Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
  • C07D215/20—Oxygen atoms
  • C07D215/22—Oxygen atoms attached in position 2 or 4
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
  • C07D215/18—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
  • C07D215/20—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
  • C07D217/24—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• the invention relates to quinolin-2- (1 H) -one derivatives of the formula I.
• R 1 , R 2 and R 3 each independently of one another are H, Hai, A or OA,
• This invention also relates to the use of these compounds and their physiologically acceptable salts for the treatment of neurodegenerative changes in the CNS functions.
• quinoline-2- (1 H) -one derivatives which act as antagonists of the glutamate receptors, in particular the NMDA receptors. Because of these properties, the compounds are considered suitable for treatment of acute neurodegenerative disorders that are caused by stroke or hypoglycemia, cerebral palsy, transient cerebral ischemic attacks, cerebral ischemia during cardiopulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, Huntington's disease, chorea, Alzheimer's disease Lateral sclerosis, Parkinson's disease, cerebellar shrinkage, drowning anoxia, spinal cord and head injuries, poisoning from exogenous and endogenous NMDA receptor agonists or neurotoxins, including those of the environment.
• appropriate compounds should be suitable for the prevention of neurodegenerative disorders or, due to their NMDA receptor-antagonistic properties, may be used as anticonvulsants, painkillers, agents against vomiting, or for preventing or reducing the dependency potential of narcotics.
• the object of the present invention was therefore to provide compounds with improved neuroprotective activity.
• the compounds according to the invention are also suitable for the prevention of corresponding neurodegenerative disorders, such as occur in Alzheimer's disease, Parkinson's disease, cerebellar shrinkage, amyotrophic lateral sclerosis or poisoning from environmental toxins. They are also suitable for the treatment of psychoses due to excessive amino acid levels.
• Pain relievers especially for migraines, agents for depression or anxiety, agents for vomiting or for prevention or
• the compounds according to the invention can be used effectively in all indications which are associated with an extraordinary increase in the extracellular glutamate concentration in the brain and in which both the activity of the NMDA and the AM PA receptors is increased. It is therefore particularly preferred to use it in situations in which an immediate influence on the NMDA receptors is desired, for example in the case of disorders of the brain functions due to vascular damage or occlusion or due to a lack of oxygen combined with a lack of energy in the brain. In such cases it is possible to administer the compounds according to the invention by injection and / or infusion, which is particularly advantageous in this situation. Since there is very little time available therapeutically in these cases, the faster the active ingredient reaches the site of action, the better the prospects for a possible and complete cure for the patient.
• the compounds can therefore be used as active pharmaceutical ingredients in human and veterinary medicine. They are also suitable as intermediates for the production of other compounds with valuable properties.
• the invention accordingly relates to compounds of the formula I, their salts and their use, and suitable processes for the preparation of the compounds according to the invention.
• A represents alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, in particular methyl or ethyl, but also propyl, isopropyl, butyl, isobutyl, sec-butyl, tert. Butyl.
• the group OA is accordingly preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy, the group -NA- preferably N-methyl-, the group -NHA NH-methyl.
• R 1 is H preferred shark or preferably A. Particularly R 1 is H or Hal.
• R 2 is preferably a halogen or an alkoxy group OA. It is particularly preferably F or Cl.
• R 3 preferably represents H or A.
• R 4 preferably denotes H or - (CH 2 ) m -NR 6 R 7 with R 6 H, A or together with R 7 - (CH 2 ) 4 - or - (CH 2 ) 5 -, and with R 7 H, A or - (CH 2 ) m - with a bond to the same or adjacent ring, or together with R 6 - (CH 2 ) 4 - or - (CH 2 ) 5 -.
• R 5 preferably denotes H or - (CH 2 ) n -NR 6 R 7 with R 6 H, A or together with R 7 also - (CH 2 ) 4 - or - (CH 2 ) 5 -, and with R 7 H, A or - (CH 2 ) m - with a bond to the same or adjacent ring, or together with R 6 - (CH 2 ) 4 - or - (CH 2 ) 5 -.
