CN111821459A - 用于联合治疗骨肉瘤的喹啉类化合物 - Google Patents
用于联合治疗骨肉瘤的喹啉类化合物 Download PDFInfo
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- CN111821459A CN111821459A CN202010305356.1A CN202010305356A CN111821459A CN 111821459 A CN111821459 A CN 111821459A CN 202010305356 A CN202010305356 A CN 202010305356A CN 111821459 A CN111821459 A CN 111821459A
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- osteosarcoma
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Abstract
本发明属于医药领域,提供用于联合治疗骨肉瘤的喹啉类化合物或其药学上可接受的盐,具体涉及治疗有效量的1‑[[[4‑(4‑氟‑2‑甲基‑1H‑吲哚‑5‑基)氧基‑6‑甲氧基喹啉‑7‑基]氧基]甲基]环丙胺或其药学上可接受的盐与第二治疗剂联合在制备用于治疗骨肉瘤的联用药物中的应用。
Description
技术领域
本发明属于医药领域,本发明属于药物制剂技术领域,具体用于联合治疗骨肉瘤的喹啉类化合物或其药学上可接受的盐。
背景技术
骨肉瘤为最常见的原发性恶性骨肿瘤,恶性程度高,预后极差,几乎所有转移均经血液转移至肺,可于数月内出现肺部转移,少数转移至脑、内脏、肾及经淋巴管至淋巴结,患者全身健康逐渐下降至衰竭,截肢后3~5年存活率仅为5~20%,对患者的生命危害甚大。
骨肉瘤发病机理不明,主要从间质细胞系发展而来,肿瘤迅速生长是由于肿瘤经软骨阶段直接或间接形成肿瘤骨样组织和骨组织。下肢负重骨在外界因素,例如理化因素(如放射)、病毒及遗传因素(如染色体畸形、P53、RB基因异常改变使细胞突变)等,均与骨肉瘤的形成有密切关系。
骨组织的任何部分均能产生骨肉瘤,发生在股骨下端及胫骨上端的约占所有骨肉瘤的40%,其它处如肱骨、股骨上端、腓骨、脊椎、髂骨等亦可发生。发病年龄可发生在任何年龄,但大多在10~25岁,男性较多。由于膨胀的肿瘤组织破坏骨皮质,刺激骨膜神经末梢,导致骨肉瘤常见症状为骨肉瘤部位发生不同程度的疼痛。早期疼痛为的间歇性,数周后发展为持续性,且疼痛的程度逐渐增强,患者由肢体疼痛而引发的避痛性跛行,患病时间长者可以出现关节活动受限和肌肉萎缩。隨着病情发展,患病部位会出现肿胀,肿块表面皮温增高和浅表静脉显露,肿块表面和附近软组织可有不同程度的压痛。严重者,可以从外观上发现肿块。同时,肿块因骨化程度的不同,硬度各异,将造成患者关节活动受限和肌肉萎缩。诊断明确时,患者全身状况一般较差,通常表现为发热、不适、体重下降、贫血以至衰竭。个别病例肿瘤增长很快,早期就发生肺部转移,致全身状况恶化。瘤体部位的病理骨折使症状更加明显。
根据肿瘤性成骨细胞分化程度的不同,可将骨肉瘤分为成骨型骨肉瘤或溶骨型骨肉瘤两种,多数为溶骨型,也有少数为成骨型。典型的骨肉瘤源于骨内,另一类是与骨皮质并列的骨肉瘤,源于骨外膜和附近的结缔组织。后者较少见,预后稍好。
骨肉瘤治疗中,不论是传统的以截肢治疗为主,放疗和化疗为辅;还是近年来提出的大剂量多药联合化疗,化疗都是目前骨肉瘤治疗中不可缺少的重要治疗手段。目前认为,骨肉瘤的化疗应尽早进行,骨肉瘤治疗中的化学药物,常选用大剂量阿霉素、顺铂、甲氨蝶呤、异环磷酰胺,但单纯化疗效果并不理想,常用化疗方案包括阿霉素和顺铂联用化疗方案、大剂量甲氨蝶呤联合顺铂及阿霉素的方案。然而化疗药物大多具有细胞毒性,例如阿霉素、甲氨蝶呤、异环磷酰胺有较强的心脏毒性,损害心肌细胞,病人出现心慌、心悸、胸闷、心前区不适、气短等症状,甚至出现心力衰竭;顺铂导致近端肾小管的损害,使细胞空泡化,管腔扩张,出现透明管型,血中尿素氮和肌酐升高等等问题。临床上因较大的剂量强度导致的化疗药物毒副作用过大造成化疗中断或终止者并不少见。同时,近年来关于骨肉瘤各种化疗方案中的药物剂量强度与疗效相关性的争议越来越多,有研究显示,对于新辅助化疗不敏感患者,提高化疗剂量或更换化疗方案并不能提高疗效及改善预后。多年来,骨肉瘤总体疗效并无明显提高,显示出骨肉瘤传统化疗药物及治疗方案目前已处于研究瓶颈。
基于目前大剂量多药联合化疗较强的副作用以及其他治疗选择的缺乏,对于进一步提高疗效的十分必要和急迫。
发明内容
化合物一方面,本发明提供治疗有效量的化合物I或其药学上可接受的盐与治疗有效量的第二治疗剂联合在制备用于治疗骨肉瘤的联用药物中的应用,化合物I的化学名称为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺,其具有如下的结构式:
另一方面,本发明提供一种治疗骨肉瘤的方法,所述方法包括对需要治疗的患者给予治疗有效量的化合物I或其药学上可接受的盐,以及治疗有效量的第二治疗剂。
再一方面,本发明提供一种治疗骨肉瘤的联用药物,该联用药物包括治疗有效量的化合物I或其药学上可接受的盐,以及治疗有效量的第二治疗剂。
骨肉瘤
本申请中,所述的骨肉瘤包括但不限于原发性骨肉瘤和/或继发性骨肉瘤。
在一些实施方案中,所述的骨肉瘤包括但不限于在先治疗失败的骨肉瘤;优选的,所述骨肉瘤为放疗和/或化疗药物治疗失败的骨肉瘤。在一些实施方案中,所述骨肉瘤选自甲氨蝶呤、异环磷酰胺、顺铂和/或阿霉素治疗失败的骨肉瘤。在一些实施方案中,所述骨肉瘤的主体接受过化疗和/或放射治疗后疾病发生进展。进一步的,所述的骨肉瘤为在先接受过手术切除的骨肉瘤。所述的骨肉瘤为在先尚未接受手术切除的骨肉瘤。
在一些实施方案中,所述的骨肉瘤包括但不限于成骨型骨肉瘤和/或溶骨型骨肉瘤。
在一些实施方案中,所述的骨肉瘤为去分化型骨肉瘤和/或高分化型骨肉瘤。在一些实施方案中,所述的骨肿瘤为髓内高分化骨肉瘤。
在一些实施方案中,所述的骨肉瘤包括但不限于成骨细胞型骨肉瘤、成软骨细胞型骨肉瘤或成纤维细胞型骨肉瘤。具体的,包括但不限于:低级别中心性骨肉瘤、普通型骨肉瘤、成软骨型骨肉瘤、成纤维型骨肉瘤、成骨型骨肉瘤、毛细血管扩张型骨肉瘤、小细胞骨肉瘤、继发性骨肉瘤、骨旁骨肉瘤、骨膜骨肉瘤、高级别表面骨肉瘤、骨纤维肉瘤、成软骨母细胞型骨肉瘤。
第二治疗剂
在一些实施方案中,所述的第二治疗剂为化疗药物,包括但不限于烷化剂、鬼臼类、喜树碱类、紫杉类、抗代谢类、抗生素类抗肿瘤药物中的一种或多种,可以列举的实例包括但不限于铂类药物(例如奥沙利铂、顺铂、卡铂、奈达铂、双环铂(dicycloplatin))、氟嘧啶衍生物(例如吉西他滨、卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷)、紫杉烷类(例如紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇)、喜树碱类(例如喜树碱、羟基喜树碱、伊立替康、拓扑替康)、长春碱类(长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁(vinflunine))、培美曲塞、依托泊苷(足叶乙苷)、替尼铂苷、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、吡柔比星、氨柔比星、甲氨蝶呤、苯达莫司汀、表阿霉素、阿霉素、替莫唑胺、LCL-161、KML-001、Sapacitabine、普那布林(plinabulin)、曲奥舒凡(treosulfan)、地匹福林盐酸盐(tipiracil hydrochloride)、153Sm-EDTMP、替吉奥和encequidar中的一种或多种。在一些实施方案中,所述化疗药物选自甲氨蝶呤、异环磷酰胺、顺铂、阿霉素、多烯紫杉醇、吉西他滨、吡柔比星、氮烯咪胺、环磷酰胺、拓扑替康、卡铂、153Sm-EDTMP、替尼铂苷、依托泊苷(足叶乙苷)、长春瑞滨、伊立替康、丝裂霉素、喜树碱、羟基喜树碱及其衍生物中的一种或多种。在一个具体的实施方案中,所述化疗药物为吉西他滨。
在一些实施方案中,所述的第二治疗剂为小分子靶向抗肿瘤药物,包括但不限于蛋白激酶抑制剂。其中,所述的蛋白激酶抑制剂包括但不限于酪氨酸激酶抑制剂、丝氨酸和/或苏氨酸激酶抑制剂,所述抑制剂的靶点包括但不限于EGFR(表皮生长因子受体)、间变性淋巴瘤(ALK)、MET基因、ROS1基因、HER2基因、RET基因、BRAF基因、PI3K信号通路、DDR2(盘状死亡受体2)基因、FGFR1(成纤维生长因子受体1)、NTRK1(神经营养酪氨酸激酶1型受体)基因、KRAS基因;所述小分子靶向抗肿瘤药物的靶点还包括COX-2(环氧酶-2)、APE1(脱嘌呤脱嘧啶核酸内切酶)、VEGFR-2(血管内皮生长因子受体-2)、CXCR-4(趋化因子受体-4)、MMP(基质金属蛋白酶)、IGF-1R(胰岛素样生长因子受体)、Ezrin、PEDF(色素上皮衍生因子)、AS、ES、OPG(骨保护因子)、Src、IFN、ALCAM(白细胞活化黏附因子)、HSP、JIP1、GSK-3β(糖原合成激酶3β)、CyclinD1(细胞周期调节蛋白)、CDK4(细胞周期素依赖性激酶)、TIMP1(组织金属蛋白酶抑制物)、THBS3、PTHR1(甲状旁腺素相关蛋白受体1)、TEM7(人肿瘤血管内皮标志物7)、COPS3、组织蛋白酶K。