CN105960399A - 酶抑制剂环氧酮化合物 - Google Patents
酶抑制剂环氧酮化合物 Download PDFInfo
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- CN105960399A CN105960399A CN201580002532.1A CN201580002532A CN105960399A CN 105960399 A CN105960399 A CN 105960399A CN 201580002532 A CN201580002532 A CN 201580002532A CN 105960399 A CN105960399 A CN 105960399A
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Abstract
本发明公开的新化合物和药物组合物可作为蛋白酶体的抑制剂,这些化合物具有改进的蛋白酶体抑制活性和选择性以及增强的水溶性,可以用于治疗多种与蛋白酶体相关的疾病或病症。
Description
相关申请的交叉引用
本申请要求2014年7月14日提交的美国临时专利申请62/024,024的优先权,其内容在此参考并入。
技术领域
本发明涉及多肽环氧酮结构的化合物。这些化合物可以用于抑制蛋白酶体的活性。.
发明背景
蛋白酶体是一个具有多催化功能的蛋白酶复合体,在细胞内蛋白的降解过程中起关键作用。通常认为蛋白酶体在体内以26S蛋白酶体存在,其分子量约为2000kDa,包含有一个20S核心颗粒(20S蛋白酶体)和两个19S调节颗粒。20S核心颗粒为中空结构,将降解蛋白质的活性位点围在空腔中。核心颗粒的每一端都连接着一个19S调节颗粒,每个调节颗粒都含有多个ATP酶活性位点和泛素结合位点;调节颗粒可以识别多泛素化的蛋白质,并将它们传送到核心颗粒中。除了19S调节颗粒外,还存在另一种调节颗粒,即11S颗粒;11S调节颗粒可以以类似于19S颗粒的方式与核心颗粒结合;11S颗粒可能在降解外源肽上发挥作用。核心颗粒20S蛋白酶体分子量约为700kDa,有28个亚基构成4个环。在酵母和其它真核生物中,两个外环各由7个α亚基构成,两个内环各由七个β亚基组成。α环是19S或11S调节复合体的结合位点,也是两个β内环的物理屏障。两个β内环含有蛋白酶的催化活性位点,蛋白质的降解由20S核心颗粒中的β亚基进行。在体内,抑制20S蛋白酶体很容易与抑制26S蛋白酶体直接关联。有两种形式的蛋白酶体:一种是组成型蛋白酶体,存在于绝大多数真核生物的细胞内;另一种是免疫蛋白酶体,主要存在于造血细胞及暴露于炎性细胞因子的细胞中。蛋白酶体介导的蛋白质降解是一个高度有规律可循的过程,是细胞内各种生化过程所必需的的程序。通过使用不同的肽底物,已定义了真核生物蛋白酶体的三个主要蛋白酶活性:糜蛋白酶样活性(Chymotrypsin-Like,简写为CT-L),其功能为水解大的疏水氨基酸残基;胰蛋白酶样活性(Trypsin-Like,简写为T-L),其功能为水解碱性氨基酸残基;肽基谷氨酰肽水解活性(Peptidyl Glutamyl Peptide Hydrolyzing,简写为PGPH),其功能为水解酸性氨基酸残基。很长时间以来蛋白酶体一直被认为是药物开发有吸引力的分子靶标,并且在抗肿瘤药物领域获得了临床验证(Orlowski and Kuhn,Clin.Cancer Res.(2008),14,1649-1657)。
已有几类小分子化合物被用来抑制蛋白酶体活性,这些化合物包括肽硼酸,β内酯和多肽环氧酮(Bennett and Kirk,Current Opinion in Drug Discovery&Development(2008),11,616-625;Borissenko and Groll,Chem.Rev.(2007)107,687-717)。然而,这些化合物通常缺乏适当的特异性与生物活性,难以用来在分子水平,细胞水平及体内充分开发和利用蛋白酶体。例如,多肽硼酸和β-内酯都是非特异性的20S蛋白酶体抑制剂,因为它们也可以抑制其他蛋白酶(Borissenko and Groll,Chem.Rev.(2007)107,687-717;Myunget al.,Medicinal Research Reviews(2001),21,245-273;)。这就可能导致这些抑制剂在体内除了抑制蛋白酶体以外也抑制其它蛋白酶,从而产生非靶向毒性。另一方面,在专利US8088741B2,US6831099B1,WO2005/105827,CN101044157A,US7687452B2 and US2007/0105786A1中描述的多肽环氧酮作为20S蛋白酶体的抑制剂具有较高的选择性。然而,这些多肽环氧酮有较差的水溶性和/或欠优化的蛋白酶体抑制活性。因此,有必要开发新的有改良药学性能和/或生物特性的蛋白酶体抑制剂。
发明概述
本发明涉及的是具有三肽环氧酮结构的化合物,这些化合物具有改进的水溶性和对蛋白酶体的抑制特性。
在某些实施例中,本发明的化合物具有下式(I)所示的结构,及其对映异构体,非对映异构体,互变异构体,其药学上可接受的盐或溶剂化物或前药:
结构式(Ⅰ)
其中R1是-(CH2)m-R4,其中m=0或1,R4选自以下基团:
C1-10烷基,
其中
任一R5独立的选自H,羟基,C1-10烷基,C1-10烷氧基,C1-10羟烷基,C1-10烷氧烷基,NH2,NHR6,-R7-O(C=O)-R8,-R7-(C=O)X-R8,-R7-OPO3M1M2,
其中
R6是C1-10烷基,苯基,-(C=O)C1-6烷基,或-(C=O)苯基;
任一R7和R9独立的为不存在或-C1-10亚烃基;
任一R8独立的选自H,羟基,金属离子,C1-10烷基,-C1-10亚烃基,-NR10R11,和-OPO3M1M2,
任一R10和R11独立的选自H,C1-10烷基(如C1-6烷基)和取代的C1-10烷基(如C1-6烷基);
任一M1,M2是独立的为H,或金属离子;
X为不存在或O;
Y为不存在或-(C=O)-;
Z为不存在或O。
任一R2和R3独立的选自下组:C1-10烷基,C1-10烯烃,C1-10羟烷基,C1-10烷氧烷基,芳基,C1-10芳烷基,杂芳基,C1-10杂芳烷基,杂环基,C1-10杂环烷基,碳环基和C1-10碳环醇烷基,
其中当R1是和R2是异丁基时,R3不是4-吡啶甲基。
在某些实施例中,结构式(I)化合物具有下述结构(II)
结构(II)
其中任一R1,R2和R3基团如上所述。
在某些实施例中,R4选自以下基团:
甲基,
在某些实施例中,R1选自以下基团:
甲基
在某实些施例中,R2是C1-10烷基,C1-10烷氧烷基,芳基,杂芳基,C1-10芳烷基或C1-10杂芳烷基。
在某些实施例中,R2是甲氧基甲基,4-吡啶甲基,异丁基,苄基,4-噻唑基甲基。
在某些实施例中,R3是C1-10烷基,芳基,杂芳基,C1-10芳烷基或C1-10杂芳烷基。
在某些实施例中,R3是异丁基,4-吡啶甲基或苄基。
一方面,本发明提供的三肽环氧酮可以抑制20S蛋白酶体的催化活性。在某些实施例中,本发明涉及的三肽环氧酮对20S蛋白酶体的CT-L催化活性的半抑制浓度IC50是约500nM,250nM,100nM,50nM,10nM,或5nM。
另一方面,本发明提供的化合物有改进的水溶性。在某些实施例中,本发明涉及的三肽环氧酮的水溶性至少是约0.02,0.05,0.1,0.5or 1mg/mL。
另一方面,本发明也提供了可用于治疗人类各种疾病的药物组合物。这些药物组合物包括有效剂量的本发明提供的蛋白酶体抑制剂和药用载体;人类疾病包括但不限于癌症、炎症、神经退行性疾病(例如老年性痴呆)、肌肉萎缩症、慢性传染病、发烧、肌肉废用,去神经支配,神经损伤,和免疫相关的疾病等。
在某些实施方式中,药物组合物包括约10-9克至约10克本发明提供的化合物。合适的剂量范围为每人每天约0.01毫克至约5克。
在某些实施方式中,本发明提供的化合物和药物组合物可以配方成适当的制剂以便通过注射途径给药(如皮下,静脉,肌肉,动脉,鞘膜,囊内,眼框内,心脏内,皮层内,腹膜内,经气管,表皮下,关节内,囊下,蛛网膜下,脊柱内,胸骨内,和/或输液)和非注射途径给药(如口服,肠道,口腔,鼻,鼻内,经粘膜,表皮,贴膏,皮肤,眼药,肺部,舌下,直肠,阴道或局部给药)。
另一方面,本发明提供了治疗与蛋白酶体相关的疾病的方法,这些方法包括施用有效剂量的本发明提供的蛋白酶体抑制剂。
另一方面,本发明提供了制备多肽环氧酮的方法。
本发明的其它特点和优势可见下面的详细叙述和权利要求书。
附图的简要说明
图1说明的是BALB/c小鼠经本发明的化合物给药处理后血液蛋白酶体的百分残留活性。小鼠经溶媒给药处理后血液蛋白酶体的活性为百分之百(对照组);本发明的化合物以静脉注射(IV)或灌胃(PO)对小鼠给药处理后血液蛋白酶体的活性与对照组比较得到百分残留活性。静脉注射剂量为10mg/kg;灌胃给药剂量为30mg/kg。
图2A说明的是CX13-103对经皮下注射移植于小鼠的人源大肠腺癌HT-29的抗肿瘤疗效。使用双向方差检验(2-way ANOVA)对数据进行统计分析。
图2B说明的是CX13-103对经皮下注射移植于小鼠的人源淋巴癌RL的抗肿瘤疗效。使用双方向方差检验(2-way ANOVA)对数据进行统计分析。
发明详述
化合物及其盐
一方面,本发明的化合物含有式(I)的结构,和其对映异构体,非对映异构体,互变异构体,其药学上可接受的盐或溶剂化物或前药:
结构式(I)
其中R1是-(CH2)m-R4,其中m=0或1,R4选自下述基团:C1-10烷基,
其中
任一R5独立的选自H,羟基,C1-10烷基,C1-10烷氧基,C1-10羟烷基,C1-10烷氧基烷基,NH2,NHR6,-R7-O(C=O)-R8,-R7-(C=O)X-R8,-R7-OPO3M1M2,
其中
R6是C1-10烷基,苯基,-(C=O)C1-6烷基,或-(C=O)苯基;
任一R7和R9独立的为不存在,或-C1-10亚烃基;
任一R8独立的为H,羟基,金属离子,C1-10烷基,-C1-10亚烃基,-NR10R11,或-OPO3M1M2,
任一R10和R11独立的为H,C1-10烷基(如C1-6烷基)或取代的C1-10烷基(如C1-6烷基);
任一M1,M2独立的为H,或金属离子;
X为不存在,或是O;
Y为不存在,或是-(C=O)-;
Z为不存在,或是O。
任一R2和R3独立的选自下组:C1-10烷基,C1-10烯烃,C1-10羟烷基,C1-10烷氧烷基,芳基,C1-10芳烷基,杂芳基,C1-10杂芳烷基,杂环基,C1-10杂环烷基,碳环基和C1-10碳环醇烷基,
其中当R1是并且R2是异丁基时,R3不是4-吡啶基甲基。
