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WO2009144253A1 - Composés comprenant un noyau 3-pyridinol ou 5-pyrimidinol à substituant organoséléno ou organotelluro utilisés comme anti-oxydants - Google Patents

Composés comprenant un noyau 3-pyridinol ou 5-pyrimidinol à substituant organoséléno ou organotelluro utilisés comme anti-oxydants Download PDF

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WO2009144253A1
WO2009144253A1 PCT/EP2009/056468 EP2009056468W WO2009144253A1 WO 2009144253 A1 WO2009144253 A1 WO 2009144253A1 EP 2009056468 W EP2009056468 W EP 2009056468W WO 2009144253 A1 WO2009144253 A1 WO 2009144253A1
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alkyl
compound
alkoxy
reducing agent
alkylamino
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Lars Engman
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Karolinska Institutet Innovations AB
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Karolinska Institutet Innovations AB
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K15/00—Anti-oxidant compositions; Compositions inhibiting chemical change
    • C09K15/04—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds
    • C09K15/32—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing two or more of boron, silicon, phosphorus, selenium, tellurium or a metal
    • C09K15/328—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing two or more of boron, silicon, phosphorus, selenium, tellurium or a metal containing boron, silicon, selenium or tellurium

Definitions

  • the present invention relates to compounds and their medical and non-medical uses as antioxidants.
  • the present invention relates to derivatives of 3-pyridinol and 5-pyrimidinol.
  • Antioxidants prevent or inhibit the oxidation of substances. Oxidation can result in damage to or degradation of biological systems as welt as man-made materials. Antioxidants can work via various mechanisms. Chain-breaking antioxidants intercept the radical cycle whereby organic material is oxidised. Antioxidants which reduce peroxyl radicals and decompose hydroperoxides are particularly useful in addressing the harmful effects that can be caused by such substances. There are a wide variety of applications including the treatment, prevention or amelioration of conditions or disorders caused by or involving free radical - mediated or oxidative tissue damage, or the stabilization or treatment of man-made or natural materials.
  • antioxidants which are suitable for various uses.
  • many known natural and man-made antioxidant systems are based on the phenol group (shown below).
  • Alpha-tocopherol shown below
  • a component of vitamin E contains a phenol moiety fused to a further ring
  • several structurally similar compounds have been targets for synthesis and testing as antioxidants.
  • Polymer chemists use antioxidants to control polymerisation in the manufacture of rubber, plastics and paint and for the stabilization of polymeric materials during processing and use.
  • the oil industry makes extensive use of antioxidants in the design of better automobile fuels and lubricating oils.
  • Provided toxicity and environmental problems associated with increasing antioxidant use can be coped with, disease prevention/extending the lifetime of various materials is obviously of significant benefit to man and society.
  • Chain-breaking donating antioxidants donate hydrogen atoms to peroxyl radicals before they can propagate the peroxidation reaction.
  • the cycle to the left in Scheme 1 shows different ways of initiation of the autoxidation process.
  • peroxide decomposition is brought about by enzymatic systems: Catalasc containing ferric haeme groups catalyze decomposition of hydrogen peroxide into oxygen and water.
  • a family of closely related selenium-containing glutathione peroxidases (GPxs) catalyzes the reduction of hydrogen peroxide and organic hydroperoxides into water and alcohols, respectively.
  • the stoichiometric reducing agent in these processes is the tripeptide glutathione, GSH ( ⁇ -glutamyl cysteinyl glycine) which is oxidized to the corresponding disulfide, GSSG (eqn 1).
  • Vitamin E is the most important lipophilic., chain-breaking antioxidant in vivo. Tts antioxidant activity stems from the ability to transfer the phenolic hydrogen to peroxyl radicals at a rate much faster than the chain-propagating H-atom transfer step of autoxidation (Scheme 1). Thus, it serves to protect DNA, proteins, lipids, carbohydrates and other important biomolecules from becoming oxidatively damaged by radical processes involving reactive oxygen and nitrogen species.
  • ⁇ -Tocopherol ( ⁇ -T0II) is the most reactive component of Vitamin E 5 and is known to trap two peroxyl radicals before it is converted into non-radical products.
  • US 6,835,216 (Vanderbilt University) relates to antioxidants and discloses various 5- pyrimidinol and 3-pyridinol compounds. It theorises on the antioxidant activity of compounds in relation to natural vitamins including alpha-tocopherol, and discloses compounds which have a nitrogen- or oxygen- containing ring fused onto the pyrimidinc or pyridine ring. Various substitucnts arc disclosed, but the only heteroatoms which are attached to the pyrimidine or pyridine rings in this document are nitrogen or oxygen atoms.
  • the present invention provides the use of a 3-pyridinol or 5- pyrimidinol compound carrying an organoseleno- or organotelluro- substitucnt on the pyridine or pyrimidine ring, as an antioxidant.
  • X is Te or Se, wherein R' is an organic moiety, and wherein there may be further substitucnts on the rings.
  • the compound may also be in a salt form.
  • heteroaromatic compounds pyridine and pyrimidine have hydroxyl groups in particular positions, and contain selenium or tellurium which on one side is bonded to the heteroaromatic ring and on ihe other side to an organic group.
  • X is selected from Te and Se
  • Ri is selected from
  • - aryl which is optionally substituted with C1-C 5 alkyl.
  • R 2 , R3, and R4 arc the same or different and are each selected from
  • alkyl groups are branched or unbranched and contain 1-5 carbon atoms, NH 2 , OH, SH;
  • - aryl optionally substituted with C1-C5 alkyl, OH, alkoxy, SH, NH 2 , JV-alkylamino, 7V,JV-dialkylamino, COOH, CHO, NO 2 . F, Cl, Br, and I groups;
  • any alkyl moiety is a branched or unbranched C 1 -C 30 alkyl, any aryl moiety is a C ⁇ -C 1O aryl, and any heteroaryl moiety is 5-6 membered and contains one or several heteroatoms selected
  • the compound according to formula I may be represented by any one of the following formulas II-VI:
  • R 1 , R 2 , R3 and R4 are as defined herein above.
  • X is Te
  • Ri is selected from branched or uiibranched alkyl and aryl.
  • R 2 , R 3 and R 4 are independently selected from H, alkyl, alkoxy, TV.N-dialkylamino and JV-alkylamino.
  • the compound is according to formula TT, III or IV; in another embodiment the compound is according to formula V or VI.
  • Tn one embodiment, in a compound as defined herein above, the group R 1 X is in an ortho position in relation to the hydroxy group on the nitrogen-containing heteroaromatic ring.
  • the compound is according to formula II as defined herein above, wherein R 2 and R 4 are hydrogen or alkyl and R 3 is an electron donating group such as JV,JV-d ⁇ alkylamino, iV-alkylamino, alkoxy or alkyl.
  • the compound is according to formula III as defined herein above, wherein one of R 2 and R3 is an electron donating group such as N 1 N- dialkylamino, JV-aikylamino, alkoxy or alkyl and tlie other one is hydrogen or alkyl and R 4 is hydrogen or alkyl.
  • R 2 and R3 is an electron donating group such as N 1 N- dialkylamino, JV-aikylamino, alkoxy or alkyl and tlie other one is hydrogen or alkyl and R 4 is hydrogen or alkyl.
  • the compound is according to formula IV as defined herein above, wherein R 2 and R 4 are hydrogen or alkyl and R 3 is an electron donating group such as JV.iV-dialkylamino, JV-alkylamino, alkoxy or alkyl.
  • the compound is according to formula V as defined herein above, wherein R 2 is hydrogen or alkyl and R 3 is an electron donating group such as ⁇ JV-dialkylamino, jV-alkylamino, alkoxy or alkyl.
  • the compound is according to formula VT as defined herein above, wherein one of R 2 and R 3 is an electron donating group such as N r N- dialky ⁇ amino, iV-alkylamino, alkoxy or alkyl and the other one is hydrogen or alkyl.
  • the compounds of the present invention may be prepared by methods known to the person of ordinary skill within the field of synthetic organic chemistry.
  • a compound of the invention according to formula 1 having a hydroxy group in position n and an R 1 X group in position m on the nitrogen containing heteroaromatic cycle (pyridinol or pyrimidinol) may be prepared by a process comprising: - substituting a halogen for the hydroxy function of a pyridinol or pyrimidinol having said hydroxy function in the position corresponding to position m in the inventive compound ("in m position") and having a cyano moiety in the position corresponding to position n in the inventive compound ("in n position");
  • R 1 i.e. the substituenL on Te or Se
  • R 1 is not aryl.
  • Non-aryl substituents for example alkyl substituents., arc preferred for R 1 .
  • preferred alkyl lengths for R are Ci-C 30 alkyl, C 1 -C 1 ⁇ alkyl, C 1 -C 16 alkyl, C r C 8 alkyl, or C 2 -C 6 alkyl.
  • the alkyl may be straight-chain or branched.
  • the alkyl may be saturated or unsaturated. For example, there may be no double bond present, or one, or more than one.
  • X may be Te or Se ? in general it is preferred that X is Te rather than Se.
  • XRi is ortho or para to the hydroxy group
  • XRj is bonded to a carbon atom which is both ortho to the hydroxy group and adjacent to a nitrogen atom of the heteroaromatic ring.
  • Suitable electron-donating groups are for example as defined above.
  • suitable electron-donating groups include alkyl (preferably Ci-Q alkyl, e.g. methyl), alkoxy (preferably C ⁇ -C$ alkoxy, e.g. methoxy), dialkylamino (preferably where each alkyl is independently selected from Ci-C ⁇ ; alkyl, e.g. methyl) or monoalkylamino (preferably where the alkyl is independently selected from Ci-Ce alkyl, e.g. methyl).
  • the XRi group is ortho or para to the hydroxy group and there are one or two electron-donating substituents in the remaining ortho/para positions, preferably two. More preferably the XR] group is on a carbon atom which is both ortho to the hydroxy group and adjacent to a nitrogen of the heteroaromatic ring, and there is an electron-donating substituent in the other ortho position and/or in the para position relative to the hydroxy group.
  • a further preferred group ofcompounds are those of formula VIT wherein R 1 is C 1 - C 30 alkyl, e.g. CpC 16 alkyl, C]-C 10 alkyl or C 2 -Cs alkyl.
  • a further preferred group ofcompounds are those of formula VII wherein Ri is Ci- C30 alkyl, e.g. Ci-C 1 S alkyl, C 1 -CiO alkyl or C 2 -Cg alkyl, and wherein z is CH or C- (C 1 -C 6 alkyl), or C-(C 1 -C 6 alkoxy).
  • a further preferred group of compounds are those of formula VlT wherein R 1 is C 1 - C 30 alkyl, e.g.
  • a further preferred group of compounds arc those of formula VII or any of the further preferred sub-groups of formula VII, wherein X is Tc. Alternatively X may be Se.
  • the compound may be one of formula VII or any of the preferred subgroups of formula VIT, wherein R 2 is Me or II, R 3 is Me or H, z is CH or C-OMe, and Ri is C1-C1 6 alkyl for example ethyl or octyl, and optionally wherein X is Te.
  • Salt forms of the compounds of the compounds defined herein may also be used.
  • the compounds of the present invention may be as described herein, excluding 2-(mcthylseleno)- ⁇ yridin-3-ol:
  • the compounds of the present invention may be as described herein, excluding 2-(phenylseleno)-6-methyi-pyridin-3-ol and 2-(phenyltelluro)-6-methyl- pyridin-3-ol:
  • the 3-pyridinol or 5-pyrimidinol compound according to the present invention may optionally be used as a catalytic antioxidant.
  • it may be used under conditions which allow its regeneration, either because the system in which it is used inherently regenerates the compound and cycles the catalyst, or because an additional component is used to regenerate the catalyst.
  • the 3-pyridinol or 5-pyrimidinol compound according to the present invention may also be combined with, or used in combination with, a reducing agent.
  • the reducing agent may for example be a mild reducing agent.
  • suitable reducing agents include those which are suitable for regenerating the catalyst without causing undesirable side-effects.
  • One suitable class of suitable reducing agents is the class of thiols. Specific examples include N-acetylcystcinc, cysteine, dithiothreitol, glutathione, ascorbic acid and sodium ascorbate. Further examples arc given below.
  • Catalytic use is economically and environmentally advantageous and minimizes the preparation and use of potentially hazardous materials. It allows the use of reducing agents which are low-cost, readily available and safe.
  • the compounds of the present invention can be used in a stoichiometric sense, but in that case they only have a finite effect, and for example can only destroy a limited number of peroxyl radicals before they are themselves converted to inactive compounds. It is therefore preferable for them to be regenerated by cheap, nontoxic stoichiometric reducing agents in a similar fashion as has been proposed for the catalytic action of alpha-tocopherol in the presence of ascorbate and other co- reductants (eqn 2-4).
  • the compounds can act as chain-breaking antioxidants by catalyzing the decomposition of peroxyl radicals in the presence of mild reducing agents, and can also act as preventive peroxide-decomposing antioxidants by catalyzing the reduction of hydrogen peroxide and organic hydroperoxides in the presence of mild reducing agents.
