WO2015095970A1 - Conjugués acide lipoïque-édaravone et leurs utilisations - Google Patents

Conjugués acide lipoïque-édaravone et leurs utilisations Download PDF

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Publication number
WO2015095970A1
WO2015095970A1 PCT/CA2014/051261 CA2014051261W WO2015095970A1 WO 2015095970 A1 WO2015095970 A1 WO 2015095970A1 CA 2014051261 W CA2014051261 W CA 2014051261W WO 2015095970 A1 WO2015095970 A1 WO 2015095970A1
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Prior art keywords
compound
linkage
edaravone
disease
lipoic acid
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PCT/CA2014/051261
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English (en)
Inventor
Tarek Saleh
Bobby KHAN
Inan KUCUKKAYA
Alaa ABD-EL-AZIZ
Barry CONNELL
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University Of Prince Edward Island
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Publication of WO2015095970A1 publication Critical patent/WO2015095970A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms

Definitions

  • the present invention relates generally to conjugates of lipoic acid and edaravone, compositions comprising these compounds, and compounds that may be used as neuroprotectants, or in the prevention or treatment of diseases, disorders, or conditions related to oxidative stress, neurodegenerative diseases, stroke, ischemia, and/or reperfusion injury.
  • ROS reactive oxygen species
  • I/R free radicals generated during cerebral ischemia/reperfusion
  • Lipoic acid for example a-lipoic acid, is an antioxidant with strong free radical scavenging abilities (Biewengo et al., 1997).
  • LA Lipoic acid
  • DL mixed RS
  • Lipoic acid is a naturally occurring eight-carbon fatty acid that is synthesized by plants and animals, including humans. The natural configuration is "R", although the mixed RS (DL) lipoic acid is extensively used commercially. (Biewenga et al., 1997) It is chemically named 1 ,2-dithiolane-2-pentanoic acid (also referred to as thioctic acid). It is an important cofactor in the mitochondrial respiratory chain and serves as a cofactor for many enzyme reactions.
  • LA has also been shown to have a neuroprotective effect.
  • Connell et al., 2011; Richard et al., 2011 LA has a very short half-life in the bloodstream as it undergoes rapid metabolism in the liver.
  • Dosing 3-4 times daily is necessary to accomplish reasonable blood levels. This rather limited bioavailability of LA could be extended by suitably incorporating chemical groups to attenuate the metabolic process in the liver.
  • Oxidative mechanisms are associated with central nervous system disorders such as stroke and dementia. Increased production of reactive oxygen species (ROS) has been implicated in various chronic diseases, including neurodegenerative diseases (Farooqui et al., 2000). Oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, fibrosis, angiogenesis, and rarefaction (Victor et al., 2009). There continues to be a need for additional neuroprotectants, and methods to treat oxidative stress, stroke, ischemia, and/or reperfusion injury. SUMMARY OF THE INVENTION
  • An object of the invention is to provide covalent conjugates of lipoic acid and edaravone.
  • an object of the invention is also to provide compounds that are useful, for example, for reducing or preventing cell damage caused by reactive oxygen species (ROS), or which can be used for treating diseases, disorders, or conditions related to oxidative stress.
  • ROS reactive oxygen species
  • X represents an ester linkage, thioester linkage, amide linkage, alkyl linkage, -NH- or - N(alkyl)- linkage, ether linkage, thioether linkage, or disulfide linkage; n is 1, 2, 3, 4, 5 or 6; m is 0, 1 or 2; and
  • R 1 and R 2 are independently selected from the group consisting of H, Ci_ 6 alkyl and C(0)Ci -6 alkyl, or
  • R 1 and R 2 are absent and the two sulfur atoms are bonded together to form, together with the carbon atoms between them, a 4, 5 or 6 membered ring, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the compound may be represented by formula (la) or (lb):
  • the Edaravone derivative may be a derivative as shown in Table 1.
  • n may be 3, 4 or 5, and in further embodiments, n is 4.
  • n may be 1 or 2, and in specific embodiments m is 2.
