CN103864781A - Novel 1,9-disubstituted tetrahydrocarboline derivative preparation, and application of 1,9-disubstituted tetrahydrocarboline derivatives in anti-tumor drugs - Google Patents
Novel 1,9-disubstituted tetrahydrocarboline derivative preparation, and application of 1,9-disubstituted tetrahydrocarboline derivatives in anti-tumor drugs Download PDFInfo
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- CN103864781A CN103864781A CN201210537185.0A CN201210537185A CN103864781A CN 103864781 A CN103864781 A CN 103864781A CN 201210537185 A CN201210537185 A CN 201210537185A CN 103864781 A CN103864781 A CN 103864781A
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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
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to the technical field of medicinal chemistry, and specifically relates to novel 1,9-disubstituted tetrahydrocarboline derivative preparation, and an application of the 1,9-disubstituted tetrahydrocarboline derivatives in anti-tumor drugs, wherein the series of the compounds belong to new compounds. According to the present invention, the angles and the space distance of two groups on site 1 and site 9 are changed to research the EP3 receptor; and currently a new and efficient synthesis route is developed to research a series of the derivatives, and all the compounds are subjected to structure identification through NMR and LC-MS, wherein the target compounds provide important effects in antibacterial, antitumor, analgesia, anti-platelet aggregation, promotion of sodium and water re-absorption on kidney site, uterine contraction, regulation of neurotransmitter release, promotion of adipose tissue lipolysis, and anti-arrhythmia.
Description
Technical field
The present invention relates to the bromo-9-of a kind of 8-(2 '-acetic ester)-1-(phenyl)-2 of new replacement, 3,4,9-tetrahydrochysene-1H-pyrido [3,4] application in preparation and the antitumor drug thereof of indole derivatives, transforms slightly to its DG-041 core texture, develops the anticoagulation medicine of the autonomous innovation of high-efficiency low-toxicity, with other biological screening active ingredients, EP
3distributing maximum is brain, cloth and whole central nervous system, heating and the hyperalgesia of mediation body.EP
3also be extensively present in the organs such as stomach, kidney and uterus, can gastric acid secretion inhibiting, promote heavily absorbing, shrinks uterus, adjusting release, the steatolysis of promotion fatty tissue etc. of neurotransmitter of kidney position sodium and water.
Technical background
Indoles and corresponding derivative thereof, itself be the elementary cell of many Structures of Natural Products, is mainly present in many alkaloids with the form of various derivatives.The aromatic heterocycle organic compound that contains twin nuclei, it is a kind of important fine chemical material, resource is very abundant.The fields such as medicine, dyestuff, plant growth agent are wherein much widely used in.Carboline compounds and derivative thereof have multiple biological activity, comprise the aspects such as antibacterial, antitumor, analgesia, platelet aggregation-against, anti-arrhythmia.This compounds source is very extensive, its derivative can be found lead compound and obtain through structural modification from natural phant, the tricyclic antidepressants indoles that DG-041 core texture is transformed slightly of our invention, also there were in the past many reports, but there is a large amount of problems, we,, by 1 and 9 bit architectures are changed, can solve water-soluble problem and steric hindrance and space structure problem, also can increase its activity to EP3 acceptor.We introduce substituent pattern and never see document and patent report by carrying out structure of modification to 1 and 9; The examination of the space length of these two angles is also very important to EP3 acceptor research, and we develop a new efficient synthetic route research of a series of derivatives is had to very important research meaning at present.
Be exactly using 7-bromaniline as starting raw material herein; through cyclisation, reduction; the series reaction such as P-S cyclization, alkylation, deprotection, hydrolysis obtain having the bromo-9-of 8-(the methyl acetate)-1-(phenyl)-2 of potential source biomolecule activity first; 3; 4; 9-tetrahydrochysene-1H-pyrido [3,4] indoles) and derivative.
Invention summary
First, the invention provides formula (I) compound
Formula (I)
Wherein:
X is preferably: halogen (wherein preferred Br and C1), Otf, hydrogen.
R2 is preferably: bromine (chlorine) methyl acetate, bromine (chlorine) ethyl acetate, bromine (chlorine) acetic acid.
