CN101033226A - 1-furylmethyl-3-substituted indolin-2-one derivative - Google Patents
1-furylmethyl-3-substituted indolin-2-one derivative Download PDFInfo
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- furfuryl
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Abstract
This invention relates to a derivant of 1-furan methyl-3-replaced indole-2-ketone derivant especially to indole-2-ketone derivant replaced by 1-(5 replaced furan methyl) indole-2-ketone compound in three bits, its preparation method and the application on medicine. This invented compound has fine anti-cancer activation compared with anode contrast to anti-cancer medicine.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate to 1-furfuryl-3-substituted Indolinyl-2-ketone derivatives, preparation method and application.Be specifically related to a kind of 3 1-(5-substituted furan methyl) indole-2-ketone compounds that have pyrroles's methylene radical to replace, and preparation method thereof and in medically application.
Background technology
Malignant tumour has become the common disease of serious harm people's life health.According to incompletely statistics, the whole world has 2,000 ten thousand new cases every year approximately; The new cases in China every year are about 160-200 ten thousand, dead 1,300,000.Because tumour has the ability of transfer in early days, about 50% patient has produced the amphi position transfer in the clinical diagnosis primary tumo(u)r, fast, easily variation that tumour cell increases, thereby generation multidrug resistance, cause the chemotherapy failure, according to the relevent statistics, wherein the multidrug resistance with tumour cell is relevant more than 90%, and the antitumor drug of using clinically far can not satisfy the requirement of treatment at present.
The anti-tumor activity of indole-2-ketone compounds is noticed in relevant research.Found antitumor drugs such as Indirubin wherein, Indirubin has obvious restraining effect to kinds of tumors; It is suitable with busulfan to the leukocytic curative effect of chronic granulocyte, and it is reliable to have a clinical efficacy, and toxic side effect is little, marrow is not had characteristics such as obvious restraining effect.The main drawback of Indirubin is that solvability is not good, and is water-soluble and fat-soluble all relatively poor, and oral administration administration influence absorbs, and the clinical application produce effects is slower, and gastrointestinal side effect is arranged.
3-replacement-2-indole ketone compound is that a class has vascular endothelial growth factor (VEGF) receptor tyrosine kinase and suppresses active compound, has research to change the activity of this compounds by the transformation to indolone parent nucleus 3 bit substituents.Sugen company obtains a collection of candidate compound with lateral reactivity by high flux screening, and representation compound has SU5416, SU6668 and SU11248.This compounds and ATP competitiveness are incorporated into the tyrosine kinase domain of multiple growth factor receptors, suppress the Tyrosylprotein kinase autophosphorylation, the transduction of blocking-up bio signal.Wherein Sutent (Sunitinib, SU11248) is ratified by FDA in January, 2006.Clinical oral administration can be used for treating the invalid malignant gastrointestinal that maybe can not tolerate of standard care and asks matter knurl or metastatic renal cell cancer.
Summary of the invention:
The purpose of this invention is to provide new indole quinoline-2-ketone compounds, be specifically related to a kind of 3 1-(5-substituted furan methyl) indole-2-ketone compounds that have pyrroles's methylene radical to replace with good resistance tumor promotion.
Another object of the present invention provides above-mentioned 3 preparation methods that 1-(5-substituted furan methyl) the indole-2-ketone compounds of pyrroles's methylene radical replacement is arranged.
New indole quinoline of the present invention-2-ketone compounds has the structure of following general formula (I):
Wherein
R1=hydrogen or halogen or methyl;
R2=-CHO or
Novel cpd of the present invention is by preliminary pharmacodynamic study, and the anti tumor activity in vitro test result shows that described compound has good activity, can develop to be new type antineoplastic medicine.
