Compositions containing N-amino- and N-hydroxy-quinazolinones and methods for preparing libraries thereof
AssigneeSepracor Inc.
InventorYun Gao
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Abstract
The present invention is directed to certain N-amino- and N-hydroxy-quinazolinone compounds and synthetic methods for synthesis thereof, which compounds may find use in combinatorial libraries. More specifically, the invention is directed to the synthesis of 3-hydroxy- and 3-amino-4(1H)-quinazolinones via the reaction of an appropriate 2-aminobenzamide compound with a carboxylic acid or acyl halide at ambient temperature performed on a solid support or in solution.
Claims23
A solid phase reaction component comprising a solid support, substantially insoluble in aqueous or organic reaction media, carrying a plurality of compounds of Formula I 6
- wherein R1 is an independently selected mono-, di-, tri-, or quad-substitution on the phenyl ring, and where R1 is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl optionally substituted with halogen, hydroxy, C1-C6 alkoxy and aryl, or hydroxy, C1-C6 alkoxy, NO2, SO2Ph, phenyl SO2NR344, OCOR5, SR5, CO2R5;
- NHCOR5;
- or R1, when disubstituted, can be taken together to form a 5-7 membered carbocyclic aromatic group or heterocyclic aromatic group wherein the heterocyclic aromatic group is selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or indolyl;
- R2 is branched or straight chain C1-C6 alkyl, C1-C6 alkoxy, a nitrogen-protected amino acid, phenyl, benzyl, C1-C6 alkenyl, hydroxy, SO2Ph, SO2NR3R4, NR3R4, OCOR5, SR5, CO2R5, NHCOR5, or a heterocyclic aromatic group, whereby R2 is unsubstituted or substituted;
- R3 and R4 are independently hydrogen, C1-C6 alkyl or, taken together are (CH2)f where f is 3-6;
- R5 is C1-C6 alkyl, benzyl, phenyl, or, substituted phenyl with 1-3 substituents independently selected from the group consisting of C1-C6 alkoxy, NO2, CF3, or CN;
- and
- Y is an appropriate cleavable linker such as NHCO2CH2— or —O—CH2—, linked to a suitable solid support.
A method for synthesizing a 3-hydroxy quinazolinone, comprising:
- (a) reacting a free amine moiety bound to a solid support with an appropriate isatoic anhydride to afford a 2-aminobenzamide bound to said solid support;
- (b) reacting said 2-aminobenzamide with a carboxylic acid in the presence of an activating agent to afford a 3-hydroxy quinazolinone bound to said solid support.
A method of synthesizing an N-hydroxy quinazolinone on a solid support which comprises:
- (a) selecting a solid support comprising at least one compound covalently attached to said solid support which compound comprises a moiety having at least one nucleophilic site;
- (b) reacting said moiety of said compound covalently attached to said solid support with a diverse array of isatoic anhydrides in an aprotic organic solvent at an appropriate temperature range to afford a 3-alkoxy-2-aminobenzamide;
- (c) reacting said 3-alkoxy-2-aminobenzamide bound to said solid support with a carboxylic acid in the presence of an activating agent or an acid chloride and a coupling agent to afford a 3-alkoxy quinazolinone bound to said solid support.
A method for synthesizing a 3-amino quinazolinone, comprising:
- (a) reacting a hydrazine moiety with a free amino group bound to a solid support with an appropriate isatoic anhydride to afford a 1,2 disubstituted anthraniloylhydrazine;
- (b) reacting said 1,2 disubstituted anthraniloylhydrazine with a carboxylic acid in the presence of an activating agent to afford a 3-amino quinazolinone bound to said solid support.
A method of synthesizing an N-amino quinazolinone on a solid support which comprises:
- (a) selecting a solid support comprising at least one compound covalently attached to said solid support which compound comprises a moiety having at least one nucleophilic site;
- (b) reacting said moiety of said compound covalently attached to said solid support with a diverse array of isatoic anhydrides in an aprotic solvent to afford a 1,2 disubstituted anthraniloyl hydrazine;
- and
- (c) reacting said 1,2 disubstituted anthraniloyl hyrdrazine bound to said solid support with a carboxylic acid in the presence of a coupling agent to afford a 3-hydrazino-quinazolinone bound to said solid support.
Dependencies are inferred from the claim text.