CN107056723A - It is a kind of that there is the compound for suppressing vascular endothelial growth factor receptor signal transduction - Google Patents
It is a kind of that there is the compound for suppressing vascular endothelial growth factor receptor signal transduction Download PDFInfo
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- CN107056723A CN107056723A CN201710265852.7A CN201710265852A CN107056723A CN 107056723 A CN107056723 A CN 107056723A CN 201710265852 A CN201710265852 A CN 201710265852A CN 107056723 A CN107056723 A CN 107056723A
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- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 title claims abstract description 8
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
It is a kind of that there is the compound for suppressing vascular endothelial growth factor receptor signal transduction, it is related to field of medicaments, and in particular to a kind of Benzooxazole kind medicine, specially 2 Fang bases benzoxazoles virtue amide compound.The compound has the activity of very high suppression growth of tumour cell, has significant inhibition particularly with the growth of the human colon cancer cell of the hypotype of vascular epidermal growth factor acceptor 2 height expression, available for antineoplastic.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of Benzooxazole kind medicine.
Background technology
Tumour is the product of cell unconventionality expression, and it is divided into benign and malignant tumour.At present, malignant tumour has become
Threaten a big killer of human health.In recent years, global cancer stricken number sharp increase, it is contemplated that the whole world was because of cancer in 2025
Death toll may increase to 19,000,000.Traditional tumor therapeuticing method has different degrees of toxicity, can also produce sometimes
Tolerance and there is complication, it is difficult to fundamentally treat tumour.
The one of the main reasons of Cancer death is that cancer of late stage tumour cell can be shifted.It is now recognized that tumour cell
Transfer is main in three kinds of forms：First, tumour cell immersion blood vessel forms transfer stove；Second, pass through Lymphatic Circulation system
System, and then enter lympho-hematological circulatory system formation transfer stove；3rd, directly come off from tumour parent, into perienchyma.
The growth of tumour is divided into avascular slow growth period and has the fast breeding phase of blood vessel.Tumour needs new green blood
Pipe supply nutrition ability fast breeder, if without new vessels, parent tumor is typically not over 1-2mm, once there is new life
Angiogenesis, tumour cell will be shifted, and then cause death.
VEGF (VEGF), also referred to as permeability factor (VPF), it is to promote the numerous mediations of angiogenesis
Mostly important growth factor in the factor.It not only rises heavy to closing during embry ogenesis, cell migration and angiogenesis
The adjustment effect wanted, and have very strong inducing action to angiogenic growth.VEGF that tumor cell secretion goes out need by with blood
Endothelial cell growth factor receptors (VEGFR) is combined, and blood vessel is produced a series of stimulation, and blood vessel endothelium
Growth factor acceptor 2 (VEGFR-2) is VEGF main acceptor, is also the topmost mediated factor of angiogenesis.
The activity of very strong EGFR-TK is shown when VEGFR-2 is combined with VEGF, causes endothelial cell proliferation and transfer,
Induction of vascular grows to tumor entity, into the oxygen uptake scope of tumour cell, ultimately forms the blood capillary for being wrapped in tumor entity
Managed network, so as to provide superior growing environment for tumour growth and finally cause metastases.As can be seen here, blood vessel endothelium
Cell propagation depends on VEGFR-2, and can effectively to suppress blood vessel new for the signal transduction of cut-out VEGFR-2 and downstream albumen
It is raw.Research at present has shown the growth of VEGFR-2 unconventionality expression and tumour in tumour cell, migrates all relevant, so resistance
Disconnected VEGF/VEGFR-2 signal paths can effectively disturb the new life of entity tumor blood vessel, cause the tumour cell in growth
Required blood flow is slow, or even tumour cell is stopped growth because lacking nutrition.Therefore, VEGFR-2 kinases becomes
For target spot ideal in antineoplastic vascular new life treatment.
