氟马西尼杂质18 | 78755-82-5

• 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: 氟马西尼杂质18
• 英文名称: methyl 8-fluoro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
• 英文别名: methyl flumazenil ester；methyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
• CAS: 78755-82-5
• 化学式: C₁₄H₁₂FN₃O₃
• 分子量: 289.266
• InChiKey: JXEPEXMMOWPOCX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  64.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  氟马西尼 、 potassium cyanide 在 乙酸乙酯 作用下， 以 甲醇 为溶剂， 反应 2.5h， 以there is obtained methyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 195°-196.5° C.的产率得到氟马西尼杂质18
  参考文献：
  名称：

  Imidazodiazepine derivatives

  摘要：

  公式为##STR1##的咪唑二氮杂苯并二氮杂环衍生物，其中A与表示为α和β的两个碳原子一起从以下组中选择：##STR2##虚线表示(a)和(b)中存在的双键，D是>C.dbd.O或>C.dbd.S，R.sup.1从以下组中选择：氰基，低烷酰基和公式--COOR.sup.4的基团，R.sup.4从甲基，乙基，异丙基和2-羟乙基的组中选择，R.sup.5从氢，三氟甲基和卤素的组中选择，R.sup.6从氢，三氟甲基，卤素和低烷基的组中选择，R.sup.2要么是氢，R.sup.3是氢或低烷基，要么R.sup.2和R.sup.3一起是三亚甲基或丙烯亚甲基，表示为γ的碳原子具有S-或R，S-构型，以及其药学上可接受的盐。它们有用于拮抗具有镇静作用的1,4-苯二氮䓬类药物的中枢抑制，肌肉松弛，共济失调，降压和呼吸抑制特性。例如，它们可以用作中毒的解毒剂，在这种情况下，过量摄入具有镇静作用的1,4-苯二氮䓬类药物，或用于缩短由这些1,4-苯二氮䓬类药物引起的麻醉。它们还可以用于抑制在其他适应症领域使用的1,4-苯二氮䓬类药物对中枢神经系统的活性，例如对血吸虫活性的1,4-苯二氮䓬类药物，例如(+)-5-(o-氯苯基)-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮䓬啶-2-酮。还提供了生产咪唑二氮杂苯并二氮杂环衍生物及其中间体的过程。

  公开号：

  US04346030A1

文献信息

• Imidazodiazepine derivatives
  申请人：Hoffman-La Roche Inc.

  公开号：US04316839A1

  公开（公告）日：1982-02-23

  Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted as .alpha. and .beta. is selected from the group consisting of ##STR2## the dotted line represents the double bond present in groups (a) and (b), D is >C.dbd.O or >C.dbd.S, R.sup.1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR.sup.4, R.sup.4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R.sup.5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R.sup.6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R.sup.2 is hydrogen and R.sup.3 is hydrogen or lower alkyl or R.sup.2 and R.sup.3 together are trimethylene or propenylene and the carbon atom denoted as .gamma. has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonizing the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillizing participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2 -one. Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.

  本发明提供了以下式子的咪唑二氮杂苯并二氮杂环衍生物：##STR1## 其中A与标记为α和β的两个碳原子一起选自以下组：##STR2## 虚线代表(a)和(b)组中存在的双键，D为>C.dbd.O或>C.dbd.S，R.sup.1选自氰基，低烷酰基和公式--COOR.sup.4的基团，R.sup.4选自甲基，乙基，异丙基和2-羟乙基，R.sup.5选自氢，三氟甲基和卤素，R.sup.6选自氢，三氟甲基，卤素和低烷基，R.sup.2为氢，R.sup.3为氢或低烷基或R.sup.2和R.sup.3一起为三亚甲基或丙烯基，标记为γ的碳原子具有S-或R，S-构型，以及其药学上可接受的盐。本发明的咪唑二氮杂苯并二氮杂环衍生物可用于拮抗具有镇静作用的1,4-苯二氮䓬类药物的中枢抑制，肌肉松弛，共济失调，降低血压和呼吸抑制特性。例如，在过量摄入具有镇静作用的1,4-苯二氮䓬类药物的中毒情况下，可以使用它们作为解毒剂，或者缩短由这些1,4-苯二氮䓬类药物引起的麻醉。它们还可用于抑制在其他适应症领域使用的1,4-苯二氮䓬类药物对中枢神经系统的活性，例如对血吸虫活性的1,4-苯二氮䓬类药物，如(+)-5-(邻氯苯基)-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮䓬啶-2-酮。本发明还提供了制备咪唑二氮杂苯并二氮杂环衍生物及其中间体的方法。
• Process for preparing imidazodiazepines
  申请人：Hoffmann-La Roche Inc.

