Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-23
1996-07-16
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549414, 549415, 546183, 514299, 5142352, A61K 3135, A61K 31435, C07D40714, C07D40706
Patent
active
055367453
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB 93/01331 filed Jun. 24, 1993.
This invention relates to a novel class of compounds having antibacterial and antimycoplasmal activity, to processes for their preparation and to their use in human and veterinary medicine, and also to intermediates for use in the preparation of such compounds.
Mupirocin, the compound of formula (A): ##STR1## exhibits good activity against Gram positive bacteria. H.infiuenzae. Legionella and mycoplasma. It is marketed as a topical formulation by Beecham Group p.l.c. under the Trade Mark `Bactroban`. Mupirocin (formerly known as pseudomonic acid A) is rapidly hydrolysed in vivo to monic acid A, the compound of formula (B): ##STR2## which is inactive.
Various proposals have been made in the past to improve the metabolic stability of mupirocin with respect to enzymatic hydrolysis, by modification of the C-1 ester functional group, for instance, by changing it to a C-1 heterocyclic derivative (EP-A-0 087 953 and EP-A-0 123 578. Beecham Group) or to a C-1 amide (EP-A-0 001 914. Beecham Group). In addition, EP-A-0029 665 (Beecham Group) discloses derivatives of monic acids A, B and C characterised in having a ketone functionality at C-1. including inter alia aryl and heterocyclic ketones. More recently, Klein et al have reported (in a poster presented at the Third Annual Chemical Congress of North America, Toronto, June 1988, some aspects of which are also discussed in J. Med. Chem. 1989, 32, 151) the preparation and properties of a limited group of C-1 aryl and heteroaryl ketones.
It has now been surprisingly found that enhanced antibacterial activity may be obtained if an element of conformational rigidity is introduced about the carbonyl moiety of a C-1 aryl or heteroaryl ketone. Improvements to in vitro activity and in vivo stability may be observed.
Accordingly, the present invention provides a compound of formula (I): ##STR3## in which X denotes the residue of an aryl or a heteroaryl ring.
Suitably the aryl ring of which X forms a residue is benzene or naphthalene and preferably benzene, which may be unsubstituted or substituted by up to four, preferably up to two substituents.
Suitably the heteroaryl ring of which X forms a residue includes both single and fused rings, with each ring suitably comprising up to four heteroatoms each selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three substituents. Each heteroaryl ring may have from 4 to 7, preferably 5 or 6, ring atoms. A fused heteroaryl ring may include an aryl ring and need include only one heteroaryl ring. Suitable fused heteroaryl rings include bicyclic systems. Preferably the heteroaryl ring of which X forms a residue is a monocyclic heteroaryl ring, for instance pyridine or furan.
In compounds of formula (I), preferred examples of the moiety: ##STR4## in each of which the aryl or heteroaryl ring may be optionally substituted. It will be appreciated that in these instances, the aryl ring of which X forms a residue is benzene and the heteroaryl ring of which X forms a residue is furan or pyridine.
Suitable substituents for the X residue (aryl or heteroaryl) ring, as defined above, include: salts, sulpho, sulphonate salts, or oxo; sulphonamido, in each of which groups a nitrogen may be further optionally substituted by one or two groups (which may be the same or different) selected from the groups listed in subparagraphs (d), (e) and (f); each of which groups hydrogen may be replaced by one of the groups listed in subparagraphs (d), (e) and (f); moiety; each of which may be optionally substituted by up to three groups (the same or different) chosen from those groups listed in subparagraphs (a), (b), (c), (d), (e) and (f); and (C.sub.3-7)cycloalkyl, (C.sub.2-6)alkenyl, (C.sub.3-8)cycloalkenyl or (C.sub.2-6)alkynyl, each of which may be optionally substituted by up to three groups (which may be the same or different) chosen from the groups listed in subparagraphs (a), (b), (c), (d) and (f): and R.sup.q SCO--, R.sup.p SO--,
Cross Laura R.
Dustman Wayne J.
Lentz Edward T.
Richter Johann
SmithKline Beecham p.l.c.
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