Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-21
2002-11-26
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S341000
Reexamination Certificate
active
06486199
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions and methods for treating malaria. Specifically, this invention relates to pharmaceutical compositions including spiro and dispiro trioxolanes, and methods of their use and manufacture.
BACKGROUND OF THE INVENTION
Malaria is an acute and often chronic infectious disease resulting from the presence of protozoan parasites within red blood cells. Caused by single-celled parasites of the genus Plasmodium, malaria is transmitted from person to person by the bite of female mosquitos.
Although once prevalent in North America and other temperate regions of the world, today malaria occurs mostly in tropical and subtropic countries. Each year, between 400 million and 600 million people contract the disease, and 1.5 million to 2.7 million die of the disease.
Four species of Plasmodium protozoan parasites are generally responsible for malaria, including
Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae
, and
Plasmodium ovale
. Of the four,
Plasmodium falciparum
is the most dangerous, accounting for half of all clinical cases of malaria and 90% of deaths from the disease.
The transmission of malaria begins when a female mosquito bites a human already infected with the malaria parasite. When the infected mosquito bites another human, sporozoites in the mosquito's saliva are transferred into the blood, which then travel to the liver. In the liver, the sporozoites divide rapidly, then enter the bloodstream where they invade red blood cells. Inside these blood cells, the merozoites multiply rapidly until they cause the red blood cells to burst, releasing into the blood stream a new generation of merozoites that then infect other red blood cells.
The symptoms associated with malaria are generally associated with the bursting of the red blood cells. The destruction of the red blood cells spills wastes, toxin, and other debris into the blood. This in turn causes an intense fever that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by
Plasmodium falciparum
include anemia, severe headaches, convulsions, delirium and, in some instances, death.
The treatment of malaria has been especially difficult due to the ability of malaria parasites to develop resistance to drugs. Quinine, an antimalarial compound that is extracted from the bark of the South American cinchona tree, is one of the oldest and most effective pharmaceuticals in existence. The downside to quinine is that it is short-acting, and fails to prevent disease relapses. Further, quinine is associated with side effects ranging from dizziness to deafness.
Chloroquine is a synthetic chemical similar to quinine. It became the drug of choice for malaria when it was developed in the 1940s due to its effectiveness, ease of manufacture, and general lack of side effects. However, in the last few decades, malaria parasites in many areas of the world have become resistant to chloroquine.
Mefloquine is another synthetic analog of quinine that has been used in the treatment of malaria. Malaria parasites have also developed resistance to mefloquine, however. Mefloquine is also associated with undesirable central nervous side effects in some patients, including hallucinations and vivid nightmares.
Antifolate drugs are effective against malaria parasites by inhibiting their reproduction. Although the parasites have also developed a resistance to antifolate drugs, the drugs can still be used effectively in combination with other types of antimalarials. The use of combination therapies in treating malaria has the drawbacks of being inconvenient and expensive, however.
More recent developments in the treatment of malaria have involved the use of the peroxide functional group, as exemplified by the drug artemisinin, which contains a unique 1,2,4-trioxane heterocyclic pharmacophore. The antimalarial action of artemisinin is due to its reaction with the iron in free heme molecules in the malaria parasite with the generation of free radicals leading to cellular destruction.
Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence, neurotoxicity, (Wesche et al., 1994) and metabolic instability. (White, 1994). Although many synthetic antimalarial 1,2,4-trioxanes have since been prepared (Cumming et al., 1996; Jefford, 1997), there exists a need in the art to identify new peroxide antimalarial agents, especially those which are easily synthesized, are devoid of neurotoxicity, and which possess improved pharmacokinetic properties, e.g. improved stability, oral absorption, etc.
Accordingly, it is a primary objective of the present invention to provide compositions and methods for prophylaxis and treatment of malaria using Spiro and dispiro 1,2,4-trioxolanes.
It is a further objective of the present invention to provide a composition and method for prophylaxis and treatment of malaria using Spiro and dispiro 1,2,4-trioxolanes that is nontoxic.
It is a further objective of the present invention to provide a composition and method for prophylaxis and treatment of malaria using Spiro and dispiro 1,2,4-trioxolanes that is metabolically stable and orally active.
It is yet a further objective of the present invention to provide a composition and method for prophylaxis and cost-effective treatment of malaria using Spiro and dispiro 1,2,4-trioxolanes.
It is a further objective of the present invention to provide compositions and methods for prophylaxis and treatment of malaria using Spiro and dispiro 1,2,4-trioxolanes that can be used either as stand-alone medicaments or in combination with other agents.
The method and means of accomplishing each of the above objectives as well as others will become apparent from the detailed description of the invention which follows hereafter.
SUMMARY OF THE INVENTION
The invention describes a method and composition for treating malaria with Spiro and dispiro 1,2,4-trioxolanes, their prodrugs and analogues. The trioxolanes of this invention are sterically hindered on one side of the trioxolane heterocycle in order to provide chemical and metabolic stability to the trioxolane ring for better in vivo activity. The spiro and dispiro trioxolanes are preferably sterically hindered with an unsubstituted, mono-, di-, or poly-substituted C
5
-C
12
spiro cycloalkyl group, which is most preferably spiroadamantane. The spiro and dispiro trioxolanes also preferably include a spirocyclohexyl that is preferably functionalized or substituted at the 4-position or a spiropiperidyl ring that is functionalized or substituted at the nitrogen atom. The invention embraces achiral, achiral diastereomers, racemic mixtures, as well as enantiomeric forms of the compounds.
The trioxolanes of this invention possess excellent potency and efficacy against Plasmodium parasites, and a low degree of neurotoxicity. In addition, several of the trioxolanes are suitable for both oral and non-oral administration. Moreover, in comparison to artemisinin semisynthetic derivatives, the compounds of this invention are structurally simple, easy and inexpensive to synthesize, and can be used effectively alone or in conjunction with other antimalarials.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention relates to the development of spiro and dispiro 1,2,4-trioxolanes for use in the prophylaxis and treatment of malaria. The present invention is predicated upon the unexpected discovery that trioxolanes that are relatively sterically hindered on at least one side of the trioxolane heterocycle provide metabolic and chemical stability to the trioxolane ring, thereby providing better in vivo activity, especially with respect to oral administration.
As used herein the term “prophylaxis-effective amount” refers to a concentration of compound of this invention that is effective in inhibiting or preventing infection and subsequent disease by malarial parasites. Likewise, the term “treatment-effectiv
Chollet Jacques
Dong Yuxiang
Matile Hugues
Vennerstrom Jonathan L.
McKee Voorhees & Sease, P.L.C.
Medicines for Malaria Venture MMV International Centre Cointrin
Trinh Ba K.
LandOfFree
Spiro and dispiro 1,2,4-trioxolane antimalarials does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Spiro and dispiro 1,2,4-trioxolane antimalarials, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Spiro and dispiro 1,2,4-trioxolane antimalarials will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2935134