CN117624161A - 一种吡啶羧酸胺衍生物及其应用 - Google Patents
一种吡啶羧酸胺衍生物及其应用 Download PDFInfo
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- CN117624161A CN117624161A CN202210961181.9A CN202210961181A CN117624161A CN 117624161 A CN117624161 A CN 117624161A CN 202210961181 A CN202210961181 A CN 202210961181A CN 117624161 A CN117624161 A CN 117624161A
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- acid amine
- carboxylic acid
- isomer
- pharmaceutically acceptable
- pyridine carboxylic
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Abstract
本发明公开了结构如通式I所示的吡啶羧酸胺衍生物或其异构体、药学上可接受的盐;其中,X1选自N或CH;X2、X3分别独立的选自N或C(R2),且X2、X3不能同时为N;R1选自氢、卤素、C1‑4烷基、C1‑4卤代烷基;R2选自氢或氟。吡啶羧酸胺衍生物对PARP1具有高度的选择性抑制活性,而对PARP2以及PARP其他家族成员不具有抑制活性。本发明还公开了吡啶羧酸胺类化合物或其异构体、药学上可接受的盐在制备PARP1抑制剂的应用,尤其是在制备治疗PARP1异常表达相关疾病的药物的应用。本发明还公开了一种药物组合物,它是以吡啶羧酸胺类化合物或其异构体、药学上可接受的盐为活性成分或主要活性成分。
Description
技术领域
本发明属于药物化学领域,涉及一种吡啶羧酸胺衍生物及其应用。
背景技术
在细胞的生长过程中,DNA不可避免地会受到外源或内源因素的作用产生DNA损伤。因此,细胞必须建立多种DNA损伤发现和修复体系,及时的修复受损的DNA,以维持细胞的正常生理功能。聚二磷酸腺苷核糖聚合酶[poly(ADP-ribose)polymerase,PARP]被称为DNA修复酶,密切参与DNA单链损伤的碱基切除修复,维持基因组稳定,近年来已成为肿瘤治疗领域的热门靶点。PARP存在于细胞核内,是参与聚腺苷二磷酸核糖(poly(ADP- ribose),PAR)合成的酶,即一种ADP-核糖通过核糖基化-核糖键相连的多聚体。
目前,全球共有4款获批上市的PARP抑制剂,包括奥拉帕利、鲁卡帕利、尼拉帕利以及他拉唑帕利。
已上市的PARP抑制剂均为PARP1/PARP2抑制剂,无选择性。临床用药过程中易出现血液毒性,限制了已有药物在临床的治疗效果。研究表明,血液毒性的产生与抑制PARP2有关。因此,发现高选择性PARP1抑制剂有望解决血液毒性问题,意义重大。
发明内容
本发明的目的在于提供一种吡啶羧酸胺衍生物,所述的吡啶羧酸胺衍生物对PARP1(聚 ADP-核糖聚合酶1)具有高度的选择性抑制活性,而对PARP2以及PARP其他家族成员不具有抑制活性,有望解决现有PARP抑制剂的毒性问题,提高治疗窗口,可用于制备治疗PARP1相关疾病的药物,尤其是制备PARP1异常表达相关肿瘤的药物。
本发明的目的是通过以下技术方案实现的:
结构如通式I所示的吡啶羧酸胺衍生物或其异构体、药学上可接受的盐:
其中,X1选自N或CH;
X2、X3分别独立的选自N或C(R2),且X2、X3不能同时为N;
R1选自氢、卤素、C1-4烷基、C1-4卤代烷基;
R2选自氢或氟。
优选的,R1选自氢或甲基。
具体的,所述的吡啶羧酸胺类化合物选自以下化合物:
所述的异构体为结构如通式I所示的吡啶羧酸胺类化合物的互变异构体、顺反异构体、对映异构体、非对映异构体及外消旋体;所述的对映异构体,包括(-)-和(+)-对映体、(R)-和 (S)-对映体、(D)-异构体、(L)-异构体;烷基等取代基中可存在另外的不对称碳原子。
所述的吡啶羧酸胺衍生物还包括与本文中记载的那些相同的,但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的吡啶羧酸胺衍生物。可结合到吡啶羧酸胺衍生物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素,诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
所述的吡啶羧酸胺衍生物还可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有立体异构体都包括在本发明的保护范围之内,如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。
所述的吡啶羧酸胺衍生物可以作为异构体的混合物或优选纯的异构体存在。
本发明的另一个目的是提供结构如通式I所示的吡啶羧酸胺衍生物的制备方法,合成路线如下:
X1,X2,X3,R1定义同前述,X4选自Cl、Br。
本发明的另一个目的是提供结构如通式I所示的吡啶羧酸胺类化合物或其异构体、药学上可接受的盐在制备PARP1抑制剂的应用,尤其是在制备治疗PARP1异常表达相关疾病的药物的应用。
本发明的另一个目的是提供一种药物组合物,它是以本发明所述的吡啶羧酸胺类化合物或其异构体、药学上可接受的盐为活性成分或主要活性成分,与药学上可接受的辅料制成的药学上可接受的剂型。
药学上可接受的辅料包括赋形剂、溶剂、分散剂、稳定剂、乳化剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和/或矫味剂。
所述的剂型为固态、半固态、液态或气态制剂,具体可以选自片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。给予吡啶羧酸胺衍生物或其异构体、药学上可接受的盐的典型给药途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
所述的药物组合物可以采用本领域众所周知的方法制成药学上可接受的剂型,如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中,药物组合物是口服形式。对于口服给药,可以通过将活性成分与本领域熟知的药学上可接受的辅料混合,制成适合口服形式的药剂。这些辅料能使本发明的吡啶羧酸胺类化合物或其异构体、可药用盐被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等,用于对患者的口服给药。
在一些实施方案中,可以通过常规的混合、填充或压片方法制备固体口服剂型。例如,可通过下述方法获得:将活性成分与固体辅料混合,任选地碾磨所得的混合物,如果需要则加入其它合适的辅料,然后将该混合物加工成颗粒,得到片剂或糖衣剂的核心。
所述的药物组合物还可适用于肠胃外给药,如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
所述的药物组合物的治疗剂量可根据例如以下而定:治疗的具体用途、给予化合物的方式、患者的健康和状态,以及签处方医师的判断。所述的吡啶羧酸胺衍生物或其异构体、药学上可接受的盐在药物组合物中的比例或浓度可不固定,取决于包括剂量、化学特性(例如疏水性)和给药途径在内的多种因素。例如可通过含约0.1~10%w/v有效成分的生理缓冲水溶液提供所述的吡啶羧酸胺衍生物或其异构体、药学上可接受的盐,用于肠胃外给药。某些典型剂量范围为约1μg/kg~约1g/kg体重/日。在某些实施方案中,剂量范围为约0.01mg/kg~约100mg/kg体重/日。剂量很可能取决于此类变量,如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推,得到有效剂量。
本发明的另一个目的是提供所述的药物组合物在制备PARP1抑制剂的应用,尤其是在制备治疗PARP1异常表达相关疾病的药物的应用。
所述的PARP1异常表达相关疾病为癌症、神经退行性疾病或缺血性疾病。
所述的癌症为乳腺癌、卵巢癌、肝癌、黑素瘤、前列腺癌、结肠癌或胃癌。
