CN114890965A - Selective targeting vimentin small molecule compound and preparation method and application thereof - Google Patents
Selective targeting vimentin small molecule compound and preparation method and application thereof Download PDFInfo
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- CN114890965A CN114890965A CN202210536404.7A CN202210536404A CN114890965A CN 114890965 A CN114890965 A CN 114890965A CN 202210536404 A CN202210536404 A CN 202210536404A CN 114890965 A CN114890965 A CN 114890965A
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Abstract
Hair brushDisclosed are a small molecular compound of selective target vimentin and a preparation method and application thereof, wherein the structural formula of the small molecular compound is as shown in the formula
Description
The invention relates to a divisional application of an invention patent application with the application date of 2021.01.27 and the application number of 202110110479.4, which is named as 'selective targeting vimentin small molecule compound and a preparation method and application thereof'.
Technical Field
The invention belongs to the technical field of medicines and chemical engineering, and particularly relates to a small molecular compound of selective targeting vimentin, and a preparation method and application thereof.
Background
Cancer is one of the major diseases threatening human life health, wherein the invasion and metastasis of cancer are the main causes of the death of patients with solid tumors due to tumor spread and poor prognosis of patients. The existing anti-tumor migration drugs are still very deficient, and the development of the anti-tumor migration drugs has a plurality of problems and challenges, so the development of good anti-tumor drugs is always an important research direction in pharmacology.
Vimentin (vimentin) is the highest expressed component of the intermediate silk skeleton protein. Related researches show that the vimentin plays an important role in the metastatic deformation of tumors and tumor-related signal pathways, and the vimentin has abnormal expression and modification in various malignant tumors, including prostate cancer, melanoma, hepatocellular carcinoma, breast cancer, endometrial cancer and the like. However, the only chemotherapeutic drug targets currently known are cytoskeletal proteins (e.g., tubulin). Therefore, the development of a drug capable of targeting the proliferation and migration of vimentin against tumors is urgently needed.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides a small molecular compound which has stable chemical property, can target the vimentin and has the functions of resisting tumor proliferation and migration.
In a first aspect of the present invention, there is provided:
the structure of the small molecule compound is shown as the formula (II):
wherein, in the formula (II), X is selected from carbon, oxygen, nitrogen, sulfur, ester group, carbonyl or amide;
r is selected from any open chain compound, carbocycle, heterocycle, halogen, nitryl, cyano, amido, hydroxyl or sulfhydryl;
n is any integer of 1-4.
According to an embodiment of the present invention, at least the following advantages are provided: the micromolecular compound prepared by the invention has small molecular weight, is beneficial to quick absorption, and simultaneously has small steric hindrance, thereby being beneficial to the combination of the micromolecular compound and protein; secondly, the micromolecule compound prepared by the invention has certain linear structure and hydrophobicity, and the efficient combination of the micromolecule compound and the vimentin containing hydrophobic amino acid is promoted; furthermore, the small molecule compound prepared by the invention contains an ipsilateral double-chain structure, and can be helpful for the alpha-helix combination with the vimentin.
Furthermore, compared with the conventional vimentin binding molecule PQ7 (polyquaternium-7, CAS: 26590-05-6), it has anti-tumor activity, but because of its large molecular weight and large steric hindrance, it is not suitable for rapid absorption as a drug and is not favorable for binding with protein. Moreover, PQ7 has poor water solubility, thus reducing the drug potency. The micromolecule compound prepared by the invention overcomes the problems, has more stable chemical property and more obvious drug effect (combining vimentin and antitumor activity), and has multiple advantages of proper molecular size, good water solubility, strong drug forming property and the like.
Preferably, according to the first aspect of the invention, the small molecule compound does not comprise:
(1) r is bromine;
(2) n is 2 and R is a structure represented by formula 29;
(3) n is 3 and R is a structure represented by formula 30;
wherein, the structure shown in formula 29 is:
the structure shown in formula 30 is:
preferably, according to the first aspect of the present invention, the small molecule compound includes a compound having a structure represented by formula 6 to formula 18;
of course, the compounds having the structures represented by the above formulas 6 to 18 are only preferable compounds in the present invention, and the compounds related to the present invention include, but are not limited to, the compounds having the structures represented by the above formulas 6 to 18.
In a second aspect of the present invention, there is provided:
a composition comprising a small molecule compound according to the first aspect of the invention.
In a third aspect of the present invention, there is provided:
the preparation method of the small molecule compound according to the first aspect comprises the following steps:
demethylating anisoyl in an acidic solution, adding a dibromoalkane chain, adjusting the pH to be alkaline, and adding a cyclic compound or a nitrogen-containing open-chain compound to obtain a micromolecular compound with a structural formula shown in a formula (II);
the alpha helical structure is mainly in the secondary structure of the vimentin, and the hydrophobic amino acids in the structure can cause two vimentin monomers to be intertwined with each other to form a dimer. The preparation method provided by the third aspect of the present invention can synthesize a small molecule compound having a small molecular weight and having both linear and hydrophobic structures by using anisoyl as a raw material, and the small molecule compound can bind to the alpha helix of vimentin through the structures of two branches on the same side, thereby inhibiting dimerization of vimentin monomers.
According to the third aspect of the present invention, the cyclic compound includes an aromatic compound or a heterocyclic compound.
In some preferred embodiments of the present invention, the aromatic compound comprises: an aromatic compound containing dimethylamino group, an aromatic compound containing diethylamino group, an aromatic compound containing piperidyl group, an aromatic compound containing piperazinyl group, and benzene.
In some preferred embodiments of the present invention, the heterocyclic compound comprises: piperidinyl-containing heterocyclic compounds, piperazinyl-containing heterocyclic compounds, thiophenes, furans, tetrahydropyrrole, and morpholines.
The nitrogen-containing open chain compound comprises a dimethylamino open chain compound and a diethylamino open chain compound.
In some preferred embodiments of the invention, the dibromoalkane chain comprises 1, 2-dibromoethane, 1, 3-dibromoethane, and 1, 4-dibromoethane.
In some preferred embodiments of the invention, the demethylating agent is hydrobromic acid and the acidity regulator is acetic acid.
In a fourth aspect of the present invention, there is provided:
a medicament comprising a small molecule compound according to the first aspect of the invention or a pharmaceutically acceptable salt thereof.
Of course, the person skilled in the art can reasonably process the small molecule compound of the first aspect of the present invention further to obtain its stereoisomer or its prodrug molecule according to the actual situation.
According to the fourth aspect of the invention, the medicament further comprises pharmaceutically acceptable auxiliary materials.
