(1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2,2,2]octan-3-one | 329041-30-7

• 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: (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2,2,2]octan-3-one
• 英文别名: (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one；(1R,4R)-5-(4-hydroxyphenyl)sulfonyl-8,8-dimethyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one
• CAS: 329041-30-7
• 化学式: C₁₄H₁₇NO₅S
• 分子量: 311.359
• InChiKey: UXCQUFHEIVIRPQ-PWSUYJOCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  92.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2,2,2]octan-3-one 、 alkaline earth salt of/the/ methylsulfuric acid 在 caesium carbonate 作用下， 以 乙腈 为溶剂， 生成
  参考文献：
  名称：

  Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13

  摘要：

  A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyaryl-sulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.03.105
• 作为产物：
  描述：

  (1 R ,4 R)-5-(4-Benzyloxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one 在 palladium 10% on activated carbon 氢气 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 1.5h， 生成 (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2,2,2]octan-3-one
  参考文献：
  名称：

  Selective inhibition of aggrecanase in osteoarthritis treatment

  摘要：

  这项发明涉及一种治疗骨关节炎的方法，涉及抑制aggrecanase的抑制剂，其IC50小于20 nM，并且对基质金属蛋白酶（MMPs）和脱粒蛋白酶（ADAMs或reprolysins）表现出差异的效力。这项发明还涉及化合物、治疗方法和Formula I的组成： 或其治疗上可接受的盐，其中X为碳或氮； R1和R2分别选自氢、羟基和甲基组成的群，其中至少一个为甲基； R3和R4分别选自氢、羟基和甲基组成的群，或R3和R4可一起形成一个羰基；以及 R5和R6是正交位、间位或对位的独立取代基，分别选自氢、卤素、氰基、甲基和乙基；附加条件： 当X为碳时，R7和R8都是氢，且至少一个R1、R2、R3和R4为羟基； 当X为碳且R5为对位卤素时，至少一个R6、R3和R4不是氢； 当X为氮时，R8不存在且R7为氢或一个公式的基团： 其中，Y为—CH2—NH2或—NH—CH3；以及 当X为氮且R7为H时，R3和R4一起形成一个羰基。

  公开号：

  US20050227997A1
• 作为试剂：
  描述：

  (1 R ,4 R)-5-(4-Benzyloxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one 、 氢气 在 钯 (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2,2,2]octan-3-one 作用下， 以 甲醇乙酸乙酯 为溶剂， 反应 1.5h， 以Concentration of the filtrate afforded 2.4 g (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVIII) as a colorless solid的产率得到(1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2,2,2]octan-3-one
  参考文献：
  名称：

  Selective inhibition of aggrecanase in osteoarthritis treatment

  摘要：

  本发明涉及一种治疗骨关节炎的方法，涉及抑制剂，其IC50小于20 nM，并且对基质金属蛋白酶（MMP）和脱粘蛋白酶（ADAM或重复蛋白酶）具有差异的效力。本发明还涉及化合物、治疗方法和组合物，其化学式为I：或其治疗上可接受的盐，其中X为碳或氮；R1和R2独立地选自氢、羟基和甲基的组，其中至少一个是甲基；R3和R4独立地选自氢、羟基和甲基的组，或R3和R4可以一起形成羰基基团；R5和R6是正交、间位或对位的独立取代基，选自氢、卤素、氰基、甲基和乙基的组；但是：当X为碳时，R7和R8都是氢，且R1、R2、R3和R4中至少有一个是羟基；当X为碳且R5为对位卤素时，R6、R3和R4中至少有一个不是氢；当X为氮时，R8不存在，且R7为氢或公式的基团，其中Y为—CH2—NH2或—NH—CH3；当X为氮且R7为H时，R3和R4一起形成羰基基团。

  公开号：

  US20050227997A1

文献信息

• Selective inhibitors of aggrecanase in osteoarthritis treatment
  申请人：Pfizer Products Inc.

  公开号：EP1081137A1

  公开（公告）日：2001-03-07

  This invention relates to a method of treatment for osteoarthritis involving inhibitors of aggrecanase that demonstrate IC50s of less than 20 nM and demonstrate differential potency against matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs or reprolysins). This invention also relates to compounds, methods of treatment and composition of Formula I: or a therapeutically acceptable salt thereof, wherein X is carbon or nitrogen; R1 and R2 are independently selected from the group consisting of hydrogen, hydroxy, and methyl, wherein at least one of R1 and R2 is methyl; R3 and R4 are independently selected from the group consisting of hydrogen, hydroxy, and methyl, or R3 and R4 may be taken together to form a carbonyl group; and R5 and R6 are independent substituents in the ortho, meta, or para positions and are independently selected from the group consisting of hydrogen, halogen, cyano, methyl, and ethyl; with the provisos: when X is carbon, then R7 and R8 are both hydrogen and at least one of R1, R2, R3, and R4 is hydroxy; when X is carbon and R5 is para-halo, then at least one of R6, R3, and R4 is not hydrogen; when X is nitrogen, then R8 is not present and R7 is hydrogen or a group of the formula: wherein, Y is -CH2-NH2 or -NH-CH3; and when X is nitrogen and R7 is H, then R3 and R4 are taken together to form a carbonyl group.

