Patent Application: US-5062708-A

Abstract:
the invention relates to radioactively labeled derivatives of - 1 -- 1h - imidazole - 5 - carboxylic acid esters , uses , and methods for preparing these compounds .

Description:
the present invention provides a compound of the general formula i : r 1 is linear or branched c 1 - c 4 alkyl , and is optionally substituted with a halogen selected from the groups consisting of f , cl , i or br ; r 2 denotes an alkyl group containing 1 or 2 carbon atoms ; and r 3 is phenyl , optionally substituted with a halogen ; as used herein , the expression “ alkyl ” includes methyl and ethyl groups , and linear or branched propyl groups . particular alkyl groups are methyl , ethyl , 2 - fluoroethyl , n - propyl , and 2 - propyl . the term “ halogen ” as used herein , includes iodine , bromine , chlorine , fluorine , and astatine . the substituent r 1 on the carboxylic ester group may be transformed to other substituents encompassed by the definition of r 1 by suitable reactions known in the art for the modification of carboxylic acid functions , i . e ., by hydrolysis and esterification and / or transesterification . the starting materials for the preparation of the novel compounds of formula ( i ) are known or they have been obtained by enantioselective synthesis disclosed herein . particularly preferred novel compounds in accordance with the present invention are those ester compounds wherein r 1 is alkyl substituted with a halogen , preferably with a radioactive halogen . the compound of formula ( i ) in accordance with the present invention is suitably a radiolabeled derivative of formula ia : r 1 is linear or branched c 1 - c 4 alkyl , and is optionally substituted with an □- halogen ; said halogen being selected from fluorine , preferably radioactive fluorine ; r 2 denotes an alkyl group containing 1 or 2 carbon atoms ; and r 3 is phenyl ; preferred are compounds of formula ia , wherein r 1 is 2 - fluoroethyl and said halogen is 18 f . the compound of formula ( i ) in accordance with the present invention is suitably a compound wherein phenyl is substituted with a halogen of formula ib : r 1 is linear or branched c 1 - c 4 alkyl , and is optionally substituted with a halogen , selected from the groups consisting of f , cl , i or br ; r 2 denotes an alkyl group containing 1 or 2 carbon atoms ; and x is a halogen , selected from the groups consisting of i , br , f , or cl ; halogenated compounds of formula ib serve as intermediary derivatives for the synthesis of stannylated precursors , which provide access to radiolabelled derivatives of formula ic : r 1 is linear or branched c 1 - c 4 alkyl , and is optionally substituted with a halogen selected from the groups consisting of f , cl , i or br ; r 2 denotes an alkyl group containing 1 or 2 carbon atoms ; and x is a radioactive halogen , selected from the group consisting of , 123 i , 124 i , 125 i 131 i , 76 br , 82 br , 211 at , or 18 f ; preferred are compounds of formula ic , wherein said halogen is 123 i , 124 i 131 i , or 18 f . the present invention includes within its scope stannylated derivatives of formula ii : r 1 is linear or branched c 1 - c 4 alkyl , optionally substituted with a halogen selected from f , cl , i or br ; r 2 denotes an alkyl group containing 1 or 2 carbon atoms ; and l represents trimethylstannyl , triethylstannyl , tri - n - propylstannyl , and tri - n - butylstannyl ; compounds of formula ii contain a leaving group l , suitably selected from trimethylstannyl , triethylstannyl , tri - n - propylstannyl , and tri - n - butylstannyl , especially trimethylstannyl . stannylated derivatives are key intermediates for radiotracer synthesis by oxidative radiohalogenido destannylation . the trialkylstannyl group in an aromatic ring is replaced under mild conditions by radiohalogen to yield the respective radioactively labelled compounds of formula ( ic ). the compound of formula ( ii ) in accordance with the present invention is suitably a compound wherein l is the trimethylstannyl substituent of formula iia : the invention concerns a process of synthesizing compounds of formula ( i ) by a stereoselective and regioselective new approach . the compounds according to the invention may be prepared by