(11S,11Sa)-8-(3-tert-butoxycarbonylaminopropoxy)-11-hydroxy-7-methoxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester | 864672-66-2

• 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: (11S,11Sa)-8-(3-tert-butoxycarbonylaminopropoxy)-11-hydroxy-7-methoxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester
• 英文别名: prop-2-enyl (6S,6aS)-6-hydroxy-2-methoxy-3-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propoxy]-11-oxo-6a,7,8,9-tetrahydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate
• CAS: 864672-66-2
• 化学式: C₂₅H₃₅N₃O₈
• 分子量: 505.568
• InChiKey: RJSUCINRKYODHE-JTSKRJEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  127
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (11S,11Sa)-8-(3-tert-butoxycarbonylaminopropoxy)-11-hydroxy-7-methoxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 、 水 为溶剂， 以100%的产率得到(11S,11Sa)-8-(3-aminopropoxy)-11-hydroxy-7-methoxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester
  参考文献：
  名称：

  一种不对称的C8 / C8'-三吡咯连接的序列选择性吡咯并[2,1-c] [1,4]苯并二氮杂（PBD）二聚体DNA跨链交联剂，跨越11个DNA碱基对。

  摘要：

  已经合成了新颖的序列选择性扩展的PBD二聚体4，其以高亲和力结合跨越11个DNA碱基对的链间交联位点。尽管其分子量（984.07）和长度，该分子在许多肿瘤细胞系中仍具有显着的DNA链间交联能力（比临床使用的药物melphalan约大100倍）和亚微摩尔的细胞毒性，这表明它很容易穿透细胞膜和核膜以达到其DNA靶标。

  DOI：

  10.1016/j.bmcl.2008.01.096
• 作为产物：
  描述：

  tert-butyl (S)-(3-(5-(((allyloxy)carbonyl)amino)-4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-2-methoxyphenoxy)propyl)carbamate 在 2,2,6,6-tetramethyl-piperidine-N-oxyl 、 碘苯二乙酸 作用下， 以 二氯甲烷 为溶剂， 以72%的产率得到(11S,11Sa)-8-(3-tert-butoxycarbonylaminopropoxy)-11-hydroxy-7-methoxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester
  参考文献：
  名称：

  一种不对称的C8 / C8'-三吡咯连接的序列选择性吡咯并[2,1-c] [1,4]苯并二氮杂（PBD）二聚体DNA跨链交联剂，跨越11个DNA碱基对。

  摘要：

  已经合成了新颖的序列选择性扩展的PBD二聚体4，其以高亲和力结合跨越11个DNA碱基对的链间交联位点。尽管其分子量（984.07）和长度，该分子在许多肿瘤细胞系中仍具有显着的DNA链间交联能力（比临床使用的药物melphalan约大100倍）和亚微摩尔的细胞毒性，这表明它很容易穿透细胞膜和核膜以达到其DNA靶标。

  DOI：

  10.1016/j.bmcl.2008.01.096

文献信息

• [EN] C8, C8' LINKED 5-OXO-1,2,3,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE DIMERS WITH 1H-PYRROLE-DICARBOXYLIC ACID AMIDE LINKERS AND OLIGOMERIC ANALOGS THEROF AS WELL AS RELATED COMPOUNDS FOR THE TREATMENT OF PROLIFERATIVE DISEASES<br/>[FR] DIMERES DE C8,C8' 5-OXO-1,2,3, 11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE LIES PAR DES LIEURS D'AMIDE D'ACIDE 1-H-PYRROLE-DICARBOXYLIQUE ET LEURS ANALOGUES OLIGOMERES AINSI QUE DES COMPOSES CONNEXES DESTINES AU TRAITEMENT DE MALADIES PROLIFERATIVES
  申请人：SPIROGEN LTD

  公开号：WO2005085250A1

  公开（公告）日：2005-09-15

  Compounds of formula (I): PBD-A-Y-X- (Het)na-L- (Het)nb-L- (Het)nc-T- (Het')nd-L- (Het')ne-L- (Het')nf-X' -Y' -A' -PBD' and salts, solvates and chemically protected forms thereof, are disclosed wherein the PBD units have the formulae (PBD) (PBD') with the bonds at the 8 position on each molecule bond to the A and A' groups respectively ; A is selected from O, S, NH or a single bond , and each Het and Het' is respectively an amino-heteroarylene-carbonyl group ; X and X' are both either NH or C (=O) -Q-C (=O) - wherein Q is a divalent group such that HY = R ; in a second aspectm the invention comprises compounds of the general formula (II) : PBD-A-Y-X-(Het)ng-[L-(Het)nh] nj-X' -Y' -A' -PBD'. Wherein : PBD and PBD' are as defined above, X and X' are either NH and C(=O) respectively or C(O) and NH respectively ; the other substituents are defined in the claims. Further aspects of the present invention relate to their use in the manufacture of a medicament for the treatment of a proliferative disease.

