CN109280054A - 氘代3-奎宁环酮类化合物、制备方法及用途 - Google Patents
氘代3-奎宁环酮类化合物、制备方法及用途 Download PDFInfo
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- CN109280054A CN109280054A CN201710603970.4A CN201710603970A CN109280054A CN 109280054 A CN109280054 A CN 109280054A CN 201710603970 A CN201710603970 A CN 201710603970A CN 109280054 A CN109280054 A CN 109280054A
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Abstract
本发明涉及一类如下通式I所示的化合物及其药学上可接受的盐、异构体或其混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药、其制备方法及在药学上的应用，如对癌症、自身免疫性疾病等治疗上的应用。
Description
技术领域
本发明涉及一类氘代3-奎宁环酮类化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药、药物组合物、制备方法和治疗相关疾病的用途。
背景技术
癌症的高死亡率和对癌症的常规疗法的耐药性仍然是人类健康事业面临的主要挑战。目前新的治疗策略侧重于发现针对癌症特异性靶标的新的非化学疗法。p53基因是重要的抑癌基因，其在细胞周期调控、DNA修复、细胞凋亡等方面起着关键作用，并在至少50％的肿瘤中发现突变的p53基因，大多数通过诱导DNA损伤的化疗药物需要功能性p53来发挥其抗肿瘤作用，而通过突变或间接机制使p53失活增加了传统药物的耐药性，具有携带突变p53基因肿瘤的治疗是目前面临的一大挑战，因此p53成为抗肿瘤药的一个重要的靶点基因。
p53基因有野生型和突变型两种，野生型p53是人体内重要的抑癌基因，但是突变型p53分子构象发生改变并失去抑癌功能，而且还会抑制野生型p53的转录活性，使其失去对细胞生长的抑制作用，从而引起细胞异常繁殖并转化为恶性细胞，目前与p53基因突变密切相关的恶性肿瘤已有肝癌、胃癌、结肠癌、食管癌、肺癌、乳腺癌、淋巴癌、卵巢癌、宫颈癌等。目前以p53为靶点的药物主要几种作用方式，一是基因治疗，如药物Gendicine和Advexin；二是p53-MDM2作用机制，小分子药物干扰p53-MDM2复合物的合成，阻止p53蛋白泛素化讲解，如药物Idasanutlin、HDM-201和AMG-232等；三是突变p53蛋白构象的改变，小分子化合物通过共价键的方式与氨基酸进行结合，从而改变或修饰p53的结构，使其构象发生改变，恢复抑癌基因活性功能，如化合物APR-246/PRIMA-1MET，从化合物库中筛选出来，其在体内代谢成亚甲基奎宁酮MQ，成为Michael受体，通过半胱氨酸蛋白的硫醇基团加成结合，共价键修饰DNA，改变p53蛋白构象，从而激活转录活性，目前该化合物进入临床二期研究，用来治疗食管癌、前列腺癌、急性骨髓性白血病、卵巢癌和骨髓增生性肿瘤等。
APR-246为亚甲基奎宁酮的前药形式，APR-246在体内代谢成亚甲基奎宁酮。药物的药效合毒副作用与药物的药代动力学特性及其稳定性密切相关，通过氘代有可能改善药物的药代动力学，改善药物的稳定性和药物在体内的代谢，增加药效，降低剂量以及减少毒副作用。本发明提供一种新型的氘代的3-奎宁环酮类化合物，具有优异的药代性质和抗肿瘤活性。。
发明内容
本发明的目的是提供一类氘代3-奎宁环酮类化合物，其制备方法和用途。
第一方面，本发明涉及一种如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药；
式中，
R1选自氘代或非氘代的取代或未取代的、无支链或有支链、饱和或非饱和的C1-10烷基或C3-12环烷基、氘代或非氘代的取代或未取代的芳基；氘代或非氘代的取代或未取代的饱和或非饱和的杂环；-L1-L2，L1选自氘代或非氘代的取代或未取代C1-10烷基，L2选自氘代或非氘代的芳基或杂环，杂原子选自N、O、S或P；
R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R14各自独立地选自氢或氘：当R1基团不含氘原子时，R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R14中至少有一个为氘原子。
