-2.04(m,2H),2.28(s,3H),2.34-2.42(dd,1H,J1=14.9Hz, J2= 7.4Hz),2.45-2.54(m,1H),2.62-2.65(d,2H),3.07-3.17(m,3H),3.32-3.40(m,1H),3.50- 3.56 (m, 1H), 3.59-3.65 (m, 1H), 6.88-6.90 (d, 1H), 7.12-7.17 (t, 1H, J=7.7Hz), 7.30-7.33 (d,1H),7.37(s,1H),8.26(s,1H).13C NMR(75MHz,CD3OD):δ19.40,21.48,26.02,26.21, 28.38,31.10,33.44,36.50,38.47,44.34,53.57,54.07,55.59,64.31,80.88,118.06, 121.62,125.40,128.76,137.91,138.78,155.73,172.42.HRMS(ESI):m/z[M+H]+calcd for C27H42N3O3:456.3221；found:456.3219.
Embodiment 19: tert-butyl (1R, 3aS, 3a1S, 10aR) -1- (4- ((3- nitrobenzophenone) amino) -4- oxo butyl) The preparation of octahydro -1H, 4H- pyrido [1,6] naphthyridines -2 (3H)-carboxylic acid tert-butyl ester (6f)
Other conditions are changed to 3- nitroaniline, yield 77% with embodiment 14, by 3- fluoroaniline.1H NMR(400MHz, CD3OD):δ1.49(s,10H),1.63-1.77(m,5H),1.80-1.91(m,8H),2.04-2.05(d,1H),2.31(s, 1H), 2.47-2.51 (m, 2H), 2.94-3.02 (m, 2H), 3.43-3.45 (t, 1H, J=3.6Hz), 3.47-3.49 (dd, 2H, J1=8.7Hz, J2=3.9Hz), 3.82-3.88 (dd, 1H, J1=14.0Hz, J2=6.7Hz), 7.52-7.56 (t, J= 8.2Hz), 7.83-7.85 (m, 1H), 8.67-8.68 (t, 1H, J=1.9Hz), 7.91-7.94 (m, 1H)13C NMR (100MHz,CD3OD):δ19.84,20.26,23.28,26.76,27.78,28.59,32.74,34.01,37.28,38.93, 42.69,54.91,56.07,56.38,64.23,82.22,115.21,119.24,126.36,130.84,141.23, 149.76,157.29,174.36.HRMS(ESI):m/z[M+H]+calcd for C26H39N4O5:487.2915；found: 487.2919.
Embodiment 20: tert-butyl (1R, 3aS, 3a1S, 10aR) -1- (4- oxo -4- (pyridine -2- base amino) butyl) eight The preparation of hydrogen -1H, 4H- pyrido [1,6] naphthyridines -2 (3H)-carboxylic acid tert-butyl ester (6g)
Other conditions are changed to 2-aminopyridine, yield 97% with embodiment 14, by 3- fluoroaniline.1H NMR(400MHz, CD3OD):δ1.49(s,10H),1.68-1.75(m,5H),1.79-1.86(m,8H),2.01(s,1H),2.31(s,1H), 2.47-2.52(dd,2H,J1=7.5Hz, J2=6.8Hz), 2.91-2.98 (m, 2H), 3.39 (s, 1H), 3.44-3.46 (d, 2H), 3.79-3.84 (m, 1H), 7.09-7.12 (m, 1H), 7.74-7.78 (t, 1H, J=7.8Hz), 8.07-8.09 (d, 1H) .13C NMR(100MHz,CD3OD):δ19.87,20.35,23.38,26.88,28.02,28.60,32.49,34.42,38.98, 42.16,54.85,56.07,56.37,64.07,82.27,115.60,116.77,120.93,130.04,139.42, 149.02,157.30.HRMS(ESI):m/z[M+H]+calcd for C25H39N4O3:443.3017；found:443.3017.
