Polymeric compositions for capturing small molecules

Abstract

The present invention relates to methods for preparing polymeric compositions comprising phenylglyoxalaldehyde derivatives. The invention also relates to the polymeric compositions themselves and methods of using the polymeric compositions. The polymeric compositions are useful for carrying out subsequent reactions with small molecules, for example, to remove small molecules from solution.

Description

Detailed Description of the Invention

[0001] [Technical field to which the invention belongs] The present invention relates to methods for preparing polymeric compositions comprising phenylglyoxalaldehyde derivatives. The invention also relates to the polymeric compositions themselves and methods of using the polymeric compositions. The polymeric compositions are useful for carrying out subsequent reactions with small molecules, for example, to remove small molecules from solution.

[0002] [Background technology] Patients with end-stage kidney disease (ESKD) or severe acute renal failure undergo dialysis (either hemodialysis or HD or peritoneal dialysis or PD) to replace kidney function. Although lifesaving, traditional dialysis has significant drawbacks. The process is time-consuming and inefficient in removing waste molecules and excess water, significantly contributing to reduced quality of life, serious health problems, and a high mortality rate (15-20% per year). The cost of treatment is very high.

[0003] In dialysis, patient fluids are typically dialyzed against a dialysis fluid, which is then discarded. It is desirable to regenerate the dialysis fluid to allow for the use of smaller volumes. In efforts to miniaturize, patient fluids are dialyzed against a relatively small volume of dialysis fluid, called dialysate. During this process, waste solutes from the patient fluid migrate toward the dialysate by diffusion and / or convection, often through a membrane, such as a semipermeable membrane. If the waste solutes are later removed from the dialysate, it can be reused, which is called dialysate regeneration. Efficient regeneration of dialysate reduces the need for large volumes of dialysis fluid, making dialysis more practical to perform, reducing resource dependency, and reducing waste streams.

[0004] Miniaturized artificial kidney machines represent a major breakthrough in renal replacement therapy. Worldwide, an estimated 3.4 million dialysis patients are on dialysis (see www.fresenius.com / media_library / Fresenius_Annual_Report_2018.pdf). Currently, approximately 89% of dialysis patients use HD technology, either at centers (>96%) or at home (<4%) (see ERA-EDTA Registry Annual Report 2017). While center-based HD requires lengthy and frequent visits to the hospital (approximately three times per week, 4 hours per session), home HD offers greater flexibility and autonomy. However, home HD still requires bulky dialysis machines and large volumes of urea-trapping dialysis fluid (at least 20 L per treatment) or bulky fixed water purification systems. A user-friendly, lightweight HD device that does not rely on a fixed water urea trapping capacity or the urea trapping capacity of large volumes of dialysis fluid would increase patient mobility, allowing patients to remain active in their social lives and move freely.

[0005] The large fluctuations in water balance and uremic toxin levels between dialysis treatments with standard three times weekly HD can be attenuated by continuous or more frequent HD, which may improve patient outcomes (Nesrallah 2012; Ting 2003; Susantitaphong 2012). A more liberal diet is permitted. Significant cost savings are achieved through reduced need for dialysis personnel and related infrastructure, fewer medications, and fewer hospitalizations due to reduced complications.

[0006] PD is currently used by approximately 11% of dialysis patients (see Fresenius 2018 Annual Report). While PD offers the opportunity for continuous dialysis, in contrast to HD, this technique has several major drawbacks: low uremic toxin removal (Evenpoel 2006), time-consuming exchange procedures, and a high rate of technical failure due to a high incidence of peritoneal infection (peritonitis) and membrane failure (median technical survival time of 3.7 years) (Perl 2012). Low dialysis efficiency is primarily due to the rapid dissipation of the concentration gradient between dwelling plasma and peritoneal dialysate, thereby limiting solute transport (Gotch 2001). Miniaturized PD devices that continuously regenerate dialysate and thereby maintain the plasma-dialysate concentration gradient significantly increase PD efficiency. This allows for a reduction in the number of time-consuming exchanges while still improving waste solute removal. Additionally, reducing the number of connections will reduce the risk of contamination and lower the peritonitis rate (Piraino 2010; De Fijter, 1991). Continuous glucose infusion with mini-PD devices reduces functional deterioration of the peritoneal membrane by avoiding the extremely toxic glucose concentrations applied in conventional PD (Gotch 2001). By preventing the two major causes of technical failure in conventional PD (recurrent infection and functional loss of the peritoneal membrane), mini-artificial kidneys significantly prolong technical survival.

[0007] Therefore, a user-friendly wearable or portable dialysis device that provides dialysis outside of a hospital would represent a major breakthrough for dialysis patients, significantly improving their quality of life. The device would allow for continuous or more frequent dialysis, which would improve the removal of waste solutes and excess fluid, thus improving patient health. A miniaturized design independent of a fixed hydrourea trapping capacity would provide patients with freedom and autonomy.

[0008] In recent years, miniaturized prototype dialysis devices have been constructed that adequately remove several organic waste solutes and waste ions. However, to date, no suitable strategy for urea removal exists that allows for miniaturization to truly wearable proportions, which is one of the major obstacles to the successful realization of miniaturized artificial kidney devices. Urea is the waste solute with the highest daily production (the major waste product of nitrogen metabolism) and exerts toxic effects at high plasma concentrations. However, urea is difficult to capture and has low reactivity.

[0009] DE2305186A1 / US3933753A discloses a polymeric composition in which a polystyrene-like scaffold is post-modified to contain glyoxal moieties, achieving a conversion of 0.72 glyoxal moieties per monomer in the composition. This composition was shown to capture up to 1 mmol / g of urea and to be more suitable for the removal of clinically irrelevant aniline. This material was further developed as described in US4012317, but the urea capture level remained at a similar level. WO2004078797A1 discloses a similar ketoaldehyde material that reaches a urea capture capacity of 1.5 mmol / g.

[0010] EP121275A1 / US4897200A discloses a ninhydrin-type adsorbent formed from a polymerized styrene composition in a six-step synthetic sequence. At clinically relevant urea concentrations, a urea retention capacity of 1.2 mmol / g dry adsorbent was demonstrated in 8 hours. However, for effective miniaturization, higher urea retention capacities are required. WO2019110557 discloses a ninhydrin-type adsorbent with a urea retention capacity of greater than 2 mmol / g.

[0011] US4178241A discloses polystyrene-type adsorbents with para-thio, para-nitro, or para-amino moieties. For the thio moieties, urea uptake was again shown to be about 1.5 mmol / g. Other functional groups performed less well. On the other hand, creatinine was shown to capture well over 90% of the daily production of a normal adult for each functional group.

[0012] WO2017116515A1 discloses the use of charged membranes to improve urea separation from dialysate and suggests the use of electro-oxidation of the separated urea. The drawback of this method is that reactive oxygen species are generated as a by-product.

[0013] WO2011102807A1 discloses epoxide-coated substrates. Epoxides can be used to recover solutes from solution. They are also used to immobilize urease enzymes, which aid in the treatment of urea. Disadvantages of urease enzymes include their sensitivity to environmental factors, their expensive and laborious preparation, and the fact that ammonium is produced by their reaction, which then requires removal using cation exchangers containing toxic substances such as zirconium phosphate. WO2016126596 uses a very different substrate, namely reduced graphene oxide. High urea capture capacity was demonstrated, but the captured urea represented less than 15% of the initial urea concentration.

[0014] To enable the development of improved artificial kidney devices, there is a continuing need for easily prepared sorbents that capture greater amounts of urea without the risk of leaching components into the dialysate and without producing harmful by-products.

[0015] [Summary of the Invention] The present invention relates to a method for preparing a phenylglyoxalaldehyde (PGA) type adsorbent, comprising the steps of: i) providing a monomer of general formula (I); [ka] where Q is H or -CH3; 1 , h 2 and h 3 are each independently H, halogen, -OH, -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon) or -N(C 1-6 hydrocarbons)2; or h1 and h 2 together to form =O; or h 1 and h 2 Let's get together -o 1 -(C 1-4 hydrocarbon)-o 2 -, where o 1 and o 2 are independently O, S, NH, or N(C 1-4and X is O, S, or NH; then ii) polymerizing the provided monomer to obtain a polymer; and iii) converting the polymerized monomer of general formula (I) that is not a PGA-type monomer into a PGA-type monomer. The monomer of general formula (I) is preferably 1-(4-ethenylphenyl)ethan-1-one, 1-(3-ethenylphenyl)ethan-1-one, 1-(4-isopropenylphenyl)ethan-1-one, 1-(3-isopropenylphenyl)ethan-1-one, 2-bromo-1-(4-ethenylphenyl)ethan-1-one, or 2-bromo-1-(3-ethenylphenyl)ethan-1-one. , 2-bromo-1-(4-isopropenylphenyl)ethan-1-one, 2-bromo-1-(3-isopropenylphenyl)ethan-1-one, 2-chloro-1-(4-ethenylphenyl)ethan-1-one, 2-chloro-1-(3-ethenylphenyl)ethan-1-one, 2-chloro-1-(4-isopropenylphenyl)ethan-1-one, 2-chloro-1-(3-isopropenylphenyl)ethan-1-one 2,2-dihydroxy-1-(4-ethenylphenyl)ethan-1-one, 1-(4-ethenylphenyl)ethan-1,2-dione, 1-(3-ethenylphenyl)ethan-1,2-dione, 1-(4-isopropenylphenyl)ethan-1,2-dione, 1-(3-isopropenylphenyl)ethan-1,2-dione, 2,2-dihydroxy-1-(4-ethenylphenyl)ethan-1-one, 2,2-dihydroxy-1-(3-ethenylphenyl)ethan-1-one, 2,2-dihydroxy-1-(4-ethenylphenyl)ethan-1-one, 2,2-dihydroxy-1-(3-ethenylphenyl)ethan-1-one, 2,2-dihydroxy-1-(4-isopropenylphenyl)ethan-1-one, and 2,2-dihydroxy-1-(3-isopropenylphenyl)ethan-1-one. Preferably, a comonomer is provided together with the monomer of general formula (I). Preferably, the polymer is crosslinked after or during polymerization. The conversion in step iii) preferably comprises a step selected from a) halogenation, preferably halogenation using hydrohalic acid; or b) oxidation, preferably oxidation using dimethyl sulfoxide (DMSO).Preferably, in step iii), more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 95%, or 100% of the monomers of general formula (I) are converted to PGA-type monomers. Preferably, Q is H; and / or h. 1 and h 2 are each independently H, halogen, -OH, and -O(C 1-4 or together form =O; preferably, h 1 and h 2 are both H, or both -OH, or together form =O; and / or h 3 is H; and / or X is O.

[0016] The present invention also provides a PGA-type adsorbent obtainable by this method, having a urea capture capacity of greater than 1.60 mmol of urea per gram of adsorbent. Preferably, at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the polymerized monomers are PGA-type monomers. The present invention also provides a composition comprising a PGA-type adsorbent and a pharmaceutically acceptable excipient. The adsorbent and composition may be used as a pharmaceutical, preferably for the treatment of diseases or conditions associated with urea accumulation.

[0017] The present invention also provides a method for removing nucleophilic waste solutes from a fluid, comprising the steps of: i) providing a fluid containing the nucleophilic waste solutes; and iia) contacting the fluid with a PGA-type sorbent of the present invention or a composition as defined above; or iib) contacting the fluid with a dialysis fluid through a membrane, wherein the dialysis fluid is in contact with a PGA-type sorbent as defined in claim 9 or 10 or a composition as defined in claim 11; and iii) optionally recovering the fluid.

[0018] The present invention further provides a cartridge for use in a dialysis device, comprising the PGA-type sorbent defined above or the composition defined above. Also provided is a dialysis device comprising the PGA-type sorbent defined above, the composition defined above, or the cartridge defined above.

[0019] [Description of the embodiment] The present invention provides an improved phenylglyoxalaldehyde (PGA)-type adsorbent with increased capacity for nucleophilic waste solutes. Adsorbents are materials that capture target substances; in this case, the adsorbent captures nucleophiles such as urea. The inventors have invented a polymeric dicarbonyl compound with high urea-trapping capacity and fast binding kinetics, making this material suitable for use as an adsorbent. The improved adsorbent allows for the miniaturization of adsorbent cartridges, thus representing an important step toward miniaturized artificial kidney devices.

[0020] The sorbent can be advantageously used in (hemo)dialysis for the removal of urea, where blood is conducted through a membrane, such as a semipermeable membrane, that separates the blood from a small volume of dialysis fluid. It can also be used in peritoneal dialysis to remove urea from the peritoneal dialysate or for the regeneration of the peritoneal dialysate, for example, in continuous-flow (or tidal-flow) peritoneal dialysis with (continuous) regeneration of the dialysate. The sorbent then captures nucleophilic waste solutes, such as urea, so that diffusion of these solutes across the semipermeable membrane continues and is not slowed down by saturation.

[0021] Because effective urea removal is important for successful dialysate regeneration, an object of the present invention is to provide a sorbent with a high retention capacity suitable for application in mini-artificial kidney devices, for example, by fabricating a cartridge loaded with the sorbent. The sorbent of the present invention has a higher retention capacity than known PGA-type sorbents. As demonstrated in Example 4, the sorbent of the present invention can retain at least 1.8 mmol of urea per gram of sorbent, and even greater amounts. A sorbent prepared according to known methods (i.e., that of WO2004078797A1) retains approximately 1.4 mmol / gram (WO2004078797 reports 1.5 mmol / gram). Another object of the present invention is to provide a cost-effective method for producing such improved sorbents, preferably by using low-cost reactants, thereby enabling reduced medical costs. Another object of the present invention is to provide a method for removing nucleophilic solutes, such as urea or biological agents, from solutions using such sorbents, compositions, or cartridges.

[0022] The present inventors have surprisingly found that improved PGA-type adsorbents can be formed by polymerizing precursor monomers and subsequently converting these polymerized precursor monomers to PGA monomers. In the state-of-the-art, PGA is formed based on styrene. The present invention uses monomers that are more structurally similar to PGA, such as vinylphenylethan-1-one (VPE, also known as 1-(4-ethenylphenyl)ethan-1-one and p-acylstyrene), vinylphenylethane-1,2-dione, or their (hemi)acetals. Surprisingly, the adsorbents formed by the present method have improved urea capture capabilities, thus enabling improved methods for their use. A key improvement lies in the increased adsorption capacity of the adsorbents produced.

[0023] The present inventors have surprisingly found that improved PGA-type adsorbents can be obtained by using precursor monomers that more closely resemble PGA than styrene. As part of the present invention, a family of suitable precursor monomers has been discovered. Thus, in a first aspect, the present invention provides a method for producing a PGA-type adsorbent, comprising: i) providing a monomer of general formula (I); [ka] where Q is H or -CH3; h 1 , h 2 and h 3 are each independently H, halogen, -OH, -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon) or -N(C 1-6 hydrocarbons)2; or h 1 and h 2 together to form =O; or h 1 and h 2 Let's get together -o 1 -(C 1-4 hydrocarbon)-o 2 -, where o 1 and o 2 are independently O, S, NH, or N(C 1-4 hydrocarbons); and X is O, S or NH; ii) polymerizing the provided monomers to obtain a polymer; and iii) converting a polymerizable monomer of general formula (I) that is not a PGA-type monomer into a PGA-type monomer; The present invention provides a method comprising:

[0024] Hereinafter, such a method is referred to as the "production method of the present invention." The PGA type adsorbent obtained by the production method of the present invention is hereinafter referred to as the PGA type adsorbent of the present invention.

