CN105330666A

CN105330666A - Novel tryptanthrin derivative, synthetic method and medicinal application thereof

Info

Publication number: CN105330666A
Application number: CN201510853001.5A
Authority: CN
Inventors: 候宝龙; 王翠玲
Original assignee: Northwest University
Current assignee: Northwest University
Priority date: 2015-11-27
Filing date: 2015-11-27
Publication date: 2016-02-17
Anticipated expiration: 2035-11-27
Also published as: CN105330666B

Abstract

The invention relates to a novel tryptanthrin (indole[2,1-b] quinazoline-6,12-diketone) derivative, a synthetic method and a medicinal application thereof. A general structural formula is as follows (see the description). The novel tryptanthrin derivative is synthesized through biomimetic synthesis, the general chemical structural formula of the novel derivative is shown in Figure 1, wherein in the formula, R,R1,R2,R3 are halogen, nitro, amido, hydroxy, alkyl, alkoxy and aryl, R1is morpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, isonipecotic acid, piperazine, 1-(2-pyridyl) piperazine, dimethylamine, diethylamine, 1-(2-ethoxy) piperazine and 1-(2-furoyl) piperazine, and an o-aminobenzoic acid derivative reacts with an indole quinone derivative in solvents of methylbenzene, methyl alcohol, ethyl alcohol, dichloromethane, isopropanol and the like, so as to prepare the novel tryptanthrin derivative. The novel tryptanthrin derivative which has a good inhibiting effect and a good antibacterial effect on cancer cells is preliminarily screened through an MTT experiment and an antibacterial experiment, and the medicine has pharmacological effects in the aspects of tumor resistance, antibiosis and inflammation diminishing.

Description

Couroupitine A novel derivative, synthetic method and pharmaceutical usage thereof

Technical field

The present invention relates to medical art, be specifically related to couroupitine A novel derivative, synthetic method and pharmaceutical usage thereof.

Background technology

Couroupitine A (Fig.1), belong to indole quinazoline Alkaloid, chemistry indoles [2 by name, 1-b] quinazoline-6,12-diketone (indolo [2,1-b] quinazolin-6,12-dione), be one of the main component of Chinese medicine indigo naturalis and Leaf of Indigowoad and medicinal plant acanthaceous indigo (Strobilanthescusia) thereof, indigo plant (PolygonumtinctorumLour) and woaded blue (IsatisEinetorial).Couroupitine A and derivative thereof have good antibacterial, anti-inflammatory and the effect such as anticancer.

The structure of Fig.1 couroupitine A.

The natural origin of couroupitine A is little, obtains mainly through synthesis.The synthetic method of couroupitine A and derivative thereof mainly with istain and the istain of replacement thereof and the isatoic anhydride of isatoic anhydride and replacement thereof for Material synthesis.Istain derivative commercial source is comparatively easy, also has substituent derivative by site any on Sandmeyer method synthesis of indole quinone phenyl ring.But isatoic anhydride derivative is difficult to obtain, thus couroupitine A 1-4 bit derivant is more difficult to get.This seminar once have studied couroupitine A biosynthetic process, confirmed that its biosynthesizing precursor is istain and anthranilic acid, and obtained couroupitine A and derivative thereof by bio-mimetic syntheses.

Summary of the invention

For overcoming above-mentioned the deficiencies in the prior art, the object of the present invention is to provide couroupitine A novel derivative and pharmaceutical usage thereof.Couroupitine A structure is simple, and biological activity is extensive, and carry out structural modification to it and likely find active better with transformation, bioavailability is high, likely the novel derivative of patent medicine, and therefore, couroupitine A is the desirable lead compound in medicament research and development.Although reported the synthesis of a large amount of couroupitine As and derivative thereof and antitumor, antibacterial isoreactivity, medicine listing not relevant so far, in order to find the better couroupitine A novel derivative of biological activity, to provide basis for new drug development; Object of the present invention is just to provide new has couroupitine A derivative that is antitumor, anti-microbial activity; The present invention adopts bio-mimetic syntheses route, has synthesized a series of couroupitine A derivative, and introduces aliphatic amide and little heterocycle at 7 further, obtains a series of novel derivative; Adopt the method for bio-mimetic syntheses, avoid use isatoic anhydride derivative, cheaper starting materials is easy to get, and reaction conditions is gentle, and productive rate is high, simple to operate; Synthesized couroupitine A novel derivative has good inhibition tumor cell system and anti-inflammatory, anti-microbial activity.

For achieving the above object, the technical solution used in the present invention is: couroupitine A novel derivative, has following general structure:

Wherein, R is the individual respective independently substituting group of n (n=0-4) on 1-4 position, R ₁for the individual respective independently substituting group of n (n=0-3) on 8-10 position, R, R ₁=halogen, nitro, amido, hydroxyl, alkyl, alkoxyl group, aryl; R ₂=morpholine, piperidines, N-methyl piperidine, piperazine, isonipecotic acid, 1-(2-pyridyl) piperazine, dimethylamine, diethylamine, 1-(2-hydroxyethyl) piperazine, 1-(2-furancarbonyl) piperazine.

Work as R, R ₃for hydrogen, R ₁for 8-fluorine, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 2a described in formula 1; Work as R, R ₁for hydrogen, R ₂for fluorine, R ₃during for chlorine, described couroupitine A novel derivative is the derivative 2b described in 1:

When R is 3-chlorine, R ₁and R ₃for hydrogen, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 4 described in formula 2:

When R is 3-chlorine, R ₁and R ₃for hydrogen, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 5 described in formula 3:

When R is 3-chlorine, R ₁for chlorine, R ₂for fluorine, R ₃during for hydrogen, described couroupitine A novel derivative is the derivative 6a described in formula 4; When R is 3-chlorine, R ₁for hydrogen, R ₂for fluorine, R ₃during for chlorine, described couroupitine A novel derivative is the derivative 6b described in formula 4:

When R is 1,2-chlorine, R ₁for chlorine, R ₂for fluorine, R ₃during for hydrogen, described couroupitine A novel derivative is the derivative 7 described in formula 5:

When R is 1,2-chlorine, R ₁, R ₂, R ₃during for hydrogen, described couroupitine A novel derivative is the derivative 8 described in formula 6:

When R is 1,2-chlorine, R ₁and R ₃for hydrogen, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 9 described in formula 7:

When R is 1-chlorine and 2-fluorine, R ₁, R ₂, R ₃during for hydrogen, described couroupitine A novel derivative is the derivative 10 described in formula 8:

When R is 1-chlorine and 2-fluorine, R ₁and R ₃for hydrogen, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 11 described in formula 9:

When R is 1-chlorine and 2-fluorine, R ₁and R ₃for hydrogen, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 12 described in formula 10:

When R is 1-chlorine and 2-fluorine, R ₁for chlorine, R ₂for fluorine, R ₃during for hydrogen, described couroupitine A novel derivative is the derivative 13a described in formula 11; When R is 1-chlorine and 2-fluorine, R ₁for hydrogen, R ₂for fluorine, R ₃during for chlorine, described couroupitine A novel derivative is the derivative 13b described in formula 11:

When R is 1-chlorine and 2-fluorine, R ₁, R ₂for chlorine, R ₃during for hydrogen, described couroupitine A novel derivative is the derivative 14a described in formula 12; When R is 1-chlorine and 2-fluorine, R ₁for hydrogen, R ₂, R ₃during for chlorine, described couroupitine A novel derivative is the derivative 14b described in formula 12:

As R and R ₃for hydrogen, R ₁for 7-piperidin-1-yl, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 15 described in formula 13:

As R and R ₃for hydrogen, R ₁for 7-piperazine-1-base, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 16 described in formula 14:

As R and R ₃for hydrogen, R ₁for 7-morpholine-1-base, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 17 described in formula 15:

As R and R ₃for hydrogen, R ₁for 7-(4-methyl) piperazine-1-base, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 18 described in formula 16:

As R and R ₃for hydrogen, R ₁for 7-(4-(2-hydroxyethyl) piperazine-1-base, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 19 described in formula 17:

