4-[(氨基羰基)氨基]-N-[芴甲氧羰基]-D-苯丙氨酸 | 324017-22-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 4-[(氨基羰基)氨基]-N-[芴甲氧羰基]-D-苯丙氨酸
• 中文别名: Fmoc-D-Aph(Cbm)-OH
• 英文名称: Fmoc-D-Aph(Cbm)-OH
• 英文别名: (2R)-3-[4-(carbamoylamino)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid
• CAS: 324017-22-3
• 化学式: C₂₅H₂₃N₃O₅
• 分子量: 445.475
• InChiKey: HFPDOFBZCSQAEJ-JOCHJYFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  131
• 氢给体数：
  4
• 氢受体数：
  5

安全信息

• 储存条件：
  存储条件：密封、干燥、避光，适宜温度为2-8°C。

反应信息

• 作为反应物：
  描述：

  Fmoc-Rink resin 、 Fmoc-L-亮氨酸 、 N-FMOC-N’-BOC-N’-异丙基-L-赖氨酸 、 N-[芴甲氧羰基]-4-[[[(4S)-六氢-2,6-二氧代-4-嘧啶基]羰基]氨基]-L-苯丙氨酸 、 Fmoc-L-脯氨酸 、 FMOC-O-叔丁基-L-丝氨酸 、 乙酸酐 、 Fmoc-D-丙氨酸 、 芴甲氧羰基-3-(2-萘)-D-丙氨酸 、 FMOC-D-4-氯苯丙氨酸 、 4-[(氨基羰基)氨基]-N-[芴甲氧羰基]-D-苯丙氨酸 、 N-(9-芴甲氧羰基)-3-吡啶基-D-丙氨酸 在 叔丁胺 、 N,N'-二异丙基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以67%的产率得到醋酸地加瑞克
  参考文献：
  名称：

  克服高纯GnRH拮抗剂Degarelix固相合成中的化学挑战。第2部分

  摘要：

  在存在碱的情况下，二氢激素（Hor）残基的水解和重排导致乙内酰脲（Hyd）杂质的形成，是制造促性腺激素释放激素拮抗剂Degarelix的主要问题之一。为了找到克服该问题的有效策略，我们进行了有机碱的筛选，以选择在固相合成过程中既能快速进行Fmoc脱保护又能避免这种特殊重排的有机碱。在测试的碱基中，只有叔丁胺不影响肽分子，并且能够快速去除Fmoc。使用叔叔用于合成Degarelix的丁胺可制得纯度和产率极佳的产品，而没有可检测量的乙内酰脲杂质。因此，我们表明叔丁胺可以替代哌啶用于工业规模生产Degarelix或其他含Hor的肽类药物。

  DOI：

  10.1021/acs.oprd.9b00540
• 作为产物：
  描述：

  三甲基硅基异氰酸酯 、 D-苯基丙氨酸 以 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 以85%的产率得到4-[(氨基羰基)氨基]-N-[芴甲氧羰基]-D-苯丙氨酸
  参考文献：
  名称：

  GnRH Antagonists:  A New Generation of Long Acting Analogues Incorporating p-Ureido-phenylalanines at Positions 5 and 6

