公开(公告)号：US09273003B2

公开(公告)日：2016-03-01

申请号：US14324510

申请日：2014-07-07

Applicant: GlaxoSmithKline Intellectual Property Development Limited

Inventor： Alan Hornsby Davidson ,  David Festus Charles Moffat ,  Francesca Ann Day ,  Alastair David Graham Donald

IPC: A61K31/4965 ,  A01N37/18 ,  A61K31/445 ,  C07D213/56 ,  C07C311/19 ,  C07D215/22 ,  C07D241/04 ,  C07D333/70 ,  C07D409/12 ,  C07D471/04

CPC classification number: C07C259/06 ,  C07C311/19 ,  C07C2601/08 ,  C07C2601/14 ,  C07D211/34 ,  C07D211/58 ,  C07D213/56 ,  C07D215/22 ,  C07D241/04 ,  C07D333/70 ,  C07D409/12 ,  C07D471/04

Abstract: Compounds of formula (I) inhibit HDAC activity: wherein A, B and D independently represent ═C— or ═N—; W is a divalent radical —CH═CH— or CH2CH2—; 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; z is 0 or 1; and Y, L1, and X1 are as defined in the claims.

Abstract translation: 式（I）的化合物抑制HDAC活性：其中A，B和D独立地表示= C-或= N-; W是二价基团-CH = CH-或CH 2 CH 2 - ; R1是羧酸基团（-COOH）或可被一个或多个细胞内羧酸酯酶水解成羧酸基团的酯基; R2是天然或非天然α氨基酸的侧链; z为0或1; Y，L1和X1如权利要求中所定义。

公开(公告)号：US09636409B2

公开(公告)日：2017-05-02

申请号：US15017853

申请日：2016-02-08

Applicant: GlaxoSmithKline Intellectual Property Development Limited

Inventor： Alan Hastings Drummond ,  Alan Hornsby Davidson ,  David Festus Charles Moffat ,  Alastair David Graham Donald ,  Stephen John Davies

IPC: C07D211/70 ,  C07D211/82 ,  C07D213/55 ,  C07D213/56 ,  A61K31/44 ,  A61K47/48 ,  C07D213/73 ,  C12Q1/48 ,  A61K31/4418

CPC classification number: A61K47/48038 ,  A61K31/4418 ,  A61K47/542 ,  C07D213/73 ,  C12Q1/485

Abstract: Covalent conjugates of an α,α-disubstituted glycine ester and a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid and the α,α-disubstituted glycine ester is conjugated to the modulator at a position remote from the binding interface between the inhibitor and the target enzyme or receptor pass into cells and the active acid hydrolysis product accumulates within the cells, as in the following compound:

公开(公告)号：US20180000952A1

公开(公告)日：2018-01-04

申请号：US15650031

申请日：2017-07-14

Applicant: GlaxoSmithKline Intellectual Property Development Limited

Inventor： Alan Hornsby Davidson ,  Alan Hastings Drummond ,  Lindsey Ann Needham

IPC: A61K47/54 ,  C07D277/46 ,  C07D213/73 ,  C07C237/22 ,  C07D471/04 ,  C07D215/233 ,  C07C2601/08

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

Abstract: Covalent conjugation of an alpha amino acid ester to a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid, leads to accumulation of the carboxylic acid hydrolysis product in the cell and enables improved or more prolonged enzyme or receptor modulation relative to the unconjugated modulator.

公开(公告)号：US09725407B2

公开(公告)日：2017-08-08

申请号：US15004039

申请日：2016-01-22

Applicant: GlaxoSmithKline Intellectual Property Development Limited

Inventor： Alan Hornsby Davidson ,  David Festus Charles Moffat ,  Francesca Ann Day ,  Alastair David Graham Donald

IPC: C07C259/06 ,  C07D211/58 ,  C07D211/34 ,  C07C311/19 ,  C07D213/56 ,  C07D215/22 ,  C07D241/04 ,  C07D333/70 ,  C07D409/12 ,  C07D471/04

CPC classification number: C07C259/06 ,  C07C311/19 ,  C07C2601/08 ,  C07C2601/14 ,  C07D211/34 ,  C07D211/58 ,  C07D213/56 ,  C07D215/22 ,  C07D241/04 ,  C07D333/70 ,  C07D409/12 ,  C07D471/04

Abstract: Compounds of formula (I) inhibit HDAC activity: wherein A, B and D independently represent ═C— or ═N—; W is a divalent radical —CH═CH— or CH2CH2—; R1 is an ester group; R2 is the side chain of a natural or non-natural alpha-amino acid; z is 0 or 1; and Y, L1, and X1 are as defined in the claims.

公开(公告)号：US20160151509A1

公开(公告)日：2016-06-02

申请号：US15017853

申请日：2016-02-08

Applicant: GlaxoSmithKline Intellectual Property Development Limited

Inventor： Alan Hastings Drummond ,  Alan Hornsby Davidson ,  David Festus Charles Moffat ,  Alastair David Graham Donald ,  Stephen John Davies ,  Margaret Struthers Drummond

IPC: A61K47/48 ,  A61K31/4418

CPC classification number: A61K47/48038 ,  A61K31/4418 ,  A61K47/542 ,  C07D213/73 ,  C12Q1/485

Abstract: Covalent conjugates of an α,α-disubstituted glycine ester and a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid and the α,α-disubstituted glycine ester is conjugated to the modulator at a position remote from the binding interface between the inhibitor and the target enzyme or receptor pass into cells and the active acid hydrolysis product accumulates within the cells.

Abstract translation: α，α-二取代的甘氨酸酯的共价轭合物和靶细胞内酶或受体的活性的调节剂，其中缀合物的酯基可被一个或多个细胞内羧酸酯酶可水解成相应的酸和α，α 二取代的甘氨酸酯在远离抑制剂和靶酶或受体之间的结合界面的位置与调节物缀合，进入细胞，并且活性酸水解产物积聚在细胞内。