U.S. patent application number 11/178823 was filed with the patent office on 2006-02-02 for peptide deformylase inhibitors.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Kelly M. Aubart, Siegfried B. IV Christensen, Maxwell D. Cummings, Xiangmin Liao, Jia-Ning Xiang.
Application Number | 20060025412 11/178823 |
Document ID | / |
Family ID | 32298380 |
Filed Date | 2006-02-02 |
United States Patent
Application |
20060025412 |
Kind Code |
A1 |
Aubart; Kelly M. ; et
al. |
February 2, 2006 |
Peptide deformylase inhibitors
Abstract
PDF inhibitors and novel methods for their use are provided.
Inventors: |
Aubart; Kelly M.;
(Collegeville, PA) ; Xiang; Jia-Ning; (Palo Alto,
CA) ; Christensen; Siegfried B. IV; (Collegeville,
PA) ; Liao; Xiangmin; (Collegeville, PA) ;
Cummings; Maxwell D.; (Strafford, PA) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
32298380 |
Appl. No.: |
11/178823 |
Filed: |
October 14, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10469434 |
Aug 28, 2003 |
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PCT/US02/06258 |
Mar 1, 2002 |
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11178823 |
Oct 14, 2005 |
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60272446 |
Mar 1, 2001 |
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Current U.S.
Class: |
514/235.2 ;
514/254.01; 514/256; 514/326; 514/372; 514/378; 514/381; 514/397;
514/406; 514/424; 544/141; 544/333; 544/372; 546/207; 548/400;
548/543 |
Current CPC
Class: |
C07D 405/12 20130101;
C07D 401/06 20130101; C07D 413/06 20130101; C07D 401/12 20130101;
C07D 417/06 20130101; C07D 207/26 20130101 |
Class at
Publication: |
514/235.2 ;
548/400; 514/254.01; 514/326; 514/256; 514/372; 514/378; 514/397;
514/406; 514/381; 514/424; 544/141; 544/333; 544/372; 546/207;
548/543 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/496 20060101 A61K031/496; A61K 31/454
20060101 A61K031/454; A61K 31/506 20060101 A61K031/506; A61K
31/4015 20060101 A61K031/4015; A61K 31/4025 20060101
A61K031/4025 |
Claims
1. A compound according to formula (I): ##STR24## wherein: R1 is
selected from the group consisting of C.sub.1-6alkyl,
--C.sub.1-2alkylAr, and Ar; R2 is selected from the group
consisting of hydrogen, C.sub.1-6alkyl, --(CH.sub.2).sub.mOH,
--(CH.sub.2).sub.nAr', --(CH.sub.2).sub.nHet, --Ar', --SO.sub.2R3,
--C(O)R3, --C(O)NHR3, --C(O)OR3, --CH(R4)CONR5R6, and
--CH(R4)CO.sub.2R7; R3 is selected from the group consisting of
C.sub.1-6alkyl, --C.sub.1-2alkylAr', and Ar'; R4 is hydrogen, or
C.sub.1-6alkyl; R5 and R6 are independently selected from the group
consisting of hydrogen, C.sub.1-6alkyl, --C.sub.1-2alkylAr', and
Ar'; or R5, R6 together form a five or six membered cycloalkyl ring
which is optionally mono-substituted by --CH.sub.2OR7; R7 is
selected from the group consisting of hydrogen, and C.sub.1-3alkyl;
Ar is selected from the group consisting of phenyl, furyl, and
thienyl, all of which may be optionally substituted by one or more
Z.sub.1 groups; Ar' is selected from the group consisting of
phenyl, naphthyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl,
pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl,
benzofuranyl, indolyl, thiazolidinyl, isoxazolyl, oxadiazolyl,
thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, and
pyrimidyl, all of which may be optionally substituted by one or
more Z.sub.2 groups; Het is selected from the group consisting of
tetrahydrofuranyl and piperidinyl; Z.sub.1 is independently
selected from the group consisting of hydrogen, C.sub.1-3alkyl,
--CN, F, Cl, Br, and I; Z.sub.2 is independently selected from the
group consisting of hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy,
--(CH.sub.2).sub.nCO.sub.2R4, --C(O)NR5R6, --CN,
--(CH.sub.2).sub.nOH, --NO.sub.2, F, Cl, Br, I, --NR5R6, and
--NHC(O)R1; m is 2 to 5; and n is 0 to 5; or a pharmaceutically
acceptable salt thereof.
2. A compound according to claim 1 selected from the group
consisting of:
N-[(3S,4R)-4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hy-
droxyformamide;
N-[(3R,4S)-4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hyd-
roxyformamide;
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(t-butylcarboxy)pyrrolidin-3-yl-meth-
yl]-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformam-
ide;
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-pentanoylpyrrolidin-3-yl-methyl-
)-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(2-phenylethanoyl)pyrrolidin-3-yl-me-
thyl]-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(1-phenylmethanoyl)pyrrolidin-3-yl-m-
ethyl]-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-(1-Benzenesulfonyl-4-butyl-2-oxopyrrolidin-3-yl-methy-
l)-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-[1-(Butane-1-sulfonyl)-4-butyl-2-oxopyrrolidin-3-yl-m-
ethyl]-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(naphthalen-2-ylmethanoyl)-2-oxopyrrolidin-
-3-yl-methyl]-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-(1-Benzyl-4-butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydr-
oxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[1-(4-ethoxyphenyl)methanoyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[1-(3-ethoxyphenyl)methanoyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[1-(2-ethoxyphenyl)methanoyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-pyridin-3-ylmethylpyrrolidin-3-yl-me-
thyl)-N-hydroxyformamide;
N-((3S,4R)-4-Butyl-1-{(S)-1-[1-((S)-2-methoxymethyl-pyrrolidin-1-yl)metha-
noyl]-3-methylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;
N-((3R,4S)-4-Butyl-1-{(S)-1-[1-((S)2-methoxymethylpyrrolidin-1-yl)-methan-
oyl]-3-methylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;
N-((3S,4R)-4-Butyl-1-{(S)-1-[1-(dimethylamino)methanoyl]-3,3-dimethylbuty-
l}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(4-ethoxybenzyl)-2-oxopyrrolidin-3-yl-meth-
yl]-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-met-
hyl]-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(2-morpholin-4-yl-2-oxoethoxy)benzyl]-2-
-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(4-carboxy-1-butoxy)benzyl]-2-oxopyrrol-
idin-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(3-hydroxybenzoxy)benzyl]-2-oxopyrrolid-
in-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-2-oxo-1-[4-(tetrahydrofuran-2-ylmethoxy)benz-
yl]pyrrolidin-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(furan-2-ylmethoxy)benzyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(3-hydroxypropoxy)benzyl]-2-oxopyrrolid-
in-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-2-oxo-1-[4-(piperidin-3-ylmethoxy)benzyl]pyr-
rolidin-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-2-oxo-1-[4-(pyridin-3-ylmethoxy)benzyl]pyrro-
lidin-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(5-hydroxypentoxy)benzyl]-2-oxopyrrolid-
in-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(2,3-dichlorobenzyl)-2-oxopyrrolidin-3-yl--
methyl]-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(3,4-dichlorobenzyl)-2-oxopyrrolidin-3-yl--
methyl]-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-phenylpyrrolidin-3-yl-methyl]-N-hydr-
oxyformamide;
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[2-(2-hydroxyphenyl)-2-oxoethyl]-2-oxopyrr-
olidin-3-yl-methyl}-N-hydroxyformamide;
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(3,5-dimethylisoxazol-4-ylmethyl)-2-oxopyr-
rolidin-3-yl-methyl]-N-hydroxyformamide; and
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(2-methylthiazol-4-ylmethyl)-2-oxopyrrolid-
in-3-yl-methyl]-N-hydroxyformamide; or pharmaceutically acceptable
salt thereof.
3. A method of treating a bacterial infection by administering to a
subject in need of treatment a compound according to claim 1.
4. A pharmaceutical composition comprising a compound according to
claim 1 and one or more pharmaceutically-acceptable excipients.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the use of novel
anti-bacterial compounds, and pharmaceutical compositions
containing these compounds as peptide deformylase inhibitors.
BACKGROUND OF THE INVENTION
[0002] Bacterial initiator methionyl tRNA is modified by methionyl
tRNA formyltransferase (FMT) to produce formyl-methionyl tRNA. The
formyl methionine (f-met) is then incorporated at the N-termini of
newly synthesized polypeptides. Polypeptide deformylase (PDF or
Def) then deformylates primary translation products to produce
N-methionyl polypeptides. Most intracellular proteins are further
processed by methionine amino peptidase (MAP) to yield the mature
peptide and free methionine, which is recycled. PDF and MAP are
both essential for bacterial growth, and PDF is required for MAP
activity. This series of reactions is referred to as the methionine
cycle (FIG. 1).
