CN103382207B - A kind of methyl benzofuran quinoline and preparation method thereof and the application as antitumor drug - Google Patents

A kind of methyl benzofuran quinoline and preparation method thereof and the application as antitumor drug Download PDF

Info

Publication number
CN103382207B
CN103382207B CN201310255481.6A CN201310255481A CN103382207B CN 103382207 B CN103382207 B CN 103382207B CN 201310255481 A CN201310255481 A CN 201310255481A CN 103382207 B CN103382207 B CN 103382207B
Authority
CN
China
Prior art keywords
compound
methyl
methyl benzofuran
reaction
benzofuran quinoline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201310255481.6A
Other languages
Chinese (zh)
Other versions
CN103382207A (en
Inventor
黄志纾
古练权
杜刚
花闻钊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Yat Sen University
Original Assignee
Sun Yat Sen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Yat Sen University filed Critical Sun Yat Sen University
Priority to CN201310255481.6A priority Critical patent/CN103382207B/en
Publication of CN103382207A publication Critical patent/CN103382207A/en
Application granted granted Critical
Publication of CN103382207B publication Critical patent/CN103382207B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to medicine and chemical field, disclose a kind of methyl benzofuran quinoline and preparation method thereof and the purposes as cancer therapy drug.The present invention discloses the preparation method of methyl benzofuran quinoline and the purposes as cancer therapy drug thereof.Experiment proves, the methyl benzofuran quinoline involved in the present invention expression to the proto-oncogene such as telomeric dna and c-myc DNA has very strong restraining effect, to multiple JEG-3, there is significant restraining effect, and little to normal cytotoxicity, there is wide application space preparing on cancer therapy drug.

