Title: Heterocyclic mutilin esters and their use as antibacterials
Abstract: Pleuromutilin compounds of the formula: ##STR1##are of use in anti-bacterial therapy.
Patent Number: 6,878,704 Issued on 04/12/2005 to Aitken, et al.
| Inventors:
|
Aitken; Steven (Harlow, GB);
Brooks; Gerald (Harlow, GB);
Dabbs; Steven (Harlow, GB);
Frydrych; Colin Henry (Harlow, GB);
Howard; Steven (Cambridge, GB);
Hunt; Eric (Harlow, GB)
|
| Assignee:
|
SmithKline Beecham p.l.c. (Brentford, GB)
|
| Appl. No.:
|
343596 |
| Filed:
|
October 17, 2003 |
| PCT Filed:
|
August 2, 2001
|
| PCT NO:
|
PCT/EP01/08949
|
| 371 Date:
|
October 17, 2003
|
| 102(e) Date:
|
October 17, 2003
|
| PCT PUB.NO.:
|
WO02/12199 |
| PCT PUB. Date:
|
February 14, 2002 |
Foreign Application Priority Data
| Current U.S. Class: |
514/231.2; 514/252.1; 514/258; 514/350; 514/354; 514/356; 546/301; 546/326; 544/106; 544/250; 544/251; 544/336 |
| Intern'l Class: |
C07D 213//02; A61K 031//44 |
| Field of Search: |
546/326,301
514/354,356,252.1,258,350,231.2
544/106,250,251,336
|
References Cited [Referenced By]
| Foreign Patent Documents |
| WO 97/25309 | Jul., 1997 | WO.
| |
| WO 00/07974 | Feb., 2000 | WO.
| |
| WO 00/27790 | May., 2000 | WO | .
|
| WO 00/37074 | Jun., 2000 | WO.
| |
| WO 00/73287 | Dec., 2000 | WO.
| |
Primary Examiner: Davis; Zinna Northington
Attorney, Agent or Firm: Hall; Linda E., Venetianer; Stephen, Kinzig; Charles M.
Claims
What is claimed is:
1. A compound of formula (IA) or (IB):
##STR266##
in which:
R.sup.1 is:
a 5- or 6-membered aromatic or heteroaromatic ring attached via a ring
carbon atom and having a substituent selected from halo, R.sup.7 O--,
R.sup.7 S-- or R.sup.8 R.sup.9 N-- on a ring carbon adjacent to the carbon
of attachment; or
a 5- or 6-membered dihydro heteroaromatic ring attached via a ring carbon
atom and having one oxygen or one or two nitrogen atoms and optionally
fused to phenyl, a 5- or 6-membered heteroaryl ring having one or two
nitrogen atoms or a 5- or 6-membered heterocyclyl ring having a sulphur,
oxygen or nitrogen atom and further having a substituent selected from oxo
or thioxo on a ring carbon adjacent to the carbon of attachment;
a 6-membered tetrahydro heteroaromatic ring attached via a ring carbon atom
having one or two nitrogen atoms and further having two substituents
independently selected from oxo or thioxo wherein one of the substituents
is on a ring carbon adjacent to the carbon of attachment; or
a bicyclic heteroaryl ring attached via a ring carbon atom and having nine
or ten ring atoms and from one to four nitrogen atoms;
wherein the ring of R.sup.1 may be optionally further substituted;
R.sup.2 is vinyl or ethyl;
R.sup.3 is H, OH or F and R.sup.4 is H, or R.sup.3 is H and R.sup.4 is F
and R.sup.5 and R.sup.6 together form an oxo group; or R.sup.3 and R.sup.4
is each H and R.sup.5 is H, or OH and R.sup.6 is H or R.sup.5 is H and
R.sup.6 is H or OH;
R.sup.7 is optionally substituted C.sub.(1-6) alkyl; and
R.sup.8 and R.sup.9 are independently selected from hydrogen or optionally
substituted C.sub.(1-6) alkyl.
2. A compound as claimed in claim 1 in which the ring in R.sup.1 is
selected from pyrazole, pyrazine, pyridine, pyrimidine, and pyran which
may be optionally fused with a 6 membered aromatic or non-aromatic ring,
optionally containing up to two nitrogen atoms.
3. A compound as claimed in claim 1 in which the ring in R.sup.1 is
selected from:
##STR267##
4. A compound as claimed in claim 1 in which the ring for R.sup.1 is
selected from:
##STR268##
5. A compound as claimed in claim 1 in which the ring of R.sup.1 is
selected from:
##STR269##
6. A compound as claimed in claim 1 in which a substituent for a carbon
atom of a ring in R.sup.1 is selected from (C.sub.1-6)alkyl,
(C.sub.1-6)alkylthio, amino, mono- and di-N-(C.sub.1-6)alkylamino,
R.sup.10 (C.sub.1-6)alkylamino, imidazolinyl, piperidinyl, piperazinyl
(optionally substituted on N by R.sup.11), pyridyl, hydrazino,
N-(C.sub.1-3)alkylhydrazino, aminomethylcarbonylhydrazino,
heterocyclyl(C.sub.1-3)alkyl in which heterocyclyl comprises a 6-membered
ring with 1 nitrogen atom and optionally an oxygen or a second nitrogen,
and in which:
R.sup.10 is hydroxy, amino, heteroaryl in which heteroaryl comprises a 5 or
6-membered ring with 1 or 2 nitrogen atoms, heterocyclyl in which
heterocyclyl comprises a 6-membered ring with 1 nitrogen atom and
optionally an oxygen or a second nitrogen, R.sup.11 -amino, in which:
R.sup.11 is (C.sub.1-3)alkyl, hydroxy(C.sub.1-3)alkyl, carbamoyl,
methylsulfonyl, or amino(C.sub.1-3)alkylcarbonyl.
7. A compound as claimed in claim 1 in which a substituent for a nitrogen
atom of a ring in R.sup.1 is selected from R.sup.12 (C.sub.1-6)alkyl,
amino, mono- or di-(C.sub.1-6)alkylamino,
N-(pyridyl(C.sub.1-3)alkyl)-N-(C.sub.1-3)alkylamino (in which pyridyl is
optionally substituted by (C.sub.1-6)alkoxy and/or amino, mono- or
di-(C.sub.1-6)alkylamino), acyl- or sulfonyl amino, acyl- or
sulfonyl-mono(C.sub.1-6)alkylamino, optionally substituted phenyl,
R.sup.13 C.dbd.N--, R.sup.14 (C.sub.1-4)alkylN(H/Me)-, R.sup.15 CON(H/Me)-
and R.sup.16 N(CHO)--, in which:
R.sup.12 is hydrogen, halo, nitrilo, amino, (C.sub.1-6)alkoxy,
(C.sub.1-3)alkoxy(C.sub.1-6)alkoxy, (C.sub.1-6)alkylcarboxy,
(C.sub.1-6)alkoxy, heteroaryl, heteroarylcarbonyl, imidazolylthio,
heterocyclyl, optionally substituted phenyl;
R.sup.13 is (C.sub.0-4)alkylheteroaryl in which the heteroaryl ring is 5-
or 6-membered and has 1 or 2 nitrogen atoms and which may be substituted
by 1 or 2 substituents, chosen from: (C.sub.1-6)alkoxy, nitro, amino,
(C.sub.16)alkylamino, di-(C.sub.1-6)alkylamino, or oxo;
R.sup.14 is (C.sub.1-4)alkylheteroaryl in which the heteroaryl ring is 5 or
6 membered and has 1 or 2 nitrogen atoms, and which may be substituted by
1 or 2 substituents, chosen from: (C.sub.1-6)alkoxy, nitro, amino,
(C.sub.1-6)alkylamino, di-(C.sub.1-6)alkylamino, or oxo;
R.sup.15 is (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, aminomethyl, mono or
dialkyl(C.sub.1-6)aminomethyl, a 4, 5 or 6 membered heterocyclic ring
comprising a heteroatom selected from NH, NMe, and, for pyrrolidine,
optionally substituted by hydroxy or methoxy, dioxothietane, imidazole,
pyridine, pyridazine, pyrimidine, or pyrazine; and
R.sup.16 is hydrogen, (C.sub.1-6)alkyl, benzyl or pyridinylmethyl.