[0003] To date, polypeptide deformylase homologous genes have been
found in bacteria, in chloroplast-containing plants, in mice and in
humans. The plant proteins are nuclear encoded but appear to carry
a chloroplast localisation signal. This is consistent with the
observation that chloroplast RNA and protein synthesis processes
are highly similar to those of eubacteria. While there is limited
information on protein expression of mammalian PDF gene homologs
(Bayer Aktiengesellschaft, Pat. WO2001/42431), no functional role
for such proteins has been demonstrated to date (Meinnel, T.,
Parasitology Today 16(4), 165-168, 2000).
[0004] Polypeptide deformylase is found in all eubacteria for which
high coverage genomic sequence information is available. Sequence
diversity among PDF homologs is high, with as little as 20%
identity between distantly related sequences. However, conservation
around the active site is very high, with several completely
conserved residues, including one cysteine and two histidines which
are required to coordinate the active site metal (Meinnel, T. et
al, 1997, Journal of Molecular Biology, 267, 749-761).
[0005] PDF is recognized to be an attractive anti-bacterial target,
as this enzyme has been demonstrated to be essential for bacterial
growth in vitro (Mazel, D. et al, EMBO J. 13 (4), 914-923, 1994),
is not believed to be involved in eukaryotic protein synthesis
(Rajagopalan et al, J. Am. Chem. Soc. 119, 12418-12419, 1997), and
is universally conserved in prokaryotes (Kozak, M., Microbiol. Rev.
47, 1-45, 1983). Therefore PDF inhibitors can potentially serve as
broad spectrum anti-bacterial agents.
SUMMARY OF THE INVENTION
[0006] The present invention involves novel anti-bacterial
compounds represented by Formula (I) hereinbelow and their use as
PDF inhibitors.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1: Provides a graph of the methionine cycle.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The compounds useful in the present methods are selected
from Formula (I) hereinbelow: ##STR1## wherein: [0009] R1 is
selected from the group consisting of: C.sub.1-6alkyl,
--C.sub.1-2alkylAr, and Ar; [0010] R2 is selected from the group
consisting of hydrogen, C.sub.1-6alkyl, --(CH.sub.2).sub.mOH,
--(CH.sub.2).sub.nAr', --(CH.sub.2).sub.nHet, --Ar', --SO.sub.2R3,
--C(O)R3, --C(O)NHR3, --C(O)OR3, --CH(R4)CONR5R6, and
--CH(R4)CO.sub.2R7; [0011] R3 is selected from the group consisting
of: C.sub.1-6alkyl, --C.sub.1-2alkylAr', and Ar'; [0012] R4 is
hydrogen, or C.sub.1-6alkyl; [0013] R5 and R6 are independently
selected from the group consisting of hydrogen, C.sub.1-6alkyl,
--C.sub.1-2alkylAr', and Ar'; or R5, R6 together form a five or six
membered cycloalkyl ring which is optionally mono-substituted by
--CH.sub.2OR7; [0014] R7 is selected from the group consisting of
hydrogen, and C.sub.1-3alkyl; [0015] Ar is selected from the group
consisting of phenyl, furyl, and thienyl, all of which may be
optionally substituted by one or more Z.sub.1 groups; [0016] Ar' is
selected from the group consisting of: phenyl, naphthyl, furyl,
pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl,
tetrazolyl, imidazolyl, imidazolidinyl, benzofuranyl, indolyl,
thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl,
piperidinyl, piperazinyl, pyrrolyl, and pyrimidyl, all of which may
be optionally substituted by one or more Z.sub.2 groups; [0017] Het
is selected from the group consisting of tetrahydrofuranyl and
piperidinyl; [0018] Z.sub.1 is independently selected from the
group consisting of C.sub.1-3alkyl, --CN, F, Cl, Br, and I; [0019]
Z.sub.2 is independently selected from the group consisting of
C.sub.1-6alkyl, --OR2, --(CH.sub.2).sub.nCO.sub.2R4, --C(O)NR5R6,
--CN, --(CH.sub.2).sub.nOH, --NO.sub.2, F, Cl, Br, I, --NR5R6, and
--NHC(O)R 1; [0020] m is 2 to 5; and [0021] n is 0 to 5.
[0022] As used herein, "alkyl" refers to a hydrocarbon group joined
together by single carbon-carbon bonds. The alkyl hydrocarbon group
may be linear, branched or cyclic.
[0023] Preferred compounds useful in the present invention are
selected from the group consisting of: [0024]
(3S,4R)--N-[4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hy-
droxyformamide; [0025]
(3R,4S)--N-[4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hy-
droxyformamide; [0026]
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(t-butylcarboxy)pyrrolidin-3-yl-meth-
yl]-N-hydroxyformamide; [0027]
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformam-
ide; [0028]
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-pentanoylpyrrolidin-3-yl-methyl)-N-h-
ydroxyformamide; [0029]
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(2-phenylethanoyl)pyrrolidin-3-yl-me-
thyl]-N-hydroxyformamide; [0030]
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(1-phenylmethanoyl)pyrrolidin-3-yl-m-
ethyl]-N-hydroxyformamide; [0031]
(.+-.)-(3RS,4SR)--N-(1-Benzenesulfonyl-4-butyl-2-oxopyrrolidin-3-yl-methy-
l)-N-hydroxyformamide; [0032]
(.+-.)-(3RS,4SR)--N-[1-(Butane-1-sulfonyl)-4-butyl-2-oxopyrrolidin-3-yl-m-
ethyl]-N-hydroxyformamide; [0033]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(naphthalen-2-ylmethanoyl)-2-oxopyrrolidin-
-3-yl-methyl]-N-hydroxyformamide; [0034]
(.+-.)-(3RS,4SR)--N-(1-Benzyl-4-butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydr-
oxyformamide; [0035]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[1-(4-ethoxyphenyl)methanoyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide; [0036]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[1-(3-ethoxyphenyl)methanoyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide; [0037]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[1-(2-ethoxyphenyl)methanoyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide; [0038]
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-pyridin-3-ylmethylpyrrolidin-3-yl-me-
thyl)-N-hydroxyformamide; [0039]
N-((3S,4R)-4-Butyl-1-{(S)-1-[1-((S)-2-methoxymethylpyrrolidin-1-yl)methan-
oyl]-3-methylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;
[0040]
N-((3R,4S)-4-Butyl-1-{(S)-1-[1-((S)-2-methoxymethylpyrrolidin-1-y-
l)methanoyl]-3-methylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamid-
e; [0041]
N-((3S,4R)-4-Butyl-1-{(S)-1-[1-(dimethylamino)methanoyl]-3,3-dimethylbuty-
l}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide; [0042]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(4-ethoxybenzyl)-2-oxopyrrolidin-3-yl-meth-
yl]-N-hydroxyformamide; [0043]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-met-
hyl]-N-hydroxyformamide; [0044]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(2-morpholin-4-yl-2-oxoethoxy)benzyl]-2-
-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide; [0045]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(4-carboxy-1-butoxy)benzyl]-2-oxopyrrol-
idin-3-yl-methyl}-N-hydroxyformamide; [0046]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(3-hydroxybenzoxy)benzyl]-2-oxopyrrolid-
in-3-yl-methyl}-N-hydroxyformamide; [0047]
(.+-.)-(3RS,4SR)--N-{4-Butyl-2-oxo-1-[4-(tetrahydrofuran-2-ylmethoxy)benz-
yl]-pyrrolidin-3-yl-methyl}-N-hydroxyformamide; [0048]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(furan-2-ylmethoxy)benzyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide; [0049]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(3-hydroxypropoxy)benzyl]-2-oxopyrrolid-
in-3-yl-methyl}-N-hydroxyformamide; [0050]
(.+-.)-(3RS,4SR)--N-{4-Butyl-2-oxo-1-[4-(piperidin-3-ylmethoxy)benzyl]pyr-
rolidin-3-yl-methyl}-N-hydroxyformamide; [0051]
(.+-.)-(3RS,4SR)--N-{4-Butyl-2-oxo-1-[4-(pyridin-3-ylmethoxy)benzyl]pyrro-
lidin-3-yl-methyl}-N-hydroxyformamide; [0052]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(5-hydroxypentoxy)benzyl]-2-oxopyrrolid-
in-3-yl-methyl}-N-hydroxyformamide; and [0053]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(2,3-dichlorobenzyl)-2-oxopyrrolidin-3-yl--
methyl]-N-hydroxyformamide; [0054]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(3,4-dichlorobenzyl)-2-oxopyrrolidin-3-yl--
methyl]-N-hydroxyformamide; [0055]
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-phenylpyrrolidin-3-y-methyl]-N-hydro-
xyformamide; [0056]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[2-(2-hydroxyphenyl)-2-oxoethyl]-2-oxopyrr-
olidin-3-yl-methyl}-N-hydroxyformamide; [0057]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(3,5-dimethylisoxazol-4-ylmethyl)-2-oxopyr-
rolidin-3-yl-methyl]-N-hydroxyformamide; [0058]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(2-methylthiazol-4-ylmethyl)-2-oxopyrrolid-
in-3-yl-methyl]-N-hydroxyformamide.
