Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-07-14
2002-10-08
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
Reexamination Certificate
active
06462182
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel analogs of fusidic acid. In particular, the present invention relates to novel glycosylated analogs of fusidic acid. The present invention also relates to novel glycosylated analogs of fusidic acid that have different solubility properties than unmodified fusidic acid and that act as chemotherapeutic agents.
BACKGROUND OF THE INVENTION
The discovery of antibiotics was possibly the most important medical breakthrough of the twentieth century, making many previously lethal microbial infections easily treatable. However, the benefits of antibiotic therapy have gradually given rise to a dangerous development, namely antibiotic-resistant microorganisms. Through the constant use, and often overuse, of antibiotics, mankind has begun the process of selecting strains of bacteria which are resistant to many types of antibiotics.
Physicians employ many strategies to deal with antibiotic resistance, including: aggressively searching for new antibiotics, prescribing existing antibiotics in a more prudent and less frequent manner, and using combinations of diverse antibiotics to treat infections. In order to successfully employ the latter strategy, it is necessary to utilize a combination of antibiotics that have very different biochemical modes of action.
Fusidic acid is just such an antibiotic. Having a mode of action different than most antibiotics, fusidic acid is unlikely to have cross-resistance with other antibiotics against microorganisms.
A relatively new antibiotic, fusidic acid was discovered in 1962 by Godtfresden and coworkers [See Godtfresden et al., Lancet 1:928 (1962); and, Verbist, J. Antimicrob. Chemotherapy 25: Supp. B:1 (1990)]. It was isolated from the fermentation broth of the fungus
Fusidium coccineum
. It is a steroid-like antibiotic belonging to the class of the fusidanes, chemically related to cephalosporin P
1
and to helvolic acid. Of these fusidanes, however, only fusidic acid has been used clinically with success.
Fusidic acid is most effective against Gram-positive bacteria. In particular,
Staphylococcus aureus, S. epidermidis
, Clostridium spp. and corynebacteria are highly susceptible [See Verbist supra]. In addition, a few Gram-negative bacteria are susceptible, including Neisseria and Bacteroides spp. However, most Gram negative organisms, including Gram-negative bacilli and fungi, all enterobacteria, Psuedomonas spp., and other non-fermenters are resistant to treatment with fusidic acid. Fusidic acid exhibits moderate efficacy against streptococci, mycobacteria, and Nocardia spp.
Unquestionably, what gives fusidic acid its inherent usefulness in the treatment of microorganisms resistant to other antibiotics is its unique mode of action. Fusidic acid inhibits bacterial protein synthesis by interference with the elongation factor G [See Tanaka et al., Biochem. & Biophys. Res. Commun. 30:278 (1968)]. Such a unique mode of action explains the absence of intrinsic cross-resistance between fusidic acid and any other antibiotics. For example, methicillin-resistant staphylococci are usually susceptible to fusidic acid.
In addition to its usefulness against Gram-positive organisms and bacterial resistance to other antibiotics, there have been recent discoveries related to the use of fusidic acid, which may provide even more clinical benefits.
The use of fusidic acid in treating staphylococcal bone and joint infections has been described [See Coombs, J. Antimicrob. Chemotherapy 25: Supp. B:53 (1990)]. The usefulness of fusidic acid in the treatment of acute osteomyelitis, septic arthritis, chronic osteomyelitis, and other infections encountered in orthopedic surgery merits continued research into the use of fusidic acid for other orthopedic maladies.
Fusidic acid has also recently been shown to be highly effective in treating recurrent bronchopulmonary infections with
Staphylococcus aureus
suffered by patients having cystic fibrosis [See Jensen et al, J. Antimicrob. Chemotherapy 25: Supp. B:45 (1990)].
Perhaps the most exciting recent discovery is the possible use of fusidic acid in the treatment of AIDS. As described by Barnes in a
Science review
[238:276 (1994)], fusidic acid was found by researchers in Denmark to have in vitro effectiveness against HIV as well as “striking clinical improvement” in a 58-year-old Danish man stricken with AIDS. These discoveries have led to immediate efforts to determine whether or not fusidic acid will be useful in the treatment of AIDS. So far, the clinical data have been mixed [See Youle et al, J. Acquired Immune Deficiency Syndromes 2:59 (1989); and, Hording et al, Scand. J. Infect. Disease 22:649 (1990)].
With numerous current uses as well as promising future applications, fusidic acid will remain an important pharmaceutical product for the foreseeable future. However, fusidic acid is practically insoluble in water, and the method of choice for oral delivery of the drug is a film coated formulation of sodium fusidate (the sodium salt) or diethanolamine fusidate (the diethanolamine salt). Both derivatives possess significant side-effects including rashes, gastro-intestinal upset, jaundice and other changes in liver function, venospasm, thrombophlebitis, and hemolysis. Clearly, there remains a need for different means of formulation which allows for administration of the agent without inducing serious side-effects.
SUMMARY OF THE INVENTION
The present invention relates to novel analogs of fusidic acid. In particular, the present invention relates to novel glycosylated analogs of fusidic acid. The present invention also relates to novel glycosylated analogs of fusidic acid that have different solubility properties than unmodified fusidic acid and that act as chemotherapeutic agents.
A fusidic acid “derivative” or “analog” of the present invention has the fundamental structure of fusidic acid (see FIG.
1
), namely a fused four-ring molecule possessing a steroid-like structure and an alkyl/alkenyl side chain, with either one or more carbohydrate groups attached. The analogs of the present invention have numerous uses. First, they may be successfully employed as standards for analytical techniques (e.g., HPLC) so that new derivatives can be easily identified. Second, the present invention contemplates in vivo use; in accordance with the present invention, a member from the class of novel fusidic acid derivatives is to be delivered as a chemotherapeutic agent, and, in one possible application, to fight anti-microbial infections in the body.
The present invention contemplates derivatives of fusidic acid that have different solubility properties than fusidic acid. These different solubility properties are important because the glycosylated analogs of fusidic acid can be delivered for in vivo use in an admixture with diluent or excipient. It is not intended that the present invention be limited by the nature of the mixture. In one embodiment, the diluent or excipient is propylene glycol. Propylene glycol is miscible in water and a number of organic solvents. Propylene glycol is often used as a substitute for ethylene glycol or glycerol. It can be used as a solvent for oral and injectable drugs and is employed in ointments. [See Goodman and Gilman, The Pharmacological Basis of Therapeutics 9477; and, U.S.P. N.F. 1247]. Dextrose dissolved in an aqueous solution is another diluent or excipient contemplated for this purpose. The aqueous solution used with dextrose can be a buffer or other aqueous solution. For the different diluents or excipient, water or aqueous solutions can be used to dilute the diluent or excipient.
In one embodiment, the present invention contemplates a fusidic acid derivative modified at the C-3 position by chemical, enzymatic, or biological means, such that it contains a carbohydrate unit (See, e.g.,
FIGS. 2
,
3
,
10
, and
11
). In another embodiment, the present invention contemplates a fusidic acid derivative modified at the C-24 and C-25 positions by chemical, enz
Koreeda Masato
Shull Brian Keith
Tuinman Roeland
Medlen & Carroll LLP
Peselev Elli
The University of Michigan
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