CN103382207A - Methylbenzofuran quinoline derivative, preparation method thereof, and application of derivative as antitumor drug - Google Patents

Methylbenzofuran quinoline derivative, preparation method thereof, and application of derivative as antitumor drug Download PDF

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CN103382207A
CN103382207A CN2013102554816A CN201310255481A CN103382207A CN 103382207 A CN103382207 A CN 103382207A CN 2013102554816 A CN2013102554816 A CN 2013102554816A CN 201310255481 A CN201310255481 A CN 201310255481A CN 103382207 A CN103382207 A CN 103382207A
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furoquinoline
methyl
derivative
methyl benzo
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CN103382207B (en
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黄志纾
古练权
杜刚
花闻钊
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Sun Yat Sen University
National Sun Yat Sen University
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Abstract

The invention discloses a methylbenzofuran quinoline derivative, a preparation method thereof and application of the derivative as an antitumor drug, which belongs to the fields of medicine and chemical engineering. The invention also discloses the preparation method for the methylbenzofuran quinoline derivative and application of the derivative as the antitumor drug. According to results of experiments, the methylbenzofuran quinoline derivative in the invention has a powerful inhibitory effect on the expression of protooncogenes of DNA like telomeric DNA and c-myc, a substantial inhibitory effect on a variety of cancer cell lines, small toxicity to normal cells and wide application prospects in preparation of antitumor drugs.

Description

A kind of methyl benzo furoquinoline derivative and preparation method thereof and as the application of antitumor drug
Technical field
The present invention relates to methyl benzo furoquinoline derivative field, more specifically, relate to a kind of methyl benzo furoquinoline derivative and preparation method thereof and as the application of antitumor drug.
Background technology
Cancer is one of principal disease threatened human health and life security.According to statistics, the annual newly-increased cancer patients in the whole world reaches 4,000,000 people left and right.The research and development of cancer therapy drug are the focuses that chemist and medicine scholar pay close attention to always.Find efficient, highly selective, cancer therapy drug that toxic side effect is little is one of important directions of drug development research.Take DNA as the synthetic cancer therapy drug of shot design,, for the special higher structure design synthesized micromolecule inhibitor of the proto-oncogene DNA such as the telomeric dna with important physiological significance and c-myc, is particularly the important method of Development of Novel cancer therapy drug.
There are some common constitutional featuress with the interactional micromolecular compound of telomeric dna: the plane aromatic ring structure that three or more are arranged; An or positively charged side chain under several physiological conditions.Its mechanism of anticancer action is mainly by the interaction with telomeric dna, the telomerase activation of anticancer, thereby the copying of anticancer.
The skatole quinolines is the more rare a kind of alkaloid of occurring in nature, structure with four plane aromatic rings, cryptolepine (cryptolepine) is the Typical Representative of this compounds, at nature, often with the form of quaternary ammonium salt, exists, and is with a positive charge on 5 N.This compound was separated from the plant Cryptolepis sanguinolenta of West Africa first as far back as nineteen twenty-nine.This compound has the physiologically active widely such as good antibiotic, anti-inflammatory, antiviral, anti-malarial.K.Bonjeam in 1998 etc. have been reported to 5-skatole quinoline at biochemistry, and by disturbing type Ⅱ topoisomerase to suppress the B16 melanoma, (biochemistry 1998,37,5136-5146).Derivative and the physiologically active thereof of the 5-skatole quinoline of after this series of modification are reported in succession, but these modifications are all to concentrate on the parent of Fourth Ring, and this research group has successively reported skatole quinoline derivatives (the J. Med. Chem. 2005 of a series of 11 bit amino side substitution, 48,7315-7321; J. Med. Chem. 2008,51,6381-6392), by with telomere G-tetra-serobila DNA, interacting and suppress telomerase activation, multiple JEG-3 had to significant restraining effect.
G-tetra-serobilas are a kind of four chains the DNA spiralstructure is to be connected to one by four quadrangleand form, owing to being rich in series connectionthe guanine base (G) repeated, so this structure is also referred to as " G4-DNA ".Research in the past only thinks that this structure can only synthetic, but the current research of 2013 finds, " four spirals " DNA of " G-tetra-serobilas " also is present in the mankind genein group.This four chain DNA spirane structures are found in the human cancer cell, because the division of cancer cells is very fast, and usually have defect on telomere, and therefore four chain spirane structures are a kind of exclusive features of cancer cells.If really so talk about, any cancer treatment method for this structure all will can not hurt normal healthy cell.The formation of telomeric dna G-tetra-chain body structures can suppress the activity of Telomerase effectively, thereby target telomeric dna G-tetra-serobilas make its stable part become the new direction of cancer therapy drug research.
Although the anticancer effect of skatole quinolines is confirmed, but because the selective power of current existing multiple skatole quinolines to G-tetra-serobila DNA still remains to be improved, while is due to the resource-constrained of occurring in nature indoles quinolines, at present, the parent nucleus of skatole quinoline of take carries out structure of modification as basis, be an important channel of finding to have better antitumour activity lead compound.
Summary of the invention
The object of the present invention is to provide the preparation method of such methyl benzo furoquinoline derivative.
Another object of the present invention is to provide this application of methyl benzo furoquinoline derivative in preparing antitumor drug.
A further object of the invention is for the deficiencies in the prior art, provides that a kind of toxicity is little, anticancer effect good, is convenient to the methyl benzo furoquinoline derivative of synthetic.
The present invention is according to the constitutional features of some and the interactional micromolecular compound of telomeric dna (cryptolepine derivative), two different positionss that are precursor skeleton at methyl benzo furoquinoline are introduced two fat amido side chains, obtain and telomeric dna or the interactional methyl benzo of promoter region C-MYC DNA furoquinoline derivative.
Above-mentioned technical purpose of the present invention is to be achieved through the following technical solutions above-mentioned purpose:
the invention provides a kind of methyl benzo furoquinoline derivative, chemical structural formula is as shown in I:
Figure 2013102554816100002DEST_PATH_IMAGE001
（I）
Wherein, n is 1,2,3 or 4;
R 1for-OH ,-NH 2,-NHR 4,-NR 5r 6, nitrogenous C 3-5cycloalkyl, piperidyl, azatropylidene base, morpholinyl, piperazinyl Huo Bi Evil quinoline base or
Figure 2013102554816100002DEST_PATH_IMAGE002
;
R 2for nitrogen-atoms with the piperidyl of positive charge, nitrogen-atoms with the morpholinyl of positive charge,
Figure 142163DEST_PATH_IMAGE003
,
Figure 2013102554816100002DEST_PATH_IMAGE004
,
Figure 2013102554816100002DEST_PATH_IMAGE005
,
Figure 2013102554816100002DEST_PATH_IMAGE006
or-N +cH 3r 5r 6;
R 3for H, F, Cl, Br, C 1-6alkyl or C 3-6cycloalkyl;
R 4for C 1-6alkyl;
R 5, R 6for C 1-6alkyl;
X is C 1-6alkyl or unsubstituted.
Described R 1be preferably
Figure DEST_PATH_IMAGE007
,
Figure 2013102554816100002DEST_PATH_IMAGE008
,
Figure DEST_PATH_IMAGE009
or , described R 2be preferably
Figure DEST_PATH_IMAGE011
,
Figure 2013102554816100002DEST_PATH_IMAGE012
, or .
Described R 3be preferably H, described X is preferably methyl.
