CN101163707A - 噻吩并吡啶类化合物 - Google Patents
噻吩并吡啶类化合物 Download PDFInfo
- Publication number
- CN101163707A CN101163707A CNA2006800138250A CN200680013825A CN101163707A CN 101163707 A CN101163707 A CN 101163707A CN A2006800138250 A CNA2006800138250 A CN A2006800138250A CN 200680013825 A CN200680013825 A CN 200680013825A CN 101163707 A CN101163707 A CN 101163707A
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- Prior art keywords
- phenyl
- aminocarboxyl
- pyridine
- diamino
- thieno
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及新的式I噻吩并吡啶衍生物,在式I中,R1、R2、R3、R4和Y与权利要求1中的定义相同,所述衍生物为HSP90抑制剂,因此可以用于制备治疗HSP90的抑制、调节和/或调控起作用的疾病的药物。
Description
背景技术
本发明的目的是寻找新的有价值的新化合物,特别是能够用作药物的化合物。
本发明涉及在HSP90的抑制、调节和/或调控中起作用的化合物,此外涉及包含这些化合物的药物组合物以及这些化合物在治疗HSP90起作用的疾病中的用途。
细胞中的蛋白质的正确折叠和构象由分子伴侣作保证,并且蛋白质的正确折叠和构象对蛋白质合成和降解平衡的调节而言十分重要。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)
组织细胞对例如热、缺氧、氧化应激或例如重金属或醇的毒性物质等外部应激产生反应,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致使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个体的HSPs的重要分子伴侣功能进行了描述。即各种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、细胞内定位和功能化或调控的降解。
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,在阿尔茨海默氏病、朊病毒疾病、亨廷顿综合征情况中,错误折叠的蛋白质导致蛋白质聚合,引起神经退行性变性。错误的蛋白折叠还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在细胞中的许多重要的致瘤信号途径中起作用,以及某些具有抑癌活性的天然化合物以HSP90为靶点的事实,致使人们提出抑制HSP90的功能将可以治疗肿瘤疾病的概念。HSP90抑制剂,格尔德霉素(geldanamycin)的衍生物17-烯丙氨基-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陪伴分子的蛋白质(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)改变原来折叠的蛋白相互作用而在细胞应激响应中起关键作用,以恢复原来的折叠或保护蛋白避免聚集(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折叠来实现这种作用(Rutherford和Lindquist,1998)。
另外,HSP90还具有调节的重要性。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client关键蛋白的构象稳定性和成熟的细胞平衡中起作用。可以将上述关键蛋白分为三类:甾类激素受体、Ser/Thr或酪氨酸激酶(例如ERBB2、RAF-1、CDK4和LCK)和各种蛋白质的集合,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。在人类中存有的HSP90家族包含四个基因,胞质HSP90α、诱导型HSP90β同种型(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)。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client蛋白上。例如,ERBB2是GRP94的特异性client蛋白(Argon等人,1999),而已发现肿瘤坏死因子的1型受体(TNFR1)或成视网膜细胞瘤蛋白(Rb)为TRAP1的client(Song等人,1995;Chen等人,1996)。
HSP90与许多与大量client蛋白或调节蛋白的复杂相互作用有关(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射线晶体分析法进行的生化实验和研究已经逐渐能够译解HSP90的陪伴分子功能的详情(Prodromou等人,1997;Stebbins等人,1997)。即,HSP90是ATP依赖的分子伴侣(Prodromou等人,1997),对于ATP水解而言,形成二聚体是重要的。ATP结合导致形成环形的二聚体结构,其中两个N-端区域相互密切接触,并作为构象的开关(Prodromou和Pearl,2000)。
公知的HSP90抑制剂
已发现的第一类HSP90抑制剂是包括除莠霉素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的恶性表型的回复突变(Uehara等人,1985)。
后来,它们的强抗肿瘤活性在体外(Schulte等人,1998)和体内动物模型中得以证明(Supko等人,1995)。
对亲和基质的免疫沉淀及研究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的内源的ATP酶活性(Prodromou等人,1997;Panaretou等人,1998)。这阻止形成多聚的HSP90复合物,依靠其作为client蛋白的分子伴侣的性质。结果,通过泛素-蛋白酶体途径将client蛋白降解。
在细胞培养和异种移植肿瘤模型中,格尔德霉素衍生物17-烯丙氨基-17-脱甲氧基格尔德霉素(17AAG)显示了在抑制HSP90、client蛋白降解和抗肿瘤活性方面的未改变的性质(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。
大环抗生素根赤壳菌素显示同样可以修正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)。作为抑制HSP90的后果,根赤壳菌素降解许多信号蛋白(Schulte等人,1998)。X射线晶体学研究显示根赤壳菌素同样可以结合到HSP90的N-端区域,并抑制内源的ATP酶活性(Roe等人,1998)。
众所周知,香豆素型抗生素结合至细菌中的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至HSP90的羧基末端,例如,与苯醌-安莎霉素类化合物和根赤壳菌素相比,在HSP90中的结合位点不同,后两者结合在HSP90的N-末端(Marcu等人,2000b)。
新生霉素对HSP90的抑制导致大量HSP依赖的信号蛋白的降解(Marcu等人,2000a)。
信号蛋白(例如ERBB2)的降解用由嘌呤衍生的HSP90抑制剂PU3进行证明。PU3引起细胞循环停滞,以及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HSP90参与调节大量的肿瘤表型中非常重要的信号传导途径,并且由于发现某些天然产物通过抑制HSP90的活性而表现出生物活性,所以目前正将HSP90作为开发肿瘤治疗药物的新靶点进行研究(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结合至蛋白N-末端的ATP结合位点,从而抑制HSP的内源的ATP酶活性(见,例如Prodromou等人,1997;Stebbins等人,1997;Panaretou等人,1998)。抑制HSP90的ATP酶活性阻止辅陪伴分子的募集并利于HSP90杂络物的形成,该杂络物导致client蛋白通过泛素-蛋白酶体途径降解(见,例如,Neckers等人,1999;kelland等人,1999)。用HSP90抑制剂处理肿瘤细胞导致选择性降解例如在细胞增殖、细胞循环的调节和凋亡等过程中具有根本重要性的重要蛋白质。这些过程在肿瘤中通常失调(见,例如,Hostein等人,2001)。
开发HSP90抑制剂的吸引人的原理是,可以在降解与转化的表型相关的多数蛋白的同时,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、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,WO02/09696;Degranco等人,WO99/51223;Gold,US6210974B1);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,所述疾病例如痒病、Creutzfeldt-Jakob病、亨廷顿病或阿尔茨海默氏病(Sittler,人类分子遗传学(Hum.Mol.Genet.),10,1307,2001;Tratzelt等人,Proc.Nat.Acad.Sci.,92,2944,1995;Winklhofer等人,生物化学杂志(J.Biol.Chem.),276,45160,2001)。WO01/72779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,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(Ewing’s tumour)、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、鳞状上皮细胞癌、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(haemangioblastoma)、听神经瘤、少突神经胶质瘤、脑膜瘤、黑素瘤、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、瓦尔登斯特伦巨球白血症、重链病等的肉瘤和癌。
A.Kamal等人在分子医学趋势(Trends in Molecular Medicine),Vol.10 No.6 2004年6月刊中描述了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的小分子化合物是合乎需要的,并且是本发明的目的。
已发现式I化合物和其盐具有非常重要的药理学性质,同时可以被很好地耐受。特别是,它们具有抑制HSP90的性质。
因此,本发明涉及作为治疗和/或预防上述疾病的药物和/或药物活性成分的式I化合物,以及式I化合物在制备治疗和/或预防上述疾病的药物中的用途,还涉及治疗上述疾病的方法,该方法包括将一种或多种式I化合物给予需要这种治疗的患者。
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。用动物模型进行实验研究,在此,它们提供了用于治疗人类疾病的模型。
现有技术
作为HSP90抑制剂的其它吡啶并噻吩衍生物在WO2005/034950和WO2005/021552中进行了描述。
WO2005/00300A1对三唑衍生物作为HSP90抑制剂进行了描述。
WO00/53169描述了用香豆素或香豆素衍生物作为HSP90抑制剂。
WO03/041643A2描述了抑制HSP90的玉米赤霉醇(zearalanol)衍生物。
对抑制HSP90的3-或5-位为芳基取代的吡唑衍生物在WO2004/050087A1和WO2004/056782A1中进行了描述。
WO03/055860A1描述了3,4-二芳基吡唑化合物作为HSP90抑制剂。
具有HSP抑制特性的嘌呤化合物在WO02/36075A2中进行了描述。
WO01/72779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(Ewing’s tumour)、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、鳞状上皮细胞癌、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(haemangioblastoma)、听神经瘤、少突神经胶质瘤、脑膜瘤、黑素瘤、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、瓦尔登斯特伦巨球白血症、重链病等的肉瘤和癌。
此外,WO01/72779描述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、流行性感冒病毒、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、equinovirus、虫媒病毒、huntavirus、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)。
此外,WO01/72779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生物活性在个体中引起免疫反应、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/再灌注或它们的组合相关的病症,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、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、阿尔茨海默氏病、亨廷顿病、肌萎缩侧索硬化(ALS)或新生儿应激(neonatal stress)等造成的后果。
最后,WO01/72779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位置的紧随局部缺血状态的细胞反应的药物中用途,上述改变是通过用GRP94蛋白调节剂治疗上述组织位置处的细胞,以使细胞中的GRP94活性增加至可使紧随局部缺血状态的细胞反应发生改变的程度实现的,其中所述局部缺血状态优选为心脏停搏、心搏停止、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、阿尔茨海默氏病、亨廷顿病、肌萎缩侧索硬化(ALS)或新生儿应激等造成的后果,或其中所述组织位置是移植的供体组织。
