CN102827061A - 5,6,7- trimethoxy indole derivative, preparation method and use thereof - Google Patents

5,6,7- trimethoxy indole derivative, preparation method and use thereof Download PDF

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CN102827061A
CN102827061A CN2012103465980A CN201210346598A CN102827061A CN 102827061 A CN102827061 A CN 102827061A CN 2012103465980 A CN2012103465980 A CN 2012103465980A CN 201210346598 A CN201210346598 A CN 201210346598A CN 102827061 A CN102827061 A CN 102827061A
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formula
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compound
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trimethoxy
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高坤
赵登高
胡步荣
陈建军
李亚
马燕燕
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Lanzhou University
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Lanzhou University
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Abstract

The invention provides a 5,6,7-thrimethoxy indole derivative and a preparation method of such compounds. The compound of the invention is predicted to be used for preparing antitumor drugs and/or angiostatin drugs. The preparation method of the compound provided by the invention comprises the following steps of using 5,6,7-trimethoxy indole as raw material, using ethyl format reagent, aluminum trichloride and zinc chloride (mol ratio being 2: 1: 2 to 1: 1: 2) as catalysts to react with substituted benzoyl chloride in anhydrous methylene chloride, so as to obtain the target compound.

Description

5,6,7-trimethoxy indole derivatives, Preparation method and use
Technical field
The present invention relates to a kind of organic cpds and preparation thereof and purposes, the present invention relates to organic cpds 5,6 exactly, 7-trimethoxy indole derivatives, and the preparation method and the purposes of this compound.
Background technology
Vasoinhibitor is one type of very promising new type antineoplastic medicine, and it causes to make up sophisticated blood vessel and blastogenesis capillary vessel obstruction through the target tumor vascular endothelial cell, thereby causes tumour cell for want of nutriment and oxygen and big area is downright bad.Compare with traditional antitumor drug, it has the selectivity height, toxicity is little, instant effect, eutherapeutic characteristics.At present existing kinds of tumors vasoinhibitor gets into clinical trial in American-European countries.
Natural product Combretastatin family is one type of antineoplastic compound with bright prospects, and wherein anti-tumor activity particularly becomes the research focus to the tumor vascular endothelial cell specific effect to Compound C ombretastatinA-4 (CA-4) because of it has efficiently.Its analog AC-7739. AVE-8082A and phosphoric acid vinegar disodium salt CA-4P, CA-1P etc. have got into clinical study.Particularly Compound C A-4P has specific effect to vascular endothelial cell, and it gets into the clinical III phase in American-European countries as the tumor vessel suppressor factor and tests.
In recent years, lot of domestic and international research group has carried out a large amount of structural modification work around guide's thing CA-4, obtains structural derivative efficient, low toxicity with expectation.The research of structure activity relationship shows, substitutes phenyl among the CA-4 with heterocycle and can obtain that structure is more stable, the better verivate of the property of medicine, and be very promising research direction.
Summary of the invention
The present invention provides one type 5,6,7-trimethoxy indole derivatives, and this compound prediction will can be used for preparing antitumor drug and/or vaso inhibitor thing.
Compound of the present invention for suc as formula 1 show 5,6,7-trimethoxy indole derivatives,
Formula 1
Wherein: R 1Be H or CH 3R 2Be H or CH 3R 3Be CH 2Or CO; R 4Be 2-OCH 3, or 3-OCH 3, or 4-OCH 3, or 4-CH 3, or 3,4,5-tri-OCH 3, or 3-OH-4-OCH 3, or 3-F-4-OCH 3, or 3-Cl-4-OCH 3, or 3-I-4-OCH 3Chemical combination perhaps of the present invention
Figure 331091DEST_PATH_IMAGE002
Formula 2
Thing suc as formula 2 show 5,6,7-trimethoxy indole derivatives, wherein: R 5Be CO or CH 2: R 6Be 4-OCH 3Or 3-OH-4-OCH 3
The present invention shows R in the compound suc as formula 1 3For the preparing method's of the compound of CO reaction suc as formula 3
Figure 598124DEST_PATH_IMAGE003
Formula 3
Show; With chemical compounds I (5 in the formula 3; 6,7-trimethoxy indoles) being raw material, is that catalyzer reacts with II (substituted benzoyl chloride) in anhydrous methylene chloride and obtains the target compound III with ethyl grignard reagent, aluminum chloride and zinc chloride; Wherein add catalyzer ethyl grignard reagent: aluminum chloride: the mol ratio of zinc chloride equals 2:1:2～1:1:2, in the formula 3: R 1Be H or CH 3R 2Be H or CH 3R 4Be 2-OCH 3, or 3-OCH 3, or 4-OCH 3, or 4-CH 3, or 3,4,5-tri-OCH 3, or 3-OH-4-OCH 3, or 3-F-4-OCH 3, or 3-Cl-4-OCH 3, or 3-I-4-OCH 3
The present invention shows R in the compound suc as formula 2 6Be 4-OCH 3Compound the preparation method reaction as
Figure 672390DEST_PATH_IMAGE004
Formula 4
Formula 3 is shown, is raw material with chemical compounds I in the formula 4, with the potassium tert.-butoxide be catalyzer in anhydrous tetrahydro furan with formula 4 in compound ii (substituted benzoyl chloride) reaction, obtain the target compound VI.In the reaction formula 4: R 5Be CO or CH 2
Formula 1 is shown R in the compound 3For CH 2The preparation method reaction of compound suc as formula shown in 5,
Figure 216635DEST_PATH_IMAGE005
Formula 5
With chemical compounds I in the formula 5 is raw material, with bicarbonate of ammonia be catalyzer in the aqueous acetone solution that contains volume ratio 20% with formula 5 in compound V (replace benzyl bromine) the compound VI that reacts and obtain target, R in the formula 5 5Be CO, CH 2
Formula 2 is shown R in the compound 6Be 3-OH-4-OCH 3The preparation method reaction of compound suc as formula shown in 6, be to be raw material with chemical compounds I in the formula 5,
Figure 85365DEST_PATH_IMAGE006
Formula 6
With the potassium tert.-butoxide is that catalyzer is showing that with formula 6 compound V (replacing the benzyl bromine) reaction obtains target compound VII, R in the formula 6 in anhydrous tetrahydro furan 5Be 3-OH-4-OCH 3
Provided by the invention 5,6,7-trimethoxy indole derivatives can be used in preparation antitumor drug and vaso inhibitor thing.Preliminary in-vitro screening structure shows them to various tumor cell strains, comprises that people's small cell carcinoma of lung A549, HOS HT1080, human cervical carcinoma Hela, people's liver cancer Hepg2 and activated Human umbilical vein endothelial cells (HUVEC) etc. all have the value-added effect of inhibition.Wherein part of compounds reaches sub-micro mole level to the half-inhibition concentration of various tumor cell strains and activated Human umbilical vein endothelial cells (HUVEC); Particularly compound to reaching of activated Human umbilical vein endothelial cells 220-300 selectivity doubly, well beyond the selectivity of positive control NSC-757. and CA-4.
