(Z)-5-((1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazol-5-yl)methylene)-3-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione | 1351571-43-1

• 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: (Z)-5-((1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazol-5-yl)methylene)-3-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione
• 英文别名: (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(3S,4S)-(3-fluoro-1-methylpiperidin-4-yl)-1,3-thiazolidine-2,4-dione；(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(trans-3-fluoro-1-methylpiperidin-4-yl)-1,3-thiazolidine-2,4-dione；(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-[(3S,4S)-3-fluoro-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione
• CAS: 1351571-43-1
• 化学式: C₂₅H₂₁ClF₄N₄O₂S
• 分子量: 552.98
• InChiKey: BQNYTHNYGPJDQV-NHPVNLLWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  83.7
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  在 哌啶 、 sodium carbonate 作用下， 以 二氯甲烷 、 水 、 甲苯 为溶剂， 生成 (Z)-5-((1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazol-5-yl)methylene)-3-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione
  参考文献：
  名称：

  Process Development for Scale-Up of a Novel 3,5-Substituted Thiazolidine-2,4-dione Compound as a Potent Inhibitor for Estrogen-Related Receptor 1

  摘要：

  The development of a reproducible process for multihundred gram production of (Z)-5-((1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazol-5-yl)methylene)-3-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione (26), a potent and selective inhibitor of estrogen-related receptor 1 (ERR!), is described. This multihundred gram synthesis was achieved via magnesium perchlorate-catalyzed regioselective epoxide ring-opening of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (9) with thiazolidine-2,4-dione (6, TZD) to form a diastereomeric mixture tert-butyl 4-(2,4-dioxothiazolidin-3-yl)-3-hydroxypiperidine-1-carboxylate (17), of which the 3-hydroxyl group was functionally transformed to 3-fluoro derivative 19 after treatment with Deoxo-Fluor. Chiral separation of 19 provided the desired diastereomer (3R,4R)-21 that was converted to the secondary amine 23 TFA salt. Reductive amination of 23 produced the key intermediate N-methyl 24. Knoevenagel condensation of 24 with 1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazole-5-carbaldehyde (5) produced the final product 26 in 10% overall yield (99.7% HPLC area% with >= 99.5% de) after a convergent eight synthetic steps with the only column purification being the chiral HPLC separation of 3R,4R-21 from 3S,4S-22.

  DOI：

  10.1021/op400325r

文献信息

• SUBSTITUTED THIAZOLIDINEDIONE INDAZOLES, INDOLES AND BENZOTRIAZOLES AS ESTROGEN-RELATED RECEPTOR-a MODULATORS
  申请人：Bignan Gilles

  公开号：US20110294780A1

  公开（公告）日：2011-12-01

  The present invention relates to compounds of Formula (I), methods for preparing these compounds, compositions, intermediates and derivatives thereof and for treating a condition including but not limited to ankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoid arthritis, infectious arthritis, childhood arthritis, psoriatic arthritis, reactive arthritis), bone-related diseases (including those related to bone formation), breast cancer (including those unresponsive to anti-estrogen therapy), cardiovascular disorders, cartilage-related disease (such as cartilage injury/loss, cartilage degeneration, and those related to cartilage formation), chondrodysplasia, chondrosarcoma, chronic back injury, chronic bronchitis, chronic inflammatory airway disease, chronic obstructive pulmonary disease, diabetes, disorders of energy homeostasis, gout, pseudogout, lipid disorders, metabolic syndrome, multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis, Paget's disease, periodontal disease, polymyalgia rheumatica, Reiter's syndrome, repetitive stress injury, hyperglycemia, elevated blood glucose level, and insulin resistance.

