Kinase inhibitors

a kinase inhibitor and inhibitor technology, applied in the field of kinase inhibitors, can solve the problems of high toxicity of inhibitors, hindering the utility of p38 map kinase inhibitors in the treatment of human chronic inflammatory diseases, and patient toxicity, and achieve good anti-inflammatory properties

Inactive Publication Date: 2015-06-18
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0029]We have now discovered, surprisingly, that certain aniline-substituted diarylureas inhibit one or more of p38 MAP kinase, Syk and Src family kinases and therefore possess good anti-inflammatory properties.

Problems solved by technology

Early classes of inhibitors were highly toxic due to the broad tissue distribution of these isoforms which resulted in off-target effects of the compounds.
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.
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 undesirable.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-morpholinoethyl)benzamide

[0550]

(i) 3-Amino-5-bromo-N-(2-morpholinoethyl)benzamide

[0551]T3P (50% w / w in EtOAc, 56.2 mL, 94 mmol), was added carefully to a solution of 3-amino-5-bromobenzoic acid (13.6 g, 63.0 mmol), 2-morpholinoethanamine (16.52 mL, 126 mmol) and Et3N (26.3 mL, 189 mmol) in DCM (200 mL). An ice bath was used sporadically to prevent temperature rising above 35° C. Reaction stirred at room temperature for 1 h. Partitioned with sat. aq. NaHCO3 solution (250 mL). Aqueous separated and partitioned with fresh DCM (250 mL). Organics separated, bulked and partitioned with 20% w / w NaCl solution (250 mL). The organic layer was separated, dried (MgSO4), filtered and solvent evaporated. The crude product was dissolved in DCM (100 mL) and the sub-title compound (13 g) crystallised out on standing as a light tan crystalline solid.

[0552]1H NMR (400 MHz,...

example 2

3-Ethynyl-5-((4-((4-(3-(3-fluoro-5-morpholinophenyl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide

[0572]

(i) Phenyl(3-fluoro-5-morpholinophenyl)carbamate

[0573]A stirred suspension of 3-fluoro-5-morpholinoaniline (1.00 g, 5.10 mmol) and sodium bicarbonate (0.878 g, 10.45 mmol) in DCM (10 mL) and THF (4 mL) was treated dropwise with phenyl chloroformate (0.7 mL, 5.57 mmol). After ˜0.1 mL had been added the mixture became very thick and difficult to stir, so it was diluted with more DCM (5 mL) and THF (2 mL) and stirred overnight. The mixture was treated with more sodium bicarbonate (0.086 g, 1.019 mmol) and phenyl chloroformate (0.07 mL, 0.557 mmol) and stirred over the weekend. The mixture was diluted with DCM (30 mL), was washed with water (30 mL) and filtered through a phase-separating cartridge. The filtrate was evaporated and the residue was purified on a 40 g redisep silica cartridge using a gradient of 0 to 50% of ethyl acetate in isohexane as e...

example 3

3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxyl)ethoxy)ethyl)benzamide

[0586]

(i) 3-Amino-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide

[0587]3-Amino-5-methoxybenzoic acid (1.0 g, 5.98 mmol) was added to an ice cold suspension of 2-(2-(2-methoxyethoxyl)ethoxy)ethanamine (1.2 g, 7.35 mmol), 50% T3P in ethyl acetate (4.50 mL, 7.56 mmol) and TEA (2.5 mL, 17.94 mmol) in ethyl acetate (15 mL). The mixture was allowed to warm to rt and stir overnight. Saturated aq. NaHCO3 solution (20 mL) was added and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to yield a yellow oil. The oil was purified by chromatography on the Companion (40 g column, 0-100% acetone / toluene) to afford a pale yellow oil. The oil was purified by chromatography on the Companion (4...

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Abstract

There is provided a compound of formula I,which compound has 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, e.g., Src and Lck) and has 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]This invention relates, inter alia, to compounds which are antiinflammatory agents (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes (referred to herein as p38 MAP kinase inhibitors), for example the alpha kinase sub-type thereof; Syk kinase; and the Src family of tyrosine kinases). The invention also relates to the use of such compounds in therapy, including in mono- and combination therapies, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung (such as asthma and chronic obstructive pulmonary disease (COPD)), eye (such as uveitis) and gastrointestinal tract (such as Crohn's disease and ulcerative colitis).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 gene...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D213/74A61K31/5377
CPCA61K31/5377C07D213/74C07D403/12C07D401/12C07D413/12C07D239/47C07D211/86A61K31/44A61K31/506C07D405/12C07D405/14A61K31/444A61K31/4427A61K31/505A61K31/541A61K31/551A61K31/553C07D233/90A61P1/04A61P11/00A61P11/02A61P11/06A61P17/00A61P17/06A61P27/02A61P27/06A61P27/12A61P29/00A61P37/00A61P37/06A61P37/08A61P43/00A61P9/12C07C311/08C07C317/28C07C317/48
Inventor FYFE, MATTHEW COLIN THOR
Owner RESPIVERT
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