diethyl 2-((2-(3-(dimethylcarbamoyl)-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)phenyl)acetoxy)methyl)-2-phenylmalonate | 916683-32-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: diethyl 2-((2-(3-(dimethylcarbamoyl)-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)phenyl)acetoxy)methyl)-2-phenylmalonate
• 英文别名: 2-(2-{3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic acid diethyl ester；2-(2-{3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonic acid diethyl ester；2-(2-{3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonic acid diethyl ester；Granotapide；diethyl 2-[[2-[3-(dimethylcarbamoyl)-4-[[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]phenyl]acetyl]oxymethyl]-2-phenylpropanedioate
• CAS: 916683-32-4；594842-13-4
• 化学式: C₃₉H₃₇F₃N₂O₈
• 分子量: 718.727
• InChiKey: FPUQGCOBYOXAED-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  52
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  128
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  diethyl 2-((2-(3-(dimethylcarbamoyl)-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)phenyl)acetoxy)methyl)-2-phenylmalonate 、 alkaline earth salt of/the/ methylsulfuric acid 以 aq. phosphate buffer 为溶剂， 反应 1.0h， 生成 2-(3-(dimethylcarbamoyl)-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)phenyl)acetic acid 、 2-苯基丙烯酸
  参考文献：
  名称：

  基于2-苯基-2-（2-芳基乙酰氧基）甲基丙二酸二乙酯酯基微粒体甘油三酸酯转移蛋白（MTP）抑制剂的新型水解机理的见解

  摘要：

  抑制肠道和肝脏微粒体甘油三酸酯转移蛋白（MTP）是治疗血脂异常和相关代谢紊乱的潜在策略。但是，抑制肝MTP会导致肝转氨酶升高，肝脂肪沉积增加，与肝脂肪变性相一致。2-（（2-（3-（二甲基氨基甲酰基）-4-（4'-（三氟甲基）-[1,1'-联苯] -2-基羧酰胺基）苯基）乙酰氧基）甲基）二乙基丙二酸二乙酯（JTT- 130）是MTP的一种肠特异性抑制剂，在血脂异常患者的短期临床试验中，不会引起转氨酶升高。通过肝脏特异性羧酸酯酶快速水解其酯键，可以选择性抑制肠道MTP，从而形成无活性的羧酸代谢物1。在围绕MTP的组织特异性抑制剂的发现工作中，详细研究了JTT-130水解的机理。JTT-130在H 2 18 O存在下在人肝微粒体中温育后，在1中缺乏18 O掺入表明，水解不是通过酯键的简单裂解而发生的。萎缩酸（2-苯基丙烯酸）作为代谢产物的特征与水解途径一致，该水解途径涉及侧链丙二酸乙酯侧基之一

  DOI：

  10.1021/tx300243v
• 作为产物：
  描述：

  2-(3-(dimethylcarbamoyl)-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)phenyl)acetic acid 、 hydroxymethyl-phenyl-malonic acid diethyl ester 在 hydroxymethyl-phenyl-malonic acid diethyl ester 作用下， 生成 diethyl 2-((2-(3-(dimethylcarbamoyl)-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)phenyl)acetoxy)methyl)-2-phenylmalonate
  参考文献：
  名称：

  ESTER COMPOUND AND MEDICINAL USE THEREOF

  摘要：

  一种治疗高脂血症的新型药物，其为酯化合物，由式(1")表示（其中：R1和R2均为氢原子或可选择取代的芳基等；X为-COO-或-CON(R10)-；R3和R4均为氢原子、C1-C6烷基或C1-C6烷氧基等；R5、R6和R7均为氢原子、C1-C6烷基或C1-C6烷氧基等；R8和R9各自独立地为氢原子、C1-C6烷基、-CON(R18)(R19)或-COO(R20)等；环A、环B和环C各自独立地为芳基或杂环残基等；Alk1和Alk2各自独立地为脂肪二亚基等；l和m均为0或1至3的整数），或其前药，或其药学上可接受的盐。该治疗剂能够选择性地抑制小肠中的MTP，因此不会引起脂肪肝等副作用。