As R and R ₃for hydrogen, R ₁for 7-(4-(2-pyridyl)) piperazine-1-base, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 20 described in formula 18:

As R and R ₃for hydrogen, R ₁for 7-(N, N-dimethyl) is amino, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 21 described in formula 19:

As R and R ₃for hydrogen, R ₁for 7-(N, N-diethyl) is amino, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 22 described in formula 20:

As R and R ₃for hydrogen, R ₁for 7-piperidin-1-yl, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 23 described in formula 21:

As R and R ₃for hydrogen, R ₁for 7-piperazine-1-base, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 24 described in formula 22:

As R and R ₃for hydrogen, R ₁for 7-morpholine-1-base, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 25 described in formula 23:

As R and R ₃for hydrogen, R ₁for 7-(4-methyl)-piperazine-1-base, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 26 described in formula 24:

As R and R ₃for hydrogen, R ₁for 7-(4-(2-hydroxyethyl)) piperazine, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 27 described in formula 25:

As R and R ₃for hydrogen, R ₁for 7-(4-(2-pyridyl)) piperazine-1-base, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 28 described in formula 26:

As R and R ₃for hydrogen, R ₁for 7-(3-formic acid) piperidin-1-yl, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 28 described in formula 27:

As R and R ₃for hydrogen, R ₁for 7-(N, N-dimethyl) is amino, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 30 described in formula 28:

As R and R ₃for hydrogen, R ₁for 7-(N, N-diethyl) is amino, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 31 described in formula 29:

Work as R, R ₂, R ₃for hydrogen, R ₁during for 7-piperidin-1-yl, described couroupitine A novel derivative is the derivative 32 described in formula 30:

Work as R, R ₂, R ₃for hydrogen, R ₁during for 7-(4-(2-hydroxyethyl)) piperazine-1-base, described couroupitine A novel derivative is the derivative 33 described in formula 31:

Work as R, R ₂, R ₃for hydrogen, R ₁during for 7-(4-(2-pyridyl)) piperazine-1-base, described couroupitine A novel derivative is the derivative 34 described in formula 32:

As R and R ₃for hydrogen, R ₁for 7-piperidin-1-yl, R ₂during for methyl, described couroupitine A novel derivative is the derivative 35 described in formula 33:

As R and R ₃for hydrogen, R ₁for 7-piperazine-1-base, R ₂during for methyl, described couroupitine A novel derivative is the derivative 36 described in formula 34:

As R and R ₃for hydrogen, R ₁for 7-morpholine-1-base, R ₂during for methyl, described couroupitine A novel derivative is the derivative 37 described in formula 35:

As R and R ₃for hydrogen, R ₁for 7-(4-methyl) piperazine-1-base, R ₂during for methyl, described couroupitine A novel derivative is the derivative 38 described in formula 36:

As R and R ₃for hydrogen, R ₁for 7-(4-(2-hydroxyethyl)) piperazine-1-base, R ₂during for methyl, described couroupitine A novel derivative is the derivative 39 described in formula 37:

As R and R ₃for hydrogen, R ₁for 7-(4-(2-pyridyl)) piperazine-1-base, R ₂during for methyl, described couroupitine A novel derivative is the derivative 40 described in formula 38:

Work as R, R ₃for hydrogen, R ₁for 7-(N, N-dimethyl) amino-1-base, R ₂during for methyl, described couroupitine A novel derivative is the derivative 41 described in formula 39:

Work as R, R ₃for hydrogen, R ₁for 7-(2-furancarbonyl) piperazine-1-base, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 42 described in formula 40:

Work as R, R ₃for hydrogen, R ₁for 7-(2-furancarbonyl) piperazine-1-base, R ₂during for fluorine, described couroupitine A novel derivative is the derivative 43 described in formula 41:

Described couroupitine A novel derivative is the pharmaceutical composition of activeconstituents.

Described couroupitine A novel derivative is the pharmaceutical preparation of bulk drug.

The application of described couroupitine A novel derivative in preparation tumor.

The application of described couroupitine A novel derivative in preparation treatment anti-inflammatory drugs.

The application of described couroupitine A novel derivative in preparation treatment antibacterials.

Described pharmaceutical preparation is tablet, capsule, granule, soft capsule, pill, pellet, oral liquid, aqueous injection, infusion solution, powder injection or lyophilized injectable powder.

The synthetic method of couroupitine A derivative:

Anthranilic acid (or derivatives thereof) 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1.0h, stopped reaction; Decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂, then in flask, add the istain (or derivatives thereof) of 0.01moL and the methylene dichloride of 15mL, continue back flow reaction 1.0h, be cooled to room temperature, filter, obtain yellow solid couroupitine A (or derivatives thereof); By methanol wash, methylene dichloride or re crystallization from toluene, synthesize couroupitine A and derivative 2-14 in this approach;

The synthesis of couroupitine A derivative 15-43:

Take chlorine couroupitine A 10 μm of ol and piperidines (or other heterocycle, aliphatic amides etc.) 10 μm of ol of 7-replacement, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2.0h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, filter, filter cake methyl alcohol lotion, obtains couroupitine A derivative, synthesizes tryptamines ketone derivatives 15-43 in this approach.

The active testing of couroupitine A derivative:

1) MTT experiment:

A549 (HCT116 or the MDA-MB-231) cell being in logarithmic phase is seeded in 96 well culture plates by proper density, and every hole 15 μ L, is positioned over 5%CO ₂, in 37 constant incubators, after overnight incubation, according to 100 μMs, 50 μMs, 25 μMs, 12.5 μMs, 6.25 μMs, 3.125 μMs and 1.56 μMs of 7 concentration, 3 the repeating hole dosings of each concentration, and establish blank, DMSO contrast and positive control (Gefitinib or camptothecine), add the MTT (20 μ L/ hole) of 5mg/mL after 24h, continue to cultivate 4.0h.Discard culture supernatant, then add DMSO (200 μ L/ hole), measure every hole absorbance by microplate reader at 490nm, calculate inhibition rate of tumor cell.

Adopt with the inhibiting rate (%) of following formulae discovery compound on tumor Growth of Cells:

Cell inhibitory rate=(experimental group OD value-DMSO control group OD value)/blank group OD value × 100%; Then SPSS19.0 is adopted to calculate IC ₅₀value.

2) antibacterial experiment:

Cultured mono-clonal bacterium is inoculated in 96 orifice plates, adds the medicine of various concentration, measure the inhibit activities size of medicine to access bacterial classification, obtain minimal inhibitory concentration.

The invention has the beneficial effects as follows:

The present invention has designed and synthesized a series of couroupitine A novel derivative, and simple synthetic method, compared with the couroupitine A derivative reported in a large number, this type of compound solubility improves relative to couroupitine A, good inhibit activities is had for tumour cell, to staphylococcus aureus Mu50, streptococcus aureus RN4220 and streptococcus aureus NewmanWT bacterium have stronger germicidal action, have the potentiality being developed as antitumor, antibacterial and anti-inflammatory drug.

Accompanying drawing explanation

Fig. 1 is the inhibit activities result histogram of compound 1-14 of the present invention to A549.

Fig. 2 is the inhibit activities result histogram of 15-43 of the present invention to A549, HCT116, MDA-MB-231.

Fig. 3 is compound 1,2,3,4,7,13 of the present invention, the inhibit activities result histogram of 14 couples of streptococcus aureus Mu50, RN4220 and Newman.

Fig. 4 be compound of the present invention for Mu50 inhibition figure, compound concentration is 1mg/mL; Wherein in Fig. 4 a, top is compound 3,6,7,22 couples of Mu50 inhibition figure; Be compound 14 to below, 28,29,30 couples of Mu50 inhibition figure; Fig. 4 (b) is compound Isosorbide-5-Nitrae, 13 and DMSO to Mu50 inhibition figure; Fig. 4 (c) for the inhibition figure of positive control vancomycin, Fig. 4 (d) be compound 2,3,13 couples of Mu50 inhibition figure.

