Dihydrochromene derivatives

Patent metadata

Field	Value
Publication number	US-10807993-B2
Application number	US-202016808246-A
Country	US
Kind code	B2
Filing date	Mar 3, 2020
Priority date	Mar 20, 2018
Publication date	Oct 20, 2020
Grant date	Oct 20, 2020

Abstract

The present invention relates to the compound of formula (I) wherein R 1A , R 1B , R 1C , and R 1D are hydrogen atom, etc., R 2A and R 2B are hydrogen atom, etc., R 3A , R 3B , R 3C , and R 3D are hydrogen atom, etc., L is bond, etc., V is C 1-6 alkylene, Q is optionally-substituted imidazole, or a pharmaceutically acceptable salt thereof, as a novel anti-tumor agent that targets CSCs which are thought to be closely involved in the persistent proliferation of malignant tumor, metastasis or recurrence of cancer, and resistance to anti-tumor agents.

First claim

The invention claimed is:

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran],
(4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran],
(4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran],
(4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran],
(4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran], and
(4′aR,10′bR)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,11′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aR,10′bR)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].

8. The compound of claim 1 wherein the salt is a phosphate.

9. The compound of claim 8 , which is (4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-y)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.

10. The compound of claim 8 , which is (4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.

11. The compound of claim 8 , which is (4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.

12. The compound of claim 8 , which is (4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.

13. The compound of claim 8 , which is (4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.

14. The compound of claim 8 , which is (4′aR,10′bR)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-y)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.

15. The compound of claim 1 wherein the salt is a fumurate.

16. The compound of claim 15 , which is (4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.

17. The compound of claim 15 , which is (4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazo-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.

18. The compound of claim 15 , which is (4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.

19. The compound of claim 15 , which is (4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.

20. The compound of claim 15 , which is (4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.

21. The compound of claim 15 , which is (4′aR,10′bR)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.

22. The compound of claim 1 wherein the salt is a p-toluenesulfonate.

23. The compound of claim 22 , which is (4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.

24. The compound of claim 22 , which is (4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.

25. The compound of claim 22 , which is (4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.

26. The compound of claim 22 , which is (4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.

27. The compound of claim 22 , which is (4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.

28. The compound of claim 22 , which is (4′aR,10′bR)-9′-fluoro-5′5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.

Assignees

• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Ban Hitoshi
• Kamioka Seiji
• Sawayama Yusuke
• Hashizume Miki

Classifications

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title

• A61K31/436

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D491/20 Primary

  Spiro-condensed systems · CPC title