CN103945848B - 被取代的喹唑啉酮的口服即释制剂 - Google Patents
被取代的喹唑啉酮的口服即释制剂 Download PDFInfo
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- CN103945848B CN103945848B CN201280053263.8A CN201280053263A CN103945848B CN 103945848 B CN103945848 B CN 103945848B CN 201280053263 A CN201280053263 A CN 201280053263A CN 103945848 B CN103945848 B CN 103945848B
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- hydroxyl
- oxethyl
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- dimethoxyquinazoline
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Abstract
本公开内容涉及口服即释制剂固体药物制剂和它们的制备方法。本公开内容还部分提供了使用用于调节载脂蛋白A‑I(ApoA‑I)的表达的药物制剂的方法,及它们用于治疗和预防心血管疾病和包括胆固醇‑或脂质‑相关障碍、例如动脉粥样硬化的相关疾病状态的应用。
Description
流行病学数据表明,在高密度脂蛋白胆固醇(HDL-C)的循环水平与临床上显著的动脉粥样硬化的发病率之间存在反相关。HDL-C血清水平每增加1mg/dl,则心血管风险减少2-3%;LDL-C降低1%可使冠心病(CHD)风险减少2%(Gordon等人(1997)Am.J.Med.62,707-714)。实验证据进一步支持了HDL-C抵抗心血管疾病的保护作用。例如,在具有低HDL-C的受治疗者中,施用吉非贝齐使HDL-C水平增加6%,相应地使CHD风险减少22%(Rubins等人(1999)N.Engl.J.Med.341,410-418)。在与由ApoA-I表达减少引起的低HDL-C有关的遗传病中的观察结果也表明,高CHD风险与低HDL-C之间存在联系。
HDL-C显示其通过介导胆固醇逆行转运(RCT)而发挥抗动脉粥样硬化的作用,在胆固醇逆行转运中胆固醇从外周组织中募集并被转运至肝。此外,HDL-C还发挥抗炎和抗氧化作用以及促进纤维蛋白溶解作用。HDL-C颗粒可防止LDL氧化,LDL氧化是促进动脉巨噬细胞摄取胆固醇的重要起始步骤。HDL-C存在两种主要形式,一种含有载脂蛋白A-I(ApoA-I)和载脂蛋白A-II(ApoA-II)两者,另一种含有ApoA-I但不含ApoA-II(Schultz等人(1993)Nature365,762-764)。HDL-C的心脏保护作用主要但不是唯一地可由ApoA-I引起。
临床和实验数据表明,ApoA-I的产生是循环HDL-C的关键决定因素。例如,患有家族性高α脂蛋白血症(高ApoA-I)的人显示出可避免动脉粥样硬化,而ApoA-I缺乏(低α脂蛋白血症)的那些人显示出心血管疾病加速。此外,增加ApoA-I产生的各种实验操作伴随有致动脉粥样化减少。例如,人ApoA-I在转基因动物模型中是保护性的(Shah等人(1998)Circulation97,780-785;Rubin等人(1991)Nature353,265-267),在人类患者中用ApoA-IMilano进行治疗可阻止动脉粥样硬化病变和使动脉粥样硬化斑块消减(Nissen等人(2003)JAMA290,2292-2300)。另外的研究路线证明,ApoA-I在增强胆固醇逆行转运、减弱氧化应激、提高对氧磷酶活性、增强抗凝血活性和提高抗炎活性方面发挥作用(Andersson(1997)Curr.Opin.Lipidol.8,225-228)。因此,ApoA-I是对治疗干预而言有吸引力的靶标。
目前可获得的增加ApoA-I血浆浓度的治疗剂、例如重组ApoA-I或模拟ApoA-I的肽在例如储存过程中的稳定性、活性产物的传递和体内半衰期方面具有潜在的缺点。因此,增量调节内源性ApoA-I产生的小分子化合物、例如ApoA-I表达的增量调节剂作为心血管疾病的新治疗剂将是非常有吸引力的。
多酚类被认为是有助于预防包括癌症和心血管疾病在内的多种疾病的一类的化合物。多酚类存在于大多数植物源的食品和饮料中,且是最丰富的膳食抗氧化剂(Scalbert&Williamson(2000)J.Nutr.130,2073S-2085S)。然而,尚未完全实现多酚类的保护性质(Manach等(2005)Am.J.Clin.Nutr.81,230S-242S),这是因为生物利用度差、在多个报道的评价它们的研究中缺乏临床意义(Williamson&Manach(2005)Am.J.Clin.Nutr.81,243S-255S)和在较高剂量浓度时的有害作用。例如,丰富和可获得的白藜芦醇(众所周知的均二苯乙烯多酚)的来源为红葡萄酒(Wu等(2001)Int.J.Mol.Med.8,3-17)。然而,由于过量饮酒有众多的被充分记载的有害作用,所以在每日基础上不能消耗治疗有效量的红葡萄酒。白藜芦醇的作用在没有醇存在的情况下可能更好或更安全。
若干涉及多种食品或饮料中的多种多酚的抗氧化作用的人临床研究就主要治疗终点(诸如氧化性应激、脂血症和炎症)而言未能证实明确的益处(Williamson&Manach(2005)Am.J.Clin.Nutr.81,243S-255S)。例如,在十二例最近的不同多酚源的介入研究中,六例显示对脂质参数无作用,且六例显示对脂质参数有改善(Manach(2005)Curr.Opin.Lipidol.16,77-84)。此类不确定的数据限制了多酚类的潜在应用,尽管它们具有多种有益的性质。
天然存在的多酚类作为潜在的治疗药物的用途也已受到体内不能达到有效水平的阻碍,部分是由于生物利用度差(Manach等(2005)Am.J.Clin.Nutr.81,230S-242S)。任何给定的多酚的生物利用度在不同的个体中差别很大(1-26%)。由于吸收、代谢和***速度的不同,在将不同的多酚施用于相同的个体时同样观测到这种差异性。例如,已报导多酚黄酮类化合物、诸如五羟黄酮在口服施用后具有低于1%的肠吸收(Gugler等(1975)Eur.J.Clin.Pharm.9,229-234)。此外,已知一些多酚代谢产物对于母体化合物的生物活性具有负面影响(Manach等(2005)Am.J.Clin.Nutr.81,230S-242S)。这类代谢物在毒性、功效和在血浆中残留的持续时间方面经常不同于母体化合物。另一个限制因素是许多多酚的差的溶解度,其限制了潜在的施用途径。这些因素和其他因素使得难以测定天然存在的多酚类、柚苷配基或白藜芦醇用于人类的适合剂量。
