1,3-dihydro-5-methyl-3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one | 157837-04-2

• 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: 1,3-dihydro-5-methyl-3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one
• 英文别名: (5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamic acid benzyl ester；(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-methyl-1H-1,4-benzodiazepin-2-one；3-[(benzyloxycarbonyl)amino]-5-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one；phenylmethyl [2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate；(5-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamic acid benzyl ester；Phenylmethyl [2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepin-3yl]carbamate；benzyl N-(5-methyl-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl)carbamate
• CAS: 157837-04-2
• 化学式: C₁₈H₁₇N₃O₃
• 分子量: 323.351
• InChiKey: AXWZQHIFAVSNPX-UHFFFAOYSA-N

物化性质

• 沸点：
  561.2±50.0 °C(Predicted)
• 密度：
  1.28±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  79.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1,3-dihydro-5-methyl-3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one 在 氢溴酸 、 溶剂黄146 作用下， 反应 0.5h， 以857 mg的产率得到3-氨基-5-甲基-1,3-二氢-2H-1,4-苯并二氮杂卓-2-酮
  参考文献：
  名称：

  1,4-Benzodiazepines as Inhibitors of Respiratory Syncytial Virus

  摘要：

  Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as a serious threat to patient groups with poorly functioning immune systems. Our approach to finding a novel inhibitor of this virus was to screen a 20 000-member diverse library in a whole cell XTT assay. Parallel assays were carried out in the absence of virus in order to quantify any associated cell toxicity. This identified 100 compounds with IC50's less than 50 mu M. A-33903 (18), a 1,4-benzodiazepine analogue, was chosen as the starting point for lead optimization. This molecule was moderately active and demonstrated good pharmacokinetic properties. The most potent compounds identified from this work were A-58568 (47), A-58569 (44), and A-62066 (46), where modifications to the aromatic substitution enhanced potency, and A-58175 (42), where the amide linker was modified.

  DOI：

  10.1021/jm051185t
• 作为产物：
  描述：

  (Benzotriazol-1-yl-chlorocarbonyl-methyl)-carbamic acid benzyl ester 在 N-甲基吗啉 、 氨 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 36.0h， 生成 1,3-dihydro-5-methyl-3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one
  参考文献：
  名称：

  1,4-Benzodiazepines as Inhibitors of Respiratory Syncytial Virus

  摘要：

  Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as a serious threat to patient groups with poorly functioning immune systems. Our approach to finding a novel inhibitor of this virus was to screen a 20 000-member diverse library in a whole cell XTT assay. Parallel assays were carried out in the absence of virus in order to quantify any associated cell toxicity. This identified 100 compounds with IC50's less than 50 mu M. A-33903 (18), a 1,4-benzodiazepine analogue, was chosen as the starting point for lead optimization. This molecule was moderately active and demonstrated good pharmacokinetic properties. The most potent compounds identified from this work were A-58568 (47), A-58569 (44), and A-62066 (46), where modifications to the aromatic substitution enhanced potency, and A-58175 (42), where the amide linker was modified.

  DOI：

  10.1021/jm051185t

文献信息

• Benzodiazepine derivatives, compositions containing them and their use
  申请人：Merck Sharp & Dohme Ltd.

  公开号：US05451582A1

  公开（公告）日：1995-09-19

  Compounds of formula (I), and salts and prodrugs thereof ##STR1## wherein: R.sup.1 is H, certain optionally substituted C.sub.1.6 alkyl, or C.sub.3-7 cycloalkyl; R.sup.2 is (CH.sub.2).sub.q -tetrazolyl optionally substituted in the tetrazole ring by C.sub.1-4 alkyl, (CH.sub.2).sub.q -imidazolyl (where q is 0, 1, 2 or 3), CONHSO.sub.2 R.sup.9, SO.sub.2 NHCOR.sup.9 (where R.sup.9 is C.sub.1-6 alkyl, optionally substituted aryl or trifluoromethyl). SO.sub.2 NHR.sup.10 (where R.sup.10 is a nitrogen containing heterocycle), cyclopropyl or (CH.sub.2), CO.sub.2 H, where n is 1 or 2; R.sup.3 is C.sub.1-6 alkyl, halo or NR.sup.6 R.sup.7 ; R.sup.4 is C.sub.1-7 straight or branched chain alkyl; and x is 0, 1, 2 or 3; are CCK and/or gastrin receptor antagonists. They and compositions thereof are useful in therapy.