R3 is preferably: phenyl aldehyde, 3,4-dichlorobenzaldehyde, 3,5-dichlorobenzaldehyde, 4-trifluoromethylated benzaldehyde, 4-nitrobenzaldehyde, 4-methoxybenzaldehyde, 3,4-dimethoxy benzaldehyde, 3,5-dimethylbenzaldehyde, 3-tolyl aldehyde, 4-tolyl aldehyde.
R4 is preferably: the carbonic acid tert-butyl ester or hydrogen
Specilization compound of the present invention comprises
(1) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(2) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(3,4-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(3) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(3,5-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(4) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(5) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(4-nitrophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(6) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(4-p-methoxy-phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(7) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(8) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(9) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(10) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(4-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(11) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(12) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(3,4-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(13) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(3,5-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(14) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(15) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(4-nitrophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(16) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(4-p-methoxy-phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(17) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(18) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(19) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(20) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-ethyl acetate)-1-(4-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(21) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(22) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(3,4-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(23) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(3,5-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(24) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(25) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(4-nitrophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(26) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(4-p-methoxy-phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(27) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(28) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(29) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(30) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(4-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(31) the bromo-9-of 8-(2 '-methyl acetate)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(32) the bromo-9-of 8-(2 '-methyl acetate)-1-(3,4-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(33) the bromo-9-of 8-(2 '-methyl acetate)-1-(3,5-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(34) the bromo-9-of 8-(2 '-methyl acetate)-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(35) the bromo-9-of 8-(2 '-methyl acetate)-1-(4-nitrophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(36) the bromo-9-of 8-(2 '-methyl acetate)-1-(4-p-methoxy-phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(37) the bromo-9-of 8-(2 '-methyl acetate)-1-(3,4-dimethoxy-benzyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(38) the bromo-9-of 8-(2 '-methyl acetate)-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(39) the bromo-9-of 8-(2'-methyl acetate)-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(40) the bromo-9-of 8-(2 '-methyl acetate)-1-(4-methyl benzyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(41) 8-bromine 9-(2 '-methyl acetate)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(42) the bromo-9-of 8-(2 '-methyl acetate)-1-(3,4-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(43) the bromo-9-of 8-(2 '-methyl acetate)-1-(3,5-dichlorophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(44) the bromo-9-of 8-(2 '-methyl acetate)-1-(4-trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(45) the bromo-9-of 8-(2 '-methyl acetate)-1-(4-nitrophenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(46) the bromo-9-of 8-(2 '-methyl acetate)-1-(4-p-methoxy-phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(47) the bromo-9-of 8-(2 '-methyl acetate)-1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(48) the bromo-9-of 8-(2 '-methyl acetate)-1-(3,5-Dimethoxyphenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(49) the bromo-9-of 8-(2 '-methyl acetate)-1-(3-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
(50) the bromo-9-of 8-(2 '-methyl acetate)-1-4-aminomethyl phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
Detailed Description Of The Invention
The synthetic route of formula (I)
Illustrate 1
7-bromo indole diketone
Get 7-bromaniline (10g, 5.8mmol) put into 500mL round-bottomed flask, add 250mL water, under stirring state, add anhydrous sodium sulphate (63.56g, 45.2mmol) and oxammonium hydrochloride (13.24g, 19.1mmol), then add 2mol/L hydrochloric acid soln 10mL, under room temperature, stir 5 minutes, finally add Chloral Hydrate (10.6g, 11.6mol).By reaction mixture stirring at room temperature 15 minutes, then react 2h at 90 ℃, after reaction 2h, TLC detects raw material and disappears, then cooling under room temperature, suction filtration, vacuum-drying, obtains yellow solid 13.4g.
Get the 40mL vitriol oil and join in 100mL round-bottomed flask, at 50 ℃, the yellow solid of 13.4g is slowly joined in the vitriol oil, add completely at latter 65 ℃ and react 30min.After reaction finishes, be cooled to room temperature, then reaction mixture be poured in mixture of ice and water, stir 30min, suction filtration obtains red solid, dry under vacuum drying oven, obtains 7-bromo indole diketone 11.4g, yield 84%.For red solid.
