Rimegepant waa daawada kaliya ee adduunka ee ka soo horjeeda soo-dhoweeyaha CGRP ee adeegsata tiknoolajiyada kiniinka ee afka ka burburaya ee shatiga haysta, waana daawada ugu horreysa adduunka ee loo isticmaali karo daaweynta iyo ka hortagga weerarrada madax-xanuunka daran.
Febraayo 27, 2020, Maamulka Cuntada iyo Dawooyinka ee Mareykanka (FDA) ayaa ansixiyay suuqgeynta kiniiniyada remdesivir panicol sulfate oo lagu magacaabo Nurtec® ODT.
Ilaa hadda, waddooyinka ugu muhiimsan ee loo maro daawada firfircoon ee remepiride waa laba waddo oo uu shaaciyay soo-saaraha asalka ah, Bristol-Myers Squibb, isagoo adeegsanaya (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsilyl]oxy]-5H-cycloheptatrienepyridin-5-one (isku-darka 1) sida agabka bilowga ah.
Wadada 1aad: Remegapan waxaa lagu diyaariyaa falgal lix tallaabo ah oo ay ku jiraan: dhimista kooxda ketone oo leh sodium borohydride, koloriin ku darista kooxda hydroxyl oo leh triphenylphosphine iyo N-chlorosuccinimide, beddelka atamka chlorine oo leh sodium azide, desiliconization oo leh tetrabutylammonium fluoride, isku xidhka, iyo yaraynta kooxda azide oo leh trimethylphosphine. Wadada waxaa lagu muujiyay hoos (Jaantuska 3):
Wadada 2aad: Iyada oo la adeegsanayo isku-dhafka 1aad oo ah agabka bilowga ah, remepam waxaa lagu sameeyay saddex tallaabo (falcelin hal-tallaabo ah oo tetraisopropoxytitanium, alumina, iyo palladium ah oo ku socota kaarboonka si loo soo saaro furaha dhexe ee 2a, ka-hortagga ilaalinta si loo soo saaro furaha dhexe ee 2b, iyo isku-xidhka). Wadada waxaa lagu muujiyay hoos (Jaantuska 4aad):
Sida laga arki karo qaacidada qaab-dhismeedka, maaddada daawada firfircoon ee Remegapan molecule waxay leedahay saddex xarumood oo chiral ah. Abuuritaanka chiral amine oo ku yaal booska 5-aad ee cycloheptane waxay caqabad weyn ku tahay kor u qaadista wax soo saarka daawada firfircoon. Cilmi-baaris dheeraad ah ayaa diiradda saari doonta hagaajinta habka isku-darka ee dhexdhexaadiyeyaasha muhiimka ah 2a/2b.
Patent CN114957247A wuxuu qeexayaa hab loo diyaariyo dhexdhexaadiyeyaasha muhiimka ah 2a/2b: iyadoo la adeegsanayo isku-dhafka 3a oo ah walxo bilow ah, falgal furitaan giraan ah oo stereoselective ah ayaa dhaca iyadoo la adeegsanayo Lewis reagent si loo sameeyo isku-dhafka 3b, kaas oo markaa mara falgalka Suzuki, ilaalinta silanization, beddelka, iyo ka-hortagga si loo helo furaha dhexdhexaadka ah ee 2b qiyaastii 54% wax-soo-saarka guud. Habka waxaa lagu muujiyay hoos (Jaantuska 5):
Patent CN116768938A wuxuu qeexayaa hab loo diyaariyo furaha dhexe ee 2a: iyadoo la adeegsanayo isku-darka carbonyl (4a) oo ah walxo bilow ah, dhexdhexaadka 1 waxaa lagu diyaariyaa dhimista, ilaalinta TIPS, iyo falcelinta 2,3-difluorobromobenzene. Dhexdhexaadka 1 wuxuu maraa falcelin dhimis aan sinnayn oo hoos timaada ficilka FeⅡ/EDTA ee isku-dhafka ah ka dibna wuxuu maraa ammonolysis oo leh 20% amooniyam biyood ah si loo soo saaro furaha dhexe ee 2a (Jaantuska 6a).
