Amphotericin B is known as a drug having microbicidal effect by binding to ergosterol of cell membrane of fungi and forming ostium to membrane from long ago. Amphoteiricn B is used as formulation using deoxycholic acid or liposome due to its low water solubility and high toxicity. However, the formulation using deoxycholic acid is still high toxicity, so satisfactory administration and long-term treatment cannot be achieved. The formulation using liposome can greatly avoid possibility of hepatotoxicity and nephrotoxicity compared with the formulation using deoxycholic acid, but effective treatment is not still actually achieved because of decrease of drug efficacy (Non-patent Document 1, 2).
Therefore, chemical modification of amphotericin B has been tried for the improvement of its water solubility or the avoidance of its toxicity. For example, amphotericin B derivative having amide at 16th position (Patent Document 1, 3, 4, 5, 10) and ester derivative (Patent Document 2, 6, 7, 9, 11) are disclosed. In addition, amphotericin B derivatives having a modification at amino sugar part are disclosed as Patent Documents 1 to 4, 6 to 8, and 11. However, amphotericin B derivative having 16th position urea structure at is not disclosed in the above documents (Non-patent Document 3).
Moreover, amphotericin B derivatives having urea structure at 16th position wherein the end of urea is methyl, amino or carboxy are presented by Martin D Burke et al. at congress of American Chemical Society (ACS) on Mar. 18, 2014 (Non-patent Document 4), and such the derivatives were disclosed in Patent Document 11 and released as scientific journal (Non-patent Document 5). It was suggested there that amphotericin B derivative having amino at the end part has lower nephrotoxicity than that of having carboxy at the end part.
USPTO Backgrounds
USPTO Backgrounds