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Amide derivative or pharmaceutically acceptable salt thereof and preparation method and application thereof

A technology of derivatives and amides, applied in the field of amide derivatives and their preparation, can solve the problems of AIDS derivatives with HIV-1 protease activity and reverse transcriptase activity that have not yet been seen.

Active Publication Date: 2018-09-21
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 can be applied to the treatment of AIDS

Method used

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  • Amide derivative or pharmaceutically acceptable salt thereof and preparation method and application thereof
  • Amide derivative or pharmaceutically acceptable salt thereof and preparation method and application thereof
  • Amide derivative or pharmaceutically acceptable salt thereof and preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0096] The invention provides a preparation method of the amide derivatives, comprising the following steps:

[0097] The present invention also provides a preparation method of the amide derivatives, comprising the following steps:

[0098] 1) When Rx is methoxy, methylthio, nitro or aminomethyl in the compound of structure shown in formula I:

[0099] When X is -CH 2 - or without any substituting group, when R is Ra, Rb, Rc, Rd or Rg:

[0100] Condensing the compound having the structure shown in formula II-1 with the amine derivative under the action of a catalyst to obtain the compound having the structure shown in formula I;

[0101]

[0102] In formula II-1, n=0 or 1;

[0103] The Ra is The Rb is The Rc is The Rd is The Rg is

[0104] Among them, M 1 C or N, M 2 O or S; L 1 C or N, L 2 is O or S; R 1 ~R 7 independently hydrogen, hydroxyl, hydroxymethyl, amino, halogen, carbonyl, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C1...

Embodiment 1

[0235] 1. Synthesis of N-((2R,3S)-2-hydroxy-3-amino-4-phenylbutane)-N-isobutyl-4-methoxybenzenesulfonamide (intermediate III1a):

[0236] 1), Synthesis of (1S,2R)-1-benzyl-2-hydroxyl-3-(isobutylamine)carbamate tert-butyl ester (intermediate 2):

[0237]

[0238](S)-1-((S)-Oxiran-2-yl)-2-phenylethylcarbamate tert-butyl ester (starting material 1, 75.94 mmol), acetonitrile 80 mL and isobutylamine (189.46 mmol) were added Transfer to a 200mL eggplant-shaped bottle, and stir the reaction 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 from a mixture of ethyl acetate and n-hexane with a mass ratio of 1:9 to obtain a white product, Intermediate 2 (21.2 g, 83%). LC-MS of intermediate 2 (ESI, M+H + ) m / z 337.2.

[0239] 2), Synthesis of (1S,2R)-1-benzyl-2-hydroxy-3-(N-isobutylamine-4-methoxyphenylsulfonamide) tert-butyl c...

Embodiment 2

[0250] 1. Preparation of N-((2R,3S)-2-hydroxyl-3-amino-4-phenylbutane)-N-isobutyl-4-nitrobenzenesulfonamide (intermediate III1b) synthesis

[0251] The synthesis of intermediate III1b is similar to the synthesis of intermediate III1a in Example 1, the only difference is that 4-methoxybenzenesulfonyl chloride is replaced by 4-nitrobenzenesulfonyl chloride.

[0252] 2. 4-Hydroxy-3,5-dimethoxyphenyl-N-[(2S,3R)-3-hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamide)- Synthesis of 1-phenylbutyl-2-yl]-carboxamide (intermediate 12)

[0253]

[0254] The synthesis of intermediate 12 is similar to the synthesis of compound 1 in Example 1, the only difference is that raw material 10 is replaced by 3,5-dimethoxy-4-hydroxybenzoic acid (raw material 11), and intermediate III1a is replaced by intermediate Body III1b, the reaction gave a white powder solid, namely Intermediate 12 (0.16.g, 52%), the LC-MS of Intermediate 12 (ESI, M+H + ) m / z 602.5.

[0255] 3. 4-Hydroxy-3,5-dimethoxyphenyl-N-...

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Abstract

The invention provides an amide derivative or a pharmaceutically acceptable salt thereof with the structure as shown in formula I. A compound or the pharmaceutically acceptable salt thereof has significant activity in inhibiting HIV protease and reverse transcriptase; toxicity study shows that the compound or the pharmaceutically acceptable salt thereof has better druggability, and the compound has better application prospect in using as anti-Aids drugs. According to experimental data, the compound has inhibiting activity both on HIV-1 protease and HIV-1 reverse transcriptase and has lower cytotoxicity. The compound or the pharmaceutically acceptable salt thereof is expected to be a double-target inhibitor which can inhibit the HIV protease and the reverse transcriptase.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to an amide derivative and its preparation method and application. Background technique [0002] Acquired Immune Deficiency Syndrome (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 people is relatively small. [0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/18C07C303/40C07C311/41C07C311/18C07C311/29C07F9/44C07F9/6512C07H13/12C07H1/00A61P31/18C07C381/10
CPCA61P31/18C07B2200/07C07C311/18C07C311/29C07C311/41C07C381/10C07C2601/14C07D311/18C07F9/4419C07H1/00C07H13/12
Inventor 王玉成朱梅王菊仙张国宁董飚彭宗根岑山王宇佳杜潇楠王明华赵跃李云鸽张煊笛邵端阳牛伟萍
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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