Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Patent
1998-12-04
2000-02-01
Geist, Gary
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
514 23, 5142312, 514252, 514277, 514305, 514315, 514340, 514359, 514363, 514364, 514378, 514381, 514383, 514396, 514461, 514650, 544 59, 544224, 544242, 546 1, 546184, 546340, 546341, A01N 4710, C07C26100
Patent
active
060203684
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medical therapy, particularly antibacterial therapy.
Pleuromutilin, the compound of formula (1), is a naturally occurring antibiotic which has antimycoplasmal activity and modest antibacterial activity. It has been shown that the antimicrobial activity can be improved by replacing the glycolic ester moiety at position 14 by an R--X--CH.sub.2 CO.sub.2 -- group, where R is an aliphatic or aromatic moiety and X is O, S, or NR' (H Egger and H Reinshagen, J Antibiotics, 1976, 29, 923). Tiamulin, the compound of formula (2), which is used as a veterinary antibiotic, is a derivative of this type (G Hogenauer in Antibiotics, Vol. V, part 1, ed. F E Hahn, Springer-Verlag, 1979, p.344). ##STR2##
In this application, the non-conventional numbering system which is generally used in the literature (G Hogenauer, loc.cit.) is used.
We have found that pleuromutilin analogues containing a 14-O-carbamoyl group, also have improved antimicrobial properties.
Accordingly, in its broadest aspect, the present invention provides a 14-O-carbamoyl derivative of mutilin or 19,20-dihydromutilin, in which the N-atom of the carbamoyl group is unsubstituted, mono- or di-substituted.
More specifically, this invention provides a compound of general formula (3) ##STR3## in which: R.sup.1 is vinyl or ethyl; substituted, C.sub.1 to C.sub.6 hydrocarbon group; cyclic hydrocarbon group; atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring, a heterocyclic group or an aromatic group; or selected from SO.sub.2 R.sup.4, COR.sup.5, OR.sup.5 and NR.sup.6 R.sup.7 where unsaturated, optionally substituted, C.sub.1 to C.sub.6 hydrocarbon group; a saturated or unsaturated, optionally substituted, C.sub.3 to C.sub.8 cyclic hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted aryl group; an optionally substituted C.sub.1 to C.sub.6 alkyl amino group; and an optionally substituted aryl amino group; or unsaturated, optionally substituted, C.sub.1 to C.sub.6 hydrocarbon group; a saturated or unsaturated, optionally substituted, C.sub.3 to C.sub.8 cyclic hydrocarbon group; an optionally substituted heterocyclic group; and an optionally substituted aryl group; hydrogen; a straight or branch chained, saturated or unsaturated, optionally substituted, C.sub.1 to C.sub.6 hydrocarbon group; a saturated or unsaturated, optionally substituted, C.sub.3 to C.sub.8 cyclic hydrocarbon group; an optionally substituted heterocyclic group, and an optionally substituted aryl group; or together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring, a heterocyclic group or an aromatic group.
Suitable C.sub.1 to C.sub.6 hydrocarbon groups include straight and branched chain alkyl groups having from 1 to 6 carbon atoms, for instance methyl, ethyl, n-propyl and iso-propyl, preferably methyl.
Suitable C.sub.3 to C.sub.8 cyclic hydrocarbon groups include cyclopropyl, cyclopentyl and cyclohexyl.
Suitable optional substituents for the (C.sub.1-6)alkyl groups and the (C.sub.3-8)cycloalkyl groups include, for example, halogen, hydroxy, (C.sub.1-6)alkoxy, aryloxy, carboxy and salt thereof, (C.sub.1-6)alkoxycarbonyl, carbamoyl, mono- or di(C.sub.1-6)alkylcarbamoyl, sulphamoyl, mono- and di(C.sub.1-6)alkylsulphamoyl, amino, mono- and di(C.sub.1-6)alkylamino, (C.sub.1-6)acylamino, ureido, (C.sub.1-6)alkoxycarbonylamino, aryl, heterocyclyl, oxo, hydroxyimino, acyl, (C.sub.1-6)alkylthio, arylthio, (C.sub.1-6)alkane-sulphinyl, arylsulphinyl, (C.sub.1-6)alkanesulphonyl, arylsulphonyl.
When used herein, the term "aryl" includes phenyl and naphthyl. Suitably an aryl group, including phenyl and naphthyl, may be optionally substituted by up to five, preferably up to three substituents. Suitable substituents include
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patent: 3919290 (1975-11-01), Egger et al.
patent: 3979423 (1976-09-01), Riedl
patent: 4148890 (1979-04-01), Czok et al.
patent: 4278674 (1981-07-01), Egger et al.
patent: 4428953 (1984-01-01), Berner et al.
Hinks Jeremy David
Hunt Eric
Takle Andrew Kenneth
Geist Gary
Gimmi Edward R.
King William T.
Kinzig Charles M.
Oh Taylor Victor
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