Bis-octahydrophenanthrene carboxamides and protein conjugates thereof

Patent metadata

Field	Value
Publication number	US-12338199-B2
Application number	US-202117494762-A
Country	US
Kind code	B2
Filing date	Oct 5, 2021
Priority date	May 18, 2017
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

Provided herein are compounds, compositions and methods for the treatment of diseases and disorders associated with the liver X receptor, including bis-octahydrophenanthrene carboxamides and protein (e.g., antibody) drug conjugates thereof.

First claim

What is claimed is:

1. A compound of Formula A

or a pharmaceutically acceptable salt, or stereoisomeric form thereof, wherein
L is a linker or X—Y—Z, wherein
X is —NH— or —O—;
Y is an enzymatically cleavable moiety; a self-immolative group; an acid-labile moiety comprising an alkoxamine, ketoxamine, carbonate, or phosphonate; PEG n ; a sugar moiety comprising a glucuronide; and/or an enhancement group comprising a cyclodextrin and/or an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid; and
Z is a binding agent linker (BL) wherein Z is covalently bound to BA;

BA is an antibody or antigen binding fragment thereof;
k ranges from about one to about eight, representing an average number of units of a payload conjugated to BA;
each of Q 1 and Q 2 is independently —CH 2 , C(O)—, —C(H)(OH)—, or —C(OH) 2 —;
W is —CH 2 —, —N(H)—, or —O—;
R is independently hydrogen, —OH, C 1-6 alkyl, or —OP (O)(OR 6 )(OH); and
each R 6 is, independently in each instance, hydrogen, an amino acid residue, a peptide, or alkyl; and
each R 7 is independently halo, C 1-6 alkyl, C 1-6 alkoxy, —CN, O-glucose, O-amino acid residue, or O-PEG n , wherein each n is an integer from zero to three.

2. The compound of claim 1 , comprising BA linked via a linker L to a compound selected from the group consisting of

or a regioisomer, stereoisomeric form, pharmaceutically acceptable salt, or solvate thereof; wherein k ranges from about one to about four, representing an average number of units of a payload conjugated to BA.

3. The compound of claim 1 , comprising BA linked to a compound selected from the group consisting of

or a regioisomer, stereoisomeric form, pharmaceutically acceptable salt, or solvate thereof; wherein k ranges from about one to about four, representing an average number of units of a payload conjugated to BA.

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

or a regioisomer, stereoisomeric form, pharmaceutically acceptable salt, or solvate thereof; wherein k ranges from about one to about four, representing an average number of units of a payload conjugated to BA.

5. The compound of claim 4 , wherein k is about two.

6. The compound of claim 4 , wherein k is about four.

7. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof having binding specificity for an antigen selected from the group consisting of class A-J scavenger receptors.

8. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof having binding specificity for an antigen selected from the group consisting of MSR1, MARCO, SRCL, SCARA5, COLEC12, CD36, LIMPII, SRBI, SRBII, CD68, LAMP, LOX-1, Dectin-1, SREC-I, SREC-II, MEGF, CXCL16, Fasciclin, FEEL-1, FEEL-2, CD163, RAGE, C-type lectin superfamily members, DEC205, CD206, Dectin-2, Mincle, DC-SIGN, DNGR-1, VSIG4, CSFIR, ASGPR, and APLP-2.

9. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof having binding specificity for Her2 or PRLR.

10. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof having binding specificity for MSR1.

11. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof linked through one or more N295 residues.

12. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof linked through one or more N295 and N297Q residues.

13. The compound of claim 1 , having the structure

wherein BA is a binding agent; and k ranges from about one to about four, representing an average number of units of a payload conjugated to BA.

14. The compound of claim 1 , having the structure

wherein BA is a binding agent; and k ranges from about one to about eight, representing an average number of units of a payload conjugated to BA.

15. The compound of claim 1 , having the structure

wherein BA is a binding agent; and k ranges from about one to about eight, representing an average number of units of a payload conjugated to BA.

16. The compound of claim 1 , having

Assignees

• Regeneron Pharma

Inventors

• Han Amy
• Murphy Andrew J
• Olson William

Classifications

• A61K47/6803

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K47/64 Primary

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• C07C237/52 Primary

  having the nitrogen atom of at least one of the carboxamide groups further acylated · CPC title