因此,存在将多酚-样化合物发展为治疗剂的需求,所述治疗剂用于治疗和预防心血管疾病和相关疾病,特别是胆固醇-或脂质-相关障碍,例如,动脉粥样硬化。因此本发明的目的之一是提供增量调节ApoA-I的表达的化合物。此外,所述化合物可具有比天然存在的多酚类更有利的药理性质。
癌症是一组由失调的细胞增殖引起的疾病。治疗方法旨在通过抑制细胞复制或通过诱导癌细胞分化或死亡来减少癌细胞的数量,但对于更有效的治疗剂仍有显著未满足的医学需求。癌细胞累积了改变细胞生长和代谢的遗传和后生变化,以促进细胞增殖并增加对于程序性细胞死亡或细胞凋亡的抗性。这些变化中的一些包括肿瘤抑制基因的失活、癌基因的激活、以及染色质结构调节的修饰。Watson,Cancer Discovery1:477-480(2011);Morin等,Nature476:298-303(2011)。
已经表征了染色质中组蛋白的许多修饰,包括在组蛋白H3和H4中多个赖氨酸的乙酰化。Peserico和Simone,J.Biomed.Biotechnol.2011:371832(2011)。组蛋白乙酰化由乙酰基转移酶(HATs)以及脱乙酰酶(HDACs)控制,且小分子HDAC抑制剂已经被开发作为癌症的指示物。Hoshino和Matsubara,Surg.Today40:809-815(2010)。组蛋白乙酰化通过招募经由溴结构域(bromodomain)直接结合于乙酰化的赖氨酸的蛋白质复合物来控制基因表达。Sanchez和Zhou,Curr.Opin.Drug Discov.Devel.12(5):659-665(2009)。一个该类家族(溴结构域和额外终端结构域(BET)蛋白)包括Brd2、Brd3、Brd4和BrdT,其各自包含两个串联的可以独立地与乙酰化的赖氨酸结合的溴结构域。Wu和Chiang,J.Biol.Chem.282(18):13141-13145(2007)。BET蛋白质通过招募正转录延伸因子b(p-TEFb)对转录产生一些作用,正转录延伸因子b通过磷酸化RNA聚合酶II的C-端结构域而刺激转录延伸,并导致生长促进基因(例如c-Myc和非常确定的癌症靶点AuroraB)的表达增加。Filippakopoulos等,Nature468:1067-1073(2010)。
结合于BET蛋白质并防止它们与染色质结合的分子抑制转录并阻止细胞复制,其可用于癌症治疗法和其他情况(settings)。例如,已显示小分子抑制剂例如JQ1、I-BET和I-BET151可以从染色质替换BET蛋白质,所述小分子抑制剂与BET蛋白质溴结构域的乙酰基-赖氨酸结合袋特异性竞争,由此阻止它们的靶基因的转录延伸。Filippakopoulos等(2010);Nicodeme等,Nature468:1119-1123(2010);Dawson等,Nature478:529-533(2011)。
对BET溴结构域-启动子相互作用的抑制导致myc转录和蛋白水平随后降低。这在多种白血病和淋巴瘤细胞系中导致G1阻滞和大量的细胞凋亡。Mertz等,PNAS108(40):16669-16674(2011)。在25-35%的所有人类癌症中原-癌基因的Myc家族(c-myc、l-myc、n-myc)被激活。Vita和Henrickson,Seminars in Cancer Biol.16:318-330(2006)。由c-myc的过量表达驱动的癌症的小鼠模型表明短暂抑制c-myc表达可以引起肿瘤退化、细胞死亡,且在一些癌症、诸如白血病中实现疾病缓解。Soucek等,Nature455:679-683(2008)。c-myc的明确的配体-结合域的缺乏使得开发抑制剂成为艰巨的挑战,因此必须发展靶向c-myc转录的替代的策略。Delmore等,Cell146:904-917(2011)。其中c-myc过量表达的侵袭性的人成神经管细胞瘤的小鼠模型表明BET抑制剂可用于治疗myc-扩增的成神经管细胞瘤。Kawauchi等,Cancer Cell21:168-180(2012);Pei等,Cancer Cell21:155-167(2012)。类似地,经由RNA干扰对n-myc的抑制在成神经细胞瘤小鼠模型中显著减少肿瘤生长。Jiang等,Biochem.Biophs.Res.Commun.410:364-370(2011)。在使用反义寡核苷酸抑制l-myc扩增的小细胞肺癌细胞系中显示对1-myc有类似作用。Dosaka-Akita等,Cancer Res.55:1559-1564(1995)。因此BET抑制剂具有有效治疗多种类型的癌症的潜力。
事实上,已证实靶向BET家族成员的溴结构域的小分子在治疗癌症中具有潜在的治疗用途。参见,例如Dawson等(2011),显示BET家族的小分子抑制剂通过早期细胞周期(early cell cycle)停滞和细胞凋亡对人和鼠科动物混合谱系白血病(MLL)-融合细胞系具有强的功效。其作用机制为选择性消除至染色质的Brd3/4招募。已在鼠科动物的NUT(睾丸中的核内蛋白)中线癌(NMC)(罕见但致命的癌症形式)的异种移植物模型中证实BET抑制剂JQ1具有强力的抗肿瘤活性。NMC肿瘤细胞生长由Brd4基因至nutlin1基因的易位驱动。Filippakopoulos等,(2010)。还显示JQ1在多发性骨髓瘤中为强效的抗增殖剂(antiproliferator),其与细胞周期停滞和细胞衰老相关。Delmore等(2011)。
BET抑制剂还被期望是其它类型的癌症的潜在的治疗剂。例如,在急性髓样白血病(AML)中,需要Brd4维持myc表达和延续疾病进展。Zuber等,Nature478:524-8(2011)。此外,Brd4的失活在它们扩增的细胞系中导致原-癌基因c-myc和n-myc的转录的快速和强力的减量调节。Dawson等(2011);Delmore等(2011);Zuber等(2011);Mertz等(2011)。因此,使用BET治疗具有c-myc的激活的肿瘤,通过使c-myc转录失活,导致肿瘤消退。还期望BET抑制剂在多发性骨髓瘤中具有应用,因为牵涉该疾病的多发性骨髓瘤SET结构域(MMSET)也与BET蛋白质结合。Dawson等(2011)。
