[(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester | 329041-21-6

• 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: [(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester
• 英文别名: tert-butyl 2-[4-oxopentyl-(4-phenylmethoxyphenyl)sulfonylamino]acetate
• CAS: 329041-21-6
• 化学式: C₂₄H₃₁NO₆S
• 分子量: 461.579
• InChiKey: QWPBXSRETWHKCR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  32
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  98.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  [(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester 在 potassium tert-butylate 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 生成 1-[4-benzyloxy-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxyic acid tert-butyl ester
  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
• 作为产物：
  描述：

  4-(苄氧基)苯-1-磺酰氯 在 三乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 [(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester
  参考文献：
  名称：

  Discovery of 3-OH-3-methylpipecolic hydroxamates: Potent orally active inhibitors of aggrecanase and MMP-13

  摘要：

  A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.05.037
• 作为试剂：
  描述：

  [(4-benzyloxy-benzenesulfonyl)-pent-4-enyl-amino]-acetic acid tert-butyl ester 、 、 N,N-二甲基甲酰胺 、 水 、 氧气 在 氯化钯 乙酸乙酯 、 水 、 Sodium sulfate-III 、 [(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester 作用下， 以 盐酸 为溶剂， 反应 72.0h， 以giving 83 g of [(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester (compound of formula XVII) as a colorless syrup的产率得到[(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester
  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-OH-3-methylpipecolic hydroxamates: Potent orally active inhibitors of aggrecanase and MMP-13
  作者：Mark C. Noe、Vijayalakshmi Natarajan、Sheri L. Snow、Lilli A. Wolf-Gouveia、Peter G. Mitchell、Lori Lopresti-Morrow、Lisa M. Reeves、Sue A. Yocum、Ivan Otterness、Marcia A. Bliven、Thomas J. Carty、John T. Barberia、Francis J. Sweeney、Jennifer L. Liras、Marcie Vaughn

  DOI：10.1016/j.bmcl.2005.05.037

  日期：2005.7

  A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described. (c) 2005 Elsevier Ltd. All rights reserved.