  • R 1 and R 2 may independently be H, or C(0)Ci_ 4 alkyl, and for example, may independently be H, CH 3 or C(0)CH 3 . In further non-limiting embodiments, R 1 and R 2 are the same, and may both be hydrogen.
  • R 1 and R 2 may both be absent, and the two sulfur atoms bonded together to form, together with the carbon atoms between them, a 5 or 6 membered ring. In a non-limiting embodiment, the two sulfur atoms are bonded together to form a 5 membered ring.
  • the compound may have the formula:
  • a compound, or a pharmaceutically acceptable salt thereof that is a covalent conjugate between lipoic acid (LA), or a derivative thereof, and edaravone, or a derivative thereof, wherein the conjugate linkage is an ester linkage, thioester linkage, amide linkage, alkyl linkage, -NH- or -N(alkyl)- linkage, ether linkage, thioether linkage, or disulfide linkage.
  • composition comprising at least one compound as described above, and a pharmaceutically acceptable carrier.
  • a method for preventing or treating a disease, disorder, or condition related to oxidative stress which comprises administering a compound or pharmaceutical composition as described above to a subject in need thereof.
  • the disease, disorder or condition may be a cerebral disease, disorder, or condition, or a heart, kidney, liver, or skeletal muscle disease, disorder, or condition.
  • the disease, disorder, or condition may include stroke, ischemia, reperfusion injury, neurodegenerative disease, inflammatory disease, neurovascular disorder, dementia, Multiple Sclerosis, Parkinson's disease, myocardial infarction, heart failure, renal failure, collagen vascular disease, metabolic disorder, cardiac disease, or combinations thereof.
  • an anti-thrombolytic drug may also be provided for co-administration with the compound or pharmaceutical composition described above.
  • the anti-thrombolytic drug may be streptokinase, tPA (tissue plasminogen activator), or rtPA (Recombinant Tissue Plasminogen Activator).
  • the above described compound and composition may also be used in methods for reducing or preventing cell damage caused by reactive oxygen species (ROS).
  • the reducing or preventing cell damage may occur in vitro, or may occur in vivo.
  • LA lipoic acid
  • edaravone of the formula:
  • the process comprises reacting edaravone, of the formula:
  • lipoic acid in the presence of a coupling agent, under conditions effective to form an ester linkage between the edaravone and lipoic acid moieties and form said LA-edaravone conjugate, in particular, between the oxygen of the carbonyl group of edaravone and the carboxyl group of lipoic acid.
  • the coupling agent may be a carbodiimide, for example, ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC).
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • FIGURE 1 Synthesis of a lipoic acid-edaravone conjugate (UPEI-300) from edaravone and lipoic acid.
  • edaravone Sigma-Aldridge; St. Louis, MO, USA
  • DMAP dimethylaminopyridine
  • LA 0.5 mmol lipoic acid
  • DCC Dicyclohexylcarbodiimide
  • FIGURE 2 Effect of UPEI-300 on LDH release from cultured neuronal cells normalized to vehicle-treated controls and expressed as a percent cytotoxicity. Each bar represents the mean ⁇ S.E.M. for 6 separate experiments with 4-5 replicates per treatment/plate. Asterisk denotes significantly different from vehicle-treated OGD group (Veh; p ⁇ 0.05);
  • B Effect of UPEI-300 administered 30 minutes prior to permanent (6 hour) MCAO on infarct volume (mm 3 ) calculated from TTC stained, 1 mm thick coronal slices throughout the extent of the infarct. Each bar represents the mean ⁇ S.E.M; and
  • FIGURE 4 Effect of UPEI-300 or vehicle (50 % EtOH) administered 15 minutes prior to the beginning of reperfusion (-15), immediately prior to suture removal and the start of reperfusion (0), or 30, 60 or 90 minutes following reperfusion on infarct volume (mm 3 ).
  • Each bar represents the mean ⁇ S.E.M. and * indicates significance (p ⁇ 0.05) from the vehicle control group.
