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WO1997007790A1 - Compositions pharmaceutiques destinees au traitement de maladies infectieuses - Google Patents

Compositions pharmaceutiques destinees au traitement de maladies infectieuses Download PDF

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WO1997007790A1
WO1997007790A1 PCT/US1996/013672 US9613672W WO9707790A1 WO 1997007790 A1 WO1997007790 A1 WO 1997007790A1 US 9613672 W US9613672 W US 9613672W WO 9707790 A1 WO9707790 A1 WO 9707790A1
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compound
alkyl
haloalkyl
oxidant
alkylamine
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PCT/US1996/013672
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WO1997007790A9 (fr
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Rolf Walter Winter
Michael Kevin Riscoe
David J. Hinrichs
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Interlab Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D311/86—Oxygen atoms, e.g. xanthones
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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

  • TECHNICAL FIELD This invention pertains to therapeutic compositions for the treatment of infectious diseases, including parasitic diseases such as malaria. More specifically, the invention concerns therapeutic compositions that act synergistically with oxidant agents which induce "oxidant stress.”
  • Protozoan parasites cause diseases such as malaria, trypanosomiasis, Chagas' disease, leishmaniasis, giardiasis, and amoebiasis. These and other protozoan parasite diseases have historically occurred in tropical and sub-tropical areas where they cause widespread damage to human populations. Although they receive little attention in the Western world, protozoan diseases affect more people worldwide than diseases brought on by any other biological cause
  • malaria The global importance of just one parasitic protozoan disease, malaria, can be appreciated by considering that historically, almost half of the human race has died from malaria.
  • malaria remains the most destructive single infectious disease in the developing world. It is responsible for more human energy loss, more debilitation, more loss of work capacity, and more economic damage than any other human ailment facing the world today (Heyneman, 1988).
  • the World Health Organization estimates that 1 to 2 million deaths are caused by malaria each year in Africa alone; most of these are children under the age of five (World Health Organization, 1991).
  • World Health Organization 1991
  • over 300 million people worldwide are believed to be chronically-infected, and each year nearly one third of these individuals will suffer acute manifestations of the disease.
  • AIDS Advanced Immunodeficiency Syndrome
  • AIDS depletes the immune system of affected individuals; this allows opportunistic agents which would be defeated by an active immune system to infect AIDS patients.
  • protozoans have emerged as important opportunistic infections in AIDS patients including Cryptosporidium parvum, Entamoeba histolytica, Giardia lamblia, Pneumocystis carinii (which may be a fungal or protozoal pathogen), and Toxoplasmosis gondii.
  • Cryptosporidium parvum Entamoeba histolytica
  • Giardia lamblia Giardia lamblia
  • Pneumocystis carinii which may be a fungal or protozoal pathogen
  • Toxoplasmosis gondii Despite the prevalence and significance of protozoan infections, therapy for these diseases is generally poor or in need of improvement.
  • chemotherapeutic agents used to treat protozoan infections are non-specific cytotoxins that are highly toxic and cause severe side effects in patients.
  • these drugs are used because there are no better alternatives.
  • metromdazole a nitroimidazole
  • the use of this drug is clouded by its mutagenic potential (Campbell, 1986) and its adverse interaction with alcohol.
  • trypanosomiasis and leishmaniasis standard therapies (suramin, melarsoprol, and pentavalent antimonials) are dangerously toxic, occasionally fatal, and often ineffective (Mebrahtu, 1989; Grogl et al., 1992).
  • the anti-malarial oxidant agents are structurally diverse and include seemingly unrelated compounds such as methylene blue, ascorbic acid, Atovaquone ® (a hydroxynapthoquinone), tetracyclines, ketoconazole, artemisinin, and the active metabolites of primaquine, (Vennerstrom et al., 1988). Despite their structural diversity these agents share the ability to produce or liberate free radical oxygen species, or to render the parasites or their host cells more susceptible to oxygen radical attack.
  • Certain of these compounds are currently in use as anti-malarial agents (e.g., artemisinin, tetracycline and primaquine) or are in the later stages of clinical development (e.g., Atovaquone) (Hong et al., 1994; Hudson et al., 1991).
  • anti-malarial agents e.g., artemisinin, tetracycline and primaquine
  • Atovaquone e.g., Atovaquone
  • the present invention is based on the discovery that certain compounds, based on fo ⁇ nula 1 below, act synergistically with oxidant drugs.
