Programmable dendritic drugs

Patent metadata

Field	Value
Publication number	US-12290571-B2
Application number	US-201816639499-A
Country	US
Kind code	B2
Filing date	Oct 5, 2018
Priority date	Oct 5, 2017
Publication date	May 6, 2025
Grant date	May 6, 2025

Abstract

Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I) or a stereoisomer, tautomer or salt thereof, wherein R 1 , R 2 , R 3 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , M, m, and p are as defined herein. Methods associated with preparation and use of such compounds is also provided.

First claim

What is claimed is:

1. A compound having the following structure (IA):

or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein:
M is, at each occurrence, independently a biologically active moiety selected from an non-steroidal anti-inflammatory drug (NSAID), a kinase inhibitor, an anthracycline, an epidermal growth factor receptor (EGFR) inhibitor, an alkylating agent, and an anti-cancer drug, or a fluorescent dye, provided at least one occurrence of M is not a fluorescent dye;
L 1 and L 2 are, at each occurrence, independently an alkylene, heteroalkylene, or heteroatomic linker, wherein the heteroatomic linker is one or more heteroatoms;
L 4 is, at each occurrence, independently an alkylene or heteroalkylene, or absent;
L 5 is, at each occurrence, independently an alkylene or absent;
L 6 is, at each occurrence, independently a linker comprising an amide bond, an ester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a ketone, a diol, a cyano, a nitro or combinations thereof;
L 7 and L 8 are, at each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene or heteroalkynylene linker;
R 1 is, at each occurrence, independently H, alkyl or alkoxy;
R 2 is —OP(═R a )(R b )R c ;
R 3 is, at each occurrence, independently OH, —OP(═R a )(R b )R c , Q or has the following structure:

R a is O or S;
R b is OH, SH, O − , S − , OR d or SR d ;
R c is OH, SH, O − , S − , OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkylether, alkoxyalkylether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether;
R d is a counter ion;
R 4 is, at each occurrence, independently OH, SH, O − , S − , OR d or SR d ;
R 5 is, at each occurrence, independently oxo, thioxo or absent;
Q is, at each occurrence, independently a moiety having one of the following structures:

wherein:
each X is independently a halogen; and
EWG is an electron withdrawing group;

L′ is, at each occurrence, independently a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a linker comprising a covalent bond to a nucleoside or a linker comprising a covalent bond to a further compound of structure (IA), wherein the targeting moiety is an antibody or cell surface receptor antagonist;
L 2 ′ is, at each occurrence, independently a direct bond, an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatomic linker;
L 3 is, at each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene linker, or absent;
n is, at each occurrence, independently an integer of one or greater;
m is, at each occurrence, independently an integer of one or greater;
p is, at each occurrence, independently an integer of one to ten; and
q is, at each occurrence, independently an integer of zero or greater;
wherein R 2 or at least one of occurrence of R 3 has the following structure:

2. The compound of claim 1 , wherein at least one occurrence of R 3 has the following structure:

wherein:
L 2 ′ is a direct bond.

3. The compound of claim 1 , wherein L 3 is a heteroalkylene linker.

4. The compound of claim 1 , wherein m is, at each occurrence, independently an integer from 1 to 25.

5. The compound of claim 1 , wherein n is, at each occurrence, independently an integer from 1 to 10.

6. The compound of claim 1 , wherein R 3 is each independently OH or —OP(═R a )(R b )R c .

7. The compound of claim 1 , wherein R 3 is Q.

8. The compound of claim 1 , wherein R 3 is each independently —OP(═R a )(R b )R c .

9. The compound of claim 8 , wherein R c is OL′.

10. The compound of claim 9 , wherein L′ is a targeting moiety or a linker to a targeting moiety.

11. The compound of claim 1 , wherein R 2 or R 3 has one of the following structures:

12. The compound of claim 1 , wherein M is, at each occurrence, independently an anti-cancer drug, and the targeting moiety is an antibody specific for a tumor cell antigen.

13. The compound of claim 1 , wherein the compound has one of the following structures:

wherein N′ or I′ is M,
wherein N′ has the following structure:

wherein I′ has the following structure:

wherein dT is a deoxythymidine (dT) group and has the following structure:

wherein: R is H.

14. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

15. A method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , wherein each M is independently a biologically active moiety effective for treating the disease.

16. The compound of claim 1 , wherein M, at each occurrence, independently has one of the following structures:

Assignees

• Sony Group Corp

Inventors

• Matray Tracy
• Sherif Hesham

Classifications

• A61K47/6801

  Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent · CPC title

• A61K47/59 Primary

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title