Bioorthogonal compositions

Patent metadata

Field	Value
Publication number	US-12296017-B2
Application number	US-202117550731-A
Country	US
Kind code	B2
Filing date	Dec 14, 2021
Priority date	Apr 7, 2017
Publication date	May 13, 2025
Grant date	May 13, 2025

Abstract

Cyclooctene conjugates of therapeutic or diagnostic agents have improved aqueous solubility and can release the agents upon contact with a tetrazine-containing biomaterial. The cyclooctene conjugates provide site-selective delivery of agents at the location of the tetrazine-containing biomaterial in a subject. The compositions and methods have applications in the treatment of various diseases or conditions including cancer, tumor growths, and bacterial infections.

First claim

The invention claimed is:

1. A method of treating a cancer or bacterial infection comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I-A), or a pharmaceutically acceptable salt thereof,

wherein
R 1a is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R 1b is selected from the group consisting of G 1 , OH, —NR 1c —C 1-4 alkylene-G 1 , —NR 1c —C 1-4 alkylene-N(R 1d ) 2 , —N(R 1c )CHR 1e CO 2 H, —N(R 1c )—C 1-6 alkylene-CO 2 H, —N(R 1f )—C 2-4 alkylene-(N(C 1-4 alkylene-CO 2 H)—C 2-4 alkylene) n -N(C 1-4 alkylene-CO 2 H) 2 , —N(R 1c )CHR 1e C(O)OC 1-6 alkyl, —N(R 1c )—C 1-6 alkylene-C(O)OC 1-6 alkyl, and —N(R 1f )—C 2-4 alkylene-(N(C 1-4 alkylene-C(O)OC 1-6 alkyl)-C 2-4 alkylene) n -N(C 1-4 alkylene-C(O)OC 1-6 alkyl) 2 ;
R 1c and R 1d , at each occurrence, are independently hydrogen or C 1-4 alkyl;
R 1e is —C 1-4 alkylene-CO 2 H, —C 1-4 alkylene-CONH 2 , or —C 1-4 alkylene-OH;
R 1f is hydrogen, C 1-6 alkyl, or C 1-4 alkylene-CO 2 H;
D, at each occurrence, is independently a therapeutic agent selected from an anti-cancer agent and an antibiotic agent;
L 1 - is a linker;
L 2 - is selected from the group consisting of —C(O)— and C 1-3 alkylene;
G 1 is an optionally substituted heterocyclyl;
m is 1, 2, or 3;
n is 0, 1, 2, or 3; and
p is 0, 1, or 2;
and administering a therapeutic support composition, the therapeutic support composition comprising a biocompatible support and a tetrazine-containing group of formula

wherein
R 20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF 3 , CF 2 —R′, NO 2 , OR′, SR′, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O) 2 R″, S(═O) 2 NR′R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′R″, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O) SR″, NR′C(═S) SR″, OC(═O)NR′R″, SC(═O)NR′R″, OC(═S)R′R′″, SC(═S)R′R″, NR′C(═O)NR″R″, and NR′C(═S)NR″R″;
R′ and R″ at each occurrence are independently selected from hydrogen, aryl and alkyl;
R″ at each occurrence is independently selected from aryl and alkyl;
R 30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; halalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
R a , R 31a and R 31b are each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl; and
t is 0, 1, 2, 3, or 4.

2. The method of claim 1 , wherein the method is a method of treating is a cancer and the therapeutic agent is an anticancer agent.

3. The method of claim 2 , wherein the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer.

4. The method of claim 2 , wherein the cancer is a solid tumor.

5. The method of claim 2 , wherein the cancer is a soft tissue sarcoma.

6. The method of claim 5 , wherein the soft tissue sarcoma is a fibrosarcoma, rhabdomyosarcoma, or Ewing's sarcoma.

7. The method of claim 2 , wherein the cancer is a diffuse intrinsic pontine glioma.

8. The method of claim 1 , wherein the method is a method of treating a bacterial infection.

9. The method of claim 8 , wherein the bacterial infection is an antibiotic resistant infection.

10. The method of claim 1 , wherein the biocompatible support is a hyaluronic acid, or a salt thereof.

11. The method of claim 10 , wherein the biocompatible support comprises substituted hyaluronic acid units of formula (II),

wherein G 2 is

 and
R 22 is a linker of 1 to 100 linking atoms.

12. The method of claim 1 , wherein the compound of formula (I-A) is administered in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

13. The method of claim 2 , wherein the anticancer agent is doxorubicin.

14. The method of claim 13 , wherein the compound of formula (I-A) is

Assignees

• Tambo Inc
• Univ New York State Res Found

Inventors

• Mejia Oneto Jose Manuel
• Yee Nathan
• Royzen Maksim
• Srinivasan Sangeetha
• Miller Ethan

Classifications

• A61K49/0054

  Macromolecular compounds, i.e. oligomers, polymers, dendrimers · CPC title

• A61K49/0052

  Small organic molecules (oligomers, polymers, dendrimers A61K49/0054) · CPC title

• A61K49/0043

  Fluorescein, used in vivo · CPC title

• A61K49/0041

  Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal (in vivo G01N) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title