  • Formula 1 :
  • A is selected from the group consisting of
  • R is H, OH, alkyl, haloalkyl, alkylamine, or haloalkylamine and N
  • R ' , and R ' 2 are independently either H, OH, alkyl, haloalkyl, alkylamine, or haloalkylamine;
  • R--R- 0 are independently selected from the group consisting of OH, H, halogen,
  • alkyl in any of the named substituents is preferably a C,. 20 alkyl (including straight chain, branched and cyclic alkyls), more preferably a C,. 10 alkyl and most preferably a C,. 5 alkyl.
  • the diphenyl compound 2,3,3',4,4',5'- hexahydroxybenzophenone also known as exifone or adlone
  • fo ⁇ nula 2 acts synergistically with the oxidant drug rufigallol, enhancing anti-malarial activity 350 fold.
  • Rufigallol (l,2,3,5,6,7,-hexahydroxy-9,10-anthraquinone) is shown below as formula 3.
  • the anti-malarial activity of rufigallol is also demonstrated for the first time in this invention.
  • Formula 2 (exifone)
  • the invention comprises the combination of a compound according to formula 1 with an oxidant agent, wherein the oxidant agent is a drug useful in treating an infectious disease.
  • the oxidant agent may be rufigallol and the fo ⁇ nula I compound may be 2,3,4,3',4',5' hexahydroxybenzophenone (such that A is carbonyl, R--R 3 and R 7 -R are hydroxy and R ⁇ R ⁇ and R I0 are hydrogen) (exifone).
  • the combination of the oxidant drug with the formula 1 compound produces a synergistic effect against the infectious agent, allowing lower doses of the oxidant drug to be employed while maintaining or enhancing efficacy, and reducing the likelihood for development of resistance to the oxidant drug.
  • the oxidant agent used in combination with the formula 1 compound need not be a conventional drug used against infectious diseases because formula 1 compounds are effective against infectious agents when activated by a wide range of oxidant agents, including ascorbic acid (vitamin C). Activation may also be achieved by the use of gamma irradiation, an oxidant agent known to kill parasitized cells as a result of oxygen radical production. Accordingly, in another embodiment, the invention comprises the combination of the compound according to formula 1 with an oxidant compound, such as ascorbic acid.
  • the oxidant agent may be ascorbic acid (vitamin C) and the formula I compound may be 2,3,4,2',3',4' hexahydroxybenzophenone (isofone).
  • Another aspect of the invention is the use of rufigallol (1,2,3,5,6,7,-hexahydroxy- 9,10-antnraquinone) and certain analogs of this compound as an anti-malarial drug.
  • Fig. 1 is a graphical representation of the anti-malarial activity of rufigallol against the mefloquine-resistant D6 strain of P. falciparum.
  • Fig. 2 is an isobolar analysis of the synergistic drug combination of rufigallol and exifone.
  • Fig. 3 is an isobolar analysis of the synergistic combination of ascorbic acid and exifone.
  • oxygen radicals refers to free radicals containing oxygen, including superoxide radicals and hydroxy radicals.
  • Oxidant compound an oxidant compound is one that produces oxygen radicals, particularly when heated or when reacted with other compounds.
  • the oxidant compounds described herein produce oxygen radicals in or on the body of an animal when administered to the animal.
  • An example of an oxidant compoimd is ascorbic acid, which yields oxygen radicals in the presence of oxygen and a transition metal.
  • Oxidant drug is a pharmaceutical or therapeutic substance that is used to treat a particular condition in animals, such as an infectious disease, wherein the drug either causes enhanced production of oxygen radicals inside cells, or renders cells more susceptible to attack by oxygen radicals, or is capable of oxidizing another compound.
  • An example of an oxidant drug is tetracycline.
  • Oxidant agent a term encompassing oxidant compoimds, oxidant drugs and other agents having the ability to produce or liberate free radical oxygen species or to render parasites or their host cells more susceptible to oxygen radical attack, or is capable of oxidizing another compound.
  • Ascorbic acid, hydrogen peroxide and tetracycline are oxidant agents, as is gamma radiation. Indeed, the "respiratory burst" of a macrophage or granulocyte is also an oxidant.
  • anthraquinones were purchased from the Aldrich Chemical Company (Milwaukee, Wisconsin): l,5-dihydroxy-9,10-anthraquinone; 2,6-dihydroxy-9,10-anthraquinone; and l,2,4-trihydroxy-9,10-anthraquinone.
