Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Reexamination Certificate
2002-03-19
2004-12-28
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
C514S924000
Reexamination Certificate
active
06835755
ABSTRACT:
BACKGROUND OF THE INVENTION
THIS invention relates to the treatment and control of
tuberculosis
caused by
Mycobacterium tuberculosis
and in particular to the use of naphthoquinone derivatives in such treatment and control.
Tuberculosis
(
TB
) remains a serious health problem in many regions of the world, especially in developing nations. It is a contagious disease and is becoming epidemic in some parts of the world. It is estimated that 30-60% of adults in developing countries are infected with
Mycobacterium tuberculosis
. Approximately 8-10 million individuals develop clinical
TB
and 3 million die of
TB
each year (WHO/IUATLD, 1989).
In South Africa, over 3 in every thousand people die of
TB
, the highest rate in the world, while one out of every 200 people suffers from active
tuberculosis. Tuberculosis
is the most commonly notified disease in South Africa and the fifth largest cause of death among the black population (South African
Tuberculosis
Association, 1998).
In the United States, the number of
TB
cases steadily decreased until 1986 when an increase was noted. Since then
TB
cases have continued to rise. Ten million individuals are infected in the U.S.A., with approximately 26000 new cases of active disease each year (National Jewish Medical and Research Center, 1994).
Individuals infected with Human Immunodeficiency Virus (HIV) are very susceptible to
tuberculosis
and often develop this disease before other manifestations of AIDS become apparent (Grange and Davey, 1990). Control of the
TB
epidemic linked with HIV infection will depend largely on the adequate treatment of
TB
, and possibly of effective chemoprophylaxis, not just for HIV-infected persons but for communities as well (WHO/IUATLD, 1989).
TB
therapy has been revolutionized and the present treatment regimes for
TB
are based on multidrug therapy with usually 3 or 4 antituberculosis drugs. However, the problem of multidrug resistant
tubercle bacilli
is emerging for various drugs such as isoniazid, ethambutol, rifampicin and streptomycin, for example (Girling, 1989; Grange and Davey, 1990). Drug-resistant
TB
is very difficult to treat requiring greater numbers and varieties of medications for a longer period of treatment. The need for new antituberculosis agents is urgent due to the increasing resistance of
mycobacteria
to these classic antituberculosis drugs. A recent WHO report states that, globally, 2% of all cases of
tuberculosis
are multidrug resistant—by definition, resistance to rifampicin plus isoniazid (plus/minus other resistances). Such cases can be treated in the USA and other high resource regions but at a great cost (>US$ 250,000 per case!) and using very long courses of rather toxic drugs, thereby raising serious problems of compliance (WHO, 1997). South Africa is witnessing an explosion in the number of cases of drug-resistant
tuberculosis
. In some parts of South Africa, 1 in 10 cases of
TB
is resistant to treatment (New Scientist, March 1997). It is essential to have new antituberculosis agents, preferably those that can readily and simply be produced from some local source.
SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided a naphthoquinone derivative of Formula 1:
wherein,
R represents an OH group, methyl ether, ethyl ether or a similar ether;
R1 represents a methyl, ethyl or similar aliphatic hydrocarbon derivative;
R2 and R3 each independently represent hydrogen or a group selected from:
wherein R5 represents an OH group, methyl ether, ethyl ether or a similar ether and R6 represents a methyl, ethyl or similar aliphatic hydrocarbon derivative;
R4 represents hydrogen or a group selected from:
wherein R7 represents an OH group, methyl ether, ethyl ether or a similar ether and R8 represents a methyl, ethyl or similar aliphatic hydrocarbon derivative:
or pharmaceutically acceptable salts thereof, for use in a method of treating and/or controlling
tuberculosis
in a patient caused by
Mycobacterium tuberculosis.
According to a second aspect of the invention there is provided the use of a naphthoquinone derivative having the Formula 1 as set out above in the manufacture of a medicament for use in a method of treating and/or controlling
tuberculosis
in a patient caused by
Mycobacterium tuberculosis.
According to a third aspect of the invention there is provided a method of treating and/or controlling
tuberculosis
caused by
Mycobacterium tuberculosis
comprising administering to a patient in need thereof an effective amount of a naphthoquinone derivative having the Formula 1 as set out above.
The naphthoquinone derivative of Formula 1 is typically a compound of Formula 1a or Formula 1b:
wherein R and R1 are as defined for Formula 1 above.
R in the compound of Formula 1a or 1b is preferably an OH group.
R1 in the compound of Formula 1a or 1b is preferably a CH
3
group.
In particular, the naphthoquinone derivative of Formula 1 is 5,5′ dihydroxy 7,7′ binaphthoquinone (diospyrin) or 5-hydroxy-7-methyl-1,4-naphtoquinone (methyljuglone).
REFERENCES:
patent: 4837399 (1989-06-01), Baker et al.
Vichkanova et al., “Search for antimicrobial drugs among quinones of plant orgin”, Restit. Resur. (1979), 15(2), pp. 167-177, abstract enclosed.*
Evans et al., Plumbagin from Diospyros olen, MDPI, Apr. 16, 2004, Molecules 1999, 4, M93.
Osman et al., “Synthesis of Sulfanilamido-Naphthoquinones as Potential Antituberculous Agents”, pp. 68-71, Jan. 1983, Journal of Pharmaceutical Sciences vol. 2, No. 1.
Adeniyi, B. A. et al: “Antibacterial activity of diospyrin, isodiospyrin and bisisodiospyrin from the root of Diospyros piscatoria (Gurke) (Ebenaceae)” Phytother. Res. (2000), 14 (2), 112-117, XP000978371—the whole document.
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Yardley, Vanessa et al: “In vitro activity of diospyrin and derivatives agianst Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei brucei” Phytother. Res. (1996), 10(7), 559-562, XP000978369—the whole document.
Hazra, Banasri et al: “Biological acitivity of diospyrin towards Ehrlich ascites carcinoma in Swiss A mice” Planta Med. (1984), 50(4), 295-7, XP000978377—the whole document.
Hazra, Banasri et al: “New diospyrin derivatives with improved tumor inhibitory activity towards Ehrlich ascites carcinoma” Med. Sci. Res. (1994), 22(5), 351-3, XP000978374—the whole document.
Oeriu I: “Relation between the chemical structure and the antitubercular effect of alpha-naphthoquinone derivatives substituted in 2 and 3 positions.” Pharmazi, (May 1961) 16 266-72., XP000971910 table 5.
Oeriu I: “Zusammenhange zwischen der chemischen Struktur und der antituberkulosen Wirkung der in Stellung 2 und 3 substituieren Derivate des alpha-Naphthochinons” Pharmazi, DD, Veb Verlag Volk Und Gesundheit, Barlin, No. 16, 1961, pp. 320-327, XP002078405 ISSN: 0031-7144, table 8.
Lall Namrita
Meyer Jacobus Johannes Marion
Nixon & Peabody LLP
Studebaker Donald R.
University of Pretoria
Weddington Kevin E.
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