1H?NMR(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
Under anhydrous and oxygen-free condition, getting 7-bromo indole diketone 3g (13.3mmol) puts in 250mL round-bottomed flask, add anhydrous THF 10mL and make its dissolving, at 0 ℃, dropwise add 30mL (30mmol) borine (1M in THF), finish, after being raised to room temperature reaction 48h, TLC detects raw material disappearance, is cooled to room temperature, adds successively 50mL methyl alcohol and 100mL water.Then ethyl acetate extraction (200mL × 3), merges organic phase, anhydrous sodium sulfate drying, and desolventizing is revolved in decompression, and column chromatography is purified with sherwood oil 100-200 order silicagel column.Obtain 7-bromo indole 800mg, yield 32%.
1HNMR(d6-DMSO，400MHz)：δ/ppm?11.29(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
Under anhydrous and oxygen-free condition, be cooled to 0 ℃ with icy salt solution, get dry DMF (2.5g, 34mmol) in 100mL round-bottomed flask, POCl3 (1.4g, 8.5mmol) slowly drip, within about 10 minutes, dropwise, 0 ℃ is continued reaction 30 minutes, then get 7-bromo indole (1.1g, 5.7mmol) be dissolved in 10mL DMF and then slowly drop in reaction flask, within approximately 30 minutes, dropwise at 0 ℃, slowly be raised to room temperature, react 5 hours, after TLC detection reaction is complete, saturated NaCO3 solution will be added in first reaction soln, be adjusted to PH for alkalescence, there is a large amount of white solids to occur simultaneously, filter, with 100mL washing filter cake washing 3 times, dry to product 1.2g, productive rate 94%.
1HNMR(d6-DMSO，400MHz)：δ/ppm?12.35(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-indoles
Get 3-formaldehyde-7-bromo indole (10g, 44.8mmol) and ammonium acetate (3.4g, 44.8mmol) put into 250mL round-bottomed flask, add Nitromethane 99Min. 100mL, be slowly heated to 75 ℃, about 2 hours, the reaction of some plate finishes, and Slow cooling to 0 ℃ has a large amount of yellow solids to separate out, and filters, solid with 95% ethyl alcohol recrystallization to the bromo-3-of product (Z)-7-(2-nitroethylene)-1H-indoles 9g, yield 75%.
1HNMR(d6-DMSO，400MHz)：δ/ppm?12.37(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).
ESI-MS，m/z：267(M+)，269(M+)
Illustrate 5
2-(the bromo-1H-indol-3-yl of 7-) ethamine
Under anhydrous and oxygen-free condition, get NaBH4850mg (22.5mmol) and put into 100mL round-bottomed flask, get the anhydrous THF of 5mL and make its dissolving, at 0 ℃ BF329mL (30mmol, 1M in Et20) be dropwise added drop-wise in reaction flask, within 15 minutes, dropwise, 0 ℃ is stirred 30 minutes, then bromo-(Z)-7-3-(2-nitroethylene)-1H-indoles (1g, 3.7mmol) be dissolved in the anhydrous THF of 10mL, 0 ℃ adds reaction system gradually, within 30 minutes, dropwise, 34 ℃ are continued to stir 20 hours, the reaction of TLC point plate finishes, add the cancellation of 20mL methyl alcohol, obtain the tetrahydrofuran solution of 2-(the bromo-1H-indol-3-yl of 7-) ethamine, concentrated, column chromatography obtains target compound 800mg (75%).
Illustrate 6
The bromo-1-of 8-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
Get previous step water and put into the triangular pyramidal bottle of 250mL, slowly add 3N NaOH to make its water PH=8 left and right, add EA (50mLx3) extraction, merge organic phase, then vacuum concentration.Obtain 740mg solid, then this solid is added in the round-bottomed flask of 50mL, with the dissolving of 15mL acetonitrile, add respectively trifluoroacetic acid (851mg, 7.4mmol), phenyl aldehyde (657mg, 6.2mmol), reacts 6 days at 34 ℃ of threes, revolve to steam and remove unnecessary acetonitrile, add 50mL water, with EA (50mL x3) extraction merging organic phase, then vacuum concentration.With eluent (sherwood oil: ethyl acetate=30: 1 removes impurity, and ethyl acetate obtains product), 100-200 order purification by silica gel column chromatography.Obtain the bromo-1-of 8-(phenyl)-2,3,4, the crude product of 9-tetrahydrochysene-1H-pyrido [3,4-b] indoles, directly next step.
