Actagardine derivatives, and pharmaceutical use thereof

A compound of formula (I):

• wherein:
• X is H or an amino acid;
• p is 0 or 1;
• X1 is —CH(CH3)2 or —CH2CH(CH3)2;
• X2 is —CH(CH3)CH2CH3 or —CH(CH3)2;
• R3 is —OH or —ZNR4R5;
• Z is a bond or an amino acid;
• R4 is hydrogen, or a C1-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents and/or optionally bears one 5- to 6-membered heterocyclyl;
• R5 is hydrogen, —RA-L-Ar1 or a C1-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents and/or optionally bears one 5- to 6-membered heterocyclyl, or
• R4 together with R5 and the nitrogen to which they are attached form a 5- or 6-membered heterocyclic group optionally including a further heteroatom selected from N, O or S, wherein the heterocyclic group is optionally substituted by:
• a C0-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents, the alkyl chain optionally substituted by:
• C3-7 cycloalkyl;
• 5- to 6-membered heteroaryl;
• 5- to 6-membered heterocyclyl;
• C3-7 aryl;
• YAr1, or
• wherein the heteraryl, heterocyclyl and aryl are optionally substituted by a C1-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents, or
• C3-7 cycloalkyl;
• 5- to 6-membered heteroaryl;
• 5- to 6-membered heterocyclyl;
• C3-7 aryl;
• YAr1, or
• wherein the heteraryl, heterocyclyl and aryl are optionally substituted by a C1-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents;
• RA is a bond, —C0-9 alkylC6-10aryl, —C0-9 alkylC5-11heteroaryl, —C0-9 alkylC3-6cycloalkyl, or —C0-9 alkylC5-11heterocycle;
• L is a straight or branched C0-15 alkyl chain wherein optionally one, two or three carbon atoms are replaced by a heteroatom independently selected from N, O or S, wherein the chain is optionally substituted by one or more oxo or nitro groups, with the proviso that a replacement heteroatom is not bonded directly to the N of the group —NR3R4;
• Y is a straight or branched C0-15 alkyl chain wherein optionally one or more carbon atoms are replaced by a heteroatom independently selected from N, O or S, wherein the chain is optionally substituted by one or more oxo or nitro groups;
• Ar1 is phenyl substituted by one or two NO2 groups or one to five halogen groups, or one or two C1-3 haloalkyl groups, or a combination thereof, wherein the amino acid at position 15 and optionally 1, 2, or 3 amino acid(s) at position 2, 3, 4, 5, 8, 10, 11, 13, 16 or 18 in formula (I) includes replacement by an alternative amino acid, wherein
• the replacement amino acid at position 2 is selected from the group consisting of Ala, Asp, Glu, Gly, Ile, Asn, Gln, Thr and Val;
• the replacement amino acid at position 3 is selected from the group consisting of Ala and Ser;
• the replacement amino acid at position 4 is selected from the group consisting of His and Phe;
• the replacement amino acid at position 5 is selected from the group consisting of Ala, Glu, Phe, Ile, Leu, Met, Ser, Thr and Trp;
• the replacement amino acid at position 8 is selected from the group consisting of Phe, Ile, Met and Val;
• the replacement amino acid at position 10 is selected from the group consisting of Phe, His, Leu, Met, Ser, Thr and Val;
• the replacement amino acid at position 11 is Asp;
• the replacement amino acid at position 13 is selected from the group consisting of Ala and Ser;
• the replacement amino acid at position 15 is selected from the group consisting of Ala, Phe, Gly, His, Ile, Met, Gln, Arg, Thr and Trp;
• the replacement amino acid at position 16 is selected from the group consisting of Phe, Leu, Met, Asn, Gln, Ser, Thr and dehydrobutyrine;
• and
• the replacement amino acid at position 18 is selected from the group consisting of Gly, Ile, Asn, Ser, Thr and Val;
• with the proviso that when the amino acids are unchanged at positions 2, 3, 4, 5, 6, 10, 11, 13 and 18:
• and X is selected from the group consisting of H, Ala, Lys and Ile, and p is 1, then positions 15 and 16 are not Val and Ile respectively;
• and or X is selected from the group consisting of H and Ala, and p is 0, then positions 15 and 16 are not Val and Ile respectively;
• or X is selected from the group consisting of H and Ala, and p is 1, then positions 15 and 16 are not Leu and Val;
• Val and Val;
• or Leu and Ile respectively;
• or X is selected from the group consisting of H, Ala, Ile, Phe, Val, Lys and Trp, and p is 0, then positions 15 and 16 are not Leu and Val respectively;
• and with the proviso that the compound is not V15F Actagardine (3,5-dichlorobenzylamine) monocarboxamide, and the compound is not V15F Actagardine.