  • LA lipoic acid
  • edaravone edaravone
  • covalent linkages may include those comprising or consisting of an ester linkage, thioester linkage, amide linkage, alkyl linkage (such as Ci_ 6 alkyl, or -CH 2 -), -NH- or -N(alkyl)- linkage, ether linkage, thioether linkage, disulfide linkage, biocleavable linkage, biocleavage-resistant linkage, or other appropriate linkage as will be known to one of skill in the art.
  • the covalent linkage may replace or modify a portion of the lipoic acid and/or edaravone structure.
  • a covalent linkage between lipoic acid (LA), or a derivative thereof, and Edaravone, or a derivative thereof may be any biocleavage resistant linkage having a suitable metabolic profile such that the lipoic acid and Edaravone components of the conjugate remain linked in vitro or in vivo for at least a brief duration of time.
  • the covalent conjugate between LA and edaravone may be a compound of Formula (I):
  • X represents an ester linkage, thioester linkage, amide linkage, alkyl linkage, -NH- or - N(alkyl)- linkage, ether linkage, thioether linkage, or disulfide linkage; n is 1, 2, 3, 4, 5 or 6; m is 0, 1 or 2; and
  • R 1 and R 2 are independently selected from the group consisting of H, Ci_ 6 alkyl and C(0)Ci -6 alkyl, or
  • R 1 and R 2 are absent and the two sulfur atoms are bonded together to form, together with the carbon atoms between them, a 4, 5 or 6 membered ring, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the covalent conjugate between LA and edaravone may be represented by formula (la) or (lb):
  • the covalent conjugate between LA and ederavone may be:
  • the LA-edaravone conjugate may be synthesized from edaravone (or an appropriate derivative thereof) and lipoic acid (or an appropriate derivative thereof) using any appropriate coupling agent as will be known to those of skill in the art.
  • the coupling agent may be a carbodiimide.
  • the carbodiimide may be ⁇ , ⁇ '- dicyclohexylcarbodiimide (DCC).
  • lipoic acid in the presence of a coupling agent, under conditions effective to form an ester linkage between the edaravone and lipoic acid moieties and form the the LA-edaravone conjugate.
  • the compounds provided herein may be used as antioxidants.
  • compounds provided herein may be used for research or therapeutic applications.
  • the research or therapeutic applications may involve oxidative stress and/or reactive oxygen species.
  • the compounds and/or compositions provided herein may be used for the prevention or treatment of diseases, disorders, or conditions related to oxidative stress.
  • the diseases, disorders, or conditions may be stroke, ischemia, reperfusion injury, or combinations thereof.
  • the diseases, disorders, or conditions may be cerebral diseases, disorders, or conditions.
  • diseases, disorders, or conditions related to oxidative stress may include neurodegenerative disease, stroke, inflammatory disease, neurovascular disorder, dementia, Multiple Sclerosis, Parkinson's disease, myocardial infarction, heart failure, renal failure, collagen vascular disease, metabolic disorder, or cardiac disease.
  • the diseases, disorders, or conditions related to oxidative stress, ischemia, reperfusion injury, or combinations thereof may be cerebral, heart, kidney, liver, or skeletal muscle diseases, disorders, or conditions.
  • the disease, disorder, or condition may be any ischemia/reperfusion injury.
  • the disease, disorder, or condition may be neurodegeneration and/or inflammation.
  • the compounds and/or compositions provided herein may be used in combination with an anti-thrombolytic drug and/or a clot-busting drug.
  • the anti-thrombolytic drug may be tPA (Tissue Plasminogen Activator) or rtPA (recombinant tissue plasminogen activator).
  • the compounds and/or compositions provided herein may be used in combination with the anti-thrombolytic drug, for example, tPA or rtPA, for preventing and/or treating ischemia/reperfusion injury.
  • the anti-thrmobolytic may be streptokinase.
  • the compounds provided herein may be used for reducing/preventing cell damage caused by reactive oxygen species (ROS), either in vitro or in vivo.
  • ROS reactive oxygen species
  • LA-edaravone conjugates as provided herein may be considered co-drugs.
