CN101570524A - Substituted andrographolidume derivative, preparation method thereof and application thereof - Google Patents

Substituted andrographolidume derivative, preparation method thereof and application thereof Download PDF

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CN101570524A
CN101570524A CNA2009100332218A CN200910033221A CN101570524A CN 101570524 A CN101570524 A CN 101570524A CN A2009100332218 A CNA2009100332218 A CN A2009100332218A CN 200910033221 A CN200910033221 A CN 200910033221A CN 101570524 A CN101570524 A CN 101570524A
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desoxyandrographolide
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aminomethylene
acid
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CN101570524B (en
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徐浩
黄文龙
冯琦
权继才
姚成
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China Pharmaceutical University
Nanjing Tech University
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Nanjing Tech University
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Abstract

The invention relates to a substituted andrographolidume derivative, a preparation method thereof and application thereof. In alcoholic solution, andrographolidume and nitromethane are subjected to Michael reaction under the action of a catalyst to generate 12-nitromethyl-14-deoxyandrographolide; secondly, a reducing agent and the prepared 12-nitromethyl-14-deoxyandrographolide are added into acid solution, then acetic anhydride is added into the acid solution, and the mixture is subjected to reductive acylation reaction to form N-acetyl-12-aminomethylene-14-deoxyandrographolide; and finally, in an organic solvent, the N-acetyl-12-aminomethylene-14-deoxyandrographolide is mixed with carboxylic acid, a dehydrating agent and the catalyst are added into the mixture to carry out esterification reaction, and a target compound is obtained by washing, extracting, drying, condensing and separating. The synthetic route has the advantages of low production cost, simple post treatment and the like; and the obtained partial new compounds show stronger inhibiting effect on cancer cells than the prior anti-cancer medicaments in anti-tumor activity experiments.

Description

Andrographolidume derivative that replaces and its production and use
Technical field
The andrographolidume derivative that the present invention relates to replace, preparation method and its usage.
Background technology
Malignant tumour is serious threat human life's common disease and a frequently-occurring disease, effectively prevents and treat tumour, still is a great problem that the 21 century mankind face.And extensively exist various biologically active substance in the herbal medicine, plant medicines natural products, people have turned to nature to sight in recent years, seek antitumor drug and the antitumour auxiliary drug that toxic side effect is little, effect is unique from herbal medicine, plant.
Rographolide is one of the main effective constituent with herbal medicine Herba Andrographis of extensive physiologically active.Studies show that: rographolide can improve the patient's that carries HIV CD4+ lymphocyte level, can also be as the synergistic agent of triptolide, make it increase by 10 times and do not have untoward reaction to the COX-2 selective inhibitory activity, it is except that colorectal carcinoma, adenoma polyp are had the chemoprophylaxis effect, and is also effective to multiple cancers such as cancer of the stomach, the esophageal carcinoma, tongue cancer, skin carcinomas.Just, also make people that strong interest and concern have been taken place for the structure of modification and the modification of rographolide because rographolide has pharmacological action so widely.
(CA.1988,109:236982Z; Chen Pingsheng, etc., practical combination of Chinese tradiational and Western medicine magazine, 11,1 (4): 176; Matsuda, T.et al, Chem.Pharm.Bull (Tokyo) 1994,42 (6): 1216-25; Department of Gynecology andObstetrics of the People ' s Hospital in Meixian Prefecture.Chinese J.of Med.1977.12:755; Liao Shihuang, etc. Chinese TCM Ophthalmology magazine .1992,2 (1): 5; Ajoy Basak et al, Biochem.J, 2001,353 (p13): 537-545; Liu Feifei, etc. Jiangxi medicine, 2001,36 (3): 185; Zhang Yiping, etc. Chinese medicine company, 2000,9 (8): 11.)
Summary of the invention
The object of the invention is to provide a kind of Preparation method and use of andrographolidume derivative of new replacement.