Characteristics of the present invention are that compounds process for production thereof is easy, and compound structure is novel, representes that through related experiment most compound of the present invention has the value-added effect of obvious suppression to tumour cell, point out it in the preparation antitumor drug, to use.Part of compounds has shown the high selectivity to the activated human umbilical vein endothelial cell, points out it in preparation vaso inhibitor thing or reagent, to use.
Embodiment
Embodiment 1: (5,6, the preparation of 7-trimethoxy-1-hydrogen-indoles-3-yl) (4-p-methoxy-phenyl) ketone (abbreviating compound III-1 as)
Add 249mg (1.2mmol) 5,6 under the argon shield in the there-necked flask of 25ml, 7-trimethoxy indoles; Anhydrous methylene chloride 10ml, Zinc Chloride Anhydrous 327mg (2.4mmol) drips ethyl grignard reagent (3M) 0.8ml (2.4mmol); Room temperature reaction 1 hour adds the 4-methoxy benzoyl chloride of 1.8mmol and the solution of 10ml anhydrous methylene chloride, and room temperature continues reaction 1 hour; Add 159mg (1.2mmol) aluminum chloride, after room temperature reaction 5 hours, TLC detect the raw material disappearance; Add the reaction of going out of cold water collection, methylene dichloride (10ml * 3) extraction, Anhydrous potassium carbonate drying; Get yellow oil after the removal of solvent under reduced pressure, crude product gets faint yellow solid (compound III-1), yield 44% behind silica gel column chromatography. 1H?NMR?(400MHz,?CDCl 3)?δ?9.3?(brs,?1H),?7.82?(d,?J?=?8?Hz,?2H),?7.67?(s,?1H),?7.54?(d,?J?=?2?Hz,?1H),?6.95?(d,?J?=?8?Hz,?2H),?4.05?(s,?3H),?3.91?(s,?3H),?3.91?(s,?3H),?3.86?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?190.4,?162.2,?151.3,?138.7,?138.7,?133.1,?132.4,?130.8,?124.7,?122.5,?113.5,?113.5,?117.1,?98.6,?61.4,?61.1,?56.2,?55.3.?HRMS?calcd?for?C 19H 19NO 5?[M+H] +?:?342.1336,?found:?342.1341.。
Embodiment 2: (5,6, the preparation of 7-trimethoxy-1-hydrogen-indoles-3-yl) (2-p-methoxy-phenyl) ketone (abbreviating compound III-2 as)
Add 249mg (1.2mmol) 5,6 under the argon shield in the there-necked flask of 25ml, 7-trimethoxy indoles; Anhydrous methylene chloride 10ml, Zinc Chloride Anhydrous 327mg (2.4mmol) drips ethyl grignard reagent (3M) 0.4ml (1.2mmol); Room temperature reaction 1 hour adds the 2-methoxy benzoyl chloride of 1.8mmol and the solution of 10ml anhydrous methylene chloride, and room temperature continues reaction 1 hour; Add 159mg (1.2mmol) aluminum chloride, after room temperature reaction 5 hours, TLC detect the raw material disappearance; Add the reaction of going out of cold water collection, methylene dichloride (10ml * 3) extraction, Anhydrous potassium carbonate drying; Get yellow oil after the removal of solvent under reduced pressure, crude product obtains white solid (compound III-2), yield 41% behind silica gel column chromatography. 1H?NMR?(400?MHz,?CDCl 3)?δ?8.99?(brs,?1H),?7.67?(s,?1H),?7.39?(m,?3H),?6.98?(m,?2H),?4.10?(s,?3H),?3.93?(s,?3H),?3.90?(s,?3H),?3.75?(s,?3H);? 13C?NMR?(100?MHz,?CDCl 3)?δ?191.8,?156.7,?151.4,?138.7,?130.9,?130.7,?128.7,?124.7,?120.1,?118.8,?111.5,?98.8,?61.4?,61.2,?56.2,?55.7.?HRMS?calcd?for?C 19H 19NO 5?[M+H] +?:?342.1336,?found:?342.1328.。
Embodiment 3: the preparation of (1-ethanoyl-5,6,7-trimethoxy-1-hydrogen-indol-3-yl) (4-p-methoxy-phenyl) ketone (abbreviating compound III-3 as)
Operating process is identical with embodiment 1, and just with 1-ethanoyl 5,6,7-trimethoxy indoles replaces 5,6, and 7-trimethoxy indoles obtains off-white color solid (compound III-3), yield 51%. 1H?NMR?(400MHz,?CDCl 3)?δ?7.89?(s,?1H),?7.85?(d,?J?=?8.0?Hz,?2H),?7.63?(s,?1H),?6.97?(d,?J?=?8.0?Hz,?2H),?3.98?(s,?3H),?3.94?(s,?3H),?3.92?(s,?3H),?3.87?(s,?3H),?2.69?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?189.9,?169.5,?163.0,?152.4,?141.6,?141.4,?134.0,?131.9,?131.1,?131.1,?126.2,?123.0,?119.4,?113.7,?113.7,?99.6,?61.2,?61.2,?56.2,?55.4,?25.4.?HRMS?calcd?for?C 21H 21NO 6?[M+H] +?:?384.1442,?found:?384.1439.。
Embodiment 4: the preparation of (1-benzenesulfonyl-5,6,7-trimethoxy-1-hydrogen-indol-3-yl) (4-p-methoxy-phenyl) ketone (abbreviating compound III-4 as)