  • treatment with LA-edaravone conjugates may produce neuroprotection while at least partially reducing the edaravone-induced renal toxicity associated with a correspondingly effective dose of edaravone alone.
  • treatment with LA-edaravone conjugates as provided herein may reduce infarct volume in ischemia/reperfusion injury.
  • LA-edaravone conjugates provided herein may be administered prior to an ischemia/reperfusion event, during a period of ischemia, during a period of reperfusion, following an ischemia/reperfusion event, or any combination thereof.
  • LA-edaravone conjugates provided herein may be administered to a subject using any appropriate method known in the art.
  • Methods of administration may include I.V. administration, subcutaneous injection, intraperitoneal injection, direct injection, or any other appropriate method of administration.
  • the dosages of the compound or composition provided herein may be formulated in a number of ways. For example, without wishing to be limiting, they may be formulated as an oral supplement, as a food/feed additive, or as pharmaceutical or nutraceutical compositions.
  • the compounds or compositions described herein may be formulated or combined with one or more acceptable additives, carriers or excipients suitable for preparation of the desired dosage form(s).
  • the compounds and compositions described herein can be employed in methods of treating or preventing diseases, disorders, or conditions related to oxidative stress. Such methods comprise administering the compounds or compositions provided herein to a subject in need thereof in an amount sufficient to ameliorate or prevent the diseases, disorders, or conditions related to oxidative stress, and/or to prevent or treat stroke, ischemia, reperfusion injury, or combinations thereof.
  • Therapeutic uses of the compounds and compositions described herein are also provided, whereby the compounds or compositions as described herein, or isomer, derivative, pharmaceutically acceptable salt or ester thereof, are used for treating or preventing diseases, disorders, or conditions related to oxidative stress, and/or to prevent or treat stroke, ischemia, reperfusion injury, or combinations thereof.
  • diseases, disorders, or conditions related to oxidative stress include, but are not limited to, stroke, ischemia, reperfusion injury, or combinations thereof.
  • compositions described herein can be suitably formulated into one or more than one separate pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application also includes a pharmaceutical composition comprising one or more compounds or compositions and a pharmaceutically acceptable carrier.
  • the compounds or compositions may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • a compound may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • the compounds or compositions may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or the compounds may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the food of the diet.
  • the compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Oral dosage forms also include modified release, for example immediate release and timed-release, formulations.
  • modified-re lease formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed- release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet.
  • coatings that inhibit degradation of the compounds of the application by esterases for example plasma esterases, are used in the oral administration forms.
  • Timed-release compositions can be formulated, e.g. liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc.
  • Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • compositions may also be administered parenterally.
  • Solutions of one or more compounds or compositions can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • Compounds or compositions may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • Compounds or compositions may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • compounds or compsitions may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • Compounds or compositions may be used alone or in combination with other known agents useful for treating diseases, disorders, or conditions related to oxidative stress and/or blood clotting. Compounds or compositions may also be used in combination with agents that inhibit esterases, such as plasma esterases. When used in combination with other agents useful in treating diseases, disorders, or conditions related to oxidative stress and/or blood clotting, it is an embodiment that the compounds or compositions are administered contemporaneously with those agents.
  • "contemporaneous administration" of two substances to a subject means providing each of the two substances so that they are both biologically active in the individual at the same time.
  • the exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art.
  • two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances.
  • a combination of agents may be administered to a subject in a non- contemporaneous fashion.
  • the other known agents may be clot-busting drugs, or anti-thrombolyic drugs.
  • the anti-thrombolytic drug may be tPA.
  • the dosage of compounds can vary depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • Compounds of the application may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.
  • oral dosages of one or more compounds of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day.
  • compositions are formulated for oral administration and the compounds are suitably in the form of tablets containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient per tablet.
  • Compounds of the application may be administered in a single daily dose or the total daily dose may be divided into two, three or four daily doses.
  • Treatment or prevention methods comprise administering to a subject or a cell, a therapeutically effective amount of the compounds or compositions, and optionally consists of a single administration, or alternatively comprises a series of administrations.