[0059] Also included in the present invention are pharmaceutically
acceptable salts and complexes, such as the hydrochloride,
hydrobromide and trifluoroacetate salts, and the sodium, potassium,
and magnesium salts. The compounds of the present invention may
contain one or more asymmetric carbon atoms and may exist in
racemic and optically active forms. All of these compounds and
diastereomers are contemplated to be within the scope of the
present invention.
[0060] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes, which are merely illustrative of the methods by which the
compounds of the invention may be prepared and are not intended to
limit the scope of the invention as defined in the appended
claims.
[0061] The present invention provides compounds of formula (I):
##STR2## that can be prepared by a process consisting of: [0062]
treating an aldehyde of Formula (2) R1CHO (2) with
Ph.sub.3P.dbd.CHCO.sub.2Et in a solvent, such as tetrahydrofuran,
to give an .alpha.,.beta.-unsaturated ester of Formula (3).
##STR3##
[0063] Treatment of a compound of Formula (3) with nitromethane in
the presence of Triton B leads to a Michael addition product of
Formula (4). ##STR4##
[0064] Reduction of the nitro group in a compound of Formula (4)
under hydrogenolysis conditions followed by an intramolecular
cyclization, at appropriate temperature in an appropriate solvent,
such as toluene, affords a lactam of Formula (5). ##STR5##
[0065] A compound of Formula (5) can be converted to a compound of
Formula (6) wherein R2 is other than H through an alkylation
reaction. ##STR6##
[0066] Treatment of an enolate generated from a lactam of Formula
(6) with an appropriate formylating agent, such as isopropyl
formate, in an appropriate solvent, such as dry tetrahydrofuran,
affords an aldehyde of Formula (7). ##STR7##
[0067] Coupling of an aldehyde of Formula (7) with a suitable
reagent, such as benzyloxyamine hydrochloride, in a suitable
solvent, such as dry pyridine, affords a compound of Formula (8).
##STR8##
[0068] Reduction of a compound of Formula (8) with a suitable
reagent, such as sodium cyanoborohydride, in an appropriate
solvent, such as acetic acid, affords a compound of Formula (9).
##STR9##
[0069] Formylation of a compound of Formula (9) with a suitable
reagent, such as formyl acetyl anhydride, in a suitable solvent,
such as methylene chloride, affords a compound of Formula (10).
##STR10##
[0070] Removal of the protecting group(s) in a compound of Formula
(10) affords a compound of Formula (I).
[0071] Alternatively, the lactam nitrogen of a compound of Formula
(5) can be protected using an appropriate protecting group, such as
a Boc group, under standard conditions to give a versatile
intermediate of Formula (11). ##STR11##
[0072] Conversion of a lactam of Formula (11) to the .alpha.-formyl
lactam of Formula (12) can be achieved by treatment of an enolate
generated from a lactam of Formula (11) with an appropriate
formylating agent such as isopropyl formate, or alternatively, by
using Bredereck's reagent followed by acidic hydrolysis.
##STR12##
[0073] Alternatively, a compound of Formula (12) can be derived
from the Boc-protected .alpha.,.beta.-unsaturated pyrrolidinone
(13) through 1,4-addition with an organometallic reagent, such as
R1MgX, followed by quenching with an electrophile, such as
isopropyl formate or methyl bromoacetate. ##STR13##
[0074] Reductive amination of an aldehyde of Formula (12) with
sodium cyanoborohydride and an amine, such as benzyloxyamine, in a
suitable solvent provides an amine of Formula (14). ##STR14##
[0075] Treatment of a compound of Formula (14) with formic acid in
the presence of acetic anhydride and triethylamine provides a
compound of Formula (15). ##STR15##
[0076] Removal of the Boc group compounds of Formula (15) using an
appropriate acid, such as trifluoroacetic acid, gives a compound of
Formula (16). ##STR16##
[0077] A lactam of Formula (16) is then readily converted to the
target compound of Formula (I) by treatment with an alkyl halide, a
sulfonyl chloride, an acid chloride or an isocyanate followed by
deprotection of the benzyl group under hydrogenolysis
conditions.
[0078] Alternatively, treating an unsaturated lactone of Formula
(17) ##STR17## with, e.g., a Grignard reagent R1MgX in the presence
of catalytic ammount of a copper salt, such as copper (I) bromide,
HMPA and chlorotrimethylsilane at an appropriate temperature,
affords a lactone of Formula (18). ##STR18##
[0079] Treatment of a lactone of Formula (18) with an amine of
Formula (19) R2-NH.sub.2 (19) in a suitable solvent, such as
toluene in the presence of a Lewis acid, such as AlMe.sub.3,
followed by an intramolecular cyclization under Mitsunobu
conditions, affords a lactam of Formula (6).
[0080] Alternatively, the lactone ring in a compound of Formula
(18) can be hydrolyzed using appropriate base, such as sodium
hydroxide. The resulting carboxylate is then coupled with an amine
of Formula (19) followed an intramolecular cyclization to afford a
lactam of Formula (6).
[0081] Alternatively, a lactone of Formula (18) is treated with a
base, such as lithium diisopropylamine, and chloromethyl benzyl
ether to give a compound of Formula (20). ##STR19## A lactone of
Formula (20) is then converted to a lactam of Formula (21) under
similar conditions described above for conversion of a compound of
Formula (18) to a compound of Formula (6). ##STR20##
[0082] Removal of the benzyl group in a compound of Formula (21)
followed by oxidation of the alcohol using an appropriate oxidant,
such as Dess-Martin reagent, affords an aldehyde of Formula
(7).
[0083] An optically active compound of Formula (I) can be prepared
by treating a lactone of Formula (18) with a chiral amine, such as
(S)-methylphenyl amine, in the presence of a catalyst, such as
2-hydroxypyridine, in a suitable solvent, such as toluene, at
reflux to afford a mixture of two diastereomers of Formula (22) and
(23), which can be readily separated by silica gel flash column
chromatography. ##STR21##
[0084] Intramolecular Mitsunobu reaction of a compound of Formula
(22) or (23), followed by removal of the N-protecting group with
sodium in liquid ammonia affords an optically pure lactam of
formula (24) or (25), respectively. ##STR22## Conversion of a
chiral lactam of Formula (24) or (25) to the chiral target compound
of Formula (I) can then be achieved using reagents and conditions
described above for transformation of a compound of Formula (5) to
a compound of Formula (1).
[0085] Alternatively, treatment of a compound of Formula (22) or
(23) with an appropriate acid, e.g., 1 M H.sub.2SO.sub.4, in an
appropriate solvent, such as dioxane, affords a chiral lactone of
Formula (26) or (27), respectively. ##STR23##
[0086] Using reagents and conditions described above for
transformation of a compound of Formula (18) to a compound of
Formula (I), a chiral lactone of Formula (26) or (27) can then be
converted to the chiral target compound of Formula (I).
[0087] The present compounds are further exemplified by the
following Examples which are intended to be illustrative of the
present invention and not limiting in any way.
EXAMPLE 1
Preparation of
N-[(3S,4R)4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydr-
oxyformamide
1(a) (R)-3-Hydroxymethylheptanoic acid, (S)-1-phenylethylamide
[0088] A mixture of (.+-.)-4-butyldihydrofuran-2-one (3.9 g, 27.4
mmol), 2-hydroxypyridine (3.1 g, 32.9 mmol) and
(S)-1-phenylethylamine (7.8 mL, 60.3 mmol) in dry toluene (50 mL)
was heated to reflux overnight. The reaction mixture was cooled to
room temperature and diluted with ethyl acetate (100 mL), washed
with 1 N HCl (2.times.50 mL) and brine (50 mL), dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified by
flash column chromatography (silica gel, 4:1 EtOAc/hexanes) to
afford two compounds as white solids. The first eluted fraction was
(S)-3-hydroxymethylheptanoic acid, (S)-1-phenylethylamide (2.8 g,
39%) which is used in Example 2. .sup.1H NMR (CDCl.sub.3) .delta.
