Inhibitors of SOX18 protein activity for treating angiogenesis-and/or lymphangiogenesis-related diseases

Patent metadata

Field	Value
Publication number	US-11434190-B2
Application number	US-201716472882-A
Country	US
Kind code	B2
Filing date	Dec 21, 2017
Priority date	Dec 23, 2016
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

Abstract

Disclosed are compounds of a formula provided herein that show efficacy in the inhibition of SOX18 protein activity, and in particular with respect to the ability of SOX18 to bind DNA and/or particular protein partners. Further, methods of treating angiogenesis- and/or lymphangiogenesis-related diseases, disorders or conditions, such as cancer metastasis and vascular cancers, are provided herein.

First claim

The invention claimed is:

1. A method of treatment of an angiogenesis and/or lymphangiogenesis-related disease, disorder or condition, comprising administering to a subject an effective amount of a compound of Formula 1:

wherein,
R 1 is selected from the group consisting of OH and OR 6 wherein R 6 is C 1-4 alkyl;
R 2 is selected from the group consisting of H, COOR 7 , and C(O)NR 8 R 9 wherein R 7 , R 8 and R 9 are independently selected from the group consisting of H and C 1-4 alkyl;
R 3 is L-A wherein L is a linker selected from the group consisting of C 2-8 alkyl, C 2-8 alkenyl and C 2-8 alkoxyalkyl and A is an optionally substituted naphthyl;
R 4 is selected from the group consisting of H, OR 10 , halo and C 1-4 alkyl wherein R 10 is selected from the group consisting of H and C 1-4 alkyl; and
R 5 is selected from the group consisting of H, OR 11 , halo and C 1-4 alkyl wherein R 11 is selected from the group consisting of H and C 1-4 alkyl;
or a pharmaceutically effective salt, solvate or prodrug thereof; and

wherein the angiogenesis and/or lymphangiogenesis-related disease, disorder or condition is a SOX7, SOX17, or SOX18-dependent cancer selected from the group consisting of sarcomas, carcinomas, lymphomas, leukemias, and blastomas.

2. The method according to claim 1 , wherein the cancer is SOX18-dependent and is selected from the group consisting of prostate cancer, breast cancer, lung cancer, bladder cancer, renal cancer, ovarian cancer, cervical cancer, uterine cancer, colon cancer, colorectal cancer, gastric cancer, head and neck cancer, liver cancer, kidney cancer, skin cancer, pancreatic cancer, pituitary cancer, musculoskeletal cancer, hemangioma, angioma, angiosarcoma, hepatoma, and hepatocellular carcinoma.

3. The method according to claim 2 , wherein cancer metastasis is inhibited.

4. The method according to claim 1 , wherein the compound of Formula I selectively inhibits SOX18-mediated transcription.

5. The method according to claim 1 , wherein the compound of Formula I inhibits both DNA binding and transcription factor protein partner recruitment of SOX18.

6. The method according to claim 1 , wherein the compound of Formula I inhibits SOX18 homodimerisation.

7. The method according to claim 1 , wherein the compound of Formula I inhibits SOX18-RBPJ heterodimerisation.

8. The method according to claim 1 , wherein for the compound of Formula 1:
R 1 is selected from the group consisting of OH and OR 6 wherein R 6 is C 1-4 alkyl;
R 2 is selected from the group consisting of H, COOR 7 , and C(O)NR 8 R 9 wherein R 7 , R 8 and R 9 are independently selected from H and C 1-4 alkyl;
R 3 is L-A wherein L is a linker selected from the group consisting of C 2-8 alkyl, C 2-8 alkenyl and C 2-8 alkoxyalkyl and A is an optionally substituted naphthyl, and wherein the substituted groups are selected from the group consisting of halo, C 1-4 alkyl, OC 1-4 alkyl, NH 2 , NH(C 1-4 alkyl), and N(C 1-4 alkyl) 2 ;
R 4 is selected from the group consisting of H, OR 10 , halo and C 1-4 alkyl wherein R 10 is selected from H and C 1-4 alkyl; and
R 5 is selected from the group consisting of H, OR 11 , halo and C 1-4 alkyl wherein R 11 is selected from the group consisting of H and C 1-4 alkyl.

