CN102405209A - 二酰基乙二胺化合物 - Google Patents

二酰基乙二胺化合物 Download PDF

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CN102405209A
CN102405209A CN2010800174268A CN201080017426A CN102405209A CN 102405209 A CN102405209 A CN 102405209A CN 2010800174268 A CN2010800174268 A CN 2010800174268A CN 201080017426 A CN201080017426 A CN 201080017426A CN 102405209 A CN102405209 A CN 102405209A
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河野友昭
米德康博
花泽毅
二川原充启
福留裕树
盛谷浩史
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Astellas Pharma Inc
Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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Abstract

本发明提供一种可用作抗肥胖药的化合物。本发明人对有望用作用于治疗肥胖、II型糖尿病、脂肪肝、以及由它们引起的相关疾病的药物组合物的有效成分、并且具有DGAT1抑制作用的化合物进行了研究，发现本发明的二酰基乙二胺化合物具有优异的DGAT1抑制作用，从而完成本发明。即，本发明的二酰基乙二胺化合物具有DGAT1抑制作用，可用作肥胖、II型糖尿病、脂肪肝、以及相关疾病的预防剂和/或治疗剂。

Description

二酰基乙二胺化合物
技术领域
本发明涉及可用作医药组合物(例如，用于治疗肥胖症的医药组合物)的有效成分的二酰基乙二胺化合物。
背景技术
肥胖症是这样一种状态：在生物体内，能量摄取与能量消耗的平衡破坏，剩余的能量以中性脂肪(主要是甘油三酸酯)的形式过剩地蓄积在脂肪组织中；肥胖症与耐胰岛素性、糖尿病、动脉硬化、非酒精性脂肪性肝炎、或高血压等疾病的发病、发展密切相关。另外，已知的是，除了在脂肪组织中之外，过剩的甘油三酸酯在肝脏、肌肉等中的蓄积也会引起这些组织中的功能障碍。近年来，随着生活习惯的改变，肥胖症患者有所增加，但是，针对这些肥胖症患者的治疗方法有限，人们期望开发新的肥胖治疗药物。
DGAT是与甘油三酸酯生物合成途径的最终阶段(即，由二酰基甘油和脂肪酸酰基CoA生成甘油三酸酯的反应)有关的酶，据报告，DGAT有DGAT1、DGAT2亚型。已知DGAT1与DGAT2的氨基酸序列的同源性低，而与ACAT的同源性高(Proc.Nat.Acad.Sci.95：13018-13023，1998；J.Biol.Chem.276：38870-38876，2001)。作为DGAT1敲除小鼠的表现形式，据报道有对由高脂肪食物诱发的肥胖的耐性、耐胰岛素性改善、瘦素(leptin)感受性亢进、肝脏中脂肪量降低、能量消耗亢进等(Nature Genetics 25：87-90，2000；J.Clin.Invest.109：1049-1055，2002)。另外，由于DGAT1杂合子敲除小鼠显示出介于野生型小鼠和纯合子缺失小鼠之间的表现形式(Arterioscler.Thromb.Vasc.Biol.25；482-486，2005)，因此据认为，DGAT1抑制可有望作为肥胖、II型糖尿病、脂肪肝、以及由它们引起的相关疾病的药物治疗的目标。
例如，据报道，下式所示化合物具有DGAT1抑制作用(专利文献1)。
Figure BPA00001447484600021
[式中的符号参见该公报]
另外，据报道，下式所示化合物具有DGAT1抑制作用(专利文献2)。
Figure BPA00001447484600022
[式中的符号参见该公报]
另外，据报道，下式所示化合物具有DGAT1抑制作用(专利文献3)。
Figure BPA00001447484600031
[式中的符号参见该公报]
进一步，除了上述之外，有人还报道了具有DGAT1抑制作用的化合物(专利文献4、专利文献5、专利文献6、专利文献7)。
另外，也有几个关于二酰基乙二胺化合物的报道(专利文献8、非专利文献1)。
但是，上述文献中均没有公开或暗示本发明涉及的式(I)所示化合物或其盐。
现有技术文献
专利文献
专利文献1：国际公开WO 2006/082952号小册子
专利文献2：国际公开WO 2008/011130号小册子
专利文献3：国际公开WO 2008/011131号小册子
专利文献4：国际公开WO 2007/141517号小册子
专利文献5：国际公开WO 2007/138304号小册子
专利文献6：国际公开WO 2007/138311号小册子
专利文献7：国际公开WO 2006/064189号小册子
专利文献8：国际公开WO 2009/076618号小册子
非专利文献
非专利文献1：Chemical Research in Chinese Universities，2009年、第25卷、第2期、178～182页
发明内容
本发明要解决的问题
本发明提供一种可用作医药组合物(例如，用于治疗肥胖症的医药组合物)的有效成分的二酰基乙二胺化合物。
解决问题的手段
本发明人对具有DGAT1抑制作用的化合物进行了深入研究，结果发现本发明的二酰基乙二胺化合物具有DGAT1抑制作用，从而完成本发明。
即，本发明涉及式(I)所示化合物或其盐、以及含有式(I)所示化合物或其盐及可药用赋形剂的医药组合物。
Figure BPA00001447484600041
(式中，
A为可被取代的芳基、可被取代的环烷基、可被取代的芳香族杂环、可被取代的非芳香族杂环、或式(II)所示基团，
R11和R12相同或不同，为-H、C1-6烷基、可被取代的芳基、可被取代的C3-8环烷基，但是，R11和R12不同时为-H，
此处，R11和R12可以与所结合的氮原子一起形成一体而形成可被取代的环氨基；
环B1为亚苯基、吡啶二基、萘二基或1，2，3，4-四氢萘二基，这些基团分别可以被选自由-OH、可被1个以上的卤素取代的C1-6烷基、可被1个以上的卤素取代的-O-C1-6烷基、C3-8环烷基和卤素构成的组中的1个以上的基团取代；
W为-O-、键、-O-C1-6亚烷基、-NH-、或C1-6亚烷基；
环B2为环己烷二基、环戊烷二基或桥环，这些基团分别可被C1-6烷基取代，在W为键的情况下，环B2可以为哌啶二基或8-氮杂双环[3.2.1]辛烷二基；
Y为键、C1-6亚烷基、或-O-C1-6亚烷基；
Z为：-CO2H或其生物电子等排体；可被选自由C1-6烷基(该C1-6烷基可被氨基或羧基取代)、苯基及苄基构成的组中的1个或2个基团取代的氨基甲酰基；-CO-(可被1个或2个C1-6烷基取代的环氨基)；-OH；可被1个或2个C1-6烷基取代的氨基；-NH-C(＝O)-C1-6烷基；或-NH-C(＝O)-C3-8环烷基。)
另外，只要没有特别的记载，当本说明书中的某个化学式中的符号也用于其他化学式中时，相同的符号表示相同的意思。
另外，本发明还涉及含有式(I)所示化合物或其盐的用于预防或治疗肥胖的医药组合物。另外，该医药组合物包括含有式(I)所示化合物或其盐的肥胖预防剂或治疗剂。
本发明还涉及式(I)所示化合物或其盐用于制备预防或治疗肥胖用医药组合物的用途、用于预防或治疗肥胖的式(I)所示化合物或其盐、以及包括给对象施予有效量的式(I)所示化合物或其盐的预防或治疗肥胖的方法。此外，所谓“对象”是指需要该预防或治疗的人或其他动物，作为某些实施方案，为需要该预防或治疗的人。
发明效果
式(I)所示化合物或其盐具有DGAT1抑制作用，可用作肥胖的预防剂和/或治疗剂。
具体实施方式
以下对本发明进行详细说明。
本说明书中，所谓“烷基”包括直链烷基及支链烷基。因此，“C1-6烷基”是指直链或支链的碳数为1～6的烷基，例如，甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基等，作为其他实施方案为甲基、乙基、丙基、异丙基，进一步作为其他实施方案为甲基、乙基，更进一步作为其他实施方案为甲基。
所谓“亚烷基”为将上述“烷基”中的任意1个氢原子除去后形成的二价基团。因此，“C1-6亚烷基”是指直链或支链的碳数为1～6的亚烷基，例如，亚甲基、亚乙基、三亚甲基、四亚甲基、五亚甲基、六亚甲基、甲基亚甲基、二甲基亚甲基、乙基亚甲基、甲基亚乙基、二甲基亚乙基、乙基亚乙基等，作为其他实施方案为亚甲基、亚乙基，进一步作为其他实施方案为亚甲基。
所谓“芳基”为碳数6～14的单环至三环芳香烃环基。具体来说，例如为苯基、萘基，作为其他实施方案为苯基，进一步作为其他实施方案为萘基。
所谓“环烷基”是指3～8元环的饱和环烃基，该环烷基可具有桥环，可以与苯环稠合，一部分键可以为不饱和的。具体来说，可以列举(例如)环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环辛基、环辛二烯基、降冰片烯基、双环[2.2.2]辛基、双环[3.1.1]庚基、双环[4.1.0]庚基、双环[3.2.1]辛基、金刚烷基、茚满基、茚基、1，2-二氢萘基、1，2，3，4-四氢萘基等。
所谓“桥环”是指具有6～10元桥环的饱和烃环的2价基团。具体来说，可以列举(例如)双环[3.1.0]己烷、降莰烷、双环[2.2.2]辛烷、双环[3.1.1]庚烷、双环[4.1.0]庚烷、双环[3.2.1]辛烷、金刚烷等的2价基团。
所谓“芳香族杂环”是指含有选自O、N和S中的1个以上杂原子作为环构成原子的5～6元芳香族杂环基，该芳香族杂环可以与苯环或者噻吩环稠合。具体来说，可以列举(例如)吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、
Figure BPA00001447484600061
唑基、噻唑基、二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并
Figure BPA00001447484600063
唑基、苯并噻唑基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、硫代吡啶基、硫代嘧啶基、硫代吡嗪基等。
所谓“非芳香族杂环”是指含有选自O、N和S中的1个以上杂原子作为环构成原子的3～7元非芳香族杂环基，该非芳香族杂环可以与苯环、噻吩环或环己烷环稠合，并且一部分键可以是不饱和的。另外，作为环构成原子的硫原子可以被氧化。具体来说，可以列举(例如)吖丙啶基、吖丁啶基、吡咯烷基、哌啶基、氮杂环庚烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、硫杂环丁基、四氢噻吩基、四氢硫代吡喃基、1，1-二氧代四氢硫代吡喃基、
Figure BPA00001447484600071
唑烷基、噻唑烷基、1，1-二氧代噻唑烷基、异唑烷基、异噻唑烷基、1，1-二氧代异噻唑烷基、哌嗪基、吗啉基、硫代吗啉基、1，1-二氧代硫代吗啉基、二
Figure BPA00001447484600073
烷基、二氢吲哚基、异二氢吲哚基、二氢喹啉基、四氢喹啉基、二氢异喹啉基、四氢异喹啉基、十氢异喹啉基、四氢硫代吡啶基、四氢苯并氮杂
Figure BPA00001447484600074
四氢苯并二氮杂
Figure BPA00001447484600075
二氢苯并呋喃基、二氢苯并噻吩基、二氢苯并吡喃基、二氢苯并噻喃基、二氢苯并二
Figure BPA00001447484600076
烷基、苯并二氧杂环戊二烯基等。
所谓“环氨基”是指上述“非芳香族杂环”中具有氮原子的基团，并且为在该氮原子上具有结合键的非芳香族杂环基，具体来说，可以列举(例如)吡咯烷-1-基、哌啶-1-基、氮杂环庚烷-1-基、
Figure BPA00001447484600077
唑烷-3-基、噻唑烷-3-基、1，1-二氧代噻唑烷-3-基、异
Figure BPA00001447484600078
唑烷-2-基、异噻唑烷-2-基、1，1-二氧代异噻唑烷-2-基、哌嗪-1-基、吗啉-4-基、硫代吗啉-4-基、1，1-二氧代硫代吗啉-4-基、二氢吲哚-1-基、异二氢吲哚-2-基、1，2，3，4-四氢喹啉-1-基、1，2，3，4-四氢异喹啉-2-基、十氢喹啉-1-基、十氢喹啉-2-基、4，5，6，7-四氢噻吩并[3，2-c]吡啶-5-基等。
所谓“卤素”是指-F、-Cl、-Br、-I，作为其他实施方案为-F、-Cl、-Br，进一步作为其他实施方案为-F、-Cl，再进一步作为其他实施方案为-F。
所谓“-CO2H或其生物电子等排体”是指-CO2H、或者具有与-CO2H同等的电子或立体构型并且具有可释放出酸性质子的共同的生物学性质的其他原子或原子团。可以列举(例如)-CO2H、-CO-NH-OH、-CO-NH-O-C1-6烷基、-CO-NH-CN、-CO-NH-SO2-C1-6烷基、-CO-NH-SO2-N(C1-6烷基)2，或者四唑基、二唑酮基、二唑硫酮基、氧杂噻二唑基、噻二唑酮基、三唑硫酮基、羟基异唑基等，作为其他实施方案为-CO2H、-CO-NH-SO2-C1-6烷基、-CO-NH-SO2-N(C1-6烷基)2或四唑基，进一步作为其他实施方案为-CO2H。
作为“亚苯基”的一些实施方案，为1，4-亚苯基；作为“吡啶二基”的一些实施方案，为吡啶-2，5-二基、或吡啶-3，6-二基；作为“萘二基”的一些实施方案，为萘-2，6-二基、或萘-3，7-二基；作为“1，2，3，4-四氢萘二基”的一些实施方案，为1，2，3，4-四氢萘-2，6-二基、或1，2，3，4-四氢萘-3，7-二基；作为“环己烷二基”的一些实施方案，为环己烷-1，4-二基；作为“环戊烷二基”的一些实施方案，为环戊烷-1，3-二基；作为“哌啶二基”的一些实施方案，为哌啶-1，4-二基；作为“8-氮杂双环[3.2.1]辛烷二基”的一些实施方案，为8-氮杂双环[3.2.1]辛烷-3，8-二基。
在本说明书中，所谓“可以被取代”是指未被取代、或者具有1～5个取代基。而且，具有多个取代基时，那些取代基可以相同，也可以相互不同。
作为式(I)的A中“可被取代的芳基”、“可被取代的环烷基”、“可被取代的芳香族杂环”、及“可被取代的非芳香族杂环”中的可容许的取代基，可以列举：
(1)卤素、
