CN105829317A - 咪唑并吡嗪酮衍生物 - Google Patents
咪唑并吡嗪酮衍生物 Download PDFInfo
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- CN105829317A CN105829317A CN201480070682.1A CN201480070682A CN105829317A CN 105829317 A CN105829317 A CN 105829317A CN 201480070682 A CN201480070682 A CN 201480070682A CN 105829317 A CN105829317 A CN 105829317A
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- pharmaceutically acceptable
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- salt
- stereoisomer
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Abstract
式(I)的化合物,其中R1和R2具有权利要求1中指示的含义,其为端锚聚合酶抑制剂,并且可尤其用于治疗诸如癌症、心血管疾病、中枢神经系统损伤和不同形式炎症的疾病。
Description
发明背景
本发明目的为发现具有有价值性质的新化合物,特别是可用于制备药物的那些化合物。
本发明涉及抑制端锚聚合酶(TANK)和聚(ADP-核糖)聚合酶PARP-1的活性的咪唑并吡嗪酮衍生物。因此,本发明的化合物用于治疗诸如癌症、多发性硬化、心血管疾病、中枢神经系统损伤和不同形式炎症的疾病。本发明也提供制备这些化合物的方法、包含这些化合物的药物组合物和用包含这些化合物的药物组合物治疗疾病的方法。
核酶聚(ADP-核糖)聚合酶-1(PARP-1)为PARP酶族的成员。该增长中的酶族由PARP(例如,PARP-1、PARP-2、PARP-3和Vault-PARP)和端锚聚合酶(TANK)(例如TANK-1和TANK-2)组成。PARP也称为聚(腺苷5'-二磷酸核糖)聚合酶或PARS(聚(ADP-核糖)合成酶)。
TANK-1似乎是有丝分裂纺锤体相关的聚(ADP-核糖)聚合所需的。TANK-1的聚(ADP-核糖基)化活性可能对纺锤体两极性的精确形成和维持至关重要。另外,TANK-1的PARP活性已显示是在分裂后期之前正常端粒分离所需的。干扰端锚聚合酶PARP活性导致异常有丝分裂,这造成可能由于纺锤体检查点活化导致的瞬时细胞周期停滞,随后细胞死亡。因此,预料抑制端锚聚合酶对增生肿瘤细胞具有细胞毒素作用(WO 2008/107478)。
PARP抑制剂由M. Rouleau等人描述于Nature Reviews, Volume 10, 293-301,clinical cancer studies(临床癌症研究)(表2, 第298页)。
根据Horvath和Szabo的综述(Drug News Perspect 20(3), 2007年4月, 171-181),最近研究证明,PARP抑制剂促进癌细胞死亡主要是因为它们在不同水平干扰DNA修复。更近的研究也已证明,PARP抑制剂通过抑制生长因子表达或通过抑制生长因子诱导的细胞增殖应答来抑制血管生成。这些发现也可能涉及PARP抑制剂的体内抗癌作用的模式。
Tentori等人的一项研究(Eur. J. Cancer, 2007, 43 (14) 2124-2133)也显示,PARP抑制剂中止VEGF或胎盘生长因子诱导的迁移,防止基于细胞的系统中形成小管状网络,并削弱体内血管生成。研究还显示,在PARP-1敲除小鼠中缺乏生长因子诱导的血管生成。研究结果提供靶向PARP抗血管生成的证据,对用PARP抑制剂治疗癌症增加新的治疗结论。
熟知保守信号传导途径中的缺陷在基本所有癌症的起源和行为中起关键作用(E.A.Fearon, Cancer Cell, Vol. 16, Issue 5, 2009, 366-368)。Wnt途径是抗癌治疗的靶。Wnt途径的关键特征是β-联蛋白通过β-联蛋白破坏复合体的调节蛋白水解(降解)。在降解过程中涉及如WTX、APC或Axin的蛋白。β-联蛋白适当降解对避免已在很多癌症中观察到的Wnt途径的不适当活化是重要的。端锚聚合酶抑制Axin活性,并因此抑制β-联蛋白降解。因此,端锚聚合酶抑制剂增加β-联蛋白降解。在Nature期刊中的一篇文章不仅对调节Wnt信号传导的蛋白提供重要的新见解,而且进一步支持拮抗β-联蛋白水平和通过小分子定位的途径(Huang等人, 2009; Nature, Vol 461, 614-620)。化合物XAV939抑制DLD-1癌细胞的生长。他们发现,XAV9393通过提高AXIN1和AXIN2蛋白的水平阻止β-联蛋白的Wnt刺激积累。作者随后的工作确立了XAV939通过抑制端锚聚合酶1和2(TNKS1和TNKS2)调节AXIN水平,两种酶均为聚(ADP-核糖)聚合酶(PARP)蛋白族的成员(S.J. Hsiao等人, Biochimie90, 2008, 83-92)。
已发现,本发明的化合物及其盐具有很有价值的药理学性质,同时良好耐受。
本发明特别涉及抑制端锚聚合酶1和2的式I的化合物,包含这些化合物的组合物,及其用于治疗TANK诱导疾病和病痛的方法。
此外,式I的化合物可用于分离和研究TANK的活性或表达。另外,它们特别适用于与未调节或干扰的TANK活性相关的疾病的诊断方法。
宿主或患者可属于任何哺乳动物种类,例如灵长类,特别是人;啮齿类,包括小鼠、大鼠和仓鼠;兔;马、母牛、狗、猫等。动物模型对试验研究有意义,提供治疗人疾病的模型。
特定细胞对用本发明化合物治疗的易感性可由体外检验确定。一般使细胞培养物与本发明的化合物以不同浓度结合,经足以使活性剂(例如,抗IgM)诱导细胞应答的时间,例如表面标记的表达,通常在约1小时和1星期之间。体外检验可用来自血液或来自活检样品的培养细胞进行。表达的表面标记的量用识别标记的特异抗体通过流式细胞术评估。
剂量取决于所用的具体化合物、具体疾病和患者状态等而变化。治疗剂量一般足以显著减少靶组织中不期望的细胞群体,同时保持患者的活力。治疗一般继续到显著减少已出现,例如,细胞负荷减少至少约50%,并且可继续到在身体中基本不再检测到不期望的细胞。
现有技术
E. Wahlberg等人, Nature Biotechnology (2012), 30(3), 283.
H. Bregman等人, Journal of Medicinal Chemistry (2013), 56(3), 1341
其它端锚聚合酶抑制剂描述于WO 2013/012723、WO 2013/010092、WO 2012/076898和WO 2013/008217。
WO2011/089400 (CNIO, Centro Nacional de Investigaciones Oncologicas )公开描述为中间体的经取代咪唑并吡嗪酮,例如,
。
Jpn. Kokai Tokkyo Koho (2005), JP 2005089352 A(语言:日语)描述制备咪唑并[1,5-a]吡嗪衍生物,包含它们的药物组合物及其用于预防或治疗蛋白酪氨酸激酶相关疾病的用途(由Mukoyama, Harunobu; Nishimura, Toshihiro; Nakayama, Akiko;Kikuchi, Shinji; Komatsu, Yoshimitsu; Onoda, Hideki)。
经取代咪唑并吡嗪酮作为中间体,例如
R = H, 4-Br, 2-OMe, 3-OMe, 4-OMe, 4-CN, 4-F
。
发明概述
本发明涉及式I的化合物及其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,
其中
R1表示H或甲基,
R2表示A或Het,
A表示具有1-8个C-原子的非支化或支化烷基,其中一个或二个非相邻CH-和/或CH2-基团可由N-或O-原子代替,和/或其中1-7个H-原子可由F或Cl代替,
Het表示嘧啶基、吡啶基、哒嗪基、吡嗪基、哌啶基、吡咯烷基、吡唑基、噻唑基、咪唑基、呋喃基、噻吩基、吡咯基、噁唑基、三唑基、噁二唑基或噻二唑基,各基团未取代或由Hal、A、CN、OH和/或OA单取代或二取代,
Hal表示F、Cl、Br或I,
其条件为如果R1为H,则R2不为4-OMe。
本发明也涉及这些化合物的光学活性形式(立体异构体)、对映异构体、外消旋体、非对映异构体和水化物和溶剂化物。
另外,本发明也涉及式I化合物的药学上可接受的衍生物。
术语“化合物的溶剂化物”应认为指由于其相互吸引力形成的惰性溶剂分子在化合物上的加合物。溶剂化物为例如一水化物或二水化物或醇化物。
应了解,本发明也涉及盐的溶剂化物。
术语“药学上可接受的衍生物”应认为指例如本发明的化合物的盐和所谓前药化合物。
如本文所用且除非另外指明,术语“前药”指可水解、氧化或以其它方式在生物条件(体外或体内)下反应以提供活性化合物(特别是式I的化合物)的式I化合物的衍生物。前药的实例包括但不限于式I化合物的衍生物和代谢物,包括生物可水解部分,例如,生物可水解酰胺、生物可水解酯、生物可水解氨基甲酸酯、生物可水解碳酸酯、生物可水解酰脲和生物可水解磷酸酯类似物。在某些实施方案中,具有羧基官能基的化合物的前药为羧酸的低级烷基酯。羧酸酯通过使分子上存在的任何羧酸部分酯化很方便地形成。前药一般可用熟知方法制备,例如Burger 's Medicinal Chemistry and Drug Discovery 6th ed.(Donald J. Abraham ed., 2001, Wiley)和Design and Application of Prodrugs(H.Bundgaard ed., 1985, Harwood Academic Publishers Gmfh)所述的那些方法。