According to a fourth aspect of the invention, the dosage form of the medicament comprises an injection, a tablet, a pill, a capsule, a suspension or an emulsion.
In a fifth aspect of the present invention, there is provided:
the use of a small molecule compound according to the first aspect of the invention in the preparation of a vimentin detection formulation.
In a sixth aspect of the present invention, there is provided:
the small molecule compound of the first aspect of the invention is used for preparing an anti-tumor medicament.
According to a sixth aspect of the invention, the tumour comprises one or more of ovarian cancer, cervical cancer, breast cancer, lung adenocarcinoma, colon cancer, liver cancer, leukaemia, non-small cell lung cancer, skin cancer, epithelial cell cancer, prostate cancer, nasopharyngeal carcinoma, glioblastoma, lymphoma or melanoma.
In some embodiments of the invention, the tumor is lung cancer, liver cancer, breast cancer, and colorectal cancer.
Drawings
The invention is further described with reference to the following figures and examples, in which:
FIG. 1 is a scheme showing the synthesis of compounds represented by general formulae (II) and (I);
FIG. 2 is a graph showing the response of the interaction between the compound prepared in the example of the present invention and vimentin (SPR);
FIG. 3 is a graphical representation of Western blot of compounds prepared in the examples of the present invention to promote autophagy of MDA-MB-231 tumor cells.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
The term "anisoyl" in reference to the following embodiments includes structurally identical compounds under different names as would be understood by one of skill in the art, including: 4,4 '-dimethoxyphenol ester and 4,4' -dimethoxybenzil.
Process for the preparation of compounds of the general formulae (II) and (I)
The synthetic scheme of the compounds in the examples of the invention is shown in figure 1.
As shown in fig. 1, anisoyl (compound 1) undergoes demethylation reaction in the environment of 40% hydrobromic acid acetic acid solution to obtain compound 2 (structural formula is shown in formula 2); reacting the compound 2 with dibromo alkane chains with different lengths to obtain an intermediate 3 (the structural formula is shown in the formula 3), an intermediate 4 (the structural formula is shown in the formula 4) and an intermediate 5 (the structural formula is shown in the formula 5); intermediate 3, intermediate 4 and intermediate 5 are respectively reacted with different nitrogen-containing aliphatic heterocyclic or nitrogen-containing non-heterocyclic substituent compounds under alkaline conditions (using K) 2 CO 3 Adjusting pH), reacting to obtain the compound shown as the general formula (II).
The compound shown in the general formula (II) is mixed with sodium acetate, and then acetic acid is used as a reaction solvent to react with 1, 2-phenylenediamine to obtain the compound shown in the general formula (I).
Wherein, the structural formula of the compound 2 in the above embodiment is:
the structural formula of the intermediate 3 is as follows:
the structural formula of the intermediate 4 is as follows:
the structural formula of the intermediate 5 is as follows:
the structural formula of the compound represented by the general formula (II) is:
the structural formula of the compound shown in the general formula (I) is as follows:
EXAMPLE 1 preparation of Compound 2
Mixing 4,4' -dimethoxybenzil (anisoyl, 18.50mmol) and 50mL of 40% hydrobromic acid acetic acid solution, stirring at 120 ℃ for reaction for 36 hours, monitoring the reaction completion by a TLC (thin layer chromatography) spot plate, and removing most of acid liquor in the solution by rotary evaporation, wherein an acid absorption device is adopted as the acid liquor removal mode. And (3) after rotary evaporation is carried out until a small amount of solution is remained, stirring in ice water until a yellow solid is separated out, carrying out suction filtration, and carrying out vacuum drying to obtain a yellow solid, namely the compound 2.
The compound 2 yield in this example was: 95.98 percent.
The hydrogen spectrum of compound 2 in this example is:
1 H NMR(400MHz,DMSO)δ10.82(s,2H),7.76–7.72(m,4H),6.95–6.90(m,4H)。
EXAMPLE 2 preparation of intermediate 3
5.00g of the compound 2(20.64mmol) prepared in example 1 above were taken in admixture with 23.27g of 1, 2-dibromoethane (123.85mmol) and 17.12g K 2 CO 3 (123.85mmol), adding appropriate amount of acetone or acetonitrile as solvent, stirring at 80 deg.C in oil bath for about 16h, monitoring by TLC spot plate, filtering to remove solid precipitate, and purifying by column chromatography with mobile phase of petroleum ether: 1-dichloromethane: 1 to give intermediate 3 as a pale yellow solid.
The yield of intermediate 3 in this example was: 40.53 percent.
The hydrogen spectrum of intermediate 3 in this example is:
1 H NMR(400MHz,CDCl3)δ7.93(d,J＝8.9Hz,4H),6.95(d,J＝8.9Hz,4H),4.08(t,J＝5.9Hz,4H),3.48(t,J＝6.4Hz,4H),2.11–2.04(m,4H),2.02–1.94(m,4H)。
EXAMPLE 3 preparation of intermediate 4
5.00g of the compound 2(20.64mmol) prepared in example 1 above were taken in admixture with 25.00g of 1, 3-dibromopropane (123.85mmol) and 17.12g K 2 CO 3 (123.85mmol), adding appropriate amount of acetone or acetonitrile as solvent, stirring at 80 deg.C in oil bath for about 16h, monitoring by TLC spot plate, filtering to remove solid precipitate, and purifying by column chromatography with mobile phase of petroleum ether: 1-dichloromethane: 1 to give intermediate 4 as a pale yellow solid.
The yield of intermediate 4 in this example was: 41.53 percent.
The hydrogen spectrum of intermediate 4 in this example is:
1 H NMR(400MHz,CDCl3)δ7.94(d,J＝8.9Hz,4H),6.97(d,J＝8.9Hz,4H),4.19(t,J＝5.8Hz,4H),3.60(t,J＝6.3Hz,4H),2.34(p,J＝6.1Hz,4H)。
EXAMPLE 4 preparation of intermediate 5
5.00g of the compound 2 prepared in example 1 (20.64mmol) were taken together with 26.74g of 1, 4-dibromobutane (123.85mmol) and 17.12g K 2 CO 3 (123.85mmol), adding appropriate amount of acetone or acetonitrile as solvent, stirring at 80 deg.C in oil bath for about 16h, monitoring by TLC spot plate, filtering to remove solid precipitate, and purifying by column chromatography with mobile phase of petroleum ether: 1-dichloromethane: 1 to give intermediate 5 as a pale yellow solid.
The yield of intermediate 5 in this example was: 20.22 percent.
