YM-62899

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: YM-62899
• 英文别名: N-[6-(2-fluoroethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide；(E)-N-[6-(2-fluoroethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]-2-phenylethenesulfonamide
• 化学式: C₂₅H₂₂FN₅O₅S
• 分子量: 523.545
• InChiKey: XAKFXLLXYYWMMT-SFQUDFHCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  37
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  134
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  波生坦中间体(I) 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 YM-62899
  参考文献：
  名称：

  Ethenesulfonamide Derivatives, a Novel Class of Orally Active Endothelin-A Receptor Antagonists

  摘要：

  在本文章中，我们希望报告通过改造ETA/ETB非选择性拮抗剂Ro47-0203（博生坦，1）发现一种新型ETA选择性内源性血管收缩素（ET）受体拮抗剂。将1的苯磺酰胺基团替换为2-苯基乙烯磺酰胺基团，得到化合物5a，并改善了ETA选择性。对连接在核心嘧啶环上的烷氧基侧链进行优化，得到2-氟乙氧基衍生物（5n），进一步提高了ETA选择性。[IC50 = 2.1 nM，ETB/ETA比率=1200]。口服给药后，化合物5n抑制了大剂量ET-1在麻醉大鼠中的压升反应，DR2值为2.6 mg/kg，并且在清醒的大鼠中表现出强效的拮抗活性。

  DOI：

  10.1248/cpb.49.606

文献信息

• ARYLETHENESULFONAMIDE DERIVATIVES AND DRUG COMPOSITION CONTAINING THE SAME
  申请人：YAMANOUCHI PHARMACEUTICAL CO., LTD.

  公开号：EP0882719A1

  公开（公告）日：1998-12-09

  Novel arylethenesulfonamide derivatives having a high affinity for drugs, especially endoserine receptors, and represented by general formula (I); pharmacologically acceptable salts thereof; and drugs comprising the same as the active ingredient, especially endoserine receptor antagonists, wherein Ar represents optionally substituted aryl or optionally substituted five- or six-membered heteroaryl; X represents oxygen, sulfur, or the group represented by -NH-; Y represents oxygen or sulfur; R1 represents hydrogen, lower alkyl optionally substituted with halogeno, cycloalkyl, optionally substituted aryl, or optionally substituted five- or six-membered heteroaryl; R2 represents lower alkyl, lower alkenyl, or lower alkynyl each optionally substituted with one to three groups selected among hydroxy, lower alkoxys, cycloakyls, halogens, carboxy, and lower alkoxycarbonyls; R3 represents phenyl optionally substituted with one to four groups selected among optionally halogenated lower alkyls, lower alkoxys, halogens, lower alkylthios, lower alkylsulfinyls, lower alkanesulfonyls, carboxy, lower alkoxycarbonyls, and carbamoyl; and R4 and R5 are the same or different and each represents hydrogen or lower alkyl.

  通式(I)表示的对药物，特别是对内丝氨酸受体具有高亲和力的新型芳基乙烯磺酰胺衍生物；其药理学上可接受的盐；以及以其为活性成分的药物，特别是内丝氨酸受体拮抗剂，其中Ar代表任选取代的芳基或任选取代的五元或六元杂芳基；X 代表氧、硫或由 -NH- 代表的基团； Y 代表氧或硫； R1 代表氢、任选被卤素取代的低级烷基、环烷基、任选被取代的芳基或任选被取代的五元或六元杂芳基；R2 代表低级烷基、低级烯基或低级炔基，各自任选被一至三个选自羟基、低级烷氧基、环烷基、卤素、羧基和低级烷氧羰基的基团取代；R3 代表苯基，可任选被一至四个基团取代，这些基团选自任选卤化的低级烷基、低级烷氧基、卤素、低级烷硫基、低级烷基亚磺酰基、低级烷磺酰基、羧基、低级烷氧基羰基和氨基甲酰基；以及 R4 和 R5 相同或不同，各自代表氢或低级烷基。
• US6083955A
  申请人：——

  公开号：US6083955A

  公开（公告）日：2000-07-04
• [EN] PHARMACEUTICAL AND VETERINARY USES OF ENDOTHELIN ANTAGONISTS<br/>[FR] UTILISATIONS PHARMACEUTIQUES ET VETERINAIRES D'ANTAGONISTES DE L'ENDOTHELINE ET APPLICATIONS ASSOCIEES
  申请人：TEXAS BIOTECHNOLOGY CORP

  公开号：WO2001049289A1

  公开（公告）日：2001-07-12

  Pharmaceutical and veterinary uses of endothelin antagonists are provided. In particular, methods of treatment of laminitis, such as equine and bovine laminitis, by administration of one or more endothelin antagonists are provided. Methods of treatment, prevention, or amelioration of one or more symptoms of menopause; osteoporosis and metabolic bone disorders; climacteric disorders including hot flushes or flashes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in women; pre-eclampsia; and control and management of labor during pregnancy by administration of endothelin antagonists are also provided.
• Ethenesulfonamide Derivatives, a Novel Class of Orally Active Endothelin-A Receptor Antagonists
  作者：Hironori HARADA、Jun-ichi KAZAMI、Susumu WATANUKI、Ryuji TSUZUKI、Katsumi SUDOH、Akira FUJIMORI、Akihiro TANAKA、Shin-ichi TSUKAMOTO、Isao YANAGISAWA

  DOI：10.1248/cpb.49.606

  日期：——

  In the present article we wish to report the discovery of a novel class of ETA-selective endothelin (ET) receptor antagonists through the modification of the ETA/ETB non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ETA-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ETA-selectivity. [IC50=2.1 nM for ETA receptor, ETB/ETA ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.

  在本文章中，我们希望报告通过改造ETA/ETB非选择性拮抗剂Ro47-0203（博生坦，1）发现一种新型ETA选择性内源性血管收缩素（ET）受体拮抗剂。将1的苯磺酰胺基团替换为2-苯基乙烯磺酰胺基团，得到化合物5a，并改善了ETA选择性。对连接在核心嘧啶环上的烷氧基侧链进行优化，得到2-氟乙氧基衍生物（5n），进一步提高了ETA选择性。[IC50 = 2.1 nM，ETB/ETA比率=1200]。口服给药后，化合物5n抑制了大剂量ET-1在麻醉大鼠中的压升反应，DR2值为2.6 mg/kg，并且在清醒的大鼠中表现出强效的拮抗活性。