Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Amorphous solid form of a bet protein inhibitor

Inactive Publication Date: 2017-05-04
INCYTE
View PDF1 Cites 21 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a solid form of a compound that inhibits the BET protein. This compound can be prepared through a series of intermediate compounds. The technical effects of this invention include a more efficient method for preparing the BET protein inhibitory compound and the discovery of new intermediate compounds during this process.

Problems solved by technology

Genetic knockdown of BRD2, BRD3 and BRD4 has been shown to impair the growth and viability of a wide range of hematological and solid tumor cells.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Amorphous solid form of a bet protein inhibitor
  • Amorphous solid form of a bet protein inhibitor
  • Amorphous solid form of a bet protein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Amorphous Solid Form of Compound 1-(S)

[0128]

Preparation of Starting Material 2-bromo-1-pyridin-2-ylethanone hydrobromide

[0129]Bromine (Br2, 198 g, 1240 mmol) dissolved in acetic acid (100 mL) was added slowly to a mixture of 1-(pyridin-2-yl)ethanone (150 g, 1238 mmol) in acetic acid (1500 mL) at rt. The red reaction solution was heated to 105° C. for 1 hour to give an off-white slurry. The mixture was stirred for 1 hour at rt, cooled in a water bath (caution acetic acid freezes), filtered, then the solids were washed with acetic acid (150 mL) and ethyl acetate (250 mL). The solid was suspended in acetic acid (1500 mL) and heated to 105° C. for 1 h (note: material did not completely dissolve). The reaction was allowed to cool to rt in a water bath. The precipitate was filtered, washed with acetic acid 100 mL and ethyl acetate 300 mL, and dried under house vacuum at rt to give crude 2-bromo-1-pyridin-2-ylethanone hydrobromide (305 g, 87%) as an off-white powder, which w...

example 2

X-Ray Powder Diffraction (XRPD) of Amorphous Compound 1-(S)

[0137]Amorphous Compound 1-(S) was characterized by XRPD. The X-Ray Power Diffraction (XRPD) was obtained from Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedures for XRPD were: (1) X-ray radiation from copper at 1.054056 Å with Kβ filter; (2) X-ray power at 30 KV, 15 mA; and (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: Start Angle 3 degrees; Stop Angle 45 degrees; Sampling 0.02 degrees; and Scan speed 2 degree / min. The XRPD pattern displays an amorphous halo as shown in FIG. 1.

example 3

Differential Scanning Calorimetry (DSC) of Amorphous Compound 1-(S)

[0138]Amorphous Compound 1-(S) was characterized by DSC. The DSC was obtained from TA Instruments Differential Scanning calorimetry, Model Q200 with autosampler. The DSC instrument conditions were as follows: 30-350° C. at 10° C / min; Tzero aluminum sample pan and lid; and nitrogen gas flow at 50 mL / min. The DSC thermogram is shown in FIG. 2. The DSC thermogram revealed one exothermic event at an onset temperature of 181.7° C. with a peak temperature of 213.4° C. which corresponds to the decomposition of the compound. The endothermic event below 100° C. is believed to be due to dehydration. No melting point was observed due to the amorphous nature of the compound.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
Temperatureaaaaaaaaaa
Fractionaaaaaaaaaa
Fractionaaaaaaaaaa
Login to View More

Abstract

The present invention relates to an amorphous solid form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one, and processes for its preparation, which is an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and is useful in the treatment of various diseases such as cancer.

Description

FIELD OF THE INVENTION[0001]The present invention relates to an amorphous solid form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one, and processes for its preparation, which is an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and is useful in the treatment of various diseases such as cancer.BACKGROUND OF THE INVENTION[0002]The BET (Bromodomain and Extra-Terminal) family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t) that share a conserved structural organization containing tandem N-terminal bromodomains capable of binding to acetylated lysine residues of histones and other proteins. BRD2, BRD3 and BRD4 are ubiquitously expressed while BRD-t is restricted to germ cells. BRD proteins play essential, but non-overlapping roles in regulating gene transcription and controlling cell growth. BET proteins are associated with large protein complexes including Mediator, PAFc and su...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D498/04C07D413/04
CPCC07D413/04C07D498/04A61K31/535A61P35/00
Inventor CHEN, SHILIFRIETZE, WILLIAMJIA, ZHONGJIANGLIU, PINGLIZHOU, JIACHENG
Owner INCYTE
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com