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

Deuterated derivative of ruxolitinib

A drug and representative technology, applied in the field of deuterated derivatives of ruxolitinib, which can solve the problems of reduced metabolic clearance, variability, and unpredictability

Active Publication Date: 2019-09-13
CONCERT PHARMA INC
View PDF11 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Results reported for those studies measuring the effect of deuterium substitution on overall metabolic stability are variable and unpredictable
For some compounds, deuteration causes decreased metabolic clearance in vivo

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
  • Deuterated derivative of ruxolitinib
  • Deuterated derivative of ruxolitinib
  • Deuterated derivative of ruxolitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0091]

[0092]

[0093]

[0094] or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present in its natural isotopic abundance.

[0095] In one embodiment, the compound is a compound of formula I, wherein Y 6 , Y 7 and Y 8 Each is deuterium, and the compound is selected from any compound (Cmpd) listed in Table 2 (below):

[0096] Table 2: Exemplary Embodiments of Formula I

[0097]

[0098]

[0099] or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present in its natural isotopic abundance.

[0100] In another set of embodiments, any atom not designated as deuterium in any of the above embodiments is present in its natural isotopic abundance.

[0101] The following compounds are useful in the preparation of various compounds of the invention:

[0102]

[0103] as well as

[0104] or a salt thereof, wherein any atom not designated as deuterium is present in its n...

Embodiment 1

[0170] Example 1. (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(2,2,5 ,5-d 4 -Synthesis of cyclopentyl)propionitrile (compound 107).

[0171] Scheme 3. Preparation of compound 107

[0172]

[0173]

[0174] Step 1. 2,2,5,5-d 4 -Diethyl cyclopentane-1,1-dicarboxylate (32) . To a solution of diethyl malonate (6.57mL, 43.3mmol) in ethanol (40mL) was added 21% by weight sodium ethoxide in ethanol (32.3mL, 86.6mmol), followed by the addition of 1,1,4,4-tetra Deuterium-1,4-dibromobutane (31, 5.53 mL, 45.5 mmol, CDN Isotopes, 98 atomic % deuterium). The resulting solution was stirred at reflux for 2 hours, then cooled to room temperature and diluted with excess water. Most of the ethanol was then removed by distillation, and the resulting aqueous solution was extracted with ethyl acetate (3 x 75 mL). The organic layers were combined, washed with brine, and dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give 32 as a yellow oil,...

Embodiment 2

[0183] Example 2. (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(3,3,4 ,4-d 4 -Synthesis of cyclopentyl)propionitrile (Compound 103).

[0184] Scheme 4. Preparation of compound 103

[0185]

[0186] Step 1. 3,3,4,4-d 4 -Diethyl cyclopentane-1,1-dicarboxylate (40) . To a solution of diethyl malonate (3.25 mL, 21.4 mmol) in ethanol (20 mL) was added 21% by weight sodium ethoxide in ethanol (16.0 mL, 42.8 mmol) followed by 2,2,3,3-Tetra Deutero-1,4-dibromobutane (39, 4.95 g, 22.5 mmol, CDN Isotopes, 98 atomic % deuterium). The resulting solution was stirred at reflux for 2 hours, then cooled to room temperature and diluted with excess water. Most of the ethanol was then removed by distillation, and the resulting aqueous solution was extracted with ethyl acetate (3 x 75 mL). The organic layers were combined, washed with brine, and dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give 40 as a yellow oil, which was carried on to th...

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
chiral purityaaaaaaaaaa
Login to View More

Abstract

The present invention discloses a deuterated derivative of ruxolitinib. One embodiment provides a compound of a formula A, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and a method for treating indications disclosed in the specification.

Description

[0001] This application is a divisional application of the No. 201310700192.2 invention patent application with the filing date of December 18, 2013 and the invention title of "Deuterated Derivatives of Ruxolitinib (ruxolitinib)". Background technique [0002] Many current drugs suffer from poor absorption, distribution, metabolism and / or excretion (ADME) properties, which prevent their widespread use or limit their use in certain indications. Poor ADME performance is also the main reason why drug candidates fail in clinical trials. Although formulation techniques and prodrug strategies can in some cases be used to improve certain ADME properties, these approaches often fail to address the fundamental ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism, which causes many drugs that are supposed to be highly effective in treating a disease to be cleared from the body too quickly. A possible solution to rapid drug clearance is frequ...

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
Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P35/02A61P17/06A61P7/06A61P7/00
CPCC07D487/04
Inventor I·R·西尔弗曼J·F·刘A·J·摩根B·潘德雅S·L·哈比森
Owner CONCERT PHARMA INC
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