CN109843849A - 酰胺化合物、其药物组合物及其使用方法 - Google Patents
酰胺化合物、其药物组合物及其使用方法 Download PDFInfo
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- CN109843849A CN109843849A CN201780063087.9A CN201780063087A CN109843849A CN 109843849 A CN109843849 A CN 109843849A CN 201780063087 A CN201780063087 A CN 201780063087A CN 109843849 A CN109843849 A CN 109843849A
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- C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
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- C07C235/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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Abstract
公开了酰胺化合物。还公开了包含所述化合物的药物组合物以及治疗神经退行性疾病的方法,所述方法涉及向受试者施用所述化合物或药物组合物。
Description
技术领域
通常,本领域是药用化合物和药物组合物。更具体地,本发明涉及药用酰胺化合物。酰胺化合物可以表现出改善的向中枢神经系统的转运。
相关申请
本申请要求2017年8月12日提交的美国临时专利申请号62/374,657的优先权。
本申请与2015年2月20日提交的US 62/119,001;2016年2月19日提交的PCT/US16/18732;2016年2月19日提交的US 15/048,672;2016年5月18日提交的US 62/338,178;2013年5月3日提交的US 61/819,467;2013年8月5日提交的PCT/US13/53640;2014年2月5日提交的PCT/US14/14943;和2015年11月2日提交的US 14/888,577有关。上述申请的全部内容通过引用并入本文。
背景技术
人们越来越关注激活脑中特定的甲状腺激素信号传导通路来治疗某些CNS疾病,特别是那些涉及髓鞘缺陷的疾病(Fourcade S等,Mol Pharmacol 63,1296-1303(2003)和Baxi EG等,Glia 62,1513-1529(2014);这两篇文献均通过引用并入本文)。甲状腺激素T4和T3不适合作为这些适应症的治疗剂,因为没有将所需的治疗效果与甲状腺功能亢进相关的不良反应(如心动过速、肌肉萎缩和骨质疏松症)分开的T4和T3的治疗指数(Yen PM等,Physiol Rev 81,1097-1142(2001);Yen PM等,Mol Cell Endocrinol 246,121-127(2006);Biondi B和Klein I,Endocrine 24,1-13(2004);以及Klein I和Ojamaa K,Endocrinol Metab Clin North Am 27,51-62(1998);所有这些都通过引用并入本文)。这一问题可能通过某些显示组织选择性甲状腺激素作用的合成的T3激动剂来有效解决(Joharapurkar AA等,J Med Chem 55,5649-5675(2012);通过引用并入本文。)
苏比替罗(Sobetirome)(也称为GC-1)是过去15年来广泛研究的一个实例(Scanlan TS,Heart Fail Rev 15,177-182(2010);通过引用并入本文)。据信,苏比替罗和T3通过刺激肝脏胆固醇清除机制影响LDL胆固醇降低。有利地,苏比替罗产生这种效果,而基本上不会对心脏、肌肉或骨骼产生有害影响(Grover GJ等,Endocrinology 145,1656-1661(2004);通过引用并入本文)。先前公开了使用苏比替罗治疗神经退行性疾病的用途(WO 2014/178931)。对于靶向神经退行性疾病的治疗剂,通常需要改善向CNS分布的效率。需要具有改善的CNS分布的化合物用于治疗神经退行性疾病(例如,脱髓鞘疾病)。
发明内容
一方面,本发明的特征为式I的化合物:
或其药学上可接受的盐,其中R1是酰胺。
在该方面的一些实施方案中,化合物为式II:
或其药学上可接受的盐,其中R2是烷基氨基。
在该方面的一些实施方案中,化合物为式II:
或其药学上可接受的盐,其中R2是氨基。
在一些实施方案中,化合物为式III:
式III,或其药学上可接受的盐,其中R3和R4各自独立地为H、烷基、环烷基、取代的烷基、未取代的烷基、杂烷基、饱和烷基、不饱和烷基、芳基、氨基或乙氧基。在一些特定的实施方案中,R3是甲基并且R4是甲基。
在一些实施方案中,化合物为式IV:
或其药学上可接受的盐,其中R3为H、羟基、氨基、甲基、乙基、丙基、环丙基、2-羟基乙基、1-羟基丙-2-基、2-羟基丙基、2-氨基乙基乙酸酯、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、苯基、(4-硝基)苯基、2-苯基乙基、2-(2-羟基苯基)乙基、2-(3-羟基苯基)乙基、2-(3,4-二羟基苯基)乙基、3-氟乙基;S-甲基磺酰基、1-(2-羟基乙基)-2-羟基乙基、2-丙烯基、2-丙炔基、甲氧基、2-乙基磺酸钠、氰基甲基或氧杂环丁烷基。
在一些实施方案中,化合物为式III:
或其药学上可接受的盐,其中R4选自H和C1-6烷基;并且R3是:(a)H、OH、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、C2-6烯基、C2-6炔基、C3-6环烷基、或含有一个选自O、N和S的杂原子的3-至6-元杂环基环;或(b)任选被1、2或3个取代基取代的C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环,或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或(c)任选被1、2或3个取代基取代的-O-C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或(d)任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基。
在一些实施方案中,化合物为式IV:
或其药学上可接受的盐,其中R3是:(a)H、OH、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、C2-6烯基、C2-6炔基、C3-6环烷基,或含有一个选自O、N和S的杂原子的3-至6-元杂环基环;或(b)任选被1、2或3个取代基取代的C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或(c)任选被1、2或3个取代基取代的-O-C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或(d)任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基。
在式IV化合物的具体实施方案中,R3是:(a)H、OH、NH2、-SO2H、-SO2(C1-3烷基)、C2-3烯基、C2-3炔基、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环;或(b)任选被1、2或3个取代基取代的C1-4烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-3烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或(c)任选被1、2或3个取代基取代的-O-C1-4烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;和(d)任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基。
在式IV化合物的具体实施方案中,R3是:(a)H、OH、NH2、-SO2H、-SO2(CH3)、C2-3烯基、C2-3炔基、C3-6环烷基、含有一个氧杂原子的3-至6-元杂环基环;或(b)任选被1、2或3个取代基取代的C1-4烷基,所述取代基各自独立地选自OH、F、NH2、-SO2H、-SO2(CH3)、CN、C3-6环烷基、含有一个氧杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代的苯基;或(c)任选被1、2或3个取代基取代的-O-C1-4烷基,所述取代基各自独立地选自OH、F、NH2、-SO2H、-SO2(CH3)、CN、C3-6环烷基、含有一个氧杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代的苯基;或(d)任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代的苯基。
在一些实施方案中,化合物为式IV:
或其药学上可接受的盐,其中R3是-(CH2)n1-苯基,并且其中n1是选自0、1、2、3或4的整数,并且苯环任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是-(CH2)n2-苯基,其中n2是选自0、1或2的整数,并且苯环任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是-(CH2)n2-苯基,其中n2是选自0、1或2的整数,并且苯环任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是-(CH2)-苯基,其中苯环任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是任选被1、2或3个取代基取代的C1-6烷基,所述取代基各自独立地选自由以下组成的组:OH、F、NH2、-SO2H、-SO2(CH3)、CN、C3-6环烷基和含有一个氧杂原子的3-至6-元杂环基环。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是任选被1、2或3个取代基取代的C1-4烷基,所述取代基各自独立地选自由以下组成的组:OH、F、NH2、-SO2H、-SO2(CH3)、CN、C3-6环烷基和含有一个氧杂原子的3-至6-元杂环基环。
在一些实施方案中,化合物为式IV:
或其药学上可接受的盐,其中R3是任选被1、2或3个取代基取代的C1-6烷基,所述取代基各自独立地选自由OH、F、NH2、CN、-SO2H和-SO2(C1-6烷基)组成的组。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是任选被1、2或3个OH取代基取代的C1-6烷基。
在一些实施方案中,化合物为式IV:
或其药学上可接受的盐,其中R3是任选被1、2或3个OH取代基取代的C1-4烷基。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是任选被1、2或3个F取代基取代的C1-6烷基。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是任选被1、2或3个F取代基取代的C1-4烷基。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是任选被1、2或3个F取代基取代的-O-C1-6烷基。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是任选被1、2或3个F取代基取代的-O-C1-4烷基。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是-O-C1-6烷基。
在一些实施方案中,化合物为式IV:或其药学上可接受的盐,其中R3是-O-C1-4烷基。
在一些实施方案中,化合物为式III:或其药学上可接受的盐,其中R3和R4各自独立地为H、取代的脂族、未取代的脂族、取代的苯基、未取代的苯基、ORN1、-N(RN1)2或-SO2(RN2),其中RN1各自独立地为H、取代的脂族或未取代的脂族,并且RN2是OH、未取代的脂族或取代的脂族;前提是如果一个RN是ORN1、-N(RN1)2或-SO2(RN2),则另一个RN是H、取代的脂族、未取代的脂族、取代的苯基或未取代的苯基。在特定的实施方案中,R3是H或未取代的脂族。在特定的实施方案中,R4是H、取代的脂族或未取代的脂族。在特定的实施方案中,R3是甲基。在特定的实施方案中,R4是甲基。
另一方面,本发明的特征在于选自由以下组成的组的化合物:
或其药学上可接受的盐。
在本发明第一方面的一些实施方案中,化合物选自由以下组成的组:
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-羟基乙基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(1-羟基丙-2-基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-羟基丙基)乙酰胺;
2-(2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰氨基)乙烷-1-乙酸铵;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
N-(2,2-二氟乙基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2,2,2-三氟乙基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-甲基乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-羟基苯基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-N-(3-羟基苯基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-(甲基磺酰氨基)乙基)乙酰胺;
N-(1,3-二羟基丙-2-基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-丙基乙酰胺;
N-(2-氟乙基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
N-烯丙基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(丙-2-炔-1-基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-甲氧基乙酰胺;
N-(3,4-二羟基苯乙基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-苯乙基乙酰胺;
N-羟基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰肼;
2-(2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰氨基)乙烷-1-磺酸盐
N-环丙基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N,N-二甲基乙酰胺;
N-乙基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
N-(氰基甲基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
N-(3-氟苯基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(氧杂环丁烷-3-基)乙酰胺;和
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(4-硝基苯基)乙酰胺;或其药学上可接受的盐。
另一方面,本发明的特征在于药物组合物,其包含药学上有效量的本文所述的化合物(例如,前述方面中任一项的化合物)或其药学上可接受的盐,和一种或多种药学上可接受的载体。