除癌症之外,还期望BET抑制剂具有抗炎和免疫调节性质。Lamotte等,Bioorganic&Med.Chem.Letters(February24,2012);Prinjha等,TrendsPharmacol.Sci.33(3):146-153(2012)。BET抑制剂I-BET和I-BET151在体内降低IL-6表达。已显示I-BET带来针对脂多糖-诱导的内毒素性休克和细菌-诱导的脓毒症的保护作用,且显示I-BET151在鼠科动物模型中抑制细菌-诱导的炎症和脓毒症。Nicodeme等(2010);Lamotte等(2012)。此外,BET抑制剂可调节对病毒和细菌感染(包括HIV、疱疹和头状瘤病毒)的应答。
本发明提供了即释制剂(immediate release formulation),其包含
(i)作为活性成分的式I化合物
或其可药用盐、立体异构体、水合物或互变异构体,其中:
R1和R3各自独立地选自烷氧基、烷基和氢;
R6和R8各自独立地选自烷氧基、烷基、卤素和氢;
R7选自烷氧基、烷基、醚、氢和羟基;或
两个相邻的选自R1、R3、R6、R7、R8的取代基连接形成选自芳基、杂芳基、环烷基和杂环基的基团;
条件是如果R1是氢,则R3是烷氧基;
条件是如果R3是氢,则R1是烷氧基;且
条件是如果R7选自烷基、羟基和烷氧基,则R6和R8中至少一个独立地选自烷基或烷氧基;
(ii)至少一种助流剂;和
(iii)至少一种崩解剂。
固体药物制剂的制备期间的重要的考虑因素包括活性成分的化学和物理性质的保护、生物利用度的增强、施用的方便性和总体稳定性。在各情况中,制剂必须基于活性/药物物质的性质、平衡因素如崩解、溶出、粒度、单元尺寸、组分的配伍性和稳定性(参见,例如The Pharmaceutical Codex,Principles and Practice of Pharmaceutics.Walter Lund编撰;2008,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems,Lippincott Williams&Wilkins,2010,Pharmaceutical Dosage forms:Tablets.第1,2卷.Liberman、Lachman和Schwartz编撰.第2版)。
崩解和溶出对吸收是必要的步骤,且这些步骤的效率能影响活性/药物物质的生物利用度。对于弱酸和碱的溶解度及由此的溶出度受胃肠液的pH影响。对于在中性和碱性环境如小肠中具有降低的溶解度、且在胃pH下具有较高溶解度的化合物来说在酸性胃液中的快速崩解和溶出对于在小肠中的吸收至关重要(Principles of Drug Absorption(药物吸收原理),Michael Mayersohn.Modern Pharmaceutics:Drugs and the PharmaceuticalSciences,第72卷,James Swarbrick编撰)。
包括式I化合物在内的许多活性化合物具有差的水溶性,由此降低从胃肠道吸收它们的可能性。处理低溶水性的化合物的挑战是难以改善溶解度而不减少化合物的稳定性,从而使储存期减少至不可接受的水平。当用可电离的碱性取代基诸如胺和/或酰胺取代时,可以改变式I化合物的疏水性,为当口服施用时从酸性胃环境增加溶解和吸收提供了机会。然而,由于胃肠道腔中增加的pH梯度(pH3至7),溶出和吸收的机会依赖于溶出的速度。因此,如果这些化合物没有在正确的胃环境中溶解,则在小肠中的吸收和生物利用度减少或损失。因此,任何用可电离的碱性取代基取代式I化合物而获得的改善的生物活性是妥协的,因为它们在小肠中的溶解度减少,这导致活性药物物质的总的效力和疗效降低。
因为已经显示式I化合物调节Apo-A1的表达,且给出了增加的Apo-A1表达与治疗或预防心血管和胆固醇-或脂质-相关障碍之间的相互关系,所以有开发包含被取代的喹唑啉酮、诸如本文所述的那些化合物的固体药物制剂的需要,其中所述药物制剂改善喹唑啉酮药物物质的溶出,
具有良好的生物利用度,方便施用,其在延长的时期内稳定。
本发明提供了含如上文定义的式I化合物的新的固体药物制剂及它们的制备方法。本发明的制剂稳定,且具有改善的式I化合物的崩解和溶出性质和改善的该药物物质的生物利用度。本发明还部分提供了使用本发明的药物制剂的方法,所述药物制剂可用于调节载脂蛋白A-I(ApoA-I)的表达和用作BET抑制剂,用于治疗和预防心血管疾病和胆固醇-或脂质-相关的障碍,其包括例如代谢综合征、炎性疾病、阿尔茨海默病、动脉粥样硬化、糖尿病和癌症。可使用本发明的方法治疗或预防的癌症包括对结合于BET家族蛋白的溴结构域的化合物敏感的癌症,其包括NUT中线癌;显示c-myc过量表达的癌症,包括但不限于伯基特淋巴瘤、急性髓性白血病、多发性骨髓瘤、侵袭性人成神经管细胞瘤;过量表达n-myc的癌症;和依赖p-TEFb的招募以调节激活的癌基因、例如NOTCH1的癌症。
该说明书中使用的术语“活性成分”是指式I化合物。这些化合物可如美国专利申请编号11/670,238(美国专利8,053,440)、美国专利申请编号12/490,877(美国专利8,114,995)和2012年4月19日提交的美国临时专利申请编号61/635,726中所述制备,将这些专利申请引入本文作为参考。
不在两个字母或符号之间的破折号(“-“)用于表示用于取代基的连接点。例如,-CONH2通过碳原子连接。
本文所用的表述″单位剂型″是指适于待治疗的个体的药物制剂的物理上离散的单位。单个单位剂型的总重量由单位剂型中添加的所有组分的重量决定,且不包括可应用于所述单位剂型上的任何包衣或可装载所述单位剂型的胶囊的重量。将单一单位剂型的总重量用作计算组成所述单位剂型的各个组分的重量百分比的基础。
本文所用的“W/W%”意指以重量计的总重量的百分比。
术语″约″旨在表示近以地、在范围中、粗略或左右。当术语″约″与数值范围一起使用时,其通过往上或往下延长所述数值的边界来调整该范围。通常,术语“约”旨在以设定值的≤10%的差异向上或向下调整数值。
式I化合物可作为互变异构体存在。任何活性成分、即式I化合物的描述意欲包括所述化合物的所有互变异构形式,即使只描述了一个互变异构结构或只例举了一个化合物名称也亦然。例如,应理解以下活性成分A的任何描述同样表示单独的或作为混合物的互变异构体结构B和C,且反之亦然。
如本文使用的术语“水合物”是指具有掺入的化学计算量或非化学计算量的水的式I化合物的晶形。
如本文使用的术语“烷氧基”是指与氧连接的烷基(-O-烷基-)。“烷氧基”还包括与氧相连的链烯基(“链烯基氧基”)或与氧相连的炔基(“炔基氧基”)。示例性的烷氧基包括但不限于具有1-22、1-8或1-6个碳原子的烷基、链烯基或炔基的基团,在本文中分别称作(C1-C22)烷氧基、(C1-C8)烷氧基和(C1-C6)烷氧基。示例性的烷氧基包括但不限于甲氧基和乙氧基。
