WO2003105990A2 - Filter material for toxins, bacteria, viruses, and other harmful physiological substances - Google Patents

Abstract

The invention relates to a filter material for toxins, bacteria, viruses, and other harmful physiological substances, which can be used during hemoperfusion in order to rid physiological liquids of such harmful substances. Said filter material is based on compounds belonging to the class of calixarenes and resorcinarenes. The physiological liquids can be blood, plasma, or urine, for example.

Description

 Filter aterial for toxins, bacteria, viruses and other physiological pollutants

The invention relates to a filter material for toxins, bacteria, viruses and other physiological pollutants, which can be used in hemoperfusion to rid the blood of such pollutants. The filter material is based on compounds from the class of calixarenes and reosrcinarene.

Hemoperfusion is one of the (most effective measures for extracorporeal elimination of toxins and pollutants.

It is previously known from the prior art to pass the blood drawn from the patient through adsorber cartridges, to bind the toxins or pollutants to the adsorbents and thus to withdraw them from the blood. So far, materials with known good adsorption properties, such as coated ac- tiv carbon or neutral resins. Additional adsorbent materials are based on functionalized polymer matrices. In all of these cases, however, there are a large number of substances and classes of substances which can be poorly or not at all bound and thus separated. An example of this are bacteria and viruses, for which no adsorber materials exist so far.

In contrast to hemodialysis, hemoperfusion is able to eliminate lipophilic substances that are not suitable for dialysis from the blood. However, hemoperfusion is usually superior to substances capable of dialysis. An important side effect, which has not yet been eliminated, is the undesired adsorption of throinocytes, which can be in a range up to about 40%.

Proceeding from this, it was an object of the present invention to provide a filter material for hemoperfusion which does not have the disadvantages known from the prior art, which is highly efficient with regard to the filter properties and which can be easily adapted to special tasks in the field of hemoperfusion can be adjusted, -,

This object is achieved by the filter material with the features of claim 1. The further dependent claims show advantageous developments. In claim 9, the use of the filter material is described.

According to the invention, a filter material is provided which consists of a compound of the general formula I

it R = H, alkyl, aryl, alkyloxy, aryloxy, amine, amide, carboxylic acids and sulfonic acids with ^• 1 to 12 carbon atoms, amino acids, sugar or crown ether,

Ri = H, alkyl, aryl, alkyloxy, aryloxy, amine, amide, carboxylic acids and sulfonic acids with 1 to 12 carbon atoms, sulfonamides, amino acids, sugars, crown ethers, cyclodextrins, purine bases or pyridine bases,

X = methylene, S, 0, N or P and

m = ^** 4, 5, 6 or 8

and / or a compound of the general formula II

with R = H, alkyl, aryl, alkyloxy, aryloxy, amine, amide, carboxylic acids and sulfonic acids with 1 to 12 carbon atoms or amino acids, Ri = H, alkyl, aryl, alkyloxy, aryloxy, amine, amide, carboxylic acids and sulfonic acids with 1 to 12 carbon atoms, sulfona ide, amino acids, sugar, crown ethers, cyclodextrins, purine bases or pyrimidine bases,

R ₂ ^* = alkyl or aryl,

X = methylene, S, 0, N or P,

r = 4, 5, 6 or 8,

and

R ₃ = hydroxyl and R ₄ = H

or

R ₃ and ₄ = 0, where R ₃ and R are bridged together via methylene, ethylene or quinoxaline

and at least one carrier and / or additive. The designated aromatic systems can be any heteroatoms, e.g. B. 0, S, N, have.

The peculiarity of the solution according to the invention is based on the fact that the macromolecules used from the group of the calixarenes and resorcinarenes are easily accessible synthetically and can be modified universally. So you can open them up. Optimize various requirements regarding the substance classes of the toxins to be eliminated. It is particularly interesting in view of the fact that a large number of substances have hitherto been insufficiently eliminated, for example B. Paraquat and Diquat.

Any matrices known from the prior art can be used as the carrier. Prefers commercially available matrices based on polymers or inorganic oxides or matrices, for example silica gel, aluminum oxide, tungsten oxide or zeolites, are used. However, it is also possible for the filter material to contain or consist of biomatrixes such as cotton or cellulose.

