AR-C 155858; (S)-6-[(3,5-二甲基-1H-吡唑-4-基)甲基]-5-[(4-羟基异噁唑烷-2-基)羰基]-1-异丁基-3-甲基噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮 | 496791-37-8

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 中文名称: AR-C 155858; (S)-6-[(3,5-二甲基-1H-吡唑-4-基)甲基]-5-[(4-羟基异噁唑烷-2-基)羰基]-1-异丁基-3-甲基噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮
• 中文别名: AR-C155858;(S)-6-[(3,5-二甲基-1H-吡唑-4-基)甲基]-5-[(4-羟基异噁唑烷-2-基)羰基]-1-异丁基-3-甲基噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮；(S)-6-[(3,5-二甲基-1H-吡唑-4-基)甲基]-5-[(4-羟基异唑烷-2-基)羰基]-1-异丁基-3-甲基噻吩并[2,3-D]嘧啶-2,4(1H,3H)-二酮
• 英文名称: AR-C155858
• 英文别名: 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione；6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[(4S)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-dione
• CAS: 496791-37-8
• 化学式: C₂₁H₂₇N₅O₅S
• 分子量: 461.542
• InChiKey: ISIVOJWVBJIOFM-ZDUSSCGKSA-N

物化性质

• 熔点：
  198-202∶C
• 沸点：
  763.1±70.0 °C(Predicted)
• 密度：
  1.395
• 溶解度：
  不溶于水； DMSO 中≥52.5 mg/mL；乙醇中≥57.8 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  147
• 氢给体数：
  2
• 氢受体数：
  7

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H320,H335

反应信息

• 作为反应物：
  描述：

  2-碘代丙烷 、 potassium carbonate 、 AR-C 155858; (S)-6-[(3,5-二甲基-1H-吡唑-4-基)甲基]-5-[(4-羟基异噁唑烷-2-基)羰基]-1-异丁基-3-甲基噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮 在 乙酸乙酯 、 四氢吡咯 、 magnesium sulfate 、 Acetonitrile ammonium acetate 作用下， 以 N,N-二甲基甲酰胺 、 水 为溶剂， 反应 19.0h， 以to give the title compound (58 mg) as a foam的产率得到5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Thienopyrimidinediones and their use in the modulation of autoimmune disease

  摘要：

  本发明涉及化合物的公式（1）;其中：R1和R2各自独立地表示C1-6烷基，C3-6烯基，C3-6环烷基C1-3烷基或C3-6环烷基;每个基团可以选填1至3个卤素原子; R3是异氧氮-2-基甲酰基或四氢异噁唑-2-基甲酰基，其中每个环可以选填一个羟基; Q是CO-或C（R4）（R5）-（其中R4是氢原子或C1-4烷基，R5是氢原子或羟基）; Ar是一个5-至10-成员的芳香环系统，其中最多4个环原子可以是氮，氧和硫，该环系统可以选填一个或多个定义在规范中的取代基。它还涉及制备，含有该化合物的制药组合物以及使用公式（1）的化合物的方法，特别是在自身免疫性疾病的调节中使用。

  公开号：

  US07384950B2
• 作为产物：
  描述：

  methyl 6-bromomethyl-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate 在 sodium hydroxide 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 为溶剂， 反应 20.75h， 生成 AR-C 155858; (S)-6-[(3,5-二甲基-1H-吡唑-4-基)甲基]-5-[(4-羟基异噁唑烷-2-基)羰基]-1-异丁基-3-甲基噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮
  参考文献：
  名称：

  Optimization of Monocarboxylate Transporter 1 Blockers through Analysis and Modulation of Atropisomer Interconversion Properties

  摘要：

  We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.

  DOI：

  10.1021/jm060995h

文献信息

• [EN] PH RESPONSIVE BLOCK COPOLYMER COMPOSITIONS AND MICELLES THAT INHIBIT MCT 1 AND RELATED PROTEINS<br/>[FR] COMPOSITIONS DE COPOLYMÈRE SÉQUENCÉ SENSIBLE AU PH ET MICELLES QUI INHIBENT MCT 1 ET DES PROTÉINES ASSOCIÉES
  申请人：UNIV TEXAS

  公开号：WO2021217111A1

  公开（公告）日：2021-10-28

  Described herein are therapeutic pH responsive compositions comprising a block copolymer and a therapeutic agent useful for the treatment of cancer.

  本文描述了一种治疗癌症的治疗pH响应性组合物，包括一个嵌段共聚物和一个治疗剂。
• THIENOPYRIMIDINEDIONES AND THEIR USE IN THE MODULATION OF AUTOIMMUNE DISEASE
  申请人：AstraZeneca AB

  公开号：EP1414825B1

  公开（公告）日：2007-09-26
• Thienopyrimidinediones and Their Use in the Modulation of Autoimmune Disease
  申请人：Reynolds Rachel Heulwen

  公开号：US20080207642A1

  公开（公告）日：2008-08-28

  The invention relates to a compound of formula (1): in which R 1 and R 2 each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkylC 1-3 alkyl or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms; R 3 is isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally substituted by one hydroxy group; Q is —CO— or —C(R 4 )(R 5 )— in which R 4 is a hydrogen atom or C 1-4 alkyl and R 5 is a hydrogen atom or hydroxy group; and Ar is a 5- to 10-membered aromatic ring system in which up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents as defined in the specification. It also relates to methods of preparing, pharmaceutical compositions containing and methods of using the compound of the formula (1), particularly in the modulation of autoimmune disease.
• METHODS OF TREATING TUMORS HAVING ELEVATED MCT1 EXPRESSION
  申请人：Whitehead Institute for Biomedical Research

  公开号：US20140142180A1

  公开（公告）日：2014-05-22

  In some aspects, compositions and methods useful for classifying tumor cells, tumor cell lines, or tumors according to predicted sensitivity to 3-bromopyruvate (3-BrPA) are provided. In some aspects, methods of identifying subjects with cancer who are candidates for treatment with 3-BrPA are provided. In some aspects, compositions useful for subjects with cancers that express increased levels of MCT1 are provided. In some aspects, methods of treating subjects with cancers that express increased levels of MCT1 are provided. In some aspects, methods of identifying anti-tumor agents the efficacy of which is at least in part dependent on transporter-mediated uptake are provided.
• MCT PROTEIN INHIBITOR-RELATED PROGNOSTIC AND THERAPEUTIC METHODS
  申请人：Thomas Jefferson University

  公开号：US20140378477A1

  公开（公告）日：2014-12-25

  This invention provides a method of identifying one or more subgroups of cancer patients that are likely to benefit from treatment with a monocarboxylate transporter (MCT) protein inhibitor comprising: (a) obtaining a sample of a cancer/tumor tissue from each of said cancer patients; (b) determining the expression level of stromal MCT4 protein in each of said samples of cancer/tumor tissue to obtain a first dataset; and (c) using the expression level of the stromal MCT4 protein from said first dataset to classify each of said sets of one or more cancer patients as stromal MCT4-positive or stromal MCT4-negative, wherein the cancer patients classified as stromal MCT4-positive are patients that are more likely to benefit from treatment with said MCT protein inhibitor. This invention also provides related methods for treating a cancer/tumor whose stromal component expresses the MCT4 protein in a patient.