a process , which comprises coupling a compound of formula iii : r 1 represents a straight or branched alkyl chain containing from 1 to 4 carbon atoms , wherein the alkyl group is optionally substituted with a halogen ; r 2 represents a straight alkyl chain in ( s )- configuration containing from 1 to 2 carbon atoms ; x is a halogen . the reaction between compounds iii and iv proceeds with inversion of configuration , to give compounds of formula ib : r 1 is linear or branched c 1 - c 4 alkyl , and is optionally substituted with a halogen , selected from the groups consisting of f , cl , i or br ; r 2 denotes an alkyl group containing 1 or 2 carbon atoms ; and x is a halogen , selected from the groups consisting of i , br , f , or cl ; the reaction between compounds iii and iv is based on the known mitsunobu reaction ( mitsunobu , 1981 ). the alcohol ( s )- 1 -( 4 - iodophenyl ) ethanol ( iii ) is reacted with methyl imidazole - 5 - carboxylate ( iv ) in the presence of triphenylphosphane and a dialkyl azodicarboxylate ( preferably di - t - butyl azodicarboxylate ). triphenyl phosphinoxide and the hydrazo ester are by - products of the reaction . the reaction conditions favour activation of the alcohol to generate the reactive alkoxyphosphonium salt . methyl imidazole - 5 - carboxylate is expected to be deprotonated , thus n − 1 and n − 3 could react as nucleophile with the alkoxyphosphonium cation to give a mixture of two isomeric n - substituted imidazoles . yet , when coupling iii and iv at low temperature , alkylation is observed exclusively at n - 3 with clean inversion . ( s )- iii is a key intermediate and needs to be synthesized ; methyl imidazole - 5 - carboxylate iv is commercially available . since not commercially available , the ( s )- alcohol of formula iii is prepared by a novel synthetic approach , described hereafter and in scheme 1 : starting from 4 - iodophenyl methyl ketone , which is reduced to the racemic alcohol and converted to (±)- 1 -( 4 - iodophenyl ) ethyl chloroacetate , the racemic ester is subjected to stereoselective enzyme hydrolysis . the remaining ( s )- isomer of the ester is separated from the ( r )- alcohol and transesterified to give ( s )- 1 -( 4 - iodophenyl ) ethanol ( ee & gt ; 98 %) iii . laumen & amp ; schneider ( 1988 ) reported that lipase sam ii hydrolizes acetates and chloroacetates of secondary benzyl alcohols with high enantioselectivity , therefore , schneider &# 39 ; s procedure is applied to the resolution of racemic 1 -( 4 - iodophenyl ) ethanol . lipase sam ii is known to hydrolyze preferentially the ( r )- esters of secondary benzylic alcohols ; however , application with the substrate described in the invention is new . ( r )- 4 - iodo - metomidate is derived exclusively from the ( s )- alcohol of the ester , which is not accepted as substrate by lipase sam ii . coupling of ( s )- 1 -( 4 - iodophenyl ) ethanol with methyl imidazole - 5 - carboxylate yields ( r )- 4 - iodo - metomidate with clean inversion . this novel reaction offers a versatile approach to the synthesis of compounds described by formula i . ( s )- 1 -( 4 - iodophenyl ) ethanol ( ee & gt ; 98 %) iii is synthesized by lipase - catalyzed resolution and coupled with methyl imidazole - 5 - carboxylate iv . the two fragments are joined regioselectively at n − 3 with clean inversion of configuration producing ( r )- methyl 3 -[ 1 -( 4 - iodophenyl ) ethyl ]- 1h - imidazole - 5 - carboxylate ( 4 - iodo - mto ). compounds of formula ia and ib , labeled with a radiohalogen are obtained by alternate routes . compounds of formula ia typically represent radiohalogenated esters , whilst compounds of formula ib comprise the various esters of phenyl halogenated derivatives . the substituent r 1 on the carboxylic ester group may be transformed to other substituents defined as r 1 by suitable reactions known in the art for the modification of carboxylic acid functions . however , introducing a positron emitter requires special techniques , esterification is generally performed on - line using closed synthesis modules . compounds containing a radiolabelled phenyl ring r 3 are labelled by oxidative destannylation of especially synthesized precursors , which facilitate rapid labelling under mild