Suugaan kale (Warshadaha Kiimikada Zhejiang, 2022, 53(8). 13-18.), hab loogu diyaariyo furaha dhexe ee 2b ayaa lagu sharraxay: iyadoo la adeegsanayo isku-dhafka 2 oo ah walxo cayriin ah, furaha dhexe ee 2b waxaa laga helaa iyada oo loo marayo AlⅢ/EDTA catalysis. Habkani waa sida soo socota (Jaantuska 6b):
Shatiyada CN116640811A/CN116083385A waxay qeexayaan hab loo diyaariyo dhexdhexaadiyeyaasha muhiimka ah 2a/2b: iyadoo la adeegsanayo isku-dhafka 1/2 oo ah agab bilow ah, dhexdhexaadiyeyaasha muhiimka ah ee chiral 2a/2b waxaa si toos ah loogu soo saaraa falgalka transaminase hal-tallaabo ah. Hawshani ma aha oo kaliya inay leedahay tallaabo kooban oo isku-dhafan laakiin sidoo kale waxay si weyn u hagaajinaysaa xulashada chiral iyo wax-soo-saarka dhexdhexaadiyeyaasha muhiimka ah 2a/2b. Intaa waxaa dheer, habka diyaarinta waxaa lagu gartaa xaaladaha falcelinta khafiifka ah iyo hawlgallada ka dambeeya farsamaynta badbaadada leh, kuwaas oo buuxiya shuruudaha wax-soo-saarka warshadaha (Jaantuska 7).
Isku-darka khamriga Chiral 4b waa horudhac u ah dhexdhexaadiyeyaasha muhiimka ah ee chiral amine 2a/2b. Waqtigan xaadirka ah, waddooyinka isku-dhafka ah ee dadweynaha laga heli karo waxay u qaybsan yihiin laba qaybood: kiimiko iyo chemoenzymatic.
Suugaanta (Organic Letters, 2012, 14(18): 4938–4941), shirkadda samaysay daraasadda asalka ah waxay qeexday waddo lagu sameeyo 4b iyada oo loo marayo hoos u dhac aan sinnayn: iyada oo la adeegsanayo dimethyl 2,3-pyridinedicarboxylate (5a) oo ah walxo bilow ah, 4a dhexdhexaad ah ayaa laga helay iyada oo loo marayo wareegga Dieckmann iyo falcelinta decarboxylation, ka dibna isku-darka khamriga chiral waxaa lagu sameeyay iyada oo loo marayo hoos u dhac aan sinnayn iyada oo la adeegsanayo kiciye bir ah Rh-(R-Binapine)(COD)BF₄ oo leh beddel 100% iyo ee≥99.9% (Jaantuska 8).
Markii hore, shirkadda cilmi-baarista waxay ku xustay shatiga CN102066358B in isku-darka diketone (4a) loo dhimay 4b iyadoo la adeegsanayo habka enzymatic, laakiin ma aysan shaacin macluumaad gaar ah oo ku saabsan falcelinta; markii dambe, waxaa lagu soo warramey suugaanta (Organic Letters, 2012, 14(18):4938-4941) in isku-darka diketone loo dhimay 4b iyadoo la raacayo catalysis-ka ketone reductase ES-KRED-119 iyadoo wax-soo-saar falgal ah uu yahay 81% iyo qiimaha ee uu yahay 99.2% (Jaantuska 9).
Ketone reductase ES-KRED-119 ee loo isticmaalay habka enzymatic-ka ee kor ku xusan waxaa laga soo iibsaday Shangke Biopharmaceutical (Shanghai) Co., Ltd. Shangke Biopharmaceutical waxay wax ka beddeshay ensaymka ku jira patent-ka CN202410502187.9, fiirsashada substrate-kuna waxay gaari kartaa 100 g/L.
Hoos u dhigista aan sinnayn ee enzymatic-ka ayaa si fiican ugu habboon shuruudaha warshadaha ee isku-darka isku-dhafka khamriga chiral (4b). Daraasadaha xiga waxay diiradda saareen hagaajinta katalisyada ama baaritaanka iyo hagaajinta reductases-ka ketone, kuwaas oo aan si faahfaahsan looga hadli doonin halkan.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN et al. Habka loo soo saaro cycloheptapyridine oo ka soo horjeeda soo-dhoweeyaha CGRP: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, iwm. Hababka isku-dhafka ah ee loogu talagalay rimegepant iyo dhexdhexaadiyayaashiisa: Shiinaha, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Habka loo diyaariyo kicinta birta iyo wax soo saarka dhexdhexaadka ah ee rimexam: Shiinaha, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Daraasad horudhac ah oo ku saabsan tignoolajiyada isku-darka ee qaybta chiral ee fluorinated ee CGRP receptor antagonist Remegapan iyada oo loo marayo habka amination catalytic asymmetric [J]. Warshadaha Kiimikada Zhejiang, 2022, 53(8):13-18.
[6] He Lingyun, Chen Binhui, Yu Yang. Habka diyaarinta rimexam dhexe: Shiinaha, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, iwm. Isku-darka aadka u hufan ee dhexdhexaadiyeyaasha muhiimka ah ee polymer-ka iyadoo la adeegsanayo transaminase wax laga beddelay [J]. Cilmi-baarista iyo Horumarinta Habka Dabiiciga ah, 2022, 26(7):1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, iwm. Isku-darka enantioselective ee hufan oo la miisaami karo ee ka soo horjeeda CGRP [J]. Letters Organic, 2012, 14(18): 4938–4941.
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