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

Fluorinated epoxyketone-based compounds and uses thereof as proteasome inhibitors

A compound and solvate technology, applied in the field of novel fluorinated epoxy ketone series compounds, can solve problems such as damage or burden cell cycle control and abnormal regulation of signal transduction

Inactive Publication Date: 2015-07-22
特里乌姆治疗公司
View PDF4 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Impairment or overloading of the UPP may lead to dysregulation of cell cycle control and signal transduction

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
  • Fluorinated epoxyketone-based compounds and uses thereof as proteasome inhibitors
  • Fluorinated epoxyketone-based compounds and uses thereof as proteasome inhibitors
  • Fluorinated epoxyketone-based compounds and uses thereof as proteasome inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0318] III. Preparation of the compounds of the present application

[0319]The compounds of the present application can be prepared by a variety of synthetic methods. The choice of particular structural features and / or substituents can influence the choice of one approach over another. The choice of a particular method for preparing a given compound of formula I is within the skill of the art. Some of the starting materials used to prepare the compounds of the present application can be obtained from commercial chemical sources. Other starting materials, such as those described below, are readily prepared from available precursors using concise transformations well known in the art.

[0320] In one embodiment, compounds of formula I are generally prepared according to the method shown in Scheme I. The variables in the following schemes are as defined above for formula I unless otherwise specified.

[0321]

[0322] route I

[0323] In one embodiment, as shown in Sch...

Embodiment 1

[0480] Scheme XIII outlines the compound of formula I of Example 1 2-methylthiazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-(( R)-2-Methyloxinyl)-2-oxoethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)amide preparation.

[0481]

[0482] Route XIII

[0483] Reagents and conditions for route XIII: (i) HBTU, HOBt, DIPEA, THF, 0°C to RT / ON; (ii) H 2 , Pd / C (10%), THF, RT / 2hrs.; (iii) HBTU, HOBt, DIPEA, THF, 2-methylthiazole-5-carboxylic acid, 0°C to RT / ON.

[0484] (a)((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxopropyl)-2-oxoethyl Preparation of tert-butylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)carbamate (XIV(a)):

[0485]

[0486] To compound of formula II(b)(i) at 0°C (S)-2-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxypropionylamino)-3-methoxy propionic acid (2.75 g, 7.028 mmol) and compound of formula S,R-III(a) (S)-2-amino-1-((R)-2-methyloxopropyl)-3- Phenylpropan-1-one trifluoroacetate (12.04 g, 6.389 ...

Embodiment 25

[0497] The compound of formula I of Example 25 (2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino] was prepared according to the following synthetic procedure Propionyl]amino]-N-[(1S)-3-methyl-1-[(2R)-2-methyloxirane-2-carbonyl]butyl]-3-phenylpropanamide.

[0498] (a) Preparation of tert-butyl 2-morpholinoacetate:

[0499]

[0500] To a stirred solution of tert-butyl bromoacetate (8.47 mL, 57.4 mmol) in THF (50 mL) was added dropwise a 1:1 mixture of triethylamine (8 mL, 57.4 mmol) and morpholine (5.02 mL, 57.4 mmol) (observed to a slight exotherm) and the resulting white suspension was stirred at 60 °C for 2 h. The mixture was diluted with water (100 mL) and saturated sodium carbonate (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with saturated sodium carbonate (100 mL), water (3 x 50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, then chromatographed in h...

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

No PUM Login to View More

Abstract

The present application relates to novel fluorinated epoxyketone-based compounds, compositions comprising these compounds and their use, in particular for the treatment of diseases, disorders or conditions mediated by proteasome inhibition, in particular, the present application includes compounds of Formula I, and compositions and uses thereof:

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims priority to co-pending US Provisional Application No. 61 / 682,836, filed August 14, 2012, the contents of which are incorporated herein by reference in its entirety. Field of Invention [0003] The present invention relates to novel fluorinated epoxy ketone-based compounds, methods for their preparation, compositions containing them, and their use in therapy. More particularly, the present application relates to use in the treatment of diseases, disorders or conditions mediated by or associated with proteasome inhibition. Background of the Invention [0004] Multicatalytic proteasomes are ubiquitous proteases found in cells throughout the plant and animal kingdoms that are responsible for the ubiquitin-dependent degradation of intracellular proteins. Thousands of copies are found in all cells (ie, in the cytoplasm and nucleus), which constitute up to 3% of all cellular protein content. The prote...

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): C07K5/083A61K38/06A61P35/00C07K5/08
CPCA61K38/00C07K5/06008C07K5/06078C07K5/0827C07K5/06043A61K38/06A61P1/04A61P1/16A61P3/04A61P3/10A61P5/14A61P9/00A61P9/10A61P11/06A61P17/00A61P17/06A61P19/02A61P19/10A61P21/00A61P21/02A61P25/14A61P25/16A61P25/28A61P27/02A61P27/06A61P27/12A61P29/00A61P31/04A61P31/12A61P31/18A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08A61P43/00
Inventor A·斯拉斯P·达夫
Owner 特里乌姆治疗公司
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