  • the compounds may be administered to the subject in a series of administrations, for example about 1, 2, 3, 4, 5 or 6 times daily for 1 or more days either before or after the onset of the disease, disorder or condition.
  • the length of the treatment period depends on a variety of factors, such as the cause of the disease, disorder or condition, severity of the disease, disorder or condition, the age of the subject, the concentration of the compounds, the activity of the compounds, and/or a combination thereof.
  • the effective dosage of the compound used for the treatment or prevention may increase or decrease over the course of a particular treatment or prevention regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
  • the compounds are administered to the subject in an amount and for a duration sufficient to treat the subject.
  • a derivative of LA refers to a compound that is derived from a parent compound by modification of one or more of the functional groups in the parent molecule.
  • a derivative of LA may be a reduced form (dithiol) of LA, or a reduced form in which the thiol groups are substituted with, for example, a C 1-6 alkyl group or a C 1-6 acyl group.
  • a derivative of edaravone may be a compound according to Table 1.
  • subject includes all members of the animal kingdom including mammals, and suitably refers to humans.
  • pharmaceutically acceptable means compatible with the treatment of subjects, in particular humans.
  • pharmaceutically acceptable salt means an acid addition salt which is suitable for, or compatible with, the treatment of patients.
  • acid addition salt which is suitable for, or compatible with, the treatment of patients
  • acid addition salt means any non-toxic organic or inorganic salt of any basic compound.
  • Basic compounds that form an acid addition salt include, for example, compounds comprising a thiol group.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids.
  • Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art.
  • a desired compound salt is achieved using standard techniques.
  • the basic compound is treated with an acid in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.
  • solvate as used herein means a compound or its pharmaceutically acceptable salt, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate”.
  • solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
  • compounds and compositions described herein have at least one asymmetric center. These compounds exist as enantiomers. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (e.g. less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the application having alternate stereochemistry. For example, compounds that are described or shown without any stereochemical designations are understood to be racemic mixtures. However, it is to be understood that all enantiomers and diastereomers are included within the scope of the present application, including mixtures thereof in any proportion.
  • treating means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable.
  • Treating and “treatment” as used herein also include prophylactic treatment.
  • a subject can be treated to prevent onset or progression, or alternatively a subject in post-stroke or post- infarct can be treated with a compound or composition as described herein to reduce injury or prevent recurrence.
  • Treatment methods comprise administering to a subject a therapeutically effective amount of the compounds described.
  • the term "effective amount” or “therapeutically effective amount” means an amount effective, at dosages and for periods of time necessary to achieve the desired result. Effective amounts may vary according to factors such as the disease state, age, sex and/or weight of the subject.
  • the amount of a given compound that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • treatment with the compounds or compositions provided herein may be long-term treatments for chronic conditions, or may be single dose treatments for acute conditions. It will be appreciated that the embodiments described herein are for illustrative purposes, and not intended to be limiting in any way. The following examples are provided for the purposes of illustration, and may demonstrate embodiments of at least some of the compounds and uses provided herein.
  • EXAMPLE 1 USE OF UPEI-300 FOR NEUROPROTECTION IN ISCHEMIA/ REPERFUSION INJURY
  • UPEI-300 a new co-drug that is a covalent conjugate between LA and edaravone.
  • the current investigation examines whether UPEI-300 can produce neuroprotection in an in vitro model of ischemia using embryonic cortical cells and/or an in vivo rodent model of stroke.
  • neocortical cultures containing both neurons and glia, were prepared from fetal rats at 17- 18 days gestation. Briefly, embryonic tissue was extracted from untimed pregnant Sprague- Dawley rats by cesarean section and transferred to ice-cold Hanks Balanced Salt Solution (Invitrogen). Cortical brain tissue was carefully isolated by fine dissection using asceptic techniques. Cortices were minced in cold HBSS using a sterile razor blade prior to digestion with 0.0125% trypsin.