Preferred compound of the present invention has the structure of following compound 1,2,3,4,5,6,7,8:
Above-claimed cpd 1 or 5 preparation process are as follows:
Compound 1 or 5 preparation technology comprise: with 5-formyl radical-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid, ethyl ester and indole-2-ketone condensation obtain 2; 4-dimethyl-5-[(1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate; further under the potassium alkaline condition, carry out 1 N hydrocarbonylation and obtain compound 1, obtain compound 5 with the indole-2-ketone condensation again with the chloromethyl Furan Aldehydes.
The compounds of this invention 2 and 6 preparation process are as follows:
Compound 2 or 6 preparation technology comprise: with 5-formyl radical-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid, ethyl ester and the condensation of 5-bromo-indole-2-ketone obtain 2; 4-dimethyl-5-[(5-bromo-1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate; further under the potassium alkaline condition, carry out 1 N hydrocarbonylation and obtain compound 2, obtain compound 6 with the indole-2-ketone condensation again with the chloromethyl Furan Aldehydes.
The compounds of this invention 3 or 7 preparation process are as follows:
Compound 3 or 7 preparation technology comprise: with 5-formyl radical-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid, ethyl ester and the condensation of 5-fluoro-indole-2-ketone obtain 2; 4-dimethyl-5-[(5-fluoro-1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate; further under the potassium alkaline condition, carry out 1 N hydrocarbonylation and obtain compound 3, obtain compound 7 with the indole-2-ketone condensation again with the chloromethyl Furan Aldehydes.
The compounds of this invention 4 or 8 preparation process are as follows:
Compound 4 or 8 preparation technology comprise: with 5-formyl radical-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid, ethyl ester and 5-methyl-indole-2-ketone condensation obtain 2; 4-dimethyl-5-[(5-methyl isophthalic acid; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate; further under the potassium alkaline condition, carry out 1 N hydrocarbonylation and obtain compound 4, obtain compound 8 with the indole-2-ketone condensation again with the chloromethyl Furan Aldehydes.
3 1-(5-substituted furan methyl) indole-2-ketone derivatives that have pyrroles's methylene radical to replace involved in the present invention have anti tumor activity in vitro, can further prepare antitumor drug.Described compound is by preliminary pharmacodynamic study, and to the anti tumor activity in vitro experiment of SPC-A1 lung cancer tumor line, the result shows that described compound has good antineoplastic activity.Compound is for the anti tumor activity in vitro IC of SPC-A1 lung cancer tumor line
50Be worth all less than 40 μ M, wherein the extracorporeal anti-tumor IC of 5,6,7 or 8 pairs of SPC-A1 lung cancer tumor lines of compound
50Value is better than positive control antitumor drug Sutent all less than 5 μ M.Experimental result confirms that The compounds of this invention has the anti tumor activity in vitro of SPC-A1 lung cancer tumor line, can further develop new type antineoplastic medicine.
Embodiment:
Embodiment 1: synthetic compound 1,2,4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
1) Synthetic 2; 4-dimethyl-5-[(1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate adds 5-formyl radical-2 in the 50ml flask; 4-dimethyl-1H-pyrroles-3-carboxylic acid 0.70 gram (3.59mmol), 1; 3-dihydro-indol-2-one 0.40 gram (3mmol), ethanol 9ml, piperidines number droplet, a large amount of solids appear in stirring and refluxing under the nitrogen protection after 3 hours.Cool off the back suction filtration, and get orange/yellow solid 0.83 gram, yield 89.3% with small amount of ethanol washing, vacuum-drying.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, J=7.10, COOCH
2C
H 3), 2.49 (s, 3H, pyrrole-3-C
H 3), 2.54 (s, 3H, pyrrole-5-C
H 3), 4.21 (q, 2H, J=7.10, COOC
H 2CH
3), 6.89 (d, 1H, J=7.66, indole-H
7), 7.00 (t, 1H, J=7.56, indole-H
6), 7.15 (t, 1H, J=7.57, indole-H
5), 7.65 (s, 1H, thiazolinyl H), 7.80 (d, 1H, J=7.46, indole-H
4), 10.95 (s, 1H, indole-2-ketone NH), 13.88 (s, 1H, pyrrole-NH).
