Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms

Definitions

• the present invention relates to 3-substituted piperidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
• the present invention therefore provides, in a first aspect, compounds of structure (I) :
• R is C 1 -8 alkyl (phenyl) p, C 2-8 alkenyl (phenyl) p,
• p is 0 to 2 ;
• n 0 to 6 ;
• A is a bond, oxygen, sulphur or NR 1 ;
• R 1 is hydrogen, C 1 -8 alkyl or phenylC 1-4 alkyl
• n 0 to 3;
• Ar is aryl or heteroaryl, each of which may be
• R is C 1-8 alkyl(phenyl)p, C 2-8 alkenyl- (phenyl)p, C 2-8 alkynyl(phenyl)p, C 3-8 cycloalkyl or
• R is C 1-8 alkyl(phenyl)p in which p is 0 or 1, i.e. C 1-8 alkyl, such as n-pentyl, or phenylC 1-8 alkyl such as phenylpropyl, or R is C 2-8 alkenyl(phenyl)p wherein p is 1, such as cinnamyl.
• n is 0 to 6; preferably n is 0 to 3; most preferably n is 1.
• m is 0 to 3; preferably m is 0 or 1; most preferably m is 0.
• A is a bond, oxygen, sulphur or NR 1 ;
• A is oxygen or sulphur; most preferably A is. oxygen.
• A is oxygen
• n is preferably 1 and m is preferably 0.
• Ar is optionally substituted aryl or heteroaryl; preferably Ar is optionally substituted aryl.
• Suitable aryl groups include, for example,
• unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to 10 carbon atoms, such as, for example, phenyl, naphthyl and
• Suitable substituted phenyl rings include, for example, phenyl rings substituted by a C 1-2 alkylenedioxy group such as a 3,4-methylenedioxy group or by 1 to 3 substituents selected from halogen, C 1-4 alkoxy,
• CN optionally substituted phenyl, optionally substituted phenylC 1-4 alkyl and optionally substituted phenylC 1-4 alkoxy.
• Suitable optionally substituted phenylC 1-4 alkyl groups include, for example benzyl.
• Suitable optionally substituted phenylC 1-4 alkoxy groups include, for example
• Suitable substituents for said optionally substituted phenyl, phenylC 1-4 alkyl and phenylC 1-4 alkoxy groups include for example halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro and trifluoromethyl groups.
• Suitable heteroaryl rings include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to 10 carbon atoms containing at least one heteroatom, such as pyridyl, thienyl, guinolinyl, tetrahydroquinolinyl and imidazolyl rings. The heteroaryl ring can be linked to the
• Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen, C 1-4 alkyl and C 1-4 alkoxy.
• Alkyl groups present in the compounds of structure (I), alone or as part of another group, can be straight or branched. It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically
• salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts.
• Other nonpharmaceutically acceptable salts may be used for
• Particular compounds of the invention include:
• structure (I) may contain one or more asymmetric centres, in particular at the 3-position of the piperidine ring. Such compounds will exist as optical isomers
• the compounds of the present invention can be prepared by processes analogous to those known in the art.
• the present invention therefore provides in a further aspect, a process for the preparation of a compound of structure (I) which comprises:
• R and n are as described for structure (I) and A 1 is O, S or NR 1 , with a compound of structure
• R, A, Ar m and n are as hereinbefore defined and x ⁇ is a counter ion; and optionally thereafter forming a salt.
• fluoro-substituted aryl compound F-Ar is employed in process (a), the reaction is effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as dimethylformamide.
• a strong base such as sodium hydride
• an inert organic solvent such as dimethylformamide.
• the aryl group is substituted by an activating group such as CF 3 or NO 2 .
• a 1 is oxygen or sulphur the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
• Such a reaction is known as the Mitsunobu reaction (as described in Synthesis 1981, 1).
• the leaving group L 1 may be for example a halogen atom or a sulphonyloxy group eg. methanesulphonyloxy or p-toluene sulphonyloxy.
• the reaction may be effected in the presence or absence of solvent and at temperature in the range 0 to 200oC.
• the reduction of a compound of structure (IV) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride.
• a compound of structure (IV) can be prepared (for example as described below) and reduced in a
• reaction of a compound of structure (VI) with RL 2 according to process (e) may be effected in
• the leaving group L 2 may be for example a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a sulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy.
• L 2 is a halide
• reaction is preferably carried out in the presence of a weak base such as potassium carbonate, and when L 2 is sulphonyloxy, a strong base such as sodium hydride or potassium t-butoxide may be employed.
• a weak base such as potassium carbonate
• a strong base such as sodium hydride or potassium t-butoxide
• Reduction of a compound of formula (VII) may be effected using standard reducing agents such as lithium aluminium hydride.
• Reduction of a compound of formula (VIII) may be effected for example by hydrogenation, using a noble metal catalyst such as platinum, palladium or platinum oxide, suitably in a solvent such as an alcohol eg.
• a noble metal catalyst such as platinum, palladium or platinum oxide
• the compounds of structure (II) can be prepared from the corresponding compounds in which R is hydrogen, by alkylation under standard conditions.
• compounds of structure (II) in which R is n-pentyl can be prepared from the corresponding precursor in which R is hydrogen by reaction with an n-pentylhalide such as n-pentyl bromide in a suitable solvent, such as methyl ethyl ketone, or a C 1-4 alkanol such as ethanol, in the presence of a base, such as potassium carbonate, or dimethylformamide in the presence of an iodoalkane.