The preparation method of a kind of as above 1 described methyl benzo furoquinoline derivative is provided according to demand again, comprises the following steps:
Figure 340505DEST_PATH_IMAGE015
first with Mono Chloro Acetic Acid, carry out hydrocarbyl reaction in alkaline environment, then carry out chlorination with sulfur oxychloride again, obtain compound
Figure DEST_PATH_IMAGE016
; By its again with
Figure 361813DEST_PATH_IMAGE017
carry out condensation reaction, obtain compound
Figure DEST_PATH_IMAGE018
; Carry out ring-closure reaction with polyphosphoric acid (PPA) again, obtain compound
Figure 113868DEST_PATH_IMAGE019
; Again it is carried out to chlorination, obtain compound
Figure DEST_PATH_IMAGE020
; Utilize subsequently boron tribromide to slough the methyl on methoxyl group, obtain compound ; Recycling name reaction's (mitsunobu reaction), with
Figure DEST_PATH_IMAGE022
reacted, obtained compound
Figure 327998DEST_PATH_IMAGE023
; Subsequently itself and methyl iodide are carried out to methylation reaction, obtain compound ; Finally ethylene glycol ethyl ether do under the condition of solvent with
Figure 227032DEST_PATH_IMAGE025
reaction, obtain various methyl benzo furoquinoline derivatives, and structural formula is
。
Concrete process is as follows
Figure 833594DEST_PATH_IMAGE027
Aromatic nucleus nitrogen-atoms and R in described compound 2in nitrogen-atoms utilize methyl iodide to be methylated simultaneously.
Described
Figure DEST_PATH_IMAGE028
with reacting of amine chain, be to carry out under the condition be solvent at ethylene glycol ethyl ether.
Described
Figure 826958DEST_PATH_IMAGE029
in methyl utilize boron tribromide to slough.
Described compound with
Figure 768238DEST_PATH_IMAGE022
reaction utilize name reaction mitsunobu to be reacted.
The application of a kind of methyl benzo furoquinoline derivative as above in preparing cancer therapy drug is provided according to demand again.
Related methyl benzo furoquinoline derivative of the present invention has very strong interaction with the telomeric dna that is rich in guanine, shows the Telomerase in cancer cells is had to good inhibition activity.Further experiment proves, methyl benzo furoquinoline derivative involved in the present invention is inhibited to multiple JEG-3, and toxicity is less, therefore can be used for preparing cancer therapy drug.
The present invention discloses simultaneously and has protected methyl benzo furoquinoline derivative in the purposes prepared on cancer therapy drug; And the cancer therapy drug that contains methyl benzo furoquinoline derivative.
Methyl benzo furoquinoline derivative of the present invention can mix with pharmaceutically acceptable auxiliary, prepares the antitumor drug of various formulations, as tablet, pill, capsule, injection, suspension agent or emulsion etc.
Two substituent methyl cumarone quinolines involved in the present invention are the novel G-tetra-serobila small molecules parts according to a series of side substitution of small molecules part and the interactional constructional feature appropriate design of G-tetra-serobila.Mechanism of action is mainly the tetrad plane generation pi-pi accumulation effect by the secondary structure of small molecules part and the formation of rich guanine sequence, and the electrostatic interaction to a certain degree in the negative electricity zone of the positive charge of part parent nucleus and tetrad planar central.And two fat amido side chains of part, can increase sterically hindered when double-stranded DNA is combined of small molecules part, also increased the groove contact ability to G-tetra-serobilas simultaneously, and the positive charge of a side chain also can further increase its groove contact ability to G-tetra-serobilas, thereby finally reach, improve the selective power of G-tetra-serobilas and the purpose of affinity.
Compared with prior art, the present invention has following beneficial effect:
1. novel methyl benzo furoquinoline derivative of the present invention has very strong interaction with the telomeric dna that is rich in guanine, shows the inhibition activity good to the Telomerase in cancer cells, thereby multiple JEG-3 is had to significant restraining effect;
2. novel methyl benzo furoquinoline derivative of the present invention is little to normal cytotoxicity, safe in the application for preparing cancer therapy drug;
3. novel methyl benzo furoquinoline derivative of the present invention can be made the cancer therapy drug of various formulations, has very high medical value and wide market outlook.
Embodiment
Further describe the present invention below in conjunction with specific embodiment.Unless stated otherwise, reagent, equipment and the method that the present invention adopts is the conventional commercial reagent of the art, equipment and the conventional method of using.
Embodiment mono-: compound 8M7's is synthetic
The 0.3mol Mono Chloro Acetic Acid is dissolved in 60ml water, adjust PH to 9 with sodium hydroxide, add again the 0.2mol MEHQ, 100 ℃ of backflows, obtain M1, then adding sulfur oxychloride to carry out chlorination, obtain M2, boil off the sulfur oxychloride solvent and obtain brown liquid, carry out condensation reaction with anthranilic acid again, obtain M3, then PPA being preheated to 130 ℃ adds M3 to carry out combination reaction, obtain compound M4, M4 and sulfur oxychloride are carried out to chlorination 80 ℃ of backflows, obtain compound M5, in methylene dichloride, utilize afterwards boron tribromide to slough 7 methyl, obtain compound M6.
Then do under the condition of solvent at chloroform (300mL), add 6.0g triphenylphosphine, 2.0g M6,6mL 4-hydroxyethyl morpholine, 6mL diisopropyl azodiformate, N 2under protection, drip diisopropyl azodiformate, drip rear normal-temperature reaction and spend the night.Filter, revolve and steamed the laggard row chromatographic column separation of solvent, obtain sterling: white solid.
Productive rate: 80%; Fusing point: 186.2-187.9 ℃; 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=8.4 Hz, 1H), (8.31 d, J=8.5 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.71 (t, J=6.0 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 4.29 (t, J=5.5 Hz, 2H), 3.82 – 3.74 (m, 4H), 2.90 (t, J=5.5 Hz, 2H), 2.69 – 2.58 (m, 4H); C 21h 19clN 2o 3, LC-MS m/z: 383[M+H] +.
Figure 505250DEST_PATH_IMAGE031
Compound 8M7
Embodiment bis-: compound 9M7's is synthetic
Method is with embodiment mono-, and difference is to replace the 4-hydroxyethyl morpholine with the N-hydroxyethyl piperidine, obtains compound 9M7.
Productive rate: 84%; Fusing point: 178.4-180.1 ℃; 1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8.4,0.8 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.78 (dd, J=8.4,1.4 Hz, 1H), 7.70 (dd, J=11.1,4.1 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.28 (dd, J=8.8,2.5 Hz, 1H), 4.27 (t, J=5.9 Hz, 2H), 2.87 (t, J=5.9 Hz, 2H), 2.59 (m, 4H), 1.71 – 1.59 (m, 4H), 1.51 – 1.44 (m, 2H), C 22h 21clN 2o 2, LC-MS m/z:381[M+H] +.
Figure DEST_PATH_IMAGE032
Compound 9M7
Embodiment tri-: compound 6M8's is synthetic
Method is with embodiment mono-, different is to use N, the N-dimethylethanolamine replaces the 4-hydroxyethyl morpholine, and reaction product is added to product in single neck bottle of 100mL after crossing the post separation, after add the tetramethylene sulfone of 15mL and the methyl iodide of 10mL, 68 ℃ of reactions added a large amount of ether after three days, filtered drying, obtain compound 6M8, orange red solid.
Productive rate: 92%; Fusing point: 297.2-298.4 ℃; 1H NMR (400 MHz, DMSO) δ 8.83 (d, J=9.0 Hz, 1H), (8.59 d, J=8.4 Hz, 1H), 8.32 (t, J=8.0 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.20 (d, J=9.2 Hz, 1H), 8.12 (t, J=7.8 Hz, 1H), 7.81 (dd, J=9.2,2.3 Hz, 1H), 4.93 (s, 3H), 4.75 (t, J=3.6 Hz, 2H), 3.92 (t, J=3.6 Hz, 2H), 3.27 (s, 9H); C 21h 23clI 2n 2o 2, ESI-MS m/z:185 [M-2I] 2+/ 2.
Compound 6M8
Embodiment tetra-: compound 7M8's is synthetic
Method is with embodiment tri-, and different is to use N, and the N-dimethyl propanol amine replaces N, and the N-dimethylethanolamine, obtain orange red solid chemical compound.