  公开号：US04363762A1

  公开（公告）日：1982-12-14

  Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted as .alpha. and .beta. is selected from the group consisting of: ##STR2## the dotted line represents the double bond present in groups (a) and (b), D is >C.dbd.O or >C.dbd.S, R.sup.1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR.sup.4, R.sup.4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R.sup.5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R.sup.6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R.sup.2 is hydrogen and R.sup.3 is hydrogen or lower alkyl or R.sup.2 and R.sup.3 together are trimethylene or propenylene and the carbon atom denoted as .gamma. has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonising the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillising activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillising participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2 -one. Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.

  本发明涉及式（I）的咪唑二氮杂苯衍生物，其中A与表示为α和β的两个碳原子一起从以下组中选择：##STR2##其中虚线表示(a)和(b)中存在的双键，D是>C.dbd.O或>C.dbd.S，R.sup.1从以下组中选择：氰基，低烷酰基和公式--COOR.sup.4的基团，R.sup.4从甲基，乙基，异丙基和2-羟乙基的组中选择，R.sup.5从氢，三氟甲基和卤素的组中选择，R.sup.6从氢，三氟甲基，卤素和低烷基的组中选择，且R.sup.2为氢且R.sup.3为氢或低烷基，或者R.sup.2和R.sup.3一起为三亚甲基或丙烯亚甲基，表示为γ的碳原子具有S-或R，S-构型。还提供了其药学上可接受的盐，并具有对具有镇静作用的1,4-苯二氮䓬类化合物的中枢抑制、肌肉松弛、共济失调、降低血压和呼吸抑制特性的拮抗作用。例如，在过量摄入具有镇静作用的1,4-苯二氮䓬类药物的中毒情况下，它们可以用作解毒剂，或者用于缩短由这些1,4-苯二氮䓬类药物引起的麻醉。它们还可用于抑制用于其他适应症领域的1,4-苯二氮䓬类药物对中枢神经系统的活性，例如对血吸虫杀虫活性的1,4-苯二氮䓬类药物，如(+)-5-(o-氯苯基)-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮䓬啶-2-酮。还提供了制备咪唑二氮杂苯衍生物及其中间体的方法。
• Thienodiazepinone and benzodiazepinone intermediates
  申请人：Hoffmann-La Roche Inc.

  公开号：US04346033A1

  公开（公告）日：1982-08-24

  Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted as .alpha. and .beta. is selected from the group consisting of ##STR2## the dotted line represents the double bond present in groups (a) and (b), D is >C.dbd.O or >C.dbd.S, R.sup.1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR.sup.4, R.sup.4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R.sup.5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R.sup.6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R.sup.2 is hydrogen and R.sup.3 is hydrogen or lower alkyl or R.sup.2 and R.sup.3 together are trimethylene or propenylene and the carbon atom denoted as .gamma. has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonizing the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillizing participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2 -one. Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.

  本发明提供了公式## STR1 ##的咪唑二氮杂环衍生物，其中A与表示为α和β的两个碳原子一起从以下组中选择## STR2 ##点线代表(a)和(b)组中存在的双键，D是> C.dbd.O或> C.dbd.S，R.sup.1选择从氰基，低烷酰基和公式--COOR.sup.4的群中选择，其中R.sup.4选择从甲基，乙基，异丙基和2-羟乙基的群中选择，R.sup.5选择从氢，三氟甲基和卤素的群中选择，R.sup.6选择从氢，三氟甲基，卤素和低烷基的群中选择，R.sup.2为氢且R.sup.3为氢或低烷基，或R.sup.2和R.sup.3一起为三亚甲基或丙烯亚甲基，表示为γ的碳原子具有S-或R，S-构型，以及其药学上可接受的盐，用于拮抗具有镇静作用的1,4-苯二氮平具有中枢抑制，肌肉松弛，共济失调，降低血压和呼吸抑制特性。例如，它们可用作中毒情况下的解毒剂，在这种情况下，过量摄入具有镇静作用的1,4-苯二氮平参与，或用于缩短由这种1,4-苯二氮平引起的麻醉。它们还可用于抑制用于其他适应症领域的1,4-苯二氮平对中枢神经系统的活性，例如对于血吸虫杀虫作用的1,4-苯二氮平，如（+）-5-（o-氯苯基）-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮平-2-酮。还提供了制备咪唑二氮杂环衍生物及其中间体的过程。
• Process for preparing imidazodiazepine derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US04346036A1

  公开（公告）日：1982-08-24

  Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted as .alpha. and .beta. is selected from the group consisting of ##STR2## the dotted line represents the double bond present in groups (a) and (b), D is >C.dbd.O or >C.dbd.S, R.sup.1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR.sup.4, R.sup.4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R.sup.5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R.sup.6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R.sup.2 is hydrogen and R.sup.3 is hydrogen or lower alkyl or R.sup.2 and R.sup.3 together are trimethylene or propenylene and the carbon atom denoted as .gamma. has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonising the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillizing participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2 -one. Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.

  该专利介绍了公式为##STR1##的咪唑二氮杂苯并二氮䓬衍生物，其中A连同α和β表示的两个碳原子被选自以下组合：##STR2## 虚线代表(a)和(b)组中存在的双键，D为>C.dbd.O或>C.dbd.S，R.sup.1被选自氰基、低级脂肪酰基和式为--COOR.sup.4的基团，R.sup.4被选自甲基、乙基、异丙基和2-羟乙基，R.sup.5被选自氢、三氟甲基和卤素，R.sup.6被选自氢、三氟甲基、卤素和低级烷基，R.sup.2为氢，R.sup.3为氢或低级烷基，或R.sup.2和R.sup.3一起为三亚甲基或丙烯亚甲基，表示为γ的碳原子具有S-或R,S-构型，并且其药学上可接受的盐具有拮抗1,4-苯二氮䓬酮的中枢抑制、肌肉松弛、共济失调、降低血压和呼吸抑制等性质的功效，这些化合物可以用作拮抗具有镇静作用的1,4-苯二氮䓬酮中毒的解毒剂，或者缩短由这些1,4-苯二氮䓬酮诱导的麻醉时间。它们还可以用于抑制其他领域中使用的1,4-苯二氮䓬酮对中枢神经系统的活动，例如对血吸虫活性的1,4-苯二氮䓬酮（如(+)-5-(o-氯苯基)-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮䓬酮-2-酮）的活性。此外，还介绍了制备咪唑二氮杂苯并二氮䓬衍生物及其中间体的方法。
• Imidazodiazepin-Derivate, Verfahren und Zwischenprodukte zu ihrer Herstellung, diese enthaltende Arzneimittel und deren therapeutische Verwendung
  申请人：F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft

  公开号：EP0027214A1

  公开（公告）日：1981-04-22

  Imidazodiazepin-Derivate der allgemeinen Formel worin A zusammen mit den beiden mit a und β bezeichneten Kohlenstoffatomen eine der Gruppen und die gestrichelte Linie die in Fällen (a) und (b) vorliegende Doppelbindung bedeuten, DC= 0 oder C= S, R1 Cyano, niederes Alkanoyl oder einen Rest der Formel -COOR4, R4 Methyl, Aethyl, isopropyl oder 2-Hydroxyäthyl, R5 Wasserstoff, Trifluormethyl oder Halogen und R6 Wasserstoff, Trifluormethyl, Halogen oder niederes Alkyl bedeuten und entweder R'Wasserstoff und R3 Wasserstoff oder niederes Alkyl bedeuten oder R2 und R'zusammen Trimethylen oder Propenylen bedeuten und das mit y bezeichnete Kohlenstoffatom die S-oderR,S-Konfiguration aufweist, sowie pharmazeutisch annehmbare Salze davon sind neu und eignen sich zur Antagonisierung der zentral dämpfenden, muskelrelaxierenden, ataktischen, blutdrucksenkenden und atemdepressiven Eigenschaften von tranquilisierend wirksamen 1,4-Benzodiazepinen, beispielsweise als Antidot bei Intoxikationen, bei welchen übermässige Einnahme von tranquilisierend wirksamen 1,4-Benzodiazepinen beteiligt ist, zur Abkürzung einer durch solche 1,4-Benzodiazepine eingeleiteten Anaesthesie usw.; sie können auch zur Unterdrückung der Wirkungen auf das zentrale Nervensystem von in anderen Indikationsgebieten eingesetzten 1,4-Benzodiazepinen verwendet werden, z.B. von schistosomiazid wirksamen 1,4-Benzodiazepinen, wie (+)-5-(o-Chlorphenyl)-1, 3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-on. Sie können nach verschiedenen Methoden ausgehend von teilweise neuen Ausgangsstoffen hergestellt und in galenische Darreichungsformen gebracht werden.

  通式如下的咪唑二氮卓衍生物 其中 A 连同标有 a 和 β 的两个碳原子代表其中一个基团 R1 表示氰基、低级烷酰基或式 -COOR4 的基团，R4 表示甲基、乙基、异丙基或 2-羟乙基，R5 表示氢、三氟甲基或卤素，R6 表示氢、R6 表示氢、三氟甲基、卤素或低级烷基，R'表示氢，R3 表示氢或低级烷基，或 R2 和 R'一起表示三亚甲基或亚丙烯，且 y 指定的碳原子具有 S 或 R、S构型，以及它们的药学上可接受的盐是新颖的，适用于拮抗镇静性1,4-苯并二氮杂卓的中枢抑制、肌肉松弛、共济失调、抗高血压和呼吸抑制特性，例如作为涉及过量摄入镇静性1,4-苯并二氮杂卓的中毒的解毒剂，缩短这类1,4-苯并二氮杂卓引起的麻醉等；它们也可用于抑制镇静性1,4-苯并二氮杂卓的作用。它们还可用于抑制用于其他适应症的 1,4-苯并二氮杂卓的中枢神经系统效应，例如具有血吸虫活性的 1,4-苯并二氮杂卓，如 (+)-5-(o-chlorophenyl)-1, 3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one 等。 它们可以用各种方法生产，在某些情况下可以用新的起始材料生产，并可转化为 galenic 剂型。