CN101684123A - Preparation method of 2-formamido thienopyridine derivatives and medical uses - Google Patents
Preparation method of 2-formamido thienopyridine derivatives and medical uses Download PDFInfo
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- CN101684123A CN101684123A CN200810046188A CN200810046188A CN101684123A CN 101684123 A CN101684123 A CN 101684123A CN 200810046188 A CN200810046188 A CN 200810046188A CN 200810046188 A CN200810046188 A CN 200810046188A CN 101684123 A CN101684123 A CN 101684123A
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Abstract
The invention discloses preparation method of 2-formamido thienopyridine derivatives and uses in preparing antineoplastic medicine compositions, The experiment results show that the 2-formamido thienopyridine derivatives has antitumor action, which can be used as main active components to prepare new antineoplastic medicine and provide new selection for treatment of tumour.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the purposes of 2-formamido thienopyridine derivatives in the preparation antineoplastic pharmaceutical compositions.
Background technology
Malignant tumour has become the important killer that harm humans is healthy and survive, and particularly in recent years, along with the deterioration of environment, tangible ascendant trend has appearred in the sickness rate of malignant tumour.Although along with the application that chemotherapeutics of new generation such as taxol, gemcitabine, Gree are defended etc., patient's existence obtains certain benefit, most of cancer patientss' prognosis is still relatively poor, and the mortality ratio height is typical in liver cancer and prostate cancer etc.Therefore, research and development novel particularly have the antitumor drug of brand-new precursor structure or from existing compound the antitumor drug that makes new advances of screening become the task of top priority.
The contriver is through discovering that the 2-formamido thienopyridine derivatives has anti-tumor activity.Its structural formula is as follows:
In the formula, R
1Be hydrogen, amino or hydroxyl; R
2Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy; R
3Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy.
And the contriver further finds compound 3-amino-N-(4-chlorobenzyl)-7-(3-methoxyphenyl)-4H-thiopyrano[2 under study for action, 3-b] pyridine-2-carboxamide, be a kind of be the compound of precursor structure with the 2-formamido thienopyridine, be one of 2-formamido thienopyridine derivatives, this compound has tangible anti-tumor activity.Its relative molecular mass is 423.915, is yellow powder, and is water-soluble relatively poor, dissolves in dimethyl sulfoxide (DMSO) (DMSO) and ethanol equal solvent.Its structural formula is as follows:
Also do not report at present about the medicinal use of this compound and other 2-formamido thienopyridine derivatives.
Summary of the invention
The contriver is through discovering that the 2-formamido thienopyridine derivatives has anti-tumor activity, 3-amino-N-(4-chlorobenzyl)-7-(3-methoxyphenyl)-4H-thiopyrano[2 particularly, 3-b] pyridine-2-carboxamide, can be used for preparing the pharmaceutical composition for the treatment of tumor disease.The 2-formamido thienopyridine derivatives has structure shown in the formula I:
Its reaction formula is as follows:
Wherein, R
1Be hydrogen, amino or hydroxyl; R
2Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy; R
3Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy.
Further, R
1Be hydrogen or amino; R
2Be hydrogen or methoxyl group; R
3Be hydrogen or chlorine.
Preferably, R
1Be amino; R
2Be methoxyl group; R
3Be chlorine.
The contriver finds to have better antitumor activity as shown in the formula the II compound in the 2-formamido thienopyridine derivatives especially, relative molecular mass 423.915, and structural formula is as follows:
Formula II is a yellow powder, is insoluble in water, dissolves in dimethyl sulfoxide (DMSO) (DMSO) and ethanol equal solvent.Its chemistry is by name: English name: 3-amino-N-(4-chlorobenzyl)-7-(3-methoxyphenyl)-4H-thiopyrano[2,3-b] pyridine-2-carboxamide; Chinese named: 3-amino-N-(4-benzyl chloride base)-7-(3-p-methoxy-phenyl)-4H-thiophene [2,3-b] pyridine-2-carboxamide.Employed in the following embodiments 2-formamido thienopyridine derivatives all refers to this compound.
