Furopyridine antibacterials

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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Details

C514S302000, C546S090000, C546S092000, C546S116000

Reexamination Certificate

active

06277860

ABSTRACT:

TECHNICAL FIELD
This invention relates to furopyridine antibacterials, and particularly to furopyridine antibacterials produced by fermentation of a fungus
Cladobotryum varium
(FERM BP-5732) and to their biotransformation products by the microorganisms
Calonectria decora
(FERM BP-6124),
Cunninghamella echinulata
var.
elegans
(FERM BP-6126), or an unidentified bacterium (FERM BP-6125). This invention also relates to pharmaceutical compositions comprising the same, which are useful in the treatment of diseases, disorders and adverse conditions caused by infection by various bacteria, including multidrug resistant strains of Staphylococcus sp., Streptococcus sp. and Enterococcus sp.
BACKGROUND ART
People have received great health care benefit from many kinds of anti-infectives since penicillin was found (A. Fleming, 1929) and developed (H. W. Florey et. al., 1941). However, there has been an alarming increase, recently, in the incidence of multidrug resistant infections that is limiting the utility of many standard agents, such as &bgr;-lactams, macrolides and quinolones. For an example, methicillin-resistant
Staphylococcus aureus
(MRSA) and vancomycin-resistant Enterococcus species are now co-resistant to essentially all other antibiotic classes. Multidrug resistant
Streptococcus pneumoniae
is also one of the most important bacterial pathogens due to its frequency in upper and lower respiratory tract infections in both children and adults.
S. pneumoniae
is rapidly becoming resistant to all presently available therapies. Commonly prescribed anti-infectives such as &bgr;-lactams and the current macrolides are no longer reliably effective.
These multidrug resistant bacteria are not limited to hospitals but also occur in a variety of human communities world-wide. In many cases, multidrug resistant infections can lead to potentially fatal conditions and require hospitalization. The emergence of such multidrug resistant bacteria prompted drug discovery programs. For example, dipeptides are described as new antibiotics with potent antibacterial activity against MRSA (R. M. Williams et al., J. Antibiotics, 51(2), 189-201, 1998). To provide a compound having good activity against various bacteria, including multidrug resistant bacteria such as Staphylococcus sp., Streptococcus sp. and Enterococcus sp., is not only required by serious medical need, but by the overall health care cost savings achieved by minimizing treatment failures, laboratory testing, and hospitalization.
The object of the present invention is to provide furopyridine compounds which have good antibacterial activity against various bacteria, including multidrug resistant bacteria, and to provide a pharmaceutical composition comprising the same. A variety of furopyridine compounds are known. For example, in German patent publication DE 4218978 A1, furopyridine compounds are disclosed as liquid crystal materials. Also, International Publication Number WO 97/11076 discloses furopyridine compounds as fungicides.
Another object of the present invention is to provide processes for producing the furopyridine compounds.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a furopyridine compound of formula (I):
or pharmaceutically acceptable salts thereof, wherein
X
1
and X
2
are C or N;
R
1
and R
2
are independently phenyl optionally substituted with a hydroxy group with proviso that X
1
and X
2
are not simultaneously C or N; when X
1
is N, R
1
is absent; and when X
2
is N, R
2
is absent;
R
3
is methyl or hydroxymethyl;
R
4
is formyl, hydroxymethyl or hydroxy C
3-6
alkenyl; and
R
5
is hydroxy, C
3-6
alkenyl or hydroxy C
3-6
alkenyl; or
R
4
and R
5
, together with the carbon atoms in the furopyridine ring to which they are attached, may form the following ring (to be fused with the furopyridine ring):