1HNMR(CDCl3，400MHz)：δ/ppm?7.636(s，1H，Ar-H)，7.47-7.50(d，1H，Ar-H)，7.29-7.39(m，5H，Ar-H)，5.24(s，1H，CH)，3.35-3.39(m，1H，CH2)，3.15-3.19(m，1H，CH2)，2，83-2.93(m，2H，CH2)，1.38(s，1H，NH).
Illustrate 7
The bromo-1-of the 2-carbonic acid tert-butyl ester-8-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
Get the bromo-1-of previous step 8-(phenyl)-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] crude product (1g of indoles, 4.0mmol) put into 100mL round-bottomed flask, add 10mL DCM to make its dissolving, add again triethylamine (929mg, 9.2mmol), getting BOC acid anhydrides (1.1g 4.8mmol) is dissolved in 10mL DCM and slowly adds in reaction flask, add room temperature reaction 2h, after TLC detection reaction is complete, dichloromethane extraction (20mL × 3), collect organic phase, concentrated, with sherwood oil: ethyl acetate=30: 1, 100-200 order purification by silica gel column chromatography.Obtain the bromo-1-of the product 2-carbonic acid tert-butyl ester-8-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles .1.25g, yield 96%.
Illustrate 8
The bromo-9-of the 2-carbonic acid tert-butyl ester-8-(methyl acetate)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
Get the bromo-1-of the 2-carbonic acid tert-butyl ester-8-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles (0.5g, 1.2mmol) put into 50mL round-bottomed flask, cool to 0 ℃ with ice bath, add successively methyl bromoacetate (217mg, 1.4mmol), NaH (106mg, 2.6mmol) and 6mL DMF. keep 0 ℃, make its reaction 20min.After TLC detection reaction is complete, be cooled to room temperature, 30mL adds water, with EA (30mL x3) extraction three times, merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, uses sherwood oil: ethyl acetate=25: 1,100-200 order purification by silica gel column chromatography.Obtain 0.45g, productive rate 77%.
1HNMR(CDCl3，400MHz)：δ/ppm?7.51(s，1H，Ar-H)，7.28-7.35(m，6H，Ar-H)，6.51(t，1H，Ar-H)，5.03(s，1H，CH)，4.77-4.82(d，1H，CH2)，4.20-4.33(d，1H，CH2)，3.58(s，3H，CH3)，2，81-2.98(m，4H，CH2)，1.28(s，9H，CH3).
Illustrate 9
The bromo-9-of the 2-carbonic acid tert-butyl ester-8-(acetic acid)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
Get the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(methyl acetate)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles (0.1g, 0.20mmol) is put into 25mL round-bottomed flask, add 1mL methyl alcohol and 2N NaOH 1mL to react 5h at 50 ℃, vacuum concentration is removed methyl alcohol, under low temperature, is adjusted to the EA of acidic ph=4. extraction with 2N HCl hydrochloric acid, and vacuum concentration obtains product 92mg yield 95%.
Illustrate 10
The bromo-9-of 8-(methyl acetate)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
Get the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(methyl acetate)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles (0.2g, 0.5mmol) is put into the round-bottomed flask of 50mL, add the DCM of 10mL, add 3mL trifluoroacetic acid.At 50 ℃, react 4h.After TLC detection reaction is complete, to the aqueous solution that adds 2N NaOH in reaction mixture, be adjusted to weakly alkaline, ph=9. add 10mL water, then add EA (30mL x3) extraction extraction 3 times, merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration obtains product 150mg, yield 84%.
1HNMR(CDCl3，400MHz)：δ/ppm?7.45-7.47(d，1H，Ar-H)，7.28-7.35(m，5H，Ar-H)，7.20-7.23(d，1H，Ar-H)，5.22(s，1H，CH)，4.99-5.23(d，1H，CH2)，4.60-4.66(d，1H，CH2)，3.51(s，1H，CH3)，3.08-3.11(t，2H，CH2)，2，84-2.88(t，2H，CH2)，1.35(s，1H，NH).