[0025] PGA type adsorbent Adsorbents are materials designed to bind, absorb, or adsorb other substances. Adsorbents for binding nucleophilic waste solutes are known in the art and have already been described for use in hemodialysis devices (EP 121275 A1). In the context of the present invention, an adsorbent is a polymeric composition that can be a dissolved or partially dissolved solid, suspended solid, colloidal suspension, aggregate, resin, or polymer. It can bind nucleophilic waste solutes, which can then be recovered from the mixture. Binding can be covalent or non-covalent, such as by electrostatic or hydrophobic interactions. Preferably, binding of nucleophilic waste solutes by adsorbents, particularly the PGA-type adsorbents of the present invention, is covalent.

[0026] PGA-type adsorbents are adsorbents containing a PGA-type moiety. PGA is phenylglyoxalaldehyde or 1-phenylethane-1,2-dione or phenyloxalaldehyde. The PGA-type moiety is preferably a short aliphatic structure, preferably having only two carbon atoms, attached to an aromatic ring or aromatic ring system, preferably a phenyl or substituted phenyl moiety (e.g., substituted on the polymer backbone), characterized by two vicinal carbonyl groups (or their hydrates). Glyoxalaldehyde and its hydrates are easily converted into each other, and it should be understood that a reference to PGA generally also includes a reference to its hydrate. Generally, glyoxalaldehyde hydrates are produced in non-dry environments, and glyoxalaldehyde can be dehydrated by heating. In aqueous environments, both species generally coexist in equilibrium. Preferred examples of PGA-type moieties are selected from the group consisting of ortho-oxalaldehyde phenyl, meta-oxalaldehyde phenyl, and para-oxalaldehyde phenyl, and hydrates thereof, wherein the phenyl ring may be further substituted as needed. In some embodiments, the PGA-type moiety is selected from the group consisting of ortho-oxalaldehyde phenyl and meta-oxalaldehyde phenyl. In other embodiments, the PGA-type moiety is selected from the group consisting of ortho-oxalaldehyde phenyl and para-oxalaldehyde phenyl. In some embodiments, the PGA-type moiety is selected from the group consisting of meta-oxalaldehyde phenyl and para-oxalaldehyde phenyl. Most preferably, the PGA-type moiety is para.

[0027] The PGA-type adsorbents of the present invention are suitable for capturing nucleophilic waste solutes and do so at high capacities. These solutes react with the PGA-like moieties contained in the adsorbent. Thus, in a second aspect, the present invention provides PGA-type adsorbents of the present invention obtainable by the manufacturing method of the present invention, wherein the adsorbent has a urea capture capacity of greater than 1.60 mmol, preferably greater than 1.80 mmol, and more preferably greater than 2.00 mmol of urea per gram of adsorbent.

[0028] Urea is a small, highly polar molecule that is highly soluble in water (400 mg / ml) and in protic organic solvents such as methanol, ethanol, and glycerol due to its polarity and ability to participate in hydrogen bond formation. Although urea's role in biochemistry is essential and it is an industrially important molecule, such as a nitrogen source for fertilizers and a polymer precursor, it is often important to remove urea from fluid solutions.

[0029] The manufacturing method of the present invention results in PGA-type adsorbents with surprisingly high capacities for capturing nucleophilic waste solutes, such as urea. Urea typically reacts with dehydrated PGA-type adsorbents (see FIG. 1). Without wishing to be bound by theory, it is speculated that more efficient conversion of precursor monomers to PGA-type monomers contributes to this increased binding capacity. In a preferred embodiment of this aspect, the present invention provides PGA-type adsorbents of the present invention, wherein the adsorbents have a urea capture capacity of greater than 1.51 mmol of urea per gram of adsorbent. In a more preferred embodiment of this aspect, the present invention provides PGA-type adsorbents of the present invention, wherein the adsorbents have a urea capture capacity of greater than 1.60 mmol of urea per gram of adsorbent. In a further preferred embodiment of this aspect, the invention provides a PGA-type adsorbent of the invention, wherein the adsorbent has a PGA content of 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2029, 2030, 2 4, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3 , 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or more preferably, the sorbent has a urea uptake capacity of greater than 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.6, 2.7, 2.8, 2 ... More preferably, the sorbent has a urea uptake capacity of greater than 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, or 4.9 mmol of urea per gram of sorbent, and even more preferably, the sorbent has a urea uptake capacity of greater than 1.80, 1.90, 2.00, 2.10, 2.20, 2.25, 2.30, 2.35, 2.40, 2.50, 2.60, 2.70, 2.80, 2.90, 3.10, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.30, 3.31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.40, 3.41, 3.42, 3.43, 3.44, 3.45, 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 3.54, 3.55, 3.56,or 4.9 mmol of urea, and even more preferably the sorbent has a urea capture capacity of greater than 2.00, even more preferably greater than 2.20, and even more preferably greater than 4.5, 2.50, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, or 4.9 mmol of urea, has a urea capture capacity of greater than 2.40, 2.45, 2.50, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, or 4.9 mmol urea per gram of sorbent, e.g., greater than 2.5 or 2.6 mmol urea per gram of sorbent. Alternatively, the adsorbents were 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.10, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.30, 3.31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.40, 3.41, 3.42, 3.43, 3.44, 3.45, 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 3.54, 3.55, 3.56, 3.57, 3 , 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5 times higher urea uptake capacity, where the reference sorbent is preferably the sorbent described in Experiment 9 of WO 2004 / 078797, which is reported in Experiment 16 of that publication to have the highest urea uptake of that publication (i.e., 90 mg urea per gram of sorbent). In this embodiment, the present invention also provides PGA-type sorbents of the present invention, which have a urea uptake capacity of greater than 1.8 mmol urea per gram of sorbent, preferably greater than 2 mmol urea per gram of sorbent, or more preferably greater than 2.1 mmol urea per gram of sorbent, which is particularly suitable for miniaturization of artificial kidney or (hemo)dialysis machines.

[0030] In this context, the urea trapping capacity is preferably the maximum urea trapping capacity, which can be determined after incubating the adsorbent with excess urea in a solution (such as about 30 mM) at about 70°C for about 24 hours. The amount of trapped urea can be determined by directly analyzing the amount of urea trapped by the adsorbent, by analyzing the difference in the amount of urea present in the solution before and after exposure to the adsorbent, or by regenerating the adsorbent by dissociating the trapped urea and subsequently determining the amount of urea released. The urea concentration can be determined by any method known in the art, such as elemental analysis, as described in WO2004078797A1. Alternatively, the amount of ammonia released by the urease enzyme can be used to indirectly quantify the urea concentration. Alternatively, a PAB reagent solution containing approximately 4% (w:v) 4-(dimethylamino)benzaldehyde and 4% (v:v) sulfuric acid in absolute ethanol can be used for UV-VIS analysis (422 nm) of urea reaction adducts using a pre-prepared calibration curve, as described in WO2016126596A1. Various kits, including instructions for use, for determining urea concentration are commercially available.

[0031] In the PGA-type adsorbent of the present invention, preferably at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the polymerized monomers are PGA-type monomers. Preferred PGA-type adsorbents of the present invention are those in which at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, preferably at least 50%, more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90%, of the polymerized monomers are PGA-type monomers. In further preferred PGA-type adsorbents of the present invention, at least 50% and at most 90% of the polymerized monomers are PGA-type monomers. In more preferred embodiments, 55% to 90% of the polymerized monomers are PGA-type monomers. In even more preferred embodiments, 70% to 90% of the polymerized monomers are PGA-type monomers. In the most preferred embodiments, 70% to 80% of the polymerized monomers are PGA-type monomers. The amount of PGA-type monomer is preferably reported as the amount of monomer of general formula (I) used during polymerization. Alternatively, the amount of PGA-type monomer can be estimated using conventional techniques known in the art (e.g., solid-state NMR or IR spectroscopy), as illustrated in the Examples.

[0032] In certain embodiments of this aspect, the present invention provides PGA-type adsorbents of the present invention, in which 100% of the polymerized monomers are PGA-type monomers. Such polymers are particularly suitable for use outside of resins, such as in compositions for oral administration or pharmaceutical compositions.

[0033] In a preferred embodiment, the PGA type adsorbent of the present invention can be obtained by the production method of the present invention, in which the polymerization is suspension polymerization. In a preferred embodiment, the PGA type adsorbent of the present invention can be obtained by the production method of the present invention, in which a crosslinking monomer is used in an amount of up to 50%, preferably up to 35%, more preferably up to 25%, even more preferably up to 20%, and most preferably up to 10%.

[0034] The PGA type adsorbent of the present invention can be obtained by the manufacturing method of the present invention and can therefore contain the comonomers and crosslinkers described for the method of the present invention.

[0035] Manufacturing method As mentioned above, the first aspect of the present invention is i) providing a monomer of general formula (I); [ka] where Q is H or -CH3; h 1 , h 2 and h 3 are each independently H, halogen, -OH, -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon) or -N(C 1-6 hydrocarbons)2; or h 1 and h 2 together to form =O; or h 1 and h 2 Let's get together -o 1 -(C 1-4 hydrocarbon)-o 2 -, where o 1 and o 2 are independently O, S, NH, or N(C 1-4 hydrocarbons); and X is O, S or NH; ii) polymerizing the provided monomers to obtain a polymer; and iii) converting a polymerizable monomer of general formula (I) that is not a PGA-type monomer into a PGA-type monomer; The present invention provides a method comprising:

[0036] Step i) - Providing the Monomer In step i), a monomer is provided. The monomer can be synthesized using conventional techniques, as illustrated in the Examples, or can be procured from a commercial urea scavenging source. The monomer may already have a PGA-type moiety or can be converted to a monomer having a PGA-type moiety through a subsequent reaction step. Such a monomer requiring conversion is referred to herein as a precursor monomer. Preferably, the precursor monomer can be converted to a monomer containing a PGA-type moiety in one, two, three, or four reaction steps, more preferably in one, two, or three reaction steps, even more preferably in one or two reaction steps, and most preferably in one reaction step. Since the monomer of general formula (I) encompasses both a monomer having a PGA-type moiety and a precursor monomer, it is preferred that the monomer of general formula (I) can be converted to a monomer containing a PGA-type moiety in zero, one, two, three, or four reaction steps, more preferably in zero, one, two, or three reaction steps, even more preferably in zero, one, or two reaction steps, and most preferably in zero or one reaction step. The reactions and reaction steps are defined later in the section detailing step iii) herein.

[0037] The monomer features a polymerization handle that is a vinyl (when Q is -H) or methylvinyl (when Q is -CH3) moiety. Vinyl is also called ethenyl, and methylvinyl is also called isopropenyl, and should be interpreted as a propenyl bonded at its central carbon atom. This moiety containing Q is linked to the ring that is the aromatic part of the PGA-type moiety after the conversion in step iii). It can be in the ortho, meta, or para position of the PGA-type moiety. Preferred monomers are of general formula (Ip) or (Im), of which (Ip) is more preferred. When a less hydrophobic or more flexible PGA-type adsorbent according to the present invention is desired, it is preferable to use a monomer of general formula (I) in which Q is -H, since this leads to a more flexible and more aliphatically bulky backbone of the resulting polymer.

[0038] The monomer is further divided into -C(=X)-C(h 1 )(h 2 )(h 3 ) moiety, which allows the monomer to be easily and efficiently converted to a PGA-type moiety in step iii), or already forms a PGA-type moiety. Those skilled in the art will understand the valence of atoms and will understand that the monomers of general formula (I) conform to such valence.

[0039] X is O, S, or NH; wherein X forms a ketone, thione (thioketone), or imine (ketamine). In a preferred embodiment, X is S or NH. In another preferred embodiment, X is S or O. In another preferred embodiment, X is O or NH. In another preferred embodiment, X is S. In another preferred embodiment, X is NH. Most preferably, X is O.

[0040] h 1 , h 2 and h 3 form the remainder of the PGA type monomer or precursor monomer of general formula (I). They are each independently H, halogen, —OH, —O(C 1-6 hydrocarbon), -S(C1-6 hydrocarbon), NH(C 1-6 hydrocarbon), or N(C 1-6 hydrocarbons)2; 1 and h 2 together form =O;h 1 and h 2 Let's get together -o 1 -(C 1-4 hydrocarbon)-o 2 -, wherein o 1 and o 2 are independently O, S, NH, or N(C 1-4 hydrocarbons) which form PGA-type monomers (e.g., 1 and h 2 When together form =O, and h 3 is H and X is O) or form a precursor which can be readily converted to a PGA type monomer as described later in this specification.

[0041] h 1 , h 2 and h 3 When each of the groups form an H, they form a -CH3 moiety together with the carbon atom to which they are attached. This can be advantageous when the carbon atom is oxidized to form a PGA-type moiety. In a preferred embodiment, h 1 , h 2 , and h 3 each form the same type of moiety, preferably H or halogen, more preferably H.

[0042] h 1 and h 2 are both -OH, and h 3 When is H, the result is a PGA-type moiety that is a hydrate, also known as the geminal diol of glyoxalaldehyde. Such a group can be advantageous when the hydrate is converted to a PGA-type moiety by dehydration. In a preferred embodiment, h 1 and h 2are the same moiety or together form a single moiety. In another preferred embodiment, h 1 and h 2 together form a single part. For any of these, h 3 is preferably H or halogen, more preferably H. For any of these, h 1 and h 2 When not taken together to form a single moiety, h is preferably -OH or halogen, more preferably -OH. 1 and h 2 do not together form a single part.

[0043] h 1 , h 2 and h 3 Either -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon) or -N(C 1-6 When forming a -O(C hydrocarbon), the resulting moiety can be hydrolyzed to give -OH or, in the case of a productive moiety, =O. 1-6 -S(C) may contribute to the formation of acetals or hemiacetals. 1-6 hydrocarbons) can contribute to the formation of thioketals or hemithioketals, -NH(C 1-6 hydrocarbons) and -N(C 1-6 Both hydrocarbons can contribute to the formation of aminals or hemiaminals. 1 , h 2 and h 3 At least one of the following is -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon) or -N(C 1-6 When forming hydrocarbon)2, h 1 , h 2 and h 3 At least one other of the 1-6hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon), -N(C 1-6 It is preferred to form a hydrocarbon)2 or -OH, preferably -OH. In a preferred embodiment, h 1 , h 2 , and h 3 At least one of the following is -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon), or -N(C 1-6 When forming hydrocarbon)2, h 1 , h 2 , and h 3 The second of these is also -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon), or -N(C 1-6 Forms hydrocarbon)2.

[0044] As used herein, C 1-6 A hydrocarbon is a hydrocarbon having 1 to 6 carbon atoms. As is clear from the context, it can be a single radical, such as a methyl moiety, or a biradical forming a bridge between two moieties, as shown. It can be straight or branched, saturated or unsaturated, and optionally interrupted or substituted with heteroatoms (e.g., O, N, or S) or substituted by methyl or phenyl. C 1-6 A preferred embodiment of the hydrocarbon is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C6 aryl, and C 5-6 Heteroaryl. C 1-6 A more preferred embodiment of the hydrocarbon is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6In a preferred embodiment, C 1-6 indicates the number of carbon atoms in the longest internal chain of the hydrocarbon. In another preferred embodiment, it indicates the total number of carbon atoms in the hydrocarbon. In a preferred embodiment, C 1-6 Hydrocarbons are C 1-4 , more preferably C 1-3 , more preferably C 1-2 Those skilled in the art will be able to select the appropriate hydrocarbon. 1-6 Examples of hydrocarbons are methyl, ethyl, n-propyl, isopropyl, butyl (including n-butyl, sec-butyl, tert-butyl, and isobutyl), pentyl, cyclopentyl, imidazolyl, phenyl, furyl, tetrahydrofuryl, and cyclohexyl. 1-6 When two examples of hydrocarbons are bonded to the same atom, they can combine with said atom to form a ring structure, preferably a 3- to 8-membered ring structure. 1-4 Examples of hydrocarbons are preferably C 1-3 or C 1-2 , or preferably C 2-3 , most preferably C2. The hydrocarbon linking the two moieties (i.e., it is not terminal) is preferably at least a C2 hydrocarbon, such as -CH2CH2-. 1 -(C 1-4 hydrocarbon)-o 2 Regarding -, a preferred embodiment is -o 1 -C(phenyl)-o 2 -It is.

