依福地平 | 111011-63-3

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 依福地平
• 英文名称: (-)-2-[benzyl(phenyl)amino]ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-pyridinecarboxylate
• 英文别名: (-)-efonidipine；(-)-2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate；Efonidipine；2-(N-benzylanilino)ethyl 5-(5,5-dimethyl-2-oxo-1,3,2λ5-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate
• CAS: 111011-63-3
• 化学式: C₃₄H₃₈N₃O₇P
• 分子量: 631.665
• InChiKey: NSVFSAJIGAJDMR-UHFFFAOYSA-N

物化性质

• 熔点：
  169-170℃
• 沸点：
  746.9±60.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)
• 溶解度：
  DMF:30.0(最大浓度 mg/mL);47.49(最大浓度 mM)乙醇:40.0(最大浓度 mg/mL);63.32(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  45
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  123
• 氢给体数：
  1
• 氢受体数：
  9

ADMET

代谢

有人提出，非洛地平相较于其药物类别中的其他成员，不太可能受到首过效应的影响，并且其二氢吡啶环主要在侧链代谢后进行氧化。非洛地平具有高度亲脂性，这使得它能够进入富含磷脂的细胞膜，并到达钙通道靶点的二氢吡啶结合位点。非洛地平主要在肝脏中代谢。其代谢产物包括去苯基非洛地平（DPH）、脱氨非洛地平（AL）和去苄基非洛地平（DBZ）。这些代谢产物都表现为钙通道拮抗剂。在一项研究中，DBZ和DPH的血管舒张能力分别约为未代谢药物的三分之二和三分之一。研究表明，口服非洛地平氢氯酸盐后的大多数药理效应归功于未改变的药物，其代谢产物在其治疗效应中起的作用很小。在一项对六名健康志愿者的研究中，尿液中未发现显著量的未改变药物。在口服非洛地平后24小时内收集的尿液中，剂量的1.1%以脱氨非洛地平的形式排出，0.5%以脱氨非洛地平的吡啶类似物形式排出。

It has been suggested that efonidipine is less likely to be subject to the first-pass than other members of its drug class, and and that its dihydropyridine ring is oxidized primarily after metabolism of the side chain. Efonidipine is highly lipophilic and this allows for its entry into the phospholipid-rich cell membrane and reach the dihydropyridine binding site of the calcium channel targets. Efonidipine is mainly metabolized in the liver. Its metabolites are N-dephenylated Efonidipine (DPH), deaminated efonidipine (AL) and N-debenzylated Efonidipine (DBZ). Both metabolites behave as calcium antagonists. In one study, the vasodilating capabilities of DBZ and DPH were about two-thirds and one-third respectively than that of the unmetabolized drug. Research suggests that the majority of the pharmacological effect after oral dosing of efonidipine hydrochloride is due to unchanged drug and its metabolites play little role in its therapeutic effect. In a study of six healthy volunteers, no significant amount of unchanged drug was excreted in urine. The urine samples collected for 24 h after oral efonidipine administration, 1.1% of the dose was excreted as deaminated-efonidipine, and 0.5% as a pyridine analogue of deaminated-efonidipine.

来源:DrugBank

吸收、分配和排泄

• 吸收

伊福地平在大鼠体内的代谢进行了研究。从胆汁和尿液排泄的放射性总和估算的吸收比率约为62%。放射性在胃肠道和肝脏中较高，其次是肾上腺，这表明这些区域代谢率较高。 摄入后2小时内，血浆中未改变的药物占总放射性的47.7%，与同类其他药物相比，显示出较低的首过效应。在血浆中，NZ-105的主要代谢物包括：N-脱苄基化合物（DBZ）、N-脱苯基化合物（DPH）、氧化脱氨化合物（AL）、AL对应的吡啶化合物（ALP）、未知代谢物M-1和M-25。NZ-105通过N-脱苄基化、N-脱苯基化、氧化脱氨、酯水解以及1,4-二氢吡啶环氧化为其相应的吡啶化合物来进行代谢。