(2)可被选自由卤素、芳基、-OH、-O-C1-6烷基、-O-芳基、C3-8环烷基及氧代所构成的组中的1个以上的基团取代的C1-6烷基、
(3)分别可被选自由卤素、C3-8环烷基、-O-C1-6烷基、芳基(该芳基可被1个以上的卤素取代)及非芳香族杂环构成的组中的1个以上的基团取代的-O-C1-6烷基或-S-C1-6烷基、
(4)分别可被选自由卤素、C1-6烷基(该C1-6烷基可被1个以上的卤素取代)、-O-C1-6烷基(该C1-6烷基可被1个以上的卤素取代)、C3-8环烷基及氰基构成的组中的1个以上的基团取代的芳基或-O-芳基、
(5)分别可被1个以上的C1-6烷基取代的C3-8环烷基或-O-C3-8环烷基、
(6)分别可被选自由卤素、C1-6烷基及C3-8环烷基构成的组中的1个以上的基团取代的芳香族杂环或-O-芳香族杂环、
(7)分别可被选自由C1-6烷基(该C1-6烷基可被1个以上的芳基取代)及芳基构成的组中的1个以上的基团取代的氨基或环氨基、
(8)分别可被1个以上的卤素取代的-CO-C1-6烷基或-SO2-C1-6烷基、
(9)-OH。
作为式(I)的R11或R12中“可被取代的芳基”、“可被取代的环烷基”、“可被取代的环氨基”中的可容许的取代基，可以列举：
(1)卤素、
(2)可被选自由卤素、芳基、-OH、-O-C1-6烷基、-O-芳基、C3-8环烷基以及氧代所构成的组中的1个以上基团取代的C1-6烷基、
(3)分别可被选自由卤素、C3-8环烷基、-O-C1-6烷基、芳基(该芳基可被1个以上的卤素取代)以及非芳香族杂环所构成的组中的1个以上基团取代的-O-C1-6烷基或-S-C1-6烷基、
(4)分别可被选自卤素、C1-6烷基(该C1-6烷基可被1个以上的卤素取代)、-O-C1-6烷基(该C1-6烷基可被1个以上的卤素取代)、C3-8环烷基以及氰基所构成的组中的1个以上基团取代的芳基或-O-芳基、
(5)分别可被1个以上的C1-6烷基取代的C3-8环烷基或-O-C3-8环烷基。
以下示出式(I)所示的化合物或其盐的一些实施方案。
(1)式(I)所示的化合物或其盐，其中，A为可被取代的芳基、可被取代的环烷基、可被取代的芳香族杂环、可被取代的非芳香族杂环、或式(II)所示基团；R11及R12相同或不同，为-H、可被取代的芳基、可被取代的C3-8环烷基，但是，R11和R12不同时为-H，此处，R11和R12可以与所结合的氮原子一起形成一体而形成可被取代的环氨基。作为其他实施方案，式(I)所示的化合物或其盐，其中A为分别可被选自由氟、氯、甲基及环丙基所构成的组中的1个以上基团取代的苯基、萘基、噻吩基或苯并噻吩基。进一步作为其他实施方案，式(I)所示的化合物或其盐，其中A为萘基。进一步作为其他实施方案，式(I)所示的化合物或其盐，其中A为可被卤素取代的噻吩基。进一步作为其他实施方案，式(I)所示的化合物或其盐，其中A为可被卤素取代的苯并噻吩基。进一步作为其他实施方案，式(I)所示的化合物或其盐，其中A为可被选自氯、甲基及环丙基所构成的组中的1个以上基团取代的苯基。
(2)式(I)所示的化合物或其盐，其中，环B1为式(III)所示基团，
Figure BPA00001447484600101
其中X1为N或CR3；X2为N或CR4；R1、R2、R3及R4相同或不同，为-H、-OH、可被1个以上的卤素取代的C1-6烷基、可被1个以上的卤素取代的-O-C1-6烷基、C3-8环烷基或卤素。作为其他实施方案，式(I)所示的化合物或其盐，其中环B1为可被1个以上的卤素取代的1，4-亚苯基。进一步作为其他实施方案，式(I)所示的化合物或其盐，其中环B1为可被1个或2个氟取代的1，4-亚苯基。
(3)式(I)所示的化合物或其盐，其中W为-O-或键。作为其他实施方案，式(I)所示的化合物或其盐，其中W为-O-。
(4)式(I)所示的化合物或其盐，其中环B2为环己烷-1，4-二基。
(5)式(I)所示的化合物或其盐，其中Y为键或C1-6亚烷基。作为其他实施方案，式(I)所示的化合物或其盐，其中Y为键或亚甲基。进一步作为其他实施方案，式(I)所示的化合物或其盐，其中Y为键。进一步作为其他实施方案，式(I)所示的化合物或其盐，其中Y为亚甲基。
(6)式(I)所示的化合物或其盐，其中Z为-CO2H或其生物电子等排体、或-CONH2。作为其他实施方案，式(I)所示的化合物或其盐，其中Z为-CO2H。
(7)式(I)所示的化合物或其盐，其是上述(1)～(6)所述基团中的2者以上的组合。
本发明包含如上述(7)所记载的、上述(1)～(6)所述基团中的2者以上组合的化合物或其盐，作为其具体例子，可以列举以下实施方案。
(8)式(I)所示的化合物或其盐，其中，A为可被取代的芳基、可被取代的环烷基、可被取代的芳香族杂环、可被取代的非芳香族杂环、或式(II)所示基团；R11及R12相同或不同，为-H、可被取代的芳基、可被取代的C3-8环烷基，但是，R11和R12不同时为-H，此处，R11和R12可以与所结合的氮原子一起形成一体而形成可被取代的环氨基；环B1为式(III)所示基团；X1为N或CR3；X2为N或CR4；R1、R2、R3及R4相同或不同，为-H、-OH、可被1个以上的卤素取代的C1-6烷基、可被1个以上的卤素取代的-O-C1-6烷基、C3-8环烷基或卤素；W为-O-或键；环B2为环己烷-1，4-二基；Y为键或C1-6亚烷基；Z为-CO2H或其生物电子等排体、或-CONH2。
(9)式(I)所示的化合物或其盐，其中，环B1为可被1个以上的卤素取代的1，4-亚苯基，W为-O-，环B2为环己烷-1，4-二基，Y为键或亚甲基，Z为-CO2H。
(10)上述(9)所述的化合物或其盐，其中环B1为可被1个或2个氟取代的1，4-亚苯基。
(11)上述(10)所述的化合物或其盐，其中Y为键。
作为式(I)所示化合物或其盐所包含的具体化合物的例子，可以列举以下化合物。
顺式-4-[4-({2-[(4-环丙基苯甲酰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸、
顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-[4-({2-[(4-氯-3-甲基苯甲酰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸、
顺式-4-(3-氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-(3，5-二氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-(2，3-二氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-(2，5-二氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-{4-[(2-{[(3-氯-1-苯并噻吩-2-基)羰基]氨基}乙基)氨基甲酰基]苯氧基}环己烷羧酸、
顺式-4-{4-[(2-{[(5-氯噻吩-2-基)羰基]氨基}乙基)氨基甲酰基]-2，3-二氟苯氧基}环己烷羧酸、
顺式-4-{3-氟-4-[(2-{[(5-氟-1-苯并噻吩-2-基)羰基]氨基}乙基)氨基甲酰基]苯氧基}环己烷羧酸、
[顺式-4-(2，5-二氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己基]乙酸、
以及它们的盐。
根据取代基的种类，式(I)所示化合物中可存在互变异构体或几何异构体。在本说明书中，虽然仅记载了式(I)所示化合物的异构体的一种形态，但是除此之外其他的异构体、异构体经分离后得到的物质、或这些异构体的混合物也包括在本发明之内。
另外，当式(I)所示化合物中具有不对称碳原子或轴不对称时，可以存在基于这些不对称碳原子或轴不对称的光学异构体。本发明也包括式(I)所示化合物的光学异构体经分离后得到的物质、或者它们的混合物。
此外，本发明还包括式(I)所示化合物的可药用的前药。可药用的前药为具有这样的基团的化合物，该基团通过溶剂分解或者在生理学条件下可以转换为氨基、羟基、羧基等。作为形成前药的基团，可以列举(例如)在Prog.Med.，5，2157-2161(1985)或“医薬品の開発”(廣川书店、1990年)第7卷 分子设计第163-198页中所记载的基团。
而且，式(I)所示化合物的盐为式(I)所示化合物的可药用的盐，根据取代基的种类，有时候形成酸加成盐或者与碱形成盐。具体而言，可以列举与无机酸(例如，盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等)形成的酸加成盐、与有机酸(例如，甲酸、醋酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、扁桃酸、酒石酸、二苯甲酰酒石酸、二对甲基苯甲酰酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、天门冬氨酸、谷氨酸等)形成的酸加成盐、与无机碱(例如，钠、钾、镁、钙、铝等)形成的盐、与有机碱(例如，甲胺、乙胺、乙醇胺、赖氨酸、鸟氨酸等)形成的盐、与各种氨基酸(例如，乙酰基亮氨酸等)以及氨基酸衍生物形成的盐、或铵盐等。
此外，本发明还包括式(I)所示化合物及其盐的各种水合物、溶剂合物以及多晶态物质。而且，本发明还包括用各种放射性同位素或非放射性同位素标记的化合物。
(制备方法)
式(I)所示化合物及其盐，可利用基于其基本骨架或取代基种类的特征，采用各种已知的合成方法来制备。在制备过程中，根据官能团的种类，在原料至中间体的阶段中，采用适当的保护基(其是能够容易地转化成为该官能团的基团)来替换该官能团，这在制备技术上有时是有效的。作为这样的保护基团，可以列举(例如)在P.G.M.Wuts和T.W.Greene著的“Greene’s Protective Groups in OrganicSynthesis(第4版，2006年)”中所记载的保护基等，并且可以根据它们的反应条件来适当地选择使用这些保护基。在这样的方法中，引入该保护基团并进行反应之后，根据需要除去该保护基团，从而可以得到所期望的化合物。
另外，与上述保护基的情况相同，在原料至中间体的阶段中引入特定的基团、或者使用所获得的式(I)所示化合物来进一步进行反应，从而可以制备式(I)所示化合物的前药。可采用通常的酯化、酰胺化、脱水等本领域技术人员公知的方法来进行所述反应。
以下，对式(I)所示化合物的代表性制备方法进行说明。也可以参照本说明书随附的参考文献来进行各制备方法。另外，本发明的制备方法并不局限于以下所示的例子。
(第一制备方法)
Figure BPA00001447484600141
(式中，-CO2R表示烷基酯或苄基酯等酯基(例如，甲氧基羰基、乙氧基羰基、叔丁氧基羰基、苄氧基羰基等))
本制备方法是将化合物1a水解以制备作为本发明化合物的化合物(I-a)的方法。
水解反应可以参照前述的“Greene’s Protective Groups in OrganicSynthesis(第4版，2006年)”来进行。
(第二制备方法)
Figure BPA00001447484600142
(式中，Z1表示-CONH2或-CO2H的生物电子等排体)
本制备方法为这样的步骤：将第一制备方法所制备的作为本发明化合物的化合物(I-a)的羧基转变为甲酰胺基或羧基的生物电子等排体。
例如，在Z1为-CO-NH-SO2-C1-6烷基或-CO-NH-SO2-N(C1-6烷基)2的情况下，可以通过与对应的磺酰胺等进行稠合反应而制得；例如，在Z1为-CONH2的情况下，可以通过使用了氯化铵、氢氧化铵、氨水溶液等的稠合反应来制备；例如，在Z1为四唑基的情况下，诱导为甲酰胺之后，通过常规方法脱水以诱导为硝基，并且与叠氮化钠作用，从而制备。另外，可以采用本领域技术人员已知的方法将羧基转化为其生物电子等排体。
(原料合成1)
Figure BPA00001447484600151
(式中，A1表示分别可被取代的芳基、环烷基、芳香族杂环、或非芳香族杂环)
本制备方法为制备化合物2c的方法，该化合物2c为在作为第一制备方法的原料化合物的化合物1a中A为分别可被取代的芳基、环烷基、芳香族杂环、或非芳香族杂环的化合物。
(第一步骤)
本步骤为这样的步骤：将乙二胺加成到根据国际公开第WO2007/115935号小册子中记载的方法或基于该方法的方法而制备的化合物2a上。化合物2b例如可以这样制备：使其中一个氨基被保护了的乙二胺与化合物2a缩合，并且除去氨基的保护基。
可以在缩合剂的存在下，在对于反应呈惰性的溶剂中，在从冷却至加热的条件下、优选在-20℃～60℃下，使用等摩尔或者其中一者为过量的化合物2a和其中一个氨基被保护了的乙二胺，通常搅拌0.1小时～5天，以进行缩合反应。此处，对所用溶剂的例子没有特别的限定，可以列举芳烃类(例如苯、甲苯、二甲苯等)、卤代烃类(例如二氯甲烷、1，2-二氯乙烷、氯仿等)、醚类(例如二乙醚、四氢呋喃(THF)、二
Figure BPA00001447484600161
烷、二甲氧基乙烷等)、N，N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、醋酸乙酯、乙腈、水、或者它们的混合物。作为缩合剂的例子，可以列举1-(3-二甲氨基丙基)-3-乙基碳化二亚胺、二环己基碳化二亚胺、1，1′-羰基二咪唑、叠氮磷酸二苯酯、三氯氧磷等，但是并不局限于这些。有时使用1-羟基苯并三唑等添加剂对反应的进行是有利的。另外，有时使用有机碱(例如三乙胺、N，N-二异丙基乙胺、N-甲基吗啉等)、或者无机碱(例如碳酸钾、碳酸钠、氢氧化钾等)对于反应的进行是有利的。
氨基的保护基的除去反应可以参照前述的“Greene’s ProtectiveGroups in Organic Synthesis(第4版，2006年)”来进行。
(第二步骤)
本步骤是将化合物2b酰基化的步骤。
酰基化时，可以采用化合物2b和对应的羧酸(A1-CO2H)、并利用本制备方法第一步骤前段的方法来进行，除此之外，也可以在将对应的羧酸转化为反应性衍生物之后再与化合物2b反应来进行。作为羧酸的反应性衍生物的例子，可以列举与三氯氧磷、亚硫酰氯等卤化剂反应而得到的酰卤化物、与氯甲酸异丁酯等反应而得到的混合酸酐、与1-羟基苯并三唑等缩合而得到的活性酯等。在对于反应呈惰性的溶剂中，在冷却至加热的条件下、优选在-20℃～60℃下，通常搅拌0.1小时～5天，以进行这些反应性衍生物与化合物2b的反应。此处对于所用溶剂的例子没有特别限定，可以列举卤代烃类、醚类、芳香烃类、或者它们的混合物。
(原料合成2)
[化学式10]