Description

A kind of methyl benzofuran quinoline and preparation method thereof and the application as antitumor drug
Technical field
The present invention relates to methyl benzofuran quinoline field, more specifically, relate to a kind of methyl benzofuran quinoline and preparation method thereof and the application as antitumor drug.
Background technology
Cancer is one of principal disease threatening human health and life security.According to statistics, the whole world is about newly-increased cancer patients reaches 4,000,000 people every year.The research and development of cancer therapy drug are the focuses that chemist and medicine scholar pay close attention to always.Finding the cancer therapy drug efficient, highly selective, toxic side effect are little is one of important directions of drug development research.Being that shot design synthesizes cancer therapy drug with DNA, particularly for the special higher structure design and synthesis micromolecular inhibitor of the proto-oncogene DNA such as telomeric dna and c-myc with important physiological significance, is the important method of Development of Novel cancer therapy drug.
With the interactional micromolecular compound of telomeric dna, there are some common constitutional featuress: the plane aromatic ring structure having three or more; Or one positively charged under several physiological conditions side chain.Its mechanism of anticancer action mainly by the interaction with telomeric dna, the telomerase activation of anticancer, thus the copying of anticancer.
Skatole quinolines is the more rare a kind of alkaloid of occurring in nature, there is the structure of four plane aromatic rings, cryptolepine (cryptolepine) is the Typical Representative of this compounds, often exists with the form of quaternary ammonium salt at nature, and 5 N are with a positive charge.This compound was separated from the plant Cryptolepissanguinolenta of West Africa first as far back as nineteen twenty-nine.This compound has the physiologically active widely such as good antibacterial, anti-inflammatory, antiviral, anti-malarial.K.Bonjeam in 1998 etc. have been reported to 5-skatole quinoline to suppress B16 melanoma (biochemistry1998,37,5136-5146) by interference type Ⅱ topoisomerase at biochemistry.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 concentrate on the parent of Fourth Ring, and this research group successively reports the skatole quinoline derivatives (J.Med.Chem.2005 of a series of 11 bit amino side substitution, 48,7315-7321; J.Med.Chem.2008,51,6381-6392) suppress telomerase activation by interacting with telomere G-tetra-serobila DNA, to multiple JEG-3, there is significant restraining effect.
G-tetra-serobila is a kind of four chains dNA spiralstructure is 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-serobila " is also present in the mankind genein group.This four chain DNA spirane structures are found in human cancer cell, because the division of cancer cells is very fast, and on telomere usual existing defects, therefore four chain spirane structures are a kind of exclusive features of cancer cells.If really so talked about, any cancer treatment method for this structure all can not hurt normal healthy cell.The formation of telomeric dna G-tetra-stranded structure can suppress the activity of Telomerase effectively, and thus target telomeric dna G-tetra-serobila the part making it stable 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 has much room for improvement, simultaneously due to the resource-constrained of occurring in nature indoles quinolines, at present, based on the parent nucleus of skatole quinoline, carry out structure of modification, be the important channel 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 benzofuran quinoline.
Another object of the present invention is to provide this methyl benzofuran quinoline preparing the application in 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, be convenient to the methyl benzofuran quinoline 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 being precursor skeleton at methyl benzofuran quinoline introduce two fat amido side chains, obtain and telomeric dna or the interactional methyl benzofuran quinoline of promoter region C-MYCDNA.
Above-mentioned technical purpose of the present invention is achieved through the following technical solutions above-mentioned purpose:
The invention provides a kind of methyl benzofuran quinoline, chemical structural formula is as shown in I:
（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 ;
R 2for nitrogen-atoms with the piperidyl of positive charge, nitrogen-atoms with positive charge morpholinyl,
, , , 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 , , or , described R 2be preferably , , or .
Described R 3be preferably H, described X is preferably methyl.
Reoffer the preparation method of the methyl benzofuran quinoline described in a kind of as above 1 according to demand, comprise the following steps:
first in alkaline environment, carry out hydrocarbyl reaction with Mono Chloro Acetic Acid, then carry out chlorination with sulfur oxychloride again, obtain compound ; By its again with carry out condensation reaction, obtain compound ; Carry out ring-closure reaction with polyphosphoric acid (PPA) again, obtain compound ; Carried out chlorination again, obtained compound ; Utilize boron tribromide to slough methyl on methoxyl group subsequently, obtain compound ; Recycling name reaction (mitsunobu reaction), with react, obtain compound ; Subsequently itself and methyl iodide are carried out methylation reaction, obtain compound ; Last under ethylene glycol ethyl ether makes the condition of solvent with reaction, obtain various methyl benzofuran quinoline, structural formula is
。
Concrete process is as follows
Aromatic nucleus nitrogen-atoms and R in described compound 2in nitrogen-atoms utilize methyl iodide to methylate simultaneously.
Described carry out under ethylene glycol ethyl ether is the condition of solvent with the reaction of amine chain.
Described in methyl utilize boron tribromide to slough.
Described compound with reaction utilize name reaction mitsunobu to react.
Reoffer a kind of methyl benzofuran quinoline as above according to demand and prepare the application in cancer therapy drug.
Involved methyl benzofuran quinoline of the present invention has very strong interaction with the telomeric dna being rich in guanine, shows and has good inhibit activities to the Telomerase in cancer cells.Further experiment proves, methyl benzofuran quinoline 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 protects methyl benzofuran quinoline and preparing the purposes on cancer therapy drug; And the cancer therapy drug containing methyl benzofuran quinoline.
Methyl benzofuran quinoline of the present invention can mix with pharmaceutically acceptable auxiliary, prepares the antitumor drug of various formulation, as tablet, pill, capsule, injection, suspension agent or emulsion etc.
Two substituent methyl cumarone quinolines involved in the present invention are novel G-tetra-serobila smaller ligand of a series of side substitution according to smaller ligand and G-tetra-serobila interactional constructional feature appropriate design.The tetrad plane generation pi-pi accumulation effect of the secondary structure that mechanism of action is mainly formed by smaller ligand and rich guanine sequence, and the electrostatic interaction to a certain degree in the negative electricity region of the positive charge of part parent nucleus and tetrad planar central.And two of part fat amido side chains, can increase smaller ligand and double-stranded DNA in conjunction with time sterically hindered, too increase the groove contact ability to G-tetra-serobila simultaneously, and the positive charge of a side chain also can increase its groove contact ability to G-tetra-serobila further, thus finally reach and improve the selective power of G-tetra-serobila and the object of affinity.