8. A compound as claimed in claim 1 in which R.sup.1 is selected from:
##STR270##
in which:
R.sup.15 is (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, aminomethyl, mono or
dialkyl(C.sub.1-6)aminomethyl, a 4, 5 or 6 membered heterocyclic ring
comprising a heteroatom selected from NH, NMe, and, for pyrrolidine,
optionally substituted by hydroxy or methoxy, dioxothietane, imidazole,
pyridine, pyridazine, pyrimidine, or pyrazine;
R.sup.17 is hydrogen or (C.sub.1-6)alkyl;
R.sup.18 is R.sup.10 (C.sub.1-6)alkyl, and R.sup.19 is hydrogen, or
R.sup.18 R.sup.19 N-- form a piperazinyl ring optionally substituted on N
by R.sup.11,
in which:
R.sup.10 is hydroxy, amino, heteroaryl(C.sub.1-3)alkyl in which heteroaryl
comprises a 5 or 6-membered ring with 1 or 2 nitrogen atoms,
heterocyclyl(C.sub.1-3)alkyl in which heterocyclyl comprises a 6-membered
ring with 1 nitrogen atom and optionally an oxygen or a second nitrogen,
or R.sup.11 -amino,
in which:
R.sup.11 is (C.sub.1-3)alkyl, hydroxy(C.sub.1-3)alkyl, carbamoyl,
methylsulfonyl, or amino(C.sub.1-3)alkylcarbonyl.
9. A compound as claimed in claim 8 in which moiety R.sup.15 NCO is derived
from (D)- or (L)-proline.
10. A compound as claimes in claim 1 in which R.sup.3 and R.sup.4 are both
hydrogen, and R.sup.5 and R.sup.6 together form an oxo group.
11. A compound according to claim 1 selected from:
(4-Oxo-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidine-3-carboxylic acid)
mutilin 14-ester;
[2-(3-Morpholino-propylamino)-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic
acid) mutilin 14-ester;
(8-Ethyl-2-piperazin-1-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbo
xylic acid) mutilin 14-ester;
{1,6-Dihydro-1-[N-methyl-N-(D)-prolylamino]-6-oxo-pyridazine-5-carboxylic
acid} mutilin 14-ester;
{1,2-Dihydro-1-[N-methyl-N-(D)-prolylamino]-2-oxo-pyridine-3-carboxylic
acid} mutilin 14-ester;
{1,6-Dihydro-1-[N-methyl-N-(L)-prolylamino]-6-oxo-pyridazine-5-carboxylic
acid} mutilin 14-ester; and
{1,6-Dihydro-1-[N-methyl-N-(L)-trans-methoxy-prolylamino]-6-oxo-pyridazine-
5-carboxylic acid} mutilin 14-ester.
12. A method of preparing a compound of formula (IA) or (IB) according to
claim 1 which comprises reacting a compound of formula (IIA) or (IIB):
##STR271##
in which:
P is hydrogen or an hydroxy-protecting group;
R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A and R.sup.6A are R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 as defined for formulae (IA) and (IB) or a
group convertible to R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
respectively; and is as hereinbefore defined;
with a compound of formula (III):
##STR272##
in which:
R.sup.1A is R.sup.1 as defined for formulae (IA) and (IB) or a group
convertible to R.sup.1 ;
in an esterification reaction and thereafter, and if so needed;
converting P to hydrogen, and if necessary
converting an R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A and R.sup.6A group to
an R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 group.
13. A pharmaceutical composition comprising a compound according to claim
1, and a pharmaceutically acceptable carrier or excipient.
14. A method of treating microbial infections in humans and in domesticated
mammals, which comprises administering a compound according to claim 1, to
a patient in need thereof.
15. A method of treating recurrent otitis media or recurrent acute
bacterial sinusitis in humans, which comprises nasally administering a
compound according to claim 1, to a patient in need thereof.
16. A method of treatment of skin and soft tissue infections and in the
treatment of acne in humans, which comprises topically administering a
compound according to claim 1, to a patient in need thereof.
17. A compound of formula (IA) or (IB):
##STR273##
in which:
R.sup.1 is:
a 5- or 6-membered aromatic or heteroaromatic ring attached via a ring
carbon atom and containing a substituent selected from R.sup.7 O--,
R.sup.7 S-- or R.sup.8 R.sup.9 N-- on a ring carbon adjacent to the carbon
of attachment; or
a 5- or 6-membered dihydro heteroaromatic ring attached via a ring carbon
atom and containing a substituent selected from oxo or thioxo on a ring
carbon adjacent to the carbon of attachment; or
a 6-membered tetrahydro heteroaromatic ring attached via a ring carbon atom
and containing two substituents independently selected from oxo or thioxo
wherein one of the substituents is on a ring carbon adjacent to the carbon
of attachment;
wherein the ring of R.sup.1 may be optionally further substituted and/or
may be fused to a second optionally substituted 5, 6, or 7 membered
aromatic or non-aromatic ring, optionally containing up to four
heteroatoms, each of which is selected from oxygen, nitrogen and sulphur;
R.sup.2 is vinyl or ethyl;
R.sup.3 is H, OH or F; and R.sup.4 is H; or R.sup.3 is H and R.sup.4 is F;
R.sup.5 is OH or H and R.sup.6 is H; or R.sup.5 is H and R.sup.6 is OH or
H; or R.sup.5 and R.sup.6 together form an oxo group;
R.sup.7 is optionally substituted alkyl;
R.sup.8 and R.sup.9 are independently selected from hydrogen or optionally
substituted alkyl; or
R.sup.7, R.sup.8 or R.sup.9, together with the atom to which they are
attached, may form a second aromatic or non-aromatic ring fused to
R.sup.1.
18. A compound according to claim 17 in which R.sup.1 is
4-substituted-quinolin-3-yl, 2-substituted-pyridin-3-yl, quinolin-8-yl,
pyrazolo[1,5-a]pyrimidin-3-yl, 4-oxo-1,4-dihydro-quinolin-3-yl,
2-oxo-1,2-dihydro-pyridin-3-yl, 4-oxo-4-H-chromen-3-yl,
6-oxo-1,6-dihydro-pyridazin-5-yl,
2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl,
4-oxo-3,4-dihydro-pyrimidin-5-yl,
4-oxo-1,4-dihydro-[1,8]naphthyridin-3-yl, and
5-oxo-2,3-dihydro-5-H-thiazolo[3,2-a]pyrimidin-6-yl, all of which may be
optionally substituted.
