POLYMIXIN DERIVATIVE OF THE GENERAL FORMULA (I); COMBINATION PRODUCT; PHARMACEUTICAL COMPOSITION; METHOD FOR THE TREATMENT, RELIEF OR IMPROVEMENT OF AN INFECTION, IN A PATIENT, CAUSED BY A GRAM-NEGATIVE BACTERIA; METHOD FOR SENSITIZING GRAM-NEGATIVE BACTERIA TO AN ANTIBACTERIAL AGENT; METHOD FOR THE DEVELOPMENT OF UNPUBLISHED ANTIBIOTICS; METHODS FOR REDUCING THE TOXICITY OF POLYMIXINS, NATURAL OCTAPEPTINS AND THEIR DERIVATIVES DURING THE APPLICATION OF THE SAME IN THE TREATMENT OF INFECTIONS IN AN INDIVIDUAL; METHOD TO IMPROVE PHARMACOKINETIC PROPERTIES, OF POLYMIXINS, NATURAL OCTAPEPTINS AND THEIR DERIVATIVES; METHOD FOR THE AWARENESS OF CLINICALLY IMPORTANT GRAM-NEGATIVE BACTERIA TO A DEFENSE MECHANISM COMPLEMENT IN THE SERUM; USE OF A DERIVATIVE; AND PROCESS FOR THE PREPARATION OF A POLYMIXIN DERIVATIVE OF FORMULA (I)

摘要

POLYMIXIN DERIVATIVE OF GENERAL FORMULA (I); COMBINATION PRODUCT; PHARMACEUTICAL COMPOSITION; Method of treating, relieving or ameliorating an infection in a patient caused by a GRAM-NEGATIVE BACTERIA; METHOD FOR AWARENING GRAM NEGATIVE BACTERIA TO AN ANTIBACTERIAL AGENT; METHOD FOR DEVELOPING ANTIBIOTICS; METHOD FOR REDUCING THE TOXICITY OF POLYMIXINES, NATURAL OCTAPEPTINS AND THEIR DERIVATIVES DURING APPLICATION OF THE SAME IN THE TREATMENT OF INFECTIONS IN AN INDIVIDUAL; METHOD FOR IMPROVING PHARMACOKINETIC PROPERTIES, AND POLYMIXINS, NATURAL OCTAPEPTINS AND THEIR DERIVATIVES; METHOD FOR SENSITIZING CLINICALLY IMPORTANT GRAN NEGATIVE BACTERIA TO A SERUM DEFENSE MECHANISM COMPLEMENT; Use of a derivative and process for the preparation of a polymyxin derivative of formula (I). The present invention relates to a polymyxin derivative in R1, R2 and R3 are optional and R1, R2, R3, R5, R8, R9 are selected cationic or neutral amino acid residues such that the total number of positive charges to a physiological pH is at least two, but not above three; and to a combination product comprising at least two such derivatives. The invention further relates to a method for treating, alleviating or ameliorating an infection in a patient caused by a Gram-negative bacterium by administering a therapeutically effective amount of a derivative according to the present invention; a method for sensitizing Gram-negative bacteria to an antibacterial agent by administering, simultaneously or sequentially, in any order, a therapeutically effective amount of the antibacterial agent and a derivative according to the present invention to the patient; methods for developing novel antibiotics to reduce nephrotoxicity, to improve the pharmacokinetic properties of natural polymyxins and octapeptins; and for sensitization of clinically important bacteria to a complement of host defense mechanism present in serum. Finally, the present invention relates to a process for the preparation of such polymyxin derivatives.