Compared with prior art, the present invention has following beneficial effect:
1. novel methyl benzofuran quinoline of the present invention has very strong interaction with the telomeric dna being rich in guanine, shows the inhibit activities good to the Telomerase in cancer cells, thus has significant restraining effect to multiple JEG-3;
2. novel methyl benzofuran quinoline of the present invention is little to normal cytotoxicity, and in the application preparing cancer therapy drug, security is high;
3. novel methyl benzofuran quinoline of the present invention can make the cancer therapy drug of various formulation, has very high medical value and wide market outlook.
Embodiment
The present invention is further described below in conjunction with specific embodiment.Unless stated otherwise, the present invention adopts reagent, equipment and method are conventional commercial reagent, equipment and the conventional method used of the art.
Embodiment one: the synthesis of compound 8M7
0.3mol Mono Chloro Acetic Acid is dissolved in 60ml water, PH to 9 is adjusted with sodium hydroxide, add 0.2mol MEHQ again, 100 DEG C of backflows, obtain M1, then carry out chlorination adding sulfur oxychloride, obtain M2, boil off sulfur oxychloride solvent and obtain brown liquid, condensation reaction is carried out again with anthranilic acid, obtain M3, then PPA is preheated to 130 DEG C to add M3 and carry out combination reaction, obtain compound M4, M4 and sulfur oxychloride are carried out chlorination 80 DEG C of backflows, obtain compound M5, in methylene dichloride, utilize boron tribromide to slough 7 methyl afterwards, obtain compound M6.
Then, under chloroform (300mL) makes the condition of solvent, 6.0g triphenylphosphine, 2.0gM6,6mL4-hydroxyethyl morpholine, 6mL diisopropyl azodiformate is added, 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 DEG C; 1HNMR (400MHz, CDCl3) δ 8.37 (d, J=8.4Hz, 1H), 8.31 (d, J=8.5Hz, 1H), 7.82 (d, J=1.9Hz, 1H), 7.79 (d, J=8.4Hz, 1H), 7.71 (t, J=6.0Hz, 1H), 7.59 (d, J=9.0Hz, 1H), 7.30 (d, J=2.4Hz, 1H), 4.29 (t, J=5.5Hz, 2H), 3.82 – 3.74 (m, 4H), 2.90 (t, J=5.5Hz, 2H), 2.69 – 2.58 (m, 4H); C 21h 19clN 2o 3, LC-MSm/z:383 [M+H] +.
Compound 8M7
Embodiment two: the synthesis of compound 9M7
Method is with embodiment one, and difference replaces 4-hydroxyethyl morpholine with N-hydroxyethyl piperidine, obtains compound 9M7.
Productive rate: 84%; Fusing point: 178.4-180.1 DEG C; 1HNMR (400MHz, CDCl3) δ 8.36 (dd, J=8.4,0.8Hz, 1H), 8.30 (d, J=8.5Hz, 1H), 7.81 (d, J=2.6Hz, 1H), 7.78 (dd, J=8.4,1.4Hz, 1H), 7.70 (dd, J=11.1,4.1Hz, 1H), 7.58 (d, J=9.0Hz, 1H), 7.28 (dd, J=8.8,2.5Hz, 1H), 4.27 (t, J=5.9Hz, 2H), 2.87 (t, J=5.9Hz, 2H), 2.59 (m, 4H), 1.71 – 1.59 (m, 4H), 1.51 – 1.44 (m, 2H); C 22h 21clN 2o 2, LC-MSm/z:381 [M+H] +.
Compound 9M7
Embodiment three: the synthesis of compound 6M8
Method is with embodiment one, unlike with N, N-dimethylethanolamine replaces 4-hydroxyethyl morpholine, and product is added in single neck bottle of 100mL after crossing post separation by reaction product, after add the tetramethylene sulfone of 15mL and the methyl iodide of 10mL, 68 DEG C of reactions added a large amount of ether after three days, filtered, dry, obtain compound 6M8, Orange red solid.
Productive rate: 92%; Fusing point: 297.2-298.4 DEG C; 1HNMR (400MHz, DMSO) δ 8.83 (d, J=9.0Hz, 1H), 8.59 (d, J=8.4Hz, 1H), 8.32 (t, J=8.0Hz, 1H), 8.27 (d, J=2.1Hz, 1H), 8.20 (d, J=9.2Hz, 1H), 8.12 (t, J=7.8Hz, 1H), 7.81 (dd, J=9.2,2.3Hz, 1H), 4.93 (s, 3H), 4.75 (t, J=3.6Hz, 2H), 3.92 (t, J=3.6Hz, 2H), 3.27 (s, 9H); C 21h 23clI 2n 2o 2, ESI-MSm/z:185 [M-2I] 2+/ 2.
Compound 6M8
Embodiment four: the synthesis of compound 7M8
Method, with embodiment three, replaces N, N-dimethylethanolamine unlike with N, N-dimethyl propanol amine, obtains Orange red solid compound.
Productive rate: 91%; Fusing point: 282.9-285.1; 1HNMR (400MHz, DMSO) δ 8.83 (d, J=8.5Hz, 1H), 8.61 (d, J=7.5Hz, 1H), 8.34 (t, J=7.2Hz, 1H), 8.23 – 8.11 (m, 2H), 7.86 (d, J=10.1Hz, 1H), 7.77 (d, J=8.6Hz, 1H), 4.92 (s, 3H), 4.31 (d, J=30.7Hz, 2H), 3.66 – 3.53 (m, 2H), 3.17 (s, 9H), 2.29 (s, 2H); C 22h 25clI 2n 2o 2, ESI-MSm/z:192 [M-2I] 2+/ 2.
Compound 7M8
Embodiment five: the synthesis of compound 8M8
8M7 is added in single neck bottle of 100mL, after add the tetramethylene sulfone of 15mL and the methyl iodide of 10mL, 68 DEG C reaction three days after add a large amount of ether, filter, obtain compound 8M8, Orange red solid.
Productive rate: 93%; Fusing point: 273.0-275.6 DEG C; 1HNMR (400MHz, DMSO) δ 8.84 (d, J=9.0Hz, 1H), 8.62 (d, J=7.7Hz, 1H), 8.35 (t, J=8.0Hz, 1H), 8.27 (s, 1H), 8.22 (d, J=9.2Hz, 1H), 8.14 (t, J=7.6Hz, 1H), 7.83 (dd, J=9.2,2.4Hz, 1H), 4.94 (s, J=1.1Hz, 3H), 4.79 (t, J=1.8Hz, 2H), 4.08 (t, J=1.8Hz, 2H), 4.02 (t, J=4.4Hz, 4H), 3.71 – 3.57 (m, 4H), 3.34 (s, 3H); C 23h 25clI 2n 2o 3, ESI-MSm/z:206 [M-2I] 2+/ 2.
Compound 8M8
Embodiment six: the synthesis of compound 9M8
Method is with embodiment five, and different replaces 8M7 with 9M7, obtains Orange red solid compound.
Productive rate: 89%; Fusing point: 286.9-288.1 DEG C; 1HNMR (400MHz, DMSO) δ 8.84 (d, J=9.2Hz, 1H), 8.62 (d, J=8.4Hz, 1H), 8.35 (t, J=7.8Hz, 1H), 8.26 (d, J=2.4Hz, 1H), 8.22 (d, J=9.2Hz, 1H), 8.15 (t, J=7.6Hz, 1H), 7.82 (dd, J=9.2,2.5Hz, 1H), 4.94 (s, 3H), 4.75 (t, J=4.0Hz, 2H), 3.94 (t, J=4.4Hz, 2H), 3.57 – 3.45 (m, 4H), 3.22 (s, 3H), 1.93 – 1.87 (m, 4H), 1.66 – 1.53 (m, J=6.2Hz, 2H); C 24h 27clI 2n 2o 2, ESI-MSm/z:205 [M-2I] 2+/ 2.
Compound 9M8
Embodiment seven: the synthesis of compound 10M8
Method, with embodiment three, replaces N, N-dimethylethanolamine unlike with N-methyl 4-piperidine carbinols, obtains Orange red solid compound.
Productive rate: 90%; Fusing point: 273.8-275.9 DEG C; 1HNMR (400MHz, DMSO) δ 8.82 (d, J=8.7Hz, 1H), 8.59 (d, J=8.4Hz, 1H), 8.37 – 8.28 (m, 1H), 8.22 – 8.11 (m, 3H), 7.76 (dd, J=13.4,7.7Hz, 1H), 4.92 (s, 3H), 4.19 (dd, J=32.2,5.6Hz, 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=12.4Hz, 1H); C 24h 27clI 2n 2o 2, ESI-MSm/z:205 [M-2I] 2+/ 2.
Compound 10M8
Embodiment eight: the synthesis of compound 6MA
Get the embodiment three 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, N-dimethyl amine, 120 DEG C of reaction 0.5h, add a large amount of ether, filter after having reacted, drying, obtains compound 6MA, gray solid.
Productive rate: 88%; Fusing point: 245.1-247.2 DEG C; 1HNMR (400MHz, DMSO) δ 8.68 (d, J=8.2Hz, 1H), 8.42 (d, J=8.8Hz, 1H), 8.10 (d, J=9.2Hz, 2H), 7.96 (d, J=9.1Hz, 1H), 7.80 (t, J=7.5Hz, 1H), 7.61 (d, J=9.0Hz, 1H), 4.72 (t, J=2.6Hz, 2H), 4.58 (s, 3H), 4.21 (t, J=5.8Hz, 2H), 3.91 (t, J=4.6Hz, 2H), 3.27 (s, 9H), 2.78 (t, J=6.0Hz, 2H), 2.33 (s, 6H); C 25h 34i 2n 4o 2, ESI-MSm/z:211 [M-2I] 2+/ 2.
Compound 6MA
Embodiment nine: the synthesis of compound 6MB
Method is with embodiment eight, and different replaces N, N-dimethyl amine to react with N, N-dimethyl propylamine, obtains sterling, red brown solid.
Productive rate: 89%; Fusing point: 242.2-244.6 DEG C; 1HNMR (400MHz, MeOD) δ 8.61 (d, J=8.5Hz, 1H), 8.35 (d, J=9.0Hz, 1H), 8.15 – 8.08 (m, 2H), 7.92 (d, J=9.2Hz, 1H), 7.81 (t, J=7.7Hz, 1H), 7.66 (dd, J=0.8Hz, 1H), 4.77 (t, J=2.0Hz, 2H), 4.68 (s, 3H), 4.39 (t, J=6.8Hz, 2H), 4.00 (t, J=4.2Hz, 2H), 3.37 (s, 9H), 3.36 (s, J=2.6Hz, 2H), 2.96 (t, J=6.8Hz, 2H), 2.49 (s, 6H); C 26h 36i 2n 4o 2, ESI-MSm/z:218 [M-2I] 2+/ 2.
Compound 6MB
Embodiment ten: the synthesis of compound 6MC
Method is with embodiment eight, and different replaces N, N-dimethyl amine to react with N, N-diethyl ethanamine, obtains sterling, gray solid.