Fig. 5 is RN4220 inhibition figure of the present invention, and concentration is 1mg/mL; Wherein in Fig. 5 (a), top is compound 1-4, and below is 22,28,29,30 couples of RN4220 inhibition figure; Fig. 5 (b) top be compound 6,7,13,14, below is compound 25,31 and DMSO to RN4220 inhibition figure.

Fig. 6 is that compound of the present invention is to Newman inhibition figure, concentration 1mg/mL; Wherein in Fig. 6 (a), top is compound 1-4, and below is compound 9-12; Fig. 6 (b) top is compound 5-8, and below is that compound 13-16 (concentration 1mg/mL) is to Newman inhibition figure; Fig. 6 (c) upper left is compound 17-20, and upper right is compound 21-24, and below is compound 26,27 and DMSO to Newman inhibition figure.

Embodiment

Below in conjunction with specific embodiment, the invention will be further described.

Embodiment 1. synthesizes couroupitine A

Anthranilic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1.0h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂.In flask, add the istain of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene.M.p.268-269 DEG C (thermometer is not calibrated).Productive rate 90%.Synthesize following target product in this approach.

With the compound obtained for activeconstituents forms pharmaceutical composition, or be prepared into pharmaceutical preparation.The characterization of compound obtained is as follows:

Molecular formula: C ₁₅h ₈n ₂o ₂.The structural characterization of couroupitine A:

Fig.1 indoles [2,1-b] quinazoline-6,12-diketone

IR(KBr):3087,1727,1685,1594,1460,1313,757cm ^-1； ¹HNMR(400MHz,CDCl ₃)δ8.64(d,J＝8.1Hz,1H),8.45(d,J＝7.8Hz,1H),8.04(d,J＝8.1Hz,1H),7.92(d,J＝7.4Hz,1H),7.86(t,J＝7.7Hz,1H),7.80(t,J＝7.8Hz,1H),7.68(t,J＝7.6Hz,1H),7.46(t,J＝7.5Hz,1H)；ESI-MSforC ₁₅H ₈N ₂O ₂[M+H] ⁺:calcd249.2,found:249.2.

Embodiment 2. synthesizes 8-fluoro-9-chloro-indole [2,1-b] quinazoline-6,12-diketone/8-fluoro-7-chloro-indole [2,1-b] quinazoline-6,12-diketone

Anthranilic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, add toluene 15mL, dry SOCl ₂3mL, backflow 1.0h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂.In flask, add the 4-chloro-5-fluoro indole quinone of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1.0h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene.Synthesize following target product in this approach.

Fig.28-fluoro-9-chloro-indole [2,1-b] quinazoline-6,12-diketone/8-fluoro-7-chloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 85%.m.p.>300 DEG C; IR (KBr): 3044,1731,1685,1593,1471,776cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.78 (d, J=5.8Hz, 1H), 8.43 (d, J=7.7Hz, 1H), 8.08 – 7.98 (m, 1H), 7.87 (t, J=7.5Hz, 1H), 7.76 – 7.62 (m, 2H). ¹hNMR (400MHz, CDCl ₃) δ 8.60 (dd, J=8.7,3.5Hz, 1H), 8.43 (d, J=7.7Hz, 1H), 8.08 – 7.98 (m, 1H), 7.87 (t, J=7.5Hz, 1H), 7.76 – 7.62 (m, 1H), 7.53 (t, J=8.7Hz, 1H) .ESI-MSm/z:301.0 [M+H] ⁺.Anal.calcdforC ₁₅h ₆clFN ₂o ₂: C59.92, H2.01, N9.32; FoundC59.88, H2.04, N9.35.

Embodiment 3. synthesizes 7,8-dichloro-indole [2,1-b] quinazoline-6,12-diketone/8,9-dichloro-indole [2,1-b] quinazoline-6,12-diketone

Anthranilic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1.0h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂.In flask, add 4, the 5-dichloro-indole quinones (5,6-dichloro-indole quinone) of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1.0h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene.Synthesize following target product in this approach.

Fig.37,8-dichloro-indole [2,1-b] quinazoline-6,12-diketone/8,9-dichloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 80%; M.p.>300 DEG C; IR (KBr): 3061,1732,1685,1584,1435,1337,1179,773cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.81 (s, 1H), 8.44 (d, J=7.7Hz, 1H), 8.09 – 8.02 (m, 1H), 7.98 (s, 1H), 7.89 (t, J=7.7Hz, 1H), 7.71 (td, J=7.6,3.7Hz, 1H); ¹hNMR (400MHz, CDCl ₃) δ 8.57 (d, J=8.6Hz, 1H), 8.44 (d, J=7.7Hz, 1H), 8.09 – 8.02 (m, 1H), 7.89 (t, J=7.7Hz, 1H), 7.84 (d, J=8.6Hz, 1H), 7.71 (td, J=7.6,3.7Hz, 1H) .ESI-MSm/z:316.9 [M+H] ⁺.Anal.calcdforC ₁₅h ₆cl ₂n ₂o ₂: C56.81, H1.91, N8.83; FoundC56.77, H1.88, N8.89.

Embodiment 4. synthesizes 8-fluoro-3-chloro-indole [2,1-b] quinazoline-6,12-diketone

2-amino-4-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add the 5-fluoro indole quinone of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene. synthesize following target product in this approach.

Fig.48-fluoro-3-chloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 35%.m.p.298-300 DEG C; IR (KBr): 3052,1734,1678,1592,1485,1309,846cm- ¹; ¹hNMR (400MHz, CDCl ₃) δ 8.56 (dd, J=8.5,3.7Hz, 1H), 8.30 (d, J=8.3Hz, 1H), 7.94 (s, 1H), 7.58 (d, J=8.5Hz, 1H), 7.52 (d, J=4.1Hz, 1H), (7.44 t, J=8.6Hz, 1H) .Anal.calcdforC ₁₅h ₆clFN ₂o ₂: C59.92, H2.01, N9.32; FoundC59.98, H2.06, N9.22.

Embodiment 5. synthesizes 3,8-dichloro-indole [2,1-b] quinazoline-6,12-diketone

2-amino-4-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add the 5-chloro-indole quinone of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene. synthesize following target product in this approach.

Fig.53,8-dichloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 35%.m.p.>300 DEG C; IR (KBr): 3084,1738,1676,1585,1458,1184cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.46 (d, J=8.6Hz, 1H), 8.32 (d, J=8.6Hz, 1H), 8.10 (s, 1H), (8.00 s, 1H), 7.94 (d, J=8.5Hz, 1H), 7.81 (d, J=8.3Hz, 1H) .Anal.calcdforC ₁₅h ₆cl ₂n ₂o ₂: C56.81, H1.91, N8.83; FoundC56.90, H1.89, N8.85.

Embodiment 6. synthesizes 8-fluoro-3,7-dichloro-indoles [2,1-b] quinazoline-6,12-diketone/8-fluoro-3,9-dichloro-indoles [2,1-b] quinazoline-6,12-diketone

2-amino-4-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add the 5-fluoro-6-chloro-indole quinone (5-fluoro-4-chloro-indole quinone) of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene. synthesize following target product in this approach.

Fig.68-fluoro-3,7-dichloro-indoles [2,1-b] quinazoline-6,12-diketone/8-fluoro-3,9-dichloro-indoles [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 60%, m.p.>300 DEG C; IR (KBr): 3080,1730,1680,1585,1461,1291,1181cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.58 (d, J=5.8Hz, 1H), 8.45 (m, 1H), 8.33 (d, J=8.5Hz, 2H), (8.12 m, 2H), 7.91 (t, J=8.0Hz1H), 7.82 (d, J=6.4Hz, 2H), 7.37 (s, 1H) .Anal.calcdforC ₁₅h ₅cl ₂fN ₂o ₂: C53.76; H1.50, N8.36; FoundC53.80; H1.46, N8.42.

Embodiment 7. synthesizes 1,2,7,8-tetra-chloro-indole [2,1-b] quinazoline-6,12-diketone

2-amino-4-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add 5 of 0.01moL again, 6-dichloro-indole quinone (4,5-dichloro-indole quinone) and the methylene dichloride of 15mL, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene. synthesize following target product in this approach.