[0045] The above is h 1 and h 2 Together -o 1 -(C 1-4 hydrocarbon)-o 2 -(in the formula, o 1 and o 2 are independently O, S, NH, or N(C 1-4 This is reflected in the fact that it is also possible to form diol protecting groups for the precursors of PGA-type monomers. For example,1 and o 2 If both are O and the bonded hydrocarbon is -CH2CH2-, h 1 and h 2 effectively forms an acetal-protected PGA-type monomer. 1 and o 2 are the same. In a preferred embodiment, 1 and o 2 is selected from O, S, or NH. In a more preferred embodiment, o 1 and o 2 is selected from O or S, most preferably o 1 and o 2 is O. 1 and o 2 C concatenates 1-4 The hydrocarbon is preferably C 1-3 N(C 1-4 When present in a hydrocarbon), it is preferably methyl, ethyl or (iso)propyl, more preferably methyl or ethyl, most preferably methyl.

[0046] In a preferred embodiment, h 1 and h 2 together, -o 1 -(C 1-4 hydrocarbon)-o 2 -, where o 1 and o 2 are independently O, S, NH, or N(C 1-4 Hydrocarbon). More preferably, h 1 and h 2 Let's get together -o 1 -(C 1-4 hydrocarbon)-o 2 -, where o 1 and o 2 are independently O, S or NH. Even more preferably, h 1 and h 2 together -O-(C 1-4Even more preferably, h 1 and h 2 Let's get together -o 1 -(C 2-4 hydrocarbon)-o 2 -, where o 1 and o 2 are independently O, S or NH. Even more preferably, h 1 and h 2 Let's get together -0-(C 2-3 Forms hydrocarbon)-O-.

[0047] h 1 , h 2 and h 3 If none of the above together form a single moiety as described above, the following is a preferred embodiment: 1 , h 2 and h 3 are each independently a halogen, -OH, -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon) or -N(C 1-6 hydrocarbons); or H, -OH, -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon), or -N(C 1-6 hydrocarbons); or H, halogen, -O(C 1-6 hydrocarbon), -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon) or -N(C 1-6 hydrocarbons); or H, halogen, -OH, -S(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon), or -N(C 1-6 hydrocarbons); or H, halogen, -OH, -O(C 1-6 hydrocarbon), -NH(C 1-6 hydrocarbon), or -N(C 1-6 hydrocarbons); or H, halogen, -OH, -O(C 1-6hydrocarbon), or -S(C 1-6 or from H, halogen, or -OH; or from H, halogen, -OH, or -O(C 1-6 or from H or halogen; or from H or —OH; or from —OH or halogen.

[0048] Halogen in the monomer of general formula (I) is preferably fluorine, chlorine, bromine or iodine, more preferably chlorine, bromine or iodine, even more preferably bromine or iodine, most preferably bromine.

[0049] In the preferred monomers of general formula (I) Q is H, and / or h 1 and h 2 are each independently H, halogen, -OH, and -O(C 1-4 or together form =O; preferably, h 1 and h 2 are both H, or both -OH, or together form =O; and / or h 3 is H; and / or X is O.

[0050] In other preferred monomers of general formula (I), Q is H; and h 1 and h 2 are each independently H, halogen, -OH, and -O(C 1-4 or together form =O; preferably, h 1 and h 2 are both H, or both -OH, or together form =O;h 3 is H; X is O. In other preferred monomers of general formula (I), Q is H; h 1 and h 2are both H, or both -OH, or together form =O; and / or h 3 is H; and / or X is O.

[0051] The monomer of general formula (I) can be of general formula (Io), general formula (Ih), general formula (I-Ac), general formula (I-PGA), or general formula (I-PGAH) as shown below. [Table A]

[0052] In a preferred embodiment, the monomer of general formula (I) is of general formula (Io), wherein Q is -H or -CH3, and h 1 and h 2 and h 3 is as defined above. Monomers of general formula (Io) are referred to herein as ketone-type monomers.

[0053] In a preferred embodiment, the monomer of general formula (I) is of general formula (Ih), where Q is -H or -CH3, and h 1 and h 2 is as defined above but is not H, and is preferably h 1 and h 2 are taken together to form a single moiety, or are both the same but are not H, more preferably are taken together to form a single moiety, or are both halogen or -OH, most preferably are both -OH. Monomers of general formula (Ih) are referred to herein as ketal-type monomers because these monomers are particularly useful as acetals of PGA-type moieties.

[0054] In a preferred embodiment, the monomers of general formula (I) are monomers of general formula (I-Ac) where Q is -H or -CH. Monomers of general formula (I-Ac) are referred to herein as VPE-type monomers because these monomers are particularly useful as vinylphenylethan-1-one analogs.

[0055] In a preferred embodiment, the monomer of general formula (I) is a monomer of general formula (I-PGA) or (I-PGAH), preferably (I-PGA), where Q is -H or -CH. These monomers are referred to herein as PGA-type monomers. In another preferred embodiment, the monomer is of general formula (II-p) or (II-m), of which (II-p) is preferred.

[0056] Preferred monomers of general formula (I) are shown below, with the names given below the structures: [Table B]

[0057] In a preferred embodiment of this aspect, the monomer of general formula (I) is 1-(4-ethenylphenyl)ethan-1-one, 1-(3-ethenylphenyl)ethan-1-one, 1-(4-isopropenylphenyl)ethan-1-one, 1-(3-isopropenylphenyl)ethan-1-one, 2-bromo-1-(4-ethenylphenyl)ethan-1-one, 2-bromo-1-(3-ethenylphenyl)ethan-1-one, 2-bromo-1-(4-isopropenylphenyl)ethan-1-one, 2-bromo-1-(3-isopropenylphenyl)ethan-1-one, 2-chloro-1-(4-ethenylphenyl)ethan-1-one, 2-chloro-1-(3-ethenylphenyl)ethan-1-one, 2-chloro-1-(4-isopropenylphenyl)ethan-1-one, 2-chloro-1-(3-isopropenylphenyl)ethan-1-one, 1-(4-ethenylphenyl)ethane-1,2-dione, 1-(3-ethenylphenyl)ethane-1,2-dione, 1-(4-isopropenylphenyl)ethane-1,2-dione, 1-(3-isopropenylphenyl)ethane-1,2-dione, 2,2-Dihydroxy-1-(4-ethenylphenyl)ethan-1-one, 2,2-dihydroxy-1-(3-ethenylphenyl)ethan-1-one, 2,2-dihydroxy-1-(4-isopropenylphenyl)ethan-1-one and 2,2-dihydroxy-1-(3-isopropenylphenyl)ethan-1-one The polymer contains at least one monomer selected from:

[0058] In a further preferred embodiment, the present invention provides an inventive process, wherein at least one monomer of general formula (I) comprises at least 1-(4-ethenylphenyl)ethan-1-one, 1-(3-ethenylphenyl)ethan-1-one, 2-bromo-1-(4-ethenylphenyl)ethan-1-one, or 2-bromo-1-(3-ethenylphenyl)ethan-1-one, or isopropenyl analogues thereof.

[0059] In a more preferred embodiment, the present invention provides a process according to the invention, wherein the monomer of general formula (I) is 1-(4-ethenylphenyl)ethan-1-one or 2-bromo-1-(4-ethenylphenyl)ethan-1-one, or isopropenyl analogues thereof, optionally selected from these.

[0060] In a further preferred embodiment, the present invention provides a process according to the invention, wherein the monomer of general formula (I) is 1-(4-ethenylphenyl)ethan-1-one or its isopropenyl analogue.

[0061] It is specifically envisaged that providing a monomer of general formula (I) may require providing a mixture of monomers of general formula (I). Preferably, the compounds present in such a mixture differ only in their position of attachment of the Q-containing moiety. Thus: Where either 1-(4-ethenylphenyl)ethan-1-one or 1-(3-ethenylphenyl)ethan-1-one is provided, preferably mixtures of each of these monomers may also be provided; When providing either 1-(4-isopropenylphenyl)ethan-1-one or 1-(3-isopropenylphenyl)ethan-1-one, it is also possible to provide preferably a mixture of each of these monomers; Similarly, 2-bromo-1-(4-ethenylphenyl)ethan-1-one and 2-bromo-1-(3-ethenylphenyl)ethan-1-one; 2-bromo-1-(4-isopropenylphenyl)ethan-1-one and 2-bromo-1-(3-isopropenylphenyl)ethan-1-one; 2-chloro-1-(4-ethenylphenyl)ethan-1-one and 2-chloro-1-(3-ethenylphenyl)ethan-1-one; 2-chloro-1-(4-isopropenylphenyl)ethan-1-one and 2-chloro-1-(3-isopropenylphenyl)ethan-1-one; 1-(4-ethenylphenyl)ethan-1-one The same is true for the pairs 1-(4-isopropenylphenyl)ethane-1,2-dione and 1-(3-isopropenylphenyl)ethane-1,2-dione; 1-(4-isopropenylphenyl)ethane-1,2-dione and 1-(3-isopropenylphenyl)ethane-1,2-dione; 2,2-dihydroxy-1-(4-ethenylphenyl)ethan-1-one and 2,2-dihydroxy-1-(3-ethenylphenyl)ethan-1-one; 2,2-dihydroxy-1-(4-isopropenylphenyl)ethan-1-one and 2,2-dihydroxy-1-(3-isopropenylphenyl)ethan-1-one.

[0062] The same applies to any of the isopropenyl analogs listed above. Due to the synthetic availability of various monomers, it is unlikely that the isopropenyl and ethenyl analogs will be provided as a mixture; they require different reactants.

[0063] Step ii) - Polymerization In step ii), the monomers prepared in step i) are polymerized to obtain a polymer. A polymer is a substance composed of macromolecules, where macromolecules are molecules of high relative molecular weight and whose structure essentially comprises multiple repeats of units actually or conceptually derived from molecules of lower relative molecular weight. A polymer can be a single chain composed of one type of monomer, or it can also be a large cross-linked network composed of many different monomers. As known in the art, polymerization is the process of forming a polymer from monomers.

[0064] Polymerization occurs via the Q-containing moiety and can be via any method known in the art (see, for example, SM Ashraf "A Laboratory Manual of Polymers" IK International Pvt Ltd, 8 December 2008). Suitable methods for polymerizing vinyl or methyl vinyl type monomers, such as those of general formula (I), are radical polymerization, bond insertion polymerization, and ionic polymerization. Examples of ionic polymerization are anionic polymerization and cationic polymerization. An example of bond insertion polymerization is Ziegler-Natta polymerization. Examples of radical polymerization are free radical polymerization, atom transfer radical polymerization (ATRP), and radical addition-fragmentation chain transfer polymerization (RAFT). Suspension polymerization using an immiscible solvent is a preferred method because it can result in a particulate adsorbent. Those skilled in the art will know how to carry out such polymerizations.

[0065] The solvent can also be present as an inert solvent. These are preferably dissolving inert solvents. Depending on the context, the inert solvent can be a mixture of inert solvents. The inert solvent can affect the porosity of the resulting adsorbent. The inert solvent can also be called a porogen. A more polar inert solvent can result in increased porosity. A less polar inert solvent can result in a denser adsorbent. A more polar inert solvent can decrease the mechanical stability of the resulting adsorbent. A less polar inert solvent can result in a higher mechanical stability of the resulting adsorbent. Therefore, the inert solvent preferably has a polarity that combines the desired porosity with the desired mechanical stability.

[0066] Suitable inert solvents are known in the art. They include pentane, hexane, heptane, cyclohexane, benzene, toluene, xylene, nitrobenzene, nitromethane, furan, tetrahydrofuran, 1,4-dioxane, isoparaffinic aliphatic hydrocarbons such as ShellSolTD (CAS 64761-65-7; Shell Chemicals product code for Europe: Q7411) or ShellSolT (CAS 64761-65-7; Shell Chemicals product code for Europe: Q7412), or mixtures thereof. Preferred inert solvents are pentane, hexane, heptane, cyclohexane, benzene, toluene, xylene, nitrobenzene, nitromethane, furan, tetrahydrofuran, 1,4-dioxane, ShellSolTD, ShellSolT, or mixtures thereof. More preferred inert solvents are pentane, hexane, heptane, cyclohexane, benzene, toluene, xylene, nitrobenzene, nitromethane, ShellSolTD, ShellSolT, or mixtures thereof. Even more preferred inert solvents are heptane, toluene, nitrobenzene, ShellSolTD, optionally nitromethane, or mixtures thereof. Toluene is most preferred.

[0067] Mixtures of inert solvents are advantageous when a particular polarity is desired; for example, if more porosity is desired, an inert solvent with a higher polarity should be selected. Examples of suitable mixtures of inert solvents are toluene:nitromethane, toluene:nitrobenzene, toluene:heptane, and toluene:ShellSolTD. Preferred mixtures of inert solvents are toluene:nitrobenzene (1:1); toluene:heptane (1:4); toluene:heptane (1:1); toluene:ShellSolTD (1:4). More preferred mixtures of inert solvents are toluene:nitrobenzene (1:1); toluene:heptane (1:4); toluene:heptane (1:1).

[0068] In a preferred embodiment, the inert solvent or the mixture of inert solvents is not more polar than nitrobenzene and / or not less polar than heptane. In a more preferred embodiment, the inert solvent or the mixture of inert solvents is not more polar than nitrobenzene and not less polar than heptane. In an even more preferred embodiment, the inert solvent or the mixture of inert solvents is not more polar than nitrobenzene and / or not less polar than heptane:toluene (4:1). In a most preferred embodiment, the inert solvent or the mixture of inert solvents is not more polar than nitrobenzene and / or not less polar than heptane:toluene (4:1). Polarity preferably refers to the average polarity of the inert solvent or the average polarity of the mixture of inert solvents. It can be determined by any known method, such as that described in Katritzky et al., Chem. Rev. (2004) DOI: 10.1021 / cr020750m.

[0069] In the manufacturing method of the present invention, step ii) preferably involves polymerizing the provided monomers to obtain a polymer using radical polymerization, more preferably free radical polymerization. This is because the free radical polymerization process is easy to carry out and does not require complicated setup or conditions. Suitable initiators for free radical polymerization include azobisisobutyronitrile (AIBN), benzoyl peroxide, benzoyl peroxide blends with dicyclohexyl phthalate, 1,1'-azobis(cyclohexanecarbonitrile) (ABCN), di-tert-butyl peroxide, acetone peroxide, methyl ethyl ketone peroxide, and peroxodisulfates such as sodium persulfate, potassium persulfate, or ammonium persulfate. For aqueous systems, AIBN and / or peroxydisulfates, especially potassium persulfate, are preferred. For suspension polymerization, preferred initiators are benzoyl peroxide and / or benzoyl peroxide blends with dicyclohexyl phthalate.

