Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-23
2004-02-10
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S366000, C544S133000, C544S368000, C548S150000
Reexamination Certificate
active
06689777
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to substituted naphthothiazolium; aromatic guanylhydrazones, and other compounds and compositions with anti-malarial activity useful for the treatment and prophylaxis of malaria.
BACKGROUND OF THE INVENTION
Malaria continues to be a major disease in most of the developing world. The estimated 300 million cases that occur per year result in considerable morbidity (e.g. fever, malaise, anorexia, anemia) and mortality of over 2 million children under the age of five (1). The intracellular protozoa,
P. falciparum
, accounts for greater than 95% of the malaria deaths. An important contributor to the increase in the incidence of malaria over the past 30 years has been the development of resistance of the malarial parasite to quinoline-containing anti-malarials such as chloroquine and quinine (2). In addition, it has been recognized that a number of complications, such as anemia, failure to gain weight and immunosuppression, associated with malaria infections continue to occur for weeks and even months after the parasites are cleared from the body (3,4,5).
The malaria pigment, hemozoin, is a unique polymer of heme molecules produced by the malaria parasite as a product of hemoglobin catabolism within the food vacuole (6) that serves to protect the parasite from potentially toxic free heme, as well as to induce pathology in the infected host. Over time, the intraerythrocytic parasite exhausts this energy and protein supply and then begins the next stage of its life cycle. Through a series of DNA and membrane divisions, each trophozoite will form 8-12 merozoites and one large “garbage bag” containing polymerized hemozoin. When the infected red blood cell bursts, the merozoites go o to infect new cells and the hemozoin is released into the blood stream where it is scavenged by macrophages. The hemozoin is extremely stable and remains undegraded in the host organism for an extended period of time (years), mostly concentrated in the liver, kidneys and spleen.
Studies have demonstrated that hemozoin, either chemically made or isolated from the natural source, stimulates the production of tumor necrosis factor (TNF), and the macrophage inflammatory proteins, MIP-1&agr; and MIP-1&bgr;, in both murine macrophages and in human peripheral blood monocytes in vitro. This cytokine release is specific for hemozoin and not secondary to ingestion of particulate matter (e.g., latex beads), heme-containing compounds (hematin or hemin crystals) or to contamination with endotoxin (25). Administration of chemically synthesized hemozoin to rats provoked a dysregulation of temperature comparable to that observed with the administration of endogenous pyrogens, such as TNF and MIP-1&agr;.
In contrast to induction of cytokines by lipopolysaccharide (LPS) which peaks within hours and is promptly shut off, the indigestible hemozoin continues to induce TNF for 72 hours. This prolonged stimulation of cytokines is believed responsible for the elevated serum levels of TNF that are observed many weeks after malaria infections have been cured in children (28). The indigestible hemozoin continues to stimulate the macrophage to produce cytokines for long periods prolonging the time needed for recovery after resolution of the infection. Furthermore, macrophages laden with hemozoin have a number of impaired effector functions (7,8,9). These include decreased ability to mount an oxidative burst, decreased killing of pathogens, antigen presentation and a depression of cellular immunity.
Since plasmodia have evolved this unique mechanism to detoxify potentially toxic heme, interfering with its production would adversely effect the parasites since they have no mechanism to rid heme from the food vacuole. In contrast, mammals use heme oxygenase to break down heme to bilirubin. It has been proposed that the mechanism of action of quinoline containing drugs such as chloroquine and quinine was by interference with the heme polymerization process in the food vacuole of the parasite (26,27). This inhibition would lead to the accumulation of free heme which would be toxic to the parasite. The structure of hemozoin and the prevention of its formation by chloroquine has been confirmed by several workers (10,11,12).