The preparation method of formula II compound is: with p-methoxy-acetophenone 1 is raw material, elder generation and N, dinethylformamide dimethylacetal (DMF-DMA) reaction obtains enamine ketone 2, close ring with cyano-thioacetamide again and obtain 3, after obtain formamido thienopyridine class target product with acid amides 5 condensations again, 3 step reactions obtain formula II target product with 32% overall yield.
This preparation method's advantage is: reactions steps is brief, and desired raw material reagent is cheap and easy to get, does not need column chromatography purification, and whole process only needs 1 recrystallization, can obtain target product with high purity.
Second technical problem to be solved by this invention provides a kind of antineoplastic pharmaceutical compositions.This antineoplastic pharmaceutical compositions is to be that main active ingredient is added pharmaceutically acceptable complementary composition and is prepared from the 2-formamido thienopyridine derivatives shown in the formula I:
Wherein, R
1Be hydrogen, amino or hydroxyl; R
2Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy; R
3Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy.
Further, R
1Be hydrogen or amino; R
2Be hydrogen or methoxyl group; R
3Be hydrogen or chlorine.
Preferably, R
1Be amino; R
2Be methoxyl group; R
3Be chlorine.
Beneficial effect of the present invention is, has creatively proved that by experiment in vivo and vitro the 2-formamido thienopyridine derivatives has favorable anti-tumor effect, can be used to prepare antineoplastic pharmaceutical compositions.For the antitumor drug preparation field provides a kind of new selection, have good market outlook.
Description of drawings
Fig. 1 SKLB-703 is to the inhibited proliferation of different people JEG-3
Fig. 2 SKLB-703 is to the inhibited proliferation of different mouse cancer cells
Fig. 3 SKLB-703 is to the effect of Mice Bearing Lewis Lung Cancer growth-inhibiting
Fig. 4 SKLB-703 is to the effect of people A549 lung cancer growth-inhibiting
Embodiment
Below in conjunction with embodiment and Figure of description the present invention is further set forth but be not limitation of the present invention.
The preparation of preparation embodiment 3-amino-N-(4-benzyl chloride base)-7-(3-p-methoxy-phenyl)-4H-thiophene [2,3-b] pyridine-2-carboxamides (SKLB-703)
Employed 2-formamido thienopyridine derivatives is that the contriver is synthetic voluntarily among the present invention, relative molecular mass 423.915, and structural formula is suc as formula shown in the II:
The preparation method of formula II compound is: with p-methoxy-acetophenone 1 is raw material, elder generation and N, dinethylformamide dimethylacetal (DMF-DMA) reaction obtains enamine ketone 2, close ring with cyano-thioacetamide again and obtain 3, after obtain the Thienopyridines target product with acid amides 5 condensations again, 3 step reactions obtain formula II target product with 32% overall yield.
Experimental implementation and data division:
1, the preparation of enamine ketone:
With p-methoxy-acetophenone 1 (3.19g, 21.2mmol) and N, and dinethylformamide dimethylacetal (DMF-DMA) (5.5ml, 32.2mmol) the stirring and refluxing reaction is 20 hours, TLC shows that raw material reaction is complete, directly casts step reaction (productive rate is in 90%) after reaction solution is chilled to room temperature.