  • methyl ethers of rufigallol and otiier selected anthraquinones were synthesized from the free hydroxy compounds by refluxing in the presence of potassium carbonate in acetone with an excess of dimethyl sulfate.
  • Rufigallol-hexamethyl ether was converted to the dibromide form with trifluoroacetyl-hypobromite.
  • Hexaacetyl rufigallol (1,2,3,5,6,7 hexaacetoxy-9, 10- anthraquinone) was obtained by treatment of rufigallol with acetic anhydride.
  • Octahydroxy-9,10-anthraquinone was synthesized according to Georgievics, 1911.
  • the flask which was placed in a sand bath on a hot plate, was brought to a temperature of 120°C. After this period, clumps formed in the flask. The temperature of the sand bath was gradually raised to 150°C and this temperature was maintained for an additional 30 minutes. During this elevation in temperature, at ca. 150°C, a dark syrup formed which could be stirred. After allowing the reaction mixture to cool to room temperature, 100ml of distilled water was added and the resulting solution was heated until ebullition. Upon cooling, the dark clear solution developed a thick crystalline precipitate. The material was re-crystallized three times from 400ml of water.
  • Exifone is also available commercially from Pfaltz and Bauer Inc., Waterbury, CT, and Acros Organics, Pittsburgh, PA. Exifone and isofone may also be synthesized by the methods described in Grover et al. (1956).
  • the D6 strain of P. falciparum was cultured in Group A + human erythrocytes and suspended at a 3.3% hematocrit in RPMI-1640 (containing 4g/L glucose, 50mg/L gentamicin and
  • test compounds 10% group A + human serum), buffered with 25mM HEPES and 25 mM NaHC0 3 (Larrey, 1989). Cultures were maintained at 37°C in a gas mixture of 3% oxygen, 5% C0 2 , and 92% nitrogen.
  • In vitro anti-malarial activity of test compounds was measured by the [ 3 H]-ethanolamine inco ⁇ oration method as described in Elabbadi et al., 1992, with minor modifications. Briefly, experiments were conducted in 96 well plates in a total volume of 200 ⁇ l at a final red blood cell concentration of 3.3% (v/v). An initial parasitemia of 0.2 to 0.5% was attained by addition of normal uninfected red cells.
  • Radiolabelled ethanolamine was added after 48 hours of incubation and the experiment was terminated after 72 hours by collecting the cells onto glass fiber filters with an automated multiwell harvester.
  • Stock solutions of exifone and the various benzophenones were made by dissolving each compound into dimethylsulfoxide (DMSO) at lOmM. (Ethanol, dimethylformamide, or propylene glycol could be substituted for DMSO without altering any of the results). All dilutions were made into medium containing 10% human serum. The final concentration of DMSO never exceeded 1 % (v/v) which control experiments demonstrated was not sufficient to influence the rate of radiolabel incorporation into parasitized erythrocytes. The concentration of drug giving 50% inhibition of label incorporation (IC 50 ) relative to control (i.e., drug-free) conditions was calculated from the dose-response curve. 3. Examples of oxidant drugs
  • Oxidant sensitivity of malaria infected erythrocytes has been recognized for some time. This sensitivity likely arises from the generation of oxygen radicals by the parasite itself and from a weakening of the oxidant defense mechanisms of the host erythrocyte by the parasite. Oxidant drugs such as the hydroxynaphthoquinones exploit this weakness by causing the formation of toxic oxygen radicals (and hence additional oxidant "stress") inside parasitized cells.
  • oxidant anti-malarial drugs are structurally diverse but share the ability to liberate or cause the enhanced production of intracellular free radical oxygen species or to render parasitized cells more susceptible to oxygen radicals.
  • Putative oxidant anti-malarial drugs include methylene blue, ascorbic acid, tetracycline, ketoconazole and the active metabolite of primaquine.
  • One group of oxidant anti-malarial drugs that has received considerable recent attention is the hydroxynaphthoquinones. i. Hydroxynaphthoquinones
  • Atovaquone ® a new hydroxynaphthoquinone, termed Atovaquone ® .
  • This drug appears to block dihydro-orotate dehydrogenase, effectively preventing pyrimidine biosynthesis in the malarial parasite which does not possess the biochemical machinery for salvaging pyrimidines (Sherman, 1979).
