4-(4-methyl-1,4-diazepan-1-yl)benzoic acid | 730933-25-2

• 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: 4-(4-methyl-1,4-diazepan-1-yl)benzoic acid
• 英文别名: 4-(4-Methyl-[1,4]diazepan-1-yl)-benzoic acid；4-(4-Methyl-1,4-diazepan-4-ium-1-yl)benzoate
• CAS: 730933-25-2
• 化学式: C₁₃H₁₈N₂O₂
• mdl: MFCD11168679
• 分子量: 234.298
• InChiKey: UHGWCXACFHTELK-UHFFFAOYSA-N

物化性质

• 沸点：
  407.0±40.0 °C(Predicted)
• 密度：
  1.154±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.461
• 拓扑面积：
  43.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(4-methyl-1,4-diazepan-1-yl)benzoic acid 在 吡啶 、 氯化亚砜 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 6.0h， 生成 4'-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide
  参考文献：
  名称：

  Discovery of N-[2-Hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (Darexaban, YM150) as a Potent and Orally Available Factor Xa Inhibitor

  摘要：

  Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound la that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of la without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 141 is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.

  DOI：

  10.1021/jm200868m
• 作为产物：
  描述：

  N-甲基高哌嗪 在 水 、 potassium carbonate 、 sodium hydroxide 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 生成 4-(4-methyl-1,4-diazepan-1-yl)benzoic acid
  参考文献：
  名称：

  通过基于片段的虚拟筛选，设计和合成新型1H-1,2,4-三唑，苯并噻唑和吲唑基衍生物，作为有效的FGFR1抑制剂。

  摘要：

  成纤维细胞生长因子受体（FGFR）是癌症治疗的潜在靶标。通过基于片段的虚拟筛选，我们设计了三种新型的带有吲唑，苯并噻唑和1H-1,2,4-三唑支架的FGFR1抑制剂。在体外评估所有新合成的化合物对FGFR1的抑制活性。首先将带有吲唑支架的化合物9d鉴定为具有优良激酶抑制活性（IC50 = 15.0 nM）和适度的抗增殖活性（IC50 = 785.8 nM）的命中化合物。通过两轮优化，吲唑衍生物9 u是最强的FGFR1抑制剂，具有最佳的酶抑制活性（IC50 = 3.3 nM）和细胞活性（IC50 = 468.2 nM）。此外，9 u还表现出良好的激酶选择性。此外，

  DOI：

  10.1080/14756366.2019.1673745

文献信息

• Npy antagonists, preparation and uses
  申请人：Botez Iuliana

  公开号：US20090233910A1

  公开（公告）日：2009-09-17

  The present invention concerns novel compounds, their preparation and their uses, therapeutic uses in particular. More specifically it concerns derivative compounds having at least two aromatic cycles, their preparation and their uses, in particular in the area of human or animal health. These compounds have an affinity for the biological receptors of neuropeptide Y, NPY, present in the central and peripheral nervous systems. The compounds of the invention are preferably NPY antagonists, and more particularly antagonists of sub-type NPY Y1, and can therefore be used for the therapeutic or prophylactic treatment of any disorder involving NPY. The present invention also concerns pharmaceutical compositions containing said compounds, their preparation and their uses, as well as treatment methods using said compounds.

  本发明涉及新颖化合物，它们的制备和用途，特别是在治疗方面的用途。更具体地说，它涉及至少具有两个芳香环的衍生化合物，它们的制备和用途，特别是在人类或动物健康领域。这些化合物对存在于中枢和外周神经系统中的神经肽Y（NPY）的生物受体具有亲和力。本发明的化合物优选为NPY拮抗剂，更具体地说是NPY Y1亚型的拮抗剂，因此可用于治疗或预防涉及NPY的任何疾病。本发明还涉及含有所述化合物的药物组合物，其制备和用途，以及使用所述化合物的治疗方法。
• Development of second generation EP2 antagonists with high selectivity
  作者：Thota Ganesh、Jianxiong Jiang、Ray Dingledine

  DOI：10.1016/j.ejmech.2014.05.076

  日期：2014.7

  EP2 receptor has emerged as an important biological target for therapeutic intervention. In particular, it has been shown to exacerbate disease progression of a variety of CNS and peripheral diseases. Deletion of the EP2 receptor in mouse models recapitulates several features of the COX-2 inhibition, thus presenting a new avenue for anti-inflammatory therapy which could bypass some of the adverse side effects observed by the COX-2 inhibition therapy. We have recently reported a cinnamic amide class of EP2 antagonists with high potency, but these compounds exhibited a moderate selectivity against prostanoid receptor DP1. Moreover they possess acrylamide moiety in the structure, which may result in liver toxicity over longer period of use in a chronic disease model. Thus, we now developed a second generation compounds that devoid of the acrylamide functionality and possess high potency and improved (>1000-fold) selectivity to EP2 over other prostanoid receptors. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Synthesis and biological activity of novel 1,2-disubstituted benzene derivatives as factor Xa inhibitors
  作者：Hiroyuki Koshio、Fukushi Hirayama、Tsukasa Ishihara、Ryouta Shiraki、Takeshi Shigenaga、Yuta Taniuchi、Kazuo Sato、Yumiko Moritani、Yoshiyuki Iwatsuki、Seiji Kaku、Naoko Katayama、Tomihisa Kawasaki、Yuzo Matsumoto、Shuichi Sakamoto、Shin-ichi Tsukamoto

  DOI：10.1016/j.bmc.2004.11.005

  日期：2005.2

  Factor Xa (fXa) is a serine protease that plays a pivotal role in the coagulation cascade. High-tbroughput screening of the Yamanouchi compound library yielded lead compound I with the ability to inhibit fXa at micromolar concentrations. To improve its fXa inhibitory activity and its oral anticoagulant activity, the linker between benzamidine and the central benzene ring was modified and a carboxyl group was introduced at the central benzene ring. The resulting compounds 40b (YM-203552), 41a (YM-202054), and 41c (YM-203558) exhibited potent fXa inhibitory activity and oral anticoagulant activity. In particular, YM-203558 exhibited the most potent oral anticoagulant activity, prolonging PT more than 3-fold at 0.5 and 2.0h. Additionally, these compounds showed a high degree of selectivity for other serine proteases. (C) 2004 Elsevier Ltd. All rights reserved.
• US7307074B2
  申请人：——

  公开号：US7307074B2

  公开（公告）日：2007-12-11
• USRE43481E1
  申请人：——

  公开号：USRE43481E1

  公开（公告）日：2012-06-19