ʻO Rimegepant wale nō ka mea hoʻouka kaua CGRP o ka honua e hoʻohana ana i ka ʻenehana papa hoʻoheheʻe waha i hoʻopaʻa ʻia a ʻo ia ka lāʻau lapaʻau mua ma ka honua e hiki ke hoʻohana ʻia no ka mālama ʻana a me ka pale ʻana i nā hōʻeha migraine koʻikoʻi.
Ma Pepeluali 27, 2020, ua ʻāpono ka US Food and Drug Administration (FDA) i ke kūʻai aku ʻana o nā papa remdesivir panicol sulfate ma lalo o ka inoa inoa ʻo Nurtec® ODT.
A hiki i kēia lā, ʻo nā ala hana nui i ka mea hana lāʻau lapaʻau remepiride ʻelua mau ala i hōʻike ʻia e ka mea hana mua, ʻo Bristol-Myers Squibb, me ka hoʻohana ʻana i ka (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsilyl]oxy]-5H-ʻo cycloheptatrienepyridin-5-one (hui 1) ma ke ʻano he mea hoʻomaka.
Ala 1: Hoʻomākaukau ʻia ʻo Remegapan ma o kahi hopena ʻeono-ʻanuʻu e pili ana, ma waena o nā mea ʻē aʻe: ka hōʻemi ʻana o ka hui ketone me ka sodium borohydride, ka chlorination o ka hui hydroxyl me ka triphenylphosphine a me N-chlorosuccinimide, ka pani ʻana o ka ʻātoma chlorine me ka sodium azide, ka desiliconization me ka tetrabutylammonium fluoride, ka hoʻopili ʻana, a me ka hōʻemi ʻana o ka hui azide me ka trimethylphosphine. Hōʻike ʻia ke ala ma lalo nei (Kiʻi 3):
Ala 2: Me ka hoʻohana ʻana i ka hui 1 ma ke ʻano he mea hoʻomaka, ua hana ʻia ʻo remepam i ʻekolu mau ʻanuʻu (ka hopena hoʻokahi ʻanuʻu o ka tetraisopropoxytitanium, alumina, a me ka palladium ma ke kalapona e hana i ka waena waena 2a, ka deprotection e hana i ka waena waena 2b, a me ka hoʻopili ʻana). Ua hōʻike ʻia ke ala ma lalo nei (Kiʻi 4):
E like me ka mea i ʻike ʻia mai ke ʻano hoʻonohonoho, ʻo ka mea hana lāʻau lapaʻau ikaika ʻo Remegapan molekala he ʻekolu mau kikowaena chiral. ʻO ka hana ʻana i kahi amine chiral ma ke kūlana 5 o ka cycloheptane he pilikia nui ia no ka hoʻonui ʻana i ka hana ʻana o ka mea hana lāʻau lapaʻau ikaika. E kālele ana ka noiʻi hou aku i ka hoʻomaikaʻi ʻana i ke kaʻina hana synthesis no nā mea waena koʻikoʻi 2a/2b.
Ua wehewehe ka Palapala Sila Nui CN114957247A i kahi ʻano hana no ka hoʻomākaukau ʻana i nā mea waena koʻikoʻi 2a/2b: me ka hoʻohana ʻana i ka hui 3a ma ke ʻano he mea hoʻomaka, hana ʻia kahi hopena wehe apo stereoselective me kahi reagent Lewis e hana i ka hui 3b, a laila e hana ʻia kahi hopena Suzuki, pale silanization, pani, a me ka deprotection e hāʻawi i ka mea waena koʻikoʻi 2b ma kahi o 54% o ka huina. Ua hōʻike ʻia ke ʻano hana ma lalo nei (Kiʻi 5):
Ua wehewehe ka Palapala Sila Nui CN116768938A i kahi ʻano hana no ka hoʻomākaukau ʻana i ka waena koʻikoʻi 2a: me ka hoʻohana ʻana i ka hui carbonyl (4a) ma ke ʻano he mea hoʻomaka, ua hoʻomākaukau ʻia ka waena 1 ma o ka hōʻemi ʻana, ka pale ʻana o TIPS, a me ka hopena me 2,3-difluorobromobenzene. Ke hana nei ka waena 1 i kahi hopena hōʻemi-amination asymmetric ma lalo o ka hana a kahi mea hoʻouluulu FeⅡ/EDTA a laila ke hana nei i ka ammonolysis me 20% aqueous ammonia e hua mai i ka waena koʻikoʻi 2a (Kiʻi 6a).
