tert-butyl (11S,11aS)-8-hydroxy-7-methoxy-2-methylene-5-oxo-11-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate | 864665-77-0

• 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: tert-butyl (11S,11aS)-8-hydroxy-7-methoxy-2-methylene-5-oxo-11-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate
• 英文别名: (11S,11aS)-10-(tert-butyloxycarbonyl)-8-hydroxy-7-methoxy-2-methylidene-11-(tetrahydropyran-2-yloxy)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one；tert-butyl (6S,6aS)-3-hydroxy-2-methoxy-8-methylidene-6-(oxan-2-yloxy)-11-oxo-6,6a,7,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate
• CAS: 864665-77-0
• 化学式: C₂₄H₃₂N₂O₇
• 分子量: 460.527
• InChiKey: GDNJASYCTUHBEM-BGKUMUJYSA-N

物化性质

• 沸点：
  641.1±55.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  97.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl (11S,11aS)-8-hydroxy-7-methoxy-2-methylene-5-oxo-11-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate 在 chloro-(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butyl ether adduct 、 四丁基碘化铵 、 potassium carbonate 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 、 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.5h， 生成 N-(15-(4-(3,5-bis((((S)-7-methoxy-2-methylene-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl)oxy)methyl)phenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamide
  参考文献：
  名称：

  Pyrrolobenzodiazepine Dimer Antibody–Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers

  摘要：

  Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 mu g/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In-vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/kg, and 3-6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models.

  DOI：

  10.1021/acs.jmedchem.7b00736
• 作为产物：
  描述：

  2-硝基-4-苄氧基-5-甲氧基苯甲酸 在 甲醇 、 锂硼氢 、 草酰氯 、 2,2,6,6-四甲基哌啶氧化物 、 tin(II) chloride dihdyrate 、 碘苯二乙酸 、 palladium 10% on activated carbon 、 potassium tert-butylate 、 氢气 、 对甲苯磺酸 、 溶剂黄146 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， -20.0~20.0 ℃ 、206.85 kPa 条件下， 反应 97.67h， 生成 tert-butyl (11S,11aS)-8-hydroxy-7-methoxy-2-methylene-5-oxo-11-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate
  参考文献：
  名称：

  Pyrrolobenzodiazepine Dimer Antibody–Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers

  摘要：

  Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 mu g/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In-vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/kg, and 3-6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models.

  DOI：

  10.1021/acs.jmedchem.7b00736

文献信息

• PYRROLOBENZODIAZEPINE ANTIBODY DRUG CONJUGATES AND METHODS OF USE
  申请人：Genentech, Inc.

  公开号：US20170095570A1

  公开（公告）日：2017-04-06

  The invention provides antibody-drug conjugates comprising an antibody conjugated to a pyrrolobenzodiazepine drug moiety via a disulfide linker, pyrrolobenzodiazepine linker-drug intermediates, and methods of using the antibody-drug conjugates.

  本发明提供了包含通过二硫键连接器将抗体与吡咯并苯二氮卓药物部分连接的抗体药物偶联物、吡咯并苯二氮卓连接器-药物中间体，以及使用抗体药物偶联物的方法。
• [EN] PYRROLOBENZODIAZEPINES<br/>[FR] PYRROLOBENZODIAZÉPINES
  申请人：MEDIMMUNE LTD

  公开号：WO2017129652A1

  公开（公告）日：2017-08-03

  A compound with the formula I, wherein R2 is of formula ΙI, where A is a C5-7 aryl group, X is selected from the group consisting of: OH, SH, CO2H, COH, N=C=0, NHNH2, CONHNH2, (III), (IV), and NHRN, wherein RN is selected from H and C1-4 alkyl, and either: (i) Q1 is a single bond, and Q2 is selected from a single bond and -Z-(CH2)n-, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or (ii) Q1 is -CH=CH-, and Q2 is a single bond;and its conjugates.

  具有化学式I的化合物，其中R2的化学式为ΙI，其中A是C5-7芳基，X选自以下组合之一：OH、SH、CO2H、COH、N=C=0、NHNH2、CONHNH2、(III)、(IV)和NHRN，其中RN选自H和C1-4烷基，且：(i) Q1是单键，Q2选自单键和-Z-(CH2)n-，其中Z选自单键、O、S和NH，n为1至3；或者(ii) Q1是-CH=CH-，Q2是单键；及其共轭物。
• PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF
  申请人：GENENTECH, INC.

