CN107827888A - It is a kind of（S）Tetrahydrochysene Angustine derivatives and preparation and use - Google Patents

It is a kind of（S）Tetrahydrochysene Angustine derivatives and preparation and use Download PDF

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CN107827888A
CN107827888A CN201710944260.8A CN201710944260A CN107827888A CN 107827888 A CN107827888 A CN 107827888A CN 201710944260 A CN201710944260 A CN 201710944260A CN 107827888 A CN107827888 A CN 107827888A
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pyrido
ethyls
naphthyridines
indoles simultaneously
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邹宏斌
蔡云瑞
祝华建
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Zhejiang University ZJU
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    • 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
    • C07D471/12—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 three hetero rings
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Abstract

The present invention provides a kind of（S）Tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt, the different lima bean glycosides that tryptamines and the synthesis of driffractive ring strychnia are catalyzed using strictosidine synthase is starting material, is obtained by a series of structural modifications.The present invention has synthesized the polycyclic parent nucleus compound of a kind of single chiral that traditional medicinal chemistry is difficult to synthesize, such compound has prominent external topoisomerase I inhibitory activity and external anti-HepG2 tumor promotions, can be applied in topoisomerase I inhibitor series antineoplastic medicament is prepared.With with following formula (I) general structure：

Description

A kind of (S)-tetrahydrochysene Angustine derivatives and preparation and use
Technical field
The invention belongs to pharmaceutical chemistry and area of pharmacology, is related to a kind of (S)-tetrahydrochysene Angustine derivatives and preparation, with And purposes of such compound as topoisomerase I inhibitor in antineoplastic is prepared.
Background technology
Strictosidine synthase (Strictosidine Synthase, STR) is monoterpene indoles alkaloid biosynthesis One of important enzyme, be the enzyme that the first being found from nature can be catalyzed Pictet-Spengler (PS) reactions.Should Enzyme reacts to obtain 3 α (S)-different lima bean glycosides by being catalyzed tryptamines with driffractive ring strychnia generation PS, and 3 α (S)-different lima bean glycosides is The precursor of more than 2000 kinds of alkaloid biosynthesis.These alkaloids often have extensive activity, such as the text of vasodilator effect More spirit, ajmaline, vincaines；The quinine of anti-malarial effect；Vinblastine of antitumor action etc. is all some conventional Clinical medicine.Although chemical method, which can also be catalyzed PS reactions, low yield, and product, contains two kinds of configurations of R, S, separation is complicated. And enzymatic chemical synthesis has the characteristics that efficient, green, stereoselectivity, it has also become in chemistry and biology crossing domain most One of active research field.
Topoisomerase I (Topo I) is a very important enzyme during DNA uncoiling, is widely present in lactation life In thing.It is phosphate-based on the OH group nucleophilic attack DNAs of tyrosine in TopoI avtive spot in DNA uncoiling Group, make a DNA fracture, the DNA being then broken rotates around unbroken DNA, finally makes DNA uncoiling.Anticancer The research and development of medicine are one of heat subjects of current drug research, and Topo I are the important target spots of oncotherapy.From being distributed in Obtained camptothecine is extracted in Central-South, the southwestern camplotheca acuminata of China, as the topoisomerase I inhibitor of classics, is had outstanding Antitumor activity, and derive a series of camptothecin cancer therapy drugs, such as TPT, Irinotecan.
Tetrahydrochysene Angustine alkaloids are found to be distributed widely in Nauclea sections plant, their indoles simultaneously [2': 3',3:4] pyrido [1,2-b] naphthyridines mother nucleus structure has attracted the attention of chemists, and several fully synthetic methods are also carried Go out, but the problems such as tediously long reaction scheme, severe reaction conditions, low yield be present, and (S)-tetrahydrochysene Angustine alkaloids Chirality synthesis is not also reported.In addition, tetrahydrochysene Angustine alkaloids are only reported with anti-T-24, MK tumour cell Proliferation activity and anti-inflammatory activity, its pharmacological activity still need to be explored.
The content of the invention
It is an object of the invention to provide a kind of (S)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt, has following The general structure of formula (I)：
Wherein：Acyl group, saturation or the unsaturated alkane of the benzoyls of different substitutions on phenyl ring, 1-5 carbon can be selected in R Base, hydrogen.Its preferable formula (I) compound is：
I-a：(S) -1- ethyls -7,8,13b, 14- tetrahydro indole simultaneously [2', 3':3,4] pyrido [1,2-b] [2,7] naphthalene Pyridine -5 (13H) -one；
I-b：(S) -1- ethyls -13- (4- chlorobenzene formacyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyridine And [1,2-b] [2,7] -5 (13H) -one；
I-c：(S) -1- ethyls -13- acetyl group -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2- B] [2,7] naphthyridines -5 (13H) -one；
I-d:(S) -1- ethyls -13- benzoyls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1, 2-b] [2,7] naphthyridines -5 (13H) -one；
I-e:(S) -1- ethyls -13- (4- fluoro benzoyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyridine And [1,2-b] [2,7] -5 (13H) -one；
I-f:(S) -1- ethyls -13- (4- nitro benzoyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrrole Pyridine simultaneously [1,2-b] [2,7] -5 (13H) -one；
I-g:(S) -1- ethyls -13- (4- methyl benzoyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrrole Pyridine simultaneously [1,2-b] [2,7] -5 (13H) -one；
I-h:(S) -1- ethyls -13- (4- methoxybenzoyls base) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] Pyrido [1,2-b] [2,7] -5 (13H) -one；
I-i:(S) -1- ethyls -13- (3- chlorobenzene formacyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyridine And [1,2-b] [2,7] -5 (13H) -one；
I-j:(S) -1- ethyls -13- (2- chlorobenzene formacyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyridine And [1,2-b] [2,7] -5 (13H) -one；
I-k:(S) -1- ethyls -13- propionos -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2- B] [2,7] naphthyridines -5 (13H) -one；
I-l:(S) 1- ethyls -13- isobutyryls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2- B] [2,7] naphthyridines -5 (13H) -one；
I-m:(S) -1- ethyls -13- cyclopropyl formoxyls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one；
I-n:(S) -13- methyl isophthalic acids-ethyl -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one；
I-o:(S) -1,13- diethyl -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2, 7] naphthyridines -5 (13H) -one；
I-p:(S) -1- ethyls -13- propyl group -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one；
I-q:(S) -1- ethyls -13- acetonitrile-bases -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2- B] [2,7] naphthyridines -5 (13H) -one；
I-r:(S) -1- ethyls -13- pi-allyls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2- B] [2,7] naphthyridines -5 (13H) -one；
I-s:(S) -1- ethyls -13- isopentene group bromos -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one.
The preferred formula (I) compound of table 1
It is a further object to provide the preparation side of (S)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt Method, realized by following scheme：Tryptamines (II) and driffractive ring strychnia (III) occur PS condensation reactions under STR catalysis and obtain 3 α (S)-different lima bean glycosides (IV), 3 α (S)-different lima bean glycosides (IV) are in Na2CO3Compound V is made in lactamize under alkalescence condition, then With hydrogen (H2) the obtained works of compound VI, compound VI in glucuroide (Glucosldase) of 10%Pd reducing compounds V Under, slough glucose and compound VII, compound VII and ammonium acetate (NH is made4OAc) react and compound VIII, chemical combination is made Thing the VIII obtained compound I-a under p-methyl benzenesulfonic acid (p-TsOH) catalysis, compound I-a in the presence of inorganic base, with R-X (acyl chlorides or halogenated hydrocarbons reagent) occurs substitution reaction and compound I is made, wherein used inorganic when preparing I by compound I-a Alkali is from any one in sodium hydride, potassium tert-butoxide, sodium hydroxide.Synthetic reaction formula is：
It is different as topology it is yet another object of the invention to provide (S)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt Application of the structure enzyme I inhibitor in antineoplastic is prepared.Topoisermerase I Inhibition test shows in vitro, (S)-tetrahydrochysene Angustine derivatives have good inhibitory action to topoisermerase I；Pharmacological evaluation shows in vitro, (S)-tetrahydrochysene Angustine derivatives have the IC for preferably suppressing value-added effect, especially compound I-j in vitro to HepG2 cell lines50Value reaches 1.8μM。
The different lima bean glycosides that the present invention is catalyzed and synthesized using strictosidine synthase is starting material, is repaiied by a series of structures Decorations, a kind of (S)-tetrahydrochysene Angustine derivatives are obtained, and wherein there is prominent TopoI inhibitory activity to resist with external for discovery The compound of HepG2 tumor promotions.The present invention has synthesized one kind that traditional medicinal chemistry is difficult to synthesize by way of enzymology The polycyclic parent nucleus compound of single chiral, and the topoisermerase I inhibitory activity of this kind of compound is explored, show good Anti- HepG2 proliferative activity o f tumors.
Brief description of the drawings
Fig. 1 is synthesis (S)-tetrahydrochysene Angustine derivatives (200 μM) to the external inhibitory activity results of TopoI.
Embodiment
Below in conjunction with the accompanying drawings the present invention is further illustrated with specific embodiment.Following embodiments give representative chemical combination The synthesis of thing and dependency structure appraising datum.Mandatory declaration, following embodiments are to be used to illustrate rather than to the present invention Limitation.The scope of protection of present invention is belonged to according to the simple modifications that the essence of the present invention is carried out to the present invention.
Embodiment 1：It is prepared by the immobilized enzyme method of 3 α (S)-different lima bean glycosides (IV)
The STR (0.5mg) that purification is obtained is dissolved in 5mL KPi buffer solutions (50mM, pH=7.0), and by its It is fixed on Ni-NTA posts.Compound II (0.4g, 2.5mmol) and compound III (1.1g, 2.5mmol) are dissolved in respectively KPi (50mM, pH=7.0,200ml), at 5 DEG C, it is pumped into by constant flow pump and is loaded with STR and obtains on Ni-NTA posts, controlling stream Speed is 0.5ml/min, collects efflux, removes inorganic salts with methanol after freeze-drying, column chromatography purifying, obtains 3 α (S)-different Hu Beans glycosides (VI) 1.26g, yield 84%.
Embodiment 2：The preparation of the different lima bean glycosides (V) of 3 α (S)-lactamize
Compound IV (5.00g, 9.30mmol) is added into 5% sodium carbonate liquor (500mL), reacts 2 at 70 DEG C Hour, after the completion of question response, it is evaporated under reduced pressure and removes solvent, crude product carries out rapid column chromatography, obtains yellow solid 4.56g, receives Rate 95%.
Embodiment 3：The preparation of the different lima bean glycosides (VI) of 3 α (S)-dihydro lactamize
Compound V (3.00g, 6.00mmol) is dissolved in 50ml methanol, adds 10% palladium carbon (300mg) and at room temperature Reaction overnight, is filtered to remove palladium carbon, is evaporated under reduced pressure and removes solvent, obtains yellow solid 2.98g, yield 98%.
Embodiment 4:The preparation of the different lima bean glycosides aglycon (VII) of 3 α (S)-dihydro lactamize
Compound VI (300mg, 0.6mmol) is dissolved in acetic acid-sodium acetate buffer solution (pH=5.0,100ml), added 5.0mg glucuroides, it is incubated 3 days at 37 DEG C, is then extracted with ethyl acetate (50mL × 3), merges organic phase, be concentrated under reduced pressure Crude product is obtained, then carries out rapid column chromatography, obtains white oil liquid 163mg, yield 81%.
Embodiment 5:(1R, 13bS, 14aS) -1- ethyl -2- hydroxyls -1,2,3,7,8,13b, 14,14a- octahydros indoles is simultaneously [2',3':3,4] preparation of pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one (VIII)
Compound VII (150mg, 0.44mmol) is dissolved in 1mL ethanol, ammonium acetate (340mg, 4.4mmol) is added, 80 DEG C reaction 6 hours.After the completion of reaction, it is evaporated under reduced pressure and removes ethanol, and carry out rapid column chromatography, obtain product 130mg, directly throws Enter the next step.
Embodiment 6:(S) -1- ethyls -7,8,13b, 14- tetrahydro indole simultaneously [2', 3':3,4] pyrido [1,2-b] [2,7] The preparation of naphthyridines -5 (13H) -one (I-a)
Compound VIII (130mg) is dissolved in 5mL toluene, adds the p-methyl benzenesulfonic acid of catalytic amount, 80 DEG C are reacted 5 hours. After the completion of question response, it is evaporated under reduced pressure removing toluene and obtains crude product, yellow solid 42mg, yield 42% are obtained through column chromatography.1H NMR(500MHz,CDCl3):δ=9.22 (1H, s), 8.55 (1H, s), 7.60 (1H, d, J=8.0Hz), 7.42 (1H, d, J= 8.0Hz), 7.26 (1H, t, J=8.0Hz), 7.20 (1H, t, J=8.0Hz), 5.26 (1H, dd, J=13.0,5.0Hz), 5.05 (1H, d, J=13.0Hz), 3.49 (1H, dd, J=16.0,3.5Hz), 3.04 (1H, td, J=12.0,3.5Hz), 2.96 (1H, M), 2.94 (1H, dd, J=16.0,13.0Hz), 2.77 (2H, q, J=7.5Hz), 1.27 (3H, t, J=7.5Hz)；13C NMR (125MHz,CHCl3):δ=163.7,152.2,148.4,142.3,136.6,134.9,131.6,126.7,124.3, 122.7,120.2,118.6,111.0,110.4,51.2,39.3,31.4,23.0,20.8,14.6.HRESI-MS[M+H]+ 318.1606。
Embodiment 7:(S) -1- ethyls -13- (4- chlorobenzene formacyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] The preparation of pyrido [1,2-b] [2,7] -5 (13H) -one (I-b)
Compound I-a (10mg, 0.03mmol) is dissolved in 1mL tetrahydrofurans, under nitrogen protection, is added dropwise to the t- of ice In BuOK (8mg, 0.06mmol) THF (0.5mL) suspension, stir 20 minutes, then by 4- chlorobenzoyl chlorides (0.05mmol) Add in reaction system, reaction 3-4 hours.After the completion of question response, add saturated ammonium chloride solution and be quenched, ethyl acetate extraction (3 × 3mL), merge organic phase, be evaporated under reduced pressure and remove organic solvent, obtain crude product, obtained through column chromatography, yellow solid 8mg, receive Rate 61%.1H NMR(500MHz,CDCl3):δ=9.18 (1H, s), 8.51 (1H, s), 7.80 (2H, d, J=8.0Hz), 7.59 (2H, d, J=8.0Hz), 7.56 (1H, t, J=7.5Hz), 7.27 (1H, d, J=7.0Hz), 7.11 (1H, t, J=7.5Hz), 6.66 (1H, d, J=7.5Hz), 5.51 (1H, d, J=13.0Hz), 5.31 (1H, dd, J=13.0,5.0Hz), 3.45 (1H, Dd, J=16.0,3.5Hz), 3.10 (1H, td, J=12.0,3.5Hz), 3.01 (1H, m), 2.95 (1H, m), 2.75 (1H, dd, ), J=16.0,13.0Hz 2.55 (2H, q, J=7.5Hz), 1.13 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3): δ=168.3,163.7,152.0,148.1,143.1,140.4,137.0,134.8,133.0,13 1.4,130.9,129.6, 128.6,124.4,123.4,119.6,119.0,114.3,52.0,38.2,30.9,23.0,21.4,14.1.HRESI-MS[M+ H]+456.1479。
Embodiment 8:(S) -1- ethyls -13- acetyl group -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] pyrido The preparation of [1,2-b] [2,7] -5 (13H) -one (I-c)
Operating process simply replaces 4- chlorobenzoyl chlorides with chloroacetic chloride, obtains white solid, yield referring to embodiment 7 41%.1H NMR(500MHz,CDCl3):δ=9.17 (1H, s), 8.55 (1H, s), 7.75 (1H, d, J=8.0Hz), 7.59 (1H, d, J=8.0Hz), 7.43 (1H, t, J=8.0Hz), 7.38 (1H, t, J=8.0Hz), 5.51 (1H, d, J=13.0Hz), 5.25 (1H, dd, J=13.0,5.0Hz), 3.72 (1H, dd, J=16.0,3.5Hz), 3.03 (1H, td, J=12.0, 3.5Hz), 2.96 (1H, m), 2.90 (1H, s), 2.86 (1H, m), 2.71 (2H, q, J=7.5Hz), 2.61 (1H, dd, J= ), 16.0,13.0Hz 1.26 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=168.2,163.8,152.0, 148.0,141.8,136.0,135.3,131.9,129.6,125.0,123.6,122.1,119.5,119.3,114.5,53.7, 38.0,31.6,27.6,23.2,21.5,14.7.HRESI-MS[M+H]+360.1712。
Embodiment 9:(S) -1- ethyls -13- benzoyls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] pyrido The preparation of [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-d)
Operating process simply replaces 4- chlorobenzoyl chlorides with chlorobenzoyl chloride, obtains white solid, yield referring to embodiment 7 68%.1H NMR(500MHz,CDCl3):δ=9.18 (1H, s), 8.52 (1H, s), 7.75 (1H, t, J=7.5Hz), 7.58 (5H, m), 7.26 (1H, d, J=7.5Hz), 7.09 (1H, t, J=7.5Hz), 6.64 (1H, d, J=7.5Hz), 5.49 (1H, d, ), J=13.0Hz 5.31 (1H, dd, J=13.0,5.0Hz), 3.48 (1H, dd, J=16.0,3.5Hz), 3.12 (1H, td, J= ), 12.0,3.5Hz 3.03 (1H, d, J=16Hz), 2.94 (1H, m), 2.76 (1H, dd, J=16.0,13.0Hz), 2.56 (2H, Q, J=7.5Hz), 1.12 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=169.5,163.7,152.0, 148.1,137.3,135.1,134.8,133.4,133.2,132.0,130.1,129.4,128.7,127.3,124.4, 123.2,119.4,118.9,114.5,52.1,38.2,30.9,23.0,21.5,14.3.HRESI-MS[M+H]+422.1869。
Embodiment 10:(S) -1- ethyls -13- (4- fluoro benzoyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3, 4] preparation of pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-e)
Operating process simply replaces 4- chlorobenzoyl chlorides with 4- fluorobenzoyl chlorides, obtains white solid referring to embodiment 7, Yield 43%.1H NMR(500MHz,CDCl3):δ=9.19 (1H, s), 8.51 (1H, s), 8.15 (2H, dd, J=8.0, 5.5Hz), 7.57 (1H, d, J=8.0Hz), 7.28 (1H, t, J=8.0Hz), 7.16 (2H, t, J=8.0Hz), 7.11 (1H, t, ), J=8.0Hz 6.66 (1H, d, J=8.0Hz), 5.51 (1H, d, J=13.0Hz), 5.31 (1H, dd, J=13.0,5.0Hz), 3.45 (1H, dd, J=16.0,3.5Hz), 3.12 (1H, td, J=12.0,3.5Hz), 3.02 (1H, m), 2.95 (1H, m), 2.76 (1H, dd, J=16.0,13.0Hz), 2.55 (2H, q, J=7.5Hz), 1.12 (3H, t, J=7.5Hz) 13C NMR (125MHz,CHCl3):δ=168.2,163.6,151.9,148.0,143.2,140.3,137.1,134.8,132.7, 132.7,130.6,129.8,128.5,124.4,123.3,119.4,119.0,115.7,51.9,38.2,30.9,23.0, 21.4,14.3.HRESI-MS[M+H]+440.1774。
Embodiment 11:(S) -1- ethyls -13- (4- nitro benzoyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3': 3,4] preparation of pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-f)
Operating process simply replaces 4- chlorobenzoyl chlorides with 4- nitrobenzoyl chlorides, obtains yellow and consolidate referring to embodiment 7 Body, yield 64%.1H NMR(500MHz,CDCl3):δ=9.19 (1H, s), 8.53 (1H, s), 8.47 (2H, d, J=8.0Hz), 7.99 (2H, d, J=8.0Hz), 7.59 (1H, d, J=7.5Hz), 7.30 (1H, t, J=7.5Hz), 7.08 (1H, d, J= 7.5Hz), 6.43 (1H, d, J=7.5Hz), 5.55 (1H, d, J=13.0Hz), 5.32 (1H, dd, J=13.0,5.0Hz), 3.54 (1H, dd, J=16.0,3.5Hz), 3.11 (1H, td, J=12.0,3.5Hz), 3.03 (1H, m), 2.95 (1H, m), 2.79 (1H, dd, J=16.0,13.0Hz), 2.59 (2H, q, J=7.5Hz), 1.16 (3H, t, J=7.5Hz)；13C NMR (125MHz,CHCl3):δ=167.2,163.7,152.2,150.4,148.3,142.9,140.4,136.5,135.0, 134.9,130.1,129.0,124.7,124.4,124.2,123.9,120.7,119.3,114.2,52.3,38.1,31.1, 23.0,21.5,14.4.HRESI-MS[M+H]+467.1719。
Embodiment 12:(S) -1- ethyls -13- (4- methyl benzoyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3': 3,4] preparation of pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-g)
Operating process simply replaces 4- chlorobenzoyl chlorides with 4- methyl benzoyl chlorides, it is solid to obtain white referring to embodiment 7 Body, yield 54%.1H NMR(500MHz,CDCl3):δ=9.17 (1H, s), 8.50 (1H, s), 7.75 (2H, d, J=8.0Hz), 7.56 (1H, d, J=7.5Hz), 7.39 (2H, d, J=8.0Hz), 7.26 (1H, t, J=7.5Hz), 7.10 (1H, d, J= 7.5Hz), 6.75 (1H, d, J=7.5Hz), 5.46 (1H, d, J=13.0Hz), 5.30 (1H, dd, J=13.0,5.0Hz), 3.44 (1H, dd, J=16.0,3.5Hz), 3.11 (1H, td, J=12.0,3.5Hz), 3.01 (1H, m), 2.95 (1H, m), 2.74 (1H, dd, J=16.0,13.0Hz), 2.54 (3H, s), 2.53 (2H, q, J=7.5Hz), 1.11 (3H, t, J= 7.5Hz)；13C NMR(125MHz,CHCl3):δ=169.4,163.7,151.9,148.0,144.6,140.2,137.3, 135.2,134.7,131.7,129.7,129.1,128.3,124.2,124.0,123.0,118.9,118.8,114.4,51.9, 38.2,30.8,23.0,21.8,24.1,14.3.HRESI-MS[M+H]+436.2025。
Embodiment 13:(S) -1- ethyls -13- (4- methoxybenzoyls base) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] preparation of pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-h)
Operating process simply replaces 4- chlorobenzoyl chlorides with 4- methoxy benzoyl chlorides, it is solid to obtain white referring to embodiment 7 Body, yield 49%.1H NMR(500MHz,CDCl3):δ=9.17 (1H, s), 8.50 (1H, s), 7.86 (2H, d, J=8.0Hz), 7.57 (1H, d, J=7.5Hz), 7.26 (1H, t, J=7.5Hz), 7.12 (1H, d, J=7.5Hz), 7.06 (2H, d, J= 8.0Hz), 6.85 (1H, d, J=7.5Hz), 5.45 (1H, d, J=13.0Hz), 5.30 (1H, dd, J=13.0,5.0Hz), 3.97 (1H, s), 3.40 (1H, dd, J=16.0,3.5Hz), 3.11 (1H, td, J=12.0,3.5Hz), 3.02 (1H, m), 2.95 (1H, m), 2.73 (1H, dd, J=16.0,13.0Hz), 2.51 (2H, q, J=7.5Hz), 1.09 (3H, t, J= 7.5Hz)；13C NMR(125MHz,CHCl3):δ=168.8,164.0,163.7,152.0,148.1,143.0,140.5, 137.4,135.0,134.7,132.2,128.3,126.4,124.2,124.1,122.8,118.8,118.5,114.2,55.5, 51.8,38.3,30.8,23.0,21.4,14.3.HRESI-MS[M+H]+452.1974。
Embodiment 14:(S) -1- ethyls -13- (3- chlorobenzene formacyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3, 4] preparation of pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-i)
Operating process simply replaces 4- chlorobenzoyl chlorides with 3- chlorobenzoyl chlorides, obtains white solid referring to embodiment 7, Yield 53%.1H NMR(500MHz,CDCl3):δ=9.19 (1H, s), 8.55 (1H, s), 7.82 (1H, s), 7.72 (1H, dq, J =8.0,1.0Hz), 7.69 (1H, dt, J=8.0,1.0Hz), 7.57 (1H, d, J=7.5Hz), 7.27 (1H, t, J= 7.5Hz), 7.12 (1H, t, J=7.5Hz), 7.02 (1H, m), 6.62 (1H, d, J=7.5Hz), 5.51 (1H, d, J= 13.0Hz), 5.31 (1H, dd, J=13.0,5.0Hz), 3.49 (1H, dd, J=16.0,3.0Hz), 3.11 (1H, td, J= ), 12.0,3.5Hz 3.00 (1H, m), 2.93 (2H, m), 2.76 (1H, dd, J=16.0,13.0Hz), 2.58 (2H, q, J= 7.5Hz), 1.16 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=167.9,163.6,152.0,148.1, 143.1,137.0,136.5,135.1,134.8,133.3,130.4,129.2,128.7,127.6,127.3,124.6, 124.2,123.5,119.9,119.0,114.4,52.2,38.2,31.0,23.0,21.5,14.3.HRESI-MS[M+H]+ 456.1479。
Embodiment 15:(S) -1- ethyls -13- (2- chlorobenzene formacyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3, 4] preparation of pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-j)
Operating process simply replaces 4- chlorobenzoyl chlorides with 2- chlorobenzoyl chlorides, obtains white solid referring to embodiment 7, Yield 47%.1H NMR(500MHz,CDCl3):δ=9.19 (1H, s), 8.55 (1H, s), 7.64 (2H, m), 7.55 (3H, m), 7.27 (1H, t, J=7.5Hz), 7.02 (1H, t, J=7.5Hz), 6.05 (1H, d, J=7.5Hz), 5.69 (1H, d, J= 13.0Hz), 5.31 (1H, dd, J=13.0,5.0Hz), 3.87 (1H, d, J=16.0Hz), 3.11 (1H, td, J=12.0, 3.5Hz), 2.99 (1H, m), 2.93 (1H, m), 2.76 (1H, dd, J=16.0,13.0Hz), 2.70 (2H, q, J=7.5Hz), 1.23 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=168.3,163.6,152.0,148.0,143.1, 137.0,136.5,135.1,134.8,133.3,130.4,129.2,128.7,127.6,127.5,124.5,124.2, 123.5,119.0,114.3,52.0,38.2,30.8,23.0,21.4,14.1.HRESI-MS[M+H]+456.1479。
Embodiment 16:(S) -1- ethyls -13- propionos -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] pyrido The preparation of [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-k)
Operating process simply replaces 4- chlorobenzoyl chlorides with propionyl chloride, obtains white solid, yield referring to embodiment 7 49%.1H NMR(500MHz,CDCl3):δ=9.17 (1H, s), 8.55 (1H, s), 7.76 (1H, d, J=8.0Hz), 7.59 (1H, d, J=8.0Hz), 7.41 (1H, t, J=8.0Hz), 7.37 (1H, t, J=8.0Hz), 5.56 (1H, d, J=13.0Hz), 5.25 (1H, dd, J=13.0,5.0Hz), 3.67 (1H, dd, J=16.0,3.5Hz), 3.26 (1H, m), 3.13 (1H, m), 3.04 (1H, td, J=12.0,3.5Hz), 2.97 (1H, m), 2.89 (1H, m), 2.71 (2H, q, J=7.5Hz), 2.61 (1H, Dd, J=16.0,13.0Hz), 1.40 (3H, t, J=7.5Hz), 1.27 (3H, t, J=7.5Hz)；13C NMR(125MHz, CHCl3):δ=168.3,163.6,150.2,148.5,142.4,136.6,134.8,131.9,129.5,12 5.2,123.6, 122.2,118.9,117.9,114.0,52.8,38.0,31.6,28.6,23.2,21.5,14.7,9.0.HRESI-MS[M+H]+ 374.1869。
Embodiment 17:(S) -1- ethyls -13- isobutyryls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] pyridine And the preparation of [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-l)
Operating process simply replaces 4- chlorobenzoyl chlorides with isobutyryl chloride, obtains white solid, yield referring to embodiment 7 57%.1H NMR(500MHz,CDCl3):δ=9.17 (1H, s), 8.52 (1H, s), 7.68 (1H, d, J=8.0Hz), 7.56 (1H, d, J=8.0Hz), 7.41 (1H, t, J=8.0Hz), 7.37 (1H, t, J=8.0Hz), 5.53 (1H, d, J=13.0Hz), 5.23 (1H, dd, J=13.0,5.0Hz), 3.70 (1H, m), 3.49 (1H, dd, J=16.0,3.5Hz), 3.02 (1H, td, J= ), 12.0,3.5Hz 2.93 (1H, m), 2.83 (1H, m), 2.65 (2H, q, J=7.5Hz), 2.58 (1H, dd, J=16.0, 13.0Hz), 1.50 (2H, d, J=7.0Hz), 1.39 (2H, d, J=7.0Hz), 1.24 (3H, t, J=7.5Hz)；13C NMR (125MHz,CHCl3):δ=176.7,162.7,151.1,147.1,142.6,134.4,134.3,134.0,128.4, 124.0,123.3,122.4,118.3,118.3,113.1,52.3,36.9,34.4,30.2,22.2,20.4,19.2,17.7, 13.7.HRESI-MS[M+H]+388.2025。
Embodiment 18:(S) -1- ethyls -13- cyclopropyl formoxyls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] The preparation of pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-m)
Operating process simply replaces 4- chlorobenzoyl chlorides with Cyclopropyl carbonyl chloride, obtains white solid referring to embodiment 7, Yield 29%.1H NMR(500MHz,CDCl3):δ=9.16 (1H, s), 8.55 (1H, s), 7.97 (1H, d, J=8.0Hz), 7.61 (1H, d, J=8.0Hz), 7.40 (1H, t, J=8.0Hz), 7.36 (1H, t, J=8.0Hz), 5.45 (1H, d, J= 13.0Hz), 5.25 (1H, dd, J=13.0,5.0Hz), 3.61 (1H, dd, J=16.0,3.5Hz), 3.04 (1H, td, J= ), 12.0,3.5Hz 3.01 (1H, m), 2.91 (1H, m), 2.69 (2H, q, J=7.5Hz), 2.66 (1H, dd, J=16.0, 13.0Hz), 1.33 (4H, m), 1.28 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=169.1,163.3, 152.1,148.7,143.3,136.6,134.9,131.9,129.3,125.8,123.6,122.2,118.2,117.3, 113.1,51.7,38.1,30.8,28.6,23.3,21.1,14.9,10.2.HRESI-MS[M+H]+386.1869。
Embodiment 19:(S) -13- methyl isophthalic acids-ethyl -7,8,13b, 14- tetrahydro indole simultaneously [2', 3':3,4] pyrido [1, 2-b] [2,7] naphthyridines -5 (13H) -one (I-n) preparation
Operating process simply replaces 4- chlorobenzoyl chlorides with iodomethane, obtains white solid, yield referring to embodiment 7 59%.1H NMR(500MHz,CDCl3):δ=9.21 (1H, s), 8.59 (1H, s), 7.62 (1H, d, J=7.5Hz), 7.37 (1H, d, J=7.5Hz), 7.21 (1H, t, J=7.5,1.0Hz), 7.20 (1H, t, J=7.5Hz), 5.22 (1H, d, J= 13.0Hz), 5.05 (1H, dd, J=13.0,3.5Hz), 3.80 (2H, d, J=4.5Hz), 3.51 (3H, s), 3.00 (2H, m), 2.97 (1H, m), 2.85 (1H, dd, J=16.0,13.0Hz), 2.76 (2H, q, J=7.5Hz), 1.28 (3H, t, J= 7.5Hz)；13C NMR(125MHz,CHCl3):δ=163.8,152.1,148.2,143.0,138.1,134.8,132.8, 126.0,124.5,122.3,119.8,118.6,110.3,109.1,51.2,39.4,32.0,30.6,23.2,21.3, 14.8.HRESI-MS[M+H]+332.1763。
Embodiment 20:(S) -1,13- diethyl -7,8,13b, 14- tetrahydro indole simultaneously [2', 3':3,4] pyrido [1,2- B] [2,7] naphthyridines -5 (13H) -one (I-o) preparation
Operating process simply replaces 4- chlorobenzoyl chlorides with iodoethane, obtains white solid, yield referring to embodiment 7 60%.1H NMR(500MHz,CDCl3):δ=9.21 (1H, s), 8.59 (1H, s), 7.61 (1H, d, J=8.0Hz), 7.41 (1H, d, J=8.0Hz), 7.30 (1H, t, J=8.0Hz), 7.20 (1H, t, J=8.0Hz), 5.21 (1H, dd, J=13.0, 5.0Hz), 5.03 (1H, d, J=13.0Hz), 4.19 (2H, m), 3.49 (1H, dd, J=16.0,3.5Hz), 3.01 (1H, dd, J =13.0,2.0Hz), 2.94 (2H, m), 2.88 (1H, dd, J=16.0,13.0Hz), 2.76 (2H, q, J=7.5Hz), 1.49 (3H, t, J=7.5Hz), 1.28 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=163.8,152.1, 148.4,143.1,137.1,134.7,132.2,126.5,124.5,122.3,119.8,118.7,110.5,109.5,51.2, 39.3,38.9,32.5,23.3,21.4,15.3,14.7.HRESI-MS[M+H]+346.1919。
Embodiment 21:(S) -1- ethyls -13- propyl group -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] pyrido [1, 2-b] [2,7] naphthyridines -5 (13H) -one (I-p) preparation
Operating process simply replaces 4- chlorobenzoyl chlorides with positive propyl bromo, obtains white solid, yield referring to embodiment 7 49%.1H NMR(500MHz,CDCl3):δ=9.22 (1H, s), 8.59 (1H, s), 7.61 (1H, d, J=8.0Hz), 7.38 (1H, d, J=8.0Hz), 7.29 (1H, t, J=8.0Hz), 7.19 (1H, td, J=8.0Hz), 5.22 (1H, d, J= 13.0Hz), 5.04 (1H, d, J=13.0Hz), 4.17 (1H, m), 3.98 (1H, m), 3.49 (1H, dd, J=16.0,3.5Hz), 3.22 (1H, d, J=7.0Hz), 3.02 (1H, m), 2.96 (2H, td, J=12.0,3.5Hz), 2.85 (1H, dd, J=16.0, 13.0Hz), 2.75 (2H, q, J=7.5Hz), 1.29 (3H, t, J=7.5Hz), 1.15 (2H, m), 0.99 (3H, t, J= 7.5Hz)；13C NMR(125MHz,CHCl3):δ=168.3,163.6,150.2,148.5,142.4,136.6,134.8, 131.9,129.5,125.2,123.6,122.2,118.9,117.9,114.0,52.8,38.0,31.6,28.6,23.2, 21.5,14.7,9.0.HRESI-MS[M+H]+360.2076。
Embodiment 22:(S) -1- ethyls -13- acetonitrile-bases -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] pyrido The preparation of [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-q)
Operating process simply replaces 4- chlorobenzoyl chlorides with bromoacetonitrile, obtains white solid, yield referring to embodiment 7 31%.1H NMR(500MHz,CDCl3):δ=9.21 (1H, s), 8.61 (1H, s), 7.64 (1H, d, J=8.0Hz), 7.41 (2H, m), 7.11 (1H, t, J=7.5Hz), 5.23 (1H, dd, J=10.5,5.0Hz), 5.06 (1H, d, J=10.5Hz), 5.01 (2H, s), 3.59 (1H, dd, J=16.0,3.5Hz), 2.99 (4H, m), 2.81 (2H, q, J=7.5Hz), 1.03 (3H, T, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=162.7,151.4,147.3,141.4,136.6,134.1, 130.9,125.8,123.1,122.8,120.5,118.3,113.3,112.7,107.8,49.7,38.0,31.5,31.3, 22.2,20.2,13.7.HRESI-MS[M+H]+357.1715。
Embodiment 23:(S) -1- ethyls -13- pi-allyls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] pyrido The preparation of [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-r)
Operating process simply replaces 4- chlorobenzoyl chlorides with allyl bromide, bromoallylene, obtains white solid, yield referring to embodiment 7 40%.1H NMR(500MHz,CDCl3):δ=9.20 (1H, s), 8.57 (1H, s), 7.62 (1H, d, J=8.0Hz), 7.30 (1H, t, J=7.5Hz), 7.27 (1H, dd, J=7.5,1.0Hz), 7.21 (1H, td, J=7.5,1.0Hz), 6.10 (1H, m), 5.33 (1H, d, J=10.5Hz), 5.22 (1H, d, J=13.0Hz), 5.02 (1H, d, J=13.0Hz), 4.99 (1H, d, J= 10.5Hz), 4.74 (2H, m), 3.52 (1H, dd, J=16.0,3.5Hz), 3.05 (2H, td, J=12.0,3.5Hz), 2.96 (1H, m), 2.78 (1H, dd, J=16.0,13.0Hz), 2.70 (2H, q, J=7.5Hz), 1.09 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=163.9,152.1,148.3,143.2,137.7,134.9,132.9,132.8,126.3, 124.5,122.4,120.0,118.6,117.1,110.6,109.8,51.1,46.2,39.2,32.4,23.2,21.3, 14.7.HRESI-MS[M+H]+358.1919。
Embodiment 24:(S) -1- ethyls -13- isopentene groups -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] pyridine And the preparation of [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-s)
Operating process simply replaces 4- chlorobenzoyl chlorides with isoprenyl bromide, obtains white solid, receive referring to embodiment 7 Rate 40%.1H NMR(500MHz,CDCl3):δ=9.21 (1H, s), 8.57 (1H, s), 7.61 (1H, d, J=8.0Hz), 7.32 (1H, t, J=7.5Hz), 7.28 (1H, dd, J=7.5,1.0Hz), 7.20 (1H, td, J=7.5,1.0Hz), 5.30 (1H, t, J =5.5Hz), 5.21 (1H, d, J=11.0Hz), 5.03 (1H, d, J=13.0Hz), 4.73 (2H, dd, J=11.0,5.5Hz), 3.56 (1H, dd, J=16.0,3.5Hz), 3.03 (2H, m), 2.95 (1H, m), 2.81 (1H, dd, J=16.0,13.0Hz), 2.69 (2H, qd, J=7.5,3.0Hz), 1.83 (3H, s), 1.79 (3H, s), 1.24 (3H, t, J=7.5Hz)；13C NMR (125MHz,CHCl3):δ=163.8,152.1,148.3,143.3,137.5,135.3,134.8,132.6,126.2, 124.5,122.2,120.9,119.8,118.6,110.3,109.6,51.2,42.5,39.3,32.4,25.4,23.1,21.3, 18.4,14.6.HRESI-MS[M+H]+386.2236。
Essence for a better understanding of the present invention, the present invention is further illustrated below by Pharmacological Examples.Pharmacology is real Apply the amount of activated data that example gives representative compound.Mandatory declaration, following Pharmacological Examples are to be used to illustrate the present invention Rather than limitation of the present invention, the simple modifications carried out according to the essence of the present invention to the present invention belong to application claims and protected The scope of shield.
Embodiment 25:Anti-tumor biological method of testing：
Tumour cell cultured in vitro：Tumour cell HepG2 is chosen in 37 DEG C, 5%CO2It is incubated in cell culture incubator, band is thin After born of the same parents' density grows to 70-90%, passed on after being digested with Puck ' s EDTA, for test later needed for.
Mtt assay determines external antiproliferative effect of (S)-tetrahydrochysene Angustine derivatives to HepG2 tumour cells：
HepG2 tumour cells in exponential phase are diluted to 4 × 104Individual cell/ml, in 96 porocyte culture plates In per hole add 0.1ml, then add concentration be 20.0 μM, 10.0 μM, 5.0 μM, 1.0 μM of testing compound, jointly in 37 DEG C, 5%CO2It is incubated 72 hours in cell culture incubator, is control with DMSO (1%).After 72 hours, add final concentration of 0.25mg/ml MTT, in 7 DEG C, 5%CO2It is incubated 4 hours in cell culture incubator, blots solvent afterwards, 100 μ L is added per hole DMSO, absorbance (OD values) is determined with enzyme linked immunological instrument at 570nm, and the data obtained is used to calculate IC50.Acquired results are shown in Table 2.
Table it is 2-in-1 into (S)-tetrahydrochysene Angustine derivatives to the IC of HepG2 tumour cells50(μM) value
It can be seen that compound I series shows good suppression work to human liver cancer HepG2 tumor cell lines from upper table 2 With, it is possible to develop into the new medicine with antihepatocarcinoma effect.
Embodiment 26：Angustine analog derivatives are to the external inhibitory activity method of testing of topoisermerase I：
Each 1 μ l of sample are taken, is mixed with the μ l of 10 × Topo I reaction buffer 1, adds the μ l of 0.1%BSA 1, The μ l of 1 μ l and Topo I (0.2U/ μ l) of pBR322DNA (50ng/ μ l) 1, are finally settled to 10 μ l with DEPC water, put 37 DEG C.Water-bath Reacting 30min, [every group of experiment is all provided with blank control and negative control.Blank control is that Topo I and drug sample are not added with system (200 μM), volume is supplied with DEPC water；Negative control is that drug sample is not added with system, equally supplies volume with DEPC water].