另一方面,本发明的特征在于一种通过向患有神经退行性疾病的受试者施用药学上有效量的本文所述的化合物(例如,前述方面中任一项的化合物)或其药学上可接受的盐,或本文所述的药物组合物来治疗所述受试者从而治疗神经退行性疾病的方法。
在该方面的一些实施方案中,神经退行性疾病是脱髓鞘疾病。在该方面的一些实施方案中,神经退行性疾病是X-连锁的肾上腺脑白质营养不良或多发性硬化。
在该方面的一些实施方案中,神经退行性疾病选自由以下疾病组成的组:急性播散性脑脊髓炎、急性出血性脑白质炎、成人雷夫叙姆病(adult Refsum disease)、亚历山大病(Alexander disease)、阿尔茨海默氏病(Alzheimer’s disease)、巴洛同心硬化症(Baloconcentric sclerosis)、卡纳万病(Canavan disease)、脑桥中央髓鞘溶解症、脑瘫、脑腱性黄瘤病(cerebrotendineous xanthomatosis)、慢性炎性脱髓鞘性多发性神经病、德维克氏综合征(Devic’s syndrome)、弥漫性髓鞘硬化症、格林-巴利综合征(Guillain-Barrésyndrome)、特发性炎性脱髓鞘病、婴儿雷夫叙姆病(infantile Refsum disease)、克拉伯病(Krabbe disease)、莱伯遗传性视神经病变(Leber hereditary optic neuropathy)、马尔堡多发性硬化症(Marburg multiple sclerosis)、Marchiafava-Bignami病、异染性脑白质营养不良、多灶性运动神经病变、副蛋白质脱髓鞘多发性神经病、Pelizaeus-Merzbacher病、腓骨肌萎缩症、进行性多灶性脑白质病、横贯性脊髓炎、热带痉挛性下肢瘫痪、范德纳氏病(van der Knaap disease)、X连锁肾上腺脑白质营养不良和齐维格综合症(Zellwegersyndrome)。
另一方面,本发明的特征在于一种通过向患有阿尔茨海默氏病的受试者施用药学上有效量的本文所述的化合物(例如,前述方面中任一项的化合物)或其药学上可接受的盐,或本文所述的药物组合物来治疗所述受试者从而治疗阿尔茨海默氏病的方法。
另一方面,本发明的特征在于一种通过对患有由以下组成的组的疾病或病症的受试者施用药学上有效量的本文所述化合物(例如,前述方面中任一项所述的化合物)、或其药学上可接受的盐、或本文所述的药物组合物治疗所述受试者,从而治疗所述疾病或病症的方法:急性播散性脑脊髓炎(ADEM)、急性出血性脑白质炎(AHL或AHLE)、成人雷夫叙姆病、婴儿雷夫叙姆病、亚历山大病、阿尔茨海默氏病、巴洛同心硬化症、卡纳万病、脑桥中央髓鞘溶解症(CPM)、脑瘫、脑腱性黄瘤病、慢性炎性脱髓鞘性多发性神经病(CIDP)、德维克氏综合征、弥漫性髓鞘硬化症、脑脊髓炎、格林-巴利综合征、特发性炎性脱髓鞘疾病(IIDD)、克拉伯病、莱伯遗传性视神经病变、脑白质营养不良、马尔堡多发性硬化症、Marchiafava-Bignami病、异染性脑白质营养不良(MLD)、多灶性运动神经病变(MMN)、多发性硬化症(MS)、副蛋白脱髓鞘性多发性神经病、Pelizaeus-Merzbacher病(PMD)、进行性多灶性脑白质病(PML)、热带痉挛性下肢瘫痪(TSP)、X-连锁肾上腺脑白质营养不良(X-ALD、ALD或X-连锁的ALD)和齐维格综合症。
另一方面,本发明的特征在于本文所述的化合物(例如,前述方面中任一项的化合物),或其药学上可接受的盐,或本文所述的药物组合物,用于治疗神经退行性疾病(例如,脱髓鞘疾病、X-连锁的肾上腺脑白质营养不良或多发性硬化症)。
在一些实施方案中,所述化合物或其药学上可接受的盐或药物组合物用于治疗选自由以下组成的组的神经退行性疾病;急性播散性脑脊髓炎、急性出血性脑白质炎、成人雷夫叙姆病、亚历山大病、阿尔茨海默氏病、巴洛同心硬化症、卡纳万病、脑桥中央髓鞘溶解、脑瘫、脑腱性黄瘤病、慢性炎性脱髓鞘性多发性神经病、德维克氏综合征、弥漫性髓鞘硬化症、格林-巴利综合征、特发性炎性脱髓鞘病、婴儿雷夫叙姆病、克拉伯病、莱伯遗传性视神经病变、马尔堡多发性硬化症、Marchiafava-Bignami病、异染性脑白质营养不良、多灶性运动神经病变、副蛋白质脱髓鞘多发性神经病、Pelizaeus-Merzbacher病、腓骨肌萎缩、进行性多灶性脑白质病、横贯性脊髓炎、热带痉挛性下肢瘫痪、范德纳氏病、X-连锁肾上腺脑白质营养不良和齐维格综合征。
另一方面,本发明的特征在于本文所述的化合物(例如,前述方面中任一项的化合物),或其药学上可接受的盐,或本文所述的药物组合物,其用于治疗阿尔茨海默氏病。
另一方面,本发明的特征在于本文所述的化合物(例如,前述方面中任一项的化合物),或其药学上可接受的盐,或本文所述的药物组合物,用于治疗由以下组成的组的疾病或病症:急性播散性脑脊髓炎(ADEM)、急性出血性脑白质炎(AHL或AHLE)、成人雷夫叙姆病、婴儿雷夫叙姆病、亚历山大病、阿尔茨海默氏病、巴洛同心硬化症、卡纳万病、脑桥中央髓鞘溶解症(CPM)、脑瘫、脑腱性黄瘤病、慢性炎性脱髓鞘性多发性神经病(CIDP)、德维克氏综合征、弥漫性髓鞘硬化症、脑脊髓炎、格林-巴利综合征、特发性炎性脱髓鞘病(IIDD)、克拉伯病、莱伯遗传性视神经病变、脑白质营养不良、马尔堡多发性硬化症、Marchiafava-Bignami病、异染性脑白质营养不良(MLD)、多灶性运动神经病变(MMN)、多发性硬化症(MS)、副蛋白脱髓鞘性多发性神经病、Pelizaeus-Merzbacher病(PMD)、进行性多灶性脑白质病(PML)、热带痉挛性下肢瘫痪(TSP)、X-连锁的肾上腺脑白质营养不良(X-ALD、ALD或X-连锁的ALD)和齐维格综合征。
附图说明
图1是本文公开的CNS靶向化合物的一般方法。
图2A是腹膜内施用于小鼠后苏比替罗(GC-1)或所公开化合物的脑浓度的图。
图2B是腹膜内施用于小鼠后苏比替罗(GC-1)或所公开化合物的血清浓度的图。
图2C是腹膜内施用于小鼠后苏比替罗(GC-1)或所公开化合物的脑浓度与血清浓度之比的图。
具体实施方式
定义
除非另外特别定义,否则本文所用的技术术语具有本领域所理解的其正常含义。提供以下术语和方法的解释以更好地描述本发明化合物、组合物和方法,并指导本领域普通技术人员实施本公开。还应当理解,本公开所使用的术语仅出于描述特定实施方案和实施例的目的,且并不意图加以限制。
如本文所用,除非上下文另外明确指出,否则单数术语“一”、“一种(个)”和“所述(该)”包括复数指示物。类似地,除非上下文另外明确指出,否则词“或”旨在包括“和”。此外,如本文所用,术语“包含”意指“包括”。因此,“包含A或B”意指包括A、B或A和B。
除非另有说明,否则在整个公开内容中使用的诸如R的变量,包括其所有子变量(例如R1、R2等)与先前定义的变量相同。
施用:是指提供化合物、化合物的前药或包含本文所述的化合物或前药的药物组合物。化合物或组合物可以由另一个人施用于受试者,或者它可以由受试者自我施用。施用途径的非限制性实例是口服、肠胃外(例如,静脉内)或局部。
脂族:具有1至6个碳原子的支链、直链或环状非芳族烃基。脂族基团是饱和的或不饱和的。不饱和脂族基团含有一个碳-碳双键或三键。取代的脂族基团是被1至5个化合价允许的取代基取代的脂族基团。取代的脂族基团中的每个取代基独立地选自由卤素、-ORA、-N(RB)2、-SO2(RC)、氰基、取代的苯基和未取代的苯基组成的组;其中RA是H、未取代的脂族,未取代的苯基或取代的苯基;每个RB独立地为未取代的脂族,未取代的苯基,取代的苯基或SO2(RC);并且RC独立地为-OH、未取代的脂族或未取代的苯基、取代的苯基。
烷基:支链或无支链饱和烃基,例如但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十四烷基、十六烷基、二十烷基、二十四烷基等。低级烷基是具有1至6个碳原子的饱和支链或无支链烃(C1-6烷基)。术语烷基还包括环烷基。不饱和烷基可以是烯基(例如,含有一个或多个碳-碳双键的基团)或炔基(例如,含有一个或多个碳-碳三键的基团)。烷基还包括取代的烷基,其为烷基,其中一个或多个氢原子被取代基替换,所述取代基例如但不限于烷基、炔基、烯基、芳基、卤化物、硝基、氨基、酯、醚、酮、醛、羟基、羧基、氰基、酰氨基、卤代烷基、卤代烷氧基或烷氧基。术语烷基还包括杂烷基。杂烷基含有替换一个或多个碳的至少一个杂原子,例如氮、氧、硫或磷。取代的杂烷基也包括在术语烷基中。
在一些实施方案中,任选取代的烷基可含有例如1-20、1-18、1-16、1-14、1-12、1-10、1-8、1-6、1-4或1-2个碳原子,如果烷基被取代,则不包括取代基中存在的碳原子。在一些实施方案中,任选取代的烯基或任选取代的炔基可含有例如2-20、2-18、2-16、2-14、2-12、2-10、2-8、2-6或者2-4个碳原子,如果链烯基或炔基被取代,则不包括取代基中存在的碳原子。
烷基氨基:杂烷基,其中一个或多个碳原子被氮替换。烷基氨基可以是直链、支链或环烷基氨基。烷基氨基通常具有结构-NX1X2或-NX1X2X3 +其中X1、X2和X3各自独立地选自例如H、任选取代的烷基(例如,取代的烷基或未取代的烷基,如上文所定义的术语)、任选取代的烯基(例如,任选取代的C2-6烯基)、任选取代的炔基(例如,任选取代的C2-6炔基)、任选取代的环烷基(例如,任选取代的C3-6环烷基)、任选取代的杂环基环(例如,含有一个选自O、N和S的杂原子的任选取代的3-至6-元杂环基环)、任选取代的芳基(例如,任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基)、任选取代的-O-C1-6烷基(例如,任选被1、2或3个取代基取代的-O-C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基)、酰基、OH、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H或-SO2(C1-6烷基)。
在一些实施方案中,烷基氨基具有结构-NX1X2其中X1是H或任选取代的C1-6烷基并且X2是任选被1、2或3个取代基取代的C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基。
在一些实施方案中,烷基氨基具有结构-NX1X2其中X1是H或任选取代的C1-6烷基并且X2是任选被1、2或3个取代基取代的-O-C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基。
在一些实施方案中,烷基氨基具有结构-NX1X2其中X1是H或任选取代的C1-6烷基并且X2是任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基。
在一些实施方案中,烷基氨基具有结构-NX1X2其中X1和X2各自独立地选自H、取代的脂族、未取代的脂族、取代的苯基、未取代的苯基、ORN1、-N(RN1)2或-SO2(RN2),其中每个RN1独立地为H、取代的脂族或未取代的脂族,并且RN2是OH、未取代的脂族或取代的脂族。在一些实施方案中,如果一个RN是ORN1、-N(RN1)2或者-SO2(RN2),则另一个RN是H、取代的脂族、未取代的脂族、取代的苯基或未取代的苯基。
在一些实施方案中,烷基氨基具有结构-NX1X2其中X1是H并且X2是H、羟基、氨基、甲基、乙基、丙基、环丙基、2-羟基乙基、1-羟基丙-2-基、2-羟基丙基、2-氨基乙基乙酸酯、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、苯基、(4-硝基)苯基、2-苯基乙基、2-(2-羟基苯基)乙基、2-(3-羟基苯基)乙基、2-(3,4-二羟基苯基)乙基、3-氟乙基;S-甲基磺酰基、1-(2-羟基乙基)-2-羟基乙基、2-丙烯基、2-丙炔基、甲氧基、2-乙基磺酸钠、氰基甲基或氧杂环丁烷基。
烷基氨基的实例包括但不限于以下结构:-NHCH3、-N(CH3)2、-NH(CH3)2 +、-N(CH3)3 +、-NHCH2CH3、-NH2CH2CH3 +、
-NCH3CH2CH3、-N(CH2CH3)2和-NHCH3CH2CH3 +。烷基氨基还包括其中一个或多个碳原子被氮替换和/或另外,一个或多个其它碳原子被另一个杂原子如氧、硫或磷替换的杂烷基。
术语烷基氨基也包括与氮键合,与非末端碳形成键的烷基,形成环烷基氨基结构,例如X1NHX3,其中X1和X3是彼此形成共价键的烷基。这些包括4元单氮(氮杂环丁烷基)、5元单氮(吡咯烷基)或6元单氮(哌啶基)结构,以及双氮结构、取代的环烷基氨基结构,包括X1NX2X3其中X1和X3形成共价键并且X2是烷基。烷基氨基进一步由CH2CH2-NHR2结构例示,其中R2是乙基并且与第一碳形成共价键,以形成4-元环。
酰胺:结构-CH2-CONX1X2的基团,其中X1和X2各自独立地为H或有机基团,例如任选取代的烷基或任选取代的芳基。在一些实施方案中,酰胺具有结构-CH2-CONX1X2,其中X1和X2各自独立地为H、任选取代的烷基(例如,取代的烷基或未取代的烷基,如上文所定义的术语)、任选取代的烯基(例如,任选取代的C2-6烯基)、任选取代的炔基(例如,任选取代的C2-6炔基)、任选取代的环烷基(例如,任选取代的C3-6环烷基)、任选取代的杂环基环(例如,含有一个选自O、N和S的杂原子的任选取代的3-至6-元杂环基环)、任选取代的芳基(例如,任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基)、任选取代的-O-C1-6烷基(例如任选被1、2或3个取代基取代的-O-C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环、或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基)、酰基、OH、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H或-SO2(C1-6烷基)。
氨基:结构-N(RN)2的基团,其中每个RN独立地为H、取代的脂族、未取代的脂族、取代的苯基、未取代的苯基、-ORN1、-N(RN1)2或-SO2(RN2),其中每个RN1独立地为H、取代的脂族或未取代的脂族,并且RN2是-OH、未取代的脂族或取代的脂族;前提是只要一个RN是-ORN1、-N(RN1)2或-SO2(RN2),则另一个RN是H、取代的脂族、未取代的脂族、取代的苯基或未取代的苯基。
芳基:任何碳基芳族基团包括但不限于苯、萘和苯基。术语芳基还涵盖取代的芳基,其中一个或多个氢被一个或多个基团取代,所述基团包括但不限于烷基、炔基、烯基、芳基、卤化物、硝基、氨基、酯、醚、酮、醛、羟基、羧酸、氰基、酰氨基、卤代烷基、卤代烷氧基或烷氧基。术语芳基也涵盖杂芳基,其中一个或多个碳被杂原子替换。杂原子的实例包括但不限于氮、氧、硫和磷。取代的杂芳基也包括在术语芳基中。取代的苯基是被1、2、3、4或5个独立地选自-OR、-NO2、未取代的脂族和卤素的取代基取代的苯基,其中R是H或未取代的脂族。芳基是指任何单环或稠环双环或三环体系,其在整个环体系中在电子分布方面具有芳族性特征,例如苯基、萘基或菲。在一些实施方案中,环体系含有5 15个环成员原子或5-10个环成员原子。芳基可具有例如5至15个之间的碳(例如,C5-6、C5-7、C5-8、C5-9、C5-10、C5-11、C5-12、C5-13、C5-14或C5-15芳基)。
酰基:具有以下结构的基团:其中Rz是任选取代的烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂烷基、杂烯基、杂炔基、杂环烷基、杂环烯基、杂环炔基或杂芳基。
环烷基:由至少三个碳原子组成的非芳族碳基环。环烷基的实例包括但不限于环丙基、环丁基、环戊基和环己基。环烷基还包括取代的环烷基和杂环烷基(也称为“杂环基”基团),其中至少一个碳原子被杂原子如氮、硫或磷替换。其中一个或多个碳被氮替换的杂环烷基在本文中也称为环烷基氨基。该术语还包括取代的杂环烷基。用于本文的实施方案中的含氧杂环基包括但不限于环氧乙烷基、氧杂环丁烷基、四氢呋喃基和四氢吡喃基。
任选取代的:具有0、1或多个取代基例如0-25、0-20、0-10或0-5个取代基的基团(例如,烷基、烯基、炔基、环烷基或芳基)。取代基包括但不限于烷基、烯基、炔基、芳基、烷芳基、酰基、杂芳基、杂烷基、杂烯基、杂炔基、杂烷芳基、卤素、氧代、氰基、硝基、氨基、烷氨基、羟基、烷氧基、烷酰基、羰基、氨基甲酰基、胍基、脒基、脲基、上述任何基团或部分,以及上述任何基团或部分的杂合形式。取代基包括但不限于F、Cl、甲基、苯基、苄基、OR、NR2、SR、SOR、SO2R、OCOR、NRCOR、NRCONR2、NRCOOR、OCONR2、RCO、COOR、烷基-OOCR、SO3R、CONR2、SO2NR2、NRSO2NR2、CN、CF3、OCF3、R3Si和NO2,其中每个R独立地是H、烷基、烯基、芳基、杂烷基、杂烯基或杂芳基,并且其中相同或相邻原子上的两个任选的取代基可以连接形成含有3-8个成员的稠合的、任选取代的芳族或非芳族的、饱和或不饱和的环。
