CN101583605A - 作为hsp90抑制剂的三唑衍生物 - Google Patents
作为hsp90抑制剂的三唑衍生物 Download PDFInfo
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- CN101583605A CN101583605A CNA2007800499639A CN200780049963A CN101583605A CN 101583605 A CN101583605 A CN 101583605A CN A2007800499639 A CNA2007800499639 A CN A2007800499639A CN 200780049963 A CN200780049963 A CN 200780049963A CN 101583605 A CN101583605 A CN 101583605A
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Abstract
5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺是一种HSP90抑制剂,可以用于制备治疗其中HSP90的抑制、调节和/或调控起作用的疾病的药物。
Description
发明背景
本发明的目的是寻找具有有价值的性质的新化合物,特别是能够用于制备药物的那些化合物。
本发明涉及在HSP90的抑制、调节和/或调控中起作用的化合物,还涉及包含该化合物的药物组合物,以及所述化合物在治疗其中HSP90起作用的疾病中的用途。
细胞中蛋白质的正确折叠和构象由分子伴侣来保证,并且蛋白质的正确折叠和构象对调控蛋白质合成和降解的平衡而言十分重要。分子伴侣对细胞的许多重要功能例如细胞增殖和凋亡的调节来讲,是非常重要的(Jolly和Morimoto,2000;Smith等人,1998;Smith,2001)。
热休克蛋白(HSPs)
组织的细胞对例如热、缺氧、氧化应激或毒性物质如重金属或醇的外部应激产生反应,同时激活许多公知术语为“热休克蛋白”(HSPs)的分子伴侣。
HSPs的活化保护细胞避免上述应激因素引起的损伤,加快生理状态的恢复并导致细胞处于应激耐受状态。
除了最初发现的由HSPs对抗外部应激引发的保护机制外,随时间的推移,人们还对正常无应激情况下各种HSPs的重要分子伴侣功能进行了描述。因此,各种HSPs可以调节,例如大量生物学重要的细胞蛋白质的正确折叠、细胞内定位和功能或受控的降解。
HSPs形成具有不同基因产物的基因家族,这些基因产物在不同细胞中的细胞表达、功能和定位不同。在该家族内根据它们的分子量进行命名和分类,例如HSP27、HSP70、HSP90。
一些人类疾病是由错误的蛋白质折叠导致的(见综述,例如Tytell等人,2001;Smith等人,1998)。因此,开发涉及分子伴侣依赖性的蛋白质折叠机制的治疗方案在某些情况中可能是有用的。例如,在阿尔茨海默病、朊病毒疾病或亨廷顿综合征的情况中,错误折叠的蛋白质导致蛋白质聚集,引起神经变性。错误的蛋白折叠还可导致野生型功能丧失,这可能产生错误地调节分子功能和生理功能的后果。
还已对HSPs在肿瘤疾病中的重要性进行了描述。例如有迹象表明某些HSPs的表达与肿瘤进展阶段有关(Martin等人,2000;Conroy等人,1996;Kawanishi等人,1999;Jameel等人,1992;Hoang等人,2000;Lebeau等人,1991)。
HSP90在细胞中许多重要的致癌信号途径中起作用以及某些具有抑癌活性的天然产物以HSP90为靶点的事实,致使人们提出抑制HSP90的功能可以治疗肿瘤疾病的概念。一种HSP90抑制剂,格尔德霉素衍生物,即17-烯丙基氨基-17-脱甲氧基格尔德霉素(17AAG),目前正在进行临床实验。
HSP90
HSP90约占细胞蛋白质总质量的1-2%。它在细胞中通常以二聚体形式存在,并伴随有许多所谓辅分子伴侣的蛋白质(参见,例如Pratt,1997)。对于细胞的活力而言,HSP90至关重要(Young等人,2001),并且HSP90通过与许多已经被外部应激(例如热休克)改变了正常折叠的蛋白相互作用而在对细胞应激的响应中起关键作用,以恢复原始的折叠或防止蛋白聚集(Smith等人,1998)。
还有迹象表明,HSP90是对抗突变作用的重要缓冲物质,推测其通过校正由突变引起的错误的蛋白折叠来实现此作用(Rutherford和Lindquist,1998)。
另外,HSP90还具有调节的重要作用。在生理条件下,HSP90与其在内质网中的同系物GRP94一起,在确保各种关键的客户(client)蛋白的构象稳定和成熟的细胞平衡中起作用。可以将上述客户蛋白分为三类:甾类激素受体、Ser/Thr或酪氨酸激酶(例如ERBB2、RAF-1、CDK4和LCK)以及多种蛋白质的集合,例如突变的p53或端粒末端转移酶hTERT的催化亚单位。这些蛋白质中的每一种都在细胞的生理和生化过程的调节中起关键作用。
在人类中保存的HSP90家族包含四种基因,胞质HSP90α、诱导型HSP90β亚型(Hickey等人,1989)、内质网中的GRP94(Argon等人,1999)和线粒体基质中的HSP75/TRAP1(Felts等人,2000)。人们假设该家族内的所有成员有相似的作用模式,但是由于它们在细胞中的位置不同,它们结合到不同的客户蛋白上。例如,已发现ERBB2是GRP94的特异性客户蛋白(Argon等人,1999),而肿瘤坏死因子的1型受体(TNFR1)或成视网膜细胞瘤蛋白(Rb)为TRAP1的客户蛋白(Song等人,1995;Chen等人,1996)。
HSP90参与了多种与大量客户蛋白和调节蛋白之间的复杂相互作用(Smith,2001)。尽管精确的分子细节还仍没有得到阐明,但是近年来借助于X射线晶体学进行的生化实验和研究已经逐渐能够译解HSP90的分子伴侣功能的详情(Prodromou等人,1997;Stebbins等人,1997)。因此,HSP90是ATP依赖性的分子伴侣(Prodromou等人,1997),对于ATP水解而言其二聚化是重要的。ATP的结合导致形成环形的二聚体结构,其中两个N-末端结构域彼此密切接触并作为构象的开关(Prodromou和Pearl,2000)。
已知的HSP90抑制剂
已发现的第一类HSP90抑制剂是包括除莠霉素A和格尔德霉素的苯醌安莎霉素类化合物。最初,用它们测定由v-Src致癌基因转化诱导的成纤维细胞恶性表型的逆转(Uehara等人,1985)。
后来,它们的强抗肿瘤活性在体外(Schulte等人,1998)和体内(Supko等人,1995)动物模型中得以证明。
接着,对亲和基质的免疫沉淀和观察显示格尔德霉素的主要作用机制包括与HSP90结合(Whitesell等人,1994;Schulte和Neckers,1998)。此外,X射线晶体研究显示格尔德霉素竞争ATP结合位点,并抑制HSP90固有的ATP酶活性(Prodromou等人,1997;Panaretou等人,1998)。这阻止了多聚化的HSP90复合物的形成,该复合物具有作为客户蛋白的分子伴侣的性质。结果,通过泛素-蛋白酶体途径将客户蛋白降解。
在细胞培养物和异种移植肿瘤模型中,格尔德霉素衍生物17-烯丙基氨基-17-脱甲氧基格尔德霉素(17AAG)显示了在抑制HSP90、降解客户蛋白和抗肿瘤活性方面未改变的性质(Schulte等人,1998;Kelland等人,1999),但是与格尔德霉素相比肝毒性显著降低(Page等人,1997)。目前17AAG正在进行I/II期临床实验。
根赤壳菌素是一种大环抗生素,其同样表现出修正v-Src和v-Ha-Ras诱导的成纤维细胞的恶性表型(Kwon等人,1992;Zhao等人,1995)。由于抑制HSP90,根赤壳菌素降解了许多信号蛋白(Schulte等人,1998)。X射线晶体学研究显示根赤壳菌素同样结合到HSP90的N-末端区域,并且抑制固有的ATP酶活性(Roe等人,1998)。
众所周知,香豆素型抗生素结合细菌中的HSP90同系物DNA促旋酶的ATP结合位点。香豆素类化合物新生霉素结合到HSP90的羧基末端,即,结合到HSP90中与苯醌-安莎霉素类和根赤壳菌素不同的位点,苯醌-安莎霉素类和根赤壳菌素结合在HSP90的N-末端(Marcu等人,2000b)。
新生霉素对HSP90的抑制导致大量HSP90依赖的信号蛋白的降解(Marcu等人,2000a)。
信号蛋白(例如ERBB2)的降解用衍生自嘌呤的HSP90抑制剂PU3进行证明。PU3引起细胞周期停滞,并在乳腺癌细胞系中引起分化(Chiosis等人,2001)。
HSP90作为治疗靶点
由于HSP90参与调节大量在肿瘤表型中非常重要的信号传导途径,并且发现某些天然产物通过抑制HSP90的活性而发挥其生物学效应,所以目前将HSP90作为开发肿瘤治疗剂的新靶点进行试验(Neckers等人,1999)。
格尔德霉素、17AAG和根赤壳菌素的主要作用机制包括抑制ATP结合到蛋白质N-末端的ATP结合位点,从而抑制HSP90固有的ATP酶活性(参见,例如Prodromou等人,1997;Stebbins等人,1997;Panaretou等人,1998)。抑制HSP90的ATP酶活性阻止辅分子伴侣的募集并帮助HSP90杂复合物的形成,其导致客户蛋白通过泛素-蛋白酶体途径降解(参见,例如Neckers等人,1999;kelland等人,1999)。用HSP90抑制剂处理肿瘤细胞导致在例如细胞增殖、细胞周期的调节和凋亡等过程中具有基础重要性的重要蛋白的选择性降解。这些过程在肿瘤中经常失控(参见,例如Hostein等人,2001)。开发HSP90抑制剂的吸引人的原因是,可以通过同时降解与转化表型相关的多种蛋白来达到强的肿瘤治疗作用。