Figure BPA00001447484600171
本制备方法为制备在作为第一制备方法的原料化合物的化合物1a中，A为式(II)所示基团的化合物3a的方法。
本制备方法为将氨基羰基加成到化合物2b上以制备化合物3c的方法。
使用胺(HN(-R11)(-R12))时，可以将1，1’-羰基二咪唑、光气、三光气等用作羰基来源。该反应可以这样进行：使用等摩尔或者其中任意一者过剩的化合物2b、对应的胺以及羰基来源，将它们的混合物在对反应呈惰性的溶剂中，在冷却至加热下、优选在室温至回流条件下，通常搅拌0.1小时～5天。此处对于所用溶剂的例子没有特别限定，可以列举醚类、卤代烃类、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲基亚砜、或者它们的混合物。有时使用三乙胺、N，N-二异丙基乙胺、N-甲基吗啉、吡啶等碱对于反应的进行是有利的。
另外，在-R11和-R12中的一者为-H时(例如，-R12为-H时)，可以使用对应的异氰酸酯(R11-N＝C＝O)，在这种情况下，使用等摩尔或其中任意一者过剩的化合物2b和对应的异氰酸酯，将它们的混合物在对反应呈惰性的溶剂中，在冷却至加热下、优选在加热或加热回流条件下，通常搅拌0.1小时～5天来进行。此处对于所用溶剂的例子没有特别限定，可以列举醚类、卤代烃类、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲基亚砜、或者它们的混合物。另外，例如，也可以通过使用了对应的羧酸和叠氮磷酸二苯酯的Curtius重排，在反应体系中生成异氰酸酯以进行使用。
(原料合成3)
[化学式11]
Figure BPA00001447484600181
本制备方法为制备在作为第一制备方法的原料化合物的化合物1a中，W为-O-的化合物4e的方法。
(第一步骤)
本步骤为将化合物4b缩合至根据Journal of MedicinalChemistry、1993年、第36卷、第24期、第3968-3970页中记载的方法或基于该方法而制备的化合物4a上的步骤。
缩合反应可以采用原料合成1第一步骤前段中所记载的方法、或第二步骤中所记载的方法来进行。
(第二步骤)
本步骤为使化合物4c和化合物4d缩合的步骤。
缩合反应中，可以采用本领域技术人员通常采用的光延反应。光延反应可以这样进行：使用等摩尔或其中一者过剩的化合物4c和化合物4d，使用它们的混合物、以及由三丁基膦、三苯基膦等磷化合物与偶氮二甲酸乙酯、1，1’-(偶氮二甲酰)二哌啶等偶氮二甲酰基化合物调制的活化剂、或者氰基亚甲基三丁基膦等试剂，在对反应呈惰性的溶剂中，在冷却至加热下、优选在室温～加热条件下，通常搅拌0.1小时～5天。此处对于所用溶剂的例子没有特别的限定，可以列举卤代烃类、醚类、芳香烃类、或者它们的混合物。
另外，本步骤中，也可以采用烷基化反应。进行烷基化反应时，可以这样进行：将化合物4c或化合物4d的羟基转换成离去基团(例如，氯、溴、碘等卤素、或者诸如甲磺酰基氧基、乙磺酰基氧基、苯磺酰基氧基、4-甲基苯磺酰基氧基、三氟甲磺酰基氧基等磺酰基氧基)，在适当的碱的存在下，在对反应呈惰性的溶剂中，在冷却至加热下、优选在室温～加热下，通常搅拌0.1小时～5天。
式(I)所示的化合物被分离并纯化成为游离化合物、其盐、水合物、溶剂合物或者多晶态物质。可通过常规的成盐反应来制备式(I)所示化合物的盐。
可采用萃取、分步结晶、各种分段色谱法等常规的化学操作来进行分离、纯化。
可通过选择适当的原料化合物来制备各种异构体、或者利用异构体间的物理化学性质的差别来分离各种异构体。例如，可以采用常用的外消旋体光学拆分法(例如，诱导外消旋体与光学活性的碱或酸形成非对映异构体盐以便分步结晶、或者利用手性柱等的色谱法等)来制得光学异构体，另外也可以由合适的光学活性原料化合物来制备光学异构体。
通过以下的试验确认了式(I)所示化合物的药理活性。
试验例1 DGAT1抑制活性试验
(1)Bacmid-hDGAT1的制作
对编码人DGAT1(hDGAT1)的碱基序列(Genbank Accession No.NM_012079中CDS的1467个碱基)进行克隆，连接至pFastBacTM1(Invitrogen公司)，制作了pFastBac1-hDGAT1。使用Bac-to-Bac(注册商标)Baculovirus Expression System(Invitrogen公司)，由该质粒制备重组杆状病毒液(Bacmid-hDGAT1)。
(2)来自Sf9细胞的DGAT1表达微粒体部分的制备
将Sf9细胞播种在225cm2 Flask Angled Neck(CORNING公司)上使得汇合度(confluency)为80％，用EX-CELLTM 420 INSECTSERUM-FREE MEDIUM(SAFC Biosciences公司)，在27℃恒温培养器中静置培养。24小时后，除去培养液，添加将1.67mL重组杆状病毒液(Bacmid-hDGAT1)用3.33mL的EX-CELLTM 420INSECTSERUM-FREE MEDIUM稀释后的液体，在恒温培养器中于27℃下振摇培养1小时。然后，添加25mL的EX-CELLTM 420 INSECTSERUM-FREE MEDIUM，在恒温培养器中于27℃下培养72小时。回收感染细胞，将其混悬在含有Complete Protease Inhibitor Cocktail(Roche Diagnostics K.K.)的1.5mL缓冲液A(含有100mM Sucrose、50mM KCl的40mM磷酸缓冲液(pH 7.2))中，利用SONIFER 250(BRANSON公司)进行超声波降解。在10000×g下将该混悬液离心5分钟，回収上清液。在100000×g下将该上清液离心60分钟后，将得到的沉淀溶解在600μL的缓冲液A中，再次进行超声波降解，制得混悬液。将该混悬液作为hDGAT1表达Sf9细胞微粒体。
(3)DGAT1活性测定
测定DGAT1活性时，将100mM Tris-HCl(pH 8.0)、2mMMgCl2、0.01％BSA、溶解在二甲基亚砜(DMSO)中的被测试物质(DMSO中的最终浓度为2％)、以及hDGAT1表达Sf9细胞微粒体、200μM二油酸甘油酯或二棕榈酸甘油酯、8.9μM[14C]oleoyl-CoA、1.68％丙酮加入到phospholipid FlashPlate(PerkiElmer Life Science)中。30℃下反应60分钟后，加入反应液2倍量(100μL)的异丙醇∶0.1M碳酸缓冲液(pH 9.0)＝1∶1以使反应停止。第二天，通过TopCount多孔板闪烁计数器(PerkinElmer Life Science)来计数。
不添加被测试物质时的计数作为对照(添加DMSO时的TG)。不添加被测试物质及微粒体时的计数作为空白TG。根据下述计算式来求出被测试物质的DGAT1抑制率。
抑制率(％)＝(添加被测试物质时的TG-空白TG)÷(添加DMSO时的TG-空白TG)×100
求出被测试物质在反应液中的浓度为1、10、100、1000nM时的DGAT1抑制率。将得到的抑制率进行线性回归，利用SAS 8.2software package(SAS Institute Japan，Ltd.，Tokyo，Japan)求出使DGAT1活性被抑制50％时所需要的被测试物质浓度(IC50)。
结果，在上述试验中，几个式(I)所示化合物，以IC50值计，显示出50nM以下的DGAT1抑制作用。表1中示出了本试验中几个式(I)所示化合物的结果。
[表1]
Figure BPA00001447484600211
试验例2对施予脂肪所引起的血浆中甘油三酸酯(TG)升高的抑制作用
使8-15周龄的雄性C57BL/6J小鼠禁食4小时，经口施予被测试物质。将被测试物质混悬在0.5％甲基纤维素液中后施予。20小时后经口施予脂肪(イントラリピツド20％，テルモ株式会社(フレゼニウス)，10mL/kg)。在马上要施予脂肪之前、以及施予脂肪后2小时时从尾静脉采血，得到血浆。测定血浆中TG时，使用甘油三酸酯Eテストワコ一(和光纯薬株式会社)，算出由施予脂肪所引起的血浆中TG升高值。将0.5％甲基纤维素施予组的血浆中TG升高值作为对照，求出施予被测试物质时的TG升高抑制率。
结果，在后述实施例化合物中，实施例79的化合物在施予量为0.3mg/kg时的TG上升抑制率为79％；实施例169的化合物在施予量为0.3mg/kg时的TG上升抑制率为75％；实施例454的化合物在施予量为0.3mg/kg时的TG上升抑制率为106％；实施例469的化合物在施予量为0.3mg/kg时的TG上升抑制率为109％；实施例490的化合物在施予量为0.3mg/kg时的TG上升抑制率为92％。
试验例3D10小鼠中的抗肥胖作用
给9周龄雄性C57BL/6J小鼠喂食高脂肪食物(リサ一チダイエツトD12492，60kcal％fat)。为了驯化小鼠，从第4周开始施予试验所用的溶剂。从第5周开始每日1次或2次经口施予被测试物质。被测试物质混悬在0.5％甲基纤维素液中并施予。反复施予2周时间或4周时间，观察由施予被测试物质所引起的体重变化。以试验过程中溶剂施予组的体重增加量为100％，算出被测试物质的体重增加抑制率。
结果，在后述实施例化合物中，实施例454的化合物在施予次数为1日1次、施予时间为2周、施予量为1mg/kg的条件下的体重增加抑制率为93％；实施例490的化合物在施予次数为1日1次、施予时间为2周、施予量为1mg/kg的条件下的体重增加抑制率为98％，显示出了体重增加抑制效果。
根据上述试验结果，确认了式(I)所示化合物在饮食性肥胖模型中具有抗肥胖作用，可用于予防和/或治疗肥胖、II型糖尿病、脂肪肝等。
使用本领域中通常所使用的赋形剂(即，药用赋形剂或药用载体等)，根据通常采用的方法，可以制备含有以一种或一种以上的式(I)所示化合物或其盐作为有效成分的药物组合物。
给药时，可以通过片剂、丸剂、胶囊剂、颗粒剂、散剂、液体制剂等口服给药，或者通过关节内、静脉内、肌肉内等的注射剂、栓剂、滴眼剂、眼软膏、经皮用液体制剂、软膏剂、经皮贴剂、经粘膜液体制剂、经粘膜贴剂、吸入剂等非经口给药中的任意一种形式。
作为用于经口给药的固体组合物，可以使用片剂、散剂、颗粒剂等。在这种固体组合物中，将一种或一种以上的有效成分与至少一种惰性赋形剂混合。按照常规方法，组合物也可以含有惰性添加剂，例如润滑剂、崩解剂、稳定剂和溶解助剂。根据需要，片剂或丸剂也可以用糖衣或者胃溶性或肠溶性物质的膜进行包衣。
用于经口给药的液体组合物包括可药用的乳液剂、溶液剂、悬浮剂、糖浆剂或酏剂等，并且含有通常可使用的惰性稀释剂，例如纯化水或乙醇(EtOH)。除了惰性稀释剂以外，该液体组合物中也可以含有诸如增溶剂、润湿剂、悬浮剂之类的助剂以及甜味剂、矫味剂、芳香剂、防腐剂。
用于非经口给药的注射剂包括无菌的水性或非水性溶液制剂、悬浮剂或乳剂。水性溶剂包括(例如)注射用蒸馏水或生理盐水。非水性溶剂包括(例如)醇类(如，乙醇)。该组合物还可以含有等渗剂、防腐剂、润湿剂、乳化剂、分散剂、稳定剂、或溶解助剂。例如，可以采用通过可截留细菌的过滤器进行过滤、添加杀菌剂或者进行辐射的方法来对所述组合物进行灭菌。此外，也可以将这些组合物制成无菌的固体组合物，在使用前用无菌水或无菌的注射用溶剂来溶解或混悬而使用。
外用剂包括软膏剂、硬膏剂、霜剂、凝胶剂、贴剂、喷雾剂、洗液、滴眼剂、眼软膏等。这种外用剂含有常用的软膏基剂、洗液基剂、水性或非水性的液体制剂、悬浮剂、乳剂等。
吸入剂或经鼻剂等经粘膜剂，可以以固体、液体或半固体的状态使用，并且可以按照以往的公知方法来制备这些经粘膜剂。还可以适当地添加(例如)公知的赋形剂、还有pH调节剂、防腐剂、表面活性剂、润滑剂、稳定剂或增稠剂等。给药时可以使用合适的用于吸入或吹送的装置。例如，可以使用计量给药吸入装置等公知的装置或喷雾器，将化合物单独地或作为配方后的混合物的粉末来给药、或者可以将化合物与可药用的载体组合后作为溶液或悬浮液来给药。干燥粉末吸入器等可用于单次给药或多次给药，并可以使用干燥粉末或含有粉末的胶囊。另外，也可以采用加压气溶胶喷雾等形式，通过使用适当的抛射剂(例如，氯氟烷烃、氢氟烷烃或二氧化碳等适当的气体)来给药。
通常口服给药时，1天的给药量按体重约为0.001～100mg/kg，优选为0.1～30mg/kg，更优选为0.1～10mg/kg，并将该给药量1次服用或分2～4次服用。静脉内给药时，1天的给药量按体重约为0.0001～10mg/kg是适当的，并将该给药量每日一次或分为多次给药。而且，使用经粘膜剂时，按体重约为0.001～100mg/kg，每日一次或分多次给药。应考虑症状、年龄和性别等，根据每个患者的情况，来适当地选择给药量。
虽然根据给药途径、剂型、给药部位、赋形剂或添加剂的种类而有所不同，但是，本发明的药物组合物中含有0.01～100重量％的一种或一种以上的式(I)所示化合物或其盐作为有效成分，作为一种实施方案，含有0.01～50重量％的一种或一种以上的式(I)所示化合物或其盐作为有效成分。
式(I)所示的化合物或其盐可以与认为上述式(I)所示化合物或其盐对其有效的那些疾病的各种治疗剂或预防剂并用。在并用时，可以同时给药，或者分别连续给药、或按所希望的时间间隔给药。同时给药时的制剂可以分别制成制剂，也可以是含有上述式(I)所示化合物或其盐对其有效的那些疾病的各种治疗剂或预防剂和式(I)所示的化合物或其盐的药物组合物。
实施例
以下基于实施例对式(I)所示化合物或其盐的制备方法进行更详细的说明。而且，本发明并不局限于以下实施例中所记载的化合物。此外，将原料化合物的制备方法示于制备例中。另外，式(I)所示化合物的制备方法并不只局限于以下所示的具体实施例的制备方法，可以通过这些制备方法的组合或本领域技术人员已知的方法来制备式(I)所示化合物。
此外，在实施例、制备例和下述表中，有时使用以下缩写。
Pr：制备例编号(在制备例编号的后面记载有“/Cl”的制备例化合物表示该制备例化合物以盐酸盐的形式被分离得到，在制备例编号的后面记载有“/TF”的制备例化合物表示该制备例化合物以三氟乙酸盐的形式被分离得到。另外，制备例编号上带有“*”的化合物表示该化合物为光学活性体)，Ex：实施例编号(另外，实施例编号上带有“*”的化合物表示该化合物为光学活性体)，No：化合物编号，Structure：化学结构式(Me：甲基，Et：乙基，iPr：异丙基，tBu：叔丁基，nPen：正戊基，Ph：苯基，Bn：苄基)，Syn：制备方法(表示该化合物是通过采用与记载在该栏中的实施例编号的化合物相同的制备方法而制备的)，PSy：制备方法(表示该化合物是通过采用与记载在该栏中的制备例编号的化合物相同的制备方法而制备的)，Data：物理学数据(示出了该化合物的以下数据。EI：EI-MS；ESP：ESI-MS(Pos)；ESN：ESI-MS(Neg)；FP：FAB-MS(Pos)；FN：FAB-MS(Neg)；NMR1：DMSO-d6中1H-NMR的特征峰的δ(ppm)；NMR2：CDCl3中1H-NMR的特征峰的δ(ppm))。
