siponimod | 800379-64-0

• 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: siponimod
• 英文别名: 1-{4-[1-(4-cyclohexyl-3-trifluoromethylbenzyloxyimino)ethyl]-2-ethylbenzyl}azetidine-3-carboxylic acid；BAF312；1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid；1-[[4-[N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid
• CAS: 800379-64-0
• 化学式: C₂₉H₃₅F₃N₂O₃
• 分子量: 516.604
• InChiKey: KIHYPELVXPAIDH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  62.1
• 氢给体数：
  1
• 氢受体数：
  8

ADMET

毒理性

• 肝毒性

在大规模的多发性硬化症患者中进行的西波尼莫德控制试验中，血清ALT升高是常见的，通常发生在治疗的前3个月内，并持续整个治疗期间。这些升高通常是轻微且无症状的，在停止治疗后3个月内恢复到基线值。在接受西波尼莫德的患者中，有6%至8%的患者转氨酶升高超过正常上限（ULN）的3倍，而安慰剂组不到2%。在这些上市前的临床试验中，没有出现急性肝炎或临床上明显的肝损伤的病例，但肝功能测试升高导致1%的患者停止治疗。因此，在治疗期间轻度至中度且短暂的血清酶升高并不少见，但由于西波尼莫德引起的临床上明显的肝损伤和黄疸尚未有报道，尽管其使用经验有限。

In large controlled trials of siponimod in patients with multiple sclerosis, serum ALT elevations were common, typically arising during the first 3 months and persisting throughout the treatment period. The elevations were generally mild and asymptomatic, and they returned to baseline values within 3 months of stopping. Aminotransferase elevations above 3 times upper limit of normal (ULN) were reported in 6% to 8% of siponimod recipients compared to less than 2% of placebo recipients. In these prelicensure clinical trials, there were no cases of acute hepatitis or clinically apparent liver injury but elevations in liver tests led to discontinuation in 1% if subjects. Thus, mild-to-moderate and transient serum enzyme elevations during therapy are not uncommon, but clinically apparent liver injury with jaundice due to siponimod has not been reported, although the clinical experience with its use has been limited.

来源:LiverTox

反应信息

• 作为反应物：
  描述：

  siponimod 、 富马酸 以 异丙醇 为溶剂， 以0.34 g的产率得到siponimod fumaric acid salt
  参考文献：
  名称：

  [EN] SIPONIMOD MALEIC ACID AND FUMARIC ACID SALT
  [FR] SEL D'ACIDE MALÉIQUE ET D'ACIDE FUMARIQUE SIPONIMOD

  摘要：

  所提出的发明涉及Siponimod与富马酸（1:1）的盐及其固体形式1和2。所提出的发明还涉及Siponimod与马来酸（1:1）的盐及其固体形式1、2、3、4、5、6、7、8和9。

  公开号：

  WO2020234423A1
• 作为产物：
  描述：

  在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 15.0h， 以79%的产率得到siponimod
  参考文献：
  名称：

  CN114835618

  摘要：

  公开号：
• 作为试剂：
  描述：

  1-(3-ethyl-4-hydroxymethylphenyl)ethanone O-(4-cyclohexyl-3-trifluoromethylbenzyl)oxime 、 3-吖丁啶羧酸 、 三乙胺 、 氰基硼氢化钠 在 二氧化锰 甲醇 、 siponimod 作用下， 以 1,4-二氧六环 为溶剂， 反应 0.67h， 以results in 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid的产率得到siponimod
  参考文献：
  名称：

  USE OF IMMUNOSUPPRESSANT COMPOUNDS IN A NEW INDICATION

  摘要：

  本发明披露了多种免疫抑制剂及其盐和多晶形式，可用于治疗各种疾病，包括外周神经病。该发明还披露了利用这些免疫抑制剂制备的药物配方，单独或与其他化合物结合使用，可用于治疗外周神经病等疾病。本发明还披露了一种利用本文披露的免疫抑制剂治疗外周神经病的方法。

  公开号：

  US20140011797A1

文献信息

• Immunosuppressant compounds and compositions
  申请人：Pan Shifeng

  公开号：US20050014728A1

  公开（公告）日：2005-01-20

  The present invention relates to immunosuppressant, process for their production, their uses and pharmaceutical compositions containing them. The invention provides a novel class of compounds useful in the treatment or prevention of diseases or disorders mediated by lymphocyte interactions, particularly diseases associated with EDG receptor mediated signal transduction.

  本发明涉及免疫抑制剂，其生产过程，它们的用途以及含有它们的制药组合物。本发明提供了一种新的化合物类别，用于治疗或预防通过淋巴细胞相互作用介导的疾病或疾病，特别是与EDG受体介导的信号转导有关的疾病。
• IMMUNOSUPPRESANT COMPOUNDS AND COMPOSITIONS
  申请人：Pan Shifeng

  公开号：US20090036423A1

  公开（公告）日：2009-02-05

  The present invention relates to immunosuppressant, process for their production, their uses and pharmaceutical compositions containing them. The invention provides a novel class of compounds useful in the treatment or prevention of diseases or disorders mediated by lymphocyte interactions, particularly diseases associated with EDG receptor mediated signal transduction.

  本发明涉及免疫抑制剂，其生产过程，它们的用途以及含有它们的制药组合物。本发明提供了一种新的化合物类别，可用于治疗或预防由淋巴细胞相互作用介导的疾病或紊乱，特别是与EDG受体介导的信号转导相关的疾病。
• Immunosuppresant compounds and compositions
  申请人：Novartis AG

  公开号：US07939519B2

  公开（公告）日：2011-05-10

  The present invention relates to immunosuppressant, process for their production, their uses and pharmaceutical compositions containing them. The invention provides a novel class of compounds useful in the treatment or prevention of diseases or disorders mediated by lymphocyte interactions, particularly diseases associated with EDG receptor mediated signal transduction.