  • another site of action of Atovaquone ® appears to be the diversion or blockage of electrons which normally flow from dihydro-orotate dehydrogenase through a ubiquinone-linked electron transport system (Fry et al., 1992).
  • Atovaquone ® may act as a catalytic oxidizing agent capable of undergoing cyclic one-electron oxidation-reduction reactions.
  • Such futile "redox-cycling" would lead to the catalytic reduction of oxygen to superoxide ( * 0 2 -) at the expense of reducing equivalents such as NAD(P)H (Vennerstrom et al., 1988).
  • the reactive superoxide radical anion could be converted to the highly-reactive hydroxyl radical (*OH) via the metal-catalyzed Fenton reaction (Golenser et al., 1991). Both superoxide and hydroxyl radicals have the capacity to modify proteins, lipids, and nucleic acids of the parasite and the red cell host, thereby killing the parasite.
  • Anthraquinone derivatives have the capacity to modify proteins, lipids, and nucleic acids of the parasite and the red cell host, thereby killing the parasite.
  • One aspect of the present invention is the discovery that certain anthraquinone derivatives, and in particular l,2,3,5,6,7,-hexahydroxy-9,10-anthraquinone, also known as rufigallol, have potent anti-malarial activity.
  • rufigallol is noted to be an extremely potent anti-malarial agent. As shown in Table 1, the concentration of rufigallol required to inhibit the growth of P. falciparum by 50% (i.e., to produce an IC 50 ) is approximately 35nM. Chloroquine, a standard anti-malarial agent has an IC 50 under these test conditions of 20nM. Nicoigallol is equally effective against the multi-drug resistant form of P. falciparum strain W2 (data not shown).
  • the tetrahydroxy- and octahydroxy-derivatives of rufigallol are moderately effective, exhibiting IC 50 values of 300nM and 800nM, respectively.
  • the hexacetoxy derivative of rufigallol is also moderately effective, having an IC 50 value of 350nM.
  • the hexamethyl ether form is significantly less potent (IC 50 of >5000nM, data not shown).
  • Exifone represented in Table 1 as a rufigallol analog lacking one of the keto moieties and thus the internal aromatic ring, exhibits only weak antiplasmodial activity (IC 50 of approximately 4100nM).
  • Chloroquine a standard 20 antimalarial agent
  • telomeres The anti-malarial activity of rufigallol against the D6 strain of P. falciparum is shown in Fig. 1. As noted above, rufigallol exhibits an IC 50 for P. falciparum infected erythrocytes of roughly 35nM.
  • Toxicity tests were carried out to determine the effects of rufigallol on the growth and differentiation of normal human bone marrow stem cells in vitro.
  • human granulocyte-macrophage progenitor cells were grown in agar with a standard source of colony-stimulating activity (Burgess et al., 1986). Tne results are shown below in Table 2, expressed as the average colony count of colony forming units of granulocyte/macrophage (CFU- GM) after incubation at 37°C for 10 days in a humidified 5% C0 2 incubator with rufigallol.
  • X and X' are the same or different and are independently selected from the group consisting of alkyl, haloalkyl, diaminoalkyl, haloaminoalkyl, amino, nitro and azido.
  • an "alkyl” is preferably a C,. 20 straight chain, branched or cyclic alkyl, and more preferably a C s alkyl.
  • a patient suffering from malaria can be treated by administration of rufigallol or an analog of rufigallol according to the formula above.
  • the compound may be administered by any known administration technique, for example orally (such as in the form of a pill) or by intramuscular or intravascular injection.
  • the compound is combined with a pharmaceutically acceptable excipient prior to administration.
  • a patient is preferably given a dose of rufigallol or a rufigallol analog, as discussed above, in the range of 10-2,000 mg kg/day.
  • the dosage will vary depending on known factors, such as the age and condition of the patient. It will be appreciated that a therapeutically effective dosage is one which preferably results in complete remission of the malaria. However, a therapeutically effective dosage also encompasses those dosages which slow or limit the further development of the malarial infection.
  • hydroxyanthraquinones such as rufigallol
  • rufigallol is futile redox cycling leading to the catalytic reduction of oxygen to superoxide and, ultimately to the formation of hydroxyl radicals.
  • DFMO difluoromethylornithine
  • melarsoprol and stibogluconate for the treatment of leishmaniasis and trypanosamiasis
  • metronidazole for giardiasis and ameobiasis among others
  • buparvaquone for leishmaniasis
  • artemisinin for malaria
  • hydrogen peroxide and benzoyl peroxide for bacterial infections
  • ascaridole and bischloroethyl nitrosurea for helminth infections.