  • Dissociated cells were plated in poly-L-lysine (lmg/ml) coated 96 well plates at a seeding density of 45 000 cells/well in warm Dulbecco's Modified Eagle Medium (Invitrogen) containing 10% iron-supplemented bovine calf serum (Fisher) and 1% antibiotic/antimycotic (Invitrogen). Cultures were allowed to adhere overnight in a humidified 37°C incubator having 5% C0 2 and atmospheric oxygen. The following day, the media was replaced with warmed Neurobasal A Medium containing 0.5mM L-glutamine (Invitrogen) and supplemented with 1% B27, N 2 and antibiotic/antimycotic (Invitrogen). Half-volume media changes were made every 4 days thereafter with experiments being carried out on 14 - 16 day old cultures.
  • LDH lactate dehydrogenase
  • the sutures were positioned so that the middle of each suture applied pressure to the underside of the MCA and impeded blood flow (ischemia) as previously confirmed using laser Doppler flowmetry (OxyFlo, Oxford-Optronix, Oxford, UK; Connell and Saleh 2010).
  • This 3-point placement of surgical sutures produced a highly reproducible and consistent focal ischemic lesion restricted to the prefrontal cerebral cortex. Blood flow was allowed to return to the area (reperfusion) for an additional 5.5 hours following the removal of the sutures.
  • UPEI-300 stock solutions (10 mg/ml) were prepared in 100% ethanol.
  • Physiological saline (0.9%) sodium chloride) was used for all further dilutions of UPEI-300.
  • All dilutions used in the in vivo studies contained a final concentration of 50% ethanol, and thus we used a 50% v/v ethanol solution as our vehicle control.
  • UPEI-300 was neuroprotective when administered during the 30 minute period of occlusion
  • injections of UPEI-300 at a dose which produced optimal neuroprotection based on the dose-response-curve described above were made 15 minutes following the onset of MCAO. After a further 15 minutes, the sutures were removed to allow for an additional 5.5 hours of reperfusion.
  • UPEI-300 was neuroprotective on ischemia-induced cell death only (no reperfusion)
  • the experiments were terminated at the end of 6 hours of occlusion (pMCAO).
  • the infarct area for both sides of each brain section was calculated using a computer-assisted imaging system (Scion Corporation; Frederick, MD, USA). The infarct areas for each side for each individual section were averaged and multiplied by the width of each section (1mm) to give the infarct volume for each section. The sum total of all the individual infarct volumes provided the infarct volume for each rat.
  • UPEI-300 was tested in mixed neocortical cultures in an OGD paradigm. LDH levels were significantly decreased following the introduction of 50, 100, 200 and 500 mmol of UPEI- 300 into the media (p ⁇ 0.05; Fig. 2).
  • UPEI-300 was then tested in a rodent model of I/R- induced injury.
  • I/R ischemia-reperfusion
  • the dose of UPEI-300 required to produce significant neuroprotection was 5 fold less compared to the dose required of either edaravone or lipoic acid on their own (Connell and Saleh 2010; Connell et al., 2010).
  • UPEI-300 In order to more closely mimic the clinical situation where a patient would present to a hospital during a stroke, the optimal dose of UPEI-300 from Fig.3A (1.0 mg/kg) was administered either during the 30 minute of MCAO occlusion or following the return of blood flow (reperfusion). Administration of UPEI-300 (1.0 mg/kg) 15 minutes following the onset of MCAO resulted in significant neuroprotection when compared to the administration of vehicle (p ⁇ 0.05; Fig. 4). The effect of UPEI-300 on reperfusion injury was determined only by measuring the infarct volume following drug administration immediately prior to suture removal (time 0), or 30, 60 and 90 minutes following the start of reperfusion.
  • Oxidative stress associated with excessive production of reactive oxygen species is a fundamental mechanism of brain damage in reperfusion injury following ischemic stroke (Bedard and Krause, 2007; Chan 2001).
  • the multiplicity of mechanisms involved in ischemia- and reperfusion-induced neuronal damage following an occlusive stroke remains an obstacle in providing treatment in clinical settings (Minnerup and Schabitz , 2009).