  本发明涉及免疫抑制剂、其生产过程、其用途以及含有它们的药物组合物。本发明提供了一种新的化合物类别，可用于治疗或预防由淋巴细胞相互作用介导的疾病或障碍，特别是与EDG受体介导的信号转导有关的疾病。
• COMPOUNDS FOR THE TREATMENT OF PERIPHERAL NEUROPATHIES
  申请人：Leppert David

  公开号：US20110144082A1

  公开（公告）日：2011-06-16

  A compound of formula A1 or A2 for use in the treatment of a demyelinating peripheral neuropathy: wherein A is COOR 5 , OPO(OR 5 ) 2 , PO(OR 5 ) 2 , SO 2 OR 5 , POR 5 OR 5 or 1H-tetrazol-5-yl, R 5 being H or an ester-forming group, optionally C 1-6 alkyl; W is a bond, C 1-3 alkylene or C 2-3 alkenylene; Y is C 6-10 aryl or C 2-9 heteroaryl eg C 3-9 heteroaryl, optionally substituted by 1 to 3 radicals selected from halogen, OH, NO 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy; Z is chosen from: wherein the asterisks of Z indicate the point of attachment between —C(R 3 )(R 4 )— and A of Formula Ia or Ib, respectively; R 6 is chosen from hydrogen and C 1-6 alkyl; and J 1 and J 2 are independently methylene or a heteroatom chosen from S, O and NR 5 ; wherein R 5 is chosen from hydrogen and C 1-6 alkyl; and any alkylene of Z can be further substituted by one to three radicals chosen from halo, hydroxy, C 1-6 alkyl; or R 6 can be attached to a carbon atom of Y to form a 5-7 member ring; R 1 is C 6-10 aryl or C 2-9 heteroaryl eg C 3-9 heteroaryl, optionally substituted by C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, C 3-9 heteroaryl, C 3-9 heteroarylC 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-4 alkyl, C 3-8 heterocycloalkyl or C 3-8 heterocycloalkylC 1-4 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 1 may be substituted by 1 to 5 groups selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and halo substituted-C 1-6 alkyl or —C 1-6 alkoxy; R 2 is H, C 1-6 alkyl, halo substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; and each of R 3 and R 4 , independently, is H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy or halo substituted C 1-6 alkyl or C 1-6 alkoxy; and the N-oxide derivatives thereof or prodrugs thereof, or a pharmacologically acceptable salt, solvate or hydrate thereof.

  公式A1或A2的化合物，用于治疗脱髓鞘性周围神经病变：其中A为COOR5，OPO（OR5）2，PO（OR5）2，SO2OR5，POR5OR5或1H-四唑-5-基，R5为H或酯形成基，可选C1-6烷基；W为键，C1-3烷基或C2-3烯基；Y为C6-10芳基或C2-9杂芳基，例如C3-9杂芳基，可选地被1至3个基团取代，所述基团选自卤素、OH、NO2、C1-6烷基、C1-6烷氧基；卤素取代的C1-6烷基和卤素取代的C1-6烷氧基；Z选自：其中Z的星号表示Z的—C（R3）（R4）—和式Ia或Ib的A之间的连接点；R6选自氢和C1-6烷基；J1和J2独立地为亚甲基或选自S、O和NR5的杂原子；其中R5选自氢和C1-6烷基；Z的任何烷基可以进一步被选自卤素、羟基、C1-6烷基的1至3个基团取代；或者R6可以连接到Y的一个碳原子上形成5-7成员环；R1为C6-10芳基或C2-9杂芳基，例如C3-9杂芳基，可选地被C1-6烷基、C6-10芳基、C6-10芳基C1-4烷基、C3-9杂芳基、C3-9杂芳基C1-4烷基、C3-8环烷基、C3-8环烷基C1-4烷基、C3-8杂环烷基或C3-8杂环烷基C1-4烷基取代；其中R1的任何芳基、杂芳基、环烷基或杂环烷基可以被选自卤素、C1-6烷基、C1-6烷氧基和卤素取代的C1-6烷基或C1-6烷氧基的1至5个基团取代；R2为H、C1-6烷基、卤素取代的C1-6烷基、C2-6烯基或C2-6炔基；R3和R4各自独立地为H、卤素、OH、C1-6烷基、C1-6烷氧基或卤素取代的C1-6烷基或C1-6烷氧基；以及其N-氧化物衍生物或前药，或其药理学上可接受的盐，溶剂或水合物。
• Use of immunosuppressant compounds in a new indication
  申请人：Leppert David

  公开号：US08809316B2

  公开（公告）日：2014-08-19

  The present invention discloses various immunosuppressants, salts and polymorphs thereof useful in the treatment of various disorders, including peripheral neuropathy. The invention also discloses pharmaceutical formulations utilizing the immunosuppressants, alone or in combination with other compounds, useful in treating disorders such as peripheral neuropathy. The present invention also discloses a method of treating peripheral neuropathy with immunosuppressants disclosed herein.

  本发明揭示了多种免疫抑制剂，其盐和多晶形式，可用于治疗各种疾病，包括外周神经病。本发明还揭示了利用免疫抑制剂的制剂，单独或与其他化合物联合使用，用于治疗外周神经病等疾病。本发明还揭示了一种利用此处披露的免疫抑制剂治疗外周神经病的方法。