dimethyl 3-(3-biphenyl)-2-oxopropanephosphonate | 431989-81-0

• 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: dimethyl 3-(3-biphenyl)-2-oxopropanephosphonate
• 英文别名: (3-biphenyl-3-yl-2-oxo-propyl)-phosphonic acid dimethyl ester；dimethyl (3-biphenyl-3-yl-2-oxopropyl)phosphonate；1-Dimethoxyphosphoryl-3-(3-phenylphenyl)propan-2-one
• CAS: 431989-81-0
• 化学式: C₁₇H₁₉O₄P
• 分子量: 318.309
• InChiKey: KHKYLTTZTQTAGN-UHFFFAOYSA-N

物化性质

• 沸点：
  454.2±33.0 °C(Predicted)
• 密度：
  1.174±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  dimethyl 3-(3-biphenyl)-2-oxopropanephosphonate 在 硼烷四氢呋喃络合物 、 sodium hydride 、 (R)-2-甲基-CBS-恶唑硼烷 作用下， 以 四氢呋喃 、 甲苯 、 mineral oil 为溶剂， 反应 4.66h， 生成 n-butyl 4-((2-[(2R)-2-((1E,3S)-4-[1,1'-biphenyl-3-yl]-3-hydroxy-1-buten-1-yl)-5-oxo-1-pyrrolidinyl]ethyl) thio)butanoate
  参考文献：
  名称：

  Synthesis and evaluation of γ-lactam analogs of PGE2 as EP4 and EP2/EP4 agonists

  摘要：

  To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl omega-chain moiety of the gamma-lactam 5-thia prostaglandin E analog and the 2-mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.04.008
• 作为产物：
  描述：

  2-([1,1-联苯]-3-基)乙酸 在 正丁基锂 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 正己烷 、 甲苯 、 乙腈 为溶剂， 反应 4.0h， 生成 dimethyl 3-(3-biphenyl)-2-oxopropanephosphonate
  参考文献：
  名称：

  Synthesis and evaluation of novel modified γ-lactam prostanoids as EP4 subtype-selective agonists

  摘要：

  To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified gamma-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the gamma-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.12.009

文献信息

• EP4 receptor selective agonists in the treatment of osteoporosis
  申请人：——

  公开号：US20020065308A1

  公开（公告）日：2002-05-30

  This invention is directed to EP4 receptor selective prostaglandin agonists of the Formula I, 1 wherein R 2 , X, Z and Q are as defined in the specification. This invention is also directed to pharmaceutical compositions containing those compounds. This invention is also directed to methods of treating conditions which present with low bone mass, particularly osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a mammal comprising administering those compounds.

  这项发明针对公式I中的EP4受体选择性前列腺素激动剂，其中R2、X、Z和Q的定义如规范中所述。该发明还涉及含有这些化合物的药物组合物。该发明还涉及治疗低骨密度症状的方法，特别是骨质疏松症、虚弱、骨折、骨缺损、儿童特发性骨量减少、牙槽骨丧失、下颌骨丧失、骨折、骨切开术、与牙周炎相关的骨丧失或哺乳动物体内假体生长中的骨丧失，包括给予这些化合物。
• Methods of treatment with selective EP4 receptor agonists
  申请人：——

  公开号：US20030207925A1

  公开（公告）日：2003-11-06

  The present invention provides a method of treating hypertension, liver failure, loss of patency of ductus arteriosus, glaucoma or ocular hypertension in a patient, comprising administering to the patient a therapeutically effective amount of a selective EP 4 receptor agonist of Formula I 1 or a prodrug thereof, a pharmaceutically acceptable salt of the selective EP 4 receptor agonist or prodrug or a stereoisomer or diastereomeric mixture of the EP 4 receptor agonist, prodrug or salt, wherein the variables X, Z, Q, , and R 2 are as defined in the specification.

  本发明提供了一种治疗患有高血压、肝功能衰竭、动脉导管未开放、青光眼或眼压增高的患者的方法，包括向患者施用公式I1中的选择性EP4受体激动剂或其前药的治疗有效量、选择性EP4受体激动剂的药学上可接受的盐或前药的盐，或EP4受体激动剂、前药或盐的立体异构体或对映体混合物，其中变量X、Z、Q、和R2如规范所定义。
• 8-AZAPROSTAGLANDIN DERIVATIVES AND MEDICAL USE THEREOF
  申请人：Kambe Tohru

  公开号：US20080033033A1

  公开（公告）日：2008-02-07

  The pharmaceutical composition comprising the compound of the invention having 8-azaprostaglandin skeleton represented by formula (I) (wherein, all the symbols have the same meanings as that of the specification.) a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof, or a prodrug thereof and them as active ingredient have EP 4 agonistic action and thus are considered useful for the prevention and/or treatment of immunological diseases, asthma, neuronal cell death, arthritis, lung failure, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, shock and glaucoma, etc. Furthermore, the compounds also have an action of accelerating bone formation, so it is expected to be useful for the prevention and/or treatment of diseases associated with loss in bone mass, for example, primary osteoporosis, secondary osteoporosis, bone metastasis of cancer, hypercalcemia, Paget's disease, bone loss, osteonecrosis, bone formation after bone operation, alternative treatment for bone grafting.

  本发明的化合物具有8-氮杂前列腺素骨架，其化学式为(I)，其中所有符号的含义与规范相同。该药物组合物包括该化合物、其盐、溶剂化物或环糊精包合物，或其前药，作为活性成分具有EP4激动作用，因此被认为对预防和/或治疗免疫性疾病、哮喘、神经细胞死亡、关节炎、肺功能衰竭、肺纤维化、肺气肿、支气管炎、慢性阻塞性肺疾病、肝损伤、急性肝炎、肾炎、肾功能不全、高血压、心肌缺血、全身炎症反应综合征、败血症、血液嗜酸细胞综合征、巨噬细胞激活综合征、斯蒂尔氏病、川崎病、烧伤、全身性肉芽肿病、溃疡性结肠炎、克隆氏病、透析时的高细胞因子血症、多器官衰竭、休克和青光眼等具有用处。此外，这些化合物还具有加速骨形成的作用，因此有望用于预防和/或治疗与骨量减少有关的疾病，例如原发性骨质疏松症、继发性骨质疏松症、骨转移性癌症、高钙血症、帕吉特病、骨质流失、骨坏死、骨手术后的骨形成、骨移植的替代治疗。
• Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists
  作者：Tohru Kambe、Toru Maruyama、Yoshihiko Nakai、Hideyuki Yoshida、Hiroji Oida、Takayuki Maruyama、Nobutaka Abe、Akio Nishiura、Hisao Nakai、Masaaki Toda

  DOI：10.1016/j.bmc.2012.02.018

  日期：2012.4

  To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of c-lactam prostaglandin E analogs bearing a 16-phenyl x-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration. (C) 2012 Elsevier Ltd. All rights reserved.
• 8-AZAPROSTAGLANDIN DERIVATIVES AND MEDICINAL USES THEREOF
  申请人：ONO PHARMACEUTICAL CO., LTD.

  公开号：EP1586564B1

  公开（公告）日：2012-11-28