Productive rate: 91%; Fusing point: 282.9-285.1; 1H NMR (400 MHz, DMSO) δ 8.83 (d, J=8.5 Hz, 1H), 8.61 (d, J=7.5 Hz, 1H), 8.34 (t, J=7.2 Hz, 1H), 8.23 – 8.11 (m, 2H), (7.86 d, J=10.1 Hz, 1H), (7.77 d, J=8.6 Hz, 1H), (4.92 s, 3H), 4.31 (d, J=30.7 Hz, 2H), 3.66 – 3.53 (m, 2H), 3.17 (s, 9H), (2.29 s, 2H); C 22h 25clI 2n 2o 2, ESI-MS m/z:192 [M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE034
Compound 7M8
Embodiment five: compound 8M8's is synthetic
8M7 is added in single neck bottle of 100mL, after add the tetramethylene sulfone of 15mL and the methyl iodide of 10mL, 68 ℃ of reactions added a large amount of ether after three days, filtered, and obtained compound 8M8, orange red solid.
Productive rate: 93%; Fusing point: 273.0-275.6 ℃; 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=9.0 Hz, 1H), 8.62 (d, J=7.7 Hz, 1H), 8.35 (t, J=8.0 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J=9.2 Hz, 1H), 8.14 (t, J=7.6 Hz, 1H), 7.83 (dd, J=9.2,2.4 Hz, 1H), 4.94 (s, J=1.1 Hz, 3H), 4.79 (t, J=1.8 Hz, 2H), 4.08 (t, J=1.8 Hz, 2H), 4.02 (t, J=4.4 Hz, 4H), 3.71 – 3.57 (m, 4H), 3.34 (s, 3H), C 23h 25clI 2n 2o 3, ESI-MS m/z:206[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE035
Compound 8M8
Embodiment six: compound 9M8's is synthetic
Method is with embodiment five, and different replaces 8M7 with 9M7, obtains orange red solid chemical compound.
Productive rate: 89%, fusing point: 286.9-288.1 ℃, 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=9.2 Hz, 1H), 8.62 (d, J=8.4 Hz, 1H), 8.35 (t, J=7.8 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.22 (d, J=9.2 Hz, 1H), 8.15 (t, J=7.6 Hz, 1H), 7.82 (dd, J=9.2, 2.5 Hz, 1H), 4.94 (s, 3H), 4.75 (t, J=4.0 Hz, 2H), 3.94 (t, J=4.4 Hz, 2H), 3.57 – 3.45 (m, 4H), 3.22 (s, 3H), 1.93 – 1.87 (m, 4H), 1.66 – 1.53 (m, J=6.2 Hz, 2H), C 24h 27clI 2n 2o 2, ESI-MS m/z:205[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE036
Compound 9M8
Embodiment seven: compound 10M8's is synthetic
Method is with embodiment tri-, and different is to replace N with N-methyl 4-piperidine carbinols, and the N-dimethylethanolamine, obtain orange red solid chemical compound.
Productive rate: 90%; Fusing point: 273.8-275.9 ℃; 1H NMR (400 MHz, DMSO) δ 8.82 (d, J=8.7 Hz, 1H), (8.59 d, J=8.4 Hz, 1H), 8.37 – 8.28 (m, 1H), 8.22 – 8.11 (m, 3H), 7.76 (dd, J=13.4,7.7 Hz, 1H), 4.92 (s, 3H), 4.19 (dd, J=32.2,5.6 Hz, 2H), 3.65 – 3.41 (m, 4H), (3.13 s, 3H), 2.84 (s, 3H), 2.19 – 1.99 (m, 4H), (1.58 d, J=12.4 Hz, 1H); C 24h 27clI 2n 2o 2, ESI-MS m/z:205[M-2I] 2+/ 2.
Compound 10M8
Embodiment eight: compound 6MA's is synthetic
Get the embodiment tri-gained compound 6M8 of 150mg in single neck bottle of 100mL, after add the ethylene glycol ethyl ether of 5mL and the N of 3mL, the N-dimethyl amine, 120 ℃ of reaction 0.5h, add a large amount of ether after having reacted, filter, drying, obtain compound 6MA, gray solid.
Productive rate: 88%; Fusing point: 245.1-247.2 ℃; 1H NMR (400 MHz, DMSO) δ 8.68 (d, J=8.2 Hz, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.10 (d, J=9.2 Hz, 2H), 7.96 (d, J=9.1 Hz, 1H), 7.80 (t, J=7.5 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 4.72 (t, J=2.6 Hz, 2H), 4.58 (s, 3H), 4.21 (t, J=5.8 Hz, 2H), 3.91 (t, J=4.6 Hz, 2H), 3.27 (s, 9H), 2.78 (t, J=6.0 Hz, 2H), 2.33 (s, 6H), C 25h 34i 2n 4o 2, ESI-MS m/z:211[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE038
Compound 6MA
Embodiment nine: compound 6MB's is synthetic
Method is with embodiment eight, the different N that use, and the N-dimethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, the sorrel solid.
Productive rate: 89%, fusing point: 242.2-244.6 ℃, 1H NMR (400 MHz, MeOD) δ 8.61 (d, J=8.5 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.15 – 8.08 (m, 2H), 7.92 (d, J=9.2 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.66 (dd, J=0.8 Hz, 1H), 4.77 (t, J=2.0 Hz, 2H), 4.68 (s, 3H), 4.39 (t, J=6.8 Hz, 2H), 4.00 (t, J=4.2 Hz, 2H), 3.37 (s, 9H), 3.36 (s, J=2.6 Hz, 2H), 2.96 (t, J=6.8 Hz, 2H), 2.49 (s, 6H), C 26h 36i 2n 4o 2, ESI-MS m/z:218[M-2I] 2+/ 2.
Compound 6MB
Embodiment ten: compound 6MC's is synthetic
Method is with embodiment eight, the different N that use, and N-diethyl ethamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, gray solid.
Productive rate: 89%, fusing point: 240.2-243.0 ℃, 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=8.3 Hz, 1H), 8.41 (d, J=8.9 Hz, 1H), 8.15 – 8.05 (m, 2H), 7.94 (d, J=9.2 Hz, 1H), 7.82 (t, J=7.8 Hz, 1H), 7.61 (dd, J=9.2, 2.3 Hz, 1H), 4.70 (t, J=4.0 Hz, 2H), 4.57 (s, 3H), 4.19 (t, J=6.0 Hz, 2H), 3.89 (t, J=3.8 Hz, 2H), 3.25 (s, 9H), 2.84 (t, J=6.1 Hz, 2H), 2.57 (d, J=6.3 Hz, 4H), 0.90 (t, J=6.9 Hz, 6H), C 27h 38i 2n 4o 2, ESI-MS m/z:225[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE040
Compound 6MC
Embodiment 11: compound 6MD's is synthetic
Method is with embodiment eight, and different is to use N, and N-diethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, orange red solid.
Productive rate: 85%, fusing point: 262.0-263.1 ℃, 1H NMR (400 MHz, DMSO) δ 8.64 (d, J=8.1 Hz, 1H), 8.40 (d, J=8.7 Hz, 1H), 8.09 (t, J=7.4 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=9.1 Hz, 1H), 7.81 (t, J=6.4 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 4.56 (s, 3H), 4.30 (t, J=2.6 Hz, 2H), 4.18 (t, J=4.2 Hz, 2H), 3.61 (t, J=7.3 Hz, 2H), 3.17 (s, 9H), 2.88 (s, 2H), 2.69 – 2.55 (m, 4H), 2.34 – 2.22 (m, 2H), 1.13 – 0.73 (m, 6H), C 28h 40n 4i 2o 2, ESI-MS m/z:232[M-2I] 2+/ 2.
Figure 450837DEST_PATH_IMAGE041
Compound 6MD
Embodiment 12: compound 6ME's is synthetic
Method is with embodiment eight, and different is to replace N with the N-aminoethyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, brown solid.
