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HDAC inhibitors

a technology of hdac inhibitors and inhibitors, which is applied in the field of hdac inhibitors, can solve the problems of increasing potency and duration of action, and achieve the effects of overcoming the poor pharmacokinetic properties of parent drugs, enhancing the delivery to target organs and tissues, and reducing the risk of side effects

Inactive Publication Date: 2013-08-01
GLAXOSMITHKLINE INTPROP DEV LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a new class of substances that can treat diseases like cancer or inflammation by inhibiting a protein called HDAC. These substances have a special structure that allows them to easily enter cells and accumulate there in high concentrations. This high concentration results in more powerful and longer-lasting treatment of the disease. This new group of substances is characterized by having a special part called an "esterase motif" that is attached to a larger molecule. When the substances enter cells, an enzyme breaks them open and the active ingredient is released. This makes the treatment more effective and longer-lasting.

Problems solved by technology

This leads to increases in potency and duration of action.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

(2S)-[({3-[(1E)-3-(Hydroxyamino)-3-oxoprop-1-en-1-yl]phenyl}sulfonyl)amino](phenyl)acetate

[0142]

[0143]The title compound was prepared by the following methodology:

Stage 1—Preparation of 3-formylbenzenesulfonate sodium salt

[0144]Benzaldehyde (10 g, 94 mmol) was added dropwise to 20% sulfur trioxide in fuming sulfuric acid (25 mL) and stirred under an atmosphere of nitrogen, maintaining the reaction temperature below 40° C. The reaction was stirred at 40° C. for 18 h. The reaction was then quenched onto ice (60 g) and the aqueous extracted with EtOAc (100 mL). The aqueous phase was treated with CaCO3 until the evolution of CO2 ceased (pH ˜6). The resultant precipitate was filtered, washed with water and the filtrate basified with Na2CO3 to pH ˜8. The precipitate was removed by filtration and the filtrate evaporated to dryness in vacuo. The residue was washed with MeOH, filtered and the washings concentrated to give the desired product as a white solid (7.94 g, 81%). 1H NMR (300 MHz, C...

example 5

Cyclopentyl (2S)-cyclohexyl({3-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzoyl}amino)acetate

[0152]

[0153]The title compound was prepared by the following methodology:

Stage 1—Preparation of 3-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]benzoic acid

[0154]3-Carboxybenzaldehyde (25 g, 0.167 mol) and K2CO3 (69 g, 0.499 mol) were added to water (250 mL) and cooled to 0-5° C. Trimethyl phosphonoacetate (32.3 mL, 0.2 mol) was charged dropwise maintaining the reaction temperature below 15° C. The reaction was warmed and stirred at RT for 17 h. The mixture was acidified to pH ˜1, filtered and dried in vacuo to afford the product as an off-white solid (37.25 g, >100%—slightly wet). 1H NMR (300 MHz, CD3OD) δ: 8.23 (1H, s), 8.06 (1H, d, J=7.8 Hz), 7.86 (1H, d, J=7.5 Hz), 7.75 (1H, d, J=15.9 Hz), 6.61 (1H, d, J=16.2 Hz), 7.54 (1H, t), 3.81 (3H, s).

Stage 2—Preparation of methyl (2E)-3-(3-{[(1S)-1-cyclohexyl-2-(cyclopentyloxy)-2-oxoethyl]carbamoyl}phenyl)acrylate

[0155]Stage 1 product (5 g, 24 mmol) was a...

example 9

Cyclopentyl (2S)-cyclohexyl[(3-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]phenoxy}propyl)amino]acetate

[0160]

[0161]The title compound was prepared by the following methodology:

Stage 1—Preparation of (2E)-3-(4-hydroxyphenyl)-N-(1-isobutoxyethoxy)acrylamide

[0162]4-Hydroxycinnamic acid (1 g, 6.1 mmol), EDCl (1.76 g, 9.1 mmol) and HOBt (1.24 g, 9.1 mmol) were added to DCM (20 mL) and stirred at RT for 45 minutes. Intermediate I (4.2 mL, 30.5 mmol) and triethylamine (4.1 mL, 30.5 mmol) were added and the reaction stirred at RT for 1.5 h. The reaction was separated with water, the aqueous phase extracted with DCM (20 mL) and the combined organics dried (MgSO4) and concentrated in vacuo. The crude material was purified by column chromatography to afford the product as a clear oil (1.39 g, 82%). m / z=278 [M−H]−.

Stage 2—Preparation of (2E)-3-[4-(3-bromopropoxy)phenyl]-N-(1-isobutoxyethoxy)acrylamide

[0163]Stage 1 product (0.66 g, 2.4 mmol), 3-bromopropan-1-ol (0.24 mL, 2.6 mmol) and tripheny...

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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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of co-pending application Ser. No. 12 / 443,096, filed Apr. 17, 2009, which is a National Stage application of co-pending PCT application PCT / GB2007 / 003504 filed Sep. 14, 2007, which claims the benefit of Great Britain application number 0619753.7 filed Jun. 10, 2006. These applications are incorporated herein by reference in their entireties.[0002]This invention relates to compounds which inhibit members of the histone deacetylase family of enzymes and to their use in the treatment of cell proliferative diseases, including cancers, polyglutamine diseases, for example Huntingdon disease, neurogenerative diseases for example Alzheimer disease, autoimmune disease for example rheumatoid arthritis and organ transplant rejection, diabetes, haematological disorders, inflammatory disease, cardiovascular disease, atherosclerosis, and the inflammatory sequelia of infection.BACKGROUND TO THE INVENTION[0003]In eukary...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D213/56
CPCC07C311/19C07D213/56C07D215/22C07D471/04C07D333/70C07D409/12C07D241/04C07C2601/08C07C2601/14C07D211/34C07D211/58A61P1/04A61P11/00A61P11/06A61P17/00A61P17/02A61P17/06A61P19/02A61P25/00A61P25/14A61P25/18A61P25/28A61P29/00A61P3/00A61P31/00A61P35/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/00A61P9/00A61P9/10A61P3/10C07D295/088A61K31/223C07C259/06
Inventor DAVIDSON, ALAN HORNSBYMOFFAT, DAVID CHARLES FESTUSDAY, FRANCESCA ANNDONALD, ALASTAIR DAVID GRAHM
Owner GLAXOSMITHKLINE INTPROP DEV LTD
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