N-[5-(aminocarbonyl)-3-ethyl-1H-pyrazol-4-yl]-5-iodo-2-propoxynicotinamide | 335078-02-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[5-(aminocarbonyl)-3-ethyl-1H-pyrazol-4-yl]-5-iodo-2-propoxynicotinamide
• 英文别名: N-[3-(Aminocarbonyl)-5-ethyl-1H-pyrazol-4-yl]-5-iodo-2-propoxy-nicotinamide；N-(3-carbamoyl-5-ethyl-1H-pyrazol-4-yl)-5-iodo-2-propoxypyridine-3-carboxamide
• CAS: 335078-02-9
• 化学式: C₁₅H₁₈IN₅O₃
• 分子量: 443.244
• InChiKey: RYWKDWNVZJRFLV-UHFFFAOYSA-N

物化性质

• 沸点：
  534.5±50.0 °C(Predicted)
• 密度：
  1.680±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-[5-(aminocarbonyl)-3-ethyl-1H-pyrazol-4-yl]-5-iodo-2-propoxynicotinamide 在 丙醇 、 bis-triphenylphosphine-palladium(II) chloride 、 potassium fluoride 、 copper(l) iodide 、 双(三甲基硅烷基)氨基钾 、 caesium carbonate 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 tert-butyl 4-[3-ethyl-5-(5-ethynyl-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-piperidinecarboxylate
  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-5-碘烟酸 在 吡啶 、 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 生成 N-[5-(aminocarbonyl)-3-ethyl-1H-pyrazol-4-yl]-5-iodo-2-propoxynicotinamide
  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

• 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可能患有与女性性功能障碍相关的一种或多种疾病或病况的患者施用一种治疗有效量的化合物，该化合物减弱了agouti相关蛋白与黑素皮质素受体的结合，但不影响α-黑素细胞刺激激素与黑素皮质素受体的结合。本发明还提供了一种识别对治疗或预防女性性功能障碍有用的化合物的方法，该方法包括以下步骤：1）确定化合物是否影响agouti相关蛋白与黑素皮质素受体的结合；2）确定化合物是否影响α-黑素细胞刺激激素与黑素皮质素受体的结合；以及3）选择一种减弱agouti相关蛋白与黑素皮质素受体结合的化合物，但不影响α-黑素细胞刺激激素与黑素皮质素受体的结合。
• 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.

  本发明涉及治疗厌食症、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厌食症、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。本发明还涉及术后增加胃肠道蠕动和在接受降低胃肠道蠕动试剂的患者中增加胃肠道蠕动。
• Treatment of neuropathy
  申请人：——

  公开号：US20030162782A1

  公开（公告）日：2003-08-28

  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.

  这项发明涉及使用环鸟苷3′,5′-单磷酸磷酸二酯酶五型（cGMP PDE5）抑制剂，特别是包括化合物西地那非，用于治疗神经病变，特别是治疗糖尿病神经病变。
• 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.

  本发明涉及一种用于治疗对体内睾酮水平升高敏感的病症的方法和药物组合物，以及用于制造用于治疗对体内睾酮水平升高敏感的病症的药物的雌激素激动剂/拮抗剂的使用。该组合物由雌激素激动剂/拮抗剂和药用可接受的载体、载体或稀释剂组成。这些组合物有效用于治疗男性主体性功能障碍和女性主体包括绝经后妇女的胆怯，并且有效用于增加女性主体包括绝经后妇女的性欲。在男性主体性功能障碍的情况下，该组合物还可以包括一种提高环鸟苷酸3′,5′-单磷酸（cGMP）水平的化合物。此外，该组合物对其他病因是由于睾酮缺乏或可以通过增加体内睾酮水平改善的病症也是有效的。本发明的方法包括治疗对睾酮水平升高敏感的病症，如治疗男性主体性功能障碍和女性主体包括绝经后妇女的胆怯，以及增加女性主体包括绝经后妇女的性欲。该治疗方法在实质上减少了与睾酮给药相关的不良作用的同时是有效的。
• Novel process for the preparation of pyrazoles
  申请人：——

  公开号：US20020022732A1

  公开（公告）日：2002-02-21

  A “one-pot” process is described herein for the production of pyrazole compounds of general formula (II) 1 comprising the steps of reacting a compound of general formula (III) 2 with an acylating agent in the presence of a base and an optional activating agent followed by the addition of a hydrazine compound in situ.

  本文描述了一种“一锅法”工艺，用于生产通式（II）的吡唑化合物，包括以下步骤：在碱和可选活化剂的存在下，将通式（III）的化合物与酰化剂反应，然后现场加入肼化合物。