N-Benzyl-α-aminomethylphosphonsaeure | 49622-09-5

• 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: N-Benzyl-α-aminomethylphosphonsaeure
• 英文别名: (benzylamino)methylphosphonic acid；N-benzylaminomethylphosphonic acid；[(Benzylamino)methyl]phosphonic acid
• CAS: 49622-09-5
• 化学式: C₈H₁₂NO₃P
• 分子量: 201.162
• InChiKey: YTSVWPKOWYIUDR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.7
• 重原子数：
  13
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  69.6
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  聚合甲醛 、 N-Benzyl-α-aminomethylphosphonsaeure 在 次磷酸 、 溶剂黄146 作用下， 以 水 为溶剂， 反应 48.0h， 以49%的产率得到
  参考文献：
  名称：

  磷酸-曼尼希反应从次磷酸中选择性清洁合成氨烷基-H-次膦酸

  摘要：

  氨基烷基-H-次膦酸，也称为氨基烷基亚膦酸，被研究作为羧酸氨基酸的生物活性类似物和/或作为合成其他氨基烷基磷酸的有价值的中间体。它们的合成主要是通过 P-H 前体、醛和胺的 phospha-Mannich 反应完成的。该反应很少是干净和高产的。在这里，H 3 PO 2与仲胺和甲醛在湿 AcOH 中的反应以几乎定量的产率产生氨甲基-H-次膦酸，并且几乎没有副产物。令人惊讶的是，反应结果取决于胺的碱性。p K a胺> 7-8 给出了所需的产品。对于弱碱性胺，还原性N-甲基化与H 3 PO 2氧化成H 3 PO 3相结合成为相关的副反应。伯胺的反应不太明显，只有非常碱性的胺才能获得氨基-双(甲基-H-次膦酸)。醛含量较高的反应产率较低。获得了源自多胺的独特的羧酸-次膦酸-膦酸以及聚（H-次膦酸）。氨基烷基-H的合成用途-次膦酸在 P-H 键氧化及其对双键的加成以及选择性胺脱保护中得到说明。具有乙

  DOI：

  10.1039/d0ra03075a
• 作为产物：
  描述：

  N-benzyl-N-hydroxymethyl-formamide 在 三氯化磷 、 盐酸 、 methyloxirane 作用下， 以 水 为溶剂， 生成 N-Benzyl-α-aminomethylphosphonsaeure
  参考文献：
  名称：

  作为脲酶抑制剂的 N-取代氨基甲烷膦酸和氨基甲烷-P-甲基次膦酸

  摘要：

  基于具有共价碳磷键的二酰氨基磷酸盐结构的未扩展小分子被开发为一组新的抑制剂，以控制微生物尿素分解。应用基于结构的抑制剂设计方法，利用细菌脲酶的可用晶体结构，设计并合成了氨基甲基膦酸和P-甲基-氨基甲基次膦酸的N-取代衍生物。在使用来自巴氏杆菌和Canavalia ensiformis 的脲酶的抑制研究中，两种先导结构的N , N -二甲基衍生物在低微摩尔范围内的解离常数 ( K i ) 下最有效。  = 13 ± 0.8 和 0.62 ± 0.09 μM，分别）。上的尿素分解菌株全细胞研究奇异变形杆菌表现出的高效率N，N-二甲基和aminomethane- N-甲基衍生物P -methylphosphinic酸用于病原性细菌的尿素酶的抑制作用。使用 NMR 技术在 30 天内证实了所选抑制剂的高水解稳定性。

  DOI：

  10.1007/s00726-011-0920-4

文献信息

• Process for the preparation of N-phosphonomethylglycine and derivatives thereof
  申请人：Coleman P. James

  公开号：US20050054871A1

  公开（公告）日：2005-03-10

  N-phosphonomethylamines are produced by reaction of an amine substrate with a halomethylphosphonic acid or salt thereof, a hydroxymethylphosphonic acid or salt thereof, or a dehydrated self-ester dimer, trimer or oligomer of hydroxymethylphosphonic acid. Among the products that may be prepared according to the process are N-phosphonomethylaminocarboxylic acids such as (e.g.) glyphosate, N-phosphonomethylaminoalkanols such as (e.g.) hydroxyethlaminomethylphosphonic acid, and N-acylaminomethylphosphonic acids such as (e.g.) N-carbamylaminomethylphosphonic acid. Certain reactions are conducted with a substantial excess of amine reactant in order to drive the conversion while avoiding excessive formation of bis(N-phosphonomethyl)amine by-products. Other reactions use a secondary amine substrate (such as iminodiacetic acid) and can be conducted at substantial equimolar ratios of halomethylaminomethylphosphonic acid or hydroxyaminomethylphosphonic acid to secondary amine reactant without significant formation of bis(phosphonomethyl)amine by-products. Further disclosed is a process for the preparation of hydroxymethylphosphonic acid self-ester dimers, trimers and oligomers by azeotropic dehydration.

  N-磷酸甲基胺是通过胺底物与卤甲基膦酸或其盐、羟甲基膦酸或其盐，或羟甲基膦酸的脱水自酯二聚体、三聚体或寡聚体反应而制备的。根据该过程可制备的产品包括N-磷酸甲基氨基羧酸，如草甘膦，N-磷酸甲基氨基烷醇，如羟乙氨基甲基膦酸，以及N-酰氨基甲基膦酸，如N-氨基甲基膦酸。为了推动转化并避免过多形成双(N-磷酸甲基)胺副产物，某些反应中使用大量过量的胺试剂。其他反应使用二次胺底物（如亚胺二乙酸）并可在相当量的卤甲基氨甲膦酸或羟氨甲膦酸与二次胺试剂的摩尔比下进行，而不会显著形成双(磷酸甲基)胺副产物。还公开了通过共沸脱水制备羟甲基膦酸自酯二聚体、三聚体和寡聚体的方法。
• COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS
  申请人：Charmot Dominique

  公开号：US20120263670A1

  公开（公告）日：2012-10-18

  The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.

