Steroids and protein-conjugates thereof

Patent metadata

Field	Value
Publication number	US-11760775-B2
Application number	US-202016858458-A
Country	US
Kind code	B2
Filing date	Apr 24, 2020
Priority date	Nov 8, 2016
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

Described herein are protein steroid conjugates that are useful, for example, for the target-specific delivery of glucocorticoids (GCs) to cells.

First claim

What is claimed is:

1. A conjugate compound comprising an antibody or antigen binding fragment thereof conjugated to a compound of Formula (A):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or derivative thereof,
wherein:
R 1 and R 2 are, independently, —H, alkyl, alkyl-C(O)—O—, —OH, or halo; or
R 1 and R 2 together form

wherein R 4 is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl, wherein the alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl are, independently in each instance, optionally substituted with —NR a R b ;

R 3 is —NR a R b ;
R 5 is, independently in each instance, —OH, halo, alkyl, or arylalkyl and each R 5 is positioned on any ring atom;
R a and R b are, independently in each instance, —H, alkyl, or optionally substituted aryl; or
R a and R b cyclize to form cycloheteroalkyl with three to six ring atoms, including one hetero atom, which is the N to which they are attached; and
hetero atom, which is the N to which they are attached; and
n is an integer from 0-19; and
the antibody or antigen binding fragment thereof is covalently bonded to R 3 .

2. A conjugate compound according to Formula 1200:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein:
R 1 and R 2 are, independently, selected from the group consisting of —H, —OH, alkyl, —O—C(O)-alkyl, and halo; or
R 1 and R 2 together form

either (a) or (b):
(a) R 3 is —NR a R b ; and
R 4 is selected from the group consisting of -alkylene-NR a R b , —X-arylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent or —CH 2 —; and Y is absent;

or
(b) R 3 is —NR a R b ; and
R 4 is alkyl;

R 5 is, independently in each instance, selected from a substituent in the group consisting of —OH, halo, and alkyl; n is an integer from 0-16; and each R 5 is positioned on any ring atom;
R a and R b are, independently in each instance, selected from the group consisting of —H and alkyl; or R a and R b cyclize to form cycloheteroalkyl with three to six ring atoms, including one hetero atom, which is the N to which they are attached;
BA is an antibody or antigen binding fragment thereof;
each L is an optional linker;
BA or L is covalently bonded to R 3 ; and
x is an integer from 1 to 30.

3. The conjugate compound of claim 2 according to Formula 1210, 1220, 1230, or 1240:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein R 3 is covalently bonded to L or BA.

4. The conjugate compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof;
wherein each L is an optional linker;
each BA is an antibody or antigen binding fragment thereof; and
each x is an integer from 1 to 30.

5. The conjugate compound of claim 1 selected from the group consisting of:

wherein x is an integer from 1 to 30;
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

6. The conjugate compound of claim 1 wherein the compound of Formula (A) is

7. The conjugate compound of claim 1 wherein the compound of Formula (A) is

8. The conjugate compound of claim 1 , wherein the compound of Formula (A) is

9. The conjugate compound of claim 1 , wherein the compound of Formula (A) is a compound of the formula:

Assignees

• Regeneron Pharma

Inventors

• Han Amy
• Murphy Andrew J
• Olson William

Classifications

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title

• A61K47/6803 Primary

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• C07J71/0026 Primary

  cyclic ketals · CPC title

• C07J41/005

  the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives · CPC title

• C07J71/0031 Primary

  at positions 16, 17 · CPC title