[0070] During the polymerization, comonomers other than those of general formula (I) can also be present. The comonomer is a further monomer that undergoes polymerization in step ii) in the same mixture as the monomer provided in step i), and the comonomer is covalently incorporated into the resulting polymer. Such resulting polymers are often called copolymers, but for clarity, in this specification, reference will be made only to the polymer itself, when the context makes clear whether copolymers can also be referred to. In the context of the present invention, two classes of comonomers are particularly relevant: hydrophilic comonomers and crosslinking comonomers.

[0071] In a preferred embodiment, the present invention provides a comonomer together with the monomer of general formula (I), the comonomer being preferably styrene, isopropenylbenzene, divinylbenzene, vinylbenzenesulfonic acid, acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, acrylonitrile, 2-hydroxylethyl 2-methylprop-2-enoate (HEMA), 2-hydroxypropyl 2-methylprop-2-enoate, ... The present invention provides a method for producing a vinyl sulfonamide, wherein the vinyl sulfonamide is selected from the group consisting of prop-2-enoate, N-(2-hydroxyethyl)methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, telechelic N,N'-alkylenebisacrylamide such as N,N'-methylenebisacrylamide (NMAA), N-isopropylacrylamide (NIpAM), divinyl sulfone, butadiene, methacrylonitrile, vinyl sulfonamide, N-alkylvinylsulfonamide such as N-methylvinylsulfonamide, and N,N-dialkylvinylsulfonamide such as N,N-dimethylvinylsulfonamide. In a more preferred embodiment, the present invention provides a process in which a comonomer is provided together with the monomer of general formula (I), the comonomer being selected from the group consisting of divinylbenzene, vinylbenzenesulfonic acid, acrylic acid, (meth)acrylonitrile, vinylsulfonamide, N-alkylvinylsulfonamide, N,N-dialkylvinylsulfonamide, and 2-hydroxyethyl 2-methylprop-2-enoate (HEMA). Even more preferably, the comonomer is selected from the group consisting of divinylbenzene and vinylbenzenesulfonic acid. Most preferably, both divinylbenzene and vinylbenzenesulfonic acid are provided together with the monomer of general formula (I).

[0072] In the context of the present invention, divinylbenzene can be either 1,2-diethenylbenzene, 1,3-diethenylbenzene, or 1,4-diethenylbenzene, or a mixture thereof. 1,4-diethenylbenzene or a mixture containing 1,4-diethenylbenzene is preferred because it provides more extensive crosslinking and improves the solvent permeability of the resulting polymer.

[0073] In the context of the present invention, vinylbenzenesulfonic acid can be either 2-vinylbenzenesulfonic acid, 3-vinylbenzenesulfonic acid, or 4-vinylbenzenesulfonic acid, or a mixture thereof. 4-vinylbenzenesulfonic acid is preferred due to its favorable polymerization kinetics. Vinylbenzenesulfonic acid can be provided as a salt, such as sodium or calcium (vinylbenzenesulfonate)2. Providing a salt of vinylbenzenesulfonic acid can improve the solubility of this comonomer, making it particularly suitable for polymerizations conducted in aqueous or other highly polar media.

[0074] For crosslinked adsorbents, it is preferred that at least one crosslinking comonomer be provided with the monomer of general formula (I). The crosslinking comonomer generally has two or more reactive moieties capable of participating in a polymerization reaction. Preferably, such a crosslinking comonomer is selected from the group consisting of divinylbenzene, telechelic N,N'-alkylenebisacrylamides such as N,N'-methylenebisacrylamide (NMAA), divinylsulfone, and butadiene, with divinylbenzene being preferred when providing the monomer of general formula (I). Alternatively, the polymer can be crosslinked after polymerization in step ii), for example, by reacting the polymer chains with each other, optionally via the side chains of the comonomer. Thus, in a preferred embodiment, the present invention provides a method of manufacturing the polymer, in which the polymer is crosslinked after or during polymerization. Preferably, the polymer is crosslinked during polymerization, more preferably using a crosslinking comonomer.

[0075] In the context of the present invention, the amount of crosslinking is defined as the amount of crosslinking comonomer present in the polymerization mixture during step ii). A higher amount of crosslinking results in a denser adsorbent. A lower amount of crosslinking results in a more porous or macroporous adsorbent. Preferably, at most 10% crosslinking comonomer is used. More preferably, up to 5% crosslinking comonomer is used. Even more preferably, for crosslinked adsorbents, 0.1% to 5% crosslinking comonomer is used, more preferably 0.2% to 4% crosslinking comonomer is used, even more preferably 0.4% to 4% crosslinking comonomer is used, and most preferably 0.8% to 3% crosslinking comonomer is used, e.g., about 1% to about 2%, or about 2%.

[0076] In preferred embodiments, less than 80% cross-linking comonomer is used. In more preferred embodiments, less than 67% cross-linking comonomer is used. In very preferred embodiments, less than 50% cross-linking comonomer is used. In most preferred embodiments, less than 10% cross-linking comonomer is used. Thus, preferred embodiments use 1% to 10% cross-linking comonomer. In more preferred embodiments, 2% to 10% cross-linking comonomer is used. In even more preferred embodiments, 2% to 8% cross-linking comonomer is used. In even more preferred embodiments, 2% to 7% cross-linking comonomer is used. In most preferred embodiments, 3% to 6% cross-linking comonomer is used.

[0077] Adsorbents containing hydrophilic comonomers are referred to herein as hydrophilic adsorbents. The hydrophilic comonomer allows aqueous solvents to more easily permeate the adsorbent, which in turn allows nucleophilic waste solutes to more easily permeate the adsorbent. This allows the interior of the adsorbent to also participate in binding nucleophilic waste solutes. A balance exists, since hydrophilic comonomers generally cannot bind nucleophilic waste solutes in the same manner as PGA-type moieties. Thus, increasing the hydrophilic comonomer content makes PGA-type moieties more effective but reduces their number.

[0078] For hydrophilic adsorbents, it is preferred that at least one hydrophilic comonomer is provided together with the monomer of general formula (I). Preferably, such hydrophilic comonomer is selected from the group consisting of vinylbenzenesulfonic acid, acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, 2-hydroxyethyl 2-methylprop-2-enoate (HEMA), 2-hydroxypropyl 2-methylprop-2-enoate, ... prop-2-enoate, N-(2-hydroxyethyl)methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, and N-isopropylacrylamide (NIPAm), more preferably vinylbenzenesulfonic acid, acrylic acid, methacrylic acid, 2-hydroxyethyl 2-methylprop-2-enoate (HEMA), 2-hydroxypropyl 2-methylprop-2-enoate, 2-hydroxyethyl prop-2-enoate, 2-hydroxypropyl Preferably, the monomer of formula (I) is selected from the group consisting of prop-2-enoate, N-(2-hydroxyethyl)methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-hydroxyethyl)acrylamide, and N-(2-hydroxypropyl)acrylamide, and more preferably vinylbenzenesulfonic acid. Those skilled in the art will appreciate that some comonomers, such as methyl methacrylate, can be easily post-modified to become hydrophilic by hydrolysis of their esters. Preferably, up to 60% of the hydrophilic comonomer is present. More preferably, up to 50% of the hydrophilic comonomer is present.Even more preferably, with respect to the hydrophilic adsorbent, 0% to 50% hydrophilic comonomer is present, more preferably 0% to 40% hydrophilic comonomer is present, even more preferably 5% to 40% hydrophilic comonomer is present, even more preferably 10% to 35% hydrophilic comonomer is present, even more preferably 15% to 35% hydrophilic comonomer is present, and most preferably 20% to 30% hydrophilic comonomer, for example about 25%.

[0079] Step iii) - Conversion of precursor monomers The polymer obtained in step ii) contains monomers of general formula (I), and these monomers may be precursor monomers that are not already PGA-type monomers. In step iii), the precursor monomers contained in the polymer obtained in step ii) are converted into PGA-type monomers by carrying out a conversion reaction. The conversion reaction may include one, two, or three steps. In a preferred embodiment, the present invention provides a production method of the present invention, in which step iii) comprises converting a polymerized monomer of general formula (I) that is not already a PGA-type monomer into a PGA-type monomer using one, two, or three reaction steps, preferably using one or two reaction steps, and more preferably using one reaction step. If the monomer of general formula (I) already contains a PGA-type moiety, step iii) is effectively absent if no other monomer of general formula (I) is present.

[0080] General methods for converting molecules such as those of general formula (I) are known in the art, and a person skilled in the art can select which reaction is suitable for converting any particular monomer of general formula (I) into a PGA-type monomer. The conversion reaction depends on which monomer of general formula (I) is converted. Thus, in a preferred embodiment, the present invention provides a production method of the present invention, wherein in step iii) a conversion reaction is used comprising a step selected from the group consisting of: a) halogenation, preferably using hydrohalic acid or Br2, Cl2, or I2; b) oxidation, preferably using dimethyl sulfoxide (DMSO) or ethyl acetoacetate or an oxidizing agent such as SeO2; c) Hydrolysis, preferably by heating to about 80°C in an aqueous environment.

[0081] Preferred oxidation methods include Swern oxidation, using DMSO and oxalyl chloride and a base, for example, a trialkylamine such as trimethylamine; Dess-Martin oxidation, for example, using Dess-Martin periodinane; Corey-Kim oxidation, using, for example, an N-halosuccinimide, for example, N-chlorosuccinimide, and dimethyl sulfide, and a base, for example, a trialkylamine such as trimethylamine; Oppenauer oxidation, for example, using aluminum isopropoxide and optionally a polyvalent iodine species; Kornblum oxidation, for example, using DMSO and oxalyl chloride and a base, for example, a trialkylamine such as trimethylamine, or omitting the base if following halogenation; oxidation, using halogen species such as iodine species, preferably polyvalent iodine species; direct oxidation, using oxides such as SeO2, OsO4, or MnO2 (see Jong et al., 2019, ACS Omega, DOI: 10.1021 / acsomega.9b01177); (2015, DOI: 10.1016 / j.tetlet.2015.02.086) is a assisted direct oxidation using oxides such as SeO2, OsO4, or MnO2. A highly preferred oxidation method is halogenation followed by Kornblum oxidation using dimethyl sulfoxide (DMSO) or ethyl acetoacetate and a hydrohalic acid such as HBr, HI, or HCl, preferably using DMSO and a hydrohalic acid such as HBr.

[0082] Halogenation can be carried out using methods known in the art. Preferred methods use Br2, Cl2, or I2, or an N-halosuccinimide (e.g., N-bromosuccinimide, N-chlorosuccinimide, or N-iodosuccinimide), or a hydrohalic acid, optionally in the presence of DMSO. In a preferred embodiment, halogenation is carried out using Br2, Cl2, or I2. In another preferred embodiment, halogenation is carried out using an N-halosuccinimide, such as N-bromosuccinimide, N-chlorosuccinimide, or N-iodosuccinimide. Halogenation can also be advantageously carried out using a hydrohalic acid in DMSO, which allows for subsequent oxidation in one pot by Kornblum oxidation.

[0083] Hydrolysis can be carried out using any known method for the hydrolysis of ketals, thioketals, aminals, and their hemi-modifications. A preferred method of hydrolysis is by heating to about 80° C. in an aqueous environment, preferably in the presence of a catalytic amount of acid. Hydrolysis is preferably not carried out in a basic environment.

[0084] More preferably, in step iii) a conversion reaction is used which comprises the steps selected from the group consisting of: a) halogenation, preferably using hydrohalic acid in DMSO at about 80°C; b) oxidation, preferably using dimethyl sulfoxide (DMSO) at about 80° C.; and c) Hydrolysis, preferably by heating to about 80° C. in an aqueous environment, more preferably in the presence of a catalytic acid.

[0085] Most preferably, the above steps a) and b) are included. This is particularly useful for (I-Ac) type monomers. Those skilled in the art will understand that the above various steps are mechanistic steps and can be carried out simultaneously, for example, by oxidizing using DMSO at 80°C in the presence of a halogen source such as molecular dihalogen, hydrohalic acid, or N-halogen-succinimide, resulting in both halogenation and oxidation.

[0086] In particular, monomers of general formula (I-PGA) or (I-PGAH) generally do not require conversion because they already contain a PGA-type moiety. Monomers of general formula (I-PGAH) can be dehydrated to form monomers of general formula (I-PGA), and monomers of general formula (I-PGA) can be hydrated to form monomers of general formula (I-PGAH). Such dehydration is preferably via incubation in a dry solvent, more preferably at elevated temperatures, such as above 60, 80, or 100°C. Hydration occurs spontaneously in the presence of water, preferably at ambient conditions.

[0087] In particular, monomers of general formula (I-Ac) are generally successfully converted to PGA-type monomers in two steps in a single pot using dimethyl sulfoxide (DMSO) and a hydrohalic acid such as HCl, HBr, or HI. In such a reaction, the acetyl moiety is first halogenated and then oxidized with DMSO. For example, when polymerized VPE is used in this reaction, this one-pot reaction directly yields a PGA-type adsorbent. After such conversion, the adsorbent is preferably washed with water, more preferably until the pH of the washing solution is in the range of 5 to 9. Therefore, in a preferred embodiment, the present invention provides a production method of the present invention, in which step i) comprises providing a monomer of general formula (I-Ac), and step iii) comprises converting the polymerized monomer of general formula (I-Ac) to a PGA-type monomer using dimethyl sulfoxide (DMSO) and a hydrohalic acid, preferably DMSO and a hydrohalic acid such as HBr.

[0088] In particular, h 1 and h 2 Monomers of general formula (Ih), in which at least one of the groups is halogen, are generally successfully converted to PGA-type monomers in a single oxidation step, preferably using dimethyl sulfoxide (DMSO). This is similar to the conversion of general formula (I-Ac) described above, but omitting the halogenation step. Thus, in a preferred embodiment, the present invention provides a method in which step i) is carried out by the addition of a methyl group to a PGA-type monomer. 1 and h 2 and step iii) comprises converting the polymerized monomer of general formula (Ih) into a PGA-type monomer using dimethyl sulfoxide (DMSO). 1 and h 2 Monomers of general formula (Ih) which together form a single moiety (such as a ketal) or form a (hemi)ketal, (hemi)thioketal, or (hemi)aminal can be converted to PGA-type monomers using hydrolysis at elevated temperatures such as 80° C., preferably using a catalytic acid such as about 1% by volume acetic acid.

[0089] In a preferred embodiment, the present invention provides a production method of the present invention, in which in step iii) 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more, or 100% of the monomers of general formula (I) are converted to PGA-type monomers. In a more preferred embodiment, the present invention provides a production method of the present invention, in which in step iii) 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more, or 100% of the monomers of general formula (I) are converted to PGA-type monomers. In an even more preferred embodiment, the present invention provides a production method of the present invention, in which in step iii) 55% to 100% of the monomers of general formula (I) are converted to PGA-type monomers. In a most preferred embodiment, the present invention provides a production method of the present invention, in which in step iii) 55% to 90% of the monomers of general formula (I) are converted to PGA-type monomers.

[0090] In a particular embodiment of the present invention, in step iii), 0% of the monomers of general formula (I) are converted into PGA-type monomers, in particular when all polymerized monomers of general formula (I) are already PGA-type monomers.

[0091] Compositions and other products In a third aspect of the present invention, the present invention provides a composition comprising the PGA-type adsorbent of the present invention and a pharmaceutically acceptable excipient. Hereinafter, such a composition will be referred to as the composition of the present invention. Such a composition is preferably a pharmaceutical composition.

[0092] The composition and pharmaceutical composition of the present invention can be prepared by methods well known in the art.For example, by conventional mixing, dissolving, granulating, sugar-coating, lecithinizing, emulsifying, encapsulating, entrapping or lyophilizing process, liposome preparation, coacervate, oil-in-water emulsion, nanoparticle / microparticle powder or any other shape or form can be produced.Therefore, the composition for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of active compounds into pharmaceutical preparations.Appropriate formulation depends on the selected route of administration.

[0093] Oral and parenteral administration can be used, where the compounds or compositions of the present invention can be easily formulated by combining the compounds or compositions of the present invention with pharmaceutically acceptable carriers well known in the art, or by using the compounds or compositions of the present invention as food additives. Such strategies allow the compounds or compositions of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the treated subject. Preparations for oral use or pharmacological preparations can be made using solid excipients, and if necessary, the resulting mixture is milled, and if desired, suitable auxiliary agents are added, and the granular mixture is processed to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, cellulose preparations such as methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP).If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salt (e.g., sodium alginate) can be added.In addition, co-formulations can be made with uptake enhancers known in the art.

[0094] Alternatively, one or more of the ingredients of the composition may be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use. The ingredients of the composition may also be provided separately.

[0095] The compositions or pharmaceutical compositions of the present invention may also comprise suitable solid or gel phase carriers or excipients, examples of which include, but are not limited to, calcium carbonate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0096] The pharmaceutical compositions of the present invention may also comprise a further pharmaceutically active substance, preferably a further pharmaceutically active substance, for the treatment of a disease or condition associated with the accumulation of urea or inadequate clearance of urea, such as acute renal failure or end-stage renal disease (ESKD).

[0097] The compositions of the present invention or the PGA-type sorbents of the present invention can be advantageously used in renal replacement therapy, such as peritoneal dialysis or hemodialysis. During such use, the sorbents or compositions are typically present in a cartridge or membrane that can be replaceably inserted into a (hemo)dialysis machine or, for example, a peritoneal dialysis machine. Accordingly, the present invention provides cartridges for use in dialysis machines, comprising the PGA-type sorbents of the present invention or the compositions of the present invention. Such dialysis machines can be hemodialysis machines or machines for regenerating peritoneal dialysate in peritoneal dialysis. Accordingly, the present invention provides membranes for use in dialysis machines, comprising the PGA-type sorbents of the present invention or the compositions of the present invention. Such dialysis machines can be hemodialysis machines or machines for regenerating peritoneal dialysate in peritoneal dialysis. Accordingly, the present invention provides dialysis machines comprising the PGA-type sorbents of the present invention, the compositions of the present invention, or the cartridges of the present invention. Such dialysis machines can be hemodialysis machines or machines for regenerating peritoneal dialysate in peritoneal dialysis.

[0098] In addition to the PGA-type sorbents or compositions of the present invention contained in cartridges, membranes, or dialysis devices, such cartridges, membranes, and dialysis devices are known in the art. In certain embodiments, the cartridge is a disposable cartridge. In certain embodiments, the cartridge is a reusable cartridge. The cartridge may also be referred to as a cassette. Preferably, the cartridge is adaptable for use with a variety of different types of components and arranged in various ways. The cartridge may also include an additional sorbent. By removing nucleophilic waste solutes, the cartridge at least partially regenerates the dialysate and / or filtrate used during dialysis. The cartridge preferably includes a body having a fluid inlet and a fluid outlet. The interior of the cartridge is preferably configured and arranged so that fluid entering the interior through the inlet flows through the sorbent and then through the outlet.

[0099] Membranes for use in dialysis devices are preferably semipermeable. They are sheet-like and can separate two volumes by acting as a wall or part of a wall. They can also be in the form of a fiber bundle connecting the two volumes. A highly suitable fiber bundle is described in WO2006019293A1, which describes a bundle of hollow or solid fibers with multiple coaxially arranged porous layers. In such a bundle, one of the layers can contain functionalized or active particles that are fully accessible to the fluid flowing through the membrane. In a preferred embodiment of the present invention, the PGA-type sorbent of the present invention is contained in a membrane, such as a fiber bundle with multiple concentric layers, preferably in one of the layers of such fibers, and is preferably configured to contact the fluid passing through the membrane or a fluid passing through the membrane, and preferably further configured to capture nucleophilic waste solutes in the fluid. Such membranes can act as a combined membrane and sorbent, allowing for further miniaturization.

[0100] A dialysis machine is a closed, sterile system. It comprises one or two fluid circuits. It typically comprises two circuits: a so-called patient loop, through which a subject's fluid, such as blood or peritoneal dialysis fluid, flows; and a so-called regeneration loop, through which dialysis fluid, such as dialysate and / or filtrate, is circulated through the cartridge as described above. The two circuits are separated from each other by a (semi-permeable) membrane through which waste solutes can diffuse or pass from the subject's fluid into the dialysis fluid. Air, moisture, pathogens, and fluids from the environment surrounding the dialysis machine cannot enter the fluid circuits. The dialysis system only allows fluids (e.g., ultrafiltrate) and air to exit or enter these fluid circuits under controlled conditions.

[0101] Medical Use In a fourth aspect, the present invention provides medical uses of the PGA-type adsorbents of the present invention and the compositions of the present invention.Accordingly, this aspect provides the PGA-type adsorbents of the present invention or the compositions of the present invention for use as a medicine, preferably for use in the treatment of diseases or conditions associated with urea accumulation or inadequate clearance of urea.Such adsorbents or compositions are referred to herein as products for use according to the present invention.

[0102] In a specific embodiment of this aspect, the present invention provides a PGA-type adsorbent of the present invention or a composition of the present invention for use as a medicament for use in the treatment of diseases or conditions associated with ammonia accumulation or inappropriate clearance of ammonia. In a further specific embodiment of this aspect, the present invention provides a PGA-type adsorbent of the present invention or a composition of the present invention for use as a medicament, wherein the PGA-type adsorbent is for capturing urea. In a further specific embodiment of this aspect, the present invention provides a PGA-type adsorbent of the present invention or a composition of the present invention for use as a medicament, wherein the PGA-type adsorbent is for capturing ammonia.

[0103] Treatment of disease or condition can be the improvement, suppression, prevention, delay, cure or prevention of disease or condition or its symptoms, and preferably the suppression of the symptoms of disease or condition.In the case of renal failure, urea may accumulate or not be fully removed.The examples of diseases or conditions associated with urea accumulation or inadequate clearance of urea are end-stage renal disease (ESKD); severe acute renal failure; for example, increased hepatic production of urea due to gastrointestinal bleeding; increased protein catabolism due to trauma, such as major surgery or extreme starvation accompanied by muscle destruction; increased renal reabsorption of urea due to any cause of renal hypoperfusion, such as congestive heart failure, shock, severe diarrhea; iatrogenic conditions due to drug therapy that increases urea production, such as urea infusion for diuresis, treatment with tetracycline or corticosteroids; chronic renal failure; and urinary outflow obstruction.

[0104] The product for use in the present invention can be administered to a subject in need thereof, allowing the product for use in the present invention to capture nucleophilic waste solutes in the subject. Such administration is preferably in an effective amount. The use of other adsorbents in such methods is known in the art (Gardner et al., Appl Biochem Biotechnol. 1984;10:27-40).

[0105] Administration can be via methods known in the art, preferably via oral ingestion in any formulation known in the art (e.g., capsules, pills, lozenges, gel capsules, push-fit capsules, controlled release formulations), or via rectal administration as an enema or suppository, and can be once per week, 6, 5, 4, 3, 2, or 1 time per week, daily, twice a day, or three times a day, or four times a day.

[0106] The product for use according to the invention is suitable for use in a method of treatment, which may comprise administering to a subject, preferably a subject in need thereof, an amount, preferably an effective amount, of the product for use according to the invention.

[0107] Regarding dialysis therapy, the present invention can be used in a variety of different dialysis therapies to treat renal failure. Dialysis therapy, as used throughout this specification and similar terms, is meant to include and encompass any and all forms of treatment for removing waste products, toxins, and excess water from a subject suffering from a disease or condition. Blood therapies, such as hemodialysis, hemofiltration, and hemodiafiltration, include both intermittent therapies and continuous therapies used in continuous renal replacement therapy (CRRT). Continuous therapies include, for example, slow continuous ultrafiltration (SCUF), continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), continuous arteriovenous hemodiafiltration (CAVHDF), continuous ultrafiltration cyclic intermittent hemodialysis, and the like. The present invention may also be used during peritoneal dialysis, including, for example, continuous ambulatory peritoneal dialysis, automated peritoneal dialysis, tidal peritoneal dialysis, intermittent peritoneal dialysis, continuous flow peritoneal dialysis, flow-through peritoneal dialysis, etc. Additionally, while the present invention may, in certain embodiments, be utilized in methods of providing dialysis therapy to subjects with acute or chronic renal failure or disease, it should be understood that the present invention may also be used for acute dialysis needs, for example, in an emergency room setting. However, it should be understood that the compositions of the present invention may be effectively utilized in a variety of different applications (both physiological and non-physiological) in addition to dialysis.

[0108] How to use The PGA-type adsorbents of the present invention are surprisingly effective in capturing nucleophilic solutes, preferably nucleophilic waste solutes. In a fifth aspect, the present invention provides a method for removing nucleophilic waste solutes from a fluid, comprising: i) providing a fluid containing a nucleophilic waste solute; iia) contacting said fluid with a PGA type sorbent of the invention, or a composition of the invention, or a cartridge of the invention, or alternatively iib) contacting said fluid with a dialysis fluid through a membrane, said dialysis fluid being in contact with a PGA-type sorbent of the invention, or a composition of the invention, or a cartridge of the invention; and iii) optionally recovering the fluid The present invention provides a method comprising:

[0109] Such a method is hereinafter referred to as the capture method of the present invention. The method can be a continuous process in which the urea capture capacity of a fluid containing a nucleophilic waste solute is determined by the urea capture capacity of a continuous flow of the fluid. In such a case, step iii) is preferably not optional and is also performed continuously. The binding method of the present invention always includes step i), step ii) (either step iia) or step iib)), and optionally step iii).

[0110] Nucleophilic waste solutes are dissolved substances that are nucleophilic and whose removal is desirable. For example, in human blood, urea is a waste solute. In unpurified water intended for drinking water, most organic nucleophiles are waste solutes. Examples of nucleophilic waste solutes are ammonia, urea, creatinine, and small organic amines, thiols, or alcohols. The chemical binding properties make the PGA-type sorbents of the present invention well suited for a variety of different applications exposed to physiological and / or non-physiological conditions. In one embodiment, the PGA-type sorbents of the present invention can be used to remove metabolic waste products, such as urea, creatinine, uric acid, and / or others, such as uremic toxins, biological substances, proteinaceous substances, etc., from blood, peritoneal dialysis fluid, and / or solutions used to dialyze and / or filter blood, e.g., dialysate and / or filtrate. Due to their relevance as described elsewhere herein, highly preferred nucleophilic waste solutes are urea and ammonia. In a preferred embodiment, the nucleophilic waste solute is ammonia. In another preferred embodiment, the nucleophilic waste solute is urea.

[0111] In step i), a fluid containing a nucleophilic waste solute is provided. This may be wastewater to be purified, a waste solvent to be purified, or a (body) fluid from a subject (e.g., blood or peritoneal dialysis fluid). When the fluid in step i) is a fluid from a subject, it is preferably blood or peritoneal dialysis fluid, most preferably blood, and is preferably a fluid previously obtained from the subject.

[0112] In step ii), two options exist. In one option, step iia), the fluid itself is directly contacted with the PGA-type sorbent of the present invention, the composition of the present invention, or the membrane or cartridge of the present invention. Step iia) is well suited to purifying solvents or fluids not intended for consumption or medical purposes after removal of waste solutes. Step iib) separates the bound sorbent from the fluid provided in step i) by using dialysis fluid and / or filtrate. Step iib) is particularly suited to removing nucleophilic waste solutes from pharmaceutical solutions or fluids obtained from a subject (e.g., a subject's body fluid). The contact preferably lasts for 24 hours, 12 hours, 6 hours, 4 hours, 3 hours, 2 hours, 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute or less. The contacting may also be in a continuous flow through the adsorbent, in which case the total amount of waste solute removed is more relevant.

[0113] The membranes for use in step iib) are preferably semipermeable membranes. These are known in the art and may be, for example, the semipermeable membranes present in conventional (hemo)dialysis machines. The membranes of the present invention as described above may also be used. Dialysis fluids are known in the art and may range from ultrapure water to physiological buffers. Non-limiting examples of dialysis fluids are media containing known amounts of, for example, Na, K, Ca, Mg, Cl, acetate, HCO3, and glucose (e.g., those available from MDN Netherlands GmbH (Neubrandenburg, Germany) or Baxter (Deerfield, Illinois, USA) or Dirinco BV (Oss, the Netherlands)).

[0114] In optional step iii), the fluid is recovered. The PGA-type adsorbents of the present invention are often porous, macroporous, or swellable in aqueous media so that fluid can flow through and permeate them. Recovery of the fluid that has contacted the adsorbent is easily achieved by filtration, centrifugation, or removal of the cartridge containing the adsorbent. Recovery of the fluid allows for further processing or its return to the subject. In a preferred embodiment within this aspect, the fluid is recovered.

[0115] Preferably, when the fluid is collected in step iii), the relevant physiological parameters are then analyzed and adjusted, if appropriate. Examples are ion concentration, osmolality, pH, and in particular Na concentration, Ca concentration, and Mg concentration. Therefore, a preferred step iii) is to collect the fluid, after which at least one of the fluid pH, fluid sodium concentration, fluid magnesium concentration, and fluid calcium concentration is determined and optionally adjusted to a reference value. A preferred reference value is a physiological value corresponding to the type of fluid. The adjustment can be performed by any suitable method known in the art. The adjustment is preferably performed when a deviation from the reference value is detected.

[0116] In a preferred embodiment of the binding method, at least 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 200, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2029, 2030, 2030, 2030, 20 85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, preferably at least 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, more preferably at least 1.60, even more preferably at least 1.80, and most preferably at least 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, or 2.50 mmol of nucleophilic waste solute per gram of sorbent is removed. This removal preferably involved the removal of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% or more of the initial concentration of the particular nucleophilic waste solute from the fluid provided in step i), more preferably at least 50% or more.

[0117] General definition In this specification and claims, the verb "to comprise" and its conjugations are used in their open-ended sense to mean that the items following the word are included, but that items not specifically mentioned are not excluded. Furthermore, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of that element is present, unless the context clearly requires that only one of that element is present. Thus, the indefinite article "a" or "an" typically means "at least one." The term "about" or "approximately," when used in connection with a numerical value (e.g., about 10), means "about" or "approximately." Preferably, means that a value may be within 5% of a given value.

[0118] The molecules provided in the present invention may be optionally substituted. Suitable optional substitutions are the replacement of -H with halogen. Preferred halogens are F, Cl, Br and I. Further suitable optional substitutions are the replacement of one or more -H with -NH, -OH, =O, alkyl, alkoxy, haloalkyl, haloalkoxy, alkene, haloalkene, alkyne, haloalkyne, and cycloalkyl. Alkyl groups can be represented by the general formula C n H 2n+1 or may be straight or branched chain. Unsubstituted alkyl groups may also include cyclic moieties, and thus have the accompanying general formula C n H 2n-1

[0023] The alkyl group may be optionally substituted with one or more substituents as further specified herein. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, t-butyl, 1-hexyl, 1-dodecyl, and the like.

