6-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione | 78755-95-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: 6-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione
• 英文别名: 6-Fluoro-4-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione；6-fluoro-4-methyl-1,3-dihydro-1,4-benzodiazepine-2,5-dione
• CAS: 78755-95-0
• 化学式: C₁₀H₉FN₂O₂
• 分子量: 208.192
• InChiKey: NJLZFBSRXZEKNR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione 在 titanium(IV) isopropylate 、 sodium hydride 、 氯磷酸二乙酯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 propan-2-yl 7-fluoro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
  参考文献：
  名称：

  潜在的新型氟18标记放射性示踪剂，用于对GABA A受体进行成像

  摘要：

  使用示踪剂[ 11 C]氟马西尼的正电子发射断层扫描（PET）已显示出在一系列神经系统疾病和损伤状态下GABA A受体的分布和表达发生了变化。我们旨在开发一种氟18标记的PET试剂，其性能与[ 11 C]氟马西尼相当。在这项研究中，我们将目前已知的18氟标记的GABA A放射性示踪剂与新型咪唑并苯并二氮杂ze配体进行直接比较。设计并合成了新化合物的聚焦库，其中含氟部分和连接位置发生了变化。22种化合物对GABA A的体外亲和力测量受体。由于效能低，因此消除了含有氟代烷基酰胺或较长链酯基的化合物。对每种结构类型的一种化合物的氟18放射化学进行了评估，以确认以高收率进行自动放射合成是可行的。被评估的11种新化合物似乎适合作为PET示踪剂进行体内评估。

  DOI：

  10.1016/j.bmcl.2012.11.066
• 作为产物：
  描述：

  2-氨基-6-氟苯甲酸 以 1,4-二氧六环 、 二甲基亚砜 为溶剂， 反应 3.0h， 生成 6-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione
  参考文献：
  名称：

  潜在的新型氟18标记放射性示踪剂，用于对GABA A受体进行成像

  摘要：

  使用示踪剂[ 11 C]氟马西尼的正电子发射断层扫描（PET）已显示出在一系列神经系统疾病和损伤状态下GABA A受体的分布和表达发生了变化。我们旨在开发一种氟18标记的PET试剂，其性能与[ 11 C]氟马西尼相当。在这项研究中，我们将目前已知的18氟标记的GABA A放射性示踪剂与新型咪唑并苯并二氮杂ze配体进行直接比较。设计并合成了新化合物的聚焦库，其中含氟部分和连接位置发生了变化。22种化合物对GABA A的体外亲和力测量受体。由于效能低，因此消除了含有氟代烷基酰胺或较长链酯基的化合物。对每种结构类型的一种化合物的氟18放射化学进行了评估，以确认以高收率进行自动放射合成是可行的。被评估的11种新化合物似乎适合作为PET示踪剂进行体内评估。

  DOI：

  10.1016/j.bmcl.2012.11.066

文献信息

• Imidazodiazepines
  申请人：Hoffmann-La Roche Inc.

  公开号：US05665718A1

  公开（公告）日：1997-09-09

  The invention relates to compounds of the formula ##STR1## wherein A together with the two carbon atoms denoted by .alpha. and .beta. is one of the residues ##STR2## Q is one of the residues ##STR3## R.sup.1 and R.sup.2 each independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower hydroxyalkyl, lower alkoxy-lower alkyl, (C.sub.3 -C.sub.6)-cycloalkyl, (C.sub.3 -C.sub.6)-cycloalkyl-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl or aryl-lower alkyl or together with the nitrogen atom are a 5- to 8-membered membered heterocycle optionally containing a further hetero atom or a fused benzene ring, R.sup.3 is hydrogen and R.sup.4 is lower alkyl or R.sup.3 and R.sup.4 together are dimethylene or trimethylene and R.sup.5 and R.sup.6 each independently are hydrogen, halogen, trifluoromethyl, lower alkoxy or nitro, the compounds of formula I having the (S) configuration with reference to the carbon atom denoted by .gamma. when R.sup.3 and R.sup.4 together are dimethylene or trimethylene, and pharmaceutically acceptable acid addition salts thereof. These compounds and salts have pronounced anxiolytic, anticonvulsant, muscle relaxant and sedative-hypnotic properties.