Ma kekahi palapala ʻē aʻe (Zhejiang Chemical Industry, 2022, 53(8). 13-18.), ua wehewehe ʻia kahi ʻano hana no ka hoʻomākaukau ʻana i ka mea waena koʻikoʻi 2b: me ka hoʻohana ʻana i ka hui 2 ma ke ʻano he mea maka, loaʻa ka mea waena koʻikoʻi 2b ma o ka AlⅢ/EDTA catalysis. Penei ke ʻano hana (Kiʻi 6b):
Hōʻike nā Palapala Sila Nui CN116640811A/CN116083385A i kahi ʻano hana no ka hoʻomākaukau ʻana i nā mea waena koʻikoʻi 2a/2b: me ka hoʻohana ʻana i ka hui 1/2 ma ke ʻano he mea hoʻomaka, hoʻopuka pololei ʻia nā mea waena chiral koʻikoʻi 2a/2b ma o kahi hopena transaminase hoʻokahi-ʻanuʻu. ʻAʻole wale kēia kaʻina hana i kahi ʻanuʻu synthetic pōkole akā hoʻomaikaʻi nui hoʻi i ke koho chiral a me ka hua o nā mea waena koʻikoʻi 2a/2b. Eia kekahi, ua hōʻike ʻia ke ʻano hoʻomākaukau e nā kūlana hopena akahai a me nā hana palekana ma hope o ka hana ʻana, kahi e hoʻokō ai i nā koi hana ʻoihana (Kiʻi 7).
ʻO ka hui waiʻona chiral 4b kahi mea mua i nā waena amine chiral koʻikoʻi 2a/2b. I kēia manawa, hāʻule nā ala synthetic i loaʻa i ka lehulehu i ʻelua mau māhele: kemika a me ka chemoenzymatic.
Ma nā palapala (Organic Letters, 2012, 14(18): 4938–4941), ua wehewehe ka hui nāna i hana i ke aʻo mua i kahi ala e synthesize ai i ka 4b ma o ka hoʻemi asymmetric: me ka hoʻohana ʻana i ka dimethyl 2,3-pyridinedicarboxylate (5a) ma ke ʻano he mea hoʻomaka, ua loaʻa ka 4a waena ma o ka Dieckmann cyclization a me ka decarboxylation reaction, a laila ua synthesized ʻia ka hui waiʻona chiral ma o ka hoʻemi asymmetric me ka hoʻohana ʻana i kahi mea hoʻouluulu metala Rh-(R-Binapine)(COD)BF₄ me ka hoʻololi ʻana o 100% a me ee≥99.9% (Kiʻi 8).
I ka wā mua, ua ʻōlelo ka ʻoihana noiʻi ma ka palapala Sila Nui CN102066358B ua hoʻemi ʻia ka hui diketone (4a) i 4b e kahi ʻano enzymatic, akā ʻaʻole i hōʻike i ka ʻike kikoʻī e pili ana i ka hopena; ma hope mai, ua hōʻike ʻia ma ka palapala (Organic Letters, 2012, 14(18):4938-4941) ua hoʻemi ʻia ka hui diketone i 4b ma lalo o ka catalysis o ketone reductase ES-KRED-119 me ka hopena hopena o 81% a me ka waiwai ee o 99.2% (Kiʻi 9).
Ua kūʻai ʻia ke ketone reductase ES-KRED-119 i hoʻohana ʻia ma ke ʻano enzymatic i luna mai Shangke Biopharmaceutical (Shanghai) Co., Ltd. Ua hoʻololi ʻo Shangke Biopharmaceutical i ka enzyme ma ka palapala Sila Nui CN202410502187.9, a hiki i ka nui o ka substrate ke hiki i 100 g/L.
ʻOi aku ka maikaʻi o ka hoʻemi ʻana o ka asymmetric enzymatic i nā koi ʻoihana no ka synthesis o nā hui waiʻona chiral (4b). Ua kālele nā haʻawina ma hope aku i ka hoʻomaikaʻi ʻana i nā catalysts a i ʻole ka nānā ʻana a me ka hoʻonui ʻana i nā ketone reductases, ʻaʻole e kūkākūkā kikoʻī ʻia ma aneʻi.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN et al. Ke ʻano hana no ka hana ʻana i ka CGRP receptor antagonist cycloheptapyridine: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, et al. Nā ʻano hana synthetic no ka rimegepant a me kāna mau mea waena: Kina, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Ke ʻano hana no ka hoʻomākaukau ʻana i ka mea hoʻoulu hao a me ka huahana waena o ka rimexam: Kina, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Haʻawina mua ma ka ʻenehana synthesis o ka fluorinated chiral moiety o ka CGRP receptor antagonist Remegapan ma o ke ʻano asymmetric catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] He Lingyun, Chen Binhui, Yu Yang. Ke ala no ka hoʻomākaukau ʻana i ka rimexam waena: Kina, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, et al. Hana ʻana i nā mea waena polymer koʻikoʻi me ka hoʻohana ʻana i kahi transaminase i hoʻololi ʻia [J]. Noiʻi a me ka Hoʻomohala ʻana i ke Kaʻina Hana Organic, 2022, 26(7):1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, et al. Hoʻohuihui enantioselective kūpono a hiki ke hoʻonui ʻia o nā mea kūʻē CGRP [J]. Nā Leka Organic, 2012, 14(18): 4938–4941.
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