US 11,666,658 B2
Rifamycin analogs and antibody-drug conjugates thereof
Thomas Nittoli, Pearl River, NY (US); Seungyong Sean Choi, Bristol, PA (US); and Mrinmoy Saha, Bristol, PA (US)
Assigned to Regeneran Pharmaceuticals, Inc., Tarrytown, NY (US)
Filed by Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US)
Filed on Dec. 20, 2019, as Appl. No. 16/722,958.
Claims priority of provisional application 62/844,860, filed on May 8, 2019.
Claims priority of provisional application 62/783,506, filed on Dec. 21, 2018.
Prior Publication US 2020/0368361 A1, Nov. 26, 2020
Int. Cl. A61K 47/68 (2017.01); C07D 498/18 (2006.01)
CPC A61K 47/6803 (2017.08) [C07D 498/18 (2013.01)] 32 Claims
 
1. An antibody-drug conjugate comprising an antibody, or an antigen-binding fragment thereof, conjugated via a linker or through a linker-spacer to a rifamycin analog having the structure of Formula (XXI):

OG Complex Work Unit Chemistry
wherein:
X is selected from —O—, —S—, and —NR*—;
R5 is selected from a bond; an aliphatic C1-C20 hydrocarbon which further comprises 0-8 heteroatoms selected from halogen, O, N, and S;

OG Complex Work Unit Chemistry
or

OG Complex Work Unit Chemistry
wherein Y is C or N;
R2, R3, and R4 are independently selected from a hydrogen, a straight chained, branched or cyclic aliphatic C3-C20 hydrocarbon, or —(C═O)—R*, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S;
R* is independently at each occurrence selected from hydrogen, an aliphatic C1-C20 hydrocarbon, an aromatic C5-C20 hydrocarbon, a heteroaromatic C1-C20 hydrocarbon, a cyclic aliphatic C3-C20 hydrocarbon, a heterocyclic C1-C20 hydrocarbon, and combinations thereof, which further comprises 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof, and
R5c is a bond or an aliphatic C1-C8 hydrocarbon;
wherein the group R5 is bonded to the linker.
 
7. An antibody-drug conjugate comprising an antibody, or an antigen-binding fragment thereof, conjugated via a linker or through a linker-spacer to a compound selected from the group consisting of:

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry
wherein the

OG Complex Work Unit Chemistry
is the bond to the linker, and when the compound comprises an ammonium salt, the counterion is an anion selected from F−, Cl−, Br−, I−, OH−, −BF4, CF3SO3−, monobasic sulfate, dibasic sulfate, monobasic phosphate, dibasic phosphate, or tribasic phosphate, NO3−, PF6−, NO2−, carboxylate, CeFf, wherein e=2-10 and f=2e+1, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, camsylate, carbonate, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollyalarsanilate, hexanoate, hydrabamine, hydroxynaphthoate, isthionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, mucate, napsylate, octanoate, oleate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, teoclate, tosylate, or triethiiodide.
 
8. An antibody-drug conjugate having the structure of Formula (XXII):

OG Complex Work Unit Chemistry
wherein:
BA is an antibody, or an antigen-binding fragment thereof;
L is a linker having the formula

OG Complex Work Unit Chemistry
wherein
RG is selected from a maleimide, a N-hydroxysuccinimide, or a succinimide;
SP1 and SP2 are independently absent or a spacer group selected from the group consisting of

OG Complex Work Unit Chemistry
C1-6 alkyl, —NH—, —C(O)—, —CH2—CH2—C(O)—NH—, —(CH)u—C(O)—NH—, (—CH2—CH2—O)e, —NH—CH2—CH2—(—O—CH2—CH2)e—C(O)—, —C(O)—(CH2)u—C(O)—, —C(O)—NH—(CH2)v—, and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8;
AA2-4 is a dipeptide selected from valine-citrulline; citrulline-valine; valine-alanine; alanine-valine; valine-glycine, or glycine-valine, and
PEG is a polyethylene glycol chain comprising between 1 and 30 polyethylene glycol residues;
SP is a spacer group selected from

OG Complex Work Unit Chemistry
Y is C or N; wherein the custom character symbol represents the point of attachment; and R′, R″ and R′″ are selected from a hydrogen, a C1-C6 aliphatic hydrocarbon, and a protecting group selected from Fluorenylmethyloxycarbonyl (FMOC) and tert-Butyloxycarbonyl (BOC), or wherein R′ and R″ together form an aliphatic monocyclic, an aliphatic bicyclic, or an aliphatic polycyclic structure; or wherein the

OG Complex Work Unit Chemistry
has a structure:

OG Complex Work Unit Chemistry
R* is independently at each occurrence selected from hydrogen, an aliphatic C1-C20 hydrocarbon, an aromatic C5-C20 hydrocarbon, a heteroaromatic C1-C20 hydrocarbon, a cyclic aliphatic C3-C20 hydrocarbon, a heterocyclic C1-C20 hydrocarbon, and combinations thereof, which further comprises 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof, and
X is selected from —O—, —S—, and —NR*.