At present, the micromolecular inhibitor of VEGFR-2 signal pathways, the first generation is Sorafenib (Sorafenib) and easypro Buddhist nun
For Buddhist nun (Sunitinib), in addition with the little molecules in inhibiting of Axitinib (Axitinib), pazopanib (Pazopanib) etc.
Agent has been listed, and the candidate small molecule medicine of also at least 100 is carrying out the clinical test of different phase.Find newcooperative medical system
Structure is learned, the lead compound for suppressing VEGFR-2 is the popular class of major drugmakers of the current world and scientific research institutions
Topic.
The content of the invention
Suppress the new of vascular endothelial growth factor receptor signal transduction effect it is an object of the present invention to provide a kind of new having
Compound.
To realize object above, the present invention is achieved by the following technical programs.
It is a kind of that there is the compound for suppressing vascular endothelial growth factor receptor signal transduction, it is characterised in that the compound
For the fragrant amide compound of 2- Fang bases benzoxazole, with following structure：
Wherein R1, R2, R3, R4, R5, R6Any one in H, Me, OMe, F, Cl, Br is selected for its substituent；
N=0 or 1.
It is preferred that, the fragrant amide compound of above-mentioned 2- Fang bases benzoxazole has following 37 kinds of structures, table 2 specific as follows.
Table 2
In upper table, the numbering of the preferred chemical structural formula of serial number, R in table1, R2, R3, R4, R5, R6It is corresponding for the change
Learn the selected substituent of structural formula.
The synthetic reaction of the compounds of this invention is as follows：
Specifically include following steps：
(1) synthesis of 2- Fang bases benzoxazole (compound 3).By 2,4 diaminophenols (compound 1) and substituted benzoyl
Sour (compound 2) is dissolved in polyphosphoric acids (PPA), is heated with stirring to 170 DEG C of reaction 12h, TLC detection raw material reactions and is finished, stops
Only stir, neutrality is neutralized to dense KOH solution, the precipitation for having dark brown is generated, and suction filtration obtains the solid of dark brown.Dark brown
Solid dissolving is washed with 50 × 2mL of water and saline solution 50mL respectively in 50mL ethyl acetate.Organic phase anhydrous sodium sulfate
After drying, yellow or faint yellow cotton shape 2- Fang bases benzoxazole (compound 3) are separated to obtain with silica gel column chromatography.
(2) prepared by target product.In 50mL round-bottomed flasks, substituted benzoic acid or substituted phenylacetic acid (compound are added
4), it is dissolved in DMF (DMF), sequentially adds HOBT, EDCI and TEA, then magnetic agitation at normal temperatures
Device stirring 10min or so, adds the 2- Ben bases benzoxazoles (compound 3) dissolved with DMF, and stirring at normal temperature reacts 2-4h,
TLC detection raw material reactions are finished, and are stopped stirring, are added ethyl acetate extraction, washed with watery hydrochloric acid 2 times, the anhydrous sulphur of organic phase
Sour sodium is dried, and yellow, desired product as white solid can be obtained obtaining with silica gel column chromatography separation.
The present invention compound be used for antineoplastic, the tumour include but is not limited to colon cancer, duodenal cancer,
Prostate cancer, breast cancer, melanoma, duct carcinoma, liver cancer, cancer of pancreas, kidney, carcinoma of endometrium, stomach cancer, non-small cell lung cancer,
Neurological malignancies and hematologic malignancies.
The noval chemical compound displaying of the fragrant acid amides of 2- Fang bases benzoxazole of the present invention has very high suppression growth of tumour cell
Activity, has significant suppression particularly with the growth of the human colon cancer cell of the hypotype of vascular epidermal growth factor acceptor 2 height expression
Effect processed, its IC50Value can reach 7.6 μM or so, and in chick embryo allantois membrane modle there is good anti-angiogenesis to live
Property, with preferable anti-vegf stimulate HUVEC after cell breed ability and anti-vegf stimulate HUVEC after breed it is special
Property.Specific implementation situation is as follows.