在本发明的一个优选例中，R1选自氘代或非氘代的取代或未取代的C1-10烷基，优选氘代或非氘代的取代或未取代的C1-6烷基。
在本发明的一个优选例中，R1选自-L1-L2，L1选自氘代的或非氘代的取代或未取代C1-6烷基，更优选氘代会非氘代的C1-3烷基，优选L2选自氘代或非氘代的芳基或杂环。
在本发明的一个优选例中，R1选自甲基，且R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R14中至少有一个为氘原子。
在本发明的一个优选例中，通式I具有以下式Ia结构式，
其中R1选自CH2D、CHD2或CD3。
在本发明的一个优选例中，所述化合物具有如下结构：
第二方面，本发明还提供一种制备通式I所示的化合物、其药学上可接受的盐、异构体或其混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药的方法，该方法包括：
原料氘代或非氘代的3-奎宁环酮在碱性条件下，同甲醛或氘代甲醛和氘代或非氘代的醇R1OH反应得到通式I化合物；通式I化合物的手性异构体可以通过手性柱分离制备或者化学拆分法制得。
其中R15和R16选自氢或氘原子，其它基团R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R14的定义如前文式I所定义；
提供的碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于六甲基二硅基氨基锂、六甲基二硅基氨基钠、六甲基二硅基氨基钾、二异丙基氨基锂、正丁基锂、仲丁基锂、三乙胺、吡啶、2，6-二甲基吡啶、N，N-二异丙基乙基胺、叔丁醇钾、叔丁醇钠、叔丁醇锂、四丁基氟化铵或N-甲基吗啡啉等。所述的无机碱类包括但不限于碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾、氢氧化锂、氟化铯、碳酸铯、碳酸锂、磷酸钾、氢化钠或氢化钾等。
第三方面，本发明涉及一种药物组合物，所述的药物组合物包括有效量的通式I的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药，以及药学上可接受的载体、稀释剂或赋形剂。
第四方面，本发明涉及第一方面所述的通式I的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药或第三方面所述的药物组合物在制备用于预防、缓解和/或治疗可通过P53突变相关疾病的药物中的应用。
本发明进一步，所述可通过P53突变相关疾病选自癌症、炎症性疾病、自身免疫性疾病、心血管疾病、心脏病、病毒感染等的药物。
本发明进一步，所述的癌症选自卵巢癌、前列腺癌、骨髓瘤(如：骨髓增生异常)、食管癌、胃癌、急性髓细胞样白血病、慢性骨髓单核细胞性白血病、急性或慢性白血病等。
第五方面，本发明通式I的化合物、其药学上可接受的盐、异构体或其混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药可以与另外一种或多种抗癌剂联合使用。
本发明进一步，所述的抗癌剂选自烷化剂、铂类药物、拓扑异构酶抑制剂、DNA甲基转移酶、脂质体、生物碱、抗体药物、激素抗癌剂、蛋白酶体抑制剂、HDAC抑制剂、CDK激酶抑制剂、VEGFR或EGFR抑制剂、m-TOR抑制剂、PI3K激酶抑制剂、B-Raf抑制剂、PARP抑制剂、c-Met激酶抑制剂、ALK激酶抑制剂、AKT抑制剂、ABL抑制剂、FLT3抑制剂、PD-1单抗、PD-L1单抗等。
第六方面，本发明涉及通式I的化合物、其药学上可接受的盐、异构体或其混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药在制备治疗癌症中的药物用途，其中所述的药物可以与另外一种或多种抗癌剂联合使用。
本发明进一步，所述的抗癌剂选自烷化剂(如：环磷酰胺、盐酸氮芥、二溴甘露醇、卡莫司汀、达卡巴嗪、美法仑等)、铂类药物(如：顺铂、卡铂、环硫铂、奈达铂、奥沙利铂、洛铂等)、拓扑异构酶抑制剂(如：拓扑替康、伊力替康、卢比替康、伊沙替康、勒托替康、吉马替康、二氟替康)、DNA/RNA合成抑制剂(如：5-Fluoracil，5-FU等)、DNA甲基转移酶(如：Azacitidine、Decitabine等)、脂质体(如：PLD等)、代谢拮抗剂(如：甲氨蝶呤、卡培他滨、培美曲塞等)、生物碱(如：多西他赛、紫杉醇、长春碱等)、抗体药物(如：曲妥单抗、帕曲妥单抗、贝伐单抗等)、激素抗癌剂(如：亮丙瑞林、度他雄胺、地塞米松等)、蛋白酶体抑