Patent GB-1378025-A (GB)
Title: Polymyxin derivatives
IPC: A61K38/00
Filed: 1972-02-01
Abstract: 1378025 Polymyxins RHONE-POULENC SA 1 Feb 1972 [2 Feb 1971] 4730/72 Headings C2A and C2C [Also in Division C3] Antibiotic polymyxins having the general Formula(I) wherein A is C 1-2  alkyl substituted by a mono- or polycyclic cycloalkyl radical or a phenyl radical which may be substituted by halogen or C 1-4  alkoxy; straight or branched chain C 3-4  alkyl optionally substituted by hydroxy, amino or cyano or a mono- or polycyclic cycloalkyl radical or a phenyl radical which may be substituted by halogen or C 1-4  alkoxy; straight or branched chain C 5-8  alkyl optionally substituted by hydroxy, amino or cyano; or phenyl optionally substituted by halogen or C 1-4  alkoxy; X is a carbonyl or sulphonyl radical, and Y-Z represents DPhe-Leu, D-Leu-Leu or D-Leu-Ileu in which the amino acids have the L-configuration unless otherwise indicated, which compounds are novel when A-X is a group other than n-octanoyl, L-6-methyloctanoyl and 6-methylheptanoyl if Y-Z is D-Phe-Leu or D-Leu-Leu and A-X is a group other than L-6-methyloctanoyl and 6- methylheptanoyl if Y-Z is D-Leu-Ileu, are prepared by reacting a cyclopeptide of Formula (II) (wherein Y-Z has the aforesaid meaning, and G is a radical which protects the γ-amino group of the α,γ-diaminobutyric acid moiety and has the formula Py-CH 2 -OCO- in which Py is pyridyl or pyridyl-N-oxide optionally substituted by methyl) with a compound of Formula (III) (wherein X has the aforesaid meaning, Q is a radical which protects the γ-amino group of the α,γ-diaminobutyric acid moiety, A 0  represents the group A having any amino groups protected or a group convertible into the group A under the reaction conditions used for removal of amino-protective groups, and B is -OH or an activating group for the carbonyl group of the α,γ-diaminobutyric acid moiety), followed by removing amino-protective groups by a conventional method together with conversion of A 0  to A when applicable, and if desired converting the resulting polymyxin into a salt. B may be an azido or chloro group or a group forming an activated ester (e.g. the p-nitrophenol; 2,4,5-trichlorophenol or N-hydroxysuccinimide ester) or mixed anhydride with the carboxyl group of the adjacent diaminobutyric acid moiety. Q may be a group removable by hydrolysis or hydrogenolysis, e.g. benzyloxycarbonyl or t-butoxycarbonyl, or may be the group G as defined above, the latter also being removable by hydrogenolysis. Groups A 0  which are convertible into the group A are groups containing double or triple carbon to carbon bonds or carbonyl groups, which are convertible into single bonds and hydroxy groups respectively during the removal of amino-protective groups by hydrogenolysis.  The compounds (III) are prepared by a conventional peptide-forming procedure from the appropriate amino acids, e.g. by condensing an N-protected amino acid with an ester of an amino acid in the presence of a carbodiimide, or with an azide, activated ester or mixed anhydride of an amino acid. The preferred procedure employs the Merrifield solid phase condensation method, wherein an N-protected amino acid is reacted with a chloromethylated styrene-divinylbenzene resin to give a solid intermediate resin-amino acid derivative which is then de-protected on the α-amino group and condensed with a second amino acid in the presence of a condensing agent. Subsequent condensations with the solid phase derivative are carried out until the desired peptide chain is obtained, and the resin-peptide is treated with hydrazine hydrate to remove the peptide as its hydrazide. This is reacted with alkali metal nitrite in acid medium to give the peptide azide i.e. the compound (III) wherein B is an azido group. The condensation to provide the terminal carboxylic acid of the compound (III), i.e. wherein X is -CO-, can be effected by reacting the terminal amino group of the tripeptide with a compound A 0 COB wherein A 0  and B are as previously defined. Analogous reaction with a sulphonyl halide A 0 -SO 2 -Cl gives the compounds (III) in which X is SO 2 . The cyclopeptides of Formula (II) are prepared by enzymic hydrolysis of an N-protected polymyxin as described in Specification 1,323,362.  The polymyxins (I) have antibacterial activity and may be used in pharmaceutical compositions together with a pharmaceutical carrier or coating.