表述“有效量”指引起例如研究人员或医师寻求或希望的组织、系统、动物或人的生物或医学反应的药物或药物活性成分的量。
另外,表述“治疗有效量”是指与未接受这种量的相应受试者比较,具有以下结果的量:改善治疗、治愈、预防或消除疾病、综合症、病症、病痛、紊乱或副作用或者也降低疾病、病痛或紊乱进展。
表述“治疗有效量”也包括有效提高正常生理功能的量。
本发明也涉及式I化合物的混合物的用途,例如,比例1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000的两种非对映异构体的混合物。
这些特别优选为立体异构体化合物的混合物。
“互变异构体”指相互平衡的化合物的异构形式。异构形式的浓度取决于在其中发现化合物的环境,并且可取决于例如化合物是否为固体或在有机或水溶液中而不同。
本发明涉及式I的化合物及其盐,还涉及制备式I的化合物及其药学上可接受的盐、溶剂化物、互变异构体和立体异构体的方法,其特征在于
使式II的化合物脱苄基,
其中R1和R2具有权利要求1中指示的含义,
和/或
使式I的碱或酸转化成其盐之一。
以上和以下基团R1和R2具有关于式I指示的含义,除非另外明确说明。
A表示烷基,该烷基为非支化(线性)或支化的,并且具有2、3、4、5、6、7或8个C原子。A优选表示乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,另外也表示戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,此外优选例如三氟甲基。A特别优选表示具有2、3、4、5或6个C原子的烷基,优选乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、三氟甲基、五氟乙基或1,1,1-三氟乙基。另外,A优选表示CH2OCH3、CH2CH2OH或CH2CH2OCH3。A也优选表示具有1-8个C-原子的非支化或支化烷基,其中一个或二个非相邻CH2-基团可由O-原子代替,和/或其中1-3个H-原子可由F代替。
Het优选表示嘧啶基、吡啶基、哒嗪基、吡嗪基、哌啶基、吡咯烷基、吡唑基、噻唑基、咪唑基、呋喃基、噻吩基、吡咯基、噁唑基、三唑基、噁二唑基或噻二唑基,各基团未取代或由A单取代。
在整个本发明中,多于一次出现的所有基团可相同或不同,即,相互独立。
式I的化合物可具有一个或多个手性中心,因此可以不同的立体异构形式存在。式I包括所有这些形式。
因此,本发明特别涉及式I的化合物及其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中至少一个所述基团具有以上所示优选含义之一。化合物的一些优选基团可由以下子式Ia至Id表示,它符合式I,且其中未更详细指定的基团具有关于式I指示的含义,但其中
在Ia中,A表示具有1-8个C-原子的非支化或支化烷基,其中一个或二个非相邻CH2-基团可由O-原子代替,和/或其中1-3个H-原子可由F代替;
在Ib中,Het表示嘧啶基、吡啶基、哒嗪基、吡嗪基、哌啶基、吡咯烷基、吡唑基、噻唑基、咪唑基、呋喃基、噻吩基、吡咯基、噁唑基、三唑基、噁二唑基或噻二唑基,各基团未取代或由A单取代;
在Ic中,R1表示H或甲基,
R2表示A或Het,
A表示具有1-8个C-原子的非支化或支化烷基,其中一个或二个非相邻CH2-基团可由O-原子代替,和/或其中1-3个H-原子可由F代替,
Het表示嘧啶基、吡啶基、哒嗪基、吡嗪基、哌啶基、吡咯烷基、吡唑基、噻唑基、咪唑基、呋喃基、噻吩基、吡咯基、噁唑基、三唑基、噁二唑基或噻二唑基,各基团未取代或由A单取代。
另外,式I的化合物及其制备原料通过本身已知的方法制备,如文献中所述(例如,标准著作,如Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry](有机化学方法), Georg-Thieme-Verlag, Stuttgart),确切地讲,在已知且适用于所述反应的反应条件下。也可利用在此未详述的本身已知的变化。
式II的起始化合物一般已知。然而,如果它们是新的,则可通过本身已知的方法制备。
式I的化合物可优选通过式II的化合物脱苄基获得。
反应一般在咪唑存在下进行。
根据所用条件,反应时间在数分钟和14天之间,反应温度在约60°和250°之间,一般在80°和200°之间,具体地讲,在约100°和约180°之间。
优选在没有溶剂存在下进行反应。
药物盐和其它形式
依据本发明的所述化合物可以其最终的非盐形式使用。另一方面,本发明也包括这些化合物以其药学上可接受的盐形式的用途,所述盐可通过本领域已知的程序衍生自各种有机和无机酸和碱。式I化合物的药学上可接受的盐形式大部分通过常规的方法制备。如果式I化合物含有羧基,其合适的盐之一可通过化合物与合适的碱反应以得到相应的碱-加成盐来形成。这样的碱为例如碱金属氢氧化物,包括氢氧化钾、氧化钠和氢氧化锂;碱土金属氢氧化物,例如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;和各种有机碱,例如哌啶、二乙醇胺和N-甲基葡糖胺。同样包括式I化合物的铝盐。在某些式I化合物的情况下,酸加成盐可通过用以下物质处理这些化合物而形成:药学上可接受的有机和无机酸,例如氢卤酸,例如盐酸、氢溴酸或氢碘酸;其它矿物酸及其对应的盐,例如硫酸盐、硝酸盐或磷酸盐等;和烷基磺酸盐和单芳基磺酸盐,例如乙烷磺酸盐、甲苯磺酸盐和苯磺酸盐;和其它有机酸及其对应的盐,例如乙酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此,式I化合物的药学上可接受的酸加成盐包括以下:乙酸盐、己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate)、亚硫酸盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯代苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、甲酸盐、半乳糖酸盐(galacterate) (得自粘酸)、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙烷磺酸盐、碘化物、羟乙基磺酸盐(isethionate)、异丁酸盐、乳酸盐、乳糖醛酸盐(lactobionate)、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲烷磺酸盐、甲基苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、棕榈酸盐(palmoate)、果胶酸盐(pectinate)、过硫酸盐、苯乙酸盐、3-苯丙酸盐、磷酸盐、膦酸盐、酞酸盐,但这不表示限制。
此外,依据本发明的化合物的碱盐包括铝、铵、钙、铜、铁(III)、铁(II)、锂、镁、锰(III)、锰(II)、钾、钠和锌盐,但这并不意图表示限制。在上述盐中,优选铵;碱金属钠盐和钾盐,和碱土金属钙盐和镁盐。由药学上可接受的有机无毒碱衍生的式I化合物的盐包括以下物质的盐:伯胺、仲胺和叔胺、取代胺,也包括天然存在的取代胺、环胺,和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、N,N'-二苄基乙二胺(苄星)、二环己胺、二乙醇胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡糖、组胺酸、海巴明、异丙基胺、利多卡因、赖氨酸、甲葡胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟甲基)-甲基胺(氨丁三醇),但这并不意图表示限制。
含有碱性含氮基团的本发明化合物可使用以下试剂季铵化:例如(C1 C4)烷基卤化物,例如甲基、乙基、异丙基和叔丁基的氯化物、溴化物和碘化物;二(C1-C4)烷基硫酸盐,例如二甲基、二乙基和二戊基硫酸盐;(C10-C18)烷基卤化物,例如癸基、十二烷基、月桂基、肉豆蔻基和十六烷基的氯化物、溴化物和碘化物;和芳基(C1-C4)烷基卤化物,例如苄基氯和苯乙基溴。依据本发明的水溶性和油溶性化合物两者可使用这样的盐制备。
优选的以上提及的药物盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙基磺酸盐、扁桃酸盐、甲葡胺、硝酸盐、油酸盐、膦酸盐、三甲基乙酸盐、磷酸钠、硬脂酸盐、硫酸盐、碱式水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这并不意图表示限制。
特别优选使用盐酸盐、二盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、磷酸盐、硫酸盐和琥珀酸盐。
碱性式I化合物的酸加成盐通过使游离碱形式与足够量的所需酸接触,以常规方式导致盐形成来制备。游离碱可通过使盐形式与碱接触并以常规方式分离游离碱来再生。游离碱形式在某些方面(关于某些物理特性,例如在极性溶剂中的溶解度)不同于对应的其盐形式;然而,为了本发明的目的,所述盐另外地对应于其相应的游离碱形式。
如已提及的,式I化合物的药学上可接受的碱加成盐用金属或胺形成,例如碱金属和碱土金属或有机胺。优选的金属是钠、钾、镁和钙。优选的有机胺是N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N 甲基-D-葡糖胺和普鲁卡因。
依据本发明的酸性化合物的碱加成盐通过使游离酸形式与足够量的所需碱接触,以常规方式导致盐的形成来制备。游离酸可通过使盐形式与酸接触并以常规方式分离游离酸来再生。游离酸形式在某些方面(关于某些物理特性,例如在极性溶剂中的溶解度)不同于对应的其盐形式;然而,为了本发明的目的,所述盐另外地对应于其相应的游离酸形式。