9. The method according to claim 1 , wherein for the compound of Formula 1:
R 1 is selected from the group consisting of OH and OR 6 wherein R 6 is C 1-4 alkyl;
R 2 is selected from the group consisting of COOR 7 and C(O)NR 8 R 9 wherein R 7 , R 8 and R 9 are independently selected from the group consisting of H and C 1-4 alkyl;
R 3 is L-A wherein L is a linker selected from the group consisting of C 2-8 alkyl, C 2-8 alkenyl and C 2-8 alkoxyalkyl and A is an optionally substituted naphthyl;
R 4 is selected from the group consisting of H, OR 10 , halo and C 1-4 alkyl wherein R 10 is selected from the group consisting of H and C 1-4 alkyl; and
R 5 is H.

10. The method according to claim 1 , wherein for the compound of Formula 1:
R 1 is selected from the group consisting of OH and OR 6 wherein R 6 is C 1-4 alkyl;
R 2 is selected from the group consisting of H, COOR 7 , and C(O)NR 8 R 9 wherein R 7 , R 8 and R 9 are independently selected from the group consisting of H and C 1-4 alkyl;
R 3 is L-A wherein L is a linker selected from the group consisting of C 2-8 alkyl, C 2-8 alkenyl and C 2-8 alkoxyalkyl and A is selected from the group consisting of an unsubstituted naphthyl or a naphthyl substituted with one or more groups selected from the group consisting of halo, C 1-4 alkyl, OC 1-4 alkyl, NH 2 , NH(C 1-4 alkyl), and N(C 1-4 alkyl) 2 ;
R 4 is selected from the group consisting of H, OR 10 , halo and C 1-4 alkyl wherein R 10 is selected from the group consisting of H and C 1-4 alkyl; and
R 5 is selected from the group consisting of H, OR 11 , halo and C 1-4 alkyl wherein R 11 is selected from the group consisting of H and C 1-4 alkyl.

11. The method according to claim 1 , wherein for the compound of Formula 1:
R 1 is selected from the group consisting of OH and OR 6 wherein R 6 is C 1-4 alkyl;
R 2 is selected from the group consisting of COOR 7 and C(O)NR 8 R 9 wherein R 7 , R 8 and R 9 are independently selected from the group consisting of H and C 1-4 alkyl;
R 3 is L-A wherein L is a linker selected from the group consisting of C 2-8 alkyl, C 2-8 alkenyl and C 2-8 alkoxyalkyl and A is an optionally substituted naphthyl;
R 4 is H; and
R 5 is H.

12. The method according to claim 1 , wherein for the compound of Formula 1:
R 1 is OH;
R 2 is COOR 7 , wherein R 7 is selected from the group consisting of H and C 1-4 alkyl;
R 3 is L-A wherein L is a linker selected from the group consisting of C 2-8 alkyl, C 2-8 alkenyl and C 2-8 alkoxyalkyl and A is an optionally substituted naphthyl;
R 4 is H; and
R 5 is H.

13. The method according to claim 1 , wherein for the compound of Formula 1:
R 1 is OH;
R 2 is COOH;
R 3 is L-A wherein L is a linker selected from the group consisting of C 2-8 alkyl, C 2-8 alkenyl and C 2-8 alkoxyalkyl and A is an optionally substituted naphthyl;
R 4 is H; and
R 5 is H.

14. The method according to claim 1 , wherein for the compound of Formula 1:
R 1 is OH;
R 2 is COOH;
R 3 is L-A wherein L is C 2-8 alkyl and A is an optionally substituted naphthyl;
R 4 is H; and
R 5 is H.

15. The method according to claim 1 , wherein for the compound of Formula 1:
R 1 is OH;
R 2 is COOH;
R 3 is L-A wherein L is C 2-8 alkyl and A is an unsubstituted naphthyl or a naphthyl substituted with one or more groups selected from the group consisting of halo, C 1-4 alkyl, OC 1-4 alkyl, NH 2 , NH(C 1-4 alkyl), and N(C 1-4 alkyl) 2 ;
R 4 is H; and
R 5 is H.

Assignees

• Univ Queensland

Inventors

• Francois Mathias
• Zuegg Johannes
• Overman Jeroen
• Mamidyala Sreeman Kumar
• Salim Angela Aguslyarti
• Fontaine Frank Roger
• Cooper Matthew Allister
• Capon Robert John
• Robertson Avril Alexis Barbara

Classifications

• A61K31/05

  Phenols {(cannabinoids A61K31/658)} · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/166

  having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61K31/09

  having two or more such linkages · CPC title