Use of (+)mefloquine for the treatment of malaria

Details Use of (+)mefloquine for the treatment of malaria Use of (+)mefloquine for the treatment of malaria

1999-11-22

2003-12-16

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S895000, C546S152000, C546S176000

Reexamination Certificate

active

06664397

ABSTRACT:

The present invention relates to the use of an enantiomer of &agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol (mefloquine) as an anti-malarial.
Malaria is an infectious parasitic disease transmitted by mosquitoes. It is characterized by periodic fever and an enlarged spleen. Malaria affects some 200 million people a year. Malaria in humans is caused by 4 species of parasitic protozoa belonging to the genus Plasmodium. Of these,
P. falciparum
produces the severe disease while
P. malariae, P. vivax
and
P. ovale
cause milder forms.
Malaria is transmitted by infected female Anopheline mosquitoes. The Plasmodia parasite matures in the insect, and is then transferred when the mosquito bites a human. Inside the human, the parasite settles first in the liver, multiplies and then invades the red blood cells. This is when the symptoms of malaria become evident.
Despite numerous attempts at eradication, malaria remains a serious endemic disease in many areas of Africa, Latin America and Oceania, with a worldwide mortality rate of approximately 1 million per year (WHO Scientific Group on the Chemotherapy of Malaria 1990). One of the major factors contributing to the continued presence of malaria is the emergence of malaria parasites that are resistant to one or more anti-malarial compounds.
Mefloquine is an anti-malarial compound which is effective against strains of the Plasmodium parasite which have developed resistance to conventional anti-malarial agents (for a review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy, see Palmer et al, Drugs, 1993, 45, 430-475). However, mefloquine resistance has now been reported in a number of areas including areas of Thailand (see Palmer et al.). Nevertheless, mefloquine is still one of the most effective anti-malarial mono-therapies and its use has increased greatly. Recently, the drug has attracted considerable adverse publicity owing to the incidence of severe neuropsychiatric side-effects, e.g. depression, psychosis, panic attacks, generalised anxiety. Although central nervous system (CNS) side-effects had been reported previously (particularly from its use by the armed forces in tropical areas; Croft & World (Neuropsychiatric reactions with mefloquine chemoprophylaxis. Lancet, 1996, 347, 326); Gullahorn et al. (Anaesthesia emergence delerium after mefloauine prophylaxis. Lancet, 1993, 341, 632)), their incidence had been regarded as sufficiently low to be of little concern. However, the widespread use of the drug by holidaymakers has resulted in a greatly increased number of CNS side-effect reports. A recent study (Barrett et al. (Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers. (British Medical Journal, 1996, 313, 525-528), in which 3851 travellers taking prophylactic anti-malarial medication were surveyed, has confirmed that there is a significant excess of adverse neuropsychiatric events associated with mefloquine administration compared with an alternative prophylactic treatment (proguanil plus chloroquine).
Clinical reports indicate that mefloquine may be proconvulsant (Ruff et al. (Seizure associated with mefloquine for malaria prophylaxis. Med. J. Aust., 1994, 161, 453)), anxiogenic (Hennequin et al. (Severe psychiatric side effects observed during prophylaxis and treatment with mefloquine. Arch. Intern. Med., 1994, 154, 2360-2362)), induce vertigo and dizziness (Sowunmi et al. (Neuropsychiatric side effects of mefloquine in Africans. Trans. Roy. Soc. Trop. Med. Hyg., 1993, 87, 462-463)) and may have central anticholinergic actions (Speich and Heller (Central anticholinergic syndrome with the antimalarial drug mefloquine. N. Engl. J. Med., 1994, 331, 57-58)).
Mefloquine is a molecule having two asymmetric carbon atoms and is usually used clinically as a racemic mixture of erythro ((±) (R*,S*)) isomers. Both of the mefloquine enantiomers have been reported to be equally effective against
Plasmodium falciparum
(Basco et al. (In vitro activity of the enantiomers of mefioquine, halofantrine and enpiroline against
Plasmodium falciparum
. Br. J. clin. Pharmac., 1992, 33, 517-520)), although another study claimed that the (+)-enantiomer was more potent than the (−)-enantiomer by a factor of 1.69-1.81 (Karle et al. (
Plasmodium falciparum
: role of absolute stereochemistry in the antimalarial activity of synthetic amino alcohol antimalarial agents. Exp. Parasitol., 1993, 76, 345-351)).
Mefloquine hydrochloride was introduced to the market as an anti-malarial agent in 1985. There have been over 40 families of patent applications on mefloquine covering: the use of the compound for treating malaria and other parasitic diseases; various processes for its preparation; and different formulations. The compound and its preparation was first described by Ohnmacht et al. (
J. Med. Chem
. 1971, 14, 926) in 1971. A more detailed account of the stereochemistry, synthesis, and anti-malarial activity of the isomers of mefloquine is given by Carroll and Blackwell (
J. Med. Chem
. 1974, 17, 210-219) in 1974.
It has now been found that the (+)-(11R,2′S)-enantiomer of &agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol is effective as an anti-malarial and has reduced side-effects compared to the racemic (±)-(R*,S*)-&agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. The structures of the (+)-(11R,2′S)-enantiomer and the (−)-(11S,2′R)-enantiomer of &agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol are shown below.
In particular, it has been found that the (−)-enantiomer of mefloquine binds to CNS adenosine receptors, while the (+)-enantiomer is without significant activity at this binding site. The blocking of central adenosine receptors by the (−)-enantiomer is believed to result in the neuropsychiatric symptoms associated with mefloquine.
According to the present invention there is provided use of (+)-(11R,2′S)-&agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol or a pharmaceutically acceptable salt thereof substantially free of its (−)-enantiomer in the manufacture of a medicament having reduced side-effects compared to the racemic (±)-(R*,S*)-&agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol for treating or preventing malaria.
According to a further aspect of the present invention there is provided a method of treating or preventing malaria with reduced side-effects compared to the racemic (±)-(R*,S*)-&agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol comprising administration to a subject in need of such treatment an effective dose of (+)-(11R,2′S)-&agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol or a pharmaceutically acceptable salt thereof substantially free of its (−)-enantiomer.
The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
(+)-(11R,2′S)-&agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol may be employed in the present invention in an admixture with one or more other anti-malarial drugs such as, for example, chloroquine, pyrimethamine, sulfadoxine, amodiaquine, quinine/quinidine, halofantrine, artemether/artesunate, tovaquone, proguanil, doxycycline and dapsone. Combination with pyrimethamine and sulfadoxine is particularly preferred. According to a further aspect of the invention, (+)-(11R,2′S)-&agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol and the other anti-malarial drug(s) may be in separate formulations, for use simultaneously or sequentially.
The term “a method for treating or preventing malaria” as used herein, means relief from malaria, preventing or inhibiting infection by parasitic protozoa of the genus Plasmodium which cause malaria and clearance of parasitic protozoa.
The term “substantially fre

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