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发明内容
本发明涉及式I化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体以及立体异构体,包括它们的任何比例的混合物:
其中
Y 指OH、OA、SH、SA、NH2、NHA、NAA’或NHR5,
R1 指Hal、OH、OA、SH、SA、H或A,
R2,R3 相互独立,分别指-NHCO-(X)s-Q、-CONH-(X)s-Q、-CONA-(X)s-Q、-NH(CO)NH-(X)s-Q、-NH(CO)O-(X)s-Q、-NHSO2-(X)s-Q、-SO2NH-(X)s-Q、-SO2NA-(X)s-Q、-(X)s-Q或H,
其中,如果R2≠H,则R3=H或Cl,或者
如果R3≠H,则R2=H或Cl,
R4 指H、Hal、CN、NO2、A、OH、OA、SH、SA、(CH2)nCOOH、
(CH2)nCOOA、CONH2、CONHA、CONAA’、NH2、NHA、NAA’、NHCOOA、NHCONH2、NHCONHA、SOA、SO2A、SO2NH2、SO2NHA和/或SO2NAA’,
选自基团R1、R2、R3、R4的两个相邻的基团还可以一起指亚甲二氧基或亚乙二氧基,
R5 指-(CH2)o-Het1、-(CH2)o-NH2、-(CH2)o-NHA或-(CH2)o-NA2,A,A’相互独立,分别指无支链的或支链的含有1-10个C原子且其中1-5个氢原子可以被F、Cl和/或Br取代的烷基、Alk或含有3-7个C原子的环烷基
A和A’一起还指含有2、3、4、5或6个C原子的亚烷基,其中一个或两个CH2基团可以被O、S、SO、SO2、NH、NA和/或N-COOA取代,
Alk 指含有2-6个C原子的链烯基,
X 指无支链的或支链的C1-C10亚烷基或C2-C10亚烯基,它们分别为未取代的或被下列基团单取代、双取代、三取代或四取代:A、OA、OH、SH、SA、Hal、NO2、CN、Ar、OAr、COOH、COOA、CHO、C(=O)A、C(=O)Ar、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’、NACONAA’和/或=O,并且其中一个、两个或三个C基可以被O、S、SO、SO2、NHCO、NACO、CONH、CONA、SO2NH、SO2NA、NHSO2和/或NH基团替换,
Q 指H、Carb、Ar或Het,
Carb 指含有3-7个C原子的环烷基或含有3-7个C原子的环烯基,它们分别是未取代的或被下列基团单取代、双取代、三取代、四取代或五取代:A、OA、OH、SH、SA、Hal、NO2、CN、(CH2)nAr’、(CH2)nCOOH、(CH2)nCOOA、CHO、COA、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’和/或NACONAA’,
Ar 指苯基、萘基或联苯基,它们分别是未取代的或被下列基团单取代、双取代、三取代、四取代或五取代:A、OA、OH、SH、SA、Hal、NO2、CN、(CH2)nAr’、(CH2)nCOOH、(CH2)nCOOA、CHO、COA、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’、NACONAA’、NHCO(CH2)nNH2和/或-O(CH2)o-Het1,
Ar’ 指苯基、萘基或联苯基,它们分别是未取代的或被下列基团单取代、双取代或三取代:A、OA、OH、SH、SA、Hal、NO2、CN、(CH2)n苯基、(CH2)nCOOH、(CH2)nCOOA、CHO、COA、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’和/或NACONAA’,
Het 指含有1-4个N、O和/或S原子的单环或双环饱和的、未饱和的或芳香族杂环,其可被下列基团单取代、双取代或三取代:A、OA、OH、SH、SA、Hal、NO2、CN、(CH2)nAr’、(CH2)nCOOH、(CH2)nCOOA、CHO、COA、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’、NACONAA’、SO2A、=S、=NH、=NA和/或=O(羰基氧),
Het1 指含有1-2个N和/或O原子的单环饱和杂环,其可被A、OA、OH、Hal和/或=O(羰基氧)单取代或双取代,
Hal 指F、Cl、Br或I,
n 指0、1、2、3或4,
o 指1、2、3或4,
s 指0或1。
本发明涉及式I化合物和其盐,以及制备根据权利要求1-14的式I化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体以及立体异构体的方法,其特征在于,
a)将式II化合物:
其中
R1、R2和R3与权利要求1所定义的相同,
与式III化合物反应:
Y-CO-CH2-Z III
其中Y与权利要求1所定义的相同,并且
Z指Cl、Br、I或游离或反应性功能修饰的OH基团,或
b)通过下面反应将式I化合物中的一个或多个基团R1、R2、R3、R4和/或Y转变为另外的一个或多个基团R1、R2、R3、R4和/或Y,
所述反应,例如
i)将硝基还原为氨基,
ii)将酯基水解为羧基,
iii)通过还原胺化反应,将氨基转化为烷基化的胺,
iv)将羟基和/或氨基烷基化和/或酰化,和/或将式I的碱或酸转化为其盐。
本发明还涉及这些化合物的水合物和溶剂合物。化合物的溶剂合物指惰性溶剂分子加合在化合物上的加合物,该加合物是通过它们之间的相互吸引力形成的。溶剂合物,例如,是单或二水合物或醇化物。
本发明的式I化合物还可以以互变异构体形式存在。式I包括所有这些互变异构体形式。
药学上可用的衍生物指,例如,本发明化合物的盐,还指所谓的前药化合物。
前药衍生物指已经被例如烷基或酰基、糖或寡肽修饰的,并在有机体中迅速裂解从而提供有效的本发明化合物。
前药衍生物还包括本发明化合物的生物可降解的多聚物的衍生物,例如Int.J.Pharm.115,61-67(1995)中所描述的。
“有效量”的表述指引起例如研究者或医师所寻求或期望的在组织、系统、动物或人类中引起生物或医疗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受试者相比,有下列后果的量:康复治疗提高;康复;预防或消除疾病、病象(diseasepicture)、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。
本发明还涉及根据本发明的式I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化合物的混合物。
对于所有出现超过一次的基团而言,意味着它们相互之间是独立的。
在上下文中,除非另外特别指明,基团和参数R1、R2、R3、R4和Y与式I中定义的相同。
A或A’优选指无支链(直链)或支链且含有1、2、3、4、5、6、7、8、9或10个C原子的烷基。A或A’特别优选指甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外还有戊基;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。
A或A’极优选指含有1、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,此外还有氟甲基、二氟甲基或溴甲基。
A或A’还指环烷基。环烷基优选指环丙基、环丁基、环戊基、环己基或环庚基。
A或A’还指Alk。Alk指含有2-6个C原子的烯基,例如乙烯基或丙烯基。
环烷基亚烷基指,例如,环己基甲基、环己基乙基、环戊基甲基或环戊基乙基。
C1-C10亚烷基优选指亚甲基;亚乙基;亚丙基;亚丁基;亚戊基;亚己基;亚庚基;亚辛基;亚壬基或亚癸基;异亚丙基;异亚丁基;仲亚丁基;1-、2-或3-甲基亚丁基;1,1-、1,2-或2,2-二甲基亚丙基;1-乙基-亚丙基;1-、2-、3-或4-甲基亚戊基;1,1-、1,2-、1,3-、2,3-或3,3-二甲基亚丁基;1-或2-乙基亚丁基;1-乙基-1-甲基亚丙基;1-乙基-2-甲基亚丙基;1,1,2-或1,2,2-三甲基亚丙基;特别优选亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或亚己基。
亚烯基指含有2-10个C原子、含有2个自由化合价且含有至少一个双键的烃链。
Ac指乙酰基,Bzl指苄基,Ms指-SO2CH3。
Y优选指氨基;NHA优选甲氨基;NAA’优选二甲氨基或二乙氨基;NHR5优选-NH-(CH2)o-NA2,例如,2-二甲氨基乙氨基,或-NH-(CH2)o-Het1,例如2-(吗啉-4-基)乙氨基。
Y特别优选指NH2。
R1优选指H、OH或OA,例如甲氧基。
R2,R3互相独立,分别优选指-NHCO-(X)s-Q、-CONH-(X)s-Q、-NH(CO)NH-(X)s-Q、-NH(CO)O-(X)s-Q、-(X)s-Q或H,
其中,如果R2≠H,则R3=H或Cl,或者
如果R3≠H,则R2=H或Cl,
R4优选指H或Hal,特别优选H。
X优选指无支链的或支链的C1-C10亚烷基,该亚烷基是未取代或被下列基团单取代、双取代、三取代或四取代:OA、OH、Hal、COOH、CONH2、NH2和/或NHCOOA,并且其中一个、两个或三个C基团可以被O、NHCO、CONH、SO2NH、NHSO2和/或NH基团替换。
Ar指,例如苯基;邻、间或对甲苯基;邻、间或对乙基苯基;邻、间或对丙基苯基;邻、间或对异丙基苯基;邻、间或对叔丁基苯基;邻、间或对羟基苯基;邻、间或对硝基苯基;邻、间或对氨基苯基;邻、间或对-(N-甲氨基)苯基;邻、间或对-(N-甲基-氨基羰基)苯基;邻、间或对乙酰氨基苯基;邻、间或对甲氧基苯基;邻、间或对乙氧基苯基;邻、间或对乙氧基羰基苯基;邻、间或对-(N,N-二甲氨基)苯基;邻、间或对-(N,N-二甲氨基羰基)苯基;邻、间或对-(N-乙氨基)苯基;邻、间或对-(N,N-二乙氨基羰基)苯基;邻、间或对氟苯基;邻、间或对溴苯基;邻、间或对氯苯基;邻、间或对-(甲基亚磺酰氨基)苯基;邻、间或对-(甲基磺酰基)苯基;邻、间或对氰基苯基;邻、间或对脲基苯基;邻、间或对甲酰基苯基;邻、间或对乙酰基苯基;邻、间或对氨磺酰基苯基;邻、间或对羧基苯基;邻、间或对羧甲基苯基;邻、间或对羧甲氧基苯基;此外优选2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基;2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基;2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二溴苯基;2,4-或2,5--二硝基苯基;2,5-或3,4--二甲氧基苯基;3-硝基-4-氯苯基;3-氨基-4-氯-、2-氨基-3-氯-、2-氨基-4-氯-、2-氨基-5-氯-或2-氨基-6-氯苯基;2-硝基-4-N,N-二甲氨基-或3-硝基-4-N,N-二甲氨基苯基;2,3-二氨基苯基;2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基;2,4,6-三甲氧基苯基;2-羟基-3,5-二氯苯基;对碘苯基;3,6-二氯-4-氨基苯基;4-氟-3-氯苯基;2-氟-4-溴苯基;2,5-二氟-4-溴苯基;3-溴-6-甲氧基苯基;3-氯-6-甲氧基苯基;3-氯-4-乙酰氨基苯基;3-氟-4-甲氧基苯基;3-氨基-6-甲基苯基;3-氯-4-乙酰胺基苯基或2,5-二甲基-4-氯苯基。
Ar优选指未取代的或被A、Hal、OA、(CH2)nCOOH、(CH2)nCOOA、NHCO(CH2)nNH2和/或-O(CH2)o-Het1单取代、双取代、三取代、四取代或五取代的苯基。
Ar特别优选指未取代的或被A、Hal、(CH2)nCOOH、(CH2)nCOOA、NHCO(CH2)nNH2和/或-O(CH2)o-Het1单取代或双取代的苯基。
Ar’优选指,例如,未取代的或被Hal单取代、双取代或三取代的苯基。
不考虑进一步取代,Het指,例如,2-或3-呋喃基;2-或3-噻吩基;1-、2-或3-吡咯基;1-、2-、4-或5-咪唑基;1-、3-、4-或5-吡唑基;2-、4-或5-唑基;3-、4-或5-异唑基;2-、4-或5-噻唑基;3-、4-或5-异噻唑基;2-、3-或4-吡啶基;2-、4-、5-或6-嘧啶基;此外优选1,2,3-三唑-1-、-4-或-5-基;1,2,4-三唑-1-、-3-或-5-基;1-或5-四唑基;1,2,3-二唑-4-或-5-基;1,2,4-二唑-3-或-5-基;1,3,4-噻二唑-2-或-5-基;1,2,4-噻二唑-3-或-5-基;1,2,3-噻二唑-4-或-5-基;3-或4-哒嗪基;吡嗪基;1-、2-、3-、4-、5-、6-或7-吲哚基;4-或5-异吲哚基;1-、2-、4-或5-苯并咪唑基;1-、2-、3-、4-、5-、6-或7-吲唑基;1-、3-、4-、5-、6-或7-苯并吡唑基;2-、4-、5-、6-或7-苯并唑基;3-、4-、5-、6-或7-苯并异唑基;2-、4-、5-、6-或7-苯并噻唑基;2-、4-、5-、6-或7-苯并异噻唑基;4-、5-、6-或7-苯并-2,1,3-二唑基;2-、3-、4-、5-、6-、7-或8-喹啉基;1-、3-、4-、5-、6-、7-或8-异喹啉基;3-、4-、5-、6-、7-或8-噌啉基;2-、4-、5-、6-、7-或8-喹唑啉基;5-或6-喹喔啉基;2-、3-、5-、6-、7-或8-2H-苯并-1,4-嗪基;此外,优选1,3-苯并间二氧杂环戊烯-5-基;1,4-苯并二氧六环-6-基;2,1,3-苯并噻二唑-4-或-5-基或者2,1,3-苯并二唑-5-基。
杂环基团还可以是部分或完全氢化的。
因此,Het还可以指,例如,2,3-二氢-2-、-3-、-4-或-5-呋喃基;2,5-二氢-2-、-3-、-4-或5-呋喃基;四氢-2-或-3-呋喃基;1,3-二氧戊环-4-基;四氢-2-或-3-噻吩基;2,3-二氢-1-、-2-、-3-、-4-或-5-比咯基;2,5-二氢--1-、-2-、-3-、-4-或-5-吡咯基;1-、2-或3-吡咯烷基;四氢-1-、-2-或-4-咪唑基;2,3-二氢-1-、-2-、-3-、-4-或-5-吡唑基;四氢-1-、-3-或-4-吡唑基;1,4-二氢-1-、-2-、-3-或-4-吡啶基;1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-或-6-吡啶基;1-、2-、3-或4-哌啶基;2-、3-或4-吗啉基;四氢-2-、-3-或-4-吡喃基;1,4-二烷基;1,3-二烷-2-、-4-或-5-基;六氢-1-、-3-或-4-哒嗪基;六氢-1-、-2-、-3-、-4-或-5-嘧啶基;1-、2-或3-哌嗪基;1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基;1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-异喹啉基;2-、3-、-5-、6-、7-或8-3,4-二氢-2H-苯并-1,4-嗪基;此外优选2,3-亚甲二氧基苯基;3,4-亚甲二氧基苯基;2,3-亚乙二氧基苯基;3,4-亚乙二氧基苯基;3,4-(二氟亚甲二氧基)苯基;2,3-二氢苯并呋喃-5-或-6-基;2,3-(2-氧代亚甲二氧基)苯基或3,4-二氢-2H-1,5-苯并二氧杂(dioxepin)-6-或-7-基;此外,优选2,3-二氢苯并呋喃基或2,3-二氢-2-氧代呋喃基。