  式(I)的化合物，以及其盐和前药##STR1##其中：R.sup.1是H，某些可选择地取代的C.sub.1.6烷基，或C.sub.3-7环烷基；R.sup.2是(CH.sub.2).sub.q-四唑基，四唑环可选择地被C.sub.1-4烷基取代，(CH.sub.2).sub.q-咪唑基（其中q为0, 1, 2或3），CONHSO.sub.2 R.sup.9，SO.sub.2 NHCOR.sup.9（其中R.sup.9是C.sub.1-6烷基，可选择地取代的芳基或三氟甲基）。SO.sub.2 NHR.sup.10（其中R.sup.10是含氮杂环），环丙基或(CH.sub.2)，CO.sub.2 H，其中n为1或2；R.sup.3是C.sub.1-6烷基，卤素或NR.sup.6 R.sup.7；R.sup.4是C.sub.1-7直链或支链烷基；x为0, 1, 2或3；均为CCK和/或胃泌素受体拮抗剂。它们及其组合物在治疗中有用。
• Benzodiazepine derivatives as app modulators
  申请人：——

  公开号：US20040082572A1

  公开（公告）日：2004-04-29

  A novel class of 1,4- and 1,5-benzodiazepines of formula (I) is disclosed. The compounds modulate the processing of amyloid precursor protein by &ggr;-secretase, and hence find use in the treatment or prevention of conditions associated with the deposition of &bgr;-amyloid, such as Alzheimer's disease. 1

  公开了一种式(I)的新型1,4-和1,5-苯二氮平类化合物。这些化合物调节&ggr;-分泌酶对淀粉样前体蛋白的加工作用，因此可用于治疗或预防与&bgr;-淀粉样蛋白沉积相关的疾病，如阿尔茨海默病。
• 1,4-benzodiazepinones and their uses as CCK antagonists
  申请人：Fujisawa Pharmaceutical Co., Ltd.

  公开号：US20020183313A1

  公开（公告）日：2002-12-05

  Benzodiazepine derivatives of the formula: 1 wherein R 1 is heterocyclic(lower)alkyl which may have one or more suitable substituent(s), etc., R 2 is lower alkyl, etc., R 3 is indolyl, etc., R 4 is hydrogen, etc., or a pharmaceutically acceptable salt thereof, which are useful as a medicament.

  公式为1的苯二氮平衍生物，其中R1为杂环（较低）烷基，可以有一个或多个合适的取代基等，R2为较低的烷基等，R3为吲哚基等，R4为氢等，或其药学上可接受的盐，可用作药物。
• Benzodiazepinones
  申请人：Glaxo Group Limited