  • Other drugs, such as doxorubicin for cancer treatment also have oxidant activity.
  • oxidant drugs Apart from drugs that have oxidant activity, many other compounds are known to possess oxidant activity. Such compounds include: isoascorbic acid, quercetin, and alloxan. 5. Potentiation of oxidant drugs bv formula 1 compounds
  • fo ⁇ nula 1 compounds to potentiate the efficacy of oxidant drugs is illustrated by the combination of the formula 1 compound exifone with the oxidant anti-malarial drug rufigallol.
  • the potentiation of rufigallol by exifone was demonstrated by combining the two compounds in varying concentrations and utilizing the inco ⁇ oration of radioactive ethanolamine into parasite lipids as described in Materials and Methods as an objective measure of parasite growth. These experiments were initiated with synchronized mature trophozoites. Mature trophozoites were produced by incubating synchronized ring forms (selected by the sorbitol lysis technique described by Lambros et al., (1979)) for 16-24 hours. Standard isobolar analysis was employed for evaluating synergism between the drug combinations.
  • Table 3 shows the drug concentrations of rufigallol and exifone required to achieve an ICso (alone or in combination).
  • striking synergy was observed between rufigallol and exifone. This synergy is shown in the graphical representation of these experiments shown in Fig. 2.
  • the striking synergy is indicated in Fig. 2 by the downward deviation of the values relative to the theoretical line of addition.
  • the combination of InM rufigallol with lOnM exifone delivered the same growth inhibitory effect as either drug alone at their respective IC 50 dose.
  • an aspect of the present invention is the discovery that oxidant drugs such as those discussed above act synergistically with fo ⁇ nula 1 compounds such as 2,3,4,3',4',5'-hexahydroxybenzophenone (exifone).
  • fo ⁇ nula 1 compounds such as 2,3,4,3',4',5'-hexahydroxybenzophenone (exifone).
  • exifone 2,3,4,3',4',5'-hexahydroxybenzophenone
  • Activation of formula 1 compounds is shown above to occur in the presence of oxidant drugs, such as rufigallol.
  • the oxidant activation of formula 1 compounds may also be achieved through the action of other oxidant compounds.
  • data showing the activation of formula 1 compounds by ascorbic acid (vitamin C) is presented below.
  • Candle jar (- 15% 0 2 ) 0.72 ⁇ 0.3 0.095 ⁇ 0.05 a IC 50 values represent the mean ⁇ standard deviation from at least 5 separate experiments each performed in duplicate.
  • exifone and rufigallol were no more toxic in these mammalian cell systems than the sum of their respective inhibitory activities.
  • malaria parasites are extremely susceptible to the inhibitory effects of exifone and rufigallol in combination, mammalian cells appear to be much less affected. This indicates that a therapeutic drug combination of exifone and an oxidant drug may exhibit a high therapeutic index.
  • compositions comprising a fo ⁇ nula 1 compound and an oxidant compound.
  • the invention will be better understood by reference to the following examples, which are intended to merely illustrate the best mode now known for practicing the invention. The scope of the invention is not to be considered limited thereto, however.
  • A is selected from the group consisting of
  • R is OH, alkyl, haloalkyl, alkylamine, or haloalkylamine
  • R • • and R ⁇ 2 are independently either H, OH, alkyl, haloalkyl, A I A alkylamine, or haloalkylamine;
  • A can be carbonyl, oxygen, nitrogen (substituted or unsubstituted), sulphur (substituted or unsubstituted) or carbon (substituted or unsubstituted));
  • R.-R 10 are independently selected from the group consisting of OH, H, halogen, OAc,
  • R, R 5 , Rg and R 10 is OH, NH 2 , N0 2 or OAc and at least one other of R protagonist R j ,
  • EXAMPLE 2 Scope of oxidant agents and methods for determining oxidant activity
  • the present invention lies in the combination of a formula 1 compound with an oxidant agent.
  • any oxidant agent may be used to activate the formula 1 compound.
  • a preferred embodiment will be the combination of a formula 1 compound together with a known oxidant drug that is conventionally used to treat the disease, such as Atovaquone ® .
  • Oxidant drugs either directly or indirectly cause enhanced formation of oxygen radicals in living systems.