Productive rate: 90%, fusing point: 261.3-262.9 ℃, 1H NMR (400 MHz, DMSO) δ 8.68 (d, J=8.4 Hz, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.15 – 8.08 (m, 2H), 7.98 (d, J=9.2 Hz, 1H), 7.82 (t, J=4.0 Hz, 1H), 7.61 (dd, J=9.1, 1.9 Hz, 1H), 4.72 (t, J=2.2 Hz, 2H), 4.60 (s, 3H), 4.22 (t, J=5.8 Hz, 2H), 3.91 (t, J=1.8 Hz, 2H), 3.50 (t, J=2.0 Hz, 4H), 3.27 (s, 9H), 2.78 (t, J=6.3 Hz, 2H), 2.60 – 2.51 (m, 4H), C 27h 36n 4i 2o 3, ESI-MS m/z:232[M-2I] 2+/ 2.
Compound 6ME
Embodiment 13: compound 6MF's is synthetic
Method is with embodiment eight, and different is to replace N with the N-aminopropyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, yellow solid.
Productive rate: 88%, fusing point: 249.9-250.7 ℃, 1H NMR (400 MHz, DMSO) δ 8.69 (d, J=8.4 Hz, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.15 – 8.07 (m, 2H), 7.98 (d, J=9.2 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 4.71 (t, J=1.6 Hz, 2H), 4.58 (s, 3H), 4.19 (t, J=6.4 Hz, 2H), 3.90 (t, J=2.0 Hz, 2H), 3.53 – 3.45 (m, 4H), 3.26 (s, 9H), 2.93 – 2.78 (m, 2H), 2.40 – 2.28 (m, 4H), 2.03 – 1.97 (m, 2H), C 28h 38n 4i 2o 3, ESI-MS m/z:239[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE043
Compound 6MF
Embodiment 14: compound 6MG's is synthetic
Method is with embodiment eight, and different is to replace N with the N-aminopropyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, gray solid.
Productive rate: 85%, fusing point: 259.0-259.9 ℃, 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=6.6 Hz, 1H), 8.41 (d, J=6.4 Hz, 1H), 8.09 (d, J=6.4 Hz, 1H), 8.00 (d, J=4.8 Hz, 1H), 7.89 (t, J=8.3 Hz, 1H), 7.80 (d, J=6.7 Hz, 1H), 7.58 (t, J=5.8 Hz, 1H), 4.69 (t, J=6.3 Hz, 2H), 4.56 (s, 3H), 4.18 (t, J=6.0 Hz, 2H), 3.59 (t, J=8.3 Hz, 2H), 3.16 (s, 9H), 2.88 (s, 2H), 2.69 – 2.58 (m, 4H), 1.08 – 0.76 (m, 6H), C 27h 38n 4i 2o 2, ESI-MS m/z:231[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE044
Compound 6MG
Embodiment 15: compound 7MA's is synthetic
Get the embodiment tetra-gained compound 7M8 of 150mg in single neck bottle of 100mL, after add the ethylene glycol ethyl ether of 5mL and the N of 3mL, the N-dimethyl amine, 120 ℃ of reaction 0.5h, add a large amount of ether after having reacted, filter, drying, obtain compound 7MA, yellow solid.
Productive rate: 90%, fusing point: 261.2-263.0 ℃, 1H NMR (400 MHz, DMSO) δ 8.68 (d, J=7.5 Hz, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.11 (t, J=9.8 Hz, 1H), 8.02 (s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.83 (t, J=11.3 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 4.58 (s, 3H), 4.31 (t, J=2.2 Hz, 2H), 4.23 (t, J=2.8 Hz, 2H), 3.60 (t, J=4.2 Hz, 2H), 3.17 (s, 9H), 2.83 (s, 2H), 2.36 (s, 6H), 2.33 – 2.23 (m, 2H), C 26h 36n 4i 2o 2, ESI-MS m/z:218 [M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE045
Compound 7MA
Embodiment 16: compound 7MB's is synthetic
Method is with embodiment 15, the different N that use, and the N-dimethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, the sorrel solid.
Productive rate: 90%, fusing point: 246.8-247.9 ℃, 1H NMR (400 MHz, DMSO) δ 8.57 (d, J=8.4 Hz, 1H), 8.39 (d, J=8.9 Hz, 1H), 8.08 (t, J=7.6 Hz, 1H), 7.98 (d, J=1.9 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.80 (t, J=8.4 Hz, 1H), 7.56 (dd, J=9.2, 2.1 Hz, 1H), 4.54 (s, 3H), 4.29 (t, J=5.6 Hz, 2H), 4.14 (t, J=6.9 Hz, 2H), 3.64 – 3.57 (m, 2H), 3.17 (s, 9H), 2.64 (t, J=4.9 Hz, 2H), 2.34 (s, 6H), 2.30 – 2.24 (m, 2H), 2.01 (t, J=6.9 Hz, 2H), C 27h 38i 2n 4o 2, ESI-MS m/z:225[M-2I] 2+/ 2.
Compound 7MB
Embodiment 17: compound 7MC's is synthetic
Method is with embodiment 15, the different N that use, and N-diethyl ethamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, gray solid.
Productive rate: 85%, fusing point: 223.8-225.9 ℃, 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=7.8 Hz, 1H), 8.41 (d, J=8.3 Hz, 1H), 8.11 (t, J=6.6 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.82 (t, J=6.8 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 4.57 (s, 3H), 4.30 (t, J=4.2Hz, 2H), 4.19 (t, J=4.9Hz, 2H), 3.59 (t, J=5.2Hz, 2H), 3.16 (s, 9H), 2.87 (t, J=5.4Hz, 2H), 2.68 – 2.56 (m, 4H), 2.29 (t, J=3.8Hz, 2H), 1.06 – 0.81 (m, 6H), C 28h 40i 2n 4o 2, ESI-MS m/z:232[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE047
Compound 7MC
Embodiment 18: compound 7MD's is synthetic
Method is with embodiment 15, and different is to use N, and N-diethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, the sorrel solid.
Productive rate: 88%, fusing point: 243.1-245.5 ℃, 1H NMR (400 MHz, DMSO) δ 8.56 (d, J=7.8 Hz, 1H), 8.37 (d, J=8.7 Hz, 1H), 8.06 (t, J=7.7 Hz, 1H), 7.96 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.79 (t, J=7.0 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 4.53 (s, 3H), 4.30 (t, J=2.6 Hz, 2H), 4.15 (t, J=5.9 Hz, 2H), 3.62 (t, J=5.8 Hz, 2H), 3.20 (s, 9H), 2.67 (t, J=4.2 Hz, 2H), 2.61 – 2.54 (m, 4H), 2.29 (t, J=4.8 Hz, 2H), 1.95 (t, J=5.6 Hz, 2H), 1.04 – 0.89 (m, 6H), C 29h 42n 4i 2o 2, ESI-MS m/z:239[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE048
Compound 7MD
Embodiment 19: compound 7ME's is synthetic
Method is with embodiment 15, and different is to replace N with the N-aminoethyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, the khaki color solid.
Productive rate: 90%, fusing point: 244.1-246.9 ℃, 1H NMR (400 MHz, MeOD) δ 8.58 (d, J=8.5 Hz, 1H), 8.33 (d, J=8.9 Hz, 1H), 8.13 (t, J=8.2 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.60 (dd, J=9.2, 2.3 Hz, 1H), 4.66 (s, 3H), 4.41 – 4.37 (m, 2H), 3.81 (d, J=8.3 Hz, 2H), 3.78 – 3.74 (m, 2H), 3.72 (dd, J=8.4, 3.9 Hz, 4H), 3.31 (s, 9H), 2.96 (t, J=6.5 Hz, 2H), 2.71 (t, J=8.6 Hz, 4H), 2.51 – 2.41 (m, 2H), C 28h 38n 4i 2o 3, ESI-MS m/z:239[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE049
Compound 7ME
Embodiment 20: compound 7MF's is synthetic
Method is with embodiment 15, and different is to replace N with the N-aminopropyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, yellow solid.
