CN109553608B - 一类五元六元杂环化合物及其制备方法和治疗肿瘤的用途 - Google Patents
一类五元六元杂环化合物及其制备方法和治疗肿瘤的用途 Download PDFInfo
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Abstract
本发明涉及一种通式(I)化合物及其药学上可接受的盐及其制备方法和用途。所述通式(I)化合物中,X为‑芳基‑、‑杂芳基‑、‑杂芳基‑杂芳基‑、‑杂环基‑;R1相同或不同,独立地选自H、C1‑6烷基、C1‑6烷氧基、C2‑6烯基、C2‑6炔基、卤素、氨基、磺酸基、硝基、‑CN、‑CO‑R、‑CO‑OR、‑O‑R、芳基、杂芳基、杂环基,其中R为C1‑6烷基、芳基、杂芳基、杂环基;R2相同或不同,独立地选自H、C1‑6烷基、C1‑6烷氧基。本发明化合物可用于治疗肿瘤。
Description
技术领域
本发明涉及医药领域,具体涉及一类五元六元杂环化合物及其制备方法和治疗肿瘤的用途。
背景技术
肿瘤是一个异质性的组织,基础医学研究认为肿瘤的生长是肿瘤组织中一小部分具有干细胞性质的肿瘤细胞增殖分化的结果,由此提出了“肿瘤干细胞假说”:肿瘤干细胞(cancer stem cell,CSC)增殖过程中发生不均一分裂,一个CSC分裂形成一个新的CSC和另一个可最终分化成包括肿瘤细胞在内的各种细胞的子细胞,其结果是维持CSC数目稳定并产生肿瘤。CSC数目极其稀少,其成瘤能力较普通肿瘤细胞高数百倍,是肿瘤发生、发展与维持的基础。
目前研究认为CSC与成体干细胞有相似,两者都具有分化和自我复制能力。但与成体干细胞不同的是,CSC的自我复制能力是一种不受限的自我生长。肿瘤抑制因子PTEN失活以及下游调控的PI3K/AKT信号通路的异常在许多类型的肿瘤中均有发现,比如T-ALL。
传统的化疗药物的开发主要是筛选能杀灭分裂中肿瘤细胞的化合物。肿瘤干细胞理论认为,虽然根除非肿瘤干细胞可达到肿块缩小的目的,但只要存在CSC,肿瘤就仍可复发,不可能治愈,所以肿瘤治疗的焦点是杀伤CSC。但是CSC通常处于静止状态,只是在增殖时才开始快速分裂产生子细胞。所以按照传统方法筛选出来的肿瘤治疗药物与杀灭CSC的要求差异巨大。
科学界希望通过分析CSC与相应成体干细胞基因表达特征的不同,利用这种差异,可能会出现既直接针对CSC,又能保护成体干细胞的治疗手段。
急性淋巴细胞白血病(ALL)是儿童常见的恶性肿瘤,是一种起源于淋巴细胞的B系或T系细胞的恶性肿瘤性疾病。根据ALL的免疫表型分为B细胞型、T细胞型及T/B混合型,其中T细胞型(T-ALL)占ALL的15-25%。随着白血病发病机制、化疗方案、特异靶向治疗和造血干细胞移植等研究的不断深入,ALL的治愈率显著提高,长期无病存活率已达70-80%,但仍有20-30%的患儿复发而导致治疗失败。其中,T-ALL发病时年龄偏大,初诊白细胞数常大于50×109/L,肿瘤负荷较高,病情进展迅速,且易发生纵膈及中枢神经系统浸润,具有不同于B-ALL的独特的临床、免疫学、细胞遗传学和分子生物学特点:细胞突变快,细胞凋亡率低,残留白血病克隆多,决定了它易复发(高达30%以上)且复发早,预后不良,与B-ALL相比总体预后较差。
发明内容
本发明目的是提供一种用于治疗肿瘤的通式(I)化合物及其制备方法。
本发明的又一目的是提供上述通式(I)化合物用于治疗肿瘤的用途。
本发明目的通过如下技术方案实现:
一种通式(I)化合物及其药学上可接受的盐,
其中,
X为-芳基-、-杂芳基-、-杂芳基-杂芳基-、-杂环基-;
R1相同或不同,独立地选自H、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤素、氨基、磺酸基、硝基、-CN、-CO-R、-CO-OR、-O-R、芳基、杂芳基、杂环基,其中R为C1-6烷基、芳基、杂芳基、杂环基;
R2相同或不同,独立地选自H、C1-6烷基、C1-6烷氧基;
上述基团中的C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、芳基、杂芳基、杂环基任选被一个或多个选自如下基团所取代:H、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤素、氨基、磺酸基、硝基、芳基、杂芳基;
前提是,所述通式(I)化合物不为如下化合物或其盐:
在一个实施方案中,R1相同或不同,独立地选自H、C1-6烷基、C1-6烷氧基、卤素、氨基、硝基、-CN、-CO-R、-CO-OR、-O-R、芳基、杂芳基;
在一个实施方案中,所述X可以为如下结构:
其中,X1、X2、X3、X4独立地选自NH、S、O、Se;
R3、R4相同或不同,独立地选自H、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤素、氨基、磺酸基、硝基、芳基、杂芳基;
在一个实施方案中,R3、R4相同或不同,独立地选自H、C1-6烷基、C1-6烷氧基、卤素、氨基、磺酸基、硝基、芳基、杂芳基;
作为一个实施方案,本发明的通式(I)化合物可以选自如下但不限于如下化合物:
本发明还提供一种上述通式(I)化合物的制备方法,包括:将式(II)化合物与式(III)化合物进行反应,得到通式(I)化合物;任选地,将所述式(I)化合物与药学上可接受的有机酸或无机酸反应得到式(I)所示的药学上可接受的盐;
其中,式(II)、式(III)中各取代基的定义如式(I)所定义。
根据本发明,所述方法中,将式(II)化合物与式(III)化合物在苯醌下进行反应,所述反应优选在惰性气体(例如氩气)下反应。反应溶剂优选为醇类溶剂,例如乙醇。
根据本发明,所述化合物的盐可以通过式(I)化合物与酸(例如有机酸或无机酸)反应得到,例如将式(I)化合物与氯化氢反应,得到化合物的盐酸盐。
本发明化合物是PU.1蛋白的小分子抑制剂,能靶向高表达PU.1的细胞,并杀伤这类细胞。
本发明化合物,可以用于治疗肿瘤。
本发明化合物,可以用于抑制PU.1高表达的细胞,包括但不限于T细胞、B细胞等免疫细胞。
本发明化合物,可以用于治疗PU.1高表达所致疾病,包括但不限于,自身免疫性疾病,例如银屑病、系统性红斑狼疮等。
本发明的化合物,可以用于治疗耐药的肿瘤,所述耐药是指对作用于分裂和增殖状态的肿瘤细胞的抗肿瘤药物耐药。
本发明化合物,优选用于治疗表达PU.1的肿瘤。
本发明的化合物,优选用于治疗T-ALL或T/B混合型ALL,优选为耐药的T-ALL或T/B混合型ALL。
本发明还提供一种药物组合物,包含本发明通式(I)所示的化合物、其药学可接受的盐。
根据本发明,所述药物组合物还可任选包含至少一种药学上可接受的辅料,例如载体、赋形剂等。作为实例,所述辅料可以为选自下列中的一种或多种:崩解剂、助流剂、润滑剂、稀释剂、填充剂、粘合剂、着色剂、泡腾剂、矫味剂、防腐剂、包衣材料等。
根据本发明,所述药物组合物可以为包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型的形式。
在一些实施方案中,所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液,用于胃肠外注射的无菌溶液、悬浮液或乳液,或者用于直肠给药的栓剂。
在其它实施方案中,所述药物组合物为适合单次施予精确剂量的单位剂型。
在其它实施方案中,所述化合物的量在约0.001mg/kg体重/天-约1000mg/kg体重/天的范围内。
在其它实施方案中,所述化合物的量的范围为约0.1mg/kg体重/天-约50mg/kg体重/天。
在其它实施方案中,所述化合物的量的范围为约0.1mg/kg体重/天-约10mg/kg体重/天。
在一些实施方案中,以单剂量施用所述化合物,每天一次。
在其它实施方案中,以多剂量施用所述化合物,每天不止一次。
在一些实施方案中,每天施用两次所述化合物。
在其它实施方案中,每天施用三次或三次以上所述化合物。
在一些实施方案中,所述药物组合物施用于的个体为哺乳动物。
在其它实施方案中,所述哺乳动物是人。
在其它实施方案中,所述药物组合物还包含至少另一种治疗剂(即制成一种剂型)。
在一些实施方案中,所述药物组合物和至少一种治疗剂分别以独立的剂型组合成组合产品,如套装药品(kit of part)。
在一些实施方案中,所述药物组合物含有本发明的化合物和另一种或多种抗肿瘤药物。
在一些实施方案中,所述药物组合套装含有两种或多种独立包装的药物组合物,其中一种独立包装的药物组合物含有新的通式化合物,其余的独立包装的药物组合物分别含有一种或多种抗肿瘤药物。
所述抗肿瘤药物包括但不限于:细胞毒性药物、激素类药物、生物反应调节剂、单克隆抗体、小分子靶向药物等。
细胞毒性药物包括但不限于:作用于DNA化学结构的药物,例如烷化剂、氮芥类、塞替派类、亚硝脲类、甲基磺酸酯类、铂类化合物、丝裂霉素等,具体如:氮芥、苯丁酸氮芥、环磷酰胺、异环磷酰胺、塞替派、卡莫司汀、司莫司汀、白消安、顺铂、奥沙利铂、卡铂、草酸铂、丝裂霉素等;影响核酸合成的药物,例如二氢叶酸还原酶抑制剂、胸腺核苷合成酶抑制剂、嘌呤核苷合成酶抑制剂、核苷酸还原酶抑制剂、DNA多聚酶抑制剂,具体如:甲氨蝶呤、5-FU、FT-207、卡培他滨、6-巯基嘌呤、6-TG、羟基脲、阿糖胞苷、吉西他滨、培美曲塞等;作用于核酸转录的药物,例如放线菌素D、柔红霉素、阿霉素、表阿霉素、阿克拉霉素、光辉霉素等;作用于DNA复制的拓扑异构酶I抑制剂,例如伊立替康、拓扑替康、羟基喜树碱等;作用于有丝分裂M期干扰微管蛋白合成的药物,例如紫杉醇、多西他赛、长春花碱、长春瑞滨、鬼臼碱类、高三尖杉酯碱等。
