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1. 发明申请

US20100113425A1 PYRROLOBENZODIAZEPINES 有权
标题翻译： PYRROBOBENZODIAZEPINES
公开(公告)号：US20100113425A1
公开(公告)日：2010-05-06
申请号：US12610478
申请日：2009-11-02
申请人： Philip Wilson Howard , Zhizhi Chen , Stephen John Gregson
发明人： Philip Wilson Howard , Zhizhi Chen , Stephen John Gregson
IPC分类号： A61K31/551 , A61P35/02 , A61P35/00 , C07D487/04
CPC分类号： C07D519/00
摘要： Compounds of the formula I: or solvate thereof, wherein: R2 is an optionally substituted C5-20 aryl group; R6 and R9 are independently 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 C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo; R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings; X is selected from O, S, or NH; z is 2 or 3; M is a monovalent pharmaceutically acceptable cation; R2′, R6′, R7′, R9′, X′ and M′ are selected from the same groups as R2, R6, R7, R9, X and M respectively, or M and M′ may together represent a divalent pharmaceutically acceptable cation.
摘要翻译：式I化合物或其溶剂化物，其中：R2是任选取代的C5-20芳基; R 6和R 9独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，硝基，Me 3 Sn和卤素; 其中R和R'独立地选自任选取代的C 1-12烷基，C 3-20杂环基和C 5-20芳基; R 7选自H，R，OH，OR，SH，SR，NH 2，NHR，NHRR'，硝基，Me 3 Sn和卤素; R“是C3-12亚烷基，该链可被一个或多个杂原子和/或芳环中断; X选自O，S或NH; z是2或3; M是一价药学上可接受的阳离子; R 2'，R 6'，R 7'，R 9'，X'和M'分别选自与R 2，R 6，R 7，R 9，X和M相同的基团，或M和M'可以一起表示二价药学上可接受的阳离子。

2. 发明授权

US07741319B2 11-hydroxy-5h-pyrrolo[2,1-c][1,4] benzodiazepin-5-one derivatives as key intermediates for the preparation of c2 substituted pyrrolobenzodiazepines 有权
标题翻译： 11-羟基-5H-吡咯并[2,1-c] [1,4]苯并二氮杂-5-酮衍生物作为制备c2取代的吡咯并苯并二氮杂的关键中间体
公开(公告)号：US07741319B2
公开(公告)日：2010-06-22
申请号：US10598518
申请日：2005-03-01
申请人： Philip Wilson Howard , Stephen John Gregson
发明人： Philip Wilson Howard , Stephen John Gregson
IPC分类号： C07D487/04 , C07D519/00 , A61K31/5517 , A61P35/00
CPC分类号： C07D487/04 , Y02P20/55
摘要： The present inventors have developed a key intermediate for the production of C2 substituted PBDs, which has a leaving group at the C2 position, a carbamate protecting group at the N10 position and a protected hydroxy group at the C11 position. In a first aspect, the present invention comprises a compound with a the formula (I), wherein: R10 is a carbamate-based nitrogen protecting group; R11 is an oxygen protecting group; and R2 is a labile leaving group. In a further aspect, the present invention comprises a method of synthesising a compound of formula (III), or a solvate thereof, from a compound of formula (I) as defined in the first aspect, R16 is either O—R11, wherein R11 is as defined in the first aspect, or OH, or R10 and R16 together form a double bond between N10 and C11; and R15 is R. The other substituents are defined in the claims. Further aspects of the present invention relate to compounds of formula (III) (including solvates thereof when R10 and R16 form a double bond between N10 and C11, and pharmaceutical salts thereof), pharmaceutical compositions comprising these, and their use in the manufacture of a medicament for the treatment of a proliferative disease.
摘要翻译：本发明人已经开发了用于生产在C2位具有离去基团的C2取代的PBD的关键中间体，N10位的氨基甲酸酯保护基和C11位的被保护的羟基。在第一方面，本发明包括具有式（I）的化合物，其中：R 10是氨基甲酸酯基氮保护基; R11为氧保护基; R2是不稳定的离去组。在另一方面，本发明包括由第一方面定义的式（I）化合物合成式（III）化合物或其溶剂合物的方法，R 16为O-R 11，其中R 11 在第一方面中定义，或OH或R 10和R 16一起形成N10和C11之间的双键; R 15为R。其它取代基在权利要求中限定。本发明的其它方面涉及式（III）化合物（包括当R 10和R 16在N 10和C 11之间形成双键时的溶剂合物及其药用盐），包含它们的药物组合物及其在制备用于治疗增殖性疾病的药物。

