TWI685341B - 阿帕替尼和c-Met抑制劑聯合在製備治療腫瘤的藥物中的用途 - Google Patents
阿帕替尼和c-Met抑制劑聯合在製備治療腫瘤的藥物中的用途 Download PDFInfo
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- TWI685341B TWI685341B TW107133335A TW107133335A TWI685341B TW I685341 B TWI685341 B TW I685341B TW 107133335 A TW107133335 A TW 107133335A TW 107133335 A TW107133335 A TW 107133335A TW I685341 B TWI685341 B TW I685341B
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Abstract
本發明關於阿帕替尼和c-Met抑制劑聯合在製備治療腫瘤的藥物中的用途。具體而言，本發明關於阿帕替尼與化合物(1)或其可藥用鹽聯合在製備治療腫瘤的藥物中的用途，與單獨給藥相比，聯合用藥顯示出更好的腫瘤抑制作用。
Description
本申請要求申請日為2017年9月22日的中國專利申請CN201710865846.5的優先權。本申請引用上述中國專利申請的全文。
本發明是關於一種阿帕替尼和c-Met抑制劑聯合在製備治療腫瘤的藥物中的用途。
腫瘤是一種常見的多發疾病，其中惡性腫瘤已嚴重影響人類的生存時間和生活品質。隨著醫學進步，研究發現腫瘤增殖一般通過多種通路調控，單一靶點藥物已難以滿足多種復發難治性腫瘤的臨床治療。聯合使用一種以上靶點各異又相互關聯的抗腫瘤藥物，充分發揮各組分優勢，既能提高單藥的抗腫瘤活性又可降低藥物毒性，是一種被普遍接受的抗腫瘤療法。
目前，對血管內皮生長因子（VEGF）和肝細胞生長因子受體或酪氨酸蛋白激酶Met（c-Met）在抗腫瘤治療的研究已逐步深入。腫瘤新生血管生成是指腫瘤細胞誘發的毛細血管新生及微循環網形成的過程，多種訊號分子被報導參與調控腫瘤新生血管的生成，其中VEGF是迄今證實最為重要的正性調控蛋白，VEGF通過與其受體亞型VEGFR-2結合，引起VEGFR-2磷酸化，並進而活化一系列級聯反應，引起血管內皮細胞增殖，誘導血管生成；c-Met激酶是蛋白酪氨酸激酶（PTK）的一個重要成員，c-Met激酶在正常細胞和腫瘤細胞中均有表現，其持續活化是組織細胞癌變或癌細胞增殖亢進的重要原因，c-Met異常發現於多種類型的腫瘤，例如肝癌、非小細胞肺癌、胃癌、結腸癌等。很多研究發現表明同時抑制c-Met和VEGFRs小分子抑制劑可能產生更廣泛和更多有效的抗腫瘤功效（[J]. Molecular cancer therapeutics, 2013, 12(6): 913-924），其中Lynn的報導表明給予抗VEGF抗體貝伐珠單抗可以有效阻止c-Met依賴型腫瘤的轉移和侵襲（[J]. Cancer discovery, 2012, 2(3): 211-213）。
WO2012044577公開了一種c-Met/VEGF雙靶點化合物、以及含選自一種或多種c-Met抑制劑與阿帕替尼的組合物用於治療骨癌和前列腺癌。WO2017127495公開了一種長效死亡促進劑和激酶抑制劑聯合用於治療敏感性癌症，其中激酶抑制劑選自包含阿帕替尼在內VEGFR抑制劑和c-Met抑制劑。Yongxin Ren等人報導c-Met抑制劑Savolitinib與VEGFR抑制劑Fruquintinib聯合在透明細胞腎細胞癌異種移植模型中抑瘤效果，其結果顯示，與單獨給藥相比，聯合用藥顯示出更好的腫瘤抑制作用，並對腎細胞癌的臨床治療具有啟示意義（[J]. Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA）。Yakes等人報導VEGFR2/ MET雙靶點抑制劑Cabozantinib的體內外研究表明可同時抑制轉移，血管生成和腫瘤生長（[J]. Molecular cancer therapeutics, 2011, 10(12): 2298-2308）。雖然已有多種VEGFR抑制劑和c-Met抑制劑聯合用於治療腫瘤，但是進入臨床試驗的後的高失敗率也不容忽視，目前進入III期臨床的c-Met抑制劑僅有阿斯利康的savolitinib和Angion公司的BB-3，但根據2016年公開的savolitinib用於治療晚期乳突腎細胞癌的單臂研究顯示，在MET驅動組患者中，其客觀緩解率也僅為18%，而不良反應發生率較高，一名患者因savolitinib引發肝性腦病死亡（[J]. Journal of Clinical Oncology, 2017: JCO. 2017.72. 2967）；因此選擇合適的VEGFR抑制劑和c-Met抑制劑聯用用於治療復發難治性腫瘤依然是臨床研究有待解決的難題。
本發明提供了一種新的VEGFR抑制劑和新的c-Met抑制劑用於製備治療腫瘤藥物，其中VEGFR抑制劑選自阿帕替尼或其可藥用鹽，其結構如下所示：
阿帕替尼於2014年在中國批准上市的VEGFR2抑制劑，用於治療胃癌，專利CN1281590C公開了其製備方法；c-Met抑制劑選自化合物(1)或其可藥用鹽，其結構如下所示：
專利WO2014180182公開了化合物(1)的製備方法、製備治療癌症的藥物中的用途，以及同時調節VEGFR和c-Met酪氨酸激酶的催化活性的用途。
本發明關於阿帕替尼或其可藥用鹽聯合一種c-Met抑制劑在製備治療腫瘤的藥物中的用途。
在本發明優選的實施例方案中，所述c-Met抑制劑選自化合物(1)或其可藥用鹽，。
在本發明另外優選的實施例方案中，所述c-Met抑制劑還可選自SPH-3348、SAIT-301、HOPE-777、ABBV-399、SAB-Y14、Sym-015、sitravatinib、JNJ-61186372、NOV-1105、crizotinib、ARGX-111、cabozantinib、emibetuzumab、ABT-700、MM-131、ficlatuzumab、onartuzumab、CBA-0710、FS-101、KTN-0073、HH-SCC-244、capmatinib、savolitinib、TAS-115、JNJ-38877618、OMO-1、HS-10241、merestinib、tepotinib、MP-0250、altiratinib、BB-3、SIMM-559、Eos-004、doxorubicin、ningetinib、RXDX-106、PLB-1001、AMC-303、NDX-1017、glesatinib、OMO-2、ASLAN-002、NK4、bispecific-centyrins、SAR-125844、CM-118、ABN-401、REG-101、BPI-9016M、ChronSeal、AL-2846、REG-103、HQP-8361、PRS-110、NX-125、QBH-196、KRC-00831、LS-177、PIG-KM、APG-8361、bicyclol valine ester、Debio-1144、X-379、SL-188、SL-186、SL-012、SCR-1515、LMV-12，優選自Sym-015、sitravatinib、emibetuzumab 、ficlatuzumab、capmatinib、savolitinib、crizotinib、TAS-115、merestinib、tepotinib、MP-0250、BB-3、glesatinib、glesatinib glycolate、ASLAN-002、SAR-125844、APG-8361。