[0119] Unless otherwise specified, -H represents C1-C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C3-C 12 Cycloalkyl groups, C5-C 12 Cycloalkenyl groups, C8-C 12 Cycloalkynyl groups, C1-C12 Alkoxy groups, C2-C 12 Alkenyloxy group, C2-C 12 Alkynyloxy group, C3-C 12 cycloalkyloxy groups, halogens, amino groups, oxo and silyl groups, the silyl groups being of the formula (R 2 )3Si-(wherein, R 2 are independently C1-C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C3-C 12 Cycloalkyl groups, C1-C 12 Alkoxy groups, C2-C 12 Alkenyloxy group, C2-C 12 Alkynyloxy groups and C3-C 12 cycloalkyloxy groups (wherein the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyloxy groups are optionally substituted, and the alkyl, alkoxy, cycloalkyl and cycloalkoxy groups may be interrupted by one or more heteroatoms selected from the group consisting of O, N and S);

[0120] Although a structural formula or chemical name is understood by those skilled in the art to have chiral centers, if the chirality is not indicated, all three are individually referred to for each chiral center: the racemic mixture, the pure R enantiomer, and the pure S enantiomer. When two moieties are said to join together to form a bond, this means that these moieties are not present as atoms and that valence compliance is met by substitution electron bonding. This is all known in the art.

[0121] Whenever parameters of a substance are discussed in the context of the present invention, unless otherwise specified, it is assumed that the parameters are determined, measured, or determined under physiological conditions. Physiological conditions are known to those skilled in the art and include aqueous solvent systems, atmospheric pressure, pH values ​​between 6 and 8, temperatures ranging from room temperature to about 37°C (about 20°C to about 40°C), and appropriate concentrations of buffer salts or other components. It is understood that charge is often related to equilibrium. A moiety that is said to have or carry a charge is one that is found in such a state more frequently than one that does not have or carry such a charge. Thus, as will be understood by those skilled in the art, atoms shown as charged in this disclosure may be uncharged under certain conditions, and neutral moieties may become charged under certain conditions.

[0122] In the context of the present invention, a decrease or increase in an evaluated parameter refers to a change of at least 5% in the value corresponding to that parameter. More preferably, a decrease or increase in value refers to a change of at least 10%, even more preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 90%, or 100%. In this latter case, there may no longer be a detectable value associated with the parameter.

[0123] The use of a substance as a medicament described herein can also be interpreted as the use of said substance in the manufacture of a medicament.Similarly, whenever a substance is used for treatment or as a medicine, it can also be used for the manufacture of a medicine for treatment.A product for use is suitable for use in a method of treatment.

[0124] Throughout this specification, when percentages are used to express the amounts of monomers and comonomers in a mixture, molar percentages are intended unless otherwise stated or clearly evident from the context. Throughout this application, (hemo)dialysis refers to both hemodialysis and dialysis. In general, dialysis equipment can refer to any type of dialysis equipment described herein.

[0125] The present invention has been described above with reference to several exemplary embodiments. Modifications and alternative implementations of several parts or elements are possible and fall within the scope of protection defined in the appended claims. All citations to literature and patent documents are incorporated herein by reference. [Brief explanation of the drawings]

[0126] [Figure 1] Reaction of PGA / PGAH derivatives with urea. For PGA-type adsorbents, R can be the polymer backbone. [Figure 2A] Synthesis of PGA-type adsorbents from styrene. R1 = optional crosslinker, R2 = unmodified styrene, R3 = by-products of the conversion reaction. [Figure 2B] Synthesis of PGA-type adsorbents from precursor monomers (VPE). R1 ​​= optional crosslinker, R2 = optional by-product of the conversion reaction. [Figure 3] Oxidation of PS-Ac or pVPE with HBr and DMSO. PGA = phenylglyoxalaldehyde, PGAH = phenylglyoxalaldehyde hydrate, PGOA = phenylglyoxylic acid. [Figure 4] Urea trapping capacity of pVPE beads (Table 2, entry 2) as a function of pVPE oxidation time. Oxidation conditions: pVPE (500 mg) in DMSO (5.0 mL) and 48% aqueous HBr (1.45 mL) was stirred at 80 °C for 4 to 12 hours using a Teflon blade stirrer. At each time point, ±150 mg of beads were removed from the suspension and tested for urea trapping. [Figure 5] IR spectra of PGAH, PS-AC-Ox@urea, pVPE-Ox-(4)@urea, and the 2:1 adduct of PGAH and urea. The adduct designated as 3'a was synthesized as described in Jong, JAW et al., ACS Omega 2019, 4 (7), 11928-11937. [Figure 6A] Urea uptake by PS-Ac-Ox and pVPE-Ox-(4) over time, expressed as mmol urea / g adsorbent. [Figure 6B] Relative urea uptake (percentage of maximum uptake capacity). Conditions: sorbent (10 mg / mL) in 30 mM urea solution in PBS at 37° C. (N=4). Triangles represent pVPE-Ox and squares represent PS-Ac-Ox.

[0127] [Example] Example 1 - Materials and Methods 1.1 NMR, UV and IR spectroscopy NMR spectra were recorded at room temperature (RT) on a Bruker 600 MHz BBI probe. Residual solvent signals were used as internal standards (H: δ 7.26 ppm, C(H): δ 77.16 ppm for CDCl3). Chemical shifts (δ) are given in ppm, and coupling constants (J) are given in Hertz (Hz). Resonances are reported as s (singlet), d (doublet), t (triplet), q (quartet), bs (broad singlet), and m (multiplet), or combinations thereof. UV absorption spectra were recorded in triplicate on a BMG LABTECH SpectroStar Nano plate reader using a UV-Star Microplate 96-well from Greiner Bio-One (Alphen aan de Rijn, the Netherlands). Infrared (IR) spectra were recorded directly on a PerkinElmer ATRU Spectrum 2.

[0128] 1.2 Determination of pseudo-first-order rate constants [ka] PGAH (1a) and two PGAH derivatives (1b and 1c) (0.3 mmol, 1.0 equiv.) were dissolved in a 1:1 v / v mixture of PBS:dimethyl sulfoxide (DMSO) (10 mL). Urea (901 mg, 15 mmol, 50 equiv.) was dissolved in the PGAH solution, followed by magnetic stirring at 50 °C. Samples (50 μL) from the reaction mixture were taken at different time points and diluted 10-fold (1a) or 15-fold (1b and 1c) with 1:1 v / v DMSO:PBS (500 or 700 μL), followed by a further 10-fold dilution using the same solvent mixture (thus resulting in a final 100- or 150-fold dilution, respectively). The concentrations of PGAH (derivatives) 1a–c in the 100- or 150-fold diluted samples were measured by UV spectroscopy (260, 263, and 270 nm for 1a, 1b, and 1c, respectively). A calibration curve was prepared from a stock solution of PGAH (derivative) (30 mM) in 1:1 (v / v) DMSO:PBS using a dilution series in a 1:1 v / v mixture of PBS:DMSO (final concentrations varied from 0.030 to 0.360 mM). PFO Values ​​were determined from the slope of a plot of log[PGAH] versus time.

[0129] 1.3 Preparation of 10% polymethacrylic acid sodium salt solution in water Polymethacrylic acid (10 grams) was dissolved in water (84 mL) in a glass reactor equipped with a mechanical stirrer by heating to 80°C and stirring for 30 minutes. A 50% aqueous NaOH solution (2.67 mL; 68 mmol NaOH) was then added, and stirring was continued for 60 minutes at the same temperature. The resulting viscous solution was transferred to a Falcon tube and stored at 4°C for later use as a thickener for the aqueous phase in suspension polymerization.

[0130] 1.4 Suspension polymerization of styrene For the suspension polymerization of styrene, we essentially used the method described by Jong (Jong, GJD Ion exchangers from poly(aminostyrene) and ethyleneimine. 1971), but used ShellSol TD and poly(methacrylic acid) sodium salt solution instead of hexane and polyacrylic acid sodium salt. The detailed procedure was as follows: An aqueous phase was prepared by adding NaCl (340 mg), poly(methacrylic acid) sodium salt solution (8.32 g of a 10% aqueous solution), and CaHPO (3.06 g) to water (540 mL) in a glass reactor equipped with a Teflon blade stirrer. The aqueous phase was stirred at room temperature for 30 minutes, and the pH was 6.9. An organic phase was prepared by mixing styrene (229 mL, 2.0 mol), ShellSol TD (276 mL), and toluene (27 mL) in a beaker. Next, 55% technical purity divinylbenzene (DVB) (13 mL, 50 mmol, 2.5 mol%) and a 50% benzoyl peroxide blend with dicyclohexyl phthalate (6.0 g, 12.4 mmol, 0.6 mol%) were added to the organic phase and stirred until the initiator dissolved and a homogeneous solution was formed at room temperature (RT). The organic phase was then added to the aqueous phase in a glass reactor with continuous mechanical stirring at 180 rpm, forming an oil-in-water emulsion. Oxygen was removed by flushing with nitrogen gas for 20 minutes. The emulsion was then heated at 73°C in an oil bath under mechanical stirring for 16 hours. The resulting suspension was cooled to room temperature, poured onto a sieve (200 μm cutoff, Veco BV), and washed with acetone and water. The white beads were collected and dried over PO under vacuum, yielding 216 g of polystyrene (PS) beads. TGA analysis indicated the presence of approximately 14% volatiles, indicating a yield of approximately 186 grams (86%) of solid material. Thus, macroporous polystyrene beads (PS) were synthesized by suspension copolymerization of styrene with a low content of divinylbenzene (DVB, 2.5%) in a cylindrical reactor equipped with a mechanical stirrer. A mixture of toluene and ShellSolTD® (9:91 v / v) was used as the nonsolvating porogen, and spherical beads were obtained in 97% yield. The average diameter of the beads measured by optical microscopy was 0.49 ± 0.18 mm. Scanning electron microscopy (SEM) analysis showed that pores were clearly visible on the surface of the beads. The surface area of ​​the beads (S), determined by nitrogen physisorption, was 0.49 ± 0.18 mm. BET ) and pore volume are 36.3 m, respectively. 2 / g and 0.32 mL / g. A plot of pore volume versus pore diameter showed that the pores present in the material were primarily in the 50-100 nm range, demonstrating that the resulting beads were indeed macroporous.

[0131] 1.5 Friedel-Crafts acetylation of polystyrene In a glass reactor equipped with a Teflon blade stirrer, PS beads (80.9 g, 0.77 mol aromatic groups, 1.0 equiv.) were swollen in 1,2-dichloroethane (DCE, 750 mL) under mechanical stirring for 30 min. Anhydrous AlCl3 (156 g, 1.17 mol, 1.5 equiv.) was added to the suspension in portions (3–5 grams) over 15 min. After all the AlCl3 had been added, acetyl chloride (66 mL, 0.94 mol, 1.2 equiv.) was slowly added, and the suspension was heated to 50 °C in an oil bath for 5 h, after which the formation of HCl gas (caused by the reaction of the aromatic groups with acetyl chloride) was stopped. The suspension was cooled to room temperature and then filtered (200 μm cutoff). The residue was suspended in 500 mL of 6 M HCl solution in an ice bath at 0 °C and stirred for 30 min to remove aluminum salts. This process was repeated twice. The suspension was filtered (cutoff 200 μm, Veco BV) and washed with acetone and water until the pH of the filtrate was > 5. The residue was dried under vacuum over P2O5 to give acetylated polystyrene (PS-Ac, 71.6 g).

[0132] 1.6 Halogenation and Kurnblum oxidation of acetylated polystyrene In a glass reactor equipped with a Teflon blade stirrer, PS-Ac beads (60.0 g) were swollen in DMSO (600 mL, 8.45 mol) under continuous stirring for 30 minutes, after which 48% aqueous HBr solution (175 mL, 1.55 mol) was slowly added. One of the reactor outlets was capped with a septum containing a needle, allowing the escape of the formed Me2S. The suspension was stirred at 80 °C for 8 hours, after which the reaction mixture was filtered (200 μm cutoff, Veco BV). The residue was washed with water until the pH of the filtrate was >5. The residue was dried over PO5 under vacuum to give PS-Ac-Ox (55.2 grams).

[0133] 1.7 Scanning electron microscope analysis of adsorbent particles The morphology of the beads was analyzed by scanning electron microscopy (SEM, Phenom, FEI Company, the Netherlands). The dried beads were transferred onto 12 mm diameter aluminum specimen stubs (Agar Scientific Ltd., England) using double-sided adhesive tape. Prior to analysis, the beads were coated with platinum using an ion coater under vacuum. The samples were imaged using a 5 kV electron beam.

[0134] 1.8 Bead size measurement using an optical microscope Bead diameters were measured using an optical microscope utilizing a size-calibrated Nikon eclipse TE2000-U microscope equipped with a digital camera (Nikon DS-2Mv camera and Nikon DS-U1 digital adapter, 4x magnification) and the NIS-elements basic research software package. Images of beads were taken dry, and for 30 random beads, three points on the periphery of the bead were identified to allow the program to calculate the circular diameter. The mean diameter and standard deviation are reported.

[0135] 1.9 Quantitative analysis of different beads 13 C solid state NMR analysis solid 13For C NMR measurements, the beads were crushed and transferred to a 3.2 mm rotor for magic angle spinning (MAS) solid-state NMR analysis. Sample analysis was performed on either a Bruker 700 MHz wide-bore magnet or a Bruker 400 MHz spectrometer equipped with an AVANCE-III console. Spectra were recorded at room temperature (298 K) using magic angle spinning (MAS) frequencies between 10 and 14 kHz, chosen to minimize signal overlap with spinning sidebands. 13 For C direct excitation spectra, 30° pulses were applied at field strengths of 55 kHz and 80 kHz SPINAL64. 1 H decoupling was applied during acquisition. 13 C T1 relaxation times were determined using inversion recovery and * The T was used to establish the repetition time for different samples. Except for the pVPE-Ox-(4) sample, which showed a very short relaxation time of 1 s, the T varied from 40 to 80 s for the other samples. NMR spectra were processed with 200 Hz line broadening and analyzed on a Bruker Topspin 3.5.

[0136] 1.10 Measuring the surface area of ​​beads using nitrogen physisorption N2 physical adsorption isotherms were measured at -196 °C using Micromeritics Tristar 3000 and TriStar II Plus instruments. Prior to analysis, samples were vacuum dried at room temperature for 16 h. The Brunauer-Emmett-Teller (BET) method was used to determine the bead surface area, and the total pore volume was derived from the amount of N2 adsorbed at p / p = 0.995. Barrett-Joyner-Halenda (BJH) analysis was used to determine the pore size / volume distribution of the samples using the Harkins-Jura thickness curve. Due to the shrinkage and pore collapse of porous polymer beads with increasing pressure, and subsequent expansion with decreasing pressure, dead volume correction is inaccurate; by default, the solid fraction of the sample is assumed to remain constant in volume with pressure. Because the dead volume was determined at p / p ≈ 0 and assumed to be constant throughout the measurement, the default dead volume-corrected isotherm slightly decreased with increasing pressure, which is physically meaningless. The relative deviation is due to the low surface area (<5m) of the measuring tube, such as pVPE-Ox. 2 / g) and is greatest for high material volume functions. This deformation, i.e., the change in dead volume with pressure, is corrected using a linear swelling function (V adjusted = a·(p / p0)+V original These isotherms were applied by σ (where a represents the swelling coefficient relative to the volume of the material at p / p≈0) until dV / d(p / p)>0 was achieved at all pressures. The values ​​of a ranged from 1.2 to 7.2, indicating significant deformation of these materials. The S of pVPE-Ox beads BET Surface areas were calculated from isotherms corrected for these volume changes as a function of pressure.