具体而言,本发明涉及抑制、调节和/或调控HSP90的化合物以及包含这些化合物的组合物和它们用于治疗HSP90诱导的疾病的方法,所述疾病例如肿瘤疾病;病毒性疾病,例如乙型肝炎(Waxman,2002);移植中的免疫抑制(Bijlmakers,2000和Yorgin,2000);炎症诱导的疾病(Bucci,2000),例如类风湿性关节炎、哮喘、多发性硬化症、1型糖尿病、红斑狼疮、银屑病和炎性肠疾病;囊性纤维化(Fuller,2000);与血管生成相关的疾病(Hur,2002和Kurebayashi,2001),例如糖尿病性视网膜病、血管瘤、子宫内膜异位和肿瘤血管生成;传染性疾病;自身免疫疾病;局部缺血;促进神经再生(Rosen等人,WO 02/09696;Degranco等人,WO 99/51223;Gold,US 6,210,974B1);纤维生成性疾病,例如硬皮病、多发性肌炎、系统性狼疮、肝硬化、疤痕疙瘩形成、间质性肾炎和肺纤维化(Strehlow,WO02/02123)。
本发明还涉及根据本发明的化合物在保护正常细胞对抗化疗引起的毒性中的用途,以及在错误的蛋白折叠或聚集为主要致病因素的疾病中的用途,所述疾病例如瘙痒病、克雅氏病、亨廷顿病或阿尔茨海默病(Sittler,人类分子遗传学(Hum.Mol.Genet.),10,1307,2001;Tratzelt等人,美国国家科学院学报(Proc.Nat.Acad.Sci.),92,2944,1995;Winklhofer等人,生物化学杂志(J.Biol.Chem.),276,45160,2001)。WO 01/72779描述了嘌呤化合物和它们在治疗GRP94(HSP90的同系物或旁系同源物)诱导的疾病中的用途,所述疾病例如肿瘤疾病,其中癌组织包括选自纤维肉瘤、粘液肉瘤、脂肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、骨髓癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、维尔姆斯瘤、宫颈癌、睾丸瘤、肺癌、小细胞肺癌、膀胱癌、上皮细胞癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症和重链病等的肉瘤或癌。
A.Kamal等人在分子医学趋势(Trends in Molecular Medicine),卷10No.6,2004年6月中描述了HSP90活化的治疗和诊断应用,特别是治疗中枢神经系统疾病和心血管疾病。
因此,发现特异性抑制、调节和/或调控HSP90的小分子化合物是需要的,并且是本发明的目的。
已发现5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和其盐具有非常有价值的药理学性质,同时可以被很好地耐受。
特别地,它们具有抑制HSP90的性质。
因此,本发明涉及作为治疗和/或预防所述疾病的药物和/或药物活性成分的5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺,涉及5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺在制备治疗和/或预防所述疾病的药物中的用途,以及治疗所述疾病的方法,该方法包括向需要这类给药的患者施用5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺。
宿主或患者可以属于任何哺乳动物物种,例如灵长类物种,特别是人类;啮齿类动物,包括小鼠、大鼠和仓鼠;兔;马;牛;狗;猫等。用来进行实验研究的动物模型是令人感兴趣的,在此它们提供了治疗人类疾病的模型。
现有技术
WO 2006/087077公开了其他用作HSP90抑制剂的三唑衍生物。
本发明应当被视为其的选择发明。
应当被提及的最接近的现有技术是化合物5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丙基-苯甲酰胺(“A47”)。
WO 00/53169描述了用香豆素或香豆素衍生物抑制HSP90。
WO 03/041643A2公开了抑制HSP90的泽拉诺(zearalanol)衍生物。
抑制HSP90的3-或5-位为芳基取代的吡唑衍生物在WO 2004/050087A1和WO 2004/056782A1中公开。
WO 03/055860A1描述了作为HSP90抑制剂的3,4-二芳基吡唑类。
具有HSP抑制特性的嘌呤衍生物公开在WO 02/36075A2中。
WO 01/72779描述了嘌呤化合物和它们在治疗GRP94(HSP90的同系物或旁系同源物)诱导的疾病中的用途,所述疾病例如肿瘤疾病,其中癌组织包括选自纤维肉瘤、粘液肉瘤、脂肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、骨髓癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、维尔姆斯瘤、宫颈癌、睾丸瘤、肺癌、小细胞肺癌、膀胱癌、上皮细胞癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症和重链病等的肉瘤或癌。
WO 01/72779进一步公开了其中提到的化合物在治疗病毒性疾病中的用途,其中病毒病原体选自甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、流感病毒、水痘病毒、腺病毒、单纯性疱疹I-型病毒(HSV-I)、单纯性疱疹II-型病毒(HSV-II)、牛瘟病毒、鼻病毒、埃可病毒、轮状病毒、呼吸道合胞病毒(RSV)、乳头瘤病毒、乳多孔病毒、巨细胞病毒、棘状病毒(equinovirus)、虫媒病毒、汉坦病毒(huntavirus)、柯萨奇病毒、腮腺炎病毒、麻疹病毒、风疹病毒、脊髓灰质炎病毒、人类免疫缺陷病毒I型(HIV-I)和人类免疫缺陷病毒II型(HIV-II)。
此外,WO 01/72779还描述了其中提到的化合物在GRP94调控中的用途,其中调控的GRP94生物学活性在个体中导致免疫反应、从内质网中的蛋白质转运、从低氧/缺氧应激中恢复、从营养不良中恢复、从热应激恢复或上述的组合,和/或其中病症为癌症、传染性疾病、与扰乱的从内质网中的蛋白质转运相关的病症、与局部缺血/再灌注相关的病症或它们的组合,其中与局部缺血/再灌注相关的病症是由心脏停搏、心搏停止和延迟型室性心律失常、心脏手术、心肺搭桥术、器官移植、脊髓创伤、头创伤、中风、血栓栓塞性中风、出血性中风、脑血管痉挛、张力减退、低血糖、癫痫持续状态、癫痫发作、焦虑症、精神分裂症、神经变性病症、阿尔茨海默病、亨廷顿病、肌萎缩性侧索硬化(ALS)或新生儿应激造成的后果。
最后,WO 01/72779描述了有效量的GRP94蛋白调节剂在制备用于改变个体中组织部位的局部缺血状态后的细胞反应的药物中的用途,上述改变是通过用GRP94蛋白调节剂处理上述组织部位处的细胞,以使细胞中的GRP94活性增加到可使局部缺血状态后的细胞反应发生改变的程度来实现的,其中所述的后续缺血病症优选为心脏停搏、心搏停止和延迟型室性心律失常、心脏手术、心肺搭桥术、器官移植、脊髓创伤、头创伤、中风、血栓栓塞性中风、出血性中风、脑血管痉挛、张力减退、低血糖、癫痫持续状态、癫痫发作、焦虑症、精神分裂症、神经变性病症、阿尔茨海默病、亨廷顿病、肌萎缩性侧索硬化(ALS)或新生儿应激等造成的后果,或者其中所述的组织部位是移植的供体组织。
以下提及的说明书描述了HSP90抑制剂格尔德霉素与其他药物活性成分的组合:WO 2004/108080A2、WO 2005/002506A2、WO 2005/000211A2、WO 2005/000212A2、WO 2005/000213A2、WO 2005/000214A2、WO 2005/000314A1。
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发明概述
本发明涉及化合物5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和其药学上可用的衍生物、盐、溶剂化物、互变异构体和立体异构体,包括它们的任何比例的混合物。
具体而言,本发明涉及化合物5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和其药学上可用的衍生物、互变异构体和立体异构体,包括它们的任何比例的混合物。
本发明特别优选地涉及化合物5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺以及单-和二磷酸衍生物、硫代衍生物、单-和二葡萄糖醛酸衍生物、其互变异构体和立体异构体,包括它们的任何比例的混合物。
本发明非常特别优选地涉及化合物5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺。
本发明还涉及这些化合物的水合物及溶剂化物。化合物的溶剂化物是指惰性溶剂分子加合在所述化合物上的加合物,该加合物是通过它们之间的相互吸引力形成的。溶剂化物例如是单或二水合物或醇化物。
本发明的化合物也可以以下述互变异构形式存在:
药学上可用的衍生物是指,例如本发明化合物的盐,还指所谓的前药化合物。
前药衍生物是指已经被例如烷基或酰基、糖或寡肽修饰的本发明化合物,其在有机体中迅速裂解从而提供活性的本发明化合物。
前药衍生物还包括本发明化合物的生物可降解的聚合物的衍生物,例如在国际药剂学杂志(Int.J.Pharm.)115,61-67(1995)中所描述的。
特别优选的前药是磷酸酯衍生物,例如单-和/或二磷酸酯衍生物;糖衍生物,例如单-和/或二葡萄糖醛酸苷或5-硫代衍生物。
“有效量”的表述指在组织、系统、动物或人类中引起例如研究者或医师所寻求或期望的生物学或医学响应的药物或药物活性成分的量。
此外,“治疗有效量”的表述指与没有接受该量的相应的个体相比,具有下列后果的量:改善的治愈性治疗;康复;预防或消除疾病、病象(disease picture)、疾病状态、不适(complaint)、病症或副作用;或减缓疾病、不适或病症的进程。
术语“治疗有效量”还包括对增强正常生理功能有效的量。
本发明还涉及本发明化合物的混合物,例如两种非对映异构体的混合物,例如其比例为1∶1、1∶2、1∶3、1∶4、1∶5、1∶10、1∶100或1∶1000。
所述混合物特别优选立体异构的化合物的混合物。
此外,本发明化合物和用于制备它们的起始原料是按照如文献(例如标准著作,例如Houben-Weyl,Methoden der organischen chemie[有机化学方法(Methods of Organic Chemistry)],Georg-Thieme-Verlag,Stuttgart)中所述的其本身已知的方法,在公知的和适合进行该反应的精确反应条件下制备的。也可以采用本身已知的变通方法,在此不再详细说明。
如果需要的话,起始原料还可以在原位形成,不将它们从反应混合物中分离,而是立即将它们进一步转化为本发明化合物。
一般而言,起始化合物是已知的。但是,如果它们是新的,则它们可以通过本身已知的方法制备。
本发明化合物按照如WO 2006/087077所述的方法进行制备。
用本领域技术人员公知的方法进行反应。
反应在适当的惰性溶剂中进行。
适当的惰性溶剂的示例是烃类,例如己烷、石油醚、苯、甲苯或二甲苯;氯代烃类,例如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇类,例如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚类,例如乙醚、异丙醚、四氢呋喃(THF)或二噁烷;乙二醇醚类,例如乙二醇单甲醚或单乙醚、乙二醇二甲醚(二甘醇二甲醚);酮类,例如丙酮或丁酮;酰胺类,例如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈类,例如乙腈;亚砜类,例如二甲基亚砜(DMSO);二硫化碳;羧酸类,例如甲酸或乙酸;硝基化合物类,例如硝基甲烷或硝基苯;酯类,例如乙酸乙酯;或上述溶剂的混合物。
特别优选的溶剂是例如四氢呋喃。
根据所用的条件,反应时间为几分钟到14天,反应温度范围为约-30℃到140℃,通常为-10℃到130℃,特别为约30℃到约125℃。
保护基团可通过本领域技术人员公知的方法除去。
醚例如甲醚的裂解在如上文所述的适当溶剂中进行,优选地加入三溴化硼。
所述反应特别优选在二氯甲烷中进行,反应温度在约-30℃至50℃之间,通常在-20℃至20℃之间,特别是在约-15℃至约0℃之间。
本发明的化合物还可以通过溶剂解、尤其是水解作用或氢解作用,将它们从其官能衍生物中释放来获得。
用于溶剂解或氢解反应的优选的起始原料是那些包含相应的被保护的氨基和/或羟基基团,而非一个或多个游离氨基和/或羟基基团的化合物,这些化合物优选地在N原子上带有氨基保护基团而非H原子,例如那些符合式I、但其包含NHR′基团(其中R′代表氨基保护基团,例如BOC或CBZ)来代替NH2基团的化合物。
还优选带有羟基保护基团来代替羟基上的H原子的起始原料,例如那些符合式I、但其包含R″O-苯基基团(其中R″代表羟基保护基团)来代替羟基苯基基团的化合物。
还可能有多种(相同或不同的)被保护的氨基和/或羟基基团存在于起始原料的分子中。如果存在彼此不同的保护基团,其在很多情况下可以选择性地被脱去。
术语“氨基保护基团”是已知的通用术语,涉及适用于保护(阻断)氨基基团避免发生化学反应,但在分子的其它位置所需要的化学反应完成后易于脱去的基团。具体而言,通常的此类基团是未取代或取代的酰基、芳基、芳烷氧基甲基或芳烷基基团。由于所述氨基保护基团是在所需反应(或反应次序)后脱去,因此其类型和大小不是决定性的;然而,优选那些具有1-20个、尤其是1-8个碳原子的保护基团。术语“酰基基团”应当理解为在最广泛的意义上与本方法相关。其包括衍生自脂肪族、芳香脂肪族、芳族或杂环的羧酸或磺酸,并且特别是烷氧基羰基、芳氧基羰基,并且尤其是芳烷氧基羰基的酰基基团。此类酰基基团的实例是链烷酰基,例如乙酰基、丙酰基和丁酰基;芳烷酰基,例如苯乙酰基;芳酰基,例如苯甲酰基和甲苯甲酰基;芳氧基烷酰基,例如POA;烷氧基羰基,例如甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC和2-碘乙氧基羰基;芳烷氧基羰基,例如CBZ(“苄氧羰基”)、4-甲氧基苄氧基羰基和FMOC;以及芳基磺酰基,例如Mtr、Pbf或Pmc。优选的氨基保护基团是BOC和Mtr,以及CBZ、Fmoc、苄基和乙酰基。
术语“羟基保护基团”同样是已知的通用术语,涉及适用于保护羟基基团避免发生化学反应,但在分子的其它位置所需要的化学反应完成后易于脱去的基团。通常的此类基团是上文所述的未取代或取代的芳基、芳烷基或酰基基团,此外还包括烷基基团。因为其在所需化学反应或反应次序后脱去,因此所述羟基保护基团的性质和大小不是决定性的;优选那些具有1-20个、尤其是1-10个碳原子的保护基团。羟基保护基团的实例尤其是苄基、对-硝基苯甲酰基、对-甲苯磺酰基、叔丁基和乙酰基,其中特别优选苄基和叔丁基。COOH基团优选以其叔丁基酯的形式保护。
将本发明的化合物从其官能衍生物中释放出来,取决于所用的保护基团,例如用强酸,有利地使用TFA或高氯酸,也可以使用其它强无机酸,例如盐酸或硫酸,强有机羧酸,例如三氯乙酸,或者磺酸,例如苯磺酸或对甲苯磺酸。反应可能存在额外的惰性溶剂,但并不总是必需的。适合的惰性溶剂优选有机溶剂,例如羧酸如乙酸,醚类如四氢呋喃或二噁烷,酰胺类如DMF,卤代烃如二氯甲烷,此外还有醇类,如甲醇、乙醇或异丙醇,以及水。此外上述溶剂的混合物也是适合的溶剂。优选过量地使用TFA而不加入其它溶剂,而高氯酸优选以乙酸和70%高氯酸以9∶1的比例的混合物形式来使用。用于裂解的反应温度有利地在约0℃至约50℃之间,优选15-30℃(室温)。
例如,BOC、OBut、Pbf、Pmc和Mtr基团可以优选地使用TFA的二氯甲烷溶液或者使用大约3-5N的HCl的二噁烷溶液,在15-30℃下脱去,而FMOC基团可以使用大约5-50%的二甲胺、二乙胺或哌啶在DMF中的溶液在15-30℃下脱去。
可以通过催化氢化除去的保护基团(例如CBZ或苄基)可以例如在催化剂(例如贵金属催化剂,例如钯,其有利地在支持物例如炭上)的存在下通过用氢气处理脱去。此处合适的溶剂是那些上文指出的溶剂,具体而言,例如醇类如甲醇或乙醇,或者酰胺类如DMF。一般而言,氢解是在约0-100℃的温度下和约1-200巴的压力下进行,优选在20-30℃和1-10巴下进行。例如,CBZ的氢解反应在5-10%的Pd/C上在甲醇中完成,或者使用甲酸铵(代替氢气)在Pd/C上在甲醇/DMF中于20-30℃下完成。
药用盐和其它形式
所述的本发明化合物可以以其最终的非盐形式使用。另一方面,本发明还包括药学上可接受的盐形式的该化合物的用途,可以根据本领域公知的方法从各种有机和无机酸和碱衍生得到上述盐。药学上可接受的盐形式的本发明化合物大部分通过常规方法制备。可以通过将该化合物与适当的碱反应得到相应的碱加成盐,从而生成该化合物的适当的盐。所述的碱为,例如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,例如氢氧化钡和氢氧化钙;碱金属的醇盐,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-谷氨酰胺。本发明化合物的铝盐同样也包括在内。也可以通过用药学上可接受的有机或无机酸处理该化合物而形成酸加成盐,所述酸例如卤化氢,例如氯化氢、溴化氢或碘化氢;其它无机酸和其相应的盐,例如硫酸盐、硝酸盐或磷酸盐等;烷基和单芳基磺酸盐,例如乙磺酸盐、甲苯磺酸盐和苯磺酸盐;和其它有机酸及其相应的盐,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,本发明化合物的药学上可接受的酸加成盐包括下列盐: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、硫酸氢盐、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、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡萄糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、半乳糖二酸盐(得自半乳糖二酸)、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酰胺盐、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、氢溴化物、氢碘化物、2-羟基乙磺酸盐、碘化物、羟乙磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、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、扑酸盐(palmoate)、果胶酸盐、过硫酸盐、苯乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这不表示对本发明的限制。
此外,本发明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,但这不意味着限制本发明。在上面提到的盐中,优选铵盐;钠和钾碱金属盐;及钙和镁碱土金属盐。由药学上可接受的有机非毒性碱衍生的本发明化合物的盐包括与下列碱形成的盐,所述碱包括:伯、仲和叔胺,取代的胺,还包括天然存在的取代的胺、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(benzathine)、二环己胺、二乙醇胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基-吗啉、N-乙基-哌啶、葡糖胺(glucamine)、葡糖胺(glucosamine)、组胺、哈胺、异丙胺、利多卡因、赖氨酸、葡甲胺、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(氨基丁三醇),但这不意味着限制本发明。