Operating process is identical with embodiment 1, and just with 1-benzenesulfonyl-5,6,7-trimethoxy indoles replaces 5,6, and 7-trimethoxy indoles obtains yellowish solid (compound III-4), yield 46%. 1H?NMR?(400?MHz,?CDCl 3)?δ?8.20?(s,?1H),?7.92?(d,?J?=?8.8?Hz,?2H),?7.87?(d,?J?=?8.4?Hz,?2H),?7.63?(s,?1H),?7.58?(m,?1H),?7.49?(m,?2H),?7.03?(d,?J?=?2?Hz,?2H),?3.91?(s,?6H),?3.81?(s,?3H),?3.79?(s,?3H);? 13C?NMR?(100?MHz,?CDCl 3)?δ?189.7,?163.2,?152.5,?141.4,?140.9,?138.8,?135.1,?133.8,?131.8,?131.3,?131.3,?129.1,?129.1,?127.4,?127.4,?125.9,?123.0,?118.9,?113.9,?113.9,?99.3,?61.1,?61.0,?56.2,?55.5.?HRMS?calcd?for?C 25H 23NO 7S?[M+H] +?:?482.1268,?found:?482.1272.。
Embodiment 5: the preparation of (5,6,7-trimethoxy-1-hydrogen-indol-3-yl) (3-p-methoxy-phenyl) ketone (abbreviating compound III-5 as)
Operating process is identical with embodiment 1, just replaces the 4-methoxy benzoyl chloride with the 3-methoxy benzoyl chloride, obtains white solid (compound III-2), yield 49%. 1H?NMR?(400?MHz,?CDCl 3)?δ?8.65?(brs,?1H),?7.70?(s,?1H),?7.61?(d,?J?=?3.2?Hz,?1H),?7.39?(m,?3H),?7.10?(m,?1H),?4.10?(s,?3H),?3.97?(s,?3H),?3.92?(s,?3H),?3.86?(s,?3H);? 13C?NMR?(100?MHz,?CDCl 3)?δ?191.0,?159.5,?151.6,?141.9,?138.8,?138.6,?132.6,?129.2,?124.6,?122.2,?121.1,?117.4,?117.3,?113.4,?98.7,?61.4,?61.2,?56.3,?55.4.?HRMS?calcd?for?C 19H 19NO 5?[M+H] +?:?342.1336,?found:?342.1327.。
Embodiment 6: the preparation of (5,6,7-trimethoxy-1-hydrogen-indol-3-yl) (4-aminomethyl phenyl) ketone (abbreviating compound III-6 as)
Operating process is identical with embodiment 1, just replaces the 4-methoxy benzoyl chloride with the 4-methyl benzoyl chloride, obtains white solid (compound III-6), yield 55%. 1H?NMR?(400?MHz,?CDCl 3)?δ?8.93?(brs,?1H),?7.73?(d,?J?=?8?Hz,?2H),?7.70?(s,?1H),?7.56?(d,?J?=?2?Hz,?1H),?7.27?(d,?J?=?8?Hz,?2H),?4.08?(s,?3H),?3.95?(s,?3H),?3.92?(s,?3H),?2.43?(s,?3H);? 13C?NMR?(100?MHz,?CDCl 3)?δ?191.2,?151.4,?141.7,?138.8,?138.6,?137.9,?132.5,?128.9,?128.8,?128.8,?124.6,?122.3,?117.3,?98.7,?61.4,?61.2,?56.3,?21.5.?HRMS?calcd?for?C 19H 19NO 4?[M+H] +?:?326.1387,?found:?326.1377.。
Embodiment 7: the preparation of (5,6,7-trimethoxy-1-hydrogen-indol-3-yl) (3,4, the 5-trimethoxyphenyl) ketones (abbreviating compound III-7 as)
Operating process is identical with embodiment 1, and just with 3,4, the 5-trimethoxy-benzoyl chloride replaces the 4-methoxy benzoyl chloride, obtains off-white color solid (compound III-7), yield 62%. 1H?NMR?(400MHz,?CDCl 3)?δ?9.07?(brs,?1H),?7.67?(s,?1H),?7.63?(d,?J?=?2.8?Hz,?1H),?7.11?(s,?2H),?4.09?(s,?3H),?3.96?(s,?3H),?3.93?(s,?3H),?3.93?(s,?3H),?3.92?(s,?3H),?3.89?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?190.4,?152.9,?152.9,?151.5,?140.9,?138.9,?138.7,?135.9,?132.4,?124.7,?122.4,?117.0,?106.3,?106.3,?98.6,?61.4,?61.2,?61.0,?56.3,?56.2.?HRMS?calcd?for?C 21H 23NO 7?[M+H] +?:?402.1557,?found:?402.1554.。
Embodiment 8: the preparation of (5,6,7-trimethoxy-1-hydrogen-indol-3-yl) (3-hydroxyl 4-p-methoxy-phenyl) ketone (abbreviating compound III-8 as)
Operating process is identical with embodiment 1, just replaces the 4-methoxy benzoyl chloride with 3-hydroxyl 4-methoxy benzoyl chloride, obtains off-white color solid (compound III-8), yield 42%. 1H?NMR?(400?MHz,?CDCl 3)?δ?9.42?(brs,?1H),?7.67?(s,?1H),?7.54?(t,?J?=?2?Hz),?7.44?(d,?J?=?2?Hz,?1H),?7.38?(d,?J?=?8?Hz,?1H),?6.88?(s,?1H),?4.04?(s,?3H),?3.91?(s,?3H),?3.90?(s,?3H);? 13C?NMR?(100?MHz,?CDCl 3)?δ?190.4,?151.3,?149.5,?145.2,?138.7,?133.8,?133.0,?132.9,?124.7,?122.7,?121.9,?116.9,?115.3,?110.0,?98.7,?61.4,?61.2,?56.3,?56.0.?HRMS?calcd?for?C 19H 19NO 6?[M+H] +?:?358.1285,?found:?358.1277.。
Embodiment 9: the preparation of (5,6,7-trimethoxy-1-hydrogen-indol-3-yl) (3-chloro-4-p-methoxy-phenyl) ketone (abbreviating compound III-9 as)
Operating process is identical with embodiment 1, just replaces the 4-methoxy benzoyl chloride with 3-chloro-4-methoxy benzoyl chloride, obtains off-white color solid (compound III-9), yield 45%. 1H?NMR?(400MHz,?CDCl 3)?δ?8.94?(brs,?1H),?7.91?(s,?1H),?7.76?(dd,?J?=?8.8?Hz,?J?=?2.8?Hz,?1H),?7.63?(s,?1H),?7.56?(d,?J?=?2.8?Hz,?1H),?7.00?(d,?J?=?8.8?Hz,?1H),?4.09?(s,?3H),?3.98?(s,?3H),?3.95?(s,?3H),?3.92?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?188.9,?157.5,?151.6,?138.9,?138.7,?133.8,?132.2,?131.0,?129.0,?124.7,?122.4,?122.3,?117.0,?111.4,?98.5,?61.4,?61.3,?56.3,?56.3.?HRMS?calcd?for?C 19H 18ClNO 5?[M+H] +?:?376.0946,?found:?376.0944.。
Embodiment 10: the preparation of (5,6,7-trimethoxy-1-hydrogen-indol-3-yl) (3-iodo-4-p-methoxy-phenyl) ketone (abbreviating compound III-10 as)