  • the antioxidant use may be the stabilization of a man-made or natural material, or the prevention or inhibition of oxidation or degradation of a man-made or natural material.
  • man-made and natural materials include polymers, plastics, rubber, paint, oils, lubricants, greases, fuels, paper and pulp products.
  • the present invention provides a man-made or natural material containing a compound according to the present invention, and optionally a reducing agent. It will be understood that the man-made or natural material may otherwise be more susceptible to degradation, oxidation or instability.
  • compounds of the present invention quench reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • inventive compounds or pharmaceutically acceptable salts thereof may be used as medicaments for the treatment of disorders caused by or involving free radical-mediated or oxidative tissue damage, e.g. a disorder selected from ischemic or reperfusion injuries, thrombosis, embolism, neoplasms, cancer, Parkinson's disease, Alzheimer's disease, artherosclerosis, allergic/inflammatory conditions such as bronchitis, asthma, rheumatoid arthritis, ulcerative cholitis, Crohn's disease, cataract, respiratory distress syndrome, damage caused by chemicals, radiation, antineoplastic or immunosuppressive agents, ischcmia/rcpcrfusion injury in the heart, kidney and CSN and post-operative ischemia/reperfiision injury. Additionally, the compounds may be used for organ preservation, to treat burn injury, or to treat IBS (irritable bowel syndrome).
  • IBS irritable bowel syndrome
  • the present invention provides a compound according to the present invention, optionally in combination with a reducing agent, for use in therapy. Medical uses of the compounds of the present invention have not hitherto been disclosed.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and additionally other components, for example a pharmaceutically acceptable diluent or other pharmaceutical additive or excipient.
  • the present invention relates to 3-pyridinol and 5-pyrimid ⁇ nol compounds useful as chain-breaking antioxidants, ⁇ n particular, the invention relates to 3-pyridinol and 5- pyrimidinol compounds suitable for prevention or treatment of disorders caused by or involving free radical-mediated or oxidative tissue damage such as atherosclerosis, inflammation, Alzheimer's and Parkinson's disease, cataract and heart and lung disease.
  • the invention also relates to the use of the inventive 3-pyridinol and 5- pyrimidinol compounds for the stabilization of man-made and natural materials such as polymers, plastics, rubber, paint, oils, lubricants, greases, fuels and paper and pulp products during processing and use.
  • One object of the present invention is to provide compounds capable of acting as chain-breaking antioxidants by catalyzing the decomposition of peroxyl radicals in the presence of mild reducing agents and capable also of acting as preventive peroxide- decomposing antioxidants by catalyzing the reduction of hydrogen peroxide and organic hydroperoxides in the presence of mild reducing agents.
  • One further object of the present invention is to provide compounds capable of acting as chain-breaking antioxidants and capable also of acting as preventive peroxide- decomposing antioxidants, that may be regenerated by stoichiometric reducing agents, e.g cheap, nontoxic reducing agents.
  • the present inventors have discovered that compounds comprising a 3-pyridinol or 5- pyrimidinol core carrying an organoseleno- ot organogel luro- substituent on the pyridine or pyrimidine ring, act as effective regenerable chain-breaking antioxidants in the presence of suitable stoichiometric reducing agents. Thus, under these conditions, they act as catalysts for the quenching of peroxyl radicals.
  • compounds of the invention have a significantly improved antioxidant performance.
  • the regenerability and catalytic mode of action of compounds of formula I allow their administration as protective agents in much lower concentrations, and the duration of the antioxidant protection in principle is determined by the amount of an inexpensive reducing agent present.
  • An additional advantage, when protection in a biological system is considered, is that the reducing agent may already be present in substantial amounts (glutathione; ascorbate).
  • Patent 6835216 is that compounds represented by the formula I have a capacity, due to the presence of readily oxidized organylseleno- or organyltelluro groups, to act as catalysts for the reduction of hydrogen peroxide and organic hydroperoxides in the presence of mild reducing agents.
  • compounds represented by the formula I act as catalytic, multifunctional (chain-breaking and peroxide decomposing) antioxidants.
  • the present invention relates to novel regenerable 3-pyridinol and 5-pyriniidmol compounds, or any salts or prodrugs thereof, which can act hi a catalytic fashion in the presence of mild reducing agents to quench peroxyl radicals and reduce hydrogen peroxide and organic hydroperoxides.
  • the present invention also relates to the pharmacological use of the inventive compounds as well as pharmacological formulations containing them and to their use for the stabilization of man-made and natural organic materials, such as polymers, plastics, rubber, paint, oils, lubricants, greases j fuels and paper and pulp products during processing and use.
  • the efficacy of compounds based on a 3- pyridinol or 5-pyri ⁇ dinol core carrying an organoseleno- or organotelluro- substituent on the pyridine or pyrimidine ring could in part be due to the favourable ionization potential and O-H bond dissociation enthalpy.
  • the hydrogen atom of the hydroxy group may transfer to peroxyl radicals quickly, perhaps due to polar effects in the transition state of the atom transfer reaction,
  • a pharmaceutical composition comprising a compound as defined herein above, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition suitably also comprises a pharmaceutically acceptable, mild reducing agent, e.g. ⁇ -acetylcysteine, cysteine, dithiothreitol, glutathione, ascorbic acid or sodium ascorbate.
  • a pharmaceutically acceptable, mild reducing agent e.g. ⁇ -acetylcysteine, cysteine, dithiothreitol, glutathione, ascorbic acid or sodium ascorbate.
  • the invention relates to a compound for the treatment of a disorder caused by or involving free radical-mediated or oxidative tissue damage, e.g. a disorder selected from ischemic or rcpcrfusion injuries, thrombosis, embolism, neoplasms, cancer, Parkinson's disease, Alzheimer's disease, artherosclerosis, allergic/inflammatory conditions such as bronchitis, asthma, rheumatoid arthritis, ulcerative cholitis.
  • a disorder selected from ischemic or rcpcrfusion injuries, thrombosis, embolism, neoplasms, cancer, Parkinson's disease, Alzheimer's disease, artherosclerosis, allergic/inflammatory conditions such as bronchitis, asthma, rheumatoid arthritis, ulcerative cholitis.
  • the invention relates to an antioxidant composition
  • a compound according to the invention and a mild reducing agent, useful for preserving a liquid, solid or semi-solid organic material, e.g. a polymer, elastomer, oil, lubricant, grease, fuel or paint composition or a paper or pulp product against oxidative degradation.
  • the invention also provides such a liquid, solid or semi-solid material comprising the antioxidant composition of the invention.
  • the invention relates to a method of preserving a polymer, elastomer, oil, lubricant, grease, fuel or paint composition or a paper or pulp product against oxidative degradation, by adding an. antioxidant composition according to the invention to the polymer, elastomer, oil, lubricant, grease fuel or paint composition or paper or pulp product.
