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

Methyl/fluoro-pyridyl-methoxy substituted pyridone-pyridyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridone-pyridyl compounds

A picoline and methyl pyrimidine technology, applied in the treatment of p38 kinase-mediated diseases, disease treatment, pyridone-pyridyl compounds, can solve the problems of difficult dose adjustment, neutralizing antibody response, high treatment costs, etc.

Active Publication Date: 2018-06-22
ACLARIS THERAPEUTICS +3
View PDF15 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The superior efficacy of these latter agents is somewhat offset by potential disadvantages including the need for parenteral administration, difficulty in dose adjustment, poor reversibility due to long plasma half-life, induction of host neutralizing antibody responses, and high treatment costs

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
  • Methyl/fluoro-pyridyl-methoxy substituted pyridone-pyridyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridone-pyridyl compounds
  • Methyl/fluoro-pyridyl-methoxy substituted pyridone-pyridyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridone-pyridyl compounds
  • Methyl/fluoro-pyridyl-methoxy substituted pyridone-pyridyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridone-pyridyl compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment B

[0273] Compound No. 65, Example B: 3-Chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)pyrimidine-4- base)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

[0274]

[0275] The title compound was prepared according to Compound 49, Example A through Step E, but substituting 4-(chloromethyl)-5-fluoropyrimidine for 2-(chloromethyl)-3,5-difluoropyridine to make 3-chloro -4-Hydroxy-2'-(2-(2-hydroxyprop-2-yl)pyrimidin-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2 - Alkylation of ketones to produce the desired dibenzyl ethers. The title compound was prepared according to the general procedure of Compound 49, Step F of Example A.

[0276] E. Treatment

[0277] The present disclosure also provides methods for treating a condition in a patient suffering from or susceptible to such a condition by administering to the subject a therapeutically effective amount of one or more compounds as described above. In one embodiment, the treatment is prophylactic treatment. In anot...

Embodiment C

[0341]Example C: p38 Inhibition Potency and p38 / MK2 Substrate Selectivity: This study evaluated the potency of compounds of the invention in inhibiting the p38 pathway. p38 activates MK2 and PRAK through phosphorylation, which then interact with Hsp27, leading to increased inflammation and reduced ability to handle shock. This study examined half the amount of compounds of the invention required to inhibit MK2 and PARK activation. This is a measure of the effectiveness of the compounds of the invention in helping to reduce the inflammatory response, which is useful in the treatment of many diseases, including autoimmune conditions, lymphoma and rheumatoid arthritis. The novel MK2 substrate selective inhibition mechanism of compounds was evaluated in an enzymatic assay comparing the potency of inhibitors in blocking p38 / MK2 versus p38 / PRAK induced phosphorylation of HSP-27 derived peptide substrates. The ability of compounds to inhibit activated phosphorylated p38α was evaluat...

Embodiment D

[0344] Example D: Cytokine regulation in human monocytes: The p38 pathway has been shown to be critical for the biosynthesis of several pro-inflammatory cytokines including TNFα, IL-1β and IL-6. Thus, inhibition of the p38 MAPK pathway reduces inflammatory responses by reducing the biosynthesis of pro-inflammatory cytokines. This study shows half the amount of the compounds of the invention required to inhibit the biosynthesis of TNF[alpha], IL-6 and IL-1[beta] (pro-inflammatory cytokines). This is a reflection of the effect of the compounds of the invention in helping to reduce inflammation, which is useful in the treatment of many diseases, including autoimmune conditions, lymphomas and rheumatoid arthritis. The potency and efficacy of p38 inhibitors to block cytokine production was evaluated using the human U937 cell line. The U937 human promonocytic cell line was obtained from the American Type Culture Collection (Rockville, MD). These cells differentiate into monocyte p...

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 disclosure provides methyl / fluoro-pyridyl-methoxy substituted pyridinone-pyridyl for use in the treatment of p38 kinase-mediated diseases, such as lymphoma and autoinflammatory diseases, including rheumatoid arthritis. Compounds and fluoro-pyrimidinyl-methoxy substituted pyridone-pyridyl compounds, which have the structure of formula (I): wherein R1, R2, R3, R4, R5 and X are as defined in the detailed description; comprising at least one pharmaceutical compositions of the compounds; and methods of using the compounds for the treatment of p38 kinase-mediated diseases.

Description

[0001] Cross References to Related Applications [0002] This application is a non-provisional application claiming the benefit and priority of Provisional Application No. 61 / 832,736, filed June 7, 2013, the entire disclosure of which is incorporated herein by reference. field of invention [0003] The present disclosure relates generally to compounds having enzyme inhibitory activity, pharmaceutical compositions comprising the same, and methods for treating disease. More specifically, the present disclosure relates to a class of pyridone-pyridyl compounds, pharmaceutical compositions comprising the compounds, and methods for treating p38 kinase-mediated diseases. Background of the invention [0004] Mitogen-activated protein kinases (MAPKs) are a conserved family of enzymes that transmit and transmit external stimuli using a phosphorylation cascade to generate a coordinated cellular response to the environment. MAPKs are proline-directed serine / threonine-specific protein k...

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 Patents(China)
IPC IPC(8): C07D213/69A61K31/506A61K45/06
CPCC07D213/69C07D401/14A61K45/06A61K31/506A61K31/444A61P1/00A61P1/04A61P11/00A61P17/00A61P17/02A61P17/06A61P19/02A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P3/00A61P31/04A61P35/00A61P35/02A61P37/02A61P37/06A61P43/00A61P5/14A61P7/04A61P9/00A61P9/10A61P3/10
Inventor 苏珊·L·霍克曼约瑟夫·B·莫纳汉肖恩·R·赛尔尼斯
Owner ACLARIS THERAPEUTICS
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