US 12,134,631 B2
Hydrophilic linkers for antibody drug conjugates
Amy Han, Hockessin, DE (US)
Assigned to REGENERON PHARMACEUTICALS, INC., Tarrytown, NY (US)
Appl. No. 16/761,493
Filed by REGENERON PHARMACEUTICALS, INC., Tarrytown, NY (US)
PCT Filed Nov. 6, 2018, PCT No. PCT/US2018/059495
§ 371(c)(1), (2) Date May 4, 2020,
PCT Pub. No. WO2019/094395, PCT Pub. Date May 16, 2019.
Application 16/761,493 is a continuation in part of application No. PCT/US2017/060434, filed on Nov. 7, 2017.
Application 16/761,493 is a continuation in part of application No. 15/806,197, filed on Nov. 7, 2017, granted, now 10,711,032.
Claims priority of provisional application 62/669,034, filed on May 9, 2018.
Prior Publication US 2021/0332080 A1, Oct. 28, 2021
Int. Cl. A61K 31/566 (2006.01); A61K 31/58 (2006.01); A61K 47/61 (2017.01); A61K 47/68 (2017.01); A61K 47/69 (2017.01); A61P 29/00 (2006.01); C07J 41/00 (2006.01); C07J 71/00 (2006.01)
CPC C07J 71/0026 (2013.01) [A61K 31/566 (2013.01); A61K 31/58 (2013.01); A61K 47/61 (2017.08); A61K 47/6801 (2017.08); A61K 47/6803 (2017.08); A61K 47/6849 (2017.08); A61K 47/6889 (2017.08); A61K 47/6951 (2017.08); A61P 29/00 (2018.01); C07J 41/005 (2013.01); C07J 41/0088 (2013.01); C07J 71/0031 (2013.01)] 29 Claims
 
1. A compound, pharmaceutically acceptable salt, stereoisomer, regioisomer, or a mixture of regioisomers thereof of Formula (Va), (Vb), (Vc) or (Vd) respectively:

OG Complex Work Unit Chemistry
wherein:
BA is an antibody or antigen binding fragment thereof;
RG1 and RG2 are independently a reactive group residue selected from the group consisting of

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry
wherein the

OG Complex Work Unit Chemistry
indicates the atom through which the RG1 or RG2 is bonded to the adjacent groups in the formula;
PA is a payload residue;
AA2 is a dipeptide, tripeptide, or tetrapeptide residue comprising amino acid residues selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and citrulline;
PAB is

OG Complex Work Unit Chemistry
wherein the

OG Complex Work Unit Chemistry
indicates the atom through which the PAB is bonded to the adjacent groups in the formula;
subscript e is an integer from 0 to 6;
subscript n is an integer from 1 to 30;
subscript p is 0 or 1;
subscript q is 0 or 1; and
HG is selected from the following:
(a)

OG Complex Work Unit Chemistry
(b)

OG Complex Work Unit Chemistry
(c)

OG Complex Work Unit Chemistry
or
(d)

OG Complex Work Unit Chemistry
wherein the

OG Complex Work Unit Chemistry
indicates the atom through which the HG is bonded to the adjacent groups in the formula.