如果依据本发明的化合物含有一个以上的能够形成这种类型的药学上可接受的盐的基团,则本发明也涵盖多盐。典型的多盐形式包括,例如,酒石酸二盐(bitartrate)、二乙酸盐、富马酸二盐(difumarate)、二甲葡胺、二磷酸盐、二钠和三盐酸盐,但这并不意图表示限制。
关于以上所述,可以见到,在本文中采用表述"药学上可接受的盐”意指活性成分,其包括形式为其盐中的一种的式I化合物,特别是如果与游离形式的活性成分或较早使用的活性成分的任何其它盐形式比较,这种盐形式赋予所述活性成分改进的药代动力学特性。活性成分的药学上可接受的盐形式也可首次提供具有所需药代动力学特性的这种活性成分,所述药代动力学特性是其早先没有的并可甚至对这种活性成分关于其在体内的治疗效果的药效学具有正面的影响。
同位素
此外,预期使式I化合物包括其同位素-标记的形式。同位素-标记形式的式I化合物与这种化合物是相同的,但除了以下事实:化合物的一个或多个原子已被具有不同于通常天然存在的原子的原子质量或质量数的原子质量或质量数的一个或多个原子替代。可容易经市售获得的和可通过熟知的方法结合到式I化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别为例如2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36CI。预期含有一个或多个上述同位素和/或其它原子的其它同位素的式I化合物、其前药,或药学上可接受的盐为本发明的一部分。同位素-标记的式I化合物可以许多有益的方式使用。已掺入例如放射性同位素(例如3H或14C)的同位素-标记的式I化合物适用于药物和/或底物组织分布测定。这些放射性同位素,即氚(3H)和碳-14 (14C),由于制备简单和优良的可检测性而为特别优选的。较重的同位素,例如氘(2H),结合到式I化合物中,由于这种同位素-标记的化合物的较高代谢稳定性而具有治疗优势。较高的代谢稳定性直接转化为增加的体内半衰期或较低的剂量,其在大多数情况下将代表本发明的优选实施方案。同位素-标记的式I化合物通常可通过进行在合成方案和相关描述中、在本文的实施例部分和在制备部分中公开的程序,用可容易获得的同位素-标记的反应物替代非同位素-标记的反应物来制备。
氘(2H)也可掺入式I化合物中,目的是为了通过初级动力学同位素作用而操控化合物的氧化代谢。初级动力学同位素作用是改变由同位素核的交换引起的化学反应的速率,同位素核的交换转而通过在这种同位素交换后共价键形成所必需的基态能量变化而引起。较重同位素的交换通常导致化学键的基态能量的降低并因此引起速率限制性断键(rate-limiting bond breakage)的速率下降。如果键结断裂发生在沿着多产物反应坐标的鞍点区或鞍点区附近,则产物分配率可基本改变。为了解释:如果氘在非可交换的位置结合于碳原子,则kM/kD = 2-7的比率差分(rate differences)是典型的。如果这种比率差分成功应用于易受氧化作用影响的式I化合物,则这种化合物体内的分布可被极大的改变并导致改进的药代动力学特性。
当发现和开发治疗剂时,本领域技术人员试图使药代动力学参数最优化,同时保留所需的体外特性。合理的是假定许多具有不良药代动力学特性的化合物易受氧化代谢的影响。目前可获得的体外肝微粒体测定提供关于这种类型氧化代谢的过程的有价值的信息,其进而允许合理的设计具有通过抵抗这样的氧化代谢而具有改进稳定性的氘化式I化合物。由此获得式I化合物的药代动力学特性中的重大改进,并可根据体内半衰期(t/2)的增加、在最大疗效的浓度(Cmax)、剂量应答曲线(AUC)下的面积和F,并根据减少的清除率、剂量和材料成本进行定量表示。
以下旨在说明上文:具有受氧化代谢攻击的多个潜在位点(例如苯甲型氢原子和键结于氮原子的氢原子)的式I化合物经制备为一系列类似物,其中氢原子的多种组合被氘原子替代,以使这些氢原子中的一些、大多数或全部已被氘原子替代。半衰期测定能够有利和精确地测定抵抗氧化代谢改进的改进程度。这样,由于这种类型的氘-氢交换,确定母化合物的半衰期可延长最多至100%。
式I化合物中的氘-氢交换也可用于实现起始化合物的代谢谱的有利改善,以减少或消除不期望的毒性代谢物。例如,如果毒性代谢物通过氧化性碳-氢(C-H)键断裂而产生,则可合理地假定氘化类似物将极大地减少或消除不需要的代谢物的产生,即使特殊的氧化不是速控步骤。更多的关于涉及氘-氢交换的技术发展现状的信息可见于例如Hanzlik等,J. Org. Chem. 55, 3992-3997, 1990, Reider等, J. Org. Chem. 52, 3326-3334,1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette等, Biochemistry 33(10)2927-2937, 1994,和Jarman等. Carcinogenesis 16(4), 683-688, 1993。
本发明还涉及药物,该药物包含至少一种式I化合物和/或其药学上可接受的衍生物、溶剂化体和立体异构体,包括它们按所有比例的混合物,和任选的赋形剂和/或辅助剂。
药物制剂可以每剂量单位包含预定量的活性成分的剂量单位形式给药。这样的单位可包含,例如0.5 mg-1 g,优选1 mg-700 mg,特别优选5 mg-100 mg的依据本发明的化合物,这取决于所治疗的病症、给药方法和患者的年龄、体重和身体状况,或者药物制剂可以剂量单位形式给药,该计量单位包含预定量的活性成分/剂量单位。优选的剂量单位制剂为包含日剂量或如上指明的部分剂量,或其活性成分对应部分的那些制剂。此外,这种类型的药物制剂可使用制药领域通常已知的方法制备。
药物制剂可适合于经由任何期望的合适方法,例如通过口服(包括颊下或舌下)、直肠、鼻、局部(包括颊下、舌下或透皮)、阴道或胃肠外(包括皮下、肌内、静脉内或皮内)方法给药。这样的制剂可使用制药领域已知的所有方法,通过例如使活性成分与赋形剂或辅助剂组合来制备。
适合于口服给药的药物制剂可作为分开的单位,例如胶囊或片剂;散剂或颗粒剂;在水性或非-水性液体中的溶液剂或混悬剂;可食用泡沫剂或发泡食物;或水包油液体乳剂或油包水液体乳剂给药。
因此,例如,在以片剂或胶囊的形式口服给药的情况下,活性成分组分可与口服的、非毒性的和药学上可接受的惰性赋形剂,例如像乙醇、甘油、水等结合。散剂通过将化合物粉碎为合适的细尺寸并使其与以类似的方法粉碎的药物赋形剂(例如可食用碳水化合物,例如像淀粉或甘露醇)混合来制备。同样可存在矫味剂、防腐剂、分散剂和染料。
胶囊通过制备如上所述的粉末混合物并用其填充成形的明胶壳来制备。助流剂和润滑剂,例如,诸如高分散性硅酸、滑石粉、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇,可加入到粉末混合物中,然后进行填充操作。同样可加入崩解剂或增溶剂,例如,像琼脂、碳酸钙或碳酸钠,以改进胶囊被摄取后药物的可利用度。
此外,如果需要或必要,可同样将合适的粘合剂、润滑剂和崩解剂以及染料掺入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖(例如葡萄糖或β-乳糖)、由玉米制得的甜味剂、天然和合成橡胶(例如像阿拉伯胶、黄蓍胶或藻酸钠)、羧甲基纤维素、聚乙二醇、蜡等。用于这些剂型的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括,但不限于,淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。片剂通过以下配制:例如制备粉末混合物,将该混合物制粒或干压,加入润滑剂和崩解剂并压制整个混合物以得到片剂。粉末混合物通过将以合适的方式粉碎的化合物与如上所述的稀释剂或基质,和任选与粘合剂(例如像羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮)、溶解阻滞剂例如像石蜡,吸收促进剂例如像季胺盐,和/或吸收剂(例如像膨润土、高岭土或磷酸二钙)混合来制备。粉末混合物可通过将其用粘合剂例如糖浆、淀粉糊、阿拉伯胶或纤维素或聚合物材料的溶液湿润并将其压过筛来制粒。作为对制粒的备选方案,可使粉末混合物通过压片机,得到不均匀形状的块状物,将其破碎以形成颗粒。颗粒可通过加入硬脂酸、硬脂酸盐、滑石粉或矿物油进行润滑,以防止粘附在片剂铸模上。然后压制经润滑的混合物,得到片剂。依据本发明的化合物也可与自由流动的惰性赋形剂组合,然后无需进行制粒或干压步骤而直接压制,得到片剂。可存在由虫胶密封层、糖或聚合物材料层和蜡的光泽层组成的透明或不透明的保护层。可将染料加入到这些包衣料中,以便能够在不同的剂量单位之间进行区分。
口服液体,例如,诸如溶液、糖浆和酏剂,可以剂量单位的形式制备,以使给定的量包含预定量的化合物。糖浆剂可通过将化合物溶于含合适的矫味剂的水性溶液中制备,而酏剂使用无毒的醇性媒介物制备。混悬剂可通过将化合物分散于无毒的媒介物中来配制。同样可加入增溶剂和乳化剂,例如,诸如乙氧基化异硬脂醇和聚氧乙烯山梨醇醚、防腐剂、香料添加剂,例如薄荷油或天然甜味剂或糖精,或其它人工甜味剂等。
如果需要,可将供口服给药的剂量单位制剂封装到微囊中。也可以一定方式来制备所述制剂,例如,诸如通过将颗粒原料包衣或包埋在聚合物、蜡等中,使得延长或延迟释放。
式I化合物及其药物盐、互变异构体和立体异构体也可以脂质体传递系统的形式给药,例如像小单层囊泡、大单层囊泡和多层囊泡。脂质体可由多种磷脂,例如像胆固醇、硬脂胺或卵磷脂形成。
式I化合物及其盐、互变异构体和立体异构体也可使用作为化合物分子偶联的单个载体的单克隆抗体来传递。化合物也可偶联于作为靶向药物载体的可溶性聚合物。这样的聚合物可以包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰氨基苯酚、聚羟乙基天门冬氨酰基苯酚或聚氧化乙烯聚赖氨酸(被棕榈酰基取代)。化合物可以进一步偶合于一类可生物降解的聚合物,其适合于实现药物的控制释放,所述聚合物有例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯和水凝胶的交联或芳脂族嵌段共聚物。
