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Serine hydrolase inhibitors

A compound and heterocyclic technology, applied in the field of disease compounds, can solve problems such as neutrophil elastase activity cannot be controlled, tissue damage, etc.

Inactive Publication Date: 2009-09-16
KYORIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when there is an imbalance between neutrophil elastase and endogenous inhibitors due to excessive release of neutrophil elastase at sites of inflammation or due to decreased levels of inhibition, the activity of neutrophil elastase cannot be controlled, tissue damage

Method used

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Examples

Experimental program
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Effect test

preparation example Construction

[0179] Compound preparation

[0180] The compounds provided by the present invention can be prepared by methods known to those skilled in the art and similar to the following procedures described in the Examples section herein and routine modifications thereof.

[0181] Some exemplary reaction schemes for compound preparation are shown below:

[0182] Process 1:

[0183]

[0184] The leaving group can be any leaving group known to those skilled in the art, such as Br, Cl and F.

[0185] Process 2

[0186]

[0187] Exemplary coupling reagents for the reaction include, but are not limited to: HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium hexafluorophosphate), DCC (N, N'-dicyclohexylcarbodiimide), BOP (benzotriazol-1-yl-oxy-tris-(dimethylammonia)-phosphorus hexafluorophosphate) and others skilled in the art known coupling agents. Any base known to those skilled in the art can be used, exemplary bases are DBU (diazabicyclo[5.4.0]undec-7-ene), DIEA (diisopro...

Embodiment 1

[0317] Example 1. Preparation of 2-(2-imidazol-1-yl-pyridin-3-yl)-5-methyl-4H-benzo[d][1,3]oxazin-4-one (A)

[0318]

[0319]A solution of 2-fluoro-nicotinic acid (2.4 g, 17 mmol) and N,N'-carbonyldiimidazole (CDI, 2.76 g, 17.0 mmol) in anhydrous acetonitrile (12 mL) was stirred at ambient temperature for 30 min, then heated to 65°C for 1 hour. 2-Amino-6-methyl-benzoic acid (2.57 g, 17 mmol) was added to the reaction mixture, followed by stirring at 65°C for 1 hour. Additional CDI (2.76 g, 17 mmol) was added to the stirring reaction mixture and heating was continued to 100 °C for 1 hour. The reaction mixture was then concentrated by rotary evaporator. This crude material was loaded onto a silica gel column. Impurities were removed with a gradient of 0-60% EtOAc / hexanes, and compound 2 was eluted from the column with 100% EtOAc (modified by 5% triethylamine). Rotary evaporation afforded Compound A (2.28 g, 44% yield) as a yellow powder. 1 H-NMR δ(CDCl 3 ): 8.70(dd, 1H,...

Embodiment 2

[0320] Example 2.2-[2-(3-Dimethylamino-pyrrolidin-l-yl)-pyridin-3-yl]-5-methyl-4H-benzo[d][1,3]oxazine- Preparation of 4-keto(46)

[0321]

[0322] Preparation of 2-fluoronicotinic acid esterified Wang resin (B): To a suspension of Wang resin (1.2 mmol / g, 15 g, 18 mmol) in dichloromethane (DCM, 150 mL) was added 2-fluoro-nicotinic acid ( 3.3g, 23.4mmol) and a DC solution (30mL) of 1-hydroxyl 4H-benzotriazole (HOBt, 3.58g, 23.4mmol) and N, N'-dimethylformamide (DMF, 15mL), then add 4 - Dimethylampyridine (DMAP, 286 mg, 2.34 mmol) and N,N'-diisopropylcarbodiimide (DIC, 3.65 g, 23.4 mmol). The mixture was stirred at room temperature for 12 hours. The resin was washed successively with DCM and MeOH, and dried under vacuum to obtain Resin B (17.54 g, 100%).

[0323] Preparation of 2-(3-dimethylamino-pyrrolidin-l-yl)-nicotinic acid (C): To a pyridine suspension (12 mL) of resin B (1.2 mmol / g, 5.0 g, 8.0 mmol) at room temperature Dimethyl-pyrrolidin-3-yl-amine (1.37 mL, 12 mmo...

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Abstract

Provided herein are benzoxazinone compounds of formula (I) and compositions containing the compounds. The compounds and compositions are useful in the methods of inhibiting the action of serine hydrolase, including neutrophil elastase. In certain embodiments, the compounds and compositions are useful in the prevention, amelioration or treatment of serine hydrolase-mediated diseases.

Description

1. Technical field [0001] The present invention provides compounds, compositions and methods for treating, preventing or improving serine hydrolase-mediated diseases, including but not limited to neutrophil elastase-mediated diseases. Compounds provided by the present invention are benzoxazinones, which are serine hydrolase inhibitors. 2. Background technology [0002] Serine hydrolases are one of the largest and most diverse enzyme families in higher eukaryotes, which include a variety of serine proteases, lipases, esterases and amidases. Human neutrophil elastase is a class of serine hydrolases released from the granules of neutrophils that arise in infectious or inflammatory diseases. Neutrophil elastase is an enzyme that hydrolyzes proteins such as elastin, collagen, mucin, fibronectin, and other proteins that constitute the interstitium of connective tissues in living bodies such as lungs, cartilage, blood vessel walls, and skin. In addition, neutrophil elastase is kn...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D413/14A61K31/536A61P29/00
CPCC07D413/04C07D413/14A61P1/02A61P1/04A61P1/16A61P1/18A61P7/02A61P9/10A61P11/00A61P11/06A61P11/08A61P15/00A61P17/06A61P19/02A61P27/02A61P29/00A61P31/04A61P37/06A61P43/00A61K31/536
Inventor 凯文·施莱德胡毅阿里斯特·费舍河野靖小岛秋彦石山准一
Owner KYORIN PHARMA CO LTD
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