在某些实施例中,R5是-R7-O(C=O)-R8,R7和R8定义如上所述。在某些实施例中,R7为不存在,R8选自H,C1-10烷基(如C1-4烷基,C1-6烷基),-C1-10亚烃基,-NR10R11,其中R10和R11定义如上所述。在某实施例中,R7是-C1-10亚烃基(如-CH2-,-C2H4-,-C3H7-等),R8选自H,C1-10烷基(如C1-6烷基),-C1-10亚烃基,-NR10R11,其中R10和R11定义如上所述。
在某些实施例中,R5是-R7-(C=O)X-R8,R7和R8定义如上所述。在某些实施例中,R7不存在,X是O,R8选自H,金属离子(比如Na,K),NH4,C1-10烷基(如C1-6烷基),-C1-10亚烃基,-NR10R11,其中R10和R11定义如上所述。在某些实施例中,R7不存在,X不存在,R8选自-NR10R11,其中R10和R11定义如上所述。
在某些实施例中,R5是NH2,NHCOMe,NHCOEt,NHCOC3H7,或NHBoc。
在某些实施例中,R5是或R7,R9,X,Y,and Z定义如上所述。在某些实施例中,R7,R9,X,Y,and Z中至少其中之一是存在的。在某些实施例中,X,Y,Z and R7都不存在,R9是-C1-10亚烃基(比如-CH2-,-C2H4-,-C3H7-等)。在某些实施例中,R7,R9和X不存在,Y是-(C=O)-,Z是O。在某些实施例中,R7和X都不存在,R9是C1-10亚烃基(比如-CH2-,-C2H4-,-C3H7-等),Y是-(C=O)-,Z是O。在某些实施例中,R9和X都不存在,R7是C1-10亚烃基(比如-CH2-,-C2H4-,-C3H7-等),Y是-(C=O)-,Z是O。
在某些实施例中,X不存在,R7和R9独立的为C1-10亚烃基(比如-CH2-,-C2H4-,-C3H7-等),Y是-(C=O)-,Z是O。在某些实施例中,R7,R9,X和Z都不存在,Y是-(C=O)-。
在某些实施例中,任一R5独立的是H,-CH3,-C2H5,C3H7,或
在某些实施例中,任一R5独立的为-OH,-OCH3,-OC2H5,-OC3H7,-OPO3Na2,-OC(=O)CH3,-OC(=O)C2H5,-OC(=O)C3H7,-OC(=O)C4H9,-OC(=O)CH2NH2,-OC(=O)CH2N(CH3)2,-OC(=O)CH2N(C2H5)2,-OC(=O)NH2,-OC(=O)N(CH3)2,-OC(=O)N(C2H5)2,
在某实施例中,任一R5独立的为-CH2OH,-C2H5OH,-C3H7OH,-CH2OC(=O)CH3,-CH2OC(=O)C2H5,-CH2OC(=O)C3H7,-CH2OC(=O)C4H9,-CH2OPO3Na2,-CH2OC(=O)CH2NH2,-CH2OC(=O)CH2N(CH3)2,-CH2OC(=O)CH2N(C2H5)2,-CH2OC(=O)NH2,-CH2OC(=O)N(CH3)2,-CH2OC(=O)N(C2H5)2,或
在某些实施例中,任一R5独立的为-(C=O)OH,-(C=O)ONa,-(C=O)ONH4,-(C=O)OCH3,-(C=O)OC2H5,-(C=O)OC3H7,or-(C=O)OC4H9。
在某些实施例中,任一R5独立的为-CONH2,-CON(CH3)2,-CON(C2H5)2,
在某些实施例中R1选自下述基团:甲基,
在某些实施例中,R2和R3独立的为C1-10烷基,C1-10烷氧基烷基,芳香基,杂芳基,C1-10芳烷基或C1-10杂芳烷基。
在某些实施例中,R2和R3独立的为–(CH2)nR12,R12is C1-6烷基,苯基,吡啶基,-O-C1-6烷基,噻唑基,其中n=0,1,2,3,4,5。
在某些实施例中,R2是甲氧基甲基(methyl-oxy-methyl),4-吡啶甲基,异丁基,苄基或4-噻唑基-甲基。
在某些实施例中,R3是异丁基,4-吡啶甲基或苄基。
含有结构式(I)的化合物包括但不局限如下所示的化合物:
其中,结构式(I)中的任一手性碳原子均可为独立的R构型或S构型。
在某些实施例中,结构式(I)的化合物有结构式(II)所示的构型,其中R1,R2,R3定义如上所述。
结构式(II)
在某些实施例中,本发明提供的化合物有以下所列的结构以及其对映异构体,非对映异构体,互变异构体,其药学上可接受的盐或溶剂化物或前体药物:
药学上可接受的盐可以是生理上可接受的和适合给药的任何盐或酯。例如,药学上可接受的盐包括酸加成盐(如盐酸盐,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,泛酸盐、胆碱盐,抗坏血酸盐,琥珀酸盐,顺丁烯二酸盐,富马酸盐,葡萄糖酸盐,葡萄糖醛酸酯,蔗糖酸盐,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)和碱盐(如铝盐,钙盐,锂盐,镁盐,钾盐,钠盐,锌盐,和二乙醇胺盐)。
定义
术语“Cx-y烷基”是指取代或未取代的饱和碳氢基团,包括含有X-Y个碳原子的直链烷基和支链烷基。
术语“C2.y烯基”和“C2-y炔基”是指取代或未取代的不饱和脂肪基团,分别含有至少一个双键或者三键,长度与上述的烷基相似,且可以被烷基取代。
术语“烷氧基”是指烷基上连接有一个氧原子。具有代表性的烷氧基基团有甲氧基,乙氧基,丙氧基,叔丁氧基等等。醚是2个烃基共价连接1个氧原子。因此,烷基的取代是烷基化生成醚或者烷氧基。
术语“C1-10烷氧烷基”是指C1-10烷基上有一个烷氧基取代,从而形成醚。
本文使用的术语“C1-10芳烷基”是指C1.10烷基上有芳香基取代。
本文使用的术语“C1-10杂芳烷基”是指C1-10烷基上有杂芳基取代。
本文使用的术语“芳香基”是指5-,6-,和7-元取代或未取代的单环芳香基,其中环上的每个原子都是碳原子。
术语“杂芳基”是指取代或未取代的5-7元芳香环结构,最优选的是5-6元环,其环结构上包括1-4个杂环原子。
本文使用的术语“碳环”和“碳环基”是指取代或未取代的非芳香环,其中环上的每个原子都是碳原子。
术语“杂环基”或“杂环基团”是指取代或未取代的非芳香3-10元环结构,最优选的是3-7元环,其环结构上含有1-4个杂原子。
术语“C1-10羟烷基”是指一个C1-10烷基上有一个羟基取代。
术语“前药”指在生理条件下可以转化为治疗活性成分的化合物。制备前药的一个通常方法是在活性分子上选择性的加上某种成分,可以在生理条件下通过水解释放所需的活性分子。在其他实施例中,前药也可以由宿主动物中的酶活性进行转化。
生物活性,选择性和可溶性
本发明提供的化合物具有抑制蛋白酶体催化活性的生物性能。蛋白酶体的活性可以通过本领域已知的实验方法确定,这些方法在Stein et al.,Biochemistry(1996),35,3899-3908、Lightcap et al.,Clinical Chemistry,2000,46,673-683、Kisselev et al.,Journal of Biological Chemistry,(2006),281,8582-8590以及美国专利申请09/569748中均有描述。20S蛋白酶体的CT-L,PGPH和T-L活性通过使用荧光底物检测方法来确定。该方法使用succinyl-Leu-Leu-Val-Tyr-AMC、Z-leu-Leu-Glu-AMC和Boc-Leu-Arg-Arg-AMC分别作为CT-L,PGPH和T-L的底物,反应在缓冲液中完成,分解出的自由荧光团7-胺基-4-甲基香豆素(AMC)用荧光光度计进行检测,可以测得20S蛋白酶体的CT-L,PGPH和T-L活性。
本发明提供的化合物有用,部分原因在于它们能抑制蛋白酶体的催化活性。
在某些实施例中,本发明提供的化合物当浓度低于约500nM,250nM,100nM(比如,CX13-130),50nM(比如CX13-104,CX13-137,CX13-601,CX13-603),10nM(比如CX13-135,CX13-605,CX13-606,CX13-705)或5nM(比如CX13-103,CX13-105,CX13-107,CX13-133,CX13-600,CX13-608)时,对20S蛋白酶体的CT-L活性有抑制作用(比如至少50%的抑制作用)。在某些实施例中,本发明提供的化合物当浓度低于约500nM(比如CX13-133,CX13-606,CX13-608)时,对20S蛋白酶体的T-L活性也有抑制作用。
另一方面,本发明提供的化合物有增强的水溶性。在某些实施例中,本发明提供的三肽环氧酮的水溶性至少为约0.02,0.05,0.1,0.5或1mg/mL。
另一方面,本发明提供的三肽环氧酮化合物同时具有增强的水溶性和改进的蛋白酶体抑制作用。在某些实施例中,本发明提供的化合物的水溶性至少约为0.1,0.5或1mg/mL;当其浓度低于约100nM,50nM,10nM或5nM时对20S蛋白酶体的CT-L活性有抑制作用。
化合物的用途
本发明提供了抑制蛋白酶体活性的方法,包括通过给予有效剂量的本发明化合物进行治疗。“治疗有效剂量”是指足以使接受化合物的的个体产生预计治疗效果或活性的化合物剂量。有效剂量可能会根据不同的因素而变化,比如接受治疗者的年龄,性别,健康状况,化合物的剂型,病情的严重性等。治疗有效剂量由医生根据包括上面提到的因素在内的各种因素来确定。
另一方面,本发明提供了治疗与蛋白酶体相关的疾病的方法。该方法包括给予有效剂量的本发明提供的化合物。这些化合物可以用来治疗与蛋白酶体有关的各种症状或疾病,包括但不限于下面列举的这些。
已知有多种疾病或状况与蛋白酶体的催化功能有关。蛋白酶体抑制剂已被建议用来预防或治疗多种疾病,包括癌症,神经中毒/退行性疾病,阿尔兹海默症,缺血性疾病,炎症,免疫相关的疾病,HIV感染,器官移植排斥,感染性休克,抗原递呈抑制,寄生虫感染,酸血症有关的疾病,黄斑变性,肺部疾病,肌肉萎缩症,纤维化疾病,骨骼和毛发生长疾病。因此,诸如本发明描述的多肽环氧酮的蛋白酶体抑制剂为上述疾病提供了一种治疗的途径。
蛋白酶体抑制剂已被临床证明具有治疗恶性肿瘤功能。因此,本文所描述的化合物可用于治疗癌症。示例的可被治疗的癌症包括白血病,淋巴瘤,骨髓瘤,实体肿瘤肝细胞癌等。本发明所述的化合物还可以用来治疗以下癌症:肾上腺皮质癌,艾滋病相关的癌症,星形细胞瘤,骨癌,骨肉瘤,多形性神经母细胞瘤,恶性纤维组织细胞瘤,黑素瘤,恶性间皮细胞瘤,嗜铬细胞瘤,成松果体细胞瘤和原始神经外胚层肿瘤,神经母细胞瘤,子宫肉瘤,胆管癌,膀胱癌,乳房癌,肠胃癌,宫颈癌,结肠癌,直肠癌,食道癌,眼癌,卵巢癌,头颈部癌,肾癌,嘴唇和口腔癌,肺癌,鼻腔及副鼻窦癌,鼻窦癌,阴茎癌,前列腺癌,移行细胞癌,唾腺癌,软组织癌,皮肤癌,甲状腺和副甲状腺癌,阴道癌等。