制备例1
在冰冷却下，向反式-4-羟基环己烷羧酸乙酯(8g)、4-羟基苯甲酸苄基酯(11.69g)、1，1’-(偶氮二羰基)二哌啶(15.24g)、THF(150ml)的混合物中滴加三丁基膦(14.9ml)，在室温下搅拌2小时后，在60℃下搅拌10小时。将反应混合物恢复至室温后，过滤，用THF洗涤后，将滤液减压浓缩。用硅胶柱色谱法(己烷∶乙酸乙酯＝85∶15)来纯化所得到的残留物，得到4-{[顺式-4-(乙氧基羰基)环己基]氧基}苯甲酸苄基酯的无色油状物8.55g。
制备例2
向4-{[顺式-4-(乙氧基羰基)环己基]氧基}苯甲酸苄基酯(8.5g)和EtOH(150ml)的混合物中，加入负载有10％钯的活性碳(850mg)，在氢气氛(气球压力)中于室温下搅拌4小时。将反应混合物用硅藻土(Celite)过滤，用EtOH洗涤后，将得到的滤液减压浓缩，得到4-{[顺式-4-(乙氧基羰基)环己基]氧基}苯甲酸的无色固体5.8g。
制备例3
向4-{[顺式-4-(乙氧基羰基)环己基]氧基}苯甲酸(4g)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(3.4g)、1-羟基苯并三唑一水合物(2.7g)、三乙胺(2.9ml)、DMF(60ml)的混合物中，加入(2-氨乙基)氨基甲酸叔丁酯(2.6ml)，在室温下搅拌14小时。向反应混合物中加水，并过滤得到所析出的固体后，用二异丙醚洗涤，得到顺式-4-[4-({2-[(叔丁氧基羰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸乙酯的无色固体5.34g。
制备例4
向顺式-4-[4-({2-[(叔丁氧基羰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸乙酯(5.34g)、二
Figure BPA00001447484600251
烷(80ml)的混合物中，加入4M氯化氢/二
Figure BPA00001447484600261
烷(40ml)，在室温下搅拌3小时。将反应混合物减压浓缩，将残留物用二异丙醚洗涤，得到顺式-4-{4-[(2-氨乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯盐酸盐的无色固体4.55g。
制备例5
向4-{4-[(2-氨乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯盐酸盐(150mg)、氯仿(5ml)、三乙胺(0.17ml)的混合物中，加入异氰酸苯酯(0.053ml)，在室温下搅拌1小时。向反应混合物中加入饱和碳酸氢钠水溶液，进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(氯仿∶甲醇(MeOH)＝90∶10)纯化，得到4-[4-({2-[(苯胺基羰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸乙酯的无色固体164mg。
制备例6
向顺式-4-{4-[(2-氨乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯盐酸盐(200mg)、三乙胺(0.08ml)、二氯甲烷(10ml)的混合物中，在0℃下加入羰基二咪唑(100mg)，在0℃下搅拌10分钟后，加入4-苯基哌啶(110mg)，并在室温下搅拌3天。向反应混合物中加水，用氯仿进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝100∶0～95∶5)纯化，得到顺式-4-{4-[(2-{[(4-苯基哌啶-1-基)羰基]氨基}乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯的无色固体288mg。
制备例7
将4-{4-[(2-氨乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯盐酸盐(100mg)、4-苯基环己烷羧酸(66mg)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(67mg)、1-羟基苯并三唑一水合物(54mg)、THF(1.5ml)的混合物在室温下搅拌9小时。向反应混合物中加入饱和碳酸氢钠水溶液，用氯仿进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(氯仿)纯化，得到4-{4-[(2-{[(4-苯基环己基)羰基]氨基}乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯的无色固体123mg。
制备例8
向反式-4-{4-[(2-氨乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯盐酸盐(100mg)、氯仿(10ml)、三乙胺(0.14ml)的混合物中，在0℃下加入苯甲酰氯(0.038ml)，在0℃下搅拌1小时。将反应混合物加入到饱和碳酸氢钠水溶液中，用氯仿进行萃取操作，将有机层用饱和氯化钠水溶液洗涤，并用无水硫酸镁干燥后，减压浓缩。将残留物用二异丙醚洗涤，得到反式-4-(4-{[2-(苯甲酰基氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸乙酯的无色固体118mg。
制备例9
将N-(2-氨乙基)-4-氯苯甲酰胺盐酸盐(400mg)、2-氟-4-羟基苯甲酸(320mg)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(500mg)、1-羟基苯并三唑一水合物(400mg)、三乙胺(0.4ml)、DMF(10ml)的混合物在室温下搅拌过夜。向反应混合物加水，用氯仿进行萃取操作，将有机层用饱和氯化钠水溶液洗涤并用无水硫酸镁干燥后，减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝100∶0～95∶5)纯化，得到N-{2-[(4-氯苯甲酰基)氨基]乙基}-2-氟-4-羟基苯甲酰胺的无色固体410mg。
制备例10
向N-{2-[(4-氯苯甲酰基)氨基]乙基}-2-氟-4-羟基苯甲酰胺(400mg)、反式-4-羟基环己烷羧酸乙酯(220mg)、三苯基膦(350mg)、THF(4ml)的混合物中，在室温下加入2.2M的偶氮二羧酸二乙酯的甲苯溶液(0.58ml)，在60℃下搅拌过夜。向反应混合物中加水，用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤并用无水硫酸镁干燥后，减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝100∶0～95∶5)纯化，得到顺式-4-[4-({2-[(4-氯苯甲酰基)氨基]乙基}氨基甲酰基)-3-氟苯氧基]环己烷羧酸乙酯的无色固体457mg。
制备例11
向顺式-4-羟基环己烷羧酸乙酯(800mg)、三苯基膦(1.34g)、THF(15ml)、4-氟苯酚(521mg)的混合物中，在冰冷却下，花费10分钟时间滴加2.2M偶氮二羧酸二乙酯的甲苯溶液(2.3ml)后，在60℃下搅拌4小时。将反应混合物加入到饱和碳酸氢钠水溶液中，用乙酸乙酯进行萃取操作。之后，将有机层用饱和氯化钠水溶液洗涤并用无水硫酸镁干燥后，减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝85∶15)进行粗纯化。向该粗产物(685mg)以及THF(5ml)、EtOH(5ml)的混合物中，加入1M氢氧化钠水溶液，在室温下搅拌14小时。将溶剂减压蒸去后，向残留物中加水，并用乙酸乙酯进行萃取操作，然后向水层中加入1M盐酸使pH为3，用乙酸乙酯进行萃取操作。将有机层用无水硫酸镁干燥后减压浓缩，得到反式-4-(4-氟苯氧基)环己烷羧酸的无色固体242mg。
制备例12
将3-氟-4-羟基苯甲酸(5g)、溴化苄(4.19ml)、DMF(33ml)、碳酸钾(4.9g)的混合物在40℃下搅拌6小时。将反应混合物放冷后，用乙酸乙酯稀释，并用水洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(氯仿∶乙酸乙酯＝100∶0～50∶50)纯化，得到3-氟-4-羟基苯甲酸苄酯的无色固体1.7g。
制备例13
向4-[(顺式-4-氨基甲酰基环己基)氧基]-N-{2-[(4-氯苯甲酰基)氨基]乙基}苯甲酰胺(330mg)、THF(20ml)的混合物中加入三氟乙酸酐(0.29ml)，在室温下搅拌30分钟后，继续加入三氟乙酸酐(0.07ml)并搅拌10分钟。向反应混合物中加入饱和碳酸氢钠水溶液，用乙酸乙酯进行萃取操作。之后，将有机层用饱和氯化钠水溶液洗涤，并用无水硫酸镁干燥后，减压浓缩。向所得到的残留物中加入二异丙醚和EtOH后，过滤获得固体，并用EtOH洗涤，得到4-氯-N-[2-({4-[(顺式-4-氰基环己基)氧基]苯甲酰基}氨基)乙基]苯甲酰胺的无色固体168mg。
制备例14
向4-(4-氧代环己基)苯甲酸甲酯(1.3g)、甲苯(10ml)的混合物中加入(叔丁氧基羰基亚甲基)三苯基膦烷(2.5g)，在105℃下搅拌24小时。向反应混合物中加入乙酸乙酯和水进行萃取操作，将有机层用饱和氯化钠水溶液洗涤，并用无水硫酸镁干燥后，减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝100∶0～90∶10)纯化，得到4-[4-(2-叔丁氧基-2-氧代亚乙基)环己基]苯甲酸甲酯的无色固体1.35g。
制备例15
向4-[4-(2-叔丁氧基-2-氧代亚乙基)环己基]苯甲酸甲酯(1.3g)、MeOH(20ml)、THF(6ml)的混合物中加入负载有10％钯的活性碳(130mg)，在氢气氛(3个大气压)中于室温下搅拌4小时。将反应混合物用硅藻土(Celite)过滤并用MeOH洗涤后，将所得的滤液减压浓缩，得到{4-[4-(甲氧基羰基)苯基]环己基}乙酸的无色固体1.11g。
制备例16
向{4-[4-(甲氧基羰基)苯基]环己基}乙酸(1.1g)、二氯甲烷(15ml)的混合物中，在0℃下加入草酸酰氯(0.7ml)，在室温下搅拌3小时。将该反应混合物减压浓缩后，加入叔丁醇(15ml)和二异丙基乙胺(1.4ml)，室温下搅拌过夜。将反应混合物减压浓缩，并用乙酸乙酯稀释后，将该混合物依次用饱和碳酸氢钠水溶液、饱和氯化钠水溶液洗涤，并用无水硫酸镁干燥后，减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝100∶0～80∶20)纯化，得到4-[4-(2-叔丁氧基-2-氧代乙基)环己基]苯甲酸甲酯的无色固体1.14g。
制备例17
向4-[4-(2-叔丁氧基-2-氧代乙基)环己基]苯甲酸甲酯(1.1g)、THF(11ml)、MeOH(11ml)的混合物中，在室温下加入1M氢氧化钠水溶液(5ml)，室温下搅拌5小时后在50℃下搅拌1小时。将反应混合物恢复至室温后，减压浓缩，加水，然后加入10％柠檬酸水溶液直至pH为5，过滤获得所析出的固体，从而得到4-[4-(2-叔丁氧基-2-氧代乙基)环己基]苯甲酸的无色固体835mg。
制备例18
将3-氯-4-羟基苯甲酸乙酯(2g)、碘化钾(165mg)、溴代甲基环丁烷(1.7ml)、碳酸钾(2.8g)、DMF(50ml)的混合物在60℃下搅拌5小时。将反应混合物放冷后，用乙酸乙酯稀释，依次用水以及饱和氯化钠水溶液洗涤，并用无水硫酸镁干燥后，减压浓缩，得到油状物。向该油状物以及THF(20ml)、MeOH(20ml)的混合物中，加入1M氢氧化钠水溶液(20ml)，搅拌过夜。向反应混合物中加入1M盐酸(20ml)后减压浓缩以蒸去有机溶剂，过滤获得所析出的固体，从而得到3-氯-4-(环丁基甲氧基)苯甲酸的无色固体1.31g。
制备例19
将4-氟-3-羟基苯甲酸(2g)、碘化钾(250mg)、溴代甲基环丙烷(3.7ml)、碳酸钾(5.3g)、DMF(27ml)的混合物在60℃下搅拌过夜。向反应混合物中加入乙酸乙酯后，依次用水以及饱和氯化钠水溶液洗涤，并用无水硫酸镁干燥后，减压浓缩得到油状物。向该油状物以及THF(30ml)、MeOH(30ml)的混合物中加入1M氢氧化钠水溶液(30ml)，搅拌5小时。向反应混合物中加入1M盐酸(30ml)后，减压浓缩以蒸去有机溶剂，过滤获得所析出的固体，得到3-(环丙基甲氧基)-4-氟苯甲酸的无色固体2.55g。
制备例20
将4-溴-3-氟苯甲酸乙酯(1g)、环丙基硼酸一水合物(643mg)、四(三苯基膦)钯(235mg)、磷酸钾(3.1g)、甲苯(10ml)、水(1ml)的混合物在110℃下剧烈搅拌过夜。向反应混合物中加水，并用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤并用无水硫酸镁干燥后，减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝85∶15)进行粗纯化后，向该粗产物和THF(20ml)、MeOH(20ml)的混合物中加入1M氢氧化钠水溶液(20ml)，在室温下搅拌过夜。向反应混合物中加入1M盐酸(20ml)后减压浓缩以蒸去有机溶剂，过滤获得所析出的固体，得到4-环丙基-3-氟苯甲酸的无色固体600mg。
制备例21
将4-溴-3-氯苯甲酸乙酯(1g)、环丙基硼酸一水合物(602mg)、四(三苯基膦)钯(220mg)、磷酸钾(2.8g)、甲苯(10ml)、水(1ml)的混合物加热回流并搅拌过夜。向反应混合物中加水，用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤并用无水硫酸镁干燥后，减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝100∶0～90∶10)纯化，得到3-氯-4-环丙基苯甲酸乙酯的无色油状物770mg。
制备例22