Het优选指含有1-4个N、O和/或S原子的单环或双环的饱和、不饱和或芳香族杂环,该杂环可以被A、OA、Hal和/或=O(羰基氧)单取代、双取代或三取代。
Het特别优选指含有1-2个N和/或O原子的单环或双环的饱和、不饱和或芳香族的杂环,该杂环可以被A和/或=O(羰基氧)单取代或双取代,其中A优选指甲基、乙基、丙基、丁基、戊基、己基、异丙基或三氟甲基。
在另外的实施方案中,Het特别优选指哌啶、哌嗪、吡咯烷、吡啶、吡咯、吲哚、吲唑、吗啉或异唑,它们分别是未取代的或被A和/或=O单取代或双取代,其中A优选指甲基、乙基、丙基、丁基、戊基、己基、异丙基或三氟甲基。
Het1优选指含有1-2个N和/或O原子的单环饱和杂环,该杂环可以被A和/或=O(羰基氧)单取代或双取代,特别优选指4-甲基-哌嗪基。
式I化合物可以有一个或多个手性中心,因此会出现很多立体异构形式。式I包括所有这些立体异构形式。
因此,本发明特别涉及其中至少一个基团为上面指明的优选基团的式I化合物。一些优选的化合物可以用下面的亚式Ia-Im表示,所述亚式与式I一致,且其中没有详细指定的基团同式I中定义的相同,但是其中
在Ia中Y 指NH2或NHR5;
在Ib中R1 指H、OH或OA;
在Ic中R2,R3 相互独立,分别指-NHCO-(x)s-Q、-CONH-(X)s-Q、-NH(CO)NH-(X)s-Q、-NH(CO)O-(X)s-Q、-(X)s-Q或H,
其中,如果R2≠H,则R3=H或Cl,或者
如果R3≠H,则R2=H或Cl;
在Id中R4 指H或Hal;
在Ie中R5 指-(CH2)o-Het1或-(CH2)o-NA2;
在If中X 指无支链的或支链的C1-C10亚烷基,该亚烷基或是未取代或被下列基团单取代、双取代、三取代或四取代:OA、OH、Hal、COOH、CONH2、NH2和/或NHCOOA,并且其中一个、两个或三个C基团可以被O、NHCO、CONH、SO2NH、NHSO2和/或NH基团替换,
在Ig中Q 指H、Ar或Het;
在Ih中Ar 指未取代的或被A、Hal、OA、(CH2)nCOOH、(CH2)nCOOA、NHCO(CH2)nNH2和/或-O(CH2)o-Het1单取代、双取代、三取代、四取代或五取代的苯基;
在Ii中Het 指含有1-4个N、O和/或S原子的单环或双环的饱和、不饱和或芳香族杂环,该杂环可以被A、OA、Hal和/或=O(羰基氧)单取代、双取代或三取代;
在Ij中Het 指含有1-2个N和/或O原子的单环或双环的饱和、不饱和或芳香族的杂环,该杂环可以被A和/或=O(羰基氧)单取代或双取代;
在Ik中Het1 指含有1-2个N和/或O原子的单环饱和杂环,该杂环可以被A和/或=O(羰基氧)单取代或双取代;
在II中A 指含有1-6个C原子的无支链的或支链的烷基,其中1-5个氢原子可以被F和/或Cl替换,
在Im中Y 指NH2或NHR5;
R1 指H、OH或OA,
R2,R3 相互独立,分别指-NHCO-(X)s-Q、-CONH-(X)s-Q、-NH(CO)NH-(X)s-Q、-NH(CO)O-(X)s-Q、-(X)s-Q或H,
其中,如果R2≠H,则R3=H或Cl,或者
如果R3≠H,则R2=H或Cl,
R4 指H或Hal,
R5 指-(CH2)o-Het1或-(CH2)o-NA2,
X 指无支链的或支链的C1-C10亚烷基,该亚烷基或是未取代或被下列基团单取代、双取代、三取代或四取代:OA、OH、Hal、COOH、CONH2、NH2和/或NHCOOA,并且其中一个、两个或三个C基团可以被O、NHCO、CONH、SO2NH、NHSO2和/或NH基团替换,
Q 指H、Ar或Het,
Ar 指未取代的或被A、Hal、OA、(CH2)nCOOH、(CH2)nCOOA、NHCO(CH2)nNH2和/或-O(CH2)o-Het1单取代、双取代、三取代、四取代或五取代的苯基,
Het 指含有1-4个N、O和/或S原子的单环或双环的饱和、不饱和或芳香族杂环,该杂环可以被A、OA、Hal和/或=O(羰基氧)单取代、双取代或三取代,
Het1 指优选指含有1-2个N和/或O原子的单环饱和杂环,该杂环可以被A和/或=O(羰基氧)单取代或双取代,
A 指含有1-6个C原子的无支链的或支链的烷基,其中1-5个氢原子可以被F和/或Cl替换,
Hal 指F、Cl、Br或I,
n 指0、1、2、3或4,
o 指1、2、3或4,
s 指0或1;
和其药学上可用的衍生物、溶剂合物、盐、互变异构体和立体异构体,包括它们的任何比例的混合物。
式I化合物优选选自“A35”、“A36”、“A37”和“A38”。
此外,本发明化合物和用于制备它们的起始原料是按如文献(例如标准著作中,例如Houben-weyl,Methoden der organischen chemie[有机化学方法(Methods of Organic Chemistry)],Georg-Thieme-Verlag,Stuttgart)中所述的其本身为公知的方法,在公知的适于进行该反应的精确条件下制备的。也可以采用已知的变通方法,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公知的方法制备。
式I化合物可以优选通过将式II化合物与式III化合物反应制得。
一般而言,式II和式III化合物是公知的。但是,如果它们不是公知的,则它们可以由本身公知的方法制备。
在式III化合物中,Z优选指Cl、Br、I或为反应性修饰的OH基团,例如含有1-6个C原子的烷基磺酰氧基(优选甲磺酰氧基)或含有6-10个C原子的芳基磺酰氧基(优选苯基磺酰氧基或对甲苯基磺酰氧基)。Z特别优选指Cl。
用本领域技术人员公知的方法进行反应。
反应优选在碱性条件下进行。适当的碱优选碱金属氢氧化物,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,例如吡啶或二乙醇胺。
反应在适当的惰性溶剂中进行。
适当的惰性溶剂的示例包括烃,例如己烷、石油醚、苯、甲苯或二甲苯;氯代烃,例如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿、二氯甲烷;醇,例如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,例如乙醚、异丙醚、四氢呋喃(THF)或二烷;乙二醇醚,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,例如丙酮或丁酮;酰胺,例如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,例如乙腈;亚砜,例如二甲基亚砜(DMSO);二硫化碳;羧酸,例如甲酸或乙酸;硝基化合物,例如硝基甲烷或硝基苯;酯,例如乙酸乙酯,或上述溶剂的混合物。
溶剂特别优选,例如水和/或四氢呋喃。
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℃,通常为约-10到130℃,特别为30到125℃。
此外,可以通过将一个或多个基团R1、R2、R3、R4和/或Y转变为另外的一个或多个基团R1、R2、R3、R4和/或Y,从而将式I化合物转变为另一种式I化合物,这是通过下列反应实现的,例如将硝基还原为氨基,这是例如在诸如甲醇或乙醇的惰性溶剂中,在兰尼镍或Pd/碳上进行氢化实现的,和/或
将酯基转变为羧基,和/或
通过还原胺化反应,将氨基转化为烷基化的氨基,和/或
通过与醇反应将羧基酯化,和/或
通过与胺反应,将酰氯转化为酰胺,和/或
将羟基烷基化,例如用烷基卤。
此外,例如可以按常规方法,在例如二氯甲烷或THF中,和/或在例如三乙胺和吡啶的碱存在下,以及于-60℃至+30℃条件下,方便地用酰氯或酸酐酰化或用未取代或取代的烷基卤化物烷基化游离的氨基。
此外,可以通过溶剂解(特别是水解)或氢解,将式I化合物从它们的功能化的衍生物中释放出来,从而获得式I化合物。
用于溶剂解或氢解的优选起始原料为那些含有代替一个或多个游离氨基和/或羟基的相应保护的氨基和/或羟基的原料,优选由氨基保护基团代替键合在N原子上的H原子的起始原料,例如符合式I,但是含有代替NH2基团的NHR'(其中,R’指氨基保护基,例如BOC或CBZ)的起始原料。
此外,优选羟基保护基团代替羟基氢原子的起始原料,例如符合式I,但是含有代替羟基苯基的R”O-苯基(其中,R”指羟基保护基)的起始原料。
在起始原料分子中还可以存在大量相同或不同保护的氨基和/或羟基。如果存在的保护基相互不同,在许多情况下,可以将它们进行选择性脱除。
术语“氨基保护基”是公知的一般术语,它是指适于保护(阻断)氨基避免化学反应,但在分子中的其它位置进行需要的反应后,很容易将其脱除的基团。典型的此类基团,特别是,未取代或取代的酰基、芳基、芳烷氧基甲基或芳烷基基团。由于在所需反应(或系列反应)完成后,将氨基保护基脱除,因此它们的类型和大小不是至关重要的;然而,优选含有1-20(特别是1-8)个碳原子的保护基。在本发明的方法中,术语“酰基”应当理解为具有最广泛的意义。它包括衍生自脂肪族的、芳脂肪族的、芳香族的或杂环的羧酸或磺酸的酰基,具体来讲为,烷氧羰基、芳氧羰基,特别是芳烷氧羰基。这些酰基的示例是烷酰基,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,苯甲酰基和甲苯基;芳氧烷酰基,例如POA;烷氧羰基,例如甲氧羰基、乙氧羰基、2,2,2-三氯乙氧羰基、BOC和2-碘乙氧羰基;芳烷氧羰基,例如CBZ(“苄氧羰基”)、4-甲氧基-苄氧羰基和FMOC;和芳磺酰基,例如Mtr、Pbf或Pmc。优选的氨基保护基为BOC和Mrt,此外还有CBZ、Fmoc、苄基和乙酰基。
术语“羟基保护基”同样也是公知的一般术语,它是指适于保护羟基避免化学反应,但在分子中的其它位置进行需要的反应后,很容易将其脱除的基团。典型的此类基团是上面提到的未取代或取代的芳基、芳烷基或酰基基团以及烷基基团。由于在所需反应或系列反应完成后,将羟基保护基脱除,因此它们的性质和大小不是至关重要的;然而,优选含有1-20(特别是1-10)个碳原子的保护基。羟基保护基的示例,特别是,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。对COOH优选以它们的叔丁酯形式进行保护。
根据所用的保护基,例如用强酸(如TFA或高氯酸)可以方便地将式I化合物从它们的功能化的衍生物中释放出来,还可以用其它无机强酸,例如盐酸或硫酸;强有机羧酸,例如三氯乙酸;或磺酸,例如苯磺酸或对甲苯磺酸。可以存在添加的惰性溶剂,但其不总是必需的。适当的惰性溶剂优选有机的,例如羧酸,例如乙酸;醚,例如四氢呋喃或二烷;酰胺,例如DMF;卤代烃,例如二氯甲烷;此外还有醇,例如甲醇、乙醇或异丙醇;和水。此外,上述溶剂的混合物也是适合的。优选使用过量的TFA同时不添加其它溶剂,高氯酸优选以比例为9∶1的乙酸和70%高氯酸的混合物的形式使用。裂解的反应温度在约0-50℃时是有利的,优选15-30℃(室温)。
BOC、OBut、Pbf、Pmc和Mtr基团,可以例如优选在15-30℃下,用TFA的二氯甲烷溶液或约3-5N HCl的二烷溶液进行裂解,FMOC基团,可以在15-30℃下,用约5-50%二甲胺、二乙胺或哌啶的DMF溶液进行裂解。
药用盐和其它形式
所述的本发明化合物可以以它们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这些化合物的用途,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式I化合物大部分通过常规方法制备。如果式I化合物含有羧基,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,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。式I化合物的铝盐同样也包括在内。在某些式I化合物情况中,可以通过用药学上可接受的有机或无机酸处理这些化合物,从而形成酸加成盐,所述酸例如卤化氢,例如氯化氢、溴化氢或碘化氢;和其它无机酸,其相应的盐为,例如硫酸盐、硝酸盐或磷酸盐等;烷基和单芳基磺酸盐,例如乙基磺酸盐、甲苯磺酸盐和苯磺酸盐;和其它有机酸和其相应的盐,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,式I化合物的药学上可接受的酸加成盐包括下面的盐: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(besylate)、重硫酸盐、重亚硫酸盐、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、乙基磺酸盐、反丁烯二酸盐、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、氢氯化物、氢溴化物、氢碘化物、2-羟基乙基磺酸盐、碘化物、羟乙磺酸盐、异丁酸盐、乳酸盐、乳糖醛酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲基磺酸盐、甲基苯甲酸盐、磷酸氢盐、2-萘基磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、扑酸盐(palmoate)、果胶酸盐、过硫酸盐、苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这不用于限制本发明。
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,但这不用于限制本发明。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式I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(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)甲胺(tromethamine),但这不用于限制本发明。
