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Pyridine-2-aryl-3-sulfonamide compound and its synthesis method and application

A technology of sulfonamides and synthesis methods, applied in the preparation of anti-tumor drugs or tubulin polymerization inhibitors, pyridine-2-aryl-3-sulfonamides and their synthesis fields, can solve the problem of high structural toxicity, Toxic side effects, drug resistance and other issues

Active Publication Date: 2022-04-05
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since there are already anti-tumor drugs at the site of paclitaxel and vinblastine, such as paclitaxel and vincristine, they are commonly used anti-tumor drugs in clinical practice, but drug resistance will appear in tumor patients after taking them for a period of time, and they have certain toxic side effect
In addition, although colchicine can be well bound to the colchicine site of tubulin, its structural toxicity is high, making it difficult to be drugged. Therefore, researchers have focused on the effect on the colchicine site The research and development of specific tubulin depolymerization agents, such as ABT-751 developed by Abbott, has entered the clinical phase II, but reports have shown that ABT-751 has certain neurotoxicity, and there has been no progress in its clinical phase III trials

Method used

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  • Pyridine-2-aryl-3-sulfonamide compound and its synthesis method and application
  • Pyridine-2-aryl-3-sulfonamide compound and its synthesis method and application
  • Pyridine-2-aryl-3-sulfonamide compound and its synthesis method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The preparation of embodiment 1 representative compound HP1:

[0037] 1. Synthesis of intermediate 2-(2-methoxyphenyl)pyridine-3-amino (step a): Weigh 2-bromo-3-aminopyridine (1,500 mg) and 2-methoxyphenylboronic acid ( 483mg, 1.1eq) was dissolved in toluene / water mixed solvent (2 / 1, v / v), potassium carbonate (1.6g, 4eq) and Pd(PPh 3 ) 4 (167mg, 0.05eq) was used as a catalyst, and the reaction bottle was stirred and reacted for 8 hours at 80°C under a nitrogen atmosphere, and then the reaction was terminated. The solvent was distilled off under reduced pressure, extracted 3 times with ethyl acetate / water, the ethyl acetate layer was taken, spin-dried, and purified by silica gel column chromatography to obtain the intermediate 2-(2-methoxyphenyl)pyridine-3- Amino group (310 mg, 60% yield).

[0038]2. Synthesis of the final product HP1 (step b): Weigh and dissolve the intermediate 2-(2-methoxyphenyl)pyridine-3-amino (100mg) and 4-dimethylaminopyridine (DMAP, 61mg, 1eq)...

Embodiment 2

[0040] The preparation of embodiment 2 representative compound HP2:

[0041] 1. The synthesis of intermediate 2-(3-methoxyphenyl)pyridine-3-amino: the reaction conditions and post-treatment method are the same as the preparation step a of the representative compound HP1, the difference is that the reaction raw material 2-methoxy Phenylboronic acid was replaced by 3-methoxyphenylboronic acid, and the yield was 70%.

[0042] 2. Synthesis of the final product HP2: the reaction conditions and post-treatment method are the same as the preparation step b of the representative compound HP1, the difference is that the reaction raw material intermediate 2-(2-methoxyphenyl)pyridine-3-amino is replaced by 2-(3-Methoxyphenyl)pyridin-3-amino, 65% yield.

[0043] Compound (HP2): 4-methoxy-N-(2-(3-methoxyphenyl)pyridin-3-yl)benzenesulfonamide. white solid. Melting point: 132.3-133.1°C. 1 H NMR (400MHz, DMSO-d 6 )δ (ppm): 9.73 (1H, s), 8.48 (1H, dd), 7.54 (1H, dd), 7.47 (2H, d), 7.34-7.2...

Embodiment 3

[0044] The preparation of embodiment 3 representative compound HP3:

[0045] 1. The synthesis of intermediate 2-(4-methoxyphenyl)pyridine-3-amino: the reaction conditions and post-treatment method are the same as the preparation step a of the representative compound HP1, the difference is that the reaction raw material 2-methoxy Phenylboronic acid was replaced by 4-methoxyphenylboronic acid, yield 75%.

[0046] 2. Synthesis of the final product HP3: the reaction conditions and post-treatment method are the same as the preparation step b of the representative compound HP1, the difference is that the reaction raw material intermediate 2-(2-methoxyphenyl)pyridine-3-amino is replaced by 2-(4-Methoxyphenyl)pyridin-3-amino, 60% yield.

[0047] Compound (HP3): 4-methoxy-N-(2-(4-methoxyphenyl)pyridin-3-yl)benzenesulfonamide. Pale yellow solid. Melting point: 166.8-167.7°C. 1 H NMR (400MHz, CDCl 3 )δ(ppm):8.38(1H,dd),8.01(1H,dd),7.53(2H,d),7.23(1H,dd),7.04(2H,d),6.91(2H,d),6.86( ...

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Abstract

The invention discloses a pyridine-2-aryl-3-sulfonamide compound, its synthesis method and its application in the preparation of antitumor drugs or tubulin polymerization inhibitors. The pyridine-2-aryl-3-sulfonamide compound of the present invention has the general structural formula (I), X, Y, Z are taken from C or N atom, R 1 Represents a monosubstituted or polysubstituted group; R 2 Represents a monosubstituted or polysubstituted group; R 3 Represents hydrogen or benzenesulfonyl substituted by different C1-5 alkoxy groups. The application of pyridine-2-aryl-3-sulfonamide compounds in the preparation of medicines is used as an active ingredient for the preparation of antitumor medicines or tubulin polymerization inhibitors. The antitumor drugs are anti-colon cancer, anti-breast cancer, anti-liver cancer, anti-lung cancer, anti-gastric cancer or anti-pancreatic cancer drugs.

Description

technical field [0001] The invention relates to the technical field of tubulin polymerization inhibitors, in particular to pyridine-2-aryl-3-sulfonamide compounds and their synthesis methods and applications for the preparation of antitumor drugs or tubulin polymerization inhibitors. Background technique [0002] As an important component of eukaryotic cells, microtubules participate in the construction of the cytoskeleton and play an important role in maintaining cell shape, signal transduction, material transport and cell division. Microtubules are mainly assembled by α-tubulin and β-tubulin heterodimers, and are hollow tubular after assembly. In addition, γ-tubulin, although not a component of microtubules, is involved in the assembly of microtubules. Microtubules have certain dynamic characteristics, including polymerization and depolymerization processes. Microtubules aggregate into spindles in the early stage of mitosis, which can pull chromosomes to move to the two ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/76A61P35/00
CPCC07D213/76A61P35/00
Inventor 潘远江朱和平金洪传应士龙梁霄
Owner ZHEJIANG UNIV
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