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Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure, and preparation method thereof

A technology of biphenyl diarylmethylpyrimidine and aromatic heterocycle, which is applied in the field of biphenyldiarylmethylpyrimidine derivatives and their preparation, and can solve problems such as poor water solubility

Inactive Publication Date: 2021-10-01
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the rapid emergence of virus mutants and the poor water solubility of these compounds (ETR, <<1μg / mL; RPV, 20ng / mL) and the side effects caused by long-term administration limit their clinical use. Therefore, the further development of new high-efficiency non-nucleoside reverse transcriptase inhibitors with broad-spectrum antiviral activity and excellent pharmacokinetic properties has become one of the hot spots of medicinal chemists.

Method used

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  • Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure, and preparation method thereof
  • Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure, and preparation method thereof
  • Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure, and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: the preparation of target product (Ia)

[0035]

[0036] At room temperature, 4-((4-((4-bromo-2,6-difluorophenyl)amino)5-methylpyrimidine-2-)amino)benzonitrile (1.0mmol), cesium carbonate ( 1.0mmol), Pd(dppf)Cl 2 (0.01mmol) and 4-pyridineboronic acid (1.2mmol) were added into 1,4-dioxane (6mL), and the 2 Replaced three times, adjusted the reaction temperature to 110°C, and stirred for 4h. As detected by TLC (PE / EA=1 / 1), the starting material disappeared and the reaction was complete. Adjust the reaction temperature to room temperature, wash with saturated sodium sulfite solution (20mL×2), saturated sodium carbonate solution (20mL×2), water (20mL×2), saturated brine (20mL×2) successively, and wash the organic phase with anhydrous sulfuric acid Sodium dry overnight. Filtration, concentration, and methanol recrystallization gave a solid—the target compound (Ia).

[0037] Characterization results of the target product (Ia): white powdery solid; yield 7...

Embodiment 2

[0038] Embodiment 2: the preparation of target product (Ib)

[0039]

[0040] At room temperature, 4-((4-((4-bromo-2,6-difluorophenyl)amino)5-methylpyrimidine-2-)amino)benzonitrile (1.0mmol), cesium carbonate ( 2.0mmol), Pd(dppf)Cl 2 (0.01mmol) and 3-pyridineboronic acid (1.2mmol) were added into 1,4-dioxane (5mL), and the 2 Replaced three times, adjusted the reaction temperature to 150°C, and stirred for 4h. As detected by TLC (PE / EA=1 / 1), the starting material disappeared and the reaction was complete. Adjust the reaction temperature to room temperature, wash with saturated sodium sulfite solution (20mL×2), saturated sodium carbonate solution (20mL×2), water (20mL×2), saturated brine (20mL×2) successively, and wash the organic phase with anhydrous sulfuric acid Sodium dry overnight. Filtration, concentration, and methanol recrystallization gave a solid—the target compound (Ib).

[0041] Characterization results of the target product (Ir): white powdery solid; yield 8...

Embodiment 3

[0042] Embodiment 3: the preparation of target product (Ic)

[0043]

[0044] At room temperature, 4-((4-((4-bromo-2,6-difluorophenyl)amino)5-methylpyrimidine-2-)amino)benzonitrile (1.0mmol), cesium carbonate ( 2.0mmol), Pd(dppf)Cl 2 (0.01mmol) and 5-pyrimidineboronic acid (1.0mmol) were added to 1,4-dioxane (6mL), and the 2 Replaced three times, adjusted the reaction temperature to 80°C, and stirred for 4h. As detected by TLC (PE / EA=1 / 1), the starting material disappeared and the reaction was complete. Adjust the reaction temperature to room temperature, wash with saturated sodium sulfite solution (20mL×2), saturated sodium carbonate solution (20mL×2), water (20mL×2), saturated brine (20mL×2) successively, and wash the organic phase with anhydrous sulfuric acid Sodium dry overnight. Filtration, concentration, and methanol recrystallization gave a solid—the target compound (Ic).

[0045] Characterization results of the target product (Ic): white powdery solid; yield 93...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diaryl methyl pyrimidine derivative containing an aromatic heterocyclic structure, and a preparation method thereof. According to the present invention, the structure optimization and the salt formation optimization are performed on a diaryl pyrimidine non-nucleoside reverse transcriptase inhibitor, and the pharmacological toxicology of the diaryl pyrimidine non-nucleoside reverse transcriptase inhibitor is investigated to obtain the novel efficient non-nucleoside reverse transcriptase inhibitor with excellent antiviral activity and pharmacokinetic characteristics, comprising pharmaceutically acceptable salts, stereochemical isomers, hydrates or solvates. An in-vitro cellular level anti-HIV-1 activity experiment result shows that the compound has relatively high anti-HIV-1 biological activity, can be used for remarkably inhibiting virus replication in MT-4 cells infected by an HIV-1 virus, and has relatively low cytotoxicity. The invention also comprises a pharmaceutical composition which is used for preventing and treating AIDS and contains the compound.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a compound against HIV-1 virus strains-biphenyl diarylmethylpyrimidine derivatives containing aromatic heterocyclic structure and a preparation method thereof. Background technique [0002] AIDS, Acquired Immunodeficiency Syndrome (AIDS), is caused by human immunodeficiency virus (Human Immunodeficiency virus, HIV-1) infection leading to immunodeficiency, which leads to a series of major epidemics of pathogenic infections and tumors STDs. Since the U.S. Centers for Disease Control (CDC) confirmed the first case in 1981, AIDS has spread rapidly around the world and has become a major global public health problem, causing more than 32 million deaths so far. [0003] Reverse transcriptase (Reverse transcriptase, RT) plays a key role in the life cycle of HIV virus replication, responsible for the reverse transcription of viral RNA into DNA-RNA hybrids and the degradatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D239/48C07D405/12C07D409/12A61K31/506A61P31/18
CPCC07D401/12C07D239/48C07D405/12C07D409/12A61P31/18
Inventor 陈芬儿庄春林定力
Owner FUDAN UNIV
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