有效量,治疗有效量或药学上有效量:足以在用特定剂治疗的受试者中达到所需效果的一定量的该剂。理想地,剂的有效量是足以抑制或治疗疾病而不会在受试者中引起显著毒性的量。剂的有效量将取决于所治疗的受试者、痛苦的严重程度和药物组合物的施用方式。本领域技术人员根据本公开内容将理解确定足以在受试者中实现期望效果的本公开化合物的有效量的方法。
衍生物:衍生自或理论上可衍生自母体化合物的化合物或化合物的一部分。
出血:血液从血管中出血或流出。
缺氧:身体组织缺氧供应低于正常水平。
杂环:包含杂芳基和杂环烷基杂环的基团,可以是单环或多环。示例性杂环包括但不限于氮杂卓基、氮丙啶基、氮杂环丁二烯基、氮杂环丁烷基、二氮杂卓基、二噻二嗪基、二氧氮杂卓基(dioxazepinyl)、二氧戊环基(dioxolanyl)、二噻唑基、呋喃基、异噁唑基、异噻唑基、咪唑基、吗啉基、氧杂环丁烷基、噁二唑基、环氧乙烷基(oxiranyl)、噁嗪基、噁唑基、哌嗪基、吡嗪基、哒嗪基、嘧啶基、哌啶基(piperidyl)、哌啶基(piperidino)、吡啶基、吡喃基、吡唑基、吡咯基、吡咯烷基、噻三唑基(thiatriazolyl)、四唑基、噻二唑基、三唑基、噻唑基、噻吩基、四嗪基、噻二唑基、三嗪基、噻嗪基、硫代吡喃基、呋喃并异噁唑基(furoisoxazolyl)、咪唑并噻唑基、噻吩并异噻唑基(thienoisothiazolyl)、噻吩并噻唑基、咪唑并吡唑基、环戊吡唑基、吡咯并吡咯基、噻吩并噻吩基、噻二唑并嘧啶基、噻唑并噻嗪基、噻唑并嘧啶基、噻唑并吡啶基、噁唑并嘧啶基、噁唑并吡啶基、苯并噁唑基、苯并异噻唑基、苯并噻唑基、咪唑并吡嗪基、嘌呤基、吡唑并嘧啶基、咪唑并吡啶基、苯并咪唑基、吲唑基、苯并氧硫杂环戊烯基(benzoxathiolyl)、苯并二氧杂环戊基、苯并二硫杂环戊基、中氮茚基(indolizinyl)、二氢吲哚基、异吲哚啉基、呋喃并嘧啶基、呋喃并吡啶基、苯并呋喃基、异苯并呋喃基、噻吩并嘧啶基、噻吩并吡啶基、苯并噻吩基、环戊氧基吖嗪基、环戊呋喃基、苯并噁嗪基、苯并噻嗪基、喹唑啉基、萘啶基、喹啉基、异喹啉基、苯并吡喃基、吡啶并哒嗪基和吡啶并嘧啶基。该术语还涵盖了取代的杂环,包括上述所有种类的取代形式。
损伤:指对细胞、组织或身体的任何类型的物理损坏。在某些情况下,神经系统(例如,CNS或PNS)损伤导致脱髓鞘和/或脱髓鞘疾病。
缺血:血管现象,其中例如由一个或多个血管的收缩或阻塞引起对身体器官、组织或部分的血液供应减少。缺血有时是由血管收缩、血栓形成或栓塞引起的。由于供氧减少导致的细胞死亡,缺血可导致直接缺血性损伤、组织损坏。在某些情况下,缺血可导致脱髓鞘。
髓鞘:在某些神经纤维的轴突周围形成鞘(称为髓鞘)的脂质物质。髓鞘是一种电绝缘体,用于加速神经纤维中神经冲动的传导。“髓鞘形成(Myelination)”(也称“髓鞘形成(myelinization)”)是指在神经纤维周围发展或形成髓鞘。类似地,“髓鞘再生(remyelination)”(也称为“髓鞘再生(remyelinization)”)是指髓鞘的修复或重建,例如在损伤、暴露于毒性剂或炎症反应之后,或在脱髓鞘疾病的过程中。
药物组合物:含有药学上有效量的一种或多种本文所述的化合物或其药学上可接受的盐的组合物,其与药学上可接受的载体一起配制,所述组合物还可包括其它添加剂,并且经政府监管机构批准制造或销售作为治疗哺乳动物疾病治疗方案的一部分。可以配制药物组合物,例如,以单位剂型用于口服施用(例如,片剂、胶囊、囊片、囊形片或糖浆);用于局部施用(例如,如霜、凝胶、洗液或软膏);用于静脉内施用(例如,作为不含颗粒栓子的无菌溶液和适合静脉内使用的溶剂系统);或在本文所述的任何其它制剂中。用于选择和制备合适制剂的常规方法和成分描述于例如,Remington:The Science and Practice ofPharmacy,第21版,Gennaro,编,Lippencott Williams&Wilkins(2005)以及The UnitedStates Pharmacopeia:The National Formulary(USP 36 NF31),于2013年出版。
药学上可接受的载体:除所公开的化合物之外的任何成分,或其药学上可接受的盐(例如,一种能够悬浮或溶解活性化合物的载体),并且具有在患者体内无毒和无炎性的特性。赋形剂可包括,例如:抗粘附剂、抗氧化剂、粘合剂、包衣剂、压缩助剂、崩解剂、染料(颜色)、软化剂、乳化剂、填充剂(稀释剂)、成膜剂或包衣、调味剂、香味剂、助流剂(流动增强剂)、润滑剂、防腐剂、印刷油墨、吸附剂、助悬剂或分散剂、甜味剂或水合水。示例性赋形剂包括但不限于:丁基化羟基甲苯(BHT)、碳酸钙、磷酸钙(二元酸)、硬脂酸钙、交联羧甲基纤维素、交联聚乙烯吡咯烷酮、柠檬酸、交聚维酮、半胱氨酸、乙基纤维素、明胶、羟丙基纤维素、羟丙基甲基纤维素、乳糖、硬脂酸镁、麦芽糖醇、甘露醇、蛋氨酸、甲基纤维素、对羟基苯甲酸甲酯、微晶纤维素、聚乙二醇、聚乙烯吡咯烷酮、聚维酮、预凝胶淀粉、对羟基苯甲酸丙酯、棕榈酸视黄酯、虫胶、二氧化硅、羧甲基纤维素钠、柠檬酸钠、羧基乙酸淀粉钠、山梨糖醇、淀粉(玉米)、硬脂酸、硬脂酸、蔗糖、滑石粉、二氧化钛、维生素A、维生素E、维生素C和木糖醇。
药学上可接受的盐:通过常规方法制备的盐。这些包括无机和有机酸的碱性盐,例如但不限于盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、苹果酸、乙酸、草酸、酒石酸、柠檬酸、乳酸、富马酸、琥珀酸、马来酸、水杨酸、苯甲酸、苯乙酸和扁桃酸。本发明公开的化合物的“药学上可接受的盐”还包括由阳离子形成的那些,所述阳离子例如但不限于钠、钾、铝、钙、锂、镁、锌;和由碱形成的那些,所述碱例如氨、乙二胺、N-甲基-谷氨酰胺、赖氨酸、精氨酸、鸟氨酸、胆碱,N,N'-二苄基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙胺、二乙胺、哌嗪、三(羟甲基)氨基甲烷和四甲基氢氧化铵。这些盐可以通过标准方法制备,例如通过游离酸与合适的有机或无机碱反应。本说明书中列举的任何化合物也可以以其药学上可接受的盐替代施用。药学上可接受的盐也包括所公开化合物的游离酸、碱和两性离子形式。可以在Stahl和Wermuth,编,Handbook of Pharmaceutical Salts;Properties,Selectionand Use,Wiley VCH(2008)中发现示例性药学上可接受的盐的描述。当本文公开的化合物包括酸性基团如羧基时,则用于羧基的合适的药学上可接受的阳离子对是本领域技术人员公知的,包括但不限于碱金属、碱土金属、铵和季铵阳离子。这些盐是本领域技术人员已知的。类似地,当本文公开的化合物包括碱性基团如氨基时,则碱性基团的合适的药学上可接受的阴离子对同样是众所周知的,并且包括卤离子、氢氧根、高卤酸根、石盐根、次卤酸根、硫酸根、亚硫酸根、磷酸根、亚磷酸根、硝酸根、亚硝酸根和本领域技术人员已知的其它物质。有关药理学上可接受的盐的其它实例,请参见Berge等,J.Pharm.Sci.66,1(1977)。
苏比替罗:合成的二芳基甲烷化合物,临床上被研究作为高胆固醇血症的潜在治疗剂(参见美国专利号5,883,294,其通过引用并入本文)。苏比替罗是2-[4-[[4-羟基-3-(1-甲基乙基)苯基]甲基]3,5-二甲基苯氧基乙酸。在文献和监管文件中找到的苏比替罗的其它名称包括QRX-431和GC-1。
受试者:动物(例如,哺乳动物,例如人)。根据本文描述的方法待治疗的受试者可以是已被诊断患有神经退行性疾病的受试者,所述神经退行性疾病涉及脱髓鞘、髓鞘形成不足或髓鞘发育不足,例如,被诊断患有多发性硬化或脑瘫的受试者,或处于发展病症的风险的受试者。可以通过本领域已知的任何方法或技术进行诊断。本领域技术人员将理解,根据本公开内容待治疗的受试者可能已经过标准测试或者可能已被鉴定,未经检查,由于存在与疾病或病症相关的一种或多种风险因素而处于风险中。
治疗:改善疾病或病理状态的体征或症状的干预。如本文所用,关于疾病、病理状态或症状的术语“治疗(treatment)”、“治疗(treat)”和“治疗(treating)”也指治疗的任何可观察的有益效果。有益效果可以通过例如易感受试者中疾病的临床症状的延迟发作、疾病的一些或全部临床症状的严重程度降低、疾病进展缓慢、疾病复发次数减少、受试者整体健康或安康的改善、或对特定疾病特定的本领域公知的其它参数来证明。预防性治疗是对没有表现出疾病迹象或仅表现出早期迹象的受试者施用的治疗,目的是降低发生病理学的风险。治疗性治疗是在疾病的迹象和症状发展后施用于受试者的治疗。
神经退行性疾病:
急性播散性脑脊髓炎(ADEM):免疫介导的中枢神经系统的脱髓鞘疾病。ADEM通常在病毒感染后发生,但也可能在接种疫苗后或细菌或寄生虫感染后出现。在一些情况下,ADEM会自发性发展。该疾病涉及自身免疫性脱髓鞘,类似于多发性硬化症,因此被认为是多发性硬化症边缘疾病。ADEM在脑和脊髓中,特别是在白质中产生多种炎性病变。病变通常见于大脑半球、小脑、脑干和脊髓的皮质下和中央白质和皮质灰白色交界处,但也可能涉及脑室周围白质和皮质、丘脑和基底神经节的灰质。当患者患有多于一种脱髓鞘发作时,该疾病被称为复发性播散性脑脊髓炎或多相播散性脑脊髓炎。
急性出血性脑白质炎(AHL或AHLE):一种超急性且常常致命的ADEM形式。这种疾病也称为急性坏死性脑病(ANE)、急性出血性脑脊髓炎(AHEM)、急性坏死性出血性脑白质炎(ANHLE)、韦斯顿-赫斯特综合征(Weston-Hurst syndrome)或赫斯特氏病(Hurst'sdisease)。
成人雷夫叙姆病:一种常染色体隐性神经系统疾病,与细胞和组织中植烷酸的过度积累有关。成人雷夫叙姆病分为成人雷夫叙姆病亚型1和成人雷夫叙姆病亚型2。患有雷夫叙姆病的个体表现出神经损伤、小脑变性和周围神经病变。虽然发生停滞或缓解期,但发病最常见于儿童/青春期,并伴有进行性进程。症状还包括共济失调、鳞状皮肤(鱼鳞病)、听力困难和眼睛问题,包括白内障和夜盲症。
亚历山大病:一种非常罕见的先天性脱髓鞘疾病。该疾病主要影响婴儿和儿童,导致发育迟缓和身体特征的变化。亚历山大病是一种脑白质营养不良。
阿尔茨海默氏病:最常见形式的痴呆症。阿尔茨海默氏病的症状包括记忆力减退、精神错乱、易怒、攻击性、情绪波动和语言障碍。该疾病的特征在于大脑皮质和某些皮质下区域中神经元和突触的丧失。损失导致受影响区域的严重萎缩,包括颞叶的退化,以及额叶皮层和扣带回的部分。通过显微镜观察患有该疾病的人的脑中可见淀粉样斑块和神经原纤维缠结。阿尔茨海默氏病的病因不明;然而,存在一些假设,包括该疾病是由脑中年龄相关的髓鞘分崩解引起的。
巴洛同心硬化症:类似于标准多发性硬化症的脱髓鞘疾病,但具有脱髓鞘组织形成同心层的特殊性。患有该疾病的患者可以存活和/或具有自发缓解。通常,临床过程是原发性进展性的,但已报道复发缓解过程。
卡纳万病:一种常染色体隐性退行性病症,可导致脑中神经细胞的进行性损伤。卡纳万病是一种脑白质营养不良,是婴儿期最常见的退行性脑病之一。这种疾病也被称为Canavan-Van Bogaert-Bertrand病、天冬氨酸酰基转移酶缺乏症和氨基酰化酶2缺乏症。
脑桥中央髓鞘溶解症(CPM):由脑干(更准确地说是在称为脑桥的区域)中神经细胞的髓鞘严重损伤引起的神经系统疾病。最常见的原因是低血钠水平的快速校正(低钠血症)。在这种病症中经常观察到的症状是突然的下肢轻瘫或四肢轻瘫、吞咽困难、构音障碍、复视和意识丧失。患者可能会经历锁定综合症,其中认知功能完好无损,但除了眨眼之外,所有肌肉都会瘫痪。
脑瘫:用于导致身体残疾的一组永久性非进行性运动障碍的术语。脑瘫是由发育中的脑的运动控制中心的损伤引起的,并且可以在怀孕期间、分娩期间或出生后直至大约3岁时发生。脑瘫患者表现出髓鞘的损伤。
脑腱性黄瘤病:一种遗传性病症,与脑和其它组织中一种胆固醇(胆甾烷醇)的沉积有关,并且血浆中胆固醇水平升高但总胆固醇水平正常。其特征在于青春期后开始的进行性小脑性共济失调和青少年白内障、青少年或婴儿期慢性腹泻发作、儿童神经功能缺损和腱或结节性黄瘤。这种病症是黄瘤病的常染色体隐性形式。它属于一组称为脑白质营养不良的遗传性病症。
慢性炎性脱髓鞘性多发性神经病(CIDP):一种获得性免疫介导的周围神经系统的炎性病症。这种病症有时被称为慢性复发性多发性神经病(CRP)或慢性炎性脱髓鞘性多神经根神经病(因为它涉及神经根)。CIDP与格林-巴利综合征密切相关,被认为是该急性疾病的慢性对应病。其症状也与进行性炎性神经病相似。CIDP的不对称变型被称为Lewis-Sumner综合征。该疾病的病理标志是髓鞘的丧失。
脱髓鞘疾病:包括神经系统的任何疾病,其中髓鞘被损坏或丢失,或其中髓鞘的生长或发育受损。脱髓鞘抑制受影响神经中信号的传导,导致感觉、运动、认知或涉及神经的其它功能受损。脱髓鞘疾病有许多不同的原因,可以是遗传性的或获得性的。在一些情况下,脱髓鞘疾病由感染因子、自身免疫反应、毒性剂或创伤性损伤引起。在其它情况下,脱髓鞘疾病的原因是未知的(“特发性”)或因多种因素的组合发展而来。
德维克氏综合征:一种自身免疫性炎性病症,其中一个人的免疫系统攻击视神经和脊髓,导致视神经炎症(视神经炎)和脊髓炎症(脊髓炎)。脊髓损伤导致腿或手臂的不同程度的虚弱或麻痹、感觉丧失和/或膀胱和肠功能障碍。虽然炎症也可能影响脑,但病变与MS中观察到的不同。德维克氏综合征与MS类似,因为身体的免疫系统攻击神经细胞周围的髓鞘。与标准MS不同,攻击不被认为是由免疫系统的T细胞介导,而是由称为NMO-IgG的抗体介导。这些抗体靶向星形胶质细胞的细胞膜中称为水通道蛋白4的蛋白质,所述蛋白质作为水通过细胞膜转运的通道。德维克氏综合征也称为德维克氏综合征或视神经脊髓炎(NMO)。
弥漫性髓鞘硬化症:一种罕见的神经退行性疾病,临床上呈现为假性肿瘤样脱髓鞘病变。它通常始于童年,影响5至14岁的儿童;但是,成年人中的病例也是可能的。这种疾病被认为是MS的边缘形式之一,有时也被称为谢耳德氏病(Schilder's disease)。
脑脊髓炎:脑和脊髓的炎症。
实验性自身免疫性脑脊髓炎(EAE):MS的动物模型(例如,参见Gold等,Brain 129,1953-1971(2006)。EAE动物表现出在整个中枢神经系统中传播的组织损伤的特征性斑块。斑块显示淋巴细胞、浆细胞和巨噬细胞对神经组织的浸润,其导致脑和脊髓中神经细胞轴突周围的髓鞘破坏。在一些情况下,通过用髓鞘或髓鞘的各种组分免疫易感动物,例如小鼠、大鼠、豚鼠或非人灵长类动物来诱导EAE。例如,EAE可以通过用髓鞘的组分免疫来诱导,所述组分例如髓鞘碱性蛋白、蛋白脂质蛋白或髓鞘少突胶质细胞糖蛋白(MOG)。EAE是一种有用且广泛接受的模型,用于研究自身免疫性CNS组织损伤的机制以及用于测试MS的潜在疗法。EAE还包括“被动EAE”,其在供体动物中以相同方式诱导,但涉及将从供体动物的淋巴结收获的活化T细胞转移至首次接受实验的受体动物。
格林-巴利综合征:急性多发性神经病,一种影响周围神经系统的病症。上升的瘫痪、从脚和手开始的虚弱和向躯干移动是最典型的症状,并且一些亚型引起感觉或疼痛的改变,以及自主神经系统的功能障碍。它可能导致危及生命的并发症,特别是如果呼吸肌受到影响或如果涉及自主神经系统。这种疾病通常由感染引发。急性炎性脱髓鞘性多发性神经病(AIDP)是该疾病最常见的亚型。其它格林-巴利综合征亚型包括Miller Fischer综合征、急性运动轴索性神经病(中国麻痹综合征)、急性运动感觉轴索性神经病、急性全自主神经性神经病和Bickerstaff脑干脑炎。
特发性炎性脱髓鞘疾病(IIDD):广泛的中枢神经系统病症,通常可以根据临床、影像学、实验室和病理结果进行区分。特发性炎性脱髓鞘疾病有时被称为多发性硬化症的边缘形式。IIDD通常指多种硬化变异疾病的集合,包括但不限于视神经脊髓MS、德维克氏病、ADEM、急性出血性脑白质炎、巴洛同心硬化症、希尔德病、马尔堡多发性硬化、肿瘤性多发性硬化和孤立性硬化(solitary sclerosis)。
婴儿雷夫叙姆病:与非常长链脂肪酸和支链脂肪酸(例如植烷酸)的分解代谢和纤溶酶原生物合成缺陷相关的过氧化物酶体生物发生病症。婴儿雷夫叙姆病是一种罕见的常染色体隐性先天性病症,也是属于过氧化物酶体生物发生病症的Zellweger谱的三种过氧化物酶体生物发生病症之一。
克拉伯病:一种罕见的、通常致命的退行性病症,其影响神经系统的髓鞘。它是鞘脂病(sphingolipidosis)的一种形式,因为它涉及鞘脂的代谢功能障碍。这种病症以常染色体隐性模式遗传。克拉伯病也称为球形细胞脑白质营养不良或半乳糖神经酰胺脂质沉积症。
莱伯遗传性视神经病变:线粒体遗传(从母亲传给后代)的视网膜神经节细胞(RGC)及其轴突的变性,导致急性或亚急性中央视力丧失;这主要影响年轻的成年男性。
脑白质营养不良:指一组影响髓鞘的生长或发育的疾病。
