2,3-dioxabicyclo[3.3.1]nonane derivatives and antimalarial pharm

Details 2,3-dioxabicyclo[3.3.1]nonane derivatives and antimalarial pharm 2,3-dioxabicyclo[3.3.1]nonane derivatives and antimalarial pharm

2000-05-11

2000-12-26

Dentz, Bernard

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

549360, 549363, A61K 31335, C07D31902

Patent

active

061660655

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention is in the field of antiparasitic drugs and particularly relates to novel antimalarial 2,3-dioxabicyclo[3.3.1]nonane compounds.


BACKGROUND OF THE INVENTION

Malaria is the world's most widespread infectious disease. More than 300 million people are infected, and about 2 million die of it each year..sup.1 Curing malaria by treatment with alkaloids like quinine and chloroquine is becoming less effective due to the continuous emergence of malaria parasites resistant to these drugs.
A new approach to malaria chemotherapy, which is raising high expectations, is based on the use of cyclic peroxides..sup.2 Indeed, artemisinin, an endoperoxide sesquiterpene, was introduced in China as a drug in 1987..sup.3 In Western countries several compounds structurally related to artemisinin were clinically tested, but due to pharmacokinetic drawbacks and incomplete toxicological profiles, none of them were approved as a drug. Cyclic peroxide yingzhaosu A was isolated from a Chinese folk medicine, but no significant physiological and pharmacological data have so far been reported..sup.4
Recently, scientists at Hoffmann-La Roche reported on the synthesis, antimalarial screening and clinical trials of 7-oxo-2,3-dioxabicyclo[3.3.1]nonanes, bearing at C(4) alkyl- or alkenyl substituents..sup.5-7 In vitro and in vivo antimalarial screening, as well as clinical trials of arteflene, the most active compound in this series, gave encouraging results. ##STR1##
Biological evaluation of a variety of cyclic peroxides indicates that a number of them are effective non-toxic antiparasitic agents. However, parasitic infections, particularly malaria, remain a serious and widespread public health problem, and concern exists about possible side-effects of compounds developed to date. For example, neurotoxicity has been seen in rats which were administered high doses of artemether, and in mouse neuroblastoma cells treated with dihydroarte-mesinin..sup.8
It would be highly desirable to develop improved therapeutic agents for prevention and treatment of malaria.


SUMMARY OF THE INVENTION

The object of the present invention is to provide novel compounds for the treatment of parasitic infections, particularly malaria.
To accomplish this goal, the present invention provides 2,3-dioxabicyclo[3.3.1]nonane derivatives, carrying, at position 4, a sulfur-containing functionality selected from the group consisting of sulfonyl, sulfinyl and sulfenyl, adhered to C(4) via methylene group, represented by general structural formula A. ##STR2## wherein: X is hydrogen; hydroxy; alkyloxy, optionally substituted by alkoxy or acyloxy; aralkoxy or acyloxy optionally substituted by alkoxy or aryloxy; and by acyl or acyloxy; aralkoxy; arylalkenyloxy; oxalyloxy substituted by alkoxy, di(alkyl)amino or alkyl(aryl)amino; di(aralalkyl)amino or carbonyloxy substituted by aryloxy, di(alkyl)amino, di(aralkyl)amino and alkyl(aryl)amino; or either Z is a radical R--S(=O).sub.n -- and Y is hydrogen, or cycloalkyl; or aryl or aralkyl optionally substituted by alkyl, halogen or CF.sub.3 ; and
The term "alkyl" as used herein for R stands for a straight or branched C1-C20, preferably C4-C14, alkyl radical such as, but not being limited to, n-butyl, tert-butyl, 3-octyl, and n-dodecyl, and "substituted alkyl" includes radicals such as octyloxyethyl and ethoxycarbonylmethyl.
The term "cycloalkyl" as used herein for R stands for a C.sub.5 -C.sub.7 cycloalkyl, preferably cyclohexyl.
The term "aryl" as used herein for R stands for a C6-C12 aryl, optionally mono or disubstituted by C1-C12 alkyl, halogen such as chloro and fluoro, or CF.sub.3 such as, but not being limited to phenyl, biphenyl, naphthyl, 4-methylphenyl, 2,4-dimethylphenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-trifluoromethylphenyl, 2,4-[di(trifluoromethyl)]phenyl and 3,5-[di(trifluoromethyl)]phenyl.
The term "arylkyl" as used herein for R stands for a C7-C25, preferably C7-C19, radical optionally substituted by alkyl, halogen such as chloro and fluoro, or C

REFERENCES:
Xu et al., "Total Synthesis of (+)-Yingzhaosu A," Tetrahedron Letters, vol. 32, No. 41, pp. 5785-5788, 1991.
Jacquet et a, "Antimalarial activity of the bicyclic peroxide Ro 42-1611 (arteflene) in experimental models," Trop. Med. Parasitol, 45, (1994), 266-271.
Hofheinz et al., "Ro 42-1611 (arteflene), a new effective antimalarial: chemical structure and biological activity," Trop. Med. Parasitol, 45, 1994), 261-265.

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