Modified carbazoles as therapeutic agents

Patent metadata

Field	Value
Publication number	US-11420967-B2
Application number	US-201916960541-A
Country	US
Kind code	B2
Filing date	Jun 12, 2019
Priority date	Jun 12, 2018
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

Abstract

This disclosure relates to compounds that target microtubules, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases. More particularly, this disclosure relates to modified carbazole compounds and pharmaceutical compositions thereof, methods of targeting microtubules with these compounds, and methods of treating diseases affected by microtubule disruption.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer thereof, wherein
each independently represents a single or double bond, provided that the bond satisfies the valence requirement of the C and/or N atoms;
X 1 and X 2 are independently selected from CH and N;
Y is C(R 4 ) 2 or NR 4 when represents a single bond, or Y is CR 4 or N when represents a double bond;
wherein each R 4 is independently hydrogen or C 1 -C 6 alkyl optionally substituted with one or more R 5 ;

R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl optionally substituted with one or more R 6 , C 2 -C 6 alkenyl optionally substituted with one or more R 6 , C 2 -C 6 alkynyl optionally substituted with one or more R 6 , —O(C 1 -C 6 alkyl), and —CO(C 1 -C 6 alkyl) optionally substituted with one or more R 6 ;
R 2 is selected from the group consisting of C 1 -C 6 alkyl optionally substituted with one or more R 7 , C 2 -C 6 alkenyl optionally substituted with one or more R 7 , C 2 -C 6 alkynyl optionally substituted with one or more R 7 ,—CO(C 1 -C 6 alkyl) optionally substituted with one or more R 7 , aryl(C 0 -C 6 alkyl) optionally substituted with one or more R 8 , heteroaryl(C 0 -C 6 alkyl) optionally substituted with one or more R 8 , heterocyclyl(C 0 -C 6 alkyl) optionally substituted with one or more R 7 , and cycloalkyl(C 0 -C 6 alkyl) optionally substituted with one or more R 7 ; and
R 3 is —OH, —O(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —SH, or —S(C 1 -C 6 alkyl),
wherein:
each R 5 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), amino(C 1 -C 6 alkyl), —CONH 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO 2 H, and —CO 2 (C 1 -C 6 alkyl);
each R 6 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), amino(C 1 -C 6 alkyl), —CONH 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO 2 H, and —CO 2 (C 1 -C 6 alkyl);
each R 7 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), amino(C 1 -C 6 alkyl), —CONH 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO 2 H, and —CO 2 (C 1 -C 6 alkyl), or two R 7 groups when attached to the same carbon atom form ═O; and
each R 8 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), amino(C 1 -C 6 alkyl), —CONH 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO 2 H, and —CO 2 (C 1 -C 6 alkyl).

2. The compound of claim 1 , comprising compounds of formula (I-2):

3. The compound of claim 1 , wherein each R 4 is independently hydrogen or C 1 -C 6 alkyl.

4. The compound of claim 1 , comprising compounds of formula (I-4):

5. The compound of claim 1 , wherein Y is N.

6. The compound of claim 1 , wherein Y is CR 4 .

7. The compound of claim 1 , wherein R 1 is hydrogen, halogen, or C 1 -C 6 alkyl.

8. The compound of claim 1 , wherein R 2 is C 1 -C 6 alkyl optionally substituted with one or more R 7 , aryl(C 1 -C 2 alkyl) optionally substituted with one or more R 8 , heteroaryl(C 1 -C 2 alkyl) optionally substituted with one or more R 8 , heterocyclyl(C 1 -C 2 alkyl) optionally substituted with one or more R 7 , or cycloalkyl(C 1 -C 2 alkyl) optionally substituted with one or more R 7 .

9. The compound of claim 1 , wherein R 2 is C 1 -C 4 alkyl.

10. The compound of claim 1 , wherein R 3 is —OH, —O(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 .

11. The compound of claim 1 , wherein the compound of formula (I) is substantially enantiomerically pure.

12. The compound of claim 1 , wherein the compound of formula (I) is (−)-enantiomer.

13. The compound of claim 1 , wherein the compound of formula (I) is (+)-enantiomer.

14. The compound of claim 1 , which is:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , which is: (9-ethyl-9H-carbazol-3-yl)(quinolin-5-yl)methanol, (9-ethyl-9H-carbazol-3-yl)(quinolin-8-yl)methanol, or (9-ethyl-9H-carbazol-3-yl)(4-methylnaphthalen-1-yl)methanol, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

16. A pharmaceutical composition including one or more compounds according to claim 1 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

17. A method of treating cancer, comprising administering one or more compounds according to claim 1 to a subject in need thereof.

18. The method of claim 17 , further comprising administering one or more secondary therapeutic agents.

19. The method of claim 18 , wherein the secondary therapeutic agents is selected from an antimetabolite, nucleoside analog, taxane, vinca alkaloid, microtubule inhibitor, alkylating agent, and a BRAF inhibitor.

20. The method of claim 17 , wherein the cancer is selected from: BRAF-mutant cancers, melanoma, brain cancer, colorectal cancers, lung cancer, breast cancer, head and neck tumors, and lymphoma.

21. The method of claim 17 , wherein the cancer is glioblastoma.

22. A method of disrupting MT function in a cell, comprising administering one or more compounds according to claim 1 to the cell.

23. The method of claim 17 wherein the cancer develops in peripheral tissues and metastasizes to the brain.

24. The compound of claim 1 , which is (9-ethyl-9H-carbazol-3-yl)(quinolin-5-yl)methanol, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

Assignees

• Univ Washington
• The Univ Of Montana

Inventors

• Stella Nephi
• Diaz Philippe

Classifications

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D209/86 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system · CPC title