19. A compound according to claim 17 in which R.sup.1 is a 6-membered
dihydro or tetrahydro heteroaromatic ring with an oxo substituent adjacent
to the atom of attachment which rings may be optionally further
substituted.
20. A compound according to claim 17 in which R.sup.1 is optionally
substituted 2-pyridone or 4-pyridone.
Description
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. Mutilin and other compounds with a free OH at C-14 are inactive.
The impact of further modification at C-14 on the activity of
pleuromutilin has been investigated (H. Egger and H. Reinshagen, J.
Antibiotics, 1976, 29, 923). Replacing the hydroxy group of the glycolic
ester moiety at position 14 by another O, S or N-linked group was found to
improve anti-microbial activity. Thus, introducing a diethylaminoethylthio
group gives the compound of formula (B), also known as Tiamulin, which is
used as a veterinary antibiotic (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.
WO 97/25309 (SmithKline Beecham) describes further modification of the
acyloxy group, disclosing inter alia 14-O-acylcarbamoyl (R.sup.a
CONR.sup.b CO.sub.2 --) derivatives of mutilin in which R.sup.a may have a
range of values, including optionally substituted heterocyclic and R.sup.b
is a selected from a variety of monovalent groups.
WO 98/05659 (SmithKline Beecham) describes further 14-O-carbamoyl
derivatives of mutilin in which the N-atom of the carbamoyl group is
acylated by a group which includes an azabicyclic moiety.
WO 99/21855 (SmithKline Beecham) describes further derivatives of mutilin
or 19,20-dihydromutilin, in which the glycolic ester moiety at position 14
is replaced by the group R.sup.2 (CH.sub.2).sub.m X(CH.sub.2).sub.n
CH.sub.2 COO-- in which R.sup.2 is a non-aromatic mono- or bicyclic group.
WO 00/27790 (SmithKline Beecham) describes C-14 spirocyclic, acylcarbamate,
heteroaryalkyl carboxylate or arylalkoxyalkyl carboxylate derivatives of
mutilin or 19,20-dihydromutilin.
WO 00/37074 (SmithKline Beecham) describes further derivatives of mutilin
or 19,20-dihydromutilin having a heteroaryl acetate substituent at the
C-14 position.
WO 01/14310 (SmithKline Beecham) describes further derivatives of mutilin
or 19,20-dihydromutilin having a .beta.-keto ester substituent at the C-14
position.
In addition, 19,20-Dihydro-2.alpha.-hydroxy-mutilin is described by G.
Schulz and H. Berner in Tetrahedron, 1984, vol. 40, pp 905-917.
The present invention is based on the unexpected discovery that certain
novel C-14 ester derivatives of mutilin have potent antimicrobial
activity.
Accordingly the present invention provides a compound of formula (IA) or
(IB):
##STR3##
in which:
R.sup.1 is:
a 5- or 6-membered aromatic or heteroaromatic ring attached via a ring
carbon atom, preferably pyridyl, and comprising a substituent selected
from halo, R.sup.7 O--, R.sup.7 S-- or R.sup.8 R.sup.9 N-- on a ring
carbon adjacent to the carbon of attachment; or
a 5- or 6-membered dihydro heteroaromatic ring attached via a ring carbon
atom and comprising one oxygen or one or two nitrogen atoms and optionally
fused to phenyl, a 5- or 6-membered heteroaryl ring comprising one or two
nitrogen atoms or a 5- or 6-membered heterocyclyl ring comprising a
sulphur, oxygen or nitrogen atom and further comprising a substituent
selected from oxo or thioxo on a ring carbon adjacent to the carbon of
attachment;
a 6-membered tetrahydro heteroaromatic ring attached via a ring carbon atom
comprising one or two nitrogen atoms and farther comprising two
substituents independently selected from oxo or thioxo wherein one of the
substituents is on a ring carbon adjacent to the carbon of attachment; or
a bicyclic heteroaryl ring attached via a ring carbon atom and comprising
nine or ten ring atoms and from one to four nitrogen atoms;
wherein the ring of R.sup.1 may be optionally further substituted;
R.sup.2 is vinyl or ethyl;
R.sup.3 is H, OH or F and R.sup.4 is H, or R.sup.3 is H and R.sup.4 is F
and R.sup.5 and R.sup.6 together form an oxo group;
or R.sup.3 and R.sup.4 is each H and R.sup.5 is H, or OH and R.sup.6 is H
or R.sup.5 is H and R.sup.6 is H or OH;
R.sup.7 is optionally substituted C.sub.(1-6) alkyl; and
R.sup.8 and R.sup.9 are independently selected from hydrogen or optionally
substituted C.sub.(1-6) alkyl.
Examples of compounds of formula (IA) include those in which R.sup.3 and
R.sup.4 are both hydrogen, and R.sup.5 and R.sup.6 together form an oxo
group.
Examples of rings for R.sup.1 include pyrazole, pyrazine, pyridine,
pyrimidine, and pyran which may be optionally fused with a 6 membered
aromatic or non-aromatic ring, optionally containing up to two nitrogen
atoms, for instance quinoline, azaquinolone, diazaquinilone,
pyrimido[4,5-c]-pyridazine, chromane, in particular, the following:
##STR4##
Preferred monocyclic examples of the ring for R.sup.1 include:
##STR5##
in particular those comprising the moiety
##STR6##
for example:
##STR7##
Preferred bicyclic examples of the ring for R.sup.1 include:
##STR8##
Examples of groups for R.sup.7 include (C.sub.1-6)alkoxy, e.g. methoxy and
ethoxy.
Examples of groups for R.sup.8 and R.sup.9 include hydrogen.
When further substituted, an R.sup.1 group may comprise up to three
substituents, preferably one or two, and may be substituted on a carbon
atom and/or on a nitrogen atom.
Examples of optional substituents for carbon atoms of R.sup.1 include
halogen, (C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, (C.sub.1-6)alkoxy,
(C.sub.1-6)alkoxy(C.sub.1-6)alkyl, aryl(C.sub.1-6)alkoxy, hydroxy, nitro,
cyano, azido, amino, mono- and di-N-(C.sub.1-6)alkylamino, acylamino,
arylcarbonylamino, acyloxy, carboxy esters, carbamoyl, mono- and
di-N-(C.sub.1-6)alkylcarbamoyl, (C.sub.1-6)alkoxycarbonyl,
aryloxycarbonyl, hydrazino, ureido, guanidino, (C.sub.1-6)alkylguanidino,
amidino, (C.sub.1-6)alkylamidino, sulphonylamino, aminosulphonyl,
(C.sub.1-6)alkylthio, (C.sub.1-6)alkylsulphinyl,
(C.sub.1-6)alkylsulphonyl, heterocyclyl, heteroaryl,
heterocyclyl(C.sub.1-6)alkyl and heteroaryl(C.sub.1-6)alkyl.