  公开号：

  EP1479666A1

文献信息

• Ester compound and medicinal use thereof
  申请人：Hagiwara Atsushi

  公开号：US20050075367A1

  公开（公告）日：2005-04-07

  A novel therapeutic agent for hyperlipidemia, which is an ester compound represented by the formula (1″) (wherein R 1 and R 2 are each hydrogen atom or optionally substituted aryl, etc.; X is —COO— or —CON(R 10 )—; R 3 and R 4 are each hydrogen atom, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, etc.; R 5 , R 6 and R 7 are each hydrogen atom, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, etc.; R 8 and R 9 are each independently hydrogen atom, C 1 -C 6 alkyl, —CON(R 18 )(R 19 ) or —COO(R 20 ), etc.; ring A, ring B and ring C are each independently aryl or heterocycle residue, etc.; Alk 1 and Alk 2 are each independently alkanediyl, etc.; l and m are each an integer of 0 or 1 to 3) or a prodrug thereof, or a pharmaceutically acceptable salt of either. The therapeutic agent selectively inhibits MTP in the small intestine, thus causes no such side effect as a fatty liver.

  一种治疗高脂血症的新型药物，其为酯化合物，由式（1”）所表示（其中，R1和R2分别为氢原子或可选取代的芳基等；X为—COO—或—CON(R10)—；R3和R4分别为氢原子、C1-C6烷基或C1-C6烷氧基等；R5、R6和R7分别为氢原子、C1-C6烷基或C1-C6烷氧基等；R8和R9分别独立地为氢原子、C1-C6烷基、—CON(R18)(R19)或—COO(R20)等；环A、环B和环C分别独立地为芳基或杂环残基等；Alk1和Alk2分别独立地为脂肪二亚基等；l和m分别为0或1至3的整数），或其前药，或其药学上可接受的盐。该治疗剂能够选择性地抑制小肠中的MTP，从而不会引起脂肪肝等副作用。
• ESTER COMPOUND AND MEDICAL USE THEREOF
  申请人：Hagiwara Atsushi

  公开号：US20100158996A1

  公开（公告）日：2010-06-24

  A novel therapeutic agent for hyperlipidemia, which is an ester compound represented by the formula (1″) (wherein R 1 and R 2 are each hydrogen atom or optionally substituted aryl, etc.; X is —COO— or —CON(R 10 )—; R 3 and R 4 are each hydrogen atom, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, etc.; R 5 , R 6 and R 7 are each hydrogen atom, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, etc.; R 9 and R 9 are each independently hydrogen atom, C 1 -C 6 alkyl, —CON(R 18 ) (R 19 ) or —COO(R 20 ), etc.; ring A, ring B and ring C are each independently aryl or heterocycle residue, etc.; Alk 1 and Alk 2 are each independently alkanediyl, etc.; l and m are each an integer of 0 or 1 to 3) or a prodrug thereof, or a pharmaceutically acceptable salt of either. The therapeutic agent selectively inhibits MTP in the small intestine, thus causes no such side effect as a fatty liver.

  一种治疗高脂血症的新型药物，其为酯化合物，由式（1″）所表示（其中R1和R2分别为氢原子或可选择取代的芳基等；X为—COO—或—CON(R10)—；R3和R4分别为氢原子、C1-C6烷基或C1-C6烷氧基等；R5、R6和R7分别为氢原子、C1-C6烷基或C1-C6烷氧基等；R8和R9分别独立地为氢原子、C1-C6烷基、—CON(R18)(R19)或—COO(R20)等；环A、环B和环C分别独立地为芳基或杂环残基等；Alk1和Alk2分别独立地为脂肪二亚基等；l和m分别为0或1至3的整数），或其前药，或其药学上可接受的盐。该治疗剂选择性地抑制小肠中的MTP，从而不会引起脂肪肝等副作用。
• THERAPEUTIC OR PREVENTIVE DRUG FOR DIABETES, OBESITY, OR ARTERIOSCLEROSIS
  申请人：Japan Tobacco, Inc.

