Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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 present invention relates to dihydroartemisinin and dihydroartemisitene dimers and their use in the treatment of cancer and as antiprotzoal agents.
• Natural products have historically been a rich source of new, successful prototype classes of lead compounds from which analogs have been developed. According to a recent review, 60% of the anti-infective and anti-cancer drugs that have successfully advanced to the clinic are derived from natural products (2). Examples of these among currently used anti-cancer agents include the anthracycline class (e.g., doxorabicin), the Catharanthus (Vinca) alkaloids, paclitaxel, and derivatives of podophyllotoxin and camptothecin.
• a recently published tabulation of natural product-based anti-tumor drugs shows more than 25 agents currently in Phase I or II (3). This and other recent reviews are important reminders of the critical role of natural products as a resource for the discovery of new anti-tumor agents (4,5).
• the natural product artemisinin (1) is a sesquiterpene endoperoxide first isolated in 1971 from the Chinese plant Artemisia annua (6).
• the compounds as numbered herein are depicted in Figure 1.
• the compound was shown to have anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum.
• artemisinin had been reported to have cytotoxic effects against EN-2 tumor cells (7), P-388, A549, HT-29, MCF-7, and KB-tumor cells (8).
• As more analogs were evaluated for anti-tumor activity it was reported that the unsymmetrical dimer (2) showed strong cytotoxic activity and was more potent than cisplatin (9).
• the symmetrical dimer (3) also showed pronounced cytotoxic activity (10).
• compositions containing dihydroartemisinin and dihydroartemisitene dimers with activity as anticancer agents and anti-protozal, including anti-malarial and anti-leishmanial properties This invention also describes methods of preparation of these compositions and methods of use of such compositions for the treatment of cancer, and protozoal infections, including malaria, or leishmaniasis.
• the compositions of this invention have not been previously described.
• the compounds of this invention represent a potential new class of anti- tumor agents, one that has shown promising activity against solid tumors, and with a pattern of selectivity that suggests a possible new mechanism of action.
• Administration of the instant dimers may be by any of the conventional routes of administration, for example, oral, subcutaneous, intraperitoneal, intramuscular, intravenous or rectally.
• the compound is administered in combination with a pharmaceutically-acceptable carrier which may be solid or liquid, dependent upon choice and route of administration.
• acceptable carriers include, but are not limited to, starch, dextrose, sucrose, lactose, gelatin, agar, stearic acid, magnesium stearate, acacia, and similar carriers.
• liquids include saline, water, edible oils, e.g. peanut and corn.
• the compound and diluent carrier When administered in solid form, the compound and diluent carrier may be in the form of tablets, capsules, powders, lozenges, suppositories prepared by any of the well known methods.
• the mixture of active compound and liquid diluent carrier When given as a liquid preparation, the mixture of active compound and liquid diluent carrier may be in the form of a suspension administered as such.
• the compound is administered in a non-toxic dosage concentration sufficient to inhibit the growth and/or destroy cancer or to destroy protozoal organisms such as malaria and leishmania.
• the actual dosage unit will be determined by the well recognized factors as body weight of the patient and/or severity and type of pathological condition the patient might be suffering with. With these considerations in mind, the dosage unit for a particular patient can be readily determined by the medical practitioner in accordance with the techniques known in the medical arts.
• the compounds of this invention have been prepared by reaction of dihydroartemisinin or dihydroartemistene with a variety of optionally substituted 1,2-, 1-3- or 1,4 glycols under acidic conditions (borontrifluoride etherate) in dry ether followed by chromatography of the reaction mixture to isolate the desired product.
• Optional substitutients include, for example, alkoxy or acyloxy groups.
• the dimers of the present invention can also be prepared by the reaction of dihydroxy ketones such as, for example, dihydroxyacetqne, with DHA or dihydroartemistene followed by reduction of the keto-group and reaction of the hydroxy group formed in the reduction of the ketone with hydroxy reactive compounds such as mono or dicarboxylic acids as their acid halides and acid anhydrides.
• the starting material (dihydroartemisinin) is prepared by sodium borohydrite reduction of the natural product artemisimn (1).
• the latter compoimd is isolated from the leaves of Artemisia annua following the procedures previously described (15, 16).
• the compounds of the invention were tested in the NCI anti- tumor screen and in the anti-malarial and anti-Leishmanial screens. The activities are shown in Tables 1-8 as shown in Figures 2A, 2B, 3 A, 3B, 4A, 4B and Figures 5 to 9.
