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WO1993007119A1 - Nouveaux peroxydes antipaludiques et procedes pour leur production et utilisation - Google Patents

Nouveaux peroxydes antipaludiques et procedes pour leur production et utilisation Download PDF

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Publication number
WO1993007119A1
WO1993007119A1 PCT/US1992/008391 US9208391W WO9307119A1 WO 1993007119 A1 WO1993007119 A1 WO 1993007119A1 US 9208391 W US9208391 W US 9208391W WO 9307119 A1 WO9307119 A1 WO 9307119A1
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WO
WIPO (PCT)
Prior art keywords
tetraoxanes
compound
malaria
dimethyl
synthesis
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Application number
PCT/US1992/008391
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English (en)
Inventor
Jonathan L. Vennerstrom
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Board Of Regents Of The University Of Nebraska
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Filing date
Publication date
Application filed by Board Of Regents Of The University Of Nebraska filed Critical Board Of Regents Of The University Of Nebraska
Publication of WO1993007119A1 publication Critical patent/WO1993007119A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • C07D323/04—Six-membered rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • this invention relates to Dispiro-1, 2 ,4,5-tetraoxan which are active against chloroquine-resistant malaria. BACKGROUND OF THE INVENTION
  • 1,2,4-trioxanes were not disclosed. More recently, Jefford et al. (1988) reported that ten 1, 2 ,4-trioxanes were either inactive or much less active than was artemisinin again P. berghei in mice. Finally, Kepler et al. (1988) synthesized ten 1,2,4-trioxanes that were inactive against P. berghei ; the most active compounds in this series had IC 50 's of between 24. and 100 ng/ml against P. falciparum in vitro.
  • 1,2,4,5-tetraoxanes (hereinafter tetraoxanes) and their stereoisomers and regei isomers are provided.
  • these compounds can be depicted by the following formula:
  • Tetraoxanes derived from 5, 6, and 7 membered cyclic ketones, i.e., where n in the above formula is 1, 2, or 3, are preferred as antimalarials.
  • the following tetraoxanes (1-3) are exemplary of the antimalarial activity of the compounds of thi invention. 1 and 2 were isolated as mixtures of meso and d,l stereoisomers, whereas 3 was isolated as a single meso isomer. Each of these compounds exhibits curative, single dose, in vivo activity against P. berghei (3 is as active as artemisinin in Thompson test and has a higher therapeutic index). Compound 3 (IC 50 3-7 nM) is nearly equipotent to artemisinin (IC 50 2-5 nM) against both drug-sensitive and -resistant strains of P.
  • the tetraoxanes of this invention constitute a new class of peroxide antimalarial drugs. A substantial advantage of these compounds with respect to artemisinin and its derivatives
  • a method for the treatment of malaria constitutes another embodiment of this invention. This method comprises
  • the effective dose for treating malaria is that dose which is toxic to the malaria parasite infecting the host, but below the threshold of significant toxicity to the host.
  • this dose ranges from about 5 mg to about 100 mg per kilogram of host body weight. Because the compounds of this invention exhibit high therapeutic indices, it is possible, but generally not economically practical, to employ higher doses up to even 500 mg/kg and higher. Normally, because the compounds of this invention have such high antimalarial activity, doses of between about 5 and about 50 mg/kg host boddy weight are employed.
  • Tetraoxanes A1-A5 are isolated as a single isomer.
  • tetraoxanes and those in the following category are analogs of the two preceding classes (b. and c. ) with different geometries inherent in cyclohexene and cyclopentene rings compared with their saturated counterparts.
  • the synthesis of olefinic tetraoxanes have been previously reported (Bailey et al., 1965). Isomeric analogs can be obtained from the
  • 1,2,4,5-tetraoxane ring in a fixed boat conformation each have a methyl group corresponding to the methyl at C-3 in artemisinin rather than a spiro-fused cyclohexane ring as with I1-I8.
  • K2-K4 demonstrate methyl substitution on the cyclohexane ring
  • ozonation of ß-pinene afforded the corresponding diperoxide (tetraoxane G3) via dimerization of the Criegee carbonyl oxide zwitterion (Overton and Owen, 1973).
  • Tetraoxanes are also formed by treatment of ozonides with
  • the target tetraoxanes can be purified by crystallization, flash column or prep HPLC chromatography and their structures and purity confirmed by analytical HPLC, ⁇ and 13 C NMR, IR, MS, vapor-pressure osmometry, melting point and elemental analysis.
  • the target 1,2,4,5-tetraoxanes (thermodynamic products) and the 1,2,4,5,7,8-hexaoxonanes (kinetic products) (Story et al., 1970) produced in the acid-catalyzed peroxyketalization reaction between ketones and hydrogen peroxide must be distinguished.
  • 1,2,4,5-tetraoxanes and 1,2,4,5,7,8-hexaoxonanes each give the same elemental analysis and very similar IR spectra (Story and Busch, 1972).
  • Vapor-pressure osmometry is a very useful analytical procedure as it is based on
  • HPLC is a preferred procedure based on the ability to conveniently conduct preparative scale
  • cyclopentanone, cyclohexanone, cycloheptanone, cyclooctanone) required for the synthesis of A1-A5 are available from Aldrich Chemical Co.
  • cyclohexanols, and 7,7-dimethyl-2-norbornanol are available and can be easily oxidized by chromium reagents to the correspond ketones required for the synthesis of B1, B3, B18, B20, B26, and G4, respectively (Bowden et al., 1946; Ungnade and McLaren, 1944; Brown and Garg, 1961; Firouzabadi and Ghaderi, 1978).
