WO1998034646A2 - Anti-oxydants cibles - Google Patents

Anti-oxydants cibles Download PDF

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Publication number
WO1998034646A2
WO1998034646A2 PCT/GB1998/000359 GB9800359W WO9834646A2 WO 1998034646 A2 WO1998034646 A2 WO 1998034646A2 GB 9800359 W GB9800359 W GB 9800359W WO 9834646 A2 WO9834646 A2 WO 9834646A2
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compound
antioxidant
moiety
hydroxy
precursor
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PCT/GB1998/000359
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English (en)
Inventor
Christopher Kenneth Atterwill
Wendy Maria Purcell
Fyaz Mahmood Daud Ismail
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University Of Hertfordshire
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Priority to AU59966/98A priority Critical patent/AU5996698A/en
Publication of WO1998034646A2 publication Critical patent/WO1998034646A2/fr

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    • 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

Definitions

  • the present invention relates to antioxidants for use in medicine and clinical research.
  • the invention relates to antioxidants which are targeted to particular areas of the body and, especially, the brain and central nervous system.
  • Reactive oxygen species are constantly formed in biological systems but, normally, free radical production and consequent tissue damage are controlled by a series of naturally occurring antioxidant defence mechanisms. Oxidative phosphorylation primarily takes place in mitochondria where reactive oxidant species are tightly bound and can be safely reduced to water. The superoxide radical is dismutated by superoxide dismutase to hydrogen peroxide which can then be removed by either catalase or glutathione peroxidase. Chain breaking antioxidants or free radical scavengers such as ⁇ - tocopherol (vitamin E) can react directly with free radicals and thereby spare more critical molecules.
  • oxidation reactions can be influenced by the regional concentration of a transition metal. Recycling of iron from its oxidised state to its reduced state by tissue ascorbate. glutathione or dopamine can drive oxidation reactions and the formation of a cascade of free radicals. Iron is more likely to participate in redox reactions when it is in a low oxidation state, usually complexed to ATP or citrate. Proteins such as transferrin or ferritin which bind iron and maintain it in a relatively non-reactive state thus serve as another important antioxidant defence mechanism.
  • Oxidative stress is associated with many medical conditions because of the tissue damage caused by free radicals.
  • the superoxide radical may react with endogenous nitrogen monoxide to give peroxynitrite which can then be protonated to form the nitrosyl radical which decomposes to give the hydroxyl radical.
  • Peroxynitrite is a highly reactive oxidising agent capable of causing tissue damage and the reaction between superoxide and nitrogen monoxide has been proposed to mediate toxicity associated with excitatory amino acids and with ischemia and reperfusion and tissue damage and can be blocked by agents that inhibit superoxide or nitrogen monoxide formation.
  • Brain cells appear to be at particular risk from free radical damage.
  • the mammalian brain contains large amounts of substrates, such as unsaturated lipids and catecholamines, which are susceptible to free radical attack.
  • Polyunsaturated fatty acids are a major constituent of cell membranes and a substrate for lipid peroxidation.
  • iron which promotes cytotoxic radical formation, accumulates in specific brain regions, such as the globus pallidus and the substantia nigra, in concentrations which exceed those found in the liver.
  • Defense mechanisms in the brain are relatively deficient as the brain contains almost no catalase and has reduced concentrations of glutathione, glutathione peroxidase and vitamin E. Iron binding capacity appears to be limited in the CNS.
  • any imbalance of cellular redox status in favour of greater oxidative activity can lead to several kinds of macromolecular damage such as disruption of genomic function by alterations to DNA or impairment of membrane properties by attack on proteins and lipids.
  • Lipid peroxidative events are especially hazardous since lipoperoxy radicals can initiate chain reactions.
  • the high lipid content of myelin makes nervous tissue especially susceptible to oxidative stress.
  • antioxidants may be of clinical use in the treatment of several types of diseases and conditions, in particular, diseases and conditions associated with oxidative damage to brain tissue.
  • DAT ATOP deprenyl and tocopherol antioxidative therapy of Parkinsonism
  • 6-Hydroxydopamine (6-OHDA), a dopamine neurotransmitter analogue generates cytolytic oxygen radicals in neuroblastoma cells that take it up.
  • This analogue is, however, systemically toxic due to its spontaneous oxidation; this toxicity is particularly severe in the sympathetic nervous system since such tissues selectively concentrate dopamine and its analogues. Lowering the dose of 6-OHDA below systemic toxic levels prohibitively compromises its antitumour effect.
  • the group administered an antioxidant (Tempol, 250 mg/kg, i.p.) prior to giving 6-OHDA. This combination of pretreatment with an antioxidant followed by treatment with 6-OHDA reduced the cancer mortality and systemic toxic effects due to 6-OHDA.
  • Lazaroids are inhibitors of free radical formation and lipid peroxidation.
  • the effects of two lazaroids, U-74389G (21-aminosteroid) and U-83836E (combines the piperazinyl pyrimidine portion of 21-aminosteriod with the antioxidant ring of ⁇ -tocopherol) were studied on the survival of cultured rat dopamine neurons (Frodl et al, NeuroReport, (1994), 5, 2393-2396 and Nakao et al, Proc, .Natl. Acad. Sci. USA, (1994) 91, 12408- 12412).
  • the lazaroids were shown to enhance the survival of dopaminergic neurons in vitro but the total number of neurons was also increased by lazaroids and therefore the lazaroids did not specifically target the dopaminergic neurons.