激素类药物包括但不限于:抗雌激素,例如三苯氧胺、托瑞米芬、依西美坦等;芳香化酶抑制剂,例如氨鲁米特、兰特隆、来曲唑、阿那曲唑等;孕激素,例如甲孕酮、甲地孕酮等;性激素,例如睾丸酮、雌激素等;抗雄激素,例如氟它氨等;RH-LH激动剂/拮抗剂,例如戈舍瑞林、醋酸亮丙瑞林等;糖皮质激素,例如地塞米松、波尼松龙等。
生物反应调节剂包括但不限于:干扰素,IL-2,胸腺肽类等。
单克隆抗体包括但不限于:贝伐单抗、利妥昔单抗、曲妥珠单抗、西妥昔单抗、群司珠单抗等。
小分子靶向药物包括但不限于:吉非替尼、伊马替尼、舒尼替尼、厄洛替尼、甲苯磺酸索拉菲尼、来那度胺、沙利度胺等。
还有其他类型的抗肿瘤药物,包括但不限于:硼替佐米、左旋门冬酰胺酶等。
优选抗肿瘤药物为:柔红霉素、阿霉素、去甲氧柔红霉素、米托蒽醌、Rapamycin、利妥昔单抗、伊马替尼、来那度胺、沙利度胺、硼替佐米、地塞米松、波尼松龙、阿糖胞苷、环磷酰胺、6-巯基嘌呤、左旋门冬酰胺酶、甲氨碟呤、长春新碱和/或达沙替尼。
在一些实施方案中,所述药物组合物含有本发明的化合物和一种或多种DNA甲基化抑制剂。
在一些实施方案中,所述药物组合套装含有两种或多种独立包装的药物组合物,其中一种独立包装的药物组合物含有本发明的化合物,其余的独立包装的药物组合物分别含有一种或多种DNA甲基化抑制剂。
所述甲基化抑制剂包括但不限于:核苷类药物,例如地西他滨、阿扎胞苷、折布拉林、法扎拉宾、二氢-5’-胞苷、5-氟-2-脱氧胞苷、二氢-5-氮杂胞苷等;非核苷类药物,例如氨基苯甲酸类、茶多酚类、肼类、邻苯二酰胺类、反义寡核苷酸类等,具体如普鲁卡因、普鲁卡因胺、表没食子儿茶素没食子酯酸、肼屈嗪、RG108、MG98、三氧化二砷。
在本发明的一个实施方式中,所述甲基化抑制剂选自5-氮-2-脱氧胞苷、地西他滨和三氧化二砷的任一种或其组合。
本发明还提供如上通式(I)化合物及其药学可接受的盐、或上述药物组合物在制备治疗肿瘤的药物中的用途。
所述肿瘤包括实体瘤和非实体瘤,可以是良性的和恶性的。
所述实体瘤包括但不限于:来源于上皮组织的良性或恶性肿瘤,例如:乳头状瘤、鳞状细胞癌、基底细胞癌、腺瘤、腺癌、移行上皮癌、恶性多形性腺瘤等;来源于间叶组织的良性或恶性肿瘤,例如:纤维肉瘤、脂肪肉瘤、平滑肌肉瘤、横纹肌肉瘤、血管肉瘤、骨肉瘤、恶性巨细胞瘤、软骨肉瘤等;来源于淋巴组织的恶性肿瘤,例如:恶性淋巴瘤;来源于神经组织的良性或恶性肿瘤,例如:神经纤维肉瘤、恶性胶质细胞瘤、神经母细胞瘤;来源于其他组织的良性或恶性肿瘤,例如:恶性黑色素瘤、绒毛膜上皮癌、间质细胞瘤等。
所述非实体瘤包括但不限于:来自于造血组织的恶性肿瘤,例如:各种白血病,多发性骨髓瘤等。
所述恶性淋巴瘤包括:何杰金病、非何杰金淋巴瘤、Burkitt淋巴瘤、蕈样霉菌病。
所述白血病包括:急性淋巴细胞性白血病(ALL),慢性淋巴细胞性白血病(CLL),急性粒细胞性白血病(AML),慢性粒细胞性白血病(CML)。
急性淋巴细胞性白血病(ALL)包括:T细胞性ALL(T-ALL),B细胞性ALL(B-ALL)和混合性ALL(T/B-ALL)。
优选所述肿瘤为耐药的肿瘤,所述耐药是指对作用于分裂和增殖状态的肿瘤细胞的抗肿瘤药物耐药。
在本发明的一个实施方式中,所述肿瘤优选所述肿瘤为恶性淋巴瘤和白血病。
在本发明的一个实施方式中,所述肿瘤为ALL,尤其是T-ALL或T/B混合型ALL,优选为耐药的T-ALL或T/B混合型ALL。
不受特殊理论的限制,本发明化合物治疗肿瘤的机理之一是,其杀伤了表达PU.1的肿瘤细胞。
本发明还提供了一种治疗肿瘤的方法,其中包括将肿瘤与有效量的上述化合物或其药学可接受的盐接触。
优选地,该方法可以用于体内,也可以用于体外。
本发明还提供一种治疗PU.1高表达所致疾病的方法,其中包括将所述疾病与有效量的上述化合物或其药学可接受的盐接触。所述PU.1高表达所致疾病包括但不限于,自身免疫性疾病,例如银屑病、系统性红斑狼疮等。
根据本发明,所述的药物组合物或者药物组合套装可以同时给药,或顺序给药,或间隔一段时间后先后给药,或将上述给药方案结合使用。例如同时使用新的通式化合物和抗肿瘤药物或者甲基化抑制剂;或者先给药新的通式化合物,之后紧接着给药抗肿瘤药物或者甲基化抑制剂;或者先给药抗肿瘤药物或者甲基化抑制剂,之后紧接着给药新的通式化合物;或者先给药抗肿瘤药物或者甲基化抑制剂一段时间后,再给药新的通式化合物;或者先同时给药新的通式化合物和抗肿瘤药物或者甲基化抑制剂一段时间后,再给药新的通式化合物。