  • the invention relates to a method of treatment of a mammal in need thereof, by administering to said mammal a therapeutically effective amount of a compound according to the invention
  • Compounds H-VI can form salts with either acids or bases. All physiologically acceptable salts are contemplated as useful as active medicaments; however, sodium, potassium, ammonium, calcium and magnesium salts and salts with hydrochloric, hydrobromic, phosphoric and sulfuric acids and with organic acids such as oxalic, fumaric, tartaric, malonic, acetic, citric and succinic acids are preferred. Likewise preferred are organic bases such as lysine, argininc, choline, ethylendiamine, 2-amino-2-methyl-l,3-propanediol, cystamine, diethylaminc, ethanolamine and piperazine.
  • compounds II- VI (or other compounds disclosed herein) of the present invention, or salts or prodrugs thereof are regenerablc and act in a catalytic fashion to quench peroxyl radicals and to reduce hydrogen peroxide and organic hydroperoxides.
  • the compounds which are going to act as stoichiometric reducing agents in the presence of the catalytically active compounds H-Vl either have to be present in the system where the antioxidant protection is desired or they have to be co-administered with the catalytic antioxidants.
  • Mild reducing agents which have been found suitable to regenerate the catalytic antioxidants must have a capacity to donate hydrogen atoms or electrons.
  • Such compounds include, but are not limited to, thiols, ascorbic acid or derivatives thereof such as sodium ascorbate, phenolic compounds, JV-hydroxy derivatives of certain amines and salts of readily oxidized metals.
  • a suitable thiol reducing agent is an alkane, an arene or a heteroarene containing one or several sulfhydryl (SH) groups, including all kinds ofpolymer-supported thiols or hyperbranched polyethcr, polyester or polyamide compounds with terminal sulfhydryl groups, wherein
  • the alkane type compound is a straight or branched hydrocarbon chain with 1-30 carbon atoms, wherein the carbon atoms may be optionally substituted with one or several groups such as OH, alkoxyl, NH 2 , iV-alkyiamino, ⁇ iV-dialkylamuio, COOH, aryl which is optionally substituted with C 1 -C 5 alkyl, OH, alkoxyl, SII, NII 2 , N- alkylamino.
  • the arene type compound could be benzene, naphthalene or any other polyaromatic compound wherein the carbon atoms may be optionally substituted with one or several groups such as OH, alkoxyl, NH2, N-alkylamino, iV ⁇ -dialkylamino, COOH, aryl which is optionally substituted with C 1 -C 5 alkyl, OH, alkoxyl, SH 5 NH 2 , N- alkylamino, JV.iV-dialkylamino, COOIL, CITO, NO 2 , V, CI, Br, 1 groups, and heteroaryl which is optionally substituted with C]-C 5 alkyl, OH, alkoxyl, SII 5 NI-I 2 , N- alkylamino, iV,iV-dialkyIammo, COOH, CHO, NO 2 , F, Cl, Br, and I groups;
  • the heteroarene type compound could be furan, thiophene, pyrrole, pyridine or any other heteroaromatic compound wherein the carbon atoms may be optionally substituted with one or several groups such as OH, alkoxyl, NH 2 , iV-alkylamino, N 1 N- dialkylamino, COOH, aryl which is optionally substituted with C 1 -Cs alkyl, OH, alkoxyl, SH, NH 2 , JV-alkylamino, ⁇ / ⁇ /V-dialkylamino, COOII, CIIO, NO 2 , F, Cl, Br 1 1 groups, and hctcroaryl which is optionally substituted with C 1 -C 5 alkyl, OH, alkoxyi, SH, NH 2 , iV-alkylamino, N,JV-dialkylamiao, COOH, CHO, NO 2 , F, Cl, Br, and I groups.
  • groups
  • Preferred mild reducing agents which have been found suitable to regenerate the catalytic antioxidants H-VI are N-acetylcysteine, cysteine, dithiothreitol. glutathione, ascorbic acid or sodium ascorbatc.
  • Figure 1 is a schematic illustration of a two-phase model used for studying regeneration of chain-breaking antioxidants
  • Figure 2 is a graph showing peroxidation traces (Hnoleic acid hydroperoxide concentration vs time) recorded using compound 16a and ⁇ -TOH as antioxidants in the chlorobenzene layer in the presence of NAC (1 mM) in the aqueous phase;
  • Figure 3 is a graph showing concentration of ⁇ -acetylcysteine in the aqueous phase with time during a normal peroxidation experiment using antioxidant 16a;
  • Figure 4 is a graph showing inhibition time recorded with compound 16a (40 ⁇ M) in the presence of various amounts of ⁇ -acetylcysteine (1.0, 0.75, 0.5, 0.25, and 0 mM) in the aqueous phase.
  • Figure 5 is a graph showing reactive oxygen species (ROS) production in macrophages (THP-I) as a function of time as determined by luminescence measurements. Curves for telluride 17a (60 ⁇ M), NAC (0.1 mM) and the combination of 17a (60 ⁇ M) and NAC (0.1 mM) are shown together with a control (HBSS).
  • ROS reactive oxygen species
  • alkyl refers to a monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to thirty carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, hexadecyl, and the like.
  • Alkoxy refers to a moiety of the formula -OR, wherein R is an alkyl moiety as defined herein.
  • alkoxy moieties include, but are not limited to, methoxy, ethoxy. isopropoxy, and the like.
  • 'W-alkylamino refers to a moiety of the formula -NRH wherein R is an alkyl moiety as defined herein.
  • Examples of jY-alkylamino moieties include, but are not limited to, methylaminOi ethylamino, propylamino, and the like.
  • N 1 N- dialkylamino moieties include, but are not limited to, dimethylamino, diethylamino, dipropylamino, methylethylamino, mefhylpropylamino, cthylpropylamino, and the like.
  • heteroaryl refers to an monovalent aromatic cyclic radical of 5 or 6 ring atoms and containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrroly ⁇ , furanyl, thienyl t thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, pyriinidinyl or pyrazinyl.
  • pharmaceutically acceptable refers to that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • a “pharmaceutically acceptable salt” of a compound refers to a salt that is pharmaceutically acceptable, and that possesses the desired pharmacological activity of the parent compound.
  • Such salts generally include: acid addition salts formed with inorganic acids; or formed with organic acids; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion or an alkaline earth ion; or coordinates with an organic or inorganic base, e.g. diethanolaminc, ethanolamine, N-methylglucamine, aluminum hydroxide, calcium hydroxide, sodium carbonate and sodium hydroxide, and the like.