Operating process is identical with embodiment 1, just replaces the 4-methoxy benzoyl chloride with 3-iodo-4-methoxy benzoyl chloride, obtains off-white color solid (compound III-10), yield 37%. 1H?NMR?(400MHz,?CDCl 3)?δ?9.11?(brs,?1H),?8.29?(d,?J?=?2.0?Hz,?1H),?7.83?(dd,?J?=?8.4?Hz,?J?=?2.0?Hz,?1H),?7.62?(s,?1H),?7.56?(d,?J?=?3.2?Hz,?1H),?6.88(d,?J?=?8.4?Hz,?1H),?4.07?(s,?3H),?3.95?(s,?3H),?3.94?(s,?3H),?3.91?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?188.7,?160.5,?151.5,?140.3,?138.9,?138.7,?134.9,?132.3,?130.8,?124.7,?122.4,?117.0,?110.2,?98.6,?85.5,?61.5,?61.3,?56.6,?56.4.?HRMS?calcd?for?C 19H 18INO 5?[M+H] +?:?468.0302,?found:?468.0304.。
Embodiment 11: the preparation of (5,6,7-trimethoxy-1-hydrogen-indol-3-yl) (3-fluoro-4-p-methoxy-phenyl) ketone (abbreviating compound III-11 as)
Operating process is identical with embodiment 1, just replaces the 4-methoxy benzoyl chloride with 3-fluoro-4-methoxy benzoyl chloride, obtains off-white color solid (compound III-11), yield 41%. 1H?NMR?(400MHz,?DMSO- d6)?δ?12.12?(d,?J?=?2.1?Hz?1H),?7.80(d,?J?=?3.2?Hz,?1H),?7.65?(dd,?J?=?8.4?Hz,?J?=?1.2?Hz,?1H),?7.60?(dd,?J?=?12?Hz,?J?=?2.0?Hz,?1H),?7.30(t,?J?=?8.4?Hz,?1H),?3.97(s,?3H),?3.93(s,?3H),?3.84(s,?3H),?3.79(s,?3H);? 13C?NMR?(100MHz,?DMSO- d6)?δ?187.4,?152.2,?150.5,?149.7,?139.0,?138.4,?134.2,?133.1,?125.7,?124.6,?122.5,?115.8,?115.1,?113.2,?98.5,?61.2,?60.9,?56.2,?55.9. HRMS?calcd?for?C 19H 18FNO 5?[M+H] +?:?360.1242,?found:?360.1239.。
Embodiment 12: the preparation of (5,6,7-trimethoxy-2-methyl isophthalic acid-hydrogen-indol-3-yl) (3-hydroxyl-4-p-methoxy-phenyl) ketone (abbreviating compound III-12 as)
Operating process is identical with embodiment 1, just replaces the 4-methoxy benzoyl chloride with 3-hydroxyl-4-methoxy benzoyl chloride, with 5; 6,7-trimethoxy-2-methyl-indoles replaces 5,6; 7-trimethoxy indoles obtains off-white color solid (compound III-12), yield 52%. 1H?NMR?(400MHz,?CDCl 3)?δ?8.40?(brs,?1H),?7.38?(d,?J?=?2?Hz,?1H),?7.34?(dd,?J?=?8.4Hz,?2?Hz,?1H),?6.90?(d,?J?=?8.4?Hz,?1H),?6.89?(s,?1H),?5.68?(brs,?1H),?4.07?(s,?3H),?3.97?(s,?3H),?3.89?(s,?6H),?3.77?(s,?3H),?2.45?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?191.8,?150.3,?149.5,?145.3,?141.4,?138.0,?137.8,?134.5,?123.6,?122.8,?122.3,?115.4,?114.6,?109.8,?98.2,?61.4,?61.2,?56.3,?56.1,?14.6.?HRMS?calcd?for?C 20H 21NO 6?[M+H] +?:?372.1442,?found:?372.1445.。
Embodiment 13: the preparation of (5,6,7-trimethoxy-1-methyl-indol-3-yl) (4-p-methoxy-phenyl) ketone (abbreviating compound III-13 as)
Operating process is identical with embodiment 1, and just with 5,6,7-trimethoxy-1-methyl-indoles replaces 5,6, and 7-trimethoxy indoles obtains off-white color solid (compound III-13), yield 50%. 1H?NMR?(400MHz,?CDCl 3)?δ?7.81?(d,?J?=?8.4?Hz,?2H),?7.73?(s,?1H),?7.35?(s,?1H),?6.97?(d,?J?=?8.4?Hz,?2H),?4.03?(s,?3H),?4.00?(s,?3H),?3.96?(s,?3H),?3.92?(s,?3H),?3.92?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?189.7,?162.1,?151.2,?140.4,?139.7,?137.9,?133.6,?130.8,?130.8,?124.9,?124.4,?115.1,?113.5,?113.5,?99.1,?62.0,?61.3,?56.2,?55.4,?36.5. HRMS?calcd?for?C 20H 21NO 5?[M+H] +?:?356.1492,?found:?356.1496.。
Embodiment 14: the preparation of (5,6,7-trimethoxy-1-methyl-indol-3-yl) (3-hydroxyl-4-p-methoxy-phenyl) ketone (abbreviating compound III-14 as)
Operating process is identical with embodiment 1, just with 5,6; 7-trimethoxy-1-methyl-indoles replaces 5,6,7-trimethoxy indoles; Replace the 4-methoxy benzoyl chloride with 3-hydroxyl-4-methoxy benzoyl chloride, obtain off-white color solid (compound III-14), yield 49%. 1H?NMR?(400MHz,?CDCl 3)?δ?7.74?(s,?1H),?7.43?(d,?J?=?1.6?Hz,?1H),?7.39?(d,?J?=?8.8?Hz,?1H),?7.38?(s,?1H),?6.92?(dd,?J?=?1.6?Hz,?8.4?Hz,?1H),?4.03?(s,?3H),?3.99?(s,?3H),?3.95?(s,?6H),?3.91(s,?3H)?;? 13C?NMR?(100MHz,?CDCl 3)?δ?189.6,?151.2,?149.2,?145.2,?140.4,?139.7,?138.1,?134.3,?124.9,?124.4,?121.7,?115.2,?115.0,?110.0,?99.2,?62.0,?61.3,?56.2,?56.1,?36.5.?HRMS?calcd?for?C 20H 21NO 6?[M+H] +:?372.1442,?found:?372.1443.。
Embodiment 15: the preparation of (5,6,7-trimethoxy-1-methyl-indol-3-yl) (3-fluoro-4-p-methoxy-phenyl) ketone (abbreviating compound III-15 as)