在本發明優選的實施例方案中，所述腫瘤選自惡性腫瘤、良性腫瘤；所述惡性腫瘤選自惡性上皮腫瘤、肉瘤、骨髓瘤、白血病、淋巴瘤、黑色素瘤、頭頸部腫瘤、腦部腫瘤、混合型腫瘤、兒童惡性腫瘤；所述惡性上皮腫瘤選自肺癌、乳癌、肝癌、胰腺癌、結直腸癌、胃癌、食管癌、小腸癌、賁門癌、子宮內膜癌、卵巢癌、輸卵管癌、外陰癌、睪丸癌、前列腺癌、陰莖癌、腎癌、膀胱癌、肛門癌、膽囊癌、膽管癌、畸胎瘤、心臟腫瘤；所述頭頸部腫瘤選自鼻咽癌、喉癌、甲狀腺癌、舌癌、口腔癌；所述肉瘤選自Askin瘤、軟骨肉瘤、尤文氏肉瘤、惡性血管內皮瘤、惡性神經鞘瘤、骨肉瘤、軟組織肉瘤；所述骨髓瘤選自孤立型骨髓瘤、多發性骨髓瘤、瀰漫型骨髓瘤、白血病型骨髓瘤、髓外型骨髓瘤；所述白血病選自急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性骨髓性白血病、多毛細胞性白血病、T細胞淋巴細胞白血病、大顆粒淋巴細胞性白血病、成人T細胞白血病；所述淋巴瘤選自非霍奇金淋巴瘤、霍奇金淋巴瘤；所述腦部腫瘤選自神經上皮組織腫瘤、顱神經和脊髓神經腫瘤、腦膜組織腫瘤；所述兒童惡性腫瘤選自腎母細胞瘤、神經母細胞瘤、視網膜母細胞瘤、兒童生殖細胞腫瘤。
在本發明另外一個優選的實施例方案中，所述肺癌選自所述肺癌選自非小細胞肺癌、小細胞肺癌，優選非小細胞肺癌；所述乳癌選自所述乳癌選自激素受體（HR）陽性乳癌、人表皮生長因子受體-2（HER2）陽性乳癌、三陰乳癌；所述腎癌選自透明腎細胞癌、乳突腎細胞癌、難染細胞性腎細胞癌、集合管癌；所述神經上皮組織腫瘤選自優選星形細胞瘤、分化不良星形細胞瘤、膠質母細胞瘤；所述肝癌選自原發性肝癌、繼發性肝癌，所述原發性肝癌選自肝細胞癌、膽管細胞癌、混合性肝癌；所述結直腸癌選自結腸癌、直腸癌。
在本發明優選的上述實施例方案中，所述腫瘤選自VEFGR過度表現型和/或c-Met中度表現腫瘤、VEFGR過度表現型和/或c-Met過度表現型腫瘤。
在本發明優選的上述實施例方案中，所述腫瘤選自中晚期腫瘤、復發難治性腫瘤、經一線化療藥物治療失敗和/或復發腫瘤、放療失敗和/或復發腫瘤、靶向藥物治療失敗和/或復發腫瘤的一種或多種，化療藥物選自烷化劑、鉑絡合劑、代謝拮抗劑、植物生物鹼（如長春鹼類、三尖杉酯鹼類）、激素抗癌劑、蛋白酶體抑制劑、芳香化酶抑制劑、免疫調節劑的一種或多種；在另外優選的實施例方案中，所述化療藥物包括但不限於環磷醯胺、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、順鉑、卡鉑、奧沙利鉑、奈達鉑、甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他濱、卡培他濱、氟維司群、培美曲塞、蒽環類抗生素、絲裂黴素、博萊黴素類、放線菌素、長春鹼類、喜樹鹼類、紫杉醇類、長春新鹼、長春鹼、長春地辛、依託泊苷、多西他賽、紫杉醇、白蛋白結合型紫杉醇、紫杉醇脂質體、伊立替康、長春瑞濱、米托蒽醌、長春氟寧、拓撲替康、亮丙瑞林、戈舍瑞林、度他雄胺、氟維司群、地塞米松、他莫昔芬、硼替佐米、來那度胺等、依西美坦、來曲唑、阿那曲唑。
在本發明優選的上述實施例方案中，所述的靶向藥物選自EGFR抑制劑、ALK抑制劑、PARP抑制劑、CDK抑制劑、MEK抑制劑、VEGF抗體和VEGFR抑制劑、mTOR抑制劑中的一種或多種治療。這些靶向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、西妥昔單抗、曲妥珠單抗中的一種或幾種；ALK抑制劑可以選自克唑替尼、和色瑞替尼、阿西替尼、Brigatinib；VEGF抗體選自貝伐珠單抗；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。腫瘤免疫治療選自nivolumab、pembrolizumab、atezolizumab和SHR-1210中的一種或幾種。