  • references to pharmaceutically acceptable sails also include solvent addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salt.
  • a "mammal” as referred to herein is any member of the mammalia class including, but not limited to, humans; animals such as non-human primates, farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like.
  • “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
  • the “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated j the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
  • Treating" or “treatment” of a disease includes e.g. preventing the disease, as well as inhibiting the disease state, Le,, arresting the development of the disease state or its clinical symptoms, and relieving the disease, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • the reference to a "compound of formula I" and “a compound according to formula 1" are used interchangeably with “a compound I” and thus a compound I is a compound that may be represented by the formula I, as defined herein. Similar considerations also apply analogously to the compounds II- Vl and VlL
  • Azo-initiated peroxidation of linoleic acid or derivatives thereof has frequently been used for studying the anti oxidative properties of synthetic and natural compounds.
  • a two-phase variant of this system has been designed which allows the study of antioxidant regeneration by water soluble co -antioxidants (Vessman ? K.; Ekstrom, M.; Berglund, M.; Andersson, C-M.; Engman, L. J Org. Cham. 1995, 60, 4461-4467), Tn the experimental setup used (schematically shown in Figure I) 5 linoleic acid and the antioxidant to be evaluated were vigorously stirred in chlorobenzene at 42 0 C with an aqueous solution of JV-acetylcysteine (NAC).
  • NAC JV-acetylcysteine
  • AMVN 2,2'- ⁇ zobis(2,4-dimetiiylvaIeror ⁇ trile)
  • HPLC conjuggated diene hydroperoxide formation
  • R in j t the inhibited rate of peroxidation
  • Tj ir ⁇ r the duration of the inhibited phase
  • R inh was only slightly higher (32 and 27 ⁇ M/h, respectively) than that recorded using ⁇ -tocopherol ⁇ M/h) as an antioxidant under identical conditions.
  • the inhibition period for compound 7a was 70 min only, antioxidant 8a was clearly regenerable with an inhibition time, T m h, of 200 min.
  • the selenium (7b, 8b) and sulftir (7c, 8c) analogues were markedly poorer quenchers of peroxyl radicals (115 ⁇ R ⁇ ⁇ 203 ⁇ M/h) than the organotelluriums and the addition of thiol to the aqueous phase always caused an increase (17-100 %) in ⁇ ) nh (Table 1).
  • inventive compounds may be prepared by the method as generally outlined herein above.
  • Scheme 1 represents the preparation of a 4,6-dimethylated derivative 16a from the commercially available 2-pyridinol 11.
  • the 3-cyano-group serves as a source of a phenol via hydrolysis to an amide, IIofmann rearrangement and diazotization/aromatic iiucleophilic substitution.
  • the chalcogen is introduced into the 2-position in the final step by lithiation, insertion of tellurium and alkylation of an arenetellurolate.
  • Compound 16a quenched peroxyl radicals three times as efficiently as ⁇ -tocopherol ⁇ M/h) in the presence of JV- acetyl-cysteine in the aqueous phase. Regenerability was also excellent (T inh >409 min).
  • Organochalcogen compounds seem to possess some unique properties which make them interesting as antioxidants. They are quite reactive towards hydrogen peroxide, organic hydroperoxides and a variety of other two-electron oxidizing agents such as peroxynitrite, hypochlorite, ozone and singlet oxygen. In all these processes the chalcogen is oxidized to the tetravalent state. The nice feature about these hypervalent species is that they can be reduced to the divalent state under very mild conditions by reductants such as thiols and ascorbate. This redox cycling is especially facile for organ ⁇ tellurium compounds and allows for their use as catalysts for the decomposition of hydroperoxides.
  • these materials are biomimetic in the sense that they can mimic the action of the selenium containing glutathione peroxidase enzymes.
  • glutathione peroxidase-likc activity There are several methods in use for the assessment of glutathione peroxidase-likc activity of simple synthetic compounds, hi the method most commonly used today, the initial rate of reduction of hydrogen peroxide (v 0 ) is calculated by monitoring the formation of diphenyl disulfide from lhiophenol by UV spectroscopy at 305 ran (Iwaoka, M.; Toraoda, S. J. Am. Chem. Soc. 1994, 116, 2557- 2561 ). Thus, what is measured here is thiol peroxidase activity rather than glutathione peroxidase activity.
  • the rate of thiol formation was corrected for the slow spontaneous thiol oxidation by subtracting the rate of disulfide formation in a control experiment run without added catalyst. All investigated compounds showed a better thiol peroxidase activity (1.52 ⁇ vo ⁇ 17.80 ⁇ Mmin " ') than diphenyl disclenide (0.67 ⁇ Mmin "1 ) which has often been used as a benchmark when catalytic activity of synthetic compounds were compared.
  • the present invention describes novel, regenerable compounds, and any acid or base addition salt or prodrug thereof, which are capable of acting as chain-breaking antioxidants by catalyzing the decomposition of peroxyl radicals in the presence of mild reducing agents and which act as preventive peroxide-decomposing antioxidants by catalyzing the reduction of hydrogen peroxide and organic hydroperoxides in the presence of mild reducing agents.
  • Compounds according to the present invention interfere with pathophysiological ⁇ important reactions in man and animals and thus effectively hamper the degradation of tissue constituent molecules as well as to act to remove harmful products from such degradation.
  • the compounds possess a unique ability to protect tissues against oxidative damage induced by overreacting host defence systems.
  • Compounds according to the present invention are therefore useful for the pharmacological treatment of diseases in which free radical-mediated or oxidative tissue degradation occurs or where oxidants trigger pro-inflammatory receptors on cell surfaces.
  • the stoichiometric reducing agents required for a catalytic mode of action of compounds according to formula I could either be exogenous and present in the environment where the antioxidant effect is desired (for example glutathione or ascorbate) or they have to be supplemented together with compounds according to the present invention.
  • Diseases such as inflammatory (including autoimmune inflammatory) conditions like asthma, bronchitis, various allergic skin and systemic disorders, Crohn's disease, ulcerative colitis, rheumatoid arthritis and other kinds of arthritis could be considered for such treatment.
  • Compounds according to the present invention together with suitable stoichiometric reducing agents may also be used for intervention of cataract and the respiratory distress syndrome. Further, the involvement of oxidative damage in atherosclerosis and in ischemia/reperfusion injury in the heart, kidney, CSN or post-operative ischemia/reperfusion injury as well as in thrombosis and embolism makes these disorders liable to intervention by the compounds according to the present invention together with suitable stoichiometric reducing agents.
  • the free radical dependent pathology of ageing and neoplasm development as well as disorders such as Parkinson's and Alzheimer's diseases may also be influenced in a favorable manner by the compounds according to the present invention together with suitable stoichiometric reducing agents.