Micelle formers or compounds from the group cyclodextrins are preferably contained as additives.

Due to the high hydroxyl functionality, cyclodextrins are significantly more polar and hydrophilic than calixarenes or resorcinarenes, which means that. certain applications a higher hydrophilicity of the filter material than can be realized.

The calixarenes or resorcinarenes of the general formulas I and II must be modified depending on the pollutant to be eliminated. The modification takes place from the point of view of optimizing the interaction between the filter material and the relevant target molecule, ie. H. the pollutant. At the same time, hydrophilic groups in the compounds are necessary to ensure water solubility.

Various modification options of the filter material are to be mentioned here only by way of example in order to implement special applications. This includes, on the one hand, modifying the filter material with sugars that can interact with bacteria, making them accessible for hemoperfusion, so that they can be filtered out of physiological fluids. By modifying the filter material with amino acids, an interaction with viruses can also be made possible, so that these can also be separated using hemoperfusion.

Another advantageous development of the filter material provides that the compound of the general formulas I and II are modified with antibodies. This enables the rapid elimination of antigens due to antigen-antibody interactions. With aggressive viruses in particular, there is the possibility of removing antigens from the organism until the immune system has stabilized.

Another particular advantage of the filter material is based on the fact that the compounds of the general formulas I and II have a high temperature resistance, which can be exploited in such a way that recyclable filter materials can be provided. Appropriate thermal treatment thermally decomposes the pollutants eliminated from the blood, while the compounds of the general formulas I and II contained in the filter material remain stable. Such thermal treatments are preferably carried out above 300 ° C. Compared to the filter materials known from the prior art, the inventive materials thus have a significantly higher thermal stability.

The filter material is preferably integrated into common filter devices. This includes, for example, cartridges, frits, disks or membranes.

The filter material according to the invention is preferably used for the hemoperfusion of physiological liquids. Blood, plasma or urine are only examples of physiological fluids. The subject according to the invention is intended to be explained in more detail with reference to the following figure and the examples, without restricting it to the exemplary embodiments mentioned.

1 shows a schematic structural model of the tetrasulfonic acid calix [4] arene-paraquat complex.

1 shows the incorporation of a paraquat molecule into a tetrasulfonic acid calix [4] arene system. The paraquat is bound to the filter material via different interactions. This includes a cation-OH interaction 1, a cation-π interaction 2, a CH-π interaction 3 and a π-π interaction 4. The complex formation constant is very large and can be in the range 10 ⁵ are up to 10 ^δ . This means that paraquat is stored irreversibly and can thus be permanently removed from the bloodstream, for example by hemoperfusion.

example 1

Synthesis of ^' 5, 11, 17, 23-tetrasulfonic acid calix [4] arenes

The representation follows the reaction scheme shown in Formula III:

Folgende Ausgangsverbindungen wurden eingesetzt: Calix[4] aren (7 mmo1' 3 g Schwefelsäure (98%) 30 ml Methanol, Ethylacetat.

The following starting compounds were used: Calix [4] arene (7 mm 3 -3 g sulfuric acid (98%) 30 ml methanol, ethyl acetate.

The sulfuric acid is added all at once to the calix [4] arene in a 100 ml three-necked flask with gas inlet and outlet devices. The apparatus is flushed with argon and the reaction mixture is stirred at 80 ° C. for about 4 hours. The course of the reaction is followed by taking a sample and checking the solubility in water. If the mixture is soluble in water without a residue, the reaction is stopped. The crude product is filtered off with a glass frit (4 A), dissolved in methanol (in order to remove remaining sulfuric acid) and precipitated with ethyl acetate. The white precipitate is dried in an oil pump vacuum-

The yield was 4.25 g (68% of lit.).

The following analytical characteristics could be determined:

IR (KBr, RT):

3372, 3224, 3125 (V _0H ); 1473, 1461 (δ _CH2 ) 1171 (Vso ₂ ).

