Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-05
2003-12-16
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252100
Reexamination Certificate
active
06664257
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to anti-mycobacterial compounds, pharmaceutical compositions thereof, methods of synthesizing such compounds and methods for using such compounds to treat animals infected with a pathogenic microorganisms, specifically mycobacteria. The invention relates in particular to compositions of matter and pharmaceutical compositions thereof for the treatment of tuberculosis and other Mycobacterium-caused diseases.
2. Background of the Related Art
Tuberculosis is a human disease caused by infection with
Mycobacterium tuberculosis.
This disease typically arises in phagocytic macrophages in the lung after inhalation, where characteristic localized sites of infection (termed tubercules) are formed and comprise sites of further systemic infection. Although previously well-controlled by antibiotics such as pyrazinamide, the development of drug-resistance by the infectious agent, and the increased numbers of immune-compromised individuals being affected by the AIDS crisis has created a near epidemic of tuberculosis cases world-wide. In 1997, the World Health Organization reported tuberculosis to be the world's top infectious killer.
About one-third of new tuberculosis cases are resistant to the current drug-treatment regimens, and estimates are that drug-resistant tuberculosis accounts for between 2% and 14% of total tuberculosis cases worldwide. As tuberculosis is spread by air-borne droplets from coughing by infected individuals, and its spread being further facilitated in crowded environments such as cities, there is a great potential for a precipitous increase in tuberculosis infections, which will not be easily controlled by conventional medicinal intervention, such as pyrazinamide administration. Lethal strains of tuberculosis have the potential for rapid spread, since only about one in ten patients receives the medical treatment necessary to contain and successfully treat the disease. Thus, there exists in this art a need to develop new and better treatments for tuberculosis, particularly tuberculosis infections resistant to traditional antibiotic treatments.
There is also a need in the art for more effective anti-tuberculosis drugs to which
M. tuberculosis
is not resistant and, most advantageously, drugs having a low resistance development potential.
In addition, there are a number of other human and animal diseases caused by mycobacteria, including for example leprosy (Hansen's disease), lymphadenitis, a variety of pulmonary and skin diseases, and wound infection. Although less prevalent, each of these diseases is associated with morbidity, mortality and economic costs such as lost production time and the cost of medical treatment. Resistance to drugs used heretofore to control and treat such diseases is also a current problem, thus raising a further need in this art for more effective drugs against many different Mycobacterium species.
SUMMARY OF THE INVENTION
The present invention is directed to improved antibiotic compounds, specifically pharmaceutical compositions thereof, and methods for producing and administering such pharmaceutical compositions, for treatment of diseases having a Mycobacterium etiology. In particular, the invention is directed towards delivery of antimycobacterial compounds, drugs and agents specific for treatment of tuberculosis and other Mycobacterium-caused diseases in humans.
The invention provides improved antimycobacterial drugs that are derivatives of pyrazinamide. Pyrazinamide is a so-called “first-line” anti-tubercular drug that has been widely used in humans, and is the drug of choice in countries such as China and the republics of the former Soviet Union (Hou et al., 2000
, Epidemiol. Infect.
124: 227-232; Hoashi et al., 1999
, Kekkaku
74: 441-445; Martilla et al., 1999
, Antimicrob. Agents Chemother.
43: 1764-1766). Pyrazinamide is the prodrug form of the biologically active drug pyrazinoic acid, which has been shown to have specific antibiotic activity against
M. tuberculosis
(Heifets et al., 1989
, Antimicrob. Agents Chemother.
33: 1232-1234). However, pyrazinoic acid cannot be administered directly because it is a charged species at physiological pH and cannot cross the
M. tuberculosis
cell membrane (Raynaud et al., 1999
, Microbiol.
145: 1359-1367). Pyrazinamide is converted in the mycobacterium to the active form by an amidase, but the precise mechanism of antimycobacterial activity is unknown. Neither the prodrug nor active drug form is toxic to humans in therapeutically-effective dosages.
The effectiveness of pyrazinamide has been reduced by the development of resistant strains of
M. tuberculosis
(Raynaud et al., ibid.; Mestdagh et al., 1999
, Antimicrob. Agents Chemother.
43: 2317-2319). A significant source of pyrazinamide resistance is a mutation in a mycobacterial gene, pncA (Cheng & Thiebert, 2000
, Antimicrob. Agents Chemother.
43: 537-542), responsible for converting the drug from prodrug (pyrazinamide, Structure I below) to active drug (pyrazinoic acid, Structure II below) (Sun & Zhang, 1999; Cheng & Thiebert, 2000
, Antimicrob. Agents Chemother.
44: 528-532). The invention provides alternative embodiments of pyrazinamides that are secondary amides (generic Structure III below). These compounds provide alternative routes for pyrazinamide activation in
M. tuberculosis
that bypass the mutant pncA gene, by activation through mycobacterial aminohydrolases, most preferably one or a multiplicity of non-specific aminohydrolases.
The invention thus provides as a composition of matter pyrazinamide derivatives having generic structure III, wherein R
1
or R
2
can each independently be H, lower alkyl (C
1
to C
10
), alkoxy, lower cycloalkyl including bridgehead compounds and — and O— cyclized bridgehead compounds such as bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane, cycloalkoxy, lower alkyl carboxy including fatty acids, C
1
to C
10
alkenyl comprising 1 to 3 alkenyl (C═C) moieties, aryl or substituted aryl, benzyl or C
1
to C
10
arylalkyl or substituted arylalkyl, heterocyclic aryl or arylalkyl, naphthyl, alkylamino, halogenated derivatives thereof, or
D
- or
L
-amino acids or di- or tripeptides comprised of any mixture thereof, provided that at least one of R
1
or R
2
are not H. In preferred embodiments, R
1
or R
2
is methyl, ethyl, methoxy, ethoxy, carboxymethyl, &bgr;-lactam, or
D
- or
L
-amino acids, or di- or tripeptides. It is expected that resistance is less likely to be developed against these drugs.
Particularly preferred targets of the pharmaceutical compositions of the invention are phagocytic cells, preferably macrophages and phagocytic neutrophiles and most preferably macrophages, mononuclear cells and phagocytic neutrophiles from lung tissue that are infected with
M. tuberculosis, M. africanum, M. bovis
or any other microorganism that causes tuberculosis in an animal, most preferably a human. Also preferred targets are cells infected with
M. leprae, M. avium, M. intracellulare, M. scrofulaceum, M. kansasii, M. xenopi, M. marinum, M. ulcerans, M. fortuitum
and
M. chelonae.
The anti-mycobacterial compounds of the invention are advantageous because, inter alia, the compounds are inhibitors of a target enzyme specific for mycobacterial cells. Inhibition of this enzyme is unlikely to be disadvantageous to infected animals, since neither the prodrug (pyrazimamide) or the active drug (pyrazinoic acid) is toxic to human or animal cells at therapeutic dosages. In addition, the anti-mycobacterial compounds and pharmaceutical compositions thereof are provided in a form that is activated once the drug has passed into the mycobacterial cell in a human or animal cell, most preferably phagocytic cells, infected to Mycobacteria species and thus should not be generally available in mammalian cells in vivo.
The invention provides a method of killing a microorganism infecting a mammalian cell, preferably a phagocytic mammalian cell. This method comprises contacting an infected phagocytic mammal
Pederson Richard L.
Yatvin Milton B.
EnzRel Inc.
Weddington Kevin E.
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