  • the determination of whether a drug or other compound has oxidant activity may be made by ascertaining whether the biological activity of the drug or compound can be neutralized by an anti-oxidant agent (e.g., ⁇ -tocopherol or dithiothreitol).
  • an anti-oxidant agent e.g., ⁇ -tocopherol or dithiothreitol.
  • a number of other methods of evaluating the ability of a drug to induce the formation of oxygen radicals in living cells are also known. Any of these known methods may be utilized to determine whether a particular drug or compound has oxidant activity, such that it may be used in combination with formula 1 compounds in practicing the present invention.
  • Marva et al. (1992) describe a method of determining whether a drug or other compound has oxidant activity by exposing cells to salicylic acid (ortho-hydroxybenzoic acid) in the presence of the suspected oxidant drug and following the conversion of salicylic acid to the corresponding 2, 3 and 2,5-dihydroxy-benzoic acid by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • living cells produce a background level of oxygen radicals resulting in the detection of small quantities of the two dihydroxy compounds.
  • An oxidant drug therefore can be expected to increase the rate of formation of hydroxyl radicals leading to a corresponding increase in the levels of the 2,5 and 2,3-dihydroxy salicylic acid derivatives.
  • the method is performed by the addition of lOmM salicylic acid to living cells in the presence or absence of a suspected "oxidant drug" under conditions in which the drug exerts growth inhibitory activity.
  • suspensions of cells are centrifuged and the resulting pellets and supernatant are separated. Both fractions are treated with an equal volume of trichloroacetic acid (TCA) to precipitate macromolecules which are separated from the supernatant by centrifugation at 12,000g for 10 min.
  • TCA trichloroacetic acid
  • the supernatant, containing salicylic acid and its dihydroxy derivatives is dried in vacuo in a vacuum centrifuge. The dried residue is dissolved in water and applied to an HPLC.
  • a Lichrospher 100 (reverse phase, C 18 , RP-18, 5 ⁇ m particle size) is used for separation of salicylic acid and its hydroxylation products.
  • the mobile phase contains 0.03M citric acid, 0.03M acetic acid, 1 % methanol (vol), and 0.28 g/1 sodium azide (adjusted to pH 3.6).
  • the flow rate is lml/min.
  • the biological samples are compared to standard curves of 2,5-dihydroxy and 2,3- dihydroxybenzoic acid using either an electrochemical or uv detector. This method is also described in Halliwell et al. (1988).
  • An alternative method for determining the level of "oxidant stress" (the relative level of oxygen centered radicals) in a living system is to monitor the presence of malondialdehyde (MDA). This method is known as the malondialdehyde test (or the deoxyribose assay).
  • Malondialdehyde arises from the decomposition of deoxyribose (or DNA) by hydroxyl radicals.
  • the product of this decomposition, MDA will react with thiobarbituric acid (TBA) to form a colored adduct which can be detected spectroscopically.
  • TSA thiobarbituric acid
  • the precipitable material is removed by centrifugation at 980g and 0.9 ml of the supernatant is incubated with 0.3 ml of 59mM thiobarbituric acid for 25 min at 100°C.
  • the absorbance is determined according to the formula x 156 and related to the number of cells or erythrocytes in the original suspension. Additional sensitivity can be accomplished by taking advantage of the fact that the adduct is fluorescent and can be detected by standard fluorometry with an excitation wavelength of 360nm and emission wavelength of 440nm.
  • the treatment of infectious diseases would be achieved by the administration of a formula 1 compound to a patient in combination with an oxidant agent.
  • the formula 1 compound and the oxidant agent may be combined in a preparation prior to administration, or, they may be administered sequentially (preferably within 24 hours of each other).
  • the formula 1 compound (either alone or in combination with an oxidant agent) will preferably be formulated with a pharmaceutically acceptable excipient prior to administration.
  • the formula 1 compound will be administered in a therapeutically effective dosage of 20-2,000 mg/kg/day and the oxidant agent will be administered in a therapeutically effective dosage of 0.1-2,000 mg/kg/day.
  • the dosage chosen will depend on the particular formula 1 compound chosen and the particular oxidant agent chosen, as well as the usual clinical factors (age of patient, severity of infection, whether other medicines are being administered etc.)
  • a "therapeutically effective dosage” is a dosage that results in complete remission of the disease.