1st, to the part of compounds cell in vitro level in above-mentioned 37 kinds of compounds (5-1 to 5-37 compounds) in table 2
Anti- HCT116, SW480, MDA-MB-231 tested.
Cell viability, influence of the observation sample to tumor cell proliferation, to evaluate the anti-of sample are detected with SRB decoration methods
Tumor effect.The positive reference compound used is Sutent (Sunitinib) and Sorafenib (Sorafenib).
Cell needs to be inoculated in 96 orifice plates, and incubated overnight adds sample (T), while being not added with control sample (C) and dosing
Preceding control (T0).(T is compareed before dosing0) cell add TCA be fixed, retain it is standby.
Add sample (T) and the cell without control sample (C) continues to fix again after cultivating 48 hours.All fix
Cell is dyed with SRB dye liquors, then washes away free dyestuff with acetum, and Tris alkali is added after being air-dried, and vibration dissolving is mixed
Even rear 490nM determines OD values.Growth rate, experimental result such as table 1 are calculated according to OD values.
If T >=T0, growth rate=(T-T0)/(C-T0) × 100%；If T ＜ T0, (T-T0)/T0×100.During primary dcreening operation
Each sample list concentration sets duplicate hole, is repeated twice, and the sample that growth inhibition ratio is more than 50% determines IC50Value, it is every during measure
Individual sample gradient dilutes five concentration, and each concentration sets duplicate hole.
The compound on intracellular of Tabel 1. strain inhibitory activity IC50(μg/mL)
Test result indicates that：This kind of 2- Fang bases benzoxazole amides compound is the tumour that a class has preferably activity
Growth inhibitor, the inhibitory activity to SW480 is more obvious.
2nd, chick embryo method screening anti-angiogenic compounds experiment is carried out, experimental procedure is as follows：
(1) agarose particle is prepared.First, given the test agent be dissolved in it is standby in analytically pure DMSO, then at 79 DEG C
When, reserve liquid and 2% agarose solution are mixed and made into 10 μ L agarose particle (quality is 5-100 μ g).
(2) culture of fertilized eggs.It is in the incubator of automatic hatching that 37.5 DEG C and relative humidity are 62% in temperature
Cultivate fertilized eggs.After the Egg-white for cultivating 70h and removal 8mL, an osculum is opened on egg shell, can be on eggshell
It was found that the sprouting layer grown.Then, with transparent adhesive tape after the closing of this osculum, fertilized eggs are sent back to phase again
It is in 90% incubator not turned to humidity.
(3) anti-angiogenesis is tested.Cultivate after 75h, agarose particle is placed on after angiosomes, 24h, can be grabbed
Obtain the picture of the anti-angiogenesis in sample treatment area.
(4) the suppression picture of obtained picture and positive control sample is contrasted, blood vessel is compared with carefully similar to control sample
It is seen as positive inhibitory activity.
From result figure, the compounds of this invention, which has, preferably suppresses angiogenic activity.
Chicken embryo experiment display, generation of these compounds to the new vessels of chicken embryo has obvious inhibition, this kind of 2-
Fang base Benzooxazole kind compounds are the tumor growth inhibitors of the new construction of a class high activity.
Brief description of the drawings
Fig. 1 is the molecular structure of the present invention.
Fig. 2 is new to the anti-chicken embryo of compound 5-12 to 5-37 and physiological saline, positive control drug Sorafenib, Sutent
The compares figure of angiogenic nucleus formation；
Wherein, compound library consumption 20nmol/ eggs.
Embodiment
To make the purpose, technical scheme and advantage of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention
Technical solution of the present invention is clearly and completely described, it is clear that described embodiment is a part of embodiment of the invention,
Rather than whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art are not making creative labor
The every other embodiment obtained under the premise of dynamic, belongs to the scope of protection of the invention.
Embodiment 1：Prepare the chloro- N- of the bromo- 4- of compound 5-3, i.e. 3- in above-mentioned table 2 (2- phenyl -5- benzoxazolyls) benzene
The preparation of formamide.