向3-氯-4-环丙基苯甲酸乙酯(760mg)、THF(10ml)、EtOH(10ml)的混合物中加入1M氢氧化钠水溶液(10ml)，在室温下搅拌过夜。将反应混合物减压浓缩并用水稀释。之后，加入1M盐酸(20ml)使得pH为2，过滤获得所析出的固体，从而得到3-氯-4-环丙基苯甲酸的无色固体666mg。
制备例23
向3-氟苯酚(400mg)、顺式-4-羟基环己烷羧酸乙酯(770mg)、三苯基膦(1.4g)、THF(5ml)的混合物中，在冰冷却下加入2.2M偶氮二羧酸二乙酯的甲苯溶液(2ml)，室温下搅拌过夜。向反应混合物中加入乙酸乙酯(20ml)、饱和氯化钠水溶液(20ml)，进行萃取操作，将有机层用无水硫酸镁干燥后减压浓缩。向残留物中加入己烷(16ml)、乙酸乙酯(4ml)，滤除沉淀物后，将所得滤液减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝100∶0～93∶7)纯化，得到反式-4-(3-氟苯氧基)环己烷羧酸乙酯的无色油状物357mg。
制备例24
向反式-4-(3-氟苯氧基)环己烷羧酸乙酯(350mg)、THF(4ml)、EtOH(4ml)的混合物中加入1M氢氧化钠水溶液(4ml)，室温下搅拌过夜。将反应混合物减压浓缩以蒸去有机溶剂后，加入1M盐酸(5ml)，轻轻搅拌，过滤获得所析出的固体，从而得到反式-4-(3-氟苯氧基)环己烷羧酸的无色固体278mg。
制备例116
将6-羟基烟酸(1.5g)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(2.5g)、1-羟基苯并三唑一水合物(2.0g)、三乙胺(2.5ml)、(2-氨乙基)氨基甲酸叔丁酯(1.8ml)、DMF(30ml)的混合物在室温下搅拌过夜。向反应混合物中加水，并用氯仿和异丙醇的混合溶剂(3∶1)进行萃取操作，将有机层用无水硫酸镁干燥后减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝100∶0～90∶10)纯化，向所得产物中加入己烷-乙酸乙酯(＝1∶1)，使得形成固体，然后过滤获得固体，洗涤，得到(2-{[(6-羟基吡啶-3-基)羰基]氨基}乙基)氨基甲酸叔丁酯的无色固体1.91g。
制备例117
向(2-{[(6-羟基吡啶-3-基)羰基]氨基}乙基)氨基甲酸叔丁酯(1.9g)、反式-4-羟基环己烷羧酸乙酯(1.3g)、三苯基膦(2.7g)、THF(50ml)的混合物中，在0℃下加入2.2M偶氮二羧酸二乙酯的甲苯溶液(3.7ml)，室温下搅拌过夜。向反应混合物中加水，并用氯仿进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝100∶0～95∶5)纯化，得到顺式-4-{[5-({2-[(叔丁氧基羰基)氨基]乙基}氨基甲酰基)吡啶-2-基]氧基}环己烷羧酸乙酯的无色固体1.41g。
制备例118
将4-{[顺式-4-(乙氧基羰基)环己基]氧基}-2-羟基苯甲酸苄基酯(530mg)、碘甲烷(0.4ml)、碳酸钾(220mg)、DMF(5ml)的混合物在室温下搅拌3.5小时后，在45℃下搅拌1小时。之后，加入碳酸钾(175mg)，室温下搅拌过夜。向反应混合物中加水(20ml)，用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后用无水硫酸镁干燥，然后减压浓缩，得到4-{[顺式-4-(乙氧基羰基)环己基]氧基}-2-甲氧基苯甲酸苄基酯的褐色油状物605mg。
制备例119
将2-氯-4-{[顺式-4-(乙氧基羰基)环己基]氧基}苯甲酸苄基酯(500mg)、环丙基硼酸一水合物(190mg)、四(三苯基膦)钯(70mg)、磷酸钾(894mg)、甲苯(5ml)、水(0.5ml)的混合物加热回流，并搅拌过夜。向反应混合物中加水，并用乙酸乙酯进行萃取操作，将有机层用无水硫酸镁干燥后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝90∶10)纯化，得到2-环丙基-4-{[顺式-4-(乙氧基羰基)环己基]氧基}苯甲酸苄基酯的无色油状物320mg。
制备例120
向4-氟-2-(三氟甲基)苯甲酸苄基酯(4.1g)、2-(甲磺酰基)乙醇(2.53g)、DMF(50ml)的混合物中，在冰冷却下加入叔丁醇钾(4.67g)，室温下搅拌3小时。向反应混合物加入1M盐酸和水，用乙酸乙酯进行萃取操作，将有机层用水、饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝90∶10～80∶20)纯化，得到4-羟基-2-(三氟甲基)苯甲酸苄基酯的淡黄色油状物1.19g。
制备例121
向2-氯-4-{[顺式-4-(乙氧基羰基)环己基]氧基}苯甲酸(1.8g)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(1.37g)、1-羟基苯并三唑一水合物(1.10g)、三乙胺(1.15ml)、DMF(50ml)的混合物中加入(2-氨乙基)氨基甲酸叔丁酯(0.96ml)，室温下搅拌过夜。向反应混合物中加水(200ml)，过滤获得所析出的固体。向该固体与二
Figure BPA00001447484600331
烷(30ml)的混合物中加入4M氯化氢/二
Figure BPA00001447484600332
烷(15ml)，室温下搅拌5小时。将反应混合物减压浓缩，将残留物用己烷-二异丙醚的混合溶剂洗涤，得到顺式-4-{4-[(2-氨乙基)氨基甲酰基]-3-氯苯氧基}环己烷羧酸乙酯盐酸盐的无色固体2.09g。
制备例122
向[反式-4-(4-羟基苯基)环己基]乙酸甲酯(1.25g)、二氯甲烷(25ml)、N-乙基-N-异丙基丙-2-胺(1.05ml)的混合物中，在0℃下加入三氟甲磺酰氯(0.636ml)，室温下搅拌过夜。向反应混合物中加入饱和碳酸氢钠水溶液，用氯仿进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝100∶0～50∶50)纯化，得到[反式-4-(4-{[(三氟甲基)磺酰基]氧基}苯基)环己基]乙酸甲酯的无色固体1.38g。
制备例123
将[反式-4-(4-{[(三氟甲基)磺酰基]氧基}苯基)环己基]乙酸甲酯(200mg)、DMF(10ml)、N-(2-氨乙基-4-氯-3-甲基苯甲酰胺盐酸盐(200mg)、1，1′-双(二苯基膦基)二茂铁-二氯化钯(II)-二氯甲烷络合物(90mg)、三乙胺(0.2ml)的混合物在1大气压的一氧化碳下于90℃下搅拌18小时。将反应混合物恢复至室温后，加水(50ml)，并过滤获得所析出的固体。将该固体用硅胶柱色谱法(氯仿∶MeOH＝100∶0～95∶5～90∶10)纯化，得到{反式-4-[4-({2-[(4-氯-3-甲基苯甲酰基)氨基]乙基}氨基甲酰基)苯基]环己基}乙酸甲酯的褐色固体96mg。
制备例124
向顺式-4-(羟基甲基)环己烷羧酸(5g)、乙醇(50ml)的混合物中，在室温下加入浓硫酸(0.3ml)，并加热回流8小时。将反应混合物恢复至室温，并减压浓缩。将残留物加入到饱和碳酸氢钠水溶液中，用氯仿进行萃取操作，将有机层用无水硫酸镁干燥后减压浓缩，得到顺式-4-(羟基甲基)环己烷羧酸乙酯的无色油状物5.8g。
制备例125
向1-甲基-4-氧代环己烷羧酸乙酯(3g)、乙醇(30ml)的混合物中，在0℃下加入硼氢化钠(616mg)并搅拌2小时。向反应混合物中加入水以及乙酸乙酯，并用乙酸乙酯进行萃取操作，将有机层依次用饱和碳酸氢钠水溶液、饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝100∶0～90∶10～80∶20)纯化，得到顺式-4-羟基-1-甲基环己烷羧酸乙酯的无色油状物1.27g。
制备例126
将顺式-4-[4-({2-[(4-羟基苯甲酰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸乙酯(50mg)、DMF(2ml)、碳酸钾(30mg)、2-氯溴化苄(0.019ml)的混合物在60℃下搅拌过夜。向反应混合物中加水，用氯仿进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝100∶0～95∶5)纯化后，将所得固体用二异丙醚洗涤，得到顺式-4-(4-{[2-({4-[(2-氯苄基)氧基]苯甲酰基}氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸乙酯的无色固体53mg。
制备例127
将4-氟苯甲酸苄酯(1.5g)、DMSO(10ml)、哌啶-4-基乙酸甲酯盐酸盐(1.26g)、碳酸钾(1.81mg)的混合物在100℃下搅拌20小时。将反应混合物加入到水中，用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝80∶20)纯化，得到4-[4-(2-甲氧基-2-氧代乙基)哌啶-1-基]苯甲酸苄酯的无色固体1.475g。
制备例128
向4-{[顺式-4-(乙氧基羰基)环己基]氧基}-2，5-二氟苯甲酸叔丁酯(4g)、二
Figure BPA00001447484600351
烷(40ml)的混合物中，加入4M氯化氢/二
Figure BPA00001447484600352
烷溶液(60ml)，室温下搅拌1小时后，在60℃下搅拌5小时。将反应混合物减压浓缩，将残留物用二异丙醚洗涤，得到4-{[顺式-4-(乙氧基羰基)环己基]氧基}-2，5-二氟苯甲酸的无色固体3.36g。
制备例129
向4-(苄氧基)-2，5-二氟苯甲酸叔丁酯(7.47g)和THF(101ml)的混合物中加入负载有10％钯的活性碳(747mg)，在氢气氛(气球压力)中于室温下搅拌5小时。将反应混合物用硅藻土(Celite)过滤，用乙醇洗涤后，将所得滤液减压浓缩。将残留物用硅胶柱色谱法(氯仿∶乙酸乙酯＝98∶2～50∶50)纯化，得到2，5-二氟-4-羟基苯甲酸叔丁酯的无色固体4g。
制备例130
向(2-氨乙基)氨基甲酸叔丁酯(4.88ml)、三乙胺(4.49ml)、DMF(100ml)的混合物中，加入2-萘甲酰氯(5.59g)，室温下搅拌2小时。将反应混合物减压浓缩后加水(200ml)，过滤获得所析出的固体。向该固体与二
Figure BPA00001447484600353
烷(200ml)的混合物中，加入4M氯化氢/二
Figure BPA00001447484600354
烷溶液(100ml)，室温下搅拌过夜。将反应混合物过滤，过滤获得固体后用二异丙醚洗涤，得到N-(2-氨乙基)-2-萘甲酰胺盐酸盐的无色固体7.7g 。
制备例131
向(2-氨乙基)氨基甲酸叔丁酯(4.34ml)、三乙胺(4.5ml)、二氯甲烷(50ml)的混合物中加入异氰酸2-氯苯酯(3.8g)，室温下搅拌2小时。将反应混合物减压浓缩后加水(200ml)，过滤获得所析出的固体。向该固体与二
Figure BPA00001447484600355
烷(20ml)的混合物中加入4M氯化氢/二
Figure BPA00001447484600356
烷溶液(50ml)，室温下搅拌5小时。将反应混合物减压浓缩，并将残留物用二异丙醚洗涤，得到1-(2-氨乙基)-3-(2-氯苯基)脲盐酸盐的无色固体5.89g。
制备例132
向苄醇(2.23ml)、THF(30ml)的混合物中，在5℃下加入叔丁醇钾(4.67g)并搅拌0.5小时。在-65℃下将该反应混合物加入到3，4，5-三氟苯甲酸叔丁酯(5g)与THF(50ml)的混合物中，并在-65℃下搅拌1小时，然后在室温下搅拌5小时。向反应混合物中加水(150ml)，用乙醚进行萃取操作，将有机层依次用水、饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。向该残留物与THF(80ml)的混合物中加入负载有10％钯的活性碳(500mg)，在氢气氛(气球压力)中于室温下搅拌2小时。将反应混合物用硅藻土(Celite)过滤，用THF洗涤后，将所得滤液减压浓缩。将残留物用硅胶柱色谱法(氯仿∶乙酸乙酯＝98∶2～50∶50)纯化，得到3，5-二氟-4-羟基苯甲酸叔丁酯的无色固体3.22g。
制备例133
向二异丙胺(0.94ml)、THF(10ml)的混合物中，在-55℃下花费5分钟时间加入1.6M正丁基锂的己烷溶液(4.4ml)，然后在-68℃下花费10分钟加入2-氯-3-环丙基噻吩(960mg)的THF溶液(5ml)，并搅拌50分钟。之后，向反应混合物中加入干冰，并恢复至室温。向反应混合物中加入水(30ml)和1M氢氧化钠水溶液(10ml)后，用己烷洗涤水层。向水层中加入1M盐酸(30ml)，用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后用无水硫酸镁干燥，然后减压浓缩，得到5-氯-4-环丙基噻吩-2-羧酸的淡黄色固体765mg。
制备例134
向4-氯-3-羟基苯甲酸甲酯(500mg)、5-氯-2，3-二氟吡啶(801mg)、DMF(10ml)的混合物中加入碳酸钾(1.48g)，在80℃下搅拌16小时。将反应混合物恢复至室温，加水，并用乙酸乙酯进行萃取操作，将有机层依次用水、饱和氯化钠水溶液洗涤后用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝100∶0～90∶10)纯化，得到4-氯-3-[(5-氯-3-氟吡啶-2-基)氧基]苯甲酸甲酯的无色固体521mg。
制备例135
利用Microweb反应装置，将3-氯-4-(三氟甲基)苯甲酸乙酯(1g)、环丙基三氟硼酸钾(644mg)、2-二氯己基膦基-2′，4′，6′-三异丙基联苯(189mg)、碳酸钾(1.64g)、乙酸钯(II)(44mg)、THF(12ml)、水(1.2ml)的混合物在100℃下搅拌12小时。向反应混合物中加水，并用乙酸乙酯进行萃取操作，将有机层用无水硫酸镁干燥后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝95∶5)进行粗纯化，得到油状物。利用该油状物进行相同的操作后，向所得油状物中加入MeOH(15ml)、EtOH(15ml)、1M氢氧化钠水溶液(15ml)，室温下搅拌过夜。向反应混合物中加入1M盐酸(15ml)，减压浓缩以蒸去有机溶剂，过滤获得所析出的固体，从而得到3-环丙基-4-(三氟甲基)苯甲酸的无色固体120mg。
制备例136
