tert-butyl 3-(3-ethyl-7-oxo-5-{2-propoxy-5-[(trimethylsilyl)ethynyl]-3-pyridinyl}-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-1-azetidinecarboxylate | 335077-45-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: tert-butyl 3-(3-ethyl-7-oxo-5-{2-propoxy-5-[(trimethylsilyl)ethynyl]-3-pyridinyl}-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-1-azetidinecarboxylate
• 英文别名: tert-Butyl 3-(3-ethyl-7-oxo-5-{2-propoxy-5-[(trimethylsilyl)ethynyl]-3-pyridinyl}-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-1-azetidinecarboxylate；tert-Butyl3-(3-ethyl-7-oxo-5-{2-propoxy-5-[(trimethylsilyl)ethynyl]-3-pyridinyl}-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-1-azetidinecarboxylate；tert-butyl 3-[3-ethyl-7-oxo-5-[2-propoxy-5-(2-trimethylsilylethynyl)pyridin-3-yl]-6H-pyrazolo[4,3-d]pyrimidin-2-yl]azetidine-1-carboxylate
• CAS: 335077-45-7
• 化学式: C₂₈H₃₈N₆O₄Si
• 分子量: 550.733
• InChiKey: SSYTVAVRJBSAHL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.55
• 重原子数：
  39
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  111
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-(3-ethyl-7-oxo-5-{2-propoxy-5-[(trimethylsilyl)ethynyl]-3-pyridinyl}-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-1-azetidinecarboxylate 在 potassium fluoride 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 以85%的产率得到tert-butyl 3-[3-ethyl-5-(5-ethynyl-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-azetidinecarboxylate
  参考文献：
  名称：

  A Novel Series of Potent and Selective PDE5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability

  摘要：

  Sildenafil ( 5-[ 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one), a potent and selective phosphodiesterase type 5 ( PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C-max of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-( 5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-( 1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one ( 2) was selected for progression into the clinic.

  DOI：

  10.1021/jm060113e
• 作为产物：
  描述：

  2-丙氧基烟酸 在 吡啶 、 丙醇 、 bis-triphenylphosphine-palladium(II) chloride 、 N-碘代丁二酰亚胺 、 copper(l) iodide 、 草酰氯 、 双(三甲基硅烷基)氨基钾 、 caesium carbonate 、 三乙胺 、 N,N-二甲基甲酰胺 、 三氟乙酸 、 三氟乙酸酐 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 22.0h， 生成 tert-butyl 3-(3-ethyl-7-oxo-5-{2-propoxy-5-[(trimethylsilyl)ethynyl]-3-pyridinyl}-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-1-azetidinecarboxylate
  参考文献：
  名称：

  A Novel Series of Potent and Selective PDE5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability

  摘要：

  Sildenafil ( 5-[ 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one), a potent and selective phosphodiesterase type 5 ( PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C-max of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-( 5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-( 1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one ( 2) was selected for progression into the clinic.

  DOI：

  10.1021/jm060113e

文献信息

• Compositions and methods of treatment for conditions responsive to testosterone elevation
  申请人：——

  公开号：US20010044434A1

  公开（公告）日：2001-11-22

  This invention relates to methods and pharmaceutical compositions useful in the treatment of conditions that are responsive to the elevation of testosterone levels in the body and the use of estrogen agonists/antagonists for the manufacture of medicaments for the treatment of conditions that are responsive to the elevation of testosterone levels in the body. The compositions are comprised of an estrogen agonist/antagonist and a pharmaceutically acceptable vehicle, carrier or diluent. These compositions are effective in treating male subject sexual dysfunction and timidity in female subjects including post-menopausal women and are effective in increasing libido in female subjects including post-menopausal women. In the case of male subject sexual dysfunction, the compositions may also include a compound which is an elevator of cyclic guanosine 3′,5′-monophosphate (cGMP). Additionally, the compositions are effective in other conditions whose etiology is a result of testosterone deficiency or which can be ameliorated by increasing testosterone levels within the body. Methods of the invention include the treatment of conditions that are responsive to elevation of testosterone levels such as treating male subject sexual dysfunction and timidity in female subjects including post-menopausal women and the increase of libido of female subjects including post-menopausal women. The methods of treatment are effective while substantially reducing the concomitant liability of adverse effects associated with testosterone administration.

  本发明涉及用于治疗对体内睾酮水平升高有响应的情况的方法和药物组合物，以及使用雌激素激动剂/拮抗剂制造治疗对体内睾酮水平升高有响应的情况的药物。该组合物由雌激素激动剂/拮抗剂和药学上可接受的载体、载体或稀释剂组成。这些组合物有效地治疗男性性功能障碍和女性主体的胆怯，包括绝经后的妇女，并有效地增加女性主体的性欲，包括绝经后的妇女。在男性性功能障碍的情况下，该组合物还可以包括一种升高环鸟苷酸3′，5′-单磷酸（cGMP）的化合物。此外，该组合物对其他由睾酮缺乏引起的或可以通过提高体内睾酮水平改善的情况也有效。本发明的方法包括治疗对升高睾酮水平有响应的情况，例如治疗男性性功能障碍和女性主体的胆怯，包括绝经后的妇女，并增加女性主体的性欲，包括绝经后的妇女。该治疗方法在显著降低睾酮管理相关的不良反应的同时，也是有效的。
• Treatment of neuropathy
  申请人：Pfizer Inc

  公开号：US20040122010A1

  公开（公告）日：2004-06-24

  This invention relates to the use of cyclic guanosine 3′,5′-monophosphate phosphodiesterase type five (cGMP PDE5) inhibitors, including in particular the compound sildenafil, for the treatment of neuropathy, including in particular the treatment of diabetic neuropathy.

