Dipyridodiazepinone deriv. 37 | 135795-25-4

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: Dipyridodiazepinone deriv. 37
• 英文别名: 2-cyclopropyl-5-methoxy-9-methyl-2,4,9,15-tetrazatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-10-one
• CAS: 135795-25-4
• 化学式: C₁₆H₁₆N₄O₂
• 分子量: 296.329
• InChiKey: NWGYHPLUCAMQRY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  58.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Dipyridodiazepinone deriv. 37 在 bis-triphenylphosphine-palladium(II) chloride 、 四丁基氟化铵 、 氢溴酸 、 溶剂黄146 、 N,N-二异丙基乙胺 、 lithium chloride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 11-Cyclopropyl-5,11-dihydro-5-methyl-2-(3-pyrrolyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one
  参考文献：
  名称：

  Novel Non-nucleoside Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase. 4. 2-Substituted Dipyridodiazepinones as Potent Inhibitors of Both Wild-Type and Cysteine-181 HIV-1 Reverse Transcriptase Enzymes

  摘要：

  The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT), An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wildtype and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 8-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.

  DOI：

  10.1021/jm00024a010
• 作为产物：
  描述：

  5-氨基-2-甲氧基吡啶 在 吡啶 、 溴 、 sodium acetate 、 sodium hydride 、 二甲基亚砜 作用下， 以 二氯甲烷 、 溶剂黄146 、 xylene 为溶剂， 反应 1.16h， 生成 Dipyridodiazepinone deriv. 37
  参考文献：
  名称：

  Novel Non-nucleoside Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase. 4. 2-Substituted Dipyridodiazepinones as Potent Inhibitors of Both Wild-Type and Cysteine-181 HIV-1 Reverse Transcriptase Enzymes

  摘要：

  The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT), An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wildtype and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 8-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.

  DOI：

  10.1021/jm00024a010

文献信息

• [EN] PROCESS FOR PREPARATION OF PYRIMIDINE DERIVATIVES<br/>[FR] PROCEDE DE PREPARATION DE DERIVES DE PYRIMIDINE
  申请人：YUHAN CORPORATION

  公开号：WO1997042186A1

  公开（公告）日：1997-11-13

  (EN) The present invention relates, first to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by formula (I) and its acid addition salts, second, to a process for preparation of an intermediate for preparing the compound (I), and, third, to a novel intermediate compound. More specifically, the present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl,1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by formula (I), and its acid addition salts by reacting a pyrimidine derivative represented by formula (II-A), in which Hal represents a halogen, with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by formula (III), second, to a process for preparating of the pyrimidine derivative of formula (II-A) and the compound of formula (III); and, third, to a novel intermediate compound including the pyrimidine derivative of formula (II-A).(FR) L'invention concerne premièrement un procédé de préparation de 5,6-diméthyl-2-(4-fluorophénylamino)-4-(1-méthyl-1,2,3,4-tétrahydroisoquinoléin-2-yl)pyrimidine représenté par la formule (I) et ses sels d'addition d'acide, deuxièmement un procédé de préparation d'un intermédiaire pour la préparation du composé de formule (I) et troisièmement un nouveau composé intermédiaire. L'invention porte plus spécifiquement, premièrement sur un procédé de préparation de 5,6-diméthyl-2-(4-fluorophénylamino)-4(1-méthyl-1,2,3,4-tétrahydroisoquinoléin-2-yl)pyrimidine représenté par la formule (I) et sur ses sels d'addition d'acide par la mise en réaction d'un dérivé de pyrimidine représenté par la formule (II-A), dans laquelle Hal représente un halogène, avec 1-méthyl-1,2,3,4-tétrahydroisoquinoléine représenté par le formule (III). Elle se rapporte deuxièmement à un procédé de préparation du dérivé de pyrimidine de formule (II-A) et du composé de formule (III), et troisièmement à un nouveau composé intermédiaire comprenant le dérivé de pyrimidine de formule (II-A).

  本发明涉及首先制备5,6-二甲基-2-(4-氟苯基氨基)-4-(1-甲基-1,2,3,4-四氢异喹啉-2-基)嘧啶(I式)及其酸加成盐的方法，其次是制备用于制备化合物(I)的中间体的方法，第三是一种新的中间体化合物。具体而言，本发明首先涉及通过将式(II-A)所表示的嘧啶衍生物（其中Hal表示卤素）与式(III)所表示的1-甲基-1,2,3,4-四氢异喹啉反应来制备化合物(I)及其酸加成盐的方法，其次是制备式(II-A)的嘧啶衍生物和式(III)的化合物的方法；第三是包括式(II-A)的嘧啶衍生物的新的中间体化合物。
• 5,11-Dihydro-6H-dipyrido[3,2-b:2',3'-e] [1,4]diazepines and their use in the prevention or treatment of HIV infection
  申请人：BOEHRINGER INGELHEIM PHARMACEUTICALS INC.

  公开号：EP0429987B1

  公开（公告）日：1999-03-17
• PROCESS FOR PREPARATION OF PYRIMIDINE DERIVATIVES
  申请人：Yuhan Corporation

  公开号：EP0900214A1

  公开（公告）日：1999-03-10
• Novel Non-nucleoside Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase. 4. 2-Substituted Dipyridodiazepinones as Potent Inhibitors of Both Wild-Type and Cysteine-181 HIV-1 Reverse Transcriptase Enzymes
  作者：John R. Proudfoot、Karl D. Hargrave、Suresh R. Kapadia、Usha R. Patel、Karl G. Grozinger、Daniel W. McNeil、Ernest Cullen、Mario Cardozo、Liang Tong

  DOI：10.1021/jm00024a010

  日期：1995.11

  The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT), An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wildtype and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 8-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.