Classifications

• • 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
  • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
  • C07D493/20—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • 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

• the invention relates to the design, synthesis and use of novel peroxide-based antimalarials
• a first aspect of the present invention relates to antimalarial compounds of the following general formula:
• a second aspect of the present invention therefore, relates to a process of production of the above-specified antimalarial compounds via a TMSOTf7AgClO4 catalysed DHA-phenol derivative coupling reaction.
• This invention is concerned with the preparation of several, novel antimalarial phenoxy derivatives of dihydroartemisinin (DHA) that have been designed to prevent oxidative biotransformation to (DHA) in vivo.
• DHA dihydroartemisinin
• the compounds that have been designed should be less neurotoxic and should have longer half-lives than the currently available derivatives. All of the compounds examined have potent antimalarial potency in vitro.
• the parent phenoxy derivative and the 7-trifluoromethyl phenoxy derivative (7) demonstrated outstanding antimalarial activity in vivo against Plasmodium berghei in the mouse model.
• the oxonium ion being a chemically reactive intermediate, could either react once formed with a phenol to give the phenyl ether, or by loss of a proton give the byproduct, anhydroartemisinin. Both reactions compete for the oxonium ion.
• the Mitsunobu reaction is used to synthesise esters from a carboxylic acid and an alcohol in the presence of triphenylphosphine and an azodicarboxylate (typically the diisopropyl or diethyl derivative). 10 ' n
• the dihydroartemisinin lactol can be recognised as a pyranose sugar with a free anomeric hydroxyl group. 12
• studies by Suzuki have been carried out in investigate the O to C glycoside rearrangment of phenoxy glycosides. 15
• phenoxy derivative is prepared in situ and allowed to rearrange into the corresponding C-aryl glycoside.
• Such two stage reactions proceed in one pot in the presence of Lewis acids.
• Lewis acid promoters have been used, including BF3 etherate, SnC and Cp2HfCl2-AgCl ⁇ 4 with varying success.
• Suzuki noted that the anomeric composition was largely ⁇ , with a small amount of ⁇ anomer. This stereochemical aspect was explained by the thermodynamic equilibration to the more stable ⁇ anomer from the initially formed anomeric mixture.
• the most potent ⁇ -isomers were the phenyl, 4-methylphenyl and 4-fluorophenyl DHA derivatives. These were all more potent than artemether.
• the phenyl, 4-methylphenyl, 4-methoxyphenyl and fused phenyl derivatives of DHA were all more potent than artemether.
• the 4-trifluorornethylphenyl ether was of comparable activity to artemether.
• this compound Based on the excellent stereoselectivity obtained for the /?ara-trifluoromethyl derivative, this compound along with the parent phenyl substituted derivative, were selected for in vivo biological evaluation against Plasmodium berghei in the mouse model.
• Plasmodium falciparum from Thailand Two strains of Plasmodium falciparum from Thailand were used in this study: a) the uncloned Kl strain which is known to be chloroquine resistant and b) the cloned T9.96 strain which is sensitive to all antimalarials. Parasites were maintained in continuous culture using a method derived from that of Jensen and Trager. 18 Cultures were maintained in culture flasks containing human erythrocytes (2-5 %) with parasitaemia ranging from 0.1-10% suspended in RPMI 1640 medium supplemented with 25mM HEPES buffer, 32mM NaHCO3 and 10% human serum (complete medium). Cultures were gassed with a mixture of 3% O2, 4% CO2 and 93% N2.
• Antimalarial activity was assessed using an adaptation of the 48 hour sensitivity assay of
• Desjardins et al using [-1H]- hypoxanthine incorporation as an assessment of parasite growth Stock drug solutions were dissolved in 100% ethanol and diluted to an appropriate concentration with complete medium (final concentrations contained less than 1% ethanol). Assays were performed in sterile 96 well microlitre plates, each well containing lOO ⁇ L of medium which was seeded with lO ⁇ L of a parasitised red blood cell mixture to give a resulting initial parasitaemia of 1% with a 5% haematocrit. Control wells (which constituted 100% parasite growth) consisted of the above, with the omission of the drug.
• IC50 values were calculated by interpolation of the probit transformation of the log-dose response curve. Each compound was tested against both strains to ensure reproducibility of the results.
• compounds of the invention may also find a use for other purposes and particularly in the treatment of cancer and proliferative disorders (eg. psoriasis).
• Antimalarial trioxanes based on artemisinin and arteether have previously been shown to possess anti-proliferative and anti-tumour activities in vitro, as evidenced by their effects on the growth of normal murine keratinocytes and a range of cancer cell lines respectively 20 and, accordingly, compounds of the invention may be used in this context.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Tropical Medicine & Parasitology (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=10856876

Family Applications (1)

Country Status (4)

Families Citing this family (8)

Family Cites Families (3)

• 1999
  • 1999-07-09 GB GBGB9916012.9A patent/GB9916012D0/en not_active Ceased
• 2000
  • 2000-07-07 AU AU58334/00A patent/AU5833400A/en not_active Abandoned
  • 2000-07-07 EP EP00944098A patent/EP1278753A2/de not_active Withdrawn
  • 2000-07-07 WO PCT/GB2000/002518 patent/WO2001004123A2/en not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events