Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use
The invention provides compounds, compositions and methods to treat certain inflammatory conditions and/or oncology by administering a compound that inhibits PI3K isoforms, particularly the delta isoform. It further provides specific stereoisomers of a compound useful for these methods. In particular, the compound is an optically active atropisomer of 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one.
1. An optically active compound comprising an atropisomer of formula 1(S)
or a pharmaceutically acceptable salt thereof;
wherein the atropisomer of formula 1(S) or a pharmacetically acceptable salt thereof, is present in excess of its corresponding enantiomer or a pharmaceutically acceptable salt thereof.
2. The optically active compound according to claim 1 , substantially free of the corresponding enantiomer or a pharmaceutically acceptable salt thereof.
3. An optically active compound comprising an atropisomer of formula 1(R)
or a pharmaceutically acceptable salt thereof;
wherein the atropisomer of formula 1(R) or a pharmaceutically acceptable salt thereof, is present in excess of its corresponding enantiomer or a pharmaceutically acceptable salt thereof.
4. The optically active compound according to claim 3 , substantially free of the corresponding enantiomer or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising an optically active compound of formula 1 (S),
or a pharmaceutically acceptable salt thereof, and
at least one pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising an optically active compound of formula 1 (R)
or a pharmaceutically acceptable salt thereof, and
at least one pharmaceutically acceptable carrier.
7. A method of treating rheumatoid arthritis (RA) in a mammal, which comprises administering to a mammal in need thereof a therapeutically effective amount of the optically active compound according to claim 1 .
8. A method of treating rheumatoid arthritis (RA) in a human,
which comprises administering to a human in need thereof a therapeutically effective amount of an optically active atropisomer having the formula
or a pharmaceutically acceptable salt thereof.
9. An optically active compound obtained by separation of a racemic mixture of formula 1
or a pharmaceutically acceptable salt thereof;
wherein the optically active compound comprises an atropisomer of formula 1 or a pharmaceutically acceptable salt thereof, in excess of its enantiomer or pharmaceutically acceptable salt thereof, and
wherein the optically active compound is characterized by a shorter retention time on a normal phase chiral column compared to its enantiomer or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 9 , consisting of the compound of formula 1(S) or a pharmaceutically acceptable salt thereof, substantially free of the compound of formula 1(R), or a pharmaceutically acceptable salt thereof,
wherein 1(S) and 1(R) are depicted below:
11. The compound according to claim 9 , consisting of the compound of formula 1(R) or a pharmaceutically acceptable salt thereof, substantially free of the compound of formula 1(S), or a pharmaceutically acceptable salt thereof,
wherein 1(S) and 1(R) are depicted below:
12. An optically active compound obtained by separation of a racemic mixture of formula 1
or a pharmaceutically acceptable salt thereof;
wherein the optically active compound comprises an atropisomer of formula 1 or a pharmaceutically acceptable salt thereof, in excess of its enantiomer or pharmaceutically acceptable salt thereof, and
wherein the optically active compound is characterized by a longer retention time on a normal phase chiral column compared to its enantiomer or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 12 , consisting of the compound of formula 1(S) or pharmaceutically acceptable salt thereof, substantially free of the compound of formula 1(R), or a pharmaceutically acceptable salt thereof,
wherein 1(S) and 1(R) are depicted below:
14. The compound according to claim 12 , consisting of the compound of formula 1(R) or a pharmaceutically acceptable salt thereof, substantially free of the compound of formula 1(S) or a pharmaceutically acceptable salt thereof,
wherein 1(S) and 1(R) are depicted below: