Carbamoyloxy derivatives of mutiline and their use as...

Details Carbamoyloxy derivatives of mutiline and their use as... Carbamoyloxy derivatives of mutiline and their use as...

1999-12-21

2001-05-29

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C514S023000, C514S231200, C514S252010, C514S277000, C514S305000, C514S315000, C514S340000, C514S359000, C514S363000, C514S364000, C514S378000, C514S381000, C514S383000, C514S396000, C514S461000, C514S650000, C544S224000, C544S242000, C546S001000, C546S184000, C546S340000, C560S157000, C560S162000, C560S115000, C560S148000, C560S160000, C560S070000

Reexamination Certificate

active

06239175

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 (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
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 (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).
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 proyldes 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 proyldes a compound of general formula (3)
in which:
R
1
is vinyl or ethyl;
R
2
and R
3
are the same or different groups selected from hydrogen;
a straight or branch chained, saturated or unsaturated, optionally substituted, C
1
to C
6
hydrocarbon group;
a saturated or unsaturated, optionally substituted, C
3
to C
8
cyclic hydrocarbon group;
an optionally substituted heterocyclic group;
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; or
R
2
is one of the above monovalent groups and R
3
is a group selected from SO
2
R
4
, COR
5
, OR
5
and NR
6
R
7
where
R
4
is selected from a straight or branch chained, saturated or unsaturated, optionally substituted, C
1
to C
6
hydrocarbon group; a saturated or unsaturated, optionally substituted, C
3
to C
8
cyclic hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted aryl group; an optionally substituted C
1
to C
6
alkyl amino group; and an optionally substituted aryl amino group;
R
5
is selected from hydrogen; a straight or branch chained, saturated or unsaturated, optionally substituted, C
1
to C
6
hydrocarbon group; a saturated or unsaturated, optionally substituted, C
3
to C
8
cyclic hydrocarbon group; an optionally substituted heterocyclic group; and an optionally substituted aryl group;
R
6
and R
7
are the same or different groups selected from hydrogen; a straight or branch chained, saturated or unsaturated, optionally substituted, C
1
to C
6
hydrocarbon group; a saturated or unsaturated, optionally substituted, C
3
to C
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
1
to C
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
3
to C
8
cyclic hydrocarbon groups include cyclopropyl, cyclopentyl and cyclohexyl.
Suitable optional substituents for the (C
1-6
)alkyl groups and the (C
3-8
)cycloalkyl groups include, for example, halogen, hydroxy, (C
1-6
)alkoxy, aryloxy, carboxy and salt thereof, (C
1-6
)alkoxycarbonyl, carbamoyl, mono- or di(C
1-6
)alkylcarbamoyl, sulphamoyl, mono- and di(C
1-6
)alkylsulphamoyl, amino, mono- and di(C
1-6
)alkylamino, (C
1-6
)acylamino, ureido, (C
1-6
)alkoxycarbonylamino, aryl, heterocyclyl, oxo, hydroxyimino, acyl, (C
1-6
)alkylthio, arylthio, (C
1-6
)alkane-sulphinyl, arylsulphinyl, (C
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 halogen, (C
1-6
)alkyl, aryl(C
1-4
)alkyl, (C
1-6
)alkoxy, (C
1-6
)alkoxy(C
1-6
)alkyl, halo(C
1-6
)alkyl, hydroxy, nitro, amino, mono- and di-N-(C
1-6
)alkylamino, acylamino, 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
1-4
)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 term “heteroaryl” includes aromatic single and fused rings containing up to four heteroatoms 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 heteroaryl ring suitably has 5 or 6 ring atoms. A fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl 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 heteroatoms 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 a substituent for a heteroaryl or a heterocyclyl group is selected from halogen, (C
1-6
)alkyl, aryl(C
1-4
)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 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
1-4
)alkyl.
Particularly suitable values for R
2
and R
3
are hydrogen, hydroxy, methoxy, phenyl, methyl, iso-propyl, phenylsulphonyl, methoxyphenyl, nitrophenyl, trichloroacetyl, benzyl, hydroxyiminobenzyl, benzylamino-sulfonyl, dichloropyridinyl, hydroxyethyl, 2-phenylethyl, 1-(R)-phenyl-2-hydroxyethyl, 2-(methoxycarbonyl)ethyl, 2-carboxyethyl, dimethylamino, dimethylaminopropyl, methanesulphonylamino, methanesulphonyl, benzoylamino, benzoyl optionally substituted by trifluoromethyl, carboxy, methoxy, hydroxy, acetoxy, amino or nitro, furoyl, nicotinoyl, isonicotinoyl, acetyl, phenylacetyl, and phenoxy. Particularly suitable values for cyclic groups R
2
R
3
N are indolino and morpholino.
In a further aspect the present invention proyldes a method for preparing compounds of the invention, which comprises reacting a compound of formula (4) where X is hydrogen or a hydroxyl protecting group, such as an acyl group, or a compound of formula (5) with an appropriately substituted carbamate-forming reagent.
General methods for preparing carbamates are described, for example, by A F Hegarty in
Comprehensive Organic Chemistry
, Vol. 2, ed. I O Sutherland, Pergamon Press, 1979, p. 1083. Typical procedures are reaction with an isocyanate or a carbamoyl chloride, or reaction with phosgene or a phosgene equivalent followed by reaction with an amine.
More particularly, in one aspect the present invention proyldes a

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