Productive rate: 88%, fusing point: 250.9-253.2 ℃, 1H NMR (400 MHz, MeOD) δ 8.56 (d, J=8.0 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.11 (t, J=8.0 Hz, 1H), 8.00 (s, 1H), 7.87 – 7.76 (m, 2H), 7.59 (d, J=9.2 Hz, 1H), 4.65 (s, 3H), 4.38 (d, J=5.7 Hz, 2H), 3.76 (t, J=6.4 Hz, 2H), 3.74 – 3.68 (m, 4H), 3.63 (t, J=7.0 Hz, 2H), 3.33 (s, 9H), 2.96 (t, J=2.2 Hz, 2H), 2.77 – 2.69 (m, 4H), 2.50 – 2.39 (m, 2H), 1.20 (t, J=6.8 Hz, 2H), C 29h 40n 4i 2o 3, ESI-MS m/z:246[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE050
Compound 7MF
Embodiment 21: compound 7MG's is synthetic
Method is with embodiment 15, and different is to use the N-(2-aminoethyl) piperidines replacement N, the N-dimethyl amine is reacted, and obtains sterling, gray solid.
Productive rate: 85%; Fusing point: 246.3-248.4 ℃; 1H NMR (400 MHz, DMSO) δ 8.69 (d, J=8.2 Hz, 1H), 8.43 (d, J=8.7 Hz, 1H), 8.12 (t, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.83 (t, J=6.9 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H), 4.58 (s, 3H), 4.36 – 4.21 (m, 4H), 3.66 – 3.52 (m, 4H), 3.16 (s, 9H), 2.34 – 2.22 (m, 4H), 1.82 (t, J=5.8 Hz, 2H), 1.60 – 1.36 (m, 6H), C 28h 40n 4i 2o 2, ESI-MS m/z:238[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE051
Compound 7MG
Embodiment 22: compound 8MA's is synthetic
Get the embodiment five gained compound 8M8 of 150mg in single neck bottle of 100mL, after add the ethylene glycol ethyl ether of 5mL and the N of 3mL, the N-dimethyl amine, 120 ℃ of reaction 0.5h, add a large amount of ether after having reacted, filter, drying, obtain compound 8MA, gray solid.
Productive rate: 85%, fusing point: 263.5-265.7 ℃, 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=8.3 Hz, 1H), 8.43 (d, J=8.9 Hz, 1H), 8.13 – 8.06 (m, 2H), 7.99 (d, J=9.2 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.62 (dd, J=9.1, 2.3 Hz, 1H), 4.75 (t, J=6.2 Hz, 2H), 4.58 (s, 3H), 4.18 (t, J=6.6 Hz, 2H), 4.06 (d, J=3.4 Hz, 2H), 4.05 – 3.99 (m, 4H), 3.64 (dd, J=12.3, 6.6 Hz, 4H), 3.36 (s, 3H), 2.23 (s, 6H), 1.98 (t, J=6.7 Hz, 2H), C 27h 36n 4i 2o 3, ESI-MS m/z:232[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE052
Compound 8MA
Embodiment 23: compound 8MB's is synthetic
Method is with embodiment 22, the different N that use, and the N-dimethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, yellow solid.
Productive rate: 89%, fusing point: 243.0-245.0 ℃, 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=8.4 Hz, 1H), 8.41 (d, J=8.9 Hz, 1H), 8.08 (dd, J=13.9, 5.0 Hz, 2H), 7.97 (d, J=9.2 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.61 (dd, J=9.2, 2.4 Hz, 1H), 4.73 (t, J=2.5 Hz, 2H), 4.56 (s, 3H), 4.16 (t, J=7.0 Hz, 2H), 4.05 (t, J=2.1 Hz, 2H), 4.04 – 3.98 (m, 4H), 3.63 (ddd, J=21.9, 13.0, 4.8 Hz, 4H), 3.35 (s, 3H), 2.56 – 2.51 (m, 2H), 2.24 (s, 6H), 2.00 – 1.94 (m, 2H), C 28h 38i 2n 4o 3, ESI-MS m/z:239[M-2I] 2+/ 2.
Compound 8MB
Embodiment 24: compound 8MC's is synthetic
Method is with embodiment 22, the different N that use, and N-diethyl ethamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, the field gray solid.
Productive rate: 85%, fusing point: 259.8-262.7 ℃, 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=8.4 Hz, 1H), 8.39 (d, J=8.8 Hz, 1H), 8.11 – 8.03 (m, 2H), 7.94 (d, J=9.2 Hz, 1H), 7.78 (t, J=8.2 Hz, 1H), 7.60 (d, J=6.9 Hz, 1H), 4.73 (t, J=5.2 Hz, 2H), 4.56 (s, 3H), 4.18 (t, J=6.5 Hz, 2H), 4.08 – 3.98 (m, 6H), 3.68 – 3.56 (m, 4H), 3.35 (s, 3H), 2.83 (t, J=6.6 Hz, 2H), 2.57 (dd, J=14.0, 7.0 Hz, 4H), 0.90 (t, J=7.0 Hz, 6H), C 29h 40i 2n 4o 3, ESI-MS m/z:246[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE054
Compound 8MC
Embodiment 25: compound 8MD's is synthetic
Method is with embodiment 22, and different is to use N, and N-diethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, brown solid.
Productive rate: 89%, fusing point: 239.4-241.6 ℃, 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=8.2 Hz, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.14 – 8.06 (m, 2H), 7.96 (d, J=9.3 Hz, 1H), 7.81 (t, J=7.3 Hz, 1H), 7.62 (d, J=9.1 Hz, 1H), 4.75 (t, J=3.2 Hz, 2H), 4.57 (s, 3H), 4.19 (t, J=5.9 Hz, 2H), 4.08 (t, J=2.8 Hz, 2H), 4.06 – 4.01 (m, 4H), 3.74 – 3.57 (m, 4H), 3.38 (s, 3H), 2.67 (t, J=2.9 Hz, 2H), 2.61 – 2.53 (m, 4H), 1.96 (t, J=4.4 Hz, 2H), 0.98 (t, J=6.5 Hz, 6H), C 30h 42n 4i 2o 3, ESI-MS m/z:253[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE055
Compound 8MD
Embodiment 26: compound 8ME's is synthetic
Method is with embodiment 22, and different is to replace N with the N-aminoethyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, the khaki color solid.
Productive rate: 89%, fusing point: 245.9-248.7 ℃, 1H NMR (400 MHz, DMSO) δ 8.68 (d, J=8.5 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.18 – 8.07 (m, 2H), 8.00 (d, J=9.2 Hz, 1H), 7.85 (t, J=7.7 Hz, 1H), 7.63 (dd, J=9.2, 2.0 Hz, 1H), 4.75 (t, J=1.8 Hz, 2H), 4.60 (s, 3H), 4.25 (t, J=2.6 Hz, 2H), 4.07 (t, J=3.2 Hz, 2H), 4.02 (t, J=4.2 Hz, 4H), 3.68 – 3.61 (m, 4H), 3.52 (t, J=2.0 Hz, 4H), 3.37 (s, 3H), 2.87 – 2.76 (m, 2H), 2.65 – 2.53 (m, 4H), C 29h 38n 4i 2o 4, ESI-MS m/z:253[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE056
Compound 8ME
Embodiment 27: compound 8MF's is synthetic
Method is with embodiment 22, and different is to replace N with the N-aminopropyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, orange red solid.
Productive rate: 84%, fusing point: 251.2-253.5 ℃, 1H NMR (400 MHz, DMSO) δ 8.64 (d, J=8.2 Hz, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.05 – 7.98 (m, 2H), 7.91 (d, J=9.2 Hz, 1H), 7.71 (t, J=7.3 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 4.74 (t, J=6.3 Hz, 2H), 4.49 (s, 3H), 4.15 (t, J=6.3 Hz, 2H), 4.08 (t, J=3.4 Hz, 2H), 4.06 – 4.00 (m, 4H), 3.65 (dd, J=24.6, 12.4 Hz, 4H), 3.51 – 3.46 (m, 4H), 3.38 (s, 3H), 2.47 (d, J=3.4 Hz, 2H), 2.40 – 2.29 (m, 4H), 1.99 – 1.93 (m, 2H), C 30h 40n 4i 2o 4, ESI-MS m/z:260[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE057
Compound 8MF
Embodiment 28: compound 8MG's is synthetic
Method is with embodiment 22, and different is to use the N-(2-aminoethyl) piperidines replacement N, the N-dimethyl amine is reacted, and obtains sterling, gray solid.
