methyl 4-(4-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate | 1428305-98-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: methyl 4-(4-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate
• 英文别名: Methyl 4-(4-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate；methyl 4-[[4-(4-aminophenyl)-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carboxylate
• CAS: 1428305-98-9
• 化学式: C₁₉H₂₀N₄O₃
• 分子量: 352.393
• InChiKey: IMWTWOGNUVGCHL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  91.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(10-(allyloxycarbonyl)-7-methoxy-5-oxo-11-(tetrahydro-2H-pyran-2-yloxy)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)butanoic acid 、 methyl 4-(4-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 prop-2-enyl (6aS)-2-methoxy-3-[4-[4-[5-[(5-methoxycarbonyl-1-methylpyrrol-3-yl)carbamoyl]-1-methylpyrrol-3-yl]anilino]-4-oxobutoxy]-6-(oxan-2-yloxy)-11-oxo-6a,7,8,9-tetrahydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate
  参考文献：
  名称：

  GC-Targeted C8-Linked Pyrrolobenzodiazepine–Biaryl Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor Activity in Mouse Models

  摘要：

  DNA binding 4-(1-methyl-1H-pyrrol-3-yl)-benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-kappa B with its cognate DNA binding sequence.

  DOI：

  10.1021/jm301882a
• 作为产物：
  描述：

  1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-2,2,2-trichloroethan-1-one 在 盐酸 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 水 、 sodium hydride 、 potassium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 mineral oil 为溶剂， 反应 18.7h， 生成 methyl 4-(4-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate
  参考文献：
  名称：

  [EN] PYRROLOBENZODIAZEPINES
  [FR] PYRROLOBENZODIAZÉPINES

  摘要：

  发现具有（1-甲基-1H-吡咯-3-基）苯基氨基残基的吡咯苯并二氮杂环烃（PBDs）是具有改善的细胞毒性和DNA结合性能的高效化合物。

  公开号：

  WO2013164593A1

文献信息

• [EN] PYRROLOBENZODIAZEPINES<br/>[FR] PYRROLOBENZODIAZÉPINES
  申请人：UCL BUSINESS PLC

  公开号：WO2013164592A1

  公开（公告）日：2013-11-07

  A compound of formula (I) or a salt or solvate thereof, wherein the dotted double bond indicates the presence of a single or double bond between C2 and C3; R2 is selected from -H, -OH, =O, =CH2, -CN, -R, OR, halo, dihalo, =CHR, =CHRR', -O- SO2-R, CO2R and COR; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R10 and R11 either together form a double bond, or are selected from H and QRQ respectively, where Q is selected from O, S and NH and RQ is H or C1-7 alkyl or H and SOxM, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; A is selected from (A1), (A2), (A3), (A4) or (A5) where X1 and Y1 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; X2 and Y2 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; Z1 is selected from O and S; Z2 is selected from CH and N; F is selected from a single bond and –(E-F1)m-; each E is independently selected from a single bond, and –C(=O)-NH-; each F1 is independently a C3-20 heteroarylene group; m is 1, 2 or 3; G is selected from hydrogen, C1-4alkyl, -C(=O)-O-C1-4alkyl, -(CH2)n-C3-20 heterocycloalkyl, and –O-(CH2)n-C3-20 heterocycloalkyl group; each n is 0-4; provided that A2 is not A2', where X1 and Y1 of A2' are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and provided that A3 is not A3', where X2 and Y2 of A3' are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; B is either a single bond or (B1), where X and Y of B1 are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and R1 is C1-4 alkyl.

