(1S,2R,3R)-1-[5-(4-methoxypyrazol-1-yl)thiophene-2-sulfonylamino]-3-phenylcyclopropane-1-carboxylic acid | 856450-81-2

• 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: (1S,2R,3R)-1-[5-(4-methoxypyrazol-1-yl)thiophene-2-sulfonylamino]-3-phenylcyclopropane-1-carboxylic acid
• 英文别名: (1S,2R,3R)-1-[5-(4-Methoxypyrazol-1-yl)thiophene-2-sulfonylamino]-2-methyl-3-phenylcyclopropanecarboxylic Acid；(1S,2R,3R)-1-[[5-(4-methoxypyrazol-1-yl)thiophen-2-yl]sulfonylamino]-2-methyl-3-phenylcyclopropane-1-carboxylic acid
• CAS: 856450-81-2
• 化学式: C₁₉H₁₉N₃O₅S₂
• 分子量: 433.509
• InChiKey: DSLRBIQFKOUGKT-LLSQANQASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  147
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  C₈H₈N₂OS 在 吡啶 、 盐酸 、 氯磺酸 作用下， 反应 32.0h， 生成 (1S,2R,3R)-1-[5-(4-methoxypyrazol-1-yl)thiophene-2-sulfonylamino]-3-phenylcyclopropane-1-carboxylic acid
  参考文献：
  名称：

  Discovery of (1S,2R,3R)-2,3-Dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: Novel and Highly Selective Aggrecanase Inhibitors

  摘要：

  Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A cries of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, aid orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazin e-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo [1,2-a]-pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.

  DOI：

  10.1021/jm101609j

文献信息

• Cyclopropane compounds and pharmaceutical use thereof
  申请人：Inaba Takashi

  公开号：US20060199826A1

  公开（公告）日：2006-09-07

  The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1): wherein R 1 is —(CH 2 ) m —X—(CH 2 ) n -A 1 etc., wherein m and n are the same or different and each is 0 to 6, X 1 is a single bond, etc. and A 1 is a substituted C 3-14 hydrocarbon ring group, etc.; R 2 and R 3 are the same or different and each is a hydrogen atom, —(CH 2 ) p —X 1 -(CH 2 ) q -A 2 , etc., wherein p and q are the same or different and each is 0 to 6, X 1 is a single bond, etc. and A 2 is an optionally substituted C 3-14 hydrocarbon ring group, etc.; R 4 is —CO 2 R 9 , etc., wherein R 9 is a hydrogen atom, etc.; and R 20 and R 21 are the same or different and each is a hydrogen atom, —(CH 2 ) m12 —X 12 —(CH 2 ) m12 —R 30 , etc., wherein m12 and m12 are the same or different and each is 0 to 6, X 12 is a single bond, etc. and R 30 is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

  本发明提供了一种具有抗软骨素酶活性和MMP-13抑制活性的化合物，可用作治疗骨关节炎、类风湿性关节炎等疾病的治疗剂，更具体地，是一种环丙烷化合物，其化学式为（1）：其中，R1为—（CH2）m—X—（CH2）n-A1等，其中m和n相同或不同，且每个为0至6，X1为单键等，A1为取代的C3-14碳氢环基等；R2和R3相同或不同，且每个为氢原子，—（CH2）p—X1-（CH2）q-A2等，其中p和q相同或不同，且每个为0至6，X1为单键等，A2为可选取代的C3-14碳氢环基等；R4为—CO2R9等，其中R9为氢原子等；且R20和R21相同或不同，且每个为氢原子，—（CH2）m12—X12—（CH2）m12—R30等，其中m12和m12相同或不同，且每个为0至6，X12为单键等，R30为氢原子等；或其前药或其药学上可接受的盐。
• CYCLOPROPANE COMPOUNDS AND PHARMACEUTICAL USE THEREOF
  申请人：INABA Takashi

  公开号：US20080261994A1

  公开（公告）日：2008-10-23

  The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1): wherein R 1 is —(CH 2 ) m —X—(CH 2 ) n -A 1 etc., wherein m and n are the same or different and each is 0 to 6, X is a single bond, etc. and A 1 is a substituted C 3-14 hydrocarbon ring group, etc.; R 2 and R 3 are the same or different and each is a hydrogen atom, —(CH 2 ) p —X 1 —(CH 2 ) q -A 2 , etc., wherein p and q are the same or different and each is 0 to 6, X 1 is a single bond, etc. and A 2 is an optionally substituted C 3-14 hydrocarbon ring group, etc.; R 4 is —CO 2 R 9 , etc., wherein R 9 is a hydrogen atom, etc.; and R 20 and R 21 are the same or different and each is a hydrogen atom, —(CH 2 ) m12 —X 12 —(CH 2 ) m12 —R 30 , etc., wherein m12 and m12 are the same or different and each is 0 to 6, X 12 is a single bond, etc. and R 30 is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

  本发明提供了一种具有抑制aggrecanase和MMP-13活性的化合物，可用作治疗骨关节炎，类风湿性关节炎等疾病的治疗剂，更具体地说，是式（1）的环丙烷化合物：其中，R1为—（CH2）m—X—（CH2）n-A1等，其中m和n相同或不同，每个为0至6，X为单键等，A1为取代的C3-14烃环基等；R2和R3相同或不同，每个为氢原子，—（CH2）p—X1—（CH2）q-A2等，其中p和q相同或不同，每个为0至6，X1为单键等，A2为可选取代的C3-14烃环基等；R4为—CO2R9等，其中R9为氢原子等；以及R20和R21相同或不同，每个为氢原子，—（CH2）m12—X12—（CH2）m12—R30等，其中m12和m12相同或不同，每个为0至6，X12为单键等，R30为氢原子等；或其前药或其药学上可接受的盐。
• CYCLOPROPANE DERIVATIVES AND PHARMACEUTICAL USE THEREOF
  申请人：Japan Tobacco, Inc.

  公开号：EP1694410B1

  公开（公告）日：2010-04-14
• US7351825B2
  申请人：——

  公开号：US7351825B2

  公开（公告）日：2008-04-01
• Discovery of (1<i>S</i>,2<i>R</i>,3<i>R</i>)-2,3-Dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: Novel and Highly Selective Aggrecanase Inhibitors
  作者：Makoto Shiozaki、Katsuya Maeda、Tomoya Miura、Masayuki Kotoku、Takayuki Yamasaki、Isamu Matsuda、Kenta Aoki、Katsutaka Yasue、Hiroto Imai、Minoru Ubukata、Akira Suma、Masahiro Yokota、Takahiro Hotta、Masahiro Tanaka、Yasunori Hase、Julia Haas、Andrew M. Fryer、Ellen R. Laird、Nicole M. Littmann、Steven W. Andrews、John A. Josey、Takayuki Mimura、Yuichi Shinozaki、Hiromi Yoshiuchi、Takashi Inaba

  DOI：10.1021/jm101609j

  日期：2011.4.28

  Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A cries of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, aid orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazin e-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo [1,2-a]-pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.