  • the oxidative damage to tissues caused by radiation, but also by antineoplastic or immunosuppressive agents and other xenobiotics can be prevented or limited by the use of compounds according to the present invention together with suitable stoichiometric reducing agents.
  • R 1 suitably is selected from branched or unbranchcd C1-C 30 alkyl and aryl, such as phenyl, in particular from C 1 -Cs 0 alkyl.
  • the CJ-C30 alkyl is more specifically selected from C 1 -C 11 ; alkyl, e.g. from C 1 -C ⁇ alkyl, from Q-C 10 alkyl or from CpCg alkyl.
  • Ri is selected from C 3 -C1 6 alkyl, e.g. from C 4 -C ⁇ alkyl or C 6 -C 1O alkyl.
  • R 2 , R3 and R4 are independently selected from H, Ci-C 6 alkyl, CI-C O alkoxy, TV.JV-di-Ci-Cg alkylamino and N-C]-Ce alkylammo, e.g. from from H, C 1 -Ce alkyl and CI-C G alkoxy.
  • any Ci-C 6 alkyl moiety (including those present in an alkoxy or amino function) more specifically may be selected from C 1 -C 4 alkyl or from C 1 -Cs alkyl.
  • the compound according to formula 1 may be represented by any of the formulas II- VI
  • the compound is according to formula II, III or IV; in another the compound is according to formula V or VI.
  • R 1 X is in an ortho position in relation to the OH group on the nitrogen-containing hete ⁇ oaromatic cycle, i.e. the pyridinol or pyrimidinol, viz. the compound is a compound according to formula II, IV or V, for example according to formula II or IV.
  • the compound is according to formula II as defined herein above, wherein X is Te; Rj is alkyl; and R 2 and R 4 are hydrogen or alkyl and R 3 is an electron donating group such as iV,iV-dialkylammo, iV-alkylamino, alkoxy or alkyl.
  • Ri is Ci-Cie alkyl
  • R 2 and R 4 are hydrogen or Ci-C 6 alkyl
  • R 3 is an electron donating group such as N,N ⁇ d ⁇ C ⁇ -C6 alkylamino, JV-C1-C6 alkylamino, C1-C6 alkoxy or Cl- C ⁇ alkyl.
  • the compound is according to formula TII as defined herein above, wherein X is Te; Rj is alkyl; and one OfR 2 and R 3 is an electron donating group such as ⁇ N-dialkylamino, iV-alkylamino, alkoxy or alkyl and the other one is hydrogen or alkyl and R 4 is hydrogen or alkyl.
  • Rj is C 1 - C 16 alkyl
  • one of R2 and R 3 is an electron donating group such as N,N-di-C ⁇ -C6 alkylamino, /V-C1-C6 alkylamino, C1-C6 alkoxy or C1-C6 alkyl and the other one is hydrogen or alkyl and R 4 is hydrogen or C1-C6 alkyl.
  • the compound is according to formula IV as defined herein above, wherein X is Te; Ri is alkyl; and R 2 and R 4 are hydrogen or alkyl and R 3 is an electron donating group such as ⁇ iV-dialkylamino, N-alkylamino, alkoxy or alkyl.
  • Ri is Cr Ci 6 alkyl
  • R 2 and R 4 are hydrogen or alkyl
  • R 3 is an electron donating group such as N,N-di- C1-C6 alkylamino, N- C1-C6 alkylamino, C1-C6 alkoxy or C1-C6 alkyl.
  • the compound is according to formula V as defined herein above, wherein X is Te; R 1 is alkyl; and R 2 is hydrogen or alkyl and R 3 is an electron donating group such as JV, /V-dia ⁇ kylamino, ⁇ f-alkylamino, alkoxy or alkyl.
  • Ri is Ci-C ⁇ alkyl; and R2 is hydrogen or C1-C6 alkyl and R 3 is an electron donating group such as N,N-di- C1-C6 alkylamino, N- C1-C6 alkylamino, C1-C6 alkoxy or C1-C6 alkyl.
  • the compound is according to formula VI as defined herein above, wherein X is Te; Rj is alkyl; and one OfR 2 and R 3 is an electron donating group such as ⁇ JV-dialkylamino, ⁇ -alkyiamino, alkoxy or alkyl and the other one is hydrogen or alkyl.
  • R 1 is Cj- C] e alkyl; and one of R 2 and R 3 is an electron donating group such as N,N- ⁇ i- C1-C6 alkylamino, JV- C1-C6 alkylamino, C1-C6 alkoxy or C1-C6 alkyl and' the other one is hydrogen or C1-C6 alkyl .
  • R is Cj- C] e alkyl; and one of R 2 and R 3 is an electron donating group such as N,N- ⁇ i- C1-C6 alkylamino, JV- C1-C6 alkylamino, C1-C6 alkoxy or C1-C6 alkyl and' the other one is hydrogen or C1-C6 alkyl .
  • the alkyl may be more particularly selected from C1-C4 alkyl, or C1 -C3 alkyl., e.g. methyl, ethyl and propyl.
  • any electron donating group in R 2 , R 3 and/or R 4 is selected from alkoxy and alkyl as defined herein above.
  • a compound according to formula I having a hydroxy group in position n and an RiX group in position m on the nitrogen-containing heteroaromatic cycle (pyr ⁇ dinol or pyrimidinol) may be prepared, starting from a pyridinol or pyrimidmol, respectively, wherein the hydroxy function is in the position corresponding to position m in the inventive compound ("in m position"), and wherein the pyridinol or pyrimidinol additionally carries a cyano substitucnt in the position corresponding to position n in the inventive compound ("in n position"), by a method comprising a series of steps as outlined herein below.
  • Step 1 is a halogcnation, wherein a halogen, such as chlorine, bromine or iodine, is sub-stituted for the hydroxy group in m-position.
  • a halogen such as chlorine, bromine or iodine
  • Such substitution e.g. may be effected by reaction with tetrabutyl ammonium halogenide (Bu4NHal; Hal is Cl, Br or 1) in the presence of phosphorous pentoxide (P2O5).
  • Step 2 is the transformation of the cyano function in n-position into a carboxamide function. This may be achieved by acid hydrolysis, e.g. using a mineral acid such as sulfuric acid (H 2 SO 4 ) and water.
  • the carboxamide function is transformed into a primary amine function by a Hofmann rearrangement (Ilofinann degradation), e.g. using Br 2 in an aqueous alkaline solution.
  • Step 4 is a diazotization reaction wherein the primary amine function is transformed into a diazonium function, e.g. by reacting with nitrous acid (HNO 2 ) or sodium nitrite (NaNO 2 ) in the presence of a mineral acid, such as tetrafiuoroboric acid (HBF 4 ).