The chloro- N- of the bromo- 4- of 3- (2- phenyl -5- benzoxazolyls) benzamide, with following chemical structural formula：
Described compound 5-3 preparation methods are as follows：
From 1mmol substituted benzoic acids or substituted phenylacetic acid 4, add in 20mL round-bottomed flasks, take 20mL DMF to dissolve,
1.5mmol HOBT, 1.5mmol EDCI, 2mmol TEA triethylamines are sequentially added, normal temperature magnetic stirring apparatus is then used
10min or so is stirred, the substitution 2- Ben bases benzoxazole 3 dissolved with DMF is added, stirring at normal temperature reacts 2-4h, TLC detections
Raw material reaction is finished, and stops stirring, adds ethyl acetate 15mL extraction, then is washed 2 times with watery hydrochloric acid 50mL, and organic phase is with anhydrous
Sodium sulphate dries 30min, with silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) separation can obtain obtaining white-yellowish solid product
The as compound 5-3 of the present embodiment.
Nuclear magnetic spectrogram data are：Yellow solid；Mp 207.8–209.7℃；IR(KBr):3370,3269,3072,
2913,1642,1540,1475,1422,702,617；1H NMR(500MHz,DMSO-d6):δ=7.59-7.64 (m, 3H,
), ArH 7.72-7.80 (m, 3H, ArH), 7.99-8.01 (m, 1H, ArH), 8.18-8.19 (d, J=6.40 Hz, 2H, ArH),
8.26 (s, 1H, ArH), 8.36-8.37 (d, J=1.65Hz, 1H, ArH), 10.55 (s, 1H, NH)；13CNMR(125MHz,
DMSO-d6):δ=110.99,111.82,119.21,121.99,127.62,128.98,128.98,129.66,130.91,
130.91,132.31,133.12,135.42,136.27,142.00,147.19, 163.44；HRMS(TOF ES+):m/z
calcd for C20H12BrClN2O2[M+Na]+,448.9650；found, 448.9663.
Embodiment 2：Prepare the fluoro- N-2- of the bromo- 3- of compound 5-1, i.e. 4- in above-mentioned table 2 (2- Ben base benzoxazole -5- bases)
The preparation of benzamide.Preparation method such as embodiment 1, with following chemical structural formula：
Nuclear magnetic spectrogram data are：Yellow solid；Mp 227.9–229.9℃；IR(KBr):3334,3064,1650,
1544,1483,1279,1046,870,764,690；1HNMR(500MHz,DMSO-d6):δ=7.58-7.61 (d, J=
7.20Hz, 3H, ArH), 7.73-7.96 (m, 5H, ArH), 8.16-8.18 (d, J=7.15Hz, 2H, ArH), 8.27 (s, 1H,
ArH),10.53(s,1H,ArH)；13CNMR(125MHz,DMSO-d6):δ=110.91,111.80,116.08,116.27,
119.17,125.63,126.74,127.58,127.58,129.59,129.59,132.24, 133.99,136.26,
136.64,141.96,147.18,157.45,159.40；HRMS(TOF ES+):m/z calcd for C20H12BrFN2O2[M+
Na]+,432.9952；found,432.9958.
Embodiment 3：Prepare the fluoro- N-2- of the chloro- 3- of compound 5-2, i.e. 4- in above-mentioned table 2 (2- Ben base benzoxazole -5- bases)
The preparation of benzamide.Preparation method such as embodiment 1, with following chemical structural formula：
Nuclear magnetic spectrogram data are：Yellow solid；Mp 216.9–218.5℃；IR(KBr):3346,3064,1654,
1548,1479,1426,1058,812,694,637；1H NMR(500MHz,DMSO-d6):δ=7.60-7.62 (d, J=
6.95Hz, 3H, ArH), 7.75-7.89 (m, 4H, ArH), 7.99-8.02 (d, J=10.00Hz, 1H, ArH), 8.17-8.20
(d, J=7.20Hz, 2H, ArH), 8.27 (m, 1H, ArH)；13C NMR(125MHz, DMSO-d6):δ=110.97,111.86,
116.35,116.53,119.25,125.38,126.74,127.61, 127.61,129.63,129.63,131.13,
132.29,135.99,136.26,141.97,147.21,163.37,163.60； HRMS(TOF ES+):m/z calcd for
C20H12ClFN2O2[M+Na]+,389.0466；found,389.0464.