蛋白酶体抑制剂与NF-κB活性抑制相关。NF-κB是一种高效的转录因子,可以调节诸如肿瘤坏死因子、白细胞介素1、环氧化酶和细胞间粘附分子等可以引发炎症的分子的基因的转录。因此,本发明中化合物作为一种免疫抑制剂能用于治疗炎症性疾病,如过敏,哮喘,器官/组织移植排斥反应,自身免疫性红斑狼疮,风湿性关节炎,牛皮癣,多发性硬化和炎性肠病。可以对患有上述疾病的患者给予有效剂量的本发明中提供的化合物,该化合物可以包括在药物组合物中,以治疗这些疾病。
已发现蛋白酶体抑制剂可以减少肌肉蛋白质的降解,因而在抑制肌肉萎缩和肌纤维萎缩中很有用。因此本发明中涉及的化合物可用于治疗瘦弱症和肌肉萎缩症,例如慢性感染性疾病,发烧,肌肉废用和去神经,神经损伤,因酸毒症引起的肾功能衰竭,肝功能衰竭。可以对患有上述疾病的患者给予有效剂量的本发明中提供的化合物,该化合物可以包括在药物组合物中,从而减慢或降低肌肉蛋白、细胞内蛋白或p53蛋白的降解。
本发明中提供的化合物也可用于治疗神经退行性疾病和症状,包括中风,神经系统缺血性损伤,神经创伤(例如敲击后脑损伤,脊髓损伤,神经系统外损伤),多发性硬化和其它免疫介导性神经病(如急性感染性多发性神经炎和它的变异体,急性运动轴索型神经病,急性炎症性脱髓鞘性多发性神经病,菲希尔综合征),艾滋病病毒/艾滋病痴呆综合症,糖尿病神经病变,帕金森综合症,亨丁顿舞蹈症,多发性硬化,细菌性斑点病,寄生虫、真菌和病毒性脑膜炎,脑炎,血管性痴呆症,多发性脑梗死性痴呆,路易体痴呆,额叶痴呆如皮克氏病,皮质下痴呆(如亨丁顿或进行性核上性麻痹),焦皮质萎缩综合征(如原发性进行性失语),代谢有毒痴呆,因感染引起的痴呆(如梅毒或慢性脑膜炎)。
本发明中提供的化合物还可以用于调节与细胞外β淀粉样蛋白沉积相关的蛋白的处理过程,β淀粉样蛋白是阿兹海默症的主要原因。因此,本发明中提供的化合物对治疗阿兹海默症很有用,例如通过降低β淀粉样蛋白调控过程的速度,降低β淀粉样蛋白的空斑形成的速度,降低β淀粉样蛋白的生成速度和减少阿兹海默症的临床症状。
蛋白酶体抑制对降低纤维化症状也有帮助。因此,本发明中提供的化合物可用于治疗纤维化相关的疾病,例如糖尿病肾病,肾小球硬化症,IgA肾病,肝硬化,胆道闭锁,充血性心力衰竭,硬皮病,放射性纤维化,肺纤维化,心肌纤维化。
药物组合物成分和给药方式
另一方面,本发明提供由本发明提供的化合物及药学上可接受的载体组成的药物组合物。
在此提到的术语“药学上可接受的载体”是指一种药学上可接受的物质、成分或溶媒,比如液体或固体填充剂、稀释剂、辅料、溶剂或灌封材料,其参与将本发明提供的化合物从身体的某一位置、某种体液、某一组织、某一器官(内部或外部),或身体的某一部分传递到另一位置、另一体液,另一器官(内部或外部),或另一部分。药学上可接受的载体可以是溶媒、稀释剂、辅料或其它没有过度毒副作用并能与动物组织相接触的材料。典型的药学上可接受的载体包括糖类,淀粉,纤维素类,麦芽糖,黄蓍胶,明胶,林格氏溶液,海藻酸,生理盐水,缓冲剂等。
每种药学上可接受的载体应该与其它组成成分相容,例如与本发明中提供的化合物形成制剂,对生物活体组织或者器官没有过度毒性、刺激、过敏性反应、免疫原性或其它问题或并发症,且有较合理的效益风险比。
一些药学上可接受的载体的物质包括:(1)糖类,比如乳糖,葡萄糖和蔗糖;(2)淀粉,比如玉米淀粉和马铃薯淀粉;(3)纤维素和其衍生物,比如羧甲基纤维素钠,乙基纤维素,醋酸纤维素;(4)西黄蓍胶粉;(5)麦芽糖;(6)明胶;(7)滑石粉;(8)赋形剂,比如可可脂和栓剂蜡;(9)油类,比如花生油,棉籽油,红花油,芝麻油,橄榄油,玉米油和大豆油;(10)二醇类,比如丙二醇;(11)多元醇类,比如甘油,山梨醇,甘露醇和聚乙二醇;(12)脂类,比如油酸乙酯,月桂酸乙酯;(13)琼脂胶;(14)缓冲剂,比如氢氧化镁和氢氧化铝;(15)海藻酸;(16)灭菌无热原水;(17)生理盐水;(18)林格氏溶液;(19)醇类,比如乙醇和丙醇;(20)磷酸缓冲液;(21)其它在药物剂型中可相容无毒性的物质,比如丙酮。
药物组合物可能包括药学上可接受的用于模拟生理条件的辅料,比如pH调节剂和缓冲剂,毒性调节剂等,如乙酸钠,氯化钠,氯化钾,氯化钙,乳酸钠等。
药物组合物可制成任何合适的剂型,如固体剂型(例如片剂,胶囊,粉末,颗粒等)和液体剂型(例如水溶液,乳浊液,酏剂,糖浆等)。药物组合物的制备方法已众所周知,可根据如在由Remington所著的“The Science and Practice of Pharmacy”(Gennaro ed.20thedition,Williams&Wilkins PA,USA,2000)书中所描述的常规方法进行制备。
在某些实施例中,药物组合物包括约10-9g至约10g的本发明提供的化合物(比如约0.01mg至约10g,约0.1mg至约10g,约1mg至约10g,约5mg至约10g,约10mg至约10g,约20mg至约10g,约30mg至约10g,约40mg至约10g,约50mg至约10g,约80mg至约10g,约100mg至约10g,约150mg至约10g,约200mg至约10g,约300mg至约10g,约400mg至约10g,约500mg至约10g,约600mg至约10g,约700mg至约10g,约800mg至约10g,约900mg至约10g,约1g至约10g,约10mg至约5g,约10mg至约3g,约10mg至约1g,约10mg至约900mg,约10mg至约700mg,约10mg至约500mg,或约10mg至约300mg)。合理的剂量为每人每天约0.01mg至约5g。
在某些实施例中,本发明中提供的化合物或药物组合物可以被制成适当的剂型以便通过非肠道途径给药(如皮下,静脉,肌肉,动脉,鞘膜,囊内,框内,心脏内,真皮内,腹膜内,经气管,表皮,关节内,囊下,蛛网膜下,脊柱内,胸骨内,和/或输液)和通过肠道途径给药(如口服,肠道,口腔,鼻,鼻内,粘膜,表皮,贴膏剂,真皮,眼药,肺部,舌下,直肠,阴道或表皮局部给药)。在某些实施例中,本发明中提供的化合物或药物组合物可以被制成适当的剂型以便通过口服给药。
合适的剂型包括但不局限于可以通过非肠道途径给药的制剂(如适用于注射的乳状液,溶液和混悬液)、可以通过口服给药的制剂(如片剂,胶囊,丸剂,糖衣丸,粉末和颗粒)、可以通过局部用药或经皮肤吸收的制剂(如喷剂,软膏,糊剂,乳霜,乳液,凝胶,溶液,药物贴片和吸入剂),以及可以通过阴道或直肠给药的制剂(如栓剂)。这些剂型可在适当条件下通过把化合物与辅料混合制备,制备方法及工艺众所周知,如在由Remington所著的“The Science and Practice of Pharmacy”(Gennaro ed.20th edition,Williams&Wilkins PA,USA,2000)书中描述。
药物组合物可通过任何合适的途径给药,比如通过口服,静脉,鼻内,外用,肌注,真皮内注射,经皮给药或皮下途径。
在某些实施方式中,本发明提供的化合物或药物组合物可以与第二种活性物质同时施用,这样能在生物体内达到叠加甚至协同的作用。例如,本发明提供的化合物可以和第二种活性物质制成一个药物组合物,或以单独的组合物同时给药,或以单独的组合物依次给药。能与本发明化合物同时使用、用于治疗癌症的第二种活性物质包括但不局限于:氟尿嘧啶,阿霉素,柔红霉素,它莫西芬,亮丙瑞林,戈舍瑞林,氟他米特,尼鲁米特,非那雄胺,地塞米松,氨鲁米特,安吖啶、阿那曲唑,天冬酰胺酶,卡介苗,比卡鲁胺、博来霉素、临床、白消安,喜树碱,卡培他滨,卡铂,卡莫司汀,苯丁酸氮芥,顺铂,克拉屈滨,秋水仙碱,环磷酰胺、药物、环丙孕酮、阿糖胞苷、达卡巴嗪,放线菌素d,正定霉素,双烯雌酚、己烯雌酚、多西紫杉醇、阿霉素,亚德里亚霉素、表柔比星、雌二醇,雌氮芥、依托泊苷、依西美坦,非格司亭,氟达拉滨,氟氢可的松、氟尿嘧啶、氟甲睾酮、氟他米特,吉西他滨,染料木黄酮,戈舍瑞林,三苯氧胺、替尼泊苷、睾酮、二氯化二茂钛,拓普泰康,曲妥单抗、维甲酸、长春花碱、羟基脲,伊达比星,异环磷酰胺、伊马替尼、干扰素、伊立替康,伊立替康、来曲唑、甲酰四氢叶酸,喷司他丁,光神霉素、甲基苄肼、雷替曲塞卟菲尔,利妥昔链脲菌素,苏拉明,亮丙瑞林、左旋咪唑,环己亚硝脲、氮芥、甲羟孕酮、甲地孕酮,美法仑、巯嘌呤、巯乙磺酸钠、甲氨蝶呤、丝裂霉素、米托坦、米托蒽醌,尼鲁米特,诺考达唑、奥曲肽、铂、紫杉醇、帕米磷酸,硫鸟嘌呤,三胺硫磷、氯甲烷、拓扑替康二茂钛,曲妥单抗,维甲酸、长春花碱,长春新碱、长春地辛,长春瑞斌。
在某些实施方案中,本发明提供的化合物可与非化学方法同时使用进行癌症治疗。在某些实施方案中,本发明提供的化合物可与放射疗法同时进行。在某些实施方案中,本发明提供的化合物可与外科手术,肿瘤热治疗,超音波聚焦疗法,冷冻疗法或以上几种疗法结合使用。
在某些实施方案中,本发明提供的化合物可与类固醇同时使用。合适的类固醇包括但不局限于:安西缩松、倍氯米松,倍他米松,布地奈德,氯泼尼松,氯倍他索,皮质甾酮,可的松,羟泼尼缩松,去羟米松,地塞米松,双氟拉松,双氟米松,二氟孕甾丁酯,甘草次酸,氟扎可松,氟米松,氟尼缩松,氟氯奈德,肤轻松醋酸酯,氟轻松醋酸酯,氟可丁丁酯,氟可龙,丙酮缩氟氢羟龙,醋酸氟培龙,醋酸氟泼尼定,氟泼尼龙,氟氢缩松,丙酸氟、醛基缩松,丙酸氯倍他索,哈西缩松,卤米松,氢化可的松,氯替泼诺碳酸乙酯,甲哌地强龙,甲羟松,甲泼尼松,6-甲氢化泼尼松,在任糠酸盐,帕拉米松,泼尼松龙,地塞米松,和25-二乙胺醋强的松龙。
在某些实施方案中,本发明提供的化合物可与免疫治疗剂同时使用。合适的免疫治疗剂包括:肿瘤细胞多药耐药性逆转剂(比如维拉帕米),雷帕霉素,霉酚酸酯,沙利度胺,环磷酰胺,环孢霉素,和单克隆抗体类。
实施例
下面列举了本发明的一些三肽环氧酮化合物及其合成、蛋白酶体活性抑制特性、抗肿瘤活性和水溶性。
本发明提供的化合物的合成在以下列举的例子中作了图解说明。这些方案方案仅是说明性的,并不意味着仅限于这些方案来合成本发明提供的化合物。此外,方案方案中的步骤是为更好地说明,可以视情况进行改变。以下列举的化合物的合成都在海外完成,是为了研究用途和潜在的向管理机构递交材料的需要。
在一般的实验方法中,使用1H-NMR谱图得到化合物的结构信息,采用四极杆质谱系统在正电喷雾离子化(ESI)模式下进行液相色谱-质谱(LC-MS)检测,纯度用带有UV检测器的高效液相仪(HPLC)测定,在有需要时用高效液相制备色谱进行分离纯化。
实施例1
化合物CX13-103的合成
方案1.CX13-103的合成
C103-2的合成
在0℃下将5ml SOCl2滴加到150ml甲醇中,然后加入C103-1(10g,42mmol),加热回流过夜。冷至室温后,在真空中浓缩干燥得到纯产品C103-2(11g),MS(ESI)m/z:181[M+H]+。
C103-6的合成