Embodiment 21: tert-butyl (1R, 3aS, 3a1S, 10aR) -1- (4- (naphthalene -2- base amino) 4- oxo butyl) octahydro - The preparation of 1H, 4H- pyrido [1,6] naphthyridines -2 (3H)-carboxylic acid tert-butyl ester (6h)
Other conditions are changed to 2- naphthylamines, yield 81% with embodiment 14, by 3- fluoroaniline.1H NMR(400MHz, CD3OD):δ1.27-1.46(m,1H),1.50(s,9H),1.62-1.65(d,2H),1.71-1.85(m,11H),2.16(s, 1H),2.46-2.52(m,2H),2.81-2.89(m,2H),3.29(s,1H),3.35-3.41(m,2H),3.77-3.81(t, 1H, J=6.7Hz), 7.40-7.52 (m, 2H), 7.61-7.65 (dd, 1H, J1=8.8Hz, J2=2.0Hz), 7.79-7.88 (dd,3H,J1=15.1Hz, J2=8.7Hz)13C NMR(75MHz,CD3OD):δ19.65,20.13,23.55,26.61, 27.77,28.55,32.25,34.30,37.44,38.71,42.02,54.65,55.88,56.19,63.88,82.18, 117.76,121.37,126.02,127.54,128.46,128.59,129.56,131.91,135.08,137.30,157.15, 174.16.HRMS(ESI):m/z[M+H]+calcd for C30H42N3O3:492.3221；found:492.3224.
Embodiment 22: other conditions are changed to HBTU, yield 20% with embodiment 14, by coupling reagent.
Embodiment 23: other conditions are changed to TBTU, yield 54% with embodiment 14, by coupling reagent.
Embodiment 24: other conditions are changed to PyBOP, yield 60% with embodiment 14, by coupling reagent.
Step 6: the preparation of 16-H kuh-seng acid amide
Embodiment 25:4- ((1R, 3aS, 3a1S, 10aR)-decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base)-N- (3- Fluorophenyl) butyramide (7a) preparation
At 0 DEG C, compound 6a (1g, 2.73mmol) is dissolved in methylene chloride (10mL), hydrogen chloride gas is passed through, until Reaction terminates, and 10% sodium carbonate liquor is added and is adjusted to pH=7-8, by reaction solution filtering and concentrating, obtains yield 95%.1H NMR (300MHz,CD3OD):δ1.44-1.58(m,4H),1.66-1.67(m,5H),1.73-1.87(m,3H),1.90-2.10(m, 5H),2.25(s,1H),2.47-2.52(m,2H),2.82-2.88(dd,J1=12.1Hz, J2=4.7Hz), 3.35-3.41 (m, 3H),6.82-6.89(m,1H),7.29-7.41(m,2H),7.61-7.66(m,1H).13C NMR(75MHz,CD3OD):δ 21.64,21.71,21.96,27.18,28.39,31.99,36.16,37.50,40.91,45.99,53.24,58.15, 58.24,64.54,107.79,108.14,111.11,111.40,116.32,116.36,121.04,128.41,131.05, 131.17,141.61,144.76,148.73,162.59,165.80,174.HRMS(ESI):m/z[M+H]+calcd for C21H31FN3O:360.2446；found:360.2451.
Embodiment 26:4- ((1R, 3aS, 3a1S, 10aR)-decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base)-N- (3- Chlorphenyl) butyramide (7b) preparation
Other conditions are changed to compound 6b, yield 97% with embodiment 25, by compound 6a.1H NMR(400MHz, CD3OD):δ1.44-1.72(m,9H),1.75-1.88(m,4H),1.92-1.97(m,1H),2.04-2.06(d,3H),2.27 (s, 1H), 2.46-2.49 (t, 2H, J=6.5Hz), 2.80-2.86 (m, 2H), 2.99-3.03 (dd, 1H, J1=12.3Hz, J2 =4.2Hz), 3.42-3.49 (t, 1H, J=12.8Hz), 3.59-3.63 (m, 1H), 7.05-7.07 (dd, 1H, J1=7.9Hz, J2=1.2Hz), 7.24-7.28 (t, 1H, J=8.1Hz), 7.39-7.41 (m, 1H), 7.78-7.79 (t, 1H, J=1.9Hz) .13C NMR(100MHz,CD3OD):δ20.84,21.17,26.66,27.64,30.62,34.39,36.91,39.26,44.97, 54.12,57.74,57.81,63.12,116.52,119.05,119.43,120.86,124.81,131.04,135.28, 141.22,173.75.HRMS(ESI):m/z[M+H]+calcd for C21H31ClN3O:376.2150；found:376.2155.