制剂(硼砂佐米、艾莎佐米、来那度胺等)、CDK激酶抑制剂(palbociclib、ribociclib等)、VEGFR或EGFR抑制剂(如：阿法替尼、伊马替尼、吉非替尼、厄洛替尼等)、m-TOR抑制剂(如：依维莫司、西罗莫司等)、PI3K激酶抑制剂(如：艾拉利司等)、B-Raf抑制剂(如：索拉菲尼、维罗菲尼、瑞伐菲尼等)、其它PARP抑制剂(如：olaparib、niraparib等)、HDAC抑制剂(如：西达苯胺、帕比司他、伏立诺他等)c-Met激酶抑制剂(如：克唑替尼)、ALK激酶抑制剂(如：色瑞替尼、阿来替尼等)、AKT抑制剂(如：哌立福新等)、ABL抑制剂、FLT3抑制剂、PD-1单抗(如：Opdivo、Keytruda等)、PD-L1单抗(如：Atezolizumab)等。
发明详述
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义：
术语“烷基”是指饱和的脂肪族烃基团，包括1～20个碳原子的直链或支链基团。优选1～10个碳原子的烷基，更优选1～8个碳原子，非限制实施例包括但不限于：甲基、乙基、正丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、2-甲基丁基、3-甲基丁基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、正己基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2，3-二甲基丁基、3，3-二甲基丁基、1，1，2-三甲基丙基、1-乙基-2-甲基丙基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，2-二甲基戊基、2，3-二甲基戊基、2，4-二甲基戊基、3，3-二甲基戊基、3，4-二甲基戊基、2-乙基戊基、3-乙基戊基、幸基、壬基、癸基、十一烷基、十二烷基，以及它们的各种异构体等。烷基可以是取代的或未取代的，当被取代时可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个基团，独立地选自烷基、卤素、羟基、巯基、氰基、烯基、炔基、烷氧基、烷巯基、烷基氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷巯基、杂环烷巯基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基等。当“烷基”和其前缀在此处使用，都包含直链和支链的饱和碳键。
术语“环烷基”是指饱和或部分不饱和单环或多环环状取代基，包括3～20个碳原子，优选3～12个碳原子，更优选3～10个碳原子，最优选包括3～6个碳原子，单环环烷基的非限制实施例包括但不限于：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基等。多环环烷基的非限制实施例包括但不限于螺环、稠环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，所述取代基优选为一个或多个基团，独立地选自烷基、卤素、羟基、巯基、氰基、烯基、炔基、烷氧基、烷巯基、烷基氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷巯基、杂环烷巯基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基等。
术语“芳基”指任何稳定的6～18个碳原子的共轭烃环体系基团，优选6～10个碳原子，其可以为单环、双环、三环或更多环的芳香族基团，例如苯基、萘基和蒽等，所述芳基环可以稠合与杂芳基、杂环烷基或环烷基环上。芳基可以是取代或未取代的，当被取代时，所述取代基优选为一个或多个基团，独立地选自烷基、卤素、羟基、巯基、氰基、烯基、炔基、烷氧基、烷巯基、烷基氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷巯基、杂环烷巯基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基等。
