Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-12-30
2001-02-27
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S248000, C514S307000, C514S311000, C514S415000, C514S457000
Reexamination Certificate
active
06194421
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to compositions and methods useful in the treatment of certain infectious diseases. More specifically, the invention relates to compositions which inhibit proteases, such as malaria cysteine protease. Compounds that inhibit these proteases are useful in the prevention and treatment of malaria, schistosomiasis and other infectious diseases.
This invention was made with Government support Contract No. MDA 972-91-J-1013, awarded by DARPA (now called ARPA), a division of the Department of Defense; and Grant No. 890499 awarded by UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). The Government has certain rights in this invention.
Proteases are involved in many important biological processes including protein turnover, blood coagulation, complement activation, hormone processing, and cancer cell invasion. Thus, they are frequently chosen as targets for drug design and discovery. The critical role certain proteases play in the life cycle of parasitic organisms also makes them attractive drug design targets for certain infectious diseases.
Schistosomiasis (bilharziasis) is a parasitic disease caused by schistosomes (blood flukes) that generally live in the veins of the gut and liver of a human host. Adult women can survive up to 20 years. Female adult worms release thousands of eggs each day, which often find their way to tissues such as liver, brain, and lung, where they cause considerable damage by stimulating the body to form inflammation and scar tissue around them. Most eggs pass through the bladder or wall of the gut. Once outside, they hatch and infect water snails. The parasite multiplies inside the snail, giving rise to thousands of cercariae that exit the small and swim free in search of a host in which to complete their life cycle.
Malaria is another well known infectious disease caused by protozoa of the genus Plasmodium, which are transmitted by bites of infected mosquitoes. Infection with
Plasmodium falciparum,
the most virulent human malarial pathogen, is estimated to be responsible for over 1 million deaths each year. The most valuable of the heretofore developed classes of antimalarial drugs are the quinoline-containing compounds, such as chloroquine and mefloquine; chloroquine has been especially effective as both a preventative and a curative. A serious problem in the treatment and control of malaria has been the increasing resistance of populations of
P. falciparum
to these known antimalarial drugs. In addition, reports of multi-drug resistance makes the search for novel therapies especially urgent. Thus, there remains a great need to identify new compounds that have antimalarial capabilities.
During the trophozoite stage, the parasites infect red blood cells (erythrocytes) where they reproduce asexually. At the completion of each asexual cycle, the red blood cells lyse and merozoites are released which invade new red blood cells. This cycle of lysis and re-infection is responsible for the major clinical manifestations of malaria.
Most anti-malarials are blood schizontocides which are active against the parasites during the intra-erythrocytic stage of its life cycle. Sulphones and sulphonamides inhibit the synthesis of dihydrofolic acid, while biguanides and diaminopyrimidines inhibit the synthesis of tetrahydrofolic acid. Although the mechanism of these anti-malarials is known to involve interference with the parasites' ability to synthesize nucleic acids [Bruce-Chwatt, L. J.,
Essential Malariology
(Wiley, New York (1985)], the mechanism of action of the quinoline-containing compounds has until recently been surprisingly elusive. Recent work provides evidence that the quinoline derivatives work by interfering with the detoxification activity of a heme polymerase [Slater and Cerami,
Nature
355, 167 (1992)], although this has recently been called into question [Dorn et al.,
Nature
374, 269 (1995)].
During the erythrocytic phase, the parasites degrade hemoglobin as a primary source of amino acids. Rosenthal and co-workers have identified a critical cysteine protease involved in the degradation of hemoglobin, the parasites' primary source of amino acids [Rosenthal, P. J. et al.,
J. Clin. Invest.
82, 1560 (1988)]. Blocking this enzyme with cysteine protease inhibitors (such as E-64 and Z-Phe-Arg-FMK) in culture arrests further growth and development of the parasites [Rosenthal, P. J. et al.,
Mol. Biochem. Parasitol.
35, 177 (1989)]. Because humans (and, probably, most other mammals) do not have an analogous hemoglobinase, inhibition of this protease (either alone or in conjunction with established therapies) provides an attractive strategy for the treatment of malaria. Moreover, inhibition of analogous proteases present in other metazoan parasites would similarly provide potentially valuable techniques for treatment of human and animal patients infected with those parasites.
The aforementioned PCT published application WO 94/06280, the entire disclosure of which is hereby incorporated by reference, describes various classes of metazoan protease inhibitors containing specific structural elements which bind to the S
2
subsite and at least one of the S
1
and S
1
′ subsites of the metazoan parasite protease. The protease inhibitors described therein generally include at least two homoaromatic or heteroaromatic ring systems, each comprising one to three rings, joined together by suitable linkers. The linkers concretely exemplified therein in every instance comprise at least two nitrogen atoms as a part of the backbone thereof.
It is an object of the present invention to provide compositions and methods for treatment of malaria and other infectious diseases caused by metazoan parasites.
SUMMARY OF THE INVENTION
In accordance with the present invention, there are provided compositions and methods for treatment a patient infected with a metazoan parasite by inhibiting the enzymatic action of the metazoan parasite protease, wherein there is employed at least one compound of general formula I
A——B
wherein A is a substituted or unsubstituted homoaromatic or heteroaromatic ring system comprising one to three rings which binds to at least one of the S
2
, S
1
and S
1
′ subsites;
B is a substituted or unsubstituted homoaromatic or heteroaromatic ring system comprising one to three rings which binds to at least one of the S
1
′, S
1
and S
2
subsites; and
X is —C═C—C(═O)—.
These compositions and methods have particular utility in the treatment of schistosomiasis, malaria, and other infectious diseases. The compositions of the present invention are useful, for example, to inhibit the action of trophozoite cysteine protease, thereby preventing degradation of hemoglobin, the primary source of amino acids for the pathogen that causes human malaria. The methods of the present invention comprise administrative to a patient infected with a metazoan parasite of at least one metazoan protease inhibitor of general formula I in an amount effective to inhibit the protease of the metazoan parasite, thereby killing the parasite.
REFERENCES:
patent: 4273776 (1981-06-01), Hoehn
patent: 4317831 (1982-03-01), Hoehn
patent: WO 93/17671 (1993-09-01), None
patent: WO 94/06280 (1994-03-01), None
patent: WO 95/06628 (1995-03-01), None
Proceeding of the Nationa Academy of Sciences, vol. 90, Issued Apr. 1993, Ring et al., “Structural-Based Inhibitor Design by using Protein Models for the Development of Antiparasitic Agents”, pp. 3583-3587, see entire Document Especially p. 3584 Figures.
Chemical Abstracts, vol. 115, No. 4, Issued 1991, Rheinberger et al., “Incorporated of Flourescent Substances into Dental Materials for Differentiation from Surronding Tissue,” see abstract No. 142380, Ger. Offen, DE 3939998.
Chemical Abstracts, vol. 81 No. 12, Issued 1974, Mucke, H., “Possibilities of Coloring Peracetic Acid for Skin Disinfection” See Abstract No. 38513, Pharmazie 29(3), 206-7.
Chemical Abstracts,
Chen Xiaowu
Cohen Fred E.
Gong Baoqing
Kenyon George L.
Li Rongshi
Spivack Phyllis G.
The Regents of the University of California
Townsend and Townsend / and Crew LLP
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