Operating process is identical with embodiment 1, just with 5,6; 7-trimethoxy-1-methyl-indoles replaces 5,6,7-trimethoxy indoles; Replace the 4-methoxy benzoyl chloride with 3-fluoro-4-methoxy benzoyl chloride, obtain off-white color solid (compound III-14), yield 47%. 1H?NMR?(400MHz,?CDCl 3)?δ?7.73?(s,?1H),?7.57–7.62?(m,?2H),?7.35?(s,?1H),?7.03?(t,?J?=?8.0?Hz,?1H),?4.04?(s,?3H),?4.02?(s,?3H),?3.96?(s,?6H),?3.95?(s,?3H),?3.92?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?188.3,?153.1,?151.4,?150.3,?140.5,?139.9,?137.8,?133.8,?125.5,?124.9,?124.3,?116.6,?114.8,?112.5,?99.1,?62.0,?61.3,?56.3,?56.2,?36.6.HRMS?calcd?for?C 20H 20FNO 5?[M+H] +:?374.1398,?found:?374.1395.。
Embodiment 16: the preparation of (5,6,7-trimethoxy-1,2-dimethyl--indol-3-yl) (3-hydroxyl-4-p-methoxy-phenyl) ketone (abbreviating compound III-16 as)
Operating process is identical with embodiment 1, just with 5,6, and 7-trimethoxy-1; 2 dimethyl--indoles replaces 5,6,7-trimethoxy indoles; Replace the 4-methoxy benzoyl chloride with 3-hydroxyl-4-methoxy benzoyl chloride, obtain off-white color solid (compound III-16), yield 50%. 1H?NMR?(400MHz,?CDCl 3)?δ?8.40?(brs,?1H),?7.38?(d,?J?=?2?Hz,?1H),?7.34?(dd,?J?=?8.4Hz,?2?Hz,?1H),?6.90?(d,?J?=?8.4?Hz,?1H),?6.89(s,?1H),?5.68?(brs,?1H),?4.07?(s,?3H),?3.97?(s,?3H),?3.89?(s,?6H),?3.77?(s,?3H),?2.45?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?191.8,?150.3,?149.5,?145.3,?141.4,?138.0,?137.8,?134.5,?123.6,?122.8,?122.3,?115.4,?114.6,?109.8,?98.2,?61.4,?61.2,?56.3,?56.1,?14.6.?HRMS?calcd?for?C 20H 23NO 6?[M+H] +?:?386.1598,?found:?386.1598.。
Embodiment 17: the preparation of (5,6,7-trimethoxy indoles-1-yl) (4-p-methoxy-phenyl) ketone (abbreviating compound IV-1 as)
Add 350mg (1.69mmol) 5,6 in the single port bottle of 25ml, 7-trimethoxy indoles, anhydrous tetrahydro furan 5ml; Potassium tert.-butoxide 284mg (2.54mmol), stirring at room drips the solution of 4-methoxy benzoyl chloride (2.54mmol) and 5ml anhydrous tetrahydro furan, room temperature reaction 2 hours, removal of solvent under reduced pressure after 15 minutes; Add 10ml water, the anhydrous diethyl ether extraction, anhydrous magnesium sulfate drying filters; Removal of solvent under reduced pressure obtains off-white color solid (compound IV-1), yield 61%. 1H?NMR?(400MHz,?CDCl 3)?δ?7.82?(d,?J?=?8.8?Hz,?2H),?7.23?(d,?J?=?3.6?Hz,?1H),?6.97?(d,?J?=?8.8?Hz,?2H),?6.84?(s,?1H),?6.48?(d,?J?=?3.2?Hz,?1H),?3.92?(s,?3H),?3.89?(s,?3H),?3.88?(s,?6H);? 13C?NMR?(100MHz,?CDCl 3)?δ?166.9,?163.4,?151.3,?142.3,?140.7,?132.4,?132.4,?129.0,?127.5,?126.3,?124.0,?113.8,?113.8,?106.9,?97.9,?61.1,?60.4,?56.2,?55.5.?HRMS?calcd?for?C 19H 19NO 5[M+H] +:?342.1336,?found:?342.1339.。
Embodiment 18: the preparation of (5,6,7-trimethoxy indoles-1-yl) (3-hydroxyl 4-p-methoxy-phenyl) ketone (abbreviating compound IV-2 as)
Operating process is identical with embodiment 18, just replaces the 4-methoxy benzoyl chloride with 3-hydroxyl-4-methoxy benzoyl chloride, obtains off-white color solid (compound IV-2), yield 55%. 1H?NMR?(400MHz,?CDCl 3)?δ?7.44?(d,?J?=?2.4?Hz,?1H),?7.42?(dd,?J?=?8.4Hz,?2?Hz,?1H),?7.24?(d,?J?=?3.6?Hz,?1H),?6.92?(d,?J?=?8.4?Hz,?1H),?6.80?(s,?1H),?6.47?(d,?J?=?3.6?Hz,?1H),?3.97?(s,?3H),?3.92?(s,?3H),?3.91?(s,?6H),?3.89?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?166.8,?151.4,?150.5,?145.5,?142.3,?140.7,?129.1,?127.6,?127.1,?123.9,?123.6,?116.3,?110.0,?106.9,?97.9,?61.2,?60.4,?56.2,?56.1.?HRMS?calcd?for?C 19H 19NO 6[M+H] +:?358.1285,?found:?358.1287.。
Embodiment 19:3-(4-methoxy-benzyl)-5,6, the preparation of 7-trimethoxy-1H-indoles (abbreviating compound VI-1 as)
Add 650mg (3.14mmol) 5,6 in the single port bottle of 25ml, 7-trimethoxy indoles, 4ml water; 16ml acetone, bicarbonate of ammonia 100mg (1.29mmol), stirring at room drips 4-anisole methylbenzyl bromine 130mg (0.65mmol), room temperature reaction 2 hours after 5 minutes;, add 20ml water, anhydrous diethyl ether extraction, anhydrous magnesium sulfate drying; Filter removal of solvent under reduced pressure, the silica gel column chromatography (eluent: sherwood oil: diethyl=3:1) obtain not having oily matter (compound VI-1), yield 44% of purifying. 1H?NMR?(400MHz,?CDCl 3)?δ?8.0q?(brs,?1H),?7.21?(d,?J?=?8.4?Hz,?2H),?6.84?(d,?J?=?8.8?Hz,?2H),?6.82?(d,?J?=?0.8?Hz,?1H),?6.68?(s,?1H),?4.06?(s,?3H),?4.00?(s,?2H),?3.90?(s,?3H),?3.85?(s,?3H),?3.80?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?157.8,?148.9,?138.7,?138.1,?133.2,?129.5,?129.5,?124.8,?123.1,?121.9,?116.5,?113.7,?113.7,?96.0,?61.4,?61.0,?56.4,?55.2,?30.8.?HRMS?calcd?for?C 19H 21NO 4?[M+H] +?:?328.1543,?found:?328.11550.。