在C103-5(7.05g,50mmol)和四氯化碳(250mL)溶液中,加入NBS(11.5g,65mmol)和AIBN(820mg,5mmol)。加热回流过夜。冷至室温后,将反应液倒至水中,水相用二氯甲烷提取两次,合并有机相,用饱和碳酸氢钠溶液洗涤,用硫酸钠干燥,然后过滤并真空浓缩,得到的油状物用快速硅胶色谱纯化得到C103-6(5.56g,收率51%)。MS(ESI)m/z:221[M+H]+。
C103-7的合成
在预冷至0℃的吗啡(4.8g,55mmol)和四氢呋喃(20mL)溶液中滴加溶解于20mL四氢呋喃的C103-6(5.56g,25.5mmol)溶液,然后于0℃搅拌30min,倒至水中,水相用乙酸乙酯提取两次,合并有机相,用卤水洗涤,用硫酸钠干燥,然后过滤并真空浓缩。得到的油状物用快速硅胶色谱纯化得到C103-7(4.03g,收率70%)。MS(ESI)m/z:227[M+H]+。
C103-8的合成
C103-7(4g,17.7mmol)溶解于四氢呋喃(30mL)和甲醇(30mL)中并预冷至0℃,加入2N LiOH(13mL,26mmol),室温搅拌1h,加盐酸溶液调pH至5,真空浓缩,得到的残留物用色谱法纯化得到C103-8(2.65g,收率71%)。MS(ESI)m/z:213[M+H]+。
C103-10的合成
C103-9(5.81g,20.8mmol)+溶解于DMF(80mL)中并预冷至0℃,加入HATU(8.3g,21.8mmol)和DIEA(14.3mL,85mmol),0℃搅拌30min,加入C103-2(5.22g,20.8mmol)。反应液在氮气保护下室温搅拌1h,倒至水中,用乙酸乙酯提取两次,合并有机相,用硫酸钠干燥,然后过滤并真空浓缩。得到的残留物经制备高效液相色谱纯化得到C103-10(7.9g,收率86%)。MS(ESI)m/z:442[M+H]+。
C103-11的合成
C103-10(7.9g,17.9mmol)溶解于DCM(40mL)中,于0℃缓慢加入TFA(10mL),室温搅拌1h,真空浓缩得到粗品,不经纯化直接用于下一步反应。MS(ESI)m/z:342[M+H]+。
C103-12的合成
C103-8(2.65g,12.5mmol)溶解于DMF(50mL)溶液中并预冷至0℃,加入HATU(6.18g,16.25mmol)和DIEA(10mL,60mmol),0℃搅拌30min,加入C103-11,在氮气保护下室温搅拌1h,反应液倒至水中,用乙酸乙酯提取两次,合并有机相,用硫酸钠干燥,然后过滤并真空浓缩。得到的残留物用色谱法纯化得到C103-12(5.3g,收率79%)。MS(ESI)m/z:536[M+H]+。
C103-13的合成
C103-12(5.3g,9.88mmol)溶解于THF(30mL)和MeOH(30mL)并预冷至0℃,加入2NLiOH(7.5mL,16mmol),室温搅拌1h,加盐酸溶液调pH至5,真空浓缩,得到的残留物经色谱法纯化得到C103-13(3.4g,收率66%)。MS(ESI)m/z:522[M+H]+。
CX13-103的合成
C103-13(3.4g,6.53mmol)溶解于DMF(20mL)并预冷至0℃,加入HATU(3.23g,8.5mmol)和DIEA(5mL,30mmol),于0℃搅拌30min,再加入C103-4(C103-4的合成请见专利PCT/US2013/052143),氮气保护下室温搅拌1h,倒至水中,用乙酸乙酯提取两次,合并有机相,用硫酸钠干燥,然后过滤并真空浓缩。得到的油状残留物经制备高效液相纯化得到CX13-103(1.12g,收率25%)。
1H-NMR(400MHz,甲醇-d4)δ8.37(d,2H),7.32(d,2H),7.29-7.25(m,2H),7.20-7.18(m,3H),6.71(s,1H),4.77(dd,1H),4.56-4.51(m,2H),3.82(s,2H),3.74-3.72(m,4H),3.25(d,1H),3.23(dd,1H),3.01(dd,1H),2.95(d,1H),2.70-2.50(m,6H),2.20-1.95(m,2H),1.80-1.60(m,1H),1.52-1.20(m,5H),0.91(d,3H),0.89(d,3H);MS(ESI)m/z:675[M+H]+;纯度>95%。
实施例2
化合物CX13-104的合成
中间体C104-7的合成
方案2:中间体C104-7的制备
C104-1的合成
将9.6g(40mmol)L-3-(4-吡啶基)-丙氨酸盐酸盐加入到200ml 1N氢氧化钠水溶液和200ml THF中,搅拌下,滴加20ml二碳酸二叔丁酯,加完后搅拌2h,反应液中加入300ml水,用乙酸乙酯洗涤(200ml×2次)。水相中加入5%硫酸氢钾水溶液调pH约为4,然后用正丁醇提取(4次×200ml),有机相减压浓缩,过滤,干燥后得到8.0g白色固体C104-1,MS(ESI)m/z:267.2[M+H]+。
C104-02的合成
室温下将8.0g(30mmol)C104-1溶于100ml DMF,冷至4℃,加入N,O-二甲基羟胺盐酸盐(4.4g,45mmol),再加入HBTU(17g,45mmol),HOBt(6.1g,45mmol)和DIEA(12ml,90mmol)。反应液缓慢升至室温搅拌过夜,次日,用300ml乙酸乙酯稀释,连续用饱和氯化钠溶液洗涤两次(2×100ml)。有机相用硫酸钠干燥,然后过滤并减压浓缩。用柱层析纯化(DCM(1%TEA))得到黄色油状化合物C104-2(6.2g,66%)。MS ESI)m/z:310.3[M+H]+。
C104-3的合成
将C104-2(6.2g,20mmol)溶于200ml THF中,冷至0℃(冰盐水冷却),缓慢加异丙烯溴化镁(0.5M in THF;200ml;100mmol),20min加完。于0℃搅拌4h,缓慢倒至0℃饱和氯化铵水溶液中。减压除去THF,用乙酸乙酯提取三次(3×100ml)。合并有机相,分别用饱和碳酸氢钠溶液,水,饱和氯化钠溶液洗涤。有机相用硫酸钠干燥,然后过滤并减压浓缩,柱层析纯化(DCM(1%TEA))得到黄色油状物化合物3(5.0g,86%).MS(ESI)m/z:291。4[M+H]+。
C104-4的合成
将化合物C104-3(5.0g,17mmol)溶于100ml甲醇中,冷至0℃,加入三氯化铈(8.2g,22mmol),再加入硼氢化钠(0.85g,22mmol)。0℃搅拌3h,缓慢倒至0℃的200ml饱和氯化铵水溶液中,用乙酸乙酯提取(4×100ml),合并有机相,分别用饱和碳酸氢钠,水和盐水。有机相用硫酸钠干燥,然后过滤并减压浓缩,柱层析纯化(DCM(1%TEA))得到黄色固体C104-4(4.5g,90%)。MS(ESI)m/z:293.4[M+H]+。
C104-5的合成
化合物C104-4(4.5g,15mmol)溶于100ml DCM中,冷至0℃,加入氧化二乙酰丙酮合钒(0.12g,0.45mmol)和叔丁基过氧化氢(5.0-6.0M癸烷溶液;12ml,60mmol),缓慢升至室温过夜。分别用饱和碳酸氢钠,水和盐水洗涤,有机相用硫酸钠干燥,过滤,减压浓缩,得到C104-5,不经纯化直接用于下一步反应。MS(ESI)m/z:309.4[M+H]+。
C104-6的合成
化合物C104-5(4.5g,15mmol)溶于100ml DCM中,冷至0℃,加入戴斯马丁氧化剂(13g,30mmol),缓慢升至室温,24h后反应液冷至4℃,再加入戴斯马丁氧化剂(6.4g,15mmol),然后再缓慢升至室温。3h后反应液用硅藻土过滤,滤液分别用饱和硫代硫酸钠,饱和碳酸氢钠,水和盐水洗涤,有机相硫酸钠干燥,过滤,减压浓缩,柱层析纯化(DCM(2%MeOH))得到棕色油状物C104-6(0.35g,7.5%):1H-NMR(氯仿-d)δ(ppm):8.37-8.61(m,2H),7.13(d,J=5.2Hz,2H),5.13(br.s.,1H),4.61(d,1H),3.19(d,1H),2.68-2.90(m,3H),1.54(s,3H),1.39(s,9H);MS(ESI)m/z:307.4[M+H]+。
C104-7的合成
化合物C104-6(1.3g,4.2mmol)溶于50ml DCM中,冷至0℃,加入50ml TFA,缓慢升至室温,减压浓缩得到C104-7TFA盐,MS(ESI)m/z:207.4[M+H]+。
方案3:CX13-104的制备
C104-8的合成
将(S)-2-氨基-4-苯基丁酸(5.0g,28mmol),苯甲醇(6.0g,55mmol),对甲苯磺酸一水合物(9.5g,55mmol)和200ml甲苯混合,加热回流16h(装载有迪安-斯塔克装置)。该苯溶液然后用5%碳酸氢钠水溶液和卤水洗涤,用硫酸镁粉干燥,过滤,减压蒸干,残留物在正己烷中结晶得到无色针状晶体C104-8(9.0g,80%)。MS(ESI)m/z:270.5(M+H)+。
C104-9的合成
C103-8(1.8g,8.5mmol),C104-8(3.7g,8.5mmol)和HBTU(4.8g,13mmol)的DMF(20mL)溶液中通过滴加漏斗缓慢加3ml DIEA,反应16h用20ml乙酸乙酯和20ml卤水稀释。分层后,水相用乙酸乙酯提取(2×30ml),合并有机相,用硫酸钠干燥,过滤除去固体,减压蒸馏除去易挥发物,硅胶层析纯化(PE:EA=5:1)得到白色固体C104-9(2.4g,61%收率)。MS(ESI)m/z:463.5(M+H)+。
C104-10的合成
C104-9(2.4g)的THF溶液中加入Pd/C(0.24g),H2气氛下搅拌2h,过滤,浓缩得到产品104-5,不经纯化直接用于下一步。MS(ESI)m/z:374.5(M+H)+。
C104-11的合成
C104-10(1.8g,8.5mmol),(S)-苄基2-氨基-4-戊酸甲酯(1.9g,8.5mmol),HBTU(4.8g,13mmol)的DMF(20mL)混合溶液中通过滴加漏斗缓慢加入3ml DIEA。室温反应16h,用20ml乙酸乙酯和20ml卤水稀释。水相用乙酸乙酯提取(2×30ml),合并有机相,硫酸钠干燥,过滤除去固体,减压蒸馏除去易挥发物,硅胶层析纯化(PE:EA=5:1)得到白色固体104-11(2.4g,61%收率)。MS(ESI)m/z:577.5(M+H)+。
C104-12的合成
C104-11(2.4g)的THF溶液中加入Pd/C(0.24g),H2气氛下搅拌2h,过滤,浓缩得到产品C104-12,不经纯化直接用于下一步。MS(ESI)m/z:487.5(M+H)+。
CX13-104的合成
C104-12(0.40g,0.82mmol),C104-7(0.17g,0.82mmol),HOBt(0.20g 1.5mmol)和HBTU(0.56g,1.5mmol)的THF(5mL)溶液保持-5℃,滴加1ml DIEA,于-5℃反应0.5h,用10ml乙酸乙酯和10ml卤水稀释。分层后水相用乙酸乙酯提取(2÷5ml),合并有机相,硫酸钠干燥,过滤除去固体,减压蒸馏除去易挥发物,粗品经硅胶层析(DCM:MeOH=50:1)和制备高效液相纯化得到化合物CX13-104(50mg6.2%)。
