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    ENZYME INHIBITORS
    4.
    发明授权
    ENZYME INHIBITORS 有权
    酶抑制剂

    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.

    ENZYME INHIBITORS
    6.
    发明公开
    ENZYME INHIBITORS 有权
    酶抑制剂

    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。

    ALPHA AMINOACID ESTER-DRUG CONJUGATES HYDROLYSABLE BY CARBOXYLESTERASE
    7.
    发明公开
    ALPHA AMINOACID ESTER-DRUG CONJUGATES HYDROLYSABLE BY CARBOXYLESTERASE 有权
    DURCH羧甲基纤维素水解酶ALPHA-AMINOSÄUREESTER-ARZNEIKONJUGATE

    公开(公告)号：EP1877098A2

    公开(公告)日：2008-01-16

    申请号：EP06727008.2

    申请日：2006-05-04

    申请人： Chroma Therapeutics Limited

    发明人： DAVIDSON, Alan Hornsby ,  DRUMMOND, Alan Hastings ,  NEEDHAM, Lindsey Ann

    IPC分类号： A61K47/48

    CPC分类号： A61K47/542 ,  A61K47/54 ,  C07C237/22 ,  C07C2601/08 ,  C07D213/73 ,  C07D215/233 ,  C07D277/46 ,  C07D471/04

    摘要： Covalent conjugation of an alpha amino acid ester to a modulator of the activity of a target intr acellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by intracellular carboxylesterase enzyme hCE1 and not by hCE2 or hCE3 to the corresponding acid, leads to selective accumulation of the carboxylic acid hydrolysis product in monocyte/macrophage cell and enables improved or more prolonged enzyme or receptor modulation in those cells relative to the unconjugated modulator.

    摘要翻译： α氨基酸酯与靶细胞内酶或受体活性的调节剂的共价轭合，其中缀合物的酯基可通过细胞内羧酸酯酶hCE1而不是通过hCE2或hCE3可水解成相应的酸，导致 羧酸水解产物在单核细胞/巨噬细胞中的选择性积累，并且使得相对于未偶联的调节剂在这些细胞中能够改善或延长酶或受体调节。