PARP1抑制剂单药对BRCA1/2突变的乳腺癌及卵巢癌细胞有明显抑制作用。若肿瘤细胞存在HR修复缺陷(如BRCA1/2突变),DSB将无法修复,即导致所谓的PARP1抑制剂和 HR修复缺陷对肿瘤细胞的合成致死作用。HR修复是个复杂的过程,许多基因和蛋白成分参与其中,包括ATM、ATR、CHK1、EMSY、PTEN、RAD51及其同系物如FANC蛋白、 MRE11、RAD50、NBS1等,BRCA1/2只是其中的重要成分之一。HR修复途径中的任一基因突变或表达沉默,即会引起HR修复途径缺陷,PARP1抑制剂即可能通过合成致死作用发挥抗肿瘤活性。另外,PARP1抑制剂还可作为放(化)疗增敏剂发挥抗肿瘤作用。许多化疗药物(如烷化剂、铂类、拓朴异构酶Ⅰ/Ⅱ抑制剂等)和放疗均通过直接或间接损伤DNA来发挥对肿瘤细胞的杀伤作用。由于PARP1在DNA损伤修复中起关键作用,可将PARP1抑制剂作为放(化)疗增敏剂与放(化)疗联用,增强抗肿瘤疗效。同时,还可因此减少放(化)疗用药或放射剂量,降低毒副作用。
与现有技术相比,本发明具备以下有益效果:
本发明吡啶羧酸胺衍生物吡啶羧酸胺衍生物或其异构体、可药用盐能选择性抑制PARP1活性,而不具有PARP2抑制活性,具有良好的成药前景,能应用于制备PARP1抑制剂,尤其是应用于制备治疗PARP1相关疾病的药物,特别是用于制备治疗PARP1异常表达相关肿瘤的药物。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。此外,下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
除非另有说明,本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照本领域普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
“卤”或“卤素”是指氟、氯、溴和碘。
“烷基”是指具有1至7个碳原子(C1-7烷基)或1至4个碳原子(C1-4烷基)的支链或直链的烃基。烷基的代表性的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、 2,3-二甲基戊基、正庚基等。
“卤代烷基”是指具有被一个或多个卤素取代取代的烷基。例如,“卤代烷基”包括单 -、二-和三氟甲基。
本发明所述的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
具体实施方式的化学反应是在合适的溶剂中完成的,所采用的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明所述的化合物,有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
在一些实施方案中,本发明所述的吡啶羧酸胺化合物可以由有机合成领域技术人员参考以下合成路线来制备:
X1,X2,X3,R1定义同前述,X4选自Cl、Br。
目标化合物采用硅胶柱层析进行分离纯化,洗脱剂的体系可以采用二氯甲烷和甲醇体系,溶剂的体积比根据目标化合物的极性不同进行调节。
本发明采用下述缩略词:DMF代表N,N-二甲基甲酰胺;DIPEA代表二异丙基乙胺。
实施例1
化合物1-c的制备方法:
在1000mL反应瓶中,加入化合物1-a(32g,138mmol)、化合物1-b(27g,145mmol)、碳酸铯(90g,278mmol)和1,4-二氧六环(300mL),氮气保护下,加入Ruphos Pd G3(4g,5mmol);搅拌,升温至110℃,反应6小时,冷却至室温,反应液减压蒸干,通过硅胶柱层析(二氯甲烷/甲醇洗脱)分离纯化,得到黄色固体(化合物1-c,26g,77mmol)。收率:55.8%。ESI- MS:m/z=422.32[M+H]+。
化合物1-d的制备方法:
在500mL反应瓶中,加入化合物1-c(18g,54mmol)和甲醇(100mL),搅拌溶解;再加入 40%甲氨水溶液(50mL,578mmol),室温搅拌反应4小时;反应液浓缩,向残余物中加入氯化铵水溶液和二氯甲烷,分层,水相用二氯甲烷萃取二次,合并有机相,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩得到黄色固体(化合物1-d,18g,收率:99.7%)。ESI- MS:m/z=336.32[M+H]+。
化合物1-e的制备方法:
在250mL反应瓶中,加入化合物1-d(18g,54mmol)和甲醇(25mL),搅拌;再加入氯化氢的1,4-二氧六环溶液(4M,75mL,300mmol),室温搅拌反应4小时;减压蒸除约80ml溶液,向残余物中加入异丙醚(100mL),搅拌,过滤,真空干燥得到化合物1-e(12.5g,收率: 100%)。ESI-MS:m/z=236.25[M+H]+。
化合物1的制备方法:
250mL反应瓶中,加入DMF(0.114mL,1.47mmol)、二氯甲烷(60mL)和化合物1-f(3g,14.69mmol,参考专利WO2021013735第15页lntermediate 12的制备方法制备得到化合物1-f),搅拌均匀,降温至0℃,滴加氯化亚砜(6.41mL,88.14mmol),滴毕,升至室温,继续搅拌反应6小时;反应液浓缩,向残余物中加入乙腈(50.00mL)、化合物1-e(4.31g,14.69mmol)和碘化钾(0.488g,2.94mmol),搅拌溶解;再加入DIPEA(12.83mL,73.45mmol),加热升温至80℃反应2小时;反应结束后,反应液减压蒸干,用水稀释,再用碳酸氢钠溶液调节pH值至9.0~10.0,乙酸乙酯萃取,无水硫酸钠干燥,浓缩得到粗品;通过硅胶柱层析(二氯甲烷/甲醇洗脱)纯化,得到化合物1(3.93g,收率:65.8%)。ESI-MS:m/z=422.32[M+H]+。
实施例2
用等摩尔量化合物2-a替代化合物1-a,使用“实施例1化合物1”同样的制备方法制备得到化合物2。ESI-MS:m/z=436.33[M+H]+。
实施例3
参考专利WO2009053373中第53页中intermediate4的制备方法得到化合物3-f。
在100mL反应瓶中,加入化合物3-f(1g,3.7mmol)、乙腈(20.00mL)、化合物1-e(0.9g, 3.7mmol),搅拌溶解,再加入碳酸钾(1.8g,13mmol),加热升温至80℃,反应3小时;反应结束后,反应液减压蒸干,用水稀释,乙酸乙酯萃取,无水硫酸钠干燥,浓缩得到粗品;通过硅胶柱层析(二氯甲烷/甲醇洗脱)纯化,得到化合物3。ESI-MS:m/z=421.33[M+H]+。
实施例4
用等摩尔量化合物2-e替代化合物1-e,使用“实施例3化合物3”同样的制备方法制备得到化合物4。ESI-MS:m/z=435.33[M+H]+。
实施例5
参考专利WO2021013735中第11页intermediate 6的制备方法得到化合物5-f。
用等摩尔量化合物5-f替代化合物3-f,使用“实施例3化合物3”同样的制备方法制备得到化合物5。ESI-MS:m/z=422.31[M+H]+。
实施例6
用等摩尔量化合物2-e替代化合物1-e,用化合物5-f替代化合物3-f,使用“实施例3 化合物3”同样的制备方法制备得到化合物6。ESI-MS:m/z=436.33[M+H]+。
实施例7
参考专利WO2021013735中第23页intermediate 30的制备方法得到化合物7-f。
用等摩尔量化合物7-f替代化合物3-f,使用“实施例3化合物3”同样的制备方法制备得到化合物7。ESI-MS:m/z=422.31[M+H]+。
实施例8
用等摩尔量化合物2-e替代化合物1-e,用化合物7-f替代化合物3-f,使用“实施例3 化合物3”同样的制备方法制备得到化合物8。ESI-MS:m/z=436.33[M+H]+。
实验例9
MDA-MB-436细胞增殖抑制活性测定
MDA-MB-436细胞用完全培养基(DMEM高糖含10%FBS、1×胰岛素-转铁蛋白-硒(ITS-G)、16μg/mL还原型谷胱甘肽)调整细胞密度至2×104个/mL,100μL/孔接种于96孔板,培养过夜加化合物,设置对照孔。细胞培养箱中继续培养7d后,10μL/孔加入CCK-8 检测试剂(同仁化学),细胞培养箱孵育约1小时后测450nm处吸光值,四参数分析,拟合量效曲线,计算IC50。
实验例10
PARP蛋白活性
