Compound and application thereof

A technology for compounds and uses, applied in the field of compounds, can solve the problems of inconvenient storage and transportation, unstable activity, short half-life, etc., and achieve the effects of convenient treatment plan, short preparation period and stable properties

Active Publication Date: 2020-11-27
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In view of the above-mentioned defects of the prior art, the technical problem to be solved by the present invention is to address the drug resistance of existing AIDS treatment drugs and the short half-life of protein drugs, high cost, unstable activity, and inconvenient storage and transportation.

Method used

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  • Compound and application thereof
  • Compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1 compound synthesis

[0071] Exemplarily, in this example, a compound with the structure shown in the following formula was synthesized, wherein the structure shown in the linker, the substituent R and the compound number are listed in Table 1:

[0072]

[0073] Table 1 Compound numbers and corresponding substituents

[0074]

[0075] (1) Synthesis of Compounds 1a-1e

[0076] 1) Synthetic method of compound 18a-b

[0077]

[0078] Reagents and conditions: (i) Boc-Tyramine, K2CO3, DMF, 80°C, 12h; (c) AcCl, CH3OH, 0°C-room temperature, 24h; (ii) bis(carboxymethyl)trithiocarbonate, Et3N, DME, MW, 90 ℃, 15min.

[0079] 1. Compound 17a

[0080] Potassium carbonate (2.4g, 17.5mmol) and 80% propyne bromide (16a 2.0mL, 17mmol) were successively added to a 30mL DMF solution of Boc-tyramide (3.5g, 14.7mmol), heated to 80°C for 12h, and stopped Heating, after the reaction was cooled to room temperature, extracted with ethyl acetate, washed with water, washed...

Embodiment 2

[0184] Example 2 Compound Structural Characterization

[0185] The structures of the compounds were characterized by NMR and mass spectrometry.

[0186] Compound 1a: 56 mg of orange solid product was prepared from S1a (50 mg, 95.4 μmol) and S2a (30 mg, 105 μmol), with a yield of 72%.

[0187] 1 H NMR (400MHz, DMSO-d 6 )δ13.71(br s,1H),11.02(s,1H),9.26(t,J=6.0Hz,1H),8.22(s,1H),7.93(dd,J=11.2,2.0Hz,2H) ,7.74-7.66(m,3H),7.59(t,J=8.8Hz,1H),7.48(d,J=4.0Hz,1H),7.40-7.37(m,1H),7.14(d,J=8.4 Hz, 2H), 6.96(d, J=8.4Hz, 2H), 5.08(s, 2H), 4.57(t, J=5.6Hz, 2H), 4.19(t, J=7.6Hz, 2H), 3.70- 3.66(m,2H,),2.87(t,J=7.6Hz,2H); 13 C NMR (100MHz, DMSO-d 6 )δ193.54,166.27,159.67,158.45,157.94,156.77,155.51,149.70,137.18,138.08,130.49,129.81,129.65,124.75,122.92,119.15,118.09,117.32,117.29,114.69,114.44,111.48,108.60,108.34,61.04 , 48.17, 45.40, 31.24; ESI-MS (m / z) 809 [M-H] - .

[0188] Compound 1b: 60 mg of red solid product was obtained from S1b (60 mg, 105 μmol) and S2a (33 mg, 116 μmol),...

Embodiment 3

[0206] The inhibitory effect of each compound of embodiment 3 to laboratory adaptation strain HIV-1IIIB

[0207] According to literature (Xu, W.; Pu, J.; Su, S.; Hua, C.; Su, X.; Wang, Q.; Jiang, S.; Lu, L., Revisiting the mechanism of enfuvirtide and designing An analog with improvedfusion inhibitory activity by targeting triple sites in gp41.Aids 2019, 33, 1545-1555) was used to detect the inhibitory effect of the compound prepared in Example 1 on the replication of laboratory-adapted strain HIV-1IIIB.

[0208] In the examples of this application, the HIV-1IIIB strain is provided by the AIDS Reagent and Reference Project of the US NIH, catalog number 398.

[0209] HIV-1IIIB (X4) was amplified on MT-2 cells (provided by the AIDS Reagent and Reference Project of the US NIH, catalog number 237) and its titer was determined, and the aliquots were stored at -80°C. To determine the antiviral activity of the compounds, each compound was dissolved in DMSO, and the initial concentra...

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Abstract

The invention discloses a compound shown as a formula I or pharmaceutically acceptable salt thereof, wherein X1, X2, X3, R, R1, R2, R3 and linker are as defined in the invention. The invention also provides a method for preparing the compound and application of the compound in preparation of medicines for preventing and / or treating human immunodeficiency virus (HIV) infection.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to a compound and its application. Background technique [0002] Currently, 27 inhibitors and 9 combination inhibitors that have been approved by the FDA for clinical treatment of AIDS mainly play roles in various stages of HIV-1 infection target cell cycle, including CD4 receptor binding, co-receptor (CXCR4 or CCR5 ) binding, membrane fusion, reverse transcription, DNA integration, and protein synthesis. Although highly active antiretroviral therapy (HAART), consisting mainly of reverse transcriptase inhibitors and protease inhibitors, has reduced morbidity and mortality among HIV-1-infected individuals, the emergence of drug-resistant strains has increased the probability of treatment failure ; In addition, because these drugs act on the stage after the virus enters the target cell, they cannot prevent the virus from entering the cell, and the high-frequency mutation of reverse...

Claims

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Application Information

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IPC IPC(8): C07D417/14C07D417/06A61K31/427A61K31/454A61P31/18
CPCC07D417/14C07D417/06A61P31/18
Inventor 姜世勃陆路蒲静王茜
Owner FUDAN UNIV
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