Kinase inhibitors

a technology of kinase inhibitors and inhibitors, applied in the field of kinase inhibitors, can solve the problems of multiple off-target effects, high toxicity, and discontinuation of development of a substantial number of inhibitors, and achieve the effect of enhancing the therapeutic profile and low affinity

Inactive Publication Date: 2014-02-27
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0042]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 minimising toxicity in vivo.
[0043]In at least some embodiments, compounds of the present invention have p59-HCK inhibitory activity which may also augment their advantageous therapeutic profile.

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 hospitalisation.
Data accumulated over the last decade indicates that a failure to manage effectively the underlying inflammatory component of the disease in the lung is the most likely reason that exacerbations occur.
Whilst upper respiratory tract viral infections are a cause of considerable morbidity and mortality in those patients with underlying disease or other risk factors; they also represent a significant healthcare burden in the general population and are a major cause of missed days at school and lost time in the workplace (Rollinger, J. M. and Schmidtke, M., Med. Res. Rev., 2010, Doi 10.1002 / med.20176).
However, the wide range of rhinovirus serotypes makes this a particularly challenging approach to pursue and may explain why, at the present time, a medicine for the prophylaxis and treatment of rhinovirus infections has yet to be approved by any regulatory agency.
However, these findings are not completely consistent with other groups reporting no effect with p38 inhibitors (Malamut G. et al., Dig. Dis. Sci, 2006, 51:1443-1453).
Micronucleus formation is implicated in, or associated with, disruption of mitotic processes and is therefore an undesirable manifestation of potential toxicity.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

3-((4-((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide

[0680]

[0681]To a solution of Intermediate A8 (74 mg, 0.32 mmol) in DCM (1.0 mL) was added CDI (54 mg, 0.34 mmol) and the reaction mixture kept at 40° C. for 2 hr. An aliquot of this solution (310 μL, 0.099 mmol), containing the pre-formed pyrazole CDI adduct, was added to a solution of Intermediate B1 (50 mg, 0.078 mmol) in THF (1.0 mL) at RT and the resulting mixture maintained at this temperature for 18 hr. A second aliquot of the pyrazole CDI adduct (160 μL, 0.05 mmol) was then added and after 3 hr at RT the reaction mixture was partitioned between EtOAc (50 mL) and saturated aq NaHCO3 (50 mL). The organic phase was separated and was washed sequentially with saturated aq NaHCO3 (2×50 mL), water (2×50 mL) and brine (2×50 mL) and then dried and evaporated in vacuo. The residue was purified by preparative HPLC to afford the title compound, E...

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)benzamide

[0682]

[0683]To a suspension of Intermediate F1 (50 mg, 0.080 mmol) in THF (1.5 mL) was added DIPEA (28 μL, 0.16 mmol) and HATU (36 mg, 0.096 mmol) and after 10 min at RT the reaction mixture was treated with NH4Cl (4.7 mg, 0.088 mmol). The resulting mixture was maintained at RT for 18 hr and was then partitioned between saturated aq NaHCO3 (3.0 mL) and EtOAc (3.0 mL). The organic phase was separated and was washed with hydrochloric acid (1.0 M, 3.0 mL) and with brine (3.0 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 4.0 g, MeOH in EtOAc, 0-100%, gradient elution) to afford the title compound, Example 2, as a white solid (8 mg, 16%); Rt 2.30 min (Method 2 acidic); m / z 627 (M+H)+ (ES+); m / z 625 (M−H)− (ES−); 1H NMR δ: 1.29 (9H, s), 2.40 (3H, s), 6.42 (1H, s), 6.55 (1H, d), 6.99 (1H, m), 7.23 (1H, br s), 7.29 (1H...

example 3

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

[0684]

[0685]To a suspension of Intermediate F1 (680 mg, 1.08 mmol) in DCM (10 mL) at 0° C. was added oxalyl chloride (110 μL, 1.30 mmol) and DMF (1 drop) and the resulting red mixture maintained at 0° C. for 20 min and then warmed to RT. After 1 hr a second aliquot of oxalyl chloride (110 μL, 1.30 mmol) was added and the resulting mixture kept at RT for 2 hr and then evaporated in vacuo to afford a red solid (800 mg). This material was used in the subsequent amide coupling without purification or characterization. To a suspension of a portion of the solid obtained above (60 mg, 0.080 mmol) in DCM (1.5 mL) was added DIPEA (32 μL, 0.19 mmol) and 2-morpholinoethanamine (13 μL, 0.10 mmol) and the reaction mixture maintained at RT for 3 hr. The resulting mixture was washed sequentially with saturated aq. NaHCO3 (5.0 mL), water (5.0 mL) and with brine (5....

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Abstract

There are provided compounds of formula I,wherein R, R1, 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

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/12A61K31/5377C07D401/14A61K31/506C07D405/14C07D409/14A61K45/06C07D403/12
CPCC07D401/12A61K45/06A61K31/5377C07D401/14A61K31/506C07D405/14C07D409/14C07D403/12A61P1/04A61P3/10A61P9/04A61P11/00A61P11/02A61P11/06A61P19/02A61P27/02A61P27/06A61P27/12A61P29/00A61P31/12A61P31/16A61P35/00A61P37/06A61P37/08
Inventor CARIOU, CLAIRE ANNE MARIECHARRON, CATHERINE ELISABETHFORDYCE, EUAN ALEXANDER FRASERFYFE, MATTHEW COLIN THORHAMZA, DANIELITO, KAZUHIROKING-UNDERWOOD, JOHNMURRAY, PETER JOHNONIONS, STUART THOMASTHOM, STEPHEN MALCOLMWATSON, HAYLEY TEGAN ANGELAWILLIAMS, JONATHAN GARETH
Owner RESPIVERT
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