RWJ-69442

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: RWJ-69442
• 英文别名: (S)-2-[4-(dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide；2-(4-Dimethylamino-phenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid {2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-1-yl]-propyl}-amide；2-[4-(dimethylamino)phenyl]-N-[(2S)-2-hydroxy-3-[4-(2-propan-2-yloxyphenyl)piperazin-1-yl]propyl]-1,3-dioxoisoindole-5-carboxamide
• 化学式: C₃₃H₃₉N₅O₅
• 分子量: 585.703
• InChiKey: LQTJOPPTSIYEES-SANMLTNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  43
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N,N-二甲基-对苯二胺 在 溶剂黄146 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 34.0h， 生成 RWJ-69442
  参考文献：
  名称：

  Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines:  A Novel Series of Potent and Selective α_1a-Adrenergic Receptor Antagonists

  摘要：

  Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than those of the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers had slightly lower binding affinity at alpha(1a)-AR but gained more than 2-fold selectivity for alpha(1a)-AR over alpha(1b)-AR, and 2- to 6-fold selectivity for alpha(1a)-AR over alpha(1d)-AR. They also had less cross activities against a panel of 25-35 peripheral and CNS receptors. The S-hydroxy enantiomers 23 and 24 (K-i = 0.29 nM, 0.33 nM; alpha(1b)/alpha(1a) >5690, >6060; alpha(1d)/alpha(1a) = 186, 158, respectively) were slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K-i = 0.13 nM, alpha(1d)/alpha(1a)= 14.8, alpha(1d)/alpha(1a) = 1.4). In the functional assay, the S-hydroxy enantiomers 20, 23, and 24 were less potent than tamsulosin in inhibiting contractions of rat prostate tissue but more selective in the inhibition of tissue contractions of rat prostate versus rat aorta. Compound 24 was selected as the development candidate for the treatment of BPH.

  DOI：

  10.1021/jm9905918

文献信息

• Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
  申请人：Ortho-McNeil Pharmaceutical, Inc.

  公开号：US06362338B1

  公开（公告）日：2002-03-26

  This invention relates to a series of substituted piperazines of Formula II, as well as enantiomers thereof These compounds are useful in the manufacture of pharmaceutical compositions.

  这项发明涉及到一系列Formula II的替代哌嗪，以及其对映体。这些化合物在制药组合物的制造中是有用的。
• An improved synthesis of enantiomerically pure RWJ 69442, a development candidate for the treatment of benign prostatic hyperplasia
  作者：Gee-Hong Kuo、Catherine Prouty、William V. Murray、Rekha D. Shah

  DOI：10.1002/jhet.5570380433

  日期：2001.7

  This report describes an improved synthesis of enantiomerically pure (S)-2-[4-(Dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)-phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide (RWJ 69442), a potent and selective αla-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. The synthesis highlights less hazardous reagents, easier purification

  该报告描述了对映体纯的（S）-2- [4-（二甲基氨基）苯基] -2,3-二氢-N- [2-羟基-3- [4- [2-（1-甲基乙氧基） -苯基] -1-哌嗪基〕丙基〕-1,3-二氧代-1- ħ -异吲哚-5-甲酰胺（RWJ 69442），一个有效的和选择性α拉-肾上腺素能受体拮抗剂用于治疗良性前列腺增生的治疗。该合成突出显示了较少的危险试剂，更易于纯化和更高的对映体纯度。所述Ñ苄基N-叔丁氧羰基胺6可以作为对映体纯的手性结构单元为不对称合成。
• [EN] PHTALIMIDO ARYLPIPERAZINES AS ALPHA 1A RECEPTOR ANTAGONISTS USEFUL IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA<br/>[FR] PHTALIMIDO-ARYLPIPERAZINES UTILES DANS LE TRAITEMENT DE L'HYPERPLASIE PROSTATIQUE BENIGNE EN TANT QU'ANTAGONISTES DU RECEPTEUR ALPHA IA
  申请人：ORTHO-McNEIL PHARMACEUTICAL, INC.

  公开号：WO1999042445A1

  公开（公告）日：1999-08-26

  (EN) This invention relates to a series of heterocyclic substituted piperazines of Formula (I), pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention selectively inhibit binding to the $g(a)-1a adrenergic receptor, a receptor which has been implicated in benign prostatic hyperplasia. As such the compounds are potentially useful in the treatment of this disease.(FR) L'invention concerne une série de pipérazines hétérocycliques substituées représentées par la formule I: (I), ainsi que des compositions pharmaceutiques contenant ces pipérazines et des intermédiaires utilisé dans la préparation de ces dernières. Ces composés inhibent de manière sélective la liaison au récepteur adrénergique $g(a)-1a, un récepteur dont on a démontré le rôle dans l'hyperplasie prostatique bénigne. Ces composés présentent par conséquent une utilité potentielle pour le traitement de cette pathologie.

  该发明涉及一系列Formula (I)的杂环取代哌嗪、包含它们的制药组合物和用于其制造的中间体。该发明的化合物选择性地抑制与$g(a)-1a肾上腺素能受体的结合，该受体已被证明在良性前列腺增生中起作用。因此，这些化合物在治疗该疾病方面具有潜在的用途。
• Phthalimido arylpiperazines as alpha 1A receptor antagonists useful in the treatment of benign prostatic hyperplasia
  申请人：Ortho-McNeil Pharmaceutical, Inc.

  公开号：EP1346983A2

  公开（公告）日：2003-09-24

  This invention relates to a series of heterocyclic substituted piperazines of Formula (I), pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention selectively inhibit binding to the α-1a adrenergic receptor, a receptor which has been implicated in benign prostatic hyperplasia. As such the compounds are potentially useful in the treatment of this disease.

  本发明涉及一系列式（I）的杂环取代哌嗪类化合物、含有这些化合物的药物组合物以及用于制造这些化合物的中间体。本发明的化合物可选择性地抑制与 α-1a 肾上腺素能受体的结合，该受体与良性前列腺增生症有关。因此，本发明化合物可用于治疗这种疾病。
• Novel phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
  申请人：——

  公开号：US20020077476A1

  公开（公告）日：2002-06-20

  This invention relates to a series of heterocyclic substituted piperazines of Formula I 1 pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention selectively inhibit binding to the &agr;-1 a adrenergic receptor, a receptor which has been implicated in benign prostatic hyperplasia. As such the compounds are potentially useful in the treatment of this disease.

  本发明涉及一系列式 I 的杂环取代的哌嗪类化合物 1 含有这些化合物的药物组合物以及用于制造这些化合物的中间体。本发明的化合物可选择性地抑制与 &agr;-1 a 肾上腺素能受体（一种与良性前列腺增生有关的受体）的结合。因此，本发明化合物可用于治疗这种疾病。