Productive rate: 89%; Fusing point: 240.2-243.0 DEG C; 1HNMR (400MHz, DMSO) δ 8.65 (d, J=8.3Hz, 1H), 8.41 (d, J=8.9Hz, 1H), 8.15 – 8.05 (m, 2H), 7.94 (d, J=9.2Hz, 1H), 7.82 (t, J=7.8Hz, 1H), 7.61 (dd, J=9.2,2.3Hz, 1H), 4.70 (t, J=4.0Hz, 2H), 4.57 (s, 3H), 4.19 (t, J=6.0Hz, 2H), 3.89 (t, J=3.8Hz, 2H), 3.25 (s, 9H), 2.84 (t, J=6.1Hz, 2H), 2.57 (d, J=6.3Hz, 4H), 0.90 (t, J=6.9Hz, 6H); C 27h 38i 2n 4o 2, ESI-MSm/z:225 [M-2I] 2+/ 2.
Compound 6MC
Embodiment 11: the synthesis of compound 6MD
Method, with embodiment eight, replaces N, N-dimethyl amine to react unlike with N, N-diethyl propylamine, obtains sterling, Orange red solid.
Productive rate: 85%, fusing point: 262.0-263.1 DEG C, 1HNMR (400MHz, DMSO) δ 8.64 (d, J=8.1Hz, 1H), 8.40 (d, J=8.7Hz, 1H), 8.09 (t, J=7.4Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=9.1Hz, 1H), 7.81 (t, J=6.4Hz, 1H), 7.57 (d, J=9.0Hz, 1H), 4.56 (s, 3H), 4.30 (t, J=2.6Hz, 2H), 4.18 (t, J=4.2Hz, 2H), 3.61 (t, J=7.3Hz, 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-MSm/z:232 [M-2I] 2+/ 2.
Compound 6MD
Embodiment 12: the synthesis of compound 6ME
Method, with embodiment eight, replaces N, N-dimethyl amine to react unlike with N-aminoethyl morpholine, obtains sterling, brown solid.
Productive rate: 90%; Fusing point: 261.3-262.9 DEG C; 1HNMR (400MHz, DMSO) δ 8.68 (d, J=8.4Hz, 1H), 8.44 (d, J=9.0Hz, 1H), 8.15 – 8.08 (m, 2H), 7.98 (d, J=9.2Hz, 1H), 7.82 (t, J=4.0Hz, 1H), 7.61 (dd, J=9.1,1.9Hz, 1H), 4.72 (t, J=2.2Hz, 2H), 4.60 (s, 3H), 4.22 (t, J=5.8Hz, 2H), 3.91 (t, J=1.8Hz, 2H), 3.50 (t, J=2.0Hz, 4H), 3.27 (s, 9H), 2.78 (t, J=6.3Hz, 2H), 2.60 – 2.51 (m, 4H); C 27h 36n 4i 2o 3, ESI-MSm/z:232 [M-2I] 2+/ 2.
Compound 6ME
Embodiment 13: the synthesis of compound 6MF
Method, with embodiment eight, replaces N, N-dimethyl amine to react unlike with N-aminopropyl morpholine, obtains sterling, yellow solid.
Productive rate: 88%; Fusing point: 249.9-250.7 DEG C; 1HNMR (400MHz, DMSO) δ 8.69 (d, J=8.4Hz, 1H), 8.43 (d, J=8.8Hz, 1H), 8.15 – 8.07 (m, 2H), 7.98 (d, J=9.2Hz, 1H), 7.82 (t, J=7.6Hz, 1H), 7.63 (d, J=8.2Hz, 1H), 4.71 (t, J=1.6Hz, 2H), 4.58 (s, 3H), 4.19 (t, J=6.4Hz, 2H), 3.90 (t, J=2.0Hz, 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-MSm/z:239 [M-2I] 2+/ 2.
Compound 6MF
Embodiment 14: the synthesis of compound 6MG
Method, with embodiment eight, replaces N, N-dimethyl amine to react unlike with N-aminopropyl morpholine, obtains sterling, gray solid.
Productive rate: 85%; Fusing point: 259.0-259.9 DEG C; 1HNMR (400MHz, DMSO) δ 8.65 (d, J=6.6Hz, 1H), 8.41 (d, J=6.4Hz, 1H), 8.09 (d, J=6.4Hz, 1H), 8.00 (d, J=4.8Hz, 1H), 7.89 (t, J=8.3Hz, 1H), 7.80 (d, J=6.7Hz, 1H), 7.58 (t, J=5.8Hz, 1H), 4.69 (t, J=6.3Hz, 2H), 4.56 (s, 3H), 4.18 (t, J=6.0Hz, 2H), 3.59 (t, J=8.3Hz, 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-MSm/z:231 [M-2I] 2+/ 2.
Compound 6MG
Embodiment 15: the synthesis of compound 7MA
Get the embodiment four 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, N-dimethyl amine, 120 DEG C of reaction 0.5h, add a large amount of ether, filter after having reacted, drying, obtains compound 7MA, yellow solid.
Productive rate: 90%; Fusing point: 261.2-263.0 DEG C; 1HNMR (400MHz, DMSO) δ 8.68 (d, J=7.5Hz, 1H), 8.42 (d, J=7.6Hz, 1H), 8.11 (t, J=9.8Hz, 1H), 8.02 (s, 1H), 7.95 (d, J=7.2Hz, 1H), 7.83 (t, J=11.3Hz, 1H), 7.58 (d, J=7.8Hz, 1H), 4.58 (s, 3H), 4.31 (t, J=2.2Hz, 2H), 4.23 (t, J=2.8Hz, 2H), 3.60 (t, J=4.2Hz, 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-MSm/z:218 [M-2I] 2+/ 2.
Compound 7MA
Embodiment 16: the synthesis of compound 7MB
Method is with embodiment 15, and different replaces N, N-dimethyl amine to react with N, N-dimethyl propylamine, obtains sterling, red brown solid.
Productive rate: 90%, fusing point: 246.8-247.9 DEG C, 1HNMR (400MHz, DMSO) δ 8.57 (d, J=8.4Hz, 1H), 8.39 (d, J=8.9Hz, 1H), 8.08 (t, J=7.6Hz, 1H), 7.98 (d, J=1.9Hz, 1H), 7.94 (d, J=9.2Hz, 1H), 7.80 (t, J=8.4Hz, 1H), 7.56 (dd, J=9.2, 2.1Hz, 1H), 4.54 (s, 3H), 4.29 (t, J=5.6Hz, 2H), 4.14 (t, J=6.9Hz, 2H), 3.64 – 3.57 (m, 2H), 3.17 (s, 9H), 2.64 (t, J=4.9Hz, 2H), 2.34 (s, 6H), 2.30 – 2.24 (m, 2H), 2.01 (t, J=6.9Hz, 2H), C 27h 38i 2n 4o 2, ESI-MSm/z:225 [M-2I] 2+/ 2.
Compound 7MB
Embodiment 17: the synthesis of compound 7MC
Method is with embodiment 15, and different replaces N, N-dimethyl amine to react with N, N-diethyl ethanamine, obtains sterling, gray solid.
Productive rate: 85%, fusing point: 223.8-225.9 DEG C, 1HNMR (400MHz, DMSO) δ 8.65 (d, J=7.8Hz, 1H), 8.41 (d, J=8.3Hz, 1H), 8.11 (t, J=6.6Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.8Hz, 1H), 7.82 (t, J=6.8Hz, 1H), 7.57 (d, J=9.0Hz, 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-MSm/z:232 [M-2I] 2+/ 2.
Compound 7MC
Embodiment 18: the synthesis of compound 7MD
Method, with embodiment 15, replaces N, N-dimethyl amine to react unlike with N, N-diethyl propylamine, obtains sterling, red brown solid.
Productive rate: 88%, fusing point: 243.1-245.5 DEG C, 1HNMR (400MHz, DMSO) δ 8.56 (d, J=7.8Hz, 1H), 8.37 (d, J=8.7Hz, 1H), 8.06 (t, J=7.7Hz, 1H), 7.96 (s, 1H), 7.89 (d, J=9.0Hz, 1H), 7.79 (t, J=7.0Hz, 1H), 7.55 (d, J=8.6Hz, 1H), 4.53 (s, 3H), 4.30 (t, J=2.6Hz, 2H), 4.15 (t, J=5.9Hz, 2H), 3.62 (t, J=5.8Hz, 2H), 3.20 (s, 9H), 2.67 (t, J=4.2Hz, 2H), 2.61 – 2.54 (m, 4H), 2.29 (t, J=4.8Hz, 2H), 1.95 (t, J=5.6Hz, 2H), 1.04 – 0.89 (m, 6H), C 29h 42n 4i 2o 2, ESI-MSm/z:239 [M-2I] 2+/ 2.
Compound 7MD
Embodiment 19: the synthesis of compound 7ME
Method, with embodiment 15, replaces N, N-dimethyl amine to react unlike with N-aminoethyl morpholine, obtains sterling, khaki color solid.
Productive rate: 90%, fusing point: 244.1-246.9 DEG C, 1HNMR (400MHz, MeOD) δ 8.58 (d, J=8.5Hz, 1H), 8.33 (d, J=8.9Hz, 1H), 8.13 (t, J=8.2Hz, 1H), 8.01 (d, J=2.3Hz, 1H), 7.85 (d, J=9.2Hz, 1H), 7.80 (t, J=7.6Hz, 1H), 7.60 (dd, J=9.2, 2.3Hz, 1H), 4.66 (s, 3H), 4.41 – 4.37 (m, 2H), 3.81 (d, J=8.3Hz, 2H), 3.78 – 3.74 (m, 2H), 3.72 (dd, J=8.4, 3.9Hz, 4H), 3.31 (s, 9H), 2.96 (t, J=6.5Hz, 2H), 2.71 (t, J=8.6Hz, 4H), 2.51 – 2.41 (m, 2H), C 28h 38n 4i 2o 3, ESI-MSm/z:239 [M-2I] 2+/ 2.
Compound 7ME
Embodiment 20: the synthesis of compound 7MF
Method, with embodiment 15, replaces N, N-dimethyl amine to react unlike with N-aminopropyl morpholine, obtains sterling, yellow solid.
Productive rate: 88%, fusing point: 250.9-253.2 DEG C, 1HNMR (400MHz, MeOD) δ 8.56 (d, J=8.0Hz, 1H), 8.31 (d, J=8.6Hz, 1H), 8.11 (t, J=8.0Hz, 1H), 8.00 (s, 1H), 7.87 – 7.76 (m, 2H), 7.59 (d, J=9.2Hz, 1H), 4.65 (s, 3H), 4.38 (d, J=5.7Hz, 2H), 3.76 (t, J=6.4Hz, 2H), 3.74 – 3.68 (m, 4H), 3.63 (t, J=7.0Hz, 2H), 3.33 (s, 9H), 2.96 (t, J=2.2Hz, 2H), 2.77 – 2.69 (m, 4H), 2.50 – 2.39 (m, 2H), 1.20 (t, J=6.8Hz, 2H), C 29h 40n 4i 2o 3, ESI-MSm/z:246 [M-2I] 2+/ 2.
Compound 7MF
Embodiment 21: the synthesis of compound 7MG
Method with embodiment 15, unlike using N-(2-aminoethyl) piperidines replaces N, N-dimethyl amine to react, and obtains sterling, gray solid.
Productive rate: 85%; Fusing point: 246.3-248.4 DEG C; 1HNMR (400MHz, DMSO) δ 8.69 (d, J=8.2Hz, 1H), 8.43 (d, J=8.7Hz, 1H), 8.12 (t, J=8.0Hz, 1H), 8.02 (s, 1H), 7.95 (d, J=8.7Hz, 1H), 7.83 (t, J=6.9Hz, 1H), 7.58 (d, J=8.9Hz, 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=5.8Hz, 2H), 1.60 – 1.36 (m, 6H); C 28h 40n 4i 2o 2, ESI-MSm/z:238 [M-2I] 2+/ 2.
Compound 7MG
Embodiment 22: the synthesis of compound 8MA
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, N-dimethyl amine, 120 DEG C of reaction 0.5h, add a large amount of ether, filter after having reacted, drying, obtains compound 8MA, gray solid.
Productive rate: 85%, fusing point: 263.5-265.7 DEG C, 1HNMR (400MHz, DMSO) δ 8.60 (d, J=8.3Hz, 1H), 8.43 (d, J=8.9Hz, 1H), 8.13 – 8.06 (m, 2H), 7.99 (d, J=9.2Hz, 1H), 7.83 (t, J=7.7Hz, 1H), 7.62 (dd, J=9.1, 2.3Hz, 1H), 4.75 (t, J=6.2Hz, 2H), 4.58 (s, 3H), 4.18 (t, J=6.6Hz, 2H), 4.06 (d, J=3.4Hz, 2H), 4.05 – 3.99 (m, 4H), 3.64 (dd, J=12.3, 6.6Hz, 4H), 3.36 (s, 3H), 2.23 (s, 6H), 1.98 (t, J=6.7Hz, 2H), C 27h 36n 4i 2o 3, ESI-MSm/z:232 [M-2I] 2+/ 2.
Compound 8MA
Embodiment 23: the synthesis of compound 8MB