1H-NMR(400MHz，CDCl3)：δ2.90(s，3H)，3.12(s，3H)，3.80(s，3H)，5.80(d，J＝12.2Hz，1H)，6.95(d，J＝8.6Hz，2H)，7.66(d，J＝12.2Hz，1H)，7.88(d，J＝8.6Hz，1H)ppm；
2, the preparation of intermediate product 3
(back drips 10% potassium hydroxide aqueous solution 15ml for 2.20g, 19ml aqueous solution 22.0mmol), is warming up to 30-35 ℃ of reaction 30 minutes, the follow-up continuous 40-45 ℃ of reaction 5 hours that be warming up to add cyano-thioacetamide to above-mentioned reaction solution earlier under the room temperature.With this reaction solution put naturally be chilled to room temperature after, it is neutral dripping concentrated hydrochloric acid 3.2ml adjusting pH, the red solid of separating out is water successively, normal hexane and ethanol are washed, naturally obtain red solid 3.1 grams after drying, two step productive rates 60% (in p-methoxy-acetophenone), this solid not recrystallization are directly cast the step reaction.
1H-NMR(400MHz，DMSO-d6)：δ3.86(s，3H)，7.14(d，J＝7.6Hz，1H)，7.22(d，J＝8.0Hz，1H)，7.34(d，J＝8.0Hz，1H)，7.36(s，1H)，7.45(t，J＝8.0Hz，1H)，8.69(d，J＝8.0Hz，1H)，10.39(s，1H)，11.39(s，1H)，13.83(s，1H)ppm；
HRMS(Maldi)Calcd?for?C13H11N20S：243.0593，Found?243.0598；
3, the preparation of reactant 5
Ice-water bath stirs down, to to chlorobenzylamine (19.74g, 140mmol) and salt of wormwood (22.8g, methylene dichloride 165mmol) (250ml) hanging drop adds chloroacetyl chloride (18.47g, 165mmol), drip back temperature rising reflux reaction 4 hours, TLC shows the raw material complete reaction, is poured in the frozen water after being chilled to room temperature naturally, water extracts with methylene dichloride (150ml3), merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying, filter, filtrate being spin-dried for obtains white solid 29 grams, and productive rate 95%, this solid not recrystallization are directly cast the step reaction.
1H-NMR(400MHz，CDCl3)：δ3.81(s，3H)，4.09(s，2H)，4.43(d，J＝5.6Hz，2H)，6.80(s，1H)，6.88(d，J＝8.8Hz，2H)，6.88(d，J＝8.8Hz，2H)，7.23(d，J＝8.4Hz，2H)ppm；
4, the preparation of target product
Under the stirring at room, to 3 (10.1g, the KOH solution 23.4ml of adding 10% in DMF 41.7mmol) (80ml) suspension, back adding 5 (10.93g, 50mmol), stirring reaction is 15 minutes under the room temperature, after add 10% KOH solution 23.4ml again, be warming up to 80-85 ℃ of reaction 7 hours, the cooling reaction solution, a large amount of solids are separated out, filter, solid is water successively, second alcohol and water (v: v=1: 1) wash, dry and obtain solid 12.06 gram, the crude product productive rate is 68%.
Get crude product 4 grams, obtain 3.2 grams, recrystallization productive rate 80% with ethanol 100ml recrystallization.
1H-NMR(400MHz，DMSO-d6)：δ3.84(s，3H)，4.40(d，J＝6.0Hz，2H)，7.07(d，J＝8.8Hz，2H)，7.21(s，broad，2H)，7.37(dd，J＝8.4，9.2Hz，4H)，7.99(d，J＝8.4Hz，1H)，8.14(d，J＝8.8Hz，2H)，8.30(t，J＝5.8Hz，1H)，8.46(d，J＝8.8Hz，1H)ppm；
13C-NMR(100MHz，DMSO-d6)：δ42.22，55.74，97.03，114.72(2C)，116.04，124.96，128.62(2C)，128.90(2C)，129.59(2C)，130.83，131.66，132.01，139.64，146.23，156.78，159.21，161.10，165.53ppm；
ESI-MS(m/z，％)422.3(M-H)-；
The tumor cell in vitro proliferation inhibition test of EXPERIMENTAL EXAMPLE 12-formamido thienopyridine derivatives
1, experiment material
1.1 main agents
(InvitrogenCorporation, USA), thiazole bromide blue tetrazolium (MTT), methyl-sulphoxide (DMSO) are Sigma company (USA) product available from Gibco BRL company for RPMI-1640, DMEM, foetal calf serum, pancreatin etc.The 2-formamido thienopyridine derivatives is bought from Specs company (Holland), is the chemical standard product, is mixed with the 20mg/ml storage liquid with DMSO during experiment in vitro, puts 4 ℃ of refrigerators and keeps in Dark Place standbyly, faces the time spent to be diluted to desired concn with complete culture solution.
