New hirudin-poly:alkylene glycol conjugate(s) - used as anticoagulants for treatment and prophylaxis of myocardial infarct, arterial occlusion, venous thrombosis and pulmonary embolism

摘要

Hirudin-polyalkylene glycol conjugates (I) (A-(CH2)n-(O-(CH2)n)m-B-)pHir are new. In (I): A=OH, NH2, CH3CONH, COOH, COOR or OR; R = 1-4C alkyl; B = direct bond or a linker; Hir = hirudin, desulphatohirudin or hirudin mutein gp. linked via serine, threonine or lysine chain(s); m = 100-1000; n = 2-5; p = 1-4. Pref. the linker is (a) -O-(CH2)n-1-CH= or -O-(CH2)n-1-CO-; or (b) -X-CO-, -X-CO-NH-Z-NH-CO-, -X-CH2-p-Ph-N2-, -X-CH2-CH(OH)-CH2-p-Ph-N2-, -X-CO-CH2-CH2-CO-, -X-CH2-CO- or gp. of formula (i); R1 = H, Cl or OH; X = -S-, -O-, -N(H, CH3 or C2H5)-; and Z = 2-6C alkylene or p-phenylene. USE/ADVANTAGE - (I) are anticoagulants in human and veterinary medicine to treat and prevent e.g. myocardial infarct, peripheral arterial occlusions, deep vein thrombosis and pulmonary embolism. They are administered i.v. or i.m. (I) have a half-life of 1-100 hours, compared with 50 mins. for hirudin itself and 7 hours for hirudin-dextran. Further, (I) have high activity with only very slight antigenicity.