TW201726136A - 一種ｅｇｆｒ／ｈｅｒ２受體酪氨酸激酶抑制劑在製備治療ｈｅｒ２突變癌症藥物中的用途 - Google Patents
一種ｅｇｆｒ／ｈｅｒ２受體酪氨酸激酶抑制劑在製備治療ｈｅｒ２突變癌症藥物中的用途 Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
本發明涉及一種EGFR/HER2受體酪胺酸激酶抑制劑在製備治療HER2突變癌症藥物中的用途。具體而言涉及式A所示化合物或其可藥用鹽在製備治療HER2突變的癌症的藥物中的用途。□
Description
一種EGFR/HER2受體酪胺酸激酶抑制劑在製備治療HER2突變癌症的藥物中的用途。
在世界範圍內，無論男性還是女性，肺癌均已成為癌症死亡的主要原因。根據《2015年中國腫瘤登記年報》的統計表明，在中國肺癌的發病率和死亡率都佔據了首位。肺癌的發病率和死亡率均隨年齡增長而上升，一般40歲以後肺癌的發病率明顯上升，到75歲左右達到高峰，之後有所下降(石元凱，孫燕.臨床腫瘤內科手冊.北京：人民衛生出版社，2015：315-341)。在肺癌中，非小細胞肺癌(NSCLC)大約占所有肺癌患者的85%(Siegel R,Ma J,Zou Z,et al.Cancer statistics.CA Cancer J Clin,2014,64(1)：9-29)。發達國家中，腺癌是非小細胞肺癌中最常見的病理類型，約占40%。大多數NSCLC就診時就處於局部晚期或遠處轉移，
無法進行手術切除。
轉移性NSCLC的一線治療根據病理類型及基因改變情況而定。對EGFR基因突變陽性的患者建議進行EGFR-TKI治療，ALK陽性的患者建議給予克唑替尼治療(石元凱，孫燕.臨床腫瘤內科手冊.北京：人民衛生出版社，2015：315-341)。上述基因表達陰性的非鱗癌患者建議培美曲塞或其他含鉑兩藥聯合方案化療，在化療基礎上可聯合血管內皮抑素(YH-16)或西妥昔單抗(Cetuximab)。對一線治療達到疾病控制(完全緩解、部分緩解和穩定)的患者，可選擇維持治療。目前循證醫學證據支持的藥物有培美曲塞(非鱗癌)和吉西他濱，對於EGFR基因突變患者可選擇表皮生長因子受體酪胺酸激酶抑制劑(EGFR-TKI)維持治療。二線治療可選用多西紫杉醇、培美曲塞和EGFR-TKI。而三線治療目前並沒有明確的推薦治療方案，大量的臨床試驗正在探索其他的有效治療方法(石元凱，孫燕.臨床腫瘤內科手冊[M].北京：人民衛生出版社，2015：315-341)。除以上提及的靶點外，肺癌的研究還發現了諸多基因異常的改變，包括MET和FGFR1的擴增，PIK3CA、AKT、KRAS、NRAS、BRAF、MEK1、AKT1、FGFR2、DDR2和HER2突變，以及RET和ROS1重排等(Mazières J,Peters S,Lepage B,et al‧Lung cancer that harbors an HER2 mutation：Epidemiologic characteristics and therapeutic perspectives‧J Clin Oncol,2013，31(16)：1997-2003)。
其中人表皮因子受體2(HER2)基因屬於HER酪胺酸受
體家族的一員，HER2突變主要出現在20外顯子，約占NSCLC患者的2-4%(Clin Cancer Res.2012,18：4910-4918；Cancer Res.2005,65：1642-1646；Lung Cancer.2011,74：139-144.)。但2013年Barlesi等在一大型分子標記物研究中發現，10,000例晚期NSCLC患者中HER2突變率占0.9%(J Clin Oncol,2013,31(suppl)：abstr 8000)。Mazières等報導檢測了3800例肺腺癌患者中檢測到65例(1.7%)HER2突變的患者(J Clin Oncol,2013，31(16)：1997-2003)。HER2突變與其他驅動基因異常(EGFR、KRAS、BRAF突變及ALK重排等)互相排斥(Lung Cancer,2015,87(1)：14-22)。