1.2 clone and cultivation
Human hepatoma cell strain (HepG2), Human Prostate Cancer Cells strain (PC-3), human breast cancer cell strain (MCF-7), human lung carcinoma cell line (A549), human colon cancer cell strain (HCT-116) that this experiment is used, people's squamous cell cancer (A431), mouse colonic cell strain (CT26), the ATCC company in the U.S. is all purchased in Mice Bearing Lewis Lung Cancer cell strain (LL2) and mouse mastopathy cell strain (4T1), is preserved by this laboratory.
DMEM perfect medium, 5%CO2, the 37 ℃ of cultivations that contain 10% foetal calf serum, 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates of human liver cancer cell (HepG2) and Mice Bearing Lewis Lung Cancer cell (LL2).RPMI-1640 perfect medium, 5%CO2, the 37 ℃ of cultivations that contain 10% foetal calf serum, 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates of Human Prostate Cancer Cells (PC-3), human breast cancer cell (MCF-7), human colon cancer cell (HCT-116), mouse colonic cell (CT26), mouse mastopathy cell (4T1) and human lung carcinoma cell (A549).
2 experimental techniques and result
2.1 experimental technique (mtt assay)
Adjusting cell concn with complete culture solution is 1-2 * 104/mL, is inoculated in 96 orifice plates, every hole 200 μ L, overnight incubation, use respectively next day various dose the 2-formamido thienopyridine derivatives (final concentration is respectively 20,5,1.25,0.31g/ml) the processing cell, establish the negative control group and the isopyknic solvent control group that do not contain medicine simultaneously, DMSO concentration is 0.1%, and each dosage group is established 5 multiple holes, 37 ℃, 5%CO2 cultivates.Cultivate after 48 hours, every hole adds 5mg/mL MTT reagent 20 μ L, continues to cultivate 2-4h, abandon supernatant, add DMSO 150 μ L again, vibration mixing 15min, (λ=570nm) measure absorbancy (A) value (the A value is directly proportional with viable count) gets its mean value with microplate reader.Relative cell proliferation inhibition rate (%)=(control group A 570-experimental group A 570)/control group A 570 * 100%.Experiment repeats 3 times at least.Experimental data is represented with mean ± standard deviation, adopts SPSS 13.0 statistical softwares to handle.Measurement data adopts the t check, and there is statistical significance P＜0.05 for difference.(the control group here is meant the solvent control group, and the acellular inhibited proliferation of solvent control group is not so list especially)
2.2 experimental result
Behind the different cells of different concns SKLB-703 effect, increase with drug level, cell inhibitory effect is obvious more, and each dosage group is compared with control group, and cell proliferation inhibition rate difference all has statistical significance (P＜0.05) (referring to Fig. 1 and Fig. 2).The half-inhibition concentration (IC50) that SKLB-703 handles MCF-7, A549, HepG2, PC-3 cell, A431 cell and HCT116 cell 48h is respectively 9.89 μ g/ml, 13.38 μ g/ml, 2.67 μ g/ml, 7.42 μ g/ml, 38.3 μ g/ml and 35.42 μ g/ml.The half-inhibition concentration (IC50) that SKLB-703 handles LL2 cell, CT26 cell and 4T1 cell 48h is respectively 5.49 μ g/ml, 4.1 μ g/ml and 9.18 μ g/ml (referring to table 1).
