CN111821302A - 用于联合治疗软骨肉瘤的喹啉类化合物 - Google Patents
用于联合治疗软骨肉瘤的喹啉类化合物 Download PDFInfo
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- CN111821302A CN111821302A CN202010305976.5A CN202010305976A CN111821302A CN 111821302 A CN111821302 A CN 111821302A CN 202010305976 A CN202010305976 A CN 202010305976A CN 111821302 A CN111821302 A CN 111821302A
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- acid
- chondrosarcoma
- compound
- pharmaceutically acceptable
- acceptable salt
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Abstract
本发明属于医药领域,提供用于联合治疗软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软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,具体用于联合治疗软骨肉瘤的喹啉类化合物或其药学上可接受的盐。
背景技术
软骨肉瘤为仅次于骨肉瘤的第二大恶性骨肿瘤。其病因不明,主要为从软骨细胞或间胚叶组织发生,并起源于躯体任何软骨内化骨的骨骼,可能与染色体的异常有关,实验性病理认为软骨肉瘤与病毒感染有关,而边缘型软骨肉瘤与遗传因素有关。
软骨肉瘤在全身骨骼的任何部分均能产生,好发于长管状骨,骨盆、股盆、及肱骨等部位,也可见于椎骨、骶骨、锁骨、肩胛骨和足骨。软骨肉瘤可发生在任何年龄,多见于成人,30岁以下少见,40岁以后发病率逐渐增高,且男性多于女性。
组织学上将软骨肉瘤分为透明型、黏液样型、纤维软骨型、混合型及透明细胞型。一般认为,透明型恶性程度较低,而纤维型、纤维软骨型、混合型则属高度恶性。从发病情况上又将软骨肉瘤分为原发性和继发性两大类,原发性从开始就有肉瘤特性,继发性是指继发于畸形性骨炎、纤维结构不良、孤立性骨囊肿、Maffucci综合征、Ollier病、多发性遗传性骨疣、软骨母细胞瘤、软骨黏液样纤维瘤等良性软骨性肿瘤等衍变而成,这也是发病年龄较晚的原因之一。从部位上,软骨肉瘤分为中央型和边缘型;还有皮质旁或骨膜软骨肉瘤,以及骨外黏液样软骨肉瘤等。此外,还有一般软骨肉瘤、间叶性软骨肉瘤、和透明细胞软骨肉瘤。
软骨肉瘤多数瘤体较大,一般肿瘤最大直径均超过4cm,大的可达到20cm以上。患者早期感觉患处不适,几天或几周后出现肿胀及肿块,晚期可出现静脉曲张,局部皮肤温度升高及充血发红。患者会感觉关节周围疼痛,最初是间歇性疼痛,以后逐渐加重,转为持续性疼痛,夜间更为明显,止痛药无效。患者的关节活动受限,部分病人可发生关节积液,甚至会发生病理性骨折。
软骨肉瘤最有效的治疗是手术切除。过去认为软骨肉瘤对放射治疗不敏感,因而很少采用单独的放疗来治疗软骨肉瘤。近年来,研究发现有一部分软骨肉瘤对放射治疗有一定的敏感性,可作为治疗软骨肉瘤的辅助治疗手段。但软骨肉瘤血供和淋巴循环较差,对传统的化疗药物不敏感。因此,直至目前,仍尚无有效的治疗软骨肉瘤的化疗方案。因此,目前的软骨肉瘤治疗方法为,根据具体情况考虑作局部大块切除、节段截除或截肢术。多数软骨肉瘤的外科手术应力求局部彻底切除,对复发者或原发恶性程度高、发展快的病例作截肢或关节离断术。软骨肉瘤的常用辅助药物为复方环磷酰胺片、甲氨蝶呤片、顺铂注射液、扎托洛芬、双氯芬酸、吲哚美辛、奥沙普秦、对乙酰氨基酚以及酮洛芬等等。
基于目前治疗选择的缺乏,提示了针对在软骨肉瘤传统治疗药物的基础上,提供新选择的必要性和急迫性。
发明内容
化合物I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软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软骨肉瘤的方法,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软骨肉瘤的联用药物,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。
软骨肉瘤
本申请中所述软骨肉瘤为原发性软骨肉瘤和/或继发性软骨肉瘤。
在一些实施方案中,所述软骨肉瘤为去分化型软骨肉瘤和/或高分化型软骨肉瘤。
在一些实施方案中,所述软骨肉瘤为中央型软骨肉瘤、边缘型软骨肉瘤、骨皮质旁软骨肉瘤、骨膜软骨肉瘤或骨外黏液样软骨肉瘤。
在一些实施方案中,所述软骨肉瘤为低度恶性软骨母细胞瘤、中度恶性软骨母细胞瘤、高度恶性软骨母细胞瘤。
在一些实施方案中,所述软骨肉瘤为一般软骨肉瘤、间叶性软骨肉瘤、透明细胞软骨肉瘤。
在一些实施方案中,所述软骨肉瘤为晚期和/或转移性软骨肉瘤。
在一些实施方案中,所述软骨肉瘤包括但不限于在先治疗失败的软骨肉瘤;优选的,所述软骨肉瘤为放疗和/或化疗药物治疗失败的软骨肉瘤。在一些实施方案中,,所述软骨肉瘤选自甲氨喋呤、异环磷酰胺、顺铂和/或阿霉素治疗失败的软骨肉瘤。在一些实施方案中,所述软骨肉瘤的主体接受过化疗和/或放射治疗后疾病发生进展。在一些实施方案中,所述的软骨肉瘤为在先接受过手术切除的软骨肉瘤。所述的软骨肉瘤为在先尚未接受手术切除的软骨肉瘤。
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、拓扑异构酶抑制剂、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)、拓扑异构酶I抑制剂(例如喜树碱及其衍生物、羟基喜树碱、伊立替康、拓扑替康)、拓扑异构酶Ⅱ抑制剂(例如依托泊苷(足叶乙苷)、替尼铂苷)、长春碱类(长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁(vinflunine))、吡柔比星、培美曲塞、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、环磷酰胺、异环磷酰胺、阿霉素、伊立替康、铂类、足叶乙甙、替尼铂甙、喜树碱、羟基喜树碱、吉西他滨、紫杉醇、多烯紫杉醇、长春花碱、环磷酰胺、丝裂霉素中的一种或多种。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(***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。
