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US 6,429,311 B2Granted
Compositions containing N-amino- and N-hydroxy-quinazolinones and methods for preparing libraries thereof
AssigneeSepracor Inc.
InventorYun Gao
Life of this patent
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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.
Claims9
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
- wherein
- R1 is an independently selected mono-, di-, tri-, or quad-substituent on the phenyl ring, wherein R1 is independently hydrogen or halogen;
- C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each optionally substituted with halogen, hydroxy, C1-C6 alkoxy or C4-C10 aryl;
- or hydroxy, C1-C6 alkoxy, NO2, SO2Ph, phenyl, SO2NR3R4, OCOR5, SR5, CO2R5, or 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 furo, thieno, pyrido, pyrrolo, oxazolo, thiazolo, imidizolo, pyrazolo, isoxazolo, isothiazolo, pyridazino, pyrimidino, pyrazino, and indolo;
- R2 is a 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 5-7 membered heterocyclic aromatic group;
- R3 and R4 are independently hydrogen, or 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, and CN;
- and
- Y is a cleavable linker selected from the group consisting of —NHCO2CH2— and —O—CH2—;
- linked to a suitable solid support.
8 more elements
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 2-aminobenzamide with a carboxylic acid in the presence of an activating agent or with an activated form of a carboxylic acid to afford a 3-hydroxy quinazolinone bound to said solid support;
- and
- (c) reacting said 3-hydroxy quinazolinone bound to said solid support under acidic hydrolysis conditions to yield unbound 3-hydroxy quinazolinone;
- wherein said carboxylic acid or activated form of a carboxylic acid is represented by the formula:
- R2—CHY—CO—X or W—CO—X
- wherein
- X is OH, Cl, F, Br or a carboxylic acid activating group;
- Y is NR3R4, Cl, Br, F or I;
- R2 is C1-C6 alkyl, C4-C10 aryl, 5-7 membered-heteroaryl C1-C10 or C1-C10 aralkyl group;
- R3 and R4 are suitable NH protecting groups;
- and
- W is a 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 5-7 membered heterocyclic aromatic group.
10 more elements
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;
- and
- (d) reacting said solid support bound 3-alkoxy-4(1H)-quinazolinone under acidic hydrolysis conditions to yield a N-hydroxy-4(1H)-quinazolinone of the formula
- wherein
- R1 is an independently selected mono-, di-, tri-, or quad-substituent on the phenyl ring, and where R1 is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, optionally substituted with halogen, hydroxy, C1-C6 alkoxy and aryl, or hydroxy, C1-C6 alkoxy, NO2, SO2Ph, phenyl, SO2NR3R4, OCOR5, SR5, CO2R5, or 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 furo, thieno, pyrido, pyrrolo, oxazolo, thiazolo, imidizolo, pyrazolo, isoxazolo, isothiazolo, pyridazino, pyrimidino, pyrazino, and indolo;
- and
- 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.
7 more elements
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 organic solvent to afford a 1,2 disubstituted anthraniloyl hydrazine;
- (c) reacting said 1,2 disubstituted anthraniloyl hydrazine 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;
- and
- (d) reacting said solid support bound 3-hydrazino-4 (1H)-quinazolinone under acidic hydrolysis conditions to yield an N-amino-4 (1H)-quinazolinone of the formula
- wherein
- R1 is an independently selected mono-, di-, tri-, or quad-substituent 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, SO2NR3R4, 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 furo, thieno, pyrido, pyrrolo, oxazolo, thiazolo, imidizolo, pyrazolo, isoxazolo, isothiazolo, pyridazino, pyrimidino, pyrazino, and indolo;
- 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;
- and
- R3 is hydrogen or C1-C6 alkyl.
9 more elements
Dependencies are inferred from the claim text.