Tenofovir bis-l-amino acid ester and preparation method thereof

A tenofovir and amino acid ester technology, applied in the field of medicinal chemistry, can solve the problems of maintaining sufficient drug concentration at the infection site and poor membrane permeability

Active Publication Date: 2020-10-20
ZHEJIANG STARRY PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the released original drug is also rapidly excreted from the body due to poor membrane permeability, and it is difficult to maintain a sufficient drug concentration at the infected site, resulting in a human bioavailability of only about 28%.

Method used

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  • Tenofovir bis-l-amino acid ester and preparation method thereof
  • Tenofovir bis-l-amino acid ester and preparation method thereof
  • Tenofovir bis-l-amino acid ester and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1、9

[0062] Embodiment 1, 9-[2-(phosphonomethoxy) propyl] adenine bis-L-valine methyl ester

[0063] Tenofovir (0.50g, 1.74mmol), N-Boc-L-valine-1-bromomethyl ester (1.85g, 6.96mmol) and N,N-dicyclohexyl-4-morpholine amidine ( 1.23g, 4.18mmol) was dissolved in 5mL of dry DMF, stirred at room temperature for 8h, then continued to stir at 80°C for 6h, TLC detected that the reaction of raw materials was complete. Concentrate under reduced pressure, add 30 mL of 1% citric acid to the residue, stir at room temperature for 1 h, extract 3 times with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain a white foamy solid and It was dissolved in 5mL of dry dioxane, hydrogen chloride gas was passed through, and stirred at room temperature for 4h. Evaporate to dryness under reduced pressure, add ethanol to the residue, stir at 0°C for 15 minutes, then add diethyl ether, continue stirring at 0°C ...

Embodiment 2、9

[0066] Embodiment 2, 9-[2-(phosphonomethoxy) propyl group] adenine bis-L-valine ethyl ester

[0067] The preparation method is the same as in Example 1, tenofovir is reacted with N-Boc-L-valine-2-bromoethyl ester to obtain a white foamy solid.

[0068] 1 H NMR (500MHz, CD 3 OD)8.41(s,1H,8-H),8.37(s,1H,2-H),4.55(d,J=6.0Hz,2H),4.30-4.50(m,10H),3.81-4.09(m ,3H),2.31(m,2H),1.21(m,3H),1.13(d,J=7.0Hz,6H),1.09(d,J=6.5Hz,6H).

[0069] MS-ESI(m / z):574.53(M+H).

[0070] The title compound (70 mg, 0.13 mmol) was dissolved in 5 mL of dry dioxane, hydrogen chloride gas was passed through, and stirred at room temperature for 4 h. Evaporate to dryness under reduced pressure, add ethanol to the residue, stir at 0°C for 15 minutes, then add diethyl ether, continue stirring at 0°C for 30 minutes, filter with suction, rinse the filter cake with a small amount of ether, and dry it in vacuum at 35°C to obtain 9-[2- (Phosphonomethoxy)propyl]adenine bis-L-valine ethyl ester hydrochloride 78 mg,...

Embodiment 3、9

[0076] Example 3, 9-[2-(phosphonomethoxy) propyl] adenine bis-L-leucine propyl ester

[0077] The preparation method is the same as in Example 1, tenofovir is reacted with N-Boc-L-leucine-3-bromopropyl ester to obtain a white foamy solid.

[0078] 1 H NMR (500MHz, CD 3 OD)8.41(s,1H,8-H),8.35(s,1H,2-H),4.52(d,J=7.0Hz,2H),4.30-4.50(m,6H),3.81-4.19(m ,7H),2.35(m,4H),2.20(m,2H),1.25(m,3H),1.22(m,4H),1.08(d,J=7.5Hz,6H),1.01(d,J= 6.5Hz,6H).

[0079] MS-ESI(m / z):630.54(M+H).

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Abstract

The invention relates to a tenofovir bis-L-amino acid ester compound as shown in a formula (I), a preparation method and medical application of the compound, and an anti-hepatitis B medicine composition taking the compound as an effective component. More specifically, the invention relates to a 9-[2-(phosphonylmethoxy)propyl]adenine bis-L-amino acid ester compound, wherein R represents isopropyl,isobutyl, sec-butyl or benzyl, X represents oxygen or sulfur, and n represents a number selected from 1-3.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to tenofovir bis-L-amino acid ester compounds with anti-hepatitis B virus (HBV) activity, a preparation method thereof, and an anti-hepatitis B pharmaceutical composition containing them; more specifically, the present invention The invention relates to 9-[2-(phosphonomethoxy)propyl]adenine bis-L-amino acid ester compounds and 9-[2-(phosphonomethoxy)propyl]adenine bis-L-thio Amino acid ester compounds. Background technique [0002] Nucleoside compounds are an important class of clinical antiviral (HIV, HBV, HCV, influenza virus, herpes virus, etc.) drugs, but their drug resistance is increasing year by year, and has become a major public health and social problem of global concern. Compared with cyclic nucleoside reverse transcriptase inhibitors, non-cyclic nucleoside drug tenofovir [(R)-PMPA] has significant advantages in the prevention and treatment of viral drug resistance. For...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/20
CPCC07F9/65616Y02P20/55
Inventor 刘明亮李玉环郭慧元李宵宁汪阿鹏吕凯刘洪涛魏增泉陈仕洪
Owner ZHEJIANG STARRY PHARMA
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