可以列举的小分子靶向抗肿瘤药物包括但不限于厄洛替尼(Erlotinib)、阿法替尼(Afatinib)、克唑替尼(Crizotinib)、色瑞替尼(Ceritinib)、威罗菲尼(Vemurafenib)、达拉菲尼(Dabrafenib)、卡博替尼(Cabozantinib)、吉非替尼(Gefitinib)、达可替尼(Dacomitinib)、奥希替尼(Osimertinib)、艾乐替尼(Alectinib)、布格替尼(Brigatinib)、劳拉替尼(Lorlatinib)、曲美替尼(Trametinib)、拉罗替尼(Larotrectinib)、埃克替尼(icotinib)、拉帕替尼(Lapatinib)、凡德他尼(Vandetanib)、司美替尼(Selumetinib)、索拉非尼(Sorafenib)、奥莫替尼(Olmutinib)、沃利替尼(Savolitinib)、呋喹替尼(Fruquintinib)、恩曲替尼(Entrectinib)、达沙替尼(Dasatinib)、恩沙替尼(Ensartinib)、乐伐替尼(Lenvatinib)、itacitinib、吡咯替尼(Pyrotinib)、比美替尼(Binimetinib)、厄达替尼(Erdafitinib)、阿西替尼(Axitinib)、来那替尼(Neratinib)、考比替尼(Cobimetinib)、阿卡替尼(Acalabrutinib)、法米替尼(Famitinib)、马赛替尼(Masitinib)、伊布替尼(Ibrutinib)、rociletinib、尼达尼布(nintedanib)、来那度胺、依维莫斯、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、palbociclib、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、poziotinib、DS-1205c、capivasertib、SH-1028、二甲双胍、seliciclib、OSE-2101、APL-101、berzosertib、idelalisib、lerociclib、ceralasertib、PLB-1003、tomivosertib、AST-2818、SKLB-1028、D-0316、LY-3023414、allitinib、MRTX-849、AP-32788、AZD-4205、lifirafenib、vactosertib、mivebresib、napabucasin、sitravatinib、TAS-114、molibresib、CC-223、rivoceranib、CK-101、LXH-254、simotinib、GSK-3368715、TAS-0728、masitinib、tepotinib、HS-10296、AZD-4547、merestinib、olaptesed pegol、galunisertib、ASN-003、gedatolisib、defactinib、lazertinib、CKI-27、S-49076、BPI-9016M、RF-A-089、RMC-4630、AZD-3759、antroquinonol、SAF-189s、AT-101、TTI-101、naputinib、LNP-3794、HH-SCC-244、ASK-120067、CT-707、epitinibsuccinate、tesevatinib、SPH-1188-11、BPI-15000、copanlisib、niraparib、olaparib、veliparib、talazoparib tosylate、DV-281、Siremadlin、Telaglenastat、MP-0250、GLG-801、ABTL-0812、bortezomib、帕比司他(panobinostat)、tucidinostat、vorinostat、resminostat、epacadostat、tazemetostat、entinostat、mocetinostat和quisinostat中的一种或者多种。在一些实施方案中,所述的小分子靶向抗肿瘤药物为索拉非尼、依维莫斯、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、尼达尼布中的一种或者多种。
在一些实施方案中,所述的第二治疗剂为AP方案,具体为阿霉素和顺铂。
在一些实施方案中,所述的第二治疗剂为IE方案,具体为异环磷酰胺、美司钠和依托泊苷。
在一些实施方案中,所述的第二治疗剂为MAID方案,具体为阿霉素、异环磷酰胺、美司钠和氮烯咪胺;
在一些实施方案中,所述的第二治疗剂为HDMAP方案,具体为甲氨蝶呤、甲酰四氢叶酸钙(CF)、阿霉素和顺铂。
在一些实施方案中,所述的第二治疗剂为IEM方案,具体为异环磷酰胺、美司钠、依托泊苷、甲氨蝶呤和醛氢叶酸。
在一些实施方案中,所述的第二治疗剂为ES方案,具体为索拉非尼和依维莫斯。
在一些实施方案中,所述的第二治疗剂为ITP方案,具体为异环磷酰胺、顺铂、吡柔比星。
本申请中,所述的用途、方法或联用药物中,可进一步含有化疗辅助药物,所述的化疗辅助药物包括但不限于甲酰四氢叶酸钙(CF)、醛氢叶酸、美司钠、双膦酸盐、氨磷汀、造血细胞集落刺激因子(CSFs)、恩丹西酮。在一些实施方案中,所述的化疗辅助药物为甲酰四氢叶酸钙(CF)、美司钠、醛氢叶酸。
化合物I