7.33 (m, 5 H), 6.07 (bs, 1 H), 5.11 (q, 1 H), 3.63 ,(m, 1 H), 3.48
(m, 1 H), 3.29 (bs, 1 H), 2.29 (m, 2 H), 1.95 (m, 1 H), 1.50 (d, 2
H), 1.28 (m, 6 H), 0.88 (t, 3 H). MS(ES) m/e 264 [M+H].sup.+. The
second eluted fraction (R)-3-hydroxymethylheptanoic acid,
(S)-1-phenylethylamide (2.6 g, 36%). .sup.1H NMR (CDCl.sub.3)
.delta. 7.29 (m, 5 H), 6.34 (bs, 1 H), 5.09 (q, 1 H), 3.64 (m, 1
H), 3.57 (bs, 1 H), 3.48 (m, 1 H), 2.28 (m, 2 H), 1.93 (m, 1 H),
1.48 (d, 2 H), 1.28 (m, 6 H), 0.88 (t, 3 H). MS(ES) m/e 264
[M+H].sup.+.
1(b) (R)-4-Butyl-1-[(S)-1-phenylethyl]pyrrolidin-2-one
[0089] To a solution of di-t-butyl azodicarboxylate (2.1 g, 9.1
mmol) in tetrahydrofuran (25 mL) under argon was added
tributylphosphine (2.27 mL, 9.1 mmol). The mixture was stirred for
5 minutes and was added slowly to a solution of
(R)-3-hydroxymethylheptanoic acid, (S)-1-phenylethylamide (1.84 g,
7.0 mmol) in dry THF (10 mL) at 0.degree. C. The reaction was
warmed up to rt and stirred overnight. Saturated NaHCO.sub.3 (100
mL) was added and the resulting mixture was extracted with
CH.sub.2Cl.sub.2 (2.times.100 mL). The combined organic extracts
were dried (Na.sub.2SO.sub.4), filtered and concentrated. The
residue was purified by flash column chromatography (silica gel,
1:4 EtOAc/hexanes) to afford 1.4 g (82%) of
(R)-4-butyl-1-[(S)-1-phenylethyl]pyrrolidin-2-one as a colorless
oil: .sup.1H NMR (CDCl.sub.3) .delta. 7.33 (m, 5 H), 5.48 (q, 1 H),
3.06 (t, 1 H), 2.92 (t, 1 H), 2.53 (q, 1 H), 2.06 (m, 2 H), 1.51
(d, 3 H), 1.20-1.46 (m, 6 H), 0.88 (t, 3 H). MS(ES) m/e 246
[M+H].sup.+.
1(c) (R)-4-Butylpyrrolidin-2-one
[0090] To a solution of
(R)-4-butyl-1-[(S)-1-phenylethyl]pyrrolidin-2-one (1.4 g, 5.7 mmol)
in dry tetrahydrofuran (10 mL) at -78.degree. C. was added
condensed liquid ammonia (100 mL). Freshly cut sodium (0.66 g, 28.5
mmol) was added and the resulting mixture was stirred at
-78.degree. C. for 2 h. The reaction was quenched with solid
ammonium chloride. Ammonia was evaporated by warming up the
reaction mixture slowly to room temperature. Water (50 mL) was
added and the mixture was extracted with ethyl acetate (3.times.50
mL). The combined organic extracts were dried (Na.sub.2SO.sub.4),
filtered and concentrated. The residue was purified by flash column
chromatography (silica gel, 4:1 EtOAc/acetone) to afford 0.7 g
(87%) of (R)-4-butylpyrrolidin-2-one as a colorless oil:
[.alpha.].sub.D=+0.95.sup.o (c=0.60, CH.sub.2Cl.sub.2) {lit.
[.alpha.].sub.D=-0.67.sup.o (c=0.60, CH.sub.2Cl.sub.2) for
(S)-enantiomer, Meyers, A. I. and Snyder, L. 1993, J. Org. Chem 58,
36-42}; .sup.1H NMR (CDCl.sub.3) .delta. 6.07 (bs, 1 H), 3.48 (t, 1
H), 3.02 (t, 1 H), 2.45 (m, 2 H), 1.99 (m, 1 H), 1.22-1.50 (m, 6
H), 0.90 (t, 3 H). MS(ES) m/e 142 [M+H].sup.+.
1(d) (R)-1-(5-Benzyloxypentyl)-4-butylpyrrolidin-2-one
[0091] To a solution of (R)-4-butylpyrrolidin-2-one (0.42 g, 2.9
mmol) in dry dimethylformamide (10 mL) under argon was slowly added
sodium hydride (60% in mineral oil, 0.14 g, 3.5 mmol) at 0.degree.
C. After stirring at 0.degree. C. for 30 minutes, 5-benzyloxypentyl
bromide (0.9 g, 3.5 mmol) was added dropwise. The resulting mixture
was stirred at room temperature overnight and then diluted with
ethyl acetate (50 mL). The organic solution was washed with water
(4.times.30 mL) and brine (30 mL), dried (Na.sub.2SO.sub.4) and
concentrated. The residue was purified by flash column
chromatography (silica gel, 1:1 EtOAc/hexanes) to afford 0.73 g
(95%) of (R)-1-(5-benzyloxypentyl)-4-butylpyrrolidin-2-one as a
colorless oil: .sup.1H NMR (CDCl.sub.3) .delta. 7.33 (m, 5 H), 4.51
(s, 2 H), 3.45 (m, 3 H), 3.27 (t, 2 H), 2.99 (dd, 1 H), 2.32 (m, 1
H), 2.06 (m, 1 H), 1.24-1.71 (m, 12 H), 0.93 (t, 3 H). MS(ES) m/e
318 [M+H].sup.+.
1(e)
[(3S,4R)-3-(Benzyloxyaminomethyl)-1-(5-benzyloxypentyl)-4-butyl-pyrro-
lidin-2-one
[0092] A solution of
(R)-1-(5-benzyloxypentyl)-4-butylpyrrolidin-2-one (0.25 g, 0.79
mmol) in dry THF (3 mL) was slowly added to a 2 M solution of
lithium diisopropylamide (0.47 mL, 0.94 mmol) in THF (2 mL) at
-78.degree. C. under argon. The reaction mixture was stirred at the
same temperature for 1 h. Isopropyl formate (0.047 mL, 0.94 mmol)
was then added dropwise. The resulting mixture was stirred for 3 h
and then quenched with saturated ammonium chloride (10 mL). The
mixture was extracted with ethyl acetate (3.times.10 mL) and the
combined organic extracts were dried (Na.sub.2SO.sub.4), filtered,
and concentrated. The residue was dissolved in dry pyridine (5 mL),
and treated with benzyloxyamine hydrochloride (0.13 g, 0.79 mmol)
at room temperature for 2 h. After removing the solvent under
reduced pressure, the residue was dissolved in acetic acid (5 mL)
and treated with NaCNBH.sub.3 (0.22 g, 1.03 mmol) at room
temperature for 2 h. The mixture was diluted with ethyl acetate (10
mL) and neutralized with 10% aqueous NaOH. The organic phase was
separated, washed with brine, dried (Na.sub.2SO.sub.4), and
concentrated. The residue was purified by HPLC to give 0.11 g (31%)
of
[(3S,4R)-3-benzyloxyaminomethyl)-1-(5-benzyloxypentyl)-4-butyl-pyrrolidin-
-2-one as a colorless oil: .sup.1H NMR (CDCl.sub.3) .delta. 7.32
(m, 10 H), 6.45 (bs, 1 H), 4.72 (s, 2 H), 4.51 (s, 2 H), 3.47 (t, 2
H), 3.39 (t, 1 H), 3.06-3.33 (m, 4 H), 2.93 (t, 1 H), 2.43 (m, 1H),
2.03 (m, 1 H), 1.23-1.73 (m, 12 H), 0.93 (t, 3 H). MS(ES) m/e 453
[M+H].sup.+.