Representative examples of optional substituents for carbon atoms of
R.sup.1 include (C.sub.1-6)alkyl, (C.sub.1-6)alkylthio, amino, mono- and
di-N-(C.sub.1-6)alkylamino, R.sup.10 (C.sub.1-6)alkylamino, imidazolinyl,
piperidinyl, piperazinyl (optionally substituted on N by R.sup.11),
pyridyl, hydrazino, N-(C.sub.1-3)alkylhydrazino,
aminomethylcarbonylhydrazino, heterocyclyl(C.sub.1-3)alkyl in which
heterocyclyl comprises a 6-membered ring with 1 nitrogen atom and
optionally an oxygen or a second nitrogen, and in which:
R.sup.10 is hydroxy, amino, heteroaryl in which heteroaryl comprises a 5 or
6-membered ring with 1 or 2 nitrogen atoms, heterocyclylin which
heterocyclyl comprises a 6-membered ring with 1 nitrogen atom and
optionally an oxygen or a second nitrogen, R.sup.11 -amino, in which:
R.sup.11 is (C.sub.1-3)alkyl, hydroxy(C.sub.1-3)alkyl, carbamoyl,
methylsulfonyl, amino(C.sub.1-3)alkylcarbonyl, for instance glycyl,
aminocarbonyl(C.sub.1-3)alkyl.
Examples of optional substituents for nitrogen atoms of R.sup.1, in
particular nitrogen of a pyridine, pyridazine, pyrimidine or pyrazine
ring, include R.sup.12 (C.sub.1-6)alkyl (preferably R.sup.12
(C.sub.1-3)alkyl), amino, mono- or di-(C.sub.1-6)alkylamino,
N-(pyridyl(C.sub.1-3)alkyl)-N-(C.sub.1-3)alkylamino (in which pyridyl is
optionally substituted, for example by (C.sub.1-6)alkoxy and/or amino,
mono- or di-(C.sub.1-6)alkylamino), acyl- or sulfonyl amino, acyl- or
sulfonyl-mono(C.sub.1-6)alkylamino, optionally substituted phenyl,
R.sup.13 C.dbd.N--, R.sup.14 (C.sub.1-4)alkylN(H/Me)-, R.sup.15 CON(H/Me)-
and R.sup.16 N(CHO)--, in which:
R.sup.12 is hydrogen, halo, nitrilo, amino, (C.sub.1-6)alkoxy,
(C.sub.1-3)alkoxy(C.sub.1-6)alkoxy, (C.sub.1-6)alkylcarboxy,
(C.sub.1-6)alkoxy, heteroaryl, heteroarylcarbonyl, imidazolylthio,
heterocyclyl, optionally substituted phenyl;
R.sup.13 is (C.sub.0-4)alkylheteroaryl in which the heteroaryl ring is 5-
or 6-membered and has 1 or 2 nitrogen atoms, for example pyridine,
pyrazine and imidazole and which may be substituted by 1 or 2
substituents, for instance by (C.sub.1-6)alkoxy, nitro, amino,
(C.sub.1-6)alkylamino, di-(C.sub.1-6)alkylamino, oxo;
R.sup.14 is (C.sub.1-4)alkylheteroaryl in which the heteroaryl ring is 5 or
6 membered and has 1 or 2 nitrogen atoms, for example pyridine, and which
may be substituted by 1 or 2 substituents, for instance by
(C.sub.1-6)alkoxy, nitro, amino, (C.sub.1-6)alkylamino,
di-(C.sub.1-6)alkylamino, oxo,
R.sup.15 is (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, aminomethyl, mono or
dialkyl(C.sub.1-6)aminomethyl, a 4, 5 or 6 membered heterocyclic ring
comprising a heteroatom selected from NH, NMe, and, for pyrrolidine,
optionally substituted by hydroxy or methoxy, dioxothietane, imidazole,
pyridine, pyridazine, pyrimidine, pyrazine; and
R.sup.16 is hydrogen, (C.sub.1-6)alkyl, benzyl or pyridinylmethyl.
Preferably, the ring in R.sup.1 comprises one substituent.
Preferred values of R.sup.1 include:
##STR9##
in which R.sup.15 is as hereinbefore defined, preferably such that the
moiety R.sup.15 NCO is derived from (D)- or (L)-proline, more preferably
(L)-proline, and R.sup.17 is hydrogen or (C.sub.1-6)alkyl, preferably
methyl, and
##STR10##
in which:
R.sup.18 is R.sup.10 (C.sub.1-6)alkyl, and R.sup.19 is hydrogen, or
R.sup.18 R.sup.19 N-- form a piperazinyl ring optionally substituted on N
by R.sup.11,
in which R.sup.10 and R.sup.11 are as hereinbefore defined.
R.sup.1 groups containing a substituent selected from oxo or thioxo on a
ring carbon adjacent to the carbon of attachment are referred to as
.beta.-oxo and .beta.-thioxo groups respectively.
When used herein, the term "aryl" refers to, unless otherwise defined,
phenyl or naphthyl. A substituted aryl group comprises up to five,
preferably up to three substituents.
Suitable substituents for an aryl group, including phenyl when forming part
of a benzyl group, include, for example, and unless otherwise defined,
halogen, (C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, (C.sub.1-6)alkoxy,
(C.sub.1-6)alkoxy(C.sub.1-6)alkyl, halo(C.sub.1-6)alkyl,
aryl(C.sub.1-6)alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and
di-N-(C.sub.1-6)alkylamino, acylamino, arylcarbonylamino, acyloxy,
carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and
di-N-(C.sub.1-6)alkylcarbamoyl, (C.sub.1-6)alkoxycarbonyl,
aryloxycarbonyl, ureido, guanidino, (C.sub.1-6)alkylguanidino, amidino,
(C.sub.1-6)alkylamidino, sulphonylamino, aminosulphonyl,
(C.sub.1-6)alkylthio, (C.sub.1-6)alkylsulphinyl,
(C.sub.1-6)alkylsulphonyl, heterocyclyl, heteroaryl,
heterocyclyl(C.sub.1-6)alkyl and heteroaryl(C.sub.1-6)alkyl. In addition,
two adjacent ring carbon atoms may be linked by a (C.sub.3-5)alkylene
chain, to form a carbocyclic ring.
When used herein, the terms "alkyl" and "alkenyl" refer to (individually or
as part of alkoxy or alkenyloxy) straight and branched groups containing
up to six carbon atoms.
When used herein, the terms "cycloalkyl" and "cycloalkenyl" refer to groups
having from three to eight ring carbon atoms.
When substituted, an alkyl, alkenyl, cycloalkyl or cycloalkenyl group may
comprise up to four substituents, preferably up to two substituents.
Suitable substituents for alkyl, alkenyl, cycloalkyl or cycloalkenyl
groups include aryl, heteroaryl, 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, amide, ureido, guanidino,
(C.sub.1-6)alkylguanidino, amidino, (C.sub.1-6)alkylamidino,
(C.sub.1-6)acyloxy, azido, hydroxy, and halogen.
When used herein the terms "heterocyclyl" and "heterocyclic" refer to,
unless otherwise defined, 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. Each heterocyclic ring preferably 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.