可以用下列试剂将含有碱性的含氮基团的本发明化合物季铵化,所述试剂例如(C1-C4)烷基卤化物,例如甲基、乙基、异丙基和叔丁基氯化物、溴化物和碘化物;二(C1-C4)烷基硫酸酯,例如二甲基、二乙基和二戊基硫酸酯;(C10-C18)烷基卤化物,例如癸基、十二烷基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物;和芳基(C1-C4)烷基卤化物,例如苄基氯和溴乙基苯。用这些盐可以制备在水和油中都可溶的本发明化合物。
优选的上面提到的药用盐包括乙酸盐、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、氢溴化物、羟乙磺酸盐、扁桃酸盐、葡甲胺盐、硝酸盐、油酸盐、膦酸盐、新戊酸盐、磷酸钠盐、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨基丁三醇盐,但这不意味着限制本发明。
本发明化合物的酸加成盐可以按照常规方法将游离碱形式的该化合物与足量的所需酸接触而制备。可以通过将盐形式与碱接触,并用常规方法分离游离的碱而重新得到游离的碱。就某些物理性质例如在极性溶剂中的溶解性而言,游离的碱形式与其相应的盐形式在某些方面不同;然而,就本发明目的而言,盐与其相应的游离碱形式是相同的。
如上所述,本发明化合物的药学上可接受的碱加成盐是与金属或胺形成的,例如与碱金属和碱土金属或有机胺形成的。优选的金属为钠、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。
可以以常规方法通过将游离的酸形式与足量的所需碱接触而形成盐,从而制备本发明化合物的碱加成盐。可以将盐形式与酸接触,并用常规方法分离游离的酸,从而重新得到游离的酸。就某些物理性质例如在极性溶剂中的溶解性而言,游离的酸形式与其相应的盐形式在某些方面不同;然而,就本发明目的而言,盐与其相应的游离酸形式是相同的。
就上述来讲,可以明白,本发明中的“药学上可接受的盐”的表述是指包括某种盐形式的本发明化合物的活性成分,特别是在如果该盐形式与活性成分的游离形式或以前所用的该活性成分的其它任何盐形式相比,活性成分的药物动力学性质得以改善的情况下。活性成分的药学上可接受的盐形式还可以首次提供该活性成分从前没有、但又需要的药物动力学性质,就其在体内的疗效而言,它甚至可以对该活性成分的药效学有积极的影响。
此外,本发明涉及本发明的化合物和/或其生理上可接受的盐在制备药物(药物组合物)中的用途,特别是通过非化学方法。在此可以将它们与至少一种固体、液体和/或半液体的赋形剂或辅助剂,以及如果需要的话还有一种或多种另外的活性成分,一起转化为适当的剂型。
此外,本发明还涉及药物,该药物包含5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和/或其药学上可用的衍生物、盐、溶剂化物、互变异构体和立体异构体(包括它们任何比例的混合物),以及任选的赋形剂和/或辅助剂。
药物制剂可以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。根据所治疗的疾病情况、给药方法和患者的年龄、体重和状况,该剂量单位可以包含例如0.1mg至3g、优选1-700mg、特别优选5-100mg的本发明化合物,或者可以以每剂量单位包含预定量的活性成分的剂量单位形式施用药物制剂。优选的剂量单位制剂包含如上所示的日剂量或部分剂量或活性成分的其相应部分。而且,该类型的药物制剂可以用药学领域众所周知的方法制备。
药物制剂可以调配为通过任何所需的适当方法给药,例如经口(包括含服或舌下)、直肠、鼻、局部(包括颊、舌下或经皮)、阴道或胃肠外(包括皮下、肌内、静脉内或皮内)的方法。这些制剂可以使用所有药学领域公知的方法通过例如将活性成分与赋形剂或辅助剂混合来制备。
适合于口服给药的药物制剂可以以分离的单位给药,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;可食用的泡沫剂或泡沫食品;或水包油型的液体乳剂或油包水型的液体乳剂。
因此,例如在片剂或胶囊的口服给药情况中,活性成分组分可以与口服的非毒性的及药学上可接受的惰性赋形剂例如乙醇、甘油、水等混合。散剂是通过将化合物研细至适当微细尺寸,并将其与用相似方法研细的药用赋形剂混合而制备,所述赋形剂例如可食用的碳水化合物,例如淀粉或甘露醇。也可以存在矫味剂、防腐剂、分散剂和染料。
胶囊是通过制备如上面所述的粉末混合物并随后填装进成形的明胶壳中来制备的。在填装操作前可以向粉末混合物中加入助流剂和润滑剂,例如高分散的硅酸、滑石粉、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇。同样可以加入崩解剂或助溶剂,例如琼脂、碳酸钙或碳酸钠,以提高胶囊服用后的药物利用度。
另外,如果需要或必要的话,也可以向混合物中掺入适当的粘合剂、润滑剂和崩解剂及染料。适当的粘合剂包括淀粉;明胶;天然的糖,例如葡萄糖或β-乳糖;由玉米制得的甜味剂;天然和合成的橡胶,例如阿拉伯胶、黄蓍胶;或藻酸钠;羧甲基纤维素;聚乙二醇;蜡等。在这些剂型中所用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。片剂是通过下面方法制备的,所述方法包括例如制备粉末混合物、制粒或干燥压制该混合物、加入润滑剂和崩解剂并将全部的混合物压片得到片剂。粉末混合物是通过将用适当方法研细的化合物与如上面所述的稀释剂或基质以及任选的以下物质混合制得的,所述物质包括粘合剂,例如羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮;溶出缓速剂,例如石蜡;吸收促进剂,例如季盐;和/或吸收剂,例如膨润土、高岭土或磷酸二钙。可以如下将粉末混合物制粒:将其用粘合剂例如糖浆、淀粉糊、阿拉伯胶(acadia)胶浆或者纤维素或多聚物材料的溶液润湿,并将其压过筛网。制粒的另一方法是,可以将粉末混合物通过制片机,得到非规则形状的块,将其打碎形成颗粒。可以向这些颗粒中加入硬脂酸、硬脂酸盐、滑石粉或矿物油进行润滑,以防止其粘附在片剂铸型中。然后,将润滑的混合物压制成片剂。本发明化合物还可以与自由流动的惰性赋形剂组合,然后不经制粒或干压步骤,直接压成片剂。还可以存在透明的或遮光的保护层,其包括虫胶封装层、糖或多聚物材料层和光泽的蜡层。可以向这些包衣中加入染料,以便能够区别不同的剂量单位。
口服液体,例如溶液剂、糖浆剂和酏剂,可以以剂量单位形式制备,以使其包含指定量的化合物。可以将化合物溶解在含有适当矫味剂的水溶液中制得糖浆剂,而酏剂可以用非毒性的醇溶媒制得。可以通过将化合物分散于无毒溶媒中来制备混悬剂。同样可以加入增溶剂和乳化剂,例如乙氧化的异硬脂醇和聚氧乙烯山梨醇醚;防腐剂;矫味添加剂,例如薄荷油;或天然甜味剂或糖精;或其它人工甜味剂等。
如果需要的话,用于口服的剂量单位制剂可以装入微胶囊中。还可以通过例如将颗粒原料包衣或包埋在聚合物、蜡等材料中,以制备释放延长释放或延缓释放的制剂。
本发明化合物和/或其药学上可接受的衍生物、盐、溶剂化物、互变异构体和立体异构体(包括它们所有比例的混合物),和任选的赋形剂和/或辅助剂和盐、溶剂化物和生理学上的功能衍生物还可以以脂质体递药系统形式给药,例如小单层微囊、大单层微囊和多层微囊。脂质体可以用各种磷脂例如胆固醇、硬脂胺或磷脂酰胆碱形成。
本发明化合物和其盐、溶剂化物和生理学上的功能衍生物还可以用单克隆抗体作为个体载体进行递送,该载体上偶联着上述化合物分子。还可以将化合物偶联在作为靶向药物载体的可溶性多聚物上。所述多聚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、聚羟乙基天冬酰胺基苯酚或聚环氧乙烷聚赖氨酸,其被棕榈酰基取代。此外还可以将这些化合物偶联至适合于控制药物释放的一类生物可降解的聚合物上,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、聚氰基丙烯酸酯和交联或两亲的水凝胶嵌段共聚物。
适合于经皮给药的药物制剂可以以与受者的表皮发生扩展的密切接触的独立贴剂进行给药。因此,例如可以通过电离子透入疗法从贴剂中递送活性成分,如在药学研究(Pharmaceutical Research),3(6),318(1986)的一般术语中所描述的。
适合于局部给药的药物化合物可以制成软膏剂、乳膏剂、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。
对于治疗眼或其它外部组织,例如口腔和皮肤而言,制剂优选以局部的软膏剂或乳膏剂使用。在制剂为软膏剂的情况下,活性成分可以与石蜡或与水混溶的乳膏基质一起应用。或者,可以将活性成分与水包油型乳膏基质或油包水型基质一起制成乳膏剂。
适合于眼局部用药的药物制剂包括滴眼剂,其中将活性成分溶解或混悬在适当的载体、特别是水性溶剂中。
适合于口腔局部用药的药物制剂包括锭剂、软锭剂和漱口剂。
适合于直肠给药的药物制剂可以以栓剂或灌肠剂形式给药。
载体物质为固体的适合于鼻腔给药的药物制剂包含粒度为例如20-500微米的粗粉末,该粗粉末通过鼻吸入的方式给药,即从靠近鼻子的含有该粉末的容器中通过鼻道快速吸入。由液体作为载体物质的用于鼻喷雾剂或滴鼻剂给药的合适制剂包括活性成分的水或油溶液。
适合于吸入给药的药物制剂包含微细颗粒的粉尘或雾,它们可以由如气雾器、喷雾器或吹入器的不同类型的加压分散器产生。
适合于阴道给药的药物制剂可以以阴道栓剂、卫生栓、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾剂给药。
适合于胃肠外给药的药物制剂包括水性或非水性的无菌注射溶液,该溶液包含抗氧化剂、缓冲剂、抑菌剂和溶解物,这些溶解物使制剂与所治疗的受者的血液等渗;以及水性或非水性的无菌混悬剂,其包含混悬介质和增稠剂。制剂可以以单剂量或多剂量的容器例如密封的安瓿和管形瓶给药,并以冷冻干燥(冻干)状态保存,以便在使用前只需立即加入无菌载体液体例如注射用水即可。
根据配方制备的注射溶液和混悬液可以由无菌的粉末、颗粒或片制备。
无需说明,除了上面特别提到的成分外,制剂还可以包含用于特定类型制剂的其它在本领域中常用的物质;因此,例如,适合于口服给药的制剂可以包含矫味剂。