脑白质病:影响脑的白色物质的一组疾病;可以具体指几种疾病,包括例如“具有消失的白质的脑白质病”和“有毒的脑白质病”。脑白质病是类脑白质营养不良的疾病。
马尔堡多发性硬化症:中枢神经系统具有多个脱髓鞘病变的病症,其具有标准多发性硬化症的非典型特征。该疾病是多发性硬化的边缘形式,也称为肿瘤性多发性硬化或暴发性多发性硬化。它被称为肿瘤性(tumefactive),因为病变是“肿瘤样的”并且它们在临床上、放射学上和有时在病理学上与肿瘤类似。
Marchiafava-Bignami病:一种进行性神经系统疾病,其特征为胼胝体脱髓鞘和坏死以及随后的萎缩。它通常与长期酗酒有关。
异染性脑白质营养不良(MLD):溶酶体贮积病,通常列于脑白质营养不良家族,以及鞘脂沉积病类,因为它影响鞘脂的代谢。MLD直接由芳基硫酸酯酶A缺乏引起。
多灶性运动神经病变(MMN):四肢肌肉逐渐衰弱的逐渐恶化的病症。这种病症,一种运动神经病变综合征,有时被误认为是肌萎缩侧索硬化症(ALS),因为临床表现相似,特别是如果存在肌肉颤抖。MMN通常是不对称的,被认为是自身免疫性的。
多发性硬化症(MS):缓慢进展的CNS疾病,其特征是在脑和脊髓中散布的脱髓鞘斑块,导致多种多样的神经症状和体征,通常伴有缓解和恶化。MS的病因尚不清楚,但怀疑存在免疫异常。家庭发病率增加表明遗传易感性,女性比男性更容易受到影响。MS的症状包括虚弱、缺乏协调、感觉异常、语言障碍和视力障碍,最常见的是复视。更具体的体征和症状取决于病变的位置以及炎症和硬化过程的严重性和破坏性。复发缓解型多发性硬化症(RRMS)是MS的临床过程,其特征在于明确定义的急性发作,具有完全或部分恢复并且在发作之间没有疾病进展。继发进展型多发性硬化症(SPMS)是MS的临床过程,最初是复发缓解,然后以可变的速率变为进行性的,可能偶尔复发和轻微缓解。原发性进行性多发性硬化症(PPMS)最初呈进行性形式。临床孤立综合征是第一次神经系统发作,其由CNS中一个或多个部位的炎症/脱髓鞘引起。进行性复发性多发性硬化症(PRMS)是一种罕见的MS形式(约5%),其特征是发病时疾病状态稳定恶化,急性复发但无缓解。
神经退行性疾病:指任何以神经系统进行性恶化为特征的疾病类型。
神经病:周围神经系统功能紊乱或病理改变。轴突神经病是指破坏轴突正常功能的病症。
副蛋白质脱髓鞘多发性神经病:一种周围神经病类型,其特征在于针对髓鞘相关糖蛋白(MAG)的自身抗体。抗MAG抗体抑制髓鞘的产生,从而导致神经病变。
Pelizaeus-Merzbacher病(PMD):一种罕见的中枢神经系统病症,其中协调、运动能力和智力功能被推迟到不同程度。该疾病是一组统称为脑白质营养不良的遗传性病症中的一种。
腓骨肌萎缩症(PMA):遗传性和临床异质性的外周神经系统遗传性病症组,其特征在于肌肉组织和身体各部位的触觉的进行性丧失。这种疾病也被称为Charcot-Marie-Tooth病(CMT)、Charcot-Marie-Tooth神经病和遗传性运动和感觉神经病(HMSN)。
进行性多灶性脑白质病(PML):一种罕见且通常致命的病毒性疾病,其特征在于多个部位的脑白质的进行性损伤或炎症。PML几乎全部发生在患有严重免疫缺陷的人群中。PML的病因是一种称为JC病毒的多瘤病毒。这种病毒很普遍,86%的普通人群都有抗体,但它通常是潜伏的,只有在免疫系统被严重削弱时才会引发疾病。PML是一种脱髓鞘疾病,其中覆盖神经细胞轴突的髓鞘逐渐被破坏,从而损害神经冲动的传递。这种疾病可能发生在具有严重免疫缺陷的受试者(例如人)中,例如使用免疫抑制药物的移植患者或接受某些药物治疗的患者。例如,PML与利妥昔单抗(用于治疗多发性硬化症的说明书外的用途)的施用相关。它会影响白质,白质主要由来自大脑最外部分(皮层)的轴突组成。症状包括虚弱或瘫痪、视力丧失、言语受损和认知能力下降。
横贯性脊髓炎:由脊髓灰质和白质的炎症过程引起的神经病症,导致轴突脱髓鞘。脱髓鞘在感染或接种疫苗后或由于多发性硬化症而特发性地出现。症状包括四肢无力和麻木以及运动、感觉和括约肌缺陷。在疾病发作时,一些患者可能会出现严重的背痛。
热带痉挛性下肢瘫痪(TSP):人T淋巴细胞病毒感染脊髓,导致下肢瘫痪、腿部无力。TSP也称为HTLV相关的脊髓病或慢性进行性脊髓病。顾名思义,这种疾病在热带地区(包括加勒比海和非洲)最为常见。
范德纳氏病:一种形式的遗传性CNS脱髓鞘疾病。这种疾病是一种脑白质营养不良,也被称为伴有皮层下囊肿的巨脑性脑白质病(MLC)。
X连锁肾上腺脑白质营养不良(X-ALD、ALD或X连锁ALD):一种罕见的、遗传性代谢病症,导致进行性脑损伤、精神恶化、肾上腺衰竭、肌肉痉挛、失明和最终死亡。ALD是一组称为脑白质营养不良的遗传性疾病中的一种疾病。肾上腺脑白质营养不良逐渐损害髓鞘。X连锁ALD男性患者可分为7种表型:儿童大脑(进行性神经退行性衰退导致植物人状态)、青春期(与儿童期脑形态相似但进展缓慢)、肾上腺神经病变(进行性神经病变、下肢瘫痪、可进展至大脑受累)、成人脑(痴呆、与儿童大脑形态相似的进展)、橄榄桥脑小脑(olivo-ponto-cerebellar)(脑和脑干受累)、艾迪生病(Addison disease)(肾上腺皮质功能不全)、无症状(无临床表现、亚临床肾上腺皮质功能不全或AMN表型)。X连锁ALD女性患者可分为5种表型:无症状(无神经或肾上腺受累)、轻度脊髓病、中度至重度脊髓病(类似于男性AMN表型)、脑(进行性痴呆和衰退)和肾上腺(原发性肾上腺功能不全)。X连锁ALD患者可能在其一生中从一种表型发展到另一种表型。ALD也称为Addison-Schilder病或Siemerling-Creutzfeldt病。
Zellweger综合症:一种罕见的先天性病症,其特征在于个体细胞中功能性过氧化物酶体的减少或缺失。该疾病被归类为脑白质营养不良,并且是属于过氧化物酶体生物发生病症的Zellweger谱的三种过氧化物酶体生物发生病症之一。
本发明的酰胺化合物
全身施用的苏比替罗主要分布在肝脏。一些先前的研究有间接证据表明苏比替罗分布到CNS(Takahashi N等,Biol Pharm Bull 37,1103-1108(2014);Trost S等,Endocrinology 141,3057-3064(2000),Bernal J,Nat Clin Pract Endrocrinol Metab3,249-259(2007);Oppenheimer JH和Schwartz HL,Endocr Rev 18,462-475(1997);以及Bernal J,J Endocrinol Invest 25,268-288(2002);所有这些都通过引用并入本文)。
通常,在0.3-1.0范围内的脑/血清比率对于CNS药物通常是优选的(Doran A等,Drug Metab Dispos 33,165-174(2005)和Reichel A,Curr Drug Metab 7,183-203(2006);这两篇文献均通过引用并入本文)。如通过脑/血清比率测量的,本发明的化合物可以表现出改善的血脑屏障(BBB)渗透。在非限制性实例中,本发明化合物可提供至少0.3(例如,至少0.4或至少0.5)的脑/血清比率。这些化合物在外周组织中可表现出降低的GC-1样活性或没有GC-1样活性。不希望受理论束缚,本发明的化合物可以通过驻留的水解酶在CNS中未掩蔽以产生GC-1,从而产生高的CNS内GC-1浓度(图1)。GC-1可以在CNS中被离子捕获,从而产生允许CNS中的治疗效果(例如,髓鞘再生)。本发明化合物的较高的脑/血清比率可以有利地产生减少的外周作用或没有外周作用。
通过引用并入本文的美国非临时专利申请15/048,672描述了酯化合物,其在水解时可以产生苏比替罗(GC-1)。观察到包含2-氨基乙醇酯基序的酯化合物有效地穿过血脑屏障。在某些生理条件下,这些化合物可以重排成相应的酰胺产物(方案1)。对酰胺产物的分析表明,升高的脑GC-1水平可归因于该酰胺转化产物而不是母体酯化合物。本发明的化合物是在此开发和公开的。
方案1-苏比替罗氨基乙醇酯在体内转化为酰胺。
相对于酯,本发明化合物可显示出增加的化学和生物稳定性。通过水解可以证明它们不易发生自发水解(关于水解速率的讨论,参见Mabey W&Mill T,J Phys Chem RefData 7,383-415(1978))。另外,其它化合物可能受到体内酶大家族的作用(Fukami T和Yokoi T,Drug Metab Pharmacokinet 27,466-477(2012);Casey Laizure S等,Pharmacotherapy 33,210-222(2013);所有这些都通过引用并入本文),其可导致过早水解。本发明化合物的水解可以对某些脑驻留的酰胺酶具有特异性。不希望受理论束缚,非肽酰胺的酶促裂解在范围上可能比其它化合物更受限制。
公开了式I的化合物:
或其药学上可接受的盐,其中R1是酰胺。
还公开了式II的化合物:
或其药学上可接受的盐,其中R2是烷基氨基或氨基。
还公开了式III的化合物:
或其药学上可接受的盐,其中R3和R4各自为本文详细描述的那样。
还公开了式IV的化合物:
或其药学上可接受的盐,其中R3如本文详细描述的那样。
此外,本公开包括药物组合物,其包含药学有效量的本文所述化合物或其药学上可接受的盐,和一种或多种药学上可接受的载体。
治疗方法
应理解,本文所述的每种化合物或其药学上可接受的盐可用于治疗本文所述的每种疾患或疾病的方法中。每种治疗方法包括向有需要的受试者,例如有需要的人,施用药学上有效量的如本文所述的化合物或其药学上可接受的盐。
例如,提供了治疗受试者(例如人受试者)的神经退行性疾病的方法,所述方法包括向所述受试者施用药学上有效量的本文的化合物或其药学上可接受的盐。
还提供了治疗受试者(例如人受试者)的脱髓鞘疾病的方法,所述方法包括向所述受试者施用药学上有效量的本文的化合物或其药学上可接受的盐。
还提供了治疗受试者(例如人受试者)的X-连锁的肾上腺脑白质营养不良的方法,所述方法包括向所述受试者施用药学上有效量的本文的化合物或其药学上可接受的盐。
还提供了治疗受试者(例如人受试者)的多发性硬化的方法,所述方法包括向所述受试者施用药学上有效量的本文的化合物或其药学上可接受的盐。
还提供了治疗受试者(例如人受试者)的阿尔茨海默氏病的方法,所述方法包括向所述受试者施用药学上有效量的本文的化合物或其药学上可接受的盐。
还提供了治疗选自由以下组成的组的疾病或病症的方法:急性播散性脑脊髓炎(ADEM)、急性出血性脑白质炎(AHL或AHLE)、成人雷夫叙姆病、婴儿雷夫叙姆病、亚历山大病、阿尔茨海默氏病、巴洛同心硬化症、卡纳万病、脑桥中央髓鞘溶解症(CPM)、脑瘫、脑腱性黄瘤病、慢性炎性脱髓鞘性多发性神经病(CIDP)、德维克氏综合征、弥漫性髓鞘硬化症、脑脊髓炎、格林-巴利综合征、特发性炎性脱髓鞘病(IIDD)、克拉伯病、莱伯遗传性视神经病变、脑白质营养不良、马尔堡多发性硬化症、Marchiafava-Bignami病、异染性脑白质营养不良(MLD)、多灶性运动神经病变(MMN)、多发性硬化症(MS)、副蛋白质脱髓鞘多发性神经病、Pelizaeus-Merzbacher病(PMD)、进行性多灶性脑白质病(PML)、热带痉挛性下肢瘫痪(TSP)、X连锁肾上腺脑白质营养不良(X-ALD、ALD或X-连锁的ALD)和Zellweger综合征。所述方法包括向有需要的受试者(例如人受试者)施用药学有效量的本文所述的化合物或其药学上可接受的盐。
还应理解,本文所述的每种化合物或其药学上可接受的盐可用于制备可用于治疗本文所述的每种疾患或疾病的药物。每种治疗方法包括向有需要的受试者,例如有需要的人,施用药学上有效量的如本文所述的化合物或其药学上可接受的盐。
例如,提供了本文所述化合物或其药学上可接受的盐在制备用于治疗受试者(例如人受试者)的神经退行性疾病的药物中的用途。
例如,提供了本文所述的化合物或其药学上可接受的盐在制备用于治疗受试者(例如人受试者)的脱髓鞘疾病的药物中的用途。
例如,提供了本文所述的化合物或其药学上可接受的盐在制备用于治疗受试者(例如人受试者)的肾上腺脑白质营养不良的药物中的用途。
例如,提供了本文所述的化合物或其药学上可接受的盐在制备用于治疗受试者(例如人受试者)的多发性硬化症的药物中的用途。
例如,提供了本文所述的化合物或其药学上可接受的盐在制备用于治疗受试者(例如人受试者)的阿尔茨海默氏病的药物中的用途。
还提供了如本文所述的化合物或其药学上可接受的盐在制备用于治疗受试者(例如人受试者)的疾病或病症的药物中的用途,所述疾病或病症选自由以下组成的组:急性播散性脑脊髓炎(ADEM)、急性出血性脑白质炎(AHL或AHLE)、成人雷夫叙姆病、婴儿雷夫叙姆病、亚历山大病、阿尔茨海默氏病、巴洛同心硬化症、卡纳万病、脑桥中央髓鞘溶解症(CPM)、脑瘫、脑腱性黄瘤病、慢性炎性脱髓鞘性多发性神经病(CIDP)、德维克氏综合征、弥漫性髓鞘硬化症、脑脊髓炎、格林-巴利综合征、特发性炎性脱髓鞘疾病(IIDD)、克拉伯病、莱伯遗传性视神经病变、脑白质营养不良、马尔堡多发性硬化症、Marchiafava-Bignami病、异染色症脑白质营养不良(MLD)、多灶性运动神经病变(MMN)、多发性硬化症(MS)、副蛋白质脱髓鞘多发性神经病、Pelizaeus-Merzbacher病(PMD)、进行性多灶性脑白质病(PML)、热带痉挛性下肢瘫痪(TSP)、X连锁肾上腺脑白质营养不良(X-ALD、ALD或X-连锁的ALD)和Zellweger综合征。
实施例
以下实施例仅用于说明。鉴于本公开内容,本领域技术人员将认识到,这些实施例的变化和所公开发明的其它实施例是可能的,无需过多的实验。
实施例1-动物研究
实验方案符合美国国立卫生研究院实验动物护理和使用指南,并经俄勒冈健康与科学大学机构动物护理和使用委员会批准。野生型雄性C57Bl/6小鼠,8-10周龄,饲养在气候控制室内,12小时光照-黑暗循环,随意获取食物和水。对于GC-1浓度的体内单一时间点分析,用3.05μmol/kg的苏比替罗和前药腹膜内(i.p.)注射小鼠一次。1小时后对三只小鼠进行安乐死,收获组织和血液。立即冷冻组织并将血液保持在冰上至少30分钟,然后以7,500×G离心15分钟。收集血清(100μL)并与组织一起储存在-80℃直至处理样品。血清处理:将血清样品温热至室温,向其中加入10μL 2.99μM内标(d6-苏比替罗)。加入乙腈(500μL)并将样品涡旋20秒。然后将样品在4℃下以10,000×G离心15分钟。接下来,将90%的上清液转移到玻璃试管中,并使用speedvac在45℃下浓缩1.5小时。然后将干燥的样品溶解在400μL50:50的乙腈:H2O中并涡旋20秒。将得到的混合物转移到Eppendorf中,并以10,000×G离心15分钟。用0.22μM离心过滤器过滤上清液并进行LC-MS/MS分析以量化游离的苏比替罗的数量。用来自8-10周龄小鼠的100μL血清制备标准曲线,所述小鼠仅接受载体注射。除了过滤后将样品分成6个小瓶之外,进行完全相同的处理。向6个小瓶中的5个小瓶中添加苏比替罗以使基质中的最终浓度为(0.1pg/μL、1pg/μL、10pg/μL、100pg/μL和1000pg/μL)。
脑处理:将脑样品温热至室温并转移至具有GoldSpec 1/8铬钢球(AppliedIndustrial Technologies)的均化器管。将所得管称重,然后加入1mL H2O,然后加入10μL2.99μM内标(d6-苏比替罗)。将管用Bead均化30秒,然后转移到含有3mL乙腈的Falcon管中。使用乙腈(1mL)洗涤均化器管,并将溶液转移回Falcon管。除了使用speedvac在45℃下将样品在玻璃管中浓缩4小时之外,然后使用相同的方法处理样品用于血清处理。然后使用血清处理方法处理样品用于LC-MS/MS分析。
结果在表1中示出。
表1
实施例2-一般化学
1H NMR在Bruker上进行。将所有1H NMR校准至NMR溶剂参比峰(DMSO-d6、氯仿-d、甲醇-d4)。具有电喷雾电离的高分辨率质谱(HRMS)由波特兰州立大学的生物分析MS设施进行。在通过小柱干燥剂的氩气下进行惰性气氛反应并在火焰-干燥的rbfs中进行。从Seca溶剂系统获得无水四氢呋喃(THF)、二氯甲烷(DCM)和二甲基甲酰胺(DMF)。使用的所有其它溶剂均购自Sigma-Aldrich或Fisher。先前已经描述了苏比替罗(GC-1)的合成(Chiellini G等,Bioorg Med Chem Lett 10,2607-2611(2000)和Placzek AT等,Tetrahedron 71,5946-5951(2015);两者都是通过引用并入本文)。先前公开了O-苄基GC-1(2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸)的合成。所有其它试剂均购自Fisher、Sigma或TCI并按原样使用。通过HPLC确定最终化合物的纯度分析>95%。在具有Grace Alltima C18,5μm柱(4.6×250mm)的梯度(溶剂A:95:5水:MeCN,0.2%Et3NH3PO4,pH2.5;溶剂B:MeCN)的Varian ProStar HPLC上进行分析型HPLC分析,B在20分钟内为40%至100%,流速为1mL/min。在Varian Dynamax Microscrob 100-5μM C18,21.4×250mm(溶剂A:水+0.1%甲酸;溶剂B:MeCN+0.1%甲酸)上进行制备型HPLC,在20分钟内使用B梯度为20-100%,流速为25mL/min。