在本發明優選的上述實施例方案中，所述阿帕替尼或其可藥用鹽與化合物(1)或其可藥用鹽的重量比例選自0.01-100:1，優選自1:12、1:10、1:9、1:8、2:15、1:7、1:6、1:5、5:24、2:9、1:4、4:15、5:18、2:7、3:10、5:16、1:3、5:14、3:8、2:5、5:12、3:7、4:9、1:2、8:15、5:9、4:7、7:12、3:5、5:8、2:3、7:10、5:7、3:4、7:9、4:5、5:6、6:7、7:8、8:9、9:10、14:15、15:16、1:1、6:5、5:4、4:3、3:2、8:5、2:1、5:2、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1，更優選自1:1、1:6、1:5、1:4、1:3、2:5、5:12、1:2、3:5、5:8、2:3、3:4、4:5、5:6、6:5、5:4、4:3、3:2、8:5、2:1、5:2、3:1、4:1、5:1。
在本發明優選的上述實施例方案中，所述阿帕替尼或其可藥用鹽劑量選自100-1000mg，優選自200mg、250mg、300mg、350mg、375mg、400mg、450mg、500mg、550mg、600mg、700mg、750mg、800mg、850mg、900mg、1000mg，更優選自250mg、300mg、350mg、400mg、450mg、500mg、600mg、700mg、750mg；化合物(1)或其可藥用鹽劑量選自10-1200mg，優選自20mg、50mg、55mg、60mg、75mg、100mg、110mg、200mg、220mg、250mg、260mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、700mg、750mg、800mg、900mg、1000mg，更優選100mg、110mg、200mg、220mg、250mg、260mg、300mg、350mg、400mg、450mg、500mg。
在本發明優選的上述實施例方案中，所述阿帕替尼或其可藥用鹽選自甲磺酸鹽、鹽酸鹽，優選自甲磺酸鹽；所述化合物(1)或其可藥用鹽選自鹽酸鹽、甲磺酸鹽、馬來酸鹽、蘋果酸鹽、苯磺酸鹽，優選自甲磺酸鹽。
本發明關於「聯合」是一種給藥方式，是指在一定時間期限內給予至少一種劑量的阿帕替尼和至少一種劑量的化合物(1)或其可藥用鹽，其中兩種物質都顯示藥理學作用。所述的時間期限為一個給藥週期，優選24小時以內，更優選12小時以內。可以同時或依次給予阿帕替尼和化合物(1)或其可藥用鹽。這種期限包括這樣的治療，其中通過相同給藥途徑或不同給藥途徑給予阿帕替尼和化合物(1)或其可藥用鹽。本發明所述聯合的給藥方式選自同時給藥、獨立地配製並共給藥或獨立地配製並相繼給藥。
本發明所述聯合的給藥途徑選自經口給藥、胃腸外給藥、經皮給藥，所述胃腸外給藥包括但不限於靜脈注射、皮下注射、肌肉注射。
本發明進一步關於阿帕替尼或其可藥用鹽與化合物(1)或其可藥用鹽聯合在製備預防或治療糖尿病和/或糖尿病併發症的藥物中的用途，其中阿帕替尼或其可藥用鹽的給藥頻次為一日一次、一日二次、一日三次、一周一次、二週一次、三週一次、一月一次，優選一日一次；化合物(1)或其可藥用鹽的給藥頻次為一日一次、一日二次、一日三次、一周一次、二週一次、三週一次、一月一次，優選一日一次或一日二次。
本發明還關於一種含阿帕替尼或其可藥用鹽、化合物(1)或其可藥用鹽的藥物組合物，包含任選的一種或多種藥用載體、賦形劑和/或稀釋劑。所述藥物組合物可以製成藥學上可接受的任一劑型。例如，包含阿帕替尼或其可藥用鹽、化合物(1)或其可藥用鹽的藥物製劑，可以配製為片劑、膠囊劑、丸劑、顆粒劑、溶液劑、混懸劑、糖漿劑、注射劑（包括注射液、注射用無菌粉末與註射用濃溶液）、栓劑、吸入劑或噴霧劑。
