Pyronin antibacterials, process and novel intermediates thereto

Details Pyronin antibacterials, process and novel intermediates thereto Pyronin antibacterials, process and novel intermediates thereto

2000-05-18

2001-05-29

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S292000, C549S294000

Reexamination Certificate

active

06239291

ABSTRACT:

FIELD OF THE INVENTION
The present invention is in the field of pyronin antibiotics. In particular, the present invention relates to processes for the preparation of myxopyronins and corallopyronins, compounds useful as antibacterial therapeutics. The present invention also provides novel compositions of matter which are useful as intermediates for preparing the pyronin antibiotics.
Throughout this application, various publications are referred to, each of which is hereby incorporated by reference in its entirety into this application to more fully describe the state of the art to which the invention pertains.
BACKGROUND OF THE INVENTION
Myxopyronins and corallopyronins are 2-pyrone-containing antibiotics which present a significant opportunity in antibacterial therapy. They constitute a synthetically accessible, unexploited series of low molecular weight bacterial RNA polymerase (RNAP) inhibitors with favorable properties: selectivity vs. human RNAP, cell penetration (minimal inhibitory concentrations (MICs) at concentrations comparable to in vitro bacterial RNAP IC
50
s), and potency against rifampicin-resistant
S. aureus
equal to that against a rifampicin-susceptible strain.
Corallopyronin A/B and myxopyronin A/B are natural products isolated from gliding bacteria (
Corallococcus coralloides; Myxococcus fulvus
) and discovered to be RNAP inhibitors. Reichenbach, H., Höfle, G., Irschik, H., Kohl, W., Liebigs Ann. Chem., 1983, 1656; Reichenbach, H., Höfle, G., Irschik, H., Kohl, W., Liebigs Ann. Chem., 1984, 1088;
Reichenbach, H., Höfle, G., Irschik, H., Jansen, R., Liebigs Ann. Chem., 1985, 822. The structures of these compounds are closely related having in common a 3-acyl-4-hydroxy-2-pyrone with an alkyl chain at the 6-position bearing a vinyl carbamate functionality, a feature atypical of natural products. They differ only in the substitution on the alkyl chain attached to the 3-position of the pyrone, the corallopyronins being more elaborate (FIG.
1
(
a
)). The pyronins have good intrinsic activity in antibacterial assays against both
E. coli
and
S. aureus
RNA polymerase. This activity is specific with respect to human or SP6 polymerases. MIC data (see Table I) show that these compounds, like rifampicin, are not absorbed well by
E. coli
but that they have intrinsic activity against both gram positive and gram negative bacteria.
TABLE I
In Vitro IC
50
(&mgr;M)
MIC (&mgr;m/ml)
E. coli
S. aureus
Human
SP6
E. coli
E. coli
Compound
RNAP
RNAP
RNAP
RNAP
Rev/RRE
S. aureus
MCR
BAS
Myxopyronin A/B
10
10
>200
>200
100
4
 180
1.6
Corallopyronin A/B
 6
10
>200
>200
100
4
>200
0.4
An attractive feature of this series of compounds is their activity against strains resistant to rifampicin. The MIC for rifampicin is ca. 10 nM against susceptible strains, but falls off against resistant strains (MIC>10 &mgr;M). The use of rifampicin is limited by the development of bacterial resistance. Both myxo- and corallopyronins are equiactive against Rif-susceptible and Rif-resistant
S. aureus.
Pyrones have been used in the prior art to elicit a biological effect in a few instances, but in none of these instances have they been used as an antibacterial agent. 2H-Pyran-2,6(3H)-dione derivatives are reported to be active at reasonable doses in a passive cutaneous anaphylaxis model in rats when administered by either the intravenous or oral route. Snader, K. M. et al.,
J. Med. Chem.,
1979, 22, 706; Chahrin, L. W., Snader, K. M., Williams, C. R., 2H-Pyran-2,6(3H)-dionederivate. German Patent 25 33 843. In a second case, simple 3-(1-oxoalkyl)-4-hydroxy-6-alkyl-2-pyrones were found to be effective in vitro in the inhibition of human sputum elastase. Cook, L., Ternai, B., Ghosh, P., J. Med. Chem., 1987, 30, 1017. Lastly, a series of pyrone derivatives were found to be effective inhibitors of HIV protease in both enzymatic assays and cell culture (FIG.
1
(
b
)). Skulnick, H. I., et al.,
J. Med. Chem.,
1995, 38, 4968. No synthetic investigations or medicinal uses of pyronin antibacterials have been reported in the literature.
The present invention provides novel intermediates useful in the synthesis of myxopyronin A and derivatives thereof. In addition, the present invention provides processes for synthesizing myxopyronin A and derivatives thereof as well as corallopyronins.
SUMMARY OF THE INVENTION
One object of the present invention is to provide processes for the preparation of myxopyronins and corallopyronins, compounds useful as antibacterial therapeutics.
Another object of the present invention is to provide various compositions of matter useful as intermediates in the preparation of the antibiotic myxopyronin.
A further object of the present invention is to provide methods of preparing such intermediates.


REFERENCES:
Hu, T. et al., J. Org. Chem. 63:7401-7406, 1998.
Jansen et al., Chemical Abstract, 103:3291, 1985.
Jarolim et al., Chemical Abstract, 85:123296, 1976.
Kohl et al., Chemical Abstract, 101:87146, 1984.
Kohl et al., Leibigs Ann Chem. 6:1088-93, 1984.
Sharma et al., Chemical Abstract, 99:38646, 1982.

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