Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-05-19
2002-12-24
Riley, Jezia (Department: 1637)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S001000, C514S008100, C514S023000
Reexamination Certificate
active
06498238
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel derivatives of natural products, methods for their preparation, and the determination of their activity. In particular, the present invention relates to novel derivatives of glycopeptide antibiotics, such as vancomycin, methods for their preparation and their uses for the treatment of bacterial infection.
In the preferred embodiment, the present invention relates to vancomycin-derived glycopeptide antibacterial agents, which are characterized by a heptapeptide structure that is covalently linked to at least one saccharide group. The saccharide group(s) can be substituted with various substituent groups as described herein.
BACKGROUND OF THE INVENTION
An example of a known glycopeptide antibiotic is vancomycin, which contains a disaccharide substituent linked to a heptapeptide structure. See Malabarba A., et al., Med. Res. Rev., 17(1):69-137 (1997a); Nagarajan R. et al., J. Chem. Soc. Chem. Comm. 1306-1307(1988); Nagaranjan R., Antimicr. Agents Chemother., 35:605-609 (1991); and Nagaranjan R., J. Antibiotics, 46:1181-1195 (1993). Vancomycin is effective against gram positive bacteria. However, vancomycin resistant strains have been recently observed, thus increasing the need for new and effective therapeutic agents.
The glycopeptides of the present invention are useful against many gram positive microorganisms, including vacomycin resistant enterococcus (VRE), methicillin resistant
Staphylococcus aureus
(MRSA), methicillin resistant
Staphylococcus epidermidis
(MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). The antibacterial compounds of the present invention thus comprise an important new contribution to the development of therapeutic regimens for treating infections caused by these difficult to control pathogens and resistant strains.
There is an increasing need for agents effective against such pathogens, which are at the same time relatively free from undesirable side effects. Moreover, the physicochemical and pharmacological characteristics of candidate drugs, including their solubility, charge, hygroscopic characteristics, lipophilicity, bioavailability, tissue distribution, serum half-life and the like can play important roles in determining the success or failure of a candidate drug in the clinic. For example, it has been reported that a vancomycin analog in the Phase III clinical studies, which bears a chlorophenylbenzyl (also referred elsewhere in this application as chlorobiphenyl; other substituents are described in, e.g., Rodriguez, M. J., J. Antibiotics, 51(6):560-569 (1998)) substituent on the amine nitrogen of vancosamine and a free hydroxyl group on the C-6 position of glucose, exhibits a serum half-life in excess of two weeks. It has also been reported that traces of this vancomycin analog can be detected in patients up to a year after drug administration. Clearly, should a patient experience any adverse reaction to any drug, it would be beneficial if the patient's body could metabolize and/or clear the drug relatively quickly, e.g., within about 24 or less, preferably within about 12 hours or less, most preferably within about 6-8 hours or less.
It should be noted that antibiotics of the type that include vancomycin are typically administered parenterally, that is intravenously. Hence, a relatively high clearance rate would not typically be a disadvantage, and as stated above, would be of potential great benefit to certain patients. Such intravenous formulations impose certain requirements on a drug, not the least of which is adequate solubility in the formulation medium. Thus, poorly soluble drugs may be unsuitable as a practical matter because the clinician is unable to dissolve the drug in a formulation, much less deliver adequate amounts of the drug via intravenous drip. Generally, the pH of the formulation is buffered to correspond to physiological pH, which is about 7.4. While some leeway is possible in the pH of an intravenous formulation, pain at the site of injection typically limits the useful range of pH to no less than about 5 to no greater than about 8. Preferably, the pH of an intravenous formulation ranges from about 6-8, more preferably from about 7-8 and most preferably at or about physiological pH (e.g., about 7.2-7.6).
Hence, there has been an on-going search for compounds that exhibit not only increased potency against resistant strains but also the physicochemical and pharmacological characteristics that enhance the effectiveness of a candidate compound and which may determine ultimately its acceptance in the clinic and resulting commercial success.
SUMMARY OF THE INVENTION
The present invention provides new analogs of vancomycin, which exhibit enhanced biological activity and improved physicochemical and pharmacological characteristics. The overall properties of these analogs exhibit substantial potential as drug candidates for treating infections caused by certain pathogens, including various strains of drug resistant bacteria. Accordingly, a general method is provided for the preparation of such compounds, along with methods of using them for the treatment of vertebrate conditions, including those afflicting mammals and especially those suffered by humans. Such conditions typically, although not exclusively, involve infections and other pathological conditions caused by bacteria and other microorganisms.
In particular, it has been observed that certain substituents positioned at the amine nitrogen of vancosamine and at the C-6 position of the glucose of vancomycin provide enhanced biological activity according to in vitro and in vivo assays and give rise to desirable physicochemical and pharmacological characteristics, all of which improve a candidate drug's chances of success beyond the lab bench and in the clinic. More particularly, the present invention provides for lipid-like substituents on the amine nitrogen of vancosamine, which include at least two aryl moieties that are joined (i.e., covalently bound) together with a flexible linker moiety. By “lipid-like” substituent is meant a “lipophilic” substituent which refers to the tendency of the compound or substituent thereon to lack an affinity for, to repel or to fail to absorb water, or to be immiscible in water. The term “lipophilic” is not meant to exclude compounds or substituents thereon that are not completely immiscible in water. By “flexible linker” is meant that the linker or linking groups provides at least some degree of flexible movement in the substituent containing the lipid-like substituent. The flexible linker moiety joining the two aryl moieties of the lipid-like substituent on the vancosamine nitrogen is not a single bond directly joining the two aryl moieties. The flexible linker moiety appears to increase the lipophilicity of the molecule, as a whole, while potentially providing a site of attack for the metabolic and/or clearance processes of the body.
While a wide range of flexible linker moieties are potentially useful in the present invention, such as alkylene groups, alkylene ethers, alkylene thioethers, ethers, thioethers, acyls, sulfonyls, sulfoxides, alkylene amines, unsaturated aliphatic groups and the like, the preferred embodiments are those that (together with at least the first or second aryl moiety and possibly other functional groups present in the substituent) give rise to benzyl, benzylamino, benzyloxy, benzylthioether groups, phenyl ketones, or combinations thereof. Doubtless, one of ordinary skill in the art could contemplate other flexible linker moieties, which could give rise to increased lipophilicity and increased likelihood of breakdown/clearance by the body. The same or a different flexible linker moiety is also present to join the amine nitrogen of vancosamine to the first aryl moiety part of the lipid-like substituent. In a preferred embodiment of the invention, the lipid-like substituent comprises the formula K—Ar
1
—Z—Ar
2
, as defined further below but which generally includes first and second aryl moieties, Ar
1
and Ar2, and fl
Chapman Kevin T.
Kahne Daniel E.
Kim Ronald M.
Princeton University
Riley Jezia
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