本發明所述的含阿帕替尼或其可藥用鹽、化合物(1)或其可藥用鹽的藥物組合物，可以單獨給藥，或者與一種或多種治療劑聯合使用。
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製本發明的範圍。
實施例1
1、受試藥物
藥物來源：市售甲磺酸阿帕替尼；化合物(1)甲磺酸鹽參照專利WO2016015653所述方法製備。
配製方法：甲磺酸阿帕替尼用0.5%羧甲基纖維素溶液配製；化合物(1)甲磺酸鹽用0.5% 羧甲基纖維素混合0.1%吐溫80溶液配製。
2、實驗動物和組織來源
BALB/c裸小鼠，6-8週齡，雄性，購自北京維通利華實驗動物技術有限公司。實驗動物使用許可證號：SCXK（滬）2015-0022；動物合格證號：11400700166108飼養環境：SPF級。
LIV#061腫瘤組織來源於51歲女性患者，病理診斷為肝細胞癌 （HCC，T1N0M0），腫瘤組織為基因KDR Q472H位點突變，c-MET中度表現。
3、實驗步驟
將病人肝癌腫瘤組織LIV#061于1640培養液中剪成為15-30 mm3
的小塊接種到裸鼠的皮下，待腫瘤長至600-700 mm3
後在裸鼠身上進行傳代。待第六代（P6）腫瘤長至600-700 mm3
時，將腫瘤在1640培養液中剪成為15-30 mm3
的小塊用於實驗裸鼠皮下接種。待腫瘤生長至150-250 mm3
後，將動物隨機分組（D0）並給藥。給藥劑量和給藥方案見表1。每週測2-3次瘤體積，稱鼠重，記錄數據。腫瘤體積（V）計算公式為： V＝1/2×a×b2
，其中 a、b分別表示長、寬。
T/C(%)=(T-T0)/(C-C0)×100%，其中T、C為實驗結束時的腫瘤體積；T0、C0為實驗開始時的腫瘤體積。
4、結果
結果如表1所示，甲磺酸阿帕替尼單用（75mg/kg）能夠抑制人肝癌LIV#061裸小鼠皮下移植瘤的生長。在給藥第21天時，腫瘤抑制率為62.3%。而化合物(1)甲磺酸鹽單用（30mg/kg）未見明顯抑制人肝癌裸小鼠皮下移植瘤的生長。在給藥第21天時，腫瘤抑制率為14.4%。化合物(1)甲磺酸鹽（30 mg/kg，每日給藥一次，給藥21天）與甲磺酸阿帕替尼（75 mg/kg，每日給藥一次，給藥21天）聯用抗腫瘤作用顯著，與二者單用相比抑制率具有顯著性差異，腫瘤抑制率為85.7%。所有荷瘤小鼠均沒有出現明顯的體重下降情況，表明荷瘤小鼠對該劑量下藥物單用或聯用的耐受性良好。 表1. 甲磺酸阿帕替尼、化合物(1)甲磺酸鹽聯用對人肝癌LIV#061裸小鼠皮下移植瘤的療效 
D0：第一次給藥時間；QD：每日給藥一次；PO：經口給藥；P值指與溶劑相比；採用單因子變異數分析（one way Anova）。實驗開始時小鼠數目：n=6。
實施例2
化合物(1)甲磺酸鹽聯合甲磺酸阿帕替尼在晚期實體瘤患者中的耐受性、安全性、藥代動力學及療效的I期臨床研究。
1、受試藥物
藥物來源：市售甲磺酸阿帕替尼；化合物(1)甲磺酸鹽參照專利WO2016015653所述方法製備。
2、入組標準：（1）年齡18-75歲（含兩端值），男女均可；（2）標準治療方案無效或無標準有效治療方案的病理學確診的晚期實體瘤患者；（3）無影響口服藥物的多種因素（比如無法吞嚥、慢性腹瀉和腸梗阻等）；（4）ECOG PS 評分0～1 分；（5）預期生存期不少於3個月。
3、給藥方案
化合物(1)甲磺酸鹽：片劑；規格100 mg/片；口服，劑量為200 mg/天；每日2次； 甲磺酸阿帕替尼片：規格250 mg/片；口服，每日一次，500 mg/天； 甲磺酸阿帕替尼片：規格375 mg/片；口服，每日一次。
4、結果
截止目前：化合物(1)甲磺酸鹽（200mg）聯合阿帕替尼（500mg）已入組3例受試者，食管癌（1例）、直腸癌（1例）喉癌（1例），最佳療效評價為SD，其中1例接受研究藥物治療4週期，該劑量組受試者目前均已PD出組。化合物(1)甲磺酸鹽（200mg）聯合阿帕替尼（375mg）已入組3例受試者，乳癌（1例）直腸癌（2例），最佳療效評價為均為SD。
