(2S,4R)-2-{[5-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-thiophene-2-carbonyl]-amino}-4-fluoro-pentanedioic acid diisopropyl ester | 194809-41-1

• 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: (2S,4R)-2-{[5-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-thiophene-2-carbonyl]-amino}-4-fluoro-pentanedioic acid diisopropyl ester
• 英文别名: dipropan-2-yl (2R,4S)-2-fluoro-4-[[4-methyl-5-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]thiophene-2-carbonyl]amino]pentanedioate
• CAS: 194809-41-1
• 化学式: C₂₃H₃₅FN₂O₇S
• 分子量: 502.605
• InChiKey: GEPMTNZFASMYPI-CVEARBPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  34
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  140
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2S,4R)-2-{[5-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-thiophene-2-carbonyl]-amino}-4-fluoro-pentanedioic acid diisopropyl ester 在 barium dihydroxide 、 水 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 为溶剂， 反应 32.0h， 生成 (2S,4R)-2-({5-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-4-methyl-thiophene-2-carbonyl}-amino)-4-fluoro-pentanedioic acid
  参考文献：
  名称：

  Synthesis and Evaluation of Novel Fluorinated Methotrexate Derivatives for Application to Rheumatoid Arthritis Treatment

  摘要：

  An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure L-erythro- or L-threo-gamma-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3'-substituted phenyl or methylthiophene ring skewed potent immunosuppressive activities, including in vitro inhibition of mitogen responses of both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong eiectronegativity of fluorine, which increases the acidity of the gamma-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.

  DOI：

  10.1021/jm970085n
• 作为产物：
  描述：

  2-[N-(tert-butoxycarbonyl)-N-methylamino]-3-methylthiophene 在 氰基磷酸二乙酯 、 三乙胺 、 lithium diisopropyl amide 作用下， 以 乙二醇二甲醚 为溶剂， 反应 32.5h， 生成 (2S,4R)-2-{[5-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-thiophene-2-carbonyl]-amino}-4-fluoro-pentanedioic acid diisopropyl ester
  参考文献：
  名称：

  Synthesis and Evaluation of Novel Fluorinated Methotrexate Derivatives for Application to Rheumatoid Arthritis Treatment

  摘要：

  An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure L-erythro- or L-threo-gamma-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3'-substituted phenyl or methylthiophene ring skewed potent immunosuppressive activities, including in vitro inhibition of mitogen responses of both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong eiectronegativity of fluorine, which increases the acidity of the gamma-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.

  DOI：

  10.1021/jm970085n

文献信息

• Synthesis and Evaluation of Novel Fluorinated Methotrexate Derivatives for Application to Rheumatoid Arthritis Treatment
  作者：Yoshitsugu Kokuryo、Kyozo Kawata、Takuji Nakatani、Akira Kugimiya、Yoshinori Tamura、Kenji Kawada、Mitsunobu Matsumoto、Ryuji Suzuki、Kenji Kuwabara、Yozo Hori、Mitsuaki Ohtani

  DOI：10.1021/jm970085n

  日期：1997.9.1

  An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure L-erythro- or L-threo-gamma-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3'-substituted phenyl or methylthiophene ring skewed potent immunosuppressive activities, including in vitro inhibition of mitogen responses of both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong eiectronegativity of fluorine, which increases the acidity of the gamma-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.