Compounds and anti-tumor NQO1 substrates

Patent metadata

Field	Value
Publication number	US-9611266-B2
Application number	US-201614993029-A
Country	US
Kind code	B2
Filing date	Jan 11, 2016
Priority date	Oct 14, 2011
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

Compounds of Formula (I) can be selectively lethal toward a variety of different cancer cell types. The compounds are useful for the management, treatment, control, or adjunct treatment of diseases, where the selective lethality is beneficial in chemotherapeutic therapy.

First claim

What is claimed is:

1. A compound of the Formula (I):

wherein
R 1 is alkyl;
R 3 is H;
R 2 and R 4 are each independently —X—R;
each X is independently a direct bond, —C(═O)—, or (C 1 -C 20 )alkyl;
each R is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, (cycloalkyl)heteroalkyl, aryl, heteroaryl, alkoxy, (alkoxy)alkyl, or saccharide;
wherein any alkyl or aryl can be optionally substituted with one or more hydroxy, amino, cyano, nitro, or halo groups;
provided that R 1 , R 2 , and R 4 are not each methyl;
or a salt or solvate thereof
provided that when R 1 , R 2 , and R 3 are methyl, R 4 is not H or methyl; and provided that when R 1 , R 3 , and R 4 are methyl, the group —X—R of R 2 is not acyloxy.

2. The compound of claim 1 wherein R 1 is a straight chain or branched (C 1-20 )alkyl group.

3. The compound of claim 1 wherein R 2 or R 4 is a straight chain or branched (C 1-20 )alkyl group.

4. The compound of claim 1 wherein R 1 is methyl, R 2 is methyl, or R 1 and R 2 are both methyl.

5. The compound of claim 1 wherein R 4 is methyl.

6. The compound of claim 1 wherein:
R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is ethyl; propyl; isopropyl; n-butyl; tert-butyl; isobutyl; n-pentyl; n-hexyl; 3-methybutyl; 3,3-dimethylbutyl; C 8-12 alkyl; cyclooctyl; cyclopropyl; methylcyclopropyl; ethylcyclopropyl; —CH 2 OPO 3 Na 2 ; —CH 2 CH 2 OPO 3 Na 2 ; —CH 2 OH; —CH 2 CH 2 OH; or hydroxypropyl;
R 1 and R 2 are ethyl; R 3 is hydrogen; and R 4 is alkyl;
R 1 and R 2 are propyl; R 3 is hydrogen; and R 4 is alkyl;
R 1 is methyl; R 2 is propyl; R 3 is hydrogen; and R 4 is alkyl;
R 1 is propyl; R 2 is methyl; R 3 is hydrogen; and R 4 is alkyl;
R 1 and R 4 are methyl; R 3 is hydrogen; and R 2 is ethyl, propyl; C 8-12 alkyl; —CH 2 OPO 3 Na 2 ; or —CH 2 OH; or
R 2 and R 4 are methyl, R 3 is hydrogen; and R 1 is ethyl, propyl, C 8-12 alkyl; —CH 2 OPO 3 Na 2 ; or —CH 2 OH.

7. The compound of claim 1 wherein the compound is a compound of Formula IA:

wherein
R 4 is —X—R;
X is a direct bond, —C(═O)—, or (C 1 -C 20 )alkyl;
each R is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, (cycloalkyl)heteroalkyl, aryl, heteroaryl, alkoxy, or saccharide;
wherein any alkyl or aryl can be optionally substituted with one or more hydroxy, amino, cyano, nitro, or halo groups;
or a salt or solvate thereof.

8. The compound of claim 1 wherein the compound is:

or a salt or solvate thereof.

9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9 wherein the composition comprises a cyclodextrin.

11. The pharmaceutical composition of claim 9 wherein the composition is a liquid for injection or infusion.

12. The pharmaceutical composition of claim 9 wherein the composition is a solid for oral administration.

13. The compound of claim 1 wherein R 1 is a straight chain or branched (C 1-20 )alkyl group and wherein R 2 or R 4 is a straight chain or branched (C 1-20 )alkyl group.

14. The compound of claim 1 wherein R 1 is a straight chain or branched (C 1-12 )alkyl group and wherein R 2 or R 4 is a straight chain or branched (C 1-12 )alkyl group.

15. The compound of claim 7 wherein X is a direct bond and R is (C 1 -C 20 )alkyl.

16. The compound of claim 7 wherein X is a direct bond and R is a substituted (C 1 -C 12 )alkyl.

17. The compound of claim 7 wherein X is a direct bond and R is an unsubstituted (C 1 -C 12 )alkyl.

18. The compound of claim 7 wherein the compound is:

19. A pharmaceutical composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 wherein the composition comprises a cyclodextrin.

Assignees

• Univ Illinois
• Univ Texas

Inventors

• Hergenrother Paul J
• Boothman David A
• Bair Joseph S
• Palchaudhuri Rahul
• Parkinson Elizabeth I

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61K31/4745 Primary

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · 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