适于经皮给药的药物制剂可以作为与接受者的表皮长期、紧密接触的独立糊剂来给药。因此,例如,活性成分可以通过离子电渗疗法(如Pharmaceutical Research,3(6),318 (1986)的通用术语中所述),由该糊剂来传递。
适于局部给药的药物化合物可以被配制成软膏、乳膏、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶、喷雾剂、气雾剂或油。
对于眼睛或其它外部组织例如口腔和皮肤的治疗而言,所述制剂优选作为局部软膏或乳膏施用。在给药软膏制剂的情况中,活性成分可以与石蜡或者水可混溶的乳膏基质一起使用。或者,可以将活性成分用水包油乳膏基质或油包水基质配制而得到乳膏。
适于局部施用于眼睛的药物制剂包括滴眼剂,其中活性成分被溶解或混悬于适宜的载体,特别是水性溶剂中。
适于局部施用于口腔的药物制剂包括锭剂、软锭剂和漱口剂。
适于直肠给药的药物制剂可以按栓剂或灌肠剂的形式给药。
其中所述载体物质为固体的适于鼻给药的药物制剂包含粒径为例如范围在20-500微米的粗粉末,其以用鼻吸入的方式给药,即通过经由鼻道从举到鼻子附近的包含所述粉末的容器中快速吸入来给药。用于以具有作为载体物质的液体的鼻喷雾或滴鼻剂给药的适宜制剂包含在水或油中的活性成分溶液。
适于通过吸入进行给药的药物制剂包含细颗粒粉尘或雾,其可以通过各种类型的具有气雾剂的加压分配器、喷雾器或吸入器来产生。
适于阴道给药的药物制剂可以作为阴道栓、棉塞、乳膏、凝胶、糊剂、泡沫剂或喷雾制剂给药。
适于胃肠外给药的药物制剂包括水性或非水性无菌注射溶液,其包含抗氧化剂、缓冲剂、抑菌剂和使制剂与待治疗的接受者的血液等渗的溶质;和可包含混悬介质和增稠剂的水性和非水性无菌混悬液。该制剂可以按单剂量或多剂量容器(例如密封安瓿和瓶)给药,并且以冷冻干燥(冻干)状态储存,从而使得必需在临用前即刻仅加入无菌的液体载体,例如注射用水。根据处方制备的注射溶液和混悬液可以由无菌的粉末、颗粒和片剂来制备。
不言而喻,除上面特别提及的组分外,对特定类型的制剂而言,所述制剂还可包含本领域中常用的其它剂;因此,例如适于口服给药的制剂可包含矫味剂。
式I化合物的治疗有效量取决于许多因素,包括例如动物的年龄和体重、需要治疗的准确病情及其严重性、制剂的性质和给药方法,并且最终由进行治疗的医生或兽医确定。然而,依据本发明的化合物的有效量通常在每天0.1至100mg/kg接受者(哺乳动物)体重的范围内,并且特别典型地在每天1至10mg/kg体重的范围内。因此,对体重为70kg的成年哺乳动物而言,每天的实际数量通常为70至700mg,其中该量每天可以作为单剂量给药或者通常按每天一系列部分剂量(例如像两份、三份、四份、五份或六份)给药,从而使得总的日剂量相同。盐或溶剂化物或其生理学上的官能衍生物的有效量可以作为依据本发明的化合物本身有效量的分数来确定。可以推定相似的剂量也适用于治疗上述的其它病症。
可通过同时、连续或分开分配单独治疗组分实现此类型的组合治疗。此类型的组合产品利用本发明的化合物。
本发明还涉及药物,该药物包含至少一种式I化合物和/或其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,和至少一种另外的药物活性成分。
本发明也涉及药物套装(试剂盒),其由以下分开的包组成:
(a) 有效量的式I化合物和/或其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,
和
(b) 有效量的另外的药物活性成分。
药物套装包含合适的容器,例如盒、单个瓶、袋或安瓿。药物套装可例如包含分开的安瓿,每个安瓿含有有效量的式I化合物和/或其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,
和溶解或冻干形式的有效量的另外的药物活性成分。
本文所用“治疗”是指完全或部分缓解与紊乱或疾病相关的症状、减缓或终止那些症状进一步发展或恶化、防止或预防受试者的疾病或紊乱处于疾病或紊乱发展风险。
与式(I)化合物相关的术语“有效量”可以指能够完全或部分缓解与紊乱或疾病相关的症状、减缓或终止那些症状进一步发展或恶化、防止或预防受试者的疾病或紊乱具有或处于本文所述疾病(例如,炎性疾病、免疫疾病、癌症或代谢疾病)发展风险的量。
在一个实施方案中,式(I)化合物的有效量为例如体外或体内抑制细胞中端锚聚合酶的量。在一些实施方案中,与未处理细胞中端锚聚合酶的活性比较,式(I)化合物的有效量抑制细胞中端锚聚合酶10%、20%、30%、40%、50%、60%、70%、80%、90%或99%。例如,在药物组合物中式(I)化合物的有效量可以为发挥所需效果的水平,例如,对于口服和胃肠外给药二者,在单位剂量中为约0.005mg/kg受试者体重至约10mg/kg受试者体重。
用途
本发明的化合物适合作为药物活性成分用于治疗哺乳动物(尤其是人)的癌症、多发性硬化、心血管疾病、中枢神经系统损伤和不同形式的炎症。
本发明包括式I的化合物和/或其药学上可接受的盐、互变异构体和立体异构体用于制备治疗或预防癌症、多发性硬化、心血管疾病、中枢神经系统损伤和不同形式炎症的药物的用途。
炎性疾病的实例包括类风湿性关节炎、牛皮癣、接触皮炎、延迟过敏反应等。
本发明也包括式I的化合物和/或其药学上可接受的盐、互变异构体和立体异构体用于制备治疗或预防哺乳动物的端锚聚合酶诱导疾病或端锚聚合酶诱导病症的药物的用途,其中对于此方法,向需要这种治疗的患病哺乳动物给药治疗有效量本发明的化合物。治疗量根据特定疾病改变,并且可由本领域的技术人员不太费力地决定。
表述“端锚聚合酶诱导疾病或病症”是指取决于一种或多种端锚聚合酶的活性的病理疾病。与端锚聚合酶活性相关的疾病包括癌症、多发性硬化、心血管疾病、中枢神经系统损伤和不同形式的炎症。
本发明特别涉及式I的化合物及其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,用于治疗其中抑制、控制和/或调节抑制端锚聚合酶起作用的疾病。
本发明特别涉及式I的化合物及其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,用于抑制端锚聚合酶。
本发明特别涉及式I的化合物及其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,用于治疗癌症、多发性硬化、心血管疾病、中枢神经系统损伤和不同形式炎症。
本发明特别涉及治疗或预防癌症、多发性硬化、心血管疾病、中枢神经系统损伤和不同形式炎症的方法,所述方法包括向需要的受试者给药有效量的式I的化合物或其药学上可接受的盐、互变异构体、立体异构体或溶剂化物。
式I化合物可用于治疗或预防的代表性癌症包括但不限于头、颈、眼、口、咽喉、食道、支气管、喉、咽、胸、骨、肺、结肠、直肠、胃、前列腺、膀胱、子宫、宫颈、乳房、卵巢、睾丸或其它生殖器官、皮肤、甲状腺、血液、淋巴结、肾、肝、胰、脑、中枢神经系统的癌症,实体瘤和血源性瘤。
式I化合物可用于治疗或预防的代表性心血管疾病包括但不限于再狭窄、动脉粥样硬化及其后果(例如,中风)、心肌梗塞、对心、肺、肠、肾、肝、胰、脾或脑的缺血性损伤。
本发明涉及一种治疗增生、自身免疫、抗炎或感染疾病的方法,所述方法包括向需要的受试者给药治疗有效量的式I的化合物。
本发明优选涉及其中疾病为癌症的方法。
本发明特别优选涉及其中疾病为癌症的方法,其中给药与至少一种其它活性药剂的给药同时、相继或交替。
公开的式I的化合物可与其它已知治疗剂组合给药,包括抗癌剂。本文所用术语“抗癌剂”是指向癌症患者给药用于治疗癌症的任何剂。
以上限定的抗癌治疗可用作单治疗,或者,除了本文公开的式I的化合物外,可包括常规手术或放射治疗或药物治疗。这种药物治疗,例如化疗或靶向治疗,可包括一种或多种但优选一种以下抗癌剂:
烷化剂
例如,六甲蜜胺、苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、氮芥、环磷酰胺、达卡巴嗪、异环磷酰胺、英丙舒凡、甲苯磺酸盐、洛莫司汀、美法仑、二溴甘露醇、二溴卫茅醇、尼莫司汀、雷莫司汀、替莫唑胺、塞替派、曲奥舒凡、氮芥、卡波醌;阿帕齐醌、福莫司汀、葡磷酰胺、帕利伐米、哌泊溴烷、曲磷胺、乌拉莫司汀、TH-3024、VAL-0834;
铂化合物
例如,卡铂、顺铂、依他铂、水合米铂、奥沙利铂、洛铂、奈达铂、吡铂、沙铂;洛铂、奈达铂、吡铂、沙铂;
DNA修改剂
例如,氨柔比星、比生群、地西他滨、米托蒽醌、丙卡巴肼、曲贝替定、氯法拉滨;安吖啶、brostallicin、匹杉琼、拉罗莫司汀1,3;
拓扑异构酶抑制剂
例如,依托泊苷、伊立替康、雷佐生、索布佐生、替尼泊苷、托泊替康;氨萘非特、贝洛替康、依利醋铵、voreloxin;
微管改性剂
例如,卡巴他赛、多西他赛、艾日布林、伊沙匹隆、紫杉醇、长春碱、长春新碱、长春瑞滨、长春地辛、长春氟宁;fosbretabulin、tesetaxel;
抗代谢药
例如,天冬酰胺酶3、阿扎胞苷、左亚叶酸钙、卡培他滨、克拉屈滨、阿糖胞苷、依诺他滨、氟尿苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯基嘌呤、甲氨蝶呤、奈拉滨、培美曲塞、普拉曲沙、硫唑嘌呤、硫鸟嘌呤、卡莫氟;去氧氟尿苷、艾西拉滨、雷替曲塞、沙帕他滨、替加氟2,3、三甲曲沙;
抗癌抗生素
例如,博来霉素、放线霉素、多柔比星、表柔比星、伊达比星、左旋咪唑、米替福新、丝裂霉素C、罗米地新、链佐星、戊柔比星、净司他丁、佐柔比星、daunurobicin、普卡霉素;阿柔比星、培洛霉素、吡柔比星;
激素/拮抗剂