2) Synthetic 2,4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 2; 4-dimethyl-5-[(1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate 0.40 restrains (1.3mmol), salt of wormwood 0.27 gram (1.94mmol), DMF 9ml, stirring at room adds chloromethyl furtural 0.28 gram (1.94mmol), potassiumiodide 30mg after 30 minutes, and nitrogen protection continued stirring at room 3 hours down.TLC shows that reaction finishes, and adds 30ml ethyl acetate and 30ml water, stirs the back separatory, and the water ethyl acetate extraction merges the organic phase after washing and washs saturated common salt water washing three times, anhydrous magnesium sulfate drying five times.Get yellow solid 0.45 gram, yield 82.8% after filtering evaporate to dryness.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, J=7.06, COOCH
2C
H 3), 2.50 (s, 3H, pyrrole-3-C
H 3), 2.55 (s, 3H, pyrrole-5-C
H 3), 4.22 (q, 2H, J=7.06, COOC
H 2CH
3), 5.15 (s, 2H, furan-C
H 2), 6.74 (d, 1H, J=2.97, furan-H), 7.05-7.10 (t, 1H, J=7.45, indole-H
6), 7.11-7.16 (d, 1H, J=7.78, indole-H
7), 7.19-7.24 (t, 1H, J=7.61, indole-H
5), 7.48 (d, 1H, J=2.95, furan-H), 7.73 (s, 1H, thiazolinyl H), 7.85-7.90 (d, 1H, J=7.50, indole-H
4), 9.50 (s, 1H, CHO), 13.70 (s, 1H, pyrrole-NH).ESI-MS：m/z[M+H]
+419
Embodiment 2: synthetic compound 5,2,4-dimethyl-5-[1-[[5-[(indole-2-ketone-3-thiazolinyl) methyl]-furans-2-yl] methyl]-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 2; 4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate 0.16 gram (0.383mmol), 1; 3-dihydro-indol-2-one 0.049 gram (0.37mmol), ethanol 4ml, piperidines number droplet, a large amount of solids appear in stirring and refluxing under the nitrogen protection after 3 hours.Cool off the back suction filtration, and get orange/yellow solid 0.15 gram, yield 76.1% with small amount of ethanol washing, vacuum-drying.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, COOCH
2C
H 3), 2.50 (s, 3H, pyrrole-3-C
H 3), 2.55 (s, 3H, pyrrole-5-C
H 3), 4.25 (m, 2H, COOC
H 2CH
3), 5.35 (s, 2H, furan-C
H 2), 6.68 (d, 1H, furan-H), 6.78 (m, 1H, indole-H), 6.95 (m, 1H, indole-H), 7.12 (d, 2H, indole-H), and 7.24-7.37 (m, 4H, indole-H, thiazolinyl H, furan-H), (7.73 s, 1H, thiazolinyl H), 7.88 (m, 1H, indole-H), 8.15 (m, 1H, indole-H), 10.95 (s, 1H, indole-2-ketone NH), 13.70 (s, 1H, pyrrole-NH).ESI-MS：m/z[M+H]
+534
Embodiment 3: synthetic compound 2,2,4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-5-bromo-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
1) Synthetic 2,4-dimethyl-5-[(5-bromo-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 5-formyl radical-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid 0.38 gram (1.97mmol), 5-bromo-1; 3-dihydro-indol-2-one 0.35 gram (1.65mmol), ethanol 7ml, piperidines number droplet, a large amount of solids appear in stirring and refluxing under the nitrogen protection after 3 hours.Cool off the back suction filtration, and get orange/yellow solid 0.60 gram, yield 93.5% with small amount of ethanol washing, vacuum-drying.