  • a therapeutically effective dosage also encompasses dosages which slow or limit the further development of the disease process or which inhibit the growth of the disease pathogen.
  • Administration of the formula 1 compound and oxidant agent may be by any conventional means, including oral administration, intravenous injection and intramuscular injection.
  • a patient suffering from malaria caused by P. falciparum could be treated by a single oral administration of a combined preparation of exifone and rufigallol.
  • the preferred dosage range of these components would be 20-2,000 mg/kg (exifone) and
  • a patient suffering from malaria caused by P. falciparum could be treated by a oral administration of exifone followed within 24 hours by oral administration of rufigallol, both in the same dosage range as described above.
  • kits containing comprising a formula 1 compound and an oxidant agent.
  • a kit may be used to kill or inhibit the growth of P. falciparum in vitro, as well as providing a convenient package for use in administering the compounds to patients suffering from an infectious disease.
  • Fieser L.F., M.Z. Nazer, S. Archer, D.A. Berberian, and R.G. Slighter (1967b), Naphthoquinone antimalarials.
  • XXX 2-Hydroxy-3-[.omega.-(-adamentyl)alkyl]-l,4- naphthoquinones, J. Med. Ehcm.. .10:517-21.
  • Fieser L.F., J.P. Schirmer, S. Archer, R.R. Lorenz, and P.I. Pfaffenbach (1967c),

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

On décrit la combinaison synergétique de certains composés diphényle pontés et d'agents oxydants destinée à traiter des maladies infectieuses. Ces composés diphényle sont représentés par exemple par 2,3,4,3',4',5'-hexahydroxybenzophénone.
PCT/US1996/013672 1995-08-28 1996-08-23 Compositions pharmaceutiques destinees au traitement de maladies infectieuses WO1997007790A1 (fr)

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* Cited by examiner, † Cited by third party
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EP0888052A1 (fr) * 1996-03-20 1999-01-07 Interlab Corporation Analogues de xanthone pour traiter des maladies infectieuses
WO2001098279A2 (fr) * 2000-06-20 2001-12-27 Pharmacia & Upjohn Company Bis-arylsulfones
US6506798B1 (en) 1997-07-01 2003-01-14 Warner-Lambert Company 4-Arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective MEK inhibitors
US6525094B1 (en) 1999-06-01 2003-02-25 The University Of Texas Southwestern Medical Center Method of treating hair loss using diphenylether derivatives
US6586592B2 (en) 2000-06-20 2003-07-01 Pharmacia & Upjohn Company Bis-arylsulfones
US6646005B1 (en) 1999-06-01 2003-11-11 The University Of Texas Southwestern Medical Center Method of treating hair loss using sulfonyl thyromimetic compounds
US6680344B1 (en) 1999-06-01 2004-01-20 The University Of Texas Southwestern Medical Center Method of treating hair loss using diphenylmethane derivatives
US6770778B2 (en) 2002-01-23 2004-08-03 Pfizer Inc N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US6891066B2 (en) 2002-01-23 2005-05-10 Warner-Lambert Company N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US7001905B2 (en) 2000-03-15 2006-02-21 Warner-Lambert Company Substituted diarylamines as MEK inhibitors
US7544497B2 (en) 2003-07-01 2009-06-09 President And Fellows Of Harvard College Compositions for manipulating the lifespan and stress response of cells and organisms
US20120034176A1 (en) * 2009-04-08 2012-02-09 Pierre Fabre Dermo-Cosmetique Sulphurated derivatives of resorcinol, preparation of same and cosmetic uses thereof
US8242171B2 (en) 2003-12-29 2012-08-14 President And Fellows Of Harvard College Method for reducing the weight of a subject or inhibiting weight gain in a subject
US8841477B2 (en) 2004-01-20 2014-09-23 Brigham Young University Sirtuin activating compounds and processes for making the same
US8846724B2 (en) 2003-12-29 2014-09-30 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US9241916B2 (en) 2005-06-14 2016-01-26 President And Fellows Of Harvard College Cognitive performance with sirtuin activators
US20180021269A1 (en) * 2015-04-02 2018-01-25 Guangzhou Jtreat Biosci. Ltd. Uses of hydroxybenzophenone in preparation of antiviral and antitumor drugs

