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Substituted benzofuran, benzopyrrole, benzothiophene, and structurally related complement inhibitors

An unsubstituted, halogenated alkyl technology, used in medical formulations containing active ingredients, allergic diseases, drug combinations, etc., can solve problems such as destroying healthy cells and tissues

Active Publication Date: 2021-01-26
BIOCRYST PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While complement plays an important role in protecting the body from foreign organisms, it also destroys healthy cells and tissues

Method used

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  • Substituted benzofuran, benzopyrrole, benzothiophene, and structurally related complement inhibitors
  • Substituted benzofuran, benzopyrrole, benzothiophene, and structurally related complement inhibitors
  • Substituted benzofuran, benzopyrrole, benzothiophene, and structurally related complement inhibitors

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Embodiment

[0452] Having now described the invention in detail, it will be more clearly understood by reference to the following examples, which are included for purposes of illustration only and are not intended to be limiting.

[0453] plan 1

[0454]

[0455] 2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetic acid (1h ) preparation

[0456] Step 1: Preparation of 2-chloro-4-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazine (1b)

[0457] 2,4-Dichloropyrrolo[2,1-f][1,2,4]triazine (1a) (3g, 15.96mmol, CAS#918538-05-3) in DMF (50mL) under Ar atmosphere ) were added 1-ethoxyvinyltri-n-butyltin (7.07mL, 20.74mmol, CAS#97674-02-7) and bis(triphenylphosphine)palladium(II) chloride (0.56g, 0.8 mmol). The mixture was heated with stirring at 100 °C for 30 min, cooled to room temperature and diluted with EtOAc (150 mL). The reaction mixture was washed with water (50 mL), brine (30 mL), dried, filtered and concentrated to dryness in vacuo. The resulting re...

Embodiment 534

[5927]ICs for compounds were calculated according to the procedure reported in U.S. Patent 6,653,340 B1, e.g., column 74 (incorporated by reference) 50 value (ie, the concentration of compound that inhibits 50% of the enzyme activity).

[5928] Specifically, compounds were dissolved in DMSO stock solutions at 10.0 or 100 mM. Add a portion of this stock solution to the assay buffer in a final volume of 50 µL. Controls included buffer alone and enzyme solutions with DMSO added. Substrate is added to the wells either immediately or after incubation at room temperature. Reaction rates were measured spectrophotometrically by product formation at 405 nm for 600 seconds. For each well, the background absorbance at 690 nm was measured and subtracted from the absorbance at 405 nm.

[5929] The reaction rate of the enzyme alone is compared to the rate of the enzyme in the presence of the inhibitor and the percent inhibition is calculated as follows:

[5930] Inhibition percentage =...

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Abstract

Disclosed are compounds of formulae I and II, and pharmaceutically acceptable salts and prodrugs thereof, which are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising such a compound, and methods of using the compounds and compositions in the treatment or prevention of a disease or condition characterized by aberrant complement system activity.

Description

[0001] related application [0002] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 654,108 filed April 6, 2018. Background technique [0003] The complement system is a branch of an organism's immune system that enhances the ability of antibodies and phagocytes to destroy and remove foreign particles (eg, pathogens) from an organism. The complement system consists of a group of plasma proteins that work together to attack extracellular forms of pathogens and induce a cascade of inflammatory responses to help fight infection. Complement activation can occur through several pathways. For example, complement activation can occur spontaneously in response to certain pathogens, or through antibodies that bind the pathogen. When complement proteins are activated, a cascade reaction is triggered whereby one complement protein induces the activation of the next protein in the sequence. Activation of a small number of complement ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/50
CPCA61K9/50C07D239/70C07D487/04C07D471/04C07D403/10C07D307/79C07D407/10C07D209/08C07D405/12C07D407/04C07D409/12C07D333/54C07D261/20C07D231/56C07D235/08A61P9/00A61P13/12A61P25/28A61P37/00C07D307/81C07D209/12C07D307/80C07D333/64C07D401/10C07D401/12C07D405/10A61K31/4178C07D491/048A61K31/53A61P25/00C07D333/56C07D413/04C07D495/04A61K31/5377A61K31/343A61P27/02C07D263/54C07D307/83C07D401/04C07D405/04
Inventor P·L·科蒂安Y·S·巴布张维河吕鹏程吴明万吕魏阮澄宣党昭V·R·钦塔雷迪V·S·库马K·拉曼
Owner BIOCRYST PHARM INC
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