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     替格瑞洛(Ticagrelor,BRILINTA) 274693-27-5調研報告

    一、基本信息:
     
    商品名:BRILINTA
    通用名:Ticagrelor
    別名:替卡格雷
    中文名:替格瑞洛
    CAS 登錄號274693-27-5
    英文化學名:(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)
    cyclopropylamino]-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol
    適應癥用于減少急性冠脈綜合征(ACS)患者的心血管死亡和心臟病發作
    藥物作用機制:替格瑞洛(也稱替卡格雷,英文名:ticagrelor)能可逆性地作用于血管平滑肌細胞上的嘌呤2 受體亞型P2Y12 ,不需要代謝激活,對二磷酸腺苷(ADP) 引起的血小板聚集有明顯的抑制作用,且口服使用后起效迅速,能有效改善急性冠心病患者的癥狀。因為替格瑞洛的抗血小板作用是可逆的,所以對于那些需在先期進行抗凝治療后再行手術的病人尤為適用。
    上市時間:歐洲:2010.12.03;美國:2011.7.20;中國:2012.11.22
    藥物公司:AstraZeneca AB
    專利信息:
    化合物專利:WO0034283/CN1334816A,申請日:1999-12-02,到期日:2019-12-02,法律狀態:有效;
    晶型專利:CN1432018A,CN1817883A,申請日:2001-05-31,到期日:2021-05-31,法律狀態:有效;
    中間體專利:CN1432017A,申請日:2001-05-31,到期日:2021-05-31,法律狀態:有效;
    工藝專利:CN1680340A,申請日:2001-05-31,到期日:2021-05-31,法律狀態:有效;CN102149716A,申請日:2009-09-08,法律狀態:審中;
    化合物專利有效期: 2019年12月2日
    國內申報注冊情況:目前已有35家廠家在申報注冊;
    替格瑞洛及關鍵中間體
    4,6-二氯-2-(丙硫基)-5-氨基嘧啶(145783-15-9)
    2-[[(3aR,4S,6R,6aS)-6-氨基四氫-2,2-二甲基-4H-環戊烯并-1,3-二氧雜環戊烷-4-基]氧基]乙醇 L-酒石酸鹽(376608-65-0)
    (1R,2S)-2-(3,4-二氟苯基)環丙胺(R)-扁桃酸鹽(376608-71-8)
     
     
    二、市場前景:
        替格瑞洛專利保護期至2019年,即將到期,目前該產品及相關中間體國內外生產廠家眾多,全球現有數十家供應商生產或定制kg級產品。
    替卡格雷(替格瑞洛)屬于環戊基三唑嘧啶類新型抗凝劑,是首個可逆結合的、直接起效的、口服給藥的血小板二磷酸腺苷P2Y12受體拮抗劑,比氯吡格雷起效更快,對血小板凝集的抑制作用更強、更持久。2011年7月20日,美國FDA批準替格瑞洛用于降低急性冠脈綜合征(acute coronary syndrome,ACS)患者的血栓性心血管事件的發生率。
    替卡格雷(替格瑞洛)在全球85個國家得到批準,被列入29個國家的醫療保險目錄,進入31個國家病人自付目錄。2010年12月替格瑞洛(ticagrelor)在歐洲率先上市,2011年7月得到美國食品與藥物管理局(FDA)批準。替格瑞洛已經被多部國際治療指南推薦用于ACS患者的治療,其中包括歐洲心臟病學會(ESC)指南、美國心臟病學會(ACC)指南和美國心臟學會(AHA)指南等。 
     

     