Suzuki等(Lung Cancer,2015,87(1)：14-22)也報導了HER2突變是浸潤性非小細胞肺腺癌患者預後較差的獨立影響因素(p=0.005)。臨床試驗中，Tomizawa等觀察到1例經鉑類藥為基礎的化療和吉非替尼治療無效的HER2突變女性肺腺癌患者對曲妥珠單抗聯合長春瑞濱(作為第三線治療)有效(Lung Cancer,2011,7：139-144)。另一項研究Mazières等對HER2突變的NSCLC患者的臨床特徵和療效的分析結果顯示：共16例HER2突變的非小細胞肺腺癌患者接受了HER2標靶藥物治療，其中部分患者接受了2種(3例)或4種(1例)不同的HER2標靶藥物(J Clin Oncol,2013，31(16)：1997-2003)。總計16例HER2突變的非小細胞肺腺癌的患者接受了22次HER2標靶藥物治療並有可評估的療效結果，其中有4例疾病進展(PD)，7例疾病穩定(SD，32%)，11例部分緩解(PR，50%)，疾病控制率(DCR)為82%。其中15例
使用含曲妥珠單抗(trastuzumab)治療的患者DCR為96%，4例使用阿法替尼(afatinib)的患者DCR為100%，2例使用拉帕替尼(lapatinib)和1例使用masatinib的患者療效評價為PD。其中一線使用HER2標靶藥物的15例患者的中位PFS為5.1個月(Mazières J et al,J Clin Oncol,2013，31(16)：1997-2003)。另一項來那替尼單藥或聯合替西羅莫司(temsirolimus)治療HER2突變非小細胞肺癌的臨床研究(NCT01827267)，2014年9月發佈結果顯示：13例服用來那替尼單藥的受試者中，PR 0例，SD占54%，SD12周占31%；即ORR為0，DCR為54%。14例服用來那替尼聯合替西羅莫司的患者中PR 3例(21%)，SD 11例(79%)，SD12周9例(64%)；即ORR為21%，DCR為100%。來那替尼單藥或聯合替西羅莫司用藥組的PFS分別為2.9個月和4個月(http：//www.bioportfolio.com/resources/trial/131948/Neratinib-With-and-Without-Temsirolimus-for-Patients-With-HER2-Activating-Mutations-in.html)。上述多個試驗結果顯示，一些HER2和/或EGFR標靶藥物可能對HER2突變的非小細胞肺癌患者有抗腫瘤療效，而有一些HER2和/或EGFR標靶藥物則無效，至於一種具體的HER2和/或EGFR標靶藥物對於HER2突變的癌症是否有效則難以預測。
CN102471312B公開了如下式A所示的化合物(化學名(E)-N-[4-[[3-氯-4-(2-吡啶基甲氧基)苯基]胺基]-3-氰基-7-乙氧基-6-喹啉基]-3-[(2R)-1-甲基吡咯烷-2-基]丙-2-烯醯胺)，並公開了其具有很強的EGFR和HER2的抑制作用，
並預期其可能用於治療EGFR和HER2過度表達的癌症，
CN102933574B公開了式A化合物的一系列可藥用鹽。CN103974949B公開了式A化合物的二馬來酸鹽的晶型。
然而上述文獻均沒有公開式A化合物對於治療HER2突變的癌症的作用。
本發明驚奇地發現，化合物A或其可藥用鹽，對於治療HER2突變的癌症有著驚人的效果，從而完成了本發明。
在本發明較佳的實施方案中，該癌症是肺癌、乳腺癌或胃腸道癌症。較佳的該肺癌是非小細胞肺癌，更進一步地較佳為HER2突變的非小細胞肺腺癌，特別是HER2突變的晚期非小細胞肺腺癌患者。較佳的該胃腸道癌症為胃癌。