  • HNO 2 nitrous acid
  • NaNO 2 sodium nitrite
  • HPF 4 tetrafiuoroboric acid
  • Step 5 is a lithium-halogen exchange reaction wherein the halogen in m position is replaced by a lithium atom using a suitable alkyllithium, such as fert-butyllithium.
  • step 6 the lithiated species is reacted with elemental elemental tellurium or selenium so as to provide a lithium tellurolate or selenolate.
  • step 7 finally, the lithium is replaced by the moiety Rj, e.g. in a nucleophilic substitution reaction.
  • inventive compounds may be used as a medicament, c.g for the treatment of a disorder caused by or involving free radical-mediated or oxidative tissue damage.
  • the disorder may be e.g.
  • ischemic or reperfusion injuries selected from ischemic or reperfusion injuries, thrombosis, embolism, neoplasms, cancer, Parkinson's disease, Alzheimer's disease, arthcrosclerosis, allergic/inflammatory conditions such as bronchitis, asthma, rheumatoid arthritis, ulcerative cholitis, Crohn's disease, cataract, respiratory distress syndrome, damage caused by chemicals, radiation, antineoplastic or immunosuppressive agents, ischemia/reperfusion injury in the heart, kidney and CSN and post-operative ischemia/reperfusion injury.
  • a pharmaceutical composition comprising a compound as defined herein above, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may comprise any pharmaceutically acceptable excipients including, for example, vehicles, adjuvants, carriers or diluents, as are well- known to those who are skilled in the art and readily available to the public.
  • the pharmaceutically acceptable carrier may be one which is chemically inert to the active compounds and which have no detrimental side effects or toxicity under the conditions of use. Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy. A. R. Gcnnaro, Editor. Lippincott, Williams and WiU ⁇ ns, 20th edition (2000).
  • composition according to the invention may be prepared for any route of administration, e.g. oral or parenteral, e.g. intravenous, intramuscular, by inhalation or intraperitoneal.
  • routes of administration e.g. oral or parenteral
  • a parenterally acceptable aqueous solution is suitably employed, which is pyrogen free and has requisite pH, isotonicity, and stability.
  • Those skilled in the art are well able to prepare suitable solutions and numerous methods are described in the literature.
  • composition can be used in any standard dosage unit form, such as tablets, capsules, lozenges, elixirs, emulsions, suspensions and, in cases wherein topical application is preferred, by suppository or sub-lingual administration.
  • pharmaceutical composition can be utilized as a micronized powder and administered from a powder-inhaler with or without pharmaceutically inert carrier.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammaL over a reasonable lirne frame.
  • dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage/severity of the disease.
  • the dose will also be determined by the route (administration form), timing and frequency of administration.
  • the compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of disorder caused by or involving tree radical-mediated or oxidative tissue damage.
  • additional drugs useful in the treatment of disorder caused by or involving tree radical-mediated or oxidative tissue damage.
  • the disorder is a cancer
  • such an additional drug may be a cytostatic drug.
  • the components may be in the same fonnulation or in separate formulations for administration simultaneously or sequentially.
  • the compounds of the present invention may also be used or administered in combination with other treatment, such as e.g. irradiation for the treatment of cancer.
  • the pharmaceutical composition also comprises at least one pharmaceutically acceptable, mild reducing agent, as defined herein above.
  • the reducing agent may be selected from //-acetylcysteine, cysteine, dithiothreitol, glutathione, ascorbic acid and sodium ascorbate.
  • the invention relates to an antioxidant composition
  • an antioxidant composition comprising a compound according to the invention or a suitable salt thereof, and a mild reducing agent for use in the preservation of a liquid, solid or semi-solid material against oxidative degradation.
  • the material to be preserved may be organic or inorganic and natural or synthetic, e.g. a polymer, elastomer, oil, lubricant, grease, fuel or paint composition o ⁇ a paper or pulp product, comprising the antioxidant composition.
  • the invention relates to a method of preserving a liquid * solid or semi-solid organic material, as defined herein above, against oxidative degradation, by adding an antioxidant composition according to the invention to the polymer, elastomer, oil, lubricant, grease fuel or paint composition or paper or pulp product.
  • the antioxidant composition may suitably be added e.g. at the preparation or processing of the material or may be added al any point to an already prepared material with a view to preserving it against oxidative degradation.
  • the antioxidant composition of the invention is added to a material susceptible to oxidative degradation, whereby a homogenous mixture of the material and the antioxidant composition is produced, e.g. using mixing equipment well-known to the skilled in the art.
  • Examples 1, 12-19, 26 and 27 relate to the preparation of intermediary compounds, useful in the preparation of compounds according to the invention.
  • Examples 2, 3, 5, 6, 8, 9, 2O 5 21 ? 23, 24, 25, 28 and 29 relate to the preparation of compounds according to the invention;
  • Examples 4, 7, 10, 22 and 30 relate to the preparation of related compounds, not according to the invention.
  • the toluene layer was decanted and washed with a saturated solution of NaHC ⁇ 3 (30 mL) and then with water (50 mL). To the oily residue left in the flask was added water (50 mL) and then powdered NaHCO 3 portionwise until there were no further evolution of gas. The mixture was extracted with CH 2 Cl 2 (ca. 250 mL), washed with brine (50 mL x 2) and then with water (30 mL). The toluene and CH 2 Cl 2 solutions were combined and dried (MgSO 4 ).
  • 2-Bromo-5-methoxy-4,6-dimethylpyridine 3-Amino-2-bromo-5-methoxy-4,6- dimethylpyridine (231 mg, 1.00 mmol) was dissolved in HBF 4 (0.5 mL, 50 % aq. solution), water (0.5 mL) was added and the resulting brownish solution cooled to O 0 C. NaNO 2 (83 mg, 1.2 mmol) in water (0.5 mL) was added dropwise at O 0 C. The resulting solution was stirred for 1 Ii at this temperature when hypophosphorous acid (0.491 mL 50% in H 2 O 5 4.74 mmol) was quickly added.
  • Thiol peroxidase activity was determined spectrophotometrically as recently described.
  • THP-I oxygen free radicals over time from macrophages
  • Greiner 96-wel ⁇ white optiplates
  • Diogenes chemilumincsccnce kit National Diagnostics
  • Approximately 200 000 THP-I cells diluted in HBSS containing various amounts of organoteliurium 17 and JV-acetylcysteine (NAC) was added per well to a 96 well plate together with the Diogenes reagent 20 v/% (folio whig the manufacturer's recommendations) and 40 micro-M phorbol myristate acetate (PMA).