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。
上面提到的药用盐优选包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、反丁烯二酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、氢氯化物、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、硫代水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和三(羟甲基)甲胺盐,但这不用于限制本发明。
碱性式I化合物的酸加成盐可以通过将游离碱形式的该化合物与足量的所需酸接触,从而根据常规方法形成盐。可以通过将盐与碱接触,并用常规方法分离游离的碱,重新得到游离的碱。游离的碱形式与其相应的盐形式在某些方面不同,例如某些物理性质,例如在极性溶剂中的溶解度;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,式I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。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。
可以通过将游离的酸形式与足量的所需碱接触,以常规方法形成盐,从而制备酸性的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。游离的酸形式与其相应的盐形式在某些方面不同,例如某些物理性质,例如在极性溶剂中的溶解度;然而,就本发明目的而言,盐与其各应的游离酸形式是相同的。
如果本发明化合物含有不止一个能够形成此种类型药学上可接受的盐的基团,那么本发明还包括多重盐。典型的多重盐形式包括,例如二酒石酸盐、二乙酸盐、二反丁烯二酸盐、二葡甲胺盐、二磷酸盐、二钠盐和三盐酸盐,但这不用于限制本发明。
就上述来讲,可以明白,本发明中的“药学上可接受的盐”的表述指包括盐形式的式I化合物的活性成分,特别是如果该盐形式与活性成分的游离形式或以前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。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而又是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有积极的影响。
根据其分子结构,本发明的式I化合物可以是手性的,因此可能出现各种对映体形式。因而这些化合物可以以外消旋形式或旋光活性形式存在。
由于式I化合物的外消旋物或立体异构体的药学活性可能不同,因此可能需要使用对映体。在这些情况中,可以通过本领域技术人员公知的化学或物理方法将终产物或甚至中间体分离为对映体化合物,或者不经分离直接用于合成。
在外消旋胺的情况中,通过与旋光活性的拆分试剂反应,从混合物中制得非对映异构体。适当的拆分试剂的示例是旋光活性的酸,例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种旋光活性的樟脑磺酸。还可以利用有旋光活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸聚合物)帮助的色谱对映体拆分法。用于此目的的适当的溶剂是水或醇溶剂的混合物,例如,己烷/异丙醇/乙腈,例如比例为82∶15∶3。
此外,本发明涉及化合物和/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/或半液体赋形剂或佐剂,如果需要的话,还与一种或多种另外的活性成分一起转变为适当的剂型。
此外,本发明还涉及药物,该药物包含至少一种式I化合物和/或其药学上可用的衍生物、溶剂合物和立体异构体(包括它们任何比例的混合物),以及任选赋形剂和/或佐剂。
药物制剂可以以每剂量单位包含预定量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、体重或状况,每剂量单位可以包括,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活性成分的剂量单位形式给予药物制剂。优选的剂量单位制剂包含如上面所示的日剂量或部分次日剂量或其相应的部分的活性成分。此外,该类型的药物制剂可以用药学领域一般公知的方法制备。
药物制剂可以经所需的适当的方法给药,例如经口(包括颊或舌下)、直肠、鼻、局部(包括颊、舌下或经皮)、阴道或肠胃外(包括皮下、肌内、静脉内或皮内)的方法。这些制剂可以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佐剂混合制备。
适于口服给药的药物制剂可以以分开的单位给药,所述单位例如胶囊或片剂;粉末剂或颗粒剂;水或非水溶剂的溶液剂或混悬剂;可食用的泡沫剂或泡沫食品;或水包油型的乳化剂或油包水型的乳化剂。
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及药学上可接受的例如乙醇、甘油、水等惰性赋形剂混合。粉末剂是通过将化合物研细至适当微细尺寸并与用相似方法研细的药学上的赋形剂混合制得的,所述赋形剂例如可食用的碳水化合物,例如淀粉或甘露醇。香味剂、防腐剂、分散剂和染料同样可以存在。
通过制备如上面所述的粉末混合物并随后填装进成形的胶囊壳中制备胶囊。在填装操作前可以将助流剂和润滑剂,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,加入到粉末混合物中。同样可以加入例如琼脂、碳酸钙或碳酸钠的崩解剂或助溶剂,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,适当的粘合剂、润滑剂和崩解剂及染料同样可以加入到混合物中。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;天然或合成的橡胶,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,并任选与以下试剂混合制得的,所述试剂包括粘合剂,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。可以用例如糖浆、淀粉糊、acadia mucilage或者纤维素或多聚物材料的溶液的粘合剂使粉末混合物润湿成粒,并将其压过筛网。制粒的另一选择是,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。可以在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,以防止其粘到铸型中。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不透明的包含虫胶封装层、糖或多聚物材料层和光泽的蜡层的保护层。可以向这些包衣中加入染料,以使能够区别不同的剂量单位。口服液体剂,例如溶液剂、糖浆剂和酏剂,可以以剂量单位形式制得,以得到包含指定量的化合物。可以将化合物溶解在含有适当香味剂的水溶液中制得糖浆剂,且可以用非毒性的醇溶媒制得酏剂。可以通过将化合物分散于无毒溶媒中制备混悬剂。同样可以加入增溶剂和乳化剂,例如乙氧基化的异硬脂醇和聚氧乙烯山梨糖醇醚;防腐剂、香味添加剂,例如薄荷油;或天然甜味剂或糖;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用聚合物和蜡等材料包衣或包埋,制备释放延长或延缓的制剂。
式I化合物和其盐、溶剂合物和生理上功能化衍生物还可以以例如小单层微囊、大单层微囊和多层微囊的脂质体递药系统形式给药。脂质体可以用例如胆固醇、硬脂胺或磷脂酰胆碱的各种磷脂形成。
式I化合物和其盐、溶剂合物和生理上的功能化衍生物还可以用单克隆抗体作为个体载体进行递药,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、聚羟丙基异丁烯酰氨基苯酚、聚羟乙基天冬酰胺基苯酚或聚环氧乙烷聚赖氨酸,可以被棕榈酰基取代。此外还可以将这些化合物偶联至适于控制药物释放的生物可降解类聚合物上,例如聚乳酸、聚己内酯(poly-epsilon-caprolcatone)、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叉或两亲嵌段共聚物。
适于经皮给药的药物制剂可以作为独立的与接受者的表皮较大范围密切接触的贴剂。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。
可以将适于局部给药的药物化合物制成膏剂、乳膏剂、混悬剂、洗液剂、粉末剂、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,制剂优选使用局部的膏剂或乳膏剂。在制剂为膏剂的情况下,活性成分可以与石蜡或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中,特别是含水溶剂。
适于口腔局部用药的药物制剂包括锭剂(lozenges)、软锭剂(pastilles)和漱口剂。
适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于鼻腔给药的药物制剂包含有颗粒大小(例如20-500微米)的粗粉,该粗粉通过鼻吸方式给药,例如由鼻道从靠近鼻子的含有该粉末的容器中快速吸入。由液体作为载体物质的用于鼻喷雾剂或滴鼻剂给药的适当的制剂包括活性成分的水或油溶液。
适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、喷雾器或吹入器的加压分散器产生。
适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。
适于肠胃外给药的药物制剂包括含水或无水的无菌注射溶液,该溶液包含抗氧化剂、缓冲剂、抑菌剂和溶解物,这些物质使制剂与治疗的受试者的血液等渗;以及含水或无水的包含混悬介质和稠化剂的无菌混悬剂。制剂可以在单剂量或多剂量容器中给药,例如封闭的安瓿和管形瓶,并以冷冻干燥(冻干)状态保存,从而只需在使用前立即加入例如注射用水的无菌载体液体即可。
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。
不用说,除了上面特别提到的成分外,制剂还可以包括与特殊类型制剂相关的其它在本领域中常用的物质;因此,例如适于口服给药的制剂可以包含香味剂。
式I化合物的治疗有效量依赖于很多因素,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它的严重性、制剂的性质和给药方法,最终要靠实施治疗的医生或兽医确定。然而,本发明化合物的有效量通常为每天0.1-100mg/kg受试者(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,该量可以以每天单独剂量给药或通常以每天一系列分剂量(例如二、三、四、五或六剂量)给药,但总的日剂量是相同的。可以将其盐或溶剂合物或生理上功能化的衍生物的有效量作为式I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,相似的剂量是适合的。
此外,本发明还涉及药物,该药物包含至少一种式I化合物和/或其药学上可用的衍生物、溶剂合物和立体异构体,包括任何比例的混合物,和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物质,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物质;此处优选VEGF受体抑制剂,包括定向至VEGF受体的核酶(robozyme)和反义物质(antisense)、制管张素和内皮抑制素。
可以与本发明化合物组合使用的抗肿瘤物质的示例通常包括烷化剂、抗代谢药;表鬼臼毒素(epidophyllotoxin);抗肿瘤酶;拓扑异构酶抑制剂;丙卡巴肼;米托蒽醌或铂配位复合物。
抗肿瘤物质优选选自下面类别化合物:蒽环类抗生素、长春花属药物、丝裂霉素类、博来霉素类、细胞毒性核苷类、埃博霉素类(epothilones)、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、methopterin、二氯甲氨蝶呤、丝裂霉素C、泊非霉素、5-氟尿嘧啶、5-氟脱氧尿苷一磷酸、阿糖胞苷、5-氮杂胞苷、硫鸟嘌呤、硫唑嘌呤、腺苷、喷司他丁、erythrohydroxynonyladenine、克拉屈滨、6-巯基嘌呤、吉西他滨、cytosinarabinoside、鬼臼素毒或鬼臼素毒衍生物(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、多西紫杉醇和紫杉醇。其它优选的抗肿瘤药物选自discormolide、埃博霉素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(leuprolide)、pyridobenzoindole衍生物、干扰素和白介素。
另外的药物活性成分优选抗生素。优选的抗生素选自放线菌素D、柔红霉素、伊达比星、表柔比星、米托蒽醌、博来霉素、普卡霉素、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脱乙酰基酶抑制剂(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多聚物(例如RNA)从细胞核中输出。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(Wyeth)、RAD001(Novartis)、AP23573(AriadPharmaceuticals)。
本发明还涉及套盒(试剂盒),该套盒包含独立包装的
(a)有效量的式I化合物和/或其药学上可用的衍生物、溶剂合物和立体异构体,包括它们的任何比例的混合物,和
(b)有效量的另外的药物活性成分。
该套盒包括适当的容器,例如盒子、单独的瓶、袋或安瓿。该套盒可以,例如,包括独立的安瓿,每个安瓿中包含溶解或冻干状态的有效量的式I化合物和/或其药学上可用的衍生物、溶剂合物和立体异构体,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
本发明化合物适于作为治疗在哺乳动物特别是人类中的HSP90参与的疾病的药物活性成分。
因此,本发明涉及式I化合物和/或其药学上可用的衍生物、溶剂合物和立体异构体,包括它们的任何比例的混合物,在制备治疗HSP90的抑制、调节和/或调控起作用的疾病的药物中的用途。