化合物I可以以它的游离碱形式给药,也可以以其盐、水合物和前药的形式给药,该前药在体内转换成化合物I的游离碱形式。例如,化合物I药学上可接受的盐在本发明的范围内,可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
在一些实施方案中,所述其药学上可接受的盐为化合物I与任意如下酸所形成的盐:盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸;优选为盐酸盐或马来酸盐的形式,更优选为二盐酸盐。
在一些实施方案中,以化合物I盐酸盐的形式给药。在一些实施方案中,以化合物I一盐酸盐的形式给药。在一些实施方案中,以化合物I二盐酸盐的形式给药。在一些实施方案中,以化合物I盐酸盐的晶体形式给药。在特定的实施方案中,以化合物I二盐酸盐的晶体形式给药。在一些实施方案中,以化合物I马来酸盐的形式给药。
在一些实施方案中,化合物I或其药学上可接受的盐的给予量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中,给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克。在一些实施方案中,给予化合物I或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中,给予化合物I或其药学上可接受的盐的日剂量为8毫克至16毫克。在一些实施方案中,给予化合物I或其药学上可接受的盐的日剂量为8毫克至14毫克。在一个特定的实施方案中,给予化合物I或其药学上可接受的盐的日剂量为8毫克。在一个特定的实施方案中,给予化合物I或其药学上可接受的盐的日剂量为10毫克。在一个特定的实施方案中,给予化合物I或其药学上可接受的盐的日剂量为12毫克。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中,每天一次给予化合物I或其药学上可接受的盐。
化合物I给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
优选的,以间隔给药的方式给予化合物I或其药学上可接受的盐。所述的间隔给药包括给药期和停药期,在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐,然后停药期内停止给药一段时间,接着给药期,然后停药期,如此可以反复进行多次。其中,给药期和停药期的以天数计的比值为2:0.5~5,优选2:0.5~3,较优选2:0.5~2,更优选2:0.5~1。
在一些实施方案中,化合物I或其药学上可接受的盐采用如下方式间隔给药方式中的一种:连续给药2周停药2周、连续给药2周停药1周或连续给药5天停药2天;所述间隔给药方式可以反复进行多次。
其中,治疗有效量的化合物I或其药学上可接受的盐优选适于口服的制剂,包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等,优选片剂和胶囊剂。其中片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片,胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。所述的口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。填充剂包括淀粉、乳糖、甘露醇、微晶纤维素等;吸收剂包括硫酸钙、磷酸氢钙、碳酸钙等;润湿剂包括水、乙醇等;粘合剂包括羟丙甲纤维素、聚维酮、微晶纤维素等;崩解剂包括交联羧甲基纤维素钠、交联聚维酮、表面活性剂、低取代羟丙基纤维素等;润滑剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉等。药用辅料还包括着色剂、甜味剂等。
在一个实施方案中,该药物组合物是适于口服的固体制剂。该组合物例如可以是片剂或胶囊的形式。在一个特定的实施方案中,该药物组合物是胶囊。在本发明的一个特定实施方案中,口服固体制剂的药学上可接受的载体包括甘露醇、微晶纤维素、羟丙纤维素、硬脂酸镁。
本申请中,所述骨肉瘤的联用药物为适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮下、脂肪内、关节内、腹膜内或鞘内任意给药方式的制剂。
优选的,所述治疗有效量的化合物I或其药学上可接受的盐,以及治疗有效量的第二治疗剂采用同时给药、间隔或者依次序先后单独给药。
在某些特定的实施方案中,采用化合物I或其药学上可接受的盐与AP方案联用。方法为:阿霉素25~30mg/m2,第1~3天静脉点滴;顺铂80~100mg/m2,第2天静脉点滴;化合物I或其药学上可接受的盐可选自但不限于每日3~30mg的剂量一次或多次的口服给药,以连续给药2周,停药1周的给药方式给药;21天为一周期。