在本發明中，該HER2突變的癌症指的是在這些癌症患者中可檢測出HER2基因的癌症驅動突變(driver mutation)，突變的類型主要為第20號外顯子的非移碼插入突變，其次是酪胺酸激酶結構域內和其他區段的一些錯義突變和小的插入和缺失突變，例如772-775 YVMA duplication(本來蛋白質中772-775位置的胺基酸是一個YVMA，由於基因中插入12個鹼基形成了另外一對YVMA，造成YVMA了的重複)，G776delinsVC(由於相應位點3個鹼基的插入造成776號胺基酸G變成了V，並插入了胺基酸C，也可表示成insG776V C或G776>VC)，P780_Y781insGSP(由於相應位點9個鹼基的插入造成780-781號胺基酸之間插入GSP三個胺基酸)，V777L(由於一個鹼基的錯義突變造成777號胺基酸V變成L),L755S,S310F,S310Y,G309A,G309E,D769Y,D769H,V842I,L866M,R896C，L755_E757delinsS(由於相應位點6個鹼基的缺失造成755-757號3個胺基酸被一個胺基酸S取代)，L869R，L841V，G776V，L755-T759Del(由於相應位點15個鹼基的缺失造成755-759號胺基酸缺失)，G776L，V777L，L755P，和S779_P780insVGS(由於相應位點9個鹼基的插入造成779-780號胺基酸之間插入VGS三個胺基酸)(胺基酸序列號參照P04626 ERBB2_HUMAN)。
在本發明一個較佳的實施方案中，該癌症是EGFR突變陰性或ALK融合基因陰性的癌症，或者二者均為陰性的癌症。
在本發明較佳的實施方案中，該癌症是經過化療、放
療或標靶治療後仍然進展的癌症。即患有該癌症的患者在經過化療、放療或標靶治療後疾病得不到控制，仍然繼續進展。其中該化療可以是使用各種常規的化療藥物治療，例如烷化劑(例如環磷醯胺、異環磷醯胺、美法侖、白消安、尼莫司丁、雷莫司汀、達卡巴嗪、替莫唑胺、鹽酸氮芥、二溴甘露醇等)、鉑絡合劑(例如順鉑、卡鉑、奧沙利鉑等)、代謝拮抗劑(例如甲胺蝶呤、5-氟尿嘧啶、替加氟、吉西他濱、卡培他濱、氟維司群、培美曲塞等)、植物生物鹼(例如長春新鹼、長春鹼、長春地辛、依託泊苷、多西他賽、紫杉醇、伊立替康、長春瑞濱、米托蒽醌、長春氟寧、拓撲替康等)、激素抗癌劑(例如亮丙瑞林、戈舍瑞林、度他雄胺、地塞米松、他莫昔芬等)、蛋白酶體抑制劑(例如硼替佐米、來那度胺等)、芳香化酶抑制劑(例如依西美坦、來曲唑、阿那曲唑等)、較佳是經過選自卡鉑、順鉑、奧沙利鉑、培美曲塞、吉西他濱或多西他賽中的一種或多種進行化療。該標靶治療可以是使用選自EGFR抑制劑和VEGFR抑制劑中的一種或多種治療。這些標靶藥物是本領域熟知的，例如EGFR抑制劑可以選自吉非替尼、厄洛替尼、埃克替尼和阿法替尼中的一種或幾種；VEGFR抑制劑選自舒尼替尼、阿帕替尼、法米替尼中的一種或幾種。
在本發明中，化合物A在實際使用時，較佳是其可藥用鹽的形式，特別是馬來酸鹽或二馬來酸鹽。
在本發明中，化合物A或其可藥用鹽的每日用量範圍可以是1mg/kg~20mg/kg，較佳是2mg/kg~10mg/kg，更佳是
4~8mg/kg。對於成年人類，較佳是以化合物A計，100mg~1000mg，較佳是240至560mg，更佳是320至480mg。其中，對於亞洲人，每日用量範圍還可在240至400mg之間，特別是400mg。
化合物A或其可藥用鹽也可以與藥學上可接受的載體一起製成本領域熟知的組成物形式，如片劑、膠囊、顆粒劑、注射劑等。本發明還涉及使用含有化合物A的醫藥組成物用於HER2突變的癌症的用途。
第1圖顯示化合物A和拉帕替尼對體外培養腫瘤細胞增殖的抑制作用(量-效曲線)。
以下結合實施例用於進一步描述本發明，但這些實施例並非限制本發明的範圍。
實施例1：化合物A和拉帕替尼對體外培養ATCC H1781細胞增殖的影響。
藥物名稱：化合物A的二馬來酸鹽(批號S0915100514)、拉帕替尼二對甲苯磺酸鹽(批號20090105)。配製方法：均用DMSO配製。
ATCC H1781細胞來自上海肺科醫院，該細胞為HER2突變(InsG776V，C)，患者為66歲婦性高加索人肺腺癌患者，用含10%胎牛血清(FBS)的PRIM 1640培養基培養。
PRIM 1640購自Gibco BRL公司；胎牛血清購自Gibco公司；多功能酶標儀購自BioTek公司；磺醯羅丹明B(Sulforhodamine B，SRB)購自Sigma公司。
