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1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors

a technology of histone deacetylase and derivatives, which is applied in the field of 1, 2, 4oxadiazole derivatives, can solve the problems of toxic side effects and significant side effects of pan-hdac inhibitors

Inactive Publication Date: 2020-10-29
ORYZON GENOMICS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a compound of Formula (I) and its salt, which are inhibitors of HDACs, particularly HDAC6. These compounds have potential to treat diseases associated with HDAC6 such as cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathy, diseases of the nervous system, mental or behavioral disorder, infectious disease, cardiovascular disease, muscle atrophy or cachexia. The compounds can be used as pharmaceutical compositions or medications for the treatment of these diseases.

Problems solved by technology

Pan-HDAC inhibitors are known to exhibit significant side effects; in particular, toxic side effects have been associated with inhibition of certain HDAC class I isoforms, particularly HDAC1 and HDAC2.

Method used

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  • 1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors
  • 1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors
  • 1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

2-(Trimethylstannyl)isonicotinonitrile

[0321]To a stirred solution of 2-bromoisoniconitrile (2 g, 10.92 mmol) in toluene (20 mL), hexamethylditin (4.6 g, 14.20 mmol), and Pd(PPh3)4 (1.2 g, 1.09 mmol) were added at rt. The resulting solution was degassed with nitrogen for 10 min and heated to 110° C. for 16 h. The reaction mixture was evaporated under reduced pressure and the crude compound was purified by flash column chromatography on neutral alumina using 50% EtOAc in petroleum ether to afford the title compound (1.5 g, 51.7%).

[0322]LC-MS (method 1): Rt=1.93 min; m / z=269.08 (M+H+)

reference example 2

5-Bromo-1-butyl-1H-pyrrolo[2,3-c]pyridine

[0323]To a stirred suspension of 60% NaH (0.146 g, 6.091 mmol) in DMF (20 mL), 5-bromo-1H-pyrrolo[2,3-c]pyridine (0.8 g, 4.06 mmol) was added at 0° C. and stirred for 15 min. Then, 1-bromo butane (0.66 g, 4.873 mmol) was added to the reaction mixture at 0° C. The resulting mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was quenched with water and extracted EtOAc and the organic layer was dried over anhydrous Na2SO4, and it was concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 10% EtOAc in pet ether as an eluent to afford the title compound (0.78 g, 67%).

[0324]LC-MS (method 2): Rt=2.27 min; m / z=253.17 (M+H+).

[0325]Following a similar procedure to that described in reference example 2, but using in each case the corresponding starting materials, the following compounds were obtained:

ReferenceStartingHPLCRt exampleCompound namematerialmethod(min)m / z2a5-Bromo-1-...

reference example 3

5-Bromo-1-butyl-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Step a. 5-Bromo-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0326]To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (500 mg, 2.07 mmol) in DMF, dimethyl amine hydrochloride (168 mg, 2.07 mmol), TEA (1.49 g, 10.37 mmol) and T3P (1.97 g, 6.21 mmol) were added at 0° C. The resulting mixture was allowed to stir at rt for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted at 5% MeOH in DCM to afford the title compound (450 mg, 78%).

[0327]LC-MS (method 4): Rt=1.75 min; m / z=270.15 (M+H++2).

Step b. 5-Bromo-1-butyl-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0328]To a stirred solution of the compound obtained in the previous section, step a (1.4 g, 5.24 mmol) in DMF, 60...

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PUM

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Abstract

The invention relates to compounds of Formula (I) as described herein, useful as histone deacetylase 6 (HDAC6) inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy.

Description

TECHNICAL FIELD[0001]The invention relates to 1,2,4-oxadiazole derivatives useful as histone deacetylase 6 inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy.BACKGROUND[0002]Histone deacetylases (HDACs) are part of a large family of enzymes that catalyze the removal of acetyl group from histones and non-histone proteins. HDACs have crucial roles in numerous biological processes, largely through their repressive influence on transcription. In humans, there are four classes of HDACs which include a total of 18 proteins: class I HDACs are HDAC1, HDAC2, HDAC3 and HDAC8; class II HDACs are HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10; class III HDACs are Sir2-like proteins SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7; and class IV HDACs, which is HDAC11. The class II enzymes are further divided into two subclasses, class IIa (HDAC4, HDAC5, HDAC7 and HDAC9) and class IIb (HDAC6 and HDAC10).[0003]Histone deacet...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D413/14
CPCC07D471/04C07D413/14A61P31/00A61P25/00A61P9/00A61K45/06A61K31/444A61P35/00A61P29/00
Inventor CARCELLER GONZÁLEZ, ELENAORTEGA MUÑOZ, ALBERTOSALAS SOLANA, JORGE
Owner ORYZON GENOMICS SA
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