  化合物的化学式(I)或其盐或溶剂化合物，其中点虚线表示C2和C3之间存在单键或双键；R2选自-H、-OH、=O、=CH2、-CN、-R、OR、卤素、二卤素、=CHR、=CHRR'、-O-SO2-R、CO2R和COR；R7选自H、R、OH、OR、SH、SR、NH2、NHR、NRR'、硝基、Me3Sn和卤素；其中R和R'分别独立选自可选择的取代C1-7烷基、C3-20杂环烷基和C5-20芳基；R10和R11要么一起形成双键，要么分别选自H和QRQ，其中Q选自O、S和NH，RQ为H或C1-7烷基或H和SOxM，其中x为2或3，M为一价的药用可接受阳离子；A选自(A1)、(A2)、(A3)、(A4)或(A5)，其中X1和Y1选自：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；以及CH和O，依此类推；X2和Y2选自：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；以及CH和O，依此类推；Z1选自O和S；Z2选自CH和N；F选自单键和-(E-F1)m-；每个E独立选自单键和-C(=O)-NH-；每个F1独立为C3-20杂芳基；m为1、2或3；G选自氢、C1-4烷基、-C(=O)-O-C1-4烷基、-(CH2)n-C3-20杂环烷基和-O-(CH2)n-C3-20杂环烷基；每个n为0-4；条件是A2不是A2'，其中A2'的X1和Y1选自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；条件是A3不是A3'，其中A3'的X2和Y2选自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；B要么是单键，要么是(B1)，其中B1的X和Y选自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；R1为C1-4烷基。
• PYRROLOBENZODIAZEPINES
  申请人：UCL BUSINESS PLC

  公开号：US20150126495A1

  公开（公告）日：2015-05-07

  A compound of formula (I) or a salt or solvate thereof, wherein the dotted double bond indicates the presence of a single or double bond between C2 and C3; R 2 is selected from —H, —OH, ═O, ═CH 2 , —CN, —R, OR, halo, dihalo, ═CHR, ═CHRR′, —O—SO 2 —R, CO 2 R and COR; R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo; where R and R′ are independently selected from optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; R 10 and R 11 either together form a double bond, or are selected from H and QR Q respectively, where Q is selected from O, S and NH and R Q is H or C 1-7 alkyl or H and SO x M, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; A is selected from (A1), (A2), (A3), (A4) or (A5) where X 1 and Y 1 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; X 2 and Y 2 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; Z 1 is selected from O and S; Z 2 is selected from CH and N; F is selected from a single bond and -(E-F 1 ) m -; each E is independently selected from a single bond, and —C(═O)—NH—; each F 1 is independently a C 3-20 heteroarylene group; m is 1, 2 or 3; G is selected from hydrogen, C 1-4 alkyl, —C(═O)—O—C 1-4 alkyl, —(CH 2 ) n —C 3-20 heterocycloalkyl, and —O—(CH 2 ) n —C 3-20 heterocycloalkyl group; each n is 0-4; provided that A2 is not A2′, where X 1 and Y 1 of A2′ are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and provided that A3 is not A3′, where X 2 and Y 2 of A3′ are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; B is either a single bond or (B1), where X and Y of B1 are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and R 1 is C 1-4 alkyl.

  化合物的化学式为（I）或其盐或溶剂化物，其中点虚线表示C2和C3之间存在单键或双键；R2选择自-H，-OH，═O，═CH2，-CN，-R，OR，卤素，二卤代基，═CHR，═CHRR′，-O-SO2-R，CO2R和COR；R7选择自H，R，OH，OR，SH，SR，NH2，NHR，NRR'，硝基，Me3Sn和卤素；其中R和R'分别选择自可选取的取代的C1-7烷基，C3-20杂环基和C5-20芳基；R10和R11要么共同形成双键，要么选择自H和QRQ，其中Q选择自O，S和NH，RQ是H或C1-7烷基或H和SOxM，其中x为2或3，M是单价的药用可接受阳离子；A选择自（A1），（A2），（A3），（A4）或（A5），其中X1和Y1选择自：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；和CH和O，依此类推；X2和Y2选择自：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；和CH和O，依此类推；Z1选择自O和S；Z2选择自CH和N；F选择自单键和-(E-F1)m-；每个E独立选择自单键和-C(═O)-NH-；每个F1独立为C3-20杂环芳烃基；m为1、2或3；G选择自氢、C1-4烷基、-C(═O)-O-C1-4烷基、-(CH2)n-C3-20杂环烷基和-O-(CH2)n-C3-20杂环烷基；每个n为0-4；提供A2不是A2'，其中A2'的X1和Y1选择自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；并且提供A3不是A3'，其中A3'的X2和Y2选择自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；B要么是单键，要么是（B1），其中B1的X和Y选择自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；R1是C1-4烷基。
• Pyrrolobenzodiazepines as antiproliferative agents
  申请人：MEDIMMUNE LIMITED

  公开号：US09376440B2

  公开（公告）日：2016-06-28

  Novel pyrrolobenzodiazepines (PBDs) having a (1-methyl-1H-pyrrol-3-yl)phenyl based amino acid residue and use thereof as antiproliferative agents are disclosed herein.

