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Pyridine-containing triazole compound as well as preparation method and application thereof

A technology of pyridine bitriazole and compounds, which is applied in the field of inhibitor preparation, and can solve problems such as adverse reactions and drug resistance

Active Publication Date: 2022-05-06
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Small molecule tyrosine kinase inhibitors targeting Bcr-Abl are currently on the market, but there are problems such as drug resistance and other clinical adverse reactions.

Method used

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  • Pyridine-containing triazole compound as well as preparation method and application thereof
  • Pyridine-containing triazole compound as well as preparation method and application thereof
  • Pyridine-containing triazole compound as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0063] A kind of pyridine triazole compound, R is H, R' is Boc, or R is acetyl, when R' is H, the preparation method is as follows:

[0064] 1) Synthesis of 2-amino-5-(trimethylsilyl)ethynylpyridine: 2-amino-5-bromopyridine (2.79g, 16.12mmol), copper iodide (10%, 0.31g, 1.61mmol ), and tetrakis(triphenylphosphine)palladium (10%, 1.86g, 1.61mmol) were added to a 100mL double-neck round bottom flask equipped with a condenser and magnetic stirring. The vessel was then sealed with a rubber stopper, evacuated and backfilled with nitrogen 3 times. With triethylamine (30mL) as the base and solvent, inject with a syringe. After 5min at room temperature, trimethylsilylacetylene (4.74mL, 48.36mmol) was added, heated to reflux for 12h, and the reaction was complete according to TLC. The reaction was cooled to room temperature and quenched with 50 mL of water. The solution was then diluted with 50 mL of ethyl acetate and filtered. The filtrate was washed with water until the blue colo...

Embodiment 2

[0074] A kind of pyridyl triazole compound, when R is H, and R' is H, the preparation method is as follows:

[0075] Step 1) to step 7) are the same as in Example 1 to obtain (2S,4S)-4-(4-(6-aminopyridin-3-yl)-1H-1,2,3-triazole-1- yl)-2-((4-chloro-3-trifluoromethylphenyl)carbamoyl)pyrrole-1-carboxylic acid tert-butyl ester (PTZ1).

[0076] Step 8) is the same as Step 9) of Example 1, and the Boc protecting group is removed to obtain 0.25 g of compound PTZ2 with a yield of 76%. Mp 101.9~102.6℃; EI-MS (m / z) 452.10[M+H] + ,450.10[M-H] - .HRMS m / z versus C 19 h 18 CIF 3 N 7 O([M+H] + ) The calculated value is 452.12135, and the measured value is 452.12273. 1 H NMR (400MHz, DMSO-d 6 )δ10.44(s,1H),8.52(s,1H),8.33(d,J=2.3Hz,1H),8.26(d,J=2.6Hz,1H),7.97(dd,J=8.8,2.5 Hz,1H),7.73(dd,J=8.5,2.4Hz,1H),7.64(d,J=8.7Hz,1H),6.48(d,J=8.7Hz,1H),6.12(s,2H), 5.18–5.11(m,1H),4.06–4.00(m,1H),3.53–3.49(m,1H),3.36–3.31(m,1H),2.85–2.81(m,1H),2.47–2.38(m ,1H).

[0077] The synthesis steps of...

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Abstract

The invention provides a pyridine-containing triazole compound as well as a preparation method and application thereof, a target compound is synthesized through acylation, an amethylenetetramine reaction, click chemistry, condensation and other reactions, a compound library is constructed, and the compound is a Bcr-Abl small-molecule tyrosine kinase inhibitor with a novel molecular structure. The compound can be used for preparing antitumor drugs, has certain activity of inhibiting Bcr-AblWT and Bcr-AblT315I kinase, and has certain cell proliferation inhibition activity on K562 cells. According to the present invention, by introducing the pyridine-triazole structure, the structural diversity of the Bcr-Abl kinase inhibitor can be expanded, and the activity test results show that the pyridine-triazole structure provides important effects for the inhibition activity of the compound, can improve the affinity between the receptor and the compound, and can be used as the hinge region action drug effect fragment of the Bcr-Abl tyrosine kinase inhibitor;

Description

technical field [0001] The invention belongs to the technical field of inhibitor preparation, and relates to a compound containing pyridine bitriazoles and its preparation method and application Background technique [0002] Chronic myeloid leukemia (CML) is a malignant clonal proliferative disease that occurs in bone marrow hematopoietic stem cells, accounting for 15% to 20% of adult leukemia patients. It is characterized by the detection of Ph chromosomes in CML patients. The Ph chromosome is a breakpoint aggregation cluster formed by the reciprocal translocation of normal chromosome 22 and chromosome 9-Alberson (Bcr-Abl) fusion gene, which encodes Bcr that produces continuous activation of tyrosine kinase activity -Abl fusion protein. Small molecule tyrosine kinase inhibitors targeting Bcr-Abl are currently on the market, but they all have problems such as drug resistance and other clinical adverse reactions. Subsequently, the research and development of novel Bcr-Abl t...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P35/02A61K31/4439
CPCC07D401/14A61P35/02Y02P20/55
Inventor 张杰潘晓艳卢闻柳南辛刘钰莹李彦宸王凯
Owner XI AN JIAOTONG UNIV
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