公开(公告)号：EP1879895B1

公开(公告)日：2011-06-08

申请号：EP06726982.9

申请日：2006-05-04

申请人： Chroma Therapeutics Limited

发明人： DAVIDSON, Alan Hornsby ,  PATEL, Sanjay Ratilal ,  MAZZEI, Francesca Ann ,  DAVIES, Stephen John ,  DRUMMOND, Alan Hastings ,  MOFFAT, David Festus C. ,  BAKER, Kenneth William John ,  DONALD, Alistair David Graham

IPC分类号： C07D487/04 ,  C07D295/18 ,  C07D217/12 ,  C07D333/62 ,  A61K31/4045 ,  A61K31/4353 ,  A61K31/4965 ,  A61P35/00

CPC分类号： C07C237/40 ,  C07C259/06 ,  C07C275/24 ,  C07C311/46 ,  C07C317/50 ,  C07C2601/08 ,  C07C2601/14 ,  C07D207/416 ,  C07D209/42 ,  C07D213/40 ,  C07D217/02 ,  C07D217/22 ,  C07D217/26 ,  C07D295/185 ,  C07D295/192 ,  C07D333/70 ,  C07D471/04

摘要： Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R2 is the side chain of a natural or non-natural alpha amino acid; Y is a bond, -C(=O)-, -S(=O)2-, -C(=O)O-, -C(O)NR3-, -C(=S)-NR3 , -C(=NH)NR3 or -S(=O)2NR3- wherein R3 is hydrogen or optionally substituted C1-C6 alkyl; L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)p- wherein m, n and p are independently 0 or 1 , Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula -X2-Q1- or -Q1-X2- wherein X2 is -O-, S- or NRA- wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, AIk1 and AIk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, C1-C6 alkylene, C2-C6 alkenylene ,or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl; X1 represents a bond; -C(=O); or -S(=O)2-; -NR4C(=O)-, -C(=O)NR4-, -NR4C(=O)NR5- , -NR4S(=O)2-, or -S(=O)2NR4-wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; z is 0 or 1 ; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R1R2NH-Y-L1-X1-[CH2]Z- and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONHOH, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms.

公开(公告)号：EP1879895A1

公开(公告)日：2008-01-23

申请号：EP06726982.9

申请日：2006-05-04

申请人： Chroma Therapeutics Limited

发明人： DAVIDSON, Alan Hornsby ,  PATEL, Sanjay Ratilal ,  MAZZEI, Francesca Ann ,  DAVIES, Stephen John ,  DRUMMOND, Alan Hastings ,  MOFFAT, David Festus C. ,  BAKER, Kenneth William John ,  DONALD, Alistair David Graham

IPC分类号： C07D487/04 ,  C07D295/18 ,  C07D217/12 ,  C07D333/62 ,  A61K31/4045 ,  A61K31/4353 ,  A61K31/4965 ,  A61P35/00

CPC分类号： C07C237/40 ,  C07C259/06 ,  C07C275/24 ,  C07C311/46 ,  C07C317/50 ,  C07C2601/08 ,  C07C2601/14 ,  C07D207/416 ,  C07D209/42 ,  C07D213/40 ,  C07D217/02 ,  C07D217/22 ,  C07D217/26 ,  C07D295/185 ,  C07D295/192 ,  C07D333/70 ,  C07D471/04

摘要： Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R2 is the side chain of a natural or non-natural alpha amino acid; Y is a bond, -C(=O)-, -S(=O)2-, -C(=O)O-, -C(O)NR3-, -C(=S)-NR3 , -C(=NH)NR3 or -S(=O)2NR3- wherein R3 is hydrogen or optionally substituted C1-C6 alkyl; L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)p- wherein m, n and p are independently 0 or 1 , Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula -X2-Q1- or -Q1-X2- wherein X2 is -O-, S- or NRA- wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, AIk1 and AIk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, C1-C6 alkylene, C2-C6 alkenylene ,or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl; X1 represents a bond; -C(=O); or -S(=O)2-; -NR4C(=O)-, -C(=O)NR4-, -NR4C(=O)NR5- , -NR4S(=O)2-, or -S(=O)2NR4-wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; z is 0 or 1 ; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R1R2NH-Y-L1-X1-[CH2]Z- and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONHOH, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms.

摘要翻译： 式（I）化合物是组蛋白脱乙酰酶活性的抑制剂，并且可用于治疗例如癌症，其中R 1是羧酸基团（-COOH），或可被一个或多个细胞内水解的酯基 羧酸酯酶转化为羧酸基团; R2是天然或非天然α氨基酸的侧链; （= O）2，-C（= O）O - ， - C（= O） （= NH）NR 3或-S（= O）2 NR 3 - ，其中R 3为氢或任选取代的C 1 -C 6烷基; L1是式 - （Alk1）m（Q）n（Alk2）p-的二价基团，其中m，n和p独立地为0或1，Q为（i）任选取代的二价单环或双环碳环或杂环基 （ii）在m和p均为0的情况下，具有式-X 2 -Q 1 - 或-Q 1 -X 2 - 的二价基团，其中X 2是-O-，S-或NRA - 其中RA是氢或任选取代的C 1 -C 3烷基，并且Q 1是任选取代的具有5-13个环成员的二价单环或双环碳环或杂环基团，Alk1和Alk2独立地表示任选取代的二价C3-C7环烷基基团，或 （-O-），硫醚（-S-）或氨基（-NRA-）的任选取代的直链或支链的C1-C6亚烷基，C2-C6亚烯基或C2-C6亚炔基， 其中RA是氢或任选取代的C 1 -C 3烷基; X1代表一个键; -C（= O）; 或-S（= O）2 - ; （= O） - ， - C（= O）NR 4 - ， - NR 4 C（= O）NR 5 - ，-NR 4 S（= O）2 - 或-S（= O）2 NR 4 - 氢或任选取代的C 1 -C 6烷基; z是0或1; A代表任选取代的单环，双环或三环碳环或杂环系统，其中基团R 1 R 2 NH-Y-L 1 -X 1 - [CH 2] Z-和HONHCO- [连接基] - 连接不同的环原子; 和 - [连接基团] - 表示连接A中的环原子和异羟肟酸基团CONHOH的二价连接基团，连接基团的长度从与A的环原子连接的末端原子到与异羟肟基连接的末端原子 酸基相当于3-10个碳原子的无支链饱和烃链。