  摘要：

  A series of antagonists of gonadotropin-releasing hormone (GnRH) of the general formula Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph/4Amf(P)-D4Aph/D4Amf( Q)-Leu-ILys-Pro-DAla-NH2 was synthesized, characterized, and screened for duration of inhibition of luteinizing hormone release in a castrated male rat assay. Selected analogues were tested in a reporter gene assay (IC50 and pA(2)) and an in vitro histamine release assay. P and Q contain urea/carbamoyl functionalities designed to increase potential intra- and intermolecular hydrogen bonding opportunities for structural stabilization and peptide/receptor interactions, respectively. These substitutions resulted in analogues with increased hydrophilicity and a lesser propensity to form gels in aqueous solution than azaline B [Ac-D2Nal-D4Cpa-n3Pal-Ser-4Aph(Atz)-D4Aph(Atz)-Leu-ILys-Pro-DAla-NH2 with Atz = 3'-amino-1H-1',2',4'-triazol-5'-yl, 5], and in some cases they resulted in a significant increase in duration of action after subcutaneous (sc) administration. Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(L-hydroorotyl)-D4Aph(carbamoyl)-Leu-ILys-Pro-DAla-NH2 (acetate salt is FE200486) (31) and eight: other congeners (20, 35, 37, 39, 41, 45-47) were identified that exhibited significantly longer duration of action than acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(Ac)-Leu-ILys-Pro-DAla-NH2] (6) when administered subcutaneously in castrated male rats at a dose of 50 mug in 100 muL Of phosphate buffer No correlation was found between retention times on a C-18 reverse phase column using a triethylammonium phosphate buffer at pH 7.0 (a measure of hydrophilicity) or affinity in an in vitro human GnRH report gene assay (pA(2)) and duration of action. FE200486 was selected for preclinical studies, and some of its properties were compared to those of other clinical candidates. In the intact rat, ganirelix, abarelix, azaline B, and FE200486 inhibited plasma testosterone for 1, 1, 14, and 57 days, respectively, at 2 mg/kg sc in 5% mannitol (injection volume = 20 muL). Based on the information that 31, 33, 35 and 37 were significantly shorter acting than acyline or azaline B after intravenous administration (100 mug/rat), we surmised that the very long duration of action of the related FE200486 (for example) was likely due to unique physicochemical properties such as solubility in aqueous milieu, comparatively low propensity to form gels, and ability to diffuse at high concentrations in a manner similar to that described for slow release formulations of peptides. Indeed, in rats injected sc with FE200486 (2 mg/kg), plasmatic concentrations of FE200486 remained above 5 ng/mL until day 41, and the time after which they dropped below 3 ng/mL and plasma LH levels started rising until full recovery was reached at day 84 with levels of FE200486 hovering around 1 ng/mL. Additionally, FE200486 was less potent at releasing histamine from isolated rat mast cells than any of the GnRH antagonists presently described in preclinical reports.

  DOI：

  10.1021/jm0003900

文献信息

• [EN] SOLID-PHASE SYNTHESIS METHOD FOR DEGARELIX<br/>[FR] PROCÉDÉ DE SYNTHÈSE EN PHASE SOLIDE DE DÉGARÉLIX<br/>[ZH] 一种地加瑞克的固相合成方法
  申请人：HYBIO PHARMACEUTICAL CO LTD

  公开号：WO2021103458A1

  公开（公告）日：2021-06-03

  提供了一种地加瑞克的固相合成方法，包括：1)肽树脂的偶联：按照Fmoc固相合成方法，逐个偶联氨基酸Fmoc-D-Ala-OH、Fmoc-Pro-OH、Fmoc-Lys(Boc,iPr)-OH、Fmoc-Leu-OH、Fmoc-D-4Aph(Cbm)-OH、Fmoc-4Aph(Hmb,Hor)-OH、Fmoc-Ser(tBu)-OH、Fmoc-D-3Pal-OH、Fmoc-D-4Cpa-OH以及Fmoc-D-2Nal-OH至固相载体上；2)肽树脂N端乙酰化；3)肽树脂裂解后获得地加瑞克粗肽。
• GnRH Antagonists:  A New Generation of Long Acting Analogues Incorporating <i>p</i>-Ureido-phenylalanines at Positions 5 and 6
  作者：Guangcheng Jiang、Jacek Stalewski、Robert Galyean、John Dykert、Claudio Schteingart、Pierre Broqua、Audrey Aebi、Michel L. Aubert、Graeme Semple、Peter Robson、Karen Akinsanya、Robert Haigh、Pierre Riviere、Jerzy Trojnar、Jean Louis Junien、Jean E. Rivier