例如,阿巴瑞克、阿比特龙、比卡鲁胺、布舍瑞林、卡鲁睾酮、氯烯雌醚、地加瑞克、地塞米松、雌二醇、氟可龙氟甲睾酮、氟他胺、氟维司群、戈舍瑞林、组胺瑞林、亮丙瑞林、甲地孕酮、米托坦、那法瑞林、诺龙、尼鲁米特、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺素α、托瑞米芬、曲洛司坦、曲普瑞林、己烯雌酚;
阿考比芬、达那唑、地洛瑞林、环硫雄醇、orteronel、恩杂鲁胺1,3;
芳香酶抑制剂
例如,氨鲁米特、阿那曲唑、依西美坦、法倔唑、来曲唑、睾内酯;
福美坦;
小分子激酶抑制剂
例如,克唑替尼、达沙替尼、厄洛替尼、伊马替尼、拉帕替尼、尼洛替尼、帕唑帕尼、瑞格非尼、鲁索利替尼、索拉非尼、舒尼替尼、凡德他尼、威罗菲尼、伯舒替尼、吉非替尼、阿西替尼;
阿法替尼、alisertib、达拉非尼、dacomitinib、dinaciclib、多韦替尼、恩扎啕林、nintedanib、lenvatinib、linifanib、linsitinib、马赛替尼、米哚妥林、莫替沙尼、来那替尼、orantinib、哌立福新、帕纳替尼、拉多替尼、力格赛狄、替匹法尼、tivantinib、tivozanib、曲美替尼、pimasertib、brivanib alaninate、西地尼布、阿帕替尼4、S-苹果酸卡赞替尼1,3、拉铁尼伯1,3、埃克替尼4、buparlisib2、西帕替尼4、cobimetinib1,3、idelalisib1,3、fedratinib1、XL-6474;
光敏剂
例如,甲氧沙林3;
卟吩姆钠、他拉泊芬、替莫泊芬;
抗体
例如,阿仑珠单抗、贝索单抗、布妥昔单抗酯、西妥昔单抗、地舒单抗、依匹木单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、群司珠单抗、贝伐珠单抗、帕妥珠单抗2,3;
卡妥索单抗、埃罗妥珠单抗、依帕珠单抗、farletuzumab、mogamulizumab、necitumumab、尼妥珠单抗、阿托珠单抗、ocaratuzumab、奥戈伏单抗、雷莫芦单抗、rilotumumab、siltuximab、托珠单抗、扎芦木单抗、扎木单抗、马妥珠单抗、dalotuzumab1 ,2,3、onartuzumab1,3、racotumomab1、tabalumab1,3、EMD-5257974、nivolumab1,3;
细胞因子
例如,阿地白介素、干扰素α2、干扰素α2a3、干扰素α2b2,3;西莫白介素、他索纳明、替西白介素、奥普瑞白介素1,3、重组干扰素β-1a4;
缀合物药物
例如,denileukin diftitox、ibritumomab tiuxetan(替伊莫单抗)、iobenguaneI123、泼尼莫司汀、trastuzumab emtansine、雌莫司汀、吉妥珠单抗、奥佐米星、阿柏西普;贝辛白介素、依度曲肽、伊珠单抗奥佐米星、naptumomab estafenatox、oportuzumabmonatox、technetium (99mTc) arcitumomab1,3、vintafolide1,3;
疫苗
例如,sipuleucel3;vitespen3、emepepimut-S3、oncoVAX4、rindopepimut3、troVax4、MGN-16014、MGN-17034;
杂类
阿利维甲酸、贝沙罗汀、硼替佐米、依维莫司、伊班膦酸、咪喹莫特、来那度胺、香菇多糖、甲酪氨酸、米伐木肽、帕米膦酸、培门冬酶、喷司他丁、西普鲁塞3、西佐喃、他米巴罗汀、坦罗莫司、沙利度胺、维甲酸、维莫德吉、唑来膦酸、伏林司他;塞来考昔、西仑吉肽、恩替诺特、依他硝唑、ganetespib、伊屈诺昔、iniparib、ixazomib、氯尼达明、尼莫唑、帕比司他、peretinoin、普利肽新、泊马度胺、丙考达唑、ridaforolimus、他喹莫德、telotristat、胸腺法新、替拉扎明、托舍多特、trabedersen、乌苯美司、伐司扑达、gendicine 4、picibanil4、reolysin4、retaspimycin hydrochloride1,3、trebananib2,3、virulizin4、carfilzomib1,3、endostatin4、immucothel4、belinostat3、MGN-17034;
1Prop. INN (Proposed International Nonproprietary Name)(提议国际非专利药品名称)
2Rec. INN(Recommended International Nonproprietary Names)(推荐国际非专利药品名称)
3USAN(United States Adopted Name)(美国采用名称)
4非INN。
以下缩写分别指以下定义:
aq(水性),h(小时),g(克),L(升),mg(毫克),MHz(兆赫兹),min.(分钟),mm(毫米),mmol(毫摩尔),mM(毫摩尔浓度),m.p.(熔点),eq(当量),mL(毫升),L(微升),ACN(乙腈),AcOH(乙酸),CDCl3(氘代氯仿),CD3OD(氘代甲醇),CH3CN(乙腈),c-hex(环己烷),DCC(二环己基碳二亚胺),DCM(二氯甲烷),DIC(二异丙基碳二亚胺),DIEA(二异丙基乙基胺),DMF(二甲基甲酰胺),DMSO(二甲基亚砜),DMSO-d6(氘代二甲亚砜),EDC(1-(3-二甲基氨基丙基)-3-乙基碳二亚胺),ESI(电喷雾离子化),EtOAc(乙酸乙酯),Et2O(二乙醚),EtOH(乙醇),HATU(六氟磷酸二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基铵),HPLC(高效液相色谱),i-PrOH(2-丙醇),K2CO3(碳酸钾),LC(液相色谱),MeOH(甲醇),MgSO4(硫酸镁),MS(质谱),MTBE(甲基·叔丁基醚),NaHCO3(碳酸氢钠),NaBH4(硼氢化钠),NMM(N-甲基吗啉),NMR(核磁共振),PyBOP(六氟磷酸苯并三唑-1-基-氧基-三-吡咯烷基-磷鎓),RT(室温),Rt(保留时间),SPE(固相萃取),TBTU(四氟硼酸2-(1-H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓),TEA(三乙胺),TFA(三氟乙酸),THF(四氢呋喃),TLC(薄层色谱),UV(紫外)。
体外测定说明
缩写:
GST=谷胱甘肽-S-转移酶
FRET=荧光共振能量转移
HTRF®=(均相时间分辨荧光)
HEPES=4-(2-羟基乙基)-1-哌嗪乙磺酸缓冲剂
DTT=二硫苏糖醇
BSA=牛血清白蛋白
CHAPS=清洁剂
CHAPS=3-[(3-胆酰胺丙基)二甲基铵基]-1-丙磺酸内盐
链霉抗生物素蛋白-XLent®是一种高级链霉抗生物素蛋白-XL665缀合物,对于一些测定,特别是需要高灵敏度的那些测定,偶联条件已对该缀合物优化,以得到具有提高性能的缀合物。
端锚聚合酶1和2的生化活性检验:自动聚腺苷二磷酸核糖基化测定
自动聚腺苷二磷酸核糖基化测定在两个步骤进行:酶反应,其中GST标记端锚聚合酶-1和端锚聚合酶-2分别使生物素化ADP-核糖从作为共底物的生物素化NAD转移到自身;和检测反应,其中分析结合到酶的GST标记的穴状化合物标记抗GST和结合生物素-聚腺苷二磷酸核糖基化残基的Xlent®标记链霉抗生物素蛋白之间的时间分辨FRET。自动聚腺苷二磷酸核糖基化活性可直接通过HTRF信号增加检测。
自动聚腺苷二磷酸核糖基化测定在Greiner低体积nb 384孔微量滴定板中按384孔HTRF®(Cisbio, Codolet, France)测定形式进行,并用于高通量筛。将250nM GST标记的端锚聚合酶-1(1023-1327 aa)和约250nM GST标记的端锚聚合酶-2(873-1166 aa)分别和作为共底物的5µM bio-NAD(Biolog, Life science Inst., Bremen, Germany)在总体积5µl(50mM HEPES, 4mM氯化镁, 0.05% Pluronic F-68, 1.4mM DTT, 0.5% DMSO, pH7.7)中在试验化合物(10倍稀释浓度)不存在或存在下在30℃培养90min。反应通过加入1µl50mM EDTA溶液中止。加入2µl检测溶液(1.6µM SA-Xlent®(Cisbio, Codolet, France),7.4nM Anti-GST-K® (Eu-标记的抗-GST, Cisbio, Codolet, France), 在50mM HEPES中, 800mM KF, 0.1% BSA, 20mM EDTA, 0.1% CHAPS, pH 7.0)。在室温培养1h后,用Envision多模式读数器(Perkin Elmer LAS Germany GmbH)在激发波长340nm(激光模式)和发射波长615nm和665nm处检测HTRF。测定发射信号之比。所用完全值为无抑制剂反应。所用药理学0值为XAV-939(Tocris),在5µM最终浓度。用程序Symyx Assay Explorer®或Condosseo®(来自GeneData)测定抑制值(IC50)。
端锚聚合酶细胞抑制检测
由于已描述端锚聚合酶调节Axin2的细胞水平(Huang等人, 2009; Nature),因此,用Axin2水平增加作为读出,在基于Luminex的测定中测定端锚聚合酶的细胞抑制。