术语“杂环”指单环、双环、三环或四环体系，包括稠和环体系、桥环体系或螺环体系，其中环上一个或多个原子独立任选地被杂原子所取代，杂原子选自氮、氧、硫、磷和硼等，环可以是完全饱和的或包含一个或多个不饱和度，但非芳香族类；其杂环基中的氮、碳、磷或硫原子可任选地被氧化；氮原子可任选地被季胺化；杂环体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。一个或多个环上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。杂环的实例包括但不限于：吡咯烷基、吡唑烷基、吗啉基、哌嗪基、哌啶基、硫代吗啉基、吡喃基、四氢吡喃基、咪唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、噻唑烷基、异噻唑烷基、异噁唑烷基、氮杂环丁烷基等。
术语“杂芳基”指至少1个环上的碳原子被选自N、O或S的杂原子置换所形成的芳香环体系，优选为5～7元单环结构或7～12元双环结构，更优选为5～6元杂芳基，例如吡咯基、咪唑基、吡啶基、嘧啶基、噻唑基、噻吩基、吡嗪基、三唑基、四唑基、噁唑基、吲唑基等，所述的杂芳基环可以稠合与芳基、杂环烷基或环烷基环上。杂芳基可以是取代或未取代的，当被取代时，所述取代基优选为一个或多个基团，独立地选自烷基、卤素、羟基、巯基、氰基、烯基、炔基、烷氧基、烷巯基、烷基氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷巯基、杂环烷巯基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基等。
“取代的”是指基团中的一个或多个氢或氘原子，优选为1～5个氢或氘原子彼此独立地被相应数目的取代基所取代。
“药学上可接受的盐”是指能够保留游离碱的生物有效性而无其它毒副作用的，它可以是酸性基团、碱性基团或两性基团，非限制实施例包括但不限于：酸性盐包括盐酸盐、氢溴酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、硝酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、甲酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、苯甲酸盐、甲基苯甲酸盐、邻苯二甲酸盐、马来酸盐、甲磺酸盐、对甲苯磺酸盐、苯磺酸盐、(D，L)-酒石酸、柠檬酸盐、马来-酸盐、(D，L-)苹果酸盐、富马酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、谷氨酸盐、天冬氨酸盐、三氟甲磺酸盐、扁桃体酸盐、抗败血酸盐、水杨酸盐等。当本发明化合物含有酸性基团是，其药学上可接受的盐还可以包括：碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如钙盐或镁盐)、有机碱盐(例如烷基芳香基氨类、氨基酸等)。
“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的聚集体(或缔合物)。形成的溶剂化物的溶剂包括，但不限于：水、二甲亚砜、甲醇、乙醇、异丙醇、乙酸等。
“多晶型物”是指本发明的化合物在固态状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相，它可以存在单一晶型或多晶型混合物。
“稳定的同位素衍生物”是指本发明的化合物任意的氢原子被1～5氘原子取代所得到的同位素取代衍生物、或任意的碳原子被1～3个C14原子取代所得到的同位素取代衍生物、或任意的氧原子被1～3个O18原子取代所得到的同位素衍生物。
“前药”表示可在生理学条件下(例如体内)或通过溶剂分解而被转化成本发明的生物活性化合物的化合物，可以理解为药学上可接受的代谢前体。前药可以为非活性物质或者比活性母体化合物活性小，但是可以在体内迅速转化产生本发明的母体化合物，可以改善其在动物体内的溶解度以及某些代谢特性，前药包括例如氨基保护基、羧基保护基、磷脂类等。
“药物组合物”是指含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其它化学组分的混合物，以及其它组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收而发挥生物活性。
“异构体”是指立体异构体，包括：对映异构体和非对映异构体，顺反异构体是非对映异构体的一种。本分明的化合物中的异构体可以是其对映异构体、非对映异构体以及它们的任意混合物，包括游离或成盐的形成存在。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参考IUPAC-IUBC Commission on BiochemicalNomenclature(参见Biochem.1972，11，942-944)。
具体实施方式