实施例3-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-羟基乙基)乙酰胺(化合物1)
将2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,130mg,0.31mmol,1当量)在DCM(2mL)中的搅拌溶液在0℃用草酰氯(110μL,1.23mmol,4当量)处理。加入DMF(1滴)并将反应物搅拌3小时,同时升温至室温。减压除去溶剂,粗制中间体用DCM(5mL)处理,随后减压除去。将粗制中间体用1.5mL DCM处理,然后滴加乙醇胺(114mg,1.87mmol,6当量)。将反应在室温下搅拌1小时。通过快速色谱法(25-100%EtOAc的己烷溶液)纯化反应混合物,得到为白色固体的中间产物(48mg,0.1mmol,33%)。在氩气下,用1:1的MeOH:EtOAc(1mL)处理苄基保护的中间体(48mg,0.104mmol,1当量)。将碳钯(10重量%,22mg)加入到反应中,并逐滴加入三乙基硅烷(132μL,0.83mmol,8当量)。将反应搅拌过夜。加入另外等份的三乙基硅烷(50μL,0.31mmol,3当量)并将反应物搅拌1小时。将反应混合物倒在硅藻土塞上并用MeOH洗涤。通过快速色谱法(1-10%MeOH的DCM溶液)纯化浓缩的反应溶液,得到为白色固体的产物(29mg,0.076mmol,73%)。1H NMR(400MHz,氯仿-d)δ7.11(b,1H),6.93(d,J=2Hz,1H),6.64-6.55(m,4H),5.36(b,1H),4.52(s,2H),3.91(s,2H),3.79(t,J=4.8Hz,2H),3.55(q,J=5.5Hz,2H),3.19(七重峰,J=6.9,1H),2.22(s,6H),1.25(d,J=6.8Hz,6H)。HRMS(ESI)m/z[M+H+]C22H30NO4+需要372.2169,实测值372.2182。
实施例4-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(1-羟基丙烷-2-基)乙酰胺(化合物2)
将2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,87mg,0.207mmol,1当量)在DCM(1.3mL)中的搅拌溶液在0℃用草酰氯(73μL,0.83mmol,4当量)处理。加入DMF(1滴)并将反应物搅拌3小时,同时升温至室温。减压除去溶剂,粗制中间体用DCM(5mL)处理,随后减压除去。将粗制中间体用1.5mL DCM处理,然后滴加(+/-)-丙氨醇(93mg,1.24mmol,6当量)。将反应在室温下搅拌1小时。通过快速色谱法(25-100%EtOAc的己烷溶液)纯化反应混合物,得到为白色固体的中间产物(48mg,0.1mmol,48%)。在氩气下,用1:1MeOH:EtOAc(1mL)处理苄基保护的中间体(40mg,0.085mmol,1当量)。将碳钯(10重量%,22mg)加入到反应中,并逐滴加入三乙基硅烷(108μL,0.68mmol,8当量)。将反应搅拌过夜。加入另外等份的三乙基硅烷(50μL,0.31mmol,3.7当量)并将反应物搅拌1小时。将反应混合物倒在硅藻土塞上并用MeOH洗涤。通过快速色谱法(1-10%MeOH的DCM溶液)纯化浓缩的反应溶液,得到为白色固体的产物(21mg,0.055mmol,64%)。1H NMR(400MHz,氯仿-d)δ7.28(b,1H),6.93(d,J=2Hz),6.73-6.53(m,4H),5.04(b,1H),4.50(s,2H),4.19(m,1H),3.92(s,2H),3.72-3.61(m 2H),3.19(s,J=6.9Hz,1H),2.65(s,1H),2.24(s,6H),1.23(m,9H)。HRMS(ESI)m/z[M+H+]C23H32NO4 +要求386.2326,实测值386.2335。
实施例5-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-羟丙基)乙酰胺(化合物3)
将2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,87mg,0.207mmol,1当量)在DCM(1.3mL)中的搅拌溶液在0℃用草酰氯(73μL,0.83mmol,4当量)处理。加入DMF(1滴)并将反应物搅拌3小时,同时升温至室温。减压除去溶剂,粗制中间体用DCM(5mL)处理,随后减压除去。将粗制中间体用1.5mL DCM处理,然后滴加1-氨基-2-丙醇(93mg,1.24mmol,6当量)。将反应在室温下搅拌1小时。通过快速色谱法(25-100%EtOAc的己烷溶液)纯化反应混合物,得到为白色固体的中间产物(66mg,0.14mmol,68%)。在氩气下,用1:1MeOH:EtOAc(1mL)处理苄基保护的中间体(40mg,0.085mmol,1当量)。将碳钯(10重量%,22mg)加入到反应中,并逐滴加入三乙基硅烷(108μL,0.68mmol,8当量)。将反应搅拌过夜。加入另外等份的三乙基硅烷(50μL,0.31mmol,3.7当量)并将反应物搅拌1小时。将反应混合物倒在硅藻土塞上并用MeOH洗涤。通过快速色谱法(1-10%MeOH的DCM溶液)纯化浓缩的反应溶液,得到为白色固体的产物(43mg,0.11mmol,73%)。1H NMR(400MHz,氯仿-d)δ7.11(b,1H),6.93(d,J=2Hz),6.61-6.51(m,4H),5.84(b,1H),4.49(s,2H),3.96(m,1H),3.91(s,2H),3.51(m,1H),3.19(m,2H),2.27(s,6H),1.20(m,9H).HRMS(ESI)m/z[M+H+]C23H32NO4 +要求386.2326,实测值386.2335。
实施例6-2-(2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰氨基)乙烷-1-乙酸铵(化合物4)
将2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,441mg,1.05mmol,1当量)在DCM(7mL)中的搅拌溶液在0℃用草酰氯(542μL,6.3mmol,6当量)处理。加入DMF(1滴)并将反应物搅拌3小时,同时升温至室温。减压除去溶剂,粗制中间体用DCM(10mL)处理,随后减压除去。将粗制中间体用3mL DCM处理,然后滴加2-氨基乙基氨基甲酸苄酯(408mg,2.1mmol,2当量)。将反应在室温下搅拌1小时。通过快速色谱法(0-50%EtOAc的己烷溶液)纯化反应混合物,得到为白色固体的中间产物(380mg,0.643mmol,61%)。在氩气下,用THF(2mL)和乙酸(0.2mL)处理苄基保护的中间体(380mg,0.64mmol,1当量)。将碳钯(10重量%,270mg)加入到反应中,并逐滴加入三乙基硅烷(818μL,5.11mmol,8当量)。将反应搅拌过夜。将反应混合物倒在硅藻土塞上并用MeOH洗涤。浓缩溶液,然后溶于最少量的DCM和MeOH中,并减压再浓缩。将粗产物用DCM(0.25mL)用几滴MeOH再处理。将己烷(3mL)缓慢加入溶液中,这导致产物沉淀。用移液管除去己烷上清液,用己烷洗涤白色产物,并减压彻底干燥,得到白色粘性固体产物(57mg,0.132mmol,21%)。1H NMR(400MHz,d6-DMSO)δ8.40(b,1H),6.83(d,J=2Hz,1H),6.82-6.44(m,4H),4.42(s,2H),3.71(s,2H),3.31(t,J=6Hz,2H),3.19(七重峰,J=6.9Hz,1H),2.79(m,2H),2.16(s,6H),1.83(s,3H),1.09(d,J=6.9Hz,6H).HRMS(ESI)m/z[M+H+]C22H31N2O3 +要求371.2335,实测值371.2329。
实施例7-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物5)
在密封管中用MeOH(3mL)处理GC-1(250mg,0.76mmol,1当量)。加入硫酸(1滴),密封反应,然后在搅拌下加热至65℃1小时。使反应达到室温。TLC分析(1:30MeOH:DCM)显示完全转化为中间体甲酯。向中间反应混合物中加入氨(7N的MeOH溶液,0.76mL,7当量)。将反应重新密封,并再次加热至65℃持续1小时。使反应烧瓶恢复至室温并在分液漏斗中加入0.5NNaOH(20mL)中,随后用DCM(3×100mL)萃取。合并有机层,用Na2SO4干燥并浓缩。通过快速色谱法(0-6%MeOH的DCM溶液)纯化,得到为白色固体的产物(157mg,0.48mmol,63%)。1H NMR(400MHz,氯仿-d)δ6.93(b,1H),6.65-6.56(m,5H),5.85(b,1H),5.19(s,1H),4.51(s,2H),3.92(s,2H),3.19(七重峰,J=6.9,1H),2.24(s,6H),1.23(d,J=6.9Hz,6H)。HRMS(ESI)m/z[M+Na+]C20H25NNaO3 +要求350.1727,实测值350.1737。
实施例8-N-(2,2-二氟乙基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物6)
用无水THF(5mL)和CDI(140mg,0.86mmol,2.4当量)处理2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,300mg,0.72mmol,2当量)的搅拌溶液然后加热至45℃持续2小时。将反应物减压浓缩并溶解在THF(5mL)中。将一半反应物用于下一步骤(0.36mmol,1当量)并用THF(2.5mL)处理。以在THF(0.2mL)中的溶液的形式加入二氟乙胺(87mg,1.075mmol,3当量)。将反应物在室温下搅拌1小时。将反应溶液用乙醚(20mL)稀释,并用0.5N HCl(2×20mL)洗涤,然后用盐水(20mL)洗涤。用Na2SO4干燥有机层并减压浓缩。将粗制中间体溶于DCM(3mL)中并置于氩气下。加入五甲基苯(106mg,0.72mmol,2当量),并将反应冷却至-78℃。缓慢加入BCl3的溶液(1M DCM,0.72mL,2当量)并将反应物搅拌15分钟。通过加入饱和NaHCO3溶液(2mL)淬灭反应,并使烧瓶温热至室温。将反应混合物用水(10mL)稀释,并用DCM(2×20mL)萃取。合并有机层,用Na2SO4干燥,并减压浓缩。通过快速色谱法(2-40%EtOAc的己烷溶液)纯化,得到为透明的结晶固体的产物(79mg,0.2mmol,56%)。1H NMR(400MHz,氯仿-d)δ6.94(m,2H),6.65-6.55(m,4H),5.91(tt,J=55.8,4.1Hz,1H),5.19(s,1H),4.55(s,2H),3.93(s,2H),3.77(m,2H),3.20(七重峰,J=6.9,1H),2.24(s,6H),1.23(d,J=6.9Hz,6H)。HRMS(ESI)m/z[M+H+]C22H28F2NO3 +要求=392.2032,实测值392.2040。
实施例9-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2,2,2-三氟乙基)乙酰胺(化合物7)
用无水THF(5mL)和CDI(140mg,0.86mmol,2.4当量)处理2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,300mg,0.72mmol,2当量)的搅拌溶液然后加热至45℃持续2小时。将反应物减压浓缩并溶解在THF(5mL)中。将一半反应物进行下一步(0.36mmol,1当量)。以THF(0.2mL)中的溶液的形式加入三氟乙胺盐酸盐(87mg,1.075mmol,3当量)和DMAP(13mg,0.11mmol,0.3当量)。将反应物在室温下搅拌1小时。将反应溶液用乙醚(20mL)稀释,并用0.5N HCl(2×20mL)洗涤,然后用盐水(20mL)洗涤。用Na2SO4干燥有机层并减压浓缩。将粗制中间体溶于DCM(3mL)中并置于氩气下。加入五甲基苯(106mg,0.72mmol,2当量),并将反应冷却至-78℃。缓慢加入BCl3的溶液(1M DCM,0.72mL,2当量)并将反应物搅拌15分钟。通过加入饱和NaHCO3溶液(2mL)淬灭反应,并使烧瓶温热至室温。将反应混合物用水(10mL)稀释,并用DCM(2×20mL)萃取。合并有机层,用Na2SO4干燥,并减压浓缩。通过快速色谱法(2-40%EtOAc的己烷溶液)纯化,得到为白色固体的产物(89mg,0.22mmol,61%)。1H NMR(400MHz,氯仿-d)δ6.93(m,2H),6.65-6.57(m,4H),4.80(s,1H),4.58(s,2H),4.05(m,2H),3.93(s,2H),3.18(七重峰,J=6.8,1H),2.24(s,6H),1.23(d,J=6.8Hz,6H)。HRMS(ESI)m/z[M+Na+]C22H26F3NNaO3 +要求=432.1757,实测值432.1762。
实施例10-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-甲基乙酰胺(化合物8)
将2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(GC-1,155mg,0.47mmol)溶于密封管中的3ml MeOH和1滴硫酸。然后将密封的反应混合物在搅拌下加热至65℃1小时。冷却至室温后,混合物的TLC表明完全转化为甲酯中间体。然后向中间体溶液中加入610μL(7.05mmol,15当量)40%甲胺的水溶液,并将反应混合物在密封管中再次加热至65℃保持1小时。将反应物从200mL的0.5N NaOH中萃取到3x50mL的DCM中。合并有机层,经Na2SO4干燥,过滤并浓缩,然后在二氧化硅上纯化(10%MeOH的DCM溶液),得到为白色固体的产物(144mg,90%)。1H NMR(400MHz,CD3CN):6.98(br,1H),6.89(s,1H),6.68(s,2H),6.62(d,1H,J=8.6Hz),6.54(dd,1H,J=8.4,2.4Hz),4.37(s,2H),3.87(s,2H),3.16(七重峰,1H,J=6.9Hz),2.75(d,3H,J=4.9Hz),2.20(s,6H),1.12(d,6H,J=6.9Hz)。C21H27NO3[M+Na-]+:精确质量计算值m/z 364.18831。实测值m/z 364.18904。
实施例11-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-羟基苯基)乙酰胺(化合物9)
将2-[4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(250mg,0.6mmol)溶于圆底烧瓶中的6ml无水DMF中。向其中加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)(230mg,1.2mmol)、1-羟基苯并三唑(HOBt)(162mg,1.2mmol)和二异丙基乙胺(DIEA)(418uL,2.4mmol)并在室温下搅拌1小时。然后一次性加入2-氨基苯酚(130mg,1.2mmol),将反应混合物在室温下搅拌过夜。然后加入乙酸乙酯(15ml),依次用0.5NHCl(2×5ml)、饱和NaHCO3溶液(2×5ml)和饱和NaCl溶液(1×10ml)洗涤反应混合物。然后将其经无水MgSO4干燥,并且真空除去溶剂。通过Biotage快速色谱法纯化粗产物,用10%至40%乙酸乙酯的己烷溶液洗脱,得到纯的苄基保护的GC-1乙酰胺(154mg,0.3mmol)。1H NMR(400MHz,CDCl3):δ8.72(s,1H),8.573(s,1H),7.38-6.61(m,14H),5.30(s,2H),4.68(s,2H),3.95(s,2H),3.37(m,1H),2.25(s,6H),1.22(d,J=6.57Hz,6H).
