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Prodrug, preparation method therefor, pharmaceutical compositions and use thereof

A prodrug and compound technology, applied in the field of anti-hepatitis C drugs, can solve the problems of increasing the economic burden of patients and poor patient compliance

Active Publication Date: 2017-06-23
HANGZHOU HERTZ PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, allowing patients to take antiviral drugs and liver-protecting drugs at the same time not only leads to poor patient compliance, but also increases the financial burden of patients

Method used

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  • Prodrug, preparation method therefor, pharmaceutical compositions and use thereof
  • Prodrug, preparation method therefor, pharmaceutical compositions and use thereof
  • Prodrug, preparation method therefor, pharmaceutical compositions and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0217] Embodiment 1: the synthesis of compound II-A-1

[0218] Method A:

[0219]

[0220] Step 1: Dissolve 529mg (1.0mmol) III-1 in 10mL of anhydrous acetone, add 680mg (1.5mmol) IV-A-1 and 414mg (3.0mmol) potassium carbonate at room temperature, heat, stir and reflux for 6h, and detect the reaction by TLC completely. After filtration, the filtrate was diluted with dichloromethane (30 mL), washed with water (10 mL) and saturated brine (10 mL) successively, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography to obtain 710 mg of white solid V-A-1, with a yield of 75%, ESI-MS: m / z[M+H] + =947.

[0221] Step 2: Dissolve 200mg (0.21mmol) V-A-1 in 10mL of anhydrous dichloromethane, add 2mL at room temperature (volume ratio: dichloromethane / triisopropylsilane / trifluoroacetic acid=5 / 1 / 1) Solution, reacted for about 1 h, TLC det...

Embodiment 2

[0227] Embodiment 2: the synthesis of compound II-A-1a

[0228]

[0229] Compound VII-1 was freshly prepared according to step 1 of method B in Example 1 (3 mmol of compound III-1 as the starting material), dissolved in 12 mL of anhydrous dichloromethane (DCM), cooled in an ice bath under argon protection, Add 18 mg (0.15 mmol) 4-dimethylaminopyridine (DMAP) and 0.75 g (3.9 mmol) 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl) successively, And 1.93g (3.6mmol) compound VIII-A-1a (prepared from chiral tiopronin, S configuration chiral purity 97%, analysis method: AD-H column temperature: 25C; detection wavelength: 210nm; flow rate: 1.0ml / min; mobile phase: n-Hex:EtOH:TFA=90:10:0.1 isocratic elution), then slowly rise to room temperature and stir the reaction for about 12 hours, and the reaction is complete as detected by TLC. Add 30 mL of dichloromethane, wash with saturated aqueous sodium bicarbonate solution and saturated brine successively, separate t...

Embodiment 3

[0231] Embodiment 3: the synthesis of compound II-A-1b

[0232]

[0233] According to Step 1 and Step 2 of Example 2, VIII-A-1b (prepared from chiral tiopronin, R configuration chiral purity 95%, analysis method: AD-H column temperature: 25C; detection wavelength: 210nm ; Flow rate: 1.0ml / min; Mobile phase: n-Hex:EtOH:TFA=90:10:0.1 isocratic elution) replace VIII-A-1a, can prepare 8.7 with 5.3g (10mmol) compound III-1 g Intermediate IX-A-1b, yield 73% (two steps).

[0234] According to step 3 of Example 2, the compound IX-A-1b (2.9 mmol) continued to remove the protecting group, and 1.7 g of white solid product II-A-1b could be prepared, with a yield of 86%. ESI-MS: m / z[ M+H] + =705.

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Abstract

The invention belongs to the field of pharmaceutical chemistry and particularly relates to a tiopronin structure containing prodrug represented by a general formula I shown in the description or tautomers, stereomers, stereomer mixtures or pharmaceutically-acceptable solvates thereof, preparation methods for the prodrug or the tautomers, stereomers, stereomer mixtures or pharmaceutically-acceptable solvates thereof, pharmaceutical compositions and use of the pharmaceutical compositions as hepatitis C resisting drugs. The compounds or pharmaceutical compositions thereof can be applied to the treatment of hepatitis C and meanwhile play roles in protecting hepatic tissue and hepatic cells and improving hepatic functions.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a compound represented by the following general formula I or its tautomers, stereoisomers, stereoisomer mixtures, prodrugs, pharmaceutically acceptable salts or solvates thereof , its preparation method, pharmaceutical composition and its use as anti-hepatitis C medicine. Background technique [0002] Hepatitis C is a liver disease caused by hepatitis C virus (hereinafter referred to as HCV), which seriously threatens human health. In 1978, hepatitis C virus was discovered for the first time; in 1989, the gene sequence was determined, and HCV was confirmed as another major pathogen of non-A and non-B hepatitis. According to the heterogeneity of HCV genome, it can be divided into 6 types and 30 subtypes. The type of infection has strong regional characteristics, and type 1 is the main type in my country. A study in 2011 showed that among Chinese...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00C07C323/58A61K31/7072A61K45/06A61P1/16A61P31/14
CPCA61K31/7072A61K45/06C07B2200/13C07C323/58C07C323/59C07C323/60C07H1/00C07H19/10Y02P20/55
Inventor 周星露刘兴国董晓武
Owner HANGZHOU HERTZ PHARMA
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