Productive rate: 85%, fusing point: 257.4-259.1 ℃, 1H NMR (400 MHz, DMSO) δ 8.67 (d, J=8.4 Hz, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.16 – 8.07 (m, 2H), 7.96 (d, J=9.1 Hz, 1H), 7.83 (t, J=7.3 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 4.76 (t, J=6.1 Hz, 2H), 4.59 (s, 3H), 4.22 (t, J=5.7 Hz, 2H), 4.08 (t, J=7.3 Hz, 2H), 4.07 – 3.96 (m, 4H), 3.70 – 3.60 (m, 4H), 3.38 (s, 3H), 2.76 (t, J=5.2 Hz, 2H), 2.68 – 2.53 (m, 4H), 1.54 – 1.39 (m, 4H), 1.39 – 1.28 (m, 2H), C 29h 40n 4i 2o 3, ESI-MS m/z:252[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE058
Compound 8MG
Embodiment 29: compound 9MA's is synthetic
Get the embodiment six gained compound 9M8 of 150mg in single neck bottle of 100mL, after add the ethylene glycol ethyl ether of 5mL and the N of 3mL, the N-dimethyl amine, 120 ℃ of reaction 0.5h, add a large amount of ether after having reacted, filter, drying, obtain compound 9MA, gray solid.
Productive rate: 87%, fusing point: 235.9-238.0 ℃, 1H NMR (400 MHz, DMSO) δ 8.68 (d, J=8.2 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.13 – 8.04 (m, 2H), 7.96 (d, J=9.2 Hz, 1H), 7.79 (t, J=6.9 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 4.72 (t, J=3.2 Hz, 2H), 4.55 (s, 3H), 4.21 (t, J=6.0 Hz, 2H), 3.93 (t, J=3.9 Hz, 2H), 3.60 – 3.48 (m, 4H), 3.23 (s, 3H), 2.73 (t, J=6.0 Hz, 2H), 2.29 (s, 6H), 1.95 – 1.83 (m, 4H), 1.65 – 1.54 (m, 2H), C 28h 38n 4i 2o 2, ESI-MS m/z:231[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE059
Compound 9MA
Embodiment 30: compound 9MB's is synthetic
Method is with embodiment 29, the different N that use, and the N-dimethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, the sorrel solid.
Productive rate: 89%, fusing point: 233.8-236.2 ℃, 1H NMR (400 MHz, DMSO) δ 8.59 (d, J=8.6 Hz, 1H), 8.42 (d, J=8.5 Hz, 1H), 8.14 – 8.05 (m, 2H), 7.98 (d, J=9.4 Hz, 1H), 7.83 (t, J=7.4 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 4.70 (t, J=3.2 Hz, 2H), 4.57 (s, 3H), 4.18 (t, J=4.7 Hz, 2H), 3.91 (t, J=2.9 Hz, 2H), 3.55 – 3.47 (m, 4H), 3.21 (s, 3H), 2.34 (t, J=1.9 Hz, 2H), 2.22 (s, 6H), 1.97 (t, J=2.1 Hz, 2H), 1.93 – 1.85 (m, 4H), 1.60 (t, J=2.5 Hz, 2H), C 29h 40i 2n 4o 2, ESI-MS m/z:238[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE060
Compound 9MB
Embodiment 31: compound 9MC's is synthetic
Method is with embodiment 29, the different N that use, and N-diethyl ethamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, gray solid.
Productive rate: 88%, fusing point: 242.7-244.1 ℃, 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=7.9 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.12 – 8.03 (m, 2H), 7.92 (d, J=9.1 Hz, 1H), 7.77 (t, J=6.3 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 4.71 (t, J=3.2 Hz, 2H), 4.54 (s, 3H), 4.18 (t, J=4.7 Hz, 2H), 3.93 (t, J=3.5 Hz, 2H), 3.59 – 3.49 (m, 4H), 3.23 (s, 3H), 2.89 – 2.78 (m, 2H), 2.63 – 2.53 (m, 4H), 1.97 – 1.82 (m, 4H), 1.68 – 1.55 (m, 2H), 1.05 – 0.75 (m, 6H), C 30h 42i 2n 4o 2, ESI-MS m/z:245[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE061
Compound 9MC
Embodiment 32: compound 9MD's is synthetic
Method is with embodiment 29, and different is to use N, and N-diethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, the khaki color solid.
Productive rate: 89%, fusing point: 234.3-236.1 ℃, 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=8.2 Hz, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.14 – 8.06 (m, 2H), 7.96 (d, J=9.3 Hz, 1H), 7.81 (t, J=7.3 Hz, 1H), 7.62 (d, J=9.1 Hz, 1H), 4.75 (t, J=3.2 Hz, 2H), 4.57 (s, 3H), 4.19 (t, J=5.9 Hz, 2H), 4.08 (t, J=2.8 Hz, 2H), 4.06 – 4.01 (m, 4H), 3.74 – 3.57 (m, 4H), 3.38 (s, 3H), 2.67 (t, J=2.9 Hz, 2H), 2.61 – 2.53 (m, 4H), 1.96 (t, J=4.4 Hz, 2H), 0.98 (t, J=6.5 Hz, 6H), C 31h 44n 4i 2o 2, ESI-MS m/z:252[M-2I] 2+/ 2.
Compound 9MD
Embodiment 33: compound 9ME's is synthetic
Method is with embodiment 29, and different is to replace N with the N-aminoethyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, brown solid.
Productive rate: 89%, fusing point: 195.7-199.3 ℃, 1H NMR (400 MHz, DMSO) δ 8.63 (d, J=7.2 Hz, 1H), 8.28 (d, J=7.8 Hz, 1H), 8.06 – 7.97 (m, 2H), 7.92 (d, J=8.8 Hz, 1H), 7.69 (t, J=8.4 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 4.71 (t, J=1.2 Hz, 2H), 4.48 (s, 3H), 4.20 (t, J=4.5 Hz, 2H), 3.93 (t, J=4.4 Hz, 2H), 3.63 – 3.43 (m, 8H), 3.23 (s, 3H), 2.75 (t, J=3.5 Hz, 2H), 2.39 (d, J=24.6 Hz, 4H), 1.96 – 1.82 (m, 4H), 1.60 (t, J=4.5 Hz, 2H), C 30h 40n 4i 2o 3, ESI-MS m/z:252[M-2I] 2+/ 2.
Figure 40475DEST_PATH_IMAGE063
Compound 9ME
Embodiment 34: compound 9MF's is synthetic
Method is with embodiment 29, and different is to replace N with the N-aminopropyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, yellow solid.
Productive rate: 84%, fusing point: 226.8-228.4 ℃, 1H NMR (400 MHz, MeOD) δ 8.51 (d, J=8.2 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.88 (t, J=7.2 Hz, 1H), 7.73 (d, J=9.1 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 4.75 (t, J=5.4 Hz, 2H), 4.39 (s, 3H), 4.21 (t, J=6.9 Hz, 2H), 4.03 (t, J=5.4 Hz, 2H), 3.75 – 3.68 (m, 4H), 3.69 – 3.56 (m, 4H), 3.35 (s, 3H), 2.65 (t, J=7.0 Hz, 2H), 2.54 (t, J=5.3 Hz, 4H), 2.17 – 1.98 (m, 6H), 1.81 (dd, J=12.0, 6.0 Hz, 2H), C 31h 42n 4i 2o 3, ESI-MS m/z:259[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE064
Compound 9MF
Embodiment 35: compound 9MG's is synthetic
Method is with embodiment 29, and different is to use the N-(2-aminoethyl) piperidines replacement N, the N-dimethyl amine is reacted, and obtains sterling, the khaki color solid.