3. 发明授权

US08592576B2 Unsymmetrical pyrrolobenzodiazepine-dimers for treatment of proliferative diseases 有权
标题翻译：用于治疗增殖性疾病的不对称吡咯并苯并二氮杂二聚体
公开(公告)号：US08592576B2
公开(公告)日：2013-11-26
申请号：US13123327
申请日：2009-10-16
申请人： Philip Wilson Howard , Stephen John Gregson , Luke Masterson
发明人： Philip Wilson Howard , Stephen John Gregson , Luke Masterson
IPC分类号： C07D487/04
CPC分类号： C07D487/04
摘要： Claimed are unsymmetrical Pyrrolobenzodiazepine-dimers (PBD-dimers) of formula (I), that are unsymmetrical due at least to the values that the variables R12 and R2 represent. Formula (I), wherein: R2 is of formula (II), where A is a C5-7 aryl group, X is selected from the group comprising: OH, SH, CO2H, COH, N═C═O, NHRN, wherein RN is selected from the group comprising H and C1-4 alkyl, and (OC2H4)mOCH3, where m is 1 to 3, 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; R12 is a C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene. The other variables are as defined in the claims. The compounds are useful for the treatment of proliferative diseases.
摘要翻译：声称是式（I）的不对称吡咯并苯并二氮杂二聚体（PBD-二聚体），其至少与变量R12和R2表示的值不对称。式（I）其中：R2为式（Ⅱ），其中A为C5-7芳基，X选自OH，SH，CO2H，COH，N = C = O，NHRN，其中 RN选自H和C 1-4烷基，和（OC 2 H 4）m OCH 3，其中m为1至3，以及：（i）Q1为单键，Q2选自单键和-Z - （CH 2）n - ，其中Z选自单键，O，S和NH，n为1至3; 或（ii）Q1为-CH = CH-，Q2为单键; R 12是任选被一个或多个选自以下的取代基取代的C 5-10芳基：卤素，硝基，氰基，醚，C 1-7烷基，C 3-7杂环基和双 - 氧C 1-3亚烷基。其他变量如权利要求中所定义。该化合物可用于治疗增殖性疾病。

4. 发明授权

US08487092B2 Pyrrolobenzodiazepines 有权
标题翻译：吡咯并苯并二氮杂卓
公开(公告)号：US08487092B2
公开(公告)日：2013-07-16
申请号：US13124232
申请日：2009-10-16
申请人： Philip Wilson Howard , Stephen John Gregson , ZhiZhi Chen , Arnaud Charles Tiberghien , Luke Masterson
发明人： Philip Wilson Howard , Stephen John Gregson , ZhiZhi Chen , Arnaud Charles Tiberghien , Luke Masterson
IPC分类号： C07D519/00
CPC分类号： C07D519/00
摘要： The invention relates to certain pyrrolobenzodiazepines (PBDs), and in particular pyrrolobenzodiazepine dimers bearing C2 substitutions, including compounds of formula (T): wherein: R2 is CHR2A, and R2A is independently selected from H, R, CO2R, COR, CHO, CO2H, and halo; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo; R7 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo; R8 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo; R is independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; or the compound is a dimer with each monomer being of formula (M), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers; wherein R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), and/or aromatic rings, e.g. benzene or pyridine; and each X is independently selected from O, S, or N(H); or any pair of adjacent groups from R6 to R9 together form a group —O—(CH2)p—O—, where p is 1 or 2, and salts and solvates thereof, and their use as intermediates for the preparation of other PBD compounds.
摘要翻译：本发明涉及某些吡咯并苯并二氮杂（PBD），特别是含有C2取代的吡咯并苯并二氮杂二聚体，包括式（T）化合物：其中：R2为CHR2A，R2A独立地选自H，R，CO2R，COR，CHO，CO2H ，和卤素; R 6和R 9独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，NO 2，Me 3 Sn和卤素; R 7独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，NO 2，Me 3 Sn和卤素; R 8独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，NO 2，Me 3 Sn和卤素; R独立地选自任选取代的C 1-12烷基，C 3-20杂环基和C 5-20芳基; 或者化合物是每个单体具有式（M）的二聚体，其中每个单体的R 7基团或R 8基团一起形成具有式-X-R“-X-连接单体的二聚体桥; 其中R“是C 3-12亚烷基，该链可被一个或多个杂原子间隔，例如， O，S，N（H）和/或芳环，例如。苯或吡啶; 并且每个X独立地选自O，S或N（H）; 或R6至R9的任何一对相邻基团一起形成-O-（CH 2）p -O-基团，其中p为1或2，以及其盐和溶剂化物，以及它们作为制备其它PBD化合物的中间体的用途。