Technical scheme of the present invention is:
The present invention has synthesized the andrographolidume derivative of a series of replacements, and its general structure (I) is:
Figure A20091003322100041
Wherein R representative:
Or (CH 3) 2CHCH 2NHCOOC (CH 3) 3CH 2
The present invention also provides the preparation method of above-mentioned compound of Formula I, and its concrete steps are:
A. in alcoholic solution, the Michael reaction takes place with mol ratio 1: 10～11 in rographolide and Nitromethane 99Min. under the effect of catalyzer, becomes to reaction solution and clarifies, and generates 12-nitro methyl isophthalic acid 4-desoxyandrographolide;
B. in acid solution, add reductive agent and the above-mentioned 12-nitro methyl isophthalic acid 4-desoxyandrographolide that makes, add acetic anhydride again, reductive acylation reaction 8～14h obtains N-ethanoyl-12-aminomethylene-14-desoxyandrographolide;
C. in organic solvent; N-ethanoyl-12-aminomethylene-14-desoxyandrographolide mixes with mol ratio 1: 5～6 with carboxylic acid; add dewatering agent and catalyzer esterification 10～48h, through washing, extraction, dry, concentrate, column chromatography separates and obtains target compound I.
Alcoholic solution among the above-mentioned steps A is the alcoholic solution of C1～C4; Catalyzer is any one in the sodium alkoxide of C1～C4, and the mol ratio of catalyst consumption and rographolide is 1～3: 1; Acid solution among the step B is formic acid, acetate or hydrochloric acid, and its consumption and 12-nitro methyl isophthalic acid 4-desoxyandrographolide mol ratio are 3～5: 1; Described reductive agent is iron powder or zinc powder, its consumption and 12-nitro methyl isophthalic acid 4-desoxyandrographolide mol ratio 5～10: 1; The consumption of acetic anhydride and 12-nitro methyl isophthalic acid 4-desoxyandrographolide mol ratio are 5～6: 1; Dewatering agent among the step C is 1,3-dicyclohexyl carbodiimide (DCC), phosphorus oxychloride or triphenylphosphine, its consumption and N-ethanoyl-12-aminomethylene-14-desoxyandrographolide mol ratio 5～10: 1; Catalyzer is triethylamine or 4-Dimethylamino pyridine (DMAP), its consumption and N-ethanoyl-12-aminomethylene-14-desoxyandrographolide mol ratio 1: 5～10; Organic solvent is methylene dichloride or ethylene dichloride.
Wherein the carboxylic acid structure formula among the step C is ROOH, and wherein R is:
Figure A20091003322100053
Or (CH 3) 2CHCH 2NHCOOC (CH 3) 3CH 2
Concrete reactions steps is:
Figure A20091003322100061
When wherein R is different group, corresponding Compound I respectively 1～I 6
Figure A20091003322100062
The present invention also provides the purposes of andrographolidume derivative in antitumor drug of above-mentioned replacement.
Beneficial effect:
Synthetic route of the present invention has advantages such as production cost is low, and aftertreatment is simple, and the part new compound that obtains has demonstrated the ratio anticarcinogen restraining effect stronger to cancer cells in the past in the anti-tumor activity experiment.
Embodiment:
Embodiment 1:
3, and 19-two (4-isobutyl--Alpha-Methyl phenylacetyl)-N-ethanoyl-12-(R, S)-aminomethylene-14-desoxyandrographolide (I 1) preparation:
25g rographolide (compound 1) is dissolved in the 100mL methyl alcohol, adds the 40mL Nitromethane 99Min., in 30 ℃ of solution that drip 10.4g sodium methylate and 80mL methyl alcohol, about 1h drips, restir 4h.Reaction solution is poured in the 300mL icy salt solution, extract with ethyl acetate (300mL * 3), merge organic layer, use saturated aqueous common salt (200mL * 3) to wash organic layer anhydrous sodium sulfate drying, filtering and concentrating again, the 30mL re-crystallizing in ethyl acetate, obtain 9g white solid 12-nitro methyl isophthalic acid 4-desoxyandrographolide (compound 2), molecular weight 393.47, productive rate 32.0%.
mp?43.0～44.0℃。[α] D 20-19.50(c?1.0，C 2H 5OH)； 1H?NMR(CDCl 3，300MHz)：7.29(br?s，1H，H-14)，4.96(s，1H，H-17α)，4.87(s，2H，H-15)，4.75～4.71(m，1H，-CHNO 2)，4.59～4.53(m，2H)，4.17～4.14(d，J＝10.2Hz，1H，H-19α)，1.22(s，3H，H-18)，0.64(s，3H，H-20).
