10,11-dihydro-11-hydroxymethylpyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide | 180905-77-5

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 10,11-dihydro-11-hydroxymethylpyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide
• 英文别名: (10,10-Dioxo-4,5-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepin-4-yl)methanol
• CAS: 180905-77-5
• 化学式: C₁₂H₁₂N₂O₃S
• 分子量: 264.305
• InChiKey: MZSPEPDDMPJPRB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  79.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  甲基磺酰氯 、 10,11-dihydro-11-hydroxymethylpyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide 在 吡啶 作用下， 反应 5.0h， 以70%的产率得到(10,10-Dioxo-4,5-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepin-4-yl)methyl methanesulfonate
  参考文献：
  名称：

  5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs): A novel class of non-nucleoside reverse transcriptase inhibitors

  摘要：

  With the aim of developing novel inhibitors of human immunodeficiency virus, various derivatives (10-17) related to SH-pyrrolo[1,2-b][1,2,5]benzothiadiazepine (PBTD) were prepared and tested in vitro. The title tricyclic derivatives were obtained by intramolecular cyclization of the open-chain intermediate arylpyrrylsulfones, followed by N-alkylation at position 10. Among test derivatives some 10-alkyl-5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-one-5,5-dioxides were found to exert potent and specific activity against HIV-1. In particular, 7-chloro derivatives 11i and j showed a potency comparable to that of nevirapine. However, when the chloro atom was shifted to the 8 position, the related products were scarcely active or totally inactive. Replacement of the pyrrole with pyrrolidine led to inactive products and the reduction of SO2 to S strongly diminished the antiviral potency. PBTD derivatives active in cell cultures were also inhibitory to the recombinant HIV-1 RT in enzyme assays, thus allowing the conclusion that PBTDs are a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0968-0896(96)00075-2
• 作为产物：
  描述：

  1-(2-aminobenzenesulfonyl)-1H-pyrrole 在 lithium hydroxide 、 lithium aluminium tetrahydride 、 三氯化铝 、 对甲苯磺酸一水合物 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 27.0h， 生成 10,11-dihydro-11-hydroxymethylpyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide
  参考文献：
  名称：

  吡咯并[1,2-b] [1,2,5]苯并噻二氮杂pine（PBTDs）：在慢性粒细胞性白血病K562细胞以及发病患者中对伊马替尼耐药的细胞中具有高凋亡活性的一类新型药剂。

  摘要：

  吡咯并[1,2-b] [1,2,5]苯并噻二氮杂5,5-二氧化物（PBTDs）诱导表达人BCR-ABL的白血病细胞凋亡。在原发性白血病母细胞中也观察到了细胞凋亡活性，该原发性白血病母细胞是从慢性粒细胞性白血病（CML）患者发作时或爆炸危险中且对伊马替尼具有耐药性的患者获得的。在BCR-ABL蛋白表达和酪氨酸磷酸化受到影响并激活凋亡途径中的不同胱天蛋白酶之前，化合物5和14诱导了细胞凋亡。PBTD是治疗CML的一类新的有效候选药物。

  DOI：

  10.1021/jm0602716

文献信息

• Benzodiazepine Derivatives and Uses Thereof on Medical Field
  申请人：Silvestri Romano

  公开号：US20080249080A1

  公开（公告）日：2008-10-09

  The invention concerns benzodiazepine derivatives of formula wherein Y it is SO 2 or NR, wherein R is H or C 1 -C 6 alkyl; X is H, C 1 -C 12 alkyl, —CO, —SO, —SO 2 , or —CO—R 2 , SO—R 2 , SO 2 —R 2 , wherein R 2 is selected from H, C 1 -C 12 alkyl, (C 3-C 8 cycloalkyl) C 0 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkoxycarbonyl, phenyl, benzyl, naphtyl, biphenyl, or heterocycle, each para-, meta- or ortho-substituted independently of each other with 0 to 3 substituents selected from halogen, —CN, —NH 2 , —OH, —NO 2 , COOR 3 , wherein R 3 is selected from H, C 1 -C 12 alkyl, (C 3 -C 8 cycloalkyl) C 0 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 2 -C 6 alkoxy carbonyl; phenyl, benzyl, naphtyl, biphenyl, or heterocycle n is 0-6; R 4 is selected from H, OH, COOH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkoxycarbonyl, —CO, —SO, —SO 2 , or —CO—R 5 , SO—R 5 , SO 2 —R 2 , —OCO—R 5 , OSO—R 5 , SO 2 —R 5 , COOR 5 , SOOR 5 , SO 2 OR 5 , NHR 5 , NHCOR 5 , NHSO 2 R 5 , SR 5 , SCOR 5 , wherein R 5 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 2 -C 6 alkoxycarbonyl, phenyl, benzyl, naphtyl, biphenyl, or heterocycle, each para-, meta- or ortho-substituted independently of each other with 0 to 3 substituents selected from halogen, —CN, —NH 2 , OH, —NO 2 , COOR 5′ , wherein R 5 is selected from H, C 1 -C 12 alkyl, (C 3 -C 8 cycloalkyl) C 0 -C 6 alkyl, phenyl, benzyl, naphtyl, biphenyl, or heterocycle, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 2 -C 6 alkoxy carbonyl; R 6 and R 7 independently of each other are selected from the group consisting of H, OH, halogen, CN, NH 2 , NO 2 , COOR 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 2 -C 6 alkoxy carbonyl; R 3 is H, C 1 -C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or physiologically acceptable salts and uses thereof in medical field, particularly as anti-tumoral agents.

