US 12,419,963 B2
Diels-Alder conjugation methods
Thomas Nittoli, Orangeburg, NY (US)
Assigned to REGENERON PHARMACEUTICALS, INC., Tarrytown, NY (US)
Filed by Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US)
Filed on May 12, 2023, as Appl. No. 18/196,863.
Application 18/196,863 is a continuation of application No. 17/232,854, filed on Apr. 16, 2021, granted, now 11,701,427.
Claims priority of provisional application 63/010,903, filed on Apr. 16, 2020.
Prior Publication US 2024/0207412 A1, Jun. 27, 2024
Int. Cl. A61K 47/68 (2017.01); A61K 31/395 (2006.01); A61K 31/5383 (2006.01); A61K 31/5517 (2006.01); A61K 38/07 (2006.01); A61K 38/17 (2006.01); A61K 47/54 (2017.01); A61K 47/55 (2017.01); A61K 47/65 (2017.01); A61K 49/00 (2006.01); A61K 51/10 (2006.01); A61P 31/04 (2006.01); A61P 35/00 (2006.01)
CPC A61K 47/6803 (2017.08) [A61K 31/395 (2013.01); A61K 31/5383 (2013.01); A61K 31/5517 (2013.01); A61K 38/07 (2013.01); A61K 38/1729 (2013.01); A61K 47/542 (2017.08); A61K 47/545 (2017.08); A61K 47/55 (2017.08); A61K 47/65 (2017.08); A61K 47/68031 (2023.08); A61K 47/68035 (2023.08); A61K 47/6849 (2017.08); A61K 49/0052 (2013.01); A61K 49/0058 (2013.01); A61K 51/1093 (2013.01); A61P 31/04 (2018.01); A61P 35/00 (2018.01)] 16 Claims
 
1. A method of producing the compound of Formula (1B):

OG Complex Work Unit Chemistry
wherein
BA is an antibody;
Gln is a glutamine residue of said BA;
SP is

OG Complex Work Unit Chemistry
wherein subscripts u, w, x, and v are independently an integer from 1 to 20;
Z is

OG Complex Work Unit Chemistry
wherein R′ is independently H, C1-3 alkyl, or two R′ together constitute a CHR, CHR—CHR, or O bridge;
R is independently at each occurrence H, C1-3 alkyl, —OC1-3 alkyl, or —NHC1-3 alkyl;
J is CH;
K is N;
L is

OG Complex Work Unit Chemistry
D is a therapeutic moiety, wherein the therapeutic moiety is a maytansinoid, a tubulysin, an auristatin, a dolastatin, a camptothesin, a pyrrolobenzodiazepine, an antibiotic, an antiviral agent, an anti-inflammatory agent, an immunomodulator, an antifungal agent, a steroid, or D is an imaging agent moiety;
d is an integer from 1 to 2,
the method comprising the steps of:
a.) contacting: i) a compound having a structure according to Formula (V-x):

OG Complex Work Unit Chemistry
wherein:
X is independently at each occurrence selected from

OG Complex Work Unit Chemistry
I is an integer from 1 to 2;
with ii) a compound according to Formula (VI-y):
Y-L-D  (VI-y);
wherein:
Y is a moiety according to

OG Complex Work Unit Chemistry
to produce a compound having a structure according to Formula (V-x′z):

OG Complex Work Unit Chemistry
b.) contacting the compound according to Formula (V-x′z) with a compound according to Formula (VI-y): Y-L-D (VI-y); and
c.) isolating the produced compound of Formula (1B).