如本文使用的术语“烷基”是指饱和的直链或支链的烃,诸如直链或支链的1-22、1-8或1-6个碳原子的基团,在本文中分别称作(C1-C22)烷基、(C1-C8)烷基和(C1-C6)烷基。示例性的烷基包括但不限于甲基、乙基、丙基、异丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基和辛基。
如本文使用的术语“芳基”是指一-、二-或其他的多-碳环、芳族环***。芳基可以任选地稠合于一个或多个选自芳基、环烷基和杂环基的环。本发明的制剂中使用的化合物的芳基可以被选自以下基团取代:烷氧基、芳氧基、烷基、链烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、硝基、磷酸酯(phosphate)、硫化物、亚硫酰基、磺酰基、磺酸、磺酰胺和硫酮。示例性的芳基包括但不限于苯基、甲苯基、蒽基、芴基、茚基、薁基和萘基以及苯并-稠合的碳环基团、诸如5,6,7,8-四氢萘基。示例性的芳基还包括但不限于单环芳族环***,其中所述环包含6个碳原子,在本文中称为″(C6)芳基″。
如本文使用的术语“环烷基”是指源自环烷烃的3-12个碳或3-8个碳的饱和的或不饱和的环状、二环或桥联二环烃基,在本文中称为″(C3-C8)环烷基″。示例性的环烷基包括但不限于环己烷、环己烯、环戊烷和环戊烯。环烷基可被烷氧基、芳氧基、烷基、链烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、硝基、磷酸酯(phosphate)、硫化物、亚硫酰基、磺酰基、磺酸、磺酰胺和硫酮取代。环烷基可以稠合于其它的饱和的或不饱和的环烷基、芳基或杂环基。
术语“醚”是指结构-RlO-Rm-,Rl和Rm可以独立地是烷基、链烯基、炔基、芳基、环烷基、杂环基和醚。醚可以通过Rl或Rm连接于母体分子基团。示例性的醚包括但不限于烷氧基烷基和烷氧基芳基。醚还包括聚醚,例如,其中Rl和Rm中的一个或两个是醚。
术语“卤代”和“卤素”可以互换且是指F、Cl、Br或I。
如本文使用的术语“杂芳基”是指单-、二-或多-环、芳族环***,其包含一个或多个杂原子、例如1-3个杂原子、诸如氮、氧和硫。杂芳基可以被一个或多个包括以下取代基取代:所述取代基包括烷氧基、芳氧基、烷基、链烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、硝基、磷酸酯、硫化物、亚硫酰基、磺酰基、磺酸、磺酰胺和硫酮。杂芳基还可以稠合于非-芳族环。杂芳基的说明性实例包括但不限于吡啶基、哒嗪基、嘧啶基、吡嗪基(pyrazyl)、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-和(1,2,4)-***基、吡嗪基、pyrimidilyl、四唑基、呋喃基、噻吩基、异唑基、噻唑基、呋喃基、苯基、异唑基和唑基。示例性的杂芳基包括但不限于单环芳族环,其中所述环包含2-5个碳原子和1-3个杂原子,在本文中称为″(C2-C5)杂芳基”。
如本文使用的术语“杂环”、“杂环基”或“杂环的”是指饱和的或不饱和的3-、4-、5-、6-或7-元环,其包含1、2或3个独立地选自氮、氧和硫的杂原子。杂环可以是芳族的(杂芳基)或非芳族的。杂环可以被一个或多个以下取代基取代:所述取代基包括烷氧基、芳氧基、烷基、链烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、硝基、磷酸酯(phosphate)、硫化物、亚硫酰基、磺酰基、磺酸、磺酰胺和硫酮。杂环还包括二环、三环和四环基团,其中任何上述杂环稠合于一个或两个独立地选自芳基、环烷基和杂环的环。示例性的杂环包括吖啶基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并唑基、生物素基、噌啉基、二氢呋喃基、二氢吲哚基、二氢吡喃基、二氢噻吩基、二噻唑基、呋喃基、高哌啶基、咪唑烷基、咪唑啉基、咪唑基、吲哚基、异喹啉基、异噻唑烷基、异噻唑基、异唑烷基、异唑基、吗啉基、二唑基、唑烷基、唑基、哌嗪基、哌啶基、吡喃基、吡唑烷基、吡嗪基、吡唑基、吡唑啉基、哒嗪基、吡啶基、嘧啶基、嘧啶基、吡咯烷基、吡咯烷-2-酮基、吡咯啉基、吡咯基、喹啉基、喹喔啉基(q uinoxaloyl)、四氢呋喃基、四氢异喹啉基、四氢吡喃基、四氢喹啉基、四唑基、噻二唑基、噻唑烷基、噻唑基、噻吩基、硫代吗啉基、噻喃基和***基。
“烷基”可以被至少一个选自以下的基团取代或中断或分支:烷氧基、芳氧基、烷基、链烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、酮、杂芳基、杂环基、羟基、硝基、磷酸酯、硫化物、亚硫酰基、磺酰基、磺酸、磺酰胺、硫酮、脲基和N。所述取代基可以被分支以形成被取代的或未被取代的杂环或环烷基。
“烷氧基”可以被至少一个选自以下的基团取代或中断或分支:烷氧基、芳氧基、烷基、链烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羰基、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、硝基、磷酸酯、硫化物、亚硫酰基、磺酰基、磺酸、磺酰胺、硫酮、脲基和N。所述取代基可以被分支以形成被取代的或未被取代的杂环或环烷基。
术语″可药用盐″是指可在式I化合物中存在的酸性或碱性基团的盐。本质上是碱性的式I化合物能与多种无机和有机酸形成众多的盐。可用于制备该类碱性化合物的可药用酸加成盐的酸为形成无毒酸加成盐、即含药理学上可接受的阴离子的盐的那些,所述盐包括但不限于硫酸盐、枸橼酸盐、苹果酸盐(matate)、乙酸盐、草酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸性磷酸盐、异烟酸盐、醋酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡糖酸盐、葡糖醛酸盐(glucaronate)、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和扑酸盐(即1,1′-亚甲基-双-(2-羟基-3-萘甲酸盐))。除了以上提到的酸外,包含氨基的式I化合物还可以与多种氨基酸形成可药用盐。本质上是酸性的式I化合物能够与各种药理学上可接受的阳离子形成碱盐。这类盐的实例包括碱金属或碱土金属盐以及特别是钙、镁、钠、锂、锌、钾和铁盐。
式I化合物可以含有一个或多个手性中心和/或双键,因此可以以立体异构体如几何异构体、对映异构体或非对映异构体存在。术语“立体异构体”当在本文使用时包括所有几何异构体、对映异构体或非对映异构体。根据立体形成碳原子周围的取代基的构型,这些化合物可以用符号“R”或“S”来标明。式I化合物包括立体异构体及其混合物。立体异构体包括对映异构体和非对映异构体。对映异构体或非对映异构体的混合物可以根据命名法标明“(±)”,但是技术人员将知道结构可包含隐含的手性中心。
式I化合物的单独的立体异构体可以由含有不对称或立体形成中心的可市售得到的原料经合成来制备,或者通过制备外消旋混合物、然后通过本领域普通技术人员众所周知的拆分方法来制备。这些拆分方法包括但不限于(1)将对映异构体的混合物与手性助剂连接,通过重结晶或色谱法分离产生的非对映异构体混合物和从助剂释放出旋光纯的产物,(2)采用具有旋光活性的拆分剂形成盐,或者(3)在手性色谱柱上直接分离旋光对映异构体的混合物。立体异构混合物还可以通过众所周知的方法拆分为其组分立体异构体,所述方法包括但不限于手性相气相色谱法、手性相高效液相色谱法、使化合物以手性盐复合物结晶和/或使化合物在手性溶剂中结晶。立体异构体还可以由立体异构纯的中间体、试剂和催化剂通过众所周知的不对称合成方法而得到。
式I化合物还可以作为几何异构体或其混合物存在,所述几何异构体或其混合物来自碳-碳双键周围的取代基的排列或碳环周围的取代基的排列。碳-碳双键周围的取代基标明为是“Z”或“E”构型,其中术语“Z”和“E”按照IUPAC标准进行使用。除非另有说明,描绘双键的结构既包括E异构体也包括z异构体。
或者,碳-碳双键周围的取代基可以被称为“顺式”或“反式”,其中“顺式”表示取代基在双键的同侧,“反式”表示取代基在双键的对侧。碳环周围的取代基的排列被标明为“顺式”或“反式”。术语“顺式”表示取代基在环平面的同侧,术语“反式”表示取代基在环平面的对侧。其中取代基既排列在环平面的同侧又排列在对侧的式I化合物的混合物被标明为“顺式/反式”。
本发明的一个示例性的实施方案是药物制剂,其包含作为活性成分的式I化合物,其中:
R1和R3各自独立地选自烷氧基、烷基和氢;
R6和R8各自独立地选自烷基、烷氧基和氢;
R7选自烷基、羟基和烷氧基;
条件是如果R1是氢,则R3是烷氧基;
条件是如果R3是氢,则R1是烷氧基;且
条件是如果R7选自烷基、羟基和烷氧基,则R6和R8中至少一个独立地选自烷基或烷氧基。
在一个实施方案中,本发明的制剂包含作为活性成分的式I化合物,其中:
R1和R3各自是烷氧基;
R6和R8各自是烷基;且
R7选自被羟基取代的烷氧基。
在某些实施方案中,本发明的制剂包含作为活性成分的式I化合物,其中:
R1和R3各自是甲氧基;
R6和R8各自是甲基;且
R7选自被羟基取代的烷氧基。
在某些实施方案中,本发明的制剂包含活性成分,其中R7选自羟基和被羟基取代的烷氧基。在其他的实施方案中,R7是被烷氧基取代的羟基。在另外的实施方案中,R7是2-羟基乙氧基。
在一些实施方案中,活性成分是2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮或其可药用盐、立体异构体、水合物或互变异构体。
在其他的实施方案中,活性成分是2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮的盐酸盐或其立体异构体或互变异构体。
在其他的实施方案中,本发明的制剂包含选自以下的活性成分:
2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)喹唑啉-4(3H)-酮;
2-(3-氯-4-(2-羟基乙氧基)苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
2-(4-(2-羟基乙氧基)-3-甲氧基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
2-(4-羟基-3-(2-羟基乙基)苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲基喹唑啉-4(3H)-酮;
2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5-甲氧基喹唑啉-4(3H)-酮;和
2-(4-(2-羟基乙氧基)-3-甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮或其可药用盐、立体异构体、水合物或互变异构体。
在某些实施方案中,式I的活性成分的相应的酸的pKa为<3。在一些实施方案中,活性成分的粒度范围为约1-250微米、约1-100微米或约1-10微米。
在某些实施方案中,本发明的制剂在延长的时期稳定。例如,在一些实施方案中,制剂稳定至少两年。
在一些实施方案中,本发明的制剂中的至少一种助流剂以1-10%w/w或2-4%w/w或2.5%w/w的量存在。在一些实施方案中,助流剂是胶态二氧化硅、例如Cab-O-Sil。
本发明的制剂中的至少一种崩解剂可以以约0-25%w/w、约4-25%w/w、约0-10%w/w、约0-8%w/w、约1-8%w/w、约2-5%w/w、约2-4%w/w或约4%w/w的量存在。在一些实施方案中,至少一种崩解剂以约4%w/w至约25%w/w的量存在。适合的崩解剂包括例如,粉状纤维素、硅酸钙、交聚维酮、藻酸钙、甲基纤维素、脱乙酰壳多糖、羧甲基纤维素、交联羧甲纤维素钠、羧甲基淀粉、藻酸钠、羟乙酸淀粉钠(例如,ExploTab)、预胶化淀粉及其混合物。参见,例如,The Pharmaceutical Codex,Principles and Practice ofPharmaceutics.Walter Lund编撰;2008。
在某些实施方案中,本公开的制剂包含式I活性成分、胶态二氧化硅和至少一种选自羟乙酸淀粉钠、交联羧甲纤维素钠及其混合物的崩解剂。
在某些实施方案中,胶态二氧化硅以约2.5%w/w的量存在,且羟乙酸淀粉钠和交联羧甲纤维素钠各自分别以约4%w/w至约25%w/w的量存在。
在其他的实施方案中,胶态二氧化硅以约2.5%w/w的量存在,且羟乙酸淀粉钠以约4%w/w的量存在。
除活性成分、至少一种助流剂和至少一种崩解剂之外,所述制剂还可包含一种或多种填充剂或稀释剂。在一些实施方案中,填充剂/稀释剂以至多85%w/w或约15-65%w/w或约20-45%w/w的量存在。适合的填充剂/稀释剂包括例如,微晶纤维素、甘露醇、乙基纤维素、山梨醇、淀粉、蔗糖、磷酸钙、粉状纤维素、硅化微晶纤维素及其混合物。
在一些实施方案中,填充剂/稀释剂是微晶纤维素。在某些实施方案中,微晶纤维素是Avicel PH-301。
所述制剂还可包含一种或多种润滑剂。在一些实施方案中,润滑剂以约0-2%w/w、约0-1%w/w或约0.5%w/w的量存在。适合的润滑剂包括例如,硬脂酸镁、硬脂酸、硬脂酰醇富马酸钠、山嵛酸甘油酯、氢化植物油、硬脂酸锌、硬脂酸钙、蔗糖硬脂酸酯、聚乙烯醇、十二烷基硫酸镁及其混合物。在一些实施方案中,润滑剂是硬脂酸镁。