Illustrate 11
The bromo-9-of 8-(2 '-acetic ester)-1-(phenyl)-2,3,4, the experiment that 9-tetrahydrochysene-1H-pyrido [3,4] indole derivatives suppresses K562, TH-29, HepG2 selectivity
Cell K562, HT-29, HepG2 are purchased from Shanghai cell bank, get in K562, TH-29, the HepG2 cell of growth logarithmic phase and are inoculated in 96 orifice plates, every hole 5 × 10
3individual cell/100 μ L at 37 ℃, passes into 5% CO simultaneously
2under condition, cultivate 24 hours.Medicine is dissolved in to 5 different pharmaceutical concentration of preparation in dimethyl sulfoxide (DMSO) (being dissolved in hydrochloric acid Virahol for measuring the medicine of K562) and prepares against mensuration (drug level scope is 0-10 μ M), the drug solution of getting 0.5 each concentration gradient of μ L adds in 96 orifice plates and at 37 ℃, continues to cultivate 48 hours, (K562 is suspension cell to discard nutrient solution, without discarding nutrient solution), every hole adds the tetramethyl-azo azoles indigo plant (MTT) of 0.5g/mL, under 490 wavelength, measure the optical density(OD) OD value (measuring the optical density(OD) of K562 under 570 wavelength) in 96 each hole of orifice plate.3-4 parallel hole established in each test, repeats 3-4 time.
Medicine growth inhibition ratio (%)=(the average OD value of the average OD value-medication of solution control group group) average OD value of/control group to cell, the then IC of the growth inhibition ratio to cell (%) calculating medicine according to different pharmaceutical concentration
50value.
The bromo-9-of 8-(2'-acetic ester)-1-(phenyl)-2,3,4, the inhibiting experimental result of 9-tetrahydrochysene-1H-pyrido [3,4] indole derivatives to K562, HepG2, HT-29 cell proliferation
We choose K562, HepG2, the HT-29 cancer cells as experiment, can be found out by chart: compound 1,21,31,50 couples of K562, HepG2 and HT-29 have optionally restraining effect.
Above-mentioned embodiment is the specific embodiment for absolutely proving that the present invention enumerates only, and protection scope of the present invention is as the criterion with the content of claims, and is not limited to embodiment.Being equal to of flesh and blood of the present invention that what those skilled in the art did on basis of the present invention do not depart from substitutes or conversion, and 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, comprise summary and accompanying drawing, and institute in disclosed any method or process is in steps, all can arbitrary combination, unless some feature or step are the combinations of mutually repelling, each feature disclosed by the invention, comprises summary and accompanying drawing, can be reached identical, be equal to or the alternative features of similar object, unless separately there is clear and definite elaboration, therefore, unless
Separately have clear and definite illustrating, each feature disclosed by the invention just has and is equal to or a concrete example of the universal serial of similar features.Except described herein, for professional and technical personnel in the field, give to describe herein in content basis can be apparent to various modifications of the present invention.These modifications also should drop in this accessory claim scope.
accompanying drawing explanation:
Fig. 1 is the bromo-9-of the compound 2-carbonic acid tert-butyl ester-8-(2 '-methyl acetate)-1-(phenyl)-2,3,4 in specification sheets, the hydrogen nuclear magnetic resonance spectrogram of 9-tetrahydrochysene-1H-pyrido [3,4-b] indoles.
Fig. 2 is compound in specification sheets) the bromo-9-of the 2-carbonic acid tert-butyl ester-8-(2 '-acetic acid)-1-(phenyl)-2,3,4, the hydrogen nuclear magnetic resonance spectrogram of 9-tetrahydrochysene-1H-pyrido [3,4-b] indoles.
Fig. 3 is the bromo-9-of compound 8-(2 '-methyl acetate)-1-(phenyl)-2,3,4 in specification sheets, the hydrogen nuclear magnetic resonance spectrogram of 9-tetrahydrochysene-1H-pyrido [3,4-b] indoles.
Claims (7)
1. the compound shown in structural formula (I).Or its pharmaceutically acceptable solvated compounds, inner complex, non-covalent complex or prodrug,
Structural formula (I)
It is characterized in that:
R3 is selected from phenyl, all kinds of containing substituent phenyl.
R2 is selected from acetic ester, containing substituent acetoxyl, and acetic acid.
R4 is selected from the carbonic acid tert-butyl ester, the acyl compounds of lower paraffin hydrocarbons.
2. the compound under claim structural formula 1 is that X is bromine, R2 is chosen as methyl acetate, R4 is the carbonic acid tert-butyl ester, R3 is phenmethyl, 3,4-dichlorobenzene methyl, 3,5-dichlorobenzene methyl, 4-trifluoromethyl phenmethyl, 4-oil of mirbane methyl, 4-mehtoxybenzyl, 3,4-dimethoxy phenmethyl, 3,5-dimethyl benzene methyl, 3-methylbenzene methyl, 4-methylbenzene methyl.