优选式I化合物和/或其药学上可用的衍生物、溶剂合物和立体异构体(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,所述疾病包括肿瘤疾病,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(Ewing’s tumour)、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、鳞状上皮细胞癌、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、瓦尔登斯特伦巨球白血症、重链病等的肉瘤和癌;
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、流行性感冒病毒、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、echinovirus、虫媒病毒、huntavirus、柯萨奇病毒、流行性腮腺炎病毒、麻疹病毒、风疹病毒、脊髓炎病毒、人免疫缺陷病毒I型(HIV-I)和人免疫缺陷病毒II型(HIV-II);
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、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、子宫内膜异位和肿瘤血管生成;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;
式I化合物可以抑制,特别是,癌生长及肿瘤细胞和肿瘤的转移,因此适于治疗肿瘤。
此外,本发明包括式I化合物和/或其生理上可接受的盐和溶剂合物在制备保护正常细胞对抗化疗引起的毒性的药物及治疗错误蛋白折叠或聚集是主要致病因素的疾病(例如痒病、Creutzfeldt-Jakob病、亨廷顿氏病或阿尔茨海默氏病)的药物中的用途。
本发明还涉及式I化合物和/或其生理上可接受的盐和溶剂合物在制备治疗中枢神经系统、心血管和恶病质疾病的药物中的用途。
在另外的实施方案中,本发明还涉及式I化合物和/或其生理上可接受的盐和溶剂合物在制备用于HSP90调控的药物中的用途,其中调控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和与局部缺血/再灌注或它们的组合相关的病症,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、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、阿尔茨海默氏病、亨廷顿病、肌萎缩侧索硬化(ALS)或新生儿应激等造成的后果。
在另外的实施方案中,本发明还涉及式I化合物和/或其生理上可接受的盐和溶剂合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、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、阿尔茨海默氏病、亨廷顿病、肌萎缩侧索硬化(ALS)或新生儿应激等造成的后果。
测定HSP90抑制剂的实验方法
可以利用格尔德霉素或17-烯丙氨基-17-脱甲氧格尔德霉素(17AAG)结合至HSP90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,应用了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-烯丙氨基格尔德霉素,[3H]17AAG。该过滤结合实验可以用于靶向寻找干扰ATP结合位点的抑制剂。
材料
重组人HSP90α(大肠杆菌表达的,95%纯度);
[3H]17AAG(17-烯丙氨基格尔德霉素,[烯丙氨基-2,3-3H]。比活性:1.11×1012Bq/mmol(Moravek,MT-1717);
HEPES过滤缓冲液(50mM HEPES,pH7.0,5mM MgCl2,BSA0.01%)
Multiscreen FB(1μm)过滤板(Millipore,MAFBNOB50)。
方法
首先将96-孔微滴定过滤板冲洗,并用0.1%聚乙烯亚胺包被。
在下面的条件下进行实验:
反应温度22℃
反应时间:30分钟,在800rmp下摇动
实验体积:50μl
终浓度
50mM HEPES HCl,pH7.0,5mM MgCl2,0.01%(w/v)BSA
HSP901.5μg/实验
[3H]17AAG:0.08μM。
在反应末,用真空多支管(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(Microscint20,Packard)测定滤板。
由“每分钟计数”值测定“对照的百分数(%)”,并且由此可以计算出化合物的IC50值。
上本文中,所有的温度是以℃为单位表示的。在下面的实施例中,“常规处理”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,进行相分离,将有机相用硫酸钠干燥,并蒸干,通过色谱在硅胶上和/或通过结晶将产物纯化。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HP1100系列Hewlett Packard System:离子源:电喷雾(正性模式);扫描:100-1000m/e;断裂电压:60V;气体温度:300℃,DAD:220nm。
流速:2.4ml/min。所用的分流器将对于MS的流速在DAD后减至0.75ml/min。
柱:Chromolith SpeedROD RP-18e 50-4.6
溶剂:来自Merck KGaA的液相色谱纯级
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指的保留时间Rf[min]和M+H+数据MN为LC-MS的测定结果。
实施例1
制备R2指酰化的氨基的式I化合物的通用反应流程图:
制备2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(3-三氟甲基苯甲酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A1”)
1.1将10.9g氰基硫代乙酰胺和9ml 4-甲基吗啉加入到10g 4-甲氧基-3-硝基苯甲醛的100ml乙醇溶液中,将该混合物在室温下搅拌48小时。加入10%HCl至pH为5,将混合物再搅拌16小时。将沉淀物质分离出来,用乙醇和正庚烷洗涤,干燥,得到9.6g 6-氨基-3,5-二氰基-4-(4-甲氧基-3-硝基苯基)-2-硫代-1,2-二氢吡啶(“1”)。
1.2将1当量溶于水中的KOH加入到30.7g“1”的100ml DMF溶液中。然后加入8.8g 2-氯乙酰胺,将混合物再搅拌1小时。再加入1当量溶于水中的KOH,将混合物在室温下搅拌16小时,接着在100℃下再搅拌1小时。用同量的水将混合物稀释,将沉淀物分离出来,用水洗涤,干燥,得到17g 2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-硝基苯基)噻吩并[2,3-b]吡啶(“2”)。
1.3按标准方法用5%Pd/C(56%的水溶液)作催化剂将100ml DMF中的1.8“2”氢化。分离出催化剂,除去溶剂,以定量产率得到2-氨基羰基-3,6-二氨基-5-氰基-4-(3-氨基-4-甲氧基苯基)噻吩并[2,3-b]吡啶(“3”),
1H NMR 250 MHz,DMSO-d6)δ15.00(b),7.62(d,1H),7.51(d,1H),7.48(d,1H),4.06(s,3H)。
1.4将47μl 4-甲基吗啉加入到45μl 3-(三氟甲基)苯甲酰氯和48mg1-羟基苯并三唑水合物的1ml DMF溶液中,将该混合物在室温下搅拌1小时。加入100mg“3”,将混合物再搅拌16小时。将混合物搅拌加入到10ml水中,将沉淀物分离出来,用水洗涤,用色谱法(RP快速色谱法;IscoCompanion)纯化,得到24mg“A1”,M+H+527.50
类似的,将“3”与下列试剂反应,所述试剂为
乙酰氯,
三氟乙酰氯,
戊二酸单甲酯单酰氯,
1H-吡啶-2-酮-4-甲酰氯,
4-甲氧基羰基苯甲酰氯,
氯羰基甲氧基乙酸甲酯,
3-三氟甲基苯磺酰氯,
得到下列化合物,
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-乙酰氨基苯基)噻吩并[2,3-b]吡啶(“A2”),M+H+397.43;
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-三氟乙酰氨基苯基)噻吩并[2,3-b]吡啶(“A3”),M+H+451.40;
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-甲氧基-羰基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A4a”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(1H-吡啶-2-酮-4-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A5”),M+H+476.49;
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-甲氧基-羰基苯甲酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A6a”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-甲氧基-羰基甲氧基乙酰氨基)苯基]噻吩并[2,3-b]吡啶(“A7a”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(3-三氟甲基苯磺酰氨基)苯基]噻吩并[2,3-b]吡啶(“A9”),M+H+563.55。
实施例2
在标准条件下,
对“A4a”进行酯水解得到化合物2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-羧基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A4”),M+H+469.49;
对“A6a”进行酯水解得到化合物2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-羧基苯甲酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A6”),M+H+503.51;
对“A7a”进行酯水解得到化合物2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-羧基甲氧基乙酰氨基)苯基]噻吩并[2,3-b]吡啶(“A7”),M+H+471.46;
实施例3
将82mg N-(3-二甲氨基丙基)-N-乙基碳二亚胺盐酸盐(DAPECI)和47μl 4-甲基吗啉加入至55mg BOC-甘氨酸(BOC-Gly-OH)和48mg 1-羟基苯并三唑水合物的1ml DMF溶液中,将该混合物在室温下搅拌1小时。加入100mg“3”,将混合物再搅拌16小时。将混合物搅拌加入10ml水中,分离出沉淀物,用水洗涤,得到
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-[(叔丁氧羰基)氨基]乙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A10”),
类似地,将“3”与下列化合物反应,所述试剂为
BOC-β-Ala-OH(BOC-β-丙氨酸),
BOC-GABA-OH(BOC-γ-氨基丁酸),
1H-吲哚-7-甲酸,
BOC-His-OH(BOC-组氨酸),
BOC-Asn-OH(BOC-天冬酰胺),
N-(2-氨基甲酰乙酰)甘氨酸,
1H-吲唑-7-甲酸,
BOC-Ser(O-叔丁基)-OH(BOC-(S)-丝氨酸叔丁酯),得到下列化合物:
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{3-[(叔丁氧羰基)氨基]丙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A11”),M+H+526.59;
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{4-[(叔丁氧羰基)氨基]丁酰氨基}苯基)噻吩并[2,3-b]吡啶(“A12”),M+H+540.61;
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(吲哚-7-基-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A13”),M+H+498.54;
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-[(叔丁氧羰基)氨基]-3-(1H-咪唑-4-基)丙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A14a”),
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-[(叔丁氧羰基)氨基]-3-氨基羰基丙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A15a”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-[2-氨基甲酰基乙酰基氨基)-乙酰基氨基]苯基]噻吩并[2,3-b]吡啶(“A16”),M+H+497.51;
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(吲唑-7-基-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A17”),M+H+499.52;
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-[(叔丁氧羰基)氨基]-3-(叔丁氧基)丙酰基氨基}苯基)噻吩并[2,3-b]吡啶(“A18a”)。
实施例4
将
“A11”
“A12”
“A14a”
“A15a”
“A18a”
的BOC保护基脱除,并在HCl/二烷中将叔丁基醚裂解,得到下列化合物
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(3-氨基-丙酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A21”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-氨基-丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A22”),M+H+440.50;