Embodiment 20:3-(3,4,5-trimethoxy benzyl)-5,6, the preparation of 7-trimethoxy-1H-indoles (abbreviating compound VI-2 as)
Operating process is identical with embodiment 19, and just with 3,4,5-trimethoxy benzyl bromo obtains colorless oil (compound IV-2), yield 55% for 4-methoxybenzyl bromine. 1H?NMR?(400MHz,?CDCl 3)?δ?8.07?(brs,?1H),?6.84?(d,?J?=?2.4?Hz,?1H),?6.71?(s,?1H),?6.53?(s,?2H),?4.06?(s,?3H),?3.99?(s,?2H),?3.96?(s,?3H),?3.90?(s,?3H),?3.83?(s,?3H),?3.80?(s,?6H);? 13C?NMR?(100MHz,?CDCl 3)?δ?153.1,?153.1,?149.0,?138.8,?138.1,?136.7,?136.2,?124.9,?123.1,?122.0,?115.8,?105.8,?105.8,?95.9,?61.4,?61.0,?60.8,?56.5,?56.1,?56.1,?32.1.?HRMS?calcd?for?C 21H 25NO 6[M+H] +?:?388.1755,?found:?388.1759.。
Embodiment 21:3-(3-fluoro-4-methoxy-benzyl)-5,6, the preparation of 7-trimethoxy-1H-indoles (abbreviating compound VI-3 as)
Operating process is identical with embodiment 19, just replaces 4-methoxybenzyl bromine with 3-fluoro-4-methoxybenzyl bromo, obtains colorless oil (compound IV-3), yield 53%. 1H?NMR?(400MHz,?CDCl 3)?δ?8.02?(brs,?1H),?7.00?(d,?J?=?2.0?Hz,?1H),?6.98?(d,?J?=?7.2?Hz,?1H),?6.89?(d,?J?=?8.4?Hz,?1H),?6.85?(d,?J?=?2.0?Hz,?1H),?6.34?(s,?1H),?4.06?(s,?3H),?3.97?(s,?2H),?3.89?(s,?3H),?3.86?(s,?3H),?3.84?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?152.3?(d,?J?=?244?Hz),?149.1,?145.7,?138.8,?138.1,?134.3,?124.9,?123.9,?123.0,?122.0,?116.3,?115.6,?113.3,?95.8,?61.4,?61.0,?56.5,?56.4,?30.7.?HRMS?calcd?for?C 19H 20FNO 4?[M+H] +?:?346.1449,?found:?346.1445.。
Embodiment 22:3-(3-fluoro-4-methoxy-benzyl)-5,6, the preparation of 7-trimethoxy-1H-indoles (abbreviating compound VI-3 as)
Operating process is identical with embodiment 19, just replaces 4-methoxybenzyl bromine with 3-fluoro-4-methoxybenzyl bromo, obtains colorless oil (compound IV-3), yield 53%. 1H?NMR?(400MHz,?CDCl 3)?δ?8.02?(brs,?1H),?7.00?(d,?J?=?2.0?Hz,?1H),?6.98?(d,?J?=?7.2?Hz,?1H),?6.89?(d,?J?=?8.4?Hz,?1H),?6.85?(d,?J?=?2.0?Hz,?1H),?6.34?(s,?1H),?4.06?(s,?3H),?3.97?(s,?2H),?3.89?(s,?3H),?3.86?(s,?3H),?3.84?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?152.3?(d,?J?=?244?Hz),?149.1,?145.7,?138.8,?138.1,?134.3,?124.9,?123.9,?123.0,?122.0,?116.3,?115.6,?113.3,?95.8,?61.4,?61.0,?56.5,?56.4,?30.7.?HRMS?calcd?for?C 19H 20FNO 4?[M+H] +?:?346.1449,?found:?346.1445.。
Embodiment 23:2-methoxyl group-5-(preparation of (5,6,7-trimethoxy-1H-indoles-3-yl) methyl) phenol (abbreviating compound VI-4 as)
Operating process is identical with embodiment 19, just replaces 4-methoxybenzyl bromine with 3-hydroxyl-4-methoxybenzyl bromo, obtains colorless oil (compound IV-4), yield 51%. 1H?NMR?(400MHz,?CDCl 3)?δ?7.98?(brs,?1H),?6.87?(d,?J?=?2.4?Hz,?2H),?6.78?(s,?2H),?6.70?(s,?1H),?5.56?(s,?1H),?4.06?(s,?3H),?3.97?(s,?2H),?3.90?(s,?3H),?3.87?(s,?3H),?3.86?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?148.9,?145.5,?144.8,?138.7,?138.1,?134.5,?124.9,?123.2,?121.9,?119.9,?116.2,?114.9,?110.6,?96.0,?61.4,?61.0,?56.5,?56.0,?31.0.?HRMS?calcd?for?C 19H 21NO 5?[M+H] +:?344.1492,?found:?344.1495.。
Embodiment 24:3-(3-fluoro-, 4-methoxy-benzyl-5,6, preparation of 7-trimethoxy-1-Methyl-1H-indole (abbreviating compound VI-5 as)
Operating process is identical with embodiment 19, just replaces 4-methoxybenzyl bromine with 3-fluoro-4-methoxybenzyl bromo, and with 1-methyl-5,6,7 trimethoxy benzyl bromos obtain colorless oil (compound IV-5), yield 49% for 5,6,7 trimethoxy benzyl bromines. 1H?NMR?(400MHz,?CDCl 3)?δ?6.99?(m,?1H),?6.97?(s,?1H),?6.87?(t,?J?=?8.8?Hz,?1H),?6.63?(s,?1H),?6.59?(s,?1H),?4.00?(s,?3H),?3.93?(s,?2H),?3.91?(s,?3H),?3.90?(s,?3H),?3.86?(s,?3H),?3.84?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?152.3?(d,?J?=?243?Hz),?148.5,?145.7?(d,?J?=?11?Hz),?140.4,?139.0,?134.5?(d,?J?=?6?Hz),?128.2,?124.8,?124.4,?123.9?(d,?J?=?3Hz),?116.3?(d,?J?=?18?Hz),?113.5,?113.4?(d,?J?=?4?Hz),?96.0,?61.9,?61.3,?56.4,?56.4,?35.2,?30.5. HRMS?calcd?for?C 20H 22FNO 4?[M+H] +?:?360.1606,?found:?360.1602.。
Embodiment 25:3-(3-hydroxyl-4-methoxy-benzyl-5,6, the preparation of 7-trimethoxy-1-Methyl-1H-indole (abbreviating compound VI-6 as)