1(f)
N-[(3S,4R)-4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-
-hydroxyformamide
[0093] A mixture of formic acid (0.011 mL, 0.29 mmol) and acetic
anhydride (0.026 mL, 0.28 mmol) was heated to 50.degree. C. for 1
h. To this mixture at room temperature was added a mixture of
[(3S,4R)-3-(benzyloxyaminomethyl)-1-(5-benzyloxypentyl)-4-butyl-pyrrolidi-
n-2-one (65 mg, 0.14 mmol) and triethylamine (0.02 mL, 0.18 mmol)
in methylene chloride (3 mL). The resulting mixture was stirred at
room temperature for 30 minutes. The reaction was diluted with
methylene chloride (5 mL) and quenched with water (5 mL). The
organic phase was washed with brine (5 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
dissolved in methanol (3 mL) and stirred under a hydrogen balloon
in the presence of palladium on activated carbon (40 mg) for 4 h.
The reaction mixture was filtered, concentrated, and the residue
was purified by HPLC to afford 25 mg (58%) of
N-[(3S,4R)-4-butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hyd-
roxyformamide as a colorless glass: .sup.1H NMR (CD.sub.3OD)
.delta. 8.33 (s, 0.5 H), 7.98 (s, 0.5 H), 3.80 (m, 1 H), 3.57 (m, 3
H), 3.3 (m, 3 H), 3.07 (t, 1H), 2.55 (m, 1 H), 2.12-2.26 (m, 1H),
1.33-1.71 (m, 12 H), 0.94 (t, 3 H). MS(ES) m/e 301 [M+H].sup.+.
EXAMPLE 2
Preparation of
N-[(3R,4S)-4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hyd-
roxyformamide
[0094] Following the procedure of Example 1(a)-1(f), except
substituting (R)-1-(5-benzyloxypentyl)4-butylpyrrolidin-2-one with
(S)-1-(5-benzyloxypentyl)-4-butylpyrrolidin-2-one, the title
compound was prepared. It has the identical .sup.1H NMR and MS as
the compound of Example 1(f).
EXAMPLE 3
Preparation of
(.+-.)-(3RS,4SR)--N-(1-Benzyl-4-butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydr-
oxyformamide
3(a) 4-Butylpyrrolidin-2-one
[0095] To a solution of 3-nitromethylheptanoic acid ethyl ester (10
g, 49.2 mmol) in methanol (100 mL) under argon was added Raney Ni
(5 g). The mixture was stirred under 50 psi of hydrogen for 48 h,
flushed with argon, filtered through a Celite pad, and concentrated
under vacuum to afford 4-butylpyrrolidin-2-one as a colorless oil
(6.3 g, 91%). MS(ES) m/e 142 [M+H].sup.+.
3(b)
(.+-.)-(3RS,4SR)--N-(1-Benzyl-4-butyl-2-oxopyrrolidin-3-yl-methyl)-N--
hydroxyformamide
[0096] Following the procedure of Example 1(d)-1(f), except
substituting compound (R)-4-butylpyrrolidin-2-one with
4-butylpyrrolidin-2-one, and substituting 5-benzyloxypentyl bromide
with benzyl bromide,
(.+-.)-(3RS,4SR)--N-(1-benzyl-4-butyl-2-oxopyrrolidin-3-ylmethyl)-N-hydro-
xyformamide was prepared as a colorless oil. MS(ES) m/e 305
[M+H].sup.+.
[0097] Proceeding in a similar manner, except substituting
appropriate intermediates for the benzyl bromide above, the
following compounds were synthesized: [0098]
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-pyridin-3-ylmethylpyrrolidin-3-yl-me-
thyl)-N-hydroxyformamide. MS(ES) m/e 306 [M+H].sup.+. [0099]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(4-ethoxybenzyl)-2-oxopyrrolidin-3-yl-meth-
yl]-N-hydroxyformamide. MS(ES) m/e 349 [M+H].sup.+. [0100]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(2,3-dichlorobenzyl)-2-oxopyrrolidin-3-yl--
methyl]-N-hydroxyformamide. MS(ES) m/e 373 [M+H].sup.+. [0101]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(3,4-dichlorobenzyl)-2-oxo-pyrrolidin-3-yl-
-methyl]-N-hydroxyformamide. MS(ES) m/e 373 [M+H].sup.+. [0102]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(3,5-dimethylisoxazol-4-yl-methyl)-2-oxopy-
rrolidin-3-yl-methyl]-N-hydroxyformamide. MS(ES) m/e 324
[M+H].sup.+. [0103]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(2-methylthiazol-4-yl-methyl)-2-ox-
opyrrolidin-3-yl-methyl]-N-hydroxyformamide. MS(ES) m/e 326
[M+H].sup.+.
EXAMPLE 4
Preparation of
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-met-
hyl]-N-hydroxyformamide
4(a)
(.+-.)-(3RS,4SR)--N-[1-(4-Allyloxybenzyl)-4-butyl-2-oxopyrrolidin-3-y-
l-methyl]-N-benzyloxyformamide
[0104] Following the procedure of Example 1(d)-1(f), except
substituting compound (R)-4-butylpyrrolidin-2-one with the compound
of Example of 3(a), and 5-benzyloxypentyl bromide with
4-allyloxybenzyl bromide,
(.+-.)-(3RS,4SR)--N-[1-(4-allyloxybenzyl)-4-butyl-2-oxopyrrolidin-3-yl-me-
thyl]-N-benzyloxyformamide was prepared as a colorless oil. MS(ES)
m/e 451 [M+H].sup.+.
4(b)
(.+-.)-(3RS,4SR)--N-Benzyloxy-N-[4-butyl-1-(4-hydroxybenzyl)-2-oxopyr-
rolidin-3-yl-methyl]formamide
[0105] To a solution of
(.+-.)-(3RS,4SR)--N-[1-(4-allyloxybenzyl)-4-butyl-2-oxopyrrolidin-3-yl-me-
thyl]-N-benzyloxyformamide (2.6 g, 5.77 mmol) in dichloromethane
(60 mL) under argon was added morpholine (6 mL), water (1.2 mL) and
then tetrakis(triphenylphosphine)palladium (0.33 g, 0.28 mmol). The
reaction mixture was stirred at rt for 1 h, filtered through a
Celite pad and concentrated. The residue was purified by flash
column chromatography (silica gel, ethyl acetate/hexanes 4:1) to
afford
(.+-.)-(3RS,4SR)--N-benzyloxy-N-[4-butyl-1-(4-hydroxybenzyl)-2-oxopyrroli-
din-3-yl-methyl]formamide as a white solid (2.1 g, 88%). MS(ES) m/e
411 [M+H].sup.+.
4(c)
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-
-methyl]-N-hydroxyformamide
[0106]
(.+-.)-(3RS,4SR)--N-Benzyloxy-N-[4-butyl-1-(4-hydroxybenzyl)-2-oxo-
pyrrolidin-3-ylmethyl]formamide (0.13 g, 0.32 mmol) was dissolved
in methanol (5 mL) and stirred under a hydrogen balloon in the
presence of palladium on activated carbon (30 mg) for 4 h. The
reaction mixture was filtered, concentrated and the residue was
purified by HPLC to afford the title compound as a white solid
(0.071 g, 70%). MS(ES) m/e 321 [M+H].sup.+.
EXAMPLE 5
Preparation of
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-[4-(furan-2-ylmethoxy)benzyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide
5(a) (.+-.)
-(3RS,4SR)--N-Benzyloxy-N-{4-butyl-1-[4-(furan-2-ylmethoxy)benzyl]-2-oxo--
pyrrolidin-3-yl-methyl}formamide
[0107] To a solution of
(.+-.)-(3RS,4SR)--N-benzyloxy-N-[4-butyl-1-(4-hydroxybenzyl)-2-oxopyrroli-
din-3-yl-methyl]formamide (0.1 g, 0.24 mmol) in tetrahydrofuran (3
mL) under argon was added furan-2-yl-methanol (0.041 mL, 0.048
mmol) and triphenylphosphine (0.07 g, 0.27 mmol). The solution was
cooled to 0.degree. C. and diethyl azodicarboxylate (0.042 mL, 0.27
mmol) was added dropwise. The reaction mixture was warmed up to rt
and stirred overnight. The reaction was quenched with saturated
aqueous NaHCO.sub.3 (10 mL) and extracted with dichloromethane
(3.times.10 mL). The combined extractions were dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by flash column chromatography (silica gel, ethyl
acetate/hexanes 1:1) to afford
(.+-.)-(3RS,4SR)--N-benzyloxy-N-{4-butyl-1-[4-(furan-2-yl-methoxy)benzyl]-
-2-oxopyrrolidin-3-yl-methyl}formamide as a colorless oil (0.075 g,
63%). MS(ES) m/e 491 [M+H].sup.+.