Fig.71,2,7,8-tetra-chloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 23%, m.p.>300 DEG C; IR (KBr): 3061,1733,1684,1574,1467,1432,1345,1238,1165,1047,833cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.16 (d, J=8.5Hz, 1H), 8.03 (d, J=8.4Hz, 1H), 7.91 (d, J=8.7Hz, 1H), 7.82 (d, J=8.3Hz, 1H) .Anal.calcdforC ₁₅h ₄cl ₄n ₂o ₂: C46.67, H1.04, N7.26; FoundC46.71, H1.00, N7.30.

Embodiment 8. synthesizes 1,2-dichloro-indole [2,1-b] quinazoline-6,12-diketone

2-amino-5-fluorine-6-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add 5 of 0.01moL again, 6-dichloro-indole quinone (4,5-dichloro-indole quinone) and the methylene dichloride of 15mL, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene. synthesize following target product in this approach.

Fig.81,2-dichloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 57%, m.p.>300 DEG C; IR (KBr): 3064,1730,1685,1599,1461,1291,756cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.67 (d, J=8.2Hz, 1H), 7.91 (m, 2H), 7.81 (t, J=7.9Hz, 1H), 7.51 – 7.42 (m, 2H) .ESI-MSm/z:316.9 [M+H] ⁺.Anal.calcdforC ₁₅h ₆cl ₂n ₂o ₂: C56.81, H1.91, N8.83; FoundC56.90, H1.93, N8.78.

Embodiment 9.1,2,8-tri-chloro-indole [2,1-b] quinazoline-6,12-diketone

2-amino-5-fluorine-6-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add the 5-chloro-indole quinone of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene. synthesize following target product in this approach.

Fig.91,2,8-tri-chloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 32%, m.p.>300 DEG C; IR (KBr): 3070,1736,1681,1571,1459,1310,1184,842cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.62 (dd, J=8.8,4.0Hz, 1H), 8.15 (d, J=8.4Hz, 1H), 8.10 (d, J=6.6Hz, 1H), 7.60 (dd, J=6.5,2.7Hz, 1H), 7.54 – 7.48 (m, 1H) .Anal.calcdforC ₁₅h ₅cl ₃n ₂o ₂: C51.24, H1.43, N7.97; FoundC51.25, H1.40, N7.85

Embodiment 10.2-fluoro-1-chloro-indole [2,1-b] quinazoline-6,12-diketone

2-amino-5-fluorine-6-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add the istain of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene. synthesize following target product in this approach.

Fig.102-fluoro-1-chloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 68%, m.p.>300 DEG C; IR (KBr): 3087,3038,1736,1678,1597,1464,1426,1357,1320,921,763,781cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.61 (d, J=8.1Hz, 1H), 8.16 (d, J=8.4Hz, 1H), 8.10 (d, J=6.6Hz, 1H), 7.93 (d, J=7.2Hz, 1H), 7.82 (t, J=8.1Hz, 1H), (7.47 t, J=7.5Hz, 1H) .Anal.calcdforC ₁₅h ₆clFN ₂o ₂: C59.92, H2.01, N9.32; FoundC59.91, H2.04, N9.28.

Embodiment 11. synthesizes 2-fluoro-1,8-dichloro-indole [2,1-b] quinazoline-6,12-diketone

Fig.112-fluoro-1,8-dichloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 50%, m.p.>300 DEG C; IR (KBr): 3076,1736,1682,1597,1461,1421,1336,1307,1183,797cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.57 (d, J=8.6Hz, 1H), 8.15 (d, J=8.4Hz, 1H), 8.10 (d, J=6.6Hz, 1H), 7.89 (d, J=2.1Hz, 1H), 7.78 (dd, J=8.1Hz, 2.1Hz, 1H) .Anal.calcdforC ₁₅h ₅cl ₂fN ₂o ₂: C53.76, H1.50, N8.36; FoundC53.65, H1.43, N8.43.

Embodiment 12. synthesizes 2,8-bis-fluoro-1-chloro-indole [2,1-b] quinazoline-6,12-diketone

2-amino-5-fluorine-6-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add the 5-fluoro indole quinone of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or first recrystallization. synthesize following target product in this approach.

Fig.122,8-bis-fluoro-1-chloro-indole [2,1-b] quinazoline-6,12-diketone

Yellow solid, productive rate 47%, m.p.>300 DEG C; IR (KBr): 3087,3052,1736,1675,1599,1475,1314,1209,855cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.62 (dd, J=8.8,4.0Hz, 1H), 8.15 (d, J=8.4Hz, 1H), 8.10 (d, J=6.6Hz, 1H), 7.60 (dd, J=6.5,2.6Hz, 1H), 7.51 (d, J=2.7Hz, 1H) .Anal.calcdforC ₁₅h ₅clF ₂n ₂o ₂: C56.54, H1.58, N8.79; FoundC56.48, H1.51, N8.84.

Embodiment 13. synthesizes 2,8-bis-fluoro-1,7-dichloro-indole [2,1-b] indoles-6,12-diketone/1,8-bis-fluoro-2,9-dichloro-indoles [2,1-b] indoles-6,12-diketone

2-amino-5-fluorine-6-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add the 5-fluoro-4-chloro-indole quinone (5-fluoro-6-chloro-indole quinone) of 0.01moL and the methylene dichloride of 15mL again, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene. synthesize following target product in this approach.

Fig.132,8-bis-fluoro-1,7-dichloro-indole [2,1-b] indoles-6,12-diketone/1,8-bis-fluoro-2,9-dichloro-indoles [2,1-b] indoles-6,12-diketone

Yellow solid, productive rate 41%.m.p.>300 DEG C; IR (KBr): 3089,3041,1741,1678,1599,1471,1430,1355,1261,1234,842cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.74 (d, J=5.8Hz, 1H), 8.62 (dd, J=8.9,3.6Hz, 1H), 8.56 (dd, J=8.7,3.6Hz, 1H), 8.48 (s, 1H), 8.12 (d, J=6.7Hz, 1H), 7.91 (d, J=4.2Hz, 1H), 7.66 (d, J=6.6Hz, 1H), 7.54 (t, J=8.1Hz, 1H) .Anal.calcdforC ₁₅h ₄cl ₂f ₂n ₂o ₂: C51.02, H1.14, N7.93; FoundC51.00, H1.13, N7.81.

Embodiment 14. synthesizes fluoro-1,7,8-tri-chloro-indole [2,1-b] indoles-6, the 12-diketone/1-bis-of 2-fluoro-2,8,9-dichloro-indoles [2,1-b] indoles-6,12-diketone

2-amino-5-fluorine-6-chloro-benzoic acid 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1h, stopped reaction, decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂. in flask, add 4 of 0.01moL again, 5-dichloro-indole quinone (5,6-dichloro-indole quinone) and the methylene dichloride of 15mL, continue back flow reaction 1h, be cooled to room temperature, filter, obtain yellow solid, use methyl alcohol lotion, methylene dichloride or re crystallization from toluene. synthesize following target product in this approach.

Fluoro-1,7,8-tri-chloro-indole [2,1-b] indoles-6, the 12-diketone/1-bis-of Fig.142-fluoro-2,8,9-dichloro-indoles [2,1-b] indoles-6,12-diketone

Yellow solid, productive rate 41%.m.p.>300 DEG C; IR (KBr): 3064,2918,2849,1739,1682,1587,1470,1345,1267,1242,833cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.80 (d, J=5.8Hz, 1H), 8.62 (dd, J=8.8,3.7Hz, 1H), 8.23 – 8.17 (m, 2H), 8.15 (d, J=6.5Hz, 1H), 7.72 (d, J=6.7Hz, 1H), (7.60 t, J=8.0Hz, 2H) .Anal.calcdforC ₁₅h ₄cl ₃fN ₂o ₂: C48.75, H1.09, N7.58; FoundC49.00, H1.10, N7.50.

