Substituted 1,2,4-trioxanes as antimalarial agents and a...

Details Substituted 1,2,4-trioxanes as antimalarial agents and a... Substituted 1,2,4-trioxanes as antimalarial agents and a...

2000-03-31

2001-11-13

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S368000

Reexamination Certificate

active

06316493

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel substituted 1,2,4-trioxanes useful as anti-malarial agents. The invention also relates to a process for the preparation of novel substituted 1,2,4-trioxanes. More particularly, the invention relates to a process for the preparation of 6-[(&agr;-(hydroxyalkoxy substituted aryl)vinyl-1,2,4-trioxanes and their esters useful as novel anti-malarial agents.
BACKGROUND OF THE INVENTION
Malaria is a killer disease in tropical countries. It is caused by Plasmodium. The four species of Plasmodium that infect human beings are
P. vivax, P. malariae, P. ovale
and
P. falciparium.
Some of the species that infect animals are
P. yoelii
in mice and
P. cynomolgi
in monkeys. These species cause severe complications in the patient that cause the patient to lapse into a coma and ultimately leads to death. In many parts of the world, there are several strains of Plasmodium that are resistant to drugs such as chloroquinone, mefloquine, halofantrine, quinine, etc. More than 270 million people suffer from the disease and more than 1.2 to 1.7 million die every year. Mortality among children under the age of 5 is common because such children are sensitive on account of their lack of immunity to the disease.
The need of the hour therefore is to develop novel anti-malarial drugs that can counter drug-resistant malarial infections.
OBJECTS OF THE INVENTION
The main objective of the invention is to provide novel substituted 1,2,4-trioxanes useful as anti-malarial agents.
Another objective of the present invention is to provide novel intermediate compounds also capable of being used as anti-malarial agents.
Yet another objective of the present invention is to provide a process for the preparation of hydroxy-functionalized thoxanes and their esters of general formula 1, a new series of anti-malarial agents.
Still another object is to provide a process for the preparation of intermediate compounds that exhibit anti-malarial properties.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the invention provides novel substituted 1,2,4-trioxanes useful as anti-malarial agents. The invention also provides a process for the preparation of hydroxy-functionalized trioxanes and their esters having general formula 1, wherein R
1
and R
2
represent a hydrogen, an alkyl group such as methyl, ethyl, propyl; R
3
and R
4
represent a hydrogen, an alkyl group such as methyl, ethyl, an aryl such as phenyl, naphthyl or part of a cyclic system; R
5
represents hydrogen, alkyl group such as methyl, ethyl, propyl, aryl such as phenyl or a carboxy alkyl group such as CH
2
CH
2
CO
2
H; X represents hydrogen or lower alkoxy such as OMe,
Z represents O or OCO. These compounds have been tested against multi-drug resistant
P. yoelii
in mice and several of them show promising anti-malarial activity. Some of these compounds with promising anti-malarial activity have been tested against
P. cynomolgi
in monkeys and have been found effective. The invention thus relates to the pharmaceutical industry. The trioxanes of general formula 1 are new chemical entities and they have not been prepared earlier. Trioxanes of general formula 1 are oil-soluble and can be administered as solution in oil such as groundnut oil. Some of the compounds of formula 1 are hemisuccinate derivatives and are soluble both in oil and aqueous NaHCO
3
solution and can be administered as a solution in groundnut oil or aqueous NaHCO
3
. The mode of administration can be oral, intra-muscular, subcutaneous or intravenous. The said compounds, the preferred compounds and the intermediate compounds are described herein below with reference to the accompanying drawings and examples which have been provided merely to illustrate the invention and should not be construed as limitations on the inventive concept.


REFERENCES:
patent: 5225437 (1993-07-01), Posner et al.
patent: 5817692 (1998-10-01), Posner
patent: 5932591 (1999-08-01), Posner et al.
patent: 6136847 (2000-10-01), Posner et al.
patent: 6166065 (2000-12-01), Bachi et al.
Singh et al, Synthesis of in vivo potent antimalarial 1,2,4-trioxanes, Chem. Abs. No. 119:139191, 1993.

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