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Pyranoindole compound as well as preparation method and application thereof in preparation of anti-aids drugs

A compound, indole technology, applied in medicine, pyranoindole compound and its preparation field, can solve the problems such as unclear biological activity

Inactive Publication Date: 2017-10-24
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the potential biological activities of these small molecules with novel structures are still unclear

Method used

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  • Pyranoindole compound as well as preparation method and application thereof in preparation of anti-aids drugs
  • Pyranoindole compound as well as preparation method and application thereof in preparation of anti-aids drugs
  • Pyranoindole compound as well as preparation method and application thereof in preparation of anti-aids drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1 (S)-2-amino-3-cyano-4-(trifluoromethyl)pyrano[2,3-b]indole-4,9(4H)-dicarboxylic acid 9-( tert-butyl)-4-ethyl ester (compound 1) and 2-amino-3-cyano-4-(trifluoromethyl)pyrano[2,3-b]indole-4,9(4H) -Preparation of 9-(tert-butyl)-4-ethyl ester (compound 1-a) of dicarboxylic acid

[0126] The preparation method comprises the following steps:

[0127] (1)

[0128]

[0129] In a 50 mL reaction flask, indolinone (1.33 g, 10 mmol) was dissolved in toluene (20 mL), and ethyl trifluoropyruvate (1.98 mL, 15 mmol) and piperidine (0.27 mL, 3 mmol) were added. React at 110°C for 4 hours. After the reaction was completed, it was concentrated, and 2.28 g of the product was obtained by column chromatography, with a yield of 70%. 1 H NMR (500MHz, CDCl 3)δ8.89(br,1H),7.73(d,J=8.0Hz,1H),7.37-7.40(m,1H),7.07-7.10(m,1H),6.90(d,J=7.5Hz,1H ), 4.46(q, J=9.0Hz, 2H), 1.42(t, J=7.0Hz, 3H)ppm; 13 C NMR (125MHz, CDCl 3 )δ166.8, 162.9(d, J=2.9Hz), 143.3, 133.3, 132.8(d, J=4Hz), 12...

Embodiment 2

[0136] Example 2 (S)-9-acetyl-2-amino-3-cyano-4-(trifluoromethyl)-4,9-dihydropyrano[2,3-b]indole-4 -ethyl carboxylate (compound 2) and 9-acetyl-2-amino-3-cyano-4-(trifluoromethyl)-4,9-dihydropyrano[2,3-b]ind Preparation of Indole-4-Carboxylic Acid Ethyl Ester (Compound 2-a)

[0137]

[0138] Referring to the synthesis method of the compound in Example 1, compounds 2 and 2-a were prepared. Yield 73%, ee 47%. 2-a Yield 98%.

[0139] 1 H NMR (500MHz, CDCl 3 )δ8.41(d, J=8.1Hz, 1H), 7.48(d, J=7.7Hz, 1H), 7.32(td, J=22.1, 7.5, 1.1Hz, 2H), 7.26(s, 1H), 5.48(s,2H),4.69–3.96(m,2H),2.72(s,3H),1.27(dd,J=13.7,6.5Hz,4H)ppm; 13 C NMR(126MHz,DMSO)δ168.79,165.68,161.69,142.60,131.11,124.89(q,J=283.8Hz),124.37(d,J=14.3Hz),123.23,118.04,117.28,116.01,86.97,62.048,52 (q, J=28.8Hz), 50.71, 26.70, 13.80ppm; 19 F NMR (471MHz, CDCl 3 )δ-70.66(s,3F)ppm; The enantiomeric excess is determined by HPLC with a ChiralpakIC-H column(hexanes:isopropanol=95:5, flow rate:1.0mL / min,λ=254nm):t R =16...

Embodiment 3

[0140] Example 3 9-benzyl 4-ethyl (S)-2-amino-3-cyano-4-(trifluoromethyl)pyrano[2,3-b]indole-4,9(4H )-dicarboxylate (compound 3) and 9-benzyl 4-ethyl-2-amino-3-cyano-4-(trifluoromethyl)pyrano[2,3-b]indole- Preparation of 4,9(4H)-dicarboxylate (compound 3-a)

[0141]

[0142] Referring to the synthesis method of the compound in Example 1, compounds 3 and 3-a were prepared. Yield 96%, ee value 93%. 3-a Yield 98%.

[0143] 1 H NMR (400MHz, CDCl 3 )δ8.25–7.94(m,1H),7.60–7.37(m,6H),7.35–6.93(m,3H),5.59–5.37(m,2H),5.28(s,2H),4.49–4.18( m, 2H), 1.27 (t, J = 7.1Hz, 3H) ppm; 13 C NMR (126MHz, CDCl 3 )δ165.65,161.43,149.36,142.55,134.53,131.46,129.29,129.03,128.71,124.89,124.55,124.59(q,J=283.8Hz),123.76,119.89,117.01,115.29,89.22,77.41,77.16,76.91,69.75 ,63.40,55.79,52.45(q,J=30.0Hz),14.10ppm; 19 F NMR (471MHz, CDCl 3 )δ-70.78(s,3F)ppm; The enantiomeric excess is determined by HPLC with a Chiralpak IC-H column(hexanes:isopropanol=95:5, flow rate:1.0mL / min,λ=254nm):t R =22...

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Abstract

The invention provides a pyranoindole compound as well as a preparation method and an application thereof in preparation of anti-aids drugs. The pyranoindole compound has a structure as shown in a formula I. The pyranoindole compound, or a pharmacologically acceptable salt, isomer, raceme, prodrug cocrystal compound, aquo-complex or solvate thereof is capable of effectively activating an HIV virus repository, can be used for treating aids, and is simple in preparation method and wide in application prospect, and industrialized production is easy to implement.

Description

technical field [0001] The invention belongs to the field of biochemistry and medicine, and relates to a pyranoindole compound, a preparation method thereof and an application in preparation of anti-AIDS drugs. Background technique [0002] According to the latest report of UNAIDS, by the end of 2015, 36.7 million people in the world were infected with HIV, with 2.1 million new infections every year, and 1.1 million deaths due to HIV every year. More than thirty years have passed since the discovery of HIV, and there is still no cure for the disease. At present, HIV-infected patients are treated with antiretroviral therapy (ART). The combination of two or more highly effective antiretroviral drugs can effectively inhibit the replication of HIV virus, but ART treatment cannot completely eliminate infected patients. The HIV virus in the body will cause the latent virus in the body to rebound quickly after ART is stopped. Therefore, HIV-infected people need to take ART drugs f...

Claims

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Application Information

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IPC IPC(8): C07D491/052C07D491/147A61K31/407A61K31/437A61P31/18
CPCC07D491/052C07D491/147
Inventor 孙彩军赵军岭陈凌杨晴丁宇洋
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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