Chroman derivatives, medicaments and use in therapy
Novel chroman derivatives and intermediate compounds, compositions containing same, methods for their preparation and uses thereof as therapeutic agents particularly as anti-cancer and chemotherapeutic selective agents are described.
1. A compound of the formula (I-a) or a pharmaceutically acceptable salt thereof:
wherein
R 1 is hydrogen;
R 2 and R 3 are independently hydrogen, hydroxy, C 1-6 alkoxy, halo or C 1-6 alkyl, with the exception that R 2 and R 3 are not both hydrogen; and
R 4 , R 5 and R 6 are independently hydrogen, hydroxy, C 1-6 alkoxy, or C 1-6 alkyl.
2. A process for the preparation of a compound of formula (I-a):
wherein
R 1 is hydrogen;
R 2 and R 3 are independently hydrogen, hydroxy, C 1-6 alkoxy, halo or C 1-6 alkyl, with the exception that R 2 and R 3 are not both hydrogen; and
R 4 , R 5 and R 6 are independently hydrogen, hydroxy, C 1-6 alkoxy, or C 1-6 alkyl;
comprising the step of reacting the 4-keto group of a compound of the formula (II):
wherein
R 1 is alkyl or Si(R 10 ) 3 ;
R 2 and R 3 are independently hydrogen, C 1-6 alkoxy, halo, or OSi(R 10 ) 3 , with the exception that R 2 and R 3 are not both hydrogen; and
R 10 is independently alkyl or aryl;
with an arylating agent W − M + ;
wherein
W − is optionally substituted aryl; and
M + is one or more counter ions;
to form the intermediate tertiary alcohol (III):
or a salt thereof and which is dehydrated to form a compound of formula (IV):
which is subsequently hydrogenated and deprotected to form a compound of formula (I-a).
3. The compound of claim 1 , wherein R 2 is C 1-6 alkoxy or hydroxy.
4. The compound of claim 1 , wherein R 2 is methoxy or hydroxy.
5. The compound of claim 1 , wherein R 3 hydrogen.
6. The compound of claim 1 , wherein R 4 is C 1-6 alkoxy or hydroxy.
7. The compound of claim 1 , wherein R 4 is methoxy or hydroxy.
8. The compound of claim 1 , wherein
R 2 and R 3 are independently hydrogen, hydroxy, or methoxy;
R 4 is methoxy or hydroxy; and
R 5 and R 6 are hydrogen;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 , wherein the compound has the structure:
10. A composition comprising one or more compounds of formula (I-a) of claim 2 , or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutical carriers, excipients, auxiliaries and/or diluents.
11. The composition of claim 10 , further comprising an anti-cancer agent.
12. The composition of claim 11 , wherein the anti-cancer agent is cisplatin, dehydroequol, taxol, gemcitabine, doxorubicin, topotecan, camptothecin, or combinations thereof.
13. The composition of claim 10 , wherein the compound of formula (I-a) is:
14. The composition of claim 13 , further comprising an anti-cancer agent.
15. The composition of claim 14 , wherein the anti-cancer agent is cisplatin, dehydroequol, taxol, gemcitabine, doxorubicin, topotecan, camptothecin, or combinations thereof.