(2R,3S)-1-tert-butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-1-(3-chloro-4-cyano-2-methyl-phenylamino)-ethyl]pyrrolidine | 757247-76-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (2R,3S)-1-tert-butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-1-(3-chloro-4-cyano-2-methyl-phenylamino)-ethyl]pyrrolidine
• 英文别名: (2R,3S)-1-tert-Butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-1-(3-chloro-4-cyano-2-methyl-phenylamino)ethyl]pyrrolidine；tert-butyl (2R,3S)-3-[tert-butyl(dimethyl)silyl]oxy-2-[(1S)-1-(3-chloro-4-cyano-2-methylanilino)ethyl]pyrrolidine-1-carboxylate
• CAS: 757247-76-0
• 化学式: C₂₅H₄₀ClN₃O₃Si
• 分子量: 494.149
• InChiKey: WXWKENZCRBMSSJ-RBDMOPTHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.72
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  74.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R,3S)-1-tert-butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-1-(3-chloro-4-cyano-2-methyl-phenylamino)-ethyl]pyrrolidine 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 4.17h， 生成 4-[(1S,7S,7aR)-7-tert-Butyldimethylsilanoxy-1-methyl-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-2-yl]-2-chloro-3-methylbenzonitrile
  参考文献：
  名称：

  Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold Modifications

  摘要：

  A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR K-i = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.

  DOI：

  10.1021/jm070312d
• 作为产物：
  描述：

  3-氯-2-甲基苯胺 在 tris(dibenzylideneacetone)dipalladium (0) 、 chiral ferrocenyl catalyst 盐酸 、 copper(l) iodide 、 亚硝酸特丁酯 、 乙醇 、 溴 、 caesium carbonate 、 溶剂黄146 作用下， 以 乙醇 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 59.5h， 生成 (2R,3S)-1-tert-butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-1-(3-chloro-4-cyano-2-methyl-phenylamino)-ethyl]pyrrolidine
  参考文献：
  名称：

  Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold Modifications

  摘要：

  A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR K-i = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.

  DOI：

  10.1021/jm070312d

文献信息

• Bicyclic modulators of androgen receptor function
  申请人：Nirschl Alexandra

  公开号：US20050197359A1

  公开（公告）日：2005-09-08

  The present invention relates to bicyclic compounds according to formula I, pharmaceutical compositions containing such compounds and methods of using such compounds in the treatment of androgen receptor-associated conditions, such as age-related diseases, for example sarcopenia, wherein R 1 , R 2 , R 5 , X, Y and n are defined herein.

  本发明涉及按照式I的双环化合物，包含这种化合物的药物组合物以及使用这种化合物治疗与雄激素受体相关疾病的方法，例如与年龄相关的疾病，例如肌少症，其中R1、R2、R5、X、Y和n在此处定义。
• Sulfonylpyrrolidine modulators of androgen receptor function and method
  申请人：Hamann G. Lawrence

  公开号：US20050187267A1

  公开（公告）日：2005-08-25

  Compounds are provided which are useful in the treatment of androgen receptor-associated conditions, such as age-related diseases, which compounds have the structure wherein R 1 is hydrogen (H), alkyl or substituted alkyl, alkenyl or substituted alkenyl, arylalkyl or substituted arylalkyl, CO 2 R 4a , CONR 4a R 4b , and CH 2 OR 4a ; R 2 is hydrogen (H), OR 3 , SR 3 , halo, NHR 3 , NHCOR 4c 1 , NHCO 2 R 4c 1 , NHCONR 4c R 4d and NHSO 2 R 4c ; R 3 in each functional group is hydrogen (H), alkyl or substituted alkyl, CHF 2 , CF 3 and CON 4e ; R 4 , R 4a , R 4b , R 4c , R 4c 1 , R 4d , R 4e , R 4f , R 4g , or R 4h in each functional group are the same or different and are hydrogen(H), alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, or heteroaryl or substituted heteroaryl; R 5 and R 5 ′ are the same or different and are hydrogen(H), alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, or heteroaryl or substituted heteroaryl, wherein at least one of R 5 and R 5 ′ is hydrogen, or R 5 and R 5 ′ taken together form a double bond with oxygen (O), sulfur (S), NR 7 or CR 7 R 7 ′; where R 7 and R 7 ′ are as defined herein; G is an aryl, heterocyclo or heteroaryl group, wherein said group is mono- or polycyclic, and which is optionally substituted; and n is an integer of 1 or 2, m is an integer of 1 or 2, Z is oxygen (—O—) or NR 4h , a prodrug ester, all stereoisomers thereof and a pharmaceutically acceptable salt. A method for treating androgen receptor-associated conditions such as age-related diseases is also provided.