本发明的制剂还可包含表面活性剂。在一些实施方案中,表面活性剂以约0-5%w/w、约0-3%w/w或约1%w/w的量存在。适合的表面活性剂包括例如,月桂基硫酸钠、十二烷基硫酸钠、聚山梨酯(诸如Tween20和Tween80)、泊洛沙姆(诸如Poloxamer188)、单油酸甘油酯及其混合物。在一些实施方案中,表面活性剂是Poloxamer188、十二烷基硫酸钠及其混合物。
在本发明的一个示例性的实施方案中,药物制剂包含式I的活性成分、10-85%微晶纤维素、1-8%羟乙酸淀粉钠、0.5-2%硬脂酸镁、1-10%胶态二氧化硅、0-2%十二烷基硫酸钠和0-25%交联羧甲纤维素钠。
在其他的实施方案中,所述制剂包含式I的活性成分、10-85%微晶纤维素、4%羟乙酸淀粉钠、0.5%硬脂酸镁和2.5%胶态二氧化硅。
在某些实施方案中,所述制剂包含式I的活性成分、10-85%微晶纤维素、4%羟乙酸淀粉钠、25%交联羧甲纤维素钠、0.5%硬脂酸镁和2.5%胶态二氧化硅。
在一个示例性的实施方案中,本发明的制剂包含:
(i)约10-12%w/w2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
(ii)约82-83%w/w Avicel PH301;
(iii)约2.5%w/w胶态二氧化硅;
(iv)约4%w/w羟乙酸淀粉钠;和
(v)约0.5%w/w硬脂酸镁。
在一个供选择的实施方案中,可用2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮的盐酸盐代替该制剂中的2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮。
在另一个示例性的实施方案中,本发明的制剂包含:
(i)约20-22%w/w2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
(ii)约70-72%w/w Avicel PH301;
(iii)约2.5%w/w胶态二氧化硅;
(iv)约4%w/w羟乙酸淀粉钠;和
(v)约0.5%w/w硬脂酸镁。
在一个供选择的实施方案中,可用2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮的盐酸盐代替该制剂中的2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮。
在另一个示例性的实施方案中,本发明的制剂包含:
(i)约31-33%w/w2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
(ii)约60-62%w/w Avicel PH301;
(iii)约2.5%w/w胶态二氧化硅;
(iv)约4%w/w羟乙酸淀粉钠;和
(v)约0.5%w/w硬脂酸镁。
在一个供选择的实施方案中,可用2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮的盐酸盐代替该制剂中的2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮。
在另一个示例性的实施方案中,本发明的制剂包含:
(i)约41-43%w/w2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
(ii)约50-51%w/w Avicel PH301;
(iii)约2.5%w/w胶态二氧化硅;
(iv)约4%w/w羟乙酸淀粉钠;和
(v)约0.5%w/w硬脂酸镁。
在一个供选择的实施方案中,可用2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮的盐酸盐代替该制剂中的2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮。
在另一个示例性的实施方案中,本发明的制剂包含:
(i)约10-12%w/w2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮或其盐酸盐;
(ii)约56-57%w/w Avicel PH301;
(iii)约2.5%w/w胶态二氧化硅;
(iv)约4%w/w羟乙酸淀粉钠;
(v)约0.5%w/w硬脂酸镁;和
(vi)约25%w/w交联羧甲纤维素钠。
在一个供选择的实施方案中,可用2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮的盐酸盐代替该制剂中的2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮。
在另一个示例性的实施方案中,本发明的制剂包含:
(i)约42-43%w/w2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮或其盐酸盐;
(ii)约24-25%w/w Avicel PH301;
(iii)约2.5%w/w胶态二氧化硅;
(iv)约4%w/w羟乙酸淀粉钠;
(v)约0.5%w/w硬脂酸镁;
(vi)约25%w/w交联羧甲纤维素钠;和
(vii)约1%w/w十二烷基硫酸钠。
在一个供选择的实施方案中,可用2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮的盐酸盐代替该制剂中的2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮。
所述制剂的物理和化学稳定性可以以常规方式测试,例如,溶出或崩解时间或含水量的测量,或者在不同的温度和相对湿度储存不同的时期后的活性成分或降解产物的含量测定。
本发明的药物制剂可使用对治疗疾病有效的任何量施用。所需的确切量在不同的个体将根据个体的种类、年龄和一般状况、疾病和/或障碍的严重程度、特定活性成分、其施用模式等而变化。在一个方面中,为易于施用和剂量均一,将药物制剂调配成口服药物单位剂型。然而,应理解本发明的药物制剂的总每日用法将由主治医师在合理医学判断的范围内确定。
任何特定个体的具体有效剂量水平将取决于多种因素,其包括例如所治疗的疾病和所述疾病的严重程度;所用特定化合物的活性;所用特定组合物;个体的年龄、体重、一般健康状况、性别和饮食;施用时间;和所用特定化合物的***速率;治疗持续时间;与所用特定化合物组合或同时使用的药物;以及医学领域中众所周知的类似因素。
在一些实施方案中,单位剂型包含25-150mg的活性药物成分。在一些实施方案中,单位剂型包含约25、50、75、100或150mg的活性药物成分。