^α H-NMR (400 MHz, D ₂ 0, δ = 4.65 ppm):

7.40 (s, 8H, Ar-H); 3.82 (br s, 8H, Ar-CH ₂ -Ar)

¹³ C-NMR (400 MHz, D ₂ 0, CH ₃ OH, δ = 50, 2 pp):

153, 29 (C-OH); 137, 24 (C-SO3H); 129, 83 (C _a --CH ₂ -); 128.03 (C _ar ) ^' ; 32.05 (C _ar -CH ₂ -C _ar ). MS (MALDI-TOF): m / e = 7 67, l [M + Na] ^' (calculated for C ₂ 8H ₂₄ O ₁₆ S ₄ : M = 744, 8 g / mol)

Example 2

Hemoperfusion to detoxify paraquat

In the investigation of the interactions of 5, 11, 17, 23-tetrasulfonic acid calix [4] arene with paraquat, commercial paraquat from the company Sig a was used. In addition to this most common trivial name, it is often referred to as a methyl iologist. The systematic name according to IUPAC is: 1, 1 '-dimethyl-4, 4' - bispyridinium dichloride (formula IV).

Paraquat is a very effective contact herbicide and as such has been widely used for many decades. The toxic effect on plants is based on the inhibition of photosynthesis by the formation of radical intermediates which prevent the NADP reduction. This hinders the transmission of energy. It is 'non-toxic to rapidly oxygen, reduced well waser- soluble compounds, whereby it is a good way to carry out the control of weeds in time selectively and relatively ^{umweitschonend'} in the field in the presence of light and. Paraquat has repeatedly resulted in numerous acute and chronic poisonings in humans when used in agriculture or when attempting suicide. Symptoms such as eye damage, kidney and liver damage, gastritis and lung diseases occur until death from suffocation. Therapeutic measures are limited because there is no specific antidote. Adsorption on activated carbon or carbon filters is weak, which is why stronger interactions with adsorbents are sought.

Claims

claims Filter material for toxins, bacteria, viruses and other physiological pollutants from the group of calixarenes of the general formula I

with R = H, alkyl, aryl, alkyloxy, aryloxy, amine, amide, carboxylic acids and sulfonic acids with 1 to 12 carbon atoms, amino acids, sugar or crown ether, Ri = H, alkyl, aryl, alkyloxy, aryloxy, amine, amide, carboxylic acids and sulfonic acids with 1 to 12 carbon atoms, sulfonamides, amino acids, sugar, crown ethers, cyclodextrins, purine bases or pyrimidine bases, X = methylene, S, 0, N or P and = 4, 5, 6 or 8 and / or the resorcinarenes of the general formula II

with R = H, alkyl, aryl, alkyloxy, aryloxy, amine, amide, carboxylic acids and sulfonic acids with 1 to 12 carbon atoms or amino acids, Rx = H, alkyl / aryl, alkyloxy, aryloxy, amine, amide, carboxylic acids and sulfonic acids 1 to 12 carbon atoms, sulfonamides, amino acids, sugar, crown ethers, cyclodex. trine, purine bases or pyrimidine bases, R ₂ = alkyl, aryl, X. = Methylene, S, O, N or P, r = 4, 5, 6 or 8, and - R ₃ = hydroxyl and R ₄ = H or R ₃ and R ₄ = 0, where R ₃ and R _{4 are} methylene, Ethylene or quinoxaline are bridged to one another and the aromatic systems can have heteroatoms, ^• and further carriers and / or additives. 2. Filter material according to claim 1, characterized in that the carrier material ^{* is} selected from the group polymer, inorganic oxides and matrices, for example silica gel, aluminum oxide, tungsten oxide or zeolites, or biological matrices, such as cotton or cellulose. 3. Filter material according to at least one of claims 1 or 2, characterized in that micelle or cyclodextrins are used as additives. 4. Filter material according to at least one of claims 1 to 3, characterized in that at least one of the radicals R and / or Ri is a sugar. 5. Filter material according to at least one of claims 1 to 3, characterized in that at least one of the radicals R and / or Ri is an amino acid. 6. Filter material according to at least one of claims 1 to 5, characterized in that the filter material is modified with antibodies. 7. Filter material according to at least one of claims 1 to 6, characterized in that the filter material can be regenerated by thermal treatment above 250 ° C. 8. Filter material according to at least one of claims 1 to 7, characterized in that the filter material is integrated in filter devices, for example cartridges, frits, disks or membranes. Use of the filter material according to at least one of claims 1 to 8 for the hemoperfusion of physiological liquids, such as blood, plasma or urine.