• X preferably denotes -CHR 5 -, O or -NR 5 -, wherein R 5 preferably denotes H if R 4 - (CH 2 ) m -NR 6 R 7 denotes. Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can also be expressed by the formulas below which correspond to the formula I and in which the radicals not specified have the meanings given for the formula I, but in which
• Suitable pharmaceutically usable salts of the compounds according to formula I are alkali metal salts, such as lithium, sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, or salts formed with quaternary ammonium compounds.
• compounds of the formula I can also be present as salts of physiologically compatible acids.
• they can be present as salts of hydrochloric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, malic acid, formic acid or phosphoric acid.
• Compounds of the formula I according to the invention can have centers of asymmetry and can accordingly occur in several enantiomeric or diastereomeric forms. They can therefore be in racemic or optically active form due to one or more chiral centers. All these forms and their mixtures are included in the formula I. Since the pharmaceutical effectiveness of the individual manifestations can differ, it may be desirable to use the pure isomers or enantiomers. In these special cases, the end product can be separated into enantiomerically pure compounds by chemical measures known to the person skilled in the art, but in individual cases also by mechanical measures. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent. Suitable release agents are, for. B.
• optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid.
• Enantiomer separation using a column filled with an optically active separating agent eg dinitrobenzoylphenylglycine
• an optically active separating agent eg dinitrobenzoylphenylglycine
• the invention also relates to the preparation of quinolin-2- (IH) -on-derivatives of the formula I according to claim 1 and the salts thereof.
• compounds of the formula I can be prepared by a cyclization reaction in which a suitable compound of the formula II
• a reactive carboxylate group can be an ester group, preferably an alkyl ester group with one to four carbon atoms in the alkyl part, or a mixed anhydride, e.g. B. an anhydride of an acid with one to four carbon atoms; an acid halide group such as e.g. B. an acid chloride group, an ortho ester group or a primary, secondary or tertiary amide.
• Preferred reactive carboxylate groups are methoxycarbonyl or ethoxycarbonyl.
• the cyclization can be carried out according to methods known per se under mild conditions in the presence of a base, such as. B. sodium hydride or potassium hexamethyl disilazide can be carried out (J. Heterocycl. Chem. (1975) 12, 351). Working up takes place under mild, weakly acidic conditions.
• the cyclization of a suitable compound in which G is a cyano group leads to a quinoline-2- (1 H) -one derivative of the formula I which, however, is substituted in the 4-position by an amino group. This amino group can be converted into the desired hydroxyl group by known methods, provided that further amino groups contained in the compound are inaccessible to the reaction through protective groups.
• up to two - identical or different - protected amino groups can be present in the molecule of the starting material. If the protective groups present are different from one another, they can be split off selectively in many cases.
• amino protecting group is generally known and refers to groups which are suitable for protecting an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at another point in the molecule Unsubstituted or substituted acyl, aryl (e.g. dinitrophenyl (DNP), aralkoxymethyl (e.g. benzoxymethyl (BOM)) or aralkyl groups (e.g. benzyl, 4- Nitrobenzyl, triphenylmethyl) Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical, but those with 1-20, in particular 1-8, carbon atoms are preferred.
• DNP dinitrophenyl
• BOM aralkoxymethyl
• aralkyl groups e.g. benzyl, 4- Nitrobenzyl, triphenylmethyl
• acyl group is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
• acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenacetyl; aroyl such as benzoyl or tolyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert.
• alkanoyl such as acetyl, propionyl, butyryl
• aralkanoyl such as phenacetyl
• aroyl such as benzoyl or tolyl
• aryloxyalkanoyl such as phenoxyacetyl
• alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl
• 2,2,2-trichloroethoxycarbonyl isopropoxycarbonyl, tert.