應用SRB蛋白染色法檢測藥物對腫瘤細胞增殖生長的抑制作用。主要步驟如下：接種對數生長期細胞於96孔培養板，加入相應濃度的藥物(1-10000nM)，每個濃度設複孔，同時設相應濃度的溶媒對照。腫瘤細胞在37℃、5%CO2條件下培養72h。細胞用SRB室溫中染色，最後加入Tris溶液溶解，酶標儀(BioTek)510nm波長下測定OD值，以下列公式計算細胞生長抑制率：抑制率=(OD值對照孔-OD值給藥孔)/OD值對照孔×100%
根據各濃度抑制率，根據非線性回歸方法計算半數抑制濃度IC50。
試驗結果表明化合物A對HER2突變的肺腺癌細胞有很好的抑制效果，而拉帕替尼效果較差，具體結果如表1和第1圖所示：
R為相關係數。
實施例2：化合物A和拉帕替尼對體外HER2重組蛋白酶活性的影響
化合物A(批號SHR120201-002-06)，和拉帕替尼(批號SHR115758-010-17)都由江蘇恒瑞醫藥提供，星形孢菌素購自美國MedChem(Monmouth Junction,NJ)(批號MC-2104)。
重組人蛋白HER2 WT(Lot # W353-1)和5個HER2突變蛋白(A775_G776insYVMA：lot# Z1251-6；D769H：lot# K1683-5；D769Y：lot# P1688-9；V777_G778insCG：lot# Z1287-3；V777L：lot# K1850-3)都購自SignalChem(Richmond,BC V6V 2J2,CANADA).這些重組蛋白是HER2蛋白676號胺基酸到C末端1255號胺基酸的多肽，都是由桿狀病毒在Sf9昆蟲細胞裏表達的，而且N末端被GST標記。EGFR基因索引號是NM_004448。WT HER2和四個HER2突變蛋白(A775_G776insYVMA,D769H,D769Y,V777_G778insCG)的蛋白純度大於85%，另外一個HER2
突變蛋白V777L純度大於90%。
以牛血清白蛋白(BSA)作為受質，向反應體系(20mM Hepes(pH7.5)，10mM MgCl2，1mM EGTA，0.02%Brij35，0.02mg/ml BSA，0.1mM Na3VO4,2mM DTT,1%DMSO)中加入10μM-0.5nM的待測化合物(化合物A或陽性對照物星形孢菌素)，再加入33P-ATP 0.01μ Ci/μl(Perkin Elmer)來啟動磷酸化反應，以測定EGFR的酶活性。實驗結果表明，化合物A對重組人野生型EGFR和第20號外顯子插入性突變的酶活性都有較強的抑制作用，且隨著化合物A的濃度的不斷增加，EGFR全酶活性逐漸降低，呈現濃度依賴性關係。以濃度的對數為橫坐標，相應濃度抑制率的概率單位為縱坐標，用Prism4軟體(GraphPad)計算IC50值。
試驗結果表明化合物A對HER2突變的肺腺癌細胞有較好的抑制效果，其中拉帕替尼，來那替尼和星形孢菌素作為對照化合物。具體結果如表2所示：
實施例3：化合物A和拉帕替尼對體外培養HER2突變MCF10A細胞系增殖的影響。
藥物名稱：化合物A(批號S0915151219)、拉帕替尼(批號SHR115758-010-17)。配製方法：均用DMSO配製。
MCF10A細胞購自ATCC，以該細胞為母細胞，用載體GV341包裝過表達慢病毒，然後用慢病毒感染建立19個混合選殖穩定細胞株，包括空載體對照(NC),HER2 WT，HER2 YVMAdup，P780_Y781insGSP，G776>VC，V777L，L755S，D769H，G776R，G776C，L755P，V842I，L866M，R896C，S310F，S310Y，G309A，G309E和D769Y。所有細胞培養都用DMEM/F12培養基加5%馬血清，20ng/ml EGF,10μg/ml胰島素(insulin),0.5μg/ml氫化可的松(hydrocortisone)，1%盤尼西林(penicillin)/鏈黴素(streptomycin)(P/S)和100ng/ml
霍亂毒素(Cholera Toxin)。