  • Luminescence intensity was read every 6 min. All measurements were performed in quadruplicate (error-bars shown).

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Abstract

L'invention porte sur des composés comprenant un noyau 3-pyridinol ou 5-pyrimidinol portant un substituant organoséléno ou organotelluro sur le noyau pyridine ou pyrimidin et présentant des propriétés anti-oxydantes utiles. Les composés peuvent, par exemple, être conformes à la formule suivante (I) telle que définie ici. Les propriétés anti-oxydantes de rupture de chaîne catalytique de décomposition d'hydropéroxyde sont également décrites. De plus, les composés peuvent être utilisés en combinaison avec un agent réducteur. Les composés sont utiles pour la stabilisation de matières synthétiques et naturelles, ou pour la prévention ou le traitement de troubles provoqués ou mettant en jeu un dommage tissulaire à médiation par radicaux libres ou oxydants.
PCT/EP2009/056468 2008-05-29 2009-05-27 Composés comprenant un noyau 3-pyridinol ou 5-pyrimidinol à substituant organoséléno ou organotelluro utilisés comme anti-oxydants Ceased WO2009144253A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8877766B2 (en) 2013-02-15 2014-11-04 Peter F. Kador Neuroprotective multifunctional antioxidants and their monofunctional analogs
WO2018131924A1 (fr) * 2017-01-13 2018-07-19 영남대학교 산학협력단 Dérivé de pyridinol ou sel pharmaceutiquement acceptable de ce dernier, et composition pharmaceutique pour prévenir ou traiter des maladies autoimmunes contenant ce dernier en tant que principe actif
CN114436952A (zh) * 2020-11-02 2022-05-06 杭州珠联医药科技有限公司 2-甲氧基-3-氨基-5-吡啶硼酸频哪醇酯及其中间体的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4550168A (en) * 1982-07-14 1985-10-29 A. Nattermann & Cie Gmbh Benzisoselenazolones and a process for the treatment of inflammatory diseases
EP0723778A1 (fr) * 1994-12-29 1996-07-31 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) Compostion modulant d'apoptose comprenant un facteur influençant le taux intracellulaire de méthional ou de malondialdéhyde
WO2002000683A2 (fr) * 2000-06-23 2002-01-03 Vanderbilt University Nouveaux antioxydants a rupture de chaine
WO2004047925A2 (fr) * 2002-11-22 2004-06-10 Exeter Antioxidant Therapeutics Limited Catalyseurs d'oxydation therapeutiques
EP1541145A1 (fr) * 2002-06-19 2005-06-15 Institute of Materia, Chinese Academy of Medical Sciences Utilisation de composes benzisoselenazolones contre les lesions myocardiques ischemiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4550168A (en) * 1982-07-14 1985-10-29 A. Nattermann & Cie Gmbh Benzisoselenazolones and a process for the treatment of inflammatory diseases
EP0723778A1 (fr) * 1994-12-29 1996-07-31 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) Compostion modulant d'apoptose comprenant un facteur influençant le taux intracellulaire de méthional ou de malondialdéhyde
WO2002000683A2 (fr) * 2000-06-23 2002-01-03 Vanderbilt University Nouveaux antioxydants a rupture de chaine
EP1541145A1 (fr) * 2002-06-19 2005-06-15 Institute of Materia, Chinese Academy of Medical Sciences Utilisation de composes benzisoselenazolones contre les lesions myocardiques ischemiques
WO2004047925A2 (fr) * 2002-11-22 2004-06-10 Exeter Antioxidant Therapeutics Limited Catalyseurs d'oxydation therapeutiques

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AGRAWAL K C ET AL: "Comparative studies of the antineoplastic activity of 5-hydroxy-2-formylpyridine thiosemicarbazone and its seleno- semicarbazone, guanylhydrazone and semicarbazone analogs", BIOCHEMICAL PHARMACOLOGY, PERGAMON, OXFORD, GB, vol. 23, no. 17, 1 September 1974 (1974-09-01), pages 2421 - 2429, XP025524262, ISSN: 0006-2952, [retrieved on 19740901] *
CHEN, WEI-MIN ET AL: "3,3'-[Diselenobis(methylene)]bis[5-hydroxy-6-methyl-4-pyridinemethanol]", MOLECULES [ELECTRONIC PUBLICATION] , 3(8), M90 CODEN: MOLEFW; ISSN: 1420-3049 URL: HTTP://WWW.MDPI.ORG/MOLBAND/M0090.HTM, 1998, XP008111492 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 12 January 1991 (1991-01-12), TOKAMI, KENJIROU ET AL: "Carbon-13 nuclear magnetic resonance spectroscopy of organic selenide and diselenide compounds", XP002544759, retrieved from STN Database accession no. 1991:5691 *
KUMAR, SANGIT ET AL: "Catalytic Chain-Breaking Pyridinol Antioxidants", ORGANIC LETTERS , 10(21), 4895-4898 CODEN: ORLEF7; ISSN: 1523-7060, October 2008 (2008-10-01), XP002544757 *
KUMAR, SANGIT ET AL: "Microwave-assisted copper-catalyzed preparation of diaryl chalcogenides", JOURNAL OF ORGANIC CHEMISTRY , 71(14), 5400-5403 CODEN: JOCEAH; ISSN: 0022-3263, 2006, XP002544758 *
SMITH, KEITH ET AL: "Chemistry of phenoxathiins and isosterically related heterocycles. XXXVI. Novel heterocyclic systems. Part 28. Preparation and characterization of the 1,6-, 1,7-, 1,8-, and 1,9-diazaphenoxaselenines: an unexpected divergence between closely related sulfur and selenium systems", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY (1972-1999) , (12), 2839-43 CODEN: JCPRB4; ISSN: 0300-922X, 1987, XP008111557 *
WAKAYAMA KOGYO KOTO SENMON GAKKO KENKYU KIYO , 24, 52-6 CODEN: KKWGD7; ISSN: 0287-5381, 1989 *

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* Cited by examiner, † Cited by third party
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US8877766B2 (en) 2013-02-15 2014-11-04 Peter F. Kador Neuroprotective multifunctional antioxidants and their monofunctional analogs
WO2018131924A1 (fr) * 2017-01-13 2018-07-19 영남대학교 산학협력단 Dérivé de pyridinol ou sel pharmaceutiquement acceptable de ce dernier, et composition pharmaceutique pour prévenir ou traiter des maladies autoimmunes contenant ce dernier en tant que principe actif
CN114436952A (zh) * 2020-11-02 2022-05-06 杭州珠联医药科技有限公司 2-甲氧基-3-氨基-5-吡啶硼酸频哪醇酯及其中间体的合成方法

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