with the proviso that when R
3
is methyl and R
5
is 2-buten-2-yl, X
2
is not N.
This invention also provides a compound having the following characteristics:
1) a molecular formula C
19
H
19
NO
2
;
2) absorption maxima in methanol in the ultraviolet light region of the spectrum at 206.0 and 247.0 nm;
3) an optical rotation of [&agr;]
D
24
=+13.3° at a concentration of 6% in methanol;
4) characteristic absorption in the infrared region, when pelleted in KBr, at the following wavelengths (cm
−1
): 3378, 2963, 1647, 1614, 1450, 1427, 1228, 1042, 823, 774 and 694;
5)
1
H NMR spectrum (270 MHz) having major peaks at &dgr; 7.52 (m, 2H), 7.47 (s, 1H), 7.31 (m, 2H), 7.24 (m, I H), 5.36 (brs, 1H), 3.13 (brs, 1H), 2.78 (q, J=7.3 Hz, 1H), 1.67 (s, 3H), 1.58 (s, 3H), 1.18 (d, J=7.3 Hz, 3H); and
6)
13
C NMR spectrum (67.5 MHz) having major peaks at &dgr; 165.03 (s), 162.55 (s), 151.38 (s), 135.38 (d), 130.23 (s), 129.71 (d×2), 128.79 (d×2), 128.15 (d), 127.81 (d), 114.34 (s), 111.06 (s), 104.28 (s), 58.32 (d), 50.30 (d), 26.97 (q), 20.93 (q), 15.28 (q);
or pharmaceutically acceptable salts thereof.
The furopyridine compounds of the present invention exhibit antibiotic activities against bacteria including multidrug resistant strains of Staphylococcus sp., Streptococcus sp. and Enterococcus sp. Therefore, the present invention also provides a pharmaceutical composition for use in the treatment of infectious diseases caused by bacteria, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount effective in such treatments; and a pharmaceutically acceptable carrier.
Also, the present invention is directed to a method of treating infectious diseases caused by bacteria, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
DETAILED DISCLOSURE OF THE INVENTION
As used herein, the term “multidrug resistant” means a microorganism that is resistant to such antibiotics as macrolides and &bgr;-lactams. The antibiotics include penicillin, erythromycin, methicillin and vancomycin.
This invention includes any possible stereoisomers and tautomers of compounds of the formula (I).
More specific compounds of this invention are those of formula (I), wherein
X
1
is C, X
2
is N, R
1
is phenyl, R
2
is absent, R
3
is methyl, R
4
and R
5
together form the following ring to be fused with furopyridine ring:
X
1
is C, X
2
is N, R
1
is phenyl, R
2
is absent, R
3
and R
4
are hydroxymethyl, and R
5
is 2-buten-2-yl;
X
1
is C, X
2
is N, R
1
is phenyl, R
2
is absent, R
3
is methyl, R
4
is formyl, and R
5
is 4-hydroxy-2-buten-2-yl;
X
1
is C, X
2
is N, R
1
is phenyl, R
2
is absent, R
3
is methyl, R
4
is hydroxymethyl, and R
5
is 4-hydroxy-2-buten-2-yl;
X
1
is N; X
2
is C; R
1
is absent; R
2
is phenyl; R
3
is methyl; R
4
is hydroxymethyl; and R
5
is 2-buten-2-yl;
X
1
is N; X
2
is C; R
1
is absent; R
2
is phenyl; R
3
is methyl; R
4
and R
5
, together with the carbon atoms to which they are attached, form the following ring to be fused with furopyridine ring:
X
1
is N; X
2
is C; R
1
is absent; R
2
is phenyl; R
3
is methyl; R
4
is 3-hydroxy-2-methyl-1-buten-1-yl; and R
5
is OH.
Specific individual compounds of this invention are selected from
2R*,3R*-2,3-dihydro-2-[(E)-2-buten-2-yl]-4-hydroxy-3-hydroxymethyl-3-methyl-7-phenylfuro[3,2-c]pyridine or its salts;
2R*,4aR*,9aS*-4a,9a-dihydro-5-hydroxy-8-phenyl-2,3,4a-trimethyl-2H-pyrano[2,3-b]furo[3,2-c]pyridine or its salts;
1R*,4bS*-1,3,4a,4b-tetrahydro-9-hydroxy-4b-methyl-8-phenyl-4-(E)-ethylidenepyrano[4,3-b]furo[2,3-b]pyridine or its salts;
2,3-dihydro-2-[(E)-2-buten-2-yl]-3,3-di-(hydroxymethyl)-4-hydroxy-5-phenylfuro[2,3-b]pyridine or its salts;
2R*,3S*-2,3-dihydro-2,4-dihydroxy-3-[(E)-3-hydroxy-2-methyl-1-butenyl]-7-phenylfuro[3,2-c]pyridine or its salts;
2R*,3R*-2,3-dihydro-4-hydroxy-2-[(E)-4-hydroxy-2-buten-2-yl]-3-methyl-5-phenylfuro[2,3-b]pyridine-3-carbaldehyde or its salts;
2R*,3S*-2,3-dihydro-4-hydroxy-2-[(E)-4-hydroxy-2-buten-

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