  • This study indicates that reduction of free radical formation is effective in reducing neuronal loss relevant to the pathogenesis of neural disease such as Parkinson's disease.
  • Antioxidants such as vitamin E are also used as dietary supplements and have been shown to ameliorate renal injury in an experimental model of immune-mediated nephropathy (Trachtman et al, Paed. Res. , (1996), 40, 620-626) and supported the use of dietary treatment with this antioxidant in patients with similar disease.
  • Vitamin E supplementation was also shown to reduce iron-induced oxidative stress in the liver (Parkkila et al, Am. J. Ph siol - GI & Liver Physiol. , (1996), 33, 376-384). High dose vitamin E may also slow the rate of motor function decline in the course of Huntington's disease.
  • antioxidants could be useful agents for the treatment of various diseases and conditions, particularly neurological diseases or conditions but also other conditions such as renal disease.
  • various diseases and conditions particularly neurological diseases or conditions but also other conditions such as renal disease.
  • problems with the use of antioxidants in the treatment of such conditions the main problem being that it is difficult to target the antioxidant to the required tissue. This problem is particularly acute for diseases of the central nervous system.
  • a compound comprising an antioxidant moiety chemically joined to a targeting moiety capable of targeting specific populations of cells by exploiting endogenous uptake systems for biological chemicals.
  • the antioxidant is targeted to the particular cells where it is required and, secondly, the targeting moiety will metabolise to form a compound which will replenish biological cellular chemicals important in homeostasis.
  • an antioxidant moiety with a targeting moiety to form a targeted antioxidant permits targeted delivery of the antioxidant directly to specific groups of cells, including neurons, where cellular stress is associated with pathology, including that associated with normal ageing and neurodegenerative disorders. While antioxidant therapy has been explored for therapeutic efficacy in a number of pathological conditions, joining the antioxidant to a group capable of targeting a specific population of dying cells has not previously been considered.
  • the antioxidant moiety may be either an enzymatic or a non-enzymatic antioxidant which possesses the ability to reduce the formation and/or production of free radical species generated by redox reactions of oxygen and nitrogen occurring in biological systems.
  • antioxidants include ⁇ -tocopherol (vitamin E), other tocopherols, ⁇ -carotene, ascorbic acid (vitamin C) and many others.
  • Analogues of ⁇ -tocopherol may also be used as antioxidants and suitable antioxidants based on ⁇ -tocopherol and its analogues are represented by general formula I:
  • R 1 is C,-C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, aryl or heteroaryl, any of which may optionally be substituted with one or more fluoro, chloro, bromo, amino, nitro, azo or diazo groups
  • R 2 , R 4 , R 5 , R 7 and R 8 is, independently, hydrogen, fluoro, chloro, bromo or
  • R is hydrogen or, together with R or R , may form a double bond
  • R 6 is OH, NHR 9 ,SH, Cl, Br or F;
  • R 9 is C,-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
  • n 0 or 1.
  • C,-C 6 alkyl refers to a straight or branched alkyl group having from one to six carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isobutyl and tertiary butyl. References to C r C 8 alkyl and C,-C 24 alkyl should be construed accordingly.
  • C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having from two to six carbon atoms and one or more carbon-carbon double bonds. Examples of such groups include ethenyl, propenyl, 1-butenyl, 2-butenyl and isoprenyl. References to C 2 - C 8 alkenyl and C 2 -C 24 alkenyl should be construed accordingly.
  • C 2 -C 6 alkynyl refers to a straight or branched alkynyl group having from two to six carbon atoms and one or more carbon-carbon triple bonds. Examples of such groups include ethynyl, propynyl, 1-butynyl and 2-butynyl. References to C 2 -C 8 alkynyl and C 2 -C 24 alkynyl should be construed accordingly.
  • aryl refers to an aromatic carbocyclic ring system having from five to 14 carbon atoms and one or more aromatic rings. Examples of such systems include phenyl, naphthalenyl and anthracenyl.
  • the aryl group may be partially saturated, for example tetrahydronaphthalenyl, provided that it retains aromatic character.
  • heteroaryl refers to an aromatic ring system having one or more aromatic rings and from 5 to 14 atoms, at least one of which is a heteroatom selected from nitrogen, oxygen or sulphur.
  • the hetroaryl group many be partially saturated, provided that it retains aromatic character.
  • heteroaryl groups include pyridyl, pyrimidyl, furanyl, pyranyl, benzofiiranyl, imidazolyl, imidazolinyl and benzimidazolinyl.
  • Preferred compounds include those in which R 6 is OH or NH 2 and R 1 is C 2 -C 24 alkenyl optionally substituted by one or more azo or diazo groups, R 5 , R 7 and R 8 are methyl or ethyl and n is 1, and fluorinated derivatives of such compounds.
  • Particularly preferred compounds are ⁇ -tocopherol itself (R 1 is OH R 2 is phytyl, R 3 , R 4 and R 5 are methyl and n is 1), ⁇ -tocopherol .and their derivatives in which the phytyl group is substituted by one or more azo or diazo groups.
  • Compounds of formula I are particularly suitable for inclusion in compounds which are intended to treat disorders of the central nervous system.
  • antioxidants examples include: ⁇ -tocopherol;
  • the antioxidant may be a compound which can trap oxidising radicals at low tension environments.
  • Such compounds include carotene-like substances, for example retinoic acid.
  • a targeting moiety may be a group which is the precursor of a biological cellular chemical and which can be taken up by specific populations of cells, including neurons, via various routes, for example diffusion, facilitated diffusion, carrier systems and active processes.