  公开号：EP1769793A1

  公开（公告）日：2007-04-04

  Because the compound of the invention represented by the formula (1): or its pharmaceutically acceptable salt has excellent antidiabetic effect, anti-obesity effect and anti-arteriosclerosis effect, a medicine containing the compound of formula (1) as the active ingredient is useful as an agent for the prevention or treatment of diabetes (especially non-insulin dependent diabetes mellitus), obesity (especially visceral fat obesity), or arteriosclerosis.

  因为本发明的化合物由式（1）表示： 或其药学上可接受的盐具有很好的抗糖尿病作用、抗肥胖作用和抗动脉硬化作用，因此含有式（1）化合物作为活性成分的药物可作为预防或治疗糖尿病（尤其是非胰岛素依赖型糖尿病）、肥胖（尤其是内脏脂肪性肥胖）或动脉硬化的药物。
• SOLID MEDICINAL PREPARATION IMPROVED IN SOLUBILITY AND STABILITY AND PROCESS FOR PRODUCING THE SAME
  申请人：Japan Tobacco, Inc.

  公开号：EP1806149A1

  公开（公告）日：2007-07-11

  The present invention relates to a solid formulation with improved solubility and maintained stability including a chemical substance poorly soluble in water as a pharmaceutically active ingredient formulated in an improved manner. More specifically, the present invention relates to a solid formulation having improved water-solubility which comprises a chemical substance poorly soluble in water as a pharmaceutically active ingredient, a water-soluble polymer substance and an inorganic porous substance, characterized in that (1) the chemical substance poorly soluble in water forms a solid dispersion together with the water-soluble polymer substance, (2) the water-soluble polymer substance forming the solid dispersion is in the form of fine pieces, and (3) the water-soluble polymer substance is in the form of fine pieces is maintained to be adsorbed on and/or adhered to the surface of the inorganic porous substance. The solid formulation can be produced by stirring and mixing a solution obtained by dissolving a chemical substance poorly soluble in water as a pharmaceutically active ingredient and a water-soluble polymer substance in an organic solvent with an inorganic porous substance and then granulating and drying the mixture.

  本发明涉及一种固体制剂，它具有更好的溶解性和稳定性，包括以改进方式配制的一种难溶于水的化学物质作为药物活性成分。 更具体地说，本发明涉及一种具有更好水溶性的固体制剂，它包括一种作为药物活性成分的难溶于水的化学物质、一种水溶性聚合物物质和一种无机多孔物质，其特征在于 (1) 难溶于水的化学物质与水溶性高分子物质形成固体分散体、 (2) 形成固体分散体的水溶性高分子物质呈细小块状，以及 (3) 细粒形式的水溶性高分子物质被吸附和/或附着在无机多孔物质的表面。 固体制剂可通过将溶于水的化学物质（作为药物活性成分）和水溶性高分子物质溶解在有机溶剂中得到的溶液与无机多孔物质搅拌混合，然后将混合物造粒和干燥而制成。
• Agent for the treatment or prevention of diabetes, obesity or arteriosclerosis
  申请人：Japan Tobacco, Inc.

  公开号：EP2397129A1

  公开（公告）日：2011-12-21

  Because the compound of the invention represented by the formula (1): or its pharmaceutically acceptable salt has excellent antidiabetic effect, anti-obesity effect and anti-arteriosclerosis effect, a medicine containing the compound of formula (1) as the active ingredient is useful as an agent for the prevention or treatment of diabetes (especially non-insulin dependent diabetes mellitus), obesity (especially visceral fat obesity), or arteriosclerosis.

  因为本发明的化合物由式（1）表示： 或其药学上可接受的盐具有很好的抗糖尿病作用、抗肥胖作用和抗动脉硬化作用，因此含有式（1）化合物作为活性成分的药物可作为预防或治疗糖尿病（尤其是非胰岛素依赖型糖尿病）、肥胖（尤其是内脏脂肪性肥胖）或动脉硬化的药物。