Composition for caspase inhibitor prodrug injection

A composition and injection technology, applied in the directions of drug combination, drug delivery, antipyretic drugs, etc., can solve the problems of in vitro drug release period limitation, loss of drugs, low encapsulation efficiency, etc., and achieve improved encapsulation efficiency and release period. added effect

Pending Publication Date: 2022-01-04
LG CHEM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, when niflecasan is prepared as a polymer microsphere formulation in a sustained-release formulation, according to its physicochemical properties, a large amount of drug is lost during the preparation process, resulting in low encapsulation efficiency, and also exists for the in vitro drug release period. limit

Method used

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  • Composition for caspase inhibitor prodrug injection
  • Composition for caspase inhibitor prodrug injection
  • Composition for caspase inhibitor prodrug injection

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0058] Preparation 1: (2S,3S)-2-(fluoromethyl)-3-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-diacetic acid hydrogen iso Azole-5-carboxamido)-5-oxotetrahydrofuran-2-yl ester

[0059]

[0060] Niflecagen ((R)-N-((2S,3S)-2-(fluoromethyl)-2-hydroxy-5-oxotetrahydrofuran-3-yl]-5-isopropyl-3- (isoquinolin-1-yl)-4,5-dihydroiso Azole-5-carboxamide; 5.0g, 12.0mmol) was dissolved in dichloromethane (50mL), and then acetyl chloride (0.94mL, 13.2mmol, 1.1 equivalents), triethylamine (2.52mL, 18.0mmol, 1.5 eq) and 4-dimethylaminopyridine (0.15 g, 1.2 mmol, 0.1 eq) while maintaining the temperature at 5°C or lower. The reaction mixture was stirred at 25 °C for about 2 hours and quenched by the addition of 10% aqueous sodium bicarbonate (25 mL). After adding water (25 mL) and stirring, the organic layer was separated and distilled under reduced pressure. The resulting mixture was recrystallized in a 1:5 mixture of ethyl acetate and hexane (EtOAc:hexane=1:5) to obtain 3.0 g (yield...

preparation example 2

[0062] Preparation 2: Propionic acid (2S,3S)-2-(fluoromethyl)-3-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-di hydrogen iso Azole-5-carboxamido)-5-oxotetrahydrofuran-2-yl ester

[0063]

[0064] Niflecason (1.0g, 2.4mmol) was dissolved in dichloromethane (20mL), then propionyl chloride (0.23mL, 2.65mmol, 1.1 equivalents), triethylamine (0.5mL, 3.61mmol, 1.5 eq) and 4-dimethylaminopyridine (0.03g, 0.24mmol, 0.1 eq) while maintaining the temperature at 5°C or lower. The reaction mixture was stirred at 25°C for about 2 hours and quenched by the addition of 10% aqueous sodium bicarbonate (10 mL). After adding water (10 mL) and stirring, the organic layer was separated and distilled under reduced pressure. The obtained mixture was subjected to column separation by using a 1:2 mixture of ethyl acetate and hexane (EtOAc:hexane=1:2), to obtain 0.25 g (yield: 23%) of the title compound.

[0065] 1 H NMR (400 MHz, CDCl 3 )δ9.12(d,1H),8.55(d,1H),7.87(d,1H),7.74-7.69(m,3H),7....

preparation example 3

[0066] Preparation 3: Isobutyric acid (2R,3S)-2-(fluoromethyl)-3-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5- dihydroiso Azole-5-carboxamido)-5-oxotetrahydrofuran-2-yl ester

[0067]

[0068] Niflecason (1.0g, 2.4mmol) was dissolved in dichloromethane (20mL), and then wasobutyryl chloride (0.73g, 2.65mmol, 1.1 equivalents), triethylamine (0.5mL, 3.61mmol, 1.5 eq) and 4-dimethylaminopyridine (0.03 g, 0.24 mmol, 0.1 eq) while maintaining the temperature at 5°C or lower. The reaction mixture was stirred at 25°C for about 2 hours and quenched by the addition of 10% aqueous sodium bicarbonate (10 mL). After adding water (10 mL) and stirring, the organic layer was separated and distilled under reduced pressure. The obtained mixture was subjected to column separation by using a 1:2 mixture of ethyl acetate and hexane (EtOAc:hexane=1:2), to obtain 0.06 g (yield: 5%) of the title compound.

[0069] 1 H NMR (400MHz, CDCl 3 )δ9.12(d,1H),8.55(d,1H),7.88(d,1H),7.74-7.69(m,3H),...

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Abstract

The present invention relates to a pharmaceutical composition for a caspase inhibitor prodrug injection and, more particularly, to a pharmaceutical composition for injection, the composition comprising a caspase inhibitor prodrug or a pharmaceutically acceptable salt or isomer thereof as an active ingredient, and a biocompatible polymer.

Description

technical field [0001] The invention relates to a pharmaceutical composition for injecting prodrugs of caspase inhibitors. More specifically, the present invention relates to a pharmaceutical composition for injection comprising, as an active ingredient, a prodrug of a caspase inhibitor or a pharmaceutically acceptable salt or isomer thereof and Biocompatible polymers. Background technique [0002] Caspases are enzymes and cysteine ​​proteases that exist as α2β2 tetramers. Caspase inhibitors interfere with the activity of these caspases, thereby regulating inflammation or apoptosis caused by the action of the caspases. Diseases whose symptoms can be eliminated or alleviated by administration of these compounds include osteoarthritis, rheumatoid arthritis, degenerative arthritis, destructive bone disease, liver disease caused by hepatitis virus, acute hepatitis, cirrhosis, Brain injury, human fulminant liver failure, sepsis, organ transplant rejection, ischemic heart disea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/08A61K31/4725A61K47/34A61P19/02A61P29/00A61P19/08
CPCA61K31/4725A61K9/08A61K9/0019A61K47/34A61P19/02A61P29/00A61P19/08A61K9/0024A61K9/1647A61K9/16
Inventor 金成垣金福泰崔世铉白宰旭
Owner LG CHEM LTD
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