在氩气下向用5ml甲醇中的约55%水(60mg)浸湿的该受保护的乙酰胺(150mg,0.29mmol)和10%Pd-C的搅拌悬浮液中滴加三乙基硅烷(441uL,2.9mmol)。在室温下将反应混合物搅拌2小时。反应完成(TLC)后,将其通过硅藻土过滤并真空除去溶剂。通过Biotage快速色谱法纯化粗产物,用10%至40%乙酸乙酯的己烷溶液洗脱,得到最终的乙酰胺(通过HPLC测得79mg,0.18mmol,64%收率,纯度98.9%)。1HNMR(400MHz,CDCl3):δ8.70(s,1H),8.57(s,1H),7.16(m,1H),7.08(m,1H),6.92(m,2H),6.72(s,2H),6.59(m,2H),4.68(s,2H),3.93(s,2H),3.13(m,1H),2.26(s,6H),1.22(d,J=6.98Hz,6H).C26H29NO4的HRMS(M+Na)计算值442.19888,实测值442.19903。
实施例12-2-(4-(4-羟基-3-异丙基苄基)-N-(3-羟基苯基)乙酰胺(化合物10)
将2-[4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(250mg,0.6mmol)溶于6ml无水DMF中。向其中加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)(230mg,1.2mmol)、1-羟基苯并三唑(HOBt)(162mg,1.2mmol)和二异丙基乙胺(DIEA)(418μL,2.4mmol)并在室温下搅拌1小时。向该溶液中一次性加入2-氨基苯酚(130mg,1.2mmol)并在室温下搅拌过夜。向其中加入乙酸乙酯(15ml),用0.5N HCl(2×10ml)、饱和NaHCO3溶液(2×10ml)和饱和NaCl溶液(1×10ml)洗涤反应混合物。然后将其经无水MgSO4干燥,并且真空除去溶剂。通过Biotage快速色谱法纯化粗产物,用10%至40%乙酸乙酯的己烷溶液洗脱,得到纯的苄基保护的GC-1乙酰胺(186mg,0.36mmol)。1H NMR(400MHz,CDCl3):δ8.35(s,1H),7.64(s,1H),7.43-7.33(m,5H),7.21-6.85(m,4H),6.76-6.61(m,5H),5.0(s,2H),4.6(s,2H),3.97(s,2H),3.36(m,1H),2.25(s,6H),1.19(d,J=6.94Hz,6H)
将受保护的乙酰胺(180mg,0.35mmol)溶解在甲醇和THF(5ml+6ml)(11ml)的混合物中,因为它不完全溶于仅甲醇。向其中加入用约55%水浸湿的10%Pd-C(72mg,0.035mmol),并且在氩气下将三乙基硅烷(532uL,3.5mmol)滴加到搅拌的悬浮液中。在2小时内完成反应(TLC)后,将混合物通过硅藻土过滤,并真空除去溶剂。通过Biotage快速色谱法纯化粗产物,用20%至60%乙酸乙酯的己烷溶液洗脱,得到最终的乙酰胺(75mg,0.17mmol,61%收率)。1HNMR(400MHz,CDCl3):δ7.28(m,1H),7.16(t,J=7.89Hz,1H),6.88(m,1H),6.83(m,1H),6.67(s,1H),6.63(m,1H),6.59(d,J=7.89Hz,1H),6.49(m,1H),4.56(s,2H),3.88(s,2H),3.12(m,1H),2.22(s,6H),1.16(d,J=6.85Hz,6H).C26H29NO4的HRMS(M+Na)计算值442.19888,实测值442.19939。
实施例13-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-(甲基磺酰胺基)乙基)乙酰胺(化合物11)
将2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(苄化的GC-1,275mg,0.66mmol)溶于1mL无水DMF中。向该羧酸溶液中加入DIEA(686μL,3.94mmol)、EDCHCl(253mg,1.31mmol)和HOBt(178mg,1.31mmol),将该溶液在室温下搅拌1小时。然后加入胺,N-(2-氨基乙基)甲磺酰胺(160mg,1.16mmol),将反应混合物在室温下搅拌18小时。用10mL EtOAc稀释反应混合物,然后用2x5mL 1N HCl洗涤,用1x 5mL饱和碳酸氢钠水溶液洗涤,并用2x 5mL盐水洗涤。用MgSO4干燥所得有机层,过滤并浓缩,得到粗制中间体产物(319mg,90%)。通过1H NMR使粗制产物足够纯净,无需进一步纯化即可进行。
在-78℃下将苄基化的中间体2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-(甲基磺酰胺基)乙基)乙酰胺(319mg,0.592mmol)和五甲基苯(292mg,1.97mmol)溶于10mL无水DCM中。在-78℃下向该搅拌溶液中加入BCl3(3.3ml,3.3mmol),将反应混合物搅拌2小时,然后用10mL 9:1CHCl3:MeOH淬灭并蒸发至残余物。将该残余物用己烷洗涤,得到粗白色固体,将其在二氧化硅上色谱纯化(DCM中的10%MeOH)。最终产物是灰白色固体(244mg,92%)。1H NMR(400MHz,CD3CN):7.29(br,1H),6.89(s,1H),6.69(s,2H),6.62(d,1H,J=8.2Hz),6.54(d,1H,J=8.4,2.0Hz),4.43(s,2H),3.88(s,2H),3.39(m,2H),3.16(m,3H),2.88(s,3H),2.20(s,6H),1.12(d,6H,J=6.9Hz).C23H32N2O5S[M+Na]+的HRMS精确质量计算值:m/z 471.19241。实测值m/z 471.19335。
实施例14-N-(1,3-二羟基丙烷-2-基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物12)
用DCM(6mL)处理GC-1的搅拌溶液(411mg,1.25mmol,1当量),然后加入DCC(283mg,1.34mmol,1.1当量)和N-羟基琥珀酰亚胺(158mg,1.34mmol,1.1当量)。反应搅拌4小时,在此期间形成白色沉淀。将尿素副产物过滤掉,并通过快速色谱法(0-80%EtOAc的己烷溶液)纯化中间体NHS酯,得到白色产物(323mg,0.76mol,60%)。将中间体NHS酯(55mg,0.129mmol,1当量)用THF(1mL)和三乙胺(27μL,0.19mmol,1.5当量)处理。用(+/-)-丝氨醇(17mg,0.19mmol,1.5当量)处理反应并搅拌30分钟。通过快速色谱法直接纯化反应混合物,得到为白色固体的产物(14mg,0.035mmol,27%)。1H NMR(400MHz,氯仿-d)δ6.87(s,1H),6.60-6.45(m,4H),4.45(s,2H),3.94(m,1H),3.85(s,2H),3.72-3.61(m 2H),3.19(s,J=6.9Hz,1H),2.65(s,1H),2.24(s,6H),1.23(b,8H).HRMS(ESI)m/z[M+Na+]C23H31NNaO5 +要求=424.2094,实测值424.2099。
实施例15-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-丙基乙酰胺(化合物13)
将2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(GC-1)(100mg,0.3mmol)溶解在密封管中的甲醇中。向其中加入浓缩的H2SO4(1滴)并在65℃下加热。在1小时内观察到甲酯的总转化率(TLC)。向其中加入丙胺(246uL,3mmol),然后将其再次在65℃加热1小时。反应未完成。因此向其中加入另外100uL丙胺,反应在30分钟内完成(TLC)。用冰水浴将其冷却至0℃,向其中加入0.5N NaOH(10ml),用二氯甲烷(3×50ml)萃取反应混合物。合并有机层并经MgSO4干燥。通过Biotage快速色谱法纯化粗产物,用20%至60%乙酸乙酯洗脱,得到纯的丙基乙酰胺(通过HPLC测得46mg,0.12mmol,41%收率,纯度99.3%)。1HNMR(400MHz,CDCl3):δ6.91(s,1H),6.63-6.53(m,5H),4.48(s,2H),3.90(s,2H),3.31(m,2H),3.15(m,1H),2.22(s,6H),1.59(m,2H),1.21(d,J=6.94Hz,6H),0.94(t,J=7.5Hz,3H)。C23H31NO3的HRMS(M+Na)计算值392.21962,实测值392.22036。
实施例16-N-(2-氟乙基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物14)
用无水THF(5mL)和CDI(140mg,0.86mmol,2.4当量)处理2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,150mg,0.36mmol,1当量)的搅拌溶液,然后加热至45℃持续2小时。将反应物减压浓缩并溶解在THF(2.5mL)中。将反应溶液用2-氟乙胺盐酸盐(87mg,1.075mmol,3当量)处理,并在室温下搅拌1小时。将反应溶液用乙醚(20mL)稀释,并用0.5N HCl(2×20mL)洗涤,然后用盐水(20mL)洗涤。将有机层经Na2SO4干燥并减压浓缩。将粗制中间体溶于DCM(3mL)中并置于氩气下。加入五甲基苯(106mg,0.72mmol,2当量),并将反应冷却至-78℃。缓慢加入BCl3的溶液(1M DCM,0.72mL,2当量)并将反应物搅拌15分钟。通过加入饱和NaHCO3溶液(2mL)淬灭反应,并使烧瓶温热至室温。将反应混合物用水(10mL)稀释,并用DCM(2×20mL)萃取。合并有机层,用Na2SO4干燥,并减压浓缩。通过快速色谱法(2-40%EtOAc的己烷溶液)纯化,得到为白色固体的产物(70mg,0.19mmol,52%)。1HNMR(400MHz,氯仿-d)δ7.03(s,1H),6.94(d,J=2.1Hz,1H),6.68–6.52(m,4H),4.76(s,1H),4.62(dt,J=47.4,4.8Hz,1H),4.53(s,2H),3.93(s,2H),3.71(dq,J=27.8,5.0Hz,2H),3.17(七重峰,J=7.0Hz,1H),2.24(s,6H),1.23(d,J=6.9Hz,6H).
实施例17-N-烯丙基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物15)
用无水THF(5mL)和CDI(140mg,0.86mmol,2.4当量)处理2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,300mg,0.72mmol,2当量)的搅拌溶液然后加热至45℃持续2小时。将反应物减压浓缩并溶解在THF(5mL)中。将一半反应物用于下一步骤(0.36mmol,1当量)并用THF(2.5mL)处理。将盐酸烯丙胺(90mg,1.075mmol,3当量)加入到反应溶液中,将其在室温下搅拌过夜。将反应溶液用乙醚(20mL)稀释,并用0.5N HCl(2×20mL)洗涤,然后用盐水(20mL)洗涤。用Na2SO4干燥有机层并减压浓缩。将粗制中间体溶于DCM(3mL)中并置于氩气下。加入五甲基苯(106mg,0.72mmol,2当量),并将反应冷却至-78℃。缓慢加入BCl3的溶液(1M DCM,0.72mL,2当量)并将反应物搅拌15分钟。通过加入饱和NaHCO3溶液(2mL)淬灭反应,并使烧瓶温热至室温。将反应混合物用水(10mL)稀释,并用DCM(2×20mL)萃取。合并有机层,用Na2SO4干燥,并减压浓缩。通过快速色谱法纯化(2-40%EtOAc的己烷溶液)得到为白色固体的产物(70mg,0.2mmol,55%)。1H NMR(400MHz,氯仿-d)δ6.94(d,J=2.1Hz,1H),6.75(s,1H),6.68–6.52(m,4H),5.96–5.81(m,1H),5.27–5.14(m,2H),4.96(s,1H),4.54(s,2H),4.02(tt,J=5.8,1.6Hz,2H),3.93(s,2H),3.19(七重峰,J=6.9Hz,1H),2.24(s,6H),1.23(d,J=6.9Hz,6H).
实施例18-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(丙-2-炔-1-基)乙酰胺(化合物16)
用无水THF(5mL)和CDI(140mg,0.86mmol,2.4当量)处理2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,300mg,0.72mmol,2当量)的搅拌溶液然后加热至45℃持续2小时。将反应物减压浓缩并溶解在THF(5mL)中。将一半反应物用于下一步骤(0.36mmol,1当量)并用THF(2.5mL)处理。将THF(0.2mL)中的溶液的形式的炔丙胺(90mg,1.075mmol,3当量)加入到反应溶液中。将反应物在室温下搅拌1小时。将反应溶液用乙醚(20mL)稀释,并用0.5N HCl(2×20mL)洗涤,然后用盐水(20mL)洗涤。用Na2SO4干燥有机层并减压浓缩。将粗制中间体溶于DCM(3mL)中并置于氩气下。加入五甲基苯(106mg,0.72mmol,2当量),并将反应冷却至-78℃。缓慢加入BCl3的溶液(1M DCM,0.72mL,2当量)并将反应物搅拌15分钟。通过加入饱和NaHCO3溶液(2mL)淬灭反应,并使烧瓶温热至室温。将反应混合物用水(10mL)稀释,并用DCM(2×20mL)萃取。合并有机层,用Na2SO4干燥,并减压浓缩。通过快速色谱法(2-40%EtOAc的己烷溶液)纯化得到为灰白色固体的产物(88mg,0.24mmol,67%)。1H NMR(400MHz,氯仿-d)δ6.92(t,J=3.5Hz,2H),6.63(d,J=8.1Hz,1H),6.63(s,2H),6.53(dd,J=8.2,2.2Hz,1H),5.69(s,1H),4.51(s,2H),4.16(dd,J=5.5,2.6Hz,2H),3.90(s,2H),3.20(七重峰,J=6.9Hz,1H),2.22(s,6H),1.21(d,J=6.9Hz,6H).
实施例19-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-甲氧基乙酰胺(化合物17)
用无水THF(5mL)和CDI(140mg,0.86mmol,2.4当量)处理2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,300mg,0.72mmol,2当量)的搅拌溶液然后加热至45℃持续2小时。将反应物减压浓缩并溶解在THF(5mL)中。将一半反应物用于下一步骤(0.36mmol,1当量)并用THF(2.5mL)处理。将甲氧基胺盐酸盐(83mg,1.075mmol,3当量)加入到反应溶液中,将其在室温下搅拌过夜。将反应溶液用乙醚(20mL)稀释,并用0.5N HCl(2×20mL)洗涤,然后用盐水(20mL)洗涤。用Na2SO4干燥有机层并减压浓缩。将粗制中间体溶于DCM(3mL)中并置于氩气下。加入五甲基苯(106mg,0.72mmol,2当量),并将反应冷却至-78℃。缓慢加入BCl3的溶液(1M DCM,0.72mL,2当量)并将反应物搅拌15分钟。通过加入饱和NaHCO3溶液(2mL)淬灭反应,并使烧瓶温热至室温。将反应混合物用水(10mL)稀释,并用DCM(2×20mL)萃取。合并有机层,用Na2SO4干燥,并减压浓缩。通过快速色谱法(2-40%EtOAc的己烷溶液)纯化,得到为白色固体的产物(94.5mg,0.26mmol,72%)。1H NMR(400MHz,氯仿-d)δ9.06(s,1H),6.93(d,J=2.1Hz,1H),6.66–6.52(m,4H),4.74(s,1H),4.59(s,2H),3.92(s,2H),3.86(s,3H),3.18(七重峰,J=6.9Hz,1H),2.24(s,6H),1.23(d,J=6.9Hz,6H)。
实施例20-N-(3,4-二羟基苯乙基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物18)
将2-[4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(200mg,0.48mmol)溶于圆底烧瓶中的10ml无水THF中。向其中加入1,1'-羰基二咪唑(CDI)(78mg,0.48mmol)并在45℃搅拌3小时。通过TLC监测反应,当观察到完全转化为酰基咪唑内酯时,将混合物在真空中浓缩至干燥以除去所有CO2。然后将其溶于无水THF(8mL)中,向其中缓慢加入盐酸多巴胺(118.33mg,0.624mmol,1.3当量)在2ml无水MeOH中的溶液。将反应混合物在45℃下搅拌过夜.然后冷却,在真空中蒸发溶剂。向其中加入乙酸乙酯(25mL),依次用0.5N HCl(2×5mL)和饱和NaCl溶液(1×10mL)洗涤反应混合物。将其在无水MgSO4上干燥并在真空中除去溶剂。通过Biotage快速色谱法纯化粗产物,用10%至40%乙酸乙酯的己烷溶液洗脱。苄基保护的GC-1乙酰胺从氯仿(100mg,0.17mmol)中结晶。1H NMR(400MHz,甲醇-d4):δ7.48-7.26(m,3H),6.93(d,J=2.3Hz,1H),6.82(dd,J=8.5,1.3Hz,1H),6.71-6.62(m,3H),6.51(dd,J=8.1,2.0Hz,1H),5.03(s,1H),4.47(d,J=1.4Hz,1H),3.95(s,1H),3.45(dd,J=8.1,6.7Hz,1H),3.38-3.26(m,1H),2.67(t,J=7.4Hz,1H),2.22(s,3H),1.16(dd,J=6.9,1.3Hz,3H).
在氩气下向该受保护的乙酰胺(75mg,0.13mmol)和用5mL甲醇溶液中约55%水(27.6mg)浸湿的10%Pd-C的搅拌溶液中滴加三乙基硅烷(198μL,1.3mmol)。在室温下将反应混合物搅拌3小时。在反应完成(TLC)后,将其通过硅藻土过滤并在真空中除去溶剂。通过Biotage快速色谱法纯化粗产物,用30%至80%二氯甲烷的乙酸乙酯溶液洗脱,得到最终的乙酰胺(通过HPLC测得42mg,0.18mmol,67%收率,纯度99%)。1H NMR(400MHz,CDCl3):δ6.84(d,J=2.1Hz,1H),6.69(d,J=6.8Hz,4H),6.63-6.49(m,3H),4.48(s,2H),3.92(s,2H),3.47(t,J=7.4Hz,2H),3.22(七重峰,J=6.9Hz,1H),2.69(t,J=7.4Hz,2H),2.23(s,6H),1.32(s,1H),1.15(d,J=6.9Hz,6H),0.93(t,J=7.0Hz,2H).
实施例21-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-苯乙基乙酰胺(化合物19)
将2-[4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(200mg,0.48mmol)溶于圆底烧瓶中的10ml无水THF中。向其中加入1,1'-羰基二咪唑(78mg,0.48mmol)并在45℃下搅拌3小时。通过TLC监测反应,当观察到完全转化为酰基咪唑内酯时,将混合物真空浓缩至干,以除去所有CO2。然后将其溶于无水THF(8mL)中,向其中逐滴加入在2mL无水THF中的2-苯基乙胺(157.5mg,1.44mmol,1.33当量)溶液。将反应混合物在45℃下搅拌过夜。然后冷却,在真空中蒸发溶剂。将其溶于乙酸乙酯(25mL)中,依次用0.5NHCl(2×5mL)和饱和NaCl溶液(1×10mL)洗涤。然后将其在无水MgSO4上干燥并在真空中除去溶剂。通过Biotage快速色谱法纯化粗产物,用10%至40%乙酸乙酯的己烷溶液洗脱。1HNMR(400MHz,氯仿-d)δ7.46-7.14(m,11H),6.98(d,J=2.1Hz,1H),6.73(dd,J=8.4,1.2Hz,1H),6.70-6.55(m,4H),5.02(s,2H),4.47(s,2H),3.93(s,2H),3.66-3.56(m,2H),3.35(七重峰,J=6.9Hz,1H),2.85(t,J=7.0Hz,2H),2.23(s,6H),1.20(dd,J=7.0,1.2Hz,6H).
用BCl3将由此制备的乙酰胺的苄基脱保护。将乙酰胺(220mg,0.42mmol)溶于无水二氯甲烷(10mL)中,并向其中加入五甲基苯(125mg,0.84mmol)。然后使用干冰/丙酮浴将溶液冷却至-78℃并且向其中非常缓慢地加入1ml 1M的BCl3在二氯甲烷中的溶液(117mg,1mmol)。在-78℃下搅拌20分钟,并且通过TLC观察向产物的总转化。然后在-78℃下加入饱和碳酸氢钠溶液(5mL)。然后将反应混合物在室温下加热。然后向其中加入二氯甲烷(25mL)和水(5mL),并收集有机层。水层用二氯甲烷(2×10mL)萃取,合并的有机层用无水硫酸镁干燥。通过Biotage快速色谱法纯化粗产物,用20%至60%乙酸乙酯的己烷溶液洗脱,得到最终的乙酰胺(通过HPLC测得134mg,0.31mmol,74%收率,纯度为99.6%)。1H NMR(400MHz,CDCl3):δ7.34-7.12(m,5H),6.92(d,J=2.1Hz,1H),6.67(s,1H),6.62·-6.50(m,4H),4.67(s,1H),4.46(s,2H),3.90(s,2H),3.61(q,J=6.8Hz,2H),3.15(七重峰,J=6.9Hz,I H),2.84(t,J=7.0Hz,2H),2.22(5,6H),1.21(d,J=6.9Hz,6H).