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US4670265A (en) * 1983-07-22 1987-06-02 Sydiskis Robert J Aloe emodin and other anthraquinones and anthraquinone-like compounds from plants virucidal against herpes simplex viruses

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US3050440A (en) * 1960-10-13 1962-08-21 Velsicol Chemical Corp New fungicidal compositions of matter
US3947594A (en) * 1973-05-07 1976-03-30 Gaf Corporation 4-Halo-1-hydroxyanthraquinone containing fungicidal composition
US4311710A (en) * 1980-01-08 1982-01-19 Eli Lilly And Company Anticoccidial formulation and method
US4670265A (en) * 1983-07-22 1987-06-02 Sydiskis Robert J Aloe emodin and other anthraquinones and anthraquinone-like compounds from plants virucidal against herpes simplex viruses

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0888052A4 (fr) * 1996-03-20 2002-05-22 Interlab Corp Analogues de xanthone pour traiter des maladies infectieuses
EP0888052A1 (fr) * 1996-03-20 1999-01-07 Interlab Corporation Analogues de xanthone pour traiter des maladies infectieuses
US6506798B1 (en) 1997-07-01 2003-01-14 Warner-Lambert Company 4-Arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective MEK inhibitors
US6646005B1 (en) 1999-06-01 2003-11-11 The University Of Texas Southwestern Medical Center Method of treating hair loss using sulfonyl thyromimetic compounds
US6680344B1 (en) 1999-06-01 2004-01-20 The University Of Texas Southwestern Medical Center Method of treating hair loss using diphenylmethane derivatives
US6525094B1 (en) 1999-06-01 2003-02-25 The University Of Texas Southwestern Medical Center Method of treating hair loss using diphenylether derivatives
US7001905B2 (en) 2000-03-15 2006-02-21 Warner-Lambert Company Substituted diarylamines as MEK inhibitors
US6579870B2 (en) 2000-06-20 2003-06-17 Pharmacia & Upjohn Company Bis-arylsulfones
US6586592B2 (en) 2000-06-20 2003-07-01 Pharmacia & Upjohn Company Bis-arylsulfones
WO2001098279A3 (fr) * 2000-06-20 2002-08-01 Upjohn Co Bis-arylsulfones
WO2001098279A2 (fr) * 2000-06-20 2001-12-27 Pharmacia & Upjohn Company Bis-arylsulfones
US6770778B2 (en) 2002-01-23 2004-08-03 Pfizer Inc N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US6891066B2 (en) 2002-01-23 2005-05-10 Warner-Lambert Company N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US7078438B2 (en) 2002-01-23 2006-07-18 Warner-Lambert Company N-(4 substituted phenyl)-anthranilic acid hydroxamate esters
US7544497B2 (en) 2003-07-01 2009-06-09 President And Fellows Of Harvard College Compositions for manipulating the lifespan and stress response of cells and organisms
US8242171B2 (en) 2003-12-29 2012-08-14 President And Fellows Of Harvard College Method for reducing the weight of a subject or inhibiting weight gain in a subject
US8846724B2 (en) 2003-12-29 2014-09-30 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US9597347B2 (en) 2003-12-29 2017-03-21 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US8841477B2 (en) 2004-01-20 2014-09-23 Brigham Young University Sirtuin activating compounds and processes for making the same
US9241916B2 (en) 2005-06-14 2016-01-26 President And Fellows Of Harvard College Cognitive performance with sirtuin activators
US20120034176A1 (en) * 2009-04-08 2012-02-09 Pierre Fabre Dermo-Cosmetique Sulphurated derivatives of resorcinol, preparation of same and cosmetic uses thereof
US8859819B2 (en) * 2009-04-08 2014-10-14 Pierre Fabre Dermo-Cosmetique Sulphurated derivatives of resorcinol, preparation of same and cosmetic uses thereof
KR101728178B1 (ko) * 2009-04-08 2017-04-18 삐에르화브르데르모-코스메띠끄 레조르시놀 황화 유도체, 이의 제조방법 및 이의 화장품 용도
US20180021269A1 (en) * 2015-04-02 2018-01-25 Guangzhou Jtreat Biosci. Ltd. Uses of hydroxybenzophenone in preparation of antiviral and antitumor drugs
US20190209490A1 (en) * 2015-04-02 2019-07-11 Guangzhou Jtreat Biosci. Ltd. Method for preventing or treating viral infection and tumor
US10716769B2 (en) * 2015-04-02 2020-07-21 Guangzhou Jtreat Biosci. Ltd. Method for preventing or treating viral infection and tumor

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