5(b)
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(furan-2-yl-methoxy)benzyl]-2oxopyr-
rolidin-3-yl-methyl}-N-hydroxyformamide
[0108] Following the procedure of Example 4(c),
(.+-.)-(3RS,4SR)--N-{4-butyl-1-[4-(furan-2-yl-methoxy)benzyl]-2-oxopyrrol-
idin-3-yl-methyl}-N-hydroxyformamide was prepared as a colorless
glass. MS(ES) m/e 401 [M+H].sup.+.
[0109] Proceeding in a similar manner, but substituting appropriate
intermediates for the furan-2-yl-methanol, the following compounds
were synthesized: [0110]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(2-morpholin-4-yl-2-oxoethoxy)benzyl]-2-
-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide. MS(ES) m/e 448
[M+H].sup.+. [0111]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(4-carboxy-1-butoxy)benzyl]-2-oxopyrrol-
idin-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 407 [M+H].sup.+.
[0112]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(3-hydroxybenzoxy)benzyl]-2-oxopyrrolid-
in-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 427 [M+H].sup.+.
[0113]
(.+-.)-(3RS,4SR)--N-{4-Butyl-2-oxo-1-[4-(tetrahydrofuran-2-ylmethoxy)benz-
yl]pyrrolidin-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 405
[M+H].sup.+. [0114]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(3-hydroxypropoxy)benzyl]-2-ox-
o-yrrolidin-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 379
[M+H].sup.+. [0115]
(.+-.)-(3RS,4SR)--N-{4-Butyl-2-oxo-1-[4-(piperidin-3-ylmethoxy)-b-
enzyl]pyrrolidin-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 418
[M+H].sup.+. [0116]
(.+-.)-(3RS,4SR)--N-{4-Butyl-2-oxo-1-[4-(pyridin-3-ylmethoxy)benzyl]pyrro-
lidin-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 412 [M+H].sup.+.
[0117]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[4-(5-hydroxypentoxy)benzyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 407
[M+H].sup.+.
EXAMPLE 6
Preparation of
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-phenylpyrrolidin-3-yl-methyl)-N-hydr-
oxyformamide
6(a) 3-Hydroxymethyl-heptanoic acid phenylamide
[0118] To a solution of aniline (0.36 mL, 4.0 mmol) in toluene (10
mL) was added trimethylaluminum in toluene (2M, 2.5 mL, 5 mmol).
After 20 min, a solution of (.+-.)4-butyldihydrofuran-2-one (0.4 g,
4 mmol) in toluene (1 mL) was added and the reaction mixture was
refluxed for 3 h. The reaction was cooled to 0.degree. C. and
carefully quenched with 1 M HCl (15 mL), and then extracted with
dichloromethane (3.times.15 mL). The combined extractions were
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by flash column chromatography (silica gel, ethyl
acetate/hexanes 3:2) to afford 3-hydroxymethylheptanoic acid
phenylamide as a white solid (0.66 g, 70%). MS(ES) m/e 236
[M+H].sup.+.
6(b) 4-Butyl-1-phenylpyrrolidin-2-one
[0119] To a solution of 3-hydroxymethylheptanoic acid phenylamide
(0.61 g, 2.6 mmol) in THF (30 mL) under argon was added
triphenylphosphine (1.36 g, 5.2 mmol). The solution was cooled to
0.degree. C. and diethyl azodicarboxylate (0.61 mL, 3.9 mmol) was
added dropwise. The reaction mixture was warmed up to rt and
stirred overnight. The reaction was quenched with saturated aqueous
NaHCO.sub.3 (50 mL) and extracted with dichloromethane (3.times.50
mL). The combined extractions were dried (Na.sub.2SO.sub.4),
filtered and concentrated. The residue was purified by flash column
chromatography (silica gel, ethyl acetate/hexanes 1:2) to afford
4-butyl-1-phenylpyrrolidin-2-one as a white solid (0.4 g, 72%).
MS(ES) m/e 218 [M+H].sup.+.
6(c)
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-phenylpyrrolidin-3-yl-methyl)-N--
hydroxyformamide
[0120] Following the procedure of Example 1(e)-1(f),
(.+-.)-(3RS,4SR)--N-(4-butyl-2-oxo-1-phenylpyrrolidin-3-yl-methyl)-N-hydr-
oxyformamide was prepared as a colorless glass. MS(ES) m/e 291
[M+H].sup.+.
EXAMPLE 7
Preparation of
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(t-butylcarboxy)pyrrolidin-3-yl-meth-
yl]-N-hydroxyformamide
7(a) 4-Butyl-2-oxopyrrolidine-1-carboxylic acid tert-butyl
ester
[0121] To a solution of 4-butylpyrrolidin-2-one (4.1 g, 29.0 mmol)
in dry acetonitrile (45 mL) was added triethylamine (6.1 mL, 43.6
mmol), di-tert-butyl dicarbonate (7.6 g, 34.8 mmol) and then
4-dimethylaminopyridine (0.3 g, 2.5 mmol). The reaction was stirred
at rt for 4 h. The solvent was removed under vacuum, and the
residue was dissolved in ethyl acetate (50 mL) and washed with
water (30 mL) and brine (30 mL), dried (Na.sub.2SO.sub.4), filtered
and concentrated. The residue was purified by flash column
chromatography (silica gel, ethyl acetate/hexanes 1:9) to afford
4-butyl-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester as a
white solid (5.2 g, 75%). MS(ES) m/e 242 [M+H].sup.+.
7(b)
(.+-.)-(3RS,4SR)-3-[(Benzyloxyformylamino)methyl]-4-butyl-2-oxopyrrol-
idin-1-carboxylic acid tert-butyl ester
[0122] Following the procedures of Example 1(e)-1(f), except
omitting the final hydrogenation step,
(.+-.)-(3RS,4SR)-3-[(benzyloxyformylamino)methyl]-4-butyl-2-oxopyrrolidin-
-1-carboxylic acid tert-butyl ester was prepared as a colorless
oil. MS(ES) m/e 405 [M+H].sup.+.
7(c)
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(t-butylcarboxy)pyrrolidin-3-yl--
methyl]-N-hydroxyformamide;
[0123] Following the procedure of Example 4(c), the title compound
was prepared as a colorless glass. MS(ES) m/e 315 [M+H].sup.+.
EXAMPLE 8
Preparation of
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformam-
ide
8(a)
(.+-.)-(3RS,4SR)--N-Benzyloxy-N-(4-butyl-2-oxopyrrolidin-3-yl-methyl)-
formamide
[0124]
(.+-.)-(3RS,4SR)-3-[(Benzyloxyformylamino)methyl]-4-butyl-2-oxopyr-
rolidin 1 -carboxylic acid tert-butyl ester (1.7 g, 4.2 mmol) was
dissolved in 5% TFA/1,2-dichloroethane (100 mL) and the reaction
was stirred at rt for 3 h. The solvents were removed under vacuum,
the residue was dissolved in dichloromethane and washed with
saturated aq. NaHCO.sub.3. The organic solution was dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by flash column chromatography (silica gel, ethyl acetate)
to afford
(.+-.)-(3RS,4SR)--N-benzyloxy-N-(4-butyl-2-oxopyrrolidin-3-yl-methyl)form-
amide as a white solid (0.95 g, 74%). MS(ES) m/e 305
[M+H].sup.+.
8(b)
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyfo-
rmamide
[0125] Following the procedure of Example 4(c),
(.+-.)-(3RS,4SR)--N-(4-butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformam-
ide was prepared as a colorless glass. MS(ES) m/e 215
[M+H].sup.+.
EXAMPLE 9
Preparation of
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(1-phenylmethanoyl)pyrrolidin-3-yl-m-
ethyl]-N-hydroxyformamide
9(a)
(.+-.)-(3RS,4SR)--N-Benzyloxy-N-[4-butyl-2-oxo-1-(1-phenylmethanoyl)p-
yrrolidin-3-yl-methyl)formamide
[0126] To a solution of
(.+-.)-(3RS,4SR)--N-benzyloxy-N-(4-butyl-2-oxopyrrolidin-3-yl-methyl)form-
amide (0.18 g, 0.59 mmol) in dry THF (3 mL) at -78.degree. C. under
argon was added dropwise lithium bis(trimethylsilyl)amide in THF (1
M, 0.71 mL). After 20 min, benzoyl chloride (0.077 mL, 0.89 mmol)
was added dropwise and stirring continued for 2 h. The reaction was
warmed up to 0.degree. C., quenched with saturated aq. NH.sub.4Cl
(10 mL) and extracted with dichloromethane (3.times.10 mL). The
combined organic solution was dried (Na.sub.2SO.sub.4), filtered
and concentrated. The residue was purified by flash column
chromatography (silica gel, ethyl acetate/hexanes 1:1) to afford
(.+-.)-(3RS,4SR)--N-benzyloxy-N-[4-butyl-2-oxo-1-(1-phenylmethanoyl)pyrro-
lidin-3-yl-methyl)formamide as a white solid (0.12 g, 50%). MS(ES)
m/e 409 [M+H].sup.+.