实施例22-N-羟基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物20)
将2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(苄基化的GC-1,150mg,0.36mmol)溶于6mL无水THF中。在氩气下向该羧酸溶液中加入1,1'-羰基二咪唑(70mg,0.43mmol),将该溶液在50℃下搅拌2小时。然后加入盐酸羟胺(30mg,0.43mmol)的3mL MeOH溶液,将反应混合物在50℃下搅拌18小时。然后将反应混合物真空蒸发至干,溶于10mL DCM中,用2x 5mL1N HCl和2x 5mL盐水洗涤。用MgSO4干燥所得有机层,过滤并浓缩以得到粗中间体产物(139mg,90%)。通过1H NMR使粗制产物足够纯净,无需进一步纯化即可进行。
在-78℃下将苄基化的中间体2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)-N-羟基乙酰胺(139mg,0.321mmol)和五甲基苯(160mg,1.07mmol)溶解在10mL无水DCM中。在-78℃下向该搅拌溶液中加入BCl3(1.1ml,1.1mmol)并将反应混合物搅拌2小时,然后用10mL 9:1CHCl3:MeOH淬灭并蒸发至残余物。将该残余物用己烷洗涤,得到粗白色固体,将其在二氧化硅上色谱纯化(DCM中的10%MeOH)。最终产物是灰白色固体(51mg,46%)。该产物在TLC上用氯化铁(III)测试阳性(红橙色染色)。1H NMR(400MHz,MeOD):6.78(s,1H),6.65(s,2H),6.54(d,1H,J=8.3Hz),6.48(dd,1H,J=8.3,2Hz),4.48(s,2H),3.85(s,2H),3.15(sept.1H),2.16(s,6H),1.08(d,6H,J=6.9Hz).
实施例23-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰肼(化合物21)
将2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(苏比替罗,50mg,0.15mmol)溶于密封管中的3ml MeOH和1滴硫酸。然后将密封的反应混合物在搅拌下加热至65℃1小时。冷却至室温后,混合物的TLC表明完全转化为甲酯中间体。然后向中间体溶液中加入44μL(0.9mmol,6当量)一水合肼,并将反应混合物在密封管中搅拌1小时。将反应物从50mL水中萃取到3x 20mL DCM中。合并有机层,用Na2SO4干燥,过滤并浓缩,然后在二氧化硅(DCM中的10%MeOH)上纯化,得到为白色固体的产物(44mg,86%)。该产物在TLC上用茚三酮测试为阳性。1H NMR(400MHz,MeOD):6.77(s,1H),6.64(s,2H),6.53(d,1H,J=8.2Hz),6.46(dd,1H,J=8.3,2Hz),4.48(s,2H),3.83(s,2H),3.16(sept.1H),2.16(s,6H),1.08(d,6H,J=6.9Hz.
实施例25-2-(2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰氨基)乙烷-1-磺酸钠(化合物23)
在密封管中用MeOH(5mL)处理GC-1(100mg,0.3mmol,1当量)。加入硫酸(1滴),密封反应,然后在搅拌下加热至65℃1小时。使反应达到室温。TLC分析(1:30MeOH:DCM)显示完全转化为中间体甲酯。向中间体反应混合物中加入以在氢氧化钠(73mg,1.83mmol,6当量)水溶液(2mL)中的溶液的形式的牛磺酸(229mg,1.83mmol,6当量)。将反应重新密封,并再次加热至65℃过夜。减压除去一部分溶剂,用另外的水将溶液的总体积调节至约5mL。将溶液通过0.22μm过滤器过滤,并通过制备型HPLC纯化。将合并的产物级分合并,通过稳定的空气流浓缩,然后减压得到白色固体(7.8mg,0.02mmol,5%)。1H NMR(400MHz,9:1氯仿-d:甲醇-d4)δ6.85(d,J=2.2Hz,1H),6.61–6.52(m,3H),6.43(dd,J=8.2,2.3Hz,1H),4.40(s,2H),3.83(s,2H),3.72(t,J=6.0Hz,2H),3.37(s,6H),3.17(七重峰,J=6.9Hz,1H),3.02(t,J=6.0Hz,2H),2.15(s,6H),1.13(d,J=6.9Hz,6H).
实施例26-N-环丙基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物24)
用无水THF(5mL)和CDI(140mg,0.86mmol,2.4当量)处理2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,300mg,0.72mmol,2当量)的搅拌溶液然后加热至45℃持续2小时。将反应物减压浓缩并溶解在THF(5mL)中。将一半反应物用于下一步骤(0.36mmol,1当量)并用THF(2.5mL)处理。将环丙胺(60mg,1.075mmol,3当量)加入到反应溶液中,将其在室温下搅拌过夜。将反应溶液用乙醚(20mL)稀释,并用0.5N HCl(2×20mL)洗涤,然后用盐水(20mL)洗涤。用Na2SO4干燥有机层并减压浓缩。将粗制中间体溶于DCM(3mL)中并置于氩气下。加入五甲基苯(106mg,0.72mmol,2当量),并将反应冷却至-78℃。缓慢加入BCl3的溶液(1M DCM,0.72mL,2当量)并将反应物搅拌15分钟。通过加入饱和NaHCO3溶液(2mL)淬灭反应,并使烧瓶温热至室温。将反应混合物用水(10mL)稀释,并用DCM(2×20mL)萃取。合并有机层,用Na2SO4干燥,并减压浓缩。通过快速色谱法(2-40%EtOAc的己烷溶液)纯化,得到为白色固体的产物(63mg,0.17mmol,48%)。1H NMR(400MHz,氯仿-d)δ6.93(d,J=2.1Hz,1H),6.76(s,1H),6.67(d,J=8.1Hz,1H),6.62(s,2H),6.54(dd,J=8.2,2.2Hz,1H),5.94(s,1H),4.48(s,2H),3.92(s,2H),3.23(七重峰,J=6.9Hz,1H),2.82(tq,J=7.2,3.7Hz,1H),2.23(s,6H),1.23(d,J=6.9Hz,6H),0.95–0.80(m,2H),0.71–0.56(m,2H).
实施例27-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N,N-二甲基乙酰胺
用无水THF(5mL)和CDI(140mg,0.86mmol,2.4当量)处理2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,300mg,0.72mmol,2当量)的搅拌溶液,然后加热至45℃保持2小时。将反应物减压浓缩并溶解在THF(5mL)中。将一半反应物用于下一步骤(0.36mmol,1当量)并用THF(2.5mL)处理。将盐酸二甲胺(88mg,1.075mmol,3当量)加入到反应溶液中,将其在室温下搅拌过夜。将反应溶液用乙醚(20mL)稀释,并用0.5N HCl(2×20mL)洗涤,然后用盐水(20mL)洗涤。将有机层经Na2SO4干燥并减压浓缩。将粗制中间体溶于DCM(3mL)中并置于氩气下。加入五甲基苯(106mg,0.72mmol,2当量),将反应冷却至-78℃。缓慢加入BCl3(1M DCM,0.72mL,2当量)的溶液,并将反应物搅拌15分钟。通过加入饱和NaHCO3溶液(2mL)淬灭反应,使烧瓶温热至室温。将反应混合物用水(10mL)稀释,并用DCM(2×20mL)萃取。合并有机层,用Na2SO4干燥,并减压浓缩。通过快速色谱法(2-40%EtOAc的己烷溶液)纯化,得到为白色固体的产物(38mg,0.11mmol,30%)。1H NMR(400MHz,氯仿-d)δ6.95(d,J=2.1Hz,1H),6.65(d,J=9.9Hz,3H),6.53(dd,J=8.2,2.2Hz,1H),5.58(s,1H),4.68(s,2H),3.90(s,2H),3.21(h,J=6.9Hz,1H),3.13(s,3H),3.02(s,3H),2.20(s,6H),1.23(d,J=6.8Hz,6H).
实施例28-N-乙基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺
在密封管中用MeOH(3mL)处理GC-1(100mg,0.304mmol,1当量)。加入硫酸(1滴),密封反应,然后在搅拌下加热至65℃1小时。使反应达到室温。TLC分析(1:30MeOH:DCM)显示完全转化为中间体甲酯。向中间体反应混合物中加入乙胺(33%水溶液,0.25mL,1.84mmol,6当量)。将反应重新密封,并再次加热至65℃持续1小时。使反应烧瓶恢复至室温并在分液漏斗中加入0.5N NaOH(20mL),随后用DCM(3×100mL)萃取。合并有机层,用Na2SO4干燥并浓缩。通过快速色谱法(0-6%MeOH的DCM溶液)纯化,得到为白色固体的产物(82mg,0.23mmol,76%)。1H NMR(400MHz,氯仿-d)δ6.94(d,J=2.2Hz,1H),6.72–6.61(m,4H),6.55(dd,J=8.1,2.2Hz,1H),5.77(d,J=17.7Hz,1H),4.50(s,2H),3.92(s,2H),3.43(qd,J=7.3,5.8Hz,2H),3.22(七重峰,J=6.8Hz,1H),2.24(s,6H),1.32–1.15(m,9H)。
实施例29-N-(氰基甲基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物27)
在火焰干燥的圆底烧瓶中,将2-[4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(200mg,0.48mmol)溶于10mL无水THF中。向其中加入1,1'-羰基二咪唑(85mg,0.52mmol,1.1当量)并在45℃搅拌3小时。通过TLC监测反应,当观察到完全转化为酰基咪唑内酯时,将混合物在真空中浓缩至干燥以除去所有CO2。然后将其溶于无水THF(8mL)中,并一次性加入氨基乙腈盐酸盐(133mg,1.44mmol,3当量)。将反应混合物在45℃下搅拌过夜。从反应混合物中沉淀出白色固体。将其冷却并在真空中除去THF。将固体溶解在乙酸乙酯(25mL)中,依次用0.5N HCl(2×5mL)和饱和NaCl溶液(1×10mL)洗涤反应混合物。然后将其在无水MgSO4上干燥并在真空中除去溶剂。所得混合物在保存在冰箱中时固化。用己烷洗涤,NMR显示其纯度大于90%。1HNMR(400MHz,甲醇-d4)δ7.50-7.27(m,5H),6.94(d,J=2.3Hz,1H),6.85(d,J=8.3Hz,1H),6.74(s,2H),6.69(dd,J=8.4,2.3Hz,1H),5.06(s,2H),4.59(s,1H),4.27(s,2H),3.96(s,2H),2.31(s,1H),2.24(s,6H),1.18(dd,J=6.9,1.5Hz,6H),0.95(d,J=6.7Hz,1H).
苄基保护基团被BCl3裂解。将乙酰胺(175mg,0.38mmol)溶于无水二氯甲烷(10ml)中,并向其中加入五甲基苯(113mg,0.76mmol)。然后使用干冰/丙酮浴将溶液冷却至-78℃并且向其中非常缓慢地加入1M的BCl3在二氯甲烷中的溶液(789uL,89mg,0.76mmol)。TLC显示在-78℃搅拌25分钟后主要转化为产物。然后在-78℃下向其中加入饱和碳酸氢钠溶液(5ml)。然后将反应混合物在室温下加热。然后向其中加入二氯甲烷(25ml)和水(5ml),收集有机层。水层用二氯甲烷(2×10ml)萃取,合并的有机层用无水硫酸镁干燥。通过Biotage快速色谱法纯化粗产物,用10%至50%乙酸乙酯的己烷溶液洗脱,得到最终的乙酰胺(85mg,0.23mmol,60%收率,HPLC纯度为99.6%)。1H NMR(400MHz,甲醇-d4)δ6.83(d,J=2.2Hz,1H),6.72(s,2H),6.62-6.49(m,2H),4.57(d,J=1.6Hz,2H),4.25(d,J=1.6Hz,2H),3.90(s,2H),3.21(七重峰,1H),2.22(d,J=1.5Hz,6H),1.14(dd,J=7.0,1.7Hz,6H).
实施例30-N-(3-氟苯基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺(化合物28)
将2-[4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(200mg,0.48mmol)溶于圆底烧瓶中的10mL无水THF中。向其中加入1,1'-羰基二咪唑(78mg,0.48mmol)并在45℃下搅拌3小时。通过TLC监测反应,当观察到完全转化为酰基咪唑时,将混合物在真空中浓缩至干以除去所有CO2。然后将其溶于无水THF(8mL)中,并向其中滴加3-氟苯胺(144.4mg,1.44mmol,1.33当量)在2mL无水THF中的溶液。然后将反应混合物在45℃下搅拌过夜。冷却反应混合物并在真空中蒸发溶剂。然后加入乙酸乙酯(25mL),依次用0.5NHCl(2×5mL)和饱和NaCl溶液(1×10mL)洗涤反应混合物。然后将其在无水MgSO4上干燥并在真空中除去溶剂。通过Biotage快速色谱法纯化粗产物,用10%至40%乙酸乙酯的己烷溶液洗脱。1H NMR(400MHz,氯仿-d)δ8.34(s,1H),7.56(dt,J=10.7,2.3Hz,1H),7.44-7.18(m,7H),6.95(d,J=2.3Hz,1H),6.84(tdd,J=8.2,2.5,1.1Hz,1H),6.73(d,J=8.4Hz,1H),6.68(s,2H),6.60(dd,J=8.4,2.3Hz,1H),5.00(s,2H),4.59(s,2H),3.92(s,2H),3.34(七重峰,J=6.9Hz,I H),2.23(s,6H),1.18(d,J=6.9Hz,6H).
将乙酰胺(200mg,0.39mmol)溶于无水二氯甲烷(10ml)中,并向其中加入五甲基苯(116mg,0.78mmol)。然后使用干冰/丙酮浴将溶液冷却至-78℃,并且向其中非常缓慢地加入1M的BCl3在二氯甲烷(777μL,91mg,0.78mmol)中的溶液。TLC显示在-78℃下在搅拌15分钟内向产物的总转化。然后在-78℃下向其中加入饱和碳酸氢钠溶液(5mL)。然后将反应混合物在室温下加热。然后向其中加入二氯甲烷(25mL)和水(5mL),并收集有机层。水层用二氯甲烷(2×10mL)萃取,合并的有机层用无水硫酸镁干燥。通过Biotage快速色谱法纯化粗产物,用10%至50%乙酸乙酯的己烷溶液洗脱,得到最终的乙酰胺(通过HPLC测得150mg,0.35mmol,91%收率,纯度96.8%)。1H NMR(400MHz,氯仿-d)δ8.34(s,1H),7.34-7.17(m,2H),6.92-6.79(m,2H),6.68(s,2H),6.61-6.49(m,2H),4.58(s,3H),3.90(s,2H),3.13(七重峰,J=6.8Hz,1H),1.19(d,J=6.9Hz,6H).
实施例31-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(氧杂环丁烷-3-基)乙酰胺(化合物29)
将2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(苄基化的GC-1,200mg,0.48mmol)溶于6mL无水THF中。在氩气下向该羧酸溶液中加入1,1’-羰基二咪唑(93mg,0.57mmol),将该溶液在50℃下搅拌2小时。然后加入氧杂环丁烷-3-胺(30mg,0.43mmol)的3mL THF溶液,并将反应混合物回流2小时。然后将反应混合物真空蒸发至干,溶于10mL DCM中,用2x 5mL1N HCl和2x 5mL盐水洗涤。用MgSO4干燥所得有机层,过滤并浓缩,得到粗中间体产物(196mg,86%)。通过1H NMR使粗制产物足够纯净,无需进一步纯化即可进行。
将苄基化的中间体2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(氧杂环丁烷-3-基)乙酰胺(196mg,0.41mmol)溶于5mL加入了1mL THF和10%Pd/C(100mg)的无水甲醇以产生悬浮液。将反应混合物抽真空约1分钟,然后置于氩气下约1分钟。将该过程重复三次以确保混合物适当地脱气。然后将三乙基硅烷(1mL,6.3mmol)滴加到悬浮液中,并将反应混合物在室温下搅拌4小时。用甲醇在硅藻土垫上过滤,真空浓缩,经快速色谱纯化(二氧化硅,DCM中的10%MeOH),得到为白色固体的所需产物(121mg,77%收率)。1H NMR(400MHz,CDCl3):7.14(d,J=8.0Hz,1H),6.92(s,1H),6.65(s,2H),6.60(d,1H,J=8.2Hz),6.54(dd,1H,J=8.1,2.2Hz),5.18(六重峰,1H,J=7.6Hz),4.97(t,2H,J=7.2Hz),4.68(s,0H),4.57(t,2H,J=7.0Hz),4.49(s,2H),3.91(s,2H),3.15(sept.,1H,J=6.9Hz),2.23(s,6H),1.21(d,6H,J=6.9Hz).
