CN113248496A - Pyrrolopyridine compound, salt thereof and use thereof - Google Patents
Pyrrolopyridine compound, salt thereof and use thereof Download PDFInfo
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- CN113248496A CN113248496A CN202110492881.3A CN202110492881A CN113248496A CN 113248496 A CN113248496 A CN 113248496A CN 202110492881 A CN202110492881 A CN 202110492881A CN 113248496 A CN113248496 A CN 113248496A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a pyrrolopyridine compound and a salt and application thereof. The structure is as follows. The pyrrolopyridine compound has a remarkable anti-tumor effect, can be used as an anti-tumor medicament for treating malignant tumors such as lung cancer, liver cancer and the like, and can also be used as a lead compound of a potential anti-tumor medicament for further optimization research.
Description
Technical Field
The invention relates to the field of biological medicines, in particular to a pyrrolopyridine compound and a salt and application thereof.
Background
Prevention and treatment of malignant tumors is a medical problem that is urgently needed to be solved. The receptor tyrosine kinase c-Met was found to be highly expressed and abnormally activated in most cancers. It is located at the cross point of multiple tumor signal paths, is a key node protein and can interact with other kinases, receptors and the like.
The HGF/c-Met signal transduction pathway is widely present in various cells and has important physiological regulation effect on the growth and development of various tissues and organs. Under normal physiological conditions, HGF/c-Met can promote epithelial cells to disperse, enhance the motility of the cells, promote the proliferation, differentiation, contraction, movement, secretion, mitosis and other processes of the cells, and has important biological significance for promoting the development of placenta and embryos, and regulating the development and structure formation of organs such as lungs, nervous systems, kidneys, mammary glands and the like. Abnormal activation of the HGF/c-Met signaling pathway is closely related to growth, division, angiogenesis, invasiveness, metastasis, drug resistance and the like of tumors. c-Met exhibits abnormally high expression, mutation and activity change in various tumor tissues, such as lung cancer, breast cancer, colon cancer, prostate cancer and the like.
The study of small molecule c-Met kinase inhibitors was initiated relatively late and currently only two drugs of Crizotinib (Crizotinib) and cabozantinib (Carbozantinib) are on the market. Crizotinib (Crizotinib) is a multi-target protein kinase inhibitor developed by the company Perey, can act on protein kinases such as ALK and ROS besides c-Met, and is mainly approved to treat patients with advanced non-small cell lung cancer. Cabozantinib (Carbozantinib) is a small molecule multi-target kinase inhibitor developed by Exelixis company in the United states, and can act on kinase targets such as MET, VEGFR, ROS1, RET, AXL, NTRK, KIT and the like. The FDA approved cabozotate in 2012 for the treatment of metastatic Medullary Thyroid Cancer (MTC) patients; cabozantinib was approved in 2016 for the treatment of advanced Renal Cell Carcinoma (RCC) patients treated with anti-angiogenesis therapy; cabozantinib was approved in 2017 for first-line treatment of middle-and high-risk advanced renal cancer patients; cabozantinib was approved in 2018 for the treatment of advanced hepatocellular carcinoma patients who progressed after receiving sorafenib or other standard systemic treatment.
At present, kinases such as Met, ALK and VEGFR are the current research hotspots, and development of a multi-target kinase inhibitor with good drug resistance, high selectivity and low toxicity by taking Crizotinib (Crizotinib) and cabozantinib (Carbozantinib) as lead compounds has important value significance.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a pyrrolopyridine compound which shows a remarkable inhibiting effect on tumor cells of lung cancer, liver cancer and the like, a salt thereof and application thereof.
The technical scheme is as follows: the invention provides a pyrrolopyridine compound and a salt thereof, which have the following structures:
R1is hydrogen, halogen or alkyl, R2Is alkyl, aryl or heterocyclic radical, R3、R4、R5And R6Is hydrogen or halogen, and n is 1-6.
Further, the halogen refers to fluorine, chlorine, bromine, and iodine. Chlorine is preferred.
Further, the alkyl group means a straight or branched saturated hydrocarbon group. Preferably 1 to 6 carbon atoms.
Further, the aryl is phenyl, substituted phenyl or bicyclic aromatic hydrocarbon. Preferably, at least one hydrogen on the phenyl ring is substituted with its isotope, halogen, cyano, C1-4 alkyl, methoxy, and the like.
Further, the heterocyclic group is a ternary heterocyclic ring, a quaternary heterocyclic ring, a five-membered heterocyclic ring and a six-membered heterocyclic ring, preferably a five-membered heterocyclic ring or a six-membered heterocyclic ring.
Further, the salt is a hydrochloride, phosphate, sulfate, nitrate, acetate, maleate, oxalate, methanesulfonate, p-toluenesulfonate or benzenesulfonate.
The application of the pyrrolopyridine compound and the salt thereof in preparing antitumor drugs.
The anti-tumor medicine contains an active ingredient of pyrrolopyridine compounds and salts thereof, and also contains pharmaceutically acceptable carriers, auxiliary agents or diluents.
Has the advantages that: the pyrrolopyridine compound has a remarkable anti-tumor effect, can be used as an anti-tumor medicament for treating malignant tumors such as lung cancer, liver cancer and the like, and can also be used as a lead compound of a potential anti-tumor medicament for further optimization research.
Detailed Description
Example 1, the compound 4- (4- ((4-chloro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) methyl) -1H-1, 2, 3-triazol-1-yl) -N- (4-fluorobenzyl) benzamide is prepared according to the following reaction scheme:
the preparation steps are as follows:
step 1: weighing the compound a (0.2g, 1.23mmol), dissolving in 8ml of anhydrous dichloromethane, adding HATU (0.56g, 1.47mmol) and DIPEA (0.31g, 2.46mmol), under nitrogen protection, magnetically stirring for 1h, adding p-fluorobenzylamine (0.15g, 1.23mmol), reacting overnight, after the reaction is finished, adding water for extraction, separating an organic phase, concentrating under reduced pressure, and drying under vacuum to obtain a target product b.
Step 2: compound c (2.0g, 13.11mmol) was weighed out and dissolved in 40ml of anhydrous DMF and bromopropyne (1.8g, ]5.73mmol) and anhydrous potassium carbonate (5.44g, 39.33mmol) were added, and the mixture was magnetically stirred at 50 ℃ under nitrogen for 8 h. And after the reaction is finished, extracting with ethyl acetate, separating an organic phase, concentrating under reduced pressure, and drying in vacuum to obtain a target product d.
And step 3: weighing compound b (0.2g, 0.74mmol), d (0.14g, 0.74mmol) and dissolving in 8ml tetrahydrofuran and 8ml water, adding anhydrous copper sulfate (0.05g, 0.20mmol), sodium ascorbate (0.08g, 0.40mmol), 50 deg.C, under nitrogen protection, and magnetically stirring for 6 h. After the reaction is finished, extracting with water, separating an organic phase, concentrating under reduced pressure to obtain a crude product, and separating and purifying the product by using a column chromatography to obtain the target compound 1.1H NMR(400MHz，DMSO)δ9.27(t，J＝5.8Hz，1H)，8.89(d，J＝15.9Hz，1H)，8.32(d，J＝5.2Hz，1H)，8.13(d，J＝8.7Hz，2H)，8.06(d，J＝8.6Hz，2H)，7.86(d，J＝3.5Hz，1H)，7.43(dd，J＝8.1，5.9Hz，2H)，7.33(d，J＝5.1Hz，1H)，7.26-7.16(m，2H)，6.66(d，J＝3.5Hz，1H)，5.74(s，2H)，4.53(d，J＝5.8Hz，2H).
Example 2 preparation of the Compound 4- (4- ((4-chloro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) methyl) -1H-1, 2, 3-triazol-1-yl) -N- (4-cyanobenzyl) benzamide
The preparation method comprises the following steps: the procedure of example 1 was repeated except for replacing p-fluorobenzylamine with 4- (aminomethyl) benzonitrile in step 1 of example 1.1H NMR(600MHz，DMSO)δ9.34(t，J＝5.9Hz，1H)，8.88(s，1H)，8.31-8.25(m，1H)，8.11(t，J＝7.5Hz，2H)，8.04(d，J＝8.7Hz，2H)，7.83(dd，J＝10.9，6.4Hz，3H)，7.55(t，J＝7.8Hz，2H)，7.27(t，J＝9.3Hz，1H)，6.60(t，J＝16.8Hz，1H)，5.71(s，2H)，4.61(t，J＝10.3Hz，2H).
Example 3 preparation of the Compound 4- (4- ((4-chloro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) methyl) -1H-1, 2, 3-triazol-1-yl) -N- (pyridin-3-ylmethyl) benzamide
The preparation method comprises the following steps: the procedure of example 1 was repeated except for replacing p-fluorobenzylamine with pyridin-3-ylmethylamine in step 1 of example 1.1H NMR(400MHz，DMSO)δ9.26(t，J＝5.9Hz，1H)，8.87(s，1H)，8.58(s，1H)，8.48(d，J＝3.8Hz，1H)，8.27(d，J＝5.2Hz，1H)，8.09(d，J＝8.8Hz，2H)，8.02(d，J＝8.8Hz，2H)，7.78(dd，J＝22.6，5.7Hz，2H)，7.38(dd，J＝7.7，4.8Hz，1H)，7.28(d，J＝5.2Hz，1H)，6.61(d，J＝3.6Hz，1H)，5.70(s，2H)，4.53(d，J＝5.8Hz，2H).
EXAMPLE 4 preparation of the compound 4- (4- ((4-chloro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) methyl) -1H-1, 2, 3-triazol-1-yl) -N- (thien-3-ylmethyl) benzamide
The preparation method comprises the following steps: the procedure of example 1 was repeated except for replacing p-fluorobenzylamine with thien-3-ylmethylamine in step 1 of example 1.1H NMR(400MHz，DMSO)δ8.23(t，J＝5.4Hz，1H)，7.95(d，J＝10.1Hz，1H)，7.94-7.84(m，2H)，7.79-7.70(m，2H)，7.46(d，J＝3.5Hz，1H)，7.32(dd，J＝12.4，9.1Hz，2H)，7.25(d，J＝13.7Hz，1H)，7.12(t，J＝6.1Hz，1H)，7.03(t，J＝8.5Hz，1H)，6.61(t，J＝5.9Hz，1H)，5.62(d，J＝38.2Hz，2H)，4.63(dd，J＝16.1，5.5Hz，2H).
Example 5 preparation of the Compound 4- (4- ((4-chloro-1H-pyrrolo [2, 3-b ] pyridin-l-yl) methyl) -1H-1, 2, 3-triazol-1-yl) -N- (3-morpholinopropyl) benzamide
Preparation ofThe method comprises the following steps: the procedure of example 1 was repeated except for replacing p-fluorobenzylamine in step 1 of example 1 with 3-morpholinopropan-1-amine.1H NMR(400MHz，DMSO)δ8.84(s，1H)，8.60(t，J＝5.3Hz，1H)，8.28(d，J＝5.1Hz，1H)，8.04(d，J＝8.8Hz，2H)，8.00(d，J＝8.7Hz，2H)，7.80(d，J＝3.5Hz，1H)，7.29(d，J＝5.1Hz，1H)，6.60(t，J＝11.9Hz，1H)，5.67(d，J＝23.3Hz，2H)，3.61-3.55(m，4H)，2.44-2.23(m，8H)，1.76-1.69(m，2H).
Example 6 preparation of the Compound 4- (4- ((4-chloro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) methyl) -1H-1, 2, 3-triazol-1-yl) -N- (3, 4-dichlorophenyl) benzamide
The preparation method comprises the following steps: the procedure of example 1 was repeated except for changing p-fluorobenzylamine to 3, 4-dichloroaniline in step 1 of example 1.1H NMR(400MHz，DMSO)S10.34(s，1H)，8.42(s，1H)，8.10(d，J＝5.4Hz，1H)，7.98(d，J＝8.9Hz，2H)，7.93(d，J＝8.5Hz，2H)，7.79(t，J＝5.2Hz，1H)，7.60(dd，J＝19.4，11.1Hz，2H)，7.35-7.19(m，2H)，7.43(d，J＝7.2Hz，1H)，7.27(d，J＝3.4Hz，1H)，6.10(d，J＝7.5Hz，1H)，5.14(d，J＝5.8Hz，2H).
Example 7 preparation of the compound 4- (4- ((4-chloro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) methyl) -1H-1, 2, 3-triazol-1-yl) -N- (m-tolylbenzamide
The preparation method comprises the following steps: the same procedure as in example 1 was repeated except that p-fluorobenzylamine in step 1 of example 1 was changed to m-methylaniline.1H NMR(400MHz，DMSO)δ10.31(s，1H)，8.90(s，1H)，8.28(d，J＝5.2Hz，1H)，8.16(d，J＝8.7Hz，2H)，8.07(d，J＝8.7Hz，2H)，7.81(t，J＝5.5Hz，1H)，7.60(dd，J＝19.5，1 1.3Hz，2H)，7.35-7.19(m，2H)，6.95(d，J＝7.5Hz，1H)，6.62(d，J＝3.5Hz，1H)，5.70(d，J＝7.7Hz，2H)，2.31(d，J＝11.2Hz，3H).
Example 8 preparation of 4- (4- ((4-chloro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) methyl) -1H-1, 2, 3-triazol-1-yl) -N- (4-fluorophenyl) benzamide
The preparation method comprises the following steps: the p-fluorobenzylamine in step 1 of example 1 was replaced with p-fluoroaniline, and the rest wasThe procedure was the same as in example 1.1H NMR(400MHz，DMSO)S10.20(t，J＝5.7Hz，1H)，8.42(d，J＝15.9Hz，1H)，8.08(d，J＝5.2Hz，1H)，7.97(d，J＝8.7Hz，2H)，7.60(d，J＝8.6Hz，2H)，7.43(d，J＝3.5Hz，1H)，7.27(d，J＝8.1，5.9Hz，1H)，7.15(d，J＝5.1Hz，1H)，7.26-7.16(m，2H)，6.09(d，J＝3.5Hz，1H)，5.11(d，J＝5.8Hz，2H).
The inhibition effect of the pyrrolopyridine compound on lung cancer cells (A549) and liver cancer cells (HepG) is examined
Culturing the cells in a cell flask of culture medium at 37 deg.C and 5% CO2In a sterile incubator. Cells with good growth status were seeded into 96-well plates and cultured in an incubator for 24 h. Adding the test medicine, and culturing for 72 h. After staining the cells with 10. mu.L of MTT (5mg/mL) solution for 5 hours, the supernatant was discarded, and 150. mu.L of dimethylsulfoxide was added to dissolve formazan produced. The absorbance at 570/630nm was recorded for each well by using an enzyme marker. After three parallel experiments, IC is obtained by calculation of SPSS software50The values are shown in table 1 below.
TABLE 1 IC of partial compounds of the invention for A549 and HepG50Value of
Note: n is 1, R1＝Cl，R3、R4、R5And R6＝H，
As can be seen from the above table, the compound of the present invention has a significant inhibitory effect on lung cancer cells (a549) and liver cancer cells (HepG). Wherein, the inhibition effect of the compounds 4, 8 and 12 on two kinds of cancer cells is equivalent to the positive control effect, and the compounds can be further optimized and researched as lead compounds of potential antitumor drugs.
Claims (9)
1. A pyrrolopyridine compound and a salt thereof have the following structures:
R1is hydrogen, halogen or alkyl, R2Is alkyl, aryl or heterocyclic radical, R3、R4、R5And R6Is hydrogen or halogen, and n is 1-6.
2. The pyrrolopyridine compound and the salt thereof according to claim 1, wherein: the halogen refers to fluorine, chlorine, bromine and iodine.
3. The pyrrolopyridine compound and the salt thereof according to claim 1, wherein: the alkyl group means a straight or branched saturated hydrocarbon group.
4. The pyrrolopyridine compound and the salt thereof according to claim 1, wherein: the aryl is phenyl, substituted phenyl or bicyclic arene.
5. The pyrrolopyridine compound and the salt thereof according to claim 1, wherein: the heterocyclic group is a ternary heterocyclic ring, a quaternary heterocyclic ring, a five-membered heterocyclic ring and a six-membered heterocyclic ring.
6. The pyrrolopyridine compound and the salt thereof according to claim 1, wherein: the salt is hydrochloride, phosphate, sulfate, nitrate, acetate, maleate, oxalate, methanesulfonate, p-toluenesulfonate or benzenesulfonate.
7. Use of the pyrrolopyridines compound according to claim 1 and salts thereof for the preparation of a medicament for the treatment of tumor cells.
8. Use according to claim 7, characterized in that: the anti-tumor medicine contains an active ingredient of pyrrolopyridine compounds and salts thereof, and also contains pharmaceutically acceptable carriers, auxiliary agents or diluents.
9. Use according to claim 7, characterized in that: the tumor cell is lung cancer or liver cancer.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103517903A (en) * | 2011-03-14 | 2014-01-15 | 癌症研究科技有限公司 | Pyrrolopyridineamino derivatives as MPS1 inhibitors |
| CN104606197A (en) * | 2014-12-31 | 2015-05-13 | 芜湖杨燕制药有限公司 | Application of compound in tumor resistance |
| CN105246890A (en) * | 2013-03-14 | 2016-01-13 | 艾伯维公司 | Pyrrolo[2, 3-b]pyridine cdk9 kinase inhibitors |
| CN108727386A (en) * | 2018-07-16 | 2018-11-02 | 广州医科大学 | A kind of Pyrazolopyrimidines and its preparation method and application |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103517903A (en) * | 2011-03-14 | 2014-01-15 | 癌症研究科技有限公司 | Pyrrolopyridineamino derivatives as MPS1 inhibitors |
| CN105246890A (en) * | 2013-03-14 | 2016-01-13 | 艾伯维公司 | Pyrrolo[2, 3-b]pyridine cdk9 kinase inhibitors |
| CN104606197A (en) * | 2014-12-31 | 2015-05-13 | 芜湖杨燕制药有限公司 | Application of compound in tumor resistance |
| CN108727386A (en) * | 2018-07-16 | 2018-11-02 | 广州医科大学 | A kind of Pyrazolopyrimidines and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| SURESH NARVA ET AL.: ""Synthesis and biological evaluation of pyrrolo[2,3-b]pyridine analogues as antiproliferative agents and their interaction with calf thymus DNA"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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