Operating process is identical with embodiment 19, just replaces 4-methoxybenzyl bromine with 3-hydroxyl-4-methoxybenzyl bromo, and with 1-methyl-5,6,7 trimethoxy benzyl bromos obtain colorless oil (compound IV-6), yield 50% for 5,6,7 trimethoxy benzyl bromines. 1H?NMR?(400MHz,?CDCl 3)?δ?6.85?(d,?J?=?1.2?Hz,?1H),?6.77?(s,?1H),?6.76?(s,?1H),?6.67?(s,?1H),?6.59?(s,?1H),?4.00?(s,?3H),?3.91?(s,?2H),?3.89?(s,?3H),?3.86?(s,?3H),?3.85?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?148.4,?145.4,?144.8,?140.3,?138.8,?134.6,?128.2,?124.7,?124.5,?119.9,?114.9,?114.1,?110.5,?96.0,?61.9,?61.3,?56.3,?56.0,?35.1,?30.8.?HRMS?calcd?for?C 20H 23NO 5?[M+H] +?:?358.1649,?found:?358.1652.。
Embodiment 26:1-(4-methoxy-benzyl)-5,6, the preparation of 7-trimethoxy-1H-indoles (abbreviating compound VII-1 as)
Add 350mg (1.69mmol) 5,6 in the single port bottle of 25ml, 7-trimethoxy indoles, anhydrous tetrahydro furan 5ml; Potassium tert.-butoxide 284mg (2.54mmol), stirring at room drips the solution of 4-methoxybenzyl bromine (2.54mmol) and 5ml anhydrous tetrahydro furan, room temperature reaction 2 hours, removal of solvent under reduced pressure after 15 minutes; Add 10ml water, the anhydrous diethyl ether extraction, anhydrous magnesium sulfate drying filters; Removal of solvent under reduced pressure obtains off-white color solid (compound VII-1), yield 39%. 1H?NMR?(400MHz,?CDCl 3)?δ?7.00?(d,?J?=?8.8?Hz,?2H),?6.96?(d,?J?=?3.2?Hz,?1H),?6.83?(d,?J?=?2.4?Hz,?1H),?6.82?(d,?J?=?8.4?Hz,?2H),?6.39?(d,?J?=?2.8?Hz,?1H),?5.48?(s,?2H),?3.89?(s,?3H),?3.88?(s,?3H),?3.76?(s,?3H),?3.74?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?158.8,?148.9,?140.5,?138.8,?131.4,?129.3,?127.7,?127.7,?125.4,?123.7,?113.9,?113.9,?101.5,?97.5,?61.3,?61.2,?56.2,?55.2,?51.2.?HRMS?calcd?for?C 19H 21NO 4?[M+H] +?:?328.1543,?found:?328.1550.。
Embodiment 27:1-(3-hydroxyl-4-methoxy-benzyl)-5,6, the preparation of 7-trimethoxy-1H-indoles (abbreviating compound VII-2 as)
Operating process is identical with embodiment 26, just replaces 4-methoxybenzyl bromine with 3-hydroxyl-4-methoxybenzyl bromo, obtains off-white color solid (compound VII-2), yield 36%. 1H?NMR?(400MHz,?CDCl 3)?δ?6.95?(d,?J?=?3.2?Hz,?1H),?6.82?(s,?1H),?6.71?(d,?J?=?8.4?Hz,?1H),?6.68?(d,?J?=?1.6?Hz,?1H),?5.68?(s,?1H),?5.43?(s,?2H),?3.87?(s,?3H),?3.87?(s,?3H),?3.79?(s,?3H),?3.74?(s,?3H);? 13C?NMR?(100MHz,?CDCl 3)?δ?148.7,?145.6,?145.6,?140.3,?138.6,?132.4,?129.2,?125.2,?123.5,?117.7,?112.8,?110.5,?101.4,?97.4,?61.2,?61.1,?56.1,?55.7,?51.1.?HRMS?calcd?for?C 19H 21NO 5?[M+H] +:?344.1492,?found:?344.1497.。
It below is compound correlation test of the present invention
One, compound of the present invention (5,6,7-trimethoxy indole derivatives) is to the vitro inhibition effect of human lung carcinoma cell A-549
1. experiment material
Cell strain: human lung carcinoma cell A-549
Substratum: RPMI 1640 substratum contain 10% foetal calf serum
Medicine and preparation: with the foregoing description synthetic compound is that medicine is dissolved in respectively among the DMSO, and the medicine in the Comparative Examples is that NSC-757. and CA-4 also are dissolved among the DMSO respectively.
2. experimental technique
Select the tumour cell of logarithmic phase for use, be made into 4 * 10 with the RPMI l640 substratum that contains 10% foetal calf serum 4The cell suspension of individual/ml is seeded in 96 well culture plates, and 100 μ l, 37 ℃, 5% CO are inoculated in every hole 2Cultivate 24 h.Control wells adds 100 μ l fresh cultures, and experimental port adds the medicine to be measured of 100 μ l desired concns, establishes 3 parallel holes, 37 ℃, 5% CO for every group 2Cultivate after 72 hours, inhale and remove supernatant, add 10 μ lCCK-8 solution and 90 μ lRPMI l640 substratum, continue to cultivate one hour.Measure the OD value of each aperture in 570 nm wavelength with ELIASA.Mapping obtains dose response curve to growth of tumour cell inhibiting rate (%T/C) with the different concns of same sample, can therefrom obtain the half-inhibition concentration IC of sample 50Value.
3. experimental result
Majority 5,6,7-trimethoxy indole derivatives all has different restraining effect to human lung carcinoma cell A-549, wherein the half-inhibition concentration IC of compound III 14, III 16, VI 4,6 pairs of multiple strain cells of VI 50Value has reached sub-micro mole level, has shown the anti-tumor activity of wide spectrum.The half-inhibition concentration IC of compound IV 14 and VI 6 particularly 50Be worth quite with the positive control NSC-757., concrete outcome is referring to table 1 and table 2.