Table 1SKLB-703 is to different tumor cell line inhibited proliferations (inhibiting rate %)
The anti-tumor in vivo experiment of EXPERIMENTAL EXAMPLE 22-formamido thienopyridine derivatives
1, experiment material
Referring to EXPERIMENTAL EXAMPLE 1.
2.1 experimental technique
Set up mouse tumor model: Mice Bearing Lewis Lung Cancer model, animal model adopt the female C57BL/6 mouse about 6～8 ages in week, the about 18-20g of body weight.Available from experimentation on animals center, Sichuan University West China.Raise in this laboratory animal room, animal freely advances diet, and alternately begin experiment daytime at night after animal conforms.LL/2 cell inoculation flank behind the mouse is subcutaneous, and every inoculation about 5 * 105 cells (0.1ml) treat that tumour is long timely to laying one's hand on, and mouse are divided into two groups at random: solvent control group, 60mg/kg SKLB-703 treatment group, 10 every group.SKLB-703 is dissolved in 20%PEG and 10% ethanolic soln, every day intraperitoneal administration, successive administration 15 days.Measured gross tumor volume and mouse body weight in per three days.
A549 people's lung cancer model: animal model adopts the female BALB/C nude mice about 6～8 ages in week, the about 18-20g of body weight, available from experimentation on animals center, Sichuan University West China.Raise in this laboratory animal room, animal freely advances diet, and alternately begin experiment daytime at night after animal conforms.A549 cell inoculation flank behind the mouse is subcutaneous, and every inoculation about 5 * 106 cells (0.1ml) treat that tumour is long to 50-100mm3, is divided into two groups at random with mouse: solvent control group, 60mg/kg SKLB-703 treatment group, 5 every group.Every day intraperitoneal administration, successive administration 30 days.Observation index is the same.
2.2 experimental result
We find that the SKLB-703 processing can obviously suppress Mice Bearing Lewis Lung Cancer tumour and people A549 lung cancer tumor growth.Compare with the solvent control group, the inhibiting rate to Mice Bearing Lewis Lung Cancer tumour and people A549 lung cancer tumour after the SKLB-703 administration reaches 50% and 67% respectively, has compared significant difference (P＜0.05) (referring to Fig. 3 and Fig. 4) with the solvent control group.During administration, the physiological saline control group, tangible untoward reaction does not all appear in solvent control group and SKLB-703 treatment group mouse, and the change relevant with medication all do not appear in generalized cases such as the fur of mouse, diet, behavior.
The preparation of example of formulations 1 coating tablet
The label prescription:
The compounds of this invention 10.0g
Lactose 50.0g
Starch 40.0g
Hydroxypropylcellulose 4.0g
10% pregnant dimension ketone is an amount of
Magnesium Stearate 0.5g
Get mentioned component and mix, the whole grain that sieves after the granulation, drying, compressing tablet is made 100
The coating liquid prescription:
Opadry (Opadry) 5g, an amount of dressing of 80% ethanol.
The preparation of example of formulations 2 capsules:
Prescription:
The compounds of this invention 100g
Starch 10g
Carboxymethyl starch is received 20g
The low replacement through the third Mierocrystalline cellulose 10g
Sodium lauryl sulfate 8g
1000 of No. 0 gastric-dissolved capsules
Make 1000 capsules.
The preparation method:
Get the formula ratio supplementary material, sieve respectively, add 5% polyvinylpyrrolidone liquid and tween 80 system softwood, get 20 mesh sieves and granulate, under 15 ℃ of room temperatures, dry, add sodium lauryl sulphate, mix, by the 0.27g/S gastric-dissolved capsule of packing into No. 0, sample examination, the stripping limit is Q=80%, and content should be the 90-110% of labelled amount.