Embodiment 4：Prepare compound 5-4 in above-mentioned table 2, i.e. 2- (3,4- Dimethoxyphenyl)-N-2- (2- phenyl benzos
Oxazole -5- bases) acetamide preparation.Preparation method such as embodiment 1, with following chemical structural formula：
Nuclear magnetic spectrogram data are：White solid；Mp 170.1–170.6℃；IR(KBr):3269,3060,2991,
2835,1650,1520,1471,1266,1152,1021,796,702,604；1HNMR(500MHz, DMSO-d6):δ=3.61
(s,2H,CH2),3.73(s,3H,OCH3),3.76(s,3H,OCH3),6.90-7.00 (m,3H,ArH),7.55-7.72(m,
5H,ArH),8.16-8.18(m,3H,ArH),10.33(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=43.30,
55.88,55.88,110.30,111.05,112.24,113.48, 117.90,121.51,126.77,127.58,127.58,
128.67,129.62,129.62,132.25,136.91,142.04, 146.67,148.04,148.94,163.28,
169.81；HRMS(TOF ES+):m/z calcd for C23H20N2O4 [M+Na]+,411.1312；found,411.1315.
Embodiment 5：Prepare compound 5-5 in above-mentioned table 2, i.e. N- (2- Ben base benzoxazole -5- bases) -2- (3,4,5- tri-
Methoxyphenyl) acetamide preparation.Preparation method such as embodiment 1, with following chemical structural formula：
Nuclear magnetic spectrogram data are：White solid；Mp 175.7–177.6℃；IR(KBr):3252,3056,2987,
2933,2835,1642,1593,1540,1467,1328,1242,1127,1005,792,698,604；1HNMR (500MHz,
DMSO-d6):δ=3.62 (s, 2H, CH2),3.64(s,3H,OCH3),3.78(s,6H,OCH3), 6.50-6.90(s,2H,
ArH),7.55-7.73(m,5H,ArH),8.17-8.19(m,3H,ArH),10.34(s,1H, NH)；13CNMR(125MHz,
DMSO-d6):δ=43.95,56.20,56.20,60.33,106.93,106.93,110.34,111.08,117. 94,
126.77,127.59,127.59,129.60,129.60,131.83,132.29,136.66, 136.86,142.04,
146.70,153.08,163.29,169.48；HRMS(TOF ES+):m/z calcd for C25H22N2O5[M+Na]+,
441.1418；found,441.1421.
Embodiment 6：Prepare (2- (4- chlorphenyl benzoxazole -5- the bases) -3- of the bromo- N- of compound 5-6, i.e. 4- in above-mentioned table 2
The preparation of fluorobenzamide.Preparation method such as embodiment 1, with following chemical structural formula：
Nuclear magnetic spectrogram data are：Yellow solid；Mp 261.0–262.3℃；IR(KBr):3346,3068,1654,
1544,1479,1099,821,731,637,498；1H NMR(500MHz,DMSO-d6):δ=7.51-8.27 (m, 10H,
ArH),10.43-10.48(d,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=110.81,111.83,116.03,
116.23,119.30,125.52,128.68,129.18,129.64,129.90,133.88, 136.30,137.10,
141.90,147.19,157.46,159.42,162.34,163.56；HRMS(TOF ES+):m/z calcd for
C20H11BrClFN2O2[M+Na]+,466.9567；found,466.9569.
