Novel compounds useful as s100-inhibitors
The technology of a compound, R16, is applied in the field of new compounds that can be used as S100-inhibitors, which can solve the problems of unknown exact role of S100A9
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[0437] The preparation of the compounds according to the invention is well within the capabilities of a person of ordinary skill in the art. For example, compounds of formula (I) can be prepared in a reaction sequence as generally illustrated in Reaction Scheme 1 . Thus, in a general process for the preparation of compounds of formula (I) as defined herein, first in the presence of an organic base such as pyridine or triethylamine in a suitable solvent medium such as DMF, DMSO or N-methylpyrrolidine reaction of a primary amide 1 with an alkyl 3,3,3-trifluoro-2-oxopropionate 2, where R' is an alkyl group such as C1-C3 alkyl such as methyl, followed by addition of a reagent such as Sulfuryl chloride or oxalyl chloride to provide the "acyl imide intermediate" of general formula 3.
[0438] Acyl imide 3 is then reacted with aminobenzimidazole 4 in a suitable solvent medium such as DMF, DMSO or N-methylpyrrolidine to provide compounds of formula (I), wherein R A、 R A、 R B , R ...
Embodiment 1
[0711] 6-chloro -N- [10,11-Dimethyl-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.0 2,6 ]-dodeca-1(8),6,9,11-tetraen-3-yl]pyridine-2-carboxamide (ABR 239471)
[0712]To a stirred solution of 6-chloropyridine-2-carboxamide (1.00 g, 13.0 mmol) in DMF (8 mL) under argon was added pyridine (1.05 mL, 13.0 mmol) and 3,3,3- Ethyl trifluoro-2-oxo-propionate (1.73 mL, 13.0 mmol). The reaction mixture was stirred at room temperature for 1 hour, then thionyl chloride (0.95 mL, 13.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for an additional 16 hours, then concentrated to provide the imide intermediate. The amidoimide intermediate was dissolved in DMF (5 mL) and added to 5,6-dimethyl-1H-1,3-benzodiazol-2-amine (2.03 g, 13.0 mmol) in DMF (7 mL), followed by the addition of triethylamine (1.80 mL, 13.0 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction was diluted with brine (25 mL) and extracted with EtOAc...
Embodiment 2
[0714] N -[10,11-Dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),6,8,10-tetraen-3-yl]-6-fluoropyridine-2-carboxamide (ABR 239472)
[0715] To a solution of 6-fluoropyridine-2-carboxamide (700 mg, 4.75 mmol) in DMF (7 mL) under argon was added ethyl 3,3,3-trifluoro-2-oxopropanoate ( 629 µL, 4.75 mmol) and pyridine (383 µL, 4.75 mmol). The reaction mixture was stirred at room temperature for 1 hour, then thionyl chloride (344 µL, 4.75 mmol) was added dropwise. Stirring was continued for an additional 2.5 hours, then the reaction was concentrated to provide the imide intermediate. The resulting acyl imide intermediate was dissolved in DMF (5 mL), then added to 5,6-dichloro-1H-1,3-benzodiazol-2-amine (519 mg, 2.57 mmol) in DMF (5 mL) solution. Triethylamine (0.35 ml, 2.56 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with brine (30 mL) and extracted with EtOAc (2 x 50 mL). The...
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