四乙基(4-氨基-1,1-丁烷二基)二(膦酸酯) | 90315-14-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 中文名称: 四乙基(4-氨基-1,1-丁烷二基)二(膦酸酯)
• 英文名称: tetraethyl 4-aminobutylidene-1,1-bisphosphonate
• 英文别名: 4,4-Bis(diethoxyphosphoryl)butan-1-amine
• CAS: 90315-14-3
• 化学式: C₁₂H₂₉NO₆P₂
• 分子量: 345.313
• InChiKey: HNDLSFPAWVPPTH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  21
• 可旋转键数：
  13
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  97.1
• 氢给体数：
  1
• 氢受体数：
  7

安全信息

• 海关编码：
  2922499990

反应信息

• 作为反应物：
  描述：

  四乙基(4-氨基-1,1-丁烷二基)二(膦酸酯) 、 N3-<(2,6-dioxomorpholino)ethyl>-N6-<(ethoxycarbonyl)methyl>-3,6-diazaoctane diacid 在 碘代三甲硅烷 、 三乙胺 作用下， 生成 {(2-{[2-(Bis-carboxymethyl-amino)-ethyl]-carboxymethyl-amino}-ethyl)-[(4,4-bis-phosphono-butylcarbamoyl)-methyl]-amino}-acetic acid
  参考文献：
  名称：

  Development of phosphonate derivatives of gadolinium chelates for NMR imaging of calcified soft tissues

  摘要：

  We have synthesized several classes of gadolinium (Gd) complexes for use as NMR contrast agents in the detection of soft-tissue calcification. Class I was made up of strongly chelated GdDTPA complexes with one carboxylate arm coupled to a phosphonate-containing molecule through an amide link. Class II complexes were formed by Gd with several aminophosphonates and phosphono carboxylic acids. Class III were Gd complexes of weak chelates containing no phosphonate. The calcium-seeking ability of each complex was assessed by in vivo bone uptake. Tissue distribution in normal rats showed that only the complexes of GdDTPA modified with a diphosphonate group and GdEDTMP (EDTMP is ethylenediaminetetrakis(methylenephosponate] showed adequate bone localization at the concentrations required for NMR contrast enhancement (approximately 20% of a 100 mumol/kg dose).

  DOI：

  10.1021/jm00121a026
• 作为产物：
  描述：

  tetraethyl 4-hydroxybutylene-1,1-bisphosphonate 在 sodium azide 、 水 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成 四乙基(4-氨基-1,1-丁烷二基)二(膦酸酯)
  参考文献：
  名称：

  A NEW EFFICIENT SYNTHESIS OF ω-AMINOALKYLIDENE-1,1-BISPHOSPHONATE TETRAETHYLESTERS

  摘要：

  Bisphosphonates are interesting therapeutic agents in the management of bone diseases and since several years our laboratory has been developing the chemistry of 1,1-bisphosphonates, This paper describes an original synthesis of two aminoalkylidenebisphosphonates by first preparing the intermediate hydroxyalkylidenebisphosphonates which are transformed into amines via the azides.

  DOI：

  10.1080/10426509808036988

文献信息

• Guanidinoalkyl-1,1-bisphosphonic acid derivatives, process for their
  申请人：Hoechst Aktiengesellschaft

  公开号：US05294608A1

  公开（公告）日：1994-03-15

  The invention describes tautomeric compounds of the formula Ia, Ib or Ic ##STR1## and/or their physiologically tolerable salts, in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are a hydrogen atom, substituted (C.sub.1 -C.sub.7)-alkyl, (C.sub.3 -C.sub.10)-cycloalkyl, substituted phenyl or (C.sub.1 -C.sub.4)-alkylphenyl, R.sup.2 is substituted phosphoric acid, R.sup.2 and R.sup.3, R.sup.2 and R.sup.5 or R.sup.4 and R.sup.5 form a monocyclic 5- to 7-membered saturated or unsaturated heterocyclic ring which is mono- or polysubstituted, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are a hydrogen atom or (C.sub.1 -C.sub.5)-alkyl, X is a hydrogen atom, hydroxyl or halogen, l and n are an integer from 0 to 7, m is an integer from 0 to 2, and the sum of the numbers l, m and n is less than or equal to 10, a process for the preparation of the compounds of the formula Ia, Ib or Ic, pharmaceuticals and their use for the prophylaxis or treatment of osteoporosis.

  该发明描述了公式Ia、Ib或Ic的互变异构化合物及/或其生理耐受盐，其中R.sup.1、R.sup.2、R.sup.3、R.sup.4、R.sup.5、R.sup.6和R.sup.7是氢原子，取代的（C.sub.1 -C.sub.7）-烷基，（C.sub.3 -C.sub.10）-环烷基，取代的苯基或（C.sub.1 -C.sub.4）-烷基苯基，R.sup.2是取代的磷酸，R.sup.2和R.sup.3，R.sup.2和R.sup.5或R.sup.4和R.sup.5形成单环5-至7-成员饱和或不饱和杂环环，该环是单取代或多取代的，R.sup.8、R.sup.9、R.sup.10和R.sup.11是氢原子或（C.sub.1 -C.sub.5）-烷基，X是氢原子、羟基或卤素，l和n是0至7之间的整数，m是0至2之间的整数，l、m和n的总和小于或等于10，一种制备公式Ia、Ib或Ic化合物的方法，以及用于预防或治疗骨质疏松症的药物及其使用。
• NOVEL FLUORINE-CONTAINING BISPHOSPHONIC ACID DERIVATIVE AND USE THEREOF
  申请人：NAGASAKI UNIVERSITY

  公开号：US20180022769A1

  公开（公告）日：2018-01-25

  A series of fluorine-containing bisphosphonic acids in which an alkylamine side chain is added, a series of fluorine-containing bisphosphonic acids in which an amino group substituted by a heterocyclic group or a heterocyclic group containing a nitrogen atom is added, to the carbon atom of P—C(F)—P, and a series of fluorine-containing bisphosphonate derivatives in which the acid moiety thereof is esterified by an alkoxymethyl group such as POM group, n-butanoyloxymethyl (BuOM) group and the like, that is, the fluorine-containing bisphosphonic acid and fluorine-containing bisphosphonate derivative represented by the following formula (I): wherein each symbol is as defined in the DESCRIPTION, can efficiently induce proliferation of peripheral blood γδ T cells that express Vγ2Vδ2 T cell receptor having superior cytotoxicity against tumor cells and virus infected cells, immunize tumor cells and virus infected cells, and can induce cytotoxicity by γδ T cells.

  一系列含氟双膦酸，其中添加了烷胺侧链，一系列含氟双膦酸，其中添加了由杂环基团取代的氨基或含氮原子的杂环基团，连接到P-C(F)-P的碳原子上，以及一系列含氟双膦酸衍生物，其中其酸基部分通过POM基团、正丁酰氧甲基（BuOM）基团等烷氧甲基基团酯化，即以下式（I）所代表的含氟双膦酸和含氟双膦酸衍生物： 其中每个符号如描述中所定义，可以有效诱导表达具有对肿瘤细胞和病毒感染细胞具有优越细胞毒性的Vγ2Vδ2 T细胞受体的外周血γδ T细胞增殖，免疫肿瘤细胞和病毒感染细胞，并且可以通过γδ T细胞诱导细胞毒性。
• Synthesis and Immunomodulatory Activity of Fluorine‐Containing Bisphosphonates
  作者：Satoshi Mizuta、Mohammed S. O. Tagod、Masashi Iwasaki、Yoichi Nakamura、Hiroaki Senju、Hiroshi Mukae、Craig T. Morita、Yoshimasa Tanaka

  DOI：10.1002/cmdc.201800764

  日期：2019.2.19

  T cells kill almost all types of tumor cells that have been treated with bisphosphonates. In this study, we synthesized a series of fluorine-containing bisphosphonates based on current drugs and found that they stimulated Vγ2Vδ2 T cell killing of tumor cells. A fluorine-containing prodrug analogue of zoledronate where phosphonate moieties were masked with pivaloyloxymethyl groups markedly enhanced Vγ2Vδ2

  使用抗PD-1 / PD-L1或抗CTLA-4单克隆抗体（mAbs）的免疫检查点封锁彻底改变了癌症治疗方法。但是，许多类型的癌症均无反应，而只有少数患者会持续缓解。因此，肿瘤免疫学家正在努力通过利用免疫效应细胞（例如αβT细胞和γδT细胞）开发用于非造血系统肿瘤的过继细胞疗法。与在MHC I类或II类分子的背景下识别肽的常规αβT细胞相反，表达Vγ2Vδ2T细胞受体（也称为Vγ9Vδ2）的γδT细胞被异戊二烯代谢产物（磷酸抗原）刺激，但在丁苯丙氨酸丁酯中是异戊烯基二磷酸。 3A1依赖方式。Vγ2Vδ2T细胞杀死几乎所有用双膦酸盐治疗的肿瘤细胞。在这项研究中，我们基于现有药物合成了一系列含氟双膦酸酯，发现它们刺激了Vγ2Vδ2T细胞杀死肿瘤细胞。唑来膦酸盐的含氟前药类似物，其中膦酸酯部分被新戊酰氧基甲基掩盖，可显着增强Vγ2Vδ2T细胞介导的细胞毒性，并且还促进外周血Vγ2Vδ2T细胞的扩增
• Gem-diphosphonic acids, and pharmaceutical compositions containing them
  申请人：Boehringer Mannheim Italia S.p.A.