向N-{2-[(4-氨基苯甲酰基)氨基]乙基}-2-萘甲酰胺盐酸盐(200mg)、4-环己酮羧酸乙酯(108mg)、乙酸钠(50mg)、二氯甲烷(5ml)的混合物中加入乙酸(0.05ml)，室温下搅拌1小时后，加入三乙酰氧基硼氢化钠(180mg)并搅拌2小时。之后，加入DMF(2ml)，搅拌过夜。向反应混合物中加入饱和碳酸氢钠水溶液，用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝100∶0～95∶5)纯化，得到4-[(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯基)氨基]环己烷羧酸乙酯的无色油状物96mg。
制备例137
向4-[(4-羟基环己基)氧基]苯甲酸苄基酯(800mg)、溴乙酸叔丁酯(726mg)、THF(10ml)的混合物中加入60％油性氢化钠(110mg)，室温下搅拌16小时。向反应混合物中加入饱和氯化铵水溶液，用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝95∶5～75∶25)纯化，得到4-{[4-(2-叔丁氧基-2-氧代乙氧基)环己基]氧基}苯甲酸苄基酯的无色油状物272mg。
制备例138
将4-(1，4-二氧杂螺[4.5]癸烷-8-基氧基)苯甲酸苄基酯(3.0g)、1M盐酸(20ml)、THF(20ml)、EtOH(20ml)的混合物在室温下搅拌过夜后，在45℃下搅拌40分钟。将反应混合物放冷至室温后，加入1M盐酸(7.5ml)，在室温下搅拌4.5小时。将反应混合物减压浓缩以蒸去EtOH和THF，然后用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝95∶5～65∶35)纯化，得到4-[(4-氧代环己基)氧基]苯甲酸苄基酯的无色油状物2.5g。
制备例139
向4-[(二甲氧基膦酰基)甲基]苯甲酸苄基酯(1.44g)、THF(6.8ml)的混合物中，在冰冷却下加入叔丁醇钾(448mg)，并在0℃下搅拌1小时后，加入4-氧代环己烷羧酸乙酯(680mg)，在0℃下搅拌3小时。向反应混合物中加入乙酸乙酯和水后，用乙酸乙酯进行萃取操作，将有机层依次用水、饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(己烷∶乙酸乙酯＝90∶10)纯化，得到油状物。向该油状物和THF(10ml)的混合物中，加入负载有10％钯的活性碳(5mg)，在氢气氛(气球压力)中于室温下搅拌3小时。将反应混合物用硅藻土(Celite)过滤，用THF洗涤后，将所得滤液减压浓缩。向所得残留物中加入己烷(5ml)，过滤获得所析出的固体，从而得到4-{[4-(乙氧基羰基)环己基]甲基}苯甲酸的无色固体10mg。
制备例140
将N-(2-{[4-(1，4-二氧杂螺[4.5]癸烷-8-基氧基)苯甲酰基]氨基}乙基)-2-萘甲酰胺(2.0g)、水(20ml)、乙酸(100ml)的混合物在65℃下搅拌0.5小时。将反应混合物减压浓缩后加水，过滤获得所析出的固体，用二异丙醚洗涤，得到N-[2-({4-[(4-氧代环己基)氧基]苯甲酰基}氨基)乙基]-2-萘甲酰胺的无色固体1.8g。
实施例1
向反式-4-(4-{[2-(苯甲酰基氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸乙酯(102mg)、EtOH(3ml)、THF(3ml)的混合物中，在室温下加入1M氢氧化钠水溶液(0.9ml)，并在室温下搅拌5小时。将反应混合物减压浓缩并加水后，加入1M盐酸直至pH为3，过滤获得所析出的固体，得到反式-4-(4-{[2-(苯甲酰基氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸的无色固体85mg。
实施例2
向顺式-4-{4-[(2-氨乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯盐酸盐(100mg)、氯仿(1ml)、三乙胺(0.11ml)的混合物中，加入异氰酸反式-2-苯基环丙基酯(45mg)，在室温下搅拌3小时后，将反应混合物减压浓缩，得到残留物。向该残留物中加入EtOH(3ml)、THF(3ml)后，加入1M氢氧化钠水溶液(0.5ml)，室温下搅拌过夜。向反应混合物中加入1M盐酸(2.5ml)并搅拌，过滤获得所析出的固体，得到rel-顺式-4-(4-{[2-({[(1R，2S)-2-苯基环丙基]氨基甲酰基}氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸的无色固体110mg。
实施例3
向顺式-4-{4-[(2-氨乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯盐酸盐(100mg)、1-苯并呋喃-5-羧酸(53mg)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(65mg)、1-羟基苯并三唑一水合物(45mg)、DMF(2ml)的混合物中加入三乙胺(0.12ml)，室温下搅拌6小时。向反应混合物中加水(8ml)并搅拌后，过滤获得所析出的固体，干燥，得到无色固体。向该固体中加入EtOH(3ml)、THF(3ml)后，再加入1M氢氧化钠水溶液(1ml)，室温下搅拌过夜。向反应混合物中加入1M盐酸(1.1ml)并搅拌后，减压浓缩以蒸去EtOH和THF，过滤获得所析出的固体，用水洗涤，得到顺式-4-[4-({2-[(1-苯并呋喃-5-基羰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸的无色固体105mg。
实施例4
向顺式-4-{4-[(2-氨乙基)氨基甲酰基]-2-氟苯氧基}环己烷羧酸乙酯盐酸盐(52mg)、二氯甲烷(2ml)、三乙胺(0.05ml)的混合物中，在0℃下加入3-氟-4-(三氟甲基)苯甲酰氯(0.027ml)，室温下搅拌过夜。将反应混合物减压浓缩后加水，过滤获得所析出的固体。向该固体中加入MeOH(2ml)、THF(2ml)后，加入1M氢氧化钠水溶液(2ml)，在50℃下搅拌2小时。向反应混合物中加入1M盐酸(2ml)，减压浓缩以蒸去溶剂，过滤获得所析出的固体，得到顺式-4-{2-氟-4-[(2-{[3-氟-4-(三氟甲基)苯甲酰基]氨基}乙基)氨基甲酰基]苯氧基}环己烷羧酸的无色固体58mg。
实施例5
向顺式-4-{4-[(2-氨基乙基)氨基甲酰基]苯氧基}环己烷羧酸乙酯盐酸盐(100mg)、二氯甲烷(5ml)、三乙胺(0.045ml)的混合物中，在0℃下加入羰基二咪唑(48mg)，在0℃下搅拌10分钟后，加入1-苯基哌嗪(0.049ml)，室温下搅拌过夜。将通过对反应混合物进行减压浓缩而得到的残留物用硅胶柱色谱法(氯仿∶MeOH＝97.5∶2.5)纯化，得到无色固体。向该固体中加入EtOH(3ml)、THF(3ml)后，加入1M氢氧化钠水溶液(3ml)，室温下搅拌6小时。向反应混合物中加入1M盐酸(3ml)，减压浓缩以蒸去EtOH和THF，过滤获得所析出的固体，得到顺式-4-{4-[(2-{[(4-苯基哌嗪-1-基)羰基]氨基}乙基)氨基甲酰基]苯氧基}环己烷羧酸的无色固体70mg。
实施例6
向{4-[4-({2-[(4-氯苯甲酰基)氨基]乙基}氨基甲酰基)苯基]环己基}乙酸叔丁酯(197mg)、二氯甲烷(3ml)的混合物中，在0℃下加入三氟乙酸(1ml)，室温下搅拌3小时。将反应混合物减压浓缩后加水，过滤获得所析出的固体，得到{4-[4-({2-[(4-氯苯甲酰基)氨基]乙基}氨基甲酰基)苯基]环己基}乙酸的无色固体140mg。
实施例7
向顺式-4-[4-({2-[(4-氯苯甲酰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸(100mg)、THF(4ml)、DMF(1ml)的混合物中加入羰基二咪唑(55mg)，在60℃下搅拌40分钟后，在冰冷却下加入甲磺酰胺(40mg)、1，8-二氮杂双环[5.4.0]十一碳-7-烯(0.045ml)，室温下搅拌3天。向反应混合物中加入1M盐酸(10ml)和乙酸乙酯(10ml)，过滤获得不溶物，从而得到4-氯-N-(2-{[4-({顺式-4-[(甲磺酰基)氨基甲酰基]环己基}氧基)苯甲酰基]氨基}乙基)苯甲酰胺的无色固体41mg。
实施例8
将顺式-4-[4-({2-[(4-氯苯甲酰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸(400mg)、氯化铵(60mg)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(225mg)、1-羟基苯并三唑一水合物(160mg)、DMF(5ml)、三乙胺(0.16ml)的混合物在室温下搅拌5小时。向反应混合物中加水(10ml)，过滤获得固体，用水洗涤，得到4-[(顺式-4-氨基甲酰基环己基)氧基]-N-{2-[(4-氯苯甲酰基)氨基]乙基}苯甲酰胺的无色固体372mg。
实施例9
将4-氯-N-[2-({4-[(顺式-4-氰基环己基)氧基]苯甲酰基}氨基)乙基]苯甲酰胺(298mg)、叠氮化钠(220mg)、三乙胺盐酸盐(480mg)、1-甲基-2-吡咯烷酮(3ml)的混合物在140℃下搅拌11小时。向反应混合物中加入水、氯仿，过滤获得不溶物，将该固体用硅胶柱色谱法(氯仿∶MeOH＝95∶5～80∶20)纯化后，将所得固体用乙酸乙酯洗涤，得到4-氯-N-{2-[(4-{[顺式-4-(1H-四唑-5-基)环己基]氧基}苯甲酰基)氨基]乙基}苯甲酰胺的褐色固体16mg。
实施例200
将N-(2-氨乙基)-4-氯苯甲酰胺盐酸盐(32mg)、4-{[顺式-4-(乙氧基羰基)环己基]氧基}-2-甲氧基苯甲酸(58mg)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(35mg)、1-羟基苯并三唑一水合物(30mg)、THF(3ml)、三乙胺(0.075ml)的混合物在室温下搅拌16小时。向反应混合物中加水，并用乙酸乙酯进行萃取操作，将有机层依次用饱和碳酸氢钠水溶液、1M盐酸、饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。向残留物中加入EtOH(2ml)、THF(2ml)、1M氢氧化钠水溶液(0.6ml)，在45℃下搅拌3小时。向反应混合物中加入1M盐酸(0.6ml)、水(5ml)并搅拌后，减压浓缩以蒸去EtOH和THF。将残留物用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后用无水硫酸镁干燥，然后减压浓缩。向残留物中加入乙酸乙酯和己烷，过滤获得所析出的固体，水洗，得到顺式-4-[4-({2-[(4-氯苯甲酰基)氨基]乙基}氨基甲酰基)-3-甲氧基苯氧基]环己烷羧酸的无色固体46mg。
实施例201
向N-{2-[(4-羟基苯甲酰基)氨基]乙基}-2-萘甲酰胺(170mg)、(反式-4-羟基环己基)乙酸甲酯(80mg)、三苯基膦(140mg)、THF(2ml)的混合物中，在室温下加入2.2M偶氮二羧酸二乙酯的甲苯溶液(0.24ml)，室温下搅拌过夜。将反应混合物加入到饱和碳酸氢钠水溶液中，用氯仿进行萃取操作，将有机层用饱和氯化钠水溶液洗涤并用无水硫酸镁干燥后，减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝100∶0～95∶5)纯化，向所得产物中加入EtOH(5ml)、THF(5ml)、1M氢氧化钠水溶液(2ml)，室温下搅拌过夜。将反应混合物减压浓缩以蒸去EtOH和THF。向残留物中加水后，加入10％柠檬酸水溶液直至pH4，过滤获得所析出的固体。将该固体用硅胶柱色谱法(氯仿∶MeOH＝100∶0～90∶10)纯化，得到[顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己基]乙酸的无色固体20mg。
实施例202
向顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸乙酯(100mg)、二氯甲烷(3ml)的混合物中，在冰冷却下加入1.0M氢化二异丁基铝的甲苯溶液(0.5ml)，并在该温度下搅拌45分钟。之后，继续加入1.0M氢化二异丁基铝的甲苯溶液(0.5ml)，并搅拌15分钟后，再次加入1.0M氢化二异丁基铝的甲苯溶液(0.5ml)并搅拌1小时。向反应混合物中加入1M盐酸(5ml)和饱和酒石酸钾钠水溶液(5ml)，用乙酸乙酯进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝98∶2～90∶10)纯化，向所得产物中加入乙酸乙酯和己烷，过滤获得所析出的固体，得到N-{2-[(4-{[顺式-4-(羟甲基)环己基]氧基}苯甲酰基)氨基]乙基}-2-萘甲酰胺的无色固体20mg。
实施例203
将顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸(50mg)、甲胺盐酸盐(10mg)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(30mg)、1-羟基苯并三唑一水合物(22mg)、DMF(1ml)、三乙胺(0.05ml)的混合物在室温下搅拌过夜。向反应混合物中加水，过滤获得所析出的固体，得到N-{2-[(4-{[顺式-4-(甲基氨基甲酰基)环己基]氧基}苯甲酰基)氨基]乙基}-2-萘甲酰胺的无色固体48mg。
实施例204
将顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸(50mg)、(2-氨乙基)氨基甲酸叔丁酯(20mg)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(30mg)、1-羟基苯并三唑一水合物(22mg)、DMF(1ml)、三乙胺(0.04ml)的混合物在室温下搅拌过夜。向反应混合物中加水，过滤获得所析出的固体。向该固体中加入二
Figure BPA00001447484600431
烷(1ml)和4M盐酸/乙酸乙酯(1ml)，室温下搅拌4小时。将反应混合物减压浓缩，用二异丙醚使残留物形成固体，并洗涤，得到N-(2-{[4-({顺式-4-[(2-氨基乙基)氨基甲酰基]环己基}氧基)苯甲酰基]氨基}乙基)-2-萘甲酰胺盐酸盐的无色固体28mg。
实施例205
将顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸(50mg)、甘氨酸乙酯盐酸盐(18mg)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(30mg)、1-羟基苯并三唑一水合物(22mg)、DMF(1ml)、三乙胺(0.05ml)的混合物在室温下搅拌过夜。向反应混合物中加水，过滤获得所析出的固体。向该固体中加入EtOH(2ml)、THF(2ml)、1M氢氧化钠水溶液(0.5ml)，在50℃下搅拌4小时。将反应混合物减压浓缩以蒸去EtOH和THF，向残留物中加水后，加入10％柠檬酸水溶液直至pH4，过滤获得所析出的固体，从而得到N-{[顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己基]羰基}甘氨酸的无色固体34mg。
实施例206
将顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸(50mg)、3-羟基丁-2-酮(14mg)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(30mg)、1-羟基苯并三唑一水合物(22mg)、DMF(1ml)、三乙胺(0.04ml)的混合物在室温下搅拌过夜。向反应混合物中加水，过滤获得所析出的固体。向该固体中加入乙酸(2ml)和乙酸铵(50mg)，加热回流过夜。向反应混合物中加入水及饱和碳酸氢钠水溶液，用氯仿进行萃取操作，将有机层用饱和氯化钠水溶液洗涤后，用无水硫酸镁干燥，然后减压浓缩。将残留物用硅胶柱色谱法(氯仿∶MeOH＝100∶0～90∶10)纯化，得到N-{2-[(4-{[顺式-4-(4，5-二甲基-1，3-
Figure BPA00001447484600441
唑-2-基)环己基]氧基}苯甲酰基)氨基]乙基}-2-萘甲酰胺的无色固体4mg。
实施例207
向N-[2-({4-[(4-氧代环己基)氧基]苯甲酰基}氨基)乙基]-2-萘甲酰胺(100mg)、甲醇(10ml)的混合物中，在0℃下加入硼氢化钠(9mg)并搅拌0.5小时。将反应混合物减压浓缩后加入1M盐酸，用氯仿进行萃取操作，将有机层用无水硫酸镁干燥后减压浓缩。将残留物用二异丙醚洗涤，得到N-[2-({4-[(4-羟基环己基)氧基]苯甲酰基}氨基)乙基]-2-萘甲酰胺的无色固体48mg。
实施例208
向N-[2-({4-[(4-氧代环己基)氧基]苯甲酰基}氨基)乙基]-2-萘甲酰胺(100mg)、乙醚(10ml)的混合物中，在0℃下加入3.0M甲基溴化镁的乙醚溶液(0.4ml)并搅拌0.5小时。将反应混合物减压浓缩后加入1M盐酸，用氯仿进行萃取操作，将有机层用无水硫酸镁干燥后减压浓缩。将残留物用二异丙醚洗涤，得到N-[2-({4-[(4-羟基-4-甲基环己基)氧基]苯甲酰基}氨基)乙基]-2-萘甲酰胺的无色固体56mg。
实施例209
将[顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己基]氨基甲酸叔丁酯(623mg)、4M氯化氢/乙酸乙酯(7ml)的混合物在室温下搅拌过夜。将反应混合物减压浓缩，在100℃下向所得残留物中加入乙酸乙酯、乙醇、水以形成溶液，然后在室温下放冷。之后，过滤获得所析出的固体，得到N-[2-({4-[(顺式-4-氨基环己基)氧基]苯甲酰基}氨基)乙基]-2-萘甲酰胺盐酸盐的无色固体368mg。
实施例210
向N-[2-({4-[(顺式-4-氨基环己基)氧基]苯甲酰基}氨基)乙基]-2-萘甲酰胺盐酸盐(70mg)、二氯甲烷(3ml)的混合物中，加入三乙胺(0.065ml)、乙酰氯(0.016ml)，在室温下搅拌3小时。之后，蒸去溶剂，并向残留物中加水，轻轻搅拌后过滤获得固体，从而得到N-[2-({4-[(顺式-4-乙酰氨基环己基)氧基]苯甲酰基}氨基)乙基]-2-萘甲酰胺的无色固体69mg。
下表2～表42中示出了制备例化合物的化学结构式。另外，下表43～表133中示出了实施例化合物的化学结构式。
另外，下表134～表144中示出了制备例化合物的制备方法及物理学数据。而且，下表145～表169中示出了实施例化合物的制备方法及物理学数据。
[表2]
Figure BPA00001447484600461
[表3]
Figure BPA00001447484600471
[表4]
Figure BPA00001447484600481
[表5]
Figure BPA00001447484600491
[表6]
Figure BPA00001447484600501
[表7]
[表8]
Figure BPA00001447484600521
[表9]
Figure BPA00001447484600531
[表10]
Figure BPA00001447484600541
[表11]
Figure BPA00001447484600551
[表12]
Figure BPA00001447484600561
[表13]
[表14]
Figure BPA00001447484600581
[表15]
Figure BPA00001447484600591
[表16]
[表17]
Figure BPA00001447484600611
[表18]
Figure BPA00001447484600621
[表19]
Figure BPA00001447484600631
[表20]
Figure BPA00001447484600641
[表21]
Figure BPA00001447484600651
[表22]
Figure BPA00001447484600661
[表23]
Figure BPA00001447484600671
[表24]
Figure BPA00001447484600681
[表25]
Figure BPA00001447484600691
[表26]
Figure BPA00001447484600701
[表27]
Figure BPA00001447484600711
[表28]
Figure BPA00001447484600721
[表29]
Figure BPA00001447484600731
[表30]
Figure BPA00001447484600741
[表31]
Figure BPA00001447484600751
[表32]
Figure BPA00001447484600761
[表33]
Figure BPA00001447484600771
[表34]
Figure BPA00001447484600781
[表35]
Figure BPA00001447484600791
[表36]
Figure BPA00001447484600801
[表37]
Figure BPA00001447484600811
[表38]
Figure BPA00001447484600821
[表39]
Figure BPA00001447484600831
[表40]
Figure BPA00001447484600841
[表41]
Figure BPA00001447484600851
[表42]
Figure BPA00001447484600861
[表43]
[表44]
Figure BPA00001447484600881
[表45]
[表46]
Figure BPA00001447484600901
[表47]
Figure BPA00001447484600911
[表48]
Figure BPA00001447484600921
[表49]
Figure BPA00001447484600931
[表50]
Figure BPA00001447484600941
[表51]
Figure BPA00001447484600951
[表52]
Figure BPA00001447484600961
[表53]
Figure BPA00001447484600971
[表54]
[表55]
Figure BPA00001447484600991
[表56]
Figure BPA00001447484601001
[表57]
Figure BPA00001447484601011
[表58]
Figure BPA00001447484601021
[表59]
Figure BPA00001447484601031
[表60]
Figure BPA00001447484601041
[表61]
Figure BPA00001447484601051
[表62]
Figure BPA00001447484601061
[表63]
Figure BPA00001447484601071
[表64]
Figure BPA00001447484601081
[表65]
Figure BPA00001447484601091
[表66]
Figure BPA00001447484601101
[表67]
Figure BPA00001447484601111
[表68]
Figure BPA00001447484601121
[表69]
Figure BPA00001447484601131
[表70]
Figure BPA00001447484601141
[表71]
Figure BPA00001447484601151
[表72]
Figure BPA00001447484601161
[表73]
Figure BPA00001447484601171
[表74]
Figure BPA00001447484601181
[表75]
Figure BPA00001447484601191
[表76]
Figure BPA00001447484601201
[表77]
Figure BPA00001447484601211
[表78]
Figure BPA00001447484601221
[表79]
Figure BPA00001447484601231
[表80]
Figure BPA00001447484601241
[表81]
Figure BPA00001447484601251
[表82]
Figure BPA00001447484601261
[表83]
Figure BPA00001447484601271
[表84]
Figure BPA00001447484601281
[表85]
[表86]
[表87]
Figure BPA00001447484601311
[表88]
[表89]
Figure BPA00001447484601331
[表90]
Figure BPA00001447484601341
[表91]
[表92]
[表93]
Figure BPA00001447484601371
[表94]
[表95]
Figure BPA00001447484601391
[表96]
Figure BPA00001447484601401
[表97]
Figure BPA00001447484601411
[表98]
[表99]
Figure BPA00001447484601431
[表100]
Figure BPA00001447484601441
[表101]
Figure BPA00001447484601451
[表102]
Figure BPA00001447484601461
[表103]
Figure BPA00001447484601471
[表104]
Figure BPA00001447484601481
[表105]
[表106]
Figure BPA00001447484601501
[表107]
Figure BPA00001447484601511
[表108]
Figure BPA00001447484601521
[表109]
Figure BPA00001447484601531
[表110]
[表111]
Figure BPA00001447484601551
[表112]
Figure BPA00001447484601561
[表113]
Figure BPA00001447484601571
[表114]
Figure BPA00001447484601581
[表115]
Figure BPA00001447484601591
[表116]
Figure BPA00001447484601601
[表117]
Figure BPA00001447484601611
[表118]
[表119]
Figure BPA00001447484601631
[表120]
Figure BPA00001447484601641
[表121]
[表122]
Figure BPA00001447484601661
[表123]
Figure BPA00001447484601671
[表124]
Figure BPA00001447484601681
[表125]
Figure BPA00001447484601691
[表126]
Figure BPA00001447484601701
[表127]
Figure BPA00001447484601711
[表128]
Figure BPA00001447484601721
[表129]
Figure BPA00001447484601731
[表130]
Figure BPA00001447484601741
[表131]
[表132]
Figure BPA00001447484601761
[表133]
Figure BPA00001447484601771
[表134]
Figure BPA00001447484601781
[表135]
Figure BPA00001447484601791
[表136]
  Pr   PSy   Data
  49   10   ESP：491.
  50   7   ESP：445.
  51   7   ESP：445.
  52   7   ESP：479.
  53   7   ESP：507.
  54   8   ESP：445.
  55   8   ESP：469.
  56   8   ESP：457.
  57   8   ESP：523.
  58   7   ESP：555.
  59   7   ESP：517.
  60   7   ESP：517.
  61   7   ESP：507.
  62   7   ESP：507.
  63   7   ESP：479.
  64   7   ESP：503.
  65   7   ESP：515.
  66   8   ESP：525.
  67   8   ESP：489.
  68   7   ESP：489.
