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A nucleic acid base compound or a pharmaceutically acceptable salt thereof and its preparation method and application

A technology of nucleic acid bases and compounds, applied in the field of nucleic acid bases, can solve the problems of AIDS derivatives with HIV-1 protease activity and reverse transcriptase activity, etc.

Active Publication Date: 2019-10-15
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, there have been no related reports on derivatives that can inhibit HIV-1 protease activity and reverse transcriptase activity and be used in the treatment of AIDS

Method used

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  • A nucleic acid base compound or a pharmaceutically acceptable salt thereof and its preparation method and application
  • A nucleic acid base compound or a pharmaceutically acceptable salt thereof and its preparation method and application
  • A nucleic acid base compound or a pharmaceutically acceptable salt thereof and its preparation method and application

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preparation example Construction

[0084] The present invention provides the preparation method of nucleic acid base compound described in above-mentioned technical scheme, comprises the following steps:

[0085] When X in the compound of the structure shown in formula I is -CH 2 -, when R is Ra or Rb, the compound having the structure shown in Formula II-1 is condensed with the amine derivative under the action of a catalyst to obtain the compound having the structure shown in Formula I;

[0086]

[0087] In formula II-1, R is Ra or Rb, and said Ra is The Rb is Among them, R 2 is hydrogen, hydroxyl, amino or halogen; R 3 is hydrogen, hydroxy, amino, halogen or methyl; R 4 is hydrogen or methyl;

[0088] When X in the compound of the structure shown in formula I is -CH 2 -, -O-, -S- or -NH-, when R is Rc or Rd, the compound having the structure shown in formula II-2, trichloromethyl carbonate and amine derivatives are subjected to a condensation reaction under the action of a catalyst , to obtain a ...

Embodiment 1

[0165] Add 6-chloropurine (0.62g, 4mmol) and anhydrous potassium carbonate (1.66g, 12mmol) into a 10mL eggplant-shaped flask, add 2mL of anhydrous solvent N,N-dimethylformamide (DMF), and The reaction was vigorously stirred at room temperature under protection for 1 h; bromoacetic acid (0.64 g, 4.6 mmol) was dissolved in 1 mL of anhydrous solvent N,N-dimethylformamide (DMF), and slowly added dropwise to the reaction solution. After the addition was complete, continue The reaction was stirred overnight at room temperature. Add 5 mL of distilled water to the reaction solution, filter the solution with diatomaceous earth, wash with water to obtain a yellow clear liquid, adjust the pH to 3.0 with 4M HCl under ice bath stirring, stir for 10 min under ice bath, stand still, suction filter, filter The cake was washed with a small amount of water and dried to obtain the target product as a yellow-green powder solid, Intermediate 1 (0.37 g, 43.4%). LC-MS of Intermediate 1 (ESI, M+H +...

Embodiment 2

[0172] Add 8-methylpurine (1.34g, 10mmol) into a 50mL eggplant-shaped flask, add 10mL of anhydrous DMF, place in an ice bath, slowly add sodium hydride (0.44g, 11mmol) in batches, and transfer to room temperature The reaction was carried out for 1 h, ethyl bromoacetate (1.84 g, 11 mmol) was slowly added dropwise, and the reaction was continued for 1 h. After terminating the reaction, 10 mL of water was added, extracted with ethyl acetate (15×3 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily crude product. The crude product was purified by flash column (eluents used were ethyl acetate and hexane, volume ratio, ethyl acetate: hexane = 1:2) to obtain colorless needle crystals, intermediate 2 (1.53 g, 69.6%). LC-MS of intermediate 2 (ESI, M+H + ) m / z 221.4.

[0173] NaOH (0.65g, 16.2mmol) was dissolved in 5mL of water, added to a 100mL eggplant-shaped flask containing intermediate 2 (1.19g, 5.4mmol), stirred at room temper...

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Abstract

The invention provides a nucleic acid base compound or a medically acceptable salt thereof. The compound or the medically acceptable salt thereof has the obvious inhibitory HIV protease and / or reversetranscriptase activity; toxicity studies show that the compound has the good druggability, it is indicated that the compound has a good application prospect by serving as an anti-AIDs drug. Accordingto experimental data, the compound has inhibitory activity on HIV-1 protease and HIV-1 reverse transcriptase, and low cytotoxicity exits. The nucleic acid base compound or the medically acceptable salt thereof is expected to become a double-target inhibitor inhibiting the HIV protease and the reverse transcriptase simultaneously.

Description

technical field [0001] The invention relates to the technical field of nucleic acid bases, in particular to a nucleic acid base compound or a pharmaceutically acceptable salt thereof and a preparation method and application thereof. Background technique [0002] Acquired Immune Deficiency Syndrome (AIDS), also known as AIDS, is a syndrome in which human immunodeficiency is caused by human immunodeficiency virus (Human Immunodeficiency Virus, HIV), and causes a series of opportunistic infections and tumors . HIV is currently known to be the most differentiated and mutated virus, and can be divided into two subtypes: HIV-1 and HIV-2 according to serological responses, gene sequence differences, and geographical distribution characteristics. HIV-1 is the pathogen that causes the global epidemic of AIDS, accounting for 95% of the absolute advantage in the number of infected people; HIV-2 is mainly confined to some areas in central and western Africa, and the number of infected ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/40C07D473/00C07D239/54C07D239/553C07D405/04C07F9/6512A61P31/18
Inventor 王玉成朱梅王菊仙白晓光张国宁董飚彭宗根岑山王宇佳王明华赵跃杜潇楠张煊笛邵端阳李云鸽
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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