  • -hexanones are formed most commonly via the lithium enolate formed by treatment with LDA or by exposure of the corresponding silyl enol ethers to methyl lithium; alkyl iodides are the preferred electrophilic agents (Larock, 1990). Both chiral and achiral enamines of cyclohexanone are also widely used for a-alkylation. 2-methyl-, 2-ethyl-, 2-propyl-, 2-allyl-, and 2-butylcyclohexanones and 2-ethyl- and 2-propylcyclopentanones may be accessed by this route (Whitesell and Felman, 1977;
  • 2-propylcyclohexanones is a useful variant on enamine chemistry. 2,2-dimethylcyclohexanone is obtained by treatment of
  • 3-ethyl-, and 3-propylcyclopentanone can all be obtained by the conjugate addition of the appropriate lithium dialkyl cuprate to commercially available enones (Corey et al, 1986; Suzuki et al, 1980; House et al., 1966). Chiral versions of this reaction are available using mixed cuprates containing a chiral anionic ligand (Corey et al., 1986). Treatment of the enol acetates of
  • 3,4-Dimethylcyclopentanone can be formed in a [3+2] cyclocoupling reaction using 1,3-dibromoacetone, cis- or trans-2-butene, and an diiron ennecarbonyl (Noyori and Hayakawa, 1983).
  • bicyclic ketones G7, and G9-G11 are available by diverse methodology.
  • Bicyclo[2.2.1]hept-2-en-5-one is obtained by oxidative decarboxylation via oxygenation of its acid dianion (Wasserman and Lipshutz, 1975) whereas
  • 5-methyl-2-cyclopentanonecarboxylate are obtained via a reversed Dieckmann cleavage of ethyl 2-cyclohexanonecarboxylate and ethyl 2-cyclopentanonecarboxylate, respectively (Meyer et al., 1965; Sisido et al., 1964; Taber et al., 1987), or by a direct
  • ketones are all known compounds and are purified by distillation (bulb-to-bulb or fractional), crystallization, flash column or prep HPLC chromatography and their structures and purity confirmed by TLC or analytical HPLC, ⁇ and 13 C NMR, IR, and melting point analysis for solids.
  • [ 3 H]hypoxanthine is measured using a Beckman scintillation spectrophotometer. Concentration -response data is analyzed by nonlinear regression and the IC 50 (ng/mL) values calculated.
  • Test compounds are dissolved in peanut oil and administered sc on day 3
  • Erythrocytes with 0.25 to 0.5% parasitemie are added to each well of a 96-well microdilution plate to give a final hematocrit of 1.5%. Inhibition of uptake of tritiated hypoxanthine is used as an index of antimalarial activity.
  • the compounds of this invention can be administered to the host or patient as an active ingredient in a variety of dosage forms.
  • the active ingredient which may be in the form of a pharmaceutically-acceptable derivative, such as a
  • processing of the active compound into suitable pharmaceutica preparations can be used to formulate these compositions.
  • Tetraoxanes of this invention are active orally, dosage forms designed for oral administration are preferred. Exemplary are tablets, capsules, and dragees. In some cases, for example, where the host is seriously ill and time is of the essence, it may be necessary to administer the compounds of this inventioon parenterally. In such cases intravenous administration is usually preferred. However, other dosage forms designed for parenteral administration can also be employed, e.g.,
  • Appropriate formulations for parenteral administration include aqueous solutions of the active compound prepared in a water-soluble or water-dispersible form.
  • the active compounds may be administered as suspensions in appropriate oily injection carriers, i.e., in suitable lipophilic carriers, such as fatty oils (sesame oil being an example), or synthetic fatty acid esters (ethyl oleate or triglycerides being examples).
  • compositions prepared for aqueous injection may contain substances which increase the viscosity or the suspension such as, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the therapeutic tetraoxanes of the present invention may also be administered encapsulated in liposomes.
  • the active compound is contained in corpuscles which consist of concentric aqueous layers interspersed between hydrophobic lipidic layers.
  • the bisquinolines depending upon their solubility, may be present both in the aqueous layer and in the lipidic layer, or in what is generally termed a liposomic suspension.
  • the hydrophobic layer generally but not
  • sphingomyelin such as cholesterol, more or less ionic surfactants such as a diacetylphosphate, stearylamine, or
  • phosphatidic acid and/or other materials of a hydrophobic nature which are generally well known in the art.
  • compositions within the scope of the present invention include those
  • compositions where the tetraoxane contained in an effective amount sufficient to kill the malaria-inducing parasite without causing unacceptable toxicity for the host or patient The therapeutic amount which represents an effective anti-malaria dose sufficient for treatment of each of the various types of malaria remains to be determined empirically by those skilled in the art of designing and administering anti-malarials. However, it has been determined that the tetraoxanes this invention appear to have high therapeutic indices, thus presenting a wide range of effective dosage options and strategies.
  • a preferred dosage range is from about 5 to about 100 milligrams of tetraoxanes pea milligram of host body weight, given three times a day.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention se rapporte à de nouveaux tétraoxannes pour le traitement du paludisme et à des procédés de production de ces nouveaux composés. L'invention se rapporte également à des procédés pour le traitement du paludisme et, en particulier, pour le traitement des souches de paludisme résistant à la chloroquine. Ces composés sont représentés par la formule (I).
PCT/US1992/008391 1991-10-04 1992-10-02 Nouveaux peroxydes antipaludiques et procedes pour leur production et utilisation WO1993007119A1 (fr)