  公开号：US05300671A1

  公开（公告）日：1994-04-05

  Diphosphonic acids of formula (I), wherein R.sub.1 and R.sub.2 are hydrogen or C.sub.1 -C.sub.4 alkyl; (A) is hydrogen, halogen, hydroxy or C.sub.1 -C.sub.12 alkyl; (B) is a bond, a C.sub.1 -C.sub.8 alkylene chain, a cycloalkylalkylene chain, an alkylene chain substituted by cyclohexyl or cyclopentyl groups, or an aralkyl chain, an alkyl chain containing an heteroatom (O, S or N--CH.sub.3) or an ureido residue --(CH.sub.2).sub.nl --NHCONH--(CH.sub.2).sub.n --with n ranging from 1 to 5, R.sub.3 is hydrogen, C.sub.1 -C.sub.9 alkyl, C.sub.3 -C.sub.6 cycloalkyl, benzyl, phenyl or p-methoxybenzyl; (C) is C.sub.1 -C.sub.5 alkyl, phenyl or an aralkyl chain; R.sub.4 is hudrogen, C.sub.1 -C.sub.5 alkyl or an amino group optionally substituted by alkyl, phenyl, benzyl, p-methoxybenzyl, acyl, amminoacidic or peptide groups; R.sub.5 and R.sub.6 are 2-haloethyl or together form a 1-aziridinyl residue, are useful as antitumor agent.

  式(I)的二膦酸，其中R.sub.1和R.sub.2为氢或C.sub.1-C.sub.4烷基；(A)为氢，卤素，羟基或C.sub.1-C.sub.12烷基；(B)为键，C.sub.1-C.sub.8烷基链，环烷基烷基链，被环己基或环戊基基团取代的烷基链，或者是芳基烷基链，含有杂原子(O，S或N-CH.sub.3)或尿素基残基-(CH.sub.2).sub.nl-NHCONH-(CH.sub.2).sub.n，其中n为1至5，R.sub.3为氢，C.sub.1-C.sub.9烷基，C.sub.3-C.sub.6环烷基，苄基，苯基或对甲氧基苄基；(C)为C.sub.1-C.sub.5烷基，苯基或芳基烷基链；R.sub.4为氢，C.sub.1-C.sub.5烷基或氨基，氨基可以选择性地被烷基，苯基，苄基，对甲氧基苄基，酰基，氨基酸或肽基团取代；R.sub.5和R.sub.6为2-卤乙基或一起形成1-氮杂环丙基残基，用作抗肿瘤剂。
• Fluorine-containing bisphosphonic acid derivative and use thereof
  申请人：NAGASAKI UNIVERSITY

  公开号：US10280188B2

  公开（公告）日：2019-05-07

  A series of fluorine-containing bisphosphonic acids in which an alkylamine side chain is added, a series of fluorine-containing bisphosphonic acids in which an amino group substituted by a heterocyclic group or a heterocyclic group containing a nitrogen atom is added, to the carbon atom of P—C(F)—P, and a series of fluorine-containing bisphosphonate derivatives in which the acid moiety thereof is esterified by an alkoxymethyl group such as POM group, n-butanoyloxymethyl (BuOM) group and the like, that is, the fluorine-containing bisphosphonic acid and fluorine-containing bisphosphonate derivative represented by the following formula (I): wherein each symbol is as defined in the DESCRIPTION, can efficiently induce proliferation of peripheral blood γδ T cells that express Vγ2Vδ2 T cell receptor having superior cytotoxicity against tumor cells and virus infected cells, immunize tumor cells and virus infected cells, and can induce cytotoxicity by γδ T cells.

  在 P-C(F)-P.的碳原子上加入烷基胺侧链的含氟双膦酸系列、在 P-C(F)-P.的碳原子上加入被杂环基团或含氮原子的杂环基团取代的氨基的含氟双膦酸系列、以及在 P-C(F)-P.的碳原子上加入被烷氧基甲基基团（如 POM 基团、正丁酰氧基甲基）酯化的酸基的含氟双膦酸衍生物系列、以及一系列含氟双膦酸衍生物，其中酸基被烷氧基甲基如 POM 基团、正丁酰氧基甲基 (BuOM) 基团等酯化，即下式 (I) 所代表的含氟双膦酸和含氟双膦酸衍生物： 其中各符号如说明书中定义，能有效诱导表达Vγ2Vδ2 T细胞受体的外周血γδT细胞增殖，对肿瘤细胞和病毒感染细胞具有优异的细胞毒性，免疫肿瘤细胞和病毒感染细胞，并能诱导γδT细胞产生细胞毒性。