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,联用药物中,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。
本申请中,所述软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、***、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。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,对软骨肉瘤的杀伤作用,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)抑制软骨肉瘤的肺转移;
(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)。
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
细胞株:
人软骨肉瘤细胞株CAL-78,SW1353(来源:ATCC)。
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);甲氨蝶呤;环磷酰胺;奥沙普秦。
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甲氨蝶呤、环磷酰胺、奥沙普秦稀释液混合,以确定化合物I的二盐酸盐联合后是否具有更好的效果。
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软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,将细胞加入化合物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)分别联合10μg/ml的甲氨蝶呤、40μg/ml的奥沙普秦、150μg/ml的环磷酰胺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,以确定化合物I的二盐酸盐联合后是否具有更好的效果。
2.化合物I的二盐酸盐与治疗软骨肉瘤的药物第二治疗剂联合对软骨肉瘤细胞凋亡的影响
流式细胞仪检测细胞凋亡将CAL-78,SW1353细胞加入到0、0.5、1、3、6、8、10、12、16、30μg/ml的化合物I的二盐酸盐+10μg/ml的甲氨蝶呤;0、0.5、1、3、6、8、10、12、16、30μg/ml的化合物I的二盐酸盐+150μg/ml的环磷酰胺;0、0.5、1、3、6、8、10、12、16、30μg/ml的化合物I的二盐酸盐+40μg/ml的奥沙普秦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+甲氨蝶呤;化合物I的二盐酸盐+环磷酰胺;化合物I的二盐酸盐+奥沙普秦对软骨肉瘤细胞株的体外药效学作用显示,化合物I的二盐酸盐与治疗软骨肉瘤的药物上述药物联合,对CAL-78,SW1353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,不同浓度的化合物I的二盐酸盐能够分别显著地增强甲氨蝶呤、环磷酰胺、奥沙普秦引起的软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)的软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联用的临床试验。
化合物I或其药学上可接受的盐以每日12mg的剂量一次的口服给药,连续用药2周,停2周的给药方式给药;甲氨蝶呤以5~10mg的日剂量,每日一次口服给药,每周1~2次。
化合物I或其药学上可接受的盐以每日12mg的剂量一次的口服给药,连续用药2周,停1周的给药方式给药;环磷酰胺150mg的日剂量,每日一次或多次口服给药。
化合物I或其药学上可接受的盐以每日12mg的剂量一次的口服给药,连续给药5天停药2天;奥沙普秦以600mg的日剂量,每日一次或多次口服给药。
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。
临床试验结果:
化合物I的二盐酸盐与上述药物联合对软骨肉瘤的治疗有效,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,所述软骨肉瘤为原发性软骨肉瘤和/或继发性软骨肉瘤。
3.根据权利要求1所述的应用,其特征在于,所述软骨肉瘤为中央型软骨肉瘤、边缘型软骨肉瘤、骨皮质旁软骨肉瘤、骨膜软骨肉瘤或骨外黏液样软骨肉瘤。
4.根据权利要求1所述的应用,其特征在于,所述软骨肉瘤为低度恶性软骨母细胞瘤、中度恶性软骨母细胞瘤、高度恶性软骨母细胞瘤。
5.根据权利要求1所述的应用,其特征在于,所述软骨肉瘤为一般软骨肉瘤、间叶性软骨肉瘤、透明细胞软骨肉瘤。
6.根据权利要求1-5任一项所述的应用,其特征在于,所述的第二治疗剂为化疗药物和/或非甾体抗炎药和/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、拓扑异构酶抑制剂、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、拓扑异构酶I抑制剂、拓扑异构酶Ⅱ抑制剂、长春碱类、培美曲塞、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,所述拓扑异构酶I抑制剂为喜树碱及其衍生物、羟基喜树碱、伊立替康、拓扑替康中的一种或多种,所述拓扑异构酶Ⅱ抑制剂为依托泊苷、替尼铂苷中的一种或多种,所述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,所述非甾体抗炎药为扎托洛芬、双氯芬酸、吲哚美辛、奥沙普秦、对乙酰氨基酚、酮洛芬中的一种或多种;
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。
7.根据权利要求1-6任一项所述的应用,其特征在于,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。
8.根据权利要求1-7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。
9.根据权利要求1-8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。
10.根据权利要求1-9任一项所述的应用,其特征在于,所述软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、***、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。
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