本发明化合物的治疗有效量依赖于很多因素,包括例如人或动物的年龄和体重、需要治疗的精确的疾病状况和其严重程度、制剂的性质和给药方法,并且最终由主治医生或兽医确定。然而,本发明化合物的有效量通常为每天0.1-100mg/kg受者(哺乳动物)体重,特别是每天1-10mg/kg体重。因此,对于体重70kg的成年哺乳动物的每天实际用量通常为70-700mg,其中,该量可以以每天单次剂量给药或通常以每天一系列的分份剂量(例如二、三、四、五或六次)给药,但总的日剂量是相同的。可以将其盐或溶剂化物或生理学上的官能衍生物的有效量按照本发明化合物本身的有效量的部分进行确定。可以假定对于治疗上面提到的其它病症而言,类似的剂量是合适的。
此外,本发明还涉及药物,该药物包含至少一种本发明化合物和/或其药学上可用的衍生物、溶剂化物和立体异构体(包括其任何比例的混合物),以及至少一种另外的药物活性成分。
另外的药物活性成分优选化疗剂,特别是抑制血管生成并因此抑制肿瘤细胞生长和扩散的化疗剂;此处优选VEGF受体抑制剂,包括针对VEGF受体的核酶和反义物质,以及血管生成抑制因子和内皮抑素。
可以与本发明化合物组合使用的抗肿瘤药的实例通常包括烷化剂、抗代谢药;表鬼臼毒素;抗肿瘤酶;拓扑异构酶抑制剂;丙卡巴肼;米托蒽醌或铂配位络合物。
抗肿瘤药优选地选自下面类别的化合物:蒽环类、长春花属药物、丝裂霉素类、博来霉素类、细胞毒的核苷类、埃坡霉素类、淅皮海绵内酯类(discormolides)、蝶啶类、diynenes和鬼臼毒素类。
上述类别化合物中特别优选例如洋红霉素、柔红霉素、氨基蝶呤、甲氨蝶呤、甲基叶酸、二氯甲氨蝶呤、丝裂霉素C、泊非霉素、5-氟尿嘧啶、5-氟脱氧尿嘧啶单磷酸盐、阿糖胞苷、5-氮杂胞苷、硫鸟嘌呤、硫唑嘌呤、腺苷、喷司他丁、赤式羟基壬基腺嘌呤、克拉屈滨、6-巯基嘌呤、吉西他滨、阿糖胞苷、鬼臼毒素或鬼臼毒素衍生物(例如依托泊苷、磷酸依托泊苷或替尼泊苷)、美法仑、长春碱、长春瑞滨、长春新碱、异长春碱、长春地辛、长春罗新、多西紫杉醇和紫杉醇。其它优选的抗肿瘤药选自discormolide、埃坡霉素D、磷雌氮芥、卡铂、顺铂、奥沙利铂、环磷酰胺、博来霉素、吉西他滨、异环磷酰胺、美法仑、六甲密胺、塞替派、idatrexate、三甲曲沙、达卡巴嗪、L-天冬酰胺酶、喜树碱、CPT-11、托泊替康、阿糖胞苷、比卡鲁胺、氟他胺、亮丙瑞林、吡啶并苯并吲哚衍生物、干扰素和白介素。
另外的药物活性成分优选抗生素。优选的抗生素选自更生霉素、柔红霉素、伊达比星、表柔比星、米托蒽醌、博来霉素、光神霉素、丝裂霉素。
另外的药物活性成分优选酶抑制剂。优选的酶抑制剂选自组蛋白去乙酰抑制剂(例如辛二酰苯胺异羟肟酸[SAHA])和酪氨酸激酶抑制剂(例如ZD1839[Iressa])。
另外的药物活性成分优选核输出抑制剂。核输出抑制剂阻止生物聚合体(例如RNA)从细胞核输出。优选的核输出抑制剂选自Callystatin、来普霉素B、Ratjadone。
另外的药物活性成分优选核输出抑制剂。核输出抑制剂阻止生物聚合体(例如RNA)从细胞核输出。优选的核输出抑制剂选自Callystatin、来普霉素B、Ratjadone。
另外的药物活性成分优选免疫抑制剂。优选的免疫抑制剂选自雷帕霉素、CCI-779(惠氏(Wyeth)公司)、RAD001(诺华(Novartis)公司)、AP23573(Ariad制药公司)。
本发明还涉及套盒(药盒),该套盒包含独立包装的
(a)有效量的本发明化合物和/或其药学上可用的衍生物、溶剂化物和立体异构体,包括它们任何比例的混合物,和
(b)有效量的另外的药物活性成分。
该套盒包含适当的容器,例如盒子、单独的瓶、袋或安瓿。该套盒可以例如包含分离的安瓿,每个安瓿中包含溶解或冻干形式的有效量的本发明化合物和/或其药学上可用的衍生物、溶剂化物和立体异构体(包括它们的所有比例的混合物)以及有效量的另外的药物活性成分。
用途
本发明化合物适合于作为治疗哺乳动物特别是人类中HSP90起作用的疾病的药物活性成分。
因此,本发明涉及5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和其药学上可用的衍生物、溶剂化物和立体异构体(包括它们的任何比例的混合物)在制备治疗其中HSP90的抑制、调节和/或调控起作用的疾病的药物中的用途。
本发明包括5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺及其药学上可用的衍生物、溶剂化物和立体异构体(包括它们的任何比例的混合物)在制备治疗下列疾病的药物中的用途:肿瘤疾病,例如纤维肉瘤、粘液肉瘤、脂肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、骨髓癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、维尔姆斯瘤、宫颈癌、睾丸瘤、肺癌、小细胞肺癌、膀胱癌、上皮细胞癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症和重链病;
病毒性疾病,其中病毒病原体选自甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、流感病毒、水痘病毒、腺病毒、单纯性疱疹I型病毒(HSV-I)、单纯性疱疹II型病毒(HSV-II)、牛瘟病毒、鼻病毒、埃可病毒、轮状病毒、呼吸道合胞病毒(RSV)、乳头瘤病毒、乳多孔病毒、巨细胞病毒、棘状病毒、虫媒病毒、汉坦病毒、柯萨奇病毒、腮腺炎病毒、麻疹病毒、风疹病毒、脊髓灰质炎病毒、人免疫缺陷病毒I型(HIV-I)和人免疫缺陷病毒II型(HIV-II);
用于移植中的免疫抑制;炎症诱导的疾病,例如类风湿性关节炎、哮喘、多发性硬化症、1型糖尿病、红斑狼疮、银屑病和炎性肠疾病;囊性纤维化;与血管生成相关的疾病,例如糖尿病性视网膜病、血管瘤、子宫内膜异位、肿瘤血管生成;传染性疾病;自身免疫疾病;局部缺血;神经再生的促进;纤维生成性疾病,例如硬皮病、多发性肌炎、系统性狼疮、肝硬化、疤痕疙瘩形成、间质性肾炎和肺纤维化;
5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺可以抑制特别是癌、肿瘤细胞和肿瘤转移灶的生长,因此适合于肿瘤治疗。
此外,本发明包括5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和/或其生理上可接受的盐和溶剂化物在制备保护正常细胞对抗化疗引起的毒性的药物以及治疗错误的蛋白折叠或聚集是主要致病因素的疾病(例如瘙痒病、克雅氏病、亨廷顿病或阿尔茨海默病)的药物中的用途。
本发明还涉及5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和/或其生理上可接受的盐和溶剂化物在制备治疗中枢神经系统疾病、心血管病和恶病质的药物中的用途。
在另外的实施方案中,本发明还涉及5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和/或其生理上可接受的盐和溶剂化物在制备用于HSP90调控的药物中的用途,其中调控的HSP90生物活性引起个体的免疫反应、从内质网中的蛋白质转运、从低氧/缺氧应激中恢复、从营养不良中恢复、从热应激中恢复或上述的组合,和/或其中病症为癌症、传染性疾病、与扰乱的从内质网中的蛋白质转运相关的病症、与局部缺血/再灌注相关的病症或它们的组合,其中与局部缺血/再灌注相关的病症是由心脏停搏、心搏停止和延迟型室性心律失常、心脏手术、心肺搭桥术、器官移植、脊髓创伤、头创伤、中风、血栓栓塞性中风、出血性中风、脑血管痉挛、张力减退、低血糖、癫痫持续状态、癫痫发作、焦虑症、精神分裂症、神经变性病症、阿尔茨海默病、亨廷顿病、肌萎缩性侧索硬化(ALS)或新生儿应激造成的后果。
在另外的实施方案中,本发明还涉及5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和/或其生理上可接受的盐和溶剂化物在制备治疗局部缺血的药物中的用途,所述局部缺血是由心脏停搏、心搏停止和延迟型室性心律失常、心脏手术、心肺搭桥术、器官移植、脊髓创伤、头创伤、中风、血栓栓塞性中风、出血性中风、脑血管痉挛、张力减退、低血糖、癫痫持续状态、癫痫发作、焦虑症、精神分裂症、神经变性病症、阿尔茨海默病、亨廷顿病、肌萎缩性侧索硬化(ALS)或新生儿应激造成的后果。
测定HSP90抑制剂的实验方法
可以利用格尔德霉素或17-烯丙基氨基-17-脱甲氧基格尔德霉素(17AAG)与HSP90的结合以及它们的竞争性抑制作用,测定本发明化合物的抑制活性(Carreras等人,2003;Chiosis等人,2002)。
在具体的方案中,使用放射性配体过滤结合实验。此处所用的放射性配体是氚标记的17-烯丙基氨基格尔德霉素,[3H]17AAG。该过滤结合实验可用于靶向寻找干扰ATP结合位点的抑制剂。
材料:
重组人HSP90α(大肠杆菌表达,95%纯度);
[3H]17AAG(17-烯丙基氨基格尔德霉素,[烯丙基氨基-2,3-3H]。比活性:1.11×1012Bq/mmol(Moravek,MT-1717);
HEPES过滤缓冲液(50mM HEPES,pH 7.0,5mM MgCl2,BSA0.01%)
Multiscreen FB(1μm)过滤板(Millipore,MAFBNOB 50)。
方法:
首先将96-孔微滴定过滤板用0.1%聚乙烯亚胺冲洗和涂覆。
在下面的条件下进行实验:
反应温度22℃
反应时间:30分钟,在800rpm下振荡
实验体积:50μl
终浓度:
50mM HEPES HCl,pH 7.0,5mM MgCl2,0.01%(w/v)BSA
HSP90:1.5μg/试验
[3H]17AAG:0.08μM。
在反应终止时,用多头真空仪器(Multiscreen Separation System,Millipore)通过吸取将过滤板中的上清液除去,并将滤板洗涤两次。
然后在β计数器(Microbeta,Wallac)下用闪烁器(Microscint 20,Packard)测定滤板。
根据“每分钟计数”的值确定“对照的百分数(%)”,并由此计算出化合物的IC50值。