下面通过实施例进一步描述本说明，但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规方法和条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
本发明所有化合物的结构可通过核磁共振(NMR)或质谱(MS)来确定。NMR位移(δ)以10-6(ppm)的单位记录。NMR的测定仪器是Bruker AVANCE-400光谱仪进行。测试的氘代溶剂为氘代氯仿(CDCl3)、氘代甲醇(MeOD)、氘代二甲基亚砜(DMSO-D6)，内标为四甲基硅烷(TMS)。
低分辨率质谱(MS)是由Agilent 6120 quadruple LCMS质谱仪测定。
HPLC纯度的测定是由安捷伦高效液相色谱仪Agilent 1260/1220色谱仪(AgilentZorbax Bonus RP 3.5μm×4.6mm×150mm或Boston pHlex ODS 4.6mm×150mm×3μm或Sepax BR-C18(4.6mm x 150mm x3μm)
本发明化合物及其中间体的纯化可以使用常规的制备级HPLC、硅胶板、柱色谱或使用快速分离仪进行分离纯化。
薄层层析硅胶板使用烟台黄海、烟台新诺化工的HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是2.5x 5cm，0.2mm～0.25mm，薄层层析分离法(pre-TLC)纯化产品采用的的规格是1mm或者0.4mm～0.5mm，20x 20cm。
柱色谱(硅胶柱层析)一般使用的规格是100～200目或200～300目或300～400目。
快速分离仪使用的仪器型号是Agela Technologies MP200，色谱柱规格一般为Flash column silica-CS。
制备级HPLC(Pre-HPLC)使用的仪器是Gilson GX-281，柱子型号：Welch ultimateXB-C18 21.2mm X 250mm X 10μm。
手性测试柱的型号为CHIRALCEL OD-H、OJ-H或者CHIRALPAK AD-H、AS-H 4.6mm X250mm X 5μm，制备柱型号为CHIRALCEL OD-H、OJ-H或者CHIRALPAK AD-H、AS-H 10mm X250mm X 5μm，
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或从供应商sigma-Aldrich、ACROS、Alaf、TCI、百灵威、安耐吉化学、韶远化学、麦克林、思言化学等公司购买所得。
无水溶剂例如无水四氢呋喃、无水二氯甲烷、无水N，N-二甲基乙酰胺等都购自上述化学公司。
实施例中无特殊说明，反应一般是在氮气或氩气氛围中进行，氮气或氩气氛围是指反应瓶连接一个约1L容积大小的氮气或者氩气的气球并进行三次抽气置换。
实施例中无特殊说明，反应的温度为室温，温度为15～25℃。
实施例中的反应一般采用LCMS或者TLC进行监测，其中LCMS仪器见上所述，TLC所使用的展开剂体系一般为：二氯甲烷和甲醇、石油醚和乙酸乙酯、二氯甲烷和乙酸乙酯、石油醚和二氯甲烷、乙酸乙酯和甲醇等体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量(0.1％～10％)的碱(例如三乙胺或37％的氨水等)或酸(例如醋酸等)进行调节。
纯化化合物采用的prep-TLC、柱层析或者Agela制备体系，洗脱溶剂体系一般为：二氯甲烷和甲醇、石油醚和乙酸乙酯、二氯甲烷和乙酸乙酯、石油醚和二氯甲烷、乙酸乙酯和甲醇等体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量(0.1％～10％)的碱(例如三乙胺或37％的氨水等)或酸(例如醋酸等)进行调节。
实施例1：
消旋2-(羟甲基-D3)-2-(甲氧基甲基)奎宁环-3-酮
25℃下，将3-奎宁环酮盐酸盐(16.2g)、碳酸钾(16.0g)、37％甲醛(37.5mL，0.5mol)加入到氘代甲醇和水体系中，加热到95℃反应5h，将反应体系冷却至室温，用aq.NaOH调节pH至12～13，用二氯甲烷萃取，浓缩得粗品，柱层析纯化得消旋2-(羟甲基-D3)-2-(甲氧基甲基)奎宁环-3-酮，5.0g，收率25％。
MS(ESI)，m/z，203.1[M+H]+.
1H-NMR(400MHz，CDCl3)δ(ppm)3.96(t，J＝11.2Hz，1H)，3.86-3.76(m，3H)，3.37-3.27(m，2H)，3.04-2.89(m，3H)，2.41(p，J＝3.0Hz，1H)，2.13-1.94(m，4H).
