HYDROXAMIC ACIDS, DERIVATIVES OF 4-AMINOQUINAZOLINE-7-CARBOXYLIC ACID AS INHIBITORS OF HISTONE DEACETYLASE, AND METHOD FOR SYNTHESIS THEREOF Russian patent published in 2022 - IPC A61K31/517 C07D239/94 A61P35/00 A61P25/28 

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 4-aminoquinazoline-7-carboxylic acid, and pertains directly to new derivatives of 4-aminoquinazoline-7-carboxylic acid containing hydroxamic acid, usable in medicine for treating a number of diseases by inhibiting histone deacetylases, e.g., in treating oncological and neurodegenerative diseases. Proposed are new hydroxamic acids, derivatives of 4-aminoquinazoline-7-carboxylic acid, as inhibitors of histone deacetylase, by the following general formula I wherein R₁, R₂, R₃, R₄ independently constitute hydrogen, halogen, methyl, OMe, ethyne, and R₂, R₃=-OSN₂CH₂O-; R₅ constitutes hydrogen or halogen; n=4, 5. Also proposed is a method for synthesising the new hydroxamic acids, derivatives of 4-aminoquinazoline-7-carboxylic acid, by the general formula I, implemented as follows: derivatives of methyl 4-hydroxyquinazoline-7-carboxylate, produced by cyclisation of derivatives of dimethyl-2-aminoterephthalate in formamide by interaction with phosphoryl chloride in the presence of diethylaniline, are converted into derivatives of methyl 4-chloroquinazoline-7-carboxylate, wherein the latter on interaction with substituted anilines in dimethylformamide at room temperature are converted into derivatives of methyl 4-((phenyl)amino)quinazoline-7-carboxylates; the latter are subjected to alkaline hydrolysis and are converted into the corresponding derivatives of 4-[(aryl)amino]quinazoline-7-carboxylic acids; then methyl ethers of 6-aminohexanoic or 7-aminoheptanoic acids are added to the latter, using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as a condensing agent and trimethylamine as a base; the resulting compounds are then subjected to aminolysis with 10-fold molar excess of hydroxylamine in anhydrous methanol in the presence of 3 equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), performed at room temperature for 20 to 26 hours until the target product is formed, released by evaporating the reaction mass in vacuum, neutralising with glacial acetic acid to a pH of 5, filtering, followed by washing with water.

EFFECT: method for synthesising new hydroxamic acids, derivatives of 4-aminoquinazoline-7-carboxylic acid, is characterised by a low labour intensity of the process, availability of reagents, and production of target compounds with a purity satisfying the requirements of the pharmaceutical industry, and is easily scalable to industrial production due to the simplicity of performed operations and applied equipment.

3 cl, 7 tbl, 10 ex