Method is with embodiment 22, and different replaces N, N-dimethyl amine to react with N, N-dimethyl propylamine, obtains sterling, yellow solid.
Productive rate: 89%, fusing point: 243.0-245.0 DEG C, 1HNMR (400MHz, DMSO) δ 8.58 (d, J=8.4Hz, 1H), 8.41 (d, J=8.9Hz, 1H), 8.08 (dd, J=13.9, 5.0Hz, 2H), 7.97 (d, J=9.2Hz, 1H), 7.82 (d, J=7.7Hz, 1H), 7.61 (dd, J=9.2, 2.4Hz, 1H), 4.73 (t, J=2.5Hz, 2H), 4.56 (s, 3H), 4.16 (t, J=7.0Hz, 2H), 4.05 (t, J=2.1Hz, 2H), 4.04 – 3.98 (m, 4H), 3.63 (ddd, J=21.9, 13.0, 4.8Hz, 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-MSm/z:239 [M-2I] 2+/ 2.
Compound 8MB
Embodiment 24: the synthesis of compound 8MC
Method is with embodiment 22, and different replaces N, N-dimethyl amine to react with N, N-diethyl ethanamine, obtains sterling, field gray solid.
Productive rate: 85%, fusing point: 259.8-262.7 DEG C, 1HNMR (400MHz, DMSO) δ 8.65 (d, J=8.4Hz, 1H), 8.39 (d, J=8.8Hz, 1H), 8.11 – 8.03 (m, 2H), 7.94 (d, J=9.2Hz, 1H), 7.78 (t, J=8.2Hz, 1H), 7.60 (d, J=6.9Hz, 1H), 4.73 (t, J=5.2Hz, 2H), 4.56 (s, 3H), 4.18 (t, J=6.5Hz, 2H), 4.08 – 3.98 (m, 6H), 3.68 – 3.56 (m, 4H), 3.35 (s, 3H), 2.83 (t, J=6.6Hz, 2H), 2.57 (dd, J=14.0, 7.0Hz, 4H), 0.90 (t, J=7.0Hz, 6H), C 29h 40i 2n 4o 3, ESI-MSm/z:246 [M-2I] 2+/ 2.
Compound 8MC
Embodiment 25: the synthesis of compound 8MD
Method, with embodiment 22, replaces N, N-dimethyl amine to react unlike with N, N-diethyl propylamine, obtains sterling, brown solid.
Productive rate: 89%, fusing point: 239.4-241.6 DEG C, 1HNMR (400MHz, DMSO) δ 8.60 (d, J=8.2Hz, 1H), 8.42 (d, J=8.8Hz, 1H), 8.14 – 8.06 (m, 2H), 7.96 (d, J=9.3Hz, 1H), 7.81 (t, J=7.3Hz, 1H), 7.62 (d, J=9.1Hz, 1H), 4.75 (t, J=3.2Hz, 2H), 4.57 (s, 3H), 4.19 (t, J=5.9Hz, 2H), 4.08 (t, J=2.8Hz, 2H), 4.06 – 4.01 (m, 4H), 3.74 – 3.57 (m, 4H), 3.38 (s, 3H), 2.67 (t, J=2.9Hz, 2H), 2.61 – 2.53 (m, 4H), 1.96 (t, J=4.4Hz, 2H), 0.98 (t, J=6.5Hz, 6H), C 30h 42n 4i 2o 3, ESI-MSm/z:253 [M-2I] 2+/ 2.
Compound 8MD
Embodiment 26: the synthesis of compound 8ME
Method, with embodiment 22, replaces N, N-dimethyl amine to react unlike with N-aminoethyl morpholine, obtains sterling, khaki color solid.
Productive rate: 89%, fusing point: 245.9-248.7 DEG C, 1HNMR (400MHz, DMSO) δ 8.68 (d, J=8.5Hz, 1H), 8.46 (d, J=9.0Hz, 1H), 8.18 – 8.07 (m, 2H), 8.00 (d, J=9.2Hz, 1H), 7.85 (t, J=7.7Hz, 1H), 7.63 (dd, J=9.2, 2.0Hz, 1H), 4.75 (t, J=1.8Hz, 2H), 4.60 (s, 3H), 4.25 (t, J=2.6Hz, 2H), 4.07 (t, J=3.2Hz, 2H), 4.02 (t, J=4.2Hz, 4H), 3.68 – 3.61 (m, 4H), 3.52 (t, J=2.0Hz, 4H), 3.37 (s, 3H), 2.87 – 2.76 (m, 2H), 2.65 – 2.53 (m, 4H), C 29h 38n 4i 2o 4, ESI-MSm/z:253 [M-2I] 2+/ 2.
Compound 8ME
Embodiment 27: the synthesis of compound 8MF
Method, with embodiment 22, replaces N, N-dimethyl amine to react unlike with N-aminopropyl morpholine, obtains sterling, Orange red solid.
Productive rate: 84%, fusing point: 251.2-253.5 DEG C, 1HNMR (400MHz, DMSO) δ 8.64 (d, J=8.2Hz, 1H), 8.30 (d, J=8.6Hz, 1H), 8.05 – 7.98 (m, 2H), 7.91 (d, J=9.2Hz, 1H), 7.71 (t, J=7.3Hz, 1H), 7.56 (d, J=9.0Hz, 1H), 4.74 (t, J=6.3Hz, 2H), 4.49 (s, 3H), 4.15 (t, J=6.3Hz, 2H), 4.08 (t, J=3.4Hz, 2H), 4.06 – 4.00 (m, 4H), 3.65 (dd, J=24.6, 12.4Hz, 4H), 3.51 – 3.46 (m, 4H), 3.38 (s, 3H), 2.47 (d, J=3.4Hz, 2H), 2.40 – 2.29 (m, 4H), 1.99 – 1.93 (m, 2H), C 30h 40n 4i 2o 4, ESI-MSm/z:260 [M-2I] 2+/ 2.
Compound 8MF
Embodiment 28: the synthesis of compound 8MG
Method with embodiment 22, unlike using N-(2-aminoethyl) piperidines replaces N, N-dimethyl amine to react, and obtains sterling, gray solid.
Productive rate: 85%, fusing point: 257.4-259.1 DEG C, 1HNMR (400MHz, DMSO) δ 8.67 (d, J=8.4Hz, 1H), 8.44 (d, J=8.8Hz, 1H), 8.16 – 8.07 (m, 2H), 7.96 (d, J=9.1Hz, 1H), 7.83 (t, J=7.3Hz, 1H), 7.62 (d, J=9.2Hz, 1H), 4.76 (t, J=6.1Hz, 2H), 4.59 (s, 3H), 4.22 (t, J=5.7Hz, 2H), 4.08 (t, J=7.3Hz, 2H), 4.07 – 3.96 (m, 4H), 3.70 – 3.60 (m, 4H), 3.38 (s, 3H), 2.76 (t, J=5.2Hz, 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-MSm/z:252 [M-2I] 2+/ 2.
Compound 8MG
Embodiment 29: the synthesis of compound 9MA
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, N-dimethyl amine, 120 DEG C of reaction 0.5h, add a large amount of ether, filter after having reacted, drying, obtains compound 9MA, gray solid.
Productive rate: 87%, fusing point: 235.9-238.0 DEG C, 1HNMR (400MHz, DMSO) δ 8.68 (d, J=8.2Hz, 1H), 8.38 (d, J=8.5Hz, 1H), 8.13 – 8.04 (m, 2H), 7.96 (d, J=9.2Hz, 1H), 7.79 (t, J=6.9Hz, 1H), 7.59 (d, J=9.0Hz, 1H), 4.72 (t, J=3.2Hz, 2H), 4.55 (s, 3H), 4.21 (t, J=6.0Hz, 2H), 3.93 (t, J=3.9Hz, 2H), 3.60 – 3.48 (m, 4H), 3.23 (s, 3H), 2.73 (t, J=6.0Hz, 2H), 2.29 (s, 6H), 1.95 – 1.83 (m, 4H), 1.65 – 1.54 (m, 2H), C 28h 38n 4i 2o 2, ESI-MSm/z:231 [M-2I] 2+/ 2.
Compound 9MA
Embodiment 30: the synthesis of compound 9MB
Method is with embodiment 29, and different replaces N, N-dimethyl amine to react with N, N-dimethyl propylamine, obtains sterling, red brown solid.
Productive rate: 89%, fusing point: 233.8-236.2 DEG C, 1HNMR (400MHz, DMSO) δ 8.59 (d, J=8.6Hz, 1H), 8.42 (d, J=8.5Hz, 1H), 8.14 – 8.05 (m, 2H), 7.98 (d, J=9.4Hz, 1H), 7.83 (t, J=7.4Hz, 1H), 7.60 (d, J=8.7Hz, 1H), 4.70 (t, J=3.2Hz, 2H), 4.57 (s, 3H), 4.18 (t, J=4.7Hz, 2H), 3.91 (t, J=2.9Hz, 2H), 3.55 – 3.47 (m, 4H), 3.21 (s, 3H), 2.34 (t, J=1.9Hz, 2H), 2.22 (s, 6H), 1.97 (t, J=2.1Hz, 2H), 1.93 – 1.85 (m, 4H), 1.60 (t, J=2.5Hz, 2H), C 29h 40i 2n 4o 2, ESI-MSm/z:238 [M-2I] 2+/ 2.
Compound 9MB
Embodiment 31: the synthesis of compound 9MC
Method is with embodiment 29, and different replaces N, N-dimethyl amine to react with N, N-diethyl ethanamine, obtains sterling, gray solid.
Productive rate: 88%, fusing point: 242.7-244.1 DEG C, 1HNMR (400MHz, DMSO) δ 8.65 (d, J=7.9Hz, 1H), 8.36 (d, J=8.8Hz, 1H), 8.12 – 8.03 (m, 2H), 7.92 (d, J=9.1Hz, 1H), 7.77 (t, J=6.3Hz, 1H), 7.58 (d, J=9.1Hz, 1H), 4.71 (t, J=3.2Hz, 2H), 4.54 (s, 3H), 4.18 (t, J=4.7Hz, 2H), 3.93 (t, J=3.5Hz, 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-MSm/z:245 [M-2I] 2+/ 2.
Compound 9MC
Embodiment 32: the synthesis of compound 9MD
Method, with embodiment 29, replaces N, N-dimethyl amine to react unlike with N, N-diethyl propylamine, obtains sterling, khaki color solid.
Productive rate: 89%, fusing point: 234.3-236.1 DEG C, 1HNMR (400MHz, DMSO) δ 8.60 (d, J=8.2Hz, 1H), 8.42 (d, J=8.8Hz, 1H), 8.14 – 8.06 (m, 2H), 7.96 (d, J=9.3Hz, 1H), 7.81 (t, J=7.3Hz, 1H), 7.62 (d, J=9.1Hz, 1H), 4.75 (t, J=3.2Hz, 2H), 4.57 (s, 3H), 4.19 (t, J=5.9Hz, 2H), 4.08 (t, J=2.8Hz, 2H), 4.06 – 4.01 (m, 4H), 3.74 – 3.57 (m, 4H), 3.38 (s, 3H), 2.67 (t, J=2.9Hz, 2H), 2.61 – 2.53 (m, 4H), 1.96 (t, J=4.4Hz, 2H), 0.98 (t, J=6.5Hz, 6H), C 31h 44n 4i 2o 2, ESI-MSm/z:252 [M-2I] 2+/ 2.
Compound 9MD
Embodiment 33: the synthesis of compound 9ME
Method, with embodiment 29, replaces N, N-dimethyl amine to react unlike with N-aminoethyl morpholine, obtains sterling, brown solid.
Productive rate: 89%, fusing point: 195.7-199.3 DEG C, 1HNMR (400MHz, DMSO) δ 8.63 (d, J=7.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.06 – 7.97 (m, 2H), 7.92 (d, J=8.8Hz, 1H), 7.69 (t, J=8.4Hz, 1H), 7.53 (d, J=7.9Hz, 1H), 4.71 (t, J=1.2Hz, 2H), 4.48 (s, 3H), 4.20 (t, J=4.5Hz, 2H), 3.93 (t, J=4.4Hz, 2H), 3.63 – 3.43 (m, 8H), 3.23 (s, 3H), 2.75 (t, J=3.5Hz, 2H), 2.39 (d, J=24.6Hz, 4H), 1.96 – 1.82 (m, 4H), 1.60 (t, J=4.5Hz, 2H), C 30h 40n 4i 2o 3, ESI-MSm/z:252 [M-2I] 2+/ 2.
Compound 9ME
Embodiment 34: the synthesis of compound 9MF
Method, with embodiment 29, replaces N, N-dimethyl amine to react unlike with N-aminopropyl morpholine, obtains sterling, yellow solid.
Productive rate: 84%, fusing point: 226.8-228.4 DEG C, 1HNMR (400MHz, MeOD) δ 8.51 (d, J=8.2Hz, 1H), 7.98 – 7.91 (m, 2H), 7.88 (t, J=7.2Hz, 1H), 7.73 (d, J=9.1Hz, 1H), 7.53 (t, J=7.4Hz, 1H), 7.47 (d, J=9.1Hz, 1H), 4.75 (t, J=5.4Hz, 2H), 4.39 (s, 3H), 4.21 (t, J=6.9Hz, 2H), 4.03 (t, J=5.4Hz, 2H), 3.75 – 3.68 (m, 4H), 3.69 – 3.56 (m, 4H), 3.35 (s, 3H), 2.65 (t, J=7.0Hz, 2H), 2.54 (t, J=5.3Hz, 4H), 2.17 – 1.98 (m, 6H), 1.81 (dd, J=12.0, 6.0Hz, 2H), C 31h 42n 4i 2o 3, ESI-MSm/z:259 [M-2I] 2+/ 2.