实施例2：
2-(羟甲基-D3)-2-(甲氧基甲基)奎宁环-3-酮(对映异构体1)
将消旋体2-(羟甲基-D3)-2-(甲氧基甲基)奎宁环-3-酮用手性柱CHIRALPAK AS-H(10mm x 250mm，5μm)进行分离制备，得到手性2-(羟甲基-D3)-2-(甲氧基甲基)奎宁环-3-酮(对映异构体1)(ee＞98％)。
MS(ESI)，m/z，203.1[M+H]+.
1H-NMR(400MHz，CDCl3)δ(ppm)3.98(d，J＝11.8Hz，1H)，3.87-3.73(m，3H)，3.41-3.28(m，2H)，3.08-2.76(m，3H)，2.42(p，J＝3.0Hz，1H)，2.17-1.89(m，4H).
实施例3：
2-(羟甲基-D3)-2-(甲氧基甲基)奎宁环-3-酮(对映异构体2)
将消旋体2-(羟甲基-D3)-2-(甲氧基甲基)奎宁环-3-酮用手性柱CHIRALPAK AS-H(10mm x 250mm，5μm)进行分离制备，得到手性2-(羟甲基-D3)-2-(甲氧基甲基)奎宁环-3-酮(对映异构体2)(ee＞95％)。
MS(ESI)，m/z，203.1[M+H]+.
1H-NMR(400MHz，CDCl3)δ(ppm)3.99(d，J＝11.8Hz，1H)，3.89-3.71(m，3H)，3.44-3.23(m，2H)，3.10-2.75(m，3H)，2.47-2.36(m，1H)，2.19-1.96(m，4H).
实施例4：
消旋2-(羟甲基)-2-(甲氧基甲基)奎宁环-3-酮
25℃下，将3-奎宁环酮盐酸盐(50.0g)、碳酸钾(50.0g)、37％甲醛(105mL)混于甲醇和水体系中，加热到70℃反应5h，将反应体系冷却至室温，用aq.NaOH调节pH至12～13，二氯甲烷萃取，浓缩得粗品，柱层析纯化得消旋2-(羟甲基)-2-(甲氧基甲基)奎宁环-3-酮，24.0g，收率40％。
MS(ESI)，m/z，200.1[M+H]+
1H NMR(400MHz，CDCl3)δ(ppm)3.96(d，J＝11.8Hz，1H)，3.88-3.73(m，3H)，3.39(s，3H)，3.37-3.25(m，2H)，3.06-2.88(m，3H)，2.39(dd，J＝6.0，3.0Hz，1H)，2.10-1.94(m，4H).
实施例5：2-(羟甲基)-2-(甲氧基甲基)奎宁环-3-酮(对映异构体1)
将消旋体2-(羟甲基)-2-(甲氧基甲基)奎宁环-3-酮用手性柱CHIRALPAK AS-H(10mm x 250mm，5μm)进行分离制备，得到2-(羟甲基)-2-(甲氧基甲基)奎宁环-3-酮(对映异构体1)(ee＞98％)。
1H-NMR(400MHz，CDCl3)δ(ppm)3.98(d，J＝11.8Hz，1H)，3.88-3.75(m，3H)，3.41(s，3H)，3.33(ddd，J＝16.6，7.8，4.0Hz，2H)，3.06-2.84(m，3H)，2.42(p，J＝3.0Hz，1H)，2.15-1.91(m，4H).
实施例6：2-(羟甲基)-2-(甲氧基甲基)奎宁环-3-酮(对映异构体2)
将消旋体2-(羟甲基)-2-(甲氧基甲基)奎宁环-3-酮用手性柱CHIRALPAK AS-H(10mm x 250mm，5μm)进行分离制备，得到2-(羟甲基)-2-(甲氧基甲基)奎宁环-3-酮(对映异构体2)(ee＞95％)。
1H-NMR(400MHz，CDCl3)δ(ppm)3.97(d，J＝11.8Hz，1H)，3.88-3.74(m，3H)，3.44-3.36(m，3H)，3.38-3.27(m，2H)，3.05-2.82(m，3H)，2.40(dd，J＝6.0，3.0Hz，1H)，2.14-1.93(m，4H).