The hydrogen spectrum of intermediate 5 in this example is:
1 H NMR(400MHz,CDCl3)δ7.95(d,J＝9.0Hz,4H),6.98(d,J＝9.0Hz,4H),4.37(t,J＝6.2Hz,4H),3.66(t,J＝6.2Hz,4H)。
EXAMPLE 5 preparation of Compound C-1
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 3(2.19mmol) prepared in example 2 was taken and 448.03mg of piperidine (5.26mmol) and the appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plates, filtering to remove solid precipitates, and performing column chromatography separation and purification, wherein the mobile phase conditions are methanol: dichloromethane ═ 2: 25 and a small amount of ammonia was added to give compound C-1 as a pale yellow solid.
The structural formula of compound C-1 in this example is shown in formula 6:
the yield of compound C-1 in this example was: 74.66 percent.
The hydrogen spectrum of compound C-1 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.96(d,J＝8.9Hz,4H),4.21(t,J＝5.9Hz,4H),2.83(t,J＝5.9Hz,4H),2.55(s,8H),1.67–1.59(m,8H),1.51–1.41(m,8H)。
the carbon spectrum of compound C-1 in this example is:
13 C NMR(126MHz,CDCl3)δ193.58,164.19,132.42,126.35,114.91,66.44,57.64,55.11,25.90,24.15.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-1 in this example was:
[M+H] + m/z＝465.2748,calcd for 464.2675。
compound C-1 in this example was found to be 95.1% pure by HPLC.
EXAMPLE 6 preparation of Compound C-2
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 3(2.19mmol) prepared in example 2 are taken and 237.22mg of dimethylamino (5.26mmol) and the appropriate amount of K are added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) monitoring the complete reaction by TLC plates, filtering to remove solid precipitates, and performing column chromatography separation and purification, wherein the mobile phase is methanol: dichloromethane ═ 2: 25, Compound C-2 was obtained as a pale yellow solid.
The structural formula of compound C-2 in this example is shown in formula 7:
the yield of compound C-2 in this example was: 53.22 percent.
The hydrogen spectrum of compound C-2 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.97(d,J＝8.9Hz,4H),4.14(t,J＝5.6Hz,4H),2.76(t,J＝5.6Hz,4H),2.34(s,12H)。
the carbon spectrum of compound C-2 in this example is:
13 C NMR(101MHz,CDCl3)δ193.49,164.09,132.36,126.34,114.82,66.34,57.96,45.85.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-2 in this example was:
[M+H] + m/z＝385.2122,calcd for 384.2049。
compound C-2 in this example was found to be 95.6% pure by HPLC.
EXAMPLE 7 preparation of Compound C-3
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 3(2.19mmol) from example 2 are taken and added with tetrahydropyrrole (5.26mmol) and the appropriate amount of K 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plates, filtering to remove solid precipitates, and performing column chromatography separation and purification, wherein the mobile phase conditions are methanol: 1-dichloromethane: 20, Compound C-3 was obtained as a pale yellow solid.
The hydrogen spectrum of compound C-3 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.8Hz,1H),6.98(d,J＝8.9Hz,1H),4.19(t,J＝5.8Hz,1H),2.94(t,J＝5.8Hz,1H),2.65(s,2H),1.82(s,2H)。
the carbon spectrum of compound C-3 in this example is:
13 C NMR(101MHz,CDCl3)δ193.60,163.84,132.27,126.22,114.83,66.66,54.58,54.42,50.01,23.28.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-3 in this example was:
[M+H] + m/z＝437.2435,calcd for 436.2362。
compound C-3 in this example was 98.3% pure by HPLC.
EXAMPLE 8 preparation of Compound C-4
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 3(2.19mmol) prepared in example 2 are taken and 458.41mg of morpholine ring (5.26mmol) and the appropriate amount of K are added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plates, filtering to remove solid precipitates, and performing column chromatography separation and purification, wherein the mobile phase conditions are methanol: methylene dichloride1: 20, Compound C-4 was obtained as a pale yellow solid.
The structural formula of compound C-4 in this example is shown in formula 9:
the yield of compound C-4 in this example was: 75.65 percent.
The hydrogen spectrum of compound C-4 in this example is:
1 H NMR(400MHz,CDCl3)δ7.95(d,J＝8.9Hz,1H),6.98(d,J＝8.9Hz,1H),4.21(t,J＝5.6Hz,1H),3.79–3.67(m,2H),2.85(t,J＝5.6Hz,1H),2.65–2.54(m,2H)。
the carbon spectrum of compound C-4 in this example is:
13 C NMR(101MHz,CDCl3)δ193.60,163.84,132.27,126.22,114.83,66.66,54.58,54.42,50.01,23.28.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-4 in this example was:
[M+H] + m/z＝469.2333,calcd for 486.2260。
compound C-4 in this example was 94.2% pure by HPLC.
EXAMPLE 9 preparation of Compound C-5
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 3(2.19mmol) prepared in example 2 are taken and 453.23mg of pyridine (5.26mmol) and the appropriate amount of K are added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) monitoring the complete reaction by TLC plates, filtering to remove solid precipitates, and performing column chromatography separation and purification, wherein the mobile phase is methanol: dichloromethane ═ 2: 25, Compound C-5 was obtained as a pale yellow solid.
The structural formula of compound C-5 in this example is shown in formula 10:
the yield of compound C-5 in this example was: 30.26 percent.
The hydrogen spectrum of compound C-5 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,1H),6.96(d,J＝8.9Hz,1H),4.17(t,J＝5.8Hz,1H),2.99–2.87(m,2H),2.81(t,J＝5.8Hz,1H),2.55(s,2H),2.55(s,2H),2.05(s,1H)。
the carbon spectrum of compound C-5 in this example is:
13 C NMR(101MHz,CDCl3)δ193.56,164.15,132.49,126.45,114.93,66.38,57.58,54.87,46.01.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-5 in this example was:
[M+H] + m/z＝467.2653,calcd for 466.2580。
compound C-5 in this example was 96.2% pure by HPLC.
EXAMPLE 10 preparation of Compound C-6
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 4(2.07mmol) prepared in example 2 are taken and 233.48mg of piperidine (4.96mmol) and the appropriate amount of K are added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After TLC plate counting monitoring reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the flow phenomenon is methanol: 1-dichloromethane: 100, Compound C-5 was obtained as a pale yellow solid.
The structural formula of compound C-6 in this example is shown in formula 11:
the yield of compound C-6 in this example was: 43.83 percent.