5. 发明申请

US20110201803A1 PYRROLOBENZODIAZEPINES 有权
标题翻译： PYRROBOBENZODIAZEPINES
公开(公告)号：US20110201803A1
公开(公告)日：2011-08-18
申请号：US13124232
申请日：2009-10-16
申请人： Philip Wilson Howard , Stephen John Gregson , Zhizhi Chen , Arnaud Charles Tiberghien , Luke Masterson
发明人： Philip Wilson Howard , Stephen John Gregson , Zhizhi Chen , Arnaud Charles Tiberghien , Luke Masterson
IPC分类号： C07D487/04
CPC分类号： C07D519/00
摘要： The invention relates to certain pyrrolobenzodiazepines (PBDs), and in particular pyrrolobenzodiazepine dimers bearing C2 substitutions, including compounds of formula (T): wherein: R2 is CHR2A, and R2A is independently selected from H, R, CO2R, COR, CHO, CO2H, and halo; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo; R7 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo; R8 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo; R is independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; or the compound is a dimer with each monomer being of formula (M), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers; wherein R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), and/or aromatic rings, e.g. benzene or pyridine; and each X is independently selected from O, S, or N(H); or any pair of adjacent groups from R6 to R9 together form a group —O—(CH2)p—O—, where p is 1 or 2, and salts and solvates thereof, and their use as intermediates for the preparation of other PBD compounds.
摘要翻译：本发明涉及某些吡咯并苯并二氮杂（PBD），特别是含有C2取代的吡咯并苯并二氮杂二聚体，包括式（T）化合物：其中：R2为CHR2A，R2A独立地选自H，R，CO2R，COR，CHO，CO2H ，和卤素; R 6和R 9独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，NO 2，Me 3 Sn和卤素; R 7独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，NO 2，Me 3 Sn和卤素; R 8独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，NO 2，Me 3 Sn和卤素; R独立地选自任选取代的C 1-12烷基，C 3-20杂环基和C 5-20芳基; 或者化合物是每个单体具有式（M）的二聚体，其中每个单体的R 7基团或R 8基团一起形成具有式-X-R“-X-连接单体的二聚体桥; 其中R“是C 3-12亚烷基，该链可被一个或多个杂原子间隔，例如。 O，S，N（H）和/或芳环，例如。苯或吡啶; 并且每个X独立地选自O，S或N（H）; 或从R6至R9的任何一对相邻基团一起形成-O-（CH 2）p -O-基团，其中p为1或2，以及其盐和溶剂化物，以及它们作为制备其它PBD化合物的中间体的用途。

