瑞米唑仑 | 308242-62-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 中文名称: 瑞米唑仑
• 中文别名: 瑞马唑仑
• 英文名称: Remimazolam
• 英文别名: methyl 3-[(4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate；CNS 7056；methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
• CAS: 308242-62-8
• 化学式: C₂₁H₁₉BrN₄O₂
• 分子量: 439.311
• InChiKey: CYHWMBVXXDIZNZ-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  69.4
• 氢给体数：
  0
• 氢受体数：
  5

ADMET

代谢

雷米马唑仑似乎不会通过肝脏细胞色素P450酶进行生物转化，也不会诱导或抑制这些酶。它的主要代谢途径是通过肝脏羧酸酯酶-1（CES1）水解，生成无活性的CNS7054代谢物，然后在进行葡萄糖醛酸化和羟基化之后排出体外。与母药相比，CNS7054对GABA(A)受体的亲和力降低了300倍。

Remimazolam does not appear to undergo biotransformation via hepatic cytochrome P450 enzymes, nor does it induce or inhibit these enzymes. Its primary route of metabolism is hydrolysis via hepatic carboxylesterase-1 (CES1) to yield the inactive CNS7054 metabolite, which then undergoes glucuronidation and hydroxylation prior to elimination. CNS7054 possesses a 300-fold lesser affinity for GABA(A) receptors as compared to the parent drug.

来源:DrugBank

毒理性

• 肝毒性

雷米马唑仑，像其他静脉注射的苯二氮䓬类药物一样，并未与血清ALT升高有关联，并且没有报告出现临床上明显的雷米马唑仑引起的肝损伤。有报道称口服苯二氮䓬类药物，包括阿普唑仑、氯氮䓬、氯硝西泮、地西泮、氟硝西泮和三唑仑，罕见出现临床上明显的肝损伤。苯二氮䓬类药物引起的急性肝损伤的临床模式通常仅在连续或间歇治疗1至6个月后出现，且损伤模式通常为胆汁淤积型。苯二氮䓬类药物引起的损伤通常为轻至中度严重。发热和皮疹不常见，自身抗体的形成也不常见。

Remimazolam, like other intravenously administered benzodiazepines, has not been associated with serum ALT elevations and no instances of clinically apparent liver injury from remimazolam have been reported. Rare cases of clinically apparent liver injury have been reported with oral benzodiazepines including alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam and triazolam. The clinical pattern of acute liver injury from benzodiazepines usually arises only after 1 to 6 months of continuous or intermittent therapy and the pattern of injury is typically cholestatic. The injury from benzodiazepine is usually mild-to-moderate in severity. Fever and rash are uncommon as is autoantibody formation.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：目前没有关于哺乳期间使用雷米马唑仑的信息。由于该药作用时间非常短，建议哺乳母亲在服药后5小时内泵奶并丢弃。特别是在哺乳新生儿或早产儿时，可能更愿意选择其他药物。 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：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the use of remimazolam during breastfeeding. Because it is very short acting, it is recommended that nursing mothers pump and discard breast milk for 5 hours after a dose. An alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

雷米马唑仑在血浆中与蛋白质的结合率大于91%，主要与血清白蛋白结合。

Remimazolam is >91% protein-bound in plasma, primarily to serum albumin.

来源:DrugBank

吸收、分配和排泄

• 吸收

静脉给药0.01至0.5 mg/kg后，Cmax和AUC0-∞分别为189至6,960 ng/mL和12.1至452 ng∙h/mL，似乎与剂量成正比。无效代谢物CNS7054的Tmax大约为20-30分钟，其AUC0-∞范围为231至7,090 ng∙h/mL。

The Cmax and AUC0-inf following intravenous administration of 0.01 to 0.5 mg/kg were 189 to 6,960 ng/mL and 12.1 to 452 ng∙h/mL, respectively, and appear to be relatively dose proportional. The Tmax of the inactive CNS7054 metabolite is approximately 20-30 minutes and its AUC0-inf ranges from 231 to 7,090 ng∙h/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在行结肠镜检查的患者中，大约0.003%的给药剂量以未改变的原药形式从尿液中排出，而50-60%以CNS7054的形式从尿液中排出。在健康受试者中，超过80%的给药剂量以CNS7054的形式从尿液中排出。

In patients undergoing colonoscopy, approximately 0.003% of the administered dose is excreted in the urine as unchanged parent drug and 50-60% is excreted in the urine as CNS7054. In healthy subjects, >80% of the administered dose is excreted in the urine as CNS7054.

来源:DrugBank

吸收、分配和排泄

• 分布容积

分布容积大约为0.76 - 0.98 L/kg。

The volume of distribution is approximately 0.76 - 0.98 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

瑞马唑仑的清除率大约为24-75 L/h，且与体重无关。

The clearance of remimazolam is approximately 24 - 75 L/h and is independent of body weight.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  瑞米唑仑 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 0.17h， 以2.5 g的产率得到
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF REMIMAZOLAM AND SOLID STATE FORMS OF REMIMAZOLAM SALTS
  [FR] PROCÉDÉ DE PRÉPARATION DE RÉMIMAZOLAM ET FORMES À L'ÉTAT SOLIDE DE SELS DE RÉMIMAZOLAM

  摘要：

  本公开涉及新型用于制备短效苯二氮卓类药物的工艺，以及该工艺中的新型中间体。更具体地，该公开涉及用于制备甲基3-[(4S)-8-溴-1-甲基-6-(吡啶-2-基)-4H-咪唑[1,2-a][1,4]苯二氮卓-4-基]丙酸甲酯，通常称为雷米咪唑的工艺和中间体。本公开还涉及雷米咪唑盐的固态形式、其制备工艺、药物配方/组合物以及使用方法。

  公开号：

  WO2018148361A1
• 作为产物：
  描述：

  methyl 3-((S)-2-(2,2-dimethoxypropylamino)-7-bromo-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propanoate 在 盐酸 作用下， 以 甲醇 为溶剂， 以16.6 g的产率得到瑞米唑仑
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF REMIMAZOLAM AND SOLID STATE FORMS OF REMIMAZOLAM SALTS
  [FR] PROCÉDÉ DE PRÉPARATION DE RÉMIMAZOLAM ET FORMES À L'ÉTAT SOLIDE DE SELS DE RÉMIMAZOLAM

  摘要：

  本公开涉及新型用于制备短效苯二氮卓类药物的工艺，以及该工艺中的新型中间体。更具体地，该公开涉及用于制备甲基3-[(4S)-8-溴-1-甲基-6-(吡啶-2-基)-4H-咪唑[1,2-a][1,4]苯二氮卓-4-基]丙酸甲酯，通常称为雷米咪唑的工艺和中间体。本公开还涉及雷米咪唑盐的固态形式、其制备工艺、药物配方/组合物以及使用方法。

  公开号：

  WO2018148361A1

文献信息

• OXIDATION REACTION EXCELLENT IN CONVERSION RATE
  申请人：PAION UK LIMITED

  公开号：US20160009680A1

  公开（公告）日：2016-01-14

  A process for preparing 3-[(S)-7-bromo-2-(2-oxo-propylamino)-5-pyridin-2-yl-3H-1,4,-benzodiazepin-3-yl]propionic acid methyl ester at a high conversion rate with good reproducibility by oxidizing 3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid methyl ester in the presence of an oxidation catalyst is provided by defining the ammonium ion content of 3-[(S)-7-bromo-2-(2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid methyl ester.