1H-NMR (DMSO-d
6) δ (ppm): 1.29 (t, 3H, J=7.03, COOCH
2C
H 3), 2.49 (s, 3H, pyrrole-3-C
H 3), 2.52 (s, 3H, pyrrole-5-C
H 3), 4.19 (q, 2H, J=7.03, COOC
H 2CH
3), 6.79-6.82 (d, 1H, J=8.25, indole-H
7), 7.24-7.28 (dd, 1H, J=8.25,1.84, indole-H
6), 7.79 (s, 1H, thiazolinyl H), 8.12 (d, 1H, J=1.83, indole-H
4), 11.05 (s, 1H, indole-NH), 13.85 (s, 1H, pyrrole-NH).
2) synthetic compound 2,4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-5-bromo-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 2; 4-dimethyl-5-[(5-bromo-1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate 0.40 restrains (1.03mmol), salt of wormwood 0.21 gram (1.54mmol), DMF 6ml, stirring at room adds chloromethyl furtural 0.22 gram (1.54mmol), potassiumiodide 30mg after 30 minutes, and nitrogen protection continued stirring at room 3 hours down.TLC shows that reaction finishes, and adds 30ml ethyl acetate and 30ml water, stirs the back separatory, and the water ethyl acetate extraction merges the organic phase after washing and washs saturated common salt water washing three times, anhydrous magnesium sulfate drying five times.Get yellow solid 0.40 gram, yield 78.3% after filtering evaporate to dryness.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, J=7.07, COOCH
2C
H 3), 2.52 (s, 3H, pyrrole-3-C
H 3), 2.56 (s, 3H, pyrrole-5-C
H 3), 4.21 (q, 2H, J=7.07, COOC
H 2CH
3), 5.20 (s, 2H, furan-C
H 2), 6.74 (d, 1H, J=3.42, furan-H), 7.10 (d, 1H, J=8.78, indole-H
7), 7.33-7.37 (dd, 1H, J=8.29,1.95, indole-H
6), 7.49 (d, 1H, J=3.42, furan-H), 7.90 (s, 1H, thiazolinyl H), 8.23 (d, 1H, J=1.95, indole-H
4), 9.50 (s, 1H, CHO), 13.60 (s, 1H, pyrrole-NH).ESI-MS：m/z[M+H]
+498
Embodiment 4: synthetic compound 6,2,4-dimethyl-5-[1-[[5-[(indole-2-ketone-3-thiazolinyl) methyl]-furans-2-yl] methyl]-5-bromo-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 2; 4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-5-bromo-1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate 0.14 gram (0.28mmol), 1; 3-dihydro-indol-2-one 0.036 gram (0.27mmol), ethanol 5ml, piperidines number droplet, a large amount of solids appear in stirring and refluxing under the nitrogen protection after 3 hours.Cool off the back suction filtration, and get orange/yellow solid 0.15 gram, yield 87% with small amount of ethanol washing, vacuum-drying.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, J=7.03, COOCH
2C
H 3), 2.52 (s, 3H, pyrrole-3-C
H 3), 2.60 (s, 3H, pyrrole-5-C
H 3), 4.20 (q, 2H, J=7.03, COOC
H 2CH
3), 5.35 (s, 2H, furan-C
H 2), 6.62-6.67 (t, 1H, J=8.04, indole-H
5 '), 6.73-6.77 (d, 1H, J=7.31, indole-H
7), 6.94 (d, 1H, J=3.42, furan-H), 7.05-7.10 (t, 1H, J=7.31, indole-H
6 '), 7.18-7.21 (m, 3H, indole-H, thiazolinyl H, furan-H), 7.34-7.37 (dd, 1H, J=8.54,1.95, indole-H
6), 7.93 (s, 1H, thiazolinyl-H), 8.10 (d, 1H, J=7.80, indole-H), 8.25 (d, 1H, J=1.95, indole-H
4), 10.46 (s, 1H, indole-2-ketone NH), 13.80 (s, 1H, pyrrole-NH).ESI-MS：m/z[M+H]
+613
Embodiment 5: synthetic compound 3,2,4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-5-fluoro-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