在某些特定的实施方案中,采用化合物I或其药学上可接受的盐与IE方案联用。方法为:异环磷酰胺1.5~2.0g/m2,1~5d静滴;每次用异环磷酰胺时0、4、8小时静推美司钠400mg,依托泊苷0.1~120mg/m2,1~4d静滴;化合物I或其药学上可接受的盐可选自但不限于每日3~30mg的剂量一次或多次的口服给药,连续给药5天停药2天;28天为一周期。
在某些特定的实施方案中,采用化合物I或其药学上可接受的盐与MAID方案联用。方法为:阿霉素20mg/m2,1~3d静滴;异环磷酰胺2.5g/m2,1~3d静滴;美司钠1.5g/m2,1~4d静滴;氮烯咪胺300mg/m2,1~3d静滴;化合物I或其药学上可接受的盐可选自但不限于每日3~30mg的剂量一次或多次的口服给药,连续给药5天停药2天;21天为一周期。
在某些特定的实施方案中,采用化合物I或其药学上可接受的盐与HDMAP方案联用。方法为:甲氨蝶呤8g/m2第1天静脉滴注6小时,使用后4小时配合甲酰四氢叶酸钙(CF)解救14~17次;阿霉素60mg/m2第9天静脉滴注8小时,顺铂120mg/m2,第7~9天静脉滴注96小时;化合物I或其药学上可接受的盐可选自但不限于每日3~30mg的剂量一次或多次的口服给药,连续给药5天停药2天;28天为一周期。
在某些特定的实施方案中,采用化合物I或其药学上可接受的盐与IEM方案联用。方法为:异环磷酰胺2.5g/m2,1~3d静滴;美司钠2.5g/m2,1~3d静滴;依托泊苷150mg/m2,1~3d静滴;甲氨蝶呤8g/m2,10~14d静滴;醛氢叶酸5~15mg在甲氨蝶呤给药后6小时开始Q6H口服给药。化合物I或其药学上可接受的盐可选自但不限于每日3~30mg的剂量一次或多次的口服给药,连续给药5天停药2天;28天为一周期。
在某些特定的实施方案中,采用化合物I或其药学上可接受的盐与ES方案联用。方法为:采用同时给药的方式,索拉非尼800mg/天、依维莫斯5mg/天,联合化合物I或其药学上可接受的盐可选自但不限于每日3~30mg的剂量一次或多次的口服给药,连续给药5天停药2天。
在某些特定的实施方案中,采用化合物I或其药学上可接受的盐与ITP方案联用。方法为:顺铂(DDP)30~80mg/m2,分2d,加入1000ml生理盐水静滴,充分水化利尿,并应用昂丹司琼等5-HT3受体拮抗剂止吐,第1~2天;吡柔比星(THP)45~90mg/m2静滴,第1天;异环磷酰胺(IFO)1.2~2.0g/m2/day溶于生理盐水1000ml静滴3~4h,同时辅加美司钠1.2g/m2,或恩丹西酮、集落刺激因子,于IFO用药后1、4、8h分析静脉注入,第3~5天。化合物I或其药学上可接受的盐可选自但不限于每日3~30mg的剂量一次或多次的口服给药,以连续给药2周,停药1周的给药方式给药。
与现有技术相比,本发明的联用将有助于:
(1)化合物I或其药学上可接受的盐能够明显增强药物,尤其是化疗药物,对骨肉瘤的杀伤作用,增强疗效;
(2)化合物I或其药学上可接受的盐能够降低化疗药物的使用剂量,从而降低副作用;
(3)抑制骨肉瘤的肺转移;
(4)与单独给予该组合中的任一药物相比,在减少肿瘤的生长或甚至消除肿瘤方面产生更好的疗效;
(5)与该组合中的单一药物给药相比,提供更少量的给药;
(6)提供在患者中具有良好耐受的治疗,与单一给予的药物相比,其不良反应和/或并发症更少;
(7)提供在所治疗患者之中的更好的疾病控制率;
(8)提供在所治疗的患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期);或者提供更长时间的疾病缓解持续时间(DOR)。除非另有说明,为本申请的目的,本说明书和权利要求书中所用的下列术语应具有下述含义。
“患者”是指哺乳动物,优选人。在本文中,“患者”、“受试者”或“主体”可互换使用。
如文本所用,术语“联用药物组合物”是指同时或先后施用的两种或两种以上的活性成分(以各自的活性成分本身的形式施用,或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。在本文中,术语“联用药物组合物”、“联用药物”和“药物组合”可互换使用。
如本文所用,“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。
“药学上可接受的”是指其用于制备药物组合物,该药物组合物通常是安全、无毒的并且既不在生物学上或其它方面不合乎需要,并且包括其对于人类药物使用是可接受的。
“药学上可接受的盐”包括,但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等等形成的酸加成盐;或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸等形成的酸加成盐。
“治疗有效量”意指化合物被给予人用于治疗疾病时,足以实现对该疾病控制的使用量。
“治疗”意指治疗上有效量的化合物的任何施用,并且包括:
(1)抑制正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即,阻止所述病理学和/或症状学的进一步发展),或
(2)改善正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即逆转所述病理学和/或症状学)。
本申请的一些实施方案中,所述的治疗包括抑制骨肉瘤生长和/或转移,包括但不限于肺转移。进一步的,所述的骨肉瘤转移是指迁移和/或侵袭。本申请的一些实施方案中,所述的治疗骨肉瘤是指抑制骨肉瘤的复发。
在本文中,除非另有说明,否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述,意味着除所列出的要素、组分和步骤外,还可涵盖其它未指明的要素、组分和步骤。
为了描述和公开的目的,以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息,并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且,在任何国家,在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
下述是结合具体实施例和实验例,进一步阐述本发明。但这些实施例仅限于说明本发明而不是用于限制本发明的范围。下列实施例中未注明具体实验条件的实验方法,按照常规条件。实施例1 1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐
参照WO2008112407中实施例24的方法制备得到1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺,然后参照WO2008112407说明书中“盐形式的实施例”的制备方法,制备得到标题化合物。
或者参照中国专利申请CN102344438A中公开的方法制备得到。
实施例2 1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(化合物Ⅰ的二盐酸盐)的胶囊的制备
将化合物Ⅰ的二盐酸盐粉碎,过80目筛;然后与甘露醇、羟丙纤维素混合均匀;接着加入处方量的微晶纤维素,混合均匀,过0.8mm筛网;最后加入处方量的硬脂酸镁混合均匀,并填充胶囊。
对于化合物I的二盐酸盐为其它含量的胶囊,可参照上述相同的比例和处方制备得到。
实施例3体外实验
实验目的:
顺铂(DDP)与阿霉素(ADM)联用,以及大剂量甲氨蝶呤(HDMTX)与顺铂(DDP)、阿霉素(ADM)联用是治疗骨肉瘤有效的方案,本实验通过比较ADM+DDP、化合物I的二盐酸盐+ADM+DDP;HDMTX+ADM+DDP、化合物I的二盐酸盐+HDMTX+ADM+DDP分别作用于人骨肉瘤细胞株143B,U20S,MG-63和SJSA(来源:ATCC),以确定化合物I的二盐酸盐联合后是否具有更好的效果。
受试药物:
1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(简称化合物I的二盐酸盐);顺铂(DDP);阿霉素(ADM);甲氨蝶呤(MTX)。
配制方法:
以上样品均用二甲基亚砜溶解,配成100mmol/L的母液,于-20℃保存,备用。使用时用DMEM血清培养液配制成所需浓度,并将化合物I的二盐酸盐稀释液分别与ADM+DDP、HDMTX+ADM+DDP混合。
细胞培养:
受试细胞培养于含10%胎牛血清和0.1g/L链霉素与青霉素(终浓度为100U·mL-1)的DMEM完全培养液中,恒温37℃置于5%CO2培养箱中培养。待细胞融合度达到85%左右时,用0.02EDTA%+0.25%胰蛋白酶混合消化,收集细胞,1000r/min离心,传代培养。
试验方法:
1.化合物I的二盐酸盐与第二治疗剂联合对于抑制骨肉瘤细胞增殖的影响
可按照本领域通常的方法(例如MTT法)来测定IC50值,也可按照如下的方法(MTT法)来测定:
接种一定数量的对数生长期细胞于96孔培养板(180μl/孔,105个细胞/孔)。在37℃、5%CO2条件下生长24小时,分别加入化合物I的二盐酸盐(梯度为0、0.5、1、3、6、8、10、12、16、30μg/ml浓度的溶液)联合60μg/ml的ADM+20μg/ml的DDP;化合物I的二盐酸盐(梯度为0、0.5、1、3、6、8、10、12、16、30μg/ml浓度的溶液)联合1000μg/ml的HDMTX+60μg/ml的ADM+20μg/ml的DDP的培养液中进行培养,每个浓度设两复孔,每孔加20μL,同时设相应浓度的生理盐水溶媒对照及无细胞调零孔。
肿瘤细胞在37℃、5%CO2条件下再培养24小时(即总共48小时)。药物作用结束后,每孔加入MTT工作液,4小时后,三联液溶解,37℃过夜。次日用酶标仪(SPECTRA max 190)570nm和630nm波长下测定OD值(所有在570nm波长下测得的OD值,减去对照波长630nm波长OD值后再计算),以下列公式计算细胞生长抑制率:
抑制率=(OD值对照孔-OD值给药孔)/OD值对照孔×100%
根据各浓度抑制率,采用GraphPad Prism 5软件计算半数抑制浓度IC50。
2.化合物I的二盐酸盐与第二治疗剂联合对骨肉瘤细胞凋亡的影响
流式细胞仪检测细胞凋亡将143B,U2OS,MG-63和SJSA细胞加入到、0、0.5、1、3、6、8、10、12、16、30μg/ml化合物I的二盐酸盐+60μg/ml的ADM+20μg/ml的DDP、0、0.5、1、3、6、8、10、12、16、30μg/ml化合物I的二盐酸盐+1000μg/ml的HDMTX+60μg/ml的ADM+20μg/ml的DDP的培养液中进行培养,24h后收集细胞,1000r/min离心3-5min,PBS清洗。然后使用Annexin-V-FITC/PI细胞凋亡检测试剂盒检测其凋亡情况,将细胞加入到100μL1×Binding缓冲液中重悬,添加5μLAnnexinV-FITC和2.5μLPI染料,进行避光振荡混匀,室温反应15min,然后再加入300μL1×Binding缓冲液,混匀,上流式细胞仪进行检测。重复试验3次。
试验结果:
1.化合物I的二盐酸盐+ADM+DDP以及阳性对照ADM+DDP、化合物I的二盐酸盐+HDMTX+ADM+DDP以及阳性对照HDMTX+ADM+DDP对骨肉瘤细胞株的体外药效学作用显示,化合物I的二盐酸盐与上述药物联合,对143B,U2OS,MG-63和SJSA细胞的增殖有明确的抑制作用。
2.采用经典的Annexin-V-FITC/PI细胞凋亡检测方法,结果表明,化合物I的二盐酸盐能够显著的增强ADM+DDP方案和HDMTX+ADM+DDP方案引起的骨肉瘤细胞系的凋亡。
实施例4临床试验
在有可测量病灶(根据RECIST 1.1)的骨肉瘤患者中开展化合物I的二盐酸盐胶囊与第二治疗剂(HDMAP方案)联用的临床试验,患者组中的患者包括之前接受过化疗的患者,以及未接受过化疗的患者,化合物I的二盐酸盐胶囊与化疗联用,评价指标包括疗效指标:无进展生存期(PFS)、客观缓解率(ORR)、缓解持续时间(DOR)、疾病稳定(SD)率、临床获益率(CBR)、总生存期(OS)等;安全性指标:不良反应发生率及严重程度;生活质量等。
甲氨蝶呤8g/m2第1天静脉滴注6小时,使用后4小时配合甲酰四氢叶酸钙(CF)解救14~17次;阿霉素60mg/m2第9天静脉滴注8小时,顺铂120mg/m2,第7~9天静脉滴注96小时;化合物I或其药学上可接受的盐以每日一次12mg的剂量口服给药,连续用2周停1周。
临床试验结果:
化合物I的二盐酸盐与HDMAP方案联合,对骨肉瘤的治疗有效,可延长总生存期等。
Claims (10)
2.根据权利要求1所述的应用,其特征在于,所述骨肉瘤为原发性骨肉瘤和/或继发性骨肉瘤;或者,所述骨肉瘤为在先治疗失败的骨肉瘤,优选的,所述骨肉瘤为放疗和/或化疗药物治疗失败的骨肉瘤;或者,所述骨肉瘤为成骨型骨肉瘤和/或溶骨型骨肉瘤;或者,所述骨肉瘤为成骨细胞型骨肉瘤、成软骨细胞型骨肉瘤和/或成纤维细胞型骨肉瘤。
3.根据权利要求1或2所述的应用,其特征在于,所述第二治疗剂为化疗药物和/或小分子靶向抗肿瘤药物;
优选的,所述化疗药物为烷化剂、鬼臼类、喜树碱类、紫杉类、抗代谢类、抗生素类抗肿瘤药物中的一种或多种;
更优选的,所述化疗药物为铂类药物、氟嘧啶衍生物、紫杉烷类、喜树碱类、长春碱类、培美曲塞、依托泊苷、替尼铂苷、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、吡柔比星、氨柔比星、甲氨蝶呤、苯达莫司汀、表阿霉素、阿霉素、替莫唑胺、LCL-161、KML-001、Sapacitabine、普那布林、曲奥舒凡、地匹福林盐酸盐、153Sm-EDTMP、替吉奥和encequidar中的一种或多种;
进一步优选的,所述铂类药物为奥沙利铂、顺铂、卡铂、奈达铂、双环铂中的一种或多种,所述氟嘧啶衍生物为吉西他滨、卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷中的一种或多种,所述紫杉烷类为紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇中的一种或多种,所述喜树碱类为喜树碱、羟基喜树碱、伊立替康、拓扑替康中的一种或多种,所述的长春碱类为长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁中的一种或多种;
优选的,所述小分子靶向抗肿瘤药物为蛋白激酶抑制剂;
更优选的,所述小分子靶向抗肿瘤药物为酪氨酸激酶抑制剂、丝氨酸和/或苏氨酸激酶抑制剂;
