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1,2,4-trioxolane antimalarials

A technology of trioxane and oxoxane, which can be used in anti-infective drugs, anti-tumor drugs, drug combinations and other directions, can solve problems such as neurotoxicity, recurrence, and metabolic instability, and achieve low neurotoxicity, simple structure, and ease of use. and cheap synthetic effects

Inactive Publication Date: 2004-11-10
MMV MEDICINES FOR MALARIA VENTURE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Although clinically useful semi-synthetic artemisinin derivatives are fast-acting and potent antimalarials, they suffer from several disadvantages, including relapse, neurotoxicity (Wesche et al., 1994) and metabolic instability (White, 1994)
Many of these compounds are quite active in vitro, but most suffer from low oral activity (White, 1994; van Agtmael et al., 1999)

Method used

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  • 1,2,4-trioxolane antimalarials
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  • 1,2,4-trioxolane antimalarials

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] General method for the preparation of 1,2,4-trioxolane

[0144] Synthesis of O-methyl 2-adamantanone oxime (representative method)

[0145] To a solution of 2-adamantanone (4.51 g, 30 mmol) in methanol (30 ml) was added pyridine (4.5 ml) and methoxylamine hydrochloride (3.76 g, 45.0 mmol). The reaction mixture was stirred at room temperature for 48 h, concentrated in vacuo, and washed with CH 2 Cl 2 (50ml) and water (50ml) to dilute. The organic layer was separated and washed with CH 2 Cl 2 (30ml) to extract the aqueous layer. The combined organic extracts were washed with 1M HCl (30ml×2) and saturated aqueous NaCl (30ml), and washed with MgSO 4 dry. Evaporation in vacuo gave O-methyl 2-adamantanone oxime (4.77 g, 89%) as a colorless solid. mp70-71℃; 1 H NMR (300MHz, CDCl 3 ) δ 1.60-2.10 (m, 12H), 2.54 (s, 1H), 3.47 (s, 1H), 3.82 (s, 3H).

[0146] References: Corey, E.J.; Niimura, K.; Konishi, Y.; Hashimoto, S.; Hamada, Y.A New Synthetic Route to Pr...

Embodiment 2

[0707] Antimalarial activity of OZ01-OZ270

[0708] Each trioxolane was screened against the chloroquine-resistant K1 strain and the chloroquine-sensitive NF54 strain of Plasmodium falciparum in vitro. In a single-dose STI in vivo screen, Moro genus infected with the ANKA strain of P. berghei (P. SPF or NMRI mice (groups of three mice). Trioxolane was administered subcutaneously and orally in a single 10 mg / kg dose. Trioxolane was also administered as a single 10 mg / kg dose in a standard suspension vehicle (SSV). SSV consisted of 0.5% w / v CMC, 0.5% v / v benzyl alcohol, 0.4% v / v Tween 80 and 0.9% w / v sodium chloride in water. Antimalarial activity was determined by the percent reduction in parasitemia and survival time at day 3 post-infection compared to untreated controls. Survival to day 30 post-infection was considered cured. Regarding the comparative analysis, Table 1 below shows the data for OZ01-OZ270 and the control group, fenozan, artemisinin, artethe...

Embodiment 3

[0975] Activity of trioxane against Plasmodium berghei

[0976] As shown in Table 2 below, the trioxane compounds have significant in vivo antimalarial activity against Plasmodium berghei as determined in a 4-day Peters assay. According to oral ED 50 / ED 90 value, OZ23 is the compound with the strongest oral activity among all trioxolanes and control compounds.

[0977] Table 2

[0978] Compound Plasmodium berghei Plasmodium yoelii (P.yoelii)

[0979] ED 50 / ED 90 (mg / kg) ED 50 / ED90 (mg / kg)

[0980] Oral Subcutaneous Subcutaneous

[0981] OZ03 1.0 / 2.7 0.6 / 1.1 1.6 / 3.1

[0982] OZ05 1.5 / 6.1 0.6 / 1.0 1.4 / 2.5

[0983] OZ10 1.3 / 3.0 0.5 / 0.9 1 / 2.2

[0984] OZ11 1.8 / 3.1 0.5 / 0.9 1.0 / 2.1

[0985] OZ12 6.8 / 10.5 0.8 / 1.4 1.1 / 2.3

[0986] OZ15 2.9 / 6.3 0.7 / 1.1 1.4 / 3.6

[0987] OZ23 0.9 / 2.0 0.5 / 0.9 0.7

[0988] OZ25 1.2 / 3.7 2.2 / 3.7 2.7 / 4.3

[0989] OZ27 1.3 / 2.6 0.2 / 0.9 4.4 / 10.2

[0990] OZ32 2.6 / 5.1 0.6 / 1.3 1.2 / 3.5

[0991] Fen...

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Abstract

A means and method for treating malaria, schistosomiasis, and cancer using a spiro or dispiro 1,2,4-trioxolane is described. The preferred 1,2,4-trioxolanes include a spiroadamantane group on one side of the trioxolane group, and a spirocyclohexyl on the other side of the trioxolane group, whereby the spirocyclohexyl ring is preferably substituted at the 4-position. In comparison to artemisinin semisynthetic derivatives, the compounds of this invention are structurally simple, easy to synthesize, non-toxic, and potent against malarial parasites.

Description

technical field [0001] The present invention relates to compositions and methods for treating malaria. In particular, the present invention relates to pharmaceutical compositions comprising spiro and dispirotrioxolanes and methods of their use and preparation. Background technique [0002] Malaria is an acute and often chronic infectious disease caused by the presence of protozoan parasites in red blood cells. Malaria is caused by single-celled parasites of the genus Plasmodium, which are transmitted from person to person through the bite of female mosquitoes. [0003] Although malaria was once endemic in North America and other temperate regions of the world, it is now mainly found in tropical and subtropical countries. Between 400 million and 600 million people are infected and between 1.5 million and 2.7 million die from the disease each year. [0004] Malaria is usually caused by four of the protozoan parasites of the Plasmodium genus, including Plasmodium vivax, Plas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/335A61K31/357A61K31/382A61K31/4035A61K31/4178A61K31/4196A61K31/422A61K31/427A61K31/438A61K31/444A61K31/4709A61K31/496A61K31/497A61K31/5377A61P33/06A61P33/12A61P35/00C07D323/02C07D405/06C07D405/12C07D405/14C07D413/10C07D417/04C07D417/06C07D417/12C07D491/10C07D491/113C07D493/10C07D495/10
CPCC07D405/14C07D493/10C07D405/12C07D495/10A61K31/357C07D323/02A61K31/335C07D491/10A61P33/00A61P33/06A61P33/12A61P35/00Y02A50/30A61K2300/00
Inventor 乔纳森·L·文纳斯特罗姆雅克·肖莱董玉湘于格·马蒂勒马尼扬·帕德马尼拉炎唐元清威廉·N·查曼
Owner MMV MEDICINES FOR MALARIA VENTURE
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