2-([2-((2R)-2-((1E,3S)-4-[3-(5-chloro-1,3-benzoxazol-2-yl)phenyl]-3-hydroxybut-1-enyl)-5-oxopyrrolidin-1-yl)ethyl]sulfanyl)-1,3-thiazole-4-carboxylic acid | 729611-19-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-([2-((2R)-2-((1E,3S)-4-[3-(5-chloro-1,3-benzoxazol-2-yl)phenyl]-3-hydroxybut-1-enyl)-5-oxopyrrolidin-1-yl)ethyl]sulfanyl)-1,3-thiazole-4-carboxylic acid
• 英文别名: (15α,13E)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzoxazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene；2-[2-[(2R)-2-[(E,3S)-4-[3-(5-chloro-1,3-benzoxazol-2-yl)phenyl]-3-hydroxybut-1-enyl]-5-oxopyrrolidin-1-yl]ethylsulfanyl]-1,3-thiazole-4-carboxylic acid
• CAS: 729611-19-2
• 化学式: C₂₇H₂₄ClN₃O₅S₂
• 分子量: 570.09
• InChiKey: GITXCHGAXFCMKG-CNIPWFDFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  38
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  170
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3-碘苯甲酸 在 盐酸 、 正丁基锂 、 硼烷四氢呋喃络合物 、 三乙酰氧基硼氢化钠 、 sodium hydride 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 、 (R)-2-甲基-CBS-恶唑硼烷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 1,3-二甲基-2-咪唑啉酮 、 甲醇 、 乙二醇二甲醚 、 乙醇 、 正己烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 、 mineral oil 为溶剂， 反应 53.99h， 生成 2-([2-((2R)-2-((1E,3S)-4-[3-(5-chloro-1,3-benzoxazol-2-yl)phenyl]-3-hydroxybut-1-enyl)-5-oxopyrrolidin-1-yl)ethyl]sulfanyl)-1,3-thiazole-4-carboxylic acid
  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

文献信息

• 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。
• 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
• US7256211B1
  申请人：——

  公开号：US7256211B1

  公开（公告）日：2007-08-14
• Synthesis and evaluation of γ-lactam analogs of PGE2 as EP4 and EP2/EP4 agonists
  作者：Tohru Kambe、Toru Maruyama、Yoshihiko Nakai、Hiroji Oida、Takayuki Maruyama、Nobutaka Abe、Akio Nishiura、Hisao Nakai、Masaaki Toda

  DOI：10.1016/j.bmc.2012.04.008

  日期：2012.6

  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.