Patent Application: US-80370110-A

Abstract:
the present invention discloses pyridoindolobenzox - and thiazepine compositions of formula 1 , wherein a is — ch — x —, — xch —; — co — x — or — x — co —; x is — o —, — s —, — so —, or — so 2 —. y is a single bond or a double bond . d and e are independently — n —; and ‘ n ’ varies from 0 to 2 . r 1 to r 9 are various electron donating , electron withdrawing , hydrophilic , or lipophilic groups selected to optimize the physicochemical and biological properties of compounds of formula i .

Description:
the present invention relates to pentacyclic compounds of formula i , wherein d and e are independently —( ch 2 ) n —, and ‘ n ’ varies from 0 to 2 ; r 1 is selected from the group consisting of hydrogen , c 1 - c 10 alkyl , c 1 - c 10 hydroxyalkyl , c 5 - c 10 aryl unsubstituted or substituted with electron donating groups ( edg ) or electron withdrawing groups ( ewg ), c 6 - c 15 aroylalkyl , and c 1 - c 10 alkxoycarbonylalkyl , c 6 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; r 2 to r 9 are independently selected from the group consisting of hydrogen , c 1 - c 10 alkyl , hydroxyl , c 1 - c 10 alkoxyl , — nr 10 r 11 , c 1 - c 10 hydroxyalkyl , halogen , trihaloalkyl , cyano , carboxyl , c 1 - c 10 acyl , c 1 - c 10 alkxoyalkyl , c 1 - c 10 alkxoycarbonyl , c 5 - c 10 aryl unsubstituted or substituted with edg or ewg , and c 6 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; and r 10 and r 11 are independently hydrogen or c 1 - c 10 alkyl , and r 10 and r 11 may optionally be tethered together from rings . the phrase , ‘ electron donating group ( edg )’ and ‘ electron withdrawing group ( ewg )’ are well understood in the art . edg comprises alkyl , hydroxyl , alkoxyl , amino , acyloxy , acylamino , mercapto , alkylthio , and the like . ewg comprises halogen , acyl , nitro , cyano , trihaloalkyl , carboxyl , alkoxycarbonyl , sulfonyl , and the like . the first embodiment of the present invention is represented by formula i , wherein a is — ch ( r 9 ) x —; x is — o —, — s —, — so —, or — so 2 —; y is a single bond or a double bond ; d and e are —( ch 2 ) n —, and ‘ n ’ is 1 ; r 1 is selected from the group consisting of hydrogen , c 1 - c 10 alkyl , c 1 - c 10 hydroxyalkyl , c 5 - c 10 aryl unsubstituted or substituted with electron donating or electron withdrawing groups , c 1 - c 15 aroylalkyl , and c 1 - c 10 alkxoycarbonylalkyl , c 6 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; r 2 to r 9 are independently selected from the group consisting of hydrogen , c 1 - c 10 alkyl , hydroxyl , c 1 - c 10 alkoxyl , — nr 10 r 11 , c 1 - c 10 hydroxyalkyl , halogen , trihaloalkyl , cyano , carboxyl , c 1 - c 10 acyl , c 1 - c 10 alkxoyalkyl ; c 1 - c 10 alkxoycarbonyl ; c 5 - c 10 aryl unsubstituted or substituted with edg or ewg , and c 6 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; and r 10 and r 11 are independently hydrogen or c 1 - c 10 alkyl , and r 10 and r 11 may optionally be tethered together from rings . a is — xch ( r 9 )—; x is — o —, — s —, — so —, or — so 2 —; y is a single bond or a double bond ; d and e are —( ch 2 ) n —, and ‘ n ’ is 1 ; r 1 is selected from the group consisting of hydrogen , c 1 - c 10 alkyl , c 1 - c 10 hydroxyalkyl , c 5 - c 10 aryl unsubstituted or substituted with electron donating or electron withdrawing groups , c 6 - c 15 aroylalkyl , and c 1 - c 10 alkxoycarbonylalkyl , c 6 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; r 2 to r 9 are independently selected from the group consisting of hydrogen , c 1 - c 10 alkyl , hydroxyl , c 1 - c 10 alkoxyl , — nr 10 r 11 , c 1 - c 10 hydroxyalkyl , halogen , trihaloalkyl , cyano , carboxyl , c 1 - c 10 acyl , c 1 - c 10 alkxoyalkyl , c 1 - c 10 alkxoycarbonyl , c 5 - c 10 aryl unsubstituted or substituted with edg or ewg , and c 6 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; and r 10 and r 11 are independently hydrogen or c 1 - c 10 alkyl , and r 10 and r 11 may optionally be tethered together from rings . a is — ch ( r 9 ) x —; x is — o —, — s —, — so —, or — so 2 —; y is a single bond or a double bond ; d and e are —( ch 2 ) n —, and ‘ n ’ is 1 ; r 1 is hydrogen , c 1 - c 10 alkyl , c 6 - c 10 arylalkyl , or c 6 - c 15 aroylalkyl ; each of r 2 , r 3 , r 5 , r 6 , r 8 , and r 9 is hydrogen ; and each of r 4 and r 7 are independently hydrogen , c 1 - c 10 alkyl , or halogen . a is — xch ( r 9 )—; x is — o —, — s —, — so —, or — so 2 —; y is a single bond or a double bond ; d and e are —( ch 2 ) n —, and ‘ n ’ is 1 ; r 1 is hydrogen , c 1 - c 10 alkyl , c 6 - c 10 arylalkyl , or c 6 - c 15 aroylalkyl ; each of r 2 , r 3 , r 5 , r 6 , r 8 , and r 9 is hydrogen ; and each of r 4 and r 7 are independently hydrogen , c 1 - c 10 alkyl , or halogen . the compounds belonging to formula i can be synthesized according to standard methods as outlined in fig1 and 2 starting from the known tricyclic dibenzoxazepine and dibenzothiazepine [ 14 , 15 ]. compounds of the present invention may exist as a single stereoisomer or as mixture of enantiomers and diastereomers whenever chiral centers are present . individual enantiomers can be isolated by resolution methods or by chromatography using chiral columns . the diastereomers can be separated by standard purification methods such as fractional crystallization or chromatography . compounds of the present invention may exist in the form pharmaceutically acceptable salts , including but not limited to acetate , adipate , citrate , tartarate , benzoate , phosphate , glutamate , gluconate , fumarate , maleate , succinate , oxalate , chloride , bromide , hydrochloride , sodium , potassium , calcium , magnesium , ammonium , and the like . the phrase “ pharmaceutically acceptable ” means those formulations which are , within the scope of sound medical judgment , suitable for use in contact with the tissues of humans and animals without undue toxicity , irritation , allergic response and the like , and are commensurate with a reasonable benefit / risk ratio . the compounds of the present invention represented by formula i , commonly referred to as ‘ active pharmaceutical ingredient ( api )’ or ‘ drug substance ’ is typically formulated with pharmaceutically acceptable salts , buffers , diluents , carriers , adjuvants , preservatives , and excipients . the formulation technology for manufacture of the drug product is known in the art , and are described in “ remington , the science and practice of pharmacy ” [ 16 ], incorporated herein by reference in its entirety . the final formulated product , commonly referred to as ‘ drug product ,’ may be administered enterally , parenterally , or topically . enteral route includes oral , rectal , topical , buccal , ophthalmic , and vaginal administration . parenteral route includes intravenous , intramuscular , intraperitoneal , intrasternal , and subcutaneous injection or infusion . the drug product may be delivered in solid , liquid , or vapor forms , or can be delivered through a catheter for local delivery at a target . it may also be administered alone or in combination with other drugs if medically necessary . compositions suitable for parenteral injection may comprise physiologically acceptable , sterile aqueous or nonaqueous isotonic solutions , dispersions , suspensions or emulsions , and sterile powders for reconstitution into sterile injectable solutions or dispersions . the compositions may also optionally contain adjuvants such as preserving , wetting , emulsifying , dispensing , and antimicrobial agents . examples of suitable carriers , diluents , solvents , vehicles , or adjuvants include water ; alcohols such as ethanol , propyleneglycol , polyethyleneglycol , glycerol , and the like ; vegetable oils such as cottonseed , groundnut , corn , germ , olive , castor and sesame oils , and the like ; organic esters such as ethyl oleate and suitable mixtures thereof ; and phenol , parabens , sorbic acid , and the like . injectable formulations may also be suspensions that contain suspending agents such as ethoxylated isostearyl alcohols , polyoxyethylene sorbitol and sorbitan esters , microcrystalline cellulose , aluminum metahydroxide , bentonite , agar - agar and tragacanth , or mixtures of these substances , and the like . prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption , for example , aluminum monostearate and gelatin . proper fluidity can be maintained , for example , by the use of coating materials such as lecithin , by the maintenance of the required particle size in the case of dispersions , and by the use of surfactants . in some cases , in order to prolong the effect of the drug , it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection . this can be accomplished by the use of a liquid suspension . the rate of absorption of the drug then depends upon its rate of dissolution which , in turn , may depend upon crystal size and crystalline form . alternatively , delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle . injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers . depending upon the ratio of drug to polymer and the nature of the particular polymer employed , these compositions release the active ingredient ( s ) only , or preferentially , in a certain part of the intestinal tract , and optionally , in a delayed manner . thus , the rate of drug release and the site of delivery can be controlled . examples of embedding compositions include , but are no limited to polylactide - polyglycolide poly ( orthoesters ), and poly ( anhydrides ), and waxes . the technology pertaining to controlled release formulations are described in “ design of controlled release drug delivery systems ,” [ 17 ] incorporated herein by reference in its entirety . formulations for oral administration include capsules ( soft or hard ), tablets , pills , powders , and granules . such formulations may comprise the api along with at least one inert , pharmaceutically acceptable ingredients selected from the following : ( a ) buffering agents such as sodium citrate or dicalcium phosphate ; ( b ) fillers or extenders such as starches , lactose , sucrose , glucose , mannitol , and silicic acid ; ( c ) binders such as carboxymethylcellulose , alginates , gelatin , polyvinylpyrrolidone , sucrose , and acacia ; ( d ) humectants such as glycerol ; ( e ) disintegrating agents such as agar - agar , calcium carbonate , potato or tapioca starch , alginic acid , certain silicates , and sodium carbonate ; ( f ) solution retarding agents such as paraffin ; ( g ) absorption accelerators such as quaternary ammonium compounds ; ( h ) wetting agents such as cetyl alcohol and glycerol monostearate ; ( i ) absorbents such as kaolin and bentonite clay and ( j ) lubricants such as talc , calcium stearate , magnesium stearate , solid polyethylene glycols , sodium lauryl sulfate , and mixtures thereof ; ( k ) coatings and shells such as enteric coatings , flavoring agents , and the like . liquid dosage forms for oral administration include pharmaceutically acceptable emulsions , solutions , suspensions , syrups and elixirs . in addition to the api , the liquid dosage forms may contain inert diluents , solubilizing agents , wetting agents , emulsifying and suspending agents , sweetening , flavoring , and perfuming agents used in the art . formulations for topical administration include powders , sprays , ointments and inhalants . these formulations include the api along with suitable non - irritating excipients or carriers such as cocoa butter , polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound . compounds of the present invention can also be administered in the form of liposomes . any non - toxic , physiologically acceptable and metabolizable lipid capable of forming liposomes can be used . the present compositions in liposome form can contain , in addition to a compound of the present invention , stabilizers , preservatives , excipients and the like . the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines ( lecithins ) used separately or together . methods to form liposomes are known in the art and are described in “ liposomes ,” [ 18 ], which is incorporated herein by reference in its entirety . the compounds of the present invention can also be administered to a patient in the form of pharmaceutically acceptable ‘ prodrugs .’ prodrugs are generally used to enhance the bioavailability , solubility , in vivo stability , or any combination thereof of the api . they are typically prepared by linking the api covalently to a biodegradable functional group such as a phosphate that will be cleaved enzymatically or hydrolytically in blood , stomach , or gi tract to release the api . a detailed discussion of the prodrug technology is described in “ prodrugs : design and clinical applications ,” [ 19 ] incorporated herein by reference . the dosage levels of api in the drug product can be varied so as to achieve the desired therapeutic response for a particular patient . the phrase “ therapeutically effective amount ” of the compound of the invention means a sufficient amount of the compound to treat disorders , at a reasonable benefit / risk ratio applicable to any medical treatment . it will be understood , however , that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment . the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated ; the severity of the disorder ; activity of the specific compound employed ; the specific composition employed ; age , body weight , general health , sex , diet of the patient ; the time of administration ; route of administration ; and rate of excretion of the specific compound employed ; and the duration of the treatment . the total daily dose of the compounds of this invention administered may range from about 0 . 0001 to about 1000 mg / kg / day . for purposes of oral administration , more preferable doses can be in the range from about 0 . 001 to about 5 mg / kg / day . if desired , the effective daily dose can be divided into multiple doses for optimal therapeutic effect . the following examples illustrate specific embodiments and utilities of the invention , and are not meant to limit the invention . as would be apparent to skilled artisans , various modifications in the composition , operation , and method are possible , and are contemplated herein without departing from the concept and scope of the invention as defined in the claims . synthesis of a compound of formula i , wherein a is — ch 2 x —; x is — s —; y is double bond ; d and e are — ch 2 —; r 1 is methyl ; r 2 - r 9 are hydrogens ( 2 ) step 1 . to a well stirred solution of compound 1 ( 6 . 98 g , 32 . 7 mmol ) in thf ( 30 ml ) and acoh ( 9 ml ), a concentrated solution of nano 2 ( 7 . 03 g , 101 . 9 mmol ) in water ( 12 ml ) was added dropwise at ambient temperature . the reaction was stirred at ambient temperature for 20 min and treated with water ( 100 ml ). the product was filtered , washed with water , and dried to give 7 . 67 g ( 97 %) of the nitroso compound . step 2 . to a stirred solution of nitroso compound from step 1 ( 14 . 6 g , 61 . 1 mmol ) and n - methyl 4 - pyridone ( 9 . 04 g , 79 . 9 mmol ) in ethanol ( 150 ml ) and acetic acid ( 20 ml ) at 55 ° c ., was added zinc dust ( 12 . 0 g , 183 . 5 mmol ) in three equal portions allowing 10 mins between the additions . the reaction was stirred for another 5 minutes and filtered hot . the solid washed with ethanol , and the resultant solution was heated to reflux for 30 minutes , and thereafter the solvent was removed in vacuo . the residue was treated with 8 ml of acetic acid , and heated to reflux for about 16 hours . the solvent was removed in vacuo , and the residue was dissolved in methylene chloride ( 500 ml ). the solid impurity was removed by filtration , and the filtrate was washed with 10 % naoh solution . the combined organic layer was washed with water and brine , dried over anhydrous sodium sulfate , filtered an the filtrate taken to dryness in vacuo . the crude product was purified by flash chromatography on silica gel using 0 - 5 % meoh / chloroform as the eluent to give 3 . 0 g ( 16 %) of the desired product 2 . lrms : m / z , 307 ( m + h + ). synthesis of a compound of formula i , cis isomer wherein a is — ch 2 x —; x is — s —; y is single bond ; d and e is — ch 2 —; r 1 is methyl ; r 2 - r 9 are hydrogens ( 3 ) to a cold solution of compound 2 from example 1 ( 0 . 50 g , 1 . 63 mmol ) in trifluoroacetic acid ( 6 . 5 ml ) at − 5 ° c ., was carefully treated with solid sodium cyanoborohydride ( 0 . 125 g , 1 . 