  • the targeting moiety may be a transport system amino acid.
  • targeting moieties include amine precursors such as levodopa, 5- hydroxytryptophan, choline and histidine, which are the precursors respectively of dopamine, 5-hydroxytryptamine, acetylcholine and histamine; poly amine precursors such as spermine, spermidine and putrescine and amino acids such as glutamate and aspartate, which are transport systems for glutamatergic and gabaergic cells respectively.
  • amine precursors such as levodopa, 5- hydroxytryptophan, choline and histidine, which are the precursors respectively of dopamine, 5-hydroxytryptamine, acetylcholine and histamine
  • poly amine precursors such as spermine, spermidine and putrescine and amino acids such as glutamate and aspartate, which are transport systems for glutamatergic and gabaergic cells respectively.
  • a protected version of the targeting moiety may be used and this is particularly useful for precursors such as levodopa, which is sparingly soluble in organic solvents making it difficult to prepare the compounds of the present invention.
  • Suitable protected targeting groups include boc, neuropeptides, peptides or ⁇ -alkylated amino acid peptides (peptoids). These protected forms of the targeting moiety can be chemically joined to the anti-oxidant with or without an intervening link in the molecule of the present invention and administered to a patient as prodrugs. In the case of levodopa, it is advantageous to protect both the phenolic and the carboxylic portions of the molecule to prevent premature oxidation of such groups.
  • the targeting moiety and the anti-oxidant may be chemically joined by means of a covalent bond.
  • superior results have been obtained when the anti-oxidant and the targeting moiety are joined via a linking group, which preferably contains nitrogen.
  • linker groups include -NH-, methylene chains of from 1 to 50 carbon atoms and optionally containing one or more hetero atoms, which may either interrupt the methylene chain or be at one or both ends of the chain. Shorter linkers of from 1 to
  • the linker is formed from a diamine and, thus, has an -NH- group at either end of the chain.
  • linkers of this type include ethane- 1,2-diamine; propane-l,2-diamine; racemic, RR and SS forms of cyclohexane 1,2-diamine; propane 1,3-diamine; butane-
  • 1,4-diamine pentane-l,5-diamine; 2-methylpentane-l,5-diamine; hexane-l,6-diamine; heptane- 1,7-diamine; octane- 1,8-diamine; nonane-l,9-diamine; decane -1,10-diamine; dodecane-l,12-diamine; putrescine, cadavarine, spermine and spermidine.
  • the linker group may be an aromatic, heteroaromatic, carbocyclic or alicyclic ring having from 5 to 14 atoms and one or more rings.
  • Such ring systems may link the antioxidant and the targeting moiety via nitrogen atoms, for example in diaminocyclohexyl and 1,3-diaminoadamantyl.
  • the compounds of the present invention may be prepared in a variety of ways depending upon the nature of the anti-oxidant, the precursor and the chemical linkage.
  • Anti-oxidants of general formula I may be prepared by methods known to those skilled in the art. For example, a phenol or hydroquinone derivative may be reacted with isoprene or a propenol or butenol derivative. Greater details of such syntheses are given in Example 1 below and in the literature, for example Vitamin E: A Comprehensive Treatise, L J Machlin (Ed), Marcel Dekker, New York (1980), L J Machlin in Handbook of Vitamins, Nutrittonal, Biochemical and Clinical Aspects, Chapter 3, L J Machlin (Ed) Marcel Dekker, New York (1984) pages 7-65 and Ismail et al Tetrahedron Lett. 33(26) 3795-3796 (1992).
  • the anti-oxidant and the targeting moiety may be coupled by any suitable technique which would be familiar to one skilled in the art of chemistry.
  • the targeting moiety or the anti-oxidant contains a free amine group
  • the following method can be used. The same method is appropriate for coupling an antioxidant moiety to a linker group (which may already have been joined to a targeting moiety) and in which either the antioxidant moiety or the linker contains a free terminal amine group.
  • the amine group is referred to as being on the targeting moiety or linker but the method would be equally effective when the free amine group is on the anti-oxidant.
  • a halogenated derivative of the anti-oxidant moiety is prepared.
  • the halogenated derivative is preferably a brominated or a chlorinated derivative and may be prepared using any conventional method.
  • Brominated derivatives of antioxidants of general formula I may be synthesised by reacting the compound of general formula I with one mole equivalent of bromine in a dry solvent under an atmosphere of either nitrogen or, preferably, argon. Bromine preferentially attacks at allylic positions within the molecule.
  • the reaction may be conducted in the presence or absence of UV light, which can influence the site of bromination. The particular effects of UV light in such reactions will be familiar to those skilled in the art.
  • reaction solvents examples include chloroform, dichloromethane and carbon tetrachloride.
  • the reaction can also be conducted in suitable hydrocarbon solvents and is only limited by the solubility of the compounds that require bromination. Fluorocarbon solvents can also be used provided the reaction is cooled to ensure that the solvent remains liquid. The cooling may be carried out by any of a variety of techniques known to those skilled in the art.
  • the preferred reaction solvent is carbon tetrachloride.
  • the reaction can also be conducted using N-methylpyrrolidin-2-one. If desired, the reaction may be assisted by use of an acid scavenger such as sodium hydrogen carbonate or, preferably, triethylamine. Any other suitable tertiary amine can be used, provided that it is not unsaturated, for example trimethylamine, tripropylamine, etc.