The metabolism of efonidipine was studied in rats. The absorption ratio of radioactivity estimated from the sum of biliary and urinary excretions was found to be approximately 62%. The radioactivity was high in the gastrointestinal tract and liver, followed by the adrenal glands, suggesting high rates of metabolism in these regions. The unchanged drug in the plasma accounted for 47.7% of radioactivity at 2hr after ingestion, demonstrating a lower first-pass effect in comparison with other drugs in the same class. In plasma, major metabolites of NZ-105 were: N-debenzylated compound (DBZ), N-dephenylated compound (DPH), oxidative deaminated compound (AL), AL-corresponding pyridine compound (ALP), unknown metabolite M-1 and M-25. NZ-105 was metabolized by N-debenzylation, N-dephenylation, oxidative deamination, ester hydrolysis and oxidation of 1, 4-dihydropyridine ring to its corresponding pyridine.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Efonidipine 也被称为 NZ-105，研究发现它主要通过胆汁系统消除。

Efonidipine is also referred to as NZ-105 and has been found to be mainly eliminated by the biliary system.

来源:DrugBank

安全信息

• 储存条件：
  -20℃

制备方法与用途

生物活性

Efonidipine (NZ-105) 是一种L型和T型钙离子通道阻滞剂，能够引起血管舒张并降低心脏自律性。它还能抑制醛固酮从肾上腺分泌。

靶点

Target	Value
T-type calcium channel	（）

反应信息

• 作为反应物：
  描述：

  N-(2-氯乙基)吗啉盐酸盐 、 依福地平 在 sodium hydride 作用下， 生成 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1-morpholinoethyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid 2-[benzyl(phenyl)amino]ethyl ester
  参考文献：
  名称：

  EP1698340

  摘要：

  公开号：
• 作为产物：
  描述：

  2-丙酮基-5,5-二甲基-2-氧代-1,3,2-二氧杂磷杂环己烷 在 哌啶 、 溶剂黄146 作用下， 以 甲苯 、 苯 为溶剂， 反应 11.5h， 生成 依福地平
  参考文献：
  名称：

  Synthesis of 1,4-Dihydropyridine-5-phosphonates and Their Calcium-Antagonistic and Antihypertensive Activities. Novel Calcium-Antagonist 2-(Benzyl(phenly)amino)ethyl 5-(5,5-Dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate Hydrochloride Ethanol(NZ-105) and Its Crystal Structure.

  摘要：

  研究了3-羧酸酯变体在2,2-二甲基三甲基烯-3-烷氧羰基-4-芳基-1,4-二氢-2,6-二甲基-5-吡啶膦酸酯(1)中与钙拮抗和降压活性相关的影响：合成了含有不超过12个碳的烷基和羧酸酯部分含有氨基功能团的类似物，以检测其生物活性。其中，2-[苄基(苯基)氨基]乙基5-(5,5-二甲基-2-氧-1,3,2-二氧膦杂环己烷-2-基)-1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3-吡啶羧酸酯盐酸盐乙醇(NZ-105)显示出特别有益的活性，并被选中进行进一步的药理学研究和临床开发。描述了通过X射线晶体学分析获得的NZ-105的结构-活性关系和固态结构的一些方面。

  DOI：

  10.1248/cpb.40.2362

文献信息

• Dibenzyl Amine Compounds and Derivatives
  申请人：Chang George

  公开号：US20070213371A1

  公开（公告）日：2007-09-13

  Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

  二苯基胺化合物及其衍生物，含有这种化合物的药物组合物以及使用这种化合物提高某些血浆脂质水平，包括高密度脂蛋白胆固醇，并降低其他一些血浆脂质水平，如低密度脂蛋白胆固醇和甘油三酯，并据此治疗由高密度脂蛋白胆固醇水平低和/或低密度脂蛋白胆固醇和甘油三酯水平高加重的疾病，如动脉粥样硬化和心血管疾病在某些哺乳动物，包括人类。
• Aromatic amine derivative and use thereof
  申请人：Taniguchi Takahiko

  公开号：US20090325956A1

  公开（公告）日：2009-12-31

  The present invention provides a novel SCD inhibitor. An SCD inhibitor containing a compound represented by the formula [I] wherein ring A is an optionally substituted aromatic ring, ring B is an optionally substituted ring, ring C is an optionally substituted aromatic ring, R is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and X is a spacer having 1 to 5 atoms in the main chain, or a salt thereof, or a prodrug thereof.

