Pleuromutilin derivatives as antimicrobials

Details Pleuromutilin derivatives as antimicrobials Pleuromutilin derivatives as antimicrobials

2000-04-27

2001-08-28

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S133000, C546S112000, C546S183000, C548S452000, C514S299000, C514S412000, C514S413000

Reexamination Certificate

active

06281226

ABSTRACT:

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 (A), 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
2
CO
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 (B), 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).
In this application, the non-conventional numbering system which is generally used in the literature (G Hogenauer, loc.cit.) is used.
WO 97/25309 (SmithKline Beecham) describes further modification of the acyloxy group, disclosing 14-O-carbamoyl derivatives of mutilin or 19, 20-dihydromutilin, in which the N-atom of the carbamoyl group is unsubstituted, mono- or di-substituted.
WO 98/05659 (SmithKline Beecham) discloses 14-O-carbamoyl derivatives 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.
WO 98/14189 (SmithKline Beecham. International Publication Date Apr. 9, 1998) discloses the use of the topical antibacterial agent mupirocin for treating bacterial infections associated with the colonisation of the nasopharynx by pathogenic organisms, in particular, the prophylatic treatment of recurrent sinusistis and recurrent otitis media. especially with novel spray or cream formulations adpated for administration to the nasopharynx. In addition, Nsouli (Annals of Allergy, Asthma and Immunology, January 1996, 76(1), 117) has described a clinical study involving the use of a 0.2% aqueous solution of mupirocin in reducing the attacks of sinusitis.
We have now found that further novel pleuromutilin derivatives have improved antimicrobial properties.
Accordingly, the present invention provides a compound of general formula (IA) or (EB):
in which:
each of n and m is independently 0, 1 or 2;
X is selected from —O—, —S—, —S(O)—, —SO
2
—, —CO.O—, —NH—, —CONH—, —NHCONH— and a bond;
R
1
is vinyl or ethyl;
R
2
is a non-aromatic monocyclic or bicyclic group containing one or two basic nitrogen atoms and attached through a ring carbon atom;
R
3
is H or OH; or the moiety R
2
(CH
2
))
m
X(CH
2
)
n
COO at position 14 of (IA) or (IB) is replaced by R
a
R
b
C═CHCOO in which one of R
a
and R
b
is hydrogen and the other is R
2
or R
a
and R
b
together form R
2
, or
a pharmaceutically acceptable salt thereof.
When R
2
is monocyclic, it typically contains from 4 to 8 ring atoms, and, when bicyclic, it typically contains from 5 to 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 bc carried by either a bridgehead or a non-bridgehead carbon atom. In addition, the or each nitrogen atom may be substituted by oxygen, to form an N-oxide, or by mono- or dialkyl, in which case it will be appreciated that a quaternary cation can be formed. The counterion may be a halide ion such as chloride or bromide, preferably chloride. The aza ring system additionally may contain one or more double bonds.
Representative bicyclic and monocyclic groups for R
2
include piperidinyl, pyrrolidyl, quinuclidinyl, azabicyclo[2.2.1]heptyl, azabicyclo[4,3,0]nonyl, azabicyclo[3.2.1]octyl, azabicyclo[3,3,0]octyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octenyl, azabicyclo[3.3.1]nonyl and azabicyclo[4.4.0]decyl, all of which may be substituted or unsubstituted. Preferred examples for R
2
include quinuclidinyl.
The compounds of formula (IA) in which R
3
is hydroxy have the (2S) configuration at the carbon bearing this hydroxy group.
Preferably, n is 0. Preferably, m is 0 or 1.
Preferred compounds are those of formula (IA).
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
1-6
)alkoxy, (C
1-6
)alkylthio, aryl(C
1-6
)alkoxy, aryl(C
1-6
)alkylthio, amino, mono- or di-(C
1-6
)alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, amides of carboxy, ureido, carbamimidoyl (amidino), guanidino, alkyl-sulfonyl, amino-sulfonyl (C
1-6
)acyloxy, (C
1-6
)acylamino, azido, hydroxy, and halogen.
Cycloalkyl and cycloalkenyl groups referred to herein include groups having from three to 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. Representative 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 five, preferably up to three substituents. Suitable substituents include halogen, (C
1-6
)alkyl, aryl, aryl(C
1-6
)alkyl, (C
1-6
)alkoxy, (C
1-6
)alkoxy(C
1-6
)alkyl, halo(C
1-6
)alkyl, aryl(C
1-6
)alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and di-N-(C
1-6
)alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C
1-6
)alkylcarbamoyl, (C
1-6
)alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, sulphonylamino, aminosulphonyl, (C
1-6
)alkylthio, (C
1-6
)alkyl sulphinyl, (C
1-6
)alkylsulphonyl, heterocyclyl and heterocyclyl (C
1-6
)alkyl. In addition, two adjacent ring carbon atoms may be linked by a (C
3-5
)alkylene chain, to form a carbocyclic ring.
When used herein the terms “heterocyclyl” and “heterocyclic” suitably include, unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four hetcroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings, may be unsubstituted or substituted by, for example, up to three substituents. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
Preferably substituents for a heterocyclyl group are selected from halogen, (C
1-6
)alkyl, aryl(C
1-6
)alkyl, (C
1-6
)alkoxy, (C
1-6
)alkoxy(C
1-6
)alkyl, halo(C
1-6
)alkyl, hydroxy, amino, mono- and di-N-(C
1-6
)alkyl-amino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C
1-6
)alkylcarbonyl, aryloxycarbonyl, (C
1-6
)alkoxycarbonyl(C
1-6
)alkyl, aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, (C
1-6
)alkylthio, (C
1-6
)alkylsulphinyl, (C
1-6
)alkylsulphonyl, heterocyclyl and heterocyclyl(C
1-6
)alkyl.
Depending on the position of attachment of substituents, two or more diastereoisomers may be possible. In that situation the present invention includes the individual diastereoisomers and mixtures thereof.
Preferred examples of compounds of the invention include:
Mutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate;
Mutilin 14-(quinuclid-4-ylmethylsulfanyl)-acetate;
Mutilin-14-(1-methylpiperid-4-ylsulfanyl)-acetate, and
Mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate.
The compounds of this invention may be in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, especially hydrated. This invention includes within its scope stoichiometric hydrates as well as compounds containing varia

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