方法详见BPS公司PARP1蛋白活性检测试剂盒(货号80551)说明书。简述如下:化合物组、阳性组和空白组。按50μL/孔在96孔板中加入1×组蛋白,4℃孵育过夜。200μL/孔加PBST缓冲液(含0.05%Tween-20)清洗3次,去除液体后每孔加入200μL封闭缓冲液3,室温封闭60-90min,去除封闭液,再用PBST缓冲液清洗3次,去除液体后每孔加入 25μLMaster Mix(含2.5μL 10×PARP缓冲液、2.5μL 10×含生物素化底物分析混合物、5μL5×活化DNA、15μL水),再加5μL/孔化合物或diluent solution。空白对照组加入20μL 1× PARP缓冲液,其他组加入20μL PARP1酶(0.33ng/μL),室温孵育1h后用200μL的PBST缓冲液清洗3次,去除液体后按50μL/孔加链霉亲和素-HRP(用封闭缓冲液3以1:50稀释),室温孵育30min。PBST洗三次,去除孔中液体,临用前在冰上按1:1混合ECL底物A和ECL 底物B,每孔加入100μL。检测化学发光值,四参数分析,拟合量效曲线,计算IC50。
实施例11
PARP1蛋白Trap活性测定
方法详见BPS公司PARPtrapTM检测试剂盒(货号78296-1)说明书。简述如下:设高FP组、低FP组、化合物组、对照组和空白组,提前配制Master Mix(由5×PARPtrapTM assaybuffer、25nM Fluorescent labeled DNA和水组成),在黑色384孔板每孔加入10μL MasterMix(空白组除外),2.5μL化合物(其余组加2.5μL Diluent solution),再加入10μl用 1×PARPtrapTM assay buffer制备的0.5ng/μL PARP1(对照组加入10μL 1×PARPtrapTM assaybuffer,空白组不加),空白组加15μL水和10μL 5×PARPtrapTM assay buffer,室温孵育60min 后加2.5μL 10×NAD+(高FP组加2.5μL水),再室温孵育60min。FP模块下检测480/530偏振值(FP),计算mP,mP=1000*(S-G*P)/(S+G*P):S表示垂直光荧光强度,P表示平行光荧光强度,G表示校正因子。四参数分析,拟合量效曲线,计算EC50。
Claims (10)
1.结构如通式I所示的吡啶羧酸胺衍生物或其异构体、药学上可接受的盐:
其中,X1选自N或CH;
X2、X3分别独立的选自N或C(R2),且X2、X3不能同时为N;
R1选自氢、卤素、C1-4烷基、C1-4卤代烷基;
R2选自氢或氟。
2.根据权利要求1所述的吡啶羧酸胺类化合物,其特征在于:R1选自氢或甲基。
3.根据权利要求1所述的吡啶羧酸胺类化合物,其特征在于:所述的吡啶羧酸胺类化合物选自以下化合物:
4.根据权利要求1所述的吡啶羧酸胺类化合物,其特征在于:所述的异构体为结构如通式I所示的吡啶羧酸胺类化合物的互变异构体、顺反异构体、对映异构体、非对映异构体及外消旋体;所述的对映异构体,包括(-)-和(+)-对映体、(R)-和(S)-对映体、(D)-异构体、(L)-异构体;取代基中存在的不对称碳原子。
5.一种权利要求1所述的的吡啶羧酸胺衍生物的制备方法,其特征在于:合成路线如下:
其中,X4选自Cl、Br。
6.权利要求1-4任一项所述的吡啶羧酸胺类化合物或其异构体、药学上可接受的盐在制备PARP1抑制剂的应用。
7.权利要求1-4任一项所述的吡啶羧酸胺类化合物或其异构体、药学上可接受的盐在制备治疗PARP1异常表达相关疾病的药物的应用。
8.根据权利要求7所述的应用,其特征在于:所述的PARP1异常表达相关疾病为癌症、神经退行性疾病或缺血性疾病;所述的癌症为乳腺癌、卵巢癌、肝癌、黑素瘤、前列腺癌、结肠癌或胃癌。
9.一种药物组合物,其特征在于:它是以权利要求1-4任一项所述的吡啶羧酸胺类化合物或其异构体、药学上可接受的盐为活性成分或主要活性成分,与药学上可接受的辅料制成的药学上可接受的剂型。
10.权利要求9所述的药物组合物在制备制备PARP1抑制剂的应用,优选在制备治疗PARP1异常表达相关疾病的药物的应用。
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