1H-NMR(400MHz,甲醇-d4)δ(ppm):0.88-0.99(m,7H)1.26-1.35(m,2H)1.40-1.47(m,1H)1.49-1.55(m,4H)1.64(d,J=6.45Hz,1H)1.98-2.18(m,2H)2.53-2.67(m,6H)2.79(dd,J=13.97,9.94Hz,1H)2.99(d,J=4.84Hz,1H)3.18(dd,J=14.10,3.63Hz,1H)3.30(s,1H)3.67-3.77(m,4H)3.79-3.87(m,2H)4.42(dd,J=8.73,6.31Hz,1H)4.53(dd,J=8.33,5.64Hz,1H)4.79(dd,J=9.81,3.63Hz,1H)6.73(s,1H)7.16-7.22(m,3H)7.22-7.32(m,3H)7.37(d,J=5.91Hz,2H)8.40(d,J=5.37Hz,2H);MS(ESI)m/z:675.5(M+H)+。
实施例3
CX13-105的合成
方案4:CX13-105的制备
C105-2的合成
预冷至0℃的C105-1(10g,33.2mmol),EDCI(8.3g,43.2mmol)和HOBt(7g,51.1mmol)的DMF(40mL)溶液中加入DIEA(14.3mL,85.2mmol)。于0℃搅拌30min,加入N,O-二甲基羟胺盐酸盐(3.2g,33.2mmol),氮气保护下室温搅拌1h,倒至水中,用乙酸乙酯提取两次,合并有机相,硫酸钠干燥,过滤,真空浓缩,得到的油状残留物经硅胶柱纯化,得到所需化合物C105-2(8.0g,收率72.7%)。MS(ESI)m/z:343[M+H]+。
C105-3的合成
预冷至0℃的C105-2(8g,23.2mmol)THF(50mL)溶液中于0℃加入异丙烯溴化镁(0.5MTHF溶液,200mL,100mmol),0℃搅拌3h,将反应液缓慢倒至饱和NH4Cl溶液中,用浓盐酸调pH至1.5,用乙酸乙酯提取,合并有机相,硫酸钠干燥,过滤,真空浓缩,得到的油状残留物经硅胶柱纯化得到所需化合物C105-3(5.8g,收率77%).
C105-4的合成
C105-3(5.8g,18mmol)溶于甲醇和THF(20mL)中,预冷至0℃,于0℃加入NaBH4(1.21g,31.8mmol)和CeCl3.7H2O(11.8g,31.8mmol),氮气保护下于0℃搅拌3h,加入5ml水终止反应,真空下除去所有的易挥发物,残留物用乙酸乙酯提取,合并有机相,硫酸钠干燥,过滤,真空浓缩,得到的油状残留物经硅胶柱纯化得到所需化合物C105-4(4.37g,收率72%)。MS(ESI)m/z:326[M+H]+。
C105-5的合成
预冷至0℃的C105-4(4.37g,13.4mmol)的DCM(20mL)溶液中,加入乙酰丙酮氧钒(344mg,1.3mmol)和t-BuO2H(5.5M癸烷溶液,2.6mL,14.3mmol)。加完后室温搅拌2h,加入5mL水终止反应。反应液用硅藻土过滤,水相用DCM提取,合并有机相,用亚硫酸氢钠溶液和盐水洗涤,硫酸钠干燥,真空浓缩,得到的油状残留物不经纯化直接用于下一步,MS(ESI)m/z:342[M+H]+。
C105-6的合成
预冷至0℃的C105-5的DCM(20mL)溶液中,加入戴斯-马丁氧化剂(13g,32.5mmol),室温搅拌1h,通过硅藻土过滤,滤饼用DCM洗涤两次,合并有机相,分别用亚硫酸氢钠溶液,饱和碳酸氢钠和盐水洗涤,硫酸钠干燥,真空浓缩,得到的油状残留物经硅胶柱纯化得到所需化合物C105-6(2g,收率29%)。MS(ESI)m/z:340[M+H]+。
C105-7的合成
C105-6(2g,5.88mmol)溶解于MeOH(10mL)和TFA(1mL)中,预冷至0℃,加入钯碳(400mg,40%wt),在氢气气氛下(3.5atm)于0℃搅拌6h,然后硅藻土过滤,滤液真空浓缩得到粗品,不经纯化直接用于下一步反应。MS(ESI)m/z:206[M+H]+。
CX13-105的合成
预冷至0℃的C104-7(311mg,0.74mmol),HATU(422mg,1.11mmol)和DMF(5mL)的溶液中,加入DIEA(0.62mL,3.7mmol),于0℃搅拌30min,加入C105-7的DCM(2mL)溶液,氮气保护下室温搅拌1h,然后倒至水中,用乙酸乙酯提取两次,合并有机相,硫酸钠干燥,过滤,真空浓缩,得到的残留物经制备高效液相纯化得到CX13-105(70mg,收率16%)。
1H-NMR(400MHz,甲醇-d4)δ7.32-7.09(m,10H),6.72(s,1H),4.76(dd,1H),4.55(dd,1H),4.46(dd,1H),3.83(s,2H),3.73-3.71(m,4H),3.28(d,1H),3.11(dd,1H),2.94(d,1H),2.76-2.60(m,3H),2.59-2.55(m,4H),2.11-2.02(m,2H),1.65-1.61(m,1H),1.54-1.51(m,2H),1.45(s,3H),0.94(d,3H),0.90(d,3H);MS(ESI)m/z:674[M+H]+;纯度>95%。
实施例4
CX13-107的合成
方案5:CX13-107的制备
C107-3的合成
预冷至0℃的C107-1(10g,35.8mmol)的DMF(40mL)溶液中,加入EDCI(8.5g,44.3mmol),HOBt(7g,51.1mmol)和DIEA(14.3mL,85.2mmol)。于0℃搅拌30分钟,再加入C107-2(6.2g,34.1mmol),氮气保护下室温搅拌1h,倒至水中,用乙酸乙酯提取两次,合并有机相,硫酸钠干燥,过滤,真空浓缩,得到的油状残留物用快速硅胶柱色谱纯化得到C107-3(13.5g,收率97.8%)。MS(ESI)m/z:351[M+H-55]+。
C107-4的合成
预冷至0℃的C107-3(13.5g,33.3mmol)的DCM(50mL)溶液中,加入20ml TFA,室温搅拌1h,真空浓缩得到粗品,不经纯化直接用于下一步反应。MS(ESI)m/z:307[M+H]+。
C107-6的合成
预冷至0℃的C107-5(1.8g,12.4mmol)的DMF(20mL)溶液中,加入HATU(5.8g,15.3mmol)和DIEA(10mL,60mmol),于0℃搅拌30分钟,加入C107-4,在氮气保护下室温搅拌1h,将反应液倒至水中,用乙酸乙酯提取两次,合并有机相,硫酸钠干燥,过滤,真空浓缩,得到的油状残留物经快速硅胶柱色谱纯化得到C107-6(4.5g,收率88%)。MS(ESI)m/z:434[M+H]+。
C107-7的合成
C107-6(4.5g,10.1mmol)溶解于THF(10mL)和MeOH(10mL)中,预冷至0℃,加入2NLiOH(10mL,20mmol),室温搅拌1h,加入盐酸溶液调pH至5,得到的固体用水洗,真空干燥得到所需化合物(3.8g,收率90%)。
CX13-107的合成
C107-7(311mg,0.74mmol),HATU(445mg,1.17mmol)和DIEA(0.5mL,2.2mmol)溶于DMF(5mL),于0℃搅拌30分钟,加入C105-7,氮气保护下室温搅拌1h,将反应液倒至水中,用乙酸乙酯提取两次,合并有机相,硫酸钠干燥,过滤,真空浓缩,得到的油状残留物经制备高效液相纯化得到产品(70mg,收率16%)。
1H-NMR(400MHz,甲醇-d4),δ7.20-6.98(m,10H),4.67(dd,1H),4.36-4.31(m,2H),3.68-3.62(m,4H),3.21(d,1H),3.02(dd,1H),2.96(dd,2H),2.85(d,1H),2.63(dd,1H),2.50-2.40(m,6H),1.96-1.78(m,2H),1.55-1.43(m,1H),1.43-1.36(m,2H),1.22(s,3H),0.85(d,3H),0.81(d,3H);MS(ESI)m/z:607[M+H]+;纯度>95%。
实施例5
化合物CX13-130的合成
方案6:CX13-130的制备
C130-2的合成
室温下往C130-1(1.5g,5.4mmol)的DMF(30mL)溶液中加入(S)-苄基2-氨基-3-(吡啶基-4-基)丙酸酯(1.38g,5.4mmol),HBTU(3.1g,8.1mmol)和DIEA(4mL),在室温下反应16h,用80ml乙酸乙酯和40ml卤水稀释,分层,水相用乙酸乙酯提取两次(2×40ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经硅胶层析(PE:EA=10:1)纯化得到白色固体化合物130-2(2.0g,72%收率),MS(ESI)m/z:518.3(M+H)+。
C130-3的合成
C130-2(1.5g,2.9mmol)的THF(25mL)的溶液中加入10%Pd/C(0.15g),在氢气气氛下于50℃搅拌16h,过滤,浓缩得到化合物C130-3(1100mg,90%收率),不经纯化,直接用于下一步反应,MS(ESI)m/z:428.3(M+H)+。
C130-4的合成
往C130-3(1.1g,2.6mmol)的DMF(15mL)溶液中加入C103-4(0.69g,2.6mmol),HBTU(1.5g,3.9mmol),HOBt(0.53g,3.9mmol)和DIEA(2mL),室温下搅拌16h,用60ml乙酸乙酯和20ml卤水稀释,分层,水相用乙酸乙酯提取两次(2×30ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经硅胶层析(PE:EA=1:1)纯化得到白色固体化合物C130-4(510mg,34%收率),MS(ESI)m/z:581.4(M+H)+。
C130-5的合成
向C130-4(510mg,0.88mmol)的DCM(10mL)溶液中于0℃加入4ml TFA,0℃下反应2h,减压除去易挥发物得到白色固体化合物130-5(500mg,100%收率),MS(ESI)m/z:481.4(M+H)+。
CX13-130的合成
室温下往C130-5(110mg,0.19mmol)的DMF(2mL)溶液中加入乙酸(14mg,0.23mmol),HBTU(108mg,0.29mmol),HOBt(39mg,0.29mmol)和DIEA(0.2mL),室温下反应16h,用40ml乙酸乙酯和10ml盐水稀释,分层,水相用乙酸乙酯提取两次(2×20ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经硅胶柱层析(DCM:MeOH=40:1)和制备高效液相纯化得到白色固体CX13-130(25mg,21%)。
