(R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone | 1429557-45-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并吡嗪类
• 英文名称: (R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone
• 英文别名: [(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-(4-thiophen-2-ylphenyl)methanone
• CAS: 1429557-45-8
• 化学式: C₂₀H₁₈N₆OS₂
• 分子量: 422.535
• InChiKey: DHRKQJQSMYHSPN-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  133
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine 在 N-甲基吗啉 、 盐酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 9.42h， 生成 (R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone
  参考文献：
  名称：

  Discovery and Optimization of Novel Antagonists to the Human Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part I)

  摘要：

  Neurokinin-3 receptor (NK3R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. We therefore decided to explore NK3R antagonists as therapeutics for sex-hormone disorders that can potentially benefit from lowering GnRH pulsatility with consequent diminished levels of plasma luteinizing hormone (LH) and correspondingly attenuated levels of circulating androgens and estrogens. The discovery and lead optimization of a novel N-acyl-triazolopiperazine NK3R antagonist chemotype achieved through bioisosteric lead change from the high-throughput screening (HTS) hit is described. A concomitant improvement in the antagonist bioactivity and ligand lipophilic efficiency (LLE) parameter were the principal guidelines in the lead optimization efforts. Examples of advanced lead analogues to demonstrate the amenability of this chemotype to achieving a suitable pharmacokinetic (PK) profile are provided as well as pharmacokinetic-pharmacodynamic (PKPD) correlations to analyze the trends observed for LH inhibition in castrated rats and monkeys that served as preliminary in vivo efficacy models.

  DOI：

  10.1021/jm5017413

文献信息

• [EN] NOVEL CHIRAL N-ACYL-5,6,7,(8-SUBSTITUTED)-TETRAHYDRO-[1,2,4]TRIAZOLO[4,3-a]PYRAZINES AS SELECTIVE NK-3 RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITION, METHODS FOR USE IN NK-3 RECEPTOR MEDIATED DISORDERS AND CHIRAL SYNTHESIS THEREOF<br/>[FR] NOUVELLES N-ACYL-5,6,7,8-TÉTRAHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZINES 8-SUBSTITUÉES CHIRALES UTILISÉES COMME ANTAGONISTES SÉLECTIFS DES RÉCEPTEURS NK-3, COMPOSITION PHARMACEUTIQUE, PROCÉDÉS DESTINÉS À ÊTRE UTILISÉS DANS DES TROUBLES À MÉDIATION PAR LE RÉCEPTEUR NK-3 ET LEUR SYNTHÈSE CHIRALE
  申请人：EUROSCREEN SA

  公开号：WO2013050424A1

  公开（公告）日：2013-04-11

  The present invention relates to novel compounds of Formula I and their use in therapeutic treatments. The invention further relates to a novel chiral synthesis of 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines using N-sp3 protective groups. The invention also provides intermediates for use in the synthesis of compounds of Formula I.

  本发明涉及公式I的新化合物及其在治疗治疗中的应用。该发明还涉及使用N-sp3保护基对5,6,7,(8-取代)-四氢-[1,2,4]三唑并[4,3-a]吡嗪进行新的手性合成。该发明还提供了用于合成公式I化合物的中间体。
• Synthesis and evaluation of piperazinotriazoles. Discovery of a potent and orally bioavailable neurokinin-3 receptor inhibitor
  作者：Liang Ye、Yifei Yang、Chunmei Li、Jianzhao Zhang、Wenyan Wang、Mingxu Ma、Hengwei Xu、Wenjing Zhang、Fangxia Zou、Zhengping Hu、Hongbo Wang、Jingwei Tian

  DOI：10.1016/j.ejmech.2023.115486

  日期：2023.9

  target compound exhibited promising inhibitory activity against NK3R (IC = 430.60 nM) with excellent membrane permeability (Papp, A-B = 37.6 × 10 cm/s, ER < 1) and oral bioavailability (F% = 93.6%). Our in vivo studies demonstrated that was orally active, efficacious, and well-tolerated in ovariectomy (OVX) model to suppress blood luteinizing hormone levels, which suggests that 16x is a viable lead compound

  神经激肽-3 受体 (NK3R) 是识别神经激肽的三种受体之一。使用口服 NK3R 拮抗剂药理阻断神经激肽 B (NKB) 信号传导可以显着改善潮热症状，且与任何激素效应无关，这一发现强烈表明 NK3R 是一个可行的药物靶点，并且针对该受体的药物可能是新型药物疗法。目前还没有 NK3R 配体被批准用于治疗人类疾病。在此，我们设计并合成了一系列新型咪唑哌嗪衍生物（）并进行分子对接验证了该设计，其中目标化合物对NK3R表现出良好的抑制活性（IC = 430.60 nM），并具有优异的膜通透性（Papp，AB = 37.6） × 10 cm/s，ER < 1) 和口服生物利用度 (F% = 93.6%)。我们的体内研究表明，16x 在卵巢切除 (OVX) 模型中具有口服活性、有效且耐受性良好，可抑制血液黄体生成激素水平，这表明 16x 是一种可行的先导化合物，可用于进一步优化和开发。
• NOVEL CHIRAL N-ACYL-5,6,7,(8-SUBSTITUTED)-TETRAHYDRO-[1,2,4]TRIAZOLO[4,3-A]PYRAZINES AS SELECTIVE NK-3 RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITION, METHODS FOR USE IN NK-3 RECEPTOR MEDIATED DISORDERS AND CHIRAL SYNTHESIS THEREOF
  申请人：Euroscreen S.A.

  公开号：EP3029042A1

  公开（公告）日：2016-06-08

  The present invention relates to novel compounds of Formula I and their use in therapeutic treatments. The invention further relates to a novel chiral synthesis of 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines using N-sp3 protective groups. The invention also provides intermediates for use in the synthesis of compounds of Formula I.

  本发明涉及式 I 的新型化合物 及其在治疗中的用途。本发明还涉及一种利用 N-sp3 保护基团手性合成 5,6,7,(8-取代)-四氢-[1,2,4]三唑并[4,3-a]吡嗪的新方法。本发明还提供了用于合成式 I 化合物的中间体。
• Chiral N-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof
  申请人：Euroscreen S.A.

  公开号：US10065961B2

  公开（公告）日：2018-09-04

  The present invention relates to novel compounds of Formula I and their use in therapeutic treatments. The invention further relates to a novel chiral synthesis of 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines using N-sp3 protective groups. The invention also provides intermediates for use in the synthesis of compounds of Formula I.

  本发明涉及式 I 的新型化合物及其在治疗中的应用。本发明还涉及一种利用 N-sp3 保护基团手性合成 5,6,7,(8-取代)-四氢-[1,2,4]三唑并[4,3-a]吡嗪的新方法。本发明还提供了用于合成式 I 化合物的中间体。
• Chiral N-acyl-5,6,7(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-A]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof
  申请人：Ogeda SA

  公开号：US10683295B2

  公开（公告）日：2020-06-16

  The present invention relates to novel compounds of Formula I and their use in therapeutic treatments. The invention further relates to a novel chiral synthesis of 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines using N-sp3 protective groups. The invention also provides intermediates for use in the synthesis of compounds of Formula I.

  本发明涉及式 I 的新型化合物及其在治疗中的应用。本发明还涉及一种利用 N-sp3 保护基团手性合成 5,6,7,(8-取代)-四氢-[1,2,4]三唑并[4,3-a]吡嗪的新方法。本发明还提供了用于合成式 I 化合物的中间体。