Mutilin derivatives and their use as antibacterials
A compound of formula wherein R 2 is arylene or heterocyclene; or R and R 2 together with the nitrogen atom to which they are attached form non-aromatic heterocyclene; and the other residues have various meanings, useful as pharmaceuticals, e.g. antimicrobials.
1. A compound of formula
wherein
R is hydrogen or alkyl;
R 1 is hydrogen or a group of formula
wherein
X is sulphur, oxygen, NR 10 , wherein R 10 is hydrogen or alkyl, or N + (R′ 10 ) 2 wherein
R′ 10 is alkyl in the presence of an appropriate anion;
R 9 is amino, alkyl, aryl, heterocyclyl or mercapto; and, if X is oxygen, R 9 is additionally hydrogen;
R 2 is phenylene;
R 4 is hydrogen or alkyl;
R 5 is hydrogen or alkyl; and
R 3 , R 3 ′, R 6 , R 7 and R 8 independently of each other are hydrogen or deuterium.
2. A compound of formula I as defined in claim 1 wherein
R is hydrogen;
R 1 is hydrogen or a group of formula
wherein X is sulphur, oxygen, NR 10 , wherein R 10 is hydrogen or alkyl, or N + (R′ 10 ) 2
wherein R′ 10 is alkyl in the presence of an appropriate anion;
R 9 is amino, alkyl, heterocyclyl or mercapto; and, if X is oxygen, R 9 is additionally hydrogen;
R 2 is phenylene;
R 4 is hydrogen or alkyl;
R 5 is hydrogen;
R 3 and R 3 ′ are hydrogen; and
R 6 , R 7 and R 8 are hydrogen or deuterium.
3. A compound according to claim 1 in the form of a salt, or in the form of a salt and in the form of a solvate, or in the form of a solvate.
4. A compound of formula
wherein R 1s is hydrogen or a group of formula
wherein R 6s is hydrogen or deuterium;
R 2s is hydrogen, methyl or tert-butyl;
R 7s is hydrogen or methyl; and
R 3s , R 4s and R 5s are hydrogen or deuterium.
5. A compound which is selected from the group consisting of
14-O-(3-amino)phenyl-sulfanylacetyl)-mutilin;
14-O-(3-amino)phenyl-sulfanylacetyl)-2,2,4-trideutero-mutilin;
14-O-(3-(piperidin-2-yl-carbonylamino)-phenyl-sulfanylacetyl)mutilin;
14-O-(3-(piperidin-2-yl-carbonylamino)-phenyl-sulfanylacetyl)-2,2,4-trideutero-mutilin;
14-O-(3-(piperidin-2-yl-carbonylamino)-2,5-dimethyl-phenylthio-methylcarbonyl)mutilin;
14-O-(3-(piperidin-2-yl-carbonylamino)-2,5-dimethyl-phenylthio-methylcarbonyl)-2,2,4-trideutero-mutilin;
14-O-(3-(piperidin-2-yl-carbonylamino)-5 -tert.butyl-phenyl-sulfanylacetyl)mutilin; and
14-O-(3-(piperidin-2-yl-carbonylamino)-5-tert.butyl-phenyl-sulfanylacetyl)-2,2,4-trideutero-mutilin.
6. A pharmaceutical composition comprising a compound of claim 1 in free form or in the form of a pharmaceutically acceptable salt in association with at least one pharmaceutical carrier or diluent.