It is towards the development of new antimalarial compounds which depolymerize hemozoin, both to kill parasites and reduce hemozoin toxicity in the host, that the present application is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
In accordance with the present invention,a method is provided for treating a mammal suffering from malaria or the sequelae of malarial infection comprising administering a therapeutically effective amount of a compound of the formula:
wherein R
1
is hydrogen, alkenyl, hydroxy(lower)alkyl, di[(lower)alkyl]amino(lower)alkyl, a heterocyclic, group, or a lower alkyl group optionally substituted by a heterocyclic group; R
2
is cycloalkyl, alkenyl, lower alkyl, hydroxy(lower alkyl), di[hydroxy(lower)alkyl]amino(lower)alkyl, a heterocyclic group, or an aryl group optionally substituted by a 1-(guanylhydrazono)alkyl group; R
3
is hydrogen or a 1-(guanylhydrazono)alkyl group; or a pharmaceutically acceptable salt therefor. R
1
may be for example hydroxyethyl, allyl; dimethylaminopropyl, morpholinopropyl, or an ethyl group. R
2
may be for example a cyclohexyl, allyl, phenyl, morpholinopropyl, methylpiperazinopropyl, di(hydroxyethyl)aminopropyl, ethyl, propyl, hydroxyethyl, or 3-[1-(guanylhydrazono)ethyl]phenyl group. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Preferred compounds include but are not limited to:
1-ethyl-2-(ethylimino)-1,2-dihydro-4-methylnaphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-1,4-dimethyl-2-[[3-(4-methyl-1-piperazinyl)propyl]imino]naphtho[1,2-d]thiazol-5-ol;
2-(cyclohexylimino)-1,2-dihydro-4-methyl-1-[3-(dimethylamino)propyl]naphtho[1,2-d]thiazol-5-ol;
2-[[3-[1-[2-(aminoiminomethyl)hydrazono]ethyl]phenyl]amino]-4-methylnaphtho[1,2-d]thiazol-5-ol;
2-[[3-[bis(2-hydroxyethyl)amino]propyl]imino]-1,2-dihydro-1,4-dimethylnaphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-4-methyl-1-(2-propenyl)-2-(2-propenylimino)naphtho[1,2-d]thiazol-5-ol;
4-methyl-2-(2-propenylamino)naphtho[1,2-d]thiazol-5-ol;
2-(cyclohexylimino)-5-hydroxy-4-methylnaphtho[1,2-d]thiazole-1(2H)-ethanol;
1,2-dihydro-2-[(2-hydroxyethyl)imino]-1,4-dimethylnaphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-1,4-dimethyl-2-(phenylimino)naphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-4-methyl-2-(phenylimino)naphtho[1,2-d]thiazol-5-ol;
4-methyl-2-[[3-(4-morpholino)propyl]amino]naphtho[1,2-d]thiazol-5-ol;
8-[1-[2-(aminoiminomethyl)hydrazono]ethyl]-2-(butylimino)-1,2-dihydro-1,4-dimethylnaphtho[1,2-d]thiazol-5-ol;
2-(cyclohexylimino)-1,2-dihydro-4-methyl-1-[3-(4-morpholino)propyl]naphtho[1,2-d]thiazol-5-ol;
2-(cyclohexylimino)-1,2-dihydro-4-methyl-1-[3-(4-methyl-1-piperazinyl)propyl]naphtho[1,2-d]thiazol-5-ol;
2-[[3-(dimethylamino)propyl]imino]-1,2-dihydro-1,4-dimethylnaphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-4-methyl-1-[3-(dimethylamino)propyl]-2-(1-methylethyl)aminonaphtho[1,2-d]thiazol-5-ol.
The present invention is also directed to a method for treating a mammal suffering from malaria or the sequelae of malaria infection comprising administering a therapeutically effective amount of a compound of the formula:
wherein X and Y are independently N or CH, with the proviso that X and Y are not both N; R
1
and R
2
are both hydrogen or lower alkyl groups; wherein R
3
and R
4
are independently hydrogen
Cerami Anthony
Ulrich Peter C.
Davis Zinna Northington
Hamble Frederick J.
Kenneth S. Warren Institute
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