Adding 45mL acetic acid, 10mL heavily steam in having the three-necked bottle of electronic stirring aceticanhydride, 8.4g iron powder, 8.05 g2, stirring at room 14h.Suction filtration; the saturated common salt washing; ethyl acetate (100mL * 3) extraction; organic layer is washed with saturated sodium bicarbonate, saturated sodium-chloride successively, anhydrous sodium sulfate drying, filtering and concentrating; through silica gel column chromatography; (V: V=4: 1) wash-out obtains 3.1g oily liquids N-ethanoyl-12-aminomethylene-14-desoxyandrographolide (compound 3), molecular weight 405.53, productive rate 31.6% to petroleum ether-ethyl acetate.
1H?NMR(CDCl 3，300MHz)7.21(s，1H，H-14)，6.07(br?s，1H，CH 3CON H)，4.90(s，1H，H-17α)，4.86～4.83(d，J＝8.6Hz，2H，H-15)，4.55(s，1H，H-17β)，4.30～4.28(d，J＝7.0Hz，1H，H-19α)，3.32～3.25(m，2H，CH 2N)，2.03(s，3H，CH 3CO)，1.11(3H，s，H-18)，0.66(d，J＝4.4Hz，3H，H-20)；
MS(70eV)m/z：428.3[M+Na] +，442.1[M+Ka] +；
In the 200mL methylene dichloride, add 0.2g (1.5mmol) 2-(4-isobutyl phenenyl) propionic acid, 0.5g 1,3-dicyclohexyl carbodiimide, 0.1g (0.25mmol) 3,0.006g 4-Dimethylamino pyridine, stirring at room 48h, filter, the washed with dichloromethane filter cake, filtrate is washed with the 50mL copper/saturated copper sulphate, methylene dichloride (20mL * 3) extraction, merge organic layer, the copper/saturated copper sulphate of usefulness (30mL * 2) is washed anhydrous sodium sulfate drying again, filtering and concentrating, through silica gel column chromatography, (V: V=1: 1) wash-out obtains 0.06g white solid I to petroleum ether-ethyl acetate 1, molecular weight 812.13, yield 12.9%, 57.0～59.0 ℃ of mp.
1H?NMR(DMSO-d 6，300MH
Figure A20091003322100071
)：7.78～7.03(m，9H，H-14?and?ArH)，4.81～4.76(m，3H)，4.10～3.76(m，2H，H-19)，3.68～3.55(m，2H，2ArC HCH 3)，3.17～3.09(m，2H，CH 2N)，2.39～2.37(m，4H，2CHC H 2Ar)，0.83～0.80(m，12H，2(C H 3) 2CH)，0.40(m，3H，H-20)；
IR(KBr)v：3327，2929，1626，1243，1088，640cm -1；
MS(70eV)m/z：782.6[M+H] +，804.6[M+Na] +.
Embodiment 2
3,19-two phenylacetyl-N-ethanoyl-12-(R, S)-preparation of aminomethylene-14-desoxyandrographolide (I2):
25g rographolide (compound 1) is dissolved in the 100mL ethanol, adds the 45mL Nitromethane 99Min., in 20 ℃ of dropping 10.4g sodium tert-butoxides and 80mL alcoholic acid solution, about 1h drips, restir 4h.Reaction solution is poured in the 300mL icy salt solution, extract with ethyl acetate (300mL * 3), merge organic layer, use saturated aqueous common salt (200mL * 3) to wash organic layer anhydrous sodium sulfate drying, filtering and concentrating again, the 30mL re-crystallizing in ethyl acetate, obtain 9g white solid 12-nitro methyl isophthalic acid 4-desoxyandrographolide (compound 2), molecular weight 393.47, productive rate 32.0%.