When substituted, a heterocyclyl group may comprise up to three
substituents. Preferably a substituent for a heterocyclyl group is
selected from oxo, and the group hereinbefore defined as suitable aryl
substituents.
When used herein, the term "heteroaryl" suitably includes, unless otherwise
defined, a mono- or bicyclic heteroaromatic ring system comprising up to
four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen
and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring
atoms. A bicyclic heteroaromatic ring system may include a carbocyclic
ring.
When substituted, a heteroaryl group may comprise up to three substituents.
Preferably a substituent for a heteroaryl group is selected from the group
hereinbefore defined as suitable aryl substituents.
When used herein, the term "acyl" includes formyl and
(C.sub.1-6)alkylcarbonyl.
When used herein the term "sulfonyl" includes (C.sub.1-6)alkylsulfonyl.
The term halo or halogen includes fluoro, chloro, bromo and iodo.
Depending on the substituents, two or more diastereoisomers may be
possible. In that situation the present invention includes the individual
diastereoisomers and mixtures thereof.
The 2-hydroxy-substituted compounds of formula (I) are of the 2 (S)
configuration.
Preferred compounds of the invention include:
(4-Oxo-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidine-3-carboxylic acid)
mutilin 14-ester;
[2-(3-Morpholino-propylamino)-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic
acid) mutilin 14-ester;
(8-Ethyl-2-piperazin-1-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbo
xylic acid) mutilin 14-ester;
{1,6-Dihydro-1-[N-methyl-N-(D)-prolylamino]-6-oxo-pyridazine-5-carboxylic
acid} mutilin 14-ester;
{1,2-Dihydro-1-[N-methyl-N-(D)-prolylamino]-2-oxo-pyridine-3-carboxylic
acid} mutilin 14-ester;
{1,6-Dihydro-1-[N-methyl-N-(L)-prolylamino]-6-oxo-pyridazine-5-carboxylic
acid} mutilin 14-ester; and
{1,6-Dihydro-1-[N-methyl-N-(L)-trans-methoxy-prolylamino]-6-oxo-pyridazine-
5-carboxylic acid} mutilin 14-ester.
The compounds of this invention may be in crystalline or non-crystalline
form, and, if crystalline, may optionally be hydrated or solvated. This
invention includes within its scope stoichiometric hydrates as well as
compounds containing variable amounts of water.
The compounds according to the invention are suitably provided in
substantially pure form, for example at least 50% pure, suitable at least
60% pure, advantageously at least 75% pure, preferably at least 85% pure,
more preferably at least 95% pure, especially at least 98% pure, all
percentages being calculated as weight/weight.
Compounds of the invention that contain a basic group such as an amino
substituent may be in the form of a free base or an acid addition salt.
Compounds having an acidic group such as a carboxy substituent may be in
the form of a pharmaceutically acceptable salt. Compounds of the invention
having both a basic and an acidic centre may be in the form of
zwitterions, acid addition salt of the basic centre or alkali metal salts
(of the carboxy group). Pharmaceutically acceptable salts are preferred.
Pharmaceutically acceptable acid-addition salts include those described by
Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Suitable
salts include the hydrochloride, maleate, and methanesulphonate;
particularly the hydrochloride.
Pharmaceutically acceptable salts for acidic groups include those described
by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Suitable
salts include alkali metal salts such as the sodium and potassium salts.
Compounds of the present invention may be readily prepared from a mutilin
or a 19,20-dihydro-mutilin derivative by adapting procedures well known in
the art for forming ester groups. Suitable procedures are reviewed in, for
example, I. O. Sutherland in Comprehensive Organic Chemistry, Vol. 2, ed.
I. O. Sutherland, p. 871-907, Pergamon, 1979.
Accordingly, the present invention provides a process for preparing a
compound of formula (IA) or (IB) which comprises reacting a compound of
formula (IIA) or (IIB):
##STR11##
in which:
P is hydrogen or an hydroxy-protecting group;
R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A and R.sup.6A are R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 as defined for formulae (IA) and (IB) or a
group convertible to R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
respectively; and is as hereinbefore defined;
with a compound of formula (III):
##STR12##
in which:
R.sup.1A is R.sup.1 as defined for formulae (IA) and (IB) or a group
convertible to R.sup.1 ;
in an esterification reaction and thereafter, and if so needed;
converting P to hydrogen, and if necessary
converting an R.sup.1A, R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A and R.sup.6A
group to an R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 group.
Suitable ester forming conditions include an organic solvent such as
dichloromethane at a temperature of 10.degree. C. to 30.degree. C., in the
presence of either silver oxide or an organic base such as pyridine or
triethylamine.
In a further aspect, the present invention provides a process for preparing
a compound of formula (IA) or (IB) in which R.sup.1 contains an oxo or
thioxo moiety on the ring adjacent to the carbon of attachment (i.e. a
.beta.-oxo or .beta.-thioxo group) which comprises reacting a compound of
formula (IVA) or (IVB):
##STR13##
in which P, R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A and R.sup.6A are as
hereinbefore defined;
with a compound of formula (V):
##STR14##
in which R.sup.1B is R.sup.1 as hereinbefore defined containing a
.beta.-oxo or .beta.-thioxo substituent, and X is a salt forming group;
and thereafter treating the resulting mixed anhydride with
4-dimethylaminopyridine and thereafter, and if so needed;
converting P to hydrogen, and if necessary
converting an R.sup.1A, R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A and R.sup.6A
group to an R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 group.
X is preferably sodium or triethylamine.
Suitable anhydride formation conditions are well known in the art and
include an organic solvent such as dichloromethane, at a temperature of
-20.degree. C. to 20.degree. C. (preferably -10.degree. C. to 5.degree.
C.).
In a yet further aspect, the present invention provides a process for
preparing a compound of formula (IA) or (IB) in which R.sup.1 contains a
.beta.-oxo or .beta.-thioxo group which comprises reacting a compound of
formula (V) as hereinbefore defined, with phosgene and thereafter treating
the resulting intermediate with a compound of formula (IIA) or (IIB) as
hereinbefore defined, and thereafter and if so needed;
converting P to hydrogen, and if necessary
converting an R.sup.1A, R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A and R.sup.6A
group to an R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 group.
Suitable conditions for the reaction of phosgene with compounds of formula
(V) are well known in the art and include an organic solvent such as
dichloromethane or N,N-dimethylformamide at a temperature of 0.degree. C.
to 40.degree. C. (preferably 15.degree. C. to 25.degree. C.).
Conversion of an R.sup.1A, R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A and
R.sup.6A group to an R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 group typically arises if a protecting group is needed during the
above reactions or during the preparation of the reactants by the
procedures described below.
When P is a hydroxyl protecting group, a preferred protecting group is
acyl, for example so that --OP is trifluoroacetoxy or dichloroacetoxy.