  • an acid scavenger such as sodium hydrogen carbonate or, preferably, triethylamine.
  • Any other suitable tertiary amine can be used, provided that it is not unsaturated, for example trimethylamine, tripropylamine, etc.
  • the reaction is performed with external cooling and must be below 0°C during the addition of bromine.
  • reaction products may be separated from one another using gravity column, flash column medium or high pressure liquid chromatography and capillary zone electrophoresis.
  • the preferred material for separation is either silica or alumina. Higher molecular weight compounds are preferably separated using medium pressure liquid chromatography or gel exclusion/permeation chromatography.
  • Suitable solvents include halogenated solvents such as carbon tetrachloride, chloroform or dichloromethane or other non-polar or polar aprotic solvents such as diethyl ether, n- hexane, petroleum ether, dioxane or tetrahydrofuran.
  • the reaction temperature may be from -50 to 10°C, preferably from about -30 to -5°C and typically about -25 to -20°C. It is preferred that the reaction is carried out under an inert atmosphere such as nitrogen or argon.
  • the product of this reaction is an ammonium halide derivative and this may be converted to the required compound by reaction with a base, typically a strong base such as an alkali metal hydroxide, typically sodium hydroxide.
  • a base typically a strong base such as an alkali metal hydroxide, typically sodium hydroxide.
  • the reaction may be carried out in an organic solvent such as dichloromethane or, alternatively, in aqueous solution if the ammonium halide is insoluble or sparingly soluble in organic solvents.
  • This method is particularly useful for the coupling of tocopherols and other antioxidants of general formula I to targeting moieties and linkers such as levodopa, 5-HT, choline, histidine, spermine, spermidine, putrescine, glutamate and aspartate.
  • moieties and linkers such as levodopa, 5-HT, choline, histidine, spermine, spermidine, putrescine, glutamate and aspartate.
  • a linker may be coupled to the targeting moiety either before, after, or simultaneously with the coupling reaction to the anti-oxidant.
  • standard methods may be used, for example, a linker with a terminal amino group may be coupled to a targeting moiety with a halo or ester group or a linker with a terminal ester or halo group may be coupled to a targeting moiety with a free amino group using standard methods known to those skilled in the art.
  • the linker is symmetrical and has two terminal amino groups and the targeting moiety is halogenated, the coupling reactions of the linker to the targeting moiety and the anti-oxidant can be carried out simultaneously. This method is appropriate for both chain and cyclic linkers.
  • the above method may be used in the following ways: a) reacting a brominated antioxidant with a targeting moiety having a free amine group; b) reacting a halogenated antioxidant with a targeting moiety attached to a linker having a free amine group; c) reacting a halogenated antioxidant and a halogenated targeting moiety simultaneously with a linker having two free amine groups; d) reacting a halogenated targeting moiety with an antioxidant having a free amine group; or e) reacting a targeting moiety attached to a halogenated linker with an antioxidant having a free amine group.
  • the targeting moiety may be reacted with an anti-oxidant precursor so that an antioxidant moiety is formed during the course of the reaction.
  • an amine-containing targeting moiety such as dopa with trimethyl tetrahydroquinone and formaldehyde leads to the formation of a 1,3-oxazoline ring system in which the nitrogen atom is the nitrogen atom of dopamine.
  • the reaction may be conducted simply by heating the reactants under reflux in an appropriate solvent such as N-methyl pyrrolidone or a mixture of dimethylsulfoxide and dimethylformamide.
  • novel compounds of the present invention are useful in a variety of therapeutic indications and therefore in a further aspect of the present invention, there is provided a compound comprising an antioxidant moiety chemically joined to a precursor chemical moiety capable of targeting specific populations of cells by exploiting endogenous uptake systems for biological chemicals for use in medicine.
  • the present invention is of use in the treatment of neurodegenerative disorders, including those associated with aging.
  • the central nervous system is particularly susceptible to the cytotoxic activities of free radical attack because of its high lipid content, high rate of oxidative metabolism and relatively low levels of endogenous free radical scavenging systems.
  • various areas of the CNS are rich in iron, for example the substantia nigra and corpus striatum. For this reason, the invention is particularly useful for targeting cells of the CNS.
  • ⁇ -tocopherol and its variants of formula I have been found to be particularly suitable antioxidants.
  • the reason for this is that ⁇ -tocopherol has been found to be protective against chemically induced neurotoxicity (Bondy NeuroToxicol. (1992) 13 87-100).
  • the primary biological function of ⁇ -tocopherol is the protection of polyunsaturated fats in membranes against oxidation. It is incorporated into cell membranes and thereby protects against free-radical attack in the lipid phase.
  • brain concentrations of vitamin E and other antioxidants are reduced. Provision of the vitamin E or other antioxidants to the specific neuronal population undergoing oxidative stress by joining the antioxidant to a suitable targeting moiety, such as an amine, enables targeted delivery of the antioxidant to the neurone population under stress.
  • the majority of endogenous antioxidant systems in the CNS are present in neural cells other than neurons. This means that neurons are particularly vulnerable to the effects of oxidative stress. Therefore, it is especially preferred that, in the present invention, the cells which are targeted by the targeting moiety are neurons, for example dopaminergic, serotoninergic, cholinergic or histaminergic neurons.
  • the targeting moiety is preferably an amine required for the production of neurotransmitter chemicals.
  • the targeting moiety may be levodopa, 5-hydroxytryptophan, choline or histidine, the precursors respectively of the neurotransmitters dopamine, serotonin (5-hydroxytryptamine), acetylcholine and histamine.
