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Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition

A tiopronin and prodrug technology, applied in the field of medicinal chemistry, can solve the problems of poor patient compliance and increased financial burden on patients

Inactive Publication Date: 2016-02-24
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 containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition
  • Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition
  • Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Embodiment 1: the synthesis of compound II-A-1

[0077]

[0078] step one:

[0079] Dissolve 529mg (1.0mmol) of III-1 in 10mL of anhydrous acetone, add 680mg (1.5mmol) of IV-1 and 414mg (3.0mmol) of potassium carbonate at room temperature, heat, stir and reflux for 6h, and TLC detects that the reaction is complete. 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-1 with a yield of 75%. 1 HNMR (400MHz, CDCl 3 )δ8.90(s,1H),7.51–7.38(m,7H),7.35–7.25(m,9H),7.22(dd,J=10.2,4.2Hz,5H),7.17(d,J=7.6Hz ,1H),6.41(dt,J=72.5,5.3Hz,1H),6.15(d,J=17.9Hz,1H),5.52(d,J=8.2Hz,1H),5.17(dd,J=19.9, 8.7Hz, 1H), 4.97(dq, J=12.6, 6.3Hz, 1H), 4.49(dt, J=5.4, 4.7Hz, 1...

Embodiment 2

[0083] Embodiment 2: the synthesis of compound II-A-2

[0084]

[0085] step one:

[0086]Dissolve 529mg (1.0mmol) III-1 in 10mL of anhydrous acetone, add 680mg (1.5mmol) IV-2 and 414mg (3.0mmol) potassium carbonate at room temperature, heat, stir and reflux for 6h, and TLC detects that the reaction is complete. 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 306 mg of white solid V-1 with a yield of 38%.

[0087] 1 HNMR (400MHz, CDCl 3 )δ8.90(s,1H),7.51-7.38(m,7H),7.35-7.25(m,9H),7.22(dd,J=10.2,4.2Hz,5H),7.17(d,J=7.6Hz ,1H),6.65(q,J=6.5Hz,1H),6.19(d,J=17.9Hz,1H),5.10-4.94(m,1H),4.52(dd,J=11.4,5.7Hz,1H) ,4.39-4.21(m,3H),4.22-4.05(m,2H),3.98(tt,J=11.5,5.8Hz,1H),3.57-3....

Embodiment 3

[0091] Embodiment 3: the synthesis of compound II-B-1

[0092]

[0093] step one:

[0094] Dissolve 529mg (1.0mmol) of III-1 in 10mL of anhydrous acetone, add 690mg of IV-3 and 414mg (3.0mmol) of potassium carbonate at room temperature, heat, stir and reflux for 6h, and TLC detects that the reaction is complete. 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 300 mg of V-3, which was directly used in the next reaction.

[0095] Step two:

[0096] Dissolve 200 mg (0.21 mmol) of V-3 in 10 mL of anhydrous dichloromethane, add 2 mL (volume ratio: dichloromethane / triisopropylsilane / trifluoroacetic acid=5 / 1 / 1) solution at room temperature, and react After about 1 h, TLC detec...

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Abstract

The invention belongs to the field of medicinal chemistry. Specifically, the invention relates to a prodrug containing a tiopronin structure showed by the following general formula I or a tautomer and a stereisomer of the prodrug, a stereisomer mixture or pharmaceutically acceptable solvate of the stereisomer mixture, a preparation method of the prodrug, a pharmaceutical composition, and application of the pharmaceutical composition serving as an anti-hepatitis c drug. This type of compounds or pharmaceutical compositions thereof can be used for curing hepatitis c, and also has the effects of protecting hepatic tissues and hepatic cells, and improving hepatic function.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a prodrug containing tiopronin structure shown in the following general formula I or its tautomer, stereoisomer, stereoisomer mixture or its pharmaceutically acceptable solvent compound, its preparation method, pharmaceutical composition and its use as anti-hepatitis C medicine. The compound or its pharmaceutical composition can be used for the treatment of hepatitis C, and at the same time has the functions of protecting liver tissue, liver cells and improving liver function. Background technique [0002] Hepatitis C is a liver disease that seriously threatens human health caused by hepatitis C virus (hepatitis C virus, hereinafter referred to as HCV). 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00A61K31/7072A61P31/14A61K31/198
CPCA61K31/7072A61K45/06C07B2200/13C07C323/58C07C323/59C07C323/60C07H1/00C07H19/10Y02P20/55
Inventor 周星露董晓武刘兴国施雄伟
Owner HANGZHOU HERTZ PHARMA
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