Antitumor agents
The invention provides compounds of formula I: wherein Y is F, Cl, Br, methyl or methoxy; and pharmaceutically acceptable salts thereof. The compounds are effective antitumor agents. The invention also provides pharmaceutical compositions comprising a compound of formula I or a salt thereof, intermediates useful for preparing a compound of formula I, and therapeutic methods comprising administering a compound of formula I or a salt thereof to a mammal in need thereof.
1. A compound of formula I:
wherein
Y is F, Cl, Br, methyl or methoxy; and
Z is a Na cation, K cation, Li cation, Rb cation, Cs cation, Ca cation, or Mg cation.
2. The compound of claim 1 wherein Y is Cl or Br.
3. The compound of claim 2 wherein Z is a sodium cation or a potassium cation.
4. The compound of claim 3 wherein the configuration of the carbon indicated by the asterisk in formula I is the (R) configuration.
5. The compound of claim 4 wherein the compound is (R) 2[4-(7-chloroquinolin-2-yloxy)phenoxy]propionic acid sodium salt.
6. The compound of claim 4 wherein the compound is (R) 2[4-(7-bromoquinolin-2-yloxy)phenoxy]propionic acid sodium salt.
7. A composition comprising the compound of claim 1 in combination with a pharmaceutically acceptable diluent or carrier.
8. A composition comprising the compound of claim 3 in combination with a pharmaceutically acceptable diluent or carrier.
9. A composition comprising the compound of claim 4 in combination with a pharmaceutically acceptable diluent or carrier.
10. A method for preparing a compound of formula I:
wherein Y is F, Cl, Br, methyl or methoxy; or a pharmaceutically acceptable salt thereof,
comprising contacting a compound of formula II:
wherein Y is F, Cl, Br, methyl or methoxy, with a compound of formula III:
in the presence of a base and a solvent to form a mixture;
heating the mixture; and
contacting the mixture with an acid, to provide the compound of formula I.
11. The method of claim 10 wherein Y is F, Cl or Br.
12. The method of claim 10 wherein Y is —OMe or methyl.
13. The method of claim 10 wherein the configuration of the carbon indicated by the asterisk in formula I is the (R) configuration.
14. The method of claim 10 wherein the configuration of the carbon indicated by the asterisk in formula I is the (S) configuration.
15. The method of claims 11 wherein the compound of formula I is 2-[4-(7-chloroquinolin-2-yloxy)phenoxy]propanoic acid or a pharmaceutically acceptable salt thereof.
16. The method of claim 11 wherein the compound of formula I is (R) 2-[4-(7-chloroquinolin-2-yloxy)phenoxy]propanoic acid or a pharmaceutically acceptable salt thereof.
17. The method of claim 10 wherein the base comprises sodium hydride or potassium carbonate, the solvent comprises dimethylformamide, and the heating is carried out under refluxing conditions.
18. The method of claim 10 wherein the acid is aqueous hydrochloric acid.
19. The method of claim 10 further comprising purifying the compound of formula I by chromatography or crystallization.