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Vonoprazan salt as well as preparation method and application thereof

A technology of complexes and organic acids, applied in the field of salts of pyrrole compounds and salts formed by complexes, can solve the problems of acid rebound, research on biological activity and its bioavailability, influence on therapeutic effects, etc. Improved availability, good solubility and stability, and increased efficacy

Active Publication Date: 2021-05-25
HINYE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are serious defects in this type of drug: acid rebound phenomenon will occur at night, which will affect the therapeutic effect
The above-mentioned patent application investigated the solubility and stability of different vonorazan salts, but did not study the biological activity and bioavailability of each salt

Method used

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  • Vonoprazan salt as well as preparation method and application thereof
  • Vonoprazan salt as well as preparation method and application thereof
  • Vonoprazan salt as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] This example prepares the salt formed by the complex of vonoprazan, citric acid and bismuth.

[0052] 1. The chemical formula of the salt formed by the complex of Vonorazan with citric acid and bismuth is C 29 h 29 BiFN 3 o 16 S, molecular weight is 935.59; Its molecular structure is as shown in formula II below:

[0053]

[0054] 2. The preparation method of the salt formed by the complex of Vonorazan and citric acid and bismuth in this embodiment, its synthetic route is as follows:

[0055]

[0056] Specifically include the following steps:

[0057] (1) Vonorazan can be obtained through commercial channels or synthesized through existing technologies.

[0058] Compound IX is the fumarate salt of Vonorazan. DCM is dichloromethane.

[0059] The synthetic method of compound I Vonorazan in the present embodiment is as follows:

[0060] Compound IX (4.0g, 8.67mmol, 1.0eq) was added to a mixture of 20mL water and 20mL DCM, keeping the temperature at 25°C, and ...

Embodiment 2

[0070] This example prepares the salt formed by the complex of vonorazan, tartaric acid and bismuth.

[0071] 1. The chemical formula of the salt formed by the complex of Vonorazan, tartaric acid and bismuth is C 29 h 31 BiFN 3 o 20 S, molecular weight is 1001.61; Its molecular structure is as shown in formula III below:

[0072]

[0073] 2. The preparation method of the salt formed by the complex of Vonorazan and tartaric acid and bismuth of the present embodiment, its synthetic route is as follows:

[0074]

[0075] Specifically include the following steps:

[0076] (1) Synthesis of Compound VII Bismuth Potassium Tartrate:

[0077] Bismuth nitrate (6.0g, 15.2mmol, 1.0eq) was added to 30mL water, stirred for 30min, 6.16g of 25wt% KOH aqueous solution was added dropwise, the pH was measured to be 2, and the stirring was continued for 30min, and a white solid was obtained by suction filtration, which was added to In 20mL water, add dropwise the KOH aqueous solution ...

Embodiment 3

[0085] Bioactive Pharmacokinetic Testing

[0086] Experimental test drugs: HYH2002001 (control group 1, commercially available vonoprazan fumarate), HYH2002002 (example 1, the salt formed by the complex of vonoprazan, citric acid and bismuth), HYH2002004 ( Example 2, the salt formed by the complex of vonoprazan, tartaric acid and bismuth), HYH2002005 (control group 2, commercially available bismuth potassium citrate and vonoprazan fumarate according to the molar ratio of 1:1 than physical mixing);

[0087] Experimental method: 60 male SD rats (200-250g) were randomly divided into four groups, and HYH2002001 (8.4g kg-1), HYH2002002 (15.4g kg-1), HYH2002004 (17.7g kg -1), HYH2002005 (23.4g·kg-1), wherein HYH2002001, HYH2002002, HYH2002004, and HYH2002005 are administered with equimolar vonoprazan, and the administration volume is 5ml·kg-1. Blood was collected at 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, and 8h after administration, and plasma was collected by centrifugation...

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Abstract

The invention discloses vonoprazan salt as well as a preparation method and application thereof, and the vonoprazan salt is salt formed by vonoprazan and a complex of organic acid and bismuth. The invention also comprises a preparation method of the vonoprazan salt and application of the vonoprazan salt in preparation of drugs for treating gastric acid diseases. Compared with the existing vonoprazan salt, the salt formed by the vonoprazan and the complex of organic acid and bismuth has many satisfactory advantages, such as good solubility and stability, improvement of bioavailability, synergistic increase of drug effect and the like.

Description

technical field [0001] The present invention belongs to the field of chemical medicines, and specifically relates to a salt of an pyrrole compound with a proton pump inhibitory effect, more specifically to a salt formed of a complex of vonoprazan, an organic acid and bismuth, and a preparation method and use thereof . Background technique [0002] Gastric acid-related diseases are diseases caused by excessive gastric acid secretion or special sensitivity to gastric acid, such as peptic ulcer, gastroesophageal reflux, and digestive system diseases caused by non-steroidal anti-inflammatory drugs. At present, the strongest drugs for the treatment of hyperacidity are proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, etc. However, this type of drug has a serious defect: acid rebound occurs at night, which affects the therapeutic effect. The emergence of potassium ion competitive acid blockers (P-CAB) drugs (such as Vonorazan) has solved this type of problem very ...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C59/255C07C51/41C07C51/02A61P1/04
CPCC07D401/12C07C59/255C07C51/418C07C51/41A61P1/04
Inventor 刘军华蒋海港王衡新邓俐丽宋志林
Owner HINYE PHARM CO LTD
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