reaction conditions . therefore , 4 - iodo - metomidate or 4 - iodo - etomidate , respectively , is converted to the 4 - trimethylstannyl derivative of formula iia to serve as a precursor for labelling metomidate and etomidate with a suitable radiohalogen . compounds of formula ii wherein l represents a leaving group , may be prepared by standard stannylation techniques . the exchange of halogen for the trialkylstannyl substituent ( l ) is catalyzed by tetrakis ( triphenylphosphane ) palladium to yield a stannylated compound of formula iia . radiohalogenated compounds of formula ic are conveniently prepared with high specific activities by reacting a compound of formula iia with a radiohalogen ( iodine - 123 ; iodine - 131 ; bromine - 76 , fluorine - 18 , and others ) in the presence of an oxidizing agent , at room temperature . the radioligand 131 i - mto is produced with a specific activity of & gt ; 50 gbq / μmol , resp . & gt ; 1 . 35 ci / μmol . the compounds in accordance with the present invention potently and selectively bind to adrenocortical membranes ( cytochrome p - 450c11 ). the present invention is described below in more detail in connection with the synthesis of an r 1 derived labelled ester , namely ( r )- 2 -[ 18 f ] fluoroethyl 1 -( 1 - phenylethyl )- 1h - imidazole - 5 - carboxylate and r 3 derived radiotracer ( r )- 1 -[ 1 -( 4 -[ 131 i ] iodophenyl ) ethyl ]- 1h - imidazole - 5 - carboxylic acid methyl ester ( 131 i - imto ); the example is given merely for illustrative purposes and shall in no way be understood as a limitation of the scope of the present invention which is given by the patent claims . a solution of substituted ( s )- alcohol ( 1 . 98 g , 7 . 98 mmol , ee & gt ; 98 %) in dry thf ( 14 . 5 cm 3 ) was added dropwise to a stirred solution of methyl 1h - imidazole - 5 - carboxylate ( 1 . 008 g , 7 . 98 mmol ) and triphenylphosphane ( 2 . 503 g , 9 . 43 mmol ) in dry thf ( 22 . 0 cm 3 ) in an atmosphere of argon − 30 ° c . then , a solution of di - t - butyl azodicarboxylate ( 2 . 204 g , 9 . 57 mmol ) in dry thf ( 14 . 5 cm 3 ) were added and the stirred reaction mixture was allowed to warm up from − 30 ° c . to 0 ° c . within 2 . 5 hr . no alcohol could by detected by tlc ( diethyl ether - diisopropylamine 10 : 1 ). the reaction mixture was concentrated under reduced pressure . the residue was mixed with diethyl ether ( 36 cm 3 ) and stirred for 2 h . the crystals ( triphenylphosphanoxide and hydrazo ester ) were collected and washed with diethyl ether ( 3 × 15 cm 3 ). the filtrate was evaporated and reduced pressure to leave a residue , which was purified by flash chromatography ( hexanes - diethyl ether - diisopropylamine 50 : 30 : 1 ; tlc : diethyl ether - diisopropylamine 10 : 1 , r f = 0 . 44 for iodide , 0 . 54 for metomidate ) on silica gel to give p - iodo - metomidate ( 1 . 91 g , 67 %, ee 99 %); [ a ] 20 d =+ 76 . 0 ( c 1 . 09 in acetone ). anal . ( c 13 h 13 in 2 o 2 ) c , h , n . generally , the synthesis of radiolabeled phenyl derivatives is performed shortly before use by oxidative radiohalogenido destannylation of a suitable precursor molecule . substitution with a radiohalogen in the phenyl ring offers access to diagnostic as well as therapeutic mto - derivatives . radionuclides for therapy are beta - and alpha - emitting halogens , e . g ., 131 i , 82 br , and 211 at . hexamethylditin ( 0 . 645 g . 3 . 2 mmol , 6 . 5 cm 3 of a solution of 1 . 0 g hexamethylditin in 10 cm 3 of dry toluene ), tetrakis ( triphenylphosphane ) palladium ( 58 mg , 5 mol %) and triethylamine ( 1 . 6 cm 3 , 11 . 6 mmol ) were added to a stirred solution of iodometomidate ( 0 . 368 g . 1 . 03 mmol , ee & gt ; 98 %) in an atmosphere of argon and refluxed ( bath temperature 135 ° c .) for 17 hr . the cooled solution was concentrated under reduced pressure and the residue was purified by flash chromatography ( hexane - diethyl ether - diisopropylamine 60 : 30 : 1 ; tlc : diethyl ether - diisopropylamine 10 : 1 , r f = 0 . 71 for stannane , r f = 0 . 50 for iodometomidate ) on silica gel to give stannane ( 0 . 377 g , 96 %) as a crystalline solid ( found : c , 48 . 7 ; h , 5 . 6 n , 7 . 1 , c 16 h 22 n 2 o 2 sn requires c , 48 . 9 ; h , 5 . 6 ; n , 7 . 