进一步优选的,所述小分子靶向抗肿瘤药物为厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、索拉非尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、rociletinib、尼达尼布、来那度胺、依维莫斯、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、palbociclib、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、poziotinib、DS-1205c、capivasertib、SH-1028、二甲双胍、seliciclib、OSE-2101、APL-101、berzosertib、idelalisib、lerociclib、ceralasertib、PLB-1003、tomivosertib、AST-2818、SKLB-1028、D-0316、LY-3023414、allitinib、MRTX-849、AP-32788、AZD-4205、lifirafenib、vactosertib、mivebresib、napabucasin、sitravatinib、TAS-114、molibresib、CC-223、rivoceranib、CK-101、LXH-254、simotinib、GSK-3368715、TAS-0728、masitinib、tepotinib、HS-10296、AZD-4547、merestinib、olaptesed pegol、galunisertib、ASN-003、gedatolisib、defactinib、lazertinib、CKI-27、S-49076、BPI-9016M、RF-A-089、RMC-4630、AZD-3759、antroquinonol、SAF-189s、AT-101、TTI-101、naputinib、LNP-3794、HH-SCC-244、ASK-120067、CT-707、epitinib succinate、tesevatinib、SPH-1188-11、BPI-15000、copanlisib、niraparib、olaparib、veliparib、talazoparib tosylate、DV-281、Siremadlin、Telaglenastat、MP-0250、GLG-801、ABTL-0812、bortezomib、帕比司他、tucidinostat、vorinostat、resminostat、epacadostat、tazemetostat、entinostat、mocetinostat和quisinostat中的一种或者多种;
更进一步优选的,所述小分子靶向抗肿瘤药物为索拉非尼、依维莫斯、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、尼达尼布中的一种或者多种。
4.根据权利要求1-3中任一项所述的应用,其特征在于,所述第二治疗剂为阿霉素和顺铂的组合;
或者,所述第二治疗剂为异环磷酰胺、美司钠和依托泊苷的组合;
或者,所述第二治疗剂为阿霉素、异环磷酰胺、美司钠和氮烯咪胺的组合;
或者,所述第二治疗剂为甲氨蝶呤、甲酰四氢叶酸钙、阿霉素和顺铂的组合;
或者,所述第二治疗剂为异环磷酰胺、美司钠、依托泊苷、甲氨蝶呤和醛氢叶酸的组合;
或者,所述第二治疗剂为索拉非尼和依维莫斯的组合;
或者,所述第二治疗剂为异环磷酰胺、顺铂、吡柔比星的组合。
5.根据权利要求1-4中任一项所述的应用,其特征在于,所述第二治疗剂为AP方案、IE方案、MAID方案、HDMAP方案、IEM方案、ES方案或ITP方案。
6.根据权利要求1-5任一项所述的应用,其特征在于,所述药学上可接受的盐为化合物I与任意如下酸所形成的盐:盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸;优选为盐酸盐或马来酸盐的形式,更优选为二盐酸盐。
7.根据权利要求1-6任一项所述的应用,其特征在于,所述给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克,优选为5毫克至20毫克,更优选为8毫克至16毫克,进一步优选为8毫克至14毫克,最优选为8毫克、10毫克、12毫克。
8.根据权利要求1-7任一项所述的应用,其特征在于,所述治疗有效量的化合物I或其药学上可接受的盐,以及治疗有效量的第二治疗剂采用同时给药、间隔给药或依次给药。
9.根据权利要求1-8任一项所述的应用,其特征在于,所述骨肉瘤的联用药物为适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮下、脂肪内、关节内、腹膜内或鞘内任意给药方式的制剂。
10.根据权利要求1-9任一项所述的应用,其特征在于,所述治疗有效量的化合物I或其药学上可接受的盐,以及治疗有效量的第二治疗剂分别单独给药。
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