Embodiment 15. synthesizes 7-(piperidin-1-yl)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Take 7,8-dichloro couroupitine A, 10 μm of ol and piperidinyl-1 0 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.157-(piperidin-1-yl)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 90%.m.p.248-250 DEG C; IR (KBr): 2929,2857,1706,1683,1552,1483,1463,1337,1152,1098,771cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.42 (d, J=7.8Hz, 1H), 8.10 (d, J=8.2Hz, 1H), 8.00 (d, J=8.1Hz, 1H), 7.84 (t, J=7.1Hz, 1H), 7.68 – 7.60 (m, 2H), 3.45 (m, 4H), 1.78 (m, 6H).

Embodiment 16. synthesizes 7-(piperazine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Take 7,8-dichloro couroupitine A, 10 μm of ol and piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.167-(piperazine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 84%.m.p.261-263 DEG C; IR (KBr): 3417,2918,2796,2688,2607,2473,1709,1681,1589,1559,1460,1338,1166,1106,774cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 9.06 (s, 1H), 8.33 (d, J=7.9Hz, 1H), 8.19 (d, J=8.5Hz, 1H), 7.96 (d, J=3.7Hz, 2H), 7.91 (d, J=8.5Hz, 1H), 7.75 (dd, J=7.8,4.5Hz, 1H), 3.58 (m, 4H), 3.32 – 3.26 (m, 4H).

Embodiment 17. synthesizes 7-(morpholine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Take 7,8-dichloro couroupitine A, 10 μm of ol and morpholine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.177-(morpholine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 80%.m.p.248-250 DEG C; IR (KBr): 3068,2951,2842,1711,1682,1588,1555,1479,1443,1336,1292,1162,1107,774cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.42 (dd, J=8.0,1.3Hz, 1H), 8.19 (d, J=8.3Hz, 1H), 8.01 (d, J=8.0Hz, 1H), 7.89 – 7.81 (m, 1H), 7.66 (d, J=8.3Hz, 2H), 3.99 – 3.91 (t, J=4Hz, 4H), 3.60 – 3.50 (t, J=4Hz, 4H)

Embodiment 18. synthesizes 7-(4-methylpiperazine-1-yl)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Take 7,8-dichloro couroupitine A, 10 μm of ol and N methyl piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.187-(4-methylpiperazine-1-yl)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 67%.m.p.256-259 DEG C; IR (KBr): 3068,2971,2939,2836,2785,1711,1684,1591,1552,1446,1338,1289,1155,1104,772cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.45 – 8.39 (d, J=7.7Hz, 1H), 8.15 (d, J=8.3Hz, 1H), 8.00 (d, J=7.7Hz, 1H), 7.87 – 7.81 (t, J=8.3Hz, 1H), (7.65 dd, J=7.6,5.4Hz, 2H), 3.57 (t, J=4.0Hz, 4H), 2.67 (t, J=4.0Hz, 4H), 2.41 (s, 3H)

Embodiment 19. synthesizes 7-(N-(4-hydroxyethyl) piperazine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Take 7,8-dichloro couroupitine A, 10 μm of ol and N-(2-hydroxyethyl) piperazine, 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leave standstill, filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.197-(4-N-(2-hydroxyethyl) piperazine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 70%.m.p.221-223 DEG C; IR (KBr): 3179,3066,2934,2826,1709,1684,1591,1552,1455,1338,1159,1105,771cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.31 (d, J=7.8Hz, 1H), 8.07 (d, J=8.4Hz, 1H), 7.94 (d, J=3.7Hz, 2H), 7.83 (d, J=8.3Hz, 1H), 7.76 – 7.69 (m, 1H), 4.48 (t, J=5.4Hz, 2H), 3.57 (dd, J=6.0,4.0Hz, 2H), 3.39 (d, J=4.5Hz, 4H), 2.63 (m, 4H)

Embodiment 20. synthesizes 7-(4-(2-pyridyl) piperazine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Take 7,8-dichloro couroupitine A, 10 μm of ol and 1-(2-pyridyl) piperazine, 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leave standstill, filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.207-(4-1-(2-pyridyl) piperazine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 56%.m.p.235-237 DEG C; IR (KBr): 3067,2996,2833,1710,1684,1593,1555,1436,1480,1436,1337,1232,1158,1107,979,772cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.46 – 8.41 (m, 1H), 8.29 – 8.19 (m, 2H), 8.02 (d, J=7.4Hz, 1H), 7.88 – 7.82 (m, 1H), 7.68 (m, 2H), 6.76 (s, 2H), 3.94 – 3.86 (m, 2H), 3.67 (d, J=4.7Hz, 2H), 3.54 (m, 2H), 3.49 (d, J=5.3Hz, 2H)

Embodiment 21. synthesizes 7-(N, N dimethyl) amino-8-chloro-indole [2,1-b] indoles-6,12-diketone

Take 7,8-dichloro couroupitine A, 10 μm of ol and dimethylamine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.217-(N, N dimethyl) amino-8-chloro-indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 51%.m.p.296-298 DEG C; IR (KBr): 3439,3082,2927,1734,1686,1585,1554,1439,1338,1285,1224,1165,773cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.58 (d, J=8.6Hz, 1H), 8.43 (d, J=7.8Hz, 1H), 8.05 (d, J=8.2Hz, 1H), 7.92 – 7.80 (m, 1H), 7.70 (t, J=7.6Hz, 1H), 7.67 – 7.58 (m, 1H), 3.23 (s, 3H).

Embodiment 22. synthesizes 7-(N, N-diethyl) amino-8-chloro-indole [2,1-b] indoles-6,12-diketone

Take 7,8-dichloro couroupitine A, 10 μm of ol and diethylamine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.227-(N, N-diethyl) amino-8-chloro-indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 50%.m.p.228-230 DEG C; IR (KBr): 3073,2969,1711,1683,1584,1553,1461,1438,1336,1281,1168,1103,770cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.47 (d, J=8.6Hz, 1H), 8.32 (m, 1H), 8.11 (t, J=9.1Hz, 1H), 7.98 (d, J=3.7Hz, 1H), 7.94 (d, J=4.0Hz, 1H), 7.77 (m, 1H), 3.42 (q, J=7.1,4.2Hz, 2H), 1.02 (t, J=7.1Hz, 3H).

Embodiment 23. synthesizes 7-(piperidin-1-yl)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-fluorine couroupitine A 10 μm of ol and piperidinyl-1 0 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.237-(piperidin-1-yl)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 92%.m.p.225-227 DEG C; IR (KBr): 3042,2928,2851,1683,1597,1510,1485,1409,1247,772cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.28 (t, J=7.1Hz, 2H), 8.06 (d, J=7.4Hz, 1H), 7.91 (m, 5H), 7.76 – 7.67 (m, 2H), 7.61 (d, J=12.4Hz, 1H), 7.50 (dd, J=14.2,8.4Hz, 1H), 3.40 (m, 8H), 1.70 (m, 12H).

Embodiment 24. synthesizes 7-(piperazine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-fluorine couroupitine A 10 μm of ol and piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.247-(piperazine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 88%.m.p.>300 DEG C; IR (KBr): 3201,3046,2936,2853,1679,1602,1564,1510,1461,1357,1295,1234,1204,1182,824,769cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.43 (d, J=7.0Hz, 1H), 8.15 (d, J=8.7Hz, 1H), 8.01 (d, J=8.3Hz, 1H), 7.85 (d, J=7.5Hz, 1H), 7.67 (s, 1H), 7.40 – 7.32 (m, 1H), 4.02 (m, 1H), 3.93 (m, 1H), 3.75 (m, 2H), 3.55 (m, 4H).

Embodiment 25. synthesizes 7-(morpholine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-fluorine couroupitine A 10 μm of ol and morpholine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.257-(morpholine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 56%.m.p.269-270 DEG C; IR (KBr): 3066,2964,2889,2844,1707,1682,1596,1494,1395,1296,1240,1112,891,774cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.48 – 8.35 (m, 2H), 8.17 (d, J=7.1Hz, 1H), 8.10 – 7.96 (m, 3H), 7.85 (dd, J=7.1,5.2Hz, 2H), 7.67 (dd, J=11.0,4.4Hz, 2H), 7.50 (d, J=11.9Hz, 1H), 7.31 (d, J=8.4Hz, 1H), 4.00 – 3.93 (m, 4H), 3.93 – 3.86 (m, 4H), 3.55 (m, 4H), 3.53 – 3.40 (m, 4H).