The hydrogen spectrum of compound C-6 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.95(d,J＝9.0Hz,4H),4.11(t,J＝6.2Hz,4H),2.57(t,J＝25.5Hz,12H),2.13–2.04(m,4H),1.68(s,8H),1.53–1.44(m,4H)。
the carbon spectrum of compound C-6 in this example is:
13 C NMR(126MHz,CDCl3)193.42,164.29,132.35,126.07,114.73,77.41,77.09,76.77,66.75,66.45,55.24,53.61,25.99.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-6 in this example was:
[M+H] + m/z＝493.3061,calcd for 492.2988。
compound C-6 in this example was found to be 95.1% pure by HPLC.
EXAMPLE 11 preparation of Compound C-7
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 4(2.07mmol) prepared in example 2 was taken and 233.48mg of dimethylamine (4.96mmol) and the appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After TLC plate counting monitoring reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the flow phenomenon is methanol: 1-dichloromethane: 100, Compound C-7 was obtained as a pale yellow solid.
The structural formula of compound C-7 in this example is shown in formula 12:
the yield of compound C-7 in this example was: 43.83 percent.
The hydrogen spectrum of compound C-7 in this example is:
1 H NMR(400MHz,CDCl3)δ7.91(d,J＝8.9Hz,4H),6.95(d,J＝8.9Hz,4H),4.08(t,J＝6.4Hz,4H),2.45(t,J＝7.2Hz,4H),2.25(s,12H),1.97(dt,J＝13.4,6.6Hz,4H)。
the carbon spectrum of compound C-7 in this example is:
13 C NMR(126MHz,CDCl3)δ193.67,164.43,132.48,126.32,114.86,66.65,56.18,45.43,27.19.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-7 in this example was:
[M+H] + m/z＝413.2435,calcd for 412.2362。
compound C-7 in this example was 94.7% pure by HPLC.
EXAMPLE 12 preparation of Compound C-8
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 4(2.07mmol) from example 2 are taken and 352.54mg of tetrahydropyrrole (4.96mmol) and the appropriate amount of K are added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) after TLC plate counting monitoring reaction is completely carried out, filtering to remove solid precipitate, and carrying out column chromatography separation and purification, wherein the separation conditions are methanol: dichloromethane ═ 2: 25, Compound C-8 was obtained as a pale yellow solid.
The structural formula of compound C-8 in this example is shown in formula 13:
the yield of compound C-8 in this example was: 73.54 percent.
The hydrogen spectrum of compound C-8 in this example is:
1 H NMR(400MHz,CDCl3)δ7.91(d,J＝8.9Hz,4H),6.95(d,J＝8.9Hz,4H),4.11(t,J＝6.4Hz,4H),2.68–2.60(m,4H),2.56(t,J＝5.8Hz,8H),2.09–1.99(m,4H),1.82–1.75(m,8H)。
the carbon spectrum of compound C-8 in this example is:
13 C NMR(126MHz,CDCl3)δ193.65,164.34,132.49,126.35,114.86,66.66,54.27,53.01,28.16,23.56.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-8 in this example was:
[M+H] + m/z＝465.2748,calcd for464.2675。
compound C-8 in this example was 93.6% pure by HPLC.
EXAMPLE 13 preparation of Compound C-9
According to the general formulae (II) and (I)) A process for the preparation of the compound shown in the specification, wherein 1g of intermediate 4(2.07mmol) prepared in example 2 is charged with 431.85mg of morpholine (4.96mmol) and the appropriate amount of K 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) after TLC plate counting monitoring reaction is completely carried out, filtering to remove solid precipitate, and carrying out column chromatography separation and purification, wherein the separation conditions are methanol: 1-dichloromethane: 20, Compound C-9 was obtained as a pale yellow solid.
The structural formula of compound C-9 in this example is shown in formula 14:
the yield of compound C-9 in this example was: 75.22 percent.
The hydrogen spectrum of compound C-9 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.8Hz,4H),6.95(d,J＝8.8Hz,4H),4.10(t,J＝6.3Hz,4H),3.75–3.67(m,8H),2.52(t,J＝7.2Hz,4H),2.46(s,8H),2.04–1.94(m,4H)。
the carbon spectrum of compound C-9 in this example is:
13 C NMR(126MHz,CDCl3)δ193.60,164.40,132.50,126.36,114.85,66.88,66.57,55.39,53.75,26.14.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-9 in this example was:
[M+H] + m/z＝465.2748,calcd for 496.2573。
compound C-9 in this example was 96.4% pure by HPLC.
EXAMPLE 14 preparation of Compound C-10
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 4(2.07mmol) prepared in example 2 was taken and 426.97mg of pyridine (4.96mmol) and the appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plates, filtering to remove solid precipitates, and performing column chromatography separation and purification, wherein the conditions of a mobile phase are as follows: 25, and adding lessAmmonia water was metered in to give Compound C-10 as a pale yellow solid.
The structural formula of compound C-10 in this example is shown in formula 15:
the yield of compound C-10 in this example was: 21.52 percent.
The hydrogen spectrum of compound C-10 in this example is:
1 H NMR(500MHz,CDCl3)δ7.92(d,J＝8.4Hz,1H),6.96(d,J＝8.9Hz,1H),4.09(t,J＝4.8Hz,1H),2.91(s,2H),2.63–2.47(m,2H),2.05–1.93(m,1H)。
the carbon spectrum of compound C-10 in this example is:
13 C NMR(101MHz,CDCl3)δ193.60,163.84,132.27,126.22,114.83,66.66,54.58,54.42,50.01,23.28.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-10 in this example was:
[M+H] + m/z＝495.2966,calcd for 494.2893。
compound C-10 in this example was 94.1% pure by HPLC.
EXAMPLE 15 preparation of Compound C-11
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 5(1.95mmol) from example 2 are taken and 398.96mg of piperidine (4.69mmol) and the appropriate amount of K are added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) monitoring the complete reaction by TLC plates, filtering to remove solid precipitates, and performing column chromatography separation and purification, wherein the mobile phase is methanol: dichloromethane ═ 2: 25, Compound C-11 was obtained as a pale yellow solid.
The structural formula of compound C-11 in this example is shown in formula 16:
the yield of compound C-11 in this example was: 72.44 percent.
The hydrogen spectrum of compound C-11 in this example is:
1 H NMR(400MHz,DMSO)δ7.84(d,J＝8.9Hz,4H),7.12(d,J＝8.9Hz,4H),4.11(t,J＝6.5Hz,4H),2.37–2.23(m,12H),1.79–1.69(m,4H),1.60–1.51(m,4H),1.50–1.43(m,4H),1.41–1.33(m,4H)。
the carbon spectrum of compound C-11 in this example is:
13 C NMR(126MHz,CDCl3)δ193.68,164.47,132.46,126.23,114.82,68.27,58.82,54.53,27.21,25.75,24.35,23.19.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-11 in this example was:
[M+H] + m/z＝521.3374,calcd for520.3301。
compound C-11 in this example was 93.8% pure by HPLC.