  这项发明涉及苯二氮卓啉衍生物，其化学式为其中Y为SO2或NR，其中R为H或C1-C6烷基；X为H、C1-C12烷基、—CO、—SO、—SO2或—CO—R2、SO—R2、SO2—R2，其中R2选择自H、C1-C12烷基、(C3-C8环烷基)C0-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6氧代羰基、苯基、苄基、萘基、联苯基或杂环烷基，每个对位、间位或邻位独立地与0至3个卤素、—CN、—NH2、—OH、—NO2、COOR3等选择的取代基取代；n为0-6；R4选择自H、OH、COOH、CN、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C2-C6氧代羰基、—CO、—SO、—SO2或—CO—R5、SO—R5、SO2—R2、—OCO—R5、OSO—R5、SO2—R5、COOR5、SOOR5、SO2OR5、NHR5、NHCOR5、NHSO2R5、SR5、SCOR5，其中R5选择自H、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C2-C6氧代羰基、苯基、苄基、萘基、联苯基或杂环烷基，每个对位、间位或邻位独立地与0至3个卤素、—CN、—NH2、OH、—NO2、COOR5′等选择的取代基取代，其中R5选择自H、C1-C12烷基、(C3-C8环烷基)C0-C6烷基、苯基、苄基、萘基、联苯基或杂环烷基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C2-C6氧代羰基；R6和R7独立地选择自H、OH、卤素、CN、NH2、NO2、COOR3、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基和C2-C6氧代羰基；R3为H、C1-C6烷基、C2-C6烯基、C2-C6炔基或生理上可接受的盐，并在医学领域中的用途，特别是作为抗肿瘤剂。
• WO2007/15280
  申请人：——

  公开号：——

  公开（公告）日：——
• BENZODIAZEPINE DERIVATIVES AND USES THEREOF IN MEDICAL FIELD
  申请人：Universita' degli Studi di Roma " Tor Vergata"

  公开号：EP1910383B1

  公开（公告）日：2009-09-16
• [EN] BENZODIAZEPINE DERIVATIVES AND USES THEREOF IN MEDICAL FIELD<br/>[FR] DÉRIVÉS DE BENZODIAZÉPINE ET UTILISATIONS DE CEUX-CI DANS LE DOMAINE MÉDICAL
  申请人：UNIV ROMA