• BOC BOC
• 2-iodoethoxycarbonyl 2-iodoethoxycarbonyl
• aralkyloxycarbonyl such as benzoyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmeth- oxycarbonyl (FMOC).
• Preferred amino protecting groups are BOC, DNP and BOM, furthermore CBZ, benzyl and acetyl.
• Q represents a reactive carboxylate group as given above.
• Q is preferably an acid halide group, preferably an acid chloride group.
• a compound of the formula IV, in which Q represents an acid chloride group can be prepared in a simple manner by methods known to those skilled in the art by treatment with thionyl chloride or with oxalyl chloride from a compound in which Q corresponds to the corresponding acid group -COOH .
• This reaction is carried out under suitable conditions in an inert solvent such as dichloromethane or 1, 2-dichloroethane.
• an inert solvent such as dichloromethane or 1, 2-dichloroethane.
• the reaction mixture is heated with stirring.
• the reaction is preferably carried out under reflux conditions, as a result of which the temperature adjusts to the boiling point of the solvent used.
• Compounds of the formulas III and IV which are required as intermediates for the preparation of compounds of the formula I according to the invention can, insofar as they are not commercially available, be prepared by methods known or modified for the corresponding compounds. Manufacturing methods are described, for example, in EP-A1-
• R 1 , R 2 , R 3 and R 4 and X have the meanings given
• Q 1 is a reactive carboxylate group which may have the meanings given above, but preferably an alkyl ester group having 1 -4 C atoms in the alkyl such as methoxycarbonyl or ethoxycarbonyl, is subjected to a cyclization reaction and optionally converted into the desired compound of the formula I by subsequent hydrolysis.
• a compound V obtained as an intermediate, in which Q 1 is an alkyl ester group, can be obtained from the compounds of the formulas III and IV, in which the two substituents G and Q are each alkyl ester groups with 1 to 4 carbon atoms in the alkyl, can be obtained by Claisen ester condensation.
• the reaction takes place in the presence of a strong base, such as, for example, potassium hexamethyldisilazide, at elevated temperature. It is preferred to work under reflux conditions so that the temperature adjusts itself approximately to the boiling point of the solvent.
• the cyclization of a compound of the formula V to a compound of the formula I can be carried out under conditions known per se to the person skilled in the art or slightly varied. This reaction is preferably carried out in the presence of an acid. The cyclization reaction can take place directly in the same reaction solution without isolating the previously prepared compound.
• R 3 , R 4 and X have the meaning given above and R is an alkyl having 1-6 C atoms, with suitable compounds of the formula VIII
• R 1 and R 2 have the meanings given above, are reacted under suitable conditions. Conditions such as those in J. Heterocycl are particularly suitable. Chem. (1988), 25, 857. Depending on the substituents, the reaction conditions can be varied slightly. Preferably, the compounds of formulas VII and VIII are heated together in a suitable solvent for about 15 to 20 hours. It is preferred to work under reflux conditions, the reaction temperature consequently adjusting to the boiling point of the solvent used.
• compounds of the formula I which have been prepared by one of the processes described above, if necessary, can be converted into other compounds of the formula I by methods known per se. In particular, it is often necessary, following the cyclization reaction, to remove protective groups previously introduced using suitable methods.
• the separation of the isomeric compounds can be carried out chromatographically.
• the compounds can form as a racemate mixture, can be specifically synthesized as an individual enantiomer, or can subsequently be separated into the pure enantiomers by utilizing different solubilities of the salts in certain solvents.
• the corresponding salts which can be separated by fractional crystallization, are prepared from the enantiomers according to the invention and suitable optically active acids by methods known to the skilled worker. Optically active natural substances or their derivatives are preferably used for this purpose.
• Corresponding optically active acids are, for example, (-) - di-p-tolyl- (D) -tartaric acid and / or (+) - di-p-tolyl- (D) -tartaric acid.