EXAMPLE 16 preparation of Compound C-12
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 5(1.95mmol) from example 2 are taken and 333.23mg of tetrahydropyrrole (4.69mmol) and the appropriate amount of K are added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) monitoring the complete reaction by a TLC (thin layer chromatography) plate, filtering to remove solid precipitates, and performing column chromatography separation and purification, wherein the mobile phase conditions are methanol: dichloromethane ═ 2: 25, Compound C-12 was obtained as a pale yellow solid.
The structural formula of compound C-12 in this example is shown in formula 17:
the yield of compound C-12 in this example was: 48.13 percent.
The hydrogen spectrum of compound C-12 in this example is:
1 H NMR(400MHz,CDCl3)δ7.89(d,J＝8.7Hz,4H),6.92(d,J＝8.7Hz,4H),4.04(t,J＝6.3Hz,4H),2.61–2.47(m,12H),1.86–1.65(m,16H)。
the carbon spectrum of compound C-12 in this example is:
13 C NMR(126MHz,CDCl3)δ193.57,164.36,132.34,126.11,114.71,68.14,55.95,54.12,27.08,25.24,23.39.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-12 in this example was:
[M+H] + m/z＝493.3061,calcd for 492.2988。
compound C-12 in this example was 96.8% pure by HPLC.
EXAMPLE 17 preparation of Compound C-13
According to the preparation of the compounds of the general formulae (II) and (I), 1g of intermediate 5(1.95mmol) from example 2 are taken and 408.19mg of morpholine (4.69mmol) and the appropriate amount of K are added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plates, filtering to remove solid precipitates, and performing column chromatography separation and purification, wherein the mobile phase conditions are methanol: 1-dichloromethane: 20, Compound C-13 was obtained as a pale yellow solid.
The structural formula of compound C-13 in this example is shown in formula 18:
the yield of compound C-13 in this example was: 66.52 percent.
The hydrogen spectrum of compound C-13 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.94(d,J＝8.9Hz,4H),4.06(t,J＝6.3Hz,4H),3.76–3.66(m,8H),2.52–2.36(m,12H),1.89–1.79(m,4H),1.74–1.63(m,4H)。
the carbon spectrum of compound C-13 in this example is:
13 C NMR(101MHz,CDCl3)δ193.61,164.38,132.45,126.14,114.79,68.11,66.65,58.42,53.55,26.94,22.72.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound C-13 in this example was:
[M+H] + m/z＝525.2934,calcd for 524.2886。
compound C-13 in this example was 96.8% pure by HPLC.
EXAMPLE 18 preparation of Compound B-1
According to the preparation method of the compounds represented by the general formulae (II) and (I), 200mg of the compound C-1(452.38mmol) prepared in the above example 5 was taken, 49.54mg of 1, 2-phenylenediamine (458.14mmol) and an appropriate amount of sodium acetate were added, and the mixture was stirred and reacted at 120 ℃ for 24 hours with acetic acid as a solvent. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, Compound B-1 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-1 in this example is shown in formula 19:
the yield of compound B-1 in this example was: 52.25 percent.
The hydrogen spectrum of compound B-1 in this example is:
1 H NMR(400MHz,CDCl3)δ8.10(dd,J＝6.3,3.4Hz,2H),7.69(dd,J＝6.4,3.4Hz,2H),7.46(d,J＝8.7Hz,4H),6.86(d,J＝8.7Hz,4H),4.12(t,J＝6.0Hz,4H),2.77(t,J＝6.0Hz,4H),2.50(s,8H),1.60(dt,J＝11.0,5.6Hz,8H),1.48–1.38(m,4H)。
the carbon spectrum of compound B-1 in this example is:
13 C NMR(101MHz,CDCl3)δ159.16,152.99,141.08,131.91,131.27,129.59,129.02,114.46,57.65,54.97,25.42,23.82.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-1 in this example was:
[M+H] + m/z＝537.3224,calcd for 536.3151。
compound B-1 in this example was 94.7% pure by HPLC.
EXAMPLE 19 preparation of Compound B-2
According to the preparation of the compounds of the general formulae (II) and (I), 200mg of the compound C3 (458.46mmol) prepared in example 7 above were taken, 59.49mg of 1, 2-phenylenediamine (550.16mmol) and an appropriate amount of sodium acetate were added, and the mixture was stirred with acetic acid as a solvent at 120 ℃ for 24 hours. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, obtaining a crude product, and purifying by thin layer chromatography (big plate) under the conditions of methanol: ammonia water: dichloromethane 10: 1: 300, Compound B-2 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-2 in this example is shown in formula 20:
the yield of compound B-2 in this example was: 48.75 percent.
The hydrogen spectrum of compound B-2 in this example is:
1 H NMR(400MHz,CDCl3)δ8.14(dd,J＝6.4,3.4Hz,1H),7.73(dd,J＝6.4,3.4Hz,1H),7.49(d,J＝8.8Hz,2H),6.90(d,J＝8.8Hz,2H),4.17(t,J＝5.9Hz,2H),2.95(t,J＝5.9Hz,2H),2.68(t,J＝6.0Hz,4H),1.84(t,J＝5.1Hz,4H)。
the carbon spectrum of compound B-2 in this example is:
13 C NMR(126MHz,CDCl3)δ159.46,153.15,141.17,131.89,131.34,129.64,129.11,114.55,67.02,55.07,54.87,23.59.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-2 in this example was:
[M+H] + m/z＝509.2911,calcd for 508.2838。
compound B-2 in this example was 93.3% pure by HPLC.
EXAMPLE 20 preparation of Compound B-3
According to the preparation method of the compounds represented by the general formulas (II) and (I), 200mg of the compound C6(405.96mmol) prepared in the above example 10 was taken, 52.68mg of 1, 2-phenylenediamine (487.15mmol) and a proper amount of sodium acetate were added, and the mixture was stirred and reacted at 120 ℃ for 24 hours with acetic acid as a solvent. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, Compound B-3 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-3 in this example is shown in formula 21:
the yield of compound B-3 in this example was: 45.24 percent.
The hydrogen spectrum of compound B-3 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.3,3.4Hz,2H),7.72(dd,J＝6.4,3.4Hz,2H),7.47(d,J＝8.7Hz,4H),6.88(t,J＝9.1Hz,4H),4.15(t,J＝5.9Hz,4H),2.81(t,J＝5.9Hz,4H),2.58(d,J＝17.9Hz,8H),1.68–1.60(m,8H),1.49–1.43(m,4H),1.25(s,4H)。
the carbon spectrum of compound B-3 in this example is:
13 C NMR(126MHz,CDCl3)δ159.39,153.14,141.21,131.98,131.38,129.69,129.15,122.34,114.59,65.84,57.83,55.13,29.84,25.72,24.07.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-3 in this example was:
[M+H] + m/z＝509.2911,calcd for 508.2838。
compound B-3 in this example was found to be 95.5% pure by HPLC.