下表显示本发明化合物与最接近的现有技术的化合物“A47”的比较测定。本发明的化合物“C1”在抑制HSP90方面具有高出约10倍的活性。
试验结果:
表1
HSP90的抑制作用
在上下文中,所有的温度是以℃为单位表示的。在下面的实施例中,“常规后处理”是指:如果需要的话,加入水,如果需要的话,根据终产物的组成调节pH至2-10,将混合物用乙酸乙酯或二氯甲烷萃取,分离各相,将有机相用硫酸钠干燥并蒸发,产物通过硅胶色谱法和/或通过结晶纯化。Rf值为在硅胶上的值;洗脱剂:乙酸乙酯/甲醇9∶1。
LC-MS条件
采用具有下列特征的HP 1100系列Hewlett Packard System:离子源:电喷雾(阳极模式);扫描:100-1000m/e;断裂电压:60V;气体温度:300℃,DAD:220nm。
流速:2.4ml/min。在DAD后,所用的分流器将对于MS的流速减至0.75ml/min。
柱:Chromolith SpeedROD RP-18e 50-4.6
溶剂:来自Merck KGaA的LiChrosolv级
溶剂A:H2O(0.01%TFA)
溶剂B:ACN(0.008%TFA)
梯度:
20%的B→100%的B:0分钟至2.8分钟
100%的B:2.8分钟至3.3分钟
100%的B→20%的B:3.3分钟至4分钟
在下面的实施例中所述的保留时间Rf或Rt[min]和M+H+数据MW为LC-MS的测定结果。
参考实施例1
制备5-(2,4-二羟基-5-苯乙基苯基)-4-(2-氟苯基)-3-羟基-4H-1,2,4-三唑(“A1”):
1.1将15g的5-溴-2,4-二羟基苯甲酸、14.4ml碘甲烷和62.9g碳酸铯在100ml的N,N-二甲基甲酰胺(DMF)中回流加热16小时。将该混合物进行常规后处理,得到16.7g的5-溴-2,4-二甲氧基苯甲酸(“1”)。
1.2将4g的“1”和2滴DMF在40ml亚硫酰氯中的混合物在室温下搅拌16小时。除去溶剂得到4.3g的5-溴-2,4-二甲氧基苯甲酰氯(“2”),Rf1.610;MW 280.5。该产物不需进一步纯化直接进行反应。
1.3将3.8g的“2”在25ml二氯甲烷中的溶液在冰冷却下逐滴加入1.314ml的2-氟苯胺和1.13ml吡啶在25ml二氯甲烷的溶液中,并将该混合物在室温下搅拌5小时。常规后处理并从异丙醇中结晶得到4.5g的5-溴-N-(2-氟苯基)-2,4-二甲氧基苯甲酰胺(“3”),Rf 2.217;MW 355.2。
1.4将2.9g的PCl5在氮气中加入4.5g的“3”在60ml甲苯的溶液中,并将该混合物回流加热3小时。除去溶剂,将残余物溶于100ml的THF中,并将该溶液在0℃下逐滴加至138ml的1M肼在THF的溶液中。再搅拌该混合物16小时,进行常规后处理并从异丙醇中结晶,得到3.6g的N-(2-氟苯基)-3-溴-4,6-二甲氧基苯甲酰胺腙(“4”),Rf 0.952;MW 369.2
1.5将1.86g的1,1′-羰基二咪唑(“5”)加至3.6g的“4”在300ml的THF的溶液中,并将该混合物再搅拌16小时。将该混合物进行常规后处理,残余物与MTB醚共沸并冷却,分离结晶,得到700mg的5-(2,4-二甲氧基-5-溴苯基)-4-(2-氟苯基)-3-羟基-4H-1,2,4-三唑(“6”),Rf1.413;MW 395.2。
1.6将600mg的“6”、178.4μl苯乙烯(稳定化的)、430.2μl三乙胺、14.1mg醋酸钯(II)(47%的钯)、19.17mg三-邻甲苯基膦和4ml乙腈装入一个10ml的小瓶中。将该混合物在170℃下在微波中照射30分钟。加入少量催化剂,并将该混合物再进行第二次照射。将甲苯加入该混合物中,其随后用水萃取多次。将有机相干燥并蒸发。残余物经RP色谱纯化,得到140mg的“7”,Rf1.765;MW 418.4,以及40mg的“8”
1.7将140mg的“7”在标准条件下在10ml THF中在0.14g的Pt/C(5%)存在下氢化。随后分离除去催化剂,进行常规后处理,得到140mg的“9”,Rf 1.920;MW 420.5
1.8将158.5μl三溴化硼在-10℃下加至140mg的“9”在2ml二氯甲烷的溶液中,并将该混合物在室温下再搅拌16小时。在0℃下加入甲醇,分离溶剂,并将残余物经RP色谱纯化,得到74mg的“A1”,Rf 1.537;MW 392.4,以及27mg的“A2”,Rf1.884;MW 398.4
参考实施例2
制备5-[4-(2-氟苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丙基苯甲酰胺(“A46”)
2.1将100mg的5-(2,4-二甲氧基-5-溴苯基)-4-(2-氟苯基)-3-羟基-4H-1,2,4-三唑(“6”)、7mg的[(R)-(+)-2,2′-二-(二苯基膦基)-1,1′-联萘基]氯化钯(II)、5.7ml一氧化碳和35μl三乙胺在20ml甲醇中的溶液在100℃和7.5巴的条件下在高压锅中处理20小时。随后将所得溶液浓缩并在乙醇中结晶,得到91mg的5-[4-(2-氟苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二甲氧基苯甲酸甲酯
2.2与实施例1.8类似,90mg的5-[4-(2-氟苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二甲氧基苯甲酸甲酯的反应得到57.2mg的化合物5-[4-(2-氟苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基苯甲酸,Rt0.598分钟,m/e 332。
2.3将55mg的5-[4-(2-氟苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基苯甲酸、2摩尔当量的叔丁基二甲基氯硅烷和3摩尔当量的咪唑在2ml的THF中的溶液在室温下搅拌3小时,得到
2.4将2.3中所得的产物溶于1.5ml的THF中,并加入2当量的1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸化物。室温下1小时后,加入1.2当量的丙基甲基胺,将该混合物再搅拌18小时。然后加入3当量的四甲基氟化铵,将该混合物在室温下搅拌2小时。浓缩后,分离产物,得到42mg的“A46”;Rt 1.139分钟,m/e 387;MW 386
以下化合物采用类似方法获得:
5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丙基苯甲酰胺(“A47”),MW 383.4。
实施例1
本发明化合物5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基苯甲酰胺(“C1”)采用与制备“A47”类似的方法获得;
1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),9.92(s,1H),7.28-7.23(m,2H),7.14-7.10(m,1H),7.03-7.01(m,1H),6.88(s,1H),6.26(s,1H),3.16(宽m,2H),2.73(宽s,3H),2.14(s,3H),1.40(宽m,2H),1.15(宽m,2H),0.81(宽m,3H)。
实施例2
“C1”的合成可以按照下式进行:
2.15-溴-2,4-二羟基苯甲酸(1):
将3.55kg的2,4-二羟基苯甲酸溶于30升冰醋酸中。随后在15℃下历经8小时逐滴加入1060ml溴在10升冰醋酸中的溶液。然后在20℃下继续搅拌16小时,将该混合物真空蒸发,将该结晶状残余物在20升二氯甲烷中浆体化并搅拌1小时。过滤并在空气中干燥,得到4.9kg白色粗产物。在30升甲苯/乙腈(1∶1)中重结晶并干燥,得到3.549kg(66%产率)的5-溴-2,4-二羟基苯甲酸(熔点210-211.5℃;MW 233.0)。
2.25-溴-2,4-二羟基苯甲酸甲酯(2):
将8.9kg的5-溴-2,4-二羟基苯甲酸溶于70升甲醇中并加热至55℃。然后定量加入800ml硫酸(w=95-98%),并将该混合物在温和回流下搅拌4天,每天额外加入500ml硫酸(w=95-98%)(3次)。将该反应混合物加入9kg碳酸氢钠在100升水的冷却溶液中并搅拌。过滤并在50℃真空干燥,得到7.87kg(83%)的5-溴-2,4-二羟基苯甲酸甲酯(白色结晶),MW 247.1。
2.32,4-二苄氧基-5-溴苯甲酸甲酯(3):
在0℃下将7.86kg(83%)的5-溴-2,4-二羟基苯甲酸甲酯和9.65g碳酸钾悬浮于100升乙腈中。随后将该混合物加热至80℃,并通过滴液漏斗历经40分钟加入7575ml苄基溴。在80℃下搅拌16小时后,过滤该混合物,并将收集的滤液在真空中蒸发:12.95kg(95%)的2,4-二苄氧基-5-溴苯甲酸甲酯(淡黄色结晶);MW 427.3。
2.42,4-二苄氧基-5-溴苯甲酸(4):
将6.4kg的2,4-二苄氧基-5-溴苯甲酸甲酯在18升THF中的溶液加入3kg氢氧化钠在30升水的溶液中。在68℃下搅拌过夜后,将该混合物冷却至10℃,并通过滴液漏斗加入7.5升HCl(w:37%)(pH 1)。将该混合物搅拌1小时并随后过滤。将残余物在60℃真空干燥至恒重;5.687kg(91%)的2,4-二苄氧基-5-溴苯甲酸(熔点150-152℃;MW 413.3)。
2.52,4-二苄氧基-5-溴-N-邻-甲苯基苯甲酰胺(5):
将80ml的DMF加入42升亚硫酰氯。将该混合物冷却至2-9℃,并历经1小时加入11.55kg的2,4-二苄氧基-5溴苯甲酸。在此温度下继续搅拌1小时,然后在25℃下搅拌16小时。然后在真空中(300毫巴,46℃)蒸馏去亚硫酰氯。向所得残余物中加入3升甲苯,并将该混合物再次蒸发至干,并将该方法再重复两次。所得产物不需进一步纯化直接用于以下反应。13.6kg(含甲苯)。