  本发明提供了一种新型SCD抑制剂。一种包含由下式[I]表示的化合物的SCD抑制剂 其中环A是可选择取代的芳香环，环B是可选择取代的环，环C是可选择取代的芳香环，R是氢原子，可选择取代的碳氢基团或可选择取代的杂环基团，X是具有主链中1到5个原子的间隔物，或其盐，或其前药。
• [EN] FUSED RING COMPOUNDS AND USE THEREOF<br/>[FR] COMPOSÉS CYCLIQUES CONDENSÉS ET UTILISATION DE CEUX-CI
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2009125873A1

  公开（公告）日：2009-10-15

  The present invention aims to provide a glucokinase activator useful as a pharmaceutical agent such as an agent for the prophylaxis or treatment of diabetes, obesity and the like. The present invention provides a glucokinase activator containing a compound represented by the formula (I): wherein each symbol is defined in the specification, or a salt thereof or a prodrug thereof.

  本发明旨在提供一种葡萄糖激酶激活剂，可用作药用剂，如用于预防或治疗糖尿病、肥胖等疾病的药剂。本发明提供一种包含由式(I)表示的化合物的葡萄糖激酶激活剂：其中每个符号在规范中有定义，或其盐或前药。
• [EN] FUSED QUINOLINE DERIVATIVE AND USE THEREOF<br/>[FR] DÉRIVÉ DE QUINOLINE FUSIONNÉE ET UTILISATION DE CELUI-CI
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2005105802A1

  公开（公告）日：2005-11-10

  The present invention aims at provision of a quinoline derivative having a neurokinin 2 (NK2) receptor antagonistic action and relates to a compound represented by the formula (I) wherein Rl is a hydrogen atom and the like; R2 is a hydrogen atom, a hydrocarbon group optionally having substituent(s) and the like; R3 is unsubstituted (i.e., absence), a hydrogen atom and the like; R4 and R5 are the same or different and each is a hydrogen atom, a hydrocarbon group optionally having substituent(s), and the like; R6 is (cyclic group optionally having substituent(s)) -carbonyl, and the like; R7, R8, R9 and R10 are the same or different and each is a hydrogen atom, halogen and the like; or R7 and R8, R8 and R9, and R9 and R10 may form a ring together with the adjacent carbon atoms; n is an integer of 1 to 5; --- represents unsubstituted (i.e., absence) or a single bond; and --- represents a single bond or a double bond, or a salt thereof, and the like.

  本发明旨在提供一种具有神经激肽2（NK2）受体拮抗作用的喹啉衍生物，并涉及一种由式（I）表示的化合物，其中R1是氢原子等；R2是氢原子，可选地具有取代基的碳氢基团等；R3是未取代的（即缺失），氢原子等；R4和R5相同或不同，每个是氢原子，可选地具有取代基的碳氢基团等；R6是（环状基团，可选地具有取代基）-羰基等；R7、R8、R9和R10相同或不同，每个是氢原子，卤素等；或R7和R8、R8和R9、以及R9和R10可以与相邻的碳原子一起形成环；n是1到5的整数；---表示未取代的（即缺失）或单键；---表示单键或双键，或其盐等。
• [EN] AGENT FOR PREVENTING OR TREATING NEUROPATHY<br/>[FR] AGENT POUR LA PRÉVENTION OU LE TRAITEMENT DE NEUROPATHIE
  申请人：TAKEDA CHEMICAL INDUSTRIES LTD

  公开号：WO2004039365A1

  公开（公告）日：2004-05-13

  The present invention provides an agent for preventing or treating neuropathy having superior action and low toxicity. This agent comprises a compound represented by the formula:wherein ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s);B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;X is a divalent acyclic hydrocarbon group;Z is -O-, -S-, -NR2-, -CONR2- or -NR2CO- (R2 is a hydrogen atom or an optionally substituted alkyl group);Y is a bond or a divalent acyclic hydrocarbon group;R1 is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be -O-, or a salt thereof.

  本发明提供了一种具有优越作用和低毒性的预防或治疗神经病的药剂。该药剂包括一个由以下式表示的化合物：其中环A是含有2个或更多氮原子的5元芳香杂环，可能进一步具有取代基；B是一个可选择取代的碳氢基团或可选择取代的杂环基团；X是二价的无环碳氢基团；Z是-O-，-S-，-NR2-，-CONR2-或-NR2CO-（R2是氢原子或可选择取代的烷基基团）；Y是键或二价的无环碳氢基团；R1是可选择取代的环基团，可选择取代的氨基团或可选择取代的酰基团，但当环A表示的5元芳香杂环是咪唑时，Z不应为-O-，或其盐。