DNA binding agents with a minor groove binding tail

Patent metadata

Field	Value
Publication number	US-10358439-B2
Application number	US-201615759884-A
Country	US
Kind code	B2
Filing date	Sep 16, 2016
Priority date	Sep 16, 2015
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

Abstract

Provided herein are compounds which intercalate into the DNA of a cell and are capable of crossing the blood brain barrier of a formula provided herein. Pharmaceutical compositions of the compounds and methods of treating cancer, for example brain, lung, or pancreatic cancer, are also provided herein.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
X 1 , X 2 , X 3 , X 6 , and X 7 are each independently hydrogen, halo, hydroxy, carboxy, ester (C≤12) , substituted ester (C≤12) , alkoxy (C≤12) , or substituted alkoxy (C≤12) ;
X 4 is acyl (C≤18) or substituted acyl (C≤18) ;
X 5 is hydrogen, hydroxy, alkoxy (C≤12) , or substituted alkoxy (C≤12) ;
Y 1 , Y 2 , and Y 3 are each independently O, S, or NH;
A is O or S;
R 1 , R 1 ′, R 2 , R 2 ′, R 3 , and R 3 ′ are each independently hydrogen, amino, halo, hydroxy, mercapto, or
alkyl (C≤8) , alkoxy (C≤8) , alkylthio (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , or a substituted version of any of these groups;

Y 4 is a covalent bond; or
arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups;

each X 8 is independently —X 9 -heteroarenediyl (C≤12) or substituted —X 9 -heteroarenediyl (C≤12) , wherein:
X 9 is —NHC(O)— or —C(O)NH—;

R 4 is hydrogen, amino, nitro, alkylamino (C≤12) , dialkylamino (C≤12) , amido (C≤12) , substituted alkylamino (C≤12) , substituted dialkylamino (C≤12) , or substituted amido (C≤12) ;
m is 0, 1, 2, or 3; and
n is 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the formula is further defined as:

wherein:
X 2 , X 3 , X 6 , and X 7 are each independently hydrogen, halo, hydroxy, carboxy, ester (C≤12) , substituted ester (C≤12) , alkoxy (C≤12) , or substituted alkoxy (C≤12) ;
X 4 is acyl (C≤18) or substituted acyl (C≤18) ;
X 5 is hydrogen, hydroxy, alkoxy (C≤12) , or substituted alkoxy (C≤12) ;
Y 1 , Y 2 , and Y 3 are each independently O, S, or NH;
A is O or S;
R 1 and R 2 are each independently hydrogen, amino, halo, hydroxy, mercapto, or
alkyl (C≤8) , alkoxy (C≤8) , alkylthio (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , or a substituted version of any of these groups;

Y 4 is a covalent bond; or
arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups;

each X 8 is independently —X 9 -heteroarenediyl (C≤12) or substituted —X 9 -heteroarenediyl (C≤12) , wherein:
X 9 is —NHC(O)— or —C(O)NH —;

R 4 is hydrogen, amino, nitro, alkylamino (C≤12) , dialkylamino (C≤12) , amido (C≤12) , substituted alkylamino (C≤12) , substituted dialkylamino (C≤12) , or substituted amido (C≤12) ;
m is 0, 1, 2, or 3; and
n is 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the formula is further defined as:

wherein:
X 7 is hydrogen, halo, hydroxy, carboxy, alkoxy (C≤12) , substituted alkoxy (C≤12) , ester (C≤12) , or substituted ester (C≤12) ;
X 4 is acyl (C≤18) or substituted acyl (C≤18) ;
R 1 and R 2 are each independently hydrogen, amino, halo, hydroxy, mercapto, or
alkyl (C≤8) , alkoxy (C≤8) , alkylthio (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , or a substituted version of any of these groups;

Y 4 is a covalent bond, arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups;
each X 8 is independently —X 9 -heteroarenediyl (C≤12) or substituted —X 9 -heteroarenediyl (C≤12) , wherein:
X 9 is —NHC(O)— or —C(O)NH—;

R 4 is hydrogen, amino, nitro, alkylamino (C≤12) , dialkylamino (C≤12) , amido (C≤12) , substituted alkylamino (C≤12) , substituted dialkylamino (C≤12) , or substituted amido (C≤12) ;
m is 0, 1, 2, or 3; and
n is 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein X 7 is halo, alkoxy (C≤12) or substituted alkoxy (C≤12) .

5. The compound of claim 1 , wherein X 4 is acyl (C≤8) or substituted acyl (C≤8) .

6. The compound of claim 5 , wherein X 4 is —C(O)CH 3 or —C(O)CH 2 OH.

7. The compound of claim 1 , wherein R 1 is alkyl (C≤8) or substituted alkyl (C≤8) .

8. The compound of claim 7 , wherein R 1 is methyl.

9. The compound of claim 7 , wherein R 1 is fluoromethyl, difluoromethyl, trifluoromethyl, or hydroxymethyl.

10. The compound of claim 1 , wherein R 2 is hydroxy.

11. The compound of claim 1 , wherein m is 1.

12. The compound of claim 1 , wherein Y 4 is arenediyl (C≤12) or a covalent bond.

13. The compound of claim 1 , wherein X 8 is —X 9 -heteroarenediyl (C≤12) .

14. The compound of claim 13 , wherein X 8 is:

15. The compound of claim 14 , wherein X 8 is:

16. The compound of claim 1 , wherein R 4 is hydrogen, nitro, or amido (C≤12) .

17. The compound of claim 1 , wherein the compound is formulated as a pharmaceutically acceptable salt.

18. A compound selected from

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising:
(a) a compound of claim 1 ; and
(b) a pharmaceutically acceptable carrier.

20. A method of treating cancer in a patient comprising administering a therapeutically effective amount of a compound of claim 1 to the patient in need thereof.

Assignees

• Univ Texas

Inventors

• Priebe Waldemar
• Guo Liwei
• Kazimierski Arkadiusz
• Fokt Izabela
• Conrad Charles
• Madden Timothy

Classifications

• C07D309/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07H15/24

  Condensed ring systems having three or more rings · CPC title

• C07H15/244

  Anthraquinone radicals, e.g. sennosides · CPC title

• C07C13/66

  the condensed ring system contains only four rings · CPC title