  69   9   ESP：320.
  70   10   ESP：474.
  71   9   ESP：320.
  72   10   ESP：474.
  73   9   ESP：333.
  74   10   ESP：487.
  75   9   ESP：487.
  76   1   ESP：397.
  77   2   ESP：307.
  78   7   ESP：541.
  79   7   ESP：557.
  80   8   ESP：525.
  81   1   ESP：401.
  82   2   ESN：309.
  83   3   ESP：453.
  84   4   ESP：353.
[表137]
Figure BPA00001447484601811
[表138]
Figure BPA00001447484601821
[表139]
[表140]
Figure BPA00001447484601841
[表141]
[表142]
Figure BPA00001447484601861
[表143]
Figure BPA00001447484601871
[表144]
Figure BPA00001447484601881
[表145]
Figure BPA00001447484601891
[表146]
Figure BPA00001447484601901
[表147]
Figure BPA00001447484601911
[表148]
Figure BPA00001447484601921
[表149]
Figure BPA00001447484601931
[表150]
Figure BPA00001447484601941
[表151]
Figure BPA00001447484601951
[表152]
Figure BPA00001447484601961
[表153]
Figure BPA00001447484601971
[表154]
Figure BPA00001447484601981
[表155]
Figure BPA00001447484601991
[表156]
  Ex   Syn   Data
  200   200   ESP：475.
  201   201   ESP：475.
  202   202   ESP：447.
  203   203   ESP：474.
  204   204   ESP：503.
  205   205   ESP：518.
  206   206   ESP：512.
  207   207   ESP：433.
  208   208   ESP：447.
  209   209   ESN：430.
  210   210   ESP：474.
  211   3   ESP：464.
  212   3   ESP：517.
  213   3   ESP：480.
  214   3   ESP：521.
  215   3   ESP：513，515.
  216   3   ESP：491.
  217   3   ESP：461.
  218   3   ESP：463，465.
  219   3   ESP：513，515.
  220   3   ESP：529，531.
  221   3   ESP：477.
  222   3   ESP：477.
  223   3   ESP：491.
  224   3   ESP：527.
  225   3   ESP：543.
  226   4   ESP：511.
  227   3   ESP：527.
  228   3   ESP：527.
  229   3   ESP：477.
  230   3   ESP：489，491.
  231   3   ESP：493，495.
  232   3   ESP：499.
  233   3   ESP：465.
  234   3   ESP：475.
  235   3   ESP：465.
  236   3   ESP：469.
[表157]
  Ex   Syn   Data
  237   3   ESP：443.
  238   3   ESP：463.
  239   3   ESP：497.
  240   3   ESP：439
  241   3   ESP：479，481.
  242   3   ESP：509.
  243   3   ESP：487.
  244   1   ESN：478.
  245   1   ESN：488.
  246   1   ESN：450.
  247   1   ESN：471.
  248   1   ESP：513.
  249   1   ESP：477.
  250   1   ESN：471.
  251   3   ESP：485.
  252   3   ESP：499.
  253   3   ESP：503.
  254   3   ESP：478.
  255   3   ESP：548.
  256   3   ESP：532.
  257   3   ESP：498.
  258   3   ESP：483.
  259   3   ESP：495.
  260   2   ESP：528.
  261   2   ESP：474.
  262   200   ESP：485.
  263   1   ESN：457.
  264   1   ESN：457.
  265   1   ESP：513.
  266   3   ESP：459.
  267   3   ESP：483.
  268   3   ESP：465.
  269   4   ESP：475.
  270   4   ESP：495.
  271   3   ESP：511.
  272   3   ESP：495.
  273   3   ESP：503.
[表158]
Figure BPA00001447484602021
[表159]
Figure BPA00001447484602031
[表160]
  Ex   Syn   Data
  339   3   ESP：515，517.
  340   3   ESP：537，539.
  341   3   ESP：569.
  342   3   ESP：441.
  343   3   ESP：590，592.
  344   3   ESP：530.
  345   3   ESP：443.
  346   3   ESP：491.
  347   4   ESP：475.
  348   3   ESP：485.
  349   3   ESP：537.
  350   3   ESP：475.
  351   3   ESP：509.
  352   3   ESP：485.
  353   3   ESP：547.
  354   1   ESP：439.
  355   1   ESP：465.
  356   1   ESP：453.
  357   1   ESP：467.
  358   1   ESP：469.
  359   200   ESP：545.
  360   2   ESN：488.
  361   3   ESP：507.
  362   3   ESP：491.
  363   3   ESP：485.
  364   3   ESP：457.
  365   3   ESP：475.
  366   3   ESP：481.
  367   3   ESP：495.
  368   3   ESP：479.
  369   3   ESP：521.
  370   3   ESP：605.
  371   3   ESP：464.
  372   3   ESN：480，482.
  373   3   ESP：505.
  374   3   ESP：519.
  375   3   ESP：535.
[表161]
  Ex   Syn   Data
  376   3   ESP：501.
  377   3   ESP：479.
  378   3   ESP：519，521.
  379   3   ESN：455.
  380   3   ESN：473.
  381   3   ESN：473.
  382   1   ESN：451.
  383   1   ESN：475.
  384   1   ESN：475.
  385   1   ESN：457.
  386   1   ESP：517.
  387   1   ESP：535.
  388   4   ESP：479.
  389   3   ESP：495.
  390   3   ESP：507.
  391   3   ESP：481.
  392   4   ESP：461.
  393   3   ESP：501.
  394   3   ESP：485.
  395   3   ESP：485.
  396   3   ESP：535.
  397   3   ESP：521.
  398   3   ESP：535.
  399   3   ESP：539.
  400   3   ESP：513.
  401   3   ESP：513.
  402   3   ESP：509.
  403   3   ESP：482.
  404   1   ESP：469.
  405   1   ESP：551.
  406   1   ESP：551.
  407   1   ESP：551.
  408   1   ESP：531.
  409   1   ESP：531.
  410   3   ESP：491.
  411   3   ESP：509.
  412   3   ESP：527.
[表162]
Figure BPA00001447484602061
[表163]
Figure BPA00001447484602071
[表164]
[表165]
  Ex   Syn   Data
  497   5   ESP：460.
  498   5   ESP：480.
  499   3   ESN：478.
  500   3   ESN：492.
  501   5   ESP：462.
  502   5   ESP：488.
  503   5   ESN：526.
  504   5   ESN：544.
  505   5   ESN：452.
  506   5   ESN：470.
  507   5   ESN：484.
  508   3   ESP：483.
  509   3   ESP：483.
  510   3   ESP：483.
  511   3   ESP：483.
  512   3   ESP：499，501.
  513   3   ESP：499，501.
  514   3   ESP：499，501.
  515   3   ESP：465.
  516   3   ESP：537，539.
  517   3   ESP：537，539.
  518   3   ESP：537，539.
  519   3   ESP：521.
  520   3   ESP：521.
  521   3   ESP：537，539.
  522   3   ESP：537，539.
  523   3   ESP：537，539.
  524   3   ESP：521.
  525   3   ESP：521.
  526   3   ESP：521.
  527   3   ESP：521.
  528   3   ESP：519.
  529   3   ESP：519.
  530   3   ESP：519.
[表166]
[表167]
Figure BPA00001447484602111
[表168]
  Ex   Syn   Data
  592   200   ESP：494.
  593   200   ESP：496.
  594   200   ESP：494.
  595   200   ESP：497.
  596   3   ESP：496.
  597   200   ESP：511.
  598   3   ESP：501.
  599   203   ESP：488.
  600   203   ESP：530.
  601   203   ESP：543.
  602   200   ESP：536，538.
  603   200   ESN：493.
  604   200   ESP：536，538.
  605   200   ESN：493.
  606   200   ESP：518，520.
  607   200   ESN：475.
  608   200   ESP：478.
  609   200   ESP：476.
  610   203   ESP：536.
  611   203   ESP：550.
  612   3   ESN：460.
  613   4   ESP：497.
  614   3   ESP：495，497.
  615   3   ESP：487.
  616   3   ESP：530.
  617   3   ESN：496.
  618   200   ESN：495.
  619   3   ESN：457.
  620   200   ESP：486.
  621   3   ESP：503.
  622   3   ESP：537，539.
  623   3   ESP：521.
  624   3   ESP：487.
  625   3   ESP：495，497.
  626   3   ESP：487.
  627   3   ESP：503.
  628   3   ESN：449.
[表169]
  Ex   Syn   Data
  629   200   ESP：497.
  630   200   ESP：487，489.
  631   200   ESP：503.
  632   5   ESN：478.
  633   200   ESP：511.
  634   200   ESP：509.
  635   200   ESP：501.
  636   200   ESP：510.
  637   1   ESP：460.
  638   202   ESP：477.
  639   200   ESP：447.
  640   200   ESN：443.
  641   200   ESP：487.
  642   200   ESN：435.
  643   200   ESP：447.
  644   200   ESP：445.
  645   200   ESP：487.
  646   200   ESP：437.
  647   6   ESP：491.
  648   201   ESP：515.
  649   200   ESP：459.
  650   3   ESN：466.
  651   1   ESP：459.
  652   210   ESP：500.
工业实用性
式(I)所示化合物或其盐具有DGAT1抑制作用，可用作肥胖、II型糖尿病、脂肪肝、以及相关疾病的予防剂和/或治疗剂。

Claims (11)

1.式(I)所示化合物或其盐，
式中，
A为可被取代的芳基、可被取代的环烷基、可被取代的芳香族杂环、可被取代的非芳香族杂环、或式(II)所示基团，
Figure FPA00001447484500012
R11和R12相同或不同，为-H、C1-6烷基、可被取代的芳基、可被取代的C3-8环烷基，但是，R11和R12不同时为-H，
此处，R11和R12可以与所结合的氮原子一起形成一体而形成可被取代的环氨基；
环B1为亚苯基、吡啶二基、萘二基或1，2，3，4-四氢萘二基，这些基团分别可以被选自由-OH、可被1个以上的卤素取代的C1-6烷基、可被1个以上的卤素取代的-O-C1-6烷基、C3-8环烷基和卤素构成的组中的1个以上的基团取代；
W为-O-、键、-O-C1-6亚烷基、-NH-、或C1-6亚烷基；
环B2为可被C1-6烷基取代的环己烷二基、可被C1-6烷基取代的环戊烷二基或可被C1-6烷基取代的桥环，在W为键的情况下，环B2可以为哌啶二基或8-氮杂双环[3.2.1]辛烷二基；
Y为键、C1-6亚烷基、或-O-C1-6亚烷基；
Z为：-CO2H或其生物电子等排体；可被选自由C1-6烷基、苯基及苄基构成的组中的1个或2个基团取代的氨基甲酰基，其中，所述C1-6烷基可被氨基或羧基取代；-CO-(可被1个或2个C1-6烷基取代的环氨基)；-OH；可被1个或2个C1-6烷基取代的氨基；-NH-C(＝O)-C1-6烷基；或-NH-C(＝O)-C3-8环烷基。
2.权利要求1所述的化合物或其盐，其中，
A为可被取代的芳基、可被取代的环烷基、可被取代的芳香族杂环、可被取代的非芳香族杂环、或式(II)所示基团，
R11和R12相同或不同，为-H、可被取代的芳基、可被取代的C3-8环烷基，但是，R11和R12不同时为-H，此处，R11和R12可以与所结合的氮原子一起形成一体而形成可被取代的环氨基；
环B1为式(III)所示基团，
Figure FPA00001447484500021
X1为N或CR3；X2为N或CR4；R1、R2、R3及R4相同或不同，为-H、-OH、可被1个以上的卤素取代的C1-6烷基、可被1个以上的卤素取代的-O-C1-6烷基、C3-8环烷基或卤素；
W为-O-或键；
环B2为环己烷-1，4-二基；
Y为键或C1-6亚烷基；
Z为-CO2H或其生物电子等排体、或-CONH2。
3.权利要求1所述的化合物或其盐，其中，
环B1为可被1个以上的卤素取代的1，4-亚苯基，W为-O-，环B2为环己烷-1，4-二基，Y为键或亚甲基，Z为-CO2H。
4.权利要求3所述的化合物或其盐，其中，
环B1为可被1个或2个氟取代的1，4-亚苯基。
5.权利要求4所述的化合物或其盐，其中，Y为键。
6.权利要求1所述的化合物或其盐，其为下述化合物或其盐：
顺式-4-[4-({2-[(4-环丙基苯甲酰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸、
顺式-4-(4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-[4-({2-[(4-氯-3-甲基苯甲酰基)氨基]乙基}氨基甲酰基)苯氧基]环己烷羧酸、
顺式-4-(3-氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-(3，5-二氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-(2，3-二氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-(2，5-二氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己烷羧酸、
顺式-4-{4-[(2-{[(3-氯-1-苯并噻吩-2-基)羰基]氨基}乙基)氨基甲酰基]苯氧基}环己烷羧酸、
顺式-4-{4-[(2-{[(5-氯噻吩-2-基)羰基]氨基}乙基)氨基甲酰基]-2，3-二氟苯氧基}环己烷羧酸、
顺式-4-{3-氟-4-[(2-{[(5-氟-1-苯并噻吩-2-基)羰基]氨基}乙基)氨基甲酰基]苯氧基}环己烷羧酸、或
[顺式-4-(2，5-二氟-4-{[2-(2-萘甲酰氨基)乙基]氨基甲酰基}苯氧基)环己基]乙酸。
7.一种药物组合物，含有权利要求1所述的化合物或其盐、以及可药用赋形剂。
8.一种用于预防或治疗肥胖的药物组合物，含有权利要求1所述的化合物或其盐。
9.权利要求1所述的化合物或其盐在制备用于预防或治疗肥胖的药物组合物中的用途。
10.用于预防或治疗肥胖的权利要求1所述的化合物或其盐。
11.一种预防或治疗肥胖的方法，包括给对象施予有效量的权利要求1所述的化合物或其盐。
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