N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]-carbonyl]-L-homoglutamic acid | 156579-02-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]-carbonyl]-L-homoglutamic acid
• 英文别名: N-[[4-[(2,4-diaminopteridine-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid；N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazine-7-yl]carbonyl]-L-hoglutamic acid；MX-68；(2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl]-2,3-dihydro-1,4-benzothiazine-7-carbonyl]amino]hexanedioic acid
• CAS: 156579-02-1
• 化学式: C₂₂H₂₄N₈O₅S
• 分子量: 512.549
• InChiKey: WEEYASWRWODDTJ-ZDUSSCGKSA-N

物化性质

• 密度：
  1.557±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  236
• 氢给体数：
  5
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  4-Amino-3-(2-chloroethylsulfanyl)benzoic acid 在 吡啶 、 盐酸 、 sodium hydroxide 、 氯化亚砜 、 氢溴酸 、 sodium hydride 、 potassium carbonate 、 苯甲醚 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 甲苯 为溶剂， 反应 88.0h， 生成 N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]-carbonyl]-L-homoglutamic acid
  参考文献：
  名称：

  Antirheumatic Agents:  Novel Methotrexate Derivatives Bearing a Benzoxazine or Benzothiazine Moiety

  摘要：

  Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H,1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro, Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68) were comparable to that of MTX in these in vitro assays. Compounds 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.

  DOI：

  10.1021/jm9605288

文献信息

• Combination
  申请人：——

  公开号：US20030092706A1

  公开（公告）日：2003-05-15

  The invention relates to the combined administration of a PDE4 or PDE3/4 inhibitor and a disease modifying anti-rheumatic drug (DMARDs) or anti-rheumatic or anti-arthritic drug.

  本发明涉及 PDE4 或 PDE3/4 抑制剂与改变病情抗风湿药（DMARDs）或抗风湿或抗关节炎药物的联合用药。
• An Improved Process for the Large-Scale Preparation of Antirheumatic Agent MX-68
  作者：Noriaki Maruyama、Hirohito Shimizu、Takashi Sugiyama、Masashi Watanabe、Masashi Makino、Masahiro Kato、Makoto Shimizu

  DOI：10.1021/op049867y

  日期：2004.11.1

  A large-scale preparation route of MX-68, a novel MTX derivative bearing a dihydro-2H-1,4-benzothiazine moiety and L-homogulutamic acid, is described. The original route that is a laboratory-scale synthesis for preclinical study has been improved. The improved process involves the following features: each step does not use haloalkane solvents, corrosive reagents, and chromatographic purification, and the formation of the major impurity at the final step is minimized. This improvement has enabled us to supply sufficient quantities of MX-68, which is required for both the toxicity test and the clinical study.
• Synthesis of tritiated N-[4-(2,4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1,4-benzothiazine-7-carbonyl]-L-homo glutamic acid (MX-68)
  作者：Hiroharu Matsuoka、Toshio Kuroki、Keiichi Yano、Yasuhisa Takeda

  DOI：10.1002/(sici)1099-1344(199705)39:5<363::aid-jlcr982>3.0.co;2-o

  日期：1997.5

  Synthesis of tritiated N-[4-(2,4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1,4-benzothiazine-7-carbonyl]-L-homoglutamic acid, [9-H-3(1)]MX-68 (3), is described. [9-H-3(1)]MX-68 (3) was prepared via tritiation at the carbonyl group in 2,4-bis(butanoylamino)-6-formylpteridine (7) with sodium borotritiide.
• COMBINATION OF A PDE4 OR PDE3/4 INHIBITOR AND AN ANTI-RHEUMATIC DRUG
  申请人：ALTANA Pharma AG

  公开号：EP1448202A1

  公开（公告）日：2004-08-25
• [EN] COMBINATION OF PDE4 OR PDE3/4 INHIBITOR AND AN ANTI-RHEUMATIC DRUG<br/>[FR] COMBINAISON D'UN INHIBITEUR DE PDE4 OU DE PDE3/4 ET D'UN MEDICAMENT ANTI-RHUMATISMAL
  申请人：ALTANA PHARMA AG

  公开号：WO2003039552A1

  公开（公告）日：2003-05-15

  The invention relates to the combined administration of a PDE4 or PDE3/4 inhibitor and a disease modifying anti-rheumatic drug (DMARDs) or anti-rheumatic or anti-arthritic drug.