1) Synthetic 2,4-dimethyl-5-[(5-fluoro-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 5-formyl radical-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid 0.46 gram (2.38mmol), 5-fluoro-1; 3-dihydro-indol-2-one 0.30 gram (1.99mmol), ethanol 6ml, piperidines number droplet, a large amount of solids appear in stirring and refluxing under the nitrogen protection after 3 hours.Cool off the back suction filtration, and get orange/yellow solid 0.60 gram, yield 92.1% with small amount of ethanol washing, vacuum-drying.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, J=7.03, COOCH
2C
H 3), 2.49 (s, 3H, pyrrole-3-C
H 3), 2.53 (s, 3H, pyrrole-5-C
H 3), 4.20 (q, 2H, J=7.03, COOC
H 2CH
3), 6.81-6.85 (dd, 1H, J=8.55,4.58, indole-H
7), 6.90-6.96 (m, 1H, J=8.56,2.75, indole-H
6), 7.75 (s, 1H, thiazolinyl H), 7.77-7.81 (dd, 1H, J=9.17,2.65, indole-H
4), 10.95 (s, 1H, indole-2-ketone NH), 13.90 (s, 1H, pyrrole-NH).
2) Synthetic 2,4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-5-fluoro-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 2; 4-dimethyl-5-[(5-fluoro-1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate 0.35 restrains (1.07mmol), salt of wormwood 0.22 gram (1.60mmol), DMF 6ml, stirring at room adds chloromethyl furtural 0.23 gram (1.60mmol), potassiumiodide 30mg after 30 minutes, and nitrogen protection continued stirring at room 3 hours down.TLC shows that reaction finishes, and adds 30ml ethyl acetate and 30ml water, stirs the back separatory, and the water ethyl acetate extraction merges the organic phase after washing and washs saturated common salt water washing three times, anhydrous magnesium sulfate drying five times.Get yellow solid 0.40 gram, yield 86% after filtering evaporate to dryness.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, J=7.04, COOCH
2C
H 3), 2.50 (s, 3H, pyrrole-3-C
H 3), 2.55 (s, 3H, pyrrole-5-C
H 3), 4.20 (q, 2H, J=7.03, COOC
H 2CH
3), 5.20 (s, 2H, furan-C
H 2), 6.74 (d, 1H, J=3.67, furan-H), 6.98-7.04 (m, 1H, J=9.47,2.45indole-H
6), 7.10-7.14 (dd, 1H, J=8.86,4.58, indole-H
7), 7.47 (d, 1H, J=3.67, furan-H), 7.82 (s, 1H, thiazolinyl H), 7.87-7.92 (dd, 1H, J=9.47,2.44, indole-H
4), 9.46 (s, 1H, CHO), 13.65 (s, 1H, pyrrole-NH).ESI-MS：m/z[M+H]
+437
Embodiment 6: synthetic compound 7,2,4-dimethyl-5-[1-[[5-[(indole-2-ketone-3-thiazolinyl) methyl]-furans-2-yl] methyl]-5-fluoro-1,2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 2; 4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-5-fluoro-1; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate 0.14 gram (0.32mmol), 5-fluoro-1; 3-dihydro-indol-2-one 0.042 gram (0.31mmol), ethanol 5ml, piperidines number droplet, a large amount of solids appear in stirring and refluxing under the nitrogen protection after 3 hours.Cool off the back suction filtration, and get orange/yellow solid 0.14 gram, yield 82% with small amount of ethanol washing, vacuum-drying.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, J=7.03, COOCH
2C
H 3), 2.51 (s, 3H, pyrrole-3-C
H 3), 2.60 (s, 3H, pyrrole-5-C
H 3), 4.21 (q, 2H, J=7.02, COOC
H 2CH
3), 5.32 (s, 2H, furan-C
H 2), 6.62-6.67 (t, 1H, J=7.63, indole-H
S '), 6.74-6.77 (d, 1H, J=7.33, indole-H