Embodiment 7：Prepare (2- (4- chlorphenyl benzoxazole -5- the bases) -3- of the chloro- N- of compound 5-7, i.e. 4- in above-mentioned table 2
The preparation of fluorobenzamide.Preparation method such as embodiment 1, with following chemical structural formula：
Nuclear magnetic spectrogram data are：Yellow solid；Mp 250.2–250.7℃；IR(KBr):3350,1654,1544,
1479,1099,817,739；1HNMR(500MHz,DMSO-d6):δ=7.60-7.67 (m, 3H, ArH), 7.75 (s, 3H,
ArH),7.87-8.28(m,5H,ArH),10.50(s,1H,NH)；13CNMR(125MHz, DMSO-d6):δ=110.90,
111.93,116.32,116.50,119.43,125.28,125.65,128.73,129.26, 129.53,129.53,
129.73,129.73,129.92,131.05,136.33,136.60,137.16,141.96, 147.27,158.36,
162.42,163.56；HRMS(TOF ES+):m/z calcd for C20H11Cl2FN2O2 [M+H]+,401.0256；found,
401.0254.
Embodiment 8：Prepare (2- (the 4- chlorphenyl benzoxazoles -5- of the chloro- N- of the bromo- 4- of compound 5-8, i.e. 3- in above-mentioned table 2
Base) benzamide preparation.Preparation method such as embodiment 1, with following chemical structural formula：
Nuclear magnetic spectrogram data are：Yellow solid；Mp 237.2–238.1℃；IR(KBr):3260,3072,2917,
1642,1536,1471,829,727；1HNMR(500MHz,DMSO-d6):δ=7.65-7.74 (m, 5H, ArH), 7.98-8.00
(d, J=8.80Hz, 1H, ArH), 8.16-8.18 (d, J=6.70Hz, 2H, ArH), 8.25 (s, 1H, ArH), 8.35 (s, 1H,
ArH),10.52(s,1H,NH)；13CNMR(125MHz,DMSO-d6):δ=111.04,111.81,119.40,121.98,
125.59,128.96,129.33,129.33,129.80,129.80,130.91, 133.11,135.40,136.37,
136.81,137.08,141.88,147.21,162.41,163.43,HRMS(TOS ES+):m/z calcd for
C20H11BrCl2N2O2[M+H]+,460.9452；found,460.9454.
Embodiment 9：Prepare compound 5-9 in above-mentioned table 2, i.e. N- (2- (4- chlorphenyl benzoxazole -5- bases) -2- (3,
4 ,-Dimethoxyphenyl) acetamide preparation.Preparation method such as embodiment 1, with following chemical structural formula：
Nuclear magnetic spectrogram data are：White solid；Mp188.6–190.1℃；IR(KBr):3256,3048,2929, 2835,
1642,1524,1471,1266,1152,1086,1025,850,723,608；1HNMR(500MHz, DMSO-d6):δ=3.61
(s,2H,CH2),3.73(s,3H,OCH3),3.77(s,3H,OCH3),6.90(s, 2H,ArH),6.99(s,1H,ArH),
7.57-7.70(m,4H,ArH),8.13-8.17(m,3H,ArH),10.29 (s,1H,NH)；13CNMR(125MHz,DMSO-
d6):δ=43.29,55.86,55.92,110.30,111.08,112.29,113.54,118.10,121 .52,125.62,
128.68,129.27,129.27,129.27,129.27, 137.02,141.96,146.68,148.06,148.97,
162.31,169.78；HRMS(TOF ES+):m/z calcd for C23H19ClN2O4[M+Na]+,445.0922；found,
445.0926.