• IR spectra were obtained using AATI Mattson Genesis Series FTIR. Optical rotations were recorded at ambient temperature using JASCO, DIP-370, digital polarimeter. ID and 2D NMR spectra were obtained on Bruker Avance DRX 500 spectrometers at 500 MHz (1H ) and 125 MHz ( 13 C) or Bruker DRX 400 spectrometer using the solvent peak as the internal standard. HRESIFTMS were obtained using a Bruker Bioapex FT-MS in ESI mode. Low resolution MS were measured on a ThermoQuest aQa LC/MS.
• the preferred method of preparing Compound 4 was to first prepare the ketone precursor through condensation of dihydroxyacetone with dihydroartemisinin in the presence of boron trifluoride-etherate followed by sodium borohydride reduction of the resulting ketone to give Compound 4. This is detailed in the following examples.
• Dihydroartemisinin (284 mg, 1 mmol) and 1,3 -dihydroxyacetone dimer (45.05 mg, 0.25 mmol) were suspended in diethylether (10 mL). To the mixture (cooled to 5°C under argon) was then added 35.5 mg BF 3 .Et 2 O (0.25 mmol, 31 ⁇ L) and the mixture stirred at 5°C for 20 minutes then at room temperature for 1 hr. Workup as usual gave 319 mg of residue.
• Example 5 The fractions with R f values corresponding to the dimer prepared in Example 3 were combined and the solvent evaporated to produce 2.05 g of an oily residue which foamed in vacuum. This material was identical to that prepared under Example 3 (Compound 7).
• Example 5 The fractions with R f values corresponding to the dimer prepared in Example 3 were combined and the solvent evaporated to produce 2.05 g of an oily residue which foamed in vacuum. This material was identical to that prepared under Example 3 (Compound 7).
• Example 5 The fractions with R f values corresponding to the dimer prepared in Example 3 were combined and the solvent evaporated to produce 2.05 g of an oily residue which foamed in vacuum. This material was identical to that prepared under Example 3 (Compound 7).
• a mixture of dihydroartemisinin (10 g, 35.2 mmol) and 1,4-cyclohexanediol (cis and trans mixture) (2 g, 17.2 mmol) were suspended in 260 mL dry ether and 1.11 mL of BF 3 .Et 2 O was added at 0°C under argon. Two additional portions of BF 3 .Et 2 O (1.11 mL each) were added after 1 hr intervals.
• Example 12 The reaction of Example 12 was repeated on a larger scale (starting with 550 mg of Compound 4) where all reactants were scaled up proportionally. Purification of the reaction product in the same manner produced 355 mg of Compound 8 as amorphous white powder with the following spectral characteristics:
• GI50 is the concentration which inhibits 50% of the growth of the cells
• TGI is the concentration causing total growth inhibition
• LC50 is the concentration which kills 50% of the cells.
• NTNPR National Center for Natural Products Research
• Table 6 shows the activity of compounds of this invention against two strains of the malaria parasite (Plasmodiumfalciparum), one is chloroqume sensitive (D6 clone) and one is chloroquine resistant (W2 clone). The cytotoxicity of the compounds was also assessed using Vero cells. The data show that compounds of this invention are more active than chloroquine or artemisinin as anti- malarial drugs.
• Table 7 shows the activity of a selected group of compounds of this invention against the malaria parasite. These are from different synthetic lots than those tested in Table 6 ( Figure 7). This confirms the activity of compounds of this invention as anti-malarial agents.
• Table 8 ( Figure 9) shows the activity of compounds of this invention against the leishmania parasite with activity comparable to that of pentamidine.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Tropical Medicine & Parasitology (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2002
  • 2002-10-15 US US10/271,960 patent/US6790863B2/en not_active Expired - Lifetime
• 2003
  • 2003-10-09 MX MXPA05003920A patent/MXPA05003920A/es active IP Right Grant
  • 2003-10-09 CA CA002501942A patent/CA2501942A1/en not_active Abandoned
  • 2003-10-09 EP EP03774733A patent/EP1551389A4/en not_active Withdrawn
  • 2003-10-09 WO PCT/US2003/032049 patent/WO2004034976A2/en not_active Ceased
  • 2003-10-09 AU AU2003282543A patent/AU2003282543B2/en not_active Ceased
  • 2003-10-09 JP JP2004544832A patent/JP2006504753A/ja active Pending
• 2004
  • 2004-06-21 US US10/872,616 patent/US20040229938A1/en not_active Abandoned
  • 2004-07-21 US US10/896,192 patent/US7098242B2/en not_active Expired - Lifetime

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