Compound 9MF
Embodiment 35: the synthesis of compound 9MG
Method with embodiment 29, unlike using N-(2-aminoethyl) piperidines replaces N, N-dimethyl amine to react, and obtains sterling, khaki color solid.
Productive rate: 85%, fusing point: 238.4-241.0 DEG C, 1HNMR (400MHz, MeOD) δ 8.58 (d, J=8.4Hz, 1H), 8.34 (d, J=8.9Hz, 1H), 8.17 – 8.10 (m, 2H), 7.89 (d, J=9.5Hz, 1H), 7.82 (t, J=7.5Hz, 1H), 7.65 (d, J=8.9Hz, 1H), 4.71 (t, J=7.2Hz, 2H), 4.39 (s, 3H), 4.06 (t, J=6.6Hz, 2H), 3.81 – 3.56 (m, 6H), 3.37 (s, 3H), 2.92 (t, J=5.5Hz, 2H), 2.75 – 2.61 (m, 4H), 2.14 – 2.02 (m, 4H), 1.82 (t, J=5.0Hz, 2H), 1.72 – 1.61 (m, 4H), 1.59 – 1.49 (m, 2H), C 31h 42n 4i 2o 2, ESI-MSm/z:251 [M-2I] 2+/ 2.
Compound 9MG
Embodiment 36: the synthesis of compound 10MA
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, N-dimethyl amine, 120 DEG C of reaction 0.5h, add a large amount of ether, filter after having reacted, drying, obtains compound 10MA, khaki color solid.
Productive rate: 89%, fusing point: 259.3-261.0 DEG C, 1HNMR (400MHz, MeOD) δ 8.57 (d, J=8.4Hz, 1H), 8.30 (d, J=8.8Hz, 1H), 8.09 (t, J=8.0Hz, 1H), 7.94 (d, J=2.3Hz, 1H), 7.83 (d, J=9.3Hz, 1H), 7.78 (t, J=7.6Hz, 1H), 7.55 (dd, J=9.3, 2.3Hz, 1H), 4.64 (s, 3H), 4.37 (t, J=6.7Hz, 2H), 4.24 (d, J=6.2Hz, 2H), 3.64 (d, J=12.5Hz, 2H), 3.52 (t, J=12.8Hz, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2.97 (t, J=6.6Hz, 2H), 2.50 (s, 6H), 2.32 (s, 1H), 2.16 (d, J=12.7Hz, 2H), 2.06 (t, J=12.4Hz, 2H)., C 28h 38n 4i 2o 2, ESI-MSm/z:231 [M-2I] 2+/ 2.
Compound 10MA
Embodiment 37: the synthesis of compound 10MB
Method is with embodiment 36, and different replaces N, N-dimethyl amine to react with N, N-dimethyl propylamine, obtains sterling, khaki color solid.
Productive rate: 86%, fusing point: 258.9-260.8 DEG C, 1HNMR (400MHz, MeOD) δ 8.44 (d, J=7.9Hz, 1H), 8.29 (d, J=8.3Hz, 1H), 8.09 (t, J=8.2Hz, 1H), 7.95 (s, 1H), 7.82 (d, J=9.5Hz, 1H), 7.79 (t, J=7.1Hz, 1H), 7.56 (d, J=9.0Hz, 1H), 4.63 (s, 3H), 4.27 (t, J=6.6Hz, 2H), 4.24 (d, J=5.2Hz, 2H), 3.63 (d, J=11.1Hz, 2H), 3.53 (t, J=10.3Hz, 2H), 3.25 (s, 3H), 3.22 (s, 3H), 2.65 (t, J=6.4Hz, 2H), 2.36 (s, 6H), 2.27 (s, 1H), 2.20 – 2.01 (m, 6H), C 29h 40i 2n 4o 2, ESI-MSm/z:238 [M-2I] 2+/ 2.
Compound 10MB
Embodiment 38: the synthesis of compound 10MC
Method is with embodiment 36, and different replaces N, N-dimethyl amine to react with N, N-diethyl ethanamine, obtains sterling, gray solid.
Productive rate: 84%, fusing point: 267.3-268.9 DEG C, 1HNMR (400MHz, MeOD) δ 8.53 (d, J=8.5Hz, 1H), 8.32 (d, J=8.9Hz, 1H), 8.10 (t, J=8.7Hz, 1H), 7.97 (d, J=2.4Hz, 1H), 7.80 (dd, J=17.5, 8.8Hz, 2H), 7.58 (dd, J=9.2, 2.5Hz, 1H), 4.65 (s, 3H), 4.32 (t, J=7.2Hz, 2H), 4.24 (d, J=6.2Hz, 2H), 3.63 (d, J=12.6Hz, 2H), 3.56 – 3.48 (m, 2H), 3.25 (s, 3H), 3.22 (s, 3H), 2.99 (t, J=7.2Hz, 2H), 2.74 (dd, J=14.3, 7.1Hz, 4H), 2.32 (s, 1H), 2.16 (d, J=14.2Hz, 2H), 2.10 – 2.01 (m, 2H), 1.10 (t, J=7.1Hz, 6H), C 30h 42i 2n 4o 2, ESI-MSm/z:245 [M-2I] 2+/ 2.
Compound 10MC
Embodiment 39: the synthesis of compound 10MD
Method, with embodiment 36, replaces N, N-dimethyl amine to react unlike with N, N-diethyl propylamine, obtains sterling, brown solid.
Productive rate: 87%, fusing point: 251.7-253.4 DEG C, 1HNMR (400MHz, MeOD) δ 8.39 (d, J=8.6Hz, 1H), 8.16 (d, J=8.8Hz, 1H), 7.96 (t, J=7.2Hz, 1H), 7.81 (d, J=2.4Hz, 1H), 7.70 (d, J=9.2Hz, 1H), 7.66 (t, J=7.9Hz, 1H), 7.43 (dd, J=9.2, 2.5Hz, 1H), 4.50 (s, 3H), 4.18 (t, J=6.9Hz, 2H), 4.12 (d, J=6.2Hz, 2H), 3.53 (d, J=12.6Hz, 2H), 3.41 (t, J=8.2Hz, 2H), 3.15 (s, 3H), 3.12 (s, 3H), 2.79 (t, J=5.6Hz, 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=11.8Hz, 2H), 1.04 (t, J=7.2Hz, 6H), C 31h 44n 4i 2o 2, ESI-MSm/z:252 [M-2I] 2+/ 2.
Compound 10MD
Embodiment 40: the synthesis of compound 10ME
Method, with embodiment 36, replaces N, N-dimethyl amine to react unlike with N-aminoethyl morpholine, obtains sterling, khaki color solid.
Productive rate: 88%, fusing point: 248.7-250.4 DEG C, 1HNMR (400MHz, MeOD) δ 8.54 (d, J=8.4Hz, 1H), 8.31 (d, J=8.8Hz, 1H), 8.09 (t, J=7.6Hz, 1H), 7.96 (d, J=2.4Hz, 1H), 7.85 – 7.76 (m, 2H), 7.56 (dd, J=9.3, 2.4Hz, 1H), 4.65 (s, 3H), 4.36 (t, J=6.7Hz, 2H), 4.24 (d, J=6.2Hz, 2H), 3.74 – 3.67 (m, 4H), 3.62 (d, J=6.1Hz, 2H), 3.52 (dd, J=12.4, 9.4Hz, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2.91 (t, J=6.6Hz, 2H), 2.64 (dd, J=16.9, 3.0Hz, 4H), 2.51 (d, J=4.5Hz, 1H), 2.16 (d, J=15.5Hz, 2H), 2.05 (dd, J=25.2, 13.3Hz, 2H), C 30h 40n 4i 2o 3, ESI-MSm/z:252 [M-2I] 2+/ 2.
Compound 10ME
Embodiment 41: the synthesis of compound 10MF
Method, with embodiment 36, replaces N, N-dimethyl amine to react unlike with N-aminopropyl morpholine, obtains sterling, gray solid.
Productive rate: 88%, fusing point: 270.5-273.2 DEG C, 1HNMR (400MHz, MeOD) δ 8.56 (d, J=8.4Hz, 1H), 8.31 (d, J=8.9Hz, 1H), 8.10 (t, J=9.0Hz, 1H), 7.97 (s, 1H), 7.83 (d, J=9.2Hz, 1H), 7.79 (t, J=8.3Hz, 1H), 7.57 (d, J=9.3Hz, 1H), 4.65 (s, 3H), 4.30 (t, J=6.7Hz, 2H), 4.25 (d, J=6.0Hz, 2H), 3.72 – 3.62 (m, 6H), 3.52 (t, J=8.7Hz, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2.65 (t, J=6.8Hz, 2H), 2.55 – 2.49 (m, 4H), 2.42 (s, 1H), 2.19 – 2.10 (m, 4H), 2.04 (d, J=11.9Hz, 2H), C 31h 42n 4i 2o 3, ESI-MSm/z:259 [M-2I] 2+/ 2.
Compound 10MF
Embodiment 42: the synthesis of compound 10MG
Method with embodiment 36, unlike using N-(2-aminoethyl) piperidines replaces N, N-dimethyl amine to react, and obtains sterling, gray solid.
Productive rate: 86%, fusing point: 259.4-262.1 DEG C, 1HNMR (400MHz, DMSO) δ 8.63 (d, J=8.5Hz, 1H), 8.31 (d, J=8.7Hz, 1H), 8.04 (t, J=8.1Hz, 1H), 7.96 (s, 1H), 7.88 (d, J=9.2Hz, 1H), 7.74 (t, J=7.1Hz, 1H), 7.53 (dd, J=9.2, 2.3Hz, 1H), 4.50 (s, 3H), 4.20 (d, J=6.5Hz, 2H), 4.16 (d, J=6.1Hz, 2H), 3.52 (d, J=11.5Hz, 2H), 3.41 (t, J=12.2Hz, 2H), 3.15 (s, 3H), 3.10 (s, 3H), 2.73 (t, J=6.6Hz, 2H), 2.38 (dd, J=18.2, 12.0Hz, 4H), 2.16 – 2.09 (m, 1H), 1.99 (d, J=12.8Hz, 2H), 1.84 (t, J=5.7Hz, 2H), 1.50 (d, J=5.0Hz, 2H), 1.45 – 1.34 (m, 4H), C 31h 42n 4i 2o 2, ESI-MSm/z:251 [M-2I] 2+/ 2.
Compound 10MG
Embodiment 43: methyl benzofuran quinoline described in this patent is to the stabilization of G-tetra-serobila DNA.
Select compound prepared by embodiment eight ~ 42, 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 telomerase 3(T 2aG 3) 3]-TAMRA), the rich G sequence Pu22(FAM-d [TGAG of oncogene c-myc promoter region 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-serobila is as shown in table 1.Result shows, this patent series compound has good stabilizing power to ckit-1, has good stabilizing power to F21T, 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 DEG C.
Table 1: this patent series compound is to the Δ Tm value of G-tetra-serobila DNA stabilization.
Embodiment 44: described in this patent, methyl benzofuran quinoline is to the restraining effect of Telomerase.
Select compound prepared by embodiment eight ~ 42, adopt TRAP method to carry out cell-free system telomerase activity.From Human Lung Cancer cell line A549, extract total protein (including Telomerase), a certain amount of total protein extracting solution and medicament mixed to be measured are added in TRAP reaction mixture, after PCR reaction, utilize fluorescence gel imager or fluorescence microplate reader to detect.Compound described in this patent, when concentration is 10 μMs/L, has obvious restraining effect to Telomerase in vitro.And experimental result is consistent with other Vitro Experimental Results before, can be good at action character and structure activity relationship that this compounds is described.Therefore methyl benzofuran quinoline of the present invention can be used for the cancer therapy drug that preparation take Telomerase as target spot.
Table 2: the inhibit activities of this patent series compound when 10 μMs/L to Telomerase:

Claims (5)

1. a methyl benzofuran quinoline, is characterized in that, chemical structural formula is as shown in I:
Wherein, n is 1,2,3 or 4;
R 1for-OH ,-NH 2,-NHR 4,-NR 5r 6, C 3-5azacycloalkyl, azatropylidene base or morpholinyl;
R 2for
R 3for H;
R 4for C 1 ?6alkyl; R 5, R 6for C 1 ?6alkyl; X is methyl.
2. methyl benzofuran quinoline according to claim 1, is characterized in that, described R 1for-NR 5r 6or described R 5and R 6for C 1-3alkyl.
3. methyl benzofuran quinoline according to claim 1, is characterized in that, described R 1for
4. a preparation method for methyl benzofuran quinoline according to claim 1, is characterized in that, comprise the following steps:
first in alkaline environment, carry out hydrocarbyl reaction with Mono Chloro Acetic Acid, then carry out chlorination with sulfur oxychloride again, obtain compound by its again with carry out condensation reaction, obtain compound carry out ring-closure reaction with polyphosphoric acid again, obtain compound carried out chlorination again, obtained compound utilize boron tribromide to slough methyl on methoxyl group subsequently, obtain compound recycling mitsunobu reaction, with react, obtain compound subsequently itself and methyl iodide are carried out methylation reaction, obtain compound ; Last under ethylene glycol ethyl ether makes the condition of solvent with reaction, obtain various methyl benzofuran quinoline, structural formula is
wherein, R 2' represent unmethylated R 2.
5. methyl benzofuran quinoline according to claim 1 is preparing the application in cancer therapy drug.
CN201310255481.6A 2013-06-25 2013-06-25 A kind of methyl benzofuran quinoline and preparation method thereof and the application as antitumor drug Expired - Fee Related CN103382207B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310255481.6A CN103382207B (en) 2013-06-25 2013-06-25 A kind of methyl benzofuran quinoline and preparation method thereof and the application as antitumor drug