When the intended R.sup.3, R.sup.5 or R.sup.6 is also hydroxyl, then
R.sup.3A, R.sup.5A and R.sup.6A is also preferably acyloxy, for example
acetoxy or dichloroacetoxy. Hydroxyl groups at positions 11, 3 and 2 (as
groups OP, R.sup.5A and R.sup.6A and R.sup.3A) may be protected using, for
example, trifluoroacetic anhydride or dichloroacetic anhydride and
pyridine in tetrahydrofuran or N-trifluoroacetyl-imidazole in
tetrahydrofuran at 0.degree. C. After the reaction described above with
(III) is complete, the protecting acyl groups may be removed to restore
the hydroxyl groups, for instance by hydrolysis e.g. using NaOH in either
MeOH or tetrahydrofuran/water solution.
Suitable hydroxy, carboxy and amino protecting groups are those well known
in the art and which may be removed under conventional conditions and
without disrupting the remainder of the molecule. A comprehensive
discussion of the ways in which hydroxy, carboxy and amino groups may be
protected and methods for cleaving the resulting protected derivatives is
given in for example Protective Groups in Organic Chemistry, T. W. Greene
and P. G. M. Wuts, (Wiley-Interscience, New York, 2nd edition, 1991).
Particularly suitable hydroxy protecting groups include, for example,
triorganosilyl groups such as, for instance, trialkylsilyl and also
organocarbonyl and organooxycarbonyl groups such as, for instance, acetyl,
allyloxycarbonyl and 4-methoxybenzyloxycarbonyl. Particularly suitable
carboxy protecting groups include alkyl and aryl esters, for instance
methyl, ethyl and phenyl. Particularly suitable amino protecting groups
include alkoxycarbonyl and 4-methoxybenzyloxycarbonyl.
R.sup.2A is typically the R.sup.2 group vinyl, and this may be converted to
the alternative R.sup.2 ethyl group by hydrogenating the vinyl group to
form an ethyl group, typically by hydrogenation over a palladium catalyst
(e.g. 10% palladium-on-carbon) in a solvent such as ethyl acetate,
ethanol, dioxane, or tetrahydrofuran.
R.sup.3A is typically hydrogen, fluoro or protected hydroxyl, such as
acyloxy. After the coupling reaction, if required, protecting acyl groups
may be removed to restore the hydroxyl groups by hydrolysis e.g. using
NaOH in MeOH.
A compound of formula (IA) may also be prepared from an epi-mutilin
starting material. Accordingly, in a further aspect, the present invention
provides a process for preparing a compound of formula (IA) in which
R.sup.3 and R.sup.4 are both hydrogen and R.sup.5 and R.sup.6 form an oxo
group, which comprises reacting an epi-mutilin compound of formula (IIC):
##STR15##
wherein R.sup.2A is as hereinbefore defined;
with a compound (III), as hereinbefore defined; under ester forming
conditions as hereinbefore defined;
and then treating the product with an acid;
and where required or desired converting an R.sup.1A group to an R.sup.1
group and an R.sup.2A group to an R.sup.2 group.
In a further aspect, the present invention provides a process for the
preparation of a compound of formula (IA) in which R.sup.3 and R.sup.4 are
both hydrogen and R.sup.5 and R.sup.6 form an oxo group, which comprises
reacting a compound of formula (IIC) as hereinbefore defined with an acid
chloride of formula (III), as hereinbefore defined in the presence of
N,N-dimethylformamide; and then treating the product with an acid;
and where required or desired converting an R.sup.1A group to an R.sup.1
group and an R.sup.2A group to an R.sup.2 group.
In a yet further aspect, the present invention provides a process for
preparing a compound of formula (IA) in which R.sup.3 and R.sup.4 are both
hydrogen and R.sup.5 and R.sup.6 form an oxo group, which comprises
reacting an epi-mutilin compound of formula (VI):
##STR16##
wherein R.sup.2A is as hereinbefore defined and M is an alkali metal;
with a compound (III), as hereinbefore defined in an ester forming
reaction;
and then treating the product with an acid;
and where required or desired converting an R.sup.1A group to an R.sup.1
group and an R.sup.2A group to an R.sup.2 group.
Suitable ester forming conditions are known in the art and include an
organic solvent such as tetrahydrofuran at -78.degree. C. to 35.degree. C.
Alkali metals include lithium, sodium and potassium, particularly lithium.
In a yet further aspect, the present invention provides a process for
preparing a compound of formula (IA) in which R.sup.3 and R.sup.4 are both
hydrogen, R.sup.5 and R.sup.6 form an oxo group and R.sup.1 contains a
.beta.-oxo or .beta.-thioxo group, which comprises reacting a compound of
formula (IVC):
##STR17##
wherein R.sup.2A is as hereinbefore defined;
with a compound of formula (V) as hereinbefore defined in an anhydride
forming reaction as hereinbefore defined;
and thereafter treating the resulting mixed anhydride with
4-dimethylaminopyridine and thereafter treating the product with an acid;
and where required or desired converting an R.sup.1A group to an R.sup.1
group and an R.sup.2A group to an R.sup.2 group.
In a yet further aspect, the present invention provides a process for
preparing a compound of formula (IA) in which R.sup.3 and R.sup.4 are both
hydrogen, R.sup.5 and R.sup.6 form an oxo group and R.sup.1 contains a
.beta.-oxo or .beta.-thioxo group, which comprises reacting a compound of
formula (V) as hereinbefore defined, with phosgene and thereafter treating
the resulting intermediate with a compound of formula (IVC) as
hereinbefore defined, and thereafter treating the product with an acid;
and where required or desired converting an R.sup.1A group to an R.sup.1
group and an R.sup.2A group to an R.sup.2 group.
The acid treatment indicated above converts the epi-mutilin configuration
to the usual mutilin nucleus of formula (IIA). Typically this conversion
is carried out by treatment with conc. HCl or Lukas reagent (conc. HCl
saturated with ZnCl.sub.2) in dioxane.
It should be appreciated that it may be necessary to interconvert one
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 or R.sup.6 group to another
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 or R.sup.6 group. This
typically arises when one compound of formula (IA/B) is used as the
immediate precursor of another compound of formula (IA/B) or when it is
easier to introduce a more complex or reactive substituent at the end of a
synthetic sequence. A substituent group in R.sup.1 can be converted into
another substituent group using one of the general methods for functional
group transformation described in the literature (e.g. a carboxylic ester
can be hydrolysed to a carboxylic acid with base; an acid can be converted
into an amide; a tert-butoxycarbonylamino group can be converted into an
amine by treatment with trifluoroacetic acid; an amino group can be
alkylated or acylated), provided that the method chosen is compatible with
other functional groups in the molecule (e.g. the ketone at C-3 in the
pleuromutilin nucleus).
Functional group transformations are well known in the art and are
described in, for instance, Comprehensive Organic Functional Group
Transformations, eds. A. R. Katritzky, O. Meth-Cohn, and C. W. Rees
(Elsevier Science Ltd., Oxford, 1995), Comprehensive Organic Chemistry,
eds. D. Barton and W. D. Ollis (Pergamon Press, Oxford, 1979), and
Comprehensive Organic Transformations, R. C. Larock (VCH Publishers Inc.,
New York, 1989).
Compounds of formula (I) in which R.sup.1 :
##STR18##
in which R.sup.15 and R.sup.17 are as hereinbefore defined;
may be conveneniently prepared in a step wise fashion in which the mutilin
nucleus is fisrt coupled with an unsubstituted pyridinone, pyridazinone or
pyrazinone (R.sup.1A) to give an intermediate which is then successively
aminated, acylated (with R.sup.17 CO) and finally, if need be,
N-methylated, to give the final compounds, such reactions being carried
out under conventional conditions.