  提供一种通过在氧化催化剂存在下氧化3-[(S)-7-溴-2-(2-羟基丙基氨基)-5-吡啶-2-基-3H-苯并二氮杂环-3-基]丙酸甲酯，以高转化率和良好的可重复性制备3-[(S)-7-溴-2-(2-氧代丙基氨基)-5-吡啶-2-基-3H-1,4-苯并二氮杂环-3-基]丙酸甲酯的方法，通过确定3-[(S)-7-溴-2-(2-羟基丙基氨基)-5-吡啶-2-基-3H-苯并二氮杂环-3-基]丙酸甲酯中铵离子含量实现。
• [EN] METHOD FOR PREPARING 3-[(3S)-7-BROMO-2-OXO-5-(PYRIDIN-2-YL)-2,3-DIHYDRO-1H-[1,4]-BENZODIAZEPIN-3-YL] PROPIONIC ACID METHYL ESTER, AND COMPOUNDS USEFUL IN THAT METHOD<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ESTER MÉTHYLIQUE D'ACIDE 3-[(3S)-7-BROMO-2-OXO-5-(PYRIDIN-2-YL)-2,3-DIHYDRO-1H-[1,4]-BENZODIAZÉPIN-3-YL] PROPIONIQUE, ET COMPOSÉS UTILES DANS CE PROCÉDÉ
  申请人：MOEHS IBERICA SL

  公开号：WO2019020790A1

  公开（公告）日：2019-01-31

  The present invention relates to a method for preparing 3-[(3S)-7- bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-IH-[l,4]-benzodiazepin-3-yl] propionic acid methyl ester from (2-amino-5-bromo-phenyl)-pyridin-2- yl-methanone. The present invention also relates to new compounds useful as intermediates in that method, methyl (4S)-4-amino-5-[4- bromo-2-(pyridin-2-carbonyl)anilino]-5-oxo-pentanoate hydrobromide salt and methyl (4S)-4-(benzyloxycarbonylamino)-5-[4-bromo-2- (pyridin-2-carbonyl)anilino]-5-oxo-pentanoate.

  本发明涉及一种从(2-氨基-5-溴苯基)-吡啶-2-基甲酮制备3-[(3S)-7-溴-2-氧-5-(吡啶-2-基)-2,3-二氢-IH-[1,4]-苯二氮杂环己-3-基]丙酸甲酯的方法。本发明还涉及作为该方法中间体有用的新化合物，即甲酸甲酯(4S)-4-氨基-5-[4-溴-2-(吡啶-2-甲酰基)苯胺基]-5-氧代-戊酸氢溴酸盐和甲酸甲酯(4S)-4-(苄氧羰基氨基)-5-[4-溴-2-(吡啶-2-甲酰基)苯胺基]-5-氧代-戊酸甲酯。
• [EN] METHOD FOR PREPARING 3-[(4S)-8-BROMO-1-METHYL-6-(PYRIDIN-2-YL)-4H-IMIDAZO[1,2-A][1,4]BENZODIAZEPIN-4-YL]-PROPIONIC ACID METHYL ESTER, AND COMPOUNDS USEFUL IN SAID METHOD<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ESTER MÉTHYLIQUE D'ACIDE 3-[(4S)-8-BROMO-1-MÉTHYL-6-(PYRIDIN-2-YL)-4H-IMIDAZO[1,2-A][1,4]BENZODIAZÉPIN-4-YL]-PROPIONIQUE, ET COMPOSÉS UTILES DANS LEDIT PROCÉDÉ
  申请人：MOEHS IBERICA SL

  公开号：WO2019072944A1

  公开（公告）日：2019-04-18

  The present invention relates to a method for preparing 3- [ ( 4S ) -8-bromo-l-methyl-6- (pyridin-2-yl ) -4H-imidazo [1,2- a] [ 1, 4 ] benzodiazepin-4-yl ] -propionic acid methyl ester starting from 3- [ (3S) -7-bromo-2-oxo-5- (pyridin-2-yl ) -2, 3-dihydro-lH- [ 1, 4 ] -benzodiazepin-3-yl ] propionic acid methyl ester, and novel compounds useful as intermediates in said method, i.e., (3S) -3- [ 7-bromo-2- ( 2, 2-dimethoxypropylamino ) -5-pyridin-2-yl-3H- benzo [e] [ 1, 4 ] diazepin-3-yl ] propionic acid methyl ester.

