Kinase inhibitors

Inactive Publication Date: 2016-01-21
RESPIVERT +1
View PDF0 Cites 35 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0046]The present compounds also display low affinity for GSK3α kinase in binding assays, which is considered to be beneficial in a therapeutic context, in particular in relation to minimi

Problems solved by technology

Early classes of inhibitors were highly toxic due to the broad tissue distribution of these isoforms which resulted in multiple off-target effects of the compounds.
Furthermore, development of a substantial number of inhibitors has been discontinued due to unacceptable safety profiles in clinical studies (Pettus, L. H. and Wurz, R. P., Curr. Top. Med. Chem., 2008, 8(16):1452-67).
Kuma discussed the possibility that the conformational change caused by the binding of the inhibitor to the MAPK protein may affect the structure of both its phosphorylation site and the docking site for the upstream activator, thereby impairing the phosphorylation of p38 MAPKs or JNKs.
However, the major obstacle hindering the utility of p38 MAP kinase inhibitors in the treatment of human chronic inflammatory diseases has been the toxicity observed in patients.
This has been sufficiently severe to result in the withdrawal from clinical development of many of the compounds progressed, including all those specifically mentioned above.
Many patients diagnosed with asthma or with COPD continue to suffer from uncontrolled symptoms and from exacerbations of their medical condition that can result in hospitalizatio

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
  • Kinase inhibitors
  • Kinase inhibitors
  • Kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Example

Example 1

3-Ethynyl-5-((4-((4-(3-(3-isopropyl-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-benzamide

[0506]

[0507]Intermediate C1 (146 mg, 0.285 mmol) was dissolved in DMF (3 mL) and added to Intermediate D2 (87 mg, 0.285 mmol) and p-TSA monohydrate (27.1 mg, 0.142 mmol). Stirred at 70° C. (block temperature) for 7 h then poured into sat. NaHCO3 solution (20 mL) and the product extracted with EtOAc (2×20 mL). Organics bulked and washed with 20% w / w brine solution (20 mL), dried (MgSO4), filtered and evaporated to a yellow solid.

[0508]The crude product was preabsorbed onto silica (4 g) and purified by chromatography on silica gel (40 g column, 1% MeOH:DCM to 6%) to afford a pale brown solid. Triturated 4 times with MeCN (2 mL) to afford the title compound (60 mg) 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.09 (s, 1H), 8.78 (s, 1H), 8.51-8.40 (m, 2H), 8.13-8.01 (m, 2H), 7.94 (d, 1H), 7.87 (s, 1H), 7.82 (d, 1H), 7.68-...

Example

Example 2

3-((4-((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-benzamide

[0510]

[0511]Method 1

[0512]A suspension of Intermediate C2 (165 mg, 0.282 mmol), Intermediate D2 (173 mg, 0.564 mmol) and p-TSA monohydrate (11.0 mg, 0.058 mmol) in THF / DMF (6 mL, 1:2) was heated at 60° C. overnight. The reaction was cooled to rt and partitioned between EtOAc (40 mL) and sat. aq. NaHCO3 (30 mL). The aqueous layer was extracted with EtOAc (2×40 mL). The combined organic extracts were washed with water (2×50 mL), brine (2×50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-10% MeOH) to afford a pale yellow solid. The solid was triturated with EtOAc affording the title compound (68 mg) as a white solid.

[0513]1H NMR (DMSO-d6) 400 MHz, δ: 9.75 (s, 1H), 9.08 (s, 1H), 8.76 (s, 1H), 8.43-8.46 (m, 2H), 8.06-8.08 (m, 2H), ...

Example

Example 3

3-((4-((4-(3-(3-(tert-Butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)-ethoxy)ethyl)benzamide

[0517]

[0518]To a stirred solution of Intermediate C3 (175 mg, 0.316 mmol) and Intermediate D2 (153 mg, 0.474 mmol) in DMF (4 mL) was added p-TSA monohydrate (30 mg, 0.158 mmol). The resulting solution was heated at 60° C. overnight. The reaction was cooled to rt and partitioned between EtOAc (30 mL) and sat aq. NaHCO3 (30 mL). The aqueous phase was back extracted with EtOAc (30 mL). The combined organic extracts were washed with water (2×50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to afford an orange oil (276 mg) at 85% purity. The crude product was purified by chromatography on silica gel (40 g column, 0-10% MeOH in DCM) to afford a pink solid (188 mg), which was triturated with MeCN to afford the title compound (98 mg) as an off-white solid.

[0519]1H NMR (DMSO-d6) 400 MHz, δ...

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
Anti-inflammatoryaaaaaaaaaa
Login to view more

Abstract

There are provided compounds of formula I,
wherein:
Y represents NR2R3;
one of R2 and R3 represents —[C2-4 alkylene-O]1-12—[C2-4 alkylene]-R2a and the other of R2 and R3 has a meaning given in the description; and
R, R1, R2a, Ra, Rb, Q, X and Y have meanings given in the description,
which compounds have antiinflammatory activity (e.g., through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

Description

FIELD OF THE INVENTION[0001]The invention relates to compounds which are inhibitors of the family of p38 mitogen-activated protein kinase enzymes (referred to herein as p38 MAP kinase inhibitors), for example the alpha and gamma sub-types thereof, and of Syk kinase and the Src family of tyrosine kinases, and to their use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, in particular inflammatory diseases of the lung, such as asthma and COPD, as well as those of the gastrointestinal tract, such as ulcerative colitis and Crohn's disease, and of the eye, such as uveitis.BACKGROUND OF THE INVENTION[0002]The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.[0003]Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively), each displaying different patter...

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): C07D401/12A61K31/4439A61K31/506C07D403/12
CPCC07D401/12A61K31/4439A61K31/506C07D403/12A61K31/5377A61K31/675A61P11/00A61P29/00A61P31/16C07D401/14A61K45/06C07F9/46
Inventor FYFE, MATTHEW, COLIN, THOR
Owner RESPIVERT
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap