CN103864779B - The preparation of a kind of 1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole derivatives and the application in antitumor drug thereof - Google Patents
The preparation of a kind of 1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole derivatives and the application in antitumor drug thereof Download PDFInfo
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- CN103864779B CN103864779B CN201210531525.9A CN201210531525A CN103864779B CN 103864779 B CN103864779 B CN 103864779B CN 201210531525 A CN201210531525 A CN 201210531525A CN 103864779 B CN103864779 B CN 103864779B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to the preparation of a kind of 1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole derivatives and the application in antitumor drug thereof。Research display suppresses the activity of one or more prostaglandin receptors can effectively treat hypertension, a kind of PGE2 receptor is had at least to play vital effect in the process of RAAS system fading margin blood pressure, its EP3 receptor is studied by we by the angle and space length changing 1 and 8 these two groups, we develop a new efficient synthetic route and go to study its a series of derivants at present, whole target compounds is all new product, and all of compound carried out Structural Identification by nuclear-magnetism and liquid matter。These a little target compounds antibacterial, antitumor, analgesia, antiplatelet aggregation, promotion renal tract sodium and water the release heavily absorbing, adjusting neurotransmitter, promote that the steatolysis of fatty tissue and arrhythmia have important function。
Description
Technical field
The present invention relates to the preparation of a kind of 1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3, the 4-b] indole derivatives of new replacement and the application in antitumor drug thereof。Its DG-041 core texture is transformed slightly, develops the anticoagulation medicine of the autonomous innovation of high-efficiency low-toxicity and other biological screening active ingredients, EP3Being distributed maximum is brain, cloth and whole central nervous system, the heating of mediation body and hyperalgesia。EP3Also the organs such as stomach, kidney and uterus it are widely present in, it is possible to the steatolysis etc. heavily absorbing, shrinking uterus, the release of adjustment neurotransmitter, promotion fatty tissue of gastric acid secretion inhibiting, promotion renal tract sodium and water。
Technical background
Carboline class and corresponding derivant thereof have much been widely used in the fields such as medicine, dyestuff, plant growth agent。Its compound and derivant thereof have multiple biological activity, including the aspect such as antibacterial, antitumor, analgesia, antiplatelet aggregation, arrhythmia。This compounds source is very extensive, its derivant can be found lead compound from natural plants and obtain through structural modification, the tricyclic antidepressants indole that DG-041 core texture is transformed slightly of our invention, also there were many reports in the past, but there is substantial amounts of problem, we are by changing 8 and 1 bit architecture, it is possible to solve water solubility problems and space length problem, it is also possible to increase its activity to EP3 receptor。We introduce the pattern of substituent group and never see document and patent report by carrying out structure of modification to 8 and 1；The research of EP3 receptor is also held the balance by the examination of the space length of these two angles, and we develop a new efficient synthetic route research of a series of derivants is had critically important Research Significance at present。
It is exactly using 7-bromaniline as initiation material herein; through cyclisation, reduction; the series reaction such as P-S cyclization, alkylation, Heck, deprotection, hydrolysis obtain the 1-(phenyl)-2 with potential source biomolecule activity first; 3; 4; 9-tetrahydrochysene-1H-pyrido [3,4-b] indole derivatives。
Invention summary
First, the present invention provides formula (I) compound
Formula (I)
Wherein:
R1 is preferably: acrylic acid methyl ester., ethyl acrylate, acrylic acid。
R2 is preferably: benzaldehyde, 3,4-dichlorobenzaldehydes, 3,5-dichlorobenzaldehydes, 4-trifluoromethylated benzaldehyde, 4-nitrobenzaldehyde, 4-methoxybenzaldehyde, 3,4-dimethoxy benzaldehyde, 3,5-dimethylbenzaldehydes, 3-tolyl aldehyde, 4-tolyl aldehyde。
R2 is preferably: acrylic acid methyl ester., ethyl acrylate, acrylic acid。
R3 is preferably: t-butyl carbonate or hydrogen
Specilization compound of the present invention includes
(1) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(2) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(3,4-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(3) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(3,5-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(4) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(5) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(4-nitrobenzophenone)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(6) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(4-methoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(7) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(8) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(9) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(10) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(4-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(11) 2-t-butyl carbonate-8-[3 '-(E)-ethyl acrylate]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(12) 2-t-butyl carbonate-8-[3 '-(E)-ethyl acrylate]-1-(3,4-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(13) 2-t-butyl carbonate-8-[3 '-(E)-ethyl acrylate]-1-(3,5-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(14) 2-t-butyl carbonate-8-[3 '-(E)-ethyl acrylate]-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(15) 2-t-butyl carbonate-8-[3 '-(E)-ethyl acrylate]-1-(4-nitrobenzophenone)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(16) 2-t-butyl carbonate-8-[3 '-(E)-ethyl acrylate]-1-(4-methoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(17) 2-t-butyl carbonate-8-[3 '-(E)-ethyl acrylate]-1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(18) 2-t-butyl carbonate-8-[3 '-(E)-ethyl acrylate]-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(19) 2-t-butyl carbonate-8-[3 '-(E)-ethyl acrylate]-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(20) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(4-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(21) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(22) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(3,4-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(23) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(3,5-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(24) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(25) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(4-nitrobenzophenone)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(26) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(4-methoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(27) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(28) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(29) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(30) 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(4-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(31) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(32) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(3,4-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(33) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(3,5-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(34) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(35) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(4-nitrobenzophenone)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(36) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(4-methoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(37) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(3,4-dimethoxy-benzyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(38) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(39) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(40) 8-[3 '-(E)-acrylic acid methyl ester .]-1-(4-methyl benzyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(41) 8-[3 '-(E)-ethyl acrylate]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(42) 8-[3 '-(E)-ethyl acrylate]-1-(3,4-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(43) 8-[3 '-(E)-ethyl acrylate]-1-(3,5-Dichlorobenzene base)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(44) 8-[3 '-(E)-ethyl acrylate]-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(45) 8-[3 '-(E)-ethyl acrylate]-1-(4-nitrobenzophenone)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(46) 8-[3 '-(E)-ethyl acrylate]-1-(4-methoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(47) 8-[3 '-(E)-ethyl acrylate]-1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(48) 8-[3 '-(E)-ethyl acrylate]-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(49) 8-[3 '-(E)-ethyl acrylate]-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
(50) 8-[3 '-(E)-ethyl acrylate]-1-(4-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
Detailed Description Of The Invention
Illustrate 1
7-bromo indole diketone
Take 7-bromaniline (10g, 5.8mmol) put in 500mL round-bottomed flask, add 250mL water, add anhydrous sodium sulfate (63.56g, 45.2mmol) and oxammonium hydrochloride. (13.24g, 19.1mmol) under agitation, it is subsequently adding 2mol/L hydrochloric acid solution 10mL, stir 5 minutes under room temperature, be eventually adding chloral hydrate (10.6g, 11.6mol)。Being stirred at room temperature by reactant mixture 15 minutes, then reaction 2h at 90 DEG C, after reaction 2h, TLC detects raw material and disappears, and then cools down under room temperature, sucking filtration, vacuum drying, obtains yellow solid 13.4g。
Take 40mL concentrated sulphuric acid and join in 100mL round-bottomed flask, at 50 DEG C, the yellow solid of 13.4g is slowly added in concentrated sulphuric acid, be added completely at latter 65 DEG C and react 30min。Reaction is cooled to room temperature after terminating, and is then poured in mixture of ice and water by reactant mixture, stirs 30min, and sucking filtration obtains red solid, dry under its sky drying baker, obtains 7-bromo indole diketone 11.4g, yield 84%。For red solid。
1HNMR (DMSO) δ: 11.137 (1H, s), 7.757-7.730 (1H, t), 7.666-7.661 (1H, d), 6.891-6.870 (1H, d).
Illustrate 2
7-bromo indole
When anhydrous and oxygen-free, take 7-bromo indole diketone 3g (13.3mmol) and put in 250mL round-bottomed flask, adding anhydrous THF10mL makes it dissolve, 30mL (30mmol) borine (1MinTHF) it is added dropwise at 0 DEG C, finish, after being raised to room temperature reaction 48h, TLC detects raw material disappearance, is cooled to room temperature, is sequentially added into 50mL methanol and 100mL water。Then extraction into ethyl acetate (200mL × 3), merge organic facies, and anhydrous sodium sulfate dries, and solvent is removed in decompression rotation, column chromatography petroleum ether 100-200 order silica column purification。Obtain 7-bromo indole 800mg, yield 32%。
1HNMR (d6-DMSO, 400MHz): δ/ppm11.29 (s, 1H, NH), 7.55-7.57 (d, 1H, Ar-H), 7.28-7.30 (d, 1H, Ar-H), 7.38-7.40 (t, 1H, Ar-H), 6.94-6.96 (t, 1H, Ar-H), 6.55-6.56 (m, 1H, Ar-H).
Illustrate 3
3-formaldehyde-7-bromo indole
When anhydrous and oxygen-free, it is cooled to 0 DEG C with brine ice, take dry DMF (2.5g, 34mmol) in 100mL round-bottomed flask, POCl3 (1.4g, 8.5mmol) it is slowly added dropwise, within about 10 minutes, dropwise, 0 DEG C is continued reaction 30 minutes, then 7-bromo indole (1.1g is taken, 5.7mmol) it is dissolved in 10mLDMF to be then slowly added dropwise to reaction bulb, within about 30 minutes, dropwise at 0 DEG C, it is slowly raised to room temperature, react 5 hours, after TLC detection reacts completely, elder generation's reaction solution will add saturated NaCO3 solution, it is adjusted to PH for alkalescence, there is substantial amounts of white solid to occur simultaneously, filter, wash filter cake with 100mL to wash 3 times, dry arrives product 1.2g, productivity 94%。
1HNMR (d6-DMSO, 400MHz): δ/ppm12.35 (s, 1H, NH), 9.21 (s, 1H, COH), 8.32-8.33 (d, 1H, Ar-H), 8.04-8.06 (d, 1H, Ar-H), 7.44-7.46 (m, 1H, Ar-H), 7.10-7.15 (t, 1H, Ar-H).
Illustrate 4
(Z) the bromo-3-of-7-(2-nitroethylene)-1H-indole
Take 3-formaldehyde-7-bromo indole (10g, 44.8mmol) and ammonium acetate (3.4g, 44.8mmol) put in 250mL round-bottomed flask, add Nitrocarbol. 100mL, be heated slowly to 75 DEG C, about 2 hours, point plate reaction terminates, and progressively cooling to 0 DEG C has substantial amounts of yellow solid to precipitate out, and filters, solid arrives product (Z)-7-bromo-3-(2-nitroethylene)-1H-indole 9g, yield 75% with 95% ethyl alcohol recrystallization。
1HNMR (d6-DMSO, 400MHz): δ/ppm12.37 (s, 1H, NH), 8.28-8.38 (t, 2H, CH), 7.96-8.00 (m, 2H, Ar-H), 7.44-7.47 (m, 1H, Ar-H), 7.09-7.15 (t, 1H, Ar-H).
Illustrate 5
2-(the bromo-1H-indol-3-yl of 7-) ethamine
When anhydrous and oxygen-free, take NaBH4850mg (22.5mmol) and put in 100mL round-bottomed flask, taking the anhydrous THF of 5mL makes it dissolve, BF329mL (30mmol at 0 DEG C, 1MinEt2O) dropwise it is added drop-wise in reaction bulb, within 15 minutes, dropwise, 0 DEG C is stirred 30 minutes, then (Z)-7-bromo-3-(2-nitroethylene)-1H-indole (1g, 3.7mmol) it is dissolved in the anhydrous THF of 10mL, 0 DEG C is gradually added into reaction system, within 30 minutes, dropwise, 34 DEG C are continued stirring 20 hours, the reaction of TLC point plate terminates, add 20mL methanol cancellation, obtain the tetrahydrofuran solution of 2-(the bromo-1H-indol-3-yl of 7-) ethamine, concentration, column chromatography obtains target compound 800mg (75%)。
Illustrate 6
8-bromo-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
Take previous step 740mg solid, then this solid is added in the round-bottomed flask of 50mL, dissolve with 15mL acetonitrile, add trifluoroacetic acid (851mg respectively, 7.4mmol), benzaldehyde (657mg, 6.2mmol), reacts 6 days at three 34 DEG C, rotation is evaporated off unnecessary acetonitrile, add 50mL water, extract with EA (50mLx3) and merge organic facies, then vacuum concentration。With eluant (petroleum ether: ethyl acetate=30: 1 removes impurity, and ethyl acetate obtains product), 100-200 order purification by silica gel column chromatography。Obtain the crude product of 8-bromo-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole, directly next step。
Illustrate 7
2-t-butyl carbonate-8-bromo-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
Take the bromo-1-of previous step 8-(phenyl)-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] crude product (1g of indole, 4.0mmol) put in 100mL round-bottomed flask, adding 10mLDCM makes it dissolve, add triethylamine (929mg, 9.2mmol), take BOC anhydride (1.1g4.8mmol) to be dissolved in 10mLDCM being slowly added in reaction bulb, add room temperature reaction 2h, after TLC detection reacts completely, dichloromethane extraction (20mL × 3), collect organic facies, concentration, with petroleum ether: ethyl acetate=30: 1, 100-200 order purification by silica gel column chromatography。Obtain product 2-t-butyl carbonate-8-bromo-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole, 1.25g, yield 96%。
Illustrate 8
2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(phenyl)-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] take the bromo-1-of 2-t-butyl carbonate-8-(phenyl)-2 under indole anhydrous and oxygen-free nitrogen protection, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] indole (0.5g, 1.2mmol) put in 50mL round-bottomed flask, it is sequentially added into acrylic acid methyl ester. (148mg, 1.7mmol), palladium (25mg, 0.11mmol), triphenylphosphine (89.5mg, 0.34mmol), 2mL triethylamine and 6mL. are warmed up to 100 DEG C, it is made to react 7h。TLC detection is cooled to room temperature, adds water after reacting completely, and extracts three times with EA, merges organic facies, organic facies saturated common salt water washing, and anhydrous sodium sulfate dries, with petroleum ether: ethyl acetate=25: 1,100-200 order purification by silica gel column chromatography。Obtain 0.43g, productivity 81%。
1HNMR (CDCl3,400MHz): δ/ppm7.87-7.92 (d, 1H, CH), 7.56-7.61 (d, 1H, Ar-H), 7.40-7.42 (d, 1H, Ar-H), 7.30-7.33 (d, 5H, Ar-H), 7.17-7.19 (d, 1H, Ar-H), 6.40-6.45 (t, 1H, CH), 4.36 (s, 1H, CH), 3.79 (s, 3H, CH3), 3.09-3.18 (m, 1H, CH2), 2.91-2.98 (m, 1H, CH2), 2.78-2.89 (m, 1H, CH2), 1.53 (s, 9H, CH3)
Illustrate 9
2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
Take 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole (0.1g, 0.23mmol) put in 25mL round-bottomed flask, adding 1mL methanol and 2NNaOH reacts 15h at 50 DEG C, vacuum concentration removes methanol, is adjusted to acid ph=4. EA with 2NHCl hydrochloric acid and extracts under low temperature, vacuum concentration obtains product 75mg, yield 82%。
1HNMR (CDCl3,400MHz): δ/ppm8.54-8.60 (d, 1H, CH), 7.96-8.01 (d, 1H, Ar-H), 7.59-7.61 (d, 1H, Ar-H), 7.39-7.42 (d, 1H, Ar-H), 7.30 (m, 5H, Ar-H), 7.13-7.18 (t, 1H, Ar-H), 6.37-6.42 (d, 1H, CH), 4.30 (s, 1H, CH), 2.76-3.16 (m, 4H, CH2), 1.51 (s, 9H, CH3).
Illustrate 10
8-[3 '-(E)-acrylic acid methyl ester .]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
Take 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole (0.2g, 0.46mmol) put in the round-bottomed flask of 50mL, add the DCM of 10mL, add 3mL trifluoroacetic acid。4h is reacted at 50 DEG C。TLC detection adds the aqueous solution of 2NNaOH in reactant mixture, is adjusted to alkalescence after reacting completely, and ph=9. adds 10mL water, then add EA to extract 3 times, merge organic facies, organic facies saturated common salt water washing, anhydrous sodium sulfate dries, and vacuum concentration obtains product 135mg, yield 90%。
1HNMR (CDCl3,400MHz): δ/ppm7.84-7.89 (d, 1H, CH), 7.76 (s, 1H, Ar-H), 7.59-7.61 (d, 1H, Ar-H), 7.31-7.42 (m, 5H, Ar-H), 7.13-7.18 (t, 1H, Ar-H), 6.38-6.44 (d, 1H, CH), 5.22 (s, 1H, CH), 3.79 (s, 3H, CH3), 3.36-3.42 (m, 1H, CH2), 3.11-3.18 (m, 1H, CH2), 2.80-2.94 (m, 2H, CH2).
Illustrate 11
The experiment to K562, TH-29, HepG2 Selective depression of 8-[3 '-(E)-acrylate]-9-(benzyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3, the 4] indole derivatives
Cell K562, HT-29, HepG2 are purchased from Shanghai cell bank, take K562, TH-29, HepG2 cell being in growth logarithmic (log) phase and are inoculated in 96 orifice plates, every hole 5 × 103Individual cell/100 μ L, at 37 DEG C, passes into the CO of 5% simultaneously2Cultivate 24 hours under condition。Medicine is dissolved in dimethyl sulfoxide (medicine for measuring K562 is dissolved in hydrochloric acid isopropanol) and prepares 5 different pharmaceutical concentration in order to measuring (drug level ranges for 0-10 μM), take the drug solution of 0.5 μ each Concentraton gradient of L to add and 96 orifice plates continue at 37 DEG C cultivate 48 hours, (K562 is suspension cell to discard culture fluid, without discarding culture fluid), every hole adds the Methyl thiazoly tetrazolium assay (MTT) of 0.5g/mL, measures the optical density OD value (measuring the optical density of K562 under the wavelength of 570) in the 96 each holes of orifice plate under 490 wavelength。Each test sets 3-4 parallel hole, repeats 3-4 time。
Medicine growth inhibition ratio (%)=(solution control group mean OD value-medication group mean OD value)/matched group mean OD value to cell, then calculates the IC of medicine according to the growth inhibition ratio (%) of different pharmaceutical concentration versus cell50Value。
1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3, the 4-b] the indole derivatives inhibiting experimental result to K562, HepG2, HT-29 cell proliferation
We choose K562, HepG2, HT-29 cancerous cell as experiment, by chart it can be seen that compound 1,21,31,50 couple of K562, Hep62 and HT-29 have certain selective inhibitory action。
Above-mentioned embodiment is only the specific embodiment absolutely proving the present invention and enumerate, and protection scope of the present invention is as the criterion with the content of claims, and is not limited to detailed description of the invention。The equivalent replacement without departing from flesh and blood of the present invention that those skilled in the art does on basis of the present invention or conversion, also all within protection scope of the present invention, therefore, the spirit and scope of the invention is not limited to specific descriptions herein。
All the elements disclosed by the invention, including summary and accompanying drawing, and the institute in disclosed any method or process is in steps, all can be in any combination, unless the combination that some feature or step exclude each other, each feature disclosed by the invention, including summary and accompanying drawing, can be reached identical, the alternative features of equivalent or similar purpose, unless otherwise clear and definite elaboration, therefore, unless explicitly set forth, each feature disclosed by the invention is a concrete example of the universal serial with equivalent or similar features。Except described herein, for professional and technical personnel in the field, giving the various modifications to the present invention in content basis described herein can be apparent。These modifications also should drop in this scope。
Accompanying drawing illustrates:
Fig. 1 is the proton nmr spectra of 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid methyl ester .]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole。
Fig. 2 is the proton nmr spectra of 2-t-butyl carbonate-8-[3 '-(E)-acrylic acid]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole。
Fig. 3 is the proton nmr spectra of 8-[3 '-(E)-acrylic acid methyl ester .]-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole。
Claims (3)
1. the compound as shown in structural formula (I),
Structural formula (I)
It is characterized in that:
R2 is selected from phenyl or the phenyl containing substituent group, the described phenyl containing substituent group selected from 3,4-Dichlorobenzene base, 3,5-Dichlorobenzene base, 4-trifluoromethyl, 4-nitrobenzophenone, 4-methoxyphenyl, 3,4-Dimethoxyphenyl, 3,5-3,5-dimethylphenyls, 3-aminomethyl phenyl or 4-aminomethyl phenyl；
R1 is selected from acrylic acid methyl ester., ethyl acrylate or acrylic acid；
R3 is selected from t-butyl carbonate or H；
R4 is selected from H。
2. the preparation method of the compound described in claim 1, it is characterised in that its synthetic route is as follows:
。
3. the application in preparing antitumor drug of the compound described in claim 1。
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| CN101124229A (en) * | 2004-12-17 | 2008-02-13 | 格兰马克药品股份有限公司 | Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders |
| CN102030750A (en) * | 2005-03-22 | 2011-04-27 | 阿斯利康(瑞典)有限公司 | Novel tetrahydro-1H-pyrido [4,3-b] indole derivatives as CB1' receptor ligands |
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| CN101124229A (en) * | 2004-12-17 | 2008-02-13 | 格兰马克药品股份有限公司 | Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders |
| CN102030750A (en) * | 2005-03-22 | 2011-04-27 | 阿斯利康(瑞典)有限公司 | Novel tetrahydro-1H-pyrido [4,3-b] indole derivatives as CB1' receptor ligands |
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