• the desired bases can then be released again by simple measures.
• the formation of diastereomeric esters or amides, which can be separated chromatographically, is also suitable for enantiomer separation. After separation, the isomerically pure compounds can be released again.
• the compounds of general formula I and their physiologically harmless salts can therefore be used for the preparation of pharmaceutical preparations by adding them together with at least one carrier or auxiliary and, if desired, with one or more further active ingredients brings suitable dosage form.
• the preparations obtained in this way can be used as pharmaceuticals in human or veterinary medicine.
• Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, Glycerol triacetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose.
• tablets, coated tablets, capsules, syrups, juices or drops are used for oral use.
• Suppositories are used for rectal application, and lozenges for parenteral administration.
• the active ingredients claimed according to the invention can also be lyophilized and the lyophilizates obtained, for. B. can be used for the production of injection preparations or infusion solutions.
• the specified preparations can be sterilized and / or contain auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. B. one or more vitamins, diuretics, anti-inflammatory drugs.
• Infusion solutions which contain one or more compounds of the formula I and / or their physiologically tolerable salts are prepared by generally customary methods. However, it is also possible to add one or more of the compounds according to the invention as active substances to a suitable, commercially available infusion solution only shortly before use.
• the compounds of the formula I according to the invention are generally administered in analogy to other known preparations which are commercially available for the claimed indications, preferably in dosages between 0.1 mg and 500 mg, in particular between 5 and 300 mg per dosage unit .
• the daily dosage is preferably between about 0.01 and 250 mg / kg, in particular between 0.02 and 100 mg / kg body weight.
• the specific dose for each individual patient depends on a wide variety of factors, for example on the effectiveness of the special compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, and on Excretion rate, drug combination and severity of the respective disease, which affects the 6244 PC17EP97 / 00084
• customary work-up means: if necessary, water is added, extracted with dichloromethane, separated, the organic phase is dried over sodium sulfate, filtered, evaporated and purified by chromatography on silica gel and / or by crystallization . Temperatures are given in ° C.
• 4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenylacetic acid is the 4- [2-methyl-1, 2,3,4-tetrahydro-4- ( R, S) -isoquinolinyl] -phenylacetic acid chloride.
• the residue is dissolved in water.
• the aqueous solution is extracted with ether, acidified with hydrochloric acid and the aqueous solution is distilled off in a vacuum rotary evaporator.
• the residue is boiled up with 2 ml of dried ethanol and 0.03 ml of methanesulfonic acid.
• the reaction mixture is mixed with ether, the product precipitating.
• reaction mixture is heated to reflux temperature and stirred for one hour. About 50 ml of toluene are separated off using a water separator. The solvent is separated off and 3- (chlorophenylmethyl) phenylacetonitrile is obtained.
• Washed dichloromethane The aqueous phase is adjusted to an acidic pH with hydrochloric acid and extracted again with dichloromethane. The separated organic phase is dried. The solvent is distilled off. To further purify the oil obtained, the product is taken up in ethanol, acidified with ethereal hydrochloric acid, triturated with ether and the product obtained is filtered off with suction. 7-Chloro-3- [dimethylaminophenylmethyl) phenyl] -1, 2-dihydro-4-hydroxyquinolin-2-one hydrochloride, dihydrate, melting point ⁇ 230 ° is obtained.
• Example A Injection glasses
• a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, filtered sterile, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection glass contains 5 mg of active ingredient.
• a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool.
• Each suppository contains 20 mg of active ingredient.
• a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g
• Example D ointment
• Example E tablets
• a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
• Example F coated tablets
• Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
• Example G capsules
• each capsule contains 20 mg of the active ingredient.
• a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

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• Organic Chemistry (AREA)
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• Neurosurgery (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
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• Chemical Kinetics & Catalysis (AREA)
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• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Public Health (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Quinoline Compounds (AREA)

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