1H-NMR(400MHz,CDCl3)δ8.50(s,2H),7.38–7.25(m,4H),7.21(t,J=7.3Hz,1H),7.17(t,J=10.3Hz,3H),6.83(d,J=7.6Hz,1H),6.19(d,J=7.3Hz,1H),4.81(dd,J=13.9,7.7Hz,1H),4.57(t,J=7.6Hz,1H),4.38(dd,J=14.0,7.3Hz,1H),3.25(dd,J=16.9,5.1Hz,2H),3.05(dd,J=14.2,8.2Hz,1H),2.92(d,J=4.9Hz,1H),2.65(dd,J=14.7,6.3Hz,2H),2.13(dd,J=14.1,7.5Hz,2H),1.93(s,4H),1.67–1.47(m,5H),1.30(dd,J=16.6,6.8Hz,2H),0.92(dd,J=8.9,6.5Hz,6H);MS(ESI)m/z:523.7(M+H)+。
实施例6
化合物CX13-133的合成
方案7:CX13-133的制备
C133-2的合成
将吗啉(456mg,5.6mmol)溶解于乙腈(20mL)中,室温下加入碳酸钾(841mg,6.1mmol)和C133-1(1g,4.7mmol),50℃搅拌4h,过滤除去固体,减压除去易挥发物,经硅胶柱层析(PE:EA=4:1)纯化得到无色油状物C133-2(1.0g,81%收率),MS(ESI)m/z:264.2(M+H)+。
C133-3的合成
将C133-2(1000mg,3.8mmol)溶解于THF(16mL)和水(8mL)中,室温下加入LiOH.H2O(477mg,11.4mmol),室温搅拌16h,反应液酸化至pH=5,浓缩,层析纯化得到白色固体C133-3(750mg,84%收率)。MS(ESI)m/z:236.2(M+H)+。
CX13-133的合成
室温下往C130-5(110mg,0.19mmol)的DMF(2mL)溶液中加入133-3(54mg,0.23mmol),HBTU(108mg,0.29mmol),HOBt(39mg,0.29mmol)和DIEA(0.2mL),室温保温反应16h,用40ml乙酸乙酯和10ml卤水稀释,分层,水相用乙酸乙酯提取两次(2×20ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经硅胶柱层析(DCM:MeOH=40:1)和制备高效液相纯化得到白色固体CX13-133(55mg,41%)。
1H-NMR(400MHz,甲醇-d4)δppm 0.86-1.01(dd,6H)1.43(t,J=6.98Hz,4H)1.47-1.64(m,1H)1.88-1.96(m,2H)2.56(m,6H)2.96(m,9.94Hz,2H)3.18(dd,J=9.94Hz,1H)3.22(d,J=5.2Hz,1H)3.4-3.6(m,4H)3.6-3.66(m,4H)4.26-4.28(m,1H)4.46(d,J=4.84 1H)4.71-4.75(m,1H)7.06(d,J=5.2Hz 1H)7.16-7.20(m,1H)7.20-7.24(m,2H)7.26-7.32(m,2H)7.34(s,4H)8.36-8.38(m,2H);MS(ESI)m/z:698.4(M+H)+。
实施例7
化合物CX13-135的合成
方案8:CX13-135的制备
化合物C130-5(110mg,0.19mmol)的DMF(2mL)溶液中室温下加入5-甲基异恶唑-3-羧酸(40mg,0.23mmol),HBTU(108mg,0.29mmol),HOBt(39mg,0.29mmol)和DIEA(0.2mL),室温搅拌16h,用40ml乙酸乙酯和10ml卤水稀释,分层,水相用乙酸乙酯提取(2×20ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经硅胶柱层析(DCM:MeOH=40:1)和制备高效液相纯化得到白色固体CX13-135(18mg,16%)。
1H-NMR(400MHz,CDCl3)δ8.38(s,2H),7.35(d,J=7.9Hz,1H),7.33–7.23(m,3H),7.20(t,J=7.3Hz,1H),7.16–7.08(m,4H),6.96(d,J=8.0Hz,1H),6.68(d,J=7.7Hz,1H),6.43(d,J=0.7Hz,1H),4.75(dd,J=14.2,7.5Hz,1H),4.62–4.43(m,2H),3.26(d,J=4.9Hz,1H),3.12(dd,J=14.1,6.2Hz,1H),2.98(dd,J=14.1,7.5Hz,1H),2.91(d,J=5.0Hz,1H),2.67(t,J=7.8Hz,2H),2.58–2.45(m,3H),2.21(dt,J=14.0,7.7Hz,2H),2.04(td,J=15.6,7.9Hz,1H),1.64–1.42(m,5H),1.37–1.16(m,2H),0.89(dd,J=13.1,6.3Hz,6H);MS(ESI)m/z:590.4(M+H)+。
实施例8
化合物CX13-137的合成
方案9:CX13-137的制备
C130-5(110mg,0.19mmol)的DMF(2mL)溶液中室温下加入5-甲基异恶唑-2-羧酸(41mg,0.23mmol),HBTU(108mg,0.29mmol),HOBt(39mg,0.29mmol)和DIEA(0.2mL),室温搅拌16h,用40ml乙酸乙酯和10ml盐水稀释,分层,水相用乙酸乙酯提取(2×20ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经层析法纯化得到白色固体CX13-137(36mg,31%)。
1H-NMR(400MHz,CDCl3)δ8.32(d,J=5.6Hz,2H),8.05(s,1H),7.41(dd,J=29.1,17.6Hz,3H),7.20(dt,J=24.4,7.1Hz,3H),7.13–7.02(m,3H),4.79(dd,J=13.9,8.0Hz,1H),4.71–4.49(m,2H),3.25(d,J=4.9Hz,1H),3.11(dd,J=13.7,5.3Hz,1H),2.98–2.81(m,2H),2.76(s,3H),2.63(t,J=7.7Hz,2H),2.23–1.93(m,2H),1.76–1.41(m,5H),1.30(ddd,J=14.3,8.6,4.5Hz,2H),0.87(dd,J=17.5,6.4Hz,6H);MS(ESI)m/z:606.3(M+H)+。
实施例9
化合物CX13-600的合成
方案10:CX13-600的制备
C600-2的合成
C104-10(2.0g,5.4mmol)的DMF(30mL)溶液中室温下加入C600-1(1.38g,5.4mmol),HBTU(3.1g,8.1mmol)和DIEA(4mL),室温反应16h,用80ml乙酸乙酯和40ml卤水稀释,分层,水相用乙酸乙酯提取两次(2×40ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经硅胶柱层析(PE:EA=10:1)纯化得到白色固体化合物C600-2(1.8g,69%收率)。.MS(ESI)m/z:611.7(M+H)+。
C600-3的合成
C600-2(1.77g,2.9mmol)的THF(20mL)的溶液中加入10%Pd/C(0.15g),氢气气氛下于50℃搅拌16h,过滤,浓缩得到C600-3(1.35g,90%收率),不经纯化直接用于下一步反应。MS(ESI)m/z:521.3(M+H)+。
CX13-600的合成
C600-3(150mg,0.29mmol)、C103-4(78mg,0.29mmol)、HOBt(60g,0.51mmol)、HBTU(165g,0.51mmol)和DMF(4mL)的混合溶液预冷至0℃,加入DIEA(0.2mL),于-5℃保温反应1h,用10ml乙酸乙酯和10mL卤水稀释,分层,水相用乙酸乙酯提取两次(2×10ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,得到粗品经层析法纯化,得到化合物CX13-600(98mg,51.0%)。
1H-NMR(400MHz,CDCl3)δ7.30(br.s,1H),7.13-7.28(m,10H),6.57-6.73(m,2H),6.16(br.s.,1H),4.66(d,J=7.25Hz,1H),4.47-4.59(m,2H),3.59-3.89(br,6H),3.25(d,J=5.10Hz,1H),3.05(dd,J=6.72,3.49Hz,2H),2.90(d,J=4.84Hz,1H),2.48-2.74(m,6H),2.18-2.29(m,1H),1.96-2.11(m,1H),1.55(s,3H),1.41-1.54(m,2H),1.20(t,J=9.94Hz,1H),0.88(dd,J=13.30,5.78Hz,6H);MS(ESI)m/z:674.3(M+H)+。
实施例10
CX13-601的合成
方案11:CX13-601的制备
C601-1的合成
室温下通过滴加漏斗往C104-10(500mg,1.3mmol)、(S)-苄基2-氨基-4-甲基戊酸((335mg,1.6mmol)、TBTU(516m g,13mmol)的DMF(50mL)溶液中加入DIEA(0.3mL),室温反应16h,用10ml乙酸乙酯和10ml盐水稀释,合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经硅胶柱层析纯化(PE:EA=5:1)得到白色固体601-1(660g,87%收率),MS(ESI)m/z:565.2(M+H)+。
C601-2的合成
向C601-1(660mg)的THF溶液中加入66mg钯碳,氢气气氛下搅拌12h,过滤,浓缩得到产品C601-2,不经纯化直接用于下一步反应。MS(ESI)m/z:475.2(M+H)+。
CX13-601的合成
C601-2(150mg,0.32mmol)、C103-4(102mg,0.38mmol)、HOBt(51g,0.51mmol)、HBTU(144g,0.51mmol)和DMF(5mL)的混合溶液预冷至-5℃,加入DIEA(0.2mL),-5℃下反应1h,用15ml乙酸乙酯和15ml卤水稀释,分层,水相用乙酸乙酯提取两次(2×10ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,得到粗品经层析柱纯化,得到化合物CX13-601(70mg,35.3%)。
