Folate receptor binding conjugates of antifolates
Conjugates of antifolates, releasable linkers, and drugs, and pharmaceutical compositions containing them are described. The conjugates are useful for treating diseases arising from pathogenic cell populations. Methods for treating such diseases are also described.
1. A process of preparing EC0284:
comprising the reaction of EC0616
and EC0285
in the presence of PyBOP, NHS, and DIPEA.
2. The process of claim 1 , wherein the EC0616 is prepared by a reaction comprising the reaction of a compound of Formula I
and mercaptopropionic acid.
3. The process of claim 1 , wherein the EC0285 is prepared by a reaction comprising the reaction of EC0615
and the thiopeptide
4. The process of claim 3 , wherein TFA/TIPS is added after the reaction of EC0615 and the thiopeptide.
5. The process of claim 3 , wherein the EC0615 is prepared by a reaction comprising the reaction of EC0614
and a compound of EC283
6. The process of claim 5 , wherein the reaction is performed in the presence of HOBt, PyBOP, and Et 3 N.
7. The process of claim 5 , wherein the EC0614 is prepared by a reaction comprising the reaction of Fmoc α-(t-butyl)-L-glutamic acid and 2-(2-pyridyldithio)ethanol.
8. The process of claim 7 , wherein the reaction is performed in the presence of HOBt, DCC, and DMAP.
9. The process of claim 5 , wherein the EC283 is prepared by a reaction comprising the reaction of a compound of Formula II
and sodium hydroxide to form EC283.
10. The process of claim 9 , wherein the compound of Formula II is prepared by a reaction comprising the reaction of a compound of Formula III
and a compound of Formula IV
to form a compound of Formula II.
11. The process of claim 10 , wherein the compound of Formula III is prepared by a reaction comprising the reaction of methyl 4-aminobenzoate and propargyl bromide.
12. The process of claim 10 , wherein the compound of Formula IV is prepared by a reaction comprising the reaction of a compound of Formula V
and N-bromosuccinimide.
13. The process of claim 12 , wherein the reaction is performed in the presence of benzoyl peroxide.
14. The process of claim 12 , wherein the compound of Formula V is prepared by a reaction comprising the reaction of a compound of Formula VI
and pivaloyl chloride.
15. The compound
formed by the process of claim 1 .