  本发明涉及使用环状鸟苷酸3′,5′-单磷酸磷酸二酯酶类型五（cGMP PDE5）抑制剂，包括特别是硝苯地平化合物，用于神经病的治疗，特别是糖尿病神经病的治疗。
• Treatments for female sexual dysfunction and methods for identifying compounds useful for treating female sexual dysfunction
  申请人：——

  公开号：US20030083228A1

  公开（公告）日：2003-05-01

  The present invention provides a method of treating female sexual dysfunction, the method comprising the step of administering to a patent, having or at risk of having one or more of the disorders or conditions associated with female sexual dysfunction, a therapeutically effective amount of a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of &agr;-melanocyte stimulating hormone to melanocortin receptors. The present invention also provides a method of identifying a compound that is useful for the treatment or prevention of female sexual dysfunction, the method comprising the steps of: 1) determining if a compound affects the binding of agouti-related protein to melanocortin receptors; 2) determining if a compound affects the binding of &agr;-melanocyte stimulating hormone to melanocortin receptors; and 3) selecting a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not affect the binding of &agr;-melanocyte stimulating hormone to melanocortin receptors.

  本发明提供了一种治疗女性性功能障碍的方法，该方法包括向患有或有患上与女性性功能障碍相关的一个或多个疾病或状况的患者施用一种化合物的治疗有效量，该化合物减弱了类似鼠标的蛋白与黑素皮质素受体的结合，但不减弱α-黑色素细胞刺激素与黑素皮质素受体的结合。本发明还提供了一种识别用于治疗或预防女性性功能障碍的化合物的方法，该方法包括以下步骤：1）确定化合物是否影响类似鼠标的蛋白与黑素皮质素受体的结合；2）确定化合物是否影响α-黑色素细胞刺激素与黑素皮质素受体的结合；3）选择减弱类似鼠标的蛋白与黑素皮质素受体的结合，但不影响α-黑色素细胞刺激素与黑素皮质素受体的结合的化合物。
• Methods of treatment and kits comprising a growth hormone secretagogue
  申请人：——

  公开号：US20030105114A1

  公开（公告）日：2003-06-05

  The present invention relates to methods of treating bulimia nervosa, male erectile dysfunction, female sexual dysfunction, thyroid cancer, breast cancer, or ameliorating ischemic nerve or muscle damage. The present invention also relates to kits that can be used in the treatment of bulimia nervosa, male erectile dysfunction, female sexual dysfunction, thyroid cancer, breast cancer, or ameliorating ischemic nerve or muscle damage. The present invention further relates to increasing gastrointestinal motility after surgery and increasing gastrointestinal motility in patients who have been administered an agent that decreases gastrointestinal motility.

  本发明涉及治疗暴食症、男性勃起功能障碍、女性性功能障碍、甲状腺癌、乳腺癌或改善缺血性神经或肌肉损伤的方法。本发明还涉及可用于治疗暴食症、男性勃起功能障碍、女性性功能障碍、甲状腺癌、乳腺癌或改善缺血性神经或肌肉损伤的试剂盒。本发明进一步涉及在手术后增加胃肠道运动和在接受降低胃肠道运动的药物治疗的患者中增加胃肠道运动的方法。
• Compositions and Methods for Treating Female Sexual Dysfunction
  申请人：Lee Andrew G.

  公开号：US20090264413A1

  公开（公告）日：2009-10-22

  This invention relates to methods, pharmaceutical compositions and kits useful in treating female sexual dysfunction and the use of an estrogen agonist/antagonist for the manufacture of a medicament for the treatment of female sexual dysfunction. The compositions are comprised of an estrogen agonist/antagonist as a first active ingredient and a cyclic guanosine 3′,5′-monophosphate elevator as a second active component and a pharmaceutically acceptable vehicle, carrier or diluent. The compositions and methods of treatment are effective while substantially reducing the concomitant liability of adverse effects associated with estrogen administration.

  本发明涉及用于治疗女性性功能障碍的方法、制药组合物和试剂盒，以及使用雌激素激动剂/拮抗剂制造治疗女性性功能障碍药物。该组合物包括雌激素激动剂/拮抗剂作为第一活性成分，环磷鸟苷3'-5'-单磷酸升高剂作为第二活性成分，以及药学上可接受的载体、载体或稀释剂。该组合物和治疗方法在显著减少雌激素给药相关的不良反应的同时具有有效性。