1H-NMR(400MHz,CDCl3)δ7.33(d,J=9.94Hz,2H),7.17-7.26(m,3H),6.89(d,J=8.33Hz,1H),6.74(d,J=6.72Hz,1H),6.66(s,1H),4.58-4.67(m,2H),4.50(m,1H),3.69-3.83(m,7H),3.35-3.47(m,4H),3.30(d,J=4.84Hz,1H),2.92(d,J=4.84Hz,1H),2.76(t,J=7.92Hz,2H),2.49-2.60(m,4H),2.24-2.37(m,1H),2.12(m,1H),1.53-1.67(m,,2H),1.49-1.58(m,4H)0.89-0.98(m,6H);MS(ESI)m/z:628.3(M+H)+。
实施例11
化合物CX13-603的合成
方案12:CX13-603的制备
C601-2(200mg,0.42mmol)、C105-7(0.17g,0.82mmol)、HOBt(69m g,0.51mmol)、HBTU(191mg,0.51mmol)和DMF(5mL)的混合溶液预冷至-5℃,加入DIEA(0.5mL),-5℃下反应1h,用10ml乙酸乙酯和10ml盐水稀释,分层,水相用乙酸乙酯提取两次(2×10ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,得到粗品经层析柱纯化,得到化合物CX13-603(60mg,21.6%)。
1H-NMR(400MHz,CDCl3)δ7.35–7.23(m,7H),7.22–7.13(m,4H),7.02(d,J=7.6Hz,1H),6.81(b,1H),6.64(d,J=6.5Hz,1H),4.81(td,J=7.6,4.9Hz,1H),4.58(dd,J=13.6,7.9Hz,1H),4.42(td,J=7.3,3.9Hz,1H),3.85(b,5H),3.74(dd,J=9.1,3.8Hz,1H),3.35(s,3H),3.32(d,J=5.1Hz,1H),3.17(dd,J=14.0,4.9Hz,1H),2.95(d,J=4.9Hz,1H),2.86(dd,J=14.0,7.7Hz,1H),2.71(t,J=7.8Hz,2H),2.63(b,4H),2.23(m,1H),2.07(m,1H),1.54(s,3H);MS(ESI)m/z:662.3(M+H)+。
实施例12
化合物CX13-605的合成
方案13:CX13-605的制备
C605-2合成
通过滴加漏斗向C104-10(240mg,0.64mmol)、C605-1(143mg,0.77mmol)、HBTU(245m g,0.77mmol)和DMF(10mL)的混合液缓慢加入DIEA(0.5mL),室温下反应16h,用10ml乙酸乙酯和10ml卤水稀释,分层,水相用乙酸乙酯提取两次(2×10ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经层析柱纯化得到白色固体C605-2(310g,89%收率)。.MS(ESI)m/z:542.0(M+H)+。
C605-3的合成
C605-2(270mg,2.3mmol)的THF溶液中加入LiOH(97.4mg,3.5mmol),室温搅拌2h,蒸馏,调pH至5,蒸馏,层析法纯化得到白色固体C605-3(150mg,61%)。LC-MS:m/z 528.1(M+H)+。
CX13-605的制备
C605-3(150mg,0.28mmol)、C105-7(87mg,0.28mmol)+HOBt(58g,0.42mmol)、HBTU(160g,0.42mmol)和DMF(5mL)的混合溶液预冷至-5℃,加入DIEA(0.3mL),-5℃下反应1h,用10ml乙酸乙酯和10mL卤水稀释,分层,水相用乙酸乙酯提取两次(2×10ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,得到粗品经层析柱纯化,得到化合物CX13-605(50mg,25.1%)。
1H-NMR(400MHz,CDCl3)δ8.82(s,1H),7.15-7.41(m,10H),7.11(d,J=4.30Hz,1H),6.75(s,1H),4.67-4.78(m,2H),4.49(d,J=3.49Hz,1H),3.91(s,2H),3.67-3.79(m,4H),3.21-3.29(d,J=5.10Hz,2H),3.03-3.16(m,2H),2.94(d,J=5.10Hz,1H),2.51-2.80(m,7H).1.91-2.09(m,2H),1.44(s,3H);MS(ESI)m/z:715.3(M+H)+。
实施例13
化合物CX13-606的合成
方案14:CX13-606的制备
C606-2的合成
2.0g(17mmol)of C606-1中加入35ml 1N氢氧化钠水溶液和35ml THF,0℃搅拌下加入二碳酸二叔丁酯(4.03g,18.5mmol)的THF(15mL)溶液,室温搅拌过夜,反应液减压蒸发浓缩,水相用10%柠檬酸溶液调pH至4-5后用乙酸乙酯提取,卤水洗涤,硫酸镁干燥,蒸馏得到3.6g化合物606-2(98%收率)。MS(ESI)m/z:220.1(M+H)+。
C606-3的合成
C606-2(3.6g,16mmol)的DCM(40mL)溶液中室温下加入MeOH(2mL),DIEA(8mL)和EDCI(4.8g,25mmol),室温搅拌过夜,然后用200ml二氯甲烷和50ml卤水稀释,有机相用硫酸钠干燥,过滤除去固体,层析柱纯化得到白色固体C606-3(0.8g,20%)。.MS(ESI)m/z:234.1(M+H)+。
C606-4的合成
C606-3(800mg,3.4mmol)的DCM(8mL)溶液中于0℃加入2ml TFA,0℃下反应2h,减压除去易挥发物,得到白色固体化合物C606-4(790mg,100%收率)。MS(ESI)m/z:134.1(M+H)+。
C606-5的合成
C606-4(790mg,3.4mmol)的DMF(10mL)溶液中室温下加入(S)-2-([叔丁氧羰基]氨基)-4-苯基丁酸(950mg,3.4mmol),HBTU(1950mg,5.15mmol),HOBt(695mg,5.15mmol)和DIEA(2mL),室温下反应16h,用40ml乙酸乙酯和10ml卤水稀释,分层,水相用乙酸乙酯提取,合并有机相,硫酸钠干燥,过滤除去固体,减压馏除去易挥发物,层析柱纯化得到白色固体C606-5(1.2g,89%)。MS(ESI)m/z:395.2(M+H)+。
C606-6的合成
化合物C606-5(600mg,1.5mmol)的DCM(6mL)溶液中于0℃加入TFA(2mL),0℃保温反应2h,减压除去易挥发物,得到白色固体606-6(595mg,100%收率)。MS(ESI)m/z:295.2(M+H)+。
C606-7的合成
化合物C606-6(595mg,1.5mmol)的DMF(5mL)溶液中室温下加入C133-3(360mg,1.5mmol),HBTU(870mg,2.3mmol),HOBt(311mg,2.3mmol)和DIEA(1mL),室温下反应16h,用30ml乙酸乙酯和10mL卤水稀释,分层,水相用乙酸乙酯提取两次(2×20ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,层析柱纯化得到白色固体608-7(490mg,63%)。MS(ESI)m/z:512.3(M+H)+。
C606-8的合成
化合物C606-7(490mg,0.96mmol)+的THF(6mL)和水(2mL)溶液中室温下加入LiOH.H2O(101mg,2.4mmol),室温搅拌16h,调pH=5,用100ml乙酸乙酯提取,硫酸钠干燥,过滤除去固体,减压除去易挥发物得到白色固体606-8(440mg,92%收率)。.MS(ESI)m/z:498.3(M+H)+。
CX13-606的合成
化合物C606-8(200mg,0.4mmol)的DMF(3mL)溶液中室温下加入C103-4(107mg,0.4mmol),HBTU(227mg,0.6mmol),HOBt(82mg,0.6mmol)和DIEA(0.2mL),室温下反应16h,用30ml乙酸乙酯和10mL卤水稀释,分层,水相用乙酸乙酯提取(2×20ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,经层析柱纯化,得到白色固体CX13-606(100mg,38%)。
1H-NMR(400MHz,MeOD)δ7.33(s,4H),7.24(t,J=7.3Hz,2H),7.15(dd,J=20.9,7.1Hz,3H),4.63–4.48(m,2H),4.37(dd,J=8.3,4.9Hz,1H),3.65(dd,J=8.8,4.1Hz,4H),3.60(dd,J=6.1,3.7Hz,3H),3.54(d,J=6.0Hz,2H),3.24(d,J=5.1Hz,1H),2.93(d,J=5.1Hz,1H),2.69–2.52(m,2H),2.46(s,4H),2.18–2.04(m,1H),2.01–1.85(m,1H),1.76–1.63(m,1H),1.54–1.42(m,4H),1.35(ddd,J=13.9,9.0,3.7Hz,1H),0.91(dd,J=9.7,6.6Hz,6H);MS(ESI)m/z:652.0(M+H)+。
实施例14
化合物CX13-608的合成
方案15:CX13-608的制备
C606-8(200mg,0.4mmol)的DMF(3mL)溶液中室温下加入C105-7(107mg,0.4mmol),HBTU(227mg,0.6mmol),HOBt(82mg,0.6mmol)和DIEA(0.2mL),室温下反应16h,用30ml乙酸乙酯和10ml卤水稀释,分层,水相用乙酸乙酯提取(2×20ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,层析柱纯化得到白色固体CX13-608(100mg,36%)。
1H-NMR(400MHz,MeOD)δ7.32(s,4H),7.27–7.12(m,8H),7.11–7.08(m,2H),4.79(dd,J=8.6,4.6Hz,1H),4.47(t,J=5.3Hz,1H),4.33(dd,J=9.2,5.0Hz,1H),3.64(t,J=4.8Hz,4H),3.51-3.59(m,4H),3.50(s,2H),3.30(s,3H),3.25(d,J=5.0Hz,1H),3.07(dd,J=13.9,4.6Hz,1H),2.93(d,J=5.0Hz,1H),2.76(dd,J=13.9,8.7Hz,1H),2.64–2.49(m,2H),2.43(t,J=4.8Hz,4H),2.05(m,1H),1.91(m,1H),1.43(s,3H);MS(ESI)m/z:685.3(M+H)+。