Applications Claiming Priority (2)

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US77163491A 1991-10-04 1991-10-04
US07/771,634 1991-10-04

Publications (1)

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WO1993007119A1 true WO1993007119A1 (fr) 1993-04-15

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003076425A1 (fr) * 2002-03-11 2003-09-18 Okayama University Nouveaux composes et antipaludeens
US6906098B2 (en) 2002-02-09 2005-06-14 The United States Of America As Represented By The Secretary Of The Army Mixed steroidal 1,2,4,5-tetraoxane compounds and methods of making and using thereof
WO2008038030A3 (fr) * 2006-09-30 2008-05-15 Univ Liverpool Composés dispirotétraoxane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 83, No. issued 4, August 1975, Athens, Georgia, USA, J.R. SANDERSON, K. PAUL, P.R. STORY, D.D. DENSON AND J.A. ALFORD, "Macrocycles. Synthesis and Thermal Decomposition of Some Disubstituted Dicyclohexylidene Diperoxide", see (3), pages 159-161, the Abstract No. 432814. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6906098B2 (en) 2002-02-09 2005-06-14 The United States Of America As Represented By The Secretary Of The Army Mixed steroidal 1,2,4,5-tetraoxane compounds and methods of making and using thereof
WO2003076425A1 (fr) * 2002-03-11 2003-09-18 Okayama University Nouveaux composes et antipaludeens
US7407984B2 (en) 2002-03-11 2008-08-05 Okayama University Tetraoxaspriro anti-malarials
WO2008038030A3 (fr) * 2006-09-30 2008-05-15 Univ Liverpool Composés dispirotétraoxane
EP2233479A1 (fr) * 2006-09-30 2010-09-29 Liverpool School of Tropical Medicine Composés dispiro tetraoxane et leur utilisation pour le traitement de la malaria et/ou du cancer

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