Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-01-29
2000-09-19
Stockton, Laura L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514306, 514325, 514413, 546112, 546133, 546138, 546204, 548452, A61K 31439, A61K 314375, C07D45302, C07D45502
Patent
active
061212814
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 certain novel 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 acylated by a group which includes an azabicyclic moiety.
More specifically, this invention provides a compound of general formula (3): ##STR3## in which: R.sup.1 is vinyl or ethyl; and C.dbd.CH--; wherein each of R.sup.3 and R.sup.4 is an azabicyclic ring system or R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form an azabicyclic ring system.
The azabicyclic ring system is a bridged or fused non-aromatic ring system attached via a bridgehead or non-bridgehead ring carbon atom and containing one bridgehead nitrogen atom as the sole hetero ring atom. The ring system contains between 5 and 10 ring atoms in each ring and is optionally substituted on carbon by up to 3 substituents. Suitable substituents include alkyl, alkyloxy, alkenyl and alkenyloxy, each of which may be carried by either a bridgehead or a non-bridgehead carbon atom. In addition, the bridgehead nitrogen atom may be substituted by oxygen, to form an N-oxide, or by alkyl, to form a quaternary cation. The counterion may be a halide ion such as chloride or bromide, preferably chloride.
The azabicyclic ring system may for example be represented by formula (I): ##STR4## wherein R.sup.7 represents one or more optional substituents as set out above and each of a, b and c is between 0 and 4, such that any one ring has between 5 and 10 ring atoms. The azabicyclic ring system additionally may contain one or more double bonds.
Particular azabicyclic groups include azabicyclo[2.2.2]octyl, azabicyclo[2.2.1]heptyl, azabicyclo[3.2.1 ]octyl, azabicyclo[4.4.0]decyl, quinuclidinyl, azabicyclo[3.2.1]octenyl, and azabicyclo[3.3.1]non-5-yl.
Alkyl and alkenyl groups referred to herein include straight and branched groups containing up to six carbon atoms and are optionally substituted by one or more groups selected from the group consisting of aryl, heterocyclyl, (C.sub.1-6)alkoxy, (C.sub.1-6)alkylthio, aryl(C.sub.1-6)alkoxy, aryl(C.sub.1-6)alkylthio, amino, mono- or di-(C.sub.1-6)alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, hydroxy, and halogen.
Cycloalkyl and cycloalkenyl groups referred to herein include groups having between three and eight ring carbon atoms and are optionally substituted as described hereinabove for alkyl and alkenyl groups.
When used herein, the term "aryl" means single and fused rings suitably containing from 4 to 7, preferably 5 or 6, ring atoms in each ring, which rings. may each be unsubstituted or substituted by, for example, up to three substituents. A fused ring system may include aliphatic rings and need include only one aromatic ring.
Suitable aryl groups include phenyl and naphthyl such as 1-naphthyl or 2-naphthyl.
Suitably any aryl group, including phenyl and naphthyl, may be optionally substituted by up to
REFERENCES:
Egger et al., "New Pleuromutilin Derivatives With Enhanced Antimicrobial Activity", The Journal of Antibiotics, 29(9), p. 923927 (1976).
Hunt Eric
Naylor Antoinette
Takle Andrew Kenneth
Gimmi Edward R.
King William T.
Kinzig Charles M.
SmithKline Beecham p.l.c.
Stockton Laura L.
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