  公开号：US20140294868A1

  公开（公告）日：2014-10-02

  Conjugate compounds of formula (A): wherein: R 2 is where R 36a and R 36b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester or, when one of R 36a and R 36b is H, the other is selected from nitrile and a C 1-4 alkyl ester; R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo; R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo; Y is selected from formulae A1, A2, A3, A4, A5 and A6: L is a linker connected to a cell binding agent; CBA is the cell binding agent; n is an integer selected in the range of 0 to 48; R A4 is a C 1-6 alkylene group; either (a) R 10 is H, and R 11 is OH, OR A , where R A is C 1-4 alkyl; or (b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or (c) R 10 is H and R 11 is OSO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R and R′ are each independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring; wherein R 16 , R 17 , R 19 , R 20 , R 21 and R 22 are as defined for R 6 , R 7 , R 9 , R 10 , R 11 and R 2 respectively; wherein Z is CH or N; wherein T and T′ are independently selected from a single bond or a C 1-9 alkylene, which chain may be interrupted by one or more heteroatoms e.g. O, S, N(H), NMe, provided that the number of atoms in the shortest chain of atoms between X and X′ is 3 to 12 atoms; and X and X′ are independently selected from O, S and N(H).

  将公式（A）的共轭化合物变形：其中：R2是其中R36a和R36b分别独立选择自H、F、C1-4饱和烷基、C2-3烯基，所述烷基和烯基基团可以选择性地被C1-4烷基酰胺和C1-4烷基酯中的一种基团取代，或者当R36a和R36b中的一个是H时，另一个选择自腈和C1-4烷基酯；R6和R9独立选择自H、R、OH、OR、SH、SR、NH2、NHR、NRR′、NO2、Me3Sn和卤素；R7独立选择自H、R、OH、OR、SH、SR、NH2、NHR、NRR′、 、Me3Sn和卤素；Y选择自公式A1、A2、A3、A4、A5和A6；L是连接到细胞结合剂的连接剂；CBA是细胞结合剂；n是选择在0到48范围内的整数；RA4是C1-6烷基基团；要么（a）R10是H，而R11是OH、ORA，其中RA是C1-4烷基；或者（b）R10和R11在氮和碳原子之间形成氮-碳双键；或者（c）R10是H，而R11是OSOzM，其中z为2或3，M是一价的药用可接受阳离子；R和R′各自独立选择自选择性取代的C1-12烷基、C3-20杂环基和C5-20芳基，并且在NRR′基团方面，R和R′与它们连接的氮原子一起形成一个可选择取代的4-、5-、6-或7-成员杂环环；其中R16、R17、R19、R20、R21和R22如R6、R7、R9、R10、R11和R2所定义；其中Z为CH或N；其中T和T′独立选择自单键或C1-9烷基，该链可能被一个或多个杂原子（如O、S、N(H)、NMe）中断，前提是在X和X′之间原子最短链中原子的数量为3到12个原子；X和X′独立选择自O、S和N(H)。
• [EN] IMMUNOCONJUGATES COMPRISING ANTI-HER2 ANTIBODIES AND PYRROLOBENZODIAZEPINES<br/>[FR] IMMUNOCONJUGUÉS COMPRENANT DES ANTICORPS ANTI-HER2 ET DES PYRROLOBENZODIAZÉPINES
  申请人：GENENTECH INC

  公开号：WO2016044396A1

  公开（公告）日：2016-03-24

  The invention provides immunoconjugates comprising anti-HER2 antibodies and methods of using the same. An immunoconjugate is provided, which comprises an antibody and a cytotoxic agent, wherein the cytotoxic agent is a center-linked pyrrolobenzodiazepine. The immunoconjugate has the formula Ab-(L-D)p, wherein: a) Ab is the antibody of any one of claim 1 to 16; b) L is a linker; c) D is a center-linked pyrrolobenzodiazepine; and d) p ranges from 1-8.

  该发明提供了包含抗HER2抗体的免疫结合物及其使用方法。提供了一种免疫结合物，其中包括一种抗体和一种细胞毒性剂，其中该细胞毒性剂是一个中心连接的吡咯苯并二氮杂环。该免疫结合物的公式为Ab-(L-D)p，其中：a) Ab是权利要求1至16中的任一抗体；b) L是一个连接物；c) D是一个中心连接的吡咯苯并二氮杂环；d) p的取值范围为1-8。
• Pyrrolobenzodiazepines
  申请人：Medimmune Limited

  公开号：US10392393B2

  公开（公告）日：2019-08-27

  A compound with the formula I, wherein R2 is of formula II, where A is a C5-7 aryl group, X is selected from the group consisting of: OH, SH, CO2H, COH, N═C═O, NHNH2, CONHNH2, (III), (IV), and NHRN, wherein RN is selected from H and C1-4 alkyl, and either: (i) Q1 is a single bond, and Q2 is selected from a single bond and —Z—(CH2)n—, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or (ii) Q1 is —CH═CH—, and Q2 is a single bond; and its conjugates.

  一种式 I 的化合物，其中 R2 为式 II，其中 A 为 C5-7 芳基，X 选自以下组成的组：OH、SH、CO2H、COH、N═C═O、NHNH2、CONHNH2、(III)、(IV)和 NHRN，其中 RN 选自 H 和 C1-4 烷基，且任选其一：(i) Q1 是单键，Q2 选自单键和-Z-(CH2)n-，其中 Z 选自单键、O、S 和 NH，n 为 1 至 3；或 (ii) Q1 是-CH═CH-，Q2 是单键；及其共轭物。