無
圖1顯示甲磺酸阿帕替尼、化合物(1)甲磺酸鹽二者聯用對人肝癌PDX模型LIV#061荷瘤裸小鼠皮下移植瘤的療效。
圖2顯示甲磺酸阿帕替尼、化合物(1)甲磺酸鹽二者聯用對人肝癌PDX模型LIV#061荷瘤裸小鼠體重的影響。
Claims (16)
- 一種包含阿帕替尼或其可藥用鹽與選自化合物(1)或其可藥用鹽的c-Met抑制劑的醫藥組合在製備治療腫瘤的藥物中的用途，其中所述阿帕替尼或其可藥用鹽與化合物(1)或其可藥用鹽的重量比例選自1-5：1，所述腫瘤選自肝癌、食管癌、喉癌、結直腸癌，
- 如請求項1所述的用途，其中所述肝癌選自原發性肝癌、繼發性肝癌，所述原發性肝癌選自肝細胞癌、膽管細胞癌、混合性肝癌；所述結直腸癌選自結腸癌、直腸癌。
- 如請求項1或2所述的用途，其中所述腫瘤選自VEFGR過度表現型和/或c-Met過度表現型腫瘤，VEFGR過度表現型和/或c-Met中度表現型腫瘤。
- 如請求項1或2所述的用途，其中所述腫瘤選自中晚期腫瘤、復發難治性腫瘤、經一線化療藥物治療失敗和/或復發腫瘤、經放療失敗和/或復發腫瘤、經靶向藥物治療失敗和/或復發腫瘤；所述化療藥物選自烷化劑、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、免疫調節劑中的一種或多種；所述靶向藥物選自EGFR抑制劑、ALK抑制劑、PARP抑制劑、CDK抑制劑、MEK抑制劑、VEGF抗體、VEGFR抑制劑、BTK抑制劑、mTOR抑制劑。
- 如請求項1或2所述的用途，其中所述阿帕替尼或其可藥用鹽與化合物(1)或其可藥用鹽的重量比例選自1：1、6：5、5：4、4：3、3：2、8：5、2：1、5：2、3：1、4：1、5：1。
- 如請求項1或2所述的用途，其中所述阿帕替尼或其可藥用鹽劑量選自100-1000mg。
- 如請求項1或2所述的用途，其中所述阿帕替尼或其可藥用鹽劑量選自200mg、250mg、300mg、350mg、375mg、400mg、450mg、500mg、550mg、600mg、700mg、750mg、800mg、850mg、900mg、1000mg。
- 如請求項1或2所述的用途，其中所述阿帕替尼或其可藥用鹽劑量選自250mg、300mg、350mg、400mg、450mg、500mg、600mg、700mg、750mg。
- 如請求項1或2所述的用途，其中所述化合物(1)或其可藥用鹽劑量選自10-1200mg。
- 如請求項1或2所述的用途，其中所述化合物(1)或其可藥用鹽劑量選自20mg、50mg、55mg、60mg、75mg、100mg、110mg、200mg、220mg、250mg、260mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、700mg、750mg、800mg、900mg、1000mg。
- 如請求項1或2所述的用途，其中所述化合物(1)或其可藥用鹽劑量選自100mg、110mg、200mg、220mg、250mg、260mg、300mg、350mg、400mg、450mg、500mg。
- 如請求項1或2所述的用途，其中所述阿帕替尼或其可藥用鹽選自甲磺酸鹽、鹽酸鹽。
- 如請求項1或2所述的用途，其中所述阿帕替尼或其可藥用鹽為阿帕替尼甲磺酸鹽。
- 如請求項1或2所述的用途，其中所述化合物(1)或其可藥用鹽選自鹽酸鹽、甲磺酸鹽、馬來酸鹽、蘋果酸鹽、苯磺酸鹽。
- 如請求項1或2所述的用途，其中所述化合物(1)或其可藥用鹽為甲磺酸鹽。
- 一種藥物組合物，含有請求項1-15中任一項所述的阿帕替尼或其可藥用鹽與化合物(1)或其可藥用鹽，以及一種或多種可藥用的賦型劑、稀釋劑或載體。