9(b)
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(1-phenylmethanoyl)pyrrolidin-3--
yl-methyl]-N-hydroxyformamide
[0127] Following the procedure of Example 4(c),
(.+-.)-(3RS,4SR)--N-[4-butyl-2-oxo-1-(1-phenylmethanoyl)pyrrolidin-3-yl-m-
ethyl]-N-hydroxyformamide was prepared as a colorless glass. MS(ES)
m/e 319 [M+H].sup.+.
[0128] Proceeding in a similar manner, but substituting appropriate
intermediates for those listed above, the following compounds were
synthesized: [0129]
(.+-.)-(3RS,4SR)--N-(4-Butyl-2-oxo-1-pentanoylpyrrolidin-3-yl-methyl)-N-h-
ydroxyformamide. MS(ES) m/e 299 [M+H].sup.+. [0130]
(.+-.)-(3RS,4SR)--N-[4-Butyl-2-oxo-1-(2-phenylethanoyl)pyrrolidin-3-yl-me-
thyl]-N-hydroxyformamide. MS(ES) m/e 333 [M+H].sup.+. [0131]
(.+-.)-(3RS,4SR)--N-(1-Benzenesulfonyl-4-butyl-2-oxopyrrolidin-3-yl-methy-
l)-N-hydroxyformamide. MS(ES) m/e 355 [M+H].sup.+. [0132]
(.+-.)-(3RS,4SR)--N-[1-(Butane-1-sulfonyl)-4-butyl-2-oxopyrrolidin-3-yl-m-
ethyl]-N-hydroxyformamide. MS(ES) m/e 335 [M+H].sup.+. [0133]
(.+-.)-(3RS,4SR)--N-[4-Butyl-1-(naphthalen-2-yl-methanoyl)-2-oxopyrrolidi-
n-3-yl-methyl]-N-hydroxyformamide. MS(ES) m/e 369 [M+H].sup.+.
[0134]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[1-(4-ethoxyphenyl)methanoyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 363 [M+H].sup.+.
[0135]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[1-(3-ethoxyphenyl)methanoyl]-2-oxopyrroli-
din-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 363 [M+H].sup.+.
[0136]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[1-(2-ethoxyphenyl)-methanoyl]-2-oxopyrrol-
idin-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 363 [M+H].sup.+.
[0137]
(.+-.)-(3RS,4SR)--N-{4-Butyl-1-[2-(2-hydroxyphenyl)-2-oxoethyl]-2-oxopyrr-
olidin-3-yl-methyl}-N-hydroxyformamide. MS(ES) m/e 349
[M+H].sup.+.
EXAMPLE 10
Preparation of
N-((3S,4R)-4-Butyl-1-{(S)-1-[1-(dimethylamino)methanoyl]-3,3-dimethylbuty-
l}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide
10(a) (3S,4R)-3-Benzyloxymethyl-4-butyldihydrofuran-2-one
[0138] (R)-3-Hydroxymethylheptanoic acid, (S)-1-phenylethylamide
(8.4 g, 31.9 mmol) was dissolved in 1 M H.sub.2SO.sub.4/dioxane
(1:1, 110 mL) and the resulting solution was refluxed overnight
under argon. After cooling to rt, the reaction mixture was diluted
with ethyl acetate/hexanes (1:3, 200 mL) and washed with water
(2.times.100 mL), saturated aq. NaHCO.sub.3 (2 .times.100 mL), and
brine (100 mL). The solution was dried (Na.sub.2SO.sub.4),
filtered, and concentrated to afford pure
(R)-4-butyldihydrofuran-2-one as a colorless oil (3.5 g, 78%).
[0139] To a solution of diisopropylamine (1.28 mL, 9.1 mmol) in dry
THF (15 mL) at 0.degree. C. was dropwise added n-butyl lithium (1.6
M, 8.4 mmol). After 30 min, the solution was cooled to -78.degree.
C. and (R)-4-butyldihydrofuran-2-one (1.0 g, 7.0 mmol) was added
slowly. The mixture was stirred for an additional 30 min.
Trimethylsilyl chloride (1.78 mL, 14 mmol) was rapidly added and
the mixture was gradually warmed up to rt during a period of 3 h.
The reaction mixture was concentrated under vacuum, and hexanes (15
mL) was added to the residue. Rapid filtration and removal of the
solvent under vacuum yielded crude
t-butyl-[(R)-4-butyl-4,5-dihydrofuran-2-yloxy]silane as a colorless
oil (1.32 g, 88%). This crude intermediate was dissolved in dry
dichloromethane (20 mL) under argon. The solution was cooled to
0.degree. C. and treated with benzyloxymethyl chloride (1.5 mL, 10
mmol) followed by zinc bromide (20 mg). The reaction was warmed up
to rt and stirred overnight. Aqueous work-up and purification by
flash column chromatography (silica gel, ethyl acetate/hexanes 1:6)
afforded (3S,4R)-3-benzyloxymethyl-4-butyldihydrofuran-2-one as a
colorless oil (1.1 g, 66%). MS(ES) m/e 263 [M+H].sup.+.
10(b) (2S,3R)-2-Benzyloxymethyl-3-hydroxymethylheptanoic acid
[(S)-dimethylcarbamoyl-dimethylpropyl]amide
[0140] (3S,4R)-3-Benzyloxymethyl-4-butyldihydrofuran-2-one (0.2 g,
0.76 mmol), (S)-2-amino-3,3,N,N-tetramethylbutyramide (0.5 g, 3.16
mmol) and 2-hydroxypyridine (0.073 g, 0.76 mmol) were mixed in a
sealed tube under argon and heated to 80.degree. C. for 36 h. After
cooling to rt, the reaction mixture was treated with 1 M HCl (20
ml) and extracted with ethyl acetate (4.times.30 mL). Removal of
the solvent under vacuum and purification of the residue by HPLC
afforded (2S,3R)-2-benzyloxymethyl-3-hydroxymethylheptanoic acid
[(S)-dimethylcarbamoyl-dimethylpropyl]amide as a white solid (0.14
g, 44%). MS(ES) m/e 421 [M+H].sup.+.
10(c)
(S)-2-[(3S,4R)-3-Benzyloxymethyl-4-butyl-2-oxopyrrolidin-1-yl]-3,3,N-
,N-tetramethyl butyramide
[0141] To a solution of
(2S,3R)-2-benzyloxymethyl-3-hydroxymethylheptanoic acid
[(S)-dimethylcarbamoyl-dimethylpropyl]amide (0.14 g, 0.33 mmol) in
THF (2 mL) under argon was added a premixed solution of
tributylphosphine (0.12 mL, 0.48 mmol) and di-t-butyl
azodicarboxylate (0.11 g, 0.48 mmol) in THF (1 mL) at 0.degree. C.
The reaction was warmed up to rt and stirred overnight. Aqueous
work-up and purification of the residue by HPLC afforded
(S)-2-[(3S,4R)-3-benzyloxymethyl-4-butyl-2-oxopyrrolidin-1-yl]-3-
,3,N,N-tetramethyl butyramide as a white solid (0.08 g, 60%).
MS(ES) m/e 403 [M+H].sup.+.
10(d)
(S)-2-[(3S,4R)-3-Benzyloxyiminomethyl-4-butyl-2-oxopyrrolidin-1-yl]--
3,3,N,N-tetramethyl butyramide
[0142]
(S)-2-[(3S,4R)-3-Benzyloxymethyl-4-butyl-2-oxopyrrolidin-1-yl]-3,3-
,N,N-tetramethyl butyramide (0.08 g, 0.2 mmol) was dissolved in
methanol (2 mL) and stirred overnight under a hydrogen balloon in
the presense of palladium on activated carbon (15 mg). Filtration
followed by concentration provided a crude alcohol (58 mg) which
was dissolved in dichloromethane (5 mL) and treated with
Dess-Martin periodinane (0.13 g, 0.3 mmol) at 0.degree. C. After
warming up to rt, the reaction was stirred overnight and the
solvent was removed under vacuum. The residue was then dissolved in
pyridine (5 mL) and benzyloxyamine hydrochloride (0.064 g, 0.4
mmol) was added. After 1 h, the reaction mixture was condensed to
dryness, the residue was dissolved in 1 N aq. NaOH/dichloromethane
(2:3, 15 mL). The organic phase was separated, the aqueous phase
was extracted with dichloromethane (5 mL). The combined organic
extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated.