Embodiment 27:4- ((1R, 3aS, 3a1S, 10aR)-decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base)-N- (3- Bromophenyl) butyramide (7c) preparation
Other conditions are changed to compound 6c, yield 95% with embodiment 25, by compound 6a.1H NMR(400MHz,d6- DMSO):δ1.35(s,3H),1.43-1.52(m,5H),1.71-1.83(m,7H),1.98-2.01(d,2H),2.31-2.39 (m, 2H), 2.68-2.71 (d, 2H), 2.87-2.90 (d, 1H), 3.22-3.28 (t, 1H, J=3.1Hz), 3.44-3.48 (m, 3H),7.17-7.25(m,2H),7.49-7.51(d.1H),7.97(s,1H),10.31(s,1H).13C NMR(100MHz, CD3OD):δ20.17,21.08,26.51,27.56,29.81,30.91,35.39,36.81,40.25,45.25,52.22, 57.20,57.29,63.16,118.73,122.50,123.13,127.08,130.29,139.74,172.55.HRMS(ESI): m/z[M+H]+calcd for C21H31BrN3O:420.1645；found:420.1640.
Embodiment 28:4- ((1R, 3aS, 3a1S, 10aR)-decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base)-N- (3- Methoxyphenyl) butyramide (7d) preparation
Other conditions are changed to compound 6d, yield 98% with embodiment 25, by compound 6a.1H NMR(400MHz, CD3OD):δ1.19-1.31(m,1H),1.41-1.49(m,3H),1.51-1.55(m,1H),1.59-1.62(m,3H),1.66- 1.70(m,2H),1.73-1.87(m,3H),1.92-2.04(m,4H),2.20(s,1H),2.29(s,3H),2.42-2.45(m, 2H),2.76-2.88(m,4H),3.34-3.35(d,1H),3.40-3.45(m,1H),6.87-6.90(d,1H),7.14-7.18 (t, 1H, J=2.0Hz), 7.30-7.38 (m, 2H)13C NMR(100MHz,d6-DMSO):δ19.73,19.98,20.29, 25.51,26.44,29.08,32.43,36.02,52.39,55.01,56.37,56.46,61.56,105.11,108.49, 111.56,115.72,118.69,129.53,140.60,171.05.HRMS(ESI):m/z[M+H]+calcd for C22H34N3O2:372.2646；found:372.2651.
Embodiment 29:4- ((1R, 3aS, 3a1S, 10aR)-decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base)-N- (3- Aminomethyl phenyl) butyramide (7e) preparation
Other conditions are changed to compound 6e, yield 95% with embodiment 25, by compound 6a.1H NMR(400MHz,d6- DMSO):δ1.35-1.39(d,3H),1.45-1.56(m,5H),1.66-1.76(m,4H),1.80-1.87(m,3H),1.99- 2.01 (d, 2H), 2.28-2.40 (m, 2H), 2.72 (s, 2H), 2.87-2.91 (m, 1H), 3.23-3.28 (t, 2H, J= 2.5Hz),3.70(s,3H),6.58-6.60(m,1H),7.13-71.8(m,2H),7.30-7.31(d,1H).13C NMR (100MHz,CD3OD):δ21.50,21.58,21.79,27.01,28.13,31.52,35.51,37.31,40.33,45.64, 53.57,58.01,58.10,64.02,118.39,121.81,129.59,139.65,173.88.HRMS(ESI):m/z[M+H]+ calcd for C22H34N3O:356.2696；found:356.2696.