  提供了一些化合物，用于治疗与雄激素受体相关的疾病，如与年龄相关的疾病，这些化合物具有以下结构： 其中 R1是氢（H），烷基或取代烷基，烯基或取代烯基，芳基烷基或取代芳基烷基，CO2R4a，CONR4aR4b和CH2OR4a； R2是氢（H），OR3，SR3，卤素，NHR3，NHCOR4c1，NHCO2R4c1，NHCONR4cR4d和NHSO2R4c； 每个功能基团中的R3是氢（H），烷基或取代烷基，CHF2，CF3和CON4e； 在每个功能基团中，R4，R4a，R4b，R4c，R4c1，R4d，R4e，R4f，R4g或R4h是相同或不同的，可以是氢（H），烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基烷基或取代芳基烷基，芳基或取代芳基，或杂环芳基或取代杂环芳基； R5和R5'是相同或不同的，可以是氢（H），烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基烷基或取代芳基烷基，芳基或取代芳基，或杂环芳基或取代杂环芳基，其中R5和R5'中至少有一个是氢，或者R5和R5'一起形成与氧（O），硫（S），NR7或CR7R7'的双键； 其中R7和R7'如本文所定义；G是一个芳基，杂环或杂环芳基，其中该基团是单环或多环的，可以选择性地取代；n是1或2的整数，m是1或2的整数，Z是氧（—O—）或NR4h，一个前药酯，所有立体异构体及药学上可接受的盐。还提供了一种治疗与雄激素受体相关疾病，如与年龄相关的疾病的方法。
• BICYCLIC MODULATORS OF ANDROGEN RECEPTOR FUNCTION
  申请人：Sun Chong-Qing

  公开号：US20080108649A1

  公开（公告）日：2008-05-08

  There are provided compounds according to formula I wherein the substitutents are as described herein. Further provided are methods of using such compounds for the treatment of nuclear hormone receptor-associated conditions, such as age related diseases, for example sarcopenia. Also provided are pharmaceutical compositions containing such compounds and processes for preparing some of the compounds of the invention. Other embodiments are also disclosed.

  提供了按公式I描述的化合物，其中取代基如此描述。还提供了使用这种化合物治疗核激素受体相关疾病的方法，例如与年龄相关的疾病，例如肌肉萎缩症。还提供了含有这种化合物的药物组合物和制备本发明部分化合物的方法。还揭示了其他实施例。
• <i>N</i>-Aryl-oxazolidin-2-imine Muscle Selective Androgen Receptor Modulators Enhance Potency through Pharmacophore Reorientation
  作者：Alexandra A. Nirschl、Yan Zou、Stanley R. Krystek、James C. Sutton、Ligaya M. Simpkins、John A. Lupisella、Joyce E. Kuhns、Ramakrishna Seethala、Rajasree Golla、Paul G. Sleph、Blake C. Beehler、Gary J. Grover、Donald Egan、Aberra Fura、Viral P. Vyas、Yi-Xin Li、John S. Sack、Kevin F. Kish、Yongmi An、James A. Bryson、Jack Z. Gougoutas、John DiMarco、Robert Zahler、Jacek Ostrowski、Lawrence G. Hamann

  DOI：10.1021/jm801583j

  日期：2009.5.14

  A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.
• Synthesis and SAR of tetrahydropyrrolo[1,2-b][1,2,5]thiadiazol-2(3H)-one 1,1-dioxide analogues as highly potent selective androgen receptor modulators
  作者：Mark C. Manfredi、Yingzhi Bi、Alexandra A. Nirschl、James C. Sutton、Ramakrishna Seethala、Rajasree Golla、Blake C. Beehler、Paul G. Sleph、Gary J. Grover、Jacek Ostrowski、Lawrence G. Hamann

  DOI：10.1016/j.bmcl.2007.06.007

  日期：2007.8

  Replacement of the 3-oxo group of 2-chloro-4-[(7R,7aS)-7-hydroxy-1,3-dioxotetrahydro-IH-pyrrolo[1,2c]imidazol2(3H)-yl]-3-methylbenzonitrile resulted in a sulfamide series of selective androgen receptor modulator (SARM) agonists. (c) 2007 Elsevier Ltd. All rights reserved.