    歐 洲 
    2011年歐洲心臟病學會(ESC)指南推薦替格瑞洛為NSTE-ACS患者的一線用藥;2013年歐洲心臟病學會(ESC)推薦替格瑞洛為STEMI-ACS患者和行PCI STEMI患者的一線治療。 
    美 國
    2011年美國心臟病學會基金會/美國心臟學會/美國心血管造影和介入學會(ACCF/AHA/SCAI)共同推薦替格瑞洛為行PCI  急性冠脈綜合癥(ACS)患者的一線治療;
    2012年,美國心臟病學會(ACC)與AHA指南推薦替格瑞洛為不穩定性心絞痛(UA)/非ST段抬高心肌梗死(NSTEMI)的一線治療;2013年,ACCF/AHA指南推薦替格瑞洛為行PCI STEMI患者的一線治療。 
    中 國
    2012年中國PCI指南推薦倍林達®(替格瑞洛片)用于行PCI治療的ACS患者的一線治療。

     

    研究證實,替格瑞洛與已上市的抗凝血藥類似,也可用于病人接受冠狀動脈搭橋手術或血管成形術中清除動脈阻塞后的血栓。替格瑞洛可顯著降低ACS患者心血管事件發生風險和死亡率,是抗血小板藥物一個更為有力的選擇,與目前標準治療藥物氯吡格雷相比,,療效優勢或更為顯著,為醫生及患者帶來更多的選擇。
    據湯姆森研究報告,替格瑞洛2012年銷售額為1.02億美金,2013年2.83億美金,2014年4.76億美金,預測替格瑞洛將在2018年達到銷售峰值10億美金。
    為了進一步開發市場,阿斯利康還在繼續開發該產品的其他適應癥。2015年3月14日,阿斯利康宣布了倍林達(替格瑞洛)片劑聯合低劑量阿司匹林與安慰劑聯合低劑量阿司匹林,對于入組前1~3年內有心梗病史的患者動脈粥樣硬化血栓事件的長期二級預防療效。90 mg和60 mg研究劑量的替格瑞洛聯合阿司匹林與安慰劑相比,均顯著減少心血管(CV)死亡,心梗(MI)或卒中的復合終點。安全性方面,在兩種劑量的替格瑞洛聯合阿司匹林組均顯著高于安慰劑聯合阿司匹林。接下來阿斯利康還將繼續評估替格瑞洛對于周圍動脈疾病,缺血性卒中或短暫缺血發作患者的心血管事件預防效果,以及糖尿病和冠狀動脈粥樣硬化患者的心血管事件預防效果。
    倍林達(替格瑞洛)目前還沒有被批準用于心梗患者發病1年后,或者是外周動脈疾病,卒中,糖尿病或動脈粥樣硬化患者的動脈粥樣硬化血栓事件的二級預防。如果研究結果達到FDA審查標準從而獲批應用于更多適應癥的治療,倍林達(替格瑞洛)的市場前景將進一步擴大。
    替格瑞洛的化合物專利即將在2019年到期,目前已有35家廠家在申報注冊,研發生產該產品及中間體的廠商工藝及成本也已經相對成熟透明,國內共有約154組相關專利,全球有約891組相關專利。
    三、原料
    乙酰氨基丙二酸二乙酯:1KG
    硫脲:100KG
    溴代正丙烷:10KG
    2-溴乙醇:100kg
    3,4-二氟苯甲醛: 100kg
    3,5-二叔丁基水楊醛:50KG
    二乙基鋅:100KG
    反式-1,2-環己二胺:10kg
    二碘甲烷:100kg
    S-扁桃酸:50kg
    四、應用領域
        原料藥,用于減少急性冠脈綜合征(ACS)患者的心血管死亡和心臟病發作。
    五、相關產品
    主要相關中間體:
    4,6-二氯-2-(丙硫基)-5-氨基嘧啶(145783-15-9)
    2-[[(3aR,4S,6R,6aS)-6-氨基四氫-2,2-二甲基-4H-環戊烯并-1,3-二氧雜環戊烷-4-基]氧基]乙醇 L-酒石酸鹽(376608-65-0)
    (1R,2S)-2-(3,4-二氟苯基)環丙胺(R)-扁桃酸鹽(376608-71-8)

    地址:山東東營經濟開發區淄河路22號
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