Adding 35mL hydrochloric acid, 15mL heavily steam in having the three-necked bottle of electronic stirring aceticanhydride, 8g zinc powder, 8g2, stirring at room 10h.Suction filtration, the saturated common salt washing, ethyl acetate (100mL * 3) extraction, organic layer is washed with saturated sodium bicarbonate, saturated sodium-chloride successively, anhydrous sodium sulfate drying, filtering and concentrating, through silica gel column chromatography, (V: V=4: 1) wash-out obtains 3g oily liquids compound 3, molecular weight 405.53, productive rate 31.6% to petroleum ether-ethyl acetate.
In the 200mL methylene dichloride, add 0.2g (1.5mmol) uncle N-fourth oxygen formyl radical-L-2-amino-4-methylbutyric, 0.2g phosphorus oxychloride, 0.1g (0.25mmol) 3,0.005g triethylamine; stirring at room 40h; filter; the washed with dichloromethane filter cake; filtrate is washed with the 50mL copper/saturated copper sulphate; methylene dichloride (20mL * 3) extraction; merge organic layer; the copper/saturated copper sulphate of usefulness (30mL * 2) is washed again; anhydrous sodium sulfate drying, filtering and concentrating is through silica gel column chromatography; (V: V=1: 1) wash-out obtains 0.06g white solid I to petroleum ether-ethyl acetate 2, promptly molecular weight 671.85, yield 53.3%, 91.0～93.0 ℃ of mp;
1H?NMR(DMSO-d 6，300MH
Figure A20091003322100081
)：7.99～7.84(m，10H，ArH)，7.26(d，J＝15.7Hz，1H，H-14)，4.87～4.74(m，4H)，4.59(s，1H，H-17α)，4.39～4.21(m，2H，H-19)，3.19～3.15(m，2H，CH 2N)，0.71(d，J＝15.7Hz，3H，H-20)；
IR(KBr)v：3327，2931，1714，1276，1113，711cm -1；
MS(70eV)m/z：614.3[M+H] +；
Anal.Calcd.for?C 37H 43NO 7：C72.41，H7.06，N2.28；
Found：C2.69，H7.09，N2.27.
Embodiment 3
3, and 19-two [N-(2,4 dichloro benzene base)-2-amido phenylacetyl]-N-ethanoyl-12-(R, S)-aminomethylene-14-desoxyandrographolide (I 3) preparation:
With reference to I 1Synthetic method makes I by compound 3 and N-(2,4 dichloro benzene base)-2-aminophenyl acetic acid 3, through silica gel column chromatography, (V: V=1: 1) wash-out obtains white solid, molecular weight 991.87, yield 50.0%, 78.0～79.8 ℃ of mp to petroleum ether-ethyl acetate;
1H?NMR(DMSO-d 6，300MHz)：7.88～6.82(m，9H，H-14?and?ArH?and?ArN HAr)，4.81(m，3H)，4.55(s，2H)，4.28～4.07(m，2H，H-19)，3.78(s，2H，C H 2COO)，3.19～3.14(m，2H，CH 2N)，0.72(m，3H，H-20)；
Embodiment 4
3, and 19-two (2-acetic ester benzoyl)-N-ethanoyl-12-(R, S)-aminomethylene-14-desoxyandrographolide (I 4) preparation:
With reference to I 1Synthetic method makes I by compound 3 and 2-acetic ester phenylformic acid 4, through silica gel column chromatography, (V: V=1: 1) wash-out obtains the 0.08g white solid, molecular weight 759.87, yield 42.2%, 80.0～82.0 ℃ of mp to petroleum ether-ethyl acetate;
1H?NMR(DMSO-d 6，500MHz)：7.95～7.24(m，9H，ArH?and?H-14)，4.84～4.78(m，3H)，4.59(s，1H，H-17β)，4.33～4.00(m，2H，H-19)，3.19～3.13(m，2H，CH 2N)，0.96(m，3H，H-20)；
IR(KBr)v：3372，2940，1755，1280，1101，770cm -1；
MS(70eV)m/z：730.2[M+H] +，752.2[M+Na] +；
Embodiment 5
3, and 19-two (uncle's N-fourth oxygen formyl radical-L-2-amino-4-methylbutyryl base)-N-ethanoyl-12-(R, S)-aminomethylene-14-desoxyandrographolide (I 5) preparation:
With reference to I 1Synthetic method makes I by compound 3 and toluylic acid 5, through silica gel column chromatography, (V: V=1: 1) wash-out obtains white solid, molecular weight 834.05,88.0～90.0 ℃ of mp to petroleum ether-ethyl acetate;
1H?NMR(DMSO-d 6，300MH )：7.21(br?s，1H，H-14)，4.91(s，1H，H-17α)，4.85(s，2H，H-15)，4.56(s，1H，H-17β)，4.26～4.12(m，2H，H-19)，3.45～3.34(m，2H，CH 2N)，1.51～1.42(m，18H)，0.71(d，J＝10.3Hz，3H，H-20)；
IR(KBr)v：3500，2929，1753，1628，1089，423cm -1；
MS(70eV)m/z：854.5[M+Na] +；
Embodiment 6
3, and 19-two (3, the 5-dimethylbenzoyl)-N-ethanoyl-12-(R, S)-aminomethylene-14-desoxyandrographolide (I 6) preparation:
With reference to I 1Synthetic method, by compound 3 and 3, the 5-mesitylenic acid makes I 6, through silica gel column chromatography, (V: V=1: 1) wash-out obtains white solid, molecular weight 699.91, yield 60.0%, 86.0～89.0 ℃ of mp to petroleum ether-ethyl acetate;
1H?NMR(DMSO-d 6，300MH
Figure A20091003322100092
)：7.92～7.05(m，7H，H-14?and?ArH)，4.87～4.73(m，4H)，4.59(s，1H，H-17β)，4.37～4.31(dd，J＝7.0，7.0Hz，1H，H-19α)，4.21(d，J＝7.0Hz，1H，H-19β)，3.20～3.12(m，2H，CH 2N)，0.72(d，J＝14.3Hz，3H，H-20)；
IR(KBr)v：3327，2930，1749，1275，1108cm -1；
MS(70eV)m/z：692.2[M+Na] +；
Anal.Calcd.for?C 41H 51NO 7：C73.52，H7.67，N2.09；
Found：C73.22，H7.70，N2.08.
Compound I 1～I 6Anti-tumor activity: get respectively and be in people's adenocarcinoma of stomach cell BGC-823, human liver cancer cell SMMC-7721 in good condition and each one bottle of people's adenocarcinoma of stomach cell SGC-7901 exponential phase of growth, add 0.25% (w/w) tryptic digestive juice, attached cell is come off, counting 2 * 10 4～4 * 10 4Individual/mL, make cell suspension.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 180 μ L put constant temperature CO 2Cultivate 24h in the incubator.Change liquid, adding is subjected to the reagent thing, and every hole 20 μ L cultivate 48h.MTT is added in 96 orifice plates, and every hole 20 μ L react 4h in incubator.Supernatant liquor is removed in suction, adds DMSO, every hole 150 μ L, jolting 5min on the dull and stereotyped shaking table.Is the light absorption value that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength, and calculates cell inhibitory rate (the results are shown in Table 1).The result shows:
1. working as drug level is 10 -5During M, Compound I 1～I 6People's adenocarcinoma of stomach cell BGC-823, human liver cancer cell SMMC-7721, people's adenocarcinoma of stomach cell SGC-7901 all there are restraining effect, wherein I 1, I 2, I 4, I 5, I 6Restraining effect to BGC-823 has surpassed rographolide; I wherein 1, I 2, I 4, I 5, I 6Restraining effect to SMMC-7721 has surpassed rographolide; Selected compounds has all surpassed rographolide to the restraining effect of SGC-7901.
2. working as drug level is 10 -6During M, Compound I 1, I 2, I 3, I 4, I 6BGC-823 has restraining effect to people's adenocarcinoma of stomach cell, and wherein I1, I2 have surpassed rographolide to the restraining effect of BGC-823; Compound I 1～I 6Human liver cancer cell SMMC-7721 all there are restraining effect, wherein I 2, I 6Restraining effect to SMMC-7721 has surpassed rographolide; Compound I 1～I 6SGC-7901 all has restraining effect to people's adenocarcinoma of stomach cell, and selected compounds has all surpassed rographolide to the restraining effect of SGC-7901.