• a suitable solvent such as methyl ethyl ketone
• a C 1-4 alkanol such as ethanol
• the corresponding compounds of structure (II) in which R is hydrogen are available commercially, known in the literature or can be prepared by standard techniques; for example by reduction of the corresponding 3-hydroxyalkylpyridine.
• the compounds of structure (II) in which A 1 is oxygen can be prepared by reduction of a compound of structure (IX): in which R and n are as described for structure (I) and X- is a counter ion.
• halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
• R 4 represents -(CH 2 ) n-1 CO 2 H or an activated
• the carboxylic acid may itself be prepared for example by oxidation of the corresponding alcohol, ie. a compound of structure (II) wherein A 1 is oxygen.
• Compounds of structure (V) may be prepared in analogous manner to compounds of structure (III); where necessary the chain length may be increased using methods well known in the art.
• Suitable protecting groups include aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and acyl groups such as acetyl, trifluoroacetyl, benzoyl,
• benzyloxycarbony1 methoxycarbonyl, ethoxycarbonyl, or benzyloxycarbony1.
• An aralkyl group such as benzyl may be cleaved by
• a compound of formula (VII) may be prepared by reaction of a compound of formula (VI) with an
• appropriate acid derivative for example an acid chloride, or anhydride.
• a compound of structure (VIII) may be prepared using the general methods described in processes (a) to (e) above. When compounds of structure (I) are obtained as mixtures of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
• the compounds of the invention have been found to exhibit high calcium influx blocking activity and as such are expected to be of use in therapy in treating
• the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal.
• a method of treatment of conditions or diseases caused or exacerbated by the accumulation of calcium in the brain cells of mammals which comprises administering to a subject in need thereof an effective amount of a compound of structure (I) or a
• the present invention also provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction
• the compounds of the present invention are usually administered in a standard
• compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a
• a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water
• suspending agent preservative, flavouring or colouring agent.
• a composition in the form of a tablet can be
• Such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
• a composition in the form of a capsule can be prepared using routine encapsulation procedures.
• pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable
• compositions for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
• Compounds of the invention may also be administered parenterally, by bolus injection or continuous
• Typical parenteral compositions consist of a solution or suspension of the compound or
• a pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
• the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
• composition is in unit dose form such as a tablet or capsule.
• Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral
• administration contains preferably from 0.1 to 60 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
• the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
• the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 100mg per day.
• the compounds will be administered for a period of continuous therapy, for examele for a week or more.
• the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl 2 , 4; ATP, 2; buffered to pH 7.2 with CsOH.
• Peak voltage gated Ca 2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba 2+ as charge carrier. Currents were evoked from 3. holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage
• Compound of structure (I) 0.1 - 60 mg sodium hydroxide or hydrochloric acid to pH ca 7 polyethylene glycol 0 - 2.5 ml alcohol 0 - 2.5 ml water to 5 ml
• a toxicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.
• the title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1-pentylpiperidine (1.85g), 3-trifluoromethylphenol (1.62g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.41g), m.p. 165°C.
• the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.0g), 4-cyanophenol (1.19g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.79g), m.p. 104°C.
• the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.0g), phenol (0.94g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (1.02g), m.p. 144.5°C.
• the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.00g), 3,4-dichlorophenol (1.63g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.10g), m.p.188-190°C.
• the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.00g), 4-iso-propylphenol (1.36g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.18g), m.p.172-174°C.
• the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (1.5g), 3-iso-propylphenol (1.1g), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.8g), m.p.138-140°C.
• the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (1.50g), 4-tert-butylphenol (1.22g), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.205g), m.p.197-199°C.

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• 1991
  • 1991-08-02 IE IE276091A patent/IE912760A1/en unknown
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  • 1991-08-05 WO PCT/GB1991/001339 patent/WO1992002501A1/en not_active Application Discontinuation
  • 1991-08-05 CA CA002088490A patent/CA2088490A1/en not_active Abandoned
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