Novel triazine-based detoxification agents and their use

Inactive Publication Date: 2005-01-20
LOWE CHRISTOPHER ROBIN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

A feature of the present invention is the provision of a general tool for the removal of endotoxin contamination from biological materials. Endotoxin binds exceedingly tightly to affinity ligand-matrix conjugates of the invention. This feature enables highly efficient extraction of endotoxin from water and aqueous solutions providing a means of generating pyrogen-free water or pyrogen-free solutions. Affinity ligand-matrix conjugates of the invention are especially valuable for the removal of endotoxin which is bound to or associated with proteins, drugs or other biological compounds intended for medical or pharmaceutical applications. Certain biological compounds, particularly proteins, often bind endotoxin tightly and subsequent removal is very difficult, if not impossible, by existing means. Affinity ligand-matrix conjugates of the invention may also be applied

Problems solved by technology

Certain biological compounds, particularly proteins, often bind endotoxin tightl

Method used

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  • Novel triazine-based detoxification agents and their use
  • Novel triazine-based detoxification agents and their use
  • Novel triazine-based detoxification agents and their use

Examples

Experimental program
Comparison scheme
Effect test

Example

EXAMPLE 1

This Example illustrates the synthesis of a typical affinity ligand of General Formula (XIV) defined by the reaction of a halogenohetercyclic compound of General Formula (IV) with a compound of General Formula (V) and (VI).

A solution of 1 part cyanuric chloride in 10 parts acetone was added dropwise to a stirred solution comprising 2 parts L-arginine in 100 parts water. The mixture was stirred for 2 hours at 0-5° C. whereupon the solution was warmed to 30° C. and mixing continued for a further 16 hours. The pH was maintained within the range 5.0-7.0 throughout by titration with 1M sodium hydroxide solution. The reaction product was precipitated by the addition of solid sodium chloride to a final concentration of 20% (w / v), filtered and dried in-vacuo. TLC analysis (THF / propan-2-ol / water (1:2:1 by vol.) solvent) revealed the presence of a single reaction product (Rf 0.42). The molecular mass of the isolated compound was determined by mass spectroscopy and found to be con...

Example

EXAMPLE 2

This Example illustrates the synthesis of an optionally derivatised support matrix of General Formula (VI).

A solution of 1 part 1,6-diaminohexane in 12 parts water was added to a stirred suspension comprising 29 parts epoxy-activated agarose beads (30 μmol epoxide groups per g agarose gel) in 48 parts water and stirred for 24 h at 30° C. The amino-hexyl agarose gel was filtered and washed consecutively with 12×29 parts water and allowed to drain under gravity on completion of the final wash. Analysis of the resulting amino-hexyl agarose for the presence of primary amines (TNBS asay) and epoxide groups (thiosulphate / sodium hydroxide titration) revealed complete reaction of the epoxide groups with 1,6-diaminohexane.

Example

EXAMPLE 3

Example 2 was repeated by replacing 1,6-diaminohexane with 1,4-diaminobutane, 1,5-diaminopentane, 1,7-diaminoheptane, 1,8-diaminooctane, 1,9-diaminononane and 1,10-diaminodecane. In all cases amino-alkyl derivatised agarose matrices were obtained.

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Abstract

An affinity ligand-matrix conjugate comprises the matrix and conjugated thereto by the group Z, a ligand having general formula (I):
wherein one X is N and the other X is N, CCL or CCn; A1 and A2 are each independently O, S or N—R1 and R1 is H, C1-6 alkyl, C1-6 hydroxyalkyl, benzyl or β-phenylethyl; B1 and B2 are each independently an optionally substituted hydrocarbon linkage containing from 1 to 10 carbon atoms; D1 is H or a primary amino, secondary amino, tertiary amino, quaternary ammonium, imidazole, guanidine or amidino group; and D2 is a secondary amino, tertiary amino, quaternary ammonium, imadazole, guanidine or amidino group; or B2-D2 is —CHCOOH—(CH2)3-4—NH2; and p is 0 or 1. Such conjugates are useful for the separation, isolation, purification, characterization, identification or quantification of an endotoxin.

Description

FIELD OF THE INVENTION The present invention relates to novel affinity ligands, their preparation and attachment to matrices which may consist of solid, semi-solid, particulate or colloidal materials, or soluble polymers. The invention furthermore relates to these novel affinity ligand-matrix conjugates and the preparation and use thereof in the binding and removal of endotoxin from various fluids such as water, aqueous solutions, body fluids, blood, plasma, solutions of pharmaceutical products, proteins and other compounds of biological origin. BACKGROUND OF THE INVENTION Endotoxins are lipopolysaccharides found in the outermost membrane of Gram-negative bacteria, particularly pathogeneic bacteria of the class Enterobacteriaceae, Neisseriaceae and Chlamydiaceae. Endotoxins comprise lipid A attached to a polysaccharide of variable structure dependent upon its biological origin. The polysaccharide component of Enterobacteriaceae endotoxin is characterised by an O-specific chain reg...

Claims

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Application Information

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IPC IPC(8): A61M1/36B01J20/22B01J20/32C02F1/28C07D251/50C07D251/70C07D403/12C07D403/14
CPCC02F1/285C07D251/50C07D251/70C07D403/12C07D403/14G01N33/579B01J20/3255B01J20/265B01J20/3212B01J20/3219B01J20/3248B01J20/3251B01J20/3253B01J20/262
Inventor LOWE, CHRISTOPHER ROBINLAWDEN, KIM HILARY
Owner LOWE CHRISTOPHER ROBIN
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