fosamprenavir calcium

• 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: fosamprenavir calcium
• 英文别名: fosamprenavir calcium salt；calcium;N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[hydroxy(oxido)phosphoryl]oxy-1-phenylbutan-2-yl]-1-[(3S)-oxolan-3-yl]oxymethanimidate
• 化学式: C₂₅H₃₄N₃O₉PS*Ca
• 分子量: 623.677
• InChiKey: PMDQGYMGQKTCSX-HQROKSDRSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  0.88
• 重原子数：
  40
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  192
• 氢给体数：
  2
• 氢受体数：
  11

ADMET

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用的总结：目前没有关于哺乳期间使用福沙那韦的已发布信息。不推荐在哺乳期间使用福沙那韦。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：在接受高效抗逆转录病毒治疗的男性中报告了男性乳房发育。男性乳房发育最初是单侧的，但在大约一半的病例中会发展为双侧。没有发现血清催乳素的变化，即使继续使用该治疗方案，通常也会在一年内自发解决。一些病例报告和体外研究建议蛋白酶抑制剂可能导致一些男性患者出现高催乳素血症和乳汁分泌过多，尽管这一点存在争议。这些发现对哺乳母亲的相关性尚不清楚。已建立泌乳的母亲催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:No published information is available on the use of fosamprenavir during breastfeeding. Fosamprenavir is not recommended during breastfeeding. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

反应信息

• 作为产物：
  描述：

  仲丁醇 以 甲醇 为溶剂， 生成 fosamprenavir calcium
  参考文献：
  名称：

  SOLID STATE FORMS OF FOSAMPRENAVIR CALCIUM SALT AND PROCESSES FOR PREPARATION THEREOF

  摘要：

  该发明涉及福沙匹克钙盐的固态形式，制备该固态形式的方法以及其药物组成物。

  公开号：

  US20110165202A1

文献信息

• PROCESS FOR PREPARATION OF SUBSTANTIALLY PURE FOSAMPRENAVIR CALCIUM AND ITS INTERMEDIATES
  申请人：Arora Surinder Kumar

  公开号：US20130174651A1

  公开（公告）日：2013-07-11

  The present invention relates to fosamprenavir calcium (Ia) substantially free of isomer impurity, (3R) tetrahydro -3 -furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl carbamate (Ib), and its process for preparation thereof. The present invention also provides fosamprenavir calcium intermediate, (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (IIa) substantially free of (R)-3-tetrahydrofuranylsuccinimidyl carbonate (IIb) and its process for preparation thereof.

  本发明涉及基本上不含异构杂质的福扎韦钙（Ia），(3R)四氢呋喃基(1S,2R)-3-[[（4-氨基苯基）磺酰](异丁基)氨基]-1-苄基-2-(磷酸酯基)丙烯基氨基甲酸酯（Ib），以及其制备方法。本发明还提供福扎韦钙中间体，(S)-3-四氢呋喃基-N-琥珀酰亚胺基碳酸酯（IIa），基本上不含(R)-3-四氢呋喃基琥珀酰亚胺基碳酸酯（IIb），以及其制备方法。
• PREPARATION OF FOSAMPRENAVIR CALCIUM
  申请人：Mandava Venkata Naga Brahmeshwara Rao

  公开号：US20110224443A1

  公开（公告）日：2011-09-15

  Process for preparation of fosamprenavir and its intermediate salts using novel phthalimide intermediates.

  使用新型邻苯二甲酰亚胺中间体制备福氨普利韦及其中间盐的过程。
• Preclinical Pharmacology and Pharmacokinetics of GW433908, a Water-Soluble Prodrug of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir
  作者：Eric S. Furfine、Christopher T. Baker、Michael R. Hale、David J. Reynolds、Jo A. Salisbury、Andy D. Searle、Scott D. Studenberg、Dan Todd、Roger D. Tung、Andrew Spaltenstein