Purification of the residue by HPLC afforded
(S)-2-[(3S,4R)-3-benzyloxyiminomethyl-4-butyl-2-oxopyrrolidin-1-yl]-3,3,N-
,N-tetramethyl butyramide as a colorless oil (0.05 g, 61%). MS(ES)
m/e 416 [M+H].sup.+.
10(e)
N-((3S,4R)-4-Butyl-1-{(S)-1-[1-(dimethylamino)methanoyl]-3,3-dimethy-
lbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide
[0143] Following the procedures of 1(e)-1(f), beginning with the
sodium cyanoborohydride reduction,
N-((3S,4R)-4-Butyl-1-{(S)-1-[1-(dimethylamino)methanoyl]-3,3-dimethylbuty-
l}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide was prepared as
a colorless glass. MS(ES) m/e 356 [M+H].sup.+.
[0144] Proceeding in a similar manner, but substituting appropriate
intermediates for the ones listed above, the following compounds
were synthesized: [0145]
N-((3S,4R)-4-Butyl-1-{(S)-1-[1-((S)-2-methoxymethyl-pyrrolidin-1-yl)-meth-
anoyl]-3-methyl-butyl}-2-oxo-pyrrolidin-3-yl-methyl)-N-hydroxyformamide.
MS(ES) m/e 426 [M+H].sup.+. [0146]
N-((3R,4S)-4-Butyl-1-{(S)-1-[1-((S)-2-methoxymethyl-pyrrolidin-1-yl)-meth-
anoyl]-3-methyl-butyl}-2-oxo-pyrrolidin-3-yl-methyl)-N-hydroxyformamide.
MS(ES) m/e 426 [M+H].sup.+. [0147] With appropriate manipulation
and protection of any chemical functionality, synthesis of the
remaining compounds of Formula (1) is accomplished by methods
analogous to those above and to those described in the Experimental
section.
[0148] In order to use a compound of the Formula (1) or a
pharmaceutically acceptable salt thereof for the treatment of
humans and other mammals, it is normally formulated in accordance
with standard pharmaceutical practice as a pharmaceutical
composition.
[0149] The present compounds are useful for the treatment of
bacterial infections including, but not limited to, respiratory
tract infections and/or Gram positive infections.
[0150] Compounds of Formula (I) and their pharmaceutically
acceptable salts may be administered in a standard manner for
antibiotics, for example orally, parenterally, sub-lingually,
dermally, transdermally, rectally, via inhalation or via buccal
administration.
[0151] Compositions of Formula (I) and their pharmaceutically
acceptable salts which are active when given orally can be
formulated as syrups, tablets, capsules, creams and lozenges. A
syrup formulation will generally consist of a suspension or
solution of the compound or salt in a liquid carrier for example,
ethanol, peanut oil, olive oil, glycerine or water with a flavoring
or coloring agent. Where the composition is in the form of a
tablet, any pharmaceutical carrier routinely used for preparing
solid formulations may be used. Examples of such carriers include
magnesium stearate, terra alba, talc, gelatin, acacia, stearic
acid, starch, lactose and sucrose. Where the composition is in the
form of a capsule, any routine encapsulation is suitable, for
example using the aforementioned carriers in a hard gelatin capsule
shell. Where the composition is in the form of a soft gelatin shell
capsule any pharmaceutical carrier routinely used for preparing
dispersions or suspensions may be considered, for example aqueous
gums, celluloses, silicates or oils, and are incorporated in a soft
gelatin capsule shell.
[0152] Typical parenteral compositions consist of a solution or
suspension of a compound or salt in a sterile aqueous or
non-aqueous carrier optionally containing a parenterally acceptable
oil, for example polyethylene glycol, polyvinylpyrrolidone,
lecithin, arachis oil or sesame oil.
[0153] Typical compositions for inhalation are in the form of a
solution, suspension or emulsion that may be administered as a dry
powder or in the form of an aerosol using a conventional propellant
such as dichlorodifluoromethane or trichlorofluoromethane.
[0154] A typical suppository formulation comprises a compound of
Formula (I) or a pharmaceutically acceptable salt thereof which is
active when administered in this way, with a binding and/or
lubricating agent, for example polymeric glycols, gelatins,
cocoa-butter or other low melting vegetable waxes or fats or their
synthetic analogs.
[0155] Typical dermal and transdermal formulations comprise a
conventional aqueous or non-aqueous vehicle, for example a cream,
ointment, lotion or paste or are in the form of a medicated
plaster, patch or membrane.
[0156] Preferably the composition is in unit dosage form, for
example a tablet, capsule or metered aerosol dose, so that the
patient may administer a single dose.
[0157] Each dosage unit for oral administration contains suitably
from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg,
and each dosage unit for parenteral administration contains
suitably from 0.1 mg to 100 mg/Kg, of a compound of Formula(I) or a
pharmaceutically acceptable salt thereof calculated as the free
acid. Each dosage unit for intranasal administration contains
suitably 1-400 mg and preferably 10 to 200 mg per person. A topical
formulation contains suitably 0.01 to 5.0% of a compound of Formula
(1).
[0158] The daily dosage regimen for oral administration is suitably
about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula(I) or a
pharmaceutically acceptable salt thereof calculated as the free
acid. The daily dosage regimen for parenteral administration is
suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of Formula
(I) or a pharmaceutically acceptable salt thereof calculated as the
free acid. The daily dosage regimen for intranasal administration
and oral inhalation is suitably about 10 to about 500 mg/person.
The active ingredient may be administered from 1 to 6 times a day,
sufficient to exhibit the desired activity.
[0159] No unacceptable toxicological effects are expected when
compounds of the present invention are administered in accordance
with the present invention.
[0160] The biological activity of the compounds of Formula (I) are
demonstrated by the following test:
Biological Assay:
[0161] S. aureus or E. coli PDF activity is measured at 25.degree.
C., using a continuous enzyme-linked assay developed by Lazennec
& Meinnel, (1997) "Formate dehydrogenase-coupled
spectrophotometric assay of peptide deformylase" Anal. Biochem 244,
pp. 180-182, with minor modifications. The reaction mixture is
contained in 50 uL with 50 mM potassium phosphate buffer (pH7.6),
15 mM NAD, 0.25 U formate dehydrogenase. The substrate peptide,
f-Met-Ala-Ser, is included at the K.sub.M concentration. The
reaction is triggered with the addition of 10 nM Def1 enzyme, and
absorbance is monitored for 20 min at 340 nm.
Antimicrobial Activity Assay
[0162] Whole-cell antimicrobial activity was determined by broth
microdilution using the National Committee for Clinical Laboratory
Standards (NCCLS) recommended procedure, Document M7-A4, "Methods
for Dilution Susceptibility Tests for Bacteria that Grow
Aerobically" (incorporated by reference herein). The compound was
tested in serial two-fold dilutions ranging from 0.06 to 64 mcg/ml.
A panel of 12 strains were evaluated in the assay. This panel
consisted of the following laboratory strains: Staphylococcus
aureus Oxford, Staphylococcus aureus WCUH29, Enterococcus faecalis
I, Enterococcus faecalis 7, Haemophilus influenzae Q1, Haemophilus
influenzae NEMC1, Moraxella catarrhalis 1502, Streptococcus
pneumoniae 1629, Streptococcus pneumoniae N1387, Streptococcus
pneumoniae N1387, E. coli 7623 (AcrABEFD+) and E. coli 120
(AcrAB-). The minimum inhibitory concentration (MIC) was determined
as the lowest concentration of compound that inhibited visible
growth. A mirror reader was used to assist in determining the MIC
endpoint.
[0163] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0164] The above description fully discloses the invention
including preferred embodiments thereof. Modifications and
improvements of the embodiments specifically disclosed herein are
within the scope of the following claims. Without further
elaboration, it is believed that one skilled in the area can, using
the preceding description, utilize the present invention to its
fullest extent. Therefore the Examples herein are to be construed
as merely illustrative and not a limitation of the scope of the
present invention in any way. The embodiments of the invention in
which an exclusive property or privilege is claimed are defined as
follows.
* * * * *