CN101570524B - Substituted andrographolide derivative and preparation method and application thereof - Google Patents
Substituted andrographolide derivative and preparation method and application thereof Download PDFInfo
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- CN101570524B CN101570524B CN2009100332218A CN200910033221A CN101570524B CN 101570524 B CN101570524 B CN 101570524B CN 2009100332218 A CN2009100332218 A CN 2009100332218A CN 200910033221 A CN200910033221 A CN 200910033221A CN 101570524 B CN101570524 B CN 101570524B
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- desoxyandrographolide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical class C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title abstract 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 5
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 238000006957 Michael reaction Methods 0.000 claims abstract description 3
- 238000005917 acylation reaction Methods 0.000 claims abstract description 3
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 230000001476 alcoholic effect Effects 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- -1 sodium alkoxide Chemical class 0.000 claims description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 2
- 238000001035 drying Methods 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 239000012024 dehydrating agents Substances 0.000 abstract 1
- 230000000235 effect on cancer Effects 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 15
- 230000000452 restraining effect Effects 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 8
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 8
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical class [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 241000411851 herbal medicine Species 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- WIAPFNDQWLOVKC-UHFFFAOYSA-N 1,3,5-trimethylcyclohexa-2,4-diene-1-carboxylic acid Chemical compound CC1=CC(C)=CC(C)(C(O)=O)C1 WIAPFNDQWLOVKC-UHFFFAOYSA-N 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 241000746375 Andrographis Species 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 208000037062 Polyps Diseases 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical class [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000012747 synergistic agent Substances 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a substituted andrographolide derivative and a preparation method and application thereof. In an alcohol solution, andrographolide and nitromethane are subjected to Michael reaction under the action of a catalyst to generate 12-nitromethyl-14-deoxyandrographolide; adding a reducing agent and the prepared 12-nitromethyl-14-deoxyandrographolide into an acid solution, adding acetic anhydride, and carrying out reduction acylation reaction to obtain N-acetyl-12-aminomethylene-14-deoxyandrographolide; and finally, mixing N-acetyl-12-aminomethylene-14-deoxyandrographolide and carboxylic acid in an organic solvent, adding a dehydrating agent and a catalyst for esterification, washing, extracting, drying, concentrating and separating to obtain the target compound. The synthetic route of the invention has the advantages of low production cost, simple post-treatment and the like, and partial new compounds obtained show stronger inhibition effect on cancer cells than the prior anticancer drugs in antitumor activity experiments.
Description
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, its general structure (D is:
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:
Concrete reactions steps is:
When wherein R is different group, corresponding Compound I respectively
1～I
6
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, 8.05g2, 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，
z)：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, and 19-two phenylacetyl-N-ethanoyl-12-(R, S)-aminomethylene-14-desoxyandrographolide (I
2) preparation:
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，
：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：C?72.41，H?7.06，N?2.28；
Found：C?2.69，H?7.09，N?2.27.
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，
：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，
：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，
：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：C?73.52，H?7.67，N?2.09；
Found：C?73.22，H?7.70，N?2.08.
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
Claims (4)
1. the andrographolidume derivative of a replacement, its general structure (I) is:
2. 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); The structural formula of wherein said carboxylic acid is RCOOH, and wherein R is:
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. the andrographolidume derivative of the replacement described in claim 1 is in the purposes of preparation in the antitumor drug.
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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 |
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| 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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Non-Patent Citations (3)
| Title |
|---|
| 徐浩等.N-乙酰基-12-氨基亚甲基-14-脱氧穿心莲内酯衍生物的合成及其抗肿瘤活性.《中国药科大学学报》.2005,第36卷(第6期),第496-499页. * |
| 徐浩等.穿心莲内酯NO供体衍生物的合成.《有机化学》.2005,第25卷(第11期),第1386-1391页. * |
| 徐浩等.穿心莲内酯硝甲基衍生物的合成.《中国药物化学杂志》.2005,第15卷(第4期),第212-216页. * |
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