  DOI：10.1128/aac.48.3.791-798.2004

  日期：2004.3

  GW433908 is the water-soluble, phosphate ester prodrug of the human immunodeficiency virus type 1 protease inhibitor amprenavir (APV). A high-yield synthesis of GW433908 is achieved by phosphorylation of the penultimate precursor of APV with phosphorous oxychloride (POCl ₃ ) in pyridine. A single-dose pharmacokinetic study of GW433908 sodium salt in dogs showed that APV exposure was similar to that achieved with an equivalent molar dose of the APV clinical formulation (Agenerase) and that systemic exposure to the prodrug was minimal (0.3% of the APV exposure). However, the sodium salt of GW433908 was a hygroscopic, amorphous solid and thus not suitable for pharmaceutical development. The calcium salt was a developable crystalline solid, but oral dosing afforded only 24% of the APV exposure in dogs compared with Agenerase. Acidification of the dog stomach by coadministration of HCl increased the bioavailability of the calcium salt to levels near those of the sodium salt. Single-dose administration of GW433908 calcium salt in dogs and rats produced portal vein GW433908 concentrations that were maximally 1.72 and 0.79% of those of APV concentrations, respectively. Furthermore, GW433908 had poor transepithelial flux and APV showed significant flux across human-derived Caco-2 cell monolayers (a model of intestinal permeability). Taken together, these results suggest that GW433908 is primarily metabolized to APV at or in the epithelial cells of the intestine and that the prodrug is not substantially absorbed. Based in part on these findings, GW433908 was advanced to clinical development.

  摘要 GW433908 是人类免疫缺陷病毒 1 型蛋白酶抑制剂安非那韦（APV）的水溶性磷酸酯原药。GW433908 的高产合成是通过用氧氯化磷（POCl 3 ) 在吡啶中进行磷酸化，从而高产合成了 APV。对狗进行的 GW433908 钠盐单剂量药代动力学研究表明，APV 的暴露量与同等摩尔剂量的 APV 临床制剂（Agenerase）的暴露量相似，而且该原药的全身暴露量极小（为 APV 暴露量的 0.3%）。不过，GW433908 的钠盐是一种吸湿性无定形固体，因此不适合用于药物开发。钙盐是一种可开发的结晶固体，但与 Agenerase 相比，口服药物在狗体内只能产生 24% 的 APV 暴露量。通过同时给药盐酸来酸化狗胃，可将钙盐的生物利用度提高到接近钠盐的水平。狗和大鼠单剂量服用 GW433908 钙盐后，门静脉 GW433908 浓度最高分别为 APV 浓度的 1.72% 和 0.79%。此外，GW433908 的跨上皮通透性较差，而 APV 在人源 Caco-2 细胞单层（肠道通透性模型）上显示出显著的通透性。综上所述，这些结果表明，GW433908 主要在肠道上皮细胞内或在肠道上皮细胞内代谢为 APV，原药不会被大量吸收。部分基于这些研究结果，GW433908 被推进到临床开发阶段。
• PROCESS FOR THE PREPARATION OF FOSAMPRENAVIR CALCIUM
  申请人：Bhoge Satish Manohar

  公开号：US20120220786A1

  公开（公告）日：2012-08-30

  The present invention relates to process for the preparation of fosamprenavir calcium.

  本发明涉及一种制备磷酸阿替卡韦钙的方法。
• Process for preparation of substantially pure fosamprenavir calcium and its intermediates
  申请人：Arora Surinder Kumar

  公开号：US08877947B2

  公开（公告）日：2014-11-04

  The present invention relates to fosamprenavir calcium (Ia) substantially free of isomer impurity, (3R)tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl carbamate (Ib), and its process for preparation thereof. The present invention also provides fosamprenavir calcium intermediate, (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (IIa) substantially free of (R)-3-tetrahydrofuranylsuccinimidyl carbonate (IIb) and its process for preparation thereof.

  本发明涉及基本无异构杂质的福沙韦钙（Ia），即（3R）四氢呋喃基（1S,2R）-3- [[（4-氨基苯基）磺酰]（异丁基）氨基] -1-苄基-2-（磷酸酯氧基）丙基氨基甲酸酯（Ib）及其制备方法。本发明还提供福沙韦钙中间体，即基本无（R）-三氢呋喃基琥珀酰亚胺酯（IIb）的（S）-3-四氢呋喃基-N-琥珀酰亚胺酯（IIa）及其制备方法。