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-{4-甲氧基-3-[2-氨基-3-(1H-咪唑-4-基)丙酰氨基]苯基}噻吩并[2,3-b]吡啶(“A14”),
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-氨基-3-氨基羰基丙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A15”),
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-氨基-3-羟基丙酰氨基)苯基]噻吩并[2,3-b]吡啶(“A18”)。
实施例5
在标准条件下,将2-氨基羰基-3,6-二氨基-5-氰基-4-(2-氨基-4-甲氧基苯基)噻吩并[2,3-b]吡啶(“3a”)与3-三氟甲基苯基异氰酸酯反应,制得化合物
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-2-(3-三氟甲基苯基脲基)苯基]噻吩并[2,3-b]吡啶(“A22”)。
实施例6
类似实施例1,将2-氨基羰基-3,6-二氨基-5-氰基-4-(2-氨基-4-甲氧基苯基)噻吩并[2,3-b]吡啶(“3a”)与下列化合物反应:
苯甲酰氯,
3-氨基甲酰基丙酸,
N-(苯磺酰基)甘氨酸,
得到化合物:
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-2-苯甲酰基氨基-苯基)噻吩并[2,3-b]吡啶(“A8”),M+H+459.50;
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-2-(3-氨基甲酰基-丙酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A19”),M+H+454.48;
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-2-[2-(苯磺酰基)乙酰基氨基]苯基]噻吩并[2,3-b]吡啶(“A20”),M+H+552.60;
实施例7
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-2-[2-(3-乙基脲基)乙基氨基甲酰基]苯基]噻吩并[2,3-b]吡啶(“A23”),
7.1制备前体化合物“A23a”的反应流程图
醋酸钯(II)(Pd 47%)、1,8-二氮杂双环[5.4.0]十一碳-7-烯、THF和六羰基钼的混合物用微波在120℃下照射1小时。常规处理后,得到
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-2-(3-乙基脲基)乙基氨基甲酰基]苯基]噻吩并[2,3-b]吡啶(“A23”),M+H+497.55;
类似实施例7.2,在Mo(CO)6和Pd(OAc)2存在下,将下式化合物
与7-氨基吲唑反应,制得
2-氨基羰基-3,6-二氨基-5-氰基-4-[3-(吲唑-7-基-氨基甲酰基)苯基]噻吩
并[2,3-b]吡啶(“A24”),M+H+469.50;
类似实施例7.2,在Mo(CO)6和Pd(OAc)2存在下,将下式化合物
与4-氨基丁酰胺反应,制得
2-氨基羰基-3,6-二氨基-5-氰基-4-[5-氯-3-(氨基甲酰基丙基氨基甲酰基)苯基]噻吩并[2,3-b]吡啶(“A25”),M+H+472.93;
实施例8
将PdCl2(dppf)加入到3-氟苄基溴化锌(0.5M的THF溶液)中,在氩气气氛下,将混合物在室温下搅拌5分钟。接着滴加加入“A26a”的THF溶液,
将混合物在45℃下再搅拌30分钟,然后在65℃下搅拌1小时。将混合物冷却,并倒入饱和NH4Cl溶液中,接着进行常规处理,得到2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(3-氟苄基)苯基]噻吩并[2,3-b]吡啶(“A26”),M+H+448.49;
实施例9
9.1将“A27a”
2-乙烯基吡啶、三乙胺、醋酸钯(II)(Pd47%)、三邻甲苯基膦和乙腈的混合物用微波在160℃下照射30分钟。将甲苯加入到反应混合物中,并用水萃取数次。干燥有机相并蒸干。用色谱法(ISCO/40g柱;石油醚/乙酸乙酯:4/1至1/1)纯化产物,得到“A27b”
9.2在BCHI装置中,在1.4bar和室温条件下,将“A27b”、5%Pd/C(56%的水溶液)和THF混合物氢化16小时。除去催化剂和溶剂,得到2-氨基羰基-3,6-二氨基-5-氰基-4-{3-氯-4-甲氧基-2-[2-(吡啶-2-基)乙基]苯基}噻吩并[2,3-b]吡啶(“A27”),M+H+497.96;
类似实施例9.1,将“A26a”与丙烯酸甲酯反应,制得化合物“A28a”
然后类似实施例9.2将其氢化,并将酯裂解,得到化合物
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-羧基乙基)苯基]噻吩并[2,3-b]吡啶(“A28”),M+H+412.44;
实施例10
在N2气氛和回流条件下,将“A26a”、“A29a”、
丙醇、醋酸钯(II)、三苯基膦、碳酸钠溶液和水的混合物加热16小时,进行Suzuki反应。冷却混合物,接着进行常规处理,得到化合物
2-氨基羰基-3,6-二氨基-5-氰基-4-{4-甲氧基-3-[2-(4-甲基-哌嗪-1-基)乙氧基]苯基}噻吩并[2,3-b]吡啶(“A29”),M+H+558.68;
实施例11
类似于实施例10,将“A30a”
与“A30b”反应,
得到化合物2-氨基羰基-3,6-二氨基-5-氰基-4-{4-甲氧基-3-[3-(2-氨基乙酰基氨基)苯基]苯基}噻吩并[2,3-b]吡啶(“A30”),M+H+559.66;
实施例12
类似于实施例1,将“A31a”
与戊二酸单甲酯单酰氯反应,得到化合物“A31b”
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-氯-2-(4-甲氧羰基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A31b”)。
将“A31b”的酯裂解后,得到2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-氯-2-(4-羧基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A31”),M+H+503.94
实施例13
类似于实施例1,将“A32a”
与“A32b”反应,
得到化合物“A32”
2-氨基羰基-3,6-二氨基-5-氰基-4-{2-氯-4-二氟甲氧基-3-[3-(4-甲基哌嗪-1-基)丙酰氨基]苯基}噻吩并[2,3-b]吡啶(“A32”),M+H+580.03
实施例14
类似于实施例1,将“A33a”
与戊二酸单甲酯单酰氯反应,得到化合物“A33b”
将“A33b”的酯裂解后,得到2-(2-吗啉-4-基乙基氨基甲酰基)-3,6-二氨基-5-氰基-4-[2-(4-羧基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A33”),M+H+552.63。
实施例15
将“A34a”
与苄醇在标准条件下反应,得到化合物
2-氨基羰基-3,6-二氨基-5-氰基-4-[2-(苄氧羰基氨基)-苯基]噻吩并[2,3-b]吡啶(“A34”),M+H+489.53(“A34”)
实施例16
根据类似制备“A1”的方法,可以制得下面的化合物:
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-三氟甲基苯甲酰氨基)苯基]噻吩并[2,3-b]吡啶(“A35”),
1H NMR 250 MHz,DMSO-d6)δ9.99(b),8.16(d,1H),7.92(d,2H),7.37(d,2H),7.02(s,1H),5.90(s,1H),3.96(s,3H);
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-三氟甲基苯甲酰氨基)苯基]噻吩并[2,3-b]吡啶(“A36”),
根据类似制备“A17”的方法,可以制得下列化合物:
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(吡啶-4-基-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A37”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(丙-2-基-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A38”)。
药理数据
与受体的亲和性
表1
化合物编号 | HSP90-IC50[M] | |
“A35” | 5.9×10-6 | |
“A36” | 1.1×10-5 | |
“A37” | 1.9×10-6 | |
“A38” | 5.5×10-6 |
下面的实施例涉及药物组合物:
实施例A:注射瓶剂
用2N盐酸将100g根据本发明的活性成分和5g磷酸氢二钠的31双蒸水溶液调至pH为6.5,无菌过滤,转移至注射瓶中,在无菌条件下冻干,并在无菌条件下封装。每一注射瓶中含有5mg活性成分。
实施例B:栓剂
将20g根据本发明的活性成分与100g大豆卵磷脂和1400g可可豆脂的混合物熔化,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根据本发明的活性成分、9.38g NaH2PO4·2H2O、28.48gNa2HPO4·12H2O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,并使溶液为11,照射灭菌。该溶液可以以滴眼剂形式使用。
实施例D:膏剂
在无菌条件下,将500mg根据本发明的活性成分与99.5g凡士林混合。
实施例E:片剂
将1kg根据本发明的活性成分、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:糖衣剂
根据类似实施例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料进行包衣。
实施例G:胶囊
用常规方法,将2kg根据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
将1kg根据本发明的活性成分的60l双蒸水溶液无菌过滤,转移至安瓿中,在无菌条件下冻干,并在无菌条件下封装。每一安瓿中含有10mg的活性成分。
Claims (27)
1.式(I)化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,
其中
Y 指OH、OA、SH、SA、NH2、NHA、NAA’或NHR5,
R1 指Hal、OH、OA、SH、SA、H或A,
R2,R3 相互独立,分别指-NHCO-(X)s-Q、-CONH-(X)s-Q、-CONA-(X)s-Q、-NH(CO)NH-(X)s-Q、-NH(CO)O-(X)s-Q、-NHSO2-(X)s-Q、-SO2NH-(X)s-Q、-SO2NA-(X)s-Q、-(X)s-Q或H,
其中,如果R2≠H,则R3=H或Cl,或者
如果R3≠H,则R2=H或Cl,
R4 指H、Hal、CN、NO2、A、OH、OA、SH、SA、(CH2)nCOOH、(CH2)nCOOA、CONH2、CONHA、CONAA’、NH2、NHA、NAA’、NHCOOA、NHCONH2、NHCONHA、SOA、SO2A、SO2NH2、SO2NHA和/或SO2NAA’,
或者选自R1、R2、R3、R4的两个相邻的基团一起指亚甲二氧基或亚乙二氧基,
R5 指-(CH2)o-Het1、-(CH2)o-NH2、-(CH2)o-NHA或-(CH2)o-NA2,A,A’相互独立,分别指无支链的或支链的含有1-10个C原子且其中1-5个氢原子可以被F、Cl和/或Br取代的烷基、Alk或含有3-7个C原子的环烷基,
或者A和A’一起指含有2、3、4、5或6个C原子的亚烷基,其中一个或两个CH2基团可以被O、S、SO、SO2、NH、NA和/或N-COOA取代,
Alk 指含有2-6个C原子的烯基,
X 指无支链的或支链的C1-C10亚烷基或C2-C10亚烯基,它们分别为未取代的或被下列基团单取代、双取代、三取代或四取代:A、OA、OH、SH、SA、Hal、NO2、CN、Ar、OAr、COOH、COOA、CHO、C(=O)A、C(=O)Ar、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’、NACONAA’和/或=O,并且其中一个、两个或三个C基团可以被O、S、SO、SO2、NHCO、NACO、CONH、CONA、SO2NH、SO2NA、NHSO2和/或NH基团替换,
Q 指H、Carb、Ar或Het,
Carb 指含有3-7个C原子的环烷基或含有3-7个C原子的环烯基,它们分别是未取代的或被下列基团单取代、双取代、三取代、四取代或五取代:A、OA、OH、SH、SA、Hal、NO2、CN、(CH2)nAr’、(CH2)nCOOH、(CH2)nCOOA、CHO、COA、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’和/或NACONAA’,
Ar 指苯基、萘基或联苯基,它们分别是未取代的或被下列基团单取代、双取代、三取代、四取代或五取代:A、OA、OH、SH、SA、Hal、NO2、CN、(CH2)nAr’、(CH2)nCOOH、(CH2)nCOOA、CHO、COA、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’、NACONAA’、NHCO(CH2)nNH2和/或-O(CH2)o-Het1,
Ar’ 指苯基、萘基或联苯基,它们分别是未取代的或被下列基团单取代、双取代或三取代:A、OA、OH、SH、SA、Hal、NO2、CN、(CH2)n苯基、(CH2)nCOOH、(CH2)nCOOA、CHO、COA、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’和/或NACONAA’,