  本发明涉及具有以下公式的化合物：##STR1## 其中A与标记为α和β的两个碳原子共同构成##STR2##中的一个残基；Q是##STR3##中的一个残基；R1和R2各自独立地为氢、低级烷基、低级烯基、低级炔基、低级羟基烷基、低级烷氧基-低级烷基、(C3-C6)-环烷基、(C3-C6)-环烷基-低级烷基、氨基-低级烷基、低级烷基氨基-低级烷基、二低级烷基氨基-低级烷基或芳基-低级烷基，或者与氮原子共同形成一个含有另外一种杂原子或一个融合的苯环的5至8成员的杂环；R3是氢，R4是低级烷基，或者R3和R4共同是亚甲基或三亚甲基；R5和R6各自独立地为氢、卤素、三氟甲基、低级烷氧基或硝基；当R3和R4共同是亚甲基或三亚甲基时，相对于标记为γ的碳原子，本发明的公式I化合物具有(S)构型，以及它们的药物可接受的酸加成盐。这些化合物和盐具有显著的抗焦虑、抗惊厥、肌肉松弛和镇静催眠性质。
• Novel benzodiazepine receptor partial agonists: oxadiazolylimidazobenzodiazepines
  作者：Frank Watjen、Raymond Baker、Mogens Engelstoff、Richard Herbert、Angus MacLeod、Anthony Knight、Kevin Merchant、Jonathan Moseley、John Saunders、Christopher J. Swain、Erik Wong、James P. Springer

  DOI：10.1021/jm00130a010

  日期：1989.10.1

  The synthesis and biochemical evaluation of a series of oxadiazole derivatives of imidazobenzodiazepines related to the benzodiazepine antagonist Ro 15-1788 (2a) are reported. Although the oxadiazole ring is seen as an isosteric replacement for the ester linkage, significant differences in structure-activity trends were observed. Specifically, oxadiazoles 9-12 invariably had increased receptor efficacy

  报道了一系列与苯二氮卓拮抗剂Ro 15-1788（2a）有关的咪唑基苯并二氮杂卓的恶二唑衍生物的合成和生化评估。尽管恶二唑环被看作是酯键的等排替代物，但观察到结构活性趋势上的显着差异。具体而言，相对于相应的酯，恶二唑9-12始终具有增加的受体功效（通过测量GABA位移证明）。另外，与经典的激动剂如地西epa形成鲜明对比的是，通过7-而不是8-卤素取代基增强了对苯并二氮杂receptor受体的亲和力。根据最初基于2a的X射线结构的六点受体结合模型讨论了结果。为了比较，确定了分别具有6-氧代和6-苯基基团的两种代表性恶二唑衍生物10h和12o的晶体结构，并将数据纳入了改良的结合模型中，以说明这些化合物的更高功效。结论是2a的拮抗行为取决于酯羰基氧的氢键受体性质，而对于恶二唑系列，该位点位于咪唑氮上。
• 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.

  咪唑二氮杂环己烯衍生物的公式为##STR1##其中A与两个碳原子α和β一起从##STR2##中选择，虚线代表(a)和(b)中存在的双键，D为>C.dbd.O或>C.dbd.S，R.sup.1从氰基，较低的烷酰基和公式--COOR.sup.4的基团中选择，R.sup.4从甲基，乙基，异丙基和2-羟乙基中选择，R.sup.5从氢，三氟甲基和卤素中选择，R.sup.6从氢，三氟甲基，卤素和较低烷基中选择，R.sup.2为氢，R.sup.3为氢或较低烷基，或者R.sup.2和R.sup.3一起为三甲亚基或丙烯亚基，所述的碳原子γ具有S-或R,S-构型，及其药学上可接受的盐，用于对抗具有镇静活性的1,4-苯二氮杂环己烷的中枢抑制、肌肉松弛、共济失调、降低血压和呼吸抑制特性。它们可以用作例如，在过量摄入具有镇静活性的1,4-苯二氮杂环己烷的中毒情况下的解毒剂，或者缩短由这些1,4-苯二氮杂环己烷引起的麻醉。它们还可用于抑制其他适应领域中使用的1,4-苯二氮杂环己烷对中枢神经系统的活性，例如对于片尾蚴活性的1,4-苯二氮杂环己烷，如(+)-5-(邻氯苯基)-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮杂环己烷-2-酮。还提供了生产咪唑二氮杂环己烯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。