99 mmol ). the reaction mixture was then stirred at ambient temperature for 3 h , treated with 6n hcl solution , and heated under reflux for 30 minutes . the solution was cooled to ambient temperature , and excess trifluoroacetic acid was removed in vacuo . the residue was made alkaline treated with the treatment of 25 % naoh solution ( 10 ml ), and the product extracted with chloroform . the combined organic layer was washed with water and brine , and dried over anhydrous sodium sulfate , filtered , and the filtrate evaporated in vacuo . the crude compound was purified by flash column chromatography on silica gel using 0 - 5 % meoh / chloroform as the eluent to furnish 0 . 270 g ( 54 %) of the cis isomer 3 . lrms : m / z , 309 ( m + h + ). synthesis of a compound of formula i , trans isomer wherein a is — ch 2 x —; x is — s —; y is single bond ; d and e is — ch 2 —; r 1 is methyl ; r 2 - r 9 are hydrogens ( 4 ) the compound 2 from example 1 ( 0 . 306 g , 1 mmol ) was treated with borane - thf ( 10 ml , 1 . 0 m ) at ambient temperature , and the mixture was heated under reflux for 1 hour by which time the reaction mixture became clear . after cooling to ambient temperature , the solution was treated with water to quench excess reagent borane reagent . the solvents were removed under reduced pressure , and the residue was treated with conc . hcl ( 7 ml ). the mixture was heated to reflux for 3 hours and evaporated to dryness in vacuo , and treated with 10 % naoh solution ( 10 ml ). the product was then extracted with etoac , washed with water and brine , dried over anhydrous sodium sulfate , filtered , and the filtrate taken to dryness under reduced pressure . the crude product was purified by flash chromatography on silica gel using 0 - 5 % meoh / chloroform as the eluent to give 0 . 202 g ( 66 %) of the trans isomer 4 . lrms : m / z , 309 ( m + h + ). a sample of compound 4 was dissolved in methanol and allowed to cool slowly to give x - ray - quality crystals . the projection diagram shown in fig3 confirms the structure of 2 as designated . synthesis of a compound of formula i , wherein a is — ch 2 x —; x is — s —; y is double bond ; d and e is — ch 2 —; r 2 - r 9 are hydrogens ( 5 ) the unsaturated compound 4 from example 1 ( 1 . 0 mmol ) was dissolved in methylene chloride ( 5 ml ), and was treated with ethyl chloroformate ( ). the reaction mixture was stirred at ambient temperature for 24 hours . after complete decomposition , the solution was poured onto 1n sodium hydroxide , and extracted with methylene chloride . the combined organic extracts were washed with brine , dried over anhydrous sodium sulfate , filtered , and the filtrate evaporated in vacuo to give the crude material , which was then purified by silica gel flash chromatography to give the desmethyl compound 7 . lrms : m / z , 293 ( m + h + ). synthesis of a compound of formula i , wherein a is — ch 2 x —; x is — s —; y is double bond ; d and e is — ch 2 —; r 1 is 3 -( 4 - fluorobenzoyl ) propyl ; r 2 - r 9 are hydrogens to a solution of 12 ( 0 . 292 g , 1 . 00 mmol ) and 4 - chloro - 4 ′- fluoro - butyrophenone ( 0 . 216 g , 1 . 08 mmol ) in dmf , was added sodium ioide ( 0 . 150 g , 1 . 00 mmol ) followed by triethylamine ( 0 . 15 ml , 1 . 16 mmol ). the reaction was heated under reflux for 3 hours . the reaction mixture was poured onto water and extracted with ethyl acetate . the combined organic layers were washed with water and brine , dried over anhydrous sodium sulfate , filtered , and the filtrate evaporated in vacuo . the crude compound was purified by flash chromatography . lrms : m / z , 457 ( m + h + ). synthesis of a compound of formula i , wherein a is — ch 2 x —; x is — so 2 —; y is double bond ; d and e is — ch 2 —; r 1 is methyl ; r 2 - r 9 are hydrogens ( 7 ) a solution of the thioether derivative in example 3 , ( 0 . 75 g , 2 . 4 mmol ) in methylene chloride ( 20 ml ) is cooled to 0 ° c ., treated with trifluoroacetic acid ( 0 . 89 g , 7 . 8 mmol ), and stirred at this temperature for about 30 minutes . thereafter , 3 - chloroperoxybenzoic acid ( 1 . 26 g 7 . 