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

Therapeutic compounds and compositions, and methods of use thereof

A compound and pharmaceutical technology, applied in the field of Janus kinase such as JAK1 inhibitor compound, can solve problems such as defects

Active Publication Date: 2020-01-03
F HOFFMANN LA ROCHE & CO AG
View PDF19 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Consistent with this, primary cells derived from TYK2-deficient humans are defective in type I interferon, IL-6, IL-10, IL-12, and IL-23 signaling

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
  • Therapeutic compounds and compositions, and methods of use thereof
  • Therapeutic compounds and compositions, and methods of use thereof
  • Therapeutic compounds and compositions, and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0476]

[0477] N-(3-(5-((1R,2R)-2-cyanocyclopropyl)-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2 -Oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0478] To N-(3-(5-((1R,2R)-2-cyanocyclopropyl)-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)pyrazolo To a solution of [1,5-a]pyrimidine-3-carboxamide (Intermediate 4, 100 mg, 0.230 mmol) in DMF (10 mL) was added Cs 2 CO 3 (160 mg, 0.491 mmol). Then 2-bromo-N,N-dimethylacetamide (80 mg, 0.482 mmol) was added. The resulting mixture was stirred in a 60°C oil bath for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (8% MeOH) to afford 20.9 mg (17%) of N-(3-(5-((1R,2R)-2-cyanocyclo Propyl)-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrimidine-3-carboxamide as a white solid. LC / MS (Method A, ESI): [M+H] + =521.3,R T = 1.50min; 1...

Embodiment 2

[0480]

[0481] N-[3-[2-(Difluoromethoxy)-5-iodophenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo [1,5-a]pyrimidine-3-carboxamide

[0482] To N-[3-[2-(difluoromethoxy)-5-iodophenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide ( To a solution of intermediate 3, 160 mg, 0.322 mmol) in DMF (4.0 mL) was added Cs 2 CO 3(210 mg, 0.645 mmol). To this mixture was added 2-bromo-N,N-dimethylacetamide (107 mg, 0.645 mmol). The resulting solution was stirred in a 60°C oil bath for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2x). The organic layers were combined, washed successively with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was passed through a short pad of silica gel, eluting with dichloromethane / methanol (90 / 10). Appropriate fractions were combined and concentrated under reduced pressure. The crude...

Embodiment 3

[0484]

[0485] 2-amino-N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H -pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0486] Step 1: N-[3-([3-[5-Chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazole Synthesis of -4-yl]carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate tert-butyl ester

[0487]

[0488] To N-[3-([3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]carbamoyl)pyrazolo[1,5- a] A solution of pyrimidin-2-yl] tert-butyl carbamate (200 mg, 0.385 mmol) in DMF (5.0 mL) was added with Cs 2 CO 3 (251 mg, 0.770 mmol) and 2-bromo-N,N-dimethylacetamide (63.0 mg, 0.379 mmol). The reaction mixture was stirred in a 60°C oil bath for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (95 / 5). The appropriate fractions were combined and concentrated under reduced pressure to give 200 ...

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

Compounds and salts thereof that are useful as JAK kinse inhibitors are described herein. Also provided are pharmaceutical compositions that include such a JAK inhibitor and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.

Description

[0001] Cross References to Related Applications [0002] This patent application claims priority to U.S. Patent Application No. 62 / 640,865, filed March 9, 2018, and International Patent Application No. PCT / CN2017 / 085276, filed May 22, 2017, the disclosures of which are incorporated by reference in their entirety This article. [0003] field of invention [0004] The present invention relates to compounds that are inhibitors of Janus kinases, such as JAK1, and compositions comprising these compounds and methods of use, including, but not limited to, the diagnosis and treatment of patients with conditions responsive to inhibition of JAK kinases. [0005] Background of the invention [0006] Cytokine pathways mediate many biological functions, including many aspects of inflammation and immunity. Janus kinases (JAKs), including JAK1, JAK2, JAK3 and TYK2, are cytoplasmic protein kinases associated with type I and type II cytokine receptors and regulate cytokine signal transduction...

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): C07D487/04A61P29/00A61K31/519
CPCC07D487/04A61P29/00A61P11/06A61K31/519
Inventor M·扎克F·A·罗梅罗Y-X·成
Owner F HOFFMANN LA ROCHE & CO AG
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