Aryl ureas as kinase inhibitors
AssigneeBayer Aktiengesellschaft
InventorsJacques Dumas, William J. Scott, Bernd Riedl, Du-Shieng Chien, Ala Nassar, Wendy Lee, Susan Bjorge, Laszlo L. Musza
Life of this patent
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Abstract
This invention relates to new aryl ureas and methods for their synthesis. The inventive compounds are useful in the treatment of (i) raf mediated diseases, for example, cancer, (ii) p38 mediated diseases such as inflammation and osteoporosis, and (iii) VEGF mediated diseases such as angiogenesis disorders.
Claims73
A compound of formula (I),
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- Wherein,
- Y is OR1 or NHR2,
- Hal is chlorine or bromine,
- R1 is H or C1-C6 alkyl
- R2 is H, OH, CH3 or CH2OH,
- Z1 and Z2 are each H or OH, wherein only one of Z1 or Z2 can be OH.
- X1 to X7 are each, independently, H, OH or O(CO)C1-C4 alkyl, and
- n is 0 or 1,
- with the proviso that at least one of conditions a-c is met,
- a) Z1 or Z2 is OH,
- b) Y is NHR2 and R2 is OH,
- c) n is 1,
- or a salt thereof, or an isolated stereoisomer thereof.
A compound selected from the group consisting of:
- 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methyl-2-pyridine carboxamide 1-oxide,
- 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-hydroxymethyl-2-pyridine carboxamide 1-oxide,
- 4-{4-[({[4-bromo-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methyl-2-pyridine carboxamide 1-oxide,
- 4-{4-[({[4-bromo-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-hydroxymethyl-2-pyridine carboxamide 1-oxide,
- 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-2-pyridine carboxamide 1-oxide,
- 4-{4-[({[4-bromo-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-2-pyridine carboxamide 1-oxide, salts thereof and stereoisomers thereof.
A compound of formula (II), or a salt or stereoisomer thereof,
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- wherein,
- Y is OR1 or NHR2,
- Hal is chlorine or bromine,
- R1 is H or C1-C6 alkyl
- R2 is H, OH, CH3 or CH2OH,
- Z1 and Z2 are each H or OH, wherein only one of Z1 or Z2 is OH,
- X4 to X7 are each, independently, H, OH or O(CO)C1-C4 alkyl, and
- n is 0 or 1,
- with the proviso that at least one of conditions a-c is met,
- a) Z1 or Z2 is OH,
- b) Y is NHR2 and R2 is OH,
- c) n is 1.
38 A compound of claim 37, wherein in formula (II), at least one of X4 to X7 is OH.
A compound of formula (III), or a salt or isolated stereoisomer thereof,
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- wherein,
- Y is OR1 or NHR2,
- Hal is chlorine or bromine,
- R1 is H or C1-C6 alkyl
- R2 is H, OH, CH3 or CH2OH,
- Z1 and Z2 are each H or OH, wherein only one of Z1 or Z2 can be OH, and
- n is 0 or 1,
- with the proviso that at least one of conditions a-c is met,
- a) Z1 or Z2 is OH,
- b) Y is NHR2 and R2 is OH,
- c) n is 1.
A pharmaceutical composition comprising an effective amount of
- 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methyl-2-pyridine carboxamide 1-oxide, 4-{4-[({[4-bromo-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methyl-2-pyridine carboxamide 1-oxide,
- 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}2-pyridine carboxamide 1-oxide,
- 4-{4-[({[4-bromo-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}2-pyridine carboxamide 1-oxide or
- a pharmaceutically acceptable salt of one of these oxides, an isolated stereoisomer of one of these oxides or a mixture thereof and a physiologically acceptable carrier.
A method of preparing N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-(N-methylcarbamoyl)-1-oxo-(4-pyridyloxy)]phenyl}urea
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- comprising chemically oxidizing N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-(N-methylcarbamoyl)(4-pyridyloxy)]phenyl}urea in solution.
A method of preparing N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-carbamoyl-1-oxo-(4-pyridyloxy)]phenyl}urea
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- comprising chemically oxidizing N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-carbamoyl-(4-pyridyloxy)]phenyl}urea in solution.
Dependencies are inferred from the claim text.