以1.5x104个细胞/孔,在96孔板中平板接种结肠癌细胞系DLD1的细胞。第二天,用试验化合物系列稀释分7步一式三份处理细胞,最终DMSO浓度0.3%。24小时后,使细胞在溶解缓冲液(20mM Tris/HCl pH 8.0, 150mM NaCl, 1% NP40, 10%甘油)中溶解,溶解液由离心通过96孔滤板(0.65µm)澄清。通过用结合到荧光羧基珠粒(carboxybead)的单克隆抗-Axin2抗体(R&D Systems #MAB6078)培养,从细胞溶解液分离Axin2蛋白。然后,用多克隆抗-Axin2抗体(Cell Signaling #2151)和适合的PE-荧光二级抗体特别检测结合的Axin2。根据制造商说明书,在Luminex200机(Luminex Corporation)中通过每孔计数100个事件测定分离的Axin2蛋白的量。端锚聚合酶通过试验化合物抑制得到较高水平Axin2,这直接与可检测荧光增加相关。作为对照,细胞用单独溶剂(中性对照)和用端锚聚合酶参比抑制剂IWR-2(3E-06 M)(称为Axin2最大增加的对照)处理。为了分析,将所得数据对未处理溶剂对照进行归一化,并用Assay Explorer软件(Accelrys)拟合测定EC50值。
PARP1测定说明
PARP-1生化活性检验:自动聚腺苷二磷酸核糖基化测定
自动聚腺苷二磷酸核糖基化测定在两个步骤进行:酶反应,其中His标记Parp-1使生物素化ADP核糖/ADP-核糖从作为共底物的生物素化NAD/NAD转移到自身;和检测反应,其中分析结合到酶的His标记的穴状化合物标记抗-His抗体和结合生物素-聚腺苷二磷酸核糖基化残基的Xlent®标记链霉抗生物素蛋白之间的时间分辨FRET。自动聚腺苷二磷酸核糖基化活性可直接通过HTRF信号增加检测。
自动聚腺苷二磷酸核糖基化测定在Greiner低体积nb 384孔微量滴定板中按384孔HTRF®(Cisbio, Codolet, France)测定形式进行。将35nM His标记Parp-1(人, 重组体, Enzo Life Sciences GmbH, Lörrach, Germany)与125nM bio-NAD(Biolog, Lifescience Inst., Bremen, Germany)和800nM NAD的混合物作为共底物在总体积6 µl(100mM Tris/HCl, 4mM氯化镁, 0.01% IGEPAL® CA630, 1mM DTT , 0.5% DMSO, pH 8,13ng/µl活化DNA(BPS Bioscience, San Diego, US))中在试验化合物(10倍稀释浓度) 不存在或存在下在23℃培养150min。通过加入4µl中止/检测溶液(70nM SA-Xlent®(Cisbio,Codolet, France), 2.5nM Anti-His-K®(Eu-标记抗-His, Cisbio, Codolet, France),在50mM HEPES中, 400mM KF, 0.1% BSA, 20mM EDTA, pH 7.0)中止反应。在室温培养1h后,用Envision多模式读数器(Perkin Elmer LAS Germany GmbH)在激发波长340nm(激光模式)和发射波长615nm和665nm处检测HTRF。测定发射信号之比。所用完全值为无抑制剂反应。所用药理学0值为Olaparib(LClabs, Woburn, US),在1µM最终浓度。用程序SymyxAssay Explorer®或Condosseo®(来自GeneData)测定抑制值(IC50)。
TNKS1和TNKS2 ELISA测定说明
TNKS 1和2的生化活性检验:活性ELISA(自动聚腺苷二磷酸核糖基化测定)
为了分析TNKS 1和2的自动聚腺苷二磷酸核糖基化活性,进行活性ELISA:在第一步,在谷胱甘肽涂覆板上捕获GST标记TNKS。然后,在化合物不存在/存在下用生物素化NAD进行活性测定。在酶反应期间,GST标记TNKS使生物素化ADP-核糖从作为共底物的生物素化NAD转移到自身。为了检测,加入链霉抗生物素蛋白-HRP缀合物,缀合物结合到生物素化TNKS,从而捕获到板。生物素化的分别自动聚腺苷二磷酸核糖基化的TNKS的量用HRP的发光底物检测。发光信号水平直接与自动聚腺苷二磷酸核糖基化TNKS的量相关,因此,与TNKS的活性相关。
活性ELISA在384孔谷胱甘肽涂覆微量滴定板(表达捕获谷胱甘肽涂覆板,Biocat, Heidelberg, Germany)中进行。板用PBS预平衡。然后,板用50µl 20ng/孔GST标记Tnks-1(1023-1327 aa, 内部制备)和GST标记Tnks-2(873-1166 aa, 内部制备)分别在测定缓冲液(50mM HEPES, 4mM氯化镁, 0.05% Pluronic F-68, 2mM DTT, pH 7.7)中在4℃培养过夜。板用PBS-Tween-20洗涤3次。通过用50µl封闭缓冲液(PBS, 0.05% Tween-20,0.5% BSA)在室温培养20分钟封闭孔。随后用PBS-Tween-20洗涤板3次。在50µl反应溶液(50mM HEPES, 4mM氯化镁, 0.05% Pluronic F-68, 1.4mM DTT, 0.5% DMSO, pH 7.7)中用10µM bio-NAD(Biolog, Life science Inst., Bremen, Germany)作为共底物在试验化合物(10倍稀释浓度)不存在或存在下在30℃进行酶反应1小时。通过用PBS-Tween-20洗涤3次中止反应。为了检测,加入PBS/0.05%Tween-20/0.01%BSA中的50µl 20ng/µl链霉抗生物素蛋白, HRP缀合物(MoBiTec, Göttingen, Germany),并在室温培养平板30分钟。在用PBS-Tween-20洗涤三次后,加入50µl SuperSignal ELISA Femto最大灵敏度底物溶液(ThermoFisherScientific (Pierce), Bonn, Germany)。在室温培养1分钟后,用Envision多模式读数器(Perkin Elmer LAS Germany GmbH)在700nm检测发光信号。所用完全值为无抑制剂反应。所用药理学0值为XAV-939(Tocris),在5µM最终浓度。用程序Symyx AssayExplorer®或Condosseo®(来自GeneData)测定抑制值(IC50)。
在上下文中,所有温度均以℃表示。在以下实施例中,“常规整理”指:如果必要,加入水,如果必要,根据最终产物的组成将pH调节到2-10的值,用乙酸乙酯或二氯甲烷萃取混合物,使各相分离,使有机相经硫酸钠干燥,蒸发,并通过在硅胶上层析和/或通过结晶纯化残余物。
用氘代溶剂的残余信号作为内标,在Bruker 400或500MHz谱仪上记录1H NMR。化学位移(δ)相对于残余溶剂信号(δ=2.49ppm,对于1H NMR,在DMSO-d6中)以ppm报告。1H NMR数据如下报告:化学位移(多重性,偶合常数,和氢数)。多重性缩写如下:s(单峰),d(二重峰),t(三重峰),q(四重峰),m(多重峰),br(宽峰)。
HPLC/MS条件(A)
柱:Chromolith SpeedROD RP-18e, 50 x 4.6 mm2
梯度:A:B=96:4至0:100,3.4min
流速:2.40ml/min
洗脱剂A:水+0.05%甲酸
洗脱剂B:乙腈+0.04%甲酸
波长:220nm
质谱:正模式
实施例1
合成6-对甲苯基-7H-咪唑并[1,5-a]吡嗪-8-酮("A1")
1.1 (Z)-3-二甲基氨基-2-异氰基丙烯酸乙酯
向异氰基乙酸乙酯 (3.22ml, 29.44mmol)加入叔丁氧基双(二甲基氨基)甲烷(12.16ml, 58.88mmol),并在氩下在室温搅拌混合物14h。使反应混合物蒸发至干,残余物(5.6g(98%), 棕色油)用于下一步骤,不经进一步纯化;HPLC-MS:Rt = 1.64; [M+H] 169。
1.2 1-苄基-1H-咪唑-4-甲酸乙酯
向(Z)-3-二甲基氨基-2-异氰基丙烯酸乙酯(5.6g, 28.97mmol)加入苄胺(3.48ml,31.86mmol),并在70℃搅拌反应混合物14h。浓缩反应混合物,残余物通过快速层析纯化(洗脱剂:DCM-甲醇)。将所需级分合并,蒸发至干,得到3.93g(57%),棕色油;HPLC-MS:Rt =1.72; [M+H] 231。
1.3 1-苄基-1H-咪唑-4-甲酰胺
用氢氧化铵溶液(32%, 45mL)处理1-苄基-1H-咪唑-4-甲酸乙酯(3.93g, 17.07mmol)和氯化铵(0.27g, 5.12mmol),并在压热器中在105℃搅拌14h。使反应混合物冷却至室温,将沉淀滤出,用水洗涤,并在真空中在50℃温度干燥;产量:2.13g(61%);HPLC-MS:Rt =1.30; [M+H] 202。
1.4溴化2-苄基-8-氧代-6-对甲苯基-7,8-二氢-咪唑并[1,5-a]吡嗪-2-鎓
使1-苄基-1H-咪唑-4-甲酰胺(500mg, 2.49mmol)和2-溴-1-对甲苯基-乙酮(635.3mg,2,98mmol)溶于DMF/CH3CN - 3/7 (10mL),并在90℃搅拌14h。使反应混合物冷却至室温,将沉淀物滤出,用二乙醚洗涤,并干燥;产量:452mg(46%);HPLC-MS:Rt = 1.43; [M] 316。
1.5 6-对甲苯基-7H-咪唑并[1,5-a]吡嗪-8-酮("A1")
将溴化2-苄基-8-氧代-6-对甲苯基-7,8-二氢-咪唑并[1,5-a]吡嗪-2-鎓(451.0mg,1.138mmol)和咪唑(3.87g, 56.90mmol)的混合物在氮气氛下加热到175℃,并搅拌5h。使反应混合物冷却,并倒在冰上。通过抽吸过滤沉淀物,用二乙醚洗涤并干燥;产量:141mg(55%);HPLC-MS:Rt = 1.50; [M+H] 226;
1H NMR (500 MHz, DMSO-d6) δ = 10.93 (s, 1H), 8.25 (d, J = 0.9 Hz, 1H),7.77 (s, 1H), 7.74 (s, 1H), 7.59 - 7.54 (m, 2H), 7.31 - 7.26 (m, 2H), 2.36(s, 3H)。
类似地制备以下实施例:
6-(4-叔丁基-苯基)-7H-咪唑并[1,5-a]吡嗪-8-酮("A2")
产量:13.5mg(11%);HPLC-MS:Rt = 1.97; [M+H] 268;
1H NMR (400 MHz, DMSO-d6) δ = 10.92 (s, 1H), 8.27 (s, 1H), 7.78 (s, 1H),7.75 (s, 1H), 7.64 - 7.58 (m, 2H), 7.53 - 7.47 (m, 2H), 1.31 (s, 9H)。
6-(4-三氟甲基-苯基)-7H-咪唑并[1,5-a]吡嗪-8-酮("A3")
产量:39.5mg(20%);HPLC-MS:Rt = 1.75; [M+H] 280; 1H NMR (400 MHz, DMSO-d6) δ= 11.15 (s, 1H), 8.33 (s, 1H), 7.96 - 7.80 (m, 6H)。
实施例4
合成6-[4-(1-甲基-1H-吡唑-4-基)-苯基]-7H-咪唑并[1,5-a]吡嗪-8-酮("A4")
4.1 6-(4-溴-苯基)-7H-咪唑并[1,5-a]吡嗪-8-酮
产量:1.6g(98%);HPLC-MS:Rt = 1.65; [M+H] 291。
4.2 6-[4-(1-甲基-1H-吡唑-4-基)-苯基]-7H-咪唑并[1,5-a]吡嗪-8-酮
使6-(4-溴-苯基)-7H-咪唑并[1,5-a]吡嗪-8-酮(实施例4, 150.0mg, 0.517mmol)、1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑(118,3mg, 0,569mmol)和碳酸氢钠(52.1mg, 0,620mmol)悬浮于DMF/水- 2/1(1.5mL),用氮冲洗,并加热到40℃。加入氯化双(三苯基膦)合钯(II)(10.5mg, 0,015mmol),并将反应混合物加热到80℃经历14h。使温度升高到90℃,并搅拌反应混合物另外5h。用水稀释反应混合物。利用抽吸过滤所得沉淀物,并通过快速层析纯化;产量:17mg(11%);HPLC-MS:Rt = 1.40; [M+H] 292;
1H NMR (400 MHz, DMSO-d6) δ = 10.82 (brs, 1H), 8.21(s, 2H), 7.93 (s, 1H),7.80 (s, 1H), 7.73 - 7.61 (m, 5H), 3.87 (s, 3H)。
实施例5
合成6-(4-羟基甲基-苯基)-7H-咪唑并[1,5-a]吡嗪-8-酮("A5")
5.1 4-(8-氧代-7,8-二氢-咪唑并[1,5-a]吡嗪-6-基)-苯甲酸甲酯
在压热器中,用氮冲洗甲醇/甲苯- 1/1(16mL)中6-(4-溴-苯基)-7H-咪唑并[1,5-a]吡嗪-8-酮(500mg, 1.723mmol)和三乙胺(260mg, 2.569mmol)的溶液。加入(1,1'-双(二苯基膦基)-二茂铁]二氯合钯(II)、二氯甲烷(43mg, 0.053mmol)和1,1-双(二苯基膦基)二茂铁(39mg, 0.070mmol)。然后用一氧化碳填充压热器,并加热到100℃。利用2-4bar一氧化碳压力,在此温度保持压热器6小时。使压热器达到大气压。通过抽吸滤出沉淀物,用甲醇洗涤,并在真空下干燥;产量:314mg(68%),HPLC-MS: Rt = 1.47; [M+H] 270。
5.2 6-(4-羟基甲基-苯基)-7H-咪唑并[1,5-a]吡嗪-8-酮
使4-(8-氧代-7,8-二氢-咪唑并[1,5-a]吡嗪-6-基)-苯甲酸甲酯(100mg, 0.371mmol)悬浮于THF (5mL),用氢化铝锂(2,0mol, 在THF中, 0.371ml, 0.743mmol)处理,并在环境温度搅拌14h。反应混合物用少量甲醇猝灭,用1mL 1N盐酸酸化并过滤。用二氯甲烷萃取滤液三次,合并的有机层用水和盐水洗涤,经硫酸钠干燥,过滤,并蒸发至干。使含水层蒸发至干。合并的残余物通过层析纯化;产量:55mg(61%);HPLC-MS:Rt = 1.05; [M+H] 242;
1H NMR (400 MHz, DMSO-d6) δ = 10.96 (s, 1H), 8.27 (s, 1H), 7.79 - 7.74(m, 2H), 7.66 - 7.61 (m, 2H), 7.45 - 7.37 (m, 2H), 5.25 (t, J = 5.7 Hz, 1H),4.55 (d, J = 5.7 Hz, 2H)。
实施例6
合成6-[4-(1-羟基-1-甲基-乙基)-苯基]-7H-咪唑并[1,5-a]吡嗪-8-酮("A6")
使4-(8-氧代-7,8-二氢-咪唑并[1,5-a]吡嗪-6-基)-苯甲酸甲酯(70mg, 0.252mmol)悬浮于THF(4ml),加入氯化铈(68.4mg, 0.277mmol),并在环境温度搅拌混合物1h。加入氯化甲基镁(3M, 在THF中, 0.39ml; 1,059mmol),并在环境温度搅拌反应混合物1h。用5%柠檬酸使反应混合物猝灭。滤出生成的固体,并浓缩滤液。通过抽吸滤出生成的沉淀并干燥;产量:50mg(74%);HPLC-MS:Rt = 1.30; [M+H] 270; 1H NMR (400 MHz, DMSO-d6) δ =10.92 (s, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.64 - 7.51 (m, 4H),5.14 (s, 1H), 1.44 (s, 6H)。
实施例7
合成6-(4-叔丁基-苯基)-3-甲基-7H-咪唑并[1,5-a]吡嗪-8-酮("A7")
7.1 2-甲基-1H-咪唑-4-甲酸乙酯
使2-甲基-1H-咪唑-4-甲酸(1.43g; 11.299mmol)溶于乙醇(90.0mL)。加入二氧杂环己烷中的HCl(4M, 7.50mL),并在90℃加热混合物18h。将溶液浓缩。使残余物在乙酸乙酯和饱和NaHCO3溶液之间分配。水层用乙酸乙酯萃取两次。合并的有机层用盐水洗涤,并经Na2SO4干燥,过滤,并蒸发至干;产量:1.43g(82%)。
7.2 1-苄基-2-甲基-1H-咪唑-4-甲酸乙酯
向乙腈(80mL)中2-甲基-1H-咪唑-4-甲酸乙酯(1.43g; 9.276mmol)的溶液加入碳酸铯(6.04g; 18.551mmol)。滴加苄基溴(1.59g; 9.276mmol),并在室温搅拌反应混合物14h。在真空中浓缩反应混合物,用水稀释,并用乙酸乙酯萃取两次。经硫酸钠干燥合并的有机层,过滤并蒸发至干。将油状残余物用于下一步骤,不经任何进一步纯化;产量:940mg(29%)。
7.3 1-苄基-2-甲基-1H-咪唑-4-甲酰胺
在压热器中将1-苄基-2-甲基-1H-咪唑-4-甲酸乙酯(300.0mg, 1.228mmol)和氯化铵(20.0mg, 0.368mmol)在氢氧化铵溶液(32%, 20mL)中在105℃加热4h。使反应混合物冷却至室温,并蒸发至干。残余物用于下一步骤,不经任何进一步纯化;产量:132mg(50%)。
7.4 6-(4-叔丁基-苯基)-3-甲基-7H-咪唑并[1,5-a]吡嗪-8-酮
使1-苄基-2-甲基-1H-咪唑-4-甲酰胺(69.0mg; 0.321mmol)和1-(4-叔丁基-苯基)-2-氯乙酮(81.0mg; 0.385mmol)溶于DMF(1mL)和乙腈(3mL),并在微波装置(CEM)中在160℃加热6h。浓缩反应混合物,用水稀释,并用乙酸乙酯萃取3次。用水和盐水洗涤合并的有机层,用硫酸钠干燥,过滤,并蒸发至干。通过层析纯化油状残余物;产量:11.0mg(12%);HPLC-MS:Rt = 1.85; [M+H] 282;
1H NMR (500 MHz, DMSO-d6) δ = 10.82 (s, 1H), 7.69 - 7.63 (m, 3H), 7.53 -7.46 (m, 3H), 2.57 (s, 3H), 1.32 (s, 9H)。
实施例8
合成6-[4-(1-羟基-1-甲基-乙基)-苯基]-3-甲基-7H-咪唑并[1,5-a]吡嗪-8-酮("A8")
8.1 6-(4-溴-苯基)-3-甲基-7H-咪唑并[1,5-a]吡嗪-8-酮
如关于实施例7所述制备(步骤7.4);产量:83.0mg(33%);
HPLC-MS:Rt = 1.57; [M+H] 304-307。
8.2 4-(3-甲基-8-氧代-7,8-二氢-咪唑并[1,5-a]吡嗪-6-基)-苯甲酸甲酯
如关于实施例5所述制备(步骤5.1);产量:37.0mg(49%);
HPLC-MS:Rt = 1.40; [M+H] 284。
8.3 6-[4-(1-羟基-1-甲基-乙基)-苯基]-3-甲基-7H-咪唑并[1,5-a]吡嗪-8-酮("A8")
如关于实施例6所述制备;产量:15.0mg(40%);HPLC-MS:Rt = 1.24; [M+H] 284; 1HNMR (400 MHz, DMSO-d6) δ = 10.82 (s, 1H), 7.72 - 7.62 (m, 3H), 7.60 - 7.46(m, 3H), 5.07 (s, 1H), 2.57 (s, 3H), 1.45 (s, 6H)。
药理学数据
表1 式I化合物的端锚聚合酶抑制
IC50:< 0.3μM = A 0.3 - 3μM = B 3-50μM = C
表2 式I化合物的端锚聚合酶抑制
IC50:< 0.3μM = A 0.3 - 3μM = B 3-50μM = C
以下实施例涉及药物:
实施例A:注射瓶
用2 N盐酸将100 g的式I的活性成分和5g磷酸氢二钠在3L重蒸馏水中的溶液调节至pH6.5,无菌过滤,转移至注射瓶中,在无菌条件下冻干并在无菌条件下密封。每个注射瓶含有5mg活性成分。
实施例B:栓剂
将20 g的式I的活性成分与100g大豆卵磷脂和1400g可可酯的混合物熔化,倾入模具中并使之冷却。每个栓剂含有20mg活性成分。
实施例C:溶液