  本发明涉及一种制备3-[(4S)-8-溴-1-甲基-6-(吡啶-2-基)-4H-咪唑[1,2-a][1,4]苯二氮杂环己酮-4-基]-丙酸甲酯的方法，从3-[(3S)-7-溴-2-氧代-5-(吡啶-2-基)-2,3-二氢-1H-[1,4]-苯并二氮杂环己酮-3-基]-丙酸甲酯出发，以及在该方法中作为中间体有用的新化合物，即(3S)-3-[7-溴-2-(2,2-二甲氧基丙胺基)-5-吡啶-2-基-3H-苯并[e][1,4]二氮杂环己酮-3-基]-丙酸甲酯。
• Process for preparing 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4 H-imidazo[1,2-a][1,4]benzodiazepine-4-yl] propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process
  申请人：PAION UK Limited

  公开号：EP2305647A1

  公开（公告）日：2011-04-06

  The invention concerns a new process for preparing 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]-propionic acid methyl ester or 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester benzene sulfonate (P) which comprises reacting 3-[(S)-7-bromo-2-((R and/or S)-2-hydroxy-propylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]-propionic acid methyl ester of formula (EM) with an oxidizing agent and optionally treating the reaction product under acidic conditions, such as to produce the compound of formula (F) or the compound (P), and new compounds useful as starting material or as intermediate for performing that process.

  该发明涉及一种新的制备3-[(4S)-8-溴-1-甲基-6-(2-吡啶基)-4H-咪唑[1,2-a][1,4]苯并二氮平-4-基]-丙酸甲酯或3-[(4S)-8-溴-1-甲基-6-(2-吡啶基)-4H-咪唑[1,2-a][1,4]苯并二氮平-4-基]-丙酸甲酯苯磺酸盐（P）的新工艺，包括将式（EM）的3-[(S)-7-溴-2-((R和/或S)-2-羟基丙基氨基)-5-吡啶-2-基-3H-苯并[e][1,4]二氮平-3-基]-丙酸甲酯与氧化剂反应，可选择在酸性条件下处理反应产物，从而产生式（F）或化合物（P），以及用作该过程的起始物或中间体的新化合物。
• [EN] PROCESS FOR PREPARING 3-[(4S)-8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZOL[1,2-A][1,4]BENZODIAZEPINE-4-YL]PROPIONIC ACID METHYL ESTER OR THE BENZENE SULFONATE SALT THEREOF, AND COMPOUNDS USEFUL IN THAT PROCESS<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ESTER MÉTHYLIQUE DE L'ACIDE 3-[(4S)-8-BROMO-1-MÉTHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1,2-A][1,4]BENZODIAZÉPIN-4-YL]PROPIONIQUE OU DU SEL DE TYPE BENZÈNESULFONATE DE CELUI-CI ET COMPOSÉS UTILES DANS CE PROCÉDÉ
  申请人：PAION UK LTD

  公开号：WO2011032692A1

  公开（公告）日：2011-03-24

  The invention concerns a new process for preparing 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]-propionic acid methyl ester 3-[(4S)-8-bromo-1 -methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester benzene sulfonate (P) which comprises reacting 3-[(S)-7-bromo-2-((R and/or S)-2-hydroxy-propylamino)-5-pyridin-2- yl-3H-benzo[e][1,4]diazepin-3-yl]-propionic acid methyl ester of formula (EM) with an oxidizing agent and optionally treating the reaction product under acidic conditions, such as to produce the compound of formula (F) or the compound (P), and new compounds useful as starting material or as intermediate for performing that process.

  本发明涉及一种制备3-[(4S)-8-溴-1-甲基-6-(2-吡啶基)-4H-咪唑[1,2-a][1,4]苯并二氮平-4-基]-丙酸甲酯3-[(4S)-8-溴-1-甲基-6-(2-吡啶基)-4H-咪唑[1,2-a][1,4]苯并二氮平-4-基]丙酸甲酯苯磺酸盐（P）的新工艺，包括将式（EM）的3-[(S)-7-溴-2-((R和/或S)-2-羟基-丙基氨基)-5-吡啶-2-基-3H-苯并[e][1,4]二氮平-3-基]-丙酸甲酯与氧化剂反应，可选地在酸性条件下处理反应产物，以产生式（F）或化合物（P），以及作为执行该过程的起始物或中间体有用的新化合物。