3 mmol ) was added and the entire mixture was stirred at ambient temperature for 1 hour by which time the dark green solution turned into an orange slurry . the reaction mixture was then poured onto water ( 100 ml ) and treated with 10 % sodium hydroxide solution ( 30 ml ). the organic layer was separated , washed with water , dried over anhydrous sodium sulfate , filtered , and the filtrated evaporated in vacuo . the greenish - yellow residue was purified by flash chromatography to give the desired sulfone 7 . lrms : m / z , 339 ( m + h + ). synthesis of a compound of formula i , wherein a is — ch 2 x —; x is — o —; y is double bond ; d and e is — ch 2 —; r 1 is methyl ; r 2 - r 9 are hydrogens ( 9 ) synthesis of the oxazepine derivative 9 was prepared by nearly the same procedure as the one used for the preparation of the thiazepine analog 2 in example 1 . step 1 . to a well stirred solution of compound 8 ( 7 . 10 g , 36 mmol ) in ethanol ( 200 ml ) and glacial acetic acid ( 25 ml ), a concentrated solution of nano 2 ( 11 . 00 g , 159 mmol ) in water ( 13 ml ) was added dropwise at ambient temperature . the reaction was stirred at ambient temperature for 20 min and treated with water ( 100 ml ). the product was filtered , washed with water , and dried to give 6 . 5 g ( 80 %) of the nitroso compound . step 2 . to a stirred mixture of nitroso compound from step 1 ( 5 . 62 g , 24 . 9 mmol ) and n - methyl 4 - pyridone ( 3 . 66 g , 32 . 4 mmol ) in ethanol ( 125 ml ) and acetic acid ( 22 ml ) at − 20 ° c ., was added zinc dust ( 4 . 88 g , 74 . 63 mmol ) in three equal portions allowing 10 mins between the additions . the reaction was stirred for another 30 minutes and filtered hot . the solid washed with ethanol , and the resultant solution was treated with acetic acid ( 15 ml ) and heated to reflux for 16 hours . thereafter the solvent was removed in vacuo . the residue was treated with 8 ml of acetic acid , and heated to reflux for about 16 hours . the solvent was removed in vacuo , and the residue was dissolved in methylene chloride - ether ( 1 : 2 v / v ) ( 500 ml ). the solid impurity was removed by filtration , and the filtrate was washed with 10 % naoh solution . the combined organic layer was washed with water and brine , dried over anhydrous sodium sulfate , filtered and the filtrate taken to dryness in vacuo . the crude product was purified by flash chromatography on silica gel using 0 - 5 % meoh / chloroform as the eluent to give 0 . 4 g of the desired product 9 . lrms : m / z , 291 ( m + h + ). the ic 50 values for 5 - ht 2a , 5 - ht 2c , and d 2 receptors are shown in table 1 . all the compounds tested showed excellent receptor binding activity with compound 4 being the most potent amongst all . doses of compound 2 for these studies were selected from a pilot study that revealed robust catalepsy ( without a loss of right reflex ) with 30 mg / kg ip ddd - 016 . some locomotor reduction was seen with 10 mg / kg , and 3 mg / kg did not differentiate from vehicle ( 75 % dmso ; pilot study data not shown ). the in vivo data are shown in fig4 . effects of compound 2 on amphetamine - induced motor activity ( fig4 graph ). all rats were habituated to the motor box for 30 min followed by injection of compound 2 or vehicle . after 30 min all rats were injected with 1 mg / kg , i . p . amphetamine ( a dose that is known to elevate locomotion in rats ) and their motor activity was recorded for 2 hr . even with the small sample size , there is a trend for 10 mg / kg of 2 to reduce the effects of amphetamine . anova with post hoc newman keuls revealed a difference between 3 mg / kg and 10 mg / kg of 2 for horizontal activity ( p & lt ; 0 . 05 ). effects of compound 2 on amphetamine - induced sensorimotor gating deficits ( fig4 table ). once the compound 2 dose range was determined by motor assessments , a separate group of rats were used to study ppi . rats were treated with vehicle ( 75 % dmso ) or ddd - 016 in the dmso vehicle ; 30 min later amphetamine ( 3 mg / kg ip ) or saline was administered , and the startle session was initiated after an additional 30 min . 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