Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-01-29
2000-10-03
Seaman, D. Margaret
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514311, 5142352, 514252, 540128, 540363, 546159, 546160, A61K 3147, A61K 314706, A61K 315377, C07D45304
Patent
active
061275433
DESCRIPTION:
BRIEF SUMMARY
The invention relates to organometallic iron complexes exhibiting particularly advantageous properties as antimalarial agents. The invention relates in particular to the insertion of ferrocenyl groups into the structure of molecules possessing antimalarial properties.
For many years, malaria has continued to be a major cause of death in many developing countries. The erosion of the chemotherapeutical weaponry linked to the development of resistance in the strains is one of the principal problems encountered in the fight against malaria. Chloroquinine is the most widely used antimalarial worldwide and chloroquinine-resistant strains have appeared in all malaria zones. It is therefore possible that ultimately, the difficulties encountered in the treatment of malaria-related infections will be increasingly important. Although considerable resources are dedicated to the fight against malaria, few alternatives to the medicaments currently used have been proposed.
The inventors have discovered that by combining with molecules having a structure close to that of antimalarials one or more iron atoms, for example by means of the insertion of a ferrocenyl group inside analogs of substances such as quinine, chloroquinine, mepacrine and primaquine, the therapeutic activity of these substances was substantially increased. The inventors have also discovered that the use of the compounds of the invention makes it possible to avoid the relapses in the long term which are often associated with conventional antimalarial treatments.
The high rate of reproduction of Plasmodium falciparum and its iron use have led to attempts at destruction by the privation of iron in the use of ferrioxamine hydroxyamates. Although these tests have given satisfactory results, the inventors have oriented their strategy towards a reverse approach. It involves using instead the affinity of plasmodium for iron to increase the probability of encountering the antimalarial molecule.
The use of organometallic complexes so far remains marginal in therapeutic chemistry. Ferrocene in particular appears only in analogs of prostaglandins, Ferroceron (a drug used to combat iron deficiencies), and analogs of hexestrol.
The invention therefore relates to organometallic iron complexes comprising at least one of the structural components characteristic of a molecule possessing antimalarial properties as well as one or more iron atoms. The reference to structural components characteristic of a molecule possessing antimalarial properties is used to designate certain characteristic portions of antimalarial molecules which confer on these molecules their properties.
Structural components characteristic of molecules possessing antimalarial properties are varied and can be easily recognized by persons skilled in the art. The need to use the basic structure determining the antimalarial activity should be noted, however. For example, in the case of the quinines, the presence of an amino alcohol substituent on the quinoline is essential, just as a diamine substituent on the quinoline is essential for the modified molecules of the chloroquinine type, just as a substituent is essential for the modified molecules of the mepacrine type. For these molecules, the quinolines or the acridines are considered as basic structural components conferring the desired antimalarial properties.
It was therefore a question of reproducing as accurately as possible the basic structure of these molecules while attaching thereto, and preferably while inserting therein, substituents which make it possible to confer an organometallic character on these molecules. The invention is therefore based on the combination of an iron atom and an organic ligand close to molecules whose antimalarial properties are known. Preferably, the iron is provided by ferrocene whose chemistry is known and of which several derivatives are commercially available.
It is important to underline here that the inventors have not sought solely to graft a molecule containing iron atoms (ferrocene for example) onto existing a
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Brocard Jacques
Lebibi Jacques
Maciejewski Lucien
Gollin Michael A.
Haddaway Keith G.
Seaman D. Margaret
Universite des Sciences et Technologies de Lille
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