实施例15
化合物CX13-705的合成
方案16:CX13-705的制备
C705-2的合成
C705-1(239mg,0.81mmol)的DMF(5mL)溶液中室温下加入5-甲基噻唑-2-羧酸(116mg,0.81mmol),HBTU(370mg,0.97mmol),HOBt(131mg,0.97mmol)和DIEA(0.73mL),室温反应12h,用20ml乙酸乙酯和10ml卤水稀释,分层,水相用乙酸乙酯提取(2×150ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,层析柱纯化得到白色固体705-2(300mg,88%)。.LC-MS:m/z 420.1(M+H)+。
C705-3的合成
C705-2(340mg,0.81mmol)的THF(6mL)和水(2mL)溶液中室温下加入LiOH.H2O(68mg,1.62mmol),室温搅拌反应2h,调pH至5,用20ml乙酸乙酯提取,硫酸钠干燥,过滤除去固体,减压除去易挥发物,得到白色固体705-3(265mg,78%收率)。.MS(ESI)m/z:406.1(M+H)+。
CX13-705的制备
C705-3(265mg,0.65mmol)的DMF(3mL)溶液中室温下加入C105-7(130mg,0.72mmol),HBTU(300mg,0.79mmol),HOBt(106mg,0.79mmol)和DIEA(0.6mL),室温下反应4h,用20ml乙酸乙酯和10ml卤水稀释,分层,水相用乙酸乙酯提取(2×20ml),合并有机相,硫酸钠干燥,过滤除去固体,减压除去易挥发物,层析柱纯化得到白色固体CX13-705(90mg,23%)。
1H-NMR(400MHz,MeOD)δ8.22(s,1H),7.31-7.13(m,10H),4.80(dd,J=8.8,4.8Hz,1H),4.57–4.48(m,2H),3.66-3.52(m,2H),3.25(d,J=4.84Hz,1H),3.10(dd,J=13.97,4.57Hz,1H),2.94(d,J=5.10Hz,1H),2.66-2.82(m,6H),2.02-2.16(m,2H);MS(ESI)m/z:593.0(M+H)+。
实施例16
化合物对蛋白酶体活性的抑制作用
用纯化的人源20S蛋白酶体进行糜蛋白酶样活性(CT-L),肽基谷氨酰肽水解活性(PGPH)和胰蛋白酶样活性(T-L)活性的体外测定,20S蛋白酶体的浓度分别为2,4和8nmol/L,分别用succinyl-Leu-Leu-Val-Tyr-AMC(10μmol/L),Z-leu-Leu-Glu-AMC(10μmol/L)和Boc-Leu-Arg-Arg-AMC(50μmol/L)作为底物,反应在包含0.5mM乙二胺四乙酸、0.001%十二烷基硫酸钠(SDS)和0.05%NP-40的25mM 4-羟乙基哌嗪乙磺酸(HEPES)缓冲溶液(pH7.5)中进行。蛋白酶体抑制剂的储备液在二甲基亚砜(DMSO)中制备,在测试混合物中DMSO的最终浓度是1%。室温下反应1小时。用荧光光度计检测裂解出来的7-氨基-4-甲基香豆素荧光团,从而测定蛋白酶体活性。IC50值是抑制剂对20S蛋白酶体活性的抑制达到50%时的浓度,是抑制剂抑制活性的定量描述。在某些实施例中,本发明提供的化合物对蛋白酶体的抑制活性见表1。
实施例17
化合物的水溶性
化合物水溶性的测定方法如下:称取1-5mg化合物至小瓶中,加入1mL缓冲溶液(50mM柠檬酸盐溶液,pH=4.0),于25℃震摇24h,于1000rpm转速下离心10分钟。用0.45μm过滤膜过滤上清液,测定化合物的浓度。在某些实施例中,化合物的水溶性见表1。
实施例18
以本发明中所述的化合物为受试品以可耐受的剂量对小鼠给药处理后血液中蛋白酶体活性的抑制作用
以溶媒(20%(w/v)羟丙基-β-环糊精的10mM柠檬酸钠溶液,pH=3.5)或以本发明中所述的化合物为受试品以可耐受的剂量对Balb/c小鼠给药,溶媒通过静脉注射给药,化合物通过静脉注射(10mg/kg)或灌胃(30mg/kg)给药。给药后一小时,通过心脏穿刺采集全血标本注入含有肝素钠的试管中,在4℃下于150xg离心5分钟。离心出来的沉淀物用冰冷的磷酸盐缓冲生理盐水清洗三次。每次将沉淀物回溶于1mL冷的磷酸盐缓冲生理盐水中,在4℃下于6000xg离心10分钟。最后一次清洗后,加入100μL裂解液(含有5mM EDTA的磷酸盐缓冲生理盐水,pH 7.4)裂解1小时,然后在4℃下于6000xg离心10分钟。上清液转移至另一新的试管内,沉淀物弃之。用BCA方法测定细胞裂解物的浓度。10μg蛋白质用来检测CT-L的活性,30μg蛋白质用来检测PGPH和T-L活性,分别加入succinyl-Leu-Leu-Val-Tyr-AMC(25μmol/L)、Z-leu-Leu-Glu-AMC(10μmol/L)或Boc-Leu-Arg-Arg-AMC(10μmol/L)作为CT-L、PGPH或T-L活性测定的底物,混合液在37℃培养60分钟,用荧光光度计在360/460nm波长检测裂解出来的自由7-氨基-4-甲基香豆素荧光团从而定量测定20S蛋白酶体中CT-L,PGPH或T-活性。小鼠经溶媒给药处理后血液蛋白酶体的活性为百分之百;经本发明的化合物给药处理后血液蛋白酶体的活性与溶媒组比较得到百分抑制率。蛋白酶体活性的抑制率见图1。如图1所示,所测试的化合物对血液样品中CT-L的活性有抑制作用。特别是,通过灌胃给药的CX13-603对血液样品中CT-L的活性也有抑制作用;CX13-608能同时抑制血液样品中蛋白酶体的CT-L和T-L活性。
实施例19
本发明所述化合物对移植于裸鼠的人源肿瘤的抗肿瘤疗效
雌性小鼠(NIH III HO裸鼠,购自Charles River实验室,体重约20g,5-6周大)实验期间养殖在笼子中。将含有3×106人源结肠癌细胞(HT-29)或1×107人源B淋巴细胞(RL)的100μL磷酸盐缓冲生理盐水经皮下注射到小鼠的右胁。人源结肠癌细胞(HT-29)和人源B淋巴细胞(RL)购自(HTB-38TM和CRL38TM)。当HT-29肿瘤的平均尺寸达到约20-30mm3或RL肿瘤的平均尺寸达到约60-90mm3时,将患肿瘤的小鼠随机分成不同的组别(每组7-10个小鼠),所有的组别都有相同的肿瘤尺寸分布。对小鼠静脉注射溶媒(10%(w/v)羟丙基-β-环糊精的10mM柠檬酸溶液,pH=4.0)或配制在溶媒中的CX13-103溶液,每周第1天,第2天和第5天给药三次,共4-5周。每周用卡尺测量肿瘤尺寸2-3次,肿瘤体积=长×宽2/2。使用双方向方差检验(2-way ANOVA)对数据进行统计分析。如图2A和2B所示,CX13-103可以显著抑制肿瘤生长。
Claims (18)
1.具有式(I)所示结构的化合物,及其对映体,非对映体,互变异构体,和药物可接受的盐或溶剂化物或前药:
结构式(I)
其中R1是-(CH2)m-R4,其中m=0 or 1,R4选自下述基团:C1-10烷基,
其中
任一R5独立的为H,羟基,C1-10烷基,C1-10烷氧基,C1-10羟烷基,C1-10烷氧基烷基,NH2,NHR6,-R7-O(C=O)-R8,-R7-(C=O)X-R8,-R7-OPO3M1M2,
其中
R6是C1-10烷基,苯基,-(C=O)C1-6烷基,或-(C=O)苯基;
任一R7和R9独立的为不存在,或是-C1-10亚烃基;
任一R8独立的为H,羟基,金属离子,C1-10烷基,-C1-10亚烃基,-NR10R11,或-OPO3M1M2,
任一R10和R11独立的为H,C1-10烷基或取代的C1-10烷基;
任一M1,M2独立的为H,或金属离子;
X为不存在,或是O;
Y为不存在,或是-(C=O)-;
Z为不存在,或是O。
任一R2和R3独立的选自下述基团:C1-10烷基,C1-10烯烃,C1-10羟烷基,C1-10烷氧烷基,芳基,C1-10芳烷基,杂芳基,C1-10杂芳烷基,杂环基,C1-10杂环烷基,碳环基和C1-10碳环醇烷基,
其中当R1是并且R2是异丁基时,R3不是4-吡啶基甲基。
2.权利要求1中的化合物,有式(II)所示的的结构:
结构式(II)。
3.权利要求书1或2中的化合物,其中R4选自含以下基团:
甲基,
4.权利要求书1或2中的化合物,其中R2是C1-10烷基,C1-10烷氧烷基,芳香基,杂环芳基,C1-10芳烷基或C1-10杂环芳烷基。
5.权利要求4中的化合物,其中R2是甲基-氧基-甲基,4-吡啶甲基,异丁基,苄基或4-噻唑基-甲基。
6.权利要求1或2中的化合物,其中R3是C1-10烷基,芳香基,杂环芳基,C1-10芳烷基或C1-10杂环芳烷基。
7.权利要求6中的化合物,其中R3是异丁基,4-吡啶甲基或苄基。
8.下面所示结构式的化合物和其药学上可接受的盐、溶剂化物或前药:
9.由权利要求1-8中的任一化合物和药学上可接受的载体组成的药物组合物。
10.特异性地抑制20S蛋白酶体催化活性的方法,包括给予医疗上有效剂量的权利要求1-8中的化合物。
11.权利要求10中的方法,其中20S蛋白酶体的CT-L活性和T-L活性可以同时被抑制。
12.蛋白酶体相关的疾病或病症的治疗方法,包括给予医疗上有效剂量的权利要求1-8中的化合物。
13.权利要求12中的方法,其中化合物通过注射给药。
14.权利要求13中的方法,其中化合物通过以下途径给药:皮下给药,静脉给药,肌肉给药,动脉给药,鞘膜给药,囊内给药,眶内给药,心脏内给药,真皮内给药,腹膜内给药,经气管给药,表皮给药,关节内给药,囊下给药,蛛网膜下给药,脊柱内给药,胸骨内给药,或通过滴注给药。
15.权利要求12中的方法,其中化合物通过非注射途径给药。
16.权利要求15中的方法,其中化合物通过以下途径给药:口服,肠道,口腔,鼻,鼻内,经粘膜,表皮,贴膏剂,真皮,眼药,肺部,舌下,直肠,阴道或局部给药。
17.权利要求1-8中任一化合物在制备用于治疗与20S蛋白酶体相关的疾病的药物中的用途。
18.权利要求12中的方法或者权利要求17中的应用,其中20S蛋白酶体相关的疾病或者病症包括癌症,神经中毒/退化疾病,阿兹海默症,缺血性疾病,炎症,免疫相关的疾病,HIV感染,器官移植排斥,感染性休克,抗原递呈抑制,病毒基因表达减少,寄生虫感染,酸中毒相关的疾病,黄斑变性,肺部疾病,肌肉萎缩症,纤维化疾病,骨骼和毛发生长疾病。
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