Embodiment 10：Prepare compound 5-10 in above-mentioned table 2, i.e. N- (2- (4- chlorphenyl benzoxazole -5- bases) -2-
The preparation of (3,4,5- trimethoxyphenyls) acetamide.Preparation method such as embodiment 1, with following chemical structural formula：
Nuclear magnetic spectrogram data are：White solid；Mp 184.9–185.7℃；IR(KBr):3248,3085,2933,
2831,1659,1561,1471,1340,1238,1127,1009,850,739,674；1H NMR(500MHz, DMSO-d6):δ
=3.63 (s, 2H, CH2),3.64-3.80(s,9H,OCH3),6.69(s,2H,ArH), 7.56-8.18(m,7H,ArH),
10.34(s,1H,NH)；13CNMR(125MHz,DMSO-d6):δ=43.94,56.23,56.23,60.32,107.00,
107.00,110.37,111.10,118.14,125.62,129.28,129.28, 129.77,129.77,129.77,
131.79,136.75,137.00,141.97,146.72,153.09,162.33,169.44； HRMS(TOF ES+):m/z
calcd for C24H21ClN2O5[M+Na]+,445.0922；found,445.0926.
Claims (3)
1. a kind of have the compound for suppressing vascular endothelial growth factor receptor signal transduction, it is characterised in that the compound is 2-
Fang bases benzoxazole virtue amide compound, with following structure：
Wherein R1, R2, R3, R4, R5, R6Any one in H, Me, OMe, F, Cl, Br is selected for its substituent；N=0 or 1.
2. as claimed in claim 1 a kind of with the compound for suppressing vascular endothelial growth factor receptor signal transduction, it is special
Levy and be that the fragrant amide compound of described 2- Fang bases benzoxazole has following 37 kinds of structures, table 2 specific as follows：
Table 2
3. as claimed in claim 1 a kind of with the compound for suppressing vascular endothelial growth factor receptor signal transduction, it is special
Levy and be that the preparation technology of the compound is specific as follows：
(1) synthesis of 2- Fang bases benzoxazole：2,4 diaminophenols and substituted benzoic acid are dissolved in polyphosphoric acids (PPA), stirred
Mix and be heated to 170 DEG C of reaction 12h, TLC detects that raw materials react and finished, and stops stirring, is neutralized to neutrality with dense KOH solution, there is black
The precipitation generation of brown, suction filtration obtains the solid of dark brown.Dark brown solid is dissolved in 50mL ethyl acetate, respectively with water 50
× 2mL and saline solution 50mL washings.After organic phase anhydrous sodium sulfate drying, yellow or yellowish is separated to obtain with silica gel column chromatography
The flower-shaped 2- Fang base benzoxazoles of color cotton；
(2) prepared by target product：In 50mL round-bottomed flasks, substituted benzoic acid or substituted phenylacetic acid are added, N, N- diformazans is dissolved in
In base formamide (DMF), HOBT, EDCI and TEA are sequentially added, then magnetic stirrer 10min or so at normal temperatures,
The 2- Ben base benzoxazoles dissolved with DMF are added, stirring at normal temperature reacts 2-4h, and TLC detection raw material reactions finish, stop stirring
Mix, add ethyl acetate extraction, washed with watery hydrochloric acid 2 times, organic phase anhydrous sodium sulfate drying, can with silica gel column chromatography separation
Obtain obtaining yellow, desired product as white solid.
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|---|---|---|---|---|
| CN1638765A (en) * | 2001-07-27 | 2005-07-13 | 柯里斯公司 | Mediators of Hedgehog signaling pathways, compositions and uses related thereto |
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| WO2016033445A1 (en) * | 2014-08-29 | 2016-03-03 | Chdi Foundation, Inc. | Probes for imaging huntingtin protein |
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|---|---|---|---|---|
| CN1638765A (en) * | 2001-07-27 | 2005-07-13 | 柯里斯公司 | Mediators of Hedgehog signaling pathways, compositions and uses related thereto |
| WO2009148961A2 (en) * | 2008-05-29 | 2009-12-10 | Wisconsin Alumni Research Foundation | Drugs to prevent hpv infection |
| WO2016033445A1 (en) * | 2014-08-29 | 2016-03-03 | Chdi Foundation, Inc. | Probes for imaging huntingtin protein |
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