  公式（I）的化合物：PBD-A-Y-X-（Het）na-L-（Het）nb-L-（Het）nc-T-（Het'）nd-L-（Het'）ne-L-（Het'）nf-X'-Y'-A'-PBD'及其盐、溶剂合物和化学保护形式，其中PBD单位具有化学式（PBD）（PBD'），每个分子的8位置的键分别与A和A'基团结合；A从O、S、NH或单键中选择，每个Het和Het'分别为氨基-杂芳基-羰基基团；X和X'都是NH或C（=O）-Q-C（=O）-，其中Q是二价基团，使得HY = R；在第二方面，本发明涉及一般化学式（II）的化合物：PBD-A-Y-X-(Het)ng-[L-(Het)nh] nj-X'-Y'-A'-PBD'。其中：PBD和PBD'如上所定义，X和X'分别为NH和C（=O）或C（O）和NH；其他取代基在权利要求中定义。本发明的其他方面涉及它们在制造用于治疗增殖性疾病的药物中的用途。
• [EN] PBD ANTIBACTERIAL AGENTS<br/>[FR] AGENTS ANTIBACTÉRIENS DE TYPE PBD
  申请人：KING'S COLLEGE LONDON

  公开号：WO2017098257A1

  公开（公告）日：2017-06-15

  The invention relates to pyrrolobenzodiazepines compounds (PBDs) and to pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular, to treat bacterial infections. The PBDs are compounds of formula (I): and salts and solvates thereof; wherein: dotted lines indicates the optional presence of a double bond; X, X1, X2, X3 and X4 are connecting functional groups; L is C1-12 alkylene; R4, R5 and R6 are independently selected from phenylene, cyclopentanylene, cyclohexanylene, 5 - to 9 -membered heteroarylene and 5 - to 6-membered hetereocyclylene groups, and these groups are optionally substituted with up to three optional substituent groups; R7 is selected from N(C1-6 alkyl)(C1-6alkyl), 5 - to 6-membered nitrogen-containing hetereocyclyl groups, a monosaccharide moiety and an amino monosaccharide moiety wherein these groups are optionally substituted; and R8 and R9 either together form a double bond, or are selected from H and OR14, or R8 is a prodrug moiety and R9 is OR14; m is 0 or 1; with the proviso that when X4 is C(O)NH then the up to three optional substituents of R7 are not selected from (CH2)k -CO2R12; with the proviso that when X4 is (CH2)tO then R4 is not phenylene, m is 1 and R6 is not a 5 - to 9 -membered heteroarylene; and with the proviso that when X4 is C(O)NH or NHC(O) that R4 and/or R6 is not 5 - to 9 -membered heteroarylene.

  该发明涉及吡咯苯二氮杂环烷化合物（PBD）及其药用可接受盐，其作为药物具有治疗细菌感染的功效。PBD是具有以下结构式（I）的化合物：及其盐和溶剂化物；其中：虚线表示双键的可选存在；X、X1、X2、X3和X4是连接的功能基团；L为C1-12烷基；R4、R5和R6分别选自苯环、环戊烷基、环己烷基、5-至9-成员杂芳烃基和5-至6-成员杂环烷基，这些基团可选地被高达三个可选取代基团取代；R7选自N（C1-6烷基）（C1-6烷基）、5-至6-成员含氮杂环基团、单糖基团和氨基单糖基团，其中这些基团可选地被取代；R8和R9要么一起形成双键，要么选自H和OR14，或者R8是前药基团且R9是OR14；m为0或1；但是当X4为C（O）NH时，R7的高达三个可选取代基团不选自（CH2）k-CO2R12；但是当X4为（ ）tO时，R4不是苯环，m为1且R6不是5-至9-成员杂芳烃基；但是当X4为C（O）NH或NHC（O）时，R4和/或R6不是5-至9-成员杂芳烃基。
• PBD antibacterial agents
  申请人：KING'S COLLEGE LONDON

  公开号：US10640507B2

  公开（公告）日：2020-05-05

  The invention relates to pyrrolobenzodiazepines compounds (PBDs) and to pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular, to treat bacterial infections. The PBDs are compounds of formula (I): and salts and solvates thereof; wherein: dotted lines indicates the optional presence of a double bond; X, X1, X2, X3 and X4 are connecting functional groups; L is C1-12 alkylene; R4, R5 and R6 are independently selected from phenylene, cyclopentanylene, cyclohexanylene, 5- to 9-membered heteroarylene and 5- to 6-membered hetereocyclylene groups, and these groups are optionally substituted with up to three optional substituent groups; R7 is selected from N(C1-6 alkyl)(C1-6alkyl), 5- to 6-membered nitrogen-containing hetereocyclyl groups, a monosaccharide moiety and an amino monosaccharide moiety wherein these groups are optionally substituted; and R8 and R9 either together form a double bond, or are selected from H and OR14, or R8 is a prodrug moiety and R9 is OR14; m is 0 or 1; with the proviso that when X4 is C(O)NH then the up to three optional substituents of R7 are not selected from (CH2)k-CO2R12; with the proviso that when X4 is (CH2)tO then R4 is not phenylene, m is 1 and R6 is not a 5- to 9-membered heteroarylene; and with the proviso that when X4 is C(O)NH or NHC(O) that R4 and/or R6 is not 5- to 9-membered heteroarylene.

  本发明涉及吡咯并二氮杂卓化合物（PBDs）及其药学上可接受的盐类，它们可用作药物，特别是治疗细菌感染。PBDs 是式 (I) 的化合物：及其盐和溶解物；其中虚线表示任选存在双键；X、X1、X2、X3 和 X4 为连接官能团；L 为 C1-12 亚烷基；R4、R5 和 R6 独立选自亚苯基、环戊烯基、环己烯基、5-至 9 元杂芳基和 5-6 元对位环亚苯基，这些基团可任选被最多三个任选取代基取代；R7 选自 N(C1-6烷基)(C1-6烷基)、5 至 6 元含氮杂环烯基、单糖分子和氨基单糖分子，其中这些基团任选被取代；R8和R9或者一起形成双键，或者选自H和OR14，或者R8为原药分子，R9为OR14；m为0或1；但当X4为C(O)NH时，R7的最多三个任选取代基不选自(CH2)k-CO2R12；但当 X4 为 ( )tO 时，R4 不是亚苯基，m 为 1，R6 不是 5 至 9 元杂芳基；但当 X4 为 C(O)NH 或 NHC(O) 时，R4 和/或 R6 不是 5 至 9 元杂芳基。