  • the precursor amine moiety accesses specific nerve terminals by exploiting uptake systems present on neuronal membranes and thus makes possible the targeted delivery of the antioxidant moiety directly to specific groups of cells.
  • the compound of the present invention may be used in a method for the treatment of Parkinson's disease, the method comprising administering to a patient an appropriate amount of a compound comprising an antioxidant chemically joined to levodopa.
  • the antioxidant is preferably ⁇ -tocopherol or another compound of general formula I, although other antioxidants may also be employed.
  • Parkinson's disease is also known as striatal dopamine deficiency and involves the destruction of the dopamine neurons of the nigrostriatal pathway.
  • Dopaminergic circuitry is especially vulnerable to free radical damage and progression of the disease is associated with free radical attack leading to further loss of dopamine neurons.
  • Parkinson's disease In the early stages of Parkinson's disease, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progresses, however, the number of dopamine receptors decreases, apparendy due to the concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of highly neurotoxic hydroxyl radicals.
  • dopamine turnover is likely to be increased in surviving neurons with a resultant increase in the formation of hydrogen peroxide
  • iron concentration is increased in the substantia nigra thereby increasing the likelihood of an interaction with hydrogen peroxide and consequent formation of the hydroxyl radical;
  • lipid peroxidation is increased in the substantia nigra.
  • the compounds of the present invention in which levodopa or a protected form thereof is chemically joined to an antioxidant such as vitamin E exploit the dopamine uptake system of dopaminergic neurons and thereby deliver a non-enzymic antioxidant directly to the stressed neurons together with the precursor required in the manufacture of dopamine to restore neurotransmitter levels. Therefore, the invention provides, in a further aspect, a compound comprising an antioxidant, preferably a compound of general formula I, chemically joined to levodopa or a protected form thereof for use in the treatment of Parkinson's disease.
  • the invention also provides the use of a compound comprising an antioxidant, preferably a compound of general formula I, chemically joined to levodopa or a protected form thereof, in the preparation of an agent for the treatment of Parkinson's disease.
  • a second clinical use for the compounds of the present invention is in a method for the treatment of substituted amphetamine neuropathology arising from the recreational use of drugs such as 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy), the method comprising administering to a patient a compound comprising levodopa or a protected form thereof and/or 5-hydroxytryptophan chemically joined to an antioxidant, for example a compound of general formula I.
  • MDMA 3,4-methylenedioxymethamphetamine
  • Ecstasy 3,4-methylenedioxymethamphetamine
  • MDMA severe acute toxicity arising from abuse of MDMA and there is growing concern that it may cause long term toxic damage to serotoninergic neurons; dopaminergic pathways may also be affected.
  • the neurotoxicity of MDMA may in part be due to oxidative stress relating to dopaminergic and serotoninergic circuitry, inferred by attenuation of induced neuropathological changes by pretreatment with a variety of antioxidants.
  • a targeted antioxidant drug of the present invention comprising an antioxidant linked to 5-hydroxytryptophan and/or levodopa or a protected form thereof will be of use in the treatment of conditions arising from the use of MDMA and similar drugs.
  • the invention provides, in a further aspect, a compound comprising an antioxidant, preferably a compound of general formula I, chemically joined to levodopa or a protected form thereof and/or 5-hydroxytryptophan for use in the treatment of neuropathological conditions induced by amphetamines such as MDMA.
  • an antioxidant preferably a compound of general formula I, chemically joined to levodopa or a protected form thereof and/or 5-hydroxytryptophan for use in the treatment of neuropathological conditions induced by amphetamines such as MDMA.
  • the invention also provides the use of a compound comprising an antioxidant, preferably a compound of general formula I chemically joined to levodopa or a protected form thereof and/or 5-hydroxytryptophan in the preparation of an agent for the treatment of neuropathological conditions induced by amphetamines such as MDMA.
  • an antioxidant preferably a compound of general formula I chemically joined to levodopa or a protected form thereof and/or 5-hydroxytryptophan
  • a third clinical use for the compounds of the present invention is in a method for the treatment of Alzheimer's disease, the method comprising administering to a patient an effective amount of a compound according to the present invention and comprising an antioxidant such as a compound of general formula I chemically joined to choline and/or histidine.
  • Alzheimer's disease is the most common cause of progressive intellectual failure.
  • the lesions that develop in the brain called senile plaques, are extracellular deposits principally composed of insoluble aggregates of ⁇ -amyloid protein.
  • ⁇ -Amyloid has been shown to exert a direct toxic effect on neurons in vitro via induction of oxidant stress; the antioxidant vitamin E prevents such toxicity.
  • Alzheimer's disease is largely an age-related condition with an incidence that closely parallels increases in cellular oxidative stress and subsequent formation of dysfunctional proteins.
  • Neuronal injury in Alzheimer's disease is associated with oxidant stress.
  • Alzheimer's disease is a multisystem disorder in which cholinergic and monoaminergic (especially histamine neuroimmune interactions) neurotransmissions are altered.
  • the main focus of current therapeutic approaches is the maintenance of acetylcholine levels since basal forebrain cholinergic neurons are lost in Alzheimer's disease.
  • cognitive improvement appears short-lived and there are associated toxicity problems.
  • the compounds of the present invention will afford a novel therapeutic strategy to tackle Alzheimer's disease.
  • the invention provides a compound comprising an antioxidant, preferably a compound of general formula I, chemically joined to choline and/or histidine for use in the treatment of Alzheimer's disease.