DMEM/F12(Gibco，10-092-CVR)、馬血清(源葉生物，MP20006)、胰島素(源葉生物，11070-73-8)、表皮生長因子(Peprotech,AF-100-15-100)、霍亂毒素(sigma,9012-63-9)、
氫化可的松(源葉生物50-23-7)、胰酶(Gibco,25200-072)、嘌呤黴素(Puromycin)(翊聖，60210ES25)、RIPA裂解液(鼎國，WB-0071)、MTT(Genview，JT343)。
應用MTT藥敏試驗法檢測藥物對腫瘤細胞增殖生長的抑制作用。每種藥物10個濃度點，1個檢測時間點，2複孔。在96孔培養板每孔接種2000個細胞(培養基100μl/孔)，加入相應濃度的藥物(化合物A用0.00128-500nM；拉帕替尼用0.00128-500μM)，每個濃度設複孔，同時設相應濃度的溶媒對照。腫瘤細胞在37℃、5%CO2條件下培養72h。然後用進行MTT檢測。用酶聯免疫檢測儀OD490nm處測量各孔的吸光值，以下列公式計算細胞生長抑制率：抑制率=(OD值對照孔-OD值給藥孔)/OD值對照孔×100%
根據各濃度抑制率，根據非線性回歸方法計算半數抑制濃度IC50。
試驗結果表明化合物A對HER2突變的肺腺癌細胞有較好的抑制效果，而對照化合物拉帕替尼則抑制效果差。
具體結果如表3所示：
實施例4：一項化合物A治療HER2突變的晚期非小細胞肺腺癌的試驗
試驗方法：入組受試者為經病理學確診的晚期非小細胞肺腺癌患者，並經檢測確認存在HER2基因突變(採用廈門艾德生物醫藥科技有限公司的“人類HER2基因檢測試劑盒螢光PCR法(第1至7例、第10例)和NGS二代測序的方法(第8例、第9例、第11例)”對患者的腫瘤病理切片進行檢測)。符合入組要求的受試者均給予化合物A320mg/d和/或400mg/d口服，每天一次，連續給藥直至患者出現疾病進展/不耐受等情況為止。截止至2016年8月，已入組11例HER2突變的晚期非小細胞肺腺癌患者。受試者的平均年齡為58.4歲。所有的受試者分別經過不同的手段治療後疾病繼續進展，例如經過多西他賽或培美曲塞化療，或者經過吉非替尼、阿法替尼等標靶藥物治療。不良事件均為1~2級，包括1/2級腹瀉(4例)、2級乏力(2例)、1級皮疹(2例)和1級呼吸困難(1例)，呈臨床可控。未發生嚴重不良事件(SAE)及因不良事件導致暫停給藥、劑量下調及提前出組的情況。6例(54.5%)患者獲得PR，3例(27.3%)患者疾病穩定，2例(18.2%)患者PD，ORR為54.5%，DCR為81.8%。中位PFS為6.2個月(95%CI 1.23-11.57)。目前仍有5例患者在組治療中。
上述試驗結果提示在HER2突變的非小細胞肺腺癌患者中，化合物A320 mg/d及400mg/d的安全性、耐受性良好，臨床可控，且抗腫瘤療效顯著。
已有療效評估的患者詳細資訊如下表4。其中，各個英文縮寫的含義如下。
PD：疾病進展，直徑和比靶病灶直徑之和的最小值增加至少20%且直徑和的絕對值增加至少5mm(出現一個或多個新病灶也視為疾病進展)；SD：疾病穩定，靶病灶最大徑之和縮小未達PR，或增大未達PD PR：部分緩解，靶病灶直徑之和比基線水準減少至少30%，至少維持4周。UK：未知。
Claims (20)
- 一種式A所示化合物或其可藥用鹽在製備治療HER2突變的癌症的藥物中的用途，
- 如申請專利範圍第1項所述的用途，其中該癌症選自肺癌、乳腺癌和胃腸道癌症。
- 如申請專利範圍第2項所述的用途，其中該肺癌是非小細胞肺癌。
- 如申請專利範圍第2項所述的用途，其中該肺癌是肺腺癌。
- 如申請專利範圍第2項所述的用途，其中該肺癌是晚期肺癌。
- 如申請專利範圍第1項所述的用途，其中該癌症是經過化療、放療或標靶治療後仍然進展的癌症。
- 如申請專利範圍第6項所述的用途，其中該化療是使用選自烷化劑、鉑絡合劑、代謝拮抗劑、植物生物鹼、激素抗癌劑、蛋白酶體抑制劑、芳香化酶抑制劑中的一種或多種進行化療。
