Process and intermediates
View Patent ↗Processes for preparing N-methyl-L-alanine derivatives and novel intermediates of the process. The derivatives and intermediates are useful for preparing cell-binding agent/maytansinoid complexes.
1. An N-methyl-L-alanine containing maytansinoid conjugated to a cell-binding agent prepared by a process comprising
(1) coupling a compound of Formula VII;
where
R 4 and R 5 are independently H, linear alkyl, branched alkyl, cyclic alkyl, aryl, substituted aryl, heterocyclic, or R 4 and R 5 taken together form a bond
L is
where
R 1 is H, methyl or ethyl;
M is a direct bond, CH 2 ,
a is 0 or an integer of 1 to 9 when M is a direct bond provided that when M is one or more carbon atoms a is 0 or an integer of 1 to 8;
d is an integer of 3 to 8; and
Q is H, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted heterocyclic
with N-methyl-L-alanine to form a racemization-free compound;
(2) forming an N-methyl-L-alanine containing maytansinoid with the said racemization-free compound; and
(3) linking said N-methyl-L-alanine containing maytansinoid to the cell-binding agent to form a racemization-free N-methyl-L-alanine containing maytansinoid conjugated to a cell-binding agent.
2. The N-methyl-L-alanine containing maytansinoid conjugated to a cell-binding agent of claim 1 wherein the cell-binding agent is an antibody.
3. An N-methyl-L-alanine containing maytansinoid having an optical purity of greater than 95% enantiomeric excess conjugated to a cell-binding agent prepared by a process comprising the following steps:
(1) esterifying maytansinol with a compound of Formula I to form a disulfide-containing maytansinoid ester; wherein Formula I is
where
L is
where
R 1 is H, methyl or ethyl;
M is a direct bond, CH 2 ,
a is 0 or an integer of 1 to 9 when M is a direct bond provided that when M is one or more carbon atoms a is 0 or an integer of 1 to 8;
d is an integer of 3 to 8; and
Z is H or SR 2 , where R 2 is linear alkyl, branched alkyl, cyclic alkyl, aryl, substituted aryl or heterocyclic;
(2) reducing the disulfide-containing maytansinoid ester prepared by step (1) to a thiol-containing maytansinoid;
(3) introducing dithiopyridyl groups into a cell-binding agent; and
(4) linking the thiol-containing maytansinoid produced by step (2) to the dithiopyridyl cell-binding agent of step by (3) a disulfide link.
4. The N-methyl-L-alanine containing maytansinoid conjugated to a cell-binding agent of claim 3 wherein the cell-binding agent is an antibody.