  本发明揭示了具有（1-甲基-1H-吡咯-3-基）苯基氨基酸残基的新型吡咯苯并二氮杂环类化合物（PBDs），并将其用作抗增殖剂。
• Pyrrolobenzodiazepines
  申请人：MEDIMMUNE LIMITED

  公开号：US09321774B2

  公开（公告）日：2016-04-26

  A compound of formula (I) or a salt or solvate thereof, wherein the dotted double bond indicates the presence of a single or double bond between C2 and C3; R2 is selected from —H, —OH, ═O, ═CH2, —CN, —R, OR, halo, dihalo, ═CHR, ═CHRR′, —O—SO2—R, CO2R and COR; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo; where R and R′ are independently selected from optionally substituted C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R10 and R11 either together form a double bond, or are selected from H and QRQ respectively, where Q is selected from O, S and NH and RQ is H or C1-7 alkyl or H and SOxM, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; A is selected from (A1), (A2), (A3), (A4) or (A5) where X1 and Y1 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; X2 and Y2 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; Z1 is selected from O and S; Z2 is selected from CH and N; F is selected from a single bond and -(E-F1)m—; each E is independently selected from a single bond, and —C(═O)—NH—; each F1 is independently a C3-20 heteroarylene group; m is 1, 2 or 3; G is selected from hydrogen, C1-4alkyl, —C(═O)—O—C1-4alkyl, —(CH2)n—C3-20 heterocycloalkyl, and —O—(CH2)n—C3-20 heterocycloalkyl group; each n is 0-4; provided that A2 is not A2′, where X1 and Y1 of A2′ are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and provided that A3 is not A3′, where X2 and Y2 of A3′ are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; B is either a single bond or (B1), where X and Y of B1 are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and R1 is C1-4 alkyl.

  化合物的化学式为（I）或其盐或溶剂化物，其中点虚线表示C2和C3之间存在单键或双键；R2从—H，—OH，═O，═CH2，—CN，—R，OR，卤素，二卤素，═CHR，═CHRR′，—O—SO2—R，CO2R和COR中选择；R7从H，R，OH，OR，SH，SR，NH2，NHR，NRR′，硝基，Me3Sn和卤素中选择；其中R和R′分别从可选取的取代的C1-7烷基，C3-20杂环基和C5-20芳基中独立选择；R10和R11要么一起形成双键，要么分别从H和QRQ中选择，其中Q从O，S和NH中选择，RQ为H或C1-7烷基或H和SOxM，其中x为2或3，M为单价的药用可接受阳离子；A从（A1），（A2），（A3），（A4）或（A5）中选择，其中X1和Y1分别从：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；和CH和O中选择；X2和Y2分别从：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；和CH和O中选择；Z1从O和S中选择；Z2从CH和N中选择；F从单键和-(E-F1)m—中选择；每个E独立选择自单键和—C(═O)—NH—；每个F1独立选择自C3-20杂芳基基团；m为1、2或3；G从氢、C1-4烷基、—C(═O)—O—C1-4烷基、—(CH2)n—C3-20杂环烷基和—O—(CH2)n—C3-20杂环烷基基团中选择；每个n为0-4；前提是A2不是A2′，其中A2′的X1和Y1从：CH和NMe；COH和NMe；CH和S；N和NMe；N和S中选择；并且前提是A3不是A3′，其中A3′的X2和Y2从：CH和NMe；COH和NMe；CH和S；N和NMe；N和S中选择；B要么是单键，要么是（B1），其中B1的X和Y从：CH和NMe；COH和NMe；CH和S；N和NMe；N和S中选择；R1为C1-4烷基。
• US9321774B2
  申请人：——

  公开号：US9321774B2

  公开（公告）日：2016-04-26