Embodiment 30:4- ((1R, 3aS, 3a1S, 10aR)-decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base)-N- (3- Nitrobenzophenone) butyramide (7f) preparation
Other conditions are changed to compound 6f, yield 94% with embodiment 25, by compound 6a.1H NMR(400MHz, CD3OD):δ1.52-1.67(m,9H),1.82-1.94(m,5H),2.19(s,3H),2.51(s,3H),2.93(s,2H), 3.04-3.07 (m, 1H), 3.44-3.52 (m, 1H), 3.63-3.68 (m, 1H), 7.46-7.50 (t, 1H, J=2.0Hz), 7.85-7.90 (t, 2H, J=1.4Hz), 8.61 (s, 1H)13C NMR(100MHz,CD3OD):δ20.87,30.46,33.87, 36.97,38.79,44.69,49.84,53.89,57.43,63.05,113.55,115.43,116.46,119.35,122.26, 126.77,130.68,149.48,174.30.HRMS(ESI):m/z[M+H]+calcd for C21H31N4O3:387.2391； found:387.2401.
Embodiment 31:4- ((1R, 3aS, 3a1S, 10aR)-decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base)-N- (pyrrole Pyridine -2- base) butyramide (7g) preparation
Other conditions are changed to compound 6g, yield 90% with embodiment 25, by compound 6a.1H NMR(400MHz,d6- DMSO):δ1.34-1.37(dd,4H,J1=6.0Hz, J2=5.5Hz), 1.50-1.56 (m, 6H), 1.63-1.89 (m, 8H), 2.02 (s, 2H), 2.38-2.46 (m, 2H), 2.73-2.79 (d, 2H), 2.89-2.93 (t, 1H, J=10.0Hz), 7.04- 7.07 (m, 1H), 7.72-7.76 (m, 1H), 8.05-8.07 (d, 1H), 8.27-8.28 (dd, 1H, J1=3.8Hz, J2= 0.9Hz).13C NMR(100MHz,CD3OD):δ26.46,28.01,29.90,35.95,38.54,41.85,45.27,46.60, 52.89,61.82,63.76,65.83,71.06,75.52,125.57,128.84,130.32,147.68,157.63, 161.66.HRMS(ESI):m/z[M+H]+calcd for C20H31N4O:343.2492；found:343.2494.
Embodiment 32:4- ((1R, 3aS, 3a1S, 10aR)-decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base)-N- The preparation of (naphthalene -2- base) butyramide (7h)
Other conditions are changed to compound 6h, yield 94% with embodiment 25, by compound 6a.1H NMR(400MHz, CD3OD):δ1.13(s,1H),1.32-1.49(m,8H),1.66-1.89(m,8H),2.09(s,1H),2.63-2.69(m, 2H),2.85-2.87(d,1H),3.17-3.28(m,1H),3.48(s,1H),7.24-7.30(dd,2H,J1=4.1Hz, J2= 1.8Hz),7.41-7.43(d,1H),7.61-7.65(m,3H),8.08(s,1H).13C NMR(100MHz,CD3OD):δ 20.93,21.21,21.47,26.71,27.67,30.71,34.49,36.95,39.36,44.99,54.17,57.76, 57.85,63.12,117.84,121.26,126.00,127.47,128.49,128.57,129.53.HRMS(ESI):m/z[M+ H]+calcd for C25H34N3O:392.2696；found:392.2694.
Embodiment 33: at room temperature, compound 6a (500mg, 1.4mmol) being dissolved in methylene chloride (10mL), is added dropwise three Fluoroacetic acid (2mL), is stirred at room temperature 2h.Reaction terminates, and 10% sodium carbonate liquor is added and is adjusted to pH=7-8, filtering and concentrating, yield 78%.
