C5a Receptor Antagonists

Abstract

The present invention is related to a compound, preferably a C5a receptor antagonist, having the following structure: whereby X1 is a radical with a mass of about 1-300, whereby X1 is preferably selected from the group comprising R5-, R5-CO—, R5-N(R6)-CO—, R5-O—CO—, R5-SO 2 —, R5-N(R6)-SO 2 —, R5-N(R6)-, R5-N(R6)-CS—, R5-N(R6)-C(NH)—, R5-CS—, R5-P(O)OH—, R5-B(OH)—, R5-CH═N—O—CH 2 —CO—, whereby R5 and R6 are individually and independently selected from the group comprising H, F, hydroxy, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, alkoxy, alkoxyalkyl, substituted alkoxyalkyl, aryloxyalkyl and substituted aryloxyalkyl, X2 is a radical that mimics the biological binding characteristics of a phenylalanine unit, X3 and X4 are individually and independently a spacer, whereby the spacer is preferably selected from the group comprising amino acids, amino acid analogs and amino acid derivates, X5 is a radical that mimics the biological binding characteristics of a cyclohexylalanine or homoleucine unit, X6 is a radical that mimics the biological binding characteristics of a tryptophane unit, X7 is a radical that mimics the biological binding characteristics of a norleucine or phenylalanine unit, a chemical bond is formed between X3 and X7, and the connecting lines—in formula (I) represent chemical bonds, whereby the chemical bond is individually and independently selected from the group comprising covalent bonds, ionic bonds and coordinative bonds, whereby preferably the bond is a chemical bond and more preferably the chemical bond is a bond selected from the group comprising amide bonds, disulfide bonds, ether bonds, thioether bonds, oxime bonds and aminotriazine bonds.

1 . A method of preventing or treating a condition associated with complement activation and/or where the inhibition of the complement system leads to a relief of symptoms in a patient in need of such prevention, treatment or relief, comprising administering an effective amount of a medicament Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2 to said patient. 
     
     
         2 . The method according to  claim 1 , wherein the condition is such that the inhibition of the C5a receptor by Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2 alone or in combination with other therapeutics leads to a relief of the symptoms. 
     
     
         3 . The method according to  claim 1 , wherein the condition and/or the symptoms to be treated are selected from the group comprising autoimmune diseases, acute inflammatory diseases, trauma, local inflammations, shock and burn. 
     
     
         4 . The method according to  claim 1 , wherein the condition is selected from the group comprising rheumatoid arthritis, ankylosis spodylitis, sarcoidosis, systemic lupus erythematosus, multiple sclerosis, psoriasis, septic shock, haemorrhagic shock, systemic inflammatory response syndrome (SIRS), multiple organ failure (MOF), asthma, vasculitis, myocarditis, dermatomyositis, inflammatory bowel disease (IBD), pemphigus, myasthenia gravis, glomerulonephritis, acute respiratory insufficiency, stroke, myocardial infarction, reperfusion injury, neurocognitive dysfunction, anti-phospholipid syndrome, burn, inflammatory diseases of the eye, local manifestations of systemic diseases, inflammatory diseases of the vasculature, and acute injuries of the central nervous system. 
     
     
         5 . The method according to  claim 1 , wherein the inflammatory disease of the eye is selected from the group comprising uveitis, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, ocular pemphigoid, keratoconjunctivitis, Stevens-Johnson syndrome, and Graves opthalmopathy. 
     
     
         6 . The method according to  claim 1 , wherein the condition is a local manifestation of a systemic disease, whereby the systemic disease is selected from the group comprising rheumatoid arthritis, SLE, type I diabetes, and type II diabetes. 
     
     
         7 . The method according to  claim 1 , wherein the manifestations are selected from the group comprising manifestations at the eye, at or in the brain, at the vessels, at the heart, at the lung, at the kidneys, at the liver, at the gastro-intestinal tract, at the spleen, at the skin, at the skeletal system, at the lymphatic system, and in the blood. 
     
     
         8 . The method according to  claim 1 , wherein the inflammatory disease of vasculature is selected from the group comprising vasculitis, vascular leakage, and atherosclerosis. 
     
     
         9 . The method according to  claim 1 , wherein the medicament is used for the prevention and/or the support of surgery. 
     
     
         10 . The method according to  claim 1 , wherein the medicament is used for the prevention and/or support and/or post-operative treatment of a surgery, whereby the surgery is selected from the group comprising CABG, PACT, PTA, MidCAB, OPCAB, thrombolysis, organ transplantation, and vessel clamping. 
     
     
         11 . The method according to  claim 1 , wherein the medicament is used for thrombolytic treatment. 
     
     
         12 . The method according to  claim 1 , wherein the medicament is used in the settings of dialysis therapy, optionally before, during, and/or after such therapy. 
     
     
         13 . The method according to  claim 1 , wherein the medicament is used for the prevention of organ damage of a transplanted organ or of an organ to be transplanted. 
     
     
         14 . The method according to  claim 1 , wherein the medicament is used for the prevention or treatment of transplant rejection.