- 如申請專利範圍第7項所述的用途，其中該化療是使用選自卡鉑、順鉑、奧沙利鉑、5-氟尿嘧啶、長春瑞濱、 吉西他濱、培美曲塞或多西他賽中的一種或多種進行化療。
- 如申請專利範圍第6項所述的用途，其中該標靶治療是使用選自EGFR抑制劑和VEGFR抑制劑中的一種或多種治療。
- 如申請專利範圍第9項所述的用途，其中該EGFR抑制劑選自吉非替尼、厄洛替尼、埃克替尼和阿法替尼中的一種或幾種。
- 如申請專利範圍第9項所述的用途，其中該VEGFR抑制劑選自舒尼替尼、阿帕替尼、法米替尼中的一種或幾種。
- 如申請專利範圍第1項所述的用途，其中該化合物A的可藥用鹽為馬來酸鹽。
- 如申請專利範圍第12項所述的用途，其中該化合物A的可藥用鹽為二馬來酸鹽。
- 如申請專利範圍第1項所述的用途，其中該化合物A或其可藥用鹽以化合物A計，其每日用量為1mg/kg至20mg/kg。
- 如申請專利範圍第14項所述的用途，其中該化合物A或其可藥用鹽以化合物A計，其每日用量為2mg/kg至10mg/kg。
- 如申請專利範圍第14項所述的用途，其中該化合物A或其可藥用鹽以化合物A計，其每日用量為4至8mg/kg。
- 如申請專利範圍第1項所述的用途，其中該化合物A或其可藥用鹽以化合物A計，其每日用量為100mg至1000mg。
- 如申請專利範圍第17項所述的用途，其中該化合物A或其可藥用鹽以化合物A計，其每日用量為240至560mg。
- 如申請專利範圍第17項所述的用途，其中該化合物A或其可藥用鹽以化合物A計，其每日用量為320至480mg。
- 如申請專利範圍第1至19項中任意一項所述的用途，其中該化合物A或其可藥用鹽被製備成組成物，該組成物還含有藥學上可接受的載體。
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| CN110314159A (zh) * | 2018-07-05 | 2019-10-11 | 江苏恒瑞医药股份有限公司 | 酪氨酸激酶抑制剂联合治疗肿瘤疾病的用途 |
| CN113116879A (zh) * | 2020-01-15 | 2021-07-16 | 江苏恒瑞医药股份有限公司 | 法米替尼联合紫杉类和铂类药物在制备治疗肿瘤疾病的药物中的用途 |
| CN111110676A (zh) * | 2020-03-07 | 2020-05-08 | 天津医科大学总医院 | 阿帕替尼及联合cci-779在制备肺癌药物中的应用 |
| CN118576599A (zh) * | 2020-10-23 | 2024-09-03 | 和记黄埔医药（上海）有限公司 | 一种药物组合产品在制备用于治疗非小细胞肺癌的药物中的用途 |
| CN112451527B (zh) * | 2020-12-02 | 2022-08-16 | 北京鞍石生物科技有限责任公司 | 氨基嘧啶类化合物的用途 |
| CN115779089A (zh) * | 2022-11-28 | 2023-03-14 | 中国医学科学院肿瘤医院 | 用于治疗或改善雄性癌症及抑制其细胞系的药物的相关应用 |
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| CN102675287A (zh) * | 2011-03-11 | 2012-09-19 | 江苏恒瑞医药股份有限公司 | (e)-n-[4-[[3-氯-4-(2-吡啶基甲氧基)苯基]氨基]-3-氰基-7-乙氧基-6-喹啉基]-3-[(2r)-1-甲基吡咯烷-2-基]丙-2-烯酰胺的可药用的盐、其制备方法及其在医药上的应用 |
| CN103987700B (zh) * | 2012-03-09 | 2016-08-31 | 江苏豪森药业集团有限公司 | 4-喹唑啉胺类衍生物及其用途 |
| CN103539783A (zh) * | 2012-07-12 | 2014-01-29 | 江苏恒瑞医药股份有限公司 | 一种酪氨酸激酶抑制剂的二马来酸盐的i型结晶及制备方法 |
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