Compounds of formulae (IIA) in which R.sup.3A and R.sup.4A are hydrogen,
(IIB) and (IIC) may be readily prepared according to methods described in
the literature, for example G. Schulz and H. Berner, Tetrahedron, 1984,
40, 905, and in WO 97/25309 and WO 98/05659 (SmithKline Beecham). Where
necessary, and as hereinbefore described, saponification of the C-14 ester
may be carried out at an appropriate stage.
Compounds of formula (IIA) in which R.sup.3A is hydroxyl or fluoro may be
prepared from pleuromutilin, via an intermediate 2-diazo compound, the
preparation of which is described by G. Schulz and H. Berner in
Tetrahedron, 1984, 40, 905. Where necessary, saponification of the C-14
ester group may be carried out at an appropriate stage using conventional
techniques such as sodium hydroxide or sodium methoxide in methanol or
aqueous tetrahydrofuran solution.
The intermediate 2-diazo compound may be reacted with a carboxylic acid to
give a 2-acyloxy-mutilin derivative. Suitably, reaction with
dichloroacetic acid gives a 2-dichloroacetoxy-mutilin derivative, which
can be deprotected as described above to provide the (2S)-2-hydroxy
derivative, at an appropriate stage.
Compounds of formula (IIA) in which R.sup.3A is fluoro may be obtained by
reacting 2-diazo-mutilin with a source of hydrogen fluoride. Conveniently,
the hydrogen fluoride source is an amine complex of hydrogen fluoride such
as hydrogen fluoride-pyridine. The reaction may be carried out in an
anhydrous solvent (e.g. diethyl ether, tetrahydrofuran,
1,2-dimethoxyethane), at a temperature of -15.degree. C. to 25.degree. C.
This reaction produces (2S)-2-fluoro derivatives. (2R)-2-Fluoro-mutilin
derivatives may be prepared by treating the (2S)-isomer with a base (e.g.
sodium hydroxide or potassium hydroxide in ethanol). This will usually
produce a mixture of (2S) and (2R)-isomers that may be separated using
conventional techniques such as chromatography and crystallisation.
Compounds of formula (IIA) in which R.sup.5 is hydroxy and R.sup.6 is
hydrogen may be prepared according to methods described in the literature,
for example, by reduction of a mutilin with lithium aluminium hydride as
described by Birch et al, Tetrahedronl, 1966, supp 8 (II), 359-387; or by
reduction with lithium tri-tert-butoxyaluminohydride in dioxane as
described by G. Schultz et al, Tetrahedron, 1984, 40, 905-917.
Compounds of formula (IIA) in which R.sup.5 is hydrogen and R.sup.6 is
hydroxy may be prepared according to the methods described in the
literature, for example, by reduction of a mutilin with lithium and
methanol in liquid ammonia, as described by Birch et al, Tetrahedron,
1966, supp 8 (II), 359-387.
Compounds of formula (IIA) in which R.sup.5 and R.sup.6 are both hydrogen
may be prepared according to the method of G. Schultz et al, Tetrahedron,
1984, 40, 905-917, by reduction with potassium hydroxide and hydrazine in
refluxing diethylene glycol.
Acid chlorides of formula (III) and (IV) are available commercially, or may
be readily prepared by adapting procedures well known in the art for the
conversion of carboxylic acids to acid chlorides e.g. M. F. Ansell in The
Chemistry of Acyl Halides, ed. S. Patai, pp 35-68 (Interscience, London,
1972) and include, for example, oxalyl chloride in dichloromethane
solution in the presence of N,N-dimethylformamide.
Carboxylates salts of formula (V) are available commercially or may be
readily prepared from the carboxylic acid by methods known to those
skilled in the art.
Carboxylic acids may be prepared by adapting procedures well known in the
art for preparing such acids e.g. Comprehensive Organic Chemistry, Vol. 2,
Ed. I. O. Sutherland (Pergamon, Oxford, 1979).
Compounds of formula (VI) may be readily prepared by adapting procedures
well known in the art for preparing alkali metal salts. Lithium salts may
be prepared by the addition of an alkyl lithium (e.g. n-butyl lithium) or
a lithium amide (e.g. lithium hexamethyldisilazide) to 4-epi-mutilin in
THF at -78.degree. C. Sodium salts may be prepared using sodium hydride or
a sodium amide (e.g. sodium hexamethyldisilazide), and potassium salts may
be prepared using potassium tert-butoxide.
The compounds of the present invention may contain a chiral centre, and
therefore the above processes may produce a mixture of diastereoisomers. A
single diastereoisomer may be prepared by separating such a mixture of
diastereoisomers by conventional techniques such as chromatography or
fractional crystallisation.
The compounds of this invention may be in crystalline or non-crystalline
form, and, if crystalline, may optionally be hydrated or solvated. When
some of the compounds of this invention are allowed to crystallise or are
recrystallised from organic solvents, solvent of crystallisation may be
present in the crystalline product. Similarly, some of the compounds of
this invention may be crystallised or recrystallised from solvents
containing water. In such cases water of hydration may be present in the
crystalline product. Crystallisation procedures will usually produce
stoichiometric hydrates. Compounds containing variable amounts of water
may be produced by processes such as lyophilisation.
The compounds according to the invention are suitably provided in
substantially pure form, for example at least 50% pure, suitable at least
60% pure, advantageously at least 75% pure, preferably at least 85% pure,
more preferably at least 95% pure, especially at least 98% pure, all
percentages being calculated as weight/weight. An impure or less pure form
of a compound according to the invention may, for example, be used in the
preparation of a more pure form of the same compound or of a related
compound (for example a corresponding derivative) suitable for
pharmaceutical use.
The present invention also includes pharmaceutically acceptable salts and
derivatives of the compounds of the invention. Salt formation may be
possible when one of the substituents carries an acidic or basic group.
Salts may be prepared by salt exchange in conventional manner.
Acid-addition salts may be pharmaceutically acceptable or
non-pharmaceutically acceptable. In the latter case, such salts may be
useful for isolation and purification of the compound of the invention, or
intermediates thereto, and will subsequently be converted into a
pharmaceutically acceptable salt or the free base.
The compounds of the present invention and their pharmaceutically
acceptable salts or derivatives have antimicrobial properties and are
therefore of use in therapy, in particular for treating microbial
infections in animals, especially mammals, including humans, in particular
humans and domesticated animals (including farm animals). The compounds
may be used for the treatment of infections caused by, for example,
Gram-positive and Gram-negative bacteria and mycoplasmas, including, for
example, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus
faecalis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus
pneumoniae, Haemophilus sp., Neisseria sp., Legionella sp., Chlamydia sp.,
Moraxella catarrhalis, Mycoplasma pneumoniae, and Mycoplasma
gallisepticum.
The present invention also provides a method of treating microbial
infections in animals, especially in humans and in domesticated mammals,
which comprises administering a compound of the invention or a
pharmaceutically acceptable salt or derivative or solvate thereof, or a
composition according to the invention, to a patient in need thereof.
