6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid | 496791-38-9

• 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
• 英文名称: 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
• 英文别名: 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
• CAS: 496791-38-9
• 化学式: C₁₈H₂₂N₄O₄S
• 分子量: 390.463
• InChiKey: KNYJJWVPRDKAPK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  135
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-异噁唑烷-4-醇盐酸盐 、 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid 在 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 二氯甲烷 为溶剂， 反应 3.5h， 以62%的产率得到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
• 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 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 为溶剂， 反应 17.25h， 生成 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
  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

• Thienopyrimidinediones and their use in the modulation of autoimmune disease
  申请人：——

  公开号：US20040254198A1

  公开（公告）日：2004-12-16

  The invention relates to a compound of formula (1); wherein: R 1 and R 2 each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkyl C 1-3 alkyl or C 3-6 cycloalkyl; each of which may be optionally substituted by 1 to 3 halogen atoms; R 3 is isoxyzolidin-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 )—(wherein R 4 is a hydrogen atom or C 1-4 alkyl and R 5 is a hydrogen atom or hydroxy group); Ar is a 5- to 10-membered aromatic ring system wherein up to 4 ring atoms may be heteroatoms independently selected from 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. 1

  本发明涉及一种式子(1)的化合物; 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; 每个基团可能被1至3个卤素原子取代; R3是异噁唑啉-2-基甲酰基或四氢异噁唑啉-2-基甲酰基，其中每个环可能被一个羟基取代; 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个环原子可以独立地选自氮，氧和硫，该环系统可能被一个或多个定义在说明书中的取代基取代。它还涉及制备，含有该式（1）化合物的制药组合物以及使用该化合物的方法，特别是在自身免疫性疾病的调节中使用。
• 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.
• US7384950B2
  申请人：——

  公开号：US7384950B2

  公开（公告）日：2008-06-10
• Optimization of Monocarboxylate Transporter 1 Blockers through Analysis and Modulation of Atropisomer Interconversion Properties
  作者：Simon D. Guile、John R. Bantick、Martin E. Cooper、David K. Donald、Christine Eyssade、Anthony H. Ingall、Richard J. Lewis、Barrie P. Martin、Rukhsana T. Mohammed、Timothy J. Potter、Rachel H. Reynolds、Stephen A. St-Gallay、Andrew D. Wright

  DOI：10.1021/jm060995h

  日期：2007.1.1

  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.