Embodiment 34: other conditions are changed to compound 6b, yield 60% with embodiment 33, by compound 6a.
Embodiment 35: other conditions are changed to compound 6c, yield 75% with embodiment 33, by compound 6a.
Embodiment 36: other conditions are changed to compound 6d, yield 45% with embodiment 33, by compound 6a.
Embodiment 37: other conditions are changed to compound 6e, yield 50% with embodiment 33, by compound 6a.
Embodiment 38: other conditions are changed to compound 6f, yield 47% with embodiment 33, by compound 6a.
Embodiment 39: other conditions are changed to compound 6g, yield 65% with embodiment 33, by compound 6a.
Embodiment 40: other conditions are changed to compound 6h, yield 60% with embodiment 33, by compound 6a.
Step 7: 4- ((1R, 3aS, 3a1S, 10aR) -2- benzoyl decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- Base)-N- (tolyl) butyramide (8a) preparation
Embodiment 41: compound 7e (400mg, 1.13mmol) is dissolved in 10mL methylene chloride, and triethylamine (117 μ are added L), chlorobenzoyl chloride (156 μ L) then is added dropwise, 1h is stirred at room temperature.Concentration, column chromatographic purifying obtain 450mg white solid, and yield is 87%.1H NMR(400MHz,CDCl3): δ 1.16-1.19 (t, 1H, J=1.8Hz), 1.36 (s, 1H), 1.44-1.53 (m, 4H), 1.58-1.70 (m, 3H), 1.77-1.91 (m, 4H), 2.11 (s, 1H), 2.25 (s, 3H), 2.29-2.34 (t, 2H, J= 2.5Hz), 2.46-2.49 (m, 2H), 2.98-3.03 (q, 1H, J=1.8Hz), 3.07-3.12 (t, 2H, J=2.5Hz), 3.41-3.46(dd,1H,J1=3.5Hz, J2=1.7Hz), 3.61-3.67 (m, 1H), 4.18 (s, 1H), 6.84-6.86 (s, 1H), 7.10-7.13 (t, 1H, J=2.0Hz), 7.35-7.50 (m, 7H)13C NMR(100MHz,CDCl3):δ1.14,8.67, 19.96,21.59,22.31,26.82,27.09,35.58,36.39,38.46,46.66,56.31,63.98,117.04, 120.58,124.72,127.23,128.31,128.69,128.81,129.80,130.35,132.07,136.66,138.57, 138.69,172.14,173.53.HRMS(ESI):m/z[M+H]+calcd for C29H38N3O2:460.2959；found: 460.2960.
Embodiment 42: alkali is changed to ethylenediamine, yield 56% by other conditions such as example 41.
Embodiment 43: alkali is changed to potassium hydroxide, yield 30% by other conditions such as example 41.