  • the invention also provides the use of a compound comprising an antioxidant, preferably a compound of general formula I chemically joined to choline and/or histidine in the preparation of an agent for the treatment of Alzheimer's disease.
  • the compounds of the invention may be administered as the free bases or, if more appropriate, as physiologically compatible salts such as hydrochlorides.
  • the compounds may be used alone but will preferably be admixed with suitable excipients to form a pharmaceutical composition. Therefore, the invention provides in a further aspect a pharmaceutical or veterinary composition comprising a compound according to the present invention together with a pharmacologically or veterinarily acceptable excipient.
  • compositions may be adapted for administration by any suitable route, for example by oral, nasal, buccal or transdermal administration or by parenteral, for example intravenous or intramuscular administration.
  • compositions for oral administration may be formulated as liquids, for example solutions or suspensions which may contain liposomes or micelles, or as solids, for example as tablets or capsules.
  • Nasal formulations may be in the form of liquids, for example solutions or micellar or liposomal compositions, which can be administered as a spray and buccal and transdermal formulations may be formulated as solid slow release compositions.
  • compositions adapted for parenteral administration will generally be in the form of injectable solutions, again, these may, if necessary, have the compounds contained in micelles or liposomes.
  • the dosage of the compound will depend very much upon the condition to be treated and the particular antioxidant and precursor from which the compound is constructed. However, as a general guide, the dosage fo the compounds of the present invention may be from 1 to 500 mg kg/day.
  • Example 1 Synthesis of 6-hydroxy-2,2,5,7,8-pentamethylbenzopyran (An Antioxidant) .
  • Trimethyl quinone (6.15g, 0.39 mol) and freshly fused zinc chloride (5.24g, 0.39mol) were dissolved in acetic acid (30ml) under argon with constant stirring.
  • the solution was refluxed at 100°C (3 hrs), following which isoprene (2.78g, 0.4 mol) was added dropwise.
  • the reaction was monitored by thin layer chromatography (TLC) (ethyl acetate/30-40 o petroleum ether. 10:90) for the formation of the product.
  • TLC thin layer chromatography
  • the solution was poured into ice, neutralised with 5% w/v sodium bicarbonate (300ml)and extracted with ethyl acetate.
  • the organic layer was dried with magnesium sulphate.
  • Trimethylhydroquinone (7.66g, 0.05 mol) and trifluoroacetic acid (30 ml) were mixed together under an atmosphere of argon.
  • 2-methyl-3-buten-2-Official Letter was added slowly over a period of 2 hours.
  • the reaction was monitored by TLC (ethyl acetate/40-60 o petroleum ether 10:90). After completion of the reaction, the solution was poured onto ice, neutralised with 5% w/v sodium bicarbonate and washed with water. The organic layer was dried with magnesium sulphate and solvent was removed under vacuo.
  • Trimethylhydroquinone (12.61 g, 0.08mol) was dissolved in trifluoroacetic acid at 100°C under an atmosphere of argon.
  • 3-Methyl-2-buten-l -Official Letter (6.89g, 0.08mol) was added slowly over a period of 3 hours.
  • the reaction mixture was poured onto ice.
  • the organic layer was extracted with ethyl acetate (250ml), neutralised with 5% w/v sodium bicarbonate and washed with water (100 ml x 2).
  • the ethyl acetate was removed under reduced pressure.
  • methanol (100ml) and concentrated hydrochloric acid (5ml) were added and the solution refluxed for 1 hour. The methanol was removed under reduced pressure.
  • the solution was neutralised with 5% w/v sodium bicarbonate, extracted with ethyl acetate
  • 6-chloro-2, 2, -dimethy lbenzopy ran from p-chlorophenol and isoprene (Method 1);
  • DOPA can be in racemic form or their individual isomers.
  • the preferred form of the DOPA constituent is L-3,4-dihydroxyphenyl-alanine (chemical registry no: [59-92- 7] .
  • the method of synthesising DOPA was that of Yamada et al. Chem. Pharmaceutical. Bull. 10, 693 (1962).
  • L-3,4-dihydroxyphenylalanine i.e. L-DOPA (1.972 g, 0.01 mole) and freshly prepared 5-bromo-Vitamin E (see example 2, 5.0961g, 0.01 mole) were dissolved in anhydrous N-methyl-pyrrolidin-2-one (250ml) under argon with constant stirring and protected from light. The solution was refluxed at 180°C (24 hrs). The reaction was monitored by thin layer chromatography (TLC) on silica (Methanol/butanone/conc. Ammonia, 50:40:10) or alumina Chloroform/ methanol, 5: 1).
  • TLC thin layer chromatography
  • L-DOPA L-3,4-dihdroxyphenylalanine i.e. L-DOPA
  • 5-bromomethyl-2,3-Dihydro-6-hydroxy 2,2,6,7-tetramethyl-benzofuran 2.85g, 0.01 mol
  • the solution was refluxed at 180°C (18 hrs).
  • the reaction was monitored by thin layer chromatography (TLC) on silica (Methanol butanone/conc. Ammonia, 50:40: 10) or alumina Chloroform/ methanol, 5:1).
  • Antioxidant hexamethylene diamine: L-DOPA adduct Clinked antioxdant).
  • the acid chloride of DOPA was warmed (under argon) and added dropwise to the refluxing solution of the benzopyran-hexamethylenediamine adduct using a teflon lined needle. If required, one mole equivalent of triethylamine can be added after all the acid chloride has been added, to accelerate the reaction.