Embodiment 26. synthesizes 7-(4-methylpiperazine-1-yl)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-fluorine couroupitine A 10 μm of ol and N methyl piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.267-(4-methylpiperazine-1-yl)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 70%.m.p.246-249 DEG C; IR (KBr): 3065,2922,2794,1706,1683,1599,1494,1456,1295,1245,1140,1002,773cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.40 (td, J=8.0,1.2Hz, 1H), 8.16 (d, J=7.2Hz, 1H), 8.05 – 7.97 (m, 1H), 7.87 – 7.79 (m, 1H), 7.70 – 7.60 (m, 1H), 7.48 (d, J=9.4Hz, 1H), 7.29 (d, J=8.4Hz, 1H), 3.66 – 3.49 (m, 4H), 2.63 (m, 4H), 2.39 (d, J=7.9Hz, 3H).

Embodiment 27. synthesizes 7-(N-(4-hydroxyethyl) piperazine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-fluorine couroupitine A 10 μm of ol and N-(2-hydroxyethyl) piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.277-(N-(2-hydroxyethyl) piperazine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 64%.m.p.251-253 DEG C; IR (KBr): 3400,3046,2941,2885,2833,1709,1683,1598,1566,1493,1461,1396,1294,1242,1046,1004,773cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.36 – 8.24 (m, 1H), 8.08 (d, J=7.2Hz, 1H), 7.93 (m, 2H), (7.73 dd, J=9.8,4.4Hz, 1H), 7.66 (d, J=12.3Hz, 1H), 4.75 – 4.37 (m, 2H), 3.60 – 3.52 (m, 4H), 3.29 (d, J=5.6Hz, 2H), 2.63 (s, 4H).

Embodiment 28. synthesizes 7-(4-(2-pyridyl) piperazine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-fluorine couroupitine A 10 μm of ol and 1-(2-pyridyl) piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.287-(1-(2-pyridyl) piperazine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 60%.m.p.250-251 DEG C; IR (KBr): 3063,2844,1705,1682,1596,1487,1438,1356,1233,979,771cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.31 (s, 1H), 8.21 – 8.08 (m, 1H), 7.94 (m, 2H), 7.71 (d, J=13.8Hz, 2H), 7.61 (d, J=8.5Hz, 2H), 6.93 (dd, J=18.9,8.2Hz, 1H), 6.70 (s, 1H), 3.73 (s, 4H), 3.50 (d, J=36.2Hz, 4H).

Embodiment 29. synthesizes 7-(3-nipecotic acid-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-fluorine couroupitine A 10 μm of ol and isonipecotic acid 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.297-(3-nipecotic acid-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 47%.m.p.289-290 DEG C; IR (KBr): 3414,3200,3050,2941,2851,1729,1682,1598,1564,1500,1457,1410,1357,1208,1151,1103,773cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.30 (d, J=8.5Hz, 1H), 8.10 (d, J=7.4Hz, 1H), 7.93 (s, 2H), 7.75 (d, J=8.0Hz, 1H), 7.65 (d, J=12.3Hz, 1H), 3.75 (d, J=12.4Hz, 2H), 3.17 (s, 2H), 2.34 (s, 1H), 1.99 (s, 2H), 1.72 (d, J=10.7Hz, 2H).

Embodiment 30. synthesizes 7-(N, N dimethyl) amino-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-fluorine couroupitine A 10 μm of ol and dimethylamine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.307-(N, N dimethyl) amino-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 45%.m.p.296-298 DEG C; IR (KBr): cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.40 (dd, J=7.9,1.4Hz, 1H), 8.05 – 7.97 (m, 2H), 7.87 – 7.79 (m, 1H), 7.64 (dd, J=8.1,4.1,1.0Hz, 1H), 7.44 (d, J=13.0Hz, 1H), 3.27 (d, J=2.7Hz, 3H), (3.25 d, J=3.5Hz, 3H).

Embodiment 31. synthesizes 7-(N, N diethyl) amino-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-fluorine couroupitine A 10 μm of ol and diethylamine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.317-(N, N diethyl) amino-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 31%.m.p.240-241 DEG C; IR (KBr): 3083,2969,1733,1684,1582,1439,1336,1282,1222,1174,1108,770cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.44 – 8.36 (m, 1H), 8.06 (d, J=7.6Hz, 1H), 8.01 (d, J=8.0Hz, 1H), 7.83 (dd, J=10.6,4.7Hz, 1H), 7.63 (dd, J=10.6,5.4Hz, 1H), 7.45 (d, J=13.6Hz, 1H), 3.60 (d, J=7.0Hz, 4H), 1.35 (dd, J=8.6,5.5Hz, 6H).

Embodiment 32. synthesizes 7-(piperidin-1-yl)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take 7-chlorine couroupitine A 10 μm of ol and piperidinyl-1 0 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.327-(piperidin-1-yl)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 80%.m.p.248-250 DEG C; IR (KBr): 2926,2851,1691,1597,1559,1492,1445,1301,1246,1172,1123,779cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ 8.33 – 8.25 (m, 1H), 7.99 – 7.87 (m, 3H), 7.75 – 7.66 (m, 1H), 7.62 (d, J=8.9Hz, 1H), 6.90 (dd, J=9.0,2.2Hz, 1H), 3.62 (m, 4H), 1.67 (m, 6H).

Embodiment 33. synthesizes 7-(N-(4-hydroxyethyl) piperazine-1-base) indoles [2,1-b] indoles-6,12-diketone

Take 7-chlorine couroupitine A 10 μm of ol and N-(2-hydroxyethyl) piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.337-(N-(4-hydroxyethyl) piperazine-1-base) indoles [2,1-b] indoles-6,12-diketone

Red solid, productive rate 63%.m.p.>300 DEG C; IR (KBr): cm ^-1; ¹hNMR (400MHz, CDCl ₃) δ ¹hNMR (400MHz, DMSO) δ 8.30 (t, J=8.6Hz, 1H), (7.95 dd, J=16.3,8.3Hz, 3H), (7.67 dd, J=21.6,13.0Hz, 2H), 7.03 – 6.87 (m, 1H), 4.65 – 4.31 (m, 2H), 3.57 (s, 2H), 3.35 – 3.25 (m, 4H), (2.62 d, J=23.0Hz, 4H).

Embodiment 34. synthesizes 7-(4-(2-pyridyl) piperazine-1-base) indoles [2,1-b] indoles-6,12-diketone

Take 7-chlorine couroupitine A 10 μm of ol and 1-(2-pyridyl) piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.347-(1-(2-pyridyl) piperazine-1-base) indoles [2,1-b] indoles-6,12-diketone

Red solid, productive rate 52%.m.p.>300 DEG C; IR (KBr): 2847,1682,1592,1513,1483,1460,1438,1406,1308,1221,1133,1024,768cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.30 (d, J=7.6Hz, 1H), 8.15 (m, 1H), 8.01 (m, 1H), 7.93 (m, 1H), 7.70 (d, J=8.8Hz, 2H), 7.59 (m, 1H), 6.96 (d, J=8.9Hz, 1H), 6.86 (d, J=8.9Hz, 1H), 6.75 – 6.64 (m, 1H), 3.76 (m, 8H).

Embodiment 35. synthesizes 7-(piperidin-1-yl)-8-skatole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-methyltryptamine ketone 10 μm of ol and piperidinyl-1 0 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.357-(piperidin-1-yl)-8-skatole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 90%.m.p.245-247 DEG C; IR (KBr): 2927,2846,1682,1594,1570,1480,1461,1343,1290,1219,1122,775cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.30 (d, J=8.0Hz, 1H), 7.99 (d, J=7.8Hz, 1H), 7.93 (d, J=3.6Hz, 2H), 7.77 – 7.67 (m, 1H), 7.56 (d, J=8.0Hz, 1H), (3.24 s, 4H), 2.34 (s, 3H), 1.69 (s, 6H).

