US 11,857,565 B2
Hydrophobic Auristatin F compounds and conjugates thereof
Svetlana O. Doronina, Snohomish, WA (US); and Philip Moquist, Seattle, WA (US)
Assigned to SEAGEN INC., Bothell, WA (US)
Appl. No. 16/968,749
Filed by SEAGEN INC., Bothell, WA (US)
PCT Filed Feb. 20, 2019, PCT No. PCT/US2019/018825
§ 371(c)(1), (2) Date Aug. 10, 2020,
PCT Pub. No. WO2019/164987, PCT Pub. Date Aug. 29, 2019.
Claims priority of provisional application 62/633,059, filed on Feb. 20, 2018.
Prior Publication US 2021/0008099 A1, Jan. 14, 2021
Int. Cl. A61K 31/74 (2006.01); A61K 47/64 (2017.01); A61K 38/02 (2006.01); A61K 47/65 (2017.01)
CPC A61K 31/74 (2013.01) [A61K 38/02 (2013.01); A61K 47/64 (2017.08); A61K 47/65 (2017.08)] 12 Claims
OG exemplary drawing
 
1. A Ligand Drug Conjugate compound represented by Formula 1:
L-[LU-D′]p′  (1)
or a salt thereof, wherein
L is a Ligand Unit;
subscript p′ is an integer ranging from 1 to 24:
each -LU-D′ is a drug-linker moiety of Formula 1A:

OG Complex Work Unit Chemistry
or a salt thereof,
wherein the wavy line indicates covalent attachment to L;
LB is a ligand covalent binding moiety;
A is a first optional Stretcher Unit;
subscript a is 0 or 1, indicating the absence or presence of A, respectively;
B is an optional Branching Unit;
subscript b is 0 or 1, indicating the absence or presence of B, respectively;
LO is an optional secondary linker moiety;
subscript q is an integer ranging from 1 to 4;
D is a hydrophobic auristatin F compound represented by the structure of:

OG Complex Work Unit Chemistry
or a salt thereof, wherein
the hydrophobic auristatin F compound is conjugated to the remainder of the drug-linker moiety through its C-terminal component's carboxylic acid carbon atom:
Ar is phenyl, thienyl, 1-napthyl, 2-napthyl, or benzo[b]thiophen-3-yl;
R3 is independently selected from the group consisting of hydrogen and C1-C2 alkyl:
R1 is C1-C9 alkyl, or
R1 is (C3-C6 carbocyclyl)-alkylene- of up to 9 total carbon atoms, or
R1 is —(C2-C6 alkylene)-X—R4, wherein X is an amide or carbamate functional group and R4 is C1-C6 alkyl; and
R2 is C1-C2 alkyl,
with the proviso that the total number of carbon atoms in R2 and the (carbocyclyl)alkyl(ene) moiety of R1 is between 4 and 10, and R1 and R2 are not each methyl,
wherein, when present, LO has the formula of:

OG Complex Work Unit Chemistry
wherein the wavy line adjacent to Y indicates the site of covalent attachment to the hydrophobic auristatin F compound, and the wavy line adjacent to A′ indicates the site of covalent attachment to the remainder of the drug linker moiety;
A′ is a second optional Stretcher Unit,
subscript a′ is 0 or 1, indicating the absence or presence of A′, respectively;
W is a peptide Cleavable Unit;
Y is a peptide Spacer Unit; and
subscript y is 0 or 1, indicating the absence or presence of Y, respectively.