Het 指含有1-4个N、O和/或S原子的单环或双环饱和的、未饱和的或芳香族杂环,其可被下列基团单取代、双取代或三取代:A、OA、OH、SH、SA、Hal、NO2、CN、(CH2)nAr’、(CH2)nCOOH、(CH2)nCOOA、CHO、COA、SO2A、CONH2、SO2NH2、CONHA、CONAA’、SO2NHA、SO2NAA’、NH2、NHA、NAA’、OCONH2、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO2OA、NASO2OA、NHCONH2、NACONH2、NHCONHA、NACONHA、NHCONAA’、NACONAA’、SO2A、=S、=NH、=NA和/或=O(羰基氧),
Het1 指含有1-2个N和/或O原子的可被A、OA、OH、Hal和/或=O(羰基氧)单取代或双取代的单环饱和杂环,
Hal 指F、Cl、Br或I,
n 指0、1、2、3或4,
o 指1、2、3或4,
s 指0或1。
2.根据权利要求1的式I化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中Y指NH2或NHR5。
3.根据权利要求1或2的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中R1指H、OH或OA。
4.根据权利要求1-3中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中
R2、R3相互独立,分别指-NHCO-(X)s-Q、-CONH-(X)s-Q、-NH(CO)NH-(X)s-Q、-NH(CO)O-(X)s-Q、-(X)s-Q或H,
其中,如果R2≠H,则R3=H或Cl,或者
如果R3≠H,则R2=H或Cl。
5.根据权利要求1-4中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中R4指H或Hal。
6.根据权利要求1-5中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中R5指-(CH2)o-Het1或-(CH2)o-NA2。
7.根据权利要求1-6中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中
X指无支链的或支链的C1-C10亚烷基,该亚烷基是未取代或被下列基团单取代、双取代、三取代或四取代:OA、OH、Hal、COOH、CONH2、NH2和/或NHCOOA,并且其中一个、两个或三个C基团可以被O、NHCO、CONH、SO2NH、NHSO2和/或NH基团替换。
8.根据权利要求1-7中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中Q指H、Ar或Het。
9.根据权利要求1-8中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中
Ar指未取代的或被A、Hal、OA、(CH2)nCOOH、(CH2)nCOOA、NHCO(CH2)nNH2和/或-O(CH2)o-Het1单取代、双取代、三取代、四取代或五取代的苯基。
10.根据权利要求1-9中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中
Het指含有1-4个N、O和/或S原子的单环或双环的饱和、不饱和或芳香族杂环,该杂环可以被A、OA、Hal和/或=O(羰基氧)单取代、双取代或三取代。
11.根据权利要求1-10中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中
Het指含有1-2个N和/或O原子的单环或双环的饱和、不饱和或芳香族的杂环,该杂环可以被A和/或=O(羰基氧)单取代或双取代。
12.根据权利要求1-11中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中
Het1指含有1-2个N和/或O原子的单环饱和杂环,该杂环可以被A和/或=O(羰基氧)单取代或双取代。
13.根据权利要求1-12中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中
A指含有1-6个C原子的无支链的或支链的烷基,其中1-5个氢原子可以被F和/或Cl替换。
14.根据权利要求1-13中的一项或多项的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,其中
Y 指NH2或NHR5;
R1 指H、OH或OA,
R2,R3 相互独立,分别指-NHCO-(X)s-Q、-CONH-(X)s-Q、-NH(CO)NH-(X)s-Q、-NH(CO)O-(X)s-Q、-(X)s-Q或H,
其中,如果R2≠H,则R3=H或Cl,或者
如果R3≠H,则R2=H或Cl,
R4 指H或Hal,
R5 指-(CH2)o-Het1或-(CH2)o-NA2,
X 指无支链的或支链的C1-C10亚烷基,该亚烷基是未取代或被下列基团单取代、双取代、三取代或四取代:OA、OH、Hal、COOH、CONH2、NH2和/或NHCOOA,并且其中一个、两个或三个C基团可以被O、NHCO、CONH、SO2NH、NHSO2和/或NH基团替换,
Q 指H、Ar或Het,
Ar 指未取代的或被A、Hal、OA、(CH2)nCOOH、(CH2)nCOOA、NHCO(CH2)nNH2和/或-O(CH2)o-Het1单取代、双取代、三取代、四取代或五取代的苯基,
Het 指含有1-4个N、O和/或S原子的单环或双环的饱和、不饱和或芳香族杂环,该杂环可以被A、OA、Hal和/或=O(羰基氧)单取代、双取代或三取代,
Het1 指含有1-2个N和/或O原子的单环饱和杂环,该杂环可以被A和/或=O(羰基氧)单取代或双取代,
A 指含有1-6个C原子的无支链的或支链的烷基,其中1-5个氢原子可以被F和/或Cl替换,
Hal 指F、Cl、Br或I,
n 指0、1、2、3或4,
o 指1、2、3或4,
s 指0或1。
15.根据权利要求1的化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们任何比例的混合物,所述化合物选自
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(3-三氟甲基苯甲酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A1”),
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-乙酰氨基苯基)噻吩并[2,3-b]吡啶(“A2”),
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-三氟乙酰氨基苯基)噻吩并[2,3-b]吡啶(“A3”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-甲氧基羰基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A4a”)
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(1H-吡啶-2-酮-4-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A5”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-甲氧基-羰基苯甲酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A6a”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-甲氧基-羰基甲氧基乙酰氨基)苯基]噻吩并[2,3-b]吡啶(“A7a”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(3-三氟甲基苯磺酰氨基)苯基]噻吩并[2,3-b]吡啶(“A9”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-羧基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A4”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-羧基苯甲酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A6”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-羧基甲氧基乙酰氨基)苯基]噻吩并[2,3-b]吡啶(“A7”),
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-[(叔丁氧羰基)氨基]乙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A10”),
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{3-[(叔丁氧羰基)氨基]丙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A11”),
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{4-[(叔丁氧羰基)氨基]丁酰氨基}苯基)噻吩并[2,3-b]吡啶(“A12”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(吲哚-7-基-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A13”),
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-[(叔丁氧羰基)氨基]-3-(1H-咪唑-4-基)丙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A14a”),
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-[(叔丁氧羰基)氨基]-3-氨基羰基丙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A15a”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-[2-氨基甲酰基乙酰基氨基)-乙酰基氨基]苯基]噻吩并[2,3-b]吡啶(“A16”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(吲唑-7-基-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A17”),
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-[(叔丁氧羰基)氨基]-3-(叔丁氧基)丙酰基氨基}苯基)噻吩并[2,3-b]吡啶(“A18a”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(3-氨基-丙酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A21”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-氨基-丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A22”),
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-{4-甲氧基-3-[2-氨基-3-(1H-咪唑-4-基)丙酰氨基]苯基}噻吩并[2,3-b]吡啶(“A14”),
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-3-{2-氨基-3-氨基羰基丙酰氨基}苯基)噻吩并[2,3-b]吡啶(“A15”),
(S)-2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-氨基-3-羟基丙酰氨基)苯基]噻吩并[2,3-b]吡啶(“A18”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-2-(3-三氟甲基苯基脲基)苯基]噻吩并[2,3-b]吡啶(“A22”),
2-氨基羰基-3,6-二氨基-5-氰基-4-(4-甲氧基-2-苯甲酰基氨基-苯基)噻吩并[2,3-b]吡啶(“A8”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-2-(3-氨基甲酰基-丙酰基氨基)苯基]噻吩并[2,3-b]吡啶(“A19”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-2-[2-(苯磺酰基)乙酰基氨基]苯基]噻吩并[2,3-b]吡啶(“A20”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-2-[2-(3-乙基脲基)乙基氨基甲酰基]苯基]噻吩并[2,3-b]吡啶(“A23”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[3-(吲唑-7-基-氨基甲酰基)苯基]噻吩并[2,3-b]吡啶(“A24”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[5-氯-3-(氨基甲酰基丙基氨基甲酰基)苯基]噻吩并[2,3-b]吡啶(“A25”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(3-氟苄基)苯基]噻吩并[2,3-b]吡啶(“A26”),
2-氨基羰基-3,6-二氨基-5-氰基-4-{3-氯-4-甲氧基-2-[2-(吡啶-2-基)乙基]苯基}噻吩并[2,3-b]吡啶(“A27”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-羧基乙基)苯基]噻吩并[2,3-b]吡啶(“A28”),
2-氨基羰基-3,6-二氨基-5-氰基-4-{4-甲氧基-3-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}噻吩并[2,3-b]吡啶(“A29”),
2-氨基羰基-3,6-二氨基-5-氰基-4-{4-甲氧基-3-[3-(2-氨基乙酰基氨基)苯基]苯基}噻吩并[2,3-b]吡啶(“A30”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-氯-2-(4-甲氧羰基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A31b”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-氯-2-(4-羧基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A31”),