3. working as drug level is 10 -7During M, Compound I 1～I 6BGC-823 all has restraining effect to people's adenocarcinoma of stomach cell; Compound I 1～I6 all has restraining effect to human liver cancer cell SMMC-7721, and wherein I6 has surpassed rographolide to the restraining effect of SMMC-7721; Compound I 1～I 6SGC-7901 all has restraining effect, Compound I to people's adenocarcinoma of stomach cell 1, I 2, I 3, I 5, I 6Restraining effect to SGC-7901 has all surpassed rographolide.
Table 1
Figure A20091003322100101

Claims (5)

1, a kind of andrographolidume derivative of replacement, its general structure (I) is:
Wherein R is:
Figure A2009100332210002C2
Or (CH 3) 2CHCH 2NHCOOC (CH 3) 3CH 2
2, a kind of method for preparing derivative as claimed in claim 1, its concrete steps are:
A. in alcoholic solution, the Michael reaction takes place with mol ratio 1: 10～11 in rographolide and Nitromethane 99Min. under the effect of catalyzer, becomes to reaction solution and clarifies, and generates 12-nitro methyl isophthalic acid 4-desoxyandrographolide;
B. in acid solution, add reductive agent and the above-mentioned 12-nitro methyl isophthalic acid 4-desoxyandrographolide that makes, add acetic anhydride again, reductive acylation reaction 8～14h obtains N-ethanoyl-12-aminomethylene-14-desoxyandrographolide;
C. in organic solvent; N-ethanoyl-12-aminomethylene-14-desoxyandrographolide mixes with mol ratio 1: 5～6 with carboxylic acid; add dewatering agent and catalyzer esterification 10～48h, through washing, extraction, dry, concentrate, column chromatography separates and obtains target compound I.
3, method according to claim 2 is characterized in that the alcoholic solution described in the steps A is the alcoholic solution of C1～C4; Catalyzer is any one in the sodium alkoxide of C1～C4, and the mol ratio of catalyst consumption and rographolide is 1～3: 1; Acid solution among the step B is formic acid, acetate or hydrochloric acid, and its consumption and 12-nitro methyl isophthalic acid 4-desoxyandrographolide mol ratio are 3～5: 1; Described reductive agent is iron powder or zinc powder, its consumption and 12-nitro methyl isophthalic acid 4-desoxyandrographolide mol ratio 5～10: 1; The consumption of acetic anhydride and 12-nitro methyl isophthalic acid 4-desoxyandrographolide mol ratio are 5～6: 1; Dewatering agent among the step C is 1,3-dicyclohexyl carbodiimide (DCC), phosphorus oxychloride or triphenylphosphine, its consumption and N-ethanoyl-12-aminomethylene-14-desoxyandrographolide mol ratio 5～10: 1; Catalyzer is triethylamine or 4-Dimethylamino pyridine (DMAP), its consumption and N-ethanoyl-12-aminomethylene-14-desoxyandrographolide mol ratio 1: 5～10; Organic solvent is methylene dichloride or ethylene dichloride.
4, method according to claim 2, the structural formula that it is characterized in that the carboxylic acid described in the step C is ROOH, wherein R is:
Figure A2009100332210003C1
Or (CH 3) 2CHCH 2NHCOOC (CH 3) 3CH 2
5, the purposes of a kind of andrographolidume derivative of the replacement described in claim 1 in antitumor drug.
CN2009100332218A 2009-06-16 2009-06-16 Substituted andrographolidume derivative, preparation method thereof and application thereof Expired - Fee Related CN101570524B (en)

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CN105367558B (en) * 2015-08-27 2018-07-03 沈阳药科大学 Andrographolidume derivative and its preparation method and application
CN114015732A (en) * 2021-11-29 2022-02-08 陕西嘉禾生物科技股份有限公司 Industrial preparation method of andrographolide and dehydroandrographolide
CN114015732B (en) * 2021-11-29 2024-03-01 陕西嘉禾生物科技股份有限公司 Industrial preparation method of andrographolide and dehydroandrographolide
CN116869995A (en) * 2023-09-08 2023-10-13 中国中医科学院广安门医院 Application of andrographolide modified compound J6 or derivative thereof

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