| 摘要 |
1323362 Polymyxin derivatives RHONEPOULENC SA 4 Aug 1970 [5 Aug 1969] 37632/70 Headings C2A and C2C Novel cyclic polypeptides having the general Formula I wherein Y-Z represents one of the amino acid chains D-Leu-Thr, D-Phe-Leu, D-Leu- Leu and D-Leu-Ileu ; G is a radical of Formula II: Py-CH 9 -O-CO- in which Py is pyridyl or pyridyl-N-oxide optionally substituted by a methyl group, Dab represents α,γ-diaminobutyric acid, Thr is threonine, Phe is phenylalanine, Leu is leucine and lieu is isoleucine, the amino acids having the L configuration unless otherwise stated, are prepared by hydrolysing a polymyxin of Formula III wherein K is an n-octanoyl, L-6-methyloctanoyl or 6-methylheptanoyl radical, G and Dab are as above, and either (1) Y-Z is D-Leu-Thr and X is D-Dab or D-Serine, or (2) Y-Z is D-Phe- Leu or D-Leu-Leu and X is Dab, or when K is L-6-methyloctanoyl or 6-methylheptanoyl then Y-Z may be D-Leu-Ileu and X is Dab, and when X is Dab it optionally has a group G on the γ-amino group, by an enzyme which is a protease from B. subtilis A.T.C.C. 9524 or an exocellular protease from any appropriate strain of B. subtilis. The preferred enzymes are subtilisin, nagarse, pronase, colistinase or Alcalase (Registered Trade Mark). The compounds of Formula I are useful as intermediates for synthesizing polymyxin analogues having a modified side chain by reacylating the α-amino group on the Dab with an appropriate acid radical, and subsequently removing the protective groups G from the other amino groups e.g. by hydrogenolysis. The starting materials of Formula III are prepared by reacting a polymyxin e.g. colistin, polymyxin B, with a mixed carbonate of Formula V below suitably in an organic solvent such as dimethyl-formamide at 15‹ to 60‹ C. If desired the pyridyl group may be oxidized to the N-oxide before or after the reaction e.g. with p-nitroperbenzoic acid. Compounds having the general Formula V wherein Py is as hereinbefore defined and T is phenyl, substituted phenyl (e.g. p-nitrophenyl; 2,4,5-trichlorophenyl) or a heterocyclic radical (e.g. 8-quinolinyl or 2,5-dioxopyrrolidin-1-yl) are prepared by reacting an alcohol of formula Py-CH 2 -OH with a chloroformate of formula Cl-CO-O-T, and if required oxidizing the pyridyl radical to pyridyl-N-oxide, e.g. with p-nitroperbenzoic acid. |