2-氨基羰基-3,6-二氨基-5-氰基-4-{2-氯-4-二氟甲氧基-3-[3-(4-甲基哌嗪-1-基)丙酰氨基]苯基}噻吩并[2,3-b]吡啶(“A32”),
2-(2-吗啉-4-基乙基氨基甲酰基)-3,6-二氨基-5-氰基-4-[2-(4-羧基丁酰氨基)苯基]噻吩并[2,3-b]吡啶(“A33”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[2-(苄氧羰基氨基)-苯基]噻吩并[2,3-b]吡啶(“A34”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(4-三氟甲基苯甲酰氨基)苯基]噻吩并[2,3-b]吡啶(“A35”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(2-三氟甲基苯甲酰氨基)苯基]噻吩并[2,3-b]吡啶(“A36”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(吡啶-4-基-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A37”),
2-氨基羰基-3,6-二氨基-5-氰基-4-[4-甲氧基-3-(丙-2-基-羰基氨基)苯基]噻吩并[2,3-b]吡啶(“A38”)。
16.制备根据权利要求1-15的式I化合物和其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体的方法,其特征在于:
a)将式II化合物:
其中
R1、R2和R3与权利要求1所定义的相同,
与式III化合物反应:
Y-CO-CH2-Z III
其中Y与权利要求1所定义的相同,并且
Z指Cl、Br、I或游离或反应性功能修饰的OH基团,或
b)通过下面反应将式I化合物中的一个或多个基团R1、R2、R3、R4和/或Y转变为另外的一个或多个基团R1、R2、R3、R4和/或Y,
所述反应,例如
i)将硝基还原为氨基,
ii)将酯基水解为羧基,
iii)通过还原胺化反应,将氨基转化为烷基化的胺,
iv)将羟基和/或氨基烷基化和/或酰化,和/或将式I的碱或酸转化为其盐。
17.药物,该药物包含至少一种式I化合物和/或其药学上可用的衍生物、盐、溶剂合物、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/或佐剂。
18.式I化合物和其药学上可用的衍生物、盐、溶剂合物、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。
19.根据权利要求18的式I化合物和/或其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们任何比例的混合物,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,
用于抑制癌的生长和肿瘤细胞及肿瘤的转移,
用于保护正常细胞对抗化疗引起的毒性,
用于治疗其中错误蛋白折叠或聚集为主要致病因素的疾病。
20.根据权利要求19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、鳞状上皮细胞癌、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、瓦尔登斯特伦巨球白血症和重链病。
21.根据权利要求19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、流行性感冒病毒、水痘病毒、腺病毒、单纯性疱疹I型(HSV-I)病毒、单纯性疱疹II型(HSV-II)病毒、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、echinovirus、虫媒病毒、huntavirus、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)。
22.根据权利要求19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。
23.根据权利要求19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。
24.根据权利要求19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。
25.根据权利要求19的用途,其中错误蛋白折叠或聚集为主要致病因素的疾病为痒病、Creutzfeldt-Jakob病、亨廷顿氏病或阿尔茨海默氏病。
26.药物,该药物包含至少一种式I化合物和/或其药学上可用的衍生物、盐、溶剂合物、互变异构体和立体异构体,包括它们的任何比例的混合物,以及至少一种另外的药物活性成分。
27.套盒(试剂盒),该套盒包括独立包装的
(a)有效量的式I化合物和/或其药学上可用的衍生物、溶剂合物和立体异构体,包括它们的任何比例的混合物,和
(b)有效量的另外的药物活性成分。
Applications Claiming Priority (2)
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DE102005024245.6 | 2005-05-27 | ||
DE102005024245A DE102005024245A1 (de) | 2005-05-27 | 2005-05-27 | Thienopyridine |
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CN101163707A true CN101163707A (zh) | 2008-04-16 |
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US (1) | US7989625B2 (zh) |
EP (1) | EP1888593A2 (zh) |
JP (1) | JP2008542213A (zh) |
KR (1) | KR20080021054A (zh) |
CN (1) | CN101163707A (zh) |
AR (1) | AR057332A1 (zh) |
AU (1) | AU2006251420A1 (zh) |
BR (1) | BRPI0610204A2 (zh) |
CA (1) | CA2609385A1 (zh) |
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RU (1) | RU2415859C2 (zh) |
WO (1) | WO2006125531A2 (zh) |
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CN102459280A (zh) * | 2009-05-15 | 2012-05-16 | 勒芬天主教大学 | 作为病毒复制抑制剂的噻吩并[2,3-b]吡啶衍生物 |
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DE102007049451A1 (de) | 2007-10-16 | 2009-04-23 | Merck Patent Gmbh | 5-Cyano-thienopyridine |
US20090118276A1 (en) * | 2007-11-02 | 2009-05-07 | Wyeth | Thienopyrimidines, thienopyridines, and pyrrolopyrimidines as b-raf inhibitors |
AR077405A1 (es) | 2009-07-10 | 2011-08-24 | Sanofi Aventis | Derivados del indol inhibidores de hsp90, composiciones que los contienen y utilizacion de los mismos para el tratamiento del cancer |
FR2949467B1 (fr) | 2009-09-03 | 2011-11-25 | Sanofi Aventis | Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation |
CN102933390B (zh) | 2010-09-13 | 2017-02-08 | 艾利丹尼森公司 | 用于热密封包装的可再密封的层压材料 |
TWI458732B (zh) * | 2012-06-27 | 2014-11-01 | Univ Nat Chiao Tung | 具硼酸基團連接子及含有其之生物感測元件 |
ES2779748T3 (es) | 2012-08-23 | 2020-08-19 | Janssen Biopharma Inc | Compuestos para el tratamiento de infecciones víricas por paramixovirus |
MA41614A (fr) | 2015-02-25 | 2018-01-02 | Alios Biopharma Inc | Composés antiviraux |
WO2023213761A1 (en) * | 2022-05-03 | 2023-11-09 | Universite De Geneve | Adenosine 2a receptor modulators for use in the treatment of cancer |
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WO2005058315A1 (en) * | 2003-12-12 | 2005-06-30 | Ribapharm, Inc. | Novel heterocyclic compounds as ikk2 inhibitors with anti-hbv activity |
DE102005009440A1 (de) * | 2005-03-02 | 2006-09-07 | Merck Patent Gmbh | Thienopyridinderivate |
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2005
- 2005-05-27 DE DE102005024245A patent/DE102005024245A1/de not_active Withdrawn
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- 2006-05-11 WO PCT/EP2006/004426 patent/WO2006125531A2/de active Application Filing
- 2006-05-11 CN CNA2006800138250A patent/CN101163707A/zh active Pending
- 2006-05-11 RU RU2007147593/04A patent/RU2415859C2/ru not_active IP Right Cessation
- 2006-05-11 BR BRPI0610204-2A patent/BRPI0610204A2/pt not_active IP Right Cessation
- 2006-05-11 US US11/915,486 patent/US7989625B2/en not_active Expired - Fee Related
- 2006-05-11 KR KR1020077030243A patent/KR20080021054A/ko not_active Application Discontinuation
- 2006-05-11 CA CA002609385A patent/CA2609385A1/en not_active Abandoned
- 2006-05-26 AR ARP060102182A patent/AR057332A1/es unknown
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Publication number | Priority date | Publication date | Assignee | Title |
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CN102459280A (zh) * | 2009-05-15 | 2012-05-16 | 勒芬天主教大学 | 作为病毒复制抑制剂的噻吩并[2,3-b]吡啶衍生物 |
CN102459280B (zh) * | 2009-05-15 | 2015-10-14 | 勒芬天主教大学 | 作为病毒复制抑制剂的噻吩并[2,3-b]吡啶衍生物 |
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RU2415859C2 (ru) | 2011-04-10 |
WO2006125531A3 (de) | 2007-04-12 |
MX2007014720A (es) | 2008-02-15 |
BRPI0610204A2 (pt) | 2010-06-01 |
CA2609385A1 (en) | 2006-11-30 |
RU2007147593A (ru) | 2009-07-10 |
ZA200711142B (en) | 2008-11-26 |
AU2006251420A1 (en) | 2006-11-30 |
AR057332A1 (es) | 2007-11-28 |
JP2008542213A (ja) | 2008-11-27 |
DE102005024245A1 (de) | 2006-11-30 |
US20100048558A1 (en) | 2010-02-25 |
WO2006125531A2 (de) | 2006-11-30 |
KR20080021054A (ko) | 2008-03-06 |
EP1888593A2 (de) | 2008-02-20 |
US7989625B2 (en) | 2011-08-02 |
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