在一个实施方案中,本发明提供了作为固体口服药物剂型的药物制剂。固体口服药物剂型的实例包括例如,片剂、胶囊、丸剂、粉末和颗粒剂。在某些实施方案中,药物制剂为胶囊形式。虽然本发明的制剂根据作为示例性的剂型的胶囊来描述,但其它剂型也在本发明的范围内。
在一些实施方案中,填充胶囊的总重量为每胶囊100至500mg。在一些实施方案中,填充胶囊的总重量为每胶囊约200-250mg;且在一些实施方案中,填充胶囊的总重量为每胶囊约230mg。
如本文所用的术语“心血管疾病”指心脏和循环***的疾病和障碍。包括胆固醇-或脂质-相关障碍在内的示例性心血管疾病包括但不限于急性冠状动脉综合征、心绞痛、动脉硬化、动脉粥样硬化、颈动脉动脉粥样硬化、脑血管疾病、脑梗死、充血性心力衰竭、先天性心脏病、冠心病、冠状动脉疾病、冠脉斑块稳定(coronary plaque stabilization)、异常脂血症、异常脂蛋白血症、内皮功能障碍、家族性高胆固醇血症、家族性复合高脂血症、低α脂蛋白血症、高甘油三酯血症、高β脂蛋白血症、高胆固醇血症、高血压、高脂血、间歇性跛行、缺血、缺血再灌注损伤、缺血性心脏病、心肌缺血、代谢综合征、多发性脑梗死性痴呆、心肌梗死、肥胖症、外周血管疾病、再灌注损伤、再狭窄、肾动脉粥样硬化、风湿性心脏病、卒中、血栓形成性障碍、暂时性缺血发作以及与阿尔茨海默病、肥胖症、糖尿病、综合征x、阳痿、多发性硬化症、帕金森病和炎性疾病有关的脂蛋白异常。
如本文所定义的与“糖尿病”有关的疾病和病症指由绝对或相对胰岛素缺乏引起的慢性代谢障碍,包括但不限于高血糖、高胰岛素血症、高脂血症、胰岛素抗性、葡萄糖代谢受损、肥胖症、糖尿病性视网膜病、黄斑变性、白内障、糖尿病性肾病、肾小球硬化、糖尿病性神经病、***功能障碍、经前期综合征、血管再狭窄、溃疡性结肠炎、皮肤和***障碍、足溃疡形成、代谢性酸中毒、关节炎、骨质疏松症和葡萄糖耐量降低。
在某些实施方案中,治疗的癌症是中线癌。在一些实施方案中,癌症特征为c-myc激活或过量表达。在其他的实施方案中,癌症特征为n-myc的过量表达或激活。在某些实施方案中,癌症为伯基特淋巴瘤、急性髓性白血病、多发性骨髓瘤或侵袭性人成神经管细胞瘤。在一些实施方案中,癌症依赖于p-TEFb的招募,以调节激活的癌基因、例如NOTCH1。在一些实施方案中,通过本发明的方法治疗或预防的癌症选自血液学癌症、包括肺癌、乳腺癌和结肠癌的上皮癌、中线癌、间质癌、肝癌、肾癌和神经病学肿瘤。
某些实施方案中,将式I或式II的化合物或其互变异构体、立体异构体、可药用盐或水合物施用于罹患癌症的哺乳动物通过降低抗-细胞凋亡基因Bcl2的表达诱导癌细胞的细胞凋亡。因此,本发明的一些实施方案提供了在哺乳动物中治疗或预防疾病或障碍的方法,所述动物从增加的细胞死亡或分化或者减少的细胞增殖而获益,所述方法包括施用式I化合物或式II或其互变异构体、立体异构体、可药用盐或水合物。
通过以下的非限制性实例进一步阐述本发明。
实施例
根据美国专利申请编号11/670,238和12/490,877(将其引入本文作为参考)中描述的合成方法制备2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮(化合物1)。
含本发明的制剂的胶囊可使用任何适合的装置或方法制备。典型地,称取适量的活性药物成分并任选称取羟乙酸淀粉钠,并转移至v型混合机或料斗混合机,并以约25rpm混合例如约2分钟。将胶态二氧化硅和约1/3的需要量的填充剂/稀释剂、诸如微晶纤维素过筛,并加入同一V型混合机中,并将各成分以约25rpm混合约2分钟。将剩余的填充剂/稀释剂、诸如微晶纤维素加入同一V型混合机中,并将各成分以约25rpm混合约4分钟。
将润滑剂、诸如硬脂酸镁过30目筛,并转移至该含其他成分的V型混合机中。将最终制剂以约25rpm混合约3分钟。
当进行溶出测试时,在前5分钟期间目视观测胶囊的崩解,如通过胶囊破裂从胶囊壳释放并分散出制剂混合物所见。在37℃、在0.1N HCl中、在USP桨式II型装置中以50和/或75rpm进行溶出测试。通过在密集的时间点、诸如5、10、15、30、45、60和90分钟,对从溶出介质中的制剂中释放的API取样,测定制剂的溶出特性。通过HPLC测定样品的药物含量,并得到溶出特性。对于这些试验,溶出特性的阈值上限包括在75rpm桨速度在30分钟内或更短的时间内显示>85%的药物释放的那些。使用更低的桨速度(50rpm)来区分表现接近的制剂的溶出效能。
考虑到因素例如赋形剂的数量、混合物密度、稳定性和可量测性(scaleability),以多种API重量百分比制备了众多制剂。以下制剂提供了更高的载药水平和更高的密度,导致增加的可制造性(manufacturability),减少无活性成分对个体的曝露。此外,两种或多种崩解剂与更高水平的助流剂(例如,二氧化硅)的组合改善了崩解和溶出特性。
制剂D4(25mg/胶囊)
成分 | mg/胶囊 | %wt./wt |
化合物1 | 25.00 | 10.73 |
微晶纤维素(Avicel PH301) | 191.69 | 82.27 |
胶态二氧化硅(Cab-O-Sil M5P) | 5.83 | 2.5 |
羟乙酸淀粉钠(ExploTab) | 9.32 | 4.0 |
硬脂酸镁(植物来源) | 1.17 | 0.5 |
硬壳明胶胶囊白色/白色1号Capsugel | - | - |
总计 | 233.01 | 100.0 |
制剂D4(50mg/胶囊)
成分 | mg/胶囊 | %wt./wt |
化合物1 | 50 | 21.46 |
微晶纤维素(Avicel PH301) | 166.69 | 71.54 |
胶态二氧化硅(Cab-O-Sil M5P) | 5.83 | 2.5 |
羟乙酸淀粉钠(ExploTab) | 9.32 | 4.0 |
硬脂酸镁(植物来源) | 1.17 | 0.5 |
硬壳明胶胶囊白色/白色1号Capsugel | - | - |
总计 | 233.01 | 100.0 |
制剂D4(75mg/胶囊)
成分 | mg/胶囊 | %wt./wt |
化合物1 | 75.00 | 32.19 |
微晶纤维素(Avicel PH301) | 141.69 | 60.81 |
胶态二氧化硅(Cab-O-Sil M5P) | 5.83 | 2.5 |
羟乙酸淀粉钠(ExploTab) | 9.32 | 4.0 |
硬脂酸镁(植物来源) | 1.17 | 0.5 |
硬壳明胶胶囊白色/白色1号Capsugel | - | - |
总计 | 233.01 | 100.0 |
制剂D4(100mg/胶囊)
成分 | mg/胶囊 | %wt./wt |
化合物1 | 100.00 | 42.9 |