7), 6.95 (d, 1H, J=3.67, furan-H), 7.00-7.10 (m, 2H, indole-H), 7.19-7.24 (m, 3H, indole-H, thiazolinyl H, furan-H), 7.85 (s, 1H, thiazolinyl-H), 7.89-7.93 (dd, 1H, J=9.17,2.45, indole-H
6), 8.11-8.14 (d, 1H, J=7.33, indole-H), 10.45 (s, 1H, indole-2-ketone NH), 13.82 (s, 1H, pyrrole-NH).ESI-MS：m/z[M+H]
+552
Embodiment 7: synthetic compound 4,2,4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-the 5-methyl isophthalic acid, 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
1) Synthetic 2,4-dimethyl-5-[(5-methyl isophthalic acid, 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
Add 5-formyl radical-2 in the 50ml flask; 4-dimethyl-1H-pyrroles-3-carboxylic acid 0.56 gram (2.85mmol), 5-methyl isophthalic acid; 3-dihydro-indol-2-one 0.35 gram (2.38mmol), ethanol 8ml, piperidines number droplet, a large amount of solids appear in stirring and refluxing under the nitrogen protection after 3 hours.Cool off the back suction filtration, and get orange/yellow solid 0.68 gram, yield 88.2% with small amount of ethanol washing, vacuum-drying.
1H-NMR (DMSO-d
6) δ ((ppm): 1.30 (t, 3H, J=7.31, COOCH
2C
H 3), 2.30 (s, 3H, indole-5-C
H 3), 2.50 (s, 3H, pyrrole-3-C
H 3), 2.53 (s, 3H, pyrrole-5-C
H 3), 4.21 (q, 2H, J=7.31, COOC
H 2CH
3), 6.75-6.78 (d, 1H, J=7.80, indole-H
7), 6.93-6.97 (d, 1H, J=7.31, indole-H
6), 7.63 (s, 1H, thiazolinyl H), 7.64 (s, 1H, indole-H
4), 10.86 (s, 1H, indole-2-ketone NH), 13.85 (s, 1H, pyrrole-NH).
2) Synthetic 2,4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-the 5-methyl isophthalic acid, 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 2; 4-dimethyl-5-[(5-methyl isophthalic acid; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate 0.40 restrains (1.23mmol), salt of wormwood 0.26 gram (1.85mmol), DMF7ml, stirring at room adds chloromethyl furtural 0.27 gram (1.85mmol), potassiumiodide 30mg after 30 minutes, and nitrogen protection continued stirring at room 3 hours down.TLC shows that reaction finishes, and adds 30ml ethyl acetate and 30ml water, stirs the back separatory, and the water ethyl acetate extraction merges the organic phase after washing and washs saturated common salt water washing three times, anhydrous magnesium sulfate drying five times.Get yellow solid 0.40 gram, yield 75.3% after filtering evaporate to dryness.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, J=7.07, COOCH
2C
H 3), 2.30 (s, 3H, indole-5-C
H 3), 2.50 (s, 3H, pyrrole-3-C
H 3), 2.54 (s, 3H, pyrrole-5-C
H 3), 4.20 (q, 2H, J=7.07, COOC
H 2CH
3), 5.20 (s, 2H, furan-C
H 2), 6.71 (d, 1H, J=3.41, furan-H), 7.00 (d, 2H, J=0.97, indole-H
4, H
7), 7.47 (d, 1H, J=3.42, furan-H), 7.70 (s, 1H, thiazolinyl H), 7.70-7.72 (d, 1H, J=3.41, indole-H
6), 9.45 (s, 1H, CHO), 13.62 (s, 1H, pyrrole-NH).ESI-MS：m/z[M+H]
+433
Embodiment 8: synthetic compound 8,2,4-dimethyl-5-[1-[[5-[(indole-2-ketone-3-thiazolinyl) methyl]-furans-2-yl] methyl]-the 5-methyl isophthalic acid, 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate
In the 50ml flask, add 2; 4-dimethyl-5-[1-[(5-formylfuran-2-yl) methyl]-the 5-methyl isophthalic acid; 2-dihydro-2-oxo--indoles-3-thiazolinyl) methyl]-1H-pyrroles-3-ethyl formate 0.14 gram (0.32mmol), 5-methyl isophthalic acid; 3-dihydro-indol-2-one 0.042 gram (0.31mmol), ethanol 5ml, piperidines number droplet, a large amount of solids appear in stirring and refluxing under the nitrogen protection after 3 hours.Cool off the back suction filtration, and get orange/yellow solid 0.15 gram, yield 87.6% with small amount of ethanol washing, vacuum-drying.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (t, 3H, J=7.05, COOCH
2C
H 3), 2.30 (s, 3H, indole-5-C
H 3), 2.50 (s, 3H, pyrrole-3-C
H 3), 2.60 (s, 3H, pyrrole-5-C
H 3), 4.21 (q, 2H, J=7.05, COOC
H 2CH
3), 5.29 (d, 2H, furan-C
H 2), 6.62-6.67 (m, 1H, indole-H
5 '), 6.73-6.76 (d, 1H, J=7.82, indole-H
7), 6.94 (d, 1H, J=3.52, furan-H), 6.98-7.02 (d, 1H, indole-H), 7.05-7.11 (m, 2H, indole-H), and 7.18-7.20 (m, 2H, thiazolinyl H, furan-H), 7.72-7.76 (m, 2H, thiazolinyl H, indole-H), 8.12-8.15 (d, 1H, J=7.43, indole-H), 10.45 (s, 1H, indole-2-ketone NH), 13.80 (s, 1H, pyrrole-NH).ESI-MS：m/z[M+H]
+548
Embodiment 9: the test of extracorporeal anti-tumor cytoactive
Screening method adopts tetrazolium (microculture tetrozolium, MTT) reduction method.The MTT analytical method with metabolism reduce 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) be the basis.Have the desaturase relevant with NADP in the plastosome of viable cell, xanchromatic MTT can be reduced to the insoluble hepatic first moon for (Formazan), this enzyme of dead cell disappears, and MTT is not reduced.With detecting optical density(OD) at 570nm wavelength place with microplate reader behind the DMSO dissolving Formazan.
Used experiment material and reagent, wherein the RPMI1640 substratum is available from Gibco company; Tetrazolium (MTT) is available from source, Shanghai consor thing Science and Technology Ltd.; Microplate reader is Elx 800 (Bio-tekInstrument Inc.).SPC-A1 lung cancer tumour cell (The National Center for Drug Screening).
Screening adopts 96 hole flat boards to do little cultivation, with killing and wounding or growth-inhibiting of MTT method observation of cell.To each cell strain, each concentration is three multiple holes.According to the inferior plate specificity that the cytotoxicity that is subjected to the reagent thing has, differentiate to have optionally antitumor drug.Survey the OD570 value with microplate reader.
Calculate the inhibiting rate of analyte by following formula to growth of cancer cells.
And make regression equation with the logarithm and the inhibiting rate of compound concentration, calculate IC
50, show the anti-tumor activity that compound has.
Table 1 is the active result of the antitumor cell of The compounds of this invention.
Table 1
The result shows that compound of the present invention all demonstrates good antineoplastic activity, to the anti tumor activity in vitro IC of SPC-A1 lung cancer tumor line
50Value wherein contains compound 5 (4.09 μ M), 6 (2.80 μ M), 7 (3.09 μ M) or 8 (the 4.11 μ M) of the two indole-2-ketone structures extracorporeal anti-tumor IC to SPC-A1 lung cancer tumor line all less than 40 μ M
50Value is better than positive control antitumor drug Sutent (9.92 μ M) all less than 5 μ M.Can further develop new type antineoplastic medicine.