  公开号：US05569654A1

  公开（公告）日：1996-10-29

  Compounds of general formula (I) ##STR1## and physiologically acceptable salts thereof; wherein R.sub.1 represents CH.sub.2 CONR.sub.5 R.sub.6 or CH.sub.2 COR.sub.7 ; R.sub.2 represents a phenyl group optionally substituted by 1 or 2 substituents selected from halogen, alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, amino, substituted amino, hydroxy, alkoxy, methylenedioxy, alkoxycarbonyl, oxazolyl or oxadiazolyl; A represents a C.sub.1-4 straight or branched alkylene chain; R.sub.3 and R.sub.4 independently represent hydrogen or C.sub.1-4 alkyl or R.sub.3 and R.sub.4 together with the nitrogen atom to which they are attached form a saturated 5-7 membered heterocyclic ring, which ring may contain an additional heteroatom selected from oxygen, sulphur or nitrogen; R.sub.5 represents hydrogen or C.sub.1-4 alkyl; R.sub.6 represents C.sub.1-4 alkyl or phenyl, optionally substituted by halogen, or R.sub.5 and R.sub.6 together with the nitrogen atom to which they are attached represent a saturated 5 to 7 membered heterocyclic ring which may be optionally substituted by 1 or 2 methyl groups or fused to a benzene ring; R.sub.7 represents a group selected from C.sub.1-4 alkyl, or optionally substituted phenyl; R.sub.8 represents hydrogen or a halogen atom; n is zero, 1 or 2, are antagonists of gastrin and CCK.

  通式(I)的化合物及其生理上可接受的盐；其中R.sub.1代表CH.sub.2CONR.sub.5R.sub.6或CH.sub.2COR.sub.7；R.sub.2代表苯基，可选地被1或2个取代基所取代，所述取代基选自卤素、烷基、硝基、氰基、三氟甲基、三氟甲氧基、烷基硫基、烷基亚砜基、烷基磺酰基、氨基、取代氨基、羟基、烷氧基、亚甲二氧基、烷氧羰基、噁唑基或噻二唑基；A代表C.sub.1-4直链或支链烷基链；R.sub.3和R.sub.4独立地代表氢或C.sub.1-4烷基或R.sub.3和R.sub.4与它们所连接的氮原子一起形成饱和的5-7元杂环环，所述环可能含有一个额外的杂原子，所述杂原子选自氧、硫或氮；R.sub.5代表氢或C.sub.1-4烷基；R.sub.6代表C.sub.1-4烷基或苯基，可选地被卤素取代，或R.sub.5和R.sub.6与它们所连接的氮原子一起表示饱和的5到7元杂环环，所述环可以被1或2个甲基基团取代，或与苯环融合；R.sub.7代表选自C.sub.1-4烷基或可选地取代的苯基的基团；R.sub.8代表氢或卤素原子；n为零、1或2，是胃泌素和CCK的拮抗剂。
• Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with decreased hydrophobicity
  作者：Yasuyuki Kawanishi、Shoichi Ishihara、Tadahiko Tsushima、Sanji Hagishita、Michio Ishikawa、Yasunobu Ishihara

  DOI：10.1016/s0968-0896(97)00074-6

  日期：1997.7

  In order to study structure-activity relationships of the previously reported dual histamine H-2 and gastrin receptor antagonists and also to improve their low oral absorbability, we tried two chemical modifications. One tried to decrease the high hydrophobicity of the parent hybrid compounds to an appropriate level by incorporating a hydrophilic group into the molecule and the other by replacing the more hydrophobic groups with less hydrophobic ones. The former compounds (type I) involved hybrid compounds with a hydroxyl group at a position of a spacer, a piperidine moiety of H(2)A, or a phenyl ring at the C-5 of the benzodiazepine skeleton as well as those with a free carboxyl group in the piperidine moiety of H(2)A. The latter (type II) involved hybrid compounds with the C-5-phenyl group replaced with either a methyl group or hydrogen atom. Among them, only a type I compound, (2-[3-(3-piperidin-1-ylmethylphenoxy)propylcarbamoyl]ethylcarbamoyl}methyl)carbamic acid 3-3-[5-(3-hydroxyphenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]ureido}benzyl ester (18), showed potent dual histamine H-2 and gastrin receptor antagonistic activity, whereas others resulted in a significant decrease of histamine H-2 receptor antagonistic activity. The in vivo gastric acid antisecretory activity of 18 evaluated by Schild's rat method, however, did not suggest any notable improvement in oral absorbability. (C) 1997 Elsevier Science Ltd.