6. 发明申请

US20110196148A1 UNSYMMETRICAL PYRROLOBENZODIAZEPINE-DIMERS FOR TREATMENT OF PROLIFERATIVE DISEASES 有权
标题翻译：用于治疗增殖性疾病的非对称吡嗪二酮
公开(公告)号：US20110196148A1
公开(公告)日：2011-08-11
申请号：US13123327
申请日：2009-10-16
申请人： Philip Wilson Howard , Stephen John Gregson , Luke Masterson
发明人： Philip Wilson Howard , Stephen John Gregson , Luke Masterson
IPC分类号： C07D487/04
CPC分类号： C07D487/04
摘要： Claimed are unsymmetrical Pyrrolobenzodiazepine-dimers (PBD-dimers) of formula (I), that are unsymmetrical due at least to the values that the variables R12 and R2 represent. Formula (I), wherein: R2 is of formula (II), where A is a C5-7 aryl group, X is selected from the group comprising: OH, SH, CO2H, COH, N═C═O, NHRN, wherein RN is selected from the group comprising H and C1-4 alkyl, and (OC2H4)mOCH3, where m is 1 to 3, and either: (i) Q1 is a single bond, and Q2 is selected from a single bond and —Z—(CH2)m—, 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; R12 is a C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene. The other variables are as defined in the claims. The compounds are useful for the treatment of proliferative diseases.
摘要翻译：声称是式（I）的不对称吡咯并苯并二氮杂二聚体（PBD-二聚体），其至少与变量R12和R2表示的值不对称。式（I）其中：R2为式（II），其中A为C5-7芳基，X选自OH，SH，CO2H，COH，N = C = O，NHRN，其中 RN选自H和C 1-4烷基，和（OC 2 H 4）m OCH 3，其中m为1至3，以及：（i）Q1为单键，Q2选自单键和-Z - （CH 2）m - ，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; R 12是任选被一个或多个选自以下的取代基取代的C 5-10芳基：卤素，硝基，氰基，醚，C 1-7烷基，C 3-7杂环基和双 - 氧C 1-3亚烷基。其他变量如权利要求中所定义。该化合物可用于治疗增殖性疾病。

7. 发明授权

US07612062B2 Pyrrolobenzodiazepines 有权
标题翻译：吡咯并苯并二氮杂卓
公开(公告)号：US07612062B2
公开(公告)日：2009-11-03
申请号：US11911890
申请日：2006-04-21
申请人： Stephen John Gregson , Philip Wilson Howard , Zhizhi Chen
发明人： Stephen John Gregson , Philip Wilson Howard , Zhizhi Chen
IPC分类号： C07D519/00 , A61K31/5517 , A61P35/00
CPC分类号： C07D519/00
摘要： Compounds of the formula: (I) or solvate thereof, wherein: R2 is an optionally substituted C5-20 aryl group; R6 and R9 are independently 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 C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo; R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings; X is selected from O, S, or NH; z is 2 or 3; M is a monovalent pharmaceutically acceptable cation; R2′, R6′, R7′, R9′, X′ and M′ are selected from the same groups as R2, R6, R7, R9, X and M respectively, or M and M′ may together represent a divalent pharmaceutically acceptable cation.
摘要翻译：式（I）或其溶剂化物的化合物，其中：R 2是任选取代的C 5-20芳基; R 6和R 9独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，硝基，Me 3 Sn和卤素; 其中R和R'独立地选自任选取代的C 1-12烷基，C 3-20杂环基和C 5-20芳基; R 7选自H，R，OH，OR，SH，SR，NH 2，NHR，NHRR'，硝基，Me 3 Sn和卤素; R“是C3-12亚烷基，该链可被一个或多个杂原子和/或芳环中断; X选自O，S或NH; z为2或3; M是一价药学上可接受的阳离子; R 2'，R 6'，R 7'，R 9'，X'和M'分别选自与R 2，R 6，R 7，R 9，X和M相同的基团，或M和M'可以一起表示二价药学上可接受的阳离子。