实施例7-23：
按照实施例1～6的合成方法并采用相应的起始原料，制备得到实施例7～23的化合物如下表格：
实验例25 H1299细胞增值活性测试
细胞增值活性通过以下的方法进行测试：
本实验中使用的材料和仪器：
RPMI1640(CORNING-CELLGRO，#10-041-CVR)
Fetal Bovine Serum(BIOSERA，#FB-1280)
CellTiter-Glo Luminescent Cell Viability Assay(Promega，#G7572)
96-well plate(Corning，#3788)
96-well plate(Corning，#3797)
96-well plate，black(Corning，#3904)
Backing Tape，white(PE，#6005199)
DMSO(Sigma，#D2650)
实验方法和步骤
第1天 细胞铺板
1.胰蛋白酶化并确定细胞密度；
2.以优化的密度将细胞浆液稀释至所需体积；
3.将90μl/孔的细胞浆液分配到测定板上；
4.在37℃、5％CO2和潮湿条件下细胞孵育24小时。
第2天 添加化合物
1.准备参考化合物，根据板图(终浓度200x)在100％DMSO溶液中进行测试；
2.转移5μl的化合物到95μl的中间板上(浓度10x)；
3.转移10μl的化合物到9测试板上(浓度1x)；
4.在37℃、5％CO2和潮湿条件下进行孵育。
第5天 成像
1.使用前室温平衡分析试剂30分钟；
2.添加5μl细胞titer-Glo试剂到每个孔板上并震荡10分钟促进胞溶；
的化合物到95μl的中间板上(浓度10x)；
3.孵化2分钟稳定发光信号；
4.在Envision上读取发光数据，间隔时间为0.5s。
数据处理
抑制率＝(Max signal-Compound signal)/(Max signal-Min signal)×100
本发明化合物的细胞增值活性通过以上的实验方法进行测定，测得化合物细胞抑制活性(IC50)见下表：+表示＞100μm，++表示50-100μm，+++表示10-50μm，++++表示1-10μm，+++++表示＜1μm。
实验结果表明，氘代化合物与非氘代化合物具有相近的抗肿瘤活性(实施例1相对于实施例4；实施例8相对于实施例7)。不同手性构型的氘代化合物对肿瘤细胞的抑制活性存在明显的差别(实施例3相对于实施例2；实施例10相对于实施例9；实施例15相对于实施例16；实施例19相对于实施例18)
实验例26大鼠药代动力学测定
1.实验摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定大鼠静注和灌胃给予实施例化合物后不同时刻血浆中的药物浓度，以研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1供试药品：
本发明实施例1、2、3、4、5、6、7、8、9、10、18、19化合物
2.2供试动物
健康成年雄性SD(Sprague-Dawley)大鼠，每个供试化合物各3只，6-9周龄，体重250±50g，购自上海斯莱克实验动物有限责任公司。
2.3供试药物配制
称取适量样品，加入0.5％甲基纤维素水溶液至终体积。
2.4供试药品给药
雄性SD大鼠每个供试化合物各三只，禁食一夜后给药，静注剂量为5mg/kg，灌胃剂量10mg/kg。
3.实验操作
在给药前和后0.083-24h不同时间点与大鼠经颈静脉穿刺取血，K2-EDTA抗凝，离心，取血浆，-70℃冷冻保存直至LC/MS/MS分析。
4.药代动力学数据结果
A：IV(5mg/kg)；B：PO(10mg/kg)
实验结果表明：
1)氘代化合物与非氘代化合物相比，氘代化合物的Cmax、AUC和F％(生物利用度)显著高于非氘代化合物(实施例1相对于实施例4；实施例8相对于实施例7)
2)拆分后的手性氘代化合物与拆分后的手性非氘代化合物相比，手性氘代化合物的Cmax、AUC和F％(生物利用度)显著高于手性非氘代化合物(实施例2相对于实施例5；实施例3相对于实施例6)
3)经过拆分后得到的两个手性的氘代化合物异构体在Cmax、AUC和F％(生物利用度)表现出非常显著的差别，其中一种构型的手性氘代化合物的口服AUC比其对映异构体的口服AUC高出一倍以上(实施例3相对于实施例2；实施例10相对于实施例9；实施例19相对于实施例18)，其中一种构型的手性异构体的生物利用度与其对映异构体的生物利用度相比存在明显差别(实施例3相对于实施例2；实施例10相对于实施例9；实施例19相对于实施例18)。
实施例27稳定性比较
注：溶剂：生理盐水；浓度：9mg/mL；pH：6.30；存放温度：4℃
