C-reactive protein (CRP) is an acute phase reactant produced by the liver in response to cytokine release during inflammation. It has long been used in clinical practice to follow systemic inflammation, especially bacterial infection. More recently, epidemiological evidence has shown that basal levels of CRP, in the absence of apparent inflammatory disease may be informative in predicting future myocardial or cerebrovascular events (Ridker et al. Circulation, 2001 103, 1813). Also of interest is the fact that CRP is a potential inflammatory marker believed to be of value in the prediction of coronary events (Danesh et al. N. Engl. J. Med. 2004 350, 1387) and that CRP is a causative factor of the destructive processes observed during the weeks after myocardial infarction (Slagman et al., Blood Purif. 2011, 31, 9).
Several studies have shown the binding affinity of phosphoryl choline (PC) for CRP. Hence, PC derivatives immobilized on a solid support are widely used to isolate PC binding proteins from different biological sources. However, the most important clinical application of above mentioned PC derivatives immobilized on solid support is the extracorporeal removal of C-reactive protein and anti-phosphoryl choline antibodies from a biological fluid.
WO 90/12632 describes a method for removing CRP and anti-phosphoryl choline antibodies from biological fluids to improve the cellular immune responses thereof, and a method for removing CRP and anti-phosphoryl choline antibodies from the circulation of patients with cancer by conducting extracorporeal perfusion of a patient's blood plasma through a phosphoryl choline-matrix adsorption device so as to improve the patient's cellular immune responses against the cancer.
WO 2007/076844 describes a method for treating the risk of accumulating CRP by performing an extracorporeal perfusion of blood plasma of patients presenting a risk of cardiovascular diseases or immune dysfunctions such as autoimmune diseases by means of a column, which contains absorbent matrix material including PC derivatives to eliminate CRP from a patient's biological liquids so as to prevent and/or treat autoimmune diseases, cardiovascular diseases such as myocardial infarction, stroke, diabetes, rheumatism, and renal insufficiency.
The synthesis of PC derivative of bovine serum albumin (PC-BSA), its immobilization on Toyopearl® HW 65 and its use for CRP affinity purification was also described (Stults et al. Anal. Biochem. 1987, 161, 567). In this study, the immobilization of the PC derivative on the solid support was achieved via formation of a phosphodiester linkage. Others PC derivatives were in a similar manner immobilized on a solid support (Spande T. F. J. Org. Chem. 1980, 45, 3081; Martin, L. M. Tetrahedron Lett. 1996 37, 7921).
WO 2013/176084 A1 discloses also a silylalkyl phosphoramidate compound of general formula (1) for coating a medical device in order to suppress the adhesion of biological material, such as platelets.

WO 2012/160187 A1 provides ammonium-containing phosphonic acid derivatives for use in the treatment of an inflammatory, autoimmune and/or allergic disorder. It is postulated that the disclosed compounds exert their pharmacological activity through inhibition of the phosphoinositide 3-kinase (PI3K)/Akt kinase pathway.
At our knowledge, up to present the immobilization of PC on solid support was achieved only via formation of a phosphodiester bond. The immobilization of PC derivatives via phosphodiester bond formation has some advantages, but also severe drawbacks. The main drawback of this approach is that formation of phosphodiester bond changes the overall charge (net charge) of the molecule of PC and thereby, alters the orientation of so modified PC in a binding pocket. In addition, a phosphodiester bond can be easily cleaved by non-specific phosphodiesterases present in the biological fluids leading to instability issues of the matrices, which were substituted in such manner.
To eliminate the aforementioned drawbacks, it is the objective of the present invention to provide compounds, which can be immobilized on a solid support to provide a separation material that bind with both high affinity and high specificity CRP for prophylaxis and/or treatment of immune dysfunctions and cardiovascular diseases by extracorporeal removal of CRP and anti-phosphoryl choline antibodies.
This objective is solved by the compounds of general formula (I) according to independent claim 1, the separation material according to independent claim 5 for use in the extracorporeal removal of CRP and anti-phosphoryl choline antibodies from a biological fluid of a patient for prophylaxis and/or treatment of immune dysfunctions and cardiovascular diseases.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.
USPTO Backgrounds
USPTO Backgrounds