Table 1 compound is to the vitro inhibition effect of human lung carcinoma cell A-549
Figure 839695DEST_PATH_IMAGE007
Table 2 compound III 1-16, IV 1-2, VI 1-6, VII 1-2 are to the vitro inhibition effect of multiple cancer cells
Two, The compounds of this invention 5,6, and 7-trimethoxy indole derivatives is to the vitro inhibition effect of Human umbilical vein endothelial cells HUVEC
1.1 experiment material
Cell strain: Human umbilical vein endothelial cells (HUVEC), in 6 generations
Substratum: endotheliocyte substratum, 0.03mg/ml ECGF additive, 0.1mg/ml heparin, 10% foetal calf serum
Medicine and preparation: above-mentioned synthetic compound III 14, VI 6 medicines are dissolved among the DMSO
1.2 experimental technique
Compound is to the effect of activated Human umbilical vein endothelial cells vitro inhibition:
According to people's such as Flynn method, select for use 6 bands with interior Human umbilical vein endothelial cells, be made into 2.5 * 10 with the endotheliocyte substratum that contains 10% foetal calf serum, 0.03mg/ml ECGF additive, 0.1mg/ml heparin 4The cell suspension of individual/ml is seeded in 96 well culture plates, and 100 μ l, 37 ℃, 5% CO are inoculated in every hole 2Cultivate 24 h.Control wells adds 100 μ l fresh cultures, and experimental port adds the medicine to be measured of 100 μ l desired concns, establishes 3 parallel holes, 37 ℃, 5% CO for every group 2Cultivate after 72 hours, inhale and remove supernatant, add 10 μ lCCK-8 solution and 90 μ l endotheliocyte culture medium culturing bases, continue to cultivate one hour.Measure the OD value of each aperture in 450 nm wavelength with ELIASA.Mapping obtains dose response curve to growth of tumour cell inhibiting rate (%T/C) with the different concns of same sample, can therefrom obtain the half-inhibition concentration IC of sample 50Value.
2. compound is to the effect of immobilized Human umbilical vein endothelial cells vitro inhibition:
2.1 experiment material
Cell strain: Human umbilical vein endothelial cells, in 6 generations
Substratum: endotheliocyte substratum, 0.5% foetal calf serum
Medicine and preparation: above-mentioned synthetic compound III 14, VI 6 medicines are dissolved among the DMSO
2.2 experimental technique
Compound is to the effect of activated human umbilical vein endothelial cell vitro inhibition:
According to people's such as Flynn method, select for use 6 bands with interior human umbilical vein endothelial cell, be made into 1.5 * 10 with the endotheliocyte substratum that contains 0.5% foetal calf serum 5The cell suspension of individual/ml is seeded in 96 well culture plates, and 100 μ l, 37 ℃, 5% CO are inoculated in every hole 2Cultivate 24 h.Control wells adds 100 μ l fresh cultures, and experimental port adds the medicine to be measured of 100 μ l desired concns, establishes 3 parallel holes, 37 ℃, 5% CO for every group 2Cultivate after 72 hours, inhale and remove supernatant, add 10 μ l CCK-8 solution and 90 μ l endotheliocyte culture medium culturing bases, continue to cultivate one hour.Measure the OD value of each aperture in 450 nm wavelength with ELIASA.Mapping obtains dose response curve to growth of tumour cell inhibiting rate (%T/C) with the different concns of same sample, can therefrom obtain the half-inhibition concentration IC of sample 50Value.The half-inhibition concentration of immobilized human umbilical vein endothelial cell is drawn the opt ratio of compound with compound divided by its half-inhibition concentration to the activated human umbilical vein endothelial cell.
3. experimental result
The half-inhibition concentration IC of compound III 14, VI 6 activated human umbilical vein endothelial cells 50Value has reached sub-micro mole level; And to the half-inhibition concentration of immobilized human umbilical vein endothelial cell respectively up to 5.2 and 6.6 micromoles; This has shown that they are to the high selectivity of activated human umbilical vein endothelial cell; And their selectivity is well beyond positive control NSC-757. and CA-4, and concrete outcome is referring to table 3.
Table 3 compound III 14, the effect of 6 pairs of Human umbilical vein endothelial cells vitro inhibition of VI
Figure 850824DEST_PATH_IMAGE009

Claims (7)

  1. Show 5,6 suc as formula 1,7-trimethoxy indole derivatives,
    Figure 2012103465980100001DEST_PATH_IMAGE001
    Formula 1
    Wherein: R 1Be H or CH 3R 2Be H or CH 3R 3Be CH 2Or CO; R 4Be 2-OCH 3, or 3-OCH 3, or 4-OCH 3, or 4-CH 3, or 3,4,5-tri-OCH 3, or 3-OH-4-OCH 3, or 3-F-4-OCH 3, or 3-Cl-4-OCH 3, or 3-I-4-OCH 3
  2. Show 5,6 suc as formula 2,7-trimethoxy indole derivatives,
    Formula 2
    R 5Be CO or CH 2:
    R 6Be 4-OCH 3Or 3-OH-4-OCH 3
  3. Formula 3 is shown the preparation method of compound III, it is characterized in that reaction shows suc as formula 3, with chemical compounds I in the formula 3 does
    Figure 2012103465980100001DEST_PATH_IMAGE003
    Formula 3
    Raw material; With ethyl grignard reagent, aluminum chloride and zinc chloride be catalyzer in anhydrous methylene chloride with formula 3 in compound ii react and obtain the target compound III; Wherein add catalyzer ethyl grignard reagent: aluminum chloride: the mol ratio of zinc chloride equals 2:1:2～1:1:2, in the formula 3: R 1Be H or CH 3R 2Be H or CH 3R 4Be 2-OCH 3, or 3-OCH 3, or 4-OCH 3, or 4-CH 3, or 3,4,5-tri-OCH 3, or 3-OH-4-OCH 3, or 3-F-4-OCH 3, or 3-Cl-4-OCH 3, or 3-I-4-OCH 3
  4. Formula 4 is shown the preparation method of compound IV, it is characterized in that reaction is suc as formula shown in 4, with chemical compounds I in the formula 4
    Figure 515092DEST_PATH_IMAGE004
    Formula 4
    Be raw material, with the potassium tert.-butoxide be catalyzer in anhydrous tetrahydro furan with formula 4 in compound ii (substituted benzoyl chloride) reaction, obtain target compound.
  5. In the reaction formula 4: R 5Be CO or CH 2
  6. Formula 5 is shown the preparation method of compound VI; It is characterized in that reaction suc as formula shown in 5, is a raw material with chemical compounds I in the formula 5, with bicarbonate of ammonia be catalyzer in the aqueous acetone solution that contains volume ratio 20% with formula 5 in compound V reaction; Obtain the corresponding compounds VI, R in the formula 5 5Be CO, CH 2
    Figure 2012103465980100001DEST_PATH_IMAGE005
  7. Formula 5
    Formula 6 is shown the preparation method of compound VII, it is characterized in that reaction is suc as formula shown in 6, with chemical compounds I in the formula 6
    Formula 6
    Being raw material, is that catalyzer is showing that with formula 6 reaction of compound V obtains corresponding compounds VII, R in the formula 6 with the potassium tert.-butoxide in anhydrous tetrahydro furan 5Be CO, CH 2
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CN111675644A (en) * 2020-06-08 2020-09-18 南京医科大学 Indole diaryl methane compound and preparation method and application thereof
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CN111675644A (en) * 2020-06-08 2020-09-18 南京医科大学 Indole diaryl methane compound and preparation method and application thereof
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