Compounds of the present invention show good activity against Chlamydia
pneumoniae. This has been implicated in heart disease, in particular in
promoting vascular infection (see for instance FR 2,771,008-A1, Hoechst
Marion Roussel SA). Accordingly, in a further aspect, the present
invention provides a method of preventing C. pneumoniae-induced
atherosclerosis which method comprises treating a subject in need thereof
with an effective amount of a compound of formula (I). A compound of
formula (I) may also be used in combination with an anti-atherosclerotic
agent, to reduce the incidence of heart attack and other cardiac events.
Representative examples of anti-atherosclerotic agents include the class
of cholesterol-lowering compounds referred to generically as "statins",
for instance atorvastatin (Lipitor, Warner Lambert), pravastatin
(Pravachol), simvastatin (Lipovas, Merck) and cerivastatin (Baycol,
Bayer). It has also been suggested that Chlamydia pneumoniae may
contribute to Alzheimer's Disease. Accordingly, in a further aspect, the
present invention provides a method of treating Alzheimer's Disease which
method comprises treating a subject in need thereof with an effective
amount of a compound of formula (I).
The invention further provides the use of a compound of the invention or a
pharmaceutically acceptable salt or derivative or solvate thereof in the
preparation of a medicament for use in the treatment of microbial
infections.
Compounds of the present invention may be used to treat skin and soft
tissue infections and acne, by topical application. Accordingly, in a
further aspect the present invention provides the use of a compound of the
invention or a pharmaceutically acceptable salt or derivative or solvate
thereof in the preparation of a medicament adapted for topical
administration for use in the treatment of skin and soft tissue infections
and also in the treatment of acne in humans.
Compounds of the present invention may be also used for the elimination or
reduction of nasal carriage of pathogenic bacteria such as S. aureus, H.
influenzae, S. pneumonia and M. catarrhalis, in particular colonisation of
the nasospharynx by such organisms, by the administration of a compound of
the present invention thereto. Accordingly, in a further aspect, the
present invention provides for the use of a compound of the invention or a
pharmaceutically acceptable salt or derivative or solvate thereof in the
manufacture of a medicament adapted for administration to the nasal
cavity, for reducing or eliminating the nasal carriage of pathogenic
organisms. Preferably, the medicament is adapted for focussed delivery to
the nasopharynx, in particular the anterior nasopharynx.
Such reduction or elimination of nasal carriage is believed to be useful in
prophylaxis of recurrent acute bacterial sinusitis or recurrent otitis
media in humans, in particular in reducing the number of episodes
experienced by a patient over a given period of time or increasing the
time intervals between episodes. Accordingly, in a further aspect, the
present invention provides for the use of a compound of the invention or a
pharmaceutically acceptable salt or derivative or solvate thereof in the
manufacture of a medicament adapted for administration to the nasal
cavity, for prophylaxis of recurrent acute bacterial sinusitis or
recurrent otitis media.
Compounds of the present invention are also useful in treating chronic
sinusitis. Accordingly, in a further aspect, the present invention
provides for the use of a compound of the invention or a pharmaceutically
acceptable salt or derivative or solvate thereof in the manufacture of a
medicament, for treating of chronic sinusitis.
The compounds according to the invention may suitably be administered to
the patient at a daily dosage of from 1.0 to 50 mg/kg of body weight. For
an adult human (of approximately 70 kg body weight), from 50 to 3000 mg,
for example about 1500 mg, of a compound according to the invention may be
administered daily. Suitably, the dosage for adult humans is from 5 to 20
mg/kg per day. Higher or lower dosages may, however, be used in accordance
with normal clinical practice.
To lessen the risk of encouraging the development of resistant organisms
during prophylaxis of recurrent otitis media or recurrent acute bacterial
sinusitis, it is preferred to administer the drug on an intermittent,
rather than a continual, basis. In a suitable intermittent treatment
regimen for prophylaxis of recurrent otitis media or recurrent sinusitis,
drug substance is administered on a daily basis, for a small number of
days, for instance from 2 to 10, suitably 3 to 8, more suitably about 5
days, the administration then being repeated after an interval, for
instance, on a monthly basis over a period of months, for instance up to
six months. Less preferably, the drug substance may be administered on a
continuing, daily basis, over a prolonged period, for instance several
months. Suitably, for prophylaxis of recurrent otitis media or recurrent
sinusitis, drug substance is administered once or twice a day. Suitably,
drug substance is administered during the winter months when bacterial
infections such as recurrent otitis media and recurrent sinusitis tend to
be more prevalent. The drug substance may be administered at a dosage of
from 0.05 to 1.00 mg, typically about 0.1 to 0.2 mg, in each nostril, once
or twice a day.
More generally, the compounds and compositions according to the invention
may be formulated for administration in any convenient way for use in
human or veterinary medicine, by analogy with other antibiotics.
Accordingly, in a further aspect, the present invention provides a
pharmaceutical composition comprising a compound of the invention or a
pharmaceutically acceptable salt or derivative or solvate thereof together
with a pharmaceutically acceptable carrier or excipient.
The compounds and compositions according to the invention may be formulated
for administration by any route, for example oral, topical or parenteral.
The compositions may, for example, be made up in the form of tablets,
capsules, powders, granules, lozenges, creams, syrups, sprays or liquid
preparations, for example solutions or suspensions, which may be
formulated for oral use or in sterile form for parenteral administration
by injection or infusion.
Tablets and capsules for oral administration may be in unit dosage form,
and may contain conventional excipients including, for example, binding
agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or
polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,
calcium phosphate, sorbitol or glycine; tabletting lubricants, for example
magnesium stearate, talc, polyethylene glycol or silica; disintegrants,
for example potato starch; and pharmaceutically acceptable wetting agents,
for example sodium lauryl sulphate. The tablets may be coated according to
methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or
oily suspensions, solutions, emulsions, syrups or elixirs, or may be
presented as a dry product for reconstitution with water or another
suitable vehicle before use. Such liquid preparations may contain
conventional additives, including, for example, suspending agents, for
example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl
cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated
edible fats; emulsifying agents, for example lecithin, sorbitan monooleate
or acacia; non-aqueous vehicles (which may include edible oils), for
example almond oil, oily esters (for example glycerine), propylene glycol,
or ethyl alcohol; preservatives, for example methyl or propyl
p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring
and colour agents.
Compositions according to the invention intended for topical administration
may, for example, be in the form of ointments, creams, lotions, eye
ointments, eye drops, ear drops, nose drops, nasal sprays, impregnated
dressings, and aerosols, and may contain appropriate conventional
additives, including, for example, preservatives, solvents to assist drug
penetration, and emollients in ointments and creams. Such topical
formulations may also contain compatible conventional carriers, for
example cream or ointment bases, ethanol or oleyl alcohol for lotions and
aqueous bases for sprays. Such carriers may constitute from about 1% to
about 98% by weight of the formulation; more usually they will constitute
up to about 80% by weight of the formulation.
Compositions according to the invention intended for topical
administration, in addition to the above, may also contain a steroidal
anti-inflammatory agent; for example, betamethasone.
Compositions according to the invention may be formulated as