实施例32-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(4-硝基苯基)乙酰胺(化合物30)
用无水THF(5mL)和CDI(140mg,0.86mmol,2.4当量)处理2-(4-(4-(苄氧基)-3-异丙基苄基)-3,5-二甲基苯氧基)乙酸(O-苄基GC1,150mg,0.36mmol,1当量)的搅拌溶液,然后加热至45℃持续2小时。将反应物减压浓缩并溶解在THF(2.5mL)中。将反应溶液用4-硝基苯胺(150mg,1.075mmol,3当量)处理,并在室温下搅拌1小时。将反应溶液用乙醚(20mL)稀释,并用0.5N HCl(2×20mL)洗涤,然后用盐水(20mL)洗涤。将有机层经Na2SO4干燥并减压浓缩。通过快速色谱法(0-40%EtOAc的己烷溶液)纯化粗中间体,以确保除去过量的4-硝基苯胺。将纯化的中间体溶于DCM(3mL)中并置于氩气下。加入五甲基苯(106mg,0.72mmol,2当量),并将反应冷却至-78℃。缓慢加入BCl3的溶液(1M DCM,0.72mL,2当量)并将反应物搅拌15分钟。通过加入饱和NaHCO3溶液(2mL)淬灭反应,并使烧瓶温热至室温。将反应混合物用水(10mL)稀释,并用DCM(2×20mL)萃取。合并有机层,用Na2SO4干燥,并减压浓缩。通过快速色谱法(7-60%EtOAc的己烷溶液)纯化,得到为浅黄色固体的产物(22mg,0.05mmol,14%)。1H NMR(400MHz,氯仿-d)δ8.30–8.21(m,2H),7.87–7.78(m,2H),6.90(d,J=2.2 Hz,1H),6.71(s,2H),6.66–6.49(m,2H),4.64(s,2H),3.91(s,2H),3.20(p,J=6.9 Hz,1H),2.25(s,6H),1.28–1.16(m,6H)。
Claims (45)
1.一种式I的化合物:
或其药学上可接受的盐,
其中R1是酰胺。
2.如权利要求1所述的化合物,其中所述化合物为式II:
或其药学上可接受的盐,
其中R2是烷基氨基。
3.如权利要求1所述的化合物,其中所述化合物为式II:
或其药学上可接受的盐,
其中R2是氨基。
4.如权利要求1或2所述的化合物,其中所述化合物为式III:
或其药学上可接受的盐,
其中R3和R4各自独立地为H、烷基、环烷基、取代的烷基、未取代的烷基、杂烷基、饱和烷基、不饱和烷基、芳基、氨基或乙氧基。
5.如权利要求4所述的化合物或其药学上可接受的盐,其中R3是甲基并且R4是甲基。
6.如权利要求4所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3为H、羟基、氨基、甲基、乙基、丙基、环丙基、2-羟基乙基、1-羟基丙-2-基、2-羟基丙基、2-氨基乙基乙酸酯、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、苯基、(4-硝基)苯基、2-苯基乙基2-(2-羟基苯基)乙基、2-(3-羟基苯基)乙基、2-(3,4-二羟基苯基)乙基、3-氟乙基;S-甲基磺酰基、1-(2-羟基乙基)-2-羟基乙基、2-丙烯基、2-丙炔基、甲氧基、2-乙基磺酸钠、氰基甲基或氧杂环丁烷基。
7.如权利要求1或2所述的化合物,其中所述化合物为式III:
或其药学上可接受的盐,
其中R4选自H和C1-6烷基;并且
R3是:
(a)H、OH、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、C2-6烯基、C2-6炔基、C3-6环烷基,或含有一个选自O、N和S的杂原子的3-至6-元杂环基环;或
(b)任选被1、2或3个取代基取代的C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环,或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;
(c)任选被1、2或3个取代基取代的-O-C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环,或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或
(d)任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基。
8.如权利要求7所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是:
(a)H、OH、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、C2-6烯基、C2-6炔基、C3-6环烷基,或含有一个选自O、N和S的杂原子的3-至6-元杂环基环;或
(b)任选被1、2或3个取代基取代的C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环,或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或
(c)任选被1、2或3个取代基取代的-O-C1-6烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环,或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或
(d)任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基。
9.如权利要求7或8所述的化合物,或其药学上可接受的盐,其中R3为:
(a)H、OH、NH2、-SO2H、-SO2(C1-3烷基)、C2-3烯基、C2-3炔基、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环;或
(b)任选被1、2或3个取代基取代的C1-4烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-(C1-6烷基)2、-SO2H、-SO2(C1-3烷基)、CN、C3-6环烷基,含有一个选自O,N和S的杂原子的3-至6-元杂环基,或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或
(c)任选被1、2或3个取代基取代的-O-C1-4烷基,所述取代基各自独立地选自OH、卤素、NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-SO2H、-SO2(C1-6烷基)、CN、C3-6环烷基、含有一个选自O、N和S的杂原子的3-至6-元杂环基环,或任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基;或
(d)任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代的苯基。
10.如权利要求7-9中任一项所述的化合物,或其药学上可接受的盐,其中R3是:
(a)H、OH、NH2、-SO2H、-SO2(CH3)、C2-3烯基、C2-3炔基、C3-6环烷基、含有一个氧杂原子的3-至6-元杂环基环;或
(b)任选被1、2或3个取代基取代的C1-4烷基,所述取代基各自独立地选自OH、F、NH2、-SO2H、-SO2(CH3)、CN、C3-6环烷基、含有一个氧杂原子的3-至6-元杂环基环,或任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代的苯基;或
(c)任选被1、2或3个取代基取代的-O-C1-4烷基,所述取代基各自独立地选自OH、F、NH2、-SO2H、-SO2(CH3)、CN、C3-6环烷基、含有一个氧杂原子的3-至6-元杂环基环,或任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代的苯基;或
(d)任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代的苯基。
11.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是-(CH2)n1-苯基,并且其中n1是选自0、1、2、3或4的整数,并且苯环任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代。
12.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是-(CH2)n2-苯基,其中n2是选自0、1或2的整数,并且苯环任选被1、2或3个各自独立地选自由OH、NO2和卤素组成的组的取代基取代。
13.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是-(CH2)n2-苯基,其中n2是选自0、1或2的整数,并且苯环任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代。
14.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是-(CH2)-苯基,其中所述苯环任选被1、2或3个各自独立地选自由OH、NO2和F组成的组的取代基取代。
15.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是任选被1、2或3个取代基取代的C1-6烷基,所述取代基各自独立地选自由以下组成的组:OH、F、NH2、-SO2H、-SO2(CH3)、CN、C3-6环烷基和含有一个氧杂原子的3-至6-元杂环基环。
16.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是任选被1、2或3个取代基取代的C1-4烷基,每个取代基独立地选自由以下组成的组:OH、F、NH2、-SO2H、-SO2(CH3)、CN、C3-6环烷基和含有一个氧杂原子的3-至6-元杂环基环。
17.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是任选被1、2或3个取代基取代的C1-6烷基,所述取代基各自独立地选自由OH、F、NH2、CN、-SO2H和-SO2(C1-6烷基)组成的组。
18.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是任选被1、2或3个OH取代基取代的C1-6烷基。
19.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是任选被1、2或3个OH取代基取代的C1-4烷基。
20.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是任选被1、2或3个F取代基取代的C1-6烷基。
21.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是任选被1、2或3个F取代基取代的C1-4烷基。
22.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是任选被1、2或3个F取代基取代的-O-C1-6烷基。
23.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是任选被1、2或3个F取代基取代的-O-C1-4烷基。
24.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是-O-C1-6烷基。
25.如权利要求1、2、4和7中任一项所述的化合物,其中所述化合物为式IV:
或其药学上可接受的盐,
其中R3是-O-C1-4烷基。
26.如权利要求1或2所述的化合物,其中所述化合物为式III:
或其药学上可接受的盐,
其中R3和R4各自独立地为H、取代的脂族、未取代的脂族、取代的苯基、未取代的苯基、ORN1、-N(RN1)2或-SO2(RN2),
其中每个RN1独立地为H、取代的脂族或未取代的脂族,并且RN2是OH、未取代的脂族或取代的脂族;
前提是如果一个RN是ORN1、-N(RN1)2或-SO2(RN2),则另一个RN是H、取代的脂族、未取代的脂族、取代的苯基或未取代的苯基。
27.如权利要求26所述的化合物,或其药学上可接受的盐,其中R3是H或未取代的脂族。
28.如权利要求26或27所述的化合物,或其药学上可接受的盐,其中R4是H、取代的脂族或未取代的脂族。
29.如权利要求27所述的化合物,或其药学上可接受的盐,其中R3是甲基。
30.如权利要求26-29中任一项所述的化合物,或其药学上可接受的盐,其中R4是甲基。
31.一种化合物,其选自由以下组成的组:
或其药学上可接受的盐。
32.如权利要求1所述的化合物,其中所述化合物选自由以下组成的组:
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-羟基乙基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(1-羟基丙-2-基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-羟基丙基)乙酰胺;
2-(2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰氨基)乙烷-1-乙酸铵;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
N-(2,2-二氟乙基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2,2,2-三氟乙基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-甲基乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-羟基苯基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-N-(3-羟基苯基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(2-(甲基磺酰氨基)乙基)乙酰胺;
N-(1,3-二羟基丙-2-基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-丙基乙酰胺;
N-(2-氟乙基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
N-烯丙基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(丙-2-炔-1-基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-甲氧基乙酰胺;
N-(3,4-二羟基苯乙基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-苯乙基乙酰胺;
N-羟基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰肼;
2-(2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰氨基)乙烷-1-磺酸盐
N-环丙基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N,N-二甲基乙酰胺;
N-乙基-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
N-(氰基甲基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
N-(3-氟苯基)-2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)乙酰胺;
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(氧杂环丁烷-3-基)乙酰胺;和
2-(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)-N-(4-硝基苯基)乙酰胺,或其药学上可接受的盐。
33.一种药物组合物,其包含如权利要求1-5中任一项所述的药学上有效量的所述化合物,或其药学上可接受的盐,和一种或多种药学上可接受的载体。
34.一种治疗患有神经退行性疾病的受试者的方法,所述方法包括:向所述受试者施用如权利要求1-32中任一项所述的药学上有效量的所述化合物,或其药学上可接受的盐,或如权利要求6所述的药物组合物,从而治疗所述神经退行性疾病。
35.如权利要求34所述的方法,其中所述神经退行性疾病是脱髓鞘疾病。
36.如权利要求34或35所述的方法,其中所述神经退行性疾病是X-连锁的肾上腺脑白质营养不良或多发性硬化。
37.如权利要求34-36中任一项所述的方法,其中所述神经退行性疾病选自由以下组成的组:急性播散性脑脊髓炎、急性出血性脑白质炎、成人雷夫叙姆病、亚历山大病、阿尔茨海默氏病、巴洛同心硬化症、卡纳万病、脑桥中央髓鞘溶解症、脑瘫、脑腱性黄瘤病、慢性炎性脱髓鞘性多发性神经病、德维克氏综合征、弥漫性髓鞘硬化症、格林-巴利综合征、特发性炎性脱髓鞘病、婴儿雷夫叙姆病、克拉伯病、莱伯遗传性视神经病变、马尔堡多发性硬化症、Marchiafava-Bignami病、异染性脑白质营养不良、多灶性运动神经病变、副蛋白质脱髓鞘多发性神经病、Pelizaeus-Merzbacher病、腓骨肌萎缩症、进行性多灶性脑白质病、横贯性脊髓炎、热带痉挛性下肢瘫痪、范德纳氏病、X连锁肾上腺脑白质营养不良和齐维格综合症。
38.一种治疗患有阿尔茨海默氏病的受试者的方法,所述方法包括:向所述受试者施用如权利要求1-32中任一项所述的药学上有效量的所述化合物,或其药学上可接受的盐,或如权利要求33所述的药物组合物,从而治疗所述阿尔茨海默氏病。
39.一种治疗患有疾病或病症的受试者的方法,所述疾病或病症选自由以下组成的组:急性播散性脑脊髓炎(ADEM)、急性出血性脑白质炎(AHL或AHLE)、成人雷夫叙姆病、婴儿雷夫叙姆病、亚历山大病、阿尔茨海默氏病、巴洛同心硬化症、卡纳万病、脑桥中央髓鞘溶解症(CPM)、脑瘫、脑腱性黄瘤病、慢性炎性脱髓鞘性多发性神经病(CIDP)、德维克氏综合征、弥漫性髓鞘硬化症、脑脊髓炎、格林-巴利综合征、特发性炎性脱髓鞘病(IIDD)、克拉伯病、莱伯遗传性视神经病变、脑白质营养不良、马尔堡多发性硬化症、Marchiafava-Bignami病、异染性脑白质营养不良(MLD)、多灶性运动神经病变(MMN)、多发性硬化症(MS)、副蛋白质脱髓鞘多发性神经病、Pelizaeus-Merzbacher病(PMD)、进行性多灶性脑白质病(PML)、热带痉挛性下肢瘫痪(TSP)、X连锁肾上腺脑白质营养不良(X-ALD、ALD或X-连锁ALD)和齐维格综合症,所述方法包括:向所述受试者施用如权利要求1-32中任一项所述的药学上有效量的所述化合物,或其药学上可接受的盐,或如权利要求33所述的药物组合物,从而治疗所述疾病或病症。
40.如权利要求1-32中任一项所述的化合物,或其药学上可接受的盐,或如权利要求33所述的药物组合物,其用于治疗神经退行性疾病。
41.用于如权利要求40所述用途的所述化合物,或其药学上可接受的盐,或所述药物组合物,其中所述神经退行性疾病是脱髓鞘疾病。
42.用于如权利要求40或41所述用途的所述化合物,或其药学上可接受的盐,或所述药物组合物,其中所述神经退行性疾病是X-连锁肾上腺脑白质营养不良或多发性硬化。
43.用于如权利要求40所述用途的所述化合物,或其药学上可接受的盐,或所述药物组合物,其中所述神经退行性疾病选自由以下组成的组:急性播散性脑脊髓炎、急性出血性脑白质炎、成人雷夫叙姆病、亚历山大病、阿尔茨海默氏病、巴洛同心硬化症、卡纳万病、脑桥中央髓鞘溶解症、脑瘫、脑腱性黄瘤病、慢性炎性脱髓鞘性多发性神经病、德维克氏综合征、弥漫性髓鞘硬化症、格林-巴利综合征、特发性炎性脱髓鞘病、婴儿雷夫叙姆病、克拉伯病、莱伯遗传性视神经病变、马尔堡多发性硬化症、Marchiafava-Bignami病、异染性脑白质营养不良、多灶性运动神经病变、副蛋白质脱髓鞘多发性神经病、Pelizaeus-Merzbacher病、腓骨肌萎缩症、进行性多灶性脑白质病、横贯性脊髓炎、热带痉挛性下肢瘫痪、范德纳氏病、X连锁肾上腺脑白质营养不良和齐维格综合症。
44.如权利要求1-32中任一项所述的化合物,或其药学上可接受的盐,或如权利要求33所述的药物组合物,其用于治疗阿尔茨海默氏病。
45.如权利要求1-32中任一项所述的化合物,或其药学上可接受的盐,或如权利要求33所述的药物组合物,其用于治疗选自由以下组成的组的疾病或病症:急性播散性脑脊髓炎(ADEM)、急性出血性脑白质炎(AHL或AHLE)、成人雷夫叙姆病、婴儿雷夫叙姆病、亚历山大病、阿尔茨海默氏病、巴洛同心硬化症、卡纳万病、脑桥中央髓鞘溶解症(CPM)、脑瘫、脑腱性黄瘤病、慢性炎性脱髓鞘性多发性神经病(CIDP)、德维克氏综合征、弥漫性髓鞘硬化症、脑脊髓炎、格林-巴利综合征、特发性炎性脱髓鞘病(IIDD)、克拉伯病、莱伯遗传性视神经病变、脑白质营养不良、马尔堡多发性硬化症、Marchiafava-Bignami病、异染性脑白质营养不良(MLD)、多灶性运动神经病变(MMN)、多发性硬化症(MS)、副蛋白质脱髓鞘多发性神经病、Pelizaeus-Merzbacher病(PMD)、进行性多灶性脑白质病(PML)、热带痉挛性下肢瘫痪(TSP)、X连锁肾上腺脑白质营养不良(X-ALD、ALD或X-连锁ALD)和齐维格综合症。
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IL264765B2 (en) | 2024-03-01 |
BR112019002799A8 (pt) | 2022-07-05 |
MX2019001634A (es) | 2019-08-29 |
CA3033720A1 (en) | 2018-02-15 |
US11325886B2 (en) | 2022-05-10 |
AU2017310535A1 (en) | 2019-02-28 |
WO2018032012A1 (en) | 2018-02-15 |
IL264765B1 (en) | 2023-11-01 |
JP7140748B2 (ja) | 2022-09-21 |
CN109843849B (zh) | 2023-09-22 |
EP3497077A4 (en) | 2020-01-22 |
US20210284599A1 (en) | 2021-09-16 |
RU2019106656A (ru) | 2020-09-21 |
IL264765A (zh) | 2019-04-30 |
KR102537274B1 (ko) | 2023-05-25 |
RU2019106656A3 (zh) | 2021-01-12 |
RU2759913C2 (ru) | 2021-11-18 |
AU2017310535B2 (en) | 2021-11-11 |
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