tert-butyl 3-[3-(aminocarbonyl)-5-ethyl-4-{[(5-iodo-2-propoxy-3-pyridinyl)carbonyl]amino}-1H-pyrazol-4-yl]-1-azetidiinecarboxylate | 335078-18-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: tert-butyl 3-[3-(aminocarbonyl)-5-ethyl-4-{[(5-iodo-2-propoxy-3-pyridinyl)carbonyl]amino}-1H-pyrazol-4-yl]-1-azetidiinecarboxylate
• 英文别名: tert-butyl 3-(3-(aminocarbonyl)-5-ethyl-4-{[(5-iodo-2-propoxy-3-pyridinyl)carbonyl]amino}-1H-pyrazol-1-yl)-1-azetidinecarboxylate；tert-butyl 3-[3-carbamoyl-5-ethyl-4-[(5-iodo-2-propoxypyridine-3-carbonyl)amino]pyrazol-1-yl]azetidine-1-carboxylate
• CAS: 335078-18-7
• 化学式: C₂₃H₃₁IN₆O₅
• 分子量: 598.441
• InChiKey: MPEJUMGAXSUXEC-UHFFFAOYSA-N

物化性质

• 沸点：
  631.4±55.0 °C(Predicted)
• 密度：
  1.60±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  142
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-[3-(aminocarbonyl)-5-ethyl-4-{[(5-iodo-2-propoxy-3-pyridinyl)carbonyl]amino}-1H-pyrazol-4-yl]-1-azetidiinecarboxylate 在 丙醇 、 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 双(三甲基硅烷基)氨基钾 、 三乙胺 作用下， 以 乙腈 为溶剂， 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
• 作为产物：
  描述：

  2-丙氧基-5-碘烟酸 在 吡啶 、 草酰氯 、 caesium carbonate 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 tert-butyl 3-[3-(aminocarbonyl)-5-ethyl-4-{[(5-iodo-2-propoxy-3-pyridinyl)carbonyl]amino}-1H-pyrazol-4-yl]-1-azetidiinecarboxylate
  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

• Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-ones and intermediates thereof
  申请人：Pfizer Limited

  公开号：EP1176147A1

  公开（公告）日：2002-01-30

  A process is provided for the preparation of compounds of formula (I) herein comprising reacting a compound of formula (II), (III), (IV) or (V) in the presence of -OR3 and a hydroxide trapping agent or in the case of compounds of formula (IV) reacting in the presence of an auxiliary base and a hydroxide trapping agent (i.e. -OR3 is substituted by the auxiliary base), wherein X is a leaving group and R1 to R4 are as defined.

  提供一种用于制备式（I）化合物的方法，包括在-OR3和氢氧化物捕获剂的存在下，反应式（II）、（III）、（IV）或（V）化合物，或者在辅助碱和氢氧化物捕获剂的存在下反应式（IV）化合物（即-OR3被辅助碱取代），其中X是离去基团，R1至R4如所定义。
• 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。
• Compositions and methods of treatment for conditions responsive to testosterone elevation
  申请人：——

  公开号：US20030114440A1

  公开（公告）日：2003-06-19

  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反应的疾病的方法和制药组合物，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反应的疾病的药物。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。这些组合物对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症状有效，并且对增加女性主体包括绝经后妇女的性欲有效。对于男性主体性功能障碍的情况，该组合物还可以包括一种升高环磷鸟苷酸3'，5'-单磷酸（cGMP）的化合物。此外，该组合物对其他疾病的疗效是通过睾酮缺乏引起的或可以通过提高体内睾酮水平来改善的。本发明的方法包括治疗对睾酮水平升高有反应的疾病，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症状以及增加女性主体包括绝经后妇女的性欲。该治疗方法在显著降低睾酮治疗的不良反应同时具有疗效。
• 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。