  DOI：10.1021/jm0003900

  日期：2001.2.1

  A series of antagonists of gonadotropin-releasing hormone (GnRH) of the general formula Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph/4Amf(P)-D4Aph/D4Amf( Q)-Leu-ILys-Pro-DAla-NH2 was synthesized, characterized, and screened for duration of inhibition of luteinizing hormone release in a castrated male rat assay. Selected analogues were tested in a reporter gene assay (IC50 and pA(2)) and an in vitro histamine release assay. P and Q contain urea/carbamoyl functionalities designed to increase potential intra- and intermolecular hydrogen bonding opportunities for structural stabilization and peptide/receptor interactions, respectively. These substitutions resulted in analogues with increased hydrophilicity and a lesser propensity to form gels in aqueous solution than azaline B [Ac-D2Nal-D4Cpa-n3Pal-Ser-4Aph(Atz)-D4Aph(Atz)-Leu-ILys-Pro-DAla-NH2 with Atz = 3'-amino-1H-1',2',4'-triazol-5'-yl, 5], and in some cases they resulted in a significant increase in duration of action after subcutaneous (sc) administration. Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(L-hydroorotyl)-D4Aph(carbamoyl)-Leu-ILys-Pro-DAla-NH2 (acetate salt is FE200486) (31) and eight: other congeners (20, 35, 37, 39, 41, 45-47) were identified that exhibited significantly longer duration of action than acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(Ac)-Leu-ILys-Pro-DAla-NH2] (6) when administered subcutaneously in castrated male rats at a dose of 50 mug in 100 muL Of phosphate buffer No correlation was found between retention times on a C-18 reverse phase column using a triethylammonium phosphate buffer at pH 7.0 (a measure of hydrophilicity) or affinity in an in vitro human GnRH report gene assay (pA(2)) and duration of action. FE200486 was selected for preclinical studies, and some of its properties were compared to those of other clinical candidates. In the intact rat, ganirelix, abarelix, azaline B, and FE200486 inhibited plasma testosterone for 1, 1, 14, and 57 days, respectively, at 2 mg/kg sc in 5% mannitol (injection volume = 20 muL). Based on the information that 31, 33, 35 and 37 were significantly shorter acting than acyline or azaline B after intravenous administration (100 mug/rat), we surmised that the very long duration of action of the related FE200486 (for example) was likely due to unique physicochemical properties such as solubility in aqueous milieu, comparatively low propensity to form gels, and ability to diffuse at high concentrations in a manner similar to that described for slow release formulations of peptides. Indeed, in rats injected sc with FE200486 (2 mg/kg), plasmatic concentrations of FE200486 remained above 5 ng/mL until day 41, and the time after which they dropped below 3 ng/mL and plasma LH levels started rising until full recovery was reached at day 84 with levels of FE200486 hovering around 1 ng/mL. Additionally, FE200486 was less potent at releasing histamine from isolated rat mast cells than any of the GnRH antagonists presently described in preclinical reports.
• Overcoming Chemical Challenges in the Solid-Phase Synthesis of High-Purity GnRH Antagonist Degarelix. Part 2
  作者：Ivan Guryanov、Andrea Orlandin、Angelo Viola、Barbara Biondi、Fernando Formaggio、Antonio Ricci、Walter Cabri

  DOI：10.1021/acs.oprd.9b00540

  日期：2020.2.21

  to select those which afforded both the rapid Fmoc deprotection during the solid-phase synthesis and the absence of this peculiar rearrangement. Among the bases tested, only tert-butylamine did not affect the peptide molecule and was able to perform fast Fmoc removal. The use of tert-butylamine for the synthesis of Degarelix led to a product with excellent purity and yield without a detectable amount

  在存在碱的情况下，二氢激素（Hor）残基的水解和重排导致乙内酰脲（Hyd）杂质的形成，是制造促性腺激素释放激素拮抗剂Degarelix的主要问题之一。为了找到克服该问题的有效策略，我们进行了有机碱的筛选，以选择在固相合成过程中既能快速进行Fmoc脱保护又能避免这种特殊重排的有机碱。在测试的碱基中，只有叔丁胺不影响肽分子，并且能够快速去除Fmoc。使用叔叔用于合成Degarelix的丁胺可制得纯度和产率极佳的产品，而没有可检测量的乙内酰脲杂质。因此，我们表明叔丁胺可以替代哌啶用于工业规模生产Degarelix或其他含Hor的肽类药物。