3. the compound under claim structural formula 1 is that X is bromine, R2 is chosen as ethyl acetate, R4 is the carbonic acid tert-butyl ester, R3 is phenmethyl, 3,4-dichlorobenzene methyl, 3,5-dichlorobenzene methyl, 4-trifluoromethyl phenmethyl, 4-oil of mirbane methyl, 4-mehtoxybenzyl, 3,4-dimethoxy phenmethyl, 3,5-dimethyl benzene methyl, 3-methylbenzene methyl, 4-methylbenzene methyl.
4. the compound under claim structural formula 1 is for being bromine for X, R2 is chosen as acetic acid, R4 is the carbonic acid tert-butyl ester, R3 is phenmethyl, 3,4-dichlorobenzene methyl, 3,5-dichlorobenzene methyl, 4-trifluoromethyl phenmethyl, 4-oil of mirbane methyl, 4-mehtoxybenzyl, 3,4-dimethoxy phenmethyl, 3,5-dimethyl benzene methyl, 3-methylbenzene methyl, 4-methylbenzene methyl.
5. the compound under claim structural formula 1 is for being bromine for X, R2 is chosen as methyl acetate, R4 hydrogen, R3 is phenmethyl, 3,4-dichlorobenzene methyl, 3,5-dichlorobenzene methyl, 4-trifluoromethyl phenmethyl, 4-oil of mirbane methyl, 4-mehtoxybenzyl, 3,4-dimethoxy phenmethyl, 3,5-dimethyl benzene methyl, 3-methylbenzene methyl, 4-methylbenzene methyl.
6. the compound under claim structural formula 1 is that X is bromine, R2 is chosen as ethyl acetate, R4 hydrogen, R3 is phenmethyl, 3,4-dichlorobenzene methyl, 3,5-dichlorobenzene methyl, 4-trifluoromethyl phenmethyl, 4-oil of mirbane methyl, 4-mehtoxybenzyl, 3,4-dimethoxy phenmethyl, 3,5-dimethyl benzene methyl, 3-methylbenzene methyl, 4-methylbenzene methyl.
Compou nd synthesis route under claim structural formula 1
The bromo-9-of 7.8-(2 '-acetic ester)-1-(phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4] indole derivatives heavily absorbs, shrinks uterus, adjusts the application in steatolysis and the antiarrhythmic drug of release, promotion fatty tissue of neurotransmitter antibacterial, antitumor, the analgesia of preparation, platelet aggregation-against, gastric acid secretion inhibiting, promotion kidney position sodium and water.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108329325A (en) * | 2017-07-20 | 2018-07-27 | 天津科技大学 | A kind of synthetic method of 8- azepines chromone |
| CN108623585A (en) * | 2018-05-22 | 2018-10-09 | 中国人民解放军第二军医大学 | Beta-tetrahydro carboline class antifungal drug and its preparation method and application |
| CN115215782A (en) * | 2022-07-22 | 2022-10-21 | 常州琦诺生物科技有限公司 | Preparation method of 4-bromoindole |
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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 |
| WO2012059232A1 (en) * | 2010-11-03 | 2012-05-10 | Philip Morris Products S.A | Carbazole and carboline derivatives, and preparation and therapeutic applications thereof |
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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 |
| WO2012059232A1 (en) * | 2010-11-03 | 2012-05-10 | Philip Morris Products S.A | Carbazole and carboline derivatives, and preparation and therapeutic applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108329325A (en) * | 2017-07-20 | 2018-07-27 | 天津科技大学 | A kind of synthetic method of 8- azepines chromone |
| CN108329325B (en) * | 2017-07-20 | 2020-11-10 | 天津科技大学 | Synthesis method of 8-azachromone |
| CN108623585A (en) * | 2018-05-22 | 2018-10-09 | 中国人民解放军第二军医大学 | Beta-tetrahydro carboline class antifungal drug and its preparation method and application |
| CN115215782A (en) * | 2022-07-22 | 2022-10-21 | 常州琦诺生物科技有限公司 | Preparation method of 4-bromoindole |
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