Claims (12)
1,1-furfuryl-3-substituted Indolinyl-2-ketone derivatives, it is characterized in that the having general formula structure of (I),
Wherein, R1=hydrogen or halogen or methyl;
R2=-CHO or
2,1-furfuryl according to claim 1-3-substituted Indolinyl-2-ketone derivatives, the compound 1 that it is characterized in that having following structure,
3,1-furfuryl according to claim 1-3-substituted Indolinyl-2-ketone derivatives, the compound 2 that it is characterized in that having following structure,
4,1-furfuryl according to claim 1-3-substituted Indolinyl-2-ketone derivatives, the compound 3 that it is characterized in that having following structure
5,1-furfuryl according to claim 1-3-substituted Indolinyl-2-ketone derivatives, the compound 4 that it is characterized in that having following structure,
6,1-furfuryl according to claim 1-3-substituted Indolinyl-2-ketone derivatives, the compound 5 that it is characterized in that having following structure,
7,1-furfuryl according to claim 1-3-substituted Indolinyl-2-ketone derivatives, the compound 6 that it is characterized in that having following structure,
8,1-furfuryl according to claim 1-3-substituted Indolinyl-2-ketone derivatives, the compound 7 that it is characterized in that having following structure,
9,1-furfuryl according to claim 1-3-substituted Indolinyl-2-ketone derivatives, the compound 8 that it is characterized in that having following structure,
10, the preparation method of 1-furfuryl according to claim 1-3-substituted Indolinyl-2-ketone derivatives; it is characterized in that 5-formyl radical-2; the indole-2-ketone condensation of 4-dimethyl-1H-pyrroles-3-carboxylic acid, ethyl ester and 5 different replacements; further under the potassium alkaline condition, carry out 1 N hydrocarbonylation and obtain compound 1-4, obtain compound 5-8 with the indole-2-ketone condensation again with the chloromethyl Furan Aldehydes.
11, the purposes of the 1-of claim 1 furans-3-substituted Indolinyl-2-ketone derivatives in preparation medicine for treating tumor thing.
12, by the purposes of claim 11, it is characterized in that described tumour is a lung cancer.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101333215B (en) * | 2008-07-29 | 2011-01-12 | 南京工业大学 | Method for synthesizing sunitinib alkali |
| CN102115472A (en) * | 2010-01-04 | 2011-07-06 | 深圳市天和医药科技开发有限公司 | 3-(2-pyrromethene)azaindoline-2-one derivatives and preparation method and application thereof |
| CN102115469A (en) * | 2011-03-21 | 2011-07-06 | 浙江大学 | Preparation method for indoline-2-one derivative and application of same |
| CN101497607B (en) * | 2008-01-29 | 2012-11-28 | 上海百灵医药科技有限公司 | Process for synthesizing sunitinib |
-
2007
- 2007-04-06 CN CN200710039248A patent/CN101033226B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101497607B (en) * | 2008-01-29 | 2012-11-28 | 上海百灵医药科技有限公司 | Process for synthesizing sunitinib |
| CN101333215B (en) * | 2008-07-29 | 2011-01-12 | 南京工业大学 | Method for synthesizing sunitinib alkali |
| CN102115472A (en) * | 2010-01-04 | 2011-07-06 | 深圳市天和医药科技开发有限公司 | 3-(2-pyrromethene)azaindoline-2-one derivatives and preparation method and application thereof |
| CN102115472B (en) * | 2010-01-04 | 2013-12-04 | 深圳市天和医药科技开发有限公司 | 3-(2-pyrromethene)azaindoline-2-one derivatives and preparation method and application thereof |
| CN102115469A (en) * | 2011-03-21 | 2011-07-06 | 浙江大学 | Preparation method for indoline-2-one derivative and application of same |
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