  本发明涉及式(I)的化合物，制备这些化合物的方法，组合物，中间体及其衍生物，并用于治疗包括但不限于强直性脊柱炎，动脉粥样硬化，关节炎（如类风湿关节炎，感染性关节炎，儿童关节炎，银屑病性关节炎，反应性关节炎），与骨相关的疾病（包括与骨形成有关的疾病），乳腺癌（包括对抗雌激素治疗无效的癌症），心血管疾病，软骨相关疾病（如软骨损伤/丧失，软骨退化以及与软骨形成有关的疾病），软骨发育不良，软骨肉瘤，慢性腰部损伤，慢性支气管炎，慢性炎症性气道疾病，慢性阻塞性肺疾病，糖尿病，能量稳态紊乱，痛风，假性痛风，脂质紊乱，代谢综合征，多发性骨髓瘤，肥胖，骨关节炎，遗传性骨发育不全，骨溶解性骨转移，软骨软化症，骨质疏松症，帕金森病，牙周病，多肌痛风，Reiter综合征，重复性应激损伤，高血糖，血糖水平升高和胰岛素抵抗等病症的方法。
• Substituted thiazolidinedione indazoles, indoles and benzotriazoles as estrogen-related receptor-α modulators
  申请人：Bignan Gilles

  公开号：US08796256B2

  公开（公告）日：2014-08-05

  The present invention relates to compounds of Formula (I), methods for preparing these compounds, compositions, intermediates and derivatives thereof and for treating a condition including but not limited to ankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoid arthritis, infectious arthritis, childhood arthritis, psoriatic arthritis, reactive arthritis), bone-related diseases (including those related to bone formation), breast cancer (including those unresponsive to anti-estrogen therapy), cardiovascular disorders, cartilage-related disease (such as cartilage injury/loss, cartilage degeneration, and those related to cartilage formation), chondrodysplasia, chondrosarcoma, chronic back injury, chronic bronchitis, chronic inflammatory airway disease, chronic obstructive pulmonary disease, diabetes, disorders of energy homeostasis, gout, pseudogout, lipid disorders, metabolic syndrome, multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis, Paget's disease, periodontal disease, polymyalgia rheumatica, Reiter's syndrome, repetitive stress injury, hyperglycemia, elevated blood glucose level, and insulin resistance.

  本发明涉及化合物I式，制备这些化合物的方法，组成物，中间体和衍生物以及治疗包括但不限于强直性脊柱炎，动脉粥样硬化，关节炎（如类风湿性关节炎，感染性关节炎，儿童关节炎，银屑病性关节炎，反应性关节炎），与骨相关的疾病（包括与骨形成有关的疾病），乳腺癌（包括对抗雌激素治疗无效的乳腺癌），心血管疾病，软骨相关疾病（如软骨损伤/丢失，软骨退化以及与软骨形成有关的疾病），软骨发育不良，软骨肉瘤，慢性背部损伤，慢性支气管炎，慢性炎症性气道疾病，慢性阻塞性肺疾病，糖尿病，能量稳态失调疾病，痛风，假性痛风，脂质代谢异常，代谢综合征，多发性骨髓瘤，肥胖症，骨关节炎，成骨不全症，骨转移性溶骨病，骨软化症，骨质疏松症，Paget病，牙周病，多肌痛性类风湿，Reiter综合征，重复性应力损伤，高血糖，血糖升高和胰岛素抵抗等疾病的方法。
• Indazole-based ligands for estrogen-related receptor α as potential anti-diabetic agents
  作者：Raymond J. Patch、Hui Huang、Sharmila Patel、Wing Cheung、Guozhang Xu、Bao-Ping Zhao、Derek A. Beauchamp、Dionisios Rentzeperis、John G. Geisler、Hossein B. Askari、Jianying Liu、Jyotsna Kasturi、Meghan Towers、Micheal D. Gaul、Mark R. Player

  DOI：10.1016/j.ejmech.2017.07.015

  日期：2017.9

  Estrogen-related receptor alpha (ERR alpha) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkyithiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC(50)s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases. (C) 2017 Elsevier Masson SAS. All rights reserved.
• US7559984B2
  申请人：——

  公开号：US7559984B2

  公开（公告）日：2009-07-14
• US8796256B2
  申请人：——

  公开号：US8796256B2

  公开（公告）日：2014-08-05