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Oral complement factor D inhibitors

A free and compound technology, which is applied in the direction of medical preparations containing active ingredients, drug combinations, compounds of Group 5/15 elements of the periodic table, etc., can solve problems such as damage

Pending Publication Date: 2022-05-27
BIOCRYST PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Complement proteins then create holes, or pores, in the invading organism, causing it to be destroyed

Method used

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  • Oral complement factor D inhibitors
  • Oral complement factor D inhibitors
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Examples

Experimental program
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preparation example Construction

[0102] The preparation of such prodrug derivatives is discussed in various literature sources (examples are: Alexander et al, J. Med. Chem. 1988, 31, 318; Aligas-Martin et al, PCT WO0041531, page 30).

[0103] Prodrug forms of compounds with carboxyl groups include esters (-CO 2 R m ), where R m The group corresponds to any alcohol that will be released at pharmaceutically acceptable levels in vivo by enzymatic or hydrolytic methods. Another prodrug derived from the carboxylic acid form of the present disclosure can be the quaternary salt type structure described by Bodor et al., J. Med. Chem. 1980, 23,469.

[0104] As used herein, the terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia, gelatin, star...

Embodiment

[0274] Now that the present invention has been described 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 limit the invention.

[0275] plan 1

[0276]

[0277] Preparation of 2-(2-((7-(5-(1-aminopropyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetic acid (1j)

[0278] Step-1: Preparation of (7-bromobenzofuran-5-yl)methanol (1b)

[0279] To 7-bromobenzofuran-5-carboxylic acid (1a) (10 g, 41.5 mmol; CAS# 286836-25-7) and N-methylmorpholine (5.47 mL, 49.8 mmol) in THF ( To the stirred solution in 200 mL) was added isobutyl chloroformate (6.54 mL, 49.8 mmol). The reaction mixture was stirred for 15 minutes, filtered through a pad of celite and the precipitate was washed with THF (3 x 20 mL). The filtrate was cooled to 0°C and NaBH was added carefully (fast release of gas) 4 (4.71 g, 124 mmol) in water (10 mL). The reaction mixture was stirred for 30 minute...

Embodiment 85

[1308] ICs of compounds are calculated according to the procedure reported in US Patent 6,653,340 B1, eg, at Column 74 (incorporated by reference) 50 value (ie, the concentration of compound that inhibits 50% of the enzymatic activity).

[1309] Specifically, compounds were dissolved in DMSO stock solutions at 10.0 or 100 mM. A portion of this stock solution was added to assay buffer in a final volume of 50 μL. Controls included buffer alone and the enzyme solution to which DMSO was added. Substrate is added to the wells immediately or after incubation at room temperature. The reaction rate was measured spectrophotometrically by producing product at 405 nm for 600 seconds. The background absorbance at 690 nm was measured for each well and subtracted from the absorbance at 405 nm.

[1310] The reaction rate of the enzyme alone was compared to the rate of the enzyme in the presence of the inhibitor, and percent inhibition was calculated as follows:

[1311] Percent inhibiti...

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Abstract

Disclosed are compounds of Formula (I)-(IV) and pharmaceutically acceptable salts thereof, which are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising such compounds, and methods of using the compounds and compositions to treat or prevent diseases or conditions characterized by aberrant complement system activity.

Description

[0001] Related applications [0002] This application claims the benefit of priority from US Provisional Patent Application No. 62 / 913,021, filed on October 9, 2019. [0003] Background of the Invention [0004] The complement system is the branch of an organism's immune system that enhances the ability of antibodies and phagocytes to destroy and remove foreign particles, such as pathogens, from the organism. The complement system contains a group of plasma proteins that work together to attack the extracellular form of pathogens and induce a cascade of inflammatory responses to help fight infection. Complement activation can proceed via several pathways. For example, complement activation can occur spontaneously in response to certain pathogens or by antibodies that bind to the pathogen. When complement proteins are activated, a cascade is triggered whereby one complement protein induces the activation of the next protein in the sequence. Each successive enzymatic reaction ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/80C07D307/81A61K31/343
CPCC07D307/80C07D307/81C07D307/79C07D405/04C07D307/82C07D401/04C07D409/04C07D417/04C07D405/12C07D413/04C07D209/08C07D487/04C07F9/2475A61K31/343A61K31/443A61K31/53A61P25/00A61P25/28A61P9/00C07D407/04
Inventor P·L·科蒂安Y·S·巴布张维河吕鹏程A·E·斯保尔丁吴明万吕魏阮澄宣党昭K·拉曼
Owner BIOCRYST PHARM INC
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