α-ethyl (γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate

• 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: α-ethyl (γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate
• 英文别名: 4-[[(2S)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid
• 化学式: C₂₄H₂₉NO₅
• 分子量: 411.498
• InChiKey: PYNXFZCZUAOOQC-LFABVHOISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  30
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  92.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  α-ethyl (γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate 在 盐酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 17.0h， 生成 沙库巴曲
  参考文献：
  名称：

  Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors

  摘要：

  The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.

  DOI：

  10.1021/jm00010a014
• 作为产物：
  描述：

  methyl N-(tert-butoxycarbonyl)-O-[(trifluoromethyl)sulfonyl]-D-tyrosinate 在 palladium on activated charcoal 、 四(三苯基膦)钯 吡啶 、 盐酸 、 sodium hydroxide 、 lithium aluminium tetrahydride 、 氢气 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 80.0 ℃ 、344.73 kPa 条件下， 反应 61.33h， 生成 α-ethyl (γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate
  参考文献：
  名称：

  Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors

  摘要：

  The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.

  DOI：

  10.1021/jm00010a014

文献信息

• [EN] NEW PROCESSES AND INTERMEDIATES USEFUL IN SYNTHESIS OF NEP INHIBITORS<br/>[FR] NOUVEAUX PROCÉDÉS ET INTERMÉDIAIRES UTILES DANS LA SYNTHÈSE D'INHIBITEURS D'ENDOPEPTIDASE NEUTRE (NEP)
  申请人：NOVARTIS AG

  公开号：WO2017051326A1

  公开（公告）日：2017-03-30

  The invention relates to a novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, in particular neutral endopeptidase (NEP) inhibitors such as sacubitril, and prodrugs thereof.

  这项发明涉及一种新颖的工艺、新颖的工艺步骤和新颖的中间体，用于合成药用活性化合物，特别是中性内肽酶（NEP）抑制剂，如沙库比特利，以及其前药。
• ORGANIC COMPOUNDS
  申请人：Intra-Cellular Therapies, Inc.

  公开号：US20160039829A1

  公开（公告）日：2016-02-11

  The invention relates to novel inhibitors of phosphodiesterase 1 (PDE1), useful for the treatment of diseases or disorders characterized by disruption of or damage to certain cGMP/PKG mediated pathways (e.g., in cardiac tissue). The invention further relates to pharmaceutical composition comprising the same and methods of treatment of cardiovascular disease and related disorders, e.g., congestive heart disease, atherosclerosis, myocardial infarction, and stroke.

  本发明涉及新型磷酸二酯酶1（PDE1）抑制剂，用于治疗由于某些cGMP/PKG介导的通路（例如在心脏组织中）受到破坏或损伤而表现出的疾病或障碍。本发明还涉及包含该抑制剂的制药组合物以及用于治疗心血管疾病和相关疾病的方法，例如充血性心脏病，动脉粥样硬化，心肌梗死和中风。
• Biaryl substituted 4-amino-butyric acid amides
  申请人：Ciba-Geigy Corporation

  公开号：US05217996A1

  公开（公告）日：1993-06-08

  The invention relates to biaryl substituted 4-amino-butyric acid derivatives of formula I ##STR1## wherein COX and COX' independently represent carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester or amide; R.sub.1 represents hydrogen, lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl, aryl-lower alkyl, biaryl-lower alkyl, lower alkoxy, aryl-lower alkoxy, aryloxy, N-lower alkylamino, N,N-di-lower alkylamino, N-aryl-lower alkylamino, N,N-di-aryl-lower alkylamino, N-arylamino, N,N-diarylamino, lower alkanoylamino, aryl-lower alkanoylamino or aroylamino; R.sub.2 represents hydrogen, hydroxy, lower alkoxy, lower alkyl, aryl-lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkylthio-lower alkyl or aryl-lower alkoxy-lower alkyl; biaryl represents phenyl substituted by carbocyclic or heterocyclic aryl; A represents a direct bond, lower alkylene, phenylene or cyclohexylene; m represents 1 or zero, provided that m represents 1 when A is a direct bond; or pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.

  本发明涉及公式I的双芳基取代的4-氨基丁酸衍生物，其中COX和COX'分别表示羧基或以药学上可接受的酯或酰胺形式衍生的羧基；R1表示氢、低碳基、C3-C7-环烷基-低碳基、芳基-低碳基、双芳基-低碳基、低烷氧基、芳基-低烷氧基、芳氧基、N-低烷基氨基、N,N-二-低烷基氨基、N-芳基-低烷基氨基、N,N-二-芳基-低烷基氨基、N-芳基氨基、N,N-二芳基氨基、低烷酰胺基、芳基-低烷酰胺基或芳酰胺基；R2表示氢、羟基、低烷氧基、低碳基、芳基-低碳基、C3-C7-环烷基-低碳基、氨基-低碳基、羟基-低碳基、低烷基硫基-低碳基、低烷氧基-低碳基、芳基-低烷硫基-低碳基或芳基-低烷氧基-低碳基；双芳基表示被环烷芳基或杂环芳基取代的苯基；A表示直接键、低碳基、苯基或环己基；m表示1或零，当A为直接键时，m表示1；或其药学上可接受的盐；包含所述化合物的制药组合物；制备所述化合物和中间体的方法；以及通过将所述化合物用于需要该类治疗的哺乳动物的治疗中，抑制中性内肽酶的方法。
• Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations
  申请人：Feng Lili

  公开号：US08877938B2

  公开（公告）日：2014-11-04

  A compound of an angiotensin receptor antagonist (ARB), a neutral endopeptidase inhibitor (NEPi) and one or more monovalent cations are useful for the treatment of hypertension and/or heart failure. ARB includes S—N-valeryl-N-[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine in the anion form, NEPi includes (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester in the anion form and cation includes monovalent cations such as Na+. The compound includes trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate.

  一种包含肾素-血管紧张素系统受体拮抗剂（ARB）、中性内肽酶抑制剂（NEPi）和一种或多种一价阳离子的化合物，可用于治疗高血压和/或心力衰竭。ARB包括阴离子形式的S-N-戊酰基-N-[2′-(1H-四唑-5-基)-联苯-4-基]-甲基}-缬氨酸，NEPi包括阴离子形式的(2R,4S)-5-联苯基-4-(3-羧基丙酰氨基)-2-甲基戊酸乙酯，阳离子包括一价阳离子如Na+。该化合物包括三钠[3-((1S,3R)-1-联苯基甲基-3-乙氧羰基-1-丁基氨甲酰)丙酸-(S)-3′-甲基-2′-(戊酰2″-(四唑-5-酸盐)联苯-4′-基甲基}氨基)丁酸酯] 半五水合物。
• COMPOUND COMPRISING AN ARB AND A NEPI
  申请人：Novartis AG

  公开号：EP3685833A1

  公开（公告）日：2020-07-29

  A compound comprising the angiotensin receptor antagonist valsartan and the NEPi (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, and sodium cations in a 1:1:3 molar ratio. The compound is useful in the treatment of cardiovascular and/or renal diseases.

  一种化合物，由血管紧张素受体拮抗剂缬沙坦和 NEPi (2R,4S)-5-联苯-4-基-4-(3-羧基丙酰氨基)-2-甲基戊酸乙酯以及钠离子以 1:1:3 的摩尔比组成。该化合物可用于治疗心血管和/或肾脏疾病。