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RT/PR dual-target HIV inhibitor, preparation method and applications thereof

A technology of inhibitors and double-substituted amine groups, applied in antiviral agents, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve problems such as large doses, cross-resistance, and complex drug interactions

Active Publication Date: 2018-08-17
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

Long-term use of single-target drugs is likely to cause cross-resistance and severe side effects. At present, HAART is commonly used in clinical practice, which can relieve drug resistance to a certain extent. Due to complex interactions and poor patient compliance, pharmaceutical companies at home and abroad are committed to researching compound preparations. However, there are still problems such as cross-resistance, serious toxic and side effects, and complex pharmacokinetic properties.

Method used

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  • RT/PR dual-target HIV inhibitor, preparation method and applications thereof
  • RT/PR dual-target HIV inhibitor, preparation method and applications thereof
  • RT/PR dual-target HIV inhibitor, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1, 2-(8-methyl-3,4-dihydro-1,5-dioxo-6-oxo-anthracene-4-amino)-N-((2S,3R)-3-hydroxy -Synthesis of 4-(N-isobutyl-4-aminophenylsulfonamido)-1-phenylbutan-2-yl)-acetamide (namely compound 1)

[0059] For the synthetic route of compound 1, see figure 2 , the specific operation is as follows:

[0060] 1) Synthesis of tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamine)carbamate (intermediate 2)

[0061] (S)-1-((S)-oxirane-2-yl)-2-phenylethylcarbamate tert-butyl ester (1) (Bailingwei Technology Co., Ltd.) (20.0g, 75.94mmol), acetonitrile 80mL and isobutylamine (19.02 mL, 189.46 mmol) were added into a 200 mL eggplant-shaped flask, and the mixture was stirred at 80° C. for 5 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and concentrated under reduced pressure to remove the solvent. The crude product was recrystallized with ethyl acetate / n-hexane (1:9) to obtain a white target product (21.2 g, 83%), which was interme...

Embodiment 2

[0077] Example 2, 2-(7-hydroxyl-2-oxoquinolin-1(2H)-yl)-N-((2S,3R)-3-hydroxyl-4-(N-isobutyl-4- Synthesis of Aminophenylsulfonamido)-1-Phenylbutan-2-yl)-Acetamide (Compound 12)

[0078] The synthetic route of compound 12 is shown in image 3 , the specific operation is as follows:

[0079] 1) Synthesis of 2-oxo-1,2-dihydroquinolin-7-yl-acetate (intermediate 10)

[0080] Dissolve intermediate 9 (7-hydroxy-2-(1H)-quinolinone) (1.61g, 10mmol) (Beijing Yinuokai Technology Co., Ltd.) in 28ml of acetic anhydride, cool to 0°C, add trifluoroform Indium Sulfonate In(OTf) 3 (0.28g, 0.5mmol), raised to room temperature and stirred for 1 hour. Add ethyl acetate and 10% sodium carbonate aqueous solution, continue to stir and react for 1 hour, separate the organic phase, and wash 3 times with saturated sodium bicarbonate solution, dry over anhydrous magnesium sulfate, concentrate to obtain the target product (i.e. intermediate 10) 1.83g, Yield 90.0%. LC-MS (ESI, M+H + ) m / z 204.7.

...

Embodiment 3

[0090] Example 3, 8-(3-methyl-2-buten-1-yl)-2-oxo-2H-chroman-7-yl-(2S,3R)-3-hydroxyl-4-(N Synthesis of -isobutyl-4-aminophenylsulfonamido)-1-phenylbutan-2-yl)-carbamate (i.e. compound 18)

[0091] The synthetic route of compound 18 is shown in Figure 4 , the specific operation is as follows:

[0092] 1) Synthesis of 7-hydroxy-8-(3-methyl-2-buten-1-yl)-2H-chroman-2-one (intermediate 15)

[0093] Anhydrous aluminum trichloride (1.32g, 10.0mmol) was suspended in 20mL of anhydrous dichloromethane, and 10mL of methyl sulfide was slowly added dropwise with stirring at 0°C. After the dropwise addition, the reaction solution became clear. Osthole ( Figure 4 14, 0.98g, 4.0mmol) (Beijing Yinuokai Technology Co., Ltd.) was dissolved in 10mL of anhydrous dichloromethane, added dropwise to the reaction solution, the dropwise addition was completed within 10min, and the reaction was stirred at room temperature for 24 hours. The reaction was quenched with 30 mL of 1M cold dilute hydroc...

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Abstract

The invention discloses an RT / PR dual-target HIV inhibitor, a preparation method and applications thereof. According to the present invention, the RT / PR dual-target HIV inhibitor is prepared from a compound represented by a formula 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula 1 has obvious inhibition activity on HIV reverse transcriptase and HIVprotease; and the toxicity study results show that the compound has good drug-forming property, such that the compound as the anti-acquired immunodeficiency syndrome drug has good application prospects. The formula I is defined in the specification.

Description

technical field [0001] The invention relates to an RT / PR dual-target HIV inhibitor in the field of medicine, 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 . AIDS is a serious problem faced by the whole world. my country as a whole is a country with low prevalence of HIV-1, but some areas show high prevalence. As of the end of October 2015, there were 575,000 surviving HIV-infected patients and 177,000 deaths reported nationwide. Therefore, the development of new anti-HIV drugs is the fundamental way to treat AIDS. Since zidovudine (AZT) was the first drug officially approved for clinical use in the treatment of AIDS in 1987, more than 30 anti-AIDS drugs have been used clinically, including 1 invasion...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/18C07D493/04C07D215/227C07D498/04A61K31/37A61K31/4704A61K31/5383A61P31/18
CPCC07D215/227C07D311/18C07D493/04C07D498/04
Inventor 王玉成朱梅白晓光张国宁王菊仙岑山董飚
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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