Embodiment 36. synthesizes 7-(piperazine-1-base)-8-skatole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-methyltryptamine ketone 10 μm of ol and piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.367-(piperazine-1-base)-8-skatole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 81%.m.p.>300 DEG C; IR (KBr): 2930,2839,2793,1706,1682,1594,1569,1464,1386,1374,1334,1293,1234,1139,1002,778cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.31 (s, 1H), 8.13 (d, J=8.2Hz, 1H), 7.94 (s, 2H), 7.71 (s, 1H), 7.66 (d, J=7.7Hz, 1H), 3.30 (d, J=7.1Hz, 8H), (2.35 d, J=11.8Hz, 3H).

Embodiment 37. synthesizes 7-(morpholine-1-base)-8-skatole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-methyltryptamine ketone 10 μm of ol and morpholine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.377-(morpholine-1-base)-8-skatole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 78%.m.p.291-293 DEG C; IR (KBr): 2956,2859,1709,1685,1594,1573,1460,1372,1338,1296,1228,1108,778cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.31 (d, J=7.8Hz, 1H), 8.08 – 8.04 (m, 1H), 7.93 (d, J=3.6Hz, 2H), 7.72 (dt, J=8.2,4.3Hz, 1H), 7.60 (d, J=8.0Hz, 1H), 3.82 – 3.76 (m, 4H), 3.31 – 3.26 (m, 4H), 2.37 (s, 3H).

Embodiment 38. synthesizes 7-(4-methylpiperazine-1-yl)-8-skatole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-methyltryptamine ketone 10 μm of ol and N methyl piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.387-(4-methylpiperazine-1-yl)-8-skatole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 71%.m.p.232-233 DEG C; IR (KBr): 2930,2839,2793,1706,1682,1594,1569,1464,1386,1374,1334,1293,1234,1139,1002,778cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.30 (d, J=8.1Hz, 1H), 8.07 – 8.01 (m, 1H), 7.93 (d, J=3.4Hz, 2H), 7.72 (dd, J=8.4,4.5Hz, 1H), 7.58 (d, J=7.9Hz, 1H), 3.28 (s, 4H), 3.21 – 3.09 (m, 3H), 2.33 (d, J=12.8Hz, 3H), 2.28 (d, J=2.4Hz, 3H).

Embodiment 39. synthesizes 7-(N-(4-hydroxyethyl) piperazine-1-base)-8-skatole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-methyltryptamine ketone 10 μm of ol and N-(2-hydroxyethyl) piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.397-(N-(2-hydroxyethyl) piperazine-1-base)-8-skatole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 59%.m.p.218-220 DEG C; IR (KBr): 3407,2818,1723,1680,1595,1567,1478,1459,1340,1295,1235,1134,1058,1011,774cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.31 (d, J=7.7Hz, 1H), 8.17 (d, J=2.4Hz, 1H), 8.12 – 8.04 (m, 1H), 7.93 (d, J=3.8Hz, 2H), 7.79 – 7.68 (m, 1H), (7.60 dd, J=14.1,7.4Hz, 2H), 6.95 (d, J=8.5Hz, 1H), 6.77 – 6.66 (m, 1H), 3.68 (d, J=27.4Hz, 8H).

Embodiment 40. synthesizes 7-(4-(2-pyridyl) piperazine-1-base)-8-skatole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-methyltryptamine ketone 10 μm of ol and 1-(2-pyridyl) piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.407-(1-(2-pyridyl) piperazine-1-base)-8-skatole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 54%.m.p.227-230 DEG C; IR (KBr): 2828,1711,1682,1594,1478,1434,1378,1229,977,775cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.30 (d, J=7.8Hz, 1H), 8.03 (d, J=7.1Hz, 1H), 7.93 (d, J=3.7Hz, 2H), 7.77 – 7.68 (m, 1H), 7.58 (d, J=8.0Hz, 1H), 4.54 (s, 2H), 3.58 (s, 4H), 3.15 (s, 2H), 2.68 (d, J=11.7Hz, 4H), 2.33 (d, J=14.5Hz, 3H).

Embodiment 41. synthesizes 7-(N, N-dimethyl) amino-8-skatole [2,1-b] indoles-6,12-diketone

Take 7-chloro-8-methyltryptamine ketone 10 μm of ol and dimethylamine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, and filters, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.417-(N, N-dimethyl) amino-8-skatole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 34%.m.p.219-220 DEG C; IR (KBr): 2913,2802,1683,1595,1566,1502,1460,1344,1293,1217,1127,1062,771cm ^-1; ¹hNMR (400MHz, DMSO) δ 8.33 – 8.25 (m, 1H), 8.04 – 7.86 (m, 3H), 7.71 (dd, J=8.2,3.9Hz, 1H), 7.60 – 7.46 (m, 1H), 3.05 (s, 3H), 2.99 (s, 3H), (2.34 d, J=3.9Hz, 3H).

Embodiment 42. synthesizes 7-(4-(2-furancarbonyl) piperazine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Take 7,8-dichloro couroupitine A, 10 μm of ol and 1-(2-furancarbonyl) piperazine, 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL; 70 DEG C of reaction 2h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution; leave standstill, filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.427-(4-(2-furancarbonyl) piperazine-1-base)-8-chloro-indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 76%. ¹hNMR (400MHz, CDCl ₃) δ 8.42 (dd, J=9.7,8.4Hz, 1H), 8.20 (d, J=7.1Hz, 1H), 8.11 (dd, J=8.5,3.2Hz, 1H), 8.02 (t, J=7.6Hz, 1H), 7.91 – 7.82 (m, 1H), 7.73 – 7.63 (m, 1H), 7.54 (dd, J=7.1,4.3Hz, 1H), 7.10 (dd, J=14.3,3.4Hz, 1H), (6.57-6.51 m, 1H), 4.08 (m, 4H), 3.59 (m, 4H).

Embodiment 43. synthesizes 7-(4-(2-furancarbonyl) piperazine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Take the fluorine-based couroupitine A of the chloro-8-of 7-10 μm of ol and 1-(2-furancarbonyl) piperazine 10 μm of ol, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2h; reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill; filter, filter cake methyl alcohol lotion.Directly obtain target product.

Fig.437-(4-(2-furancarbonyl) piperazine-1-base)-8-fluoro indole [2,1-b] indoles-6,12-diketone

Red solid, productive rate 81%. ¹hNMR (400MHz, CDCl ₃) δ 8.42-8.39 (m, 1H), 8.24 (d, J=8.4Hz, 1H), 8.05 – 7.98 (m, 1H), 7.88 – 7.81 (m, 1H), 7.70 (d, J=8.4Hz, 2H), 7.57 – 7.51 (m, 1H), 7.09 (d, J=3.5Hz, 1H), 6.55-6.52 (m, 1H), 4.07 (m4H), 3.68 – 3.52 (m, 3H), 3.51 – 3.42 (m, 1H).

Embodiment 44 pairs of inhibiting tumour cells active testings

The A549 cell being in logarithmic phase is seeded in 96 well culture plates by proper density, is positioned over 5%CO ₂, in 37 constant incubators, after overnight incubation, according to 100 μMs, 50 μMs, 25 μMs, 12.5 μMs, 6.25 μMs, 3.125 μMs and 1.56 μMs of 7 concentration, 3 the repeating hole dosings of each concentration, and establish blank, DMSO contrast and positive control (camptothecine (Camptothecin), Gefitinib (Gefitinib)), add the MTT (20 μ L/ hole) of 5mg/mL after 24h, continue to cultivate 4.0h.Discard culture supernatant, then add DMSO (200 μ L/ hole), measure every hole absorbance by microplate reader at 490nm, calculate inhibition rate of tumor cell.

Cell inhibitory rate=(experimental group OD Zhi – DMSO control group OD value)/blank group OD value × 100%; IC ₅₀value adopts SPSS19.0 to calculate.