Step 8: 4- ((3aS, 3a1S, 10aR) -2- benzyl decahydro -1H, 4H- pyrido [1,6] naphthyridines -1- base)-N- The preparation of (tolyl) butyramide (8b)
Embodiment 44: compound 7e (604mg, 1.7mmol) and triethylamine (236 μ L) are dissolved in 1,2- dichloroethanes It in (7mL), is added dropwise benzaldehyde (260 μ L), reaction solution flows back after 2h, then sodium triacetoxy borohydride (540mg) is slow Slowly it is added portionwise in reaction solution, continues the 6h that flows back.It is cooled to room temperature.Concentration extraction.It is extracted 3 times with the ethyl acetate of 20mL, then With water washing 3 times of 15mL, the saturated common salt water washing of 15mL 3 times is poured into organic phase in clean conical flask, is added appropriate Anhydrous sodium sulfate dry half an hour.After column chromatographic purifying, white solid, yield 78% are obtained.1H NMR(400MHz, CDCl3):δ0.84-0.90(m,1H),1.24-1.28(m,2H),1.40-1.46(m,3H),1.51-1.61(m,4H),1.83- 2.13(m,6H),2.29(s,3H),2.41-2.50(m,2H),2.55-2.59(dd,1H,J1=3.4Hz, J2=0.9Hz), 2.75(s,1H),2.87-2.95(d,1H),3.23-3.42(d,3H),3.67-3.70(d,1H),3.85-3.92(d,1H), 6.83-6.85 (d, 1H), 7.11-7.15 (t, 1H, J=1.9Hz), 7.25-7.33 (m, 3H), 7.38-7.39 (d, 2H), 7.55 =7.57 (d, 1H), 7.67 (s, 1H)13C NMR(100MHz,CDCl3):δ14.22,18.98,19.51,20.36,21.67, 22.78,25.64,26.19,29.45,29.78,31.53,32.01,35.49,36.60,56.55,117.09,120.58, 124.44,128.00,128.52,128.72,138.48,139.00,162.65,172.17.HRMS(ESI):m/z[M+H]+ calcd for C29H40N3O:446.3166；found:446.3165.
Embodiment 45: solvent is changed to methylene chloride by 1,2- dichloroethanes by other conditions such as embodiment 44, and yield is 60%.
Embodiment 46: sodium triacetoxy borohydride is changed to sodium borohydride, yield is by other conditions such as embodiment 44 65%.
2, anticancer activity measures
It chooses HepG2 (human liver cancer cell), A549 (human lung carcinoma cell) cell strain, it is derivative to matrine with mtt assay Object does Anticancer Activity in vitro test, and matrine is selected to do control group.The cancer cell in logarithmic phase growth period is taken, is used after centrifugation RPM1640 culture solution is diluted to 1 × 104/ mL is inoculated in 96 orifice plates.For 24 hours, 21 samples of gradient concentration are added in 37 DEG C of cultures, It is incubated for 72h, 50 μ L 10%MTT solution are added, after 37 DEG C of incubators hatch 4h, 100 μ L DMSO are added in every hole.30min is shaken, 96 orifice plates are placed on automatic microplate spectrophotometer afterwards, measurement absorbs angle value at 570nm, and calculates half with Biss method Effective inhibition concentration (IC50), every group of sample carries out 3 parallel testings, and test result is as shown in table 1.
The anticancer activity of 1 matrine amide derivatives of table
aIt indicates: ND=not determined
Newly synthesized 19 compounds are measured to the inhibited proliferation of two kinds of cancer cells of HepG2 and A549, knot with mtt assay Fruit is shown in Table 1.Test result shows that benzene ring substituents are electron-withdrawing group, such as Cl, Br, NO2When, have to two kinds of cancer cells bright Aobvious antitumaous effect；And working as is donor residues CH3When, also there is obvious anticancer activity to two kinds of cells.16-Boc matrine In derivative, benzene ring substituents are Cl, CH3, NO2When, there is obvious inhibiting effect to A549 cancer cell；When benzene ring substituents For F, Cl, NO2When, there is inhibiting effect to the proliferation of HepG2 cell.It is right when substituent group is naphthalene nucleus in 16-H matrine derivative A549 cell line proliferation has certain inhibiting effect；Group is Br, CH on phenyl ring3When, there is inhibition to make in A549 and HepG2 cell With.The derivative of above-mentioned synthesis is compared with matrine, shows that it is right its is improved when benzene ring substituents are electron-withdrawing group The inhibiting effect of cancer cell multiplication.

Claims (9)

1. matrine amide derivatives, which is characterized in that the structural formula of the matrine amide derivatives are as follows:
Wherein, R1For 3- fluorophenyl, 3- chlorphenyl, 3- bromophenyl, 3- aminomethyl phenyl, 3- methoxyphenyl, 3- nitrobenzophenone, 2- Naphthalene or 2- pyridine.
