Zinc-binder based EBNA1-specific compounds

Patent metadata

Field	Value
Publication number	US-11046731-B2
Application number	US-201916249987-A
Country	US
Kind code	B2
Filing date	Jan 17, 2019
Priority date	Jan 18, 2018
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

The present disclosure relates to compounds useful in the treatment, imaging, and/or diagnosis of Epstein-Barr virus (EBV)-positive cells, such as cancer.

First claim

What we claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
m is a whole number selected from 0-4;
n is a whole number selected from 0-4;
p is a whole number selected from 0-4;
X is H 2 , S, or O;
each instance of R is independently H or alkyl;
R 1 is a polypeptide selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, wherein N* represents the N-terminal nitrogen of the polypeptide;
R 2 is H or alkyl;
R 3 is selected from the group consisting of:

each instance of R 4 is independently H or alkyl;
R 5 is H or alkyl;
each instance of R 6 is independently alkene, alkyne, cycloalkyl, aryl, heteroaryl, halide, nitrile, nitro, OR, or NR 2 ;
each instance of R 7 is independently alkene, alkyne, cycloalkyl, aryl, heteroaryl, halide, nitrile, nitro, OR, or NR 2 ;
each of R 8 and R 9 is independently H or alkyl; and
each instance of R 10 is independently alkene, alkyne, cycloalkyl, aryl, heteroaryl, halide, nitrile, nitro, OR, or NR 2 .

2. The compound of claim 1 , wherein each of R 6 , R 7 , and R 10 for each occurrence is independently selected from the group consisting of alkyl halide, nitrile, and nitro.

3. The compound of claim 1 , wherein each of R 2 and R 5 is H.

4. The compound of claim 1 , wherein each of R 4 , R 8 , and R 9 is H.

5. The compound of claim 1 , wherein X is O and R 3 is:

6. The compound of claim 5 , wherein R 6 , R 7 , and R 10 for each occurrence is independently selected from the group consisting of alkyl, halide, nitrile, and nitro.

7. The compound of claim 6 , wherein each of R 4 , R 8 , and R 9 is H.

8. The compound of claim 1 , wherein the compound has Formula II:

or a pharmaceutically acceptable salt thereof, wherein
m is a whole number selected from 0-4;
n is a whole number selected from 0-4;
p is a whole number selected from 0-4;
R 1 is a polypeptide selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, wherein N* represents the N-terminal nitrogen of the polypeptide;
R 3 is selected from the group consisting of:

each instance of R 6 is independently alkyl, alkene, alkyne, cycloalkyl, aryl, heteroaryl, halide, nitrile, nitro, OR, or NR 2 ;
each instance of R 7 is independently alkyl, alkene, alkyne, cycloalkyl, aryl, heteroaryl, halide, nitrile, nitro, OR, or NR 2 ;
each of R 8 and R 9 is independently H or alkyl; and
each instance of R 10 is independently alkyl, alkene, alkyne, cycloalkyl, aryl, heteroaryl, halide, nitrile, nitro, OR, or NR 2 .

9. The compound of claim 1 , wherein the compound has the Formula III:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is a polypeptide selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and wherein N* represents the N-terminal nitrogen of the polypeptide.

10. The compound of claim 1 , wherein X is H2 and R3 is:

11. The compound of claim 10 , wherein each of R 6 , R 7 , and R 10 , for each occurrence is independently selected from the group consisting of alkyl, halide, nitrile, and nitro.

12. The compound of claim 11 , wherein each of R 2 and R 5 is H.

13. The compound of claim 12 , wherein each of R 4 , R 8 , and R 9 is H.

14. The compound of claim 13 , wherein each of m, n, and p is 0.

15. A method of treating an Epstein-Barr virus (EBV)-positive cell in a patient in need thereof comprising administering a therapeutically effective amount of a compound of claim 1 to the patient.

16. The method of claim 15 , wherein the EBV-postive cell is a cancerous cell.

17. The method of claim 16 , wherein the cancerous cell is Burkitt's lymphoma, non-Hodgkin's lymphoma, Hodgkin's disease, T-cell lymphoma, B-cell lymphoma, transplant-associated lymphoproliferative disorders, nasopharyngeal carcinoma, gastric adenocarcinoma, parotid carcinoma, or leiomyosarcoma.

18. The method of claim 14 , wherein the compound as the Formula III:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is a polypeptide selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and wherein N* represents the N-terminal nitrogen of the polypeptide.

19. A method of imaging an EBV-positive cell comprising the step of contacting the EBV-positive cell with a compound of claim 1 and measuring the fluorescence of the compound.

20. The method of claim 19 , wherein the compound has the Formula III:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is a polypeptide selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and wherein N* represents the N-terminal nitrogen of the poly peptide.

Assignees

• Univ Hong Kong Baptist Univ

Inventors

• Wong Ka Leung
• Mak Nai Ki
• Jiang Lijun

Classifications

• C07D213/36 Primary

  Radicals substituted by singly-bound nitrogen atoms (nitro radicals C07D213/26) · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• C07K7/02

  Linear peptides containing at least one abnormal peptide link · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title