  公开号：WO2007015280A1

  公开（公告）日：2007-02-08

  [EN] The invention concerns benzodiazepine derivatives of formula (I) wherein Y it is SO2 or NR, wherein R is H or C1-C6 alkyl; X is H, C1-Ci2 alkyl, -CO, -SO, -SO2, or - CO-R2, SO-R2, SO2- R2, wherein R2 is selected from H, Ci-Ci2 alkyl, (C3-C8 cycloalkyl) C0-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-Ce alkoxycarbonyl, phenyl, benzyl, naphtyl, biphenyl, or heterocycle, each para-, meta- or ortho-substituted independently of each other with 0 to 3 substituents selected from halogen, -CN, -NH2, -OH, -NO2, COOR3, wherein R3 is selected from H, Ci-C12 alkyl, (C3-C8 cycloalkyl) C0-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, or C2-C6 alkoxy carbonyl; phenyl, benzyl, naphtyl, biphenyl, or heterocycle, n is 0-6; R4 is selected from H, OH, COOH, CN, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkoxycarbonyl, -CO, -SO, - SO2, or -CO-R5, SO-R5, SO2-R2, -OCO-R5, OSO-R5, OSO2-R5, COOR5, SOOR5, SO2OR5, NHR5, NHCOR5, NHSO2R5, SR5, SCOR5, wherein R5 is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, or C2-C6 alkoxycarbonyl, phenyl, benzyl, naphtyl, biphenyl, or heterocycle, each para-, meta- or ortho-substituted independently of each other with O to 3 substituents selected from halogen, -CN, -NH2, -OH, -NO2, COOR5', wherein R5 is selected from H, C1-C12 alkyl, (C3-C8 cycloalkyl) C0-C6 alkyl, phenyl, benzyl, naphtyl, biphenyl, or heterocycle, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, or C2-C6 alkoxy carbonyl; R6 and R7 independently of each other are selected from the group consisting of H, OH, halogen, CN, NH2, NO2, COOR3, C1-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, and C2-C6 alkoxy carbonyl; R3 is H, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or physiologically acceptable salts and uses thereof in medical field, particularly as anti-tumoral agents.
  [FR] La présente invention concerne des dérivés de benzodiazépine de formule (I) dans laquelle Y est SO2 ou NR, dans laquelle R est H ou C1-C6 alkyle ; X est H, C1-Ci2 alkyle, -CO, -SO, -SO2, ou - CO-R2, SO-R2, SO2- R2, dans laquelle R2 est choisi parmi H, Ci-Ci2 alkyle, (C3-C8 cycloalkyle) C0-C6 alkyle, C2-C6 alcényle, C2-C6 alkynyle, C2-Ce alcoxycarbonyle, phényle, benzyle, naphtyle, biphényle, ou hétérocyclique, chacun étant para-, méta- ou ortho- substitué indépendamment les uns des autres avec de 0 à 3 substituants choisis parmi halogène, -CN, -NH2, -OH, -NO2, COOR3, dans laquelle R3 est choisi parmi H, Ci-C12 alkyle, (C3-C8 cycloalkyle) C0-C6 alkyle, Ci-C6 alcoxy, C2-C6 alcényle, C2-C6 alkynyle, ou C2-C6 alcoxy carbonyle ; phényle, benzyle, naphtyle, biphényle, ou hétérocyclique, n va de 0 à 6 ; R4 est choisi parmi H, OH, COOH, CN, C1-C6 alkyle, C1-C6 alcoxy, C2-C6 alcényle, C2-C6 alkynyle, C2-C6 alcoxycarbonyle, -CO, -SO, - SO2, ou -CO-R5, SO-R5, SO2-R2, -OCO-R5, OSO-R5, OSO2-R5, COOR5, SOOR5, SO2OR5, NHR5, NHCOR5, NHSO2R5, SR5, SCOR5, dans laquelle R5 est choisi parmi H, C1-C6 alkyle, Ci-C6 alcoxy, C2-C6 alcényle, C2-C6 alkynyle, ou C2-C6 alcoxycarbonyle, phényle, benzyle, naphtyle, biphényle, ou hétérocyclique, chacun étant para-, méta- ou ortho- substitué indépendamment les uns des autres avec de 0 à 3 substituants choisis parmi halogène, -CN, -NH2, -OH, -NO2, COOR5', dans laquelle R5 est choisi parmi H, C1-C12 alkyle, (C3-C8 cycloalkyle) C0-C6 alkyle, phényle, benzyle, naphtyle, biphényle, ou hétérocyclique, C1-C6 alkyle, C1-C6 alcoxy, C2-C6 alcényle, C2-C6 alkynyle, ou C2-C6 alcoxy carbonyle ; R6 et R7 sont choisis indépendamment l'un de l'autre dans le groupe consistant en H, OH, halogène, CN, NH2, NO2, COOR3, C1-C6 alkyle, Ci-C6 alcoxy, C2-C6 alcényle, C2-C6 alkynyle, et C2-C6 alcoxy carbonyle ; R3 est H, CrC6 alkyle, C2-C6 alcényle, C2-C6 alkynyle ou des sels physiologiquement acceptables et des utilisations de ceux-ci dans le domaine médical, en particulier en tant qu'agents anti-tumoraux.
• 5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs): A novel class of non-nucleoside reverse transcriptase inhibitors
  作者：Marino Artico、Romano Silvestri、Eugenia Pagnozzi、Giorgio Stefancich、Silvio Massa、Anna Giulia Loi、Monica Putzolu、Simona Corrias、Maria Grazia Spiga、Paolo La Colla

  DOI：10.1016/0968-0896(96)00075-2

  日期：1996.6

  With the aim of developing novel inhibitors of human immunodeficiency virus, various derivatives (10-17) related to SH-pyrrolo[1,2-b][1,2,5]benzothiadiazepine (PBTD) were prepared and tested in vitro. The title tricyclic derivatives were obtained by intramolecular cyclization of the open-chain intermediate arylpyrrylsulfones, followed by N-alkylation at position 10. Among test derivatives some 10-alkyl-5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-one-5,5-dioxides were found to exert potent and specific activity against HIV-1. In particular, 7-chloro derivatives 11i and j showed a potency comparable to that of nevirapine. However, when the chloro atom was shifted to the 8 position, the related products were scarcely active or totally inactive. Replacement of the pyrrole with pyrrolidine led to inactive products and the reduction of SO2 to S strongly diminished the antiviral potency. PBTD derivatives active in cell cultures were also inhibitory to the recombinant HIV-1 RT in enzyme assays, thus allowing the conclusion that PBTDs are a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Copyright (C) 1996 Elsevier Science Ltd