在3℃下将2.8升邻-甲苯胺和2.5升吡啶加入50升二氯甲烷中。将悬浮在35升二氯甲烷中的13.6kg的2,4-二苄氧基-5-溴苯甲酰氯(含有甲苯)历经2小时加入该溶液中。随后将该混合物在23℃下搅拌过夜,滤出固体,并用二氯甲烷冲洗(2×每次5升)。将该方法所得的粗产物(8kg)溶于40升二氯甲烷中,并连续用40升蒸馏水、50升盐酸(约1mol/l;从5升HCl w:37%和50升水制备)萃取。随后用50升水洗涤有机相。用6kg硫酸钠干燥有机相3天。用抽滤漏斗抽滤除去干燥剂,并将滤液在旋转蒸发仪中蒸发至干。从乙醇(35升,65℃)中重结晶并干燥(50℃/35毫巴)至恒重,得到10.84kg(82%)的2,4-二苄氧基-5-溴-N-邻-甲苯基苯甲酰胺(熔点174.5℃-176℃;MW 502.4)。
2.65-(2,4-二苄氧基-5-溴苯基)-4-(2-甲基苯基)-3-羟基-4H-1,2,4-三唑(6):
在3℃下将1.75kg五氯化磷加入3.5kg的2,4-二苄氧基-5-溴-N-邻-甲苯基苯甲酰胺在60升甲苯的溶液中。然后将该混合物在135℃下加热4小时,并在25℃继续搅拌16小时。真空蒸发,得到3.6kg结晶物质。将后者溶于18升THF中并在3℃下历经1.5小时加入到1.38kg的Boc-肼在30升THF的溶液中。加温至25℃并搅拌16小时后,抽滤出该产物(4.3kg白色产物-含THF)并直接用于以下反应。
将该产物溶于30升THF中,在1℃下历经20分钟加入7升盐酸(w:37%)。在23℃搅拌该混合物16小时并冷却至-5℃,历经1.5小时逐滴加入7.5升氢氧化钠溶液(w:32%)。两相分离,用25升饱和氯化钠溶液(用8.75kg氯化钠和25升水制备)洗涤有机相。用6kg硫酸钠干燥有机相,抽滤出干燥剂,并将滤液在旋转蒸发仪中蒸发至干。将2×5升的甲苯加入残余物,并进行“剧烈(sharp)”蒸馏来“夹带”除去剩余的水分。该方法所得的残余物直接用于进一步的反应。
将1.3kg羰基二咪唑(CDI)溶于100升THF中。冷却至3℃后,将前一反应的产物缓慢逐滴加入25升THF中。然后在25℃下搅拌该混合物16小时,并用30升饱和氯化钠溶液萃取,然后有机相用25升1N HCl萃取。随后有机相用25升饱和氯化钠溶液洗涤并用10kg硫酸钠干燥。过滤并真空蒸发有机相得到固体残余物,将其溶于5升甲苯中并再次真空蒸发至干。在70℃将其从20升2-丙醇中重结晶,得到2.7kg(76%)的5-(2,4-二苄氧基-5-溴苯基)-4-(2-甲基苯基)-3-羟基-4H-1,2,4-三唑,MW 542.4。
2.75-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二苄氧基-N-甲基-N-丁基苯甲酰胺(7):
将2kg的5-(2,4-二苄氧基-5-溴苯基)-4-(2-甲基苯基)-3-羟基-4H-1,2,4-三唑、90g的(1,1′-二(二苯基膦基)-二茂铁)氯化钯(II)、83升一氧化碳、479g三乙胺和400g的N-甲基丁胺在25升THF中的溶液在120℃和5-10巴的条件下在高压锅中处理20小时。随后将所得溶液蒸发并从乙醇中结晶,得到1.4kg(70%)的5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二苄氧基-N-甲基-N-丁基苯甲酰胺,MW 476.7。
2.85-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基苯甲酰胺(“A1”):
将1.1kg的5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二苄氧基-N-甲基-N-丁基苯甲酰胺、5%的Pd/C(50.5%的水)和85升氢在10升THF中的溶液在23℃下在高压锅中处理7小时。随后将所得溶液蒸发并从乙醇中重结晶,得到738g(95%)的5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基苯甲酰胺(“C1”);MW 396.5。
可以分离到本发明的化合物“C1”的两种多晶型物A1和A2。
熔点:
晶型A1:熔点238.5±0.1℃(n=6)
晶型A2:熔点209.6±0.2℃(n=6)
晶型A1是热力学上更稳定的晶型。
两种多晶型物的粉末X-射线衍射光谱如图1所示。
晶型A2可以转化为A1,例如通过在例如甲醇、乙醇、丙酮、DMF、乙酸、甲酸、THF或异丙醇的溶剂中搅拌来进行。
多晶型物A1和A2的粉末XRD光谱数据:
10个特征峰各自用于评价。
样品 | XRD原始数据 |
第7批,晶型A1 | RT 162-07 |
第12批,晶型A2 | RT 2214-07 |
方法和结果:
X-射线粉末衍射(XRD)
用XRD检测全部样品
RT 162-07:
●D5000衍射仪[Bruker AXS]
●传递模式
●发生器功率30kV/40mA
●位置敏感检测器
XRD检测条件:
范围:3-65°2θ
分辨率:0.05°2θ
步进时间:1.4秒
RT 2214-07:
●Stoe粉末X-射线衍射仪系统STADIP 611 KL
●传递模式
●发生器功率40kV/40mA
●位置敏感检测器
XRD检测条件:
范围:3-65°2θ
分辨率:0.5°2θ
步进时间:15秒
晶型A1;RT 162-07:
晶型A2;RT 2214-07:
前药化合物的制备
实施例3
制备[2-(丁基甲基氨基甲酰基)-5-羟基-4-(5-氧代-4-邻甲苯基-4,5-二氢-1H-1,2,4-三唑-3-基)苯基]单磷酸酯
首先将700mg的5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-4-苄氧基-2-羟基-N-甲基-N-丁基苯甲酰胺加入冷却的20ml乙腈中,并加入10ml四氯化碳。然后在-10℃下缓慢逐滴加入0.5ml的N-乙基二异丙基胺和50mg的4-(二甲氨基)吡啶和326μl亚磷酸二苄酯。在此温度下搅拌该混合物30分钟,加入10ml的0.5M KH2PO4水溶液,并用乙醚萃取该混合物,用硫酸钠干燥,过滤并蒸发。柱色谱纯化得到550mg(51%)的5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-4-苄氧基-2-(二苄基磷酰氧基)-N-甲基-N-丁基苯甲酰胺(Rf 2.196分钟;MW 746.8)。
将550mg的5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-4-苄氧基-2-(二苄基磷酰氧基)-N-甲基-N-丁基苯甲酰胺、5%的Pd/C(50.5%的水)和49.5ml氢在10ml的THF中的溶液在23℃下在高压锅中处理19小时。然后将所得溶液蒸发,并从乙醚中结晶;280mg(79.8%)的[2-(丁基甲基氨基甲酰基)-5-羟基-4-(5-氧代-4-邻甲苯基-4,5-二氢-1H-1,2,4-三唑-3-基)苯基]单磷酸酯(Rf 0.645分钟;MW 476.4)。
实施例4
制备[4-(丁基甲基氨基甲酰基)-2-(5-氧代-4-邻甲苯基-4,5-二氢-1H-1,2,4-三唑-3-基)-5-磷酰氧基苯基]单磷酸酯(E)
采用与实施例3类似的方法进行合成;D:MW 916;Rf 2.335分钟;E:MW 556.4;Rf 0.883分钟。
实施例5
制备[4-(丁基甲基氨基甲酰基)-5-羟基-2-(5-氧代-4-邻甲苯基-4,5-二氢-1H-1,2,4-三唑-3-基)苯基]单磷酸酯(F)
采用与实施例3类似的方法进行合成:
F:MW 476.4;Rf 1.321分钟。
实施例6
制备N-丁基-2,4-二羟基-N-甲基-5-(5-硫代-4-邻-甲苯基-4,5-二氢-1H-1,2,4-三唑-3-基)苯甲酰胺(G)
实施例7
制备“C1”的葡萄糖醛酸衍生物
将4ml磷酸钾缓冲液(0.1M/pH7.4,含1.0mM MgCl2)、100mg尿苷-5′-二磷酸葡萄糖醛酸钠盐、10mg的“C1”(悬浮于1ml的20%乙腈中)和1ml猪肝匀浆物加入样品瓶中。将该批样品在37℃孵育。24小时后,加入乙腈,将该混合物离心,然后将上清蒸发至干。
使用LC-MS来进行三种位置异构体的分离和分析。
LC-MS条件
具有以下特征的Hewlett Packard HP 1100系列系统:离子源:电喷雾(阳极模式);扫描:100-1000m/e;
断裂电压:60V
气体温度:300℃
DAD:220nm。
流速:2.4ml/min。所用的分流器在DAD之后将用于MS的流速降低为0.75ml/min。
柱:Chromolith SpeedROD RP-18e 50-4.6
溶剂:来自Merck KGaA的LiChrosolv级
溶剂A:H2O(0.01%TFA)
溶剂B:乙腈(0.008%TFA)
极性梯度:
5%的B→100%的B:0分钟至3.0分钟
100%的B:3.0分钟至3.3分钟
100%的B→20%的B:3.3分钟至4分钟。
对于相同质量的三种化合物,检测出以下RT值:
1.307、1.406和1.465分钟。
异构体H通过NMR波谱法进行了明确的鉴定。
一维1H-NMR谱和二维HSQC、HMBC和ROESY谱在以下条件下获得:Bruker DRX 500波谱仪;DMSO-d6,303K,TMS作为标准物。
1H-NMR谱的归属:
δ(1H)[ppm] | 峰裂度 | 强度 | 峰的归属 |
11.97 | s | 1H | H14 |
10.2 | 宽峰 | 1H | H3 |
7.35-7.0 | m | 4H | H9,H10,H11,H12 |
6.99,6.94 | s | 1H | H1 |
6.50 | s | 1H | H2 |
5.30-5.05 | 宽峰 | 2H | 糖环的两个羟基基团 |
4.88 | d | 1H | H15 |
3.76 | d | 1H | H19 |
3.60-3.10 | m | 5H | H5,H16,H17,H18,H2O |
2.95 | m | 1H | H5′ |
2.87,2.63 | s | 3H | H4 |
2.50 | m | DMSO-d5 | |
2.17,2.16,2.14 | s | 3H | H13 |
1.55-0.95 | m | 4H | H6,H7 |
0.91,0.69 | m | 3H | H8 |