  • reaction was monitored by thin layer chromatography (TLC) on silica (Methanol butanone/conc. Ammonia, 50:40: 10) or alumina Chloroform/ methanol, 5: 1). After completion of reaction the dark solution was poured onto 2 kg of cracked ice to which 1.5 litre of ethyl acetate was added, and the mixture adjusted to neutrality using 2M aqueous ammonia. The upper oil layer was removed and concentrated in vacuum to give 1.42 g (28%) of a viscous red-brown oil.
  • TLC thin layer chromatography
  • Suitable amines are: ethane-l,2-diamine; propane- 1,2-diamine; racemic, RR and SS forms of cyclohexane 1,2-diamine; propane 1,3-diamine; butane-
  • 1,4-diamine pentane-l,5-diamine; 2-methylpentane-l,5-diamine; hexane-l,6-diamine; heptane- 1,7-diamine; octane- 1,8-diamine; nonane-l,9-diamine; decane -1,10-diamine; dodecane-l,12-diamine; putrescine, spermine and spermidine.
  • the compounds are either oils, waxes or solids and cannot be recrystallised satisfactorily. It is essential to use column chromatography or preferably MPLC to obtain compounds of pharmaceutical grade.
  • the compounds may be converted to their acetates using standard methods: e.g. reacting one mole equivalent of the antioxidant - DOPA conjugate with anhydrous acetic anhydride with 1 millimole equivalent of dimethylaminopyridine or triethylamine at reflux for 24 hours produces the acetates of such compounds, the acetate grouping being found on all three phenolic groups, but not the free amine group.
  • the free amine can also be protected using a suitable protective grouping including acetate, mesylate, trifluoroacetate and BOC using methods known to practitioners of the art.
  • the DOPA can be replaced by another targeting moiety, for example an amino acid or a dipeptide.
  • Dipeptides may be prepared by standard methods such as dicyclohexylcarbodiimide (DCC) coupling, which is described by Greene and Wuts (, Protective Groups in Organic Synthesis, 2 nd Edition, Pub. J. Wiley & Sons).
  • DCC dicyclohexylcarbodiimide
  • W is the rate of oxidation
  • k 2 is the propagation rate constant of the oxidisable system
  • ⁇ is the termination rate constant of the oxidisable system
  • W is the rate of free radical initiation
  • [RH] is the concentration of oxidisable substrate
  • Various inhibitors including a number of phenols, amines and thiols structurally related to ⁇ -tocopherol were synthesised ih order to determine their structure- antioxidant activity relationships.
  • the rate constant k 7 for abstraction by peroxy radicals of the donatable hydrogen atom from the inhibitors has been previously measured at pH 7 in phosphate buffer at 30°C.
  • the variation in k 7 can then be explained in terms of stereoelectronic and conformational features present in each inhibitor.
  • An amino, thiol or hydroxyl group on the benzenoid moiety, para to the heteroatom is essential for maximal antioxidant activity.
  • the activity decreases in the order NH 2 - OH > HS.
  • This method therefore enables the most efficient anti-oxidant moieties to be selected for combining with the precursor moiety.

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Abstract

L'invention concerne des composés dont une fraction anti-oxydante liée chimiquement à la fraction précurseur est capable de cibler des populations de cellules spécifiques en utilisant des systèmes d'absorption endogènes pour produits chimiques biologiques. Lesdits composés sont utiles dans le traitement de troubles neurodégénératifs dont la maladie de Parkinson, d'Alzheimer, ainsi que des états neuropathologiques induits par des amphétamines telles que MDMA.
PCT/GB1998/000359 1997-02-05 1998-02-05 Anti-oxydants cibles WO1998034646A2 (fr)

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AU59966/98A AU5996698A (en) 1997-02-05 1998-02-05 Targeted antioxidants

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999007667A1 (fr) * 1997-08-07 1999-02-18 Fujimoto Brothers Co., Ltd. Nouveaux derives d'ethylamine
EP0995437A1 (fr) * 1997-05-23 2000-04-26 Chugai Seiyaku Kabushiki Kaisha Derives de 2,3-dihydrobenzofurane
WO2001068065A2 (fr) * 2000-03-14 2001-09-20 Portela & Companhia S.A. Compositions comprenant des agents bloquant le transfert de la cellule renale l-dopa destines au traitement de la maladie de parkinson
WO2004018001A1 (fr) * 2002-08-22 2004-03-04 Dionysios Papaioannou Conjugues de polyamines et retinoides acides et preparation
WO2005011658A2 (fr) * 2003-02-27 2005-02-10 Wisconsin Alumni Research Foundation Anti-androgenes derives du chromane pour traiter des troubles induits par les androgenes
WO2005032544A1 (fr) * 2003-09-19 2005-04-14 Galileo Pharmaceuticals, Inc. Traitement de maladies mitochondriales
EP1808169A3 (fr) * 1999-12-30 2008-03-19 Proteotech Inc. Composés aromatiques Polyhydroxylés pour le traitement des maladies fibrilles d'amylose et $g(a)-synucléines