Productive rate: 85%, fusing point: 238.4-241.0 ℃, 1H NMR (400 MHz, MeOD) δ 8.58 (d, J=8.4 Hz, 1H), 8.34 (d, J=8.9 Hz, 1H), 8.17 – 8.10 (m, 2H), 7.89 (d, J=9.5 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 4.71 (t, J=7.2 Hz, 2H), 4.39 (s, 3H), 4.06 (t, J=6.6 Hz, 2H), 3.81 – 3.56 (m, 6H), 3.37 (s, 3H), 2.92 (t, J=5.5 Hz, 2H), 2.75 – 2.61 (m, 4H), 2.14 – 2.02 (m, 4H), 1.82 (t, J=5.0 Hz, 2H), 1.72 – 1.61 (m, 4H), 1.59 – 1.49 (m, 2H), C 31h 42n 4i 2o 2, ESI-MS m/z:251[M-2I] 2+/ 2.
Figure 870897DEST_PATH_IMAGE065
Compound 9MG
Embodiment 36: compound 10MA's is synthetic
Get the embodiment seven gained compound 10M8 of 150mg in single neck bottle of 100mL, after add the ethylene glycol ethyl ether of 5mL and the N of 3mL, the N-dimethyl amine, 120 ℃ of reaction 0.5h, add a large amount of ether after having reacted, filter, drying, obtain compound 10MA, the khaki color solid.
Productive rate: 89%, fusing point: 259.3-261.0 ℃, 1H NMR (400 MHz, MeOD) δ 8.57 (d, J=8.4 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.09 (t, J=8.0 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.55 (dd, J=9.3, 2.3 Hz, 1H), 4.64 (s, 3H), 4.37 (t, J=6.7 Hz, 2H), 4.24 (d, J=6.2 Hz, 2H), 3.64 (d, J=12.5 Hz, 2H), 3.52 (t, J=12.8 Hz, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2.97 (t, J=6.6 Hz, 2H), 2.50 (s, 6H), 2.32 (s, 1H), 2.16 (d, J=12.7 Hz, 2H), 2.06 (t, J=12.4 Hz, 2H)., C 28h 38n 4i 2o 2, ESI-MS m/z:231[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE066
Compound 10MA
Embodiment 37: compound 10MB's is synthetic
Method is with embodiment 36, the different N that use, and the N-dimethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, the khaki color solid.
Productive rate: 86%, fusing point: 258.9-260.8 ℃, 1H NMR (400 MHz, MeOD) δ 8.44 (d, J=7.9 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.09 (t, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.82 (d, J=9.5 Hz, 1H), 7.79 (t, J=7.1 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 4.63 (s, 3H), 4.27 (t, J=6.6 Hz, 2H), 4.24 (d, J=5.2 Hz, 2H), 3.63 (d, J=11.1 Hz, 2H), 3.53 (t, J=10.3 Hz, 2H), 3.25 (s, 3H), 3.22 (s, 3H), 2.65 (t, J=6.4 Hz, 2H), 2.36 (s, 6H), 2.27 (s, 1H), 2.20 – 2.01 (m, 6H), C 29h 40i 2n 4o 2, ESI-MS m/z:238[M-2I] 2+/ 2.
Figure 143746DEST_PATH_IMAGE067
Compound 10MB
Embodiment 38: compound 10MC's is synthetic
Method is with embodiment 36, the different N that use, and N-diethyl ethamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, gray solid.
Productive rate: 84%, fusing point: 267.3-268.9 ℃, 1H NMR (400 MHz, MeOD) δ 8.53 (d, J=8.5 Hz, 1H), 8.32 (d, J=8.9 Hz, 1H), 8.10 (t, J=8.7 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.80 (dd, J=17.5, 8.8 Hz, 2H), 7.58 (dd, J=9.2, 2.5 Hz, 1H), 4.65 (s, 3H), 4.32 (t, J=7.2 Hz, 2H), 4.24 (d, J=6.2 Hz, 2H), 3.63 (d, J=12.6 Hz, 2H), 3.56 – 3.48 (m, 2H), 3.25 (s, 3H), 3.22 (s, 3H), 2.99 (t, J=7.2 Hz, 2H), 2.74 (dd, J=14.3, 7.1 Hz, 4H), 2.32 (s, 1H), 2.16 (d, J=14.2 Hz, 2H), 2.10 – 2.01 (m, 2H), 1.10 (t, J=7.1 Hz, 6H), C 30h 42i 2n 4o 2, ESI-MS m/z:245[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE068
Compound 10MC
Embodiment 39: compound 10MD's is synthetic
Method is with embodiment 36, and different is to use N, and N-diethyl propylamine replaces N, and the N-dimethyl amine is reacted, and obtains sterling, brown solid.
Productive rate: 87%, fusing point: 251.7-253.4 ℃, 1H NMR (400 MHz, MeOD) δ 8.39 (d, J=8.6 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.96 (t, J=7.2 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H), 7.66 (t, J=7.9 Hz, 1H), 7.43 (dd, J=9.2, 2.5 Hz, 1H), 4.50 (s, 3H), 4.18 (t, J=6.9 Hz, 2H), 4.12 (d, J=6.2 Hz, 2H), 3.53 (d, J=12.6 Hz, 2H), 3.41 (t, J=8.2 Hz, 2H), 3.15 (s, 3H), 3.12 (s, 3H), 2.79 (t, J=5.6 Hz, 2H), 2.72 – 2.65 (m, 4H), 2.24 – 2.18 (m, 1H), 2.10 – 2.02 (m, 4H), 1.98 – 1.91 (m, J=11.8 Hz, 2H), 1.04 (t, J=7.2 Hz, 6H), C 31h 44n 4i 2o 2, ESI-MS m/z:252[M-2I] 2+/ 2.
Compound 10MD
Embodiment 40: compound 10ME's is synthetic
Method is with embodiment 36, and different is to replace N with the N-aminoethyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, the khaki color solid.
Productive rate: 88%, fusing point: 248.7-250.4 ℃, 1H NMR (400 MHz, MeOD) δ 8.54 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.8 Hz, 1H), 8.09 (t, J=7.6 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.85 – 7.76 (m, 2H), 7.56 (dd, J=9.3, 2.4 Hz, 1H), 4.65 (s, 3H), 4.36 (t, J=6.7 Hz, 2H), 4.24 (d, J=6.2 Hz, 2H), 3.74 – 3.67 (m, 4H), 3.62 (d, J=6.1 Hz, 2H), 3.52 (dd, J=12.4, 9.4 Hz, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2.91 (t, J=6.6 Hz, 2H), 2.64 (dd, J=16.9, 3.0 Hz, 4H), 2.51 (d, J=4.5 Hz, 1H), 2.16 (d, J=15.5 Hz, 2H), 2.05 (dd, J=25.2, 13.3 Hz, 2H), C 30h 40n 4i 2o 3, ESI-MS m/z:252[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE070
Compound 10ME
Embodiment 41: compound 10MF's is synthetic
Method is with embodiment 36, and different is to replace N with the N-aminopropyl morpholine, and the N-dimethyl amine is reacted, and obtains sterling, gray solid.
Productive rate: 88%, fusing point: 270.5-273.2 ℃, 1H NMR (400 MHz, MeOD) δ 8.56 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.9 Hz, 1H), 8.10 (t, J=9.0 Hz, 1H), 7.97 (s, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.79 (t, J=8.3 Hz, 1H), 7.57 (d, J=9.3 Hz, 1H), 4.65 (s, 3H), 4.30 (t, J=6.7 Hz, 2H), 4.25 (d, J=6.0 Hz, 2H), 3.72 – 3.62 (m, 6H), 3.52 (t, J=8.7 Hz, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2.65 (t, J=6.8 Hz, 2H), 2.55 – 2.49 (m, 4H), 2.42 (s, 1H), 2.19 – 2.10 (m, 4H), 2.04 (d, J=11.9 Hz, 2H), C 31h 42n 4i 2o 3, ESI-MS m/z:259[M-2I] 2+/ 2.
Figure 639898DEST_PATH_IMAGE071
Compound 10MF
Embodiment 42: compound 10MG's is synthetic
Method is with embodiment 36, and different is to use the N-(2-aminoethyl) piperidines replacement N, the N-dimethyl amine is reacted, and obtains sterling, gray solid.