8. 发明申请

US20080167293A1 Pyrrolobenzodiazepines 有权
标题翻译：吡咯并苯并二氮杂卓
公开(公告)号：US20080167293A1
公开(公告)日：2008-07-10
申请号：US11911890
申请日：2006-04-21
申请人： Philip Wilson Howard , Zhizhi Chen , Stephen John Gregson
发明人： Philip Wilson Howard , Zhizhi Chen , Stephen John Gregson
IPC分类号： A61K31/5513 , C07D487/00 , A61P35/00
CPC分类号： C07D519/00
摘要： Compounds of the formula: (I) or solvate thereof, wherein: R2 is an optionally substituted C5-20 aryl group; R6 and R9 are independently 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 C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo; R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings; X is selected from O, S, or NH; z is 2 or 3; M is a monovalent pharmaceutically acceptable cation; R2′, R6′, R7′, R9′, X′ and M′ are selected from the same groups as R2, R6, R7, R9, X and M respectively, or M and M′ may together represent a divalent pharmaceutically acceptable cation.
摘要翻译：式（I）或其溶剂合物的化合物，其中：R 2是任选取代的C 5-20芳基; R 6和R 9独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，硝基，Me 3 Sn和卤素; 其中R和R'独立地选自任选取代的C 1-12烷基，C 3-20 - 杂环基和C 5-20芳基 ; R 7选自H，R，OH，OR，SH，SR，NH 2，NHR，NHRR'，硝基，Me 3 Sn和卤素; R“是C 3-12亚烷基，该链可以被一个或多个杂原子和/或芳环中断; X选自O，S或NH; z为2或3; M是一价药学上可接受的阳离子; R 2，R 6，R 7，R 9，X'和M'分别为分别选自与R 2，R 6，R 7，R 9，X和M分别相同的基团，或M和M'可以一起表示二价药学上可接受的阳离子。

9. 发明授权

US08633185B2 Pyrrolobenzodiazepines 有权
标题翻译：吡咯并苯并二氮杂卓
公开(公告)号：US08633185B2
公开(公告)日：2014-01-21
申请号：US12610478
申请日：2009-11-02
申请人： Philip Wilson Howard , Zhizhi Chen , Stephen John Gregson
发明人： Philip Wilson Howard , Zhizhi Chen , Stephen John Gregson
IPC分类号： C07D519/00 , A61K31/5517 , A61P35/00
CPC分类号： C07D519/00
摘要： Compounds of the formula I: or solvate thereof, wherein: R2 is an optionally substituted C5-20 aryl group; R6 and R9 are independently 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 C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo; R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings; X is selected from O, S, or NH; z is 2 or 3; M is a monovalent pharmaceutically acceptable cation; R2′, R6′, R7′, R9′, X′ and M′ are selected from the same groups as R2, R6, R7, R9, X and M respectively, or M and M′ may together represent a divalent pharmaceutically acceptable cation.
摘要翻译：式I化合物或其溶剂化物，其中：R2是任选取代的C5-20芳基; R 6和R 9独立地选自H，R，OH，OR，SH，SR，NH 2，NHR，NRR'，硝基，Me 3 Sn和卤素; 其中R和R'独立地选自任选取代的C 1-12烷基，C 3-20杂环基和C 5-20芳基; R 7选自H，R，OH，OR，SH，SR，NH 2，NHR，NHRR'，硝基，Me 3 Sn和卤素; R“是C3-12亚烷基，该链可被一个或多个杂原子和/或芳环中断; X选自O，S或NH; z为2或3; M是一价药学上可接受的阳离子; R 2'，R 6'，R 7'，R 9'，X'和M'分别选自与R 2，R 6，R 7，R 9，X和M相同的基团，或M和M'可以一起表示二价药学上可接受的阳离子。

10. 发明授权

US08501934B2 Pyrrolobenzodiazepines 有权
标题翻译：吡咯并苯并二氮杂卓
公开(公告)号：US08501934B2
公开(公告)日：2013-08-06
申请号：US13055194
申请日：2009-07-22
申请人： Philip Wilson Howard , Stephen John Gregson , Zhizhi Chen , Arnaud Charles Tiberghien , Luke Masterson
发明人： Philip Wilson Howard , Stephen John Gregson , Zhizhi Chen , Arnaud Charles Tiberghien , Luke Masterson
IPC分类号： A61P35/00 , A61K31/5517 , C07D487/04
CPC分类号： C07D487/04
摘要： Methods of preparing ZC-423 (I) which result in varying enantiomeric ratios.
摘要翻译：制备ZC-423（I）的方法，其导致不同的对映异构体比例。

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