实验结果表明，氘代化合物与非氘代化合物相比，氘代化合物的稳定性优于非氘代化合物(实施例1相对于实施例4；实施例8相对于实施例7)，而且手性的氘代化合物更加稳定(实施例2、实施例3相对于实施例1)。
Claims (12)
1.一种如通式I所示的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药：
式中，
R1选自氘代或非氘代的取代或未取代的、无支链或有支链、饱和或非饱和的C1-10烷基或C3-12环烷基、氘代或非氘代的取代或未取代的芳基；氘代或非氘代的取代或未取代的饱和或非饱和的杂环；-L1-L2，L1选自氘代或非氘代的取代或未取代C1-10烷基，L2选自氘代或非氘代的芳基或杂环，杂原子选自N、O、S或P；
R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R14各自独立地选自氢或氘；当R1基团不含氘原子时，R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R14中至少有一个为氘原子。
2.根据权利要求1所述的通式I所示的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于，R1选自氘代或非氘代的取代或未取代的C1-10烷基，优选氘代或非氘代的取代或未取代的C1-6烷基。
3.根据权利要求1所述的通式I所示的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于，R1选自-L1-L2，L1选自氘代的或非氘代的取代或未取代C1-6烷基，更优选氘代或非氘代的C1-3烷基，优选L2选自氘代或非氘代的芳基或杂环。
4.根据权利要求1所述的通式I所示的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于，R1选自甲基，且R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R14中至少有一个为氘原子。
5.根据权利要求1所述的通式I所示的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于，所述通式I为式Ia：
其中R1选自CH2D、CHD2或CD3。
6.根据权利要求1所述的通式I所示的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于，所述的化合物具有如下结构：
7.一种制备根据权利要求通式I所述的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药的方法，其特征在于，所述方法包括步骤：
氘代或非氘代的3-奎宁环酮在碱性条件下，同甲醛或氘代甲醛和氘代或非氘代的醇R1OH反应得到通式I化合物；通式I化合物的手性异构体可以通过手性柱分离制备或者化学拆分法制得。
其中R15和R16选自氢或氘原子，其它基团R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R14的定义如权利要求1中所定义。
8.一种药物组合物，所述的药物组合物包括有效量的根据权利要求1所述的通式I的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药，以及药学上可接受的载体、稀释剂或赋形剂。
9.根据权利要求1所述的通式I的化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药或权利要求8所述的药物组合物在制备用于预防、缓解和/或治疗可通过P53突变相关疾病的药物中的应用。
10.根据权利要求9所述的应用，其特征在于所述的可通过P53突变相关疾病选自癌症、炎症性疾病、自身免疫性疾病、心血管疾病、心脏病、病毒感染等的药物。
11.根据权利要求10所述的应用，其特征在于所述的癌症选自卵巢癌、前列腺癌、骨髓瘤、食管癌、胃癌、急性髓细胞样白血病、慢性骨髓单核细胞性白血病、急性或慢性白血病。
12.根据权利要求1所述化合物、其药学上可接受的盐、异构体或混合物、溶剂化物、多晶型物、稳定的同位素衍生物或前药与另外一种或多种抗癌剂联合使用的用途，其中所述的抗癌剂优选烷化剂、铂类药物、拓扑异构酶抑制剂、DNA/RNA合成抑制剂、DNA甲基转移酶、脂质体、生物碱、抗体药物、激素抗癌剂、蛋白酶体抑制剂、HDAC抑制剂、CDK激酶抑制剂、VEGFR或EGFR抑制剂、m-TOR抑制剂、PI3K激酶抑制剂、B-Raf抑制剂、PARP抑制剂、c-Met激酶抑制剂、ALK激酶抑制剂、AKT抑制剂、ABL抑制剂、FLT3抑制剂、PD-1单抗、PD-L1单抗。
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