  本公开涉及化合物和方法，用于治疗与液体潴留或盐过载相关的疾病，如心力衰竭（特别是充血性心力衰竭）、慢性肾脏病、终末期肾脏病、肝病和过氧化物酶体增殖物激活受体（PPAR）γ激动剂引起的液体潴留。本公开还涉及化合物和方法，用于治疗高血压。本公开还涉及化合物和方法，用于治疗胃肠道疾病，包括治疗或减轻与胃肠道疾病相关的疼痛。
• COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDER
  申请人：Ardelyx, Inc.

  公开号：US20150190389A1

  公开（公告）日：2015-07-09

  The present disclosure is directed to compounds of the structure (X): CoreL-NHE) n (X) wherein: n is 2 or 3; NHE has the structure wherein: R 1 is H or —SO 2 —NR 7 R 8 —; R 2 is selected from H, —NR 7 (CO)R 8 , —SO 2 —NR 7 R 8 — and —NR 7 R 8 ; R 3 is hydrogen; R 7 is hydrogen; R 8 is a bond linking to L; L is a polyalkylene glycol linker; and Core has the following structure: wherein: X is selected from the group consisting of a bond, —O—, —NH—, NHC(═O)—, —NHC(═O)NH— and —NHSO 2 —; and Y is selected from the group consisting of a bond, optionally substituted C 1-6 alkylene, optionally substituted benzene, pyridinyl, a polyethylene glycol linker and —(CH 2 ) 1-6 O(CH 2 ) 1-6 —, and methods of using such compounds for the treatment of irritable bowel syndrome, chronic kidney disease and end-stage renal disease.

  本公开涉及结构为（X）：CoreL-NHE)n（X）的化合物，其中：n为2或3；NHE具有以下结构：其中：R1为H或—SO2—NR7R8—；R2选自H，—NR7（CO）R8，—SO2—NR7R8—和—NR7R8；R3为氢；R7为氢；R8为连接到L的键；L为多聚乙二醇连接剂；Core具有以下结构：其中：X选自由键，—O—，—NH—，NHC（═O）—，—NHC（═O）NH—和—NHSO2—；Y选自键，可选择性地取代的C1-6烷基，可选择性地取代的苯，吡啶基，聚乙二醇连接剂和—（CH2）1-6O（CH2）1-6—，以及使用这种化合物治疗肠易激综合征、慢性肾脏病和终末期肾脏疾病的方法。
• COMBINATIONS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS
  申请人：Ardelyx, Inc.

  公开号：EP3939964A1

  公开（公告）日：2022-01-19

  The present disclosure is directed to a pharmaceutical composition comprising a compound of formula (X), in combination with another active agent, and to the use of said composition in methods for the treatment of disorders associated with fluid retention or salt overload or gastrointestinal tract disorders, such as irritable bowel syndrome and constipation associated with cystic fibrosis. The methods generally comprise administering to a mammal in need thereof a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto.

  本公开涉及一种药物组合物，该组合物包含与另一种活性剂组合的式(X)化合物，并涉及将所述组合物用于治疗与体液潴留或盐超载相关的疾病或胃肠道疾病（如肠易激综合征和与囊性纤维化相关的便秘）的方法。这些方法一般包括向有需要的哺乳动物施用包含此类化合物的药物组合物，该组合物设计为在胃肠道（GI）中基本活跃，以抑制其中钠离子和氢离子的 NHE 介导的反转运。更具体地说，该方法包括向有需要的哺乳动物施用包含这种化合物的药物组合物，该化合物可抑制胃肠道中NHE-3、-2和/或-8介导的钠离子和/或氢离子的反转运，并且设计成基本上不渗透到上皮细胞层，或更具体地说，不渗透到胃肠道上皮细胞层。由于该化合物基本上不渗透，因此不会被吸收，从而基本上不会被全身生物利用，从而限制了其他内脏器官（如肝脏、心脏、大脑等）对该化合物的接触。
• Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
  申请人：ARDELYX, INC.

  公开号：US10543207B2

  公开（公告）日：2020-01-28

  The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract.

  本公开内容涉及用于治疗与体液潴留或盐负荷过重相关的疾病的化合物和方法，如心力衰竭（尤其是充血性心力衰竭）、慢性肾病、终末期肾病、肝病和过氧化物酶体增殖激活受体（PPAR）γ激动剂诱导的体液潴留。本公开还涉及治疗高血压的化合物和方法。本公开还涉及治疗胃肠道疾病的化合物和方法，包括治疗或减轻与胃肠道疾病相关的疼痛。这些方法一般包括向有需要的哺乳动物施用药学上有效量的化合物或包含这种化合物的药物组合物，这种化合物在胃肠道中基本具有活性，可抑制其中钠离子和氢离子的NHE介导的反转运。更具体地说，该方法包括向有需要的哺乳动物施用药学上有效量的化合物或包含该化合物的药物组合物，该化合物可抑制胃肠道中NHE-3、-2和/或-8介导的钠离子和/或氢离子的反转运，且设计成基本上不渗透上皮细胞层，或更具体地说不渗透胃肠道上皮细胞。由于该化合物基本上不渗透，因此不会被吸收，从而基本上不会被全身生物利用，从而限制了其他内脏器官（如肝脏、心脏、大脑等）对该化合物的接触。本公开内容还进一步涉及一种方法，在这种方法中，哺乳动物与吸液聚合物一起服用这种化合物，从而使这种组合起到如上所述的作用，并进一步提供封存存在于消化道中的液体和/或盐的能力。