2. the preparation method of matrine amide derivatives, which is characterized in that specific preparation step are as follows:
(1) under alkali effect, matrine is added in solvent, heating reflux reaction, post-processing obtains product, compound 2；
(2) thionyl chloride is added in solvent, low temperature is stirred to react, then compound 2 is added thereto, and is heated back after low temperature stirring Stream, post-processing obtain product Compound 3；
(3) compound 3 and 4-dimethylaminopyridine are added in dichloromethane solution, reaction are stirred at room temperature, then by two Dimethyl dicarbonate butyl ester is added thereto after being dissolved in the solution of methylene chloride, and reaction is stirred at room temperature, and obtains 16-Boc kuh-seng acid methyl esters, is changed Close object 4；
(4) under alkaline condition, 16-Boc kuh-seng acid methyl esters is added in solvent, reaction is stirred at room temperature, obtains compound 5；
(5) compound 5 and amide coupling agent are dissolved in n,N-Dimethylformamide, are added under condition of ice bath after being stirred at room temperature Enter n,N-diisopropylethylamine, continue to be stirred at room temperature, aromatic amine compound is added, 18h is stirred at room temperature, obtains amide compound Object 6；
(6) amide compound 6 is dissolved in methylene chloride, acid is added, is stirred to react, obtains kuh-seng acid amide compound 7；
(7) compound 7 is dissolved in methylene chloride, alkali is added, chlorobenzoyl chloride is then added dropwise, reaction is stirred at room temperature, be concentrated, column layer Analysis purifying, obtains matrine amide derivatives a；
Or compound 7 and triethylamine are dissolved in solvent, benzaldehyde is added dropwise, after being stirred at reflux reaction, then reducing agent is delayed Slowly it is added portionwise in reaction solution, continues to flow back, be cooled to room temperature, concentration extraction, column chromatographic purifying obtains matrine amide derivatives b。
3. the preparation method of matrine amide derivatives according to claim 2, it is characterised in that: step (1) described alkali is Sodium hydroxide or potassium hydroxide；The solvent is tetrahydrofuran or water.
4. the preparation method of matrine amide derivatives according to claim 2, it is characterised in that: step (2) described solvent For methanol, methylene chloride, chloroform or tetrahydrofuran；The low temperature whipping temp is -20-0 DEG C；Reflux temperature is 50-70 ℃。
5. the preparation method of matrine amide derivatives according to claim 2, it is characterised in that: step (4) described solvent For water, tetrahydrofuran or methanol.
6. the preparation method of matrine amide derivatives according to claim 2, it is characterised in that: step (5) described amide Coupling reagent is O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester (TBTU), hexafluorophosphoric acid benzotriazole -1- Base-oxygroup tripyrrole alkyl phosphorus (PyBOP), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) or one of O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU).
7. the preparation method of matrine amide derivatives according to claim 2, it is characterised in that: step (6) described acid is Hydrogen chloride gas, trifluoroacetic acid.
8. the preparation method of matrine amide derivatives according to claim 2, it is characterised in that: step (7) described alkali is Triethylamine, ethylenediamine or potassium hydroxide；The solvent is 1,2- dichloroethanes or methylene chloride；The reducing agent is triacetyl oxygen Base sodium borohydride or sodium borohydride.
9. the application of matrine amide derivatives according to claim 1, it is characterised in that: the matrine amide derivatives With anticancer activity, for inhibiting cancer cell multiplication.
