Cyclic compound having selective KRAS inhibitory effect on HRAS and NRAS

Patent metadata

Field	Value
Publication number	US-12410212-B2
Application number	US-202418829566-A
Country	US
Kind code	B2
Filing date	Sep 10, 2024
Priority date	May 6, 2022
Publication date	Sep 9, 2025
Grant date	Sep 9, 2025

Abstract

Cyclic compounds that selectively inhibit KRAS were found. Moreover, cyclic compounds were found to interact with an amino acid residue specific to KRAS.

First claim

The invention claimed is:

1. A compound, which is (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo [37.5.1.0 4,8 .0 26,30 ] pentatetracont-42-ene-23,l′-cyclobutane]-17-carboxamide.

2. A pharmaceutical composition comprising the compound of claim 1 .

3. A method of inhibiting KRAS in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of claim 1 .

4. A method of treating or preventing cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of claim 1 .

5. The method of claim 4 , wherein the cancer is lung cancer.

6. The method of claim 4 , wherein the subject is human.

7. A solvate of (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo [37.5.1.0 4,8 .0 26,30 ] pentatetracont-42-ene-23,1′-cyclobutane]-17-carboxamide.

8. A pharmaceutical composition comprising the solvate of claim 7 .

9. A method of selectively inhibiting KRAS in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the solvate of claim 7 .

10. A method of treating or preventing cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the solvate of claim 7 .

11. The method of claim 10 , wherein the cancer is lung cancer.

12. The method of claim 10 , wherein the subject is human.

13. The solvate according to claim 7 , which is a hydrate.

14. A pharmaceutical composition comprising the solvate of claim 13 .

15. A method of selectively inhibiting KRAS in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the solvate of claim 13 .

16. A method of treating or preventing cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the solvate of claim 13 .

17. The method of claim 16 , wherein the cancer is lung cancer.

18. The method of claim 16 , wherein the subject is human.

19. A salt of (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo [37.5.1.0 4,8 .0 26,30 ] pentatetracont-42-ene-23,1′-cyclobutane]-17-carboxamide, or a solvate thereof.

20. A pharmaceutical composition comprising the salt of claim 19 , or a solvate thereof.

21. A method of inhibiting KRAS in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the salt of claim 19 , or a solvate thereof.

22. A method of treating or preventing cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the salt of claim 19 , or a solvate thereof.

23. The method of claim 22 , wherein the cancer is lung cancer.

24. The method of claim 22 , wherein the subject is human.

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Kawada Hatsuo
• Takano Koji
• Kotake Tomoya
• Kage Mirai
• Hashimoto Satoshi
• Tamiya Minoru
• Wakamiya Yuma
• Hayashi Ryuji
• Morita Yuya

Classifications

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• A61K38/12 Primary

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title