EXAMPLE 21 preparation of Compound B-4
According to the preparation of the compounds of the general formulae (II) and (I), 200mg of the compound C7(484.81mmol) prepared in example 11 above were added with 62.91mg of 1, 2-phenylenediamine (581.78mmol) and a suitable amount of sodium acetate, and the mixture was stirred with acetic acid as a solvent at 120 ℃ for 24 hours. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, Compound B-4 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-4 in this example is shown in formula 22:
the yield of compound B-4 in this example was: 45.68 percent.
The hydrogen spectrum of compound B-4 in this example is:
1 H NMR(400MHz,CDCl3)δ8.11(dd,J＝6.4,3.4Hz,2H),7.71(dd,J＝6.4,3.4Hz,2H),7.47(d,J＝8.8Hz,4H),6.86(d,J＝8.8Hz,4H),4.04(t,J＝6.4Hz,4H),2.52–2.45(m,4H),2.28(s,12H),1.98(dt,J＝13.5,6.5Hz,4H)。
the carbon spectrum of compound B-4 in this example is:
13 C NMR(101MHz,CDCl3)δ159.62,153.11,141.07,131.63,131.27,129.56,129.02,114.36,66.23,56.38,45.49,27.42.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-4 in this example was:
[M+H] + m/z＝485.2911,calcd for 484.2838。
compound B-4 in this example was 96.1% pure by HPLC.
EXAMPLE 22 preparation of Compound B-5
According to the preparation of the compounds of the general formulae (II) and (I), 200mg of the compound C8(430.47mmol) prepared in example 12 above were taken, 55.86mg of 1, 2-phenylenediamine (516.56mmol) and an appropriate amount of sodium acetate were added, and the mixture was stirred with acetic acid as a solvent at 120 ℃ for 24 hours. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, Compound B-5 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-5 in this example is shown in formula 23:
the yield of compound B-5 in this example was: 38.25 percent.
The hydrogen spectrum of compound B-5 in this example is:
1 H NMR(400MHz,CDCl3)δ8.11(dd,J＝6.3,3.4Hz,2H),7.71(dd,J＝6.4,3.4Hz,2H),7.47(d,J＝8.7Hz,4H),6.86(d,J＝8.7Hz,4H),4.05(t,J＝6.4Hz,4H),2.74–2.61(m,4H),2.56(s,8H),2.09–1.96(m,4H),1.80(s,8H)。
the carbon spectrum of compound B-5 in this example is:
13 C NMR(101MHz,CDCl3)δ159.55,152.99,140.97,131.51,131.18,129.44,128.92,114.27,66.33,54.19,53.08,28.66,23.41.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-5 in this example was:
[M+H] + m/z＝537.3209,calcd for 536.3151。
compound B-5 in this example was found to be 95.8% pure by HPLC.
EXAMPLE 23 preparation of Compound B-6
According to the preparation of the compounds of the general formulae (II) and (I), 200mg of the compound C9(402.74mmol) prepared in example 13 were added with 52.26mg of 1, 2-phenylenediamine (483.29mmol) and a suitable amount of sodium acetate, and the mixture was stirred with acetic acid as a solvent at 120 ℃ for 24 hours. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, Compound B-6 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-6 in this example is shown in formula 24:
the yield of compound B-6 in this example was: 52.81 percent.
The hydrogen spectrum of compound B-6 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.4,3.4Hz,2H),7.72(dd,J＝6.4,3.4Hz,2H),7.48(d,J＝8.7Hz,4H),6.86(d,J＝8.8Hz,4H),4.06(t,J＝6.3Hz,4H),3.79–3.72(m,8H),2.61–2.55(m,4H),2.52(s,8H),2.02(dt,J＝13.5,6.6Hz,8H)。
the carbon spectrum of compound B-6 in this example is:
13 C NMR(126MHz,CDCl3)δ159.56,153.01,141.07,131.72,131.25,129.56,129.00,66.91,66.14,55.54,53.73,26.34.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-6 in this example was:
[M+H] + m/z＝569.3122,calcd for 568.3050。
compound B-6 in this example was 94.0% pure by HPLC.
EXAMPLE 24 preparation of Compound B-7
According to the preparation of the compounds of the general formulae (II) and (I), 200mg of the compound C11(384.09mmol) prepared in example 15 were added with 49.84mg of 1, 2-phenylenediamine (460.91mmol) and a suitable amount of sodium acetate, and the mixture was stirred with acetic acid as a solvent at 120 ℃ for 24 hours. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, Compound B-7 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-7 in this example is shown in formula 25:
the yield of compound B-7 in this example was: 33.26 percent.
The hydrogen spectrum of compound B-7 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.4,3.4Hz,2H),7.72(dd,J＝6.4,3.4Hz,2H),7.47(d,J＝8.7Hz,4H),6.85(d,J＝8.7Hz,4H),4.00(t,J＝6.2Hz,4H),2.55–2.38(m,12H),1.86–1.77(m,4H),1.75–1.69(m,4H),1.67–1.59(m,4H),1.49–1.42(m,4H)。
the carbon spectrum of compound B-7 in this example is:
13 C NMR(126MHz,CDCl3)δ159.68,153.08,141.05,131.54,131.23,129.46,128.99,114.32,67.82,59.07,54.60,27.40,25.97,24.48,23.47.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-7 in this example was:
[M+H] + m/z＝593.3848,calcd for 592.3777。
compound B-7 in this example was 98.1% pure by HPLC.
EXAMPLE 25 preparation of Compound B-8
According to the preparation of the compounds of the general formulae (II) and (I), 200mg of the compound C12(453.95mmol) prepared in example 16 were added with 58.91mg of 1, 2-phenylenediamine (544.74mmol) and a suitable amount of sodium acetate, and the mixture was stirred with acetic acid as a solvent at 120 ℃ for 24 hours. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, Compound B-8 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-8 in this example is shown in formula 26:
the yield of compound B-8 in this example was: 28.55 percent.
The hydrogen spectrum of compound B-8 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.94(d,J＝8.9Hz,4H),4.06(t,J＝6.3Hz,4H),3.76–3.66(m,8H),2.52–2.36(m,12H),1.89–1.79(m,4H),1.74–1.63(m,4H)。
the carbon spectrum of compound B-8 in this example is:
13 C NMR(126MHz,CDCl3)δ159.77,153.21,141.19,131.73,131.35,129.61,129.12,114.46,67.86,59.46,45.47,27.21,24.24.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-8 in this example was:
[M+H] + m/z＝513.3224,calcd for 512.3151。
compound B-8 in this example was 96.2% pure by HPLC.
EXAMPLE 26 preparation of Compound B-9
According to the preparation of the compounds of the general formulae (II) and (I), 200mg of the compound C13(405.95mmol) prepared in example 17 were added with 52.68mg of 1, 2-phenylenediamine (487.14mmol) and a suitable amount of sodium acetate, and the mixture was stirred with acetic acid as a solvent at 120 ℃ for 24 hours. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, Compound B-9 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-9 in this example is shown in formula 27:
the yield of compound B-9 in this example was: 40.68 percent.
The hydrogen spectrum of compound B-9 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.4,3.4Hz,2H),7.72(dd,J＝6.4,3.4Hz,2H),7.50–7.45(m,4H),6.85(d,J＝8.8Hz,4H),4.00(t,J＝6.3Hz,4H),3.76–3.70(m,8H),2.50–2.40(m,12H),1.87–1.78(m,4H),1.75–1.65(m,4H)。
the carbon spectrum of compound B-9 in this example is:
13 C NMR(126MHz,CDCl3)δ159.69,153.10,141.13,131.70,131.32,129.59,129.07,114.37,67.78,67.05,58.70,53.80,27.24,23.14.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-9 in this example was:
[M+H] + m/z＝597.3435,calcd for 564.3463。
compound B-9 in this example was 96.5% pure by HPLC.
EXAMPLE 27 preparation of Compound B-10
According to the preparation of the compounds of the general formulae (II) and (I), 200mg of the compound C14(381.20mmol) prepared in example 18 were added with 49.47mg of 1, 2-phenylenediamine (457.44mmol) and a suitable amount of sodium acetate, and the mixture was stirred with acetic acid as a solvent at 120 ℃ for 24 hours. And (3) monitoring the complete reaction by TLC (thin layer chromatography) plate, diluting with ice water, adjusting the pH of the solution to be neutral by using sodium bicarbonate, extracting with dichloromethane, washing the extract for 2-3 times, and performing column chromatography separation and purification, wherein the mobile phase conditions are that 1: 25, Compound B-10 was obtained as a yellow solid having blue fluorescence.
The structural formula of compound B-10 in this example is shown in formula 28:
the yield of compound B-10 in this example was: 15.28 percent.
The hydrogen spectrum of compound B-10 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.4,3.5Hz,2H),7.72(dd,J＝6.3,3.4Hz,2H),7.47(d,J＝8.6Hz,4H),6.85(d,J＝8.7Hz,4H),4.00(t,J＝6.1Hz,4H),3.13–3.06(m,4H),2.69–2.63(m,4H),2.52–2.46(m,4H),2.31(s,10H),1.87–1.77(m,4H),1.75–1.63(m,4H)。
the carbon spectrum of compound B-10 in this example is:
13 C NMR(101MHz,CDCl3)δ159.73,153.19,141.16,131.69,131.35,129.65,129.09,114.42,67.85,58.87,54.21,45.91,27.33,23.29.11.10。
the electrospray mass spectrum (ESI-HRMS) of Compound B-10 in this example was:
[M+H] + m/z＝595.3755,calcd for 596.3363。
compound B-10 in this example was found to be 95.1% pure by HPLC.
Assay of the binding Effect of vimentin of the Compound prepared in the above example
The surface plasmon resonance technology is used for testing the binding effect of the compound prepared in the embodiment 1-28 and the vimentin, and the specific steps are as follows:
1. the vimentin is diluted by sodium acetate solution (pH5.5) to make the final concentration be 100mM, and is marked on an NTA chip;
2. diluting the test compound to 50mM with SPR buffer, setting a program, allowing the test compound to flow through the NTA chip, and washing the NTA chip with SPR buffer after the test compound is combined with the vimentin to dissociate the test compound;
3. and fitting the equilibrium dissociation constant KD value of the compound to be tested and the vimentin.
In this case, PQ7 (polyquaternium-7, CAS: 26590-05-6) was used as a control. PQ7 is a small molecule that specifically binds vimentin.
The equilibrium dissociation constant KD values of the test compound and vimentin are shown in table 1.
TABLE 1 equilibrium dissociation constant KD values for test compounds and vimentin
Meanwhile, the response value of the compound to be detected and the vimentin is obtained through calculation, and the binding capacity and the binding mode of the compound to be detected and the vimentin are preliminarily judged according to the response value and the dissociation curve, and the result is shown in fig. 2.
From the results, it is understood that the compounds prepared in the above examples have strong binding ability to vimentin, and most of them are superior to PQ 7.
Detection of inhibitory Effect of the Compounds prepared in the above examples on the growth of tumor cells
Selecting the compound with stronger binding effect on vimentin in the above embodiment, and carrying out in vitro cytotoxicity detection on various tumor cell strains by using an MTT method.
The tumor cell strain used is: a549 human non-small cell lung cancer cell, HEK293T human embryonic kidney epithelial cell, HepG2 human liver cancer cell, MDA-MB-231 human breast cancer cell, HUVEC human umbilical vein vascular endothelial cell, SW480 human colon cancer cell, DLD-1 human colorectal adenocarcinoma epithelial cell.
The method comprises the following specific steps: adding the compounds to be detected with different concentrations into the cells in the logarithmic growth phase respectively, incubating for 24h, adding MTT, and determining the absorbance. The concentration of the compound at which the growth of the cells was inhibited by 50% (IC50 value) was calculated, and the results are shown in Table 2.
TABLE 2 inhibition of growth (IC) of various tumor cell lines by test compounds 50 Value/. mu.M)
From the results, it is understood that the IC50 of the compounds prepared in the above examples is lower than that of PQ7, indicating that the compounds prepared in the above examples have a stronger inhibitory activity against various tumor cells.
Test of the Effect of the Compounds prepared in the above examples on tumor autophagy
Western blot is adopted to detect the effect of the compound prepared in the embodiment on tumor autophagy, and the specific steps are as follows:
cells were cultured (MDA-MB-231 tumor cells were used as the subject), and total supernatant protein was extracted by adding cell lysate. The total protein concentration was measured using the BCA method, and then the protein was denatured. And (3) taking the same mass of protein for loading, and separating protein bands by SDS-PAGE electrophoresis. And (3) calculating the molecular weight according to the target protein, cutting off the electrophoresis gel band at the corresponding position, and transferring the protein band to the PVDF membrane by a wet transfer method.