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| CN110292578A (zh) * | 2019-08-13 | 2019-10-01 | 厦门大学附属第一医院 | 阿帕替尼在制备治疗急性髓系白血病的药物中的新应用 |
| CN115919741B (zh) * | 2021-08-24 | 2024-02-27 | 北京理工大学 | 一种阿帕替尼肛门栓剂及其制备方法 |
| CN113855710B (zh) * | 2021-10-09 | 2024-02-20 | 施慧达药业集团(吉林)有限公司 | 戈氏梭菌联合肿瘤血管生成抑制剂的应用 |
| CN114028586A (zh) * | 2021-11-25 | 2022-02-11 | 南昌大学附属口腔医院(江西省口腔医院) | 一种基于pdx模型研究阿帕替尼抗肿瘤作用效果的方法 |
| CN115120731A (zh) * | 2022-07-12 | 2022-09-30 | 四川大学华西医院 | 一种靶向蛋白酶体治疗乳腺癌的药物应用 |
| CN115990136B (zh) * | 2022-10-31 | 2024-09-03 | 中南大学湘雅三医院 | 一种抗肿瘤组合物、纳米制剂、制备方法和用途 |
| CN120769856A (zh) * | 2023-02-27 | 2025-10-10 | 江苏豪森药业集团有限公司 | 一种三唑并环类化合物甲磺酸盐晶型及其制备方法和应用 |
| CN117100866B (zh) * | 2023-03-31 | 2025-10-28 | 兰州大学第二医院 | 一种抗肿瘤血管生成药物增效剂、抗肿瘤药物组合物及应用 |
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- 2018-09-21 WO PCT/CN2018/106878 patent/WO2019057141A1/zh not_active Ceased
- 2018-09-21 CN CN201880035052.9A patent/CN110730663B/zh active Active
- 2018-09-21 TW TW107133335A patent/TWI685341B/zh not_active IP Right Cessation
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| WO2012044577A1 (en) * | 2010-09-27 | 2012-04-05 | Exelixis, Inc. | Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases |
| TW201443052A (zh) * | 2013-05-10 | 2014-11-16 | Jiangsu Hansoh Pharmaceutical | ［１，２，４］三唑並［４，３－ａ］吡啶類衍生物，其製備方法或其在醫藥上的應用 |
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| Publication number | Publication date |
|---|---|
| CN110730663A (zh) | 2020-01-24 |
| TW201914592A (zh) | 2019-04-16 |
| CN110730663B (zh) | 2022-09-16 |
| WO2019057141A1 (zh) | 2019-03-28 |
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