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A kind of elastase inhibitor prodrug and its application

A pharmacy and compound technology, applied in the field of prodrugs of elastase inhibitors and their uses, can solve the problems of short exposure time and limited drug efficacy, and achieve the effects of high lung exposure, increased concentration and residence time, and long half-life

Active Publication Date: 2022-04-12
SUZHOU ARK BIOPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in vivo pharmacokinetic studies in animals found that the exposure time of the compound in the lungs is too short and the elimination is rapid, which may limit its efficacy

Method used

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  • A kind of elastase inhibitor prodrug and its application
  • A kind of elastase inhibitor prodrug and its application
  • A kind of elastase inhibitor prodrug and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] Example 1: (4-(((S)-3-methyl-1-((S)-2-(((R)-2-methyl-1-((3aS, 4S, 6S, 7aR) -3a,5,5-Trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)propyl)carbamoyl)pyrrolidine- 1-yl)-1-oxobut-2-yl)carbamoyl)benzoyl)glycine

[0129]

[0130] Step 1a: Preparation of N-tert-butoxycarbonyl-L-valyl-L-proline methyl ester

[0131]

[0132] Under nitrogen protection, dissolve 55.0 g of N-tert-butoxycarbonyl-L-valine, 46.1 g of L-proline methyl ester hydrochloride and 43.1 g of N,N'-carbonyldiimidazole in 200 mL of dichloromethane , stirred at room temperature for 6 hours. HPLC monitored the reaction to be complete. The reaction solution was washed with sodium bicarbonate dissolved in dilute hydrochloric acid and water respectively. The solvent was removed by concentration under reduced pressure to obtain intermediate N-tert-butoxycarbonyl-L-valyl-L-proline methyl ester (72.0 g) as a pale yellow oil.

[0133] Step 1b: Preparation of N-tert-butoxycarbonyl-L-valyl-L-pro...

Embodiment 2

[0148] Example 2: (4-(((S)-3-methyl-1-(S)-2-(((R)-2-methyl-1-(6-methyl-4,8-di Oxygen-1,3,6,2-dioxazaborolin-2-yl)propyl)carbamoyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)carbamoyl) Benzoyl)glycine

[0149]

[0150] Step 2a: Preparation of (4-(((S)-1-((S)-2-(((R)-dihydroxyboryl-2-methylpropyl)pyrrolidin-1-yl)-3- Methyl-1-oxobut-2-yl)carbamoyl)benzoyl)glycine

[0151]

[0152] Under nitrogen protection, the intermediate (4-(((S)-3-methyl-1-((S)-2-(((R)-2-methyl-1-((3aS, 4S, 6S , 7aR)-3a,5,5-Trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborolan-2-yl)propyl)carbamoyl) Pyrrolidin-1-yl)-1-oxobut-2-yl)carbamoyl)benzoyl)glycine 7.4g, 4-trifluoromethylphenylboronic acid 2.4g were dissolved in 100mL acetonitrile and 250mL petroleum ether, Then add 10mL of concentrated hydrochloric acid, raise the temperature to 60°C and continue stirring for 4 hours, let stand to separate layers, separate the upper layer of petroleum ether, add 250mL of fresh petroleum ether and continue stirring...

Embodiment 3

[0156] Example 3: (4-(((S)-3-methyl-1-((S)-2-(((R)-2-methyl-1-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)propyl)carbamoyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)carbamoyl) Benzoyl)glycine

[0157]

[0158] Step 3a: Preparation of (4-(((S)-3-methyl-1-((S)-2-(((R)-2-methyl-1-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)propyl)carbamoyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)carbamoyl) Benzoyl)glycine

[0159]

[0160] Under nitrogen protection, (4-(((S)-1((S)-2-(((R)-dihydroxyboryl-2 methylpropyl)pyrrolidin-1-yl)-3-methanol Base-1-oxobut-2-yl)carbamoyl)benzoyl)glycine 100mg, pinacol 68mg were dissolved in 0.5mL DMSO, then heated to 120°C and continued to stir for 6 hours, LC -MS monitors that the reaction is complete. After the freeze-drying of the reaction solution, the solid is dissolved in ethyl acetate, purified with a preparative plate, and freeze-dried to obtain a white solid (4-(((S)-3-methyl-1-((S)-2 -(((R)-2-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propy...

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Abstract

The present invention provides a prodrug of an elastase inhibitor and its application. The prodrug of the elastase inhibitor is a compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, and solvate thereof , Prodrug or isotope label: Compared with compound 52 (control substance) in the patent WO2018175173A1, the elastase inhibitor prodrug compound of the present invention has the advantages of high lung exposure and long half-life. The prodrug compounds of the present invention greatly increase the concentration and residence time of the active compound (control) in the lung and have a significant improvement in in vivo PK relative to the control.

Description

technical field [0001] The present invention belongs to the field of compounds, in particular to a prodrug of a substituted boronic acid compound, in particular to a mixture or composition of a prodrug of a substituted boronic acid compound, especially a mixture or composition of a prodrug of a boronic acid compound as an elastase inhibitor Compositions for the treatment of various pulmonary diseases caused by excess elastase, including chronic obstructive pulmonary disease (COPD). Background technique [0002] Human elastase (HNE) is a 32 kDa serine protease. The pathological process of many diseases involves this protease. Excess elastase is so damaging to the human body that the liver specifically synthesizes and secretes a natural inhibitor (alpha-1 antitrypsin) to maintain the balance of elastase activity in the body. After being synthesized in neutrophils, elastase is stored in azurophilic granules, and is not secreted until neutrophils are activated by external sign...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02A61P11/00A61P29/00A61K31/69
CPCC07F5/02A61P11/00A61P29/00A61K31/69A61P43/00C07F5/022C07F5/027
Inventor 彭程周杨王严飞钱梦飞蔡兆雄邹罡袁海卿邬征
Owner SUZHOU ARK BIOPHARM CO LTD
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