A5% skim milk powder solution (w/v) was dissolved in TBST buffer (25mM NaCl, 100mM Tris, 0.2% Tween-20, pH 7.4), PVDF membrane was blocked, primary and secondary antibodies were added for incubation, and then rinsed with TBST buffer, and developed for imaging using SuperECL Plus super luminescent kit.
As shown in FIG. 3, Western Blot results prove that the compound prepared in the above example can induce tumor cell death by inducing tumor cell autophagy, and the ability of promoting tumor autophagy is far better than that of PQ7 in the control group.
In conclusion, the compound in the embodiment of the invention has much better binding capacity to vimentin, autophagy promotion effect on tumor cells and inhibition capacity on tumor cells (including lung cancer cells, liver cancer cells, breast cancer cells, colorectal cancer cells and the like) than PQ7, wherein the chemical structure of the B series compound (embodiments 18-27) is simpler than that of PQ7, and the activity of the B series compound is stronger in all aspects; the C series compounds (examples 5 to 17) have a linear structure similar to that of PQ7, but show stronger binding ability to vimentin than PQ 7.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present invention. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (10)
1. The small molecule compound is characterized in that the structure of the small molecule compound is shown as a formula (II):
wherein, in the formula (II), X is selected from carbon, oxygen, nitrogen, sulfur, ester group, carbonyl or amide;
r is selected from any open chain compound, carbocycle, heterocycle, halogen, nitro, cyano, amino, hydroxyl or sulfydryl;
n is any integer of 1-4.
2. The small molecule compound according to claim 1, wherein said small molecule compound does not comprise:
(1) r is bromine;
(2) n is 2 and R is a structure represented by formula 29;
(3) n is 3 and R is a structure represented by formula 30;
wherein, the structure shown in formula 29 is:
the structure shown in formula 30 is:
3. the small molecule compound according to claim 1, wherein the small molecule compound comprises a compound having a structure represented by formula 6 to formula 18;
4. a composition comprising a small molecule compound according to any one of claims 1 to 3.
5. A method for producing the small molecule compound according to any one of claims 1 to 3, comprising:
demethylating anisoyl in an acidic solution, adding a dibromoalkane chain, adjusting the pH to be alkaline, and adding a cyclic compound or a nitrogen-containing open-chain compound to obtain a micromolecular compound with a structural formula shown in a formula (II);
wherein the cyclic compound comprises an aromatic compound or a heterocyclic compound;
the aromatic compound includes: dimethylamino-containing aromatic compounds, diethylamino-containing aromatic compounds, piperidinyl-containing aromatic compounds, piperazinyl-containing aromatic compounds, and benzene;
the heterocyclic compound includes: piperidinyl-containing heterocyclic compounds, piperazinyl-containing heterocyclic compounds, thiophenes, furans, tetrahydropyrrole, and morpholines;
the nitrogen-containing open chain compound includes a dimethylamino open chain compound and a diethylamino open chain compound.
6. The method according to claim 5, wherein the dibromoalkane chain comprises 1, 2-dibromoethane, 1, 3-dibromoethane, and 1, 4-dibromoethane.
7. A pharmaceutical agent comprising the small molecule compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
8. The medicament of claim 7, further comprising a pharmaceutically acceptable excipient.
9. Use of the small molecule compound according to any one of claims 1 to 3 for the preparation of a vimentin detection preparation.
10. The use of a small molecule compound according to any one of claims 1 to 3 for the preparation of an anti-tumor medicament; wherein, the tumor preferably comprises lung cancer, liver cancer, breast cancer and colorectal cancer.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050213A (en) * | 2007-05-14 | 2007-10-10 | 中山大学 | Fat amido substitutional berberine derviation, preparation method, and application of anticancer drugs |
| CN107445963A (en) * | 2017-06-23 | 2017-12-08 | 中山大学 | A kind of quinoxaline derivatives and its preparation method and application |
| CN108658869A (en) * | 2017-03-29 | 2018-10-16 | 复旦大学 | Compound with anti-tumor activity and preparation method thereof and the purposes in pharmacy |
| CN111732584A (en) * | 2019-03-25 | 2020-10-02 | 复旦大学 | Diaryl substituted fused heterocyclic compound, preparation method thereof and application thereof in pharmacy |
| CN111836808A (en) * | 2018-02-27 | 2020-10-27 | 欧斯特奥纽罗根有限公司 | Novel compound for preventing, alleviating or treating fibrosis or nonalcoholic steatohepatitis and composition comprising same as active ingredient |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2480800C (en) * | 2002-04-08 | 2008-09-23 | Mark T. Bilodeau | Inhibitors of akt activity |
| KR101684671B1 (en) * | 2010-09-08 | 2016-12-09 | (주)아모레퍼시픽 | A novel quinoxaline compound for ultraviolet absorbers |
| JP2016044256A (en) * | 2014-08-25 | 2016-04-04 | 日東電工株式会社 | Light emitting ethylene copolymer, encapsulation composition for solar cell and solar cell module using the same |
-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050213A (en) * | 2007-05-14 | 2007-10-10 | 中山大学 | Fat amido substitutional berberine derviation, preparation method, and application of anticancer drugs |
| CN108658869A (en) * | 2017-03-29 | 2018-10-16 | 复旦大学 | Compound with anti-tumor activity and preparation method thereof and the purposes in pharmacy |
| CN107445963A (en) * | 2017-06-23 | 2017-12-08 | 中山大学 | A kind of quinoxaline derivatives and its preparation method and application |
| CN111836808A (en) * | 2018-02-27 | 2020-10-27 | 欧斯特奥纽罗根有限公司 | Novel compound for preventing, alleviating or treating fibrosis or nonalcoholic steatohepatitis and composition comprising same as active ingredient |
| CN111732584A (en) * | 2019-03-25 | 2020-10-02 | 复旦大学 | Diaryl substituted fused heterocyclic compound, preparation method thereof and application thereof in pharmacy |
Non-Patent Citations (2)
| Title |
|---|
| HU, MING-HAO等: "Development of a highly sensitive fluorescent light-up probe for G-quadruplexes", vol. 140, no. 13, pages 4616 - 4625, XP055854525, DOI: 10.1039/C5AN00761E * |
| TSENG, CHIH-HUA等: "Combretastatin A-4 derivatives: synthesis and evaluation of 2,4,5-triaryl-1H-imidazoles as potential agents against H1299 (non-small cell lung cancer cell)", vol. 16, no. 4, pages 697 - 709, XP037387403, DOI: 10.1007/s11030-012-9396-8 * |
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