1 %); mp 77 - 79 ° c . ( from hexane ); [□] 20 d =+ 82 . 09 ( c 2 . 06 in acetone ). ν max ( si , film )/ cm − 1 2981 , 1715 , 1437 , 1362 , 1218 , 1133 , 1110 , 1049 ; δ h ( 400 . 13 mhz , cdcl 3 ) 0 . 25 ( 9h , s , ( ch 3 ) 3 sn , 117 / 119 sn satellites , 2 × d , j 53 . 2 and 55 . 2 ), 1 . 82 ( 3h , d , j 7 . 0 , ch 3 ch ), 3 . 77 ( 3h , s , och 3 ), 6 . 30 ( 1h , q , j 7 . 0 , ch 3 ch ), 7 . 13 ( 2h , d , j 8 . 0 , 2 × h arom , 117 / 119 sn satellites , d , j 9 . 0 ), 7 . 43 ( 2h , d , j 8 . 0 , 2 × h arom , 117 / 119 sn satellites , d , j 42 . 7 ), 7 . 71 ( 1h , s , h hetarom ), 7 . 74 ( 1h s , h hetarom ); δ c ( 100 . 61 mhz , cdcl 3 ) - 9 . 61 ( 3 c , ( ch 3 ) 3 sn ), 22 . 16 ( ch 3 ch ), 51 . 40 ( och 3 ), 55 . 30 ( ch 3 ch ), 122 . 31 ( c arom ), 125 . 81 ( 2 × c , 2 × hc arom ), 117 / 119 sn satellites , d , j 45 . 9 ), 136 . 28 ( 2 × c , 2 × hc arom , 117 / 119 sn satellites , d , j 36 . 8 ), 122 . 29 ( 2 c , 2 × hc arom ), 128 . 02 ( 2 c , 2 × hc arom ), 137 . 94 ( c arom ), 138 . 23 ( hc hetarom ), 139 . 84 ( hc hetarom ), 141 . 00 ( c arom or cco ), 142 . 24 ( cco or c arom ), 160 . 68 ( co ). compounds of the general formula ( ib ) are obtained by mitsunobu coupling ( scheme 1 ). ( r )- iodometomidate is converted by treatment with hexaalkyldistannanes and a palladium catalyst to yield the stannylated precursor of formula ( iia ). transesterification of commercially available etomidate at ambient temperature in dry meoh , n - propanol , or 2 - propanol in the presence of the corresponding sodium alkoxide yielded metomidate , and the n - propyl and 2 - propyl esters , respectively . a solution of dtbad ( 0 . 128 g , 0 . 554 mmol ) in dry toluene ( 2 ml ) was added to a stirred mixture of ph 3 p ( 0 . 145 g , 0 . 554 mmol ), methyl 1h - imidazole - 5 - carboxylate ( 0 . 100 g , 0 . 462 mmol ) and 2 - fluoroethanol ( 44 mg , 0 . 040 ml , 0 . 681 mmol ) dry toluene ( 2 ml ) under an atmosphere of argon . after 18 h , water ( two drops ) was added and the mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography ( first column : 60 g of silica gel , hexane / et 2 o / ipr 2 nh 5 / 10 / 1 , r f 0 . 25 , 98 mg of mixture of 2 - fluoroethyl ester and hydrazo ester ; second flash chromatography : 40 g silica gel , et 2 o as eluent , r f 0 . 30 ) to give the product ( 38 mg , 31 %) as a crystalline solid , mp 51 ° c . ( hexane ); [□] 20 d =+ 106 . 29 ( c 0 . 72 , acetone ). anal . ( c 14 h 15 fn 2 o 2 ) c , h , n . synthesis is based on the nucleophilic radiofluorination with no - carrier - added 18 f - fluoride after kryptofix 2 . 2 . 2 .- activated nucleophilic substitution of 1 , 2 - dibromoethane in acetonitrile to yield 2 -[ 18 f ] fluoroethyl bromide for 18 f - fluoroethylation of ( r )- 1 -( 1 - phenylethyl )- 1h - imidazole - 5 - carboxylic acid as the tetrabutylammonium salt to yield the labeled fluoroethyl derivative ( 18 f - feto ). the radioligand is produced with a specific activity of approx . 40 gbq / μmol ( 1 . 1 ci / μmol ). 18 f - fluoroethylation requires special techniques for the conversion of the radionuclide to reactive 2 - 18 f - fluoroethyl bromide for subsequent esterification , which is generally performed at the site of radionuclide production . while the invention has been described in its preferred form or embodiment with some degree of particularity , it is understood that this description has been given only by way of example and that numerous changes in the details of synthesis , fabrication , and use , including the combination and arrangement of parts , may be made without departing from the spirit and scope of the invention . basmadjian g p , hetzel k r , ice r d , beierwaltes w h ( 1975 ) synthesis of a new adrenal cortex imaging agent 6 □-[ 131 i ]- iodomethyl - 19 - norcholest - 5 ( 10 ) en - 3 □- ol ( np - 59 ). j . labelled compd . & amp ; radiopharm . xi : 427 - 434 . sakar s d , ice r d , beierwaltes w h , gill s p , balanchandran s , basmadjian g p ( 1976 ) selenium - 75 - 19 - selenocholesterol — a new adrenal scanning agent with high concentration in the adrenal cortex . j nucl med 17 : 212 - 217 . beierwaltes , w . h ., wieland , d . m ., ice , r . d ., seabold , j . e ., sarkar , s . d ., gill , s . p ., mosley , s . t . 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