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310255481.6A CN103382207B (en) 2013-06-25 2013-06-25 A kind of methyl benzofuran quinoline and preparation method thereof and the application as antitumor drug

Publications (2)

Publication Number Publication Date
CN103382207A CN103382207A (en) 2013-11-06
CN103382207B true CN103382207B (en) 2016-04-20

Family

ID=49490157

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310255481.6A Expired - Fee Related CN103382207B (en) 2013-06-25 2013-06-25 A kind of methyl benzofuran quinoline and preparation method thereof and the application as antitumor drug

Country Status (1)

Country Link
CN (1) CN103382207B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104017047B (en) * 2014-06-11 2016-08-24 中山大学 A kind of peptidyl replaces double-strand benzofuran quinoline and its preparation method and application
CN104447772A (en) * 2014-11-26 2015-03-25 安徽医科大学第一附属医院 Cryptolepine derivative, application of cryptolepine derivative as antibacterial agent as well as antibacterial drug prepared from cryptolepine derivative
CN106279189B (en) * 2016-08-11 2019-02-12 中山大学 A kind of quinoline derivatives and preparation method thereof and application in preparation of anti-tumor drugs
CN108530453B (en) * 2018-03-29 2021-05-11 中山大学 2(3) -p-methylthio styryl benzofuran quinoline derivative and preparation method and application thereof
CN111153916A (en) * 2020-01-17 2020-05-15 玉林师范学院 White leaf vine zinc (II) complex and synthesis method and application thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1235882C (en) * 2003-12-05 2006-01-11 中山大学 Aliphatic amino substituted indole quinoline derivatives, their preparation method and pharmaceutical application
US8158646B2 (en) * 2006-03-31 2012-04-17 Florida Agricultural And Mechanical University Antifungal and antiparasitic indoloquinoline derivates
CN101250187B (en) * 2008-03-28 2011-01-26 中山大学 Fatty amido substituted methylindole quinoline derivatives as well as preparation method and use thereof as anti-tumour drugs
CN102206222B (en) * 2011-04-14 2013-04-10 中山大学 2-fatty-amino-substituted indole quinoline derivative and preparation method and application thereof in preparation of antitumor drugs
CN102633719B (en) * 2012-04-19 2014-08-13 广东工业大学 Anilino-substituted-methylbenzofuryl quinoline derivatives, and preparation method and application thereof

Also Published As

Publication number Publication date
CN103382207A (en) 2013-11-06

Similar Documents

Publication Publication Date Title
CN103382207B (en) A kind of methyl benzofuran quinoline and preparation method thereof and the application as antitumor drug
CN101250187B (en) Fatty amido substituted methylindole quinoline derivatives as well as preparation method and use thereof as anti-tumour drugs
CN102603743B (en) Anti-tumor benzazepine[f]azulene derivative, preparation method thereof, and purpose thereof
CN110627755B (en) Gamma-butyrolactone dimer anticancer compound and preparation method thereof
CN103341166B (en) Erlotinib-phthalocyanine conjugate as molecule-targeting anticancer photosensitizer
CN113061138A (en) Triazole [5,4-d ] pyrimidone tricyclic compound and preparation method and application thereof
CN104974182A (en) Silicon phthalocyanine complex, and preparation method and pharmaceutical application thereof
CN101250189B (en) Bisfatty amido substituted quinazolone derivatives as well as preparation method and use thereof as anti-cancer drugs
CN107417695A (en) Berbine derivative, its preparation method, pharmaceutical composition and anticancer usage
CN101967127B (en) Quinazoline derivative and preparation method thereof and application of quinazoline derivative for preparing anticancer drugs
CN102206222B (en) 2-fatty-amino-substituted indole quinoline derivative and preparation method and application thereof in preparation of antitumor drugs
CN108084177B (en) A kind of jamaicin 9- pyrazole derivatives and its preparation and application
CN102516355B (en) Peptide derivative of benzfuran quinoline and preparation method thereof and application thereof as antitumor medicament
CN104250253A (en) Substituted tetrahydronaphthalene amide compound, pharmaceutically acceptable salt thereof, and preparation method and application
CN101857595B (en) Quinnazolidone derivative, preparation method thereof and purpose of serving as anticarcinogen
CN102285934B (en) Spirocycle dienone derivates as well as preparation method and application thereof
CN103204808B (en) A kind of pair of quinoline and preparation method thereof and preparing the application in cancer therapy drug
CN106279189A (en) A kind of quinoline derivatives and preparation method thereof and the application in preparing antitumor drug
CN107141284A (en) Coptisine analog derivative, its preparation method, pharmaceutical composition and anticancer usage
CN104017047B (en) A kind of peptidyl replaces double-strand benzofuran quinoline and its preparation method and application
CN102633719B (en) Anilino-substituted-methylbenzofuryl quinoline derivatives, and preparation method and application thereof
CN105693609B (en) Polysubstituted phenyl alkylamino acridone -4- amides compound and its preparation method and application
CN104151339A (en) Boron-containing acridine derivative as well as preparation method and application thereof
CA2545876A1 (en) Crystalline topotecan hydrochloride product and process for making the same
CN104130200B (en) A kind of 2-substituted-phenyl-4-aryl amine quinazoline derivant and its preparation method and application

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20160420