CN201811578871.6A 2018-12-24 2018-12-24 Matrine amide derivative and preparation method and application thereof Active CN109369649B (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111747957A (en) * 2020-07-15 2020-10-09 天津市医药科学研究所 Multi-target antitumor quinolizidine derivatives, and preparation method and application thereof
CN113754686A (en) * 2021-10-12 2021-12-07 山西农业大学 Synthesis method of biotin labeled matrine probe
CN113956256A (en) * 2021-11-17 2022-01-21 常州大学 Derivative with modified matrine D-ring structure and application of derivative in preparation of antitumor drugs
CN114507268A (en) * 2020-11-17 2022-05-17 中国科学院上海药物研究所 Toad venom steroid diene derivative and preparation method and application thereof
CN115716830A (en) * 2022-09-01 2023-02-28 暨南大学附属第一医院（广州华侨医院） Matrine type alkaloid, preparation method thereof and application thereof in preparation of anti-lung cancer drugs
CN115850276A (en) * 2022-12-12 2023-03-28 广西大学 Benzimidazole matrine derivative, preparation method and application thereof
CN117486882A (en) * 2023-11-08 2024-02-02 吉林农业大学 Matrine alkaloid derivative and application thereof in preparation of multi-target multi-organ tissue cell injury inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104109162A (en) * 2014-06-08 2014-10-22 广西大学 Salicylic acid kind matrine derivatives, and preparing method and applications thereof
CN108558879A (en) * 2018-04-08 2018-09-21 西北农林科技大学 Kuh-seng acid/Oxymatrine acid derivative, preparation and its application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104109162A (en) * 2014-06-08 2014-10-22 广西大学 Salicylic acid kind matrine derivatives, and preparing method and applications thereof
CN108558879A (en) * 2018-04-08 2018-09-21 西北农林科技大学 Kuh-seng acid/Oxymatrine acid derivative, preparation and its application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MIN LV ET AL.: "Synthesis of matrinic amide derivatives containing 1,3,4-thiadiazole scaffold as insecticidal/acaricidal agents", 《BIOORGANIC CHEMISTRY》 *
SHENG TANG ET AL.: "Synthesis and biological evaluation of 12-benzyl matrinic amide derivatives as a novel family of anti-HCV agents", 《CHINESE CHEMICAL LETTERS》 *

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CN111747957B (en) * 2020-07-15 2022-12-09 天津市医药科学研究所 Multi-target antitumor quinolizidine derivatives, and preparation method and application thereof
CN111747957A (en) * 2020-07-15 2020-10-09 天津市医药科学研究所 Multi-target antitumor quinolizidine derivatives, and preparation method and application thereof
CN114507268B (en) * 2020-11-17 2023-06-30 中国科学院上海药物研究所 Bufonis venenum steroid diene derivative, and preparation method and application thereof
CN114507268A (en) * 2020-11-17 2022-05-17 中国科学院上海药物研究所 Toad venom steroid diene derivative and preparation method and application thereof
CN113754686A (en) * 2021-10-12 2021-12-07 山西农业大学 Synthesis method of biotin labeled matrine probe
CN113754686B (en) * 2021-10-12 2022-04-19 山西农业大学 Synthesis method of biotin labeled matrine probe
CN113956256A (en) * 2021-11-17 2022-01-21 常州大学 Derivative with modified matrine D-ring structure and application of derivative in preparation of antitumor drugs
CN115716830A (en) * 2022-09-01 2023-02-28 暨南大学附属第一医院（广州华侨医院） Matrine type alkaloid, preparation method thereof and application thereof in preparation of anti-lung cancer drugs
CN115716830B (en) * 2022-09-01 2024-03-19 暨南大学附属第一医院（广州华侨医院） Matrine type alkaloid, preparation method thereof and application thereof in preparation of medicines with lung cancer resisting effect
CN115850276A (en) * 2022-12-12 2023-03-28 广西大学 Benzimidazole matrine derivative, preparation method and application thereof
CN115850276B (en) * 2022-12-12 2024-05-14 广西大学 Benzimidazole matrine derivative, preparation method and application thereof
CN117486882A (en) * 2023-11-08 2024-02-02 吉林农业大学 Matrine alkaloid derivative and application thereof in preparation of multi-target multi-organ tissue cell injury inhibitor
CN117486882B (en) * 2023-11-08 2024-06-11 吉林农业大学 Matrine alkaloid derivative and application thereof in preparation of multi-target multi-organ tissue cell injury inhibitor

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