Semi-synthetic analogues of epipolythiodioxopiperazine alkaloids

Patent metadata

Field	Value
Publication number	US-12448398-B2
Application number	US-202017613640-A
Country	US
Kind code	B2
Filing date	May 22, 2020
Priority date	May 23, 2019
Publication date	Oct 21, 2025
Grant date	Oct 21, 2025

Abstract

Disclosed herein are compounds, compositions, and methods for inhibiting a histone methyltransferase. The compounds are verticillin derivatives that exhibit anti-proliferative activity against cancer cells. The compounds, compositions, and methods can be used to treat a subject with cancer.

First claim

What is claimed is:

1. A compound having Formula I:

wherein
R 1 and R 10 are independently unsubstituted alkyl;
R 4 and R 7 are both halogen or hydrogen; R 4 is hydrogen and R 7 is halogen; or R 4 is halogen and R 7 is hydrogen;
R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are independently hydrogen; halogen; amino; hydroxy; thiol; ester; carbamate; carbonate; sulfonate; substituted or unsubstituted alkyl, alkenyl, alkynyl, or alkoxy; and
R 11 is a hydroxy, ester, carbamate, carbonate, or sulfonate;
wherein when R 11 is a hydroxy, then R 4 and R 7 are both halogen, R 4 is hydrogen and R 7 is halogen, or R 4 is halogen and R 7 is hydrogen;
wherein when R 1 and R 10 are methyl, R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are H, and R 11 is

 then R 4 and R 7 are both halogen; R 4 is hydrogen and R 7 is halogen; or R 7 is halogen and R 4 is hydrogen;
or a pharmaceutically acceptable salt thereof.

2. A compound having Formula II:

wherein
R 1 and R 10 are independently substituted or unsubstituted alkyl;
R 12 and R 13 are both halogen; R 12 is hydrogen and R 13 is halogen; or R 12 is halogen and R 13 is hydrogen;
R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are independently hydrogen; halogen; amino; hydroxy; thiol; ester; carbamate; carbonate; sulfonate; substituted or unsubstituted alkyl, alkenyl, alkynyl, or alkoxy; and
R 11 is a hydroxy, ester, carbamate, carbonate, or sulfonate;

or a pharmaceutically acceptable salt thereof.

3. A compound having Formula III:

wherein
R 1 and R 10 are independently unsubstituted alkyl;
R 4 and R 7 are both halogen or hydrogen; R 4 is hydrogen and R 7 is halogen; or R 4 is halogen and R 7 is hydrogen;
R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are independently hydrogen; halogen; amino; hydroxy; thiol; ester; carbamate; carbonate; sulfonate; substituted or unsubstituted alkyl, alkenyl, alkynyl, or alkoxy; and
R 14 is an ester, carbamate, carbonate, or sulfonate;
wherein when R 1 and R 10 are methyl, R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are H, and R 14 is,

 then R 4 and R 7 are both halogen; R 4 is hydrogen and R 7 is halogen; or R 7 is halogen and R 4 is hydrogen;
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R 11 is a carbamate or an ester.

5. The compound of claim 3 , wherein R 14 is a carbamate or an ester.

6. The compound of claim 1 , wherein R 11 is selected from one of the following:

7. The compound of claim 3 , wherein R 14 is selected from one of the following:

8. The compound of claim 1 , wherein R 1 and R 10 are independently methyl, ethyl, or a combination thereof.

9. The compound of claim 1 , wherein R 4 and R 7 are halogen, hydrogen, or a combination thereof.

10. The compound of claim 1 , wherein R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 are hydrogen.

11. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 12 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers.

16. A method for treating cancer comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 ;
wherein the cancer is breast cancer, ovarian cancer, melanoma

Assignees

• Ohio State Innovation Foundation
• Univ Of North Carolina At Greensboro
• Univ Illinois
• Mycosynthetix Inc

Inventors

• Fuchs James Robert
• Huntsman Andrew
• Oberlies Nicholas Hunter
• Amrine Chiraz Soumia
• Raja Huzefa
• Burdette Joanna
• Pearce Cedric

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title