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Prodrug of retegravir as well as preparation method and application of prodrug

A technology of compounds and general formulas, which is applied in the direction of pharmaceutical formulas, chemical instruments and methods, medical preparations containing active ingredients, etc., can solve problems such as high risks, side effects, and inconvenient use

Active Publication Date: 2020-09-04
GUANGDONG ZHONGKE DRUG R&D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The route of administration of remdesivir is injection, which has certain limitations, inconvenient use, and greater risk and side effects than oral administration. Therefore, the structure of remdesivir is modified to obtain a drug that can improve Oral bioavailability, so that it can meet the oral requirements of new drugs has important practical significance

Method used

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  • Prodrug of retegravir as well as preparation method and application of prodrug
  • Prodrug of retegravir as well as preparation method and application of prodrug
  • Prodrug of retegravir as well as preparation method and application of prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1: (2S)-2-ethylbutyl 2-((((((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(((penta (Oxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid Synthesis of esters (Formula I-1)

[0081]

[0082] 1) Synthesis of (2S)-2-ethylbutyl 2-(((4-nitrophenyl)(phenoxy)phosphoryl)amino)propionate

[0083]

[0084] Weigh alanine-2-ethylbutyl ester hydrochloride (21.0 g, 100 mmol, 1.0 eq.) into a 500 mL three-necked round bottom reaction flask under nitrogen protection, and add anhydrous dichloromethane (200 mL). The reaction solution was cooled to -70°C, phenyl dichlorophosphate (21.0 g, 100 mmol, 1.0 eq.) was added, and TEA (20.0 g, 200 mmol, 2.0 eq.) was slowly added dropwise, and the reaction was kept constant for 2 hours. TLC tracked until the raw material alanine-2-ethylbutyl ester hydrochloride was consumed, and 4-nitrophenol (14.0g, 100mmol, 1.0eq.) in dichloromethane (20mL) was added dropwise, at a constant tempe...

Embodiment 2

[0106] Example 2. (2S)-Benzyl 2-(((((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(((pentoxy) (Carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionate Synthesis of (Formula I-2)

[0107]

[0108] Comprehensive literature preparation method, using 7-bromopyrrolo[1,2-f][1,2,4]triazine-4-amine as raw material, synthetically obtained white foamy solid (2S)-benzyl 2-(( (((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][ 1,2,4]Triazine-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionate.

[0109] 1 H NMR(CDCl 3 400MHz) δ9.67 (s, 1H), 7.47-7.18 (m, 10H), 5.89-5.72 (d, 2H), 5.34 (s, 2H), 4.53-3.65 (m, 8H), 1.62-0.90 (m ,12H).ESI-MS m / z:723.5[M+H]+.

Embodiment 3

[0110] Example 3, (2R, 3R, 4R, 5R)-2-cyano-5-((((((S)-1-(2-ethylbutoxy)-1-propionate-2-yl )Amino)(phenoxy)phosphoryl)oxy)methyl)-2-(4-(((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4] Synthesis of triazine-7-yl)tetrahydrofuran-3,4-diacetate (Formula I-3)

[0111]

[0112] Comprehensive literature preparation methods, with 7-bromopyrrolo[1,2-f][1,2,4]triazine-4-amine as raw material, a white foamy solid (2R, 3R, 4R, 5R) was synthesized by synthesis 2-cyano-5-((((((S)-1-(2-ethylbutoxy)-1-propionate-2-yl)amino)(phenoxy)phosphoryl)oxy) Methyl)-2-(4-(((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3,4-di Acetate. 1 H NMR(CDCl 3 400MHz)δ9.67(s,1H),7.37-7.21(m,5H),5.89-5.72(d,2H),5.33-3.65(m,10H),2.21-0.98(m,29H).ESI-MS m / z:801.5[M+H]+.

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Abstract

The invention discloses a prodrug of retegravir as well as a preparation method and application of the prodrug. The structural formula of the prodrug of the retegravir is shown as a formula I in the specification. A liquid chromatograph-mass spectrometer is adopted to detect the concentration of R0 in blood after gavage of the obtained compound, and remdesivir injection and gavage are adopted to perform control study, so that the modified compound is found to have good bioavailability, the concentration of R0 in blood exceeds 50% of the average value of an injection administration group, and the concentration of R0 in blood exceeds more than 3 times of that of an oral remdesivir hydrochloride administration group.

Description

Technical field [0001] The invention belongs to the field of medicine, and specifically relates to a prodrug of Redecive and its preparation method and application. Background technique [0002] Remdesivir (Remdesivir), also translated rendesivir, is a new experimental broad-spectrum antiviral drug developed by Gilead Sciences, USA, used to target Ebola virus and is believed to be effective in inhibiting respiratory epithelium Replication of SARS virus and MERS virus in cells. This is a nucleotide analog prodrug that can inhibit RNA-dependent RNA synthetase. According to a study in 2020, the combination of Remdesivir and interferon IFNB1 has a significant effect on MERS. [0003] Remdesivir is a nucleoside analog with antiviral activity. In HAE cells, the EC50 value of SARS-CoV and MERS-CoV is 74nM, and in delayed brain tumor cells, the EC50 value of mouse hepatitis virus It is 30nM. [0004] The structure of Radixivir is as follows: [0005] [0006] Remdesivir is administered by...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61P31/14A61P31/16A61P31/18A61P31/12A61K31/685
CPCC07F9/6561A61P31/14A61P31/16A61P31/18A61P31/12Y02A50/30Y02P20/55
Inventor 王庚尧
Owner GUANGDONG ZHONGKE DRUG R&D
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