Productive rate: 86%, fusing point: 259.4-262.1 ℃, 1H NMR (400 MHz, DMSO) δ 8.63 (d, J=8.5 Hz, 1H), 8.31 (d, J=8.7 Hz, 1H), 8.04 (t, J=8.1 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.74 (t, J=7.1 Hz, 1H), 7.53 (dd, J=9.2, 2.3 Hz, 1H), 4.50 (s, 3H), 4.20 (d, J=6.5 Hz, 2H), 4.16 (d, J=6.1 Hz, 2H), 3.52 (d, J=11.5 Hz, 2H), 3.41 (t, J=12.2 Hz, 2H), 3.15 (s, 3H), 3.10 (s, 3H), 2.73 (t, J=6.6 Hz, 2H), 2.38 (dd, J=18.2, 12.0 Hz, 4H), 2.16 – 2.09 (m, 1H), 1.99 (d, J=12.8 Hz, 2H), 1.84 (t, J=5.7 Hz, 2H), 1.50 (d, J=5.0 Hz, 2H), 1.45 – 1.34 (m, 4H), C 31h 42n 4i 2o 2, ESI-MS m/z:251[M-2I] 2+/ 2.
Figure DEST_PATH_IMAGE072
Compound 10MG
Embodiment 43: the stabilization of the described methyl benzo of this patent furoquinoline derivative to G-tetra-serobila DNA.
Select the compound of embodiment eight～42 preparations, adopt this series compound of FRET (fluorescence resonance energy transfer) (FRET) fusing point the effects can form the rich G sequence F21T(FAM-d[G of G-tetra-serobila DNA to the telomere end 3(T 2aG 3) 3]-TAMRA), the rich G sequence of oncogene c-myc promoter region Pu22(FAM-d[TGAG 3tG 3tAG 3tG 3tA 2]-TAMRA), the stabilizing power of ckit-1 and rich G sequence bcl-2, the Δ Tm value of its stable G-tetra-serobilas is as shown in table 1.Result shows, this patent series compound has stabilizing power preferably to ckit-1, and F21T is had to good stabilizing power, very good to the stabilizing power of Pu22, also good especially to the stabilizing power of bcl-2, wherein 9MD to the Δ Tm of bcl-2 up to 39.4 ℃.
Table 1: the Δ Tm value of this patent series compound to G-tetra-serobila DNA stabilizations.
Figure 75558DEST_PATH_IMAGE073
Embodiment 44: the restraining effect of the described methyl benzo of this patent furoquinoline derivative to Telomerase.
Select the compound of embodiment eight～42 preparations, adopt the TRAP method to carry out the cell-free system telomerase activity.Extract total protein (including Telomerase) from the Human Lung Cancer cell line A549, a certain amount of total protein extracting solution and medicament mixed to be measured are added in the TRAP reaction mixture, after the PCR reaction, utilize fluorescence gel imager or fluorescence microplate reader to be detected.The described compound of this patent, when concentration is 10 μ M/L, has obvious restraining effect to Telomerase in vitro.And experimental result is consistent with other experiment in vitro results before, can be good at illustrating effect characteristics and the structure activity relationship of this compounds.Therefore methyl benzo furoquinoline derivative of the present invention can be used for preparation and take the cancer therapy drug that Telomerase is target spot.
Table 2: this patent series compound when 10 μ M/L to the inhibition activity of Telomerase:
Figure DEST_PATH_IMAGE074
Figure 847205DEST_PATH_IMAGE075

Claims (10)

1. a methyl benzo furoquinoline derivative, is characterized in that, chemical structural formula is as shown in I:
Figure 2013102554816100001DEST_PATH_IMAGE001
（I）
Wherein, n is 1,2,3 or 4;
R 1for-OH ,-NH 2,-NHR 4,-NR 5r 6, nitrogenous C 3-5cycloalkyl, piperidyl, azatropylidene base, morpholinyl, piperazinyl Huo Bi Evil quinoline base or
Figure 290172DEST_PATH_IMAGE002
;
R 2for nitrogen-atoms with the piperidyl of positive charge, nitrogen-atoms with the morpholinyl of positive charge,
Figure 463664DEST_PATH_IMAGE003
,
Figure 474345DEST_PATH_IMAGE004
,
Figure 632182DEST_PATH_IMAGE005
,
Figure 728314DEST_PATH_IMAGE006
or-N +cH 3r 5r 6;
R 3for H, F, Cl, Br, C 1-6alkyl or C 3-6cycloalkyl;
R 4for C 1-6alkyl;
R 5, R 6for C 1-6alkyl;
X is C 1-6alkyl or unsubstituted.
2. methyl benzo furoquinoline derivative according to claim 1, is characterized in that described R 1for-NR 5r 6or
Figure 439918DEST_PATH_IMAGE002
, described R 5and R 6for C 1-3alkyl or connect R simultaneously 5and R 6c 4-5alkyl.
3. methyl benzo furoquinoline derivative according to claim 1, is characterized in that described R 1for
Figure 242789DEST_PATH_IMAGE007
,
Figure 381646DEST_PATH_IMAGE008
,
Figure 965074DEST_PATH_IMAGE002
or
Figure 401741DEST_PATH_IMAGE009
, described R 2for ,
Figure 696773DEST_PATH_IMAGE011
,
Figure 705180DEST_PATH_IMAGE012
or
Figure 758587DEST_PATH_IMAGE006
.
4. methyl benzo furoquinoline derivative according to claim 1, is characterized in that described R 3for H, described X is methyl.
5. the preparation method of a methyl benzo furoquinoline derivative according to claim 1, is characterized in that, comprises the following steps:
Figure 598367DEST_PATH_IMAGE013
first with Mono Chloro Acetic Acid, carry out hydrocarbyl reaction in alkaline environment, then carry out chlorination with sulfur oxychloride again, obtain compound
Figure 265977DEST_PATH_IMAGE014
; By its again with
Figure DEST_PATH_IMAGE015
carry out condensation reaction, obtain compound
Figure 496101DEST_PATH_IMAGE016
; Carry out ring-closure reaction with polyphosphoric acid (PPA) again, obtain compound
Figure DEST_PATH_IMAGE017
; Again it is carried out to chlorination, obtain compound
Figure 353199DEST_PATH_IMAGE018
; Utilize subsequently boron tribromide to slough the methyl on methoxyl group, obtain compound ; Recycling name reaction's (mitsunobu reaction), with
Figure 234436DEST_PATH_IMAGE020
reacted, obtained compound
Figure 885997DEST_PATH_IMAGE021
; Subsequently itself and methyl iodide are carried out to methylation reaction, obtain compound
Figure 868997DEST_PATH_IMAGE022
; Finally ethylene glycol ethyl ether do under the condition of solvent with
Figure 264206DEST_PATH_IMAGE023
reaction, obtain various methyl benzo furoquinoline derivatives, and structural formula is
Figure 20458DEST_PATH_IMAGE024
。
6. the preparation method of methyl benzo furoquinoline derivative according to claim 5, is characterized in that, aromatic nucleus nitrogen-atoms and R in compound 2in nitrogen-atoms utilize methyl iodide to be methylated simultaneously.
7. the preparation method of methyl benzo furoquinoline derivative according to claim 5, is characterized in that, described
Figure 108499DEST_PATH_IMAGE025
with reacting of amine chain, be to carry out under the condition be solvent at ethylene glycol ethyl ether.
8. the preparation method of methyl benzo furoquinoline derivative according to claim 5, is characterized in that, described
Figure 375533DEST_PATH_IMAGE018
in methyl utilize boron tribromide to slough.
9. the preparation method of methyl benzo furoquinoline derivative according to claim 5, is characterized in that described compound with
Figure 915415DEST_PATH_IMAGE020
reaction utilize mitsunobu to be reacted.
10. the application of methyl benzo furoquinoline derivative according to claim 1 in preparing cancer therapy drug.
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