具体给药顺序根据患者体内肿瘤细胞状态的检测结果进行选择和调整。
具体给药剂量,根据患者体内肿瘤细胞状态和整体身体状态,进行选择和调整。
术语定义和说明
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义,以本章的定义为准。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本申请主题作任何限制。在本申请中,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
术语“烷基”指具有1-6个碳原子的直链或支链烷基,所述烷基例如为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、新戊基。
术语“烯基”指具有2-6个碳原子的直链或支链烯基,所述烯基例如为乙烯基、丙烯基、异丙烯基。
术语“炔基”指具有2-6个碳原子的直链或支链炔基,所述炔基例如为乙炔基、丙炔基、丁炔基。
术语“烷氧基”指具有1-6个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、仲丁氧基。
术语“卤素”为氟、氯、溴、碘,优选为氟、氯、溴。
术语“芳基”应理解为优选表示具有6~20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”),特别是具有6个碳原子的环(“C6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C13芳基”),例如芴基,或者是具有14个碳原子的环(“C14芳基”),例如蒽基。
术语“杂芳基”应理解为含有5-20个环原子、5-14个环原子,或5-12个环原子,或5-10个环原子,或5-6个环原子的单环、双环和三环体系,其中至少一个环体系是芳香族的,且至少一个环体系包含一个或多个杂原子(例如N、O、S、Se等),其中每一个环体系包含5-7个原子组成的环,且有一个或多个连接点与分子其余部分相连。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中,5-10个原子组成的杂芳基包含1,2,3或4个独立选自O、S、Se和N的杂原子。在另一些实施方案中,5-6个原子组成的杂芳基包含1,2,3或4个独立选自O、S、Se和N的杂原子。
杂芳基基团的单环实例包括,但并不限于,噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
术语“杂环基”意指单环,双环或三环体系,其中环上一个或多个原子独立任选地被杂原子所取代,环可以是完全饱和的或包含一个或多个不饱和度,但不是芳香族类,有一个或多个连接点连接到其他分子上去。一个或多个环上的氢原子可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。其中一些实施例是,“杂环基”是3-7个原子组成的单环、或7-10个原子组成的的双环,其包含1-5个,优选1-3个选自N、O、S和Se的杂原子。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基、1,3-苯并噁唑基、1,3-苯并二氧杂环戊烯基。
除非另有说明,杂环基、杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
本文所用的有关术语“受试者”、“患者”或“个体”是指患有疾病、病症或病况等的个体,包括哺乳动物和非哺乳动物。哺乳动物的实施例包括但不限于哺乳动物纲的任何成员:人,非人的灵长类动物(例如黑猩猩和其它猿类和猴);家畜,例如牛、马、绵羊、山羊、猪;家养动物,例如兔、狗和猫;实验室动物,包括啮齿类动物,例如大鼠、小鼠和豚鼠等。非人哺乳动物的实施例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方式中,所述哺乳动物为人。
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状,预防其它症状,改善或预防导致症状的潜在代谢原因,抑制疾病或病症,例如阻止疾病或病症的发展,缓解疾病或病症,使疾病或病症好转,缓解由疾病或病症导致的症状,或者中止疾病或病症的症状,此外,该术语包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外,对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果,例如尽管患者可能仍然受到潜在疾病的影响,但观察到患者情况改善。就预防效果而言,可向具有患特定疾病风险的患者施用所述组合物,或者即便尚未做出疾病诊断,但向出现该疾病的一个或多个生理症状的患者施用所述组合物。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、外用和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术。在优选的实施方式中,本文讨论的化合物和组合物通过口服施用。
本文针对制剂、组合物或成分所用术语“可接受的”是指对接受治疗的受试者的一般健康情况没有长期的有害影响。
本文所用术语“药学上可接受的”是指不影响本申请化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
本文所用术语“药物组合物”是指任选地混合有至少一种药学上可接受的化学成分的生物活性化合物,所述药学上可接受的化学成分包括但不限于载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂。
本文所用术语“载体”是指相对无毒的化学化合物或试剂,其有助于将化合物引入到细胞或组织中。
本文所用术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力,并且在生物学或其它方面上没有不良作用的盐。药学上可接受的盐的实例包括但不限于,碱性残基(如胺类)的无机酸盐或有机酸盐,酸性残基(如羧酸)的碱性盐或有机盐,等。药学上可接受的盐包括由诸如无毒性的无机或有机酸形成的母体化合物的常规无毒性的盐或季铵盐。例如,这些常规的无毒性盐包括那些源自无机酸的盐,如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等;以及由有机酸制备的盐,如,乙酸、丙酸、琥珀酸、羟基乙酸、乳酸、苹果酸、酒石酸、柠檬酸、延胡索酸、甲磺酸、甲苯磺酸、水杨酸、对氨基苯磺酸等。
本发明的药学上可接受的盐可以通过常规的化学方法从含有碱性或酸性部分的母体化合物合成。通常,这种盐可以通过使这些化合物的游离酸或碱形式与化学计量的适当的碱或酸在水或有机溶剂或二者的混合物中反应制备。
具体实施方式
本发明通过下述实施例进行详细说明。但本领域技术人员了解,任何在本发明基础上做出的改进和变化,都在本发明的保护范围之内。
实施例1、DB1976的合成
DB1976通过如下合成路线进行制备:
化合物2的合成:
4-氨基-3-硝基-苯甲脒盐酸盐1(108.3mg,0.50mmol)溶于10.7mL无水乙醇中,随后加入10%的钯碳(10.8mg)。用氢气将体系完全置换后,室温下搅拌24小时。随后过滤除去钯碳,将滤液在真空条件下旋干得到黄色化合物2(98.6mg,定量反应)。
1H NMR(400MHz,CD3OD)δ7.11(dd,J=2.4,8.4Hz,1H),7.06(d,J=2.4Hz,1H),6.73(d,J=8.4Hz,1H);13C NMR(100MHz,CD3OD)δ167.7,143.9,135.3,121.3,116.3,115.4,115.2;HRMS(ESI)m/z:计算值为C25H26N3O8[M+NH4]+=496.1714,实测值=496.1715。
化合物4的合成:
将硒酚3(670.0mg,5.10mmol)和四甲基乙二胺(711.0mg,6.12mmol)溶于1.6mL的无水正己烷中,将体系使用氩气完全置换后,将氩气通入反应液中7分钟,用冰盐浴将反应体系降温至零下5℃,将叔丁基锂的正己烷溶液(8.5mL,1.3M)逐滴缓慢加入到反应体系中,加完后反应体系缓慢升温至室温并回流30分钟。
加入6.3mL新蒸四氢呋喃,并将反应体系降温至零下40℃,将无水N,N-二甲基甲酰胺(1.49g,20.4mmol)缓慢滴加进入反应体系中。加完后反应体系缓慢升温至室温,并在室温搅拌1.5小时。随后反应液缓慢倒入8.7mL的浓盐酸溶液中,加入饱和碳酸氢钠溶液调节pH值至6-7。随后用30.0mL乙醚萃取3次,有机相使用无水硫酸钠干燥。粗产品使用乙醇(4mL)重结晶,最后得到橙红色化合物4(626.1mg,66%)。
1H NMR(400MHz,CDCl3)δ9.89(s,2H),8.10(s,2H);13C NMR(100MHz,CDCl3)δ184.8,156.2 138.2。
化合物5的合成:
将化合物2(56.0mg,0.30mmol),化合物4(28.1mg,0.15mmol)和苯醌(32.4mg,0.30mmol)溶于6.0mL无水乙醇中,将反应体系充分用氩气置换后,回流8至10小时,TLC板上显示化合物4完全消失。将反应体系冷却至室温加入丙酮/乙醇(7.5mL/0.75mL)的混合溶液,充分搅拌后过滤,用无水乙醚洗涤滤出物,干燥得到黑色固体。
再将固体溶于1:1混合的热甲醇/乙醇(13.2mL/13.2mL)混合液中,再次过滤滤除不溶物。将滤液浓缩至总体积9.0mL,随后加入0.9mL的氯化氢饱和的乙醇溶液,室温搅拌过夜。随后加入50.0mL的无水乙醚稀释反应体系,过滤分离得到固体,50℃真空干燥12小时,最终得到墨绿色固体5(57.4mg,两步收率85%)。
1H NMR(400MHz,DMSO-d6)δ9.36(s,2H),9.04(s,2H),8.38(s,1H),8.16(s,1H),7.80(d,J=8.8Hz,1H),7.70(d,J=8.4Hz,1H);13C NMR(125MHz,DMSO-d6)δ165.9,149.9,141.0,139.5,137.8,132.8,123.2,122.4,115.9,114.8;HRMS(ESI)m/z:计算值C20H16N8Se[M+H]+=448.0663,实测值448.3350。
实施例2:化合物8的合成
化合物2的制备同实施例1。
化合物7的合成:
将2,2-二硒酚6(130.0mg,5mmol)和四甲基乙二胺(711.0mg,6.12mmol)溶于1.6mL的无水正己烷中,将体系使用氩气完全置换后,将氩气通入反应液中6分钟,用冰盐浴将反应体系降温至零下4℃,将叔丁基锂的正己烷溶液(8.5mL,1.3M)逐滴缓慢加入到反应体系中,加完后反应体系缓慢升温至室温并回流30分钟。加入6.5mL新蒸四氢呋喃,并将反应体系降温至零下40℃,将无水N,N-二甲基甲酰胺(1.49g,20.4mmol)缓慢滴加进入反应体系中。
加完后反应体系缓慢升温至室温,并在室温搅拌2小时。随后反应液缓慢倒入10mL的浓盐酸溶液中,加入饱和碳酸氢钠溶液调节pH值至6-7。随后用30.0mL乙醚萃取3次,有机相使用无水硫酸钠干燥。粗产品使用乙醇(5mL)重结晶,最后得到橙红色化合物7(973.5mg,62%)。
化合物8的合成:
将化合物2(56.0mg,0.30mmol),化合物7(47.1mg,0.15mmol)和苯醌(32.4mg,0.30mmol)溶于6.0mL无水乙醇中,将反应体系充分用氩气置换后,回流8至10小时,TLC板上显示化合物7完全消失。将反应体系冷却至室温加入丙酮/乙醇(7.5mL/0.75mL)的混合溶液,充分搅拌后过滤,用无水乙醚洗涤滤出物,干燥得到黑色固体。再将固体溶于1:1混合的热甲醇/乙醇(13.2mL/13.2mL)混合液中,再次过滤滤除不溶物。将滤液浓缩至总体积9.0mL,随后加入0.9mL的氯化氢饱和的乙醇溶液,室温搅拌过夜。随后加入50.0mL的无水乙醚稀释反应体系,过滤分离得到固体,50℃真空干燥12小时,最终得到墨绿色固体8(57.4mg,两步收率85%)。HRMS(ESI)m/z:计算值C24H18N8Se2[M+H]+=577.9985,实测值577.9559。
实施例3
依据实施例1同样的方法制备表1中的化合物。其中,对于化合物1制备化合物2,采用化合物1的非盐酸盐结构:
其他制备条件同实施例1。
表1:具体化合物及其质谱数据
生物学实验方法:
利用构建的PU.1过表达Blast细胞株进行生物学活性测试
1、过表达Blast细胞株的构建
通过分子克隆的方法构建MSCV-PU.1-IRES-GFP的PU.1过表达质粒。
Blast细胞取自Pten null T-ALL小鼠(参考文献:Guo W,Lasky J L,Chang C J,et al.Multi-genetic events collaboratively contribute to Pten-null leukaemiastem-cell formation[J].Nature,2008,453(7194):529-533)。
MSCV-IRES-GFP的质粒购买于addgen(Plasmid:20672),将PCR扩增的PU.1cDNA通过BgIII和EcoRI两个限制性酶切位点克隆入MSCV-IRES-GFP得到MSCV-PU.1-IRES-GFP。
将MSCV-PU.1-IRES-GFP和MSCV-IRES-GFP同时转染Phoenix细胞(来自于UCLA吴虹实验室)进行病毒的包装。24h后利用20%FBS的DMEM换液。
72h后收集细胞上清,3000rpm离心10min。转移上清至无菌的50ml的离心管中,去除细胞残渣。转移病毒至超速离心管内,4℃下以RPM25000的转速超速离心2-2.5h。离心完成后,去除上清,取20μl培养基加入离心管底部。
利用293T细胞检测病毒的滴度以备后续感染需要。
将包装完成的病毒加入培养的Blast细胞中,感染24后,对培养基进行换液处理,2-3天后利用流式细胞检测GFP阳性的细胞的比例。
待细胞扩增起来后,利用流式细胞仪分选出GFP阳性的细胞,即PU.1过表达的细胞系。用于后续实验。
2、细胞的药物处理
取1×106的Blast-GFP细胞种植于DMEM加血清的培养基中24小时,分别加入不同浓度的本发明化合物和相应体积的DMSO,给药处理24小时后,离心收集细胞,提取RNA反转录和进行实时定量PCR,检测TIM-3,CD11c,PU.1,LMO2和c-myc的表达。
3、实时定量PCR
取1×105药物处理后的细胞,按照qiagen公司的RNA提取试剂盒的步骤(QIAGEN,74106)进行RNA的提取。取200ng总的RNA用于cDNA的合成,cDNA的合成按照Vazyme(R223-01)的说明书的方法进行。
将逆转录cDNA稀释10倍后,用于Q-PCR。PCR的体系和条件按照Vazyme(Q121-01)说明书的体系和条件进行。引物如下:
c-Myc-F:5’-GTGCTGCATGAGGAGACACC-3’
c-Myc-R:5’-TTTGCCTCTTCTCCACAGACA-3’
TIM-3-F:5’-cccctgccaagtactcatgt-3’
TIM-3-R:5’-caagtgccccaggtgtagat-3’
CD11c-F:5’-GAGTCAGGGCCTCTGGAGTA-3’
CD11c-R:5’-GGTTTTTGGGGTTCCGGGTA-3’
PU.1-F:5’-AGCGATGGAGAAAGCCATAG-3’
PU.1-R:5’-TGCAGCTCTGTGAAGTGGTT-3’
Lmo2-F:5’-tgggtgaggcatttcttagg-3’
Lmo2-R:5’-gcctatcaggatggcacagt-3’。
通过本发明的生物学实验测定,本发明的化合物在体外,20μM及以下的浓度下,都能抑制过表达PU.1的Blast细胞的TIM-3,CD11c和LMO2基因的表达,同时上调myc基因的表达,即,能够抑制PU.1的作用。
Claims (39)
4.一种药物组合物,包含权利要求1或2所述的通式(I)化合物、及其药学可接受的盐。
5.如权利要求4所述的药物组合物,其中,所述药物组合物还包含至少一种药学上可接受的辅料。
6.如权利要求5所述的药物组合物,其中,所述辅料选自下列中的一种或多种:崩解剂、助流剂、润滑剂、稀释剂、填充剂、粘合剂、着色剂、泡腾剂、矫味剂、防腐剂、包衣材料、赋形剂、载体。
7.如权利要求4所述的药物组合物,其中,所述药物组合物为口服剂型、胃肠外给药剂型、外用剂型或直肠给药剂型的形式。
8.如权利要求4所述的药物组合物,其中,所述药物组合物为口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液或悬浮液,用于胃肠外注射的无菌溶液、悬浮液或乳液,或者用于直肠给药的栓剂。
9.如权利要求4-8任一项所述的药物组合物,其中,所述药物组合物还包含至少另一种治疗剂。
10.如权利要求9所述的药物组合物,其中,所述治疗剂为一种或多种抗肿瘤药物。
11.如权利要求10所述的药物组合物,其中,所述抗肿瘤药物为:细胞毒性药物、激素类药物、生物反应调节剂、单克隆抗体、或小分子靶向药物。
12.如权利要求11所述的药物组合物,其中,细胞毒性药物选自:作用于DNA化学结构的药物;影响核酸合成的药物;作用于核酸转录的药物;作用于DNA复制的拓扑异构酶I抑制剂;或作用于有丝分裂M期干扰微管蛋白合成的药物。
13.如权利要求12所述的药物组合物,其中,所述作用于DNA化学结构的药物为烷化剂、氮芥类、塞替派类、亚硝脲类、甲基磺酸酯类、铂类化合物、或丝裂霉素;所述影响核酸合成的药物为二氢叶酸还原酶抑制剂、胸腺核苷合成酶抑制剂、嘌呤核苷合成酶抑制剂、核苷酸还原酶抑制剂、或DNA多聚酶抑制剂;所述作用于核酸转录的药物为放线菌素D、柔红霉素、阿霉素、表阿霉素、阿克拉霉素、或光辉霉素;所述作用于DNA复制的拓扑异构酶I抑制剂为伊立替康、拓扑替康、或羟基喜树碱;所述作用于有丝分裂M期干扰微管蛋白合成的药物为紫杉醇、多西他赛、长春花碱、长春瑞滨、鬼臼碱类、或高三尖杉酯碱。
14.如权利要求12所述的药物组合物,其中,所述作用于DNA化学结构的药物为:氮芥、苯丁酸氮芥、环磷酰胺、异环磷酰胺、塞替派、卡莫司汀、司莫司汀、白消安、顺铂、奥沙利铂、卡铂、草酸铂、或丝裂霉素;
所述影响核酸合成的药物为:甲氨蝶呤、5-FU、FT-207、卡培他滨、6-巯基嘌呤、6-TG、羟基脲、阿糖胞苷、吉西他滨、或培美曲塞。
15.如权利要求11所述的药物组合物,其中,所述激素类药物选自:抗雌激素;芳香化酶抑制剂;孕激素;性激素;抗雄激素;RH-LH激动剂/拮抗剂;或糖皮质激素。
