2-substituted quinolines for the treatment of leishmaniasis

Details 2-substituted quinolines for the treatment of leishmaniasis 2-substituted quinolines for the treatment of leishmaniasis

1994-06-09

1996-07-30

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514312, 546153, 546155, 546181, C07D21506, C07D21520, A61K 3147

Patent

active

055411967

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FR92/00903, filed Sep. 29, 1992.
The invention relates to 2-substituted quinolines for the treatment of leishmaniasis.
The term leishmaniasis covers a group of parasitic conditions caused by zooflagellates of the family Trypanosomatidae grouped together under the genus Leishmania.
The Leishmania protozoa parasitize the reticuloendothelial system, causing cutaneous, mucocutaneous or visceral manifestations.
The treatments for leishmaniasis used to date essentially employ antimony salts, especially N-methyl-glucamine antimonate (Glucantime.TM.); 1,5-bis(4-amidinophenoxy) pentane (pentamidine) salts are also used, especially for the treatment of visceral leishmaniasis. Amphotericin B is also used in severe forms resistant to other treatments. These treatments possess the drawback of employing toxic products, which are inconvenient to use since they have to be administered parenterally and exhibit considerable side effects, thereby making them expensive to use, their use being virtually impossible in the absence of hospital facilities and hence economically prohibitive for the majority of the populations of the regions affected by leishmaniasis.
Many studies have been performed with the object of obtaining antileishmanials which are easier to use than those employed at present. To this end, various products which are already known for their anti-infectious activity have been subjected to an evaluation of their biological activity against leishmanias: these comprise, for example, antifungals, especially ketoconazole and its derivatives, or antibiotics such as rifampicin.
Antiparasitics, especially antimalarials, have also been tested: there may be mentioned, for example, primaquine [HANSON et al., Int. J. Parasitol., 7 443-447, (1977); BEVERIDGE et al., Trans. R. Soc. Trop. Med. Hyg., 74, 43-51, (1980)] or derivatives of the latter [SHETTY et al., J. Med. Chem. 21, 995-998, (1978)], and other 8-aminoquinoline derivatives such as lepidines[KINNAMON et al., Am. J. Trop. Med. Hyg., 27, 751-757, (1977)]; these different compounds have shown greater or lesser antileishmanial activity in vitro, and some of them also possess significant activity in vivo when they are administered parenterally; quinine and chloroquine have also been tested, but proved weakly active in vitro and inactive in vivo [MATTOCK and PETERS., Ann. Trop. Med. Parasitol., 69, 359-371 (1975); PETERS et al., Ann. Trop. Med. Parasitol., 74, 289-298 (1980); PETERS et al., Ann. Trap. Med. Parasitol., 74 321-335 (1980)].
Recently, BAUMANN et al. [Antimicrob. Agents Chemoter., 35, 1403-1407, (1991)] have shown the efficacy in vivo via the parenteral route and via the oral route of a polyamide analog on L.donovani; this polyamine analog is the only product to date for which significant activity via the oral route has been demonstrated.
Different plant-based treatments are also used by the indigenous populations in the regions where leishmaniasis is endemic [FOURNET et al. J. Ethnopharmacol., 24, 337 (1988)]. These plants are, in general, used in local applications, on the lesions.
The plants used in this way are more or less well identified from a botanical standpoint, and no proper evaluation of their true efficacy has been performed to date.
The inventors undertook a study of different plants recommended in the traditional pharmacopeia of the Indian populations of South America for the treatment of leishmaniasis. In this way, they came to demonstrate the effective action on Leishmania of extracts of Galipea longiflora Krause.
Galipea longiflora [KRAUSE, Notizbl. K. Bot. Gart. Berlin, 6, 143, (1914)] belongs to the genus Galipea of the family Rutaceae. It is a shrub 10 to 15 meters in height present in Bolivia and in the regions bordering on Brazil to the north east of Bolivia. Its fresh bark, reduced to paste, is used in the local traditional medicine in poultices for the topical treatment of cutaneous lesions caused by Leishmania braziliensis, as well as in a decoction for the treatment of amebic dysentery.
Some species

REFERENCES:
patent: 4209519 (1980-06-01), Kinnamon
English Translation of "Aryl-2 et Alkyl . . . ", A. Fournet, Can J Chem, 67(12), pp. 2116-2118, 1989.
A. Fournet, "Aryl-2 et Alkyl-2 Quindl eines . . . ", Can J Chem, 67(12) pp. 2116-2118, 1989.

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