Table1 compound 1-17 is for the inhibit activities of human lung cancer cell A549 and mouse bone-forming cell MC3T3-E1

^amTT tests, each 3 Duplicate Samples, degree of confidence 95%.

Be the inhibit activities result histogram of compound 1-14 to A549 see Fig. 1, Fig. 1.X-coordinate represents compound number, and ordinate zou represents the half-inhibition concentration (IC of compound ₅₀), histogram reacts intuitively, wherein compound 1, and 2,3,6,7, the inhibit activities of 13,14 is better than parent couroupitine A, compound 2,3, the half-inhibition concentration (IC of 6,7,13,14 ₅₀) be less than Gefitinib, the IC of compound 13 (0.51 μM) and 14 (0.43 μMs) ₅₀value and camptothecine are close to (0.34 μM).

Table2 compound 15-43 is for the inhibit activities of human lung cancer cell A549 and liver cancer cell HCT116 and Breast cancer lines MDA-MB-231

^amTT tests, each 3 Duplicate Samples, degree of confidence 95%.

Fig. 2 is the inhibit activities result histogram of 15-43 of the present invention to A549, HCT116, MDA-MB-231, X-coordinate is that (same compound is from left to right followed successively by A549 to compound number, the histogram of HCT116, MDA-MB-231), ordinate zou is the IC of compound ₅₀value (IC ₅₀>100 μm of ol/L does not show), wherein compound 22 and 33 is better than Gefitinib to the inhibit activities of three kinds of clone A549, HCT116, MDA-MB-231.

Embodiment 45 couples of staphylococcus aureus Mu50, the inhibit activities of streptococcus aureus RN4220 and streptococcus aureus NewmanWT

1) from milk pipe, connect bacterium, substratum is rule, put into incubator incubated overnight.

2) be inoculated into 3mLTSB liquid nutrient medium from picking mono-clonal (Mu50, RN4220, Newman) flat board, put into shaking table 37 DEG C, 220rpm, shake bacterium 3-4h.

3) survey bacterium liquid OD value with ultraviolet spectrophotometer, LB liquid medium returns to zero.Cultivate keynote bacterium liquid OD value with liquid TSB after measuring, make OD be 0.02.

4) in 96 orifice plates, the bacterium liquid that OD is 0.02 is added.Add 198 μ L bacterium liquid in first row hole, in all the other holes, all add 100 μ L bacterium liquid.In first row, add 2 μ L (1mg/ml) testing compounds respectively, pressure-vaccum mixes.

5) after first row pressure-vaccum mixing in 96 orifice plates, draw 100 μ L and add secondary series, draw 100 μ L after the mixing of secondary series pressure-vaccum and add the 3rd row, gradient dilution by column successively.Discard after last row absorption 100 μ L bacterium liquid.

7), after sealing 96 orifice plates with sealed membrane, shaking table 37 DEG C is put into, 220rpm incubated overnight.

8) within second day, observe the growing state of thalline in 96 orifice bores, record the hole count of not long bacterium, minimum inhibition concentration is the concentration corresponding to hole of not long bacterium.

9) blank DMSO, positive control medicine vancomycin (Van)

Inhibit activities result histogram.7 compounds and positive control medicine vancomycin are to Mu50, RN4220 and Newman.

Fig. 3 is compound 1,2,3,4,7,13 of the present invention, 14 couples of streptococcus aureus Mu50, RN4220 and Newman inhibit activities data see form in figure, wherein the inhibit activities of compound 2 couples of Newman and the inhibit activities of vancomycin to Newman close; The inhibit activities of compound 14 couples of Mu50 is better than the inhibit activities of vancomycin to Mu50.7 compounds all show the inhibition to RN4220.

Fig. 4 is that compound of the present invention is for Mu50 inhibition figure (compound concentration is 1mg/mL); Wherein in Fig. 4 (a), top is compound 3,6,7,22 couples of Mu50 inhibition figure; Be compound 14 to below, 28,29,30 couples of Mu50 inhibition figure; Fig. 4 (b) is compound Isosorbide-5-Nitrae, 13 and DMSO to Mu50 inhibition figure; Fig. 4 (c) for the inhibition figure of positive control vancomycin, Fig. 4 (d) be compound 2,3,13 couples of Mu50 inhibition figure.

Fig. 5 is RN4220 inhibition figure (concentration is 1mg/mL) of the present invention; Wherein in Fig. 5 (a), top is compound 1-4, and below is 22,28,29,30 couples of RN4220 inhibition figure; Be compound 6,7,13,14 above Fig. 5 b, below is compound 25,31 and DMSO to RN4220 inhibition figure.

Indicate: the present invention's reagent used is business and can purchases available reagent; The present invention's concrete technical scheme required for protection, is not limited to the concrete combination of the technical scheme expressed by above-described embodiment.

Claims

1. couroupitine A novel derivative, has following general structure:

Wherein, R is the individual respective independently substituting group of n (n=0-4) on 1-4 position, R ₁, R ₂, R ₃for (n=0-3) on 7-9 position individual respective independently substituting group.R, R ₁, R ₂, R ₃=halogen, nitro, amido, hydroxyl, alkyl, alkoxyl group, aryl; R ₁=morpholine, piperidines, N-methyl piperidine, piperazine, isonipecotic acid, 1-(2-pyridyl) piperazine, dimethylamine, diethylamine, 1-(2-hydroxyethyl) piperazine, 1-(2-furancarbonyl) piperazine.

As R and R ₃for hydrogen, R ₁for fluorine, R ₂during for chlorine, described couroupitine A novel derivative is the derivative 2a described in formula 1; As R and R ₁for hydrogen, R ₂for fluorine, R ₃during for chlorine, described couroupitine A novel derivative is the derivative 2b described in formula 1:

When R is 1-chlorine and 2-fluorine, R ₁and R ₂for chlorine, R ₃during for hydrogen, described couroupitine A novel derivative is the derivative 14a described in formula 12; When R is 1-chlorine and 2-fluorine, R ₁for hydrogen, R ₂, R ₃during for chlorine, described couroupitine A novel derivative is the derivative 14b described in formula 12:

2. couroupitine A novel derivative is the pharmaceutical composition of activeconstituents according to claim 1.

3. couroupitine A novel derivative is the pharmaceutical preparation of bulk drug according to claim 1.

4. the application of couroupitine A novel derivative according to claim 1 in preparation tumor.

5. the application of couroupitine A novel derivative according to claim 1 in preparation treatment antibacterials.

6. the application of couroupitine A novel derivative according to claim 1 in preparation treatment anti-inflammation drugs.

7. pharmaceutical preparation according to claim 3 is tablet, capsule, granule, soft capsule, pill, pellet, oral liquid, aqueous injection, infusion solution, powder injection or lyophilized injectable powder.

8. the synthetic method of couroupitine A derivative according to claim 1, is characterized in that, comprise the following steps:

Anthranilic acid or derivatives thereof 0.01mol adds in the three-necked bottle that reflux exchanger, magneton, thermometer are housed, and adds toluene 15mL, dry SOCl ₂3mL, backflow 1.0h, stopped reaction; Decompression rotary evaporation is except desolventizing and unnecessary SOCl ₂, then in flask, add the istain or derivatives thereof of 0.01moL and the methylene dichloride of 15mL, continue back flow reaction 1.0h, be cooled to room temperature, filter, obtain yellow solid couroupitine A or derivatives thereof; By methanol wash, methylene dichloride or re crystallization from toluene, synthesize couroupitine A and derivative 2-14 thereof in this approach;

The synthesis of couroupitine A derivative 15-43:

Take chlorine couroupitine A 10 μm of ol and piperidinyl-1 0 μm of ol of 7-replacement, add N-Methyl pyrrolidone (NMP) 5mL, 70 DEG C of reaction 2.0h, reaction terminates rear cooling, adds proper amount of methanol in reaction solution, leaves standstill, filter, filter cake methyl alcohol lotion, obtains couroupitine A derivative, synthesizes tryptamines ketone derivatives 15-43 in this approach.