  这项发明涉及一种治疗骨关节炎的方法，涉及抑制aggrecanase的方法，其IC50小于20 nM，并且对基质金属蛋白酶（MMPs）和脱粒蛋白酶（ADAMs或reprolysins）表现出差异的效力。该发明还涉及化合物、治疗方法和Formula I的组成： 或其治疗上可接受的盐，其中 X为碳或氮； R1和R2分别选自氢、羟基和甲基组成的群，其中至少一个为甲基； R3和R4分别选自氢、羟基和甲基组成的群，或R3和R4可一起形成羰基；以及 R5和R6是正交位、间位或对位的独立取代基，分别选自氢、卤素、氰基、甲基和乙基组成的群； 附加条件： 当X为碳时，R7和R8均为氢，且R1、R2、R3和R4中至少一个为羟基； 当X为碳且R5为对位卤素时，至少一个R6、R3和R4不是氢； 当X为氮时，R8不存在，R7为氢或下式的基团： 其中，Y为-CH2-NH2或-NH-CH3；以及 当X为氮且R7为H时，R3和R4一起形成羰基。
• US7030242B2
  申请人：——

  公开号：US7030242B2

  公开（公告）日：2006-04-18
• Selective inhibition of aggrecanase in osteoarthritis treatment
  申请人：Noe C. Mark

  公开号：US20050227997A1

  公开（公告）日：2005-10-13

  This invention relates to a method of treatment for osteoarthritis involving inhibitors of aggrecanase that demonstrate IC 50 s of less than 20 nM and demonstrate differential potency against matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs or reprolysins). This invention also relates to compounds, methods of treatment and composition of Formula I: or a therapeutically acceptable salt thereof, wherein X is carbon or nitrogen; R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy, and methyl, wherein at least one of R 1 and R 2 is methyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, hydroxy, and methyl, or R 3 and R 4 may be taken together to form a carbonyl group; and R 5 and R 6 are independent substituents in the ortho, meta, or para positions and are independently selected from the group consisting of hydrogen, halogen, cyano, methyl, and ethyl; with the provisos: when X is carbon, then R 7 and R 8 are both hydrogen and at least one of R 1 , R 2 , R 3 , and R 4 is hydroxy; when X is carbon and R 5 is para-halo, then at least one of R 6 , R 3 , and R 4 is not hydrogen; when X is nitrogen, then R 8 is not present and R 7 is hydrogen or a group of the formula: wherein, Y is —CH 2 —NH 2 or —NH—CH 3 ; and when X is nitrogen and R 7 is H, then R 3 and R 4 are taken together to form a carbonyl group.

  这项发明涉及一种治疗骨关节炎的方法，涉及抑制aggrecanase的抑制剂，其IC50小于20 nM，并且对基质金属蛋白酶（MMPs）和脱粒蛋白酶（ADAMs或reprolysins）表现出差异的效力。这项发明还涉及化合物、治疗方法和Formula I的组成： 或其治疗上可接受的盐，其中X为碳或氮； R1和R2分别选自氢、羟基和甲基组成的群，其中至少一个为甲基； R3和R4分别选自氢、羟基和甲基组成的群，或R3和R4可一起形成一个羰基；以及 R5和R6是正交位、间位或对位的独立取代基，分别选自氢、卤素、氰基、甲基和乙基；附加条件： 当X为碳时，R7和R8都是氢，且至少一个R1、R2、R3和R4为羟基； 当X为碳且R5为对位卤素时，至少一个R6、R3和R4不是氢； 当X为氮时，R8不存在且R7为氢或一个公式的基团： 其中，Y为—CH2—NH2或—NH—CH3；以及 当X为氮且R7为H时，R3和R4一起形成一个羰基。
• Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13
  作者：Mark C. Noe、Vijayalakshmi Natarajan、Sheri L. Snow、Peter G. Mitchell、Lori Lopresti-Morrow、Lisa M. Reeves、Sue A. Yocum、Thomas J. Carty、John A. Barberia、Francis J. Sweeney、Jennifer L. Liras、Marcie Vaughn、Joel R. Hardink、Joel M. Hawkins、Christopher Tokar

  DOI：10.1016/j.bmcl.2005.03.105

  日期：2005.6

  A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyaryl-sulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described. (c) 2005 Elsevier Ltd. All rights reserved.