[0137] 1.11 Determination of urea uptake Adsorbent beads (15 mg) were dispersed in 1.5 mL of 30 mM urea solution in PBS in Eppendorf tubes. The samples were placed in a 37 °C oven on a rotator. After 1, 2, 4, 8, 16, and 24 h, two Eppendorf tubes were removed for each time point, the beads were allowed to settle, and the supernatant was removed. To determine the maximum capture capacity, adsorbent beads (50 mg per vial) were incubated with 5 mL of 30 or 50 mM urea solution in PBS in two glass vials at 70 °C for 24 h. The beads were then allowed to settle, and the urea concentration in the supernatant was determined on an AU5800 routine chemistry analyzer (Beckman Coulter, Brea, CA) using a coupled enzyme reaction that yields a colorimetric (570 nm) product proportional to the urea concentration.

[0138] 1.12 Thermal analysis of monomers and beads Thermographic analysis (TGA) was performed as follows: The beads were heated in a platinum pan at a rate of 10°C / min. The weight loss (and therefore decomposition temperature) during ramp heating was measured on a TA Instruments TGA Q50. Differential scanning calorimetry (DSC) analyses of different samples were performed as follows: In an open aluminum pan, the monomer or beads were heated from -50°C to 250°C at a rate of 10°C / min, and the heat flow was monitored. The sample was then quenched from 250°C to -50°C and subsequently heated again to 250°C at a rate of 10°C / min. The Tg or melting point was determined using a TA Instruments Discovery DSC. For the beads, the results of the second experiment are reported because residual solvent evaporated during the first experiment. For the monomer (VPE), the events of the first experiment are reported.

[0139] Example 2 - Provision of Monomer 2.1 Design of the monomer of general formula (I) First, we investigated whether the reactivity of phenylglyoxalaldehyde hydrate (PGAH)-type adsorbents could be increased by appropriate substituents. The reaction kinetics of urea with para-methyl-PGAH (1b) (a PGAH derivative bearing an electron-donating group (EDG)) and para-nitro-PGAH (1c) (a PGAH derivative bearing an electron-withdrawing group (EWG)) were analyzed and compared with that of unsubstituted PGAH (1a) with urea. Regarding the influence of substituents on the reaction of ninhydrin analogs with urea, we did not investigate the meta-position of the EDG because the position of the EDG has been found to have a limiting effect on the overall reactivity of ninhydrin derivatives with urea (Jong, JAW et al., ChemistrySelect 2018, 3 (4), 1224-1229). An excess (50 equivalents) of urea was used to limit the formation of the 1:2 urea-PGA adduct. Because the urea concentration was much higher than the PGAH concentration, its concentration remained nearly constant, and therefore pseudo-first-order conditions were valid, making the reaction rate (-d[PGAH] / dt) dependent only on the PGAH concentration. The pseudo-first-order kinetics of the reaction of PGAH (and its derivatives) with urea was analyzed by determining the concentrations of 1a-c over time using UV spectroscopy. Due to the very low solubility of 1b and 1c in PBS alone, the solvent for this reaction was a 1:1 (v / v) PBS / DMSO mixture. The pseudo-first-order rate constant (k PFO ) corresponds to the negative slope in the plot of the logarithm of PGAH-(derivative) concentration versus time divided by log(e) and is reported in Table 1. This indicates that PGA analogs without the NO2 substituent are preferred.

[0140] [Table 1]

[0141] 2.2 General methods for providing monomers of general formula (I) Monomers can be purchased from commercial urea scavenger suppliers, if available, or prepared by chemical synthesis. Suitable starting materials for this purpose are acylation reactions starting from styrene or isopropenylbenzene or other commonly available derivatives. Ethynylbenzene is another suitable starting material, which can be acylated by partial hydrogenation of the triple bond to give vinyl analogs.

[0142] 2.3 Synthesis of p-(vinylphenyl)ethenone (VPE) [ka] In a three-necked round-bottom flask, p-(ethynylphenyl)ethenone (10.0 g, 69.4 mmol) was suspended in EtOH (350 mL) and Lindlar's catalyst (300 mg, 3 wt%) was added. The air was replaced with H2, and the suspension was stirred at room temperature for 2-16 h. To monitor the conversion (and thus prevent over-reduction of VPE to alkanes), samples were taken frequently from the reaction mixture, and the conversion was monitored after evaporation of EtOH under reduced pressure. 1 Determined by H-NMR (CDCl). After >90% conversion, the H-filled balloon was removed and the reaction mixture was concentrated under reduced pressure. The crude product was redissolved in CHCl and purified by filtration over Hyflo. The filtrate was concentrated under reduced pressure to give crude VPE as a yellow liquid in 99% yield (10.1 g, 69.0 mmol). Melting point 29 °C, enthalpy of fusion 90.6 J / g. 1 H-NMR (CDCl3, 600 MHz) δ 7.92 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 6.75 (dd, J =17.6 Hz, 10.9 Hz, 1H), 5.87 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 10.9 Hz, 1H),2.59 (s, 3H).

[0143] 2.4 Synthesis of 2-bromo-1-(4-ethenylphenyl)ethan-1-one [ka] In a round-bottom flask, p-(ethynylphenyl)bromo-ethenone (15.5 g, 69.4 mmol) is suspended in EtOH (350 mL) and Lindlar's catalyst (300 mg, 3 wt%) is added. The air is replaced with H2, and the suspension is stirred at room temperature for 2-16 h. Further following the procedure described in Example 2.3, the crude precursor monomer can be obtained as a yellow / brownish liquid.

[0144] 2.5 Synthesis of 2,2-dihydroxy-1-(4-ethenylphenyl)ethan-1-one [ka] VPE (146 mg, 1.0 mmol, 1.0 equiv) was dissolved in a 10:1 mixture of dioxane (3 mL) and HO (0.3 mL) in a microwave tube equipped with a magnetic stirrer. Selenium dioxide (2.0 mmol, 2.0 equiv) was added and the tube was sealed. The mixture was shaken vigorously until the selenium dioxide was completely dissolved, and the tube was placed in a microwave and heated at 180 °C for 5 min. The crude reaction mixture was impregnated onto silica and purified on silica (EtOAc:hexanes) to give pure 2,2-dihydroxy-1-(4-ethenylphenyl)ethan-1-one.

[0145] 2.6 Synthesis of 1-(4-ethenylphenyl)ethane-1,2-dione [ka] 2,2-Dihydroxy-1-(4-ethenylphenyl)ethan-1-one is dried overnight under vacuum over P2O5 to give 1-(4-ethenylphenyl)ethane-1,2-dione.

[0146] 2.7 Synthesis of (4-ethenylphenyl)(2-dioxolanyl)methanone [ka] 2,2-Dihydroxy-1-(4-ethenylphenyl)ethan-1-one (1 mmol, 1 equivalent) was dissolved in ethylene glycol and 1% by volume AcOH (5 mL) and stirred overnight at room temperature. CHCl was then added and the mixture was transferred to a separatory funnel. The organic layer was washed three times with water to remove ethylene glycol and AcOH. The organic layer was then concentrated to give (4-ethenylphenyl)(2-dioxolanyl)methanone.

[0147] Example 3 Polymerization General polymerization methods Polymerization of the monomer of general formula (I) can be carried out using any known polymerization method, such as ionic polymerization (anionic, cationic), free radical polymerization, or controlled radical polymerization (RAFT, ATRP). Any sufficiently inert dissolution solvent can be used. Suspension polymerization is an attractive method because it can result in a granular material. If a crosslinked adsorbent is desired, up to 10% of a crosslinker (e.g., divinylbenzene or butadiene) can be added to the monomer mixture before polymerization. Those skilled in the art can generally select a suitable crosslinker with two or more polymerizable moieties. Good results have been obtained using about 0.5% to about 4% of a crosslinker. If a more hydrophilic adsorbent is desired, a hydrophilic comonomer (e.g., vinylbenzenesulfonic acid or acrylic acid) can be added to the monomer mixture before polymerization. Those skilled in the art can generally select a suitable hydrophilic comonomer that has a single polymerizable moiety and also contains a highly polar group, such as a carboxylic acid or sulfonic acid. Because the polydispersity of the adsorbent is not particularly important, it is efficient to complete the polymerization, for example, by allowing the reaction to proceed overnight. This achieves high monomer economy and reduces the need for reaction monitoring. Purification can be achieved by precipitation in any solvent in which the unreacted materials dissolve, such as methanol. Alternatively, the polymerization mixture can be used as a crude mixture for further conversion.

[0148] 3.1 General solution polymerization method The monomer (0.5 mmol) was dissolved in EtOH (2–10 mL), and divinylbenzene (1–4 equiv.) and AIBN (1–3 mol%) were added. The flask was sealed, and nitrogen was bubbled through the solution for 20 minutes. The solution was heated to 60°C for 24 hours. The mixture was allowed to cool to room temperature, centrifuged, and the supernatant was removed. The resulting adsorbent was washed three times with EtOH and one final time with water. After centrifugation, the polymer was dried overnight under vacuum over PO.

[0149] 3.2 General suspension polymerization method NaCl (10.5 mg), polyacrylic acid sodium salt (468 mg of 10 wt% gel in water), and Ca3(PO4)2 (86 mg) were added to water (15 mL) in a glass reactor equipped with a mechanical stirrer and stirred for 30 minutes. Monomer (15 mmol), porogen (2-3 mL of a water-immiscible liquid), 50% benzoyl peroxide blend with 80% divinylbenzene (1-6 mol%) and dicyclohexyl phthalate (1 mol%) were mixed separately and added to the aqueous phase after dissolving the initiator. The mixture was stirred with a mechanical stirrer until an emulsion was obtained. Air was replaced with nitrogen in the glass reactor. The mixture was stirred at 73 °C for 16 hours, after which the suspension was filtered through a 200 μm filter. The resulting powder or beads in the residue were washed with acetone and water and dried under vacuum over PO2O5.

[0150] 3.3 Preparation of poly[(p-vinylphenyl)ethenone]-co-(divinylbenzene)] The same procedure as for the preparation of polystyrene beads was used, with some minor modifications. Briefly, the aqueous phase was prepared by adding NaCl (11 mg), polymethacrylic acid sodium salt solution (452 ​​mg of 10% gel in water), and CaHPO (84 mg) to water (15 mL). The organic phase consisted of VPE (2.1 g, 14.4 mmol, 2 mL), porogen (2.9 mL, see Table 2 for composition), 80% technical-grade DVB (3-6 mol%), and a 50% benzoyl peroxide blend with dicyclohexyl phthalate (174 mg, 0.36 mmol, 2.5 mol%). After mixing and polymerization (following the same procedure as in "Suspension Polymerization of Styrene"), the resulting suspension was cooled to room temperature and poured onto a filter (200 μm cutoff, Veco BV). The residue was washed with acetone and water and finally dried over P2O5 under vacuum to give pVPE (1.1-1.9 grams, 52-90% yield).

[0151] [Table 2]

[0152] Example 4 - Conversion of polymerized monomers General Methods for the Conversion of Monomers of General Formula (I) Table 3 shows suitable conversion methods for different monomers of general formula (I): Purification can be done by precipitation in any solvent in which the unreacted materials are soluble, such as methanol. [Table 3]

[0153] 4.1 Preparation of PGA-type adsorbents based on poly-VPE The different mixtures obtained in Example 3.3 were converted to PGA-type adsorbents. The conversion was carried out using halogenation and Kurnblum oxidation of pVPE for the original VPE-type material. The same procedure as for halogenation and Kurnblum oxidation of acetylated polystyrene beads was used for 12 hours (see Example 1.6), downscaled to 600 mg of PVPE per batch. After washing, 606 mg of yellow beads (pVPE-Ox) were obtained. Thus, the acetyl aromatic groups in the pVPE beads were halogenated and subsequently converted to PGAH groups by Kornblum oxidation in a one-pot procedure. To establish the optimal reaction time for these oxidation conditions to obtain the highest PGA / PGAH density, beads were collected from the reaction mixture at different time points and their urea-trapping capacity was determined (see Example 4). The urea-trapping capacity of the beads increased to over 2 mmol / g with oxidation time during the first 8 hours, demonstrating the successful oxidation of the acetyl groups to PGAH / PGA. For comparison, oxidation of acetylated PS beads (without precursor monomers) failed to achieve this binding capacity (see Example 4). At longer reaction times, the capture capacity decreased. IR analysis of the adsorbent obtained after 8 h of oxidation (Figure 5) showed a peak at 1675 cm -1 A single carbonyl peak was observed at 1740 cm -1 The adsorbent obtained after 48 hours of oxidation had a small shoulder peak at 1675 cm -1 and 1740 cm -1 The 8-hour sample showed two carbonyl peaks at 1740 cm, which are likely due to peroxidation (see Figure 3). -1 The shoulder peak at 0°C indicates that the overoxidation of PGA / PGAH to PGOA occurred already during the first 8 hours, but slower than the oxidation of the acetyl group to PGA / PGAH. To avoid this overoxidation, it is desirable to reduce the presence of HBr or shorten the reaction time. The reaction time for oxidation is preferably up to 32 hours, more preferably up to 24 hours, even more preferably up to 16 hours, and most preferably up to about 8 hours.

[0154] 4.2 Preparation of PGA-type adsorbents based on poly(VPE-Br) Essentially, this material can be treated as poly-VPE without the need for halogenation. The polymer resin (500 mg) obtained by the general suspension polymerization method described above is swollen in DMSO and stirred with a mechanical stirrer. Trimethylamine is used as the base for DMSO oxidation, which is carried out by heating the suspension to 80°C for 8 hours. After washing as in Example 1.6, a PGA-type adsorbent is obtained.

[0155] 4.3 Preparation of PGA-type adsorbents based on poly(protected PGA) This material, essentially polymerized (4-ethenylphenyl)(2-dioxolanyl)methanone (see Example 2.7), is a protected PGA-type adsorbent, i.e., a PGA-type adsorbent in which the glyoxal moiety is acetal-protected. The resin is swelled in THF, followed by the addition of catalytic acetic acid and 5% by volume of water to deprotect the glyoxal moiety. The solvent is filtered twice, after which a fresh batch of THF, water, and acetic acid is added. The adsorbent is then washed twice with water and dried as described in Example 1.6 to yield the PGA-type solvent.

[0156] Example 5 - Analysis of Adsorbents A general method for determining urea scavenging capacity. The adsorbent (10 mg or 15 mg) was suspended in urea-enriched PBS (30 mM, 1 mL or 1.5 mL) in 1.5 mL microcentrifuge tubes (Eppendorf, individual tubes for each time point) and placed at 37°C for a set time. The adsorbent was spun down in the tube (12,000 rpm for 5 minutes in a conventional tabletop centrifuge) and assayed using a commercial urease assay (urea CT purchased from DiaSys Diagnostic Systems GmbH, Holzheim, Germany). * FS ** The urea concentration in the supernatant was determined using a colorimetric test. Briefly, this test determines urea concentration via a coupled enzymatic reaction, resulting in a colorimetric (570 nm) product whose concentration is proportional to the urea concentration. To determine the maximum urea scavenging capacity, samples were placed at 70°C for 24 hours, and the urea concentration was determined in the supernatant. Alternatively, sorbent (15 mg) was suspended in 1.5 mL of urea in PBS (1.5 mL, 30 mM or 50 mM) in a 1.5 mL Eppendorf tube and placed in a rotating oven at 70 °C. After 24 h, the samples were cooled to room temperature, and the urea concentration in the supernatant was determined by a standard urease assay (a urea stock solution kept at 70 °C for 24 h was used as a negative control). The urea retention capacity of the sorbent was calculated based on the difference in urea concentration between the sorbent supernatant and the control solution.

