Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-07
2002-04-16
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S249000, C514S256000, C544S331000, C544S333000, C544S353000
Reexamination Certificate
active
06372752
ABSTRACT:
BACKGROUND OF THE INVENTION
Tuberculosis is the leading cause of death from infectious disease in the world. Virtually all cases of this disease in humans are caused by the bacterium =Mycobacterium tuberculosis. The disease is often limited to the lungs but can involve extrapulmonary sites, such as the lymph nodes, pleura, genitourinary tract, bones and joints, peritoneum and the meninges. Pulmonary tuberculosis is characterized by a persistent cough, fever and weight loss.
Tuberculosis accounted for 20% to 30% of all deaths in urban, industrialized societies during the eighteenth and nineteenth centuries. In the past century, deaths attributable to tuberculosis in the United States and other industrialized countries have declined dramatically, due in part to public health measures, such as improved sanitation and early detection programs, and the use of antibiotics. However, tuberculosis remains a significant source of mortality in developing countries, and it is estimated that half of the world's population is infected with
M. tuberculosis
, while 30 million people have the active disease. In addition, the incidence of tuberculosis in the United States has increased since 1985. This increase has been attributed to several factors, including immigration, an increase in the number of people who are homeless or living in substandard housing, an increase in the number of immune-compromised people, such as AIDS patients, and the emergence of drug-resistant strains of
M.tuberculosis.
Although the mechanism by which
M. tuberculosis
causes disease is not established, the organism has proven susceptible to a variety of antimicrobial drugs. The primary drugs used to treat active tuberculosis include isoniazid, ethambutol, rifampin, pyrazinamide and streptomycin. Prophylactic therapy, generally involving administration of isoniazid alone, is also employed when
M. tuberculosis
infection is known or suspected but active disease is not yet present. Current treatment regimens for active tuberculosis generally involve continuous treatment with two or more antibiotics, in an effort to prevent the development of resistant strains. While such treatment usually renders the patient non-infectious within one or two weeks, it must be continued for several months to rid the patient of infection. The duration of the treatment period and the need for multiple daily dosings of two or more drugs lead to a lack of patient compliance, which in turn contributes to the development of drug resistant strains. The emergence of drug resistant strains is rendered still more problematic as, except for isoniazid, the molecular targets of the commonly used antibiotics are unknown.
The mortality and morbidity associated with tuberculosis worldwide, the increasing incidence of this disease in industrialized countries and the decreasing effectiveness of current therapies all point to the need for new approaches and chemotherapeutic agents for the treatment and prophylaxis of this disease.
SUMMARY OF THE INVENTION
The present invention provides compounds that are useful for the treatment of bacterial infections, pharmaceutical compositions comprising these compounds and methods of use of these compounds and/or pharmaceutical compositions for the treatment or prophylaxis of bacterial infection.
In one embodiment, the invention provides compounds of Formula I,
wherein R
a
is a substituted or unsubstituted heterocyclic group and R is hydrogen, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl.
In another embodiment, the invention provides compounds of Formula II,
where n is 1 or 2 and R
b
is hydroxy, cycloalkenyl, substituted or unsubstituted phenyl, indolyl or diphenylmethyl.
In a further embodiment, the invention relates to compounds of Formula III,
where R
c
is a substituted or unsubstituted aryl or heteroaryl group and R
1
represents one or more substituents independently selected from hydrogen, halogen, trifluoromethyl, alkyl, alkoxy, nitro and cyano.
The invention also relates to compounds of Formula IV,
where R
f
and R
g
are each, independently, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl.
In another aspect, the invention relates to compounds of Formula V,
where n is 1, 2 or 3 and R
h
is substituted or unsubstituted aryl, arylalkyl, alkenyl or cycloalkyl
In another embodiment, the invention provides pharmaceutical compositions comprising one or more compounds of Formulas I, II, III, IV or V. These compositions can, for example, comprise a therapeutically effective amount of a compound or compounds of Formulas I, II, III, IV or V and one or more pharmaceutically acceptable carriers, diluents or excipients, or a combination thereof.
In yet another embodiment, the invention relates to a method of treating a bacterial infection in a patient. The method comprises administering to the patient a therapeutically effective amount of one or more compounds of Formulas I, II, III, IV or V. The bacterial infection can be an infection by any bacterial species, such as a pathogenic bacterial species, and is preferably an infection by a pathogenic Mycobacterium species or a Gram-negative bacterial species.
DETAILED DESCRIPTION OF THE INVENTION
The enoyl-ACP reductase (referred to herein as “InhA”) encoded by the Mycobacterium gene inhA is an essential enzyme in the biosynthesis of mycolic acid, the single most abundant component of the
Mycobacterium tuberculosis
cell wall. Thus, this enzyme is required by this organism for cell wall synthesis, and inhibition of this enzyme results in death of the bacterial cell. At least one of the antibiotics commonly used for treatment or prophylaxis of tuberculosis, isoniazid, results in inhibition of InhA. Isoniazid, however, is not a direct inhibitor of InhA, and must be converted to an active metabolite by the catalase-peroxidase encoded by the bacterial gene katG. This requirement for initial metabolism of isoniazid has provided
M. tuberculosis
with a mechanism for developing drug resistance. For example, certain isoniazid-resistant strains of
M. tuberculosis
have a mutant katG gene and consequently do not produce the active catalase-peroxidase. Other bacteria, such as Gram negative bacteria, have been shown to have a gene which is believed to encode an enoyl-ACP reductase similar to that of the Mycobacteria, and this enzyme is an appropriate drug target in the treatment of infections by these organisms as well.
The present invention relates to the discovery of compounds which are direct inhibitors of InhA; that is, these compounds are capable of inhibiting InhA without first undergoing metabolic conversion. These compounds, therefore, offer a significant advantage in treating bacterial infections compared to drugs in current use, such as isoniazid, because they eliminate at least one possible pathway for the development of drug resistance.
For the purposes of the present invention, the term “alkyl” refers to a straight chain or branched saturated hydrocarbyl group. Preferred alkyl groups include C
1
-C
12
-alkyl groups, while more preferred alkyl groups include C
1
-C
6
-alkyl groups. The term “cycloalkyl” refers to a mono-, bi- or polycyclic alkyl group. Preferred cycloalkyl groups include C
3
-C
8
-cycloalkyl groups. The term “alkoxy” refers to an alkyl-O- group or a cycloalkyl-O- group, where the preferred alkyl and cycloalkyl groups are those given above. The term “alkenyl” refers to a straight chain or branched hydrocarbyl group which includes one or more double bonds. Preferred alkenyl groups include C
2
-C
12
-alkenyl groups. The term “cycloalkenyl” refers to a cyclic hydrocarbyl group which includes one or more double bonds but is not aromatic. Preferred cycloalkenyl groups include C
5
-C
8
-cycloalkenyl groups.
The term “aryl” refers to an aromatic carbocyclic group, such as a phenyl group, a naphthyl group or a phenyl or naphthyl group which is fused with a a five or six-membered carbocyclic or heterocyclic ring.
The terms “heterocycle” and “heterocyclic group” refer
Janjigian Andrew
Sneddon Scott F.
Staveski Mark M.
Yee Christopher
Chang Ceila
Genzyme Corporation
Hamilton Brook Smith & Reynolds P.C.
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