2-oxo-1, 4-benzoxazine compounds for treatment of tuberculosis

Details 2-oxo-1, 4-benzoxazine compounds for treatment of tuberculosis 2-oxo-1, 4-benzoxazine compounds for treatment of tuberculosis

2002-05-22

2003-11-18

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S105000

Reexamination Certificate

active

06649610

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel 2-oxo-1,4-benzoxazine heterocyclics and more particularly to certain novel compounds and their close derivatives and to the use of these compounds as a bacteriostatic agent (a chemical agent that stops or inhibits the multiplication of bacteria) for human and non-humans against
Mycobacterium tuberculosis.
BACKGROUND OF THE INVENTION
The infectious disease, tuberculosis (TB), is the leading cause of death worldwide from a single human pathogen, claiming more adult lives than diseases such as acquired immunodeficiency syndrome (AIDS), malaria, diarrhea, leprosy and all other tropical diseases combined (Zumla A, Grange J. B M J (1998) 316, 1962-1964). The organism usually responsible is the tubercle bacillus,
Mycobacterium tuberculosis
(MT), discovered by Robert Koch in 1882. However,
M. bovis
, which infects cattle may also infect man and
M. africanum
is a cause of TB in West Africa. Furthermore, a number of normally non-pathogenic mycobacteria, especially
M. avium, M. intracellulare
and
M. scrofulaceum
, cause opportunistic infectious disease in patients with AIDS (Horne N. 1996. Tuberculosis and other mycobacteria diseases. In Mansons Tropical Diseases, 20
th
edn, Cook FEG (ed). W B Saunders: London; 971-1015). Pulmonary TB, the most common type of the disease, is usually acquired by inhalation of the bacillus from an infectious patient and causes irreversible lung destruction.
About one third of the world's population is currently infected with
M. tuberculosis
; 10% of those infected will develop clinical diseases, particularly those who also have the human immunodeficiency virus (HIV) infection (Zumla A, Grange J. B M J (1998) 316, 1962-1964). With the discovery of effective anti-mycobacterial agents (including ethambutol, isoniazid, pyrazinamide, rifampicin and streptomycin) and a reduction in poverty, there was a drastic decline in the number of TB cases, especially in developed nations. However, since the late 1980s, the number of cases of TB throughout the world has been increasing rapidly partly due to the emergence of multi-drug resistant
M. tuberculosis
(C. E. Barry, III, Biochemical Pharmacology (1997) 54, 1165-1172). According to the World Health Organization (World Health Organization. 1993 92. per Besra G S, Brennan P J. 1997. J Pharm Pharmacol 49 (Suppl. 1):25-30.s), it is expected that the annual death rate caused by TB will reach an overwhelming 3.5 million by the year 2000.
Thus the TB problem requires urgent attention. Short course anti-TB regiments initially using at least three first-line drugs (including isoniazid, rifampicin and pyrazinamide) are often not effective due to an increase in the number of tuberculosis strains that have become resistant to current drugs. For example the World Health Organization (WHO) recently reported that the death rate of patients with multi-drug resistant (MDR) tuberculosis in the US was approximately 70%. Current treatment is also very expensive: a 3 drugs regimen is needed (more than $500/month cost per patient). Thus the major problems faced in tuberculosis control are poor infrastructures for diagnosis and drug supply. The failure of patients to complete therapy as well as inappropriate monotherapy has led to the emergence and distribution of strains of
Mycobacterium tuberculosis
resistant to every available chemotherapy (Bloom B R and Murray C J L, Science (1992) 257, 1055-1064). Such organisms will not remain confined to the Third World or to the poor and indigent of developed countries. The recent documentation of the spread of a single clone of multi-drug-resistant
Mycobacterium tuberculosis
(the “W” strain) throughout the continental United States and Europe highlights the danger of an airborne pathogen in our global society (Bifani P J, et al., JAMA (1996) 275, 452-457).
The patent literature has numerous accounts of benzoxazine heterocyclics including:
Frechette (U.S. Pat. No. 5,696,117), Frechette (U.S. Pat. No. 5,854,242) and Frechette (U.S. Pat. No. 5,707,990) describe 148 benzoxazine and pyrido-oxazine heterocyyclic as anti-bacterial compounds;
Omedi-Sale (U.S. Pat. No. 3,862,954) shows tri-azole compounds for CNS use;
Hawkins (U.S. Pat. No. 5,274,002) describes many analogs of phenyl ethers of a substituted phenyl of the formula structure at column 1, lines 49-60 with 37 examples of specific compounds which compounds may be useful for tumor inhibition (column 22, line 64); and,
Boyd, et al (U.S. Pat. No. 6,080,790) also describes many tri-substituted phenyl derivatives according to the formula of the Abstract with 15 examples of specific compounds which may be useful for malignant skin diseases (column 5, line 46).
For half a century, the most used antimicrobial agents referenced above for prophylaxis and treatment of tuberculosis since 1952 is isoniazid (isonicotinic acid hydrazide [INH]). One of the known complications of anti-tuberculosis chemotherapy caused by this drug is liver dysfunction plus a great number of other complications. The toxicity of INH is also a serious problem frequently resulting in poisoning. It is also known to be an acute/chronic hazards since INH is an irritant of the skin, eyes, mucous membranes and upper respiratory tract.
It appears from a review of the above that the benzoxazine heterocyclic compounds of interest are not disclosed nor is there any report of activity against
Mycobacterium tuberculosis
or related mycobacteria.
Consequently, there is a need for an anti-mycobacteria drug for humans and non-humans which mitigates the above mentioned disadvantages of current drug bacteriostatic agent effectiveness against human and non-human mycobacteria.
SUMMARY OF THE INVENTION
The first objective of the present invention is to provide a bacteriostatic agent this is effective against mycobacteria.
The second object of this invention is to provide a bacteriostatic agent that is effective in human and non-humans against mycobacteria.
A third object of this invention is to provide a bacteriostatic agent that is effective in human and non-humans against
Mycobacterium tuberculosis.
A further object of this invention is to provide novel 2-oxo-1,4-benzoxazine heterocyclics.
A preferred embodiment of the invention encompasses a class of heterocyclics having the property of bacteriostatic agent activity against
Mycobacterium tuberculosis
comprising 2-oxo-1,4-benzoxazine heterocyclics and more specifically those heterocyclics: 4-benzoyl-3-benzoyloxy-2-(2-oxo-2H-1,4-benzoxazin-3-yl)pyrido[2,1-c][1,4]benzoxazin-1,5-dione; and, 2,4,6-trimethylphenyl 2-(3,4-dihydro-2-oxo-2H-1,4-benzoxazin-3-ylidene)-3-p-methoxyphenyl-3-oxo-propanoate and the use of each in human and non-humans as therapeutic means for the eradication of
Mycobacterium tuberculosis.


REFERENCES:
patent: 5274002 (1993-12-01), Hawkins
patent: 5334612 (1994-08-01), Kalden et al.
patent: 5972363 (1999-10-01), Clikeman et al.
patent: 6066670 (2000-05-01), Brown
patent: 6080790 (2000-06-01), Boyd et al.

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