16.如权利要求15所述的药物组合物,其中,所述抗雌激素为三苯氧胺、托瑞米芬、或依西美坦;所述芳香化酶抑制剂为氨鲁米特、兰特隆、来曲唑、或阿那曲唑;所述孕激素为甲孕酮、或甲地孕酮;所述性激素为睾丸酮、或雌激素;所述抗雄激素为氟它氨;所述RH-LH激动剂/拮抗剂为戈舍瑞林、或醋酸亮丙瑞林;所述糖皮质激素为地塞米松、或波尼松龙。
17.如权利要求11所述的药物组合物,其中,所述生物反应调节剂选自:干扰素、IL-2、或胸腺肽类。
18.如权利要求11所述的药物组合物,其中,所述单克隆抗体选自:贝伐单抗、利妥昔单抗、曲妥珠单抗、西妥昔单抗、或群司珠单抗。
19.如权利要求11所述的药物组合物,其中,所述小分子靶向药物选自:吉非替尼、伊马替尼、舒尼替尼、厄洛替尼、甲苯磺酸索拉菲尼、来那度胺、或沙利度胺。
20.如权利要求10所述的药物组合物,其中,其他类型的抗肿瘤药物选自:硼替佐米、或左旋门冬酰胺酶。
21.如权利要求10所述的药物组合物,其中,所述抗肿瘤药物为柔红霉素、阿霉素、去甲氧柔红霉素、米托蒽醌、Rapamycin、利妥昔单抗、伊马替尼、来那度胺、沙利度胺、硼替佐米、地塞米松、波尼松龙、阿糖胞苷、环磷酰胺、6-巯基嘌呤、左旋门冬酰胺酶、甲氨碟呤、长春新碱和/或达沙替尼。
22.如权利要求9所述的药物组合物,其中,所述治疗剂为一种或多种DNA甲基化抑制剂。
23.如权利要求22所述的药物组合物,其中,所述DNA甲基化抑制剂选自:核苷类药物;或非核苷类药物。
24.如权利要求23所述的药物组合物,其中,所述核苷类药物为地西他滨、阿扎胞苷、折布拉林、法扎拉宾、二氢-5’-胞苷、5-氟-2-脱氧胞苷、或二氢-5-氮杂胞苷;所述非核苷类药物为氨基苯甲酸类、茶多酚类、肼类、邻苯二酰胺类、或反义寡核苷酸类。
25.如权利要求23所述的药物组合物,其中,所述非核苷类药物为普鲁卡因、普鲁卡因胺、表没食子儿茶素没食子酯酸、肼屈嗪、RG108、MG98、或三氧化二砷。
26.如权利要求23所述的药物组合物,其中,所述甲基化抑制剂选自5-氮-2-脱氧胞苷、地西他滨和三氧化二砷的任一种或其组合。
27.一种通式(I)化合物及其药学可接受的盐、或含有通式(I)化合物的药物组合物在制备治疗表达PU.1的肿瘤的药物中的用途或者在制备治疗PU.1高表达所致自身免疫性疾病的药物中的用途,
其中,
X为:
X2、X3独立地选自NH、S、O、Se;R4相同或不同,独立地选自H、C1-6烷基、C1-6烷氧基、卤素、氨基、磺酸基、硝基;
R1相同或不同,独立地选自H、C1-6烷基、C1-6烷氧基、卤素、氨基、磺酸基、硝基、-CN;
R2相同或不同,独立地选自H、C1-6烷基、C1-6烷氧基;
上述基团中的C1-6烷基、C1-6烷氧基任选被一个或多个选自如下基团所取代:H、C1-6烷基、C1-6烷氧基卤素、氨基、磺酸基、硝基。
28.如权利要求27所述的用途,其中,所述肿瘤选自实体瘤和非实体瘤,所述肿瘤是良性的或恶性的。
29.如权利要求28所述的用途,其中,所述实体瘤选自:来源于上皮组织的良性或恶性肿瘤;来源于间叶组织的良性或恶性肿瘤;来源于淋巴组织的恶性肿瘤;来源于神经组织的良性或恶性肿瘤;或者来源于其他组织的良性或恶性肿瘤。
30.如权利要求29所述的用途,其中,所述来源于上皮组织的良性或恶性肿瘤为:乳头状瘤、鳞状细胞癌、基底细胞癌、腺瘤、腺癌、移行上皮癌、或恶性多形性腺瘤;所述来源于间叶组织的良性或恶性肿瘤为:纤维肉瘤、脂肪肉瘤、平滑肌肉瘤、横纹肌肉瘤、血管肉瘤、骨肉瘤、恶性巨细胞瘤、或软骨肉瘤;所述来源于淋巴组织的恶性肿瘤为:恶性淋巴瘤;所述来源于神经组织的良性或恶性肿瘤为:神经纤维肉瘤、恶性胶质细胞瘤、或神经母细胞瘤;所述来源于其他组织的良性或恶性肿瘤为:恶性黑色素瘤、绒毛膜上皮癌、或间质细胞瘤。
31.如权利要求30所述的用途,其中,所述恶性淋巴瘤选自:何杰金病、非何杰金淋巴瘤、Burkitt淋巴瘤、或蕈样霉菌病。
32.如权利要求28所述的用途,其中,所述非实体瘤选自:来自于造血组织的恶性肿瘤。
33.如权利要求32所述的用途,其中,所述来自于造血组织的恶性肿瘤为:各种白血病,或多发性骨髓瘤。
34.如权利要求33所述的用途,其中,所述白血病选自:急性淋巴细胞性白血病、慢性淋巴细胞性白血病、急性粒细胞性白血病、或慢性粒细胞性白血病。
35.如权利要求34所述的用途,其中,急性淋巴细胞性白血病选自:T细胞性ALL、B细胞性ALL或混合性ALL。
36.如权利要求27所述的用途,其中,所述肿瘤为恶性淋巴瘤或白血病。
37.如权利要求27所述的用途,其中,所述肿瘤为T-ALL或T/B混合型ALL。
38.如权利要求27所述的用途,其中所述自身免疫性疾病为银屑病、或系统性红斑狼疮。
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