0.00 | s | TMS |
下面的实施例涉及药物组合物:
实施例A:注射小瓶剂
用2N盐酸将100g本发明的活性成分和5g磷酸氢二钠的3L双蒸水溶液调至pH为6.5,无菌过滤,转移至注射小瓶中,在无菌条件下冻干,并在无菌条件下封口。每个注射小瓶中含有5mg活性成分。
实施例B:栓剂
将20g本发明的活性成分与100g大豆卵磷脂和1400g可可脂的混合物熔化,倾倒入模具中并使其冷却。每一栓剂含有20mg活性成分。
实施例C:溶液剂
将1g本发明的活性成分、9.38g的NaH2PO4·2H2O、28.48g的Na2HPO4·12H2O和0.1g苯扎氯铵溶于940ml双蒸水中,制得溶液。将该溶液pH调至6.8,并使溶液定容至1L,照射灭菌。该溶液可以以滴眼剂形式使用。
实施例D:软膏剂
在无菌条件下,将500mg本发明的活性成分与99.5g凡士林混合。
实施例E:片剂
将1kg本发明的活性成分、4kg乳糖、1.2kg土豆淀粉、0.2kg滑石粉和0.1kg硬脂酸镁的混合物用常规方法压片,得到每片含有10mg活性成分的片剂。
实施例F:糖锭剂
根据类似于实施例E的方法压制片剂,接着按常规方法用包含蔗糖、土豆淀粉、滑石粉、黄蓍胶和染料的包衣材料进行包衣。
实施例G:胶囊剂
用常规方法,将2kg本发明的活性成分装入硬明胶胶囊中,每个胶囊中含有20mg的活性成分。
实施例H:安瓿剂
将1kg本发明的活性成分在60L双蒸水中的溶液无菌过滤,转移至安瓿中,在无菌条件下冻干,并在无菌条件下封口。每一安瓿中含有10mg的活性成分。
Claims (13)
1.化合物5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和其药学上可用的衍生物、盐、溶剂化物、互变异构体和立体异构体,包括它们的任何比例的混合物。
2.根据权利要求1的化合物,其中药学上可用的衍生物选自单-和二磷酸衍生物、硫代衍生物、单-和二葡萄糖醛酸衍生物。
3.药物,该药物包含5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和/或其药学上可用的衍生物、盐、溶剂化物、互变异构体和立体异构体,包括它们的任何比例的混合物,以及任选的赋形剂和/或辅助剂。
4.5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和其药学上可用的衍生物、盐、溶剂化物、互变异构体和立体异构体,包括它们的任何比例的混合物,在制备治疗和/或预防HSP90的抑制、调节和/或调控起作用的疾病的药物中的用途。
5.根据权利要求4的5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和其药学上可用的衍生物、盐、溶剂化物、互变异构体和立体异构体,包括它们的任何比例的混合物,在制备药物中的用途,所述药物用于治疗或预防肿瘤疾病、病毒性疾病、移植中的免疫抑制、炎症诱导的疾病、囊性纤维化、与血管生成相关的疾病、传染性疾病、自身免疫疾病、局部缺血、纤维生成性疾病,
用于促进神经再生,
用于抑制癌、肿瘤细胞及肿瘤转移灶的生长,
用于保护正常细胞对抗化疗引起的毒性,
用于治疗其中错误的蛋白折叠或聚集为主要致病因素的疾病。
6.根据权利要求5的用途,其中肿瘤疾病为纤维肉瘤、粘液肉瘤、脂肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、骨髓癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、维尔姆斯瘤、宫颈癌、睾丸瘤、肺癌、小细胞肺癌、膀胱癌、上皮细胞癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症和重链病。
7.根据权利要求5的用途,其中病毒性疾病的病毒病原体选自甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、流感病毒、水痘病毒、腺病毒、单纯性疱疹I型病毒(HSV-I)、单纯性疱疹II型病毒(HSV-II)、牛瘟病毒、鼻病毒、埃可病毒、轮状病毒、呼吸道合胞病毒(RSV)、乳头瘤病毒、乳多孔病毒、巨细胞病毒、棘状病毒、虫媒病毒、汉坦病毒、柯萨奇病毒、流行性腮腺炎病毒、麻疹病毒、风疹病毒、脊髓灰质炎病毒、人免疫缺陷病毒I型(HIV-I)和人免疫缺陷病毒II型(HIV-II)。
8.根据权利要求5的用途,其中炎症诱导的疾病为类风湿性关节炎、哮喘、多发性硬化症、1型糖尿病、红斑狼疮、银屑病和炎性肠疾病。
9.根据权利要求5的用途,其中与血管生成相关的疾病为糖尿病性视网膜病、血管瘤、子宫内膜异位和肿瘤血管生成。
10.根据权利要求5的用途,其中纤维生成性疾病为硬皮病、多发性肌炎、系统性狼疮、肝硬化、疤痕疙瘩形成、间质性肾炎和肺纤维化。
11.根据权利要求5的用途,其中错误的蛋白折叠或聚集为主要致病因素的疾病为瘙痒病、克雅氏病、亨廷顿病或阿尔茨海默病。
12.药物,该药物包含5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和/或其药学上可用的衍生物、盐、溶剂化物、互变异构体和立体异构体,包括它们任何比例的混合物,以及至少一种另外的药物活性成分。
13.套盒(药盒),该套盒包含独立包装的
(a)有效量的5-[4-(2-甲基苯基)-3-羟基-4H-[1,2,4]三唑-5-基]-2,4-二羟基-N-甲基-N-丁基-苯甲酰胺和/或其药学上可用的衍生物、盐、溶剂化物、互变异构体和立体异构体,包括它们任何比例的混合物,以及
(b)有效量的另外的药物活性成分。
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DE102007002715A DE102007002715A1 (de) | 2007-01-18 | 2007-01-18 | Triazolderivat |
PCT/EP2007/010775 WO2008086857A1 (de) | 2007-01-18 | 2007-12-11 | Triazolderivat als hsp 90 inhibitor |
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CN103119028A (zh) * | 2010-10-01 | 2013-05-22 | 大正制药株式会社 | 1,2,4-三唑酮衍生物 |
CN106478531A (zh) * | 2015-08-25 | 2017-03-08 | 南京华威医药科技开发有限公司 | 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1,2,4-三唑-3-基硫基)乙酸中间体 |
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Cited By (3)
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---|---|---|---|---|
CN103119028A (zh) * | 2010-10-01 | 2013-05-22 | 大正制药株式会社 | 1,2,4-三唑酮衍生物 |
CN106478531A (zh) * | 2015-08-25 | 2017-03-08 | 南京华威医药科技开发有限公司 | 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1,2,4-三唑-3-基硫基)乙酸中间体 |
CN106478531B (zh) * | 2015-08-25 | 2019-06-28 | 南京华威医药科技集团有限公司 | 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1,2,4-三唑-3-基硫基)乙酸中间体 |
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PE20090051A1 (es) | 2009-01-26 |
MY151452A (en) | 2014-05-30 |
JP5266253B2 (ja) | 2013-08-21 |
KR20090101381A (ko) | 2009-09-25 |
AU2007344512A1 (en) | 2008-07-24 |
CN101583605B (zh) | 2013-06-19 |
WO2008086857A1 (de) | 2008-07-24 |
BRPI0720956A2 (pt) | 2014-03-18 |
AR064951A1 (es) | 2009-05-06 |
NZ579069A (en) | 2011-09-30 |
MX2009007479A (es) | 2009-08-13 |
EP2102175B1 (de) | 2014-01-22 |
ZA200905700B (en) | 2010-05-26 |
UA98320C2 (en) | 2012-05-10 |
JP2010516639A (ja) | 2010-05-20 |
CA2675737C (en) | 2015-03-24 |
EP2102175A1 (de) | 2009-09-23 |
ES2455504T3 (es) | 2014-04-15 |
CA2675737A1 (en) | 2008-07-24 |
EA015366B1 (ru) | 2011-06-30 |
US8816070B2 (en) | 2014-08-26 |
US20100113542A1 (en) | 2010-05-06 |
CL2008000134A1 (es) | 2008-05-16 |
EA200900913A1 (ru) | 2009-12-30 |
AU2007344512B2 (en) | 2012-11-01 |
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