[0157] 5.1 Analysis of styrene-derived beads Quantitative determination of PS-type adsorbent 13 The amount of PGAH groups in PS-Ac-Ox was quantified by C solid-state NMR. 13 The CH3 peak of the acetyl group detected in the C-NMR spectrum disappeared, indicating that all acetyl groups had been converted. Comparing the area under the hydrate carbon peak (80-100 ppm) with the areas under the aromatic peak (110-160 ppm) and the aliphatic peak (10-50 ppm) indicated that approximately 40% of the aromatic groups (and therefore approximately 67% of the acetyl groups) had been converted to PGAH groups. In addition, a small peak was detected around 165 ppm, which is attributed to the carboxylic acid carbonyl peak from PGOA. PS-Ac beads were oxidized for 8 hours on a 60-gram scale, and the resulting beads (PS-Ac-Ox) were characterized by SEM, optical microscopy, and nitrogen physisorption. PS-Ac-Ox exhibited similar size (0.54 ± 0.11 mm), surface area (37.0 m), and surface area (37.0 m) to PS and PS-Ac. 2 The pore volume and pore size / volume distributions were shown. This confirms that the oxidation reaction does not affect the macroporosity or degrade the beads, presumably because the reaction temperature (80 °C) is lower than the glass transition temperature (Tg) of both the PS-Ac and PS-Ac-Ox beads (Tg of the dried beads was 184 °C and >230 °C, respectively). 13 The PGAH content of the adsorbents measured by C-NMR was similar to that of the small-scale prepared adsorbents. The urea trapping capacity of Ps-Ac-Ox was 1.4 mmol / g. Table 4 shows the properties of these adsorbents. [Table 4]

[0158] 5.2 Analysis of beads derived from precursor monomers Table 2, entry 2(S BET <0.05m 2 / g) and Entry 4 (S BET =2.0m 2 Beads with a surface area of ​​1.8 mmol / g were selected for conversion. Beads with a low surface area (entry 2) were oxidized for 4 to 12 hours under the same conditions applied to PS-Ac. The urea trapping capacities of the resulting oxidized pVPE beads (pVPE-Ox-(2)) ranged from 1.8 to 2.2 mmol / g, of which the highest trapping capacity (2.2 mmol / g) was obtained after 12 hours of oxidation (see Figure 4). Accordingly, the pVPE beads with the highest surface area (entry 4) were oxidized for 12 hours, and the urea trapping capacity of these beads (pVPE-Ox-(4)) was 1.8 mmol / g. The surface area of ​​pVPE-Ox-(4), determined by nitrogen physisorption, was significantly higher than that of the corresponding pVPE beads (1.9 vs. 2.0 m). 2 / g), most likely because the reaction temperature of the oxidation reaction (80 °C) is much lower than the Tg of the pVPE beads (147 °C), and therefore the beads remain dimensionally stable under these oxidation reaction conditions. The VPE-based materials showed higher urea trapping capacities than the styrene-based materials, which may be due to the increased density of acetyl groups and therefore the higher PGAH content after oxidation (1.4 vs. 1.8–2.2 mmol / g). Surprisingly, the surface area of ​​the pVPE beads did not affect the urea trapping capacity (1.8–2.2 and 1.8 mmol / g for pVPE-Ox-(2) and pVPE-Ox-(4), respectively). This indicates that the PGAH groups are accessible to urea even in materials without macroporosity, likely due to the polar and hydrophilic carbonyl groups and, optionally, the carboxylic acid groups of PGOA, which allow the adsorbent to swell slightly but sufficiently in water (Figure 3). Additionally, upon urea trapping, the beads become more hydrophilic, further increasing their accessibility to water and urea, thereby further improving urea binding kinetics. The average size of pVPE-Ox-(4) beads, determined by optical microscopy, was slightly larger than that of pVPE beads (0.77 ± 0.20 and 0.61 ± 0.23 mm, respectively). Due to swelling / deswelling of the beads during nitrogen physisorption experiments, the pore / volume distribution of these materials was not determined. pVPE-Ox-(4) and the corresponding pVPE beads were analyzed by SEM and appeared hollow (they shrunk after drying under vacuum, suggesting core-shell phase separation during the polymerization reaction). To determine the density of PGAH groups in pVPE-Ox-(2) and pVPE-Ox-(4), these materials were analyzed. 13 The products were analyzed by C solid-state NMR spectroscopy. Comparison of the hydrate peak integrals (80-100 ppm) with the backbone peak integrals (10-50 ppm) demonstrates a PGAH content of approximately 50% for both pVPE-Ox-(2) and pVPE-Ox-(4), confirming that higher PGAH contents (approximately 50 and 40%, respectively) can be obtained using the VPE instead of styrene route.

[0159] 5.3 Analysis of urea binding behavior pVPE-Ox adsorbent beads functionalized with approximately 50% PGAH groups were found to have a urea uptake capacity of approximately 2 mmol / g. However, a 100% functionalized adsorbent contains 5.5 mmol / g of PGAH groups (including 3% crosslinker) based on the molecular weight of the monomer (178 g / mol), meaning that an adsorbent with approximately 50% PGAH groups has a urea uptake capacity of up to 2.8 mmol / g. There are two reasons why the actual urea uptake capacity of an adsorbent functionalized with PGAH groups is lower than the theoretical urea uptake capacity based on a 1:1 reaction of urea with PGAH. First, some of the PGAH groups may not be accessible to urea. Second, PGAH can react with urea in both 1:1 and 2:1 ratios (see structure 3'a in Figure 5). Therefore, one potential binding site is lost when PGAH reacts with urea in a 2:1 ratio. 13 Quantification of the inaccessible, and therefore unreacted, PGAH groups in beads with approximately 2 mmol of urea per gram of adsorbent by C-NMR spectroscopy is not possible because unreacted and reacted PGAH give rise to signals in the same region of the spectrum. Therefore, adsorbent beads reacted with urea (PS-AC-Ox@urea and pVPE-Ox-(4)@urea), along with PGAH and the 2:1 adduct of PGAH and urea (3'a), were analyzed by IR spectroscopy (Figure 5). PGAH has a peak at 1700 cm. -1 It exhibits a clear ketone-carbonyl stretching vibration at 1210cm -1 However, these peaks have lower intensity in the IR spectra of PS-Ac-Ox@urea and pVPE-Ox-(4)@urea, and the main carbonyl peak is obviously shifted (1700–1740 cm). -1 ) Based on these observations, we conclude that the majority of the PGAH groups were indeed available for and reacted with urea. This is consistent with the observation that surface area does not affect the urea capture capacity. Furthermore, the IR spectra of PS-AC-Ox@urea and pVPE-Ox-(4)@urea are more similar to that of the isolated 2:1 addition product 3'a. 3'a has a peak at 1650–1800 cm -1Several peaks arising from carbonyl stretching vibrations in the region of 1000 nm are also present in the spectra of PS-AC-Ox@urea and pVPE-Ox-(4)@urea. Therefore, we can conclude that the reaction of the 1:1 PGAH:urea adduct with the second PGA group occurs at least to some extent in the adsorbent beads, explaining the difference between the urea uptake capacity of the adsorbent (approximately 2.0 mmol / g) and the theoretical capacity (2.8 mmol / g) based on the actual PGAH content. The kinetics of urea binding for two different types of PGA-type adsorbents were investigated by incubating them in a 30 mM urea solution in phosphate-buffered saline (PBS) at 37 °C, conditions representative of dialysate regeneration. Urea capture was determined by measuring the urea concentration in the solution at different time points (Figure 6A). The PS-Ac-Ox adsorbent showed only 0.5–0.6 mmol / g capture after 24 h. The adsorbent pVPE-Ox-(4) already captured 0.5–0.6 mmol per gram at 8 h, which increased to 0.8–0.9 mmol / g after 24 h, reaching approximately 50% of its maximum capture capacity. Figure 6B shows that both materials reached approximately 45% of their maximum capture capacity after 24 h.

[0160] 5.4 Maximum binding capacity of various adsorbents The maximum urea uptake capacity was determined for different adsorbents, either in PS or precursor form. Table 5 shows the urea uptake capacity of the adsorbent beads in a urea solution (10 mg / mL) in PBS under static conditions at 70 °C for 24 h. [Table 5]

[0161] 5.5 Conclusion Phenylglyoxalaldehyde hydrate (PGAH)-containing PGA-type adsorbent beads were successfully prepared using suspension polymerization via a precursor monomer followed by monomer conversion (here, oxidation) of the precursor to PGA. The VPE route outperforms known routes using styrene and also saves one postpolymerization modification step. Importantly, it results in adsorbents with higher PGAH content (approximately 50% vs. approximately 40% for PS-type adsorbents) and concomitantly higher binding capacity (>1.8 mmol / g vs. 1.4 mmol / g for PS-type adsorbents). The accessibility of the PGAH groups in the VPE-type sorbent does not depend on the surface area of ​​the material, likely due to slight swelling of the beads. Urea adsorption kinetics from simulated dialysate showed that the capture capacity reached approximately 30% after 8 h at 37 °C. The best sorbent developed (pVPE-Ox-(4)) bound approximately 0.5–0.6 mmol / g at 8 h, demonstrating that approximately 700 grams of this PGAH-type sorbent would be required to remove 400 mmol of the daily urea produced by an end-stage renal disease patient during an 8-h dialysis session.

[0162] [References] Ashraf S. M. “A Laboratory Manual of Polymers” I. K. InternationalPvt Ltd, 8 dec. 2008; Becker and Russell, J. Org. Chem., 1963 DOI:10.1021 / jo01042a502; Evenepoel P, Bammens B, Verbeke K, Vanrenterghem Y. KidneyInt 2006;70:794-9; De Fijter CW, Oe PL, Nauta JJ, et al. Adv Perit Dial1991;7:186-9; Gardner et al., Appl Biochem Biotechnol. 1984;10:27-40; Gotch FA.Kinetic modeling of continuous flow peritoneal dialysis. Semin Dial2001;14:378-83; Katritzky et al., Chem. Rev. (2004) DOI: 10.1021 / cr020750m;Perl J, Wald R, Bargman JM, et al. Clin J Am Soc Nephrol 2012;7:1145-54;Piraino B, Sheth H. Blood Purif 2010;29:145-9; Marminon et al., (2015, DOI:10.1016 / j.tetlet.2015.02.086 ; “Metal-Catalyzed Cross-Coupling Reactions” 2 nded. (2008) DOI: 10.1002 / 9783527619535 ; Nesrallah GE et al., J Am Soc Nephrol2012;23:696-705 ; Susantitaphong P et al., Am J Kidney Dis 2012;59:689-99 ;Ting GO, Kjellstrand C, Freitas T, Carrie BJ, Zarghamee S. Am J Kidney Dis2003;42:1020-35 ; EP121275A1 / US4897200A / DE2305186A1 / US3933753A / WO2004078797A1 / US4178241A / WO2017116515A1 / WO2011102807A1 / WO2019110557 / WO2016126596.

Claims

1. 1. A method for producing a phenylglyoxalaldehyde (PGA)-type adsorbent, comprising: i) providing a monomer of general formula (II-p); 【Chemical 1】 Here, h １ , h ２ and h ３ are each independently H, halogen, —OH, —O(C １－６ hydrocarbon), -S(C １－６ hydrocarbon), -NH(C １－６ hydrocarbon) or -N(C １－６ hydrocarbons) ２ or h １ and h ２ together form =O; or h １ and h ２ Let's get together-o １ -(C １－４ Hydrocarbon)-o ２ -, where o １ and o ２ are independently O, S, NH, or N(C １－４ hydrocarbons); ii) polymerizing the provided monomers to obtain a polymer; and iii) converting polymerized monomers of general formula (II-p) that are not PGA type monomers into PGA type monomers, wherein more than 45% of the monomers of general formula (II-p) are converted into PGA type monomers. A method comprising:

2. 2. The method of claim 1, wherein the monomer of general formula (II-p) comprises a monomer selected from 1-(4-ethenylphenyl)ethan-1-one, 2-bromo-1-(4-ethenylphenyl)ethan-1-one, 2-chloro-1-(4-ethenylphenyl)ethan-1-one, 1-(4-ethenylphenyl)ethane-1,2-dione, and 2,2-dihydroxy-1-(4-ethenylphenyl)ethan-1-one.

3. The method according to claim 1 or 2, wherein a comonomer is provided together with the monomer of general formula (II-p).

4. 4. The method of claim 3, wherein the comonomer is selected from the group consisting of styrene, isopropenylbenzene, divinylbenzene, vinylbenzenesulfonic acid, acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, 2-hydroxylethyl 2-methylprop-2-enoate (HEMA), 2-hydroxypropyl 2-methylprop-2-enoate, 2-hydroxylethyl prop-2-enoate, 2-hydroxypropyl prop-2-enoate, N-(2-hydroxylethyl)methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-hydroxylethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, telechelic N,N'-alkylenebisacrylamide, N-isopropylacrylamide (NIpAM), divinyl sulfone, butadiene, acrylonitrile, methacrylonitrile, vinyl sulfonamide, N-alkylvinyl sulfonamide, and N,N-dialkylvinyl sulfonamide.

5. The method of any one of claims 1 to 4, wherein the polymer is crosslinked after or during polymerization.

6. The conversion in step iii) a) optional halogenation; and b) Oxidation The method according to any one of claims 1 to 5, comprising:

7. The method according to any one of claims 1 to 6, h １ and h ２ are each independently H, halogen, —OH, and —O(C １－４ or together form =0; and / or h ３ is H, method.

8. The method according to any one of claims 1 to 7, wherein the monomer of general formula (II-p) comprises at least 1-(4-ethenylphenyl)ethan-1-one or 2-bromo-1-(4-ethenylphenyl)ethan-1-one.

9. a polymeric PGA-type adsorbent having a urea scavenging capacity of greater than 1.60 mmol of urea per gram of adsorbent, and at least 45% of the polymerized monomers being PGA-type monomers; A PGA-type adsorbent, wherein the PGA-type monomer is 1-(4-ethenylphenyl)ethane-1,2-dione or 2,2-dihydroxy-1-(4-ethenylphenyl)ethan-1-one.

10. A composition comprising the PGA-type adsorbent of claim 9 and a pharmaceutically acceptable excipient.

11. A PGA-type adsorbent according to claim 9 or a composition according to claim 10 for use as a medicament.

12. 11. The PGA-type adsorbent of claim 9, or the composition of claim 10, for use in the treatment of a disease or condition associated with urea accumulation.

13. 1. A method for removing nucleophilic waste solutes from a fluid, comprising: i) providing a fluid containing a nucleophilic waste solute; and ii) contacting said fluid with a PGA-type adsorbent according to claim 9 or a composition according to claim 10; or alternatively iib) contacting the fluid with a dialysis fluid through a membrane, the dialysis fluid being in contact with the PGA-type sorbent of claim 9 or the composition of claim 10; and iii) optionally recovering the fluid A method comprising:

14. 11. A cartridge for use in a dialysis device comprising the PGA-type sorbent of claim 9 or the composition of claim 10.

15. A dialysis device comprising the PGA-type sorbent of claim 9, the composition of claim 10, or the cartridge of claim 14.

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