US7432305B2 (en) 2005-09-15 2008-10-07 Edison Pharmaceuticals, Inc. Tail variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US7514583B2 (en) 2002-05-31 2009-04-07 Proteotech, Inc. Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease
US8754133B2 (en) 2001-11-02 2014-06-17 Proteotech, Inc. Compounds, compositions and methods for the treatment of inflammatory diseases
US9278085B2 (en) 2006-02-22 2016-03-08 Edison Pharmaceuticals, Inc. Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US9399612B2 (en) 2008-09-10 2016-07-26 Edison Pharmaceuticals, Inc. Treatment of pervasive developmental disorders with redox-active therapeutics
US9447006B2 (en) 2005-06-01 2016-09-20 Edison Pharmaceuticals, Inc. Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6403639B1 (en) 1997-05-23 2002-06-11 Chugai Seiyaku Kabushiki Kaisha 2,3-dihydrobenzofuran derivatives
EP0995437A1 (fr) * 1997-05-23 2000-04-26 Chugai Seiyaku Kabushiki Kaisha Derives de 2,3-dihydrobenzofurane
EP0995437A4 (fr) * 1997-05-23 2002-01-30 Chugai Pharmaceutical Co Ltd Derives de 2,3-dihydrobenzofurane
US6686389B2 (en) 1997-05-23 2004-02-03 Chugai Seiyaku Kabushiki Kaisha 2,3-dihydrobenzofuran derivatives
US6214859B1 (en) 1997-08-07 2001-04-10 Fujimoto Brothers Co., Ltd. Ethylamine derivatives
WO1999007667A1 (fr) * 1997-08-07 1999-02-18 Fujimoto Brothers Co., Ltd. Nouveaux derives d'ethylamine
EP1808169A3 (fr) * 1999-12-30 2008-03-19 Proteotech Inc. Composés aromatiques Polyhydroxylés pour le traitement des maladies fibrilles d'amylose et $g(a)-synucléines
WO2001068065A3 (fr) * 2000-03-14 2002-02-21 Portela & Ca Sa Compositions comprenant des agents bloquant le transfert de la cellule renale l-dopa destines au traitement de la maladie de parkinson
AU781280B2 (en) * 2000-03-14 2005-05-12 Portela & Companhia S.A. Compositions comprising blockers of L-dopa renal cell transfer for the treatment of Parkinson's disease
JP2003526658A (ja) * 2000-03-14 2003-09-09 ポルテラ アンド コンパニーア ソシエダット アノニマ パーキンソン病の治療用ｌ−ドーパ腎臓細胞トランスファー阻害剤を含む組成物
CZ297123B6 (cs) * 2000-03-14 2006-09-13 Portela & Companhia S. A. Kompozice obsahující blokátory prenosu L-DOPA v ledvinových bunkách pro lécbu Parkinsonovy nemoci
KR100738746B1 (ko) * 2000-03-14 2007-07-12 포텔라 앤 콤파니아 에스 에이 엘도파 신세포 전달 차단제를 포함하는 파킨슨병 치료용조성물
WO2001068065A2 (fr) * 2000-03-14 2001-09-20 Portela & Companhia S.A. Compositions comprenant des agents bloquant le transfert de la cellule renale l-dopa destines au traitement de la maladie de parkinson
US8754133B2 (en) 2001-11-02 2014-06-17 Proteotech, Inc. Compounds, compositions and methods for the treatment of inflammatory diseases
US7514583B2 (en) 2002-05-31 2009-04-07 Proteotech, Inc. Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease
US8163957B2 (en) * 2002-05-31 2012-04-24 Proteotech, Inc. Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes and parkinson's disease
WO2004018001A1 (fr) * 2002-08-22 2004-03-04 Dionysios Papaioannou Conjugues de polyamines et retinoides acides et preparation
US7517913B2 (en) 2002-08-22 2009-04-14 Dionysios Papaioannou Polyamine conjugates with acidic retinoids and preparation thereof
WO2005011658A3 (fr) * 2003-02-27 2005-05-19 Wisconsin Alumni Res Found Anti-androgenes derives du chromane pour traiter des troubles induits par les androgenes
WO2005011658A2 (fr) * 2003-02-27 2005-02-10 Wisconsin Alumni Research Foundation Anti-androgenes derives du chromane pour traiter des troubles induits par les androgenes
US7709525B2 (en) 2003-02-27 2010-05-04 Wisconsin Alumni Research Foundation Chroman-derived anti-androgens for treatment of androgen-mediated disorders
WO2005032544A1 (fr) * 2003-09-19 2005-04-14 Galileo Pharmaceuticals, Inc. Traitement de maladies mitochondriales
US9447006B2 (en) 2005-06-01 2016-09-20 Edison Pharmaceuticals, Inc. Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US11021424B2 (en) 2005-06-01 2021-06-01 Ptc Therapeutics, Inc. Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US7432305B2 (en) 2005-09-15 2008-10-07 Edison Pharmaceuticals, Inc. Tail variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US9278085B2 (en) 2006-02-22 2016-03-08 Edison Pharmaceuticals, Inc. Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US9932286B2 (en) 2006-02-22 2018-04-03 Bioelectron Technology Corporation Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
US9399612B2 (en) 2008-09-10 2016-07-26 Edison Pharmaceuticals, Inc. Treatment of pervasive developmental disorders with redox-active therapeutics
US10105325B2 (en) 2008-09-10 2018-10-23 Bioelectron Technology Corporation Treatment of pervasive developmental disorders with redox-active therapeutics
US10736857B2 (en) 2008-09-10 2020-08-11 Ptc Therapeutics, Inc. Treatment of pervasive developmental disorders with redox-active therapeutics
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US10981855B2 (en) 2015-12-17 2021-04-20 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US11680034B2 (en) 2015-12-17 2023-06-20 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders

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