After water-bath, the μ L of 6 × Loading Buffer 2 are added in above-mentioned each reaction solution (10 μ l), are splined on On 0.8% Ago-Gel, electrophoresis is carried out in tbe buffer liquid, under 100V voltages 60 minutes.After 60 minutes, electrophoresis is finished Glue is placed in (EB) solution of bromination second shallow lake and dyed, and gel imaging is simultaneously analyzed.Acquired results are shown in Fig. 1.Fig. 1 results show, compound I Series has good inhibitory activity to Topo I, is expected to turn into new topoisomerase I inhibitor.

Claims (5)

1. a kind of (S)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt, have with following formula (I) general structure：
Wherein：R is from benzoyls of different substitutions on phenyl ring, acyl group, saturation or unsaturated alkyl, the hydrogen of 1-5 carbon.
2. (S)-tetrahydrochysene Angustine derivatives according to claim 1 and its pharmaceutically useful salt, there is following chemical combination Thing：
I-a：(S) -1- ethyls -7,8,13b, 14- tetrahydro indole simultaneously [2', 3':3,4] pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one；
I-b：(S) -1- ethyls -13- (4- chlorobenzene formacyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] -5 (13H) -one；
I-c：(S) -1- ethyls -13- acetyl group -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2, 7] naphthyridines -5 (13H) -one；
I-d:(S) -1- ethyls -13- benzoyls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one；
I-e:(S) -1- ethyls -13- (4- fluoro benzoyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] -5 (13H) -one；
I-f:(S) -1- ethyls -13- (4- nitro benzoyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] -5 (13H) -one；
I-g:(S) -1- ethyls -13- (4- methyl benzoyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] -5 (13H) -one；
I-h:(S) -1- ethyls -13- (4- methoxybenzoyls base) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyridine And [1,2-b] [2,7] -5 (13H) -one；
I-i:(S) -1- ethyls -13- (3- chlorobenzene formacyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] -5 (13H) -one；
I-j:(S) -1- ethyls -13- (2- chlorobenzene formacyls) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] -5 (13H) -one；
I-k:(S) -1- ethyls -13- propionos -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2, 7] naphthyridines -5 (13H) -one；
I-l:(S) 1- ethyls -13- isobutyryls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one；
I-m:(S) -1- ethyls -13- cyclopropyl formoxyls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1, 2-b] [2,7] naphthyridines -5 (13H) -one；
I-n:(S) -13- methyl isophthalic acids-ethyl -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] Naphthyridines -5 (13H) -one；
I-o:(S) -1,13- diethyl -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] naphthalene Pyridine -5 (13H) -one；
I-p:(S) -1- ethyls -13- propyl group -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2,7] Naphthyridines -5 (13H) -one；
I-q:(S) -1- ethyls -13- acetonitrile-bases -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2, 7] naphthyridines -5 (13H) -one；
I-r:(S) -1- ethyls -13- pi-allyls -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1,2-b] [2, 7] naphthyridines -5 (13H) -one；
I-s:(S) -1- ethyls -13- isopentene group bromos -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3'：3,4] pyrido [1, 2-b] [2,7] naphthyridines -5 (13H) -one.
3. the preparation method of (the S)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt described in claim 1, its feature exist In being realized by following steps：Tryptamines (II) and driffractive ring strychnia (III) occur PS condensation reactions under STR catalysis and obtain 3 α (S)-different lima bean glycosides (IV), 3 α (S)-different lima bean glycosides (IV) are in Na2CO3Compound V is made in lactamize under alkalescence condition, then Use H2, 10%Pd reducing compounds V be made compound VI, compound VI slough glucose system in the presence of glucuroide Obtain compound VII, compound VII and NH4Compound VIII is made in OAc reactions, and compound VIII is under the catalysis to p-TsOH Compound I-a, compound I-a is made in the presence of inorganic base, substitution reaction, which occurs, with R-X is made compound I, wherein R-X For acyl chlorides or halogenated hydrocarbons reagent, synthetic reaction formula is：
4. the preparation method of (S)-tetrahydrochysene Angustine derivatives according to claim 3 and its pharmaceutically useful salt, it is special Sign is that inorganic base used is selected any one in sodium hydride, potassium tert-butoxide, sodium hydroxide when preparing I by compound I-a Kind.
5. (S)-tetrahydrochysene Angustine derivatives according to claim 1 and its pharmaceutically useful salt are different as a kind of topology Application of the structure enzyme I inhibitor in antineoplastic is prepared.
CN201710944260.8A 2017-10-12 2017-10-12 It is a kind of（S）Tetrahydrochysene Angustine derivatives and preparation and use Pending CN107827888A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112625040A (en) * 2021-01-11 2021-04-09 浙江大学 Tetrahydro-beta-carboline compound containing benzimidazole ring and preparation and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
C.A.J.ERDELMEIER ET AL.: "Indole Alkaloids with in vitro Antiproliferative Activity from the Ammoniacal Extract of Nauclea orientalis", 《PLANTA MED.》 *
GUOQIANG DONG ET AL.: "Selection of Evodiamine as a Novel Topoisomerase I Inhibitor by Structure-Based Virtual Screening and Hit Optimization of Evodiamine Derivatives as Antitumor Agents", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
祝华建: "STR1表达体系优化，新底物发现与新吲哚生物碱化学法制备及杂环化合物的构建", 《中国博士学位论文全文数据库 医药卫生科技辑》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112625040A (en) * 2021-01-11 2021-04-09 浙江大学 Tetrahydro-beta-carboline compound containing benzimidazole ring and preparation and application thereof
CN112625040B (en) * 2021-01-11 2021-10-29 浙江大学 Tetrahydro-beta-carboline compound containing benzimidazole ring and preparation and application thereof

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