微晶纤维素(Avicel PH301) | 116.69 | 50.1 |
胶态二氧化硅(Cab-O-Sil M5P) | 5.83 | 2.5 |
羟乙酸淀粉钠(ExploTab) | 9.32 | 4.0 |
硬脂酸镁(植物来源) | 1.17 | 0.5 |
硬壳明胶胶囊白色/白色1号Capsugel | - | - |
总计 | 233.01 | 100.0 |
制剂F3(25mg/胶囊)
成分 | mg/胶囊 | %wt./wt |
化合物1 | 25.00 | 10.73 |
微晶纤维素(Avicel PH301) | 197.0 | 56.29 |
胶态二氧化硅(Cab-O-Sil M5P) | 5.83 | 2.5 |
羟乙酸淀粉钠(ExploTab) | 9.32 | 4.0 |
硬脂酸镁(植物来源) | 1.17 | 0.5 |
交联羧甲纤维素钠 | 58.25 | 25 |
硬壳明胶胶囊白色/白色1号Capsugel | - | - |
总计 | 233.01 | 100.0 |
制剂F3”(100mg/胶囊)
成分 | mg/胶囊 | %wt./wt |
化合物1 | 100 | 42.9 |
微晶纤维素(Avicel PH301) | 56.25 | 24.14 |
胶态二氧化硅(Cab-O-Sil M5P) | 5.83 | 2.5 |
羟乙酸淀粉钠(ExploTab) | 9.32 | 4.0 |
硬脂酸镁(植物来源) | 1.17 | 0.5 |
交联羧甲纤维素钠 | 58.25 | 25 |
十二烷基硫酸钠 | 2.33 | 1 |
硬壳明胶胶囊白色/白色1号Capsugel | - | - |
总计 | 233.01 | 100.0 |
在以上的制剂中,D4具有最少的无活性成分,且因此,具有最高水平的载药量和密度,由此减少无活性成分的不必要的暴露。表1中提供了以上制剂的溶出特性。
表1.溶出结果
因此,本发明部分提供了针对发展中的制剂存在的问题的技术方案,其增加了式I化合物的生物利用度,同时保持化合物稳定性和储存期。由于式I化合物调节ApoA-1表达和作为BET抑制剂的已知的能力,前述即释剂型还提供了治疗和预防心血管疾病和胆固醇-或脂质-相关障碍(包括例如代谢综合征、炎性疾病、阿尔茨海默病、动脉粥样硬化、糖尿病和癌症)的途径。
Claims (12)
1.口服即释制剂,其包含选自以下的活性成分:
2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)喹唑啉-4(3H)-酮;
2-(3-氯-4-(2-羟基乙氧基)苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
2-(4-(2-羟基乙氧基)-3-甲氧基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
2-(4-羟基-3-(2-羟基乙基)苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲基喹唑啉-4(3H)-酮;
2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5-甲氧基喹唑啉-4(3H)-酮;
2-(4-(2-羟基乙氧基)-3-甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮;
和其可药用盐、立体异构体或互变异构体;
其中所述制剂还包含:
(i)约10%至约85%w/w Avicel PH-301;
(ii)约4%w/w羟乙酸淀粉钠;
(iii)约0.5%w/w硬脂酸镁;和
(iv)约2.5%w/w胶态二氧化硅;
其中术语“约”以设定值的≤10%的差异向上或向下调整数值。
2.权利要求1的制剂,其中所述活性成分选自2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮和其盐酸盐,且
(a)所述活性成分以约10至约12%w/w的量存在,且所述制剂还包含:
(i)约82至约83%w/w Avicel PH 301;
(ii)约2.5%w/w胶态二氧化硅;
(iii)约4%w/w羟乙酸淀粉钠;和
(iv)约0.5%w/w硬脂酸镁;
(b)所述活性成分以约20至约22%w/w的量存在,且所述制剂还包含:
(i)约70至约72%w/w Avicel PH 301;
(ii)约2.5%w/w胶态二氧化硅;
(iii)约4%w/w羟乙酸淀粉钠;和
(iv)约0.5%w/w硬脂酸镁;
(c)所述活性成分以约31至约33%w/w的量存在,且所述制剂还包含:
(i)约60至约62%w/w Avicel PH 301;
(ii)约2.5%w/w胶态二氧化硅;
(iii)约4%w/w羟乙酸淀粉钠;和
(iv)约0.5%w/w硬脂酸镁;
或
(d)所述活性成分以约41至约43%w/w的量存在,且所述制剂还包含:
(i)约50至约51%w/w Avicel PH 301;
(ii)约2.5%w/w胶态二氧化硅;
(iii)约4%w/w羟乙酸淀粉钠;和
(iv)约0.5%w/w硬脂酸镁;
且其中术语“约”以设定值的≤10%的差异向上或向下调整数值。
3.权利要求1的制剂,其中所述制剂包含约25至约150mg的所述活性成分,且其中术语“约”以设定值的≤10%的差异向上或向下调整数值。
4.权利要求3的制剂,其中所述活性成分在制剂中存在的量选自约25、约50、约75、约100或约150mg,且其中术语“约”以设定值的≤10%的差异向上或向下调整数值。
5.权利要求1的制剂,其中所述活性成分是2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮。
6.权利要求1的制剂,其中所述活性成分是2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮的盐酸盐。
7.权利要求1的制剂,其中活性成分的粒度范围为约1-250微米、约1-100微米或约1-10微米,且其中术语“约”以设定值的≤10%的差异向上或向下调整数值。
8.权利要求1的制剂,其中所述制剂具有120秒或更短的崩解时间。
9.权利要求1至8中任意一项的药物制剂在制备药物中的应用,所述药物在有需要的人中用于治疗或预防心血管疾病、代谢综合征、炎性疾病、阿尔茨海默病、糖尿病或癌症。
10.权利要求1至8中任意一项的制剂,其中所述制剂是片剂、胶囊、丸剂、粉末和颗粒剂形式。
11.权利要求10的制剂,其中所述制剂是胶囊形式。
12.权利要求10的制剂,其中所述制剂是片剂形式。
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