  • Drugs targeting more than one mechanism of action could potentially overcome this dilemma.
  • the synthesis and development of co-drugs using simple yet biologically relevant molecules as building blocks provides the ability to simultaneously target multiple pathways involved in the pathogenesis of neurological diseases, specifically, pathways involved in the initiation of oxidative stress- induced neuronal damage following reperfusion.
  • the use of co-drugs could potentially decrease the chance of single drug induced side effects as smaller amounts of each component making up the co-drug would be present.
  • edaravone The protective effect of edaravone on brain ischemia has been measured using several different models of focal ischemia in rodents with or without reperfusion. Using the same model of focal I/R-damage as presented herein, our laboratory has previously demonstrated the neuroprotective effect of edaravone (Connell and Saleh 2010). Other studies have also demonstrated using a global or hemispheric ischemia model, edaravone facilitated the recovery of electrocorticograms and attenuated hemispheric cerebral edema (Nishi et al., 1989; Watanabe et al., 1994, 2004).
  • Edaravone used on its own, has been shown to decrease ischemic neuronal damage in humans who have suffered from acute ischemic stroke (Yoshida et al., 2006; Kikuchi et al., 2013) but because of potential edaravone associated acute kidney injury (Watanabe et al., 2008), its therapeutic use has been limited.
  • Some recent evidence has indicated that acute kidney injury may not in fact be due to edaravone administration but may be due to the age and general physical health of the patients, and, edaravone may even decrease the risk of acute kidney injury irrespective of baseline renal malfunctions (Kamouchi et al., 2013).
  • a co- drug such as UPEI-300
  • UPEI-300 produced dose-dependent neuroprotection in vitro and was subsequently tested in vivo, Male rats were anaesthetized with Inactin (100 mg kg, iv) and the middle cerebral artery was occluded for 6 hours (pMCAO), or 30 min followed by 5.5 hrs of reperfusion (ischemia/reperfusion; I/R). Pre-administration of UPEI-300 dose-dependently decreased infarct volume in the I/R model (1.0 mg/kg; p ⁇ 0.05), however this dose of UPEI-300 was ineffective in the pMCAO model of stroke.

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Abstract

L'invention concerne des conjugués covalents associant de l'acide lipoïque (LA), ou un dérivé de celui-ci, à de l'édaravone, ou un dérivé de celui-ci, qui comprennent des composés de formule (I). L'invention concerne également des méthodes thérapeutiques faisant intervenir lesdits conjugués LA-édaravone, notamment pour le traitement de maladies, troubles ou états pathologiques associés au stress oxydatif.
PCT/CA2014/051261 2013-12-23 2014-12-23 Conjugués acide lipoïque-édaravone et leurs utilisations WO2015095970A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9822104B2 (en) * 2015-08-24 2017-11-21 Yeomyung Biochem Co., Ltd. Taxifolin derivative with superior antioxidant effect and cosmetic composition containing the same
WO2019213333A1 (fr) * 2018-05-04 2019-11-07 Carnot2, Llc Polythérapies avec édaravone et promédicaments d'édaravone qui sont biodisponibles par voie orale et ont des propriétés pharmacocinétiques modifiées

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2856217A1 (fr) * 2011-11-15 2013-05-23 Tarek M. Saleh Conjugues d'apocynine-acide lipoique et leurs utilisations

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2856217A1 (fr) * 2011-11-15 2013-05-23 Tarek M. Saleh Conjugues d'apocynine-acide lipoique et leurs utilisations

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9822104B2 (en) * 2015-08-24 2017-11-21 Yeomyung Biochem Co., Ltd. Taxifolin derivative with superior antioxidant effect and cosmetic composition containing the same
WO2019213333A1 (fr) * 2018-05-04 2019-11-07 Carnot2, Llc Polythérapies avec édaravone et promédicaments d'édaravone qui sont biodisponibles par voie orale et ont des propriétés pharmacocinétiques modifiées

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