Claims (8)
1, suc as formula the preparation method of the 2-formamido thienopyridine derivatives shown in the I, its step is as follows:
Wherein, R
1Be hydrogen, amino or hydroxyl; R
2Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy; R
3Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy.
2, preparation method as claimed in claim 1 is characterized in that R
1Be hydrogen or amino R
2Be hydrogen or methoxyl group; R
3Be hydrogen or chlorine.
3, preparation method as claimed in claim 1 is characterized in that R
1Be amino; R
2Be methoxyl group; R
3Be chlorine.
4, a kind of formula I derivative is used for the treatment of the purposes of the pharmaceutical composition of tumour as activeconstituents in preparation, it is characterized in that adding pharmaceutically acceptable complementary composition and is prepared from:
Wherein, R
1Be hydrogen, amino or hydroxyl; R
2Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy; R
3Be hydrogen, bromine, chlorine, fluorine, methoxyl group or trifluoromethoxy.
5, purposes as claimed in claim 4 is characterized in that activeconstituents formula I derivative R
1Be hydrogen or amino; R
2Be hydrogen or methoxyl group; R
3Be hydrogen or chlorine.
6, purposes as claimed in claim 4 is characterized in that activeconstituents formula I derivative R
1Be amino; R
2Be methoxyl group; R
3Be chlorine.
7, as the described purposes of one of claim 4-6, the preparation method of coating tablet who it is characterized in that containing activeconstituents is as follows:
The label prescription:
Formula I compound 10.0g
Lactose 50.0g
Starch 40.0g
Hydroxypropylcellulose 4.0g
10% pregnant dimension ketone is an amount of
Magnesium Stearate 0.5g
Get mentioned component and mix, the whole grain that sieves after the granulation, drying, compressing tablet is made 100;
The coating liquid prescription:
Opadry (Opadry) 5g, an amount of dressing of 80% ethanol.
8, as the described pharmaceutical composition of one of claim 4-6, the preparation method of capsule who it is characterized in that containing activeconstituents is as follows:
1) prescription:
Formula I compound 100g
Starch 10g
Carboxymethyl starch is received 20g
The low replacement through the third Mierocrystalline cellulose 10g
Tween 80 is an amount of
Polyvinylpyrrolidone 5% ethanol liquid is an amount of
Sodium lauryl sulphate 8g
1000 of No. 0 gastric-dissolved capsules
Make 1000 capsules;
2) preparation process:
Get the formula ratio supplementary material, sieve respectively, add 5% polyvinylpyrrolidone liquid and tween 80 system softwood, get 20 mesh sieves and granulate, under 15 ℃ of room temperatures, dry, add sodium lauryl sulphate, mix, by the 0.27g/S gastric-dissolved capsule of packing into No. 0, sample examination, the stripping limit is Q=80%, and content should be the 90-110% of labelled amount.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383763A (en) * | 2018-04-26 | 2018-08-10 | 湖南文理学院 | A kind of synthetic method of β-carbonyl sulfone compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1306535A (en) * | 1998-06-26 | 2001-08-01 | 武田药品工业株式会社 | Thienopyridine compounds, their prodn. and use |
| CN1649581A (en) * | 2002-06-06 | 2005-08-03 | 贝林格尔.英格海姆药物公司 | Substituted 3-amino-thieno(2,3-b)pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses |
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2008
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1306535A (en) * | 1998-06-26 | 2001-08-01 | 武田药品工业株式会社 | Thienopyridine compounds, their prodn. and use |
| CN1649581A (en) * | 2002-06-06 | 2005-08-03 | 贝林格尔.英格海姆药物公司 | Substituted 3-amino-thieno(2,3-b)pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383763A (en) * | 2018-04-26 | 2018-08-10 | 湖南文理学院 | A kind of synthetic method of β-carbonyl sulfone compound |
| CN108383763B (en) * | 2018-04-26 | 2019-12-03 | 湖南文理学院 | A kind of synthetic method of β-carbonyl sulfone compound |
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