由1 g式I的活性成分、9.38 g NaH2PO4∙2H2O、28.48g Na2HPO4∙12 H2O和0.1 g苯扎氯铵在940ml重蒸馏水制备溶液。将pH调节至6.8,并使溶液补充至1 L并经辐照灭菌。这种溶液可用于滴眼剂形式。
实施例D:软膏剂
将500mg式I的活性成分与99.5g凡士林在无菌条件下混合。
实施例E:片剂
将1 kg式I的活性成分、4 kg乳糖、1.2 kg马铃薯淀粉、0.2 kg滑石粉和0.1 kg硬脂酸镁的混合物以常规方式压制,得到片剂,以这样一种方式得到的每一片剂含有10mg活性成分。
实施例F:糖衣丸
类似于实施例E压制片剂,随后用蔗糖、马铃薯淀粉、滑石粉、黄蓍胶和染料的包衣料以常规方式包衣。
实施例G:胶囊
将2 kg式I的活性成分以常规方式引入硬明胶胶囊,以这样一种方式获得的每粒胶囊含有20mg活性成分。
实施例H:安瓿
将1 kg式I的活性成分在60 L重蒸馏水中的溶液无菌过滤,转移至安瓿中,在无菌条件下冻干并在无菌条件下密封。每个安瓿含有10mg活性成分。
Claims (11)
1.式I的化合物及其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,
其中
R1表示H或甲基,
R2表示A或Het,
A表示具有1-8个C-原子的非支化或支化烷基,其中一个或二个非相邻CH-和/或CH2-基团可由N-或O-原子代替,和/或其中1-7个H-原子可由F或Cl代替,
Het表示嘧啶基、吡啶基、哒嗪基、吡嗪基、哌啶基、吡咯烷基、吡唑基、噻唑基、咪唑基、呋喃基、噻吩基、吡咯基、噁唑基、三唑基、噁二唑基或噻二唑基,各基团未取代或由Hal、A、CN、OH和/或OA单取代或二取代,
Hal表示F、Cl、Br或I,
其条件为如果R1为H,则R2不为4-OMe。
2.权利要求1的化合物及其药学上可接受的溶剂化物、盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
A表示具有1-8个C-原子的非支化或支化烷基,其中一个或二个非相邻CH2-基团可由O-原子代替,和/或其中1-3个H-原子可由F代替。
3.权利要求1或2的化合物及其药学上可接受的溶剂化物、盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
Het表示嘧啶基、吡啶基、哒嗪基、吡嗪基、哌啶基、吡咯烷基、吡唑基、噻唑基、咪唑基、呋喃基、噻吩基、吡咯基、噁唑基、三唑基、噁二唑基或噻二唑基,各基团未取代或由A单取代。
4.权利要求1的化合物及其药学上可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
R1表示H或甲基,
R2表示A或Het,
A表示具有1-8个C-原子的非支化或支化烷基,其中一个或二个非相邻CH2-基团可由O-原子代替,和/或其中1-3个H-原子可由F代替,
Het表示嘧啶基、吡啶基、哒嗪基、吡嗪基、哌啶基、吡咯烷基、吡唑基、噻唑基、咪唑基、呋喃基、噻吩基、吡咯基、噁唑基、三唑基、噁二唑基或噻二唑基,各基团未取代或由A单取代。
5.权利要求1的化合物及其药学上可接受的溶剂化物、盐、互变异构体和立体异构体,包括它们按所有比例的混合物,所述化合物选自
。
6.制备权利要求1至5的式I的化合物及其药学上可接受的盐、溶剂化物、互变异构体和立体异构体的方法,其特征在于
使式II的化合物脱苄基,
其中R1和R2具有权利要求1中指示的含义,
和/或
使式I的碱或酸转化成其盐之一。
7.药物,所述药物包含至少一种式I的化合物和/或其药学上可接受的盐、溶剂化物、互变异构体和立体异构体,包括它们按所有比例的混合物,和任选药学上可接受的载体、辅料或媒介物。
8.式I的化合物及其药学上可接受的盐、溶剂化物、互变异构体和立体异构体,包括它们按所有比例的混合物,用于治疗和/或预防癌症、多发性硬化、心血管疾病、中枢神经系统损伤和不同形式炎症。
9.权利要求8的化合物,用于治疗和/或预防选自以下的疾病:头、颈、眼、口、咽喉、食道、支气管、喉、咽、胸、骨、肺、结肠、直肠、胃、前列腺、膀胱、子宫、宫颈、乳房、卵巢、睾丸或其它生殖器官、皮肤、甲状腺、血液、淋巴结、肾、肝、胰、脑、中枢神经系统的癌症,实体瘤和血源性瘤。
10.药物,所述药物包含至少一种式I的化合物和/或其药学上可接受的盐、溶剂化物和立体异构体,包括它们按所有比例的混合物,和至少一种其它药物活性成分。
11.由以下的单独包装组成的套装(试剂盒):
(a)有效量的式I的化合物和/或其药学上可接受的盐、溶剂化物、盐和立体异构体,包括它们按所有比例的混合物,
和
(b)有效量的其它药物活性成分。
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TWI808055B (zh) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Hdac 抑制劑與 pd-1 抑制劑之組合治療 |
TWI794171B (zh) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Hdac抑制劑與pd-l1抑制劑之組合治療 |
TW201822637A (zh) | 2016-11-07 | 2018-07-01 | 德商拜耳廠股份有限公司 | 用於控制動物害蟲的經取代磺醯胺類 |
JP7433403B1 (ja) | 2022-12-06 | 2024-02-19 | 本田技研工業株式会社 | 内燃機関及び鞍乗型車両 |
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JP2005089352A (ja) | 2003-09-16 | 2005-04-07 | Kissei Pharmaceut Co Ltd | 新規なイミダゾ[1,5−a]ピラジン誘導体、それを含有する医薬組成物およびそれらの用途 |
CN101468988A (zh) * | 2007-12-26 | 2009-07-01 | 上海恒瑞医药有限公司 | 哌嗪类衍生物,其制备方法及其在医药上的应用 |
EP2526102B1 (en) | 2010-01-22 | 2017-03-08 | Fundación Centro Nacional de Investigaciones Oncológicas Carlos III | Inhibitors of PI3 kinase |
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CA2872334C (en) * | 2012-05-04 | 2020-06-30 | Dieter Dorsch | Pyrrolotriazinone derivatives |
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CN108403697A (zh) * | 2018-05-02 | 2018-08-17 | 吉林大学 | 吡嗪酮类小分子抑制剂在制备抗肿瘤药物中的应用 |
CN112654396A (zh) * | 2018-09-07 | 2021-04-13 | 默克专利股份公司 | 5-吗啉-4-基-吡唑并[4,3-b]吡啶衍生物 |
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RU2672885C2 (ru) | 2018-11-20 |
CN105829317B (zh) | 2019-03-29 |
HUE037606T2 (hu) | 2018-09-28 |
PL3087076T3 (pl) | 2018-01-31 |
PT3087076T (pt) | 2018-01-03 |
CA2934663A1 (en) | 2015-07-02 |
LT3087076T (lt) | 2017-12-27 |
IL246406A0 (en) | 2016-08-31 |
US20170002010A1 (en) | 2017-01-05 |
RU2016130148A3 (zh) | 2018-07-25 |
WO2015096884A1 (en) | 2015-07-02 |
RU2016130148A (ru) | 2018-01-30 |
US9718826B2 (en) | 2017-08-01 |
AU2014372896B2 (en) | 2018-08-16 |
MX364859B (es) | 2019-05-09 |
EP3087076B1 (en) | 2017-09-27 |
HRP20171783T1 (hr) | 2017-12-29 |
KR20160101188A (ko) | 2016-08-24 |
TW201605862A (zh) | 2016-02-16 |
AU2014372896A1 (en) | 2016-08-04 |
JP6446461B2 (ja) | 2018-12-26 |
SI3087076T1 (en) | 2018-01-31 |
RS56746B1 (sr) | 2018-03-30 |
SG11201605189YA (en) | 2016-07-28 |
NO3087076T3 (zh) | 2018-02-24 |
EP3087076A1 (en) | 2016-11-02 |
ES2654403T3 (es) | 2018-02-13 |
MX2016008042A (es) | 2016-09-16 |
TWI637956B (zh) | 2018-10-11 |
JP2017500353A (ja) | 2017-01-05 |
DK3087076T3 (da) | 2017-11-13 |
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